3.1 Introduction :-

Pyrazoles are very important well known nitrogen containing five member heterocyclic

compounds. The derivatives of pyrazole have played a crucial role in the history of

heterocyclic Chemistry and used extensively as important pharmacophores and synthons

in the field of Organic chemistry and Drug designing. The pyrazole meoity constitutes the

core structure of numerous biologically active compounds including drugs Viagra1 an

inhibitor of 5- phosphodiesterase used for the treatment of erectile disfunction, Celebrex2,

an inhibitor of cyclooxygenase-2 (COX-2) used as patent antinflammatory and antagonist

of the CB-1 cannabinoid receptor3, used for the treatment of obesity in addition to this

pyrazole. Pyrazoles have diverse biological activities such as anti-microbial4-7

, anti-

inflammatory8, analgesic

9, anti-cancer

10 anti-convulsant

11, anti-viral

12 and herbicidal

13

etc.

The first pyrazole derivatives was isolated by Japanese workers14

3-n-nonyl pyrazole (1)

from Houttuynia Cordata (a plant) and observed its antimicrobial activity. A pyrazolic

amino acid-levo- -(1-pyrazolyl)-alanine (2) has been isolated from water-melon-seeds15-

16.

Pyrazole is a five membered heterocyclic compound having three carbon atoms and two

nitrogen atoms in adjacent position. The molecular formula of Pyrazole is C3H4N4.

Pyrazole contains a pyrrole-like and a pyridine like N-atom at-1 and -2 positions (1, 2-

diazole).

The nuclevs of pyrazole (3) ring is planer.

(CH2)8CH3

N

N H

(1) (CH2)8CH(NH2)COOH

N

(2)

N

3

N2

4

5

The bond lengths of N1-N2 bond in the ring is 1.349 A°, N2-N3 bond is 1.331 A

°, C5-N1

bond is 1.359 and N1-H=0.998 A°. The bond angles in pyrazole ring (3) are C-N-

N=113.1°, N-N-C=104.1

°, N-C-C=119.1

°, C-C-C=104.5

°, and C-C-N=104.1

°.

The pyrazole (3) has been represented by the following three tautomers (4,5,6) with H-

prefixes to rationalize to nomenclature of the compound containing this basic skeleton17-

18.

The pyrazole (3) exists in three partially reduced forms-1-pyrazoline (7), 2-pyrazoline (8)

and 3-pyrazoline (9) with different positions of double bond.

The oxoderivatives of pyrazolines were described as pyrazolinones19

and later on

pyrazolones20

.

According to the older system of nomenclature whon the carbonyl group is adjacent to

nitrogen atoms in the ring, these were named as 5-pyrazolone, pyrazolone-5. pyrazolin-5-

one (10) and the later tavtomer-3-pyrazolin-5-one. (11)

(4H- Pyrazole)

(6)

N

N

(5)

(3H- Pyrazole)

N

N

(IH- Pyrazole)

N

N H

(4)

N

(7)

N N H

N

(8) (9)

N H

NH

(10) (11)

NH O

N H

N O

N H

N1 H

(3)

The first known 5-pyrazolone is represented by Ludwing knorr21

who carried out the

condensation of acetoaceticester with phenyl hydrazine (in 1883) and synthesized a

compound with m.p.-127°C. The correct structure

22 (12) was propounded in (1887).

The pyrazolones confirming to the structure (12), according to IUPAC system of

nomenclature are termed as 2,4-dihydro-3H-Pyrazol-3-ones.

Preparation of Pyrazoles :-

Pyrazole (14) was obtained for the first time by Buchner in 1889, on heating pyrazole-

3,4,5-tricarboxlic aced (13) at 230-240°C

23.

The most widely used method for the synthesis of pyrazole (17) is the reaction of -

dikitone (15) with hydrazine (16) or mono substituted hydrazine in the presence of an

acid24

.

(12)

CH3

N

N O

C6H5

(13)

HOOC

HOOC

COOH

COOH N

N H

230°C

(14)

+ 3CO2 N

N H

(15)

C

H2C

O

C

H3C

O

H2C

+ H2N NH2 - H2O N

CH3

H3C N H

(16) (17)

The reaction of methyl hydrazine with acetylacetaldehyde dimethylacetal (18) give

hydrazone (19). This was subsequently cyclized in acidic medium to yield a dimethyl

pyrazole (20) 25

.

Benzoylacetone (21) reacts with phenyl hydrazine to give a monophenyl hydrazone (22).

On heating with acid the phenyl hydrazone is converted into a single product 3-methyl-

1,5-diphenyl pyrazole26-27

. (23)

CH3

(18)

CO CH2

OCH3

OCH3

(19)

N

CH3 C CH

OCH3

CH

OCH3

NH CH3

CH3 NH NH2

CH3

N

(20)

N

CH3

C6H5–CO–CH2–CO–CH3 C6H5–NH–NH2 C6H5 – CO – CH2

C6H5–NH–N

C – CH2 (21)

(22)

CH3

N

(23)

H5C6

H5C6

N

The reaction between -keto ester and hydrazine results in the formation of 5-pyrazolone

(24). Howerver under favoarable experimental conditions a 5-alkoxy pyrazole (25) is

obtained along with pyrazolone28,29

.

Cyclocondensation of cyanoacetamide (27) with sodium salt of 3-hydroxyl-1-(pyridine-

3-yl)-prop-2-en-1-one (26) gave 6-oxo/thiooxo-[2,3] pyridine (28) which on reaction with

iodomethane gave bipyridine, which cyclocondensed with hydrazine to give pyrazolo [3,

4-b] pyridine30

. (29)

R-CO-CH2-COOR + R” NH-NH2 R – C – CH2 – COOR

1

N – NH – R

R1 – OH +

+ H2O

R

R ”

O N

R

(25)

R ”

N

(24)

R1

N N

N

(26)

O

O Na

NH2 H2O

i) Pip. acetate

ii) H+

(27)

EtOH NH2NHR

N N

(29)

NH2

R

+ NC N N

H

X

(28)

CN

N

X

N

The Vilsmeier –Haack reaction of the aryl hydrazones of aryl methyl Ketones is a

convenient method for the preparation of 1, 3- diaryl 4 –formyl pyrazole31

. (30)

Dimethyl-1-aryl (benzyl)-4,5-dioxo-4, 5-dihydro-1H-pyrol -2,3-dicaraboxylates (31)

reacted with phemyl hydrazine and benzyl hydrazine to give dimethyl -1 – aryl (benzyl)-

5-[aryl or benzyl] carbamoyl)-1H-pyrazole-3, 4-dicaraboxylate32

. (32)

The reaction of hydrazine and allene carbonyl compounds gives pyrazoles33

. (33)

CH2 C CH CO R N2H4 +

R N

N

H

CH3

(33)

N N

Me

N

H

N

Me

Me

DMF, POCl3 Me

N

O

N

Me

Me

Me

Me

O

(30)

Me N – N

O

Me

+

N N

Me

(32)

R2

H

NH2

N

+ -H2O

COOMe

CONHR1 N

R1

MeOCO

N

COOMe

COOMe

R1

O

O

(31)

N

Arylhydrazones of aliphatic and aromatic aldehydes condense with - ketoesters in

presence of anydrous zinc chloride at temperature ranging from 120° to 140

°C to yield the

esters of pyrazol-4-carboxylic acids34-35

.

Physical Properties:-

Pyrazole is a colourless solid, with m.p. 69-70°C. The boiling point of pyrazole is 186-

188°C at 757.9mm. It is very stable to heat and can be distilled at atomospheric pressure

without decomposition. Pyrazole shows weak basic properties with a pka value of 2.5336

.

The dipole moment of pyrazole was determined by Huckel and Coworkers,37

found a

value of 2.64D in dioxane and 1.6D ib benzene38

. Pyrazole is soluble in water and much

less soluble in benzene and cyclo haxane. The IR Spectra are generally characterized by

bands at 3485cm-1

(N-H), 1037-974cm-1

(C-H in plane) 935 and 790cm-1

(C-H. out of

plane). The U.V. region of alkyl pyrazole absorb at 210-225nm,. The pyrazole shows a

1H-NMR signal in CDCl

3 at .=13.6ppm. for CN-H-proton. The C-3 and C-5 protons

appear as a doublet (coupling with H-4) at 7.54 ppm, while the C4-proton itself appears as

a triplet at 6.24ppm in carbon tetrachlorides39

.

Chemical Reaction :-

The pyrazole ring is normally very resistant to oxidation only side chains are attacked by

oxidizing agents. Potassium permanganate, is usually in neutral or alkaline medium

converts side chains on any position of the pyrazole ring into carboxylic groups40-41

.

(34)

R

H5C2OOC R1

N

N

Ar

C2H5OOCCH2 CH

CO

R

N +

NH Ar

R1

ZnCl2

CH3

N

N

COOH

N

N

KMnO4

OH-

Nitric acid is a convenient oxidizing agent for converting 4-nitroso-pyrazoles (37) into 4-

intropyrazoles42

. (38)

Nitration of pyrazole with nitrating mixture of concentrated nitric acid and sulfuric acid

occurs at the position-4.

Pyrazoles undergo sulfonation only under vigorous reaction conditions with introduction

of sulfonic acid group at the position-4.

N

O2N

(40)

H

N H

+ HNO3 H2SO4

(39)

N

N

N

ON

H5C6

C6H5

N

N

H

C6H5

N

N

HNO3

(38)

H5C6

O2N

(37)

(H2SO4+SO3)

20% Oleum

R

Prolonged

heating

N

(41)

H

N

R HO3S

R

(42)

H

N

N

R

Halogenation of pyrazole (43) occurs at position-4. Pyrazole can be chlorinated by

chlorination reagent i.e., chlorine in carbon tetrachloride.

Pyrazoles are brominated by bromine in chlaro form give 4- bromo pyrazole. (44)

Pyrazoles are chloromercurated at the position-4 by the reaction with mercury (II)

chloride providing (45).

Cl2 in CCl4 (60ºC)

Cl

N

(43)

H N

N

N H

H N

Br2

(CCl4)

(44)

H N

Br

N

N N

H N

+ HgCl2

(45)

H N

ClHg

N

N N

The reduction of pyrazole with sodium and alcohol or by catalytic hydrogenation over

palladium results in 2-pyrazolines. (46).

3-methyl-carboxy-5-metheyl pyrazole (47) on akylation with dimethyl sulfate yields N-

alkyl-3-methyl-carboxy-5-methyl pyrazole43-44

. (48)

The irradiation of pyrazoles with nucleophilic reagents results in nucleophilic photo

substitution with the replacement of hydrogen atom by nucleophile from the position -4.

If the position-4 is already occupied, the hydrogen atom is substituted from position-545-

46.

H N

Na/C2H5OH

(46)

H N N

N N

or

H2/Pd

(48)

H

N N

N

COOH

H3C H3C

COOH

H

(47)

N

N

(CH3)2 SO4

N

N

R1 NC R1

R R

(50) (49)

N

N

CN

hυ

N

N

CH3 NC

R R

(52) (51)

N

N

NC

CN

hυ

CH3

Biological Activity and its importance :-

Pyrazoles have diverse biological activities such as antimicrobial, anti-bacterial,

antifungal, anti-inflammatory, analgesic, anticonvulsant, anti-cancer, antioxidant,

insecticide and herbicidal. Pyrazole derivatives have huge applications in agrochemical

and pharmaceutical industry as herbicides and active pharmaceuticals.

Antimicrobial Agents :-

A series of 4-chloro-2-{4-[(E)-(substituted phenylimino) methyl]-1-pyrazol-3yl}-phenols

(52) have antimicrobial activity against E. coli and S. aureus. and C. albicans47

.

Vertika Gautam et.al. synthesized 1-(4-Azidophenyl)-5-(4-chlorophenyl)-3-methyl-1H-

Pyrazoles (53) have been reported as antimicrobial agents48

.

CH3

N

C6H4Cl

N=N+=N-

N

R = C6H5,C6H4NO2

(52)

OH

HC = N–R

Cl

N NH

1-phenyl-3-(3a,6,7-trimethyl-3a,4,5,6,7-7a-hexa-hydro-1H-inden-3-yl)-1H-pyrazole (54)

have been reported as antimicrobial agents49

.

1-carbonamidipyrazolo [3,4-b] quinolines (55) were reported as antimicrobial agents50

.

Abdel-Rahman et.al. synthesized a series of pyrazole i.e., 5-(1-benzyl-1H-indol-3-yl)-2,

4-dihydro-3H-pyrazole-3-thione (56) have antimicrobial activities against S. aureus and

A. parasiticus51

.

(55)

N H

O

N

N

N

(54)

CH3

H3C

CH3

N

N

S maail Radi et.al., synthesized a series of pyrazole (57) derivatives, were evaluated for

their antimicrobial activity against E. coli and Fusarium oxysproum52

.

A series of 4,6-disubstituted-3-cyano-2-pyridones derivatives are reported antimicrobial

agents53

.

R=CH3, CO2Et

(57)

N

X OH

R

N H3C

(56)

N

S

N

N H

R= Thienyl

R1= H, 4-F, 4-Cl, etc.

R1

H N N

R O

N

N H

(58)

The compound 2-(( 1,3-Diphenyl-1H-pyrazol-4-yl) methylone)-5-5-dimethyl

cyclohexane-1, 3-dione (59) shows antimicrobial activity against A. niger, A. flavus and

E. coli and B. subtilis54

.

The compound 3 - [3 - (5-bromo-1-benzofuran-2-yl) -1H-pyrazole - 4 – yl] -1-

(substituted phenyl) prop-2-en-1-ones (60) have antimicrobial activity against. S.

epidermidis B. subtitis and. A. niger, C. albicans55

.

Ar = C6H5, OCH3C6H4 O

(60)

N NH

Br

HC=CH-C-Ar

O

(59)

O

O

C6H5

Me

X Me

N X = H

N

A series of 6/8 substituted –1N-(amido/thiocarboxamido) pyrazolo[4,5-b] quinolines

have been reported as antimicrobial agents56

.

Samir Bondock et.al., synthesized a series of substituted pyrazole derivatiues, exhibited

antimicrobial activity57

. The compound 2-(5-(4-hydroxyphenyl)-3-phenyl-4,5-

dihydropyrazol-1-yl)-N-(4-phenylthiazol-2-yl) acetamide have been reported as

antimicrobial agents58

. A series of arylazopyrazoles derivatives have been reported as

antimicrobial agents against S. aureus, E. coli and C. albican, A. niger59

. A series of

pyrazole derivatives bearing quinoline derivatives showed antimicrobial activity60

.

Ujjwall sahoo et.al., synthesized a series of bipyrazole derivatives, there derivatives have

antimicrobial activity against. E.coli, C. albicans and A. niger61

. A series of sulphur

bridged pyrazole derivatives have been reported as antimicrobial agents62

. A series of 3-

methyl-4-phenyl-5(p-substituted phenyl)-1-(p-sulphamyl-phenyl) pyrazoles have

antimicrobial activity against E. coli and C. albicans63

. The compound 4-arylazo-1-

benzothiazolyl-3,5-dimethyl pyrazoles were showed antimicrobial activity64

.

Antibacterial Agents :-

A series of 4-aryl-5-hydroxypyrazoles (61) have been reported as antibacterial agents65

.

The compound 6-Amino-3-methyl-1-phenyl-1H-pyrazolo-[3,4-b] pyridine-5-

carboxamide (62) have been reported as anti bacterial agents66

.

(61)

CH3

OH

R2

N

N

R1

CONH2

N

N

Me

A series of substituted ethyl 4-amino-1-(3-substituted-4-fluorophenyl)-5-cyano-1H-

pyrazole-3-carboxylate (63) have anti bacterial activity against S. aureus and E. colis67

.

A series of 1-(furan-2-carbonyl)-3-methyl-4-(2-phenyl hydrazono)-1H-pyrazol-5(4H)-

one have been reported as anti bacterial agents68

.

A series of N-substituted 3-benzyl-5-phenyl pyrazole (64) have antibacterial activity

against B. subtilis and B. aureus69

.

(63)

H2N COOC2H5

NC

N

R

N

F

CH2

CH3

CO

N

N

The compounds 1(unsubstituted/substituted)-3,5-dimethyl-1H-pyarazoles (65) have been

reported as anti bacterial agents70

.

Vijay V. Dabholkar et.al., synthesized a series of pyrazole derivatives as antibacterial

agents71

. A series of [CN-cinnamoyl)-2,3-dichloroanilinomalonyl] 3, 5-dimethyl-4-

(unsubstituted/substituted phenylazo) pyrazole derivatives have been reported as

antibacterial agents72

. A series of pyrazole derivatives have been reported as antibacterial

agents73

. A series of 5-amido-1-(2,4-dinitrophenyl)-1H-4-pyrazole carbonitriles exhibited

anti bacterial activity against S. aureus74

. The compound 1, 1-methyl enedipyrazole

(AM1), showed antibacterial activity75

.

Antifungal Agents :-

Radhakrishnan Sridhar et.al., synthesized a series of 1-Hpyrazole derivatives (66) showed

antifungal activity against Rhizochonia solani, F. oxysperum76

.

CH3

R

H3C

R=H, CH3 C6H5

(65)

N

N

CH3 (NO2)2

CHO

C2H5O2C

(66)

N

N

The compound 3-(2-hydroxyphenyl)-5-(4-chloro-styryl)-1H-pyrazoles have been

reported as antifungal agents77

.

A series of pyrazolyl-2, 4-thiazolidinediones have been reported as antifungal agents78

.

Antiinflammatory Agents :-

A series of 2,3- dimethyl-1-(substituted phenyl) pyrazol-5-ones showed anti-

inflammatory activity79

. The compound 1-(1,5-diphenyl-4, 5-dihydro-1H-pyrazol-3-yl)-5-

phenyl-1H-tatrazole have been reported as anti-inflammatory agent80

. The compound 5-

[(3-anilino-5-phenyl-1H-pyrazol-1-yl) carbonyl] cyclohexane-3, 5-diene-1, 2,3 triol,

showed anti-inflammatory activity81

. Flora F. Barsoum et.al., synthesized bis (3-aryl-4, 5-

dihydro-1H-pyrazol-thio carboxamide derivative have anti-inflammatory activity82

.

A series of thiazolyl and thiadiazolyl derivatives of 1H-pyrazole showed significant anti-

inflammatory activity83

. A series of pyrazole derivatives have been reported as anti-

inflammatory agents84

. A series of pyrazole incorporated 1, 2-diazonaphthalene

derivatives have been reported as anti-inflammatory agents85

. 1-acetyl/propanoyl-5-aryl-

3-(4-morpholinophenyl)-4, 5-dihydro-1H-pyrazole derivatives have anti-inflammatory

activity86

. A series of pyrazole derivatives containing benzene sulfonamides, 1, 3, 4-

oxadiazole-2-thiones have been reported as anti-inflammatory agents87

.

Anticonvulsant Agents :-

3-(4-Aminophenyl)-5-(4-chlorophenyl)-4, 5-dihydro-pyrazole-1-carbothioic acid amide

(67) have anti convulsant activity88

.

R2

N

N

R1

R1 = 4 – amino

R2 = 4 - chloro

1-[(4,5-dihydro-5-phenyl-3-(phenylamino)pyrazol-1-yl)ethanone derivatives have been

reported as anti convulsant agents89

. A series of 3, 5-dimethyl pyrazole derivatives have

anticonvulsant activity90

. 1-(unsubstituted/substituted)-3, 5-dimethyl-1H-pyrazole

derivatives have anti convulsant activity91

. A series of 3-[3-substituted phenyl)-1-

isonicotinoyl-1H-pyrazole-5-yl]-2H-Chromen-2-one derivative have anti-convulsant

activity92

.

H2N S

(67)

Analgesic Activity :-

2-{3-[(4-hydroxyphenyl) amino]-4,5-dihydro-1H-pyrazol-5-yl}phenol (68) have

analgesic activity93

.

A series of (4Z)-3-methyl-1-[2-oxo-2H-chromen-4-yl) carbonyl]-1H-pyrazol-4, 5-dione,

4-[(4-substituted phenyl)hydrazone] have analgesic activity94

.

A series of 1, 2, 4-triozole derivatives containing pyrazole ring have analgesic activity95

.

Anticancer Agents :-

N-1,3-triphenyl-1H-pyrazole-4-carboxamide derivatives showed anti cancer activity96

. 5-

benzyl-2-phenyl-pyrazolo [1,5-a] pyrazin-4, 6- (5H, 7H)-dione showed anticancer

activity97

. A series of polysubstituted fused heterocyclic ring viz pyrano [4, 3c] pyrazoles

and pyrazolo [4, 3-c] pyridines have been reported as anticancer agents98

. The compound

5-[1-aryl)-5-phenyl-1H-pyrazol-3-yl]-4-phenyl-2, 4-dihydro [1,2,4] triazole -3-thione

derivatives have anti cancer activities against breast carcinoma (MCF7) 99

. A series of

pyrazole and pyrazoline derivatives have anti cancer activity100

. 2-[3-(2-chlorophenyl)-

1Hpyrazol-5-yl]-1H-benzimidazole have been reported as anti cancer agents101

.

Xiao Hong Wang et. al., synthesized a series of pyrazole derivatives having anticancer

activity102

.

Antiviral Agents :-

A series of substituted pyrazole derivatives (69) have promising antiviral activity against

hepatitis A virus103

.

OH

NH

N

N H

(68)

OH

A series of 4, 5-disubstituted pyrazole derivatives have anti-viral activity104

.

Pyrazole compound BPR1P0034 have potent anti-influenza virus activity105

.

Antitumor Agents :-

3-(4-chlorophenyl)-4-substituted pyrazoles (70) have antitubercular activity against

Mycobacterium tuberculosis H37 Rv Strain106

.

The compound 1, 5-dimethyl-2-phenyl-4-([5-(arylamino)-1, 3,4-oxadiazol-2-yl]-methyl-

1,2-dihydro-3H-pyrazol-3-one have been reported as antitubercular agents107

. N-phenyl

acctyl (sulfonyl) 4, 5-dihydro-pyrazole derivatives have been reported as potential

antitumor agents108

. A series of (6-substituted-pyrazolo[3, 4-b] quinolin-1-yl)-(4-pyrrol-

1-yl-phenyl) methanones were reported as antitubercular agents109

. Peng-cheng LV et.al.,

synthesized a series of pyrazole derivative, having antiproliferative activity110

. A series of

trisubstituted pyrazole derivatives have been reported as antitumor agents111

. 3, 4-

disubstituted pyrazole derivatives have antitumor activity112

.

R1=CN

R2= NH2, COOEt

R

R2

R1

(69)

N

N

N NH

O N H

Cl

N

(70)

Mislleaneous Activities :-

Pyrazole as antimalarial agents :-

The compound 3-phenyl-1-(p-tolyl)-1H-pyrazole-4-carboxaldehy-e have antimalarial

activity113

.

Antihelmintic Agent :-

A series of pyrazole derivatives have been reported as antihelmintic agents114

.

Anti-oxidant Agents :-

The compound 5-methyl-5-(trifluromethyl)-4,5-dihydro-1 H-pyrazole-1-carboxamide

(72) have been reported as antioxidant agents115

.

Herbicidal & Insecticidal agents :-

The compound methyl 4-chloro-1-(2, 5-difluorophenyl)-5-(4-fluorophenyl)-pyrazole-3-

carboxylate have herbicidal activity116

.

H

O

R

N

N

(71)

H2N O

(72)

HC3

F F

F

N

N

5-amino-1-)5-chloropyridine-2-yl)-1H-pyrazole-4-carboxyl amino acids have been

reported as potent insecticidal agents117

.

The compound 3-(2-hydroxy-3, 5-dichlorophenyl)-4-benzoyl-5-butyl-1-phenyl pyrazole

have been reported, to effect the flowering plants118

.

Other activities of pyrazole derivatives :-

Benzofuran based 1, 3, 5-substituted pyrazole have been reported as anti oxidant and

antimicrobial agents119

. 4-alkynyl pyrazoles showed is inhibitors of PDE4120

. 5-(2, 3-

dihydro-1,4-benzodioxane-6-yl)-3-substituted-phenyl-4, 5-dihydro-1H-pyrazole

derivatives have been reported as anti-hepatotoxic agents121

.

1-aryl-4-(4, 5-dihydro-1H-imidazol-2-yl)-1H-pyrazole have been reported as

antileishmanial active compounds122

. 4-5-dihydro-1, 5-diaryl-1H-pyrazole-3-substituted-

heteroazole derivative have anti-inflammatory activity123

. 4-amino methylidine

derivatives of pyrazo1-5-ones have anti cancer activity124

. A series of (cyano-NNO-

azoxy)pyrazole derivatives have anti-fungal activity125

. A series of Novel pyrazolyl

chalcones and pyrazolines have been reported as antimicrobial agents126

. A series of

fluorinated pyrazoline have been reported as antifungal and antitubercular agents127

. A

series of pyrazole derivative have ACE-inhibitory activity128

. A series of pyrazolone

derivatives have anti-inflammatory and analgesic agents129

. 1-substituted-3-aryl-5-aryl

(hetaryl)-2-pyrazolines have been reported as antitumor agents130

. A series of pyrazolone

derivatives have been reported as antimicrobial agents131

. The compounds 2-

Benzylthiopyrimidinyl-4-pyrazolone have been reported as antimicrobial agents132

.

3.2 Experimental :-

All melting points of the compounds were determined in open capillary tubes and are

uncorrected. The I. R. spectra were recorded on a Perkin –Elmor-720 Spectrophotometer.

The 1H-NMR spectra were recorded in CDCl3/DMSO-ds on Varian A-60D

spectrophotometer. The chemical shifts are recorded in ppm downfield from TMS

which was used as on internal standard. The elemental analysis of C, H and N were

carried out by Coleman-carbon, hydrogen and nitrogen analyzers.

Synthesis of Starting Materials :-

3.2.1- Synthesis of 2-(2, 4-dinitrophenyl)-5-methyl-2, 4-dihydro-3H-pyrazol-3-ones.

(1)

13g (0.1mole) ethyl aceto acetate in 20-30ml. of 95% ethanol was placed in a 100ml.

round bottom flask equipped with a reflux condenser. To this 19.8g (0.1mole) of 2, 4-

dinitrophenyl hydrazine in 20-30ml. of 95% ethanol was added. The reaction was strated

immediately with evolution of heat. It was refluxed for an additional one hour. The 2-(2,

4-dintrophenyl)-5-methyl-2, 4-dihydro-3H-pyrazol-3-one were separated in the reaction

mixture, filtered and washed with a little 95% ethanol (20ml) and recrystallised from

95% ethanol. Yield (66%). This was prepared by reported known methods133-134

.

3.2.2 Synthesis of 4-Arylmethylene-2, 4-dihydro-2-(2, 4-dinitrophenyl)-5-methyl-3H-

pyrazol-3-ones (2):-

General Procedure :-

A mixture of 2-(2, 4 dinitrophenyl)-5-methyl-2,4-dihydro-3H-pyrozol-3-one 3.25g

(0.01mole), (0.01mole) of appropriate aromatic aldehyde and 0.7gm (0.01mole) sodium

acetate were dissolved in glacial acetic acid (15ml) into a beaker. The reaction mixture

was heated for 15 minutes on a sand bath and left overnight at room temperature. The

compound 4-Aryl methylene-2, 4-dihydro-2-(2, 4-dinitrophenyl)-5-methyl-3H-pyrazol-3-

ones were separated out as coloured crystals, fietered dried and recrystallised from

benzene. The physical and analytical data of compounds (2) were recorded in Table-1

3.2.3 Synthesis of 1-(2, 4-dintrophenyl)-3-methyl-1-substituted phenyl-6-

imino/phenylimino -4, 7-dihydropyrazolo-[5, 4-d]-1, 3-thiazines. (3):-

General Procedure :-

(0.01mole) of compound (2), (0.01mole) thiourea/phenyl thiourea and (0.02mole) KOH

was taken in a round bottom flask and refluxed in methanol (30ml) for 4-5 hrs. cooled the

reaction mixture at room temperature, and it was acidified with dil hydrochloric acid. The

reaction mixture was diluted by adding (20-30ml) water to get solid materials. The solid

material was filtered dried from methanol this 1-(2, 4-dinitrophenyl)-3-methyl-

4substituted phenyl-6-imino/phenylimino-4, 7-dihydropyrazolo-[5, 4-d]-1, 3, thiazines

(3) was prepared. The similar procedure was adopted in the preparation of the following

particular compounds, viz.

3a. 1-(2, 4-dinitrophenyl)-3-methyl-4-phenyl-6-imino-4, 7-dihydropyrazolo-[5, 4-d]-1, 3

thiazine.

3b. 1-(2, 4-dinitrophenyl)-3-methyl-4-(4-nitrophenyl)-6-imino-4, 7 dihydrpyrazolo-[5, 4-

d]-1, 3-thiazine.

3c. 1-(2, 4-dinitrophenyl)-3-methyl-4-(4-N, N-dimethyl aminophenyl)-6-imino-4, 7-

dihydropyrazolo-[5, 4-d]-1, 3-thiazine.

3d. 1-(2, 4-dintrophenyl)-3-methyl-4-(4-methoxy phenyl)-6-imino-4, 7-dihydropyrazolo-

[5, 4-d]-1, 3-thiazine.

3e. 1-(2, 4-dinitrophenyl)-3-methyl-4-(4-chlorophenyl)-6-imino-4, 7-dihydropyrazolo-[5,

4-d]-1, 3-thiazine.

3f. 1-(2, 4-dinitrophenyl)-3-methyl-4-(4-hydroxyphenyl)-6-imino-4, 7-dihydropyrazolo-

[5, 4-d]-1, 3-thiazine.

3g. 1-(2, 4-dinitrophenyl)-3-methyl-4-phenyl-6-phenylimino-4, 7-dihydropyrazolo-[5, 4-

d]-1,3-thiazine.

3h. 1-(2, 4-dinitropyenyl)-3-methyl-4(4-nitrophenyl)-6-phenylimino-4, 7-

dihydropyrazolo-[5, 4-d]-1,3-thiazine.

3i. 1-(2, 4-dinitrophenyl)-3-methyl-4-(4-N, N-dimethylaminophenyl)-6-phenylimino-4,

7-dihydro-pyrazolo-[5, 4-d]-1,3-thiazine.

3j. 1-(2, 4-dinitrophenyl)-3-methyl-4-(4-methoxyphenyl)-6-phenylimino-4, 7-

dihydropyrazolo-[5, 4-d]-1,3-thiazine.

3k. 1-(2, 4-dinitrophenyl)-3-methyl-4-(4-chlorophenyl)-6-phenylimino-4, 7-dihydro

pyrazolo-[5, 4-d]-1,3-thiazine.

3l. 1-(2, 4-dinitrophenyl)-3-methyl-4(4-hydroxy-phenyl)-6-phenylimino-4, 7-dihydro

pyrazolo-[5, 4-d]-1,3-thiazine.

The physical and analytical data are given in Table-2 and the spectral data are recorded in

Table-3.

Table-1

4- Arylmethylene-2, 4-dihydro-2(2, 4-dinitrophenyl)-5-methyl-3Hpyrazol-3-ones (2)

Comp. No R1 Molecular

Formula m.p. (°C) Yield (%)

Elemental Analysis (%)

C H N

2a H C17H12N4O5 202 60 57.95

(58.01)

3.40

(3.44)

15.90

(15.80)

2b p-NO2 C17H11N5O7 234 62 52.71

(52.88)

2.84

(2.90)

18.08

(18.00)

2c p-N(Me)2 C19H17N5O5 225 64 56.54

(56.34)

3.66

(3.70)

14.65

(14.50)

2d p-OMe C18H14N4O6 230 69 57.72

(58.01)

4.30

(4.22)

17.72

(17.94)

2e p-Cl C17H11N4O5Cl 252 61 52.84

(53.20)

2.84

(3.02)

14.50

(14.80)

2f p-OH C17H12N4O6 260 70 55.43

(55.33)

3.26

(3.45)

15.21

(15.07)

N

CH3

NO2

O N

CH

R1

O2N

Table-2

1- (2,4-dinitrophenyl)-3-methyl-4-substituted phenyl-6imino/phenylimino-4, 7-

dihydropyrazolo-[5, 4-d]-1, 3-thiazine (3)

Comp.

No R R1

Molecular

Formula

m.p.

(°C)

Yield

(%)

Elemental Analysis (%)

C H N

3a H H C18H14N6SO4 240 54 52.68

(52.56)

3.41

(3.50)

20.48

(20.22)

3b H p-NO2 C18H13N7SO6 264 62 47.47

(47.60)

2.85

(2.80)

21.53

(21.77)

3c H p-N(Me)2 C20H19N7SO4 254 71 52.98

(53.00)

4.19

(4.22)

21.66

(21.84)

3d H p-OMe C19H16N6SO5 251 67 51.81

(52.04)

3.63

(3.77)

19.09

(18.88)

3e H p-Cl C18H13N6SO4Cl 272 65 48.64

(48.20)

2.92

(3.10)

18.91

(18.92)

3f H p-OH C18H14N6SO5 280 70 50.70

(51.00)

3.28

(3.18)

19.71

(19.44)

3g C6H5 H C24H18N6SO4 264 57 59.25

(59.60)

3.70

(3.88)

17.28

(17.10)

3h C6H5 p-NO2 C24H17N7SO6 223 60 54.23

(54.11)

3.20

(3.44)

18.45

(18.65)

3i C6H5 p-N(Me)2 C26H23N7SO4 270 69 58.97

(59.10)

4.34

(4.64)

18.52

(18.64)

3j C6H5 p-OMe C25H20N6SO5 230 62 58.13

(58.43)

3.87

(4.01)

16.27

(16.45)

3k C6H5 p-Cl C24H17N6SO4Cl 282 67 55.38 3.26 16.15

N

NO2

N O2N

N

CH3

NO2

N NR

R1

O2N

S

H

N

(55.49) (3.28) (15.90)

3l C6H5 p-OH C24H18N6SO5 288 70 57.37

(57.56)

3.58

(3.60)

16.73

(16.64)

Table-3

1-(2,4-dinitrophenyl)-3-methyl-4-substituted phenyl-6-imino/phenylimino/-4, 7-

dihydro pyrazolo-[5, 4-d]-1, 3-thiazine (3)

Comp.

No R R1

I.R. (KBr.) υmax

cm-1

1H-NMR (CDCl3 (ppm)

3a H H 3595 (NH),

3384 (=NH),1580 (C=N)

1.9(3H,s,CH3), 3.8 (1H,s,S-CH), 6.4-7.2

(8H,m,Ar-H) 9.0 (2H,s,NH is D2Oexchangeable)

3b H p-NO2

3591 (NH),

3385 (=NH),

1574s (C=N)

1.9(3H,s,CH3), 3.6 (1H,s,S-CH), 6.2-7.0

(7H,m,Ar-H) 9.2 (2H,s,NH is D2O exchangeable)

3c H p-N(Me)2

3590 (NH),

3401 (=NH),

1575s (C=N)

2.(3H,s,CH3), 2.9 (6H, S NM2) 3.7 (1H,s,S-CH),

6.1-7.0 (7H,m,Ar-H) 9.2 (2H,s,NH is D2O

exchangeable)

3d H p-OMe

3599 (NH),

3390 (=NH),

1575s (C=N)

2.1(3H,s,CH3), 3.6 (1H,s,S-CH), 3.8 (3H, s,

OCH3), 6.2-7.2 (7H,m,Ar-H) 9.2 (2H,s,NH is

D2O exchangeable)

3e H p-Cl 3585 (NH),

3399 (=NH),1579 (C=N)

2.1 (3H,s,CH3), 3.8 (1H,s,S-CH), 6.8-7.1

(7H,m,Ar-H) 9.1 (2H,s,NH is D2O exchangeable)

3f H p-OH

3580 (-OH),

3590 (NH),3395 (=NH),

1579 (C=N)

2.0 (3H,s,CH3), 3.9 (1H,s,S-CH), 6.6 (1H, s, OH)

6.3-7.3 (7H,m,Ar-H) 9.2 (2H,s,NH is D2O

exchangeable)

3g C6H5 H

3580 (NH),

3401 (=NPh),

1579s (C=N)

1.8 (3H,s,CH3), 3.8 (1H,s,S-CH), 6.2-6.9

(13H,m,Ar-H) 8.9 (1H,s,NH is D2O exchangeable)

O2N

N

NO2

N

N

CH3

NO2

N NR

R1

S

H

N

3h C6H5 p-NO2

3586 (NH),

3411 (=Nph),

1577s (C=N)

2.0 (3H,s,CH3), 3.7 (1H,s,S-CH), 6.3-7.2

(12H,m,Ar-H) 9.1 (1H,s,NH is D2O exchangeable)

3i C6H5 p-N (Me)2

3589 (NH),

3410 (=NPh),

1575s (C=N)

2.0 (3H,s,CH3), 2.8 (6H,s,NMe2), 3.8 (1H,s, S-

CH), 6.2-7.1 (12H,m,Ar-H) 8.9 (1H,s,NH is D2O

exchangeable)

3j C6H5 p-OMe

3587 (NH),

3390 (=NPh),

1581s (C=N)

1.9 (3H,s,CH3), 3.7 (1H,s,S-CH), 4.1 (3H, s,

OCH3) 6.1-7.2 (12H,m,Ar-H) 9.2 (2H,s,NH is

D2O exchangeable)

3k C6H5 p-Cl

3575 (NH),

3392 (=NPh),

1576s (C=N)

2.0 (3H,s,CH3), 4.1 (1H,s,S-CH), 6.8-7.5

(12H,m,Ar-H) 9.0 (1H,s,NH is D2O exchangeable)

3l C6H5 p-OH

3580 (NH),

3590 (NH),3392 (=NPh),

1577(C=N)

2.1 (3H,s,CH3), 3.9 (1H,s,S-CH), 6.8 (1H, s,OH)

6.5-7.0 (12H,m,Ar-H) 9.0 (1H,s,NH is D2O

exchangeable)

3.3.1 Condensation Reaction :-

2, 4-dinitrophenyl condense with Ethyl acetoacetate in methanol to give 2-(2, 4-

dinitrophenyl)-5-methyl-2,4-dihydro-3H-pyrazol-3-ones(1).The condensation refeation of

2-(2, 4-dinitrophenyl-5-methyl-2, 4-dihydro -3H-pyrazol-3-ones with different aromatic

aldehydes in the presence of acidic media to give 4-arylmethylene -2, 4-dihydro-2-(2, 4-

dinitrophenyl)-5-methyl-3H-pyrazol-3-ones (2). The compound (2) reacts with

thiourea/phenyl thiourea and KOH in the presence of methanol to give corresponding 1-

(2, 4-dinitrophenyl)-3-methyl-4-substituted phenyl-6-imino/phenyl imino -4, 7-dihydro

pyrazolo-[5, 4-d]-1, 3-thiazines (3). (Scheme - 3)

CH3

O2N

NO2

O

CH

R1

CHO

R1

CH3COONa/gl. AcOH KOH/MeOH

(2)

H2N – C – NR

S

N

N

O2N

NO2

+ O C

NO2

O2N NH – NH2

CH3

CH

2

CH

2

C2H5

O

(1)

N

CH3

O

N

N

N

CH3

O2N

NO2

(3)

R1

H

N

NR

S

(Scheme – 3)

Compound No. R R1

3a H H

3b H p-NO2

3c H p-N-(Me)2

3d H p-OMe

3e H p-Cl

3f H p-OH

3g C6H5 H

3h C6H5 p-NO2

3i C6H5 p-N-(Me)2

3j C6H5 p-OMe

3k C6H5 p-Cl

3l C6H5 p-OH

The mechanism of the condensation reaction is well known.

3.3.2 1-(2, 4-dinitrophenyl)-3-methyl-4-phenyl-6-imino-4, 7-dihydro-[5, 4-d]-1, 3-

thiazine (3a) :-

1-(2, 4-dinitrophenyl)-3-methyl-4-phenyl-6-imino-4, 7-dihydro-[5, 4-d]-1, 3-thiazine was

synthesized by the reaction of 4-phenylmethylene-2, 4-dihydro-2-(2,4- dinitrophenyl)-5-

N

N

CH3

O2N

NO2

(3a)

H

N

NH

S

methyl-3H-pyrazol-3-ones and thiourea is the presence of KOH and methanol. The

molecular formula of the compound (3a) is C18H14N6SO4, and the elemental analysis of

the compound (3a) correspond to the molecular formula. The IR (KBr, max, cm-1) of the

compound (3a) shows 3595 (NH), 3384 (=NH), and 1580 (C=N). The 1H-NMR of the

compound (3a) shows ppm. 1.9 (3H, s, CH3), 3.8 (1H,s, S-CH), 6.4-7.2 (8H,m, Ar-H)

and 9.0 (1H, s, NH).

3.3.3 1-(2,4-dinitrophenyl)-3-methyl-4-(4-nitrophenyl)-6-imino-4,7-

dihydropyrazolo -[5, 4-d]-1, 3, thiazine (3b) :-

1-(2, 4-dinitrophenyl)-3-methyl-4-(4-nitrophenyl)-6-imino-4, 7-dihydropyraz-olo-[5, 4-

d]-1, 3-thiazine was synthesized by the reaction of 4-(4-nitrophenyl)-methylene-2, 4-

dihydro-3H-pyrazol-3H-ones and thiourea in the presence of KOH/methanol. The

molecular formula of the compound (3b) is C18H13N7SO6, and the elemental analysis of

the compound (3b) correspond to the molecular formula. The IR (KBr, max, cm-1) of

the compound (3b) shows 3591 (NH), 3385 (=NH), and 1574 (C=N). The 1H-NMR of the

compound (3b) shows 1.9 (3H, s, CH3), 3.6 (1H,s, S-CH), 6.2-7.0 (7H,m, Ar-H) and 9.2

(1H, s, NH).

3.3.4 1-(2, 4-dinitrophenyl)-3-methyl-4-(4-N, N-dimethyl aminophenyl)-6-imino-4, 7-

dihydropyrazolo-[5, 4-d]-1, 3, thiazine (3c) :-

N

N

O2N

NO2

(3b)

H

N

NH

S

NO2

CH3

1-(2,4-dinitrophenyl)-3-methyl-4-(4-N, N-dimethyl aminophenyl)-6-imino-4, 7-

dihydropyrazolo-[5, 4-d]-1, 3-thiazine was synthesiged by the reaction of 4-(4-N, N-

dimethyl aminophenyl)-methylene-2, 4-dihydro-3H-pyrazol-3-one and thiourea in the

presence of KOH/methanol. The molecular formula of the compound (3c) is

C20H19N7SO4, and the elemental analysis of the compound (3c) correspond to the

molecular formula. The IR (KBr, max, cm-1) of the compound (3c) shows 3590 (NH),

3401 (=NH), and 1575 (C=N). The 1H-NMR of the compound (3c) shows 2.0 (3H, s,

CH3), 2.9 (6H,s,NMe2) 3.7 (1H,s, S-CH), 6.1-7.0 (7H,m, Ar-H) and 9.2 (2H,s, NH).

3.3.5 1-(2, 4-dinitrophenyl)-3-methyl-4-(4-methoxyphenyl)-6-imino-4,7-

dihydropyrazolo-[5, 4-d]-1, 3, thiazine (3d) :-

CH3

NH N

N

O2N

NO2

(3d)

H

N

S

OMe

N – (Me)2

N

CH3

O2N

NO2

(3c)

H

N

S N

NH

1-(2,4-dinitrophenyl-3-methyl-4-(4-methoxyphenyl)-6-imino-4, 7-dihydropyra-zolo-[5,

4-d]-1, 3-thiazine was synthesized by the reaction of 4-(4-methoxphenyl)methylene-2, 4-

dihydro-2-(2,4-dinitrophenyl)-5-methyl-3H-pyrazol-3-one and thiourea in the presence of

KOH/methanol. The molecular formula of the compound (3d) is C19H16N6SO5. The

elemental analysis of the compound (3d) correspond to the molecular formula. The IR

(KBr, max, cm-1) of the compound (3d) shows 3599 (NH), 3390 (=NH), and 1575

(C=N). The 1H-NMR of the compound (3d) shows ppm 2.1 (3H, s, CH3), 3.6 (1H,s, S-

CH), 3.8(3H,s,OCH3), 6.2-7.2 (7H,m, Ar-H) and 9.2 (2H, s, NH).

3.3.6 1-(2,4-dinitrophenyl)-3-methyl-4-(4-Chlorophenyl)-6-imino-4,7-

dihydropyrazolo-[5, 4-d]-1, 3, thiazine (3e) :-

1-(2, 4-dinitrophenyl)-3-methyl-4-(4-Chlorophenyl)-6-imino-4, 7-dihydropyra-zolo-[5,4-

d]-1,3-thiazine was synthesized by the reaction of 4-(4-chlorophenyl)-methylene-2,4-

dihydro-2-(2,4-dinitrophenyl)-5-methyl-3H-pyra -zol-3-one and thiourea in the presence

of KOH/methanol. The molecular formula of the compound (3e) is C18H13N6SO4Cl. The

elemental analysis of the compound (3e) correspond to the molecular formula. The IR

(KBr, max, cm-1) of the compound (3e) shows 3585 (NH), 3399 (=NH), and 1579

(C=N). The 1H-NMR of the compound (3e) shows ppm 2.1 (3H, s, CH3), 3.8 (1H,s, S-

CH), 6.8-7.1 (7H,m, Ar-H) and 9.1 (2H, s, NH).

Cl

NH N

CH3

O2N

NO2

(3e)

H

N

S N

3.3.7 1-(2, 4-dinitrophenyl)-3-methyl-4-(4-hydroxyphenyl)-6-imino-4, 7-

dihydropyrazolo-[5, 4-d]-1, 3, thiazine (3f) :-

1-(2,4-dinitrophenyl)-3-methyl-4-(4-hydroxyphenyl)-6-imino-4,7-dihydropyra-zolo-[5, 4-

d]-1, 3-thiazine was synthesized by the reaction of 4-(4-hydroxyphenyl)-methylene-2, 4-

dihydro-2-(2,4-dinitrophenyl)-5-methyl-3H-pyrazol-3-one and thiourea in the presence of

KOH/methanol. The molecular formula of the compound (3f) is C18H14N6SO5. The

elemental analysis of the compound (3f) correspond to the molecular formula. The IR

(KBr, max, cm-1) of the compound (3f) shows 3580 (-OH), 3590 (NH), and 3395 (=NH)

1579 (C=N). The 1H-NMR of the compound (3f) shows 2.0 (3H, s, CH3), 3.9 (1H,s, S-

CH), 6.6 (1H,s,OH) 6.3-7.3 (7H,m, Ar-H) and 9.2 (2H, s, NH).

3.3.8 1-(2, 4-dinitrophenyl)-3-methyl-4-phenyl-6-phenylimino-4, 7-dihydro-

pyrazolo-[5, 4-d]-1, 3- thiazine (3g) :-

OH

N

CH3

O2N

NO2

(3f)

H

N

NH

S N

CH3

N O2N

NO2

(3g)

H

N

S N

NC6H5

1-(2, 4-dinitrophenyl)-3-methyl-4-phenyl-6-phenylimino-4, 7-dihydropyrazolo-[5, 4-d]-1,

3-thiazine was synthesized by the reaction of 4-phenylmethylene-2, 4-dihydro-2-(2,4-

dinitrophenyl)-5-methyl-3H-pyrazol-3-one and phenyl thiourea in the presence of

KOH/methanol. The molecular formula of the compound (3g) is C24H18N6SO4. The

elemental analysis of the compound (3g) correspond to the molecular formula. The IR

(KBr, max, cm-1) of the compound (3g) shows 3580 (NH), 3401 (=NPh) and 1579

(C=N). The 1H-NMR of the compound (3g) shows ppm. 1.8 (3H, s, CH3), 3.8 (1H,s, S-

CH), 6.2-6.9 (13H,m, Ar-H) and 8.9 (1H, s, NH).

3.3.9 1-(2, 4-dinitrophenyl)-3-methyl-4(4-nitrophenyl)-6-phenylimino-4, 7-

dihydropyrazolo-[5, 4-d]-1, 3- thiazine (3h) :-

1-(2, 4-dinitrophenyl)-3-methyl-4-(4-nitrophenyl)-6-phenylimino-4, 7-dihydro-pyrazolo-

[5, 4-d]-1, 3-thiazine was synthesized by the reaction of 4-(4-nitrophenyl)methylene-2,4-

dihydro-2-(2,4-dinitrophenyl)-5-methyl-3H- yrazol-3-one and phenyl thiourea in the

presence of KOH/methanol. The molecular formula of the compound (3h) is

C24H17N7SO6. The elemental analysis of the compound (3h) correspond to the molecular

formula. The IR (KBr, max, cm-1) of the compound (3h) shows 3586 (NH), 3411

(=NPh) and 1577 (C=N). The 1H-NMR of the compound (3h) shows ppm. 2.0 (3H, s,

CH3), 3.7 (1H,s, S-CH), 6.3-7.2 (12H,m, Ar-H) and 9.1 (1H, s, NH).

NO2

N

CH3

O2N

NO2

(3h)

H

N

S N

NC6H5

3.3.10 1-(2, 4-dinitrophenyl)-3-methyl-4-(4-N,N-dimethylaminophenyl)-6-

phenylimino-4, 7-dihydropyrazolo-[5, 4-d]-1, 3- thiazine (3i) :-

1-(2,4-dinitrophenyl)-3-methyl-4(4-N,N-dimethylaminophenyl)-6-henylimino-4, 7-

dihydropyrazolo-[5, 4-d]-1, 3-thiazine was synthesized by the reaction of 4-(4-N,N-

dimethylaminophenyl) methylene-2, 4-dihydro-2-(2,4-dinitrophenyl) -5-methyl-3H-

pyrazol-3-one and phenyl thiourea in the presence of KOH/methanol. The molecular

formula of the compound (3i) is C26H23N7SO4. The elemental analysis of the compound

(3i) correspond to the molecular formula. The IR (KBr, max, cm-1) of the compound

(3i) shows 3589 (NH), 3410 (=NPh), 1575 (C=N). The 1H-NMR of the compound (3i)

shows ppm. 2.0 (3H, s, CH3), 2.8 (6H, s, N(NMe)2) 3.8 (1H,s, S-CH), 6.2-7.1 (12H,m,

Ar-H) and 8.9 (1H, s, NH).

3.3.11 1-(2, 4-dinitrophenyl)-3-methyl-4-(4-methoxyphenyl)-6-phenylimino -4, 7-

dihydropyrazolo-[5, 4-d-]-1, 3- thiazine (3j) :-

N

CH3

O2N

NO2

(3i)

H

N

S N

N–C6H5

N Me

Me

N

CH3

O2N

NO2

(3j)

H

N

S N

N – C6H5

OMe

1-(2, 4-dinitrophenyl)-3-methyl-4-(4-methoxyphenyl)-6-phenylimino-4, 7-

dihydropyrazolo-[5, 4-d]-1, 3-thiazine was synthesized by the reaction of 4-(4-

methoxyphenyl) methylene-2, 4-dihydro-2-(2,4-dinitrophenyl)-5-methyl-3H-pyrazol-3-

one and phenyl thiourea in the presence of KOH/methanol. The molecular formula of the

compound (3j) is C25H20N6SO5. The elemental analysis of the compound (3j) correspond

to the molecular formula. The IR (KBr, max, cm-1) of the compound (3j) shows 3587

(NH), 3340 (=NPh), 1581 (C=N). The 1H-NMR of the compound (3j) shows ppm. 1.9

(3H, s, CH3), 3.7 (1H,s, S-CH), 4.1 (3H, s,OCH3) 6.1-7.2 (12H,m, Ar-H) and 9.2 (1H, s,

NH).

3.3.12 1-(2, 4-dinitrophenyl)-3-methyl-4-(4-Chlorophenyl)-6-phenylimino-4, 7-

dihydropyrazolo-[5, 4-d-]-1, 3- thiazine (3k) :-

1-(2, 4-dinitrophenyl)-3-methyl-4-(4-Chlorophenyl)-6-phenylimino-4, 7-

dihydropyrazolo-[5, 4-d]-1, 3-thiazine was synthesized by the reaction of 4-(4-

Chlorophenyl) methylene-2, 4-dihydro-2-(2,4-dinitrophenyl)-5-methyl-3H-pyrazol-3-one

and phenyl thiourea in the presence of KOH/methanol. The molecular formula of the

compound (3k) is C24H17N6SO4Cl. The elemental analysis of the compound (3k)

correspond to the molecular formula. The IR (KBr, max, cm-1) shows 3575 (NH), 3392

N

CH3

O2N

NO2

(3k)

H

N

S N

N – C6H5

Cl

(=NPh), 1576 (C=N). The 1H-NMR of the compound (3k) shows ppm. 2.0 (3H, s,

CH3), 4.1 (1H,s, S-CH), 6.8-7.5 (12H,m, Ar-H) and 9.0 (1H, s, NH).

3.3.13 1-(2, 4-dinitrophenyl)-3-methyl-4-(4-hydroxyphenyl)-6-phenylimino -4, 7-

dihydropyrazolo-[5, 4-d-]-1, 3- thiazine (3l) :-

1-(2, 4-dinitrophenyl)-3-methyl-4-(4-hydroxyphenyl)-6-phenylimino-4, 7-

dihydropyrazolo-[5, 4-d]-1, 3-thiazine was synthesized by the reaction of 4-(4-

hydroxyphenyl)-methylene-2, 4-dihydro-2-(2,4-dinitrophenyl)-5-methyl-3H-pyrazol-3-

one and phenyl thiourea in the presence of KOH/methanol. The molecular formula of the

compound (3l) is C24H18N6SO5. The elemental analysis of the compound (3l) correspond

to the molecular formula. The IR (KBr, max, cm-1) shows 3580 (-OH),3590 (NH), 3392

(=NPh), 1577 (C=N). The 1H-NMR of the compound (3l) shows ppm. 2.1 (3H, s, CH3),

3.9 (1H,s, S-CH), 6.8 (1H,s,OH), 6.5-7.0 (12H,m, Ar-H) and 9.0 (1H, s, NH).

N

CH3

O2N

NO2

(3l)

H

N

S N

N – C6H5

OH

References

1. P.J. Dunn, Org. Process Res. Dev., (2005), 1888.

2. T. D. Penning, L.F. Lee and J.W. Malech, J. Med Chem. 40 (1997). 1347.

3. M.R. Carmona, F. Barth and M. Heaulme, FEB S. Letter 350 (1994), 240.

4. Turan- Zitoun G. Ozdemir A. & Guven K, Arch Pharma, 388 2005, 96.

5. S. P. Sachchar and A. K. Singh, J. Indian chem.. Soc. LXII (1985). 142.

6. Zusholi IM, Sabai AE and Habib N. S., Egypt pharm. Sci. 16, 1975, 407.

7. A. M. Farg, A. S. Maghoub, S. E. Barakat and A. H. Bayomi, Bioorg. & Med,

Chem., 36, 1993 134.

8. Nugent R. A., Marphy M, Schlachter ST, Dunn CJ, Simith JR, et.al., J. Med

Chem., 36 1993, 134.

9. A. Gursoy, S. Demirayak, G. Capan, E. Erol and K. Vural, Euro. J. Med Chem.,

35(3), 2005, 359.

10. Y. Xia, Chaun-Dong Fan, Bauo Xiang Zhau, J. Zhao, Dong-Soo Shin and Jun

Ying Miao, Eur J. Med. Chem, 43 (2008), 2347.

11. Abdel-Aziz M, El-Din A. et.al., Eur. J. Med. Chem, 44 (2009) 3480-3487.

12. Y. Ninomiya, N. Shimma and H. Ishuitasuka, Antiviral Research, 13 (1990), 61.

13. A. Takahasi and S. Yamada, Weed Biol. Manag (13) 2001, 192.

14. Kosuge and Okdeda, J. Biochem. (Japan), 41, 183 (1954).

15. Fowden, Noe, Ridd and White, Proc. Chem, Soc., 1959, 131.

16. Sugimoto, Watanable and Ide, Tetrahedron, 11, 231 (1960).

17. Robert C. Weast, "Hand Book of Chemistry and Physics," 54th ED, CRc. Press,

Inc. 18901 Cranwood Parkway, Cleveland, Ohio, 1977-78, P. C48-C60.

18. C. A. Index Guide, 1972, 76, 677 G.

19. R. H. Wiley and P. Wiley ; "Pyrazolones, Pyrazolidones derivatives" in "The

Chemistry of heterocyclic compound." consultant Ed. A., Weissberger,

Interscience Publishers, New York, 1964, Vol, 20(1).

20. S. Ruhemann and B. A. Morell; J. Chem. Soc., 1892, 61 791.

21. L. Knorr; Ber, 1883, 16, 2597 of ref. No. 3, p.4.

22. L.Knorr; Ber, 238, 137. of ref. No. 3, p. 5.

23. Buchner, Chem. Ber, 22, 2165 (1889).

24. Heterocyclic Chemistry II (five-Member Heterocyclic) by R. R. Gupta, M. Kumar

And V. Gupta, pp. 436-437.

25. Burness, J. Org. Chem., 21, 97 (1956)

26. V. Auwers and Stuhlmann, Chem. Ber, 59, 1043 (1962).

27. Fischer and Biilow, Chem. Ber., 28, 1149 (1895).

28. Balbiano, Gazz. Chem. Ital. 19, 134 (1889).

29. Stolz, Chem. Ber., 28 635 (1895).

30. Mahmoud A. Mohamed*, Published online, 2011 in Wiley Online library (Wiley

online library. com.)

31. S. P. Ivoanin, Chem., Heterocyclic Compounds, 47 (8), 2011, (Russian Original

47, (8), 2011.)

32. P. S. Silaicheva, M. A. Chudinovab, P. A. Slepukhin*, and A. N. Maslivetsab,

Russian J. of Organic Chemistry, 2012, 48 (1), 109-112.

33. Bertrand, Compt. Rend., 245, 2036 (1957).

34. Musante, Gazz. Chem. Ital., 67, 682 (1937).

35. Minunni and Lazzarini and D'Urso, Gazz. Chem. Ital, 55, 502 (1925).

36. Albert, Goldacre and Phillips, J. Chem. soc., 1948, 2240.

37. Huckel, Datow and Simmersbach, Z. Physik. Chem., 186A, 129 (1940).

38. Jensen and Friediger, Kgl. Danske Videnskab. Selskab, Mat. Fys. Medd., 20, (20),

1, (1943).

39. Fowden, Noe, Ridd and White, Proc. Chem. Soc., 1959, 131.

40. Pino. Ann-Chim (Rome), 40, 575 (1950).

41. Knorr, Ann., 279, 217 (1894).

42. Huttel, Buchele and Jochum, Chem. Ber., 88, 1577 (1955).

43. V. Auwers and Bahr, J. Prakt. Chem., (2), 116, 65 (1927).

44. V. Auwers and Breyan, J. Prakt. Chem., 143, 259 (1935).

45. C. Olden of and J. Cornelisse. Recl. Trav. Chem. Pays-Bas 97 35 (1978).

46. P. Bouchet, G. Joncheray, R. Jacquier and J. Elguero, Tetrahedron, 35, 1931

(1979).

47. Raga Basawaraj, Wadikar Gahininath, Neelavati Chillargi, et. al., Indian J.

Heterocyclic Chem., 21, 2011, 151-156.

48. Vertika Gautam, Viney Chawla, Pankaj K. Sonar et.al., E-J. of Chem., 2010, 7,

1190-1195.

49. Rafat M. Mohareb, Hanaa. Y. Hana, Acta Pharm., 2008, 58, 29, 42.

50. Vetrivel Nadaraj and Senniappan Thamarai Selvi, Der Pharm Chemica, 2010, 2,

315-321.

51. Abdel-Rahman A. H. Farghaly., J. Chinese Chem. Soc., 2004, 51, 147-156.

52. Radi S., Salhi S. Radi A, Letters in Drug Design & Discovery, Bentham Science

Publishers Ltd. 7 (2010), 27-30.

53. Shridar Malladia, Arun M Isloarax, Peethambar S. K., Ganesh. B. M., Palusa

Sanath Kumar Goudc. Der Pharma Chemica, 2011 4(1), 43-52.

54. Magda F. Mohamed, Mervat S. Mohamed, Samia A. et.al., Apll. Biochem

Biotechnol (2012) 168: 1153-1162.

55. Vijay Kumar Tirlapur, Y. Rajendra Prasad and Raga Basawaraj. Indian J.

Heterocyclic Chem., 2010, 57-60.

56. Janardhan Nayak, K. S. Girish, M. Babu and Balakrishna Kallvraya*, Indian J.

Heterocyclic Chemistry, 19 (2009) 105-108.

57. Bondock s, Fadaly W. Metwally M. A. (2010), Eur. J. Med. Chem, Letter 10.

58. G. Saravanan, V. Alagarsamy, G. Chanukya, Int. J of Pharm and Bio Sci., 2010, 1,

1-8.

59. R. N. Sharma, K. P. Sharma., S. N. Dixit, Int. J. Chem Tech. Res., 2010, 800-806.

60. Nirav K. Shah, Manis P. Patel and Ranjan G. Patel, Indian. J. Chem, 2009, 48B,

1170-1173.

61. Ujjwal Sahoo, Dhanya B., A. K. Seth, A. K. Sen, S. Kumar. et.al., Int J. of Pharm

Res., 2010, 2, 82-87.

62. Singaravel Mohana b, Sarkkarai Ananthanb, K. R. Murugana, Int. J. Pharm Sci

and Res. 2010, 1, 391-398.

63. Essam M. Sharshira and Nagwa Mohamed M. Hamada, Molecules, 2012, 17,

4962-4971.

64. Mohd. Amir, Sadique A. Javed, Mohd. Zaheen Hassan, Med. Chem. Res. 2011,

DOI 10. 1007/S00044-011-9642-0.

65. Jay A. Cadieuxa*, Zaihuie Zhanga, Marganne Matticeb, et.al., Bioorg & Med.

Chem. Letters, 22 (2012) 90-95.

66. N. Panda1x, s. Karmakar and A. K. Jena, Chemistry of Heterocyclic compounds,

46 (12), 2011 (Russian Original 46(12) 2010).

67. Shivaji B. Bole1*, Nargund L. V. G1, Rama Nargund1, Deveraju K. S2,

Vedamurthy AB3, IJPRD, 2011 3 (6), 161-166.

68. P. J. Shan, B. P. Patel, H. S. Patel, J. of the Uni. of Chem. Tech. & Metallurgy, 47,

3, 2012, 257-262.

69. D. P. Gupta, R. S. Bhadauria, V. Soan, Int. J. Pharm & Applied Sciences. 1(2),

2010, 97-99.

70. K. Anandarajagopal, J. Anbu Jeba Sunilson, et.al., Intr. J. Chemtech. Res., 2(1),

2010, 45-49.

71. Vijay V. Dabholkar and Falsal Y. Ansari, J. Serb. Chem. Soc. 2009; 74, 1219-

1228.

72. Raj Narayan Sharma, K. P. Sharma2 et.al., Der Pharm, Chemica, 2010 2, 38-45.

73. Yuvaraj S, Sunith DK, Ahmed Riyaz et.al., HYGEIA, 1(1), 2009 36-37.

74. Mohd. Rahimizadeh, Mehdi Pardel, Mehdi Bakavoli et. al., World J. Microbiol.

Biotechnol, 2010, 26: 317-321.

75. Simona Lupsor, Florin Aonofriesei, Mircea Lovu, Med Chem. Res. 2011, DIO

10.1007/s00044-011-9839-2.

76. Sridhar R, Perumal P. J et.al., Bio-org. Med. Chem. Lett., 2004, 14, 6035-6040.

77. P. Priyadarsini, B. Ujwala, C. Venkata Rao and V. Madhava Rao, Der Pharmacia

Letter, 2012, 4(4), 1123-1128.

78. Deepak K Aneja, Poonam Lohan, Sanjiv Arora et.al., Org. & Med Chem. Lett.,

2011, 1:15.

79. Shilpa Ailawadi, Jyoti, Mithlesh yadav. et.al., Der pharma, Chemica, 2011, 3, 215-

222.

80. V. H. Bhaskar, P. B. Mohite. J. Of opto electronics and Bio Mat., 2010, 2, 231-

237.

81. S. Arun Kumar, K. Ilango, et.al., E-J. Chem, 2009, 6, 123-128.

82. Barsoum FF, Girgis A. S. Eur J. Med Chem, 2009, 44, 2172-2177.

83. Burguete A. Pontik. E, et.al., Bio.org. & Med. Chem. Lett., 2007, 17, 6439-6443.

84. A. A. Bechit, AMH Ashour, ASY Ghany et.al., Eur. J. Med. Chem. 43, 456:463.

85. Rajiv K. Tonk, Sandhya Bawa, Gita Chawala et.al., African J. Pharm and

Pharmacology 6(6), 2010, 425-433.

86. Omneya M. Khalil, Med Chem. Res. 2011, Spingerlinks.

87. Samir M. El. Mogahazy, Flora F. Barsoum et.al., Medicinal Chemistry Research,

2011, Spingerlinks.

88. Vinayaditya Singh, Argal Ameeta, Vikash Mishra et.al., Int. J. Res. Pharmacy &

Science, 2011, (3)-1, 125-146.

89. Anoop Singh and A. C. Rana, J. Chem. Pharm. Res, 2010, 2(1), 505-511.

90. Bedia Kocyight, Kaymakcloglu, Rezzan Gulhan et.al., Med. Chem. Res., 2011,

607-614.

91. K. Anand arajagopal et.al., Int. J. Chem Tech Res., 2010, 2(1), 45-49.

92. Prashant Aragade, Sadhana Kolhe, et.al., Int. J. Drug Design and Discovery, 3(1),

2012, 688-693.

93. S. K. Sahu, M. Banerjee, A. Samantray, C. Behera et.al., Trop J. Pharm. Res.,

2008,7, 961-968.

94. K. K. Sivakumar et.al., Der Pharmacia Letter, 2010, 2, 211-219.

95. Shantarm Gajanan Khanage' S. Appala Raju et.al., Advanced Pharm. Bulletin,

Oct, 2012. 1-6.

96. Xili Xiang Lu, Mang Xing, Yian-Hui Yang, Ting-Ting Zhao, et.al., Bio.org &

Med Chem. Letter, 22 (2010). 3589-3593.

97. Hong ShuiLu, Yiang-Qian Kong, Qian – Qian Mig. et.al., Bio.org. Med. Chem.

Letter, 22(3), 2010, 1844-1849.

98. Hassan M. Faidallah, Sherif A. F. Rostom et.al., JKAU Sci. 22(1) 2010, 177-191.

99. Waled A. El-Sayed, Eman M. Flefel et.al., Der Pharm Chemica, 2012, 4(1): 23-32.

100. Mohammed S. M. Al-Suadi, Saudi Pharm, J, 2008, 16, 135-145.

101. R. Kalirajan, Leela Rathore, et.al. Indian J. Pharm. Educ. Res 2010, 44, 358 -62.

102. Xiao Hong Wang, Yiao Kum Wang et.al., Chinese J. of Cancer 2010, 29, 980-987.

103. Rashad A. E. Hegab MI, et.al. (2008), Bio.org. Med Chem. 16, 7102-7106.

104. El-Sabbagh OI, Baraka MM. Ibrahim SM. et.al., Eur. J. Med. Chem, 44, 3746-

3735.

105. Shin Ru Shih, Tzu Yun Chu, Gadarla Randheer Reddy et.al., J. Biomedical

Sciecnes. 2010, 17:13.

106. Ravindra B. Pathak, P.T. Chovatia, H. H. Parekh, Bio.org. & Med Chem. Lett.,

22(15), 2012 5129-5133.

107. Mohammed Javed Ahsan, Jeyabalon Govinda Samy, et.al. Bio.org. Med. Chem.

Lett., 22(2), 2012, 969-672.

108. Xinhua Liu, Ban Feng Ruan et.al., Bio.org. & Med. Chem. Lett. 2011, 21(10),

2916-2920.

109. S.D. Joshi, Ashwini Joshi, H.M. Vagdevi et.al., Indian J. Heterocyclic Chem. (19)

2010 221-224.

110. Lu. Pengcheng, Zhu Hai-L, Li Hoan-Qin et.al., Bio.org. Med. Chem. 18, 2010,

4606-4614.

111. Christodouiou M. S., Sandra L, Kasio tis K. M., et.al., Bio.org Med. Chem. Lett.,

2010, 18, 4338-4350.

112. Lin R. Chiu G., Yuy., Connolly PJ, et.al., Bio.org. Med. Chem Lett. 17, 2007,

4557-561.

113. Adnan A. Bekhit. Ariaya Hymete, Henok Asfaw, and Alao El._Din a. Bekhit,

Arch. Pharm. Chem. Life Sci., 2012, 345, 147-154.

114. Sreenivasa G. M., Jayachandran E. Shivakumar, et.al., Arch Pharm. Sci. & Res.

2009, 1, 150-157.

115. J. S. M. Pasin, A. P. O. Ferreria et.al., Braz J. Med Bio Res., 2010. 43, 1193-1202.

116. Noriaki Kudo, Satoru Furuta, Chem Pharm. Bull. 1999, 47, 857-868.

117. K. Jagadeesh Prathap, M. Himaja and Sunil V. Mali, Indian J. Heterocyclic Chem,

19, 2010, 385-388.

118. Jaishree D Mahale, SC Manoja, N. G. Belsare et.al., Indian J. Chem, 49B, 2010,

505-511.

119. Javarappa Rangaswamy, et.al., Bio.org Med Chem. Lett. 22(1) 2012, 4773-4777.

120. Dhilli Rao Gorja, K. Shiva Kumar, Ajit Kandale, et.al., Bio.org Med. Chem.

Letter., 2012, 22(7), 2480-2487.

121. Habibullah Khalilullah, Shamshir Khan et.al. Bio.org Med. Chem., Lett., 21(24)

2011, 7251-7254.

122. Mauricio Sdos Santos, Marina L. V. Oliviira et.al., Bio.org & Med. Chem. Letter.

21(24), 2011, 7451-7454.

123. Deepak V. Dekhane, Shivaji S. Pawar, Sunil Gupta et.al., Bio.org. Med. Chem.

Letter, 21(21), 2011, 6527-6532.

124. Violeta Markovis, Slavica Eric & et.al., Bio.org & Med Chem. Letter, 21(15),

2011, 4416-4421.

125. Donatella Boschi, Stefano Gugliel et.al., Bio.org & Med Chem. Letter 21(10),

2011, 3431-3434.

126. Zeba N. Siddiqui, T. N. Mohammed Musthaya, Anish Ahmad, et.al., 2011, 21(10)

2860-2865.

127. Sharad N. Shelke, Ganesh R. Mhaske, Vasco D. B. Bonifacio et.al., Bio.org. Med.

Chem. Letter., 22(17), 2012, 5727-5730.

128. Bonesi M., Loizzo M.R., Statti G. A. et.al., 2010, Bio.org. Med. Chem. Lett, (20),

1990-1993.

129. G. Marioppan*, B.P. Saha, I. Sutharson & A. Huldeer, Indian J. Chem, 49B, 2010

,1671-1674.

130. Bravlio Instuasty et.al., Arch Pharm. Chem. Life Sci. 2012, 345, 275-286.

131. K. M. Thaker, R.M. Ghetiya, S. D. Tala, B. L. Dodiya, et.al., Indian J. Chem.,

(50B), 2011, 738-744.

132. N. M. Goudgaon, and Sheshkant B.U., Indian, J. Heterocyclic Chem. (21), 2011,

53-56.

133. Daroga Singh and D. Singh, J. Indian Chem. Soc. 68, 165 (1991).

134. H. O. Burrus and G. Powell; J. Am. Chem. Soc., 67, 1468 (1945).