22

2. LITERATURE SURVEY

2.1. Literature Survey on microwave synthesis:

Heterocycles are among the most frequently encountered

scaffolds in drugs and pharmaceutically relevant substances. Some of

the following heterocyclic compounds reported in the literature were

synthesized by using microwave technique.

1. Microwave assisted synthesis of indole and furan derivatives

possessing good anti-inflammatory and analgesic activity37. 3-

Carboxy-4-methyl pyrole-2-acetic acid and furfuryl amine were mixed

together. This mixture was subjected to microwave irradiation for 10

min at 600W power.

2. Efficient synthesis of 6-aryl-(2H-pyrido-(2,3:4,5) pyrimido(1,2-a)

(1,8)naphthyridin-12-ones under microwave irradiation38. A mixture of

3-aryl-2-chloro-1,8-napthyridine (1,0.01mole) and 2-amino nicotinic

acid(2,0.01mole)in glacial acetic acid (20ml) was intermittently heated

by microwaves at 30sec

23

3. Microwave and ultrasound assisted synthesis of 16-Methyl-8(Z)-

heptadecenoic and 16-methyl-6(Z)-heptadecenoic acid39. To a solution

of bromo alcohol (0.001 mole) in dry THF (1ml) taken in a 50 ml

conical flask was added DHP (0.00125 mole) and iodine (0.0020 mole).

The conical flask covered with a small funnel and subjected to

microwave irradiation at 350W for 30min, this reaction was cooled

and diluted with chloroform and washed with sodium thiosulphate

solution, water and dried.

4. Ceric ammonium nitrate (CAN) promoted efficient solid phase

synthesis of amide derivatives40. a mixture of carboxylic acid and urea

was ground well and mixed with CAN. The mixture was taken in a

glass tube and was irradiated at 160W for the specified time. On

completion of the reaction was cooled to RT and extracted with ethyl

acetate.

24

5. Microwave accelerated synthesis of novel spiro heterocycles41. A

dibromo compound, amidino-carbamide, fused NaOAc(2mmole) and

DMSO (8ml) were taken and subjected for microwave irradiation.

6. Synthesis of novel triazole, qionoline, oxazole and imidazole

annulated carbostyrils by microwave irradiation42. 3-Bromo

carbostyril(0.01), 4-amino-5-methyl-3-mercapto-1,2,4-triazole,

piperidine and 4ml of alcohol were taken in a flask and irradiated for 5

min. After that the reaction was poured into crushed ice then it is

filtered washed with water and dried.

7. A new and efficient method for the synthesis of 5-arylmethylene-

pyrimidine-2,4,6-trione under solvent and catalyst free conditions43. A

25

mixture of barbiturac acid and aromatic aldehyde was taken in a glass

tube and then wetted with methanol and placed the tube at the centre

of alumina-bath which was made by using 250ml glass beaker filled

with three quarter alumina. The alumina-bath was kept inside a

microwave oven and the mixture was irradiated.

8. Lithium chloride as an wfficient catalyst for Friendlader synthesis

of 1,8-napthyridine via the use of MR44. Licl (0.01 mol) was added to a

mixture of 2-amino nicotinaldehyde(0.01mole) and appropriate active

methylene compound(0.01mol), mixed thoroughly and irradiated in a

microwave oven.

9. Solvent free improved synthesis of some substituted 1,3 diarly

propanones and 3,5-diaryl-6-carbethoxy cyclohexenones under

microwave irradiation45. 1,3-Diaryl propanones were condensed with

ethyl aceto acetate using basic alumina under solvent free microwave

irradiation in a modified claisen schmidh condensation reaction for 2-

3min.

26

10. A facile microwave assisted synthesis and antimicrobial activities

of naturally occurring (E)- cinnamyl (E)-aryl cinnamates46. Silica gel is

added to a solution of benzaldehyde (0.001 mole) and

phosphorane(0.0012 mole) in dichloromethane (5ml) and the reaction

mixture was stirred for 2min, the solvent was removed and the

residual powder was dried for 2min, the solvent was removed and the

residual powder was dried in vaccume. It was spread on a Petri dish

and irradiated in microwave oven for 2-3 min.

27

11. An efficient synthesis of 2-amino benzochromene derivatives

catalyzed by TBABr under microwave irradiation in aqueous media47.

A mixture of benzaldehyde(1.06g), malono nitrile (0.66 g), alpha

naphthol (1.44g), catalyst amount of TBABr (0.80 g) and water (10ml)

are taken into pyrex cylinder tube, heated in a microwave oven at

320W. At the end of irradiation for 2min, monitored on TLC. The

contents were cooled to room temperature and extracted by diethyl

ether and acetate.

12. Synthesis of some substituted 2-oxo-1,2,3- tatrahydropyrimidines

(3,4-dihydropyrimidin-2(1H)-ones) and 2-thioxo-1,2,3,4-

tetrahydropyrimidines, catalyzed by tin(II) chloride dihydrate and tin

(II) iodide under microwave irradiation48. A mixture of 1m mole of an

alehyde,1.3m moles of thiourea and 1m mole of acetylacetone(or ethyl

acetoacetate) was mixed thoroughly with 0.15m mole of tin(11)

chloride dehydrate in a conical flask. The contents of the flask were

irradiated with microwave at 2.45GHz for 3min.

28

13. Microwave assisted facile synthesis of a new of assymetrical

diheteroarylmethanes bearing imidazopyridine moieties under solvent-

free condition49.

14. Microwave associated synthesis of substituted 4-oxo-4H-1-

benzopyran-3-carboxaldehyde using vilstmier reagent over silica gel50.

15. Microwave assisted solvent-free synthesis of 34-methyl 2-hydroxy

andand 2-methyl-4-hydroxy quinolines51. Anilines (0.01m mol), ethyl

acetoacetate (0.001mole) and p-toluene sulphonic acid (120mg) were

taken in 100ml beaker , mixed well and irradiated in a microwave

oven at the power of 320W for specified time.

29

16. Facile and efficient synthesis of 1,8-naphthyridinyl phthalazine-

1,4-diones under microwave irradiation52. A mixture of 3-aryl-3-

hydrazino-1,8-naphthyridine(0.001 mole) and phthalic anhydrine

(0.01 mole ) was thoroughly mixed in a 50ml beaker and DMF(50

drops) was added to it. The beaker was covered with a watch glass and

irradiated in a microwave oven at 400W intermetently at 30sec

intervals for the appropriate time.

17. Microwave assisted rapid and efficient synthesis of 2,1-

benzisoxazoles53. Aromatic aldehydes, acetyl acetone or ethyl

acetoacetate and piperidine were taken in a flask and placed in a

microwave oven and irradiated at 260W for 1min.

18. Microwave assisted synthesis, anticonvulsant activity and

quantum mechanical modeling of N-(4-bromo-3-methyl)

semicarbazones54. The conversion of the semicarbazones was carried

out using microwave irradiation. To the solution of 4-bromo-3-methyl

phenyl semicarbazide in ethanol was added an equimolar quantity of

appropriate aldehyde or ketone.

30

19. A simple method for deprotection of tert-butyl dimethyl ether by

using stannous chloride under microwave irradiation55. Stannous

chloride was added to asolution of tert-butyl dimethyl silyl ether (1m

mol) in ethanol (20ml) and the reaction mixture was stirred.

Microwave irradiation

R = Alkyl, Phenyl, Napthyl

20. A microwave assisted cyclocondensation approach to

pyrimidine[1,6 a] benzimidazole has been developed by Rahmouni et

al56.

31

21. KSF clay allowed the condensation of the ortho ester with o-

phenylene diamene into benzimidazoles either in refluxing toluene or

without solvent focused to microwaves. A variety of reagents react

with o-phenylene diamine to give benzimidazoles57-59 in high yields in

solvent free reaction under microwave irradiation.

22. Ten new fluorine-containing 1-thiocarbamoyl-3,5-diphenyl-2-

pyrazolines have been synthesized by a microwave-promoted solvent-

free condensation of 2,4-dichloro-5-fluoro chalcones with

thiosemiarbazide over potassium carbonate60.

2.2 Literature Survey on Isoxazoles :

Five membered heterocyclic compounds containing one oxygen

and one nitrogen atom in adjacent positions are isoxazoles and its

derivatives are collectively referred to as isoxazole systems. Isoxazoles

are extensively studied due to their applications in pharmaceutical

industry61. The selection of synthetic approach for these compounds

depend up on the selection and availability, cost of starting materials,

type of ring closure, steps and tolerance of functional groups present

in the molecule. The parent ring system (unsaturated) isoxazole is

historically old and was dormant until 1888, claisen was the first to

identify isoxazole and named it “monazole”.

General structure of isoxazole

32

Many procedures for synthesis of isoxazoles systems have been

reported in the literature. Some of the synthetic routes are mentioned

here:

1. K.M. Short et al reported a mild base promoted method to cyclize

propargyl oximes to form isoxazoles62.

NOH

R2

R1 ON

R1

R2

K2CO

3

MeOH

2. K. Tsutomu et al reported the acid catalyzed cyclization of oximes

to different isoxazoles depending on the conditions. In sulphuric acid

alone 3-methyl derivative is formed, whereas in sulphuric acid and

ethanol gives the corresponding 5-methyl isoxazole derivative63.

3. Tomio et al reported cyclo addition of alkynyl derivatives with

nitrile oxide gives 3,5-disubstitiuted isoxazoles64.

33

4. Acetylenic ketone on treatment with hydroxylamine hydrochloride

yield 3,5-disubstituted isoxazoles65-66.

5. Synthesis from halogenated alpha, beta, ethylenic aldehydes or

ketones and hydroxylamine substances containing the –CO-C=CX-

linkage react with hydroxylamine to give isoxazole derivatives by

elimination of a molecule of hydrogen halide 67-70.

6. Barnes and Dadson reported the synthesis of substituted

isoxazoles from sodium phenyl acetylene and p-methoxy benzo

hydroxylamine chloride71.

34

O

CH3

N

OH

Cl

Na

N

O

OCH

3

+

7. 1, 3-Dipolar cycloaddition of pheyl vinylic selenide to nitrile

oxides and subsequent oxidation-elimination furnished 3-substituted

isoxazoles with good yields in a one-pot, two-step transformation72.

phse HON R

ON R

PhSe

ON R

SePh

ON R

1.eq.NCS

ChCl3,r.t.,

12h

30%H

2O

2

1.05

eq.NEt3

00*C.

10min,r.t.,

20min

++

8. The dehydration of primary nitro compounds can be performed

by bases. Among the organic bases examined, DABCO gave the best

results. The reaction is applicable to activate nitro compounds and to

phenyl nitromethane and affords isoxazoline derivatives in higher

yields compared with those of other methods. The reactions, is not

compatible with nitro alkanes73.

R NO2

PhN

R

PhR R' "CO,PhSO

2,Ph

0.5 eq.DABCO

CHCl3

60oC,

20-80

h

2.5

+

35

9. 3, 5- Disbstituted isoxazoles are regioselectively obtained in

good yields by a mild and convenient one –pot, three-step procedure

utilizing a copper (I) – catalyzed cycloaddition reaction between in situ

generated nitrile oxides and terminal acetylenes74.

1)1.05eq.H2NOH.HCL,1.05eq.NaOH

t-BuOH/H20(1:1),r.t.,30 min(TLC)

2) 1.05eq. TsN(Cl)Na.3H20

R H

OON

R

R'

3)1.05eq R' ,3mol-%CuSO4

~3.7 mol-%Cu*,r.t.,6h

10. Pyrazole or isoxazole derivatives are prepared by a palladium-

catalyzed four-component coupling of a terminal alkyne, hydrazine

(hydroxylamine), carbon monoxide under ambient pressure, and an

aryl iodide75.

ArOH

NH2

1.2eq

.HCl

3eq

Ar-I

ON

Ar

Ar

1mol-% PdCl

2(PPh)

3

CO (ambient pressure)

DMF/0.5M aq.NH

3(1:1)

rt,37

h

+ +

11. The reaction of various 2-alkyn-1-one, o-methyl oximes with ICI,

I2, Br2 or PhSeBr provided 3,5-disubstituted 4-halo(seleno) isoxazoles

in good to excellent yields under mild reaction conditions76.

N

R

R'

OMe ON

IR

R'1.2 eq.ICI

CH2Cl

2,r.t

0.25

-0.75

36

12. A series of 4-alkyl-5-amino isoxazoles have been synthesized in

high yield by nucleophilic addition of lithiated alkyl nitriles to ()-

chloro oximes77.

N

R

OH

ClR' CN

ON

NH2

R'R

4eq

4eq.tBuLi

THF-78

*C,15

min Ar,alkyl,R':alkyl,benzyl,Ar

R +

13. 3-Acyl isoxazoles were synthesized by the reaction of alkenes or

alkynes with ketones (acetone or acetophenone), as both a reagent

and the solvent, by three methods : iron (III) nitrate under reflux, iron

(III) salt-nitrogen dioxide (NO2) at room temperature, and iron (III)

nitrate under microwave irradiation78.

R

N

R

O

R'O1

eq.Fe(NO3)3

R'COR'R'=Me:reflux,

5-12

h

R'=Ph:80*C,

10-15

h

14. A series of 1-[3‟-amino-2‟-methyl-6‟ monosubstituted quinazolin-

4‟(3‟H)-yl]-3-(arylidenyl) chalcones have been synthesized via

condensation of 3-acetyl amino-2-methyl-6-monosubstituted

quinazolin-4(3H)-ones with various aromatic aldehydes. Cycloaddition

with hydrazine hydrate yield 1-Acetyl-5 substituted diaryl-3-(3‟-amino-

2‟-methyl-6‟-mono substituted quinazolin-4‟(3‟H)-only]-2-pyrazolines

and cyclocondensation with hydroxylamine hydrochloride affords 5-

substituted diaryl -3-„3‟-amino-2‟-methly-6‟-monosubstituted

quinazolin-4‟-(3‟H) onyl]-isoxazolins79.

37

N

N

CH3

O

NH2

CH3COCl

N

N

CH3

NHCOCH3

O

OHC

R

N

N

CH3

NHCOCH

O

CH

R

N

N

CH3

NH

O

N

N

CH3

NH

O R

N N

COCH3

X

2%NaOH

X

R

N OX

X

NH2OH.OH

2 %NaOH

NH2NH

2.H

2O

Glacial acetic acid

+

15. 2, 4-Bis-anilino-6-(2‟-acetyl-4‟-chloro phenoxy) triazines have

been converted into chalcones by condensing with aromatic

aldehydes. These chalcones on treatment with hydrazirte hydrate and

hydroxyl amine hydrochloride give pyrazolines and isoxazolines

respectively80.

38

N N

N NHNH

O

RR

Cl

R1

N N

N NHNH

O

RR

N O

R1

Cl

N N

N NHNH

O

RR

N NH

R1

Cl

NH2NH

2.H

2O NH

2OH.HCl

O

16. 3-Aryl flavanone has been prepared by the condensation of

dibenzoyl methane with aromatic aldehyde in ethanol containing few

drops of piperidine. This compound upon refluxing with

hydroxylamine hydrochloride in DMF containing small amount of

piperidine give 4-aryl substituted isoxazoline81.

39

CH3

Cl

OH

COCH3

Cl

HOOC

POCl3

pyridine

CH3

Cl COCH3

O

Cl

O

CH3

Cl COCH2

OH Cl

O

Cl

O

O

Cl

CH3

Cl

O

Cl CHOC2H

5OH

NO

Cl

CH3

Cl

OHCl

O

+

17. S-Triazine is reacted with aniline in the presence of acetone at 0-

50c to produce 2-phenly-amino-4,6-dichloro-S-triazene. This when

trated with fluoro aniline in presence of acetone to form 2-phenyl-

amino-4(4‟-fluoro phenyl amino)-6-chloro-S-triazine. This was refluxed

with 4-acetyl-phenyl amine gave 2-phenyl-amino-4,(4‟-fluoro phenyl

amino)-6-chloro-S-triazine. This was refluxed with 4-acetyl-phenyl

amine gave 2-phenyl-amino4,-(4‟ fluoro phenyl amino)-6-(4-actyl-

phenyl amino) –S-triazine. This was treated with aldehyde gives

40

chalcones. This was treated with hydroxy amine hydrochloride gave

isoxazolines82.

N

N

N

Cl

Cl Cl

NH2

N

N

N

Cl

NH Cl

F

N

N

N

Cl

NH NH

NH COCH3

Reflux/Acetone

F

N

N

N

NH NH

NH2

COCH3

NH COCHCHR

F

N

N

N

NH NH

RCHO DMF/KOH

NH2OH.HCl

F

N

N

N

NH NH

N O

RNH

41

Table 2.1 : Therapeutically important drugs containing Isoxazole

moiety:

S.No. Drug Structure Activity

01 Isoxicam OO

NS

OH

CH3

NH

ON O

NSAID

02 Floxacillin

ON

CH3

NH

F OS

N

CH3

CH3

O COOH

H

Antibiotic

03 Cloxacillin

ON

CH3

NH

Cl OS

N

CH3

CH3

O COOH

Antibiotic

04 Dicloxacillin

ON

CH3

NH

Cl

Cl

OS

N

CH3

CH3

O COOH

Antibiotic

05 Oxacillin

ON

CH3

NH

NO

OS

N

CH3

CH3

O COOH

Antibiotic

Antineoplastic

06 Avicine

NO

CH

H

Cl

COO-

NH2

Antibacterial

07 Sulfamethoxazole

NH2

S NH

ON

CH3

O

O

Antibacterial

42

08 Sulfisoxazole

NH2

S NH

O

O

NO

CH3

CH3

Antibacterial

09 Zonisamide

NO

CH

2

S NH2

O

O

CNS

depressant

Anticonvulsant

Antiepileptic

10 Leflunomide

ON

CH3

NH

O

CF3

Anti-

inflammatory

Antibacterial

Antitumor

11 Isouron

O

CH3

CH3

CH3

NH N CH

3

CH3

O

Black

Valentine

Herbicide

12 Isoxaflutole NO

O

SO2CH

3

CF3

Pesticide

43

2.3. Literature survey on synthesis of thiocarbamoyl

pyrazolines:

Literature survey revealed that thiocarbamoyl pyrazolines possess a

broad spectrum of biological activities viz. Antibacterial,

antifungal, anti-inflammtory, hypolipidemic, antidepressant,

anticonvulsant, antiamoebic, insecticidal activities.

1. 1- Thiocarbamoy 1-3, 5-dipheny1-2 pyrazolines have been

prepared by cyclization of 1,3-diphenyl-2- pro[pene-1 ones

(chalcines) with thisosemicarbazide in presence of sodium hydroxide

resulted in –N-substituted thiocarbamoy1-3, 5--dipheny1-2

pyrazolines83.

44

2. Ten new fluorine-containing 1- thiocarbamoy1-3, 5-dipheny1-2

pyrazolines have been synthesized by a microwave -promoted

solvent-free condensation of 2, 4-dichloro-5- fluoro chalcones with

thiosemicarbazide over potassium carbonate84.

3. Ten new series of 3-aryl-5-(pyridine-3-yl)-1-thiocarbamoy1-2-

pyrazoline derivatives were prepared by the reaction of azachalcones

with thisemicarbazide in ethanolic sodium hydroxide85.

45

4. Vineet Malhotra et al synthesized substituted pyrazolines

cardiovascular activity86.

5. 1-Phenyl-, 1-thiocarbamoyl-, 1-N-substituted thiocarbamoyl-

and 1-(4‟-phenylthiazole-2-yl)- 3-(2-naphtyl)-5pheyal/(2-furyl)-2-

pyrazoline derivatives were synthssized by the reaction of

appropriate chalcones (1-naphthy-3-phenyl-3-pheny/(2-furyl)-

2propen-1-ons) with phenylhdrazine thiosemicarbazide, 4-

46

substituted thiosemicarbaides and phenacyl bromide respectively

and evaluated for antidepressant and anticonvulsant activities87.

Ar = Ph, 2- furyl

R= C6H5, CSNH2, CSNHCH3, CSNHC3H5, CSNHC6H5, 41-phenyl

thiazole-21-y

6. Goekhar nesrin et al synthesized 1-N-substituted thiocarbamoyl

-3-substituted phenyl-5- thienyl-2-pyrazolines and these compounds

showed antidepressant activity88.

7. Asha budakoti et al synthesized 1-N-substituted thiocarbamoyl-3,

5-diphenyl-2-pyrazolines which exhibited better antiamoebic activity

than the standard drug metronidazole89.

47

8. Abid Mohammed et al synthesized 1-N-substituted

thiocarbamoyl-3-phenyl-2-pyrazolines having antiamoebic activity

when tested against standard drug metronidazole90.

9. Abid Mohammed et al synthesized 1-(Thiazolo(4,5,6)Quinoxaline-

2-yl)3-phenyl-2-pyrazolines and thiocarboxamide-3-phenyl-2-

pyrazolines which showed antiamoebic activity91.

10. A novel series of 1- thiocarbamoyl-3, 5-diaryl-4, 5-dihydro-(IH)-

pyrazole derivatives have been synthesized and investigated for the

ability to inhibit selectively the activity of the monoamin oxidase

(MAO)92.

48

11. Grossurt et al synthesized 3, 4-diphenyl-1-phenyl carbamoyl-

2-pyrazolines possessing insecticidal activity93.

12. Van hes rolf et al synthesized 1-Pheny carbamoyl-2-pyrazolines

and 3,5-diphenyl-Nsubstituted thiocarbmoyl-2-pyrazolines which

showed insecticidal properties94.

2.4 Literature survey on thiazolidinones:

Heterocycles bearing thiazole moieties constitute the core structure

of a number of biologically interesting compounds. It is a 5-

membered ring in which two of the atoms are nitrogen and sulfur.

The chemistry of thiazolidine-4-one ring system is of considerable

49

interest as it is a core structure in various synthetic

pharmaceuticals displaying broad spectrum of biological activities95.

1. 2-[3-(2-Chloro quinolinyl)-3-aryl]-4 thiazolidinone were prepared

following standard chemical procedures96.

2. 2-(Aryl or substituted aryl) -3-(-31-flouro-41 choloro phenyl)

thiazodinones were prepared following standard chemical

procedure97.

50

3. 2-Aryl-3-(41-triflouro methylphenyl)-4-oxo thiazodinones were

prepared following standard chemical procedure98.

4. 2-(31-Phenoxyphenyl)-3-aryl-5-methyl-4-thiazodinones were

prepared following standard chemical procedure99.

5. 2-Thiophenyl-3-substituted phenyl-4-oxo-thiazodinone was

prepared following standard chemical procedure100.

6. 4-Thiazodinones carrying s-triazine nucleus and sulphonamido

groups were-reported101 .

51

7. 2-Aryl-3-(21-morpholinoquinoxalimido) 4-thiazodinones were

prepared following standard chemical procedures102.

8. Condensation of choloro acridine with hydrazine hydrate

afforded 9-hydrazine acridine, which on condensation with different

aromatic aldehydes gave the Schiff base Subsequent condensation

with thiolactic or thiomalic acids gave substituted 4-

thiazolidinones103.

52

9. Condensation of 2-amino nicotinaldehyde with aromatic

hydrazides in ethanol in presence of glacial acetic acid gave 2-

amino nicotinaldehyde hydraones which on condensation with

thioglycolic acid led to the formation of 2-(2-amino-3-pyridyl)-3-

substituted-benzoylamino-4-thiazolidinones in DMF containing

anhydrous ZnCl2104 - 109.

10. The azomethines (obtained from the condensation of 2-amino

thiophenol and aromatic aldehyde) on reaction with thioglycolic acid

afforded the corresponding 3-(2-mercapto phenyl) thiazolidin-4-

ones110.

53

11. 3-(N-Sulphonyl hydrazine) benzoic acid condensation with

different aromatic aldehydes gave the respective hydrazones, which

finally gave the corresponding 4-thiazolidinones111-112.

12. 2-Amino-5-hydroxy phenyl-1,3 4-thiadrazole on treatment with

aldehyde yielded Schiff bases which finally afforded the

corresponding 4-thiazolidinones113.

54

13. Anthranilamide on reaction with hydrazine hydrate formed

corresponding hydrazone which on subsequent condensation with

aromatic aldehydes afforded 3-aryl-5-o-aminophenyl-1,2,4-triazoles.

These on condensation with thioglycolic acid gave the corresponding

4-thiazolidinone derivatives114.

14. The condensation of 2-amino benzothiazole-6-carboxylic acid

with chloroacetyl chloride in refluxing chloroform in the presence of

anhydrous K2CO3 gives2-(2-chloro acetyl amino)benzothiazole-6-

carboxylicacid which on treatment with KSCN in refluxing acetone

yields 2-(2-imino-4-oxo-thiazolidin-3-yl)benzo thiazole-6-

carboxylicacidwhichupon condensationwot various aromatic

aldehydes afforts a seriesof 2-[5-(arylidene)-2-imino-4-oxo-

thiazolidin-3-yl]benzo thiazole-6 carboxylic acid the synthesized

compounds are screened for their antibacterial as well as antifungal

activity115.

55

15. The aldol condensation between 2,3-diphenyl-4-thiazolidinone

and aromatic aldehydes results in 2,3-diphenyl-5-arylidene-4-

thiazolidinone116.

16. The synthesis of new 2,3,5,6-aryl substituted tetrahydro-2H-

pyrazolo[3,4-d]-thiazoles as potential biologically active compounds

by the cyclocondensation of wphenyl hydrazine with new 5-arylidene

derivatives of 2,3-disubstituted -1,3-thiazolidin-4-ones is

reported117.

17. The reaction of 1,4,5,6-tetrahydro-6-pyridazinone-3-carbonyl

aromatic aldehyde hydrazones Heterocyclic derivatives linked 1,3,4-

oxadiazole obtained by cyclocondenstion with acetic anhydride in

56

absolute ethanol, cyclized with mercaptoacetic acid in DMF in the

presence of anhydrous ZnCl2 afforded the 1,3-thiazolidinone

derivatives118.

18. A new molecule, incorporating a p-methoxy phenylring, a

thiazolidin-4-one and a nicotinoyl moiety, was synthesized and

evaluated for its effect on serum total cholesterol, triglyceride and

transaminases in rats119.

19. Schwarz et al synthesized substituted thiazole by condensation

of chloro acetone and thioacetamide120.

57

20. Vogel‟s et al synthesized amino thiazole by condensation of 1,2

dichloroethyl ethyl ether and thiourea121.

21. Dubs. P. et al sythesized various substituted thiazole from

mercapto acetic acid and haloketone in presence of triethyl amine122.

22. Some new Schiff bses, 4-thiazolidinones have been synthesized

and tested for their antibacterial activity. Schiff bases were

synthesized by the condensation of 2-hydroxy-3-iodo-5-bromo

benzaldehyde with aromatic amine in ethnol which upon cyclisation

with mercapto acetic acid afforded corresponding 4-

thiazolidinones123.

58

2.5 Literature survey on Quinazolinones :

Among the wide variety of nitrogen heterocycles that have been

explored for developing pharmaceutically important molecules, the

compounds bearing quinazoline nucleus have played an important

role in medicinal chemistry and subsequently have emerged as an

essential pharmacophore124.

N

N1

2

345

6

7

8

Quinazoline

Quinazolin-4-one nucleus comprises of benzene ring fused with

pyrimidine ring and ketone group at fourth position. The numbering

of quinazolin-4-one is as follows.

N

NH

O

1

2

3

45

6

7

8

Quinazolin-4-one

59

1. Marston et al. (1905) reported the synthesis of 7-nitro-2-alkyl-4-

keto 1,2 dihydro quinazolines from 4-nitro acetanthranilic acid

and from 4-nitro acetanthranil125.

N

NH

RO2N

O

R=CH3,(CH

3)2

2. Marston et al. (1909) synthesized 2-methyl amino-4-quinazolone

and certain of its amino substituted derivatives126.

N

N

CH3

O

NHR

R=H , CHO , CH3CO , CONHC

6H

5

3. K.Kishore et al. (1960) reported the synthesis of a 2, 3-

disubstituted quinazolones from amino pyrimidines and 5-

amino quinoline127.

N

N

CH3

O

R

R=2-Pyridyl, 2-Pyridyl methyl, 4-Pyridyl methyl, quinolyl

4. S.Somasekhara et al. (1966) synthesized various 3-substituted-

5-chloro-2-alkyl quinazolinones128.

60

N

N

R1

OCl

R2

R1=CH

3 , C

2H

5

R2=C

3H

7, C

4H

9, C

6H

5, C

6H

5CH

2

5. John. T. Shaw et al. (1969) reported the preparation of triazino

[2, 1-b] quinazolone129.

N

N

O

NH

N

NH

C6H

5

6. A.Sammour et al. (1973) synthesized 2-cyclohexyl 3-hydroxy 4-

quinazolone by the reaction between cyclohexyl 3, 1-(4H)

benzoxazone and hydroxylamine130.

N

N

C6H

11

O

OH

7. E.P Papadopoulos et al. (1982) given the convenient preparation

of N-substituted 2-amino-4H-3, 1-benzoxazinones and 3-

substituted 2, 4-(1H, 3H) quinazolinediones131.

N

NH

O

O

R

R=H, C2H

5, C

6H

5, CH

3(CH

2)3

61

8. K.R. Desai et al. (1989) reported the synthesis of 2-mercapto 3-

(2‟, 4‟ dichloro 4-stilbenyl) 6-arylazo 4-oxoquinazoline dyes and

investigated their applications132.

N

N

SH

RN=N

O

CH=CH Cl

Cl

R = Chicago acid, Schaffer‟s acid, H-acid, R- acid

9. K.R.Desai et al. (1994) synthesized azodisperse dyes from 2-(1‟,

4‟, -bisstyryl-4” chloro)-6-arylazo-4-oxo-quinazolines and

investigated their applications133.

CH=CH CH=CHCl

NH

N

O

N=NR

R=Naphthol-aniline, Naphthol-O-Toluidine, Naphthol-O-anisidine, 1-phenyl 3-methyl 5-pyrazolone

10. A.M.F. Eissa et al. (1994) synthesized and studied the

reactions of 3-amino-2-methyl 4-(3H)-quinazolinone derivatives134.

N

N

NH2

CH3

O

11. P.S.N.Reddy et al. (1999) reported a facile synthesis of 1-aryl

4-[isopropylidine amino/methyl-4-(3H)-quinazolin 2-yl]-azetidin 2-

ones135.

62

N

N

O

R

N R1

O

R1=H, CH

3, C

2H

5, Br,R=CH

3

12. Sergiy M.Kovalenko et al. (2000) reported several methods for

the synthesis of quinazolinyl coumarin derivatives136.

R

NH

N

O

O

R=H,OCH3

13. K.Santadeepthi et al. (2000) carried out an efficient microwave

assisted solvent free DDQ mediated oxidative synthesis of 2-aryl-

quinazolin-4 (3H) ones137.

N

ArN

O

R

R=H,CH3

14. Robert S.Atkinson et al. (2002) reported the kinetic resolution

of amines with enantiopure 3-N, N diarylamino quinazolinones138.

63

N

N

R R

OOO

15. Gamal A. El-Hiti et al. (2002) synthesized and studied the

reactions of some 3-aryl-2-thioxoquinazolin-4- (3H)-ones139.

N

SN

Y

X

O

Ar

H

16. Ashok Kumar et al. (2002) synthesized 3-[3‟-(aminoacetyl

thiosemicarbazido) 4‟-oxo-2‟-(substituted aryl)-1‟-thiazolidinyl]-2-

methyl monosubstituted quinazolin-4- (3H)-ones140.

N

CH3

N

O

NHCCH2NH.NH.C

O S

N

SO

R

X

17. P.S.N.Reddy et al. (2003) synthesized 2-quinazolinonyl

imidazolinones141.

O

NH

N

N

N

CH3

O

Ar

64

18. P.S.N.Reddy et al. (2003) reported the synthesis of 1H-4-aryl [1,

2, 4] oxadiazino [5, 4-b] quinazolinone142.

N N

ON

O Ar

Ar = CH3

19. M.Bakavoli et al. (2004) reported the synthesis of 2-alkyl/aryl

quinazolinones by applying microwave irradiation in solvent free

conditions143.

N

N R

O

HR = CH

2CL ,CF

3 , C

6H

5 , P-NO

2C

6H

4 , P-CNC

6H

4

20. P.Y.Shirodkar et al. (2000) synthesized mannich bases of 6-

nitro N-arylamino methyl 1, 2, 3, 4-tetrahydro 4-oxo 2-thio

quinazolines and screened for anti-tubercular activity144.

N

NH

CH2-NH-Ar

S

O2N

O

Ar = C6H

4-P-Chloro , C

6H

4-O-NO

2

21 .R.Bhat et al. (2000) synthesize and screened for anti-

tubercular, antifungal activity of mannich bases of 7-nitro-2-

methyl 4(3H) quinazolinone145.

65

NN

N

N

N CH

2

NH

O

O2N

Ar

22. S.Plescial et al. (1994) reported the synthesis of 1-methyl 5-[2-

substituted 4-oxo 3-(4H)-quinazolinyl]-1H-pyrazole-4-acetates. The

compounds were tested for analgesic and anti-inflammatory

activities146.

NN

N

N

R

OCOOC

2H

5

CH3

R=H, CH3, C

2H

5, C

6H

5

23. K.S.Manjunatha et al. (1998) synthesized and evaluated anti-

inflammatory activity of some 6-bromo-2, 3-disubstituted 4(3H)

quinazolinones147.

N NN

R

ArN

O

CH3

CH2COOH

O

24. V.Alagarsamy et al. (2000) synthesized some novel 2-mercapto

3-(substituted methylamino)-quinazolin-4 (3H)-ones and evaluated

their analgesic and anti-inflammatory activities148.

66

N

N

SH

O

NH

CH

2

N

R1

R2

R1 + R2 = Piperazinyl, Pyrrolidino, Anilino, 1-Benzimidazolyl

25. A.S.Dhake et al. (2003) reported the synthesis of 1-phenyl 2-

substituted 4-(1H)- quinazolinones and anti-inflammatory activity

of synthesized compounds were subjected to QSAR analysis149.

N

N

O

CH2X

R

26. V.Alagarsamy et al. (2003) synthesized some novel 2-phenyl 3-

(substituted methylamino) quinazolin-4 (3H)-ones and investigated

their analgesic, and anti-inflammatory activity150.

N

O

N

S

N

R

R=-H,NHC6H

5,NH-CH

2-CH=CH

2

27. S.G.Abdel Hamide (1997) synthesized and investigated some

novel 3-hetero aryl quinazolin-4-one derivatives and their

antimicrobial activity was studied151.

67

N

N

I

C6H

5

'

O

NH2

28. B.Shivarma Holla et al. (1998) synthesized and screened their

antibacterial activity of nitro furyl vinyl quinazolinones152.

N

N CH=CH

O

O NO2

R

R = H, Br, Ch3, OCH3, NO2

29. Bimal Prasad Sharma et al. (2002) prepared 2-thioxo 3-aryl 4-

(3H) quinazolinones and screened for their antibacterial and

antifungal activities153.

N

N

X2

X3

X1

S

O

R

X1=H, Br; X2=H, Br, X3=CH3; R=CH3, OCH3, Cl

30. V. Alagarsamy et al. (2002) synthesized and reported

antibacterial and antifungal activities of some Novel 2, 3-

disubstituted quinazolin-4-one154.

68

N

N

N=C

OR1

R2

R

R R1 R2

-ph Methyl Ethyl

-SH Methyl Ethy l

-SCH3 Methyl Ethyl

31. Jawaid Ahmad et al. (2003) reported the synthesis of some

novel quinazolin-4-(3H) ones and styryl hemicyanines as

antimicrobial agents155.

N

CH3

Ar

N C=

O

N(CH3)2

X

CH

OH

Ar = C6H4OH, C6H5, C6H4Br, C6H4NO2

32. A.A.F.Wasfy (2003) synthesized 2, 2‟-disubstituted 3, 3‟-

biquinazolin-4(3H)-ones and tested for their antimicrobial

activities156.

N

O

NR

N

N

O

R1

R R1

Styryl H

Styryl CH3

Styryl C2H5

69

33. V.Murugan et al. (2003) synthesized 6‟8-dibromo-2-substituted

styryl-4-quinazolin-3- (4-benzphenyl hydrazides) and tested them

for anticancer activity157.

N

N

Br

Br

Ar

O

CONHNHC6H

5

SAr = , C

6H

4NO

2,C

6H

5CH=CH,-C

6H

5

34. V.Murugan et al. (2003) synthesized 4-chloro 1-[4-(6, 8-

disubstituted-2-chloromethyl quinazolin-4-one 3- yl)-phenyl]

butane-1‟3-dione derivatives and screened them for anticancer

activity158.

N

N

X1

X

O

CH2Cl

CH2Cl

O O

X1=H,ClX=H,Rr,I,Cl

35. Nizamuddin et al. (2000) synthesized and evaluated anti-viral

activity of 2-methyl-3-(arylthio-carbamido) quinazolin-4-(3H)-

ones159.

70

N

N

O

NHCSNH

CH3

R=-H,2-CH

3,4-CH

3,3-CH

3,4-OCH

3

2-Cl,

2,6-(CH

3),

4-CH

3,4-Cl,

2-OH,

4-OH

36. V.Alagarsamy et al. (2003) synthesized 2-substituted (1,3,4)

thiadiazolo (2,3-b)quinazolin-5-(4H). –ones and screened them for

anti-HIV activity160.

N

O

N

S

N

R

R=-H,NHC6H

5,NH-CH

2-CH=CH

2

37. P.Selvam et al. (2004) synthesized some novel 2-substitued 3-

sulphonamido) quinazolin-4-(3H)-ones and screened them for

antiviral and anti HIV activities161.

N

NR

O

R1

SO2NH

O

N

CH3

CH3

38. V.K. Pandey et al. (2004) synthesized thiadiazolyl

quinazolones and screened them for antiviral activity162.

N

O

O

CH2CH

2

N

O

N

C6H

5

NN

S R

R=CH3, C2H5, C3H7, C6H5, P-ClC6H4

71

39. S.C.Chaturvedi et al. (2004) performed quantitative structure

activity relationship study on a series of 2,3,6-substituted

quinazolinone derivatives for their AT1 selective angiotensin-II-

receptor antagonistic activity163.

N

N

R2

R3

R1

O