section: i studies on...

12

PART - I

SECTION: I

STUDIES ON 4-0XO- THIAZOLIDINES.

Introduction:

4-0xo-thiazolidines have been found important structurally as well as

pharmacologically. To exploit the properties of the system, several 4-oxo

thiazolidines have been prepared wherein the presence of >N-(-S linkage

imparts activity to the structure. 4-0xo-thiazolidines are the derivatives of

thiazolidines, which belong to an important group of heterocyclic compounds.

Thiazolidinones with carbonyl group at positions

subject of extensive study in the recent past.

2, 4 or 5 have been the

Numerous reports, which

appeared in the literature, have highlighted their chemistry and uses. Brown

F (I in 1961 gave a comprehensive review on 4-thiazolidinones. Later on,

Zolotoreva K A et al 2 in 1966 prepared an article, which dealt with the use of

thiazolidinone derivatives as stabilizers for polymeric materials. After this

Danila G3 in 1979 published a review on the preparation of rhodanines

(2-thiono-4-thiazolidinones) and their uses as intermediates in organic

synthesis. Diverse biological activities such as bactericidal, pesticidal,

fungicidal, insecticidal, anticonvulsant, tuberculostatic, antiinflammatory,

antithyroidal, etc. have been found to be associated with thiazolidinone

derivatives. Several thiazolidinones are reported as anaesthetic'-s,

analgesic6, hypnotiC>, sedativeS, anticonvulsant9

, antitubercular1o,

spasmopreventive" etc. Some thiazolidinones are employed in the synthesis

of merocyanine dyes, which are used in photographic film industryY

13

Chemistry:

Thiazolidine (I) with a carbonyl group at 4-position is known as

4-thiazolidinone (II) or 4-oxo-thiazolidine. Substituents at positions 2, 3 and

5 are known and such a group can form alkyl, aryl or aryl-alkyl thiazolidinone

(III). The oxygen attached to C-2 would make 2,4 - thiazolidinedione (IV).

°t; 5

O~):o (I) (II) (IV)

Sulfur atom attached at C-2 makes rhoda nine (V) and imino group

form 2-imino-4-thiazolidiones (VI), which is known as pseudo-thiohydantoin.

(V) (VI)

2-Sulfanylacetic acid has been recognized as a primary product of

hydrolysis of 3-phenyl-2-phenylimino-4-thiazolidinone. 13·'5 Hydrazone

derivatives of 4-thiazolidinones (VII) have been obtained by the

condensation of thiosemicarbazones and monochloroacetic acid. These

compounds were screened for antitubercular activity and maximum activity

has been observed when R, = H, R = 2-hydroxy phenyl.'6

14

+HyO

H+H CI

..

(VII)

Because of similar study of 4-thiazolidinones with an acid, it was

observed that actithiazic acid (VIII) is an antibiotic, isolated from a species of

streptomycin. It has high specific in vitro activity against Mycobacterium

tuberculosis, but is inactive in vivo, probably due to antagonisation by biotin

(IX), which contains some structural features similar to actithiazic acid and

reverses the activity of antibiotic. 17

O~ H NH OH

o ~ NH 0

(VIII) (IX)

Preparations of 4-0xo-thiazolidines:

4-0xo-thiazolidines are synthesised by cyclisation of acyclic

compounds. The cyclisation method comprises of the formation of

intermediates, which are formed by the reaction between the atoms, which

are subsequently 1 and 5, 1 and 2 or 2 and 3 of 4-oxo-thiazolidine ring in

cyclisation process. Generally, an intermediate formed was not isolated and

is appropriately substituted alkanoic acid or its ester. The ring closure occurs

between the acid group and hydrogen attached to nitrogen between atoms

3 and 4 of the 4-oxo-thiazolidine ring. 5-Carboxy methyl dithiocarbamate is

cyclised to rhodanine, which is a monomolecular reaction. 18

15

1) Reaction with Schiff bases and a -mercaptoacetic acid

Schiff bases obtained by the condensation of ketone and amines also

react with a-mercaptoacetic acid to give 2,2-disubstituted-4-thiazolidinones

(X).'9

+ ;{OH

HS a

(X)

R = different aryl groups, R, and R2 = alkyl and aryl or H

2) Reaction between acetyl thioacetamide and monochloroacetic acid.

Various N-substituted acetyl thioacetamides on treatment with

monochloroacetic acid in the presence of sodium acetate in refluxing acetic

acid, yielded 2-acetyl methylene-3-substituted-4-thiazolidinones (XI).2o

3) From dithiocarbamates and thiocarbamates.

Ammonium dithiocarbamates condense with glycidic ester to give

2-thione-3-substituted-5-( hydroxyalkyl )-4-thiazolidinones, wh ich a re readily

dehydrated in refluxing acetic acid to 2-thiono-3-substituted-S-alkylidene-4-

thiazolidines (XII).21

16

):,~, ~ Rj

(XII)

The dithiocarbamates formed by the reaction of primary amine with

carbon disulfide in the presence of a base, reacted with u-haloalkanoic acid

in presence of sodium bicarbonate to give substituted 2-thiono-4-

thiazolidinones (XIII). 22-25

+

(XIII)

Where R = -CH3, -NH2 ; R, = -H ; R2 = -C6Hs, -H ; X = halogen

In an analogous series of reactions, the substitution of carbon

oxysulfide for carbon disulfide, in preparation of dithiocarbamates, yields

2,4-thiazolidinedione. 26 This procedure can be adopted for the synthesis of 3-

substituted 2,4-thiazolidinediones (XIV). 27

C s-Y ~O + R - NH2 + KOH

Acid

(XIV)

~ R'-.,. /C'-.,._

NH S

I CI-CH2COO

o

R'-.,.N}ls~o o

17

Alkyl thiocarbamates (xanthogenamides) react with a-haloalkanoic

acid forming 2,4-thiazolidinediones. 28.31

4) From thioureas.

Substituted 2-imino-4-thiazolidinones (XV) are obtained in good yield

by the reaction of symmetrical or unsymmetrical thioureas with various

substituted or unsubstituted a-haloalkanoic acids, their esters, acid chlorides,

amides or carbamates. 32·39 The reaction proceeds through the formation of

isothiouronion salt (XV) which is the main product when temperature is

25-30 0c. Cyclisation occurs when the reaction takes place in refluxing acetic

acid, ethanol or benzene in presence of sodium acetate or pyridine. Instead

of a-haloalkanoic acid, other compounds capable of supplying the same

moiety can be used. Thiourea also reacts with a-hydroxy acids.

+

- HY

(XVI)

Where R, R 1 = alkyl/aryl or heterocyclic; R 2, R3 = H/aryl; X = halogen; Y = -~Et

18

Thiourea adds to the unsaturated carbon-carbon linkage of maleic,

fumaric or citraconic acid, and on cyclisation gives 5-substituted derivatives

of 2-imino-4-thiazolidinone (XVII).40-42 Same compound (XVII) can also be

synthesised in good yield by refluxing equimolar amounts of substituted and

unsubstituted thioureas and maleic anhydride in acetone. 43-45

I HO a a R

/ )=/1 H

~ -N

5

N Rt/ ys

/N H R

\ H H

a

a

Where R & Rl = -C4Hg (XVII)

Acetylene carboxylic acids and their dimethyl esters react with

thioureas46, dithiocarbamates, thiocarbamates, thiosemicarbazides and

thiosemicarbazones to give 4-thiazolidinones (XVIII)."

R, ~ ~R NH NH

5) Reaction with alkali thiocyanates.

The first 4-thiazolidinone reported by this method was 2,4-

thiazolidinedione that was synthesised by treating the product of the reaction

of ethylchloro acetate and KCNS with dilute HC!.48

19

The intermediate carbamoyl mercaptoacetic acid can be isolated by

the use of acid instead of ester. 49' 51 The reaction of chloro acetanilide with

thiocyanates leads to a variety of products, dependent upon the reaction

conditions and structure of components. 52

6) Reaction of a-mercapto alkanoic acids.

a-Mercapto alkanoic acids have been extensively used for the

synthesis of 4-thiazolidinones. The reaction of a-mercapto alkanoic acid with

compounds of the structure R-N=C=X is the general method of synthesis of

4-thiazolidinones. The reaction of a-mercapto alkanoic acid with

isothiocyanate form derivatives of rhodanine (XIXa),53 while isocyanate and

cyanamide give derivatives of 2,4-thiazolidinedione (XIXb)54 and 2-imino-4-

thiazolidinone respectively (XIXc).

;:S)=NH

0

JS)=x CNNH2 H~OH R-NCX

o NH o ~ R

(XIX c) Where R = -C6H5 (XIXa X=S) (XIXb X=O)

The substituted and unsubstituted a-mercapto alkanoic acids react

conveniently with Schiff bases of aromatic or heterocyclic aldehydes and

aliphatic or aromatic amines in different solvents to give a variety of

2 -substituted-4-th iazolidinones (XX). 55·61

RI

!=\ R H

f\. RI

N~ R:>yS OH R3

+

o Where R = alkyl/aryl; RI = aryl/heterocyclic; R2, R3 = H/alkyl (XX)

20

Substituted and unsubstituted a-mercapto alkanoic acid esters react

smoothly with compounds containing activated nitrile group in the presence

of an equivalent amount of alcoholate to give 4-thiazolidinones (XXI).62.63

- OR

(XXI)

Where R= -CH3, -C2HS; R,= -H, -C2Hs; R2= -H, -C2Hs, -C6HS, -C6H4-OCH 3;

R3= -H, -C6HS; R.= -COOC2Hs, -CONH2' -CN, -C6HS, etc.

Monforte P et al 64 have synthesised 4-thiazolidinones (XXII) and 2,4-

thiazolidinediones (XXIII) by reacting carbodiimides with a-mercapto

propionic acid. The acid reacts with one of the carbodiimidic >C=N groups to

give 3-substituted-2-imino-S-methyl-4-thiazolidinones. The related 3-

substituted-S-methyl-2,4-thiazolidinediones are also formed, except in the

reaction with dicycJohexyl carbodiimide.

(XXII) Where R = different aryl groups.

21

The Mechanism of Reaction:

We have found that in many instances, 4-thiazolidinones (XXIV) can

be prepared conveniently by the reaction of 2-sulfanylacetic acid with Schiff

bases refluxing in polor and non pol or solvent. By removing water

continuously, it was possible to perform the condensation reaction and to

determine the reaction time. In some cases, the Schiff bases were prepared

in the same solvent and when the calculated amount of water had separated,

2-sulfanylacetic acid was added and refluxing was continued. At the initial

stage, the addition of this group on the anil was usually accompanied with

the evolution of heat.

The reaction of 2-sulfanylacetic acid proceeds by attack of the acid on

>C=N- group of Schiff base on adding 2-sulfanylacetic acid to Schiff base6s

following the capture of a proton by nitrogen and subsequent cyclisation. In

several cases, uncyclised product has been isolated66-67 and heating open

chain compound with P20S in dioxan for 30 minutes effected the subsequent

cyclisation of certain compounds.

(XXIV)

Reactions of 4-0xo-thiazolidines:

The methylene carbon atom at position-S of 4-thiazolidinone

possesses nucleophilic activity and attacks an electrophilic center. The

reaction product loses water if it is possible to form as-unsaturated

derivative. The nucleophilic activity is influenced by adjacent carbonyl

group68 and by other electron-withdrawing group present at position-2.

22

(a) Aldol condensation with aldehyde and ketone.

The aldol condensation with aldehydes and ketones has attracted more

attention, followed, if possible, by loss of water. The product of the reaction

contains a,{3-unsaturated carbonyl group.

Where R1 = -SCCI), X = 0, R2 and R) = alkyl groups.

Various bases have been tried/9-7s out of which sodium ethoxide in

ethanol, sodium acetate in benzene or acetic acid are frequently giving good

yields. 76-77

(b) Reaction with diazonium salt.

Diazo salts undergo coupling reaction with 5-methyl group of

rhoda nine and 2,4-thiazolidinediones. 78 Under Meerwein conditions,

2-arylimino-4-thiazolidinones and diazonium salts produce, in the presence

of sodium acetate and cupric chloride, 2-arylimino-5-aryl-4-thiazolidinones in

60 to 80% yield. 79 The reaction has been used to introduce arsenophenyl

group in the 5-position. 8o

(c) Reaction with ortho esters.

Ortho esters react with active methylene group using acetic anhydride

frequently as a condensing agent, to form 5-(1-alkoxy alkylidine)

derivatives. 81

+

23

(d) Friedel-Craft reaction.

Friedel-Craft reaction with 5-arylidene-4-thiazolidinones using benzene

and anhydrous aluminium chloride as reported by Snider R H et al 82 give

rhodanine and triphenyl carbinol.

(e) Oxidation of 4-thiazolidinones.

Nitric acid breaks down the ring under drastic conditions. Hydrogen

peroxide in acetic anhydride and acetic acid forms sulfone (XXV) from 2,3-

dialkyl / 2,3-diaryl-4-thiazolidinones. 83 The same could be obtained by

potassium permanganate in aqueous acetic acid solution at 30-35 ac. 84

• (CH3CO)20

CH3COOH

Where R & R, '" alkyl or aryl groups. (XXV)

(f) Reduction of 4-thiazolidinones.

Gomes A et al8s have reported that various 4-thiazolidinone-1,1-

dioxides undergo reduction with lithium aluminum hydride, leading to the

formation of corresponding thiazolidinones (XXVI). However, reduction with

lithium aluminum hydride by refluxing in ether breaks down the heterocyclic

ring. 86

LiAI~

(XXVI)

Where Ar and Ar' '" different aryl groups.

Bhavnagar University lit;n·y.

BHAVNAGAR.

24

g) Reaction with o-phenylenediamine.

Lipnitskii V F et alB7 have reported that 2-imino-4-thiazolidinone

undergoes ring cleavage to Schiff bases on treatment with

o-phenylenediamine and further recyclise into a benzimidazole derivative.

This on hydrolysis gives 2-amino benzimidazole (XXVII).

(XN

I J-NH

~ NH h o SH

(XXVII)

(h) Reaction with benzoylchloride.

C

R - HCI

R (XXVIII)

Where R= different functional groups and R' = different aryl groups.

Kvitko Y I et alBB reported the reaction of substituted benzoylchloride

with various 2-thiono-4-thiazolidinones having above structure (XXVIII).

25

Newbould B B89 studied the antiinflammatory activity of 2-(butoxy

carbonyl)-methylene-4-thiazolidinone and the compound has been found

active against most of the models of acute inflammation. Antiproteolytic and

antihemolytic properties of several 4-thiazolidinones have been investigated

by Chaudhary A et al. 90 In vitro protection of the hypoosmotic hemolysis of

human red blood cells and the inhibition of trypsin induced hydrolysis of

bovine serum albumin. Nemeseri et al 91 have reported 2-thione-3-(3,4-

dichlorophenyl)-4-thiazolidinone as an antiparasitic agent. Pandya and

Thaker92 have synthesised 5-substituted arylidine / alkylidine-3-cyclohexyl-2-

phenyl-4-thiazolidinones and tested against E.coli and S.aureus.

2,4 -Bis- ( 2 '-a ryl- 5' -methy 1/ ca rboxy m ethyl-4' -th ia zo lid i non e -3' -Y I) -6-

hydroxy pyrimidines were synthesised and screened for their antibacterial

and antifungal activities.93.9s Bhagwat V S et al96 synthesised 3-[4'-aryl-(2'-

4'-bithiazol)-2'-yl]-2-aryl-4-thiazolidinones and their 5-methyl derivatives

and tested for antibacterial activity. The result revealed that some

compounds showed comparable activity with that of standard furazolidone97

and found that some compounds were more active than the standard.

Earlier, thiazolidines were reported as antitubercular agents.98 Several

1,3-thiazolidin-4-ones were synthesised and screened for in vitro

antibacterial and antifungal99 activities. The compounds showed varying

degrees of antimicrobial activity. Substituted bis-(4-thiazolidinones) were

reported as analgesic and sedative.lOo Sah M M et al 'OI have reported

antifungal activity of 2-aryl-3-( 4-carboxyphenyl)-4-thiazolidinones and

thiourea derivatives. Abdel Rahman R M et al '02 reported antifungal activity

of 3-benzoylamino-2,2-disubstituted-4-thiazolidinones. Rajab F A et al '03

have reported anticonvulsant activity of 4-thiazolidinones. Shah V H et al '04

have synthesised some novel 4-thiazolidinone derivatives and reported

antifungal activity. Parikh A R et alios have synthesised and screened a large

number of 4-thiazolidinones. These compounds showed antibacterial activity.

Parekh H et al '06 have reported antimicrobial activity of 2-aryl-

5H/methyl/carboxymethyl-3- [4-( 3,4,5-trimethoxybenzamido )benzoylamino 1 thiazolidine-4-ones. Recently some new 4-thiazolidinones were synthesised

26

by Muzzahir Kidwai et al. I07 These compounds showed various types of

biological activities.

Deshmukh M B et alIos have synthesised 3-(6-chloro-4-methyl-2-oxo

quinolino )-1-amidyl-2-( 4-nitrophenyl )-1, 3-thiazolidine-4 -one. This compound

was tested in vitro for antimicrobial activity against S.aureus and E.coli.

S K Srivastava et al 109 have synthesised S-arylidene-2-aryl-3-

(phenoth iazi no/benzotriazol oaceta m id yl) -1,3- th ia zol i din -4- 0 nes. These

compounds were screened for their antiinflammatory, anticonvulsant,

analgesic and antimicrobial acivities. Ulusoy Nuray et al"O have reported

the synthesis and antimicrobial activity of novel imidazo[2,1-

b ]thiazolylacetyla minot hydrazino )-4-thiazolidinones. These compounds were

evaluated for their in vitro antibacterial and antifungal activities. Ishihara

Sadao et al lll have synthesised optically active thiazolidinone derivatives.

Daulatabad C D and Bhat G GIl2 have synthesised 2-aryl-3-

(phenylthioxohexamido)-4-thiazolidinones. These compounds were screened

for their antimicrobial and antifungal activities. Hassan H Y et al 'l3 have

reported pyridine bearing thiazolidine derivatives such as 2-[aza(6-methyl(2-

pyridyl) )methylene]-3-a Ikyljaryl-l ,3-thiazolid in-4-ones. The synthesised

compounds have been tested against antimicrobial activity and most of them

showed moderate activity against gram positive bacteria. A R Parikh et al ll4

have synthesised 6-p-anisyl-S-cyano-3-N-methyl- 2 -( 2' -aryl- S'H-4'

thiazolid inon-3' -yl-amino)-3 ,4-dihydropyrimidi n-4-ones. These compounds

were screened for their in vitro growth inhibitory activity against several

microbes like B.megaterium, B.subtilis, E.coli, P.fluorescence and A.awamori.

K Mogilaiah et al"5-"

6 have reported the synthesis of 2-aryl-3-[p-(1,S

naphthyridin-2-yl )phenyl]-4-thiazolidinones and 2-aryl-3-( 2-trifl uoromethyl-

1,S-naphtyridine-3-carbonyla mino )-4-thiazolidinones. These compounds

were screened for their in vitro growth inhibitory activity against E.coli,

B.subtilis, B.mycoides and P.aeruginosa. Synthesised compounds were also

screened for their antifungal activity against Fusarium oxysporum and

Curvularia lunata.

27

Parikh A R et al l17 have studied 4-(5'H-2'aryl-4'-thiazolidinon-3'-yl)

benzophenones and compounds were screened in vitro for their antimicrobial

activity against a variety of bacterial strains such as B.megaterium, E.co/i,

B.subtilis. These compounds were screened for their antifungal activity

against A niger. The antitubercular activity of same compounds has been

carried out at a concentration of 12.5 Ilg/mL against H37R, strain of

M. tuberculosis. Pawar R P et allIS have synthesised 2-[3-methoxy-4-

methoxy-5-iodophenylj-3-[ 4'-arylphenylj-4-thiazolidinones. All the

synthesised compounds were screened for their antimicrobial activity against

E.co/i, Azotobacter, B.subtilis, S.typhi and S.dysentriae.

Joshi H D et al l19 have reported 1,4-bis[2'-methyl/ethyl/phenyl-2'

substituted styryl- 5' -H/methyl/carboxymethylj-4' -thiazolidinon- 3'-yl-a mino j

phthalazines. All the compounds were screened in vitro for their antimicrobial

activity against a variety of bacterial strains such as S.aureus, S.citrus,

E.coli, P.fluorescence, Aflavus and C.albicans. These compounds were

screened for their antihypertensive, antitumour and anti-HIV activities.

Srivastava S K et al 120 have synthesised 5-arylidene-2-aryl-3-(2-

chlorophenothiazinoacetamidyl )-1 ,3-thiazolid in-4-ones. These compound s

were tested for antifungal activity against C. albicans, R. oryzae, A niger and

C. pannical at 10°C with 500 ppm concentration. R C Sharma et al 121 have

synthesised some new 4-thiazolidinone derivatives and these compounds

have been screened in vitro for their antimicrobial and antifungal activities.

Kidwai M et al 122 have reported some thiazolidinones and compounds were

screened for their CNS and cardiovascular activities. Parikh A R et aim have

synthesised 3-aryl-2 -( 2-chloro-7 -methoxyquinoline- 3-yl )-4-th iazolidinones.

These compounds showed good to moderate activity against antifungal and

antibacterial activities. Parekh H et al l24 have prepared thiazolidinones from

hydrazinothieno[3,2-djpyrimidines as potential antimicrobial agents. These

compounds showed in vitro growth inhibitory activity against several

microbes such as B.megaterium, B.subtilis, E.coli, Aaerogenosa and

Aawamori. Maher F EI-zohry et al 12S have reported some new

spirothiazolidinones incorporated with quinazoline. Patel V M et al 126 have

28

reported antibacterial activity of 2-phenyl-3-substituted phenyl-S-arylidene-

4-thiazolidinones and tested against E.co/i, S.aureus, S.typhi and

E.aerogenes microbes.

Looking to the pharmaceutical applications of 4-oxo-thiazolidine derivatives,

in this section we have synthesised some biologically active heterocyclic

compounds.

Following compounds have been synthesised:

• Section-l (a), N-{2- [S-bromo-3-methoxy-4-( phenylmethoxy)phenyl]-4-

oxo-( 1,3-thiazolidin-3-yl) }arylcarboxa m ides.

• Section-l (b), 2- [S-bromo-3-methoxy-4-(phenylmethoxy)phenyl]-

3{ [( aryla m ino )thioxomethyl] amino }-l ,3th iazolidin-4-ones.

• Section-l (c), 2- [S-bromo-3-methoxy-4-(phenylmethoxy) phenyl]- 3-aryl-

1,3-thiazolidin-4-ones and

• Section-l(d), N-2-( {2-[S-bromo-3-methoxy-4-(phenylmethoxy)phenyl]-

4-oxo-l ,3-thiazolidin-3-yl}a mino)a rylaceta m ides.

>- Spectroscopic analysis and biological activities are described in Part: II.

SECTION - l(a)

PREPARATION OF N-{2-[S-BROMO-3-METHOXY-4-(PHENYL

M ETHOXY) PH ENYL]-4-0XO-( 1,3-TH IAZOLIDIN-3-YL)}

ARYLCARBOXAMIDES.

SCHEME-1

29

SR.

NO.

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

30

TABLE: 1

PHYSICAL CONSTANTS OF N-{1-AZA-2-[S-BROMO-3-METHOXY-4-

(PHENYLMETHOXY)PHENYLVINYL}ARYLCARBOXAMIDES.

r

R = Benzyl group

-Ar MOLECULAR M.P. YIELD %OF % OF

FORMULA °C (%) CARBON NITROGEN

FOUND REQD. FOUND REQD.

-2-NO,-C6 H. C"H1BBrN3OS 145 62 54.45 54.56 8.59 8.68 ,

-3-NO,-C6H. C"H 1BBrN3OS 120 45 54.42 54.56 8.55 8.68 :

-4-NO,-C6 H. C"H 1BBrN3OS 215 52 54.48 54.56 8.58 8.68 I

-2-CI-C6H. C"H 1B BrCIN20 3 120 40 55.69 55.78 5.80 5.91

-4-Ci-C6H. C"H 1B BrCIN20 3 220 54 55.67 55.78 5.76 5.91

-2-0H-C6 H. C"H 19 BrN2O. 197 65 57.95 58.04 6.05 6.15

-4-0H-C6 H. C"H 19 BrN2O. 140 50 57.98 58.04 6.00 6.15

-4-CHl-C6 H. C'lH 21 BrN 20 3 200 45 60.82 60.94 6.06 6.18

-CH,-C6Hs C23H21BrN20 3 185 56 60.85 60.94 6.10 6.18

-CH(OH)-C6 Hs C23 H21BrN2O. 85 62 58.75 58.86 5.88 5.97

-3-0CH)"C6H4 C23H21BrN204 205 42 58.70 58.86 5.83 5.97

-C6 Hs C"H 19 BrN20 3 205 55 60.04 60.15 6.27 6.38

-CSH4N C21H1BBrN303 215 40 57.14 57.29 9.50 9.54

SR.

NO.

L-1

L-2

L-3

L-4

L-5

L-6

L-7

L-8

L-9

L-10

L-11

TABLE: 2

PHYSICAL CONSTANTS OF N-{2-[S-BROMO-3-METHOXY-4-

(PH ENYLM ETHOXY)PHENYLj-4-0XO-( 1, 3-THIAZOLIDIN- 3-YL)}

ARYLCARBOXAMIDES.

r Ar

/0 R ~ NH~

I 0 r?

sf 0 H3CO

R = Benzyl group

-Ar MOLECULAR M.P. YIELD % OF

FORMULA °C (%) CARBON

FOUND REQD.

-2-NO,-C.H. C,.H,o BrN)O.s 103 45 51.48 51.62

-4-NO,-C.H. C,.H,o BrN)06s 270 60 51.59 51.62

-2-Cl-C6H. C,.H,o BrCIN,O.s 190 71 52.57 52.62

-4-CI-C6H. C,.H,o BrCIN,O.s 115 62 52.59 52.62

-2-0H-C6H. C,.H 21 BrN,Oss 220 58 54.41 54.45

-4-0H-C6H. C,.H 21 BrN,Oss 215 69 54.43 54.45

-CH,-C6Hs C"H" BrN,O.s 175 76 56.89 56.93

-CH(OH)-C6HS C"H" BrN,Oss 105 65 55.20 55.26

-3-0CH)-C6H. C"H'3 BrN,Oss 215 78 55.22 55.26

-C6HS C,.H 21 BrN,O.S 140 63 56.10 56.15

-CsH.N C"H,o BrN)O.S 230(d) 67 53.64 53.70

31

% OF

NITROGEN

FOUND REQD.

7.45 7.53

7.47 7.53

5.06 5.11

5.08 5.11

5.24 5.29

5.22 5.29

5.26 5.31

5.12 5.16

5.10 5.16

5.40 5.46

8.13 8.17

32

Experimental

• Preparation of 5-Bromo-3-methoxy-4-phenylmethoxy benzaldehyde

(compound A).

A mixture of 5-bromo-4-hydroxy-3-methoxybenzaldehyde (0.01 mole)

and benzyl chloride (0.01 mole) in boiling ethanolic potassium hydroxide

solution was refluxed for 2 hr on a water bath. After the completion of

reaction, solvent was distilled off till crystals commenced out. The solid

product was filtered, washed with cold water. The product was dried and

recrystallised from ethanol (99%). m.p. : 150°C; yield: 60%.

• Preparation of N-{1-aza-2-[5-bromo-3-methoxy-4-(phenylmethoxy)

phenyl] vi ny I} (2 -nitro phe ny I) ca rboxa mid e.

A mixture of compound A (0.01 mole) and N-amino(2-nitrophenyl)

carboxamide (0.01 mole) was dissolved in ethanol (95%, 25 ml). The

reaction mixture was refluxed for 6 hr. The mixture was poured into ice-cold

water, filtered, dried and recrystallised from ethanol (99%). m.p. : 145°C;

yield : 62%; Anal. Found : C, 54.45 ; H, 3.66 ; N, 8.59 ; Calc for

C22H'8BrN)Os : C, 54.56 ; H, 3.75 ; N, 8.68%.

The compounds (2-13) were prepared similarly and their physical data

are recorded in Table: 1.

• Preparation of N-{2-[5-Bromo-3-methoxy-4-(phenylmethoxy)phenyl]-4-

oxo-( 1, 3- thiazolidin-3-yl)}( 2-nitrophenyl )carboxamide.

N -{ 1-aza-2- [5-bromo- 3- methoxy-4-( phenyl methoxy) phenyl]vinyl} (2-

nitrophenyl)carboxamide (0.01 mole) in an anhydrous 1:4 dioxan (20 ml)

was added to 2-sulfanylacetic acid (0.012 mole). The mixture was refluxed

for 12 hr, cooled and then poured into aqueous saturated solution of sodium

bicarbonate to remove unreacted 2-sulfanylacetic acid. The residue was

filtered, washed with cold water, dried and recrystallised from ethanol

(99%). m.p. : 103°C; yield:45%; Anal.Found : C, 51.48 ; H, 3.55 ; N, 7.45 ;

Calc for C24H20BrN)06S: C, 51.62; H, 3.61 ; N, 7.53%.

The compounds (L-2 to L-11) were prepared similarly and their

physical data are recorded in Table: 2.

SECTION: l(b)

PREPARATION OF 2-[S-BROMO-3-METHOXY-4-PHENYLMETHOXY)

PHENYL-3-{[ARYLAMINO)THIOXOMETHYL)AMINO}-

1,3-THIAlOLIDIN-4-0NES.

H

R /0

H3CO

o

r

r

;Y

~ I

+

Ethanol (95%)

N" L ,/Ar ~ NH NH

SHCH2COOH

1:4 Dioxan

NH-Ar

f~ N 5

sJO

Ar = Different aryl groups R = Benzyl group

SCHEME-2

33

SR.

NO.

l.

2.

3.

4.

5.

6.

7.

8.

9.

10.

1l.

12.

13.

14.

15.

16.

17.

TABLE: 3

PHYSICAL CONSTANTS OF {1-AZA-2-[S-BROMO-3-METHOXY-4-

(PHENYLr-1ETHOXY)PHENYLlVINYL}AMINO)[ARYLAMINOl

METHANE-i-THroNES.

r

R = Benzyl 9 rou P



FOUND REQD.

-2-NO,-C.H. C"H 19 BrN.O.5 60 52 51.19 51.27

-3-NO,-C.H. C"H 19 BrN.O.5 115 58 51.15 51.27

-4-NO,-C.H. C"H 19 BrN.O.5 100 60 51.20 51.27

-3-Cl-C.H. C"H19BrCIN30,5 140 45 52.26 52.34

-4-CI-C6H. C"H 19BrCIN30,5 175 48 52.22 52.34

-2,5-( CH3),-C6H3 C,.H,.BrN30,5 135 72 57.76 57.83

-2,6-( CH 3),-C6H3 C,.H,.BrN30,5 178 70 57.71 57.83

-2-0CHrC6H. C'3H"BrN30 35 192 62 55.13 55.21

-3-0CHr C.H. C'3H"BrN30 35 150 55 55.10 55.21

-4-0CHrC.H. C'3H"BrN30 35 170 64 55.16 55.21

-2-CH r C•H• C23 H"BrN30,5 168 50 56.91 57.03

-3-CHr C.H. C'3H"BrN30,5 200 45 56.94 57.03

-4-CHr C.H. C23 H"BrN30,5 185 58 56.90 57.03

-3-0H-C.H. C"H,oBrN30 35 175 65 54.21 54.33

-4-0C,Hs-C.H. C,.H,.BrN30 35 180 40 55.92 56.04

-C.Hs C"H,oBrN3O,5 140 65 56.07 56.18

-1-C lOH7 C,.H"BrN30,5 125 75 59.90 60.00

r

34

%OF

NITROGEN

FOUND REQD.

10.76 10.87

10.70 10.87

10.79 10.87

8.24 8.32

8.27 8.32

8.32 8.43

8.33 8.43

8.29 8.40

8.31 8.40

8.26 8.40

8.55 8.67

8.58 8.67

8.52 8.67

8.51 8.64

8.10 8.17

8.81 8.93

7.96 8.07

: :.J~1,1"'t' .,' !, ;,.,. ( , .,j ~ i

.; ,,', ,.

SR.

NO.

L-21

L-22

L-23

L-24

L-25

L-26

L-27

L-28

L-29

L-30

L-31

L-32

L-33

L-34

L-35

TABLE: 4

PHYSICAL CONSTANTS OF 2-[S-BROMO-3-METHOXY-4-(PHENYL

METHOXY)PHENYL - 3-{ [(ARYLAMIN 0 )THIOZOM ETHYLjAMINO }-l ,3-

THIAZOLIDIN-4-0NES.

R = Benzyl group


FORMULA °C (Dfo) CARBON

FOUND REQD.

-2-NO,-C6H4 C'4H21BrN4OSS, 225 56 48.75 48.90

-3-NO,-C6H4 C'4H21BrN40SS, 205 72 48.75 48.90

-4-NO,-C6H4 C'4H21BrN40SS, 245 70 48.83 48.90

-3-Cl-C6H4 C'4H21BrCIN303S, 100 62 49.67 49.79

-4-Cl-C6H4 C'4H21BrCIN303S, 120 75 49.71 49.79

-2,6-(CH3h-C6H3 C'6H'6BrN303S, 200 66 54.48 54.54

-2-0CH3-C6H4 C'SH'4BrN304S, 150 59 52.14 52.27

-3-0CH,-C6H4 CzsH,.BrN30 4S, 205 63 52.17 52.27

-4-0CH 3-C6H4 C'SH'4BrN304S, 245 60 52.20 52.27

-2-CH3-C6H4 C'SH'4BrN303S, 130 64 53.71 53.76

-3-CH 3-C6H4 C'SH'4BrN303S, 125 69 53.69 53.76

-4-CH,-C6H4 C'SH'4BrN303S, 115 65 53.67 53.76

-3-0H-C6H4 C'4H"BrN30 4S, 110 59 51.32 51.43

-4-0C,Hs-C6H4 C'6H'6BrN304S, 190 56 53.01 53.06

-C6Hs C'4H"BrN30 3S, 255 78 52.86 52.94

35

% OF

NITROGEN

FOUND REQD.

9.42 9.50

9.38 9.50

9.44 9.50

7.18 7.26

7.15 7.26

7.25 7.34

7.23 7.31

7.19 7.31

7.24 7.31

7.45 7.52

7.42 7.52

7.40 7.52

7.45 7.50

7.04 7.14

7.63 7.71

36

Experimental

• Preparation of {1-Aza-2-[5-bromo-3-methoxy-4-(phenylmethoxy)phenyl]

vinyl}amino )(2-nitrophenyl)amino] metha ne-1-thione.

A mixture of compound A (0.01 mole) and hydrazino[(2-

nitrophenyl)amino]methane-1-thione (0.01 mole) was placed in a RBF and

ethanol (95%, 25 ml) was added to it. The reaction mixture was refluxed for

6 hr on a water bath. The excess of solvent was collected by distillation,

filtered, washed with ice-cold water, dried and recrystallised from ethanol

(99%). m.p. : 60°C; yield: 52%; Anal. Found: C, 51.19 ; H, 3.55 ; N, 10.76

; Calc for C22H19BrN404S : C, 51.27 ; H, 3.71 ; N, 10.87%.



• Preparation of 2-[5-Bromo-3-methoxy-4-(phenylmethoxy)phenyl]-3-

( {[ (2 -nitrophenyl)a mino ]thioxomethyl}a mino) -1 ,3-thiazolidin-4-one.

{l-Aza-2 - [5-bromo- 3-methoxy-4-( phenylmethoxy )phenyl]vinyl}

amino)(2-nitrophenyl)amino]methane-1-thione (0.01 mole) in an anhydrous

1:4 dioxan (25 ml) was added to 2-sulfanylacetic acid (0.012 mole). The

reaction mixture was refluxed for 12 hr, cooled and poured into aqueous

saturated solution of sodium bicarbonate to remove unreacted 2-sulfanyl

acetic acid. The residue was filtered, washed with water, dried and

recrystallised from ethanol (99%). m.p. : 225°C; yield: 56%; Anal. Found:

C, 48.75 ; H, 3.50 ; N, 9.42 ; Calc for C24H21BrN40SS2: C, 48.90 ; H, 3.59 ;

N,9.50%.



SECTION: l(c)

PREPARATION OF 2-[S-BROMO-3-METHOXY-4-(PHENYLMETHOXY)

PH ENYLj-3-ARYL -1,3-THIAZOLlDIN-4-0N ES.

r

j SHCH2COOH

1:4 Dioxan

r

Ar = Different aryl groups

R = Benzyl group

SCHEME-3

37

SR.

NO.

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

TABLE: 5

PHYSICAL CONSTANTS OF 5-[2-AZA-2-ARYLVINYL]-3-BROMO-l

METHOXY-2-(PHENYLMETHOXY)BENZENES.

r

R = Benzyl group



FOUND REQD.

-2-NO,-C6 H. C21 H,7BrN,O. 70 40 57.05 57.16

-4-NO,-C6H. C21 H17 BrN,O. 120 52 57.10 57.16

-3-Cl-C6 H. C21 H17 BrCINO, 90 35 58.44 58.56

-4-Cl-C6 H. C21 H17 BrCINO, 105 42 58.47 58.56

-2,5-(CH 3J,-C6H3 C23H"BrNO, 125 45 64.97 65.10

-2,6-(CH3J,-C6H3 C'3H"BrNO, 185 38 65.02 65.10

-2-0CH,-C6 H. C"H,oBrN03 120 45 61.84 61.98

-3-0CH,-C6 H. C"H,oBrN03 150 40 61.88 61.98

-4-0CH,-C6 H. C"H,oBrN03 85 35 61.86 61.98

-2-CH,-C6H. C"H,oBrNO, 173 48 64.31 64.40

-3-CH,-C6 H. C"H,oBrNO, 103 55 64.29 64.40

-4-CH,-C6 H. C"H,oBrNO, 125 44 64.25 64.40

-4-0C,Hs-C6H. C'3H"BrN03 235 58 62.63 62.74

-1-ClOH7 C,sH,oBrNO, 170 60 67.20 67.28

-4-Br-C6H. C21 H17BrNO, 95 40 53.00 53.08

-C6 HS C21 H,B BrNO, 100 45 63.53 63.65

-3-Cl,4-F-C6H3 C21 H,6BrCIFNO, 105 35 56.11 56.21

38

% OF

NITROGEN

FDUND REQD.

6.28 6.35

6.25 6.35

3.14 3.25

3.12 3.25

3.16 3.30

3.18 3.30

3.16 3.29

3.20 3.29

3.19 3.29

3.32 3 .41

3.34 3.41

3.27 3.41

3.10 3.18

3.03 3.14

2.84 2.95

3.47 3.54

3.00 3.12

SR.

NO.

L-52

L-53

L-54

L-55

L-56

L-57

L-58

L-59

L-60

L-61

L-62

L-63

L-64

TABLE: 6

PHYSICAL CONSTANTS OF 2-[S-BROMO-3-METHOXY-4-(PHENYL

M ETHOXY)PHENYLj-3-ARYL -1,3-THIAZOLIDIN -4-0N ES.

r

R = Benzyl group

-Ar MOLECULAR M.P YIELD % OF


FOUND REQD.

-2-NO,-C.H4 C'3H'9 BrN,OsS 175 45 53.47 53.60

-3-Cl-C.H4 C'3H'9BrCIN03S 110 63 54.63 54.72

-2,5-(CH3h-C6H3 C25H,4 BrN03S 102 64 60.12 60.24

-2,6-( CH3),-C6H3 C25H,4 BrN03S 200 55 60.14 60.24

-2-0CH3-C6H4 C'4H" BrN04S 130 58 57.49 57.61

-3-0CH3-C.H4 C'4H" BrN04S 230 62 57.53 57.61

-4-0CH,-C6H4 C'4H" BrN04S 110 57 57.52 57.61

-3-CH,-C6H4 C'4H" BrN03S 168 63 59.38 59.51

-4-CH,-C.H4 C'4H" BrN03S 100 66 59.42 59.51

-4-0C,Hs-C6H4 C25H,4 BrN04S 175 56 58.24 58.37

-1-C lOH7 C'7H" BrN03S 145 61 62.23 62.31

-C.Hs C'3H,O BrN03S 260 62 58.64 58.73

-4-Br-C6H4 C'3H'9Br,N03S 125 52 50.18 50.29

39

% OF

NITROGEN

FOUND REQD.

5.33 5.43

2.70 2.78

2.70 2.81

2.69 2.81

2.71 2.80

2.74 2.80

2.68 2.80

2.81 2.89

2.80 2.89

2.64 2.72

2.60 2.69

2.91 2.98

2.46 2.55

•

40

Experimental

• Preparation of 5-[2-Aza-2-(2-nitrophenyl)vinyl]-3-bromo-1-methoxy-2-

(phenylmethoxy)benzene.

A mixture of compound A (0.01 mole) and 2-nitrophenyl amine

(0.01 mole) was added in bOiling ethanol (95%, 25 ml). The reaction mixture

was refluxed for 6 hr on a water bath. The solvent was collected by

distillation to get the crystalline product. The solid product was filtered,

washed with cold water, dried and recrystallised from ethanol (99%). m.p. :

70°C; yield: 40%; Anal. Found: C, 57.05 ; H, 3.74 ; N, 6.28 ; Calc for

C2,H 17 BrN20 4 : C, 57.16 ; H, 3.88 ; N, 6.35%.



• Preparation of 2-[5-Bromo-3-methoxy-4-(phenylmethoxy)phenyl]-3-(2-

nitrophenyl )-1,3-thiazolidin-4-one.

5- [2 -Aza -2 -( 2 -nitrophenyl)vinyl]- 3-bromo-1- methoxy-2 -( phenyl

methoxy)benzene (0.01 mole) in an anhydrous 1:4 dioxan (20 ml) was

added to 2-sulfanylacetic acid (0.012 mole). The reaction mixture was

refluxed for 12 hr, cooled and then poured into aqueous saturated solution of

sodium bicarbonate to remove unreacted 2-sulfanylacetic acid. The residue

was filtered, washed with water, dried and recrystallised from ethanol

(99%).

m.p. : 175°C; yield: 45%; Anal. Found: C, 53.47 ; H, 3.60 ; N, 5.33 ; Calc

for C23H'9BrN20SS : C, 53.60 ; H, 3.71 ; N, 5.43%.


physical data are recorded in Table: 6 .

SECTION - ltd)

PREPARATION OF N-2-( {2-[S-BROMO-3-METHOXY-4-(PHENYL

METHOXY)PH ENYLj-4-0XO-l,3-THIAZOLIDIN-3-YL}AMINO)-

r

j SHCH2COOH

1:4 Dioxan


R = Benzyl group

SCHEME-4

41

SR.

NO.

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

TABLE: 7

PHYSICAL CONSTANTS OF 2-(1-AZA-2-[5-BROMO-3-METHOXY-4-

(PHENYLMETHOXY)PHENYLJVINYL)AMINO-N-ARYLACETAMIDES.

r

R = Benzyl group

-Ar MOLECULAR M.P. YIELD %OF


FOUND REQD.

-2-NO,-C6H. C"H21BrN.Os 160 50 53.72 53.81

-3-NO,-C6H. C"H'IBrN.Os 140 48 53.70 53.81

-4-NO,-C6H. C"H'IBrN.Os 200 62 53.67 53.81

-2-CI-C6H. C'3H21BrCIN303 105 55 54.82 54.94

-4-Cl-C6H. C'3H21BrCIN303 138 63 54.80 54.94

-2,5-( CI),-C6H3 C'3H,oBrCI,N30 3 130 45 51.30 51.42

-2,4-(CH3j,-C6H3 C'SH'6BrN30 3 110 56 60.38 60.49

-2,6-(CH3 ),-C6H3 C'SH'6BrN3 0 3 140 60 60.35 60.49

-4-0CH3-C6H. C,.H,.BrN 3O. 118 54 57.73 57.84

-2-CH r C6H4 C'4H'4BrN 30 3 136 62 59.64 59.76

-4-CH r C6H4 C,.H'4BrN 30 3 140 48 59.67 59.76

-2-0C,Hs-C6H4 C'SH'6BrN 30 • 85 55 58.47 58.60

-4-0C,Hs-C6H. C'SH'68rN30 • 114 68 58.51 58.60

-C6HS C"H,,8rN30 3 105 65 58.89 58.98

-l-C IO H, C"H,.8rN30 3 125 65 62.48 62.56

42

% OF

NITROGEN

FOUND REQD.

10.85 10.91

10.88 10.91

10.78 10.91

8.24 8.36

8.20 8.36

8.23 7.82

8.39 8.47

8.35 8.47

8.36 8.43 I

8.60 8.71

8.58 8.71

8.12 8.20 I

8.09 8.20

8.86 8.97

7.98 8.11

SR.

NO.

L-76

L-77

L-78

L-79

L-80

L-81

L-82

L-83

L-84

L-85

L-86

L-87

TABLE: 8

PHYSICAL CONSTANT OF N-2-( {2-[5-BROMO-3-METHOXY-4-

(PHENYLM ETHOXY)PHENYLj-4-0XO-l ,3-TH IAZOLIDI N - 3-YL}

AMINO)ARYLACETAMIDES.

r

R = Benzyl group



FOUND REQD.

-2-NO,-C,H4 C25H2J BrN40 6S 98 45 51.00 51.12

-3-NO,-C6H4 C"H" BrN4O,S 165 62 51.08 51.12

-4-N02-C,H4 C25H" BrN 4O,S 155 60 51.09 51.12

-2-CI-C,H4 C25H" BrCIN3O.S 165 58 52.00 52.05

-4-Cl-C,H. C2sH23 BrCIN30 4S 175 55 52.01 52.05

-2,4-(CH3),-C,H3 C27H28 BrN30.S 173 65 56.81 56.84

- 2,6-(CH3),-C,H3 C27H28 BrN30 4S 245 54 56.80 56.84

-4-CH,-C,H4 C2,H 26 BrN 30 4S 190 75 56.06 56.12

-2-0C2HS-C,H4 C27H28 BrN30SS 265 55 55.24 55.29

-4-0C2Hs-C,H4 C2,H28 BrN30SS 160 52 55.26 55.29

-C,Hs C2sH'4 BrN30 4S 300 70 55.31 55.36

-l-C lOH, C29H2, BrN30.S 170 65 58.76 58.79

43

%OF

NITROGEN

FOUND REQD.

9.40 9.54

9.52 9.54

9.49 9.54

7.25 7.28 :

7.26 7.28

7.35 7.37

7.33 7.37

7.48 7.55

7.10 7.16

7.12 7.16

7.72 7.75

7.06 7.10

44

Experimental

• Preparation of 2-( {1-Aza-2-[5-bromo-3-methoxy-4-(phenylmethoxy)

phenyl] vinyl }amino )-N-( 2 -nitrophenyl )acetamide.

Compound A (0.01 mole), 2-hydrazino-N-(2-nitrophenyl)acetamide

(0.01 mole) and ethanol (95%, 25 ml) were refluxed for 6 hr on a water

bath. The reaction mixture was poured into ice-cold water. The product was


(99%). m.p. : 160°C; yield : 50%; Anal. Found : C, 53.72 ; H, 4.01 ;

N, 10.85 ; Calc for C23H2IBrN.Os: C, 53.81 ; H, 4.12 ; N, 10.91%.



• Preparation of N-2-( {2-[5-bromo-3-methoxy-4-(phenylmethoxy)phenyl]-

4-oxo-( 1 ,3-thiazolidine-3-yl) }amino- (2 - nitrophenyl )acetamid e.

2-( {l-Aza-2- [5-bromo-3-methoxy-4-( phenyl methoxy)phenyl] vinyl}

amino)-N-(2-nitrophenyl)acetamide (0.01 mole) in an anhydrous 1:4 dioxan

(25 ml) was added to 2-sulfanylacetic acid (0.012 mole). The reaction

mixture was refluxed for 12 hr, cooled and then poured into aqueous

saturated solution of sodium bicarbonate to remove unreacted 2-sulfanyl

acetic acid. The solid product was filtered, washed with water, dried and

recrystallised from ethanol (99%). m.p. ; 98°C; yield; 45%; Anal. Found

C, 51.00 ; H, 3.82 ; N, 9.40 ; Calc for C2sH"BrN.06S ; C, 51.12 ; H, 3.95

N,9.54%.


physical data are recorded in Table; 8.

45

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-------

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46

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49

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51

SECTION: II

STUDIES ON 2-0XO-AZETIDINES.

Introduction:

The j3·lactam antibiotics comprise of two groups of therapeutic agents

of considerable clinical importance, the penicillins and cephalosporins. The

j3-lactam antibiotics inhibit bacteria exhibiting activities, which differ in

pattern and intensity. In general, they exert their biological effect by

interfering with the synthesis of essential structural components of the

bacterial cell wall. These components are absent in mammalian cells so that

synthesis of bacterial cell-wall structure can be inhibited with little or no

effect on mammalian cell metabolism.

It is over sixty years since Sir Alexander Fleming observed antibiosis

between a penicillium mould and bacterial cultures and gave the name

penicillin to the active principle. Although it was proposed in 1943 that

penicillin contained a j3-lactam ring, this was not generally accepted until an

X-ray crystallographic determination of the structure had been completed.

Discovery of penicillin in 1929 proved to be an immense turning point in the

history of chemotherapy. It opened up the way for modern chemotherapy

and led to a rapid development in the chemistry and manufacture of

antibiotics, thereby contributing to saving the lives of thousands of people by

facilitating the struggle against bacterial infection.

In addition, these antibiotics tend to be irreversible inhibitors of cell

wall synthesis and they are usually bactericidal at concentration close to their

bacteriostatic levels. As a consequence, these types of drugs are widely

used for treating bacterial infections and are regarded as highly effective

antibiotics with low toxicity. Interest in the synthesis and chemistry of

j3-lactams has been greatly accelerated since the discovery of penicillin.

52

2-0xo-azetidine and its derivatives are used as antibiotics i.e.,

penicillins, ampicillin, amoxycillin, cephalosporins, nocardicins, thienamycins,

etc. This four-member ring has inspired scientists as well as synthetic

organic chemists to develop more potential antibiotic drugs having J3-lactam

moiety.

• Penicillin is one of the most important antibiotics. It is derived from a

number of penicillium molds commonly found on breads and fruit. The

mechanism of action for the penicillins is the inhibition of cell wall

synthesis during the reproductive phase of bacterial growth and it is one

of the most effective and least toxic of the antimicrobial agents.

Penicillin is effective in the treatment of :

• Bacterial endocarditis and pneumococcal infections.

• Hemoiytic streptococcai infections.

• Clostridial infections such as gas gangrene.

• Anaerobic streptococcai infections, Anthrax.

• Vincent's angina, Syphilis and Rheumatic heart fever.

Mechanism of Action:

Beta-Iactam antibiotics inhibit bacterial cell wall synthesis. The drugs

cause nicks in the peptidoglycan net of the cell wall that allow the bacterial

protoplasm to "flow" from its protective net into the surrounding hypotonic

medium. Fluid accumulates in the naked protoplast, as the cell now devoid of

its wall is called, and it bursts resulting in death of the organism.

Chemistry:

When one of the four methylenes of cyclobutane is replaced by >NH,

the heterocyclic compound, is known as "AZETIDINE". Azetidine is the name

given to the completely saturated four-member nitrogen containing

compound, it is also designated as trimethyleneimine.

53

Azetidines were first synthesized in 1888 by the internal cyclisation of

y-bromopropylamine.

Br~NH2 Alkali

-HBr

Although azetidines were first prepared in 1888, this division of small

ring, nitrogen heterocyclic has been the least studied. The main reason for

the scarcity of information is that, in many instances, the methods used to

prepare azetidines give relatively a poor yield. In the last two decades,

however, some important progress has been made towards more productive

synthesis of these compounds. And the test in the relationship between ring

size and reactivity has stimulated these recent developments in the

investigation of four member cyclic imines. Also the discovery of naturally

occurring azetidine-2-carboxylic acid,l which has shown some unique and

potentially useful biological activity'·4 has stimulated interest in the

azetidines field. If an adjacent methylene (-CH,-) of azetidines is converted

into a ketone (>C=O), the resulting compound is known as 2-oxo-azetidine

or 2-azetidinone. It is also known as il-Iactam.

o

OH

NH

Several special and unique methods were developed to build-up this

cyclic amide which is very susceptible to reactions involving the carbonyl

group.

54

Preparations of 2-0xo-azetidines:

J3-Amino propionic acid does not yield J3-lactam, while cyclic derivatives

of such acid can easily be transformed into heterocycles by simple heating.

The success of this method has been attributed to the intermediatory of

hydroxy ketone acetenesS·6 as shown in the following chemical reaction:

Carbodiimides have displaced their use, as carbodiimide group has

been used in the total synthesis of penicillin-V. 7

o OH

O~ IV"~s CH3 Ph..... N~

N CH3

OH

o

Penicillin V

The reaction of J3-amino acid esters with Grignard reagent is often

employed to prepare J3-lactams. J3-Propiolactam can be synthesised by

reaction between H2N-CH 2-COOEt and 2,4,6-trimethyl C6H,-MgX in ether at

0-25 0c. Here MeMgX can also be used.B

55

MgX

H2~0,-- /CH 3 H3 -::?' CH3 ex CH2 + ETHER

0 ~ 0-2S 0 C 0

CH3

Gillman H et al9 chose the Reformatsky reaction for the preparation of

13-lactam. In this reaction, a mixture of ethylbromo acetate and zinc was

added to the anil linkage of benzalaniline to give 56% yield of 1,4-diphenyl

13-lactam.

Another new synthesis by base catalyzed ring closure of N-substituted

diethyl chloroacetamido malonates and intermolecular Michael-type addition

of substituted acyl amides was proposed by Sheehan J C et al.lO In this

synthesis, the amide linkage is formed first and the four member 13-lactam

ring is then made by establishing carbon-carbon bond.

/ CH2CH3

:x; CH2CH3 Ph - NH2

aN ~

~I 0

0,--B CH2CH3 / CH 2CH3

0 0 0

92% /CH2CH3

0 /CH2CH3

N(C2HSh -0

aN ~I 0

0 0,--/CH2CH3 CH2CH3 0 0

56

A novel synthesis of p-Iactam with the use of resin was given by

Chattergee B G et alII and Bose A K et al. 12

Staudinger HI3 has prepared substituted p-Iactams by the

condensation of diphenyl ketene and imine.

P 0

0 Ph Ph>=// Ph~N" -C + ;/ Ph

Ph N"

Ph Ph

A new synthesis has been developed which furnishes p-Iactam bearing

an amino function alpha to the lactam carbonyl by interaction of 2-(1,3-

dioxoisoindolin-2-yl)acetylchloride and Schiff base of benzalaniline in the

presence of triethylamine.

a-Azido-i3-lactams were synthesised by Bose A K et al. 14 These were

obtained from the reaction of a-azido acid chloride with imines. The reaction

mechanism is as under:

57

R (CzHshN

N~CI )t.)=( o H 0 H

They showed that the slow addition of azidoacetyl chloride to a

solution of benzalaniline and Et3N in CH 2CI 2 favored cis product while the

trans product was favored when the Et3N was added to a mixture of Schiff

base and azidoacetyl chloride. Ulrich H'S showed that chloro and

f1uorosulfonyl isocyanate even reacted with a number of olefins to form 1,2-

dipolar addition products. Generally, the reaction proceeds to form both, the

initial cyclic intermediate as well as the straight chain isomer.

CH3

l - + R-SOzNCO ---~ H3~CHz

Where R = halogen group

Testa E et al '6 reported that J3-bromopropionamides were cyclised by

sodamide in liq. ammonia to the corresponding l-alkyl or 1-aryl-2

azetidinones.

--------------- --

58

Calanda-Stiftung17 prepared 4,4-disubstituted azetidin-2-ones by (a)

the reaction of an ester of l3-amino carboxylic acid with an alkyl Mg halide,

(b) the reaction of halide of l3-amino carboxylic acid with tertiary organic

base, (c) heating N-alkanoyl derivative of l3-amino carboxylic acid to 150-

200°C and (d) treating l3-amino carboxylic acid with a dehydrating agent.

Where R, = hydrocarbon radical, R2 = cycloalkyl or aryl, R3 = H, alkyl or

alkenyl of 6 or less carbon, R., = H or alkyl of 6 or less carbon atoms.

The reaction involves treatment of an aziridine derivative with lithium

iodide followed by treating the reaction mixture with nickel tetra carbonyl and

finally addition of solid iodine. 1-benzyl-2-methylaziridine under these

conditions gives 1-benzyl-4-methyl-2-azetidinone in 50% yield. It is noticed

that the less substituted C-N bond is carbonylated.

(i) LiI, THF

(ii) Ni(C014

(iii) Iz work up H

o

I3-Amino acids cyclise cleanly in the presence of diphenylphosphoric

chloride to 13-lactams. N-benzyl-3-aminobutyric acid leads N-benzyl 2-

azetidinone,'8 in 72% yield. This reaction is solvent-dependent as the yield of

the product decreases by altering the solvent, THF (68%), CH 2CI 2 (61%).

59

The recent discoveries of 6-amino penicillanic acid derivative (I) on

one hand and cephalosporin (II), on the other hand, have resulted in a flow

of new [j-Iactam antibiotics having a versatility that was not possible a

decade ago. The penicillin are [j-Iactam thiazolidines and in cephalosporin,

the lactam ring is fused to dihydrothiazine ring.

OH o

Penicillin (I)

t;i t;i

N~S j-N'-.§

o

HO 0

Cephalosporin (II)

[j-Lactam drugs are still the most widely prescribed antibiotics in

medicine. Maffii G et al 19 synthesised some [j-Iactams and evaluated for

pharmacological activity. The ethyl derivative is more effective. The

compound is similar to phenobarbital in its action on mice, rats and rabbits

but differs somewhat in dogs. In further study Maffii G20 determined

60

anticonvulsant activity of some substituted p-Iactams. He further confirmed

that the substances had general depressant action on the nervous system as

manifested in the various tests. He showed that the simultaneous presence

of one aromatic and one aliphatic radical at substituent position is conducive

to high activity. Maher F EI-zohry et al21 have prepared some new

quinazoline base spiroazetidinone derivatives.

Bose A K et al 22 have evaluated antibacterial activity of p-Iactams.

They prepared nearly 16 p-Iactams, out of which seven were active in vitro

against a variety of gram-positive and gram-negative bacteria at minimum

inhibitory concentration (MIC) of 25-100 flg/ml against Brucella melitensis.

Gluditta A et al 23 synthesised some inorganic derivatives of p-Iactams.

They are used as enzyme (brain & heart) inhibitors and central nervous

system active agents. 3-Chloro-2-oxo-azetidine derivatives have been

prepared by condensation of chloroacetic acid, dichloroacetic acid, 2-chloro

propanoic acid or 2-bromopropanoic acid with Schiff bases in N,N-dimethyl

carboxamide [HCON(CH3h]' in the presence of POCI3 or POBr3'

)) )------,-N

c o

Where X= >CH-CI, >CCI2, >C-Cl-CH3' etc.,

R= different functional groups.

Nelson D A24 has obtained a number of cis and trans 3-chloro-2-oxo

azetidines by cycloaddition of chloroketone to Schiff bases in presence of

triethylamine in benzene at 70-75 0(,

Boyd D B25 synthesised nearly thirteen p-Iactams and charge

distribution quantities from CNDO/2D MO calculation on 3-substituted

p-Iactam were correlated with the p-Iactam covalent bond and the net active

Bhavna~ar University Libr.1r~.

BHAVNAGAR.

61

charge on carbonyl oxygen. He found that depending upon the 3-substituent,

p-Iactam with a more favorable energy of interaction in the molecule, tend to

exhibit better in vitro activity against gram-negative bacteria.

Shanker K et al 26 have synthesised 3-(1-arylalkyl-3-chloro-2-oxo-4-

azetidinyl)indoles. These compounds were tested for antiparkinsonian and

antigridity activities.

Bhagwat V S et al 27 reported 2-azetidinones bearing 2', 4'-bithiazole

moiety as possible antibacterial. They have synthesised some 1"-(4-aryl- (2',

4'-bithiazol-2'yl)-4'-aryl)-2"-azetidinones. The compounds were tested

against E.coli, S.aureus and P.aeruginosa. Few compounds showed good

activity against S.aureus and P.aeruginosa. Chauhan N A28 reported 1A

diaryl-3-chloro-2-azetidinones as antimicrobial agents. Compounds showed

promising activity against E.coli and S.aureus zone of inhibition varied from

28 to 38 mm.

Shah S K et al 29 have reported azetidinone derivatives as useful drugs

for treating inflammation and degenerative diseases. Compounds showed

ICso of 3 mg/ml against edema. Some modified compounds were also

prepared and tested as antiinflammatory agents and human granulocyte

elastase inhibitors. Uthale A C and Hogale M B30.31 have reported azetidinone

derivatives as antibacterial and antifungal agents. Bari S S et al32 have

synthesised 1-( 4' -aryl) -3-phenylth io-4 A-d iethoxycarbonyl-azetid i n-2 -ones.

Parekh H et aiD have synthesised some new azetidinones and tested for their

antibacterial activity.

Shah V H et al 34 have synthesised 2-azetidinones and tested for

antimicrobial and antitubercular activities. Muzaahir Kidwai and Parveen

Kumars have synthesised some 2-azetidinones and have showed various

types of biological activities. Gajare A S et al 36 synthesised some new

azetidinones which have been tested for their herbicidal activity.

Interest in the synthetic chemistry of p-Iactams has greatly

accelerated with the discovery of Penicillin. In view of the powerful antibiotic

activity shown by monocyclic p_lactams,37.38 the synthetic organic chemists

62

are currently engaged in the design of strategies leading to substituted novel

j3-lactams.

The N-substituted-2-azetidinones can serve as useful intermediates for

the synthesis of other N-substituted and fused j3_lactams.39-4o These N

substituted -2-azetidinones themselves possess good antimicrobial activity.

A number of substituted 2-azetidinones have been synthesised by

Sharma S D et al. 41 All the compounds were screened in vitro against number

of gram-positive and gram negative bacteria like B.subtilis, S.typhimurium,

E.co!i, NCTC-10418 and K. pneumonia at 100 ~g/ml concentration. Some of

the compounds inhibited the growth of S.aureus and E.co!i at this

concentration. Kalaiya S B et al 42 prepared some 2-azetidinone derivatives of

2-amino-S-benzyl-1,3,4-thiadiazoles and tested for their antibacterial

activity. The results showed that most of the compounds showed good

activity against S. typhosa. Vansdadia R N et al43 prepared some p,p'-bis-(3-

chloro-4-aryl-2-azetidinone-1-ylcarbamoylmethoxy)diphenyl- su Iphones and

evaluated their microbial activity against S.aureus, S.citrus, E.co!i. and fungi

S.cerevisiae & A. niger. The results showed that most of the compounds

were moderately active (10-20 mm, zone of inhibition). They also worked

out the order of activity viz., 4-chlorophenyl, 3-methoxy-2-hydroxyphenyl,

and 4-hydroxyphenyl.

Shah V H et al44 have synthesised some 1-aryl-4-(o-hydroxy

phenyl!styryl)-3-chloro-2-azetidinones and tested them for antibacterial and

antifungal activities. They observed that some of the compounds showed

remarkable activity against S.aureus (antibacterial) and Aniger (antifungal).

Moreover, they also tested them for anthelmintic activity and got promising

results.

Ube Industries Ltd.,<s having 2-azetidinone nucleus marketed some

agriculture fungicides, effective against plant pathogenic fungi (e.g.

Piricu!aria bryzae in rice). Abdulla R 1"'6 prepared some herbicidal

azetidinones. These compounds completely killed sicklepod and pricklyalda

and effectively controlled nightshade. Some other scientists have also

prepared 2-azetidinones and evaluated their antibacterial and antifungal

63

activities:7-48 Khanna R et al 49 have prepared azetidinone derivatives of

phenothiazine and tested their antiparkinsonian activity at lOOmg/kg in vivo.

He took l-dopa and bromocriptine as standard drug. Results are as under:

(i) Antitremor activity: Out of 18 compounds, six compounds possessed

significant activity, better than standard drugs. Three compounds

antagonized oxotremorine induced tremor similar to i-dopa.

(ii) Antirigidity activity: Four compounds significantly antagonized

reserpine induced rigidity, better than i-dopa, while three compounds

exhibited antirigidity activity similar to i-dopa.

(iii) Antihypokinetic activity: Four compounds exhibited significant anti

hypokinetic activity, which was better than that of i-dopa.

(iv) Anticatatonic activity: Four compounds possessed anticatatonic

activity better than i-dopa while four were similar to i-dopa. Only one

compound had anticatatonic action similar to bromocriptine.

Han W TSO has prepared 3-(guanidino alkyl) azetidinones and tested for

antithrombin and antitryptin activities. Singh R et alS! have carried out

oxidation studies on p-Iactam antibiotics and further determined the

structure of oxidation products of 3-hetero arylthiomethylcephalosporin using

NMR spectroscopy. Dave M A et al s2 synthesised some new 3-amino-l,4-

diarylazetidine-2-ones. These compounds were tested for antibacterial

activity. Abdel A M et al s3 reported some new p-Iactams which possessed

sulphonyl chlorides. These compounds showed good antibacterial activity.

Some 3-substituted-2-azetidinones were reported by Giorgio C et al s4

and Firestone R A et alss which were inhibitors of human leukocyte elastase.

Some sulphonyl derivatives as reported by Yang S S et al s6 were found

useful as HMG-CoA synthesis inhibitors. Some of the compounds showed rcso

of 3.5xlO-8 M against HMG-CoA synthesis in vitro. Simple 3-alkyl-4-

azetidinones have been reported as potent inhibitors of Human Leukocyte

Elastase (HLE) by Hagmann W K et al. S7 They also reported that modified

form of these simple monocyclic j3-lactams led to the development of

substituted-4-azetidinones which inhibit HLE in a time dependent manner

64

and prevent HLE-induced lung damage in hamsters. A series of 3-acylidine-

4-methylazetidin-2-ones were evaluated for platelet aggregation inhibitory

activities. 58 Most of the compounds showed potent inhibitory activities

against rabbit platelet aggregation induced by ADP or collagen in vitro.

Dorn C P et al s9 prepared several substituted azetidinones and were

found as antiinflammatory and antidegenerative agents. Few compounds

inhibited human granulocyte elastase with IDso of 0.01 to 10 mg/ml. Patolia

V N et al60 prepared 2-(3'-chloro-3'-aryl-2'-azetidinon-l'-yl)-4-(2"-methyl-4"

hydroxy-5-isopropylphenyl)-thiazoles. The compounds were screened for

antibacterial and antifungal activities at a concentration of 50 J.lg/ml against

E.coli, 5. citrus, 5.aureus, P. fluorescence, A. niger and C. albicans

respectively. Most of the compounds were found to be moderately active

(15-25 mm zone of inhibition) against all organisms.

Trivedi P B et al 61 have synthesised several phenothiazine substituted

azetidinones and screened for antibacterial (100 fl9/ml) and antitubercular

activities (0.03 flg/ml) against E.coli, 5.aureus and H37Rv of Mycobacterium

tuberculosis respectively. Some of the compounds showed very good activity.

They have concluded from the results that incorporation of groups like

bromo, iodo, dimethyl and dimethoxy in phenyl moiety increased the

antibacterial activity. Deshmukh M B et al 62 synthesised new 2-azetidinones

and reported its antimicrobial activity. Kulkarni Y D et al 63 reported some

new 3'-[a-(3-chloro-2-oxo-4-substituted phenyl / furfuryl-l-azetidinyl)]-2H

l-benzopyran-2-ones. These compounds showed anorexiginic, neuroleptic

and anticonvulsant activities. Mukhtar Hussain Khan et al 64 synthesised some

2-azetidinones and had shown antifungal and antibacterial activities.

O'Leary Aisling C et al6s have reported 3-(2-alkoxY-l-

hydroxyethyl)azetidine-2-ones as potential intermediates for the synthesis of

novel carbapenems. S S Bari et al 66 have synthesised chiral 3-hydroxy

azetidin-2-ones and 3-acetoxy-4,4'-bis(alkylthio)-azetidin-2-ones. P S N

Reddy et al67 have synthesised l-aryl-4-[3-isopropyfidene- amino/methyl-4-

(3H)-oxoquinazofin-2-yl]azetidin-2-ones. Srivastava S K et al68 have

synthesised some new carbazolyl thiadiazol-2-oxo-azetidines as

65

antimicrobial, anticonvulsant and antiinflammatory agents. These compounds

were screened for their antimicrobial activity against Ecoli, S.aureus, S.

flurxeni and S. dysentriae at 25-50 ppm. Antifungal activity was screened

against C. albicans, A. niger and R. oryzae at 100 and 500 ppm

concentration. Anticonvulsant and antiinflammatory activities were carried

out against albino mice of either sex (weighing 30-35g) and albino rats

(weighing 80-110g).

Parekh H et al69 have reported 2-(4'-aryl-3'chl;ro-2'-azetidinon-1'-yl)-

4- [2 - (p-ch lorobenzenesu I fona m i do ) p hen ylth i azoles. These compounds

showed moderate to good activity against antimicrobes such as

B.megaterium, B.subtilis, Ecoli and A.aerogenes. These compounds were

screened for antifungal and antitubercular activities. Pawar R P et al 70 have

reported 1- [4-nitroaryIJ-3-chloro -4- [3-iodo-4-hydroxy- 5- methoxyarylJ-2-

azetidinones. These compounds showed antibacterial activity against E.coli,

Azotobacter, B.subtilis, S.typhi and S.dysentriae. S D Sharma et al 71 have

synthesised some fused rJ-lactams as new cepham analogues and these

analogues showed antimicrobial activity in vitro against S.aureus, B.subtilis,

E.coli, P.aeroginosa, S. flexneri and salmonela microorganisms.

S K Srivastava et al72 have reported synthesis of 2-chloro

phenothiazinothiadiazol-2-oxo-azetidines. All the synthesised compounds

have been screened for their antimicrobial activity against Ecoli, Klebsilla

pneumonia and S. dysentriae at 25 & 50 ppm. These compounds also

showed antifungal activity against A.niger, R. oryzae and C. panical at 100

and 500 ppm. Antiinflammatory activity was tested in albino rats.

Parikh A R et al 73 have synthesised some 4-aryl-l-(4'-a

methoxyi m i noca rbmeth oxy methylth iazol-2 -yl) -3 -ch loro-2 -a zetid inones. Th ese

compounds exhibited significance antitubercular, antibacterial and antifungal

activities. Parekh H et a1 7• have reported 4-aryl-3-chloro-l-N-(6'

phenylthieno[ 3 ,2-d] pyrimid-4-yl-amino)- 2 -azetidinones. These compounds

were tested for in vitro growth inhibitory activity against several microbes

like B.megaterium, B.subtilis, Ecoli.

., ~

66

Srivastava S D et al75 have synthesised 1-[5'(N 1o-phenothiazino

methyl)-l', 3',4' -th iadiazol-2' -yl] -4-substituted-2-azetidinones. These compo

unds showed antifungal activity against C.a/bicans, R.oryzae and C.pannia/.

Pratibha Sharma et al 76 have synthesised N-sulphonamoylphenylamino-3-

chloro-4-phenylazitidin-2-ones. All the synthesized compounds have been

screened in vitro for their antibacterial activity against E.co/i, P.diminuta and

B.subti/is. Benito Alcaide et al77 have reported an efficient synthesis of highly

functionalized 4-su bstituted -2 -azetid i nones by a stereoselective

intermolecular Diels-Alder reaction. Alessandro Bongini et al 78 have reported

stereochemical aspects of a two step Staudinger reaction by asymmetric

synthesis of chiral azetidin-2-ones.

Looking to the pharmaceutical applications of J3-lactam derivatives, in this

section we have synthesised some J3-lactams.


• Section-2(a), N-{ 4- [5-bromo-3- methoxy-4-( phenyl methoxy )phenyl] 3-

ch 10 ro-2 -oxo-azeti di ny I} a ry Ica rboxa mid es.

• Section-2( b ), 4- [5-bromo-3-methoxy-4-( phenyl methoxy )phenyl] -3-

chloro-l-{ [( aryla mine )th ioxomethyl ]amino }azetidin- 2-ones.

• Section-2 (cl, 4- [5-bromo-3-methoxy-4-( phenylmethoxy) phenyl] -3-

chloro-l-arylazetidin-2-ones and

• Section-2(dl, 2-( {4-[5-bromo-3-methoxy-4-(phenylmethoxy)phenyl]-3-

chi oro -2 -oxo-azetidi ny I} ami no-N -a ry I aceta m ides

~ Spectroscopic analysis and biological activities are described in Part: II.

SECTION - 2(a)

PREPARATION OF N-{ 4-[S-BROMO-3-METHOXY-4-(PHENYLMETHOXY)

PHENYL]-3-CHLORO-2-0XO-AZmDINYL}ARYLCARBOXAMIDES.

67

SR.

NO.

L-12

L-13

L-14

L-15

L-16

L-17

L-18

L-19

L-20

TABLE: 9

PHYSICAL CONSTANTS OF N-{ 4-[S-BROMO-3-METHOXY-4-

(PHENYLMETHOXY)PHENYLj-3-CHLORO-2-0XO

AZETIDINYL}ARYLCARBOXAMIDES.

Br

l o R

CI

R = Benzyl group


FOUMULA °C (%) CARBON

FOUND REQD.

-2-NO,-C6H. C,.H I9 BrCIN30 6 130 60 51.28 51.40

-3-NO,-C6H. C,.H I9 BrCIN30 6 110 69 51.36 51.40

-4-NO,-C6H. C,.H I9 BrCIN30 6 145 70 51.38 51.40

-4-CI-C6H• C,.H I9 BrCI,N,O. 275 56 52.35 52.39

-2-0H-C6H. C'4H,oBrCIN,Os 135 68 54.18 54.21

-4-CHr C6H. C'5H"BrCIN,O. 189 74 56.64 56.68

-CH,-C6HS C,sH"BrCIN,04 300 70 56.65 56.68

-CH(OH)-C6HS C25H"BrCIN,Os 215 66 54.98 55.01

-3-(OCH3)-C6H. C25H"BrCIN,Os 178 78 54.99 55.01

68

% OF

NITROGEN

FOUND REQD.

7.40 7.49

7.47 7.49

7.42 7.49

5.06 5.09

5.22 5.27 i 5.25 5.29

5.23 5.29

5.11 5.13

5.08 5.13

69

Experimental

• Preparation of N-{1-aza-2-[5-bromo-3-methoxy-4-(phenylmethoxy)

phenyl] vi ny I} (2 -n itrophenyl) ca rboxa m i de.

A mixture of compound A (0.01 mole) and N-amino(2-

nitrophenyl)carboxamide (0.01 mole) was dissolved in ethanol (95%, 25 ml).

The reaction mixture was refluxed for 6 hr. The mixture was poured into ice

cold water, filtered, dried and recrystallised from ethanol (99%). m.p. :

145°C; yield : 62%; Anal. Found : C, 54.45 ; H, 3.66 ; N, 8.59 ; Calc for

C22H'SBrN30S : C, 54.56 ; H, 3.75 ; N, 8.68%.



• Preparation of N-{ 4-[5-bromo-3-methoxy-4-(phenylmethoxy)phenyl-3-

ch loro-2 -oxoazetid i nyl} (2 -n itroph eny I) ca rboxa m id e.

N-{ 1-aza-2- [5-bromo- 3- methoxy-4-( phenylmethoxy )phenyl] vinyl}( 2-

nitrophenyl)carboxamide (0.01 mole) was dissolved in anhydrous 1:4 dioxan

with constant stirring at room temperature. Triethylamine (0.02 mole) was

added slowly followed by dropwise addition of 2-chloroacetyl chloride

(0.02 mole). The mixture was stirred for 30 minutes. The contents were

transferred to a RBF and heated under reflux for 5 hr. The reaction mixture

was allowed to cool at room temperature, filtered and removed the insoluble

salt. Excess of solvent was distilled off, semi solid residue was poured over

crushed ice with constant stirring. The separated product was filtered,

washed with cold water, dried and recrystallised from ethanol (99%). m.p. :

130°C; yield: 60%; Anal. Found: C, 51.28 ; H, 3.29; N, 7.40 ; Calc for

C,4H,9BrCIN306: C, 51.40 ; H, 3.42 ; N, 7.49%.



SECTION: 2(b)

PREPARATION OF 4-[5-BROMO-3-METHOXY-4-(PHENYLMETHOXYl

PH ENYLj-3-CHLORO-l-{ [(ARYLAMINO lTHIOXOM ETHYLj

AMINO}-AZETIDIN-2-0NES.

r

H

/0 R

H3CO

o

r

+

I "'0001 (95%)

I CICOCH2CI, Et3N

1:4 Dioxan

HN'Ar

H~S 71 I ~

N

0

CI


R = Benzyl group

SCHEME-6

70

SR.

NO.

L-36

L-37

L-38

L-39

L-40

L-41

L-42

L-43

L-44

L-45

L-46

L-47

L-48

L-49

L-50

L-51

TABLE: 10

PHYSICAL CONSTANTS OF 4-[5-BROMO-3-METHOXY-4-

(PHENYLMETHOXY)PHENYL -3-CHWRO-1-{ [(ARYLAMINO)

THIOXOM ETHYLjAMINO }AZETIDIN-2 -ONES.

P R

CI

R = Benzyl group



FOUND REQD.

-2-NO,-C6H. C,.H 2O BrCIN.OsS 82 60 48.59 48.70

-3-NO,-C6H. C,.H,o BrCIN.OsS 160 69 48.63 48.70

-4-NO,-C6H. C,.H,o BrCIN.OsS 125 62 48.67 48.70

-3-Cl-C6H4 C,.H20BrCI,N30 3S 114 58 49.52 49.59

-4-Cl-C6H. C,.H,o BrCI,N 30 3S 125 74 49.50 49.59

-2,5-(CH3),-C6H3 C'6H,S BrCIN 30 3S 200 80 54.24 54.32

-2,6-( CH3),-C6H3 C'6H,S BrCIN30 3S 200 66 54.27 54.32

-2-0CH3-C6H. C'SH'3 BrCIN3O.S 95 80 52.01 52.05

- 3-OCH3-C6H. C,sH23 BrCIN3O.S 137 71 51.98 52.05

-4-0CHrC6H. C,sH23 BrCIN3O.S 140 68 52.00 52.05

-2-CHrC6H. C,sH23 BrCIN30 3S 125 68 53.48 53.54

-3-CHrC6H. C,sH23 BrCIN3O,S 190 60 53.51 53.54

-4-CHrC6H4 C'5H23 BrCIN30 3S 155 64 53.50 53.54

-4-0C,Hs-C6H. C'6H,S BrCIN3O.S 120 67 52.80 52.85

-C6HS C,.H 21 BrCIN30 3S 159 65 52.66 52.71

-1-C lOH7 C'8H23 BrCIN30 3S 140 85 56.31 56.34

71

% OF

NITROGEN

FOUND REQD.

9.35 9.47

9.44 9.47

9.40 9.47

7.18 7.23

7.17 7.23

7.26 7.31

7.28 7.31

7.22 7.28

7.24 7.28

7.25 7.28

7.45 7.49

7.47 7.49

7.43 7.49

7.08 7.11

7.65 7.68

7.00 7.04

72

Experimental

• Preparation of {1-Aza-2-[5-bromo-3-methoxy-4-(phenylmethoxy)phenyl]

vinyl}amino)( 2-nitrophenyl )amino] methane-1-thione.

A mixture of compound A (0.01 mole) and hydrazino[(2-

nitrophenyl)amino]methane-l-thione (0.01 mole) was placed in a RBF and

ethanol (95%, 25 ml) was added to it. The reaction mixture was refluxed for

6 hr on a water bath. The excess of solvent was collected by distillation,

filtered, washed with ice-cold water, dried and recrystallised from ethanol

(99%). m.p. : 60°C; yield: 52%; Anal. Found: C, 51.19 ; H, 3.55 ; N, 10.76

; Calc for C22Hl9BrN404S : C, 51.27 ; H, 3.71 ; N, 10.87%.




chloro-1-( {[ (2-nitrophenyl)a mino ]thioxomethyl}amino )azetidine- 2-one.

{l-Aza-2 - [5-bromo- 3-methoxy-4-(phenyl methoxy)phenyl]vinyl}

amino)(2-nitrophenyl)amino]methane-1-thione (0.01 mole) was dissolved in

anhydrous 1:4 dioxan (20 ml) with constant stirring at room temperature.

Triethylamine (0.02 mole) was added slowly followed by drop wise addition

of 2-chloroacetyl chloride (0.02 mole). The mixture was stirred for 30

minutes. The contents were transferred to a RBF and heated under reflux for

5 hr. The mixture was allowed to cool at room temperature and filtered to

remove the insoluble salt. Excess of solvent was distilled off, semi solid

residue was poured over crushed ice with constant stirring. The separated

solid was filtered, washed with saturated solution of sodium bicarbonate,

dried and recrystallised from ethanol (99%). m.p. : 82°C; yield: 60%; Anal.

Found: C, 48.59; H, 3.34 ; N, 9.35 ; Calc for C24H2oBrCIN40sS : C, 48.70 ;

H, 3.41 ; N, 9.47%.



73

SECTION: 2(c)

PREPARATION OF 4-[S-BROMO-3-METHOXY-4-(PHENYLMETHOXY)

PHENYLj-3-CH LORO-l-ARYLAZETI DIN-2 -ON ES.

c·_-- --_.- , .. --------, : Bh.~vnJQ.:.;, I. !."i\"':I~itv I

L; to"~ .-j.- f· I

t:< H _ ..... \' r ~ .~\ (~ (\ I.~

7S

Experimental

• Preparation of 5-[2-Aza-2-(2-nitrophenyl)vinyl]-3-bromo-1-methoxy-2-

(phenyl methoxy)benzene.

A mixture of compound A (0.01 mole) and 2-nitrophenyl amine (0.01

mole) was added in boiling ethanol (95%, 25 ml). The reaction mixture was

reFluxed for 6 hr on a water bath. The solvent was collected by distillation to

get the crystalline product. The solid product was filtered, washed with cold

water, dried and recrystallised from ethanol (99%). m.p. : 70°C; yield :

40%; Anal. Found: C, 57.05 ; H, 3.74 ; N, 6.28 ; Calc for C21H17BrN204 :

C, 57.16 ; H, 3.88 ; N, 6.35%.




chloro-1-( 2 -nitrophenyl )azetidine- 2-one.

5- [2 -Aza- 2-( 2-nitrophenyl )vinyl]-3-bromo-1-methoxy-2 -( phenyl

methoxy)benzene (0.01 mole) was dissolved in 1:4 dioxan (25 ml) with

constant stirring at room temperature. Triethylamine (0.02 mole) was added

slowly followed by dropwise addition of 2-chloroacetyl chloride (0.02 mole).

The mixture was stirred 30 minutes. The contents were transferred to a RBF

and heated under reflux for 5 hr. The mixture was allowed to cool at room

temperature and filtered to remove the insoluble salt. Excess of solvent was

distilled off and semisolid residue was poured over aqueous saturated

solution of sodium bicarbonate to remove unreacted 2-chloroacetyl chloride.

The separated solid was filtered, washed with water, dried and recrystallised

from ethanol (99%). m.p. : 115°C; yield: 65%; Anal. Found: C, 53.28

H, 3.38 ; N, 5.33 ; Calc for C23H1SBrCIN20S : C, 53.36 ; H, 3.50 ; N, 5.41 %.



SECTION: 2(d)

PREPARATION OF 2-({4-[5-BROMO-3-METHOXY-4-PHENYL

METHOXY)PHENYL]-3-CHLORO-2-0XO-AZmDINYL}AMINO

N-ARYLACETAMIDES.

r

R /0

~

~ H3CO

H2~ 0(0 I + NH

° A,/'NH

H

I Ethanol (95%)

r

/0 ~ H("(O R

I ~ .-'iN A"..--NH H3CO

j '''0'" ,G. "" 1:4 Dioxan

r

N H~ ° Ar

CI


R = Benzyl group

SCHEME-8

76

SR.

NO.

L-88

L-89

L-90

L-91

L-92

L-93

L-94

L-95

L-96

L-97

L-98

L-99

L-100

L-101

L-102

TABLE: 12

PHYSICAL CONSTANTS OF 2-( {4-[5-BROMO-3-METHOXY-4-

(PHENYLMETHOXY)PHENYLj-3-CHLORO-2-0XO-AZETIDINYL}

AMINO-N-ARYLACETAMIDES.

Br.

o

CI

R = Benzyl group

-Ar MOLECULAR M.P YIELD %OF


FOUND REQD.

-2-NO,-C6H4 C,sH"BrCIN40 6 135 63 50.80 50.91

-3-NO,-C6H4 C,sH"BrCIN.06 180 68 50.76 50.91

-4-NO,-C6H. C,sH"BrCIN.06 158 60 50.85 50.91

-2-Cl-C6H4 C,sH"BrCI,N,O. 165 55 51.73 51.84

-4-Cl-C6H4 C,sH"BrCI,N,O. 160 58 51.70 51.84

-2,5-(CI),-C6H, C,sH21 BrCI,N,04 100 62 48.83 48.93

-2,4-(CH 3),-C6H, C"H"BrCIN,O. 138 66 56.55 56.61

-2,5-(CH,),-C6H, C"H"BrCIN,O. 135 65 56.48 56.61

-4-0CH,-C6H4 C'6H,sBrCIN,Os 195 70 54.15 54.32

-2-CH,-C6H4 C'6H,sBrCIN,O. 170 65 55.75 55.88

-4-CH,-C6H. C'6H,sBrCIN,O. 180 72 55.73 55.88

-2-0C,Hs-C6H. C"H"BrCIN,os 185 58 54.90 55.07

-4-0C,H s-C6H. C"H'7BrCIN,Os 255 55 54.96 55.07

-C6HS C,sH23BrCIN30 4 197 56 55.04 55.11

-1-ClOH7 C'9H,sBrCIN,04 250 70 58.42 58.55

77

% OF

NITROGEN

FOUND REQD.

9.38 9.50

9.41 9.50

9.35 9.50

7.17 7.25 !

7.13 7.25

6.76 6.85

7.30 7.34

7.22 7.34

7.18 7.31

7.40 7.52

7.44 7.52

7.02 7.14

7.04 7.14

7.62 7.71

6.96 7.10

78

Experimental

• Preparation of 2-( {1-Aza-2-[5-bromo-3-methoxy-4-(phenylmethoxy)

phenyl]vinyl }amino )-N-( 2 -nitrophenyl )aceta mide.

Compound A (0.01 mole), 2-hydrazino-N-(2-nitrophenyl)acetamide

(0.01 mole) and ethanol (95%, 25 ml) were refluxed for 6 hr on a water

bath. The reaction mixture was poured into ice-cold water. The product was


(99%). m.p. : 160°C; yield: 50%; Anal. Found: C, 53.72 ; H, 4.01 ;

N, 10.85 ; Calc for CZ3HzlBrN40S: C, 53.81; H, 4.12; N, 10.91%.



• Preparation of 2-( {4-[5-Bromo-3-methoxy-4-(phenylmethoxy)phenyl]-3-

ch loro -2 -oxoazetid i n yl}a m i no -N - (2 -n itro phen yl) aceta mid e.

2 -( {l-Aza -2- [5-bromo- 3-methoxy-4-( phenylmethoxy) phenyl]vinyl}

amino)-N-(2-nitrophenyl)acetamide (0.01 mole) was dissolved in anhydrous

1:4 dioxan with stirring. Triethylamine (0.02 mole) was added slowly

followed by dropwise addition of 2-chloroacetyl chloride (0.02 mole). The

reaction mixture was stirred for 30 minutes. The contents were transferred

to a RBF and heated under reflux for 5 hr on a water bath. The mixture was

allowed to cool at room temperature, filtered and removed the insoluble salt.

Excess of solvent was distilled off and semisolid residue was poured over

aqueous saturated solution of sodium bicarbonate to remove unreacted 2-

chloroacetyl chloride. The solid product was filtered, washed with water,

dried and recrystallised from ethanol (99%). m.p. : 135°C; yield : 63%;

Anal. Found : C, 50.80 ; H, 3.38 ; N, 9.38 ; Calc for C,sHn BrCIN40 6 :

C, 50.91 ; H, 3.50 ; N, 9.50%.



79

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J Am Chern Soc, 4673 (1986).

40) Fobin R D & Bonini G; Tetrahedron Lett, 815 (1988).

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44) Shah V H, Baxi A J & Chauhan N A; J Inst Chem (India), 62, 167

(1990).

81

45) Ube Ind Ltd., Jpn Kokai, Tokkyo Koho 81, 40,662 (1979); Chem Abstr,

95,132655 (1981).

46) Abdulla R F; US Pat, 4, 075, 000 (1975); Chem Abstr, 89, 1692

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47) Soni V C & Parikh A R; Ind J Heterocyci Chem, 1,133, (1991); Chem

Abstr, 116, 151377 (1992).

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50) Han W T, US Pat, 5,037,819 (1991); Chem Abstr, 115, 232060 (1991).

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Chem Soc, 73, 584 (1996).

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58, 11311 (1963).

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56) Yang S S, Chaing Y C P, Heck J V & Chang M N; US Pat 4,983, 597 ;

Chem Abstr, 116 (1992).

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Lett, 1,545 (1991); Chem Abstr, 116, 76108 (1992).

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82

SECTION: III

STUDIES ON THIOSEMICARBAZIDES, 1,3,4-

THIADIAZOLES, 1,3, 4-0XADIAZOLES AND

5-0XO-IMIDAZOLINES.

Introduction:

83

Thiosemicarbazides and its derivatives are extensively used in

medicine especially in the treatment of tuberculosis. The tuberculostatic

activity of thiosemicarbazones and related compounds had been first

observed by Domagk G et al,I The study of the structural activity relationship

(SAR) suggests that 4-acetylamino-benzaldehyde thiosemicarbazone has

shown promising activity. This agent received extensive clinical trials and the

results sufficiently encouraged further investigation of its anti mycobacterial

activity. The parent compound thiosemicarbazide is tuberculostatic in vitro,

its derivative benzaldehyde thiosemicarbazone is more active. Various

substituents in the benzene ring alter in vitro activity.

Thiosemicarbazones are markably tuberculostatic but not bactericidal

in vitro. Thiosemicarbazides have been found most inhibitory and they are

potential therapeutic agents for the disease due to Mycobacterium

tuberculosis and Mycoleprae. Many of these compounds inhibit the growth of

pathogenic tubercular bacilli in concentration of approximately 1 l1g/ml

producing morphological alteration In the organisms. Like other

tuberculostatic agents, thiosemicarbazone arrest but do not eradicate

tubercular infection in experimental animals. Clinical study revealed some

degree of effectiveness in pulmonary tuberculosis in man. In general, tibione

(4-acetamidobenzaldehyde thiosemicarbazone) is less active than

streptomycin.

84

Thiosemicarbazones are well absorbed from the gastrointestinal tract,

and large proportion is excreted in urine. Thiosemicarbazones derived from

aromatic aldehydes are potential therapeutic agents for the disease due to

Mycobacterium tuberculosis and Mycoleprae. 2 Mayers F P and Porter J R3

tested many sulphur containing organic and inorganic compounds for their

ability to serve as a nutrient for proteus moryanii. In comparison to others,

thiosemicarbazides have been found most inhibitory.

Thiosemicarbazides are useful as insecticides e.g. many

thiosemicarbazides like I-phenyl, 1,4-diphenyl, I-phenyl-4-o-tolyl, 4-a

naphthyl, I-phenyl thiosemicarbazides have been found equal or better than

Na-fluorosilicate against screw worm larvae. 4 Donovick Ret als tested many

thiosemicarbazones and related compounds for their antitubercular activity in

mouse in which he showed that only p-substituted benzaldehyde

thiosemicarbazones have reproducible activity.

The development of acitivity is not dependent upon the sulfonamide or

sulphur nor upon the thiazole or thiadiazole but an open chain like

arrangement of Nand S atoms in thiosemicarbazones when suitably

substituted. Sulphur atom plays an important role because structurally

similar compound with absence of sulfur, like semicarbazone oxime,

hydrazone, azine and anil are inactive. 6

Thiosemicarbazides and their derivatives possess antitypanosomal,

antibacterial, anticoccodial, fungicidal, herbicidal activities. 7"

o They are used

in inhibiting the growth influenza viruses, antimicrobial and antitumor

activities are also shown by thiosemicarbazones."-12 1,3,4-Thiadiazoles and

1,3,4-oxadiazoles exhibit interesting pharmacological properties like

hypoglycemic, diuretic, antiinflammatory, antiviral, antifungal 13-14

,

herbicidal IS , antiacetylcholine stearase, 16 antitubercular, 17 pesticidal,'8-'9

tranquilizer and sedative2o-22 activities.

85

Jl /NyNf-l R NH Ar

S

Thiosemicarbazides 1,3,4-Thiadiazoies 1,3,4-oxadiazoies

(I) (II) (III)

Where Ar = different aryl groups.

Thiosemicarbazides and its derivatives are frequently used in the

treatment of tuberculosis. These compounds were prepared by the method

given by Kazakov V Ya and Vastovoskii I Ya. 23 In this method, amine is

treated with carbon disulfide, CICH2COONa and N2H4 2H 20. The

thiosemicarbazides are either obtained during reaction or crystallization on

cooling of thiocyanates and N2H4 which also imparts corresponding thiosemi

carbazides. 24

Vidya Joshi et al 25 have synthesised several N-2-diphenylhydrazine

carboxamide/carbothioamides from substituted phenylisocyanates/

phenylisothiocyanates respectively. These compounds showed antitubercular

and antifungal activities against Mycobacterium tuberculosis H37Rv and

Candida albicans, T.mentagrophytes and T.rubrum respectively.

Yemni E et al 26 have synthesised 1-(3-hydroxy-2-naphthoyl)-4-

substituted thiosemicarbazides as antibacterial agents. Ozturk R et al27 have

reported synthesis and antibacterial activity of some new 1-[ 4-( 4-

fluorobenzoyla mino )benzoyl]-4-substituted thiosemicarbazides.

Cherkashin I M, Borisova Ya E and Jichou Chen et al 28 have reported a

novel preparation of l-phenoxyacetyi-4-( S-aryl-2-furoyl )thiosemicarbazides

by using phase transfer catalysis.

86

1,3,4-Thiadiazole

In 1882, Fischer described 1,3,4-thiadiazole for the first time but the

true nature of the ring system was explained in 1890 by Freund and Kuhn.

Interest was renewed due to the discovery of sulfa drugs in thiadiazole

series. The pharmaceutical line of interest has continued, and interesting

drugs have been introduced. The structure of 1,3,4 - thiadiazole is as under:

N-N

Z) 5

(IV)

1,3,4-Thiadiazole and substituted thiadiazoles have been reported to

possess insecticidal, herbicidal, pesticidal, anthelmintic, antibacterial and

antifungal activities. 29•3

!

Methods for the Preparation of 1,3,4-Thiadiazoles:

1. Preparation of 1,3,4-thiadiazoles proceeds from thiosemicarbazide or

substituted thiosemicarbazides. Thiosemicarbazide itself was shown to cyclise

directly to 2-amino-S-methyl-1,3,4-thiadiazole with acid chloride.32

2. Hoggarth E33 has prepared a number of 2-amino-S-aryl-1,3,4-

thiadiazoles by using phosphoric acid as a dehydrating agent wherein

sulphuriC acid is found effective in these reactions.

N-N. a , II \\ )-Ph Ph~S~NH

(V)

Yadav L D 5 et al34 have observed that 1,3,4-thiadiazoles are

associated with a broad spectrum of biocidal activity35-39, possibly due to

>NCS moiety. These observations coupled with the fact that planarity of a

molecule might augment its fungicidal activity as it often does with the

herbicidal activity. 40-41

87

Khan M Hand Giri 542 have synthesised 8-[(S'-aryl-1',3',4'-thiadiazol-

2'yl)amino-methyl-7-hydroxy/acetoxy-4-methyl coumarins by Mannich

reaction and screened for their antifungal activity against A. niger and

R. oryzae at three concentrations (1000, 100 and 10 ppm) by agar growth

technique.

o

N-N

R

/ ~ 0 5 NH

R'O

(VI)

Where R = H, 2-Cl, 4-0CH 3, 2,4-Cl 2 and R' = CH 3CO-

Dubey A K and 5angwan N K43 have synthesised following bioactive

molecules and all the synthesised compounds were tested for antifungal

activity against Fusarium oxysporum, Rhizoctonia solani and Colletotrichum

capsicum.

;?"

°1 ~

R

f~ ~

..-::: N

(VII)

Where R= Different functional groups.

S"avna9ar University LIb, J'y,

BHA\"NAGAR.

88

Xu Pengfei Y X et al44 have synthesised S-(6'-nitrobenzimidazole-l-yl

methyl)-2-phenyl amino-l,3,4-thiadiazole and screened for pesticidal and

bactericidal activities:S-46

Srivastava S D et al 47 have synthesised 2-amino-S-(N 10-

phenothiazinomethyl)-1,3,4-thiadiazole and compounds were screened for

antifungal activity against C.a/bicans, R.oryzae and C.pannica/ by disc

method at 100 and 500 ppm.

Nizamuddin et al48 have synthesised several 3-substituted-l,2,4-

triazolo[3,4-b]indolo[3,2-e]-1,3,4-thiadiazoles as fungisides. The compounds

were screened for their fungicidal activity against P.oryzae, R.so/ani,

P.cubensis at a concentration of 1000, 100 and 10 ppm.

A one-pot synthesis of S-substituted -2 -merca pto-l, 3 ,4-th iadiazoles

have carried out by using microwaves. This was done by M.Kidwai et al:9

Gupta R et also have reported 3-alkyl/aryl-6-(2-chloro-2-substituted

phenyl/ethenyl)-S,6-dihydro-s-triazolo [3,4-b ]-1,3,4-thiadiazoles. All these

compounds were screened for their in vitro antibacterial and antifungal

activities against several microbes such as E.co/i, S.aureus, A.niger and

C.a/bicans respectively.

I l N-N N" ~ AXN

02 ~ N~y\d-5

(VIIl)

l,3,4-0xadiazole

Oxadiazole ring contains two carbon, two nitrogen and one oxygen

atom as hetero atoms, so four different isomeric oxadiazoles are possible.

The nomenclature listed with each formula has been used to describe

derivatives of unknown unsubstituted heterocycles.

PJ N" o

l,2,3-Qxadiazole 1,2,4-Qxadiazole 1,2,S-oxadiazole

89

N-N

Z) o

l,3,4-Qxadiazole

Therapeutically Itnportant Oxadiazole Derivatives:

No. Trade Name IUPAC Name Therapeutic uses

1. Fenadiazole 2-(2-hydroxyphenyl )-1,3 ,4-oxadiazole Hypnotic

2. Butalamine 5-[(2-(dibutylamino )ethyl)] amino-3- Peripheral

phenyl-1,2,4-oxadiazole vasodilator

3. Imolamine 3 -phenyl-4-d iethyla mi n oethy 1-5 -a m ino- Antiangial

1,2,4-oxadiazole

4, Libexin 3-( i3,i3-di phenylethyl) -5 -( 13- pi peri- Antitussive

dinoethyl)-1,2,4-oxadiazolehydrochloride

5. Oxolamine 3-phenyl-5-(i3-diethylaminoethyl)-1,2,4- In inflammatory

oxadiazole condi-tions of

respiratory tract

6. Morsydomine N-( ethoxycarbonyl)-3-( 4-morpholinyl) . Coronary vasodilator

sydnoneimine Antihypertensive

7. Mexolamine 5-[2-( diethyla mine )ethyl]- 3-( p-methoxy- Analgesic and

phenyl )-1,2,4-oxadiazole Antiinflammatory

8. Proxazole 5- [2-( diethylamino )ethyl]-3-( u- Smooth muscle

ethyl benzyl )-1,2 ,4-oxadiazole relaxant and

Analgesic and

Antiinflammatory

1,3,4-0xadiazoless1.sa are known to exhibit a wide spectrum of

physiological properties like antitubercular, bactericidal, anticonvulsant,

diuretic, antiamoebic etc.

Natural products with oxadiazole rings are unknown, while many

substances with oxadiazole ring structure are used as therapeutically

important compounds. Though oxadiazoles are used as medicines, their

90

reactions and properties remain unsolved and more efforts are still required

to fill the lack of development of a commercial use.

In recent years, several workers have taken a large number of patents

on 1,3,4-oxadiazoles. This inspired several workers to a great significance in

chemistry of 1,3 ,4-oxadiazoles. A number of 1,3,4-oxadiazolin-S-ones and

1,3,4-oxadiazolin-S-thiones showed antitubercular activity59.65 and

investigated with regard to their mode of action. Some oxadiazoles have

been active against Mycobacterium tuberculosis and Mycobacterium leprae. 66

It possesses some advantage over isonicotinic acid hydrazide. Antitubercular

activity of 2-(2-pyridyl)-1,3,4-oxadiazole-S-one has been described. 67

Oxadiazole derivatives which are derived from p-amino salicylic acid

have been extensively used as antitubercular agents. 6S-69 Vaidya V P and

Vagdevi H M70 reported 2-(2'-aryl-3'-acetyl-1',3',4'-oxadiazolyl)amino

naphtho[2,1-b]furans. Synthesised compounds were screened for

antimicrobial, anthelmintic and analgesic activities. Oxadiazolin-S-ones and

oxadiazolin-S-thiones of p-amino salicylic acid are active as

antiinflammatory, antipyretic and analgesic agents with low irritant

properties and toxicity.7I-73 The SUlphonamide derivatives of 1,3,4-

oxadiazoles are established not only as bactericidal but also as hypoglycemic

agents.74-75 Hokfelt B et al 76 synthesised some substituted l,3,4-oxadiazole

derivatives and tested for hypoglycemic activity. It was observed that

benzene ring containing halogen, -CH3 or -OCH3 generally showed significant

hypoglycemic activity and found that the oxadiazole derivatives produced

greater reduction of blood sugar concentration in rabbits than thiadiazoles.

Wildersmith En prepared some antiinflammatory, antipyretic and

analgesic agents by converting the carboxyl group of other therapeutic

agents into an oxadiazolyl group. O'Neal J B et a178-79 have prepared

oxadiazole and thiadiazole derivatives and evaluated for oral hypoglycemic

activity in rats and dogs. Bahel S C et aI SO-S! have prepared 1,3,4-oxadiazole

derivatives. They pOinted out that due to a structural analogy between

oxadiazol-2-ones, oxadiazole-2-thiones and S-substituted 1,3,4-oxadiazole-

91

2-thiones might be biologically active. They further clarified that such

compounds have >NCS and C-O-C chains which are perhaps responsible for

their fungicidal activity. They synthesised a number of compounds and

evaluated against A. flavus and A. niger. They finally came to a conclusion

that substituted oxadiazole-2-thione derivatives possessed more activity than

the parent oxadiazole. Bajaj 0 P et alB2 investigated antibacterial properties

of some 5-substituted-l,3,4-oxadiazole-2-thione derivatives against different

microorganisms like E.coli, S.aureus, S.typhos and B. megaterium.

Shahsafi M A et alB3 have synthesised some bis (1,3,4-oxadiazoles)

and antimicrobial activity of synthesised compounds was reported. Eid A I et

alB4 have prepared some 2,5-disubstituted -1,3,4-oxadiazoles and found

them as CNS active agents. Mishra H KBS has also reported some substituted

1,3,4-oxadiazoles as antibacterial, insecticidal and antiacetylcholine esterase

agents. Muscle relaxant and antitubercular activity of some disubstituted

1,3,4-oxadiazoles were reported by Swain A p.B6 Khandwala A et alB7 have

reported some 5-substituted 1,3,4-oxadiazoles for their antiallergic activity.

Antitubercular activityBB-I03 of some 1,3,4-oxadiazole compounds was

also reported. Ram V J et al l04 prepared some oxadiazol thiones and tested

for anticonvulsant activity. Bhargawa K P et alIos have reported some N

substituted-1,3,4-oxadiazoles as potential anticonvulsant agents and

pointed out that mono-, di- and tri-methyl substitution in the phenyl ring

deer-eased the anticonvulsant activity. Several 2,5-disubstituted 1,3,4-

oxadiazoles have been synthesised and screened for their antiinflammatory,

sedative and analgesic activities on rats and mice with satisfactory

results.'06-1'0

Dubey A K and Sangwan N K43 have reported the synthesis of 5-(3,5-

diphenyl pyrazol-4-yloxymethyl) -2 -( 4- methoxyphenyl)methylenea m i no-l, 3 ,4-

oxadiazole and evaluated for their in vitro growth-inhibitory activity against

F. oxysporum, Rhizoctonia solani and Colletotrichum capsicum.

92

N-NH

;::/ /

;::/

~ 0

1 ~

R ~7 0 ~

N=\ ~ N

(IX)

Where R = -OCH3

Gadaginamath G 5 et al 'll have synthesised cis-3,6-bis-[4-(5-

mercapto-l,3 ,4-oxadiazol-2-yl methoxy)benzyl] piperazine-2,5-dione. The

newly synthesised compound showed interesting pharmacological properties

and screened for their antibacterial activity against E.coli and

B.cirroflagellosus using norfloxacin as standard and for antifungal activity

against C .albicans and A. niger using Griseofulvin as standard.

o

(X)

Saad H"2 has prepared 2-(pyridyl-3-oxymethyl)-4-acetyl-5-

substituted-",2 -1,3,4-oxadiazolines and tested for in vitro biological activity

against a variety of bacteria such as S. aureus, S. lentus, E.coli. and

C. albicans .

(XI)

Where R = -CH3

93

Parikh A R et al 113 et al have reported newly synthesised oxadiazoles

having nicotinamide moiety to get better therapeutically active compounds.

All the synthesised compounds were screened for in vitro antimicrobial

activity against several bacterial strains such as E.co/i, 5. typhosa, 5. citrus,

B. megaterium and fungi such as A. niger.

~ N

N-N / >--- /R o NH

NH ~

(XII)

Where R = different aryl groups.

1,3,4-0xadiazoles have been extensively investigated by Kidwai M et

aI 114.115 due to their close association with various types of biological activities

such as antiviral and antifungal.

(XIII)

Bhavnagar 'Jni'lersity Litx;.ry,

BHAVNAGAR. '--------_--1

94

Desai N C et al '16 have synthesised some Z,5-substituted-l,3,4-

oxadiazoles as potential antimicrobial, anticancer and anti-HIV agents.

Parekh H et al 'l7 have reported Z-aryl-sulphonamido-5-[Z'-

(benzimidazol-Z" -yl) phenylj-l ,3 ,4-oxadiazoles and benzoyla m ino-5- [Z'-

(benzimidazole-Z"-yl)phenylj-l,3,4-oxadiazoles. These compounds showed

in vitro antimicrobial activity against B.megaterium, B.subtilis, P.fluorescence

and E.coli, while antifungal activity showed against A.niger at a concentration

of 50fl9. Mukherjee A et al 1l8 have reported in vitro serotonin-3-antagonist

activities of some newer 1,3,4-oxadiazole-Z-thiones. Lu Shui-Ming1l9 has

sythesised l-acyl-4-phosphoryl thiosemicarbizes and their derivatives of

1,3,4-oxadiazoles.

The biological importance of thiosemicarbazides, 1,3,4-thiadiazoles

and 1,3,4-oxadiazoles prompted us for further synthesis of the following

bioactive compounds.

• Section-3(a),

acetamides.

• Section-3(b),

amines.

• Section-3(c),

amines.

N -{ [( aryla mino )th ioxomethylja m ino} -Z -( 4-nitrophenyl)

Aryl {5- [( 4-nitrophenyl) methylj (1,3 ,4-thiadiazol-Z -yl)}

Aryl {5- [( 4-nitrophenyl) methylj (1,3 ,4-oxadiazol-Z -yl)}

~ Spectroscopic analysis and biological activities are described in Part: II.

SECTION: 3(a)

PREPARATION OF N-{[(ARYLAMINO)THIOXOMETHYLjAMINO}

-2-( 4-NITROPHENYL)ACETAMIDES.

o +

j "'''"0' (%%)

o

j Ethanol (95%)

Ar-NCS

o


SCHEME-9

95

SR.

NO.

L-103

L-104

L-105

L-106

L-107

L-108

L-109

L-110

L-111

L-112

L-113

L-114

L-115

L-116

TABLE: 13

PHYSICAL CONSTANTS OF N-{[(ARYLAMINO)THIOXOMETHYLj

AMINO}-2 -( 4-NITROPH ENYL)ACETAMIDES.

NH ~ /Ar 'NH NH

o



FOUND REQD.

-C6HS C15H'4N403S 145 55 54.46 54.54

-2-0CH,-C6H4 C'6H'6N40 4S 110 75 53.20 53.32

-3-0CH,-C6H4 C'6H'6N40 4S 190 68 53.21 53.32

-4-0CH,-C6H4 C16H'6N404S 210 80 53.22 53.32

-CH,-C6Hs C'6H16N403S 160 63 55.71 55.80

-2,4-(CH3),-C6H3 C17H'8N40 3S 175 60 56.90 56.97

-2,5-( CH3),-C6H3 C17H ,aN40 3S 200 72 56.88 56.97

-2,6-( CH3),-C6H3 C17H'8N,03S 145 68 56.85 56.97

-3-CH,-C6H4 C16H'6N403S 165 76 55.71 55.80

-4-CH,-C6H, C16H'6N40 3S 180 75 55.69 55.80

-4-F-C6H4 C15H 13N40 3S 190 60 51.64 51.72

-2-CI-C6H4 C,sH 13CIN40 3S 135 58 49.30 49.39

-3-CI-C6H4 C15H13CIN40 3S 185 62 49.28 49.39

-3-( CF3)-C6H, C'6H13F3N403S 225 55 48.17 48.24

96

% OF

NITROGEN

FOUND REQD.

16.87 16.96

15.49 15.55

15.43 15.55

15.46 15.55

16.18 16.27

15.51 15.63

15.55 15.63

15.55 15.63

16.19 16.27

16.16 16.27

16.02 16.10

15.26 15.36

15.24 15.36

13.98 14.10

97

Experimental

• Preparation of N-amino-2-( 4-nitrophenyl)acetamide.

A mixture of ethyl 2-(4-nitrophenyl)acetate (0.1 mole) and excess of

hydrazine hydrate (80%, 0.1 mole) in absolute ethanol (99%, 40 ml) was

refluxed for 6 hr. The solution was then poured into ice-cold water. The solid

product was filtered, washed with water, dried and recrystallised from

ethanol (99%). m.p. : 165°C; yield: 40%.

• Preparation of 2-( 4-Nitrophenyl)-N-{[(phenylamino )thioxomethyljamino}

acetamide.

An ethanolic solution of N-amino-2-(4-nitrophenyl)acetamide (0.01

mole) and phenyl isothiocyanate (0.01 mole) was refluxed For 4 hr on a

water bath. The resulting solution was cooled and solid was crystallised From

ethanol (99%). m.p. : 145°C; yield: 55%; Anal. Found: C, 54.46 ; H, 4.20 ;

N, 16.87 ; Calc for C,sH'4N403S : C, 54.54 ; H, 4.27 ; N, 16.96%.



SECTION :3(b)

PREPARATION OF ARYL{S-[( 4-NITROPHENYL)METHYLj

(1,3,4-THIADIAZOL -2 -YI) }AMIN ES.

a

N-N

/ ~ /Ar S NH


SCHEME-iO

98

SR.

NO.

L-117

L-118

L-119

L-120

L-121

L-122

L-123

L-124

L-125

L-126

L-127

TABLE: 14

PHYSICAL CONSTANTS OF ARYL{S-[( 4-NITROPHENYL)METHYLj

(1,3,4-THIADIAZOL -2 -YL) }AMIN ES.

N-N

I ~ /Ar S NH

-Ar MOLECULAR M.P YIELD % OF


FOUND REQD.

-C6HS Cls H12 N4O,S 260 40 57.58 57.68

-2-0CH,-C6H4 Cl6 H 14N40 3S 150 45 56.05 56.13

-CH,-C6Hs Cl6 H 14N4O,S 150 56 56.76 56.88

-2,4-(CH3h-C6H3 C17 HI6 N4O,S 155 50 59.90 59.98

-2,5- (CH3),-C6H3 Cl7 H 16 N40 ,S 220 45 59.85 59.98

-3-CH,-C6H4 Cl6Hl4N40,S 229 55 58.72 58.88

-4-CH,-C6H4 Cl6 H 14N40,S 155 48 58.74 58.88

-4-F-C6H4 Cls Hll FN4O,S 290 40 54.46 54.54

-2-CI-C6H4 CI5H 11 CIN 4O,S 135 42 51.89 51.95

99

% OF

NITROGEN

FOUND REQD.

17.88 17.94

16.25 16.36

17.05 17.17

16.38 16.46

16.32 16.46

17.07 17.17

17.02 17.17

16.89 16.96

16.08 16.16 -

-3-Cl-C6H4 Cls HllCIN 4O,S 190 38 51.84 51.95 16.10 16.16

-3-( CF3)-C6H4 Cl6HllF3N40,S 180 45 50.44 50.53 14.65 14.73

100

Experimental

• Preparation of {5-[( 4-Nitrophenyl)methyl]( 1,3,4-thiadiazol-2-yl)}phenyl

amine.

2 - (4- Nitrophenyl) -N -{ [( phenylam ino )thioxomethylj amino }aceta mide

(0.01 mole) was dissolved with cooling in con. sulphuric acid. The contents

were kept at room temperature for 3 hr. The mixture was stirred occasionally

and then poured over crushed ice. The resulting solid was filtered, washed

with ice-cold water till its pH turned neutral, dried and recrystallised from

ethanol (99%). m.p. : 260°C; yield: 40%; Anal. Found: C, 57.58 ; H, 3.82 ;

N, 17.88 ; Calc for C,sH'2N402S: C, 57.68; H, 3.87 ; N, 17.94%.



101

SECTION: 3(c)

PREPARATION OF ARYL{5-[( 4-NITROPHENYL)METHYLj

(1,3,4-0XADIAZOL-2-YL) }AMINES.

'Ar SyNH

02N -:/ HN"

NH

~ 0

j 12 / KI

NaOH (10%)

02 N N-N

/ ~ /Ar o NH


SCHEME-ll

{/S \./.1.. (

Bhavnagar University Library,

BHAVNAGAR.

SR.

NO.

L-128

L-129

L-130

L-131

L-132

L-133

L-134

L-135

L-136

L-137

L-138

L-139

L-140

TABLE: 15

PHYSICAL CONSTANTS OF ARYL{5-[( 4-NITROPHENYL)METHYLj

(1,3 ,4-0XADIAZOL -2-YL) }AMIN ES.

N-N

/ ~ /Ar o NH



FOUND REQD.

-C6HS C,sH12N403 168 52 60.71 60.81

-2-0CH,-C6H4 C16H'4N404 220 45 58.80 58.89

-3-0CH,-C6H4 C16H'4N404 175 54 58.76 58.89

-4-0CH,-C6H4 C16H'4N404 189 58 58.81 58.89

-CH,-C6Hs C16H'4N403 158 63 61.84 61.93

-2,4-( CH3),-C6H3 C17H'6N403 190 61 62.85 62.96

- 2, 5-( CH3),-C6H3 C17H'6N403 200 55 62.81 62.96

- 2,6-( CH3),-C6H3 C,7H 16N40 3 180 52 62.87 62.96

-3-CH,-C6H4 C16H'4N403 210 45 61.86 61.93

-4-CH,-C6H4 C16H'4N403 300 34 61.82 61.93

-2-Cl-C6H4 C,sH 11 CIN40 3 130 50 54.37 54.48

-3-Cl-C6H4 C,sH11CIN403 255 42 54.33 54.48

-3-(CF3)-C6H4 C'6H11F3N403 240 40 52.64 52.76

102

% OF

NITROGEN

FOUND REQD.

18.82 18.91

17.02 17.17

17.06 17.17

17.03 17.17

17.96 18.05

17.19 17.27

17.16 17.27

17.22 17.27

17.91 18.05

17.94 18.05

16.83 16:94

16.81 16.94

15.30 15.38

Experimental

• Preparation of {5-[( 4-Nitrophenyl)methyIJ (1,3,4-oxadiazol-2-yl)}

phenylamine .

103

To an ethanolic solution of 2-(4-nitrophenyl)-N-{[(phenylamino)

thioxomethylJamino}acetamide (0.01 mole) was added aq. ice-cold solution

of sodium hydroxide (10%, 10 ml). To this mixture, iodine solution in

potassium iodide (aq. 10%) was added gradually with stirring till the colour

of iodine persisted at room temperature. The contents were refluxed on a

water bath and more iodine solution was added (if necessary) till the colour

of iodine persisted. Heating was continued for 5 hr and the reaction mixture

was concentrated. The mixture was cooled and poured into ice-cold water.

The solution was filtered and the filtrate was acidified with dilute hydrochloric

acid (10%) to isolate the product. The solid obtained was filtered, washed

with cold water, dried and recrystallised from ethanol (99%). m.p. : 1680C;

yield : 52%; Anal. Found : C, 60.71 ; H, 4.07 ; N, 18.82 ; Calc for

ClsH12N403: C, 60.81 ; H, 4.12; N, 18.91%.



104

STUDIES ON 5-0XO-IMIDAZOLES.

Introduction:

During the past two decades, the incidence of fungal infections,

especially involving immunocompromised patients, has increased

dramatically.120 In particular, some forms of dermatomycoses are the cause

of a great morbidity in patients receiving antineoplastic chemotherapy, under

going organ transplants, or suffering from AIDS. These infections are

produced by dermatophytes, a group of fungi that characteristically infect the

keratinized areas of the body. Although imidazole compounds such as

clotrimazole, miconazole, Ketoconazole (1 st oral drug, 1979), Lanoconazole

(Racemic, 1994), Flutrimazole (Racemic, 1995) and econazole have proven

to be effective for the treatment of dermatophytes, these infections are

frequently very difficult to eradicate,121 and more effective new topical

antifungal agents are still needed.

Imidazole derivatives are widely used in topical antifungal

chemotherapy because of their broad spectrum and high availability.122 It has

been recognized that imidazole antifungals act with at least two distinct

mechanisms. One is the inhibition of ergosterol biosynthesis at low

concentration below 10'6 M, which is responsible for fungistatic action. The

other is direct physicochemical cell membrane damage exerted at higher

concentration between 5-10 fl9/ml, which causes the fungicidal effect. 123

Since a high concentration is necessary for the latter effect, conventional

imidazole antifungals do not act as fungicidal but fungistatic agents under

therapeutic conditions.

105

Chemistry:

Imidazoles are a planar five-member heterocyclic ring system with

three carbons and two nitrogen atoms in 1 and 3 positions. In imidazolones,

like imidazoles (I), one of the annular nitrogen bears a hydrogen atom and

can be regarded as a pyrrole type 'N', the other resembles the nitrogen in

pyridine. Hence imidazolone is a molecule which indicates properties of both

pyrrole and pyridine. The contribution of one electron from each carbon and

pyridine nitrogen and two from the pyrrole nitrogen make up an aromatic

sextet.

() I H

J:) o N

I H

(I) (II)

Imidazoline-5-ones are derivatives of imidazoline with a carbonyl

group at 5-position. Substituents in the 2, 4 and 5 pOSitions may be varied,

but the greatest difference in structure and properties is exerted by the

groups attached to carbon atoms in 2 and 4 positions and to nitrogen atom

in 1-position. Another name, according to IUPAC is 2-imidazolin-5-one (II).

The discovery of the 2-substituted-2-imidazolones dates back to the

year 1888 when Hoffman A Wl24 prepared 2-methyl-2-imidazoline (Iysidine)

by heating N1-diacetylethylenediamine in a stream of dry hydrogen chloride.

Ladenburg Al25 prepared the same compound by fusing two equivalents of

sodium acetate with one equivalent of ethylene diamine dihydrochloride.

Imidazolel26-128 or iminazoline is an azapyrrole, the nitrogen atom

being separated by one carbon atom. This compound was earlier also called

as glyoxaline as it was first prepared in 1858 from glyoxal and ammonia.

The imino nitrogen is assigned position-1 while the tertiary nitrogen

atom position-3. The imidazole nucleus is found in a number of naturally

106

occurring compounds such as histamine, histidine, pilocarpine and allantoin.

Since imidazoles also exists in tautomeric forms, either of the nitrogen atom

can bear the hydrogen atom and the two nitrogens become indistinguishable

and the numbering becomes rather complex for mono substituted imidazoles.

These are 2-imidazoline (III), 3-imidazoline (IV) and 4-imidazoline (V).

c) I

C) I

H H

(III) (IV) (V)

Preparation of 5-0xo- imidazole:

Harhash A et al 129 studied the ammonolysis of oxazolone with liquor

ammonia. Tiwari A R and Jolly V S130 have obtained a-benzamido-3-

methoxy-4-allyloxy cinnamide by refluxing a suspension of azalactone in

ethanol and ammonia. Latta and Jolly131 have synthesised 2-phenyl-4-(3'

methoxy-4' -hydroxy-5' -allylbenzylidi ne)- 5 -i midazolone by refluxing

respective azalactone in ethanol and liquor ammonia in the presence of

anhydrous K2C03.

Tiwari S Sand Satsangi R K132 have reported that substituted 5-

oxazolones on reaction with primary amines or on amination in pyridine

yielded the corresponding imidazoline-5-ones. Amides of u-acylamino acrylic

acids obtained from the azalactone and primary amine can be converted into

imidazolone (A).

Rl_NH2

CsHSN K2C03

CAl

..

X= -C6HS, R = different aryl groups, R! = alkyl or aryl amines.

107

The ring closure can be affected under a variety of conditions,

substituted anilides have been converted into imidazolones by the action of

phosphorus oxychloride. In order to get a variety of useful compounds,

reaction of azalactones have been extensively investigated with different

types of compounds such as alcohol,133 thiophenol,134 hydrazine hydrate, 135

aromatic amino acids, phenyl hydrazine 136 and ammonia. Now days, reaction

of azalactone with different aromatic amines have attracted a great

attention, because of the interesting nature of resulting compounds, their

applications and biological activities.

Different methods have been documented for the synthesis of

imidazolinones by several investigators in literature.'''!'''' As one of the

preparation describes the aminalion of azalaclone, ilnd therefore, it is

necessary to discuss azalactone chemistry. Plochi!4' prepared the first

unsaturated azalactone (oxazolone) by the condensation of benzaldehyde

with hippuric acid in the presence of Ac,O.

108

Mechanism:

Erlenmeyer et al 142 believed this synthesis to be a special type of

Perkin condensation in which reaction between aldehydes and acyl glycine

proceeds first followed by ring closure.

H3 Cy 0"-Na

° n°

(CH3COhC! HrO;

x (A)

n° + H3 Cy O

NyO

° x

(C)

-H3Cy O

+ + Na

° n° + H2O

NyO

X

(B)

:HHO+

NyO

H3yOH

x

"{no H NyO

X

(D)

°

"frio _J H NyO

X

(E)

Where X = -C6HS

109

However, convincing evidence now indicates that aldehydes condense

under the influence of base with the reactive methylene group in the

azalactone which is formed by the dehydration of benzoyl I acetyl glycine,

when the latter is heated with AC20 in presence of sodium acetate.

Therapeutic Aspects of 5- OXo- imidazoles:

Imidazolone ring system is of biological and of chemical interest since

long. Srivastava V K et al '43 have reported a new series of biologically active

analogues of imidazoline-5-ones. The imidazolinones'44 are associated with a

wide range of therapeutic activities'45-'75 such as anticonvulsant, sedative

and hypnotic, potent CNS depressant, antihistamine, antifilarial, bactericidal,

fungicidal, antiinflammatory, MAO inhibitory, antiparkinsonian,

antihypertensive and anthelmintic. Parikh A Rand coworkers'76-'77 have

synthesised imidazolinones having quinoline at 2-position, L-base of chloram

phenicol and phthalazine moieties at i-position. Parekh Hand coworkers '78

have synthesised substituted imidazolinones which have been shown to

possess good anticonvulsant activity and moderate antimicrobial activity

bearing pyrimidine '79 and s - triazine mOieties. '8o Recently several workers

have prepared some new imidazoline derivatives and reported their

antiinflammatory, herbicidal and hypertensive activities.'8'-'83

More recently, Bohmann C et al '84 have studied imidazoline derivatives

which effectively inhibit noradrenaline release in rat isolated kidney. Lacombe

C R et al '85 have studied the properties of imidazoline to stimulate insulin

release by hamster pancreatiC islets. In the present study, aromatic

aldehydes were condensed with benzoyl glycine to get oxazolinones. All

azalactones developed blood red colour on treatment with concentrated

sulfuric acid.

110

(V) (VI) (VII)

Bascou et al '86 have studied the preparation of optically active 2-

imidazoline-S-ones and thiones as agrochemical fungicides. The compound

(VII) had ICso of 37 ppm against Puccinia recondita. Takano Y et al '87 have

synthesised imidazolidinone derivatives having cholinergic (Muscarine M, )

activity and remedy for Senile dementia.

The compounds have potent and specific affinity to Muscatine M,

receptor which activate central nervous system chlorine function of dementia

patients, in particular, senile and Alzheimer type senile dementia patients.

o}- / \/ ~y'h

Ph

(VIII)

It improved the pirenzepine-induced dementia in mice by 82.7% and

68.8% at 1 and 3 mg/kg respectively. Korotkikh N I et al 'RR synthesised

imidazolones and tested for antitumor activity (VIII).

111

Takeshi M et al 189 have prepared imidazolinone derivatives as

pesticides. Marie Pascale 190 has synthesised several 2-imidazoline-S-one

derivatives and screened their fungicidal and herbicidal activities.

Kalman T 1191 has prepared imidazolinone derivatives of the type 1-[2-

deoxY-i3-D-ribo furanosylj-4-acetyl imidazoline-2-one (dIM D) and dIMD

inhibited HIV-I with ECso '" 8.1 mm in MT. celis. Kohle V et al l92 have

studied synthesis and anticancer, anti AIDS, fungicidal and antibacterial

activities of some new 1-substituted phenyl-2-(2'-chloro-S'-nitrophenyl)-4-

(p-N,N-bis-cyano ethyl amino benzylidene)-S-imidazolones (IX).

CI

(IX)

Where R '" Substituted phenyl groups.

~N

~ -N

Myoyong L et aI 193(a) have prepared substituted imidazoline-S-ones

with nicotinic acid moiety and studied herbicidal activity. Reitz D et aI 193(b)

have synthesised N-aryl, hetero aryl, and alkyl imidazol-2-one derivatives

(X). They also used N-aryl, hetero aryl, alkyl, and imidazol-2-one compounds

as angiotensin antagonists for the treatment of Circulating disorder. A class

of N-aryl, hetero aryl, alkyl, imidazol-2-one compounds is described for use

in the treatment of circulating disorders such as hypertensive and congestive

heart failure.

(X)

112

Some imidazolyl and triazolyl imidazolinones were prepared and

reported as fungicidal and plant growth regulators by Green D E and Percival

A. '94 Shukla J S and Agarwal K '95 synthesised some l-(S'-substituted

phenoxy methyl-l', 3', 4' -thiad iazol-2' -yl)-2-methyl-4-arylid ineimidazol-S

ones having useful anthelmintic activity.

2-Methyl/phenyl oxazolin-S-one derivatives are also associated with

medicinal chemistry. Oxazoles are widely reported in the literature as

antimicrobial agents. Rich S and Horsfall J G'96 noted that an unsubstituted

nucleus is seldom active but the introduction of lipophilic substituents like

alkyl, aryl or heteroaryl very often induce activity. Pandey V K and Lohani H

C'97 have reported some l-(arylidine amino ethyl)-2-methyl/ phenyl-4-

benzylidine imidazoline-S-ones and screened for CNS activity and found that

compounds were non-toxic. Nagarajan K et al '98 synthesised some nitro

derivative of imidazoles having antiamoebic activity and have also

established structural activity relationship.

Dhaneshwar S R et al '99 have synthesised some Mannich bases of 2-

methyI/2-phenyl-4-(2-hydroxybenzyl id ine )-oxazolin-S-ones a nd anti m icrob ial

activity of the synthesised compounds was evaluated against E. coli,

S. aureus and C. albicans. Neomycin and Nystatin were used as standard

antibacterial and antifungal agents.

The medicinal utilities of compounds described in this section inspired us to

synthesise some new imidazolones.


• Section -3( d), N- [S-oxo-2 -phenyl-4-( phenyl methylene ) (2-i m id azolinyl) ]-4-

pyridylcarboxamides.

»- Spectroscopic analysis and biological activities are described in Part: II.

SECTION: 3(d)

PREPARATION OF N-{4-[ARYLMETHYLENE]-5-0XO-2-PHENYL

(2 - IMIDAZOLINYL) }-4-PYRI DYLCARBOXAMIDES.

NH~ + OH

o

o

~~O :?' Ar I

~

A}yC H2N 0

N\ \ N

0

+

~

J CsHsN -H2O

Y o 0>-C~ A ~ N

N-NH -N~


SCHEME-12

/; N

113

SR.

NO.

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

--~-

14. -- -

15.

TABLE: 16

PHYSICAL CONSTANTS OF 2-PHENYL-4-(ARYLMETHYLENE)-

1, 3-0XAZOLI N-5-0N ES.

-Ar MOLECULAR M.P. YIELD %OF


FOUND REQD.

-C6HS C,6HllNO, 167 58 77.01 77.10

-2-0H-C6H4 C,6HllN03 145 61 72.40 72.45

-4-0H-C6H4 C,6HllN03 160 59 72.38 72.45

-3-0CH3-4-0H-C6H3 C17H13NO, 182 48 69.08 69.14

-2-0CHr C6H4 C17H13N03 190 56 73.02 73.19

-4-0CH3-C6H4 C17H13N03 142 65 73.05 73.19

-4-CHr C6H4 C17H13NO, 120 52 77.48 77.55

-3-Cl-C6H4 C16HlOCINO, 140 40 67.68 67.74

-4-Cl-C6H4 C,6HlOCINO, 210 58 67.68 67.74

-5-Br,2-0H -C6H3 C,6HlOBrN03 185 45 55.78 55.84

-3-NO,-C6H4 C,6HlON,04 165 55 65.25 65.31

-2,3-( OCH3),-C6H3 C18H'SN04 136 69 69.82 69.89

-5-Br,3-( OCH 3 ) ,4- C17H 12BrN04 185 45 54.48 54.57

OH-C6H, ------ - ---- . ---------_. _ .. ,--,--------- --- _._---- ------

-4-F-C(,H, C'6H iO FNO, 180 43 71.85 71.91

-3,4,5-( OCH l h-C6H, C'9H17NOS 145 64 67.18 67.25

114

% OF

NITROGEN

FOUND REQD.

5.55 5.62

5.25 5.28

5.21 5.28

4.70 4.74

4.93 5.02

4.96 5.02

5.28 5.32

4.86 4.94

4.90 4.94

4.00 4.07

9.48 9.52

4.46 4.53 -~

3.62 3.74

5.18 5.24

4.06 4.13

SR.

NO.

L-141

L-142

L-143

L-144

L-145

L-146

L-147

L-148

L-149

L-150

L-151

L-152

L-153

L-154

L-155

TABLE: 17

PHYSICAL CONSTANTS OF N-{4-[ARYLMETHYLENEj-S

OXO-2-PHENYL(2-IMIDAZOLINYL)}-4-PYRIDYLCARBOXAMIDES.

~o 0KJ~ A ~ N

N-NH -N:::-..



FOUND REQD.

-CsHs C"H,sN4O, 120 56 71.69 71.73

-2-0H-CsH4 C"H,sN40 3 170 72 68.65 68.74

-4-0H-CsH4 C"H,sN40 3 140 63 68.66 68.74

-3- (OCH3) ,4-0 H -CSH3 C'3H'8N40 4 120 68 66.58 66.66

-2-0CHr CsH4 C23 H18 N40 3 145 64 69.23 69.34

-4-0CHrCsH4 C23 H'8 N40 3 200 72 69.20 69.34

-4-CH 3-CSH4 C23 H'BN 4O, 220 65 72.15 72.24

-3-CI-CsH4 C"H,sCIN4O, 140 68 65.51 65.60

-4-CI-CsH4 C"H 'SCIN4O, 155 66 65.51 65.60

-5-Br,2-0H-CsH3 C"H 'S BrN40 3 214 70 56.94 57.04

-3-NO,-CsH4 C"H 'S Ns0 4 195 55 63.80 63.92

-2,3-(OCH3),-C6H3 C'4H,oN40 4 175 62 67.17 67.28

-5-Br, 3-( OCH 3),4- C23 H17 BrN 40 4 190 75 55.00 55.11

OH-CsH,

-4-F-CsH4 C"H,sFN4O, 175 60 68.31 68.39

-3,4,5-(OCH 3)rC6 H, C"H"N 4O, 200 58 65.38 65.50

115

% OF

NITROGEN

FOUND REQD.

15.18 15.21

14.49 14.58

14.46 14.58

13.44 13.52

13.94 14.06

13.97 14.06

14.57 14.65

13.82 13.91

13.84 13.91

12.01 12.10

16.83 16.94

12.96 13.08

11.25 11.36

.. _---1-4-:50 14.41

-. -- ---12.13 12.22

--

116

Experimental

• Preparation of 2-Pheny-4-(phenylmethylene)-1,3-oxazolin-5-one.

A mixture of benzaldehyde (0.25 mole), 2-(phenylcarbonylamino)

acetic acid (0.25 mole), acetyl acetate (0.30 mole) and anhydrous sodium

acetate (0.25 mole) was taken in a 500 ml RBF and heated on an electric hot

plate with constant stirring. As soon as the mixture liquefied completely, the

flask was transferred to a water bath and further heated around 100°C for 2

hr. The reaction mixture was cooled and then ethanol (95%, 50ml) was

added slowly to the flask and the mixture was allowed to stand overnight.

The crystalline product obtained was filtered with suction, washed with ice

cold alcohol and then with boiling water. The crude product was recrystallised

from alcohol (99%). m.p. : 167°C; yield : 58%; Anal. Found : C, 77.01

H, 4.43 ; N, 5.55 ; Calc for C16HllNOz : C, 77.10 ; H, 4.45 ; N, 5.62%.



• Preparation of N- [5-oxo-2 -phenyl-4-(phenyl methylene) (2 -imidazol inyl) j-

4-pyridlylcarboxamide.

A mixture of N-amino-4-pyridylcarboxamide (0.01 mole) and

2-phenyl-4-(phenylmethylene)-1,3-oxazoline-5-one (0.01 mole) was placed

in a RBF and 10 ml of pyridine was added to this mixture. The reaction

mixture was refluxed on a sand bath for 2 hr. The mixture was poured into

ice-cold water and then required amount of con. hydrochloric acid was added

to neutralize the reaction mixture. The solid obtained was left overnight,

filtered and washed with water. The product was dried and recrystallised

from ethanol (99%). m.p. : 120°C; yield : 56%; Anal. Found : C, 71.69 ;

H, 4.35; N, 15.18 ; Calc for CnH16N40Z: C, 71.73 ; H, 4.38; N, 15.21%.



117

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