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<strong>Saurashtra</strong> <strong>University</strong><br />
Re – Accredited Grade ‘B’ by NAAC<br />
(CGPA 2.93)<br />
Patel, Anilkumar S., 2011, “Studies on Novel Bioactive Heterocyclic<br />
Compounds”, thesis PhD, <strong>Saurashtra</strong> <strong>University</strong><br />
http://etheses.saurashtrauniversity.edu/id/eprint/544<br />
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© The Author
STUDIES ON NOVEL BIOACTIVE<br />
HETEROCYCLIC COMPOUNDS<br />
A THESIS SUBMITTED TO THE<br />
Re-Accredited Grade-B by<br />
NAAC (CGPA 2.93)<br />
IN<br />
THE FACULTY OF SCIENCE<br />
FOR<br />
THE DEGREE<br />
OF<br />
Doctor of Philosophy<br />
IN<br />
CHEMISTRY<br />
BY<br />
ANILKUMAR S. PATEL<br />
UNDER THE GUIDANCE OF<br />
Dr. YOGESH T. NALIAPARA<br />
DEPARTMENT OF CHEMISTRY<br />
SAURASHTRA UNIVERSITY<br />
RAJKOT – 360 005<br />
GUJARAT, INDIA<br />
NOVEMBER 2011
Statement under O.Ph.D.7 of <strong>Saurashtra</strong> <strong>University</strong><br />
The work included in the thesis is done by me under the supervision of Dr.<br />
Yogesh T. Naliapara and the contribution made there of is my own work.<br />
Date:<br />
Place: Rajkot<br />
Anilkumar S. Patel
SAURASHTRA UNIVERSITY<br />
Department of Chemistry<br />
Rajkot – 360 005<br />
Phone: (O) +91-281-2576802<br />
(Cell) +91-94280 36310<br />
E mail: naliaparachem@yahoo.com<br />
Re-Accredited Grade-B by<br />
NAAC (CGPA 2.93)<br />
CERTIFICATE<br />
This is to certify that the present work “Studies on Novel Bioactive Heterocyclic<br />
Compounds” submitted for the Degree of Ph. D. in the subject Chemistry is done by<br />
Mr. Anilkumar S. Patel at Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot,<br />
under my supervision and is a significant contribution in the field of synthetic organic<br />
chemistry and medicinal chemistry. His thesis is recommended for acceptance for the<br />
award of the Ph.D. degree by the <strong>Saurashtra</strong> <strong>University</strong>.<br />
Date:<br />
Place: Rajkot<br />
Dr. Yogesh T. Naliapara<br />
Assistant Professor,<br />
Department of Chemistry,<br />
<strong>Saurashtra</strong> <strong>University</strong>,<br />
Rajkot-360005<br />
Gujarat, India.
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Acknowledgement<br />
Firstly, I bow my head humbly before the Almighty God for making me<br />
capable of completing my Ph.D. Thesis; with his blessings only I have accomplished<br />
this huge task.<br />
I express deep sense of gratitude and thankfulness to my supervisor Dr.<br />
Yogesh T. Naliapara who has helped me at each and every point of my research work<br />
with patience and enthusiasm. I am much indebted to him for his inspiring guidance,<br />
affection, generosity and everlasting enthusiasm throughout the tenure of my<br />
research work.<br />
I am very thankful to the faculties of Department of Chemistry namely, Prof.<br />
P. H. Parsania, Prof. Anamik Shah, Prof. V. H. Shah, Prof. H. S. Joshi, Prof. Shipara<br />
Baluja, Dr. M. K. Shah, Dr. R. C. Khunt, for their encouragement and providing<br />
adequate research facilities.<br />
I sincerely grateful to Dr. Naval Kapuriya (jiju) and Mrs. Kalpana Kapuriya<br />
(sister) for their continuous support and inspiration during my research work and as<br />
a result, I am capable to complete this work. They had helped me all along to speed<br />
up my research work.<br />
My heartily thanks to my colleagues and labmates Piyush Pipaliya, Vipul<br />
Audichya and Gami Sagar for their kind help and support. My special thanks to Dr.<br />
Chirag Bhuva, Dr. Akshay Pansuriya, Dr. Jyoti Singh and Dr. Mahesh Savant.<br />
I offer my gratitude to my friends Dr. Satish, Dr. Rajesh, Dr. Rupesh, Dr.<br />
Bhavin, Dr. Ravi, Dr, Mehul, Dr. Jignesh, Dr. Renish, Dr. Harshad, Dr. Amit, Dr.<br />
Bhavesh, Dr. Pooja, Dr. Yogesh, Dr. Naimish, Krunal, Rakesh, Vipul, Ashish, Paresh,<br />
Bharat, Piyush(motabhai), Ramani, Punit, Gaurang, Satish, Batuk, Ashish and all the<br />
Ph.D. students for their fruitful discussion at various stages. I am also thankful to my<br />
best friends Mehul, Dr. Dinesh, Bipin(moto), Pankaj, Pintu, Parag, Sumit, Kalpesh,<br />
Nilesh and Rinkal for their help, entertainment & coordination extended by them.
I am thankful to FIST/DST and SAP/UGC for their generous financial and<br />
instrumentation support. Special thanks are due to “National Facility for Drug<br />
Discovery through New Chemical Entities (NCE's) Development & Instrumentation<br />
Support to Small Manufacturing Pharma Enterprises” Programme under Drug &<br />
Pharma Research Support (DPRS) jointly funded by Department of Science &<br />
Technology, New Delhi, Government of Gujarat Industries Commissionerate &<br />
<strong>Saurashtra</strong> <strong>University</strong>, Rajkot. I am also thankful to SAIF, CIL, Chandigarh and NRC,<br />
IISc, Bangalore for providing spectroscopic analysis.<br />
Special thanks to Open Source of Drug Discover project for giving me<br />
financial support and <strong>University</strong> of Grant Commission for finding me as Meritorious<br />
Research Fellow which is really an achievement and helpful task for me.<br />
At Last, I have no words to state anything about my parents but at this<br />
occasion, I would like to thanks my father and mother, without their support,<br />
motivation and understanding it would have been impossible for me to finish my<br />
research work. I sincerely thank to my whole family for encouraging me and<br />
providing every help to fulfill my task. My special gratitude is due to my sister and<br />
their families for their loving support during tenure of my work. To them I dedicate<br />
this thesis.<br />
Anilkumar S. Patel
Content<br />
Chapter 1<br />
Palladium Catalyzed Synthesis of Novel Highly Functionalized<br />
Pyrimidines via Suzuki-Miyaura Coupling Reaction.<br />
1.1 Introduction 1<br />
1.2 Biological Activity Associated with 4-Aryl dihydropyrimidine derivatives 2<br />
1.3 Synthetic strategies for the dihydropyrimidines (DHPMs) 7<br />
1.4 Current research work 20<br />
1.5 Results and discussion 21<br />
1.6 Conclusion 24<br />
1.7 Experimental section 25<br />
1.8 References 40<br />
Chapter 2<br />
Synthesis and Biological Activity of Novel Pyrimidine Derivatives via<br />
Wittig Reaction in Aqueous Media.<br />
2.1 Introduction 44<br />
2.2 A literature review on the biological activity associated with pyrimidine<br />
derivatives 45<br />
2.3 Various synthetic approaches for highly substituted pyrimidines 50<br />
2.4 Applications of Wittig reaction 52<br />
2.5 Application of sodium tripolyphosphate 55<br />
2.6 Current research work 56<br />
2.7 Results and discussion 57<br />
2.8 Antimicrobial sensitivity testing 60<br />
2.9 Conclusion 63<br />
2.10 Experimental section 64<br />
2.11 References 79<br />
Chapter 3<br />
Rapid Synthesis and Characterization of Novel Tri-substituted<br />
Pyrazoles/Isoxazoles Library Using Ketene Dithioacetals.<br />
3.1 Introduction 82<br />
3.2 Biological activity associated with pyrazoles and isoxazoles 83<br />
3.3 Synthetic methods for the pyrazole and isooxazole derivatives 89<br />
3.4 Some pharmaceutical molecules related to pyrazoles and isoxazoles 94<br />
3.5 Current research work 95<br />
3.6 Results and discussion 96<br />
3.7 Conclusion 100<br />
3.8 Experimental section 101<br />
3.9 References 118
Chapter 4<br />
Synthesis and Characterization of Novel Substituted and Fused<br />
Pyrazolo[1,5-a] pyrimidines Derivatives.<br />
4.1 Introduction 121<br />
4.2 Biological activity related to pyrazopyrimidine derivatives 122<br />
4.3 Various synthetic approaches for substituted pyrazolopyrimidine derivatives 126<br />
4.4 Current research work 132<br />
4.5 Results and discussion 133<br />
4.6 Conclusion 138<br />
4.7 Experimental section 139<br />
4.8 Reference 155<br />
Chapter 5<br />
Rapid Synthesis of Highly Substituted Pyrrole Derivatives: Analogs of<br />
Atorvastatin.<br />
5.1 Introduction 158<br />
5.2 Various synthetic approaches for highly substituted pyrroles 159<br />
5.3 Biological activity associated with pyrrole derivatives 167<br />
5.4 Some drugs from pyrrole nucleus 167<br />
5.5 Current research work 168<br />
5.6 Results and discussion 169<br />
5.7 Antimicrobial sensitivity testing 173<br />
5.8 Conclusion 176<br />
5.9 Experimental section 177<br />
5.10 References 197<br />
Chapter 6 Synthesis and Characterization of Some New Benzodiazepine<br />
Derivatives.<br />
6.1 Introduction 201<br />
6.2 Biological activities associated with diazepine derivatives 203<br />
6.3 Some pharmaceutical molecules related to benzodiazepines 207<br />
6.4 Synthetic methods for benzodiazepines derivatives 208<br />
6.5. Current research work 211<br />
6.6 Results and discussion 212<br />
6.7 Conclusion 215<br />
6.8 Experimental section 216<br />
6.9 References 231<br />
Summary 234<br />
List of Publications and Conferences participated 236
Abbreviations<br />
AIDS<br />
CS 2<br />
CDK<br />
DABCO<br />
DMSO<br />
DMF<br />
DMS<br />
DHP<br />
DHPM<br />
DIBAL<br />
EGFR<br />
GABA<br />
HDAC<br />
HIV<br />
HCV<br />
MDC<br />
mCPBA<br />
PAF<br />
STPP<br />
THF<br />
TMS<br />
VEGFR<br />
iPA<br />
h<br />
min<br />
rt<br />
mp<br />
Aquired immune deficiency syndrome<br />
Carbon disulfide<br />
Cyclin-dependent kinase<br />
1,4-diazabicyclo[2.2.2]octane<br />
Dimethyl sulfoxide<br />
Dimethyl formamide<br />
Dimethyl sulfate<br />
Dihydropyridine<br />
Dihydropyrimidine<br />
Diisobutylaluminium hydride<br />
Epidermal Growth Factor Receptor<br />
Gamma-aminobutyric acid<br />
Histone deacetylase<br />
Human immunodeficiency virus<br />
Hepatitis C virus<br />
Methylene dichloride<br />
meta-chloro perbenzoic acid<br />
Platelet-activating factor<br />
Sodium tripolyphosphate<br />
Tetrahydrofuran<br />
Trimethyl silane<br />
Vascular Endothelial Growth Factor Receptor<br />
iso-propyl alcohol<br />
hour (time)<br />
minute (time)<br />
room temperature<br />
melting point
Chapter – 1<br />
Palladium Catalyzed Synthesis of Novel<br />
Highly Functionalized Pyrimidines via<br />
Suzuki-Miyaura Coupling Reaction
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
1.1 Introduction<br />
The pyrimidine fragment is present in the molecules of a series of biologically<br />
active compounds, many of which have found use in medical practice (soporific, antiinflammatory,<br />
antitumor, and other products). 1,2 In this connection, great attention has<br />
recently been paid to the derivatives of pyrimidine, including their hydrogenation<br />
products. The first investigation into the synthesis of pyrimidine nucleus appeared<br />
more than a hundred years ago and subsequently several methods for the synthesis of<br />
dihydropyrimidine were reported and their physicochemical properties has been<br />
studied (e.g., the Biginelli reaction). 3 Further, the high reactivity and wide range of<br />
biological activity associated with these scaffolds have been demonstrated in the<br />
literature. For example, 2-substituted 5-alkoxycarbonyl-4-aryl-l,4-dihydropyrimidines<br />
(structural analogs of Hantzsch esters) are modulators of the transport of calcium<br />
through membranes. 4-7 Many hydrogenated pyrimidines exhibit antimicrobial, 8<br />
hypoglemic, 9 herbicidal, 10 and pesticidal 11 activity. Publications devoted to these<br />
problems have been summarized in a number of reviews. 9-14<br />
Pyrimidines have a long and distinguished history extending from the days of<br />
their discovery as important constituents of several biological molecules such as<br />
nucleic acids, cofactors, various toxins, to their current use in the chemotherapy of<br />
AIDS. All these compounds yield great promise for the treatment of retro virus<br />
infections in humans.<br />
Alloxan (1) is known for its diabetogenic action in a number of animals. 15<br />
Uracil (2), thymine (3) and cytosine (4) are the three important constituents of nucleic<br />
acids (Figure-1).<br />
Figure-1<br />
The pyrimidine ring is also found in vitamins such as thiamine (5), riboflavin<br />
(6) (Figure-2) and folic acid (7). 16 Barbitone (8) is the first barbiturate hypnotic,<br />
sedative and anticonvulsant are pyrimidine derivatives (Figure-3).<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 1
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
Figure-2<br />
Figure-3<br />
1.2 Biological Activity Associated with 4-Aryl dihydropyrimidine<br />
derivatives<br />
Among the dihydropyrimidines, 4-Aryl-1,4-dihydropyridines (DHPs, e.g.<br />
nifedipine) are the most studied class of organic calcium channel modulators. More<br />
than 30 years after the introduction of nifedipine many DHP analogs have now been<br />
synthesized and numerous second-generation commercial products have appeared on<br />
the market. 17,18<br />
Nowadays, interest has also been focused on aza-analogs such as<br />
dihydropyrimidines (DHPMs) which showed a very similar pharmacological profile<br />
to the classical dihydropyridine calcium channel modulators. 5-7, 19-20 Over the past few<br />
years several lead-compounds were developed (i.e. SQ 32,926) that are superior in<br />
potency and duration of antihypertensive activity to classical DHP drugs, and<br />
compare favorable with second-generation analogs such as amlodipine and<br />
nicardipine (Figure-4).<br />
Figure-4<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 2
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
Barrow et al. has reported in vitro and in vivo evaluation of<br />
dihydropyrimidinone C-5 amides as potent and selective r1A receptor antagonists for<br />
the treatment of benign prostatic hyperplasia (Figure-5). R1 Adrenergic receptors<br />
mediate both vascular and lower urinary tract tone, and R1 receptor antagonists such<br />
as terazosin are used to treat both hypertension and benign prostatic hyperplasia<br />
(BPH). Recently, three different subtypes of this receptor have been identified, with<br />
the R1A receptor being most prevalent in lower urinary tract tissue. Barrow et al. has<br />
also reported 4-aryldihydropyrimidinones attached to an aminopropyl-4-<br />
arylpiperidine via a C5 amide as selective R1A receptor subtype antagonists. In<br />
receptor binding assays, these types of compounds generally display Ki values for the<br />
R1a receptor subtype 20%) and half-life (>6 h) in<br />
both rats and dogs. Due to its selectivity for the R1a over the R1b and R1d receptors<br />
as well as its favorable pharmacokinetic profile, it has the potential to relieve the<br />
symptoms of BPH without eliciting effects on the cardiovascular system. 21,22<br />
F<br />
F<br />
N<br />
R 3 R 2<br />
Figure-5<br />
The 4-aryldihydropyrimidinone attached to an aminopropyl-4-arylpiperidine<br />
via a C5 amide has proved to be an excellent template for selective R1A receptor<br />
subtype antagonists. Those compounds are exceptionally potent in both cloned<br />
receptor binding studies as well as in vivo pharmacodynamic models of prostatic tone.<br />
Atwal et al. have examined a series of novel dihydropyrimidine calcium<br />
channel blockers that contain a basic group attached to either C5 or N3 of the<br />
heterocyclic ring (Figure-6).<br />
N<br />
H<br />
O<br />
R 1<br />
N<br />
H<br />
NH<br />
O<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 3
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
Structure-activity studies showed that l-(phenylmethyl)-4-piperidinylcarbamate<br />
moiety at N3 and sulfur at C2 are optimal for vasorelaxant activity in vitro and impart<br />
potent and long-acting antihypertensive activity in vivo. One of these compounds was<br />
identified as a lead, and the individual enantiomers were synthesized. Two key steps<br />
of the synthesis were (1) the efficient separation of the diastereomeric ureido<br />
derivatives and (2) the high-yield transformation of 2-methoxy intermediate to the<br />
(p-methoxybenzyl)thio intermediates. Chirality was demonstrated to be a significant<br />
determinant of biological activity, with the DHP receptor recognizing the enamines<br />
ester moiety but not the carbamate moiety. DHPM is equipotent to nifidepine and<br />
amlodipine in vitro. In the spontaneously hypertensive rat, DHPM is more potent and<br />
longer acting than both nifidepine and the long-acting amlodipine (DHP derivative).<br />
DHPM has the potential advantage of being a single enantiomer. 23,24<br />
F 3 C<br />
i-PrO 2 C<br />
N<br />
H<br />
N<br />
O 2<br />
C<br />
S<br />
N<br />
F 3 C<br />
R i-PrO 2 C<br />
Figure-6<br />
N<br />
H<br />
N<br />
O 2<br />
C<br />
S<br />
N<br />
HCl<br />
F<br />
In order to explain the potent antihypertensive activity of the modestly active<br />
(ICw = 3.2 pM) DHPM calcium channel blocker, Atwal et al. carried out drug<br />
metabolism studies in the rat and found that two of the metabolites (ICw = 16 nM)<br />
and (ICw = 12 nM), were responsible for antihypertensive activity of compound.<br />
Potential metabolism in vivo precluded interest in pursuing compounds related to it.<br />
Structure-activity studies aimed at identifying additional aryl-substituted analogues<br />
led to comparable potential in vivo, though these compounds were less potent in vitro.<br />
To investigate the effects of absolute stereochemistry on potency, authors resolved via<br />
diastereomeric ureas, prepared by treatment with (R)-α-methylbenzylamine. The<br />
results demonstrate that the active R-(-)-enantiomer is more potent and longer acting<br />
than nifedipine as an antihypertensive agent in the SHR. The in vivo potency and<br />
duration is comparable to the long-acting DHP amlodipine. The superior oral<br />
antihypertensive activity compared to that of previously described carbamates<br />
(R 2 =COOEt) could be explained by its improved oral bioavailability, possibly<br />
resulting from increased stability of the urea functionality (Figure-7). 6<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 4
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
Figure-7<br />
Authors modified the structure of previously described DHPM i.e. 3-<br />
substituted 1,4-dihydropyrimidines. Structure-activity studies using potassiumdepolarized<br />
rabbit aorta show that ortho, meta-disubstituted aryl derivatives are more<br />
potent than either ortho or meta-monosubstituted compounds. While vasorelaxant<br />
activity was critically dependent on the size of the C5 ester group, isopropyl ester<br />
being the best, a variety of substituents (carbamate, acyl, sulfonyl, and alkyl) were<br />
tolerated at N3. The results showed that DHPMs are significantly more potent than<br />
corresponding 2- heteroalkyl-l,4-dihydropyrimidines and only slightly less potent than<br />
similarly substituted 2-heteroalkyl-1-4-dihydropyridines (Figure-8). Where as DHP<br />
enantiomer usually show 10-15-fold difference in activity, the enantiomer of DHPM<br />
show more than a 1000-fold difference in activity. These results strengthen the<br />
requirement of an enaminoester for binding to the dihydropyridine receptor and<br />
indicate a nonspecific role for the N3-substituent.<br />
Figure 8<br />
2-Heterosubstituted-4-aryl-l,4-dihydro-6-methyl-5-pyrimidinecarboxylicesters<br />
(Figure 9), which lack the potential symmetry of DHP calcium channel blockers,<br />
were prepared and evaluated for biological activity. Biological assays using<br />
potassium-depolarized rabbit aorta and radio ligand binding techniques showed that<br />
some of these compounds are potent mimics of DHP calcium channel blockers. 25<br />
Figure 9<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 5
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
Bryzgalov A. O. et al. has studied the antiarrhythmic activity of 4,6-<br />
di(het)aryl-5-nitro-3,4-dihydropyrimidin-(1H)-2-ones (Figure-10) toward two types<br />
of experimental rat arrhythmia. With CaCl 2 induced arrhythmia model, several agents<br />
have demonstrated high antiarrhythmic activity and the lack of influence on arterial<br />
pressure of rats. 26 Figure 10<br />
Remennikov G. et al. 27 has synthesized some novel 4-aryl-5-nitro substituted<br />
DHPMs (Figure 11) using nitro acetone and screened as calcium modulators. They<br />
have studied the pharmacological properties of 6-methyl- and 1,6-dimethyl-4-aryl-5-<br />
nitro-2-oxo-l,2,3,4-tetrahydropyrimidines with different substituents in the aryl<br />
fragment, i.e. unsubstituted, ortho, meta, para, di, and tri-substituted compounds and<br />
observed that 5-nitro DHPMs bearing unsubstituted, ortho and tri-substitution on aryl<br />
moieties at C4 position reduced blood pressure and inhibited myocardial contractile<br />
activity. The second group consisted meta, para and di-substituted aryl moieties with<br />
DHPMs increased blood pressure and had positive inotropic effects. The compounds<br />
with the highest hypotensive activity were containing substituent in the ortho position<br />
of the phenyl fragment. Thus, compounds having substitution on aryl moieties which<br />
had pronounced vasodilator and weak cardio depressive actions, increased cardiac<br />
pump function (SV). When inhibition of myocardial contractile function<br />
predominated, there was a reduction in SV. The effect of compounds of the first group<br />
on heart rate was variable, though most reduced heart rate. In addition, a reflex<br />
increase in heart rate might be expected because of the reduction in blood pressure.<br />
The reference preparations for compounds of this group were the calcium antagonist<br />
nifedipine.<br />
Figure-11<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 6
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
The pharmacological profile of compounds of the first group was analogous to that of<br />
nifedipine. This suggests that they share a common mechanism of action - blockade of<br />
calcium ion influx.<br />
Brain C. Shook et al. 28 has synthesized a novel series of arylindenopyrimidines<br />
(Figure-12) identified as A 2A and A 1 receptor antagonists. The series was<br />
optimized for vitro activity by substituting the 8-and-9- positions with methylene<br />
amine substituents. The compounds show excellent activity in mouse models of<br />
parkinson’s disease when dosed orally.<br />
O<br />
Ar<br />
R'RN<br />
N<br />
Figure-12<br />
N<br />
NH 2<br />
1.3. Synthetic strategies for the dihydropyrimidines (DHPMs)<br />
Having tremendous important of DHPMs in medicinal chemistry, a literature<br />
survey on the synthetic methods for the biologically active dihydropyrimidines<br />
(DHPMs) has been carried out and described as follows. Various modifications have<br />
been applied to Biginelli reaction to get better yield and to synthesize biologically<br />
active analogs. Different catalysts have been reported to increase the yield of the<br />
reaction. Microwave synthesis strategies have also been applied to shorten the<br />
reaction time. Solid phase synthesis and combinatorial chemistry has made possible to<br />
generate library of DHPM analogs. The various modifications are discussed in the<br />
following section.<br />
Catalysts<br />
Min Yang and coworkers 29 have synthesized the different DHPMs by using<br />
various inorganic salts as a catalyst (Figure-13). They found that the yields of the<br />
one-pot Biginelli reaction can be increased from 20-50% to 81-99%, while the<br />
reaction time shorted for 18-24 hrs to 20-30 min. This modification was developed by<br />
using Yb(OTf) 3 and YbCl 3 as a catalyst under solvent free conditions. One additional<br />
important feature of this protocol is the catalyst can be easily recovered and reused.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 7
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
Figure-13<br />
Lewis acid such as, Indium (III) chloride was emerged as a powerful Lewis<br />
catalyst imparting high region and chemo selectivity in various chemical<br />
transformations. B. C. Ranu and co-workers 30 have reported indium (III) chloride<br />
(InCl 3 ) as an efficient catalyst for the synthesis of 3,4-dihydropyrimidn-2(1H)-ones<br />
(Figure-14). A variety of substituted aromatic, aliphatic and heterocyclic aldehydes<br />
have been subjected to this condensation very efficiently. Thiourea has been used<br />
with similar success to provide the corresponding dihydropyrimidin-2(1H)-thiones.<br />
Figure-14<br />
Majid M. Heravi et al. has reported a simple, efficient and cost-effective<br />
method for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones by one pot<br />
three-component cyclocondensation reaction of a 1,3-dicarbonyl compound, an<br />
aldehyde and urea or thiourea using 12-tungstophosphoric acid 31 and 12-<br />
molybdophosphoric acid 32 as recyclable catalyst (Figure-15).<br />
Figure-15<br />
Hydroxyapatite doped with ZnCl 2 , CuCl 2 , NiCl 2 and CoCl 2 efficiently<br />
catalyzes the three components Biginelli reaction between an aldehyde, ethyl<br />
acetoacetate and urea in refluxing toluene to afford the corresponding<br />
dihydropyrimidinones in high yields. 33<br />
Sc(III)triflate catalyzes the three-component condensation reaction of an<br />
aldehyde, a β-ketoester and urea in refluxing acetonitrile to afford the corresponding<br />
3,4-dihydropyrimidin-2(1H)-ones in excellent yields (Figure-16). The catalyst can be<br />
recovered and reused, making this method friendly and environmentally acceptable. 34<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 8
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
Figure-16<br />
Solid phase synthesis<br />
The generation of combinatorial libraries of heterocyclic compounds by solid<br />
phase synthesis is of great interest for accelerating lead discovery and lead<br />
optimization in pharmaceutical research. Multi-component reactions (MCRs) 35,36-37<br />
leading to heterocycles are particularly useful for the creation of diverse chemical<br />
libraries, since the combination of any 3 small molecular weight building blocks in a<br />
single operation leads to high combinatorial efficiency. Therefore, solid phase<br />
modifications of MCRs are rapidly become the cornerstone of combinatorial synthesis<br />
of small-molecule libraries.<br />
The first solid-phase modification of the Biginelli condensation was reported<br />
by Wipf and Cunningham 38 in 1995 (Figure-17). In this sequence, γ-aminobutyric<br />
acid derived urea was attached to Wang resin using standard procedures. The<br />
resulting polymer-bound urea was condensed with excess β-ketoester and aromatic<br />
aldehydes in THF at 55 °C in the presence of a catalytic amount of HCl to afford the<br />
corresponding immobilized DHPMs. Subsequent cleavage of product from the resin<br />
by 50 % trifluoroacetic acid (TFA) provided DHPMs in high yields and excellent<br />
purity.<br />
Figure-17<br />
Li W. and Lam Y. 39 have described the synthesis of 3,4-dihydropyrimidin-2-<br />
(1H)ones/thiones using sodium benzene sulfinate as a traceless linker (Figure-18).<br />
The key steps involved in the solid-phase synthetic procedure were sulfinate<br />
acidification, condensation of urea or thiourea with aldehydes and sulfinic acid and<br />
traceless product release by a one-pot cyclization-dehydration process. Since a variety<br />
of reagents can be used, the overall strategy appears for library generation.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 9
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
Figure-18<br />
Liquid phase synthesis<br />
In the solid phase synthesis there are some disadvantages in compared to<br />
standard solution-phase synthesis, such as difficulties to monitor reaction progress,<br />
the large excess of reagents typically used in solid-phase supported synthesis, low<br />
loading capacity and limited solubility during the reaction progress and the<br />
heterogeneous reaction condition with solid phase. 40 Recently, organic synthesis of<br />
small molecular compounds on soluble polymers, i.e. liquid phase chemistry has<br />
increasingly become attractive field. 41<br />
Moreover, owing to the homogeneity of liquid-phase reactions, the reaction<br />
conditions can be readily shifted from solution-phase systems without large changes<br />
and the amount of excessive reagents is less than that in solid-phase reactions. In the<br />
recent years, Task Specific room temperature Ionic Liquids (TSILs) has emerged as a<br />
powerful alternative to conventional molecular organic solvents or catalysts. Liu Z. et<br />
al. 42 have reported cheap and reusable TSILs for the synthesis of 3,4-<br />
dihydropyrimidin-2(1H)-ones via one-pot three component Biginelli reaction. Ionic<br />
liquid-phase bound acetoacetate reacts with thiourea and various aldehydes with a<br />
cheap catalyst to afford ionic liquid-phase supported 3,4-dihydropyrimidin-2(1H)-<br />
thiones, which has been reported by Bazureau J. P. and co- workers 43 (Figure-19).<br />
3,4-Dihydropyrimidinones were synthesized in one-pot, by the reaction of aldehydes,<br />
β-dicarbonyl compounds and urea, catalyzed by non-toxic room temperature ionic<br />
liquid 1-n-butyl-3-methylimidazolium saccharinate (BMImSac). 44<br />
Figure-19<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 10
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
Microwave assisted synthesis<br />
In general, the standard procedure for the Biginelli condensation involves one<br />
pot condensation of the three building blocks in a solvent such as ethanol using a<br />
strongly acidic catalyst that is hydrochloric acid. One major drawback of this<br />
procedure, apart from the long reaction time involving reflux temperature, is the<br />
moderate yields frequently observed when using more complex building blocks.<br />
Microwave irradiation (MW) has become accepted tool in organic synthesis, because<br />
the rate enhancement, higher yields and often, improved selectivity with respect to<br />
conventional reaction conditions. 45 The publication by Dandia A. et al. 46 described<br />
microwave-enhanced solution-phase Biginelli reactions employing ethyl acetoacetate,<br />
thiourea and a wide variety of aromatic aldehydes as building blocks (Figure-20).<br />
Upon irradiation of the individual reaction mixtures (ethanol, catalytic HCl) in an<br />
open glass beaker inside the cavity of a domestic microwave oven the reaction times<br />
were reduced from 2–24 hours of conventional heating 80 °C, reflux to 3–11 minutes<br />
under microwave activation (ca. 200 –300 W). At the same time the yields of DHPMs<br />
obtained were distinctly improved compared to those reported earlier using<br />
conventional conditions.<br />
Figure-20<br />
In recent years, solvent free reactions using either organic or inorganic solid<br />
supports have received more attention. 47 There are several advantages to perform<br />
synthesis in dry media: (i) short reaction times, (ii) increased safety, (iii) economic<br />
advantages due to the absence of solvent. In addition, solvent free MW processes are<br />
also clean and efficient. Gopalakrishnan M. and co-workers have reported Biginelli<br />
reaction under microwave irradiation in solvent-free conditions using activated fly ash<br />
as catalyst, an industrial waste (pollutant) is an efficient and novel catalyst for some<br />
selected organic reactions in solvent free conditions under microwave irradiation. 48<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 11
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
Ultrasound assisted synthesis<br />
Ultrasound as a green synthetic approach has gradually been used in organic<br />
synthesis over the last three decades. Compared with the traditional methods, it is<br />
more convenient, easier to be controlled and consumes less power. With the use of<br />
ultrasound irradiation, a large number of organic reactions can be carried out in milder<br />
conditions with shorter reaction time and higher product yields. 49 Ultrasound<br />
irradiated and amidosulfonicacid (NH 2 SO 3 H) catalyzed synthesis of 3,4-<br />
dihydropyrimidi-2-(1H)ones have been reported by Li J. T. and co-workers 50 using<br />
aldehydes, β-ketoester and urea.<br />
Liu C. et al. 51 have synthesized a novel series of 4-substituted pyrazolyl-3,4-<br />
dihydropyrimidin-2(1H)-thiones under ultrasound irradiation using magnesium<br />
perchlorate [Mg(ClO 4 ) 2 ] as catalyst (Figure-21), by the condensation of 5-<br />
chloro/phenoxyl-3-methyl-1-phenyl-4-formylpyrazole, 1,3-dicarbonyl compound and<br />
urea or thiourea in moderate yields. The catalyst exhibited remarkable reactivity and<br />
can be recycled.<br />
Figure-21<br />
Sonication of aromatic aldehydes, urea and ethyl acetoacetate in presence of<br />
solvent (ethanol) or solvent-less dry media (bentonite clay) by supporting-zirconium<br />
chloride (ZrCl 4 ) as catalyst at 35 kHz gives 6-methyl-4-substitutedphenyl-2-oxo-<br />
1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl esters proficiently in high yields,<br />
which reported by Harish Kumar et al. (Figure 22). 52<br />
Figure-22<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 12
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
<br />
Synthetic Methods for the Oxidative Dehydrogenation of DHPM Ring<br />
System<br />
The production of heteroaromatics by oxidative dehydrogenations is of<br />
fundamental importance in organic synthesis. The dehydrogenation of<br />
dihydropyrimidines and dihydropyrimidinones has received much attention because<br />
of their facile access via the Biginelli three-component coupling. Different methods<br />
were reported in the literature for oxidative dehydrogenations of DHPM, which are<br />
described as under.<br />
Hamid Reza Memarian et al. 53 have developed dehydrogenation of 5-acetyl-<br />
3,4-dihydropyrimidin-2(1H)-ones by potassium peroxydisulfate in aqueous<br />
acetonitrile under thermal and sonothermal conditions (Figure-23).<br />
O<br />
R<br />
H<br />
NH<br />
N<br />
H<br />
O<br />
K 2 S 2 O<br />
CH 3 CN/H 2 O<br />
Ultrasound/<br />
Heat<br />
O<br />
R<br />
N<br />
H<br />
N<br />
O<br />
Figure-23<br />
Sam Sik Kim et al. 54 reported that oxidation of dihydropyrimidin-2(1H)-ones<br />
by KMnO 4 formed 2-hydroxypyrimidine in excellent yield, whereas attempted direct<br />
desulfurative aromatization of dihydropyrimidin-2(1H)-thiones by KMnO 4 resulted in<br />
the formation of 2-hydroxypyrimidines (Figure-24).<br />
Figure-24<br />
Masoud Nasr-Esfahani et al. 55 reported photolytic oxidation of some ethyl 3,4-<br />
dihydropyrimidin-2(1H)-one-5-carboxylates to their corresponding ethyl pyrimidin-<br />
2(1H)-one-5-carboxylates using a TiO 2 /O 2 system under UV irradiation by a 400 W<br />
high pressure mercury lamp in acetonitrile (Figure-25).<br />
Figure-25<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 13
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
Rui Liang et al. 56 has shown the oxidation of 3,4-Dihydropyrimidin-2(1H)-<br />
ones (DHPMs) with 1.2 eq. of nitrosonium tetrafluoroborate (NO + BF - 4 ) to pyrimidin-<br />
2(1H)-ones in acetonitrile at room temperature in high yields (Figure-26).<br />
Figure-26<br />
Nandkishor N. Karade et al. 57 has achieved oxidative dehydrogenation of 3,4-<br />
dihydropyrimidin-2(1H)-ones to 1,2-dihydropyrimidines through a novel combination<br />
of (diacetoxyiodo)benzene and tert-butylhydroperoxide in CH 2 Cl 2 (Figure-27).<br />
Figure-27<br />
Kana Yamamoto et al. 58 has reported method for oxidative dehydrogenation of<br />
dihydropyrimidinones and dihydropyrimidines by using catalytic amounts of a Cu<br />
salt, K 2 CO 3 , and tert-butylhydroperoxide (TBHP) as a terminal oxidant (Figure-28).<br />
Figure-28<br />
Synthetic Methods for the Synthesis of 2-Chloropyrimidine Derivatives<br />
Several methods were reported in the literature for the chlorination of 2-<br />
hydroxypyrimidines, few of them are described herein.<br />
Driwedi Shriprakash Dhar et al. 59 has reported synthesis of 2-halopyrimidine<br />
derivative from 2-hydroxypyrimidine by using thionyl chloride and dimethyl<br />
formamide and toluene as a solvent at 80 o C (Figure-29).<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 14
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
Figure-29<br />
Atul R. Gholap et al. 60 has described the synthesis of 2-chloropyrimidine<br />
derivatives from 2-hydroxypyrimidine derivatives using N,N-dimethylaniline and<br />
POCl 3 as chlorinating agent under reflux condition (Figure-30).<br />
Figure-30<br />
<br />
Synthetic methods for the Suzuki-Miyaura coupling<br />
The well known Suzuki reaction 61 is the organic reaction of an aryl or vinylboronicacid<br />
with an aryl or vinyl-halide catalyzed by a palladium(0)complex forming<br />
carbon-carbon bond. Some reported methods are described as under.<br />
In 1981, Suzuki and Miyaura et al. have made a breakthrough in the<br />
methodology for biaryl compounds using aryl boronicacids and aryl bromide under<br />
homogeneous palladium catalyzed conditions in the presence of base 62 (Figure- 31).<br />
Z<br />
OH<br />
Br B OH<br />
3mol%Pd(Ph 3 ) 4<br />
Aq. Na 2 CO 3<br />
Benzene, refulx<br />
Figure-31<br />
Z<br />
S. Li et al. 63 have synthesized Pd(OAc) 2 -catalyzed room temperature Suzuki<br />
cross coupling reaction in aqueous media under aerobic conditions (Figure-32).<br />
Figure-32<br />
Y. M. A. Yamada et al. 64 have prepared highly active catalyst for the<br />
heterogeneous Suzuki-Miyaura reaction by assembled complex of palladium and noncross<br />
linked amphiphilic polymer (Figure-33).<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 15
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
Figure-33<br />
Zhengyin Du et al. 65 has reported an ultrafast and highly efficient ligand-free<br />
Suzuki-Miyaura cross-coupling reaction between aryl bromides/iodides and aryl<br />
boronicacids using palladium chloride as catalyst in PEG-400/H 2 O in air at room<br />
temperature. TEM showed that palladium nanoparticles were generated in situ from<br />
PdCl 2 /PEG-400/H 2 O without use of other reductants. The catalyst system can be<br />
recycled to reuse three times with good yields (Figure-34).<br />
Figure-34<br />
Yu-Long Zhao et al. 66 has prepared a highly practical and reliable Nickel<br />
catalyst for Suzuki–Miyaura coupling of aryl halides with various aryl boronicacid<br />
(Figure-35).<br />
Figure-35<br />
Sha Lou et al. 67 has developed Palladium/Tris(tert-butyl)phosphine-Catalyzed<br />
Suzuki Cross-Couplings of aryl and heteroaryl halides with aryl and heteroaryl<br />
boronic acids in the Presence of Water (Figure-36).<br />
Figure-36<br />
Ruonan Zhang et al. 68 has synthesized a series of novel 5-arylidenefuran-<br />
2(5H)-ones and 5-arylidene-4-arylfuran-2(5H)-ones via the Suzuki-Miyaura reactions<br />
(Figure-37).<br />
Figure-37<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 16
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
Yongda Zhang et al. 69 has been developed one-pot process for the synthesis of<br />
8-arylquinolines via Pd-catalyzed borylation of quinoline-8-yl halides and subsequent<br />
Suzuki-Miyaura coupling with aryl halides using n-BuPAd 2 as ligand (Figure-38).<br />
Figure-38<br />
John Spencer et al. 70 has reported synthesis of a (piperazin-1-ylmethyl)biaryl<br />
library via microwave-mediated Suzuki–Miyaura cross-couplings (Figure 39).<br />
Figure-39<br />
Qing Tang et al. 71 has developed Suzuki–Miyaura coupling reactions of 5-<br />
chloro-1-phenyl-tetrazole with various functionalized aryl boronicacids in the<br />
presence of catalytic amounts of SPhos/Pd(OAc) 2 or RuPhos/Pd(OAc) 2 (Figure-40).<br />
Figure-40<br />
V. P. Mehta et al. 72 has reported a novel and versatile entry to asymmetrically<br />
substituted pyrazine derivatives (Figure 41).<br />
Figure-41<br />
Jeanne-Marie Begouin et al. 73 has reported cobalt-catalyzed cross-coupling<br />
between in situ prepared aryl zinc halides and 2-chloropyrimidine/2-chloropyrazine<br />
(Figure- 42).<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 17
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
Figure-42<br />
Takahiro Itoh et al. 74 has discovered a direct synthesis of hetero-biaryl<br />
compounds containing an unprotected NH 2 group via Suzuki–Miyaura reaction by<br />
using Pd(OAc) 2 and D-t-BPF ligand as a catalyst (Figure-43).<br />
Figure-43<br />
Lisa C. W. Chang et al. 75 synthesized 2,6-disubstituted and 2,6,8-trisubstituted<br />
purines as adenosine receptor antagonists via Suzuki–Miyaura reaction (Figure-44).<br />
Figure-44<br />
Atul R. Gholap et al. 60 has developed an efficient synthesis of antifungal<br />
pyrimidines via palladium catalyzed Suzuki/Sonogashira cross-coupling reaction from<br />
Biginelli 3,4-dihydropyrimidin-2(1H)-ones (Figure-45).<br />
Figure-45<br />
Christoph A. et al. 76 has reported an efficient Suzuki-Miyaura coupling of<br />
(hetero)aryl chlorides with Thiophene- and Furan boronicacids in aqueous n-butanol<br />
(Figure-46).<br />
R<br />
Y<br />
Cl<br />
(HO) 2 B<br />
(HO) 2 B<br />
S<br />
or<br />
O<br />
Na 2 PdCl 4 (1mol%)/L<br />
(1:2)<br />
2.0 eq. K 2 CO 3<br />
n-butanol/water<br />
R'<br />
100 o C<br />
Figure-46<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 18<br />
R<br />
Y<br />
S<br />
or<br />
R<br />
Y<br />
O<br />
R'
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
David X. Yang et al. 77 has reported palladium-catalyzed Suzuki-Miyaura<br />
coupling of Pyridyl-2-boronic esters with aryl halides using highly active and airstable<br />
phosphine chloride and oxide Ligands (Figure-47).<br />
FG<br />
N<br />
O<br />
B<br />
O<br />
ArX<br />
or<br />
HetArX<br />
Dichloropalladiuym oxide/chloride<br />
Base, solvent<br />
FG<br />
N<br />
or<br />
Ar<br />
FG<br />
N<br />
HetAr<br />
Figure-47<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 19
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
1.4. Current research work<br />
The literature survey described above has demonstrated that the pyrimidine<br />
derivatives possesses a variety of biological activity, among which are the analgesic,<br />
antihypertensive, antipyretic, antiviral and anti-inflammatory activity. These agents<br />
are also associated with nucleic acid, antibiotic, antimalarial and anti cancer drugs.<br />
Many of the pyrimidine derivatives are reported to possess potential CNS depressant<br />
properties. However, to our knowledge functionalized pyrimidines such as 4-<br />
isopropyl-2,6-di-phenylsubstituted derivatives are less studied (Figure-48). The<br />
tremendous biological potential of pyrimidine derivatives encouraged us to prepare<br />
some novel highly functionalized pyrimidines bearing 4-isopropyl-2-6-disubstitutedphenylpyrimidine-5-carboxylate<br />
functions.<br />
R<br />
O<br />
N<br />
O<br />
R 1<br />
N<br />
ASM-4a-t<br />
Figure-48<br />
Herein we described a series of novel and efficient protocol for the synthesis<br />
of diversely substituted pyrimidines. A series of chlorinated pyrimidines were<br />
synthesized from easily available Biginelli 3,4-dihydropyrimidin-2(1H)-ones. The<br />
chlorinated pyrimidines were subjected to the Suzuki-Miyaura coupling reactions<br />
with various phenylboronicacid derivatives to obtain C-phenyl pyrimidines. The<br />
newly synthesized compounds are characterized by IR, Mass, 1 H NMR, 13 C NMR<br />
spectroscopy and elemental analysis.<br />
.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 20
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
1.5. Results and discussion<br />
Scheme:-1 Synthesis of substituted pyrimidines via Suzuki-Miyaura coupling.<br />
R<br />
R<br />
R<br />
O<br />
NH 2<br />
NH 2<br />
O<br />
+<br />
O<br />
O<br />
O<br />
DMF<br />
O<br />
HN<br />
N<br />
H<br />
O<br />
ASM-01a-e<br />
O<br />
Con. HNO 3<br />
O<br />
N<br />
N<br />
H<br />
ASM-2a-e<br />
O<br />
O<br />
POCl 3<br />
R<br />
R<br />
OH<br />
R<br />
O<br />
1 B OH<br />
O<br />
N O<br />
N O<br />
R 1<br />
N<br />
Pd(Ph 3 ) 4<br />
K Cl N<br />
2 CO 3<br />
ASM-4a-t<br />
ASM-3a-e<br />
The synthetic route for the targeted compounds (ASM-4a-t) is shown in<br />
scheme 1. Initially, various substituted 3,4-dihydropyrimidine-2-(1H)-ones (DHPMs)<br />
(ASM-01a-e) were synthesized by well-known multi-component Biginelli reaction of<br />
substituted benzaldehyde, methyl isobutyrate acetate and urea fusion at 150 o C in the<br />
presence of 2-3 drops of DMF as a catalyst (scheme-01). Thus obtained DHPMs<br />
(ASM-01a-e) were subjected the oxidative dehydrogenation using 60% Con. HNO 3 to<br />
furnish corresponding 2-hydroxypyrimidines (ASM-02a-e) in excellent yield. The<br />
reaction of compounds ASM-02a-e with POCl 3 under reflux for 2-3 hrs afforded 2-<br />
chloropyrimidine derivatives ASM-03a-e up to 85-95% yield. The chlorinated<br />
pyrimidines ASM-03a were subjected to Suzuki-Miyaura carbon-carbon coupling<br />
reaction with various phenylboronicacid derivatives using tetrakis(triphenylphosphine)<br />
palladium(0) as a catalyst in 1,4-dioxane:water (6:4) and K 2 CO 3 as a base to achieve<br />
the cross-coupled final products ASM-04a-t with good yields.<br />
The structures of ASM-02a-e, ASM-03a-e and ASM-04a-t were established<br />
on the basis of their elemental analysis and spectral data (MS, IR, 1 H NMR and 13 C<br />
NMR). Some representative examples for each step are described here.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 21
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
The analytical data for ASM-02a revealed a molecular formula C 15 H 16 N 2 O 3<br />
(m/z 273). The 1 H NMR spectrum revealed one doublet at δ = 1.42-1.44 ppm assigned<br />
to isopropyl-CH 3 , a multiplet at δ = 3.20-3.26 ppm assigned to the isopropyl-CH<br />
protons, a singlet at δ = 3.57 ppm assigned to the –OCH 3 protons, a multiplet at δ =<br />
7.44–7.51 ppm assigned to the aromatic protons, and also a doublet at δ = 7.58–7.60<br />
ppm (j=6.9Hz) assigned to the aromatic protons, one singlet at δ = 12.94 ppm<br />
assigned to -OH group.<br />
Table 1: Synthesis of substituted pyrimidines via Suzuki-Miyaura coupling.<br />
Entry R R 1 Yield Time hrs.<br />
ASM-04a H 4-CN 82 6.0<br />
ASM-04b 4-CH 3 3-N(CH 3 ) 2 80 8.0<br />
ASM-04c 4-OCH 3 4-F 87 6.5<br />
ASM-04d 3-NO 2 4-OCH 3 92 6.0<br />
ASM-04e 4-F H 83 7.5<br />
ASM-04f H 3-N(CH 3 ) 2 78 8.5<br />
ASM-04g 4-CH 3 4-F 86 7.5<br />
ASM-04h 4-OCH 3 4-OCH 3 82 7.0<br />
ASM-04i 3-NO 2 H 89 7.0<br />
ASM-04j 4-F 4-CN 87 5.5<br />
ASM-04k H 4-OCH 3 83 6.5<br />
ASM-04l 4-CH 3 H 85 7.0<br />
ASM-04m 4-OCH 3 4-CN 82 6.5<br />
ASM-04n 3-NO 2 3-N(CH 3 ) 2 75 7.5<br />
ASM-04o 4-F 4-F 80 6.0<br />
ASM-04p H H 84 7.5<br />
ASM-04q 4-CH 3 4-CN 89 6.0<br />
ASM-04r 4-OCH 3 3-N(CH 3 ) 2 80 7.5<br />
ASM-04s 3-NO 2 4-F 90 6.5<br />
ASM-04t 4-F 4-OCH 3 86 6.0<br />
The structures of ASM-03a was supported by its mass (m/z 291), which agrees<br />
with its molecular formula C 15 H 15 FN 2 O 3, its 1 H NMR spectrum had signals at δ =<br />
1.32-1.35 (d, 6H, 2 x i prCH 3 ), 3.14-3.20 (m, 1H, i prCH), 3.72 (s, 3H, OCH 3 ), 7.43-<br />
7.48 (m, 3H, Ar-H), 7.65-7.67 (t, 2H, Ar-H).<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 22
Pd(II)<br />
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
The analytical data for ASM-04a revealed a molecular formula C 22 H 19 N 3 O 2<br />
(m/z 358). Its 1 H NMR spectrum had signals at δ = 1.16-1.32 (d, 6H, 2 x i prCH 3 ),<br />
3.15-3.19 (m, 1H, i prCH), 3.66 (s, 3H, OCH 3 ), 7.39-7.42 (m, 3H, Ar-H), 7.65-7.70<br />
(m, 4H, Ar-H), 8.61-8.63 (d, 2H, Ar-H).<br />
The proposed mechanism of the Suzuki-Miyaura coupling reaction for the<br />
formation of C-phenyl pyrimidines is depicted in figure 35.<br />
N<br />
N<br />
R<br />
Pd (0)<br />
N<br />
N<br />
Cl<br />
N<br />
R<br />
N<br />
N<br />
Pd(II)<br />
N<br />
Pd(II)<br />
Cl<br />
HO<br />
OCOOK<br />
B OH<br />
OCOOK<br />
K 2 CO 3<br />
HO B OH<br />
OCOOK<br />
HO B OH<br />
N<br />
N<br />
-KCl<br />
K 2 CO 3<br />
KOOCO<br />
Figure 35: Mechanism of Suzuki-Miyaura coupling reaction leading<br />
to the formation of C-phenyl pyrimidines.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 23
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
1.6 Conclusion<br />
In conclusion, we have developed an efficient four step protocols for the<br />
synthesis of diversely substituted novel pyrimidines. A series of chlorinated<br />
pyrimidines were synthesized from easily available biginelli 3,4-dihydropyrimidin-<br />
2(1H)-ones. The chlorinated pyrimidines were then subjected to condition normally<br />
employed Suzuki-Miyaura coupling reaction with various phenylboronicacid<br />
derivatives in the presence of palladium catalyst to obtain C-phenyl pyrimidines with<br />
good yields. A variety of commercially available 1,3-diketones and various<br />
substituted aldehydes and boronic acids can be used as building blocks to generate<br />
diversity on the core pyrimidine ring systems.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 24
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
1.7 Experimental section<br />
Thin-layer chromatography was accomplished on 0.2-mm precoated plates of<br />
silica gel G60 F 254 (Merck). Visualization was made with UV light (254 and 365nm)<br />
or with an iodine vapor. IR spectra were recorded on a FTIR-8400 spectrophotometer<br />
using DRS prob. 1 H (300 MHz), 1 H (400 MHz), 13 C (75 MHz) and 13 C (100 MHz)<br />
NMR spectra were recorded on a Bruker AVANCE II spectrometer in CDCl 3 and<br />
DMSO. Chemical shifts are expressed in δ ppm downfield from TMS as an internal<br />
standard. Mass spectra were determined using direct inlet probe on a GCMS-QP 2010<br />
mass spectrometer (Shimadzu). Solvents were evaporated with a BUCHI rotary<br />
evaporator. Melting points were measured in open capillaries and are uncorrected.<br />
<br />
General synthetic procedure for the 3,4-dihydropyrimidine-2-(1H)-ones<br />
(ASM-01a-e).<br />
A 100mL round bottom flask equipped with magnetic stirrer and septum was<br />
charged with the methyl 4-methyl-3-oxopentanoate (0.01M), aldehyde (0.01M) and<br />
urea (0.015M). Few drops of DMF were added to the reaction mixture as a catalyst.<br />
The reaction mixture was then heated at 145-150 o C for 15-30 minutes. The progress<br />
of reaction was monitored by thin layer chromatography. The reaction mixture was<br />
allowed to cool at rt. Then, methanol (20 mL) was added and the resulting mixture<br />
was refluxed for 30 min. The solid separated upon cooling was filtered, washed with<br />
methanol and dried. The products thus obtained (ASM-01a-e) were directly used for<br />
the next step.<br />
<br />
General synthetic procedure for the 2-hydroxypyrimidine derivatives<br />
(ASM-02a-e).<br />
In a 100mL round bottom flask equipped with magnetic stirrer and<br />
thermometer was added nitric acid (60%) (10 mL). To the nitric acid slowly added<br />
ASM-01a-e (10 mmol) at 0 o C. After complete addition, the mixture was stirred at<br />
this temperature for 30 min. The progress of reaction was monitored by thin layer<br />
chromatography. The reaction mixture was poured into cold water and neutralized<br />
with saturated sodium bicarbonate solution. The solid separated was filtered, washed<br />
with water and dried. The crude products (ASM-02a-e) were directly used for the<br />
next step.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 25
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
<br />
General synthetic procedure for the 2-chloropyrimidine derivatives<br />
(ASM-03a-e).<br />
In a 50mL round bottom flask equipped with magnetic stirrer and thermometer<br />
was placed ASM-02a-e (10 mmol) and POCl 3 (15 mL). Reaction mixture heated up to<br />
reflux temperature and maintain for 2-3 hrs. The progress of reaction was monitored<br />
by thin layer chromatography. After completion of reaction, the mixture was poured<br />
in to crushed ice and neutralized with saturated sodium bicarbonate solution. The<br />
products was filtered, washed with water and dried. Crystallize crude product from<br />
methanol and used for next step without further purification.<br />
<br />
General synthetic procedure for the 2-substitutedpyrimidine derivatives<br />
via Suzuki-Miyaura coupling (ASM-03a-e).<br />
A mixture of 2-choropyrimidine derivatives ASM-03a-e (1.0 mmol) and<br />
phenylboronicacid derivatives (1.2 mmol) in 1,4-dioxane (12 mL) was stirred for 10<br />
min at rt. To this mixture, saturated solution of K 2 CO 3 (8 mL) was added followed by<br />
tetrakis(triphenylphosphine)palladium(0) (5 mol%). The reaction mixture was heated<br />
at 110 o C for 5-8 hrs. After completion, the reaction mixture was cooled to room<br />
temperature, diluted with ethyl acetate and filtered through pad of celite. The filtrate<br />
was washed with water (2 x 100 mL) and brine solution (100 mL). The organic layer<br />
was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was<br />
evaporated to dryness under vacuo. The residue was purified by using column<br />
chromatography using EtOAc/Ether (0.5:9.5) to afford analytically pure products<br />
ASM-04a-e.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 26
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
<br />
Spectral data for the newly prepared compounds.<br />
Methyl 1,2-dihydro-6-isopropyl-2-oxo-4-phenylpyrimidine-5-carboxylate (ASM-<br />
02a). White solid; R f 0.45 (1:1 hexane-EtOAc); mp 158-160 ° C; IR (KBr): 3459, 3070,<br />
2930, 2850, 1730, 1650, 1583, 1470, 1335, 1064, 760, 700 cm -1 ; 1 H NMR (300 MHz,<br />
CDCl 3 ): δ 1.42-1.44 (d, 6H, 2 x i prCH 3 ), 3.20-3.26 (m, 1H, i prCH), 3.57 (s, 3H,<br />
OCH 3 ), 7.44-7.51 (m, 3H, Ar-H), 7.58-7.60 (d, 2H, Ar-H, j=6.9Hz), 12.94 (s, 1H,<br />
OH); 13 C NMR (DEPT):(75 MHz, CDCl 3 ): 21.40, 31.31, 56.47, 56.58, 114.99,<br />
115.28, 131.85, 131.96; MS (m/z): 273 (M + ); Anal. Calcd for C 15 H 16 N 2 O 3 : C, 66.16;<br />
H, 5.92; N, 10.29; Found: C, 66.13; H, 5.97; N, 10.27.<br />
Methyl 4-(4-fluorophenyl)-1,2-dihydro-6-isopropyl-2-oxopyrimidine-5-carboxylate<br />
(ASM-2e). White solid; R f 0.48 (1:1 hexane-EtOAc); mp 180-182 ° C; IR (KBr):<br />
3470, 3093, 2999, 1735, 1648, 1586, 1450, 1261, 755, 700, cm -1 ; 1 H NMR (300 MHz,<br />
CDCl 3 ): δ 1.14-1.16 (d, 6H, 2 x i prCH 3 ), 3.06-3.11 (m, 1H, i prCH), 3.54 (s, 3H,<br />
OCH 3 ), 6.92-6.98 (t, 2H, Ar-H), 7.29-7.40 (d, 2H, Ar-H), 8.0 (s, 1H, NH); 13 C NMR<br />
(DEPT):(75 MHz, CDCl 3 ): 20.82, 31.98, 52.28, 115.28, 115.56, 129.82, 129.93; MS<br />
(m/z): 291 (M + ); Anal. Calcd for C 15 H 15 FN 2 O 3 : C, 62.06; H, 5.21; N, 9.65; Found: C,<br />
62.13; H, 5.17; N, 9.67.<br />
Methyl 2-chloro-4-isopropyl-6-phenylpyrimidine-5-carboxylate (ASM-03a).<br />
White solid; R f 0.62 (8:2 hexane-EtOAc); mp 138-142 ° C; IR (KBr): 3057, 3034,<br />
2972, 2931, 2872, 1828, 1726, 1687, 1572, 1541, 871, 767, 730, 702 cm -1 ; 1 H NMR<br />
(300 MHz, CDCl 3 ): δ 1.32-1.35 (d, 6H, 2 x i prCH 3 ), 3.14-3.20 (m, 1H, i prCH), 3.72<br />
(s, 3H, OCH 3 ), 7.43-7.48 (m, 3H, Ar-H), 7.65-7.67 (t, 2H, Ar-H); 13 C NMR (100<br />
MHz, CDCl 3 ): 21.63, 33.62, 52.96, 123.49, 128.29, 128.78, 130.79, 136.37, 161.26,<br />
166.15, 167.88, 176.53; MS (m/z): 291 (M + ); Anal. Calcd for C 15 H 15 FN 2 O 3 : C, 61.97;<br />
H, 5.20; N, 12.19; Found: C, 61.90; H, 5.17; N, 12.27.<br />
Methyl 2-(4-cyanophenyl)-4-isopropyl-6-phenylpyrimidine-5-carboxylate (ASM-<br />
04a). White solid; R f 0.72 (8:2 hexane-EtOAc); mp 108-110 ° C; IR (KBr): 3194, 3154,<br />
2976, 2929, 2290, 1722, 1683, 1456, 1300, 858, 829, 777, 698 cm -1 ; 1 H NMR (400<br />
MHz, CDCl 3 ): δ 1.16-1.32 (d, 6H, 2 x i prCH 3 ), 3.15-3.19 (m, 1H, i prCH), 3.66 (s, 3H,<br />
OCH 3 ), 7.39-7.42 (m, 3H, Ar-H), 7.65-7.70 (m, 4H, Ar-H), 8.61-8.63 (d, 2H, Ar-H,<br />
j=7.8Hz); 13 C NMR (100 MHz, CDCl 3 ): 21.93, 29.69, 33.55, 52.80, 114.18,<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 27
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
118.87, 123.36, 128.34, 128.72, 129.07, 130.34, 132.31, 137.82, 141.45, 162.01,<br />
163.63, 168.77, 172.48; MS (m/z): 358 (M + ); Anal. Calcd for C 22 H 19 N 3 O 2 : C, 73.93;<br />
H, 5.36; N, 11.76; Found: C, 73.90; H, 5.37; N, 11.77.<br />
Methyl 2-(3-(dimethylamino)phenyl)-4-isopropyl-6-p-tolylpyrimidine-5-carboxylate<br />
(ASM-04b). White solid; R f 0.76 (8:2 hexane-EtOAc); mp 122-124 ° C; IR (KBr):<br />
3150, 2980, 2867, 1728, 1578, 1520, 1480, 1258, 780, 708 cm -1 ; 1 H NMR (300 MHz,<br />
DMSO): δ 1.30-1.32 (d, 6H, 2 x i prCH 3 ), 2.38 (s, 3H, CH 3 ), 2.97 (s, 6H, CH 3 ), 3.13-<br />
3.15 (m, 1H, i prCH), 3.74 (s, 3H, OCH 3 ), 6.94-6.95 (d, 1H, Ar-H, j=2.1Hz), 7.32-<br />
7.37 (m, 3H, Ar-H), 7.60-7.63 (m, 2H, Ar-H, j=8.4Hz), 7.78-7.80 (d, 1H, Ar-H,<br />
j=7.8Hz), 7.85-7.87 (m, 1H, Ar-H); MS (m/z): 391 (M + ); Anal. Calcd for C 24 H 27 N 3 O 2 :<br />
C, 74.01; H, 6.99; N, 10.79; Found: C, 74.02; H, 6.97; N, 10.77.<br />
Methyl 2-(4-fluorophenyl)-4-isopropyl-6-(4-methoxyphenyl)pyrimidine-carboxylate<br />
(ASM-04c). White solid; R f 0.80 (8:2 hexane-EtOAc); mp 148-150 ° C; IR (KBr):<br />
3158, 2967, 2850, 1735, 1558, 1503, 1430, 1268, 748, 698 cm -1 ; MS (m/z): 381 (M + );<br />
Anal. Calcd for C 22 H 21 FN 2 O 3 : C, 69.46; H, 5.56; N, 7.36; Found: C, 69.45; H, 5.57;<br />
N, 7.37.<br />
Methyl 4-isopropyl-2-(4-methoxyphenyl)-6-(3-nitrophenyl)pyrimidine-5-carboxy<br />
-late (ASM-04d). Yellow solid; R f 0.75 (8:2 hexane-EtOAc); mp 104-106 ° C; IR<br />
(KBr): 3130, 3053, 2986, 2832, 1726, 1548, 1498, 1369, 1238, 700 cm -1 ; MS (m/z):<br />
408 (M + ); Anal. Calcd for C 22 H 21 FN 2 O 3 : C, 64.86; H, 5.20; N, 10.31; Found: C,<br />
64.84; H, 5.20; N, 10.32.<br />
Methyl 4-(4-fluorophenyl)-6-isopropyl-2-phenylpyrimidine-5-carboxylate (ASM-<br />
04e). White solid; R f 0.84 (8:2 hexane-EtOAc); mp 134-136 ° C; IR (KBr): 3030, 2925,<br />
2832, 1726, 1553, 1430, 1238, 720, 678 cm -1 ; MS (m/z): 352 (M + ); Anal. Calcd for<br />
C 21 H 19 FN 2 O 2 : C, 71.98; H, 5.47; N, 8.00; Found: C, 71.94; H, 5.46; N, 8.02.<br />
Methyl 2-(3-(dimethylamino)phenyl)-4-isopropyl-6-phenylpyrimidine-5-carboxylate<br />
(ASM-04f). White solid; R f 0.69 (8:2 hexane-EtOAc); mp 162-168 ° C; IR (KBr):<br />
3093, 2999, 1648, 1586, 1261, 1061, 758 cm -1 ; MS (m/z): 376 (M + ); Anal. Calcd for<br />
C 23 H 25 N 3 O 2 : C, 73.57; H, 6.71; N, 11.19; Found: C, 73.56; H, 6.72; N, 11.22.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 28
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
Methyl 2-(4-fluorophenyl)-4-isopropyl-6-p-tolylpyrimidine-5-carboxylate (ASM-<br />
04g). White solid; R f 0.73 (8:2 hexane-EtOAc); mp 117-119 ° C; IR (KBr): 3083, 2958,<br />
1731, 1503, 1430, 1352, 1282, 1050 698 cm -1 ; MS (m/z): 365 (M + ); Anal. Calcd for<br />
C 22 H 21 FN 2 O 2 : C, 72.51; H, 5.21; N, 7.69; Found: C, 72.56; H, 5.22; N, 7.62.<br />
Methyl 4-isopropyl-2,6-bis(4-methoxyphenyl)pyrimidine-5-carboxylate (ASM-<br />
04h). Yellow solid; R f 0.77 (8:2 hexane-EtOAc); mp 171-173 ° C; IR (KBr): 3028,<br />
2924, 2868, 1729, 1523, 1480, 1430, 1268, 720 cm -1 ; MS (m/z): 392 (M + ); Anal.<br />
Calcd for C 23 H 24 N 2 O 4 : C, 70.39; H, 6.16; N, 7.14; Found: C, 70.40; H, 6.12; N, 7.12.<br />
Methyl 4-isopropyl-6-(3-nitrophenyl)-2-phenylpyrimidine-5-carboxylate (ASM-<br />
04i). Yellow solid; R f 0.80 (8:2 hexane-EtOAc); mp 182-184 ° C; IR (KBr): 3056,<br />
2967, 2850, 1735, 1505, 1480, 1320, 1252, 763 cm -1 ; MS (m/z): 378 (M + ); Anal.<br />
Calcd for C 21 H 19 N 3 O 4 : C, 66.83; H, 5.07; N, 11.13; Found: C, 66.84; H, 5.06; N,<br />
11.12.<br />
Methyl 2-(4-cyanophenyl)-4-(4-fluorophenyl)-6-isopropylpyrimidine-5-carboxylate<br />
(ASM-04j). White solid; R f 0.85 (8:2 hexane-EtOAc); mp 98-100 ° C; IR (KBr):<br />
3058, 2931, 2858, 2235, 1725, 1522, 1492, 1268, 758, 704 cm -1 ; MS (m/z): 376 (M + );<br />
Anal. Calcd for C 22 H 18 FN 3 O 2 : C, 70.39; H, 4.83; N, 11.19; Found: C, 70.37; H, 4.86;<br />
N, 11.17.<br />
Methyl 4-isopropyl-2-(4-methoxyphenyl)-6-phenylpyrimidine-5-carboxylate (AS<br />
M-04k). White solid; R f 0.74 (8:2 hexane-EtOAc); mp 131-133 ° C; IR (KBr): 3083,<br />
2954, 2825, 1731,1600, 1536, 1458, 1368, 1020, 738 cm -1 ; MS (m/z): 362(M + ); Anal.<br />
Calcd for C 22 H 22 N 2 O 3 : C, 72.91; H, 6.12; N, 7.73; Found: C, 72.91; H, 6.14; N, 7.74.<br />
Methyl 4-isopropyl-2-phenyl-6-p-tolylpyrimidine-5-carboxylate (ASM-04l).<br />
Yellow solid; R f 0.83 (8:2 hexane-EtOAc); mp 143-145 ° C; IR (KBr): 3126, 2999,<br />
1740, 1648, 1586, 1261, 1061, 720, 658 cm -1 ; MS (m/z): 346(M + ); Anal. Calcd for<br />
C 22 H 22 N 2 O 2 : C, 76.28; H, 6.40; N, 8.09; Found: C, 76.29; H, 6.41; N, 8.11.<br />
Methyl 2-(4-cyanophenyl)-4-isopropyl-6-(4-methoxyphenyl)pyrimidine-5-carboxylate<br />
(ASM-04m). Brown solid; R f 0.72 (8:2 hexane-EtOAc); mp 177-179 ° C; IR<br />
(KBr): 3064, 2935, 2831, 1728, 1558, 1503, 1430, 1268, 883, 778 cm -1 ; MS (m/z):<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 29
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
387 (M + ); Anal. Calcd for C 23 H 21 N 3 O 3 : C, 71.30; H, 5.46; N, 10.85; Found: C, 71.31;<br />
H, 5.44; N, 10.86.<br />
Methyl 2-(3-(dimethylamino)phenyl)-4-isopropyl-6-(3-nitrophenyl)pyrimidine-5-<br />
carboxylate (ASM-04n). Yellow solid; R f 0.82 (8:2 hexane-EtOAc); mp 152-157 ° C;<br />
IR (KBr): 3123, 2999, 2863,1731,1648, 1586, 1261, 1053, 850, 738, cm -1 ; MS (m/z):<br />
420 (M + ); Anal. Calcd for C 23 H 24 N 4 O 4 : C, 65.70; H, 5.75; N, 13.33; Found: C, 65.71;<br />
H, 5.74; N, 13.36.<br />
Methyl 2,4-bis(4-fluorophenyl)-6-isopropylpyrimidine-5-carboxylate (ASM-04o).<br />
White solid; R f 0.68 (8:2 hexane-EtOAc); mp 194-196 ° C; IR (KBr): 3135, 3089,<br />
2856, 1726, 1580, 1436, 1358, 1050, 780, cm -1 ; MS (m/z): 368 (M + ); Anal. Calcd for<br />
C 21 H 18 F 2 N 2 O 2 : C, 68.47; H, 4.93; N, 7.60; Found: C, 68.48; H, 4.94; N, 7.61.<br />
Methyl 4-isopropyl-2,6-diphenylpyrimidine-5-carboxylate (ASM-04p). White<br />
solid; R f 0.74 (8:2 hexane-EtOAc); mp 132-134 ° C; IR (KBr): 3120, 3025, 2868, 1745<br />
1600, 1480, 1380, 1068, 790, 745, cm -1 ; MS (m/z): 332 (M + ); Anal. Calcd for<br />
C 21 H 20 N 2 O 2 : C, 75.88; H, 6.06; N, 8.43; Found: C, 75.87; H, 6.06; N, 8.44.<br />
Methyl 2-(4-cyanophenyl)-4-isopropyl-6-p-tolylpyrimidine-5-carboxylate (ASM-<br />
04q). Yellow solid; R f 0.78 (8:2 hexane-EtOAc); mp 114-116 ° C; IR (KBr): 3051,<br />
2967, 2850, 2253, 1725, 1568, 1503, 1430, 1268, 748, 698 cm -1 ; MS (m/z): 371 (M + );<br />
Anal. Calcd for C 23 H 21 N 3 O 2 : C, 74.37; H, 5.70; N, 11.31; Found: C, 74.38; H, 5.71;<br />
N, 11.34.<br />
Methyl 2-(3-(dimethylamino)phenyl)-4-isopropyl-6-(4-methoxyphenyl)pyrimidine-5-carboxylate<br />
(ASM-04r). White solid; R f 0.84 (8:2 hexane-EtOAc); mp 198-200<br />
o C; IR (KBr): 3068, 2983, 2899, 1728, 1648, 1586, 1261, 1061, 780, 712 cm -1 ; 1 H<br />
NMR (300 MHz, DMSO): δ 1.30-1.32 (d, 6H, 2 x i prCH 3 ), 2.97 (s, 6H, CH 3 ), 3.11-<br />
3.16 (m, 1H, i prCH), 3.76-7.83 (s, 6H, OCH 3 ), 6.91-6.95 (dd, 1H, Ar-H, j=2.1Hz,<br />
j=2.7Hz), 7.09-7.12 (d, 2H, Ar-H, j=9.0Hz), 7.32-7.37 (t, 2H, Ar-H), 7.69-7.72 (d,<br />
2H, Ar-H, j=9.0Hz), 7.78-7.80 (d, 1H, Ar-H, j=7.8Hz); 7.86 (s, 1H, Ar-H); MS (m/z):<br />
406 (M + ); Anal. Calcd for C 24 H 27 N 3 O 3 : C, 71.09; H, 6.71; N, 10.36; Found: C, 71.07;<br />
H, 6.73; N, 10.37.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 30
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
Methyl 2-(4-fluorophenyl)-4-isopropyl-6-(3-nitrophenyl)pyrimidine-5-carboxylate<br />
(ASM-04s). White solid; R f 0.73 (8:2 hexane-EtOAc); mp 145-147 ° C;IR (KBr):<br />
3021, 2856, 1725, 1648, 1422, 1369, 1254, 1068, 790, 720 cm -1 ; MS (m/z): 395 (M + );<br />
Anal. Calcd for C 21 H 18 FN 3 O 4 : C, 63.79; H, 4.59; N, 10.63; Found: C, 63.79; H, 4.58;<br />
N, 10.64.<br />
Methyl 4-(4-fluorophenyl)-6-isopropyl-2-(4-methoxyphenyl)pyrimidine-5-carboxylate<br />
(ASM-04t). White solid; R f 0.85 (8:2 hexane-EtOAc); mp 103-105 ° C; IR<br />
(KBr): 3158, 3036, 2869, 1735, 1658, 1450, 1356, 800, 720 cm -1 ; MS (m/z): 380<br />
(M + ); Anal. Calcd for C 22 H 21 FN 2 O 3 : C, 69.46; H, 5.56; N, 7.36; Found: C, 69.45; H,<br />
5.58; N, 7.34.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 31
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
1 H NMR spectrum of compound ASM-02a<br />
1 H NMR spectrum of compound ASM-03a<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 32
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
1 H NMR spectrum of compound ASM-04a<br />
Expanded 1 H NMR spectrum of compound ASM-04a<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 33
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
1 H NMR spectrum of compound ASM-04b<br />
Expanded 1 H NMR spectrum of compound ASM-04b<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 34
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
1 H NMR spectrum of compound ASM-04r<br />
Expanded 1 H NMR spectrum of compound ASM-04r<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 35
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
13 C NMR spectrum of compound ASM-04a<br />
Expanded 13 C NMR spectrum of compound ASM-04a<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 36
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
Mass spectrum of compound ASM-03b<br />
Mass spectrum of compound ASM-03e<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 37
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
Mass spectrum of compound ASM-04a<br />
Mass spectrum of compound ASM-04s<br />
NO 2<br />
O<br />
N<br />
O<br />
N<br />
F<br />
m/z-396<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 38
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
IR spectrum of compound ASM-03a<br />
100<br />
%T<br />
80<br />
60<br />
40<br />
3057.27<br />
3034.13<br />
2931.90<br />
1828.58<br />
2872.10<br />
1687.77<br />
1670.41<br />
1622.19<br />
1572.04<br />
1410.01<br />
1116.82<br />
1031.95<br />
999.16<br />
977.94<br />
854.49<br />
823.63<br />
729.12<br />
675.11<br />
648.10<br />
623.03<br />
563.23<br />
538.16<br />
522.73<br />
482.22<br />
457.14<br />
434 00<br />
20<br />
2972.40<br />
1494.88<br />
1444.73<br />
1338.64<br />
1296.21<br />
1182.40<br />
1076.32<br />
920.08<br />
871.85<br />
767.69<br />
702.11<br />
0<br />
1726.35<br />
1541.18<br />
1519.96<br />
1383.01<br />
1220.98<br />
-20<br />
4000<br />
3500<br />
3000<br />
2500<br />
2000<br />
1750<br />
1500<br />
1250<br />
1000<br />
750<br />
500<br />
1/cm<br />
IR spectrum of compound ASM-04a<br />
110<br />
%T<br />
100<br />
90<br />
80<br />
70<br />
3194.23<br />
3151.79<br />
2976.26<br />
2929.97<br />
1737.92<br />
1722.49<br />
1683.91<br />
1649.19<br />
1558.54<br />
1506.46<br />
1456.30<br />
1398.44<br />
1330.93<br />
1259.56<br />
1228.70<br />
1076.32<br />
858.35<br />
829.42<br />
777.34<br />
761.91<br />
698.25<br />
611.45<br />
561.30<br />
60<br />
1535.39<br />
50<br />
449.43<br />
1<br />
542.02<br />
4000<br />
3500<br />
3000<br />
2500<br />
2000<br />
1750<br />
1500<br />
1250<br />
1000<br />
750<br />
500<br />
1/cm<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 39
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
1.8 References<br />
1. Mashkovskii, M. D.; Medicinals [in Russian], 12th ed., Meditsina, Moscow 1993, Part 1, p.<br />
736; 1993, Part 2, p. 688.<br />
2. Nikolaeva, N. B. (ed.), Medicinal Products from Foreign Firms in Russia [in Russian],<br />
Astrafarmservis, Moscow, 1993, p. 720.<br />
3. Biginelli, P. Berichte, 1891, 24, 1317.<br />
4. Khanina, E. L.; Silinietse, G. O.; Ozol, Y. Y.; Dubur, G. Y.; Kimenis, A. A. Khim. Farm. Zh.,<br />
1978, 10, 72.<br />
5. Cho, H.; Ueda, M.; Shima, K.; Mizuno, A.; Hayashimatsu, M.; Ohnaka, Y.; Nakeuchi, Y.;<br />
Hamaguchi, M.; Aisaka, K.; Hidaka, T.; Kawai, M.; Takeda, M.; Ishihara, T.; Funahashi, K.;<br />
Satoh, F.; Morita, M.; Noguchi, T. J. Med. Chem., 1989, 32, 2399.<br />
6. Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D. M.; Moreland, S.; Hedberg, A.;<br />
O'Reilly, B. C. J. Med. Chem., 1991, 34, 806.<br />
7. Rovnyak, G. C.; Kimball, S. D.; Beyer, B.; Cucinotta, G.; DiMarco, J. D.; Gougoutas, J.;<br />
Hedberg, A.; Malley, M.; McCarthy, J. P.; Zhang, R.; Moreland, S.; J. Med. Chem., 1995, 38,<br />
119.<br />
8. Amine, M. S.; Nassar, S. A.; El-Hashash, M. A.; Essawy, S. A.; Hashish, A. A. Ind.J. Chem.,<br />
Sect. B, 1996, 35, 388.<br />
9. Desenko, S. M.; Lipson, V. V.; Gorbenko, N. I.; Livovarevich, L. P.; Ryndina, E. N.; Moroz,<br />
V. V.; Varavin, V. P. Khim. Farm. Zh., 1995, 4, 37.<br />
10. Jelich, K.; Babczinski, P.; Sartel, H. J.; Smidt, R.; Strang, H.; German Patent No. 3,808,122;<br />
Ref. Zh. Khim., 1990, 160433P.<br />
11. Gsell, L. Eur. Pat. Appl. EP 375,613; Chem. Abs., 1990, 113, 231399.<br />
12. Weis, A. L.; Van der Plas, H. C. Heterocycles, 1986, 24, 1433.<br />
13. Weis, A. L.; Advances in Heterocyclic Chemistry, A. R. Katritzky (ed.), Academic Press,<br />
Orlando, etc., 1985, Vol. 38, p. 3.<br />
14. Evans, R. F.; The Pyrimidines, D. J. Brown (ed.), Wiley, New York, Chichester, Brisbane,<br />
Toronto, Singapore, 1994, p. 737.<br />
15. Eussell, J. A. Annu. Rev. Biochem. 1945, 14, 309.<br />
16. Cox, R. A. Quart. Rev. 1968, 22, 499.<br />
17. Van der Plas, H. C.; Charushin, V. N.; Van Veldhuizen, B. J. Org. Chem., 1983, 48, 1354.<br />
18. Janis, R. A.; Silver, P. J.; Triggle, D. J. Adv. Drug Res. 1987, 16, 309.<br />
19. Rovnyak, G. C.; Atwal, K. S.; Hedberg, A.; Kimball, S. D.; Moreland, S.; Gougoutas, J. Z.;<br />
O´Reilly, B. C.; Schwartz, J.; Malley, M. F. J. Med. Chem. 1992, 35, 3254.<br />
20. Forray, C.; Bard, J. A.; Wetzel, J. M.; Chiu, G.; Shapiro, E.; Tang, R.; Lepor, H.; Hartig, P.<br />
R.; Weinshank, R. L.; Branchek, T. A.; Gluchowski, C.; Mol. Pharmacol. 1994, 45, 703.<br />
21. Barrow, J. C.; Nantermet, P. G.; Selnick, H. G.; Glass, K. L.; Rittle, K. E.; Gilbert, K. F.;<br />
Steele, T. G.; Homnick, C. F.; Freidinger, R. M.; Ransom, R. W.; Kling, P.; Reiss,<br />
D.;Broten,T. P.; Schorn, T. W.; Chang, R. S. L.; O’Malley, S. S.; Olah, T. V.; Ellis, J. D;<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 40
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
Barrish, A.; Kassahun, K.; Leppert, P.; Nagarathnam, D.; Forray, C. J. Med. Chem. 2000, 43,<br />
2703.<br />
22. Nagarathnam, D.; Miao, S. W.; Lagu,, B.; Chiu, G.; Fang, J.; Murali Dhar, T. G.; Zhang, J.;<br />
Tyagarajan, S.; Marzabadi, M. R.; Zhang, F.; Wong, W. C.; Sun, W.; Tian, D.; Wetzel, J. M.;<br />
Forray, C.; Chang, R. S. L.; Broten, T. P.; Ransom, R. W.; Schorn, T. W.; Chen, T. B.;<br />
O’Malley, S.; Kling, P.; Schneck, K.; Bendesky, R.; Harrell, C. M.; Vyas, K. P.; Gluchowski,<br />
C. J. Med. Chem. 1999, 42, 4764.<br />
23. Atwal, K.; Rovnyak, G. C.; Schwartz, J.; Moreland, S.; Hedberg, A.; Gougoutas, J. Z.;<br />
Malley, M. F.; Floyd, D. M. J. Med. Chem. 1990, 33, 1510.<br />
24. Atwal, K. S.; Rovnyak, G. C.; Kimball, S. D.; Floyd, D. M.; Moreland, S.; Swanson, B. N.;<br />
Gougoutas, J. Z.; Schwartz, J.; Smillie, K. M.; Malley, M. F. J. Med. Chem. 1990, 33, 2629.<br />
25. Tetko, I. V.; Tanchuk, V. Y.; Chentsova, N. P.; Antonenko, S. V.; Poda, G. I.; Kukhar, V. P.;<br />
Luik, A. I. J. Med. Chem., 1994, 37, 2520.<br />
26. Bryzgalov, A. O.; Dolgikh, M. P.; Sorokina, I. V.; Tolstikova, T. G.; Sedova, V. F.; Shkurko,<br />
O. P. Bioorg. Med. Chem. Lett., 2006, 16, 1418.<br />
27. Remennikov, G. Y.; Shavaran, S. S.; Boldyrev, I. V.; Kapran, N. A.; Kurilenko, L. K.;<br />
Sevchuk, V. G.; Klebanov, B. M. Pharm. Chem. Journal, 1994, 28, 322.<br />
28. Brian C. Shook, Stefanie Rassnick, Daniel Hall, Kennth C. Rupert, Geoffrey R. Heintzelman,<br />
Bioorganic & medicinal chemistry letters. 2010, 20, 2864<br />
29. Ma, Y.; Qian, C.; Wang, L.; Yang, M. J. Org. Chem., 2000, 65, 3864.<br />
30. Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem. 2000, 65, 6270.<br />
31. Heravi, M. M.; Derikvand, F.; Bamoharram, F. F. J. Mol. Catal. A: Chem., 2005, 242, 173.<br />
32. Heravi, M. M.; Bakhtiari, K.; Bamoharram, F. F. Catal. Comm., 2006, 7, 373.<br />
33. Badaoui, H.; Bazi, F.; Sokori, S.; Boulaajaj, S.; Lazrek, H. B.; Sebti, S; Lett. in Org. Chem.,<br />
2005, 2, 561.<br />
34. De, S. K.; Gibbs, R. A. Syn Comm, 2005 35, 2645.<br />
35. Rusinov, V. L.; Chupakhin, O. N. Nitroazines, B. M. Vlasov (ed.), Nauka, Novosibirsk, 1991,<br />
347.<br />
36. Shirini, F.; Marjani, K.; Nahzomi, H. T. ARKIVOC, 2007, 1, 51.<br />
37. Dax, S. L.; McNally, J. J.; Youngman, M. A.; Curr. Med. Chem., 1999, 6, 255.<br />
38. Wipf, P.; Cunningham, A. Tet. Lett., 1995, 36, 7819.<br />
39. Li, W.; Lam, Y.; J. Comb. Chem., 2005, 7, 721.<br />
40. Toy, P. H.; Janda, K. D. Acc. Chem. Res., 2000, 33¸546.<br />
41. (a) Gravert, D. J.; Janda, K. D. Chem. Rev., 1997, 97, 489. (b) Wentworth, P.; Janda, K. D.<br />
Chem. Comm., 1999, 19, 1917.<br />
42. Fang, D.; Luo, J.; Zhou, X.; Ye, Z.; Liu, Z. J. Mol. Catal. A: Chem., 2007, 27, 208.<br />
43. Jean, C. L.; Jean, J. V. E.; Loic, T.; Jean, P. B. ARKIVOC, 2007, 3, 13.<br />
44. Ming, L.; Si, G. W.; Rong, W. L.; Feng, L. Y.; Y. H. Zheng, J. Mol. Catal. A: Chem., 2006,<br />
258, 133.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 41
Chapter 1<br />
Synthesis of functionalized pyrimidines<br />
45. (a) Caddick, S. Tetrahedron, 1995, 51, 10403. (b) Deshayes, S.; Liagre, M.; Loupy, A.;<br />
Luche, J.; Petit, A. Tetrahedron, 1999, 55, 10851. (c) Lidstrom, P.; Tierney, J.; Wathey, B.;<br />
Westman, J.; Tetrahedron, 2001, 57, 9225. (d) Kirschning, A.; Monenschein, H.; Wittenberg,<br />
R. Angew. Chem. Int. Ed., 2001, 40, 650. (e) Varma, R. S. Pure Appl. Chem., 2001, 73, 193.<br />
(f) Loupy, A. Microwaves in Organic Synthesis, 2002, pp. 499 Wiley-VCH: Weinheim.<br />
46. Dandia, A.; Saha, M.; Taneja, H. J. Fluorine Chem., 1998, 90, 17.<br />
47. Diddams, P.; Butters, M. Solid Supports and Catalysts in Organic Synthesis, K. Smith; Ed.;<br />
Ellis Harwood and PTR Prentice Hall: New York and London, 1992, pp. 3-39.<br />
48. Gopalakrishnan, M.; Sureshkumar, P.; Kanagarajan, V.; Thanusu, J.; Govindaraju, R.<br />
ARIKVOC, 2006, 13, 130.<br />
49. (a) Stefani, H. A.; Pereira, C. M. P.; Almeida, R. B.; Braga, R. C.; Guzen, K. P.; Cella, R. Tet.<br />
Lett., 2005, 46, 6833. (b) Shen, Z. L.; Ji, S. J.; Wang, S. Y.; Zeng, X. F. Tetrahedron, 2005,<br />
61, 10552.<br />
50. Li, J. T.; Han, J. F.; Yang, J. H.; Li, T. S. Ultrasonics Sonochem, 2003, 10, 119.<br />
51. Zhang, X.; Li, Y.; Liu, C.; Wang, J. J. Mol. Catal. A: Chem., 2006, 253, 207.<br />
52. Kumar, H.; Parmar, A. Ultrasonics Sonochem., 2007, 15, 129.<br />
53. Memarian, H. R.; Farhadi, A.; Sabzyan, H.; Ultrasonics Sonochemistry, 2010, 17, 579.<br />
54. Kim, S. S.; Choi, B. S.; Lee, J. H.; Lee, K. K.; Lee, T. H.; Kim, Y. H.; Shin, H. Synlett, 2009,<br />
No. 4, 599.<br />
55. Nasr-Esfahani, M.; Montazerozohori, M.; Abdi, K. ARKIVOC, 2009 (x) 255.<br />
56. Liang, R. R.; Wu, G. L.; Wu, W. T.; Wu, L. M.; Chinese Chemical Letters, 2009, 20, 1183.<br />
57. Karade , N. N.; Gampawar, S. V.; Kondre, J. M.; Tiwari, G. B.; Tetrahedron Letters, 2008,<br />
49, 6698.<br />
58. Yamamoto, K.; Chen, Y. G.; Buono, F. G.; Org. Lett., 2005, 7, 21.<br />
59. Driwedi S. D.; Holkar A. G.; Patel D. j.; Rupapara M. L.; Patel M. R.; WO 2009/157014 A2,<br />
2009.<br />
60. Gholap, A. R.; Toti, K. S.; Shirazi, F.; Deshpande, M. V.; Srinivasan, K. V.; Tetrahedron,<br />
2008, 64, 10214.<br />
61. (a) Miyaura, N.; Yamada, K.; Suzuki, A.; Tetrahedron Letters, 1979, 20, 36, 3437.<br />
(b) Miyaura, N.; Suzuki, A.; Chem. Comm. 1979, 19, 866.<br />
62. Miyaura, N.; Yanagi, T.; Suzuki, A.; Synth. Commun. 1981, 11, 513.<br />
63. Li, S.; Lin, Y.; Cao, J.; Zhang, S.; J. Org. Chem., 2007, 72, 4067.<br />
64. Yamada, Y. M. A.; Takeda, K.; Takashashi, H.; Ikegami, S.; J. Org. Chem. 2003, 68, 7733.<br />
65. Zhengyin Du; Wanwei Zhou; Fen Wang; Jin-Xian Wang; Tetrahedron, 2011, 67, 4914.<br />
66. Yu-Long Zhao; You Li; Shui-Ming Li; Yi-Guo Zhou; Feng-Yi Sun; Lian-Xun Gao; Fu-She<br />
Hana; Adv. Synth. Catal. 2011, 353, 1543.<br />
67. Sha Lou; Gregory C. Fu; Adv. Synth. Catal. 2010, 352, 2081.<br />
68. Zhang, R.; Iskander, G.; Silva, P.; Chan, D.; Vignevich, V.; Nguyen, V.; Bhadbhade, M. M.;<br />
Black, D.; StC, Kumar, N.; Tetrahedron, 2011, 67 3010.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 42
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Synthesis of functionalized pyrimidines<br />
69. Zhang, Y.; Gao, J.; Li, W.; Lee, H.; Lu, B.Z.; Senanayake. C. H.; J. Org. Chem. 2011, 76,<br />
6394.<br />
70. Spencer, J.; Baltus, C. B.; Press, N. J.; Harrington, R. W.; Clegg, W.; Tetrahedron Letters,<br />
2011, 52, 3963.<br />
71. Tang, Q.; Gianatassio, R.; Tetrahedron Letters, 2010, 51, 3473–3476.<br />
72. Mehta, V. P.; Sharma, A.; Hecke, K. V.; Meervelt, L. V.; Eycken, E. V.; J. Org. Chem.,<br />
2008, 73, 2382.<br />
73. Begouin, J-M.; Gosmini, C.; J. Org. Chem. 2009, 74, 8.<br />
74. Itoh, T.; Mase, T.; Tetrahedron Letters, 2005, 46, 3573.<br />
75. Chang, Lisa C. W.; Spanjersberg, R. F.; Von, J. K.; Kunzel, F. D.; Thea Mulder-Krieger,;<br />
Brussee, J.; IJzerman, A. P.; J. Med. Chem. 2006, 49, 2861.<br />
76. Fleckenstein, C. A.; Plenio, H.; J. Org. Chem. 2008, 73, 3236.<br />
77. Yang, D. X.; Colletti, S. L.; Wu, K.; Song, M.; Li, G.Y.; Shen, H.C.; Org. Lett, 2009, 11, 2.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 43
Chapter – 2<br />
Synthesis and Biological Activity of<br />
Novel Pyrimidine Derivatives via Wittig<br />
Reaction in Aqueous Media
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
2.1 Introduction<br />
As described in chapter-1 the pyrimidine scaffold represents an important<br />
pharmacophore endowed with a wide range of pharmacological activities according to<br />
the specific decoration of the heterocycle. Nitrogen-containing heterocycles are<br />
widely distributed in nature and are essential to life, playing a vital role in the<br />
metabolism of all living cells. Among these, pyrimidines represent one of the most<br />
prevalent heterocycles found in natural products such as amino acid derivatives<br />
(willardiine, tingitanine), 1 vitamins (vitamin B1), 2 antibiotics (bacimethrin,<br />
sparsomycin, bleomycin), 3 alkaloids (heteromines, crambescins, manzacidins,<br />
variolins, meridianins, psammopemmins etc.), 4 and toxins. 5 From a synthetic point of<br />
view, the first pyrimidine derivative (alloxan) was obtained as early as 1818, by<br />
Brugnatelli, oxidizing uric acid with HNO 3 . 6 In 1848, a second pyrimidine synthesis<br />
was pioneered by Frankland and Kolbe, who heated propionitrile with metallic<br />
potassium to give a pure product (2,6-diethyl-5-methyl-4-pyrimidinamine), 7 while in<br />
1878 Grimaux prepared barbituric acid by condensation of malonic acid with urea.<br />
The latter procedure has been later named after Pinner who gave the name to the<br />
pyrimidine scaffold and was the first to understand the chemical nature of this<br />
structure. Pyrimidine nucleus present in rosuvastatin (Figure-1), 8 which is member of<br />
drug class of statins, used to treat high cholesterol and related condition to prevent<br />
cardiovascular diseases.<br />
Figure-1<br />
Due to the long-lasting interest in pyrimidine derivatives as potential drugs,<br />
the synthetic community has dedicated much effort to the investigation of new<br />
approaches to those derivatives. Accordingly, we have described here an overview of<br />
the most interesting synthetic strategies recently reported for the generation of highly<br />
functionalized pyrimidines.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 44
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
2.2 A literature review on the biological activity associated with<br />
pyrimidine derivatives<br />
In medicinal chemistry pyrimidine derivatives have been very well known for<br />
their therapeutic applications. Many pyrimidine derivatives have been developed as<br />
chemotherapeutic agents. Over the years, the pyrimidine system turned out to be an<br />
important pharmacophore endowed with drug like properties and a wide range of<br />
pharmacological activities depending on the decoration of the scaffold. A few<br />
illustrative examples of pyrimidine derivatives active as inhibitors of HIV, 9 HCV, 10<br />
CDK, 11 CB2, 12 VEGFR 13 and Adenosine A1/A2a/A3 14 are reported in Figure-2.<br />
Figure-2<br />
Microbes are causative agents for various types of disease like pneumonia,<br />
amoebiasis, typhoid, malaria, common cough and cold various infections and some<br />
severe diseases like tuberculosis, influenza, syphilis, and AIDS as well. Various<br />
approaches were made to check the role of pyrimidine moiety as antimicrobial agent<br />
from the discovery of molecule to the present scenario. Naik et al. 15 synthesized 2-[{2<br />
(Morpholino)-3-pyridinyl-5-thio}-2-oxoethyloxadiazolyl]-amino-4-(2,4-dichloro-5-<br />
fluorophenyl)-6-(aryl)pyrimidines, which exhibit maximum zone of inhibition against<br />
E.coli, S. aureus, S.typhiiand B.subtilis (Figure-3).<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 45
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
Figure-3<br />
Mishra et al. 16 have synthesized various derivatives of pyrimidines. The<br />
fungicidal activities of the compound were evaluated against P. infestans and C.<br />
falcatum by the usual agar plate method (Figure-4).<br />
R'<br />
N<br />
O<br />
O<br />
N NH<br />
R<br />
N NH<br />
Figure-4<br />
The pyrimidine moiety with some substitution showed to have promising<br />
antitumor activity as there are large numbers of pyrimidine based antimetabolites. The<br />
structural modification may be on the pyrimidine ring or on the pendant sugar groups.<br />
Early metabolite prepared was 5-fluorouracil, 17 a pyrimidine derivative followed by<br />
5-thiouracil which also exhibits some useful antineoplastic activities (Figure-5). 18<br />
Figure-5<br />
Palwinder Singh et al. 19 has reacted 5-benzoyl/5-carbaldehyde-/5-(3-phenyl<br />
acryloyl)-6-hydroxy-1H-pyrimidine-2,4diones with amines provided the<br />
corresponding enamines (Figure-6). The investigation for anticancer activity of<br />
molecule at 59 human tumor cell lines was done representing leukemia, melanoma<br />
and cancer of lung, colon, brain, ovary, breast as well as kidney.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 46
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
Figure-6<br />
Stephanepedeboscq et al. 20 has synthesized 4-(2-Methylanilino)<br />
benzo[b]thieno[2,3-d]pyrimidine (1) and 4-(2-Methoxyanilino)benzo[b]thieno[2,3-d]<br />
pyrimidine (2) (Figure-7), which showed a similar cytotoxicity to the standard anti-<br />
EGFR geftinib suggesting a blockade of the EGFR pathway by binding to the tyrosine<br />
kinase receptor.<br />
R 2<br />
R 1<br />
N<br />
NH<br />
NH 2<br />
N<br />
S<br />
R 1 =CH 3 , R 2 =H for (1)<br />
R 1 =OCH 3 ,R 2 =H for (2)<br />
Figure-7<br />
Fathalla et al. 21 has synthesized a series of some new pyrimidine derivatives<br />
like 7-(2-methoxyphenyl)-3-methyl-5-thioxo-5, 6-dihydro[1, 2, 4]-triazolo[4,3-c]<br />
pyrimidine-8-carbo-nitrile via reaction of ethyl cyanoacetate with thiourea and the<br />
appropriate aldehydes namely 2-methyl-benzaldehyde and 2-methoxy-benzaldehyde<br />
followed reaction with different reagents. All structures were than screened for<br />
bacterial activity and anticancer activity (Figure-8).<br />
N<br />
N<br />
N<br />
S<br />
CN<br />
NH<br />
OCH 3<br />
Figure-8<br />
Pyrimidine has a remarkable pharmacological efficiency and therefore an<br />
intensive research has been focused on anti-inflammatory activity of pyrimidine<br />
nucleus. Recently two PCT international applications have been filed for 2-<br />
thiopyrimidine derivatives possessing potent activity against inflammation and<br />
immune disorders. 22<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 47
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
Padama shale et al. 23 have been reported Naphtho[2,1-b]furo[3,2-d]pyrimidine<br />
and Carrageen induced rat paw edema method was employed for evaluating the antiinflammatory<br />
activity. The compounds were given at a dose of 80 mg/kg body weight<br />
in albino rats weighing between 150 and 200 g. The oedema was produced by<br />
injecting carrageenan solution at the left hind paw (Figure-9).<br />
O<br />
N<br />
N<br />
R<br />
R 1<br />
Figure-9<br />
Lee et al. 24 has synthesized some novel pyrimidines derivative having<br />
thiazolidinedione. These compounds were evaluated for their glucose and lipid<br />
lowering activity using pioglitazone and rosiglitazone as reference compound.<br />
Desenko et al. 25 has synthesized azolopyrimidine derivatives and compounds were<br />
evaluated for hypoglycemic activity (Figure-10).<br />
N<br />
N<br />
N<br />
Figure-10<br />
Many pyrimidine ring containing drugs have exhibited antihypertensive<br />
activity. A quinozoline derivative, prazosin, is a selective α1-adrenergic antagonist. 26<br />
Its related analogues bunazosin, 27 trimazosin 28 and terazosin 29 are potent<br />
antihypertensive agents(Figure-11).<br />
O<br />
O<br />
NH 2<br />
N<br />
N<br />
N<br />
N R<br />
Et<br />
R= O<br />
for Prazocin<br />
R= CH 2 OOCH 2 COH(CH 3 ) 2 for Bunazosin<br />
R= COCH 2 CH 2 CH 3 for Trimazosin<br />
O<br />
R=<br />
O<br />
for Terazosin<br />
Figure-11<br />
Ketanserin 30 has a similar effect and is an antagonist of both a1-adrenergic and<br />
serotonin-S2 receptors. A triaminopyrimidine derivative, minoxidil,<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 48
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
whose mechanism of action and therapeutic action are similar to prazosin, has been<br />
introduced in therapy for its side effects, in the treatment of alopecia, male baldness<br />
etc (Figure-12). 31<br />
Figure-12<br />
Rahaman et al. 32 has synthesized novel pyrimidines by the condensation of<br />
chalcones of 4΄-piperazine acetophenone with guanidine HCl (Figure-13). It showed<br />
significant antihistaminic activity when compared to the reference antihistaminic drug<br />
mepiramine.<br />
HN<br />
N<br />
R<br />
N<br />
N<br />
NH 2<br />
Figure-13<br />
A small library of 20 tri-substituted pyrimidines was synthesized by Anu et<br />
al. 33 evaluated for their in vitro anti-malarial and anti-tubercular activities. Out of all<br />
screened compound, 16 compounds have shown in-vitro anti-malarial activity against<br />
Plasmodium falciparum in the range of 0.25- 2μg/ml and 8 compounds have shown<br />
anti-tubercular activity against Mycobacterium tuberculosis at a concentration 12.5<br />
μg/ml (Figure-14).<br />
Figure-14<br />
Apart from these activities, pyrimidines also possess diuretic, antianthelmentic<br />
and calcium channel blocking activity. 34<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 49
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
2.3 Various synthetic approaches for highly substituted<br />
pyrimidines<br />
A brief literature review on the new synthetic strategies for pyrimidine<br />
derivatives is presented as follows.<br />
In recent years, several interesting Pinner-like approaches have been<br />
developed: Karpov and Muller have been reported the employment of alkynones (βketo<br />
aldehydes’ synthetic equivalents) in a three-component one-pot pyrimidine<br />
synthesis (Figure-15). 35 The coupling of acid chlorides (1) with terminal alkynes (2)<br />
under modified Sonogashira conditions (Et 3 N used in stoichiometric amount)<br />
followed by the addition of aminium or guanidinium salts (4) in the presence of<br />
sodium carbonate gave the 2,4-disubstituted or 2,4,6-trisubstituted pyrimidines (5).<br />
Figure-15<br />
Kiselyov 36 was reported an efficient one-pot approach for the synthesis of<br />
2,4,5,6-tetrasubstituted pyrimidines (Figure-16). Reaction of alkyl- or<br />
benzylphosphonates with aryl nitriles formed unstable aza-Wittig species which were<br />
converted into α,β-unsaturated imines by reaction with aromatic aldehydes. The latter<br />
intermediates were converted into the desired pyrimidine derivatives after<br />
nucleophilic attack by a bidentate nuclophile, usually guanidine or amidine.<br />
Figure-16<br />
Mohammad Movassaghi et al. 37 has described a procedure for the synthesis of<br />
pyrimidine derivatives. It was applicable to a wide range of secondary amides and<br />
nitriles using 2-chloropyridine as a base additive in the presence of Tf 2 O (Figure-17).<br />
Figure-17<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 50
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
T. Sasada et al. 38 have been reported a ZnCl 2 -catalyzed three-component<br />
coupling reaction allows the synthesis of various 4,5-disubstituted pyrimidine<br />
derivatives in a single step from functionalized enamines, triethylorthoformate, and<br />
ammonium acetate (Figure-18). The procedure can be successfully applied to the<br />
efficient synthesis of mono- and disubstituted pyrimidine derivatives, using methyl<br />
ketone derivatives instead of enamines.<br />
R<br />
H 2 N<br />
or<br />
R'<br />
R<br />
R'<br />
O<br />
3 eq. HC(OEt) 3<br />
2eq.NH 4 OAc<br />
0.1 eq. ZnCl 2<br />
Toluene<br />
100 o C, 3- 72 hrs<br />
R<br />
R'<br />
N<br />
N<br />
Figure-18<br />
M. G. Barthakur et al. 39 have been developed a novel and efficient synthesis of<br />
pyrimidine from β-formylen amide involves samarium chloride catalyzed cyclization<br />
of β-formelene amides using urea as source of ammonia under microwave irradiation<br />
(Figure-19).<br />
Figure-19<br />
P. Zhichkin et al. 40 described a method for the synthesis of 2-substituted<br />
pyrimidine-5-carboxylic esters. The sodium salt of 3, 3-dimethoxy-2-<br />
methoxycarbonylpropen-1-ol has been found to react with a variety of amidinium<br />
salts to afford the corresponding 2-substituted pyrimidine-5-carboxylic esters<br />
(Figure-20).<br />
Figure-20<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 51
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
2.4 Applications of Wittig reaction<br />
The Wittig reaction occupies a central role in organic synthesis as it generates<br />
double bond with high level of stereocontrol: non stabilized ylides give high Z-<br />
selectivity, where as stabilized ylides furnish high E-selectivity. 41 Here we discuss<br />
various synthetic approaches for synthesize new chemical entities via Wittig reaction.<br />
R. Antonioletti et al. 42 have developed a mild and practical procedure for the<br />
Wittig olefination, promoted by lithium hydroxide and triphenylbenzyl phosphonium<br />
bromide, has been set up for the synthesis of stilbenes and styrenes (Figure-21).<br />
Ph<br />
Ph<br />
P<br />
Br R CHO<br />
Ph<br />
LiOH·H2O<br />
Solvent, refulx<br />
E/Z isomer<br />
Figure-21<br />
Jesse Dambacher et al. 43 has reported that water is demonstrated to be an<br />
excellent medium for the Wittig reaction employing stabilized ylides and aldehydes.<br />
Although the solubility in water appears to be an unimportant characteristic in<br />
achieving good chemical yields and E/Z-ratios, the rate of reactions in water is<br />
unexpectedly accelerated (Figure-22).<br />
R<br />
Figure-22<br />
Elsie Ramirez et al. 44 have been developed a highly efficient and rapid<br />
protocol for the preparation of the unsaturated 7,3-lactone-a-D-xylofuranose<br />
derivatives (Versatile chiral synthon for naturally important compounds) via selective<br />
Wittig olefination in aqueous media (Figure-23).<br />
Figure-23<br />
James McNulty et al. 45 has reported direct synthesis of 1,3-dienes and 1,3,5-<br />
trienes from the reaction of semi-stabilized ylides via Wittig reaction under aqueous<br />
media employing sodium hydroxide as base (Figure-24).<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 52
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
Figure-24<br />
De-Jun Dong et al. 46 have developed a simple and efficient protocol to<br />
improve the stereoselectivity significantly for the olefination reaction of semistabilized<br />
triphenylphosphonium ylides by replacing the aldehydes used in the Wittig<br />
reaction with N-sulfonyl imines, which possess distinct electronic and steric<br />
properties relative to aldehydes (Figure-25).<br />
Figure-25<br />
Douglass F. Taber et al. 47 were utilized a Potassium hydride in paraffin KH(P)<br />
as a base in Wittig condensation of phosphonium salt with aromatic, aliphatic, and<br />
α,β-unsaturated aldehydes in THF proceeds with high Z selectivity (Figure-26).<br />
Figure-26<br />
Fulvia Orsini et al. 48 has synthesized α,β-unsaturated esters in open<br />
atmosphere via mild and efficient one-pot Wittig reactions performed in both water<br />
and sodium dodecyl sulfate (SDS)-water solution(Figure-27).<br />
Figure-27<br />
Y.k. Liu et al. 49 has discovered a highly stereoselective tandem Michael<br />
addition-Wittig reaction of (3-carboxy-2-oxopropylidene) triphenylphosphorane and<br />
α,β-unsaturated aldehydes gives multifunctional 6-carboxycyclohex-2-en-1-ones in<br />
excellent diastereo- and enantioselectivities by employing the combined catalysis of a<br />
bulky chiral secondary amine, LiClO 4 , and DABCO (Figure-28).<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 53
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
Figure-28<br />
Peter Shu-Wai Leung et al. 50 have developed chromatography free Wittig<br />
reaction by utilizing newly prepared bifunctional polymeric reagents , in this<br />
phosphine and amine functionalized material was used in one-pot Wittig reactions<br />
with an aldehyde and either an r-halo-ester, -ketone, or -amide. Due to the<br />
heterogeneous nature of the polymer, the desired alkene product of these reactions<br />
could be isolated in excellent yield in essentially pure form (Figure-29).<br />
Figure-29<br />
A. El-Batta et al. 51 was carried out Wittig reactions in water media employing<br />
stabilized ylides with aldehydes. They described the use of a saturated aqueous<br />
NaHCO 3 solution to achieve the aqueous one pot Wittig reactions at +20 to 90°Cusing<br />
Ph 3 P, R-bromoesters, and aromatic carboxaldehydes (Figure-30).<br />
Figure-30<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 54
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
2.5 Application of sodium tripolyphosphate<br />
Sodium tripolyphosphate (STPP) is white powder an inorganic compound<br />
with formula Na 5 P 3 O 10 . It is the sodium salt of the polyphosphate penta-anion, which<br />
is the conjugate base of triphosphoric acid (Figure-31). STPP is widely used in<br />
detergents, and as a preservative for seafood, meats, poultry, and animal feeds. It is<br />
also use in ceramics, anticaking, setting retarders, flame retardants, paper,<br />
anticorrosion pigments, textiles, rubber manufacture, fermentation, antifreeze.<br />
Figure-31<br />
There is some limited application of STTP in organic synthesis; however<br />
Zhiqiang Zhang et al. 52 have described a conversion of methyl lactate to acrylic acid,<br />
methyl acrylate and lactic acid via various reactions such as dehydration,<br />
decomposition, decarbonylation, hydrolysis and esterification has been determined by<br />
using sodium tripolyphosphate as a catalyst.<br />
Tert-butyl-2-bromoacetate was synthesized by a reaction of 2-bromoacetyl<br />
chloride with tert-butanol at room temp used stoichiometric sodium tripolyphosphate<br />
as catalyst and acid-scavenger, chloroform as solvent to afford 93% yield. 53 α-<br />
Bromoisobutyric acid tert-butyl ester was synthesized by reaction of tert-Bu alc. with<br />
α-bromoisobutyryl bromide using stoichiometric sodium tripolyphosphate as a base to<br />
afford 96.5% yield. 54<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 55
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
2.6 Current research work<br />
As described in earlier, the chemistry of pyrimidines is one of the most widely<br />
studied subjects because of the occurrence of such heterocycles in biologically<br />
relevant systems such as nucleic acids, cofactors, various toxins, and other products.<br />
Pyrimidine derivatives are biologically interesting molecules that have established<br />
utility for the treatment of Alzheimer’s disease and proliferative disorders; they are<br />
also capable of showing antiviral activity, anti-HIV agents, anti hypertensive agents,<br />
antimicrobial agents and fungicide. The witting product of pyrimidine derivatives<br />
such as rosuvastatin and its salt, which are HMG-CoA reductase inhibitor and useful<br />
in treatment of hypercholesteromia, hyperlipoproteinemia and atherosclerosis.<br />
The Wittig olefination reaction is regarded as one of the most strategic, widely<br />
applicable carbon–carbon double bond-forming processes available in organic<br />
synthesis. This reliable reaction allows for olefination with complete positional<br />
selectivity, predictable chemoselectivity and may be conducted in many cases with<br />
reliable and high stereocontrol.<br />
Nowadays, a great deal of effort has been focused on the field of green<br />
chemistry in adopting methods and processes. As a part of this “green” concept, toxic<br />
and/or flammable organic solvents are replaced by alternative non-toxic and<br />
nonflammable media. In this context, many efforts have been made to use aqueous<br />
media. Among alternative green solvents, water has been the solvent of choice for a<br />
variety of transformations.<br />
During the course of our ongoing interest on the synthesis various<br />
heterocycles and development of useful synthetic methodology, we have developed a<br />
small library of pyrimidines via Wittig reaction using sodium tripolyphosphate as<br />
base in aqueous media. The newly synthesized compounds were characterized by IR,<br />
Mass, 1 H NMR, 13 C NMR spectroscopy and elemental analysis. All the newly<br />
synthesized compounds were evaluated for their antimicrobial activity.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 56
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
2.7 Results and discussion<br />
Scheme:-1 Synthesis of pyrimidine derivatives via Wittig reaction in aqueous<br />
media.<br />
F<br />
F<br />
F<br />
O<br />
Cl<br />
N<br />
N<br />
O<br />
DIBAL<br />
Toluene<br />
Cl<br />
N<br />
N<br />
OH<br />
1) PBr 3 /MDC<br />
2) TPP/Toluene<br />
Cl<br />
N<br />
N<br />
P<br />
Br<br />
ASM-3e INT-01 INT-02<br />
R-CHO<br />
STPP<br />
Water<br />
F<br />
Wittig reaction<br />
N<br />
R<br />
Cl<br />
N<br />
AW-01 to AW-20<br />
The synthetic route for the targeted compounds (AW-01 to AW-20) is shown<br />
in Scheme 1. Compound ASM-03e was prepared by following the methods described<br />
in chapter-1. The reaction of ASM-03e with diisobutylaluminium hydride (DIBAL) in<br />
toluene at 0 o C for 3 h. afforded (2-chloro-4-(4-fluorophenyl)-6-isopropyl pyrimidin-<br />
5-yl)methanol (INT-01) in good yield. INT-01 was then treated with phosphorous<br />
tribromide in MDC at 0-5 o C for 2-3 h. The crude oily residue was reacted with<br />
triphenyl phosphine in toluene at reflux temperature for 3-4 h. to afford triphenyl[2-<br />
chloro-{4-(4-flourophenyl)-6-isopropyl-pyrimidin-5-ylmethyl}phosphonium]bromide<br />
(INT-02) in excellent yield.<br />
Optimization for reaction condition the pyrimidine phosphorous ylide (INT-<br />
02) was treated with benzaldehyde using various bases such as NaH 2 PO 4 , Na 2 HPO 4 ,<br />
and sodium tripolyphosphate in three different solvents, DMSO, THF, and water<br />
(Table-1). Sodium tripolyphosphate as base in aqueous media was found to be an<br />
effective method to afford highly (E)-selective product of AW-01 in moderate to good<br />
yield (Table-1).<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 57
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
Table 1: Optimization of reaction condition for synthesis of Aw-01 using variety<br />
of bases and solvents.<br />
Entry Base Solvents Yield Time hrs.<br />
1 NaH 2 PO 4 DMSO 65 7.0<br />
2 NaH 2 PO 4 THF 70 7.5<br />
3 NaH 2 PO 4 water 76 5.0<br />
4 Na 2 HPO 4 DMSO 68 6.5<br />
5 Na 2 HPO 4 THF 77 6.0<br />
6 Na 2 HPO 4 water 80 4.5<br />
7 Na 5 P 3 O 10 DMSO 85 7.0<br />
8 Na 5 P 3 O 10 THF 83 5.0<br />
9 Na 5 P 3 O 10 water 90 3.0<br />
The structure of INT-01 was established on the basis of their elemental<br />
analysis and spectral data (MS, IR, 1 HNMR, and 13 C NMR). The analytical data for<br />
INT-01 revealed a molecular formula C 14 H 14 ClFN 2 O (m/z 280). The 1 H NMR<br />
spectrum revealed doublet at δ = 1.30-1.33 ppm assigned to isopropyl-CH 3 , a singlet<br />
at δ = 2.09 ppm assigned to the –OH protons, a multiplet at δ = 3.67-3.69 ppm<br />
assigned to the isopropyl -CH protons, a singlet at δ = 4.69 ppm assigned to the –CH 2<br />
protons, two triplet at δ = 7.28-7.34 ppm and 7.88-7.92 assigned to the aromatic<br />
protons.<br />
The structure of INT-02 was established on the basis of their elemental<br />
analysis and spectral data (MS, IR, 1 H NMR, and 13 C NMR). Structure INT-02 was<br />
supported by its mass (m/z 605), which agrees with its molecular formula<br />
C 32 H 28 BrClFN 2 P , its 1 H NMR spectrum had signals at δ = 0.90 (s, 6H, 2 x i prCH 3 ),<br />
2.99-3.03 (m, 1H, i prCH), 5.67 (s, 2H, CH 2 ), 6.97-7.02 (t, 2H, Ar-H), 7.26-7.33 (m,<br />
8H, Ar-H), 7.57 (s, 6H, Ar-H), 7.75-7.80 (m, 3H, Ar-H).<br />
Reaction of pyrimidine phosphorous ylide (INT-02) with various<br />
benzaldehydes using Sodium tripolyphosphate as base in aqueous media to afford<br />
highly (E)-selective product AW-01 to AW-20 in moderate to excellent yield.<br />
Require reaction time and obtained (%) of yield summarized in Table-2.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 58
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
Table-2: Synthesis of substituted pyrimidines via Wittig reaction using sodium<br />
tripolyphosphate under aqueous media.<br />
Entry R Yield (%) Time hrs<br />
AW-01 C 6 H 4 90 3.0<br />
AW-02 4-NO 2 C 6 H 4 92 2.5<br />
AW-03 4-ClC 6 H 4 84 3.0<br />
AW-04 C 5 H 4 S 89 3.5<br />
AW-05 C 5 H 4 O 90 4.0<br />
AW-06 C 8 H 7 N 82 3.5<br />
AW-07 2-NO 2 C 6 H 4 79 3.0<br />
AW-08 4-ClC 6 H 4 85 3.5<br />
AW-09 3-0CH 3 ,4-OHC 6 H 4 93 3.5<br />
AW-10 3,4-di-OCH 3 C 6 H 3 95 3.0<br />
AW-11 4-N(CH 3 ) 2 C 6 H 4 82 3.0<br />
AW-12 4-FC 6 H 4 83 3.5<br />
AW-13 3-NO 2 C 6 H 4 94 4.0<br />
AW-14 4-BrC 6 H 4 90 4.5<br />
AW-15 2-OHC 6 H 4 88 3.0<br />
AW-16 4-OCH 3 C 6 H 4 76 3.5<br />
AW-17 2,5-di-OCH 3 C 6 H 3 89 3.0<br />
AW-18 3-BrC 6 H 4 83 4.0<br />
AW-19 4-ClC 6 H 4 81 3.0<br />
AW-20 3-OHC 6 H 4 77 4.0<br />
The structure of AW-01 to AW-20 was established on the basis of their<br />
elemental analysis, spectral data (MS, IR, 1 H NMR, and 13 C NMR) and (E)-selectivity<br />
of products was supported by NMR spectrum. Structure of AW-02 was supported by<br />
its mass (m/z 398), which agrees with its molecular formula C 21 H 17 ClFN 3 O 2, its 1 H<br />
NMR spectrum had signals at δ = 1.34-1.36 (d, 6H, 2 x i prCH 3 ), 3.44-3.49 (m, 1H,<br />
i prCH), 6.55-6.61 (d, 1H, j=16.5Hz, ethylene-H), 7.08-7.17 (m, 3H, Ar-H & ethylene-<br />
H), 7.48-7.51 (d, 2H, j=20.4Hz, Ar-H), 7.64-7.68 (t, 2H, Ar-H), 8.19-8.22 (d, 2H,<br />
j=8.4Hz, Ar-H).<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 59
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
2.8 Antimicrobial sensitivity testing<br />
WELL DIFFUSION / AGAR CUP METHOD (Lt. General Raghunath D. 1998,<br />
Ashok Rattan, 1998; Patel R., Patel K. 2004,)<br />
In vitro effectivity of antimicrobial agents can be demonstrated by observing<br />
their capacity to inhibit bacterial growth on suitable media. The production of a zone<br />
depends on two factors namely bacterial growth and concentration of antimicrobial<br />
agent. The hole/well punch method was first used by Bennett. This diffusion method<br />
has proved more effective than many other methods. According to Lt. General<br />
Raghunath the well technique is 5-6 times more sensitive than using disk method.<br />
Principle<br />
When antimicrobial substance is added in agar cup (made in a medium<br />
previously inoculated with test organism) the redial diffusion of an antimicrobial<br />
agent through the agar, produces a concentration gradient. The test organism is<br />
inhibited at the minimum inhibitory concentration (MIC), giving rise to a clear zone<br />
of inhibition.<br />
Requirements<br />
1. Young broth culture of a standard test organism<br />
2. Sterile Mueller Hinton Agar plate<br />
3. Solution of antimicrobial substance<br />
4. Cup borer<br />
5. Alcohol etc.<br />
Inoculum preparation<br />
Inoculum was prepared by selecting 4-5 colonies from slope of stock culture<br />
of the indicator organism and emulsifying them in a suitable broth. The inoculated<br />
broth was incubated at 37ºC till it equals turbidity of a 0.5 McFarland standard. This<br />
happens in 2-8 h.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 60
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
Procedure<br />
1. Inoculate test organism on the top of Mueller Hinton Agar plate with help of<br />
sterile swab. (it can be inoculated in melted agar also )<br />
2. The swab was dipped in the inoculum and surface of plate was streaked with<br />
swab.<br />
3. Streaking was repeated for 3 times and each time the plate was rotated at angle<br />
of 60º.<br />
4. Sterilize the cup-borer make four cups of the diameter of 8-10 mm. at equal<br />
distance in the plate previously inoculated with seed culture.<br />
5. The depth of well was 2.5-5.0 mm.<br />
6. The wells have been clearly punched so the surrounding medium is not lifted<br />
when the plug was removed out.<br />
7. The plates were incubated at 37ºC for 24 h. Then the zone of inhibition<br />
measured and the size of zone cited in table.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 61
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
Antibiotic Sensitivity Assay<br />
Sr.<br />
No.<br />
CODE<br />
No.<br />
Pseudomonas<br />
aeruginosa<br />
Proteus vulgaris<br />
Escherichia<br />
coli<br />
(Concentration250/500/ 1000 µG/ml)<br />
Staphylococcus<br />
aureus<br />
Candida<br />
albicans<br />
250 500 1000 250 500 1000 250 500 1000 250 500 1000 250 500 1000<br />
1. AW-01 R R 1.2 1.0 1.4 2.0 1.1 1.5 2.0 1.0 1.4 2.0 R 1.3 2.0<br />
2. AW-02 1.5 1.8 2.0 1.4 1.6 2.0 R R 1.8 R 1.2 1.8 1.0 1.4 2.0<br />
3. AW-03 1.1 1.4 2.0 1.0 1.3 2.0 R R R R R R R 1.3 2.0<br />
4. AW-04 R 1.3 1.8 R 1.1 1.4 R R 1.2 1.1 1.4 2.0 1.1 1.4 2.0<br />
5. AW-05 R 1.2 1.8 R 1.3 2.0 R 1.1 1.8 R 1.2 1.9 1.2 1.4 2.0<br />
6. AW-06 R R 1.2 R 1.2 1.8 R 1.1 1.8 1.0 1.3 2.0 R 1.2 2.0<br />
7. AW-07 1.1 1.4 2.0 R 1.2 1.8 1.0 1.3 2.0 1.1 1.4 2.0 R R 1.2<br />
8. AW-08 R 1.2 2.0 1.0 1.3 2.0 R 1.1 2.0 R 1.2 2.0 1.0 1.3 2.0<br />
9. AW-09 R R 1.2 R 1.2 2.0 1.0 1.3 2.0 R 1.0 2.0 R 1.4 2.0<br />
10. AW-10 1.1 1.3 1.8 1.5 1.8 2.0 R 1.0 1.7 R 1.2 2.0 1.0 1.3 2.0<br />
11. AW-11 R R 1.2 R R R 1.0 1.4 2.0 R 1.1 1.8 1.0 1.3 2.0<br />
12. AW-12 1.5 1.8 2.0 1.1 1.4 2.0 R 1.0 1.8 R 1.2 2.0 R 1.3 2.0<br />
13. AW-13 1.6 1.8 2.0 1.5 1.8 2.0 R 1.2 2.0 1.0 1.3 2.0 R 1.2 2.0<br />
14. AW-14 1.4 1.8 2.0 1.3 1.5 2.0 R R R R R R 1.0 1.3 2.0<br />
15. AW-15 R 1.2 1.5 R R R R R R R R R R 1.2 2.0<br />
16. AW-16 1.3 1.6 1.8 1.0 1.2 1.6 R 1.0 1.3 1.2 1.5 1.7 R 1.1 1.8<br />
17. AW-17 1.1 1.4 1.6 1.0 1.3 1.5 1.2 1.5 2.0 1.3 1.5 2.0 1.5 1.7 2.0<br />
18. AW-18 1.0 1.3 1.8 1.1 1.3 1.6 1.5 1.8 2.0 1.4 1.6 2.0 R 1.5 1.9<br />
19. AW-19 R R 1.2 R 1.3 1.8 1 1.2 2.0 1.1 1.6 2.0 1.3 1.6 2.0<br />
20. AW-20 R 1.3 1.8 1.1 1.3 1.2 1.0 1.2 1.4 1.0 1.2 1.5 1.2 1.5 1.7<br />
21. A 1.8 1.8 1.9 1.9 -<br />
22. CPD 2.2 2.1 2.1 2.2 -<br />
23. GF 1.8 1.9 2.0 2.0 -<br />
24. GRF - - - - 2.6<br />
25. FLC - - - - 2.8<br />
Note: Zone of inhibition interpretation is as follows<br />
1. Zone size < 1.0 cm- Resistent (R)<br />
2. Zone size 1.0 to 1.5 cm – Intermediate<br />
3. Zone size > 1.5 – Sensitive<br />
STD Antibiotic Sensitivity Assay Concentration 40 µg/ml<br />
A: Ampicillin GRF: Gresiofulvin<br />
CPD: Cefpodoxime FLC: Fluconazole<br />
GF: Gatifloxacin<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 62
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
2.9 Conclusion<br />
We have described a versatile synthesis of novel 2-chloro-4-(4-fluorophenyl)-<br />
6-isopropyl-5-(E)-substituted pyrimidines from triphenyl[2-chloro-{4-(4-flouro<br />
phenyl)-6-isopropyl-pyrimidin-5-ylmethyl}phosphonium]bromide with different<br />
aldehydes via Wittig reaction in the presence of sodium tripolyphosphate as a base in<br />
aqueous media. Inorganic base sodium tripolyphosphate has the further advantage of<br />
low cost, stability and low toxicity. All the synthesized compounds were evaluated<br />
for their antimicrobial activity. The investigation of antibacterial and antifungal<br />
screening data revealed that all the tested compounds AW-01 to AW-20 showed<br />
moderate to significant activity. For example, compounds AW-02, 12, 13 and 18<br />
showed comparatively good activities against all the bacterial strains and thus<br />
warrant further study.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 63
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
2.10 Experimental section<br />
Thin-layer chromatography was accomplished on 0.2-mm precoated plates of<br />
silica gel G60 F 254 (Merck). Visualization was made with UV light (254 and 365nm)<br />
or with an iodine vapor. IR spectra were recorded on a FTIR-8400 spectrophotometer<br />
using DRS prob. 1 H (300 MHz), 1 H (400 MHz), 13 C (100 MHz) and 13 C (75 MHz)<br />
NMR spectra were recorded on a Bruker AVANCE II spectrometer in CDCl 3 and<br />
DMSO. Chemical shifts are expressed in δ ppm downfield from TMS as an internal<br />
standard. Mass spectra were determined using direct inlet probe on a GCMS-QP 2010<br />
mass spectrometer (Shimadzu). Solvents were evaporated with a BUCHI rotary<br />
evaporator. Melting points were measured in open capillaries and are uncorrected.<br />
Synthesis of (2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidin-5-yl)<br />
methanol. (INT-01)<br />
To a solution of ASM-03e (0.003 mole) in toluene (100 mL) at 0 o C was<br />
added drop wise a 20% solution of diisobutylaluminium hydride (DIBAL) in toluene<br />
(85 mL). The reaction mixture was further stirred for 2-3 h. at 0 o C. The progress of<br />
reaction was monitored by thin layer chromatography. After completion, the reaction<br />
mixture was quenched with saturated ice cold hydrochloric acid. The toluene layer<br />
was washed with water and brine. The organic layer was separated, dried over<br />
anhydrous sodium sulfate and filtered. The filtrate was dried under vacuum. The solid<br />
product was purified by stirring in hexane or diisopropylether (DIPE) to give<br />
analytically pure product INT-01 with 85% yield.<br />
Synthesis of triphenyl[2-chloro-{4-(4-flourophenyl)-6-isopropylpyrimidin-5-ylmethyl}phosphonium]bromide.<br />
(INT-02)<br />
A solution of 2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidin-5-yl)<br />
methanol (INT-01, 16mmol) in MDC (50 mL) was cooled to 0-5 o C. Phosphorus<br />
tribromide (13mmol) was slowly added in to the reaction mixture at 0-5 o C and stirred<br />
for 2-3 h. The progress of reaction was monitored by thin layer chromatography.<br />
After completion, the reaction mixture was washed with 10% sodium bicarbonate<br />
solution and sodium thiosulphate solution. The organic layer was separated, dried<br />
over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness<br />
under vacuo.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 64
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
The oily residue was dissolve in toluene (80 mL) and triphenyl phosphine<br />
(30mmol) was added. The reaction mixture was heated at 115 o C for 3-4 h. After<br />
completion of the reaction determined by TLC, the reaction mixture was cooled to<br />
room temperature. The solid separated was filtered, washed with toluene and dried to<br />
afford 90% yield.<br />
<br />
General synthetic procedure for the Wittig reaction of pyrimidine yilde<br />
and aldehyde using STTP as a base in aqueous media. (AW-01 to AW-20)<br />
A mixture of pyrimidine phosphonium bromide ylide (INT-02, 1 mmol),<br />
benzaldehyde (1.3 mmol), and Sodium tripolyphosphate (3 mmol) in water (20 mL)<br />
was refluxed at 60-70 o C for 2-5 h. The progress of reaction was monitored by thin<br />
layer chromatography. After completion, the reaction mixture was cooled to room<br />
temperature, diluted with water (50 mL) and extracted with MDC (2x 50mL). The<br />
organic layer was washed with water (2 x 50 mL), organic layer dried over sodium<br />
sulfate and evaporated to dryness under vacuo. The residue was crystallized from<br />
isopropyl alcohol to afford analytically pure products AW-01 to AW-20.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 65
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
Spectral data of the synthesized compounds<br />
Methyl 2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidine-5-carboxylate (ASM-<br />
03e). White solid; R f 0.83 (8:2 hexane-EtOAc); mp 130-132 ° C; IR (KBr): 3070, 2930,<br />
2850, 1730, 1650, 1583, 1470, 1335, 1064, 830 cm -1 MS (m/z): 309 (M + ); Anal. Calcd<br />
for C 15 H 14 ClFN 2 O 2 : C, 58.35; H, 4.57; N, 9.07; Found: C, 58.38; H, 4.47; N, 9.07.<br />
(2-Chloro-4-(4-fluorophenyl)-6-isopropylpyrimidin-5-yl)methanol (INT-01).<br />
White solid; R f 0.52 (8:2 hexane-EtOAc); mp 110-112 ° C; IR (KBr): 3459, 3327, 3193,<br />
2999, 1648, 1586, 1261, 1061, 832 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 1.30-1.33 (d,<br />
6H, 2 x i prCH 3 ), 2.09 (s, 1H, OH), 3.67-3.69 (m, 1H, i prCH), 4.69 (s, 2H, CH 2 ), 7.28-<br />
7.34 (t, 2H, Ar-H), 7.88-7.92 (t, 2H, Ar-H); 13 C NMR (DEPT):(75 MHz, CDCl 3 ):<br />
21.40, 31.31, 56.47, 56.58, 114.99, 115.28, 131.85, 131.96; MS (m/z): 280 (M + );<br />
Anal. Calcd for C 14 H 14 ClFN 2 O: C, 59.90; H, 5.03; N, 9.98; Found: C, 59.93; H, 5.07;<br />
N, 9.97.<br />
Triphenyl[2-chloro-{4-(4-flourophenyl)-6-isopropyl-pyrimidin-5-ylmethyl}-<br />
phosphonium]bromide (INT-02). White solid; R f 0.16 (1;1 hexane-EtOAc); mp<br />
>320 o C ; IR (KBr): 3193, 3070, 3024, 2999, 2830, 1648, 1586, 1261, 1061, 830, 780,<br />
770, 700 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 0.90 (s, 6H, 2 x i prCH 3 ), 2.99-3.03 (m,<br />
1H, i prCH), 5.67 (s, 2H, CH 2 ), 6.97-7.02 (t, 2H, Ar-H), 7.26-7.33 (m, 8H, Ar-H), 7.57<br />
(s, 6H, Ar-H), 7.75-7.80 (m, 3H, Ar-H); 13 C NMR (DEPT):(75 MHz, CDCl 3 ): 24.92,<br />
25.53, 33.42, 116.24, 116.53, 130.35, 130.52, 131.17, 131.28, 133.97, 134.10, 135.42,<br />
135.46; MS (m/z): 605 (M + ); Anal. Calcd for C 32 H 28 BrClFN 2 P: C, 63.43; H, 4.66; N,<br />
4.62; Found: C, 63.45; H, 4.67; N, 5.67.<br />
2-Choloro-4-(4-flurophenyl)-6-isopropyl-5-(E)-styrylpyrimidine (AW-01). White<br />
solid; R f 0.75 (8:2 hexane-EtOAc); mp 80-82 ° C; IR (KBr): 3087, 3070, 3040, 2930,<br />
2856, 1658, 1450, 1430, 1368, 830, 753, 700 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): δ<br />
1.30-1.33 (d, 6H, 2 x i prCH 3 ), 3.03-3.08 (m, 1H, i prCH), 6.75-6.81 (d, 1H,<br />
j=16.4Hz,ethylene-H), 7.04-7.23 (m, 3H, Ar-H & ethylene-H), 7.53-7.56 (d, 2H, Ar-<br />
H), 7.72-7.74 (t, 2H, Ar-H), 8.23-8.26 (d, 2H, Ar-H); MS (m/z): 353 (M + ); Anal.<br />
Calcd for C 21 H 18 ClFN 2 : C, 71.49; H, 5.14; N, 7.94; Found: C, 71.43; H, 5.17; N, 7.97.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 66
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
5-((E)-(4-nitrostyryl))-2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidine (AW-<br />
02). Yellow solid; R f 0.72 (8:2 hexane-EtOAc); mp 110-112 ° C; IR (KBr): 3077, 3065,<br />
3031, 2932, 2856, 1664, 1450, 1430, 1368, 830 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): δ<br />
1.34-1.36 (d, 6H, 2 x i prCH 3 ), 3.44-3.49 (m, 1H, i prCH), 6.55-6.61 (d, 1H, j=16.5Hz,<br />
ethylene-H), 7.08-7.17 (m, 3H, Ar-H & ethylene-H), 7.48-7.51 (d, 2H, Ar-H), 7.64-<br />
7.68 (t, 2H, Ar-H), 8.19-8.22 (d, 2H, Ar-H); 13 C NMR (DEPT):(75 MHz, CDCl 3 ):<br />
21.73, 32.38, 115.48, 115.77, 124.29, 126.16, 127.09, 132.00, 132.11, 135.01; MS<br />
(m/z): 398 (M + ); Anal. Calcd for C 21 H 17 ClFN 3 O 2 : C, 63.40; H, 4.31; N, 10.56; Found:<br />
C, 63.43; H, 4.37; N, 10.50.<br />
5-((E)-(4-chlorostyryl))-2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidine (AW-<br />
03). White solid; R f 0.65 (8:2 hexane-EtOAc); mp 56-58 ° C; IR (KBr): 3095, 3084,<br />
3035, 2938, 2850, 1668, 1434, 1434, 1373, 830 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): δ<br />
1.32-1.34 (d, 6H, 2 x i prCH 3 ), 3.45-3.50 (m, 1H, i prCH), 6.43-6.49 (d, 1H, j=16.5Hz,<br />
ethylene-H), 6.88-6.93 (d, 1H, j=16.5Hz, ethylene-H), 7.05 -7.11 (t, 2H, Ar-H), 7.26-<br />
7.38 (q, 4H, Ar-H), 7.64-7.69 (t, 2H, Ar-H); 13 C NMR(DEPT):(75 MHz, CDCl 3 ):<br />
21.47, 32.19, 115.33, 115.62, 122.00, 127.71, 129.09, 132.01, 132.12, 136.01;MS<br />
(m/z): 388 (M + ); Anal. Calcd for C 21 H 17 Cl 2 FN 2 : C, 65.13; H, 4.42; N, 7.23; Found: C,<br />
65.23; H, 4.37; N, 7.35.<br />
2-Choloro-4-(4-flurophenyl)-6-isopropyl-5-[(E)-2-(thiophene-2-yl)vinyl]-<br />
pyrimidine (AW-04). White solid; R f 0.79 (8:2 hexane-EtOAc); mp 114-116 ° C; IR<br />
(KBr): 3093, 3086, 3016, 2942, 2834, 1658, 1445, 1403, 1368, 830 cm -1 ; 1 H NMR<br />
(300 MHz, CDCl 3 ): δ 1.34-1.36 (d, 6H, 2 x i prCH 3 ), 3.52 (m, 1H, i prCH), 6.67-6.73<br />
(dd, 2H, j=17.4Hz), 6.98-7.02 (d, 2H, Thiophene-H), 7.08-7.14 (t, 2H, Ar-H), 7.27-<br />
7.26 (d, 1H, Thiophene-H), 7.69-7.74 (t, 2H, Ar-H); 13 C NMR (DEPT):(75 MHz,<br />
CDCl 3 ): 21.76, 32.14, 115.35, 115.63, 120.59, 125.77, 127.23, 127.88, 130.22,<br />
132.05, 132.16; MS (m/z): 359 (M + ); Anal. Calcd for C 19 H 17 ClFN 2 S: C, 63.59; H,<br />
4.49; N, 7.81; Found: C, 63.43; H, 4.37; N, 7.70.<br />
2-Choloro-4-(4-flurophenyl)-5-[(E)-2-(furan-2-yl)vinyl]-6-isopropylpyrimidine<br />
(AW-05). White solid; R f 0.82 (8:2 hexane-EtOAc); mp 119-121 ° C; IR (KBr): 3113,<br />
2972, 1730, 1683, 1070, 881, 796, 744 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 1.34-1.36<br />
(d, 6H, 2 x i prCH 3 ), 3.44-3.49 (m, 1H, i prCH), 6.44-6.55 (d, 2H, Furan), 6.93-6.99<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 67
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
(d, 1H, j=16.2Hz, ethylene-H), 7.19-7.25 (d, 1H, j=16.2Hz, ethylene-H), 7.51-7.78 (t,<br />
3H, Ar-H & Furan), 8.19-8.22 (t, 2H, Ar-H), MS (m/z): 343 (M + ); Anal. Calcd for<br />
C 19 H 16 ClFN 2 O: C, 65.67; H, 4.70; N, 8.17; Found: C, 65.70; H, 4.77; N, 8.07.<br />
3-((E)-2(2-chloro-4-(4-flurophenyl)-6-isopropylpyrimidyl-5-yl)vinyl-1H-indole<br />
(AW-06). Yellow solid; R f 0.87 (8:2 hexane-EtOAc); mp 134-136 ° C;IR (KBr): 3063,<br />
3015, 2957, 2834, 1670, 1445, 1368, 830, 750 cm -1 ; MS (m/z): 392 (M + ); Anal. Calcd<br />
for C 23 H 19 ClFN 3 : C, 70.49; H, 4.89; N, 10.72; Found: C, 70.59; H, 4.92; N, 10.77.<br />
5-((E)-(2-nitrostyryl))-2-chloro-4-(4-flurophenyl)-6-isopropylpyrimidine(AW-07)<br />
Yellow solid; R f 0.69 (8:2 hexane-EtOAc); mp 96-98 ° C; IR (KBr): 3037, 3016, 2952,<br />
2822, 1657, 1453, 1403, 1368, 835, 753 cm -1 ; MS (m/z): 398 (M + ); Anal. Calcd for<br />
C 21 H 17 ClFN 3 O 2 : C, 63.40; H, 4.31; N, 10.56; Found: C, 63.39; H, 4.32; N, 10.57.<br />
5-((E)-(2-chlorostyryl))-2-chloro-4-(4-flurophenyl)-6-isopropylpyrimidine (AW-<br />
08). Yellow solid; R f 0.73 (8:2 hexane-EtOAc); mp 64-65 ° C; IR (KBr): 3067, 3013,<br />
2947, 2830, 1652, 1453, 1403, 1376, 838, 748 cm -1 ; MS (m/z): 388 (M + ); Anal. Calcd<br />
for C 21 H 17 Cl 2 FN 2 : C, 65.13; H, 4.42; N, 7.23; Found: C, 65.23; H, 4.37; N, 7.35.<br />
4-((E)-2-(2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidin-5-yl)vinyl)-2-<br />
methoxyphenol (AW-09). Yellow solid; R f 0.79 (8:2 hexane-EtOAc); mp 88-89 ° C;<br />
IR (KBr): 3442, 3093, 3086, 3016, 2942, 2834, 1658, 1445, 1403, 1368, 830, 783,<br />
708, cm -1 ; MS (m/z): 399 (M + ); Anal. Calcd for C 22 H 20 ClFN 2 O 2 : C, 66.25; H, 5.05; N,<br />
7.02; Found: C, 66.25; H, 5.06; N, 7.07.<br />
5-((E)-(3,4-dimethoxystyryl)-2-chloro-4-(4-flurophenyl)-6-isopropylpyrimidine<br />
(AW-10). White solid; R f 0.83 (8:2 hexane-EtOAc); mp 78-80 ° C; IR (KBr): 3028,<br />
2999, 2964, 2839, 1728, 1638, 1558, 1444, 1026, 842, 758, 702 cm -1 ; 1 H NMR (300<br />
MHz, CDCl 3 ): δ 1.25-1.34 (d, 6H, 2 x i prCH 3 ), 3.51-3.55 (m, 1H, i prCH), 3.90 (S, 6H,<br />
2 x OCH 3 ), 6.42-6.48 (d, 1H, j=16.5Hz, ethylene-H), 6.71-6.93 (m, 4H, Ar-H<br />
ðylene-H), 7.06 -7.12 (t, 2H, Ar-H), 7.70 (s, 2H, Ar-H); 13 C NMR (DEPT):(75<br />
MHz, CDCl 3 ): 21.80, 32.03, 55.96, 56.01, 108.83, 111.22, 115.24, 115.52, 119.27,<br />
119.89, 132.05, 132.16, 136.96; MS (m/z): 413 (M+); Anal. Calcd for<br />
C 23 H 22 ClFN 2 O 2 : C, 66.91; H, 5.37; N, 6.78; Found: C, 66.93; H, 5.37; N, 6.75.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 68
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
4-((E)-2-(2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidin-5-yl)vinyl)-N,Ndimethylbenzenamine<br />
(AW-11). Yellow solid; R f 0.75 (8:2 hexane-EtOAc); mp 118-<br />
120 ° C; IR (KBr): 3092, 3028, 2966, 2823, 1660, 1428, 1368, 835, cm -1 ; MS (m/z):<br />
396 (M + ); Anal. Calcd for C 23 H 23 ClFN 3 : C, 69.78; H, 5.86; N, 8.96; Found: C, 69.75;<br />
H, 5.76; N, 8.77<br />
5-((E)-(4-fluorostyryl))-2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidine (AW-<br />
12). White solid; R f 0.73 (8:2 hexane-EtOAc); mp 54-56 ° C; IR (KBr): 3096, 3065,<br />
2952, 2869, 1675, 1468, 1442, 1353, 836, cm -1 ; 1 H NMR (400 MHz, CDCl 3 ): δ 1.15-<br />
1.26 (d, 6H, 2 x i prCH 3 ), 3.36-3.43 (m, 1H, i prCH), 6.35-6.39 (d, 1H, j=16.6Hz,<br />
ethylene-H), 6.73-6.77 (dd, 1H, j=16.6Hz, ethylene-H), 6.91-7.00 (m, 4H, Ar-H), 7.21<br />
-7.24 (m, 2H, Ar-H), 7.55-7.60 (m, 2H, Ar-H); 13 C NMR (100 MHz, CDCl 3 ): 21.72,<br />
32.17, 115.53, 115.54, 115.80, 116.01, 121.11, 121.13, 125.99, 126.39, 128.13,<br />
128.21, 128.49, 128.61, 132.04, 132.12,132.35, 132.39, 133.28, 133.31, 133.38,<br />
133.41, 136.10, 150.98, 159.22, 161.62, 162.30, 164.10, 164.79, 165.66, 165.86,<br />
177.22, 177.44; MS (m/z): 372 (M + ); Anal. Calcd for C 21 H 17 ClF 2 N 2 : C, 68.02; H,<br />
4.62; N, 7.55; Found: C, 68.05; H, 4.66; N, 7.77<br />
5-((E)-(3-nitrostyryl))-2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidine (AW-<br />
13). White solid; R f 0.72 (8:2 hexane-EtOAc); mp 63-65 ° C; IR (KBr): 3130, 3083,<br />
2932, 2856, 1652, 1428, 1426, 1375, 833, 780 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): δ<br />
1.34-1.36 (d, 6H, 2 x i prCH 3 ), 3.45-3.49 (m, 1H, i prCH), 6.53-6.59 (d, 1H, j=16.5Hz,<br />
ethylene-H), 7.08-7.15 (m, 3H, Ar-H & ethylene-H), 7.52 -7.70 (m, 4H, Ar-H), 8.14-<br />
8.22 (s d, 2H, Ar-H); 13 C NMR (DEPT):(75 MHz, CDCl 3 ): 21.71, 32.37, 115.46,<br />
115.75, 121.01, 123.08, 124.68, 129.95 131.97, 132.09, 132.29, 134.90; MS (m/z):<br />
398 (M+); Anal. Calcd for C 21 H 17 ClFN 3 O 2 : C, 63.40; H, 4.31; N, 10.56; Found: C,<br />
63.43; H, 4.37; N, 10.55<br />
5-((E)-(4-bromostyryl))-2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidine(AW-<br />
14). White solid; R f 0.75 (8:2 hexane-EtOAc); mp 96-98 ° C; IR (KBr): 3082, 3057,<br />
2933, 1643, 1449, 1403, 1368, 835 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ): δ 1.23-1.25 (d,<br />
6H, 2 x i prCH 3 ), 3.35-3.40 (m, 1H, i prCH), 6.34-6.38 (d, 1H, j=16.6Hz, ethylene-H),<br />
6.82-6.86 (dd, 1H, j=16.6Hz, ethylene-H), 6.97-7.02 (t, 2H, Ar-H), 7.12-7.17 (d, 2H,<br />
Ar-H), 7.37-7.39 (d, 2H, Ar-H), 7.55-7.59 (m, 2H, Ar-H); 13 C NMR (100 MHz,<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 69
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
CDCl 3 ): 21.74, 32.20, 115.38, 115.60, 121.12, 122.58, 125.80, 126.20, 127.99,<br />
132.02, 132.05, 132.10, 133.19, 133.29, 133.32, 135.02, 136.08, 151.11, 159.34,<br />
162.33, 164.83, 165.66, 165.87, 177.15, 177.38; MS (m/z): 431 (M + ); Anal. Calcd for<br />
C 21 H 17 BrClF 2 N 2 : C, 58.42; H, 3.97; N, 6.49; Found: C, 58.55; H, 3.96; N, 6.47<br />
2-((E)-2-(2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidin-5-yl)vinyl)phenol<br />
(AW-15) White solid; R f 0.64 (8:2 hexane-EtOAc); mp 52-54 ° C; IR (KBr): 3452,<br />
3048, 2942, 1648, 1441, 1408, 1359, 835 ,785 cm -1 ; MS (m/z): 369 (M + ); Anal. Calcd<br />
for C 21 H 18 ClF 2 N 2 O: C, 68.38; H, 4.92; N, 7.60; Found: C, 68.35; H, 4.96; N, 7.57<br />
5-((E)-(4-methoxystyryl))-2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidine<br />
(AW-16). Yellow solid; R f 0.71 (8:2 hexane-EtOAc); mp 67-69 ° C; IR (KBr): 3052,<br />
3042, 2948, 1638, 1449, 1401, 1348, 835 ,782 cm -1 ; MS (m/z): 384 (M + ); Anal. Calcd<br />
for C 22 H 20 ClFN 2 O: C, 69.02; H, 5.27; N, 7.32; Found: C, 69.05; H, 5.26; N, 7.27<br />
5-((E)-(2,5-dimethoxystyryl)-2-chloro-4-(4-flurophenyl)-6-isopropylpyrimidine<br />
(AW-17). White solid; R f 0.81 (8:2 hexane-EtOAc); mp 78-80 ° C; IR (KBr): 3048,<br />
3046, 2939, 1641, 1438, 1412, 1378, 838, 754, 779 cm -1 ; MS (m/z): 414 (M+); Anal.<br />
Calcd for C 23 H 22 ClFN 2 O 2 : C, 66.91; H, 5.37; N, 6.78; Found: C, 66.93; H, 5.37; N,<br />
6.75.<br />
5-((E)-(3-bromostyryl))-2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidine (AW-<br />
18). White solid; R f 0.78 (8:2 hexane-EtOAc); mp 87-88 ° C; IR (KBr): 3043, 3051,<br />
2942, 1652, 1431, 1422, 1371, 831 ,786 cm -1 ; MS (m/z): 432 (M + ); Anal. Calcd for<br />
C 21 H 17 BrClF 2 N 2 : C, 58.42; H, 3.97; N, 6.49; Found: C, 58.55; H, 3.96; N, 6.47.<br />
5-((E)-(3-chlorostyryl))-2-chloro-4-(4-flurophenyl)-6-isopropylpyrimidine (AW-<br />
19). Yellow solid; R f 0.73 (8:2 hexane-EtOAc); mp 50-52 ° C; IR (KBr): 3052, 3061,<br />
2936, 1648, 1438, 1428, 1364, 838, 778 cm -1 ; MS (m/z): 373 (M + ); Anal. Calcd for<br />
C 21 H 17 Cl 2 FN 2 : C, 65.13; H, 4.42; N, 7.23; Found: C, 65.23; H, 4.37; N, 7.35.<br />
3-((E)-2-(2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidin-5-yl)vinyl)phenol<br />
(AW-20). White solid; R f 0.83 (8:2 hexane-EtOAc); mp 59-61 ° C; IR (KBr): 3468,<br />
3058, 2932, 1641, 1442, 1432, 1357, 832, 781 cm -1 ; MS (m/z): 369 (M + ); Anal. Calcd<br />
for C 21 H 18 ClF 2 N 2 O: C, 68.38; H, 4.92; N, 7.60; Found: C, 68.35; H, 4.96; N, 7.57.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 70
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
1 H NMR spectrum of compound AW-02<br />
F<br />
NO 2<br />
N<br />
Cl<br />
N<br />
Expanded 1 H NMR spectrum of compound AW-02<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 71
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
1 H NMR spectrum of compound AW-03<br />
F<br />
Cl<br />
N<br />
Cl<br />
N<br />
Expanded 1 H NMR spectrum of compound AW-03<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 72
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
1 H NMR spectrum of compound AW-05<br />
F<br />
N<br />
O<br />
Cl<br />
N<br />
Expanded 1 H NMR spectrum of compound AW-05<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 73
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
1 H NMR spectrum of compound AW-14<br />
F<br />
Br<br />
N<br />
Cl<br />
N<br />
Expanded 1 H NMR spectrum of compound AW-14<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 74
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
13 C NMR spectrum of compound AW-12<br />
F<br />
F<br />
N<br />
Cl<br />
N<br />
Expanded 13 C NMR spectrum of compound AW-12<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 75
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
MASS spectrum of compound AW-01<br />
F<br />
N<br />
Cl<br />
N<br />
m/z-352<br />
MASS spectrum of compound AW-06<br />
F<br />
NH<br />
N<br />
Cl<br />
N<br />
m/z-392<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 76
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
MASS spectrum of compound AW-09<br />
F<br />
O<br />
OH<br />
N<br />
Cl<br />
N<br />
m/z-398<br />
MASS spectrum of compound AW-20<br />
F<br />
OH<br />
N<br />
Cl<br />
N<br />
m/z-368<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 77
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
IR spectrum of compound AW-05<br />
90<br />
%T<br />
3113.21<br />
2972.40<br />
1730.21<br />
1683.91<br />
1635.69<br />
1070.53<br />
881.50<br />
75<br />
1604.83<br />
1558.54<br />
1383.01<br />
1321.28<br />
1261.49<br />
1159.26<br />
60<br />
45<br />
1508.38<br />
846.78<br />
418 57<br />
1014.59<br />
744.55<br />
796.63<br />
671.25<br />
30<br />
4000<br />
3500<br />
3000<br />
2500<br />
2000<br />
1750<br />
1500<br />
1250<br />
1000<br />
750<br />
500<br />
1/cm<br />
IR spectrum of compound AW-10<br />
100<br />
%T<br />
80<br />
60<br />
40<br />
3028.34<br />
2999.41<br />
2964.69<br />
F<br />
2839.31<br />
1728.28<br />
1683.91<br />
1635.69<br />
1600.97<br />
1558.54<br />
1467.88<br />
1444.73<br />
1413.87<br />
1381.08<br />
1338.64<br />
1163.11<br />
1139.97<br />
1026.16<br />
976.01<br />
927.79<br />
842.92<br />
788.91<br />
765.77<br />
702.11<br />
567.09<br />
522.73<br />
480.29<br />
451.36<br />
428 21<br />
20<br />
N<br />
O<br />
O<br />
1246.06<br />
0<br />
Cl<br />
N<br />
1516.10<br />
1267.27<br />
-20<br />
4000<br />
3500<br />
3000<br />
2500<br />
2000<br />
1750<br />
1500<br />
1250<br />
1000<br />
750<br />
500<br />
1/cm<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 78
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
2.11 References<br />
1. (a) Gmelin, R.; Hoppe-Seyler’s, Z.; Physiol. Chem., 1959, 316, 164. (b) Bell, E. A.; Foster,<br />
R. G.; Nature, 1962, 194, 91.<br />
2. Jansen, B. C. P.; Donath, W. F.; Chem. Weekblad., 1926, 23, 201.<br />
3. Tanaka, F.; Takeuchi, S.; Tanaka, N.; Yonehara, H.; Umezawa, H.; Sumiki, Y. J.; Antibiot.<br />
A, 1961, 14, 161.<br />
4. (a) Lin, Y.-L.; Huang, R.-L.; Chang, C.-M.; Kuo, Y.-H.; J. Nat. Prod., 1997, 60, 982; (b)<br />
Gerlinck, R. G. S.; Braekman, J. C.; Daloze, D.; Bruno, I.; Riccio, R.; Rogeau D.; Amade,<br />
P.; J. Nat. Prod., 1992, 55, 528.<br />
5. (a) Ohtani, I.; Moore, R. E.; Runnegar, M. T. C.; J. Am. Chem. Soc., 1992, 114, 7941; (b)<br />
Banker, R.; Teltsch, B.; Sukenik A.; Carmeli, S.; J. Nat. Prod., 2000, 63, 387.<br />
6. (a) Brugnatelli, G.; Giornale di fisica chimica, et storia Naturale (Pavia) decada seconda,<br />
1818, 1, 117; (b) Brugnatelli, G.; Ann. Chim. Phys., 1818, 8, 201.<br />
7. Frankland, E.; Kolbe, H.; Justus Liebigs Ann. Chem., 1848, 65, 269.<br />
8. Davidson, M.H.; Expert Opin Investig Drugs, 2002, 11, 125.<br />
9. Radi, M.; Maga, G.; Alongi, M.; Angeli, L.; Samuele, A.; Zanoli, S.; Bellucci, L.; Tafi, A.;<br />
Casaluce, G.; Giorgi, G.; Armand-Ugon, M.; Gonz´alez-Ortega, E.; Est´e, J. A.; Baltzinger,<br />
M.; Bec, G.; Dumas, P.; Ennifar E.; Botta, M.; J. Med. Chem., 2009, 52, 840.<br />
10. Koch, U.; Attenni, B.; Malancona, S.; Colarusso, S.; Conte, I.; DiFilippo, M.; Harper, S.;<br />
Pacini, B.; Giomini, C.; F.Thomas, S.; Incitti, I.; Tomei, L.; De Francesco, R.; Altamura, S.;<br />
Matassa ,V. G.; Narjes, J., Med. Chem., 2006, 49, 1693.<br />
11. Chu, X.-J.; DePinto, W.; Bartkovitz, D.; So, S.-S.; Vu, B. T.; Packman, K.; Lukacs, C.; Ding,<br />
Q.; Jiang, N.; Wang, K.; Goelzer, P.; Yin, X.; Smith, M. A.; Higgins, B. X.; Chen, Y.; Xiang,<br />
Q.; Moliterni, J.; Kaplan, G.; Graves, B.; Lovey, A.; Fotouhi, N.; J. Med. Chem., 2006, 49,<br />
6549.<br />
12. Giblin, G. M. P.; O’Shaughnessy, C. T.; Naylor, A.; Mitchell, W. L.; Eatherton, A. J.;<br />
Slingsby, B. P.; Rawlings, D. A.; Goldsmith, P.; Brown, A. J.; Haslam, C. P.; Clayton, N.<br />
M.; Wilson, A. W.; Chessell, I. P.; Wittington, A. R.; Green, R.; J. Med. Chem., 2007, 50,<br />
2597.<br />
13. Harris, P. A.; Boloor, A.; Cheung, M.; Kumar, R.; Crosby, R. M.; Davis-Ward, R. G.;.<br />
Epperly, A. H.; Hinkle, K.W.; Hunter, R. N.; Johnson, J. H.; Knick, V. B.; Laudeman, C. P. ;<br />
Luttrell, D. K.; Mook, R. A.; Nolte, R. T.; Rudolph, S. K.; Szewczyk, J. R.; Truesdale, A. T.;<br />
Veal, J. M.; Wangand, L.; Stafford, J. A.; J. Med. Chem., 2008, 51, 4632.<br />
14. (a) Chang, L. C. W.; Spanjersberg, R. F.; von FrijtagDrabbe, J. K.; unzel, T. K.; Mulder-<br />
Krieger.; van den Hout, G.; Beukers, M. W.; Brusseeand, J. A.; Ijzerman, P.; J. Med. Chem.,<br />
2004, 47, 6529; (b) Lanier, M. C.; Moorjani, M.; Luo, Z.; Chen, Y.; Lin, E.; Tellew, J. E.;<br />
Zhang, X.; Williams, J. P.; Gross, R. S.; Lechner, S. M.; Markison, S.; Joswig, T.; Kargo,<br />
W.; Piercey, J.; Santos, M.; Malany, S.; Zhao, M.; Petroski, R.; Crespo, M. I.; Diaz J.-L.;<br />
Saunders, J.; Wen, J.; Brien Z. O.; Jalali, K.; Madan, A.; Slee, D. H.; J. Med. Chem., 2009,<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 79
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
52, 709; (c) Cosimelli, B.; Greco, G.; Ehlardo, M.; Novellino, E.; Da Settimo, F.; Taliani, S.;<br />
La Motta, C.; Bellandi, M.; Tuccinardi, T.; Martinelli, A.; Ciampi, O.; Trincavelli M. L.;<br />
Martini, C.; J. Med. Chem., 2009, 51, 1764.<br />
15. Naik, T.A.; Chikhalia, K. H.; E-Journal of Chem., 2007, 4(1), 60.<br />
16. Mishra, A.; Singh, D.V.; Indian J. Hetero. Chem., 2004, 14, 43.<br />
17. Callery, P.; Gannett, P.; Cancer and Cancer Chemotherapy., Williams, L.; Wilkins, 2002,<br />
934.<br />
18. Safarjalani, O. N.; Zhou, X. J.; Ras, R. H.; Shi, J.; Schinazi, R. F.; Naguib, F. N.; Kouni, M.<br />
H.; Cancer Chemotherapy Pharmacology., 2005, 55, 541.<br />
19. Singh , P.; Kaur, J.; Paul, K.; Indian J. Chem., 2008, 47B, 291.<br />
20. Pedeboscq, S.; Gravier, D.; Casadebaig, F.; Hou, G.; Gissot, A.; Giorgi, F. D.; Ichas, F.;<br />
Cambar, J.; Pometan, J.; Eur. J. Med. Chem., 2010, 45, 2473.<br />
21. Fathalla, O. A.; Zeid, I. F.; Haiba, M. E.; Soliman, A. M.; Abd- Elmoez.; Serwy, W. S.;<br />
World J. Chem., 2009, 4 (2), 127.<br />
22. Belema, M.; Bunker, A.; Nguyen, V.; Beaulieu, F.; Ouellet, C.; Marinier, A.; Roy, S.;<br />
Yung, X.; Zhang Y, Martel, Zuci C.; PCT Int. Appl. WO 2003084, Through Chem. Abstr.;<br />
2003; 139; 337987x.<br />
23. Martel, Y., Zuci, C.; PCT Int. Appl. WO 2003084, Through Chem. Abstr.; 2003; 139;<br />
337987x.<br />
24. Padmashali, B.; Vaidya, V. P.; Vijaya Kumar, M. L.; Indian J. Hetero. Chem., 2002, 12, 89.<br />
25. Lee, H. W.; Kim, B. Y.; Euro. J. Med. Chem., 2005, 4, 662.<br />
26. Desenko, S. M.; Lipsum, V. V.; Gorbenko, N. I.; J. Pharm. Chem., 1995, 29, 265.<br />
27. Pfizer; US Patent; 3 511 836; 1970.<br />
28. Hara, H,.; Ichikawa, M.; Oku, H.; Shimazawa, M.; Araie, M.; Cardiovasc. Drug Rev.,<br />
2005, 23, 43.<br />
29. Meredith, P. A.; Scott, P.J.; Kelman, A.W.; Hughes, D. M.; Reid, J. L.; Am. J. Ther., 1995,<br />
2, 541.<br />
30. Honkanen, E.; Pipuri, A.; Kairisalo, P.; Nore, P.; Karppaness, H.; Paakari, I.; J. Med. Chem.,<br />
1983, 26, 143.<br />
31. Ganzevoort, W.; Rep, A.; Bonsel, G. J.; Vries, D. J.; Wolf, H;. Hypertension., 2004, 22,<br />
1235.<br />
32. Wong, W. M.; Ann. Pharmacotherapy., 1994, 28, 290.<br />
33. Rahaman, S. A.; RajendraPasad, Y.; Phani Kumar.; Bharath Kumar.; Saudi Pharmaceutical<br />
J., 2009, 17(3), 259.<br />
34. Agrawal, A.; Srivastava, K.; Puri, S. K.; Bio. Org, and Med. ChemLett., 2005, 15,5218.<br />
35. Jain, K. S.; Chitre, T.S.; Miniyar, P.B.; Kathiravan, M.K.; Bendre, V. S.; Veer, V.S.;<br />
Shahane, S. R .; Shishoo, C. J.; Current Science., 2006, 90, (6).<br />
36. Karpov, A. S.;. M¨uller, T. J. J.; Synthesis., 2003, 18, 2815.<br />
37. Kiselyov, A. S.; Tetrahedron Lett., 2005, 46, 1663.<br />
38. Movassaghi, M.; Hill, M. D.; J. Am. chem. soc.,2006, 128, 14254.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 80
Chapter 2<br />
Synthesis of substituted pyrimidines via Wittig<br />
39. Sasada, T.; Kobayashi, F.; Sakai, N.; Konakahara, T.; Org. Lett., 2009, 11, 2161.<br />
40. Barthakur, M. G.; Borthakur, M.; Devi, P.; Saikia, C. J.; Saikia, A.; Bora, U.;. Chetia A.;<br />
Boruah, R. C.; Synlett., 2007, 223.<br />
41. Zhichkin, P. ; Fairfax, D. J.; Eisenbein, S. A.; Synthesis., 2002, 720..<br />
42. Maryanoff, B. E.; Reitz, A. B.; Chem. Rev., 1989, 89, 863.<br />
43. Antonioletti, R.; Bonadies, F.; Ciammaichella, A.; Viglianti, A.; Tetrahedron., 2008, 64<br />
4644.<br />
44. Dambacher, J.; Zhao,W.; El-Batta, A.; Anness, R.; Jiang, C.; Bergdahl, M.; Tetrahedron<br />
Letters., 2005, 46, 4473.<br />
45. Ramirez, E.; Sánchez, M.; Rosa L.; Leon, M.; Quintero, L.; Sartillo-Piscil, F.; Tetrahedron<br />
Letters., 2010, 51, 2178.<br />
46. McNult, J.; Das, P.; Tetrahedron Letters., 2009, 50, 5737.<br />
47. Dong, D. J.; Li, H.-H.;Tian, S.-K.; J. Am. Chem. Soc., 2010, 132, 5018.<br />
48. Douglass F. Taber, Christopher G. Nelson, J. Org. Chem., 2006, 71, 8973-8974<br />
49. Orsini, F.; Sello, G.; Fumagalli, T.; Synlett., 2006, 1717.<br />
50. Liu,Y.-k.; Ma, C.; Jian, K.; Liu, T.-Y.; Chen, Y.-C.; Org. Lett., 2009, 11, 2848.<br />
51. Leung, P. S.-W.; Teng, Y.; Toy, P. H.; Org. Lett., 2010, 12, 4996.<br />
52. Batta, A. El.; Jiang, C.; Zhao, W.; Anness, R.; Cooksy, A. L.; Bergdahl, M.; J. Org. Chem.,<br />
2007, 72, 5244.<br />
53. Zhang, Z.; Qu, Y.; Wang, S.; Wang, J., Journal of Molecular Catalysis A: Chemical., 2010,<br />
323, 91.<br />
54. Fuxian, W.; Jichao W.; Fangfang,W.; Yanjiu, H.; 2008, 19(4), 41.<br />
55. Zhen-wang, Q.; Guang-you, Z.; Geng-xiu, Z.; Cheng-ping, L.; Xue-bo, Z.; Huagong, S.;<br />
2005, 34(2), 1.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 81
Chapter - 3<br />
Rapid Synthesis and Characterization of<br />
Novel Tri-substituted Pyrazoles/Isoxazoles<br />
Library Using Ketene Dithioacetals
Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
3.1 Introduction<br />
The development of new methods for the synthesis of five member<br />
heterocyclic compound libraries, both in solution and on solid phase, is an everexpanding<br />
area in combinatorial chemistry. Specifically, those containing the<br />
pyrazole and isoxazole nucleus have been widely used as key building blocks for<br />
pharmaceutical agents. Its derivatives are endowed with high pharmacological<br />
properties, for example, hypoglycemic, analgesic, anti-inflammatory, antibacterial,<br />
anti-HIV, and anticancer activity, 1 as well as useful activities in conditions like<br />
schizophrenia, hypertension, and Alzheimer’s disease. 2 In addition, they also have<br />
agrochemical properties including herbicidal and soil fungicidal activity, thus they<br />
have been used as pesticides and insecticides. 3 Recently, pyrazoles containing aryl<br />
substituted emerged as p38 Kinase inhibitors, antiparasitic activities. 4<br />
Pyrazoles and isoxazoles are well known five member heterocyclic<br />
compounds and several procedures for its synthesis have been extensively studied.<br />
The pyrazole ring system consists of a doubly unsaturated five member ring<br />
containing two adjacent nitrogen atoms. Isoxazole ring system consist two hetero<br />
atoms oxygen at position 1 and nitrogen at position 2 (Figure-1).<br />
Figure-1<br />
Pyrazoles and isoxazoles bearing sulfone and carboxamide moieties<br />
demonstrated to have significant pharmacological applications. For examples,<br />
cyclooxygenase-2 (COX-2) selective inhibitors, celecoxib 5 , rofecoxib 6 and<br />
valdecoxib 7 are currently prescribed for the treatment of arthritis and inflammatory<br />
diseases. These COX-2 inhibitors exhibited anti-inflammatory activity with reduced<br />
gastrointestinal side effects. Oxacillin and its derivatives are useful compounds due to<br />
their narrow spectrum antibiotic properties 8 . Recently, pyrrolyl aryl sulfones have<br />
been reported by Silvestri et al. 9 and Artico et al. 10 as a new class of human<br />
immunodeficiency virus type 1 (HIV-1) RT inhibitors acting at the non-nucleoside<br />
binding site of this enzyme. Haruna et al. 11 have been synthesized the propargylic<br />
sulfones with various planar molecules and evaluated for their DNA binding<br />
properties and DNA cleavage activity.<br />
Department of Chemistry <strong>Saurashtra</strong> university, Rajkot-360005 82
Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
Moreover, the 1-(4-methylsulfonyl)benzene and 4-(4-methylsulfonyl)benzene<br />
substituted pyrazole compound containing a nitric oxide donating group at the 3-<br />
position of the pyrazole ring, respectively, have been synthesized and evaluated for its<br />
ability to inhibit COX isoenzymes in human whole blood. 12 Pyrazoles containing<br />
sulfone group at N position have been exhibited promising antimicrobial activity. 13<br />
Further more, amide group linked with isoxazole derivatives found to have combined<br />
α 2 -adrenoceptor antagonistic and serotonine reuptake inhibiting activities. 14 The<br />
Isoxazoles containing aryl and carboxamide were also shown to have potent in vivo<br />
antithrombotic efficacy. 15<br />
3.2 Biological activity associated with pyrazoles and isoxazoles<br />
As mentioned above, pyrazoles and isoxazoles nucleus have been widely used<br />
as key building blocks for pharmaceutical agents. Its derivatives are endowed with<br />
high pharmacological properties, for example, hypoglycemic, GABA A antagonist’s<br />
analgesic, anti-inflammatory, anti-HIV, and anticancer activity as well as useful<br />
activities in conditions like schizophrenia, hypertension, and Alzheimer’s disease.<br />
Thomas D. Penning et al. 16 has described a series of pyrazole and isoxazole<br />
analogs (Figure-2) as antagonists of the α v β 3 receptor. These compounds showed low<br />
to sub-nanomolar potency against α v β 3 , as well as good selectivity against α IIb β 3 . In<br />
HT29 cells, most analogs also demonstrated significant selectivity against α v β 6 .<br />
Several compounds showed good pharmacokinetic properties in rats, in addition to<br />
anti-angiogenic activity in a mouse corneal micro pocket model. Compounds were<br />
synthesized in a straightforward manner from readily available glutarate precursors.<br />
Figure-2<br />
Ebraheem Abdu Musad et al. 17 has synthesized pyrazoles and isoxazoles<br />
(Figure-3) were screened for antioxidant and anti-microbial activities. Among that<br />
some of compounds showed higher antioxidant activity at 10μg/ml and some<br />
compounds exhibited better anti-microbial activity at 100μg/ml compared with<br />
standard vitamin C and ciprofloxacin, respectively.<br />
Department of Chemistry <strong>Saurashtra</strong> university, Rajkot-360005 83
Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
N X<br />
N<br />
N<br />
Antioxidant activity<br />
N N<br />
H H<br />
R 1 =R 3 =H,<br />
R 2 =OH,N(CH 3 ) 2<br />
Antimicrobial activity<br />
R 3 R 1 R 3 R 1<br />
R 1 =R 3 =H,<br />
R 2 R R 2 2 =N(CH 3 ) 2 ,OCH<br />
X=O,NH<br />
3<br />
Figure-3<br />
Annamaria Lilienkampf et al. 18 has developed isoxazole-based anti-TB<br />
compounds by applying rational drug design approach (Figure-4). The biological<br />
activity and the structure-activity relationships (SAR) for a designed series of 5-<br />
phenyl-3-isoxazolecarboxylic acid ethyl ester derived anti-TB compounds were<br />
investigated. Several compounds were found to exhibit nanomolar activity against the<br />
replicating bacteria (R-TB) and low micromolar activity against the non replicating<br />
bacteria (NRP-TB). The series showed excellent selectivity toward Mtb, and in<br />
general, no cytotoxicity was observed in Vero cells (IC 50 >128 μM). Notably, selected<br />
compounds also retained their activity against isoniazid (INH), rifampin (RMP), and<br />
streptomycin (SM) resistant Mtb strains. Hence, benzyloxy, benzylamino, and<br />
phenoxy derivatives of5-phenyl-3-isoxazolecarboxylic acid ethyl esters represent a<br />
highly potent, selective, and versatile series of anti-TB compounds and as such<br />
present attractive lead compounds for further TB drug development.<br />
R 1<br />
R 5<br />
R 2<br />
R 3<br />
O<br />
O N<br />
O<br />
O<br />
R 4<br />
R 1 =H, CF 3 ,Cl,F,NO 2<br />
R 2 =OCF 3 ,CH 3 ,NH 2 ,OCH 3 , CON(CH 2 CH 2 ) 2 O, H,Cl, F,<br />
R 3 =H, CF 3 ,Cl,F,<br />
R 4 =R 5 =H,F<br />
Figure-4<br />
Recently, biological evaluation of novel potent HDAC3 and HDAC8<br />
isoxazole and pyrazole-based diazide probes (Figure-5) suitable for binding ensemble<br />
profiling with photo affinity labeling (BEProFL) experiments in cells is described.<br />
Both the isoxazole and pyrazole-based probes exhibit low nanomolar inhibitory<br />
activity against HDAC3 and HDAC8, respectively. The pyrazole-based one of the<br />
most active HDAC8 inhibitors reported in the literature with an IC 50 of 17 nM.<br />
Department of Chemistry <strong>Saurashtra</strong> university, Rajkot-360005 84
Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
Docking studies suggest that unlike the isoxazole-based ligands the pyrazolebased<br />
ligands are flexible enough to occupy the second binding site of HDAC8.<br />
Probes/inhibitors some compounds exerted the antiproliferative and neuroprotective<br />
activities at micromolar concentrations through inhibition of nuclear HDACs,<br />
indicating that they are cell permeable and the presence of an azide or a diazide group<br />
does not interfere with the neuroprotection properties, orenhance cellular cytotoxicity,<br />
or affect cell permeability. 19<br />
Figure-5<br />
Maria Barceló et al. 20 has described synthesis of binding affinities on D 2 , 5-<br />
HT 2A and 5-HT 2C receptors of 6-aminomethyl-6,7-dihydro-1H-indazol-4(5H)-ones<br />
and 6-aminomethyl-6,7-dihydro-3-methyl-benzo[d]isoxazol-4(5H)-ones, as<br />
conformationallly constrained butyrophenone analogues. One of the new compounds<br />
(Figure-6) showed good in vitro binding features, and a Meltzer’s ratio characteristic<br />
of an atypical antipsychotic profile.<br />
Figure-6<br />
Celecoxib and rofecoxib analogues (Figure-7), in which the respective<br />
SO 2 NH 2 and SO 2 Me hydrogen-bonding pharmacophores were replaced by dipolar<br />
azido bioisosteric substituents, were investigated. Molecular modeling (docking)<br />
studies showed that the azido substituent of these two analogues was inserted deep<br />
into the secondary pocket of the human COX-2 binding site where it undergoes<br />
electrostatic interaction with Arg513. The azido analogue of rofecoxib is the most<br />
potent and selective inhibitor of COX-2 (COX-1 IC 50 = 159.7 µM; COX-2 IC 50 = 0.196<br />
µM; COX-2 selectivity index = 812), exhibited good oral anti-inflammatory and<br />
analgesic activity.<br />
Department of Chemistry <strong>Saurashtra</strong> university, Rajkot-360005 85
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Synthesis of trisubstituted pyrazoles/isoxazoles<br />
Figure-7<br />
Amgad G. Habeeb et al. 21<br />
also reported a 4,5-diphenyl-4-isoxazolines<br />
(Figure-8) possessing a variety of substituents (H, F, MeS, MeSO 2 ) at the para<br />
position of one of the phenyl rings were synthesized for evaluation as analgesic and<br />
selective cyclooxygenase-2 (COX-2) inhibitory anti-inflammatory (AI) agents.<br />
Although the 4,5-phenyl-4-isoxazolines (Figure-8), which do not have a C-3 Me<br />
substituent, exhibited potent analgesic and AI activities, those compounds evaluated<br />
were not selective inhibitors of COX-2. In contrast, 2,3-dimethyl-5-(4-<br />
methylsulfonylphenyl)-4-phenyl-4-isoxazoline exhibited excellent analgesic and AI<br />
activities, and it was a potent and selective COX-2 inhibitor (COX-1, IC 50 ) 258 μM;<br />
COX-2, IC 50 ) 0.004 μM).<br />
R 1<br />
R 2<br />
R 3<br />
N Me<br />
O<br />
R 1 =H,Me<br />
R 2 ,R 3 =H,F,SMe,SO 2 Me<br />
Figure-8<br />
A related compound (Figure-8) having a F substituent at the para position of<br />
the 4-phenyl ring was also a selective (SI =3162) but less potent (IC 50 =0.0316 μM)<br />
inhibitor of COX-2 than 2,3-dihydro-2,3-dimethyl-5-(4-(methylsulfonyl)phenyl)-4-<br />
phenyl isoxazole. A molecular modeling (docking study) for 4-(4-fluorophenyl)-2,3-<br />
dihydro-2,3-dimethyl-5-(4-(methylsulfonyl)phenyl)-4-phenylisoxazole showed that<br />
the S atom of the MeSO 2 substituent is positioned about 6.46 Å inside the entrance to<br />
the COX-2 secondary pocket (Val 523 ) and that a C-3 Me (2,3-dihydro-2,3-dimethyl-5-<br />
(4-(methylsulfonyl)phenyl)-4-phenylisoxazole,4-(4-fluorophenyl)-2,3-dihydro-2,3dimethyl-5-(4-(methylsulfonyl)phenyl)-4-phenylisoxazole)<br />
central isoxazoline ring<br />
substituent is crucial to selective inhibition of COX-2 for this class of compounds.<br />
Department of Chemistry <strong>Saurashtra</strong> university, Rajkot-360005 86
Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
Chih Y. Ho et al. 22 have repoted a series of (6,7-dimethoxy-2,4-<br />
dihydroindeno[1,2-c]pyrazol-3-yl)phenylamines (Figure-9) has been optimized to<br />
preserve both potent kinase inhibition activity against the angiogenesis target, the<br />
receptor tyrosine kinase of Platelet-Derived Growth Factor-BB (PDGF-BB), and to<br />
improve the broad tumor cell antiproliferative activity of these compounds. This<br />
series culminates in the discovery of (JNJ-10198409), a compound with anti-PDGFRα<br />
kinase activity (IC 50 = 0.0042 µM) and potent antiproliferative activity in six of<br />
eight human tumor cell lines (IC 50 = 0.033 µM).<br />
Figure-9<br />
Chih Y. Ho has developed antiangiogenic compounds with an additional<br />
antiproliferative activity capable of inhibiting tumor progression by controlling both<br />
the vascularization and proliferation of the tumor mass. Tumors may be regarded as a<br />
two-compartment system consisting of the vasculature supporting tumor growth<br />
composed of ‘normal’ homogeneous vascular endothelial cells, smooth muscle cells,<br />
and pericytes that are surrounded by colonies of neoplastic cancer cells. To find<br />
molecules that would affect both the vascular and transformed compartments, we<br />
identified several compounds with the potential to inhibit the PDGFR-β kinasemediated<br />
angiogenic effect and then assayed them for collateral antiproliferative<br />
activity against a panel of human tumor cell lines.<br />
Christian Peifer et al. 23 have been reported on the discovery of isoxazole<br />
(Figure-10) as a potent dual inhibitor of p38α (IC 50 = 0.45 μM) and CK1δ (IC 50 = 0.23<br />
μM). Because only a few effective small molecule inhibitors of CK1 have been<br />
described so far, we aimed to develop this structural class toward specific agents.<br />
Molecular modeling studies comparing p38α/CK1δ suggested an optimization<br />
strategy leading to design, synthesis, biological characterization, and SAR of highly<br />
potent compounds including possessing differentiated specificity. Selected<br />
compounds were profiled over 76 kinases and evaluation of their cellular efficacy<br />
showed 18 (CKP138) to be a highly potent and dual-specific inhibitor of CK1δ and<br />
p38α.<br />
Department of Chemistry <strong>Saurashtra</strong> university, Rajkot-360005 87
Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
Figure-10<br />
Small molecule inhibitors of various protein kinases are utilized extensively in<br />
research and drug development. The human kineme consists of more than 500 protein<br />
kinases, and kinase inhibitors typically bind in the highly conserved ATP pocket of<br />
these enzymes. 24 Thus the specificity of ATP competitive kinase inhibitors is of<br />
significant interest and represents a crucial factor for their use in, e.g., signal<br />
transduction research or therapeutic applications.<br />
A series of 4-aryl-5-(4-piperidyl)-3-isoxazolol GABA A antagonists have been<br />
synthesized and pharmacologically characterized. 25 The meta-phenyl-substituted<br />
compounds and the para-phenoxy-substituted compound (Figure 11) all display high<br />
affinities (K i = 10-70 nM) and antagonist potencies in the low nanomolar range (K i =<br />
9-10 nM). These potencies are significantly higher than those of previously reported<br />
4-PIOL antagonists and considerably higher than that of the standard GABA A<br />
antagonist SR 95531.<br />
Figure 11<br />
In contrast to the all osteric modulatory sites, the GABA binding site has very<br />
distinct and specific structural requirements for recognition and activation. Thus, very<br />
few different classes of structures have been reported. Within the series of compounds<br />
showing agonist activity at the GABA A receptor site are the selective GABA A<br />
agonists muscimol 26 and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol, 26-27 which<br />
have been used for the characterization of the GABA A receptors (Figure 11). 28<br />
Recently, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol has been shown to be<br />
functionally selective for a subpopulation of GABA A receptors and is currently in<br />
clinical trials as a therapeutic for the regulation of sleep.<br />
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Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
3.3 Synthetic methods for the pyrazole and isoxazole derivatives<br />
There are several methods reported in the literature for the preparation of<br />
pyrazoles and isoxazoles described as under.<br />
Pranab K. Mahata et al. 29 has synthesized 3-dimethoxymethyl-5-(methylthio)<br />
pyrazole/ isoxazole derivative (Figure-12) shown to be useful three carbon synthon<br />
for efficient regiospecific synthesis of a variety of five (pyrazole/isoxazole) with mask<br />
or unmask aldehyde functionality by cyclocondensation with bifunctional<br />
nucleophiles such as hydrazine and hydroxylamine respectively.<br />
Figure-12<br />
Sabine Kuettel et al. 30 has synthesized 4-(3-phenylpyrazole/isoxazol-5-<br />
yl)morpholine derivatives (Figure-13) by two synthetic routes, in which substituted<br />
acetophenones were reacted with carbon disulfide and methyl iodide in the presence<br />
of sodium hydride to give 4-phenoxyphenyl-2,2-bis(methylthio)vinylketones,<br />
followed by in situ cyclization of the resulting N,S-acetals with hydrazine<br />
hydrate/hydroxylamine.<br />
Figure-13<br />
Scott R. Tweedie et al. 31 has synthesized a pyrazole and isoxazole derivatives<br />
via palladium-catalyzed couplings of heteroaryl amines with aryl halides using<br />
sodium phenolate as the stoichiometric base (Figure-14).<br />
Figure-14<br />
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Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
Kewei Wang et al. 32 has reported an efficient and divergent one-pot synthesis<br />
of fully substituted 1H-pyrazoles and isoxazole derivatives. Substituted 1H-pyrazoles<br />
were synthesized from 1-carbamoyl, 1-oximyl cyclopropanes via sequential ringopening,<br />
chlorovinylation, and intramolecular aza-cyclization under Vilsmeier<br />
conditions (POCl 3 /DMF). Isoxazoles were synthesized from the cyclopropyl oximes<br />
via ring-opening and intramolecular nucleophilic vinylic substitution (S N V) reactions<br />
in the presence of POCl 3 /CH 2 Cl 2 (Figure-15).<br />
Figure-15<br />
Ebraheem Abdu Musad et al. 33 has prepared a new 3,5-(substituted) pyrazoles<br />
and isoxazoles by reaction of (N’¹E , N’³E)- N’¹, N’³-bis(3,4,5-substitutedbenzylidene)malonohydrazide<br />
with hydrazine hydrate and hydroxylamine<br />
hydrochloride respectively under solvothermal conditions involving an ecofriendly<br />
method without any environmental pollution (Figure-16).<br />
Figure-16<br />
Ch brajakishor singh et al. 34 have been synthesized a steroidal pyrazole and<br />
isoxazole derivatives form 2-ethoxymethelene-4-androsten-3-one and 2-<br />
bis(methylthio)methelene-4-androsten-3-one (Figure-17).<br />
Figure-17<br />
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Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
Alex F. C. Flores et al. 35 have been synthesized a new series of hydroxyl<br />
pyrazoles and 2-methyl-3-isoxazolones from the cyclocondensation reaction of<br />
trichloromethyl-substituted 1,3-dielectrophiles with dry hydrazine and N-methyl<br />
hydroxylamine respectively (Figure-18).<br />
Figure-18<br />
Sarvesh Kumar et al. 36 has synthesized pyrazole and isoxazole derivatives via<br />
hetero annulations of 10,11-Dihydro-11-[bis(methylthio)methylene]dibenzoxepin-10-<br />
one (α-oxoketene dithioacetal) (Figure-19).<br />
Figure-19<br />
Valentina Molteni et al. 37 have been developed an extremely simple one pot<br />
reaction for transforming diketones into the corresponding pyrazoles and isoxazoles<br />
promoted by microwave irradiation (Figure-20).<br />
O<br />
O<br />
O<br />
H 3 CO OCH<br />
R-NHNH 3<br />
2<br />
NH 2 OH<br />
n N<br />
n n N<br />
N MW H 2 O<br />
N<br />
MW<br />
O<br />
O<br />
R<br />
n= 0, 1, 2<br />
Figure-20<br />
Thomas Kurz et al. 38 has synthesized novel fluorinated ketene N,S-acetals<br />
were readily prepared by the reaction of fluorosubstituted cyanoacetamide derivatives<br />
with arylisothiocyanate in the presence of potassium hydroxide, followed by the<br />
alkylation of the produced salts with methyl iodide. The reaction of fluorinated ketene<br />
N,S-acetals with hydrazine afforded different fluorosubstituted pyrazole (Figure-21).<br />
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Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
Figure-21<br />
Galal H. Elgemeie et al. 39 have been synthesized a variety of novel α-<br />
cyanoketene S,S-acetals, readily prepared by the reaction of cyanoacetanilides or<br />
cyanothioacetamide with carbon disulfide, followed by alkylation, react smoothly<br />
with nucleophile to afford variously substituted methylthio derivatives of pyrazole<br />
(Figure-22).<br />
MeS<br />
SMe<br />
CN<br />
RNHNH 2<br />
H 2 N<br />
S<br />
EtOH, PiP, heat<br />
NH 2<br />
H 2 N<br />
N<br />
N<br />
R<br />
R= H, Ph<br />
Figure-22<br />
Jesse P. Waldo et al. 40 have been synthesized of isoxazoles (Figure-23) via<br />
electrophilic cyclization under mild reaction conditions by the reaction of 2-alkyn-1-<br />
one O-methyl oximes with ICl, I 2 , Br 2 , or PhSeBr.<br />
O<br />
SMe<br />
Figure-23<br />
David J. Burkhart et al. 41 have been synthesized ethyl 4-acetyl-5-methyl-3-<br />
isoxazoyl carboxylate (Figure-24) was smoothly lithiated at the 5-methyl position.<br />
The anion was quenched with a variety of electrophiles such as alkyl halides,<br />
aldehyde, TMSCl and Me 3 SnCl in good to excellent yields.<br />
Figure-24<br />
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Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
V. P. Kislyi et al. 42 were prepared 4-amino-5-benzoyl (acetyl) isoxazole-3-<br />
carboxamides (Figure 25) by cyclization of α-hydroxyimino nitriles O-alkylated with<br />
bromoacetophenones (bromoacetone). The purity of the target 4-aminoisoxazoles can<br />
be substantially increased by treating O-alkylated oximes with LiClO 4 before<br />
cyclization.<br />
Figure 25<br />
Wenli Ma et al. 43 have been developed an efficient three-component, two-step<br />
“catch and release” solid-phase synthesis of 3,4,5-trisubstituted pyrazoles and<br />
isoxazoles (Figure-26). The first step involves a base-promoted condensation of a 2-<br />
sulfonyl- or a 2-carbonyl-acetonitrile derivative (1 or 7) with an isothiocyanate 2 and<br />
in situ immobilization of the resulting thiolate anion on Merrifield resin. Reaction of<br />
the resin-bound sulfonyl intermediate 4 with hydrazine or hydroxylamine, followed<br />
by release from the resin and intramolecular cyclization, affords 3,5-diamino-4-<br />
(arylsulfonyl)-1H-pyrazoles 5 or isoxazoles 6, respectively. Reaction of the resinbound<br />
carbonyl intermediate 9 with hydrazine, on the other hand, leads to 3-<br />
(arylamino)-5-aryl-1H-pyrazole-4-carbonitriles 10.<br />
Figure-26<br />
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Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
3.4 Some pharmaceutical molecules related to pyrazoles and<br />
isoxazoles<br />
Pyrazole and isoxazole nucleus have been widely used as key building blocks<br />
for pharmaceutical agents. Its derivatives are endowed with high pharmacological<br />
properties, for example, hypoglycemic, analgesic, anti-inflammatory, antibacterial,<br />
anti-HIV, and anticancer activity, 3 as well as useful activities in conditions like<br />
schizophrenia, hypertension, and Alzheimer’s disease. 4<br />
N<br />
N<br />
CF 3<br />
H 3 CO 2 S<br />
N O<br />
HO NH 2<br />
SO 2 NH 2<br />
O N<br />
Celocoxib<br />
O<br />
Rofecoxib<br />
O<br />
Muscimol<br />
Agonist of GABA A<br />
receptor<br />
Cl<br />
Cl<br />
N<br />
Cl<br />
N<br />
O<br />
HN N<br />
Rimonabant<br />
anoretic antiobesity drug<br />
N<br />
N<br />
H<br />
Fomepizole<br />
inhibitor of alcohole dehydrogenase<br />
H 2 NO 2 S<br />
O<br />
R R''<br />
NH<br />
O N<br />
R'<br />
HO<br />
N O<br />
O<br />
NH 2<br />
OH<br />
Valdecoxib<br />
Oxacillin<br />
Cloxacillin<br />
Dicloxacillin<br />
Flucloxacillin<br />
Ibotenic acid<br />
Nurotoxin<br />
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Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
3.5 Current research work<br />
α-Oxoketene dithioacetals especially the dimethylthioacetals have recently<br />
received considerable attention due to their synthetic importance for the construction<br />
of a variety of alicyclic, aromatic and heterocyclic compounds. 44,45 Ketene<br />
dithioacetals, in the presence of various regents, undergo different types of reactions<br />
to yield other heterocyclic compounds, e.g., isoxazole, pyrazole, thiophenes,<br />
pyrimidines, pyridines, etc. Consequently we were interested in surveying the<br />
synthetic utility of ketene dithioacetals.<br />
Recently, we have reported solution-phase library of pyrazoles and isoxazoles<br />
functionalized with methyl, sulfone and carboxamide moieties in two steps with<br />
excellent yield and chemical purity for medicinally interesting molecules. Water was<br />
emerged as an efficient and green solvent in the condensation reaction of various<br />
ketene dithioacetals with hydrazine hydrate or hydroxyl amine hydrochloride. 46<br />
Figure-27<br />
In an extension to this work, we describe here a novel synthesis of solvent free<br />
library of trisubstituted pyrazoles (B) and isoxazoles (C) (Figure-27) by the reaction<br />
of ketene dithioacetals with hydrazine hydrate and hydroxylamine hydrochloride<br />
under microwave irradiations Thus, it has been found that reaction of substituted<br />
acetoacetanilide derivatives with carbon disulfide in the presence of potassium<br />
carbonate followed by the alkylation with methyl iodide gives the novel ketene<br />
dithioacetals (A) (Figure 27), the structures of which have been established on the<br />
basis of their elemental analysis and spectral data.<br />
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Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
3.6 Results and discussion<br />
Scheme: Synthesis of novel trisubstitited pyrazoles and isoxazoles from ketene<br />
dithioacetals<br />
Scheme-1<br />
Scheme-2<br />
R<br />
N<br />
H<br />
O<br />
O<br />
1) CS 2 /K 2 CO 3 /DMF<br />
2) CH 3 I<br />
R<br />
N<br />
H<br />
O<br />
S<br />
O<br />
S<br />
3a-o<br />
4a-o<br />
Scheme-3<br />
Where R=CH 3 , OCH 3 , F, NO 2 , Cl<br />
Various substituted 3-cyclopropyl-3-oxo-N-arylpropanamide (3a-o) were<br />
prepared by reacting substituted amines (1a-h) and methyl 3-cyclopropyl-3-<br />
oxopropanoate (2) in toluene with a catalytic amount of NaOH or KOH (Scheme 1).<br />
The reaction mixture was refluxed for 15-20 h. Fifteen different acetoacetanilide were<br />
synthesized bearing various electron donating and electron withdrawing groups such<br />
as 2,3-diCH 3 ; 3,4-diCH 3 ; 4-CH 3 ; H; 2,5-diCH 3 ; 2,4-diCH 3 ; 3-Cl-4-F; 4-F; 4-Cl; 2-Cl;<br />
2-F; 4-OCH3; 2,5-diCl and 3-NO 2 on the phenyl ring. The reaction of substituted<br />
acetoacetanilide 3a-o derivatives with carbon disulfide in the presence of potassium<br />
carbonate followed by the alkylation with methyl iodide (Scheme 2) gave the novel<br />
ketene dithioacetals 4a-o. Further treatment of 4a-o with hydrazine hydrate or<br />
hydroxyl amine hydrochloride in the presence of potassium hydroxide (Scheme-3) to<br />
furnish pyrazoles 5a-o and isoxazoles 6a-o in excellent yield. As a part of ‘green<br />
chemistry’ approaches, we have done all reaction in solvent free reaction condition and<br />
under microwave irradiation. Comparative study of reaction time and yield in<br />
conventional and microwave irradiation methods are summarized in Table-1.<br />
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Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
Table-1: 3-cyclopropyl, 5-methylthio, 4-carboxamide substituted pyrazoles and<br />
isoxazoles.<br />
Reaction time<br />
Entry R Conventional<br />
(hrs)<br />
Yield<br />
(%)<br />
MW<br />
(min.)<br />
Yield<br />
(%)<br />
5a 4-CH 3 Ph 2.0 85 13.0 88<br />
5b 4-ClPh 1.5 88 12.5 90<br />
5c 4-FPh 1.5 87 10.0 92<br />
5d 4-OCH 3 Ph 2.0 83 12.0 90<br />
5e 3,4-diClPh 2.0 90 13.0 95<br />
5f 3,Cl,4-FPh 1.5 85 12.5 88<br />
5g 2,3-diCH 3 Ph 2.0 87 14.0 90<br />
5h 4-NO 2 Ph 2.5 82 17.0 95<br />
5i 2-OCH 3 Ph 1.5 85 14.5 97<br />
5j 2-CH 3 Ph 2.0 83 13.0 93<br />
5k 4-CH 2 CH 3 Ph 2.5 80 12.5 91<br />
5l 5,Cl,2-OCH 3 Ph 2.0 82 13.5 95<br />
5m 2,5-diClPh 1.0 87 12.0 90<br />
5n 2,5-diCH 3 Ph 2.0 80 13.0 88<br />
5o 3,4-diFPh 2.5 81 14.0 87<br />
6a 4-CH 3 Ph 2.5 79 12.5 85<br />
6b 4-ClPh 2.0 83 15.0 93<br />
6c 4-FPh 3.0 82 14.5 90<br />
6d 4-OCH 3 Ph 1.5 87 13.0 92<br />
6e 3,4-diClPh 2.0 85 14.0 91<br />
6f 3,Cl,4-FPh 2.5 82 13.0 87<br />
6g 2,3-diCH 3 Ph 3.0 81 13.5 89<br />
6h 4-NO 2 Ph 2.5 90 14.0 95<br />
6i 2-OCH 3 Ph 3.0 89 15.0 94<br />
6j 2-CH 3 Ph 2.5 87 17.5 92<br />
6k 4-CH 2 CH 3 Ph 3.0 85 15.0 90<br />
6l 5,Cl,2-OCH 3 Ph 1.5 80 12.5 84<br />
6m 2,5-diClPh 1.0 88 13.0 96<br />
6n 2,5-diCH 3 Ph 2.5 87 15.5 94<br />
6o 3,4-diFPh 3.0 85 14.0 92<br />
The structures of 4a-o were established on the basis of their elemental analysis<br />
and spectral data (MS, IR, and 1 H NMR). The analytical data for 4b revealed a<br />
molecular formula C 15 H 16 ClNO 2 S 2 (m/z 342). The 1 H NMR spectrum revealed a two<br />
multiplet at δ = 1.02-1.06 and 1.21-1.24 ppm assigned two –CH 2 groups in<br />
cyclopropane ring, a multiplet at δ = 2.37-2.43 ppm assigned to the –CH protons,<br />
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Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
a singlet at δ = 2.47 ppm assigned to (2 × SCH 3 ) , a multiplet at δ = 7.26–7.59 ppm<br />
assigned to the aromatic protons, and one broad singlet at δ = 8.69 ppm assigned to -<br />
CONH groups.<br />
The structures of 5a-o were established on the basis of their elemental analysis<br />
and spectral data (MS, IR, 1 H NMR and 13 C NMR).Structure 5a was supported by its<br />
mass (m/z 287), which agrees with its molecular formula C 15 H 17 N 3 OS; its 1 H NMR<br />
spectrum had signals at δ = 0.81-0.82 and 0.96-0.99 (m, 2x CH 2 ) in cyclopropane<br />
ring, a multiplet at δ = 2.24 ppm assigned to the cyclopropyl-CH protons, a singlet at<br />
δ=2.40 assigned to -CH 3 protons, a singlet at δ=2.48 ppm assigned to (SCH 3 ), a<br />
multiplet signal at δ = 7.09-7.53 ppm related to the aromatic protons, 9.36 (broad, -<br />
CONH) and 12.84 (broad, pyrazole NH).<br />
The structures of 6a-o were established on the basis of their elemental analysis<br />
and spectral data (MS, IR, 1 H NMR and 13 C NMR).The analytical data for 6b<br />
revealed a molecular formula C 15 H 16 ClNO 2 S 2 (m/z 342). The 1 H NMR spectrum<br />
revealed a two multiplets at δ = 1.14-1.06 and 1.21-1.16 ppm assigned two –CH 2<br />
groups in cyclopropane ring, a multiplet at δ = 2.16-2.20 ppm assigned to the –CH<br />
protons, a singlet at δ = 2.68 ppm assigned to (SCH 3 ) , a multiplet at δ = 7.26–7.56<br />
ppm assigned to the aromatic protons, and one broad singlet at δ = 8.19 ppm assigned<br />
to -CONH groups.<br />
The proposed mechanism for the formation of 5a-o and isoxazoles 6a-o from<br />
the corresponding 3-cyclopropyl-3-oxo-N-arylpropanamide (3a-o) is shown in Figure<br />
28 & 29. In the ketene dithioacetal system the carbonyl carbon and β-carbon atoms<br />
regarded as hard and soft electrophilic centers, since the carbonyl carbon is adjacent<br />
to the hard-base oxygen while the β-carbon is flanked by the soft-base methylthio<br />
groups. Thus, the nucleophile hydrazine hydrate or hydroxyl amine hydrochloride<br />
may attack on β-carbon of systems and formed heterocyclic product by removal of<br />
methylthio and group as good leaving group and water molecule.<br />
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Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
Mechanism<br />
Figure 28: Proposed mechanism for the formation of pyrazole<br />
Figure 29: Proposed mechanism for the formation of isoxazole<br />
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Chapter 3<br />
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3.7 Conclusion<br />
In summary, we have synthesized a library of pyrazoles and isoxazoles<br />
functionalized with cyclopropyl, thiomethyl and carboxamide moieties in single steps<br />
with excellent yield under microwave irradiation. As a part of ‘green chemistry’<br />
approach condensation reaction of various ketene dithioacetals with hydrazine hydrate<br />
or hydroxyl amine hydrochloride in solvent free condition under microwave<br />
irradiation. The present procedure is significant over the existing methods to develop<br />
this class of molecules with excellent yield, purity and simple isolation of products.<br />
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Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
3.8 Experimental section<br />
Thin-layer chromatography was accomplished on 0.2-mm precoated plates of<br />
silica gel G60 F 254 (Merck). Visualization was made with UV light (254 and 365nm)<br />
or with an iodine vapor. IR spectra were recorded on a FTIR-8400 spectrophotometer<br />
using DRS prob. 1 H (300 MHz), 1 H (400 MHz), 13 C (75 MHz) and 13 C (100 MHz)<br />
NMR spectra were recorded on a Bruker AVANCE II spectrometer in CDCl 3 and<br />
DMSO. Chemical shifts are expressed in δ ppm downfield from TMS as an internal<br />
standard. Mass spectra were determined using direct inlet probe on a GCMS-QP 2010<br />
mass spectrometer (Shimadzu). Solvents were evaporated with a BUCHI rotary<br />
evaporator. Melting points were measured in open capillaries and are uncorrected.<br />
General synthesis of 3-cyclopropyl-3-oxo-N-arylpropanamide (3a-o).<br />
A mixture containing the primary amine (1a-h, 10 mmol), methyl 3-<br />
cyclopropyl-3-oxopropanoate (2, 10 mmol), and catalytic amount of sodium or<br />
potassium hydroxide (10 %) in toluene (50 mL) was reflux at 110 o C for the<br />
approximately 12-15 h. The reaction was monitored by TLC. After completion of<br />
reaction, the solvent was removed under vaccuo and the solid or oil was crystallized<br />
from methanol which afforded pure products.<br />
General synthesis of ketene dithioacetals (4a-o).<br />
A 100mL conical flask equipped with magnetic stirrer and septum was charged<br />
with a solution of 3-cyclopropyl-3-oxo-N-arylpropanamide (3a-o, 10 mmol) in DMF<br />
(10 mL). Dried K 2 CO 3 (20 mmol) was added and the mixture was stirred for 2 h at<br />
room temperature. CS 2 (10 mmol) was added and the mixture was stirred for an<br />
additional 2 h at room temperature. Methyl iodide (20 mmol) was added at 0-5 o C and<br />
the mixture was stirred for 4 h at room temperature. The reaction was monitored by<br />
TLC. After completion, the mixture poured into water (40 mL). The precipitated<br />
crude product was purified by filtration followed by crystallization from EtOH. When<br />
the product was oil, the organic phase was extracted with Et 2 O (3 × 10 mL). The<br />
combined organic extracts were washed with H 2 O (2 × 10 mL), dried (MgSO 4 ), and<br />
concentrated in vaccuo to afford ketene dithioacetals directly used for the next step.<br />
Department of Chemistry <strong>Saurashtra</strong> university, Rajkot-360005 101
Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
General procedure for the synthesis of trisubstituted pyrazoles5a-o.<br />
‣ Conventional method:<br />
A 25mL conical flask equipped with magnetic stirrer and septum was charged<br />
hydrazine hydrate (15 mmol) and various ketene dithioacetals (3a-o, 10 mmol) and<br />
heated up to 75-85 o C for appropriate times (Table-1). After completion of the<br />
reaction, the reaction mixture was allowed to come to room temperature and add cold<br />
water (50 mL). The separated suspension was filtered, washed with water, dried and<br />
crystallized from methanol to afford analytically pure products with 80-90% yield.<br />
‣ Microwave assisted method:<br />
A one neck flat bottom flask charged with the hydrazine hydrate (15 mmol),<br />
and various ketene dithioacetals 3a-o (10 mmol), was heated at 90 o C under<br />
microwave irradiation for appropriate time (Table-1). After completion of the<br />
reaction, the reaction mixture was allowed to attain room temperature and added cold<br />
water (50 mL). The suspension was filtered, washed with water, dried and crystallized<br />
from methanol to afford analytically pure products with 85-95% yield.<br />
General procedure for the synthesis of trisubstituted isoxazoles6a-o.<br />
‣ Conventional method:<br />
A 25mL conical flask equipped with magnetic stirrer and septum was charged<br />
with hydroxyl amine hydrochloride (15 mmol), potassium hydroxide (15 mmol) and<br />
various ketene dithioacetals (3a-o, 10mmol) and heated up to 75-85 o C for appropriate<br />
times (Table-1). After completion of the reaction, the reaction mixtures were cooled<br />
to room temperature and add cold water (50 mL). The separated solid was filtered,<br />
washed with water, dried and crystallized from methanol to afford analytically pure<br />
products with 80-90% yield.<br />
‣ Microwave assisted method:<br />
A one neck flat bottom flask charged with hydroxyl amine hydrochloride (15<br />
mmol), potassium hydroxide (15 mmol) and various ketene dithioacetals 3a-o (10<br />
mmol) and reaction mixture heated at 90 o C under microwave irradiation for<br />
appropriate time (Table-1). After completion of the reaction, the reaction mixture was<br />
allowed to come to room temperature and add cold water (50 mL). The separated<br />
solid was filtered, washed with water, dried and crystallized from methanol to afford<br />
analytically pure products with 85-95% yield.<br />
Department of Chemistry <strong>Saurashtra</strong> university, Rajkot-360005 102
Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
Spectral data of the synthesized compounds<br />
3-Cyclopropyl-N-(4-fluorophenyl)-3-oxopropanamide 3c.White solid; R f 0.42 (8:2<br />
hexane-EtOAc); IR (KBr): 3364, 2927, 1674, 1533, 1462, 1281, 1112, 873 cm -1 ; 1 H<br />
NMR (300 MHz, CDCl 3 ): δ 1.07-1.13 (q, 2H, CH 2 ), 1.14-1.20 (q, 2H, CH 2 ), 2.00-<br />
2.06 (m, 1H, CH), 3.71 (s, 2H, CH 2 ), 6.97-7.03 (m, 2H, Ar-H), 7.48-7.53 (m, 2H, Ar-<br />
H), 9.43 (s, 1H, NH); MS (m/z): 221 (M + ); Anal. Calcd for C 12 H 12 FNO 2 : C, 65.15; H,<br />
5.47; N, 6.33; Found: C, 65.17; H, 5.45; N, 6.34.<br />
N-(4-chlorophenyl)-2-(cyclopropylcarbonyl)-3,3-bis(methylsulfanyl)prop-2-<br />
enamide 4b. Yellow solid; R f 0.48 (8:2 hexane-EtOAc); IR (KBr): 3033, 2927, 1674,<br />
1533, 1462, 1281, 1112, 873 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ): δ 1.02-1.06 (m, 2H,<br />
CH 2 ), 1.21-1.24 (m, 2H, CH 2 ), 2.37-2.43 (m, 1H, CH), 2.47 (s, 6H, 2xSCH 3 ), 7.26-<br />
7.29 (d, 2H, j=9.6Hz, Ar-H), 7.53-7.59 (d, 2H, j=8.7Hz, Ar-H), 8.69 (s, 1H, NH); MS<br />
(m/z): 342 (M + ); Anal. Calcd for C 15 H 16 ClNO 2 S 2 : C, 52.70; H, 4.72; N, 4.10; Found:<br />
C, 52.72; H, 4.75; N, 4.12.<br />
2-(Cyclopropylcarbonyl)-N-(4-methoxyphenyl)-3,3-bis(methylsulfanyl)prop-2-<br />
enamide 4d. Yellow solid; R f 0.42 (9:1 Chloroform: Methanol); IR (KBr): 3364,<br />
2927, 1674, 1533, 1462, 1281, 1112, 873 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ): δ 1.02-<br />
1.04 (m, 2H, CH 2 ), 1.22 (m, 2H, CH 2 ), 2.39-2.42 (m, 1H, CH), 2.47 (s, 6H, 2x<br />
SCH 3 ), 3.84 (s, 3H, OCH 3 ), 6.85-6.88 (d, 2H, j=8.7Hz,Ar-H), 7.48-7.51 (d, 2H,<br />
j=8.7Hz,Ar-H), 8.35 (s, 1H, NH); MS (m/z): 337 (M + ); Anal. Calcd for C 16 H 19 NO 3 S 2 :<br />
C, 56.95; H, 5.68; N, 4.15; Found: C, 56.92; H, 5.65; N, 4.12.<br />
3-Cyclopropyl-5-(methylthio)-N-p-tolyl-1H-pyrazole-4-carboxamide 5a. White<br />
solid; R f 0.71 (9:1 Chloroform: Methanol); mp 155-157 o C; IR (KBr): 3284, 3151,<br />
3083, 3031, 2968, 2841, 1628, 1586, 1408, 1238, 1037, 887, 834 cm -1 ; 1 H NMR (300<br />
MHz, CDCl 3 ): δ 0.81-0.82 (m, 2H, CH 2 ), 0.96-0.99 (m, 2H, CH 2 ), 2.24 (m, 1H, CH),<br />
2.40 (s, 3H, CH 3 ), 2.48 (s, 3H, SCH 3 ), 7.09-7.11 (d, 2H, j=8.1Hz, Ar-H), 7.51-7.53<br />
(d, 2H, j=8.1Hz, Ar-H), 9.36 (s, 1H, NH), 12.84 (s, 1H, NH); MS (m/z): 287 (M + );<br />
Anal. Calcd for C 15 H 17 N 3 OS: C, 62.69; H, 5.96; N, 14.62; Found: C, 62.68; H, 5.95;<br />
N, 14.62.<br />
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Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
N-(4-chlorophenyl)-3-cyclopropyl-5-(methylthio)-1H-pyrazole-4-carboxamide<br />
5b. White solid; R f 0.68 (9:1 Chloroform: Methanol); mp 133-135 o C; IR (KBr): 3294,<br />
3259, 3153, 3020, 2953, 2895, 1681, 1589, 1485, 1251, 1006, 898, 821, 759, 732, 690<br />
cm -1 ; 13 C NMR (100 MHz, CDCl 3 ): 7.52, 120.82, 127.03, 128.23, 137.74, 161.69; MS<br />
(m/z): 307 (M + ); Anal. Calcd for C 14 H 14 ClN 3 OS: C, 54.63; H, 4.58; N, 13.65; Found:<br />
C, 54.62; H, 4.55; N, 13.62.<br />
3-Cyclopropyl-N-(4-fluorophenyl)-5-(methylthio)-1H-pyrazole-4-carboxamide<br />
5c. White solid; R f 0.71 (9:1 Chloroform: Methanol); mp 122-124 o C; IR (KBr): 3287,<br />
3136, 3081, 3014, 2968, 2833, 1641, 1584, 1251, 1024, 882, 832 cm -1 ; 1 H NMR (300<br />
MHz, CDCl 3 ): δ 0.82-0.83 (m, 2H, CH 2 ), 0.96-1.03 (m, 2H, CH 2 ), 2.26 (m, 1H, CH),<br />
2.40 (s, 3H, SCH 3 ), 7.11-7.17 (m, 2H, Ar-H), 7.63-7.67 (d, 2H, j=13.2Hz, Ar-H), 9.53<br />
(s, 1H, NH), 12.88 (s, 1H, NH); MS (m/z): 291 (M + ); Anal. Calcd for C 14 H 14 ClN 3 OS:<br />
C, 57.72; H, 4.84; N, 14.42; Found: C, 57.74; H, 4.85; N, 14.46.<br />
3-Cyclopropyl-N-(4-methoxyphenyl)-5-(methylthio)-1H-pyrazole-4-carboxamide<br />
5d. White solid; R f 0.42 (9:1 Chloroform: Methanol); mp 141-143 o C; IR (KBr): 3292,<br />
3147, 3090, 2962, 2835, 1635, 1031, 896, 830 cm -1 ; MS (m/z): 303 (M + ); Anal. Calcd<br />
for C 15 H 17 N 3 O 2 S: C, 59.38; H, 5.65; N, 13.85; Found: C, 59.36; H, 5.65; N, 13.82.<br />
N-(3,4-dichlorophenyl)-3-cyclopropyl-5-(methylthio)-1H-pyrazole-4-carboxamide<br />
5e. White solid; R f 0.69 (9:1 Chloroform: Methanol); mp 179-181 o C; IR (KBr):<br />
3298, 3142, 3086, 3001, 2956, 2829, 1631, 1415, 1245, 1023, 828, 782 cm -1 ; MS<br />
(m/z): 342 (M + ); Anal. Calcd for C 14 H 13 Cl 2 N 3 OS: C, 49.13; H, 3.83; N, 12.28; Found:<br />
C, 49.15; H, 3.85; N, 12.26.<br />
N-(3-chloro-4-fluorophenyl)-3-cyclopropyl-5-(methylthio)-1H-pyrazole-4-carboxamide<br />
5f. White solid; R f 0.65 (9:1 Chloroform: Methanol); mp 179-181 o C; IR<br />
(KBr): 3287, 3082, 2961, 1628, 1041, 835, 789 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): δ<br />
0.80-0.82 (m, 2H, CH 2 ), 0.95-1.03 (m, 2H, CH 2 ), 2.24 (m, 1H, CH), 2.41 (s, 3H,<br />
SCH 3 ), 7.33-7.39 (m, 1H, Ar-H), 7.55-7.58 (d, 1H, j=4.2Hz, Ar-H), 7.93-7.96 (d, 1H,<br />
j=6.9Hz, Ar-H), 9.71 (s, 1H, NH), 12.90 (s, 1H, NH); MS (m/z): 325 (M + ); Anal.<br />
Calcd for C 14 H 13 ClFN 3 OS: C, 51.61; H, 4.02; N, 12.90; Found: C, 51.64; H, 4.05; N,<br />
12.96.<br />
Department of Chemistry <strong>Saurashtra</strong> university, Rajkot-360005 104
Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
3-Cyclopropyl-N-(2,3-dimethylphenyl)-5-(methylthio)-1H-pyrazole-4-carboxamide<br />
5g. White solid; R f 0.81 (9:1 Chloroform: Methanol); mp 183-185 o C; IR (KBr):<br />
3289, 3136, 3094, 3013, 2958, 2826, 1638, 1587, 1418, 1239, 1028, 758, 785 cm -1 ;<br />
MS (m/z): 301 (M + ); Anal. Calcd for C 16 H 19 N 3 O 2 S: C, 63.76; H, 6.35; N, 13.94;<br />
Found: C, 63.76; H, 6.35; N, 13.93.<br />
3-Cyclopropyl-5-(methylthio)-N-(4-nitrophenyl)-1H-pyrazole-4-carboxamide 5h.<br />
White solid; R f 0.86 (9:1 Chloroform: Methanol); mp 212-215 o C; IR (KBr): 3278,<br />
3145, 3097, 3015, 2947, 2832, 1641, 1584, 1408, 1233, 1021, 834 cm -1 ; MS (m/z):<br />
318 (M + ); Anal. Calcd for C 14 H 14 N 4 O 3 S: C, 52.82; H, 4.43; N, 17.60; Found: C,<br />
52.86; H, 4.45; N, 17.63.<br />
3-Cyclopropyl-N-(2-methoxyphenyl)-5-(methylthio)-1H-pyrazole-4-carboxamide<br />
5i. White solid; R f 0.76 (9:1 Chloroform: Methanol); mp 111-113 o C; IR (KBr): 3287,<br />
3139, 3085, 3011, 2955, 2824, 1631, 1587, 1417, 1241, 1026, 744 cm -1 ; MS (m/z):<br />
303 (M + ); Anal. Calcd for C 15 H 17 N 3 O 2 S: C, 59.38; H, 5.65; N, 13.85; Found: C,<br />
59.36; H, 5.65; N, 13.82.<br />
3-Cyclopropyl-5-(methylthio)-N-o-tolyl-1H-pyrazole-4-carboxamide 5j. White<br />
solid; R f 0.63 (9:1 Chloroform: Methanol); mp 142-144 o C; IR (KBr): 3283, 3141,<br />
3088, 3016, 2967, 2836, 1641, 1593, 1412, 1231, 1037, 755 cm -1 ; MS (m/z): 287<br />
(M + ); Anal. Calcd for C 15 H 17 N 3 OS: C, 62.69; H, 5.96; N, 14.62; Found: C, 62.68; H,<br />
5.95; N, 14.62.<br />
3-Cyclopropyl-N-(4-ethylphenyl)-5-(methylthio)-1H-pyrazole-4-carboxamide<br />
5k.White solid; R f 0.71 (9:1 Chloroform: Methanol); mp 187-189 o C; IR (KBr):<br />
3287, 3147, 3091, 3008, 2958, 2828, 1638, 1584, 1410, 1248, 1028, 837 cm -1 ; MS<br />
(m/z): 301 (M + ); Anal. Calcd for C 16 H 19 N 3 O 2 S: C, 63.76; H, 6.35; N, 13.94; Found: C,<br />
63.76; H, 6.35; N, 13.93<br />
N-(5-Chloro-2-methoxyphenyl)-3-cyclopropyl-5-(methylthio)-1H-pyrazole-4-carboxamide<br />
5l. White solid; R f 0.69 (9:1 Chloroform: Methanol); mp 205-207 o C; IR<br />
(KBr): 3285, 3141, 3088, 3013, 2964, 2838, 1634, 1587, 1415, 1238, 1034, 878, 748<br />
cm -1 ; MS (m/z): 338 (M + ); Anal. Calcd for C 15 H 16 ClN 3 O 2 S: C, 53.33; H, 4.77; N,<br />
12.44; Found: C, 53.36; H, 4.75; N, 12.43<br />
Department of Chemistry <strong>Saurashtra</strong> university, Rajkot-360005 105
Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
N-(2,5-dichlorophenyl)-3-cyclopropyl-5-(methylthio)-1H-pyrazole-4-carboxamide<br />
5m. White solid; R f 0.62 (9:1 Chloroform: Methanol); mp 188-187 o C; IR (KBr):<br />
3279, 3136, 3079, 3021, 2959, 2831, 1628, 1581, 1422, 1242, 1039, 892, 761 cm -1 ;<br />
MS (m/z): 342 (M + ); Anal. Calcd for C 14 H 13 Cl 2 N 3 OS: C, 49.13; H, 3.83; N, 12.28;<br />
Found: C, 49.15; H, 3.85; N, 12.26.<br />
3-Cyclopropyl-N-(2,5-dimethylphenyl)-5-(methylthio)-1H-pyrazole-4-carboxamide<br />
5n. White solid; R f 0.78 (9:1 Chloroform: Methanol); mp 177-178 o C; IR (KBr):<br />
3281, 3087, 2955, 2841, 1631, 1591, 886, 748 cm -1 ; MS (m/z): 301 (M + ); Anal. Calcd<br />
for C 16 H 19 N 3 O 2 S: C, 63.76; H, 6.35; N, 13.94; Found: C, 63.76; H, 6.35; N, 13.93.<br />
3-Cyclopropyl-N-(3,4-difluorophenyl)-5-(methylthio)-1H-pyrazole-4-carboxamide<br />
5o. White solid; R f 0.63 (9:1 Chloroform: Methanol); mp 202-204 o C; IR (KBr):<br />
3287, 3142, 3093, 3014, 2969, 2838, 1628, 1587, 1410, 1248, 1034, 833, 786 cm -1 ;<br />
MS (m/z): 309 (M + ); Anal. Calcd for C 14 H 13 F 2 N 3 OS: C, 54.36; H, 4.24; N, 13.58;<br />
Found: C, 54.36; H, 4.25; N, 13.59.<br />
3-Cyclopropyl-5-(methylthio)-N-p-tolylisoxazole-4-carboxamide 6a. White solid;<br />
R f 0.61 (8:2 hexane-EtOAc); mp 144-146 o C; IR (KBr): 3282, 3149, 3081, 3033, 2978,<br />
2839, 1630, 1584, 1410, 1236, 1039, 883, 837 cm -1 ; MS (m/z): 288 (M + ); Anal. Calcd<br />
for C 14 H 13 F 2 N 3 OS: C, 62.48; H, 5.59; N, 9.71; Found: C, 62.49; H, 5.57; N, 9.72.<br />
N-(4-Chlorophenyl)-3-cyclopropyl-5-(methylthio)isoxazole-4-carboxamide 6b.<br />
White solid; R f 0.70 (8:2 hexane-EtOAc); mp 125-127 o C; IR (KBr): 3294, 3149,<br />
3018, 2895, 1695, 1591, 1496, 1253, 1058, 810, 759, 715, 690 cm -1 ; 1 H NMR (300<br />
MHz, CDCl 3 ): δ 1.14-1.16 (m, 2H, CH 2 ), 1.25 (m, 2H, CH 2 ), 2.16-2.20 (m, 1H, CH),<br />
2.68 (s, 3H, SCH 3 ), 7.26-7.33 (m, 1H, Ar-H), 7.53-7.56 (d, 1H, j=8.7Hz, Ar-H), 8.19<br />
(broad, 1H, CONH); 13 C NMR (100 MHz, CDCl 3 ): 6.85, 13.66, 22.72, 29.18, 110.84,<br />
121.05, 129.13, 136.09, 159.32, 162.66, 172.03; MS (m/z): 308 (M + ); Anal. Calcd for<br />
C 14 H 13 ClFN 2 OS: C, 54.46; H, 4.24; N, 9.07; Found: C, 54.44; H, 4.25; N, 9.06.<br />
3-Cyclopropyl-N-(4-fluorophenyl)-5-(methylthio)isoxazole-4-carboxamide 6c.<br />
White solid; R f 0.59 (8:2 hexane-EtOAc); mp 133-138 o C; IR (KBr): 3289, 3139,<br />
3083, 3017, 2966, 1643, 1410, 1249, 885, 836 cm -1 ; MS (m/z): 292 (M + ); Anal. Calcd<br />
for C 14 H 13 FN 2 OS: C, 57.52; H, 4.48; N, 9.58; Found: C, 57.49; H, 4.47; N, 9.52.<br />
Department of Chemistry <strong>Saurashtra</strong> university, Rajkot-360005 106
Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
3-Cyclopropyl-N-(4-methoxyphenyl)-5-(methylthio)isoxazole-4-carboxamide 6d.<br />
White solid; R f 0.67 (8:2 hexane-EtOAc); mp 120-123 o C; IR (KBr): 3288, 3147,<br />
3095, 3031, 2965, 2837, 1637, 1592, 1409, 1247, 1036, 891, 833 cm -1 ; MS (m/z): 304<br />
(M + ); Anal. Calcd for C 15 H 16 N 2 O 3 S: C, 59.19; H, 5.30; N, 9.20; Found: C, 59.19; H,<br />
5.31; N, 9.22.<br />
N-(3,4-dichlorophenyl)-3-cyclopropyl-5-(methylthio)isoxazole-4-carboxamide 6e.<br />
White solid; R f 0.62 (8:2 hexane-EtOAc); mp 180-182 o C; IR (KBr): 3295, 3148,<br />
3091, 3011, 2951, 2831, 1625, 1587, 1418, 1241, 1029, 832, 779 cm -1 ; MS (m/z): 343<br />
(M + ); Anal. Calcd for C 14 H 12 Cl 2 N 2 O 2 S: C, 48.99; H, 3.52; N, 8.16; Found: C, 48.97;<br />
H, 3.53; N, 8.12.<br />
N-(3-chloro-4-fluorophenyl)-3-cyclopropyl-5-(methylthio)isoxazole-4-carboxamide<br />
6f. White solid; R f 0.69 (8:2 hexane-EtOAc); mp 197-199 o C; IR (KBr): 3288,<br />
3139, 3072, 3017, 2969, 2834, 1631, 1587, 1417, 1237, 1046, 839, 791 cm -1 ; MS<br />
(m/z): 327 (M + ); Anal. Calcd for C 14 H 12 ClFN 2 O 2 S: C, 51.46; H, 3.70; N, 8.57;<br />
Found: C, 51.47; H, 3.73; N, 8.54.<br />
3-Cyclopropyl-N-(2,3-dimethylphenyl)-5-(methylthio)isoxazole-4-carboxamide<br />
6g. White solid R f 0.72 (8:2 hexane-EtOAc); mp 181-183 o C; IR (KBr): 3297, 3138,<br />
3089, 3015, 2952, 2823, 1631, 1591, 1421, 1237, 1025, 754, 787;MS (m/z): 302 (M + );<br />
Anal. Calcd for C 16 H 18 N 2 O 2 S: C, 63.55; H, 6.00; N, 9.26; Found: C, 63.57; H, 6.03;<br />
N, 9.24.<br />
3-Cyclopropyl-5-(methylthio)-N-(4-nitrophenyl)isoxazole-4-carboxamide 6h.<br />
White solid R f 0.58 (8:2 hexane-EtOAc); IR mp 177-179 o C; IR (KBr): 3277, 3148,<br />
3091, 3004, 2942, 2839, 1636, 1591, 1419, 1241, 1033, 837 cm -1 ;MS (m/z): 319 (M + );<br />
Anal. Calcd for C 14 H 13 N 3 O 4 S: C, 52.66; H, 4.10; N, 13.16; Found: C, 52.65; H, 4.13;<br />
N, 13.14.<br />
3-Cyclopropyl-N-(2-methoxyphenyl)-5-(methylthio)isoxazole-4-carboxamide 6i.<br />
White solid R f 0.63 (8:2 hexane-EtOAc); mp 131-133 o C; IR (KBr): 3285, 3142, 3083,<br />
3013, 2964, 2833, 1637, 1591, 1414, 1246, 1028, 746 cm -1 ;MS (m/z): 304 (M + ); Anal.<br />
Calcd for C 15 H 16 N 2 O 3 S: C, 59.19; H, 5.30; N, 9.20; Found: C, 59.19; H, 5.31; N,<br />
9.22.<br />
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Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
3-Cyclopropyl-5-(methylthio)-N-o-tolylisoxazole-4-carboxamide 6j. White solid;<br />
R f 0.67 (8:2 hexane-EtOAc); mp 155-157 o C; IR (KBr): 3285, 3145, 3091, 3003,<br />
2964, 2831, 1639, 1589, 1413, 1237, 1029, 761 cm -1 ; MS (m/z): 288 (M + ); Anal.<br />
Calcd for C 14 H 13 F 2 N 3 OS: C, 62.48; H, 5.59; N, 9.71; Found: C, 62.49; H, 5.57; N,<br />
9.72.<br />
3-Cyclopropyl-N-(4-ethylphenyl)-5-(methylthio)isoxazole-4-carboxamide 6k.<br />
White solid; R f 0.72 (8:2 hexane-EtOAc); mp 160-162 o C; IR (KBr): 3282, 3143,<br />
3093, 3013, 2952, 2822, 1631, 1586, 1418, 1241, 1031, 839 cm -1 ; MS (m/z): 302<br />
(M + ); Anal. Calcd for C 16 H 18 N 2 O 2 S: C, 63.55; H, 6.00; N, 9.26; Found: C, 63.57; H,<br />
6.03; N, 9.24.<br />
N-(5-chloro-2-methoxyphenyl)-3-cyclopropyl-5-(methylthio)isoxazole-4-carboxamide<br />
6l. White solid; R f 0.65 (8:2 hexane-EtOAc); mp 220-222 o C; IR (KBr): 3291,<br />
3139, 3092, 3005, 2968, 2842, 1639, 1582, 1425, 1231, 1029, 872, 739 cm -1 ; MS<br />
(m/z): 338 (M + ); Anal. Calcd for C 15 H 15 ClN 2 O 3 S: C, 53.17; H, 4.46; N, 8.27; Found:<br />
C, 53.19; H, 4.43; N, 8.29.<br />
N-(2,5-dichlorophenyl)-3-cyclopropyl-5-(methylthio)isoxazole-4-carboxamide<br />
6m. White solid; R f 0.73 (8:2 hexane-EtOAc); mp 202-204 o C; IR (KBr): 3281, 3139,<br />
3081, 3019, 2951, 2829, 1632, 1584, 1426, 1238, 1037, 894, 763 cm -1 ; MS (m/z): 343<br />
(M + ); Anal. Calcd for C 14 H 12 Cl 2 N 2 O 2 S: C, 48.99; H, 3.52; N, 8.16; Found: C, 48.97;<br />
H, 3.53; N, 8.12.<br />
3-Cyclopropyl-N-(2,5-dimethylphenyl)-5-(methylthio)isoxazole-4-carboxamide<br />
6n. White solid; R f 0.58 (8:2 hexane-EtOAc); mp 208-210 o C; IR (KBr): 3287, 3139,<br />
3091, 3007, 2959, 2839, 1634, 1594, 1419, 1243, 1029, 882, 742 cm -1 ; MS (m/z): 302<br />
(M + ); Anal. Calcd for C 16 H 18 N 2 O 2 S: C, 63.55; H, 6.00; N, 9.26; Found: C, 63.57; H,<br />
6.03; N, 9.24.<br />
3-Cyclopropyl-N-(3,4-difluorophenyl)-5-(methylthio)isoxazole-4-carboxamide 6o.<br />
White solid; R f 0.67 (8:2 hexane-EtOAc); mp 223-225 o C; IR (KBr): 3292, 3139,<br />
3089, 3008, 2964, 2842, 1632, 1591, 1417, 1239, 1041, 839, 779 cm -1 ; MS (m/z): 310<br />
(M + ); Anal. Calcd for C 14 H 12 Cl 2 N 2 O 2 S: C, 54.19; H, 3.90; N, 9.03; Found: C, 54.17;<br />
H, 3.93; N, 9.02.<br />
Department of Chemistry <strong>Saurashtra</strong> university, Rajkot-360005 108
Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
1 H NMR spectrum of compound 4b<br />
1 H NMR spectrum of compound 4d<br />
Department of Chemistry <strong>Saurashtra</strong> university, Rajkot-360005 109
Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
1 H NMR spectrum of compound 5b<br />
Expanded 1 H NMR spectrum of compound 5b<br />
Department of Chemistry <strong>Saurashtra</strong> university, Rajkot-360005 110
Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
1 H NMR spectrum of compound 5e<br />
Expanded 1 H NMR spectrum of compound 5e<br />
Department of Chemistry <strong>Saurashtra</strong> university, Rajkot-360005 111
Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
1 H NMR spectrum of compound 5c<br />
F<br />
O<br />
N<br />
H<br />
S<br />
N<br />
NH<br />
1 H NMR spectrum of compound 6b<br />
Department of Chemistry <strong>Saurashtra</strong> university, Rajkot-360005 112
Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
13 C NMR spectrum of compound 5b<br />
Expanded 13 C NMR spectrum of compound 5b<br />
Department of Chemistry <strong>Saurashtra</strong> university, Rajkot-360005 113
Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
13 C NMR spectrum of compound 6b<br />
Expanded 13 C NMR spectrum of compound 6b<br />
Department of Chemistry <strong>Saurashtra</strong> university, Rajkot-360005 114
Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
MASS spectrum of compound 5a<br />
N<br />
H<br />
O<br />
S<br />
N<br />
NH<br />
m/z-287<br />
MASS spectrum of compound 5d<br />
Department of Chemistry <strong>Saurashtra</strong> university, Rajkot-360005 115
Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
MASS spectrum of compound 6c<br />
MASS spectrum of compound 6d<br />
O<br />
O<br />
N<br />
H<br />
S<br />
m/z-304<br />
N<br />
O<br />
Department of Chemistry <strong>Saurashtra</strong> university, Rajkot-360005 116
Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
IR spectrum of compound 5b<br />
90<br />
%T<br />
75<br />
60<br />
3294.53<br />
3279.10<br />
3259.81<br />
3153.72<br />
3099.71<br />
3020.63<br />
2953.12<br />
2895.25<br />
2839.31<br />
1728.28<br />
1681.98<br />
1589.40<br />
1429.30<br />
1400.37<br />
1350.22<br />
1309.71<br />
1251.84<br />
1091.75<br />
1006.88<br />
898.86<br />
759.98<br />
732.97<br />
690.54<br />
661.61<br />
626.89<br />
45<br />
30<br />
9<br />
1639.55<br />
1508.38<br />
1485.24<br />
821.70<br />
592.17<br />
497.65<br />
516.94<br />
470.65<br />
4000<br />
3500<br />
3000<br />
2500<br />
2000<br />
1750<br />
1500<br />
1250<br />
1000<br />
750<br />
500<br />
1/cm<br />
IR spectrum of compound 6b<br />
100<br />
%T<br />
80<br />
1695.49<br />
60<br />
1095.60<br />
1058.96<br />
968.30<br />
40<br />
2895.25<br />
1558.54<br />
1350.22<br />
1253.77<br />
1004.95<br />
896.93<br />
759.98<br />
715.61<br />
690.54<br />
430 14<br />
20<br />
0<br />
3294.53<br />
3277.17<br />
3149.86<br />
3093.92<br />
3018.70<br />
1633.76<br />
1591.33<br />
1516.10<br />
1496.81<br />
1404.22<br />
1311.64<br />
810.13<br />
-20<br />
4000<br />
3500<br />
3000<br />
2500<br />
2000<br />
1750<br />
1500<br />
1250<br />
1000<br />
750<br />
500<br />
1/cm<br />
Department of Chemistry <strong>Saurashtra</strong> university, Rajkot-360005 117
Chapter 3<br />
Synthesis of trisubstituted pyrazoles/isoxazoles<br />
3.9 References<br />
1. Shin, K. D.; Lee, M. Y.; Shin, D. S.; Lee, S.; Son, K. H.; Koh, S.; Paik, Y. K.; Kwon, B. M.;<br />
Han, D. C. J. Biol. Chem. 2005, 280, 41439. (b) Demers, J.; Hageman, W.; Johnson, S.;<br />
Klaubert, D.; Look, R.; Moore, J. Bioorg. Med. Chem. Lett. 1994, 4, 2451. (c) Simoni, D.;<br />
Roberti, M.; Paolo, I. F.; Rondanin, R.; Baruchello, R.; Malagutti, C.; Mazzali, A.; Rossi, M.;<br />
Grimaudo, S.; Capone, F.; Dusonchet, L.; Meli, M.; Raimondi, M. V.; Landino, M.;<br />
D’Alessandro, N.; Tolomeo, M.; Arindam, D.; Lu, S.; Benbrook, D. M. J. Med. Chem. 2001,<br />
44, 2308. (d) Liu, X. H.; Cui, P.; Song, B. A.; Bhadury, P. S.; Zhu, H. L.; Wang, S. F. Bioorg.<br />
Med. Chem. 2008, 16, 4075. (e) Velaparthi, S.; Brunsteiner, M.; Uddin, R.; Wan, B.;<br />
Franzblau, S. G.; Petukhov, P. A. J. Med. Chem. 2008, 51, 1999. (f) Magedov, I. V.; Manpadi,<br />
M.; Van slambrouck, S.; Steelant, W. F. A.; Rozhkova, E.; Przheval’skii, N. M.; Rogelj, S.;<br />
Kornienko, A. J. Med. Chem. 2007, 50, 5183.<br />
2. (a) Rowley, M.; Broughton, H. B.; Collins, I.; Baker, R.; Emms, F.; Marwood, R.; Patel, S.;<br />
Ragan, C. I.; Freedman, S. B.; Leeson, P. D. J. Med. Chem. 1996, 39, 1943. (b) Wittenberger,<br />
S. J. J. Org. Chem. 1996, 61, 356. (c) Dannhardt, G.; Dominiak, P.; Laufer, S. Arznei-<br />
Forschung. 1993, 43, 441.<br />
3. (a) Pinho, E. M.; Teresa, M. V. D. Curr. Org. Chem. 2005, 9, 925. (b) Colliot, F.;<br />
Kukorowski, K. A.; Hawkins, D. W.; Roberts, D. A. Brighton Crop Prot. Conf. Pests Dis.<br />
1992, 1, 29. (c) Chen, H. S.; Li, Z. M.; Han, Y. F. J. Agric. Food. Chem. 2000, 48, 5312. (d)<br />
Vicentini, C. B.; Romagnoli, C.; Reotti, E.; Mares, D. J. Agric. Food Chem. 2007, 55, 10331.<br />
(e) Vicentini, C. B.; Mares, D.; Tartari, A.; Manfrini, M.; Forlani, G. J. Agric. Food Chem.<br />
2004, 52, 1898.\<br />
4. (a) Graneto, M. J.; Kurumbail, R. G.; Vazquez, M. L.; Shieh, H. S.; Pawlitz, J. L.; Williams,<br />
J. M.; Stallings, W. C.; Geng, L.; Naraian, A. S.; Koszyk, F. J.; Stealey, M. A.; Xu, X. D.;<br />
Weier, R. M.; Hanson, G. J.; Mourey, R. J.; Compton, R. P.; Mnich, S. J.; Anderson, G. D.;<br />
Monahan, J. B.; Devraj R. J. Med. Chem. 2007, 50, 5712. (b) Kuettel, S.; Zambon, A.; Kaiser,<br />
M.; Brun, R.; Scapozza, L.; Perozzo, R. J. Med. Chem., 2007, 50, 5833.<br />
5. Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Docter, S.;<br />
Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu,<br />
S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.;<br />
Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. J. Med. Chem.<br />
1997, 40, 1347.<br />
6. Prasit, P.; Wang, Z.; Brideau, C.; Chan, C. C.; Charleson, S.; Cromilish, W.; Ethier, D.;<br />
Evans, J. F.; Ford-Hutchinson, A. W.; Gauthier, J. Y.; Gordon, R.; Guay, J.; Gresser, M.;<br />
Kargman, S.; Kennedy, B.; Leblanc, Y.; Leger, S.; Mancini, J.; O'Neill, G. P.; Ouellet, M.;<br />
Percival, M. D.; Perrier, H.; Riendeau, D.; Rodger, I.; Tagari, P.; Therien, M.; Vickers, P.;<br />
Wong, E.; Xu, L. J.; Young, R. N.; Zamboni, R.; Boyce, S.; Rupniak, N.; Forrest, M.; Visco,<br />
D.;Patrick, D. Bioorg. Med. Chem. Lett. 1999, 9, 1773.<br />
Department of Chemistry <strong>Saurashtra</strong> university, Rajkot-360005 118
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Synthesis of trisubstituted pyrazoles/isoxazoles<br />
7. Talley, J. A.; Brown, D. L.; Carter, J. S.; Masferrer, M. J.; Perkins, W. E.; Rogers, R. S.;<br />
Shaffer, A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert, K. J. Med. Chem. 2000, 43, 775.<br />
8. (a) Lawrence, S. A.; Roth, V.; Slinger, R.; Toye, B.; Gaboury, I.; Lemyre, B. BMC<br />
Pediatr2005, 5, 49. (b) Miranda, N. G.; Leanos, M. B. E.; Vilchis, P. M.; Solorzano, S. F.<br />
Ann. Clin. Microbiol. Antimicrob.2006, 5, 25. (c) Sutherland, R.; Croydon, E. A.; Rolinson, G.<br />
N. Br. Med. J. 1970, 4, 455.<br />
9. Silvestri, R.; Artico, M.; Regina, G. L.; Martino, G. D.; Colla, M. L.; Loddo, R.; Colla, P. L.<br />
IlFarmaco2004, 59, 201.<br />
10. (a) Artico, M.; Silvestri, R.; Stefancich, G.; Massa, S.; Pagnozzi, E.; Musiu, D.; Scintu, F.;<br />
Pinna, E.; Tinti, E.; Colla, P. L. Arch. Pharm. 1995, 328, 223. (b) Artico, M.; Silvestri, R.;<br />
Massa, S.; Loi, A. G.; Corrias, S.; Piras, G.; Colla, P. L. J. Med. Chem. 1996, 39, 522. (c)<br />
Artico, M.; Silvestri, R.; Pagnozzi, E.; Bruno, B.; Novellino, E.; Greco, G.; Massa, S.; Ettorre,<br />
A.; Loi, A. G.; Scintu, F.; Colla, P. L. J. Med. Chem.2000, 43, 1886.<br />
11. Haruna, K.; Kanezaki, H.; Tanabe, K.; Daib, W. M.; Nishimotoa, S. Bioorg. Med. Chem.2006,<br />
14, 4427.<br />
12. (a) Ezawa, M.; Garvey, D. S.; Janero, D. R.; Khanapure, S. P.; Letts, L. G.; Martino, A.;<br />
Ranatunge, R. R.; Schwalb, D. J.; Young, D. V. Let. in Drug Design & Disc.2005, 2, 40. (b)<br />
Ranatunge, R. R.; Augustyniak, M.; Bandarage, U. K.; Earl, R. A.; Ellis, J. L.; Garvey, D. S.;<br />
Janero, D. R.; Letts, L. G.; Martino, A. M.; Murty, M. G.; Richardson, S. K.; Schroeder, J. D.;<br />
Shumway, M. J.; Tam, S. M.; Trocha, A. M.; Young, D. V.; J. Med. Chem. 2004, 47, 2180.<br />
13. Bonacorso, H. G.; Wentz, A. P.; Lourega, R. V.; Cechinel, C. A.; Moraes, T. S.; Coelho, H.<br />
S.; Zanatta, N.; Martins, A.P.; Hoerner , M.; Alves, S. H. J. Fluorine Chem.2006, 127, 1066.<br />
14. Andre, I.; Alcazar, J.; Alonso, J. M.; Lucas, A. I. D.; Iturrino, L.; Biesmansb, I.; Megens, A.<br />
A. Bioorg. Med. Chem. 2006, 14, 4361.<br />
15. Pruitt, J. R.; Pinto, D. J.; Estrella, M. J.; Bostrom, L. L.; Knabb, R. M.; Wong, P. C.; Wright,<br />
M. R.; Wexler, R. R.; Bioorg. Med. Chem. Lett. 2000, 10, 685.<br />
16. Penning, T. D.; Khilevich, A.; Chen, B. B.; Russell, M. A.; Boys, M. L.; Wang, Y.; Duffin, T.;<br />
Engleman, V. W.; Finn, M. B.; Freeman, S. K.; Hanneke, M. L.; Keene, J. L.; Klover, J. A.;<br />
Nickols, G. A.; Nickols. M. A.; Rader, R. K.; Settle, S. L.; Shannon, K. E.; Steininger, C. N.;<br />
Westlinc, M. M.; Westlinc, W. F.; Bioorg. Med. Chem. Lett. 2006, 16, 3156.<br />
17. Musad, E. A.; Mohamed, R.; Saeed, B. A.; Vishwanath, B. S.; Lokanatha Rai, K. M.; Bioorg.<br />
Med. Chem. Lett. 2011, 21, 3536.<br />
18. Lilienkampf, A.; Pieroni, M.; Wan, B.; Wang, Y.; Franzblau, S. G.; Kozikowski, A. P.; J.<br />
Med. Chem. 2010, 53, 2.<br />
19. Neelarapu, R.; Holzle, D. L.; Velaparthi, S.; Bai, H.; Brunsteiner, M.; Blond, S. Y.; Petukhov,<br />
P. A.; J. Med. Chem. 2011, 54, 4350.<br />
20. Barcelo, M.; Ravina, E.; Masaguer. C. F.; Dominguez, E.; Areias, F. M.; Maria, J. B.; Lozab,<br />
I.; Bioorg. Med. Chem. 2007, 17, 4873.<br />
21. Habeeb, A. G.; Rao, P. N.; Knaus, E. E.; J. Med. Chem. 2001, 44, 3039.<br />
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22. Ho, C. Y.; Ludovici, D. W.; Maharoof, U. S. M.; Mei, J.; Sechler, J. L.; Tuman, R. W.;<br />
Strobel, E. D.; Andraka, L.; J. Med. Chem.2005, 48, 8163.<br />
23. Peifer, C.; Abadleh, M.; Bischof, J.; Hauser, D; Schattel, V.; Hirner H., Knippschild, U.;<br />
Laufer, S.; J.Med. Chem. doi: 10.1021/jm9005127<br />
24. Zhang, J.; Yang, P. L.; Gray, N. S.; Nat. Rev. Cancer, 2009, 9, 28.<br />
25. Frølund, B.; Jensen, L. S.; Storustovu, S. I.; Stensbøl, T. B.; Ebert, B.; Kehler, J.; Larsen, P.<br />
K.; Liljefors, T.; J. Med. Chem. 2007, 50, 1988.<br />
26. Krogsgaard-Larsen, P.; Johnston, G. A. R.; Curtis, D. R.; Game, C. J. A.; McCulloch, R. M.;<br />
J. Neurochem. 1975, 25, 803.<br />
27. Larsen, P. K.; Johnston, G. A. R.; Lodge, D.; Curtis, D. R.; Nature. 1977, 268, 53.<br />
28. Frølund, B.; Ebert, B.; Kristiansen, U.; Liljefors, T.;. Larsen, P. K; Curr. Top. Med. Chem.<br />
2002, 2, 817.<br />
29. Mahata, P. K.; SyamKumar, U. K.; Sriram, V.; Junjappa I, H.; Junjappa, H.; Tetrahedron,<br />
2003, 59, 2631.<br />
30. Kuettel, S.; Zambon, A.; Kaiser, M.; Brun, R.; Scapozza, L.; Perozzo, R.; J. Med. Chem.<br />
2007, 50, 5833.<br />
31. Tweedie, S. R.; Schulte J. P.; Synlett, 2007, 15, 2331.<br />
32. Wang, K.; Xiang, D.; Liu, J.;. Pan, W.; Dong, D.; Organic Letters. 2008, 10, 1691. .<br />
33. Musad, E. A.; Rai, K. M. L.; Byrappa,. K.; Int J Biomed Sci. 2010, 6(1), 45-48<br />
34. Singh, C.; Singh, L W.; Indian journal of chem. 2006, 45(B), 959.<br />
35. Flores, Alex F. C.; Zanatta, N.; Rosa, A.; Brondani, S.; Martins, M. A. P.; Tetrahedron Lett ,<br />
2002, 43,5005.<br />
36. Kumar, S.; Ila, H.; Junjappa, H.; Tetrahedron., 2007, 63 10067.<br />
37. Molteni, V.; Hamilton, M. M.; Mao, L.; Crane, C. M.; Termin, A. P.; Wilson, D. M.;<br />
Synthesis., 2002, 12, 1669.<br />
38. Kurz, T.; Widyan, K.;. Elgemeie, G. H.; Phosphorus, Sulfur, and Silicon, 2006, 181, 299.<br />
39. Elgemeie, G. H.; Elghandour, A. H.; Elaziz, G. W.; Ahmed, S. A.; J. Chem. Soc. Perkin<br />
Trans., 1997, 1, 3285.<br />
40. Waldo, J. P.;. Larock, R. C.; Organic Letters, 2005, 7, 5203.<br />
41. Burkhart, D. J.; Zhou, P.; Blumenfeld, A.; Twamley, B.; Natale, N. R.; Tetrahedron 2001, 57,<br />
8039.<br />
42. Lautens, M.; Roy, A.; Organic Letters, 2000, 2 (4), 555.<br />
43. Ma, W.; Peterson, B.; Kelson, A.; Laborde, E.; J. Comb. Chem., 2009, 11 (4), 697.<br />
44. Dieter, R. K.; Tetrahedron, 1986, 42, 3029.<br />
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46. Savant, M. M.; Pansuriya, A. M.; Bhuva, C.V.; Kapuriya, N.; Patel, A. S.; Audichya, V. B.;<br />
Pipaliya, P. V.; Naliapara, Y. T.; J. Comb. Chem., 2010, 12, 176.<br />
Department of Chemistry <strong>Saurashtra</strong> university, Rajkot-360005 120
Chapter - 4<br />
Synthesis and Characterization of<br />
Novel Substituted and Fused<br />
Pyrazolo[1,5-a] pyrimidines Derivatives
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
4.1 Introduction<br />
Biaryls and heterobiaryls have attracted significant attention from the<br />
scientific community because of their relevance in medicinal chemistry. Heterobiaryls<br />
frequently can be observed in numerous bioactive small molecules, and in particular,<br />
heterobiaryls fused with various heterocycles, such as pyrazole, pyridine, and<br />
pyrimidine, have been used as key pharmacophores. 1 Pyrazolo[1,5-a]pyrimidines have<br />
attracted considerable interest because of their biological activity. For instance, this<br />
heterocyclic system is found as purine analogues and has useful properties as<br />
antimetabolites in purine biochemical reactions. 2 Several compounds of this class<br />
display interesting antitrypanosomal 3 and antischistosomal activities. 4 They are used<br />
as HMG-CoA reductaseinhibitors, 5 COX-2 selective inhibitors, 6 30,50-cyclic-AMP<br />
phosphodiesteraseinhibitors, 7 CRF 1 antagonists, 8a-d selective peripheral<br />
benzodiazepine receptor ligands, 9a-c<br />
potassium channel 10 and histamine-3 receptor<br />
ligands 11 and antianxiety agents. 12<br />
Some pyrazolopyrimidines serve as efficient sedative-hypnotic and anxiolytic<br />
drugs like zaleplon (Sonata, hypnotic), 13 indiplon (hypnotic), 14<br />
and ocinaplon<br />
(anxiolytic), 15 fasiplon (anxiolytic), 16 (Figure-1) these drugs are related to the class of<br />
nonbenzodiazepines, and their therapeutic effect is due to allosteric enhancement of<br />
the action of the inhibitory neurotransmitter GABA at the GABA A receptor. 13-14 These<br />
examples emphasize the importance of pyrazol-fused heterobiaryls, as well as<br />
pyrazolopyridines, as key pharmacophores in bioactive small molecules.<br />
N<br />
O<br />
N<br />
N N CN<br />
N<br />
N<br />
N N<br />
O<br />
N<br />
N<br />
O<br />
N N N<br />
O<br />
S<br />
O<br />
N<br />
N<br />
N<br />
N<br />
N O<br />
Zaleplon<br />
Ocinaplon<br />
Indiplon<br />
Fasiplon<br />
Figure-1<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 121
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
4.2 Biological activity related to pyrazolopyrimidine derivatives<br />
Pyrazolopyrimidines have multiple pharmacological activities including<br />
hypnotic, anti-inflammatory, anti-tumor, antimycobacterial, antidiabetic,<br />
antiphlogistic agents, antidepressants, analgesics and anti-viral. Several diverse<br />
biological activities have been reported for pyrazolopyrimidine ring systems which<br />
are described as below.<br />
Ivashchenko et al. 17 reported that substituted 3-(arylsulfonyl)pyrazolo[1,5-a]<br />
pyrimidines (Figure-2) are claimed as antagonists of serotonin 5-HT6 receptors for<br />
treating and preventing pathol. states and diseases of the central nervous system in<br />
humans and warm-blooded animals, the pathogenesis of which is caused by disorder<br />
in the serotonin 5-HT6 receptor activation.<br />
Figure-2<br />
Alexandre V. Ivachtchenko et al. 18 has described structure activity<br />
relationships for a series of novel 2-substituted 3-benzenesulfonyl-5,6-dimethylpyrazolo[1,5-a]pyrimidines.<br />
In spite of a wide, four orders of magnitude, SAR range<br />
(Ki varied from 260 pM to 2.96 mM), no significant correlation of 5-HT 6 R<br />
antagonistic potency was observed with major physiochemical characteristics, such as<br />
molecular weight, surface polar area, cLogP, or number of rotatable bonds.<br />
Statistically significant trend was only observed for size of substitute group, which<br />
was not enough to explain the deep SAR trend. Besides with the substitute group size,<br />
another factor that presumably plays a role in defining the compound potencies isa<br />
relative position of the heterocycle and sulfophenyl moieties. Among all synthesized<br />
derivatives, (3 benzenesulfonyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methylamine<br />
(Figure-3) is the most potent(Ki ¼ 260 pM) and extremely selective, 5000 to<br />
>50,000-fold relative to 55 therapeutic targets, antagonist of the 5-HT 6 receptor.<br />
Figure-3<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 122
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Synthesis of highly substituted pyrazolopyrimidine<br />
Silvia Selleri et al. 19 have been developed a new class of N,N-diethyl-(2-<br />
arylpyrazolo[1,5-a]pyrimidin-3-yl)acetamides, (Figure-4) as azaisosters of Alpidem,<br />
and their affinities for both the peripheral (PBR) and the central (CBR)<br />
benzodiazepine receptors were evaluated. Binding assays were carried out using both<br />
[ 3 H]PK 11195 and [ 3 H]Ro 5-4864 as radio ligands for PBR, whereas [ 3 H]Ro 15-1788<br />
was used for CBR, in rat kidney and rat cortex, respectively. The tested compounds<br />
exhibited a broad range of binding affinities from as low as 0.76 nM to inactivity and<br />
most of them proved to be high selective ligands for PBR. The preliminary SAR<br />
studies suggested some of the structural features required for high affinity and<br />
selectivity; particularly the substituent on the pyrimidine moiety seemed to play an<br />
important role in PBR versus CBR selectivity. A subset of the highest affinity<br />
compounds was also tested for their ability to stimulate steroid biosynthesis in C6<br />
glioma rat cells and some of these were found to increase pregnenolone formation<br />
with potency similar to RO 5-4864 and PK 11195.<br />
Figure-4<br />
John E. Tellew et al. 20 has discovered an antagonist of the corticotropinreleasing<br />
factor (CRF) neuropeptide may prove effective in treating stress and anxiety<br />
related disorders. In an effort to identify antagonists with improved physico-chemical<br />
properties a new series of CRF1 antagonists were designed to substitute the propyl<br />
groups at the C7 position of the pyrazolo[1,5-a]pyrimidine core with heterocycles.<br />
Compound (Figure-5) was identified as a high affinity ligand with a pKi value of 8.2<br />
and a functional CRF1 antagonist with IC 50 value of 7.0 in the in vitro CRF ACTH<br />
production assay.<br />
N<br />
O<br />
N<br />
H<br />
N<br />
N<br />
N<br />
N<br />
R<br />
O<br />
Figure-5<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 123
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Synthesis of highly substituted pyrazolopyrimidine<br />
Song Qing Wang et al. 21 have been designed some new 5-methyl-7-<br />
substituted–pyrazolo[1,5-a]pyrimidine-3-carbonitrile derivatives on the basis of the<br />
Zaleplon structure for studies on their hypnotic activity. The preliminary<br />
pharmacological evaluations indicated that some compounds showed hypnotic<br />
activity, among that one compound (Figure-6) was the most potent one.<br />
Figure-6<br />
Robert H. Springer et al. 22 has prepared a number of 3,7-disubstituted 6-<br />
carbethoxypyrazolo[ 1,5-a]pyrimidines and 3,7-disubstituted 6-ethoxypyrazolo-[1,5-<br />
a]pyrimidines (Figure-7) have been and evaluated as adenosine cyclic 3’,5’-<br />
phosphate (cAMP) phosphodiesterase (PDE) inhibitors vs. the low K, enzyme isolated<br />
from beef heart, rabbit lung, and kidney preparations. The results were found to be<br />
between 0.5 to 13 times as potent as theophylline as inhibitors of PDE, depending on<br />
the tissue source. A number of these PDE inhibitors exhibited significant<br />
physiological effects in different animal systems, suggesting it should be possible to<br />
obtain selective PDE inhibition in various tissues. Several of these heterocycles were<br />
found superior to adenosine in inhibiting ADP-induced platelet aggregation in vitro.<br />
N<br />
R 1<br />
N<br />
R 1<br />
O<br />
R 2<br />
N<br />
N<br />
R 1 =H, C 2 H 5 ,NO 2 , Br, COOEt<br />
R 2 =OH, NH 2 ,OC 2 H 5 ,SH,SC 2 H 5<br />
Figure-7<br />
Robin R. Frey et al. 23 have discovered 7-aminopyrazolo[1,5-a]pyrimidine urea<br />
receptor tyrosine kinase inhibitors. Investigation of structure-activity relationships of<br />
the pyrazolo[1,5-a]pyrimidine nucleus led to a series of 6-(4-N,N′-diphenyl)ureas that<br />
potently inhibited a panel of vascular endothelial growth factor receptor (VEGFR)<br />
and platelet-derived growth factor receptor (PDGFR) kinases. Several of these<br />
compounds are potent inhibitors of kinase insert domain-containing receptor tyrosine<br />
kinase (KDR) both enzymatically(
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
In addition, compound (Figure-8) possesses a favorable pharmacokinetic profile and<br />
demonstrates efficacy in the estradiol-induced murine uterine edema (UE) model<br />
(ED 50 ) 1.4mg/kg).<br />
Figure-8<br />
Rui Ding et al. 24 has synthesized compound 5-((2-aminoethylamino)methyl)-<br />
7-(4-bromoanilino)-3-cyanopyrazolo[1,5-a]pyrimidine (ABCPP) via conjugated with<br />
N-mercaptoacetylglycine (MAG), N-mercaptoacetylphenylalanine (MAF) and N-<br />
mercaptoacetylvaline (MAA), (Figure-9) respectively. These three compounds were<br />
labeled successfully with [ 99m TcN] 2+ intermediate in high radiochemical purities.<br />
Biodistribution in tumor-bearing mice demonstrated that the three new complexes<br />
showed tumor accumulation, high tumor-to muscle (T/M) ratios and fast clearance<br />
from blood and muscle. Among them, the 99mTcNMAG-ABCPP showed the most<br />
favorable characteristics, with tumor/blood and tumor/muscle ratios reaching 1.51 and<br />
2.97 at 30 min post-injection, 1.84 and 2.49 at 60 min post-injection, suggesting it<br />
could be further studied as potential tumor imaging agent for single photon emission<br />
computed tomography (SPECT).<br />
Figure-9<br />
Osama M. Ahmed et al. 25 has synthesized some new pyrazolo[1,5-<br />
a]pyrimidine derivatives, (Figure-10) which showed potent anti-tumor cytotoxic<br />
activity in vitro using different human cancer cell linesHepG2 (hepatocellular<br />
carcinoma cell line), MCF7 (breastcarcinoma cell line), HCT116 (colon carcinoma<br />
cell line), HeLa (cervix carcinoma cell line).<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 125
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Synthesis of highly substituted pyrazolopyrimidine<br />
Figure-10<br />
Naveen Mulakayala et al. 26 has synthesized some new 7-trifluoromethyl<br />
substituted pyrazolo[1,5-a]pyrimidines (Figure-11) with potent antitumor agents. The<br />
cytotoxic effects of the newly synthesized pyrazolo[1,5-a]pyrimidines against<br />
leukemiacells, K562 and human colon carcinoma cells, Colo-205 were evaluated.<br />
R 2<br />
R 1<br />
OH<br />
R 1<br />
R 2 O<br />
OH<br />
N<br />
O<br />
N<br />
N<br />
N<br />
N<br />
N<br />
CF 3<br />
R 1 =H, R 2 =H,Cl,Br,F,Me<br />
Figure-11<br />
CF 3<br />
4.3 Various synthetic approaches for substituted<br />
pyrazolopyrimidine derivatives<br />
As mention previously, pyrazolopyrimidine ring system is present in a variety<br />
of biologically active compounds (both naturally-occurring and synthetic). Although a<br />
large number of methods for their synthesis have been documented in the literature,<br />
many of them require multistep procedures using intermediates which are not readily<br />
available. Among them, few methods are discussed here.<br />
Abbas-Temirek, H. H. synthesized some new bridged nitrogen pyrazolo[1,5-<br />
a]pyrimidines from 5-amino-3-methylthio-1H-pyrazole-4-carboxylate (Figure-12)<br />
under refluxing with acetic acid. 27<br />
Figure-12<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 126
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
Yan-Chao Wu et al. 28 were established an efficient, fast and facile<br />
pyrazolo[1,5-a]pyrimidine (Figure-13) synthetic protocol for the condensation of<br />
aminopyrazoles with 1,3-dicarbonyl components in AcOH/H 2 SO 4 system.<br />
Figure-13<br />
G. G. Danagulyan et al. 29 have described condensation of ethyl 3-<br />
aminopyrazole-4-carboxylate (1) with ethyl ethoxymethylenecyanoacetate (2) was<br />
carried out with the aim of preparing diethyl 7-aminopyrazolo[1,5-a]pyrimidine-3,6-<br />
dicarboxylate (3) and subsequent study of its C–C recyclization to the isomeric 6-<br />
carbamoyl-7-hydroxypyrazolopyrimidine but the reaction did not go to completion,<br />
on the basis of NMR it was clear that a mixture of compounds including both the<br />
cyclization product (3)and the uncyclized condensation adduct ethyl 3-[(2-cyano-3-<br />
ethoxy-3-oxoprop-1-en-1-yl)amino]-1H-pyrazole-4-carboxylate (4) had been<br />
obtained. However, in basic medium both the condensed pyrazolopyrimidine (3) and<br />
the cyano derivative (4) were converted in high yield to the 6-carbamoyl-7-<br />
hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylic acid (5) (Figure-14).<br />
Figure-14<br />
Li Ming et al. 30 was reported a convenient, rapid, and highly selective method<br />
for synthesis of new Pyrazolo[1,5-a]pyrimidines (Figure-15) via the Reaction of<br />
enaminones and5-amino-1H-pyrazoles under Microwave Irradiation.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 127
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Synthesis of highly substituted pyrazolopyrimidine<br />
Figure-15<br />
Abraham Thomas et al. 31 has described a facile highly regioselective general<br />
route to substituted and fused pyrazolo[a]pyrimidines via cyclocondensation of<br />
oxoketene dithioacetals with 3-aminopyrazoles (Figure-16).<br />
Figure-16<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 128
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
Pushpak Mizar et al. 32 have been described a facile method for the synthesis of<br />
pyrazolo[1,5-a]pyrimidine (Figure-17) by reacting N-substituted or unsubstitutedpyrazol-5(4H)-one,<br />
aryl-oxoketene dithioacetals and alkyl amide.<br />
Figure-17<br />
Recently, Ibtissam Bassoude et al. 33 described one step condensation reaction<br />
of of 5(3)-amino-3(5)-arylpyrazoles with 4-hydroxy-6-methylpyran-2-one leading to<br />
new pyrazolo[1,5-a]pyrimidines(Figure-18).<br />
Figure-18<br />
V. N. Britsun was reported cyclocondensation products of N-aryl-3-<br />
oxobutanethioamides with 5-amino-3-R-4-R 1 -pyrazoles are 4-(arylamino)-2-methyl-<br />
7-R-8-R 1 -pyrazolo[1,5-a]pyrimidine and pyrazolo[1,5-a]pyrimidine-4-thione<br />
derivatives (Figure-19), the ratio of which depends on the nucleophilicity of the<br />
starting 5-amino-3-R-4-R 1 - pyrazoles and the presence of a proton donor solvent. 34<br />
Figure-19<br />
D. V. Kryl’skii et al. 35 has described Three-component condensation of 3-<br />
methyl(or methoxymethyl)-4-phenyl-1H-pyrazol-5-amine with triethylorthoformate<br />
and carbonyl compounds or nitriles containing an activated methylene group<br />
(cyclohexane-1,3-diones, acetoacetanilides, benzoylacetone, ethyl cyanoacetate,<br />
malononitrile, 1H-benzimidazol-2-yl-acetonitrile) gave substituted<br />
pyrazolopyrimidines (Figure-20).<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 129
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
Figure-20<br />
Sayed A. Ahmed et al. 36 have synthesized pyrazolo[1,5-a]pyrimidines from<br />
the appropriate 3-aminopyrazoles with the appropriate sodium (3-oxocycloalkylidene)<br />
methenolate, β-diketone, β-keto esters or 1,2-disubstitutedacrylonitrile (Figure-21).<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 130
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
Figure-21<br />
Mohamed R. Shaaban et al. 37 have described a simple, facile, efficient and one<br />
pot three-component procedure for the synthesis of pyrazolo[1,5-a]pyrimidine ring<br />
systems incorporating phenylsulfonyl moiety was developed via the reaction of 1-<br />
aryl-2-(phenylsulfonyl)ethanone derivatives with the appropriate heterocyclic amine<br />
and triethylorthoformate (Figure-22).<br />
Figure-22<br />
Baseer M. Shaikh et al. 38 has prepared pyrazolo [1, 5-a] pyrimidines derivative by the<br />
condensation of substituted of α, β- unsaturated carbonyl compounds (chalcones) with<br />
substituted 5-aminopyrazole as an alternative polyethylene glycol (PEG-400) as green<br />
reaction medium (Figure-23).<br />
Figure-23<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 131
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
4.4 Current research work<br />
The pyrazolopyrimidine derivatives have considerable chemical and<br />
pharmacological importance because of a broad range of biological activities<br />
displayed by these classes of molecules. As we demonstrated, the tremendous<br />
biological potential of pyrazolopyrimidine derivatives encouraged us to synthesize<br />
some new highly functionalized pyrazolopyrimidine derivatives. Various<br />
methodologies have been described for the synthesis of pyrazolopyrimidine<br />
derivatives. However, the existing methods are suffer with some drawbacks, such as;<br />
yield, time, product isolation, isomer formation.<br />
As a part of our ongoing interest on the synthesis of various heterocyclic<br />
compounds using ketene dithioacetals, we have demonstrated that ketene dithioacetals<br />
are versatile intermediate for the synthesis of pyrazolopyrimidine derivatives. Thus, to<br />
explore further, we sought that the reaction of various ketene dithioacetals with 5-<br />
amino-N-cyclohexyl-3-(methylthio)-1H-pyrazole-4-carboxamide in the presence of<br />
base in isopropyl alcohol could be an effective strategy to furnish the novel<br />
pyrazolopyrimidine derivatives. Here we describe the novel synthetic methodology<br />
for the fused pyrazolopyrimidines.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 132
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
4.5 Results and discussion<br />
Scheme: Synthesis of novel substituted Pyrazolo[1,5-a]pyrimidines derivatives.<br />
Scheme-01<br />
Scheme-02<br />
Scheme-03<br />
Where R= CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 , R 1 = CH 3 , OCH 3 NO 2 ,Cl<br />
Preparation of the target compounds was initiated by the reaction of<br />
ethylcynoacetate (1) with cyclohexyl amines (2) in toluene at reflux temperature to<br />
afford the cyanoacetamides (3) in 90% yields. This product undergoes reaction with<br />
carbon disulfide in the presence of base in DMF followed by methylation to afford<br />
corresponding 2-cyano-3,3-bis(methylthio)-N-phenylacrylamide (4). Which on<br />
reaction with hydrazine hydrate undergoes cyclization to form 5-amino-N-cyclohexyl-<br />
3-(methylthio)-1H-pyrazole-4-carboxamide (5) (Scheme-1).<br />
Various acetoacetanilide (8a-x) were synthesized by reacting substituted<br />
amine (7a-h) with various β-keto esters (6a-c) in toluene in the presence of catalytic<br />
amount of KOH at reflux temperature for 15-20 h.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 133
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
Twenty four different acetoacetanilide were synthesized bearing various<br />
electron donating and electron withdrawing groups such as 2,3-diCH 3 ; 3,4-diCH 3 ; 4-<br />
CH 3 ; H; 2,5-diCH 3 ; 2,4-diCH 3 ; 3-Cl-4-F; 4-F; 4-Cl; 2-Cl; 2-F; 4-OCH 3 ; 2,5-diCl and<br />
3-NO 2 on the phenyl ring. Thus, it has been found that reaction of substituted<br />
acetoacetanilide 8a-x derivatives with carbon disulfide in the presence of potassium<br />
carbonate followed by the alkylation with methyl iodide (Scheme-2) gave the novel<br />
ketene dithioacetals 9a-x. The resulting various ketene dithioacetals (9a-x) were<br />
reacted with 5-amino-N-cyclohexyl-3-(methylthio)-1H-pyrazole-4-carboxamide (5) in<br />
the presence of NaHCO 3 and methanol as a solvent to afford highly substituted<br />
pyrazolo[1,5-a]pyrimidines (10a-x) in low yield (Table-1 and 2). To optimize the<br />
reaction condition for the synthesis of compound 10a, various solvents and various<br />
bases were utilized. As a result, we found the reaction of 9a with 5 was faster and<br />
afforded the pyrazolo[1,5-a]pyrimidine10a in good yield in the presence of K 2 CO 3 as<br />
a base and isopropyl alcohol (Scheme-3).<br />
Table-1: Reaction of 9a with various solvents in the presence of base.<br />
Entry Solvent Base Time hrs Yield %<br />
1 Methanol NaHCO 3 20 65<br />
2 Ethanol NaHCO 3 18 68<br />
3 Isopropyl alcohol NaHCO 3 16 70<br />
4 Dioxane NaHCO 3 15 58<br />
5 DMF NaHCO 3 10 60<br />
6 Methanol Na 2 CO 3 14 70<br />
7 Ethanol Na 2 CO 3 13 72<br />
8 Isopropyl alcohol Na 2 CO 3 10 78<br />
9 Dioxane Na 2 CO 3 10 75<br />
10 DMF Na 2 CO 3 8 68<br />
11 Methanol K 2 CO 3 10 75<br />
12 Ethanol K 2 CO 3 10 80<br />
12 Isopropyl alcohol K 2 CO 3 8 94<br />
14 Dioxane K 2 CO 3 8 82<br />
15 DMF K 2 CO 3 7 78<br />
16 AcOH CH 3 COONa 8 65<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 134
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
Table-2: synthesis of novel substituted and fused pyrazolopyrimidine derivatives.<br />
Entry R R 1 Time hrs Yield (%)<br />
10a CH 3 4-CH 3 8.0 94<br />
10b CH 3 3-Cl 7.5 92<br />
10c CH 3 3-Cl, 4-F 7.5 90<br />
10d CH 3 4-Cl 7.0 88<br />
10e CH 3 4-F 7.0 92<br />
10f CH 3 4-NO 2 9.0 95<br />
10g CH 3 4-OCH 3 8.0 90<br />
10h CH 3 2,5diCH 3 8.5 89<br />
10i (CH 3 ) 2 CH 4-CH 3 8.0 93<br />
10j (CH 3 ) 2 CH 3-Cl 7.0 87<br />
10k (CH 3 ) 2 CH 3-Cl, 4-F 7.5 95<br />
10l (CH 3 ) 2 CH 4-Cl 7.0 94<br />
10m (CH 3 ) 2 CH 4-F 7.5 92<br />
10n (CH 3 ) 2 CH 4-NO 2 8.5 97<br />
10o (CH 3 ) 2 CH 4-OCH 3 8.0 94<br />
10p (CH 3 ) 2 CH 2,5diCH 3 8.5 90<br />
10q (CH 2 ) 2 CH 4-CH 3 8.5 88<br />
10r (CH 2 ) 2 CH 3-Cl 7.5 92<br />
10s (CH 2 ) 2 CH 3-Cl, 4-F 7.0 87<br />
10t (CH 2 ) 2 CH 4-Cl 7.5 90<br />
10u (CH 2 ) 2 CH 4-F 8.0 93<br />
10v (CH 2 ) 2 CH 4-NO 2 8.5 96<br />
10w (CH 2 ) 2 CH 4-OCH 3 7.5 90<br />
10x (CH 2 ) 2 CH 2,5diCH 3 8.0 87<br />
The structures of compound 5 were established on the basis of their elemental<br />
analysis and spectral data (MS, IR, and 1 H NMR). The analytical data for 5 revealed a<br />
molecular formula C 11 H 18 N 4 OS (m/z 254). The 1 H NMR spectrum revealed a<br />
multiplets at δ = 1.20-1.98 assigned to 10 protons of (5x CH 2 ) groups in cyclohexane<br />
ring, a singlet at δ = 2.48 ppm assigned to - SCH 3, a multiplet at δ = 3.96-3.99 ppm<br />
assigned to the –CH protons of cyclohexane ring,<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 135
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
one broad singlet at δ = 5.57 ppm assigned to –NH 2 groups, one singlet at δ = 7.28<br />
ppm assigned to –CONH groups and one broad singlet observed at δ = 11.9 ppm<br />
assigned to pyrazole -NH.<br />
The structures of 9a-x were established on the basis of their elemental analysis<br />
and spectral data (MS, IR, and 1 H NMR). The analytical data for 9i revealed a<br />
molecular formula C 16 H 21 NO 2 S 2 (m/z 323). The 1 H NMR spectrum revealed a singlet<br />
at δ = 1.18-1.20 ppm assigned to isopropyl-CH 3 , a singlet at δ = 1.57 ppm assigned to<br />
the –CH 3 protons, a singlet at δ = 2.44 ppm assigned to (2 × SCH 3 ) , a multiplet at δ =<br />
3.17-3.24 ppm assigned to the isopropyl -CH protons, a multiplets at δ = 6.99–7.54<br />
ppm assigned to the aromatic protons, and one broad singlet at δ = 8.38 ppm assigned<br />
to -CONH groups.<br />
The structures of 10a-x were established on the basis of their elemental<br />
analysis and spectral data (MS, IR, 1 H NMR and 13 C NMR). The analytical data for<br />
10b revealed a molecular formula C 23 H 26 ClN 5 O 2 S 2 (m/z 503). The 1 H NMR spectrum<br />
revealed a multiplets at δ = 1.35-1.81 assigned to 10 protons of (5x CH 2 ) groups in<br />
cyclohexane ring, a singlet at δ = 2.45 ppm assigned to - SCH 3, a singlet at δ = 2.70<br />
ppm assigned to - CH 3, a multiplet at δ = 3.79 ppm assigned to the –CH protons of<br />
cyclohexane ring, a multiplet at δ = 7.05–8.00 ppm assigned to the aromatic protons,<br />
one singlet at δ = 8.56 ppm assigned to –CONH groups attached with cyclohexane<br />
ring, and one singlet observed at δ = 12.56 ppm assigned to –CONH group attached<br />
with phenyl ring.<br />
The proposed mechanism for the cyclization is shown in Figure-24. The<br />
endocyclic-NH in compound A is the most nucleophilic center it is also the most<br />
sterically hindered site. Therefore, addition takes place at the exocyclic-NH 2 groups.<br />
The nucleophilic amino group attacks on the double bond via a Michael addition<br />
reaction, followed by loss of the thiomethane group. The intermediate D then cyclizes<br />
with subsequent dehydration E to afford the pyrazolopyrimidine derivative F.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 136
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
<br />
Mechanism:-<br />
S<br />
HN<br />
O<br />
S<br />
HN<br />
O<br />
R<br />
O<br />
R 1<br />
HN<br />
N NH 2<br />
N<br />
NH NH 2<br />
S<br />
S<br />
SCH 3<br />
HN<br />
S O<br />
N<br />
N N<br />
R 1<br />
S<br />
R<br />
F<br />
-H 2 O<br />
S<br />
A<br />
HN<br />
N<br />
N<br />
HO<br />
R 1<br />
R<br />
E<br />
O<br />
H<br />
N<br />
S<br />
B<br />
HN<br />
S<br />
N<br />
NH<br />
O<br />
R 1<br />
D<br />
O<br />
H<br />
N<br />
S<br />
R<br />
-SHCH 3<br />
N<br />
H<br />
O<br />
S<br />
H<br />
H S<br />
N<br />
NH<br />
N<br />
C<br />
O<br />
R<br />
R 1<br />
Figure 24: Proposed mechanism for the formation of pyrazolopyrimidine.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 137
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
4.6 Conclusion<br />
In summary, the heterocyclizations of various ketene dithioacetals with 5-<br />
aminopyrazole derivative were studied in details, and the influence of the reaction<br />
parameters and the aminoazole structure on the direction of the reaction was<br />
established. We found that the reaction of various ketene dithioacetal 9a-x with 5-<br />
aminopyrazole derivative 5 were faster and afforded the pyrazolo[1,5-a]pyrimidine<br />
10a-x in good yield in the presence of K 2 CO 3 as a base and isopropyl alcohol. The<br />
results of the study described above have led to the development of a simple approach<br />
for synthesis of pyrazolo[1,5-a]pyrimidines, substances that potentially interesting<br />
biological and medicinal properties.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 138
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
4.7 Experimental section<br />
Thin-layer chromatography was accomplished on 0.2-mm precoated plates of<br />
silica gel G60 F 254 (Merck). Visualization was made with UV light (254 and 365nm)<br />
or with an iodine vapor. IR spectra were recorded on a FTIR-8400 spectrophotometer<br />
using DRS prob. 1 H (300 MHz), 1 H (400 MHz), 13 C (75 MHz) and 13 C (100 MHz)<br />
NMR spectra were recorded on a Bruker AVANCE II spectrometer in CDCl 3 and<br />
DMSO. Chemical shifts are expressed in δ ppm downfield from TMS as an internal<br />
standard. Mass spectra were determined using direct inlet probe on a GCMS-QP 2010<br />
mass spectrometer (Shimadzu). Solvents were evaporated with a BUCHI rotary<br />
evaporator. Melting points were measured in open capillaries and are uncorrected.<br />
Synthesis of 2-cyano-N-cyclohexylacetamide (3).<br />
In a 250mL round bottom flask equipped with magnetic stirrer and<br />
thermometer was placed ethyl 2-cyanoacetate (0.25mol), cyclohexyl amine (0.25mol)<br />
and toluene (100 mL). The reaction mixture was heated up to 110-115 o C for 8 h. The<br />
progress of reaction was monitored by thin layer chromatography. The reaction<br />
mixture was cooled to room temperature and the solid product was filtered, washed<br />
with toluene to afford 90% yield.<br />
Synthesis of 2-cyano-N-cyclohexyl-3,3-bis(methylthio)acrylamide (4).<br />
A 100mL conical flask equipped with magnetic stirrer and septum was<br />
charged with a solution of 2-cyano-N-cyclohexylacetamide (3), (10 mmol) in DMF<br />
(10 mL). Dry K 2 CO 3 (10 mmol) was added and the mixture was stirred at room<br />
temperature for 2 h. CS 2 (30 mmol) was added and the mixture was stirred for an<br />
additional 2 h at room temperature. Then, methyl iodide (20 mmol) was added at 0-5<br />
o C and the mixture was stirred for 4 h at room temperature. The progress of the<br />
reaction was monitored by thin layer chromatography. After completion of the<br />
reaction, it was poured into 50ml cold water. The precipitated crude product was<br />
purified by filtration followed by crystallization from EtOH.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 139
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
Synthesis of 5-amino-N-cyclohexyl-3-(methylthio)-1H-pyrazole-4-<br />
carboxamide (5).<br />
A 100mL conical flask equipped with magnetic stirrer and septum was<br />
charged 2-cyano-N-cyclohexyl-3,3-bis(methylthio)acrylamide (4) (0.1mol) in<br />
isopropyl alcohol (100 mL) and hydrazine hydrate (0.1mol). The Reaction mixture<br />
was heated to reflux for 2 h. After completion of the reaction, it was poured into<br />
50mL cold water. The precipitated crude product was purified by filtration followed<br />
by crystallization from EtOH.<br />
<br />
General synthesis of Acetoacetanilide derivatives (AAA) (8a-x).<br />
A mixture containing the primary amine (7a-h) (10 mmol), β-keto esters (6ac)<br />
(10 mmol), and catalytic amount of sodium or potassium hydroxide (10 %) in<br />
toluene (50 mL) was refluxed at 110 o C for 12-15 h. The reaction was monitored by<br />
TLC. After completion of reaction, the solvent was removed under vaccuo and the<br />
residue was crystallized from methanol.<br />
General synthesis of ketene dithioacetals (9a-x).<br />
A 100mL conical flask equipped with magnetic stirrer and septum was<br />
charged with a solution of acetoacetanilide derivatives (8a-x) (10 mmol) in DMF (10<br />
mL). Dry K 2 CO 3 (20 mmol) was added and the mixture was stirred for 2 h at room<br />
temperature. CS 2 (10 mmol) was then added and the mixture was stirred for an<br />
additional 2 h at room temperature. Methyl iodide (20 mmol) was added at 0-5 o C and<br />
the mixture was stirred for 4 h at room temperature. The reaction was monitored by<br />
TLC. After completion, reaction mixture poured into water (50 mL). The precipitated<br />
crude product was purified by filtration followed by crystallization from EtOH.<br />
General synthesis of substituted and fused pyrazolopyrimidines (10a-x).<br />
A mixture of 5-amino-N-cyclohexyl-3-(methylthio)-1H-pyrazole-4-<br />
carboxamide (5) (3.0mmol), potassium carbonate (6.0mmol) and ketene dithioacetals<br />
(9a-x) (3.0mmol) in isopropyl alcohol (10 mL) was heated to reflux for 7-10 h. The<br />
progress of reaction mixture was monitored by TLC. After completion of reaction, the<br />
mixture was cooled to room temperature and solid residue was filtered and washed<br />
with 10mL of isopropyl alcohol followed by 50 ml of water. The product was<br />
crystallized from MeOH to give 10a-x in 87-97% yield.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 140
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
<br />
Spectral data of newly synthesized compounds<br />
2-(bis(methylthio) methylene)-4-methyl-3-oxo-N-p-tolylpentanamide 9i. yellow<br />
solid; mp 155-158 ° C; R f 0.54 (8:2 hexane-EtOAc); IR (KBr): 3373, 3072, 2895, 2828,<br />
1694, 1635, 1482, 1343, 1298 cm -1 ; 1 H NMR (400 MHz, DMSO): δ 1.18-1.20 (m,<br />
6H, 2 × i prCH 3 ), 1.57 (s, 3H, CH 3 ), 2.44 (s, 6H, 2 × SCH 3 ), 3.17-3.24 (m, 1H, i prCH),<br />
6.99–7.54 (m, 4H, Ar), 8.38 (br, s, 1H, -CONH); MS (m/z):323 [M + ];Anal. Calcd for<br />
C 16 H 21 NO 2 S 2 : C, 59.41; H, 6.54; N, 4.33; Found: C, 59.33; H, 6.45; N, 4.23.<br />
2-(bis(methylthio)methylene)-N-(4-methoxyphenyl)-4-methyl-3-oxopentanamide<br />
9o. yellow solid; mp 169-171 ° C; R f 0.57 (8:2 hexane-EtOAc); IR (KBr): 3439, 3007,<br />
2928, 2808, 1599, 1462, 1327, 1255 cm -1 ; 1 H NMR (400 MHz, DMSO): δ 1.18-1.20<br />
(m, 6H, 2 × i prCH 3 ), 2.44 (s, 6H, 2 × SCH 3 ), 3.17-3.24 (m, 1H, i prCH), 3.75 (s, 3H,<br />
OCH 3 ), 6.99–7.54 (m, 4H, Ar), 8.38 (br, s, 1H, -CONH); MS (m/z):339 [M + ];Anal.<br />
Calcd for C 16 H 21 NO 3 S 2 : C, 56.61; H, 6.24; N, 4.13; Found: C, 56.53; H, 6.14; N, 4.06.<br />
N-(4-chlorophenyl)-2-(cyclopropylcarbonyl)-3,3-bis(methylsulfanyl)prop-2-<br />
enamide 9t. Yello solid; mp 138-140 ° C, R f 0.52 (8:2 hexane-EtOAc); IR (KBr): 3364,<br />
2927, 1674, 1533, 1462, 1281, 1112, 873 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 1.02-<br />
1.06 (m, 2H, CH 2 ), 1.21-1.24 (m, 2H, CH 2 ), 2.37-2.43 (m, 1H, CH), 2.47 (s, 6H, 2x<br />
SCH 3 ), 7.26-7.29 (d, 2H, j=9.6Hz, Ar-H), 7.53-7.55 (d, 2H, j=8.7Hz, Ar-H), 8.69 (s,<br />
1H, NH); MS (m/z): 342 (M + ); Anal. Calcd for C 15 H 16 ClNO 2 S 2 : C, 52.70; H, 4.72; N,<br />
4.10; Found: C, 52.72; H, 4.75; N, 4.12.<br />
2-(Cyclopropylcarbonyl)-N-(4-methoxyphenyl)-3,3-bis(methylsulfanyl)prop-2-<br />
ena- mide 9w. Yello solid; mp 154-156 ° C, R f 0.61 (8:2 hexane-EtOAc); IR (KBr):<br />
3354, 2925, 1684, 1525, 1450, 1285, 1112, 880, 753 cm -1 ; 1 H NMR (300 MHz,<br />
CDCl 3 ): δ 1.02-1.04 (m, 2H, CH 2 ), 1.22 (m, 2H, CH 2 ), 2.39-2.42 (m, 1H, CH), 2.47<br />
(s, 6H, 2x SCH 3 ), 3.84 (s, 3H, OCH 3 ), 6.85-6.88 (d, 2H, j=8.7Hz, Ar-H), 7.48-7.51<br />
(d, 2H, j=8.7Hz, Ar-H), 8.35 (s, 1H, NH); MS (m/z): 337 (M + ); Anal. Calcd for<br />
C 16 H 19 NO 3 S 2 : C, 56.95; H, 5.68; N, 4.15; Found: C, 56.92; H, 5.65; N, 4.12.<br />
N 3 -cyclohexyl-7-methyl-2,5-bis(methylthio)-N 6 -p-tolylpyrazolo[1,5-a]pyrimidine-<br />
3,6-dicarboxamide 10a. White solid; mp >320 o C, R f 0.31 (9:1Chloroform:<br />
Methanol); IR (KBr): 3309, 3254, 3016, 2925, 1671, 1473, 831, 807, 758 cm -1 ;<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 141
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
MS (m/z): 484 (M + ); Anal. Calcd for C 24 H 29 N 5 O 2 S 2 : C, 59.60; H, 6.04; N, 14.48;<br />
Found: C, 59.56; H, 6.03; N, 14.45.<br />
N 6 -(3-chlorophenyl)-N 3 -cyclohexyl-7-methyl-2,5-bis(methylthio)pyrazolo[1,5-a]<br />
pyrimidine-3,6-dicarboxamide 10b. Creamish solid; mp >320<br />
o C, R f 0.40<br />
(9:1Chloroform : Methanol); IR (KBr): 3379, 3024, 2902, 1651, 1516,1483, 1332,<br />
845, 800, 756, 695 cm -1 ; 1 H NMR (300 MHz, DMSO): δ 1.35-1.81 (m, 10H,CH 2 ),<br />
2.45 (s, 6H, SCH 3 ), 2.70 (s, 3H, CH3), 3.79 (m, 1H, CH), 7.05 (s, 1H, Ar-H), 7.31-<br />
7.35 (m, 2H, Ar-H), 8.0 (s, 1H, AR-H), 8.56 (s, 1H, CONH), 12.56 (s, 1H, CONH);<br />
13 C NMR (100 MHz, DMSO): 12.40, 23.86, 25.34, 27.54, 30.54, 32.55, 45.86, 98.23,<br />
98.89, 117.29, 118.69, 121.70, 129.88, 133.31, 141.26, 148.07, 154.00, 158.20,<br />
161.85, 163.79, 165.67; MS (m/z): 503 (M + ); Anal. Calcd for C 23 H 26 ClN 5 O 2 S 2 : C,<br />
54.80; H, 5.20; N, 13.89; Found: C, 54.81; H, 5.24; N, 13.89.<br />
N 6 -(3-chloro-4-fluorophenyl)-N 3 -cyclohexyl-7-methyl-2,5-bis(methylthio)<br />
pyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide 10c. White solid; mp >320 ° C, R f<br />
0.48 (9:1Chloroform: Methanol); IR (KBr): 3323, 3026, 2908, 2856, 1674, 1630,<br />
1563, 1473, 1246, 927, 843, 798, 732, cm -1 ; MS (m/z): 522 (M + ); Anal. Calcd for<br />
C 23 H 25 ClFN 5 O 2 S 2 : C, 52.91; H, 4.83; N, 13.41; Found: C, 52.96; H, 4.83; N, 13.45.<br />
N 6 -(4-chlorophenyl)-N 3 -cyclohexyl-7-methyl-2,5-bis(methylthio)pyrazolo[1,5-a]<br />
pyrimidine-3,6-dicarboxamide 10d. Creamish solid; mp >320<br />
° C, R f 0.35<br />
(9:1Chloroform: Methanol); IR (KBr): 3379, 3024, 2902, 1651, 1516, 1483, 1332,<br />
1166, 954, 852, 822, 748, 709 cm -1 ; MS (m/z): 503 (M + ); Anal. Calcd for<br />
C 23 H 26 ClN 5 O 2 S 2 : C, 54.80; H, 5.20; N, 13.89; Found: C, 54.81; H, 5.24; N, 13.89.<br />
N 3 -cyclohexyl-N 6 -(4-fluorophenyl)-7-methyl-2,5-bis(methylthio)pyrazolo[1,5-a]<br />
pyrimidine-3,6-dicarboxamide 10e. White solid; mp >320<br />
° C, R f 0.28<br />
(9:1Chloroform: Methanol); IR (KBr): 3430, 3133, 3051, 2922, 1651, 1516, 1483,<br />
1232, 1166, 954, 883, 780, 743, 698 cm -1 ; MS (m/z): 487 (M + ); Anal. Calcd for<br />
C 23 H 26 FN 5 O 2 S 2 : C, 56.65; H, 5.37; N, 14.36; Found: C, 56.61; H, 5.34; N, 14.39.<br />
N 3 -cyclohexyl-7-methyl-2,5-bis(methylthio)-N 6 -(4-nitrophenyl)pyrazolo[1,5-a]<br />
pyrimidine-3,6-dicarboxamide 10f. Yellow solid; mp >320 ° C, R f 0.29 (9:1<br />
Chloroform: Methanol); IR (KBr): 3421, 3122, 3088, 2922, 1651, 1516, 1483, 1232,<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 142
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
1166, 954, 883, 780, 743, 698 cm -1 ; MS (m/z): 514 (M + ); Anal. Calcd for<br />
C 23 H 26 N 6 O 4 S 2 : C, 53.68; H, 5.09; N, 16.33; Found: C, 53.67; H, 5.04; N, 16.36.<br />
N 3 -cyclohexyl-N 6 -(4-methoxyphenyl)-7-methyl-2,5-bis(methylthio)pyrazolo[1,5-a]<br />
pyrimidine-3,6-dicarboxamide 10g. Creamish solid; mp >320 ° C, R f 0.36 (9:1<br />
Chloroform: Methanol); IR (KBr): 3422, 3127, 3085, 2942, 1628, 1483, 1237, 1158,<br />
883, 780, 743 cm -1 ; MS (m/z): 499 (M + ); Anal. Calcd for C 24 H 29 N 5 O 3 S 2 : C, 57.69; H,<br />
5.85; N, 14.02; Found: C, 57.67; H, 5.84; N, 14.03.<br />
N 3 -cyclohexyl-7-methyl-N 6 -(2,5-dimethylphenyl)-2,5-bis(methylthio)pyrazolo<br />
[1,5-a]pyrimidine-3,6-dicarboxamide 10h. Creamish solid; mp >320 ° C, R f 0.41<br />
(9:1Chloroform: Methanol); IR (KBr): 3430, 3133, 3051, 2922, 1651, 1516, 1483,<br />
1232, 1166, 954, 883, 780, 743, 698 cm -1 ; MS (m/z): 497 (M + ); Anal. Calcd for<br />
C 25 H 31 N 5 O 2 S 2 : C, 60.33; H, 6.28; N, 14.07; Found: C, 60.35; H, 6.25; N, 14.03.<br />
N 3 -cyclohexyl-7-isopropyl-2,5-bis(methylthio)-N 6 -p-tolylpyrazolo[1,5-a]<br />
pyrimidine-3,6-dicarboxamide 10i. White solid; mp >320<br />
° C, R f 0.35<br />
(9:1Chloroform: Methanol); IR (KBr): 3279, 3254, 3016, 2928, 2850, 1730, 1681,<br />
1566, 1313, 1246, 835, 810, 748, 667 cm -1 ; 1 H NM R(300 MHz, DMSO): δ 1.17-<br />
1.21(d, 6H, 2 × i prCH 3 ), 1.27-1.89 (m, 10H,CH 2 ), 2.48 (s, 6H, SCH 3 ), 2.54 (s, 3H,<br />
CH3), 3.79 (m, 1H, CH), 4.10-4.18 (m, 1H, i prCH), 7.09-7.19 (dd, 1H, Ar-H), 7.53-<br />
7.56 (d, 2H, Ar-H, J=8.1Hz), 8.21-8.23 (d, 1H, CONH), 11.94 (s, 1H, CONH); MS<br />
(m/z): 512 (M + ); Anal. Calcd for C 26 H 33 N 5 O 2 S 2 : C, 61.03; H, 6.50; N, 13.69; Found:<br />
C, 61.05; H, 6.53; N, 13.66.<br />
N 6 -(3-chlorophenyl)-N 3 -cyclohexyl-7-isopropyl-2,5-bis(methylthio)pyrazolo[1,5-<br />
a] pyrimidine-3,6-dicarboxamide 10j. White solid; mp >320<br />
° C, R f 0.44<br />
(9:1Chloroform: Methanol); IR (KBr): 3198, 3157, 3042, 2942, 2832, 1734, 1668,<br />
1654, 1257, 832, 806, 742 cm -1 ; MS (m/z): 532 (M + ); Anal. Calcd for<br />
C 25 H 30 ClN 5 O 2 S 2 : C, 56.43; H, 5.68; N, 13.16; Found: C, 56.45; H, 5.67; N, 13.16.<br />
N 6 -(3-chloro-4-fluorophenyl)-N 3 -cyclohexyl-7-isopropyl-2,5-bis(methylthio)<br />
pyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide 10k. Creamish solid; mp >320 ° C, R f<br />
0.41 (9:1Chloroform: Methanol); IR (KBr): 3398, 3227, 3150, 2902, 2865, 1651,<br />
1516, 1452, 1326, 880, 828, 750, 697 cm -1 ; 1 H NMR(300 MHz, DMSO):<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 143
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
δ 1.27-1.30 (d, 6H, 2 × i prCH 3 ), 1.34-1.89 (m, 10H,CH 2 ), 2.49 (s, 6H, SCH 3 ), 3.74 (m,<br />
1H, CH), 4.10-4.18 (m, 1H, i prCH), 7.31-7.37 (m, 1H, Ar-H), 7.43-7.46 (m, 1H, Ar-<br />
H), 8.10-8.12 (m, 1H, Ar-H), 8.54-8.57 (d, 1H, CONH), 12.02(s, 1H, CONH); MS<br />
(m/z): 550 (M + ); Anal. Calcd for C 25 H 29 ClFN 5 O 2 S 2 : C, 54.58; H, 5.31; N, 12.73;<br />
Found: C, 54.59; H, 5.33; N, 12.76.<br />
N 6 -(4-chlorophenyl)-N 3 -cyclohexyl-7-isopropyl-2,5-bis(methylthio)pyrazolo[1,5-<br />
a]pyrimidine-3,6-dicarboxamide 10l. White solid; mp >320<br />
° C, R f 0.38<br />
(9:1Chloroform: Methanol); IR (KBr): 3425, 3258, 3124, 2998, 2847, 1661, 1532,<br />
1425, 1318, 867, 817, 753, 689 cm -1 ; 1 H NMR (300 MHz, DMSO): δ 1.17-1.19(d,<br />
6H, 2 × i prCH 3 ), 1.27-1.38 (m, 4H,CH 2 ), 1.66-1.89 (m, 6H,CH 2 ), 2.48 (s, 6H, SCH 3 ),<br />
3.79 (m, 1H, CH), 4.10-4.18 (m, 1H, i prCH), 7.32-7.35 (d, 2H, Ar-H, J=8.1Hz), 7.67-<br />
7.70 (d, 1H, Ar-H, J=8.4Hz), 8.53-8.57 (d, 1H, CONH), 11.96(s, 1H, CONH); MS<br />
(m/z): 532 (M + ); Anal. Calcd for C 25 H 30 ClN 5 O 2 S 2 : C, 56.43; H, 5.68; N, 13.16;<br />
Found: C, 56.45; H, 5.67; N, 13.16.<br />
N 3 -cyclohexyl-N 6 -(4-fluorophenyl)-7-isopropyl-2,5-bis(methylthio)pyrazolo[1,5-<br />
a]pyrimidine-3,6-dicarboxamide 10m. Creamish solid; mp >320 ° C, R f 0.45 (9:1<br />
Chloroform: Methanol); IR (KBr): 3454, 3260, 3142, 2978, 2850, 1645, 1542, 1425,<br />
1318, 867, 750 cm -1 ; MS (m/z): 515 (M + ); Anal. Calcd for C 25 H 30 FN 5 O 2 S 2 : C, 58.23;<br />
H, 5.86; N, 13.58; Found: C, 58.25; H, 5.87; N, 13.56.<br />
N 3 -cyclohexyl-7-isopropyl-2,5-bis(methylthio)-N 6 -(4-nitrophenyl)pyrazolo[1,5-<br />
a]pyrimidine-3,6-dicarboxamide 10n. Creamishsolid; mp >320 ° C, R f 0.34<br />
(9:1Chloroform: Methanol); IR (KBr): 3460, 3367, 3242, 2956, 2845, 1647, 1538,<br />
1420, 1318, 867, 750, 700 cm -1 ; MS (m/z): 542 (M + ); Anal. Calcd for C 25 H 30 N 6 O 4 S 2 :<br />
C, 55.33; H, 5.57; N, 15.49; Found: C, 55.35; H, 5.57; N, 15.46.<br />
N 3 -cyclohexyl-7-isopropyl-N 6 -(4-methoxyphenyl)-2,5-bis(methylthio)pyrazolo<br />
[1,5-a]pyrimidine-3,6-dicarboxamide. 10o. White solid; mp >320 ° C, R f 0.23<br />
(9:1Chloroform: Methanol); IR (KBr): 3483, 3242, 3162, 3068, 2902, 1675, 1584,<br />
1425, 1332, 1066, 954, 820, 750 cm -1 ; MS (m/z): 528 (M + ); Anal. Calcd for<br />
C 26 H 33 N 5 O 3 S 2 : C, 59.18; H, 6.30; N, 13.27; Found: C, 59.20; H, 6.32; N, 13.26.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 144
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
N 3 -cyclohexyl-7-isopropyl-N 6 -(2,5-dimethylphenyl)-2,5-bis(methylthio)pyrazolo<br />
[1,5-a]pyrimidine-3,6-dicarboxamide 10p. White solid; mp >320 ° C, R f 0.22<br />
(9:1Chloroform: Methanol); IR (KBr): 3503, 3450, 3206, 3068, 2908, 1628, 1548,<br />
1420, 1342, 1066, 825, 754 cm -1 ; MS (m/z): 525 (M + ); Anal. Calcd for C 27 H 35 N 5 O 3 S 2 :<br />
C, 61.68; H, 6.71; N, 13.32; Found: C, 61.67; H, 6.72; N, 13.36.<br />
N 3 -cyclohexyl-7-cyclopropyl-2,5-bis(methylthio)-N 6 -p-tolylpyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide<br />
10q. Creamish solid; mp >320 ° C, R f 0.35 (9:1Chloroform:<br />
Methanol); IR (KBr): 3460, 3226, 3047, 2938, 1615, 1539, 1422, 1336, 1066, 834,<br />
757 cm -1 ; 1 H NMR (300 MHz, DMSO): δ 0.98-1.01 (m, 4H, 2 ×CH 2 ), 1.16-1.37 (m,<br />
4H, CH 2 ), 1.55-1.89 (m, 6H, CH 2 ), 2.25-2.27 (s, 3H, CH 3 ), 2.43.2.77 (m, 6H, SCH 3 ),<br />
3.64 (m, 2H, CH), 7.09-7.19 (dd, 2H, Ar-H, J=7.8Hz, J=8.4Hz), 7.67-7.70 (d, 1H,<br />
Ar-H, J=8.1Hz), 8.21-8.23 (d, 1H, CONH), 11.96 (s, 1H, CONH); MS (m/z): 509<br />
(M + ); Anal. Calcd for C 26 H 31 N 5 O 2 S 2 : C, 61.27; H, 6.13; N, 13.74; Found: C, 61.25; H,<br />
6.17; N, 13.76.<br />
N 6 -(3-chlorophenyl)-N 3 -cyclohexyl-7-cyclopropyl-2,5-bis(methylthio)pyrazolo<br />
[1,5-a]pyrimidine-3,6-dicarboxamide 10r. White solid; mp >320 ° C, R f 0.43<br />
(9:1Chloroform: Methanol); IR (KBr): 3457, 3345, 3147, 3038, 2952, 1615, 1539,<br />
1422, 1336, 1076, 828, 745 cm -1 ; MS (m/z): 530 (M + ); Anal. Calcd for<br />
C 25 H 28 ClN 5 O 2 S 2 : C, 56.64; H, 5.32; N, 13.21; Found: C, 56.62; H, 5.32; N, 13.24.<br />
N 6 -(3-chloro-4-fluorophenyl)-N 3 -cyclohexyl-7-cyclopropyl-2,5-bis(methylthio)<br />
pyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide 10s. Creamish solid; mp >320 ° C, R f<br />
0.40 (9:1Chloroform: Methanol); IR (KBr): 3448, 3250, 3130, 2948, 2902, 1651,<br />
1516, 1483, 1332, 1166, 850, 772, 705 cm -1 ; MS (m/z): 548 (M + ); Anal. Calcd for<br />
C 25 H 27 ClFN 5 O 2 S 2 : C, 54.78; H, 4.97; N, 12.78; Found: C, 54.76; H, 4.95; N, 12.74.<br />
N 6 -(4-chlorophenyl)-N 3 -cyclohexyl-7-cyclopropyl-2,5-bis(methylthio)pyrazolo<br />
[1,5-a]pyrimidine-3,6-dicarboxamide 10t. Creamish solid; mp >320 ° C, R f 0.46<br />
(9:1Chloroform: Methanol); IR (KBr): 3328, 3248, 3057, 2964, 2926, 1651, 1516,<br />
1483, 1328, 1158, 850, 772 cm -1 ; MS (m/z): 530 (M + ); Anal. Calcd for<br />
C 25 H 28 ClN 5 O 2 S 2 : C, 56.64; H, 5.32; N, 13.21; Found: C, 56.62; H, 5.32; N, 13.24.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 145
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
N 3 -cyclohexyl-7-cyclopropyl-N 6 -(4-fluorophenyl)-2,5-bis(methylthio)pyrazolo<br />
[1,5-a]pyrimidine-3,6-dicarboxamide 10u. White solid; mp >320 ° C, R f 0.23<br />
(9:1Chloroform: Methanol); IR (KBr): 3408, 3340, 3277, 3070, 2928, 2852, 1672,<br />
1556, 1481, 1354, 1251, 1058, 893, 833, 792, 750, 711 cm -1 ; 13 C NMR (100 MHz,<br />
CDCl 3 ): 10.96, 12.35, 13.76, 23.32, 25.29, 46.23, 98.07, 99.87, 114.93, 115.14,<br />
120.80, 120.88, 136.19, 148.46, 153.74, 156.37, 157.47, 158.75, 161.92, 165.71,<br />
166.89; MS (m/z): 513 (M + ); Anal. Calcd for C 25 H 28 FN 5 O 2 S 2 : C, 58.46; H, 5.49; N,<br />
13.63; Found: C, 58.49; H, 5.47; N, 13.64.<br />
N 3 -cyclohexyl-7-cyclopropyl-2,5-bis(methylthio)-N 6 -(4-nitrophenyl)pyrazolo[1,5-<br />
a]pyrimidine-3,6-dicarboxamide 10v. Creamish solid; mp >320 ° C, R f 0.52<br />
(9:1Chloroform: Methanol); IR (KBr): 3422, 3205, 3169, 2964, 2856, 1658, 1522,<br />
1425, 1084, 838, 736 cm -1 ; MS (m/z): 540 (M + ); Anal. Calcd for C 25 H 28 N 6 O 4 S 2 : C,<br />
55.54; H, 5.22; N, 15.54; Found: C, 55.55; H, 5.22; N, 15.54.<br />
N 3 -cyclohexyl-7-cyclopropyl-N 6 -(4-methoxyphenyl)-2,5-bis(methylthio)pyrazolo<br />
[1,5-a]pyrimidine-3,6-dicarboxamide 10w. Creamish solid; mp >320 ° C, R f 0.48<br />
(9:1Chloroform: Methanol); IR (KBr): 3445, 3247, 3038, 2952, 1628, 1539,1422,<br />
1336, 1257, 838, 745 cm -1 ; MS (m/z): 525 (M + ); Anal. Calcd for C 26 H 31 N 5 O 3 S 2 : C,<br />
59.40; H, 5.94; N, 13.32; Found: C, 59.44; H, 5.92; N, 13.34.<br />
N 3 -cyclohexyl-7-cyclopropyl-N 6 -(2,5-dimethylphenyl)-2,5-bis(methylthio)<br />
pyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide 10x. Creamish solid; mp >320 ° C, R f<br />
0.23 (9:1Chloroform: Methanol); IR (KBr): 3258, 3158, 3038, 2948, 1645, 1558,1426,<br />
1358, 1216, 835, 745,708 cm -1 ; MS (m/z): 523 (M + ); Anal. Calcd for C 27 H 33 N 5 O 2 S 2 :<br />
C, 61.92; H, 6.35; N, 13.37; Found: C, 61.94; H, 6.32; N, 13.34.<br />
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Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
1 H NMR spectrum of compound 9i<br />
Expanded 1 H NMR spectrum of compound 9i<br />
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Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
1 H NMR spectrum of compound 10b<br />
1 H NMR spectrum of compound 10k<br />
F<br />
Cl<br />
O<br />
N<br />
H<br />
S<br />
N<br />
N N<br />
O<br />
S<br />
NH<br />
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Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
1 H NMR spectrum of compound 10l<br />
Expanded 1 H NMR spectrum of compound 10l<br />
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Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
13 C NMR spectrum of compound 10b<br />
Expanded 13 C NMR spectrum of compound 10b<br />
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Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
13 C NMR spectrum of compound 10u<br />
Expanded 13 C NMR spectrum of compound 10u<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 151
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
MASS spectrum of compound 10a<br />
MASS spectrum of compound 10d<br />
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Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
MASS spectrum of compound 10o<br />
MASS spectrum of compound 10u<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 153
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
IR Spectrum of compound 10i<br />
90<br />
%T<br />
75<br />
3279.10<br />
3254.02<br />
3016.77<br />
2928.04<br />
2850.88<br />
1730.21<br />
1681.98<br />
1411.94<br />
1369.50<br />
1313.57<br />
1246.06<br />
1193.98<br />
1111.03<br />
964.44<br />
810.13<br />
748.41<br />
667.39<br />
547.80<br />
60<br />
45<br />
1627.97<br />
1591.33<br />
1566.25<br />
1550.82<br />
1506.46<br />
530.44<br />
503.44<br />
468.72<br />
451.36<br />
30<br />
1531.53<br />
1481.38<br />
15<br />
0<br />
4000<br />
3500<br />
3000<br />
2500<br />
2000<br />
1750<br />
1500<br />
1250<br />
1000<br />
750<br />
500<br />
1/cm<br />
IR Spectrum of compound 10u<br />
100<br />
%T<br />
80<br />
60<br />
40<br />
20<br />
0<br />
F<br />
3408.33<br />
3340.82<br />
3277.17<br />
3142.15<br />
3070.78<br />
3012.91<br />
N<br />
H<br />
2928.04<br />
2852.81<br />
O<br />
S<br />
N<br />
N N<br />
O<br />
S<br />
NH<br />
1672.34<br />
1620.26<br />
1604.83<br />
1556.61<br />
1533.46<br />
1504.53<br />
1481.38<br />
1444.73<br />
1354.07<br />
1317.43<br />
1251.84<br />
1209.41<br />
1095.60<br />
1058.96<br />
974.08<br />
893.07<br />
833.28<br />
792.77<br />
750.33<br />
711.76<br />
669.32<br />
557.45<br />
522.73<br />
501.51<br />
434.00<br />
-20<br />
4000<br />
3500<br />
3000<br />
2500<br />
2000<br />
1750<br />
1500<br />
1250<br />
1000<br />
750<br />
500<br />
1/cm<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 154
Chapter 4<br />
Synthesis of highly substituted pyrazolopyrimidine<br />
4.8 Reference<br />
1. PCT Int. Appl., 2007, WO 2007076092 A2 20070705.<br />
2. (a) Alexander, J. O.; Wheeler, G. R.; Hill, P. D.; Morris, M. P. Biochem. Pharmacol.1966, 15,<br />
881; (b) Elion, G. B.; Callahan, S.; Nathan, H.; Bieher, S.; Rundles, R.W.; Hitchings, G. H.<br />
Biochem. Pharmacol. 1963, 12, 85; (c) Earl, R. A.; Pugmire, R. J.; Revanker, G. R.;<br />
Townsend, L. B. J. Org. Chem. 1975, 40, 1822.<br />
3. Novinson, T.; Bhooshan, B.; Okabe, T.; Revankar, G. R.; Wilson, H. R. J. Med. Chem. 1976,<br />
19, 512.<br />
4. Senga, K.; Novinson, T.; Wilson, H. R. J. Med. Chem. 1981, 24, 610.<br />
5. Suzuki, M.; Iwasaki, H.; Fujikawa, Y.; Sakashita, M.; Kitahara, M.; Sakoda, R. Bioorg. Med.<br />
Chem. Lett. 2001, 11, 1285.<br />
6. Almansa, C. A.; Alberto, F.; Cavalcanti, F. L.; Gomez, L. A.; Miralles, A.; Merlos, M.;<br />
Garcia-Rafanell, J.; Forn, J. J. Med. Chem. 2001, 44, 350.<br />
7. Novinson, T.; Hanson, R.; Dimmitt, M. K.; Simmon, L. N.; Robins, R. K.; O’Brien, D. E.<br />
J. Med. Chem. 1974, 17, 645.<br />
8. (a) Chen, C.; Wilcoxen, K. M.; Huang, C. Q.; Xie, Y.-F.; McCarthy, J. R.;Webb, T. R.; Zhu,<br />
Y.-F.; Saunders, J.; Liu, X.-J.; Chen, T.-K.; Bozigian, H.; Grigoriadis, D. E. J. Med. Chem.<br />
2004, 47, 4787; (b) Huang, C. Q.; Wilcoxen, K. M.; Grigoriadis, D. E.; McCarthy, J. R.;<br />
Chen, C. Bioorg. Med. Chem. Lett. 2004, 14, 3943; (c) Chen, C.; Wilcoxen, K. M.; Huang, C.<br />
Q.; McCarthy, J. R.; Chen, T.; Grigoriadis, D. E. Bioorg. Med. Chem. Lett. 2004, 14, 3669;<br />
(d) Wustrow, D. J.; Capiris, T.; Rubin, R.; Knobelsdorf, A.; Akunne, H.; Davis, M. D.;<br />
MacKenzie, R.; Pugsley, T. A.; Zoski, K. T.; Heffner, T. G.; Wise, L. D. Bioorg. Med. Chem.<br />
Lett. 1998, 8, 2067.<br />
9. (a) Selleri, S.; Gratteri, P.; Costagli, C.; Bonaccini, C.; Costanzo, A.; Melani, F.; Guerrini, G.;<br />
Ciciani, G.; Costa, B.; Spinetti, F.; Martini, C.; Bruni, F. Bioorg. Med. Chem. 2005, 13, 4821;<br />
(b) Selleri, S.; Bruni, F.; Costagli, C.; Costanzo, A.; Guerrini, G.; Ciciani, G.; Costa, B.;<br />
Martini, C. Bioorg. Med. Chem. 2001, 9, 2661; (c) Selleri, S.; Bruni, F.; Costagli, C.;<br />
Costanzo, A.; Guerrini, G.; Ciciani, G.; Costa, B.; Martini, C. Bioorg. Med. Chem. 1999, 7,<br />
2705.<br />
10. Drizin, I.; Holladay, M. W.; Yi, L.; Zhang, H. Q.; Gopalakrishnan, S.; Gopalakrishnan, M.;<br />
Whiteaker, K. L.; Buckner, S. A.; Sullivan, J. P.; Carroll, W. A. Bioorg. Med. Chem. Lett.<br />
2002, 12, 1481.<br />
11. Altenbach, R.J.; Black, L.A.; Chang, S.; Cowart, M.D.; Faghih, R.; Gfesser, G.A.; Ku, Y.;<br />
Liu, H.; Lukin, K.A.; Nersesian, D.L.; Pu, Y.; Curtis, M.P.. U.S. Patent Appl. 256,309, 2005.<br />
Chem. Abstr. 2005, 144, 36332.<br />
12. Kirkpatrick,W. E.; Okabe, T.; Hillyard, I.W.; Robin, R. K.; Dren, A. T. J. Med. Chem. 1977,<br />
20, 386.<br />
13. C.F.P. George, Lancet, 2001, 358, 1623.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 155
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Synthesis of highly substituted pyrazolopyrimidine<br />
14. (a) Sullivan, S.K.; Petroski, R.E.; Verge, G.; Gross, R.S.; Foster, A.C.; Grigoriadis,<br />
D.E.; J. Pharmacol. Exp. Ther. 2004, 311, 537.(b) Wegner, F.; Deuther-Conrad, W.;.<br />
Scheunemann, M.; Brust, P.; Fischer, S.; . Hiller, A; Diekers, M.; Strecker, K.; Wohlfarth,<br />
K.; Allgaier, C.; Steinbach, J.; Hoepping, A.; Eur. J. Pharm., 2008, 580 1. (c) Hoepping, A.;<br />
Diekers, M.; Deuther-Conrad, W.; Scheunemann, M.; Fischer, S.; Hiller, A.; Wegner, F.;<br />
Steinbach, J.; Brus, P.; Bioorg. Med. Chem. 2008, 16, 1184..<br />
15. (a) Lippa, A.; Czobor, P.;. Stark, J.; Beer, B.;. Kostakis, E.; Gravielle, M.; Bandyopadhyay,<br />
S.; Russek, S.J.; Gibbs, T.T.; Farb, D.H.; Skolnick, P.; Proc. Natl. Acad. Sci. U.S.A. 2005,<br />
102, 7380. (b). Mirza, N.R.; Rodgers, R.J.; Mathiasen, L.S.; J. Pharmacol. Exp. Ther. 2006,<br />
316, 1291.<br />
16. Tully W. R.; Gardner, C. R.; Gillespie, R. J.; Westwood, R., J. Med. Chem, 1991, 34, 7<br />
17. Alexandrovich, I, A.; Vasilievich, I. A.; Filippovich, S. N. PCT Int. Appl., 2009093206,<br />
18. Ivachtchenko, A. V.; Golovina, E. S.; Kadieva, M. G.; Koryakova, A. G.; Mitkin, O. D.;<br />
Tkachenko, S. E.; Kysil, V. M.; Okun, I.; E. J. Med. Chem. 2011, 46, 1189.<br />
19. Selleri, S.; Bruni, F.; Costagli, C.; Costanzo, A.; Guerrini, G.; Ciciani, G.; Costab B.;<br />
Martinib, C.; Bioorg. Med. Chem. 2001, 9, 2661.<br />
20. Tellew, J. E.; Lanier, M.; Moorjani, M.; Lin, E.; Luo, Z.; Slee, D. H.; Zhang, X.; Hoare, S. R.<br />
J.; Grigoriadis, D. E.; Denis, Y.; Fabio, St. R. D.; Modugno, E. D.; Saunders, J.; Williams, J.<br />
P.; Bioorg. Med. Chem Lett. 2010. 20, 7259.<br />
21. Wang, S. Q.; Fang, L.; Liu, X.; Zhao, K.; Chinese Chemical Letters Vol. 2004, 15, 885.<br />
22. Springer, R. H.; Scholten, M. B.; O’Brien, D. E.; Novinson, T.; Miller, J. P.; Robins, Roland<br />
K.; J. Med. Chem. 1982, 25, 235.<br />
23. Frey, R. R.; Curtin, M. L.; Albert, D. H.; Glaser, K. B.; Pease, L. J.; Soni, N. B.; Bouska, J. J.;<br />
Reuter, D.; Stewart, K. D.; Marcotte, P.; Bukofzer, G.; Li, J.; Davidsen, S. K.; Michaelides,<br />
M. R. J. Med. Chem. 2008, 51, 3777.<br />
24. Ding, R.; He, Y.; Xu, J.; Liu, H.; Wang, X.; Feng, M.; Qi, C.; Zhang, J.; Molecules 2010, 15,<br />
8723.<br />
25. Ahmeda, O. M.; Mohamed, M. A.; Ahmed, R. R.; Ahmed, S.A; E. J. Med. Chem. 2009, 44<br />
3519,<br />
26. Mulakayala, N.; Reddy U; Chaitanya, M.; Chitta, M. H. M. Kumar, S.; Golla, N.; J. Korean<br />
Chem. Soc., 2011, 55, 4.<br />
27. Abbas-Temirek, H. H., Assiut <strong>University</strong> Journal of Chem., 35(1), 37-44; 2006<br />
28. Wu, Y.-C., Li, H.-J.; Liu, L.; Wang, D.; Yang, H.-Z.; Chen, Yong-Jun J. Fluoresc, 2008 18,<br />
357.<br />
29. Danagulyan, G. G.; Boyakhchyan, A. P.; Kirakosyan, V. G.; Chem. of Heterocyclic<br />
Compounds, 2010, 46, 6,<br />
30. Ming, L.; Shuwen, W.; Lirong, W.; Huazheng, Y.; Xiuli, Z.; J. Heterocyclic Chem. 2005, 42,<br />
925.<br />
31. Thomas, A.; Chakraborty, M.; H. Ila; Junjappa, H. Tetrahedron, 1990, 46, 577.<br />
32. Mizar, P.; Myrboh, B.; Tetrahedron Letters, 2009, 50,3088.<br />
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33. Bassoude, I.; -Raboin, S.-B.; Leger, J.-M.; Jarry, C.; Essassi, E. M.; Guillaumet, G.<br />
Tetrahedron, 2011, 67, 2279.<br />
34. Britsun, V. N.; Chemistry of Heterocyclic Compounds, 2008, 44, 10.<br />
35. Kryl’skii, D. V.; Shikhaliev, Kh. S.; Chuvashlev, A. S.; Russian Journal of Organic<br />
Chemistry, 2010, 46(3), 410–416.<br />
36. Ahmeda, S. A.; Husseina, A. M.; Hozayena, W. G. M.; El-Ghandoura, A. H. H.; Abdelhamid,<br />
A.O.; J. Heterocyclic Chem.,2007. 44, 803.<br />
37. Shaabana, M. R.; Saleh, T. S.; Mayhoub, A. S.; Farag, A. M.; E. J. Med. Chem. 2011, 46<br />
3690.<br />
38. Shaikh, B. M.; Konda, S. G.; Chobe, S. S.; Mandawad, G.G.; Yemul, O.S.;. Dawane, B.S.;<br />
J. Chem. Pharm. Res., 2011, 3(2), 435.<br />
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Chapter - 5<br />
Rapid Synthesis of Highly Substituted<br />
Pyrrole Derivatives: Analogs of<br />
Atorvastatin
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
5.1 Introduction<br />
Pyrrole is an important π-excessive aromatic heterocycle because this ring<br />
system is incorporated in as a basic structural unit in porphyrins;porphin (heam) and<br />
chlorine (chlorophyll) and corrins (vitamin B12) (Figure-1). More over the presence<br />
of pyrrole ring in system in porphobilinogen (intermediate in biosynthesis of<br />
porphyrins and vitamin B12), biliverdin and bilirubin (pyrrole-based bile pigments)<br />
and pyrrolnitrin (with antibiotic activity) has provided an impetus to the pyrrole<br />
chemistry.<br />
Figure-1<br />
Pyrrole has a planar pentagonal structure with four carbon atoms and nitrogen<br />
sp 2 -hybridized. Each ring atom forms two sp 2 -sp 2 σ -bonds to its neighbouring ring<br />
atoms and one sp 2 -sσ -bond to a hydrogen atom. The remaining unhybridized p-<br />
orbitals, one on each ring atom (with one electron on each carbon and two electron on<br />
nitrogen), are perpendicular to the plane of σ–bonds and overlap form a π-molecular<br />
system with three bonding orbitals. The six π-electrons form an aromatic sextet which<br />
is responsible for aromaticity and renders stability to the pyrrole ring. The C α -N and<br />
C α -C β bonds are shorter than normal single bonds, where as C α -C β bonds are normal<br />
than normal double bonds. The molecular dimentions of the pyrrole reflect cyclic<br />
delocalization with the environment of lone pair of electrons on the nitrogen atom.<br />
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Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
Pyrrole is extremely weak base because the lone pair of electrons on the<br />
nitrogen atom involved in the cyclic delocalization and is, therefore, less available for<br />
protonation. Moreover, pyrrole is a weaker base than pyridine and even than aniline in<br />
which lone pair on the nitrogen atom is involved in the resonance and not essentially<br />
contributes to the aromatic sexlet. The protonation of pyrrole at nitrogen or C 2 or C 3<br />
atom of the ring reduces its basicity and destroys its aromaticity. However, C- and N-<br />
alkyl substituents enhance the basicity of pyrrole but the electron withdrawing<br />
substituents on the ring make pyrrole a weaker base. 1-11<br />
5.2 Various synthetic approaches for highly substituted pyrroles.<br />
Pyrroles are generally synthesized by the cyclization reactions involving<br />
nucleophilic-electrophilic interactions. This is the most widely used method and<br />
involves the cyclizative condensation of α-aminoketones or α-amino-β-keto<br />
esters(three atom fragment with nucleophilic nitrogen and electrophilic carbonyl<br />
carbon) with β-diketones or β-ketoesters (two atom fragment with electrophilic<br />
carbonyl carbon and a nucleophilic carbon) with the formation of N-C 2 and C 3 -C 4<br />
bonds (Figure-2).<br />
Figure-2<br />
The reaction of α-aminoketones with alkynes proceeds with the nucleophilic<br />
addition of amino group to the electrophilic carbon of alkyne with the formation of<br />
enamine intermediate which on intramolecular cyclization provides pyrroles involving<br />
nucleophilc (β-carbon of the enamine intermediate)-electrophilic (carbonyl carbon)<br />
interaction with the formation of C 3 -C 4 bond (Figure-3). 12<br />
Figure-3<br />
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Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
The reaction of β-amino-α,β-unsaturated esters 91(three atom fragment) with<br />
nitroalkenes (two atom fragment) provides substituted pyrrole involving (3+2)<br />
cyclization with N-C 2 and C 3 -C 4 bonds (Figure-4). 13<br />
Figure-4<br />
Base catalyzed (3+2) cyclizative condensation of α-diketones with amines<br />
substituted with electron withdrawing substituents at α, α’-positions results in the<br />
corresponding pyrroles with the formation of C 2 -C 3 and C 4 -C 5 bonds (Figure-5). 14<br />
Figure-5<br />
The reaction of β-keto esters with α-halo ketones or aldehydes in the presence<br />
of ammonia or primary amine affords pyrroles involving (2+2+1) cyclization with the<br />
formation of N-C 2 , C 3 -C 4 and N-C 5 bonds. (Hantzsch Synthesis). The reaction<br />
proceeds via stabilized enamine intermediate which on C-alkylation and N-alkylation<br />
by α-haloketone leads to the formation of corresponding pyrrole (Figure-6).<br />
Figure-6<br />
The condensation of aliphatic aldehydes or ketones with hydrazine under<br />
strongly acidic conditions affords pyrroles involving (3+3) sigmatropic rearrangement<br />
and cyclization. (Piloty-Robinson Synthesis). This reaction can also be applied for the<br />
preparation of N-substituted pyrroles by condensing ketones with methyl hydrazine or<br />
N,N’-dimethyl hydrazine (Figure-7). 15<br />
R<br />
R<br />
H 2 N NH 2<br />
O + O<br />
R<br />
R<br />
H 3 C<br />
CH 3<br />
H + H +<br />
RH 2 C<br />
N NH H<br />
CH 2 R -NH 3<br />
RH 2 C<br />
R<br />
N<br />
H<br />
R<br />
CH 2 R<br />
Figure-7<br />
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Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
The reaction of benzoin with benzyl aryl ketones in the presence of<br />
ammonium acetate results in the formation of polyaryl substituted pyrroles involving<br />
(2+2+1) cyclization (Figure-8). 16 Figure-8<br />
The condensation of alkyl isocyanoacetates with aldehydes in 2:1 ratio<br />
proceeds to involve an initial conjugated addition followed by an anionic cyclization<br />
with the formation of C 2 -C 3 , C 3 -C 4 and C 4 -C 5 bonds (Figure-9). 17<br />
Figure-9<br />
It is the most general method and involves (4+1)cyclizative condensation of<br />
1,4-dikitones (enolizable) with ammonia or its derivatives with the formation of N-C 2<br />
and N-C 5 bonds 1-6, 18-19 . The reaction is considered to proceed with the successive<br />
attacks of nucleophilic nitrogen on the carbonyl carbon and finally followed by<br />
dehydration (aromatization) for which driving force is provided by the stability of the<br />
resulting pyrrole (Figure-10).<br />
Figure-10<br />
Metal ion assisted amination of 1,4-dienes or diynes with primary amines<br />
followed by cyclization provides N-substituted pyrroles (Figure 11 & 12). 20-21<br />
Figure 11<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 161
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
Figure 12<br />
2-Acylaziridines undergo ring expansion reactions to provide pyrroles<br />
involving ring-opened dipolar intermediates (Figure-13). 22<br />
Figure-13<br />
Vinylazirines also undergo ring expansion reactions, but two isomeric pyrroles<br />
are obtained depending on the reaction conditions. Thermal reactions involve a<br />
nitrene intermediate, while photochemical reaction proceeds via a nitrile ylide<br />
intermediate (Figure-14). 23<br />
Figure-14<br />
The complex ring systems, formed by (3+2) cycloaddition of activated alkynes<br />
substituted with electron-withdrawing substituents, with mesoionic heterocycles,<br />
undergo extrusion reactions with the cleavage of larger ring leaving the pyrrole ring<br />
system intact (Figure-15). 24-26<br />
Figure-15<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 162
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
Ethyl-3-amino-5-phenyl-1H-pyrrol-2-carboxylate found to be a useful<br />
intermediate in the synthesis of other nitrogen heterocycles. 27 However Elliott and coworkers<br />
28-29 have described that condensation of aldehyde with aminomalonate gave<br />
3-substituted enamine, which was cyclized in the presence of sodium methoxide to<br />
give 3-amino-4-benzyl-1H-pyrrol-2-carboxylate (Figure-16).<br />
Figure-16<br />
Using a similar approach toward the synthesis of pyrrole (Figure-17), Ning<br />
Chen, et al. 30<br />
were failed to synthesize 2-substituted enamine intermediate from<br />
benzoyl acetonitrile and diethyl aminomalonate using standard conditions such as<br />
azeotropic removal of water, 31<br />
dehydration with molecular sieves or Lawis acid<br />
catalysis(TiCl 4 32 , BF3.OEt 2 )<br />
NH 2<br />
COOEt<br />
Ph<br />
O<br />
CN<br />
EtOOC<br />
EtOOC<br />
EtOOC<br />
NC<br />
N<br />
H<br />
Ph<br />
EtOOC<br />
H 2 N<br />
N<br />
H<br />
Ph<br />
Figure-17<br />
Considering the lower electrophilicity of the aryl ketone compared to the<br />
aldehyde, an alternative strategy for preparing enamine was examined. Since amines<br />
are known to undergo substitution reactions with chloro- and alkylthio-substituted<br />
olefins to yield enamines 33 , a similar approach was considered and the reaction of p-<br />
toluenesulfonyl enol ester of α-cyano ketone with diethyl aminomalonate was<br />
investigated. Tosylate was prepared by reacting benzoyl acetonitrile with p-<br />
toluenesulfonic anhydride (1.2 eq.) in dichloromethane and triethylamine (1.5 eq.) in<br />
99% yield. When a mixture of tosylate and diethyl aminomalonate hydrochloride (1.2<br />
eq.) were treated with an ethanolic solution of sodium ethoxide (0.2 M, 3.5 eq.), 34 the<br />
pyrrole was directly obtained without isolation of enamine. Addition of the amine,<br />
cyclization and decarboxylation occurred in one-pot at room temperature to give a<br />
46% overall yield of from benzoyl acetonitrile (Figure-18).<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 163
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
Figure-18<br />
In continuation with this study prior work at <strong>Saurashtra</strong> <strong>University</strong> on 1Hpyrrole<br />
derrivatives clubed with substituted-1,3,4-Oxadiazoles, 1-[2,4-dimethyl-5-(5-<br />
phenyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-3-yl]ethanone derivatives were synthesized.<br />
The synthetic stretagy follows starting with acid catalyzed cyclocondensation of ethyl<br />
ester derivative of 3-amino-2-butenoic acid (generated insitu from ethylacetoacetate<br />
upon oximenation followed by reduction) with acetylacetone to afford ethyl-3-acetyl-<br />
2,4-dimethyl-1H-pyrrole-5-carboxylate, which was derivatized into corresponding<br />
hydrazide derivative on treatment with hydrazine hydrate. The hydrazide derivative<br />
on reaction with different aromatic and heteroaromatic acid, in the presence of<br />
phosphorous oxychloride affords 1-[2,4-dimethyl-5-(5-phenyl-1,3,4-oxadiazol-2-yl)-<br />
1H-pyrrol-3-yl]ethanone derivatives (Figure-19). 35-36<br />
Figure-19<br />
A range of 2,5-disubstituted and 2,4,5-trisubstituted pyrroles can be<br />
synthesized from dienyl azides at room temperature using ZnI 2 or Rh 2 (O 2 CC 3 F 7 ) 4 as<br />
catalysts (Figure-20). 37<br />
Figure-20<br />
The CuI/N,N-dimethylglycine-catalyzed reaction of amines with γ-bromosubstituted<br />
γ,δ-unsaturated ketones in the presence of K 3 PO 4 and NH 4 OAc gave the<br />
corresponding polysubstituted pyrroles in very good yields (Figure-20). 38<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 164
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
R<br />
O<br />
R 0.1 eq. CuI<br />
1<br />
+ H 0.2 eq. N,N-dimethylglycine.HCl<br />
2N R 3<br />
R 2<br />
Br<br />
2eq.K 3 PO 4 ,2eq.NH 4 OAc<br />
MeCN or toluene, reflux, 10 -20 R<br />
h<br />
1<br />
Figure-20<br />
Two methods for the regioselective synthesis of tetra- and trisubstituted N-H<br />
pyrroles from starting vinyl azides have been developed: A thermal pyrrole formation<br />
via the 1,2-addition of 1,3-dicarbonyl compounds to 2H-azirine intermediates<br />
generated in situ from vinyl azides and a Cu(II)-catalyzed synthesis with ethyl<br />
acetoacetate through a 1,4-addition (Figure-21). 39<br />
R<br />
R 3<br />
N<br />
R 2<br />
Figure-21<br />
An operationally simple, practical, and economical Paal-Knorr pyrrole<br />
condensation of 2,5-dimethoxytetrahydrofuran with various amines and sulfonamines<br />
in water in the presence of a catalytic amount of iron(III) chloride allows the synthesis<br />
of N-substituted pyrroles (Figure-22) under very mild reaction conditions in good to<br />
excellent yields. 40<br />
Figure-22<br />
A new and efficient three-component reaction between dialkyl<br />
acetylenedicarboxylates, aromatic amines, triphenylphosphine, and arylglyoxals<br />
afforded polysubstituted pyrrole derivatives in high yields (Figure-23). The reactions<br />
were performed in dichloromethane at room temperature and under neutral<br />
conditions. 41<br />
Figure-23<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 165
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
A three-component reactions of arylacyl bromides, amines, and dialkyl<br />
acetylene dicarboxylate in the presence of iron(III) chloride as a catalyst at room<br />
temperature afforded polysubstituted pyrroles in high yields (Figure-24). 42<br />
Ar<br />
O<br />
H 2 N R<br />
Br + or<br />
NH 4 OAc<br />
R<br />
+ 1 O 2 C<br />
CO 2 R 1<br />
15 mol - % FeCl 3<br />
CH 2 Cl 2 , rt, 14-16 h<br />
CO 2 R 1<br />
Ar N<br />
CO 2 R 1<br />
R<br />
Figure-24<br />
A new and efficient three-component reaction between dialkyl acetylene<br />
dicarboxylates, aromatic amines, triphenylphosphine, and arylglyoxals afforded<br />
polysubstituted pyrrole derivatives in high yields (Figure-25). The reactions were<br />
performed in dichloromethane at room temperature and under neutral conditions. 43<br />
Figure-25<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 166
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
5.3 Biological activity associated with pyrrole derivatives<br />
Pyrrole has its own pharmaceutical importance and various activities of<br />
pyrrole include:<br />
‣<br />
Selective Mono Amine Oxidase type A Inhibitors 44-57<br />
‣<br />
Antitubercular activities 58-66<br />
‣<br />
HIV-1 intigrase Inhibitors 67-69<br />
‣<br />
Antiproliferative activity 70-71<br />
‣<br />
Glycogen Synthase Kinase-3(GSK-3) Inhibitors 72-79<br />
‣<br />
Analgesic and Antiinflammatory activity 80-81<br />
‣<br />
Bactericidal activities 82-86<br />
‣<br />
Fungicides and Plant Growth Regulators 87-89<br />
‣<br />
Action on the Cardiovascular System 90-94<br />
‣<br />
Neuronal L-type Calcium channel activator 95<br />
.<br />
5.4 Some drugs from pyrrole nucleus 44-95<br />
H 3 CO<br />
O<br />
O<br />
CH 3<br />
O<br />
N<br />
N<br />
HH<br />
CH 3<br />
O<br />
N O<br />
O<br />
N<br />
O<br />
OH<br />
Anirolac<br />
COOH<br />
H<br />
Ramipril<br />
OH<br />
Ketorolac<br />
H<br />
N<br />
N<br />
H<br />
H<br />
N<br />
N<br />
H<br />
H<br />
N<br />
(CH 2 ) 6<br />
H<br />
N (CH 2 )<br />
N 6<br />
H<br />
Pyrextramine<br />
O<br />
NC<br />
O<br />
NH<br />
S<br />
S<br />
N<br />
H 3 CO<br />
N<br />
S<br />
O<br />
O<br />
C 2 H 5<br />
H 3 CO<br />
Pamicogrel<br />
O CH<br />
O<br />
3<br />
N N NH<br />
N<br />
Cl<br />
N<br />
Pirprofen,<br />
Rengasil<br />
HO<br />
N<br />
HN<br />
OH<br />
OH<br />
CH 3<br />
O<br />
CH 3<br />
O<br />
OH<br />
O<br />
Prinomide<br />
Zalderide<br />
Figure-26<br />
Atorvastatin<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 167
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
5.5 Current research work<br />
` The above literature study reveled that pyrrole derivatives contacting<br />
heterocyclic molecules showed significant biological potential. 44-95 One such highly<br />
functionalized pyrrole derivative is Atorvastatin. It is a class of statins, which act by<br />
inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the<br />
sterol by synthesis pathway; therefore, they are used in human therapy to reduce<br />
cholesterol in the level of blood. These compounds also have certain (pleiotropic)<br />
effects, e.g. decreasing inflammation and improving the endothelial functions. 96<br />
Recently reports described their inhibitory effect of the growth of different pathogenic<br />
fungi. 97-98 Sun and Singh reported that statins directly attenuate the virulence of<br />
microorganisms: modulate regulatory pathway of involved in the infection process. 99<br />
There are also sporadic new reports on the combined application of statins and<br />
different antimycotics. 100-106<br />
Figure-27<br />
Thus, to investigate the potential biological effect of some new pyrrole<br />
derivatives (AS-01 to AS-30), we set to modify position 2 and 3 of the Atrovastatin<br />
intermediate (Figure-27). To achieve the targeted compounds, we have synthesized<br />
thirty novel 1,4-diketone from easily available b-keto esters, which was further<br />
condensed with amino side chain (tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-<br />
dimethyl-1,3-dioxan-4-yl)acetate) using pivalic acid as a catalyst under microwave<br />
irradiation. The newly synthesized compounds were characterized by IR, Mass, 1 H<br />
NMR, 13 C NMR spectroscopy and elemental analysis. All synthesized compounds<br />
were evaluated for their antimicrobial activity.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 168
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
5.6 Results and discussion<br />
Scheme:Synthesis of highly substituted Atorvastatin analogs<br />
Scheme-01<br />
1<br />
O<br />
OH<br />
MDC<br />
SOCl 2<br />
O<br />
Cl<br />
ZnO<br />
F<br />
O<br />
F<br />
Br 2 /CH 3 COOH<br />
2 3 4<br />
Br<br />
O<br />
F<br />
Scheme-02<br />
Scheme-03<br />
N<br />
H<br />
O<br />
R 1<br />
5<br />
R<br />
O<br />
O<br />
H 2 N<br />
O<br />
O<br />
O<br />
O<br />
R 1<br />
Pivalic acid<br />
Cyclohexane/THF<br />
MW<br />
N<br />
H<br />
O<br />
R<br />
N<br />
O<br />
O<br />
O<br />
O<br />
F<br />
ADD-01- 30<br />
F<br />
AS-01-30<br />
Where R=CH 3 , (CH 3 ) 2 CH, (CH 2 ) 2 CH, R 1 =CH 3 , OCH 3 , Cl, NO 2<br />
Scheme 1 and 2 shows the synthetic route for the requisite starting materials.<br />
First, acid chloride of phenyl acetic acid (2) was prepared from phenylacetic acid (1)<br />
using thionyl chloride in MDC as described in literature. 107 The fridle-craft reaction of<br />
Compound 2 with fluorobenzene in the presence of ZnO 108 afforded 1-(4-<br />
fluorophenyl)-2-phenylethanone (3) with good yield. The bromination of compound 3<br />
using Br 2 /AcOH provided 2-bromo-1-(4-fluorophenyl)-2-phenylethanone (4). 109<br />
Various acetoactanilide derivatives (AAA-01-30) were prepared as described<br />
in chapter-4. The condensation reaction of these acetoactanilide derivative (AAA-01-<br />
30) with 2-bromo-1-(4-fluorophenyl)-2-phenylethanone (4) using potassium<br />
carbonate as a base in isopropyl alcohol afford the requisite 1,4-dicarbonyl<br />
compounds (ADD-01-30).<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 169
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
The final coupling reaction of 1,4-dicarbonyl compounds with amino side<br />
chain (tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate)<br />
(5) in the presence of acid catalyst under microwave irradiation afford pyrrole<br />
derivatives. For optimization of reaction condition 1,4-dicarbonyl compound (ADD-<br />
01) was react with amino side chain (5) by using various acid catalyst in various<br />
solvents or binary mixture of solvents in conventional method and under microwave<br />
irradiation method. The require reaction time and obtained (%) of yield were<br />
summarized in table-1.<br />
Table-1: Optimization of reaction condition for synthesis of AS-01 in various<br />
conditions<br />
Reaction time and yield (%)<br />
Entry Catalyst Solvents<br />
Conventional MW<br />
Time Yield Time Yield<br />
h (%) min (%)<br />
1 PTSA Toluene 38 68 120 88<br />
2 PTSA Cyclohexane 36 70 110 82<br />
3 PTSA Cyclohexane/THF (9:1) 31 78 90 86<br />
4 PTSA Toluene/THF (9:1) 32 76 96 85<br />
5 MSA Toluene 35 78 112 81<br />
6 MSA Cyclohexane 34 74 100 85<br />
7 MSA Cyclohexane/THF (9:1) 30 80 90 87<br />
8 MSA Toluene/THF (9:1) 30 77 88 82<br />
9 Sulfamic acid Toluene 40 74 140 78<br />
10 Sulfamic acid Cyclohexane 42 76 148 80<br />
11 Sulfamic acid Cyclohexane/THF (9:1) 36 72 125 75<br />
12 Sulfamic acid Toluene/THF (9:1) 35 70 130 75<br />
13 Pivalic acid Toluene 32 85 120 82<br />
14 Pivalic acid Cyclohexane 36 83 105 90<br />
15 Pivalic acid Cyclohexane/THF (9:1) 28 90 75 95<br />
16 Pivalic acid Toluene/THF (9:1) 30 84 82 88<br />
On the basis of our study we found that using pivalic acid and binary solvent<br />
Cyclohexane/THF (9:1) gave an excellent yield in short time (Table-1). Having<br />
optimized condition in our hand,<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 170
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
we carried out the reaction of various 1,4-dicarbonyl compounds (ADD-01 to 30)<br />
with amino side chain (5) in the presence of pivalic acid and cyclohexane/THF (9:1)<br />
under microwave irradiation afford pyrroles with excellent yield (Table-2).<br />
Table-2: Synthesis of highly functionalized pyrroles as atorvastatin analogs<br />
under microwave irridiation.<br />
Entry R R 1 Time (min) Yield (%)<br />
AS-01 CH 3 4-CH 3 75 95<br />
AS-02 CH 3 4-OCH 3 78 91<br />
AS-03 CH 3 4-Cl 70 94<br />
AS-04 CH 3 4-F 72 92<br />
AS-05 CH 3 4-CH 2 CH 3 80 88<br />
AS-06 CH 3 4-NO 2 82 85<br />
AS-07 CH 3 2,5diCH 3 85 86<br />
AS-08 CH 3 3-Cl,4-F 70 94<br />
AS-09 CH 3 3,4diCl 72 87<br />
AS-10 CH 3 2,3diCH 3 82 90<br />
AS-11 (CH 3 ) 2 CH 4-CH 3 78 94<br />
AS-12 (CH 3 ) 2 CH 4-OCH 3 80 90<br />
AS-13 (CH 3 ) 2 CH 4-Cl 75 95<br />
AS-14 (CH 3 ) 2 CH 4-F 73 94<br />
AS-15 (CH 3 ) 2 CH 4-CH 2 CH 3 82 90<br />
AS-16 (CH 3 ) 2 CH 4-NO 2 88 87<br />
AS-17 (CH 3 ) 2 CH 2,5diCH 3 80 92<br />
AS-18 (CH 3 ) 2 CH 3-Cl,4-F 72 94<br />
AS-19 (CH 3 ) 2 CH 3,4diCl 78 91<br />
AS-20 (CH 3 ) 2 CH 2,3diCH 3 80 85<br />
AS-21 (CH 2 ) 2 CH 4-CH 3 90 90<br />
AS-22 (CH 2 ) 2 CH 4-OCH 3 91 89<br />
AS-23 (CH 2 ) 2 CH 4-Cl 83 95<br />
AS-24 (CH 2 ) 2 CH 4-F 85 94<br />
AS-25 (CH 2 ) 2 CH 4-CH 2 CH 3 88 88<br />
AS-26 (CH 2 ) 2 CH 4-NO 2 87 95<br />
AS-27 (CH 2 ) 2 CH 2,5diCH 3 90 95<br />
AS-28 (CH 2 ) 2 CH 3-Cl,4-F 87 90<br />
AS-29 (CH 2 ) 2 CH 3,4diCl 83 94<br />
AS-30 (CH 2 ) 2 CH 2,3diCH 3 85 88<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 171
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
The structures of ADD-01-30 were established on the basis of their elemental<br />
analysis and spectral data (MS, IR, and 1 H NMR). The analytical data for (ADD-05)<br />
revealed a molecular formula C 26 H 24 FNO 3 (m/z 417). The 1 H NMR spectrum revealed<br />
a triplet at δ = 1.06-1.11 ppm assigned to isopropyl-CH 3 , a singlet at δ = 2.22 ppm<br />
assigned to the –CH 3 protons, a quartet at δ = 2.44-2.47 ppm assigned to-CH 2 protons,<br />
two doublets at δ = 4.70-4.73 ppm (j=10.8Hz) and 5.36-5.39 ppm (j=10.8Hz)<br />
assigned to the -CH protons, two multiplets at δ = 7.03-7.35 ppm and triplet at δ =<br />
8.09-8.13 ppm assigned to the aromatic protons, and one broad singlet at δ = 10.16<br />
ppm assigned to -CONH groups.<br />
The structures of AS-01-30 were established on the basis of their elemental<br />
analysis and spectral data (MS, IR, 1 H NMR and 13 C NMR). The analytical data for<br />
(AS-04) revealed a molecular formula C 38 H 42 F 2 N 2 O 5 (m/z 644). The 1 H NMR<br />
spectrum revealed a signals at δ ppm 1.03-1.07 (m, 1H, CH), 1.30-1.63 (m, 18H,<br />
CH 2 , CH & 5 x CH 3 ), 2.24-2.37 (m, 2H, CH 2 ), 2.71 (s, 3H, CH 3 ), 3.66 (m, 1H, CH),<br />
3.86-3.99 (m, 2H, CH 2 ), 4.14-4.17 (m, 1H, CH), 6.83-7.00 (m, 7H, Ar) and 7.12-<br />
7.28 (m, 7H, Ar & NH).<br />
The mechanism for the synthesis of the pyrrole proceeds via Paal-Knorr<br />
reaction, 110 in which protonated carbonyl (B) is attacked by the amine to form the<br />
hemiaminal (C). The amine attacks the other carbonyl to form a 2,5-<br />
dihydroxytetrahydropyrrole (D) derivative which undergoes dehydration in two steps<br />
give the corresponding substituted pyrrole (F).<br />
Figure 28: Proposed mechanism for the formation of pyrroles<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 172
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
5.7 Antimicrobial sensitivity testing<br />
WELL DIFFUSION / AGAR CUP METHOD (Lt. General Raghunath D. 1998,<br />
Ashok Rattan, 1998; Patel R., Patel K. 2004,)<br />
In vitro effectivity of antimicrobial agents can be demonstrated by observing<br />
their capacity to inhibit bacterial growth on suitable media. The production of a zone<br />
depends on two factors namely bacterial growth and concentration of antimicrobial<br />
agent. The hole/well punch method was first used by Bennett. This diffusion method<br />
has proved more effective then many other methods. According to Lt. General<br />
Raghunath the well technique is 5-6 times more sensitive then using disk method.<br />
Principle<br />
When antimicrobial substance is added in agar cup (made in a medium<br />
previously inoculated with test organism) the redial diffusion of an antimicrobial<br />
agent through the agar, produces a concentration gradient. The test organism is<br />
inhibited at the minimum inhibitory concentration (MIC), giving rise to a clear zone<br />
of inhibition.<br />
Requirements<br />
1. Young broth culture of a standard test organism<br />
2. Sterile Mueller Hinton Agar plate<br />
3. Solution of antimicrobial substance<br />
4. Cup borer<br />
5. Alcohol etc.<br />
Inoculum preparation<br />
Inoculum was prepared by selecting 4-5 colonies from slope of stock culture<br />
of the indicator organism and emulsifying them in a suitable broth. The inoculated<br />
broth was incubated at 37ºC till it equals turbidity of a 0.5 McFarland standard. This<br />
happens in 2-8 h.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 173
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
Procedure<br />
1. Inoculate test organism on the top of Mueller Hinton Agar plate with help of<br />
sterile swab. (it can be inoculated in melted agar also )<br />
2. The swab was dipped in the inoculum and surface of plate was streaked with<br />
swab.<br />
3. Streaking was repeated for 3 times and each time the plate was rotated at angle<br />
of 60º.<br />
4. Sterilize the cup-borer make four cups of the diameter of 8-10 mm. at equal<br />
distance in the plate previously inoculated with seed culture.<br />
5. The depth of well was 2.5-5.0 mm.<br />
6. The wells have been clearly punched so the surrounding medium is not lifted<br />
when the plug was removed out.<br />
7. The plates were incubated at 37ºC for 24 h. Then the zone of inhibition<br />
measured and the size of zone cited in table.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 174
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
Antimicrobial Sensitivity Assay<br />
(Concentration 250/500/1000 µg/ml)<br />
Sr.<br />
No.<br />
CODE<br />
No.<br />
Pseudomonas<br />
aeruginosa<br />
Proteus vulgaris Escherichia<br />
coli<br />
Staphylococcus<br />
aureus<br />
Candida<br />
albicans<br />
250 500 1000 250 500 1000 250 500 1000 250 500 1000 250 500 1000<br />
1. AS-01 R R R R R R R R R R R R R R R<br />
2. AS-02 1.5 1.7 2.0 1.4 1.6 2.0 R R R R R R R R R<br />
3. AS-03 R R R R R R R R R R R R R 1.4 2.0<br />
4. AS-04 R 1.0 1.3 R R R R R R R R R R R R<br />
5. AS-05 R R 1.0 R R R R R R 1.1 1.4 2.0 1.1 1.5 2.0<br />
6. AS-06 R R R R R R 1.3 1.6 1.8 1.5 1.8 2.0 R R R<br />
7. AS-07 1.2 1.4 1.6 1.6 1.8 2.0 1.1 1.4 2.0 1.0 1.3 2.0 R R R<br />
8. AS-08 R R R R R R R 1.2 1.8 1.1 1.4 2.0 R R R<br />
9. AS-09 R R R R R R R R 1.2 R 1.3 2.0 R R R<br />
10. AS-10 1.0 1.3 1.7 R 1.0 1.5 R R 1.2 R R 1.2 1.3 1.8 2.0<br />
11. AS-11 R R R R R R R R R R R 1.2 R R R<br />
12. AS-12 R R R R R R 1.0 1.3 1.8 1.1 1.5 2.0 R R R<br />
13. AS-13 R R R R R R 1.6 1.8 2.0 1.4 1.6 2.0 1.0 1.4 2.0<br />
14. AS-14 R R R R R R R 1.2 1.8 1.1 1.4 2.0 1.1 1.5 2.0<br />
15. AS-15 R R R R R R R 1.1 1.7 R 1.3 2.0 1.5 1.8 2.0<br />
16. AS-16 1.6 1.8 2.0 1.0 1.2 1.6 R 1.1 1.6 1.2 1.5 1.7 R 1.1 1.8<br />
17. AS-17 R 1.4 2.0 1.0 1.3 1.5 1.2 1.5 2.0 1.3 1.5 2.0 1.5 1.7 2.0<br />
18. AS-18 1.0 1.3 1.5 1.1 1.3 1.6 1.5 1.8 2.0 1.5 1.7 2.0 R 1.5 1.9<br />
19. AS-19 1.2 1.5 1.8 1.5 1.8 2.0 1 1.2 2.0 1.1 1.6 2.0 1.3 1.6 2.0<br />
20. AS-20 R 1.3 1.0 1.1 1.3 1.2 1.0 1.2 1.4 1.0 1.2 1.5 1.2 1.5 1.7<br />
21. AS-21 R 1.4 2.0 R R R R R R R R R R R R<br />
22. AS-22 R 1.4 2.0 R R R 1.2 1.4 1.6 1.5 1.7 2.0 1.6 1.8 2.0<br />
23. AS-23 1.0 1.3 2.0 R R R R R R R R R R R R<br />
24. AS-24 R 1.4 2.0 R R R R R R R 1.0 1.3 R R R<br />
25. AS-25 R 1.3 2.0 R R R 1.1 1.4 2.0 R R 1.0 R R R<br />
26. AS-26 R R 1.2 R R R 1.1 1.4 2.0 R R R R R R<br />
27. AS-27 R R 1.2 1.5 1.8 2.0 1.0 1.3 2.0 R R 1.2 R 1.5 2.0<br />
28. AS-28 1.5 1.8 2.0 R 1.2 1.8 1.1 1.4 2.0 R R R R R R<br />
29. AS-29 R 1.4 2.0 R R 1.2 R 1.3 2.0 R R R R R R<br />
30. AS-30 R 1.4 2.0 R R 1.2 R R 1.2 R R R R R R<br />
31. A 1.8 1.8 1.9 1.9 -<br />
32. CPD 2.2 2.1 2.1 2.2 -<br />
33. GF 1.8 1.9 2.0 2.0 -<br />
34. GRF - - - - 2.6<br />
35. FLC - - - - 2.8<br />
Note: Zone of inhibition interpretation is as follows<br />
1. Zone size < 1.0 cm- Resistent (R)<br />
2. Zone size 1.0 to 1.5 cm – Intermediate<br />
3. Zone size > 1.5 – Sensitive<br />
STD Antibiotic Sensitivity Assay Concentration 40 µg/ml<br />
A: Ampicillin GRF: Gresiofulvin<br />
CPD: Cefpodoxime FLC: Fluconazole<br />
GF: Gatifloxacin<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 175
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
5.8 Conclusion<br />
In summary, we have synthesized a series of highly substituted pyrroles as a<br />
atorvastain analogs from novel 1,4-dicarbonyl compounds and amino side chain using<br />
pivalic acid as a catalyst and cyclohexane and THF as binary solvent under<br />
microwave irradiation technique. All the synthesized compounds were evaluated for<br />
their antimicrobial activity. The investigation of antibacterial and antifungal screening<br />
data revealed that all the tested compounds AS-01-30 showed that some of compound<br />
gave moderate to potent activity. The compounds AS-02, 07, 16, 19, 27, and 28<br />
showed comparatively good activity against gram (+ve) bacterial stains, AS-06, 13,<br />
18, and 22 showed comparatively good activity against gram (-ve) bacterial stains and<br />
AS-15, 17 and 22 showed comparatively good activity against fungal stains.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 176
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
5.9 Experimental section<br />
Thin-layer chromatography was accomplished on 0.2-mm precoated plates of<br />
silica gel G60 F 254 (Merck). Visualization was made with UV light (254 and 365nm)<br />
or with an iodine vapor. IR spectra were recorded on a FTIR-8400 spectrophotometer<br />
using DRS prob. 1 H (300 MHz), 1 H (400 MHz), 13 C (75 MHz) and 13 C (100 MHz)<br />
NMR spectra were recorded on a Bruker AVANCE II spectrometer in CDCl 3 and<br />
DMSO. Chemical shifts are expressed in δ ppm downfield from TMS as an internal<br />
standard. Mass spectra were determined using direct inlet probe on a GCMS-QP 2010<br />
mass spectrometer (Shimadzu). Solvents were evaporated with a BUCHI rotary<br />
evaporator. Melting points were measured in open capillaries and are uncorrected.<br />
Synthesis of 2-phenylacetyl chloride 107 (2).<br />
In a 250mL round bottom flask equipped with magnetic stirrer and<br />
thermometer was placed phenylaceticacid (0.2mol) in MDC (100 mL). To this, slowly<br />
added a solution of thionyl chloride (0.25mol) in MDC (25 mL) under nitrogen<br />
atmosphere. The reaction mixture was stirred for 2 hrs. The progress of reaction was<br />
monitored by thin layer chromatography. After completion, the reaction mixture was<br />
evaporated to dryness under vacuum and the residue directly used for next step.<br />
Synthesis of 1-(4-fluorophenyl)-2-phenylethanone (3).<br />
In a 250mL round bottom flask equipped with magnetic stirrer and<br />
thermometer was placed 2-phenylacetyl chloride (2, 1 mmol) and ZnO (powder, 0.5<br />
mmol) under nitrogen atmosphere. Slowly added fluorobenzne (1 mmol) in to<br />
reaction mixture at room temperature. Color (usually pink, but in few cases green or<br />
blue) developed immediately and darkened with progress of the reaction. The reaction<br />
mixture was kept at room temperature with occasional stirring for 1 h to complete the<br />
reaction (monitored by TLC). The solid mass was then eluted with dichloromethane<br />
(20 mL) and the dichloromethane extract was then washed with an aqueous solution<br />
of sodium bicarbonate and dried over anhydrous sodium sulfate. Evaporation of<br />
solvent furnished practically pure the corresponding product with 90 % yield. 108<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 177
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
Synthesis of 2-bromo-1-(4-fluorophenyl)-2-phenylethanone (4).<br />
In a 250mL round bottom flask equipped with magnetic stirrer and<br />
thermometer was placed 1-(4-fluorophenyl)-2-phenylethanone (3, 10 mmol) in<br />
methylene chloride (80 mL), slowly added Br 2 solution (10 mmol Br 2 in acetic acid<br />
(20 mL)) at below 10 o C. Stirred reaction mixture for 2-3 hrs at below 10 o C. After<br />
completion, reaction mixture poured in to ice water and extract in methylene chloride,<br />
separated organic layer wash with saturated sodium bicarbonate solution (2 x 50 mL)<br />
and brine solution (2 x 50 mL). The organic layer was separated, dried over<br />
anhydrous sodium sulfate and evaporated to dryness under reduce pressure. The<br />
residue was crystallized from methanol to afford 87 % yield, which was directly used<br />
for next step.<br />
General synthesis of acetoacetanilide derivatives (AAA-01-30).<br />
Compounds AAA-01-30 were prepared by following the procedure described<br />
in chapter-4.<br />
General synthesis of 1,4 dicarbonyl compounds (ADD-01-30).<br />
In a 50mL round bottom flask equipped with magnetic stirrer and thermometer<br />
was placed acetoacetanilide (AAA-01-30, 10 mmol), 2-bromo-1-(4-fluorophenyl)-2-<br />
phenylethanone (4, 10mmol), potassium carbonate (15mmol) and isopropyl alcohol<br />
(20 mL). Reaction mixture was heated at 50-55 o C for 4-5 h. The progress of reaction<br />
was monitored by thin layer chromatography. After completion, the reaction mixture<br />
was cooled to rt. The precipitate was collected by filtration and washed excessively<br />
with water and dried. The recrystallized from methanol to give analytically pure<br />
products in 70-80% yield.<br />
General synthesis of highly substituted pyrroles (AS-01-30).<br />
‣ Conventional method:<br />
In a 100mL round bottom flask equipped with dean-stark apparatus, magnetic<br />
stirrer and thermometer was placed with 1,4 dicarbonyl compound (ADD-01-30, 2<br />
mmol), amino side chain (5, 2 mmol), pivalic acid (2 mmol), cyclohexane (18 mL)<br />
and THF (2 mL). The reaction mixture was heated to reflux temperature for 30-40 h.<br />
The progress of reaction was monitored by thin layer chromatography.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 178
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
After completion, the reaction mixture was cooled to rt, washed with water and 5 (%)<br />
sodium bicarbonate solution. The organic layer was separated, dried over anhydrous<br />
sodium sulfate and evaporated to dryness under reduce pressure. The residue was<br />
crystallized from isopropyl alcohol/water (11:5) to obtain the desire product (68-85 %<br />
yield).<br />
‣ Microwave assisted method:<br />
A flat bottom flask was charged with the 1,4 dicarbonyl compound (ADD-01-<br />
30, 2 mmol), amino side chain (5, 2mmol), pivalic acid (2 mmol), cyclohexane (18<br />
mL) and THF (2 mL). The reaction mixture was irradiated under microwave for<br />
appropriate time (Table-2). The progress of reaction was monitored by thin layer<br />
chromatography. After completion, the reaction mixture was cooled to and washed<br />
with water, 5 % sodium bicarbonate solution. The organic layer was separated, dried<br />
over anhydrous sodium sulfate and evaporated to dryness under reduce pressure. The<br />
residue was crystallized from isopropyl alcohol/water (11:5) to obtain the desire<br />
product (85-95 % yield).<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 179
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
Spectral data of synthesized compounds<br />
2-acetyl-N-(4-ethylphenyl)-4-(4-fluorophenyl)-4-oxo-3-phenylbutanamide ADD-<br />
05. White solid, yield 82%, mp 190-192 ° C; R f 0.42 (9:1 Chloroform: Methanol); IR<br />
(KBr): 3473, 3072, 2895, 2828, 1694, 1635, 1482, 850, 780 cm -1 ; 1 H NMR (300<br />
MHz, DMSO): δ 1.06-1.11 (t, 3H, CH 3 ), 2.22 (s, 3H, CH 3 ), 2.44-2.47 (q, 2H CH 2 ),<br />
4.70-4.73 (d, 1H, CH, j=10.8Hz), 5.36–5.39 (d, 1H, CH, j=10.8Hz), 7.03-7.15 (m,<br />
3H, Ar), 7.18-7.35 (m, 8H, Ar), 8.09-8.13 (t, 2H, Ar), 10.16 (s, 1H, NH); MS (m/z):<br />
417 [M + ]; Anal. Calcd for C 26 H 24 FNO 3 : C, 74.80; H, 5.79; N, 3.36; Found: C, 74.82;<br />
H, 5.75; N, 3.33.<br />
N-(4-chlorophenyl)-2-(cyclopropanecarbonyl)-4-(4-fluorophenyl)-4-oxo-3-phenyl<br />
butanamide ADD-23. White solid, yield 85%, mp 220-222 ° C; R f 0.42 (9:1<br />
Chloroform: Methanol); IR (KBr): 3430, 3045, 2895, 1635, 1482, 1343, 1298, 980,<br />
783, 732 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ): δ 0.90-0.93 (m, 2H, CH 2 ), 1.05-1.13 (m,<br />
2H, CH 2 ), 2.18-2.23 (m, 1H, CH), 4.77-4.80 (d, 1H, CH, j=10.84Hz), 4.49–5.51 (d,<br />
1H, CH, j=10.84Hz), 6.84-6.89 (m, 2H, Ar), 7.00-7.09 (m, 4H, Ar), 7.18-7.27 (m,<br />
3H, Ar), 7.34-7.40 (m, 2H, Ar); 13 C NMR (100 MHz, CDCl 3 ): δ 11.82, 13.12. 20.34,<br />
53.10, 66.10, 115.42, 115.90, 121.83, 122.56, 128.13, 128.70, 129.03, 129.25, 129.39,<br />
131.66, 131.75, 123.16, 132.19, 132.92, 132.95, 160.94, 167.04, 196.70, 205.50; MS<br />
(m/z): 449 [M + ]; Anal. Calcd for C 26 H 21 ClFNO 3 : C, 69.41; H, 4.70; N, 3.11; Found:<br />
C, 69.43; H, 4.75; N, 3.13.<br />
tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-methyl-3-phenyl-4-(p-tolylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate<br />
AS-01. White<br />
solid, mp 167-169 ° C; R f 0.42 (9:1 Chloroform: Methanol); IR (KBr): 3412, 3032,<br />
2977, 2872, 1731, 1659, 1479, 1029, 792, 737, 709 cm -1 ; MS (m/z): 625 [M + ]; Anal.<br />
Calcd for C 38 H 42 FN 2 O 5 : C, 72.94; H, 6.77; N, 4.48; Found: C, 72.95; H, 6.78; N, 4.50.<br />
tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-4-((4-methoxyphenyl)carbamoyl)-<br />
5-methyl-3-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate<br />
AS-02. White solid, mp 153-155 ° C; R f 0.47 (9:1 Chloroform: Methanol); IR (KBr):<br />
3477, 3037, 2981, 2928, 2878, 1729, 1665, 1567, 1542, 1482, 1288, 1083, 1035, 837,<br />
789, 741, 711 cm -1 ; MS (m/z): 656 [M + ]; Anal. Calcd for C 38 H 42 FN 2 O 6 : C, 71.32; H,<br />
6.91; N, 4.27; Found: C, 71.35; H, 6.92; N, 4.28.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 180
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
tert-butyl 2-((4R,6R)-6-(2-(3-((4-chlorophenyl)carbamoyl)-5-(4-fluorophenyl)-2-<br />
methyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate AS-<br />
03. White solid, mp 147-149 ° C; R f 0.47 (9:1 Chloroform: Methanol); IR (KBr): 3458,<br />
3035, 2988, 2932, 2881, 1731, 1675, 1564, 1547, 1486, 1291, 1087, 1037, 841 cm -1 ;<br />
MS (m/z): 660 [M + ]; Anal. Calcd for C 38 H 42 ClFN 2 O 5 : C, 69.03; H, 6.40; N, 4.24;<br />
Found: C, 69.05; H, 6.42; N, 4.28.<br />
tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-4-((4-fluorophenyl)carbamoyl)-5-<br />
methyl-3-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate AS-<br />
04. White solid, mp 153-155 ° C; R f 0.52 (9:1 Chloroform: Methanol); IR (KBr): 3411,<br />
3030, 2979, 2937, 2879, 1725, 1660, 1560, 1535, 1473, 1290, 1095, 1031, 833, 790,<br />
735, 705 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 1.03-1.07 (m, 1H, CH), 1.30-1.63 (m,<br />
18H, CH 2 , CH & 5 x CH 3 ), 2.24-2.37 (m, 2H, CH 2 ), 2.71 (s, 3H, CH 3 ), 3.66 (m, 1H,<br />
CH), 3.86-3.99 (m, 2H, CH 2 ), 4.14-4.17 (m, 1H, CH), 6.83-7.00 (m, 7H, Ar), 7.12-<br />
7.28 (m, 7H, Ar & NH); 13 C NMR (DEPT): (75 MHz, CDCl 3 ): δ 11.61, 19.62. 28.09,<br />
29.96, 36.05, 37.16, 40.23, 42.46, 65.88, 65.96, 115.11, 115.26, 115.41, 115.54,<br />
120.66, 120.77, 127.31, 128.66, 131.16, 132.84, 132.95; MS (m/z): 644 [M + ]; Anal.<br />
Calcd for C 38 H 42 F 2 N 2 O 5 : C, 70.79; H, 6.57; N, 4.34; Found: C, 70.75; H, 6.52; N,<br />
4.38.<br />
tert-butyl 2-((4R,6R)-6-(2-(3-((4-ethylphenyl)carbamoyl)-5-(4-fluorophenyl)-2-<br />
methyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate AS-<br />
05. White solid, mp 172-174 ° C; R f 0.54 (9:1 Chloroform: Methanol); IR (KBr): 3402,<br />
3063, 2995, 2974, 2875, 1724, 1660, 1533, 1255, 842, 734, 705 cm -1 ; 1 H NMR (300<br />
MHz, CDCl 3 ): δ ppm 1.16-1.18 (m, 4H, CH & CH 3 ), 1.31-1.76 (m, 18H, CH, CH 2 &<br />
5 x CH 3 ), 2.21-2.36 (m, 2H, CH 2 ), 2.53-2.55 (m, 2H, CH 2 ), 2.71 (s, 3H, CH 3 ), 3.66<br />
(m, 1H, CH), 3.89-3.97 (m, 2H, CH 2 ), 4.17 (m, 1H, CH), 6.91-6.99 (m, 7H, Ar),<br />
7.14-7.26 (m, 7H, Ar & NH); 13 C NMR (DEPT): (75 MHz, CDCl 3 ): δ 11.61, 15.72.<br />
19.62, 28.09, 28.25, 29.97, 36.05, 37.18, 40.20, 42.48, 65.89, 65.98, 115.23, 115.51,<br />
120.66, 119.30, 128.03, 128.62, 131.15, 132.87, 132.97; MS (m/z): 654 [M + ]; Anal.<br />
Calcd for C 40 H 47 FN 2 O 5 : C, 73.37; H, 7.23; N, 4.28; Found: C, 73.35; H, 7.25; N, 4.28.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 181
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-methyl-4-((4-nitrophenyl)carbamoyl)-3-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate<br />
AS-<br />
06. White solid, mp 183-185 ° C; R f 0.44 (9:1 Chloroform: Methanol); IR (KBr): 3428,<br />
3036, 2979, 2945, 2887, 1723, 1659, 1567, 1541, 1471, 1287, 1095, 1038, 834, 792,<br />
746, 712 cm -1 ; MS (m/z): 671 [M + ]; Anal. Calcd for C 38 H 42 FN 3 O 7 : C, 67.94; H, 6.30;<br />
N, 6.26; Found: C, 67.95; H, 6.25; N, 6.28.<br />
tert-butyl 2-((4R,6R)-6-(2-(3-((2,5-dimethylphenyl)carbamoyl)-5-(4-fluorophenyl)<br />
-2-methyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate<br />
AS-07. White solid, mp 143-145 ° C; R f 0.51 (9:1 Chloroform: Methanol); IR (KBr):<br />
3433, 3035, 2972, 2951, 2881, 1729, 1661, 1563, 1545, 1477, 1291, 1086, 1041, 882,<br />
839, 786, 751, 707 cm -1 ; MS (m/z): 654 [M + ]; Anal. Calcd for C 40 H 47 FN 2 O 5 : C,<br />
73.37; H, 7.23; N, 4.28; Found: C, 73.35; H, 7.25; N, 4.28.<br />
tert-butyl 2-((4R,6R)-6-(2-(3-((3-chloro-4-fluorophenyl)carbamoyl)-5-(4-fluorophenyl)-2-methyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)<br />
acetate AS-08. White solid, mp 135-138 ° C; R f 0.51 (9:1 Chloroform: Methanol); IR<br />
(KBr): 3405, 3043, 2985, 2972, 2863, 1739, 1675, 1555, 1565, 1464, 1287, 1074,<br />
1034, 839, 786, 758, 718 cm -1 ; MS (m/z): 678 [M + ]; Anal. Calcd for C 38 H 41 ClF 2 N 2 O 5 :<br />
C, 67.20; H, 6.08; N, 4.12; Found: C, 67.25; H, 6.10; N, 4.13.<br />
tert-butyl 2-((4R,6R)-6-(2-(3-((3,4-dichlorophenyl)carbamoyl)-5-(4-fluorophenyl)<br />
-2-methyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate<br />
AS-09. White solid, mp 157-159 ° C; R f 0.44 (9:1 Chloroform: Methanol); IR (KBr):<br />
3447, 3024, 2956, 2964, 2878, 1746, 1661, 1569, 1545, 1447, 1278, 1064, 1049, 831,<br />
775, 767, 713 cm -1 ; MS (m/z): 694 [M + ]; Anal. Calcd for C 38 H 41 Cl 2 FN 2 O 5 : C, 65.61;<br />
H, 5.94; N, 4.03; Found: C, 65.62; H, 5.95; N, 4.03.<br />
tert-butyl 2-((4R,6R)-6-(2-(3-((2,3-dimethylphenyl)carbamoyl)-5-(4-fluorophenyl)<br />
-2-methyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate<br />
AS-10. White solid, mp 143-145 ° C; R f 0.51 (9:1 Chloroform: Methanol); IR (KBr):<br />
3416, 3039, 2967, 2977, 2861, 1734, 1679, 1545, 1565, 1442, 1297, 1043, 1034, 842,<br />
787, 743, 719 cm -1 ; MS (m/z): 654 [M + ]; Anal. Calcd for C 40 H 47 FN 2 O 5 : C, 73.37; H,<br />
7.23; N, 4.28; Found: C, 73.34; H, 7.26; N, 4.30.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 182
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-4-((4-methoxyphenyl)-<br />
carbamoyl)-3-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate<br />
AS-12. White solid, mp 174-176 ° C; R f 0.45 (9:1 Chloroform: Methanol); IR (KBr):<br />
3412, 3031, 2989, 2935, 2868, 1737, 1671, 1558, 1554, 1474, 1298, 1087, 1047, 845,<br />
775, 734, 703 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 1.06 (m, 1H, CH), 1.30-1.65 (m,<br />
24H, CH, CH 2 & 7 x CH 3 ), 2.25-2.37 (m, 2H, CH 2 ), 3.54 (m, 3H, CH), 3.73 (m, 5H,<br />
CH 3 & 2 x CH), 4.14 (m, 2H, CH 2 ), 6.72-6.75 (d, 3H, J=7.5Hz, Ar), 6.99 (s, 4H, Ar),<br />
7.16 (s, 7H, Ar & NH); 13 C NMR (DEPT): (75 MHz, CDCl 3 ): δ 19.68, 21.64, 21.82,<br />
26.10, 28.09, 29.92, 35.97, 38.09, 40.79, 42.46, 65.90, 66.41, 113.86, 115.22, 115.50,<br />
121.47, 126.45, 128.29, 130.46, 133.14, 133.25; MS (m/z): 684 [M + ]; Anal. Calcd for<br />
C 41 H 49 FN 2 O 6 : C, 71.91; H, 7.21; N, 4.09; Found: C, 71.94; H, 7.26; N, 4.09.<br />
tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(p-tolylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate<br />
AS-11.<br />
White solid, mp 158-160 ° C; R f 0.47 (9:1 Chloroform: Methanol); IR (KBr): 3477,<br />
3037, 2987, 2939, 2878, 1735, 1651, 1567, 1529, 1474, 1291, 1082, 1037, 837, 798,<br />
731, 704 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 1.02-1.10 (m, 1H, CH), 1.30-1.66 (m,<br />
24H, CH, CH 2 & 7 x CH 3 ), 2.24-2.42 (m, 5H, CH 2 & CH 3 ), 3.53-3.84 (m, 3H, CH &<br />
CH 2 ), 4.07-4.16 (m, 2H, 2 x CH), 6.80 (s, 1H, NH), 6.98-7.26 (m, 13H, Ar); 13 C<br />
NMR (DEPT): (75 MHz, CDCl 3 ): δ 19.68, 20.83, 21.62, 21.80, 26.09, 28.09, 29.93,<br />
35.97, 38.09, 40.82, 42.46, 65.90, 66.41, 115.22, 115.51, 119.63, 126.48, 128.31,<br />
129.19, 130.47, 133.14, 133.25; MS (m/z): 668 [M + ]; Anal. Calcd for C 41 H 49 FN 2 O 5 :<br />
C, 73.63; H, 7.38; N, 4.19; Found: C, 73.64; H, 7.36; N, 4.19.<br />
tert-butyl 2-((4R,6R)-6-(2-(3-((4-chlorophenyl)carbamoyl)-5-(4-fluorophenyl)-2-<br />
isopropyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate.<br />
AS-13. White solid, yield 94%, mp 184-186 ° C; R f 0.46 (9:1 Chloroform: Methanol);<br />
IR (KBr): 3410, 3041, 2992, 2943, 2875, 1744, 1677, 1474, 1287, 1075, 1047, 846<br />
cm -1 ; 1 H NMR (400 MHz, CDCl 3 ): δ 0.92-1.01 (m, 1H, CH), 1.22 (s, 3H, CH 3 ), 1.26-<br />
1.28 (m, 4H, CH & CH 3 ), 1.35-137 (s, 9H, 3 x CH 3 ), 1.43-1.45 (d, 6H, 2 x CH 3 ),<br />
1.56-1.60 (m, 2H, CH 2 ), 2.07-2.18 (dd, 1H, CH), 2.27-2.33 (dd, 1H, CH), 3.48-3.53<br />
(m, 1H, CH), 3.60-3.62 (m, 1H, CH), 3.73-3.76 (m, 1H, CH), 3.96-4.09 (m, 2H, CH 2 ),<br />
6.76 (s, 1H, NH), 6.88-6.92 (m, 4H, Ar), 7.02-7.18 (m, 9H, Ar & NH);<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 183
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
13 C NMR: (100 MHz, CDCl 3 ): δ 19.68, 21.50, 21.67, 26.07, 28.09, 29.93, 35.96,<br />
38.07, 40.91, 42.45, 65.90, 66.39, 98.69, 114.88, 115.29, 115.50, 120.61, 121.77,<br />
126.70, 128.09, 128.12, 128.25, 128.43, 128.64, 128.93, 130.55, 133.14,<br />
133.22,134.62, 137.04, 141.93, 161.06, 163.52, 164.68, 170.20; MS (m/z): 688 [M + ];<br />
Anal. Calcd for C 40 H 46 ClFN 2 O 5 : C, 69.70; H, 6.73; N, 4.06; Found: C, 69.70; H, 6.74;<br />
N, 4.09.<br />
tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-4-((4-fluorophenyl)carbamoyl)-5-<br />
isopropyl-3-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate<br />
AS-14. White solid, mp 170-172 ° C; R f 0.48 (9:1 Chloroform: Methanol); IR (KBr):<br />
3437, 3039, 2985, 2948, 2865, 1739, 1675, 1563, 1549, 1486, 1281, 1087, 1048, 837,<br />
787, 744, 716 cm -1 ; MS (m/z): 672 [M + ]; Anal. Calcd for C 40 H 46 F 2 N 2 O 5 : C, 71.41; H,<br />
6.89; N, 4.16; Found: C, 71.41; H, 6.84; N, 4.19.<br />
tert-butyl 2-((4R,6R)-6-(2-(3-((4-ethylphenyl)carbamoyl)-5-(4-fluorophenyl)-2-<br />
isopropyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate<br />
AS-15. White solid, mp 202-204 ° C; R f 0.55 (9:1 Chloroform: Methanol); IR (KBr):<br />
3429, 3039, 2975, 2954, 2895, 1736, 1665, 1571, 1542, 1461, 1287, 1081, 1043, 831,<br />
784, 739, 713 cm -1 ; MS (m/z): 682 [M + ]; Anal. Calcd for C 42 H 51 FN 2 O 5 : C, 73.87; H,<br />
7.53; N, 4.10; Found: C, 73.81; H, 7.54; N, 4.10.<br />
tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-4-((4-nitrophenyl)<br />
carbamoyl)-3-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate<br />
AS-16. White solid, mp 188-190 ° C; R f 0.48 (9:1 Chloroform: Methanol); IR (KBr):<br />
3427, 3045, 2969, 2956, 2875, 1729, 1678, 1581, 1557, 1464, 1271, 1097, 1045, 839,<br />
781, 758, 721 cm -1 ; MS (m/z): 699 [M + ]; Anal. Calcd for C 40 H 46 FN 3 O 7 : C, 68.65; H,<br />
6.63; N, 6.00; Found: C, 68.86; H, 6.64; N, 6.05.<br />
tert-butyl 2-((4R,6R)-6-(2-(3-((2,5-dimethylphenyl)carbamoyl)-5-(4-fluorophenyl)<br />
-2-isopropyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate<br />
AS-17. White solid, mp 157-159 ° C; R f 0.41 (9:1 Chloroform: Methanol); IR (KBr):<br />
3415, 3048, 2979, 2948, 2875, 1739, 1678, 1579, 1555, 1464, 1276, 1071, 1049, 876,<br />
849, 765, 749, 716 cm -1 ; MS (m/z): 682 [M + ]; Anal. Calcd for C 42 H 51 FN 2 O 5 : C,<br />
73.87; H, 7.53; N, 4.10; Found: C, 73.84; H, 7.54; N, 4.12.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 184
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
tert-butyl 2-((4R,6R)-6-(2-(3-((3-chloro-4-fluorophenyl)carbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)<br />
acetate AS-18. White solid, mp 144-146 ° C; R f 0.46 (9:1 Chloroform: Methanol); IR<br />
(KBr): 3399, 3053, 2975, 2982, 2875, 1736, 1684, 1564, 1573, 1475, 1283, 1062,<br />
1041, 833, 781, 752, 703 cm -1 ; MS (m/z): 706 [M + ]; Anal. Calcd for C 40 H 45 ClF 2 N 2 O 5 :<br />
C, 67.93; H, 6.41; N, 3.96; Found: C, 67.94; H, 6.42; N, 3.97.<br />
tert-butyl 2-((4R,6R)-6-(2-(3-((3,4-dichlorophenyl)carbamoyl)-5-(4-fluorophenyl)<br />
-2-isopropyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate<br />
AS-19. White solid, mp 136-138 ° C; R f 0.38 (9:1 Chloroform: Methanol); IR (KBr):<br />
3425, 2964, 2974, 2863, 1756, 1672, 1575, 1549, 1457, 1288, 1068, 1053, 836, 764,<br />
772, 719 cm -1 ; MS (m/z): 722 [M + ]; Anal. Calcd for C 40 H 45 Cl 2 FN 2 O 5 : C, 66.39; H,<br />
6.27; N, 3.87; Found: C, 66.40; H, 6.30; N, 3.88.<br />
tert-butyl 2-((4R,6R)-6-(2-(3-((2,3-dimethylphenyl)carbamoyl)-5-(4-fluorophenyl)<br />
-2-isopropyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate<br />
AS-20. White solid, mp 180-182 ° C; R f 0.41 (9:1 Chloroform: Methanol); IR (KBr):<br />
3417, 3048, 2957, 2985, 2875, 1748, 1663, 1557, 1579, 1457, 1285, 1052, 1038, 857,<br />
757, 763, 709 cm -1 ; MS (m/z): 682 [M + ]; Anal. Calcd for C 42 H 51 FN 2 O 5 : C, 73.87; H,<br />
7.53; N, 4.10; Found: C, 73.84; H, 7.54; N, 4.12.<br />
tert-butyl 2-((4R,6R)-6-(2-(2-cyclopropyl-5-(4-fluorophenyl)-4-phenyl-3-(p-tolylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate<br />
AS-21.<br />
White solid, mp 163-165 ° C; R f 0.35 (9:1 Chloroform: Methanol); IR (KBr): 3441,<br />
3228, 3101, 2978, 2941, 1730, 1643, 1491. 1247, 833, 738, 704 cm -1 ; 1 H NMR (300<br />
MHz, CDCl 3 ): δ 0.77 (m, 2H, CH 2 ), 0.99-1.11 (m, 3H, CH 2 & CH), 1.21-1.59 (m,<br />
19H, 2 x CH 2 & 5 x CH 3 ), 1.91 (m, 1H, CH), 2.20-2.37 (m, 5H, CH & 2 x CH 2 ), 3.63<br />
(m, 1H, CH), 4.14 (m, 3H, CH & CH 2 ), 6.84 (s, 1H, NH), 6.99-7.26 (m, 13H, Ar); 13 C<br />
NMR (DEPT): (75 MHz, CDCl 3 ): δ 6.81, 7.54, 7.63, 19.62, 20.84, 28.09, 29.96,<br />
36.01, 37.19, 40.38, 42.50, 65.91, 66.14, 115.32, 115.61, 119.50, 126.46, 128.27,<br />
129.25, 130.42, 132.80, 132.90; MS (m/z): 666 [M + ]; Anal. Calcd for C 41 H 47 FN 2 O 5 :<br />
C, 73.85; H, 7.10; N, 4.20; Found: C, 73.84; H, 7.04; N, 4.22.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 185
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
tert-butyl 2-((4R,6R)-6-(2-(2-cyclopropyl-5-(4-fluorophenyl)-3-((4-methoxyphenyl)carbamoyl)-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)<br />
acetate AS-22. White solid, mp 163-165 ° C; R f 0.35 (9:1 Chloroform: Methanol); IR<br />
(KBr): 3421, 3045, 2975, 2948, 2852, 1742, 1664, 1569, 1567, 1461, 1291, 1079,<br />
1041, 851, 781, 745, 714 cm -1 ; MS (m/z): 682 [M + ]; Anal. Calcd for C 41 H 47 FN 2 O 6 : C,<br />
72.12; H, 6.94; N, 4.10; Found: C, 72.12; H, 6.95; N, 4.12.<br />
tert-butyl 2-((4R,6R)-6-(2-(3-((4-chlorophenyl)carbamoyl)-2-cyclopropyl-5-(4-<br />
fluorophenyl)-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)<br />
acetate AS-23. White solid, mp 193-194 ° C; R f 0.45 (9:1 Chloroform: Methanol); IR<br />
(KBr): 3452, 3052, 2987, 2939, 2884, 1753, 1679, 1564, 1559, 1482, 1267, 1065,<br />
1039, 856 cm -1 ; MS (m/z): 686 [M + ]; Anal. Calcd for C 40 H 44 ClFN 2 O 5 : C, 69.91; H,<br />
6.45; N, 4.08; Found: C, 69.95; H, 6.48; N, 4.12.<br />
tert-butyl 2-((4R,6R)-6-(2-(2-cyclopropyl-5-(4-fluorophenyl)-3-((4-fluorophenyl)<br />
carbamoyl)-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate<br />
AS-24. White solid, mp 172-174 ° C; R f 0.38 (9:1 Chloroform: Methanol); IR (KBr):<br />
3499, 3052, 2975, 2957, 2854, 1742, 1665, 1572, 1556, 1478, 1271, 1073, 1053, 831,<br />
782, 754, 726 cm -1 ; MS (m/z): 670 [M + ]; Anal. Calcd for C 40 H 44 F 2 N 2 O 5 : C, 71.62; H,<br />
6.61; N, 4.18; Found: C, 71.63; H, 6.58; N, 4.12.<br />
tert-butyl 2-((4R,6R)-6-(2-(2-cyclopropyl-3-((4-ethylphenyl)carbamoyl)-5-(4-<br />
fluorophenyl)-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)<br />
acetate AS-25. White solid, mp 112-115 ° C; R f 0.45 (9:1 Chloroform: Methanol); IR<br />
(KBr): 3438, 3043, 2965, 2943, 2887, 1736, 1645, 1562, 1532, 1456, 1272, 1061,<br />
1031, 821, 774, 729, 703 cm -1 ; MS (m/z): 680 [M + ]; Anal. Calcd for C 42 H 49 FN 2 O 5 : C,<br />
74.09; H, 7.25; N, 4.11; Found: C, 74.13; H, 7.28; N, 4.12.<br />
tert-butyl 2-((4R,6R)-6-(2-(2-cyclopropyl-5-(4-fluorophenyl)-3-((4-nitrophenyl)-<br />
carbamoyl)-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate<br />
AS-26. White solid, mp 132-134 ° C; R f 0.52 (9:1 Chloroform: Methanol); IR (KBr):<br />
3413, 3052, 2972, 2961, 2865, 1739, 1688, 1571, 1562, 1476, 1269, 1084, 1051, 842,<br />
778, 768, 728 cm -1 MS (m/z): 697 [M + ]; Anal. Calcd for C 40 H 44 FN 3 O 7 : C, 68.85; H,<br />
6.36; N, 6.02; Found: C, 68.87; H, 6.38; N, 6.08.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 186
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
tert-butyl 2-((4R,6R)-6-(2-(2-cyclopropyl-3-((2,5-dimethylphenyl)carbamoyl)-5-<br />
(4-fluorophenyl)-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)<br />
acetate AS-27. White solid, mp 210-212 ° C; R f 0.38 (9:1 Chloroform: Methanol); IR<br />
(KBr): 3440, 3053, 2987, 2951, 2868, 1746, 1687, 1554, 1571, 1445, 1268, 1061,<br />
1067, 856, 859, 774, 752, 722 cm -1 ; MS (m/z): 680 [M + ]; Anal. Calcd for<br />
C 42 H 49 FN 2 O 5 : C, 74.09; H, 7.25; N, 4.11; Found: C, 74.13; H, 7.28; N, 4.12.<br />
tert-butyl 2-((4R,6R)-6-(2-(3-((3-chloro-4-fluorophenyl)carbamoyl)-2-cyclopropyl<br />
-5-(4-fluorophenyl)-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)<br />
acetate AS-28. White solid, mp 169-171 ° C; R f 0.47 (9:1 Chloroform: Methanol); IR<br />
(KBr): 3428, 3041, 2965, 2997, 2885, 1726, 1675, 1566, 1587, 1464, 1278, 1072,<br />
1052, 836, 775, 759, 713 cm -1 ; MS (m/z): 680 [M + ]; Anal. Calcd for C 40 H 43 ClF 2 N 2 O 5 :<br />
C, 68.12; H, 6.15; N, 3.97; Found: C, 68.13; H, 6.18; N, 4.01.<br />
tert-butyl 2-((4R,6R)-6-(2-(2-cyclopropyl-3-((3,4-dichlorophenyl)carbamoyl)-5-(4-<br />
fluorophenyl)-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)<br />
acetate AS-29. White solid, mp 133-135 ° C; R f 0.35 (9:1 Chloroform: Methanol); IR<br />
(KBr): 3472, 3120, 3073, 2975, 2985, 2879, 1763, 1665, 1581, 1553, 1468, 1276,<br />
1079, 1045, 842, 771, 768, 729 cm -1 ; MS (m/z): 720 [M + ]; Anal. Calcd for<br />
C 40 H 43 Cl 2 FN 2 O 5 : C, 66.57; H, 6.01; N, 3.88; Found: C, 66.49; H, 6.10; N, 3.95.<br />
tert-butyl 2-((4R,6R)-6-(2-(2-cyclopropyl-3-((2,3-dimethylphenyl)carbamoyl)-5-<br />
(4-fluorophenyl)-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)<br />
acetate AS-30. White solid, mp 123-125 ° C; R f 0.40 (9:1 Chloroform: Methanol); IR<br />
(KBr): 3423, 3039, 2948, 2981, 2865, 1769, 1678, 1547, 1587, 1443, 1278, 1064,<br />
1045, 864, 752, 768, 718 cm -1 ; MS (m/z): 680 [M + ]; Anal. Calcd for C 42 H 49 FN 2 O 5 : C,<br />
74.09; H, 7.25; N, 4.11; Found: C, 74.13; H, 7.28; N, 4.12.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 187
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
1 H NMR spectrum of compound ADD-23<br />
Cl<br />
O<br />
N<br />
H<br />
O<br />
O<br />
F<br />
Expanded 1 H NMR spectrum of compound ADD-23<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 188
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
1 H NMR spectrum of compound AS-04<br />
Expanded 1 H NMR spectrum of compound AS-04<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 189
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
1 H NMR spectrum of compound AS-13<br />
Cl<br />
N<br />
H<br />
O<br />
N<br />
O<br />
O<br />
O<br />
O<br />
F<br />
Expanded 1 H NMR spectrum of compound AS-13<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 190
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
1 H NMR spectrum of compound AS-21<br />
Expanded 1 H NMR spectrum of compound AS-21<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 191
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
1 H NMR spectrum of compound AS-11<br />
1 H NMR spectrum of compound AS-12<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 192
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
13 C NMR spectrum of compound AS-11<br />
O<br />
N<br />
H<br />
N<br />
O<br />
O<br />
O<br />
O<br />
F<br />
13 C NMR spectrum of compound AS-13<br />
Cl<br />
N<br />
H<br />
O<br />
N<br />
O<br />
O<br />
O<br />
O<br />
F<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 193
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
MASS spectrum of compound ADD-05<br />
MASS spectrum of compound ADD-11<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 194
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
MASS spectrum of compound AS-12<br />
MASS spectrum of compound AS-13<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 195
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
IR spectrum of compound AS-05<br />
100<br />
%T<br />
75<br />
50<br />
3063.06<br />
2995.55<br />
2937.68<br />
2875.96<br />
1097.53<br />
1033.88<br />
956.72<br />
920.08<br />
734.90<br />
705.97<br />
669.32<br />
601.81<br />
25<br />
0<br />
F<br />
3402.54<br />
2974.33<br />
N<br />
H<br />
O<br />
N<br />
O<br />
1724.42<br />
O<br />
1660.77<br />
1591.33<br />
1533.46<br />
1516.10<br />
O<br />
1411.94<br />
1367.58<br />
1313.57<br />
1284.63<br />
1255.70<br />
1217.12<br />
1203.62<br />
1174.69<br />
1155.40<br />
1130.32<br />
842.92<br />
532.37<br />
468.72<br />
-25<br />
O<br />
-50<br />
F<br />
4000<br />
3500<br />
3000<br />
2500<br />
2000<br />
1750<br />
1500<br />
1250<br />
1000<br />
750<br />
500<br />
1/cm<br />
IR spectrum of compound AS-21<br />
100<br />
%T<br />
90<br />
80<br />
3441.12<br />
3228.95<br />
3101.64<br />
2978.19<br />
1491.02<br />
2941.54<br />
1730.21<br />
1643.41<br />
1593.25<br />
1539.25<br />
1394.58<br />
1367.58<br />
1329.00<br />
1247.99<br />
1201.69<br />
1109.11<br />
1010.73<br />
949.01<br />
761.91<br />
738.76<br />
704.04<br />
588.31<br />
70<br />
667.39<br />
60<br />
1506.46<br />
1153.47<br />
833.28<br />
532.37<br />
50<br />
505.37<br />
40<br />
4000<br />
3500<br />
3000<br />
2500<br />
2000<br />
1750<br />
1500<br />
1250<br />
1000<br />
750<br />
500<br />
1/cm<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 196
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
5.10 References<br />
1. Jones, R., Bean, G.; The chemistry of pyrroles, Academic press, London 1977.<br />
2. Gossauer, A.; Die chemie der pyrrole, Springer-Verleg, Berlin 1974.<br />
3. Trofimov, B.; Usp. Chim., 1989, 58 , 1703.<br />
4. Jones, R. (Ed.); Chem. Heterocycl. Compd., 1990, 48(1), Wiley Interscience, New York.<br />
5. Jones, R. in E. C. Taylor (Ed.); Chem. Heterocycl. Compd., 1992, 48(2), Wiley Interscience,<br />
New York.<br />
6. Sundberg, R. in A. R. Kartritzky and C.W.Rees(Eds.); Comprehensive Heterocyclic Chemistry,<br />
1984, 4, 313.<br />
7. Jones, R. in A. R. Kartritzky and C. W. Rees(Eds.), Comprehensive Heterocyclic Chemistry,<br />
1984, 4, 201<br />
8. Fabino, E., Golding, B.; J. Chem. Soc. Perk. Trans., 1991, 1, 3371.<br />
9. Moss, G.; Pure Appl. Chem., 1987, 59, 807.<br />
10. Curran, D., Grimshaw J., Perera S.; Chem. Soc. Rev., 1991, 20, 391.<br />
11. Sundberg, R., Nguyen, P. in H.Suschitzky and E. Scriven(Edn.),; Progress in Heterocyclic<br />
Chemistry, 1994, 6,110.<br />
12. Khetan, S., Hiriyakkanavar, J., George, M.; Tetrahedron, 1968, 24, 1567.<br />
13. Meyer, H.; Leibigs, Ann. Chem., 1981, 1534.<br />
14. Friedman, M.; J. Org. Chem., 1965, 30, 859.<br />
15. Posvic, H., Dombro, R., Ito, H., Telinski, T.; J. Org. Chem., 1974, 39, 2575.<br />
16. Tanaseichuk, B., Vlasova, S., Morozov, E.; Org. Khim Zh., 1971, 7, 1264.<br />
17. Suzuki, M., Miyoshi, M., Matsumoto, K.; J. Org. Chem., 1974, 39, 1980.<br />
18. Kartritzky, A., Suwinski, J.; Tetrahedron, 1975, 31, 1549<br />
19. Kozlov, N., Moiseenok, L., Kozintsev, S.; Khim. Geterosikl. Soedin., 1979, 1483.<br />
20. Backvall, J., Nystrom, J.; J. Chem. Soc. Chem. Commun., 1981, 59.<br />
21. Makhsumov, A., Safaev, A., Madikhanov, N.; Khim. Geterosikl. Soedin., 1970, 125.<br />
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1293.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 197
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
32. (a) Carlson, R., Nilsson, A., Stroemqvist, M.; Acta Chem. Scand., B37, 1983, 7. (b) Selva, M.,<br />
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Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 198
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
61. Heym, B., Honore, N., Truffot-Pernot, C., Banerjee, A., Schurra, C., Jacobs W., Van Embden J.,<br />
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R., Eessalu, T., Wagner, J., Campbell, R., Vaughn, R.; J. Med. Chem., 2004, 47, 3934.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 199
Chapter-5<br />
Synthesis of highly substituted pyrroles<br />
80. Dean, D. K.; Naylor, A.; Takle, A. K.; Wilson, D. M.; PCT. 2003, WO 2003022833 A1<br />
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G.; J. Org. Chem. 1991, 56, 6924.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 200
Chapter - 6<br />
Synthesis and Characterization of Some<br />
New Benzodiazepine Derivatives<br />
1
Chapter 6<br />
Synthesis of benzodiazepines<br />
6.1 Introduction<br />
The clinical importance and commercial success associated with the 1,4-<br />
benzodiazepine class of central nervous system (CNS)-active agents and the utility of<br />
1,4-diazepines as peptide mimetic scaffolds have led to their recognition by the<br />
medicinal chemistry community as privileged structures. This ring system has<br />
demonstrated considerable utility in drug design, with derivatives demonstrating a<br />
wide range of biological activities.<br />
The ring numbering and accepted system of nomenclature for 1,4-diazepines<br />
are illustrated in the structures (Figure-1). These structures are representatives of the<br />
tautomeric forms that have been most studied. Examples of all the fully unsaturated<br />
monocyclic 1,4-diazepines have been described and all are very unstable. In the<br />
dihydro-1,4-diazepines, the 2,3-dihydro-1H compounds have been studied most. For<br />
benzo-analogues the 3H series are usually more stable than 1H and although the<br />
parent compounds of both series are unknown, there is an extensive chemistry on<br />
substituted analogous especially in 3H series. The benzodiazepine-2-ones have been<br />
widely studied as benefits their commercial importance.<br />
Figure-1<br />
On the other hand, examples of the serendipitous discovery of new drugs<br />
based on an almost random screening of chemicals synthesized in the laboratory are<br />
striking. Since 1960, when chlordiazepoxide (Librium) entered in the market, efforts<br />
to discover new biologically active compounds with limited side effects in<br />
benzodiazepines are going on which are reflected by the important number of<br />
publication focused in this subject. 1-5<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 201
Chapter 6<br />
Synthesis of benzodiazepines<br />
Diazepine derivatives constitute an important class of heterocyclic compounds<br />
which possess a wide range of therapeutic and pharmacological properties.<br />
Derivatives of benzodiazepines are widely used as anticonvulsant, antianxiety,<br />
analgesic, sedative, anti-depressive, and hypnotic agents 6-7 as well as antiinflammatory<br />
agents. 8 In the last decade, the area of biological interest of 1,5-<br />
benzodiazepines has been extended to several diseases such as cancer, viral infection<br />
and cardiovascular disorders. 9-10 In addition,1,5-benzodiazepines are key<br />
intermediates for the synthesis of various fused ring systems such astriazolo-,<br />
oxadiazolo-, oxazino- or furanobenzodiazepines. 11-14 Besides, benzodiazepine<br />
derivatives are also of commercial importance as dyes for acrylic fibers in<br />
photography. 15 Owing to their versatile applications various methods for the synthesis<br />
of benzodiazepines have been reported in the literature. These include condensation<br />
reactions of o-phenylenediamines with α,β-unsaturated carbonylcompounds, 16 with<br />
ketones in the presence of BF 3·Et 2 O, NaBH 4 , polyphosphoric acid or SiO 2 ,<br />
MgO/POCl 3 , Yb(OTf) 3 , Al 2 O 3 /P 2 O 5 or AcOH under microwave conditions,<br />
Amberlyst-15 in the ionic liquid 1-butyl-3-methylimidazoliumbromide ([bmim]Br),<br />
CeCl 3·7H 2 O/NaI supported on silica gel,InBr 3 , Sc(OTf) 3 , sulfated zirconia, InCl 3 ,<br />
CAN, ZnCl 2 under thermal conditions, AgNO 3 . 17-32<br />
Among all types of benzodiazepines (1,2-,1,3-, 1,4-, 1,5-, 2,3-, & 2,4- ) only<br />
1,4- and 1,5-benodiazepines have found wide applications in medicines, during one of<br />
the most important classes of the therapeutic agents with wide spread biological<br />
activities 33 including hypnotics, sedatives, anxiolytics and antianxiety etc, effect range<br />
from their well-documented anticonvulsive or tranquilizing properties, through<br />
pesticidal 34 or antitumor 35 action and to their more recently described peptidomimetic<br />
activity. 36<br />
Recently, structural modification has been done in diazepine ring system to<br />
enhance biological activity. Diazepine ring system modified at N and 3-position has<br />
been studied extensively. They have been tested clinically as an antitrypanosomal<br />
activity, 37 antiplasmodial falcipain-2 inhibitors, 38 antileukemic agents, 39 and<br />
endothelin Receptor Antagonists. 40 V. I. Pavlovsky et al. 41 has reported that 3-<br />
arylideneand 3-hetarylidene 1,4-diazepinederivatives afford good affinity toward CNS<br />
benzodiazepine receptors.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 202
Chapter 6<br />
Synthesis of benzodiazepines<br />
6.2 Biological activities associated with diazepine derivatives<br />
Buckle et al. 42 has prepared 1H-benzo-1,5-diazepine-2,4-(3H,5H)-diones<br />
(Figure-2) from 4,2-R 2 (NH 2 )C 6 H 3 NH 2 (R 2 = H, Cl, F, COOH) by refluxing with<br />
malonic acid in 4N HCl for half an hour followed by nitration with fuming HNO 3<br />
which is antiallergic substance useful in the treatment of rhinitis, hay fever and certain<br />
type of asthma.<br />
Figure-2<br />
K. S. Andronati et al. 43 has prepared 3-Amino-1,2-dihydro-3h-1,4-<br />
benzodiazepin-2-one derivatives (Figure-3) via interaction with 3-chloro<br />
benzodiazepines, diethylamine, 1,6-diaminohexane, or p-nitroaniline, which is exhibit<br />
a pronounced anticonvulsant activity and produce significant anorexigenic effect.<br />
H<br />
N<br />
O<br />
Br<br />
N<br />
R 2<br />
R 1<br />
R 1 =H,Cl<br />
R 2 =N(C 2 H 5 ) 2 , NH(CH 2 ) 6 NH 2<br />
Figure-3<br />
More recent analogues of the Benzodiazepines have attracted interest as anti<br />
HIV compounds, such as the clinically used nevirapine and as anticancer compounds,<br />
such as the pyrrolo fused antitumor antibiotic DC-18 (Figure-4), analogues of which<br />
are in clinical development as anticancer agents. 44<br />
Figure-4<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 203
Chapter 6<br />
Synthesis of benzodiazepines<br />
Rubin et al. 45 have synthesized 4-phenyl-2-trichloromethyl-3H-1,5-<br />
benzodiazepine hydrogen sulphate and examined its pharmacological effects in mice,<br />
keeping diazepam as reference. The data suggest that this recently synthesized<br />
compound possesses anxiolytic activity and produces motor in co-ordination similar<br />
to those observed with diazepam.<br />
The synthesis of a new class of annulated 1,4-benzodiazepines with antipsychotic<br />
activity was exemplified by preparation of 10-fluoro-3-methy1-7-(2-<br />
thieny1)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine(Figure-5). The<br />
influence of variations of the fluoro-substitution pattern and variations of the fused<br />
ring system on the biological activity of the structural analogues was evaluated. 46<br />
Figure-5<br />
3-Acetyl coumarins when allowed react with isatin gave corresponding 3-(3’-<br />
hydroxy-2’-oxoindolo)acetylcoumarins, which on dehydration afforded the<br />
corresponding α,β-unsaturated ketones. Which on cyclocondensation with substituted<br />
o-phenylenediamines resulted in novel4-(2-oxo-2H-chromen-3-yl)-1,5-dihydrospiro<br />
[benzo[b][1,4]diazepine-2,3'-indolin]-2'-one (Figure-6). All the compounds have<br />
been screened for their antimicrobial and antianxiety activity in mice. 47<br />
Figure-6<br />
A library of compounds targeted to the vasopressin/oxytocin family of<br />
receptors was screened for activity at a cloned human oxytocin receptor using a<br />
reporter gene assay. Potency and selectivity were optimized to afford compound<br />
(Figure-7), EC 50 =33 nM. This series of compounds represents the first disclosed,<br />
non-peptide, low molecular weight agonists of the hormone oxytocin. 48<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 204
Chapter 6<br />
Synthesis of benzodiazepines<br />
H<br />
N<br />
N<br />
N<br />
O<br />
N<br />
H<br />
N<br />
N<br />
O<br />
S<br />
N<br />
N<br />
Figure-7<br />
A series of 2,3-dihydro-1,5-benzodiazepines were synthesized and evaluated<br />
for anti-inflammatory effects in microglia cells. 49 Among the 1,5-benzodiazepines<br />
tested, compound (Figure-8) strongly inhibited LPS-induced nitric oxide (NO)<br />
production, with an IC 50 value of 7.0 µM in the microglia cells.<br />
Figure-8<br />
A series of 2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine (Figure-9) was<br />
synthesized and evaluated for CNS activity. A new antianxiety screen for<br />
benzodiazepine-like drugs was used along with the standard anticonvulsant test.<br />
Structure activity relationships were discussed. 50<br />
Figure-9<br />
Walser A. et al. 51 have prepared [1,2,4]triazolo[4,3-a][1,4]benzodiazepines<br />
bearing an ethynyl functionality at the 8-position and the isostericthieno[3,2-f]<br />
[1,2,4]triazolo[4,3-a][1,4]diazepines (Figure-10) and evaluated as antagonists of<br />
platelet activating factor.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 205
Chapter 6<br />
Synthesis of benzodiazepines<br />
Figure-10<br />
Nakanishi et al. 52 have reported the synthesis and pharmacological activity of<br />
tetrazolo, oxadiazolo and imidazothienodiazepines derivatives (Figure-11). Some of<br />
them were found as minor tranquilizers.<br />
Figure-11<br />
Malcolm et al. 53 have been synthesized acetamido-1,4-diazepine analogs<br />
(Figure-12) which worked as inhibitor of respiratory syncytial virus(RSV) and<br />
exhibited IC 50 in the range of 10-20 íM over all three assays routinely used. This<br />
molecule also demonstrated excellent pharmacokinetic properties in the rat with a<br />
half-life of approximately 6 hand an oral bioavailability of 76%. This suggested that<br />
the core benzodiazepine was relatively stable to metabolism and a good starting point<br />
for lead optimization.<br />
Figure-12<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 206
Chapter 6<br />
Synthesis of benzodiazepines<br />
6.3 Some pharmaceutical molecules related to benzodiazepines<br />
Benzodiazepines enhance the effect of the neurotransmitter gamma-amino<br />
butyric acid (GABA), which results in sedative, hypnotic (sleep-inducing), anxiolytic<br />
(anti-anxiety), anticonvulsant, muscle relaxant and amnesic action. These properties<br />
make benzodiazepines useful in treating anxiety, insomnia, agitation, seizures, muscle<br />
spasms, alcohol withdrawal and as a premedication for medical or dental procedures.<br />
Benzodiazepines are categorized as either short-, intermediate- or long-acting. Shortand<br />
intermediate-acting benzodiazepines are preferred for the treatment of insomnia;<br />
longer-acting benzodiazepines are suggested for the treatment of anxiety. The detail<br />
of benzodiazepines related drugs is given below (Figure-13).<br />
N<br />
O<br />
H<br />
N<br />
O<br />
N<br />
O<br />
Cl<br />
N<br />
O 2 N<br />
N<br />
Cl<br />
N<br />
Cl<br />
Diazepam<br />
Anticonvulsant,<br />
muscle relaxant<br />
Clonazepam<br />
Hypnotic<br />
Tetrazepam<br />
Skeletal muscle relaxant<br />
Cl<br />
N<br />
N<br />
N<br />
N<br />
Br<br />
H 3 C<br />
S<br />
N<br />
N<br />
N<br />
N<br />
N<br />
N<br />
N<br />
S<br />
N<br />
Cl<br />
Cl<br />
Br<br />
Estazolam<br />
short-term treatment<br />
of insomnia.<br />
N<br />
Brotizolam<br />
Sedetive-Hypnotic<br />
N<br />
Ciclotizolam<br />
GABA A receptor agonist<br />
Cl<br />
N<br />
N<br />
O<br />
OH<br />
Cl<br />
N<br />
N<br />
O<br />
OH<br />
Cl<br />
N<br />
N<br />
O<br />
OH<br />
F<br />
F<br />
F<br />
Flurazepam<br />
Hypnotic<br />
Cinolazepam<br />
Hypnotic<br />
Figure-13<br />
Flutoprazepam<br />
anxiolytic<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 207
Chapter 6<br />
Synthesis of benzodiazepines<br />
6.4 Synthetic methods for benzodiazepines derivatives<br />
The most extensively used methods for preparing 1,4-benzodiazepines begins<br />
with an ortho-aminobenzophenone (1). The first method involves two-step synthesis.<br />
The first step involves treatment of the appropriate aminobenzophenone with<br />
haloacetyl halide to afford the amide (2), followed by the addition of ammonia to first<br />
displace the chlorine giving the glycinamide (3). Then cyclization by imine formation<br />
will give the benzodiazepine (4). 54-55 The other method involves treating the o-aminoketone<br />
with an amino acid ester hydrochloride in pyridine to yield (4) (Figure-14).<br />
Generally, the first method gave a higher percent yield of clean product, while the<br />
second method facilitated the conversion of o-aminoketones to benzodiazepines in<br />
one step, with a variety of substituents. 54-56<br />
Figure-14<br />
Jin-Yuan Wang et al. 57 have developed a new strategy for the synthesis of 1,4-<br />
benzodiazepine from Methyl1-arylaziridine-2-carboxylates with N-[2-Bromomethyl(phenyl)]trifluoroacetamides<br />
(Figure-15). The reaction proceeds through the<br />
N-benzylation and highly regioselective ring-opening reaction of aziridine by bromide<br />
anion followed by Et 3 N mediated intramolecular nucleophilic displacement of the<br />
bromide by the amide nitrogen.<br />
R<br />
Br<br />
NH<br />
O<br />
CF 3<br />
MeOOC<br />
N<br />
R'<br />
1) CH 3 CN, reflux 11hrs<br />
2) Et 3 N (2.0 eq.)<br />
CH 3 CN, reflux, 12hrs<br />
F 3 COC<br />
R N<br />
N<br />
COOMe<br />
R'<br />
Figure-15<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 208
Chapter 6<br />
Synthesis of benzodiazepines<br />
Recently, Joshua et al. 58 has reported the synthesis of saturated 1,4-<br />
benzodiazepines and 1,4-benzodiazepin-5-ones (Figure-16) via Pd-catalyzed<br />
carboamination reactions using sodium tert-butoxide base and xylene as a solvent at<br />
refluxing condition.<br />
Figure-16<br />
Veena Yadav et al. 59 has developed an efficient microwave assisted protocol<br />
for the exclusive one pot synthesis of N-amino-methyl substituted 1,4-<br />
benzodiazepine derivatives by the reaction of N-amino-methylsubstituted isatoic<br />
anhydride with glycine and L-proline respectively has been described (Figure-17).<br />
Figure-17<br />
Line S. Laustsen et al. 60 has developed an efficient solid-phase method has<br />
been for the parallel synthesis of 1,3-dihydro-1,4-benzodiazepine-2-one derivatives<br />
(Figure-18). A key step in this procedure involves catching crude 2-aminobenzoimine<br />
(1) products on an amino acid Wang resin (2). Mild acidic conditions then promote a<br />
ring closure and in the same step cleavage from the resin to give pure benzodiazepine<br />
products (3).These synthesis strategies involve catch and release phenomena.<br />
Figure-18<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 209
Chapter 6<br />
Synthesis of benzodiazepines<br />
New 2,4-disubstituted 1,5-benzodiazepine derivatives containing different<br />
functional groups have been synthesized and screened for their antibacterial activity.<br />
The 2,4-disubstituted 1,5-benzodiazepine derivatives were synthesized by reacting<br />
substituted chalcones synthesized using aldol condensation with o-phenylenediamine<br />
(Figure-19). QSAR studies of synthesized derivatives were performed. 61<br />
Figure-19<br />
A facile and efficient synthesis of 1,5-benzodiazepines with an aryl<br />
sulfonamido substituent at C(3) is described. 1,5-Benzodiazepine, derived from the<br />
condensation of benzene-1,2-diamine and diketene, reacts with an<br />
arylsulfonylisocyanate via an enamine intermediate to produce 1,5-benzodiazepines<br />
good yields (Figure-20). 62<br />
Figure-20<br />
Goswami and Das reports the organo catalyzed one-pot synthesis of<br />
substituted 1,5-benzodiazepinesby condensation of o-phenylenediamine, and 1,3-<br />
dicarbonyl compounds at room temperature or under reflux in the presence of<br />
catalytic amount of L-proline as shown in (Figure-20). 63<br />
Figure-20<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 210
Chapter 6<br />
Synthesis of benzodiazepines<br />
6.5. Current research work<br />
The chemistry of benzodiazepines and its derivatives has been studied for over<br />
a century due to their diverse biological activities. It has numerous pharmacological<br />
and medicinal applications viz, PAF antagonists, cardiovascular agents, CNS-active<br />
agent, hypnotic, anxiolytic, sedative and anticonvulsant. Therefore, we set to prepare<br />
some new 1H-benzo[e][1,4]diazepin-2(3H)-one derivatives for their biological studies.<br />
The requisite starting material1,4-benzodiazepines (ADZ-03) was prepared by<br />
following the reported procedure. The 2-amino-4’-flouro-benzophenone (ADZ-01)<br />
was reacted with chloroacetylchloride to afford 2-chloro-N-(2-(4’-fluorobenzoyl)<br />
phenyl)acetamide (ADZ-02). It was subsequently converted to 1,4-benzodiazepines<br />
by the modification of the known hexamethylenetetramine-(HMTM)-based<br />
cyclization reaction developed by Blazevic and Kajfez. 54-55 ADZ-03 thus obtained<br />
was reacted with a variety of alkyl halide using KOH in DMF to give 1-substituted-5-<br />
(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (ADZ-04a-j). To achieve 5-<br />
substituted 1,4-benzodiazepines (ADZ-05a-j), 5-(4-fluorophenyl)-1H-benzo[e][1,4]<br />
diazepin-2(3H)-one (ADZ-03) was treated with various aromatic aldehydes in the<br />
presence of potassium hydroxide in toluene. The newly synthesized compounds were<br />
characterized by IR, Mass, 1 H NMR, 13 C NMR spectroscopy and elemental analysis.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 211
Chapter 6<br />
Synthesis of benzodiazepines<br />
6.6 Results and discussion<br />
Scheme: Synthesis of some new benzodiazepine derivatives<br />
Scheme-01<br />
Scheme-02<br />
Where R= CH 3 , CH(CH 3 ) 2 , R 1 = CH 3 , F, Cl, NO 2 , X=Br<br />
Synthesis of 1-and 3-substituted 1,4-benzodiazepinederivatives is shown in<br />
sheme 1 and 2. The starting material, 2-amino-4’-flouro-benzophenone ADZ-01 was<br />
reacted with chloroacetyl chloride in toluene at room temperature to afforded 2-<br />
chloro-N-(2-(4’-fluorobenzoyl)phenyl)acetamide. The latter was converted in to 1,4-<br />
benzodiazepines ADZ-03 by following the literature methods using ammonium<br />
acetate and hexamine in EtOH. 54-55 The N-alkylation of 1,4-benzodiazepines with<br />
various alkyl halide in DMF at below 15 o C in the presence of potassium hydroxide<br />
proceeded smoothly to furnish a series of 1-substituted-5-(4-fluorophenyl)-1Hbenzo[e][1,4]diazepin-2(3H)-one<br />
ADZ-04a-j in good yields. Reaction time and (%)<br />
of yield is summarized in Table-1.<br />
On the other hand, the condensation of of 1,4-benzodiazepines ADZ-03 with<br />
aromatic aldehydes in the presence of potassium hydroxide in reluxing provided a<br />
series of new 3-substituted-5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one<br />
ADZ-05a-j in excellent yields (Table-2).<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 212
Chapter 6<br />
Synthesis of benzodiazepines<br />
A variety of 3-arylidine benzodiazepines bearing electron donating and electron<br />
withdrawing groups such as 3,4-diOCH 3 ; 4-OCH 3 ; H; 2,5-diOCH 3 ; 2-OH; 4-F; 4-Br;<br />
4-Cl; 4-NO 2 and 3-NO 2 were prepared.<br />
Table-1: Synthesis of 1-substituted benzodiazepine derivatives<br />
Entry R Yield (%) Time hrs<br />
ADZ-04a -CH 3 87 2.0<br />
ADZ-04b -CH 2 CH 3 83 2.5<br />
ADZ-04c -(CH 2 ) 2 CH 3 88 3.0<br />
ADZ-04d -CH(CH 3 ) 2 84 2.5<br />
ADZ-04e -(CH 2 ) 3 CH 3 80 3.0<br />
ADZ-04f -CH 2 CH(CH3) 2 89 3.5<br />
ADZ-04g (CH 2 ) 4 CH 3 90 2.5<br />
ADZ-04h -(CH 2 ) 2 CH(CH 3 ) 2 88 4.0<br />
ADZ-04i C 6 H 11 79 4.5<br />
ADZ-04j -CH 2 C 6 H 4 4-NO 2 90 4.0<br />
The structures of ADZ-03 were conformed on the basis of their elemental<br />
analysis and spectral data (MS, IR, and 1 H NMR).The analytical data for ADZ-03<br />
revealed a molecular formula C 15 H 11 FN 2 O 2 (m/z 254).The 1 HNMR spectrum revealed<br />
a singlet at 4.31ppm assigned to –CH 2 group, a four multiplet signals at δ = 7.04–<br />
7.57 ppm assigned to the aromatic protons, and one broad singlet at δ = 8.83 ppm<br />
assigned to -CONH groups.<br />
Table-2: Synthesis of 3-arylidine benzodiazepine derivatives<br />
Entry R 1 Yield (%) Time hrs<br />
ADZ-05a H 90 2.0<br />
ADZ-05b 3-NO 2 85 2.5<br />
ADZ-05c 3,4-diOCH 3 83 3.0<br />
ADZ-05d 4-OCH 3 87 2.5<br />
ADZ-05e 4-Cl 94 3.0<br />
ADZ-05f 4-F 90 3.5<br />
ADZ-05g 4-NO 2 92 2.5<br />
ADZ-05h 4-Br 89 4.0<br />
ADZ-05i 2-OH 80 4.5<br />
ADZ-05j 2,5-diOCH 3 81 4.0<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 213
Chapter 6<br />
Synthesis of benzodiazepines<br />
The newly synthesized compounds ADZ-04a-j were conformed on the basis<br />
of their elemental analysis and spectral data (MS, IR, 1 H NMR and 13 C NMR). The<br />
structure of ADZ-04a was supported by its mass (m/z 268) which agree with its<br />
molecular formula C 16 H 13 FN 2 O, its 1 H NMR spectrums held a singlet at δ =3.42 ppm<br />
assigned to -CH 3 , two doublet signals observed at δ =3.75-3.78 (1H, J=10.5Hz) and<br />
4.78-4.81 (1H, J=10.5Hz) assigned to –CH 2 group, and four multiplet signal observed<br />
at δ =7.05-7.65 assigned to the aromatic protons.<br />
All synthesized compounds ADZ-05a-j were conformed on the basis of their<br />
elemental analysis and spectral data (MS, IR, 1 H NMR and 13 C NMR).The analytical<br />
data for ADZ-05a revealed a molecular formula C 22 H 15 FN 2 O(m/z 342). Its 1 H NMR<br />
signals held at δ = 6.39 (s. 1H, CH), 7.08-7.12 (m, 1H, Ar), 7.21-7.37 (m, 7H, Ar),<br />
7.46-7.53 (m, 3H, Ar), 7.76-7.79 (m, 2H, Ar), 8.15 (s, 1H, -CONH).<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 214
Chapter 6<br />
Synthesis of benzodiazepines<br />
6.7 Conclusion<br />
In summary, we have demonstrated a simple and effective strategy for the<br />
synthesis of novel1-and 3-substituted 1,4-benzodiazepines. The reaction of 1,4-<br />
benzodiazepines either with various alkyl halide or a variety of aromatic aldehydes in<br />
the presence of potassium hydroxide afforded the desired 1-and 3-substituted 1,4-<br />
benzodiazepine derivatives (ADZ-04a-j and ADZ-05a-j) in excellent yields.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 215
Chapter 6<br />
Synthesis of benzodiazepines<br />
6.8 Experimental section<br />
Thin-layer chromatography was accomplished on 0.2-mm precoated plates of<br />
silica gel G60 F 254 (Merck). Visualization was made with UV light (254 and 365nm)<br />
or with an iodine vapor. IR spectra were recorded on a FTIR-8400 spectrophotometer<br />
using DRS prob. 1 H (300 MHz), 1 H (400 MHz), 13 C (75 MHz) and 13 C (100 MHz)<br />
NMR spectra were recorded on a Bruker AVANCE II spectrometer in CDCl 3 and<br />
DMSO. Chemical shifts are expressed in δ ppm downfield from TMS as an internal<br />
standard. Mass spectra were determined using direct inlet probe on a GCMS-QP 2010<br />
mass spectrometer (Shimadzu). Solvents were evaporated with a BUCHI rotary<br />
evaporator. Melting points were measured in open capillaries and are uncorrected.<br />
General procedure for the synthesis of 2-chloro-N-(2-(4-<br />
fluorobenzoyl)phenyl) acetamide (ADZ-02).<br />
To a solution of 2-amino-4’-fluorobenzophenone (0.0046 mol) in toluene<br />
(10mL), a solution of chloroacetyl chloride (0.0049 mol) in toluene (2 mL) was added<br />
drop wise at 0 °C within 0.5 h. The reaction mixture was further stirred at room<br />
temperature for 5 h. The resulting reaction mixture was evaporated to dryness. The<br />
crude product was triturated with ethanol (10 mL) and the crystalline solid separated<br />
was collected by filtration to give desired product ADZ-02 in 87-90% yield.<br />
<br />
General procedure for the synthesis of 5-(4-fluorophenyl)-1H-beno[e]<br />
[1,4]diazepin-2(3H)-one (ADZ-03).<br />
To a solution of 2-chloro-N-(2-(4-fluorobenzoyl)phenyl)acetamide (0.0068<br />
mol) in ethanol (40 mL), hexamethylenetetramine (HMTM; 0.015 mol) and<br />
ammonium acetate (0.015 mol) were added. The reaction mixture was stirred at reflux<br />
temperature for 3 h. Then the reaction mixture was evaporated to dryness. Distilled<br />
water (30mL) was added, and the resulting suspension was stirred at 60 °C for 0.5 h.<br />
The suspension was cooled to 20 °C and filtered. The crude product was crystallized<br />
from toluene to obtained ADZ-03 in 80-85% yield.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 216
Chapter 6<br />
Synthesis of benzodiazepines<br />
General synthesis of 1-substituted-5-(4-fluorophenyl)-1H-benzo[e]<br />
[1,4]diazepin-2(3H)-one (ADZ-04a-j).<br />
To solution of 5-(4-fluorophenyl)-1H-beno[e][1,4]diazepin-2(3H)-one (0.0039<br />
mol) in DMF (10 ml), potassium hydroxide (0.0046 mol) and appropriate alkyl halide<br />
(0.0039 mol) were added at 0 o C. The reaction mixture was stirred for 3-5 h at this<br />
temperature. The progress of reaction was monitored by thin layer chromatography.<br />
After completion of reaction mixture, it was poured into cold water. The solid<br />
separated was filtered, washed with water and dried. The crude product was<br />
recrystallized from ethanol to give analytical pure product in 79-90% yield.<br />
General synthesis of 3-benzylidene-5-(4-fluorophenyl)-1Hbenzo[e][1,4]diazepin-2(3H)-one<br />
(ADZ-05a-j)<br />
5-(4-Fluorophenyl)-1H-beno[e][1,4]diazepin-2(3H)-one (0.0039 mol),<br />
potassium hydroxide (0.0039 mol) and appropriate aromatic aldehydes (0.0039 mol)<br />
were taken in toluene (20 mL). The reaction mixture was heated to reflux for 8-10 hrs.<br />
The progress of reaction was monitored by thin layer chromatography. After<br />
completion of reaction mixture cooled to room temperature and the solid separated<br />
product was filtered, washed with cold toluene and dried. The crude product was<br />
recrystallized from ethanol to give corresponding product ADZ-05a-j in 80-94% yield.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 217
Chapter 6<br />
Synthesis of benzodiazepines<br />
Spectral data of the synthesized compounds<br />
2-chloro-N-(2-(4-fluorobenzoyl)phenyl)acetamide ADZ-02. White solid, mp 126-<br />
128 ° C; R f 0.49 (8:2 hexane-EtOAc); IR (KBr): 3373, 3072, 2895, 2828, 1694, 1635,<br />
1482, 1343, 1298 cm -1 ; MS (m/z): 291 [M + ]; Anal. Calcd for C 15 H 11 ClFN 2 O 2 : C,<br />
61.76; H, 3.80; N, 4.80; Found: C, 61.74; H, 3.82; N, 4.82.<br />
5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ-03. White solid, mp<br />
172-174 ° C; R f 0.42 (8:2 hexane-EtOAc); IR (KBr): 3182, 3120, 3068, 3051, 2955,<br />
1693, 1672, 1504, 1232, 1024, 839, 810, 731, 690 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ):<br />
δ 4.31 (S, 2H, CH 2 ), 7.04-7.09 (m, 2H, Ar), 7.15-7.19 (m, 2H, Ar), 7.26-7.33 (m, 1H,<br />
Ar), 7.49-7.57 (m, 3H, Ar), 8.83 (s, 1H, NH); MS (m/z): 254 [M + ]; Anal. Calcd for<br />
C 15 H 11 FN 2 O 2 : C, 70.86; H, 4.36; N, 11.02; Found: C, 70.84; H, 4.34; N, 11.03.<br />
5-(4-fluorophenyl)-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ-04a.<br />
White solid, mp 112-114 ° C; R f 0.38 (8:2 hexane-EtOAc); IR (KBr): 3072, 2895, 2828,<br />
1694, 1635, 1482, 1343, 1298, 1050, 880, 834, 756 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ):<br />
δ 3.42 (s, 3H, CH 3 ), 3.75-3.78 (d, 1H, CH, J=10.5Hz), 4.78-4.81 (d, 1H, CH,<br />
J=10.5Hz), 7.05-7.10 (m, 2H, Ar), 7.20-7.29 (m, 1H, Ar), 7.32-7.37 (m, 2H, Ar),<br />
7.54-7.65 (m, 3H, Ar); 13 C NMR: (100 MHz, CDCl 3 ): δ 34.23, 56.53, 114.83, 115.05,<br />
121.33, 123.69, 127.67, 129.62, 131.30, 131.39, 131.45, 134.72, 134.75, 143.54,<br />
162.19, 164.66, 168.13, 169.30; MS (m/z): 268 [M + ]; Anal. Calcd for C 16 H 13 FN 2 O: C,<br />
71.63; H, 4.88; N, 10.44; Found: C, 71.64; H, 4.84; N, 10.42.<br />
1-ethyl-5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ-04b. Yellow<br />
solid, mp 162-164 ° C; R f 0.44 (8:2 hexane-EtOAc); IR (KBr): 3078, 2865, 2821, 1686,<br />
1620, 1462, 1341, 1298, 1054, 834, 780 cm -1 ; MS (m/z): 282 [M + ]; Anal. Calcd for<br />
C 17 H 15 FN 2 O: C, 72.32; H, 5.36; N, 9.92; Found: C, 72.34; H, 5.38; N, 9.96.<br />
5-(4-fluorophenyl)-1-propyl-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ-04c.<br />
Yellow solid, mp 123-125 ° C; R f 0.30 (8:2 hexane-EtOAc); IR (KBr): 3068, 3024,<br />
2958, 2900, 1684, 1495, 1482, 808, 732, 690 cm -1 ; MS (m/z): 296 [M + ]; Anal. Calcd<br />
for C 18 H 17 FN 2 O: C, 72.95; H, 5.78; N, 9.45; Found: C, 72.95; H, 5.78; N, 9.46.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 218
Chapter 6<br />
Synthesis of benzodiazepines<br />
5-(4-fluorophenyl)-1-isopropyl-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ-04d.<br />
White solid, mp 98-100 ° C; R f 0.25 (8:2 hexane-EtOAc); IR (KBr): 3118, 3067, 3054,<br />
2958, 2901, 1683, 1582, 1469, 810, 705 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 1.22-<br />
1.24 (d, 3H, CH 3 ), 1.50-1.60 (d, 3H, CH 3 ), 3.70-3.74 (d, 1H, CH), 4.53-4.58 (m, 1H,<br />
CH), 4.68-4.71 (d, 1H, CH), 7.05-7.11 (m, 2H, Ar), 7.23-7.26 (m, 1H, Ar), 7.42-7.52<br />
(m, 3H, Ar), 7.61-7.63 (m, 2H, Ar); MS (m/z): 296 [M + ]; Anal. Calcd for<br />
C 18 H 17 FN 2 O: C, 72.95; H, 5.78; N, 9.45; Found: C, 72.97; H, 5.79; N, 9.47.<br />
1-butyl-5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ-04e. Yellow<br />
solid, mp 88-90 ° C; R f 0.28 (8:2 hexane-EtOAc); IR (KBr): 3154, 3085, 2968, 2910,<br />
1685, 1564, 1420, 1350, 1232, 854, 696 cm -1 ; MS (m/z): 310 [M + ]; Anal. Calcd for<br />
C 19 H 19 FN 2 O: C, 73.53; H, 6.17; N, 9.03; Found: C, 73.57; H, 6.19; N, 9.07.<br />
5-(4-fluorophenyl)-1-isobutyl-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ-04f.<br />
Yellow solid, mp 72-74 ° C; R f 0.34 (8:2 hexane-EtOAc); IR (KBr): 3156, 3058, 2968,<br />
2905, 1985, 1564, 1369, 810, 694 cm -1 ; MS (m/z): 310 [M + ]; Anal. Calcd for<br />
C 19 H 19 FN 2 O: C, 73.53; H, 6.17; N, 9.03; Found: C, 73.50; H, 6.11; N, 9.10.<br />
5-(4-fluorophenyl)-1-pentyl-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ-04g. White<br />
solid, mp 93-95 ° C; R f 0.25 (9:1 Chloroform: Methanol); IR (KBr): 3110, 3056, 2956,<br />
2845, 1345, 1254, 1056, 842, 730, 698 cm -1 ; MS (m/z): 324 [M + ]; Anal. Calcd for<br />
C 20 H 21 FN 2 O: C, 74.05; H, 6.53; N, 8.64; Found: C, 74.07; H, 6.59; N, 8.67.<br />
5-(4-fluorophenyl)-1-isopentyl-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ-04h.<br />
Yellow solid, mp 84-86 ° C; R f 0.23 (8:2 hexane-EtOAc); IR (KBr): 3125, 3089, 3021,<br />
2985, 1236, 1056, 854, 795, 830, 698 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ): δ 0.64-0.71<br />
(dd, 6H, 2 x CH 3 ), 1.22-1.33 (m, 1H, CH), 3.51-3.57 (m, 1H, CH), 3.63-3.66 (d, 1H,<br />
CH), 4.28-4.35 (m, 1H, CH), 4.62-4.65 (d, 1H, CH), 5.19 (s, 2H, CH 2 ), 6.95-7.00 (m.<br />
2H, Ar), 7.10-7.14 (m, 1H, Ar), 7.17-7.19 (m, 1H, Ar), 7.32-7.34 (d, 1H, J=8.28Hz<br />
Ar), 7.45-7.53 (m, 3H, Ar); 13 C NMR: (100 MHz, CDCl 3 ): δ 22.10, 22.54, 25.48,<br />
36.65, 44.74, 53.52, 57.14, 115.16, 115.37, 122.17, 124.33, 129.92, 130.13, 131.33,<br />
131.42, 131.48, 134.94, 134.97, 142.63, 162.89, 165.38, 168.93, 169.36; MS (m/z):<br />
324 [M + ]; Anal. Calcd for C 20 H 21 FN 2 O: C, 74.05; H, 6.53; N, 8.64; Found: C, 74.10;<br />
H, 6.65; N, 8.77.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 219
Chapter 6<br />
Synthesis of benzodiazepines<br />
1-cyclohexyl-5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ-04i.<br />
Yellow solid, mp 137-139 ° C; R f 0.35 (8:2 hexane-EtOAc); IR (KBr): 3074, 2856,<br />
2828, 1694, 1635, 1482, 1343, 1298, 1058, 840, 732 cm -1 ; MS (m/z): 333 [M + ]; Anal.<br />
Calcd for C 21 H 21 FN 2 O: C, 74.98; H, 6.29; N, 8.33; Found: C, 74.90; H, 6.25; N, 8.37.<br />
5-(4-fluorophenyl)-1-(4-nitrobenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ-<br />
04j. Yellow solid, mp 157-159 ° C; R f 0.49 (8:2 hexane-EtOAc); IR (KBr): 3241, 3068,<br />
3015, 2956, 2881, 1330, 1268, 1054, 834, 830,756, 701 cm -1 ; MS (m/z): 389 [M + ];<br />
Anal. Calcd for C 21 H 16 FN 3 O 3 : C, 67.86; H, 4.14; N, 10.79; Found: C, 67.90; H, 4.15;<br />
N, 10.77.<br />
3-benzylidene-5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ-05a.<br />
Yellow solid, mp 192-195 ° C; R f 0.25 (8:2 hexane-EtOAc); IR (KBr): 3450, 3110,<br />
3054, 2990, 2932, 2854, 1456, 1305, 1250, 1005, 805, 732, 695 cm -1 ; 1 H NMR (400<br />
MHz, DMSO): δ 6.39 (s. 1H, CH), 7.08-7.12 (m, 1H, Ar), 7.21-7.37 (m, 7H, Ar),<br />
7.46-7.53 (m, 3H, Ar), 7.76-7.79 (m, 2H, Ar), 8.15 (s, 1H, NH); 13 C NMR: (100 MHz,<br />
DMSO): δ 115.25, 115.46, 118.09, 121.39, 122.58, 126.58, 126.74, 127.50, 128.07,<br />
128.19, 128.92, 129.90, 129.95, 131.80, 131.89, 134.41, 134.44, 134.75, 138.93,<br />
140.54, 162.45, 164.26, 164.94, 171.00; MS (m/z): 342 [M + ]; Anal. Calcd for<br />
C 22 H 15 FN 2 O: C, 77.18; H, 4.42; N, 8.18; Found: C, 77.20; H, 4.45; N, 8.22.<br />
5-(4-fluorophenyl)-3-(3-nitrobenzylidene)-1H-benzo[e][1,4]diazepin-2(3H)-one<br />
ADZ-05b. Yellow solid, mp 202-204 ° C; R f 0.28 (8:2 hexane-EtOAc); IR (KBr): 3390,<br />
3072, 2856, 2832, 1684, 1635, 1482, 1356, 1298, 830, 750, 700 cm -1 ; 1 H NMR (300<br />
MHz, DMSO): δ 6.44 (s. 1H, CH), 7.06-7.11 (m, 1H, Ar), 7.24-7.40 (m, 4H, Ar),<br />
7.50-7.67 (m, 3H, Ar), 7.82-7.93 (m, 3H, Ar), 8.08-8.11 (d, 1H, J=8.1Hz, Ar), 8.58 (s,<br />
1H, NH); 13 C NMR: (100 MHz, DMSO): δ 120.15, 120.47, 121.01, 126.53, 126.79,<br />
127.80, 129.01, 131.73, 134.32, 135.48, 137.11, 137.15, 137.24, 139.46, 141.68,<br />
143.84, 147.81, 152.92, 175.11; MS (m/z): 387 [M + ]; Anal. Calcd for C 22 H 14 FN 3 O 3 :<br />
C, 68.21; H, 3.64; N, 10.85; Found: C, 68.20; H, 3.67; N, 10.83.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 220
Chapter 6<br />
Synthesis of benzodiazepines<br />
3-(3,4-dimethoxybenzylidene)-5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)<br />
-one ADZ-05c. Yellow solid, mp 189-191 ° C; R f 0.21 (8:2 hexane-EtOAc); IR (KBr):<br />
3232, 2997, 2906, 2833, 1683, 1670, 1506, 1363, 1265, 1026, 848, 802, 761, 731, 690<br />
cm -1 ; MS (m/z): 402 [M + ]; Anal. Calcd for C 24 H 19 FN 2 O 3 : C, 71.63; H, 4.76; N, 6.96;<br />
Found: C, 71.67; H,4.71; N, 6.93.<br />
5-(4-fluorophenyl)-3-(4-methoxybenzylidene)-1H-benzo[e][1,4]diazepin-2(3H)-<br />
one ADZ-05d. Yellow solid, mp 223-225 ° C; R f 0.24 (8:2 hexane-EtOAc); IR (KBr):<br />
3442, 3202, 2956, 2916, 2845, 1656, 1504, 1345, 1240, 834, 803, 765, 705 cm -1 ; MS<br />
(m/z): 372 [M + ]; Anal. Calcd for C 23 H 17 FN 2 O 2 : C, 74.18; H, 4.60; N, 7.52; Found: C,<br />
74.22; H,4.61; N, 7.57.<br />
3-(4-chlorobenzylidene)-5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one.<br />
ADZ-05e.Yellow solid, mp 192-194-225 ° C; R f 0.26 (8:2 hexane-EtOAc); IR (KBr):<br />
3076, 2964, 2891, 2837, 1691, 1676, 1483, 1155, 1091, 842, 761, 734, 688 cm -1 ; MS<br />
(m/z): 376 [M + ]; Anal. Calcd for C 22 H 14 ClFN 2 O: C, 70.12; H, 3.74; N, 7.43; Found: C,<br />
70.14; H,3.75; N, 7.45.<br />
3-(4-fluorobenzylidene)-5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one<br />
ADZ-05f. Yellow solid, mp 167-169 ° C; R f 0.25 (8:2 hexane-EtOAc); IR (KBr): 3373,<br />
3072, 2895, 2828, 1694, 1635, 1482, 1298, 784, 746, 698, cm -1 ; MS (m/z): 360 [M + ];<br />
Anal. Calcd for C 22 H 14 F 2 N 2 O: C, 73.33; H, 3.92; N, 7.77; Found: C, 70.35; H, 3.95; N,<br />
7.72.<br />
5-(4-fluorophenyl)-3-(4-nitrobenzylidene)-1H-benzo[e][1,4]diazepin-2(3H)-one<br />
ADZ-05g. Yellow solid, yield 93%, mp 217-219 ° C; R f 0.23 (8:2 hexane-EtOAc); IR<br />
(KBr): 3452, 3154, 3072, 2895, 2828, 1694, 1635, 1482, 1343, 1298, 784, 765, 702,<br />
684 cm -1 ; MS (m/z): 387 [M + ]; Anal. Calcd for C 22 H 14 FN 3 O 3 : C, 68.21; H, 3.64; N,<br />
10.85; Found: C, 68.23; H, 3.62; N, 10.85.<br />
3-(4-bromobenzylidene)-5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one<br />
ADZ-05h. Yellow solid, mp 183-185 ° C; R f 0.29 (8:2 hexane-EtOAc); IR (KBr): 3420,<br />
3074, 2923, 2956, 1695, 1680, 1459, 1154, 1056, 845, 761, 734, 690 cm -1 ; MS (m/z):<br />
420 [M + ]; Anal. Calcd for C 22 H 14 BrFN 2 O: C, 62.72; H, 3.35; N, 6.65; Found: C,<br />
62.75; H, 3.34; N, 6.75.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 221
Chapter 6<br />
Synthesis of benzodiazepines<br />
5-(4-fluorophenyl)-3-(2-hydroxybenzylidene)-1H-benzo[e][1,4]diazepin-2(3H)-<br />
one ADZ-05i. Yellow solid, mp 152-154 ° C; R f 0.42 (8:2 hexane-EtOAc); IR (KBr):<br />
3485, 3078, 2854, 2831, 2685, 1456, 1256, 854, 705, 684 cm -1 ; MS (m/z): 358 [M + ];<br />
Anal. Calcd for C 22 H 15 FN 2 O 2 : C, 73.73; H, 4.22; N, 7.82; Found: C, 73.75; H, 4.24; N,<br />
7.85.<br />
3-(2,5-dimethoxybenzylidene)-5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)<br />
–one ADZ-05j. Yellow solid, mp 144-145 ° C; R f 0.25 (8:2 hexane-EtOAc); IR (KBr):<br />
3473, 3078, 3045, 2954, 2895, 2828, 1684, 1645, 1484, 1325, 1250, 854, 735, 697<br />
cm -1 ; MS (m/z): 402 [M + ]; Anal. Calcd for C 24 H 19 FN 2 O 3 : C, 71.63; H, 4.76; N, 6.96;<br />
Found: C, 71.67; H,4.71; N, 6.93.<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 222
Chapter 6<br />
Synthesis of benzodiazepines<br />
1 H NMR spectrum of compound ADZ-03<br />
H<br />
N<br />
O<br />
N<br />
F<br />
1 H NMR spectrum of compound ADZ-04a<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 223
Chapter 6<br />
Synthesis of benzodiazepines<br />
1 H NMR spectrum of compound ADZ-04h<br />
Expanded 1 H NMR spectrum of compound ADZ-04h<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 224
Chapter 6<br />
Synthesis of benzodiazepines<br />
1 H NMR spectrum of compound ADZ-05a<br />
Expanded 1 H NMR spectrum of compound ADZ-05a<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 225
Chapter 6<br />
Synthesis of benzodiazepines<br />
1 H NMR spectrum of compound ADZ-05b<br />
1 H NMR spectrum of compound ADZ-05d<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 226
Chapter 6<br />
Synthesis of benzodiazepines<br />
13 C NMR spectrum of compound ADZ-04a<br />
13 C NMR spectrum of compound ADZ-05a<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 227
Chapter 6<br />
Synthesis of benzodiazepines<br />
MASS spectrum of compound ADZ-04i<br />
MASS spectrum of compound ADZ-04j<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 228
Chapter 6<br />
Synthesis of benzodiazepines<br />
MASS spectrum of compound ADZ-05e<br />
MASS spectrum of compound ADZ-05i<br />
H<br />
N<br />
N<br />
O<br />
OH<br />
F<br />
m/z-358<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 229
Chapter 6<br />
Synthesis of benzodiazepines<br />
IR spectrum of compound ADZ-03<br />
100<br />
%T<br />
80<br />
60<br />
40<br />
20<br />
3182.65<br />
3120.93<br />
3068.85<br />
2955.04<br />
2899.11<br />
1610.61<br />
1504.53<br />
1479.45<br />
1429.30<br />
1406.15<br />
1367.58<br />
1317.43<br />
1288.49<br />
1232.55<br />
1153.47<br />
1097.53<br />
1024.24<br />
945.15<br />
839.06<br />
810.13<br />
761.91<br />
731.05<br />
690.54<br />
665.46<br />
586.38<br />
0<br />
1693.56<br />
1672.34<br />
-20<br />
4000<br />
3500<br />
3000<br />
2500<br />
2000<br />
1750<br />
1500<br />
1250<br />
1000<br />
750<br />
500<br />
1/cm<br />
IR spectrum of compound ADZ-05c<br />
105<br />
%T<br />
90<br />
3232.80<br />
3070.78<br />
2997.48<br />
2906.82<br />
2833.52<br />
943.22<br />
75<br />
1481.38<br />
1419.66<br />
1363.72<br />
1319.35<br />
1155.40<br />
1138.04<br />
1026.16<br />
731.05<br />
690.54<br />
60<br />
1608.69<br />
1591.33<br />
1506.46<br />
1265.35<br />
848.71<br />
802.41<br />
630.74<br />
45<br />
1683.91<br />
1670.41<br />
761.91<br />
557.45<br />
538.16<br />
480.29<br />
30<br />
518.87<br />
453.29<br />
441 71<br />
15<br />
4000<br />
3500<br />
3000<br />
2500<br />
2000<br />
1750<br />
1500<br />
1250<br />
1000<br />
750<br />
500<br />
1/cm<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 230
Chapter 6<br />
Synthesis of benzodiazepines<br />
6.9 References<br />
1. Rohtash, K.; Lown, J. W.; Mini-Reviews in Medicinal Chemistry, 2003, 3, 323.<br />
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Chapter 6<br />
Synthesis of benzodiazepines<br />
26. Sabitha, G.; Reddy, G. S. K. K.; Reddy, K. B.; Reddy, N. M.; Yadav, J. S.; Adv. Synth. Catal.,<br />
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Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 232
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Synthesis of benzodiazepines<br />
49. Ha, S. K.; Shobha, D.; Moon, E.; Chari, M. A.; Mukkanti, K.; Kim, S. -H.; Ahn, K. -H.; Kim,<br />
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Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005 233
Research Summary<br />
The work comprised in the Thesis entitled “Studies on Novel Bioactive<br />
Heterocyclic Compounds” is summarized as follows.<br />
In Chapter 1, we have presented an efficient four step protocols for the<br />
synthesis of diversely substituted novel pyrimidines. A series of chlorinated<br />
pyrimidines were synthesized from easily available Biginelli 3,4-dihydropyrimidin-<br />
2(1H)-ones. The chlorinated pyrimidines were then subjected to condition normally<br />
employed Suzuki-Miyaura coupling reaction with various phenylboronicacid<br />
derivatives in the presence of palladium catalyst to obtain C-phenyl pyrimidines with<br />
good yields.<br />
In Chapter 2, we have described (E)-selective synthesis of novel pyrimidine<br />
derivatives from pyrimidine phosphorous ylide with a variety of aldehydes via Wittig<br />
reaction in the presence of sodium tripolyphosphate as a base in aqueous media.<br />
Sodium tripolyphosphate has the several advantages of being stable, low cost and less<br />
toxic. All the synthesized compounds were evaluated for their antimicrobial activity.<br />
The investigation of antibacterial and antifungal screening revealed that all the tested<br />
compounds showed moderate to significant activity.<br />
In Chapter 3, a facile synthesis of a library containing trisubstituted pyrazoles<br />
and isoxazoles functionalized with cyclopropyl, thiomethyl and carboxamide moieties<br />
has been described. As a part of ‘green chemistry’ approach, we employed<br />
condensation reaction of various ketene dithioacetals with hydrazine hydrate or<br />
hydroxyl amine hydrochloride in solvent free reaction condition under microwave<br />
irradiation. The present procedure is significant over the existing methods to develop<br />
this class of molecules with excellent yield, purity and simple isolation of products.<br />
In Chapter 4, the heterocyclizations of various ketene dithioacetals with 5-<br />
aminopyrazole derivative were studied in details, and the influence of the reaction<br />
parameters and the aminoazole structure on the direction of the reaction was<br />
established. We found that the reaction of various ketene dithioacetals with 5-amino-<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 234
pyrazole derivative were faster and afforded the pyrazolo[1,5-a]pyrimidine in good<br />
yield in the presence of K 2 CO 3 as a base and isopropyl alcohol. This study led to the<br />
development of a simple approach for synthesis of pyrazolo[1,5-a]pyrimidines,<br />
substances that potentially interesting biological and medicinal properties.<br />
Chapter 5 described the synthesis of a series of substituted pyrroles as a<br />
atorvastatin analogs. The targeted compound were achieved from novel 1,4-<br />
dicarbonyl compounds and amino side chain using pivalic acid as a catalyst and<br />
cyclohexane and THF as binary solvent under microwave irradiation technique. All<br />
the synthesized compounds were evaluated for their antimicrobial activity. The<br />
investigation of antibacterial and antifungal screening revealed that some of these<br />
agents posseses moderate to potent activity.<br />
In Chapter 6, we have demonstrated a simple and effective strategy for the<br />
synthesis of novel 1-and 3-substituted 1,4-benzodiazepines. The reaction of 1,4-<br />
benzodiazepines either with various alkyl halide or a variety of aromatic aldehydes in<br />
the presence of potassium hydroxide afforded the desired 1-and 3-substituted 1,4-<br />
benzodiazepine derivatives in excellent yields.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 235
List of Publications<br />
1. Water Mediated Construction of Trisubstituted Pyrazoles/Isoxazoles Library<br />
Using Ketene Dithioacetals.<br />
Mahesh M. Savant, Akshay M. Pansuriya, Chirag V. Bhuva, Naval Kapuriya,<br />
Anil S. Patel, Vipul B. Audichya, Piyush V. Pipaliya and Yogesh T. Naliapara*.<br />
Journal of Combinatorial Chemistry, 2010, 12, 176-180.<br />
2. Synthesis of some novel trifluoromethylated tetrahydropyrimidines using<br />
etidronic acid and evaluation for antimicrobial activity.<br />
Mahesh M. Savant, Akshay M. Pansuriya, Chirag V. Bhuva, Naval Kapuriya,<br />
Anil S. Patel, Vipul B. Audichya, Piyush V. Pipaliya and Yogesh T. Naliapara*.<br />
Der Pharmacia Lettre. 2009, 1 (2), 277-285.<br />
3. Tetraethylammoniumbromide mediated Knoevenagel condensation in water:<br />
Synthesis of 4-arylmethylene-3-methyl-5-pyrazolone.<br />
Akshay M. Pansuriya, Mahesh M. Savant, Chirag V. Bhuva, Naval Kapuriya,<br />
Piyush Pipaliya, Anil S. Patel, Vipul Audichya, Yogesh T. Naliapara*.<br />
E-Journal of Chemistry, (Accepted)<br />
4. Fuller’s earth catalyzed a rapid synthesis of Bis(indolyl)methanes under solvent<br />
free condition.<br />
Naval Kapuriya, Rajesh Kakadiya, Mahesh M. Savant, Akshay M. Pansuriya,<br />
Chirag V. Bhuva, Anil S. Patel, Piyush V. Pipaliya, Vipul B. Audichya, Sarala<br />
Gangadharaiah, Sridhar M. Anandalwar, Javaregowda S. Prasad, Anamik Shah,<br />
Yogesh T. Naliapara* Indian Journal of Chemistry B, Under Review.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 236
Conferences participated<br />
1. “15 th International conference on Bridging gaps in discovery and development:<br />
chemical and biological sciences for affordable health, wellness and<br />
sustainability” on 4-7 th Feb. 2011 at Department of Chemistry, <strong>Saurashtra</strong><br />
<strong>University</strong>, Rajkot-360005. (Poster Presentation)<br />
2. “National seminar on emerging Trends in polymer science and Technology” on 8-<br />
10 th Oct. 2009 (poly-2009) at Department of Chemistry, <strong>Saurashtra</strong><br />
<strong>University</strong>, Rajkot-360005.<br />
3. “Two Days National workshop on Patents & IPR related updates” on 19-20 th Sep.<br />
2009 at Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>, Rajkot-360005.<br />
4. “International seminar on recent Development in structure and ligand based Drug<br />
Design” on 23 rd Dec. 2009 at Department of Chemistry, <strong>Saurashtra</strong><br />
<strong>University</strong>, Rajkot-360005.<br />
Department of Chemistry, <strong>Saurashtra</strong> university, Rajkot-360005 237