181

CHAPTER-4
Synthesis & Characterization of Highly Substituted 1, 3-Diphenyl Pyrazole Derivatives

182 4.1 INTRODUCTION OF PYRAZOLES AND ITS DERIVATIVES Heteroaromatic compounds have attracted considerable attention in the design of biologically active molecules and advanced organic materials.1 Hence a practical method for the preparation of such compounds is of great interest in synthetic organic chemistry. Pyrazoles and its derivatives, a class of well known nitrogen containing heterocyclic compounds, occupy an important position in medicinal and pesticide chemistry with having a wide range of bioactivities such as

antimicrobial,2 anticonvulsant,5,6

anticancer,3

anti-inflammatory,4 antipyretic,8

antidepressant,5 antibacterial,9

antihyperglycemic,7

antifungal activities,10 CNS regulants,11 and selective enzyme inhibitory activities12. It has been found that these compounds have hypoglycemic activity, and are also known as inhibitors and deactivators of liver alcohol dehydrogenase and oxidoreductases.13 It has been shown in vivo that some of the pyrazole derivatives have appreciable antihypertensive activity.14 These compounds also exhibit properties such as cannabinoid hCB1 and hCB2 receptor, inhibitors of p38 Kinase, CB1 receptor antagonists15,16. As early as in 1884 Knorr discovered the anti-pyretic action of a pyrazole derivative in man, he named the compound antipyrine. This stimulated interest in pyrazole chemistry. Pyrazoles are aromatic dinitrogen heterocyclic compounds. Pyrazoles having two nitrogen atoms i.e. one basic nitrogen and neutral nitrogen the aromatic nature arises

183 from the four electrons and the unshared pair of electrons on the NH nitrogen. Care should be taken in specifying which nitrogen is basic since, in unsymmetrical derivatives resonance prevents one from isolating a specific compound 1. Physical properties Melting point 700C soluble in water almost insoluble in pet ether Boiling point - 1870C The pyrazole ring (1) is present in two different environments in the crystal and averaged molecular dimensions.

(1) The 1-phenylpyrazole motif is present in several drug candidates for treatment of various diseases such as cyclooxygenase-2 (Cox-2)

inhibitors, IL-1 synthesis inhibitors, and protein kinase inhibitors etc. Similarly a few of the 1, 5-diarylpyrazole derivatives have been shown to exhibit non-nucleoside HIV-1 reverse transcriptase inhibitory activities along with Cox-2 inhibitor.17 Several substituted pyrazolo [3, 4-d] pyrimidine derivatives have xanthine oxidase inhibitor activity18, like allopurinol which was first synthesized by Robins in 1956 and is still the drug for the treatment of hyperuricemia and gouty arthritic disease.19

184 The pyrazolo [1, 5-a] pyrimidines e.g. Indiplon (1a) and Zaleplon (1b) and the N, N-dialkyl-2- phenyl acetamido imidazo[1, 2-a]pyridines e.g. Zolpidem (2a) and Alpidem (2b) are also used for the treatment of anxiety sleep disorders, convulsions, and memory deficits.20
O N

N N O N N Indiplon O

S N

N N

N Zaleplon N-(3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl) phenyl)-N-ethylacetamide 1b

N-methyl-N-[3-[3-(thiophene-2-carbonyl) pyrazolo[5,1-b]pyrimidin-7-yl]phenyl]acetamide 1a

N N O N N N Zolpidem N,N,6-trimethyl-2-(4-methylphenyl)imidazo(1,2-a)pyridine-3-acetamide 2a Cl N Alpidem 2-[3-chloro-8-(4-chlorophenyl)-1,7-diazabicyclo[4.3.0] nona-2,4,6,8-tetraen-9-yl]-N,N-dipropyl-acetamide 2b O Cl

Urea derivatives of 5-aminopyrazoles have recently been reported as potent inhibitors of P38 kinase, TNF- production, and cholesterol acyltransferase.21 Curcuminoid pyrazoles are used as new therapeutic agents in inflammatory bowel disease. The activity of the curcuminoid pyrazoles covers domains such as anti-inflammatory (5-lipooxygenase

185 and cyclooxygenase inhibitors), antitumoral (anti-angiogenic) and drugs for the treatment of the alzheimer disease.22 The importance of pyrazole exploited from the appearance of some pesticides in the market in the name of fipronil (Colliotet al., 1992) (3), topramezon (BASF, 2006) (4), pyraelostrobin (BASF, 2001) (5) etc.23
O F S F F N N Fipronil Cl N F O S O N F O O Topramezone [3-(4,5-dihydro-3-isoxazolyl)2-methyl-4-(methylsulfonyl)phenyl] -(5-hydroxy-1 -methyl-1H-pyrazol-4-yl)methanone 4 HO

NH2 Cl F

N N

(5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]4-[(trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile); 3

O O N O N O N Cl

Pyraelestrobin methyl N-(2-{[1-(4-chlorophenyl)-1H-pyrazol-3yl]oxymethyl}phenyl)-N-methoxy carbamate 5

The pyrazole ring is a constituent of a variety of natural and synthetic products. Examples of pyrazole ring containing natural products are (S)3-pyrazolyl alanine (6), pyrazomycine (7), and 4, 5-dihydro- 3-phenyl-6Hpyrrolo [1, 2] pyrazole (8), while lonazolac (9), fezolamin (10), difenamizole (11), and mepirizole (12) are examples of biologically active synthetic pyrazole derivatives.

186

N COOH NH2

OH O

H N CONH2 OH

N N 4,5-Dihydro-3-phenyl-6H-pyrrolo[1,2-b]pyrazole 8

HO

(s)-3-pyrazolylalanine 6

OH Pyrazomycin 7

(CH2)3NMe2 N N COOH C6H4Cl

(CH2)3NMe2 N N Ph Ph Fezolamin 10

MeO O Me H N NMe2 Ph N N Ph N MeO N N N

Me

Lonazolac 9

Difenamizole 11

Me Mepirizole 12

Pyrazoles are usually prepared by condensation between a hydrazine derivative and 1, 3-dicarbonyl compound or by 1, 3-dipolar cycloaddition of diazoalkanes or nitrile imines to olefins or acetylenes.24 Most of the present diseases are due to the invasion by the pathogenic

microorganisms like bacteria, fungi, virus and ricketteseae. To treat the diseases many potent and broad spectrum antibiotics were discovered. Inflammation is the result of concerted participation of a large number of vasoactive, chemostatic and proliferates at different stages. The

mechanism of anti-inflammatory drugs is considered to be inhibition of PG synthesis at the site of injury. The anti-inflammatory potency of different compounds roughly corresponds with their ability to inhibit COX. The present work involves the preparation of some new 1, 3Diphenyl pyrazoles which possess one or the other activity of compound.

187 Substituted amine derivatives have received considerable attention during last two decades as they are endowed with variety of biological activities and have wide range of therapeutic properties. The Literature survey indicates that pyrazole derivatives possess different

pharmacological and biological activities; which of most potent activity are anti-inflammatory and analgesic activity. 4.2 PYRAZOLES AND ITS MEDICINAL PROPERTIES Some of the pyrazole derivatives that are having wide variety of activities. Table-4.1: Pyrazole containing drugs:

S.No Name of the Drug 1 Celecoxib

IUPAC Name

Structure

4-[5-(4-methylphenyl)-3(trifluoromethyl) pyrazol-1yl]benzenesulfonamide

F F N N F

O H2N

13

CDPPB

3-cyano-N-(1,3-diphenyl1H-pyrazol-5-yl) benzamide

N HN O N N

14 3 Lonazolac [3-(4-chlorophenyl)-1phenyl-1H-pyrazol-4yl]acetic acid

Cl O OH

N N

188 15 4 Crizotinib 3-[(1R)-1-(2,6-dichloro-3fluorophenyl)ethoxy]-5-(1piperidin-4-ylpyrazol-4yl)pyridin-2-amine

N N HN Cl N NH2 O Cl F

16 5 Tepoxalin 3-[5-(4-Chlorophenyl)-1-(4methoxyphenyl)pyrazol-3yl]-N-hydroxy-Nmethylpropanamide
HO N O

N N

Cl

17

AS-19

(2S)-N,N-dimethyl-5-(1,3,5trimethylpyrazol-4-yl)1,2,3,4-tetrahydro naphthalene-2-amine 5-(4-bromophenyl)-1-(2,4dichlorophenyl)-4-ethyl-N(1-piperidinyl)-1H-pyrazole3-carboxamide

N N

18 7 Surinabant
Br O N NH N N Cl Cl

19 8 Deracoxib 4-[3-(Difluoromethyl)-5-(3fluoro-4-methoxyphenyl)1H-pyrazole-1-yl] benzenesulfonamide

F O O F F N N O S NH2

20
N N N NH

Mepiprazole

1-(3-chlorophenyl)-4-[2-(5methyl-1H-pyrazol-3yl)ethyl]piperazine
Cl

21

189 10 Tartrazine Trisodium (4E)-5-oxo-1-(4sulfonatophenyl)-4-[(4sulfonatophenyl)hydrazono]3-pyrazolecarboxylate

OO S O

N O

NH O O-

N N

O
-O

22
Cl O N NH N N Cl Cl

11

Rimonabant 5-(4-Chlorophenyl)-1-(2,4dichloro-phenyl)-4-methylN-(piperidin-1-yl)-1Hpyrazole-3-carboxamide

23 Pyrazole derivative as anti-diabetic:

Froesch E.E et.al.25 has reported anti-diabetic activity in the 5-methyl Pyrazole3-carboxylic acid 24.
COOH N H3C N H 24

Pyrazole derivative as vasodilator. Brunner H.R et.al. derivative 25.

26

have reported vasodilator action in pyrazole

190

N N N

N CH3 25

Pyrazole derivative as hypoglycemic agent. Smith D.L. et.al.27 reported that 3, 5-dimethyl pyrazole 26 and 3methyl pyrazole 5-carboxylic acid 27 exhibited hypoglycemic activity.
CH3 N H3C N CH3 26 N HOOC N H 27 COOH

Pyrazole derivative as pyrimidine biosynthesis. Sweenu M.J et.al. 28 reported that pyrazofurin 28 which is a natural antibiotic was very effective in inhibiting pyrimidine biosynthesis.
H N

HO

O OH

CONH2

HO

28

Pyrazole derivative as immuno suppressant. Yamamoto et.al

29

have reported that pyrazole derivatives 29 against

gout and the Lasch-Nyhan syndrome as well as carcinostatic and immune suppressant.

191

H2NOC N H 29

N=NSR R-CH3

Pyrazole derivative as anti-inflammatory agent. Coli B et.al.30,

31

reported pyrazole derivative (30) itself has anti-

inflammatory activity eg: Benzylan (Tantum).

CH3 OCH-CH2CH2-NH CH3

N
H2C

30

30 Sarangan S et.al.
32

have synthesized number of derivatives of

pyrazole- (3, 4-d) pyrimidine-4-6-diones (31) and reported the screening for C.N.S depression properties and anti-inflammatory activity. It was also reported that some derivatives showed anti- inflammatory properties equivalent to aspirin.
O R2 O N N N H 31 N R1 R1,R2=Phenyl

4,7-Di hydro pyrazolo (3, 4-d) pyridine (32) derivatives are tested for a ca++-blocking activity33 in isolated guinea pig portal vein, anti-hypertensive activity in rats and vasodilating effect in isolated guinea pig heart.

192

NO2 COOCH3 N N N CH3 H

32

Kuczynski et.al.

34

have reported the synthesis and biological activity

of pyrazolo 3, 4-b) pyridine derivative (33). At 20 mg/kg body weight produced hypotension in rats and at 50-80 mg/kg body weight it has anti-arrhythmic activity in BaCl2-induced arrhythmia in rabbits.
OH XCH2-CH-CH3 N N R N R=H X=CH2 33

Pyrazoles (34) used in treatment of severe arthritis

n-Bu

H O N N

34

Pyrazole (35) used as cyclo-oxygenase-2-inhibitors

35.

Celecoxib is the first to market of a number of selective cyclooxygenase-2-inhibitors which show great promise as anti-inflammatory and analgesic agents without any side effects associated with other NSAIDs.

193
CF3

N N H3C

SO2NH3

35

Pyrazole derivatives (36) as fungicidals

36

Pyrazoles and their derivatives have been investigated extensively by the organic chemists due to their close association with biological activities
37, 38.
O O

O N N

H3C

N CH2CH3 36

4.3.1.

SYNTHESIS OF PYRAZOLES AND ITS DERIVATIVES

Jae Nyoung Kim et.al reported39 the expeditious synthesis of 1, 3, 4trisubstituted pyrazoles from baylis-hillman adducts (Scheme-4.1). Scheme-4.1:
OH R 37 O R1 RIINHNH2.HCl Ref.2 "R N N R1 R 38

H. Junjappa et.al reported40 the regioselective synthesis of 1-Aryl-3, 4-substituted/annulated-5-(methyl thio) pyrazoles and 1-Aryl-3-methyl thio)-4, 5-substituted/annulated pyrazoles (Scheme-4.2). Scheme-4.2:

194

R1 O

SMe R2 SMe MeS a R

1

R2

MeS N

R2

R2

39

N Ar a, ArNHNH2/ t-BuOH/

SMe

O R1 R1 N Ar 40 ; b, ArNHNH2/ EtOH/

J.T.Starr et.al reported41 that, a simple one-pot method allows the synthesis of diversely functionalized N-aryl pyrazoles from aryl

nucleophiles, di-tert-butyl azo dicarboxlate, and 1,3-dicarbonyl or equivalentcompounds (Scheme-4.3). Scheme-4.3:

1) 1.05 eq. BuLi (2.5 Min hex) THF, -70OC, 5 min O Boc 1.05 eq. R R' O R N Ar-N R 42 R R1 R: H, Me R: Cl,H

Ar-X X:Br,I

N Li Ar-N Boc 2) 1.05 eq. N-Boc Boc-N" -70OC r.t., 30 min 41

4 MHCl in dio xane / THF (5:1) 80OC, 10 min

N. S. Mani, et.al reported42 that a regioselective one-pot synthesis of substituted pyrazoles from N-monosubstituted hydrazones and

nitroolefins gives products in good yields. A key nitropyrazolidine intermediate is characterized and a plausible mechanism is proposed (Scheme-4.4). Scheme-4.4:
1.1eq. R-NHNH2 + H R1 1.1 eq. O MeOH r.t., 1h R N H N R1 1.eq. "R NO2 R N N "R 43 R" R1

R" under air r.t., 24 h

Andrew

T.Turner

et.al

reported43

one-pot

process

for

the

regioselective synthesis of 1, 3, 4-trisubstituted-1H-pyrazoles (Scheme4.5). Scheme-4.5:

195

R O H2N O

OEt 3 steps. one pot O H OEt

R N N Me

CO2Et

NH Me

30-49% 44

Vedavati G. Puranic et.al reported44, 45 that a convenient access to 1, 3, 4-trisubstituted pyrazoles carrying 5-nitrothiophene moiety via 1, 3dipolar cycloaddition of sydnones with acetylenic ketones and their antimicrobial evaluation. S. T. Heller et.al reported46 that 1, 3-diketones from acid chlorides and ketones: a rapid and general one-pot synthesis of pyrazoles (Scheme4.6) Scheme-4.6:
2.eq. O R R" 45 1) 2.1 eq. LiHMDS toulene/ THF(5.2), OOC, 1 min 2) 1 eq. R"COCl r.t.,1 min

O R
1

O R" 46

34 eq. H2N.NH2.H2O EtOH (THF) toulene/ AcOH (10:7:5:5), reflux, ~5 min

R R

H N

N R"

47

A.Mori et.al reported47 that 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 iodide (Scheme-4.7). Scheme-4.7:

196

1.2 eq. Ph

3.eq. + R N NH2 + Ar-I H

1 mol-% PdCl2(PPh)3 CO ( ambient pressure) THF/ H2O (1.1) r.t., 24-36 h

Ph

R N Ar 48

J. T. Starr et.al reported48 that a simple one-pot method allows the synthesis of diversely functionalized N-arylpyrazoles and 1, from aryl or

nucleophiles,

di-tert-butylazodicarboxlate,

3-dicarbonyl

equivalent compounds (Scheme-4.8). Scheme-4.8:

O Boc 1.05 eq. R R' O R N Ar-N R 49 R R1 R: H, Me R: Cl,H

Ar-X X:Br,I

N Li Ar-N Boc 2) 1.05 eq. N-Boc Boc-N" -78OC r.t., 30 min

1) 1.05 eq. BuLi (2.5 Min hex) THF, -78OC, 5 min

4 MHCl in dio xane / THF (5:1) 80OC, 10 min

S. L. Buchwald et.al reported49 a general, highly flexible Cu-catalyzed domino C-N coupling/hydroamination reaction constitutes a

straightforward alternative to existing methodology for the preparation of pyrroles and pyrazoles (Scheme-4.9). Scheme-4.9:

R R1

I +

1.2 eq. NHBoc NHBoc

5 mol % CuI 0.2 eq. NH Me 1.5 eq. Cs2CO3 THF, 80OC, 6-16 h

NHMe

R R1

Boc N NBoc R"

10eq. TFA CH2Cl2 r.t., 2h

R R1

Boc N NBoc R" 51

50

Aoyama T, et.al reported50 that, the reaction of diazo (trimethylsilyl) methyl magnesium bromide with aldehydes or ketones gave 2-diazo-2-

197 (trimethylsilyl) ethanols, which were applied to the synthesis of di and trisubstituted pyrazoles via [3+2] cycloaddition reaction with ethyl propiolate or dimethyl acetylenedicarboxylate (Scheme-4.10). Scheme-4.10:
OTMS R" N N2 SiMe3 N H O OR"

1.2eq.
SiMe3 N2

1) 1.2 eq. BuLi THF -78OC, 20min 2) 1.2 eq. MgBr2 10min 3) 1eq. RCOR1, 1.5 h

R1 R

OH "R

2.eq.

O OR"

R' R

R: H,Me R': Ar, alkyl R":H, CO2Me

( extractive work-up)

52

4.3.2. ITS

SYNTHESIS OF 1, 3-DIPHENYL PYRAZOLES AND

DERIVATIVES N. S. Mani et.al reported51 that a regioselective synthesis of tri or tetrasubstituted pyrazoles 53 by the reaction of hydrazones with nitroolefins mediated with strong bases such as t-BuOK exhibits a reversed exclusive 1, 3, 4-regioselectivity. Subsequent quenching with strong acids such as TFA is essential to achieve good yields. A stepwise cycloaddition reaction mechanism is proposed (Scheme-4.11). Scheme-4.11:
Ar O2N
1) 1eq. tBuOK THF, -78OC,25min

N N R R'
R: H, alkyl R': Ar, alkyl

Ar N H

Ar

+
R

R'
2) 2eq. TFA,2h 3) -78C--r.t.,a.n.

Ar

( added after 10 min)

53

N. S. Mani, et.al reported52 that two general protocols for the reaction of electron-deficient N-arylhydrazones with nitroolefins allow a

198 regioselective synthesis of 1, 3, 5-tri and 1, 3, 4, 5-tetrasubstituted pyrazoles. Studies on the stereochemistry of the key pyrazolidine intermediate suggest a stepwise cycloaddition mechanism (Scheme-4.12). Scheme-4.12:
1.2eq. Ar N N H Ar + R R1 NO2 air ethylene glycol, 120C, 16 h or 10 eq. TFA, CF3CH2OH, r.t.,2 d Ar R N N Ar R1 54 R: Ar, alkyl R1: H, alkyl

M. Hayashi et.al reported53 that, in the presence of activated carbon, Hantzsch 1, 4-dihydropyridines and 1, 3, 5-trisubstituted pyrazolines were aromatized with molecular oxygen to the corresponding pyridines and pyrazoles in excellent yields (Scheme-4.13). Scheme-4.13:
Ar Ph N N 55 Ar1 O2 (1 ATM) Activated Carbon AcOH 120OC Ar N N Ph 56 Ar1

Grabovski et.al reported54 that a highly region selective synthesis of 1aryl-3, 4, 5-substituted pyrazoles based on the condensation of 1, 3diketones with aryl hydrazines proceeds at room temperature in N, N dimethyl 4.14). acetamide and furnishes pyrazoles in good yields (Scheme-

199 Scheme-4.14:
Ar1 R

O Ar

O R

H H2N N

Ar1.HCl

Ar1 Ar

N N

HN N Ar

R= Me, CF3, CF2H

57

58

Algirdas sackus et.al reported55 that Pd-catalyzed cross-coupling reactions of halogenated 1-phenylpyrazol-3-olsand related triflates

(Scheme-4.15). Scheme-4.15:
R5 N N R3 R1 TfO Pd-catalyzed cross-coupling N N reactions HO N N OAc N N R1 R3 OAc Pd-catalyzed cross-coupling N N reactions

R4 60

R2

R2

R4 59

R1= H, Br, I R2= H, BR R3= phenyl, 2-chlorophenyl, 2-thienyl,2-(tert-butOXYcarbonyl)ethynyl, phenylethynyl R4= H, phenyl R5= phenyl, 2-thienyl, 3-thienyl

R. Pundeer et.al reported56 that one-pot synthesis of some new semicarbazone, thiosemicarbazone, and hydrazone derivativesof 1Phenyl-3-Arylpyrazole-4-Carboxaldehyde from acetophenone phenyl

hydrazones using VilsmeierHaack Reagent. Semicarbazone derivatives 3 of 1, 3-diphenylpyrazole-4-carboxaldehyde have been synthesized in high yields through a one-pot procedure involving acetophenone

phenylhydrazones 1 subjected to Vilsmeier double formylation and workup under new conditions (i.e, treatment with semicarbazide followed

200 by sodium bicarbonate). This method is even suitable for preparing other derivatives (i.e., thiosemicarbazones 4 and hydrazones 5) in high yields.
Method A NNHPh Ar 61 CH3 Ph DMF/POCl3 50-60OC Ar CH=N+Me2Clnot isolated 62 NH2NHPh/ NaHCO3 N N

NH2CONHNH2/ NaHCO3

NH2CsNHNH2/ NaHCO3

Ph N N Ar CH=NNHCONH2 Method B 63

Ph

N N Ar CH=NNHCSNH2 64

Ph

N N Ar CH=NNHPh 65

NNHPh Ar 66 CH3

Ph DMF/POCl3 50-60 C
O

N N Ar CHO isolated 67

Ph NH2NHCONH2 NaOAc

N N Ar CH-NNHCONH2 68

Rossella Fioravanti et.al. synthesized some pyrazole derivatives

and

carried out preliminary investigation of their affinity binding to Pglycoprotein. A Rhodamine 123(Rh 123) fluorescent probe (molecular probes) was used to measure the functionality of the P-glycopritein efflux pump according to the protocol of the National Cancer Institute Drug Screen57.

R N N H3C 69 O R=H

201 Patrice Vanelle et.al reported58 that 1, 3-Diphenyl pyrazole-4carboxaldehyde and 1-(4-nitrophenyl)-3-Phenyl pyrazole-4-

carboxaldehyde were obtained from the appropriated phenyl hydrazones via the VilsmeierHaack by various reaction. These two aldehydes or were

functionalized benzylamines.

substituted

anilines

substituted

H2N + O CH3 R1

H Ethanol rt CH3 N N H DMF / POCl3 80OC N N

CHO

1a R1 = H 1bR1 = NO2

R1 1a,b 2 a,b 3a,b

202 4.4. PRESENT SCHEME:

The present work embodies the synthesis of various 1, 3, 4trisubstituted pyrazoles 5(a-n) described in Table-4.2. 1, 3-

diphenylpyrazole-4-carboxaldehyde 4 was prepared in two steps. The first one was the reaction between acetophenone 1 and phenylhydrazine 2. The hydrazone derivative 3 was treated with the VilsmeierHaack reagent (DMFPOCl3) leading to the corresponding 4-carboxaldehyde functionalized pyrazole heterocyclic ring in mild operating conditions (Scheme-4.16). Present Scheme: Scheme-4.16:
O H N EtOH NH2 RT Phenyl-hydrazine 2 POCl3 R-NH2 R HN N N ZnCl2 NaCNBH3 N 1,3-Diphenyl-1H-pyrazole-4carbaldehyde 4 MDC:MeOH RT O N N-Phenyl-N'-(1-phenyl-ethylidene)-hydrazine 3 DMF H N

+
1-Phenyl-ethanone 1

5 (a-n)

203 4.5 RESULTS AND DISCUSSION The most important methods for preparing this class of

heterocycles are the reaction between hydrazines with -difunctional compounds and 1, 3-dipolar cycloadditions of diazo compounds onto triple bonds. The former process, considered to be the best method for the preparation of pyrazoles involves the double condensation of 1, 3diketones with hydrazine or its derivatives. This method has a wide scope not only because of the readily availability of 1, 3-diketones but also because one carbonyl of the diketone starting material can be replaced by an acetal, a hemiacetal, a chlorovinyl group, dihalides, etc. The 1, 3-diphenylpyrazole-4-carboxaldehyde 4 was prepared in two steps. The first one was the reaction between acetophenone 1 and phenylhydrazine 2. The hydrazone derivative 3 was treated with the VilsmeierHaack reagent (DMFPOCl3) leading to the corresponding 4carbaxaldehyde functionalized pyrazole heterocyclic ring in mild

operating conditions. Three equivalents of this reagent were necessary to obtain the aldehyde 4 in good yields. A suspension of ZnCl2 (0.043g, 0.31mmol 0.8eq) and NaCNBH3 (0.03g, 0.48 mmol, 1.2 eq) in methanol was added to a mixture of 1, 3diphenylpyrazole-4-carboxaldehyde (0.1g, 0.4mmol 1eq) and the

respective amine (0.4mmol, 1eq) in dichloromethane (2ml). The reaction mixture was stirred at room temperature overnight. Next day the reaction mixture was quenched with an aqueous solution of 2N NaOH (0.5ml) and

204 extracted with dichloromethane (3x2ml). The organic layer was then washed with water (3ml), brine (3ml), dried with anhydrous magnesium sulphate and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using a mixture of chloroform-methanol (1-5%) to obtain pure products 5(a-n). 1, 3-Diphenyl Pyrazole derivative 5a was confirmed from IR, Mass as well as NMR spectroscopy. 5a shows the NMR values as 8.02 (1H, s), 7.78-7.72(5H, m), 7.48-7.12(9H, m), 4.01(2H, s), 3.01(4H, s), 2.60(2H, s). Similarly mass spectrum of 5a show molecular ion peak at 387.15. The respective amine derivatives of pyrazoles are given in Table 4.2.

205 Table-4.2: Synthesis of various 1, 3, 4-trisubstituted pyrazoles 17a-n. S.No Aldehyde Amine Product Yield (%) 5a
O N N

Cl

Cl N N N H

H2 N

86

5b

O N N

H2N

N N N H

N N

N H

N N N H

91

5C

O N N

F H2N
N N N H

95

5d

O N N

N N

N H

85

H 2N

5e

O N N

O H 2N N
N N

O N H N

78

5f

O N N

N
H2N

N
N N N H

80

206

5g

O N N

HN
N N

76
N

5h

O N N

HN
N N N

92

5i

O N N

H 2N

N O

75
N N N H

N O

HO

5j

O N N

HN

OH
N HN

65

H 2N

5k

O N N

O S NH2 O H2N
HN

SO 2

71

207
N

5l

O N N

65

NH2

N H N N

5m

N
O N N

Cl

NH2 Cl N
N H N N

72

HO

5n

O N N

68

HO

NH2
N N

N H

208 4.6 EXPERIMENTAL SECTION

Procedure for step-1: N-Phenyl-N'-(1-phenyl-ethylidene)-hydrazine:

O EtOH NH2 RT Phenyl-hydrazine N-Phenyl-N'-(1-phenyl-ethylidene)-hydrazine H N

H N

+
1-Phenyl-ethanone

Phenyl hydrazine hydrochloride (2g, 13.8mmol, 1.0 eq) was added to a solution of acetophenone (1.8g, 15.2mmol, 1.1 eq) in 50 ml of ethanol at 0oC followed by the slow addition of glacial acetic acid 1.5ml. The reaction mixture was then refluxed for 2hours (TLC) and cooled to room temperature, when the product precipitated out of the reaction mixture, which was filtered, washed with cold ethanol (20 ml) and dried under vacuum to obtain pure acetophenone phenylhydrazone as a yellow solid (2.8g, 90%), mp.104-106oC. Procedure for synthesis of 1, 3-Diphenyl-1H-pyrazole-4Carbaldehyde:
O H N N N POCl3 DMF N-Phenyl-N'-(1-phenyl-ethylidene)-hydrazine N 1,3-Diphenyl-1H-pyrazole-4carbaldehyde

To a solution of N, N-Dimethylformamide (0.8g, 11.4 mmole, 1.2eq, 0.84ml) was added to phosphorous oxychloride (1.7g, 11.4 mmol, 1.2 eq 1.03 ml) at 0oC and stirred at the same temperature for 1h. This mixture was then slowly added to a solution of acetophenone phenylhydrazone, 1

209 (2g, 9.5 mmol, 1 eq) in N, N-dimethylformamide (5ml) was added drop wise and the reaction mixture allowed to stir for 10min at the same

temperature and then heated to 70oC for 3hours (TLC). The reaction mixture was then cooled to room temperature and basified with cold and saturated potassium carbonate, when a solid (brown color) precipitated out. The precipitate was filtered, washed with cold water (20 ml) to obtain the crude product as a colored solid. The crude products was purified by silica gel column

chromatography to obtain pure product as a (off-white) solid 2.17g, yield 92%, mp; 146-148, NMR: (DMSO; 400 MHz; ppm), 9.99(1H, s), 9.34(1H, s), 7.42-7.60(6H, m), 7.92-8.01(4H, m). EI MASS m/z: 249.2, Mol. Wt.: 248.28 (Fig.No. 4.1, 4.2). 4.6.1 General Procedure: Procedure for Preparation of (1, 3Diphenyl-1H-pyrazol-4-yl)-amine Derivatives:
R-NH2 N N ZnCl2 1,3-Diphenyl-1H-pyrazole-4carbaldehyde NaCNBH3 MDC:MeOH RT

N H N

A suspension of ZnCl2 (0.043g, 0.31mmol 0.8eq) and NaCNBH3 (0.03g, 0.48 mmol, 1.2 eq) in methanol 1ml was stirred for 2 hours at room temperature and to this added a mixture of compound-2 (0.1g, 0.4 mmol 1 eq) and the respective amine (0.4mmol, 1eq) in dichloromethane (2ml). The reaction mixture was stirred at room temperature overnight

210 Next day the reaction mixture was quenched with an aqueous solution of 2N NaOH (0.5ml) and extracted with dichloromethane (3x2ml). The organic layer was then washed with water (3ml), brine (3ml), dried with anhydrous magnesium sulphate and concentrated to obtain the crude product. The crude product was purified by silica gel column

chromatography using a mixture of chloroform-methanol (1-5%) to obtain pure products (Table-4.2).

211 4.6.2: 2-(2-chlorophenyl)-N-((1, 3-diphenyl-1H-pyrazol-yl) methyl) ethanamine (5a):

Cl N N N H

Pale yellow solid, mp: 135-138oC; MS (m/z): 388.2 (M+H)+; 1H NMR (400 MHz, CDCl3, ppm ): 7.99(1H, s), 7.74(5H, d, J=8Hz), 7.44(5H, q, J=8Hz), 7.31-7.39(2H, m), 7.26-7.31(1H, m), 7.18-7.23(1H, m), 7.137.18(1H, m), 3.99(2H, s), 3.00(2H, s), 2.62(2H, s).IR (KBr, cm-1): 3412.54, 1635.74, 11647.52, 772.05 (Fig.No. 4.3, 4.4). 4.6.3: 1-(1-((1, 3-diphenyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl)1H-benzo[d]imidazol-2(3H)-one(5b):

N N

N H

N N HN

White solid, mp: 184-186oC; MS (m/z): 450.2 (M+H)+; 1H NMR (400 MHz, ppm, CDCl3): 8.69(1H, s), 7.94(3H, t, J=12Hz), 7.78(2H, d, J=16Hz), 7.48(4H, q, J=8Hz), 7.41(1H, t, J=12Hz), 7.29(1H, t, J=12Hz), 7.35(1H, J=8.2 Hz, d), 7.20-7.29(3H, m), 4.32-4.45(1H, m), 3.62(1H, s), 3.38(1H, t, J=12Hz), 3.20(2H, J=3.2 Hz, dd), 2.42-2.55(2H, m), 2.38(1H, t, J=20Hz), 2.23(2H, t, J=16Hz). IR (KBr, cm-1): 1695.74, 1670, 698.41 (Fig.No. 4.5, 4.6). 4.6.4: 2-(4-fluorophenyl)-N-((1,3-diphenyl-1H-pyrazol-4-yl) methyl) ethanamine (5c):

212

N N

N H

White solid, mp: 148-150OC; MS (m/z): 372.2 (M+H)+; 1H NMR (400 MHz, CDCl3): 8.3(1H, s), 7.63(2H, d, J=16Hz), 7.51(2H, d, J=16Hz), 7.357.47(6H, m), 7.26-7.28(1H, m), 6.84-6.97(4H, m), 4.15(2H, s), 2.98(2H, m), 2.81(2H, m) (Fig.No. 4.7, 4.8). 4.6.5: 4-phenyl-N-((1, 3-diphenyl-1H-pyrazol-4-yl) methyl) butan-2-amine (5d):

N N

N H

White solid, mp: 153-155OC; MS (m/z): 382.2 (M+H)+; 1H NMR (400 MHz, CDCl3): 8.45(1H, s), 7.70(2H, d, J=16Hz), 7.38-7.49(7H, m), 7.28(1H, d, J=16Hz), 7.08-7.18(3H, m), 6.94(2H, d, J=12Hz), 2.91(1H, b s), 2.56(1H, m), 2.39(1H, m), 2.10(2H, m), 1.96(1H, m), 1.76(1H, m), 1.13(3H, s). IR (KBr, cm-1): 3030.57, 1657.86, 119.45, 696.14 (Fig.No. 4.9, 4.10, 4.11). 4.6.6: 2-morpholino-N-((1, 3-diphenyl-1H-pyrazol-4-yl) methyl) ethanamine (5e):

213

N N N N H

White solid, mp: 138-130oC; MS (m/z): 363.2 (M+H)+; 1H NMR (400 MHz, CDCl3): 8.37(1H, s), 7.73(2H, d, J=16Hz), 7.60(2H, d, J=16Hz), 7.427.51(5H, m), 7.31(1H, t, J=10Hz), 4.32(2H, s), 3.63(4H, m), 3.16(2H, m), 2.92(2H, m), 2.36(4H, m). IR (KBr, cm-1): 3067.57, 1657.21, 1203.20, 698.21 (Fig.No. 4.12, 4.13, 4.14). 4.6.7: 1-benzyl-N-((1, 3-diphenyl-1H-pyrazol-4-yl) methyl) pyrrolidin-3-amine (5f):

N N N N H

White white solid, mp: 144-148oC; MS (m/z): 409.2 (M+H)+; 1H NMR (400 MHz, CDCl3) : 8.40(1H, s), 7.71(2H, d, J=16Hz), 7.54(2H, d, J=12Hz), 7.38-7.47(7H, m), 7.28-7.37(3H, m), 4.18(2H, s), 4.12(2H, s), 3.253.58(4H, m), 2.89(1H, m), 2.08-2.18(2H, m). IR (KBr, cm-1): 3420.44, 1674.29, 1202.74, 771.98. (Fig.No. 4.15, 4.16): 4.6.8: N-methyl-N-((1, 3-diphenyl-1H-pyrazol-4-yl) methyl) prop2-yn-1-amine (5g):

214

N N

Off white solid, mp: 134-136oC; MS (m/z): 302.2 (M+H)+; 1H NMR (400 MHz, CDCl3): 8.45(1H, s), 7.75(2H, d, J=7.2 Hz), 7.58(2H, d, 8Hz), 7.417.51(5H, m), 7.34(1H, t, J=10Hz), 4.38(2H, s), 3.80(2H, s), 2.68(3H, s), 2.34(1H, s); IR (KBr, cm-1): 3434.86, 1675.30, 1200.54, 770.59 (Fig.No. 4.17, 4.18): 4.6.9: N-Methyl-N-((1, 3-diphenyl-1H-pyrazol-4-yl) methyl) (mtolyl) methanamine (5h):

N N

White solid, mp: 161-165oC; MS (m/z): 368.2 (M+H)+; 1H NMR (400 MHz, CDCl3): 8.59(s, 1H), 7.78(2H, d, J=20Hz), 7.42-7.57(7H, m), 7.33(1H, t, J=12Hz), 7.18-7.25(2H, m), 7.04-7.11(2H, m), 4.46(1H, m),4.26(2H, m), 3.80(1H, m), 2.44(3H, s), 2.24( 3H, s) (Fig.No. 4.19, 4.20, 4.21). 4.6.10: 3-morpholino-N-((1, 3-diphenyl-1H-pyrazol-4-yl) methyl) propan-1-amine (5i):

215

N N N N H

White solid, mp: 136-140oC; MS (m/z): 377.2 (M+H)+; 1H NMR (400 MHz, CDCl3): 8.6(s, 1H), 7.80(2H, d, J=16Hz), 7.64(2H, d, J=20Hz), 7.41-

7.52(5H, m), 7.33(1H, t, J=24, 12Hz), 4.21(2H, s), 3.36-3.42(4H, m), 3.08-3.13(2H, m), 2.53-2.60(2H, m), 2.38-2.48(4H, m), 1.89-1.96(2H, m). IR (KBr, cm-1): 3407.54, 1641.75, 772.23 (Fig.No. 4.22, 4,23, 4.24). 4.6.11: 1-((1, 3-diphenyl-1H-pyrazol-4-yl) methyl) piperidin-3-ol (5j):
HO

N HN

Off white solid, mp: 110-112oC; MS (m/z): 334.2 (M+H)+;

1H

NMR (400

MHz, CDCl3): 8.50(1H, s), 7.90-7.96(4H, m), 7.44-7.54(4H, m), 7.307.40(2H, m), 4.58(1H, d, J=4Hz), 3.38-3.49(2H, m), 3.29-3.32(2H, m), 2.70(2H, s), 2.18(2H, t, J=8Hz), 1.92-1.94(3H, m) (Fig.No. 4.25, 4.26). 4.6.12: 4-(2-((1, 3-diphenyl-1H-pyrazol-4-yl) methylamino) ethyl) benzene-1-sulfonamide (5k):

216

H2N SO2

HN

White solid; mp: 71-75oC; MS (m/z): 433.2 (M+H)+; 1H NMR (400 MHz, CDCl3): 8.45(1H, s), 7.86(4H, d, J=8Hz), 7.72(2H, d, J=8Hz), 7.52(2H, t, J=8Hz), 7.32-7.43(5H, m), 7.29(3H, d, J=12, 6Hz), 3.77(2H, s), 2.85(4H, t, J=4Hz) (Fig.No. 4.27, 4.28). 4.6.13: 6-((1, 3-diphenyl-1H-pyrazol-4-yl) methylamino) pyridine3-carbonitrile (5l):

N N N H N N

White solid, mp: 65-68oC; MS (m/z): 352.2 (M+H)+; 1H NMR (300 MHz, CDCl3): 8.36(1H, s), 7.87(1H, d, J=6Hz), 7.75(2H, t, J=6Hz), 7.597.63(3H, m), 7.38-7.49(4H, m), 7.28(1H, t, J=9Hz), 6.50(2H, d, J=9Hz), 4.67(2H, d, J=6Hz) (Fig.No. 4.29). 4.6.14: 6-chloro-N-((1, 3-diphenyl-1H-pyrazol-4-yl) methyl) pyridin-3-amine (5m):

217
Cl

N H N N

Off white solid, mp: 72-76oC; MS (m/z): 361.8 (M+H)+; 1H NMR (300 MHz, CDCl3): 7.96(1H, s), 7.82(1H, d, J=3Hz), 7.72-7.77(4H, m), 7.367.49(5H, m), 7.30(1H, t, J=9Hz), 7.77(1H, d, J=9Hz), 6.87-6.91(1H, m), 4.38(2H, d, J=3Hz) (Fig.No. 4.30). 4.6.15: 6-((1, 3-diphenyl-1H-pyrazol-4-yl) methyl amino) pyridin2-ol (5n):
HO N HN N N

White solid, mp: 68-70oC; MS (m/z): 343.4 (M+H)+; 1H NMR (300 MHz, CDCl3): 8.58(1H, s), 7.85-7.88(2H, s, J=9Hz), 7.76(2H, d, J=6Hz), 7.447.54(4H, m), 7.40(1H, d, J=6Hz), 7.32(1H, d, J=9Hz), 7.19(1H, t, J=6Hz), 6.39(1H, s), 5.56(2H, d, J=9Hz), 4.36(2H, d, J=6Hz) (Fig.No. 4.31).

218 4.7 CONCLUSION The present work embodies the synthesis of various 1, 3, 4trisubstituted pyrazoles 5(a-n) described in Table-4.2. 1, 3-

diphenylpyrazole-4-carboxaldehyde 4 was prepared in two steps. The first one was the reaction between acetophenone 1 and phenylhydrazine 2. The hydrazone derivative 3 was treated with the VilsmeierHaack reagent (DMFPOCl3) leading to the corresponding 4-carboxaldehyde functionalized pyrazole heterocyclic ring in mild operating conditions in good yields. First synthesis of 1, 3, 4-trisubstituted pyrazoles 5(a-n) such as (1, 3-Diphenyl-1H-pyrazol-4-yl)-amine derivatives through reductive

amination by using a suspension of ZnCl2 and NaCNBH3 in methanol was added to a mixture of 1, 3-diphenylpyrazole-4-carboxaldehyde and the respective amine in dichloromethane. The crude product was purified by silica gel column chromatography using a mixture of chloroformmethanol (1-5%) to obtain pure products 5(a-n).

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226

SPECTRAL REPORTS

227 Fig 4.1: NMR spectrum of 1, 3-Diphenyl-1H-pyrazole-4-carbaldehyde

Fig 4.2:

MASS spectrum of 1, 3-Diphenyl-1H-pyrazole-4Carbaldehyde

228 Fig 4.3: NMR Spectrum of [2-(2-Chloro-phenyl)-ethyl]-(1, 3diphenyl-1H-pyrazol-4-ylmethyl)-amine (5a)

Fig 4.4:

MASS Spectrum of [2-(2-Chloro-phenyl)-ethyl]-(1, 3diphenyl-1H-pyrazol-4-ylmethyl)-amine (5a)

229 Fig 4.5: NMR Spectrum of 1-[1-(1, 3-Diphenyl-1H-pyrazol-4-yl methyl)-piperidin-4-yl]-1,3-dihydro-benzimidazol-2-one (5b)

Fig 4.6:

IR Spectrum of 1-[1-(1, 3-Diphenyl-1H-pyrazol-4-yl me thyl)-piperidin-4-yl]-1, 3-dihydro benzimidazol-2-one (5b)

230 Fig 4.7: NMR Spectrum of (1, 3-Diphenyl-1H-pyrazol-4-ylmethyl)[2-(4-fluoro-phenyl)-ethyl]-amine (5c)

Fig 4.8:

MASS Spectrum of (1, 3-Diphenyl-1H-pyrazol-4ylmethyl)-[2-(4-fluoro-phenyl)-ethyl]-amine (5c)

231 Fig 4.9: NMR Spectrum of (1, 3-Diphenyl-1H-pyrazol-4-ylmethyl)(1-methyl-3-phenyl-propyl)-amine (5d)

Fig 4.10:

MASS Spectrum of (1, 3-Diphenyl-1H-pyrazol-4ylmethyl)-(1-methyl-3-phenyl-propyl)-amine (5d)

232 Fig 4.11: IR Spectrum of (1, 3-Diphenyl-1H-pyrazol-4-ylmethyl)-(1methyl-3-phenyl-propyl)-amine (5d)

Fig 4.12:

NMR Spectrum of (1, 3-Diphenyl-1H-pyrazol-4-ylmethyl)(2-morpholin-4-yl-ethyl)-amine (5e)

233 Fig 4.13: MASS Spectrum of (1, 3-Diphenyl-1H-pyrazol-4ylmethyl)-(2-morpholin-4-yl-ethyl)-amine (5e)

Fig 4.14:

IR Spectrum of (1, 3-Diphenyl-1H-pyrazol-4-ylmethyl)(2-morpholin-4-yl-ethyl)-amine (5e)

234 Fig 4.15: NMR Spectrum of (1-Benzyl-pyrrolidin-3-yl)-(1,3diphenyl-1H-pyrazol-4-ylmethyl)-amine (5f)

Fig 4.16:

MASS Spectrum of (1-Benzyl-pyrrolidin-3-yl)-(1, 3diphenyl-1H-pyrazol-4-ylmethyl)-amine (5f)

235 Fig 4.17: NMR Spectrum of (1, 3-Diphenyl-1H-pyrazol-4-ylmethyl)methyl-prop-2-ynyl-amine (5g)

Fig 4.18:

MASS Spectrum of (1, 3-Diphenyl-1H-pyrazol-4ylmethyl)-methyl-prop-2-ynyl-amine (5g)

236 Fig 4.19: NMR Spectrum of (1, 3-Diphenyl-1H-pyrazol-4-ylmethyl)methyl-(4-methyl-benzyl)-amine (5h)

Fig 4.20:

MASS Spectrum of (1, 3-Diphenyl-1H-pyrazol-4ylmethyl)-methyl-(4-methyl-benzyl)-amine (5h)

237 Fig 4.21: IR Spectrum of (1, 3-Diphenyl-1H-pyrazol-4-ylmethyl)methyl-(4-methyl-benzyl)-amine (5h)

Fig 4.22:

NMR Spectrum of (1, 3-Diphenyl-1H-pyrazol-4-ylmethyl)(3-morpholin-4-yl-propyl)-amine (5i)

238 Fig 4.23: MASS Spectrum of (1, 3-Diphenyl-1H-pyrazol-4ylmethyl)-(3-morpholin-4-yl-propyl)-amine (5i)

Fig 4.24:

IR Spectrum of (1,3-Diphenyl-1H-pyrazol-4-ylmethyl)(3-morpholin-4-yl-propyl)-amine (5i)

239 Fig 4.25: NMR Spectrum of 1-[(1, 3-Diphenyl-1H-pyrazol-4ylmethyl)-amino]-piperidin-3-ol (5j)

Fig 4.26:

MASS Spectrum of 1-[(1, 3-Diphenyl-1H-pyrazol-4ylmethyl)-amino]-piperidin-3-ol (5j)

Fig 4.27:

NMR Spectrum of 4-{2-[(1, 3-Diphenyl-1H-pyrazol-4ylmethyl)-amino]-ethyl}-benzenesulfonamide (5k)

240

Fig 4.28:

MASS Spectrum of 4-{2-[(1, 3-Diphenyl-1H-pyrazol-4ylmethyl)-amino]-ethyl}-benzenesulfonamide (5k)

241 Fig 4.29: NMR Spectrum of 6-[(1, 3-Diphenyl-1H-pyrazol-4ylmethyl)-amino]-nicotinonitrile (5l)

Fig 4.30:

NMR Spectrum of (6-Chloro-pyridin-2-yl)-(1, 3-diphenyl1H-pyrazol-4-ylmethyl)-amine (5m)

242 Fig 4.31: NMR Spectrum of 6-[(1, 3-Diphenyl-1H-pyrazol-4ylmethyl)-methyl-amino]-pyridin-2-ol (5n)