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STUDIES ON NOVEL BIOACTIVE 

HETEROCYCLIC COMPOUNDS 

A THESIS SUBMITTED TO THE 

Re-Accredited Grade-B by 

NAAC (CGPA 2.93) 

IN 

THE FACULTY OF SCIENCE 

FOR 

THE DEGREE 

OF 

Doctor of Philosophy 

IN 

CHEMISTRY 

BY 

ANILKUMAR S. PATEL 

UNDER THE GUIDANCE OF 

Dr. YOGESH T. NALIAPARA 

DEPARTMENT OF CHEMISTRY 

SAURASHTRA UNIVERSITY 

RAJKOT – 360 005 

GUJARAT, INDIA 

NOVEMBER 2011

Statement under O.Ph.D.7 of Saurashtra University 

The work included in the thesis is done by me under the supervision of Dr. 

Yogesh T. Naliapara and the contribution made there of is my own work. 

Date: 

Place: Rajkot 

Anilkumar S. Patel

SAURASHTRA UNIVERSITY 

Department of Chemistry 

Rajkot – 360 005 

Phone: (O) +91-281-2576802 

(Cell) +91-94280 36310 

E mail: naliaparachem@yahoo.com 

Re-Accredited Grade-B by 

NAAC (CGPA 2.93) 

CERTIFICATE 

This is to certify that the present work “Studies on Novel Bioactive Heterocyclic 

Compounds” submitted for the Degree of Ph. D. in the subject Chemistry is done by 

Mr. Anilkumar S. Patel at Department of Chemistry, Saurashtra University, Rajkot, 

under my supervision and is a significant contribution in the field of synthetic organic 

chemistry and medicinal chemistry. His thesis is recommended for acceptance for the 

award of the Ph.D. degree by the Saurashtra University. 

Date: 

Place: Rajkot 

Dr. Yogesh T. Naliapara 

Assistant Professor, 

Department of Chemistry, 

Saurashtra University, 

Rajkot-360005 

Gujarat, India.

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Acknowledgement 

Firstly, I bow my head humbly before the Almighty God for making me 

capable of completing my Ph.D. Thesis; with his blessings only I have accomplished 

this huge task. 

I express deep sense of gratitude and thankfulness to my supervisor Dr. 

Yogesh T. Naliapara who has helped me at each and every point of my research work 

with patience and enthusiasm. I am much indebted to him for his inspiring guidance, 

affection, generosity and everlasting enthusiasm throughout the tenure of my 

research work. 

I am very thankful to the faculties of Department of Chemistry namely, Prof. 

P. H. Parsania, Prof. Anamik Shah, Prof. V. H. Shah, Prof. H. S. Joshi, Prof. Shipara 

Baluja, Dr. M. K. Shah, Dr. R. C. Khunt, for their encouragement and providing 

adequate research facilities. 

I sincerely grateful to Dr. Naval Kapuriya (jiju) and Mrs. Kalpana Kapuriya 

(sister) for their continuous support and inspiration during my research work and as 

a result, I am capable to complete this work. They had helped me all along to speed 

up my research work. 

My heartily thanks to my colleagues and labmates Piyush Pipaliya, Vipul 

Audichya and Gami Sagar for their kind help and support. My special thanks to Dr. 

Chirag Bhuva, Dr. Akshay Pansuriya, Dr. Jyoti Singh and Dr. Mahesh Savant. 

I offer my gratitude to my friends Dr. Satish, Dr. Rajesh, Dr. Rupesh, Dr. 

Bhavin, Dr. Ravi, Dr, Mehul, Dr. Jignesh, Dr. Renish, Dr. Harshad, Dr. Amit, Dr. 

Bhavesh, Dr. Pooja, Dr. Yogesh, Dr. Naimish, Krunal, Rakesh, Vipul, Ashish, Paresh, 

Bharat, Piyush(motabhai), Ramani, Punit, Gaurang, Satish, Batuk, Ashish and all the 

Ph.D. students for their fruitful discussion at various stages. I am also thankful to my 

best friends Mehul, Dr. Dinesh, Bipin(moto), Pankaj, Pintu, Parag, Sumit, Kalpesh, 

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 

instrumentation support. Special thanks are due to “National Facility for Drug 

Discovery through New Chemical Entities (NCE's) Development & Instrumentation 

Support to Small Manufacturing Pharma Enterprises” Programme under Drug & 

Pharma Research Support (DPRS) jointly funded by Department of Science & 

Technology, New Delhi, Government of Gujarat Industries Commissionerate & 

Saurashtra University, Rajkot. I am also thankful to SAIF, CIL, Chandigarh and NRC, 

IISc, Bangalore for providing spectroscopic analysis. 

Special thanks to Open Source of Drug Discover project for giving me 

financial support and University of Grant Commission for finding me as Meritorious 

Research Fellow which is really an achievement and helpful task for me. 

At Last, I have no words to state anything about my parents but at this 

occasion, I would like to thanks my father and mother, without their support, 

motivation and understanding it would have been impossible for me to finish my 

research work. I sincerely thank to my whole family for encouraging me and 

providing every help to fulfill my task. My special gratitude is due to my sister and 

their families for their loving support during tenure of my work. To them I dedicate 

this thesis. 

Anilkumar S. Patel

Content 

Chapter 1 

Palladium Catalyzed Synthesis of Novel Highly Functionalized 

Pyrimidines via Suzuki-Miyaura Coupling Reaction. 

1.1 Introduction 1 

1.2 Biological Activity Associated with 4-Aryl dihydropyrimidine derivatives 2 

1.3 Synthetic strategies for the dihydropyrimidines (DHPMs) 7 

1.4 Current research work 20 

1.5 Results and discussion 21 

1.6 Conclusion 24 

1.7 Experimental section 25 

1.8 References 40 

Chapter 2 

Synthesis and Biological Activity of Novel Pyrimidine Derivatives via 

Wittig Reaction in Aqueous Media. 


2.2 A literature review on the biological activity associated with pyrimidine 

derivatives 45 

2.3 Various synthetic approaches for highly substituted pyrimidines 50 

2.4 Applications of Wittig reaction 52 

2.5 Application of sodium tripolyphosphate 55 



2.8 Antimicrobial sensitivity testing 60 




Chapter 3 

Rapid Synthesis and Characterization of Novel Tri-substituted 

Pyrazoles/Isoxazoles Library Using Ketene Dithioacetals. 


3.2 Biological activity associated with pyrazoles and isoxazoles 83 

3.3 Synthetic methods for the pyrazole and isooxazole derivatives 89 

3.4 Some pharmaceutical molecules related to pyrazoles and isoxazoles 94 





3.9 References 118

Chapter 4 

Synthesis and Characterization of Novel Substituted and Fused 

Pyrazolo[1,5-a] pyrimidines Derivatives. 


4.2 Biological activity related to pyrazopyrimidine derivatives 122 

4.3 Various synthetic approaches for substituted pyrazolopyrimidine derivatives 126 





4.8 Reference 155 

Chapter 5 

Rapid Synthesis of Highly Substituted Pyrrole Derivatives: Analogs of 

Atorvastatin. 


5.2 Various synthetic approaches for highly substituted pyrroles 159 

5.3 Biological activity associated with pyrrole derivatives 167 

5.4 Some drugs from pyrrole nucleus 167 



5.7 Antimicrobial sensitivity testing 173 




Chapter 6 Synthesis and Characterization of Some New Benzodiazepine 

Derivatives. 


6.2 Biological activities associated with diazepine derivatives 203 

6.3 Some pharmaceutical molecules related to benzodiazepines 207 

6.4 Synthetic methods for benzodiazepines derivatives 208 

6.5. Current research work 211 





Summary 234 

List of Publications and Conferences participated 236

Abbreviations 

AIDS 

CS 2 

CDK 

DABCO 

DMSO 

DMF 

DMS 

DHP 

DHPM 

DIBAL 

EGFR 

GABA 

HDAC 

HIV 

HCV 

MDC 

mCPBA 

PAF 

STPP 

THF 

TMS 

VEGFR 

iPA 

h 

min 

rt 

mp 

Aquired immune deficiency syndrome 

Carbon disulfide 

Cyclin-dependent kinase 

1,4-diazabicyclo[2.2.2]octane 

Dimethyl sulfoxide 

Dimethyl formamide 

Dimethyl sulfate 

Dihydropyridine 

Dihydropyrimidine 

Diisobutylaluminium hydride 

Epidermal Growth Factor Receptor 

Gamma-aminobutyric acid 

Histone deacetylase 

Human immunodeficiency virus 

Hepatitis C virus 

Methylene dichloride 

meta-chloro perbenzoic acid 

Platelet-activating factor 

Sodium tripolyphosphate 

Tetrahydrofuran 

Trimethyl silane 

Vascular Endothelial Growth Factor Receptor 

iso-propyl alcohol 

hour (time) 

minute (time) 

room temperature 

melting point

Chapter – 1 

Palladium Catalyzed Synthesis of Novel 

Highly Functionalized Pyrimidines via 

Suzuki-Miyaura Coupling Reaction

Chapter 1 

Synthesis of functionalized pyrimidines 

1.1 Introduction 

The pyrimidine fragment is present in the molecules of a series of biologically 

active compounds, many of which have found use in medical practice (soporific, antiinflammatory, 

antitumor, and other products). 1,2 In this connection, great attention has 

recently been paid to the derivatives of pyrimidine, including their hydrogenation 

products. The first investigation into the synthesis of pyrimidine nucleus appeared 

more than a hundred years ago and subsequently several methods for the synthesis of 

dihydropyrimidine were reported and their physicochemical properties has been 

studied (e.g., the Biginelli reaction). 3 Further, the high reactivity and wide range of 

biological activity associated with these scaffolds have been demonstrated in the 

literature. For example, 2-substituted 5-alkoxycarbonyl-4-aryl-l,4-dihydropyrimidines 

(structural analogs of Hantzsch esters) are modulators of the transport of calcium 

through membranes. 4-7 Many hydrogenated pyrimidines exhibit antimicrobial, 8 

hypoglemic, 9 herbicidal, 10 and pesticidal 11 activity. Publications devoted to these 

problems have been summarized in a number of reviews. 9-14 

Pyrimidines have a long and distinguished history extending from the days of 

their discovery as important constituents of several biological molecules such as 

nucleic acids, cofactors, various toxins, to their current use in the chemotherapy of 

AIDS. All these compounds yield great promise for the treatment of retro virus 

infections in humans. 

Alloxan (1) is known for its diabetogenic action in a number of animals. 15 

Uracil (2), thymine (3) and cytosine (4) are the three important constituents of nucleic 

acids (Figure-1). 

Figure-1 

The pyrimidine ring is also found in vitamins such as thiamine (5), riboflavin 

(6) (Figure-2) and folic acid (7). 16 Barbitone (8) is the first barbiturate hypnotic, 

sedative and anticonvulsant are pyrimidine derivatives (Figure-3). 

Department of Chemistry, Saurashtra University, Rajkot-360005 1

Chapter 1 


Figure-2 

Figure-3 

1.2 Biological Activity Associated with 4-Aryl dihydropyrimidine 

derivatives 

Among the dihydropyrimidines, 4-Aryl-1,4-dihydropyridines (DHPs, e.g. 

nifedipine) are the most studied class of organic calcium channel modulators. More 

than 30 years after the introduction of nifedipine many DHP analogs have now been 

synthesized and numerous second-generation commercial products have appeared on 

the market. 17,18 

Nowadays, interest has also been focused on aza-analogs such as 

dihydropyrimidines (DHPMs) which showed a very similar pharmacological profile 

to the classical dihydropyridine calcium channel modulators. 5-7, 19-20 Over the past few 

years several lead-compounds were developed (i.e. SQ 32,926) that are superior in 

potency and duration of antihypertensive activity to classical DHP drugs, and 

compare favorable with second-generation analogs such as amlodipine and 

nicardipine (Figure-4). 

Figure-4 


Chapter 1 


Barrow et al. has reported in vitro and in vivo evaluation of 

dihydropyrimidinone C-5 amides as potent and selective r1A receptor antagonists for 

the treatment of benign prostatic hyperplasia (Figure-5). R1 Adrenergic receptors 

mediate both vascular and lower urinary tract tone, and R1 receptor antagonists such 

as terazosin are used to treat both hypertension and benign prostatic hyperplasia 

(BPH). Recently, three different subtypes of this receptor have been identified, with 

the R1A receptor being most prevalent in lower urinary tract tissue. Barrow et al. has 

also reported 4-aryldihydropyrimidinones attached to an aminopropyl-4- 

arylpiperidine via a C5 amide as selective R1A receptor subtype antagonists. In 

receptor binding assays, these types of compounds generally display Ki values for the 

R1a receptor subtype 20%) and half-life (>6 h) in 

both rats and dogs. Due to its selectivity for the R1a over the R1b and R1d receptors 

as well as its favorable pharmacokinetic profile, it has the potential to relieve the 

symptoms of BPH without eliciting effects on the cardiovascular system. 21,22 

F 

F 

N 

R 3 R 2 

Figure-5 

The 4-aryldihydropyrimidinone attached to an aminopropyl-4-arylpiperidine 

via a C5 amide has proved to be an excellent template for selective R1A receptor 

subtype antagonists. Those compounds are exceptionally potent in both cloned 

receptor binding studies as well as in vivo pharmacodynamic models of prostatic tone. 

Atwal et al. have examined a series of novel dihydropyrimidine calcium 

channel blockers that contain a basic group attached to either C5 or N3 of the 

heterocyclic ring (Figure-6). 

N 

H 

O 

R 1 

N 

H 

NH 

O 


Chapter 1 


Structure-activity studies showed that l-(phenylmethyl)-4-piperidinylcarbamate 

moiety at N3 and sulfur at C2 are optimal for vasorelaxant activity in vitro and impart 

potent and long-acting antihypertensive activity in vivo. One of these compounds was 

identified as a lead, and the individual enantiomers were synthesized. Two key steps 

of the synthesis were (1) the efficient separation of the diastereomeric ureido 

derivatives and (2) the high-yield transformation of 2-methoxy intermediate to the 

(p-methoxybenzyl)thio intermediates. Chirality was demonstrated to be a significant 

determinant of biological activity, with the DHP receptor recognizing the enamines 

ester moiety but not the carbamate moiety. DHPM is equipotent to nifidepine and 

amlodipine in vitro. In the spontaneously hypertensive rat, DHPM is more potent and 

longer acting than both nifidepine and the long-acting amlodipine (DHP derivative). 

DHPM has the potential advantage of being a single enantiomer. 23,24 

F 3 C 

i-PrO 2 C 

N 

H 

N 

O 2 

C 

S 

N 

F 3 C 

R i-PrO 2 C 

Figure-6 

N 

H 

N 

O 2 

C 

S 

N 

HCl 

F 

In order to explain the potent antihypertensive activity of the modestly active 

(ICw = 3.2 pM) DHPM calcium channel blocker, Atwal et al. carried out drug 

metabolism studies in the rat and found that two of the metabolites (ICw = 16 nM) 

and (ICw = 12 nM), were responsible for antihypertensive activity of compound. 

Potential metabolism in vivo precluded interest in pursuing compounds related to it. 

Structure-activity studies aimed at identifying additional aryl-substituted analogues 

led to comparable potential in vivo, though these compounds were less potent in vitro. 

To investigate the effects of absolute stereochemistry on potency, authors resolved via 

diastereomeric ureas, prepared by treatment with (R)-α-methylbenzylamine. The 

results demonstrate that the active R-(-)-enantiomer is more potent and longer acting 

than nifedipine as an antihypertensive agent in the SHR. The in vivo potency and 

duration is comparable to the long-acting DHP amlodipine. The superior oral 

antihypertensive activity compared to that of previously described carbamates 

(R 2 =COOEt) could be explained by its improved oral bioavailability, possibly 

resulting from increased stability of the urea functionality (Figure-7). 6 


Chapter 1 


Figure-7 

Authors modified the structure of previously described DHPM i.e. 3- 

substituted 1,4-dihydropyrimidines. Structure-activity studies using potassiumdepolarized 

rabbit aorta show that ortho, meta-disubstituted aryl derivatives are more 

potent than either ortho or meta-monosubstituted compounds. While vasorelaxant 

activity was critically dependent on the size of the C5 ester group, isopropyl ester 

being the best, a variety of substituents (carbamate, acyl, sulfonyl, and alkyl) were 

tolerated at N3. The results showed that DHPMs are significantly more potent than 

corresponding 2- heteroalkyl-l,4-dihydropyrimidines and only slightly less potent than 

similarly substituted 2-heteroalkyl-1-4-dihydropyridines (Figure-8). Where as DHP 

enantiomer usually show 10-15-fold difference in activity, the enantiomer of DHPM 

show more than a 1000-fold difference in activity. These results strengthen the 

requirement of an enaminoester for binding to the dihydropyridine receptor and 

indicate a nonspecific role for the N3-substituent. 

Figure 8 

2-Heterosubstituted-4-aryl-l,4-dihydro-6-methyl-5-pyrimidinecarboxylicesters 

(Figure 9), which lack the potential symmetry of DHP calcium channel blockers, 

were prepared and evaluated for biological activity. Biological assays using 

potassium-depolarized rabbit aorta and radio ligand binding techniques showed that 

some of these compounds are potent mimics of DHP calcium channel blockers. 25 

Figure 9 


Chapter 1 


Bryzgalov A. O. et al. has studied the antiarrhythmic activity of 4,6- 

di(het)aryl-5-nitro-3,4-dihydropyrimidin-(1H)-2-ones (Figure-10) toward two types 

of experimental rat arrhythmia. With CaCl 2 induced arrhythmia model, several agents 

have demonstrated high antiarrhythmic activity and the lack of influence on arterial 

pressure of rats. 26 Figure 10 

Remennikov G. et al. 27 has synthesized some novel 4-aryl-5-nitro substituted 

DHPMs (Figure 11) using nitro acetone and screened as calcium modulators. They 

have studied the pharmacological properties of 6-methyl- and 1,6-dimethyl-4-aryl-5- 

nitro-2-oxo-l,2,3,4-tetrahydropyrimidines with different substituents in the aryl 

fragment, i.e. unsubstituted, ortho, meta, para, di, and tri-substituted compounds and 

observed that 5-nitro DHPMs bearing unsubstituted, ortho and tri-substitution on aryl 

moieties at C4 position reduced blood pressure and inhibited myocardial contractile 

activity. The second group consisted meta, para and di-substituted aryl moieties with 

DHPMs increased blood pressure and had positive inotropic effects. The compounds 

with the highest hypotensive activity were containing substituent in the ortho position 

of the phenyl fragment. Thus, compounds having substitution on aryl moieties which 

had pronounced vasodilator and weak cardio depressive actions, increased cardiac 

pump function (SV). When inhibition of myocardial contractile function 

predominated, there was a reduction in SV. The effect of compounds of the first group 

on heart rate was variable, though most reduced heart rate. In addition, a reflex 

increase in heart rate might be expected because of the reduction in blood pressure. 

The reference preparations for compounds of this group were the calcium antagonist 

nifedipine. 

Figure-11 


Chapter 1 


The pharmacological profile of compounds of the first group was analogous to that of 

nifedipine. This suggests that they share a common mechanism of action - blockade of 

calcium ion influx. 

Brain C. Shook et al. 28 has synthesized a novel series of arylindenopyrimidines 

(Figure-12) identified as A 2A and A 1 receptor antagonists. The series was 

optimized for vitro activity by substituting the 8-and-9- positions with methylene 

amine substituents. The compounds show excellent activity in mouse models of 

parkinson’s disease when dosed orally. 

O 

Ar 

R'RN 

N 

Figure-12 

N 

NH 2 

1.3. Synthetic strategies for the dihydropyrimidines (DHPMs) 

Having tremendous important of DHPMs in medicinal chemistry, a literature 

survey on the synthetic methods for the biologically active dihydropyrimidines 

(DHPMs) has been carried out and described as follows. Various modifications have 

been applied to Biginelli reaction to get better yield and to synthesize biologically 

active analogs. Different catalysts have been reported to increase the yield of the 

reaction. Microwave synthesis strategies have also been applied to shorten the 

reaction time. Solid phase synthesis and combinatorial chemistry has made possible to 

generate library of DHPM analogs. The various modifications are discussed in the 

following section. 

Catalysts 

Min Yang and coworkers 29 have synthesized the different DHPMs by using 

various inorganic salts as a catalyst (Figure-13). They found that the yields of the 

one-pot Biginelli reaction can be increased from 20-50% to 81-99%, while the 

reaction time shorted for 18-24 hrs to 20-30 min. This modification was developed by 

using Yb(OTf) 3 and YbCl 3 as a catalyst under solvent free conditions. One additional 

important feature of this protocol is the catalyst can be easily recovered and reused. 


Chapter 1 


Figure-13 

Lewis acid such as, Indium (III) chloride was emerged as a powerful Lewis 

catalyst imparting high region and chemo selectivity in various chemical 

transformations. B. C. Ranu and co-workers 30 have reported indium (III) chloride 

(InCl 3 ) as an efficient catalyst for the synthesis of 3,4-dihydropyrimidn-2(1H)-ones 

(Figure-14). A variety of substituted aromatic, aliphatic and heterocyclic aldehydes 

have been subjected to this condensation very efficiently. Thiourea has been used 

with similar success to provide the corresponding dihydropyrimidin-2(1H)-thiones. 

Figure-14 

Majid M. Heravi et al. has reported a simple, efficient and cost-effective 

method for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones by one pot 

three-component cyclocondensation reaction of a 1,3-dicarbonyl compound, an 

aldehyde and urea or thiourea using 12-tungstophosphoric acid 31 and 12- 

molybdophosphoric acid 32 as recyclable catalyst (Figure-15). 

Figure-15 

Hydroxyapatite doped with ZnCl 2 , CuCl 2 , NiCl 2 and CoCl 2 efficiently 

catalyzes the three components Biginelli reaction between an aldehyde, ethyl 

acetoacetate and urea in refluxing toluene to afford the corresponding 

dihydropyrimidinones in high yields. 33 

Sc(III)triflate catalyzes the three-component condensation reaction of an 

aldehyde, a β-ketoester and urea in refluxing acetonitrile to afford the corresponding 

3,4-dihydropyrimidin-2(1H)-ones in excellent yields (Figure-16). The catalyst can be 

recovered and reused, making this method friendly and environmentally acceptable. 34 


Chapter 1 


Figure-16 

Solid phase synthesis 

The generation of combinatorial libraries of heterocyclic compounds by solid 

phase synthesis is of great interest for accelerating lead discovery and lead 

optimization in pharmaceutical research. Multi-component reactions (MCRs) 35,36-37 

leading to heterocycles are particularly useful for the creation of diverse chemical 

libraries, since the combination of any 3 small molecular weight building blocks in a 

single operation leads to high combinatorial efficiency. Therefore, solid phase 

modifications of MCRs are rapidly become the cornerstone of combinatorial synthesis 

of small-molecule libraries. 

The first solid-phase modification of the Biginelli condensation was reported 

by Wipf and Cunningham 38 in 1995 (Figure-17). In this sequence, γ-aminobutyric 

acid derived urea was attached to Wang resin using standard procedures. The 

resulting polymer-bound urea was condensed with excess β-ketoester and aromatic 

aldehydes in THF at 55 °C in the presence of a catalytic amount of HCl to afford the 

corresponding immobilized DHPMs. Subsequent cleavage of product from the resin 

by 50 % trifluoroacetic acid (TFA) provided DHPMs in high yields and excellent 

purity. 

Figure-17 

Li W. and Lam Y. 39 have described the synthesis of 3,4-dihydropyrimidin-2- 

(1H)ones/thiones using sodium benzene sulfinate as a traceless linker (Figure-18). 

The key steps involved in the solid-phase synthetic procedure were sulfinate 

acidification, condensation of urea or thiourea with aldehydes and sulfinic acid and 

traceless product release by a one-pot cyclization-dehydration process. Since a variety 

of reagents can be used, the overall strategy appears for library generation. 


Chapter 1 


Figure-18 

Liquid phase synthesis 

In the solid phase synthesis there are some disadvantages in compared to 

standard solution-phase synthesis, such as difficulties to monitor reaction progress, 

the large excess of reagents typically used in solid-phase supported synthesis, low 

loading capacity and limited solubility during the reaction progress and the 

heterogeneous reaction condition with solid phase. 40 Recently, organic synthesis of 

small molecular compounds on soluble polymers, i.e. liquid phase chemistry has 

increasingly become attractive field. 41 

Moreover, owing to the homogeneity of liquid-phase reactions, the reaction 

conditions can be readily shifted from solution-phase systems without large changes 

and the amount of excessive reagents is less than that in solid-phase reactions. In the 

recent years, Task Specific room temperature Ionic Liquids (TSILs) has emerged as a 

powerful alternative to conventional molecular organic solvents or catalysts. Liu Z. et 

al. 42 have reported cheap and reusable TSILs for the synthesis of 3,4- 

dihydropyrimidin-2(1H)-ones via one-pot three component Biginelli reaction. Ionic 

liquid-phase bound acetoacetate reacts with thiourea and various aldehydes with a 

cheap catalyst to afford ionic liquid-phase supported 3,4-dihydropyrimidin-2(1H)- 

thiones, which has been reported by Bazureau J. P. and co- workers 43 (Figure-19). 

3,4-Dihydropyrimidinones were synthesized in one-pot, by the reaction of aldehydes, 

β-dicarbonyl compounds and urea, catalyzed by non-toxic room temperature ionic 

liquid 1-n-butyl-3-methylimidazolium saccharinate (BMImSac). 44 

Figure-19 


Chapter 1 


Microwave assisted synthesis 

In general, the standard procedure for the Biginelli condensation involves one 

pot condensation of the three building blocks in a solvent such as ethanol using a 

strongly acidic catalyst that is hydrochloric acid. One major drawback of this 

procedure, apart from the long reaction time involving reflux temperature, is the 

moderate yields frequently observed when using more complex building blocks. 

Microwave irradiation (MW) has become accepted tool in organic synthesis, because 

the rate enhancement, higher yields and often, improved selectivity with respect to 

conventional reaction conditions. 45 The publication by Dandia A. et al. 46 described 

microwave-enhanced solution-phase Biginelli reactions employing ethyl acetoacetate, 

thiourea and a wide variety of aromatic aldehydes as building blocks (Figure-20). 

Upon irradiation of the individual reaction mixtures (ethanol, catalytic HCl) in an 

open glass beaker inside the cavity of a domestic microwave oven the reaction times 

were reduced from 2–24 hours of conventional heating 80 °C, reflux to 3–11 minutes 

under microwave activation (ca. 200 –300 W). At the same time the yields of DHPMs 

obtained were distinctly improved compared to those reported earlier using 

conventional conditions. 

Figure-20 

In recent years, solvent free reactions using either organic or inorganic solid 

supports have received more attention. 47 There are several advantages to perform 

synthesis in dry media: (i) short reaction times, (ii) increased safety, (iii) economic 

advantages due to the absence of solvent. In addition, solvent free MW processes are 

also clean and efficient. Gopalakrishnan M. and co-workers have reported Biginelli 

reaction under microwave irradiation in solvent-free conditions using activated fly ash 

as catalyst, an industrial waste (pollutant) is an efficient and novel catalyst for some 

selected organic reactions in solvent free conditions under microwave irradiation. 48 


Chapter 1 


Ultrasound assisted synthesis 

Ultrasound as a green synthetic approach has gradually been used in organic 

synthesis over the last three decades. Compared with the traditional methods, it is 

more convenient, easier to be controlled and consumes less power. With the use of 

ultrasound irradiation, a large number of organic reactions can be carried out in milder 

conditions with shorter reaction time and higher product yields. 49 Ultrasound 

irradiated and amidosulfonicacid (NH 2 SO 3 H) catalyzed synthesis of 3,4- 

dihydropyrimidi-2-(1H)ones have been reported by Li J. T. and co-workers 50 using 

aldehydes, β-ketoester and urea. 

Liu C. et al. 51 have synthesized a novel series of 4-substituted pyrazolyl-3,4- 

dihydropyrimidin-2(1H)-thiones under ultrasound irradiation using magnesium 

perchlorate [Mg(ClO 4 ) 2 ] as catalyst (Figure-21), by the condensation of 5- 

chloro/phenoxyl-3-methyl-1-phenyl-4-formylpyrazole, 1,3-dicarbonyl compound and 

urea or thiourea in moderate yields. The catalyst exhibited remarkable reactivity and 

can be recycled. 

Figure-21 

Sonication of aromatic aldehydes, urea and ethyl acetoacetate in presence of 

solvent (ethanol) or solvent-less dry media (bentonite clay) by supporting-zirconium 

chloride (ZrCl 4 ) as catalyst at 35 kHz gives 6-methyl-4-substitutedphenyl-2-oxo- 

1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl esters proficiently in high yields, 

which reported by Harish Kumar et al. (Figure 22). 52 

Figure-22 


Chapter 1 


 

Synthetic Methods for the Oxidative Dehydrogenation of DHPM Ring 

System 

The production of heteroaromatics by oxidative dehydrogenations is of 

fundamental importance in organic synthesis. The dehydrogenation of 

dihydropyrimidines and dihydropyrimidinones has received much attention because 

of their facile access via the Biginelli three-component coupling. Different methods 

were reported in the literature for oxidative dehydrogenations of DHPM, which are 

described as under. 

Hamid Reza Memarian et al. 53 have developed dehydrogenation of 5-acetyl- 

3,4-dihydropyrimidin-2(1H)-ones by potassium peroxydisulfate in aqueous 

acetonitrile under thermal and sonothermal conditions (Figure-23). 

O 

R 

H 

NH 

N 

H 

O 

K 2 S 2 O 

CH 3 CN/H 2 O 

Ultrasound/ 

Heat 

O 

R 

N 

H 

N 

O 

Figure-23 

Sam Sik Kim et al. 54 reported that oxidation of dihydropyrimidin-2(1H)-ones 

by KMnO 4 formed 2-hydroxypyrimidine in excellent yield, whereas attempted direct 

desulfurative aromatization of dihydropyrimidin-2(1H)-thiones by KMnO 4 resulted in 

the formation of 2-hydroxypyrimidines (Figure-24). 

Figure-24 

Masoud Nasr-Esfahani et al. 55 reported photolytic oxidation of some ethyl 3,4- 

dihydropyrimidin-2(1H)-one-5-carboxylates to their corresponding ethyl pyrimidin- 

2(1H)-one-5-carboxylates using a TiO 2 /O 2 system under UV irradiation by a 400 W 

high pressure mercury lamp in acetonitrile (Figure-25). 

Figure-25 


Chapter 1 


Rui Liang et al. 56 has shown the oxidation of 3,4-Dihydropyrimidin-2(1H)- 

ones (DHPMs) with 1.2 eq. of nitrosonium tetrafluoroborate (NO + BF - 4 ) to pyrimidin- 

2(1H)-ones in acetonitrile at room temperature in high yields (Figure-26). 

Figure-26 

Nandkishor N. Karade et al. 57 has achieved oxidative dehydrogenation of 3,4- 

dihydropyrimidin-2(1H)-ones to 1,2-dihydropyrimidines through a novel combination 

of (diacetoxyiodo)benzene and tert-butylhydroperoxide in CH 2 Cl 2 (Figure-27). 

Figure-27 

Kana Yamamoto et al. 58 has reported method for oxidative dehydrogenation of 

dihydropyrimidinones and dihydropyrimidines by using catalytic amounts of a Cu 

salt, K 2 CO 3 , and tert-butylhydroperoxide (TBHP) as a terminal oxidant (Figure-28). 

Figure-28 

Synthetic Methods for the Synthesis of 2-Chloropyrimidine Derivatives 

Several methods were reported in the literature for the chlorination of 2- 

hydroxypyrimidines, few of them are described herein. 

Driwedi Shriprakash Dhar et al. 59 has reported synthesis of 2-halopyrimidine 

derivative from 2-hydroxypyrimidine by using thionyl chloride and dimethyl 

formamide and toluene as a solvent at 80 o C (Figure-29). 


Chapter 1 


Figure-29 

Atul R. Gholap et al. 60 has described the synthesis of 2-chloropyrimidine 

derivatives from 2-hydroxypyrimidine derivatives using N,N-dimethylaniline and 

POCl 3 as chlorinating agent under reflux condition (Figure-30). 

Figure-30 

 

Synthetic methods for the Suzuki-Miyaura coupling 

The well known Suzuki reaction 61 is the organic reaction of an aryl or vinylboronicacid 

with an aryl or vinyl-halide catalyzed by a palladium(0)complex forming 

carbon-carbon bond. Some reported methods are described as under. 

In 1981, Suzuki and Miyaura et al. have made a breakthrough in the 

methodology for biaryl compounds using aryl boronicacids and aryl bromide under 

homogeneous palladium catalyzed conditions in the presence of base 62 (Figure- 31). 

Z 

OH 

Br B OH 

3mol%Pd(Ph 3 ) 4 

Aq. Na 2 CO 3 

Benzene, refulx 

Figure-31 

Z 

S. Li et al. 63 have synthesized Pd(OAc) 2 -catalyzed room temperature Suzuki 

cross coupling reaction in aqueous media under aerobic conditions (Figure-32). 

Figure-32 

Y. M. A. Yamada et al. 64 have prepared highly active catalyst for the 

heterogeneous Suzuki-Miyaura reaction by assembled complex of palladium and noncross 

linked amphiphilic polymer (Figure-33). 


Chapter 1 


Figure-33 

Zhengyin Du et al. 65 has reported an ultrafast and highly efficient ligand-free 

Suzuki-Miyaura cross-coupling reaction between aryl bromides/iodides and aryl 

boronicacids using palladium chloride as catalyst in PEG-400/H 2 O in air at room 

temperature. TEM showed that palladium nanoparticles were generated in situ from 

PdCl 2 /PEG-400/H 2 O without use of other reductants. The catalyst system can be 

recycled to reuse three times with good yields (Figure-34). 

Figure-34 

Yu-Long Zhao et al. 66 has prepared a highly practical and reliable Nickel 

catalyst for Suzuki–Miyaura coupling of aryl halides with various aryl boronicacid 

(Figure-35). 

Figure-35 

Sha Lou et al. 67 has developed Palladium/Tris(tert-butyl)phosphine-Catalyzed 

Suzuki Cross-Couplings of aryl and heteroaryl halides with aryl and heteroaryl 

boronic acids in the Presence of Water (Figure-36). 

Figure-36 

Ruonan Zhang et al. 68 has synthesized a series of novel 5-arylidenefuran- 

2(5H)-ones and 5-arylidene-4-arylfuran-2(5H)-ones via the Suzuki-Miyaura reactions 

(Figure-37). 

Figure-37 


Chapter 1 


Yongda Zhang et al. 69 has been developed one-pot process for the synthesis of 

8-arylquinolines via Pd-catalyzed borylation of quinoline-8-yl halides and subsequent 

Suzuki-Miyaura coupling with aryl halides using n-BuPAd 2 as ligand (Figure-38). 

Figure-38 

John Spencer et al. 70 has reported synthesis of a (piperazin-1-ylmethyl)biaryl 

library via microwave-mediated Suzuki–Miyaura cross-couplings (Figure 39). 

Figure-39 

Qing Tang et al. 71 has developed Suzuki–Miyaura coupling reactions of 5- 

chloro-1-phenyl-tetrazole with various functionalized aryl boronicacids in the 

presence of catalytic amounts of SPhos/Pd(OAc) 2 or RuPhos/Pd(OAc) 2 (Figure-40). 

Figure-40 

V. P. Mehta et al. 72 has reported a novel and versatile entry to asymmetrically 

substituted pyrazine derivatives (Figure 41). 

Figure-41 

Jeanne-Marie Begouin et al. 73 has reported cobalt-catalyzed cross-coupling 

between in situ prepared aryl zinc halides and 2-chloropyrimidine/2-chloropyrazine 

(Figure- 42). 


Chapter 1 


Figure-42 

Takahiro Itoh et al. 74 has discovered a direct synthesis of hetero-biaryl 

compounds containing an unprotected NH 2 group via Suzuki–Miyaura reaction by 

using Pd(OAc) 2 and D-t-BPF ligand as a catalyst (Figure-43). 

Figure-43 

Lisa C. W. Chang et al. 75 synthesized 2,6-disubstituted and 2,6,8-trisubstituted 

purines as adenosine receptor antagonists via Suzuki–Miyaura reaction (Figure-44). 

Figure-44 

Atul R. Gholap et al. 60 has developed an efficient synthesis of antifungal 

pyrimidines via palladium catalyzed Suzuki/Sonogashira cross-coupling reaction from 

Biginelli 3,4-dihydropyrimidin-2(1H)-ones (Figure-45). 

Figure-45 

Christoph A. et al. 76 has reported an efficient Suzuki-Miyaura coupling of 

(hetero)aryl chlorides with Thiophene- and Furan boronicacids in aqueous n-butanol 

(Figure-46). 

R 

Y 

Cl 

(HO) 2 B 

(HO) 2 B 

S 

or 

O 

Na 2 PdCl 4 (1mol%)/L 

(1:2) 

2.0 eq. K 2 CO 3 

n-butanol/water 

R' 

100 o C 

Figure-46 

Department of Chemistry, Saurashtra University, Rajkot-360005 18 

R 

Y 

S 

or 

R 

Y 

O 

R'

Chapter 1 


David X. Yang et al. 77 has reported palladium-catalyzed Suzuki-Miyaura 

coupling of Pyridyl-2-boronic esters with aryl halides using highly active and airstable 

phosphine chloride and oxide Ligands (Figure-47). 

FG 

N 

O 

B 

O 

ArX 

or 

HetArX 

Dichloropalladiuym oxide/chloride 

Base, solvent 

FG 

N 

or 

Ar 

FG 

N 

HetAr 

Figure-47 


Chapter 1 


1.4. Current research work 

The literature survey described above has demonstrated that the pyrimidine 

derivatives possesses a variety of biological activity, among which are the analgesic, 

antihypertensive, antipyretic, antiviral and anti-inflammatory activity. These agents 

are also associated with nucleic acid, antibiotic, antimalarial and anti cancer drugs. 

Many of the pyrimidine derivatives are reported to possess potential CNS depressant 

properties. However, to our knowledge functionalized pyrimidines such as 4- 

isopropyl-2,6-di-phenylsubstituted derivatives are less studied (Figure-48). The 

tremendous biological potential of pyrimidine derivatives encouraged us to prepare 

some novel highly functionalized pyrimidines bearing 4-isopropyl-2-6-disubstitutedphenylpyrimidine-5-carboxylate 

functions. 

R 

O 

N 

O 

R 1 

N 

ASM-4a-t 

Figure-48 

Herein we described a series of novel and efficient protocol for the synthesis 

of diversely substituted pyrimidines. A series of chlorinated pyrimidines were 

synthesized from easily available Biginelli 3,4-dihydropyrimidin-2(1H)-ones. The 

chlorinated pyrimidines were subjected to the Suzuki-Miyaura coupling reactions 

with various phenylboronicacid derivatives to obtain C-phenyl pyrimidines. The 

newly synthesized compounds are characterized by IR, Mass, 1 H NMR, 13 C NMR 

spectroscopy and elemental analysis. 

. 


Chapter 1 


1.5. Results and discussion 

Scheme:-1 Synthesis of substituted pyrimidines via Suzuki-Miyaura coupling. 

R 

R 

R 

O 

NH 2 

NH 2 

O 

+ 

O 

O 

O 

DMF 

O 

HN 

N 

H 

O 

ASM-01a-e 

O 

Con. HNO 3 

O 

N 

N 

H 

ASM-2a-e 

O 

O 

POCl 3 

R 

R 

OH 

R 

O 

1 B OH 

O 

N O 

N O 

R 1 

N 

Pd(Ph 3 ) 4 

K Cl N 

2 CO 3 

ASM-4a-t 

ASM-3a-e 

The synthetic route for the targeted compounds (ASM-4a-t) is shown in 

scheme 1. Initially, various substituted 3,4-dihydropyrimidine-2-(1H)-ones (DHPMs) 

(ASM-01a-e) were synthesized by well-known multi-component Biginelli reaction of 

substituted benzaldehyde, methyl isobutyrate acetate and urea fusion at 150 o C in the 

presence of 2-3 drops of DMF as a catalyst (scheme-01). Thus obtained DHPMs 

(ASM-01a-e) were subjected the oxidative dehydrogenation using 60% Con. HNO 3 to 

furnish corresponding 2-hydroxypyrimidines (ASM-02a-e) in excellent yield. The 

reaction of compounds ASM-02a-e with POCl 3 under reflux for 2-3 hrs afforded 2- 

chloropyrimidine derivatives ASM-03a-e up to 85-95% yield. The chlorinated 

pyrimidines ASM-03a were subjected to Suzuki-Miyaura carbon-carbon coupling 

reaction with various phenylboronicacid derivatives using tetrakis(triphenylphosphine) 

palladium(0) as a catalyst in 1,4-dioxane:water (6:4) and K 2 CO 3 as a base to achieve 

the cross-coupled final products ASM-04a-t with good yields. 

The structures of ASM-02a-e, ASM-03a-e and ASM-04a-t were established 

on the basis of their elemental analysis and spectral data (MS, IR, 1 H NMR and 13 C 

NMR). Some representative examples for each step are described here. 


Chapter 1 


The analytical data for ASM-02a revealed a molecular formula C 15 H 16 N 2 O 3 

(m/z 273). The 1 H NMR spectrum revealed one doublet at δ = 1.42-1.44 ppm assigned 

to isopropyl-CH 3 , a multiplet at δ = 3.20-3.26 ppm assigned to the isopropyl-CH 

protons, a singlet at δ = 3.57 ppm assigned to the –OCH 3 protons, a multiplet at δ = 

7.44–7.51 ppm assigned to the aromatic protons, and also a doublet at δ = 7.58–7.60 

ppm (j=6.9Hz) assigned to the aromatic protons, one singlet at δ = 12.94 ppm 

assigned to -OH group. 

Table 1: Synthesis of substituted pyrimidines via Suzuki-Miyaura coupling. 

Entry R R 1 Yield Time hrs. 

ASM-04a H 4-CN 82 6.0 

ASM-04b 4-CH 3 3-N(CH 3 ) 2 80 8.0 

ASM-04c 4-OCH 3 4-F 87 6.5 

ASM-04d 3-NO 2 4-OCH 3 92 6.0 

ASM-04e 4-F H 83 7.5 

ASM-04f H 3-N(CH 3 ) 2 78 8.5 

ASM-04g 4-CH 3 4-F 86 7.5 

ASM-04h 4-OCH 3 4-OCH 3 82 7.0 

ASM-04i 3-NO 2 H 89 7.0 

ASM-04j 4-F 4-CN 87 5.5 

ASM-04k H 4-OCH 3 83 6.5 

ASM-04l 4-CH 3 H 85 7.0 

ASM-04m 4-OCH 3 4-CN 82 6.5 

ASM-04n 3-NO 2 3-N(CH 3 ) 2 75 7.5 

ASM-04o 4-F 4-F 80 6.0 

ASM-04p H H 84 7.5 

ASM-04q 4-CH 3 4-CN 89 6.0 

ASM-04r 4-OCH 3 3-N(CH 3 ) 2 80 7.5 

ASM-04s 3-NO 2 4-F 90 6.5 

ASM-04t 4-F 4-OCH 3 86 6.0 

The structures of ASM-03a was supported by its mass (m/z 291), which agrees 

with its molecular formula C 15 H 15 FN 2 O 3, its 1 H NMR spectrum had signals at δ = 

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- 

7.48 (m, 3H, Ar-H), 7.65-7.67 (t, 2H, Ar-H). 


Pd(II) 

Chapter 1 


The analytical data for ASM-04a revealed a molecular formula C 22 H 19 N 3 O 2 

(m/z 358). Its 1 H NMR spectrum had signals at δ = 1.16-1.32 (d, 6H, 2 x i prCH 3 ), 

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 

(m, 4H, Ar-H), 8.61-8.63 (d, 2H, Ar-H). 

The proposed mechanism of the Suzuki-Miyaura coupling reaction for the 

formation of C-phenyl pyrimidines is depicted in figure 35. 

N 

N 

R 

Pd (0) 

N 

N 

Cl 

N 

R 

N 

N 

Pd(II) 

N 

Pd(II) 

Cl 

HO 

OCOOK 

B OH 

OCOOK 

K 2 CO 3 

HO B OH 

OCOOK 

HO B OH 

N 

N 

-KCl 

K 2 CO 3 

KOOCO 

Figure 35: Mechanism of Suzuki-Miyaura coupling reaction leading 

to the formation of C-phenyl pyrimidines. 


Chapter 1 


1.6 Conclusion 

In conclusion, we have developed an efficient four step protocols for the 

synthesis of diversely substituted novel pyrimidines. A series of chlorinated 

pyrimidines were synthesized from easily available biginelli 3,4-dihydropyrimidin- 

2(1H)-ones. The chlorinated pyrimidines were then subjected to condition normally 

employed Suzuki-Miyaura coupling reaction with various phenylboronicacid 

derivatives in the presence of palladium catalyst to obtain C-phenyl pyrimidines with 

good yields. A variety of commercially available 1,3-diketones and various 

substituted aldehydes and boronic acids can be used as building blocks to generate 

diversity on the core pyrimidine ring systems. 


Chapter 1 


1.7 Experimental section 

Thin-layer chromatography was accomplished on 0.2-mm precoated plates of 

silica gel G60 F 254 (Merck). Visualization was made with UV light (254 and 365nm) 

or with an iodine vapor. IR spectra were recorded on a FTIR-8400 spectrophotometer 

using DRS prob. 1 H (300 MHz), 1 H (400 MHz), 13 C (75 MHz) and 13 C (100 MHz) 

NMR spectra were recorded on a Bruker AVANCE II spectrometer in CDCl 3 and 

DMSO. Chemical shifts are expressed in δ ppm downfield from TMS as an internal 

standard. Mass spectra were determined using direct inlet probe on a GCMS-QP 2010 

mass spectrometer (Shimadzu). Solvents were evaporated with a BUCHI rotary 

evaporator. Melting points were measured in open capillaries and are uncorrected. 

 

General synthetic procedure for the 3,4-dihydropyrimidine-2-(1H)-ones 

(ASM-01a-e). 

A 100mL round bottom flask equipped with magnetic stirrer and septum was 

charged with the methyl 4-methyl-3-oxopentanoate (0.01M), aldehyde (0.01M) and 

urea (0.015M). Few drops of DMF were added to the reaction mixture as a catalyst. 

The reaction mixture was then heated at 145-150 o C for 15-30 minutes. The progress 

of reaction was monitored by thin layer chromatography. The reaction mixture was 

allowed to cool at rt. Then, methanol (20 mL) was added and the resulting mixture 

was refluxed for 30 min. The solid separated upon cooling was filtered, washed with 

methanol and dried. The products thus obtained (ASM-01a-e) were directly used for 

the next step. 

 

General synthetic procedure for the 2-hydroxypyrimidine derivatives 

(ASM-02a-e). 

In a 100mL round bottom flask equipped with magnetic stirrer and 

thermometer was added nitric acid (60%) (10 mL). To the nitric acid slowly added 

ASM-01a-e (10 mmol) at 0 o C. After complete addition, the mixture was stirred at 

this temperature for 30 min. The progress of reaction was monitored by thin layer 

chromatography. The reaction mixture was poured into cold water and neutralized 

with saturated sodium bicarbonate solution. The solid separated was filtered, washed 

with water and dried. The crude products (ASM-02a-e) were directly used for the 

next step. 


Chapter 1 


 

General synthetic procedure for the 2-chloropyrimidine derivatives 

(ASM-03a-e). 

In a 50mL round bottom flask equipped with magnetic stirrer and thermometer 

was placed ASM-02a-e (10 mmol) and POCl 3 (15 mL). Reaction mixture heated up to 

reflux temperature and maintain for 2-3 hrs. The progress of reaction was monitored 

by thin layer chromatography. After completion of reaction, the mixture was poured 

in to crushed ice and neutralized with saturated sodium bicarbonate solution. The 

products was filtered, washed with water and dried. Crystallize crude product from 

methanol and used for next step without further purification. 

 

General synthetic procedure for the 2-substitutedpyrimidine derivatives 

via Suzuki-Miyaura coupling (ASM-03a-e). 

A mixture of 2-choropyrimidine derivatives ASM-03a-e (1.0 mmol) and 

phenylboronicacid derivatives (1.2 mmol) in 1,4-dioxane (12 mL) was stirred for 10 

min at rt. To this mixture, saturated solution of K 2 CO 3 (8 mL) was added followed by 

tetrakis(triphenylphosphine)palladium(0) (5 mol%). The reaction mixture was heated 

at 110 o C for 5-8 hrs. After completion, the reaction mixture was cooled to room 

temperature, diluted with ethyl acetate and filtered through pad of celite. The filtrate 

was washed with water (2 x 100 mL) and brine solution (100 mL). The organic layer 

was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was 

evaporated to dryness under vacuo. The residue was purified by using column 

chromatography using EtOAc/Ether (0.5:9.5) to afford analytically pure products 

ASM-04a-e. 


Chapter 1 


 

Spectral data for the newly prepared compounds. 

Methyl 1,2-dihydro-6-isopropyl-2-oxo-4-phenylpyrimidine-5-carboxylate (ASM- 

02a). White solid; R f 0.45 (1:1 hexane-EtOAc); mp 158-160 ° C; IR (KBr): 3459, 3070, 

2930, 2850, 1730, 1650, 1583, 1470, 1335, 1064, 760, 700 cm -1 ; 1 H NMR (300 MHz, 

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, 

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, 

OH); 13 C NMR (DEPT):(75 MHz, CDCl 3 ): 21.40, 31.31, 56.47, 56.58, 114.99, 

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; 

H, 5.92; N, 10.29; Found: C, 66.13; H, 5.97; N, 10.27. 

Methyl 4-(4-fluorophenyl)-1,2-dihydro-6-isopropyl-2-oxopyrimidine-5-carboxylate 

(ASM-2e). White solid; R f 0.48 (1:1 hexane-EtOAc); mp 180-182 ° C; IR (KBr): 

3470, 3093, 2999, 1735, 1648, 1586, 1450, 1261, 755, 700, cm -1 ; 1 H NMR (300 MHz, 

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, 

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 

(DEPT):(75 MHz, CDCl 3 ): 20.82, 31.98, 52.28, 115.28, 115.56, 129.82, 129.93; MS 

(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, 

62.13; H, 5.17; N, 9.67. 

Methyl 2-chloro-4-isopropyl-6-phenylpyrimidine-5-carboxylate (ASM-03a). 

White solid; R f 0.62 (8:2 hexane-EtOAc); mp 138-142 ° C; IR (KBr): 3057, 3034, 

2972, 2931, 2872, 1828, 1726, 1687, 1572, 1541, 871, 767, 730, 702 cm -1 ; 1 H NMR 

(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 

(s, 3H, OCH 3 ), 7.43-7.48 (m, 3H, Ar-H), 7.65-7.67 (t, 2H, Ar-H); 13 C NMR (100 

MHz, CDCl 3 ): 21.63, 33.62, 52.96, 123.49, 128.29, 128.78, 130.79, 136.37, 161.26, 

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; 

H, 5.20; N, 12.19; Found: C, 61.90; H, 5.17; N, 12.27. 

Methyl 2-(4-cyanophenyl)-4-isopropyl-6-phenylpyrimidine-5-carboxylate (ASM- 

04a). White solid; R f 0.72 (8:2 hexane-EtOAc); mp 108-110 ° C; IR (KBr): 3194, 3154, 

2976, 2929, 2290, 1722, 1683, 1456, 1300, 858, 829, 777, 698 cm -1 ; 1 H NMR (400 

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, 

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, 

j=7.8Hz); 13 C NMR (100 MHz, CDCl 3 ): 21.93, 29.69, 33.55, 52.80, 114.18, 


Chapter 1 


118.87, 123.36, 128.34, 128.72, 129.07, 130.34, 132.31, 137.82, 141.45, 162.01, 

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; 

H, 5.36; N, 11.76; Found: C, 73.90; H, 5.37; N, 11.77. 

Methyl 2-(3-(dimethylamino)phenyl)-4-isopropyl-6-p-tolylpyrimidine-5-carboxylate 

(ASM-04b). White solid; R f 0.76 (8:2 hexane-EtOAc); mp 122-124 ° C; IR (KBr): 

3150, 2980, 2867, 1728, 1578, 1520, 1480, 1258, 780, 708 cm -1 ; 1 H NMR (300 MHz, 

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- 

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- 

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, 

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 : 

C, 74.01; H, 6.99; N, 10.79; Found: C, 74.02; H, 6.97; N, 10.77. 

Methyl 2-(4-fluorophenyl)-4-isopropyl-6-(4-methoxyphenyl)pyrimidine-carboxylate 

(ASM-04c). White solid; R f 0.80 (8:2 hexane-EtOAc); mp 148-150 ° C; IR (KBr): 

3158, 2967, 2850, 1735, 1558, 1503, 1430, 1268, 748, 698 cm -1 ; MS (m/z): 381 (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, 5.57; 

N, 7.37. 

Methyl 4-isopropyl-2-(4-methoxyphenyl)-6-(3-nitrophenyl)pyrimidine-5-carboxy 

-late (ASM-04d). Yellow solid; R f 0.75 (8:2 hexane-EtOAc); mp 104-106 ° C; IR 

(KBr): 3130, 3053, 2986, 2832, 1726, 1548, 1498, 1369, 1238, 700 cm -1 ; MS (m/z): 

408 (M + ); Anal. Calcd for C 22 H 21 FN 2 O 3 : C, 64.86; H, 5.20; N, 10.31; Found: C, 

64.84; H, 5.20; N, 10.32. 

Methyl 4-(4-fluorophenyl)-6-isopropyl-2-phenylpyrimidine-5-carboxylate (ASM- 

04e). White solid; R f 0.84 (8:2 hexane-EtOAc); mp 134-136 ° C; IR (KBr): 3030, 2925, 

2832, 1726, 1553, 1430, 1238, 720, 678 cm -1 ; MS (m/z): 352 (M + ); Anal. Calcd for 

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. 

Methyl 2-(3-(dimethylamino)phenyl)-4-isopropyl-6-phenylpyrimidine-5-carboxylate 

(ASM-04f). White solid; R f 0.69 (8:2 hexane-EtOAc); mp 162-168 ° C; IR (KBr): 


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. 


Chapter 1 


Methyl 2-(4-fluorophenyl)-4-isopropyl-6-p-tolylpyrimidine-5-carboxylate (ASM- 

04g). White solid; R f 0.73 (8:2 hexane-EtOAc); mp 117-119 ° C; IR (KBr): 3083, 2958, 

1731, 1503, 1430, 1352, 1282, 1050 698 cm -1 ; MS (m/z): 365 (M + ); Anal. Calcd for 


Methyl 4-isopropyl-2,6-bis(4-methoxyphenyl)pyrimidine-5-carboxylate (ASM- 

04h). Yellow solid; R f 0.77 (8:2 hexane-EtOAc); mp 171-173 ° C; IR (KBr): 3028, 

2924, 2868, 1729, 1523, 1480, 1430, 1268, 720 cm -1 ; MS (m/z): 392 (M + ); Anal. 

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. 

Methyl 4-isopropyl-6-(3-nitrophenyl)-2-phenylpyrimidine-5-carboxylate (ASM- 

04i). Yellow solid; R f 0.80 (8:2 hexane-EtOAc); mp 182-184 ° C; IR (KBr): 3056, 

2967, 2850, 1735, 1505, 1480, 1320, 1252, 763 cm -1 ; MS (m/z): 378 (M + ); Anal. 

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, 

11.12. 

Methyl 2-(4-cyanophenyl)-4-(4-fluorophenyl)-6-isopropylpyrimidine-5-carboxylate 

(ASM-04j). White solid; R f 0.85 (8:2 hexane-EtOAc); mp 98-100 ° C; IR (KBr): 

3058, 2931, 2858, 2235, 1725, 1522, 1492, 1268, 758, 704 cm -1 ; MS (m/z): 376 (M + ); 


N, 11.17. 

Methyl 4-isopropyl-2-(4-methoxyphenyl)-6-phenylpyrimidine-5-carboxylate (AS 

M-04k). White solid; R f 0.74 (8:2 hexane-EtOAc); mp 131-133 ° C; IR (KBr): 3083, 

2954, 2825, 1731,1600, 1536, 1458, 1368, 1020, 738 cm -1 ; MS (m/z): 362(M + ); Anal. 

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. 

Methyl 4-isopropyl-2-phenyl-6-p-tolylpyrimidine-5-carboxylate (ASM-04l). 

Yellow solid; R f 0.83 (8:2 hexane-EtOAc); mp 143-145 ° C; IR (KBr): 3126, 2999, 

1740, 1648, 1586, 1261, 1061, 720, 658 cm -1 ; MS (m/z): 346(M + ); Anal. Calcd for 


Methyl 2-(4-cyanophenyl)-4-isopropyl-6-(4-methoxyphenyl)pyrimidine-5-carboxylate 

(ASM-04m). Brown solid; R f 0.72 (8:2 hexane-EtOAc); mp 177-179 ° C; IR 

(KBr): 3064, 2935, 2831, 1728, 1558, 1503, 1430, 1268, 883, 778 cm -1 ; MS (m/z): 


Chapter 1 


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; 

H, 5.44; N, 10.86. 

Methyl 2-(3-(dimethylamino)phenyl)-4-isopropyl-6-(3-nitrophenyl)pyrimidine-5- 

carboxylate (ASM-04n). Yellow solid; R f 0.82 (8:2 hexane-EtOAc); mp 152-157 ° C; 

IR (KBr): 3123, 2999, 2863,1731,1648, 1586, 1261, 1053, 850, 738, cm -1 ; MS (m/z): 


H, 5.74; N, 13.36. 

Methyl 2,4-bis(4-fluorophenyl)-6-isopropylpyrimidine-5-carboxylate (ASM-04o). 

White solid; R f 0.68 (8:2 hexane-EtOAc); mp 194-196 ° C; IR (KBr): 3135, 3089, 

2856, 1726, 1580, 1436, 1358, 1050, 780, cm -1 ; MS (m/z): 368 (M + ); Anal. Calcd for 

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. 

Methyl 4-isopropyl-2,6-diphenylpyrimidine-5-carboxylate (ASM-04p). White 

solid; R f 0.74 (8:2 hexane-EtOAc); mp 132-134 ° C; IR (KBr): 3120, 3025, 2868, 1745 

1600, 1480, 1380, 1068, 790, 745, cm -1 ; MS (m/z): 332 (M + ); Anal. Calcd for 


Methyl 2-(4-cyanophenyl)-4-isopropyl-6-p-tolylpyrimidine-5-carboxylate (ASM- 

04q). Yellow solid; R f 0.78 (8:2 hexane-EtOAc); mp 114-116 ° C; IR (KBr): 3051, 

2967, 2850, 2253, 1725, 1568, 1503, 1430, 1268, 748, 698 cm -1 ; MS (m/z): 371 (M + ); 

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; 

N, 11.34. 

Methyl 2-(3-(dimethylamino)phenyl)-4-isopropyl-6-(4-methoxyphenyl)pyrimidine-5-carboxylate 

(ASM-04r). White solid; R f 0.84 (8:2 hexane-EtOAc); mp 198-200 

o C; IR (KBr): 3068, 2983, 2899, 1728, 1648, 1586, 1261, 1061, 780, 712 cm -1 ; 1 H 

NMR (300 MHz, DMSO): δ 1.30-1.32 (d, 6H, 2 x i prCH 3 ), 2.97 (s, 6H, CH 3 ), 3.11- 

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, 

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, 

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): 


H, 6.73; N, 10.37. 


Chapter 1 


Methyl 2-(4-fluorophenyl)-4-isopropyl-6-(3-nitrophenyl)pyrimidine-5-carboxylate 

(ASM-04s). White solid; R f 0.73 (8:2 hexane-EtOAc); mp 145-147 ° C;IR (KBr): 

3021, 2856, 1725, 1648, 1422, 1369, 1254, 1068, 790, 720 cm -1 ; MS (m/z): 395 (M + ); 


N, 10.64. 

Methyl 4-(4-fluorophenyl)-6-isopropyl-2-(4-methoxyphenyl)pyrimidine-5-carboxylate 

(ASM-04t). White solid; R f 0.85 (8:2 hexane-EtOAc); mp 103-105 ° C; IR 

(KBr): 3158, 3036, 2869, 1735, 1658, 1450, 1356, 800, 720 cm -1 ; MS (m/z): 380 

(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, 

5.58; N, 7.34. 


Chapter 1 


1 H NMR spectrum of compound ASM-02a 



Chapter 1 



Expanded 1 H NMR spectrum of compound ASM-04a 


Chapter 1 


1 H NMR spectrum of compound ASM-04b 

Expanded 1 H NMR spectrum of compound ASM-04b 


Chapter 1 


1 H NMR spectrum of compound ASM-04r 

Expanded 1 H NMR spectrum of compound ASM-04r 


Chapter 1 


13 C NMR spectrum of compound ASM-04a 

Expanded 13 C NMR spectrum of compound ASM-04a 


Chapter 1 


Mass spectrum of compound ASM-03b 

Mass spectrum of compound ASM-03e 


Chapter 1 


Mass spectrum of compound ASM-04a 

Mass spectrum of compound ASM-04s 

NO 2 

O 

N 

O 

N 

F 

m/z-396 


Chapter 1 


IR spectrum of compound ASM-03a 

100 

%T 

80 

60 

40 

3057.27 

3034.13 

2931.90 

1828.58 

2872.10 

1687.77 

1670.41 

1622.19 

1572.04 

1410.01 

1116.82 

1031.95 

999.16 

977.94 

854.49 

823.63 

729.12 

675.11 

648.10 

623.03 

563.23 

538.16 

522.73 

482.22 

457.14 

434 00 

20 

2972.40 

1494.88 

1444.73 

1338.64 

1296.21 

1182.40 

1076.32 

920.08 

871.85 

767.69 

702.11 

0 

1726.35 

1541.18 

1519.96 

1383.01 

1220.98 

-20 

4000 

3500 

3000 

2500 

2000 

1750 

1500 

1250 

1000 

750 

500 

1/cm 

IR spectrum of compound ASM-04a 

110 

%T 

100 

90 

80 

70 

3194.23 

3151.79 

2976.26 

2929.97 

1737.92 

1722.49 

1683.91 

1649.19 

1558.54 

1506.46 

1456.30 

1398.44 

1330.93 

1259.56 

1228.70 

1076.32 

858.35 

829.42 

777.34 

761.91 

698.25 

611.45 

561.30 

60 

1535.39 

50 

449.43 

1 

542.02 

4000 

3500 

3000 

2500 

2000 

1750 

1500 

1250 

1000 

750 

500 

1/cm 


Chapter 1 


1.8 References 

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Chapter – 2 

Synthesis and Biological Activity of 

Novel Pyrimidine Derivatives via Wittig 

Reaction in Aqueous Media

Chapter 2 

Synthesis of substituted pyrimidines via Wittig 


As described in chapter-1 the pyrimidine scaffold represents an important 

pharmacophore endowed with a wide range of pharmacological activities according to 

the specific decoration of the heterocycle. Nitrogen-containing heterocycles are 

widely distributed in nature and are essential to life, playing a vital role in the 

metabolism of all living cells. Among these, pyrimidines represent one of the most 

prevalent heterocycles found in natural products such as amino acid derivatives 

(willardiine, tingitanine), 1 vitamins (vitamin B1), 2 antibiotics (bacimethrin, 

sparsomycin, bleomycin), 3 alkaloids (heteromines, crambescins, manzacidins, 

variolins, meridianins, psammopemmins etc.), 4 and toxins. 5 From a synthetic point of 

view, the first pyrimidine derivative (alloxan) was obtained as early as 1818, by 

Brugnatelli, oxidizing uric acid with HNO 3 . 6 In 1848, a second pyrimidine synthesis 

was pioneered by Frankland and Kolbe, who heated propionitrile with metallic 

potassium to give a pure product (2,6-diethyl-5-methyl-4-pyrimidinamine), 7 while in 

1878 Grimaux prepared barbituric acid by condensation of malonic acid with urea. 

The latter procedure has been later named after Pinner who gave the name to the 

pyrimidine scaffold and was the first to understand the chemical nature of this 

structure. Pyrimidine nucleus present in rosuvastatin (Figure-1), 8 which is member of 

drug class of statins, used to treat high cholesterol and related condition to prevent 

cardiovascular diseases. 

Figure-1 

Due to the long-lasting interest in pyrimidine derivatives as potential drugs, 

the synthetic community has dedicated much effort to the investigation of new 

approaches to those derivatives. Accordingly, we have described here an overview of 

the most interesting synthetic strategies recently reported for the generation of highly 

functionalized pyrimidines. 

Department of Chemistry, Saurashtra university, Rajkot-360005 44

Chapter 2 


2.2 A literature review on the biological activity associated with 

pyrimidine derivatives 

In medicinal chemistry pyrimidine derivatives have been very well known for 

their therapeutic applications. Many pyrimidine derivatives have been developed as 

chemotherapeutic agents. Over the years, the pyrimidine system turned out to be an 

important pharmacophore endowed with drug like properties and a wide range of 

pharmacological activities depending on the decoration of the scaffold. A few 

illustrative examples of pyrimidine derivatives active as inhibitors of HIV, 9 HCV, 10 

CDK, 11 CB2, 12 VEGFR 13 and Adenosine A1/A2a/A3 14 are reported in Figure-2. 

Figure-2 

Microbes are causative agents for various types of disease like pneumonia, 

amoebiasis, typhoid, malaria, common cough and cold various infections and some 

severe diseases like tuberculosis, influenza, syphilis, and AIDS as well. Various 

approaches were made to check the role of pyrimidine moiety as antimicrobial agent 

from the discovery of molecule to the present scenario. Naik et al. 15 synthesized 2-[{2 

(Morpholino)-3-pyridinyl-5-thio}-2-oxoethyloxadiazolyl]-amino-4-(2,4-dichloro-5- 

fluorophenyl)-6-(aryl)pyrimidines, which exhibit maximum zone of inhibition against 

E.coli, S. aureus, S.typhiiand B.subtilis (Figure-3). 


Chapter 2 


Figure-3 

Mishra et al. 16 have synthesized various derivatives of pyrimidines. The 

fungicidal activities of the compound were evaluated against P. infestans and C. 

falcatum by the usual agar plate method (Figure-4). 

R' 

N 

O 

O 

N NH 

R 

N NH 

Figure-4 

The pyrimidine moiety with some substitution showed to have promising 

antitumor activity as there are large numbers of pyrimidine based antimetabolites. The 

structural modification may be on the pyrimidine ring or on the pendant sugar groups. 

Early metabolite prepared was 5-fluorouracil, 17 a pyrimidine derivative followed by 

5-thiouracil which also exhibits some useful antineoplastic activities (Figure-5). 18 

Figure-5 

Palwinder Singh et al. 19 has reacted 5-benzoyl/5-carbaldehyde-/5-(3-phenyl 

acryloyl)-6-hydroxy-1H-pyrimidine-2,4diones with amines provided the 

corresponding enamines (Figure-6). The investigation for anticancer activity of 

molecule at 59 human tumor cell lines was done representing leukemia, melanoma 

and cancer of lung, colon, brain, ovary, breast as well as kidney. 


Chapter 2 


Figure-6 

Stephanepedeboscq et al. 20 has synthesized 4-(2-Methylanilino) 

benzo[b]thieno[2,3-d]pyrimidine (1) and 4-(2-Methoxyanilino)benzo[b]thieno[2,3-d] 

pyrimidine (2) (Figure-7), which showed a similar cytotoxicity to the standard anti- 

EGFR geftinib suggesting a blockade of the EGFR pathway by binding to the tyrosine 

kinase receptor. 

R 2 

R 1 

N 

NH 

NH 2 

N 

S 

R 1 =CH 3 , R 2 =H for (1) 

R 1 =OCH 3 ,R 2 =H for (2) 

Figure-7 

Fathalla et al. 21 has synthesized a series of some new pyrimidine derivatives 

like 7-(2-methoxyphenyl)-3-methyl-5-thioxo-5, 6-dihydro[1, 2, 4]-triazolo[4,3-c] 

pyrimidine-8-carbo-nitrile via reaction of ethyl cyanoacetate with thiourea and the 

appropriate aldehydes namely 2-methyl-benzaldehyde and 2-methoxy-benzaldehyde 

followed reaction with different reagents. All structures were than screened for 

bacterial activity and anticancer activity (Figure-8). 

N 

N 

N 

S 

CN 

NH 

OCH 3 

Figure-8 

Pyrimidine has a remarkable pharmacological efficiency and therefore an 

intensive research has been focused on anti-inflammatory activity of pyrimidine 

nucleus. Recently two PCT international applications have been filed for 2- 

thiopyrimidine derivatives possessing potent activity against inflammation and 

immune disorders. 22 


Chapter 2 


Padama shale et al. 23 have been reported Naphtho[2,1-b]furo[3,2-d]pyrimidine 

and Carrageen induced rat paw edema method was employed for evaluating the antiinflammatory 

activity. The compounds were given at a dose of 80 mg/kg body weight 

in albino rats weighing between 150 and 200 g. The oedema was produced by 

injecting carrageenan solution at the left hind paw (Figure-9). 

O 

N 

N 

R 

R 1 

Figure-9 

Lee et al. 24 has synthesized some novel pyrimidines derivative having 

thiazolidinedione. These compounds were evaluated for their glucose and lipid 

lowering activity using pioglitazone and rosiglitazone as reference compound. 

Desenko et al. 25 has synthesized azolopyrimidine derivatives and compounds were 

evaluated for hypoglycemic activity (Figure-10). 

N 

N 

N 

Figure-10 

Many pyrimidine ring containing drugs have exhibited antihypertensive 

activity. A quinozoline derivative, prazosin, is a selective α1-adrenergic antagonist. 26 

Its related analogues bunazosin, 27 trimazosin 28 and terazosin 29 are potent 

antihypertensive agents(Figure-11). 

O 

O 

NH 2 

N 

N 

N 

N R 

Et 

R= O 

for Prazocin 

R= CH 2 OOCH 2 COH(CH 3 ) 2 for Bunazosin 

R= COCH 2 CH 2 CH 3 for Trimazosin 

O 

R= 

O 

for Terazosin 

Figure-11 

Ketanserin 30 has a similar effect and is an antagonist of both a1-adrenergic and 

serotonin-S2 receptors. A triaminopyrimidine derivative, minoxidil, 


Chapter 2 


whose mechanism of action and therapeutic action are similar to prazosin, has been 

introduced in therapy for its side effects, in the treatment of alopecia, male baldness 

etc (Figure-12). 31 

Figure-12 

Rahaman et al. 32 has synthesized novel pyrimidines by the condensation of 

chalcones of 4΄-piperazine acetophenone with guanidine HCl (Figure-13). It showed 

significant antihistaminic activity when compared to the reference antihistaminic drug 

mepiramine. 

HN 

N 

R 

N 

N 

NH 2 

Figure-13 

A small library of 20 tri-substituted pyrimidines was synthesized by Anu et 

al. 33 evaluated for their in vitro anti-malarial and anti-tubercular activities. Out of all 

screened compound, 16 compounds have shown in-vitro anti-malarial activity against 

Plasmodium falciparum in the range of 0.25- 2μg/ml and 8 compounds have shown 

anti-tubercular activity against Mycobacterium tuberculosis at a concentration 12.5 

μg/ml (Figure-14). 

Figure-14 

Apart from these activities, pyrimidines also possess diuretic, antianthelmentic 

and calcium channel blocking activity. 34 


Chapter 2 


2.3 Various synthetic approaches for highly substituted 

pyrimidines 

A brief literature review on the new synthetic strategies for pyrimidine 

derivatives is presented as follows. 

In recent years, several interesting Pinner-like approaches have been 

developed: Karpov and Muller have been reported the employment of alkynones (βketo 

aldehydes’ synthetic equivalents) in a three-component one-pot pyrimidine 

synthesis (Figure-15). 35 The coupling of acid chlorides (1) with terminal alkynes (2) 

under modified Sonogashira conditions (Et 3 N used in stoichiometric amount) 

followed by the addition of aminium or guanidinium salts (4) in the presence of 

sodium carbonate gave the 2,4-disubstituted or 2,4,6-trisubstituted pyrimidines (5). 

Figure-15 

Kiselyov 36 was reported an efficient one-pot approach for the synthesis of 

2,4,5,6-tetrasubstituted pyrimidines (Figure-16). Reaction of alkyl- or 

benzylphosphonates with aryl nitriles formed unstable aza-Wittig species which were 

converted into α,β-unsaturated imines by reaction with aromatic aldehydes. The latter 

intermediates were converted into the desired pyrimidine derivatives after 

nucleophilic attack by a bidentate nuclophile, usually guanidine or amidine. 

Figure-16 

Mohammad Movassaghi et al. 37 has described a procedure for the synthesis of 

pyrimidine derivatives. It was applicable to a wide range of secondary amides and 

nitriles using 2-chloropyridine as a base additive in the presence of Tf 2 O (Figure-17). 

Figure-17 


Chapter 2 


T. Sasada et al. 38 have been reported a ZnCl 2 -catalyzed three-component 

coupling reaction allows the synthesis of various 4,5-disubstituted pyrimidine 

derivatives in a single step from functionalized enamines, triethylorthoformate, and 

ammonium acetate (Figure-18). The procedure can be successfully applied to the 

efficient synthesis of mono- and disubstituted pyrimidine derivatives, using methyl 

ketone derivatives instead of enamines. 

R 

H 2 N 

or 

R' 

R 

R' 

O 

3 eq. HC(OEt) 3 

2eq.NH 4 OAc 

0.1 eq. ZnCl 2 

Toluene 

100 o C, 3- 72 hrs 

R 

R' 

N 

N 

Figure-18 

M. G. Barthakur et al. 39 have been developed a novel and efficient synthesis of 

pyrimidine from β-formylen amide involves samarium chloride catalyzed cyclization 

of β-formelene amides using urea as source of ammonia under microwave irradiation 

(Figure-19). 

Figure-19 

P. Zhichkin et al. 40 described a method for the synthesis of 2-substituted 

pyrimidine-5-carboxylic esters. The sodium salt of 3, 3-dimethoxy-2- 

methoxycarbonylpropen-1-ol has been found to react with a variety of amidinium 

salts to afford the corresponding 2-substituted pyrimidine-5-carboxylic esters 

(Figure-20). 

Figure-20 


Chapter 2 


2.4 Applications of Wittig reaction 

The Wittig reaction occupies a central role in organic synthesis as it generates 

double bond with high level of stereocontrol: non stabilized ylides give high Z- 

selectivity, where as stabilized ylides furnish high E-selectivity. 41 Here we discuss 

various synthetic approaches for synthesize new chemical entities via Wittig reaction. 

R. Antonioletti et al. 42 have developed a mild and practical procedure for the 

Wittig olefination, promoted by lithium hydroxide and triphenylbenzyl phosphonium 

bromide, has been set up for the synthesis of stilbenes and styrenes (Figure-21). 

Ph 

Ph 

P 

Br R CHO 

Ph 

LiOH·H2O 

Solvent, refulx 

E/Z isomer 

Figure-21 

Jesse Dambacher et al. 43 has reported that water is demonstrated to be an 

excellent medium for the Wittig reaction employing stabilized ylides and aldehydes. 

Although the solubility in water appears to be an unimportant characteristic in 

achieving good chemical yields and E/Z-ratios, the rate of reactions in water is 

unexpectedly accelerated (Figure-22). 

R 

Figure-22 

Elsie Ramirez et al. 44 have been developed a highly efficient and rapid 

protocol for the preparation of the unsaturated 7,3-lactone-a-D-xylofuranose 

derivatives (Versatile chiral synthon for naturally important compounds) via selective 

Wittig olefination in aqueous media (Figure-23). 

Figure-23 

James McNulty et al. 45 has reported direct synthesis of 1,3-dienes and 1,3,5- 

trienes from the reaction of semi-stabilized ylides via Wittig reaction under aqueous 

media employing sodium hydroxide as base (Figure-24). 


Chapter 2 


Figure-24 

De-Jun Dong et al. 46 have developed a simple and efficient protocol to 

improve the stereoselectivity significantly for the olefination reaction of semistabilized 

triphenylphosphonium ylides by replacing the aldehydes used in the Wittig 

reaction with N-sulfonyl imines, which possess distinct electronic and steric 

properties relative to aldehydes (Figure-25). 

Figure-25 

Douglass F. Taber et al. 47 were utilized a Potassium hydride in paraffin KH(P) 

as a base in Wittig condensation of phosphonium salt with aromatic, aliphatic, and 

α,β-unsaturated aldehydes in THF proceeds with high Z selectivity (Figure-26). 

Figure-26 

Fulvia Orsini et al. 48 has synthesized α,β-unsaturated esters in open 

atmosphere via mild and efficient one-pot Wittig reactions performed in both water 

and sodium dodecyl sulfate (SDS)-water solution(Figure-27). 

Figure-27 

Y.k. Liu et al. 49 has discovered a highly stereoselective tandem Michael 

addition-Wittig reaction of (3-carboxy-2-oxopropylidene) triphenylphosphorane and 

α,β-unsaturated aldehydes gives multifunctional 6-carboxycyclohex-2-en-1-ones in 

excellent diastereo- and enantioselectivities by employing the combined catalysis of a 

bulky chiral secondary amine, LiClO 4 , and DABCO (Figure-28). 


Chapter 2 


Figure-28 

Peter Shu-Wai Leung et al. 50 have developed chromatography free Wittig 

reaction by utilizing newly prepared bifunctional polymeric reagents , in this 

phosphine and amine functionalized material was used in one-pot Wittig reactions 

with an aldehyde and either an r-halo-ester, -ketone, or -amide. Due to the 

heterogeneous nature of the polymer, the desired alkene product of these reactions 

could be isolated in excellent yield in essentially pure form (Figure-29). 

Figure-29 

A. El-Batta et al. 51 was carried out Wittig reactions in water media employing 

stabilized ylides with aldehydes. They described the use of a saturated aqueous 

NaHCO 3 solution to achieve the aqueous one pot Wittig reactions at +20 to 90°Cusing 

Ph 3 P, R-bromoesters, and aromatic carboxaldehydes (Figure-30). 

Figure-30 


Chapter 2 


2.5 Application of sodium tripolyphosphate 

Sodium tripolyphosphate (STPP) is white powder an inorganic compound 

with formula Na 5 P 3 O 10 . It is the sodium salt of the polyphosphate penta-anion, which 

is the conjugate base of triphosphoric acid (Figure-31). STPP is widely used in 

detergents, and as a preservative for seafood, meats, poultry, and animal feeds. It is 

also use in ceramics, anticaking, setting retarders, flame retardants, paper, 

anticorrosion pigments, textiles, rubber manufacture, fermentation, antifreeze. 

Figure-31 

There is some limited application of STTP in organic synthesis; however 

Zhiqiang Zhang et al. 52 have described a conversion of methyl lactate to acrylic acid, 

methyl acrylate and lactic acid via various reactions such as dehydration, 

decomposition, decarbonylation, hydrolysis and esterification has been determined by 

using sodium tripolyphosphate as a catalyst. 

Tert-butyl-2-bromoacetate was synthesized by a reaction of 2-bromoacetyl 

chloride with tert-butanol at room temp used stoichiometric sodium tripolyphosphate 

as catalyst and acid-scavenger, chloroform as solvent to afford 93% yield. 53 α- 

Bromoisobutyric acid tert-butyl ester was synthesized by reaction of tert-Bu alc. with 

α-bromoisobutyryl bromide using stoichiometric sodium tripolyphosphate as a base to 

afford 96.5% yield. 54 


Chapter 2 


2.6 Current research work 

As described in earlier, the chemistry of pyrimidines is one of the most widely 

studied subjects because of the occurrence of such heterocycles in biologically 

relevant systems such as nucleic acids, cofactors, various toxins, and other products. 

Pyrimidine derivatives are biologically interesting molecules that have established 

utility for the treatment of Alzheimer’s disease and proliferative disorders; they are 

also capable of showing antiviral activity, anti-HIV agents, anti hypertensive agents, 

antimicrobial agents and fungicide. The witting product of pyrimidine derivatives 

such as rosuvastatin and its salt, which are HMG-CoA reductase inhibitor and useful 

in treatment of hypercholesteromia, hyperlipoproteinemia and atherosclerosis. 

The Wittig olefination reaction is regarded as one of the most strategic, widely 

applicable carbon–carbon double bond-forming processes available in organic 

synthesis. This reliable reaction allows for olefination with complete positional 

selectivity, predictable chemoselectivity and may be conducted in many cases with 

reliable and high stereocontrol. 

Nowadays, a great deal of effort has been focused on the field of green 

chemistry in adopting methods and processes. As a part of this “green” concept, toxic 

and/or flammable organic solvents are replaced by alternative non-toxic and 

nonflammable media. In this context, many efforts have been made to use aqueous 

media. Among alternative green solvents, water has been the solvent of choice for a 

variety of transformations. 

During the course of our ongoing interest on the synthesis various 

heterocycles and development of useful synthetic methodology, we have developed a 

small library of pyrimidines via Wittig reaction using sodium tripolyphosphate as 

base in aqueous media. The newly synthesized compounds were characterized by IR, 

Mass, 1 H NMR, 13 C NMR spectroscopy and elemental analysis. All the newly 

synthesized compounds were evaluated for their antimicrobial activity. 


Chapter 2 


2.7 Results and discussion 

Scheme:-1 Synthesis of pyrimidine derivatives via Wittig reaction in aqueous 

media. 

F 

F 

F 

O 

Cl 

N 

N 

O 

DIBAL 

Toluene 

Cl 

N 

N 

OH 

1) PBr 3 /MDC 

2) TPP/Toluene 

Cl 

N 

N 

P 

Br 

ASM-3e INT-01 INT-02 

R-CHO 

STPP 

Water 

F 

Wittig reaction 

N 

R 

Cl 

N 

AW-01 to AW-20 

The synthetic route for the targeted compounds (AW-01 to AW-20) is shown 

in Scheme 1. Compound ASM-03e was prepared by following the methods described 

in chapter-1. The reaction of ASM-03e with diisobutylaluminium hydride (DIBAL) in 

toluene at 0 o C for 3 h. afforded (2-chloro-4-(4-fluorophenyl)-6-isopropyl pyrimidin- 

5-yl)methanol (INT-01) in good yield. INT-01 was then treated with phosphorous 

tribromide in MDC at 0-5 o C for 2-3 h. The crude oily residue was reacted with 

triphenyl phosphine in toluene at reflux temperature for 3-4 h. to afford triphenyl[2- 

chloro-{4-(4-flourophenyl)-6-isopropyl-pyrimidin-5-ylmethyl}phosphonium]bromide 

(INT-02) in excellent yield. 

Optimization for reaction condition the pyrimidine phosphorous ylide (INT- 

02) was treated with benzaldehyde using various bases such as NaH 2 PO 4 , Na 2 HPO 4 , 

and sodium tripolyphosphate in three different solvents, DMSO, THF, and water 

(Table-1). Sodium tripolyphosphate as base in aqueous media was found to be an 

effective method to afford highly (E)-selective product of AW-01 in moderate to good 

yield (Table-1). 


Chapter 2 


Table 1: Optimization of reaction condition for synthesis of Aw-01 using variety 

of bases and solvents. 

Entry Base Solvents Yield Time hrs. 

1 NaH 2 PO 4 DMSO 65 7.0 

2 NaH 2 PO 4 THF 70 7.5 

3 NaH 2 PO 4 water 76 5.0 

4 Na 2 HPO 4 DMSO 68 6.5 

5 Na 2 HPO 4 THF 77 6.0 

6 Na 2 HPO 4 water 80 4.5 

7 Na 5 P 3 O 10 DMSO 85 7.0 

8 Na 5 P 3 O 10 THF 83 5.0 

9 Na 5 P 3 O 10 water 90 3.0 

The structure of INT-01 was established on the basis of their elemental 

analysis and spectral data (MS, IR, 1 HNMR, and 13 C NMR). The analytical data for 

INT-01 revealed a molecular formula C 14 H 14 ClFN 2 O (m/z 280). The 1 H NMR 

spectrum revealed doublet at δ = 1.30-1.33 ppm assigned to isopropyl-CH 3 , a singlet 

at δ = 2.09 ppm assigned to the –OH protons, a multiplet at δ = 3.67-3.69 ppm 

assigned to the isopropyl -CH protons, a singlet at δ = 4.69 ppm assigned to the –CH 2 

protons, two triplet at δ = 7.28-7.34 ppm and 7.88-7.92 assigned to the aromatic 

protons. 

The structure of INT-02 was established on the basis of their elemental 

analysis and spectral data (MS, IR, 1 H NMR, and 13 C NMR). Structure INT-02 was 

supported by its mass (m/z 605), which agrees with its molecular formula 

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 ), 

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, 

8H, Ar-H), 7.57 (s, 6H, Ar-H), 7.75-7.80 (m, 3H, Ar-H). 

Reaction of pyrimidine phosphorous ylide (INT-02) with various 

benzaldehydes using Sodium tripolyphosphate as base in aqueous media to afford 

highly (E)-selective product AW-01 to AW-20 in moderate to excellent yield. 

Require reaction time and obtained (%) of yield summarized in Table-2. 


Chapter 2 


Table-2: Synthesis of substituted pyrimidines via Wittig reaction using sodium 

tripolyphosphate under aqueous media. 

Entry R Yield (%) Time hrs 

AW-01 C 6 H 4 90 3.0 

AW-02 4-NO 2 C 6 H 4 92 2.5 

AW-03 4-ClC 6 H 4 84 3.0 

AW-04 C 5 H 4 S 89 3.5 

AW-05 C 5 H 4 O 90 4.0 

AW-06 C 8 H 7 N 82 3.5 

AW-07 2-NO 2 C 6 H 4 79 3.0 

AW-08 4-ClC 6 H 4 85 3.5 

AW-09 3-0CH 3 ,4-OHC 6 H 4 93 3.5 

AW-10 3,4-di-OCH 3 C 6 H 3 95 3.0 

AW-11 4-N(CH 3 ) 2 C 6 H 4 82 3.0 

AW-12 4-FC 6 H 4 83 3.5 

AW-13 3-NO 2 C 6 H 4 94 4.0 

AW-14 4-BrC 6 H 4 90 4.5 

AW-15 2-OHC 6 H 4 88 3.0 

AW-16 4-OCH 3 C 6 H 4 76 3.5 

AW-17 2,5-di-OCH 3 C 6 H 3 89 3.0 

AW-18 3-BrC 6 H 4 83 4.0 

AW-19 4-ClC 6 H 4 81 3.0 

AW-20 3-OHC 6 H 4 77 4.0 

The structure of AW-01 to AW-20 was established on the basis of their 

elemental analysis, spectral data (MS, IR, 1 H NMR, and 13 C NMR) and (E)-selectivity 

of products was supported by NMR spectrum. Structure of AW-02 was supported by 

its mass (m/z 398), which agrees with its molecular formula C 21 H 17 ClFN 3 O 2, its 1 H 

NMR spectrum had signals at δ = 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, ethylene-H), 7.08-7.17 (m, 3H, Ar-H & ethylene- 

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, 

j=8.4Hz, Ar-H). 


Chapter 2 


2.8 Antimicrobial sensitivity testing 

WELL DIFFUSION / AGAR CUP METHOD (Lt. General Raghunath D. 1998, 

Ashok Rattan, 1998; Patel R., Patel K. 2004,) 

In vitro effectivity of antimicrobial agents can be demonstrated by observing 

their capacity to inhibit bacterial growth on suitable media. The production of a zone 

depends on two factors namely bacterial growth and concentration of antimicrobial 

agent. The hole/well punch method was first used by Bennett. This diffusion method 

has proved more effective than many other methods. According to Lt. General 

Raghunath the well technique is 5-6 times more sensitive than using disk method. 

Principle 

When antimicrobial substance is added in agar cup (made in a medium 

previously inoculated with test organism) the redial diffusion of an antimicrobial 

agent through the agar, produces a concentration gradient. The test organism is 

inhibited at the minimum inhibitory concentration (MIC), giving rise to a clear zone 

of inhibition. 

Requirements 

1. Young broth culture of a standard test organism 

2. Sterile Mueller Hinton Agar plate 

3. Solution of antimicrobial substance 

4. Cup borer 

5. Alcohol etc. 

Inoculum preparation 

Inoculum was prepared by selecting 4-5 colonies from slope of stock culture 

of the indicator organism and emulsifying them in a suitable broth. The inoculated 

broth was incubated at 37ºC till it equals turbidity of a 0.5 McFarland standard. This 

happens in 2-8 h. 


Chapter 2 


Procedure 

1. Inoculate test organism on the top of Mueller Hinton Agar plate with help of 

sterile swab. (it can be inoculated in melted agar also ) 

2. The swab was dipped in the inoculum and surface of plate was streaked with 

swab. 

3. Streaking was repeated for 3 times and each time the plate was rotated at angle 

of 60º. 

4. Sterilize the cup-borer make four cups of the diameter of 8-10 mm. at equal 

distance in the plate previously inoculated with seed culture. 

5. The depth of well was 2.5-5.0 mm. 

6. The wells have been clearly punched so the surrounding medium is not lifted 

when the plug was removed out. 

7. The plates were incubated at 37ºC for 24 h. Then the zone of inhibition 

measured and the size of zone cited in table. 


Chapter 2 


Antibiotic Sensitivity Assay 

Sr. 

No. 

CODE 

No. 

Pseudomonas 

aeruginosa 

Proteus vulgaris 

Escherichia 

coli 

(Concentration250/500/ 1000 µG/ml) 

Staphylococcus 

aureus 

Candida 

albicans 

250 500 1000 250 500 1000 250 500 1000 250 500 1000 250 500 1000 

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 

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 

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 

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 

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 

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 

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 

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 

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 

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 

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 

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 

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 

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 

15. AW-15 R 1.2 1.5 R R R R R R R R R R 1.2 2.0 

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 

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 

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 

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 

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 

21. A 1.8 1.8 1.9 1.9 - 

22. CPD 2.2 2.1 2.1 2.2 - 

23. GF 1.8 1.9 2.0 2.0 - 

24. GRF - - - - 2.6 

25. FLC - - - - 2.8 

Note: Zone of inhibition interpretation is as follows 

1. Zone size < 1.0 cm- Resistent (R) 

2. Zone size 1.0 to 1.5 cm – Intermediate 

3. Zone size > 1.5 – Sensitive 

STD Antibiotic Sensitivity Assay Concentration 40 µg/ml 

A: Ampicillin GRF: Gresiofulvin 

CPD: Cefpodoxime FLC: Fluconazole 

GF: Gatifloxacin 


Chapter 2 



We have described a versatile synthesis of novel 2-chloro-4-(4-fluorophenyl)- 

6-isopropyl-5-(E)-substituted pyrimidines from triphenyl[2-chloro-{4-(4-flouro 

phenyl)-6-isopropyl-pyrimidin-5-ylmethyl}phosphonium]bromide with different 

aldehydes via Wittig reaction in the presence of sodium tripolyphosphate as a base in 

aqueous media. Inorganic base sodium tripolyphosphate has the further advantage of 

low cost, stability and low toxicity. All the synthesized compounds were evaluated 

for their antimicrobial activity. The investigation of antibacterial and antifungal 

screening data revealed that all the tested compounds AW-01 to AW-20 showed 

moderate to significant activity. For example, compounds AW-02, 12, 13 and 18 

showed comparatively good activities against all the bacterial strains and thus 

warrant further study. 


Chapter 2 












Synthesis of (2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidin-5-yl) 

methanol. (INT-01) 

To a solution of ASM-03e (0.003 mole) in toluene (100 mL) at 0 o C was 

added drop wise a 20% solution of diisobutylaluminium hydride (DIBAL) in toluene 

(85 mL). The reaction mixture was further stirred for 2-3 h. at 0 o C. The progress of 

reaction was monitored by thin layer chromatography. After completion, the reaction 

mixture was quenched with saturated ice cold hydrochloric acid. The toluene layer 

was washed with water and brine. The organic layer was separated, dried over 

anhydrous sodium sulfate and filtered. The filtrate was dried under vacuum. The solid 

product was purified by stirring in hexane or diisopropylether (DIPE) to give 

analytically pure product INT-01 with 85% yield. 

Synthesis of triphenyl[2-chloro-{4-(4-flourophenyl)-6-isopropylpyrimidin-5-ylmethyl}phosphonium]bromide. 

(INT-02) 

A solution of 2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidin-5-yl) 

methanol (INT-01, 16mmol) in MDC (50 mL) was cooled to 0-5 o C. Phosphorus 

tribromide (13mmol) was slowly added in to the reaction mixture at 0-5 o C and stirred 

for 2-3 h. The progress of reaction was monitored by thin layer chromatography. 

After completion, the reaction mixture was washed with 10% sodium bicarbonate 

solution and sodium thiosulphate solution. The organic layer was separated, dried 

over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness 

under vacuo. 


Chapter 2 


The oily residue was dissolve in toluene (80 mL) and triphenyl phosphine 

(30mmol) was added. The reaction mixture was heated at 115 o C for 3-4 h. After 

completion of the reaction determined by TLC, the reaction mixture was cooled to 

room temperature. The solid separated was filtered, washed with toluene and dried to 

afford 90% yield. 

 

General synthetic procedure for the Wittig reaction of pyrimidine yilde 

and aldehyde using STTP as a base in aqueous media. (AW-01 to AW-20) 

A mixture of pyrimidine phosphonium bromide ylide (INT-02, 1 mmol), 

benzaldehyde (1.3 mmol), and Sodium tripolyphosphate (3 mmol) in water (20 mL) 

was refluxed at 60-70 o C for 2-5 h. The progress of reaction was monitored by thin 

layer chromatography. After completion, the reaction mixture was cooled to room 

temperature, diluted with water (50 mL) and extracted with MDC (2x 50mL). The 

organic layer was washed with water (2 x 50 mL), organic layer dried over sodium 

sulfate and evaporated to dryness under vacuo. The residue was crystallized from 

isopropyl alcohol to afford analytically pure products AW-01 to AW-20. 


Chapter 2 


Spectral data of the synthesized compounds 

Methyl 2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidine-5-carboxylate (ASM- 

03e). White solid; R f 0.83 (8:2 hexane-EtOAc); mp 130-132 ° C; IR (KBr): 3070, 2930, 

2850, 1730, 1650, 1583, 1470, 1335, 1064, 830 cm -1 MS (m/z): 309 (M + ); Anal. Calcd 

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. 

(2-Chloro-4-(4-fluorophenyl)-6-isopropylpyrimidin-5-yl)methanol (INT-01). 

White solid; R f 0.52 (8:2 hexane-EtOAc); mp 110-112 ° C; IR (KBr): 3459, 3327, 3193, 

2999, 1648, 1586, 1261, 1061, 832 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 1.30-1.33 (d, 

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- 

7.34 (t, 2H, Ar-H), 7.88-7.92 (t, 2H, Ar-H); 13 C NMR (DEPT):(75 MHz, CDCl 3 ): 

21.40, 31.31, 56.47, 56.58, 114.99, 115.28, 131.85, 131.96; MS (m/z): 280 (M + ); 

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; 

N, 9.97. 

Triphenyl[2-chloro-{4-(4-flourophenyl)-6-isopropyl-pyrimidin-5-ylmethyl}- 

phosphonium]bromide (INT-02). White solid; R f 0.16 (1;1 hexane-EtOAc); mp 

>320 o C ; IR (KBr): 3193, 3070, 3024, 2999, 2830, 1648, 1586, 1261, 1061, 830, 780, 

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, 

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 

(s, 6H, Ar-H), 7.75-7.80 (m, 3H, Ar-H); 13 C NMR (DEPT):(75 MHz, CDCl 3 ): 24.92, 

25.53, 33.42, 116.24, 116.53, 130.35, 130.52, 131.17, 131.28, 133.97, 134.10, 135.42, 

135.46; MS (m/z): 605 (M + ); Anal. Calcd for C 32 H 28 BrClFN 2 P: C, 63.43; H, 4.66; N, 

4.62; Found: C, 63.45; H, 4.67; N, 5.67. 

2-Choloro-4-(4-flurophenyl)-6-isopropyl-5-(E)-styrylpyrimidine (AW-01). White 

solid; R f 0.75 (8:2 hexane-EtOAc); mp 80-82 ° C; IR (KBr): 3087, 3070, 3040, 2930, 

2856, 1658, 1450, 1430, 1368, 830, 753, 700 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 

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, 

j=16.4Hz,ethylene-H), 7.04-7.23 (m, 3H, Ar-H & ethylene-H), 7.53-7.56 (d, 2H, Ar- 

H), 7.72-7.74 (t, 2H, Ar-H), 8.23-8.26 (d, 2H, Ar-H); MS (m/z): 353 (M + ); Anal. 

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. 


Chapter 2 


5-((E)-(4-nitrostyryl))-2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidine (AW- 

02). Yellow solid; R f 0.72 (8:2 hexane-EtOAc); mp 110-112 ° C; IR (KBr): 3077, 3065, 


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, 

ethylene-H), 7.08-7.17 (m, 3H, Ar-H & ethylene-H), 7.48-7.51 (d, 2H, Ar-H), 7.64- 

7.68 (t, 2H, Ar-H), 8.19-8.22 (d, 2H, Ar-H); 13 C NMR (DEPT):(75 MHz, CDCl 3 ): 

21.73, 32.38, 115.48, 115.77, 124.29, 126.16, 127.09, 132.00, 132.11, 135.01; MS 

(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: 

C, 63.43; H, 4.37; N, 10.50. 

5-((E)-(4-chlorostyryl))-2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidine (AW- 

03). White solid; R f 0.65 (8:2 hexane-EtOAc); mp 56-58 ° C; IR (KBr): 3095, 3084, 



ethylene-H), 6.88-6.93 (d, 1H, j=16.5Hz, ethylene-H), 7.05 -7.11 (t, 2H, Ar-H), 7.26- 

7.38 (q, 4H, Ar-H), 7.64-7.69 (t, 2H, Ar-H); 13 C NMR(DEPT):(75 MHz, CDCl 3 ): 

21.47, 32.19, 115.33, 115.62, 122.00, 127.71, 129.09, 132.01, 132.12, 136.01;MS 

(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, 

65.23; H, 4.37; N, 7.35. 

2-Choloro-4-(4-flurophenyl)-6-isopropyl-5-[(E)-2-(thiophene-2-yl)vinyl]- 

pyrimidine (AW-04). White solid; R f 0.79 (8:2 hexane-EtOAc); mp 114-116 ° C; IR 

(KBr): 3093, 3086, 3016, 2942, 2834, 1658, 1445, 1403, 1368, 830 cm -1 ; 1 H NMR 

(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 

(dd, 2H, j=17.4Hz), 6.98-7.02 (d, 2H, Thiophene-H), 7.08-7.14 (t, 2H, Ar-H), 7.27- 

7.26 (d, 1H, Thiophene-H), 7.69-7.74 (t, 2H, Ar-H); 13 C NMR (DEPT):(75 MHz, 

CDCl 3 ): 21.76, 32.14, 115.35, 115.63, 120.59, 125.77, 127.23, 127.88, 130.22, 

132.05, 132.16; MS (m/z): 359 (M + ); Anal. Calcd for C 19 H 17 ClFN 2 S: C, 63.59; H, 

4.49; N, 7.81; Found: C, 63.43; H, 4.37; N, 7.70. 

2-Choloro-4-(4-flurophenyl)-5-[(E)-2-(furan-2-yl)vinyl]-6-isopropylpyrimidine 

(AW-05). White solid; R f 0.82 (8:2 hexane-EtOAc); mp 119-121 ° C; IR (KBr): 3113, 

2972, 1730, 1683, 1070, 881, 796, 744 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 1.34-1.36 

(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 


Chapter 2 


(d, 1H, j=16.2Hz, ethylene-H), 7.19-7.25 (d, 1H, j=16.2Hz, ethylene-H), 7.51-7.78 (t, 

3H, Ar-H & Furan), 8.19-8.22 (t, 2H, Ar-H), MS (m/z): 343 (M + ); Anal. Calcd for 

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. 

3-((E)-2(2-chloro-4-(4-flurophenyl)-6-isopropylpyrimidyl-5-yl)vinyl-1H-indole 

(AW-06). Yellow solid; R f 0.87 (8:2 hexane-EtOAc); mp 134-136 ° C;IR (KBr): 3063, 

3015, 2957, 2834, 1670, 1445, 1368, 830, 750 cm -1 ; MS (m/z): 392 (M + ); Anal. Calcd 

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. 

5-((E)-(2-nitrostyryl))-2-chloro-4-(4-flurophenyl)-6-isopropylpyrimidine(AW-07) 

Yellow solid; R f 0.69 (8:2 hexane-EtOAc); mp 96-98 ° C; IR (KBr): 3037, 3016, 2952, 


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. 

5-((E)-(2-chlorostyryl))-2-chloro-4-(4-flurophenyl)-6-isopropylpyrimidine (AW- 



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. 

4-((E)-2-(2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidin-5-yl)vinyl)-2- 

methoxyphenol (AW-09). Yellow solid; R f 0.79 (8:2 hexane-EtOAc); mp 88-89 ° C; 

IR (KBr): 3442, 3093, 3086, 3016, 2942, 2834, 1658, 1445, 1403, 1368, 830, 783, 

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, 

7.02; Found: C, 66.25; H, 5.06; N, 7.07. 

5-((E)-(3,4-dimethoxystyryl)-2-chloro-4-(4-flurophenyl)-6-isopropylpyrimidine 


2999, 2964, 2839, 1728, 1638, 1558, 1444, 1026, 842, 758, 702 cm -1 ; 1 H NMR (300 

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, 

2 x OCH 3 ), 6.42-6.48 (d, 1H, j=16.5Hz, ethylene-H), 6.71-6.93 (m, 4H, Ar-H 

&ethylene-H), 7.06 -7.12 (t, 2H, Ar-H), 7.70 (s, 2H, Ar-H); 13 C NMR (DEPT):(75 

MHz, CDCl 3 ): 21.80, 32.03, 55.96, 56.01, 108.83, 111.22, 115.24, 115.52, 119.27, 

119.89, 132.05, 132.16, 136.96; MS (m/z): 413 (M+); Anal. 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, 6.75. 


Chapter 2 


4-((E)-2-(2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidin-5-yl)vinyl)-N,Ndimethylbenzenamine 

(AW-11). Yellow solid; R f 0.75 (8:2 hexane-EtOAc); mp 118- 

120 ° C; IR (KBr): 3092, 3028, 2966, 2823, 1660, 1428, 1368, 835, cm -1 ; MS (m/z): 

396 (M + ); Anal. Calcd for C 23 H 23 ClFN 3 : C, 69.78; H, 5.86; N, 8.96; Found: C, 69.75; 

H, 5.76; N, 8.77 

5-((E)-(4-fluorostyryl))-2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidine (AW- 


2952, 2869, 1675, 1468, 1442, 1353, 836, cm -1 ; 1 H NMR (400 MHz, CDCl 3 ): δ 1.15- 

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, 

ethylene-H), 6.73-6.77 (dd, 1H, j=16.6Hz, ethylene-H), 6.91-7.00 (m, 4H, Ar-H), 7.21 

-7.24 (m, 2H, Ar-H), 7.55-7.60 (m, 2H, Ar-H); 13 C NMR (100 MHz, CDCl 3 ): 21.72, 

32.17, 115.53, 115.54, 115.80, 116.01, 121.11, 121.13, 125.99, 126.39, 128.13, 

128.21, 128.49, 128.61, 132.04, 132.12,132.35, 132.39, 133.28, 133.31, 133.38, 

133.41, 136.10, 150.98, 159.22, 161.62, 162.30, 164.10, 164.79, 165.66, 165.86, 

177.22, 177.44; MS (m/z): 372 (M + ); Anal. Calcd for C 21 H 17 ClF 2 N 2 : C, 68.02; H, 

4.62; N, 7.55; Found: C, 68.05; H, 4.66; N, 7.77 

5-((E)-(3-nitrostyryl))-2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidine (AW- 




ethylene-H), 7.08-7.15 (m, 3H, Ar-H & ethylene-H), 7.52 -7.70 (m, 4H, Ar-H), 8.14- 

8.22 (s d, 2H, Ar-H); 13 C NMR (DEPT):(75 MHz, CDCl 3 ): 21.71, 32.37, 115.46, 

115.75, 121.01, 123.08, 124.68, 129.95 131.97, 132.09, 132.29, 134.90; MS (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: C, 

63.43; H, 4.37; N, 10.55 

5-((E)-(4-bromostyryl))-2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidine(AW- 


2933, 1643, 1449, 1403, 1368, 835 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ): δ 1.23-1.25 (d, 

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), 

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, 

Ar-H), 7.37-7.39 (d, 2H, Ar-H), 7.55-7.59 (m, 2H, Ar-H); 13 C NMR (100 MHz, 


Chapter 2 


CDCl 3 ): 21.74, 32.20, 115.38, 115.60, 121.12, 122.58, 125.80, 126.20, 127.99, 

132.02, 132.05, 132.10, 133.19, 133.29, 133.32, 135.02, 136.08, 151.11, 159.34, 

162.33, 164.83, 165.66, 165.87, 177.15, 177.38; MS (m/z): 431 (M + ); Anal. Calcd for 

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 

2-((E)-2-(2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidin-5-yl)vinyl)phenol 

(AW-15) White solid; R f 0.64 (8:2 hexane-EtOAc); mp 52-54 ° C; IR (KBr): 3452, 

3048, 2942, 1648, 1441, 1408, 1359, 835 ,785 cm -1 ; MS (m/z): 369 (M + ); Anal. Calcd 

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 

5-((E)-(4-methoxystyryl))-2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidine 

(AW-16). Yellow solid; R f 0.71 (8:2 hexane-EtOAc); mp 67-69 ° C; IR (KBr): 3052, 

3042, 2948, 1638, 1449, 1401, 1348, 835 ,782 cm -1 ; MS (m/z): 384 (M + ); Anal. Calcd 

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 

5-((E)-(2,5-dimethoxystyryl)-2-chloro-4-(4-flurophenyl)-6-isopropylpyrimidine 


3046, 2939, 1641, 1438, 1412, 1378, 838, 754, 779 cm -1 ; MS (m/z): 414 (M+); Anal. 

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, 

6.75. 

5-((E)-(3-bromostyryl))-2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidine (AW- 


2942, 1652, 1431, 1422, 1371, 831 ,786 cm -1 ; MS (m/z): 432 (M + ); Anal. Calcd for 

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. 

5-((E)-(3-chlorostyryl))-2-chloro-4-(4-flurophenyl)-6-isopropylpyrimidine (AW- 



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. 

3-((E)-2-(2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidin-5-yl)vinyl)phenol 



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. 


Chapter 2 


1 H NMR spectrum of compound AW-02 

F 

NO 2 

N 

Cl 

N 

Expanded 1 H NMR spectrum of compound AW-02 


Chapter 2 



F 

Cl 

N 

Cl 

N 



Chapter 2 



F 

N 

O 

Cl 

N 



Chapter 2 



F 

Br 

N 

Cl 

N 



Chapter 2 


13 C NMR spectrum of compound AW-12 

F 

F 

N 

Cl 

N 

Expanded 13 C NMR spectrum of compound AW-12 


Chapter 2 


MASS spectrum of compound AW-01 

F 

N 

Cl 

N 

m/z-352 


F 

NH 

N 

Cl 

N 

m/z-392 


Chapter 2 



F 

O 

OH 

N 

Cl 

N 

m/z-398 


F 

OH 

N 

Cl 

N 

m/z-368 


Chapter 2 


IR spectrum of compound AW-05 

90 

%T 

3113.21 

2972.40 

1730.21 

1683.91 

1635.69 

1070.53 

881.50 

75 

1604.83 

1558.54 

1383.01 

1321.28 

1261.49 

1159.26 

60 

45 

1508.38 

846.78 

418 57 

1014.59 

744.55 

796.63 

671.25 

30 

4000 

3500 

3000 

2500 

2000 

1750 

1500 

1250 

1000 

750 

500 

1/cm 

IR spectrum of compound AW-10 

100 

%T 

80 

60 

40 

3028.34 

2999.41 

2964.69 

F 

2839.31 

1728.28 

1683.91 

1635.69 

1600.97 

1558.54 

1467.88 

1444.73 

1413.87 

1381.08 

1338.64 

1163.11 

1139.97 

1026.16 

976.01 

927.79 

842.92 

788.91 

765.77 

702.11 

567.09 

522.73 

480.29 

451.36 

428 21 

20 

N 

O 

O 

1246.06 

0 

Cl 

N 

1516.10 

1267.27 

-20 

4000 

3500 

3000 

2500 

2000 

1750 

1500 

1250 

1000 

750 

500 

1/cm 


Chapter 2 



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Chapter 2 


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Chapter 2 


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2005, 34(2), 1. 


Chapter - 3 

Rapid Synthesis and Characterization of 

Novel Tri-substituted Pyrazoles/Isoxazoles 

Library Using Ketene Dithioacetals

Chapter 3 

Synthesis of trisubstituted pyrazoles/isoxazoles 


The development of new methods for the synthesis of five member 

heterocyclic compound libraries, both in solution and on solid phase, is an everexpanding 

area in combinatorial chemistry. Specifically, those containing the 

pyrazole and isoxazole nucleus have been widely used as key building blocks for 

pharmaceutical agents. Its derivatives are endowed with high pharmacological 

properties, for example, hypoglycemic, analgesic, anti-inflammatory, antibacterial, 

anti-HIV, and anticancer activity, 1 as well as useful activities in conditions like 

schizophrenia, hypertension, and Alzheimer’s disease. 2 In addition, they also have 

agrochemical properties including herbicidal and soil fungicidal activity, thus they 

have been used as pesticides and insecticides. 3 Recently, pyrazoles containing aryl 

substituted emerged as p38 Kinase inhibitors, antiparasitic activities. 4 

Pyrazoles and isoxazoles are well known five member heterocyclic 

compounds and several procedures for its synthesis have been extensively studied. 

The pyrazole ring system consists of a doubly unsaturated five member ring 

containing two adjacent nitrogen atoms. Isoxazole ring system consist two hetero 

atoms oxygen at position 1 and nitrogen at position 2 (Figure-1). 

Figure-1 

Pyrazoles and isoxazoles bearing sulfone and carboxamide moieties 

demonstrated to have significant pharmacological applications. For examples, 

cyclooxygenase-2 (COX-2) selective inhibitors, celecoxib 5 , rofecoxib 6 and 

valdecoxib 7 are currently prescribed for the treatment of arthritis and inflammatory 

diseases. These COX-2 inhibitors exhibited anti-inflammatory activity with reduced 

gastrointestinal side effects. Oxacillin and its derivatives are useful compounds due to 

their narrow spectrum antibiotic properties 8 . Recently, pyrrolyl aryl sulfones have 

been reported by Silvestri et al. 9 and Artico et al. 10 as a new class of human 

immunodeficiency virus type 1 (HIV-1) RT inhibitors acting at the non-nucleoside 

binding site of this enzyme. Haruna et al. 11 have been synthesized the propargylic 

sulfones with various planar molecules and evaluated for their DNA binding 

properties and DNA cleavage activity. 

Department of Chemistry Saurashtra university, Rajkot-360005 82

Chapter 3 


Moreover, the 1-(4-methylsulfonyl)benzene and 4-(4-methylsulfonyl)benzene 

substituted pyrazole compound containing a nitric oxide donating group at the 3- 

position of the pyrazole ring, respectively, have been synthesized and evaluated for its 

ability to inhibit COX isoenzymes in human whole blood. 12 Pyrazoles containing 

sulfone group at N position have been exhibited promising antimicrobial activity. 13 

Further more, amide group linked with isoxazole derivatives found to have combined 

α 2 -adrenoceptor antagonistic and serotonine reuptake inhibiting activities. 14 The 

Isoxazoles containing aryl and carboxamide were also shown to have potent in vivo 

antithrombotic efficacy. 15 

3.2 Biological activity associated with pyrazoles and isoxazoles 

As mentioned above, pyrazoles and isoxazoles nucleus have been widely used 

as key building blocks for pharmaceutical agents. Its derivatives are endowed with 

high pharmacological properties, for example, hypoglycemic, GABA A antagonist’s 

analgesic, anti-inflammatory, anti-HIV, and anticancer activity as well as useful 

activities in conditions like schizophrenia, hypertension, and Alzheimer’s disease. 

Thomas D. Penning et al. 16 has described a series of pyrazole and isoxazole 

analogs (Figure-2) as antagonists of the α v β 3 receptor. These compounds showed low 

to sub-nanomolar potency against α v β 3 , as well as good selectivity against α IIb β 3 . In 

HT29 cells, most analogs also demonstrated significant selectivity against α v β 6 . 

Several compounds showed good pharmacokinetic properties in rats, in addition to 

anti-angiogenic activity in a mouse corneal micro pocket model. Compounds were 

synthesized in a straightforward manner from readily available glutarate precursors. 

Figure-2 

Ebraheem Abdu Musad et al. 17 has synthesized pyrazoles and isoxazoles 

(Figure-3) were screened for antioxidant and anti-microbial activities. Among that 

some of compounds showed higher antioxidant activity at 10μg/ml and some 

compounds exhibited better anti-microbial activity at 100μg/ml compared with 

standard vitamin C and ciprofloxacin, respectively. 


Chapter 3 


N X 

N 

N 

Antioxidant activity 

N N 

H H 

R 1 =R 3 =H, 

R 2 =OH,N(CH 3 ) 2 

Antimicrobial activity 

R 3 R 1 R 3 R 1 

R 1 =R 3 =H, 

R 2 R R 2 2 =N(CH 3 ) 2 ,OCH 

X=O,NH 

3 

Figure-3 

Annamaria Lilienkampf et al. 18 has developed isoxazole-based anti-TB 

compounds by applying rational drug design approach (Figure-4). The biological 

activity and the structure-activity relationships (SAR) for a designed series of 5- 

phenyl-3-isoxazolecarboxylic acid ethyl ester derived anti-TB compounds were 

investigated. Several compounds were found to exhibit nanomolar activity against the 

replicating bacteria (R-TB) and low micromolar activity against the non replicating 

bacteria (NRP-TB). The series showed excellent selectivity toward Mtb, and in 

general, no cytotoxicity was observed in Vero cells (IC 50 >128 μM). Notably, selected 

compounds also retained their activity against isoniazid (INH), rifampin (RMP), and 

streptomycin (SM) resistant Mtb strains. Hence, benzyloxy, benzylamino, and 

phenoxy derivatives of5-phenyl-3-isoxazolecarboxylic acid ethyl esters represent a 

highly potent, selective, and versatile series of anti-TB compounds and as such 

present attractive lead compounds for further TB drug development. 

R 1 

R 5 

R 2 

R 3 

O 

O N 

O 

O 

R 4 

R 1 =H, CF 3 ,Cl,F,NO 2 

R 2 =OCF 3 ,CH 3 ,NH 2 ,OCH 3 , CON(CH 2 CH 2 ) 2 O, H,Cl, F, 

R 3 =H, CF 3 ,Cl,F, 

R 4 =R 5 =H,F 

Figure-4 

Recently, biological evaluation of novel potent HDAC3 and HDAC8 

isoxazole and pyrazole-based diazide probes (Figure-5) suitable for binding ensemble 

profiling with photo affinity labeling (BEProFL) experiments in cells is described. 

Both the isoxazole and pyrazole-based probes exhibit low nanomolar inhibitory 

activity against HDAC3 and HDAC8, respectively. The pyrazole-based one of the 

most active HDAC8 inhibitors reported in the literature with an IC 50 of 17 nM. 


Chapter 3 


Docking studies suggest that unlike the isoxazole-based ligands the pyrazolebased 

ligands are flexible enough to occupy the second binding site of HDAC8. 

Probes/inhibitors some compounds exerted the antiproliferative and neuroprotective 

activities at micromolar concentrations through inhibition of nuclear HDACs, 

indicating that they are cell permeable and the presence of an azide or a diazide group 

does not interfere with the neuroprotection properties, orenhance cellular cytotoxicity, 

or affect cell permeability. 19 

Figure-5 

Maria Barceló et al. 20 has described synthesis of binding affinities on D 2 , 5- 

HT 2A and 5-HT 2C receptors of 6-aminomethyl-6,7-dihydro-1H-indazol-4(5H)-ones 

and 6-aminomethyl-6,7-dihydro-3-methyl-benzo[d]isoxazol-4(5H)-ones, as 

conformationallly constrained butyrophenone analogues. One of the new compounds 

(Figure-6) showed good in vitro binding features, and a Meltzer’s ratio characteristic 

of an atypical antipsychotic profile. 

Figure-6 

Celecoxib and rofecoxib analogues (Figure-7), in which the respective 

SO 2 NH 2 and SO 2 Me hydrogen-bonding pharmacophores were replaced by dipolar 

azido bioisosteric substituents, were investigated. Molecular modeling (docking) 

studies showed that the azido substituent of these two analogues was inserted deep 

into the secondary pocket of the human COX-2 binding site where it undergoes 

electrostatic interaction with Arg513. The azido analogue of rofecoxib is the most 

potent and selective inhibitor of COX-2 (COX-1 IC 50 = 159.7 µM; COX-2 IC 50 = 0.196 

µM; COX-2 selectivity index = 812), exhibited good oral anti-inflammatory and 

analgesic activity. 


Chapter 3 


Figure-7 

Amgad G. Habeeb et al. 21 

also reported a 4,5-diphenyl-4-isoxazolines 

(Figure-8) possessing a variety of substituents (H, F, MeS, MeSO 2 ) at the para 

position of one of the phenyl rings were synthesized for evaluation as analgesic and 

selective cyclooxygenase-2 (COX-2) inhibitory anti-inflammatory (AI) agents. 

Although the 4,5-phenyl-4-isoxazolines (Figure-8), which do not have a C-3 Me 

substituent, exhibited potent analgesic and AI activities, those compounds evaluated 

were not selective inhibitors of COX-2. In contrast, 2,3-dimethyl-5-(4- 

methylsulfonylphenyl)-4-phenyl-4-isoxazoline exhibited excellent analgesic and AI 

activities, and it was a potent and selective COX-2 inhibitor (COX-1, IC 50 ) 258 μM; 

COX-2, IC 50 ) 0.004 μM). 

R 1 

R 2 

R 3 

N Me 

O 

R 1 =H,Me 

R 2 ,R 3 =H,F,SMe,SO 2 Me 

Figure-8 

A related compound (Figure-8) having a F substituent at the para position of 

the 4-phenyl ring was also a selective (SI =3162) but less potent (IC 50 =0.0316 μM) 

inhibitor of COX-2 than 2,3-dihydro-2,3-dimethyl-5-(4-(methylsulfonyl)phenyl)-4- 

phenyl isoxazole. A molecular modeling (docking study) for 4-(4-fluorophenyl)-2,3- 

dihydro-2,3-dimethyl-5-(4-(methylsulfonyl)phenyl)-4-phenylisoxazole showed that 

the S atom of the MeSO 2 substituent is positioned about 6.46 Å inside the entrance to 

the COX-2 secondary pocket (Val 523 ) and that a C-3 Me (2,3-dihydro-2,3-dimethyl-5- 

(4-(methylsulfonyl)phenyl)-4-phenylisoxazole,4-(4-fluorophenyl)-2,3-dihydro-2,3dimethyl-5-(4-(methylsulfonyl)phenyl)-4-phenylisoxazole) 

central isoxazoline ring 

substituent is crucial to selective inhibition of COX-2 for this class of compounds. 


Chapter 3 


Chih Y. Ho et al. 22 have repoted a series of (6,7-dimethoxy-2,4- 

dihydroindeno[1,2-c]pyrazol-3-yl)phenylamines (Figure-9) has been optimized to 

preserve both potent kinase inhibition activity against the angiogenesis target, the 

receptor tyrosine kinase of Platelet-Derived Growth Factor-BB (PDGF-BB), and to 

improve the broad tumor cell antiproliferative activity of these compounds. This 

series culminates in the discovery of (JNJ-10198409), a compound with anti-PDGFRα 

kinase activity (IC 50 = 0.0042 µM) and potent antiproliferative activity in six of 

eight human tumor cell lines (IC 50 = 0.033 µM). 

Figure-9 

Chih Y. Ho has developed antiangiogenic compounds with an additional 

antiproliferative activity capable of inhibiting tumor progression by controlling both 

the vascularization and proliferation of the tumor mass. Tumors may be regarded as a 

two-compartment system consisting of the vasculature supporting tumor growth 

composed of ‘normal’ homogeneous vascular endothelial cells, smooth muscle cells, 

and pericytes that are surrounded by colonies of neoplastic cancer cells. To find 

molecules that would affect both the vascular and transformed compartments, we 

identified several compounds with the potential to inhibit the PDGFR-β kinasemediated 

angiogenic effect and then assayed them for collateral antiproliferative 

activity against a panel of human tumor cell lines. 

Christian Peifer et al. 23 have been reported on the discovery of isoxazole 

(Figure-10) as a potent dual inhibitor of p38α (IC 50 = 0.45 μM) and CK1δ (IC 50 = 0.23 

μM). Because only a few effective small molecule inhibitors of CK1 have been 

described so far, we aimed to develop this structural class toward specific agents. 

Molecular modeling studies comparing p38α/CK1δ suggested an optimization 

strategy leading to design, synthesis, biological characterization, and SAR of highly 

potent compounds including possessing differentiated specificity. Selected 

compounds were profiled over 76 kinases and evaluation of their cellular efficacy 

showed 18 (CKP138) to be a highly potent and dual-specific inhibitor of CK1δ and 

p38α. 


Chapter 3 


Figure-10 

Small molecule inhibitors of various protein kinases are utilized extensively in 

research and drug development. The human kineme consists of more than 500 protein 

kinases, and kinase inhibitors typically bind in the highly conserved ATP pocket of 

these enzymes. 24 Thus the specificity of ATP competitive kinase inhibitors is of 

significant interest and represents a crucial factor for their use in, e.g., signal 

transduction research or therapeutic applications. 

A series of 4-aryl-5-(4-piperidyl)-3-isoxazolol GABA A antagonists have been 

synthesized and pharmacologically characterized. 25 The meta-phenyl-substituted 

compounds and the para-phenoxy-substituted compound (Figure 11) all display high 

affinities (K i = 10-70 nM) and antagonist potencies in the low nanomolar range (K i = 

9-10 nM). These potencies are significantly higher than those of previously reported 

4-PIOL antagonists and considerably higher than that of the standard GABA A 

antagonist SR 95531. 

Figure 11 

In contrast to the all osteric modulatory sites, the GABA binding site has very 

distinct and specific structural requirements for recognition and activation. Thus, very 

few different classes of structures have been reported. Within the series of compounds 

showing agonist activity at the GABA A receptor site are the selective GABA A 

agonists muscimol 26 and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol, 26-27 which 

have been used for the characterization of the GABA A receptors (Figure 11). 28 

Recently, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol has been shown to be 

functionally selective for a subpopulation of GABA A receptors and is currently in 

clinical trials as a therapeutic for the regulation of sleep. 


Chapter 3 


3.3 Synthetic methods for the pyrazole and isoxazole derivatives 

There are several methods reported in the literature for the preparation of 

pyrazoles and isoxazoles described as under. 

Pranab K. Mahata et al. 29 has synthesized 3-dimethoxymethyl-5-(methylthio) 

pyrazole/ isoxazole derivative (Figure-12) shown to be useful three carbon synthon 

for efficient regiospecific synthesis of a variety of five (pyrazole/isoxazole) with mask 

or unmask aldehyde functionality by cyclocondensation with bifunctional 

nucleophiles such as hydrazine and hydroxylamine respectively. 

Figure-12 

Sabine Kuettel et al. 30 has synthesized 4-(3-phenylpyrazole/isoxazol-5- 

yl)morpholine derivatives (Figure-13) by two synthetic routes, in which substituted 

acetophenones were reacted with carbon disulfide and methyl iodide in the presence 

of sodium hydride to give 4-phenoxyphenyl-2,2-bis(methylthio)vinylketones, 

followed by in situ cyclization of the resulting N,S-acetals with hydrazine 

hydrate/hydroxylamine. 

Figure-13 

Scott R. Tweedie et al. 31 has synthesized a pyrazole and isoxazole derivatives 

via palladium-catalyzed couplings of heteroaryl amines with aryl halides using 

sodium phenolate as the stoichiometric base (Figure-14). 

Figure-14 


Chapter 3 


Kewei Wang et al. 32 has reported an efficient and divergent one-pot synthesis 

of fully substituted 1H-pyrazoles and isoxazole derivatives. Substituted 1H-pyrazoles 

were synthesized from 1-carbamoyl, 1-oximyl cyclopropanes via sequential ringopening, 

chlorovinylation, and intramolecular aza-cyclization under Vilsmeier 

conditions (POCl 3 /DMF). Isoxazoles were synthesized from the cyclopropyl oximes 

via ring-opening and intramolecular nucleophilic vinylic substitution (S N V) reactions 

in the presence of POCl 3 /CH 2 Cl 2 (Figure-15). 

Figure-15 

Ebraheem Abdu Musad et al. 33 has prepared a new 3,5-(substituted) pyrazoles 

and isoxazoles by reaction of (N’¹E , N’³E)- N’¹, N’³-bis(3,4,5-substitutedbenzylidene)malonohydrazide 

with hydrazine hydrate and hydroxylamine 

hydrochloride respectively under solvothermal conditions involving an ecofriendly 

method without any environmental pollution (Figure-16). 

Figure-16 

Ch brajakishor singh et al. 34 have been synthesized a steroidal pyrazole and 

isoxazole derivatives form 2-ethoxymethelene-4-androsten-3-one and 2- 

bis(methylthio)methelene-4-androsten-3-one (Figure-17). 

Figure-17 


Chapter 3 


Alex F. C. Flores et al. 35 have been synthesized a new series of hydroxyl 

pyrazoles and 2-methyl-3-isoxazolones from the cyclocondensation reaction of 

trichloromethyl-substituted 1,3-dielectrophiles with dry hydrazine and N-methyl 

hydroxylamine respectively (Figure-18). 

Figure-18 

Sarvesh Kumar et al. 36 has synthesized pyrazole and isoxazole derivatives via 

hetero annulations of 10,11-Dihydro-11-[bis(methylthio)methylene]dibenzoxepin-10- 

one (α-oxoketene dithioacetal) (Figure-19). 

Figure-19 

Valentina Molteni et al. 37 have been developed an extremely simple one pot 

reaction for transforming diketones into the corresponding pyrazoles and isoxazoles 

promoted by microwave irradiation (Figure-20). 

O 

O 

O 

H 3 CO OCH 

R-NHNH 3 

2 

NH 2 OH 

n N 

n n N 

N MW H 2 O 

N 

MW 

O 

O 

R 

n= 0, 1, 2 

Figure-20 

Thomas Kurz et al. 38 has synthesized novel fluorinated ketene N,S-acetals 

were readily prepared by the reaction of fluorosubstituted cyanoacetamide derivatives 

with arylisothiocyanate in the presence of potassium hydroxide, followed by the 

alkylation of the produced salts with methyl iodide. The reaction of fluorinated ketene 

N,S-acetals with hydrazine afforded different fluorosubstituted pyrazole (Figure-21). 


Chapter 3 


Figure-21 

Galal H. Elgemeie et al. 39 have been synthesized a variety of novel α- 

cyanoketene S,S-acetals, readily prepared by the reaction of cyanoacetanilides or 

cyanothioacetamide with carbon disulfide, followed by alkylation, react smoothly 

with nucleophile to afford variously substituted methylthio derivatives of pyrazole 

(Figure-22). 

MeS 

SMe 

CN 

RNHNH 2 

H 2 N 

S 

EtOH, PiP, heat 

NH 2 

H 2 N 

N 

N 

R 

R= H, Ph 

Figure-22 

Jesse P. Waldo et al. 40 have been synthesized of isoxazoles (Figure-23) via 

electrophilic cyclization under mild reaction conditions by the reaction of 2-alkyn-1- 

one O-methyl oximes with ICl, I 2 , Br 2 , or PhSeBr. 

O 

SMe 

Figure-23 

David J. Burkhart et al. 41 have been synthesized ethyl 4-acetyl-5-methyl-3- 

isoxazoyl carboxylate (Figure-24) was smoothly lithiated at the 5-methyl position. 

The anion was quenched with a variety of electrophiles such as alkyl halides, 

aldehyde, TMSCl and Me 3 SnCl in good to excellent yields. 

Figure-24 


Chapter 3 


V. P. Kislyi et al. 42 were prepared 4-amino-5-benzoyl (acetyl) isoxazole-3- 

carboxamides (Figure 25) by cyclization of α-hydroxyimino nitriles O-alkylated with 

bromoacetophenones (bromoacetone). The purity of the target 4-aminoisoxazoles can 

be substantially increased by treating O-alkylated oximes with LiClO 4 before 

cyclization. 

Figure 25 

Wenli Ma et al. 43 have been developed an efficient three-component, two-step 

“catch and release” solid-phase synthesis of 3,4,5-trisubstituted pyrazoles and 

isoxazoles (Figure-26). The first step involves a base-promoted condensation of a 2- 

sulfonyl- or a 2-carbonyl-acetonitrile derivative (1 or 7) with an isothiocyanate 2 and 

in situ immobilization of the resulting thiolate anion on Merrifield resin. Reaction of 

the resin-bound sulfonyl intermediate 4 with hydrazine or hydroxylamine, followed 

by release from the resin and intramolecular cyclization, affords 3,5-diamino-4- 

(arylsulfonyl)-1H-pyrazoles 5 or isoxazoles 6, respectively. Reaction of the resinbound 

carbonyl intermediate 9 with hydrazine, on the other hand, leads to 3- 

(arylamino)-5-aryl-1H-pyrazole-4-carbonitriles 10. 

Figure-26 


Chapter 3 


3.4 Some pharmaceutical molecules related to pyrazoles and 

isoxazoles 

Pyrazole and isoxazole nucleus have been widely used as key building blocks 

for pharmaceutical agents. Its derivatives are endowed with high pharmacological 

properties, for example, hypoglycemic, analgesic, anti-inflammatory, antibacterial, 

anti-HIV, and anticancer activity, 3 as well as useful activities in conditions like 

schizophrenia, hypertension, and Alzheimer’s disease. 4 

N 

N 

CF 3 

H 3 CO 2 S 

N O 

HO NH 2 

SO 2 NH 2 

O N 

Celocoxib 

O 

Rofecoxib 

O 

Muscimol 

Agonist of GABA A 

receptor 

Cl 

Cl 

N 

Cl 

N 

O 

HN N 

Rimonabant 

anoretic antiobesity drug 

N 

N 

H 

Fomepizole 

inhibitor of alcohole dehydrogenase 

H 2 NO 2 S 

O 

R R'' 

NH 

O N 

R' 

HO 

N O 

O 

NH 2 

OH 

Valdecoxib 

Oxacillin 

Cloxacillin 

Dicloxacillin 

Flucloxacillin 

Ibotenic acid 

Nurotoxin 


Chapter 3 



α-Oxoketene dithioacetals especially the dimethylthioacetals have recently 

received considerable attention due to their synthetic importance for the construction 

of a variety of alicyclic, aromatic and heterocyclic compounds. 44,45 Ketene 

dithioacetals, in the presence of various regents, undergo different types of reactions 

to yield other heterocyclic compounds, e.g., isoxazole, pyrazole, thiophenes, 

pyrimidines, pyridines, etc. Consequently we were interested in surveying the 

synthetic utility of ketene dithioacetals. 

Recently, we have reported solution-phase library of pyrazoles and isoxazoles 

functionalized with methyl, sulfone and carboxamide moieties in two steps with 

excellent yield and chemical purity for medicinally interesting molecules. Water was 

emerged as an efficient and green solvent in the condensation reaction of various 

ketene dithioacetals with hydrazine hydrate or hydroxyl amine hydrochloride. 46 

Figure-27 

In an extension to this work, we describe here a novel synthesis of solvent free 

library of trisubstituted pyrazoles (B) and isoxazoles (C) (Figure-27) by the reaction 

of ketene dithioacetals with hydrazine hydrate and hydroxylamine hydrochloride 

under microwave irradiations Thus, it has been found that reaction of substituted 

acetoacetanilide derivatives with carbon disulfide in the presence of potassium 

carbonate followed by the alkylation with methyl iodide gives the novel ketene 

dithioacetals (A) (Figure 27), the structures of which have been established on the 

basis of their elemental analysis and spectral data. 


Chapter 3 



Scheme: Synthesis of novel trisubstitited pyrazoles and isoxazoles from ketene 

dithioacetals 

Scheme-1 

Scheme-2 

R 

N 

H 

O 

O 

1) CS 2 /K 2 CO 3 /DMF 

2) CH 3 I 

R 

N 

H 

O 

S 

O 

S 

3a-o 

4a-o 

Scheme-3 

Where R=CH 3 , OCH 3 , F, NO 2 , Cl 

Various substituted 3-cyclopropyl-3-oxo-N-arylpropanamide (3a-o) were 

prepared by reacting substituted amines (1a-h) and methyl 3-cyclopropyl-3- 

oxopropanoate (2) in toluene with a catalytic amount of NaOH or KOH (Scheme 1). 

The reaction mixture was refluxed for 15-20 h. Fifteen different acetoacetanilide were 

synthesized bearing various electron donating and electron withdrawing groups such 

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; 

2-F; 4-OCH3; 2,5-diCl and 3-NO 2 on the phenyl ring. The reaction of substituted 

acetoacetanilide 3a-o derivatives with carbon disulfide in the presence of potassium 

carbonate followed by the alkylation with methyl iodide (Scheme 2) gave the novel 

ketene dithioacetals 4a-o. Further treatment of 4a-o with hydrazine hydrate or 

hydroxyl amine hydrochloride in the presence of potassium hydroxide (Scheme-3) to 

furnish pyrazoles 5a-o and isoxazoles 6a-o in excellent yield. As a part of ‘green 

chemistry’ approaches, we have done all reaction in solvent free reaction condition and 

under microwave irradiation. Comparative study of reaction time and yield in 

conventional and microwave irradiation methods are summarized in Table-1. 


Chapter 3 


Table-1: 3-cyclopropyl, 5-methylthio, 4-carboxamide substituted pyrazoles and 

isoxazoles. 

Reaction time 

Entry R Conventional 

(hrs) 

Yield 

(%) 

MW 

(min.) 

Yield 

(%) 

5a 4-CH 3 Ph 2.0 85 13.0 88 

5b 4-ClPh 1.5 88 12.5 90 

5c 4-FPh 1.5 87 10.0 92 

5d 4-OCH 3 Ph 2.0 83 12.0 90 

5e 3,4-diClPh 2.0 90 13.0 95 

5f 3,Cl,4-FPh 1.5 85 12.5 88 

5g 2,3-diCH 3 Ph 2.0 87 14.0 90 

5h 4-NO 2 Ph 2.5 82 17.0 95 

5i 2-OCH 3 Ph 1.5 85 14.5 97 

5j 2-CH 3 Ph 2.0 83 13.0 93 

5k 4-CH 2 CH 3 Ph 2.5 80 12.5 91 

5l 5,Cl,2-OCH 3 Ph 2.0 82 13.5 95 

5m 2,5-diClPh 1.0 87 12.0 90 

5n 2,5-diCH 3 Ph 2.0 80 13.0 88 

5o 3,4-diFPh 2.5 81 14.0 87 

6a 4-CH 3 Ph 2.5 79 12.5 85 

6b 4-ClPh 2.0 83 15.0 93 

6c 4-FPh 3.0 82 14.5 90 

6d 4-OCH 3 Ph 1.5 87 13.0 92 

6e 3,4-diClPh 2.0 85 14.0 91 

6f 3,Cl,4-FPh 2.5 82 13.0 87 

6g 2,3-diCH 3 Ph 3.0 81 13.5 89 

6h 4-NO 2 Ph 2.5 90 14.0 95 

6i 2-OCH 3 Ph 3.0 89 15.0 94 

6j 2-CH 3 Ph 2.5 87 17.5 92 

6k 4-CH 2 CH 3 Ph 3.0 85 15.0 90 

6l 5,Cl,2-OCH 3 Ph 1.5 80 12.5 84 

6m 2,5-diClPh 1.0 88 13.0 96 

6n 2,5-diCH 3 Ph 2.5 87 15.5 94 

6o 3,4-diFPh 3.0 85 14.0 92 

The structures of 4a-o were established on the basis of their elemental analysis 

and spectral data (MS, IR, and 1 H NMR). The analytical data for 4b revealed a 

molecular formula C 15 H 16 ClNO 2 S 2 (m/z 342). The 1 H NMR spectrum revealed a two 

multiplet at δ = 1.02-1.06 and 1.21-1.24 ppm assigned two –CH 2 groups in 

cyclopropane ring, a multiplet at δ = 2.37-2.43 ppm assigned to the –CH protons, 


Chapter 3 


a singlet at δ = 2.47 ppm assigned to (2 × SCH 3 ) , a multiplet at δ = 7.26–7.59 ppm 

assigned to the aromatic protons, and one broad singlet at δ = 8.69 ppm assigned to - 

CONH groups. 


and spectral data (MS, IR, 1 H NMR and 13 C NMR).Structure 5a was supported by its 

mass (m/z 287), which agrees with its molecular formula C 15 H 17 N 3 OS; its 1 H NMR 

spectrum had signals at δ = 0.81-0.82 and 0.96-0.99 (m, 2x CH 2 ) in cyclopropane 

ring, a multiplet at δ = 2.24 ppm assigned to the cyclopropyl-CH protons, a singlet at 

δ=2.40 assigned to -CH 3 protons, a singlet at δ=2.48 ppm assigned to (SCH 3 ), a 

multiplet signal at δ = 7.09-7.53 ppm related to the aromatic protons, 9.36 (broad, - 

CONH) and 12.84 (broad, pyrazole NH). 


and spectral data (MS, IR, 1 H NMR and 13 C NMR).The analytical data for 6b 

revealed a molecular formula C 15 H 16 ClNO 2 S 2 (m/z 342). The 1 H NMR spectrum 

revealed a two multiplets at δ = 1.14-1.06 and 1.21-1.16 ppm assigned two –CH 2 

groups in cyclopropane ring, a multiplet at δ = 2.16-2.20 ppm assigned to the –CH 

protons, a singlet at δ = 2.68 ppm assigned to (SCH 3 ) , a multiplet at δ = 7.26–7.56 

ppm assigned to the aromatic protons, and one broad singlet at δ = 8.19 ppm assigned 

to -CONH groups. 

The proposed mechanism for the formation of 5a-o and isoxazoles 6a-o from 

the corresponding 3-cyclopropyl-3-oxo-N-arylpropanamide (3a-o) is shown in Figure 

28 & 29. In the ketene dithioacetal system the carbonyl carbon and β-carbon atoms 

regarded as hard and soft electrophilic centers, since the carbonyl carbon is adjacent 

to the hard-base oxygen while the β-carbon is flanked by the soft-base methylthio 

groups. Thus, the nucleophile hydrazine hydrate or hydroxyl amine hydrochloride 

may attack on β-carbon of systems and formed heterocyclic product by removal of 

methylthio and group as good leaving group and water molecule. 


Chapter 3 


Mechanism 

Figure 28: Proposed mechanism for the formation of pyrazole 

Figure 29: Proposed mechanism for the formation of isoxazole 


Chapter 3 



In summary, we have synthesized a library of pyrazoles and isoxazoles 

functionalized with cyclopropyl, thiomethyl and carboxamide moieties in single steps 

with excellent yield under microwave irradiation. As a part of ‘green chemistry’ 

approach condensation reaction of various ketene dithioacetals with hydrazine hydrate 

or hydroxyl amine hydrochloride in solvent free condition under microwave 

irradiation. The present procedure is significant over the existing methods to develop 

this class of molecules with excellent yield, purity and simple isolation of products. 


Chapter 3 












General synthesis of 3-cyclopropyl-3-oxo-N-arylpropanamide (3a-o). 

A mixture containing the primary amine (1a-h, 10 mmol), methyl 3- 

cyclopropyl-3-oxopropanoate (2, 10 mmol), and catalytic amount of sodium or 

potassium hydroxide (10 %) in toluene (50 mL) was reflux at 110 o C for the 

approximately 12-15 h. The reaction was monitored by TLC. After completion of 

reaction, the solvent was removed under vaccuo and the solid or oil was crystallized 

from methanol which afforded pure products. 

General synthesis of ketene dithioacetals (4a-o). 

A 100mL conical flask equipped with magnetic stirrer and septum was charged 

with a solution of 3-cyclopropyl-3-oxo-N-arylpropanamide (3a-o, 10 mmol) in DMF 

(10 mL). Dried K 2 CO 3 (20 mmol) was added and the mixture was stirred for 2 h at 

room temperature. CS 2 (10 mmol) was added and the mixture was stirred for an 

additional 2 h at room temperature. Methyl iodide (20 mmol) was added at 0-5 o C and 

the mixture was stirred for 4 h at room temperature. The reaction was monitored by 

TLC. After completion, the mixture poured into water (40 mL). The precipitated 

crude product was purified by filtration followed by crystallization from EtOH. When 

the product was oil, the organic phase was extracted with Et 2 O (3 × 10 mL). The 

combined organic extracts were washed with H 2 O (2 × 10 mL), dried (MgSO 4 ), and 

concentrated in vaccuo to afford ketene dithioacetals directly used for the next step. 


Chapter 3 


General procedure for the synthesis of trisubstituted pyrazoles5a-o. 

‣ Conventional method: 


hydrazine hydrate (15 mmol) and various ketene dithioacetals (3a-o, 10 mmol) and 

heated up to 75-85 o C for appropriate times (Table-1). After completion of the 

reaction, the reaction mixture was allowed to come to room temperature and add cold 

water (50 mL). The separated suspension was filtered, washed with water, dried and 

crystallized from methanol to afford analytically pure products with 80-90% yield. 

‣ Microwave assisted method: 

A one neck flat bottom flask charged with the hydrazine hydrate (15 mmol), 

and various ketene dithioacetals 3a-o (10 mmol), was heated at 90 o C under 

microwave irradiation for appropriate time (Table-1). After completion of the 

reaction, the reaction mixture was allowed to attain room temperature and added cold 

water (50 mL). The suspension was filtered, washed with water, dried and crystallized 

from methanol to afford analytically pure products with 85-95% yield. 

General procedure for the synthesis of trisubstituted isoxazoles6a-o. 



with hydroxyl amine hydrochloride (15 mmol), potassium hydroxide (15 mmol) and 

various ketene dithioacetals (3a-o, 10mmol) and heated up to 75-85 o C for appropriate 

times (Table-1). After completion of the reaction, the reaction mixtures were cooled 

to room temperature and add cold water (50 mL). The separated solid was filtered, 

washed with water, dried and crystallized from methanol to afford analytically pure 

products with 80-90% yield. 


A one neck flat bottom flask charged with hydroxyl amine hydrochloride (15 

mmol), potassium hydroxide (15 mmol) and various ketene dithioacetals 3a-o (10 

mmol) and reaction mixture heated at 90 o C under microwave irradiation for 

appropriate time (Table-1). After completion of the reaction, the reaction mixture was 

allowed to come to room temperature and add cold water (50 mL). The separated 

solid was filtered, washed with water, dried and crystallized from methanol to afford 

analytically pure products with 85-95% yield. 


Chapter 3 



3-Cyclopropyl-N-(4-fluorophenyl)-3-oxopropanamide 3c.White solid; R f 0.42 (8:2 

hexane-EtOAc); IR (KBr): 3364, 2927, 1674, 1533, 1462, 1281, 1112, 873 cm -1 ; 1 H 

NMR (300 MHz, CDCl 3 ): δ 1.07-1.13 (q, 2H, CH 2 ), 1.14-1.20 (q, 2H, CH 2 ), 2.00- 

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- 

H), 9.43 (s, 1H, NH); MS (m/z): 221 (M + ); Anal. Calcd for C 12 H 12 FNO 2 : C, 65.15; H, 

5.47; N, 6.33; Found: C, 65.17; H, 5.45; N, 6.34. 

N-(4-chlorophenyl)-2-(cyclopropylcarbonyl)-3,3-bis(methylsulfanyl)prop-2- 

enamide 4b. Yellow solid; R f 0.48 (8:2 hexane-EtOAc); IR (KBr): 3033, 2927, 1674, 

1533, 1462, 1281, 1112, 873 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ): δ 1.02-1.06 (m, 2H, 

CH 2 ), 1.21-1.24 (m, 2H, CH 2 ), 2.37-2.43 (m, 1H, CH), 2.47 (s, 6H, 2xSCH 3 ), 7.26- 

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 

(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: 

C, 52.72; H, 4.75; N, 4.12. 

2-(Cyclopropylcarbonyl)-N-(4-methoxyphenyl)-3,3-bis(methylsulfanyl)prop-2- 

enamide 4d. Yellow solid; R f 0.42 (9:1 Chloroform: Methanol); IR (KBr): 3364, 

2927, 1674, 1533, 1462, 1281, 1112, 873 cm -1 ; 1 H NMR (400 MHz, 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 (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 (d, 2H, 

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 : 

C, 56.95; H, 5.68; N, 4.15; Found: C, 56.92; H, 5.65; N, 4.12. 

3-Cyclopropyl-5-(methylthio)-N-p-tolyl-1H-pyrazole-4-carboxamide 5a. White 

solid; R f 0.71 (9:1 Chloroform: Methanol); mp 155-157 o C; IR (KBr): 3284, 3151, 

3083, 3031, 2968, 2841, 1628, 1586, 1408, 1238, 1037, 887, 834 cm -1 ; 1 H NMR (300 

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), 

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 

(d, 2H, j=8.1Hz, Ar-H), 9.36 (s, 1H, NH), 12.84 (s, 1H, NH); MS (m/z): 287 (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, 5.95; 

N, 14.62. 


Chapter 3 


N-(4-chlorophenyl)-3-cyclopropyl-5-(methylthio)-1H-pyrazole-4-carboxamide 

5b. White solid; R f 0.68 (9:1 Chloroform: Methanol); mp 133-135 o C; IR (KBr): 3294, 

3259, 3153, 3020, 2953, 2895, 1681, 1589, 1485, 1251, 1006, 898, 821, 759, 732, 690 

cm -1 ; 13 C NMR (100 MHz, CDCl 3 ): 7.52, 120.82, 127.03, 128.23, 137.74, 161.69; MS 

(m/z): 307 (M + ); Anal. Calcd for C 14 H 14 ClN 3 OS: C, 54.63; H, 4.58; N, 13.65; Found: 

C, 54.62; H, 4.55; N, 13.62. 

3-Cyclopropyl-N-(4-fluorophenyl)-5-(methylthio)-1H-pyrazole-4-carboxamide 

5c. White solid; R f 0.71 (9:1 Chloroform: Methanol); mp 122-124 o C; IR (KBr): 3287, 

3136, 3081, 3014, 2968, 2833, 1641, 1584, 1251, 1024, 882, 832 cm -1 ; 1 H NMR (300 

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), 

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 

(s, 1H, NH), 12.88 (s, 1H, NH); MS (m/z): 291 (M + ); Anal. Calcd for C 14 H 14 ClN 3 OS: 

C, 57.72; H, 4.84; N, 14.42; Found: C, 57.74; H, 4.85; N, 14.46. 

3-Cyclopropyl-N-(4-methoxyphenyl)-5-(methylthio)-1H-pyrazole-4-carboxamide 

5d. White solid; R f 0.42 (9:1 Chloroform: Methanol); mp 141-143 o C; IR (KBr): 3292, 


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. 

N-(3,4-dichlorophenyl)-3-cyclopropyl-5-(methylthio)-1H-pyrazole-4-carboxamide 

5e. White solid; R f 0.69 (9:1 Chloroform: Methanol); mp 179-181 o C; IR (KBr): 

3298, 3142, 3086, 3001, 2956, 2829, 1631, 1415, 1245, 1023, 828, 782 cm -1 ; 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; Found: 

C, 49.15; H, 3.85; N, 12.26. 

N-(3-chloro-4-fluorophenyl)-3-cyclopropyl-5-(methylthio)-1H-pyrazole-4-carboxamide 

5f. White solid; R f 0.65 (9:1 Chloroform: Methanol); mp 179-181 o C; IR 

(KBr): 3287, 3082, 2961, 1628, 1041, 835, 789 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 

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, 

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, 

j=6.9Hz, Ar-H), 9.71 (s, 1H, NH), 12.90 (s, 1H, NH); MS (m/z): 325 (M + ); Anal. 

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, 

12.96. 


Chapter 3 


3-Cyclopropyl-N-(2,3-dimethylphenyl)-5-(methylthio)-1H-pyrazole-4-carboxamide 

5g. White solid; R f 0.81 (9:1 Chloroform: Methanol); mp 183-185 o C; IR (KBr): 

3289, 3136, 3094, 3013, 2958, 2826, 1638, 1587, 1418, 1239, 1028, 758, 785 cm -1 ; 

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; 

Found: C, 63.76; H, 6.35; N, 13.93. 

3-Cyclopropyl-5-(methylthio)-N-(4-nitrophenyl)-1H-pyrazole-4-carboxamide 5h. 

White solid; R f 0.86 (9:1 Chloroform: Methanol); mp 212-215 o C; IR (KBr): 3278, 

3145, 3097, 3015, 2947, 2832, 1641, 1584, 1408, 1233, 1021, 834 cm -1 ; MS (m/z): 

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, 

52.86; H, 4.45; N, 17.63. 

3-Cyclopropyl-N-(2-methoxyphenyl)-5-(methylthio)-1H-pyrazole-4-carboxamide 

5i. White solid; R f 0.76 (9:1 Chloroform: Methanol); mp 111-113 o C; IR (KBr): 3287, 

3139, 3085, 3011, 2955, 2824, 1631, 1587, 1417, 1241, 1026, 744 cm -1 ; MS (m/z): 

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, 

59.36; H, 5.65; N, 13.82. 

3-Cyclopropyl-5-(methylthio)-N-o-tolyl-1H-pyrazole-4-carboxamide 5j. White 

solid; R f 0.63 (9:1 Chloroform: Methanol); mp 142-144 o C; IR (KBr): 3283, 3141, 

3088, 3016, 2967, 2836, 1641, 1593, 1412, 1231, 1037, 755 cm -1 ; MS (m/z): 287 

(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, 

5.95; N, 14.62. 

3-Cyclopropyl-N-(4-ethylphenyl)-5-(methylthio)-1H-pyrazole-4-carboxamide 

5k.White solid; R f 0.71 (9:1 Chloroform: Methanol); mp 187-189 o C; IR (KBr): 

3287, 3147, 3091, 3008, 2958, 2828, 1638, 1584, 1410, 1248, 1028, 837 cm -1 ; 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; Found: C, 

63.76; H, 6.35; N, 13.93 

N-(5-Chloro-2-methoxyphenyl)-3-cyclopropyl-5-(methylthio)-1H-pyrazole-4-carboxamide 

5l. White solid; R f 0.69 (9:1 Chloroform: Methanol); mp 205-207 o C; IR 

(KBr): 3285, 3141, 3088, 3013, 2964, 2838, 1634, 1587, 1415, 1238, 1034, 878, 748 

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, 

12.44; Found: C, 53.36; H, 4.75; N, 12.43 


Chapter 3 


N-(2,5-dichlorophenyl)-3-cyclopropyl-5-(methylthio)-1H-pyrazole-4-carboxamide 

5m. White solid; R f 0.62 (9:1 Chloroform: Methanol); mp 188-187 o C; IR (KBr): 

3279, 3136, 3079, 3021, 2959, 2831, 1628, 1581, 1422, 1242, 1039, 892, 761 cm -1 ; 

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; 

Found: C, 49.15; H, 3.85; N, 12.26. 

3-Cyclopropyl-N-(2,5-dimethylphenyl)-5-(methylthio)-1H-pyrazole-4-carboxamide 

5n. White solid; R f 0.78 (9:1 Chloroform: Methanol); mp 177-178 o C; IR (KBr): 


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. 

3-Cyclopropyl-N-(3,4-difluorophenyl)-5-(methylthio)-1H-pyrazole-4-carboxamide 

5o. White solid; R f 0.63 (9:1 Chloroform: Methanol); mp 202-204 o C; IR (KBr): 

3287, 3142, 3093, 3014, 2969, 2838, 1628, 1587, 1410, 1248, 1034, 833, 786 cm -1 ; 

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; 

Found: C, 54.36; H, 4.25; N, 13.59. 

3-Cyclopropyl-5-(methylthio)-N-p-tolylisoxazole-4-carboxamide 6a. White solid; 

R f 0.61 (8:2 hexane-EtOAc); mp 144-146 o C; IR (KBr): 3282, 3149, 3081, 3033, 2978, 


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. 

N-(4-Chlorophenyl)-3-cyclopropyl-5-(methylthio)isoxazole-4-carboxamide 6b. 

White solid; R f 0.70 (8:2 hexane-EtOAc); mp 125-127 o C; IR (KBr): 3294, 3149, 

3018, 2895, 1695, 1591, 1496, 1253, 1058, 810, 759, 715, 690 cm -1 ; 1 H NMR (300 

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), 

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 

(broad, 1H, CONH); 13 C NMR (100 MHz, CDCl 3 ): 6.85, 13.66, 22.72, 29.18, 110.84, 

121.05, 129.13, 136.09, 159.32, 162.66, 172.03; MS (m/z): 308 (M + ); Anal. Calcd for 

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. 

3-Cyclopropyl-N-(4-fluorophenyl)-5-(methylthio)isoxazole-4-carboxamide 6c. 



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. 


Chapter 3 


3-Cyclopropyl-N-(4-methoxyphenyl)-5-(methylthio)isoxazole-4-carboxamide 6d. 


3095, 3031, 2965, 2837, 1637, 1592, 1409, 1247, 1036, 891, 833 cm -1 ; MS (m/z): 304 

(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, 

5.31; N, 9.22. 

N-(3,4-dichlorophenyl)-3-cyclopropyl-5-(methylthio)isoxazole-4-carboxamide 6e. 


3091, 3011, 2951, 2831, 1625, 1587, 1418, 1241, 1029, 832, 779 cm -1 ; MS (m/z): 343 

(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; 

H, 3.53; N, 8.12. 

N-(3-chloro-4-fluorophenyl)-3-cyclopropyl-5-(methylthio)isoxazole-4-carboxamide 

6f. White solid; R f 0.69 (8:2 hexane-EtOAc); mp 197-199 o C; IR (KBr): 3288, 

3139, 3072, 3017, 2969, 2834, 1631, 1587, 1417, 1237, 1046, 839, 791 cm -1 ; MS 

(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; 

Found: C, 51.47; H, 3.73; N, 8.54. 

3-Cyclopropyl-N-(2,3-dimethylphenyl)-5-(methylthio)isoxazole-4-carboxamide 

6g. White solid R f 0.72 (8:2 hexane-EtOAc); mp 181-183 o C; IR (KBr): 3297, 3138, 

3089, 3015, 2952, 2823, 1631, 1591, 1421, 1237, 1025, 754, 787;MS (m/z): 302 (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, 6.03; 

N, 9.24. 

3-Cyclopropyl-5-(methylthio)-N-(4-nitrophenyl)isoxazole-4-carboxamide 6h. 

White solid R f 0.58 (8:2 hexane-EtOAc); IR mp 177-179 o C; IR (KBr): 3277, 3148, 

3091, 3004, 2942, 2839, 1636, 1591, 1419, 1241, 1033, 837 cm -1 ;MS (m/z): 319 (M + ); 

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; 

N, 13.14. 

3-Cyclopropyl-N-(2-methoxyphenyl)-5-(methylthio)isoxazole-4-carboxamide 6i. 

White solid R f 0.63 (8:2 hexane-EtOAc); mp 131-133 o C; IR (KBr): 3285, 3142, 3083, 

3013, 2964, 2833, 1637, 1591, 1414, 1246, 1028, 746 cm -1 ;MS (m/z): 304 (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, 5.31; N, 

9.22. 


Chapter 3 


3-Cyclopropyl-5-(methylthio)-N-o-tolylisoxazole-4-carboxamide 6j. White solid; 

R f 0.67 (8:2 hexane-EtOAc); mp 155-157 o C; IR (KBr): 3285, 3145, 3091, 3003, 

2964, 2831, 1639, 1589, 1413, 1237, 1029, 761 cm -1 ; MS (m/z): 288 (M + ); Anal. 

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, 

9.72. 

3-Cyclopropyl-N-(4-ethylphenyl)-5-(methylthio)isoxazole-4-carboxamide 6k. 


3093, 3013, 2952, 2822, 1631, 1586, 1418, 1241, 1031, 839 cm -1 ; MS (m/z): 302 


6.03; N, 9.24. 

N-(5-chloro-2-methoxyphenyl)-3-cyclopropyl-5-(methylthio)isoxazole-4-carboxamide 

6l. White solid; R f 0.65 (8:2 hexane-EtOAc); mp 220-222 o C; IR (KBr): 3291, 

3139, 3092, 3005, 2968, 2842, 1639, 1582, 1425, 1231, 1029, 872, 739 cm -1 ; MS 

(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: 

C, 53.19; H, 4.43; N, 8.29. 

N-(2,5-dichlorophenyl)-3-cyclopropyl-5-(methylthio)isoxazole-4-carboxamide 

6m. White solid; R f 0.73 (8:2 hexane-EtOAc); mp 202-204 o C; IR (KBr): 3281, 3139, 

3081, 3019, 2951, 2829, 1632, 1584, 1426, 1238, 1037, 894, 763 cm -1 ; MS (m/z): 343 


H, 3.53; N, 8.12. 

3-Cyclopropyl-N-(2,5-dimethylphenyl)-5-(methylthio)isoxazole-4-carboxamide 

6n. White solid; R f 0.58 (8:2 hexane-EtOAc); mp 208-210 o C; IR (KBr): 3287, 3139, 

3091, 3007, 2959, 2839, 1634, 1594, 1419, 1243, 1029, 882, 742 cm -1 ; MS (m/z): 302 


6.03; N, 9.24. 

3-Cyclopropyl-N-(3,4-difluorophenyl)-5-(methylthio)isoxazole-4-carboxamide 6o. 


3089, 3008, 2964, 2842, 1632, 1591, 1417, 1239, 1041, 839, 779 cm -1 ; MS (m/z): 310 


H, 3.93; N, 9.02. 


Chapter 3 


1 H NMR spectrum of compound 4b 

1 H NMR spectrum of compound 4d 


Chapter 3 



Expanded 1 H NMR spectrum of compound 5b 


Chapter 3 


1 H NMR spectrum of compound 5e 

Expanded 1 H NMR spectrum of compound 5e 


Chapter 3 


1 H NMR spectrum of compound 5c 

F 

O 

N 

H 

S 

N 

NH 



Chapter 3 


13 C NMR spectrum of compound 5b 

Expanded 13 C NMR spectrum of compound 5b 


Chapter 3 





Chapter 3 


MASS spectrum of compound 5a 

N 

H 

O 

S 

N 

NH 

m/z-287 

MASS spectrum of compound 5d 


Chapter 3 


MASS spectrum of compound 6c 


O 

O 

N 

H 

S 

m/z-304 

N 

O 


Chapter 3 


IR spectrum of compound 5b 

90 

%T 

75 

60 

3294.53 

3279.10 

3259.81 

3153.72 

3099.71 

3020.63 

2953.12 

2895.25 

2839.31 

1728.28 

1681.98 

1589.40 

1429.30 

1400.37 

1350.22 

1309.71 

1251.84 

1091.75 

1006.88 

898.86 

759.98 

732.97 

690.54 

661.61 

626.89 

45 

30 

9 

1639.55 

1508.38 

1485.24 

821.70 

592.17 

497.65 

516.94 

470.65 

4000 

3500 

3000 

2500 

2000 

1750 

1500 

1250 

1000 

750 

500 

1/cm 

IR spectrum of compound 6b 

100 

%T 

80 

1695.49 

60 

1095.60 

1058.96 

968.30 

40 

2895.25 

1558.54 

1350.22 

1253.77 

1004.95 

896.93 

759.98 

715.61 

690.54 

430 14 

20 

0 

3294.53 

3277.17 

3149.86 

3093.92 

3018.70 

1633.76 

1591.33 

1516.10 

1496.81 

1404.22 

1311.64 

810.13 

-20 

4000 

3500 

3000 

2500 

2000 

1750 

1500 

1250 

1000 

750 

500 

1/cm 


Chapter 3 



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Chapter - 4 

Synthesis and Characterization of 

Novel Substituted and Fused 

Pyrazolo[1,5-a] pyrimidines Derivatives

Chapter 4 

Synthesis of highly substituted pyrazolopyrimidine 


Biaryls and heterobiaryls have attracted significant attention from the 

scientific community because of their relevance in medicinal chemistry. Heterobiaryls 

frequently can be observed in numerous bioactive small molecules, and in particular, 

heterobiaryls fused with various heterocycles, such as pyrazole, pyridine, and 

pyrimidine, have been used as key pharmacophores. 1 Pyrazolo[1,5-a]pyrimidines have 

attracted considerable interest because of their biological activity. For instance, this 

heterocyclic system is found as purine analogues and has useful properties as 

antimetabolites in purine biochemical reactions. 2 Several compounds of this class 

display interesting antitrypanosomal 3 and antischistosomal activities. 4 They are used 

as HMG-CoA reductaseinhibitors, 5 COX-2 selective inhibitors, 6 30,50-cyclic-AMP 

phosphodiesteraseinhibitors, 7 CRF 1 antagonists, 8a-d selective peripheral 

benzodiazepine receptor ligands, 9a-c 

potassium channel 10 and histamine-3 receptor 

ligands 11 and antianxiety agents. 12 

Some pyrazolopyrimidines serve as efficient sedative-hypnotic and anxiolytic 

drugs like zaleplon (Sonata, hypnotic), 13 indiplon (hypnotic), 14 

and ocinaplon 

(anxiolytic), 15 fasiplon (anxiolytic), 16 (Figure-1) these drugs are related to the class of 

nonbenzodiazepines, and their therapeutic effect is due to allosteric enhancement of 

the action of the inhibitory neurotransmitter GABA at the GABA A receptor. 13-14 These 

examples emphasize the importance of pyrazol-fused heterobiaryls, as well as 

pyrazolopyridines, as key pharmacophores in bioactive small molecules. 

N 

O 

N 

N N CN 

N 

N 

N N 

O 

N 

N 

O 

N N N 

O 

S 

O 

N 

N 

N 

N 

N O 

Zaleplon 

Ocinaplon 

Indiplon 

Fasiplon 

Figure-1 


Chapter 4 


4.2 Biological activity related to pyrazolopyrimidine derivatives 

Pyrazolopyrimidines have multiple pharmacological activities including 

hypnotic, anti-inflammatory, anti-tumor, antimycobacterial, antidiabetic, 

antiphlogistic agents, antidepressants, analgesics and anti-viral. Several diverse 

biological activities have been reported for pyrazolopyrimidine ring systems which 

are described as below. 

Ivashchenko et al. 17 reported that substituted 3-(arylsulfonyl)pyrazolo[1,5-a] 

pyrimidines (Figure-2) are claimed as antagonists of serotonin 5-HT6 receptors for 

treating and preventing pathol. states and diseases of the central nervous system in 

humans and warm-blooded animals, the pathogenesis of which is caused by disorder 

in the serotonin 5-HT6 receptor activation. 

Figure-2 

Alexandre V. Ivachtchenko et al. 18 has described structure activity 

relationships for a series of novel 2-substituted 3-benzenesulfonyl-5,6-dimethylpyrazolo[1,5-a]pyrimidines. 

In spite of a wide, four orders of magnitude, SAR range 

(Ki varied from 260 pM to 2.96 mM), no significant correlation of 5-HT 6 R 

antagonistic potency was observed with major physiochemical characteristics, such as 

molecular weight, surface polar area, cLogP, or number of rotatable bonds. 

Statistically significant trend was only observed for size of substitute group, which 

was not enough to explain the deep SAR trend. Besides with the substitute group size, 

another factor that presumably plays a role in defining the compound potencies isa 

relative position of the heterocycle and sulfophenyl moieties. Among all synthesized 

derivatives, (3 benzenesulfonyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methylamine 

(Figure-3) is the most potent(Ki ¼ 260 pM) and extremely selective, 5000 to 

>50,000-fold relative to 55 therapeutic targets, antagonist of the 5-HT 6 receptor. 

Figure-3 


Chapter 4 


Silvia Selleri et al. 19 have been developed a new class of N,N-diethyl-(2- 

arylpyrazolo[1,5-a]pyrimidin-3-yl)acetamides, (Figure-4) as azaisosters of Alpidem, 

and their affinities for both the peripheral (PBR) and the central (CBR) 

benzodiazepine receptors were evaluated. Binding assays were carried out using both 

[ 3 H]PK 11195 and [ 3 H]Ro 5-4864 as radio ligands for PBR, whereas [ 3 H]Ro 15-1788 

was used for CBR, in rat kidney and rat cortex, respectively. The tested compounds 

exhibited a broad range of binding affinities from as low as 0.76 nM to inactivity and 

most of them proved to be high selective ligands for PBR. The preliminary SAR 

studies suggested some of the structural features required for high affinity and 

selectivity; particularly the substituent on the pyrimidine moiety seemed to play an 

important role in PBR versus CBR selectivity. A subset of the highest affinity 

compounds was also tested for their ability to stimulate steroid biosynthesis in C6 

glioma rat cells and some of these were found to increase pregnenolone formation 

with potency similar to RO 5-4864 and PK 11195. 

Figure-4 

John E. Tellew et al. 20 has discovered an antagonist of the corticotropinreleasing 

factor (CRF) neuropeptide may prove effective in treating stress and anxiety 

related disorders. In an effort to identify antagonists with improved physico-chemical 

properties a new series of CRF1 antagonists were designed to substitute the propyl 

groups at the C7 position of the pyrazolo[1,5-a]pyrimidine core with heterocycles. 

Compound (Figure-5) was identified as a high affinity ligand with a pKi value of 8.2 

and a functional CRF1 antagonist with IC 50 value of 7.0 in the in vitro CRF ACTH 

production assay. 

N 

O 

N 

H 

N 

N 

N 

N 

R 

O 

Figure-5 


Chapter 4 


Song Qing Wang et al. 21 have been designed some new 5-methyl-7- 

substituted–pyrazolo[1,5-a]pyrimidine-3-carbonitrile derivatives on the basis of the 

Zaleplon structure for studies on their hypnotic activity. The preliminary 

pharmacological evaluations indicated that some compounds showed hypnotic 

activity, among that one compound (Figure-6) was the most potent one. 

Figure-6 

Robert H. Springer et al. 22 has prepared a number of 3,7-disubstituted 6- 

carbethoxypyrazolo[ 1,5-a]pyrimidines and 3,7-disubstituted 6-ethoxypyrazolo-[1,5- 

a]pyrimidines (Figure-7) have been and evaluated as adenosine cyclic 3’,5’- 

phosphate (cAMP) phosphodiesterase (PDE) inhibitors vs. the low K, enzyme isolated 

from beef heart, rabbit lung, and kidney preparations. The results were found to be 

between 0.5 to 13 times as potent as theophylline as inhibitors of PDE, depending on 

the tissue source. A number of these PDE inhibitors exhibited significant 

physiological effects in different animal systems, suggesting it should be possible to 

obtain selective PDE inhibition in various tissues. Several of these heterocycles were 

found superior to adenosine in inhibiting ADP-induced platelet aggregation in vitro. 

N 

R 1 

N 

R 1 

O 

R 2 

N 

N 

R 1 =H, C 2 H 5 ,NO 2 , Br, COOEt 

R 2 =OH, NH 2 ,OC 2 H 5 ,SH,SC 2 H 5 

Figure-7 

Robin R. Frey et al. 23 have discovered 7-aminopyrazolo[1,5-a]pyrimidine urea 

receptor tyrosine kinase inhibitors. Investigation of structure-activity relationships of 

the pyrazolo[1,5-a]pyrimidine nucleus led to a series of 6-(4-N,N′-diphenyl)ureas that 

potently inhibited a panel of vascular endothelial growth factor receptor (VEGFR) 

and platelet-derived growth factor receptor (PDGFR) kinases. Several of these 

compounds are potent inhibitors of kinase insert domain-containing receptor tyrosine 

kinase (KDR) both enzymatically(

Chapter 4 


In addition, compound (Figure-8) possesses a favorable pharmacokinetic profile and 

demonstrates efficacy in the estradiol-induced murine uterine edema (UE) model 

(ED 50 ) 1.4mg/kg). 

Figure-8 

Rui Ding et al. 24 has synthesized compound 5-((2-aminoethylamino)methyl)- 

7-(4-bromoanilino)-3-cyanopyrazolo[1,5-a]pyrimidine (ABCPP) via conjugated with 

N-mercaptoacetylglycine (MAG), N-mercaptoacetylphenylalanine (MAF) and N- 

mercaptoacetylvaline (MAA), (Figure-9) respectively. These three compounds were 

labeled successfully with [ 99m TcN] 2+ intermediate in high radiochemical purities. 

Biodistribution in tumor-bearing mice demonstrated that the three new complexes 

showed tumor accumulation, high tumor-to muscle (T/M) ratios and fast clearance 

from blood and muscle. Among them, the 99mTcNMAG-ABCPP showed the most 

favorable characteristics, with tumor/blood and tumor/muscle ratios reaching 1.51 and 

2.97 at 30 min post-injection, 1.84 and 2.49 at 60 min post-injection, suggesting it 

could be further studied as potential tumor imaging agent for single photon emission 

computed tomography (SPECT). 

Figure-9 

Osama M. Ahmed et al. 25 has synthesized some new pyrazolo[1,5- 

a]pyrimidine derivatives, (Figure-10) which showed potent anti-tumor cytotoxic 

activity in vitro using different human cancer cell linesHepG2 (hepatocellular 

carcinoma cell line), MCF7 (breastcarcinoma cell line), HCT116 (colon carcinoma 

cell line), HeLa (cervix carcinoma cell line). 


Chapter 4 


Figure-10 

Naveen Mulakayala et al. 26 has synthesized some new 7-trifluoromethyl 

substituted pyrazolo[1,5-a]pyrimidines (Figure-11) with potent antitumor agents. The 

cytotoxic effects of the newly synthesized pyrazolo[1,5-a]pyrimidines against 

leukemiacells, K562 and human colon carcinoma cells, Colo-205 were evaluated. 

R 2 

R 1 

OH 

R 1 

R 2 O 

OH 

N 

O 

N 

N 

N 

N 

N 

CF 3 

R 1 =H, R 2 =H,Cl,Br,F,Me 

Figure-11 

CF 3 

4.3 Various synthetic approaches for substituted 

pyrazolopyrimidine derivatives 

As mention previously, pyrazolopyrimidine ring system is present in a variety 

of biologically active compounds (both naturally-occurring and synthetic). Although a 

large number of methods for their synthesis have been documented in the literature, 

many of them require multistep procedures using intermediates which are not readily 

available. Among them, few methods are discussed here. 

Abbas-Temirek, H. H. synthesized some new bridged nitrogen pyrazolo[1,5- 

a]pyrimidines from 5-amino-3-methylthio-1H-pyrazole-4-carboxylate (Figure-12) 

under refluxing with acetic acid. 27 

Figure-12 


Chapter 4 


Yan-Chao Wu et al. 28 were established an efficient, fast and facile 

pyrazolo[1,5-a]pyrimidine (Figure-13) synthetic protocol for the condensation of 

aminopyrazoles with 1,3-dicarbonyl components in AcOH/H 2 SO 4 system. 

Figure-13 

G. G. Danagulyan et al. 29 have described condensation of ethyl 3- 

aminopyrazole-4-carboxylate (1) with ethyl ethoxymethylenecyanoacetate (2) was 

carried out with the aim of preparing diethyl 7-aminopyrazolo[1,5-a]pyrimidine-3,6- 

dicarboxylate (3) and subsequent study of its C–C recyclization to the isomeric 6- 

carbamoyl-7-hydroxypyrazolopyrimidine but the reaction did not go to completion, 

on the basis of NMR it was clear that a mixture of compounds including both the 

cyclization product (3)and the uncyclized condensation adduct ethyl 3-[(2-cyano-3- 

ethoxy-3-oxoprop-1-en-1-yl)amino]-1H-pyrazole-4-carboxylate (4) had been 

obtained. However, in basic medium both the condensed pyrazolopyrimidine (3) and 

the cyano derivative (4) were converted in high yield to the 6-carbamoyl-7- 

hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylic acid (5) (Figure-14). 

Figure-14 

Li Ming et al. 30 was reported a convenient, rapid, and highly selective method 

for synthesis of new Pyrazolo[1,5-a]pyrimidines (Figure-15) via the Reaction of 

enaminones and5-amino-1H-pyrazoles under Microwave Irradiation. 


Chapter 4 


Figure-15 

Abraham Thomas et al. 31 has described a facile highly regioselective general 

route to substituted and fused pyrazolo[a]pyrimidines via cyclocondensation of 

oxoketene dithioacetals with 3-aminopyrazoles (Figure-16). 

Figure-16 


Chapter 4 


Pushpak Mizar et al. 32 have been described a facile method for the synthesis of 

pyrazolo[1,5-a]pyrimidine (Figure-17) by reacting N-substituted or unsubstitutedpyrazol-5(4H)-one, 

aryl-oxoketene dithioacetals and alkyl amide. 

Figure-17 

Recently, Ibtissam Bassoude et al. 33 described one step condensation reaction 

of of 5(3)-amino-3(5)-arylpyrazoles with 4-hydroxy-6-methylpyran-2-one leading to 

new pyrazolo[1,5-a]pyrimidines(Figure-18). 

Figure-18 

V. N. Britsun was reported cyclocondensation products of N-aryl-3- 

oxobutanethioamides with 5-amino-3-R-4-R 1 -pyrazoles are 4-(arylamino)-2-methyl- 

7-R-8-R 1 -pyrazolo[1,5-a]pyrimidine and pyrazolo[1,5-a]pyrimidine-4-thione 

derivatives (Figure-19), the ratio of which depends on the nucleophilicity of the 

starting 5-amino-3-R-4-R 1 - pyrazoles and the presence of a proton donor solvent. 34 

Figure-19 

D. V. Kryl’skii et al. 35 has described Three-component condensation of 3- 

methyl(or methoxymethyl)-4-phenyl-1H-pyrazol-5-amine with triethylorthoformate 

and carbonyl compounds or nitriles containing an activated methylene group 

(cyclohexane-1,3-diones, acetoacetanilides, benzoylacetone, ethyl cyanoacetate, 

malononitrile, 1H-benzimidazol-2-yl-acetonitrile) gave substituted 

pyrazolopyrimidines (Figure-20). 


Chapter 4 


Figure-20 

Sayed A. Ahmed et al. 36 have synthesized pyrazolo[1,5-a]pyrimidines from 

the appropriate 3-aminopyrazoles with the appropriate sodium (3-oxocycloalkylidene) 

methenolate, β-diketone, β-keto esters or 1,2-disubstitutedacrylonitrile (Figure-21). 


Chapter 4 


Figure-21 

Mohamed R. Shaaban et al. 37 have described a simple, facile, efficient and one 

pot three-component procedure for the synthesis of pyrazolo[1,5-a]pyrimidine ring 

systems incorporating phenylsulfonyl moiety was developed via the reaction of 1- 

aryl-2-(phenylsulfonyl)ethanone derivatives with the appropriate heterocyclic amine 

and triethylorthoformate (Figure-22). 

Figure-22 

Baseer M. Shaikh et al. 38 has prepared pyrazolo [1, 5-a] pyrimidines derivative by the 

condensation of substituted of α, β- unsaturated carbonyl compounds (chalcones) with 

substituted 5-aminopyrazole as an alternative polyethylene glycol (PEG-400) as green 

reaction medium (Figure-23). 

Figure-23 


Chapter 4 



The pyrazolopyrimidine derivatives have considerable chemical and 

pharmacological importance because of a broad range of biological activities 

displayed by these classes of molecules. As we demonstrated, the tremendous 

biological potential of pyrazolopyrimidine derivatives encouraged us to synthesize 

some new highly functionalized pyrazolopyrimidine derivatives. Various 

methodologies have been described for the synthesis of pyrazolopyrimidine 

derivatives. However, the existing methods are suffer with some drawbacks, such as; 

yield, time, product isolation, isomer formation. 

As a part of our ongoing interest on the synthesis of various heterocyclic 

compounds using ketene dithioacetals, we have demonstrated that ketene dithioacetals 

are versatile intermediate for the synthesis of pyrazolopyrimidine derivatives. Thus, to 

explore further, we sought that the reaction of various ketene dithioacetals with 5- 

amino-N-cyclohexyl-3-(methylthio)-1H-pyrazole-4-carboxamide in the presence of 

base in isopropyl alcohol could be an effective strategy to furnish the novel 

pyrazolopyrimidine derivatives. Here we describe the novel synthetic methodology 

for the fused pyrazolopyrimidines. 


Chapter 4 



Scheme: Synthesis of novel substituted Pyrazolo[1,5-a]pyrimidines derivatives. 

Scheme-01 

Scheme-02 

Scheme-03 

Where R= CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 , R 1 = CH 3 , OCH 3 NO 2 ,Cl 

Preparation of the target compounds was initiated by the reaction of 

ethylcynoacetate (1) with cyclohexyl amines (2) in toluene at reflux temperature to 

afford the cyanoacetamides (3) in 90% yields. This product undergoes reaction with 

carbon disulfide in the presence of base in DMF followed by methylation to afford 

corresponding 2-cyano-3,3-bis(methylthio)-N-phenylacrylamide (4). Which on 

reaction with hydrazine hydrate undergoes cyclization to form 5-amino-N-cyclohexyl- 

3-(methylthio)-1H-pyrazole-4-carboxamide (5) (Scheme-1). 

Various acetoacetanilide (8a-x) were synthesized by reacting substituted 

amine (7a-h) with various β-keto esters (6a-c) in toluene in the presence of catalytic 

amount of KOH at reflux temperature for 15-20 h. 


Chapter 4 


Twenty four different acetoacetanilide were synthesized bearing various 

electron donating and electron withdrawing groups such 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; 2-F; 4-OCH 3 ; 2,5-diCl and 

3-NO 2 on the phenyl ring. Thus, it has been found that reaction of substituted 

acetoacetanilide 8a-x derivatives with carbon disulfide in the presence of potassium 

carbonate followed by the alkylation with methyl iodide (Scheme-2) gave the novel 

ketene dithioacetals 9a-x. The resulting various ketene dithioacetals (9a-x) were 

reacted with 5-amino-N-cyclohexyl-3-(methylthio)-1H-pyrazole-4-carboxamide (5) in 

the presence of NaHCO 3 and methanol as a solvent to afford highly substituted 

pyrazolo[1,5-a]pyrimidines (10a-x) in low yield (Table-1 and 2). To optimize the 

reaction condition for the synthesis of compound 10a, various solvents and various 

bases were utilized. As a result, we found the reaction of 9a with 5 was faster and 

afforded the pyrazolo[1,5-a]pyrimidine10a in good yield in the presence of K 2 CO 3 as 

a base and isopropyl alcohol (Scheme-3). 

Table-1: Reaction of 9a with various solvents in the presence of base. 

Entry Solvent Base Time hrs Yield % 

1 Methanol NaHCO 3 20 65 

2 Ethanol NaHCO 3 18 68 

3 Isopropyl alcohol NaHCO 3 16 70 

4 Dioxane NaHCO 3 15 58 

5 DMF NaHCO 3 10 60 

6 Methanol Na 2 CO 3 14 70 

7 Ethanol Na 2 CO 3 13 72 

8 Isopropyl alcohol Na 2 CO 3 10 78 

9 Dioxane Na 2 CO 3 10 75 

10 DMF Na 2 CO 3 8 68 

11 Methanol K 2 CO 3 10 75 

12 Ethanol K 2 CO 3 10 80 

12 Isopropyl alcohol K 2 CO 3 8 94 

14 Dioxane K 2 CO 3 8 82 

15 DMF K 2 CO 3 7 78 

16 AcOH CH 3 COONa 8 65 


Chapter 4 


Table-2: synthesis of novel substituted and fused pyrazolopyrimidine derivatives. 

Entry R R 1 Time hrs Yield (%) 

10a CH 3 4-CH 3 8.0 94 

10b CH 3 3-Cl 7.5 92 

10c CH 3 3-Cl, 4-F 7.5 90 

10d CH 3 4-Cl 7.0 88 

10e CH 3 4-F 7.0 92 

10f CH 3 4-NO 2 9.0 95 

10g CH 3 4-OCH 3 8.0 90 

10h CH 3 2,5diCH 3 8.5 89 

10i (CH 3 ) 2 CH 4-CH 3 8.0 93 

10j (CH 3 ) 2 CH 3-Cl 7.0 87 

10k (CH 3 ) 2 CH 3-Cl, 4-F 7.5 95 

10l (CH 3 ) 2 CH 4-Cl 7.0 94 

10m (CH 3 ) 2 CH 4-F 7.5 92 

10n (CH 3 ) 2 CH 4-NO 2 8.5 97 

10o (CH 3 ) 2 CH 4-OCH 3 8.0 94 

10p (CH 3 ) 2 CH 2,5diCH 3 8.5 90 

10q (CH 2 ) 2 CH 4-CH 3 8.5 88 

10r (CH 2 ) 2 CH 3-Cl 7.5 92 

10s (CH 2 ) 2 CH 3-Cl, 4-F 7.0 87 

10t (CH 2 ) 2 CH 4-Cl 7.5 90 

10u (CH 2 ) 2 CH 4-F 8.0 93 

10v (CH 2 ) 2 CH 4-NO 2 8.5 96 

10w (CH 2 ) 2 CH 4-OCH 3 7.5 90 

10x (CH 2 ) 2 CH 2,5diCH 3 8.0 87 

The structures of compound 5 were established on the basis of their elemental 

analysis and spectral data (MS, IR, and 1 H NMR). The analytical data for 5 revealed a 

molecular formula C 11 H 18 N 4 OS (m/z 254). The 1 H NMR spectrum revealed a 

multiplets at δ = 1.20-1.98 assigned to 10 protons of (5x CH 2 ) groups in cyclohexane 

ring, a singlet at δ = 2.48 ppm assigned to - SCH 3, a multiplet at δ = 3.96-3.99 ppm 

assigned to the –CH protons of cyclohexane ring, 


Chapter 4 


one broad singlet at δ = 5.57 ppm assigned to –NH 2 groups, one singlet at δ = 7.28 

ppm assigned to –CONH groups and one broad singlet observed at δ = 11.9 ppm 

assigned to pyrazole -NH. 

The structures of 9a-x were established on the basis of their elemental analysis 

and spectral data (MS, IR, and 1 H NMR). The analytical data for 9i revealed a 

molecular formula C 16 H 21 NO 2 S 2 (m/z 323). The 1 H NMR spectrum revealed a singlet 

at δ = 1.18-1.20 ppm assigned to isopropyl-CH 3 , a singlet at δ = 1.57 ppm assigned to 

the –CH 3 protons, a singlet at δ = 2.44 ppm assigned to (2 × SCH 3 ) , a multiplet at δ = 

3.17-3.24 ppm assigned to the isopropyl -CH protons, a multiplets at δ = 6.99–7.54 

ppm assigned to the aromatic protons, and one broad singlet at δ = 8.38 ppm assigned 

to -CONH groups. 

The structures of 10a-x were established on the basis of their elemental 

analysis and spectral data (MS, IR, 1 H NMR and 13 C NMR). The analytical data for 

10b revealed a molecular formula C 23 H 26 ClN 5 O 2 S 2 (m/z 503). The 1 H NMR spectrum 

revealed a multiplets at δ = 1.35-1.81 assigned to 10 protons of (5x CH 2 ) groups in 

cyclohexane ring, a singlet at δ = 2.45 ppm assigned to - SCH 3, a singlet at δ = 2.70 

ppm assigned to - CH 3, a multiplet at δ = 3.79 ppm assigned to the –CH protons of 

cyclohexane ring, a multiplet at δ = 7.05–8.00 ppm assigned to the aromatic protons, 

one singlet at δ = 8.56 ppm assigned to –CONH groups attached with cyclohexane 

ring, and one singlet observed at δ = 12.56 ppm assigned to –CONH group attached 

with phenyl ring. 

The proposed mechanism for the cyclization is shown in Figure-24. The 

endocyclic-NH in compound A is the most nucleophilic center it is also the most 

sterically hindered site. Therefore, addition takes place at the exocyclic-NH 2 groups. 

The nucleophilic amino group attacks on the double bond via a Michael addition 

reaction, followed by loss of the thiomethane group. The intermediate D then cyclizes 

with subsequent dehydration E to afford the pyrazolopyrimidine derivative F. 


Chapter 4 


 

Mechanism:- 

S 

HN 

O 

S 

HN 

O 

R 

O 

R 1 

HN 

N NH 2 

N 

NH NH 2 

S 

S 

SCH 3 

HN 

S O 

N 

N N 

R 1 

S 

R 

F 

-H 2 O 

S 

A 

HN 

N 

N 

HO 

R 1 

R 

E 

O 

H 

N 

S 

B 

HN 

S 

N 

NH 

O 

R 1 

D 

O 

H 

N 

S 

R 

-SHCH 3 

N 

H 

O 

S 

H 

H S 

N 

NH 

N 

C 

O 

R 

R 1 

Figure 24: Proposed mechanism for the formation of pyrazolopyrimidine. 


Chapter 4 



In summary, the heterocyclizations of various ketene dithioacetals with 5- 

aminopyrazole derivative were studied in details, and the influence of the reaction 

parameters and the aminoazole structure on the direction of the reaction was 

established. We found that the reaction of various ketene dithioacetal 9a-x with 5- 

aminopyrazole derivative 5 were faster and afforded the pyrazolo[1,5-a]pyrimidine 

10a-x in good yield in the presence of K 2 CO 3 as a base and isopropyl alcohol. The 

results of the study described above have led to the development of a simple approach 

for synthesis of pyrazolo[1,5-a]pyrimidines, substances that potentially interesting 

biological and medicinal properties. 


Chapter 4 












Synthesis of 2-cyano-N-cyclohexylacetamide (3). 


thermometer was placed ethyl 2-cyanoacetate (0.25mol), cyclohexyl amine (0.25mol) 

and toluene (100 mL). The reaction mixture was heated up to 110-115 o C for 8 h. The 

progress of reaction was monitored by thin layer chromatography. The reaction 

mixture was cooled to room temperature and the solid product was filtered, washed 

with toluene to afford 90% yield. 

Synthesis of 2-cyano-N-cyclohexyl-3,3-bis(methylthio)acrylamide (4). 

A 100mL conical flask equipped with magnetic stirrer and septum was 

charged with a solution of 2-cyano-N-cyclohexylacetamide (3), (10 mmol) in DMF 

(10 mL). Dry K 2 CO 3 (10 mmol) was added and the mixture was stirred at room 

temperature for 2 h. CS 2 (30 mmol) was added and the mixture was stirred for an 

additional 2 h at room temperature. Then, methyl iodide (20 mmol) was added at 0-5 

o C and the mixture was stirred for 4 h at room temperature. The progress of the 

reaction was monitored by thin layer chromatography. After completion of the 

reaction, it was poured into 50ml cold water. The precipitated crude product was 

purified by filtration followed by crystallization from EtOH. 


Chapter 4 


Synthesis of 5-amino-N-cyclohexyl-3-(methylthio)-1H-pyrazole-4- 

carboxamide (5). 


charged 2-cyano-N-cyclohexyl-3,3-bis(methylthio)acrylamide (4) (0.1mol) in 

isopropyl alcohol (100 mL) and hydrazine hydrate (0.1mol). The Reaction mixture 

was heated to reflux for 2 h. After completion of the reaction, it was poured into 

50mL cold water. The precipitated crude product was purified by filtration followed 

by crystallization from EtOH. 

 

General synthesis of Acetoacetanilide derivatives (AAA) (8a-x). 

A mixture containing the primary amine (7a-h) (10 mmol), β-keto esters (6ac) 

(10 mmol), and catalytic amount of sodium or potassium hydroxide (10 %) in 

toluene (50 mL) was refluxed at 110 o C for 12-15 h. The reaction was monitored by 

TLC. After completion of reaction, the solvent was removed under vaccuo and the 

residue was crystallized from methanol. 

General synthesis of ketene dithioacetals (9a-x). 


charged with a solution of acetoacetanilide derivatives (8a-x) (10 mmol) in DMF (10 

mL). Dry K 2 CO 3 (20 mmol) was added and the mixture was stirred for 2 h at room 

temperature. CS 2 (10 mmol) was then added and the mixture was stirred for an 

additional 2 h at room temperature. Methyl iodide (20 mmol) was added at 0-5 o C and 

the mixture was stirred for 4 h at room temperature. The reaction was monitored by 

TLC. After completion, reaction mixture poured into water (50 mL). The precipitated 

crude product was purified by filtration followed by crystallization from EtOH. 

General synthesis of substituted and fused pyrazolopyrimidines (10a-x). 

A mixture of 5-amino-N-cyclohexyl-3-(methylthio)-1H-pyrazole-4- 

carboxamide (5) (3.0mmol), potassium carbonate (6.0mmol) and ketene dithioacetals 

(9a-x) (3.0mmol) in isopropyl alcohol (10 mL) was heated to reflux for 7-10 h. The 

progress of reaction mixture was monitored by TLC. After completion of reaction, the 

mixture was cooled to room temperature and solid residue was filtered and washed 

with 10mL of isopropyl alcohol followed by 50 ml of water. The product was 

crystallized from MeOH to give 10a-x in 87-97% yield. 


Chapter 4 


 

Spectral data of newly synthesized compounds 

2-(bis(methylthio) methylene)-4-methyl-3-oxo-N-p-tolylpentanamide 9i. yellow 

solid; mp 155-158 ° C; R f 0.54 (8:2 hexane-EtOAc); IR (KBr): 3373, 3072, 2895, 2828, 

1694, 1635, 1482, 1343, 1298 cm -1 ; 1 H NMR (400 MHz, DMSO): δ 1.18-1.20 (m, 

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), 

6.99–7.54 (m, 4H, Ar), 8.38 (br, s, 1H, -CONH); MS (m/z):323 [M + ];Anal. Calcd for 

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. 

2-(bis(methylthio)methylene)-N-(4-methoxyphenyl)-4-methyl-3-oxopentanamide 

9o. yellow solid; mp 169-171 ° C; R f 0.57 (8:2 hexane-EtOAc); IR (KBr): 3439, 3007, 

2928, 2808, 1599, 1462, 1327, 1255 cm -1 ; 1 H NMR (400 MHz, DMSO): δ 1.18-1.20 

(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, 

OCH 3 ), 6.99–7.54 (m, 4H, Ar), 8.38 (br, s, 1H, -CONH); MS (m/z):339 [M + ];Anal. 

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. 

N-(4-chlorophenyl)-2-(cyclopropylcarbonyl)-3,3-bis(methylsulfanyl)prop-2- 

enamide 9t. Yello solid; mp 138-140 ° C, R f 0.52 (8:2 hexane-EtOAc); IR (KBr): 3364, 


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 

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, 

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, 

4.10; Found: C, 52.72; H, 4.75; N, 4.12. 

2-(Cyclopropylcarbonyl)-N-(4-methoxyphenyl)-3,3-bis(methylsulfanyl)prop-2- 

enamide 9w. Yello solid; mp 154-156 ° C, R f 0.61 (8:2 hexane-EtOAc); IR (KBr): 

3354, 2925, 1684, 1525, 1450, 1285, 1112, 880, 753 cm -1 ; 1 H NMR (300 MHz, 

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 

(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 

(d, 2H, 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 : C, 56.95; H, 5.68; N, 4.15; Found: C, 56.92; H, 5.65; N, 4.12. 

N 3 -cyclohexyl-7-methyl-2,5-bis(methylthio)-N 6 -p-tolylpyrazolo[1,5-a]pyrimidine- 

3,6-dicarboxamide 10a. White solid; mp >320 o C, R f 0.31 (9:1Chloroform: 

Methanol); IR (KBr): 3309, 3254, 3016, 2925, 1671, 1473, 831, 807, 758 cm -1 ; 


Chapter 4 


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; 

Found: C, 59.56; H, 6.03; N, 14.45. 

N 6 -(3-chlorophenyl)-N 3 -cyclohexyl-7-methyl-2,5-bis(methylthio)pyrazolo[1,5-a] 

pyrimidine-3,6-dicarboxamide 10b. Creamish solid; mp >320 

o C, R f 0.40 

(9:1Chloroform : Methanol); IR (KBr): 3379, 3024, 2902, 1651, 1516,1483, 1332, 

845, 800, 756, 695 cm -1 ; 1 H NMR (300 MHz, DMSO): δ 1.35-1.81 (m, 10H,CH 2 ), 

2.45 (s, 6H, SCH 3 ), 2.70 (s, 3H, CH3), 3.79 (m, 1H, CH), 7.05 (s, 1H, Ar-H), 7.31- 

7.35 (m, 2H, Ar-H), 8.0 (s, 1H, AR-H), 8.56 (s, 1H, CONH), 12.56 (s, 1H, CONH); 

13 C NMR (100 MHz, DMSO): 12.40, 23.86, 25.34, 27.54, 30.54, 32.55, 45.86, 98.23, 

98.89, 117.29, 118.69, 121.70, 129.88, 133.31, 141.26, 148.07, 154.00, 158.20, 

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, 

54.80; H, 5.20; N, 13.89; Found: C, 54.81; H, 5.24; N, 13.89. 

N 6 -(3-chloro-4-fluorophenyl)-N 3 -cyclohexyl-7-methyl-2,5-bis(methylthio) 

pyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide 10c. White solid; mp >320 ° C, R f 

0.48 (9:1Chloroform: Methanol); IR (KBr): 3323, 3026, 2908, 2856, 1674, 1630, 

1563, 1473, 1246, 927, 843, 798, 732, cm -1 ; MS (m/z): 522 (M + ); Anal. Calcd for 

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. 

N 6 -(4-chlorophenyl)-N 3 -cyclohexyl-7-methyl-2,5-bis(methylthio)pyrazolo[1,5-a] 

pyrimidine-3,6-dicarboxamide 10d. Creamish solid; mp >320 

° C, R f 0.35 

(9:1Chloroform: Methanol); IR (KBr): 3379, 3024, 2902, 1651, 1516, 1483, 1332, 

1166, 954, 852, 822, 748, 709 cm -1 ; MS (m/z): 503 (M + ); Anal. Calcd for 

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. 

N 3 -cyclohexyl-N 6 -(4-fluorophenyl)-7-methyl-2,5-bis(methylthio)pyrazolo[1,5-a] 

pyrimidine-3,6-dicarboxamide 10e. White solid; mp >320 

° C, R f 0.28 



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. 

N 3 -cyclohexyl-7-methyl-2,5-bis(methylthio)-N 6 -(4-nitrophenyl)pyrazolo[1,5-a] 

pyrimidine-3,6-dicarboxamide 10f. Yellow solid; mp >320 ° C, R f 0.29 (9:1 

Chloroform: Methanol); IR (KBr): 3421, 3122, 3088, 2922, 1651, 1516, 1483, 1232, 


Chapter 4 



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. 

N 3 -cyclohexyl-N 6 -(4-methoxyphenyl)-7-methyl-2,5-bis(methylthio)pyrazolo[1,5-a] 

pyrimidine-3,6-dicarboxamide 10g. Creamish solid; mp >320 ° C, R f 0.36 (9:1 


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, 

5.85; N, 14.02; Found: C, 57.67; H, 5.84; N, 14.03. 

N 3 -cyclohexyl-7-methyl-N 6 -(2,5-dimethylphenyl)-2,5-bis(methylthio)pyrazolo 

[1,5-a]pyrimidine-3,6-dicarboxamide 10h. Creamish solid; mp >320 ° C, R f 0.41 




N 3 -cyclohexyl-7-isopropyl-2,5-bis(methylthio)-N 6 -p-tolylpyrazolo[1,5-a] 

pyrimidine-3,6-dicarboxamide 10i. White solid; mp >320 

° C, R f 0.35 


1566, 1313, 1246, 835, 810, 748, 667 cm -1 ; 1 H NM R(300 MHz, DMSO): δ 1.17- 

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, 

CH3), 3.79 (m, 1H, CH), 4.10-4.18 (m, 1H, i prCH), 7.09-7.19 (dd, 1H, Ar-H), 7.53- 

7.56 (d, 2H, Ar-H, J=8.1Hz), 8.21-8.23 (d, 1H, CONH), 11.94 (s, 1H, CONH); MS 

(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: 

C, 61.05; H, 6.53; N, 13.66. 

N 6 -(3-chlorophenyl)-N 3 -cyclohexyl-7-isopropyl-2,5-bis(methylthio)pyrazolo[1,5- 

a] pyrimidine-3,6-dicarboxamide 10j. White solid; mp >320 

° C, R f 0.44 


1654, 1257, 832, 806, 742 cm -1 ; MS (m/z): 532 (M + ); Anal. Calcd for 


N 6 -(3-chloro-4-fluorophenyl)-N 3 -cyclohexyl-7-isopropyl-2,5-bis(methylthio) 

pyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide 10k. Creamish solid; mp >320 ° C, R f 


1516, 1452, 1326, 880, 828, 750, 697 cm -1 ; 1 H NMR(300 MHz, DMSO): 


Chapter 4 


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, 

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- 

H), 8.10-8.12 (m, 1H, Ar-H), 8.54-8.57 (d, 1H, CONH), 12.02(s, 1H, CONH); MS 

(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; 

Found: C, 54.59; H, 5.33; N, 12.76. 

N 6 -(4-chlorophenyl)-N 3 -cyclohexyl-7-isopropyl-2,5-bis(methylthio)pyrazolo[1,5- 

a]pyrimidine-3,6-dicarboxamide 10l. White solid; mp >320 

° C, R f 0.38 


1425, 1318, 867, 817, 753, 689 cm -1 ; 1 H NMR (300 MHz, DMSO): δ 1.17-1.19(d, 

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 ), 

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- 

7.70 (d, 1H, Ar-H, J=8.4Hz), 8.53-8.57 (d, 1H, CONH), 11.96(s, 1H, CONH); MS 

(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; 

Found: C, 56.45; H, 5.67; N, 13.16. 

N 3 -cyclohexyl-N 6 -(4-fluorophenyl)-7-isopropyl-2,5-bis(methylthio)pyrazolo[1,5- 

a]pyrimidine-3,6-dicarboxamide 10m. Creamish solid; mp >320 ° C, R f 0.45 (9:1 


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; 

H, 5.86; N, 13.58; Found: C, 58.25; H, 5.87; N, 13.56. 

N 3 -cyclohexyl-7-isopropyl-2,5-bis(methylthio)-N 6 -(4-nitrophenyl)pyrazolo[1,5- 

a]pyrimidine-3,6-dicarboxamide 10n. Creamishsolid; mp >320 ° C, R f 0.34 


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 : 

C, 55.33; H, 5.57; N, 15.49; Found: C, 55.35; H, 5.57; N, 15.46. 

N 3 -cyclohexyl-7-isopropyl-N 6 -(4-methoxyphenyl)-2,5-bis(methylthio)pyrazolo 

[1,5-a]pyrimidine-3,6-dicarboxamide. 10o. White solid; mp >320 ° C, R f 0.23 





Chapter 4 


N 3 -cyclohexyl-7-isopropyl-N 6 -(2,5-dimethylphenyl)-2,5-bis(methylthio)pyrazolo 

[1,5-a]pyrimidine-3,6-dicarboxamide 10p. White solid; mp >320 ° C, R f 0.22 


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 : 

C, 61.68; H, 6.71; N, 13.32; Found: C, 61.67; H, 6.72; N, 13.36. 

N 3 -cyclohexyl-7-cyclopropyl-2,5-bis(methylthio)-N 6 -p-tolylpyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide 

10q. Creamish solid; mp >320 ° C, R f 0.35 (9:1Chloroform: 

Methanol); IR (KBr): 3460, 3226, 3047, 2938, 1615, 1539, 1422, 1336, 1066, 834, 

757 cm -1 ; 1 H NMR (300 MHz, DMSO): δ 0.98-1.01 (m, 4H, 2 ×CH 2 ), 1.16-1.37 (m, 

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 ), 

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, 

Ar-H, J=8.1Hz), 8.21-8.23 (d, 1H, CONH), 11.96 (s, 1H, CONH); MS (m/z): 509 

(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, 

6.17; N, 13.76. 

N 6 -(3-chlorophenyl)-N 3 -cyclohexyl-7-cyclopropyl-2,5-bis(methylthio)pyrazolo 

[1,5-a]pyrimidine-3,6-dicarboxamide 10r. White solid; mp >320 ° C, R f 0.43 




N 6 -(3-chloro-4-fluorophenyl)-N 3 -cyclohexyl-7-cyclopropyl-2,5-bis(methylthio) 

pyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide 10s. Creamish solid; mp >320 ° C, R f 



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. 

N 6 -(4-chlorophenyl)-N 3 -cyclohexyl-7-cyclopropyl-2,5-bis(methylthio)pyrazolo 

[1,5-a]pyrimidine-3,6-dicarboxamide 10t. Creamish solid; mp >320 ° C, R f 0.46 





Chapter 4 


N 3 -cyclohexyl-7-cyclopropyl-N 6 -(4-fluorophenyl)-2,5-bis(methylthio)pyrazolo 

[1,5-a]pyrimidine-3,6-dicarboxamide 10u. White solid; mp >320 ° C, R f 0.23 


1556, 1481, 1354, 1251, 1058, 893, 833, 792, 750, 711 cm -1 ; 13 C NMR (100 MHz, 

CDCl 3 ): 10.96, 12.35, 13.76, 23.32, 25.29, 46.23, 98.07, 99.87, 114.93, 115.14, 

120.80, 120.88, 136.19, 148.46, 153.74, 156.37, 157.47, 158.75, 161.92, 165.71, 

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, 

13.63; Found: C, 58.49; H, 5.47; N, 13.64. 

N 3 -cyclohexyl-7-cyclopropyl-2,5-bis(methylthio)-N 6 -(4-nitrophenyl)pyrazolo[1,5- 

a]pyrimidine-3,6-dicarboxamide 10v. Creamish solid; mp >320 ° C, R f 0.52 


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, 

55.54; H, 5.22; N, 15.54; Found: C, 55.55; H, 5.22; N, 15.54. 

N 3 -cyclohexyl-7-cyclopropyl-N 6 -(4-methoxyphenyl)-2,5-bis(methylthio)pyrazolo 

[1,5-a]pyrimidine-3,6-dicarboxamide 10w. Creamish solid; mp >320 ° C, R f 0.48 

(9:1Chloroform: Methanol); IR (KBr): 3445, 3247, 3038, 2952, 1628, 1539,1422, 

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, 

59.40; H, 5.94; N, 13.32; Found: C, 59.44; H, 5.92; N, 13.34. 

N 3 -cyclohexyl-7-cyclopropyl-N 6 -(2,5-dimethylphenyl)-2,5-bis(methylthio) 

pyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide 10x. Creamish solid; mp >320 ° C, R f 

0.23 (9:1Chloroform: Methanol); IR (KBr): 3258, 3158, 3038, 2948, 1645, 1558,1426, 

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 : 

C, 61.92; H, 6.35; N, 13.37; Found: C, 61.94; H, 6.32; N, 13.34. 


Chapter 4 


1 H NMR spectrum of compound 9i 

Expanded 1 H NMR spectrum of compound 9i 


Chapter 4 



1 H NMR spectrum of compound 10k 

F 

Cl 

O 

N 

H 

S 

N 

N N 

O 

S 

NH 


Chapter 4 


1 H NMR spectrum of compound 10l 

Expanded 1 H NMR spectrum of compound 10l 


Chapter 4 





Chapter 4 


13 C NMR spectrum of compound 10u 

Expanded 13 C NMR spectrum of compound 10u 


Chapter 4 


MASS spectrum of compound 10a 



Chapter 4 


MASS spectrum of compound 10o 

MASS spectrum of compound 10u 


Chapter 4 


IR Spectrum of compound 10i 

90 

%T 

75 

3279.10 

3254.02 

3016.77 

2928.04 

2850.88 

1730.21 

1681.98 

1411.94 

1369.50 

1313.57 

1246.06 

1193.98 

1111.03 

964.44 

810.13 

748.41 

667.39 

547.80 

60 

45 

1627.97 

1591.33 

1566.25 

1550.82 

1506.46 

530.44 

503.44 

468.72 

451.36 

30 

1531.53 

1481.38 

15 

0 

4000 

3500 

3000 

2500 

2000 

1750 

1500 

1250 

1000 

750 

500 

1/cm 

IR Spectrum of compound 10u 

100 

%T 

80 

60 

40 

20 

0 

F 

3408.33 

3340.82 

3277.17 

3142.15 

3070.78 

3012.91 

N 

H 

2928.04 

2852.81 

O 

S 

N 

N N 

O 

S 

NH 

1672.34 

1620.26 

1604.83 

1556.61 

1533.46 

1504.53 

1481.38 

1444.73 

1354.07 

1317.43 

1251.84 

1209.41 

1095.60 

1058.96 

974.08 

893.07 

833.28 

792.77 

750.33 

711.76 

669.32 

557.45 

522.73 

501.51 

434.00 

-20 

4000 

3500 

3000 

2500 

2000 

1750 

1500 

1250 

1000 

750 

500 

1/cm 


Chapter 4 


4.8 Reference 

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Chapter 4 


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Chapter 4 


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Chapter - 5 

Rapid Synthesis of Highly Substituted 

Pyrrole Derivatives: Analogs of 

Atorvastatin

Chapter-5 

Synthesis of highly substituted pyrroles 


Pyrrole is an important π-excessive aromatic heterocycle because this ring 

system is incorporated in as a basic structural unit in porphyrins;porphin (heam) and 

chlorine (chlorophyll) and corrins (vitamin B12) (Figure-1). More over the presence 

of pyrrole ring in system in porphobilinogen (intermediate in biosynthesis of 

porphyrins and vitamin B12), biliverdin and bilirubin (pyrrole-based bile pigments) 

and pyrrolnitrin (with antibiotic activity) has provided an impetus to the pyrrole 

chemistry. 

Figure-1 

Pyrrole has a planar pentagonal structure with four carbon atoms and nitrogen 

sp 2 -hybridized. Each ring atom forms two sp 2 -sp 2 σ -bonds to its neighbouring ring 

atoms and one sp 2 -sσ -bond to a hydrogen atom. The remaining unhybridized p- 

orbitals, one on each ring atom (with one electron on each carbon and two electron on 

nitrogen), are perpendicular to the plane of σ–bonds and overlap form a π-molecular 

system with three bonding orbitals. The six π-electrons form an aromatic sextet which 

is responsible for aromaticity and renders stability to the pyrrole ring. The C α -N and 

C α -C β bonds are shorter than normal single bonds, where as C α -C β bonds are normal 

than normal double bonds. The molecular dimentions of the pyrrole reflect cyclic 

delocalization with the environment of lone pair of electrons on the nitrogen atom. 


Chapter-5 


Pyrrole is extremely weak base because the lone pair of electrons on the 

nitrogen atom involved in the cyclic delocalization and is, therefore, less available for 

protonation. Moreover, pyrrole is a weaker base than pyridine and even than aniline in 

which lone pair on the nitrogen atom is involved in the resonance and not essentially 

contributes to the aromatic sexlet. The protonation of pyrrole at nitrogen or C 2 or C 3 

atom of the ring reduces its basicity and destroys its aromaticity. However, C- and N- 

alkyl substituents enhance the basicity of pyrrole but the electron withdrawing 

substituents on the ring make pyrrole a weaker base. 1-11 

5.2 Various synthetic approaches for highly substituted pyrroles. 

Pyrroles are generally synthesized by the cyclization reactions involving 

nucleophilic-electrophilic interactions. This is the most widely used method and 

involves the cyclizative condensation of α-aminoketones or α-amino-β-keto 

esters(three atom fragment with nucleophilic nitrogen and electrophilic carbonyl 

carbon) with β-diketones or β-ketoesters (two atom fragment with electrophilic 

carbonyl carbon and a nucleophilic carbon) with the formation of N-C 2 and C 3 -C 4 

bonds (Figure-2). 

Figure-2 

The reaction of α-aminoketones with alkynes proceeds with the nucleophilic 

addition of amino group to the electrophilic carbon of alkyne with the formation of 

enamine intermediate which on intramolecular cyclization provides pyrroles involving 

nucleophilc (β-carbon of the enamine intermediate)-electrophilic (carbonyl carbon) 

interaction with the formation of C 3 -C 4 bond (Figure-3). 12 

Figure-3 


Chapter-5 


The reaction of β-amino-α,β-unsaturated esters 91(three atom fragment) with 

nitroalkenes (two atom fragment) provides substituted pyrrole involving (3+2) 

cyclization with N-C 2 and C 3 -C 4 bonds (Figure-4). 13 

Figure-4 

Base catalyzed (3+2) cyclizative condensation of α-diketones with amines 

substituted with electron withdrawing substituents at α, α’-positions results in the 

corresponding pyrroles with the formation of C 2 -C 3 and C 4 -C 5 bonds (Figure-5). 14 

Figure-5 

The reaction of β-keto esters with α-halo ketones or aldehydes in the presence 

of ammonia or primary amine affords pyrroles involving (2+2+1) cyclization with the 

formation of N-C 2 , C 3 -C 4 and N-C 5 bonds. (Hantzsch Synthesis). The reaction 

proceeds via stabilized enamine intermediate which on C-alkylation and N-alkylation 

by α-haloketone leads to the formation of corresponding pyrrole (Figure-6). 

Figure-6 

The condensation of aliphatic aldehydes or ketones with hydrazine under 

strongly acidic conditions affords pyrroles involving (3+3) sigmatropic rearrangement 

and cyclization. (Piloty-Robinson Synthesis). This reaction can also be applied for the 

preparation of N-substituted pyrroles by condensing ketones with methyl hydrazine or 

N,N’-dimethyl hydrazine (Figure-7). 15 

R 

R 

H 2 N NH 2 

O + O 

R 

R 

H 3 C 

CH 3 

H + H + 

RH 2 C 

N NH H 

CH 2 R -NH 3 

RH 2 C 

R 

N 

H 

R 

CH 2 R 

Figure-7 


Chapter-5 


The reaction of benzoin with benzyl aryl ketones in the presence of 

ammonium acetate results in the formation of polyaryl substituted pyrroles involving 

(2+2+1) cyclization (Figure-8). 16 Figure-8 

The condensation of alkyl isocyanoacetates with aldehydes in 2:1 ratio 

proceeds to involve an initial conjugated addition followed by an anionic cyclization 

with the formation of C 2 -C 3 , C 3 -C 4 and C 4 -C 5 bonds (Figure-9). 17 

Figure-9 

It is the most general method and involves (4+1)cyclizative condensation of 

1,4-dikitones (enolizable) with ammonia or its derivatives with the formation of N-C 2 

and N-C 5 bonds 1-6, 18-19 . The reaction is considered to proceed with the successive 

attacks of nucleophilic nitrogen on the carbonyl carbon and finally followed by 

dehydration (aromatization) for which driving force is provided by the stability of the 

resulting pyrrole (Figure-10). 

Figure-10 

Metal ion assisted amination of 1,4-dienes or diynes with primary amines 

followed by cyclization provides N-substituted pyrroles (Figure 11 & 12). 20-21 

Figure 11 


Chapter-5 


Figure 12 

2-Acylaziridines undergo ring expansion reactions to provide pyrroles 

involving ring-opened dipolar intermediates (Figure-13). 22 

Figure-13 

Vinylazirines also undergo ring expansion reactions, but two isomeric pyrroles 

are obtained depending on the reaction conditions. Thermal reactions involve a 

nitrene intermediate, while photochemical reaction proceeds via a nitrile ylide 

intermediate (Figure-14). 23 

Figure-14 

The complex ring systems, formed by (3+2) cycloaddition of activated alkynes 

substituted with electron-withdrawing substituents, with mesoionic heterocycles, 

undergo extrusion reactions with the cleavage of larger ring leaving the pyrrole ring 

system intact (Figure-15). 24-26 

Figure-15 


Chapter-5 


Ethyl-3-amino-5-phenyl-1H-pyrrol-2-carboxylate found to be a useful 

intermediate in the synthesis of other nitrogen heterocycles. 27 However Elliott and coworkers 

28-29 have described that condensation of aldehyde with aminomalonate gave 

3-substituted enamine, which was cyclized in the presence of sodium methoxide to 

give 3-amino-4-benzyl-1H-pyrrol-2-carboxylate (Figure-16). 

Figure-16 

Using a similar approach toward the synthesis of pyrrole (Figure-17), Ning 

Chen, et al. 30 

were failed to synthesize 2-substituted enamine intermediate from 

benzoyl acetonitrile and diethyl aminomalonate using standard conditions such as 

azeotropic removal of water, 31 

dehydration with molecular sieves or Lawis acid 

catalysis(TiCl 4 32 , BF3.OEt 2 ) 

NH 2 

COOEt 

Ph 

O 

CN 

EtOOC 

EtOOC 

EtOOC 

NC 

N 

H 

Ph 

EtOOC 

H 2 N 

N 

H 

Ph 

Figure-17 

Considering the lower electrophilicity of the aryl ketone compared to the 

aldehyde, an alternative strategy for preparing enamine was examined. Since amines 

are known to undergo substitution reactions with chloro- and alkylthio-substituted 

olefins to yield enamines 33 , a similar approach was considered and the reaction of p- 

toluenesulfonyl enol ester of α-cyano ketone with diethyl aminomalonate was 

investigated. Tosylate was prepared by reacting benzoyl acetonitrile with p- 

toluenesulfonic anhydride (1.2 eq.) in dichloromethane and triethylamine (1.5 eq.) in 

99% yield. When a mixture of tosylate and diethyl aminomalonate hydrochloride (1.2 

eq.) were treated with an ethanolic solution of sodium ethoxide (0.2 M, 3.5 eq.), 34 the 

pyrrole was directly obtained without isolation of enamine. Addition of the amine, 

cyclization and decarboxylation occurred in one-pot at room temperature to give a 

46% overall yield of from benzoyl acetonitrile (Figure-18). 


Chapter-5 


Figure-18 

In continuation with this study prior work at Saurashtra University on 1Hpyrrole 

derrivatives clubed with substituted-1,3,4-Oxadiazoles, 1-[2,4-dimethyl-5-(5- 

phenyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-3-yl]ethanone derivatives were synthesized. 

The synthetic stretagy follows starting with acid catalyzed cyclocondensation of ethyl 

ester derivative of 3-amino-2-butenoic acid (generated insitu from ethylacetoacetate 

upon oximenation followed by reduction) with acetylacetone to afford ethyl-3-acetyl- 

2,4-dimethyl-1H-pyrrole-5-carboxylate, which was derivatized into corresponding 

hydrazide derivative on treatment with hydrazine hydrate. The hydrazide derivative 

on reaction with different aromatic and heteroaromatic acid, in the presence of 

phosphorous oxychloride affords 1-[2,4-dimethyl-5-(5-phenyl-1,3,4-oxadiazol-2-yl)- 

1H-pyrrol-3-yl]ethanone derivatives (Figure-19). 35-36 

Figure-19 

A range of 2,5-disubstituted and 2,4,5-trisubstituted pyrroles can be 

synthesized from dienyl azides at room temperature using ZnI 2 or Rh 2 (O 2 CC 3 F 7 ) 4 as 

catalysts (Figure-20). 37 

Figure-20 

The CuI/N,N-dimethylglycine-catalyzed reaction of amines with γ-bromosubstituted 

γ,δ-unsaturated ketones in the presence of K 3 PO 4 and NH 4 OAc gave the 

corresponding polysubstituted pyrroles in very good yields (Figure-20). 38 


Chapter-5 


R 

O 

R 0.1 eq. CuI 

1 

+ H 0.2 eq. N,N-dimethylglycine.HCl 

2N R 3 

R 2 

Br 

2eq.K 3 PO 4 ,2eq.NH 4 OAc 

MeCN or toluene, reflux, 10 -20 R 

h 

1 

Figure-20 

Two methods for the regioselective synthesis of tetra- and trisubstituted N-H 

pyrroles from starting vinyl azides have been developed: A thermal pyrrole formation 

via the 1,2-addition of 1,3-dicarbonyl compounds to 2H-azirine intermediates 

generated in situ from vinyl azides and a Cu(II)-catalyzed synthesis with ethyl 

acetoacetate through a 1,4-addition (Figure-21). 39 

R 

R 3 

N 

R 2 

Figure-21 

An operationally simple, practical, and economical Paal-Knorr pyrrole 

condensation of 2,5-dimethoxytetrahydrofuran with various amines and sulfonamines 

in water in the presence of a catalytic amount of iron(III) chloride allows the synthesis 

of N-substituted pyrroles (Figure-22) under very mild reaction conditions in good to 

excellent yields. 40 

Figure-22 

A new and efficient three-component reaction between dialkyl 

acetylenedicarboxylates, aromatic amines, triphenylphosphine, and arylglyoxals 

afforded polysubstituted pyrrole derivatives in high yields (Figure-23). The reactions 

were performed in dichloromethane at room temperature and under neutral 

conditions. 41 

Figure-23 


Chapter-5 


A three-component reactions of arylacyl bromides, amines, and dialkyl 

acetylene dicarboxylate in the presence of iron(III) chloride as a catalyst at room 

temperature afforded polysubstituted pyrroles in high yields (Figure-24). 42 

Ar 

O 

H 2 N R 

Br + or 

NH 4 OAc 

R 

+ 1 O 2 C 

CO 2 R 1 

15 mol - % FeCl 3 

CH 2 Cl 2 , rt, 14-16 h 

CO 2 R 1 

Ar N 

CO 2 R 1 

R 

Figure-24 

A new and efficient three-component reaction between dialkyl acetylene 

dicarboxylates, aromatic amines, triphenylphosphine, and arylglyoxals afforded 

polysubstituted pyrrole derivatives in high yields (Figure-25). The reactions were 

performed in dichloromethane at room temperature and under neutral conditions. 43 

Figure-25 


Chapter-5 


5.3 Biological activity associated with pyrrole derivatives 

Pyrrole has its own pharmaceutical importance and various activities of 

pyrrole include: 

‣ 

Selective Mono Amine Oxidase type A Inhibitors 44-57 

‣ 

Antitubercular activities 58-66 

‣ 

HIV-1 intigrase Inhibitors 67-69 

‣ 

Antiproliferative activity 70-71 

‣ 

Glycogen Synthase Kinase-3(GSK-3) Inhibitors 72-79 

‣ 

Analgesic and Antiinflammatory activity 80-81 

‣ 

Bactericidal activities 82-86 

‣ 

Fungicides and Plant Growth Regulators 87-89 

‣ 

Action on the Cardiovascular System 90-94 

‣ 

Neuronal L-type Calcium channel activator 95 

. 

5.4 Some drugs from pyrrole nucleus 44-95 

H 3 CO 

O 

O 

CH 3 

O 

N 

N 

HH 

CH 3 

O 

N O 

O 

N 

O 

OH 

Anirolac 

COOH 

H 

Ramipril 

OH 

Ketorolac 

H 

N 

N 

H 

H 

N 

N 

H 

H 

N 

(CH 2 ) 6 

H 

N (CH 2 ) 

N 6 

H 

Pyrextramine 

O 

NC 

O 

NH 

S 

S 

N 

H 3 CO 

N 

S 

O 

O 

C 2 H 5 

H 3 CO 

Pamicogrel 

O CH 

O 

3 

N N NH 

N 

Cl 

N 

Pirprofen, 

Rengasil 

HO 

N 

HN 

OH 

OH 

CH 3 

O 

CH 3 

O 

OH 

O 

Prinomide 

Zalderide 

Figure-26 

Atorvastatin 


Chapter-5 



` The above literature study reveled that pyrrole derivatives contacting 

heterocyclic molecules showed significant biological potential. 44-95 One such highly 

functionalized pyrrole derivative is Atorvastatin. It is a class of statins, which act by 

inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the 

sterol by synthesis pathway; therefore, they are used in human therapy to reduce 

cholesterol in the level of blood. These compounds also have certain (pleiotropic) 

effects, e.g. decreasing inflammation and improving the endothelial functions. 96 

Recently reports described their inhibitory effect of the growth of different pathogenic 

fungi. 97-98 Sun and Singh reported that statins directly attenuate the virulence of 

microorganisms: modulate regulatory pathway of involved in the infection process. 99 

There are also sporadic new reports on the combined application of statins and 

different antimycotics. 100-106 

Figure-27 

Thus, to investigate the potential biological effect of some new pyrrole 

derivatives (AS-01 to AS-30), we set to modify position 2 and 3 of the Atrovastatin 

intermediate (Figure-27). To achieve the targeted compounds, we have synthesized 

thirty novel 1,4-diketone from easily available b-keto esters, which was further 

condensed with amino side chain (tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2- 

dimethyl-1,3-dioxan-4-yl)acetate) using pivalic acid as a catalyst under microwave 

irradiation. The newly synthesized compounds were characterized by IR, Mass, 1 H 

NMR, 13 C NMR spectroscopy and elemental analysis. All synthesized compounds 

were evaluated for their antimicrobial activity. 


Chapter-5 



Scheme:Synthesis of highly substituted Atorvastatin analogs 

Scheme-01 

1 

O 

OH 

MDC 

SOCl 2 

O 

Cl 

ZnO 

F 

O 

F 

Br 2 /CH 3 COOH 

2 3 4 

Br 

O 

F 

Scheme-02 

Scheme-03 

N 

H 

O 

R 1 

5 

R 

O 

O 

H 2 N 

O 

O 

O 

O 

R 1 

Pivalic acid 

Cyclohexane/THF 

MW 

N 

H 

O 

R 

N 

O 

O 

O 

O 

F 

ADD-01- 30 

F 

AS-01-30 

Where R=CH 3 , (CH 3 ) 2 CH, (CH 2 ) 2 CH, R 1 =CH 3 , OCH 3 , Cl, NO 2 

Scheme 1 and 2 shows the synthetic route for the requisite starting materials. 

First, acid chloride of phenyl acetic acid (2) was prepared from phenylacetic acid (1) 

using thionyl chloride in MDC as described in literature. 107 The fridle-craft reaction of 

Compound 2 with fluorobenzene in the presence of ZnO 108 afforded 1-(4- 

fluorophenyl)-2-phenylethanone (3) with good yield. The bromination of compound 3 

using Br 2 /AcOH provided 2-bromo-1-(4-fluorophenyl)-2-phenylethanone (4). 109 

Various acetoactanilide derivatives (AAA-01-30) were prepared as described 

in chapter-4. The condensation reaction of these acetoactanilide derivative (AAA-01- 

30) with 2-bromo-1-(4-fluorophenyl)-2-phenylethanone (4) using potassium 

carbonate as a base in isopropyl alcohol afford the requisite 1,4-dicarbonyl 

compounds (ADD-01-30). 


Chapter-5 


The final coupling reaction of 1,4-dicarbonyl compounds with amino side 

chain (tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate) 

(5) in the presence of acid catalyst under microwave irradiation afford pyrrole 

derivatives. For optimization of reaction condition 1,4-dicarbonyl compound (ADD- 

01) was react with amino side chain (5) by using various acid catalyst in various 

solvents or binary mixture of solvents in conventional method and under microwave 

irradiation method. The require reaction time and obtained (%) of yield were 

summarized in table-1. 

Table-1: Optimization of reaction condition for synthesis of AS-01 in various 

conditions 

Reaction time and yield (%) 

Entry Catalyst Solvents 

Conventional MW 

Time Yield Time Yield 

h (%) min (%) 

1 PTSA Toluene 38 68 120 88 

2 PTSA Cyclohexane 36 70 110 82 

3 PTSA Cyclohexane/THF (9:1) 31 78 90 86 

4 PTSA Toluene/THF (9:1) 32 76 96 85 

5 MSA Toluene 35 78 112 81 

6 MSA Cyclohexane 34 74 100 85 

7 MSA Cyclohexane/THF (9:1) 30 80 90 87 

8 MSA Toluene/THF (9:1) 30 77 88 82 

9 Sulfamic acid Toluene 40 74 140 78 

10 Sulfamic acid Cyclohexane 42 76 148 80 

11 Sulfamic acid Cyclohexane/THF (9:1) 36 72 125 75 

12 Sulfamic acid Toluene/THF (9:1) 35 70 130 75 

13 Pivalic acid Toluene 32 85 120 82 

14 Pivalic acid Cyclohexane 36 83 105 90 

15 Pivalic acid Cyclohexane/THF (9:1) 28 90 75 95 

16 Pivalic acid Toluene/THF (9:1) 30 84 82 88 

On the basis of our study we found that using pivalic acid and binary solvent 

Cyclohexane/THF (9:1) gave an excellent yield in short time (Table-1). Having 

optimized condition in our hand, 


Chapter-5 


we carried out the reaction of various 1,4-dicarbonyl compounds (ADD-01 to 30) 

with amino side chain (5) in the presence of pivalic acid and cyclohexane/THF (9:1) 

under microwave irradiation afford pyrroles with excellent yield (Table-2). 

Table-2: Synthesis of highly functionalized pyrroles as atorvastatin analogs 

under microwave irridiation. 

Entry R R 1 Time (min) Yield (%) 

AS-01 CH 3 4-CH 3 75 95 

AS-02 CH 3 4-OCH 3 78 91 

AS-03 CH 3 4-Cl 70 94 

AS-04 CH 3 4-F 72 92 

AS-05 CH 3 4-CH 2 CH 3 80 88 

AS-06 CH 3 4-NO 2 82 85 

AS-07 CH 3 2,5diCH 3 85 86 

AS-08 CH 3 3-Cl,4-F 70 94 

AS-09 CH 3 3,4diCl 72 87 

AS-10 CH 3 2,3diCH 3 82 90 

AS-11 (CH 3 ) 2 CH 4-CH 3 78 94 

AS-12 (CH 3 ) 2 CH 4-OCH 3 80 90 

AS-13 (CH 3 ) 2 CH 4-Cl 75 95 

AS-14 (CH 3 ) 2 CH 4-F 73 94 

AS-15 (CH 3 ) 2 CH 4-CH 2 CH 3 82 90 

AS-16 (CH 3 ) 2 CH 4-NO 2 88 87 

AS-17 (CH 3 ) 2 CH 2,5diCH 3 80 92 

AS-18 (CH 3 ) 2 CH 3-Cl,4-F 72 94 

AS-19 (CH 3 ) 2 CH 3,4diCl 78 91 

AS-20 (CH 3 ) 2 CH 2,3diCH 3 80 85 

AS-21 (CH 2 ) 2 CH 4-CH 3 90 90 

AS-22 (CH 2 ) 2 CH 4-OCH 3 91 89 

AS-23 (CH 2 ) 2 CH 4-Cl 83 95 

AS-24 (CH 2 ) 2 CH 4-F 85 94 

AS-25 (CH 2 ) 2 CH 4-CH 2 CH 3 88 88 

AS-26 (CH 2 ) 2 CH 4-NO 2 87 95 

AS-27 (CH 2 ) 2 CH 2,5diCH 3 90 95 

AS-28 (CH 2 ) 2 CH 3-Cl,4-F 87 90 

AS-29 (CH 2 ) 2 CH 3,4diCl 83 94 

AS-30 (CH 2 ) 2 CH 2,3diCH 3 85 88 


Chapter-5 


The structures of ADD-01-30 were established on the basis of their elemental 

analysis and spectral data (MS, IR, and 1 H NMR). The analytical data for (ADD-05) 

revealed a molecular formula C 26 H 24 FNO 3 (m/z 417). The 1 H NMR spectrum revealed 

a triplet at δ = 1.06-1.11 ppm assigned to isopropyl-CH 3 , a singlet at δ = 2.22 ppm 

assigned to the –CH 3 protons, a quartet at δ = 2.44-2.47 ppm assigned to-CH 2 protons, 

two doublets at δ = 4.70-4.73 ppm (j=10.8Hz) and 5.36-5.39 ppm (j=10.8Hz) 

assigned to the -CH protons, two multiplets at δ = 7.03-7.35 ppm and triplet at δ = 

8.09-8.13 ppm assigned to the aromatic protons, and one broad singlet at δ = 10.16 

ppm assigned to -CONH groups. 

The structures of AS-01-30 were established on the basis of their elemental 

analysis and spectral data (MS, IR, 1 H NMR and 13 C NMR). The analytical data for 

(AS-04) revealed a molecular formula C 38 H 42 F 2 N 2 O 5 (m/z 644). The 1 H NMR 

spectrum revealed a signals at δ ppm 1.03-1.07 (m, 1H, CH), 1.30-1.63 (m, 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, CH), 

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- 

7.28 (m, 7H, Ar & NH). 

The mechanism for the synthesis of the pyrrole proceeds via Paal-Knorr 

reaction, 110 in which protonated carbonyl (B) is attacked by the amine to form the 

hemiaminal (C). The amine attacks the other carbonyl to form a 2,5- 

dihydroxytetrahydropyrrole (D) derivative which undergoes dehydration in two steps 

give the corresponding substituted pyrrole (F). 

Figure 28: Proposed mechanism for the formation of pyrroles 


Chapter-5 


5.7 Antimicrobial sensitivity testing 

WELL DIFFUSION / AGAR CUP METHOD (Lt. General Raghunath D. 1998, 

Ashok Rattan, 1998; Patel R., Patel K. 2004,) 

In vitro effectivity of antimicrobial agents can be demonstrated by observing 

their capacity to inhibit bacterial growth on suitable media. The production of a zone 

depends on two factors namely bacterial growth and concentration of antimicrobial 

agent. The hole/well punch method was first used by Bennett. This diffusion method 

has proved more effective then many other methods. According to Lt. General 

Raghunath the well technique is 5-6 times more sensitive then using disk method. 

Principle 

When antimicrobial substance is added in agar cup (made in a medium 

previously inoculated with test organism) the redial diffusion of an antimicrobial 

agent through the agar, produces a concentration gradient. The test organism is 

inhibited at the minimum inhibitory concentration (MIC), giving rise to a clear zone 

of inhibition. 

Requirements 

1. Young broth culture of a standard test organism 

2. Sterile Mueller Hinton Agar plate 

3. Solution of antimicrobial substance 

4. Cup borer 

5. Alcohol etc. 

Inoculum preparation 

Inoculum was prepared by selecting 4-5 colonies from slope of stock culture 

of the indicator organism and emulsifying them in a suitable broth. The inoculated 

broth was incubated at 37ºC till it equals turbidity of a 0.5 McFarland standard. This 

happens in 2-8 h. 


Chapter-5 


Procedure 

1. Inoculate test organism on the top of Mueller Hinton Agar plate with help of 

sterile swab. (it can be inoculated in melted agar also ) 

2. The swab was dipped in the inoculum and surface of plate was streaked with 

swab. 

3. Streaking was repeated for 3 times and each time the plate was rotated at angle 

of 60º. 

4. Sterilize the cup-borer make four cups of the diameter of 8-10 mm. at equal 

distance in the plate previously inoculated with seed culture. 

5. The depth of well was 2.5-5.0 mm. 

6. The wells have been clearly punched so the surrounding medium is not lifted 

when the plug was removed out. 

7. The plates were incubated at 37ºC for 24 h. Then the zone of inhibition 

measured and the size of zone cited in table. 


Chapter-5 


Antimicrobial Sensitivity Assay 

(Concentration 250/500/1000 µg/ml) 

Sr. 

No. 

CODE 

No. 

Pseudomonas 

aeruginosa 

Proteus vulgaris Escherichia 

coli 

Staphylococcus 

aureus 

Candida 

albicans 

250 500 1000 250 500 1000 250 500 1000 250 500 1000 250 500 1000 

1. AS-01 R R R R R R R R R R R R R R R 

2. AS-02 1.5 1.7 2.0 1.4 1.6 2.0 R R R R R R R R R 

3. AS-03 R R R R R R R R R R R R R 1.4 2.0 

4. AS-04 R 1.0 1.3 R R R R R R R R R R R R 

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 

6. AS-06 R R R R R R 1.3 1.6 1.8 1.5 1.8 2.0 R R R 

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 

8. AS-08 R R R R R R R 1.2 1.8 1.1 1.4 2.0 R R R 

9. AS-09 R R R R R R R R 1.2 R 1.3 2.0 R R R 

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 

11. AS-11 R R R R R R R R R R R 1.2 R R R 

12. AS-12 R R R R R R 1.0 1.3 1.8 1.1 1.5 2.0 R R R 

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 

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 

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 

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 

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 

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 

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 

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 

21. AS-21 R 1.4 2.0 R R R R R R R R R R R R 

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 

23. AS-23 1.0 1.3 2.0 R R R R R R R R R R R R 

24. AS-24 R 1.4 2.0 R R R R R R R 1.0 1.3 R R R 

25. AS-25 R 1.3 2.0 R R R 1.1 1.4 2.0 R R 1.0 R R R 

26. AS-26 R R 1.2 R R R 1.1 1.4 2.0 R R R R R R 

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 

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 

29. AS-29 R 1.4 2.0 R R 1.2 R 1.3 2.0 R R R R R R 

30. AS-30 R 1.4 2.0 R R 1.2 R R 1.2 R R R R R R 

31. A 1.8 1.8 1.9 1.9 - 

32. CPD 2.2 2.1 2.1 2.2 - 

33. GF 1.8 1.9 2.0 2.0 - 

34. GRF - - - - 2.6 

35. FLC - - - - 2.8 

Note: Zone of inhibition interpretation is as follows 

1. Zone size < 1.0 cm- Resistent (R) 

2. Zone size 1.0 to 1.5 cm – Intermediate 

3. Zone size > 1.5 – Sensitive 

STD Antibiotic Sensitivity Assay Concentration 40 µg/ml 

A: Ampicillin GRF: Gresiofulvin 

CPD: Cefpodoxime FLC: Fluconazole 

GF: Gatifloxacin 


Chapter-5 



In summary, we have synthesized a series of highly substituted pyrroles as a 

atorvastain analogs from novel 1,4-dicarbonyl compounds and amino side chain using 

pivalic acid as a catalyst and cyclohexane and THF as binary solvent under 

microwave irradiation technique. All the synthesized compounds were evaluated for 

their antimicrobial activity. The investigation of antibacterial and antifungal screening 

data revealed that all the tested compounds AS-01-30 showed that some of compound 

gave moderate to potent activity. The compounds AS-02, 07, 16, 19, 27, and 28 

showed comparatively good activity against gram (+ve) bacterial stains, AS-06, 13, 

18, and 22 showed comparatively good activity against gram (-ve) bacterial stains and 

AS-15, 17 and 22 showed comparatively good activity against fungal stains. 


Chapter-5 












Synthesis of 2-phenylacetyl chloride 107 (2). 


thermometer was placed phenylaceticacid (0.2mol) in MDC (100 mL). To this, slowly 

added a solution of thionyl chloride (0.25mol) in MDC (25 mL) under nitrogen 

atmosphere. The reaction mixture was stirred for 2 hrs. The progress of reaction was 

monitored by thin layer chromatography. After completion, the reaction mixture was 

evaporated to dryness under vacuum and the residue directly used for next step. 

Synthesis of 1-(4-fluorophenyl)-2-phenylethanone (3). 


thermometer was placed 2-phenylacetyl chloride (2, 1 mmol) and ZnO (powder, 0.5 

mmol) under nitrogen atmosphere. Slowly added fluorobenzne (1 mmol) in to 

reaction mixture at room temperature. Color (usually pink, but in few cases green or 

blue) developed immediately and darkened with progress of the reaction. The reaction 

mixture was kept at room temperature with occasional stirring for 1 h to complete the 

reaction (monitored by TLC). The solid mass was then eluted with dichloromethane 

(20 mL) and the dichloromethane extract was then washed with an aqueous solution 

of sodium bicarbonate and dried over anhydrous sodium sulfate. Evaporation of 

solvent furnished practically pure the corresponding product with 90 % yield. 108 


Chapter-5 


Synthesis of 2-bromo-1-(4-fluorophenyl)-2-phenylethanone (4). 


thermometer was placed 1-(4-fluorophenyl)-2-phenylethanone (3, 10 mmol) in 

methylene chloride (80 mL), slowly added Br 2 solution (10 mmol Br 2 in acetic acid 

(20 mL)) at below 10 o C. Stirred reaction mixture for 2-3 hrs at below 10 o C. After 

completion, reaction mixture poured in to ice water and extract in methylene chloride, 

separated organic layer wash with saturated sodium bicarbonate solution (2 x 50 mL) 

and brine solution (2 x 50 mL). The organic layer was separated, dried over 

anhydrous sodium sulfate and evaporated to dryness under reduce pressure. The 

residue was crystallized from methanol to afford 87 % yield, which was directly used 

for next step. 

General synthesis of acetoacetanilide derivatives (AAA-01-30). 

Compounds AAA-01-30 were prepared by following the procedure described 

in chapter-4. 

General synthesis of 1,4 dicarbonyl compounds (ADD-01-30). 

In a 50mL round bottom flask equipped with magnetic stirrer and thermometer 

was placed acetoacetanilide (AAA-01-30, 10 mmol), 2-bromo-1-(4-fluorophenyl)-2- 

phenylethanone (4, 10mmol), potassium carbonate (15mmol) and isopropyl alcohol 

(20 mL). Reaction mixture was heated at 50-55 o C for 4-5 h. The progress of reaction 

was monitored by thin layer chromatography. After completion, the reaction mixture 

was cooled to rt. The precipitate was collected by filtration and washed excessively 

with water and dried. The recrystallized from methanol to give analytically pure 

products in 70-80% yield. 

General synthesis of highly substituted pyrroles (AS-01-30). 


In a 100mL round bottom flask equipped with dean-stark apparatus, magnetic 

stirrer and thermometer was placed with 1,4 dicarbonyl compound (ADD-01-30, 2 

mmol), amino side chain (5, 2 mmol), pivalic acid (2 mmol), cyclohexane (18 mL) 

and THF (2 mL). The reaction mixture was heated to reflux temperature for 30-40 h. 

The progress of reaction was monitored by thin layer chromatography. 


Chapter-5 


After completion, the reaction mixture was cooled to rt, washed with water and 5 (%) 

sodium bicarbonate solution. The organic layer was separated, dried over anhydrous 

sodium sulfate and evaporated to dryness under reduce pressure. The residue was 

crystallized from isopropyl alcohol/water (11:5) to obtain the desire product (68-85 % 

yield). 


A flat bottom flask was charged with the 1,4 dicarbonyl compound (ADD-01- 

30, 2 mmol), amino side chain (5, 2mmol), pivalic acid (2 mmol), cyclohexane (18 

mL) and THF (2 mL). The reaction mixture was irradiated under microwave for 

appropriate time (Table-2). The progress of reaction was monitored by thin layer 

chromatography. After completion, the reaction mixture was cooled to and washed 

with water, 5 % sodium bicarbonate solution. The organic layer was separated, dried 

over anhydrous sodium sulfate and evaporated to dryness under reduce pressure. The 

residue was crystallized from isopropyl alcohol/water (11:5) to obtain the desire 

product (85-95 % yield). 


Chapter-5 


Spectral data of synthesized compounds 

2-acetyl-N-(4-ethylphenyl)-4-(4-fluorophenyl)-4-oxo-3-phenylbutanamide ADD- 

05. White solid, yield 82%, mp 190-192 ° C; R f 0.42 (9:1 Chloroform: Methanol); IR 

(KBr): 3473, 3072, 2895, 2828, 1694, 1635, 1482, 850, 780 cm -1 ; 1 H NMR (300 

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 ), 

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, 

3H, Ar), 7.18-7.35 (m, 8H, Ar), 8.09-8.13 (t, 2H, Ar), 10.16 (s, 1H, NH); MS (m/z): 

417 [M + ]; Anal. Calcd for C 26 H 24 FNO 3 : C, 74.80; H, 5.79; N, 3.36; Found: C, 74.82; 

H, 5.75; N, 3.33. 

N-(4-chlorophenyl)-2-(cyclopropanecarbonyl)-4-(4-fluorophenyl)-4-oxo-3-phenyl 

butanamide ADD-23. White solid, yield 85%, mp 220-222 ° C; R f 0.42 (9:1 


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, 

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, 

1H, CH, j=10.84Hz), 6.84-6.89 (m, 2H, Ar), 7.00-7.09 (m, 4H, Ar), 7.18-7.27 (m, 

3H, Ar), 7.34-7.40 (m, 2H, Ar); 13 C NMR (100 MHz, CDCl 3 ): δ 11.82, 13.12. 20.34, 

53.10, 66.10, 115.42, 115.90, 121.83, 122.56, 128.13, 128.70, 129.03, 129.25, 129.39, 

131.66, 131.75, 123.16, 132.19, 132.92, 132.95, 160.94, 167.04, 196.70, 205.50; MS 

(m/z): 449 [M + ]; Anal. Calcd for C 26 H 21 ClFNO 3 : C, 69.41; H, 4.70; N, 3.11; Found: 

C, 69.43; H, 4.75; N, 3.13. 

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 

AS-01. White 

solid, mp 167-169 ° C; R f 0.42 (9:1 Chloroform: Methanol); IR (KBr): 3412, 3032, 

2977, 2872, 1731, 1659, 1479, 1029, 792, 737, 709 cm -1 ; MS (m/z): 625 [M + ]; Anal. 

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. 

tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-4-((4-methoxyphenyl)carbamoyl)- 

5-methyl-3-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 

AS-02. White solid, mp 153-155 ° C; R f 0.47 (9:1 Chloroform: Methanol); IR (KBr): 

3477, 3037, 2981, 2928, 2878, 1729, 1665, 1567, 1542, 1482, 1288, 1083, 1035, 837, 

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, 

6.91; N, 4.27; Found: C, 71.35; H, 6.92; N, 4.28. 


Chapter-5 


tert-butyl 2-((4R,6R)-6-(2-(3-((4-chlorophenyl)carbamoyl)-5-(4-fluorophenyl)-2- 

methyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate AS- 

03. White solid, mp 147-149 ° C; R f 0.47 (9:1 Chloroform: Methanol); IR (KBr): 3458, 

3035, 2988, 2932, 2881, 1731, 1675, 1564, 1547, 1486, 1291, 1087, 1037, 841 cm -1 ; 

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; 

Found: C, 69.05; H, 6.42; N, 4.28. 

tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-4-((4-fluorophenyl)carbamoyl)-5- 



3030, 2979, 2937, 2879, 1725, 1660, 1560, 1535, 1473, 1290, 1095, 1031, 833, 790, 

735, 705 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 1.03-1.07 (m, 1H, CH), 1.30-1.63 (m, 

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, 

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- 

7.28 (m, 7H, Ar & NH); 13 C NMR (DEPT): (75 MHz, CDCl 3 ): δ 11.61, 19.62. 28.09, 

29.96, 36.05, 37.16, 40.23, 42.46, 65.88, 65.96, 115.11, 115.26, 115.41, 115.54, 

120.66, 120.77, 127.31, 128.66, 131.16, 132.84, 132.95; MS (m/z): 644 [M + ]; Anal. 

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, 

4.38. 

tert-butyl 2-((4R,6R)-6-(2-(3-((4-ethylphenyl)carbamoyl)-5-(4-fluorophenyl)-2- 



3063, 2995, 2974, 2875, 1724, 1660, 1533, 1255, 842, 734, 705 cm -1 ; 1 H NMR (300 

MHz, CDCl 3 ): δ ppm 1.16-1.18 (m, 4H, CH & CH 3 ), 1.31-1.76 (m, 18H, CH, CH 2 & 

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 

(m, 1H, CH), 3.89-3.97 (m, 2H, CH 2 ), 4.17 (m, 1H, CH), 6.91-6.99 (m, 7H, Ar), 

7.14-7.26 (m, 7H, Ar & NH); 13 C NMR (DEPT): (75 MHz, CDCl 3 ): δ 11.61, 15.72. 

19.62, 28.09, 28.25, 29.97, 36.05, 37.18, 40.20, 42.48, 65.89, 65.98, 115.23, 115.51, 

120.66, 119.30, 128.03, 128.62, 131.15, 132.87, 132.97; MS (m/z): 654 [M + ]; Anal. 

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. 


Chapter-5 


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 

AS- 


3036, 2979, 2945, 2887, 1723, 1659, 1567, 1541, 1471, 1287, 1095, 1038, 834, 792, 

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; 

N, 6.26; Found: C, 67.95; H, 6.25; N, 6.28. 

tert-butyl 2-((4R,6R)-6-(2-(3-((2,5-dimethylphenyl)carbamoyl)-5-(4-fluorophenyl) 

-2-methyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 


3433, 3035, 2972, 2951, 2881, 1729, 1661, 1563, 1545, 1477, 1291, 1086, 1041, 882, 

839, 786, 751, 707 cm -1 ; MS (m/z): 654 [M + ]; Anal. 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. 

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) 

acetate AS-08. White solid, mp 135-138 ° C; R f 0.51 (9:1 Chloroform: Methanol); IR 

(KBr): 3405, 3043, 2985, 2972, 2863, 1739, 1675, 1555, 1565, 1464, 1287, 1074, 

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 : 

C, 67.20; H, 6.08; N, 4.12; Found: C, 67.25; H, 6.10; N, 4.13. 

tert-butyl 2-((4R,6R)-6-(2-(3-((3,4-dichlorophenyl)carbamoyl)-5-(4-fluorophenyl) 



3447, 3024, 2956, 2964, 2878, 1746, 1661, 1569, 1545, 1447, 1278, 1064, 1049, 831, 

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; 

H, 5.94; N, 4.03; Found: C, 65.62; H, 5.95; N, 4.03. 




3416, 3039, 2967, 2977, 2861, 1734, 1679, 1545, 1565, 1442, 1297, 1043, 1034, 842, 


7.23; N, 4.28; Found: C, 73.34; H, 7.26; N, 4.30. 


Chapter-5 


tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-4-((4-methoxyphenyl)- 

carbamoyl)-3-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 


3412, 3031, 2989, 2935, 2868, 1737, 1671, 1558, 1554, 1474, 1298, 1087, 1047, 845, 

775, 734, 703 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 1.06 (m, 1H, CH), 1.30-1.65 (m, 

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, 

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), 

7.16 (s, 7H, Ar & NH); 13 C NMR (DEPT): (75 MHz, CDCl 3 ): δ 19.68, 21.64, 21.82, 

26.10, 28.09, 29.92, 35.97, 38.09, 40.79, 42.46, 65.90, 66.41, 113.86, 115.22, 115.50, 

121.47, 126.45, 128.29, 130.46, 133.14, 133.25; MS (m/z): 684 [M + ]; Anal. Calcd for 


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 

AS-11. 

White solid, mp 158-160 ° C; R f 0.47 (9:1 Chloroform: Methanol); IR (KBr): 3477, 

3037, 2987, 2939, 2878, 1735, 1651, 1567, 1529, 1474, 1291, 1082, 1037, 837, 798, 

731, 704 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 1.02-1.10 (m, 1H, CH), 1.30-1.66 (m, 

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 & 

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 

NMR (DEPT): (75 MHz, CDCl 3 ): δ 19.68, 20.83, 21.62, 21.80, 26.09, 28.09, 29.93, 

35.97, 38.09, 40.82, 42.46, 65.90, 66.41, 115.22, 115.51, 119.63, 126.48, 128.31, 

129.19, 130.47, 133.14, 133.25; MS (m/z): 668 [M + ]; Anal. Calcd for C 41 H 49 FN 2 O 5 : 

C, 73.63; H, 7.38; N, 4.19; Found: C, 73.64; H, 7.36; N, 4.19. 

tert-butyl 2-((4R,6R)-6-(2-(3-((4-chlorophenyl)carbamoyl)-5-(4-fluorophenyl)-2- 

isopropyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate. 

AS-13. White solid, yield 94%, mp 184-186 ° C; R f 0.46 (9:1 Chloroform: Methanol); 

IR (KBr): 3410, 3041, 2992, 2943, 2875, 1744, 1677, 1474, 1287, 1075, 1047, 846 

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- 

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 ), 

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 

(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 ), 

6.76 (s, 1H, NH), 6.88-6.92 (m, 4H, Ar), 7.02-7.18 (m, 9H, Ar & NH); 


Chapter-5 


13 C NMR: (100 MHz, CDCl 3 ): δ 19.68, 21.50, 21.67, 26.07, 28.09, 29.93, 35.96, 

38.07, 40.91, 42.45, 65.90, 66.39, 98.69, 114.88, 115.29, 115.50, 120.61, 121.77, 

126.70, 128.09, 128.12, 128.25, 128.43, 128.64, 128.93, 130.55, 133.14, 

133.22,134.62, 137.04, 141.93, 161.06, 163.52, 164.68, 170.20; MS (m/z): 688 [M + ]; 

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; 

N, 4.09. 

tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-4-((4-fluorophenyl)carbamoyl)-5- 

isopropyl-3-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 


3437, 3039, 2985, 2948, 2865, 1739, 1675, 1563, 1549, 1486, 1281, 1087, 1048, 837, 

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, 

6.89; N, 4.16; Found: C, 71.41; H, 6.84; N, 4.19. 

tert-butyl 2-((4R,6R)-6-(2-(3-((4-ethylphenyl)carbamoyl)-5-(4-fluorophenyl)-2- 

isopropyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 


3429, 3039, 2975, 2954, 2895, 1736, 1665, 1571, 1542, 1461, 1287, 1081, 1043, 831, 


7.53; N, 4.10; Found: C, 73.81; H, 7.54; N, 4.10. 

tert-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-4-((4-nitrophenyl) 



3427, 3045, 2969, 2956, 2875, 1729, 1678, 1581, 1557, 1464, 1271, 1097, 1045, 839, 


6.63; N, 6.00; Found: C, 68.86; H, 6.64; N, 6.05. 


-2-isopropyl-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 


3415, 3048, 2979, 2948, 2875, 1739, 1678, 1579, 1555, 1464, 1276, 1071, 1049, 876, 

849, 765, 749, 716 cm -1 ; MS (m/z): 682 [M + ]; Anal. Calcd for C 42 H 51 FN 2 O 5 : C, 

73.87; H, 7.53; N, 4.10; Found: C, 73.84; H, 7.54; N, 4.12. 


Chapter-5 


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) 


(KBr): 3399, 3053, 2975, 2982, 2875, 1736, 1684, 1564, 1573, 1475, 1283, 1062, 


C, 67.93; H, 6.41; N, 3.96; Found: C, 67.94; H, 6.42; N, 3.97. 

tert-butyl 2-((4R,6R)-6-(2-(3-((3,4-dichlorophenyl)carbamoyl)-5-(4-fluorophenyl) 



3425, 2964, 2974, 2863, 1756, 1672, 1575, 1549, 1457, 1288, 1068, 1053, 836, 764, 

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, 

6.27; N, 3.87; Found: C, 66.40; H, 6.30; N, 3.88. 




3417, 3048, 2957, 2985, 2875, 1748, 1663, 1557, 1579, 1457, 1285, 1052, 1038, 857, 


7.53; N, 4.10; Found: C, 73.84; H, 7.54; N, 4.12. 

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 

AS-21. 

White solid, mp 163-165 ° C; R f 0.35 (9:1 Chloroform: Methanol); IR (KBr): 3441, 

3228, 3101, 2978, 2941, 1730, 1643, 1491. 1247, 833, 738, 704 cm -1 ; 1 H NMR (300 

MHz, CDCl 3 ): δ 0.77 (m, 2H, CH 2 ), 0.99-1.11 (m, 3H, CH 2 & CH), 1.21-1.59 (m, 

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 

(m, 1H, CH), 4.14 (m, 3H, CH & CH 2 ), 6.84 (s, 1H, NH), 6.99-7.26 (m, 13H, Ar); 13 C 

NMR (DEPT): (75 MHz, CDCl 3 ): δ 6.81, 7.54, 7.63, 19.62, 20.84, 28.09, 29.96, 

36.01, 37.19, 40.38, 42.50, 65.91, 66.14, 115.32, 115.61, 119.50, 126.46, 128.27, 


C, 73.85; H, 7.10; N, 4.20; Found: C, 73.84; H, 7.04; N, 4.22. 


Chapter-5 


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) 


(KBr): 3421, 3045, 2975, 2948, 2852, 1742, 1664, 1569, 1567, 1461, 1291, 1079, 

1041, 851, 781, 745, 714 cm -1 ; MS (m/z): 682 [M + ]; Anal. Calcd for C 41 H 47 FN 2 O 6 : C, 

72.12; H, 6.94; N, 4.10; Found: C, 72.12; H, 6.95; N, 4.12. 

tert-butyl 2-((4R,6R)-6-(2-(3-((4-chlorophenyl)carbamoyl)-2-cyclopropyl-5-(4- 

fluorophenyl)-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl) 


(KBr): 3452, 3052, 2987, 2939, 2884, 1753, 1679, 1564, 1559, 1482, 1267, 1065, 

1039, 856 cm -1 ; MS (m/z): 686 [M + ]; Anal. Calcd for C 40 H 44 ClFN 2 O 5 : C, 69.91; H, 

6.45; N, 4.08; Found: C, 69.95; H, 6.48; N, 4.12. 

tert-butyl 2-((4R,6R)-6-(2-(2-cyclopropyl-5-(4-fluorophenyl)-3-((4-fluorophenyl) 



3499, 3052, 2975, 2957, 2854, 1742, 1665, 1572, 1556, 1478, 1271, 1073, 1053, 831, 

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, 

6.61; N, 4.18; Found: C, 71.63; H, 6.58; N, 4.12. 

tert-butyl 2-((4R,6R)-6-(2-(2-cyclopropyl-3-((4-ethylphenyl)carbamoyl)-5-(4- 



(KBr): 3438, 3043, 2965, 2943, 2887, 1736, 1645, 1562, 1532, 1456, 1272, 1061, 


74.09; H, 7.25; N, 4.11; Found: C, 74.13; H, 7.28; N, 4.12. 

tert-butyl 2-((4R,6R)-6-(2-(2-cyclopropyl-5-(4-fluorophenyl)-3-((4-nitrophenyl)- 



3413, 3052, 2972, 2961, 2865, 1739, 1688, 1571, 1562, 1476, 1269, 1084, 1051, 842, 

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, 

6.36; N, 6.02; Found: C, 68.87; H, 6.38; N, 6.08. 


Chapter-5 


tert-butyl 2-((4R,6R)-6-(2-(2-cyclopropyl-3-((2,5-dimethylphenyl)carbamoyl)-5- 

(4-fluorophenyl)-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl) 


(KBr): 3440, 3053, 2987, 2951, 2868, 1746, 1687, 1554, 1571, 1445, 1268, 1061, 

1067, 856, 859, 774, 752, 722 cm -1 ; MS (m/z): 680 [M + ]; Anal. Calcd for 


tert-butyl 2-((4R,6R)-6-(2-(3-((3-chloro-4-fluorophenyl)carbamoyl)-2-cyclopropyl 

-5-(4-fluorophenyl)-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl) 


(KBr): 3428, 3041, 2965, 2997, 2885, 1726, 1675, 1566, 1587, 1464, 1278, 1072, 


C, 68.12; H, 6.15; N, 3.97; Found: C, 68.13; H, 6.18; N, 4.01. 

tert-butyl 2-((4R,6R)-6-(2-(2-cyclopropyl-3-((3,4-dichlorophenyl)carbamoyl)-5-(4- 



(KBr): 3472, 3120, 3073, 2975, 2985, 2879, 1763, 1665, 1581, 1553, 1468, 1276, 


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. 

tert-butyl 2-((4R,6R)-6-(2-(2-cyclopropyl-3-((2,3-dimethylphenyl)carbamoyl)-5- 

(4-fluorophenyl)-4-phenyl-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl) 


(KBr): 3423, 3039, 2948, 2981, 2865, 1769, 1678, 1547, 1587, 1443, 1278, 1064, 


74.09; H, 7.25; N, 4.11; Found: C, 74.13; H, 7.28; N, 4.12. 


Chapter-5 


1 H NMR spectrum of compound ADD-23 

Cl 

O 

N 

H 

O 

O 

F 

Expanded 1 H NMR spectrum of compound ADD-23 


Chapter-5 


1 H NMR spectrum of compound AS-04 

Expanded 1 H NMR spectrum of compound AS-04 


Chapter-5 



Cl 

N 

H 

O 

N 

O 

O 

O 

O 

F 



Chapter-5 





Chapter-5 





Chapter-5 


13 C NMR spectrum of compound AS-11 

O 

N 

H 

N 

O 

O 

O 

O 

F 

13 C NMR spectrum of compound AS-13 

Cl 

N 

H 

O 

N 

O 

O 

O 

O 

F 


Chapter-5 


MASS spectrum of compound ADD-05 

MASS spectrum of compound ADD-11 


Chapter-5 


MASS spectrum of compound AS-12 

MASS spectrum of compound AS-13 


Chapter-5 


IR spectrum of compound AS-05 

100 

%T 

75 

50 

3063.06 

2995.55 

2937.68 

2875.96 

1097.53 

1033.88 

956.72 

920.08 

734.90 

705.97 

669.32 

601.81 

25 

0 

F 

3402.54 

2974.33 

N 

H 

O 

N 

O 

1724.42 

O 

1660.77 

1591.33 

1533.46 

1516.10 

O 

1411.94 

1367.58 

1313.57 

1284.63 

1255.70 

1217.12 

1203.62 

1174.69 

1155.40 

1130.32 

842.92 

532.37 

468.72 

-25 

O 

-50 

F 

4000 

3500 

3000 

2500 

2000 

1750 

1500 

1250 

1000 

750 

500 

1/cm 

IR spectrum of compound AS-21 

100 

%T 

90 

80 

3441.12 

3228.95 

3101.64 

2978.19 

1491.02 

2941.54 

1730.21 

1643.41 

1593.25 

1539.25 

1394.58 

1367.58 

1329.00 

1247.99 

1201.69 

1109.11 

1010.73 

949.01 

761.91 

738.76 

704.04 

588.31 

70 

667.39 

60 

1506.46 

1153.47 

833.28 

532.37 

50 

505.37 

40 

4000 

3500 

3000 

2500 

2000 

1750 

1500 

1250 

1000 

750 

500 

1/cm 


Chapter-5 



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Chapter - 6 

Synthesis and Characterization of Some 

New Benzodiazepine Derivatives 

1

Chapter 6 

Synthesis of benzodiazepines 


The clinical importance and commercial success associated with the 1,4- 

benzodiazepine class of central nervous system (CNS)-active agents and the utility of 

1,4-diazepines as peptide mimetic scaffolds have led to their recognition by the 

medicinal chemistry community as privileged structures. This ring system has 

demonstrated considerable utility in drug design, with derivatives demonstrating a 

wide range of biological activities. 

The ring numbering and accepted system of nomenclature for 1,4-diazepines 

are illustrated in the structures (Figure-1). These structures are representatives of the 

tautomeric forms that have been most studied. Examples of all the fully unsaturated 

monocyclic 1,4-diazepines have been described and all are very unstable. In the 

dihydro-1,4-diazepines, the 2,3-dihydro-1H compounds have been studied most. For 

benzo-analogues the 3H series are usually more stable than 1H and although the 

parent compounds of both series are unknown, there is an extensive chemistry on 

substituted analogous especially in 3H series. The benzodiazepine-2-ones have been 

widely studied as benefits their commercial importance. 

Figure-1 

On the other hand, examples of the serendipitous discovery of new drugs 

based on an almost random screening of chemicals synthesized in the laboratory are 

striking. Since 1960, when chlordiazepoxide (Librium) entered in the market, efforts 

to discover new biologically active compounds with limited side effects in 

benzodiazepines are going on which are reflected by the important number of 

publication focused in this subject. 1-5 


Chapter 6 


Diazepine derivatives constitute an important class of heterocyclic compounds 

which possess a wide range of therapeutic and pharmacological properties. 

Derivatives of benzodiazepines are widely used as anticonvulsant, antianxiety, 

analgesic, sedative, anti-depressive, and hypnotic agents 6-7 as well as antiinflammatory 

agents. 8 In the last decade, the area of biological interest of 1,5- 

benzodiazepines has been extended to several diseases such as cancer, viral infection 

and cardiovascular disorders. 9-10 In addition,1,5-benzodiazepines are key 

intermediates for the synthesis of various fused ring systems such astriazolo-, 

oxadiazolo-, oxazino- or furanobenzodiazepines. 11-14 Besides, benzodiazepine 

derivatives are also of commercial importance as dyes for acrylic fibers in 

photography. 15 Owing to their versatile applications various methods for the synthesis 

of benzodiazepines have been reported in the literature. These include condensation 

reactions of o-phenylenediamines with α,β-unsaturated carbonylcompounds, 16 with 

ketones in the presence of BF 3·Et 2 O, NaBH 4 , polyphosphoric acid or SiO 2 , 

MgO/POCl 3 , Yb(OTf) 3 , Al 2 O 3 /P 2 O 5 or AcOH under microwave conditions, 

Amberlyst-15 in the ionic liquid 1-butyl-3-methylimidazoliumbromide ([bmim]Br), 

CeCl 3·7H 2 O/NaI supported on silica gel,InBr 3 , Sc(OTf) 3 , sulfated zirconia, InCl 3 , 

CAN, ZnCl 2 under thermal conditions, AgNO 3 . 17-32 

Among all types of benzodiazepines (1,2-,1,3-, 1,4-, 1,5-, 2,3-, & 2,4- ) only 

1,4- and 1,5-benodiazepines have found wide applications in medicines, during one of 

the most important classes of the therapeutic agents with wide spread biological 

activities 33 including hypnotics, sedatives, anxiolytics and antianxiety etc, effect range 

from their well-documented anticonvulsive or tranquilizing properties, through 

pesticidal 34 or antitumor 35 action and to their more recently described peptidomimetic 

activity. 36 

Recently, structural modification has been done in diazepine ring system to 

enhance biological activity. Diazepine ring system modified at N and 3-position has 

been studied extensively. They have been tested clinically as an antitrypanosomal 

activity, 37 antiplasmodial falcipain-2 inhibitors, 38 antileukemic agents, 39 and 

endothelin Receptor Antagonists. 40 V. I. Pavlovsky et al. 41 has reported that 3- 

arylideneand 3-hetarylidene 1,4-diazepinederivatives afford good affinity toward CNS 

benzodiazepine receptors. 


Chapter 6 


6.2 Biological activities associated with diazepine derivatives 

Buckle et al. 42 has prepared 1H-benzo-1,5-diazepine-2,4-(3H,5H)-diones 

(Figure-2) from 4,2-R 2 (NH 2 )C 6 H 3 NH 2 (R 2 = H, Cl, F, COOH) by refluxing with 

malonic acid in 4N HCl for half an hour followed by nitration with fuming HNO 3 

which is antiallergic substance useful in the treatment of rhinitis, hay fever and certain 

type of asthma. 

Figure-2 

K. S. Andronati et al. 43 has prepared 3-Amino-1,2-dihydro-3h-1,4- 

benzodiazepin-2-one derivatives (Figure-3) via interaction with 3-chloro 

benzodiazepines, diethylamine, 1,6-diaminohexane, or p-nitroaniline, which is exhibit 

a pronounced anticonvulsant activity and produce significant anorexigenic effect. 

H 

N 

O 

Br 

N 

R 2 

R 1 

R 1 =H,Cl 

R 2 =N(C 2 H 5 ) 2 , NH(CH 2 ) 6 NH 2 

Figure-3 

More recent analogues of the Benzodiazepines have attracted interest as anti 

HIV compounds, such as the clinically used nevirapine and as anticancer compounds, 

such as the pyrrolo fused antitumor antibiotic DC-18 (Figure-4), analogues of which 

are in clinical development as anticancer agents. 44 

Figure-4 


Chapter 6 


Rubin et al. 45 have synthesized 4-phenyl-2-trichloromethyl-3H-1,5- 

benzodiazepine hydrogen sulphate and examined its pharmacological effects in mice, 

keeping diazepam as reference. The data suggest that this recently synthesized 

compound possesses anxiolytic activity and produces motor in co-ordination similar 

to those observed with diazepam. 

The synthesis of a new class of annulated 1,4-benzodiazepines with antipsychotic 

activity was exemplified by preparation of 10-fluoro-3-methy1-7-(2- 

thieny1)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine(Figure-5). The 

influence of variations of the fluoro-substitution pattern and variations of the fused 

ring system on the biological activity of the structural analogues was evaluated. 46 

Figure-5 

3-Acetyl coumarins when allowed react with isatin gave corresponding 3-(3’- 

hydroxy-2’-oxoindolo)acetylcoumarins, which on dehydration afforded the 

corresponding α,β-unsaturated ketones. Which on cyclocondensation with substituted 

o-phenylenediamines resulted in novel4-(2-oxo-2H-chromen-3-yl)-1,5-dihydrospiro 

[benzo[b][1,4]diazepine-2,3'-indolin]-2'-one (Figure-6). All the compounds have 

been screened for their antimicrobial and antianxiety activity in mice. 47 

Figure-6 

A library of compounds targeted to the vasopressin/oxytocin family of 

receptors was screened for activity at a cloned human oxytocin receptor using a 

reporter gene assay. Potency and selectivity were optimized to afford compound 

(Figure-7), EC 50 =33 nM. This series of compounds represents the first disclosed, 

non-peptide, low molecular weight agonists of the hormone oxytocin. 48 


Chapter 6 


H 

N 

N 

N 

O 

N 

H 

N 

N 

O 

S 

N 

N 

Figure-7 

A series of 2,3-dihydro-1,5-benzodiazepines were synthesized and evaluated 

for anti-inflammatory effects in microglia cells. 49 Among the 1,5-benzodiazepines 

tested, compound (Figure-8) strongly inhibited LPS-induced nitric oxide (NO) 

production, with an IC 50 value of 7.0 µM in the microglia cells. 

Figure-8 

A series of 2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine (Figure-9) was 

synthesized and evaluated for CNS activity. A new antianxiety screen for 

benzodiazepine-like drugs was used along with the standard anticonvulsant test. 

Structure activity relationships were discussed. 50 

Figure-9 

Walser A. et al. 51 have prepared [1,2,4]triazolo[4,3-a][1,4]benzodiazepines 

bearing an ethynyl functionality at the 8-position and the isostericthieno[3,2-f] 

[1,2,4]triazolo[4,3-a][1,4]diazepines (Figure-10) and evaluated as antagonists of 

platelet activating factor. 


Chapter 6 


Figure-10 

Nakanishi et al. 52 have reported the synthesis and pharmacological activity of 

tetrazolo, oxadiazolo and imidazothienodiazepines derivatives (Figure-11). Some of 

them were found as minor tranquilizers. 

Figure-11 

Malcolm et al. 53 have been synthesized acetamido-1,4-diazepine analogs 

(Figure-12) which worked as inhibitor of respiratory syncytial virus(RSV) and 

exhibited IC 50 in the range of 10-20 íM over all three assays routinely used. This 

molecule also demonstrated excellent pharmacokinetic properties in the rat with a 

half-life of approximately 6 hand an oral bioavailability of 76%. This suggested that 

the core benzodiazepine was relatively stable to metabolism and a good starting point 

for lead optimization. 

Figure-12 


Chapter 6 


6.3 Some pharmaceutical molecules related to benzodiazepines 

Benzodiazepines enhance the effect of the neurotransmitter gamma-amino 

butyric acid (GABA), which results in sedative, hypnotic (sleep-inducing), anxiolytic 

(anti-anxiety), anticonvulsant, muscle relaxant and amnesic action. These properties 

make benzodiazepines useful in treating anxiety, insomnia, agitation, seizures, muscle 

spasms, alcohol withdrawal and as a premedication for medical or dental procedures. 

Benzodiazepines are categorized as either short-, intermediate- or long-acting. Shortand 

intermediate-acting benzodiazepines are preferred for the treatment of insomnia; 

longer-acting benzodiazepines are suggested for the treatment of anxiety. The detail 

of benzodiazepines related drugs is given below (Figure-13). 

N 

O 

H 

N 

O 

N 

O 

Cl 

N 

O 2 N 

N 

Cl 

N 

Cl 

Diazepam 

Anticonvulsant, 

muscle relaxant 

Clonazepam 

Hypnotic 

Tetrazepam 

Skeletal muscle relaxant 

Cl 

N 

N 

N 

N 

Br 

H 3 C 

S 

N 

N 

N 

N 

N 

N 

N 

S 

N 

Cl 

Cl 

Br 

Estazolam 

short-term treatment 

of insomnia. 

N 

Brotizolam 

Sedetive-Hypnotic 

N 

Ciclotizolam 

GABA A receptor agonist 

Cl 

N 

N 

O 

OH 

Cl 

N 

N 

O 

OH 

Cl 

N 

N 

O 

OH 

F 

F 

F 

Flurazepam 

Hypnotic 

Cinolazepam 

Hypnotic 

Figure-13 

Flutoprazepam 

anxiolytic 


Chapter 6 


6.4 Synthetic methods for benzodiazepines derivatives 

The most extensively used methods for preparing 1,4-benzodiazepines begins 

with an ortho-aminobenzophenone (1). The first method involves two-step synthesis. 

The first step involves treatment of the appropriate aminobenzophenone with 

haloacetyl halide to afford the amide (2), followed by the addition of ammonia to first 

displace the chlorine giving the glycinamide (3). Then cyclization by imine formation 

will give the benzodiazepine (4). 54-55 The other method involves treating the o-aminoketone 

with an amino acid ester hydrochloride in pyridine to yield (4) (Figure-14). 

Generally, the first method gave a higher percent yield of clean product, while the 

second method facilitated the conversion of o-aminoketones to benzodiazepines in 

one step, with a variety of substituents. 54-56 

Figure-14 

Jin-Yuan Wang et al. 57 have developed a new strategy for the synthesis of 1,4- 

benzodiazepine from Methyl1-arylaziridine-2-carboxylates with N-[2-Bromomethyl(phenyl)]trifluoroacetamides 

(Figure-15). The reaction proceeds through the 

N-benzylation and highly regioselective ring-opening reaction of aziridine by bromide 

anion followed by Et 3 N mediated intramolecular nucleophilic displacement of the 

bromide by the amide nitrogen. 

R 

Br 

NH 

O 

CF 3 

MeOOC 

N 

R' 

1) CH 3 CN, reflux 11hrs 

2) Et 3 N (2.0 eq.) 

CH 3 CN, reflux, 12hrs 

F 3 COC 

R N 

N 

COOMe 

R' 

Figure-15 


Chapter 6 


Recently, Joshua et al. 58 has reported the synthesis of saturated 1,4- 

benzodiazepines and 1,4-benzodiazepin-5-ones (Figure-16) via Pd-catalyzed 

carboamination reactions using sodium tert-butoxide base and xylene as a solvent at 

refluxing condition. 

Figure-16 

Veena Yadav et al. 59 has developed an efficient microwave assisted protocol 

for the exclusive one pot synthesis of N-amino-methyl substituted 1,4- 

benzodiazepine derivatives by the reaction of N-amino-methylsubstituted isatoic 

anhydride with glycine and L-proline respectively has been described (Figure-17). 

Figure-17 

Line S. Laustsen et al. 60 has developed an efficient solid-phase method has 

been for the parallel synthesis of 1,3-dihydro-1,4-benzodiazepine-2-one derivatives 

(Figure-18). A key step in this procedure involves catching crude 2-aminobenzoimine 

(1) products on an amino acid Wang resin (2). Mild acidic conditions then promote a 

ring closure and in the same step cleavage from the resin to give pure benzodiazepine 

products (3).These synthesis strategies involve catch and release phenomena. 

Figure-18 


Chapter 6 


New 2,4-disubstituted 1,5-benzodiazepine derivatives containing different 

functional groups have been synthesized and screened for their antibacterial activity. 

The 2,4-disubstituted 1,5-benzodiazepine derivatives were synthesized by reacting 

substituted chalcones synthesized using aldol condensation with o-phenylenediamine 

(Figure-19). QSAR studies of synthesized derivatives were performed. 61 

Figure-19 

A facile and efficient synthesis of 1,5-benzodiazepines with an aryl 

sulfonamido substituent at C(3) is described. 1,5-Benzodiazepine, derived from the 

condensation of benzene-1,2-diamine and diketene, reacts with an 

arylsulfonylisocyanate via an enamine intermediate to produce 1,5-benzodiazepines 

good yields (Figure-20). 62 

Figure-20 

Goswami and Das reports the organo catalyzed one-pot synthesis of 

substituted 1,5-benzodiazepinesby condensation of o-phenylenediamine, and 1,3- 

dicarbonyl compounds at room temperature or under reflux in the presence of 

catalytic amount of L-proline as shown in (Figure-20). 63 

Figure-20 


Chapter 6 


6.5. Current research work 

The chemistry of benzodiazepines and its derivatives has been studied for over 

a century due to their diverse biological activities. It has numerous pharmacological 

and medicinal applications viz, PAF antagonists, cardiovascular agents, CNS-active 

agent, hypnotic, anxiolytic, sedative and anticonvulsant. Therefore, we set to prepare 

some new 1H-benzo[e][1,4]diazepin-2(3H)-one derivatives for their biological studies. 

The requisite starting material1,4-benzodiazepines (ADZ-03) was prepared by 

following the reported procedure. The 2-amino-4’-flouro-benzophenone (ADZ-01) 

was reacted with chloroacetylchloride to afford 2-chloro-N-(2-(4’-fluorobenzoyl) 

phenyl)acetamide (ADZ-02). It was subsequently converted to 1,4-benzodiazepines 

by the modification of the known hexamethylenetetramine-(HMTM)-based 

cyclization reaction developed by Blazevic and Kajfez. 54-55 ADZ-03 thus obtained 

was reacted with a variety of alkyl halide using KOH in DMF to give 1-substituted-5- 

(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (ADZ-04a-j). To achieve 5- 

substituted 1,4-benzodiazepines (ADZ-05a-j), 5-(4-fluorophenyl)-1H-benzo[e][1,4] 

diazepin-2(3H)-one (ADZ-03) was treated with various aromatic aldehydes in the 

presence of potassium hydroxide in toluene. The newly synthesized compounds were 

characterized by IR, Mass, 1 H NMR, 13 C NMR spectroscopy and elemental analysis. 


Chapter 6 



Scheme: Synthesis of some new benzodiazepine derivatives 

Scheme-01 

Scheme-02 

Where R= CH 3 , CH(CH 3 ) 2 , R 1 = CH 3 , F, Cl, NO 2 , X=Br 

Synthesis of 1-and 3-substituted 1,4-benzodiazepinederivatives is shown in 

sheme 1 and 2. The starting material, 2-amino-4’-flouro-benzophenone ADZ-01 was 

reacted with chloroacetyl chloride in toluene at room temperature to afforded 2- 

chloro-N-(2-(4’-fluorobenzoyl)phenyl)acetamide. The latter was converted in to 1,4- 

benzodiazepines ADZ-03 by following the literature methods using ammonium 

acetate and hexamine in EtOH. 54-55 The N-alkylation of 1,4-benzodiazepines with 

various alkyl halide in DMF at below 15 o C in the presence of potassium hydroxide 

proceeded smoothly to furnish a series of 1-substituted-5-(4-fluorophenyl)-1Hbenzo[e][1,4]diazepin-2(3H)-one 

ADZ-04a-j in good yields. Reaction time and (%) 

of yield is summarized in Table-1. 

On the other hand, the condensation of of 1,4-benzodiazepines ADZ-03 with 

aromatic aldehydes in the presence of potassium hydroxide in reluxing provided a 

series of new 3-substituted-5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one 

ADZ-05a-j in excellent yields (Table-2). 


Chapter 6 


A variety of 3-arylidine benzodiazepines bearing electron donating and electron 

withdrawing groups such as 3,4-diOCH 3 ; 4-OCH 3 ; H; 2,5-diOCH 3 ; 2-OH; 4-F; 4-Br; 

4-Cl; 4-NO 2 and 3-NO 2 were prepared. 

Table-1: Synthesis of 1-substituted benzodiazepine derivatives 

Entry R Yield (%) Time hrs 

ADZ-04a -CH 3 87 2.0 

ADZ-04b -CH 2 CH 3 83 2.5 

ADZ-04c -(CH 2 ) 2 CH 3 88 3.0 

ADZ-04d -CH(CH 3 ) 2 84 2.5 

ADZ-04e -(CH 2 ) 3 CH 3 80 3.0 

ADZ-04f -CH 2 CH(CH3) 2 89 3.5 

ADZ-04g (CH 2 ) 4 CH 3 90 2.5 

ADZ-04h -(CH 2 ) 2 CH(CH 3 ) 2 88 4.0 

ADZ-04i C 6 H 11 79 4.5 

ADZ-04j -CH 2 C 6 H 4 4-NO 2 90 4.0 

The structures of ADZ-03 were conformed on the basis of their elemental 

analysis and spectral data (MS, IR, and 1 H NMR).The analytical data for ADZ-03 

revealed a molecular formula C 15 H 11 FN 2 O 2 (m/z 254).The 1 HNMR spectrum revealed 

a singlet at 4.31ppm assigned to –CH 2 group, a four multiplet signals at δ = 7.04– 

7.57 ppm assigned to the aromatic protons, and one broad singlet at δ = 8.83 ppm 

assigned to -CONH groups. 

Table-2: Synthesis of 3-arylidine benzodiazepine derivatives 

Entry R 1 Yield (%) Time hrs 

ADZ-05a H 90 2.0 

ADZ-05b 3-NO 2 85 2.5 

ADZ-05c 3,4-diOCH 3 83 3.0 

ADZ-05d 4-OCH 3 87 2.5 

ADZ-05e 4-Cl 94 3.0 

ADZ-05f 4-F 90 3.5 

ADZ-05g 4-NO 2 92 2.5 

ADZ-05h 4-Br 89 4.0 

ADZ-05i 2-OH 80 4.5 

ADZ-05j 2,5-diOCH 3 81 4.0 


Chapter 6 


The newly synthesized compounds ADZ-04a-j were conformed on the basis 

of their elemental analysis and spectral data (MS, IR, 1 H NMR and 13 C NMR). The 

structure of ADZ-04a was supported by its mass (m/z 268) which agree with its 

molecular formula C 16 H 13 FN 2 O, its 1 H NMR spectrums held a singlet at δ =3.42 ppm 

assigned to -CH 3 , two doublet signals observed at δ =3.75-3.78 (1H, J=10.5Hz) and 

4.78-4.81 (1H, J=10.5Hz) assigned to –CH 2 group, and four multiplet signal observed 

at δ =7.05-7.65 assigned to the aromatic protons. 

All synthesized compounds ADZ-05a-j were conformed on the basis of their 

elemental analysis and spectral data (MS, IR, 1 H NMR and 13 C NMR).The analytical 

data for ADZ-05a revealed a molecular formula C 22 H 15 FN 2 O(m/z 342). Its 1 H NMR 

signals held at δ = 6.39 (s. 1H, CH), 7.08-7.12 (m, 1H, Ar), 7.21-7.37 (m, 7H, Ar), 

7.46-7.53 (m, 3H, Ar), 7.76-7.79 (m, 2H, Ar), 8.15 (s, 1H, -CONH). 


Chapter 6 



In summary, we have demonstrated a simple and effective strategy for the 

synthesis of novel1-and 3-substituted 1,4-benzodiazepines. The reaction of 1,4- 

benzodiazepines either with various alkyl halide or a variety of aromatic aldehydes in 

the presence of potassium hydroxide afforded the desired 1-and 3-substituted 1,4- 

benzodiazepine derivatives (ADZ-04a-j and ADZ-05a-j) in excellent yields. 


Chapter 6 












General procedure for the synthesis of 2-chloro-N-(2-(4- 

fluorobenzoyl)phenyl) acetamide (ADZ-02). 

To a solution of 2-amino-4’-fluorobenzophenone (0.0046 mol) in toluene 

(10mL), a solution of chloroacetyl chloride (0.0049 mol) in toluene (2 mL) was added 

drop wise at 0 °C within 0.5 h. The reaction mixture was further stirred at room 

temperature for 5 h. The resulting reaction mixture was evaporated to dryness. The 

crude product was triturated with ethanol (10 mL) and the crystalline solid separated 

was collected by filtration to give desired product ADZ-02 in 87-90% yield. 

 

General procedure for the synthesis of 5-(4-fluorophenyl)-1H-beno[e] 

[1,4]diazepin-2(3H)-one (ADZ-03). 

To a solution of 2-chloro-N-(2-(4-fluorobenzoyl)phenyl)acetamide (0.0068 

mol) in ethanol (40 mL), hexamethylenetetramine (HMTM; 0.015 mol) and 

ammonium acetate (0.015 mol) were added. The reaction mixture was stirred at reflux 

temperature for 3 h. Then the reaction mixture was evaporated to dryness. Distilled 

water (30mL) was added, and the resulting suspension was stirred at 60 °C for 0.5 h. 

The suspension was cooled to 20 °C and filtered. The crude product was crystallized 

from toluene to obtained ADZ-03 in 80-85% yield. 


Chapter 6 


General synthesis of 1-substituted-5-(4-fluorophenyl)-1H-benzo[e] 

[1,4]diazepin-2(3H)-one (ADZ-04a-j). 

To solution of 5-(4-fluorophenyl)-1H-beno[e][1,4]diazepin-2(3H)-one (0.0039 

mol) in DMF (10 ml), potassium hydroxide (0.0046 mol) and appropriate alkyl halide 

(0.0039 mol) were added at 0 o C. The reaction mixture was stirred for 3-5 h at this 

temperature. The progress of reaction was monitored by thin layer chromatography. 

After completion of reaction mixture, it was poured into cold water. The solid 

separated was filtered, washed with water and dried. The crude product was 

recrystallized from ethanol to give analytical pure product in 79-90% yield. 

General synthesis of 3-benzylidene-5-(4-fluorophenyl)-1Hbenzo[e][1,4]diazepin-2(3H)-one 

(ADZ-05a-j) 

5-(4-Fluorophenyl)-1H-beno[e][1,4]diazepin-2(3H)-one (0.0039 mol), 

potassium hydroxide (0.0039 mol) and appropriate aromatic aldehydes (0.0039 mol) 

were taken in toluene (20 mL). The reaction mixture was heated to reflux for 8-10 hrs. 

The progress of reaction was monitored by thin layer chromatography. After 

completion of reaction mixture cooled to room temperature and the solid separated 

product was filtered, washed with cold toluene and dried. The crude product was 

recrystallized from ethanol to give corresponding product ADZ-05a-j in 80-94% yield. 


Chapter 6 



2-chloro-N-(2-(4-fluorobenzoyl)phenyl)acetamide ADZ-02. White solid, mp 126- 

128 ° C; R f 0.49 (8:2 hexane-EtOAc); IR (KBr): 3373, 3072, 2895, 2828, 1694, 1635, 

1482, 1343, 1298 cm -1 ; MS (m/z): 291 [M + ]; Anal. Calcd for C 15 H 11 ClFN 2 O 2 : C, 

61.76; H, 3.80; N, 4.80; Found: C, 61.74; H, 3.82; N, 4.82. 

5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ-03. White solid, mp 

172-174 ° C; R f 0.42 (8:2 hexane-EtOAc); IR (KBr): 3182, 3120, 3068, 3051, 2955, 

1693, 1672, 1504, 1232, 1024, 839, 810, 731, 690 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): 

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, 

Ar), 7.49-7.57 (m, 3H, Ar), 8.83 (s, 1H, NH); MS (m/z): 254 [M + ]; Anal. Calcd for 


5-(4-fluorophenyl)-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ-04a. 

White solid, mp 112-114 ° C; R f 0.38 (8:2 hexane-EtOAc); IR (KBr): 3072, 2895, 2828, 

1694, 1635, 1482, 1343, 1298, 1050, 880, 834, 756 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): 

δ 3.42 (s, 3H, CH 3 ), 3.75-3.78 (d, 1H, CH, J=10.5Hz), 4.78-4.81 (d, 1H, CH, 

J=10.5Hz), 7.05-7.10 (m, 2H, Ar), 7.20-7.29 (m, 1H, Ar), 7.32-7.37 (m, 2H, Ar), 

7.54-7.65 (m, 3H, Ar); 13 C NMR: (100 MHz, CDCl 3 ): δ 34.23, 56.53, 114.83, 115.05, 

121.33, 123.69, 127.67, 129.62, 131.30, 131.39, 131.45, 134.72, 134.75, 143.54, 

162.19, 164.66, 168.13, 169.30; MS (m/z): 268 [M + ]; Anal. Calcd for C 16 H 13 FN 2 O: C, 

71.63; H, 4.88; N, 10.44; Found: C, 71.64; H, 4.84; N, 10.42. 

1-ethyl-5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ-04b. Yellow 

solid, mp 162-164 ° C; R f 0.44 (8:2 hexane-EtOAc); IR (KBr): 3078, 2865, 2821, 1686, 

1620, 1462, 1341, 1298, 1054, 834, 780 cm -1 ; MS (m/z): 282 [M + ]; Anal. Calcd for 

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. 

5-(4-fluorophenyl)-1-propyl-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ-04c. 

Yellow solid, mp 123-125 ° C; R f 0.30 (8:2 hexane-EtOAc); IR (KBr): 3068, 3024, 

2958, 2900, 1684, 1495, 1482, 808, 732, 690 cm -1 ; MS (m/z): 296 [M + ]; Anal. Calcd 

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. 


Chapter 6 


5-(4-fluorophenyl)-1-isopropyl-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ-04d. 

White solid, mp 98-100 ° C; R f 0.25 (8:2 hexane-EtOAc); IR (KBr): 3118, 3067, 3054, 


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, 

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 

(m, 3H, Ar), 7.61-7.63 (m, 2H, Ar); MS (m/z): 296 [M + ]; Anal. Calcd for 


1-butyl-5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ-04e. Yellow 

solid, mp 88-90 ° C; R f 0.28 (8:2 hexane-EtOAc); IR (KBr): 3154, 3085, 2968, 2910, 



5-(4-fluorophenyl)-1-isobutyl-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ-04f. 

Yellow solid, mp 72-74 ° C; R f 0.34 (8:2 hexane-EtOAc); IR (KBr): 3156, 3058, 2968, 



5-(4-fluorophenyl)-1-pentyl-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ-04g. White 

solid, mp 93-95 ° C; R f 0.25 (9:1 Chloroform: Methanol); IR (KBr): 3110, 3056, 2956, 



5-(4-fluorophenyl)-1-isopentyl-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ-04h. 

Yellow solid, mp 84-86 ° C; R f 0.23 (8:2 hexane-EtOAc); IR (KBr): 3125, 3089, 3021, 

2985, 1236, 1056, 854, 795, 830, 698 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ): δ 0.64-0.71 

(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, 

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. 

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 

Ar), 7.45-7.53 (m, 3H, Ar); 13 C NMR: (100 MHz, CDCl 3 ): δ 22.10, 22.54, 25.48, 

36.65, 44.74, 53.52, 57.14, 115.16, 115.37, 122.17, 124.33, 129.92, 130.13, 131.33, 

131.42, 131.48, 134.94, 134.97, 142.63, 162.89, 165.38, 168.93, 169.36; MS (m/z): 

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; 

H, 6.65; N, 8.77. 


Chapter 6 


1-cyclohexyl-5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ-04i. 


2828, 1694, 1635, 1482, 1343, 1298, 1058, 840, 732 cm -1 ; MS (m/z): 333 [M + ]; Anal. 

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. 

5-(4-fluorophenyl)-1-(4-nitrobenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ- 

04j. Yellow solid, mp 157-159 ° C; R f 0.49 (8:2 hexane-EtOAc); IR (KBr): 3241, 3068, 

3015, 2956, 2881, 1330, 1268, 1054, 834, 830,756, 701 cm -1 ; MS (m/z): 389 [M + ]; 


N, 10.77. 

3-benzylidene-5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one ADZ-05a. 


3054, 2990, 2932, 2854, 1456, 1305, 1250, 1005, 805, 732, 695 cm -1 ; 1 H NMR (400 

MHz, DMSO): δ 6.39 (s. 1H, CH), 7.08-7.12 (m, 1H, Ar), 7.21-7.37 (m, 7H, Ar), 

7.46-7.53 (m, 3H, Ar), 7.76-7.79 (m, 2H, Ar), 8.15 (s, 1H, NH); 13 C NMR: (100 MHz, 

DMSO): δ 115.25, 115.46, 118.09, 121.39, 122.58, 126.58, 126.74, 127.50, 128.07, 

128.19, 128.92, 129.90, 129.95, 131.80, 131.89, 134.41, 134.44, 134.75, 138.93, 

140.54, 162.45, 164.26, 164.94, 171.00; MS (m/z): 342 [M + ]; Anal. Calcd for 


5-(4-fluorophenyl)-3-(3-nitrobenzylidene)-1H-benzo[e][1,4]diazepin-2(3H)-one 

ADZ-05b. Yellow solid, mp 202-204 ° C; R f 0.28 (8:2 hexane-EtOAc); IR (KBr): 3390, 

3072, 2856, 2832, 1684, 1635, 1482, 1356, 1298, 830, 750, 700 cm -1 ; 1 H NMR (300 

MHz, DMSO): δ 6.44 (s. 1H, CH), 7.06-7.11 (m, 1H, Ar), 7.24-7.40 (m, 4H, Ar), 

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, 

1H, NH); 13 C NMR: (100 MHz, DMSO): δ 120.15, 120.47, 121.01, 126.53, 126.79, 

127.80, 129.01, 131.73, 134.32, 135.48, 137.11, 137.15, 137.24, 139.46, 141.68, 


C, 68.21; H, 3.64; N, 10.85; Found: C, 68.20; H, 3.67; N, 10.83. 


Chapter 6 


3-(3,4-dimethoxybenzylidene)-5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H) 

-one ADZ-05c. Yellow solid, mp 189-191 ° C; R f 0.21 (8:2 hexane-EtOAc); IR (KBr): 

3232, 2997, 2906, 2833, 1683, 1670, 1506, 1363, 1265, 1026, 848, 802, 761, 731, 690 

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; 

Found: C, 71.67; H,4.71; N, 6.93. 

5-(4-fluorophenyl)-3-(4-methoxybenzylidene)-1H-benzo[e][1,4]diazepin-2(3H)- 

one ADZ-05d. Yellow solid, mp 223-225 ° C; R f 0.24 (8:2 hexane-EtOAc); IR (KBr): 

3442, 3202, 2956, 2916, 2845, 1656, 1504, 1345, 1240, 834, 803, 765, 705 cm -1 ; MS 

(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, 

74.22; H,4.61; N, 7.57. 

3-(4-chlorobenzylidene)-5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one. 

ADZ-05e.Yellow solid, mp 192-194-225 ° C; R f 0.26 (8:2 hexane-EtOAc); IR (KBr): 

3076, 2964, 2891, 2837, 1691, 1676, 1483, 1155, 1091, 842, 761, 734, 688 cm -1 ; MS 

(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, 

70.14; H,3.75; N, 7.45. 

3-(4-fluorobenzylidene)-5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one 

ADZ-05f. Yellow solid, mp 167-169 ° C; R f 0.25 (8:2 hexane-EtOAc); IR (KBr): 3373, 

3072, 2895, 2828, 1694, 1635, 1482, 1298, 784, 746, 698, cm -1 ; MS (m/z): 360 [M + ]; 

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, 

7.72. 

5-(4-fluorophenyl)-3-(4-nitrobenzylidene)-1H-benzo[e][1,4]diazepin-2(3H)-one 

ADZ-05g. Yellow solid, yield 93%, mp 217-219 ° C; R f 0.23 (8:2 hexane-EtOAc); IR 

(KBr): 3452, 3154, 3072, 2895, 2828, 1694, 1635, 1482, 1343, 1298, 784, 765, 702, 

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, 

10.85; Found: C, 68.23; H, 3.62; N, 10.85. 

3-(4-bromobenzylidene)-5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one 

ADZ-05h. Yellow solid, mp 183-185 ° C; R f 0.29 (8:2 hexane-EtOAc); IR (KBr): 3420, 

3074, 2923, 2956, 1695, 1680, 1459, 1154, 1056, 845, 761, 734, 690 cm -1 ; MS (m/z): 

420 [M + ]; Anal. Calcd for C 22 H 14 BrFN 2 O: C, 62.72; H, 3.35; N, 6.65; Found: C, 

62.75; H, 3.34; N, 6.75. 


Chapter 6 


5-(4-fluorophenyl)-3-(2-hydroxybenzylidene)-1H-benzo[e][1,4]diazepin-2(3H)- 

one ADZ-05i. Yellow solid, mp 152-154 ° C; R f 0.42 (8:2 hexane-EtOAc); IR (KBr): 

3485, 3078, 2854, 2831, 2685, 1456, 1256, 854, 705, 684 cm -1 ; MS (m/z): 358 [M + ]; 

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, 

7.85. 

3-(2,5-dimethoxybenzylidene)-5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H) 

–one ADZ-05j. Yellow solid, mp 144-145 ° C; R f 0.25 (8:2 hexane-EtOAc); IR (KBr): 

3473, 3078, 3045, 2954, 2895, 2828, 1684, 1645, 1484, 1325, 1250, 854, 735, 697 

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; 

Found: C, 71.67; H,4.71; N, 6.93. 


Chapter 6 


1 H NMR spectrum of compound ADZ-03 

H 

N 

O 

N 

F 

1 H NMR spectrum of compound ADZ-04a 


Chapter 6 


1 H NMR spectrum of compound ADZ-04h 

Expanded 1 H NMR spectrum of compound ADZ-04h 


Chapter 6 


1 H NMR spectrum of compound ADZ-05a 

Expanded 1 H NMR spectrum of compound ADZ-05a 


Chapter 6 


1 H NMR spectrum of compound ADZ-05b 

1 H NMR spectrum of compound ADZ-05d 


Chapter 6 


13 C NMR spectrum of compound ADZ-04a 

13 C NMR spectrum of compound ADZ-05a 


Chapter 6 


MASS spectrum of compound ADZ-04i 

MASS spectrum of compound ADZ-04j 


Chapter 6 


MASS spectrum of compound ADZ-05e 

MASS spectrum of compound ADZ-05i 

H 

N 

N 

O 

OH 

F 

m/z-358 


Chapter 6 


IR spectrum of compound ADZ-03 

100 

%T 

80 

60 

40 

20 

3182.65 

3120.93 

3068.85 

2955.04 

2899.11 

1610.61 

1504.53 

1479.45 

1429.30 

1406.15 

1367.58 

1317.43 

1288.49 

1232.55 

1153.47 

1097.53 

1024.24 

945.15 

839.06 

810.13 

761.91 

731.05 

690.54 

665.46 

586.38 

0 

1693.56 

1672.34 

-20 

4000 

3500 

3000 

2500 

2000 

1750 

1500 

1250 

1000 

750 

500 

1/cm 

IR spectrum of compound ADZ-05c 

105 

%T 

90 

3232.80 

3070.78 

2997.48 

2906.82 

2833.52 

943.22 

75 

1481.38 

1419.66 

1363.72 

1319.35 

1155.40 

1138.04 

1026.16 

731.05 

690.54 

60 

1608.69 

1591.33 

1506.46 

1265.35 

848.71 

802.41 

630.74 

45 

1683.91 

1670.41 

761.91 

557.45 

538.16 

480.29 

30 

518.87 

453.29 

441 71 

15 

4000 

3500 

3000 

2500 

2000 

1750 

1500 

1250 

1000 

750 

500 

1/cm 


Chapter 6 



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Research Summary 

The work comprised in the Thesis entitled “Studies on Novel Bioactive 

Heterocyclic Compounds” is summarized as follows. 

In Chapter 1, we have presented an efficient four step protocols for the 

synthesis of diversely substituted novel pyrimidines. A series of chlorinated 

pyrimidines were synthesized from easily available Biginelli 3,4-dihydropyrimidin- 

2(1H)-ones. The chlorinated pyrimidines were then subjected to condition normally 

employed Suzuki-Miyaura coupling reaction with various phenylboronicacid 

derivatives in the presence of palladium catalyst to obtain C-phenyl pyrimidines with 

good yields. 

In Chapter 2, we have described (E)-selective synthesis of novel pyrimidine 

derivatives from pyrimidine phosphorous ylide with a variety of aldehydes via Wittig 

reaction in the presence of sodium tripolyphosphate as a base in aqueous media. 

Sodium tripolyphosphate has the several advantages of being stable, low cost and less 

toxic. All the synthesized compounds were evaluated for their antimicrobial activity. 

The investigation of antibacterial and antifungal screening revealed that all the tested 

compounds showed moderate to significant activity. 

In Chapter 3, a facile synthesis of a library containing trisubstituted pyrazoles 

and isoxazoles functionalized with cyclopropyl, thiomethyl and carboxamide moieties 

has been described. As a part of ‘green chemistry’ approach, we employed 

condensation reaction of various ketene dithioacetals with hydrazine hydrate or 

hydroxyl amine hydrochloride in solvent free reaction condition under microwave 

irradiation. The present procedure is significant over the existing methods to develop 

this class of molecules with excellent yield, purity and simple isolation of products. 

In Chapter 4, the heterocyclizations of various ketene dithioacetals with 5- 

aminopyrazole derivative were studied in details, and the influence of the reaction 

parameters and the aminoazole structure on the direction of the reaction was 

established. We found that the reaction of various ketene dithioacetals with 5-amino- 


pyrazole derivative were faster and afforded the pyrazolo[1,5-a]pyrimidine in good 

yield in the presence of K 2 CO 3 as a base and isopropyl alcohol. This study led to the 

development of a simple approach for synthesis of pyrazolo[1,5-a]pyrimidines, 

substances that potentially interesting biological and medicinal properties. 

Chapter 5 described the synthesis of a series of substituted pyrroles as a 

atorvastatin analogs. The targeted compound were achieved from novel 1,4- 

dicarbonyl compounds and amino side chain using pivalic acid as a catalyst and 

cyclohexane and THF as binary solvent under microwave irradiation technique. All 

the synthesized compounds were evaluated for their antimicrobial activity. The 

investigation of antibacterial and antifungal screening revealed that some of these 

agents posseses moderate to potent activity. 

In Chapter 6, we have demonstrated a simple and effective strategy for the 

synthesis of novel 1-and 3-substituted 1,4-benzodiazepines. The reaction of 1,4- 

benzodiazepines either with various alkyl halide or a variety of aromatic aldehydes in 

the presence of potassium hydroxide afforded the desired 1-and 3-substituted 1,4- 

benzodiazepine derivatives in excellent yields. 


List of Publications 

1. Water Mediated Construction of Trisubstituted Pyrazoles/Isoxazoles Library 

Using Ketene Dithioacetals. 

Mahesh M. Savant, Akshay M. Pansuriya, Chirag V. Bhuva, Naval Kapuriya, 

Anil S. Patel, Vipul B. Audichya, Piyush V. Pipaliya and Yogesh T. Naliapara*. 

Journal of Combinatorial Chemistry, 2010, 12, 176-180. 

2. Synthesis of some novel trifluoromethylated tetrahydropyrimidines using 

etidronic acid and evaluation for antimicrobial activity. 

Mahesh M. Savant, Akshay M. Pansuriya, Chirag V. Bhuva, Naval Kapuriya, 

Anil S. Patel, Vipul B. Audichya, Piyush V. Pipaliya and Yogesh T. Naliapara*. 

Der Pharmacia Lettre. 2009, 1 (2), 277-285. 

3. Tetraethylammoniumbromide mediated Knoevenagel condensation in water: 

Synthesis of 4-arylmethylene-3-methyl-5-pyrazolone. 

Akshay M. Pansuriya, Mahesh M. Savant, Chirag V. Bhuva, Naval Kapuriya, 

Piyush Pipaliya, Anil S. Patel, Vipul Audichya, Yogesh T. Naliapara*. 

E-Journal of Chemistry, (Accepted) 

4. Fuller’s earth catalyzed a rapid synthesis of Bis(indolyl)methanes under solvent 

free condition. 

Naval Kapuriya, Rajesh Kakadiya, Mahesh M. Savant, Akshay M. Pansuriya, 

Chirag V. Bhuva, Anil S. Patel, Piyush V. Pipaliya, Vipul B. Audichya, Sarala 

Gangadharaiah, Sridhar M. Anandalwar, Javaregowda S. Prasad, Anamik Shah, 

Yogesh T. Naliapara* Indian Journal of Chemistry B, Under Review. 


Conferences participated 

1. “15 th International conference on Bridging gaps in discovery and development: 

chemical and biological sciences for affordable health, wellness and 

sustainability” on 4-7 th Feb. 2011 at Department of Chemistry, Saurashtra 

University, Rajkot-360005. (Poster Presentation) 

2. “National seminar on emerging Trends in polymer science and Technology” on 8- 

10 th Oct. 2009 (poly-2009) at Department of Chemistry, Saurashtra 

University, Rajkot-360005. 

3. “Two Days National workshop on Patents & IPR related updates” on 19-20 th Sep. 

2009 at Department of Chemistry, Saurashtra University, Rajkot-360005. 

4. “International seminar on recent Development in structure and ligand based Drug 

Design” on 23 rd Dec. 2009 at Department of Chemistry, Saurashtra 

University, Rajkot-360005.

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