Report on Minor Research Project In Chemistry Under … on Minor Research Project In Chemistry Under...

Report on

Minor Research Project

In Chemistry

Under the Financial Assistance of University Grants Commission

Convenient Protocols for the Synthesis of New and Existing

Bioactive Heterocyclic Compounds File No. 472021/11(WRO)

Submitted To

University Grant Commission

Western Regional Office, Pune

Submitted By

Dr. Prashant Deoraoji Netankar

Associate Professor

Department of Chemistry

Maulana Azad College of Arts Commerce and Science

College, Aurangabad

1

September 2015

Acknowledgements

I sincerely express my gratitude to Dr. M. N. Farooqui, Principal Maulana Azad

College Aurangabad, for his encouragement and constructive suggestions throughout the

progress of the research work. I thankful to all the faculty members of Maulana Azad

College, Aurangabad, for their support during the work. I express my thanks to nonteaching

staff of the department of chemistry for their kind assistance. I am also thankful to UGC for

providing financial assistance for the completion of this research work.

Dr Prashant D. Netankar

2

Table of Contents

Sr. No. Particulars Page Nos.

1 Introduction and Scope of the Work 4

2 Schemes I 8

3 Schemes I 9

4 Experimental 10

5 Conclusion 15

6 Contribution to society 16

7 References 17

3

Introduction and Scope of the Work

Heterocyclic compounds having nitrogen /or sulphur as heteroatoms offer a high degree of

structural diversity and have proven to be broadly and economically useful as biologically active

agents. In particular heterocyclic compounds such as thiazolidinones, pyrazoles, thiazoles, triazoles

etc have proved their abilities as therapeutically active agents. Recently much attention has been

focused on 4thiazolidinone derivatives for their broad spectrum of biological activities. As a part of

interest in heterocycles that have been explored for developing pharmaceutically important

molecules, 4thiazolidinones, triazoles, pyrazoles, and thiazoles have played important role in

medicinal chemistry. Moreover they have been studied extensively because of their ready

accessibility, diverse chemical reactivity and broad spectrum of biological activity.

Thiazoles are amongst the most frequently encountered heterocycles in compounds of

biological interest along with many other applications. They have been shown to possess abroad

spectrum of biological activity depending on their particular structure. Antiinflammatory1 activities

4

are observed in thiazole derivatives. Some synthetic thiazoles have exhibited a range of biological

activities such as antimicrobial,2 biological activities,3 antibacterial, antifungal.46

Pyrazoles are the privileged scaffolds and show promising biological activities. Pyrazole is an

important core nucleus of various drugs viz. PNU32945, Zoniporide and Celecoxib. These drugs

act as HIV reverse transcriptase inhibitors,7 sodium hydrogen ion exchanger inhibitors8 and COX2

inhibitors9 respectively. Following is a brief review on the pyrazoles with antihyperglycemic /

antidiabetic activity. Pyrazoles are also emerged as potential antihyperglycemic agents.10 A number

of pyrazole compounds specially, 1, 3disubstituted Pyrazoles11 and 1, 3, 5trisubstituted Pyrazoles 6

12 have been cited in the literature and are found to elicit antihyperglycemic activity. SAH 57749, a

pyrazole derivative has shown antidiabetic activity.13

Substituted Pyrazoles14 are known for their hypoglycemic activity in vivo. Chenault et al.15

have synthesized substituted pyrazole4carboxylic acids as hypoglycemic agents that inhibiting the

activity of the ATPK+ channel of the beta cell pancreatic membrane, inducing the production of

insulin. Inhibition of the serine protease dipeptidyl peptidase IV (DPP4) has emerged as a major

field of diabetes research.16 Nordhoff et al.17 have designed a potent and selective inhibitors of

DPP4.

Thiazolidinone and its derivatives are an important class of heterocyclic compounds. They

have a wide range of biological and pharmacological activitie18, such as antiinflammatory19,

antiHIV,20 anticancer,21 antimalarial,22 antitubercular,23 anticonvulsant,24 antibacterial,25 and

antiarrythmic.26 Moreover, agents bearing sulfonyl moieties have also beenfound to display diverse

therapeutic activities, such as hypoglycemia,27 anticancer,28 and antiinflammation.29

Theliteraturerevealsthat4thiazolidinoneswith heteryl derivatives/moieties have shown potential

biodynamic activity.30

5

Thiazolidinone has an important role as a widely exploited pharmacophore in medicinal

chemistry having varied biological activity such as antifungal,31 antibacterial,3233

antimycobacterial,34 antipsychotic,35 antiinflammatory36 have been found to be associated with

thiazolidinone derivatives. Substituted thiazolidine derivatives represent important key intermediates

for the synthesis of pharmacologically active drug.

The Chemistry of Nbridged heterocycles derived from 1,2,4triazole has received

considerable attention in recent years due to their usefulness in different areas of biological activities

and as industrial intermediates. 1,2,4triazole derivatives are known to exhibit antimicrobial [1–5],37

antitubercular,38 anticancer,39 anticonvulsant,40, antiinflammatory and analgesic properties.41

The arrangement of three basic nitrogen atoms in triazole ring induces the antiviral activities

in the compounds containing triazole ring.42 1,2,4triazole nucleus has been incorporated in to a wide

variety of therapeutically interesting drug candidates including H1/H2 histamine receptor blockers,

cholinesterase active agents, CNS stimulants, antianxiety and sedatives,43antimycotic activity such as

Fluconazole, Itraconazole and Voriconazole44. Also there are some known drugs containing

1,2,4triazole moiety, eg: Triazolam45, Alprazalam,46 Etizolam,47 Furacylin48 Ribavirin,49

Hexaconazole50 Triadimefon51 Mycobutanil,52 Rizatriptan,53 Propiconazole,54 Fluotrimaole.55 A series

of 1,2,4triazole derivatives have been extensively employed in agriculture as herbicides.56 Certain

1,2,4triazoles also find applications in the preparation of photographic plates, polymers and as

analytical agents.57 Triazolothiadiazines are reported to possess wide spectrum of biological

activities.5862

In recent years, applications of ionic liquids (ILs) in organic synthesis have attracted

considerable attention due to their special properties such as good solvating capability, wide liquid

range, noninflammability, negligible vapor pressure, easy of recycling, high thermal stability and

6

rate enhancers.63 Also IL is environmentally benign media for catalytic processes, much attention has

currently been focused on organic reaction catalyzed by ILs have been reported with high

performance64. They have attracted quite justifiable enormous attention as media for green synthesis

and hence several reviews have been appeared.65

Ionic liquids have been described as a designers solvents66 this means their properties can be

adjusted to suit the requirements of particular process. Properties such as melting point, viscosity,

density, hydrophobicity can be varied by simple changes to the structure of the ions. Another

important property that changes with structure is the miscibility in water. This behavior can be of

substantial benefit when carrying out solvent extraction or product separations. As a result ionic

liquids are receiving increasing attention in last few decades that resulted into development of

different classes of ionic liquids.

In view of the above importance of pyrazole, thiazoles and PEG successful attempt has been

made in the present investigation to developed environmentally benign protocols for the proposed

compounds 1Phenyl3aryl4(4phenylthiazol2yl)1Hpyrazoles. In this protocol we successfully

employed PEG and water system as a greener reaction medium moreover it became possible to

accomplish the reaction at room temperature. The important finding of this investigation is, it could

possible to avoid the use of lachrymatric αhalo ketones which generally extensively used for such

type of reactions.

Under this project compounds like 1Phenyl3aryl4(4phenyloxazol2yl)1Hpyrazoles are

also synthesized by using same protocol.

One of the important part of this project is synthesis of

3(3mercapto5(pyridin4yl)4H1,2,4triazol4yl)2(1Phenyl3aryl1Hpyrazol4yl)thiazolidi

n4ones. In this part a molecules has been synthesized which consist of three important

7

pharmacologically active Heterocycles viz; triazoles, pyrazole and thiazolidinones. These molecules

have diverse pharmacological activities. Hence it is hopeful that such diverse activities may be

displayed by the synthesized compounds and it can be significant lead molecules for drug discovery.

Synthesis of these molecules is done in ionic liquid (IL) that is 4methyl pyridinium tosylate. Which

are proven and well recognized greener reaction medium. Moreover in this investigation we have

developed a one pot protocol for this reaction which is rarely reported.

SCHEME I

Synthesis of 1Phenyl3aryl4(4phenylthiazol2yl)1Hpyrazole.

8

SCHEME II

9

Synthesis of 3(3mercapto5(pyridin4yl)4H1,2,4triazol4yl)2(1Phenyl3aryl1Hpyrazol4yl)thiazolidin4one.

10

Experimental

11

1) Synthesis of 1Phenyl3aryl1Hpyrazole4carboxylic acids.

To the solution of 1Phenyl3aryl1Hpyrazole4 carbaldehyde (20.2 m mol) in a

mixture of H2O and tbutyl alcohol(1:1) 100 mL (24.2 m mol) KMnO4 in water (60mL) was

added drop wise over 3h while string at 75oC. Then 10% KOH was added while stirring until

the solution turned alkaline. The mixture was filtered and then the filtrate was acidified with

conc. HCl to PH 2. The solid precipitate was filtered off, washed with water and dried to yield

1Phenyl3aryl1Hpyrazole4 carboxylic acid as white solid.

R= H, F, Cl, Br, OH, CH3

2) Synthesis of 1Phenyl3aryl1Hpyrazole4carboxamides.

A mixture of acid, 1Phenyl3aryl1Hpyrazole4carboxylic acid 0.05 mole and

thionyl chloride 0.06 mole, toluene 20 mL and 23 drops of pyridine was refluxed for 45

min. The reaction mixture was then poured drop wise in ice cold liquor ammonia. The solid

obtained was filtered, dried and crystalized from ethanol.

12


3) Synthesis of 1Phenyl3aryl1Hpyrazole4carbothioamides.

1Phenyl3aryl1Hpyrazole4carboxamide (0.01 mole) and Lawesson’s reagent

(2.02 g, 0.005 mole) were mixed together and the mixture was refluxed in toluene ( 20 mL)

for 2 hr. The progress of the reaction was monitor by TLC. After completion of the reaction

toluene was then removed under reduced pressure. The residual semisolid obtained was

poured on ice. The crude solid generated was filtered, dried and crystallized from ethanol.


4) Synthesis of 1Phenyl3aryl4(4phenylthiazol2yl)1Hpyrazoles.

A mixture of aromatic Acetophenone (0.05 mol), Nbromosuccinimide (0.055 mol),

water (2mL) and PEG400 (18 mL) was heated for 1hr at 80 OC. The formation of α

bromoketones was monitored by thin layer chromatography (TLC). After completion of the

13

bromination, 1Phenyl3aryl1Hpyrazole4carbothioamide (0.055 mol) was added to the

reaction mixture and it was further heated for 1 hr at same temperature. After completion of

reaction was monitored by TLC, the reaction mass was poured in ice cold water. The solid

obtained was basified by ammonia, filtered, washed with cold water and recrystallized from

proper solvents.

R= H, F, Cl, Br, OH, CH3 R’= H, F, Cl, Br, OH, CH3

5) Synthesis of 1Phenyl3aryl4(4phenyloxazol2yl)1Hpyrazoles.

A mixture of aromatic Acetophenone (0.05 mol), Nbromosuccinimide (0.055 mol),

water (2mL) and PEG400 (18 mL) was heated for 1hr at 80OC. The formation of α

bromoketones was monitored by thin layer chromatography (TLC). After completion of the

bromination, 1Phenyl3aryl1Hpyrazole4 carboxamide (0.055 mol) was added to the

reaction mixture and it was further heated for 3 hr at same temperature. After completion of

reaction was monitored by TLC, the reaction mass was poured in ice cold water. The solid

obtained was basified by ammonia, filtered, washed with cold water and recrystallized from

proper solvents.Similarly the other compounds of the series were prepared by using the same

procedure.

14

R= H, F, Cl, Br, OH, CH3 R’= H, F, Cl, Br, OH, CH3

6) Synthesis of 4Amino5(4'pyrydyl)4H1,2,4triazole3thiols.

Isoniazide (0.07 mol) was treated with KOH (0.11 mol) solution in methanol (50 mL)

at 05OC with stirring. Then 0.11 mol of CS2 was then added slowly and reaction mixture was

stirred for overnight at room temperature. The solid product was filtered, washed with Et2O

and dried. It was directly used for next step without purification. A suspension of potassium

dithiocabazinate in water (20 mL) and excess of hydrazine hydrate was reflux for 20 h with

occasional shaking. The colour of reaction mixture changes to green with evolution of the

H2S gas. The reaction mixture was diluted with 20 mL water and acidified with concentrate

HCl. The white precipitate thus obtained was washed with cold water and crystalized from

proper solvent.

7) Synthesis of 4((1Phenyl3aryl1Hpyrazol4yl)methyleneamino)5(pyri din4yl)4H1,2,4 triazole3thiols.

15

A mixture of 4Amino5(4'pyrydyl)4H1,2,4triazole3thiol (0.01mole),

1Phenyl3aryl1H pyrazole4carbaldehyde ( 0.01 mole) was refluxed in dry ethanol for 2

hr in the presence of activated molecular sieve of size 4A°. The completion of the reaction

was monitored by TLC. The hot reaction content was filtered to remove the molecular sieves.

Then the ethanol was removed from the filtrate by rotaevaporation. The solid residue

obtained was poured in ice cold water. It was then filtered, washed with cold water and

crystallized from ethanol.


8) Synthesis of

3(3mercapto5(pyridin4yl)4H1,2,4triazol4yl)2(1Phenyl3aryl

1Hpyrazol4yl)thiazolidin4ones.

A mixture of

4((1Phenyl3aryl1Hpyrazol4yl)methyleneamino)5(pyridin4yl)4H1,2,4

triazole3thiol (0.01 mole) and mercapto acetic acid (0.012 mole) and Nmethyl pyridinium

tosylate ionic liquid (0.02 mole) was refluxed at 120°C. The progress of the reaction was

monitored by thin layer chromatography. After heating the reaction mass for 23h, the

reaction mass was allowed to cool at room temperature and then to this ice cold water (50

16

mL) was added. Excess of mercapto acetic acid is neutralized by sodium bicarbonate. The

solid separated was filtered and dried. It was further purified by crystallization. Similarly the

other compounds of the series were prepared by using the same procedure.


Conclusion

We have demonstrated here that PEG400 offers a safer medium and an efficient catalyst for

the cyclocondensation of 1Phenyl3aryl1Hpyrazole4carbothioamide with acetophenones to

afford the corresponding of 1Phenyl3aryl4(4phenylthiazol2yl)1Hpyrazole with excellent

yields. The notable advantages of this method are easy work up, no side products/clean reaction,

reduced reaction time, and easy recyclability of the solvent. Hence, this protocol would be a good

addition as a convenient and an efficient method to the methods available for the synthesis of

1Phenyl3aryl4(4phenylthiazol2yl)1Hpyrazole.

We also developed a simple, convenient protocol for the synthesis of


n4one. This new synthetic strategy markedly improve the synthetic efficiency, decreases the

17

production of chemical waste without the use of highly toxic reagents and gives


n4one (thiazolidinones) for making the library of new thiazolidinones.

Contribution to society

Those molecules which are synthesized

1) 1Phenyl3aryl4(4phenylthiazol2yl)1Hpyrazole

2) 1Phenyl3aryl4(4phenyloxazol2yl)1Hpyrazole

3)3(3mercapto5(pyridin4yl)4H1,2,4triazol4yl)2(1Phenyl3aryl1Hpyrazol4yl)

thiazolidin4one are potentially bioactive therefore the present investigation can provide

inputs for drug discovery which may discover important medicine for the welfare of

mankind.

18

In the present investigation convenient synthetic routes are developed for synthesis of

biologically important Heterocycles. The developed protocols are characterized promoting

use of greener reaction medium such as PGE, water and ionic liquid; avoiding use of

lachrymatric compounds such as αhalo ketones. This work will contribute to the society to

provide value added heterocyclic compounds with economy, efficiency and less

environmental hazards.

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