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Tala, Satish D., 2009, " Studies on heterocyclic compounds of medicinal

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Studies on Heterocyclic Compounds ofMedicinal Interest

A THESIS

SUBMITTED TO THE

SAURASHTRA UNIVERSITY

FOR THE DEGREE OF

Doctor of PhilosophyDoctor of PhilosophyDoctor of PhilosophyDoctor of PhilosophyDoctor of Philosophy

IN

THE FACULTY OF SCIENCE (CHEMISTRY)

BY

Satish D. Tala

UNDER THE GUIDANCE

OF

Dr. H. S. Joshi

DEPARTMENT OF CHEMISTRY,

(DST-FIST FUNDED, UGC-SAP SPONSORED),

SAURASHTRA UNIVERSITY,

RAJKOT - 360 005

(GUJARAT) INDIA

MAY-2009

��

�

Gram: UNIVERSITY Phone: (R) 0281-2584221Fax: 0281-2577633 (O) 0281-2578512

SAURASHTRA UNIVERSITYUniversity Road

Rajkot - 360 005

Dr. H. S. Joshi Residence:M.Sc., Ph.D., F.I.C.S. B-1, Amidhara Appartment,Associate Professor, 2- Jalaram Plot,Department of Chemistry University Road,

Rajkot - 360 005GUJARAT (INDIA)Date: - -2009

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

The work included in the thesis is my own work under the supervision of Dr. H. S.Joshi and leads to some contribution in chemistry subsidized by a number of references.

Date: - -2009 Satish D. TalaPlace: Rajkot

This is to certify that the present work submitted for the Ph.D. Degree of SaurashtraUniversity by Satish D. Tala is his own work and leads to advancement in the knowledge ofchemistry. The thesis has been prepared under my supervision.

Date: - -2009 Dr. H. S. JoshiPlace : Rajkot Associate Professor,

Department of Chemistry,Saurashtra University,

Rajkot-360 005

ACKNOWLEDGEMENTS

First and foremost I compensate my entire honor to “Guruji” without his

blessing this task would not have been accomplished. I bow my head in utter

humility and complete dedication from within my heart. Hats off to the

Omnipresent, Omniscient and wonderful chemist who create life colorful Almighty

God, The glorious fountain and continuous source of inspirations! I offer

salutation to the Omnipotent “Lord Shiva”.

I would like to express my sincere gratitude to my supervisor Dr. H. S.

Joshi for accepting me as his research student and who made this research a

success. It is with Dr. Joshi’s enthusiasm and integral view on research combined

with his willingness to provide quality chemistry and not less that kept me going

and I wish to say thank you sir. Besides being a wonderful Supervisor, Dr. Joshi

is as close as family and a very good friend and I am deeply honored to have

wonderful person like him in my life. I wish to say thank you so much again for

all the help you offered over the years both in and out of my academic life.

I feel great pleasure to acknowledge my deepest gratitude to Dr. Arti H.

Joshi for her invaluable inspiration and moral support through the course of

my research work.

I also owe to Professor and Head Dr. P. H. Parshania, and Prof. Anamik

Shah, Department of Chemistry, as I have been constantly benefited with their

lofty research methodology and the motivation as well as their highly punctual

affectionate. I am also equally thankful to Dr. N. A. Chauhan, ex-professor of

department, for his constant inspiration with keen interest and ever vigilant

guidance without which this task could not have been achieved.

I wish to thank Dr. Y. T. Naliapara and Dr. R. C. Khunt for their constant

support and valuable guidance through out my research work and Mrs. Krishna

Joshi, Department of Biochemistry, for evaluating the in vitro antimicrobial

activity.

Big thanks to the all teaching & non teaching staff at the Department of

Chemistry for their kind support.

An endeavor such as a Ph. D. is impossible to accomplish without the

generous help and support of my family, friends and colleagues. I would like to

take this opportunity to thank those whom I was fortunate to know, work and

form friendship with over the past years.

Who in this world can entirely and adequately thank the parents who have

given me everything that I possess in my life. I bow my head with utter respect

to my beloved mother Smt. Shardaben for her continuous source of inspiration,

motivation and devotion to me, and my father Shri Dhirajbhai for the

uncompromising principles that guided my life. Also younger sister Asha and my

younger brother Dharmendra, I assure them to be worthy of whatever they have

done for me.

I would like to reserve a special line for my wife Kiran, for her unwavering

love, understanding and constant support which have made my life a wonderful

experience to live. Her continuous supports encourage me to be the best that I

can be. Love you!

As with the completion of this task, I find myself in difficult position on

attempting to express my deep indebtedness to my best friends ever as the phrase

Come together is beginning,

Work together is success, and

Stay together is achievement.

I get this achievement with tremendous support and cooperation of my

friends Naval & Kalpana, Rajesh & Rekha, Vaibhav, Bhavik & Preeti, Mukesh

& Jagruti, Hitesh & Tejal, Arvind & Divya and Chirag thank you so much to be

such a wonderful friend and fill my life with full of joy and stay with me whenever

I needed.

Thanks to my friend and seniors Dr. Jignesh, Dr. Pankaj, Dr. Manoj, Dr.

Paresh, Dr. Mahesh, Dr. Mayur, Dr. Dinesh, Dr. Viral, Dr. Vijay, Dr. Vrajlal,

Dr. Shailesh, Dr. Vimal, Dr. Samir, Dr. Nikhil, Dr. Vrajesh, Dr. Viren, and Dr.

Harshad my juniors Kaushik, Vijay, Kapil, Renish, Bhavesh and Govind, my

research colleagues Axay, Bharat Bhuva, Suresh, Sandip, Punit, Bhavin,

Bharat Savalia, Ravi Chaniara, Mahesh, Rahul, Ravi Gajera, Jignesh, Nilesh,

Nayan, Mehul, Amit and Rakesh and for their help and friendship which lighten

my work and did not make me feel alone.

I also thank all well wishers and all those persons who helped me directly

or indirectly during my Ph. D. and I can’t list those names here.

I gratefully acknowledge the most willing help and co-operation shown by

SAIF, CIL, Chandigarh for spectral studies, I also thankful to Government of

Gujarat for the State Level Junior Research Fellowship.

Finally, I express my grateful acknowledgment to Department of Chemistry,

Saurashtra University for providing me the excellent laboratory facilities, and

kind furtherance for accomplishing this work.

Satish D. Tala

CONTENTS

SYNOPSIS...............................................................................................................................1

STUDIES ON HETEROCYCLIC COMPOUNDS OF MEDICINAL INTERESTIntroduction....................................................................................................................7

PART- A STUDIES ON BENZO[b]THIOPHENE DERIVATIVES1. Introduction...................................................................................................................112. Therapeutic Importance................................................................................................153. References.......................................................................................................................22

Part-I Studies on Arylaminomethyl derivatives1. Introduction...................................................................................................................262. Therapeutic Importance................................................................................................28Section-ISynthesis and biological screening of (E)-N’-Arylmethine-5-bromo-3-chlorobenzo[b]thiophene-2-carbohydrazides1. Reaction scheme.............................................................................................................332. Experimental Section.....................................................................................................343. Spectral study.................................................................................................................364. Antimicrobial activity....................................................................................................40Section-II:Synthesis and biological screening of N’-Arylmethyl-5-bromo-3-chlorobenzo[b]thiophene-2-carbohydrazides1. Reaction scheme.............................................................................................................442. Experimental Section.....................................................................................................453. Spectral study.................................................................................................................474. Antimicrobial activity....................................................................................................515. References.......................................................................................................................53

Part-II Studies on oxadiazole derivatives1. Introduction...................................................................................................................552. Therapeutic Importance.................................................................................................57Section-I:Synthesis and biological screening of 2-(5-Bromo-3-chlorobenzo[b]- thiophen-2-yl)-5-aryl-1,3,4-oxadiazoles1. Reaction scheme.............................................................................................................602. Experimental Section.....................................................................................................613. Spectral study.................................................................................................................634. Antimicrobial activity....................................................................................................675. References.......................................................................................................................69

PART- B STUDIES ON 3-ISOPROPYL-4-METHOXYBENZALDEHYDE DERIVATIVESSection-I:Synthesis and biological screening of (E)-3-(3-Isopropyl-4-methoxyphenyl)-1-aryl-prop-2-en-1-ones1. Introduction...................................................................................................................712. Therapeutic Importance................................................................................................753. Reaction scheme............................................................................................................804. Experimental Section....................................................................................................815. Spectral study................................................................................................................836. Antimicrobial activity...................................................................................................877. References......................................................................................................................89Section-II:Synthesis and biological screening of 1-Acetyl-3-aryl-5-(3-isopropyl-4-methoxyphenyl)pyrazoles1. Introduction...................................................................................................................942. Therapeutic Importance................................................................................................983. Reaction scheme............................................................................................................1034. Experimental Section....................................................................................................1045. Spectral study................................................................................................................1066. Antimicrobial activity...................................................................................................1107. References......................................................................................................................112Section-III:Synthesis and biological screening of Ethyl 4-aryl-6-(3-isopropyl-4-methoxyphenyl)-2-oxo-cyclohex-3-ene-1-carboxylates1. Introduction...................................................................................................................1172. Therapeutic Importance................................................................................................1193. Reaction scheme............................................................................................................1234. Experimental Section....................................................................................................1245. Spectral study................................................................................................................1266. Antimicrobial activity...................................................................................................1307. References......................................................................................................................132

PART- C STUDIES ON TETRAHYDROPYRIMIDINE DERIVATIVES1. Introduction...................................................................................................................1352. Therapeutic Importance................................................................................................1473. Catalytic study of molecular iodine.............................................................................155Section-I:Synthesis of N-(4-Chlorophenyl)-1,2,3,4-tetrahydro-6-isopropyl-4-aryl-2-oxo/thioxopyrimidine-5-carboxamides using conventional method and molecular iodine as catalyst and biological screening1. Reaction scheme............................................................................................................1602. Experimental Section....................................................................................................1613. Spectral study................................................................................................................1654. Antimicrobial activity...................................................................................................173

Section-II:Synthesis and biological screening of N-(4-Chlorophenyl)-3-formyl-6-isopropyl-2-oxo-4-aryl-1,2,3,4-tetrahydro-pyrimidine-5-carboxamides1. Reaction scheme............................................................................................................1772. Experimental Section.....................................................................................................1783. Spectral study.................................................................................................................1804. Antimicrobial activity....................................................................................................184Section-III:Synthesis and biological screening of N-(4-Chlorophenyl)-3-formyl-6-isopropyl-2-thioxo-4-aryl-1,2,3,4-tetrahydro-pyrimidine-5-carboxamides1. Reaction scheme.............................................................................................................1862. Experimental Section.....................................................................................................1873. Spectral study.................................................................................................................1894. Antimicrobial activity....................................................................................................1935. References.......................................................................................................................195

PART- D STUDIES ON X-RAY CRYSTALLOGRAPHIC STUDYSection-I:Synthesis, characterization and X-ray crystallographic study of 1-Phenyl-3-methylpyrazole-2-en-5-one1. Introduction...................................................................................................................2012. Reaction scheme.............................................................................................................2023. Experimental Section.....................................................................................................2024. Spectral study.................................................................................................................2045. X-Ray Diffraction Analysis.............................................................................................2066. References.......................................................................................................................211

List of Publications.....................................................................................................................212

SynopsisSynopsisSynopsisSynopsisSynopsis

1Studies on heterocyclic...

Synopsis

A comprehensive summary of the work to be incorporated in the thesis entitled

“STUDIES ON HETEROCYCLIC COMPOUNDS OF MEDICINAL INTEREST’’

included investigation pertaining to Benzo[b]thiophene ring system, derivatives of 3-

Isopropyl-4-methoxy benzaldehydes, Tetrahydropyrimidine derivatives and X-ray

crystallographic study which have been described as under:

[A] STUDIES ON BENZO[b]THIOPHENE DERIVATIVES

[B] STUDIES ON 3-ISOPROPYL-4-METHOXYBENZALDEHYDE DERIVATIVES

[C] STUDIES ON TETRAHYDROPYRIMIDINE DERIVATIVES

[D] X-RAY CRYSTALLOGRAPHIC STUDY

[A] STUDIES ON BENZO[b]THIOPHENE DERIVATIVES

Heterocyclic compounds bearing benzo[b]thiophene ring system and their

derivatives are demonstrates various biological and pharmacological activities. Our works

are paying attention on introduction of chemical multiplicity in the molecular frame work,

in order to synthesizing active molecules of widely different composition. Literature

assessment reveals that sulfur containing heterocyclic compounds have acknowledged

considerable attention in remedial science due to their biological and pharmacological

activities such as anti-HIV, antitubercular, antimicrobial, anticonvulsant, anticancer,

antiviral etc.

Considering the increasing importance of benzo[b]thiophene nucleus, we have

undertaken the synthesis of some new arylaminomethyl and oxadiazole derivatives bearing

benzo[b]thiophene nucleus, which have been described as under.

PART-I: STUDIES ON ARYLAMINOMETHYL DERIVATIVES

Arylaminomethyl derivatives represent one of the modest class of biological active

agents which have been deeply studied during search of new potential agents. These

have been reported to be active as antimicrobial, antitubercular, anticancer, insecticidal

etc. In view of these valid observations, it was contemplated to synthesize some new

arylaminomethyl derivatives possessing higher biological activity which have been

described as under.


Synopsis

SECTION-I: Synthesis and biological screening of (E)-N'-Arylmethine-5-bromo-

3-chlorobenzo[b]thiophene-2-carbohydrazides.

The azomethines of Type - (I) have been prepared by the condensation of 5-

bromo-3-chlorobenzo[b]thiophene-2-carbohydrazide with different aromatic aldehydes.

SECTION-II: Synthesis and biological screening of N'-Arylmethyl-5-bromo-3-

chlorobenzo[b]thiophene-2-carbohydrazides.

S

BrCl

NH

O

NH

R

Type – (II)

The compounds of Type - (II) have been synthesized by the reaction of arylamines

of Type - (I) with anhydrous NaBH4.

PART-II: STUDIES ON OXADIAZOLE DERIVATIVES

1,3,4-Oxadiazoles are associated with broad spectrum of pharmacological

activities like anesthetic, hypnotic, antibacterial, hypoglycemic, antifungal etc. These valid

observations prompted us to synthesize 1,3,4-oxadiazole derivatives with better

therapeutic value which have been described as under.

R = Aryl

S

BrCl

NH

O

N

R

Type – (I)

R = Aryl


Synopsis

SECTION-I: Synthes is and bio logical screening of 2- (5-Bromo-3-

chlorobenzo[b]thiophen-2-yl)-5-aryl-1,3,4-oxadiazoles.

S

BrCl

O

N N

R

Type – (III)

The oxadiazole derivatives of Type - (III) have been synthesized by the

condensation of 5-bromo-3-chlorobenzo[b]thiophene-2-carbohydrazide with various

aromatic acids in the presence of POCl3.

[B] STUDIES ON 3-ISOPROPYL-4-METHOXYBENZALDEHYDE DERIVATIVES

Chalcones are phenylstyryl ketone containing reactive ethylinic group

(-COCH=CH-). Chalcone derivatives signify various biological activities such as

analgesic, anthelmintic, antiinflmmatory, antitubercular, antifungal, antimicrobial etc. Over

and above chalcones are very good synthons for various organic molecules. This valid

observation led us to synthesize some new chalcones, acetylpyrazoline and cyclohexenone

derivatives containing 3-isopropyl-4-methoxybenzaldehyde nucleus, which have been

described as under.

SECTION-I: Synthesis and biological screening of (E)-3-(3-Isopropyl-4-

methoxyphenyl)-1-aryl-prop-2-en-1-ones.

CH3 CH3

OCH3

R

O

Type – (IV)

The chalcone derivatives of Type - (IV) have prepared by the condensation of

3-isopropyl-4-methoxybenzaldehyde with different aryl ketones in presence of 40 %

NaOH.

R = Aryl

R = Aryl


Synopsis

SECTION-II: Synthesis and biological screening of 1-Acetyl-3-aryl-5-(3-

isopropyl-4-methoxyphenyl)pyrazoles.

N N

R

CH3CH3

OCH3

O

CH3

Type – (V)Pyrazolines of Type - (V) have been synthesized by the condensation of the

chalcones of Type - (IV) with hydrazine hydrate in glacial acetic acid.

SECTION-III: Synthesis and biological screening of Ethyl 4-aryl-6-(3-isopropyl-

4-methoxyphenyl)-2-oxocyclohex-3-ene-1-carboxylates.

CH3 CH3

OCH3

R

O

O

OCH3

Type – (VI)

Cyclohexenone derivat ives of Type - (VI) have been prepared bycyclocondensation of chalcones of Type - (IV) with ethyl acetoacetate in the presenceof basic catalyst K2CO3.

[C] STUDIES ON TETRAHYDROPYRIMIDINE DERIVATIVESPyrimidine nucleus possesses remarkable pharmaceutical importance and

biological activities, some of their derivatives occur as natural products, like nucleicacids and vitamin B. Many pyrimidine derivatives have displayed diverse pharmacologicalactivities like antitumor, calcium channel blocker etc. In view of our on going interest inthe synthesis of substituted pyrimidines, the synthesis of some new potentially bioactivepyrimidine derivatives have been undertaken which have been described as under.

R = Aryl

R = Aryl


Synopsis

SECTION-I: Synthesis and biological screening of N-(4-Chlorophenyl)-1,2,3,4-tetrahydro-6-isopropyl-4-aryl-2-oxo/thioxopyrimidine-5-carboxamides using

conventional method and molecular iodine as a catalyst.

R

NH

NH

X

O

NH

Cl

CH3

CH3

Type – (VII) X = O/SPyrimidine derivatives of Type (IV) have been prepared by the multicomponent

cyclization reaction of N-(4-Chlorophenyl)-4-methyl-3-oxopentanamide with urea/thiourea and different aromatic aldehydes in the presence of molecular iodine.

SECTION-II: Synthesis and biological screening of N-(4-Chlorophenyl)-3-formyl-

6-isopropyl-2-oxo-4-aryl-1,2,3,4-tetrahydropyrimidine-5-carboxamides.

R

N

NH

O

O

NH

Cl

CH3

CH3

O

Type – (VIII)Formylated tetrahydropyrimidines of Type - (VIII) have been prepared by the

formylation of different dihydropyrimidinones with DMF and POCl3.

SECTION-III: Synthesis and biological screening of N-(4-Chlorophenyl)-3-

formyl-6-isopropyl-2-thioxo-4-aryl-1,2,3,4-tetrahydropyrimidine-5-carboxamides.

R

N

NH

S

O

NH

Cl

CH3

CH3

O

Type – (IX)Formylated tetrahydropyrimidines of Type - (IX) have been prepared by the

formylation of different dihydropyrimidinthiones with DMF and POCl3.

R = Aryl

R = Aryl

R = Aryl


Synopsis

[D] X-RAY CRYSTALLOGRAPHIC STUDY

SECTION -I: Synthesis, characterization and X-ray crystallographic study of

1-Phenyl-3-methylpyrazole-2-en-5-one.

N

N

CH3

O

Single crystal X-ray diffraction is the most common experimental method of

obtaining a detailed picture of a small molecule that allows resolution of individual atoms.

Single crystal of 1-Phenyl-3-methylpyrazole-2-en-5-one were grown by slow

evaporation technique at constant temperature using methanol as a solvent. Good quality

single crystals were harvested within 45 days.

The constitution of all the synthesized compounds have been characterized using

elemental analysis, FT-IR and 1H NMR spectroscopy and further supported by mass

spectroscopy. Purity of all the compounds have been checked by thin layer

chromatography.

All the compounds have been evaluated for their antibacterial activity towards

Gram +ve and Gram -ve bacterial strains and antifungal activity towards Aspergillus

niger at a concentration 40 μg/ml. The biological activities of the synthesized compounds

have been compared with standard drugs.

Studies on HeterocyclicStudies on HeterocyclicStudies on HeterocyclicStudies on HeterocyclicStudies on HeterocyclicCompounds of MedicinalCompounds of MedicinalCompounds of MedicinalCompounds of MedicinalCompounds of MedicinalInterestInterestInterestInterestInterest


Introduction...

GENERAL INTRODUCTION

The chemistry of the heterocyclic compounds is as logical as that of aliphatic or

aromatic compounds. This study is of great interest both from the theoretical as well as

practical stand point. A heterocyclic compound is one which possesses acyclic structure

with at least one different kinds of atom other than carbon in the ring. The most common

type, contain largely nitrogen, oxygen and sulphur heteroatoms, but many other elements,

including even phosphorous, silicon can also serve. The heterocyclic compounds

containing the less common atoms have been subject to much investigation in recent

years.

The variety of heterocyclic compounds is enormous, their chemistry is complex

and synthesizing them requires great skill. Among large number of heterocycles found in

nature, nitrogen heterocycles are most abundant than those containing oxygen or sulphur

owing to their wide distribution in nucleic acid instant and involvement in almost every

physiological process of plants and animals.

Heterocyclic systems are encountered in many groups of organic compounds

possessing great applicability in industry as well as in our life in various ways i. e. most

of the sugars and their derivatives, including vitamin C, for instant, exist largely in the

form of five membered (Furanosied str.) or six membered (Pyranoised str.) ring containing

one oxygen atom. Most members of the vitamin B group possess heterocyclic rings

containing nitrogen; one example is vitamin B6 (Pyridoxine), which is a derivative of the

pyridine essential in amino acid metabolism. Many other examples of the importance of

heterocyclic compounds in biological systems can be given.

Natural products containing heterocyclic compounds such as alkaloids and

glycosides have been used since old age, as remedial agents. Febrifagl alkaloid from

ancient Chinese drug, Chang Shan, Reserpine from Indian rouwopifia, Curen alkaloid

from arrow poison, Codenine, j-Tropine and Strychnine are all examples of heterocyclic

compounds. Many antibiotics including penicillin, cephalosporin, norfloxacin,

streptomycin etc. also contain heterocyclic ring systems. Majority of the large number

of drugs being introduced in pharmacopeias in recent years are heterocyclic compounds.

Many veterinary products like Pyrantel and Morantel are the drug of choice as

broad spectrum anthelmintics. The herbicides Atrazine and Simazine are well known


Introduction...

example of heterocyclic agrochemicals. Plant pigments such as indigo, hemoglobin and

anthiocyanins, chlorophyll has contributed much colour chemistry and many other

heterocyclic colouring matters are in use since prehistoric times. The heterocyclic

Tetraselena fulvalene was the first ionic molecular crystal to demonstrate

superconductivity.

The word drug is derived from the French word drogue which means a dry

herb. According to WHO a drug may be defined as Any substance or product which is

used or intended to be used for modifying or exploring physiological system or

pathological status for the benefit of recipient.

There are two main divisions of medicinal chemistry. The first chemotherapy,

concerns the treatment of infections, parasite or malignant disease by chemical agents,

usually substances that show selective toxicity towards the pathogen. The other division

relates to diseases of body disfunction and the agents employed are mainly compounds

that effect the functioning of enzymes, the transmission of impulses or the action of

hormones on receptors. Heterocyclic compounds are used for all these purposes; because

they have a specific chemical reactivity. The introduction of heterocyclic group into drugs

may effect their physical properties, for example the dissociation constants of sulpha

drugs or modify their patterns of absorption, metabolism or toxicity.

During the period of 1930-1950 there was an urgent need for new drug to treat

disease which had a high mortality rate, there was only limited appreciation of the hazard

such drugs might present, and toxicological studies before clinical trials were fairly

rudimentary. Proving the proverb Necessity is the mother of invention, during the

decade of 30 and 40s a large number of drugs introduced. Therefore this peroid is

regarded as Golden Period of new drug discovery.

Heterocyclic compounds are obtainable by the following methods.

a. Isolation from natural sources, i.e. alkaloids, amino acids, indigo dyes etc.

b. Degradation of natural products i.e. acridine, furfural, indol, pyridine, quinoline,

thiophene etc.

c. Synthesis: Synthesis methods for obtaining heterocyclic compounds may be

divided into ring closer reactions, addition reaction and replacement reaction.

Cyclisation is usually accomplished by elimination of some small molecules such

as water or ammonia from chain of suitable length.


Introduction...

Heterocyclic compounds have a great applicability as drugs because,

a. They have a specific chemical reactivity.

b. They resemble essential metabolism and can provide false synthons in biosynthetic

process.

The current interest in the creation of large, searchable libraries of organic

compounds has captured an imagination of organic chemists and the drug discovery

community. Efforts in numerous laboratories focused on the introduction of chemical

diversity have been recently reviewed and pharmacologically interesting compounds have

been identified for libraries of widely different compositions.

Research in the field of pharmaceutical has its most important task in the

development of new and better drugs and their successful introduction into clinical

practice. Central to these efforts, accordingly stand the search for pharmaceutical

substances and preparation which are new and original. In addition to these objectives

the searching for drug which exhibit a clear advantage over a drug already known. Such

advantages may be qualitative or quantitative improvement in activity, the absence of

undesirable side effect, a lower toxicity, improved stability or decreased cost.

It is important at the outset to note that drug discovery is not an unambiguous

term in the pharmaceutical R and D world. For example, it can be defined using either

programmatic or organizational approaches (or both), with several options on each

category. Hence, it is important first to understand this variability and to adopt a specific

definition for the purpose of this discussion.

The contribution of organic chemistry to be development of scientific medicine in

the 19th century mainly from acyclic and carbocyclic compounds, although the pyrazoline

antipyrin 1 was introduced as an antipyretic and analgesic in 1984 and the first barbiturate

baritone (veranol) 2 in 1903. Guttmann treated, malaria with methylene blue in 1891,

with slight success, and in 1912 he introduced acriflavine as trypancide, it has proved to

be more valuable as an antiseptic. Phenazopyridini (pyridium) 3 was introduced for the

same purpose in 1926, and although it is relatively ineffective it has continued to be used

since it has some analgesic action.


Introduction...

Aims and objectives

Taking in view of the applicability of heterocyclic compounds, we have undertaken

the preparation of heterocycles bearing benzo[b]thiophene, 3-isopropyl-4-

methoxybenzaldehyde and dihydropyrimidines nucleus. The placements of a wide variety

of substituents on these nuclei have been designed in order to evaluate the synthesized

products for their pharmacological profile against selected strains of bacteria and fungi.

During the course of our work, looking to the application of heterocyclic

compounds, several entities have been designed, generated and characterized using

spectral studies. The details are as under.

1. To generate several derivatives of benzo[b]thiophene and their fused derivatives

such as arylaminomethyl derivatives like Schiff’s base and it’s reduction,

oxadiazoles etc.

2. To generate chalcones, acetyl pyrazoline and cyclohexenone containing 3-

isopropyl-4-methoxybenzaldehyde as a basic core.

3. To synthesize several derivatives of oxo/thiopyrimidines under classical biginelli

condition and catalytical method like molecular iodine as a catalyst at ambient

temperature and develope their 3-formyl derivatives.

4. To check purity of all synthesized compounds using thin layer chromatography.

5. To characterize these synthesized products for structure elucidation using various

spectroscopic techniques like IR, 1H NMR, mass spectral studies and C, H, N

analysis.

6. To grow single crystal of the synthesized compounds and study there X-ray

crystallograpy for establishment of the structure.

7. To evaluate these new synthesized products for better drug potential against

different strains of bacteria and fungi.

( 1 ) ( 3 )( 2 )

NN

CH3

Ph

O

NHNH

O

OO

Et Et

N NH2

NN

Ph

Part-Part-Part-Part-Part-AAAAA

Studies on Benzo[b]thiophene Derivatives


Benzo[b]thiophene derivatives...

INTRODUCTION

Benzo[b]thiophene and its derivatives are important heterocycles which find uses

in pharmaceuticals, pesticides and in general organic synthesis1. Sulphur containing crude

petroleum is the main source of these compounds. However, separation of these

compounds from crude petroleum is a tedious process and hence the demand for these

compounds is mainly met by synthetic methods. A major stimulus to the study of

benzothiophene chemistry was the discovery of their importance in dye industry. 2-

Benzo[b]thiophene-2’-indoleindigo (1) and its substituted derivatives are useful class of

dyes and it was reviewed by Hartough and Meisel2.

Benzo[b]thiophene has also attracted interest as potential biological active agents.

It may serve as bioisosteres of indoles. Numerous benzo[b]thiophene analogs of

biologically active indole derivatives have proved to be agonists as antagonists of their

indole congeners, it was reviewed in detail by T. R. Bosin3 and E. Campaigne4. The

chemistry of benzo[b]thiophene (2) and benzo[c]thiophene (3) were reviewed by R. M.

Scrowston5 and B. Iodone6.

SYNTHETIC ASPECT

Various methods for the preparation of benzo[b]thiophene derivatives have been

cited in literature, some of the methods are as under.

S

NH

O

O( 1 )

Sa

b Sa

b

c

( 2 ) ( 3 )



1. C. Mukherjee and workers7 have synthesized benzo[b]thiophene derivatives using

direct metalation approach in synthesis.

2. o-Bromoethynylbenzene with S8 and NaBH4 in ethanol8 can be converted into

bezo[b]thiophene.

3. Substituted acetophenones to benzo[b]thiophene conversation also possible with

t-BuOK in DMSO9 but the yield of the product is 23 %.

4. M. E. Borai et al.10 have been developed benzo[b]thiophene derivative from the

thiophene-2,3-dicarbaldehyde as a starting material.

5. M. G. Reinecke and co workers11 have been synthesized the benzo[b]thiophene

derivative using thiophene-2,3-dicarboxylicacid with thiophene and acetic

anhydride.

SCH3

NEt2

O

S

LiN(Pr - i)2, -78 °C

NaBH4

Br

CH

S8, NaBH4

EtOH S

CH3

O

t - BuOK

DMSO SRR

S

O

O

H

H

+ C CH2 S CH2 C

O O

O

O

O CH3OCH3S



6. Synthesis of benzo[b]thiophene was carried out using AlPO4 and Pd/AlPO4 as a

catalyst12 from the 2-(phenylthio)ethanol.

7. Synthesis of benzo[b]thiophene from carboxylic acids and ketones was reported

by T. Higa et al.13 with 77 % yield.

8. C. M. Bonnin and co workers14 have synthesized benzo[b]thiophene derivatives

from alkoxy-substituted phenylpropiolic acids and esters with 72 % yield.

9. Benzo[b]thiophene containing various substitution has been developed by R.

Walter et al.15

SOH

S

AlPO4

Pd/AlPO4

O

OHSOCl2

S

Cl

O

Cl

R R

O

OH

OCH3

O

CH3

S

Cl

O

ClOCH3

O

CH3

SOCl2

O

OH

S

Cl

O

ClSOCl2

C5H5NR R

S

O

OH

O

OH

Ac2O

Thiophene S



10. Syntheses of dimethoxy and trimethoxy benzo[b]thiophene derivatives have been

achieved by J. G. Stuart et al.16 with good yield in two steps.

11. α-Halo,β-arylpropanoicacid can be converted in benzo[b]thiophene.17

12. Recently E. S. H. El Ashry et al.18 reported microwave assisted synthesis of

benzo[b]thiophene derivatives in short reaction time with improved 82 % yield.

13. A. H. K. Sharba et al.19 reported synthesis of hydrazide from benzo[b]thiophene-

2-acid chloride in chloroform with 73 % of yield.

14. Microwave assisted synthesis of benzo[b]thiophene hydrazide was reported by

A. A. Kassem and coworkers20.

Br

O

OH +N+

O

NH2 Ph

.Cl-SOCl2

S

Cl

O

Cl

R R

O

OHSOCl2, C5H5N

DMF, MW, 2 minS

Cl

O

Cl

S

Cl

O

Cl

S

CH3

O

NH NH2N2H4, CHCl3

Δ

S

Cl

O

Cl

S

Cl

O

NH NH2N2H4 - H2O, CHCl3

MW

OCH3

O

CH3

O

+O

OH

OOH Piperidine, C5H5N

SOCl2, C5H5N S

Cl

O

ClOCH3

O

CH3



REACTION MECHANISM

Although the preparation of acid chlorides from carboxylic acids with thionyl

chlorides is a well-known and commonly used method, this reaction is of particular interest

as it includes the sulfur from the thionyl chloride in the final benzo[b]thiophene product21.

This reaction, although taking place through a multi-step pathway, is a single pot, relatively

high-yielding reaction, which proceeds smoothly to the final cyclized product.

The proposed reaction mechanism for the formation of benzo[b]thiophene.

THERAPEUTIC IMPORTANCE

Over recent years there has been an increasing interest in the chemistry of

benzo[b]thiophene because of their biological significance.

1. Analgesic22-24

2. Antiallergic25-27

3. Antibacterial28,29

4. Anticonvulsant30

5. Antifungal31,32

6. Antihistaminic33

7. Antiinflammatory34-36

8. Antitumor37

9. Antiviral38,39

10. β-Adrenergic40,41

11. Diuretic42-44

12. Insecticidal45

O

OH

O

OH

Cl

H

H

SCl O

SOCl2

Pyridine

O

Cl

Cl

H

Cl

SCl

Pyridine - 2HCl

S

Cl

O

Cl

SOCl2

- SO2



13. Neumatocide46

14. Neuroleptic47

15. Anticancer48-51

C. Routledge et al.52 have prepared benzo[b]thiophene (4) and it’s derivatives

and evaluated for their anticonvulsant activity.

D. J. Sall et al.53 have prepared diamino benzo[b]thiophene (5) and it’s derivatives

as a active site directed thrombin inhibitors.

Kuanuniamine A (6) is the simplest member of a group of marine alkaloids which

show strong antitumor activity in vivo and in vitro. They also exhibit immunosuppressive

and antiviral properties. W. F. Reynolds et al.54 has prepared compound 4,7-

dioxobenzo[b]thiophene (7) is analogue of Kuanu-niamine A.

S

CH3 Me

S

NH

O

O

N

NH

OMe

( 4 )

S X

N

O

N

OH

OMe

( 5 ) X = CH, N

N

N

N

S

ON

N

S

O

Ph

( 6 ) ( 7 )



A. Monge et al.55 have prepared benzo[b]thiophene derivatives (8) and reported

their high affinity at the serotonin transporter and at 5-HT1A receptors.

J. A. Valderrama et al.56 have prepared benzo[b]thiophenes (9, 10) and their

application of benzo[b]thiophenequinones and naphthothiophenequinones with ortho-

amino functional on the thiophene ring possess a variety of biological properties against

human-T-cell leukemia virus (HTLV-1).

S. Brian et al.57 have prepared 3-benzylbenzo[b]thiophenes (11) which are

useful for treating diseases associated with post-menopausal syndrome, i.e. cancer of

the breast, uterus and cervix.

H. Lee et al.60 have synthesized benzo[b]thiophenes derivatives (12) and evaluated

for the NHE-1 inhibitory activity and cardioprotective efficacy both in vitro and in

vivo.

S

O

O

CO2Me

R

1 R = NAc22 R = NHAc

S

O

O NHR

CO2Me

3 R = H4 R = Ac

( 9 ) ( 10 )

SR2

R1

R3N R4

R5

R6 R1 = OH, OCO(alkyl), OCO(aryl)R2 = aryl, alkyl, cycloalkylR3 = O(CH2)2, O(CH2)3

R4 ,R5 = CO(CH2)2Me, CO(CH2)3Me, alkylR6 = O(alkyl), O(aryl), OCH2CH2CN

( 11 )

S

CH3

OH

NN R1 R = H, F

R1= 1-Naphthyl, 2-Quinolyl, 3-Quinolyl, 4-Quinolyl, 4-Indolyl, 8-quinonaldinyl

( 8 )

S

X

N

O

NH2

NH2

( 12 )



M. B. Sporn et al.58 have synthesized benzo[b]thiophenes (13) and it’s derivative

and testing for its antibreast cancer activity.

S. Yous et al.59 have synthesized and evaluated four novel benzo[b]thiophenes

derivatives (14) designed as Serotonin N-acetyltransferase (AANAT) inhibitors. Specific

AANAT inhibitors could be useful for treatment of different physiopathological disorders

encountered in diseases such as seasonal affective disorders or obesity.

K. Z. Grace et al.61 have synthesized benzo[b]thieno[2,3-c]quinolones (15, 16)

and evaluated antiproliferative effect on a series of human tumor cells and on a normal

cell line.

S

R

NHO

Br

R = COOCH3, COOH

NO2, NHSO2CH3

( 14 )

SR1

NH

O

NHCH(CH3)2

H2NCl

R1 = H, CH3, OCH3, COOCH3, Br, CN

R = H, CH3, OCH3, COOCH3, F, NO2

R1 = (CH2)3N(CH3)2

SR

N

O

R1

( 15 ) ( 16 )

SOH OCH3

O O

N

( 13 )



W. W. Wardakhan et al.62 have synthesized 2-aminothiophene-3-carboxamide

derivatives (17) and evaluated for their antimicrobial activity against gram-positive and

gram-negative bacteria.

M. S. Malamas and coworkers63 have synthesized novel benzothiophene

derivatives inhibitors of protein tyrosine phosphatase 1B with antihyperglycemic

properties. S. S. Perez et al.64 developed 5-substituted benzo[b]thiophene derivatives

with dual action at 5-HT1A serotonin receptors and serotonin transporter as a new class

of antidepressants. Synthesis and serotonergic activity of benzothiophene-4-piperazine

derivatives as novel antagonists for the vascular 5-HT1B receptor has been achieved by

G. P. Moloney and group65. S. Galiano et al.66 synthesized thiophene and

benzo[b]thiophene hydrazide derivatives and reported them as human NPY Y5

antagonists. Inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II,

and IX with benzo[b]thiophene 1,1-dioxide sulfonamides have been reported by A.

Innocenti and coworkers67. I. Jarak and coworkers68 synthesized, novel cyano and N-

isopropylamidino-substituted derivatives of benzo[b]thiophene-2-carboxanilides and

reported antitumor activity.

B. Peschke et al.69 have reported benzo[b]thiophene-2-carboxamides as potent

antagonists of the human H3-receptor. New HIV-1 reverse transcriptase inhibitors based

on a tricyclic benzothiophene scaffold has been reported by K. Krajewski et al.70 D. J.

Witter et al.71 have discovers benzo[b]thiophene based histone deacetylase inhibitors

and report it as anti-proliferative. Synthesis of 2 and 3-aminobenzo[b]thiophene

derivatives as antimitotic agents and inhibitors of tubulin polymerization have been

reported by R. Romagnoli and coworkers.72 A. J. Li et al.73 reported synthesis and

evaluation for dual 5-HT1A/SSRI activities of benzo[b]thiophene derivatives. Synthesis

and cannabinoid activity of a variety of 2,3-substituted 1-benzo[b]thiophen derivatives

was reported by G. P. Moloney and group.74

S

N

NOH

NH

SH

Ph

( 17 )



Derivatives of benzo[b]thiophene are also available as drug, some of them are

shown as under:

Work done from our laboratory

V. V. Kachhadia synthesized 6-Carbethoxy-5-aryl-3-[p-(3'-chloro-2'-

benzo[b]thiophenoylamino)phenyl]-2-cyclohexenones (18)75, heterocyclic systems

containing S/N regioselective nucleophilic competition like, thiohydantoins and

thiazolidinones (19)76 derivatives bearing benzo[b]thiophene nucleus and reported their

antitubercular and antimicrobial activity.

S

N

CH3

OH NH2

O

SOH

OH

O

O

N

S

Cl

O

N

N

Cl

Cl

RaloxifeneAnticancer/Osteroporosis

Zileuton

Antiashthamatic

Sertaconazole

Antifungal

S

Cl

O

NH

R

O

OEtS

Cl

O

N

O

N

S

R

( 18 ) ( 19 )



S. L. Vasoya reported facile synthesis of some new azetidinones and acetyl

oxadiazoles as a potent biological active agent77, thiosemicarbazides and 1,3,4-

thiadiazoles (20) as potent antitubercular and antimicrobial agents78, thiosemicarbazide

and 1,2,4-triazoles (21) heterocycles as a potent antitubercular and antimicrobial agents79

bearing benzo[b]thiophene nucleus.

K. M. Thaker synthesized and reported pharmacological evaluation of 1,3,4-

thiadiazoles80, imidazolones (22) and 1,2,4-triazoles as antimicrobial agents81, thiourea

derivatives as potential antimicrobial agents82, 1,3,4-oxadiazoles (23) and 2-

arylsulfonylhydrazinocarbonyl-3,5-dichlorobenzo[b]thiophenes and its pharmacological

evaluation83.

In view of procuring highly potent biodynamic agents after this literature survey

and on continuation of our on going work on benzo[b]thiophenes for their various methods

of synthesis and different biological activities, synthesis of benzo[b]thiophene have been

undertaken in order to achieve superior therapeutic agents. This can be summarized in

the following sections as under.

STUDIES ON BENZO[b]THIOPHENE DERIVATIVES


PART-II: STUDIES ON OXADIAZOLE DERIVATIVES

S

ClO N

S

N

NH

R

S

ClO N

N

N

SHR

S

ClCl N

O

N

RS

ClCl

O

NH NNH

R1

O

R

( 20 ) ( 21 )

( 23 )( 22 )



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Studies on Arylaminomethyl Derivatives

Part-Part-Part-Part-Part-AAAAA(Part-I)(Part-I)(Part-I)(Part-I)(Part-I)


Arylaminomethyl derivatives...

INTRODUCTION

Azomethine derivatives have been found to be potent drug in pharmaceutical

industries and possess a wide spectrum of biological activity. Azomethines are also known

as Schiff’s base and they are well known intermediate for the preparation of azetidinone,

thiazolidinone, formazone, aryl acetamide and many other derivatives. These are the

compounds contain characteristic -C=N group. B. S. Holla et al.1 have documented

azomethines (1) having triazole moiety and possess good antibacterial activity.

Azomethines are obtained mainly by warming the aldehyde and aromatic amine

together. However, it is more convenient to work in a solvent such as alcohol, dilute

acetic acid or glacial acetic acid. Some time the reaction is aided by trace of acid in

other cases the hydrochloride of the amines can be used in the synthesis.

In general Schiff’s bases do not react further with either of the reagents used in

their preparation as do most of the other types of simple intermediates.

SYNTHETIC ASPECT

Various methods for the preparation of azomethine derivatives have been cited in

literature, some of the methods are as under.

1. General account of the summary of reaction of aldehydes with amine (aromatic

or aliphatic) has been reviewed by Murray2.

2. E. C. Creencia and group3 reported synthesis from ortho substituted aniline with

55 % yield in 2 hours in benzene.

N

N

N

R

S

R1N

ON+O-

O

( 1 )

RO + R1 NH2

RN R1



3. D. Bleger et al.4 have synthesized Schiff’s base of aniline and benzaldehyde in

ethanol with short reaction time of 4 hours and reported E isomer as major

product.

4. U. K. Roy and coworkers5 have reported preparation of Schiff’s base with 100 %

of yield with toluene as a solvent.

5. L. B. Pierre and coworkers6 have synthesized (E)-N-phenyl methyleneglycine

ethyl ester by the cyclocondensation of glycine ethyl ester hydrochloride,

t-butylmethyl ether (TBME), benzaldehyde was added followed by anhydrous

Na2SO4 and triethylamine.

6. J. G. Amanda et al.7 have prepared Schiff bases by condensation of equimolar

quantity of 3,6-diformylcatechol and substituted o-phenylenediamine.

NH2

Ar

+

O

N

Ar

R

R

Benzene

2 h

NH2

+

O

EtOH

4 h

NE

NH2

+

O

NPhMe

24 h

HCl. +

O

Et3N, TBME

Na2SO4N

O

O

CH3NH2

O

O

CH3



7. L. Somogyi8 reported some azomethine derivatives of phenylhydrazide in 99 %

yield and with short reaction time of 3.5 hours in polar solvent.

8. Schiff’s base of o-phenelene diamine with substituted benzaldehyde was reported

by M. Zintl and coworkers9.


Schiff’s bases exhibit a wide range of pharmacological activities like antifungal,

antibacterial, antiviral, anti-inflammatory etc. R. H. Mehta et al.10 have synthesized

coummarin Schiff’s base derivatives (2) and examined for their antibacterial activity. A.

K. Khalafallah and M. E. Hassan11 have prepared some styryl Schiff ’s bases spiro

derivatives as potential antibacterial and antifungal activity. P. Perumal12 have synthesized

some azomethine derivatives (3) having good antibacterial activity.

O

O

OH

OH

+

OR

OR

NH2

NH2O

OH

OH

N

NH2

OR

OR

NHONH2

+

O

NΔ

3.5 hR

R

NH2

NH2

+ ArO EtOH

Δ

NAr

NAr

O ON

R

NO NR

( 3 )( 2 )



M. D. Deshmukh and A. G. Doshi13 prepared some new Schiff ’s bases show

good antimicrobial activity against test organism S. aureus, E. coli, Saigella dysenteridse

and Salmonella typhi. Wang et al.14 have synthesized diazomethines having good plant

hormone activity. Das Arima et al.15 have prepared Schiff’s bases of aminohydroxy

guanidine (SB-AHG5) and tested for antiviral activity against Herpes Simplex virus Type

I (HSV-1) and adenovirus Type-5 (Ad-5).

Ali yusuf et al.16 have synthesized some Schiff ’s base derivatives of glucose

containing acetylenic bond. The prepared Schiff bases were tested for their bactericidal

activity against E. coli and S. aureus.

B. S. Holla et al.17 have prepared Schiff ’s bases and reported them as

antimicrobial agents. Pandey Taruna et al.18 prepared azomethines and their boron

complexes and screened for their antifungal and antibacterial properties. It is evident

that azomethines along with quite toxic but their activity increased after complexation.

Omar et al.19 have determined cyclocondensation of azomethines having good

antischistosomal activity. Chohan and coworkers20,21 have synthesized a novel class of

acetyl ferrocene derived from Schiff’s bases possess antimicrobial activity. Some

azomethine derivative screened for various antibacterial strains.

Das Joydip et al.22 have synthesized trans-N-refinylidene-n-butylamine (4) which

found stabilized in liposome’s of phophatidylcholine. The rate of formation of the Schiff’s

base is found to decrease with increasing cholesterol concentration in the membrane. V.

M. Patel23 has synthesized some new Schiff’s bases having good antibacterial activity.

Ram Tilak et al.24 have synthesized some Schiff ’s bases, of 2-chloro

phenothiazines and screened against carrageenin-induced edema in albino rats.

A. Cascaval et al.25 have synthesized azomethines, which have good analgesic and

antipyretic properties. S. N. Pandeya et al.26 have synthesized Schiff’s bases showed

good activity against Vibrio cholerae non-o., Shigella boydii, Enterococcus faecalis

CH3 CH3CH3 CH3

NBut

( 4 )



and Edwaredsiella torla with MIC in the rang of 10-25 ìg/ml. Some compounds were

found to be active against Salmonellal typhi and Vibro cholerae-0, (MIC 25-150 ìg/

ml).

K. N. Venugopal et al.27 have synthesized Schiff ’s base of 4-hydroxy-6-

carboxyhaydrazino benzothiophene analog with different substituted aldehydes and

determined pharmacological study. Ergenc and coworkers28 have synthesized azomethine

derivatives having antifungal activity. B. Yadav and S. S. Sangapure29 have synthesized

some azomethines and tested for their biological activity. B. S. Holla et al.30 have prepared

some new Schiff’s bases having anticancer activity.

R. V. Chambhare et al.31 have prepared some azomethines and tested for their

antimicrobial activity. M. S. Karthikeyan et al.32 have synthesized azomethines (5) having

antibacterial and anti-inflammatory activity.


Synthesis of schiff’s bases (6) bearing benzo[b]thiophene nucleus as potential

antitubercular and antimicrobial agents was developed by K. M. Thaker33. S. L. Vasoya34

reported facile synthesis of some new azomethines (7) bearing benzo[b]thiophene nucleus

as a potent biological active agent.

T. K. Dave have been reported synthesis and pharmacological study of Mannich

bases of 4-amino-3-mercapto-5-pyridin-3'-yl-[1,2,4]-triazole (8)35 and schiff’s base

(9)36 bearing nicotinic acid nucleus with antitubercular and antimicrobial evaluation.

N

S

Cl

Cl

Cl

NHN

O

R

( 5 )

S

ClCl

O

NH NR

S

ClO

O

NH NR

( 6 ) ( 7 )



Looking to the interesting properties of azomethines, we have synthesized some

new azomethines, which have been described as under.


SECTION-I: SYNTHESIS AND BIOLOGICAL SCREENING OF (E)-N’-

ARYLMETHINE-5-BROMO-3-CHLOROBENZO[b]THIOPHENE-

2-CARBOHYDRAZIDES.

SECTION-II:SYNTHESIS AND BIOLOGICAL SCREENING OF N’-

ARYLMETHYL-5-BROMO-3-CHLOROBENZO[b]THIOPHENE-2-

CARBOHYDRAZIDES.

N

NH

O

N R

CH3 N

N

N

N

SH

N

R( 8 ) ( 9 )



SECTION-I

SYNTHESIS AND BIOLOGICAL SCREENING OF (E)-N’-ARYLMETHINE-5-

BROMO-3-CHLOROBENZO[b]THIOPHENE-2-CARBOHYDRAZIDES.

The growing patent literature of recent years demonstrates that the azomethine

derivatives are used as better therapeutic agents. In view of these findings, it appeared

of interest to synthesize Schiff ’s base by the condensation of 5-bromo-3-

chlorobenzo[b]thiophene-2-carbohydrazide with various aromatic aldehydes in order

to study their biodynamic behavior.

The constitution of the synthesized compounds have been characterized by using

Elemental analysis, Infrared, 1H Nuclear Magnetic Resonance spectroscopy and further

supported by mass spectroscopy.

All the products have been screened for their in vitro biological assay like

antibacterial activity towards Gram positive and Gram negative bacterial strains and

antifungal activity towards A. Niger at a concentration of 40 μg/ml. The biological

activities of the synthesized compounds were compared with standard drugs.



REACTION SCHEME

S

Cl

O

NH NH2Br

O

Br

+OH

O

OOH

O

OH

Br

S

Cl

O

ClBr

NH2NH2 .H2OEtOH

S

Cl

O

NH NBr

+

O

R

R

Pyridine

SOCl2Pyridine

gl. CH3COOH



EXPERIMENTAL SECTION

Melting points of all the synthesized compounds were taken in open capillary

bath on controlled temperature heating mental. The crystallization of all the compounds

was carried out in appropriate solvents. TLC was carried out on silica gel-G as stationary

phase. 20 % Ethyl acetate in Hexane was used as a mobile phase.

[A] Preparation of 3-bromocinnamicacid

Take 3-bromobenzaldehyde (1.85 gm, 0.01 mole) and anhydrous malonic acid

(2.5 gm, 0.025 mole) in 50ml RBF, to this add pyridine (10 ml). Dissolve all the content

and reflux it on oil bath for 4 hrs. at 110 °C Pour the content onto crushed ice, acidified

it with conc. HCl (pH = 4-5). Filter the solid mass under vacuo and crystallized from

methanol. Gives white to light yellow crystalline powder, Yield: 84 %, M.P.: 177-180 °C,

reported 178-182 °C.

[B] Preparation of 5-bromo-3-chlorobenzo[b]thiophene-2-carbonyl chloride

A mixture of 3-bromocinnamic acid (7.12 gm, 0.039 mole), thionyl chloride (20

ml) and pyridine (0.5 ml) was heated at 100 °C for 24 hrs. The excess of thionyl chloride

was distilled off. The content was poured into hot dioxane. The yellow crystalline product

so obtained was crystallized from Hexane. Yield: 75 %, M.P.: 102-104 °C, reported

101 °C.

[C] Preparation of 5-bromo-3-chlorobenzo[b]thiophene-2-carbohydrazide

A combination of 5-bromo-3-chlorobenzo[b]thiophene-2-carbonylchloride (3.1

gm, 0.01 mole) and hydrazine hydrate (1 gm, 0.02 mole) in methanol (25 ml) was heated

under refluxed condition for 6 hr. The solid obtained was filter and washed with water

under vacuo and the product so obtained was crystallized from dioxane. Yield: 72 %,

M.P.: 156 °C, Calc.C, 35.37%; H, 1.98%; N, 9.17% for C9H6BrClN2OS found C,

35.25%; H, 2.08%; N, 9.08%.

[D] General procedure for the preparation of (E)-N’-Arylmethine-5-bromo-3-


A mixture of 5-bromo-3-chlorobenzo[b]thiophene-2-carbohydrazide (1.53 gm,

0.005 mole) and arylaldehyde (0.005 M) in toluene (20 ml) was refluxed in presence of

glacial acetic acid in catalytic amount (0.5 ml) for 6 hr. with Dean Stark apparatus. The

solvent was removed under vacuo and the solid so isolated was crystallized from suitable

solvent. The physical constants of the product are recorded in Table-1a.



Table-1a: Physical constants of (E ) -N’ -Arylmethine-5-bromo-3-

chlorobenzo[b]- thiophene-2-carbohydrazides.

S

Cl

O

NH NBr

R

Sr.No.

SubstitutionR

Molecular Formula/Molecular Weight

M.P.oC

Yield%

% CompositionCalcd./Found

C H N

1a H C16H10BrClN2OS393.68 185-187 81 48.81

48.682.562.64

7.127.05

1b 4-OCH3C17H12BrClN2O2S

423.71 196-198 72 48.1948.11

2.852.94

6.616.48

1c 3-NO2C16H9BrClN3O3S

438.68 279-280 86 43.8143.85

2.072.15

9.589.44

1d 4-Cl C16H9BrCl2N2OS428.13 240-242 78 44.89

44.822.122.01

6.546.63

1e 3,4-(OCH3)2C18H14BrClN2O3S

453.73 200-202 73 47.6547.61

3.113.06

6.176.24

1f 2,5-(OCH3)2C18H14BrClN2O3S

453.73 223-225 66 47.6547.58

3.113.07

6.176.28

1g 2-OCH3C17H12BrClN2O2S

423.71 210-211 70 48.1948.11

2.852.94

6.616.48

1h 2-OH C16H10BrClN2O2S409.68 193-195 67 46.91

46.832.462.39

6.846.99

1i 4-NO2C16H9BrClN3O3S

438.68 275-277 82 43.8143.85

2.072.15

9.589.44

1j 3-Br C16H9Br2ClN2OS472.58 192-194 77 40.66

40.521.921.87

5.935.83

Studies on heterocyclic... 36

Arylaminomethyl Derivatives…

SPECTRAL STUDY IR spectra of (E)-N’-(4-Methoxyphenyl)methine-5-bromo-3-chlorobenzo[b]- thiophene-2-carbohydrazide.

5007501000125015001750200025003000350040001/cm

0

15

30

45

60

75

90

105

%T

3289.70

3170.11

3061.13

2955.04 2836.42

1662.69

1651.12

1593.25

1505.49

1484.27

1422.55

1343.46

1262.45

1173.72

1046.42

953.83

861.24820.74

744.55

Instrument: Shimadzu FTIR-8400 using KBr DRS techniques. The percentage transmittance is given in cm-1 and frequency range is between 400-4000cm-1.

Type Vibration Mode Frequency cm-1

Alkane -CH3

C-H str. (asym.) 2955

C-H str. (sym.) 2836

C-H str. (asym) 1484

C-H str. (sym) 1343

Aromatic

C-H str. 3061, 3170

C=C (skeleton) 1505, 1593

C-H i.p. bending 1046

C-H o.p. bending 861

Amide -NH-C=O str. 1662

Amine -N-H str. 3289

Schiff base -C=N- str. 1651

Halide -C-Cl-C-Br

744820

S

Cl

O

NH NBrOCH3



1H NMR spectra of (E)-N’-(4-Methoxyphenyl)methine-5-bromo-3-chloro-

benzo[b]thiophene-2-carbohydrazide.

Instrument: BRUKER 400 MHz (Avance - II), Internal reference: TMS, Solvent: DMSO d6 + CDCl3.

S

Cl

O

NH NBrO

CH3a

a'

b

b'

c

de

Sr.No.

Chemicalshift in ppm

Relative No.of Protons Multiplicity Inference J value

in Hz

1 3.86 3H singlet -OCH3 -

2 6.93-6.95 2H doublet Ar-Ha,a' 8.28

3 7.44-7.49 1H dd Ar-Hd 7.92, 3

4 7.61-7.65 1H doublet Ar-He 8.24

5 7.80-7.82 2H doublet Ar-Hb,b' 8.48

6 8.04-8.05 1H doublet Ar-Hc 3.92

7 8.37 1H singlet methine-H -

8 11.40 1H singlet(b) -NH (Amide) -



Inst

rum

ent:

Shi

mad

zu G

C-M

S Q

P-20

10, D

I-pr

obe,

EI-

met

hod.

EI-

Mas

s spe

ctra

of (

E)-

N’-

(4-C

hlor

ophe

nyl)

met

hine

-5-b

rom

o-3-

chlo

robe

nzo[

b] -t

hiop

hene

-2-c

arbo

hydr

azid

e.

SCl

ONHN

Br

Cl

M. W

t. =

428

.13



EI-

Mas

s spe

ctra

of (

E)-

N’-

(4-M

etho

xyph

enyl

)met

hine

-5-b

rom

o-3-

chlo

robe

nzo[

b] -t

hiop

hene

-2-c

arbo

hydr

azid

e.

Inst

rum

ent:

Shi

mad

zu G

C-M

S Q

P-20

10, D

I-pr

obe,

EI-

met

hod.

SCl

ONHN

BrO

CH3

M. W

t. =

423

.71



ANTIMICROBIAL ACTIVITY

Biological screening of (E)-N’-Arylmethine-5-bromo-3-chlorobenzo[b]thiophene-

2-carbohydrazides.

Method : Cup-Plate37

Gram positive bacteria : Staphylococcus aureus ATCC 6538

Staphylococcus epidermidis ATCC 12228

Gram negative bacteria : Escherichia coli ATCC 8739

Pseudomonas aeruginosa ATCC 1539

Fungi : Aspergillus niger ATCC 16888

Concentration : 1000 μg/ml

Solvent : Dimethyl formamide (DMF)

Standard drugs : Amoxicillin, Ciprofloxacin, Cephalexin,

Erythromycin, Griseofulvin

The antimicrobial activity was compared with standard drug viz Amoxicillin,

Ciprofloxacin, Cephalexin, Erythromycin and antifungal activity was compared with viz

Griseofulvin. The inhibition zones measured in mm.

(a) Antibacterial activity

The purified products were screened for their antibacterial activity using cup-

plate agar diffusion method. The nutrient agar broth prepared by the usual method was

dispensed in 50 ml quantities of different conical flasks. Then, add the 0.5 ml culture of

each bacteria (Staphylococcus aureus ATCC 6538, Staphylococcus epidermidis ATCC

12228, Escherichia coli ATCC 8739 and Pseudomonas aeruginosa ATCC 1539) in

nutrient agar broth and inoculate at 37°C for 24 hr.

The nutrient agar was melted at 100 °C and after cooling to 56 °C, was poured

into petri plates of 13 cm diameter in quantities of 20 ml, and left on a flat surface to

solidify and the surface of the medium was dried at 37 °C. Then, above subcultures of

each bacteria pipetted in to the nutrient agar plate. The cups (10 mm diameter) were

formed by the help of borer in agar medium and filled with 0.04 ml (40 μg) solution of



sample in DMF. The plates were incubated at 37 °C for 24 hr and the control was also

maintained with 0.04 ml of DMF in a similar manner. After the completion of incubation

period, the zone of inhibition of growth in the form of diameter in mm was measure and

recorded in Table-1b.

(b) Antifungal activity

Aspergillus niger ATCC 16888 was employed for testing antifungal activity using

cup-plate agar diffusion method. The culture was maintained on sabourauds agar slants,

sterilized sabourauds agar medium was inoculated with 72 hr. old 0.5 ml suspension of

fungal spores in a separate flask.

The sabourauds agar was melted at 100 °C and after cooling to 56 °C, was

poured into petri plates of 13 cm diameter in quantities of 20 ml, and left on a flat

surface to solidify and the surface of the medium was dried at 37 °C. Then, above

subculture of fungi pipetted in to the sabourauds agar plate. The cups (10 mm diameter)

were formed by the help of borer in agar medium and filled with 0.04 ml (40 μg) solution

of sample in DMF. The plates were incubated at 30 °C for 48 hr. and the control was

also maintained with 0.04 ml of DMF in a similar manner. After the completion of

incubation period, the zone of inhibition of growth in the form of diameter in mm was

measure and recorded in Table-1b.



Tabl

e-1b

: Ant

imic

robi

al a

ctiv

ity

of (E

)-N

’-A

rylm

ethi

ne-5

-bro

mo-

3-ch

loro

benz

o[b]

thio

phen

e-2-

carb

ohyd

razi

des.

Sr.

No.

Ant

ibac

teria

l Act

ivity

Ant

ifung

al A

ctiv

ity

S. a

ureu

sS.

epi

derm

idis

E. c

oli

P. a

erug

inos

aA

. nig

er

1a11

(0.5

5)C

1, (0

.52)

C2

(0.6

1)C

3, (0

.55)

C4

14(0

.58)

C1,

(0.5

8)C

2(0

.82)

C3,

(0.7

7)C

4

18(0

.81)

C1,

(0.7

2)C

2(0

.75)

C3,

(1.0

0)C

4

16(0

.76)

C1,

(0.6

4)C

2(0

.64)

C3,

(1.0

6)C

4

09(0

.37)

C5

1b21

(1.0

5)C

1, (1

.00)

C2

(1.1

6)C

3, (1

.05)

C4

08(0

.33)

C1,

(0.3

3)C

2(0

.47)

C3,

(0.4

4)C

4

16(0

.72)

C1,

(0.6

4)C

2(0

.66)

C3,

(0.8

8)C

4

09(0

.42)

C1,

(0.3

6)C

2(0

.36)

C3,

(0.6

0)C

4

19(0

.79)

C5

1c16

(0.8

0)C

1, (0

.76)

C2

(0.8

8)C

3, (0

.80)

C4

09(0

.37)

C1,

(0.3

7)C

2(0

.52)

C3,

(0.5

0)C

4

10(0

.45)

C1,

(0.4

0)C

2(0

.41)

C3,

(0.5

5)C

4

13(0

.61)

C1,

(0.5

2)C

2(0

.52)

C3,

(0.8

6)C

4

23(0

.95)

C5

1d09

(0.4

5)C

1, (0

.42)

C2

(0.5

0)C

3, (0

.45)

C4

16(0

.66)

C1,

(0.6

6)C

2(0

.94)

C3,

(0.8

8)C

4

13(0

.59)

C1,

(0.5

2)C

2(0

.54)

C3,

(0.7

2)C

4

17(0

.80)

C1,

(0.6

8)C

2(0

.68)

C3,

(1.1

3)C

4

08(0

.33)

C5

1e12

(0.6

0)C

1, (0

.57)

C2

(0.6

6)C

3, (0

.60)

C4

23(0

.95)

C1,

(0.9

5)C

2(1

.35)

C3,

(1.2

7)C

4

15(0

.68)

C1,

(0.6

0)C

2(0

.62)

C3,

(0.8

3)C

4

17(0

.80)

C1,

(0.6

8)C

2(0

.68)

C3,

(1.1

3)C

4

11(0

.45)

C5

1f11

(0.5

5)C

1, (0

.52)

C2

(0.6

1)C

3, (0

.55)

C4

19(0

.79)

C1,

(0.7

9)C

2(1

.11)

C3,

(1.0

5)C

4

09(0

.40)

C1,

(0.3

6)C

2(0

.37)

C3,

(0.5

0)C

4

20(0

.95)

C1,

(0.8

0)C

2(0

.80)

C3,

(1.3

3)C

4

16(0

.66)

C5



1g12

(0.6

0)C

1, (0

.57)

C2

(0.6

6)C

3, (0

.60)

C4

16(0

.66)

C1,

(0.6

6)C

2(0

.94)

C3,

(0.8

8)C

4

17(0

.77)

C1,

(0.6

8)C

2(0

.70)

C3,

(0.9

4)C

4

09(0

.42)

C1,

(0.3

6)C

2(0

.36)

C3,

(0.6

0)C

4

18(0

.75)

C5

1h10

(0.5

0)C

1, (0

.47)

C2

(0.5

5)C

3, (0

.50)

C4

19(0

.79)

C1,

(0.7

9)C

2(1

.11)

C3,

(1.0

5)C

4

18(0

.81)

C1,

(0.7

2)C

2(0

.75)

C3,

(1.0

0)C

4

15(0

.71)

C1,

(0.6

0)C

2(0

.60)

C3,

(1.0

0)C

4

16(0

.66)

C5

1i09

(0.4

5)C

1, (0

.42)

C2

(0.5

0)C

3, (0

.45)

C4

14(0

.58)

C1,

(0.5

8)C

2(0

.82)

C3,

(0.7

7)C

4

08(0

.36)

C1,

(0.3

2)C

2(0

.33)

C3,

(0.4

4)C

4

18(0

.85)

C1,

(0.7

2)C

2(0

.72)

C3,

(1.2

0)C

4

23(0

.95)

C5

1j18

(0.9

0)C

1, (0

.85)

C2

(1.0

0)C

3, (0

.90)

C4

08(0

.33)

C1,

(0.3

3)C

2(0

.47)

C3,

(0.4

4)C

4

11(0

.50)

C1,

(0.4

4)C

2(0

.45)

C3,

(0.6

1)C

4

12(0

.57)

C1,

(0.4

8)C

2(0

.48)

C3,

(0.8

0)C

4

10(0

.41)

C5

C1

2024

2221

00

C2

2124

2525

00

C3

1817

2425

00

C4

2018

1815

00

C5

0000

0000

24

Act

ivity

inde

x =

Inhi

bitio

n zo

ne o

f the

sam

ple

/ Inh

ibiti

on z

one

of th

e st

anda

rd

For a

ntib

acte

rial a

ctiv

ity: C

1 = A

mox

icill

in, C

2 = C

ipro

flox

acin

, C3 =

Cep

hale

xin,

C4 =

Ery

thro

myc

in.

For a

ntifu

ngal

activ

ity: C

5 = G

rese

oful

vin.



SECTION-II

SYNTHESIS AND BIOLOGICAL SCREENING OF N’-ARYLMETHYL-5-

BROMO-3-CHLOROBENZO[b]THIOPHENE-2-CARBOHYDRAZIDES.

Aminomethyl derivatives of heterocyclic compounds are associated with diverse

biological activities. These finding prompted us to synthesize some representative

aminomethyl derivative bearing benzo[b]thiophene moiety obtained by selective reduction

of (imine group) Schiff’s bases with sodium borohydride in controlled experimental

condition as shown in the reaction scheme.






antifungal activity towards A. niger at a concentration of 40 μg/ml. The biological activities

of the synthesized compounds were compared with standard drugs.

S

BrCl

NH

O

N

R

S

BrCl

NH

O

NH

R

Anh. NaBH4








[A] General procedure for the preparation of (E)-N’-Arylmethine-5-bromo-3-


See, Part-A, Part-1, Section-I Experimental Section [D].

[B] General procedure for the preparation of N’-Arylmethyl-5-bromo-3-


To a (E ) -N’ -ary lmethine-5-bromo-3-chlorobenzo[b ] th iophene-2-

carbohydrazides (0.01 mole) in tetrahydrofuran (25 ml), sodium borohydride (0.57 gm,

0.15 mole) was added over a period of 30 minutes at temperature 5-10 oC. The reaction

mixture was then stirr for 3 hours at room temp. After adding water the product was

extracted with ether. The ether extract was washed with water until neutral, then dried

over anhydrous Na2SO4 and finally the ether was evaporated to give solid product. The

physical constants of the product are recorded in Table-2a.

[C] Biological screening of N’-Arylmethyl-5-bromo-3-chlorobenzo[b]thiophene-

2-carbohydrazides.

Antimicrobial testing was carried out as described in Part-A, Part-1, Section-I,

Antimicrobial activity. The zone of inhibition of the test compounds are recorded in

Table 2b.



Table-2a: Physical constants of N’-Arylmethyl-5-bromo-3-chlorobenzo[b]-

thiophene-2-carbohydrazides.

S

BrCl

O

NH NH

R

Sr.No.

SubstitutionR


M.P.oC

Yield%


C H N

2a H C16H12BrClN2OS395.70 135-137 58 48.56

48.423.063.12

7.087.01


425.72 110-112 70 47.9648.03

3.313.48

6.586.49


440.69 242-243 61 43.6143.53

2.522.63

9.539.41

2d 4-Cl C16H11BrCl2N2OS430.14 200-202 65 44.68

44.602.582.54

6.516.67


455.75 170-171 78 47.4447.31

3.543.62

6.156.08


455.75 183-184 69 47.4447.35

3.543.59

6.156.21


425.72 164-166 52 47.9648.06

3.313.43

6.586.52

2h 2-OH C16H12BrClN2O2S411.70 168-170 56 46.68

46.612.943.06

6.806.69


440.69 231-233 74 43.6143.55

2.522.60

9.539.39

2j 3-Br C16H11Br2ClN2OS474.59 159-161 68 40.49

40.422.342.41

5.905.82

Studies on Heterocyclic… 47

Arylam inomethyl Derivatives…

SPECTRAL STUDY

IR spectra of N’-(4-Chloroxyphenyl)methyl-5-bromo-3-chlorobenzo[b]thiophene-2-

carbohydrazide.

5007501000125015001750200025003000350040001/cm

0

15

30

45

60

75

90

%T

3423.76

3263.66 32

50.16

3067.88

2918.40

2850.88

2837.38

1665.59

1642.44

1534.42

1513.21

1488.13

1465.95

1444.73

1392.65

1350.22

1306.82

1295.24 1284.63 12

00.73

1154.43

1100.43

1087.89

1049.31

1013.63948.04

893.07

877.64

840.03

814.95

736.83

546.84

413.74

Instrument: Shimadzu FTIR-8400 using KBr DRS techniques. The percentage transmittance is

given in cm-1 and frequency range is between 400-4000cm-1.


Alkane -CH3



C-H i.p.d (asym) 1465

C-H o.o.d (sym) 1392

Aromatic

C-H str. 3067

C=C (skeleton) 1488,1513,1534


C-H o.p bending 840

Amide -NH-NH-C=O str. 1665

Amine -N-H 3263, 3250

Halide -C-Cl-C-Br

736814

S

BrCl

O

NH NHCl



1H NMR spectra of N’-(4-Methoxyphenyl)methyl-5-bromo-3-chlorobenzo[b]-

thiophene-2-carbohydrazide.

Instrument: BRUKER 400 MHz (Avance - II), Internal reference: TMS, Solvent: DMSO d6.

S

Cl

O

NH NHBrO

CH3a

a'

b

b'

c

de

Sr.No.


Relative No.of Protons M ultiplicity Inference J value

in Hz


2 4.02 2H singlet -N-CH2-Ar -

3 6.86-6.88 2H doublet Ar-Hb,b' 8.52

4 7.33-7.35 2H doublet Ar-Ha,a' 8.52

5 7.43-7.47 1H triplet Ar-Hd 7.88

6 7.69-7.71 1H doublet Ar-Hc 7.6

7 7.87-7.85 1H doublet Ar-He 8.08

8 7.93 1H singlet(b) -NH -

9 9.73 1H singlet(b) -NH -



Inst

rum

ent:

Shi

mad

zu G

C-M

S Q

P-20

10, D

I-pr

obe,

EI-

met

hod.

EI-

Mas

s spe

ctra

of (

E)-

N’-

(4-C

hlor

ophe

nyl)

met

hine

-5-b

rom

o-3-

chlo

robe

nzo[

b] -t

hiop

hene

-2-c

arbo

hydr

azid

e.

SCl

ONHNH

Br

Cl

M. W

t. =

430

.14



EI-

Mas

s spe

ctra

of (

E)-

N’-

(4-M

etho

xyph

enyl

)met

hine

-5-b

rom

o-3-

chlo

robe

nzo[

b] -t

hiop

hene

-2-c

arbo

hydr

azid

e.

Inst

rum

ent:

Shi

mad

zu G

C-M

S Q

P-20

10, D

I-pr

obe,

EI-

met

hod.

SCl

ONH

NH

Br

OC

H3

M. W

t. =

425

.72



Tabl

e-2b

: Ant

imic

robi

al a

ctiv

ity

of N

’-A

rylm

ethy

l-5-

brom

o-3-

chlo

robe

nzo[

b]th

ioph

ene-

2-ca

rboh

ydra

zide

s.

Sr.

No.

Ant

ibac

teria

l Act

ivity

Ant

ifung

al A

ctiv

ity

S. a

ureu

sS.

epi

derm

idis

E. c

oli

P. a

erug

inos

aA

. nig

er

2a15

(0.7

5)C

1, (0

.71)

C2

(0.8

3)C

3, (0

.75)

C4

12(0

.50)

C1,

(0.5

0)C

2(0

.70)

C3,

(0.6

6)C

4

18(0

.81)

C1,

(0.7

2)C

2(0

.75)

C3,

(1.0

0)C

4

19(0

.90)

C1,

(0.7

6)C

2(0

.76)

C3,

(1.2

6)C

4

11(0

.45)

C5

2b10

(0.5

0)C

1, (0

.47)

C2

(0.5

5)C

3, (0

.50)

C4

16(0

.66)

C1,

(0.6

6)C

2(0

.94)

C3,

(0.8

8)C

4

09(0

.40)

C1,

(0.3

6)C

2(0

.37)

C3,

(0.5

0)C

4

16(0

.76)

C1,

(0.6

4)C

2(0

.64)

C3,

(1.0

6)C

4

18(0

.75)

C5

2c20

(1.0

0)C

1, (0

.95)

C2

(1.1

1)C

3, (1

.00)

C4

21(0

.87)

C1,

(0.8

7)C

2(1

.23)

C3,

(1.1

6)C

4

16(0

.72)

C1,

(0.6

4)C

2(0

.66)

C3,

(0.8

8)C

4

12(0

.57)

C1,

(0.4

8)C

2(0

.48)

C3,

(0.8

0)C

4

15 (0

.62)

C5

2d14

(0.7

0)C

1, (0

.67)

C2

(0.7

7)C

3, (0

.70)

C4

17(0

.70)

C1,

(0.7

0)C

2(1

.00)

C3,

(0.9

4)C

4

13(0

.59)

C1,

(0.5

2)C

2(0

.54)

C3,

(0.7

2)C

4

15(0

.71)

C1,

(0.6

0)C

2(0

.60)

C3,

(1.0

0)C

4

23(0

.95)

C5

2e09

(0.4

5)C

1, (0

.42)

C2

(0.5

0)C

3, (0

.45)

C4

11(0

.45)

C1,

(0.4

5)C

2(0

.64)

C3,

(0.6

1)C

4

14(0

.63)

C1,

(0.5

6)C

2(0

.58)

C3,

(0.7

7)C

4

13(0

.61)

C1,

(0.5

2)C

2(0

.52)

C3,

(0.8

6)C

4

16(0

.66)

C5

2f12

(0.6

0)C

1, (0

.57)

C2

(0.6

6)C

3, (0

.60)

C4

13(0

.54)

C1,

(0.5

4)C

2(0

.76)

C3,

(0.7

2)C

4

21(0

.95)

C1,

(0.8

4)C

2(0

.87)

C3,

(1.1

6)C

4

09(0

.42)

C1,

(0.3

6)C

2(0

.36)

C3,

(0.6

0)C

4

14(0

.58)

C5



2g19

(0.9

5)C

1, (0

.90)

C2

(1.0

5)C

3, (0

.95)

C4

10(0

.41)

C1,

(0.4

1)C

2(0

.58)

C3,

(0.5

5)C

4

11(0

.50)

C1,

(0.4

4)C

2(0

.45)

C3,

(0.6

1)C

4

20(0

.95)

C1,

(0.8

0)C

2(0

.80)

C3,

(1.3

3)C

4

18(0

.75)

C5

2h11

(0.5

5)C

1, (0

.52)

C2

(0.6

1)C

3, (0

.55)

C4

17(0

.70)

C1,

(0.7

0)C

2(1

.00)

C3,

(0.9

4)C

4

14(0

.63)

C1,

(0.5

6)C

2(0

.58)

C3,

(0.7

7)C

4

13(0

.61)

C1,

(0.5

2)C

2(0

.52)

C3,

(0.8

6)C

4

20(0

.83)

C5

2i13

(0.6

5)C

1, (0

.62)

C2

(0.7

2)C

3, (0

.65)

C4

21(0

.87)

C1,

(0.8

7)C

2(1

.23)

C3,

(1.1

6)C

4

08(0

.36)

C1,

(0.3

2)C

2(0

.33)

C3,

(0.4

4)C

4

16(0

.76)

C1,

(0.6

4)C

2(0

.64)

C3,

(1.0

6)C

4

13(0

.54)

C5

2j16

(0.8

0)C

1, (0

.76)

C2

(0.8

8)C

3, (0

.80)

C4

12(0

.50)

C1,

(0.5

0)C

2(0

.70)

C3,

(0.6

6)C

4

17(0

.77)

C1,

(0.6

8)C

2(0

.70)

C3,

(0.9

4)C

4

10(0

.47)

C1,

(0.4

0)C

2(0

.40)

C3,

(0.6

6)C

4

15 (0

.62)

C5

C1

2024

2221

00

C2

2124

2525

00

C3

1817

2425

00

C4

2018

1815

00

C5

0000

0000

24

Act

ivity

inde

x =

Inhi

bitio

n zo

ne o

f the

sam

ple

/ Inh

ibiti

on z

one

of th

e st

anda

rd

For a

ntib

acte

rial a

ctiv

ity: C

1 = A

mox

icill

in, C

2 = C

ipro

flox

acin

, C3 =

Cep

hale

xin,

C4 =

Ery

thro

myc

in.

For a

ntifu

ngal

activ

ity: C

5 = G

rese

oful

vin.



REFERENCES

1. B. S. Holla, M. K. Shivananda, S. Shenoy, G. Antony, Boll. Chim. Farm., 137(7),233-238 (1998).

2. A. S. Murray, Chemical Review, 26, 297-338 (1940).3. E. C. Creencia, K. Taguchi, T. Horaguchi, J. Het. Chem., 45(3), 837-843 (2008).4. D. Bleger, D. Kerher, F. Mathevet, G. Schull, A. Huard, L. Douillard, F. Charra,

Angew. Chemie, Int. Ed., 46(39), 7404-7407 (2007).5. U. K. Roy, S. Roy, Tet. Lett., 48(40), 7177-7180 (2007).6. L. B. Pierre, G. James, D. B. Murray, S. Jurgen, J. Org. Chem., 70(15), 5869-

5879 (2005).7. J. G. Amanda, O. P. Brian, J. M. Mark, J. Org. Chem., 69(25), 8739-8744 (2004).8. L. Somogyi, J. Het. Chem., 44(6), 1235-1246 (2007).9. M. Zintl, F. Molnar, T. Urban, V. Bernhart, B. Rieger, Angew. Chemie, Int. Ed.,

47(18), 3458-3460 (2008).10. R. H. Mehta, S. Shah, R. Vyas, J. Indian. Chem. Soc., 69(9), 590-592 (1992).11. A. K. Khalafallah, M. E. Hassan, Aswan Sci. Technol. Bull., 12, 82-90 (1991).12. P. Perumal, R. R. Nair, V. Gudaparthi, E. H. Subramanian, S. K. Sridhar, Eur. J.

Med. Chem., 40(2), 225-229 (2005).13. M. D. Deshmukh, A. G. Doshi, Orient. J. Chem., 11(1), 85-86 (1995).14. W. Yangang, Y. Wenfa, Y. Jun., L. Aihong, Wuhan Daxue Xuebao Ziran Kexueban,

42(2), 191-194 (1996).15. A. Das, E. J. Lien, S. Ren, M. D. Trousdale, Antivir. Research, 44(3), 201-208

(1999).16. Y. Ali, A. Al-Rawi, M. S. Al-Rawi, Dirasat Nat. Eng. Sci., 25(1), 94-99 (1998).17. B. S. Holla, M. Ashok, B. Poojary, Eur. J. Med. Chem., 42(8), 1095-1101 (2007).18. T. Pandey, R.V. Singh, Metal Based drug, 7(1), 7-16 (2000).19. M. T. Omar, Egypt J. Pharm. Sci., 38(4-6), 271-280 (1998).20. Z. H. Chohan, M. Praveen, Metal Based Drugs, 6(3), 149-152 (1999).21. Z. H. Chohan, S. Kausar, Chem. Pharm., Bull., 41(5), 951-953 (1993).22. J. Das, A. K. Singh, Indian J. Chem.: B, 33(7), 615-617 (1994).23. A. Solankee, P. Mistry, V. M. Patel, Orient. J. Chem., 13(3), 289-292 (1997).24. T. Ram, R. Tyagi, B. Goel, K. K. Saxena, V. K. Shrivastava, A. Kumar, Indian

Drugs, 35(4), 216-221 (1998).25. A. Cascaval, G.-Zaharia Stocia, I. Berdan, RO 106403, pp. 3 (1993).26. S. N. Pandeya, D. Sriram, Acta Pharm. Turc., 40(1), 33-38 (1998).27. K. N. Venugopal, G. K. Rao, P. N. S. Pai, J. Pharmaco. Toxicol., 2(3), 248-255

(2007).



28. N. Ergenc, N. Ulusoy, G. Capan, G. O. Sanis, M. Kiraz,; Arch. Pharm., 329(8-9),427-430 (1996).

29. B. Yadav, S. S. Sangapure, J. Indian. Chem. Soc., 80(3), 187-189 (2003).30. B. S. Holla, K. V. Malini, B. S. Rao, B. K. Sarojini, N. S. Kumari, Eur. J. Med.

Chem., 38(3), 313-318 (2003).31. R. V. Chambhare, B. G. Khadse, A. S. Bodbe, R. H. Bahekar, Eur. J. Med. Chem.,

38(1), 89-100 (2003).32. M. S. Karthikeyan, B. S. Holla, Monatshefte fuer chemie, 139(6), 691-696 (2008).33. K. M. Thaker, V. V. Kachhadia, H. S. Joshi, Indian J. Chem.: B, 42(6), 1544-

1547 (2003).34. S. L. Vasoya, M. R. Patel, S. V. Dobaria, H. S. Joshi, Indian J. Chem.: B, 44(2),

405-409 (2005).35. T. K. Dave, D. H. Purohit, J. D. Akbari, H. S. Joshi, Indian J. Chem.: B, 46(2),

352-356 (2007).36. T. K. Dave, S. D. Tala, J. D. Akbari, M. F. Dhaduk, H. S. Joshi, Int. J. syntheses

and charact., 1(2), 147-152 (2008).37. A. L. Barry, P. D. Hoeprich, M. A. Saubolle, The antimicrobial susceptibility

test: Principle and practices, edited by Lea & Febiger, (Philadelphia), pp. 236(1976).

Part-Part-Part-Part-Part-AAAAA(Part-II)(Part-II)(Part-II)(Part-II)(Part-II)

Studies on Oxadiazole Derivatives


Oxadiazole derivatives...

INTRODUCTION

Oxadiazoles belong to an important group of heterocyclic compounds having a

toxophoric –N=C-O- linkage. It is well doccumented that oxadiazole system contains

the following members which are numbered by designating the hetero atoms at particular

position.

1,3,4-Oxadiazole is a heterocyclic molecule with oxygen atom at 1 and two

nitrogen atoms at 3 and 4 position. 1,3,4-Oxadiazole is a thermally stable aromatic

molecule1. They have been known for about 80 years it is only in the last decade that

investigations in this field have been intensified. This is because of large number of

applications of 1,3,4-oxadiazoles in the most diverse areas viz. drug synthesis, dye stuff

industry, heat resistant materials, heat resistant polymers and scintillators, reviews of the

relevant literature prior to 1965 are available2.

SYNTHETIC ASPECT

Most 1,3,4-oxadiazoles are best obtained by synthesis from acyclic precursors.

Such reactions are ‘one bond’ or ‘two bond’ cyclization. Different methods for the

synthesis have been cited in literature.3-8

1. Hansong Chen et al.9 have synthesized oxadiazoles by the reaction of hydrazide

and aromatic acid in presence of POCl3.

2. D. Ramesh and B. Sreenivasan10 have synthesized 1,3,4-oxadiazoles from

semicarbazide in presence of POCl3.

ON

N

O

N

NO

N NO

N N

( 1 ) ( 2 ) ( 3 ) ( 4 )

NH

N

O

NH NH2

Cl

+ RO

OH

POCl3

NH

N

N N

O R

Cl



3. K. Mogilaiah and B. Sakram11 have prepared 1,3,4-oxadiazoles from

acetophenone-2-trifluoromethyl-1,8-naphthyridine-3-carbonylhydrazone in the

presence of acetic anhydride.

4. Yu Yuve have reported microwave assisted synthesis protocol with 91 % of the

yield12.

5. L. Somogyi13 synthesized 1,3,4-oxadiazoles from several steps, from aryl

hydrazide and aryl aldehyde.

6. Silica coated with sulfuric acid as a catalyst used for the rapid and ecofriendly

synthesis of 1,3,4-oxadiazoles at ambient temperature by M. Dabiri et al14.

NNH

CH3

O

NHNH

CH3

O

R

R1

NNH

CH3

R

R1

O

NN

CH3

POCl3

4 h

N N CF3

NH

O

N CH3

Ar

Ac2O

N N CF3

N

O

N

Ar

CH3

CH3

O

R NH

O

NH2+

R1

O

OH

POCl3

MW, 12 min O

N N

R R1

RNH

O

NH2

+ R1O

+ Ac Cl

O

N N

R R1

R C(OEt)3 + R1

NH

O

NH2

Silica, H2SO4

RT, 10 min O

N N

R R1



7. Green chemistry and one-pot, solvent-free using microwave mediated synthesis

of 1,3,4-oxadiazoles were reported by V. Polshettiwar15


2,5-Disubstituted-1,3,4-oxadiazole derivatives have been tested for various

pharmacological activities, which have been summarized as under.

1. Antibacterial16

2. Antiinflammatory17

3. Analgesic18

4. Antiviral and anticancer19

5. Antihypertensive20

6. Anticonvulsant21

7. Antiproliferative22

8. Cardiovascular23

9. Herbicidal24

10. Hypoglycemic25

11. Hypnotic and sedative26

12. MAO inhibitor27

13. Insecticidal28

Some 1,3,4-oxadiazoles possessing insecticidal activity were synthesized by

Xiumian Zheng et al.29 Takahiko Inoue et al.30 have reported oxadiazoles useful as prolyl

aminopeptidase inhibitor. H. Liszkiewicz. et al.31 have screened oxadiazoles for their

antimicrobial activity.

Virginija Jakubkiene et al.32 have screened 1,3,4-oxadiazoles for their

antiinflammatory activity. Song Cao et al.33 have investigated some oxadiazoles possessing

insecticidal activity. S. Guniz Kucukguzel et al.34 have discovered oxadiazole derivatives

and reported their antimycobacterial activity. Ali Almasired et al.35 have prepared 1,3,4-

R C(OEt)3 + R1

NH

O

NH2O

N N

R R1MW

80 °C, 10 min



oxadiazoles (5) as anticonvulsant agent. Meria Grazia Mamolo et al.36 have synthesized

3-substituted-5-(pyridine-4-yl)-3H-1,3,4-oxadiazole-2-one (6) and studied their

antimycobacterial activity.

Sahin G. et al.37 have reported antimicrobial activity of oxadiazole derivatives.

Maslat A. O. et al.38 have documented antibacterial, antifungal and genotixic activity of

bis-1,3,4-oxadiazole derivatives. Mida Malvina Buruliene et al.39 have investigated some

oxadiazoles as anti-inflammatory agents. K. Subrahmanya Bhat et al.40 have prepared

new fluorine containing 1,3,4-oxadiazoles (7) and reported them as potential antibacterial

and anticancer agents. T. P. Mohan et al.41 have synthesized 2,5-disubstituted-1,3,4-

oxadiazole derivatives (8) and screened for their insecticidal activity.

Recently, Ronald Kim et al.42 have discovered oxadiazole derivatives useful as

protease inhibitors. Mohd Amir and Kumar Shikha43 have documented antiinflammatory,

analgesic and ulserogenic activity of some newly synthesized oxadiazoles. Ali A. et al.44

have investigated some oxadiazole derivatives possessing antimicrobial and anti-HIV -

1-activity. Sherif A. et al.45 have reported oxadiazoles as potential antitumor and anti-

HIV agents. Afshin Zarghi et al.46 have synthesized substituted-5-(2-benzyloxyphenyl)-

N

O

N

O

F

NH2 N

O

N N

O

CH3

( 5 ) ( 6 )

N

O

N

F

Cl Cl

CH3O

N N

O

F

R

( 7 ) ( 8 )



1,3,4-oxadiazoles (9) possessing anticonvulsant activity. Mahamud Tareq et al.47 have

synthesized 2,5-disubstituted-1,3,4-oxadiazoles (10) useful as tyrosinase inhibitors.


Synthesis and pharmacological evaluation of 2-(3',5'-dichlorobenzo[b]thiophen-

2'-yl)-5-aryl-1,3,4-oxadiazoles (11) were reported by K. M. Thaker48.

Thus with an effort to capitalize the biological potential of the heterocyclic system

and to provide more interesting compounds for biological screening, we have under

taken the synthesis of several oxadiazoles which has been described as under.

SECTION-I: SYNTHESIS AND BIOLOGICAL SCREENING OF 2-(5-BROMO-

3-CHLOROBENZO[b]THIOPHEN-2-YL)-5-ARYL-1,3,4-

OXADIAZOLES.

N

O

N

O

NH2

FN

N

O

N

Br

( 9 ) ( 10 )

S

ClCl N

O

N

R( 11 )



SECTION-I

SYNTHESIS AND BIOLOGICAL SCREENING OF 2-(5-BROMO-3-

CHLOROBENZO[b]THIOPHEN-2-YL)-5-ARYL-1,3,4-OXADIAZOLES.

Synthesis of 1,3,4-oxadiazole derivatives has attracted considerable attention in

view of therapeutic applications. Looking to this, the synthesis of 1,3,4-oxadiazoles

was undertaken by the condensation of different aromatic acid with 5-bromo-3-

chlorobenzo[b]thiophene-2-carbohydrazide in presence of phosphorous oxychloride,

as shown in Reaction Scheme.








S

BrCl

O

N NS

BrCl

O

NH NH2

R - COOH

POCl3

R








[A] Preparation of 5-Bromo-3-chlorobenzo[b]thiophene-2-carbohydrazide

See, Part-A, Part-1, Section-I, Experimental section [C].

[B] General procedure for the preparation of 2-(5-Bromo-3-chlorobenzo[b]-

thiophen-2-yl)-5-aryl-1,3,4-oxadiazoles.

A mixture of 5-bromo-3-chlorobenzo[b]thiophene-2-carbohydrazide (1.53 gm,

0.005 mole) and substituted benzoic acid (0.005 mole) in phosphorous oxychloride (10

ml) was refluxed for 6 hr on oil bath. The content was cooled, poured onto crushed ice

and neutralized with sodium bicarbonate solution. Separated solid were filter and dried

in vacuo. Crude product was isolated and crystallized from suitable solvent to give

analytically pure product. The physical constants of the product are recorded in

Table-3a.

[C] Biological screening of 2-(5-Bromo-3-chlorobenzo[b]thiophen-2-yl)-5-aryl-

1,3,4-oxadiazoles.



Table 3b.



Table-3a: Physical constants of 2-(5-Bromo-3-chlorobenzo[b]thiophen-2-yl)-

5-aryl-1,3,4-oxadiazoles.

S

BrCl

O

N N

R

Sr.No.

SubstitutionR


M.P.oC

Yield%


C H N

3a H C16H8BrClN2OS391.66 193-194 70 49.06

48.932.062.15

7.157.11


421.69 168-170 83 48.4248.34

2.392.50

6.646.58


436.66 256-258 86 44.0144.08

1.621.51

9.629.66

3d 4-Cl C16H7BrCl2N2OS426.11 201-203 68 45.10

45.031.661.79

6.576.52


451.72 212-214 72 47.8647.78

2.682.73

6.206.09


451.72 187-188 59 47.8647.77

2.682.76

6.206.14


421.69 161-163 69 48.4248.30

2.392.49

6.646.53

3h 2-OH C16H8BrClN2O2S407.66 189-190 63 47.14

47.011.982.06

6.876.93


436.66 238-240 81 44.0144.10

1.621.53

9.629.57

3j 3-Br C16H7Br2ClN2OS470.56 166-168 66 40.84

40.791.501.58

5.955.88


Oxadiazole Derivatives…

SPECTRAL STUDY

IR spectra of 2-(5-Bromo-3-chlorobenzo[b]thiophen-2-yl)-5-(4-methoxyphenyl)-1,3,4-oxadiazole.

5007501000125015001750200025003000350040001/cm

0

15

30

45

60

75

90

%T3066.92

3013.87

2950.22

2849.92

1611.58

1588.43

1493.92

1440.87

1306.82

1263.42

1176.62

1087.89

1021.34

921.04

836.17

780.23

739.73

461.97

4-OMe-oxadiazole




Alkane -CH3





Aromatic

C-H str. 3013



C-H o.p bending 836

Oxadiazole

-C=N- str. 1611

=N-N= 1176

-C-O-C- 1021, 1263

Halide -C-Cl-C-Br

739780

S

BrCl

O

N N

O

CH3



1H NMR spectra of 2-(5-Bromo-3-chlorobenzo[b]thiophen-2-yl)-5-(4-methoxy-

phenyl)-1,3,4-oxadiazole.


Sr.No.



in Hz


2 7.09-7.11 2H dd Ar-Ha,a' 8.02 & 0.9

3 7.50-7.53 1H triplet Ar-Hd 7.88

4 7.89-7.92 1H doublet Ar-He 8.72

5 8.07-8.10 3H multiplet Ar-Hb,b'+Hc -

S

BrCl

O

N N

O

CH3a

a'

b

b'

c

de



Inst

rum

ent:

Shi

mad

zu G

C-M

S Q

P-20

10, D

I-pr

obe,

EI-

met

hod.

EI-

Mas

s spe

ctra

of 2

-(5-

Bro

mo-

3-ch

loro

benz

o[b]

thio

phen

-2-y

l)-5

-(4-

met

hoxy

phen

yl)-

1,3,

4-ox

adia

zole

.

S

Br

Cl

O NN

OCH

3

M. W

t. =

421

.69



Inst

rum

ent:

Shi

mad

zu G

C-M

S Q

P-20

10, D

I-pr

obe,

EI-

met

hod.

EI-

Mas

s spe

ctra

of 2

-(5-

Bro

mo-

3-ch

loro

benz

o[b]

thio

phen

-2-y

l)-5

-phe

nyl-

1,3,

4-ox

adia

zole

.

S

Br

Cl

O NN

M. W

t. =

391

.66



Tabl

e-3b

: Ant

imic

robi

al a

ctiv

ity

of 2

-(5-

Bro

mo-

3-ch

loro

benz

o[b]

thio

phen

-2-y

l)-5

-ary

l-1,

3,4-

oxad

iazo

les.

Sr.

No.

Ant

ibac

teria

l Act

ivity

Ant

ifung

al A

ctiv

ity

S. a

ureu

sS.

epi

derm

idis

E. c

oli

P. a

erug

inos

aA

. nig

er

3a10

(0.5

0)C

1, (0

.47)

C2

(0.5

5)C

3, (0

.50)

C4

19(0

.79)

C1,

(0.7

9)C

2(1

.11)

C3,

(1.0

5)C

4

18(0

.81)

C1,

(0.7

2)C

2(0

.75)

C3,

(1.0

0)C

4

14(0

.66)

C1,

(0.5

6)C

2(0

.56)

C3,

(0.9

3)C

4

15 (0

.62)

C5

3b13

(0.6

5)C

1, (0

.62)

C2

(0.7

2)C

3, (0

.65)

C4

23(0

.95)

C1,

(0.9

5)C

2(1

.35)

C3,

(1.2

7)C

4

12(0

.54)

C1,

(0.4

8)C

2(0

.50)

C3,

(0.6

6)C

4

21(1

.00)

C1,

(0.8

4)C

2(0

.84)

C3,

(1.4

0)C

4

09(0

.37)

C5

3c09

(0.4

5)C

1, (0

.42)

C2

(0.5

0)C

3, (0

.45)

C4

13(0

.54)

C1,

(0.5

4)C

2(0

.76)

C3,

(0.7

2)C

4

17(0

.77)

C1,

(0.6

8)C

2(0

.70)

C3,

(0.9

4)C

4

08(0

.38)

C1,

(0.3

2)C

2(0

.32)

C3,

(0.5

3)C

4

19(0

.79)

C5

3d21

(1.0

5)C

1, (1

.00)

C2

(1.1

6)C

3, (1

.05)

C4

11(0

.45)

C1,

(0.4

5)C

2(0

.64)

C3,

(0.6

1)C

4

12(0

.54)

C1,

(0.4

8)C

2(0

.50)

C3,

(0.6

6)C

4

15(0

.71)

C1,

(0.6

0)C

2(0

.60)

C3,

(1.0

0)C

4

09(0

.37)

C5

3e17

(0.8

5)C

1, (0

.81)

C2

(0.9

4)C

3, (0

.85)

C4

20(0

.83)

C1,

(0.8

3)C

2(1

.17)

C3,

(1.1

1)C

4

10(0

.45)

C1,

(0.4

0)C

2(0

.41)

C3,

(0.5

5)C

4

17(0

.80)

C1,

(0.6

8)C

2(0

.68)

C3,

(1.1

3)C

4

11(0

.45)

C5

3f15

(0.7

5)C

1, (0

.71)

C2

(0.8

3)C

3, (0

.75)

C4

08(0

.33)

C1,

(0.3

3)C

2(0

.47)

C3,

(0.4

4)C

4

19(0

.86)

C1,

(0.7

6)C

2(0

.79)

C3,

(1.0

5)C

4

13(0

.61)

C1,

(0.5

2)C

2(0

.52)

C3,

(0.8

6)C

4

08(0

.33)

C5



3g10

(0.5

0)C

1, (0

.47)

C2

(0.5

5)C

3, (0

.50)

C4

16(0

.66)

C1,

(0.6

6)C

2(0

.94)

C3,

(0.8

8)C

4

13(0

.59)

C1,

(0.5

2)C

2(0

.54)

C3,

(0.7

2)C

4

21(1

.00)

C1,

(0.8

4)C

2(0

.84)

C3,

(1.4

0)C

4

12(0

.50)

C5

3h15

(0.7

5)C

1, (0

.71)

C2

(0.8

3)C

3, (0

.75)

C4

08(0

.33)

C1,

(0.3

3)C

2(0

.47)

C3,

(0.4

4)C

4

14(0

.63)

C1,

(0.5

6)C

2(0

.58)

C3,

(0.7

7)C

4

15(0

.71)

C1,

(0.6

0)C

2(0

.60)

C3,

(1.0

0)C

4

23(0

.95)

C5

3i20

(1.0

0)C

1, (0

.95)

C2

(1.1

1)C

3, (1

.00)

C4

12(0

.50)

C1,

(0.5

0)C

2(0

.70)

C3,

(0.6

6)C

4

09(0

.40)

C1,

(0.3

6)C

2(0

.37)

C3,

(0.5

0)C

4

17(0

.80)

C1,

(0.6

8)C

2(0

.68)

C3,

(1.1

3)C

4

18(0

.75)

C5

3j13

(0.6

5)C

1, (0

.62)

C2

(0.7

2)C

3, (0

.65)

C4

19(0

.79)

C1,

(0.7

9)C

2(1

.11)

C3,

(1.0

5)C

4

16(0

.72)

C1,

(0.6

4)C

2(0

.66)

C3,

(0.8

8)C

4

10(0

.47)

C1,

(0.4

0)C

2(0

.40)

C3,

(0.6

6)C

4

17 (0

.70)

C5

C1

2024

2221

00

C2

2124

2525

00

C3

1817

2425

00

C4

2018

1815

00

C5

0000

0000

24

Act

ivity

inde

x =

Inhi

bitio

n zo

ne o

f the

sam

ple

/ Inh

ibiti

on z

one

of th

e st

anda

rd

For a

ntib

acte

rial a

ctiv

ity: C

1 = A

mox

icill

in, C

2 = C

ipro

flox

acin

, C3 =

Cep

hale

xin,

C4 =

Ery

thro

myc

in.

For a

ntifu

ngal

activ

ity: C

5 = G

rese

oful

vin.



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Part-Part-Part-Part-Part-BBBBBStudies on 3-Isopropyl-4-

methoxybenzaldehyde Derivatives

Section-I Section-I Section-I Section-I Section-ISynthesis, Characterization and

Antimicrobial screening of

chalcone Derivatives

71

Chalcone derivatives...

Studies on heterocyclic...

INTRODUCTION

The term Chalcone was first coined by Kostanecki and Tambor1, who did

pioneering work in the synthesis of natural coloring compounds. The chemistry of

chalcones has generated intensive precise studies all over the world, especially interesting

for their biological and industrial applications. Chalcones are colored compounds because

of the presence of the chromophore and auxochromes. They are known as

benzalacetophenones or benzylidene acetophenones.

Chalcones (1) are characterized by their possession of a structure in which two

aromatic rings are linked by an aliphatic three carbon chain.

The chalcones were known from different names like phenyl styryl ketones,

beanzalacetophenone, á -phenyl acrylphenone, ã-oxo-á,ã-diphenyl-á-propylene and á-

phenyl-á-benzoethylene.

SYNTHETIC ASPECT

Claisen-Schmidt condensation

A significant variety of methods are existing in literature for the synthesis of

chalcones. The most convenient way is the Claisen-Schmidt condensation which involves

aryl methyl ketones condensed with aryl aldehyde in presence of alcoholic alkali2.

Alternative synthetic routes for better yield, shorter reaction time to synthesize

new analogs

Various modifications have been applied to Claisen-Schmidt condensation to get

better yield and to synthesize biologically active analogs. Different catalysts have been

reported to increase the yield of the reaction. Microwave synthesis strategies have also

applied to shorten the reaction time. Solid phase synthesis and combinatorial chemistry

has made possible to generate library of chalcone derivatives.

O

( 1 )

72



Solid-Phase Synthesis

During the past two decades, combinatorial chemistry has appeared as one of

the most valuable tools used to accelerate drug discovery and lead optimization processes.

The emergence of this new field has promoted the transfer of solution-phase functional

group transformations to the solid phase.

A. R. Katritzky and coworker have synthesized chalcone derivatives by using

sodium methoxide as a catalyst and Wang resin as a solid support3. Jian Cao and group

reported polymer-supported selenium-induced solid - phase synthesis4. Kamal Ahmed

et al. demonstrated solid-phase synthetic protocol for the chalcone and its derivatives5.

Liquid-Phase Synthesis

In the solid phase synthesis there are some disadvantages of this methodology

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

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

low loading capacity and limited solubility during the reaction progress and the

heterogeneous reaction condition with solid phase6.

S. Yongjia et al. reported soluble polymer-supported synthesis of chalcone

derivatives7. Saravanamurugan and coworker used ZSM-5 catalyst and Liquid phase

synthesis strategy for the derivative preparation8. E. V. Stoyanov and group demonstrated

liquid phase synthesis of 2'-hydroxychalcone derivatives9.

Microwave Assisted Synthesis

Microwave irradiation (MWI) has become an established tool in organic synthesis,

because of the rate enhancements, higher yields and often, improved selectivity with

respect to conventional reaction conditions10.

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

supports have received increasing attention. K. Mogilaiah and coworker describe

synthesis of chalcones with p-toluene sulphonic acid (PTSA) as a catalyst under

microwave irradiation and solvent free conditions11, S. Katade et al. reported the synthesis

of chalcones with microwave irradiation and reported the reaction time decreases and

overall yield of the product was increases12.

73



Catalysts

The other catalysts employed in synthesis and some time with advantages are

alkali of different strength13,14, hydrochloric acid15,16, phosphorous oxychloride17,

piperidine18, anhydrous aluminium chloride19, boron trifluoride20, amino acids21, perchloric

acid22 etc. S. Ryo and group reported synthesis using ruthenium as a catalyst and get

better yield23.

Chalcones can also be synthesized by condensing several other reagents instead

of an aldehyde and ketone.

1. Nencki reaction with cinnamic acid on an aromatic compounds24.

2. Diazo coupling of phenyl diazonium chloride with benzoyl acrylic acid25.

3. Friedel craft’s cinnamoylation26.

4. Fries rearrangement of aryl cinnamates27.

REACTION MECHANISM

The following two mechanisms have been suggested for the synthesis of chalcones.

(A) Base catalysed28

(B) Acid catalysed

(A) Base catalyzed:

Two alternative mechanisms were advanced for the reaction of benzaldehyde

with acetophenone in the presence of a basic catalyst.

CH3

O

R+ OH - CH2

-O

R+ OH2

H

OR1

C+

H

O-

R1

CH2-

O

RC+

H

O-

R1 + C

H

O-

R1 CH2 C

O

R

C

H

O-

R1 CH2 C

O

R + OH2 C

H

OHR1 CH2 C

O

R + OH -

C

H

OHR1 CH2 C

O

R- H2O

CHR1 CH C

O

R

74



The intermediate aldol type products formed readily undergoes dehydration even under

mild condition, particularly when R and R’ are aryl groups.

(B) Acid catalyzed:

The formation of chalcones by the acid catalyzed condensation of acetophenones

and aldehydes has been studied29. The rate of reaction depends on the first power of the

concentration of aldehyde and the Hammet acidity function. Also the condensation step

has been shown to be the rate determining step in this reaction. The following mechanism

seems to be operable.

REACTIVITY OF CHALCONES

The chalcones have been initiated to be useful for the syntheses of multiplicity of

heterocyclic compounds are as under.

1. Chalcones with alkaline hydrogen peroxide in methylene dichloride gives oxirane.30

2. Chalcones with tertiary amine and N-methylmorpholinium salt in acetonitrile by

using o-(diphenyl phosphinyl)hydroxylamine produces aziridines.31

3. Chalcones on reaction with benzamidine hydrochloride under microwave assisted

condition in DMA affords dihydropyrimidines.32

4. Chalcones on reaction with 2-aminopyridine in glacial acetic acid affords

pyridopyrimidines.33

5. Chalcone gives imine derivatives with amine in presence of sulfuric acid as catalyst.34

6. Chalcones on condensation with malononitrile in pyridine forms 2-amino-3-

cyanopyrans.35

CH3

O

RCH2

OH

RH

O

R1 HO+

R1

H

CH2

OH

RH

O+

R1

H

+ R C CH

H

OH

C

R1

OH

R C CH

H

O+

C

R1

OHHOH H

R C C

H

C

R1

O+ H H

R C C

H

C

R1

O

R C CH

H

O+

C

R1

OHHOH

75



7. Chalcones on reaction with thiourea in presence of alkali/acid yields

2- thienopyrimidines.36

8. Chalcones react with P2S5 yielded 2-isothiazolidines.37

9. Chalcones react with sodium nitrile in presence of glacial acetic acid in ethanol

produces 2-1H-pyrimidines.38

10. Isoxazoles39 can be prepared by the treatment of chalcones with hydroxylamine

hydrochloride and sodium acetate.

11. Chalcones on condensation with 2-aminobenzothiazole in ethanol forms 2,3-

dihydro-1,5-benzothiazepine.40

12. Pyrazoline41 and its derivatives can be prepared by the condensation of

chalcones with hydrazine hydrate and acetic acid.

13. Chalcones on treatment with guanidine hydrochloride in presence of alkali

affords 2-amino pyrimidines.42

14. Cyanopyridone derivatives43 can be prepared by the condensation of

chalcones with ethyl cyanoacetate.


Chalcones are potential biocides, some naturally occurring antibiotics and amino

chalcones probably own their genetic activity due to the presence of á ,â-unsaturated

carbonyl group. Some of them are as below.

1. Antitumor44,45

2. Anticancer46,47

3. Antiviral and Antitubercular48

4. Anti HIV49

5. Fungicidal50,51

6. Antiinflammatory52

7. Antimicrobial53,54

8. Antimalarial55,56

9. Insecticidal57,58

10. Antiproliferation59

11. Antiparasitic60

12. Antiplasmodial61

76



Nakahara Kazuhiko et al.62 have synthesized chalcones as carcinogen inhibitors.

Antitubercular agents of chalcone derivatives have been prepared by Lin Yuh-Meei et

al.63 Ko Horng-Huey et al.64 have reported chalcones as anti-inflammatory agents. Some

of the chalcones have been reported for their use for treatment of glaucoma65 and

antifungal,66 aldose reductase inhibitors,67 anticancer68 activities. Satyanarayana M. et

al.69 have synthesized chalcones (2) derivatives as anti hyperglycemic activity.

Hollosy F. et al.70 have prepared some new chalcones as plant derived protein

tyrosine kinase inhibitors as anticancer agents. Meng C. Q. et al.71 have discovered

some novel heteroaryl substituted chalcones as inhibitors of TNF-alpha-induced VCAM-

1 expression. V. K.Ahluwalia et al.72 have noted that 5-cinnamoylchalcones have exposed

good as antibacterial agents. Woo Duck Seo et al.73 have synthesized chalcone derivatives

(3) reported as α-glucosidase inhibitors.

A. Araico and co-workers74 have synthesized chalcone derivatives as inhibitor

of cyclo-oxygenase-2 and 5-lipoxygenase. Alcaraz M. J. et al.75 have described the

role of nuclear factor-kappa-B and hemeoxygenase-1 in the action of an anti-

inflammatory chalcone derivatives in RAW 264.7 cells. Xue C. X. et al.76 documented

chalcones as antimalarial agents. Prem P. Yadav and co-workers77 have synthesized

nitrogen and sulfur containing furanoflavonoids and thiophenylflavonoids which have been

screened for antifungal and antibacterial activity. Opletalova Veronika et al.78 have

synthesized chalcones and screened for their cardiovascular agents. Ko H. H. et al.79

have prepared some new chalcones for potent inhibition of platelet aggregation. Khatib

O

ON

OH

CH3

CH3

R

( 2 )

O

NHSCH3

O

O

R

( 3 )

77



S. et al.80 synthesized some novel chalcones as potent tyrosinase inhibitors. Fu Y. et al.81

have demonstrated chalcones as licochalcone-A. Nerya O. et al.82 have prepared some

new chalcones as potent tyrosinase inhibitors. Sung Hee Lee and co-workers83 have

designed and synthesized chalcones and reported their anti-inflammatory activity. Paula

Boeck, Camila Alves and Bartira Rossi-Bergmann84 have synthesized some newer

chalcone analougs (4) which shows antileishmanial activity.

Xiang Wu et al.85 have synthesized ferrrocenyl chalcones and reported their

antiplasmodial activity. Ban H. S. et al.86 have synthesized some newer chalcones as

inhibition of lipopolysaccharide-induced expression of inducible nitric oxide synthase

and tumor necrosis factor-alpha by 2'-hydroxychalcone derivatives in RAW 264.7 cells.

Simon Feldbaek Nielsen et al.87 have described some chalcone derivatives (5) as

antibacterial agents.

Morever, Aneta Modzelewska et al.88 have prepared novel chalcone and bis

chalcone derivatives having anticancer activity. Seo et al.89 reported the chalcones as a

glucosidase inhibitors.


V. V. Kachhadia synthesized some chalcone derivatives (6) containing

benzo[b]thiophene nucleus90 and reported as antimicrobial and antitubercular agents.

OH

OCH3H3CO

R3

O

R1

R2

R1=NO2, R2=H, R3=HR1=H, R2=F, R3=H( 4 )

O

NH

NN

N

( 5 )

78



K. H. Popat has synthesized some chalcone derivatives (7) and use them as a synthon

for the synthesis of cyanopyran and cyanopyridine derivatives91 as biological active

molecules, thiosemicarbazone and oxirane derivatives as potent antitubercular agents92.

Synthesis, selective antitubercular and antimicrobial inhibitory activity of some

chalcone derivatives (8) have been reported by P. T. Chovatia93. D. H. Vyas94 has

reported Synthesis, antitubercular and antimicrobial activities of some new pyrazoline

and isoxazole derivatives. He also reported synthesis and antimicrobial activity of some

new cyanopiperidinones and cyanopyridones95 and synthesis and biological activity of

some pyrazoline derivatives from chalcones (9)96.

D. J . Paghdar 97 synthes ized chalcone der ivat ives (10) bear ing 4-

(methylsulfonyl)phenyl nucleus and reported as potent antitubercular and antimicrobial

agents Synthesis and evaluation of pharmacological activity of chalcone derivatives (11)

have been reported by M. R. Patel98. Synthesis of some new pyrazolo[3,4-d]pyrimidines

and thiazolo[4,5-d]pyrimidines from arylidine and evaluation of their antimicrobial

activities was reported by J. D. Akbari99.

Morever M. J. Ladani100 reported synthesis and biological study of chalcones

(12) synthesized from 2-(2,4-dichlorophenyl)imidazo[1,2-a]pyridin-3-carbaldehyde.

S

Cl

O

NHO

R O

R

Cl

N

N

O

R

S CH3

OCH3

Br

Br

O

R

( 6 ) ( 7 )

( 8 ) ( 9 )

79



These suitable scrutiny led us to explore chalcone chemistry by synthesizing several

derivatives like Pyrazolines and Cyclohexenones bearing 3-isopropyl-4-methoxy-

benzaldehyde system for curative value, in order to achieving superior therapeutic agents,

this study described as under.

SECTION-I: SYNTHESIS AND BIOLOGICAL SCREENING OF (E)-3-(3-

ISOPROPYL-4-METHOXYPHENYL)-1-ARYL-PROP-2-EN-1-

ONES.

SECTION-II: SYNTHESIS AND BIOLOGICAL SCREENING OF 1-ACETYL-

3-ARYL-5-(3-ISOPROPYL-4-METHOXYPHENYL)PYRAZOLES.

SECTION-III: SYNTHESIS AND BIOLOGICAL SCREENING OF ETHYL 4-ARYL-

6-(3-ISOPROPYL-4-METHOXYPHENYL)-2-OXOCYCLOHEX-3-

ENE-1-CARBOXYLATES.

SO

OCH3

O

R

NN

RCl

O O

N

N

Cl

Cl

OR

( 10 ) ( 11 )

( 12 )

80



SECTION-I

SYNTHESIS AND BIOLOGICAL SCREENING OF (E)-3-(3-ISOPROPYL-4-

METHOXYPHENYL)-1-ARYL-PROP-2-EN-1-ONES

With the biodynamic activities of chalcones and as a fine synthon for different

heterocyclic rings, the awareness has been paying attention on the creation of new

chalcones. With a observation to obtained compounds having better therapeutic activity,

we have synthesized (E)-3-(3-isopropyl-4-methoxyphenyl)-1-aryl-prop-2-en-1-ones by

the condensation of 3-Isopropyl-4-methoxybenzaldehyde with various aromatic ketones

by using alkali as catalyst.


elemental analysis, Infrared, 1H NMR spectroscopy and further supported by mass

spectroscopy.





CH3 CH3

OCH3

O

CH3 CH3

OCH3

O

CH3

O

40% NaOH+R

R

81








[A] General procedure for the preparation of (E)-3-(3-Isopropyl-4-methoxy-

phenyl)-1-aryl-prop-2-en-1-ones.

A solution of substituted acetophenone (0.01 mole) in minimum quantity of ethanol

(10 ml) was added to a 3-isopropyl-4-methoxybenzaldehyde (1.78 gm, 0.01 mole) in

ethanol (10 ml). To this mixture 40 % NaOH (1 ml) as catalyst was added to make it

alkaline. The reaction mixture was then stirred for 24 hr. at room temperature. The

product was isolated by filtration and crystallized from suitable solvent. The physical

constants of the product are recorded in Table-4a.

[B] Biological screening of (E)-3-(3-Isopropyl-4-methoxyphenyl)-1-aryl-

prop-2-en-1-ones.



Table-4b.

82



Table-4a: Physical constants of (E)-3-(3-Isopropyl-4-methoxyphenyl)-1-aryl-prop-

2-en-1-ones.

CH3 CH3

OCH3

O

R

Sr.No.

SubstitutionR


M.P.oC

Yield%


C H N

4a H C19H20O2280.36 148-149 76 81.40

81.337.197.28 -

4b 4-OCH3C20H22O3310.38 122-124 63 77.39

77.257.147.12 -

4c 3-NO2C19H19NO4325.35 165-167 88 70.14

70.025.895.95

4.304.19

4d 4-Cl C19H19ClO2314.80 118-120 60 72.49

72.386.086.17

-

4e 3,4-(OCH3)2C21H24O4340.41 135-137 68 74.09

73.967.117.25

-

4f 2,5-(OCH3)2C21H24O4340.41 129-131 73 74.09

74.017.117.15

-

4g 2-OCH3C20H22O3310.38 106-108 69 77.39

77.297.147.19

-

4h 2-OH C19H20O3296.36 135-137 77 77.00

69.936.806.92

-

4i 4-NO2C19H19NO4325.35 173-175 86 70.14

70.045.896.01

4.304.21

4j 3-Br C19H19BrO2359.25 142-144 65 63.52

63.535.335.24 -


Chalcone Derivatives…

SPECTRAL STUDY

IR spectra of (E)-3-(3-Isopropyl-4-methoxyphenyl)-1-(4-nitrophenyl)-prop-2-en-1-

one.

5007501000125015001750200025003000350040001/cm

0

15

30

45

60

75

90

%T3114.18

3010.98

2976.262904.89

2869.21

1657.87

1565.29

1519.96

1460.16

1419.66

1344.43

1256.67

1214.23

1157.33

1114.89

1029.06

986.62

841.96 819.77

707.90

595.06

461.97

4-NO2-chal




Alkane -CH3





Aromatic

C-H str. 3114

C=C (skeleton) 1519,1565


C-H o.p bending 841

Chalcone -C=O str. 1657

Vinyl -CH=CH- str. 819

-C-O-C- 1029

-N=O (asym.) 1460

CH3 CH3

OCH3

O

N+

O-

O


Chalcone Derivatives…

1H NMR spectra of (E)-3-(3-Isopropyl-4-methoxyphenyl)-1-(4-nitrophenyl)-prop-2-

en-1-one.


Sr.No.


Relative No.of Protons

Multiplicity InferenceJ valuein Hz

1 1.24-1.26 6H doublet Ar-CH(CH3)

27.0

2 3.29-3.36 1H multiplet Ar-CH(CH3)

2-

3 3.91 3H singlet Ar-OCH3

-

4 6.88-6.90 1H doublet Ar-Hf 8.3

5 7.32-7.35 1H doublet -Hd 15.6

6 7.48-7.51 2H multiplet Ar-He + Ar-Hg -

7 7.79-7.83 1H doublet -Hc 15.6

8 8.11-8.14 2H dd Ar-Hb,b' 9.1 & 2.1

9 8.33-8.36 2H dd Ar-Ha,a' 9.1 & 2.1

CH3 CH3

OCH3

O

N+

O-

O

a

a'

b

b'

c

def

g

85



Inst

rum

ent:

Shi

mad

zu G

C-M

S Q

P-20

10, D

I-pr

obe,

EI-

met

hod.

EI-

Mas

s spe

ctra

of (

E)-

3-(3

-Iso

prop

yl-4

-met

hoxy

phen

yl)-

1-(4

-nit

roph

enyl

)-pr

op-2

-en-

1-on

e.

CH

3C

H3

OC

H3

O

N+

O-

O

M. W

t. =

325.

35

86



EI-

Mas

s spe

ctra

of (

E)-

3-(3

-Iso

prop

yl-4

-met

hoxy

phen

yl)-

1-(4

-met

hoxy

phen

yl)-

prop

-2-e

n-1-

one.

Inst

rum

ent:

Shi

mad

zu G

C-M

S Q

P-20

10, D

I-pr

obe,

EI-

met

hod.

CH

3C

H3

OC

H3

O

OC

H3

M. W

t. =

310.

38

87



Tabl

e-4b

: Ant

imic

robi

al a

ctiv

ity

of (E

)-3-

(3-I

sopr

opyl

-4-m

etho

xyph

enyl

)-1-

aryl

-pro

p-2-

en-1

-one

s.

Sr.

No.

Ant

ibac

teria

l Act

ivity

Ant

ifung

al A

ctiv

ity

S. a

ureu

sS.

epi

derm

idis

E. c

oli

P. a

erug

inos

aA

. nig

er

4a16

(0.8

0)C

1, (0

.76)

C2

(0.8

8)C

3, (0

.80)

C4

08(0

.33)

C1,

(0.3

3)C

2(0

.47)

C3,

(0.4

4)C

4

11(0

.50)

C1,

(0.4

4)C

2(0

.45)

C3,

(0.6

1)C

4

14(0

.66)

C1,

(0.5

6)C

2(0

.56)

C3,

(0.9

3)C

4

22(0

.91)

C5

4b10

(0.5

0)C

1, (0

.47)

C2

(0.5

5)C

3, (0

.50)

C4

17(0

.70)

C1,

(0.7

0)C

2(1

.00)

C3,

(0.9

4)C

4

12(0

.54)

C1,

(0.4

8)C

2(0

.50)

C3,

(0.6

6)C

4

14(0

.66)

C1,

(0.5

6)C

2(0

.56)

C3,

(0.9

3)C

4

15 (0

.62)

C5

4c21

(1.0

5)C

1, (1

.00)

C2

(1.1

6)C

3, (1

.05)

C4

13(0

.54)

C1,

(0.5

4)C

2(0

.76)

C3,

(0.7

2)C

4

19(0

.86)

C1,

(0.7

6)C

2(0

.79)

C3,

(1.0

5)C

4

10(0

.47)

C1,

(0.4

0)C

2(0

.40)

C3,

(0.6

6)C

4

16(0

.66)

C5

4d09

(0.4

5)C

1, (0

.42)

C2

(0.5

0)C

3, (0

.45)

C4

20(0

.83)

C1,

(0.8

3)C

2(1

.17)

C3,

(1.1

1)C

4

15(0

.68)

C1,

(0.6

0)C

2(0

.62)

C3,

(0.8

3)C

4

17(0

.80)

C1,

(0.6

8)C

2(0

.68)

C3,

(1.1

3)C

4

20(0

.83)

C5

4e13

(0.6

5)C

1, (0

.62)

C2

(0.7

2)C

3, (0

.65)

C4

18(0

.75)

C1,

(0.7

5)C

2(1

.05)

C3,

(1.0

0)C

4

17(0

.77)

C1,

(0.6

8)C

2(0

.70)

C3,

(0.9

4)C

4

09(0

.42)

C1,

(0.3

6)C

2(0

.36)

C3,

(0.6

0)C

4

12(0

.50)

C5

4f17

(0.8

5)C

1, (0

.81)

C2

(0.9

4)C

3, (0

.85)

C4

09(0

.37)

C1,

(0.3

7)C

2(0

.52)

C3,

(0.5

0)C

4

10(0

.45)

C1,

(0.4

0)C

2(0

.41)

C3,

(0.5

5)C

4

20(0

.95)

C1,

(0.8

0)C

2(0

.80)

C3,

(1.3

3)C

4

11(0

.45)

C5

88



4g15

(0.7

5)C

1, (0

.71)

C2

(0.8

3)C

3, (0

.75)

C4

13(0

.54)

C1,

(0.5

4)C

2

(0.7

6)C

3, (0

.72)

C4

22(1

.00)

C1,

(0.8

8)C

2

(0.9

1)C

3, (1

.21)

C4

18(0

.85)

C1,

(0.7

2)C

2

(0.7

2)C

3, (1

.20)

C4

09(0

.37)

C5

4h20

(1.0

0)C

1, (0

.95)

C2

(1.1

1)C

3, (1

.00)

C4

09(0

.37)

C1,

(0.3

7)C

2

(0.5

2)C

3, (0

.50)

C4

17(0

.77)

C1,

(0.6

8)C

2

(0.7

0)C

3, (0

.94)

C4

23(1

.10)

C1,

(0.9

2)C

2

(0.9

2)C

3, (1

.54)

C4

13(0

.54)

C5

4i10

(0.5

0)C

1, (0

.47)

C2

(0.5

5)C

3, (0

.50)

C4

19(0

.79)

C1,

(0.7

9)C

2

(1.1

1)C

3, (1

.05)

C4

12(0

.54)

C1,

(0.4

8)C

2

(0.5

0)C

3, (0

.66)

C4

11(0

.52)

C1,

(0.4

4)C

2

(0.4

4)C

3, (0

.73)

C4

18(0

.75)

C5

4j09

(0.4

5)C

1, (0

.42)

C2

(0.5

0)C

3, (0

.45)

C4

10(0

.41)

C1,

(0.4

1)C

2

(0.5

8)C

3, (0

.55)

C4

14(0

.63)

C1,

(0.5

6)C

2

(0.5

8)C

3, (0

.77)

C4

14(0

.66)

C1,

(0.5

6)C

2

(0.5

6)C

3, (0

.93)

C4

17 (

0.70

)C5

C1

2024

2221

00

C2

2124

2525

00

C3

1817

2425

00

C4

2018

1815

00

C5

0000

0000

24

Act

ivit

y in

dex

= I

nhib

itio

n zo

ne o

f th

e sa

mpl

e / I

nhib

itio

n zo

ne o

f th

e st

anda

rd

For

ant

ibac

teri

al a

ctiv

ity

: C1 =

Am

oxic

illi

n, C

2 = C

ipro

flox

acin

, C3 =

Cep

hale

xin,

C4 =

Ery

thro

myc

in.

For

ant

ifun

gal a

ctiv

ity

: C5 =

Gre

seof

ulvi

n.

89



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Part-Part-Part-Part-Part-BBBBB(Section-II)(Section-II)(Section-II)(Section-II)(Section-II)

Synthesis, Characterization and


pyrazole derivatives


Pyrazoline derivatives...

INTRODUCTION

The chemistry of pyrazoles has been reviewed by Jarobe in 1967. Pyrazoles

have attracted attention of medicinal chemists for both with regard to heterocyclic

chemistry and the pharmacological activities associated with them. Pyrazole have been

studied extensively because of ready accessibility, diverse chemical reactivity, broad

spectrum of biological activity1 and varieties of industrial applications2.

Pyrazole has three possible tautomeric structures. But 2-pyrazole 1 consist a

unique class of nitrogen containing five member heterocycles.

As evident from the literature in recent years a significant portion of research

work in heterocyclic chemistry has been devoted to pyrazoles containing different alkyl,

aryl and heteroaryl groups as substituents.

SYNTHETIC ASPECT

Different methods are available from the literature for the preparation of 2-

pyrazole derivatives. The most common procedure for the synthesis of 2-pyrazoles is

the reaction of an aliphatic or aromatic hydrazine with α,β-unsaturated carbonyl

compounds.

ALTERNATIVE SYNTHETIC ROUTES FOR IMPROVED YIELD, SHORTER

REACTION TIME AND MILDER CONDITIONS TO SYNTHESIZE NEW

ANALOGS

( 1 )

NH

N

R1

O

R2 NH2 NHR

+ NN

R

R2

R1



Solid-Phase Synthesis

L. L. De3 reported cellulose beads as a new versatile solid support for microwave-

assisted synthesis of pyrazole and isoxazole libraries.

Wang resin supported solid - phase synthesis of pyrazoledicarboxylic acid

derivatives by functionalization of cyanoformate was reported by C. F. Morelli et al.4

Similarly many other solid phase synthesis of pyrazole moiety were reported using

different solid support such as (4-formyl-3-methyoxyphenoxy)methylpolystyrene (FMP)

resin5, polymer-supported vinylsulfone6, Kenner ‘safety catch’ resin7, KOH powder8.

Liquid-Phase Synthesis

X. L. Ren and coworkers9 have synthesized pyrazole derivatives using liquid

phase synthesis strategy.

V. N. Pathak and group reported 3,5-diarylpyrazole synthesis using phase transfer

catalyst10,11, heterocyclic pyrazole was synthesized by the W. C. Shen and coworkers12.

Cellulose NH2

R

O

YO

R1

CSA (cat.)

MW

Cellulose

R

O

Y

O

R1

NHNH2XH

MW

Cellulose NH2

XN R

Y

O R1

N

N

CH(OCH3)2

OH OCN

O

O

O NN

R3

R1

OO

R2

R1

R2 R

CH3N

NHR1

NH2R

NH2NH2 . HCl



Microwave Assisted Synthesis

Microwave irradiation and solvent-free conditions was reported for the rapid

and efficient synthesis by M. A. H. Zahran13.

New Green approaches to the synthesis of pyrazole derivatives were reported

by A. Corradi et al.14

Similarly in literature there are number of the reports that uses the microwave

irradiation for the rapid synthesis, high yield or towards the green approach of the reaction

under solvent free conditions some of them are reported as below.

S. S. Chauhan derives pyrazoles from diaryl 1,3-diketones15, it also prepared

by 1,3-dipolar cycloaddition of diazo compounds to acetylene derivatives16, by

regiospecific synthesis of 5-trifluoromethyl-4,5-dihydropyrazoles17, by microwave-

mediated combinatorial synthesis18, by dry media19, by regiospecific synthesis20, by p-

toluenesulphonic acid21, Microwave synthesis22.

P. D. Sauzem23 reported design and microwave-assisted synthesis of 5-

trifluoromethyl-4,5-dihydro-1H-pyrazoles and one step synthesis of 3,5-disubstituted

pyrazoles were carried out by M. Outirite24.

Catalysts

Many of the organic chemists prefer to use catalyst to get the desire product with

high yield and within sort reaction time and to convert the reaction condition from drastic

to easily operational with some specific catalyst.

R. Ali reported stereoselective synthesis of N-vinyl pyrazoles in solvent-free

conditions using dipotassium hydrogen phosphate powder25, zinc-catalyzed synthesis of

pyrazolines and pyrazoles via Hydrohydrazination were reported by K. Alex26.

R CHO+NH2

XH

MW NR

HOH

N

XR

H

R H

OR1

NH2NHTs, K2CO3

MW, 130 °C

H

R H

NR1

NH TsN

N

R

R1

H



In literature there are numbers of the catalysts are used for the synthesis of pyrazole

system like Conjugate base27, Iodine(III)28, Hafnium chloride29, Tungstophosphoric acid30,

p-toluenesulphonic acid31, Sulfamic acid32, Ytterbium(III)perfluorooctanoate33, Silver(I)34

and organocatalysts35.

REACTION MECHANISM

The following mechanism seems to be operable for pyrazoline by the condensation

of chalcones with hydrazine hydrate.36

Nucleophillic attack by hydrazine at the β-carbon of the α,β-unsaturated carbonyl

system I forms species II, in which the negative charge is mainly accommodated by the

electronegative oxygen atom.

Proton transfer from the nitrogen to oxygen produces an intermediate and which

simultaneously ketonises to ketoamine III. Another intramolecular nucleophillic attack

by the primary amino group of ketoamine on its carbonyl carbon followed by proton

NHNH2

+ CHOH 5 mol % Zn(OTf)2 N

N

CH3

CH3COOH, air NN

CH3

R

R R

R

O

R1R CH-

O

R1

NH2+ NH

R2

NH2NH - R2. .

H+ transfer

RC+

CH-

OH

R1

NHNH

R2

R

O

R1

NHNH

R2

N NH

R1OH

R

R2N N

H

R1

R2

R - H2O

( I ) ( II )

( III ) ( IV )( V )



transfer from nitrogen to oxygen leads ultimately to hydroxyl amine IV. The later with a

hydroxy group and amine group on the same carbon loses water easily to yield the

pyrazolines V.


From the literature survey, it was revealed that 2-pyrazolines are better therapeutic

agents. They possess valuable bioactivities like

1. Antiinflammatory37,38

2. Analgesic39,40

3. Bactericidal41

4. Fungicidal42,43

5. Anticonvulsant and Antidepressant44

6. Pesticidal45,46

7. Antidepressant47

8. Antiamoebic48

9. Insecticidal49

10. Antineoplastic50

11. Herbicidal51

12. Anticonvulsant52

M. K. Shivnanda and co-workers53 have prepared pyrazolines and reported their

antibacterial activity. Antimycotic activity of pyrazoline derivatives 2 have been reported

by Joanna Matysiak and Andrzej Niewiadomy54. J. Almstead et al.55 have prepared

pyrazolines as vascularization agent. T. Z. Gulhan and coworkers56 have prepared

pyrazolines as a hypotensive agent.

R1

R2

NH NH

N

R3

( 2 )



S. Sharma et al.57 have synthesized pyrazolines and tested their anti-inflammatory

activity. Antiamoebic activity of pyrazoline derivatives have been reported by Asha

Budakoti and co-workers58. J. H. Ahn et al.59 have reported as inhibition of cyano-

pyrazoline (3) derivatives as potent antidiabetic agents. T. S. Jeong et al.60 have

synthesized some novel 3,5-diaryl pyrazolines (4) as human acyl-Co A: cholesterol

acyltransferase inhibitors. G. Ucar et al.61 reported pyrazolines as cholinstearase and

selective monoamine oxidase-B inhibitiors for the treatment of parkinson and alzheimer’s

diseases. M. N. Nasr et al.62 have reported the synthesis of newer arylthiazolylpyrazoline

derivatives as anti-inflammatory agents. M. A. Berghot et al.63 have prepared for convergent

synthesis and antibacterial activity of pyrazole and pyrazoline derivatives of diazepam.

N. Gokhan et al.64 have synthesized the pyrazoline derivatives of 1-N-substituted

thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazolines (5) as MAO inhibitors. Mohammad Abid

and Amir Azam65 have synthesized 1-N-substituted cyclized pyrazoline of

thiosemicarbazones (6) and reported as antiamoebic agents. V. Malhotra et al.66 have

documented new pyrazolines as a cardiovascular agents. Antidepressant activity of

pyrazoline derivatives have been reported by Y. R. Prasad and co-worker67.

Abd El-Galil E. Amr et al.68 have synthesized some new 3-substituted

androstano[17,16-c]-5,2-aryl-pyrazolines and reported their antiandrogenic activity. B.

Bizzarri et al.69 have reported in vitro selective anti-helicobacter pylori activity (7) of

( 3 ) ( 4 )

N

N

CNO

NHR

N NH

OH OH

R

R2R1

t - Bu

( 5 ) ( 6 )

NN

S

S

NHR1

R NN R

CH3

Cl



pyrazoline derivatives. Bhat and co-workers70 reported cytotoxic properties of pyrazoline

derivatives. Antibacterial activity of pyrazoline derivatives have been reported by A. M.

Gandhi and co-workers71. B. Shivarama Holla et al.72 have synthesized pyrazolines as

antibacterial agents. S. P. Hiremath et al.73 have synthesized pyrazolines as analgesic,

anti-inflammatory and antimicrobial agents. Rajendra Prasad et al.74 have synthesized

some 1,3,5-triphenyl-2-pyrazolines (8) and 3-(2"-hydroxynaphthalen-1"-yl)-1,5-

diphenyl-2-pyrazolines and reported as antidepressant agents. J. H. M. Lange et al.75

synthesized and reported 3,4-diaryl pyrazoline analogues as potent and selective CB1

cannabinoid receptor antagonists. N. T. Ha- Duong et al.76 have been synthesized some

pyrazole derivatives as inhibitors for the active sites of human liver cytochromes P450

of the 2C subfamily.

X. Zhang and co-workers77 have been prepared pyrazoline derivatives (9) as

potent selective androgen receptor modulators. M. E. Camacho and co-workers78 have

been reported 4,5-dihydro pyrazoles (10) as Inhibitory nNOS activity in rat brain.

F. Chimenti and co-workers79 have been demonstrated a novel series of 1-acetyl-

3-(4-hydroxy-and 2,4-dihydroxyphenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole

derivatives (11) and investigated for the ability to selectively inhibit the activity of

monoamine oxidase (MAO). Y. R. Huang et al.80 have been prepared a series of 4-

alkyl-1,3,5-triarylpyrazoles (12) as ligands for the estrogen receptor. C. D. Cox et al.81

and J. R. Goodell et al.82 have been reported separately some pyrazoline derivatives as

anti-obesity agents by antagonizing CB1 receptors and therapeutic candidates for

NNR2

R

R1

NN

R

R1

( 7 ) ( 8 )

( 9 ) ( 10 )

NH

N

O

NH

R6

R5

R3R2

R1R4

NN

R1

R

NH2

R2



parkinson’s disease. A series of 3-(4-fluorophenyl)-4,5-dihydro-N-[4-(trifluoromethyl)-

phenyl]-4-[5-(trifluoromethyl)-2-pyridyl]-1H-pyrazole-1-carboxamide has been

synthesized and studied for their potent foliar activity against both lepidoptera and

orthoptera insects by P. K. Leonard et al.83 Bruce G. Szczepankiewicz et al.84 have been

prepared some pyrazole derivatives as antimitotic agents with activity in multi-drug

resistant cell lines.

Guniz Kuchkguzel et al.85 have synthesized pyrazolines as a antimicrobial and

anticonvulsant agents. Gulhan T. Z. and co-workers86 have prepared pyrazolines as a

hypotensive agent.


Synthesis anticancer, antitubercular and antimicrobial activity of 1-substituted 3-

aryl-5-(3’-bromophenyl)-pyrazoleines (13) have been reported by K. S. Nimavat87. D.

H. Vyas88 reported synthesis and biological activity of some pyrazoline derivatives (14)

bearing 3,5-dibromo-4-methoxybenzaldehyde nucleus.

Synthesis, selective antitubercular and antimicrobial inhibitory activity of 1-acetyl-

3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives (15) have been reported by P. T.

Chovatia89. T. K. Dave90 reported synthesis, antitubercular and antimicrobial evaluation

of pyrazole derivatives bearing nicotinic acid nucleus.

( 11 ) ( 12 )

NNO

CH3

R R1N N

CH3

R1 R2

NN

R1

O

R

Br

Br

O

CH3

NN R1

Br

R

( 13 ) ( 14 )



Synthesis of some pyrazolo[3,4-d]pyrimidines and thiazolo[4,5-d]pyrimidines

and evaluation of their antimicrobial activities with derivatives of urea91 and thiourea

(16)92 was reported by J. D. Akbari.

Literature survey reveals that the compounds bearing pyrazole moiety possess

potential drug activity. Looking to the diversified biological activities we have synthesized

some pyrazole derivatives in order to achieving better therapeutic agents. These studies

are described in following section.

SECTION-II:SYNTHESIS AND BIOLOGICAL SCREENING OF 1-ACETYL-3-

ARYL-5-(3-ISOPROPYL-4-METHOXYPHENYL)PYRAZOLES.

NN

NN RR1

SCH3

( 15 )

NH

NH

R

S

NNH

CH3CH3

( 16 )



SECTION-II

SYNTHESIS AND BIOLOGICAL SCREENING OF 1-ACETYL-3-ARYL-5-(3-

ISOPROPYL-4-METHOXYPHENYL)PYRAZOLES.

Pyrazole derivatives represent one of the most active class of compounds having

a wide spectrum of biological activities. Looking to the interesting properties of pyrazoles

it was considered worthwhile to synthesize a series of pyrazoles for obtaining biologically

potent agents which were prepared by reacting chalcones with hydrazine hydrate in

glacial acetic acid.


elemental analysis, Infrared, 1H NMR spectroscopy and further supported by mass

spectroscopy.





O

O

CH3 CH3

CH3 NN

O

OCH3CH3 CH3

CH3R

R

NH2-NH2.H2O

gl. CH3COOH






was carried out in appropriate solvents. TLC was carried out on silicagel-G as stationary


[A] Preparation of (E)-3-(3-Isopropyl-4-methoxyphenyl)-1-aryl-prop-2-en-1-

ones.

See Part-B, Section-I, Experimental section [A].

[B] General procedure for the preparation of 1-Acetyl-3-aryl-5-(3-isopropyl-

4-methoxyphenyl)pyrazoles.

A mixture of (E)-3-(3-isopropyl-4-methoxyphenyl)-1-aryl-prop-2-en-1-ones

(0.01 mole) and hydrazine hydrate (0.04 mole) in acetic acid (20 ml) was refluxed on an

oil-bath for 10-11 hrs. The resulting solution was poured on crushed ice. The solid

product was isolated and crystallized from suitable solvent. The physical constants of

the product are recorded in Table-5a.

[C] Biological screening of 1-Acetyl-3-aryl-5-(3-isopropyl-4-methoxyphenyl)-

pyrazoles.


Antimicrobial activity. The zones of inhibition of the test solution are recorded in

Table-5b.



Table-5a: Physical constants of 1-Acetyl-3-aryl-5-(3-isopropyl-4-methoxy-

phenyl)pyrazoles.

NN

O

OCH3CH3 CH3

CH3

R

Sr.No.

SubstitutionR


M.P.oC

Yield%


C H N

5a H C21H24N2O2336.42 156-158 64 74.97

75.037.197.12

8.338.20

5b 4-OCH3C22H26N2O3

366.45 144-146 59 72.1172.03

7.157.22

7.647.52

5c 3-NO2C21H23N3O4

381.42 189-190 68 66.1366.04

6.085.99

11.0211.13

5d 4-Cl C21H23ClN2O2370.87 132-134 71 68.01

68.126.256.16

7.557.51

5e 3,4-(OCH3)2C23H28N2O4

396.47 151-153 62 69.6769.63

7.127.01

7.077.13

5f 2,5-(OCH3)2C23H28N2O4

396.47 116-118 69 69.6769.60

7.127.05

7.077.11

5g 2-OCH3C22H26N2O3

366.45 113-114 53 72.1172.05

7.157.18

7.647.59

5h 2-OH C21H24N2O3352.42 128-130 56 71.57

71.476.866.94

7.957.88

5i 4-NO2C21H23N3O4

381.42 162-164 74 66.1366.04

6.085.99

11.0211.13

5j 3-Br C21H23BrN2O2415.32 131-133 66 60.73

60.795.585.47

6.746.63


Pyrazoline Derivatives…

SPECTRAL STUDY

IR spectra of 1-Acetyl-3-(4-nitrophenyl)-5-(3-isopropyl-4-methoxyphenyl)-pyrazole.

5007501000125015001750200025003000350040001/cm

-20

0

20

40

60

80

100

%T

30

67

.88

29

57

.94

28

33

.52

16

74

.27

15

98

.08

15

12

.24

14

28

.34

13

38

.64

12

46

.06 11

46

.72 1

10

9.1

1

10

23

.27

95

8.6

5

84

8.7

18

12

.06

75

1.3

06

94

.40

63

9.4

2

44

0.7

5

4-NO2-AP




Alkane -CH3





Aromatic

C-H str. 3067

C=C (skeleton) 1512,1598


C-H o.p bending 847

Pyrazoline-C=O str. 1674

-C-N str. 1146

-C-O-C- 1023

-N=O 1246

NN

O

OCH3

CH3 CH3

CH3

N+

O-

O



1H NMR spectra of 1-Acetyl-3-(4-nitrophenyl)-5-(3-isopropyl-4-methoxyphenyl)

-pyrazole.


N N

N+

O-

O

O

CH3

CH3

CH3

O

CH3

a

a'

b

b'

c

de

f

Sr.No.


Relative No.of Protons Multiplicity Inference J value in

Hz

1 1.17-1.19 6H doublet Ar-CH(CH3)2 7.0

2 2.43 3H singlet -CO-CH3 -

3 3.15-3.21 1H dd -CH2- 4.76 & 17.7

4 3.22-3.39 1H multiplet Ar-CH(CH3)2 -

5 3.70-3.76 1H dd -CH2- 5.76 & 17.7

6 3.78 3H singlet Ar-OCH3 -

7 5.59-5.63 1H dd -Hc 4.76 & 11.9

8 6.76-6.78 1H doublet Ar-He 8.4

9 6.96-6.98 1H dd Ar-Hd 2.3 & 8.4

10 7.05-7.06 1H doublet Ar-He 2.3

11 7.88-7.90 2H dd Ar-Hb,b' 8.1 & 7.2

12 8.26-8.29 2H dd Ar-Ha.a' 8.1 & 7.1



EI-

Mas

s sp

ectr

a of

1-A

cety

l-3-

(4-n

itro

ph

enyl

)-5-

(3-i

sop

rop

yl-4

-met

hox

yph

enyl

)pyr

azol

e.

Inst

rum

ent:

Shi

mad

zu G

C-M

S Q

P-2

010,

DI-

prob

e, E

I-m

etho

d.

NN

N+

O-

O

O

CH

3

CH

3

CH

3

OCH

3

M. W

t. =

381.

42



EI-

Mas

s spe

ctra

of 1

-Ace

tyl-

3-(4

-met

hoxy

phen

yl)-

5-(3

-iso

prop

yl-4

-met

hoxy

phen

yl)p

yraz

ole.

Inst

rum

ent:

Shi

mad

zu G

C-M

S Q

P-20

10, D

I-pr

obe,

EI-

met

hod.

NN

O

CH

3

CH

3

CH

3

OCH

3

OC

H3

M. W

t. =

366.

45



Tabl

e-5b

: Ant

imic

robi

al a

ctiv

ity

of 1

-Ace

tyl-

3-ar

yl-5

-(3-

isop

ropy

l-4-

met

hoxy

phen

yl)p

yraz

oles

.

Sr.

No.

Ant

ibac

teria

l Act

ivity

Ant

ifung

al A

ctiv

ity

S. a

ureu

sS.

epi

derm

idis

E. c

oli

P. a

erug

inos

aA

. nig

er

5a20

(1.0

0)C

1, (0

.96)

C2

(1.1

1)C

3, (1

.00)

C4

11(0

.45)

C1,

(0.4

5)C

2(0

.64)

C3,

(0.6

1)C

4

08(0

.36)

C1,

(0.3

2)C

2(0

.33)

C3,

(0.4

4)C

4

16(0

.76)

C1,

(0.6

4)C

2(0

.64)

C3,

(1.0

6)C

4

12(0

.50)

C5

5b10

(0.5

0)C

1, (0

.47)

C2

(0.5

5)C

3, (0

.50)

C4

16(0

.66)

C1,

(0.6

6)C

2(0

.94)

C3,

(0.8

8)C

4

19(0

.86)

C1,

(0.7

6)C

2(0

.79)

C3,

(1.0

5)C

4

17(0

.80)

C1,

(0.6

8)C

2(0

.68)

C3,

(1.1

3)C

4

11(0

.45)

C5

5c15

(0.7

5)C

1, (0

.71)

C2

(0.8

3)C

3, (0

.75)

C4

09(0

.37)

C1,

(0.3

7)C

2(0

.52)

C3,

(0.5

0)C

4

21(0

.95)

C1,

(0.8

4)C

2(0

.87)

C3,

(1.1

6)C

4

16(0

.76)

C1,

(0.6

4)C

2(0

.64)

C3,

(1.0

6)C

4

24(1

.00)

C5

5d08

(0.4

0)C

1, (0

.38)

C2

(0.4

4)C

3, (0

.40)

C4

23(0

.95)

C1,

(0.9

5)C

2(1

.35)

C3,

(1.2

7)C

4

10(0

.45)

C1,

(0.4

0)C

2(0

.41)

C3,

(0.5

5)C

4

20(0

.95)

C1,

(0.8

0)C

2(0

.80)

C3,

(1.3

3)C

4

20(0

.83)

C5

5e13

(0.6

5)C

1, (0

.62)

C2

(0.7

2)C

3, (0

.65)

C4

17(0

.70)

C1,

(0.7

0)C

2(1

.00)

C3,

(0.9

4)C

4

14(0

.63)

C1,

(0.5

6)C

2(0

.58)

C3,

(0.7

7)C

4

18(0

.85)

C1,

(0.7

2)C

2(0

.72)

C3,

(1.2

0)C

4

15 (0

.62)

C5

5f16

(0.8

0)C

1, (0

.76)

C2

(0.8

9)C

3, (0

.80)

C4

13(0

.54)

C1,

(0.5

4)C

2(0

.76)

C3,

(0.7

2)C

4

17(0

.77)

C1,

(0.6

8)C

2(0

.70)

C3,

(0.9

4)C

4

12(0

.57)

C1,

(0.4

8)C

2(0

.48)

C3,

(0.8

0)C

4

16(0

.66)

C5



5g14

(0.7

0)C

1, (0

.67)

C2

(0.7

7)C

3, (0

.70)

C4

18(0

.75)

C1,

(0.7

5)C

2(1

.05)

C3,

(1.0

0)C

4

19(0

.86)

C1,

(0.7

6)C

2(0

.79)

C3,

(1.0

5)C

4

16(0

.76)

C1,

(0.6

4)C

2(0

.64)

C3,

(1.0

6)C

4

12(0

.50)

C5

5h19

(0.9

5)C

1, (0

.91)

C2

(1.0

5)C

3, (0

.95)

C4

10(0

.41)

C1,

(0.4

1)C

2(0

.58)

C3,

(0.5

5)C

4

08(0

.36)

C1,

(0.3

2)C

2(0

.33)

C3,

(0.4

4)C

4

13(0

.61)

C1,

(0.5

2)C

2(0

.52)

C3,

(0.8

6)C

4

20(0

.83)

C5

5i09

(0.4

5)C

1, (0

.42)

C2

(0.5

0)C

3, (0

.45)

C4

14(0

.58)

C1,

(0.5

8)C

2(0

.82)

C3,

(0.7

7)C

4

16(0

.72)

C1,

(0.6

4)C

2(0

.66)

C3,

(0.8

8)C

4

21(1

.00)

C1,

(0.8

4)C

2(0

.84)

C3,

(1.4

0)C

4

09(0

.37)

C5

5j17

(0.8

5)C

1, (0

.81)

C2

(0.9

4)C

3, (0

.85)

C4

15(0

.62)

C1,

(0.6

2)C

2(0

.88)

C3,

(0.8

3)C

4

12(0

.54)

C1,

(0.4

8)C

2(0

.50)

C3,

(0.6

6)C

4

08(0

.38)

C1,

(0.3

2)C

2(0

.32)

C3,

(0.5

3)C

4

13(0

.54)

C5

C1

2024

2221

00

C2

2124

2525

00

C3

1817

2425

00

C4

2018

1815

00

C5

0000

0000

24

Act

ivity

inde

x =

Inhi

bitio

n zo

ne o

f the

sam

ple

/ Inh

ibiti

on z

one

of th

e st

anda

rd

For a

ntib

acte

rial a

ctiv

ity: C

1 = A

mox

icill

in, C

2 = C

ipro

flox

acin

, C3 =

Cep

hale

xin,

C4 =

Ery

thro

myc

in.

For a

ntifu

ngal

activ

ity: C

5 = G

rese

oful

vin.



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Part-Part-Part-Part-Part-BBBBB(Section-III)(Section-III)(Section-III)(Section-III)(Section-III)



cyclohexenone derivatives

117

Cyclohexenone derivatives...


INTRODUCTION

Cyclohexenones are derivatives of cyclohexane with carbonyl group at position-

1 and double bond at position-2. There are different types of cyclohexenone derivatives

but the greatest difference in structure and properties is exerted by the groups attached

to carbon atom.

Cyclohexenones is the parent of a series of compounds that is important in

agricultural and medicinal chemistry. Cyclohexenones can be conveniently synthesized

by the treatment of á ,â-unsaturated carbonyl compounds with ethyl acetoacetate in basic

media.

In recent years cyclohexenone derivatives have gained lot of interest because of

their prominent pharmaceutical properties.

SYNTHETIC ASPECT

Different methods for the preparation of cyclohexenone derivatives have been

described in literature.1-9

1. A review of the earlier literature by Gerald et al.10 described representative

synthetic procedure of cyclohexenone derivatives.

2. Byong-Don Chong et al.11 have been prepared cyclohexenone derivatives by

tandem michael addition-aldol condensation of â-keto esters to conjugate enones

(or enals) in t-BuOH.

O

Br

CH3

O

+

CH2

R OH

1. cat. Pd

2. H+

O

R

118



3. Andrea Buzas et al.12 have been prepared cyclohexenone by reaction of various

substituted 5-en-2-yn-1-yl acetates with using biphenyl phosphine as catalyst in

methanol in basic media.

4. Ken Tanaka et al.13 have synthesized cyclohexenone from 4-alkynals and alkynes

in presence of Rh catalyst via novel [4+2] annulation.

5. H. Surya Prakash Rao and co workers14 reported solvent-free microwave-

mediated Michael addition reactions to form cyclohexenones with 98 % yield.

CH3

O O

O

CH3

+ CH3

O t - BuOK

CH3

O

CH3

COOEt

Ph

OAc

CH3

OCH3

O

CH3Ph

K2CO3AcO

Ph

CH3

CH21. 1% A, MeOH

2. K2CO3, MeOH

Pt-Bu

t-Bu Au - NTf2

A =

O

R1

R2

R3

+

R5

R4

Rh catalyst

CH2Cl2

O

R3 H

R5

R4

R1

R2

Ph

O

Ph+R1

O

CH3

K2CO3

MW, 450 W

Ph

Ph O

R1

119



REACTION MECHANISM

The addition reaction between ethyl acetoacetate and á,â-unsaturated ketones

give cyclohexenone via Michael addition. This reaction has been carried out in basic

media by using sodium ethoxide or anhydrous K2CO3 in acetone. During the reaction

nucleophillic addition of carbanion takes place to the C=C of the acceptor. The á,â-

unsaturated compound is known as acceptor and ethyl acetoacetate is known as donor.


Cyclohexenone and its derivatives are widely used in pharmaceutical industry.

Considerable interest has been shown in the chemistry of cyclohexenone due to their

wide spectrum of therapeutic activities which are listed as under.

1. Anticancer15

2. Antitubercular16

3. Anticonvulsant17,18

4. Antithrombitics19

5. Antagonist20

6. Antibiotic21

7. Cardiovascular22

8. Antifungal23,24

9. Antiplatelet25

R

O

R1 R CH+

CH-

C

O

R1

CH3

O

COOC2H5

CH3 C

O

CH- COOC2H5

+OH-

R CH+

O

R1

+CH3CH-

O

H5C2OOC

CH3

O

H5C2OOC

R R1

O

O

H5C2OOC

R R1

-H2O

H+

[A]

+H+ R CH+

O

R1

[B]

120



Antimicrobial activities of cyclohexenones have been studied by Salama and Al-

shikh.26 Cyclohexenone possess neutropeptide α-receptor antagonist activity which was

reported by Takehiro and co-workers.27 Broughton Howard et al.28 have demonstrated

cyclohexenones as GABA a5 receptor ligands for enhancing coagulating properties.

Cyclohexenones possess inhibitory activity against the growth of lettuce seeding found

by Kimura and co-workers.29 Alekseeva L. M. and co-workers30 have synthesized

cyclohexenone derivatives which are useful as neurotropic activity. Patricia Silva Melo

et al.31 have been equipped cyclohexenone (1) as gastroprotective effect.

Erin Joseph et al.32 have been synthesized 2-crotonyloxymethyl-2-cyclohexenones

2 and reported as antitumer agents. N. D. Eddington et al.33 have prepared potential

enaminone as anticonvulsants. Chuihua Kong et al.34 have reported some cyclohexenone

derivatives as their inhibitory activity on weeds and fungal pathogens. T. Sunazuka and

co-workers35 reported cyclohexenone derivatives as potent, orally bioactive and selective

inhibitors of acetylcholinesterase. Alan J. Anderson et al.36 have synthesized

cyclohexenone derivatives and studied on the anticonvulsant activity and potential type-

IV phosphodiesterase inhibitor 3.

N

O

CH3

CH3

O

CH3

OHCH3

O

H

H

CH3

( 1 )

O

GS

NH

O

O

R1 R2

( 2 ) ( 3 )

121



Edward J. et al.37 have synthesized 2,3-dihydro-5-(3-oxo-2-cyclohexen-1-yl)-

2- benzofurancarboxylic acids and their salts which are used in the treatment of brain

injury. K. R. Scott et al.38 have documented cyclohexenone derivatives (4) and studied

on the anticonvulsant activity. Toshiyuki et al.39 have prepared some novel cyclohexenone

and screened for their allergy inhibitor, antithrombotic platelet aggregation inhibitors

and fibrinogen antagonist activity. Cyclohexenone and its derivatives have been prepared

and reported as broad spectrum of physiological properties viz bactericidal40 etc.

Y. F. Shealy et al.41 have demonstrated cyclohexenones as anticancer agents.

Mathias Alterman et al.42 have designed and fast synthesis of C-terminal duplicated potent

C2-symmetric P1/P1’-modified HIV-1 protease inhibitors. F. Nara et al.43 synthesized

some cyclohexenones as powerful and specific inhibitor of neutral sphingomyelinase

(NSMase). T. Kolter et al.44 have anticipated cyclohexenone derivatives to be a promising

agent for the treatment of ceramide-mediated pathogenic states such as inflammation

and immunological and neurological disorders. Q. Zhang and co-workers45 have prepared

glutathionylated 2-exomethylenecyclohexenone (5) as antitumer agents. The presence

of pesticidal activity among cyclohexenone derivatives is well documented.

The compound 2-{(E,Z)-1-[(2R,S)-2-(4-chlorophenoxy)propoxyimino]butyl}-

3-hydroxy-5-thian-3-yl)cyclohex-2-en)-one (6) has been marketed under the name of

‘Profoxydim’ as an herbicides.

CH3 O

NH NO

CH3

CH3 O

NH NO

CH3

CH3( 4 )

O

(oligo.).NH

( 5 )

122




Synthesis and pharmacological evaluation of 6-carbethoxy-5-(3'-bromophenyl)-

3-aryl-2-cyclohexenones (7) and 6-aryl-4-(3'-bromophenyl)-3-oxo-2,3a,4,5-

tetrahydro-2H-indazoles was reported by K. S. Nimavat46.

K. H. Popat47 have been reported synthesis, anticancer, antitubercular and

antimicrobial activity of 6-carbethoxy-5-(3'-chlorophenyl)-3-aryl-2-cyclohexenones (8)

and 6-aryl-4-(3'-chlorophenyl)-3-oxo-2,3a,4,5-tetrahydro-1H-indazoles. V. V.

Kachhadia48 reported synthesis, antitubercular and antimicrobial activity of 6-carbethoxy-

5-aryl-3-[p-(3'-chloro-2'-benzo[b]thiophenoyl amino)phenyl]-2-cyclohexenones (9).

Looking to the biological profile of cyclohexenone derivatives, we have

synthesized some new derivaties as described below.

O

Cl

CH3

ON

CH3

O

OHS

( 6 )

Br

O OEt

O

R

( 7 )

Cl

O OEt

O

R

O

OEtO

R

NH

S O

Cl

( 8 ) ( 9 )

123



SECTION-III

SYNTHESIS AND BIOLOGICAL SCREENING OF ETHYL 4-ARYL-6-(3-

ISOPROPYL-4-METHOXYPHENYL)-2-OXO-CYCLOHEX-3-ENE-1-

CARBOXYLATES.

Cyclohexenone derivatives have considerable attention in view of their potential

pharmacological properties such as antimicrobial, anticonvulsant anticancer, etc. Led

by these considerations, the preparation of cyclohexenone derivatives have been

undertaken. The synthesis was carried out by the condensation of (E)-3-(3-isopropyl-

4-methoxyphenyl)-1-aryl-prop-2-en-1-ones with ethylacetoacetate in presence of basic

catalyst like K2CO3 shown as under.








CH3 CH3

OCH3

R

O

+

CH3 CH3

OCH3

R

O

O

OCH3

CH3

O

OO

CH3K2CO3

Acetone

124








[A] Preparation of (E)-3-(3-Isopropyl-4-methoxyphenyl)-1-aryl-prop-2-en-1-

ones.

See Part-B, Section-I, Experimental section [A].

[B] General procedure for the preparation of Ethyl 4-aryl-6-(3-isopropyl-4-

methoxyphenyl)-2-oxo-cyclohex-3-ene-1-carboxylates.

A mixture of (E)-3-(3-isopropyl-4-methoxyphenyl)-1-aryl-prop-2-en-1-one

(0.01 mole), ethylacetoacetate (1.14 gm, 0.01 mole) and K2CO3 (1.38 gm, 0.01 mole)

was taken into dry acetone (25 ml) and the mixture was stirred at room temperature till

the acetone is evaporated off. The contents were neutralized with HCl and poured onto

crushed ice. The product separated was filtered and crystallized from suitable solvent to

give analytically pure product. The physical constants of the product are recorded in

Table-6a.

[C] Biological screening of Ethyl 4-aryl-6-(3-isopropyl-4-methoxyphenyl)-2-

oxo-cyclohex-3-ene-1-carboxylates.



Table-6b.

125



Table-6a: Physical constants of Ethyl 4-aryl-6-(3-isopropyl-4-methoxyphenyl)-

2-oxo-cyclohex-3-ene-1-carboxylates.

CH3 CH3

OCH3

O

O

OCH3

R

Sr.No.

SubstitutionR


M.P.oC

Yield%


C H N

6a H C25H28O4392.48 200-202 66 76.50

76.427.197.23

-

6b 4-OCH3C26H30O5422.51 189-190 71 73.91

73.977.167.05

-

6c 3-NO2C25H27NO6

437.48 248-250 81 68.6368.54

6.226.13

3.203.27

6d 4-Cl C25H27ClO4426.93 167-169 74 70.33

70.256.376.48 -

6e 3,4-(OCH3)2C27H32O6452.53 162-163 69 71.66

71.637.137.19 -

6f 2,5-(OCH3)2C27H32O6452.53 170-172 63 71.66

71.607.137.21

-

6g 2-OCH3C26H30O5422.51 154-156 68 73.91

73.997.167.01

-

6h 2-OH C25H28O5408.48 175-177 59 73.51

73.406.917.04

-

6i 4-NO2C25H27NO6

437.48 236-238 79 68.6368.51

6.226.18

3.203.22

6j 3-Br C25H27BrO4471.38 186-187 67 63.70

63.615.775.86 -


Cyclohexenone Derivatives…

SPECTRAL STUDY

IR spectra of Ethyl 4-(4-nitrophenyl)-6-(3-isopropyl-4-methoxyphenyl)-2-oxo-

cyclohex-3-ene-1-carboxylate.

5007501000125015001750200025003000350040001/cm

15

30

45

60

75

90

105

%T3

43

1.4

8

30

10

.02

29

95

.55

29

71

.44

28

35

.45

17

28

.28 1

71

1.8

81

67

3.3

0 16

01

.93

15

19

.96 1

49

6.8

1 14

59

.20

13

39

.61

12

91

.39

12

69

.20

12

49

.91

12

43

.16

11

88

.19

10

92

.71

10

29

.06

95

4.8

0

85

3.5

38

11

.09 7

58

.05

69

3.4

3

61

1.4

5

53

7.1

9




Alkane -CH3





Aromatic

C-H str. 3010

C=C (skeleton) 1519,1601,1673


C-H o.p bending 853

Cyclohexenone-C=O str. 1728

-C=O str. 1711

-C-O-C- str. 1092

-N=O str. 1339

CH3 CH3

OCH3

O

O

OCH3

N+

O-

O


Cyclohexenone Derivatives…

1H NMR spectra of Ethyl 4-(4-nitrophenyl)-6-(3-isopropyl-4-methoxyphenyl)-2-oxo-

cyclohex-3-ene-1-carboxylate.


Sr.No.


Relative No.of Protons Multiplicity Inference J value in Hz

1 1.05-1.10 3H triplet -CH2-CH3 7.88

2 1.16-1.19 6H doublet -CH(CH3)2 3.52

3 2.11-2.16 1H triplet -CH2- 13.96 & 2.96

4 2.36-2.42 1H triplet -CH2- 12.92 & 11.76

5 2.68-2.71 1H triplet -He 12.76 & 1.04

6 3.12-3.15 1H doublet -Hd 13.8

7 3.24-3.28 1H multiplet -CH(CH3)2 -

8 3.78 3H singlet Ar-OCH3 -

9 4.01-4.05 2H multiplet -CH2-CH3 -

10 5.89 1H singlet -Hc -

11 6.77-6.79 1H doublet Ar-Hg 8.64

12 7.10-7.12 2H doublet Ar-Hf+Ar-Hh 7.28

13 7.75-7.77 2H doublet Ar-Ha,a' 8.76

14 8.17-8.19 2H doublet Ar-Hb,b' 8.72

CH3 CH3

OCH3

O

O

OCH3

N+

O-

O

a

a'

b

b'

cd

efg

h

128



Inst

rum

ent:

Shi

mad

zu G

C-M

S Q

P-20

10, D

I-pr

obe,

EI-

met

hod.

EI-

Mas

s spe

ctra

of E

thyl

4-(

4-ni

trop

heny

l)-6

-(3-

isop

ropy

l-4-

met

hoxy

phen

yl)-

2-ox

o-cy

cloh

ex-3

-ene

-1-c

arbo

xyla

te.

CH

3C

H3

OC

H3

O

O

OC

H3

N+

O-

O

M. W

t. =

437.

48

129



Inst

rum

ent:

Shi

mad

zu G

C-M

S Q

P-20

10, D

I-pr

obe,

EI-

met

hod.

EI-

Mas

s spe

ctra

of E

thyl

4-p

heny

l-6-

(3-i

sopr

opyl

-4-m

etho

xyph

enyl

)-2-

oxo-

cycl

ohex

-3-e

ne-1

-car

boxy

late

.

CH

3C

H3

OC

H3

O

O

OC

H3 M

. Wt.

=39

2.48

130



Tabl

e-6b

: Ant

imic

robi

al a

ctiv

ity

of E

thyl

4-a

ryl-

6-(3

-iso

prop

yl-4

-met

hoxy

phen

yl)-

2-ox

o-cy

cloh

ex-3

-ene

-1-c

arbo

xyla

tes.

Sr.

No.

Ant

ibac

teria

l Act

ivity

Ant

ifung

al A

ctiv

ity

S. a

ureu

sS.

epi

derm

idis

E. c

oli

P. a

erug

inos

aA

. nig

er

6a16

(0.8

0)C

1, (0

.76)

C2

(0.8

9)C

3, (0

.80)

C4

09(0

.37)

C1,

(0.3

7)C

2(0

.52)

C3,

(0.5

0)C

4

11(0

.50)

C1,

(0.4

4)C

2(0

.45)

C3,

(0.6

1)C

4

10(0

.47)

C1,

(0.4

0)C

2(0

.40)

C3,

(0.6

6)C

4

15 (0

.62)

C5

6b11

(0.5

5)C

1, (0

.52)

C2

(0.6

1)C

3, (0

.55)

C4

18(0

.75)

C1,

(0.7

5)C

2(1

.05)

C3,

(1.0

0)C

4

21(0

.95)

C1,

(0.8

4)C

2(0

.87)

C3,

(1.1

6)C

4

16(0

.76)

C1,

(0.6

4)C

2(0

.64)

C3,

(1.0

6)C

4

18(0

.75)

C5

6c10

(0.5

0)C

1, (0

.47)

C2

(0.5

5)C

3, (0

.50)

C4

23(0

.95)

C1,

(0.9

5)C

2(1

.35)

C3,

(1.2

7)C

4

14(0

.63)

C1,

(0.5

6)C

2(0

.58)

C3,

(0.7

7)C

4

08(0

.38)

C1,

(0.3

2)C

2(0

.32)

C3,

(0.5

3)C

4

22(0

.91)

C5

6d19

(0.9

5)C

1, (0

.91)

C2

(1.0

5)C

3, (0

.95)

C4

08(0

.33)

C1,

(0.3

3)C

2(0

.47)

C3,

(0.4

4)C

4

22(1

.00)

C1,

(0.8

8)C

2(0

.91)

C3,

(1.2

2)C

4

17(0

.80)

C1,

(0.6

8)C

2(0

.68)

C3,

(1.1

3)C

4

12(0

.50)

C5

6e22

(1.1

0)C

1, (1

.06)

C2

(1.2

2)C

3, (1

.10)

C4

15(0

.62)

C1,

(0.6

2)C

2(0

.88)

C3,

(0.8

3)C

4

12(0

.54)

C1,

(0.4

8)C

2(0

.50)

C3,

(0.6

6)C

4

13(0

.61)

C1,

(0.5

2)C

2(0

.52)

C3,

(0.8

6)C

4

24(1

.00)

C5

6f14

(0.7

0)C

1, (0

.67)

C2

(0.7

7)C

3, (0

.70)

C4

17(0

.70)

C1,

(0.7

0)C

2(1

.00)

C3,

(0.9

4)C

4

10(0

.45)

C1,

(0.4

0)C

2(0

.41)

C3,

(0.5

5)C

4

19(0

.90)

C1,

(0.7

6)C

2(0

.76)

C3,

(1.2

6)C

4

09(0

.37)

C5

131



6g22

(1.1

0)C

1, (1

.06)

C2

(1.2

2)C

3, (1

.10)

C4

18(0

.75)

C1,

(0.7

5)C

2(1

.05)

C3,

(1.0

0)C

4

15(0

.68)

C1,

(0.6

0)C

2(0

.62)

C3,

(0.8

3)C

4

09(0

.42)

C1,

(0.3

6)C

2(0

.36)

C3,

(0.6

0)C

4

13(0

.54)

C5

6h11

(0.5

5)C

1, (0

.52)

C2

(0.6

1)C

3, (0

.55)

C4

10(0

.41)

C1,

(0.4

1)C

2(0

.58)

C3,

(0.5

5)C

4

12(0

.54)

C1,

(0.4

8)C

2(0

.50)

C3,

(0.6

6)C

4

11(0

.52)

C1,

(0.4

4)C

2(0

.44)

C3,

(0.7

3)C

4

18(0

.75)

C5

6i15

(0.7

5)C

1, (0

.71)

C2

(0.8

3)C

3, (0

.75)

C4

14(0

.58)

C1,

(0.5

8)C

2(0

.82)

C3,

(0.7

7)C

4

20(0

.90)

C1,

(0.8

0)C

2(0

.83)

C3,

(1.1

1)C

4

18(0

.85)

C1,

(0.7

2)C

2(0

.72)

C3,

(1.2

0)C

4

20(0

.83)

C5

6j08

(0.4

0)C

1, (0

.38)

C2

(0.4

4)C

3, (0

.40)

C4

11(0

.45)

C1,

(0.4

5)C

2(0

.64)

C3,

(0.6

1)C

4

09(0

.40)

C1,

(0.3

6)C

2(0

.37)

C3,

(0.5

0)C

4

14(0

.66)

C1,

(0.5

6)C

2(0

.56)

C3,

(0.9

3)C

4

11(0

.45)

C5

C1

2024

2221

00

C2

2124

2525

00

C3

1817

2425

00

C4

2018

1815

00

C5

0000

0000

24

Act

ivity

inde

x =

Inhi

bitio

n zo

ne o

f the

sam

ple

/ Inh

ibiti

on z

one

of th

e st

anda

rd

For a

ntib

acte

rial a

ctiv

ity: C

1 = A

mox

icill

in, C

2 = C

ipro

flox

acin

, C3 =

Cep

hale

xin,

C4 =

Ery

thro

myc

in.

For a

ntifu

ngal

activ

ity: C

5 = G

rese

oful

vin.

132



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42. M. Alterman, H. O. Andersson, N. Garg, G. Ahlsen, S. Lovgren, B. Classon, U. H.Danielson, I. Kvarnstromr, L. Vrang, T. Unge, B. Samuelsson, A. Hallberg, J.Med. Chem., 42(19), 3835-3844 (1999).

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Part-Part-Part-Part-Part-CCCCC

Studies on

Dihydropyrimidine

Derivatives


Pyrimidine derivatives...

INTRODUCTION

Pyrimidine is the most important member of all the diazines as this ring system

occurs widely in living organisms. Purine, uric acid, barbituric acid, anti-malarial and

anti-bacterial agents also contain the pyrimidine ring. The chemistry of pyrimidine has

been widely studied. Pyrimidine was first isolated by Gabriel and Colman in 1899. Since

pyrimidine is symmetrical about the line passing C-2 and C-5, the positions C-4 and C-

6 are equivalent and so N-1 and N-3 are equivalent. When a hydroxyl or amino group is

present at the 2-, 4- or 6- position than they are tautomeric with oxo and imino

respectively.

Although the importance of dihydroazines (particularly those containing the 1,4-

dihydropyrimidine and dihydropyridine motif1) for clarifying a wide range of theoretical,

medicinal and biological problems, the chemistry of this group of compounds is still

extremely spotty2-6. From the theoretical point of view, it is essential to predict the

structure, binding properties, chemical reactivity, etc. of dihydro compounds from the

number and positioning of nitrogen atoms in the ring, as well as from the disposition of

double bonds. Such quantum mechanical calculations also enable an evaluation of the

degree of aromatic character in potential homoaromatic and antiaromatic isomers.

Availability of novel model compounds for verifying these predictions would open up

new horizons in theoretical heterocyclic chemistry, particularly in clarifying the structures

leading to spontaneous isomerization of a derivative or in verifying its redox properties.

From the biochemical point of view, dihydroazines are of intense interest because

of presence of this group at the active site of the hydrogen transferring coenzyme

(nicotinamide adenine dinucleotied hdrogenase-NADH or reduced nicotinamide adenine

dinucleotide). This nucleotide, a central participant in metabolic processes in living

organisms, participates in the reduction of various unsaturated functionalities.

In the area of drug development, dihydroazines show great promise, particularly

since the 4-aryldihydropyridines exhibit powerful vasodilation activity via modifying the

calcium ion membrane channel7-10. Additionally, dihydropyridines have been found to

actively transport medication across biological membranes11.

Until recently, most of the information available on dihydroazines centered around

dihydropyridines, with very little data extending to the related dihydropyrimidines.



This lacuna has motivated our deep involvement in developing dihydropyrimidine

chemistry12, These molecules have long been considered unstable for oxidation,

polymerization or disproportionation reactions13.

Figure below present in the drawing five possible isomeric structures of

dihydropyrimidines, exhibiting different positions of the double bonds.

However, these structures are not easy to synthesize and, as a result, most of the

known dihydropyrimidines have either 1,2- or the tautomeric 1,4- and 1,6- geometry. On

the basis of data available in the literature14,15, the dihydropyrimidines can be conveniently

divided into two groups, within each of which interconversion between isomers is possible

under thermal conditions, namely, the 1,4-, 1,6-, and 4,5- compounds, and the 1,2- and

2,5- isomers. It is worthwhile to note that, while thermal interconversion between the two

groups is not observed, photochemical rearrangement of 1,4- (or 1,6-) dihydropyrimidines

to 1,2-isomers has been reported16,17.

It should be stressed that dihydroazines take part in various isomerization

processes, usually characterized by reversible or irreversible migrations within the ring,

the study of which is still in its infancy. Hydrogen migration, for example, is classified

either as rearrangement or tautomerism depending on its kinetic and thermodynamic

parameters, the former term is reserved for irreversible processes, while the latter is

used to describe fast reversible exchanges18. A study of isomerization in

dihydropyrimidines provides an excellent opportunity for clarifying the factors regulating

these processes.

After successfully developing versatile synthetic techniques for obtaining a variety

of 1,4- and 1,6-dihydropyrimidines19-21, as well as the observation of amidinic

tautomerism between the two22,23, A. L. Weis et al.14 examined the possibility of

preparative synthesis of similarly 1,2-dihydro derivatives and studied their properties.

Particularly important goals of this study were the possible observation of the formally

N

NH

N

NH

N

NH

N

N

N

N1 2

34

5

6

1,2- 1,4- 1,6- 2,5- 4,5-



allowed hydrogen shift23, of homoaromaticity24,25 or of imine-enamine tautomerism26 in

these compounds, behaviors of which have been seen in other systems.

To date few reports on the formation of 1,2-dihydropyrimidines exist in the

literature, and in those cases where a product could be isolated and characterized, the

material was either an N-substituted derivative or else it contained geminal disubstitution

at position 2, situations that prevent the molecule from oxidizing to the corresponding

pyrimidine.

Pyrimidine ring carrying various substituents may be built up from two or three

small fragments by the principle synthesis or by a variety of other synthesis, which are

complimentary rather than alternative to it. A second type of synthesis is the isomerisation

or break down of another heterocycles such as hydration of purine but such roots are

frequently used.

SYNTHETIC ASPECT

Biginelli Reaction

In 1893, Italian chemist Pietro Biginelli reported an acid catalyzed

cyclocondensation reaction of ethyl acetoacetate, benzaldehyde and urea. The reaction

was carried out by simply heating a mixture of the three components dissolved in ethanol

with a catalytic amount of HCl at reflux temperature. The product of this novel one-pot,

three-component synthesis that precipitated on cooling of the reaction mixture was

identified correctly by Biginelli as 3,4-dihydropyrimidin-2(1H)-one27.

Me O

O

EtO2C

O H

+ NH2

NH2 O

N

NMe O

O

EtO2CH

H

H+

EtOH



Alternative synthetic routes for better yield, shorter reaction time to synthesize

new analogs:

Various modifications have been applied to Biginelli reaction to get better yield

and to synthesize biologically active analogs. Different catalysts have been reported to

increase the yield of the reaction. Microwave synthesis strategies have also applied to

shorten the reaction time. Solid phase synthesis and combinatorial chemistry has made

possible to generate library of DHPM analogs.

Catalysts

Min Yang and coworkers28 have synthesized the different DHPMs by using

different inorganic salts as a catalyst. They found that the yields of the one-pot Biginelli

reaction can be increased from 20-50 % to 81-99 %, while the reaction time shorted for

18-24 hr to 20-30 min. This report discloses a new and simple modification of the

Biginelli type reaction by using Yb(OTf)3 and YbCl3 as a catalyst under solvent free

conditions. One additional important feature of this protocol is the catalyst can be easily

recovered and reused.

Indium(III)chloride was emerged as a powerful Lewis catalyst imparting high

region and chemo selectivity in various chemical transformations. B. C. Ranu and

coworkers29 reported indium(III)chloride (InCl3) as an efficient catalyst for synthesis of

3,4-dihydropyrimidn-2(1H)-ones. 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.

R

CHO

O

NH2

NH2

O

R1

R2O

NH

NH

RO

R1

R2 O+ Yb(OTf)3

100 °C

OR1

OR2

+

X

NH2

NH2

InCl3THF

NH

NH

RO

R2

R1 X

Where X = O or S

R

O



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

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

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

urea or thiourea using 12-tungstophosphoric acid30 and 12-molybdophosphoric acid31

as a recyclable catalyst.

A novel covalently anchored sulfonic acid onto the surface of silica was prepared

and investigated for the Biginelli reaction by Satya Paul and co-workers32. The catalyst

is highly stable, completely heterogeneous and recyclable for several times. The workup

procedure is very simple and Biginelli compounds were obtained in good to excellent

yields.

NH2

NH2 X

CH3

O

R2

O

NH

NH

R1 H

R2COO

CH3 X

Where X = O or S

R1

O

+

12 - tungstophosphoric acid/12 - molybdophosphoric acid

AcOH/reflux

SiO

2

OHOHOH S

iO2

OOO

Si SHToluene, Reflux, 24 h

(MeO)3Si SH

OOO

Si SO3H

SiO

2

i. 30 % H2O2

ii. 0.5 M H2SO4

iii. DW

CH3 O

O

OCH3

R

O H

+ NH2

NH2 X

NH

NH

R H

CH3 X

O

OCH3

Where X = O or S

Catalyst 1

Stirring, 80°C, 7 - 12 h



An efficient three-component synthesis of 3,4-dihydropyrimidinones using

trichloroisocyanuric acid (TCCA) as mild, homogeneous and neutral catalyst for Biginelli

reaction in ethanol or DMF under reflux condition33.

Many researchers34-40 have investigated an efficient Biginelli reaction under solvent-

free conditions for one-pot synthesis of 3,4-dihydropyrimidi-2-(1H)ones/thiones using

various catalyst as described under.

Solid phase synthesis

The generation of combinatorial libraries of heterocyclic compounds by solid

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

in pharmaceutical research41,42. Multi-component reactions (MCRs) leading to

heterocycles are particularly useful for the creation of diverse chemical libraries, since

the combination of any 3 small molecular weight building blocks in a single operation

leads to high combinatorial efficiancy41-43. Therefore, solid phase modifications of MCRs

are rapidly become the cornerstone of combinatorial synthesis of small-molecule

libraries41-47.

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

Wipf and Cunningham48 in 1995. In this sequence, γ-aminobutyric acid derived urea

was attached to Wang resin using standard procedures. The resulting polymer-bound

urea was condensed with excess â-ketoester and aromatic aldehydes in THF at 55 °C

in the presence of a catalytic amount of HCl to afford the corresponding immobilized

DHPMs. Subsequent cleavage of product from the resin by 50 % trifluoroacetic acid

(TFA) provided DHPMs in high yields and excellent purity.

R

O

OR1

O H

+ NH2

NH2 X

NH

NH

R X

OH

R1various catalyst

R2

Where X = O or S

R2



Weiwei Li and Yulin Lam49 described the synthesis of 3,4-dihydropyrimidin-2-

(1H)ones/thiones using sodium benzenesulfinate as a traceless linker. The key steps

involved in the solid-phase synthetic procedure include sulfinate acidification,

condensation of urea or thiourea with aldehydes and sulfinic acid and traceless product

release by a one-pot cyclization-dehydration process. Since a variety of reagents can

be used, the overall strategy appears to be applicable to library generation.

Gross et al.50 developed a protocol for based on immobilized á -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 á-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.

O

OR1

CH3R2

R

O H

O

NH2

NH

O

O

P

+O

NH

N

OH

O

R

R2

O

OR1

1. THF, HCl, 55 °C

2. TFA, CH2Cl2

SO2H

R1

O

NH2 X

NH2+DMF

SO2

NHR1

NH2

X

R3

O O

R2R2

O

O

OH

NH

NH

X

R2

O

R3

R1

NH

NH

X

R2R1

O

OH

1. KOH, EtOH

2. TsOH

1. Pyrrolidine, THF

2. TsOH



Liquid phase synthesis

In the solid phase synthesis there are some disadvantages of this methodology

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

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

low loading capacity and limited solubility during the reaction progress and the

heterogeneous reaction condition with solid phase51. Recently, organic synthesis of small

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

become attractive field52. It couples the advantages of homogeneous solution chemistry

with those of solid phase chemistry.

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

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

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

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

alternative to conventional molecular organic solvents or catalysts. Liu Zuliang et al.53

reported cheap and reusable TSILs for the synthesis of 3,4-dihydropyrimidin-2(1H)-

ones via one-pot three component Biginelli reaction.

Ionic liquid-phase bound acetoacetate react with thiourea and various aldehydes

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

thiones by Jean Pierre Bazureau and co-workers54. 3,4-Dihydropyrimidinones was

synthesized in one-pot of aldehydes, â-dicarbonyl compounds and urea, catalyzed by

non-toxic room temperature ionic liquid 1-n-butyl-3-methylimidazolium saccharinate

(BMImSac)55.

R

NHO

O

O

O

CH3

Polymer

R

NHO

O

O

O

CH3

Polymer

R1

SNH2

NH2+Cl- R

NHO

O

O

NH

CH3

Polymer

R1 SN



Microwave assisted synthesis

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

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

acidic catalyst that is hydrochloric acid56. One major drawback of this procedure, apart

from the long reaction times involving reflux temperatures, are the moderate yields

frequently observed when using more complex building blocks. Microwave irradiation

(MWI) has become recognized tool in organic synthesis, because the rate enhancement,

higher yields and often, improved selectivity with respect to conventional reaction

conditions57. The publication by Anshu Dandia et al.58 described microwave-enhanced

solution-phase Biginelli reactions employing ethyl acetoacetate, thiourea 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 °C, reflux to 3 – 11 minutes under microwave activation (ca.

200 – 300 W). At the same time the yields of DHPMs obtained were markedly improved

compared to those reported earlier using conventional conditions.

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

supports have received increasing attention59. There are several advantages to performing

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

O

NH2

NH2

OR2

CH3

O

+

N N+CH3 C4H9

NS

O

O O

"

N

N

R1

H

H

OCH3

R2CO

N

R2CO

R1

COR2

CH3CH3

H

+

R1

O

CH3 O

O

OCH3

Ar

O H

+ NH2

RNH X

NH

NCH3 X

Ar

R

O

OCH3MW

EtOH, H+



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

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

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

as a catalyst, activated fly ash, an industrial waste (pollutant) is an efficient and novel

catalyst for some selected organic reactions in solvent free conditions under microwave

irradiation60.

Ultrasound assisted synthesis

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

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

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

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

with shorter reaction time and higher product yields61. Ultrasound irradiated and

amidosulfonic acid (NH2SO3H) catalyzed synthesis of 3,4-dihydropyrimidi-2-(1H)ones

have reported by Ji-Taai Li and co-workers62 using aldehydes, â-ketoester and urea.

Chenjiang Liu et al.63 have synthesized a novel series of 4-substituted pyrazolyl-

3,4-dihydropyrimidin-2(1H)-thiones under ultrasound irradiation using magnesium

perchlorate [Mg(ClO4)2] as catalyst, by the condensation of 5-chloro/phenoxyl-3-methyl-

1-phenyl-4-formylpyrazole, 1,3-dicarbonyl compound and urea or thiourea in moderate

yields. The catalyst exhibited remarkable reactivity and can be recycled.

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

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

chloride (ZrCl4) as catalyst at 35 kHz gives 6-methyl-4-substitutedphenyl-2-oxo-1,2,3,4-

tetrahydropyrimidine-5-carboxylic acid ethyl esters proficiently in high yields reported

by Harish Kumar64.

NN

CH3CHO

Ph

R1

X

NH2 NH2

+ R3

O

O R2

NN

CH3

PhR1

NHNH

X

O R2

R3

Where X = O/S

10 mol % Mg(ClO4)2

EtOH, Δ



REACTION MECHANISM

In 1893 Biginelli reported the first synthesis of dihydropyrimidines by a simple

one-pot condensation reaction of ethyl acetoacetate, benzaldehyde and urea65.

Despite the importance and current interest in dihydropyrimidines of the Biginelli

type, the mechanism of the classical three-component Biginelli condensation has not

been elucidated with certainty66. Early work by Folkers and Johnson67 suggested that

N,N’-benzylidienebisurea (i.e. the primary bimolecular condensation product of

benzaldehyde and urea), is the first intermediate in this reaction.

R2

R3

R1

HO

NH2

NH2O CH3

O

OO

CH3

NH

N

COOEt

CH3H

O

R3

R2

R1

+

EtOH - ZrCl4/Bentonite Clay - ZrCl4

Ultrasound

Me O

O

EtO2C

O H

+ NH2

NH2 O

N

NMe O

O

EtO2CH

H

H+

EtOH

NH2

O

NH2

+RO

NH2

O

NH2

RNH

NHO

NH2

NH2

OEtOOC

OCH3R

NH

NHO

NH2

NH

OCH3OH

EtOOC

NH

NH

CH3

R

O

EtOOC



In 1973 Sweet and Fissekis proposed that a “carbenium ion mechanism”,

produced by acid-catalyzed aldol reaction of benzaldehyde with ethyl acetoacetate, is

the key intermediate and is formed in the first and limiting step of the Biginelli reaction68.

Kappe C. O.69 carried out a detailed reinvestigation of the mechanism of the

Biginelli condensation using 1H NMR and 13C NMR spectroscopy to identify possible

intermediates.

Kappe C. O. has established that the key step in this sequence involves the acid

catalyzed formation of an N-acyliminium ion intermediate of (5) from the aldehyde (2)

and urea (3) precursors. Interception of the iminium ion (5) by ethyl acetoacetate (1),

presumably through its enol tauter, produces an open chain ureide (7) which subsequently

cyclized to hexahydropyrimidine (10). Acid-catalyzed elimination of water from (10)

ultimately leads to the final DHPM product (11). The reaction mechanism can therefore

be classified as á-amidoalkylation, or more specifically as á-uridoalkylation70.

O

+CH3

O

O

EtO

CH3

O O

OEt CH3

O O

OEt

CH +

CH3

OH O

OEt

CH +

NH2 NH2

O

ONH2

NHH

CH3 O

EtO

O

- H2O

NH

NH

OCH3

O

EtO




4-Aryl-1,4-dihydropyridines (DHPs) of the nifedipine type e.g. nifedipine are

the most studied class of organic calcium channel modulators. More than 30 years after

the introduction of nifedipine (12), many DHP analogs have now been synthesized and

numerous second-generation commercial products have appeared in the market e.g.

nitrendipine, nicardipine and amlodipine71. The aza-analogs such as dihydropyrimidines

(13) which show a very similar pharmacological profile to classical dihydropyridine calcium

channel modulators72-76. Over the past several lead-compounds were developed e.g.

(13) SQ 32926 and (14) SQ 3257473,75 that are superior in potency and duration of

PhO

2

O

NH2

NH2 3

CH3 O

EtOOC

1

CH3 O

EtOOCOH

Ph

H+ -H2O

CH3 O

EtOOC CH+Ph

6

-H+ H+

CH3 O

EtOOC

Ph

H

9

O

NH2

NH2 3CH3 O

EtOOC

Ph

NH

ONH2

7

N

NH

Ph

H

OCH3

OH

EtOOC

10-H+

-H2O

N

NH

Ph

H

OCH3

EtOOC

11

O

NH2NH

OHPh

4

H+ -H2O

O

NH2N+

H

Ph H

5 3

O

NH2NH

PhNH2

OH+

8

-H+

1



antihypertensive activity to classical dihydropyridine drugs and compare favorable with

second-generation analogs such as amlodipine and nicardipine73.

Calcium ion plays a vital role in a large number of cellular processes, including

excitation-contraction and stimulus-secretion77,78. The regulation of the intracellular

concentration of this ion makes possible the control of such Ca2+ dependent processes.

One means of accomplishing this is by the use of agents known as calcium channel

antagonists, which inhibit the movement of calcium through certain membrane channel79-81.

K. S. Atwal82 prepared the 2-heterosubstituted-4-aryl-l,4-dihydro-6-methyl-5

pyrimidinecarboxylic acid esters (15), which lack the potential C3 symmetry of

dihydropyridine calcium channel blockers, were prepared and evaluated for biological

activity. Biological assays using potassium-depolarized rabbit artery 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. Dihydropyrimidines (15) were found to be 30 fold less active than

dihydropyridines. The solid-state structure of dihydropyrimidine analogue (16) shows

12 13 SQ 3926

14 SQ 32574

NH

CH3

MeOOC

CH3

COOMe

N+O-

O

N

NH

CH3 O

CONH2

O

Oi-Pr

N+O-

O

N

NH

CH3 S

CO2

O

Oi-Pr

N

FCF3



that these compounds can adopt a molecular conformation which is similar to the reported

conformation of dihydropyridine calcium channel blockers.

K. Atwal et al.83 synthesized the 3-substituted 1,4-dihydropyrimidine (17) and

documented that vasorelaxant activity was critically dependent on the size of the C5

ester group, isopropyl ester being the best, a variety of substituents (carbamate, acyl,

sulfonyl, alkyl) were tolerated at N3. The dihydropyrimidines (17) are significantly more

potent than corresponding 2-heteroalkyl-l,4-dihydropyrimidines. Dihydropyridine

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

dihydropyrimidine (18) 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 N3-substituent.

George C. Rovnyak et al.84 examined a series of novel dihydropyrimidine calcium

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

ring. One of these compounds was identified as a lead, and the individual enantiomers

15 16

NH

N

R2X CH3

COOR3

NH

N

S CH3

COOEt

N+

O-

O

R1

( 17 ) ( 18 )

NH

N

X CH3

COOR1R2

R3

NH

N

S CH3

NH2 O

O

i-Pr

N+

O-

O



(19a) (R) and (19b) (S) were synthesized. Dihydropyrimidine (19a) is equipotent to

nifedipine and amlodipine in vitro . In the spontaneously hypertensive rat,

dihydropyrimidine (19a) is more potent and longer acting than nifedipine and compares

most favorably with the long-acting dihydropyridine derivative amlodipine.

Dihydropyrimidine (19a) has the potential advantage of being a single enantiomer.

Selma Sarac and co-workers85,86 have synthesized 4-arlyl-3,4-dihydropyrimidin-

2(1H)-one/thione derivatives. The calcium channel blocker activities of all compounds

performed on isolated rat ileum. Product (20), 2-nitrophenyl derivative and (21), 2-

bromophenyl derivative have potent antispasmodic activity on BaCl2 stimulated rat ileum.

N. Dhanapalan and co-workers87 have synthesized dihydropyrimidinones and

describe compound (22) have a high binding affinity (Ki = 0.2nM) for á 1a receptor and

greater than 1500 fold selectivity over á 1b and á1d adreno receptors. Modification of the

linker in (22) gave compounds (23) and (24)88 viz μ-opioid receptor. Both these

compounds showed good á 1a binding affinity (Ki = 0.2nM) and selectivity (>800-fold

over á 1b and á 1d), also showed good selectivity over several other recombinant human

G-protein coupled receptors. They have also identified that compound (25)89 was a

lead compound with a binding and functional profile comparable to that of (22). 25 have

negligible affinity for the μ-opioid receptor.

N

NH

O

Oi-Pr

CH3 S

CO2 N

F

CF3

19a (R), 19b (S)

NH

NH

N+

O-

O

SCH3

O

OCH3 NH

NH

Br

OCH3

O

CH3

20 21



The synthesis and differential antiproliferative activity of monastrol (26a),

oxomonastrol (26b) and eight oxygenated derivatives (28a,b–31a,b) on seven human cancer

cell lines are described by Dennis Russowsky90. For all evaluated cell lines, monastrol

(26a) was shown to be more active than its oxo-analogue, except for HT-29 cell line,

suggesting the importance of the sulfur atom for the antiproliferative activity. Monastrol

(26a) and the thio derivatives (28a, 29a) and (31a) displayed relevant antiproliferative

properties with 3,4-methylenedioxy derivative (31a) being approximately more than 30

times more potent than monastrol (26a) against colon cancer (HT-29) cell line.

N

NH

O

NH2

CH3O

NH

O

F

F

N

CNPh

3N

NH

O

NH2

CH3O

NH

O

F

F

N

COOMePh

3

24 25

22 23

N

NH

H2NOC

Et O

NH

O

N

CH3

Ph

F

F

N

NH

H2NOC

Et O

NH

O

N

F

F

CH3CH3

CONH2

NH

NH

X

OH

O

EtO

CH3

NH

NH

X

O

EtO

CH3

NH

NH

X

O

EtO

CH3

OCH3

26a X = S Monastrol 27a X = S 28a X = S

26b X = O Oxo-monastrol 27b X = O 28b X = O



Y. Mizutani and co-workers91,92 identify that dihydropyrimidine dehydrogenase

(DPD) is the rate-limiting enzyme in the pathway of uracil and thymine metabolism. DPD

is also the principle enzyme involved in the degradation of 5-fluorouracil and anticancer

chemotherapeutic agent that is used clinically to treatment of bladder cancer and renal

cell carcinoma.

NEW MOLECULES UNDER CLINICAL STUDY

Many new molecules which are under study from phase-I to phase-IV clinical

trials for different pharmacological action have shown that the basic characteristic of

morpholine to behave as hidden amine has attracted many medicinal chemists to

incorporate this feature in drug design. Some interesting compounds are as under.

Treatment of Hypertension Calcium Channel Blokers

Calcium Channel Blockers Company Name: Merck & Co.

Drug Data Report, 8(1), 35 (1986). Drug Data Report, 10(3), 200 (1988).

NH

NH

X

O

EtO

CH3

OCH3

NH

NH

X

O

EtO

CH3

OCH3

O

CH3

NH

NH

X

O

EtO

CH3

OCH3

OO

29a X = S

29b X = O

30a X = S

30b X = O

31a X = S

31b X = O

NH

N

CH3 CH3

O

O

CH3

NH

NH

O CH3

O

CH3

NO2

32 33



Moreover one compound (33) is very active against non-nucleoside inhibitor of

human hepatitis B virus (IC50 = 53 nM for reduction of HBV DNA in human hepatoma

HepG2.2.15 cells) with low cytotoxicity in uninfected cells (CC50 = 7 mcM). Compound

inhibited both viral DNA and viral cores in HepG2.2.15 cells and HBV-transfected cell

lines, whereas it did not affect the activity of endopolymerase and had no effect on other

DNA or RNA viruses. In vivo in a transgenic mouse model, oral doses of 3-100 mg/kg

b.i.d. or t.i.d. for up to 28 days dose-dependently.

Decreased viral DNA in the liver and plasma with efficacy comparable to

lamivudine. However, unlike lamivudine, compound reduced cytoplasmic HBV core

antigen (HBcAg) in the liver of mice. Pharmacokinetic studies in mice showed rapid

absorption, 30 % bioavailability and dose-proportional plasma levels.

Compound Code: Bay-41-4109 Calcium Channel Blocker

Anti Hepatities B Virus Drugs Drug Data Report, 8(5), 465 (1986).

Bayer

Drug Data Report, 24(2), 165 (2002).

Leukotrine Antagonist Calcium Channel Blocker

Drug Data Report, 10(10), 826 (1988). Drug Data Report, 10(11), 899 (1988).

NH

NH

CH3

O

O

N

FF

CH3

Cl

F

4N

N

O

OO

O

CH3 CH3

NO2

34 35

N

N

NH

OH

OO

O

CH3 CH3

N

N

O

OO

OCH3

CH3 S

N

CH3

NO2

CH3

CH3MAR-99

36



Antifungal Agent Antimalarial Agent

Clin Microbiol Infect, 9, 1504 (2003). Iancet, 361 (9357), 577 (2003).

In vitro susceptibility of Candida species isolated from cancer patients against

some antifungal agents.

Acute Myocardial Infection Immunosuppressants

Treatment of Antiplatlet Therapy Oncolytic Drug

Antibacterial Drugs Anti HIV Agent

39th Intersci Conf Antimicrob Agents Chemother Reverse Transcripase Inhibitors

(Sept 26-29, San Francisco) 1999, Abst F1808 Non-nucleoside HIV-1 reverse

In vitro activity of novel 6-anilinouracils targeted transcriptase inhibitor, Compound

to DNA polymerase. was active not only against wild-type

HIV-1 strains (IC50 = 3 nM against

IIIB and NL4-3 HIV-1 strains).

N

NH

NH2

F

O N

N

NH2

NH2Cl

CH3

N

NN

N

N

N

N

N

OH

OH

OH

OH

N

NHNH

NHN

Cl

Cl

Cl

ClO CH3

O

Dipyridamole

NH

N

O

OH

NH

CH3 CH3

O

N

NH

S

CH3

CH3O

O

O

CH3

TNK-6123

Flucytosine (Flurocytosine) Primethamine



CATALYTIC STUDY OF MOLECULAR IODINE

Due to some limitations of Biginelli method and strong acidic conditions94, there

are several efficient methods developed for the synthesis of 1,4-DHPMs, which comprise

the use of Silica triflate95, Iodotrimethylsilane in acetonitrile96, Strontium(II)nitrate97,

PEG-400098, chloroacetic acid99, InBr3100, microwave101,102, KSF montmorillonite103 etc

as catalysts. However, the use of high temperatures, expensive metal precursors and

longer reaction times are limits of these methods. Due to these problems, the development

of an efficient and versatile method for the synthesis of 1,4-DHPMs is an interesting

research area and there is a scope for further improvement towards mild reaction

conditions and to improve the yields of the reaction.

Molecular iodine has attracted attention as an inexpensive, readily available catalyst

for various organic transformations104 to afford the corresponding products in excellent

yields with high selectivity. It has been used as a mild Lewis acid in the dehydration of

tertiary alcohols to alkenes, in the formation of ethers, as well as â-keto enol ethers105,

for esterification106, transesterification107, acetylation108 and benzothiophene109 formation,

but there are only few reports about its use for the synthesis of DHPMs110.

Therefore, it is worthwhile to synthesize some new 1,4-DHPMs from three-

components domino reaction promoted by a catalytic amount of molecular iodine under

mild reaction conditions. Iodine has been used as a mild Lewis acid and may play a

crucial role in accelerating the dehydrative steps and enolization of 1,3-diketone

compounds. The present methodology offers very attractive features such as short

reaction time, milder reaction condition and good to excellent product yields and

commercially available iodine as a powerful catalyst for the synthesis for one pot multi-

component condensation reactions.

A simple, inexpensive and efficient one-pot synthesis of 1,4-dihydropyridine

derivatives at room temperature using catalytic amount of iodine were reported by R.

S. Varma et al111 with excellent product yields.

REACTION MECHANISM

In accord with the literature, mechanism of the formation of DHPMs112 and role

of iodine as a catalyst113, it is possible in our reaction that iodine catalyzes the reaction

as a mild Lewis acid. The mechanism proposed by our group120 is shown below. In the

presence of iodine, 1,3-diketone 2 is in equilibrium with the enol form (I). The enol



immediately attacks the iodine-activated N-acylinium ion (II) intermediate generated

from the reaction of (1) and (3) to form intermediate (III), which then undergoes an

intramolecular cyclization to give (IV). The subsequent dehydration of (IV) results in

dihydropyrimidine (V).


Synthesis anticancer, antitubercular and antimicrobial activity of some new

pyrimidine derivatives (37) have been reported by K. S. Nimavat112, some new

thiopyrimidine and oxopyrimidine heterocycles (38) bearing 4-(methylsulfonyl)phenyl

nucleus as potent antitubercular and antimicrobial agents was developed and reported

Ph

O H O O

R2R

NH2O

NHR1

+

O OH

R2R

I2

I2N

R1

Ph

NH

O

+

NH

NH O

R1

PhO

R

R2 O

I2

NH

N

Ph

R1

OR2

OH

O

R

-H2O

NH

N

Ph

R1

OR2

O

R

213

III

III IV

V



by D. J. Paghdar113. M. R. Patel114 have reported synthesis and evaluation of

pharmacological activity of some new aminopyrimidine and thiopyrimidine derivatives.

J. D. Akbari and coworkers115 has reported following new series and activities

of some new DHPM’s synthesis of some new 1,2,3,4-tetrahydropyrimidine-2-ones and

their thiazolo[3,2-a]pyrimidine derivatives (38) as a potential biological agents. Synthesis

of some new pyrazolo[3,4-d]pyrimidines and thiazolo[4,5-d]pyrimidines116 (39) and

evaluation of their antimicrobial activities. Green chemistry approach117 to synthesis of

some new trifluoromethyl containing tetrahydropyrimidines under solvent free conditions.

Synthesis and antimicrobial activities of some new pyrazolo[3,4-d]pyrimidines and

thiazolo[4,5-d]pyrimidines118.

M. J. Ladani119 reported synthesis and biological study of oxopyrimidines and

thiopyrimidines (40) of 2-(2,4-dichlorophenyl)imidazo[1,2-a]pyridin-3-carbaldehyde,

multi-component synthesis of dihydropyrimidines (41) by iodine catalyst at ambient

temperature and in vitro antimycobacterial activity was reported by P. D. Zalavadiya120.

N

N

R

X

Br

N

NH

R

X

SOCH3

O

( 36 ) ( 37 )

N

N

R

SCH3

O

NH

Cl

NH

NH

R

S

NH

O

S

( 38 ) ( 39 )

N

N

Cl

Cl

NH

NR

X

( 40 )

RNH

N

O Cl

F

CH3OR

( 41 )



In the past years, considerable evidence has been accumulated to demonstrate

the pharmacodynamic and chemotherapeutic activities of tetrahydropyrimidine derivatives.

To further evaluate the potential of such type of compounds, the synthesis have been

carried out which have been described as under.

SECTION-I: SYNTHESIS OF N-(4-CHLOROPHENYL)-1,2,3,4-TETRAHYDRO

-6-ISOPROPYL-4-ARYL-2-OXO/THIOXOPYRIMIDINE-5-

CARBOXAMIDES USING CONVENTIONAL METHOD AND

MOLECULAR IODINE AS CATALYST AND BIOLOGICAL

SCREENING.

SECTION-II:SYNTHESIS AND BIOLOGICAL SCREENING OF N-(4-

CHLOROPHENYL)-3-FORMYL-6-ISOPROPYL-2-OXO-4-ARYL-

1,2,3,4-TETRAHYDROPYRIMIDINE-5-CARBOXAMIDES.

SECTION-III:SYNTHESIS AND BIOLOGICAL SCREENING OF N-(4-

CHLOROPHENYL)-3-FORMYL-6-ISOPROPYL-2-THIOXO-4-

A R Y L - 1 , 2 , 3 , 4 - T E T R A H Y D R O P Y R I M I D I N E - 5 -

CARBOXAMIDES.

Part-Part-Part-Part-Part-CCCCC(Section-I)(Section-I)(Section-I)(Section-I)(Section-I)

Synthesis of 1,4-Dihydropyrimidines

using conventional method and molecular

iodine as a catalyst, Characterization

and biological screening

159



SECTION-I

SYNTHESIS OF N - (4-CHLOROPHENYL)-1,2 ,3 ,4-TETRAHYDRO-6-

ISOPROPYL-4-ARYL-2-OXO/THIOXOPYRIMIDINE-5-CARBOXAMIDES

USING CONVENTIONAL METHOD AND MOLECULAR IODINE AS

CATALYST AND BIOLOGICAL SCREENING.


elemental analysis, Infrared, 1H Nuclear Magnetic Resonance spectroscopy and further






160



REACTION SCHEME

Classical Method

Catalytic Method

CH3

CH3 O

ONH

Cl

+

R

O

X

NH2

NH2

EtoH, H+

Reflux

NH

NH

R

CH3

CH3

O

NH

Cl

X

CH3

CH3 O

ONH

Cl

+

R

O

X

NH2

NH2

NH

NH

R

CH3

CH3

O

NH

Cl

X

I2

RT

161








[A] Preparation of N-(4-Chlorophenyl)-4-methyl-3-oxopentanamide.

A suspension of methylisobutryl acetate (0.01 mol, 1.44 ml) and 4-choloroaniline

(0.01 mol, 1.27 gm) in toluene (50 ml) containing catalytic amount of NaOH solution

(0.05 ml, 40 %) was refluxed on oil bath for 8 hr. After completion of the reaction (TLC

monitoring) the solvent was removed under reduced pressure, separated solid was filtered

and washed with petroleum ether and crystallized from ethanol to give analytically pure

product. M. P. 114 °C, Yield 67 %, Calcd. C, 60.13%; H, 5.89%; N, 5.84% for C,

60.04%; H, 5.98%; N, 5.78%.

Classical Method

[B] General procedure for the preparation of N-(4-Chlorophenyl)-1,2,3,4-

tetrahydro-6-isopropyl-4-aryl-2-oxo/thioxopyrimidine-5-carboxamides

The warm mixture of N-(4-chlorophenyl)-4-methyl-3-oxopentanamide (0.01 mol,

2.39 gm), substituted benzaldehyde (0.01 mol) and urea/thiourea (0.01 mol) in ethanol

(15 ml), containing 0.4 ml of concentrated HCl was heated under reflux for 18-24 hr.

After completion of the reaction, the reaction mixture was allowed to stand at RT for

several hours and precipitation was obtained. The product was filtered, washed with

chilled methanol and isolated product crystallized from suitable solvent. The physical

constants of the product are recorded in Table-7a and 8a.

162



Catalytic Method

General procedure for the preparation of N-(4-Chlorophenyl)-1,2,3,4-tetrahydro-

6-isopropyl-4-aryl-2-oxo/thioxopyrimidine-5-carboxamides using molecular iodine

as a catalyst

A mixture of substituted benzaldehyde (0.01 mole), N-(4-chlorophenyl)-4-

methyl-3-oxopentanamide (2.39 gm, 0.01 mole), urea/thiourea (0.01 mole) and iodine

(0.38 gm, 1.5 mmole) was charged in a round bottom flask containing ethanol (10 ml).

The reaction mixture was then stirred at room temperature until the reaction was

completed (4-5 hr monitored by TLC). The reaction mixture was treated with aq.

Na2S2O3 solution, extracted into ethyl acetate (2 × 20 ml). The solvent was removed in

vacuo and the resulting crude product was crystallized from the suitable solvent to give

the analytically pure product. The physical constants of the product are recorded in

Table-7a and 8a.

[C] Biological screening of N-(4-Chlorophenyl)-1,2,3,4-tetrahydro-6-isopropyl-

4-aryl-2-oxo/thioxopyrimidine-5-carboxamides



Table-7b and 8b.

163



Table-7a: Physical constants of N-(4-Chlorophenyl)-1,2,3,4-tetrahydro-6-

isopropyl-4-aryl-2-oxoyrimidine-5-carboxamides

R

NH

NH

CH3

CH3

O

O

NH

Cl

Sr.No.

SubstitutionR M. F./ Mol. Wt. M.P.

oC

ConventionalMethod

Catalyticmethod


Yield%

Time(hr)

Yield%

Time(hr) C H N

7a H C20H20ClN3O2369.84 269-270 35 22 85 5 64.95

64.865.455.52

11.3611.23

7b 4-OCH3C21H22ClN3O3

399.87 272-274 51 21 69 4.5 63.0862.97

5.555.53

10.5110.55

7c 3-NO2C20H19ClN4O4

414.84 282-284 59 18 93 4 57.9057.98

4.624.69

13.5113.44

7d 4-Cl C20H19Cl2N3O2404.28 234-236 40 22 78 4.25 59.42

59.314.744.79

10.3910.30

7e 3,4-(OCH3)2C22H24ClN3O4

429.89 227-229 47 21 82 4.75 61.4661.38

5.635.71

9.779.72

7f 2,5-(OCH3)2C22H24ClN3O4

429.89 215-217 52 21 79 4.75 61.4661.33

5.635.67

9.779.70

7g 2-OCH3C21H22ClN3O3

399.87 253-254 58 23 73 4.5 63.0863.01

5.555.50

10.5110.58

7h 2-OH C20H20ClN3O3385.84 262-263 43 24 70 4.75 62.26

62.145.225.30

10.8910.78

7i 4-NO2C20H19ClN4O4

414.84 288-290 56 22 89 4.25 57.9057.81

4.624.71

13.5113.46

7j 3-Br C20H19BrClN3O2448.74 225-227 45 21 84 4.5 53.53

53.444.274.35

9.369.29

164



Table-8a: Physical constants of N-(4-Chlorophenyl)-1,2,3,4-tetrahydro-6-

isopropyl-4-aryl-2-thioxopyrimidine-5-carboxamides

R

NH

NH

CH3

CH3

S

O

NH

Cl

Sr.No.

SubstitutionR M. F./ Mol. Wt. M.P.

oC

ConventionalMethod

Catalyticmethod


Yield%

Time(hr)

Yield%

Time(hr) C H N

8a H C20H20ClN3OS385.91 280-282 27 24 80 5.25 62.25

62.145.225.18

10.8910.77

8b 4-OCH3C21H22ClN3O2S

415.93 265-267 45 23 72 4.75 60.6460.24

5.335.14

10.109.96

8c 3-NO2C20H19ClN4O3S

430.90 278-280 36 18 89 4 55.7555.47

4.444.31

13.0012.97

8d 4-Cl C20H19Cl2N3OS420.35 245-246 42 23 81 4.25 57.15

57.014.564.44

10.009.78

8e 3,4-(OCH3)2C22H24ClN3O3S

445.96 251-253 51 21 76 4.25 59.2559.11

5.425.36

9.429.31

8f 2,5-(OCH3)2C22H24ClN3O3S

445.96 255-257 46 22 81 4.25 59.2559.08

5.425.27

9.429.21

8g 2-OCH3C21H22ClN3O2S

415.93 278-279 55 23 78 4.75 60.6460.37

5.335.21

10.109.92

8h 2-OH C20H20ClN3O2S401.90 280-281 38 21 66 5 59.77

59.565.024.92

10.4610.28

8i 4-NO2C20H19ClN4O3S

430.90 274-275 49 20 92 4.25 55.7555.61

4.444.14

13.0012.85

8j 3-Br C20H19BrClN3OS464.80 258-260 41 23 78 4.5 51.68

51.574.124.19

9.048.96


Pyrimidine Derivatives…

SPECTRAL STUDY

IR spectra of N-(4-Chlorophenyl)-1,2,3,4-tetrahydro-6-isopropyl-4-(3,4-

dimethoxyphenyl)-2-oxoyrimidine-5-carboxamide.

5007501000125015001750200025003000350040001/cm

0

15

30

45

60

75

90

%T

3330.21

3285.85 32

47.27

2996.52

2934.79

2835.45

1681.98

1657.87

1591.33

1518.031471.74

1398.44

1342.50

1269.20

1198.80

1164.08

1092.71

1029.06

851.60

813.02

737.80

674.14

594.10

469.68

3,4-diOMe-SDHPM




Alkane -CH3





Aromatic

C-H str. 2996



C-H o.p bending 851

Carbonyl -C=O 1681, 1657

Amine -NH str. 3285

Halide -C-Cl 737

NH

NH

O

NH

Cl

OCH3

CH3

OCH3

O

CH3



SPECTRAL STUDY

IR spectra of N-(4-Chlorophenyl)-1,2,3,4-tetrahydro-6-isopropyl-4-(2,5-

dimethoxyphenyl)-2-oxoyrimidine-5-carboxamide.

5007501000125015001750200025003000350040001/cm

0

25

50

75

100

%T

3373.61

3194.23

2997.48

2935.76

2904.89

2833.52

1901.88

1668.48

1591.33

1525.74

1498.741483.31

1375.29

1307.78

1238.34

1217.12 1188.19

1062.81

1030.02

979.87

837.13

705.97

584.45 501.51

DHPM-06-A Instrument: Shimadzu FTIR-8400 using KBr DRS techniques. The percentage transmittance is



Alkane -CH3





Aromatic

C-H str. 2997

C=C (skeleton) 1483,1498,1525


C-H o.p bending 837

Carbonyl -C=O 1668

Amine-NH str. 3376

-NH def. 1591

Halide -C-Cl 705

NH

NH

O

NH

Cl

SCH3

CH3

O

O

CH3

CH3



1H NMR spectra of N-(4-Chlorophenyl)-1,2,3,4-tetrahydro-6-isopropyl-4-(4-

nitrophenyl)-2-oxoyrimidine-5-carboxamide.


Sr.No.


Relative No.of Protons Multiplicity Inference J value in

Hz

1 1.53 3H singlet -CH(CH3)2 -



4 5.18-5.19 1H doublet -Ha 4.52

5 7.27-7.29 2H dd Ar-Hb,b' 9.8 & 2.9

6 7.54-7.58 2H multiplet Ar-H -

7 7.59-7.63 2H dd Ar-Ha,a' 9.9 & 2.9

8 8.12-8.14 1H doublet Ar-H 8.1

9 8.27 1H singlet Ar-H -

10 8.45 1H singlet -NH -

11 9.03 1H doublet -NH 4.64


NH

NH

O

NH

Cl

OCH3

CH3

N+

O-

O

a

a'

b

b'

c



1H NMR spectra of N-(4-Chlorophenyl)-1,2,3,4-tetrahydro-6-isopropyl-4-phenyl-2-

oxoyrimidine-5-carboxamide.


Sr.No.



in Hz

1 1.53 3H singlet -CH3 -

2 1.54 3H singlet -CH3 -

3 3.83 1H singlet -CH -

4 5.05-5.06 1H doublet chiral-H 4.52





NH

NH

O

NH

Cl

SCH3

CH3

169



EI-

Mas

s spe

ctra

of N

-(4-

Chl

orop

heny

l)-1

,2,3

,4-t

etra

hydr

o-6-

isop

ropy

l-4-

(3-n

itro

phen

yl)-

2-ox

oyri

mid

ine-

5-ca

rbox

amid

e.

Inst

rum

ent:

Shi

mad

zu G

C-M

S Q

P-20

10, D

I-pr

obe,

EI-

met

hod.

NH

N H

O

NH

Cl

OC

H3

CH

3

N+

O-

O

M. W

t. =

414

.84

170



EI-

Mas

s spe

ctra

of N

-(4-

Chl

orop

heny

l)-1

,2,3

,4-t

etra

hydr

o-6-

isop

ropy

l-4-

(3,4

-dim

etho

xyph

enyl

)-2-

oxoy

rim

idin

e-5-

carb

oxam

ide.

Inst

rum

ent:

Shi

mad

zu G

C-M

S Q

P-20

10, D

I-pr

obe,

EI-

met

hod.

NH

N H

O

NH

Cl

OC

H3

CH

3

OCH

3O

CH

3

M. W

t. =

429

.89

171



EI-

Mas

s spe

ctra

of N

-(4-

Chl

orop

heny

l)-1

,2,3

,4-t

etra

hydr

o-6-

isop

ropy

l-4-

phen

yl-2

-thi

oxoy

rim

idin

e-5-

carb

oxam

ide.

Inst

rum

ent:

Shi

mad

zu G

C-M

S Q

P-20

10, D

I-pr

obe,

EI-

met

hod.

NH

N H

O

NH

Cl

SC

H3

CH

3

M. W

t. =

385

.91

172



EI-

Mas

s spe

ctra

of N

-(4-

Chl

orop

heny

l)-1

,2,3

,4-t

etra

hydr

o-6-

isop

ropy

l-4-

(2-m

etho

xyph

enyl

)-2-

thio

xoyr

imid

ine-

5-ca

rbox

amid

e.

Inst

rum

ent:

Shi

mad

zu G

C-M

S Q

P-20

10, D

I-pr

obe,

EI-

met

hod.

NH

N H

O

NH

Cl

SC

H3

CH

3

OC

H3

M. W

t. =

415

.93

173



Tabl

e-7b

: Ant

imic

robi

al a

ctiv

ity

of N

-(4-

Chl

orop

heny

l)-1

,2,3

,4-t

etra

hydr

o-6-

isop

ropy

l-4-

aryl

-2-o

xoyr

imid

ine-

5-ca

rbox

amid

es.

Sr.

No.

Ant

ibac

teria

l Act

ivity

Ant

ifung

al A

ctiv

ity

S. a

ureu

sS.

epi

derm

idis

E. c

oli

P. a

erug

inos

aA

. nig

er

7a12

(0.6

0)C

1, (0

.57)

C2

(0.6

6)C

3, (0

.60)

C4

19(0

.79)

C1,

(0.7

9)C

2(1

.11)

C3,

(1.0

5)C

4

10(0

.45)

C1,

(0.4

0)C

2(0

.41)

C3,

(0.5

5)C

4

20(0

.95)

C1,

(0.8

0)C

2(0

.80)

C3,

(1.3

3)C

4

10(0

.41)

C5

7b14

(0.7

0)C

1, (0

.67)

C2

(0.7

7)C

3, (0

.70)

C4

23(0

.95)

C1,

(0.9

5)C

2(1

.35)

C3,

(1.2

7)C

4

12(0

.54)

C1,

(0.4

8)C

2(0

.50)

C3,

(0.6

6)C

4

14(0

.66)

C1,

(0.5

6)C

2(0

.56)

C3,

(0.9

3)C

4

15 (0

.62)

C5

7c17

(0.8

5)C

1, (0

.81)

C2

(0.9

4)C

3, (0

.85)

C4

10(0

.41)

C1,

(0.4

1)C

2(0

.58)

C3,

(0.5

5)C

4

15(0

.68)

C1,

(0.6

0)C

2(0

.62)

C3,

(0.8

3)C

4

18(0

.85)

C1,

(0.7

2)C

2(0

.72)

C3,

(1.2

0)C

4

24(1

.00)

C5

7d11

(0.5

5)C

1, (0

.52)

C2

(0.6

1)C

3, (0

.55)

C4

12(0

.50)

C1,

(0.5

0)C

2(0

.70)

C3,

(0.6

6)C

4

17(0

.77)

C1,

(0.6

8)C

2(0

.70)

C3,

(0.9

4)C

4

08(0

.38)

C1,

(0.3

2)C

2(0

.32)

C3,

(0.5

3)C

4

16(0

.66)

C5

7e20

(1.0

0)C

1, (0

.96)

C2

(1.1

1)C

3, (1

.00)

C4

16(0

.66)

C1,

(0.6

6)C

2(0

.94)

C3,

(0.8

8)C

4

13(0

.59)

C1,

(0.5

2)C

2(0

.54)

C3,

(0.7

2)C

4

12(0

.57)

C1,

(0.4

8)C

2(0

.48)

C3,

(0.8

0)C

4

19(0

.79)

C5

7f09

(0.4

5)C

1, (0

.42)

C2

(0.5

0)C

3, (0

.45)

C4

11(0

.45)

C1,

(0.4

5)C

2(0

.64)

C3,

(0.6

1)C

4

21(0

.95)

C1,

(0.8

4)C

2(0

.87)

C3,

(1.1

6)C

4

16(0

.76)

C1,

(0.6

4)C

2(0

.64)

C3,

(1.0

6)C

4

13(0

.54)

C5

174



7g13

(0.6

5)C

1, (0

.62)

C2

(0.7

2)C

3, (0

.65)

C4

09(0

.37)

C1,

(0.3

7)C

2(0

.52)

C3,

(0.5

0)C

4

22(1

.00)

C1,

(0.8

8)C

2(0

.91)

C3,

(1.2

2)C

4

15(0

.71)

C1,

(0.6

0)C

2(0

.60)

C3,

(1.0

0)C

4

10(0

.41)

C5

7h20

(1.0

0)C

1, (0

.96)

C2

(1.1

1)C

3, (1

.00)

C4

15(0

.62)

C1,

(0.6

2)C

2(0

.88)

C3,

(0.8

3)C

4

11(0

.50)

C1,

(0.4

4)C

2(0

.45)

C3,

(0.6

1)C

4

17(0

.80)

C1,

(0.6

8)C

2(0

.68)

C3,

(1.1

3)C

4

23(0

.95)

C5

7i10

(0.5

0)C

1, (0

.47)

C2

(0.5

5)C

3, (0

.50)

C4

12(0

.50)

C1,

(0.5

0)C

2(0

.70)

C3,

(0.6

6)C

4

14(0

.63)

C1,

(0.5

6)C

2(0

.58)

C3,

(0.7

7)C

4

21(1

.00)

C1,

(0.8

4)C

2(0

.84)

C3,

(1.4

0)C

4

18(0

.75)

C5

7j16

(0.8

0)C

1, (0

.76)

C2

(0.8

9)C

3, (0

.80)

C4

22(0

.91)

C1,

(0.9

1)C

2(1

.29)

C3,

(1.2

2)C

4

18(0

.81)

C1,

(0.7

2)C

2(0

.75)

C3,

(1.0

0)C

4

12(0

.57)

C1,

(0.4

8)C

2(0

.48)

C3,

(0.8

0)C

4

16(0

.66)

C5

C1

2024

2221

00

C2

2124

2525

00

C3

1817

2425

00

C4

2018

1815

00

C5

0000

0000

24

Act

ivity

inde

x =

Inhi

bitio

n zo

ne o

f the

sam

ple

/ Inh

ibiti

on z

one

of th

e st

anda

rd

For a

ntib

acte

rial a

ctiv

ity: C

1 = A

mox

icill

in, C

2 = C

ipro

flox

acin

, C3 =

Cep

hale

xin,

C4 =

Ery

thro

myc

in.

For a

ntifu

ngal

activ

ity: C

5 = G

rese

oful

vin.

175



Tabl

e-8b

: Ant

imic

robi

al a

ctiv

ity

of N

-(4-

Chl

orop

heny

l)-1

,2,3

,4-t

etra

hydr

o-6-

isop

ropy

l-4-

aryl

-2-t

hiox

oyri

mid

ine-

5-ca

rbox

amid

es.

Sr.

No.

Ant

ibac

teria

l Act

ivity

Ant

ifung

al A

ctiv

ity

S. a

ureu

sS.

epi

derm

idis

E. c

oli

P. a

erug

inos

aA

. nig

er

8a16

(0.8

0)C

1, (0

.76)

C2

(0.8

8)C

3, (0

.80)

C4

16(0

.66)

C1,

(0.6

6)C

2(0

.94)

C3,

(0.8

8)C

4

16(0

.72)

C1,

(0.6

0)C

2(0

.66)

C3,

(0.8

8)C

4

18(0

.85)

C1,

(0.7

2)C

2(0

.72)

C3,

(1.2

0)C

4

13 (0

.54)

C5

8b18

(0.9

0)C

1, (0

.85)

C2

(1.0

0)C

3, (0

.90)

C4

18(0

.75)

C1,

(0.7

5)C

2(1

.05)

C3,

(1.0

0)C

4

15(0

.66)

C1,

(0.6

0)C

2(0

.62)

C3,

(0.8

3)C

4

14(0

.66)

C1,

(0.5

6)C

2(0

.56)

C3,

(0.9

3)C

4

20 (0

.83)

C5

8c13

(0.6

5)C

1, (0

.61)

C2

(0.7

2)C

3, (0

.65)

C4

14(0

.58)

C1,

(0.5

8)C

2(0

.82)

C3,

(0.7

7)C

4

14(0

.63)

C1,

(0.5

6)C

2(0

.58)

C3,

(0.7

7)C

4

12(0

.57)

C1,

(0.4

8)C

2(0

.48)

C3,

(0.8

0)C

4

15 (0

.62)

C5

8d12

(0.6

0)C

1, (0

57)C

2(0

.66)

C3,

(0.6

0)C

4

16(0

.66)

C1,

(0.6

6)C

2(0

.94)

C3,

(0.8

8)C

4

13(0

.59)

C1,

(0.5

2)C

2(0

.54)

C3,

(0.7

2)C

4

18(0

.85)

C1,

(0.7

2)C

2(0

.72)

C3,

(1.2

0)C

4

14 (0

.58)

C5

8e19

(0.9

5)C

1, (0

.90)

C2

(1.0

5)C

3, (0

.95)

C4

14(0

.58)

C1,

(0.5

8)C

2(0

.82)

C3,

(0.7

7)C

4

14(0

.63)

C1,

(0.5

6)C

2(0

.58)

C3,

(0.7

7)C

4

21(1

.00)

C1,

(0.8

4)C

2(0

.84)

C3,

(1.4

0)C

4

16(0

.66)

C54

8f10

(0.5

0)C

1, (0

.47C

2(0

.55)

C3,

(0.5

0)C

4

12(0

.50)

C1,

(0.5

0C2

(0.7

0)C

3, (0

.66)

C4

12(0

.54)

C1,

(0.4

8)C

2(0

.50)

C3,

(0.6

6)C

4

14(0

.66)

C1,

(0.5

6)C

2(0

.56)

C3,

(0.9

3)C

4

16 (0

.66)

C54

176



8g11

(0.5

5)C

1, (0

.52)

C2

(0.6

1)C

3, (0

.55)

C4

18(0

.75)

C1,

(0.7

5)C

2(1

.05)

C3,

(1.0

0)C

4

15(0

.68)

C1,

(0.6

0)C

2(0

.62)

C3,

(0.8

3)C

4

13(0

.61)

C1,

(0.5

2)C

2(0

.52)

C3,

(0.8

6)C

4

18(0

.75)

C5

8h10

(0.5

0)C

1, (0

.47)

C2

(0.5

5)C

3, (0

.50)

C4

11(0

.45)

C1,

(0.4

5)C

2(0

.67)

C3,

(0.6

1)C

4

14(0

.63)

C1,

(0.5

6)C

2(0

.58)

C3,

(0.7

7)C

4

11(0

.52)

C1,

(0.4

4)C

2(0

.44)

C3,

(0.7

3)C

4

13(0

.54)

C5

8i18

(0.9

0)C

1, (0

.85)

C2

(1.0

0)C

3, (0

.90)

C4

12(0

.50)

C1,

(0.5

0)C

2(0

.70)

C3,

(0.6

6)C

4

10(0

.45)

C1,

(0.4

0)C

2(0

.41)

C3,

(0.5

5)C

4

17(0

.80)

C1,

(0.6

8)C

2(0

.68)

C3,

(0.8

8)C

4

18(0

.75)

C5

8j23

(1.1

5)C

1, (1

.09)

C2

(1.2

7)C

3, (1

.15)

C4

17(0

.70)

C1,

(0.7

0)C

2(1

.00)

C3,

(0.9

4)C

4

11(0

.50)

C1,

(0.4

4)C

2(0

.45)

C3,

(0.6

1)C

4

15(0

.71)

C1,

(0.6

0)C

2(0

.60)

C3,

(1.0

0)C

4

14(0

.58)

C5

C1

2024

2221

00

C2

2124

2525

00

C3

1817

2425

00

C4

2018

1815

00

C5

0000

0000

24

Act

ivity

inde

x =

Inhi

bitio

n zo

ne o

f the

sam

ple

/ Inh

ibiti

on z

one

of th

e st

anda

rd

For a

ntib

acte

rial a

ctiv

ity: C

1 = A

mox

icill

in, C

2 = C

ipro

flox

acin

, C3 =

Cep

hale

xin,

C4 =

Ery

thro

myc

in.

For a

ntifu

ngal

activ

ity: C

5 = G

rese

oful

vin.

Part-Part-Part-Part-Part-CCCCC(Section-II)(Section-II)(Section-II)(Section-II)(Section-II)


biological screening of

3-Formyl-1,4-dihydropyrimidinones



SECTION-II

SYNTHESIS AND BIOLOGICAL SCREENING OF N-(4-CHLOROPHENYL)-

3-FORMYL-6-ISOPROPYL-2-OXO-4-ARYL-1,2 ,3 ,4-TETRAHYDRO-

PYRIMIDINE-5-CARBOXAMIDES.

Much interest has been focused around dihydropyrimidinone derivatives because

of their wide variety of pharmacological properties and industrial applications. In view

of these findings and achieve to better drug potency, we have synthesized N-(4-

chlorophenyl)-3-formyl-6-isopropyl-2-oxo-4-aryl-1,2,3,4-tetrahydropyrimidine-5-

carboxamides by the formylation of N-(4-chlorophenyl)-6-isopropyl-2-oxo-4-aryl-

1,2,3,4-tetrahydropyrimidine-5-carboxamides at low temperature.








NH

NH

R

CH3

CH3

O

NH

Cl

O

DMF + POCl3

0 - 5 °C

N

NH

R

CH3

CH3

O

NH

Cl

O

O








[A] General procedure for the preparation of N-(4-Chlorophenyl)-1,2,3,4-


using molecular iodine as a catalyst

See Part-C, Section-I, Experimental Section [B], Catalytic method.

[B] General procedure for the preparation of N-(4-Chlorophenyl)-3-formyl-6-

isopropyl-2-oxo-4-aryl-1,2,3,4-tetrahydropyrimidine-5-carboxamides.

To a solution of N-(4-Chlorophenyl)-6-isopropyl-2-oxo-4-aryl-1,2,3,4-

tetrahydropyrimidine-5-carboxamide (0.01 mole) in 10 ml of dry DMF, POCl3 (0.01

mole) was added under stirring in an ice bath. The resulting solution was heated at

70 °C for 40 minutes and then was poured into 150 ml of ice water. The product was

filtered and washed with chilled methanol and isolate as crystalline powder. The physical

constants of the product are recorded in Table-9a.

[C] Biological screening of N-(4-Chlorophenyl)-3-formyl-6-isopropyl-2-oxo-4-

aryl-1,2,3,4-tetrahydropyrimidine-5-carboxamides.



Table-9b.



Table-9a: Physical constants of N-(4-Chlorophenyl)-3-formyl-6-isopropyl-2-oxo-

4-aryl-1,2,3,4-tetrahydropyrimidine-5-carboxamides.

R

N

NH

CH3

CH3

O

NH

Cl

O

O

Sr.No.

SubstitutionR


M.P.oC

Yield%


C H N

9a H C21H20ClN3O3397.85 146-148 73 63.40

63.285.075.12

10.5610.47

9b 4-OCH3C22H22ClN3O4

427.88 161-162 69 61.7561.68

5.185.23

9.829.73

9c 3-NO2C21H19ClN4O5

442.85 180-182 86 56.9556.90

4.324.39

12.6512.60

9d 4-Cl C21H19Cl2N3O3432.29 173-175 77 58.34

58.234.434.50

9.729.60

9e 3,4-(OCH3)2C23H24ClN3O5

457.90 168-170 80 60.3360.22

5.285.26

9.189.26

9f 2,5-(OCH3)2C23H24ClN3O5

457.90 165-167 81 60.3360.27

5.285.21

9.189.24

9g 2-OCH3C22H22ClN3O4

427.88 157-159 71 61.7561.66

5.185.25

9.829.76

9h 2-OH C21H20ClN3O4413.85 142-144 67 60.95

60.864.874.96

10.1510.04

9i 4-NO2C21H19ClN4O5

442.85 177-199 84 56.9556.86

4.324.42

12.6512.58

9j 3-Br C21H19BrClN3O3476.75 169-171 67 52.90

52.794.024.10

8.818.89



SPECTRAL STUDY

IR spectra of N-(4-Chlorophenyl)-3-formyl-6-isopropyl-2-oxo-4-(4-chlorophenyl)-

1,2,3,4-tetrahydropyrimidine-5-carboxamide.

5007501000125015001750200025003000350040001/cm

0

15

30

45

60

75

90

%T

3350.463216.41

3164.33 29

96.52

2852.81

2794.95

1708.99

1691.63

1664.62

1596.15

1527.67

1450.52

1399.40

1355.04

1291.39

1145.75

1112.00

1017.48

857.39

821.70

756.12

669.32 62

1.10




Alkane -CH3





Aromatic

C-H str. 3164



C-H o.p bending 857

Aldehyde -C-H 2794, 2852

Carbonyl -C=O 1708

Carbonyl -C=O 1691

Amine -NH str. 3350

Halide -C-Cl 756

N

NH

CH3

CH3

O

NH

Cl

O

O

Cl



1H NMR spectra of N-(4-Chlorophenyl)-3-formyl-6-isopropyl-2-oxo-4-(4-

chlorophenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide.


Sr.No.



in Hz




4 6.00 1H singlet -Ha -



7 9.6 1H singlet(b) -N-H -

8 9.86 1H singlet(b) -N-H -

9 10.11 1H singlet -CHO -

N

NH

CH3

CH3

O

NH

Cl

O

O

Cl

a



EI-

Mas

s of N

-(4-

Chl

orop

heny

l)-3

-for

myl

-6-i

sopr

opyl

-2-o

xo-4

-(4-

met

hoxy

phen

yl)-

1,2,

3,4-

tetr

ahyd

ropy

rim

idin

e-5-

carb

oxam

ide.

Inst

rum

ent:

Shi

mad

zu G

C-M

S Q

P-20

10, D

I-pr

obe,

EI-

met

hod.

N

N H

O

NH

Cl

OC

H3

CH

3

OC

H3

O

M. W

t. =

427

.88



EI-

Mas

s of N

-(4-

Chl

orop

heny

l)-3

-for

myl

-6-i

sopr

opyl

-2-o

xo-4

-(4-

nitr

ophe

nyl)

-1,2

,3,4

-tet

rahy

drop

yrim

idin

e-5-

carb

oxam

ide.

Inst

rum

ent:

Shi

mad

zu G

C-M

S Q

P-20

10, D

I-pr

obe,

EI-

met

hod.

N

N H

O

NH

Cl

OC

H3

CH

3

O

N+

O-

O

M. W

t. =

442

.85



Tabl

e-9b

: A

ntim

icro

bial

act

ivit

y of

N-(

4-C

hlor

ophe

nyl)

-3-f

orm

yl-6

-iso

prop

yl-2

-oxo

-4-a

ryl-

1,2,

3,4-

tetr

ahyd

ropy

rim

idin

e-5-

carb

oxam

ides

.

Sr.

No.

Ant

ibac

teria

l Act

ivity

Ant

ifung

al A

ctiv

ity

S. a

ureu

sS.

epi

derm

idis

E. c

oli

P. a

erug

inos

aA

. nig

er

9a20

(1.0

0)C

1, (0

.96)

C2

(1.1

1)C

3, (1

.00)

C4

10(0

.41)

C1,

(0.4

1)C

2(0

.58)

C3,

(0.5

5)C

4

13(0

.59)

C1,

(0.5

2)C

2(0

.54)

C3,

(0.7

2)C

4

10(0

.47)

C1,

(0.4

0)C

2(0

.40)

C3,

(0.6

6)C

4

16(0

.66)

C5

9b11

(0.5

5)C

1, (0

.52)

C2

(0.6

1)C

3, (0

.55)

C4

13(0

.54)

C1,

(0.5

4)C

2(0

.76)

C3,

(0.7

2)C

4

18(0

.81)

C1,

(0.7

2)C

2(0

.75)

C3,

(1.0

0)C

4

11(0

.52)

C1,

(0.4

4)C

2(0

.44)

C3,

(0.7

3)C

4

19(0

.79)

C5

9c14

(0.7

0)C

1, (0

.67)

C2

(0.7

7)C

3, (0

.70)

C4

18(0

.75)

C1,

(0.7

5)C

2(1

.05)

C3,

(1.0

0)C

4

12(0

.54)

C1,

(0.4

8)C

2(0

.50)

C3,

(0.6

6)C

4

17(0

.80)

C1,

(0.6

8)C

2(0

.68)

C3,

(1.1

3)C

4

22(0

.91)

C5

9d09

(0.4

5)C

1, (0

.42)

C2

(0.5

0)C

3, (0

.45)

C4

17(0

.70)

C1,

(0.7

0)C

2(1

.00)

C3,

(0.9

4)C

4

22(1

.00)

C1,

(0.8

8)C

2(0

.91)

C3,

(1.2

2)C

4

08(0

.38)

C1,

(0.3

2)C

2(0

.32)

C3,

(0.5

3)C

4

14(0

.58)

C5

9e16

(0.8

0)C

1, (0

.76)

C2

(0.8

9)C

3, (0

.80)

C4

08(0

.33)

C1,

(0.3

3)C

2(0

.47)

C3,

(0.4

4)C

4

09(0

.40)

C1,

(0.3

6)C

2(0

.37)

C3,

(0.5

0)C

4

20(0

.95)

C1,

(0.8

0)C

2(0

.80)

C3,

(1.3

3)C

4

24(1

.00)

C5

9f15

(0.7

5)C

1, (0

.71)

C2

(0.8

3)C

3, (0

.75)

C4

21(0

.87)

C1,

(0.8

7)C

2(1

.23)

C3,

(1.1

6)C

4

10(0

.45)

C1,

(0.4

0)C

2(0

.41)

C3,

(0.5

5)C

4

14(0

.66)

C1,

(0.5

6)C

2(0

.56)

C3,

(0.9

3)C

4

13(0

.54)

C5



9g13

(0.6

5)C

1, (0

.62)

C2

(0.7

2)C

3, (0

.65)

C4

09(0

.37)

C1,

(0.3

7)C

2(0

.52)

C3,

(0.5

0)C

4

22(1

.00)

C1,

(0.8

8)C

2(0

.91)

C3,

(1.2

2)C

4

13(0

.61)

C1,

(0.5

2)C

2(0

.52)

C3,

(0.8

6)C

4

21(0

.87)

C5

9h10

(0.5

0)C

1, (0

.47)

C2

(0.5

5)C

3, (0

.50)

C4

16(0

.66)

C1,

(0.6

6)C

2(0

.94)

C3,

(0.8

8)C

4

18(0

.81)

C1,

(0.7

2)C

2(0

.75)

C3,

(1.0

0)C

4

11(0

.52)

C1,

(0.4

4)C

2(0

.44)

C3,

(0.7

3)C

4

21(0

.87)

C5

9i19

(0.9

5)C

1, (0

.91)

C2

(1.0

5)C

3, (0

.95)

C4

12(0

.50)

C1,

(0.5

0)C

2(0

.70)

C3,

(0.6

6)C

4

15(0

.68)

C1,

(0.6

0)C

2(0

.62)

C3,

(0.8

3)C

4

12(0

.57)

C1,

(0.4

8)C

2(0

.48)

C3,

(0.8

0)C

4

11(0

.45)

C5

9j16

(0.8

0)C

1, (0

.76)

C2

(0.8

9)C

3, (0

.80)

C4

19(0

.79)

C1,

(0.7

9)C

2(1

.11)

C3,

(1.0

5)C

4

10(0

.45)

C1,

(0.4

0)C

2(0

.41)

C3,

(0.5

5)C

4

15(0

.71)

C1,

(0.6

0)C

2(0

.60)

C3,

(1.0

0)C

4

15 (0

.62)

C5

C1

2024

2221

00

C2

2124

2525

00

C3

1817

2425

00

C4

2018

1815

00

C5

0000

0000

24

Act

ivity

inde

x =

Inhi

bitio

n zo

ne o

f the

sam

ple

/ Inh

ibiti

on z

one

of th

e st

anda

rd

For a

ntib

acte

rial a

ctiv

ity: C

1 = A

mox

icill

in, C

2 = C

ipro

flox

acin

, C3 =

Cep

hale

xin,

C4 =

Ery

thro

myc

in.

For a

ntifu

ngal

activ

ity: C

5 = G

rese

oful

vin.

Part-Part-Part-Part-Part-CCCCC(Section-III)(Section-III)(Section-III)(Section-III)(Section-III)


biological screening of

3-Formyl-1,4-dihydropyrimidinthiones

186



SECTION-III

SYNTHESIS AND BIOLOGICAL SCREENING OF N-(4-CHLOROPHENYL)-

3-FORMYL-6-ISOPROPYL-2-THIOXO-4-ARYL-1,2,3,4-TETRAHYDRO-

PYRIMIDINE-5-CARBOXAMIDES.

Compounds containing pyrimidine ring are widely distributed in nature. Many of

these derivatives are reported to possess different biological activities. In view of these

reports, we have synthesized N-(4-chlorophenyl)-3-formyl-6-isopropyl-2-thioxo-4-aryl-

1,2,3,4-tetrahydropyrimidine-5-carboxamides by the formylation of N-(4-chlorophenyl)-

6-isopropyl-2-thioxo-4-aryl-1,2,3,4-tetrahydropyrimidine-5-carboxamides.


elemental analysis, Infrared, 1H Nuclear Magnetic Resonance spectroscopy and further






NH

NH

R

CH3

CH3

O

NH

Cl

S

DMF + POCl3

0 - 5 °C

N

NH

R

CH3

CH3

O

NH

Cl

S

O

187








[A] General procedure for the preparation of N-(4-Chlorophenyl)-1,2,3,4-


using molecular iodine as a catalyst

See Part-C, Section-I, Experimental Section [B], Catalytic method.

[B] General procedure for the preparation of N-(4-Chlorophenyl)-3-formyl-6-

isopropyl-2-thioxo-4-aryl-1,2,3,4-tetrahydropyrimidine-5-carboxamides.

To a suspension of N-(4-Chlorophenyl)-6-isopropyl-4-aryl-2-thioxo-1,2,3,4-

tetrahydropyrimidine-5-carboxamide (0.01 mole) in dry DMF (15 ml), POCl3 (3.06 ml,

0.02 mole) was added under stirring in an ice bath. Stirring was continued at room

temperature for another 20 minute and then solution was poured into 200 ml ice water.

The product was filtered and washed with chilled methanol and isolated as crystalline

powder. The physical constants of the product are recorded in Table-10a.

[C] Biological screening of N-(4-Chlorophenyl)-3-formyl-6-isopropyl-2-thioxo-

4-aryl-1,2,3,4-tetrahydropyrimidine-5-carboxamides.



Table-10b.

188



Table-10a: Physical constants of N-(4-Chlorophenyl)-3-formyl-6-isopropyl-2-

thioxo-4-aryl-1,2,3,4-tetrahydropyrimidine-5-carboxamides.

R

N

NH

CH3

CH3

O

NH

Cl

S

O

Sr.No.

SubstitutionR


M.P.oC

Yield%


C H N

10a H C21H20ClN3O2S413.92 168-170 70 60.94

60.834.874.93

10.1510.08

10b 4-OCH3C22H22ClN3O3S

443.94 151-153 75 59.5259.43

4.995.05

9.479.42

10c 3-NO2C21H19ClN4O4S

458.91 185-186 91 54.9654.91

4.174.10

12.2112.32

10d 4-Cl C21H19Cl2N3O2S448.36 172-173 80 56.25

56.134.274.35

9.379.31

10e 3,4-(OCH3)2C23H24ClN3O4S

473.97 179-180 78 58.2858.14

5.105.04

8.878.76

10f 2,5-(OCH3)2C23H24ClN3O4S

473.97 162-163 74 58.2858.17

5.105.07

8.878.80

10g 2-OCH3C22H22ClN3O3S

443.94 146-147 73 59.5259.44

4.995.03

9.479.39

10h 2-OH C21H20ClN3O3S429.91 135-136 70 58.67

58.564.694.78

9.779.70

10i 4-NO2C21H19ClN4O4S

458.91 181-182 89 54.9654.87

4.174.11

12.2112.27

10j 3-Br C21H19BrClN3O2S492.81 175-176 74 51.18

51.093.893.97

8.538.45



SPECTRAL STUDY

IR spectra of N-(4-Chlorophenyl)-3-formyl-6-isopropyl-2-thioxo-4-(2-hydroxyphenyl)-

1,2,3,4-tetrahydropyrimidine-5-carboxamide.

5007501000125015001750200025003000350040001/cm

30

40

50

60

70

80

90

100

%T3235.70

3114.18

3041.84

2980.12 2847.99

2766.01

1701.27

1539.25

1491.99

1459.20

1399.40

1288.49

1189.15

1089.82

1012.66

938.40 820.74

757.09

668.36

590.24

525.62

506.33

474.50 462.93

2-OH-SDHPM-F Instrument: Shimadzu FTIR-8400 using KBr DRS techniques. The percentage transmittance is



Alkane -CH3





Aromatic

C-H str. 3114

C=C (skeleton) 1539


C-H o.p bending 820

Aldehyde -C-H 2766, 2847

Carbonyl -C=O 1701

Amine -NH str. 3235

Halide -C-Cl 757

N

NH

CH3

CH3

O

NH

Cl

S

O

OH



1H NMR spectra of N-(4-Chlorophenyl)-3-formyl-6-isopropyl-2-thioxo-4-(4-

methoxyphenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide.


Sr.No.



in Hz





5 5.91 1H singlet -He -

6 6.82-6.86 2H dd Ar-Ha,a' 6.8 & 1.9

7 7.14-7.17 2H dd Ar-Hc,c' 8.7 & 2.1

8 7.24-7.27 2H dd Ar-Hb,b' 6.8 & 1.9

9 7.54-7.60 2H dd Ar-Hd,d' 8.8 & 2.0

10 9.75 1H singlet(b) -N-H -

11 9.97 1H singlet(b) -N-H -

12 10.09 1H singlet -CHO -

N

NH

CH3

CH3

O

NH

Cl

S

OCH3

O

a

a'

b

b' c c'

d d'

e

191



EI-

Mas

s of N

-(4-

Chl

orop

heny

l)-3

-for

myl

-6-i

sopr

opyl

-2-t

hiox

o-4-

(met

hoxy

phen

yl)-

1,2,

3,4-

tetr

ahyd

ropy

rim

idin

e-5-

carb

oxam

ide.

Inst

rum

ent:

Shi

mad

zu G

C-M

S Q

P-20

10, D

I-pr

obe,

EI-

met

hod.

N

N H

O

NH

Cl

SC

H3

CH

3

OC

H3

O

M. W

t. =

443

.94

192



EI-

Mas

s of N

-(4-

Chl

orop

heny

l)-3

-for

myl

-6-i

sopr

opyl

-2-t

hiox

o-4-

phen

yl-1

,2,3

,4-t

etra

hydr

opyr

imid

ine-

5-ca

rbox

amid

e.

Inst

rum

ent:

Shi

mad

zu G

C-M

S Q

P-20

10, D

I-pr

obe,

EI-

met

hod.

N

N H

O

NH

Cl

SC

H3

CH

3

O

M. W

t. =

413

.92

193



Tabl

e-10

b: A

ntim

icro

bial

act

ivit

y of

N-(

4-C

hlor

ophe

nyl)

-3-f

orm

yl-6

-iso

prop

yl-2

-thi

oxo-

4-ar

yl-1

,2,3

,4-t

etra

hydr

opyr

imid

ine-

5-

carb

oxam

ides

.

Sr.

No.

Ant

ibac

teria

l Act

ivity

Ant

ifung

al A

ctiv

ity

S. a

ureu

sS.

epi

derm

idis

E. c

oli

P. a

erug

inos

aA

. nig

er

10a

18(0

.90)

C1,

(0.8

6)C

2(1

.00)

C3,

(0.9

0)C

4

11(0

.45)

C1,

(0.4

5)C

2(0

.64)

C3,

(0.6

1)C

4

16(0

.72)

C1,

(0.6

4)C

2(0

.66)

C3,

(0.8

8)C

4

08(0

.38)

C1,

(0.3

2)C

2(0

.32)

C3,

(0.5

3)C

4

19(0

.79)

C5

10b

10(0

.50)

C1,

(0.4

7)C

2(0

.55)

C3,

(0.5

0)C

4

09(0

.37)

C1,

(0.3

7)C

2(0

.52)

C3,

(0.5

0)C

4

18(0

.81)

C1,

(0.7

2)C

2(0

.75)

C3,

(1.0

0)C

4

21(1

.00)

C1,

(0.8

4)C

2(0

.84)

C3,

(1.4

0)C

4

11(0

.45)

C5

10c

11(0

.55)

C1,

(0.5

2)C

2(0

.61)

C3,

(0.5

5)C

4

23(0

.95)

C1,

(0.9

5)C

2(1

.35)

C3,

(1.2

7)C

4

13(0

.59)

C1,

(0.5

2)C

2(0

.54)

C3,

(0.7

2)C

4

14(0

.66)

C1,

(0.5

6)C

2(0

.56)

C3,

(0.9

3)C

4

13(0

.54)

C5

10d

16(0

.80)

C1,

(0.7

6)C

2(0

.89)

C3,

(0.8

0)C

4

19(0

.79)

C1,

(0.7

9)C

2(1

.11)

C3,

(1.0

5)C

4

16(0

.72)

C1,

(0.6

4)C

2(0

.66)

C3,

(0.8

8)C

4

11(0

.52)

C1,

(0.4

4)C

2(0

.44)

C3,

(0.7

3)C

4

24(1

.00)

C5

10e

09(0

.45)

C1,

(0.4

2)C

2(0

.50)

C3,

(0.4

5)C

4

15(0

.62)

C1,

(0.6

2)C

2(0

.88)

C3,

(0.8

3)C

4

20(0

.90)

C1,

(0.8

0)C

2(0

.83)

C3,

(1.1

1)C

4

12(0

.57)

C1,

(0.4

8)C

2(0

.48)

C3,

(0.8

0)C

4

16(0

.66)

C5

10f

22(1

.10)

C1,

(1.0

6)C

2(1

.22)

C3,

(1.1

0)C

4

14(0

.58)

C1,

(0.5

8)C

2(0

.82)

C3,

(0.7

7)C

4

12(0

.54)

C1,

(0.4

8)C

2(0

.50)

C3,

(0.6

6)C

4

19(0

.90)

C1,

(0.7

6)C

2(0

.76)

C3,

(1.2

6)C

4

14(0

.58)

C5

194



10g

19(0

.95)

C1,

(0.9

1)C

2(1

.05)

C3,

(0.9

5)C

4

11(0

.45)

C1,

(0.4

5)C

2(0

.64)

C3,

(0.6

1)C

4

11(0

.50)

C1,

(0.4

4)C

2(0

.45)

C3,

(0.6

1)C

4

15(0

.71)

C1,

(0.6

0)C

2(0

.60)

C3,

(1.0

0)C

4

09(0

.37)

C5

10h

13(0

.65)

C1,

(0.6

2)C

2(0

.72)

C3,

(0.6

5)C

4

20(0

.83)

C1,

(0.8

3)C

2(1

.17)

C3,

(1.1

1)C

4

16(0

.72)

C1,

(0.6

4)C

2(0

.66)

C3,

(0.8

8)C

4

17(0

.80)

C1,

(0.6

8)C

2(0

.68)

C3,

(1.1

3)C

4

12(0

.50)

C5

10i

16(0

.80)

C1,

(0.7

6)C

2(0

.89)

C3,

(0.8

0)C

4

08(0

.33)

C1,

(0.3

3)C

2(0

.47)

C3,

(0.4

4)C

4

14(0

.63)

C1,

(0.5

6)C

2(0

.58)

C3,

(0.7

7)C

4

19(0

.90)

C1,

(0.7

6)C

2(0

.76)

C3,

(1.2

6)C

4

23(0

.95)

C5

10j

10(0

.50)

C1,

(0.4

7)C

2(0

.55)

C3,

(0.5

0)C

4

17(0

.70)

C1,

(0.7

0)C

2(1

.00)

C3,

(0.9

4)C

4

21(0

.95)

C1,

(0.8

4)C

2(0

.87)

C3,

(1.1

6)C

4

10(0

.47)

C1,

(0.4

0)C

2(0

.40)

C3,

(0.6

6)C

4

18(0

.75)

C5

C1

2024

2221

00

C2

2124

2525

00

C3

1817

2425

00

C4

2018

1815

00

C5

0000

0000

24

Act

ivity

inde

x =

Inhi

bitio

n zo

ne o

f the

sam

ple

/ Inh

ibiti

on z

one

of th

e st

anda

rd

For a

ntib

acte

rial a

ctiv

ity: C

1 = A

mox

icill

in, C

2 = C

ipro

flox

acin

, C3 =

Cep

hale

xin,

C4 =

Ery

thro

myc

in.

For a

ntifu

ngal

activ

ity: C

5 = G

rese

oful

vin.

195



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85. I. S. Zorkun, S. Sarac, S. Celebi, K. Erol, Bioorg. Med. Chem., 14(24), 8582–8589 (2006).

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87. N. Dhanapalan, S. W. Miao, B. Lagu, G. Chiu, J. Fang, T. G. Muralidhar, J. Zhang,S. Tyagrajan, M. R. Marzabadi, F. Zhang, W. C. Wong, W. Sun, D. Tian, J. M.Wetzel, K. P. Vyas J. Med. Chem., 42(23), 4764-4777 (1999).

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91. Y. Mizutani, H. Wada, M. Fukushima, O. Yoshida, O. Ukimura, A. Kawauchi, T.Miki, Euro. J. Cancer, 37(5), 569–575 (2001).

92. Y. Mizutani, H. Wada, O. Yoshida, M. Fukushima, H. Nakanishi, M. Nakao, T.Miki, Euro. J. Cancer, 39(4), 541–547 (2003).

93. P. Biginelli, Gazz. Chim. Ital., 23, 360-416 (1893).94. C. O. Kappe, Tetrahedron, 49(32), 6937-6963 (1993).95. F. Shirini, K. Marjani, H. T. Nahzomi, ARKIVOC, i, 51-57 (2007).

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Part-Part-Part-Part-Part-DDDDD(Section-I)(Section-I)(Section-I)(Section-I)(Section-I)


X-ray Crystallographic study of

1-Phenyl-3-methylpyrazole-2-en-5-one

201

X-Ray Crystallography...


INTRODUCTION

Pyrazolines (1) have attracted attention of medicinal chemists for both with regard

to heterocyclic chemistry and the pharmacological activities associated with them.

Amongst nitrogen containing five membered heterocycles, pyrazolones (2) have proved

to be the most useful framework for biological activities. The pharmaceutical importance

of these compounds lies in the fact that they can be effectively utilized as antibacterial,

antifungal, antiviral, antiparasitic, antitubercular and insecticidal agents. In 1967 Jarboe,

reviewed the chemistry of pyrazolines, which have been studied extensively for their

biodynamic behaviour and industrial applications.

As evident from the literature in recent years a significant portion of research

work in heterocyclic chemistry has been devoted to pyrazoles containing different alkyl,

aryl and heteroaryl groups as substituents.

SYNTHETIC ASPECT

See Part-B, Section II, Synthetic Aspect


See Part-B, Section II, Therapeutic Importance

Looking to the diversified biological activities we have synthesized some pyrazole

derivatives in order to achieving better therapeutic agents. These studies are described

in following section.

SECTION-I: SYNTHESIS CHARACTERIZATION AND X-RAY

CRYSTALLOGRAPHIC STUDY OF 1-PHENYL-3-

METHYLPYRAZOLE-2-EN-5-ONE.

( 1 )

NH

N

( 2 )

NH

NO

202



SECTION-I

SYNTHESIS CHARACTERIZATION AND X-RAY CRYSTALLOGRAPHIC

STUDY OF 1-PHENYL-3-METHYLPYRAZOLE-2-EN-5-ONE.

Pyrazole derivatives represent one of the most active class of compounds having

a wide spectrum of biological activities. Looking to the interesting properties of pyrazoles

it was considered worthwhile to synthesize a pyrazole for obtaining biologically potent

agents.

The constitution of the synthesized compound have been characterized by using

Infrared, mass spectroscopy and further supported by X-Ray crystallographic study.


[A] Preparation of 1-Phenyl-3-methylpyrazole-2-en-5-one (PMP)

A mixture of Ethyl acetoacetate (0.01 mole) and phenyl hydrazine (0.01 mole) in

methanol (10 ml) is taken in a clean dry RBF. To this reaction mixture 2 drops of acetic

acid were added and the solution was reflux for 5 hrs in water bath. After completion of

the reaction (TLC monitoring), the solvent was removed under reduced pressure,

separated solid was filtered, and resulting solid was crystallized from methanol to give

analytically pure product. M. P. 124-126 °C, (Reported1 127 °C) Yield 77 %.

[B] Growth and Characterization of 1-Phenyl-3-methylpyrazole-2-en-5-one

(PMP) crystal:

N-Phenyl, especially N-phenyl pyrazoline finds applications in building blocks

for the synthesis of chiral compounds2. Due to the medicinal properties of pyrazoline

derivatives, the crystal growth of organic material 1-Phenyl-3-methylpyrazole-2-en-5-

one (PMP) has been carried out.

N

N

CH3

OOO

CH3 O CH3

NHNH2

+AcOH

Methanol

203



[C] Growth of 1-Phenyl-3-methylpyrazole-2-en-5-one (PMP) crystals:

In the present study, methanol were selected as solvent, however, methanol

yielded good quality single crystals. The seed crystals were grown from controlled

evaporation of saturated solution of PMP in methanol and good quality crystals were

picked up for growth. A glass jar of 4 cm diameter and 7 cm length was selected as a

crystallizer. This jar was kept in a water bath with temperature control of ± 0.1 °C.

Water in the bath was stirred slowly. Supersaturated solution of PMP was poured into

crystallizer and a seed crystal was hung by using very fine nylon thread. The temperature

of the water bath was maintained at 40 °C and the evaporation rate was carefully

controlled.

Figure [1]: Photograph of the grown PMP crystals

Good quality single crystals with maximum dimension 1.5 cm X 0.75 cm were

obtained. Figures [1] show the types of crystals grown. The crystals were yellowish in

color.


X-Ray Crystallography…

SPECTRAL STUDY

IR spectra of 1-Phenyl-3-methylpyrazole-2-en-5-one (PMP).

400600800100012001400160018002000240028003200360040001/cm

-20

0

20

40

60

80

100

%T

3136.36

2962.76

2865.35

1801.57

1760.10

1599.04

1533.46

1446.66

1392.65

1363.72

1306.82

1172.76

1136.11 1068.60

1009.77 885.36

761.91

694.40

632.67

495.72

SDT




Alkane -CH3





Aromatic

C-H str. 3114

C=C (skeleton) 1539


C-H o.p bending 820

Pyrazole ring=N-N- str. 1172

-C=O str. 1760

N

N

CH3

O

205



EI-

Mas

s spe

ctra

of 1

-Phe

nyl-

3-m

ethy

lpyr

azol

e-2-

en-5

-one

(PM

P).

Inst

rum

ent:

Shi

mad

zu G

C-M

S Q

P-20

10, D

I-pr

obe,

EI-

met

hod.

N

NCH3

O

M. W

t. =

174

.20

206



Single crystal X-ray Diffraction analysis

Single crystal X-ray diffraction is the most common experimental method of

obtaining a detailed picture of a small molecule that allows resolution of individual atoms.

It is performed by analyzing the diffraction of x-rays from an ordered array of many

identical molecules. Many molecular substances, including proteins, polymers and other

solidify in to crystals under the proper conditions. When solidifying in to the crystalline

state, these individual molecules typically adapted as one of only a few possible

orientations. A crystal is a three dimensional array of those molecules that are held together

by Van der Waals and noncovalent bonding. The smallest representative unit of this

crystal is referred to as the unit cell. Understanding the unit cell of these arrays simplifies

the understanding of a crystal as a whole.

Characterization of PMP crystals

Single Crystal X-ray Diffraction and Structure Determination

The three dimensional intensity data were collected on an Enraf-Nonius CAD-4

diffractometer. The reflection data were collected at 293 K and ù /2è scan mode was

employed for data collection by using MoKá radiation (ë = 0.71073 Å). The structure

has been elucidated by direct methods using SHELEX 973. All non-hydrogen atoms of

the molecule were located from the E-map. Isotropic refinement of the structure by

least squares methods using SHELEX 974 was followed by anisotropic refinement of all

the non-hydrogen atoms. All the hydrogen atoms were fixed stereochemically. Atomic

scattering factors were taken from International tables for crystallography (1992 Vol. C

Tables 4.2.6.8 and 6.1.1.4). Geometrical and other structural calculations were performed

by using PARST5 programme. The experimental details and other measurement data are

given in Table [I]. Geometry of intra and intermolecular hydrogen interactions are given

in Table [II]. The bond lengths and bond angles are given in Table [III]. An ORTEP

diagram of the compound with atom numbering scheme is shown in figure [2], unit cell of

the PMP are shown in figure [3] and figure [4] represents the packing diagram of PMP

crystals, which showing the hydrogen-bonding network6.

207



Figure [2]: ORTEP Diagram of PMP crystals

Figure [3]: Diagram showing unit cell of PMP crystals

208



Table – I: Experimental details and other measurement data of PMP crystal

Crystal data and experimental data

Chemical Formula C10H10N2O

Relative Chemical formula weight 174.20

Crystal system Monoclinic

Space group P21/c

Cell dimensions a = 10.205 Å

b = 11.096 Å

c = 15.679 Å

Z 8

V 1767.6 (4) Å3

T 120 K

Dx 1.309 mg/m3

μ 0.82 cm-1

Recording Range θmax 27°

Radiation (Mo Ka) λ =0.71073 Å

Crystal Size 0.3 x 0.3 x 0.2 mm

F(000) 736

No. of recorded reflections 2989

No. of observed reflections 2534

No. of parameters 315

R 4.9 %

Rw 4.7 %

Refinement method Full-matrix least square on F2

Measurement ENRAF-NONIUS Detector Programme

Programme system ENRAF-NONIUS Programme

Structure Determination SHELXS97

Structure Drawing ORTEP III

Refinement SHELXL97

209



Table – II: Geometry of intra and inter molecular hydrogen interactions

Table – III: Various bonds and bond length of PMP crystals

N2-H2...N2'( 1) 2.803(.002) 1.971(.002) 162.71( 0.12)

N2-H2...N1'( 1) 3.806(.002) 2.952(.001) 172.69( 0.11)

O'-H'...O ( 1) 2.478(.002) 1.705(.001) 156.17( 0.12)

C10-H10B...O'( 2) 3.482(.004) 2.851(.002) 124.20( 0.19)

C3-H3...O( 3) 3.531(.004) 2.646(.002) 159.30( 0.20)

C3-H3...O'( 4) 3.647(.004) 2.908(.002) 137.28( 0.20)

N2'-H2'...N2( 5) 2.803(.002) 2.034(.002) 148.43( 0.12)

C10'-H10D...N2( 5) 3.660(.003) 2.925(.002) 134.25( 0.18)

C1'-H1'...N2( 5) 3.588(.003) 2.968(.002) 125.48( 0.16)

Equivalent positions: ( 0) x,y,z; ( 1) -x+1,+y-1/2,-z+1/2; ( 2) x,-y-1/2,+z+1/2; ( 3) -

x+2,+y-1/2,-z+1/2; ( 4) x+1,+y,+z; ( 5) -x+1,+y+1/2,-z+1/2.

Bond Lengths (Å)

O-C(9) 1.321(3) N(2')-C(7') 1.344(3)

N(1)-C(9) 1.356(2) N(2')-N(1') 1.379(2)

N(1)-N(2) 1.372(2) O'-C(9') 1.260(2)

N(1)-C(6) 1.415(3) N(1')-C(9') 1.378(2)

N(2)-C(7) 1.318(3) N(1')-C(6') 1.413(3)

C(6)-C(1) 1.381(3) C(9')-C(8') 1.397(3)

C(6)-C(5) 1.382(3) C(6')-C(5') 1.382(3)

C(9)-C(8) 1.366(3) C(6')-C(1') 1.390(3)

C(5)-C(4) 1.381(3) C(7')-C(8') 1.354(3)

C(1)-C(2) 1.385(4) C(7')-C(10') 1.475(3)

C(7)-C(8) 1.402(3) C(1')-C(2') 1.384(4)

C(7)-C(10) 1.487(3) C(5')-C(4') 1.371(4)

C(4)-C(3) 1.370(4) C(2')-C(3') 1.383(4)

C(2)-C(3) 1.359(5) C(3')-C(4') 1.359(4)

210



Bond Angles ( ° )

C(9)-N(1)-N(2) 110.07(16) C(7')-N(2')-N(1') 108.31(17)

C(9)-N(1)-C(6) 129.61(17) C(9')-N(1')-N(2') 108.27(16)

N(2)-N(1)-C(6) 120.31(15) C(9')-N(1')-C(6') 129.98(17)

C(7)-N(2)-N(1) 106.13(16) N(2')-N(1')-C(6') 120.53(16)

C(1)-C(6)-C(5) 120.6(2) O'-C(9')-N(1') 120.80(19)

C(1)-C(6)-N(1) 118.8(2) O'-C(9')-C(8') 133.32(19)

C(5)-C(6)-N(1) 120.58(19) N(1')-C(9')-C(8') 105.86(18)

O-C(9)-N(1) 120.15(19) C(5')-C(6')-C(1') 119.5(2)

O-C(9)-C(8) 132.27(19) C(5')-C(6')-N(1') 120.6(2)

N(1)-C(9)-C(8) 107.58(17) C(1')-C(6')-N(1') 119.9(2)

C(4)-C(5)-C(6) 119.2(2) N(2')-C(7')-C(8') 108.71(19)

C(6)-C(1)-C(2) 118.6(3) N(2')-C(7')-C(10') 119.5(2)

N(2)-C(7)-C(8) 110.78(19) C(8')-C(7')-C(10') 131.7(2)

N(2)-C(7)-C(10) 120.8(2) C(7')-C(8')-C(9') 108.66(19)

C(8)-C(7)-C(10) 128.4(2) C(2')-C(1')-C(6') 119.3(3)

C(9)-C(8)-C(7) 105.44(18) C(4')-C(5')-C(6') 119.7(2)

C(3)-C(4)-C(5) 120.7(3) C(3')-C(2')-C(1') 120.9(3)

C(3)-C(2)-C(1) 121.3(3) C(4')-C(3')-C(2') 118.8(3)

C(2)-C(3)-C(4) 119.7(2) C(3')-C(4')-C(5') 121.8(3)

211



Figure [4]: Packing diagram 1-Phenyl-3-methylpyrazole-2-en-5-one (PMP)

showing intermolecular hydrogen-bonding network

REFERENCES

1. L. M. Kulberg, Syntheses of Organic Reagents for Organic Analysis,

Goskhimizdat, Moskow, 1947 (Russian Edition).

2. G. M. Coppola and H. F. Schuster; ‘In Asymmetric Synthesis: Construction

of Chiral Molecules Using Amino Acids’, Wiley; New York, (1987).

3. G. M. Sheldrick, SHELX97, ‘Program for Crystal Structure Determination’,

University of Gottingen, Germany, (1997)a.

4. G. M. Sheldrick, SHELX97, ‘Program for Refinement of Crystal Structure’,

University of Gottingen, Germany, (1997)b.

5. M. J. Nardelli; Appl. Cryst., 28 (1995) 659.

6. L. J. Farrugia, Molecular Graphics-ORTEP-3 for windows.; J. Appl. Cryst. 30

(1997) 565.

212List of Publications...

LIST OF PUBLICATION

1. Shailesh M Dave, Vijay R. RAM, Kapil L. DUBAL, Govind J. KHER, Satish D.Tala and Hitendra S. JOSHI*. Spectrophotometric studies of Ni (II)-HMCNPcomplex for determination of Ni (II) metal ion. Analytical Chemistry: An IndianJournal, Accepted article [MS No. An35352359].

2. Shailesh M. Dave, Vijay R. Ram, Kaushik A. Joshi, Satish D. Tala, Kapil L. Dubal,Govind J. Kher, Hitendra S. Joshi*. Synthesis and Spectrophotometric studies ofZn (II)-HMCPP complex and their use as an analytical reagent. AnalyticalChemistry: An Indian Journal Accepted article [MS No. An39350202].

3. Paresh Zalavadiya, Satish Tala, Jignesh Akbari and Hitendra Joshi*. Multi-component synthesis of Dihydropyrimidines by iodine catalyst at ambienttemperature and in vitro Antimycobacterial activity. Archive der Pharmazie-Chemistry in Life Science Accepted article [Manuscript No. ARDP-2008-0224.R1] .

4. D H Vyas, S D Tala, J D Akbari, M F Dhaduk and H S Joshi*. Synthesis, antimicrobialand antitubercular activity of some cyclohexenone and indazole derivatives. IndianJournal of Chemistry, Section B: Organic Chemistry Including MedicinalChemistry. Accepted article [Manuscript No. 3/4(OC-1054)/2007].

5. Shailesh M. Dave, Vijay R. Ram, Kaushik A. Joshi, Satish D. Tala, Hitendra S.Joshi*. Synthesis and Spectrophotometric studies of Mn(II)-HMCPP complex andtheir use as an analytical reagent. Institution of Chemists. In Press article 2009[Manuscript No. 85/3].

6. Dipen H Vyas, Satish D Tala, Jignesh D Akbari, Manoj F Dhaduk, K A Joshi andHitendra S Joshi*. Synthesis and antimicrobial activity of new cyanopyridine andcyanopyrans towards Mycobacterium tuberculosis and other microorganisms.Indian Journal o f Chemis try, Sec t ion B: Organic Chemis try Inc ludingMedicinal Chemistry. In Press article 48B, June 2009 [Manuscript No. OC-1152/2008].

7. S. V. Rokad, S. D. Tala, J. D. Akbari, M. F. Dhaduk and H. S. Joshi*. Antitubercularand antimicrobial activity of some new N-aryl-1,4-dihydropyridines containing furannucleus. Journal of the Indian Chemical Society, 86, 186-191, 2009.

8. M. J. Ladani, S. D. Tala, J. D. Akbari, M. F. Dhaduk and H. S. Joshi*. Synthesisand biological study of oxopyrimidines and thiopyrimidines of 2-(2,4-dichlorophenyl)imidazo[1,2-a]pyridin-3-carbaldehyde. Journal of the IndianChemical Society, 66, 104-108, 2009.

9. D. H. Vyas, S. D. Tala, J. D. Akbari, M. F. Dhaduk and H. S. Joshi*. Synthesisand biological evaluation of some aminopyrimidine and pyranone derivatives. IndianJournal of Heterocyclic Chemistry, 18, 187-188, 2008.

Publication...

213List of Publications...

10. Tapan K. Dave, Satish D. Tala, Jignesh D. Akbari, Manoj F. Dhaduk and HitendraS. Joshi*. Synthesis, antitubercular and antimicrobial evaluation of pyrazolederivatives bearing nicotinic acid nucleus. International Journal of Synthesesand Characterization, 1(2), 147-152, 2008.

11. J. D. Akbari, S. D. Tala, P. K. Kachhadia, A. H. Bapodra, M. F. Dhaduk, K. B.Mehta , S . J . Pathak and H. S . Joshi* . Synthes is of some new 1,2 ,3 ,4-tetrahydropyrimidine-2-ones and their thiazolo[3,2-a]pyrimidine derivatives as apotential biological agents. Phosphorous, Sulfur and Silicon and the RelatedElements, 183(8), 1911-1922, 2008.

12. J. D. Akbari, S. D. Tala, M. F. Dhaduk and H. S. Joshi*. Synthesis of some newpyrazolo[3,4-d]pyrimidines and thiazolo[4,5-d]pyrimidines and evaluation of theirantimicrobial activities. Phosphorous, Sulfur and Silicon and the RelatedElements, 183(6), 1471-1477, 2008.

13. R. C. Khunt, J. D. Akbari, A. T. Manvar, S. D. Tala, M. F. Dhaduk, H. S. Joshiand Anamik Shah*. Green chemistry approach to synthesis of some newtrifluoromethyl containing tetrahydropyrimidines under solvent free conditions.ARKIVOC, xi, 277-284, 2008.

14. Jignesh D. Akbari, Satish D. Tala, Manoj F. Dhaduk and H. S. Joshi*. Moleculariodine-catalyzed one-pot synthesis of some new Hantzsch 1,4-dihydropyridines atambient temperature. ARKIVOC, xii, 126-135, 2008.

15. D. H. Vyas, S. D. Tala, J. D. Akbari, M. F. Dhaduk, H. S. Joshi*. Synthesis andantimicrobial activity of some new cyanopiperidinones and cyanopyridones.International Journal of Syntheses and Characterization, 1(1), 103-107, 2008.

16. D. H. Vyas, M. F. Dhaduk, S. D. Tala, J. D. Akbari, H. S. Joshi*. Synthesis andbiological activity of some pyrazoline derivatives. Indian Journal of HeterocyclicChemistry, 17(2), 169-172, 2007.

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18. D. H. Vyas, S. D. Tala, M. F. Dhaduk, J. D. Akbari, H. S. Joshi*. Synthesis,antitubercular and antimicrobial activities of some new pyrazoline and isoxazolederivatives. Journal of the Indian Chemical Society, 84(11), 1140-1144, 2007.

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