chapter-4 synthesis, characterization of new (1 h...

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CHAPTER-4

SYNTHESIS, CHARACTERIZATION OF NEW (1H-PYRAZOL-3-

YL)-1, 2, 4-OXADIAZOLE DERIVATIVES

120

4.1. Introduction

The simple doubly unsaturated compound containing two nitrogen and three carbon atoms in the

ring, with the nitrogen atoms neighbouring, is known as pyrazole. Pyrazole is the name given by

“LUDWIG KNORR” to this class of compounds in 1883. Pyrazole is a colorless solid, having M.p. 70

oC. This high value (compared with 1-alkyl or aryl substituted pyrazoles) is due to intermolecular

hydrogen bonding which results in a dimmer. Pyrazole is a tautomeric substance; the existence of

tautomerism cannot be demonstrated in pyrazole itself, but it can be inferred by the consideration of

pyrazole derivatives.

NH

N

1

2

34

5N

NH

1

2

34

5

211 212

Fig 4.1: Resonance structure of pyrazole

Pyrazole, a five-membered heterocycle motif found in a number of small molecules that possess

a wide range of agricultural [1] and pharmaceutical activities [2]. Moreover, some pyrazoles are used in

supramolecular and polymer chemistry, in the food industry, and as cosmetic colorings and UV

stabilizers, while some have liquid crystal properties [3].

4.1.1. Biological importance of Pyrazoles

The synthesis of pyrazoles remains of great interest due to the wide applications of such

heterocycles in the pharmaceutical and agrochemical industry. Pyrazole derivatives have a long history

of application in agrochemicals and pharmaceutical industry as herbicides and active pharmaceuticals.

A systematic investigation of this class of heterocyclic lead revealed that, pyrazole containing

pharmacoactive agents play important role in medicinal chemistry. The prevalence of pyrazole cores in

biologically active molecules has stimulated the need for elegant and efficient ways to make these

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heterocyclic lead. Among the family of heterocycles, nitrogen containing heterocycles especially

pyrazoles is an important class of heterocyclic compound and its derivatives are reported to have the

broad spectrum of biological activities such as anti-inflammatory [4], herbicidal [5], antitumour and

antiviral activities [6]. Pyrazole derivatives also act as A3 adenosine receptor antagonists [7],

neuropeptide YY5 receptor antagonists [8], hyperlipidemia and thrombopiotinmimetics [9].

Very few pyrazole derivatives are naturally occurring may be due to the difficulty of living

organisms to construct the N-N bond. Owing to the widespread applications, synthesis and biological

activity evaluation of pyrazoles and their derivatives has been a subject of intensive investigations as

revealed by enormous literature covering the subject.

Table- 4.1: Some of the drugs which are having pyrazole as core molecule

NN

SO O

NH2

F

F

O

F

213

Deracoxib

(Anti-inflammatory )

NN

SO O

NH2

F

F

214

F

Celecoxib

(Anti-inflammatory)

122

NN

Cl

215

Cl

Cl

HN

O

N

Rimonabant

(Anti-obesity )

216

NN

N N

H3CO

H3CO

Epirizole

(Analgesic, Anti-inflammatory)

NNON

O

217

Isolan

(Insecticide)

NN

O

218

Phenazone

(Analgesic)

123

Burnes et al, (1960) synthesized derivatives of phenyl butazone (219) and studied their

pharmacological activities. A metabolite of phenyl butazone, oxyphen butazone is clinically used as

analgesic and anti-inflammatory drug [10].

NN

O

O

OH

219

Fig. 4.2: 4-Butyl-1-(4-hydroxyphenyl)-2-phenylpyrazolidine-3,5-dione

L-β-Pyrazolylalanine (220) and γ-L-glutamyl-β-pyrazole-L-alanine are found in the seeds of

many species of Cucurbitaceae (Dunnill and Fowden, 1965) [11].

220

NN

CO2H

NH2

Fig. 4.3: 2-Amino-3-(1H-pyrazol-1-yl)propanoic acid

A tricyclic pyrazoles (221) have been found to possess antiarrhythmic and anti-inflammatory

activities (Hamilton et al, 1976) [12].

124

X

N N

NH

ORY

Z

221

R= Me or (CH2)2NEt2Z= CH2, (CH2)2

X & Y= Halogens

Fig. 4.4: Tricyclic pyrazolone derivatives

Thiele et al, (1981) synthesized pyrazolidine diones (222) as xanthine oxidase inhibitor. In

addition, they showed good analgesic and inflammation inhibitory activity [13].

N

NN

O

O

N

R3

R2

R1

R5

R4

222

R1 = C2-5 alkyl, R2,R3 = Me, Et

R4, R5 = H, Cl

Fig. 4.5: Pyrazolidine diones derivatives

Carl et al, (1991) reported the synthesis of 1-phenylpyrazolyl-4-heteroarylalkanoic acid (223).

These compounds were found to possess anti-inflammatory activity [14].

223

NN R1

N

S

O

R1= H, Me

Fig. 4.6: 1-Phenylpyrazolyl-4-heteroarylalkanoic acid

125

A series of 4-(5-aryl-2-furfurylidine)-1,3-disubstituted-2-pyrazolin-5-ones (224) were prepared

by Kalluraya et al, (1995). These compounds were evaluated for their antibacterial activity against

Gram +ve and Gram -ve bacteria [15].

NN

R

O

OR1

R, R1= Me, Ph, Cl-Ph

224

Fig. 4.7: 4-(5-Aryl-2-furfurylidine)-1,3-disubstituted-2-pyrazolin-5-ones

Kudo et al, (1999) synthesized series of 1,5-diaryl pyrazole carboxylates and carboxamides and

investigated for their herbicidal activities against various kinds of weeds and found that 4-chloro-1-(2,5-

difluorophenyl)-5-(4-fluorophenyl)-pyrazole-3-carboxylate (225) as a potent herbicidal agent [16].

NN

O

OCl

F F

F

225

Fig. 4.8: Methyl 4-chloro-1-(2,5-difluorophenyl)-5-(4-fluorophenyl)-1H-pyrazole-3-carboxylate

Duma et al, (2000) reported the synthesis of some new 1-phenyl-5-pyrazolyl urea derivative

(226) and its selective P38 kinase inhibition properties [17].

N NNH

NH

O

Cl

Cl

226

Fig. 4.9: 1-(3-Tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea

126

Biological activities of new series of 4-arylhydrazono-2-pyrazolin-5-ones (27) by Kucukguzel et

al, (2000) revealed that the derivatives (227, 228) are very much active against Staphylococcus aureus

[18].

NHN

NHN

O

N

HN

N

O

NHN

NN

O

N

HN

N

O

227 228

Fig. 4.10: 4-Arylhydrazono-2-pyrazolin-5-ones derivatives

Isloor et al, (2000) reported the synthesis of 3-aryl-4-(substituted pyrazolidine hydrazine-4-

thiazolyl) sydnones (229) and its analgesic, anticonvulsant activities [19].

Where, R, R1= Ph, 4-Cl-Ph, Anisyl

N

NO

O

R

N

S

NH

N

R1

229

Fig. 4.11: 3-Aryl-4-(substituted pyrazolidine hydrazine-4-thiazolyl) sydnones

Tewari et al, (2001) reported the synthesis of pyrazolopyridazines from the pyrazolone

derivative (Scheme-4.1) (Edaravone) and their anti-inflammatory activity against carragenin induced

paw edema in albino rats [20].

127

N NO

5 Steps

NNH

NHR

NHR

Where R= COPh, PhCO2H, p-Tolyl

230231

Scheme- 4.1: Preparation of pyrazolopyridazines

Synthesis and antitumor activity of novel pyrimidinyl pyrazole derivatives (232) were reported

by Naito et al, (2002) [21].

NN

NN

N N

OH

232

Fig. 4.12: Pyrimidinyl pyrazole derivative

Pyrazole (233) was synthesized by Finn et al, (2003) with significantly improved potency on

bacterial methionyl-t-RNA synthetase and selectivity over human methionyl-t-RNA synthetase [22].

N N

N

N N

NH

NCl

Cl

233

Fig. 4.13: Pyrazolo tetrazole derivative

Tanitame et al, (2004) initially reported a new class of pyrazole derivative 4-(5-(4-

(benzyloxy)phenyl)-1H-pyrazol-3-yl)piperidine (234) represents a new class of bacterial DNA gyrase

128

inhibitors have potent antibacterial activity against Staphylococcus aureus and Enterococcus faecalis.

They found that the one of the derivative 1-(3- Chlorophenyl)-5-(4-phenoxyphenyl)-3-(4-piperidyl)

pyrazole (235) have the target related antibacterial activity and improved DNA gyrase inhibition [23].

O

NHN

HN

234O

NN

HN

Cl

235

Fig. 4.14: 4-(5-(4-(Benzyloxy)phenyl)-1H-pyrazol-3-yl)piperidine derivative

The synthesis of novel series of structurally related 1H-pyrazolyl derivatives (236) described by

the Bekhit and Aziem (2004). All the newly synthesized compounds were tested for their anti-

inflammatory and antimicrobial activities. COX-1 and COX-2 inhibitory activities, ulcerogenic effects

and acute toxicity were also determined [24].

N

N NN

S

R

Br

236

R= H, C6H5CO, C6H5NHCS, CH3CO,

CHO, CH3SO2, 4-CH3C6H4SO2

Fig. 4.15: Structurally related 1H-pyrazolyl derivatives

Tanitame et al, (2005) reported the synthesis, antibacterial activity of 5-[(E)-2-arylvinyl]

pyrazoles (237) and are found to be potent antibacterial activity against quinolone resistant clinical

isolates of Gram-positive bacteria [25].

129

N N

HNR1

Cl

237

Where R1 = is differenet chloro substituted

aryl groups

Fig. 4.16: 5-[(E)-2-Arylvinyl] pyrazole derivatives

Aggarwal et al, (2006) reported the synthesis of new 1-heteroaryl-5-amino-3H-methyl-4- phenyl

pyrazoles (238, 239) and screened for their antibacterial activity. These derivatives found to be either

equipotent or more potent than the antibacterial agents Linezolid and Cefroxime axetil [26].

S

NN

N

NH2

S

NN

N

NH2

O

238 239

Fig. 4.17: 1-Heteroaryl-5-amino-3H-methyl-4- phenyl pyrazole

A series of pyrazole derivatives (240) via 1,3-dipolar addition of sydnone and nitrofuran

acetylenic ketones were reported by Rai et al, (2006) [27].

NN

O

R2

O

NO2

R1 R1 = H, Me, Cl; R2 = H, Me,-OMe

240

Fig. 4.18: Pyrazole derivatives

130

Synthesis of several 1-(4-aryl-2-thiazolyl)-3-(2-thienyl)-5-aryl-2-pyrazoline derivatives (241)

were prepared by reacting substituted 3-(2-thienyl)-5-aryl-1-thiocarbamoyl-2-pyrazolines with phenacyl

bromides in ethanol is reported by Ozdemir et al, (2007). Newly synthesized compounds were screened

for their antimicrobial activity [28].

N

N

N

Where Ar =

R1= H, CH3, OCH3, Cl, NO2 241

N NAr

NS

R1

S

Fig. 4.19: 1-(4-Aryl-2-thiazolyl)-3-(2-thienyl)-5-aryl-2-pyrazoline derivatives

Kang et al, (2008) synthesized 3-tetrazole-1, 5-diaryl-4-methyl pyrazoles and examined their

CB1 receptor binding ability, cannabinoid CB1 receptor antagonists. Few compounds (242, 243, 244)

showed good binding affinity and selectivity for CB1 receptor (IC50 =11.6nM and CB2/CB1 = 366)

[29].

N N

N N

NN

Cl

R1

ClCl

N N

N N

NN

Cl

ClCl

N N

N N

NN

Br

ClCl

R1

242 243244

Where R1 =Me, Et, n-Pr, i-Pr, n-Bu, t-Bu, n-Pentyl, n-Octyl, Ph, Benzyl, 2-

Methylpyridine, 3-Methylpyridine, 4-Methylpyridine, 2-Methylfuran, 3-

Methylfuran, 3-Methylthiophene,Cyclopropyl, Cyclobutyl, Cyclopentyl,

131

Fig. 4.20: 3-Tetrazole-1, 5-diaryl-4-methyl pyrazoles derivatives

Silvestri et al, (2008) studied the cannabinoid receptor affinity and molecular modelling studies

of substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-caboxamides (245) and found that (246) was

most selective ligand to hCB1 receptor [30].

N N

R3

O

N

R1

R4

HN R2

245

N N O

N HNCl

Cl

Cl

Cl

246

R1 = H, 4-Cl, 2,4-Cl2, 3,4-Cl2, 2,4-2F, 2,4,6-Cl3

R2 = 1-piperidine, cyclohexyl, methyl, 3,4-Cl2-

benzyl, 1-morpholine

R3 = -H, Me, CN, 3,4-Cl-2-benzyl, 1-piperidine

R4 = -H, 2,5-dimethyl

Fig. 4.21: 1-Aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-caboxamides

Dhanya et al, (2009) reported the synthesis and anticancer activity of new 3,6-disubstituted

1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles containing pyrazole moiety(247) [31].

NH

N

SN

N

NN Cl

247

Fig. 4.22: 6-(3-(4-Chlorophenyl)-1H-pyrazol-4-yl)-3-p-tolyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole

Isloor et al, (2009) reported the synthesis of Schiff and Mannich Bases containing pyrazole

moiety. The newly synthesized compounds (248) were screened for their antibacterial and antifungal

activity. Some of the compounds were found to exhibit significant antimicrobial activity [32].

132

Where R1 = Me, Ethyl

R2 = t-Butyl, 4-(chlorophenyl), cyclopropyl

248

N NH

R3N

NR

NR1

R2

S

Fig. 4.23: Oxadiazole-diarylpyrazole 4-carboxamides

Synthesis of pyrazoline derivatives bearing benzimidazoles (249) and its anticancer studies were

reported by Shaharyar et al. (2010) [33].

N

NH

N N

R

249

R= Phenyl, 4-Methoxyphenyl,

4-Chlorophenyl, 4-Bromophenyl,

4-Fluorophenyl, 3,4-Dimethoxyphenyl,

2,6-Dichlorophenyl

Fig. 4.24: Pyrazoline derivatives bearing benzimidazoles

Sulfonamides are the best-known inhibitors of carbonic anhydrase enzyme, currently used for

the treatment of glaucoma in clinical medicine. Kasimogullari et al. (2010) have reported pyrazole

derivatives which contain sulfonamide (Scheme 4.2) group have more inhibition effects to CA-I and

CA-II isoenzymes [34].

133

N

O

NN

EtO NH

O O

Ph

S

N

N

SO2NH2

NN

EtO NH

O O

Ph

S

N

N

SO2NH2

N

N

O

R1

R2

NH2

NN

EtO NH

O O

Ph

S

N

N

SO2NH2

250251

252

Scheme 4.2: Preparation of sulphonamide containing pyrazole derivatives

Singh et al, (2011) synthesized a series of 1-[(4, 5- dihydro-5-phenyl-3-(phenylamino) pyrazol-

1yl)] ethanone derivatives and evaluated for their anticonvulsant activity against electric shock induced

convulsion method. Molecule (253) found to be the most potent compound among all the synthesized

compounds [35].

N N

O

NH

253

Fig. 4.25: 1-(5-Phenyl-3-(phenylamino)-4,5-dihydropyrazol-1-yl)ethanone

Discovery of novel, potent, selective, and orally active human glucagon receptor antagonists

containing a pyrazole core were reported by Shen et al, (2011). One of the synthesized compound (254)

was selective and orally active in several in vivo preclinical models of type II diabetes [36].

134

N N

NH

O

CO2H

OCF3Cl

Cl

254

Fig. 4.26: 3-(4-((3-(3,5-Dichlorophenyl)-5-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-1-

yl)methyl)benzamido)propanoic acid

A series of novel pyrazole pyrimidines (255) structurally related to kinase inhibitor AS703569

were prepared by Curtin et al, (2012). SAR work provided analogs with significant cellular activity,

measureable aqueous solubility and moderate antitumor activity in a mouse tumor model after weekly ip

dosing. Unfortunately these compounds were pan-kinase inhibitors that suffered from narrow

therapeutic indices which prohibited their use as antitumor agents [37].

N

N

N N

R

NH

H2N O

NH

255

R= F, CH3. –OCH3, CONH2, NO2,CF3

Fig. 4.27: Pyrazole pyrimidines

The design and synthesis of 4-alkynyl pyrazole derivatives (256) and their invitro PDE4B

properties and molecular modelling studies of these compounds reported by Dhilli et al (2012) [38].

NH

N

OO

R

Cl

R=Ph,CH2OH, Cyclohexane, -CH2CH2CN

256

Fig. 4.28: 4-Alkynyl pyrazole derivatives

135

Patak et al, (2012) have reported the synthesis of 3-(4-chlorophenyl)-4-sustituted pyrazole

derivatives (257) and studied their activity against Mycobacterium tuberclosis H37Rγ strain. The results

suggest that the compounds containing pyrazole moieties would be potential antitubercular agent [39].

NNH

Cl

O

HN NS

R

O

R = H, 4-OCH3, 2-OH, 4-OH, 2-NO2, 3-

NO2, 2-Cl, 4-Cl

257

Fig. 4.29: 3-(4-Chlorophenyl)-4-sustituted pyrazole derivatives

Compounds comprising a 1,2,4-oxadiazole backbone have a wide range of biological activities

as discussed in detail in Chapter-III. As evident from the above discussions the inclusion of two

bioactive motifs like pyrazole and oxadiazole into a single carbon skeleton may further enhance the

biological activity. Keeping in view of these observations it was planned to synthesize pyrazoles

containing 1,2,4-oxadiazole group and their pharmacological evaluation.

4.2. Results and discussions

Semicarbazone intermediate (259) was prepared by the reaction of different substituted

acetophenones (258) with semicarbazide in the presence of sodium acetate in ethanol at 0oC [40].

Semicarbazone intermediate (259) was further cyclised and formylated using vilsmayer condition to get

substituted pyrazole-3 aldehydes (260) [40].. Amidoxime intermediates (262) were prepared in good

yields by treating corresponding nitriles (261) with hydroxylamine in reflux condition using Aqueous

methanol as solvent [41]. Microwave irradiation of pyrazole aldehydes with amidoximes using dimethyl

sulfoxide as solvent produced 1,2,4-oxadiazoles in 3 min (263 a-l). The synthetic strategy for

preparation of the pyrazolo-oxadiazoles is depicted in (Scheme-4.3).

136

O N

HN NH2

O

NH

N

OHR

RRNH2NHCONH2

EtOH/NaOAc/0oC

POCl3/DMF

0-80oC

R1 CN NH2OH/MeOHR1

NH2

NOH

NH

N

R O

NN

R1

Microwave

258259 260(a, c, g, j)

261 262

263(a-l)

a: R= 4-Me, R1= H; e: R= 4-Me, R

1= 4-OMe; i: R= 4-Me, R

1= 3-OMe;

b: R= 4-Me, R1= 4- Cl; f: R= Me, R

1= 2-Br,4-Cl; j: R= CF3, R

1= 4-F;

c: R= 3-OMe, R1= 4- Cl; g: R= 4- Cl, R

1= 2,4- Cl k: R= CF3, R

1= 4-N(CH3)2

d: R= 3-OMe, R1= 4- F; h; R= 3-OMe, R

1= 4-NO2 l: R= Me, R

1= Morpholine

Scheme 4.3: Preparation of (1H-Pyrazol-3yl)-1,2,4-oxadiazole derivatives 263(a-l)

Proposed mechanism for the synthesis 1H-Pyrazole-3- aldehyde

N NH

NH2

H

O

N NH

NH2

N+

N

O

N+

H

Cl

N N

N

N

ONH2

NN

NH2

O

N+

OH

N NH

NH2H

O

OH

NNH

O -CO2, NH3

NH

O

ClP

O

ClCl

N

OP

O

ClCl

HCl

137

The resulting compounds were confirmed with the NMR, Mass and IR spectroscopy. Formation

of aldehydes (260) was confirmed by aldehydes peak at 9.87 in 1H NMR and by checking the DNP

activity in TLC plate. The characterization data of aldehydes intermediates is mentioned in table-4.2.

Table-4.2: Characterization data of Aldehydes (260a, 260c, 260g, 260j)

Compound Yield M.P

(oC)

Molecular

formula

Mol

wt

M+,

m/z

1H NMR(δ, ppm)

260a, R= 4-

Methyl 60% 123-125

C11H10N2

O 186.2 187.2

2.40 (s, 3H, CH3), 7.29 (d,

2H, 2CH), 7.67 (d, 2H,

2CH), 8.00 -8.40 (d, 1H,

CHN), 9.87 s (1H, CHO),

13.63 (s, 1H, NH)

260c, R= 3-

Methoxy

40 158-160 C11H10N2

O2 202.2 203

3.77 (s, 3H, OCH3), 7.10

(d, 1H, CH), 7.42 (m, 2H,

2CH), 7.55 (t, 1H, CH),

8.34 (d, 1H, CHN), 9.90

(s, 1H, CHO), 13.81 (s,

1H, NH)

260g, R= 4-

Chloro

34 142-144 C10H7ClN

2O 206.6 207.6

7.45 (d, 2H, 2CH), 7.89

(d, 2H, 2CH), 8.12 and

8.40 (s, 1H, CHN), 9.91

(s, 1H, CHO), 13.60 (s,

1H, NH)

260j, R= 4-

Trifluoromethyl 40 172-174

C11H7F3N

2O 240.1 241.1

7.30 (d, 2H, 2CH), 7.90

(d, 2H, 2CH), 8.22 and

8.40 (d, 1H, CHN), 9.90

(s, 1H, CHO), 13.60 (s,

1H, NH)

138

Pyrazolo-oxadiazoles 260 (a-l) confirmed by 1H NMR,

13C NMR, Mass and IR spectral studies.

Presence of pyrazole –CH at δ 7.2-7.6 and appearence of C=N peak at 1599 cm-1

in IR spectrum

indicates the formation of oxadiazole. For example in case of compound 260h IR peaks at 1598 (C=N),

1545 (N-O), 1285 (C-O) cm-1 confirms the oxadiazole and nitro functional groups. In 1H NMR a

singlet peak at δ 7.63 indicates the pyrazole –CH, para patern observed at δ 8.24, 8.40 indicates

nitrophenyl group. In 13

C NMR peaks at δ 167.2, 160.0, indicates the oxadiazole carbons. Similarly in

LCMS, m/z = 364.1 confirms the molecular weight of the compound.

4.3. Synthesis

4.3.1. General procedures

4.3.1.1. General procedure for preparation of semicarbazones (259 a-l)

To a stirred solution of acetophenones (258) (1 mmol) in ethanol (5 ml) and water (10 ml) was

added sodium acetate (2.5 mmol) at 0oC. Reaction mixture stirred at 0-10 oC for 4 hours. Solid separated

was filtered off washed with cold water and suck dried.

4.3.1.2. General procedure for preparation of pyrazole-3-aldehydes (260 a-l)

Phosporousoxychloride (2 mmol) was added drop-wise to DMF (10 ml) at 0 oC and stirred at

same temperature for 30 min. Semicarbazone (259) (1 mmol) was added portion wise at 0 oC, the

reaction mixture was heated to 60 o

C for 4 hours, and poured into crushed ice. The reaction mixture was

then neutralised with 10 % sodium hydroxide solution, and heated to 60 oC for 5 min, cooled to 0

oC and

neutralised using 11N hydrochloric acid. Extracted with ethyl acetate, combined organic layer washed

with water, brine and concentrated to get crude aldehyde, which was recrystalised using ethyl acetate

and hexane to get pure product.

4.3.1.3. General procedure for preparation of Amidoximes (262 a-l)

139

To stirred solution of carbonitrile compound (261) (1 mmol) in methanol (10 ml) was added

hydroxylamine hydrochloride (2.0 mmol) and triethylamine (3 mmol) at 0 oC. Reaction mixture was

heated to reflux for 8 hours; mass analysis of reaction mixture confirms completion of reaction.

Reaction mixture was cooled to room temperature, diluted with water (100 ml), solid separated was

filtered, dried to get pure compound as yellow solid.

4.3.1.4. General procedure for preparation of 5-(4-phenyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole derivatives

(263 a-l)

To a mixture of Pyrazole aldehydes (260) (1 mmol) and amidoximes (262) (1 mmol) was added

DMSO (2 mL) and resulting paste was irradiated in microwave synthesis system at 120W power and

100 ºC temperature for 3 minutes. Mass analysis of crude reaction mixture confirms the completion of

reaction. Reaction mixture was poured to water extracted with ethylacetate, washed with brine solution

and concentrated to get crude product. Crude product was purified by column chromatography using 5-

15% of methanol in dichloromethane as eluent.

4.4. Characterization

4.4.1. Experimental data

4.4.1.1. 3-Phenyl-5-(4-p-tolyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole (263a)

Yield 75 %, Off white solid, M. p. 128-120 oC, IR (KBr, νmax cm

-1): 3143 (N-H), 3080 (C-H),

1599 (C=N), 1284 (C-O). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.2 (s, 1H, CH3), 7.20 (d, 2H, Ar-H,

J = 8 Hz), 7.33 (m, 2H, Ar-H), 7.48 (m, 2H, Ar-H), 8.4 (m, 4H, Ar-H). 13C NMR (75 MHz, DMSO-d6) δ

(ppm): 166.2, 160.8, 150.9, 140.3, 132.8, 131.3, 131.0, 130.6, 129.1, 127.1, 126.0, 121.5, 116.2, 98.0,

27.2. MS: m/z = 303.2 (M+1). Anal. calcd. for C18H14N4O: 71.51; H, 4.67; N, 18.53. Found: 71.41; H,

4.63; N, 18.50.

4.4.1.2. 3-(4-Chlorophenyl)-5-(4-p-tolyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole (263b)

140

Yield 66 %, Off white solid, M. p. 138-140 oC, IR (KBr, (KBr, νmax cm

-1): 3141 (N-H), 3080

(C-H), 1597 (C=N), 1284 (C-O). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.3 (s, 1H, CH3), 7.20 (d,

2H, Ar-H, J = 8 Hz), 7.33 (m, 2H, Ar-H), 7.48 (m, 2H, Ar-H), 8.58 (m, 4H, Ar-H). 13

C NMR (75 MHz,

DMSO-d6) δ (ppm): 166.2, 161.8, 150.9, 140.3, 132.8, 131.3, 131.0, 130.6, 129.1, 127.1, 126.0, 121.5,

116.2, 98.0, 27.2. MS: m/z = 338.7 (M+1). Anal. calcd. for C18H13ClN4O: C, 64.19; H, 3.89; N, 16.64.

Found: C, 64.39; H, 3.89; N, 16.54.

4.4.1.3. 3-(4-Chlorophenyl)-5-(4-(3-methoxyphenyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (263c)


-1): 3138 (N-H), 3070 (C-H),

1589 (C=N), 1283 (C-O). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 3.7 (s, 1H, -OCH3), 7.10 (d, 2H,

Ar-H, J = 8 Hz), 7.23 (m, 2H, Ar-H), 7.38 (m, 2H, Ar-H), 8.18 (m, 4H, Ar-H). 13

C NMR (75 MHz,

DMSO-d6) δ (ppm): 166.2, 161.8, 150.1, 140.3, 132.8, 131.3, 131.0, 130.6, 129.1, 127.1, 126.0, 121.5,

116.2, 98.0, 57.2. MS: m/z = 354.0 (M+1). Anal. calcd. for C18H13ClN4O2: C, 61.28; H, 3.71 N, 15.88.

Found C, 61.28; H, 3.68; N, 15.86.

4.4.1.4. 3-(4-Fluorophenyl)-5-(4-(3-methoxyphenyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (263d)


-1): 3137 (N-H), 3060 (C-H),

1599 (C=N), 1285 (C-O), 1102 (N-H). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 3.7 (s, 1H, -OCH3),

6.93 (d, 2H, Ar-H, J = 8 Hz), 7.03 (m, 2H, Ar-H), 7.38 (m, 4H, Ar-H), 8.18 (m, 2H, Ar-H). 13

C NMR

(75 MHz, DMSO-d6) δ (ppm): 166.5, 161.1, 152.0, 151.1, 140.3, 132.8, 131.3, 131.0, 130.6, 129.1,

127.1, 126.0, 121.5, 116.5, 98.0, 57.0. MS: m/z = 337.32 (M+1). Anal. calcd. for C18H13FN4O2: C,

64.28; H, 3.90; N, 16.66. Found C, 64.28; H, 3.94; N, 16.56.

4.4.1.5. 3-(4-Methoxyphenyl)-5-(4-p-tolyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole (263e)

Yield 74 %, White solid, M. p. 137-139 oC, IR (KBr, νmax cm

-1): 3139 (N-H), 3080 (C-H), 1598

(C=N), 1285 (C-O), 1100 (N-H). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.3 (s, 1H, CH3), 3.7 (s, 1H,

141

-OCH3), 6.93 (d, 2H, Ar-H, J = 8 Hz), 7.13 (d, 2H, Ar-H), 7.38 (m, 4H, Ar-H), 8.18 (m, 2H, Ar-H). 13

C

NMR (75 MHz, DMSO-d6) δ (ppm): 166.2, 161.8, 150.9, 140.3, 132.8, 131.3, 131.0, 130.6, 129.1,

127.1 , 121.5, 116.2, 98.0, 57.2, 27.1. MS: m/z = 333.36 (M+1). Anal. calcd. for C19H16N4O2: C, 68.66;

H, 4.85; N, 16.86. Found C, 68.59; H, 4.75; N, 16.56.

4.4.1.6. 3-(2-Bromo-4-chlorophenyl)-5-(4-p-tolyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole (263f)

Yield 74 %, White solid, M. p. 141-143 oC, IR (KBr, νmax cm

-1): 3140 (N-H), 3080 (C-H), 1596

(C=N), 1280 (C-O). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.3 (s, 1H, CH3), 7.13 (d, 2H, Ar-H),

7.38-7.50 (m, 4H, Ar-H), 8.18 (m, 2H, Ar-H). 13

C NMR (75 MHz, DMSO-d6) δ (ppm): 166.5, 161.8,

150.9, 140.3, 132.8, 131.3, 131.0, 130.6, 129.1, 127.1, 126.0, 121.5, 116.2, 98.0, 27.2. MS: m/z =

417.67 (M+2). Anal. calcd. for C18H12BrClN4O: C, 52.01; H, 2.91, N, 13.48. Found C, 52.23; H, 2.87,

N, 13.44.

4.4.1.7. 5-(4-(4-Chlorophenyl)-1H-pyrazol-3-yl)-3-(2,4-dichlorophenyl)-1,2,4-oxadiazole (263g)


-1): 3080 (C-H), 1601(C=N),

1285 (C-O). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 7.13-7.36 (m, 5H, Ar-H), 7.38 (d, 2H, Ar-H),

8.18 (m, 2H, Ar-H). 13

C NMR (75 MHz, DMSO-d6) δ (ppm): 166.2, 161.8, 150.9, 140.3, 134.2, 132.8,

131.3, 131.0, 130.6, 129.1, 127.1, 126.0, 121.5, 116.1. MS: m/z = 392.64 (M+1). Anal. calcd. for

C17H9Cl3N4O: C, 52.14; H, 2.32; N, 14.31. Found C, 52.17; H, 2.35; N, 14.24.

4.4.1.8. 5-(4-(3-Methoxyphenyl)-1H-pyrazol-3-yl)-3-(4-nitrophenyl)-1,2,4-oxadiazole (263h)

Yield 62 %, Yellow solid, M. p. 151-153 oC, IR (KBr, νmax cm-1): 3141 (N-H), 3094 (C-H), 1598

(C=N), 1545 (N-O), 1285 (C-O). 1H NMR (75 MHz, DMSO-d6) δ (ppm): 3.9 (s, 1H, -OMe), 7.20 (d,

1H, Ar-H), 7.52 ( m, 1H, Ar-H), 7.63 (s. 1H, Py-H), 7.82 (m, 1H, Ar-H), 8.24 (d, 2H, Ar-H), 8.40 (d,

2H, Ar-H). 13

C NMR (300 MHz, CDCl3) δ (ppm): 167.2, 160.0, 150.1, 134.6, 131.4, 129.0, 124.9,

142

124.7, 120.8, 120.2, 113.0, 56.0. MS: m/z = 364.1 (M+1). Anal. calcd. for C18H13N5O4: C, 59.50; H,

3.61; N, 19.28. Found C, 59.53; H, 3.61; N, 19.34.

4.4.1.9. 3-(3-Methoxyphenyl)-5-(4-p-tolyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole (263i)

Yield 69 %, Off white solid, M. p. 135-137 oC, IR (KBr, νmax cm-1): 3145 (N-H), 3080 (C-H),

1599 (C=N), 1285 (C-O). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.3 (s, 1H, CH3), 3.7 (s, 1H, -

OCH3), 6.93 (d, 2H, Ar-H, J = 8 Hz), 7.13 (d, 2H, Ar-H), 7.38 (m, 4H, Ar-H), 8.18 (m, 2H, Ar-H). 13

C

NMR (75 MHz, DMSO-d6) δ (ppm): 166.0, 161.8, 150.1, 140.3, 132.8, 131.3, 131.0, 130.6, 129.1,

127.1, 126.0, 121.5, 116.2, 98.0. MS: m/z = 333.36 (M+1). Anal. calcd. C19H16N4O2: C, 68.66; H, 4.85;

N, 16.86. Found C, 68.69; H, 4.75; N, 15.86.

4.4.1.10. 3-(4-Fluorophenyl)-5-(4-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole

(263j)

Yield 55 %, Off white solid, M. p. 128-130 oC, IR (KBr, νmax cm-1): 3143 (N-H), 3080 (C-H),

1595 (C=N), 1285 (C-O). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 7.03 (d, 2H, Ar-H, J = 8 Hz),

7.43 (d, 2H, Ar-H), 7.48-7.60 (m, 4H, Ar-H), 8.18 (m, 2H, Ar-H). 13

C NMR (75 MHz, DMSO-d6) δ

(ppm): 166.3, 161.2, 150.9, 140.3, 132.8, 131.3, 131.0, 130.6, 129.1, 127.1, 126.0, 121.5, 116.2, 98.0.

MS: m/z = 375.29 (M+1). Anal. calcd. C18H10F4N4O: C, 57.76; H, 2.69 N, 14.97. Found C, 57.86; H,

2.58, N, 14.99.

4.4.1.11. N,N-Dimethyl-4-(5-(4-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-

yl)benzenamine (263k)


-1): 3140 (N-H), 3080 (C-H),

1596 (C=N), 1282 (C-O). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.85 (s, 6H), 6.8 (d, 2H, Ar-H, J

= 8 Hz), 7.33-7.45 (m, 4H, Ar-H), 7.51-7.60 (m, 2H, Ar-H), 8.18 (m, 2H, Ar-H). 13

C NMR (75 MHz,

DMSO-d6) δ (ppm): 166.3, 161.8, 150.1, 140.3, 132.8, 131.3, 131.0, 130.6, 129.1, 127.1, 126.0, 121.5,

143

116.2, 98.0. 40.3. MS: m/z = 400.37 (M+1). Anal. calcd. C20H16F3N5O: C, 60.15; H, 4.04; 17.54. Found

C, 57.86; H, 2.58, N, 14.99.

4.4.1.12. 4-(5-(4-p-Tolyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl)morpholine (263l)

Yield 50 %, Gummy liquid, IR (KBr, νmax cm-1): 3141 (N-H), 3080 (C-H), 1599 (C=N), 1285

(C-O). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.9(bs, 4H, -NCH2), 3.62 (bs, 4H, -OCH2), 7.12 (d,

2H, Ar-H), 7.36 (m, 3H, Ar-H), 8.18 (bs, 1H, NH). 13

C NMR (75 MHz, DMSO-d6) δ (ppm): 166.2,

161.1, 150.3, 140.4, 131.8, 131.3, 130.6, 129.51, 127.1, 126.0, 116.2, 67.2, 46.0, 24.3. MS: m/z =

312.34 (M+1). Anal. Calcd C16H17N5O2: C, 61.72; H, 5.50; N, 22.49. Found C, 61.66; H, 5.50; N,

22.49.

144

4.3.2. Spectral data

Fig. 4.30: 1H NMR Spectrum of compound 263h

ON

N

O2N

NHN

O

263h

145

Fig. 4.31: 13C NMR Spectrum of compound 263h

ON

N

O2N

NHN

O

263h

146

ON

N

O2N

NHN

O

263h

C18H13N5O4Mol. Wt.: 363.33

147

Fig. 4.32: LCMS of compound 263h

Fig. 4.33: IR Spectrum of compound 263h

4.5. Conclusion

A series of novel (1H-pyrazol-3-yl)-1, 2, 4- oxadiazole derivatives were synthesized by

microwave irradiation in reasonably good yields.They were characterized by 1H NMR,

13C NMR, mass

spectrometry, IR studies and elemental analyses. All the newly synthesized compounds were screened

for antibacterial activity by MIC method. The structural activity relationship (SAR) and antimicrobial

activity of the entire compound are discussed in CHAPTER 6.

ON

N

O2N

NHN

O

263h

148

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