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Vekariya, Nikhil R., 2007, “Synthesis, Characterization and Pharmacological
Study of Some Bioactive Molecules”, thesis PhD, Saurashtra University
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SYNTHESIS, CHARACTERIZATION AND
PHARMACOLOGICAL STUDY OF
SOME BIOACTIVE MOLECULES
A THESIS SUBMITTED TO
THE SAURASHTRA UNIVERSITY
IN THE FACULTY OF SCIENCE
FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
IN
CHEMISTRY
By
Nikhil R. Vekariya
UNDER THE GUIDANCE OF
PROF. ANAMIK SHAH
DEPARTMENT OF CHEMISTRY
(DST-FIST Funded & UGC-SAP Sponsored)
SAURASHTRA UNIVERSITY
RAJKOT – 5 (GUJARAT, INDIA)
SEPTEMBER – 2007

Statement under O.Ph.D.7 of Saurashtra University
The work included in the thesis is done by me under the supervision of Prof.
Anamik Shah and the contribution made thereof is my own work.
Date:
Place:
Nikhil R. Vekariya

Certificate
This is to certify that the present work submitted for the Ph.D. degree of
Saurashtra University by Mr. Nikhil R. Vekariya has been the result of work
carried out under my supervision and is a good contribution in the field of
organic chemistry.
Date:
Place:
Prof. Anamik Shah

To My Family,
With Love

ACKNOWLEDGEMENT
I humbly bow my head before Almighty God for making me capable of
doing all that I propose, the work leading to my Ph.d. thesis
submission is one of that.
At the outset, express my deep sense of gratitude to Prof. Anamik
Shah for his advise during my doctoral research endeavor. As my
supervisor, he constantly forced me to remain focused on achieving
my goal. His observation and comments helped me to establish the
overall direction of the research and to move forward expeditiously
with investigation in depth. I thank him for providing me the
opportunity to work with numerous local and global peers.
My sincere thanks are due to Dr. P.H. Parsania, Prof. and Head,
Department of chemistry for him constant support, valuable
suggestions and making vailable entire infrastructure with all
sophisticated instruments.
I owe my special thanks to Dr. V.H. Shah, Dr. H.S. Joshi, Dr. Y.T.
Naliyapara, Dr.R.C. Khunt and all other faculty members of Department
of Chemistry For their kind support and dynamic cooperation during
my research tenure.
I am equally thankful to all of the non-teaching staff for extending
help and cooperation. I express my grateful acknowledgement to State
Government of Gujarat for Junior research Fellowship which shorted
out my financial worries to some extent.
My sincere thank to Dr. Ranjan A. Shah and Aditya for making me feel
homely throughout my research tenure.
My heartily thanks to my seniors Dr. Manvar Dinesh, Dr. Hrishikesh
Acharya, Dr. Arun Mishra, Dr. Chintan Dholakiya, Dr. Kena Raval, Dr.
Preeti Adlakha. Dr. Pravin Bochiya, Dr. Kuldip Upadhyay, Dr. Bhavin Dr.
Rokad and Dr. Vishal.

I would like to thank my dear lab mates Vijay, Atul, Rupesh, Jitender,
Jalpa, Rajesh, Naval, Vaibhav, Manoj, Paresh (Vasu), Samir (Jimmy),
Chirag, Axay, Nilay, Dhaval, Jyoti, Jignesh, Satish, Pankaj, Nayan,
Surani, Hitesh and Jagdish.
I further cherish the same spirit to my friends Bhakti, Pradip, Hardik,
Dhimant, Rajesh, Gopal, Jitesh, Vipul, Anil, Mathur, Dipak, Jignesh,
Ashutosh, Darshit, Mahendra, Ajay, Paresh, Kishor and Dr. Limbashiya.
At this juncture I am grateful to entire family for encouraging me and
providing every help to fulfill my task especially my father Shri.
Ratibhai Patel, beloved mother Hemiben, My elder brother Ashish and
Ritabhabhi, my brother Kamlesh Patel and uncle Mansukh Patel and
My loving sisters Alpa, shilpa, Maitry, Heer and My fiancée Daksha,
who blessed me with their good wishes relieving all type of distress
from me and for boosting my moral. I am gratified for their eternal
love, trust, support which was my strongest source of motivation and
inspiration. I owe a lifelong indebtness.
I would like to thank regional Sophisticated Instrumentation Centre,
Chandigarh for 1 H-NMR analysis; Department of Chemistry, Rajkot for
GC-MS and IR Facility; Dr. Roberta Loddo and Dr. Paolo La Colla, Italy
for anti viral screening; Dr. Cecil Kwong, TAACF, USA for anti
tubercular screening and Dr. Shailesh Gondaliya for antibacterial
screening.
Nikhil R. Vekariya

CONTENTS
CHAPTER 1
INTRODUCTION, SYNTHESIS AND CHARACTERIZATION OF SUBSTITUTED
ETHYL 3, 5-DIMETHYL-4-[5-(PHENYL)-4,5-DIHYDRO-1H-PYRAZOL-3-YL]-1H-
PYRROLE-2-CARBOXYLATE DERIVATIVES.
Introduction 01
Different methods for synthesis of pyrrole 02
Recent literature survey 04
Biological profile 09
New drugs molecule introduce under clinical trials 18
Synthetic aspects 21
Reaction Scheme 22
Reaction Mechanism 23
Experimental 24
Physical Data table 26
Spectral Analysis 27
Mass Fragmentation 29
Spectral Data 30
IR Spectra 36
1 H NMR Spectral 38
Mass Spectra 42
References 46
CHAPTER-2
INTRODUCTION, SYNTHESIS AND CHARACTERIZATION OF SOME
SYMMETRIC AND UNSYMMETRICAL DIHYDROPYRIMIDINE DERIVATIVES
CONTAINING NAPHTHYL RING.
Biological Profile 49
Recent Literature Survey 54

Synthetic Aspects 55
QSAR Study 59
Reaction Scheme 61
Experimental Observation 63
Experimental 64
Physical Data table 66
Spectral Analysis 68
Mass Fragmentation 71
Spectral Data 71
IR Spectra 78
1 H NMR Spectra 80
Mass Spectra 83
References 84
CHAPTER 3
A MINI REVIEW OF DIHYDROPYRIMIDINE DERIVATIVES
Biginelli reaction 88
Literature Survey 90
Ionic liquid 96
N 3 Acylated dihydropyrimidines 101
Heck Cyclization 102
Thiazines Schaffolds 105
Microwave Assisted Synthesis 111
Name Reaction 113
Rearrangement 116
Solid Phase Synthesis 119
Synthetic Aspects 121

CHAPTER- 4
SYNTHESIS & CHARACTERIZATION OF N-SUBSTITUTED PHENYL-7
METHYL-2,3 DIHYDRO-5H[1,3]THIAZOLO [3,2-A]PYRIMIDINES AND 3,4-
DIHYDRO-2H, 6H-PYRIMIDO [2,1-B] [1,3] THIAZINE-7-CARBOXAMIDES.
Reaction Scheme 124
Reaction Mechanism 127
Experimental Observation 129
Experimental 129
Physical Data table 131
Spectral Analysis 136
Mass Fragmentation 138
Spectral Data 139
IR Spectra 146
1 H NMR Spectra 148
Mass Spectra 154
13 C NMR Spectra 157
CHAPTER-5
SYNTHESIS AND CHARACTERIZATION OF N-ARYL SUBSTITUTED-1-
PHENYL-1,2,3,4-TETRAHYDROPYRIMDINES DERIVATIVES BY BIGINELLI
REACTION.
Reaction Scheme 158
Reaction Mechanism 160
Experimental 161
Physical Data table 163
Spectral Analysis 166
Mass Fragmentation 168
Spectral Data 168
IR Spectra 175
1 H NMR Spectra 178
Mass Spectra 182

CHAPTER-6
MICROWAVE ASSISTED SYNTHESIS OF N-(SUBSTITUTED PHENYL)-6-
METHYL-2-OXO AND THIOXO-4-PROPYL-1,2,3,4-
TETRAHYDROPYRIMIDINE-5-CARBOXAMIDES.
Reaction Scheme 184
Reaction Mechanism 187
Experimental 188
Physical Data table 189
Spectral Analysis 191
Spectral Data 193
IR Spectra 199
1 H NMR Spectra 202
Mass Spectra 203
References 206
CHAPTER-7
BIOLOGICAL ACTIVITY STUDY 213
Summary 234
Presentation of Papers & Conferences/workshops participated 236

General Protocol
1. 1 H NMR spectra were recorded on Bruker avance II 400 MHz NMR
spectrometer using TMS as an internal reference.
2. Mass spectra were recorded on GC-MS QP-2010 spectrometer.
3. IR spectra were recorded on Schimadzu FR-IR-8400 spectrometer using
KBr pellet method.
4. Elemental analysis was carried out on Vario EL III Carlo Erba 1108.
5. Thin layer chromatography was performed on Silica Gel (Merck 60 F254).
6. The chemicals used for the synthesis of compounds were purchased from
Spectrochem, Merck, Thomas-baker and SD fine chemical.
7. MPs were taken in open capillary and are uncorrected.
8. Microwave assisted reaction were carried out in QPro-M microwave
synthesizer.

Chapter-1
Introduction, Synthesis and Characterization of
Ethyl 4-[5-(substituted phenyl)-4, 5-dihydro-
1H-pyrazol-3-yl]-3, 5-dimethyl-1H-pyrrole-2-
carboxylate derivatives
1. Different method for synthesis of pyrrole 2
2. Recent literature survey 4
3. Synthetic aspects 21
4. Reaction scheme 22
5. Physical data table 26
6. Spectral analysis 27
7. Spectral data 30
8. IR spectra 36
9. 1 H NMR spectra 38
10. Mass spectra 42
11. References 46

1
1.1 INTRODUCTION
Though Bayer 1 determined its constitution in 1900, Runge 2 was first to
discovered pyrrole in 1834 as a certain coal tar fraction which was presumably
responsible for this by hydrochloric acid of pine shaving previously dipped in
them.
Anderson 3 characterized the structure of pyrrole in 1857 and was later
synthesized by heating the ammonium salt of music acid.
Pyrrole is an important π-electron excessive aromatic heterocycle. This ring
system is incorporated as a basic structural unit in several natural pigment
porphyrins, porphin (heme), chlorine (chlorophyll), and corrins (vitamin B 12 ).
Moreover the presence of pyrrole ring in porphobolinogen (I) (intermediate in
biosynthesis of porphyrins and vitamin B 12 ) has provided an impetus to the
pyrrole chemistry.
O
O
OH
HO
H 2 N
N
H
(I)
Many alkaloids and amino acids namely, proline and hydroxyl proline also contain
the reduce pyrrole system (pyrrolidine) 4 . Many natural products containing pyrrole
ring are also known 5-8 .
C H 3
N
H
O
O
CH 3
N
CH 3
O
HO
(II) (III) (IV)
H
O
CH 3
CH 3
HO
O
O
CH 3
Cl
O -
N +
O
Cl
N
H
(V)
N
H
(VI)

2
Their biological functions are as varied as are their structures 9-11 . Some natural
pyrrole are pheromones 12-13 , plant hormones 14 , or act as antibiotics 15 . An
important class of pyrrole derived natural products containing more than one
pyrrole ring are Neotropsin (VII) and Distamysin (VIII), which bind to the groove of
DNA 16 .
CH 3
N
NH NH
CH 3
NH
NH 2
N H 2
HN
NH
NH
CH 3
N
CH 3
O
CH 3
N
NH NH
CH 3
H
O
NH
N
CH 3
O
NH
NH
O
N
CH 3
NH 2
1.1.1 Different method for synthesis of pyrrole
Various methods for synthesis of pyrrole are as follows:
1. Knorr Pyrrole synthesis 17 :
This is the most widely used method and involves the cyclizative condensation of
α- amino ketones or α- amino β- keto esters with β- diketones or β-ketones with
formation of N-C 2 and C 3 -C 4 bonds.
H 3 C O
NH 2
R
+
O CH 3
R 1
H +
CH 3
COOH
H 3 C
CH 3
R
R 1
N
H
R=H, CH 3
, COOC 2
H 5 R 1
=COCH 3
, COOC 2
H 5

2. α-amino ketones react with alkynes, undergoes nucleophilic-electrophilic
interaction to provide pyrrole 18 .
3
H 3 C O
R
CH 3
+
O
O
O
CH 3
C H 3
(CH 3
) 3
CO - K + R N
CH H
3
O
O
O
O
CH 3
CH3
O
R=H, CH 3
, C 2
H 5
3. Piloty- Robinson Pyrrole synthesis 19
The condensation of aliphatic aldehyde or ketones with hydrazine under strongly
acidic conditions affords pyrrole. This reaction can also be applied for the
preparation of N-substituted pyrroles by condensing ketones with methyl
hydrazine or N,N-Dimethyle hydrazine.
CH 3
CH 3
H 3 C
CH 3
N
N
CH 3
CH 3
HCl
H3C
N
H
+ NH 3
H 3 C
4. Hantsch Pyrrole synthesis 20
The reaction of β- keto or β- keto esters with α-halo ketones or aldehyde in the
presence of ammonia or primary amine affords pyrroles.
Cl
+
H 3 C
O
O
O
O CH 3
H 3
O CH 3
NH 3
N
C
H
O
CH 3
CH 3

4
5. The reaction of β-amino-α, β-unsaturated esters with nitro alkenes provides
substituted pyrroles 21 .
C H 3
O
O
H 3 C
H
NHR 1
+
O 2
N
R 2
O
H 3 C
O R 2
R 1
C H 3
N
6. Condensation of α- diketones with amines substituted with electronwithdrawing
species at β ’ -position, results in the corresponding pyrrole 22 .
O
O
+
R
N
H
R
R
R
R=CN, COOC 2
H 5
1.1.2 RECENT LETRATURE SURVEY
1. An efficient, solvent-free, microwave-assisted coupling of chloroenones and
amines on the surface of silica gel gave 1,2-disubstituted homochiral pyrroles in
good yields 23 .
NH 2
O SiO 2
R
R
+ Cl
R''
Solvent free,
MW (500 W), 4-6 min
N
R'
R
R'
2. A mild, gold (I)-catalyzed acetylenic Schmidt reaction of homopropargyl azides
gave regiospecific substituted pyrroles. A mechanism in which azides serve as

nucleophiles toward gold (I)-activated alkynes with subsequent gold (I)-aided
expulsion of dinitrogen is proposed 24 .
5
R
N3N3
2.5 mol - % AU 2
Cl 2
5 mol % AgSbF 6
R
H
N
R''
R'
R''
CH 2
Cl 2
35 °C, 20 - 40 min
R'
3. An efficient and regioselective palladium-catalyzed cyclization of internal
alkynes and 2-amino-3-iodoacrylates gave good yields of highly functionalized
pyrroles 25 .
MeO
O
NH
O
CH3
+
R
R'
5 mol % Pd(OAc) 2
LiCl, K 2
CO 3
DMF, 65 °C, 1 - 24 h
H 2
O, DMF
MeO
60 °C, 3 - 6 h N
O H
R
R
4. Silver (I)-promoted oxidative cyclization of homopropargylamines at room
temperature provides pyrroles. Homopropargylamines are readily available by the
addition of a propargyl Grignard reagent to Schiff bases 26 .
R
SiMe 3
AgOAC
R'
N
H
CH 2
Cl 2
, r.t., 14 h
R
N
R'

6
5. A general, highly flexible Cu-catalyzed domino C-N coupling/hydroamination
reaction constitutes a straightforward alternative to existing methodology for the
preparation of pyrroles and pyrazoles 27 .
R
R'
R"
+
NH 2
Boc
5 mol % Cul
Cs 2
CO 3
THF, 80 °C, 4 - 15 h
R
NBoc
R' R"
6. An efficient and highly versatile microwave-assisted Paal-Knorr condensation
of various 1,4-diketones gave furans, pyrroles and thiophenes in good yields. In
addition, transformations of the methoxycarbonyl moiety, such as Curtius
rearrangement, hydrolysis to carboxylic acid, or the conversion into amine by
reaction with a primary amine in the presence of Me 3 Al, are studied 28 .
O CO 2 Me
H 3 C
CH 3 + H 2 N
O
R''
AcOH
MW 150 W, 12 min
170 °C, open vessel
R
N
R''
CO 2 Me
R'
7. The synthesis of N-acylpyrroles from primary aromatic amides and excess 2,5-
dimethoxytetrahydrofuran in presence of one equivalent of thionyl chloride offers
short reaction times, mild reaction conditions, and easy workup 29 .
Ar
O
NH 2
+
O
MeO OMe SOCl 2
50 or 80 °C
10 - 120 min
Ar
N
O

7
8. Propargyl vinyl ethers and aromatic amines are effectively converted into tetraand
pentasubstituted 5-methylpyrroles through a silver(I)-catalyzed propargyl-
Claisen rearrangement, an amine condensation, and a gold(I)- catalyzed 5-exodig
heterocyclization in a convenient one-pot process 30 .
O
R'
R
O
OEt
5 mol %
AGBF 4
CH 2
Cl 2
23 °C, 30 min
O
R'
O
R
OEt
5 mol %
(PPh 3
) AuCl
ArNH 2
38 °C, 0.5 - 4 h
R'
Ar N
C H 3
EtO
R
O
9. Various 2,3,4-trisubstituted pyrroles are easily accessible in one step from
readily available acetylenes and acceptor-substituted methyl isocyanides by
base-mediated or copper-catalyzed cycloadditions. Scope and limitations of both
pyrrole syntheses are discussed 31 .
C H 3
EWG
EWG NC + R EWG'
base
THF, 20 °C, 2 h
EWG
N
H
10. A novel and efficient multicomponent reaction of N-tosylimines, DMAD, and
isocyanides for the synthesis of 2-aminopyrrole systems was uncovered 32 .
Ar NTs+ RN C: +
CO 2 Me
r.t., 14 - 22 h
benzene
Ar
NTs
NH
CH 3
CO 2 Me
MeO2C
CO 2 Me

8
11. A new microwave-assisted rearrangement of 1,3-oxazolidines scaffolds is the
basis for a new, metal-free, direct, and modular construction of tetra substituted
pyrroles from terminal-conjugated alkynes, aldehyde, and primary amines under
very simple and environmental-friendly experimental conditions 33 .
CO 2 R'
O
+ R H
NEt 3
CH 2
Cl 2
O °C, 30 min
CO 2 R'
O
CH 3
CO 2 R'
R''NH 2
MW (900 W)
SiO 2
, neat, 8 min
CO2R'
R''
N
R
CO 2 R
12. Coupling of acetylene, nitrile, and a titanium reagent generated new
azatitanacyclopentadienes in a highly regioselective manner. The subsequent
reaction with sulfonylacetylene and electrophiles gave substituted pyridines
virtually as a single isomer. Alternatively, the reaction of
azatitanacyclopentadienes with an aldehyde or another nitrile gave furans or
pyrroles having four different substituents again in a regioselective manner 34 .
Ph
C 4 H 9
PrMgCl, Et 2
O
OMe
N
C 8 H 17
OMe
N
-50 o C, r.t.
1N HCl
r.t.15 min
MeO
Ph
N
H
C 8 H 17
C 4 H 9
CHO
13. An efficient synthesis of 2,3,4-trisubstituted pyrroles via intermolecular
cyclization of alkylidenecyclopropyl ketones with amines were observed. A
mechanism involving a distal cleavage of the C-C bond of the cyclopropane ring
is discussed 35 .

9
R 2
R 1
R 3
O
R 4
R 5 NH 2
0.5 eq. MgSO 4
MeCN, 80 °C
16 - 63 h
R 1
R 2
R 3
N
R 5
R 4
14. Several aryl-substituted pyrrole derivatives were prepared conveniently in a
microwave-assisted one pot-reaction from but-2-ene-1,4-diones and but-2-yne-1,
4-diones via Pd/C-catalyzed hydrogenation of the carbon-carbon double
bond/triple bond followed by amination-cyclization 36 .
O
Ar
O
Ar
+ R NH 2
MW, 200 W
PEG - 200
5 % Pd/C
0.5 -1 min
Ar
O
HO
Ar
NHR
Ar
N
R
A
1.1.3 Biological profile
Ghassan abdalla 37 and his coworkers has discovered [3,2-b]-pyridine-6-
carboxylic acid from 2-methyl-3-benzoyl-4-amino pyrrole as potential
antimicrobial agents.
CH 3
CH 3
O
N
C H 3
O
H
O
OH

10
Gaetano Dattolo 38 and his research group has proposed a new ring system,
pyrrolo [3,4-d]-1,2,3-trizine synthesized via diazotization of the 3-amino-4-
carboxamides under different conditions through an intramolecular coupling
reaction. This molecule is found to be a potential antineoplastic agent.
N
N
N
HN
O
CH 3
Wilson and group 39 recently synthesized a series of pyrazole oxime ether
derivatives were prepared and examined as cytotoxic agents. In particular, 5-
phenoxypyrazole was comparable to doxorubicin, while exhibiting very potent
cytotoxicity against XF 498 and HCT15.The antimalarial activity of chloroquinepyrazole
analogues, synthesized from the reaction of 1,1,1-trifluoro-4-methoxy-3-
alken-2-ones with 4-hydrazino-7-chloroquinoline, has been evaluated in vitro
against a chloroquine resistant Plasmodium falciparum clone. Parasite growth in
the presence of the test drugs was measured by incorporation of [ 3 H]
hypoxanthine in comparison to controls with number of drugs. Zhong Jin and coworkers
40 prepared novel ferrocene-containing propenones have been
synthesized from acetylferrocene via a Mannich-type intermediate. Sequential
condensation cyclization of these propenones with phenyl hydrazine afforded
highly substituted 4,5-dihydropyrazole derivatives, which structures have been
characterized by spectral data and single crystal X-ray diffraction analysis. In
addition, these new ferrocene-containing derivatives have been evaluated for in
vitro fungicidal activities against five selected fungi.
Jenny L. and coworkers 41 have described Novel Pyrazoles Cannabinoids:
Insights into CB 1 Receptor Recognition and Activation. Synthesis of an antagonist,
SR141716A, that selectively binds to brain cannabinoid (CB 1 ) receptors without
producing cannabimimetic activity in vivo, suggests that recognition and activation

11
of cannabinoid receptors are separable events. In the present study, a series of
SR141716A analogoues were synthesized and were tested for CB 1 binding
affinity and in a battery of in vivo tests, including hypo mobility, antinociception,
and hypothermia in mice. These analogoues retained the central pyrazole
structure of SR141716A with replacement of the 1-, 3-, 4-, and/or 5-substituents
by alkyl side chains or other substituents known to impart potent agonist activity in
traditional tricyclic cannabinoid compounds. Although none of the analogoues
alone produced the profile of cannabimimetic effects seen with full agonists,
several of the 3-substituent analogoues with higher binding affinities showed
partial agonism for one or more measures. Cannabimimetic activity was most
noted when the 3-substituent of SR141716A was replaced with an alkyl amide or
ketone group (B). None of the 3-substituted analogoues produced antagonist
effects when tested in combination with 3 mg/kg 9 -tetrahydrocannabinol (
THC). In contrast, antagonism of
9 -THC's effects without accompanying agonist
or partial agonist effects was observed with substitutions at positions 1, 4, and
5. These results suggest that the structural properties of 1- and 5-substituents are
primarily responsible for the antagonist activity of SR141716A.
9 -
O
C H 3
R
Cl
C H 3
N
R
N
NH
N
Cl
N
N
Cl
B
Cl
SR141716A
Antonello and silvio 42 synthesized 3-(4-Aroyl-1-methyl-1H-2-pyrrolyl)-N-hydroxy-
2-propenamides as a New Class of Synthetic Histone Deacetylase Inhibitors. 2.
Effect of Pyrrole-C2 and/or -C4Substitutions on Biological Activity.

12
-CONHOCH 3
O
-CONHNH 2
Cl
C
N
F
NO 2
CH 3
H 3 C
C
N
H
H 3
OCH 3
N
CH 3
CONHOH
H
CH 3
HNOC- OH
CH 3
O
P
H 5 C 2 O
NH
NH 2
CO NH
OH
OH
O
CH 3
O
CH 3
Chemical manipulations performed on lead compond 1a
O
N
CONHOH
1a
CH 3
O
O
1b
N
CH 3
CONHOH
1c
N
CH 3
CONHOH

13
O
X
N
O
CH 3
Y NHOH
2a,2f
X=none, CH 2
, CH=CH
Y=CH 2
, CH 2
CH 2
, CH=C(CH 3
)
O
X
O
O
N
CH 3
NHOH
X
2b
2g
N
CH 3
X= none, CH 2 X=none, CH 2
COOH
COOH
O
O
R
3a -f
n
N
CH 3
O
NHOH
N
CH 3
O
CH 3
n=2-7
4a-d
R =
CH
CH 3
H 3 C
CH 3
They investigated the effect on anti-HD2 activity of chemical substitutions
performed on the pyrrole-C2 ethene chains of 1a-c, which were replaced with
methylene, ethylene, substituted ethene, and 1,3-butadiene chains (compounds
2). Biological results clearly indicated the unsubstantiated ethene chain as the
best structural motif to get the highest HDAC inhibitory activity, the sole exception
to this rule being the introduction of the 1,3-butadienylmoiety into the 1a chemical
structure (IC50(2f) ) 0.77 íM; IC50(1a) ) 3.8 íM). IC50 values of compounds 3a-3f,
prepared as 1b homologues, revealed that between benzene and carbonyl group
sat the pyrrole-C4 position a hydrocarbon spacer length ranging from two to five
methylenes is well accepted by the APHA template, being that two methylenes
and five methylenes are more potent (2.3- and 1.4-fold, respectively) than 1b,
while the introduction of a higher number of methylene units (see 3e, f)
decreased the inhibitory activities of the derivatives. Particularly, 3a (IC50 ) 0.043
íM) showed the same potency as SAHA in inhibiting HD2 invitro, and it was 3000-
and 2.6-fold more potent than sodium valproate and HC-toxin and was4.3- and 6-
fold less potent than trapoxin and TSA, respectively. Finally, conformational
constrained forms of 1b-1c, prepared with the aim to obtain some information
potentially useful for a future 3D-QSAR study, showed the same (4a, b) or higher
(4c, d) HD2inhibiting activities in comparison with those of the reference drugs.

14
Molecular modeling and docking calculations on the designed compounds
performed in parallel with the chemistry work fully supported the synthetic effort
and gave insights into the binding mode of the more flexible APHA derivatives
(i.e., 3a). Despite the difference of potency between 1b and 3a in the enzyme
assay, the two APHA derivatives showed similar antiproliferative and cyto
differentiating activities in vivo on Friends MEL cells, being that 3a is more potent
than 1b in the differentiation assay only at the highest tested dose (48 íM).
Mark player 43 et al has synthesized 2, 7 disubstituted-5,6-dimethyl-[2,3-d]-1,3
oxazine-4-ones from 2-amino-3-tert-butoxycarbonyl-4,5-dimethyl pyrrole, which
are found to be the antifungal agents.
C H 3
O
O
C H 3
N
N
R 1
R
Said bayomi 44 found that 2-amino-3-cyno-4-(substituted phenyl)-pyrroles acts as
an antimicrobial agents.
H 3 C
N
N
H 3 C
N
NH 2
H
H 3 C
N
NH 2
H
Carsin and John 45 and his group found that pyrrolyl heteroaryl methanones and
methanols are useful as treating or modulating central nervous system disorders.
The preparation of these molecules was carried out by Friedel-Crafts acylation of
(4-choro phenyl, 1-methyl-1H-pyrrole-2-yl) methanones with isonicotinoyl chloride

in the presence of AlCl 3 in dichloro ethane for 16 hrs. This compounds exhibited
anticonvulsant activity on the mouse.
15
R 3
Z
B
Cl
O
N
A
O
R 2
N
R 1
O
CH 3
Z
A
R 3
N
R 1
B
O
R 2
A =(un)substituted aryl, heteroaryl
B =(un)substituted heteroaryl
Z =oxo, hydroxy
R 1
= (un)substituted alkyl, cycloalkyl,aryl
R 2
,R 3
=independently H, alkyl, halogen
Kaizeman 46 et al has discovered potent DNA groove binding antibacterials which
has shown improved tolerability in vivo and in vitro with excellent antibacterial
potency against broad Gram positive pathogens, including drug resistant strains
such as methicillin-resistant Staphylococcus aureus, penicillin-resistant
Streprococcus pneumonia and vancomycin-resistant Enterococcus faecalis.
R
O
NH
N
NH
N
H 3
CH 3 O
C
O
N
NH
N
NH
O
O
CH 3
Pyrrole derivatives and their salts having structure type, shown below are useful
as inhibitors of the human immunodeficiency virus (reverse transcriptase)
enzyme which is involved in viral replication and consequently may be
advantageously used as therapeutics agents for HIV mediated process. 47

16
R 3
R 4
R 1
,R 2
,R 3
,=H, alkyl, cycloalkyl, aryl
R 2
X
R
N 5
R 1
R 4
=H, alkyl, COOH, CN,
R 5
=alkyl, aryl
X=S, SO, SO 2
,O,N etc
Reduced pyrrole derivatives such as pyrrolidine-2-carboxilic acid hydrazide
derivatives for use as metalloprotease inhibitors 48 .
R 1 S
R 3
R 4
R 5
N
XR 2
O
N
Febrizio and group have synthesized 2,4-dicarboxy-pyrroles and tested as
selective non-competitive mGluR1 antagonists 49 .
H3C
CH CH 3 3
H C
O
3
O
CH 3
C H 3
N
H
O
O CH 3
Various reduce pyrrole derivatives such as pyrroline, pyrrolidine are active on the
cardiovascular apparatus and useful for preparation of structurally modified
bioactive peptides 50 .

17
O
OH
HN
OH
Wijngaarden 51 and research group have synthesized a series of 2-phenylpyrrole
Mannich bases and screened in pharmacological models for antipsychotic activity
and extrapyramidal effects. They made structure modification of 5-(4-
flourophenyl)-2-[4-(2-methoxyphenyl)-I-piperazinyl] methyl pyrrole, the prototype
of new class of sodium independent atypical dopamine D-2 anganosits and
resulted in 2-[4-(7-benzofuranyl)-I-piperazinyl] methyl-5-(flouro phenyl) pyrrole,
which was an even more potent and selective D-2 anganosits than the parent
compound. They found excellent oral activity in the apomorphine induced
climbing behavior and the conditioned avoidance response tests and the absence
of catalepsy make this compound particularly promising as a potential
antipsychotic with low propensity to induce acute extrapyramidal side effect.
F
N
H
N
F
N
H
N
N
O
CH3
N
CF 3
(I)
(II)
Demetri 52 has suggest, GIST is the most common mesenchymal cancer of the
gastrointestinal tract. Activating mutations in KIT are common in GIST, and
imatinib, which also inhibits KIT, was found to be the first RTK inhibitors to show
efficacy in this cancer, dramatically improving disease outcome 43 . However,
resistance to imatinib resulting from subsequent mutations in KIT has emerged.

18
CH 3
CH 3
N
C
O
NH
H 3
CH 3
F
N
H
O
N
H
1.1.4 NEW DRUG MOLECULE INTRODUCE UNDER CLINICAL STUDY
New drug molecules which are related to the pyrrole ring structure, are under
study for phase-I to phase- IV clinical trial for different pharmacological action.
Few selected example are showed under.
Drug Name
:
53
A-2545
Chemical Structure :
H 3 C
CH 3
HN
H 3 C
H 3 C
O
NH
N
O
O
Chemical Name
Phase
Activity
HCl
: 2,2,5,5-Tetra Methyl-N-(3-pthalimidopropyl)-2,5-
dihyro-1H-pyrrole-3-carboxamide hydrochloride
: Preclinical
: Antiarrhythnic Drug; Sodium Channel Blockers;
Calcium antagonists
Drug Name
Chemical Structure :
:
54
Anirolac, RS-37326
C H 3
O
O
N
OH
O

19
Chemical Name
Phase
Activity
: (+)-5-(4-methoxybenzoyl)-1,2-dihyro-3Hpyrrolo[1,2-a]pyrrole-1-carboxylic
acid
: Phase II
: Non-steroidal anti-inflammatory Drug
Drug Name
Chemical Structure :
:
55
ketorolac, RC-37619
Chemical Name
Phase
Activity
OH
N
O
O
: (+)-5-Benzoyl-1, 2-dihydro-3H-pyrrolo [1,2-a]
pyrrole -1-carboxylic acid
: Launched-1990
: Non-Opioid Analgesic; Non-steroidal
Antiinflammatory
Drug Name
Chemical Structure :
:
56
OP-2507
O
CH 3
O
N
CH 3
HO
H
OH
Chemical Name
Phase
Activity
: 15-cis-(4-N-propylcyclohexyl)-
16,17,18,19,20-pentanor-9-deoxy-6,9-alphanitrilo
PGF1 methyl ester
: Phase II
: Cognition-enhancing Drug; Cerebral
Antiischemics ; Hepatoprotectants

20
Drug Name
Chemical Structure :
:
57
Medosan-27
CH 3
O
O
H 3 C
N
CH 3
N
O
N
H 3 C
O
O
N
N
Chemical Name
acid-
Phase
Activity
: 1-Methyl-5-(4-methylbenzoyl)pyrrole-2-acetic
2-(thiophylline-7-yl)ethyl ester
: Phase I
: Aantiplatelet Therapy; Bronchodilators;
Thromboxane A2 Antagonists; Non-steroidal
Antiinflammatory Drug; Thromboxane Synthase
Inhibitors; Methylxanthines
Drug Name
:
58
Org-5222
Chemical Structure :
O
H
H
Cl
COOH
N
CH 3
COOH
Chemical Name
Phase
Activity
: Transe-5-chloro-2-methyl-2,3,3a-tetrahydro-
1H-dibenz [2,3:6,7] oxepine[4,5-c]pyrrole
Maleate (1:1)
: Phase II
: Antipsychotic Drugs; 5-HZ2A antagonists;
Dopamine D2 Antagonists
Drug Name : Pamicogrel, KB-3022 59

21
Chemical Structure :
CH 3
N
N
O
H 3 C
O
S
O
H 3 C
O
Chemical Name
Phase
Activity
: 2-[4,5-Bis(4-methoxyphenyl)thiazol-2-yl]
Pyrrole-1-aceticacid ethyl ester
: pre-registered
: Antiplatelet Therapy; Cyclooxygenase
Inhibitors
1.2 SYNTHETIC ASPECT
In the present chapter, the aspect was to develop the molecules of
pharmacological interest, encircled different heterocyclic ring system with pyrrole
ring which is documented as significant pharmacophore for treatment of
tuberculosis, HIV, schizophrenia, anxiety, depression, circadiac rhythm disorders,
diabetes, impaired glucose tolerance tumors, autoimmune disease and many
others.
Serving as an excellent intermediate with other chemical structures leading to
large number of heterocycles, pyrrole it self is very well explored in analytical and
pharmaceutical chemistry and their biological properties are also documented in
last few years. This data promoted us to investigate the biological properties of
this structure class.
Earlier in our laboratory, pyrrole derivatives with oxadiazole ring on side chain are
synthesized and their biological profile showed promising results. In continuation
of this work pyrrole derivatives with pyrazol ring on side chain are synthesized in
current chapter. The physical data and spectral data of synthesized compounds
are given in Section 1.6 and 1.7.

22
1.3 REACTION SCHEMES
1.3.1 Scheme 1
H 3 C O
H 3 C
HNO 2
H 3 C O
H 3 C O
O
O
O
Zn/CH 3
COOH
N
OH
C H 3
O
O
H 3 C O
NH 2
acetyl acetone
O
H 3 C
CH 3
CH 3
O
O
N
H
H 3 C
1.3.2 Scheme 2
R
O
H
H
3 C CH 3
3 C
O
+
O
N
H
CH 3
O
H
R
KOH
CH 3
OH
O
H 3 C
O
H 3 C
CH 3
O
N
H

23
1.3.3 Scheme 3
O
H
H
3 C
3 C
O
NH 2
NH 2
O
N
H
CH 3
C 2
H 5
OH, reflux
R
C H 3
O
H 3 C
CH 3
O
N
H
N
H
N
R
1.3.4 REACTION MECHANISM
H 3
RC
O
+
R 1
+H +
C
O
R 1
+H +
H 3
R
..
NH 2
O
CH 3
-H + +
NH 2
CH 3
-H +
OH
H 3
C
O
H 3
C
O
R
..
NH
OH
R 1
+H +
CH 3
-H + R
..
NH
R 1
-H 2
O
+H 2
O
CH 3
OH 2
+
H 3
C
O
R 1
H 3
C
O
R 1
-H +
+H +
R
NH
+ CH 3
+H +
R
..
NH CH 3
-H +
H 3
HR
OC
H
R
+
N
R 1
H
CH 3
R 1
H 3
-H +
HOC
-H +
+H + H +H
N
CH +
3
R H
H 3 C
R 1
H 2
O +
H ..
N
CH 3
R H
-H 2
O
+H 2
O
H 3 C
R 1
H
N + CH 3
R
H
C
-H + N
R 1
R= COOC 2
H 5
R= COCH 3
1
3
CH
RH
3
H

24
1.4 Experimental Protocols
Commercial ethylacetoacetate was used only after distillation. The zinc dust used
of minimum 80 % pure. Before the reaction mixture is refluxed, enough time
should be allowed for the zinc dust react totally; or else considerable problem
with foaming may be encountered. While addition of zinc is done in small portion
to ensure proper temperature control otherwise foaming will occur and
temperature will shoot up.
Thin layer chromatography
It was carried out on silica Gel-G as a stationary phase. The slurry was prepared
by adding 20 ml distilled water to 10 gm Silica Gel in 250 ml beaker with
continues stirring and the slurry was poured over glass plate and uniform thin
layer was prepared. The plate was kept dried at 105 o C and activated before
used. The reactions of all newly synthesized compounds and intermediate were
monitories and the purity was checked by TLC.
Mobile phase: 1. Ethyl acetate : Hexane
2. Chloroform : Methanol
Melting point
All the melting points were taken in open end capillary by using paraffin bath with
standard Zeal thermometer and they were uncorrected.
1.5 EXPERIMENTAL
1.5.1 Preparation of 1-{5-[ethoxy (hydroxy) methyl]-2, 4-dimethyl-1H-pyrrol-
3-yl} ethanone (Scheme-1)
In 250 ml conical flask provided with magnetic needle and surrounded by an ice
bath are placed 13 ml of ethyl acetoacetate and 40 ml of glacial acetic acid. To
this, then added drop wise with stirring a solution of (0.11 mole) of sodium nitrite
in 13 ml of water. The rate of addition is controlled so that the temperature does
not rise above 10 o C. After the sodium nitrite solution has been added, the
mixture is stirred for 2-3 hrs more. It is then allow to warm up to room

25
temperature and stand about 12 hrs, after which (0.12 mole) of acetyl acetone
added at one time. To the reaction mixture, 15 gm of zinc dust is added in
portions of about 2-3 gm with vigorous stirring. The rate of addition is regulated
so that temperature never rises above 60 o C. After the addition is complete, the
mixture is refluxed for 2-3 hrs on water bath until the unreacted zinc dust
collected in balls. The hot solution is then filtered and poured into ice water. The
creamy white product obtained is filtered and dried. Crude product is crystallized
from alcohol. M.P.-142-144 o C (reported M.P.-143 o C) A , Yield 45-60 %.
1.5.2 Preparation of (2E)-1-{5-[ethoxy (hydroxy) methyl]-2,4-dimethyl-1Hpyrrol-3-yl}-3-phenylprop-2-en-1-one
(Scheme-2)
General method:
In 100 ml conical flask, 1-{5-[ethoxy (hydroxy) methyl]-2,4-dimethyl-1H-pyrrol-3-
yl} ethanone (0.01 mole) and substituted aromatic aldehyde (0.01 mole) were
dissolved in chloroform. The catalytic amount of potassium hydroxide (2-3) drops
was added and the reaction mixture was refluxed for 2 hrs. The reaction progress
was monitored by TLC. After completetion of the reaction, chloroform was
distilled out completely and 10 ml methanol was added. Stirred for 20 min at 25-
30 o C. The product was filtered and dried in air oven. It was recrystallised from
methanol. Yield 50-60 %.
1.5.3 Preparation of [3, 5-dimethyl-4-(5-phenyl-4, 5-dihydro-1H-pyrazol-3-
yl)-1H-pyrrol-2-yl] (ethoxy) methanol (Scheme-3)
General method:
In 100 ml conical flask, 10 ml (0.32 mole) of hydrazine hydrate is added to the
solution of (2E)-1-{5-[ethoxy (hydroxy) methyl]-2,4-dimethyl-1H-pyrrol-3-yl}-3-
phenylprop-2-en-1-one (0.01 mole) in 20 ml ethanol and reflux with stirring in
water bath for 6-8 hrs. Pour the contain into crushed ice with stirring. The solid
obtained was filtered and washed with water. It was dried and recrystallized from
ethanol. Yield 65-70 %.
Physical data of the newly synthesized compounds are given in Table 1.6.
A Raval, K.; Ph.D. Thesis.; Saurashtra University, Rajkot, 2005.

27
1.7 SPECTRAL ANALYSIS
1.7.1 IR SPECTRAL ANALYSIS
The IR spectral data of newly synthesized pyrrole derivatives have many
significant characteristic IR peaks which are identified.
Looking to the IR spectra of newly synthesized compounds, the carbonyl group of
ester was observed at 1695-1660 cm -1 . Two methyl groups illustrate stretching
vibration at 2975-2950 cm -1 and deformation at 1485-1445 cm -1 . The -C-O
stretching of ester group observed at 1100-1001 cm -1 . The –NH deformation and
C-N stretching of secondary bonded observed at 1205-1310 cm -1 . The –CH
stretching of five member ring observed in the region of 1610-1660 cm -1 . Chloro
group was confirmed due to their frequencies which come out at 800-650 cm -1 .
The –NH stretching of pyrrole ring observed at 3230-3400 cm -1 and bending
vibration suggest itself 1580-1640 cm -1 region.
The informative bands in the spectra due to aromatic moiety occur in the low
frequency range between 900 and 675 cm -1 . These strong absorption bands
consequence from the out-of-plan banding of the ring C-H bonds. In plane
banding emerge in the region of 1300-1000 cm -1 . Skeletal vibration, involving
carbon-carbon stretching with the ring, absorb in the 1600-1585 cm -1 and 1500-
1400 cm -1 regions. Aromatic C-H stretching bands occur between 3100-3000 cm -
1 . IR spectra of the newly synthesized compounds are given on Pages 36-37.
1.7.2 1H NMR SPECTRAL ANALYSIS
Study of the
1 H NMR spectra of newly synthesized compounds shows
characterization pattern of triplet-quartet of CH 3 -CH 2 group, in which quartet of
CH 2 group was observed at 2.50-4.55 δ ppm, while that of triplet of methyl
protons 1.38-2.55 δ ppm. The two methyl groups present at 2 and 5 position of
pyrrole ring explain presence of mostly two distinct singlets at 2.20 – 4.10 δ ppm.
The aromatic protons were observed at 6.99 to 7.75 δ ppm. The –NH group of
pyrrole ring structure and –CO-NH was observed at 6.65 to 10.55 δ ppm
respectively. In case of 5-phenyl-4, 5-dihydro-1H-pyrazole ring own two types of

28
methylenic protons at dissimilar C 4 positions, as these two protons are chemically
equivalent but magnetically non equivalent. Thus these two protons establish
different region in the spectrum. Thereby these protons give multiple signals at
2.50 – 3.70 δ ppm, in place of doublet due to steric hindrance of entire ring
protons. At C 5 position 1H protons offer triplet at 4.52 to 4.68 δ ppm, outstanding
to the neighboaring two protons in the pyrazole ring at C 4 position. Although, in
case of VGM-1, due to attendance of fluorine atom in aromatic ring, nearby two
protons give triplet- triplet at 7.34-7.38 δ ppm. NMR spectra of the newly
synthesized compounds are given on Pages 38-41.
1.7.3 Elemental Analysis
Elemental analysis of the all the synthesized compounds was carried out on
Elemental Vario EL III Carlo Erba 1108 model and the results are in agreements
(within range of theoretical value) with the structures assigned.
1.7.4 Mass spectral Analysis
Molecular ion peak (M+) of the Ethyl 4-[5-(substituted phenyl)-4, 5-dihydro-1Hpyrazol-3-yl]-3,
5-dimethyl-1H-pyrrole-2-carboxylate was in total agreement with
their molecular weight.
In case of VGM-2 and VGM-6, molecular ion peak relevant to its molecular
weight. Base peak observed at 310 m/z due to lost of one methyl group from
pyrrole ring and two oxygen atoms from the nitro group, 207 peak is relevant to
subsequent loss of phenyl ring from the left behind molecular part.
In case of VGM-3 and VGM-5, base peak is observed at 327 m/z with upper limit
intensity owing to loss of one methyl group from the pyrrole ring. An additional
peak is observed at 313 m/z due to loss of second methyl group from pyrrole
nucleus.
For the Mass spectrum of VGM-7, base peak is observed at 147 m/z. M+ peak is
relevant to its molecular weight. While 342 m/e peak is also observed cause of
the loss of the methyl group. In Mass spectrum, 207 peak was observed by loss

29
of phenyl ring from molecule, base peak is observed because of subsequently
loss of ester linkage at C 5 position from the pyrrole ring.
In case of VGM-8, M+ in total agreement with its molecular weight, while base
peak is observed at 299 m/z down due to loss of one methyl group from pyrrole
focus and Cl atom from the aromatic nucleus at C4 position. 283 m/z is moreover
revealed caused by subsequently loss of second methyl group from the pyrrole
ring.
In case of ethyl 3, 5-dimethyl-4-(5-phenyl-4, 5-dihydro-1H-pyrazol-3-yl)-1Hpyrrole-2-carboxylate
base peak observed 148 m/e. 297 m/e and 283 m/e were
observed due to loss of two methyl group from the pyrrole ring. Mass spectra of
the newly synthesized compounds are given on Pages 42-45.
Mass fragmentation of Ethyl 4-[5-(4-methoxyphenyl)-4, 5-dihydro-1Hpyrazol-3-yl]-3,
5-dimethyl-1H-pyrrole-2-carboxylate (VGM-3).
H 3 C
H 3 C
O
O
O
O
N
H
N
H
H3C
O
O
NH
N
CH 3
NH
N
N
H
CH3
N
NH
4
3
OH
5
C H 3
2
H 3 C
O
O
O
O
N
H
O CH 3
H 3 C
CH 3
N
H
6
O CH 3
NH
N
CH 3
1
NH
N
7
10
H 2 C
8
C H 2
9
NH
N
N
H
H 3 C
N
H
NH
N
N
NH
C H 3
O
O
N
H
NH
N
HO
O
N
H
NH
N
O
N
H
NH
N

Mass fragmentation of Ethyl 4-[5-(4-chlorophenyl)-4, 5-dihydro-1H-pyrazol-
3-yl]-3, 5-dimethyl-1H-pyrrole-2-carboxylate (VGM-8):
30
N
H
N
Cl
H 3 C
O
N
H
N
C H 3
CH 3
H 3 C
O
O
N
H
CH 3
H 3
N N H
O
N
H
H 2
CN
H 3 C
O
N
H
N
2
1
1
9
H
N
N
O
N
H
N
H
N
CH 3
3
H 3 C
H
N
Cl
N
H 3 C
O
N CH 3
O H
7
8
N
H
H
N
N
H 3 C
O
O
N
H
4
5
6
O
N
H
N
H
N
N
N H
H 3 C
O
O
N
H
N
H
N
HO
O
N
H
HO
O
N
H
SPECTRAL DATA
Ethyl 4-[5-(4-Fluorophenyl)-4, 5-dihydro-1H-pyrazol-3-yl]-3, 5-dimethyl-1Hpyrrole-2-carboxylate
(VGM-1)
IR (KBr) cm -1 : 3206, 3145 (-NH, str.), 1556 (-NH, def.), 1392 (-C-N, str.), 1681
(-C=O, str.), 1510 (-C=C, str. of pyrrole), 1492 (-CH 2 def.), 1437 (-CH 3 , C-H def.),
2924 (-CH, asym. str. ), 2856 (-CH, sym. str.), 1238 (-CH 2 , ipd.), 796 (-CH 2 ,
oopd.), 1014-1089 (-C-O-C, sym, str.)
1 H NMR (δ ppm): 2.39 (3H,s), 2.46 (3H, s), 2.55 (2H, qt), 2.96 (1H, m), 3.86 (1H,
m), 4.48 (1H, t), 7.0-7.05 (2H, m), 7.34-7.38 (2H, t-t, J= 2.08, 2.08 Hz)
C, H, N (in %): Found: 65.67(C), 6.10(H), 12.72 (N), Cacld: 65.64(C), 6.12(H),
12.76 (N)

31
Ethyl 3,5-dimethyl-4-[5-(3-nitrophenyl)-4, 5-dihydro-1H-pyrazol-3-yl]-1Hpyrrole-2-carboxylate
(VGM-2)
IR (KBr) cm -1 : 3192, 3142 (-NH, str.), 1539 (-NH, def.), 1392 (-C-N, str.), 1681
(-C=O, str.), 1521 (-C=C, str. of pyrrole), 1491 (-CH 2 def.), 1440 (-CH 3 , C-H def.),
2937 (-CH, asym. str. ), 2851, 2835 (-CH, sym. str.), 1240 (-CH 2 , ipd.), 794 (-CH 2 ,
oopd.), 1028-1087 (-C-O-C, sym, str.)
Mass (m/e value): 356 (40), 342 (35), 324 (2), 310 (100), 307 (20, 281 (20), 279
(10), 264 (4), 249 (2), 234 (5), 220 (3), 206 (3), 188 (24), 180 (2), 161 (10), 148
(8), 133 (11), 117 (5), 104 (5), 91 (7), 77 (7), 65 (8), 44 (14), 41 (3).
C, H, N (in %): Found: 60.64(C), 5.68(H), 15.71 (N), Cacld: 60.66(C), 5.66(H),
15.72 (N)
Ethyl 4-[5-(4-methoxyphenyl)-4, 5-dihydro-1H-pyrazol-3-yl]-3, 5-dimethyl-1Hpyrrole-2-carboxylate
(VGM-3)
IR (KBr) cm -1 : 3277, 3255 (-NH, str.), 1398 (-C-N, str.), 1699 (-C=O, str.), 1512
(-C=C, str. of pyrrole), 1491 (-CH 2 def.), 1429 (-CH 3 , C-H def.), 2949, 2916 (-CH,
asym. str. ), 1249 (-CH 2 , ipd.), 771 (-CH 2 , oopd.), 1010 (-C-O-C, sym, str.)
Mass (m/e value): 341 (3), 327 (100), 313 (30), 295 (80), 293 (24), 264 (14), 250
(5), 225 (4), 220 (3), 206 (3), 188 (10), 180 (23), 161 (23), 148 (57), 135 (32), 121
(25), 107 (5), 91 (15), 77 (16), 65 (16), 44 (11), 41 (3).
C, H, N (in %): Found: 66.80(C), 6.76(H), 12.28 (N), Cacld: 66.84(C), 6.79(H),
12.31 (N)
Ethyl 4-[5-(2-chlorophenyl)-4, 5-dihydro-1H-pyrazol-3-yl]-3, 5-dimethyl-1Hpyrrole-2-carboxylate
(VGM-4)
IR (KBr) cm -1 : 3377, 3286 (-NH, str.), 1346 (-C-N, str.), 1685 (-C=O, str.), 1516
(-C=C, str. of pyrrole), 1491 (-CH 2 def.), 2939, 2910 (-CH, asym. str.), 1242 (-
CH 2 , ipd.), 740 (-CH 2 , oopd.), 1101 (-C-O-C, sym, str.)
C, H, N (in %): Found: 62.50 (C), 5.80 (H), 10.21 (N), Cacld: 62.52 (C), 5.83
(H), 10.25 (N)
Ethyl 4-[5-(3-methoxyphenyl)-4, 5-dihydro-1H-pyrazol-3-yl]-3, 5-dimethyl-1Hpyrrole-2-carboxylate
(VGM-5)
IR (KBr) cm -1 : 3245, 3210 (-NH, str.), 1542 (-NH, def.), 1388 (-C-N, str.), 1684
(-C=O, str.), 1530 (-C=C, str. of pyrrole), 1481 (-CH 2 def.), 1435 (-CH 3 , C-H def.),

32
3054 (Ar-CH, str), 2940 (-CH, asym. str. ), 2862, 2810 (-CH, sym. str.), 1244 (-
CH 2 , ipd.), 782 (-CH 2 , oopd.), 1010-1090 (-C-O-C, sym, str.)
Mass (m/e value): 341 (5), 325 (100), 313 (70), 295 (71), 293 (84), 264 (48), 266
(20), 250 (16), 224 (5), 210 (8), 206 (16), 195 (24), 180 (86), 160 (23), 148 (100),
135 (46), 121 (20), 107 (18), 92 (24), 77 (33), 65 (37), 44 (24), 41 (5).
C, H, N (in %): Found: 66.82 (C), 6.83 (H), 12.30 (N), Cacld: 66.84 (C), 6.79
(H), 12.31 (N)
Ethyl 3,5-dimethyl-4-[5-(4-nitrophenyl)-4, 5-dihydro-1H-pyrazol-3-yl]-1Hpyrrole-2-carboxylate
(VGM-6)
IR (KBr) cm -1 : 3312, 3214 (-NH, str.), 1389 (-C-N, str.), 1690 (-C=O, str.), 1520
(-C=C, str. of pyrrole), 1496 (-CH 2 def.), 1440 (-CH 3 , C-H def.), 2965, 2921 (-CH,
asym. str. ), 1251 (-CH 2 , ipd.), 774 (-CH 2 , oopd.), 1010-1086 (-C-O-C, sym, str.)
1 H NMR (δ ppm): 1.34 (3H,s), 2.38 (3H, s), 2.53 (3H, s), 3.50 (1H, m), 4.29 (2H,
qt), 4.92 (1H, t), 6.42 (-NH, s), 7.64 (2H, t, J= 1.92, 8.68 Hz), 8.17 (2H, d, J= 8.72
Hz ), 10.82 (-NH, s)
Mass (m/e value): 356 (100), 342 (14), 326 (7), 310 (100), 294 (3), 281 (39), 279
(10), 264 (10), 250 (2), 235 (8), 220 (2), 207 (3), 188 (37), 178 (3), 161 (20), 146
(10), 133 (22), 119 (8), 106 (8), 91 (11), 77 (8), 65 (12),44 (7), 41 (3).
C, H, N (in %): Found: 60.62 (C), 5.63 (H), 15.70 (N), Cacld: 60.66 (C), 5.66 (H),
15.72 (N)
Ethyl 3,5-dimethyl-4-[5-(2-nitrophenyl)-4, 5-dihydro-1H-pyrazol-3-yl]-1Hpyrrole-2-carboxylate
(VGM-7)
IR (KBr) cm -1 : 3224, 3186 (-NH, str.), 1540 (-NH, def.), 1387 (-C-N, str.), 1686
(-C=O, str.), 1520 (-C=C, str. of pyrrole), 1480 (-CH 2 def.), 1435 (-CH 3 , C-H def.),
2956, 2914 (-CH, asym. str. ), 2851, 2810 (-CH, sym. str.), 1244 (-CH 2 , ipd.), 776
(-CH 2 , oopd.), 1005-1084 (-C-O-C, sym, str.)
1 H NMR (δ ppm): 1.34-1.38 (3H, t), 2.41 (3H, s), 2.98 (1H, m), 3.49 (3H, s), 3.73
(1H, m), 4.30-4.34 (2H, qt), 5.29-5.34 (1H, t), 7.42 – 7.46 (1H, m, 1.40, 7.08 Hz),
7.62 – 7.66 (1H, t-t, J= 1.24, 6.64 Hz), 7.95 -8.00 (2H, t-t, J= 0.96, 1.16 Hz), 8.8
(1H, s)
Mass (m/e value): 356 (69), 342 (74), 322 (5), 307 (14), 292 (5), 275 (69), 263
(300, 247 (27), 235 (60), 221 (32), 207 (29), 188 (22), 180 (14), 167 (18), 147
(100), 131 (20), 119 (30), 104 (20), 91 (26), 77 (25), 65 (28), 44 (15), 41 (4).

33
C, H, N (in %): Found: 60.62(C), 5.67(H), 15.70 (N), Cacld: 60.66(C), 5.66(H),
15.72 (N)
Ethyl 4-[5-(4-chlorophenyl)-4, 5-dihydro-1H-pyrazol-3-yl]-3, 5-dimethyl-1Hpyrrole-2-carboxylate
(VGM-8)
IR (KBr) cm -1 : 3364, 3246 (-NH, str.), 1374 (-C-N, str.), 1684 (-C=O, str.), 1510
(-C=C, str. of pyrrole), 1494 (-CH 2 def.), 2956, 2914 (-CH, asym. str.), 1240 (-
CH 2 , ipd.), 779 (-CH 2 , oopd.), 1080 (-C-O-C, sym, str.)
1 H NMR (δ ppm): 2.46 (3H,t), 2.51 (3H, s), 2.75 (1H, m), 3.69 (1H, m), 3.86
(2H,qt), 4.33 (3H, m), 4.63 (1H, t), 7.24 (1H, t, J= 8.64, 8.04 Hz ), 7.32 (2H, m, J=
2.62 Hz), 7.38-7.40 (1H, m, J= 6.52 , 2.62 Hz), 8.65 (1H, s)
Mass (m/e value): 345 (58), 331 (32), 311 (20), 299 (100), 283 (41), 270 (14),
256 (5), 242 (3), 234 (4), 220 (4), 206 (5), 188 (20), 178 (4), 102 (8), 91 (10), 77
(10), 65 (14), 44 (15), 41 (3).
C, H, N (in %): Found: 62.54(C), 5.80(H), 10.21 (N), Cacld: 62.52(C), 5.83(H),
10.25 (N)
Ethyl 4 - [5 - (4-anthracene) - 4, 5- dihydro- 1H- pyrazol- 3- yl]- 3, 5- dimethyl-
1H-pyrrole-2-carboxylate (VGM-9)
IR (KBr) cm -1 : 3346, 3274 (-NH, str.), 1540 (-NH, def.), 1389 (-C-N, str.), 1686
(-C=O, str.), 1524 (-C=C, str. of pyrrole), 1492 (-CH 2 def.), 1438 (-CH 3 , C-H def.),
3024,3010 (Ar-CH, str.) 2954, 2912 (-CH, asym. str. ), 2860, 2814 (-CH, sym.
str.), 1242 (-CH 2 , ipd.), 778 (-CH 2 , oopd.), 1010-1086 (-C-O-C, sym, str.)
C, H, N (in %): Found: 75.50 (C), 6.54 (H), 10.12 (N), Cacld: 75.52 (C), 6.58 (H),
10.16 (N)
Ethyl 4-(5-cyclohexa-2,5-dien-1-yl-4,5-dihydro-1H-pyrazol-3-yl)-3,5-dimethyl-
1H-pyrrole-2-carboxylate (VGM-10)
IR (KBr) cm -1 : 3264, 3178 (-NH, str.), 1538 (-NH, def.), 1391 (-C-N, str.), 1688
(-C=O, str.), 1521 (-C=C, str. of pyrrole), 1475 (-CH 2 def.), 1436 (-CH 3 , C-H def.),
2940, 2912 (-CH, asym. str. ), 2856, 2814 (-CH, sym. str.), 1240 (-CH 2 , ipd.), 789
(-CH 2 , oopd.), 1014-1096 (-C-O-C, sym, str.)
Mass (m/e value): 311 (5), 297 (92), 283 (54), 266 (24), 265 (92), 251 (20), 236
(20), 222 (15), 206 (19), 188 (26), 180 (61), 160 (20), 148 (100), 133 (17), 122
(19), 105 (47), 91 (28), 77 (57), 65 (37), 51 (21), 41 (6).

34
C, H, N (in %): Found: 69.40 (C), 6.84 (H), 13.45 (N), Cacld: 69.43 (C), 6.80 (H),
13.49 (N)
Ethyl 4-[5-(2-flourophenyl)-4, 5-dihydro-1H-pyrazol-3-yl]-3, 5-dimethyl-1Hpyrrole-2-carboxylate
(VGM-11)
IR (KBr) cm -1 : 3314, 3262 (-NH, str.), 1344 (-C-N, str.), 1686 (-C=O, str.), 1520
(-C=C, str. of pyrrole), 1488 (-CH 2 def.), 2940, 2916 (-CH, asym. str.), 1240 (-
CH 2 , ipd.), 758 (-CH 2 , oopd.), 1089 (-C-O-C, sym, str.)
C, H, N (in %): Found: 65.66 (C), 6.10(H), 12.74 (N), Cacld: 65.64 (C), 6.12 (H),
12.76 (N)
Ethyl 4-[5-(2-methoxyphenyl)-4, 5-dihydro-1H-pyrazol-3-yl]-3, 5-dimethyl-1Hpyrrole-2-carboxylate
(VGM-12)
IR (KBr) cm -1 : 3267, 3186 (-NH, str.), 1390 (-C-N, str.), 1689 (-C=O, str.), 1514
(-C=C, str. of pyrrole), 1490 (-CH 2 def.), 1432 (-CH 3 , C-H def.), 2965 (-CH, asym.
str. ), 1244 (-CH 2 , ipd.), 775 (-CH 2 , oopd.), 1010-1024 (-C-O-C, sym, str.)
C, H, N (in %): Found: 66.82 (C), 6.82(H), 12.28 (N), Cacld: 66.84 (C), 6.79 (H),
12.31 (N)
Ethyl 4-[5-(3-chlorophenyl)-4, 5-dihydro-1H-pyrazol-3-yl]-3, 5-dimethyl-1Hpyrrole-2-carboxylate
(VGM-13)
IR (KBr) cm -1 : 3326, 3240 (-NH, str.), 1364 (-C-N, str.), 1688 (-C=O, str.), 1521
(-C=C, str. of pyrrole), 1490 (-CH 2 def.), 2940, 2911 (-CH, asym. str.), 1238 (-
CH 2 , ipd.), 784 (-CH 2 , oopd.), 1080-1040 (-C-O-C, sym, str.)
C, H, N (in %): Found: 62.54 (C), 5.80 (H), 10.22 (N), Cacld: 62.52 (C), 5.83 (H),
10.25 (N)
Ethyl 4-[5-(2-hydroxycyclohexa-2, 5-dien-1-yl)-4, 5-dihydro-1H-pyrazol-3-yl]-
3, 5-dimethyl-1H-pyrrole-2-carboxylate (VGM-14)
IR (KBr) cm -1 : 3586 (-OH, str, ) 3246, 3174 (-NH, str.), 1541 (-NH, def.), 1387 (-
C-N, str.), 1688 (-C=O, str.), 1524 (-C=C, str. of pyrrole), 1474 (-CH 2 def.), 1423
(-CH 3 , C-H def.), 2954 (-CH, asym. str. ), 2864, 2812 (-CH, sym. str.), 1240 (-
CH 2 , ipd.), 784 (-CH 2 , oopd.), 1010-1098 (-C-O-C, sym, str.)
C, H, N (in %): Found: 66.02 (C), 6.49 (H), 12.80 (N), Cacld: 66.04 (C), 6.47 (H),
12.84 (N)
Ethyl 4-[5-(3-flourophenyl)-4, 5-dihydro-1H-pyrazol-3-yl]-3, 5-dimethyl-1Hpyrrole-2-carboxylate
(VGM-15)

35
IR (KBr) cm -1 : 3320, 3246 (-NH, str.), 1340 (-C-N, str.), 1680 (-C=O, str.), 1516
(-C=C, str. of pyrrole), 1480 (-CH 2 def.), 2974, 2910 (-CH, asym. str.), 1242 (-
CH 2 , ipd.), 762 (-CH 2 , oopd.), 1080-1014 (-C-O-C, sym, str.)
C, H, N (in %): Found: 65.67 (C), 6.10 (H), 12.73 (N), Cacld: 65.64 (C), 6.12 (H),
12.76 (N)
Ethyl 4-[5-(4-hydroxycyclohexa-2, 5-dien-1-yl)-4, 5-dihydro-1H-pyrazol-3-yl]-
3, 5-dimethyl-1H-pyrrole-2-carboxylate (VGM-16)
IR (KBr) cm -1 : 3574 (-OH, str, ) 3346, 3214 (-NH, str.), 1380 (-C-N, str.), 1691 (-
C=O, str.), 1520 (-C=C, str. of pyrrole), 1470 (-CH 2 def.), 1432 (-CH 3 , C-H def.),
3014 (Ar-CH,str.) 2948 (-CH, asym. str. ), 2874, (-CH, sym. str.), 1248 (-CH 2 ,
ipd.), 781 (-CH 2 , oopd.), 1098-1012 (-C-O-C, sym, str.)
C, H, N (in %): Found: 66.05 (C), 6.45 (H), 12.82 (N), Calcld: 66.04 (C), 6.47
(H), 12.84 (N)
Ethyl 4-[5-(4-naphthalene)-4, 5-dihydro-1H-pyrazol-3-yl]-3, 5-dimethyl-1Hpyrrole-2-carboxylate
(VGM-17)
IR (KBr) cm -1 : 3318, 3240 (-NH, str.), 1538 (-NH, def.), 1392 (-C-N, str.), 1679
(-C=O, str.), 1521 (-C=C, str. of pyrrole), 1490 (-CH 2 def.), 1420 (-CH 3 , C-H def.),
3014 (Ar-CH, str.) 2964, 2910 (-CH, asym. str. ), 2864 (-CH, sym. str.), 1242 (-
CH 2 , ipd.), 784 (-CH 2 , oopd.), 1088-1014 (-C-O-C, sym, str.)
C, H, N (in %): Found: 72.72 (C), 6.90 (H), 11.54 (N), Cacld: 72.70 (C), 6.93 (H),
11.56 (N)
Ethyl 4-[5-(3-hydroxycyclohexa-2, 5-dien-1-yl)-4, 5-dihydro-1H-pyrazol-3-yl]-
3, 5-dimethyl-1H-pyrrole-2-carboxylate (VGM-18)
IR (KBr) cm -1 : 3574 (-OH, str, ) 3346, 3214 (-NH, str.), 1540 (-NH, def.), 1384 (-
C-N, str.), 1690 (-C=O, str.), 1531 (-C=C, str. of pyrrole), 1470 (-CH 2 def.), 1430
(-CH 3 , C-H def.), 2917 (-CH, asym. str.), 2874, 2810 (-CH, sym. str.), 1244 (-CH 2 ,
ipd.), 788 (-CH 2 , oopd.), 1098-1024 (-C-O-C, sym, str.)
C, H, N (in %): Found: 66.02 (C), 6.49 (H), 12.81 (N), Cacld: 66.04 (C), 6.47
(H), 12.84 (N)

IR spectrum of Ethyl 4-[5-(4-fluorophenyl)-4, 5-dihydro-1H-pyrazol-3-yl]-3, 5-
dimethyl-1H-pyrrole-2-carboxylate (VGM-1)
36
C H 3
O
O
H
N
F
N
H 3 C
CH 3
N
H
IR spectrum of Ethyl 3, 5-dimethyl-4-[5-(3-nitrophenyl)-4, 5-dihydro-1Hpyrazol-3-yl]-1H-pyrrole-2-carboxylate
(VGM-2)
C H 3
O
N
H
N
H 3 C
N + O
CH 3
O -
O
N
H

IR spectrum of Ethyl 4-[5-(4-methoxycyclohexa-1, 5-dien-1-yl)-4, 5-dihydro-
1H-pyrazol-3-yl]-3, 5-dimethyl-1H-pyrrole-2-carboxylate (VGM-3)
37
C H 3
O
O
CH
H
3
N
O
N
H 3 C
CH 3
N
H
IR spectrum of Ethyl 4-[5-(2-chlorocyclohexa-1, 5-dien-1-yl)-4, 5-dihydro-1Hpyrazol-3-yl]-3,
5-dimethyl-1H-pyrrole-2-carboxylate (VGM-4)
C H 3
O
N
H
N
H 3 C
Cl
CH 3
O
N
H

38
1 H NMR spectrum of Ethyl 4-[5-(4-fluorophenyl)-4, 5-dihydro-1H-pyrazol-3-
yl]-3, 5-dimethyl-1H-pyrrole-2-carboxylate (VGM-1).
C H 3
O
H
N F
N
H 3 C
CH 3
C H 3
O
H 3 C
CH 3
O
N
H
N
H
N
F
O
N
H

39
1 H NMR spectrum of Ethyl 3, 5-dimethyl-4-[5-(2-nitrophenyl)-4, 5-dihydro-
1H-pyrazol-3-yl]-1H-pyrrole-2-carboxylate (VGM-7).
C H 3
N
H
N
H
H 3 C
H
O
N +
H O -
O
N CH 3
O H

40
1 H NMR spectrum of Ethyl 3, 5-dimethyl-4-[5-(4-chlorophenyl)-4, 5-dihydro-
1H-pyrazol-3-yl]-1H-pyrrole-2-carboxylate (VGM-8).
C H 3
O
CH 3
H H
N Cl
H 3 C
H
N
H
O
N
H

41
1 H NMR spectrum of Ethyl 3, 5-dimethyl-4-[5-(4-nitrophenyl)-4, 5-dihydro-
1H-pyrazol-3-yl]-1H-pyrrole-2-carboxylate (VGM-6).
C H 3
O
CH 3
O
H H
N
N
N + O -
H 3 C
H
H
O
N
H

Mass spectrum of Ethyl 3, 5-dimethyl-4-[5-(3-nitrophenyl)-4, 5-dihydro-1Hpyrazol-3-yl]-1H-pyrrole-2-carboxylate
(VGM-2).
42
O
H 3 C
CH 3
O
N
H
N
H
N
N +
O -
O
C H 3
M.W.= 356.37 gm/mole
Mass spectrum of Ethyl 3, 5-dimethyl-4-[5-(4-methoxyphenyl)-4, 5-dihydro-
1H-pyrazol-3-yl]-1H-pyrrole-2-carboxylate (VGM-3)
N
H
N
H 3 C
CH 3
O
CH 3
O
O
N
H
C H 3
M.W.= 341.40 gm/mole

Mass spectrum of Ethyl 3, 5-dimethyl-4-[5-(3-methoxyphenyl)-4, 5-dihydro-
1H-pyrazol-3-yl]-1H-pyrrole-2-carboxylate (VGM-5)
43
O
H 3 C
CH 3
O
N
H
N
H
N
H 3 C
O
C H 3
M.W.= 341.40 gm/mole
Mass spectrum of Ethyl 3, 5-dimethyl-4-[5-(4-nitrophenyl)-4, 5-dihydro-1Hpyrazol-3-yl]-1H-pyrrole-2-carboxylate
(VGM-6).
O
N
H 3 C
CH 3
H N +
N
O -
O
O
N
H
C H 3
M.W.= 356.37 gm/mole

Mass spectrum of Ethyl 3, 5-dimethyl-4-[5-(2-nitrophenyl)-4, 5-dihydro-1Hpyrazol-3-yl]-1H-pyrrole-2-carboxylate
(VGM-7).
44
O
H 3 C
CH 3
O
N
H
N
H
N
O -
N +
O
C H 3
M.W.= 356.37 gm/mole
Mass spectrum of Ethyl 3, 5-dimethyl-4-[5-(4-chlorophenyl)-4, 5-dihydro-1Hpyrazol-3-yl]-1H-pyrrole-2-carboxylate
(VGM-8)
N
H
N
H 3 C
CH 3
Cl
O
O
N
H
C H 3
M.W.= 345.82 gm/mole

45
Mass spectrum of Ethyl 3, 5-dimethyl-4-[5-(phenyl)-4, 5-dihydro-1H-pyrazol-
3-yl]-1H-pyrrole-2-carboxylate (VGM-10)
N
H
N
H 3 C
CH 3
O
O
N
H
C H 3
M.W.= 311.37 gm/mole

46
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51. Wijngaarden, I. V., Kruse, C. G., Van der Heyden., Jan, A. M., and Martin, Th. M.; J. Med.
Chem., 1988, 31, 1934-1940.
52. Demetri, G. D.; Eur. J. Cancer., 2002, 38, S52- S59.
53. Hlder, K., Hankovszky, O. K., Csak, J., Bodi, I. and Frank, L.; US, 1984, 4703056.
54. Prous, J., and Castaner, J.; Drugs Fut, 1986, 011 (06), 0449.
55. Franco, F., Greenhouse, R., and Muchowaski, J. M.; J. Org. Chem., 1985, 12, 3410-3416
56. Synthline data base, Prous Science., 2000.

48
57. Tuvaro, E.; Drugs Fut, 1993, 018(12), 1117.
58. Boer, D. T., Derendsin, c. L., Vos, R. M., and Tonnaer, J. A.; Drugs Fut, 1993, 018 (12),
1117.
59. Prous, J., and Castaner, J.; Drugs Fut, 1991, 016 (02), 0105.

Chapter-2
Introduction, Synthesis and Characterization of
some symmetrical and unsymmetrical
dihydropyridine derivatives containing naphthyl
ring
1. Biological profile 49
2. Synthetic aspects 55
3. QSAR study 59
4. Reaction scheme 61
5. Physical data 66
6. Spectral analysis 68
7. Mass fragmentation 71
8. Spectral data 71
9. IR spectra 78
10. 1H NMR spectra 80
11. Mass spectra 83
12. References 84

49
2.1 INTRODUCTION
1,4-Dihydropyridines is the significant subclass of pyridines, the best known
heterocyclic compounds which are associated with good number of
pharmacological activities. 1,4 dihydropyridines whether symmetrical or
unsymmetrical, are expected for their cardiovascular and other pharmacological
properties.
Many drug molecule bearing 1,4-dihydropyridines nucleus are specifically related
with calcium channel antagonism 1 and antihypertensive 2 . Earlier it was believed
that, the dihydropyridines is useful only as calcium channel antagonism, but later
on QSAR and X-ray crystallography study of new synthetic dihydropyridines
molecules indicates that their therapeutics activities may be broaden to
ionotrophy to secretary stimulation also. Currently these drugs are target for
angina, hypertension, hypertropic cardiomyopathy, cerebral vasospasm and
other smooth muscle disorders.
Beside these, antitumor 3 , vasodilator 4 , coronary vasodilator and cardiopathic 5 ,
antimayocardiac ischemic 6 , antiulcer 7 , antiallergic activity are also reported.
2.1.1 Biological profile
Dihydropyridine (DHP) chemistry began in 1882 when Hantzsch 11-12 published
the synthesis. The simplest form of the synthesis involves heating an aldehyde
1,3-diketone ester and ammonia. The reaction almost certainly involves aldol
condensation to form the benzylidine derivative as the first step. Conjugated
addition of a second mole of 1,3-diketone ester would then afford the 1,5-
diketone. Reaction of the carbonyl group with ammonia will lead to the formation
of the dihydropyridine ring.
The DHP nucleus is common to numerous bioactive compounds which include
various vasodilator, antihypertensive, bronchodilator, antiatherosclerotic,
hepatoprotective, antitumor, antimutagenic, geroprotective, and antidiabetic
agents 13-18 .
Dihydropyridines have found commercial utility as calcium channel blockers, as
exemplified by therapeutic agents such as Nifedipine 16 , Nitrendipine 20 and
Nimodipine 21 . Second-generation calcium antagonists include DHP derivatives

50
with improved bioavailability, tissue selectivity, and/or stability, such as the
antihypertensive/antianginal drugs like Elgodipine 22 , Furnidipine 23-24 ,
Darodipine 25 , Pranidipine 26 , Lemildipine 27 , Dexniguldipine 28 , Lacidipine 29 , and
Benidipine 30 . Number of DHP calcium agonists has been introduced as potential
drug candidates for treatment of congestive heart failure 31, 32 .
The key characteristic of calcium channel blockers is their inhibition of entry of
calcium ions via a subset of channels, thereby leading to impairment of
contraction. There are three main groups of calcium channel blockers, i.e.
dihydropyridines, phenylalkylamines and benzothiazepines, typical examples of
which are nifidepine, verapamil and diltiazem, respectively 33-36 . Each has a
specific receptor on the calcium channel and a different profile of
pharmacological activity. Dihydropyridines have a less negative inotropic effect
than phenylalkylamines and benzothiazepines but can sometimes cause reflex
tachycardia. Dihydropyridines are able to reduce peripheral resistance, generally
without clinically significant cardio depression. Among DHPs with other types of
bioactivity, Cerebrocrast 37 has been recently introduced as a neuroprotectant and
cognition enhancer lacking neuronal-specific calcium antagonist properties. In
addition, a number of DHPs with platelet antiaggregatory activity have also been
discovered 38 . These recent examples highlight the level of ongoing interest
toward new DHP derivatives and have prompted us to explore this
pharmacophoric scaffold to develop a fertile source of bioactive molecules.
1,4- DHPs possess different pharmacological activities such as antitumor 39 ,
vasodilator 40 , coronary vasodilator and cardiopathic 41 , antimayocardiac ischemic,
antiulcer 42 , antiallergic 43 , antiinflammatory 44 and antiarrhythmic 45 , PAF
antagonist 46 , Adenosine A 3 receptor antagonist 47 and MDR reversal activity 48-49 .
In particular, DHP-CA (calcium channel antagonist DHP) are extensively used for
the treatment of hypertension, 50 subarachnoid hemorrhage, 51-52 myocardial
infarction 53-56 and stable 57,58 and unstable angina 59-60 even though recently their
therapeutic efficacy in myocardial infarction and angina has been questioned 61 .
This class of compounds is also under clinical evaluation for the treatment of
heart failure 62 , ischemic brain damage 63 nephropathies, and atherosclerosis 64 .
1,4-Dihydropyridines are now established as heterocycles having numerous
applications and having widened scope from its pronounced drug activity like

51
calcium channel antagonism and antihypertensive action. Many other
cardiovascular activities are associated with such compounds and they can be
presented in the structure as 2,6-dimethyl-3,5-diacetyl or dicarboxylate or
dicarbamoyl or many other homoaryl or heteroaryl carbon chain having C 2 to C 8
1,4-dihydropyridines substituted at 4-position. Some representative Ca 2+
antagonists of Dihydropyridine class are as shown below.
NO 2
Cl
H 3 COOC
COOCH 3
H 3 COOC
COOC 2 H 5
H 3 C N CH 3
H 3 C N
H
H
Nifedipine Amlodipine
O
NH 2
O
N + O -
O
O
CH 3
C H 3
O
C H 3
N
H
CH 3
O
N
Nicarcipine
A startling revelation is found recently in which the imidazolyl moiety is linked to
the phenyl ring by means of a methylene bridge, the activity tends to decrease.
Finally, the replacement of DHP itself by a pyridine ring gives an inactive
compound 65 .
Cozzi and coworkers 66 have synthesized a series of 4-phenyl-1,4-
dihydropyridines bearing imidazol-1-yl or pyridine-3-yl moieties on the phenyl
ring, with the aim of
N
N
N
N
O
H
O
O
O
C H 3
CH 3
H 3 C N CH 3
H
H 3 C
CH 3
H 3 C N CH 3

52
combining Ca 2+ antagonism and thermboxane A 2 (TxA 2 ) synthases inhibition in
the same molecules. Some of the compounds showed significant combined
activity in vitro, while other showed single activity. As far as Ca 2+ antagonism is
concerned, two points deserve comment. First, the SAR, in most cases, does not
differ substantially from that reported for classic DHP-CA, even though the
potency is lower than that found with the most potent drugs of this class as, for
example, reference compound nifidepine. In fact, Ca 2+ antagonism is dramatically
reduced by (a) replacement of DHP by a pyridine ring, (b) substitution of DHP
nitrogen N-1 by a methyl group, (c) Para substitution on the phenyl ring, and (d)
replacement of one ester function by a ketone or carboxy group. All these
variations are also detrimental in classic DHP-CA. 67
Hernandez-Gallegos and coworkers 68 have synthesized new 1,4-dihydropyridines
and evaluated their relaxant ability (rat aorta), antihypertensive activity in
spontaneously hypertensive rats and their microsomal oxidation rate (MOR) was
determined.
O
O
R
R 2
O
O R 1
H 3 C N CH 3
H
R = 3-NO2, 4-F, 3,5-di-F, 3-Br-4-F.
R 1
= R 2
= Me, Et, -CH 2
-CF 3
, -CH 2
CH 2
-OPh, -(CH 2
) 2
-N(CH 3
)-CH 3
-Ph
Christiaans and Timmerman 69 studied new molecules like CV-159 for possible
variation at 3-position.
O
N + O -
H
O
N
H 3
C
H 3 C
N
H
CH 3
N
H
H 3 C
N
CV- 159

53
Carlos et al 70 reported 1,4-DHPs derivatives with a 1,2-benzothiazol-3-one-1-
sulphoxide group, linked through an alkylene bridge to the C 3 carboxylate of the
DHP ring, with both vasoconstricting and vasorelaxant properties were obtained.
In blocking Ca 2+ evoked contractions of K + depolarized rabbit aortic strips. Many
compounds were 10 times more potent than nifidepine. Their vascular versus
cardiac selectivity was very pronounced.
CH 3
O
OH OH
O
O
H 3 C N
H
CH 3
O
O S
N
O
Sonja 76 and group have synthesized a new series of calcium channel agonists
structurally related to Bay K8644, containing NO donor furoxans and the related
furazans unable to release NO. The racemic mixtures were studied for their
action on L-type Ca 2+ channels expressed in cultured rat insulinoma RINm5F
cells. All the products proved to be potent calcium channel agonists
R
C H 3
O
O
H 3 C
N
H
O
NO 2
CH 3
N
N
O
H 3 C
O
O
H 3 C
N
H
CF 3
NO 2
CH 3
Recent reports show that efonidipine, a dihydropyridine Ca 2+ antagonist, has
blocking action on T-type Ca channels, which may produce favorable actions on
cardiovascular systems. However, the effects of other dihydropyridine Ca
antagonists on T-type Ca channels have not been investigated yet. Therefore,
Furukawa and group 77 have examined the effects of dihydropyridine compounds
clinically used for treatment of hypertension on a T-type Ca channel subtype,

54
alpha1G, expressed in Xenopus oocytes. Twelve DHPs (amlodipine, barnidipine,
benidipine, cilnidipine, efonidipine, felodipine, manidipine, nicardipine, nifedipine,
nilvadipine, nimodipine, nitrendipine) and mibefradil were tested. Cilnidipine,
felodipine, nifidipine, nilvadipine, minodipine, and nitrendipine had little effect on
the T-type channel. The blocks by drugs at 10 uM were less than 10% at a
holding potential of -100 mV. The remaining 6 drugs had blocking action on the
T-type channel comparable to that on the L-type channel. These results show
that many dihydropyridine Ca 2+ antagonists have blocking action on the alpha1G
channel subtype.
Labedipinedilol-A (II), a novel dihydropyridine-type calcium antagonist, has been
shown to induce hypotension and vasorelaxation. Liou 78 and co-workers have
studied to investigate the effect of labedipinedilol-A on vascular function of rat
aortic rings and cultured human umbilical vein endothelial cells (HUVECs).
2-Heterosubstituted-4-aryl-l,4-dihydro-6-methyl-5-pyrimidinecarboxylicacid esters
(I), which lack the potential C 3 symmetry of dihydropyridine calcium channel
blockers, were evaluated for biological activity. Biological assays using
potassium-depolarized rabbit aorta and radioligand binding techniques showed
that some of these compounds are potent mimics of dihydropyridine calcium
channel blockers. The combination of a branched ester (e.g. isopropyl, sec-butyl)
and an alkylthio group (e.g. SMe) was found to be optimal for biological activity 79 .
R
NO 2
N
COOR 3
EtOOC
COOEt
R 2 X N
H
CH 3
(I)
RX N CH 3
H
(II)
2.1.2 Recent Literature survey
Synthesis of New Dihydropyridine Glycoconjugates 85 is recently established by in
situ generated HCl as an efficient catalyst for solvent free Hantzsch rection at
room temprarute.

55
R
O
H
O
+
O
+
O
O
O
CH 3
5 mol - %Yb(OTf) 3
NH 4
OAc
EtOH, RT
CH 3
R
N
H
O
O
CH 3
Yb(OTf) 3 catalyzed an efficient, operationally simple and environmentally benign
Hantzsch reaction via a four-component coupling reaction of aldehydes,
dimedone, ethyl acetoacetate and ammonium acetate at ambient temperature
also gave polyhydroquinoline derivatives in excellent yield 86 .
R
O
H
+
R'
O
O
OR''
NH 4
OAc
RT, TCT
R''O
O
R'
R
N
H
O
R'
OR''
TCT
Cl
N
Cl
N
N
Cl
2.2 SYNTHETIC ASPECTS
In last few years, 1,4-dihydropyridine skeleton is extensively modified in our
laboratory and very interesting results are obtained with these modification to
various positions of 1,4-dihydropyridine skeleton and can be discussed as below.
3,5-dibenzoyl-1,4-dihydropyridines (BzDHPs) substituted at 4-phenyl ring were
synthesized and compared for their cytotoxic activity and multidrug resistance
reverting activity in in vitro assay systems. Among fifteen BzDHPs, 2-
trifluoromethyl, 2-chloro and 3-chloro derivatives showed the highest cytotoxic
activity 80 .
R
O
O
H 3 C N CH 3
H
R = 2-CF 3 , 3-CF 3 , 4-CF 3 , 2-Cl, 3-Cl, 4-Cl, 2-NO 2 , 3-NO 2 , 3-OPh etc.

56
3,5-Dibenzoyl-4-(3-phenoxyphenyl)-1,4-dihydropyridine-2,6-dimethylpyridine, DP-
7 a dibenzoyl dihydropyridines derivative as mdr inhibitor, was investigated for
cardiac effects in Langendorff-perfused rat heart and compared with nifidepine. It
was found that this molecule represent a lead for development of potent DHP
mdr chemosensitisers devoid of cardiac effect 81 .
Dibenzoyl-DHPs, tested for their mdr reversing activity, were found to show one
or two orders higher tumor-specific cytotoxic activity against human tumor cell
lines than human normal cells 82 . Dihydropyridine derivatives with phenyl
carbamoyl side chain on 3 and 5 positions were synthesized and evaluated for
their anti-tubercular activity. The results of anti-tubercular activity for dicarbamoyl
derivatives were studied for 2D QSAR. The study indicates the presence of
bulkier group on 4-phenyl ring contributes for the activity. The electronic influence
of substituents at carbamoyl phenyl ring is important for activity 8 .
To find out structural requirement of dicarbamoyl DHPs for anti tubercular activity,
CoMFA and CoMSIA methods were applied on a set of 33 dicarbamoyl
derivatives. The QSAR models reveal the importance of spatial properties and
conformational flexibility of side chains for anti tubercular activity 9 .
R 1
R
R 4
R 3 R 5
R 2
O
O
H
NH *
*
* NH
* *
*
H 3 C N CH 3
H
R
R 1
Dihydropyridines with N-phenyl substitution were synthesized and tested for
tumor specific cytotoxicity and mdr reversal activity to find out the effects of N-
phenyl substitution on activity. Asymmetric benzoyl DHPs with different
substitution on benzoyl aromatic ring were synthesized and evaluated for tumor
specific cytotoxicity. In continuation, dihydropyridines with phenyl carbamoyl side
chain on one arm and –CN, -COOEt, -COOMe side chain on other arm were also
synthesized and evaluated as MDR reversal dihydropyridines 83 . In continuation of
skeleton modification,

57
R 1
R
O
R 2
NH
H 3 C N
H
CH 3
R 1
R
O
H 3 C N
H
O
CH 3
R 2
O
O
H 5 C 2 O
OC 2 H 5
H 3 C N CH 3
R 1
dihydropyridines with heterocyclic systems on side chain were synthesized and
evaluated for anti tubercular activity. These derivatives showed moderate activity
and it was found that aromatic heterocyclic systems on side chain do not
enhance anti tubercular activity 84 .
NO 2
N
NO 2
N
R
R
CN
H 3 COOC
O
H 3 COOC
NH 2
H 3 C N CH 3
H
H 3 C N CH 3
H
Schramm and coworker 71 have proved that phenyl carbamoyl moiety in
dihydropyridines affords for cardiovascular selective activity.
O
Cl
O
NH
O
N
H 3 C N CH 3
H
Similarly Kelvin Cooper (Pfitzer, USA) et al 72 found that DHP can be highly
selective as platelet activating factor (PAF) antagonist. They found potent
compounds and prove that platelet aggregating activity (PAF) exhibits a wide
spectrum of biological activities elicited either directly or via the release of other
powerful mediator such as Thromboxane A 2 or the Leukotrienes. In vitro PAF
stimulates the movement and aggregation and the release there from of tissue
damaging enzymes and oxygen radicals. Accordingly compounds like UK-74505,
antagonize the action of PAF and consequently also prevent mediator release by

58
PAF, will have clinical utilities in the treatment of the variety of the allergic,
inflammatory and hypersecretory conditions such as asthama, arthritis, rhinitis,
bronchitis and utricaria 73 in future.
R 1
R 2
N
O
H 3 C
N
H
O
Y
X
Z
O
COOC 2 H
NH
5
H 3 C N
H
N
CH 3
N
UK-74505
N
Reddy and coworkers 74 synthesized 4-aryl hetroaryl-2,6-dimethyl-3,5-bis-N-(2-
methyl phenyl)carbamoyl-1,4-dihydropyridines through one-pot synthesis using
appropriate aromatic aldehydes and liquid ammonia. Pharmacological screening
of the new 1,4-dihyropyridines were also carried out for CNS depressant
(anticonvulsant and analgesic) and cardiovascular (inotropic and blood pressure)
activities by standard methods. They recently tested bronchodilatory acitivity on
2-chlorophenyl substitutents of such compounds 75 .
R
O
O
O
O
NH
NH
CH 3
H 3 C N CH 3
CH 3
H
Cl
NH
NH
H 3 C N CH 3
H
Cl
Neamati and coworkers 75 reported that a 1,4-dihydorpyridine NCS-372643 is
showing anti-HIV activity, which has opened up the synthetic as well as
pharmacological importance in antiviral area also.
O
OH
N + O -
OH
O
O
OH
NH
NH
H 3 C N
H
CH 3
NSC-372643
OH

59
QSAR STUDY
Recently Shah et al 8 synthesized and studied 2D QSAR of substituted phenyl-
2,6-dimethyl-3,5-bis-N-substituted phenyl carbamoyl-1,4-dihyropyridines as
potent antitubercular agents. It was explained that these dihydropyridines may
act as precursors and after penetration into cell wall may lead to the 3,5-
carboxylate anions by enzymatic hydrolysis. All these derivatives were screened
for their antitubercular activity against M. tuberculosis H 37 Rv, among them some
derivatives showed >90% inhibition comparable to Riampicin.
R
R'
O
O
R'
NH
NH
H 3 C N
H
CH 3
R= C 6
H 5
, Cl, NO 2
.....
R'= NO 2
, OCH 3
,Cl.....
The result of QSAR studies of all these derivatives indicates that the presence of
bulkier substituents in the phenyl ring at C 4 position of the dihydropyridines
positively contributes for the antitubercular activity.
The electronic influence of the substituents at the carbamoyl phenyl ring present
at 3 and 5 positions of dihydropyridines are important for antitubercular activity, in
the order of σ m >σ p >σ o . The presence of the electron withdrawing group at meta
and Para position increase activity, while at ortho position decrease the activity.
These electronic effects may influence the enzymatic hydrolysis of the amide
bond present at 3 and 5 position if substituted dihydropyridines to corresponding
acids inside the M. Tuberculosis.
To explore further structural requirements of 1,4 dihydropyridines for
antitubercular activity, 3D QSAR study has been carried out by Shah et al 9 . The
two methods for 3D QSAR study were performed:
1.
2.
Comparative molecular similarity indices analysis (CoMSIA) 10
Comparative molecular field analysis (CoMFA) 10

60
According to the 3D QSAR study, a low electron density in the area of 3 and 4
position of 3,5- disubstituted carbamoyl phenyl moiety, will have a positive effect
on the biological activity. The compound containing electron withdrawing groups
at these positions show more activity. The C 4 position of dihydropyridines
requires aryl group/phenyl group having electron density in the area of C 4
position.
In continuation of work on dihydropyridine skeleton modification, this chapter
reports synthesis of symmetrical 1,4-DHPs with naphthyl ring at C 3 and C 5
positions of dihydropyridines and asymmetrical derivatives with naphthyl
carbamoyl side chain.

61
2.3 REACTION SCHEMES
2.3.1 Scheme 1
NH 2
O
+
CH 3
Toluene,
NH CH 3
O
KOH,reflux
O
O
CH 3
2.3.2 Scheme 2
R
O
NH
H 3 C
O
+ O H
+
O
O CH 3
NH
Liq.NH 3
CH 3
OH
O
R
O
NH
NH
H 3 C N CH 3
H

62
2.3.3 Scheme 3
O
O
R
HN
CH 3
O
H
+
IPA+Gl.HAc
Piperidine
O
NH
R
O
CH 3
2.3.4 Scheme 4
R
H 3 C
O
O
O
CH 3
+
NH
C H 3
O
O
CH 3
CH 3
OH
Liq. NH 3
R
C H 3
O
O
H 3 C
N
H
O
CH 3
NH

63
2.4 Experimental Observation
In the preparation of acetoacetanilides, amount of caustic slurry is critical and
reaction must be refluxed for 15 hrs unless the yield loss is observed. In the last
stage of preparation of acetoacetanilide, toluene is to be distilled out, if the trace
of toluene is not removed, then isolation of product becomes tricky and takes
much time. During distillation, if excess heating done after complete distillation of
toluene then product become charred and whole reaction mass become sticky
and product can not be obtained. Temperature during distillation should be
maintained and between 110-115
o C. During isolation of acetoacetanilide
sufficient amount of ether wash is to be given to get non sticky and impurity free
product.
In the second step preparation of arylidine derivatives, the temperature is kept
between 50-60 o C. The increase in temperature results in charring of products.
Glacial acetic acid and piperidene is added only after dissolving the reactant. In
final stage, mixture of acetoacetanilide and aldehyde heated at 80-90 o C. Only
after complete dissolution, 1-2 ml of liq. ammonia is to be added. The resulting
mass converted into solid after 7-9 hrs reflux time and cooling at room
temperature and treated with chilled methanol to yield light yellow product.

64
2.5 EXPERIMENTAL
2.5.1 N-(naphthalene-5-yl)-3-oxobutanaide (Scheme-1)
A mixture of α-nephthayl amine and ethyl acetoacetate was refluxed at 110 0 C in
40 ml of toluene and catalytic amount of KOH/NaOH. The completion of the
reaction was monitored by TLC. After completion of reaction, toluene was distilled
out. The residue was cooled at room temperature and was treated with ether.
The solid was filtered and dried. (Yield: 65 %)
2.5.2 1,4-dihydro-4-(substituted phenyl)-2,6-dimethyl-N,N-di(naphthalene-1-
yl)pyridine-3,5-dicarboxamide (Scheme-2)
[General method]
A mixture of N-1-naphthyl-3-oxobutanamide (0.02 m) and substituted
benzaldehyde (0.01 m) in 10 ml methanol was refluxed on steam bath for 5-10
hrs. The reaction mixture was cooled and transferred to a beaker. On cooling,
crystalline product separated out which was recrysatllized from hot methanol.
Yield 45-62 %.
Physical data of newly synthesized compounds are given in Table 2.6.1.
2.5.3 Synthesis of substituted arylidene derivatives (Scheme-3)
[General method]
A mixture of substituted acetoacetanilide (0.01 m), substituted benzaldehyde
(0.01 m) in 4-5 ml isopropyl alchohol (IPA) was mechanically stirred in presence
of catalytic amount of glacial acetic acid and piperidene. The reaction time ranges
from 20 min to 12 hrs for different aryl amines. White solid product isolated was
filtered and washed with IPA to remove unreacted aldehyde. The compound was
recrystallized from methanol. The yield of the compounds range from 50-70 %.
2.5.4 Synthesis of substituted unsymmetrical carbamoyl DHP (Scheme-4)
[General method]
A mixture of substituted arylidene derivative (0.01 mole) and acetyl acetone (0.01
mole) was added into 10 ml methanol in a 100 ml conical flask and then 1-2 ml of
liq. ammonia was added. The reaction mixture was refluxed with stirring for 3-10

65
hrs. Pale yellow product comes out, which was isolated and filtered when hot. It
was further washed with methanol to remove the unreacted mass and other
impurities. Recrystallization was carried out in methanol. The yield of title
compounds range from 40-60 %.
Physical data of newly synthesized compounds are given in Table 2.6.2.

66
2.6 PHYSICAL DATA TABLE
2.6.1 Physical data of 1,4- dihydro-4-(substituted phenyl)-2,6-dimethyl-N 3 ,
N 5 - di(naphthalen-1-yl) pyridine-3,5-dicarboxamides (AKS 1-12)
R
O
O
NH
NH
H 3 C N CH 3
H
Code No.
R MW MP in o C
Yield
in %
Rf
value
AKS-1 4-OCH 3 553.64 276-278 62 0.42
AKS-2 3-NO 2 566.62 189-191 69 0.46
AKS-3 2-OCH 3 552.64 256-258 54 0.36
AKS-4 3,4-OCH 3 583.67 156-148 52 0.31
AKS-5 4-NO 2 566.62 178-180 61 0.41
AKS-6 2-Cl 558.06 146-148 52 0.51
AKS-7 2,3-benzo 575.68 177-179 62 *0.42
AKS-8 4-OH 539.62 156-158 54 0.38
AKS-9 3,4,5-tri-OCH 3 612.70 174-176 63 *0.51
AKS-10 3-Cl 558.06 192-194 64 0.43
AKS-11 H 523.62 187-189 60 0.37
AKS-12 2-NO 2 566.62 214-216 59 *0.42
TLC solvent system: Ethyl acetate : Hexane 3.5 ml : 1.5 ml
*Chloroform : Methanol 9.5 ml : 0.5 ml
Visualization: UV light (long)

67
2.6.2 Physical data of Methyl-5-(naphthalen-1-yl-carbamoyl)-1,4-dihydro-4-
(substituted phenyl)-2,6-dimethyl-4-phenylpyridine-3-carboxylate
(AKS 13-20)
R
O
O
C H 3
O
NH
H 3 C N CH 3
H
Code No. R MW MP in o C
Yield Rf
in % value
AKS-13 H 412.48 256-258 61 0.49
AKS-14 2-OCH 3 444.52 196-198 47 0.53
AKS-15 4-Cl 448.94 246-248 54 0.35
AKS-16 4-F 432.48 286-288 58 0.41
AKS-17 4-OCH 3 444.52 242-244 61 0.46
AKS-18 4-NO 2 459.49 174-176 62 0.51
AKS-19 3-NO 2 459.49 212-214 59 0.43
AKS-20 2-Cl 448.94 165-167 46 0.41
TLC solvent system: Ethyl acetate : Hexane (2.5 ml) : (3.0 ml)
Visualization: UV light (long)

68
2.7 SPECTRAL DISCUSSION
2.7.1 IR SPECTRAL ANALYSIS
The infrared spectrum is significant range lies between 4000 and 610 cm -1 .
Absorption bands in the spectrum effect from energy changes arise as a
consequence of molecular vibrations of the bond stretching and bending nature.
The aromaticity of the compounds is determined from the significant absorption
around 1600-1400 cm -1 and 850-660 C=C, C=O show considerable absorption
between 2500-1600 cm -1 . Similarly, assorted function groups demonstrate
specific absorption in the finger print region which become the key point in their
recognition.
Spectral data of the only key transitional and final compounds are included. Using
the instrument, SHIMADZU FT IR-8400, sample technique, KBr disc, frequency
range, 400-4000 cm -1 .
Looking to the spectral learn of the newly synthesized DHPs molecules, the
carbonyl (>C=O) of the amidic functionality stretching was observed at 1650-
1689 cm -1 . The amide (>C-N stretching) is pragmatic at 1300-1400 cm -1 .
The stretching of the secondary amide (>NH) was observed between 3100-3400
cm -1 . In all the compounds two –NH- str vibration observed for two secondary
amine groups. One of them illustrate absorption at inferior frequency due to
carbonyl group attached to it. The stretching C-N appears at 1210-1420 cm -1
which further adds up the evidence of the presence of secondary amine group.
As far as the aromatic skeleton concerned, C-C multiple bonds stretching, C-H in
plan bending and out of plan bending were observed at 1400-1600 cm -1 and 810-
730 cm -1 correspondingly. IR spectra of newly synthesized compounds are given
on Pages 78-79.
2.7.2 NMR SPECTRAL ANALYSIS
Nuclear magnetic resonance (NMR) spectroscopy is dominant instrument for the
organic chemist since instruments are now easily available ever since last
decade. The technique is only relevant to those nuclei which possess a spin
quantum number (I) greater then zero. The most significant of such nuclei as far

69
as the organic chemist is concerned are 1 H and 13 C both of which have spin
quantum number of ½. The basis of the NMR experiment is to focus the nuclei to
radiation which will result in transition from the lower energy state to higher one.
The nuclei which are in the same environment have the same energy dissimilarity
between spin orientations. So these energy differences are detected and
interpreted to know the variety of location of the nuclei in the molecule.
Instrument use for the NMR spectroscopy of the newly synthesized DHP was
BRUKER AC 300 MHz FT-NMR, where TMS was used as the internal reference
and CDCl 3 or DMSO d 6 were used as solvent. In case of AKS-2, two methyl
groups were present at C2 and C5 position of pyridine ring, both methyl group
have same environment therefore, these two methyl group revealed singlet at
2.35 δ ppm. While chiral carbon of the pyridine nucleus at C4 show at 5.72 δ ppm
with a singlet, thereby confirmed dihydropiridine nucleus. In the molecule, two
protons of the amide linkage also show singlet at 9.24 δ ppm. Even as –NH
protons of the pyridine nucleus also give singlet at 8.09 δ ppm, its give sound
evidence of pyridine nucleus. While one protons of the phenyl ring provide triplet
at 8.52 δ ppm with J value 2.06 Hz as a result of Meta coupling with one proton
and it confirmed the meta substitution in phenyl ring. Even as this protons also
give doublet at 7.94 δ ppm with J=7.76 Hz cause of the ortho coupling with
neighboring protons. Other protons also gave triplet- triplet splitting caused by
ortho-meta coupling at 8.14 δ ppm with J=2.08, 7.44 Hz (please refer 1 H NMR
spectra of AKS-2).
The NMR gives the promising evidence for the elucidation of the structure of the
DHP molecules. 1H NMR spectra of newly synthesized compounds are given on
Pages 80-82.
2.7.3 MASS SPECTRAL ANALYSIS
The MASS spectrometry is used for accurate determination of the molecular
weight. It is also provide information concerning the structure of compound by an
examination pattern. Once the organic molecule bombarded with the electrons
under high vacuum, each molecule looses electron by various fission processes
giving rise to ions and neutral fragments. The positive ions are expelled from the

70
ionization chamber and resolved by the means of magnetic field. When these
ions arrive at the detector, they are recorded. The intense of the peak in the
spectrum indicates the abundance of ions. The most intense peak is called base
peak. When a single electron is removed from the molecule it gives rise to
molecular ion peak and has uppermost molecular weight.
For the entire newly synthesized compounds, molecular ion peak are in total
agreement with their molecular weight. In case of AKS-2 and AKS-5 base peak
were observed at 255 m/e value, caused by fragmentation at both carbonyl of
dihydropiridine molecule, which was totally relevant to left behind pyridine
nucleus. For AKS-3 molecular ion peak is observed at 552 m/e, which is also
total agreement with its molecular weight. Base peak is observed at 432 due to
subsequently loss of methyl group at C 6 position and substituted phenyl ring from
C4 position from dihydropiridine ring.
Mass spectra of newly synthesized compounds are given on Page 83.
2.7.4 Elemental Analysis
Elemental analysis of the all the synthesized compounds was carried out on
Elemental Vario EL III Carlo Erba 1108 model and the results are in agreements
(within the range of theoretical value) with the structures assigned.

71
Mass Fragmentation of 1,4- dihydro-4-(4-nitrophenyl)-2,6-dimethyl-N 3 , N 5 -
di(napthalen-1-yl)pyridine-3,5-dicarboxamide (AKS-2)
O
N + O -
NH 2
O
O
O
O
NH
NH
H 3 C N CH 3
H
H 3 C CH 3
H 3 C N CH 3
H
14
O
O
CH 2 CH 3
NH
H 3
C N CH 3
H
3
2
1
O
14
13
C
O
NH
4
O
N + O -
O
12
CH 3
H 3
C
H 3
N CH 3
H
NH 2
O O
H 3 C N CH 3
H
5
base peak
6
7
NH
NH
H 3 C N CH 3
H
8
9
10
11
CH 2
CH 2 CH 2
H 3
C
C
CH 3
H 3 CH 3
N
N
H
N
H
H 3 C CH 3 H
H 3 C N H
SPECTRAL DATA
1, 4 – Dihydro – 4 - (4-methoxy phenyl) – 2, 6 - dimethyl-N 3 , N 5 -di (napthalen-
1-yl)pyridine-3,5-dicarboxamide (AKS-1)
IR (KBr, cm -1 ): 3284 (-NH), 3037-3011 (Ar-CH, str), 2924 (methyl,asym,str),
2868 (methyl,sym,str), 1674 (>C=O,amide),1340 (C-N,str), 1637-1442
(>C=C,ring skeletal vibration), 1516 (-NH Deformation)1219 (C-H, ipd), 813 (C-
H,opd),1089,1024 (C-O-C,sym,str).

72
C, H, N (in %): Found: 78.10 (C), 5.64 (H), 7.59 (N) Cacld: 78.12 (C), 5.63 (H),
7.61 (N)
1,4- Dihydro-4-(3-nitrophenyl)-2,6-dimethyl-N 3 , N 5 -di(napthalen-1-yl)pyridine
-3,5-dicarboxamide (AKS-2)
IR (KBr, cm -1 ): 3273 (-NH), 3051 (Ar-CH, str), 2924 (methyl,asym,str), 2868,2759
(methyl,sym,str), 1662 (>C=O,amide),1340 (C-N,str), 1637-1442 (>C=C,ring
skeletal vibration), 1516 (-NH Deformation)1219 (C-H, ipd), 813 (C-
H,opd),1089,1024 (C-O-C,sym,str).
1 H NMR (In δ ppm): 2.35 (s, 6H, a), 5.72 (s, 1H, b), 7.34 (m, 2H, J=1.04), 7.44
(m, 6H, f 3 , d 3 , d 1 ), 7.60 (2H,d-d, e 4 , f 1, J=7.92, 9.08 ), 7.80 (2H, d, d 2 J=8.16),
7.94 (2H, d,e 3 , J=7.76 ), 8.09 (s, 1H,b 3 ), 8.14-8.16 (t-t, 1H, e 2 , J=2.08, 7.44),
8.52 (t, 1H, e 1 J=2.08), 9.24 (s, 2H, b 1, b 2 )
Mass (m/e value): 566 (4), 424 (6), 418 (2), 397 (35), 367 (3), 281 (8), 255
(100), 239 (3), 225 (18), 209 (33), 182 (13), 169 (74), 143 (53), 135 (39), 102 (5),
89 (9), 77 (8), 63 (12), 44 (54)
C, H, N (in %): Found: 73.93 (C), 4.96 (H), 9.58 (N) Cacld: 73.96 (C), 4.94 (H),
9.60 (N)
1, 4 – dihydro -4- (2-methoxy phenyl) -2,6- dimethyl -N 3 , N 5 -di (napthalen-1-
yl)pyridine-3,5-dicarboxamide (AKS-3)
IR (KBr, cm -1 ): 3306(-NH), 3101-3068 (Ar-CH, str), 2918 (methyl,asym,str),
2868 (methyl,sym,str), 1662 (>C=O,amide),1348 (C-N,str), 1591-1427
(>C=C,ring skeletal vibration), 1591 (-NH Deformation)1247 (C-H, ipd), 773 (C-
H,opd),1069,1012 (C-O-C,sym,str).
C, H, N (in %): Found: 78.10 (C), 5.64 (H), 7.59 (N) Cacld: 78.12 (C), 5.65 (H),
7.62 (N)
1, 4- Dihydro -4- (3,4-dimethoxy phenyl) -2,6-dimethyl-N 3 , N 5 -di (napthalen-1-
yl)pyridine-3,5-dicarboxamide (AKS-4)
IR (KBr, cm -1 ): 3325,3301 (-NH), 3057-3021 (Ar-CH, str), 2936
(methyl,asym,str), 2868-2756 (methyl,sym,str), 1664 (>C=O,amide),1340
(C-N,str), 1637-1442 (>C=C,ring skeletal vibration), 1516 (-NH Deformation)1219
(C-H, ipd), 813 (C-H,opd),1089,1024 (C-O-C,sym,str).
C, H, N (in %): Found: 76.14 (C), 5.70 (H), 7.20 (N) Cacld: 76.12 (C), 5.72 (H),
7.24 (N)

73
1, 4- Dihydro - 4-(4-nitro phenyl) - 2 , 6- dimethyl - N 3 , N 5 - di (napthalen – 1 -
yl)pyridine-3,5-dicarboxamide (AKS-5)
IR (KBr, cm -1 ): 3315,3273 (-NH), 3051,3010 (Ar-CH, str), 2956, 2930
(methyl,asym,str), 2886,2725 (methyl,sym,str), 1672 (>C=O,amide),1352 (C-
N,str), 1650-1437 (>C=C,ring skeletal vibration), 1535 (-NH Deformation)1242
(C-H, ipd), 756 (C-H,opd),1091,1014 (C-O-C,sym,str).
1 H NMR (In δ ppm): 2.36 (s, 6H), 5.65 (s, 1H), 7.33 (t, 2H, J= 8.12, 7.08 Hz),
7.43 (t, 4H, J= 8.32, 7.48 Hz), 7.49 (m, 2H, J= 1.56, 4.36 Hz), 7.58 (t, 2H, J=
10.68, 8.92, 1.48 Hz), 7.68 (d, 2H, J= 8.64 Hz), 7.82 (m, 2H, J= 7.56, 8.36, 8.68
Hz), 8.13 (d, 2H, J= 7.52 Hz), 8.22 (t, 2H, J= 6.84, 1.92 Hz), 8.87 (s, 1H, -NH),
8.94 (s, 2H, -NH)
Mass (m/e value): 566 (4), 424 (7), 397 (32), 382 (6), 367 (3), 312 (2), 281 (8),
277 (2), 255 (100), 251 (4), 225 (18), 210 (5), 209 (15), 182 (9), 169 (75), 154 (4),
143 (57), 139 (20), 115 (37), 102 (4), 89 (9), 70 (10), 63 (12), 44 (23)
C, H, N (in %): Found: 73.93 (C), 4.96 (H), 9.58 (N) Cacld: 73.95 (C), 4.99 (H),
9.60 (N)
1,4-Dihydro-4-(2-chlorophenyl)-2,6-dimethyl-N 3 ,N-di(napthalen-1-yl)pyridine-
3,5-dicarboxamide (AKS-6)
IR (KBr, cm -1 ): 3326,3275 (-NH), 3024 (Ar-CH, str), 2964,2910 (methyl,asym,str),
2870, 2714 (methyl,sym,str), 1654 (>C=O,amide),1346 (C-N,str), 1610-1432
(>C=C,ring skeletal vibration), 1541 (-NH Deformation)1242 (C-H, ipd), 786 (C-
H,opd),1095,1014 (C-O-C,sym,str).
C, H, N (in %): Found: 75.32 (C), 5.06 (H), 7.53 (N) Cacld: 75.31 (C), 5.08 (H),
7.56 (N)
1,4- Dihydro -2,6- dimethyl-N 3 ,N 5 ,4-tri(napthalen-1-yl) pyridine-3,5-
dicarboxamide (AKS-7)
IR (KBr, cm -1 ): 3336,3284 (-NH), 3045 (Ar-CH, str), 2965,2941 (methyl,asym,str),
2878,2710 (methyl,sym,str), 1671 (>C=O,amide),1348 (C-N,str), 1621-1440
(>C=C,ring skeletal vibration), 1518 (-NH Deformation)1235 (C-H, ipd), 801 (C-
H,opd),1090,1034 (C-O-C,sym,str).
C, H, N (in %): Found: 81.65 (C), 5.45 (H), 7.32 (N) Cacld: 81.66 (C), 5.48 (H),
7.34 (N)

74
1,4- Dihydro -4- (4-hydroxy phenyl) -2,6- dimethyl- N 3 , N 5 -di (napthalen-1-yl)
pyridine -3,5- dicarboxamide (AKS-8)
IR (KBr, cm -1 ): 3348,3273 (-NH), 3068,3014 (Ar-CH, str), 2945,2910
(methyl,asym,str), 2878,2749 (methyl,sym,str), 1666 (>C=O,amide),1342 (C-
N,str), 1647-1440 (>C=C,ring skeletal vibration), 1526 (-NH Deformation)1220
(C-H, ipd), 789 (C-H,opd),1099,1021 (C-O-C,sym,str).
C, H, N (in %): Found: 77.90 (C), 5.42 (H), 7.79 (N) Cacld: 77.94 (C), 5.47 (H),
7.84 (N)
1,4- Dihydro-4-(3,4,5-trimethoxyphenyl)-2,6-dimethyl-N 3 , N 5 -di(napthalen-1-
yl)pyridine-3,5-dicarboxamide (AKS-9)
IR (KBr, cm -1 ): 3317,3284 (-NH), 3050,3021 (Ar-CH, str), 2965,2924
(methyl,asym,str), 2868,2724 (methyl,sym,str), 1670 (>C=O,amide),1344 (C-
N,str), 1638-1442 (>C=C,ring skeletal vibration), 1526 (-NH Deformation)1229
(C-H, ipd), 765 (C-H,opd),1097,1010 (C-O-C,sym,str).
C, H, N (in %): Found: 74.37 (C), 5.75 (H), 6.85 (N) Cacld: 74.34 (C), 5.78 (H),
6.89 (N)
1, 4- Dihydro -4- (3-chloro phenyl)- 2,6 –dimethyl -N 3 ,N 5 -di (napthalen-1-
yl)pyridine-3,5-dicarboxamide (AKS-10)
IR (KBr, cm -1 ): 3365,3252 (-NH), 3050 (Ar-CH, str), 2958,2924 (methyl,asym,str),
2874,2740 (methyl,sym,str), 1665 (>C=O,amide),1342 (C-N,str), 1647-1435
(>C=C,ring skeletal vibration), 1530 (-NH Deformation)1222 (C-H, ipd), 745 (C-
H,opd),1093,1013 (C-O-C,sym,str).
C, H, N (in %): Found: 75.32 (C), 5.06 (H), 7.53 (N) Cacld: 75.30 (C), 5.10 (H),
7.55 (N)
1,4- Dihydro - 2,6 – dimethyl - N 3 ,N 5 - di (napthalen-1-yl) -4- phenyl pyridine-
3,5-dicarboxamide (AKS-11)
IR (KBr, cm -1 ): 3405,3387,3294 (-NH), 3084,3023 (Ar-CH, str), 2965,2924
(methyl,asym,str), 2868,2745 (methyl,sym,str), 1671 (>C=O,amide),1352 (C-
N,str), 1631-1452 (>C=C,ring skeletal vibration), 1532 (-NH Deformation)1215
(C-H, ipd), 744 (C-H,opd),1091,1021 (C-O-C,sym,str).
C, H, N (in %): Found: 80.28 (C), 5.58 (H), 8.02 (N), Cacld: 80.26 (C), 5.59 (H),
8.07 (N)

75
1,4- Dihydro – 4 - (2-nitro phenyl) - 2, 6 – dimethyl - N 3 , N 5 - di (napthalen - 1 -
yl)pyridine-3,5-dicarboxamide (AKS-12)
IR (KBr, cm -1 ): 3412, 3374 (-NH), 3042,3014 (Ar-CH, str), 2962-2940-
(methyl,asym,str), 1674 (>C=O,amide), 1721 (-C=O,ester)1352 (C-N,str), 1644-
1438 (>C=C,ring skeletal vibration), 1542 (-NH Deformation)1246 (C-H, ipd), 784
(C-H,opd),1090,1008 (C-O-C,sym,str)
1 H NMR (In δ ppm): 2.32 (s, 6H), 5.66 (s, 1H), 7.32 (t, 2H, J= 7.60, 7.44), 7.42 (t,
4H, J= 7.68, 5.64), 7.49 (d, 2H, J= 7.16 Hz), 7.56 (d, 2H, J= 8.44), 7.67 (d, 2H, J=
8.04), 7.77 (m, 4H, J= 8.16, 8.84), 8.20 (d, 2H, J= 8.56), 9.17 (s, 2H)
C, H, N (in %): Found: 73.91 (C), 4.96 (H), 9.56 (N) Cacld: 73.95 (C), 4.99 (H),
9.60 (N)
Methyl –5-(naphthalene–1– yl - carbamoyl) - 1, 4 – dihydro -2,6-dimethyl-4-
phenylpyridine-3-carboxylate(AKS-13)
IR (KBr, cm -1 ): 3367,3271 (-NH), 3065,3010 (Ar-CH, str), 2974-2946-
(methyl,asym,str), 1671 (>C=O,amide), 1710 (-C=O,ester)1346 (C-N,str), 1640-
1440 (>C=C,ring skeletal vibration), 1556 (-NH Deformation)1240 (C-H, ipd), 796
(C-H,opd),1099,1014 (C-O-C,sym,str)
C, H, N (in %): Found: 75.71 (C), 5.86 (H), 6.79 (N), Cacld: 75.74 (C), 5.85 (H),
6.82 (N)
Methyl-5-(naphthalen-1-yl-carbamoyl)-1,4-dihydro-4-(2-methoxyphenyl)-2,6-
dimethyl-4-phenylpyridine-3-carboxylate(AKS-14)
IR (KBr, cm -1 ): 3345,3283 (-NH), 3070,3026 (Ar-CH, str), 2965-2924-
(methyl,asym,str), 1669 (>C=O,amide), 1714 (-C=O,ester)1352 (C-N,str), 1650-
1436 (>C=C,ring skeletal vibration), 1543 (-NH Deformation)1232 (C-H, ipd), 774
(C-H,opd),1089,1013 (C-O-C,sym,str).
C, H, N (in %): Found: 73.28 (C), 5.92 (H), 6.33 (N), Cacld: 73.26 (C), 5.90 (H),
6.34 (N)
Methyl-5-(naphthalen-1-yl-carbamoyl)-1,4-dihydro-4-(4-chlorophenyl)-2,6-
dimethyl-4-phenylpyridine-3-carboxylate(AKS-15)
IR (KBr, cm -1 ): 3412,3301 (-NH), 3074,3026 (Ar-CH, str), 2965-2946-
(methyl,asym,str), 1664 (>C=O,amide), 1717 (-C=O,ester)1342 (C-N,str), 1636-
1441 (>C=C,ring skeletal vibration), 1535 (-NH Deformation)1240 (C-H, ipd), 796
(C-H,opd),1099,1014 (C-O-C,sym,str).

76
C, H, N (in %): Found: 69.87 (C), 5.19 (H), 6.27 (N), Cacld: 69.89 (C), 5.23 (H),
6.30 (N)
Methyl-5-(naphthalen-1-yl-carbamoyl)-1,4-dihydro-4-(4-flourophenyl)-2,6-
dimethyl-4-phenylpyridine-3-carboxylate(AKS-16)
IR (KBr, cm -1 ): 3367,3271 (-NH), 3065,3010 (Ar-CH, str), 2974-2946-
(methyl,asym,str), 1671 (>C=O,amide), 1710 (-C=O,ester)1346 (C-N,str), 1640-
1440 (>C=C,ring skeletal vibration), 1556 (-NH Deformation)1240 (C-H, ipd), 796
(C-H,opd),1099,1014 (C-O-C,sym,str).
C, H, N (in %): Found: 72.54 (C), 5.39 (H), 4.44 (N), Cacld: 72.55 (C), 5.36 (H),
4.48 (N)
Methyl-5-(naphthalen-1-yl-carbamoyl)-1,4-dihydro-4-(4-methoxyphenyl)-2,6-
dimethyl-4-phenylpyridine-3-carboxylate(AKS-17)
IR (KBr, cm -1 ): 3357,3265 (-NH), 3024 (Ar-CH, str), 2968-2951-
(methyl,asym,str), 1662 (>C=O,amide), 1718(-C=O,ester)1352 (C-N,str), 1645-
1442 (>C=C,ring skeletal vibration), 1531 (-NH Deformation)1219 (C-H, ipd), 889
(C-H,opd),1093 (C-O-C,sym,str).
C, H, N (in %): Found: 73.28 (C), 5.92 (H), 6.32 (N), Cacld: 73.26 (C), 5.97 (H),
6.35 (N)
Methyl -5- (naphthalene-1-yl-carbamoyl)- 1,4-dihydro -4- (4-nitro phenyl)-2,6-
dimethyl-4-phenylpyridine-3-carboxylate(AKS-18)
IR (KBr, cm -1 ): 3371,3302, (-NH), 3037 (Ar-CH, str), 1666 (>C=O,amide), 1718(-
C=O,ester)1334 (C-N,str), 1525-1440 (>C=C,ring skeletal vibration), 1525 (-NH
Deformation)1236 (C-H, ipd), 790 (C-H,opd),1099-1039 (C-O-C,sym,str).
C, H, N (in %): Cacld: 68.26 (C), 5.07 (H), 9.14 (N), Found: 68.24 (C), 5.10 (H),
9.16 (N)
Methyl-5- (naphthalene -1-yl-carbamoyl) -1,4-dihydro -4- (3-nitro phenyl)-2,6-
dimethyl-4-phenylpyridine-3-carboxylate(AKS-19)
IR (KBr, cm -1 ): 3324,3276 (-NH), 3051,3011 (Ar-CH, str), 2975-2930-
(methyl,asym,str), 1666 (>C=O,amide), 1712 (-C=O,ester)1362 (C-N,str), 1640-
1433 (>C=C,ring skeletal vibration), 1534 (-NH Deformation)1240 (C-H, ipd), 786
(C-H,opd),1099,1011 (C-O-C,sym,str).
C, H, N (in %): Found: 68.26 (C), 5.07 (H), 9.14 (N), Cacld: 68.24 (C), 5.10 (H),
9.16 (N)

77
Methyl-5- (naphthalen-1-yl-carbamoyl) -1,4-dihydro -4- (2-chloro phenyl)-2,6-
dimethyl-4-phenylpyridine-3-carboxylate(AKS-20)
IR (KBr, cm -1 ): 3410,3342 (-NH), 3074,3043 (Ar-CH, str), 2970-2945-
(methyl,asym,str), 1668 (>C=O,amide), 1767 (-C=O,ester)1342 (C-N,str), 1644-
1442 (>C=C,ring skeletal vibration), 1550 (-NH Deformation)1251 (C-H, ipd), 801
(C-H,opd),1089,1010 (C-O-C,sym,str).
C, H, N (in %): Found: 69.87 (C), 5.19 (H), 6.27 (N), Cacld: 69.88 (C), 5.24 (H),
6.229 (N)

IR spectrum of 1,4- dihydro-4-(4-methoxyphenyl)-2,6-dimethyl-N 3 , N 5 -
di(napthalen-1-yl)pyridine-3,5-dicarboxamide (AKS-1)
78
O CH 3
O
O
NH
NH
H 3 C N CH 3
H
IR spectrum of 1,4- dihydro-4-(3-nitrophenyl)-2,6-dimethyl-N 3 , N 5 -
di(napthalen-1-yl)pyridine-3,5-dicarboxamide (AKS-2)
O
N + O -
O
O
NH
NH
H 3 C N CH 3
H

IR spectrum of 1,4- dihydro-4-(2-methoxyphenyl)-2,6-dimethyl-N 3 , N 5 -
di(napthalen-1-yl)pyridine-3,5-dicarboxamide (AKS-3)
79
O CH3
O
O
NH
NH
H 3 C N CH 3
H
IR spectrum of Methyl-5-(naphthalen-1-yl-carbamoyl)-1,4-dihydro-2,6-
dimethyl-4-phenylpyridine-3-carboxylate(AKS-13)
C H 3
O
O
O
NH
H 3 C N CH 3
H

1 H NMR spectrum of 1,4- dihydro-4-(4-nitrophenyl)-2,6-dimethyl-N 3 , N 5 -
di(napthalen-1-yl)pyridine-3,5-dicarboxamide (AKS-2)
80
.
e 2
O
N + O -
f 3 f 3
e 3
f 2
f 4
e 4 e
O 1
f
O 4 f 2
f H
1 b
f
NH
1
b NH
d 1
d 3 1 b 2 d3 d1
d2 H 3 C N CH 3 d 2
a Hb 3
a

1 H NMR spectrum of 1,4- dihydro-4-(2-nitrophenyl)-2,6-dimethyl-N 3 , N 5 -
di(napthalen-1-yl)pyridine-3,5-dicarboxamide (AKS-12)
81
O
NH
O
N + OO
-
NH
H 3 C N CH 3
H

1 H NMR spectrum of 1,4- dihydro-4-(4-nitrophenyl)-2,6-dimethyl-N 3 , N 5 -
di(napthalen-1-yl)pyridine-3,5-dicarboxamide (AKS-5)
82
O
N + O-
O
O
NH
NH
H 3 C N CH 3
H

Mass spectrum of 1,4- dihydro-4-(3-nitrophenyl)-2,6-dimethyl-N 3 , N 5 -
di(napthalen-1-yl)pyridine-3,5-dicarboxamide (AKS-2)
83
O
N + O -
O
O
NH
NH
H 3 C N CH 3
H
Mass spectrum of 1,4- dihydro-4-(4-nitrophenyl)-2,6-dimethyl-N 3 , N 5 -
di(napthalen-1-yl)pyridine-3,5-dicarboxamide (AKS-5)
O
N + O-
O
O
NH
NH
H 3 C N CH 3
H

84
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Chapter - 3
A mini review of Dihydropyrimidine Derivatives
1. Biginelli reaction 88
2. Literature survey 90
3. Ionic liquid 96
4. Name reaction 113
5. Rearrangement 116
6. Solid phase synthesis 119
7. Synthetic aspects 121

88
3.1 Biginelli Reaction
P. Biginelli reported the synthesis of functionalized 3,4-dihydropyrimidin-(1H)-
ones (DHPMs) via three-component condensation reaction of an aromatic
aldehyde, urea, and ethyl acetoacetate. In the past decade, this multicomponent
reaction (MCR) has experienced a remarkable revival, mainly due to the
interesting pharmacological properties associated with this dihydropyrimidine
scaffold to generate small libraries of diverse structure 1 .
O
H
EtOH
EtOOC
NH 2
H+
EtOOC
NH
O
H 2 N
O
N
H
O
3.1.1 Dihydropyrimidine Synthesis
Generally the reaction was carried out by heating a mixture of the three
components dissolved in ethanol with a catalytic amount of HCl at reflux
temperature. The product of this one-pot, three-component synthesis that
precipitated on cooling of the reaction mixture was identified correctly by Biginelli
as 3,4-dihydropyrimidin-2(1H)-one. Apart from a series of publications by late
Karl Folkers in the mid 1930s, the “Biginelli reaction” or “Biginelli condensation”
as it was henceforth called was largely ignored in the early part of the 20 th
century. The synthetic potential of this new heterocycle synthesis therefore
remained unexplored for quite some time. In the 1970s and 1980s, interest slowly
increased, and the scope of the original cyclocondensation reaction was
gradually extended by variation of all three building blocks, allowing access to a
large number of multifunctionalized dihydropyrimidines. 2-4
3.1.2 Mechanistic Studies of Biginelli Reaction 5-9
The mechanism of the Biginelli reaction has been the subject of some debate
over the past decades. Early work by Folkers and Johnson 3 suggested that
bisureide, i.e. the primary bimolecular condensation product of benzaldehyde and

urea, is the first intermediate in this reaction. In 1973, Sweet and Fissekis 5
proposed a different pathway and suggested that carbonium ion,
89
C H 3
R
O
O
H
R
+
N H 2
N H 2
O
H
H
H + N +
R
O
H 2 N
[1]
O
H 3 C
O
O
H 3 C
[2]
O
H 3 C
O
H 2 N
[3]
N H
O
C H 3
O
H 3 C
O
C H 3
R
[4]
N
H
O
C H 3
O
R
O
N
C H 3
C H 3
N
H
[5]
O
produced by an acid-catalyzed aldol reaction of benzaldehyde with ethyl
acetoacetate, is formed in the first and limiting step of the Biginelli condensation.
Kappe et al 6 reinvestigated the mechanism in 1997 using
1 H/ 13 C NMR
spectroscopy and trapping experiments and have established that the key step in
this sequence involves the acid-catalyzed formation of an N-acyliminium ion
intermediate [1] from the aldehyde and urea precursors. Interception of the
iminium ion by ethyl acetoacetate [2], presumably through its enol tautomer [3],
produces an open-chain ureide which subsequently cyclized to
hexahydropyrimidine [4]. Acid-catalyzed elimination of water ultimately leads to
the final DHPM product [5]. The reaction mechanism can therefore be classified
as a α-amidoalkylation, or more specifically as a α-ureidoalkylation. The
alternative “carbenium ion mechanism” does not constitute a major pathway;
however, small amounts of enone are sometimes observed as byproduct.
Although the highly reactive N-acyliminium ion species could not be isolated or
directly observed, further evidence for the proposed mechanism was obtained by
isolation of intermediates, employing sterically bulky or electron-deficient
acetoacetates respectively. The relative stereochemistry in hexahydropyrimidine
was established by an X-ray analysis. In fact, a number of hexahydropyrimidines

90
could be synthesized by using perfluorinated 1,3-dicarbonyl compounds or α-keto
esters as building blocks in the Biginelli condensation.
3.2 Literature Survey
Various modifications have been applied to Biginelli reaction to get better yield
and to synthesize biologically active analogues. Different catalysts have been
reported to increase the yield of the reaction. Microwave synthesis strategies are
also applied to shorten the reaction time. Solid phase synthesis and
combinatorial chemistry has made possible to generate library of DHPM
analogues.
3.2.1 Catalyst
Essa H. Hu et al 10 reported Biginelli reaction catalyzed with trifluoroborane
etherate, transition metal salt, and proton source to yield 80-90% Biginelli
product. They proposed a mechanism similar to that of Folkers and Johnson 3 and
to that of Kappe 5 for the Biginelli reaction wherein formation of acyl imines
intermediate formed by reaction of the aldehyde with urea and stabilized by
either trifluoroborane or the transition metal, is the key, rate limiting step.
Subsequent addition of the α-keto ester enolate, followed by cyclization and
dehydration, would afford the dihydropyrimidinone. Brindaban C. Ranu et
al 11 reported Indium Chloride as an efficient catalyst for Biginelli reaction. A wide
range of structurally varied α-dicarbonyl compound, aldehyde and urea were
coupled together by this procedure to produce the corresponding
dihydropyrimidinones.
BF 3
O
+
H 2 N N H 2
M
N
O
N H 2
H
O
BF 3
O +
F 3 B
N
O
N H 2
M
O
O Ar
R 2 OR 1
OR 1
N H
R 2
O
H 2 N
O
O
Ar
OR 1
N H
R 2
N
H
O

91
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.
O
R 3
O
O
R 1 R 2
R 3
CHO
O/S
H 2 N NH 2
InCl 3
THF
R 2
R 1
N
H
NH
O/S
Bose et al 12 used cerium (III) chloride as a catalyst and reported solvent free
synthesis of Biginelli compounds using this new catalyst. This procedure provides
higher yield, shorter reaction time and simple work up methods. Solvent free
reactions using this catalyst gave about 70% yield and reaction time was about
10 hrs. If ethanol is used as solvent, 90% yield was obtained with this catalyst. 25
mol % amount of cerium (III) chloride heptahydrate was found to be sufficient to
push the reaction forward. The increased amount did not build further advantage.
R
CHO
O/S
H 2 N NH 2
H
R
N
OH
NH 2
H +
- H 2 O
+3 Ce
R
N
H
NH 2
O
O
O
Ce +3
O
O
R
O
R
OCH 3
H 3 CO
NH
H 3 CO
NH
-
H 2 N
H +
- H 2 O
O
O
N
H
O
Enantioselective one pot synthesis of Biginelli reaction is reported with use of
lanthanide triflates/ytterbium triflates. These catalyst leads to highly
enantioselectivity and up to 99% enantioselective Biginelli reaction can be carried
out. 13

92
EtO 2 C
+
H 3 C O
O
H 2 N NH 2
+
CHO
Ln(OTF 3
)
RT
EtO 2 C
NH
C H 3
N
H
O
Entry Lewis acid Solvent Yield, %
1 La(OTf) 3 THF 83
2 Sm(OTf) 3 THF 81
3 Yb(OTf) 3 THF 87
4 Yb(OTf) 3 CH 2 Cl 2 80
5 Yb(OTf) 3 CH 3 CN 86
6 Yb(OTf) 3 CH 3 OH 88
CHO
Me
O
O
OEt
+
O
+
H2N
NH 2
Ln(OTf 3
)
RT
C H 3
O
NH
C H 3
N
H
O
Very recently, chiral phosphoric acid is reported as highly enantioselective
catalyst for Biginelli reaction. Reaction is reported in presence of 10 mol % of
chiral phosphoric acid to produce desired enantioselective product. This is the

93
first organocatalytic asymmetric Biginelli reaction. The optimal chiral phosphoric
acid afforded the reaction in high yields with excellent enantioselectivities of up to
97%. A wide variety of substrates, including aldehydes and α-keto esters, could
be tolerated. This reaction has an advantage of avoiding the contamination of
transition metals in the manufacture of the medicinally relevant chiral 3,4-
dihydropyrimidin-2-(1H)-ones. 14
O
H 2 N
NH 2
O
O
R 1
R'O
O
P
H
OH
X
R 2 OR 3
HN
X
R 2 COOR 3
R 1
NH
R'O
OR'
O
P
O
R 1 H
N
NH 2
H
O
O
R 2 OR 3
X
HN
NH 2
O
OR'
X
R 2
R 1
O
OR 3
Recently Jiang and Chen 15 reported Yb (III)-Resin catalyzed Biginelli reaction
under solvent-free conditions.
O
R 3
O
O
R 3
CHO
S
SO 3 -3 ] 3 Ln +3
R 2
NH
R 1 R 2
H 2 N NH 2
R 1
N
H
S
Heravi et al 16 recently reported synthesis of dihydropyrimidones using 12-
molybdophosphoric acid in refluxing acetic acid to catalyze this three-component
condensation reaction to afford the corresponding pyrimidinones in good yields.

94
An improved approach has been found to carry out the Biginelli reaction for the
synthesis of 3,4- dihydropyrimidin- 2(1H)-one derivatives. This synthesis was
performed in the presence of hydrochloric acid and β-cyclodextrin in ethanol
solution. Compared with the classical Biginelli reaction conditions, this new
approach has the advantage of excellent yields and short reaction time 17. An
efficient synthesis of 3,4-dihydropyrimidinones from the aldehyde, β-keto ester
and urea in ethanol, using ferric chloride hexahydrate or nickel chloride
hexahydrate as the catalyst, is described 18 . Compared with the classical Biginelli
reaction conditions, this new method has the advantage of excellent yields (53-
97%) and short reaction time (4-5 hours). 5-Alkoxycarbonyl-4-aryl-3,4-
dihydropyrimidin-2-ones are synthesized by the one-pot reactions of aldehydes,
β-ketoesters and urea using a catalytic amount of phosphotungstic acid (PTA) in
ethanol. Thus modified Biginelli cyclocondensation not only shortens the reaction
period and simplifies the operation, but also improves the yields. 19
Ruthenium (III) chloride efficiently catalyzes the three-component Biginelli
reaction of an aldehyde, a β-keto ester, and urea or thiourea under solvent-free
conditions to afford the corresponding 3,4-dihydropyrimidine-2-(1H)-ones in
excellent yields 20. The Biginelli reaction, a one-pot condensation of aldehydes,
urea or thiourea, and -dicarbonyl compounds, is efficiently catalyzed by
samarium diiodide.
Scandium (III) triflate efficiently 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. The
catalyst can be recovered and reused, making this method friendly and
environmentally acceptable 23.
O
R
R
CHO
O
O
O/S
Sc(OTf) 3
EtO
NH
OEt
H 2 N NH 2
CH 3 CN
N
H
O/S
Shailaja et al 24 have demonstrated experimentally a simple and straightforward
protocol (combination system of SnCl 2 –LiCl) which provides dihydropyrimidin-2-

95
one system in high yield and high purity while retaining the simplicity of the
Biginelli concept. Magnesium bromide efficiently catalyzes the three-component
condensation reaction of aldehyde, β-diketone and urea/thiourea under solvent
free conditions to afford the corresponding dihydropyrimidinones in high yields
and short reaction time. 25 Bismuth nitrate pentahydrate catalyzes the three
O
R 2
R 2
CHO
O
O
O/S
MgBr 2
R 1
NH
R 1
H 2 N
NH
R 3
45 to 90 min
100 C
N
O/S
R 3
component condensation reaction of an aromatic aldehyde, urea and a β-
ketoester or a β-diketone under solvent-free conditions to afford the
corresponding dihydropyrimidinones (DHPMs) in high yields. The method is also
effective for the selective condensation of aryl aldehydes in the presence of
aliphatic aldehydes 26 . The biologically active dihydropyrimidinones are also easily
synthesized in moderate to excellent yields under solvent-free conditions 21.
Hydroxyapatite doped with ZnCl 2 , CuCl 2 , NiCl 2 and CoCl 2 efficiently catalyses the
three components Biginelli reaction between an aldehyde, ethyl acetoacetate and
urea in refluxing toluene to afford the corresponding dihydropyrimidinones in high
yields 22.
NO 2
CHO
Bi(NO 3 ) 3 5 H 2 O (0.1 mmol)
O
O
CHO
urea, ethylacetoacetate, reflux, 35 min
EtO
NH
NO 2
N
H
NH
EtO
N
H
O
O
78% 0%
Sharma et al 27 reported a simple, efficient, mild and green method has been
developed for the synthesis of 3,4-dihydropyrimidin-2-ones employing dodecyl
sulfonic acid as an excellent surfactant-type Bronsted acid catalyst in aqueous
media at room temperature.

96
H 3 C CH 3 +
O O
s
O
H 2
0, RT
+
H 3 C
CH 3 H 2 N NH 2
10 mol % DSA
O
R 2
C H 3
R 1
N
H
NH
O s
Yadav et al 28 reported that Ceric ammonium nitrate efficiently catalyzes the three
component Biginelli reaction in methanol to afford the corresponding
dihydropyrimidinones in excellent yields.
O
O
CeIV
CeIII
O
O
CONH 2
N
OR
OR
R
R
N
CeIII
CeIV
R
H
N
O
CONH 2
N
H
NH
RO
O
RO
CONH 2
O
RO
O
O
O
3.2.2 Ionic liquid
Wang et al 39 reported the Biginelli reaction between an aromatic aldehyde, ethyl
acetoacetate, and urea - catalyzed by polymer-supported, re-usable, roomtemperature
ionic liquids (RTIL) - was shown to efficiently proceed in glacial
AcOH at 100° to afford the corresponding pyrimidine-5-carboxylates in yields up
to 99% within 2 h. The catalyst(s) could be reused at least five times, basically
without loss of activity, which makes this transformation not only straight-forward,
but also considerably less expensive compared to methods involving classical
RTIL catalysts.
3.3 Biologically active dihydropyrimidones
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 40, 41. In
recent years, interest has also focused on aza-analogs such as
dihydropyrimidines (DHPMs) which show a very similar pharmacological profile to

97
classical dihydropyridine calcium channel modulators 42-49 . Over the past few
years several lead-compounds were developed that are superior in potency and
duration of antihypertensive activity to classical DHP drugs, and compare
favourable with second-generation drugs such as amlodipine and nicardipine 50.
.
MeO 2 C
NO 2
CO 2 Me i-PrO 2 C CONH 2
N
NO 2
N
H
N
NO 2
i-PrO 2 C
O
CO 2 Me
N
H
O
O
Barrow et al 55 reported in vitro and in vivo evaluation of dihydropyrimidinone C-5
amides as potent and selective α 1a Receptor Antagonists for the treatment of
benign prostatic hyperplasia. α 1 adrenergic receptors mediate both vascular and
lower urinary tract tone, and α 1 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 α 1a receptor
being most prevalent in lower urinary tract tissue. 4-aryldihydropyrimidinones
attached to an aminopropyl-4-arylpiperidine via a C-5 amide as selective α 1a
receptor subtype antagonists. In receptor binding assays, these types of
compounds generally display Ki values for the α 1A receptor subtype 20%) and half-life (>6 h) in both rats and
dogs. Due to its selectivity for the α 1a over the α 1b and α 1d receptors as well as its
favourable pharmacokinetic profile, it has the potential to relieve the symptoms of
BPH without eliciting effects on the cardiovascular system. 51-55
F
F
O
N
N
H
NH
R 1
N
H
O
R 3 R 2

98
The 4-aryldihydropyrimidinone heterocycle attached to an aminopropyl-4-
arylpiperidine via a C-5 amide has proved to be an excellent template for
selective α 1a receptor subtype antagonists. These types of compounds are
exceptionally potent in both cloned receptor binding studies as well as in in vivo
pharmacodynamic models of prostatic tone.
Compounds exhibited high binding affinity and subtype selectivity for the cloned
human α 1A receptor. Systematic modifications led to identification of highly potent
and subtype-selective compounds with high binding affinity (Ki =0.2 nM) for α 1a
receptor and greater than 1500-fold selectivity over α 1b and α 1d adrenoceptors.
The compounds were found to be functional antagonists in human, rat, and dog
prostate tissues. They exhibited excellent selectively to inhibit intraurethral
pressure (IUP) as compared to lowering diastolic blood pressure (DBP) in
mongrel dogs (Kb(DBP)/Kb(IUP))suggesting uroselectivity for α 1a -selective
compounds. 56
NO 2
O
O
O
N
N
H
N
Ph
N
H
O
R
Cho et al 57 reported 3-N-substituted-3,4-dihydropyrimidine and 3-N-substituteddihydropyrimidin-2(1H)-ones
as calcium channel antagonist. Compounds
[especially [R 1 =(CH 2 ) 2 N(benzyl)(2-naphthylmethyl),R 2 =i-Pr,X=2-N0 2 ] and [R'=
(CH 2 ) 2 N(benzyl) (3,4-dichlorobenzyl),R 2 =i-Pr, X=2-NO 2 , Y=O/S] exhibited not
only more potent and longer lasting vasodilative action but also a hypertensive
activity with slow onset as compared with dihydropyridines. Moreover, some
dihydropyrimidines[R'= (CH 2 ) 2 N (benzyl) (3-phenylpropyl), R 2 =CH 2 (cyclopropyl),
X=2-NO 2 ] were weaker in blocking atrioventricular conduction in anesthetized
open-chest dogs and less toxic than the dihydropyridines.
X
R 1 OOC
N
COOR 2
Y
N

99
Atwal et al 58 examined a series of novel dihydropyrimidine calcium channel
blockers that contain a basic group attached to either C 5 or N 3 of the heterocyclic
ring. Structure-activity studies show that l-(phenyl methyl)-4-piperidinyl carbamate
moiety at N 3 and sulfur at C 2 are optimal for vmrelaxant activity in vitro and impart
potent and long-acting antihypertensive activity in vivo. One of the 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 dihydropyridine receptor
recognizing the enamino ester moiety but not the carbamate moiety.
Dihydropyrimidine is equipotent to nifidipine and amlodipine in vitro. In the
spontaneously hypertensive rat, dihydropyrimidine is both more potent and longer
acting than nifidipine and compares most favorably with the long-acting
dihydropyridine derivative amlodipine. Dihydropyrimidine has the potential
advantage of being a single enantiomer
.
HCl
i-PrO 2 C
N
CF 3
O 2
C
R i-PrO 2 C
N
N
H
CF 3
O 2
C
F
N
H
S
N
S
N
In order to explain the potent antihypertensive activity of the modestly active (ICw
= 3.2 pM) dihydropyrimidine calcium channel blocker, Atwal et al 59 carried out
drug metabolism studies in the rat and found it is metabolized. Two of the
metabolites (ICw = 16 nM) and (ICw = 12 nM), were found to be responsible for
the 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 both more potent and longer

100
acting than nifedipine as an antihypertensive agent in the SHR. The in vivo
potency and duration is comparable to the long-acting dihydropyridine
amlodipine. The superior oral antihypertensive activity compared to that of
previously described carbamates could be explained by its improved oral
bioavailability, possibly resulting from increased stability of the urea functionality.
NO 2
NO 2
NO 2
O
O
R
N
N
CO 2 Pr
R
N
N
CO 2 Pr
HN
CO 2 Pr
R
O
N
H
H
O
N
H
O
N
H
Atwal et al 60 modified the structure of previously described dihydropyrimidine 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 C 5 ester group,
isopropyl ester being the best, a variety of substituents (carbamate, acyl, sulfonyl,
and alkyl) were tolerated at N 3 . The results show dihydropyrimidines are
significantly more potent than corresponding 2- heteroalkyl-l,4-dihydropyrimidines
and only slightly less potent than similarly substituted 2-heteroalkyl-1-4-
dihydropyridines. Where as dihydropyridine enantiomer usually show 10-15-fold
difference in activity, the enantiomers of dihydropyrimidine show more than a
1000-fold difference in activity. These results strengthen the requirement of an
enamino ester for binding to the dihydropyridine receptor and indicate a
nonspecific role for the N 3 -substituent, 2-Heterosubstituted-4-aryl-l,4-dihydro-6-
methyl-pyrimidinecarbo- axcyildicesters, which lack the potential symmetry of
dihydropyridine- calcium channel blockers, were prepared and evaluated for
NO 2
R 3
R 3
X
N
R 2
COOR 1
N
N
H
R 2
X
N
H
COOR 1
EtOOC
EtX
N
H
COOEt

101
biological activity. Biological assays using potassium-depolarized rabbit aorta and
radio ligand binding techniques showed that some of these compounds are
potent mimics of dihydropyridine calcium channel blockers.
3.3.1 N 3 -Acylated dihydropyrimidines and their biological importance
Kappe et al 61-62 reported that N 3 -acylated DHPMs can be rapidly synthesized in a
high throughput fashion by combining microwave-assisted acylations with
microwave-assisted scavenging techniques. Scavenging experiments can be
carried out employing either supported nucleophilic amine sequestration reagents
or water. N-acylated DHPMs are pharmacologically important N-acylation of
DHPM can be performed as shown below.
R 4
R 4
O
E
NH
(R 3 CO) 2 O, TEA, DMAP
MW, 5-20 min, 100-180 C
E
N
R 3
R 6 N X
R 1
scavenging reagent
MW, 5 min, 80-100 C
SPE
R 6 N X
R 1
N 3 -substituted DHPMs have been identified to possess potent pharmacological
profiles, e.g. following compound exhibited high binding affinity and subtype
selectivity for the cloned human α 1a receptor 63 .
NO 2
O
O
O
N
N
H
N
Ph
N
H
O
R
Systematic modifications of above compounds led to identification of highly
potent and subtype-selective compounds with high binding affinity (Ki = 0.2 nM)
for α 1a receptor and greater than 1500-fold selectivity over α 1b and α 1d
adrenoceptors. The compounds were found to be functional antagonists in
human, rat and dog prostate tissues. Modifications to the C 5 position also play

102
O
R 1
R
NO 2
N
H
N
O
O
NH
N
Ph
CO 2 Me
Important role in potency of DHPM ring. 4-aryldihydropyrimidinones attached to
an aminopropyl-4-arylpiperidine via a C- 5 amide as selective α 1a receptor subtype
antagonists. In receptor binding assays, these types of compounds generally
display Ki values for the α 1a receptor subtype

103
Applying intramolecular Heck reaction, tricyclic ring system can be obtained as
shown below. 66
O
Br
O
Pd 2 (OAc) 2 [P(o-tolyl) 3 ] 2
O
N
H
N
O
O
MW, 150 C, 15 min
O
N
H
N
O
O
The computational experiments reveal that the formation of a tricyclic ring system
did not flatten out the overall geometry. On the contrary, the aryl ring was still
locked in a pseudo axial position, resembling other nonfused 4-aryldihydropyrimidines.
67-68 In fact, here; the intramolecular Heck strategy allows
locking of the aryl ring in the proposed bioactive, that is, the pseudo axial
orientation. 69
3.4.1 N 3 -Arylation DHPMs
N 3 -arylated DHPM analogues cannot be obtained by classical Biginelli
condensation strategies involving N-arylureas. Here, the corresponding N 1 -
substituted derivates will be formed exclusively 70-71 . Wannberg et al 11 reported
protocol using concentrated mixture of 20 mol % of cuprous iodide as catalyst,
1.5 equiv of cesium carbonate as base, and 5 mol equiv of dimethylformamide as
solvent. The reactions were conducted at 180 °C for 40 min with a set of eight
differently substituted aryl iodides.
O
O
NH
A r-I, C uI, C s 2 CO 3 , D M F
M W , 180 C, 40 min
O
O
N
Ar
N
O
N
O
R 1
R 1

104
3.4.2 Fused bicyclic systems resulting from Dihydropyrimidines
Many bicyclic fused systems can be synthesized from DHPM scaffold. Pyrazolo
[4,3-d]pyrimidine derivatives synthesized by reacting sodium azide with N-Methyl,
6-Bromomethyl DHPM. The possible mechanism of this transformation is shown
below and involves decomposition of the diazide to vinyl diazo derivative, which
undergoes spontaneous 1,5-electrocyclization to 3H-pyrazole. Subsequent
migration of the ester substituent from the tetrahedral carbon to N 2 (thermal van
Alphen-Hüttel rearrangement) yields pyrazolo [4,3-d]pyrimidine. The structure
confirming the position of the ester group at N 2 was established by an X-ray
analysis 115 . Use of the 4-chloroacetoacetate building
Ph
Ph
EtO 2 C
NH
DMF
EtO 2 C
N
N
NH
(N 3 ) 2 HC N
O N
O
-2 N 2
Ph
EtO 2 C
Ph
EtO 2 C
NH
N
N
NH
N 2
N
O
N
O
block in a Biginelli-type condensation is very useful to get variety of bicyclic
systems. The resulting functionalized DHPM appeared to be an ideal common
chemical template for the generation of a variety of interesting bicyclic scaffolds
such as furo[3,4-d]- pyrimidines, pyrrolo[3,4-d]pyrimidines, and pyrimido-[4,5-
d]pyridazines. Solid-phase and solution-phase protocols for the synthesis of
O
H
R 1
O
R 1
RO
Cl
O
O
RO
NH
Cl
H 2 N NH 2
N
H
O
O
R 2 -NH 2
R 3 -NH-NH 2
O
R 1
O
R 1
O
R 1
O
N
H
NH
O
NH
HN
NH
R 2 N
N
H
N
H
O
R 3
N
O

105
furo[3,4-d]pyrimidines, pyrrolo[3,4-d]-pyrimidines, and pyrimido[4,5-d]pyridazines
are reported. The multistep solid-phase sequence involves the initial high-speed,
microwave-promoted acetoacetylation of hydroxymethylpolystyrene resin with
methyl 4-chloroacetoacetate. The immobilized 4-chloroacetoacetate precursor
was subsequently subjected to three component Biginelli-type condensations
employing urea and a variety of aromatic aldehydes. The resulting 6-
chloromethyl-functionalized resin-bound dihydropyrimidones served as common
chemical platforms for the generation of the desired heterobicyclic scaffolds using
three different traceless cyclative cleavage strategies. The corresponding
furo[3,4-d]pyrimidines were obtained by microwave flash heating in a rapid,
thermally triggered, cyclative release. Treatment of the chloromethyl
dihydropyrimidone intermediates with a variety of primary amines followed by
high-temperature microwave heating furnished the anticipated pyrrolo[3,4-
d]pyrimidine scaffolds via nucleophilic cyclative cleavage. In a similar way,
reaction with monosubstituted hydrazines resulted in the formation of pyrimido
[4,5-d]pyridazines. All compounds were obtained in moderate to good overall
yields and purities 116 .
O
OH
O
O
R 1
O
O
R 1
N
NH
Cl
O
NH
N
H
O
O
R 1
O
R 1
O
NH
R 2
N
H
NH
N
H
O
O
R 1
HN
R 2
O
NH
HN
N
N
H
O
N
H
O
O
R 1
R 3
O
Cl
O
NH
N
H
O
H 2M
N
R 3
3.5 Chemistry and biological importance of thaizolo[3,2-a]pyrimidine and
pyrimido[2,1-b][1,3]thiazines scaffolds
Preparation of thiazolo [3,2-a]pyrimidine derivatives is very well reported in
literature. Two approaches is generally employed for synthesis. Literature survey
on synthetic methodology for thiazolo [3,2-a]pyrimidine derivatives can be

106
summarized in Chart 1 & 2 where various methods are illustrated for synthesis of
this class of compounds.
Figure 1: Thiazolo [3,2-a] pyrimidine 2 was prepared in 30% yield by the reaction
of 2-aminothiazole 1 with ethyl cyanoacetate in a sodium ethoxide/ethanol
mixture or using polyphosphoric acid or acetic acid. However,
oxothiazolopyrimidine 3 was obtained upon treatment with phosphorous
pentoxide and methanesulfonic acid. The reaction of 1 with ethyl acetoactate at
140-150°C resulted in the formation of compound that was then converted to the
Z-isomer upon heating at 250°C and cyclized to give 4. 2-Aminothiazole 5
cyclized with acetylacetone at 100°C, in the presence of methanesulfonic acidphosphorus
pentoxide or formic acid-phosphorus pentoxide, followed by
treatment with 70% perchloric acid, to give the thiazolopyrimidin-4-ium salt 5. The
ester 6 was obtained from 2-aminothiazole 1 with an excess of methyl
methanetricarboxylate in 61 % yield. Cyclocondensation of 1 with diethyl
ethoxymethylene malonate in acetic acid followed by hydrolysis of the ester gave
7. Similarly, 2-aminothiazole 1 reacted with benzylidine in ethanol to give 8.
Stanovink et al reported the synthesis of a series of thiazolopyrimidine derivatives
upon reacting 2-aminothiazole with a variety of different reagents. Thus,
dimethylaminobut- 2-enoate (or pentenoate), reacted with 1 to give
thiazolopyrimidines. 72-85
S
N
R 2
EtOOC
N
Ar
8
N
R
S
R 1
N
R 1
O
9
R
Ar
EtOOC
N
H
COOEt
COMe
H 2N
R 4
R 4
NMe 2
R 2
R 3OOC
N
S
H
NH
R 4
R 4
O
NC
NH
N
N
2
COOEt
P 2S 5
SO 3H
H 3C
S
R 1
HN
R
O
N
N
3
S
R 1
R
EtO
COOEt
1
O
R
R 1
S
N
O
N
COOH
MeOOC
COOMe
COOMe
O
COMe
COOEt
R 1
H
N
O
N
S
4 R 1
7
Figure-1
R
S
R 1
N
N
O
OH
COOMe
N
N
5
S
R
ClO 4
6

107
Figure 2: The reaction of 2-aminothiazole 1 with 2-hydropolyfluoroalk-2-enoate in
basic medium gave two isomers, 7-oxo 2 and its isomeric 5-0x0 3. The structure
of both 2 and 3 was established through 1 H NMR, 19 F NMR and mass spectra 86 .
2-Aminothiazole derivatives, (R' = H, C0 2 Et; R2 = Ph, aryl, Me), reacted with the
acetylenic derivative and ester derivative in ethanol and polyphosphoric acid,
respectively, to give the isomeric oxothiazolopyrimidine derivatives 4 and 5, in 5-
32% and 8-97 % yield, respectively 87 . Condensation of 2-aminothiazole 1 in
absolute ethanol with the sodium salt of ethyl oximinocyanoacetate gave after
acidification (pH 6) with diluted hydrochloric acid, the nitroso derivative 6 in 92%
yield 88 . Treatment of the 2-aminothiazaole derivatives 5 with the hydrazone
derivatives gave the oxothiazolo [3,2-a] pyrimidine derivatives 7. 89 2-Amino-2-
thiazoline reacted with 2-acylamino-3- dimethylamino -propenoates in acetic acid
O
COOEt
Ar
N
N
N
R 1
N
S
R 2
N
7
S
R 2
R 3
O
N
F
2
COMe
COOEt
EtOOC
NHAr
R 3
O
N
S
NC
HO
N
R 2
R 1
S
N
1
NH 2
Cl
N
R 2
R 1
COOMe
Cl
COOEt
4
Cl
N O
S
R 2
R 1
N
NO
O
O
Cl
OEt
N
S
Figure-2
6
NH 2
O
N
R 2
R 1
5
to yield 6-acylamino-5-oxo-2,3-dihydro-5-thiazolo[3,2-a]pyrimidines in 73 and
12% yields, respectively 90 .
S
Me 2 N
NHCOR
S
N
NH 2
N
H
CO 2 Me
N
NHCOR
O

108
Moreover, 2-amino-2-thiazoline reacted with an aromatic aldehyde and diethyl
malonate, to give a mixture of thiazolidino[3,2-a]pyrimidines. Furthermore,
malononitrile reacted to give following product 91-92 .
S
N
NH 2
Ar-CHO
CH 2 (CO 2 Et) 2
EtOH/piperidine
O
EtO 2C
N
N
S
Ar
EtO 2C
N
N
S
Ar
O
CH 2 (CN) 2
C 6H 4-R
N
S
NC
N
NH 2
2-Amino-thiazoline reacted with potassium 2-ethoxycarbonyl-2-fluorovinyl
alcoholate in a sodium methoxide/methanol mixture to give 6-fluoro-2,3-dihydro-
5-oxothiazolo[3,2-a]pyrimidine 93 .
S
H
OK
H
N
S
N
NH 2
F
CO 2 Et
F
N
2-(Methylthio)-24hiazoline reacted with /3-alanine to give a 5-oxothiazolo [3,2-a]-
pyrimidine derivative in 23% yield 94 .
O
O
N
H 2 N
N
MeS
S
COOH
N
S
Pyrmidinethione derivatives were alkylated with monochloroacetic acid or
chloroacetyl chloride and then cyclized to give thiazolopyrimidine derivatives. 95-105
thus; pyrimidinethione reacted in dimethylformamide 95 or in an acetic
anhydride/pyridine mixture 37 to give thiazolo-pyrimidines. Alkylation in the
presence of an aromatic aldehyde gave the ylidene. Similarly, pyrimidinethione
derivatives reacted with monochloroacetic acid in acetic acid/acetic
anhydride/sodium acetate mixture or with chloroacetyl chloride in dry dioxane to
give the corresponding thiazolopyrimidines 99-100 .

109
O
O
O
R 1
NH
ClCH 2 COOH
R 1
N
R 2 N
S R 2
N
H
ClCH 2 COCl
S
O
Ar-CHO
R 1
N
O
R 2
N
S
O
O
R 1
N
Ar
R 2
N
S
Treatment of mercaptopyrimidine derivative with 2-chloroethanol in
dimethylformamide gave the asymmetrical thioether which underwent cyclization
on refluxing with a mixture of acetic anhydride-pyridine, to give the
oxothiazolopyrimidine 109 .
O
O
O
NC
NH
Cl
OH
NC
NH
HO
NC
N
Ar
N
SH
Ar
N
S
Ar
N
S
1,3-Dibromopropan-2-ol reacted with mercaptopyrimidine derivative to give
product through the non isolated intermediates. The same reaction product was
obtained by reacting with I-bromomethyloxirane. 110
O
OH
O
R
NH
Br
Br
R
NH
H 2 N
N
SH
H 2 N
N
S
Br
OH
Br
O
R
O
N
CH 2 OH
R
O
NH
O
H 2 N
N
S
H 2 N
N
S

110
Several derivatives of 4,5-disubstituted imidazole, 2,4,5-trisubstituted pyrimidine,
2-substituted purine, thiazolo[3,2-a]purine, [1,3]thiazino[3,2-a]purine, thiazolo[2,3-
i]purine, [1,3]thiazino-[2,3-i]purine, and 6-substituted pyrazolo[3,4-d]pyrimidine
were synthesized and tested as inhibitors of the xanthine oxidase enzyme 111 .
Dihydropyrimidines are now known for calcium
O
O
S
R
N
1
N
R 2
HO
N
N
N
N
N
N
H
N
S
n
N
H
N
S
O2
N
H
N
O
Channel blockers property. According to the literature, analogous derivatives are
anti-inflammatory. Bo´szing and co-workers 112 reported the synthesis of the
pyrimidothiazines and assay these compounds for the same profile. Acute antiinflammatory
activity was tested by inhibition of the carrageen an-induced paw
edema in rats.
Adam et al 113 filed US patent for phenyl substituted thiazolo pyrimidine
derivatives synthesized from DHPM. These compounds are novel and are
distinguished by valuable therapeutic properties. Specifically, it has been found
that the compounds of general formula given below are metabotropic glutamate
receptor antagonists. These compounds are capable of high affinity binding to
group II mGlu α receptors.
R 1
O
N
R 2
R 3
R 4
N
S
R 8
R 7
R 5
R 6
R 12 R 9
R 11 R 10
Compounds displayed by general formulae given below exhibit excellent
adenosine α 3 receptor antagonism where A is an optionally substituted benzene
ring. B may be substituted and R 1 is optionally substituted cyclic group 114 .

111
A
N
B
N
O
S
R 1
3.6 Biginelli Reaction and problems associated with conventional
methods
The major limitations of Biginelli reaction are lower yield and longer reaction time.
When thiourea is used for synthesis, yield obtained is very low and reaction
completion takes longer time. Similar disadvantages are observed when different
1,3-diketone and aldehyde other than aromatic are used for the synthesis of
designed molecules. Moreover, product separation and work up also cause
problem and needed special techniques. Thus, three main disadvantages are
lower yield, longer reaction time and work up in Biginelli reaction when different
building blocks are used to synthesize library of compound.
3.7 Microwave assisted reaction
The use of microwave as energy source in organic synthesis for better yield and
shorter reaction time has been extensively investigated 117-122 . Most of the early
pioneering experiments in MAOS were performed in domestic, sometimes
modified, kitchen microwave ovens; the current trend is to use dedicated
instruments which have only become available in the last few years for chemical
synthesis. The number of publications related to MAOS has therefore increased
dramatically since the late 1990s to a point where it might be assumed that, in a
few years, most chemists will probably use microwave energy to heat chemical
reactions on a laboratory scale. Not only is direct microwave heating able to
reduce chemical reaction times from hours to minutes, but it is also known to
reduce side reactions, increase yields, and improve reproducibility. Therefore,
many academic and industrial research groups are already using MAOS as a
forefront technology for rapid optimization of reactions, for the efficient synthesis
of new chemical entities, and for discovering and probing new chemical reactivity.
A large numbers of review articles provide extensive coverage of the subject 123-

112
128 .Microwave-enhanced chemistry is based on the efficient heating of materials
by “microwave dielectric heating” effects. This phenomenon is dependent on the
ability of a specific material (solvent or reagent) to absorb microwave energy and
convert it into heat. The electric component of an electromagnetic field causes
heating by two main mechanisms: dipolar polarization and ionic conduction.
Irradiation of the sample at microwave frequencies results in the dipoles or ions
aligning in the applied electric field. As the applied field oscillates, the dipole or
ion field attempts to realign itself with the alternating electric field and, in the
process, energy is lost in the form of heat through molecular friction and dielectric
loss. The amount of heat generated by this process is directly related to the
ability of the matrix to align itself with the frequency of the applied field. If the
dipole does not have enough time to realign, or reorients too quickly with the
applied field, no heating occurs. The allocated frequency of 2.45 GHz used in all
commercial systems lies between these two extremes and gives the molecular
dipole time to align in the field, but not to follow the alternating field precisely 129-
130 .
The heating characteristics of a particular material (for example, a solvent) under
microwave irradiation conditions are dependent on its dielectric properties. The
ability of a specific substance to convert electromagnetic energy into heat at a
given frequency and temperature is determined by the so-called loss factor tanδ.
This loss factor is expressed as the quotient tanδ=e’’/e’, where e’’ is the dielectric
loss, which is indicative of the efficiency with which electromagnetic radiation is
converted into heat, and e’ is the dielectric constant describing the ability of
molecules to be polarized by the electric field. A reaction medium with a high tanδ
value is required for efficient absorption and, consequently, for rapid heating 131 .
Solvent tanδ Solvent tanδ
Toluene 0.040 Dichlorobenzene 0.280
Acetone 0.054 Nitrobenzene 0.589
Chloroform 0.091 Formic acid 0.722
Water 0.123 DMSO 0.825
Dichloroethane 0.127 Ethanol 0.941
DMf 0.161 Ethylene glycol 1.350

113
3.7.1 Name reactions
Following scheme shows an example of a standard Heck reaction involving aryl
bromides and acrylic acid to furnish the corresponding cinnamic acids.
Optimization of the reaction conditions under small-scale (2 mmol) single-mode
microwave conditions led to a protocol that employed acetonitrile as the solvent,
1 mol% palladium acetae/p-tolyl phosphine as the catalyst system, and
triethylamine as the base. The reaction time was 15 minutes at a reaction
temperature of 180ºC.
NC
Br
COOH
Pd(OAc) 2 /P(o-tolyl) 3
NEt 3 , MeCN
NC
COOH
X
MW, 180 C, 15 min
X
The Suzuki reaction (the palladium-catalyzed cross-coupling of aryl halides with
boronic acids) is arguably one of the most versatile and at the same time also
one of the most often used cross-coupling reactions in modern organic synthesis.
Carrying out high-speed Suzuki reactions under controlled microwave conditions
can be considered almost a routine synthetic procedure today, given the
enormous literature precedent for this transformation. Recent examples include
the use of the Suzuki protocol for the high-speed modification of various
heterocyclic scaffolds of pharmacological interest 132-140 . A significant advance in
Suzuki chemistry has been the observation that Suzuki couplings can be readily
carried out using water as the solvent in conjunction with microwave heating 141-
144 .
X
(HO) 2 B
Pd(OAc) 2 , TBAB, Na 2 CO 3 , H 2 O
MW, 150-175 C, 5 min
R 1
R 2
R 1 R 2
General protocols for microwave-assisted Sonogashira reactions under controlled
conditions were first reported in 2001 by ErdMlyi and Gogoll 151-152 . Many more
examples can be cited for different name reaction.

114
I H SiMe 3
[PdCl 2 (PPh 3 ) 2 ], CuI, DMF, Et 3 NH
MW, 120 C, 5 min
NH 2
SMe 3
KF.2H 2 O, MeOH, RT, 7 h
[PdCl 2 (PPh 3 ) 2 ], CuI, DMF, Et 3 NH
MW, 120 C, 5 min
MeOOC
NH 2
I
NH 2
COOMe
3.7.2 Some additional chemistry on Biginelli reaction
Kappe et al 32 recently described a high yielding and rapid microwave-assisted
protocol that allows the synthesis of gram quantities of DHPMs utilizing controlled
single-mode microwave irradiation. As the first model reaction for scale-up
experiments, they selected the standard Biginelli cyclocondensation, where in a
one-pot process equimolar amounts of benzaldehyde, ethyl acetoacetate, and
urea react under Lewis acid (FeCl 3 ) catalysis to the corresponding
dihydropyrimidine. Utilizing single-mode microwave irradiation, the reaction can
be carried out on a 4.0 mmol scale in AcOH/EtOH 3:1 at 120 o C within 10 min,
compared to 3-4 h using conventional thermal heating, providing DHPM in 88%
isolated yield and high purity (>98%).
X
X
ROOC
O
H
AcOH/EtOH 3:1, FeCl3
EtOH /HCl
MW, 10-20 min
NH 2
ROOC
NH
O
H 2 N
O
N
H
O
Dihydropyrimidines were synthesised in high yields by one-pot cyclocondensation
reaction of aldehydes, acetoacetates and urea using various acid catalysts like
Amberlyst-15, Nafion-H, KSF clay and dry acetic acid under microwave
irradiation. 33
The antimony (III) chloride impregnated on alumina efficiently catalyses a onepot,
three-component condensation reaction among an aldehyde, a β-ketoester,

115
and urea or thiourea to afford the corresponding dihydropyrimidinones in good to
excellent yields. The reactions are probed in microwave (MW), ultrasonic, and
thermal conditions and the best results are found using MW under solvent-free
conditions 34. Cupric chloride dihydrate catalyzes the three-component Biginelli
condensation between an aldehyde, a β-ketoester and urea or thiourea under
microwave irradiation in the absence of solvent to yield various substituted 3,4-
dihydropyrimidin-2(1H)-ones. The reaction is also effective when performed at
room temperature in acetonitrile or at 100 °C in a solvent free approach, without
any side reactions as observed by Biginelli and others. 35
The publications by Gupta 36 and Dandia 37 describe 26 examples of microwaveenhanced
solution-phase Biginelli reactions employing ethyl acetoacetate, (thio)
ureas, and a wide variety of aromatic aldehydes as building blocks. 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 ºC, reflux) to 3–11
minutes under microwave activation (ca. 200–300 W). At the same time, the
yields of DHPM obtained by the authors were markedly improved compared to
those reported earlier using conventional conditions.
Kappe 38 reinvestigated above reactions using a purpose-built commercial
microwave reactor with on-line temperature, pressure, and microwave power
control. Transformations carried out under microwave heating at atmospheric
pressure in ethanol solution show no rate or yield increase when the temperature
is identical to conventional thermal heating. In the case of superheating by
microwave irradiation at atmospheric pressure the observed yield and rate
increase phenomenon are rationalized as a consequence of a thermal (kinetic)
effect. Under sealed vessel conditions (20 bar, 180 ºC) the yield of products is
decreased and formation of various byproducts observed. The only significant
rate and yield enhancements are found when the reaction is performed under
“open system” conditions where the solvent is allowed to rapidly evaporate during
microwave irradiation. However, the observed rate and yield enhancements in
these experiments are a consequence of the solvent-free conditions rather than
caused specifically by microwave irradiation. This was confirmed by control
experiments of the solvent less Biginelli reaction under microwave and thermal

116
heating. Various heterocyclic systems can be synthesized in short time with high
yield. Heterocyclic systems like dihydroquinolone, triazine, dihydropyridines and
other bicyclic systems are reported in literature synthesized using microwave 145-
149 . Few examples are shown below.
R 1
NH 2
O
Sc(OTf) 3 , MeCN
R 1
N
H
R 2
R 2
R 2
MW, 140-50 C
50-60 min
N
H
R 1
NH 2
R 2 CHO
R 1
NH
Sc(OTf) 3 , (bmim)Cl-AlCl 3
MW, 100-20 C
30-60 min N R 2
H
R 1
R 2
COOMe CN
H
G 2 N
G=CN, COOMe
NH
R 4
NaOMe/MeOH
MW, 100-140 C, 10 min
O
H
N
R 4
N
R 1
R 2
N
R 3
R 3 =NH 2 , OH
3.8 Rearrangements
Ley and co-workers 150 have described the microwave assisted Claisen
rearrangement of allyl ether in their synthesis of the natural product carpanone. A
97% yield of the rearranged product could be obtained by three successive 15-
minute irradiations at 220 ºC. This is an example of microwave assisted reaction
clubbed with ionic liquid.
O
O
O
Toluene
CH 2
MW, 220 °C, 3 - 15 min
O
O
CH 3
CH 2

117
3.8.1 Cycloaddition reaction
Reaction scheme display microwave assisted Diels Alder reaction in neat
condition without using any solvent. First process gave 97% yield in 20 min. In
second process, diastereomers were obtained. 153-154
neat, MW, 165 C, 20 min
O
H
H
O
O
O
H
O
O
H
O
O
N
R
O
N
R
O
H
H
H
O
Ar
O
neat, MW, 165-200 C, 30 min
O
Ar
O
3.8.2 Oxidation
The osmium-catalyzed dihydroxylation reaction, the addition of osmium tetroxide
to olefins to produce a vicinal diol, is one of the most selective and reliable
organic transformations. Recent work by Sharpless, Fokin, and coworkers 155 has
uncovered that electron-deficient olefins can be converted into the corresponding
diols much more efficiently when the reaction medium is kept acidic.
F
F
F
F
F
F
F
F
F
F K 2 OsO 2 (OH) 4 , citric acid
Water, MW, 120 °C, 150 min
F
F
F
F
O H
O H
F
F
F
F
F
F
3.8.3 Multicomponent Reaction (MCR)
The Mannich reaction has been known since the early 1900s and has since then
been one of the most important transformations to produce β-amino ketones.
Although the reaction is powerful, it suffers from some disadvantages, such as
the need for drastic reaction conditions, long reaction times, and sometimes low

118
yields of products. Luthman and coworkers 156 have reported microwave-assisted
Mannich reactions as MCR that employed paraformaldehyde as a source of
formaldehyde, a secondary amine in the form of its hydrochloride salt, and a
substituted acetophenone.
O
H
O
dioxane, MW, 180 C, 10 min
O
N
H
H
R 1
R 2
Ar
Ar
R 1
N
R 2
O
H
N
N
PF 6
-
R 4
R 1
N
R 4
H
H R 1
R 3
R 2
CuCl, dioxane, MW, 150 C, 6-10 min
R 3
R 2
3.8.4 Nucleophilic Aromatic Substitution
A number of publications report efficient nucleophilic aromatic substitutions driven
by microwave heating involving either halogen substituted aromatic or
heteroaromatic systems. Scheme given below summarizes some heteroaromatic
systems and nucleophiles along with the reaction conditions that have been
developed by Cherng for microwave-assisted nucleophilic substitution reactions.
In general, the microwave-driven processes provide significantly higher yields of
the desired products in much shorter reaction times 157-161 .
Hetaryl - X
nucleophile
neat or NMP, HMPA, DMPU
MW, 70-110 C, 1-20 min
Hetaryl - Nu
I
X
N
N
N X N N N
X
N
Cl
Br
Br
N Cl N N

119
3.8.5 Solid Phase Organic Synthesis
Solid-phase organic synthesis (SPOS) exhibits several advantages compared
with classical protocols in solution. Reactions can be accelerated and driven to
completion by using a large excess of reagents, as these can easily be removed
by filtration and subsequent washing of the solid support. In addition, SPOS can
easily be automated by using appropriate robotics and applied to “split-and-mix”
strategies, useful for the synthesis of large combinatorial libraries 162-163
A study published in 2001 demonstrated that high temperature microwave
heating (200 8C) can be effectively employed to attach aromatic carboxylic acids
to chloromethylated polystyrene resins (Merrifield and Wang) by the cesium
carbonate method. Significant rate accelerations and higher loadings were
observed when the microwave-assisted protocol was compared to the
conventional thermal method. Reaction times were reduced from 12–48 hours
with conventional heating at 80 ºC to 3–15 minutes with microwave heating at
200 ºC in NMP in open glass vessels 164-165 .
O
Cl
O
R
R-COOH, Cs 2 CO 3 , NMP
O
MW, 200, 3-15 min
O
Kappe et al 166 have reported microwave assisted synthesis of bicyclic systems
derived from Biginelli DHPM derivatives.
O
MeO
O
Cl
OH
DCB
O
O
MW , 170 C, 15 min
Cl
O
R 1 -CHO, urea
O
R 1
dioxane, HCl
70 C, 18 h
R 2
N
NH
O
O
R 1
NH
DMF, MW, 150 C, 10 min
O
O
R 1
NH
R 2 -N H 2 , D M F, 70 C , 18 h
N
H
O
N
H
O
Cl
N
H
O
DMF, MW , 150-200 C, 10 min
R 3 -NH-NH 2, D M F, R T, 30 m in
DMF, MW , 150 C, 10 min
O
R 1
HN
NH
N
R 3
N
H
O

120
In recent years, various methods have been examined for the synthesis of DHPM
on solid phase. Li and Lam 29 describe a convenient traceless solid-phase
approach to synthesize3,4-dihydropyrimidine-2-ones. Key steps in the synthesis
are (i) sulfinate acidification, (ii) condensation of urea or thiourea with aldehydes
and sulfinic acid, and (iii) traceless product release by a one-pot cyclizationdehydration
process. Since a variety of reagents can be used in steps (ii) and (iii),
the overall strategy appears to be applicable to library generation.
HCl
SO 2 Na
DMF-H2O
R 1 O
O
R 3
O
R1-CHO
SO 2 H
X
H 2 N NH 2
HN
R 2
R 3
R 2
SO 2
X
N
H
TsOH
NH
R 1 NH 2
X
R 1
O
HN
R 2
TsOH
OH
X
N
H
OH
R 2
O
O
Very recently, Gross et al 30 developed a protocol based on immobilized α-
ketoamides to increase the diversity of DHPM. The resulting synthetic protocol
proved to be suitable for the preparation of a small library using different building
blocks. They found that the expected DHPM derivatives were formed in high
purity and yield if aromatic aldehyde- and α-ketoamide building blocks were used.
The usage of an aliphatic aldehyde leads to an isomeric DHPM mixture. Purities
and yields were not affected if thiourea was used instead of urea.
Polymer
O
R
Polymer
O
R
O
O
O
HN
O
HN
O
O
NH 2 Cl
R 1
R
O
H 2 N
S
Polymer
O
NH
O
R
N
S

121
Lusch and Tallarico 31 reported a direct, Lewis acid-catalyzed Biginelli synthesis of
3,4-dihydropyrimidinones on high-capacity polystyrene macrobeads with a
polymer O-silyl-attached N-(3-hydroxypropyl)urea.
1) ArCHO, LiTf
CH 3 CH 3
H 3 C
Si
CH 3
O HN
O
NH 2
HO
R1
N
O
O
NH
OR 3 Ar
CH 3
CN, 80 o C 2) LiOTf, CH 3
CN, 80 o C, 3) HF / Pyridine
O
R 1 CO 2 R 3
4) TMSOEt
Resin-urea was first reacted separately with either 4-bromo- or 4-
chlorobenzaldehyde or lithium trifluoromethanesulfonate in acetonitrile at 80 °C.
After washing, the beads were pooled and reacted with ethyl acetoacetate and
lithium trifluoromethanesulfonate in acetonitrile at 80 °C. Formation of only one
kind of Biginelli product per bead demonstrated the feasibility of a solid-phase
non-Atwal two-step split-and-pool synthesis of 3,4-dihydropyrimidinones.
3.9 Synthetic Aspects.
Scheme- 4
Thiazolo pyrimidine and pyrimido thiazine are very important bicyclic system in
medicinal chemistry. Various synthetic routes have been reported in literature to
synthesize these bicyclic systems. Utility of dihydropyrimidine ring to synthesize
such bicyclic system can be used to obtain derivatives with phenyl carbamoyl as
side chain on pyrimidine ring of bicyclic system.
Dihydropyrimidine ring, substituted with phenyl carbamoyl side chain at C 5
position, was synthesized by reacting acetoacetanilide, thiourea and aldehyde.
This dihydropyrimidine ring was reacted with dihalo alkane to get fused bicyclic
systems. In synthesis of thiazolo pyrimidine system, 1,2-dibromo ethane was
reacted with 2-thiodihydropyrimidine derivatives. Pyrimido-thiazine systems can
be synthesized using 1,3-dibromo propane in place of 1,2-dibromo ethane with

122
shorter reaction time and better yields as compared with synthesis of thiazolo
pyrimidine systems.
Scheme -5
N-substitution in dihydropyrimidine ring is reported to enhance activity profile.
Similarly, substitutions at C 5 position also plays key role in activity profile. N-
phenyl substituted dihydropyridines were also synthesized by our group and it
also showed interesting biological profile. Results obtained in dihydropyridine
modification, inspired to introduce phenyl carbamoyl moiety at C-5 position of
dihydropyrimidine skeleton. This modification to dihydropyrimidine skeleton
exhibited moderate biological profile. Moderate anti tubercular activity was
observed for these derivatives against Mycobacterium H 37 Rv.
Our laboratory is involved in the synthesis of modified 1,4-dihydropyridine and
dihydropyrimidine skeleton derivatives for last few years. Introduction of phenyl
carbamoyl moiety at C-3 and/or C-5 position in dihydropyridine skeleton has
showed diverse activity profile. Very promising results obtained with these
modifications to dihydropyridine skeleton. For the synthesis of N-phenyl
dihydropyrimidines we used different N-phenyl ureas with methyl substitution (-
Phenyl, -3-methylphenyl, 2,4-dimethylphenyl) were synthesized.
Acetoacetanilides were synthesized with different halogen substitutions (4-chloro,
4-flouro, 3-chloro-4-flouro). Scheme 3 is synthesis of N-phenyl substituted DHPM
derivatives by reacting N-(phenyl/3-methylphenyl/ 2,4-dimethyl) urea, (4-chloro,
4-flouro, 3-chloro-4-flouro) acetoacetanilide and aromatic aldehyde. The reaction
time was observed 8-12 hours depending on the substitution on substitutions on
4-phenyl and N-phenyl ring. The synthesized compounds are characterized by
IR, NMR and Mass spectral analysis and are under screening against
Mycobacterium H 37 Rv for anti tubercular activity.
Scheme 6
Work done earlier in our lab on 1,4-dihydropyridine and interesting results
obtained for this structural class inspire to modify aza analogs of 1,4-
dihydropyridine i.e. dihydropyrimidine. Earlier library of compounds was
generated of dihydropyrimidine derivatives with phenyl carbamoyl moiety at C 5
position. Moderate pharmacological profile obtained for this library. In

123
continuation of this work, it was planned to develop various modified compounds
associated with aliphatic chain at C4 position of dihydropyrimidines. Phenyl ring
at C 4 position of classical dihydropyrimidine is replaced with aliphatic chain. Work
deals with an aliphatic aldehyde (butyraldehyde) as a substrate to obtain a
dihydropyrimidine skeleton without phenyl or heteroaryl ring at C 4 . The aim of this
work was to develop small library of novel DHPM compounds which give diversity
from earlier ones. When the reactions carried out by conventional methods, long
reaction time (10-12 hours) was observed. To overcome these problems,
microwave irradiation technique was utilized reduce reaction time (10-15 minutes.
Different solvent were used (methanol, ethanol, THF, acetonitrile, DMF) but
methanol was found to be most suitable.

Chapter- 4
Synthesis & Characterization of N-substituted
phenyl-7 methyl-2,3 dihydro-5H[1,3]thiazolo
[3,2-a]pyrimidines and 3,4-dihydro-2h,.6Hpyrimido
[2,1-b] [1,3] thiazine-7-carboxamides.
1. Reaction scheme 124
2. Experimental observation 129
3. Physical data table 131
4. Spectral analysis 136
5. MASS fragmentation 138
6. Spectral data 139
7. IR spectra 146
8. 1 H NMR spectra 148
9. Mass spectra 154
10. 13 C spectra 157

124
INTRODUCTION
A general introduction of Chemistry of Pyrimidines and their biological activities
and related structure modifications are already mentioned as a separate Chapter
3 earlier.
The current chapter deals with the synthesis of N-(substituted phenyl)-7-methyl- 2,
3- dihydro - 5H -[1,3] thiazolo [3,2-a] pyrimidines and 3, 4- dihydro -2H, 6Hpyrimido[2,1-b][1,3]thiazine-7-carboxamides.
The title compounds are prepared by (i) Preparation of respective
acetoacetanelides [AA] (ii) Multicomponent reaction of AA with aromatic aldehyde
and thiourea leading to thiopyrimidines (iii) Cyclization of thipyrimidines into final
fused pyrimidine derivatives.
The chemistry, reaction mechanism, experimental protocols, spectral and
physical data and interpretation are given in subsequent pages.

125
4.1 REACTION SCHEMES
4.1.1 Scheme-1
NH 2
R 1 +
C H 3
O
O
COC 2
H 5
KOH/NaOH
Toluene,115 0 c
O
R 1 H 2 N
NH +
R 2
+ S
H 2 N
H 3 C O
H O
HCl
CH 3
OH
Reflux
R 2
O
R 1
NH
NH
C H 3
N
H
S

126
4.1.2 Scheme-2
R 2
O
R 1
NH
NH
+
Br
DMF, 140 0 C
C H 3
N
H
S
Br
K 2
CO 3
R 2
O
R 1
NH
N
C H 3
N
S
Where R 1
= Cl,F
R 2
= OH,Cl,OCH 3
, etc..
4.1.3 Scheme-3
R
Br
O
NH
NH
+
DMF, 140 0 C
C H 3
N
H
S
Br
K 2
CO 3
Cl
O
R
NH
N
C H 3
N
S
Where R= Cl,OH,etc...

127
4.1.4 Reaction Mechanism
H +
-H 2
O
H O H N + H
NH 2
H 2 N S
H 2 N S
O
-H +
NH
H N + H
H 3 C O
H 2 N S
-H 2
O
O
NH N H
H 3 C N S
H
NH
O
C H 3
O
O
N
NH 2
NH N H
HO
N S
H 3 C
H
H S

128
4.1.5 Reaction Mechanism
O
NH N H +
H 3 C N SH
Br
-HBr
Br
O
NH N H
H 3 C N S
Br
-HBr
O
NH
N
C H 3
N
H
S

129
4.2 Experimental Observations
The mixture of aldehyde, thiourea, and acetoacetanilide refluxed at 65-70 o C for 5
hours to give crystalline product directly.
During reaction, the quantity of Con. HCl is very significant. The permanent
monitoring of reaction is necessary, if not, an arylidene product is isolated and
cyclocondensation leftovers incomplete. The colours of crystalline products are
light yellow to orange.
Thin layer chromatography
It was approved on silica Gel-G as a stationary phase. The slurry was primed by
adding up 20 ml distilled water to 10 gm Silica Gel in 250 ml beaker with constant
stirring and the slurry was poured over glass plate and unvarying thin layer was
prepared. The plate was held in reserve dried at 105 o C in an oven and activated
before used.
The reactions of all newly synthesized compounds and intermediate were
supervised and the purity was checked by TLC.
Mobile phase: 1. Ethyl acetate : Hexane
2. Chloroform : Methanol
Melting point
All the melting points were taken in open end capillary by means of paraffin bath
with standard Zeal thermometer and they were uncorrected.
4.3 Experimental
4.3.1 4-Chloro/flouro acetoacetanilide
4-chloro/flouro aniline (0.1M) and ethyl acetoacetate (0.1 M) was refluxed at 110°
C in 40 ml of toluene and catalytic amount of KOH/NaOH. The completion of
reaction was monitored with TLC. After completion of reaction, toluene was
distilled out. The residue was cooled at room temperature and was treated with
ether. The solid was filtrated and dried. (Yield: 4-chloroacetoacetanilide – 62%, 4-
flouroacetoacetanilide – 56%. M.P.; 4-chloroacetoacetanilide - 114° C
(Reported * -115 0 C.), 4-fluoroacetoacetanilide - 129° C (Reported * – 128 o C).

130
4.3.2 N - (Substituted phenyl)- 1, 2, 3, 4 - tetrahydro-6-methyl-4-(substituted
phenyl)-2-thioxopyrimidine-5-carboxamides (Scheme-1)
[General method]
Acetoacetanilide (0.01M), aldehyde (0.01M) and thiourea (0.015M) were
dissolved in minimum quantity of methanol. It was heated for 5-10 minutes to get
the clear solution. Few drops of Con. HCl were added to the reaction mixture as a
catalyst. The reaction mixture was then refluxed in water bath for 6-10 hrs. The
progress of reaction was monitored by TLC. The reaction mixture was allowed to
cool at room temperature. The solid separated was filtered, washed with hot
methanol and dried. (2a-p) (Yield: 45-60%).
Physical data of newly synthesized compounds are given in Table 4.1.1.
4.3.3 N - (4-Chloro phenyl) – 3, 5, 8, 8a - tetrahydro-7-methyl-5-phenyl-2Hthiazolo
[3, 2-a] pyrimidine-6-carboxamide (Scheme-2 & 3)
[General method]
N-(substituted phenyl)-1,2,3,4-tetrahydro-6-methyl-4-(substituted phenyl)-2-
thioxopyrimidine-5-carboxamide (0.01M) and dibromo ethane (or dibromo
propane) were dissolved in DMF and heated at 140° C for 2-2.5 hrs. The reaction
mixture was poured on crushed ice and was extracted with chloroform. The
chloroform was removed under vacuum. (Yield: 55-65%).
Physical data of newly synthesized compounds are given in Table 4.1.2 and 4.1.3.
* Naliapara, Y. T.; Ph.D. Thesis., Saurashtra University, Rajkot (1998)

131
4.4 PHYSICAL DATA
4.4.1 Physical data of N-(substituted phenyl)-6-methyl-4-(substituted
phenyl)-2-thioxo-1,2,3,4-tetrahydropyrimidine -5-carboxamides (AKS
551-567)
R 2
O
R 1
NH
NH
C H 3
N
H
S
No. Code R 1 R 2 MW Yield
in %
R f
value
1. AKS- 551 4-Cl 4-OH 373.85 63 0.38
2. AKS- 552 4-Cl 4-N(CH 3 ) 2 400.92 51 0.51
3. AKS- 553 4-Cl 4-CL 392.303 68 0.45
4. AKS- 554 4-Cl 2-OCH 3 387.88 49 0.53
5. AKS- 554 4-Cl 2,3,5,6- 457.97 56 035
dibenzo
6. AKS- 555 4-Cl 2,3 benzo 407.91 53 0.46
7. AKS- 556 4-Cl 3-NO 2 402.89 58 0.54
8. AKS- 557 4-Cl 4-NO 2 402.89 61 0..36
9. AKS- 558 4-F 3-NO 2 386.40 55 *0.52
10. AKS- 559 4-F 2-OH 357.40 59 *0.40
11. AKS- 560 4-F 4-Cl 375.88 61 *0.38
12. AKS- 561 4-F 2-OCH 3 371.47 48 *0.45

132
13. AKS- 562 4-F 2,3,5,6- 441.51 62 *0.39
dibenzo
14. AKS- 563 4-F H 341.40 52 *0.41
15. AKS- 564 2,3-benzo 4-Cl 407.95 44 *0.35
16. AKS-565 2,3-benzo 4-OH 389.51 48 *0.54
17. AKS-566 2,3-benzo 4-NO 2 418.46 62 *0.51
18. AKS-567 2,3-benzo 2-NO 2 418.46 56 *0..37
TLC solvent system: Ethyl acetate : Hexane 3.5 ml : 6.5 ml
*CH 2 Cl 2 : MeOH 9.5 ml : 0.5 ml
Visualization: UV light (long)

133
4.4.2 Physical data of N-(substituted phenyl)-7-methyl-5-(substituted
phenyl)-2,3-dihydro-5H-1,3]thiazolo[3,2-a]pyrimidine-6-carboxamides
(AKS 570-587)
R 2
O
R 1
NH
N
C H 3
N
S
No. Code R 1 R 2 MW MP° C Yield
Rf value
in %
1 AKS-570 4-Cl 2-OH 399.89 140-142 57 0.41
2 AKS-571 4-Cl 4-N(CH 3 ) 2 426.95 210-212 69 0.49
3 AKS-572 4-Cl 3,4-Di OH 415.89 174-176 77 0.36
4 AKS-573 4-Cl 4-Cl 418.33 210-212 65 0.42
5 AKS-574 4-Cl 2-OCH 3 413.92 160-162 66 0.62
6 AKS-575 4-Cl 2-Cl 418.34 177-178 60 0.56
7 AKS-576 4-Cl 3-NO 2 428.89 214-17 59 0.58
8 AKS-577 4-F H 367.43 220-224 65 0.45
9 AKS-578 4-F 2-OCH 3 397.46 246-248 61 0.54
10 AKS-579 4-F 3-NO 2 412.43 198-200 71 *0.46
11 AKS-580 4-F 3-Cl 401.88 146-148 56 *0.39
12 AKS-581 4-F 4-Cl 401.88 174-176 75 0.41
13 AKS-582 4-F 2-NO 2 412.43 222-224 62 0.51

134
14 AKS-583 4-F 3-OCH 3 397.46 165-167 74 *0.35
15 AKS-584 4-F 4-OCH 3 397.46 212-214 53 *0.48
16 AKS-585 4-F 2-Cl 401.88 189-191 62 *0.53
17 AKS-586 2,3-Benzo 4-OCH 3 431.54 234-236 56 *0.51
18 AKS-587 2,3 -Benzo 2-Cl 433.95 184-186 53 *0.46
TLC solvent system: EA: Hexane 4 ml : 6 ml
* CH 2 Cl 2 : MeOH 9 ml : 1 ml
Visualization: UV light (long)

135
4.4.3 Physical data of compounds N-(4-chlorophenyl)-6-(substituted
phenyl)-8-methyl-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazine-7-
carboxamide (AKS-588-593)
O
R
NH
N
Cl
C H 3
N
S
No. Code R MW MP° C Yield
Rf value
in %
19 AKS-588 4-Cl 432.36 189-193 68 0.42
20 AKS-589 2-OCH 3 427.94 222-224 74 0.51
21 AKS-590 2- OH 413.92 174-176 56 0.36
22 AKS-591 4-NO 2 442.91 256-257 63 0.48
23 AKS-592 3-NO 2 442.91 185-187 71 0.41
24 AKS-593 2-Cl 432.36 212-214 47 0.35
TLC solvent system: CH 2 Cl 2 : MeOH 9 ml : 1 ml
Visualization: UV light (long)

136
4.5 SPECTRAL ANALYSIS
Spectral data of only key intermediate and final compounds are included.
Elemental analysis of the compounds was in agreements (within 0.4% of the
theoretical value) with the structures assigned. The constitution of newly
synthesized compounds was supported by IR, NMR, and MASS spectral study.
The details are as under.
4.5.1 MASS SPECTRAL ANALYSIS
Systematic fragmentation pattern was observed in mass spectral investigation.
Peaks for specific fragments were recognized in each mass spectrum. Molecular
ion peaks observed were in harmony with molecular weight of compounds.
Molecular ion peak (M + ) of the compounds were in total conformity with its
molecular weight. In presence of halogen respective M +1 peak was observed. M/e
value were obtained at 442, 431, 431, 401, and 433 in mass spectrum of
compounds AKS-592, AKS-588, AKS- 593, AKS-585 ASK-587 correspondingly.
A base peak in each spectrum was obtained as a consequence of specific
fragmentation in each molecule. Fragment obtained caused by cleavage of bond
adjacent to carbonyl double bond in the phenyl carbamoyl side chain at C 5
location gave base peak in each spectrum. Base peak obtained at 316, 305, 305,
255 and 291 m/e values in mass spectrum of compound AKS-592, AKS-588,
AKS-593, AKS-585 and AKS-587 respectively were due to precise fragmentation
pattern observed in this series.
The second characteristic peak observed in each spectrum as a result of cleave
adjacent bond to carbonyl double bond at the additional elevation. Peaks were
pragmatic at 288, 277, 277, 264 and 264 m/e values in relevant spectrum for
these fragments. Mass spectra of the synthesized compounds are given on
Pages 153-155.
4.5.2 IR SPECTRAL ANALYSIS
IR spectral study of newly synthesized compounds reveals following details.
Amide Carbonyl was observed at 1680-1645 cm -1 .The stretching of secondary
amine (>NH) appeared in the region of ~3119-3300cm -1 , its bending and C-N
stretching appears at 1345 cm -1 to 1370 cm -1 respectively. The aromatic moiety

137
show distinctive absorptions in several region of the spectrum. Absorption owing
to the C-H stretching vibration of aromatic compounds occurs near 3030 cm -1 .
There are four absorption bands in the (1667-1429 cm -1 ) region that are
particularly diagnostic of aromatic structure. These happens near ~1600, 1580,
1500, 1440 cm -1 and are caused by C=C skeletal in plan vibrations. The other
frequencies were due to aromatic moieties o.o.p. appears around at ~1085 cm -1 .
The C-H stretching of methyl group observed at 2850 cm -1 (sym.) and ~2900
(asym.) and its bending observed at ~1384 cm -1 . The numbers of absorption
bands of variable intensity appear in the 1000-670 cm -1 region that is caused by
C-H bending vibrations. This absorption depends on the number of adjacent free
hydrogen atoms aromatic nucleus contains. An aromatic compound containing
five closest hydrogen atoms absorbs in both the 750-700 cm -1 regions. If the
compound contains four hydrogen atoms, its absorbs robustly only near 750 cm -
1 . Superior degrees of substitution on the aromatic focus are usually weak and
not easily assigned. Representative IR Spectra are given Pages 145-146. The IR
data of all synthesized compounds are specified for individual compounds
separately.
4.5.3 1 H NMR SPECTRAL ANALYSIS
Following representative signals were observed in all the NMR spectra of this
series.
Looking to NMR spectra of the title compounds, methyl (CH 3 ) protons were
observed as a singlet at 2.2 -2.8 δ ppm. In most of derivatives –NH proton were
observed 7.0 -9.2 δ ppm. The aromatic protons are pragmatic between around
6.60- 8.30 δ ppm. For splitting patterns of meta phenyl functionality, two triplets
are observed in the aromatic region due to ortho/Meta dicoupling of phenyl
protons. For ortho substituted phenyl ring, three doublets are observed due to diortho/meta
coupling of phenyl protons. In NMR spectrum, we observed four to six
multiplet splitting pattern in aliphatic region as a result of the presence of 1,3 -
thiazolidine and 1,3- thiazine nucleus, where all of the protons are chemically
equivalent but magnetically nonequivalent, therefore all of these protons show
multiplet splitting pattern instead of triplet. In case of, 1, 3- thiazine nucleus, at C 5
position, two protons were shown in highly defensive region, thereby both protons

gave multiplet signal at similar region. 1 H NMR spectra of the representative
compounds are given on Pages 147-152.
138
4.5.3 ELEMENTAL ANALYSIS
Elemental analysis of the all the synthesized compounds was carried out on
Elemental Vario EL III Carlo Erba 1108 model and the results are in agreements
(within the range of theoretical value) with the structures assigned.
Mass fragmentation of N-(4-chlorophenyl)-8-methyl-6-(3-nitrophenyl)-3,4-
dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazine-7-carboxamide(AKS-592)
O
N + O -
O
O
H 3 C
NH
N + O -
N
CH 3
H 3 C
N
S
N
H 3 C
N
S
CH 3
NH
SH
H 3 C
N
N
S
3
2
1
O
13
12
CH 2
NH
4
Cl
O
N + O -
11
SH
CH 3
H 3 C
N
N
S
NH
N
10
5
C H 3
N
S
9
NH
SH
H 3 C
N
6
7
8
HN
S
CH 2
NH
SH
N
S
NH
SH
NH
S
CH 3

139
SPECTRAL DATA
N - (4-Chloro phenyl) – 5 - (2-hydroxy phenyl) – 7- methyl – 2 , 3 – dihydro -
5H - [1,3] thiazolo [3,2-a] pyrimidine – 6 - carboxamide (AKS-570).
IR(KBr) cm -1 : 3243 (-NH, str), 3019 (-CH=CH), 2928 (Ar-CH,asym), 2858 (Ar-
CH,sym),1679 (-C=O),1526 (-C-C skeletal vibration),1282 (C-S, str),1190(C-H
IPD),1089(C-O-C),758(C-H, OPD).
C, H, N (In %): Found: 60.07 (C), 4.54 (H), 10.51 (N), Cacld: 60.10 (C), 4.52 (H),
10.54 (N)
N - (4-Chlorophenyl) – 5 - (4,N,N-dimethyl) – 7 – methyl – 2 , 3 – dihydro - 5H
-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxamide (AKS-571).
IR(KBr) cm -1 : 3189 (-NH, str), 3040 (-CH=CH), 2949 (Ar-CH,asym), 2869 Ar-
CH,sym),1646 (-C=O),1563 (-C-C skeletal vibration),1245 (C-S, str),1176 (C-H
IPD),1070 (C-O-C),768 (C-H, OPD)
C, H, N (In %): Found: 61.89 (C), 5.43 (H), 13.12 (N), Cacld: 61.85 (C), 5.41 (H),
13.14 (N)
N - (4-Chloro phenyl) – 5 - (3,4-dihydroxy phenyl) – 7 – methyl – 2, 3 -
dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxamide (AKS-572).
IR(KBr)cm -1 : 3562 (-OH),3213 (-NH, str), 3023 (-CH=CH), 2910 (Ar-
CH,asym),2846 (Ar-CH,sym),1668 (-C=O),1523 (-C-C skeletal vibration),1274 (C-
S, str),1174 (C-H IPD),1083 (C-O-C),768 (C-H, OPD).
C, H, N (In %): Found: 57.76 (C), 4.36 (H), 10.10 (N), Cacld: 57.77 (C), 4.34 (H),
10.14 (N)
N , 5 – bis (4-Chloro phenyl) – 7 – methyl – 2 , 3 – dihydro - 5H -[1,3] thiazolo
[3,2-a ] pyrimidine -6 - carboxamide (AKS-573).
IR(KBR)cm -1 : 3273 (-NH, str), 3051 (-CH=CH), 2924 (Ar-CH,asym), 2868,2769
(Ar-CH,sym),1662 (-C=O),1442,1456 (-C-C skeletal vibration),1240,1269 (C-S,
str),1190 (C-H IPD),1016,1107 (C-O-C),707 (C-H, OPD).
C, H, N (In %): Found: 57.42 (C), 4.10 (H), 10.04 (N), Cacld: 57.43 (C), 4.12 (H),
10.09 (N)
N - (4-Chloro phenyl) – 5 - (2-methoxy phenyl) – 7 – methyl – 2 ,3 – dihydro -
5H - [1,3]thiazolo[ 3 , 2 – a ]pyrimidine – 6 - c arboxamide (AKS-574).

140
IR(KBr)cm -1 :3192 (-NH,str),3142 (-CH=CH),2937 (Ar-CH,asym), 2881,2835 (Ar-
CH,sym),1681 (-C=O),1460,1417 (-C-Cskeletal vibration),1240,1285 (C-S,
str),1188 (C-H IPD),1049,1026 (C-O-C),794 (C-H, OPD).
C, H, N (In %): Found: 60.94 (C), 4.87 (H), 10.15 (N), Cacld: 60.98 (C), 4.84 (H),
10.20 (N)
5 - (2-Chloro phenyl) – N - (4-chloro phenyl) – 7 – methyl - 2,3 – dihydro - 5H
- [1,3] thiazolo [3,2-a] pyrimidine – 6 – carboxamide (AKS-575).
IR(KBr) cm -1 : 3221 (-NH, str), 3036 (-CH=CH), 2925 (Ar-CH,asym), 2834 (Ar-
CH,sym),1674 (-C=O),1552 (-C-C skeletal vibration),1289 (C-S, str),1158 (C-H
IPD),1065 (C-O-C),759 (C-H, OPD).
C, H, N (In %): Found: 57.42 (C), 4.10 (H), 10.04 (N), Cacld: 57.44 (C), 4.12 (H),
10.07 (N)
N - (4-Chloro phenyl) – 7 – methyl – 5 - (3-nitro phenyl)-2,3-dihydro-5H-
1,3]thiazolo[3,2-a]pyrimidine-6-carboxamide (AKS-576).
IR(KBr) cm -1 : 3174 (-NH, str), 3021 (-CH=CH), 2926 (Ar-CH,asym), 2845 (Ar-
CH,sym),1675 (-C=O),1532 (-C-C skeletal vibration),1270 (C-S, str),1175 (C-H
IPD),1083 (C-O-C),781 (C-H, OPD).
1H NMR (CDCl 3 , δ ppm): 2.17 (3H,s,1), 3.20 (2H,m,4,5), 3.39 (1H,m,3), 3.68
(1H,2), 5.71 (1H,s,6), 7.19 (2H,m,13,14, J= 2.84, 2.92 Hz), 7.42 (2H,m,11,12, J=
2.00, 2.96 Hz), 7.53 (1H,t,8, J= 7.92, 7.88 Hz), 7.72 (1H,d,9, J= 7.64 Hz), 8.15
(1H,m,7, J= 0.64, 0.84 Hz), 8.24 (1H,t,10, J= 1.84 Hz), 8.64 (1H,s,15)
C, H, N (In %): Found: 56.01 (C), 4.00 (H), 13.06 (N), Cacld: 56.05 (C), 4.04 (H),
13.07 (N),
N-(4-Fluoro phenyl) -7-methyl- 5-phenyl- 2,3-dihydro- 5H-[1,3] thiazolo [3,2-
a]pyrimidine -6-carboxamide (AKS-577).
IR(KBr) cm -1 : 3186 (-NH, str), 3010 (-CH=CH), 2915 (Ar-CH,asym), 2834 (Ar-
CH,sym),1676 (-C=O),1526 (-C-C skeletal vibration),1276 (C-S, str),1191 (C-H
IPD),1078 (C-O-C),774 (C-H, OPD).
C, H, N (In %): Found: 65.38 (C), 4.94 (H), 11.44 (N), Cacld: 65.40 (C), 4.89 (H),
11.47 (N)
N - (4-Fluorophenyl) – 5 - (2-methoxyphenyl) – 7 - methyl - 2,3 – dihydro - 5H
-[1,3] thiazolo [3,2-a] pyrimidine – 6 - carboxamide (AKS-578).

141
IR(KBr) cm -1 : 3224 (-NH, str), 3023 (-CH=CH), 2915 (Ar-CH,asym), 2842 (Ar-
CH,sym),1663 (-C=O),1522 (-C-C skeletal vibration),1276 (C-S, str),1184 (C-H
IPD),1090 (C-O-C),765 (C-H, OPD).
C, H, N (In %): Found: 63.46 (C), 5.07 (H), 10.57 (N), Cacld: 63.48 (C), 5.08 (H),
10.60 (N)
N - (4-Fluoro phenyl) – 7 - methyl – 5 - (3-nitro phenyl)- 2,3 – dihydro - 5H -
[1,3] thiazolo [3,2-a] pyrimidine - 6- carboxamide (AKS-579).
IR(KBr) cm -1 : 3210 (-NH, str), 3036 (-CH=CH), 2916 (Ar-CH,asym), 2845 (Ar-
CH,sym),1674 (-C=O),1556 (-C-C skeletal vibration),1280 (C-S, str),1145 (C-H
IPD),1069 (C-O-C),774 (C-H, OPD).
C, H, N (In %): Found: 58.24 (C), 4.15 (H), 13.58 (N), Cacld: 58.21 (C), 4.17 (H),
13.60 (N)
5 - (3-Chloro phenyl) – N - (4-fluorophenyl) – 7 – methyl - 2,3 – dihydro - 5H -
[1,3] thiazolo [3,2-a] pyrimidine –6- carboxamide (AKS-580).
IR(KBr) cm -1 : 3174 (-NH, str), 3021 (-CH=CH), 2926 (Ar-CH,asym), 2845 (Ar-
CH,sym),1675 (-C=O),1532 (-C-C skeletal vibration),1270 (C-S, str),1175 (C-H
IPD),1083 (C-O-C),781 (C-H, OPD).
C, H, N (In %): Found: 59.77 (C), 4.26 (H), 10.46 (N), Cacld: 59.74 (C), 4.224
(H), 10.49 (N)
5 - (4-Chloro phenyl) – N - (4-fluorophenyl) – 7 – methyl - 2,3 – dihydro - 5H -
[1,3] thiazolo [3,2-a] pyrimidine -6- carboxamide (AKS-581).
IR(KBr) cm -1 : 3216 (-NH, str), 3010 (-CH=CH), 2915 (Ar-CH,asym), 2852 (Ar-
CH,sym),1668 (-C=O),1540 (-C-C skeletal vibration),1263 (C-S, str),1163 (C-H
IPD),1075 (C-O-C),768 (C-H, OPD).
C, H, N (In %): Found: 59.77 (C), 4.26 (H), 10.46 (N), Cacld: 59.79 (C), 4.29 (H),
10.47 (N)
N - (4-Fluoro phenyl) -7- methyl -5- (3-nitro phenyl) -2,3- dihydro -5H- [1,3]
thiazolo [3,2-a] pyrimidine -6- carboxamide (AKS-582).
IR(KBr) cm -1 : 3213 (-NH, str), 3023 (-CH=CH), 2923 (Ar-CH,asym), 2842 (Ar-
CH,sym),1662 (-C=O),1522 (-C-C skeletal vibration),1276 (C-S, str),1184 (C-H
IPD),1090 (C-O-C),752 (C-H, OPD).
C, H, N (In %): Found: 58.24 (C), 4.15 (H), 13.58 (N), Cacld: 58.21 (C), 4.17
(H), 13.61 (N)

142
N - (4-Fluoro phenyl) -5- (3-methoxy phenyl) -7- methyl -2,3- dihydro -5H-[1,3]
thiazolo [3,2-a] pyrimidine -6- carboxamide (AKS-583).
IR(KBr) cm -1 : 3145 (-NH, str), 3021 (-CH=CH), 2918 (Ar-CH,asym), 2834 (Ar-
CH,sym),1665 (-C=O),1526 (-C-C skeletal vibration),1276 (C-S, str),1191 (C-H
IPD),1078 (C-O-C),771 (C-H, OPD).
C, H, N (In %): Found: 63.46 (C), 5.07 (H), 10.57 (N), Cacld: 63.44 (C), 5.10 (H),
10.60 (N)
N - (4-Fluoro phenyl) -5- (4-methoxyphenyl) -7- methyl -2,3- dihydro -5H- [1,3]
thiazolo [3,2-a] pyrimidine -6- carboxamide (AKS-584).
IR(KBr) cm -1 : 3223 (-NH, str), 3025 (-CH=CH), 2932 (Ar-CH,asym), 2842 (Ar-
CH,sym),1673 (-C=O),1540 (-C-C skeletal vibration),1263 (C-S, str),1163 (C-H
IPD),1080 (C-O-C),753 (C-H, OPD).
C, H, N (In %): Found: 63.46 (C), 5.07 (H), 10.57 (N), Cacld: 63.44 (C), 5.10 (H),
10.60 (N)
5 - (2-Chloro phenyl) -N- (4-fluoro phenyl) -7- methyl -2,3- dihydro -5H-[1,3]
thiazolo [3,2-a] pyrimidine -6- carboxamide (AKS-585).
IR(KBr) cm -1 : 3214 (-NH, str), 3010 (-CH=CH), 2915 (Ar-CH,asym), 2852 (Ar-
CH,sym),1662 (-C=O),1546 (-C-C skeletal vibration),1274 (C-S, str),1168 (C-H
IPD),1075 (C-O-C),768 (C-H, OPD).
1H NMR (CDCl 3 , δ ppm): 2.17 (s,3H,1), 3.11 (m,1H,4), 3.25 (m,1H,5), 3.35
(m,1H,3) 3.74 (m,1H,2), 6.11 (s,1H,6), 6.92 (t-t,2H,7,9, J= 3.32, 2.04 Hz ), 7.25 (tt,1H,8,
J= 1.64, 2.04 Hz), 7.33 (qt-qt ,2H,13,14, J= 1.04, 3.04 Hz), 7.46
(m,2H,11,12, J= 2.04, 3.24, 4.92 Hz), 9.01 (s,1H,15), 7.60 (t,1H,10, J= 0.92, 7.00
Hz).
Mass (m/z value) : 401 (12), 386 (10), 366 (5), 295 (3), 291 (100), 255 (2), 228
(22), 213 (4), 197 (4), 187 (8), 179 (12), 163 (4), 151 (10), 127 (23), 115 (4), 110
(11), 86 (24), 83 (14), 67 (17), 42 (8), 41 (3).
C, H, N (in %): Found: 59.77 (C), 4.26 (H), 10.46 (N), Cacld: 59.74 (C), 4.224
(H), 10.49 (N)
5 - (4-Methoxy phenyl) -7- methyl - N- 1-naphthyl -2,3- dihydro -5H-[1,3]
thiazolo [3,2-a] pyrimidine -6- carboxamide (AKS-586).

143
IR(KBr) cm -1 : 3186 (-NH, str), 3025 (-CH=CH), 2916 (Ar-CH,asym), 2834 (Ar-
CH,sym),1670 (-C=O),1526 (-C-C skeletal vibration),1276 (C-S, str),1191 (C-H
IPD),1069 (C-O-C), 768 (C-H, OPD).
1H NMR(CDCl 3 ,δppm): 2.31(s,3H,1),3.10(m,1H,3),3.20(m,1H,2),3.44
(m,1H,5),3.56 (m,1H,4),3.82 (s,1H,11),5.44 (s,1H,6),7.77 ,2H,16,18,J=9.2,9.2 Hz),
7.38 (d,1H,17,J=8.2 Hz), 6.91-7.29 (m,4H,7,8,9,10,J=8.76,7.02 Hz),7.34-7.43
(m,5H,12,13,14,15,19)
13 CNMR(δppm):14.73 (C1), 22.34 (C2), 25.75 (C3), 51.12 (C4), 57.10 (C5), 107.73
(C6), 120.54 (C7), 121.16 (C8), 125.71 (C9), 125.91 (C10), 126.19 (C11), 127.34 (C12),
128.50 (C13), 128.68 (C14), 130.08 (C15), 130.31 (C16), 130.96 (C17), 132.17 (C18),
133.03 (C19), 134.08 (C20), 137.34 (C21), 146.95 (C22), 157.02 (C23), 164.95 (C24),
166.70 (C25).
C, H, N (In %): Found: 66.43 (C), 4.65 (H), 9.68 (N), Cacld: 66.44 (C), 4.67 (H),
9.70 (N)
5 - (2-Chloro phenyl) -7- methyl -N- 1-naphthyl- 2,3- dihydro -5H- [1,3]
thiazolo [3,2-a] pyrimidine -6- carboxamide (AKS-587).
IR(KBr) cm -1 : 3186 (-NH, str), 3018 (-CH=CH), 2926 (Ar-CH,asym), 2823 (Ar-
CH,sym),1671 (-C=O),1522 (-C-C skeletal vibration),1272 (C-S, str),1195 (C-H
IPD),1072 (C-O-C),765 (C-H, OPD).
Mass (m/z value) : 435 (5), 433 (10), 322 (2), 295 (3), 291 (100), 255 (85), 228
(18), 213 (4), 196 (5), 187 (5), 170 (5), 161 (4), 153 (7), 127 (17), 115 (22), 101
(4), 86 (18), 77 (4), 67 (11), 42 (5), 41 (1).
C, H, N (In %): Found: 69.91 (C), 5.40 (H), 9.78 (N), Cacld: 69.87 (C), 5.44 (H),
9.80 (N),
N- 6- Bis (4-chloro phenyl) -8- methyl -3,4- dihydro -2H ,6H- pyrimido [2,1-b]
[1,3] thiazine -7- carboxamide (AKS-588).
IR(KBr) cm -1 : 3284 (-NH, str), 3012 (-CH=CH), 2924 (Ar-CH,asym), 2868 (Ar-
CH,sym),1674 (-C=O),1516 (-C-C skeletal vibration),1263 (C-S, str),1190 (C-H
IPD),1089 (C-O-C),813 (C-H, OPD).
1H NMR (CDCl 3 , δ ppm): 2.15 (m,1H,17), 2.23 (m,1H,16), 2.23 (m,3H,1), 2.90
(m,1H,5), 2.98 (m,1H,4), 3.21 (m,1H,3), 3.33 (m,1H,2), 5.21 (s,1H,6), 7.07
(s,1H,15),7.21-7.24(t-t,2H,13,14,J=2.04,2.88HZ),7.29-7.37 (m,6H,7,8,910,11,12)

144
Mass: 435 (2), 431 (10), 416 (3), 329 (10), 323 (2), 305 (100), 290 (4), 277 (18),
263 (2), 250 (3), 237 (2), 214 (3), 204 (2), 189 (10), 167 (18), 143 (14), 127 (17),
125 (13), 100 (38), 90 (4), 72 (24), 67 (18), 42 (7), 41 (44).
C, H, N (In %): Found: 58.34 (C), 4.43 (H), 9.72 (N), Cacld: 58.31 (C), 4.41 (H),
9.74 (N),
N - (4-Chloro phenyl) -8- methyl -6- (2-methoxyphenyl) -3,4- dihydro -2H, 6Hpyrimido
[2,1-b] [1,3] thiazine -7- carboxamide (AKS-589).
IR(KBr) cm -1 : 3256 (-NH, str), 3018 (-CH=CH), 2965 (Ar-CH,asym), 2829 (Ar-
CH,sym),1668 (-C=O),1570 (-C-C skeletal vibration),1253 (C-S, str),1168 (C-H
IPD),1072 (C-O-C),786 (C-H, OPD).
1H NMR (CDCl 3 , δ ppm): 2.07-2.13 (m,1H,5), 2.16-2.29 (m,1H,4), 2.29 (s,1H,1),
2.82-2.95 (m,2H,6,7), 3.17-3.24 (m,1H,3), 3.41-3.45 (m,1H,2), 3.47 (s,3H,17),
5.80 (s,1H,12), 7.66 (d-d,1H,9,J=1.72,7.68 Hz), 7.26-7.37 (m,5H,8,10,11,13,14),
7.18-7.22 (t-t,2H,15,16, J=2.92 Hz), 7.04 (s,1H,18).
C, H, N (In %): Found: 61.74 (C), 5.18 (H), 9.82 (N), Cacld: 61.77 (C), 5.14 (H),
9.86 (N),
N - (4-Chloro phenyl) -6- (2-hydroxy phenyl) -8- methyl -3,4- dihydro -2H, 6Hpyrimido
[2,1-b] [1,3] thiazine -7- carboxamide (AKS-590).
IR(KBr) cm -1 : 3196 (-NH, str), 3034 (-CH=CH), 2945 (Ar-CH,asym), 2852 (Ar-
CH,sym),1662 (-C=O),1546 (-C-C skeletal vibration),1270 (C-S, str),1190 (C-H
IPD),1062 (C-O-C),765 (C-H, OPD).
C, H, N (In %): Found: 60.94 (C), 4.87 (H), 10.15 (N), Cacld: 60.96 (C), 4.88 (H),
10.20 (N)
N - (4-Chloro phenyl) -8- methyl -6- (4-nitro phenyl) -3,4- dihydro -2H, 6Hpyrimido
[2,1-b] [1,3] thiazine -7- carboxamide (AKS-591).
IR(KBr) cm -1 : 3292 (-NH, str), 3026 (-CH=CH), 2941,2942 (Ar-CH,asym),
2847,2866 (Ar-CH,sym),1689 (-C=O),1498,1462 (-C-C skeletal vibration),1247
(C-S, str),1188 (C-H IPD),1091 (C-O-C),775 (C-H, OPD).
C, H, N (In %): Found: 56.95 (C), 4.32 (H), 12.65 (N), Cacld: 56.92 (C), 4.36 (H),
12.67 (N),
N - (4-Chloro phenyl) -8- methyl -6- (3-nitro phenyl) -3,4- dihydro -2H, 6Hpyrimido
[2,1-b] [1,3] thiazine -7- carboxamide (AKS-592).

145
IR(KBr) cm -1 : 3216 (-NH, str), 3015 (-CH=CH), 2968 (Ar-CH,asym), 2842 (Ar-
CH,sym),1677 (-C=O),1570 (-C-C skeletal vibration),1290 (C-S, str),1182 (C-H
IPD),1075 (C-O-C),771 (C-H, OPD).
1H NMR (CDCl 3 , δ ppm): 2.25 (m,3H,1), 2.19 (m,1H,16), 2.25 (m,1H,17), 2.93
(m,1H,4), 3.02 (m,1H,15), 3.2 (m,1H,3), 3.42 (m,1H,2), 5.39 (s,1H,6), 7.23 (t-t,
2H,13,14, J= 2.92, 1.96 Hz), 7.37 (m,3H,11,12,15), 7.53 (t,1H,8, J= 7.88, 7.96
Hz), 7.76 (t,1H,9, J=1.32, 6.44 Hz), 8.15 (qt-qt,1H,10,J=1.86,1.86 Hz), 8.20
(t,1H,7, J= 1.92 Hz )
Mass: 442 (9), 425 (14), 316 (100), 288 (7), 270 (20), 242 (6), 223 (1), 200 (2),
193 (7), 168 (3), 167 (20), 153 (9), 127 (14), 115 (8), 100 (27), 90 (9), 72 (22), 67
(15), 44 (12).
C, H, N (In %): Found: 56.95 (C), 4.32 (N), 12.65 (N), Cacld: 56.98 (C), 4.34 (N),
12.67 (N)
6 - (2-Chlorophenyl) -N- (4-chloro phenyl) -8- methyl -3,4- dihydro -2H, 6Hpyrimido
[2,1-b] [1,3] thiazine -7- carboxamide (AKS-593).
IR(KBr) cm -1 : 3189 (-NH, str), 3046 (-CH=CH), 2972 (Ar-CH,asym), 2874 (Ar-
CH,sym),1686 (-C=O),1562 (-C-C skeletal vibration),1274 (C-S, str),1189 (C-H
IPD),1092 (C-O-C),768 (C-H, OPD).
Mass: 431 (8), 416 (3), 305 (100), 269 (76), 242 (5), 193 (8), 170 (5), 167 (8),
153 (4), 128 (14), 125 (7), 100 (14), 90 (4), 72 (18), 67 (16), 42 (7).
C, H, N (In %): Found: 58.34 (C), 4.43 (H), 9.72 (N), Cacld: 58.33 (C), 4.46 (H),
9.75 (N),

IR spectrum of N,6-Bis(4-chlorophenyl)-8-methyl-3,4-dihydro-2H,6Hpyrimido[2,1-b][1,3]thiazine-7-carboxamide(AKS-588).
146
Cl
Cl
O
NH
N
C H 3
N
S
IR Spectrum of N-(4-Chlorophenyl)-8-methyl-6-(4-nitrophenyl)-3,4-dihydro-
2H,6H-pyrimido[2,1-b][1,3]thiazine-7-carboxamide(AKS-591).
O
N + O-
Cl
O
NH
N
C H 3
N
S

IR Spectrum of N,5-Bis(4-chlorophenyl)-7-methyl-2,3-dihydro-5H-
[1,3]thiazolo[3,2-a]pyrimidine-6-carboxamide(AKS-573).
147
Cl
Cl
O
NH
N
C H 3
N
S
IR spectrum of N-(4-Chlorophenyl)-5-(2-methoxyphenyl)-7-methyl-2,3-
dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxamide(AKS-574).
Cl
O
O CH 3
NH
N
C H 3
N
S

1 H NMR Spectrum of 5-(2-Chlorophenyl)-N-(4-chlorophenyl)-7-methyl-2,3-
dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxamide(AKS-585)
148
9
AKS-585
8 10
O 7
Cl
14 H H
5
H
11
6 4
N
NH
H
3
F 13 15
H 3 C N S H
12
2
1

1 H NMR Spectrum of N-(4-Chlorophenyl)-7-methyl-5-(3-nitrophenyl)-2,3-
dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxamide(AKS-576).
149
AKS-576
14
11
NH
Cl 13 15
12
O
H 3 C
1
O
9
N +
8 O -
7 10
H H
5
6 H
4
N
H
3
N S H
2

150
1 H NMR Spectrum of N-(4-Chlorophenyl)-8-methyl-6-(3-nitrophenyl)-3,4-
dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazine-7-carboxamide(AKS-592)
AKS-592
14
11
NH
Cl 13 15
12
O
H 3 C
1
8
7
H
6
9
O
N + O -
10 5
H
H H17
4
N
H
16
N S H
H 3
2

151
1 H NMR Spectrum of N,6-Bis(4-chlorophenyl)-8-methyl-3,4-dihydro-2H,6Hpyrimido[2,1-b][1,3]thiazine-7-carboxamide(AKS-588).
Cl
AKS-588
14
11
NH
Cl 13 15
12
O
H 3 C
1
8
7
H
6
9
10 5
H
H4
H17
N
H
16
N S H
H 3
2

152
1 H NMR Spectrum of N,6-Bis(1-naphthyl)-8-methyl-3,4-dihydro-2H,6Hpyrimido[2,1-b][1,3]thiazine-7-carboxamide(AKS-586).
AKS-586
13
14 12
15
16 18
17
19
NH
11
O CH 3
8 9
7
O 10
H H
6 2 H 3
N H
5
H 3 C N S H
1
4

153
1 H NMR Spectrum of N-(4-Chlorophenyl)-7-methyl-5-(3-methoxy phenyl)-2,3-
dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxamide(AKS-589).
AKS-589
16
13
NH
Cl
14 15 18
O
H 3 C
1
11
8 9
10
H
12
N
CH 3
H O H
7 6 H5
N
S
H
2
17
H4
H
3

Mass Spectrum of N-(4-Chlorophenyl)-8-methyl-6-(3-nitrophenyl)-3,4-
dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazine-7-carboxamide (AKS-592)
154
O
N + O -
Cl
O
NH
N
C H 3
N
S
M.W.= 442.91 gm/mole
Mass Spectrum of N,6-Bis(4-chlorophenyl)-8-methyl-3,4-dihydro-2H,6Hpyrimido[2,1-b][1,3]thiazine-7-carboxamide
(AKS-588)
Cl
Cl
O
NH
N
C H 3
N
S
M.W.= 432.36 gm/mole

Mass Spectrum of 6-(2-Chlorophenyl)-N-(4-chlorophenyl)-8-methyl-3,4-
dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazine-7-carboxamide (AKS-593)
155
Cl
O
Cl
NH
N
C H 3
N
S
M.W.= 432.36 gm/mole
Mass Spectrum of 5-(2-Chlorophenyl)-N-(4-fluorophenyl)-7-methyl-2,3-
dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxamide (AKS-585).
O
Cl
NH
N
F
C H 3
N
S
M.W.= 401 gm/mole

Mass Spectrum of 5-(2-Chlorophenyl)-7-methyl-N-1-naphthyl-2,3-dihydro-
5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxamide (AKS-587).
156
O
Cl
NH
N
C H 3
N
S
M.W.= 433.95 gm/mole

13 C Spectra of 5-(4-methoxyphenyl)-7-methyl-N-1-naphthyl-2,3-dihydro-5H-
[1,3]thiazolo[3,2-a]pyrimidine-6-carboxamide(AKS-586)
157
4
O CH 3
22
6 7
16
10 18
11
19
17
14
21
15
9
NH
13 12
O
20
2
24 N
8
3
H 3 C 23 N 25 S
1

Chapter-5
Synthesis and Characterization of N-aryl
substituted-1-phenyl-1, 2, 3, 4 - tetrahydro
pyrimidine derivatives by Biginelli reaction.
1. Reaction scheme 158
2. Experimental 161
3. Physical data table 163
4. Spectral analysis 166
5. Mass fragmentation 168
6. Spectral data 168
7. IR spectra 175
8. 1H NMR spectra 178
9. Mass spectra 182

158
INTRODUCTION
In earlier Chapter, a synthesis of thazolo fused pyrimidine system was developed.
Though Biginelli is well explored as multicomponent rection (MCR), very few work
is reported to use this facile reaction for N-substituted Biginelli products.
On basis of previous work on N-substituted 1,4-dihydropyridines, the current
approach was to use same approach to synthesize practically N-substituted
carbamoyl bearing compounds.
The current Chapter deals with reaction scheme, plausible mechanism, physical
data, spectral data and interpretation of this newly synthesized compounds.

159
5.1 REACTOIN SCHEMES
5.1.1 Scheme-1
+ -
NH 3
Cl
R
O
+ H 2 N NH 2
gla.CH 3
COOH
Con.HCl
R
NH
O
NH 2
5.1.2 Scheme-2
NH 2
R 1
O O
+ H3C
O CH 3
KOH
Toluene,115 0 c
NH
R 1
CH 3
O
O
5.1.3 Scheme-3
O
O
HN
NH 2
R 1
+
NH
H 3 C O
R 2
H
NH
O
+
R
CH 3
OH
Con.HCl,Reflux
R 2
O
R 1
NH
H 3 C
N
O
R

160
5.1.4 REACTION MECHANISM
H
O
HN
NH 2
O
H +
-H 2
O
H
HN
H
N + O
NH
O
H 3 C
H
H
O
H
HN
H
N + O
O
NH
N H
HO
N
O
H 3 C
-H + -H 2
O
O
NH
N H
H 3 C N O

161
5.2 Experimental
5.2.1 N-Substituted phenylurea A (Scheme-1)
The base used are aniline, meta toluidine and 2,4 dimethyl aniline, they were first
converted into respective hydrochloride salts form.
Aniline (3-methyl/2,4-dimethylaniline) hydrochloride (0.2M) and urea (0.2M) were
dissolved in 100 ml of water. 2 ml of glacial acetic acid and 2 ml of conc. HCl was
added to this solution. The reaction mixture was refluxed and white crystals
appeared after 30-40 minutes. The reflux was continued for another 30 minutes.
The reaction mixture was cooled and filtered. The solid product was taken into
300 ml of water and boiled. It was filtered, and the filtrate was concentrated and
allowed to cool. The crystal of phenyl urea was filtered and dried. (Mp: 1-
phenylurea – 146-47° (Reported 147 o C) C; 1-(3-methylphenyl)-urea - 159° C
(Reported 161 o C); 1-(2,4-dimethylphenyl)-urea – 168-69° C) (Reported 166 o C).
Physical data of the synthesized compounds are specified in Table 5.3.1
5.2.2 4-Chloro/Flouro acetoacetanilide B (scheme-2)
4-chloro/flouro aniline (0.1M) and ethyl acetoacetate was refluxed at 110° C in 40
ml of toluene and catalytic amount of KOH/NaOH. The completion of reaction
was monitored with TLC. After completion of reaction, toluene was distilled out.
The residue was cooled at room temperature and was treated with ether. The
solid was filtrated and dried. (Yield: 4-chloroacetoacetanilide – 62%, 4-
flouroacetoacetanilide – 56%. Mp: 4-chloroacetoacetanilide - 114° C
(Reported115 o C), 4-fluoroacetoacetanilide - 129° C (Reported 128 o C).
Physical data of the synthesized compounds are specified in Table 5.3.2

162
5.2.3 4-(Substituted phenyl)-N-(substitutedphenyl) - 1, 2, 3, 4- tetrahydro- 6-
methyl-2-oxo-1-(substitutedphenyl) pyrimidine-5-carboxamides (Scheme-3)
[General method]
Acetoacetanilide (0.01M), aldehyde (0.01M) and N-phenyl urea (0.015M) were
dissolved in methanol and refluxed until clear solution is obtained. Few drops of
Con. HCl was added to reaction mixture and was refluxed for 8-12 hrs. The
reaction was monitored with TLC and after completion; the reaction mixture was
allowed to cool. The solid separated was filtered, washed with hot methanol and
dried. (Yield – 45-60%).
Similarly other compounds were prepared by adopting this process.
Physical data of newly synthesized compounds are specified in Table 5.3.3
A
Vogel’s text book of practical organic chemistry, 5 th Edition, Page no. 965
B Naliapara, Y. T.; Ph.D. Thesis., Saurashtra University, 1998

163
5.3 PHYSICAL DATA
5.3.1 Physical data of N-(substituted phenyl)-3-oxobutanamide (1a-1b)
H
N
R 1
N
H
NH 2
O
O
No. R 1 MW Yield in MP in o C R f value
%
1a 4-Cl 211.64 58 184-186 0.64
1b 4-F 195.19 52 165-167 0.69
5.3.2 Physical data of 1-(substituted phenyl) urea (2a-2c)
R
O
No. R 1 MW Yield in MP in o C R f value
%
2a H 136.15 55 146-148 0.41*
2b 3-CH 3 150.18 65 186-188 0.37
2c 2,4-di-CH 3 164.20 60 212-214 0.30*
TLC solvent system : Ethyl acetate : Hexane 3.0 ml : 7.0 ml
Visualization: UV light (long)
: *CH 2 Cl 2 : MeOH 9.4 ml :0.6 ml

164
5.3.3 Physical data of N-(substituted phenyl)-N-(substituted phenyl)-6-
methyl-2-oxo-4(substituted phenyl)-1, 2, 3, 4-tetrahydropyrimidine-5-
carboxamides (AKS 901-920)
R 2
O
R 1
NH
NH
H 3 C
N
O
R
Code
No.
R R 1 R 2 MW Melting
Point
Yield
in %
Rf
Value
In o C
AKS-901 H 4-Cl H 417.88 256-258 59 0.36
AKS-902 H 4-Cl 3-NO 2 462.88 241-243 53 0.42
AKS-903 H 4-Cl 2-NO 2 462.88 196-198 48 0.39
AKS-904 H 4-CL 2-Cl 452.33 214-216 58 0.50
AKS-905 H 4-CL 4-F 435.87 174-176 53 0.43
AKS-906 H 4-Cl 2,3- benzo 467.94 245-246 48 0.48
AKS-907 H 4-Cl 2-OH 433.88 194-196 47 0.52
AKS-908 H 4-F 2,3-benzo 451.49 176-178 58 0.47
AKS-909 3-CH 3 4-Cl 3-Cl 466.35 189-191 51 0.39
AKS-910 3 -CH 3 4-Cl 2,3- benzo 481.97 165-167 55 0.41
AKS-911 3- CH 3 4-Cl 4-OCH 3 461.94 185-187 57 0.43*
AKS-912 3 -CH 3 4-Cl 2,3.5,6- 532.03 244-246 48 0.36*
dibenzo
AKS-913 3- CH 3 4-Cl 3-NO 2 476.91 221-223 59 0.33*
AKS-914 2,4diCH 3 4-Cl H 445.94 274-276 57 0.46
AKS-915 2,4diCH 3 4-Cl 3-NO 2 490.93 256-258 46 0.42*

165
AKS-916 2,4diCH 3 4-Cl 3,4,5-tri
OCH 2
536.01 246-248 49 0.46
AKS-917 2,4diCH 3 4-Cl 3-Cl 480.38 185-187 61 0.52
AKS-918 H 4-F 4-OH 417.43 249-251 53 0.35*
AKS-919 H 4-F H 401.43 286-288 46 0.41
AKS-920 H 4-F 3-NO 2 446.43 196-198 56 0.52
TLC solvent system : Ethyl acetate : Hexane 3.0 ml : 7.0 ml
: *CH 2 Cl 2 : MeOH 9.4 ml : 0.6 ml
Visualization: UV light (long)

166
5.4 SPECTRAL ANALYSIS
5.4.1 MASS SPECTRAL ANALYSIS
Mass spectra were recorded on Shimadzu GC-MS-QP-2010 model using Direct
Injection Probe technique. The molecular ion peak was found in concordance
with molecular weight of the individual compound. Characteristic M +2 ion peaks
with one-third intensity of molecular ion peak were observed in case of
compounds having chlorine atom. The DHPMs made of 4-chloro acetoacetanilide
showed this characteristic peak. Various fragmentation details are obtained for
each compound in this series which are as under.
Cleavage of α-bond to double bond is predictable to give peak in mass spectrum.
Cleave of C-N bond (α-bond to >C=O bond at carbomoyl side chain at C 5
position) gave intense peak in each one spectrum. Cleavage of second α-bond to
>C=O bond of carbamoyl moiety gives an additional characteristic peak which is
observed in every mass spectra. Cleavage of methyl (-CH 3 ) group at C 6 site from
above fragment gave distinguishing peak at m/e value less than 15.Cleavage to
both α-bonds to C=O bond of DHPM ring, gives another distinctive peak for this
progression of compounds. Thus, molecular ion peak, one-third strength M +2
peak for chloro derivatives and further than characteristic peaks observed for this
series were in support to assigned structure to these compounds. Mass spectra
of the recently synthesized compounds are given on Pages 182-183.
5.4.2 IR SPECTRAL ANALYSIS
As per spectral data of newly synthesized dihydropyrimidine molecules,
mainstream of the carbonyl (>C=O) stretching observed at ~1640-1700cm -1 due
to amide carbonyl functionality. The additional conformation of the amide group is
revealed by >C-N stretching in range of 1501-1592. The stretching of secondary
amine (>NH) come forward around ~3428-3432 cm -1 , its bending and C-N
stretching come out at 1501-1592 cm -1 correspondingly. The C-H stretching of
aromatic moiety was observed at ~3030 cm -1 .

167
The supplementary characterization owing to aromatics moiety C-C multiple bond
stretching, C-H in plane bending and out of plane bending emerge around at
~1501-1592 cm -1 , ~1080 cm -1 and ~680-790 cm -1 . The C-H stretching of methyl
group observed at ~2920-2923 cm -1 (asym) and ~2831-2851(sym) and its bending
was observed at ~1383 cm -1 . IR spectra of the newly synthesized compounds are
given on Pages 175-177.
5.4.3 1 H NMR SPECTRAL ANALYSIS
It was observed during study of 1 H NMR spectra of the title compounds that
methyl protons are observed as singlet at 2.10-2.16 δ ppm. Asymmetric carbon
protons (>CH) in all compounds were observed between 5.0-5.9 δ ppm. The
amide (>NH) protons gave singlet between 7.0-9.8 δ ppm. The aromatic protons
were observed at close to 6.60-8.30 δ ppm.
Two triplets are evidently observed in the aromatic region as a result of ortho/dimeta
coupling of meta nitro phenyl protons. For the ortho substituted phenyl ring,
three doublets is observed due to di-ortho/meta coupling of phenyl protons and
for para substitution, doublet of doublet was observed in the spectrum. In case of
N-(4-chlorophenyl)-4-(4-fluorophenyl)-6-methyl-2-oxo-1-phenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide spectrum owing to ortho di coupling, triplet
–triplet splitting pattern in place of doublet- doublet, caused by the attendance of
neighboring fluorine atom.
1H NMR spectra of the recently synthesized
compounds are given on Pages 178-181.
5.4.4 ELEMENTAL ANALYSIS
Elemental analysis of the all the synthesized compounds was carried out on
Elemental Vario EL III Carlo Erba 1108 model and the results are in agreements
(within the range of theoretical value) with the structures assigned.

168
Mass fragmentation of mass spectrum of N-(3-methylphenyl)-N-(4-
chlorophenyl)-6-methyl-2-oxo-4(4-methoxyphenyl)-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (AKS-911).
O
C H 3
O
CH 3
NH
H 3
OC
N
O
CH
H 3 C
3
NH
H 3 C
N
O
CH 3
CH 3
OH
2
1
11
CH 2 CH 3
H 3 C
N
NH
O
3
O
10
NH
NH
4
Cl
H 3
OC
N
CH 3
CH 3
CH 3
9
OH
O
NH
8
N
O
5
7
OH
NH
NH 2
6
CH 3
H 3 C
CH 2
SPECTRAL DATA
4-(Phenyl) N-(4-chloro phenyl) -6- methyl -2 -oxo- 1, 4 –diphenyl - 1, 2, 3, 4 -
tetrahydropyrimidine-5-carboxamide (AKS-901).
IR(KBr,cm -1 ): 3363-3286 (-NH),3049 (Ar-CH,str), 2916 (methyl,asym,str), 2870
(methyl, sym,str), 1720(>C=O, cyclic), 1685 (>C=O,amide),1523 (C-N,str), 1597-
1491 (>C=C,ring skeletal vibration), 1170 (C-H, ipd), 798-771 (C-H,opd),1087-
1058 (C-O-C,sym,str),1242(C-O-C, asym,str). 667 (-C=C-,opd,bend).
C, H, N (in %): Found: 68.98 (C), 4.82 (H), 10.06 (N), Cacld: 68.94 (C), 4.80 (H),
10.07 (N)
4-(3-Nitro phenyl) -N- (4-chloro phenyl) -6- methyl -2-oxo- 1-phenyl -1, 2, 3,4-
tetrahydropyrimidine-5-carboxamide (AKS-902).

169
IR(KBr,cm -1 ): 3292-3228 (-NH), 3101 (Ar-CH, str), 2924, (methyl,asym,str),
2870(methyl, sym,str), 1701 (>C=O, cyclic), 1685 (>C=O,amide),1525 (C-N,str),
1591-1492 (>C=C,ring skeletal vibration), 1176(C-H, ipd), 775 (C-H,opd),1010-
1089 (C-O-C,sym,str),1244 (C-O-C, asym,str). 682 (-C=C-,opd,bend).
1 H NMR(δ ppm): 1.85 (s, 3H, a), 5.57 (d, 1H, b), 7.21 (m, 4H, c 1 , c 2 , b 3 , b 4 ), 7.39
(t, 1H, b 5 , J=1.16, 7.24 Hz), 7.46 (d-d, 2H, b 1 , b 2 , J=7.88, 1.08 Hz), 7.57 (m, 3H,
c 3 , c 4 , a 4 ), 8.07 (d, 1H, a 3 , J=3.24 Hz), 8.13 (t-t, 1H, a 2 , J=2.20 Hz), 8.39 (t, 1H,
a 1 , J=1.92 Hz), 9.90 (s, 1H, e 1 )
C, H, N (in %): Found: 62.27 (C), 4.14 (H), 12.10 (N), Cacld: 62.24 (C), 4.10 (H),
12.13 (N)
4-(2-Nitro phenyl) -N- (4-chloro phenyl) -6- methyl -2-oxo- 1-phenyl -1, 2, 3,4-
tetrahydropyrimidine-5-carboxamide (AKS-903).
IR(KBr,cm -1 ): 3315-3227 (-NH), 3093-3070 (Ar-CH, str), 2924 (methyl,asym,str),
1701 (>C=O, cyclic), 1662 (>C=O,amide),1529 (C-N,str), 1529-1475 (>C=C,ring
skeletal vibration), 1174-1130 (C-H, ipd), 790 (C-H,opd),1010-1080 (C-O-
C,sym,str),1244 (C-O-C, asym,str). 624 (-C=C-,opd,bend).
C, H, N (in %): Found: 62.27 (C), 4.14 (H), 12.10 (N), Cacld: 62.27 (C), 4.14 (H),
1.10 (N)
4-(2-Chloro phenyl) -N- (4-chloro phenyl) -6- methyl-2-oxo-1-phenyl-1, 2, 3, 4
-tetrahydropyrimidine-5-carboxamide (AKS-904).
IR(KBr,cm -1 ): 3377-3286 (-NH), 3055 (Ar-CH, str), 2949 (methyl,asym,str),
1716(>C=O, cyclic), 1666 (>C=O,amide),1548 (C-N,str), 1593-1467 (>C=C,ring
skeletal vibration), 1176-1122(C-H, ipd), 775 (C-H,opd),1093 (C-O-
C,sym,str),1253 (C-O-C, asym,str). 501 (-C=C-,opd,bend).
C, H, N (in %): Found: 63.72 (C), 4.42 (H), 9.25 (N), Cacld: 63.74 (C), 4.39 (H),
9.29 (N)
4-(4-Fluoro phenyl) -N- (4-chloro phenyl) -6-methyl-2-oxo- 1-phenyl-1, 2, 3, 4
-tetrahydropyrimidine-5-carboxamide (AKS-905).
IR(KBr,cm -1 ): 3319-3290 (-NH), 3037-3011 (Ar-CH, str), 2953-2916
(methyl,asym,str), 2854-2779 (methyl,sym,str) 1724 (>C=O, cyclic), 1654
(>C=O,amide),1531 (C-N,str), 1593-1491 (>C=C,ring skeletal vibration), 1159 (C-
H, ipd), 767 (C-H,opd),1095 (C-O-C,sym,str),1259 (C-O-C, asym,str). 505(-C=C-
,opd,bend).

170
1 H NMR(δ ppm): 1.81 (3H,s), 5.48 (1H,s), 7.21 (4H,m), 7.34 (2H,dd,J=8.52Hz,1.96Hz),
7.38 (1H,d,J=7.20Hz), 7.43 (4H,m,), 7.57 (2H,d,J=8.88Hz
,2.08Hz)
C, H, N (in %): Found: 66.11 (C), 4.34 (H), 9.61 (N), Cacld: 66.13 (C), 4.39 (H),
9.64 (N)
4- (Naphthyl) - N - (4-chloro phenyl) -6- methyl -2- oxo- 1-phenyl-1, 2, 3, 4 -
tetrahydropyrimidine-5-carboxamide (AKS-906).
IR(KBr,cm -1 ): 3325-3236 (-NH), 3176-3039 (Ar-CH, str), 2951-2920,
(methyl,asym,str), 2854-2783 (methyl,sym,str) 1724 (>C=O, cyclic), 1637
(>C=O,amide),1518 (C-N,str), 1637-2000(overtone combination region) 1593-
1491 (>C=C,ring skeletal vibration), 1136 (C-H, ipd), 794-773(C-H,opd),1078 (C-
O-C,sym,str),1282-1242 (C-O-C, asym,str). 509-435 (-C=C-,opd,bend).
Mass (m/z value): 468 (2), 392 (1), 376 (1), 305 (1), 265 (1), 249 (10, 232 (52),
218 (2), 203 (4), 188 (28), 174 (8), 161 (100), 146 (4), 133 (90), 118 (10), 104
(31), 89 (14), 77 (54), 63 (14), 51 (37)
C, H, N (in %): Found: 71.84 (C), 4.78 (H), 8.94 (N), Cacld: 71.87 (C), 4.74 (H),
8.98 (N)
4-(2-Hydroxy phenyl)-N-(4-chloro phenyl)-6-methyl-2-oxo-1-phenyl-1, 2, 3, 4-
tetrahydropyrimidine-5-carboxamide (AKS-907).
IR(KBr,cm -1 ): 3524-3612 (OH,str) 3343-3256 (-NH), 3089-3020 (Ar-CH, str),
2978-2948, (methyl,asym,str), 2866-2754 (methyl,sym,str) 1721 (>C=O, cyclic),
1686 (>C=O,amide),1545 (C-N,str), 1589-1486 (>C=C,ring skeletal vibration),
1168(C-H, ipd), 778 (C-H,opd),1082 (C-O-C,sym,str),1252 (C-O-C, asym,str).
602 (-C=C-,opd,bend).
Mass (m/z value): 434 (6), 432 (100), 415 (4), 401 (1), 388 (1), 371 (1), 355 (2),
342 (2), 326 (16), 313 (5), 298 (3), 285 (5), 270 (5), 253 (2), 242 (5), 227 (2), 214
(3), 200 (1), 188 (11), 164 (1), 151 (1), 127 (1), 114 (1), 100 (1), 91 (100), 77 (1),
65 (20), 44 (4).
C, H, N (in %): Found: 66.46 (C), 4.66 (H), 9.68 (N), Cacld: 66.41 (C), 4.65 (H),
9.68 (N)
4- (Napthyl) – N - (4-fluoro phenyl) -6- methyl -2 -oxo -1-phenyl -1, 2, 3, 4 -
tetrahydropyrimidine-5-carboxamide (AKS-908).

171
IR(KBr,cm -1 ): 3312-3215 (-NH), 3171-3026 (Ar-CH, str), 2954-2932,
(methyl,asym,str), 2858-2778 (methyl,sym,str) 1724 (>C=O, cyclic), 1645
(>C=O,amide),1519 (C-N,str), 1632-2000 (overtone combination region)1585-
1495 (>C=C,ring skeletal vibration), 1139 (C-H, ipd), 798-775(C-H,opd),1074 (C-
O-C,sym,str),1287-1249 (C-O-C, asym,str). 515-431 (-C=C-,opd,bend).
C, H, N (in %): Found: 74.47 (C), 4.94 (H), 9.30 (N), Cacld: 74.49 (C), 4.91 (H),
9.31 (N)
1-(3-Methyl phenyl) -N- (4-chloro phenyl) -6- methyl -2-oxo-4(3-clorophenyl)-
1,2,3,4-tetrahydropyrimidine-5-carboxamide (AKS-909).
IR(KBr,cm -1 ): 3325-3218 (-NH), 3085-3070 (Ar-CH, str), 2956, (methyl,asym,str),
1710 (>C=O, cyclic), 1665 (>C=O,amide),1522C-N,str), 1529-1474 (>C=C,ring
skeletal vibration), 1174-1130 (C-H, ipd), 795 (C-H,opd),1080-1012 (C-O-
C,sym,str),1254(C-O-C, asym,str). 633 (-C=C-,opd,bend).
C, H, N (in %): Found: 64.41 (C), 4.52 (H), 9.00 (N), Cacld: 64.39 (C), 4.54 (H),
9.01 (N)
N-(3-Methyl phenyl)-N-(4-chloro phenyl)-6-methyl-2-oxo-4(nepthyl)-1, 2, 3, 4
-tetrahydropyrimidine-5-carboxamide (AKS-910).
IR(KBr,cm -1 ): 3323-3217 (-NH), 3185-3020 (Ar-CH, str), 2966-2941,
(methyl,asym,str), 2846-2765 (methyl,sym,str) 1712(>C=O, cyclic), 1668
(>C=O,amide),1520 (C-N,str), 2000-1637 (overtone combination region) 1584-
1491 (>C=C,ring skeletal vibration), 1145 (C-H, ipd), 775 (C- H,opd),1077 (C-O-
C,sym,str),1283-1242 (C-O-C, asym,str). 431 (-C=C-,opd,bend).
C, H, N (in %): Found: 72.24 (C), 5.01 (H), 8.69 (N), Cacld: 72.27 (C), 5.02 (H),
8.72 (N)
N-(3-Methyl phenyl)-N-(4-chlorophenyl)-6-methyl-2-oxo-4(4-methoxyphenyl)-
1,2,3,4-tetrahydropyrimidine-5-carboxamide (AKS-911).
IR(KBr,cm -1 ): 3320-3214 (-NH), 3077-3062 (Ar-CH, str), 2956 ,(methyl,asym,str),
1711 (>C=O, cyclic), 1670 (>C=O,amide),1536 (C-N,str), 1529-1477 (>C=C,ring
skeletal vibration), 1188-1110 (C-H, ipd), 786 (C-H,opd),1085-1023 (C-O-
C,sym,str),1242(C-O-C, asym,str). 602 (-C=C-,opd,bend).
Mass (m/e): 462 (5), 448 (1), 445 (10), 411 (1), 336 (78), 334 (10), 308 (3), 294
(4), 293 (8), 265 (2), 245 (1), 213 (3), 204 (2), 187 (4), 177 (4), 153 (7), 155 (1),
127 (22), 118 (100), 103 (4), 91 (4), 77 (67), 67 (10), 44 (74).

172
C, H, N (in %): Found: 67.62 (C), 5.26 (H), 9.08 (N), Cacld: 67.60 (C), 5.24 (H),
9.10 (N)
N-(3-Methyl phenyl)-N-(4-chloro phenyl)-6-methyl-2-oxo-4(4-anthryl)-1, 2,3,4-
tetrahydropyrimidine-5-carboxamide(AKS-912).
IR(KBr,cm -1 ): 3336-3221 (-NH), 3166-3042 (Ar-CH, str), 2965-2910,
(methyl,asym,str), 2862-2784 (methyl,sym,str) 1701 (>C=O, cyclic), 1674
(>C=O,amide),1523 (C-N,str), 1630-2000 (overtone combination region) 1594-
1494 (>C=C,ring skeletal vibration), 1133(C-H, ipd), 794-763 (C-H,opd), 1078-
1025 (C-O-C,sym,str),1286-1241 (C-O-C, asym,str). 525-447 (-C=C-,opd,bend).
C, H, N (in %): Found: 74.53 (C), 4.91 (H), 7.87 (N), Cacld: 74.50 (C), 4.93 (H),
7.90 (N)
N-(3-Methyl phenyl)-N-(4-chloro phenyl) -6- methyl -2- oxo-4 (4-nitro phenyl)-
1,2,3,4-tetrahydropyrimidine-5-carboxamide(AKS-913).
IR(KBr,cm -1 ): 3324-3217 (-NH), 3110(Ar-CH, str), 2924-2865, (methyl,asym,str),
2876-2789 (methyl, sym,str), 1701 (>C=O, cyclic), 1680 (>C=O,amide),1522 (C-
N,str), 1590-1498 (>C=C,ring skeletal vibration), 1169 (C-H, ipd), 762 (C-
H,opd),1089-1025 (C-O-C,sym,str),1254 (C-O-C, asym,str). 677 (-C=C-
,opd,bend).
1 H NMR(δ ppm): 1.88 (s, 3H, a), 2.38 (s, 1H, b 4 ), 5.60 (d, 1H, b), 7.05 (d,1H, b 3
J=11.76 Hz), 7.19 (m, 3H, a 4 , c 3 , c 4 ), 7.33 (t, 1H, a 3 , J=7.72, 7.76 Hz), 7.54 (m,
3H, c 1 , c 2 , b 1 ), 7.75 (d, 1H, b 2 , J=3.04 Hz), 7.83 (t, 1H, b 5 , J=7.66, 1.20 Hz), 8.14
(t-t, 1H, a 2 , J=2.20 Hz), 8.43 (t, 1H, a 1 , J= 1.96 Hz), 9.67 (s, 1H, e 1 )
C, H, N (in %): Found: 62.98 (C), 4.41 (H), 11.72 (N), Cacld: 62.96 (C), 4.44 (H),
11.75 (N)
N-(2, 4-Di-methyl phenyl)-N-(4-chloro phenyl)-6-methyl-2-oxo-4-(phenyl)-1, 2,
3, 4-tetrahydropyrimidine-5-carboxamide (AKS-914).
IR(KBr,cm -1 ): 3320-3211 (-NH), 3110-3025 (Ar-CH, str), 2922-2889,
(methyl,asym,str), 2865-2781 (methyl, sym,str), 1711 (>C=O, cyclic), 1675
(>C=O,amide),1544 (C-N,str), 1592-1485 (>C=C,ring skeletal vibration), 1165 (C-
H, ipd), 752 (C-H,opd),1094-1021 (C-O-C,sym,str),1265 (C-O-C, asym,str). 656 (-
C=C-,opd,bend).
C, H, N (in %): Found: 70.06 (C), 5.40 (H), 9.40 (N), Cacld: 70.03 (C), 5.42 (H),
9.42(N)

173
N-(2,4-Di-methylphenyl)-N-(4-chlorophenyl)-6-methyl-2-oxo-4(3-nitrophenyl)-
1, 2, 3, 4-tetrahydropyrimidine-5-carboxamide(AKS-915).
IR(KBr,cm -1 ): 3296-3210 (-NH), 3101(Ar-CH, str), 2924, (methyl,asym,str), 2870
(methyl, sym,str), 1701 (>C=O, cyclic), 1680 (>C=O,amide),1525 (C-N,str), 1492-
1591 (>C=C,ring skeletal vibration), 1176 (C-H, ipd), 775 (C-H,opd),1010-1089
(C-O-C,sym,str),1244 (C-O-C, asym,str). 676 (-C=C-,opd,bend).
C, H, N (in %): Found: 63.63 (C), 4.74 (H), 7.19 (N), Cacld: 63.61 (C), 4.72 (H),
7.22 (N)
N- (2,4-Di-methylphenyl) -N- (4-chlorophenyl) -6- methyl -2- oxo -4 (3,4,5-trimethoxyphenyl)-1,
2, 3, 4- tetrahydropyrimidine -5- carboxamide (AKS-916).
IR(KBr,cm -1 ): 3322-3225 (-NH), 3088-3062 (Ar-CH, str), 2956-2932,
(methyl,asym,str),2868-2755 (methyl,str,sym) 1711 (>C=O, cyclic), 1675
(>C=O,amide),1531C-N,str), 1529-1457 (>C=C,ring skeletal vibration), 1190-
1120 (C-H, ipd), 776 (C-H,opd),1085-1023 (C-O-C,sym,str),1232 (C-O-C,
asym,str). 665 (-C=C-,opd,bend).
C, H, N (in %): Found: 64.96 (C), 5.60 (H), 7.82 (N), Cacld: 64.98 (C), 5.64 (H),
7.84 (N),
N- (2,4-Di-methylphenyl) -N- (4-chlorophenyl) -6- methyl- 2- oxo- 4 (3-
clorophenyl) -1, 2, 3, 4- tetrahydropyrimidine - 5- carboxamide (AKS-917).
IR(KBr,cm -1 ): 3322-3214 (-NH), 3075-3010 (Ar-CH, str), 2966 ,(methyl,asym,str),
1712 (>C=O, cyclic), 1662 (>C=O,amide),1533 (C-N,str), 1533-1484 (>C=C,ring
skeletal vibration), 1175-1122 (C-H, ipd), 789(C-H,opd),1090-1033 (C-O-
C,sym,str),1244 (C-O-C, asym,str). 656 (-C=C-,opd,bend).
C, H, N (in %): Found: 65.04 (C), 4.85 (H), 8.72 (N), Calcd: 65.01 (C), 4.83 (H),
8.75 (N),
4-(4-Hydroxy phenyl)-N-(4-fluoro phenyl)-6-methyl-2-oxo-1-phenyl-1, 2, 3, 4 -
tetrahydropyrimidine-5-carboxamide (AKS-918).
IR(KBr,cm -1 ): 3565-3622 (OH,str) 3310-3244 (-NH), 3101-3020 (Ar-CH, str),
2965-2928, (methyl,asym,str), 2877-2744 (methyl,sym,str) 1718 (>C=O, cyclic),
1680 (>C=O,amide),1542 (C-N,str), 1592-1475 (>C=C,ring skeletal vibration),
1162 (C-H, ipd), 770 (C-H,opd),1080 (C-O-C,sym,str),1256 (C-O-C, asym,str).
601 (-C=C-,opd,bend).

174
1 H NMR (δ ppm): 1.68 (3H,s), 5.48 (1H,s), 6.53 (1H,d,J=8.8), 6.87 (3H,m), 7.18
(5H,m), 7.32 (3H,t,J=8.32Hz, 9.87Hz), 7.64 (2H,d,J=8.80), 8.35 (1H,s) 9.59
(1H,s)
C,H,N(in %) : Found: 69.07 (C), 4.81 (H), 10.05 (N), Cacld: 69.05 (C), 4.83 (H),
10.07 (N
N - (4-Fluoro phenyl) - 6- methyl -2- oxo- 1, 4- diphenyl -1, 2, 3, 4
tetrahydropyrimidine -5- carboxamide (AKS-919).
IR(KBr,cm -1 ): 3356-3276(-NH),3044-2986(Ar-CH, str), 2924,(methyl,asym,str),
2856(methyl, sym,str), 17210(>C=O, cyclic), 1678(>C=O,amide),1521(C-N,str),
1593-1496(>C=C,ring skeletal vibration), 1174( C-H, ipd), 796-774 (C-
H,opd),1084-1057 (C-O-C,sym,str),1252 (C-O-C, asym,str). 645 (-C=C-
,opd,bend)
C, H, N (in %): Found: 71.84 (C), 5.06 (H), 10.44 (N), Cacld: 71.81 (C), 5.02 (H),
10.47 (N),
4-(3-Nitro phenyl)-N- (4-fluoro phenyl)- 6-methyl -2- oxo -1- phenyl-1, 2, 3, 4 -
tetrahydropyrimidine-5-carboxamide(AKS-920).
IR(KBr,cm -1 ): 3292-3210 (-NH), 3115-2986 (Ar-CH, str), 2924, (methyl,asym,str),
2877-2796 (methyl, sym,str), 1701 (>C=O, cyclic), 1680 (>C=O,amide),1525 (C-
N,str), 1593-1496 (>C=C,ring skeletal vibration), 1180 (C-H, ipd), 765 (C-
H,opd),1089-1020 (C-O-C,sym,str),1258 (C-O-C, asym,str). 680 (-C=C-
,opd,bend).
Mass (m/e): 447 (25), 321 (100), 293 (10), 278 (20), 265 (2), 250 (28), 187 (4),
177 (4), 153 (8), 127 (44), 91 (4), 77 (27), 67 (5), 44 (17).
C, H, N (in %): Found: 64.60 (C), 4.25 (H), 12.53 (N), Cacld: 64.57 (C), 4.29 (H),
12.55 (N),

IR spectrum of 4-(phenyl)-N-(4-chlorophenyl)-6-methyl-2-oxo-1-phenyl-
1,2,3,4-tetrahydropyrimidine-5-carboxamide(AKS-901)
175
Cl
O
NH
NH
H 3 C
N
O
IR spectrum of 4-(3-nitro phenyl)-N-(4-chloro phenyl)- 6- methyl- 2- oxo -1-
phenyl-1, 2, 3, 4- tetrahydropyrimidine-5-carboxamide (AKS-902)
O
N + O -
Cl
O
NH
NH
H 3 C
N
O

IR spectrum of 4-(2-nitrophenyl)-N-(4-chlorophenyl)-6-methyl-2-oxo-1-
phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (AKS-903)
176
Cl
NH
O
N + O
O -
NH
H 3 C
N
O
IR spectrum of 4-(2-chlorophenyl)-N-(4-chlorophenyl)-6-methyl-2-oxo-1-
phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (AKS-904)
Cl
O
Cl
NH
NH
H 3 C
N
O

IR spectrum of 4-(4-flourophenyl)-N-(4-chlorophenyl)-6-methyl-2-oxo-1-
phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (AKS-905)
177
F
Cl
O
NH
NH
H 3 C
N
O
IR spectrum of 4-(2,3-benzophenyl)-N-(4-chlorophenyl)-6-methyl-2-oxo-1-
phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide.
Cl
O
NH
NH
H 3 C
N
O

1 H NMR spectrum of N-(4-chlorophenyl)-4-(4-fluorophenyl)-6-methyl-2-oxo-
1-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (AKS-905).
178
F
Cl
O
NH
NH
H 3 C
N
O

1 H NMR spectrum of 4-(4-hydroxyphenyl)-N-(4-fluorophenyl)-6-methyl-2-
oxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (AKS-918).
179
OH
F
O
NH
NH
H 3 C
N
O

1 H NMR spectrum of 4-(3-nitrophenyl)-N-(4-chlorophenyl)-6-methyl-2-oxo-1-
phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (AKS-902)
180
N + O -
O
a 2
a 3
H 3 C N O
c Cl a
c 4 a 1
1 O
H
b
NH
NH
c 2 a
b 1 b 2
b 3 b 4
b 5

1 H NMR spectrum of N-(3-methylphenyl)-N-(4-chlorophenyl)-6-methyl-2-oxo-
4(4-nitroyphenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (AKS-913).
181
Cl
c 2
O
a 3
a 2
N + O -
H 3 C N O
c 1
a 4
O
H
b
a 1
NH NH
a
c 3
c 4
e 1
e 2
b 4
b 1 b 2
b 3
b 5
CH 3

Mass spectrum of N-(3-methylphenyl)-N-(4-chlorophenyl)-6-methyl-2-oxo-
4(4-methoxyphenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (AKS-911).
182
O CH 3
Cl
NH
H 3
OC
N
NH
O
CH 3
M.W.=461.94 gm/mole
Mass spectrum of 4-(3-nitrophenyl)-N-(4-fluorophenyl)-6-methyl-2-oxo-1-
phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (AKS-920)
O
N + O -
F
NH
H 3
OC
N
NH
O
M.W.= 446.43 gm/mole

Mass spectrum of 4-(2,3-benzophenyl)-N-(4-chlorophenyl)-6-methyl-2-oxo-1-
phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide(AKS-906).
183
Cl
O
NH
NH
C H 3
N
O
M.W.= 467.94 gm/mole
Mass spectrum of 4-(2-hydroxyphenyl)-N-(4-chlorophenyl)-6-methyl-2-oxo-
1-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (AKS-907).
Cl
O
OH
NH
NH
C H 3
N
O
M.W.= 433.88 gm/mole

Chapter-6
Microwave assisted synthesis of N-(substituted
phenyl)-6-methyl-2-oxo and thioxo-4-propyl-
1,2,3,4-tetrahydropyrimidine-5-carboxamides.
1. Reaction scheme 184
2. Experimental 188
3. Physical data table 189
4. Spectral analysis 191
5. Spectral data 193
6. IR spectra 199
7. 1H NMR spectra 202
8. Mass spectra 203
9. References 206

184
INTRODUCTION
The current chapter is in a sequential study of multicomponent reaction mentioned in
earlier two chapters. The introductory chapter reveals the importance of Microwave
assisted organic synthesis explored recently various scientist world over. The
current chapter is an add on study of such synthetic efforts to obtain successfully the
title compounds.
In this chapter, C 4 aromatic or heteroaromatic skeleton is removed to obtain novel
alkylated dihydropyrimidines as final products.

185
6.1 REACTION SCHEMES
6.1.1 Scheme-1
R
NH 2 NH CH3
KOH
R
O O
Toluene,115 0 c
6.1.2 Scheme-2
CH 3
R
NH
O
H 3 C
O
+
O H
+
N H 2
NH 2
O
Con. HCl
M.W.
200W
CH 3
OH
90 o C
CH 3
R
O
NH
NH
C H 3
N
H
O

186
6.1.3 Scheme-3
CH 3
R
NH
O
H 3 C
O
+
O
H
+
N H 2
NH 2
S
Con. HCl
CH 3
OH
90 o C M.W. 200 W
CH 3
R
NH
O
H 3 C
N
H
NH
S

187
6.1.4 REACTION MECHANISM
C H 3
..
N H O
-H O
2
O
O
NH
NH N H HO
N
H C
H 3 3 C N O
H
CH 3
H +
-H 2
O
H O
NH 2
H N + H
H 2 N O
H 2 N O
CH 3
CH 3
O
O
-H +
NH N
H NH
H N + H
H 3 C O
H 3 C O O
H 2 N O
..
..
NH 2
CH 3
H
CH 3

188
6.2 EXPERIMENTAL
N- (Substitutedphenyl)–6–methyl - 2-oxo–4 -1,2 3, 4–tetrahydro pyrimidine- 5 -
carboxamides (Scheme-2)
[General method]
Substituted acetanilide, butyraldehyde and urea were dissolved in methanol and few
drops of Con.HCl was added. The reaction mixture was irradiated under microwave
(200W) power at 90 o C for 10-12 minutes. Completion of reaction was monitored by
TLC. The reaction mixture was allowed to stand at room temprature. The solid
separated was filtered and recrystallized from dimethyl formamide (Yield 45-65 %).
Physical data of newly synthesized compounds are given in Table 6.3.1
N- (Substituted phenyl) – 6 – propyl – 2 – thioxo - 1,2,3,4 – tetrahyropyrimidine
- 5 - carboxamides (Scheme-3)
[General method]
Substituted acetanilide, butyraldehyde and thiourea were dissolved in methanol and
few drops of con. HCl added. The reaction mixture was irradiated with microwave
(200W) at 90 o C for 10-12 minutes. Completion of reaction was monitored by TLC.
The reaction mixture was allowed to stand at room temprature. The solid separated
was filtered and recrystallized from dimtheyl formamide (Yield 40-68 %).
Physical data of newly synthesized compounds are given in Table 6.3.2
Microwave apparatus used was QPRo-M Microwave synthesizer.

189
6.3 PHYSICAL DATA
6.3.1 Physical data of N-(2-methylphenyl)-6-methyl-2-oxo-4-propyl-1,2,3,4-
tetrahydropyrimidine-5-carboxamides (AKS 921-931)
CH 3
R
O
NH
NH
C H 3
N
H
O
Code No. R MW MP in o C Yield
in %
RF
Value
AKS-921 H 273.33 165-167 68 0.32
AKS-922 4-Cl 307.77 184-186 66 0.51*
AKS-923 4-F 291.32 154-156 67 0.52
AKS-924 4-CH 3 287.35 198-200 63 0.48
AKS-925 2-CH 3 287.35 274-276 48 0.39
AKS-926 3-CH 3 287.35 178-180 56 0.47*
AKS-927 2,3-di-CH 3 302.38 168-170 51 0.36
AKS-928 3-NO 2 319.32 224-226 61 0.42*
AKS-929 2,4-di-CH 3 302.38 147-149 49 0.41
AKS-930 2-Cl 307.77 186-188 53 0.39
AKS-931 3,4-di benzo 323.38 245-247 61 0.42
TLC solvent system Ethyl acetate : Hexane 3.0 ml : 7.0 ml
Visualization: UV light (long)
*CH 2 Cl 2 : MeOH 9.5 ml : 0.5 ml

190
6.3.2 Physical data of 6-methyl-N-(substituted phenyl)-4-propyl-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxamides (AKS 912-920)
CH 3
R
NH
O
H 3 C
N
H
NH
S
Code No. R MW MP in o C Yield
in %
Rf
Value
AKS-932 H 289.39 286-288 69 0.37
AKS-933 2-CH 3 303.42 245-247 58 0.41
AKS-934 3-CH 3 303.42 189-191 64 0.42
AKS-935 4-Cl 323.84 246-248 68 0.36
AKS-936 4-F 307.38 174-176 56 0.43*
AKS-937 2,3-di-CH 3 317.44 197-199 63 0.33*
AKS-938 2,4-di-CH 3 317.44 165-167 65 0.42
AKS-939 2,3 -di- bezo 339.45 186-188 68 0.51
AKS-940 3,4-di-benzo 339.45 145-146 70 0.53*
TLC solvent system Ethyl acetate : Hexane 3.0 ml : 7.0 ml
Visualization UV light (long)
*CH 2 Cl 2 : MeOH 9.4 ml : 0.6 ml

191
6.3 SPECTRAL ANALYSIS
6.3.1 IR SPECTRAL ANALYSIS
Spectral data of key intermediate and compounds are included. Instrument used;
SHIMADZU FT IR-8400, sample technique, KBr disc, frequency assortment, 400-
4000 cm -1 . Looking to the spectral data of recently synthesized
(dihydropyrimidines) molecules, the carbonyl (>C=O) of the amidic functionality
stretching was observed at 1655-1695 cm -1 and an extra ketonic group (-NH-CO-
NH) was observed at in the area of at 1700 cm -1 -1720 cm -1 owing to amidic
functionality. The conformation of the amide group (>C-N, str) was establish in
range of 1495-1525 cm -1 . The stretching of amine (-NH) come out approximately
close to 3150-3400 cm -1 . The stretching of C-N emerge at 1501-1596 cm -1 .The
C-O-C str (symmetric vibration) was established between 1001-1090 cm -1 .C-S str
and bending vibration at 1275-1030 cm -1 , and 650-700 cm -1 correspondingly. The
C-H str of aromatic moiety was observed at just about 2900-3040 cm -1 C-H in
plane bending and, out of plane bending was pragmatic at 1400-1630 cm -1 and
710-860 cm -1 .
IR spectra of the newly synthesized compounds are given on Pages 199-201.
6.3.2 1 H NMR SPECTRAL ANALYSIS
1 H NMR Spectrum of the N-(substituted phenyl)-6-methyl-2-oxo-4-propyl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide demonstrate signals relevant to the number
of protons and their electronic location known as chemical shift. Chemical shift
progress to either up field (shielding) or down field (dishelding), according to the
electronic locality of the consequent proton. In addition to this, each one 1 H NMR
signal supporting splitted into number of associate peaks according to the
number of neighbouring protons nearby in the skeleton of molecule. The splitting
of the NMR signal promoted significant information concerning to the degree of
interface between neighboring protons by way of spin- spin coupling constant.
1 H NMR spectra of AKS-903, shows a singlet because of the existence of three
amino groups. Both –NH proton of the dihyropirimidine ring illustrate singlet at
9.57 and 10.44 δ ppm. Even though other proton of the –NH-C=O linkage make
clear singlet at 6.87 δ ppm. Two protons of phenyl residue (d 2 , d 2 ) show a doublet

192
at 7.59 δ ppm with J value 8.81 Hz. Other two protons of the phenyl residue (d 1,
d 1 ) gave triplet-triplet at 7.19-7.23 with J value 9.84, 8.84 (Ortho coupling with d 2
protons) in place of doublet of doublet because of the being there fluorine atom at
ortho position. H c proton of the dihyropyrimidine sphere show singlet at 4.98 δ
ppm. In this molecule, alkyl chain is close to C 4 carbon of dihyropyrimidine ring
and have seven protons, even as methyl protons (3H) which is extremely
shielded show triplet at 0.95 δ ppm. Left behind four protons are chemically
correspondent but magnetically dissimilar, hence each and every one of the four
protons show diverse δ ppm. Methyl protons of dihyropyrimidine ring at C 6 should
be give singlet, but the existence of methylenic protons of an alkyl side a singlet
will join together with Hc 2 signal, consequently it shows multiplet at 1.43 δ ppm.
From the alkyl side chain, Hc 1 , Hc 2 , Hb 1 , Hb 2 demonstrate multiplet at 2.33, 1.52,
3.31 and 2.58 δ ppm correspondingly.
1 H NMR spectra of newly synthesized compounds are given on Page 202.
6.3.3 MASS SPECTRAL ANALYSIS
As EI-MS spectrum of the N-(substituted phenyl)-6-methyl-2-oxo-4-propyl-
1,2,3,4-tetrahydropyrimidine-5-carboxamide exhibited special feature like
molecular ion peak and fragmentation pattern relevant to the nature of molecule,
it become one of the most important tool for characterization of the structure of
molecule.
In the EI-MS spectrum of 6-methyl-2-oxo-N-phenyl-4-propyl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide, the appearance of an intense molecular ion
peak at m/z at 273. A fragmentation at 259 relevant to tetrahydropyrimidine
suggests that loss of methyl from the pyrimidine ring at C 5 position. Loss of two –
CH 3 and CH 2 from the alkyl chain, mass peaks observed at 245 and 231
respectively. Then cleavage from the carbonyl carbon, peak is observed at 127
due to loss of aromatic amine radical. For AKS- 917 loss of methyl group
subsequently from the pyrimide ring, alkyl side chain, and phenyl ring peak will
observed at 303, 289, 275 respectively. A peak at 231, is relevant to loss of sulfur
atom from the pyrimidine ring. Moreover, m/z 215 suggests that loss of two
hydrogen from C 2 and relevant nitrogen of pyrimidine ring. For AKS-908, a peak

193
is observed at 291 due to loss of two methyl group from pyrimidine ring at C 6 and
alkyl side chain at C 4 . For AKS-906, a peak at 259 (m/z) relevant to loss of two
methyl from the pyrimidine rings at C 6 position and second methyl from the
phenyl residue. Similarly other compounds can be interpreted for their mass
fragmentation pattern.
Mass spectra of newly synthesized compounds are given on Pages 203-205.
6.3.4 ELEMENTAL ANALYSIS
Elemental analysis of the all the synthesized compounds was carried out on
Elemental Vario EL III Carlo Erba 1108 model and the results are in agreements
(within the range of theoretical value) with the structures assigned.
SPECTRAL DATA
6- Methyl -2-oxo – N - phenyl -4- propyl -1, 2, 3, 4 – tetrahydropyrimidine - 5 -
carboxamide (AKS-921)
IR (KBr, cm -1 ): 3440 (-NH), 2923 (methyl,asym,str), 2852 (methyl,sym,str), 1676
(>C=O,amide), 1739 (-NH-CO-NH) 1350 (C-N,str), 1614-1444 (>C=C,ring
skeletone vibration), 1550 (-NH Deformation)1244 (C-H, ipd), 765 (C-
H,opd),1091,1018 (C-O-C,sym,str).
MASS (m/e value): 273 (100), 258 (8), 245 (49), 231 (13), 213 (8), 203 (3), 185
(7), 171 (23), 155 (8), 153 (39), 127 (42), 115 (12), 99 (8), 86 (32), 77 (6), 67
(22), 44 (18)
C, H, N (in %): Found: 70.33 (C), 8.48 (H), 15.37 (N), Cacld: 70.35 (C), 8.46 (H),
15.40 (N)
N-(4-Chlorophenyl)-6-methyl-2-oxo-4-propyl-1,2,3,4-tetrahydropyrimidine-5-
carboxamide (AKS-922)
IR (KBr, cm -1 ): 3440 (-NH), 2908 (methyl,asym,str), 2887 (methyl,sym,str),
1706(>C=O,amide), 1731 (-NH-CO-NH) 1368 (C-N,str), 1610-1466 (>C=C,ring
skeletone vibration), 1522 (-NH Deformation)1242 (C-H, ipd), 757 (C-
H,opd),1087,1010 (C-O-C,sym,str).
C, H, N (in %): Found: 62.43 (C), 7.20 (H), 13.66 (N), Cacld: 62.40 (C), 7.23 (H),
13.68 (N)

194
N-(4-Flourophenyl)-6-methyl-2-oxo-4-propyl-1,2,3,4-tetrahydropyrimidine-5-
carboxamide (AKS-923)
IR (KBr, cm -1 ): 3423,3224 (-NH), 3062(Ar-CH,str) 2929 (methyl,asym,str), 2854
(methyl,sym,str), 1652 (>C=O,amide), 1718 (-NH-CO-NH) 1331 (C-N,str), 1604-
1425 (>C=C,ring skeletone vibration), 1535 (-NH Deformation)1222 (C-H, ipd),
759 (C-H,opd),1022 (C-O-C,sym,str).
1 H NMR (δ ppm): 0.95 (t, 3Hb), 1.43 (m, 3Ha), 1.52(m, Hc 1 ), 2.33 (m,Hc 2 ), 2.58
(m,Hd 1 ), 3.31 (m,Hd 2 ), 4.95 (s,He), 6.87 (s, Hf 1 ), 9.57 (s, Hf 2 ), 10.44 (s,Hf 3 ), 7.59
(d, Hg 2 ), 7.19-7.23 (t-t, Hg 1 ).
C, H, N (in %): Found: 65.96 (C), 7.61 (H), 14.42 (N), Cacld: 65.93 (C), 7.58
(H), 14.44 (N)
N-(4-Methylphenyl)-6-methyl-2-oxo-4-propyl-1,2,3,4-tetrahydropyrimidine-5-
carboxamide (AKS-924)
IR (KBr, cm -1 ): 3423, 3353 (-NH), 2929 (methyl,asym,str), 2871,2736
(methyl,sym,str), 1654 (>C=O,amide), 1735 (-NH-CO-NH) 1334,1375 (C-N,str),
1625-1461 (>C=C,ring skeletone vibration), 1571 (-NH Deformation)1242 (C-H,
ipd), 734 (C-H,opd),1101,1024 (C-O-C,sym,str).
C, H, N (in %): Found: 71.04 (C), 8.77 (H), 14.62 (N), Cacld: 71.01 (C), 8.79
(H), 14.66 (N)
N-(2-Methylphenyl)-6-methyl-2-oxo-4-propyl-1,2,3,4-tetrahydropyrimidine-5-
carboxamide (AKS-925)
IR (KBr, cm -1 ): 3414, 3314 (-NH), 3040(Ar-CH, str) 2968, 2910 (methyl,asym,str),
2864,2745 (methyl,sym,str), 1666 (>C=O,amide), 1718 (-NH-CO-NH) ,1365 (C-
N,str), 1640-1442 (>C=C,ring skeletone vibration), 1561 (-NH Deformation)1246
(C-H, ipd), 778 (C-H,opd),1096,1011 (C-O-C,sym,str).
C, H, N (in %): Found: 71.01 (C), 8.75 (H), 14.61 (N), Cacld: 71.01 (C), 8.79
(H), 14.66 (N)
N-(3-Methylphenyl)-6-methyl-2-oxo-4-propyl-1,2,3,4-tetrahydropyrimidine-5-
carboxamide (AKS-926)
IR (KBr, cm -1 ): 3368 (-NH), 3064, 3012(Ar-CH, str) 2975, 2924
(methyl,asym,str), 2854,2776 (methyl,sym,str), 1680 (>C=O,amide), 1710 (-NH-
CO-NH) ,1354 (C-N,str), 1656-1443 (>C=C,ring skeletone vibration), 1555 (-NH
Deformation)1261 (C-H, ipd), 801 (C-H,opd),1099,1010 (C-O-C,sym,str).

195
C, H, N (in %): Found: 71.02 (C), 8.74 (H), 14.61 (N), Cacld: 71.01 (C), 8.79 (H),
14.66 (N)
MASS (m/e): 287 (100), 270 (18), 259 (83), 240 (18), 230 (16), 215 (23), 202
(15), 189 (15), 176 (3), 156 (5), 144 (5), 128 (14), 115 (14), 102 (17), 89 (8), 77
(19), 63 (9), 44 (32)
N - (2,3-Dimethyl phenyl) -6- methyl -2 -oxo- 4 - propyl -1, 2, 3, 4- tetrahydropyrimidine-5-carboxamide
(AKS-927)
IR (KBr, cm -1 ): 3424, 3362 (-NH), 3026 (Ar-CH, str) 2989, 2956
(methyl,asym,str), 2888,2744 (methyl,sym,str), 1674 (>C=O,amide), 1720 (-NH-
CO-NH) ,1363 (C-N,str), 1641-1448 (>C=C,ring skeletone vibration), 1551 (-NH
Deformation)1247 (C-H, ipd), 762 (C-H,opd),1078,1020 (C-O-C,sym,str).
MASS (m/e): 302 (100), 274 (1), 256 (23), 243 (1), 228 (19), 200 (17), 179 (4),
153 (23), 127 (47), 115 (12), 110 (31), 86 (65), 83 (49), 60 (52), 44 (63)
C, H, N (in %): Found: 71.72 (C), 9.03 (H), 13.94 (N), Cacld: 71.70 (C), 9.09
(H), 13.96 (N)
N-(3-Nitro phenyl) -6-methyl -2- oxo-4-propyl-1,2,3,4-tetrahydropyrimidine-5-
carboxamide (AKS-928)
IR (KBr, cm -1 ): 3456, 3314 (-NH), 3040, 3012 (Ar-CH, str) 2974, 2932
(methyl,asym,str), 2856,2755 (methyl,sym,str), 1682 (>C=O,amide), 1712 (-NH-
CO-NH) ,1362 (C-N,str), 1640-1442 (>C=C,ring skeletone vibration), 1561 (-NH
Deformation)1259 (C-H, ipd), 778 (C-H,opd),1096,1018 (C-O-C,sym,str).
MASS (m/e): 319 (57), 291 (40) 248 (13), 214 (6), 208 (4), 183 (5), 170 (18), 165
(1), 141 (13), 130 (4), 116 (7), 104 (7), 91 (100), 77 (22), 65 (39), 46 (40)
C, H, N (in %):Found: 60.36 (C), 6.97 (H), 17.60 (N), Cacld: : 60.40 (C), 6.93
(H), 17.64 (N)
N - (2,4-Dimethyl phenyl) -6- methyl -2- oxo -4- propyl - 1, 2, 3, 4-tetrahydropyrimidine-5-carboxamide
(AKS-929)
IR (KBr, cm -1 ): 3414, 3314 (-NH), 3040(Ar-CH, str) 2968, 2910 (methyl,asym,str),
2864,2745 (methyl,sym,str), 1666 (>C=O,amide), 1718 (-NH-CO-NH) ,1365 (C-
N,str), 1640-1442 (>C=C,ring skeletone vibration), 1561 (-NH Deformation)1246
(C-H, ipd), 778 (C-H,opd),1096,1011 (C-O-C,sym,str).

196
C, H, N (in %): Found: 71.72 (C), 9.03 (H), 13.94 (N), Cacld: 71.74 (C), 9.01 (H),
13.96 (N)
N-(2-Chlorophenyl)-6-methyl-2-oxo-4-propyl-1,2,3,4-tetrahydropyrimidine-5-
carboxamide(AKS-930)
IR (KBr, cm -1 ): 3424, 3310 (-NH), 3042, 3010(Ar-CH, str) 2989, 2926
(methyl,asym,str), 2874,2754 (methyl,sym,str), 1676 (>C=O,amide), 1728 (-NH-
CO-NH) ,1356 (C-N,str), 1624-1450 (>C=C,ring skeletone vibration), 1552 (-NH
Deformation)1258 (C-H, ipd), 786 (C-H,opd),1098,1022 (C-O-C,sym,str).
C, H, N (in %): Found: 62.43 (C), 7.20 (H), 13.65 (N), Cacld: 62.46 (C), 7.24
(H), 13.69 (N)
6-Methyl- N -1- naphthyl -2- oxo -4- propyl-1, 2, 3, 4 -tetrahydro pyrimidine-5-
carboxamide (AKS-931)
IR (KBr, cm -1 ): 3423, 3354 (-NH), 3024(Ar-CH, str) 2968, 2910 (methyl,asym,str),
2864,2745 (methyl,sym,str), 1666 (>C=O,amide), 1718 (-NH-CO-NH) ,1365 (C-
N,str), 1640-1442 (>C=C,ring skeletone vibration), 1540 (-NH Deformation)1254
(C-H, ipd), 788 (C-H,opd),1088,1014 (C-O-C,sym,str).
C, H, N (in %): Found: 74.27 (C), 7.79 (H), 12.99 (N), Cacld: 74.24 (C), 7.81 (H),
12.99 (N)
6 - Methyl -N- phenyl -4- propyl -2- thioxo- 1, 2, 3, 4- tetrahydropyrimidine -5-
carboxamide (AKS-932)
IR (KBr, cm -1 ): 3456, 3324 (-NH), 3010(Ar-CH, str) 2958, 2910 (methyl,asym,str),
2874 (methyl,sym,str), 1674 (>C=O,amide), 1710 (-NH-CO-NH) ,1346 (C-N,str),
1644-1432 (>C=C,ring skeletone vibration), 1554 (-NH Deformation)1262 (C-H,
ipd), 803 (C-H,opd),1094,1010 (C-O-C,sym,str).
C, H, N (in %): Found: 66.39 (C), 8.01 (H), 14.52 (N), Cacld: 66.42 (C), 8.00
(H), 14.56 (N),
6-Methyl-N-(2-methylphenyl)-4-propyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-
5-carboxamide (AKS-933)
IR (KBr, cm -1 ): 3417 (-NH), 2864, 1660 (>C=O,amide), ,1321 (C-N,str), 1598-
1469 (>C=C,ring skeletone vibration), 1055, 1205(C=S, str) 1598 (-NH
Deformation)1299 (C-H, ipd), 781 (C-H,opd),1020,1055 (C-O-C,sym,str).
C, H, N (in %): Found: 67.28 (C), 8.30 (H), 13.85 (N), Cacld: 67.30 (C), 8.34 (H),
13.88 (N)

197
6-Methyl-N-(3-methylphenyl)-4-propyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-
5-carboxamide (AKS-934)
IR (KBr, cm -1 ): 3414, 3354 (-NH), 3054 (Ar-CH, str) 2986, 2924
(methyl,asym,str), 2870,2765 (methyl,sym,str), 1671 (>C=O,amide) ,1374 (C-
N,str), 1650-1441 (>C=C,ring skeletone vibration), 1551 (-NH Deformation)1244
(C-H, ipd), 778 (C-H,opd),1094,1020 (C-O-C,sym,str).
C, H, N (in %): Found: 67.28 (C), 8.30 (H), 13.85 (N), Cacld: 67.30 (C), 8.34
(H), 13.88 (N)
6-Methyl-N-(4-chlorophenyl)-4-propyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-
5-carboxamide (AKS-935)
IR (KBr, cm -1 ): 3378 (-NH), 3065, 3014 (Ar-CH, str) 2954, (methyl,asym,str),
2877,2774 (methyl,sym,str), 1668 (>C=O,amide) ,1365 (C-N,str), 1640-1452
(>C=C,ring skeletone vibration), 1548 (-NH Deformation)1264 (C-H, ipd), 768 (C-
H,opd),1084,1011 (C-O-C,sym,str).
C, H, N (in %): Found: 59.33 (C), 6.85 (H), 12.97 (N), Cacld: 59.36 (C), 6.82 (H),
12.99 (N)
6-Methyl-N-(4-flourophenyl)-4-propyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-
5-carboxamide (AKS-936)
IR (KBr, cm -1 ): 3425, 3378 (-NH), 3054 (Ar-CH, str) 2954, 2910
(methyl,asym,str), 2868,2743 (methyl,sym,str), 1678 (>C=O,amide) ,1361 (C-
N,str), 1641-1440 (>C=C,ring skeletone vibration), 1555 (-NH Deformation)1244
(C-H, ipd), 789 (C-H,opd),1098,1014 (C-O-C,sym,str).
C, H, N (in %): Found: 62.51 (C), 7.21 (H), 13.67 (N),Cacld: 62.49 (C), 7.24 (H),
13.69 (N)
6- Methyl -N- (2,3-dimethyl phenyl) -4- propyl -2- thioxo- 1, 2, 3, 4 -tetrahydro
pyrimidine-5-carboxamide (AKS-937)
IR (KBr, cm -1 ): 3425, 3378 (-NH), 3054 (Ar-CH, str) 2954, 2910
(methyl,asym,str), 2868,2743 (methyl,sym,str), 1678 (>C=O,amide) ,1361 (C-
N,str), 1641-1440 (>C=C,ring skeletone vibration), 1555 (-NH Deformation)1244
(C-H, ipd), 789 (C-H,opd),1098,1014 (C-O-C,sym,str).
MASS (m/e): 317 (100), 303 (30), 289 (39), 273 (17), 257 (18), 245 (7), 230 (16),
215 (23), 202 (15), 189 (15), 176 (3), 156 (5), 144 (5), 128 (14), 115 (14), 102
(17), 89 (8), 77 (19), 63 (9), 44 (32)

198
C, H, N (in %): Found: 68.09 (C), 8.57 (H), 13.24 (N), Cacld: 68.12 (C), 8.55
(H), 13.28 (N)
6- Methyl -N- (2,4-dimethyl phenyl) -4- propyl -2- thioxo- 1, 2, 3, 4-tetrahydro
pyrimidine-5-carboxamide (AKS-938)
IR (KBr, cm -1 ): 3464, 3314 (-NH), 3054, 3012 (Ar-CH, str) 2978, 2920
(methyl,asym,str), 2878,2784 (methyl,sym,str), 1680 (>C=O,amide) ,1350 (C-
N,str), 1638-1438 (>C=C,ring skeletone vibration), 1535 (-NH Deformation)1258
(C-H, ipd), 789 (C-H,opd),1078,1011 (C-O-C,sym,str).
C, H, N (in %): Found: 68.08 (C), 8.55 (H), 13.22 (N), Cacld: 68.12 (C), 8.55
(H), 13.28 (N)
6-Methyl-N-1- naphthyl -4- propyl- 2- hioxo-1, 2, 3, 4 -tetrahydropyrimidine-5-
carboxamide (AKS-939)
IR (KBr, cm -1 ): 3451 (-NH), 3064, 3010 (Ar-CH, str) 2968, 2924
(methyl,asym,str), 2864,2780 (methyl,sym,str), 1671 (>C=O,amide) ,1354 (C-
N,str), 1640-1454 (>C=C,ring skeletone vibration), 1551 (-NH Deformation)1242
(C-H, ipd), 794 (C-H,opd),1084,1010 (C-O-C,sym,str).
C, H, N (in %): Found: 70.76 (C), 7.42 (H), 12.38 (N), Cacld: 70.72 (C), 7.40
(H), 12.46 (N)
6-Methyl-N-2-naphthyl-4-propyl -2- thioxo- 1, 2 ,3, 4 -tetrahydropyrimidine-5-
carboxamide (AKS-940)
IR (KBr, cm -1 ): 3389 (-NH), 3068, 3024 (Ar-CH, str) 2974, 2910
(methyl,asym,str), 2874,2756 (methyl,sym,str), 1668 (>C=O,amide) ,1348 (C-
N,str), 1651-1442 (>C=C,ring skeletone vibration), 1546 (-NH Deformation)1252
(C-H, ipd), 782 (C-H,opd),1080,1015 (C-O-C,sym,str).
C, H, N (in %): Found: 70.76 (C), 7.42 H), 12.38 (N), Cacld: 70.77 (C), 7.46 H),
12.40 (N)

IR spectrum of 6- Methyl -2-oxo- N- phenyl-4-propyl-1, 2, 3, 4-tetrahydropyrimidine-5-carboxamide
(AKS-921)
199
CH 3
O
NH
NH
C H 3
N
H
O
IR spectrum of N-(4-Chloro phenyl) -6- methyl -2- oxo- 4- propyl-1, 2 3, 4-
tetrahydropyrimidine-5-carboxamide (AKS-922)
CH 3
Cl
O
NH
NH
C H 3
N
H
O

IR spectrum of N-( 4-Flouro phenyl)- 6- methyl - 2-oxo -4- propyl-1, 2, 3, 4-
tetrahydropyrimidine-5-carboxamide (AKS-923)
200
CH 3
F
O
NH
NH
C H 3
N
H
O
IR spectrum of N-(4-Methylphenyl)-6-methyl-2-oxo-4-propyl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (AKS-924)
CH 3
H 3 C
O
NH
NH
C H 3
N
H
O

IR spectrum of 6-Methyl-N-(2-methylphenyl)-4-propyl-2-thioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (AKS-933)
201
CH 3
O
NH
NH
CH 3
C H 3
N
H
S

1 H NMR spectrum of N-(4-Fluorophenyl)-6-methyl-2-oxo-4-propyl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (AKS-923)
202
c 2 CH 3
H
b
g
F 1
d 2
g
H
2 O Hc H 1
e d
g 1
1
g2
NH NH
f 1
f 3
f 2
H 3 C
a
N
H
O

Mass spectrum of 6-Methyl-N-(3-nitrophenyl)-2-oxo-4-propyl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (AKS-928)
203
CH 3
O
N + O - O
NH
NH
C H 3
N
H
O
Mass spectrum of 6-Methyl-N-(3-methylphenyl)-2-oxo-4-propyl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (AKS-926)
CH 3
O
H 3 C
NH
NH
C H 3
N
H
O

Mass spectrum of N-(2,3-Dimethylphenyl)-6-methyl-4-propyl-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxamide (AKS-937)
204
CH 3
O
H 3 C
CH 3
NH
NH
C H 3
N
H
S
Mass spectrum of - 6- Methyl -2- oxo- N- phenyl -4- propyl- 1,2,3,4 -
tetrahydropyrimidine-5-carboxamide (AKS-921)
CH 3
O
NH
NH
CH 3
C H 3
N
H
O

Mass spectrum of N-(2,3-Dimethylphenyl)-6-methyl-2-oxo-4-propyl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (AKS-927)
205
CH 3
O
H 3 C
NH
NH
CH 3
C H 3
N
H
O

206
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Chapter-7
Biological Activity Study

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Biological Activity Study
The present work deals with the antimicrobial screening of the compounds (AKS
and VGM series) synthesized in earlier Chapters.
The minimum inhibition concentration (MIC) values were determined in the
present study.
Protocol
Determination of MIC by Agar-dilution method was carried out as per the NCCLS
guidelines M7-A5
Preparation of plates containing the antimicrobial agent
To Mueller-Hinton agar (19 ml) medium (Hi Media), cooled to approximately
500C, 1 ml of antimicrobial agent, dissolved in DMSO is added. The
antimicrobial agent is mixed thoroughly into the medium and poured into Borosil
glass petriplates of 9 cm diameter and allowed to solidify. The 7 test cultures
selected for the determination of MIC are spot-inoculated
(2 ml/spot) on a single plate prepared.
Preparation of solutions of antimicrobial agents to be incorporated into the agarbased
medium
10mg of the antimicrobial agent is dissolved in 5ml of DMSO to prepare the main
stock of the compound to be tested. 1ml of this main stock is added to 19 ml of
Mueller Hinton agar medium to make the final concentration of 100 mg/ml in the
agar medium. The main stock solution is further diluted in DMSO by two-fold
dilution procedure to obtain the desired concentration in the agar medium.
Preparation of inoculum of the test cultures
For all cultures other than M.smegmatis strains
One loopful of culture from slant is inoculated into 5mL Muellar Hinton broth
(HiMedia) in a test tube. The tube is incubated at 37 0C till the absorbance at
625nm equals that of 0.5 Mc. Farland standard (Section 5). The absorbance
readings are taken against a sterile Mueller Hinton broth blank. The cultures are
then transferred to 2-8oC temperature and maintained this temperature till the
time of inoculating the plates. Appropriate dilutions of the cultures (either 10 or

214
100 fold, depending on the culture) are made based on the viable count of the
cultures, previously done to establish the relationship between absorbance at
625mn and viable count, before inoculating the plates containing the antimicrobial
test agents. 2ml of this diluted culture is used to spot-inoculate the plates with
antimicrobial test agents.
For M.smegmatis strains
One loopful of the culture from slant is used to inoculate 25 ml Mycoseed brotha
with 2-3 glass beads. The broth is incubated at 35 0C for 5 days on 250rpm
shaker. 2 ml of undiluted, 1:10 and 1:100 fold diluted culture is spot-inoculated
on a Mueller Hinton agar control plate (section 6) and the spots are observed for
confluent growth. The maximum dilution of the culture that gives a confluent
growth of the spot on the Mueller Hinton agar control plates is selected for spot
inoculation of the plates containing the antimicrobial test agents.
Preparation of 0.5 Mc. Farland standard
The 0.5 Mc. Farland standard solution as a reference for turbidity measurement
is prepared as per the NCCLS guidelines M7-A5.
Briefly, 0.5mL of 1.175% w/v BaCl2 solution is added to 99.5 ml of 1% v/v H2SO4
solution with constant stirring. The absorbance of the solution is measured at
625nm against a D.M.water blank by a uv-visible spectrophotometer. The
absorbance lies in the range of 0.08 to 0.1. The Mc. Farland standard solution is
stored in dark at room temperature and vortexed vigorously prior to use.
Controls
Two control plates (i.e.plates without any antimicrobial agent incorporated into
the agar medium) with 1ml DMSO in 19mL Mueller Hinton agar medium are kept
with each MIC experiment to check the growth of the cultures inoculated on the
plates and the effect of the solvent (DMSO) on the cultures. 2 ml of all the test
cultures are spot-inoculated onto these two plates.

215
Incubation time and temperature
The plates are incubated at 35oC for 48 hours for M.smegmatis and 24 hours for
all other cultures before taking the results of MIC.
Evaluation of the results
The antimicrobial test compounds that show the growth of all the cultures at a
concentration of 100 mg/ml are not tested further for the determination of the MIC.
The compounds that show no growth of any of the culture at 100 mg/ml
concentration are further tested with lower doses of the test compounds for the
determination of the MIC values.
If the test culture that show 1-5 colonies per spot instead of the confluent growth
as in the control plate, it is considered to be inhibited by the test compound.
1. F. Simoncini et al.; Farmaco, 23, 559 (1968); C. A. 69, 109851 (1968).
2. Bhatt, S., Deo, K., Kundu, P., Chavda, M. & Shah, A.; Indian J. Chem., Sect 42B, 1502 (2003).
3. Chavda, M., Shah, A., Bhatt, S., Deo, K. & Kundu, P.; Arzneim-Forsch, Drug,
Res., 53, 196 (2003).

216
7.1 Antimicrobial Activity (as per protocol)
Microorganism (MIC, µg/ml)
Sr. No
Code
S.coccus
Pypgens
A77
S.aureus
SG511
S.aureus
E710
E.coccus
Faecalis
M.smegmatis
(MY-1)
M.smegmatis
(MY-1)
1. VGM-1 2.5 5.0 5.0 10.0 5.0 5.0
2. VGM-2 2.5 5.0 5.0 10.0 5.0 5.0
3. VGM-3 1.25 5.0 5.0 - 5.0 5.0
4. VGM-4 100 - - - - 50
5. VGM-5 100 - - - - 100
6. VGM-6 2.5 - - - 12.5 10
7. VGM-7 5.0 - - - 12.5 12.5
8. VGM-8 1.25 2.5 2.5 5.0 5.0 5.0
9. VGM-9 25 - 50 - 100 50
10. AKS-921 2.5 - - - 12.5 10
11. AKS-922 12.5 - - - 100 12.5
12. AKS-923 -- - - - - -
13. AKS-924 2.5 -- - - - 50
14. AKS-925 - - - - - -
15. AKS-926 - - - - 100 100
16. AKS-575 - - - - 50 -
17. AKS-576 - - - - - -
18. AKS-577 - - - - 100 100
19. AKS-578 - - - - - -
20. AKS-579 - - - - - -
21. AKS-580 - - - - - -
22. AKS-581 - - - - - -
23. AKS-582 - - - - - -
24. AKS-583 25.0 - - - 100 -
25. AKS-584 5.0 - - - 12.5 12.5
26. AKS-585 5.0 - - - 100 100
27. AKS-586 2.5 - - - 50 -
28. AKS-587 12.5 - - - - -
29. AKS-589 2.5 - -- - - -
30. AKS-590 --- - - - -
31. AKS-901 5.0 - - - - 12.5
32. AKS-902 -- - - - - -
33. AKS-903 100 - - - - -

217
34. AKS-904 -- - - - 100 100
35. AKS-905 100 - - - 100 -
36. AKS-906 -- - - - - -
37. AKS-907 100 - - - - -
38. AKS-908 100 - - - - -
39. AKS-909 -- - - - 100 -
7.2 Antimicrobial Activity data
Compound
1 mg/100ml
Gram Positive
S. aureus
Gram Negative
E. coli
VGM-12 15 -
VGM-13 14 -
VGM-14 29 -
VGM-15 25 -
AKS-910 16 -
AKS-912 - -
AKS-913 26 -
AKS-914 11 -
AKS-915 - -
* Diameter zones of growth of inhibition in mm.

218
Conclusion
Three types of antimicrobial studies were carried out.
In the first study, Protocol was followed and the minimum inhibition concentration
were determined of 40 compounds against Streptococcus pyogens A77,
S.aureus SG511, S.aureus E710, Enterococcus Faecalis,M. Smegmatis MY-1
and M. Smegmatis MY-2.
Many compounds have shown very proming MIC at 1.25 mg/ml, 2.5 mg/ml, 5
mg/ml and 10 mg/ml against some of the species discussed above.

234
SUMMARY OF WORK
The work presented in the thesis entitled “Synthesis, Characterization and
Pharmacological Study of some Bioactive Molecules” can be summarized below.
Chapter 1 covers synthesis of pyrazolo derivatives. Initially, 2, 4 dimethyl 3-acetyl
pyrrole are synthesized by Knorr Pyrrole synthesis. Further Chalcone derivatives
are synthesized from 3-acetyl pyrrole and substituted aromatic aldehyde. Target
molecules were synthesized from chalcone and hydrazine hydrate using KOH as
catalyst. In prologue part, various methods for synthesis of pyrrole and biological
profile were described. The synthesized molecules are well characterized by IR,
1 H NMR and Mass analysis.
In Chapter 2, extension of work on dihydropyridine skeleton modification, carried
out by synthesis of symmetrical 1, 4-DHPs with naphthyl ring at C 3 and C 5 site of
dihydropyridines and asymmetrical derivatives with naphthyl carbamoyl side
chain. Symmetrical dihydropyridines have been synthesized using
acetoacetanilide of α-naphthayl amine and substituted aromatic aldehyde with liq.
ammonia. Total twenty compounds (AKS 1-20) were synthesized and well
characterized by IR, 1 H NMR and Mass technique.
In Chapter 3, a mini review of pyrimidines derivatives containing thiazolo and
thiazine ring is given. Literature survey included for microwave assisted synthesis
of 2-oxo and thioxo tetrahydropyrimide derivatives. Biginelli dihydropyrimidine
synthesis and Intramolecular Heck cyclization in DHPMs skeleton were
documented. Many bicyclic fused systems synthesized from dihydropyrimidines
scaffold are discussed. Chemistry and biological importance of thiazolo
pyrimidine and thiazine pyrimidine scaffold are included in this Chapter.
In Chapter 4, thiazolo and thiazine bicyclic systems are synthezied from Biginelli
DHPMs derivatives. Thiazolo and thiazine bicyclic scheme are synthesized from
dihydropyrimidine derivatives and dibromo ethane or dibromo propane

235
correspondingly in the presence of potassium bicarbonate as a catalyst. Total
eighteen compounds are synthesized with thiazolo bicyclic system and 5
compounds as thiazine system. The synthesized compounds (AKS 551--582) are
well characterized by IR, 1 HNMR and Mass study and also by 13 C technique.
Chapter 5 covers synthesis and characterization of N-aryl tetrahydropyrimidine
derivatives by Biginelli reaction. Introduction of phenyl carbamoyl moiety at C-3
and/or C-5 position in dihydropyridine skeleton has showed diverse activity
profile. For the synthesis of N-phenyl dihydropyrimidines, different N-phenyl
ureas with substitutions (Phenyl, 3-methylphenyl, 2,4-dimethylphenyl) were
synthesized. Acetoacetanilides with different halogen substitutions (4-chloro, 4-
flouro, 3-chloro-4-flouro) were synthesized. N-phenyl substituted DHPM
derivatives were obtained by reacting N -(phenyl/3-methylphenyl/2,4-dimethyl)
urea, (4-chloro, 4-flouro, 3-chloro-4-flouro)acetoacetanilide and substituted
aromatic aldehyde. All newly synthesized compounds (AKS 901--920) are
characterized by IR, 1 H NMR and Mass spectral analysis.
In Chapter 6, microwave assisted synthesis of oxo and a thioxo
tetrahydropyrimidine derivative is covered. It was planned to develop various
modified compounds associated with aliphatic chain at C 4 position of
dihydropyrimidines. Phenyl ring at C 4 position of classical dihydropyrimidine was
replaced with aliphatic chain. Present work deals with an aliphatic aldehyde
(butyraldehyde) as a substrate to obtain a dihydropyrimidine skeleton without
phenyl or heteroaryl ring at C 4 . Microwave irradiation technique was utilized and
higher yields within shorter reaction time (10-15 minutes) were obtained. Ten new
oxopyrimidines (AKS. 921-931) and eighteen thioxopyrimidine derivatives (AKS.
923-940) are synthesized and characterized.
Total 96 compounds are synthesized and characterized in the entire work.
Representive Synthesized compounds are tested for anti microbial activity and
further screening for antitubercular and anti viral activity is under investigation.
The antimicrobial activity data are shown in last chapter

236
Presentation of Paper & Conferences/Workshop Participated
Participated and presented a poster at 9 th International Conference on”
Bioactive Heterocycles and Drug Discovery Paradigm” held at Rajkot
organized by Indian Society of Chemist & Biologist (ISCB) and Department
of Chemistry, Saurashtra University, Rajkot, Gujarat (India), January 8-10,
2005
Participated in UGC Recognized state level seminar on “Innovative Trends
in Research an Process Development in Chemical Industries: Perspective”
held at Yogidham Educational Campus, Rajkot, Gujarat, February 20,
2003
Participated and presented poster at 10 th International Conference of ISCB
on “Drug Discovery: Perspectives and Challenges jointly organized” by
University of Toronto, and CDRI, Lucknow, India, February 26, 2006.
Gujcost sponsored One Day Workshop on “Current Drug Patent Regime”,
S.J. Thakkar Pharmacy College, Rajkot, Gujarat, March 5 , 2006.
Participated and presented a poster at “International Conference on
Advance in Drug Research Discovery Research” held at Aurangabad,
India, February 24-26, 2007.
DST Workshop on “Green Chemistry” organized by Institute of pharmacy,
Nirma University of Science and Technology, Ahmedabad, Gujarat,
November 25-26, 2005.
National Workshop on “Spectroscopy and Theoretical Chemistry”
organized by Department of Chemistry, M.S. University of Baroda,
Gujarat, February 8-12, 2005.

237
Participated and presented a poster at Joint international conference on
“Building Bridges, Forging Bonds for 21 st century organic chemistry and
Chemical biology” organized by American Chemical Society, USA and
National Chemical Laboratory, Pune (India), January 6 – 9, 2006.
Participated and presented a poster at Joint International Conference on
“Advances in Organic Chemistry and Chemical Biology” organized by the
American Chemical Society, USA and Indian institute of Chemical
Technology, Hyderabad (India), January 11-12, 2006.
Participated in National workshop on “Recent advances in Chemical
Science and an Approach to Green Chemistry” held at Saurashtra University
jointly organized by Department of Chemistry and GUJCOST, Rajkot,
Gujarat, October 11-13, 2006.
Participated and presented a poster at 3 rd International conference on
“Heterocyclic Chemistry” organized by department of Chemistry, Jaipur,
India.Dec, 2006.