chapter 5 synthesis of substituted-4,5...

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CHAPTER – 5

SYNTHESIS OF SUBSTITUTED-4,5-DIHYDRO-1H-PYRAZOLO[3,4-d]PYRIMIDINES AND THEIR RELATED

DERIVATIVES.

5.1 INTRODUCTION:

This chapter describes the synthesis of some substituted-4,5-

dihydro-1H-pyrazolo[3,4-d]pyrimidines and their related derivatives.

Pyrazole and its fused heterocyclic derivatives constitute an

interesting class of heterocycles due to their synthetic versatility and

effective biological activities [173-175]. Pyrazolo[3,4-d]pyrimidine

derivatives have been found to possess antitumour and antileukemia

activities [176-179]. They are identified as general class of adenosine

receptors [180&181]. Their extensive biological activities prompted us

to synthesize new chemical entities. Therefore, it was considered

worthwhile to synthesize novel substituted-4,5-dihydro-1H-pyrazolo

[3,4-d] pyrimidines.

5.2 LITERATURE SURVEY

Several synthetic methods have been reported in the literature

for the synthesis of pyrazolo[3,4-d]pyrimidines and a few of them are

discussed below.

5.2.1 Pyrazolo[3,4-d]pyrimidines

Cheng et. al. [182&183] reported that substituted hydrazine

(204) reacted with ethoxymethylenemalononitrile (205) in boiling

alcohol to give the corresponding substituted-5-amino-4-cyano

pyrazole (206), which on acetylation with acetic anhydride gave the

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corresponding substituted-5-acetylamino-4-cyanopyrazole (207).

Treatment of 207 with hydrogen peroxide in alkaline solution at 70-80

ºC gave the hydroxy pyrazolo[3,4-d]pyrimidines (208) (Scheme-5.1).

….. Scheme - 5.1

Peat et. al. reported [184] that the cyclisation of substituted-5-

amino-4-cyanopyrazole (206) with formic acid and subsequent

treatment with POCl3 gave chloro pyrazolo[3,4-d]pyrimidines (210)

(Scheme-5.2).

….. Scheme - 5.2

Harb et. al. reported [185] that 5-amino-1-(5,6-diphenyl-3-

triazen-3-yl)-pyrazole-4-carbonitrile [186] (211) was converted into 5-

amino-1-(5,6-diphenyl-3-triazen-3-yl)-pyrazole-4-carboxamide (212) at

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room temperature by using excess of urea-hydrogen peroxide adduct

(UHP) in the presence of a catalytic amount of potassium carbonate in

an acetone-water mixture as a solvent. Heating of 212 with

triethylorthoformate and acetic anhydride under reflux resulted in the

formation of 1-(5,6-diphenyl-1,2,4-triazine-3-yl)-1,5-dihydro-4H-

pyrazolo[3,4-d]pyrimidine-4-one (213). On the other hand, heating of

212 with diethyl oxalate in ethanol under reflux yielded ethyl { [4-

(aminocarbonyl)-1-(5,6-diphenyl-1,2,4-triazin-3-yl-1H-pyrazolo-5-yl]

amino} (oxo) acetate (214) which was converted into ethyl 1-(5,6-

diphenyl-1,2,4-triazin-3-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]

pyrimidine-6-carboxylate (215) by in refluxing in glacial acetic acid

(Scheme-5.3).

….. Scheme - 5.3

It was reported by Abunada et. al. [187] that treatment of 5-

amino-3-aryl-1-(4-nitrophenyl)pyrazole-4-carbo nitrile (216) with

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excess of formic acid and formamide respectively yielded the

corresponding 3-aryl-1-(4-nitrophenyl) pyrazolo [3,4-d]pyrimidine-4-

one (217) and 4-amino-3-aryl-1-(4-nitrophenyl)pyrazolo[3,4-d]

pyrimidine (218) (Scheme-5.4).

….. Scheme - 5.4

Joshi et. al. reported [188] a novel method adopting the

knoevengal condensation of 5-isopropyl-2,4-dihydro-3-pyrazolone

(219) with different aromatic aldehyde (220) in the presence of

piperidine at reflux temperature to give 4-benzylidine-5-isopropyl-2,4-

dihydro-3-pyrazolone (221), which on treatment with urea in

ethanolic HCl yielded 3-isopropyl-4-aryl-1,4,5,7-tetrahydro pyrazolo

[3,4-d]pyrimidine -6-ones (222) (Scheme-5.5).

….. Scheme - 5.5

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Bakavoli et. al. [189] reported that Con. sulfuric acid mediated

hydrolysis of 5-amino-1-(2,4-dinitrophenyl)-1H-4-pyrazolecarbonitrile

(223) to give the corresponding 5-amino-1-(2,4-dinitrophenyl)-1H-4-

pyrazolo carboxamide (224). Oxidative cyclization of the later

compound 224 with various substituted aromatic aldehydes in the

presence of equimolar molecular iodine as a mild Lewis acid and

oxidant under neutral conditions in boiling acetonitrile gave

pyrazolo[3,4-d]pyrimidine (225) derivatives in good to excellent yield

(Scheme-5.6).

….. Scheme-5.6

5.2.2 Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine

Davoodinea et. al. [190] reported that the reaction of 1,5-

dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one [191] (226) with POCl3

gave 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (227). Treatment of chloro

derivative 227 with hydrazine hydrate at room temperature gave 4-

hydrazinyl-3-methyl-1-phenyl-1H-pyrazolo [3,4-d]pyrimidine (228).

Cyclo condensation of 228 with triethylorthoformate in ethanol under

reflux gave the desired tricyclic pyrazolo[4,3-e][1.2.4]triazolo[4,3-c]


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….. Scheme - 5.7

Mezheritsky et. al. [192] synthesized pyrazolo[4,3-d] [1,2,4]

triazolo[1,5-c]pyrimidine (Scheme-5.8) by reacting 5-amino-1H-

pyrazole-4-carbonitrile (206) with triethylorthoformate to yield ethyl

N-4-cyano-1H-pyrazol-5-ylformimidate (230). The later was reacted

with substituted hydrazide under prolonged reflux in bromobenzene to

obtain the 2-phenyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c] pyrimidine

(231).

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….. Scheme - 5.8

Abunada et. al. [187] reported that the condensation of 5-

Amino-3-aryl-1-(4-nitrophenyl)pyrazole-4-carbonitrile (216) with

triethylorthoformate under reflux afforded 5-ethoxymethylene amino

pyrazole-4-carbonitrile (232). This compound reacted with hydrazine

hydrate in tetrahydrofuran to yield 4-imino-1-(4-nitrophenyl)-3-

phenyl-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-amine (233). Cyclization of

this compound 233 with excess of triethyl orthoformate under reflux

conditions gave 7-(4-nitrophenyl)-9-phenyl-7H-pyrazolo[4,3-e][1,2,4]

triazolo[1,5-c]pyrimidine (234) (Scheme-5.9).

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….. Scheme - 5.9

Shawkat et. al. [193] reported that reaction of 2-amino-4-(8-

quinolinol-5-yl)-1-(p-tolyl)-pyrrole-3-carbonitrile (235) [194] with

triethylorthoformate and acetic anhydride under reflux condition

afforded the intermediate ethoxymethyleneamino derivative 236

which was isolated and used without purification in the next step.

Thus, stirring of 236 with hydrazine hydrate in dry benzene at

room temperature gave 5-amino-4-iminopyrrolo[2,3-d]pyrimidine

derivative (237). Cyclo condensation of 237 with

triethylorthoformate /acetyl chloride resulted in the formation of

triazolo[1,5-c]pyrrole[3,2-e] pyrimidine derivative (238) (Scheme-

5.10).

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….. Scheme - 5.10

Baraldi et. al. [195] reported that the reaction of 5-amino-4-

cyano-1-(β-hydroxyethyl) pyrazole (239) with acetic anhydride in

pyridine afforded the 1-[β-(acetyloxy) ethyl]-5-amino-4-

cyanopyrazole (240). This compound with triethylorthoformate

under reflux condition in the presence of acetic anhydride afforded

the intermediate ethoxymethyleneamino derivative 241, which was

isolated and used without purification in the next step. Thus,

stirring of 241 with furoic acid hydrazide in 2-methoxyethanol

yielded the pyrazolo[3,4-d]pyrimidine derivatives, which were

converted through a thermal induced cyclisation in diphenylether

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to the 2-(2-(furan-2-yl)-7H-pyrazolo[4,3-e] [1,2,4] triazolo[1,5-c]

pyrimidin-7-yl)ethyl acetate (242) in good yields. The compound

242 was deprotected with ammonia to give 2-(2-(furan-2-yl)-7H-

pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl)ethanol (243),

which was converted to 7-(2-(benzyloxy)ethyl)-2-(furan-2-yl)-7H-

pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (244) by benzylation

in the presence of sodium hydride (Scheme-5.11).

….. Scheme - 5.11

5.2.3 Imidazo[1,2-c]pyrazolo[4,3-e]pyrimidines

Fraghly et. al. [196] reported that the reaction of 5-amino-1-(1-

benzyl-1H-indol-3-yl carbonyl-1H-pyrazole-4-carbonitrile (245) with

ethylenediamine in the presence of catalytic amount of carbon

disulfide yielded 3-[5-amino-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-

pyrazol-1-ylcarbonyl]-1-benzyl-1H-indole (246). Treatment of 246 with

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triethylorthoformate afforded 7-(1-benzyl-1H-indol-3-ylcarbonyl)-2,3-

dihydro-7H-imidazol[1,2-c] pyrazolo [4,3-e]pyrimidine (247) (Scheme-

5.12).

….. Scheme - 5.12

Shawkat et. al. [193] reported that the condensation of 2-amino-

4-(8-quinolinol-5-yl)-1-(p-tolyl)-pyrrole-3-carbonitrile (235) [194] with

ethylenediamine in the presence of catalytic amount of carbon

disulfide yielded 2-amino-4-(8-quinolinol-5-yl-1-(p-tolyl)-3-(4,5-

dihydro-1H-imidazol-2-yl)-pyrrole (248). Treatment of 248 with

triethylorthoformate afforded 9-(8-quinolinol-5-yl)-7-(p-tolyl)-

pyrrolo[3,2-e]-1,2,4-triazolo[1,5-c] pyrimidine (249) (Scheme - 5.13).

….. Scheme - 5.13

Gatta et. al. [197] reported that 5-amino-4-cyano-1-(2 or 4-

fluoro benzyl) pyrazole (250) reacted with triethylorthoformate to

afford imidate intermediate (251). Treatment of 251 with

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aminoacetaldehyde dimethylacetal in ethyleneglycol monomethylether

under reflux temperature yielded 4-cyano-5[(2-dimethoxy ethylamino

methylene)amino]pyrazole (252) which on cyclisation in diphenylether

at reflux temperature gave imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine

(253) (Scheme-5.14).

….. Scheme - 5.14

Dewald et. al. [198] reported that the reaction of 1,2-diamines

with 5-cyano-1,3-dimethyl-1H-pyrazole-4-amine (254) in the presence

of p-toluenesulfonic acid at 120-160 ºC gave 5-(imidazolo-2-yl)-1,3-

dimethyl-1H-pyrazol-4-amine (255) which on subsequent cyclization

with triethylorthoformate to furnished imidazo[1,2-c]pyrazolo[4,3-e]


….. Scheme - 5.15

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5.3 PRESENT WORK

In this chapter, the synthesis of some new substituted-4,5-

dihydro-1H-pyrazolo[3,4-d]pyrimidines and their related derivatives

containing heteroaryl sulfonyl methyl functionality as potentially

biologically active compounds is described.

5.4 RESULTS AND DISCUSSIONS

5.4.1 Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine

Aryl hydrazine derivatives 163a (i.e. 163, R=Pyrrolidine, n=1)

was reacted with 2-(ethoxymethylene)malanonitrile (205) in ethanol at

reflux temperature to obtain a new product 5-amino-1-(4-((pyrrolidin-

1-ylsulfonyl) methyl) phenyl)-1H-pyrazole-4-carbonitrile (257a) (i.e.

257, R=pyrrolidine, n=1) (Scheme-5.16). This product was

characterized by analytical and spectral data. Its IR spectrum

(Fig.5.1) in (KBr) showed peaks at 3451 cm-1 and 3297 cm-1 conforms

the presence of primary amine –NH2 group and showed another

characteristic absorption peak at 2217 cm-1 indicates the presence of

–CN group. The absorption peak at 1639 cm-1 due to –C=N and the

peaks appeared at 1336 cm-1 and 1143 cm-1 characterstic absorption

of –SO2 group. Its 1H-NMR spectrum (CDCl3/TMS) (Fig.5.2) showed

signals at δ 1.80-1.90 (m, 4H, pyrrolidine), 3.1-3.2 (m, 4H,

pyrrolidine) 4.2 (s, 2H, -SO2CH2), 4.7 (br, s, 2H, -NH2 D2O

exchangable), 7.50-7.60 (m, 4H, Ar-H), and 7.70 (s, 1H, CH, pyrazole).

Its APCI mass spectrum (Fig. 5.3) showed M++1 ion peak at 332

corresponding to a molecular mass of 331. Its 13C NMR spectrum (Fig.

153

5.4) showed signals at δ 25.7, 48.06, 52.86, 73.94, 115.12, 124.10,

129.99, 132.23, 137.60, 142.22 and 151.62. Based on the above

spectral data, the compound was assigned the structure 257a.

….. Scheme - 5.16

The above reaction of aryl hydrazine derivatives 163(a-c) with

205 has been found to be a general one and has been extended to

other substituted hydrazines. The products 257(a-c) obtained have

been assigned structures on the basis of their spectral and analytical

data.

The condensation of 257a with triethylorthoformate at reflux

temperature afforded the corresponding ethyl N-4-cyano-1-(4-

((pyrrolidin-1-ylsulfonyl)methyl)phenyl)-1H-pyrazol-5-ylformimidate

(258a) (i.e. 258, R=Pyrrolidine, n=1) (Scheme-5.17) which was

isolated in 70 % yield. The structure of the product was established by

the elemental and spectral data.

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….. Scheme - 5.17

The above reaction of 257(a-c) with triethylorthoformate has

been found to be a general one and has been extended to other

substituted pyrazole amino nitrile derivatives. The products 258(a-c)

obtained have been assigned structures on the basis of their spectral

and analytical data. (for spectral and analytical data, Please see the

Experimental Section).

Further reaction of 258a with hydrazine hydrate in

tetrahydrofuran at ambient temperature produced the corresponding

4-Imino-1-(4-((pyrrolidin-1-ylsulfonyl)methyl)phenyl)-1H-pyrazolo[3,4-

d]pyrimidin-5(4H)-amine (259a) (i.e. 259, R=Pyrrolidine, n=1)

(Scheme- 5.18). The structure proposed for the product was

established by the elemental and spectral data.

….. Scheme - 5.18

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The above reaction of 258(a-c) with hydrazine hydrate

triethylorthoformate has been found to be a general one and has been

extended to substituted imidate derivatives. The products 259(a-c)

obtained have been assigned structures on the basis of their spectral

and analytical data. (for spectral and analytical data, Please see

the Experimental Section).

Refluxing the compound of 259a in an excess of

triethylorthoformate gave the product 7-(4-((pyrrolidin-1-ylsulfonyl)

methyl)phenyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine

(260a) (i.e. 260, R=Pyrrolidine, n=1) (Scheme-5.19). Its IR spectrum

in KBr (Fig.5.5) showed the absorption at 1646 cm-1 due to (-C=N)

and peaks at 1327 cm-1 and 1141 cm-1 due to -SO2 group. The 1H-

NMR spectra (Fig.5.6) showed signals at 9.4 and 9.5 assignable to the

triazole and the pyrimidine proton, respectively. Its 1H-NMR spectrum

(DMSO-d6/TMS) showed signals at δ 1.70-1.80 (m, 4H, pyrrolidine),

3.1-3.2 (m, 4H, pyrrolidine), 4.6 (s, 2H, -SO2CH2), 7.60 (d, J=8.4 Hz,

2H, Ar-H,), 8.1 (d, J=8.4Hz, 2H, Ar-H,), 8.70 (s, 1H, CH pyrazole), 9.43

(s, 1H, CH triazole), 9.5 (s, 1H, CH pyrimidine). Its APCI mass

spectrum (Fig.5.7) showed M++1 ion peak at 384 corresponding to a

molecular mass of 383. Its 13C NMR spectrum (Fig. 5.8) showed

signals at δ 25.74, 48.07, 53.07, 101.88, 122.35, 129.82, 132.18,

133.95, 137.16, 138.12, 139.61, 143.66 and 144.89. Based on the

above spectral data, the compound was assigned the structure 260a.

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….. Scheme - 5.19

The above reactions of 259a to 260a found to be a general one

and have been extended to other substituted derivatives. The products

260a-c obtained have been assigned on the basis of their spectral and

analytical data.

5.4.2 Pyrazolo[3,4-d]pyrimidines

Compound 257a was converted into 5-amino-1-(4-

((pyrrolidin-1-ylsulfonyl) methyl) phenyl)-1H-pyrazole-4-carboxamide

(261a) (i.e. 261, R=-Pyrrolidine, n=1) (Scheme–5.20) using Con.

sulphuric acid at room temperature. The structure was established by

the spectral data. Its IR spectrum in KBr (Fig.5.9) showed the peaks

at 3461 cm-1 and 3349 cm-1 due to -NH2 and not displayed peak in the

region 2300-2200 cm-1 shows the absence of nitrile group. The

presence of absorption band in the region 1654 cm-1 due to >C=O of –

CONH2 group. The peaks at 1327 cm-1 and 1144 cm-1 due to –SO2

group. Its 1H-NMR spectrum (DMSO-d6/TMS) (Fig.5.10) showed

signals at δ 1.80-190 (m, 4H, pyrrolidine), 3.1-3.2 (m, 4H,

pyrrolidine) 4.5 (s, 2H, -CH2SO2) 6.50 (bs, 2H, -NH2, D20

exchangable), 7.00-7.2 (bs, 2H, -CONH2 D20 Exchangable) 7.40-7.60

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(m, 4H, Ar-H), 7.90 (s, 1H, CH pyrazole). Its mass spectrum (Fig.5.11)

showed M++1 ion peak at 350 corresponding to a molecular mass of

349. Based on the above spectral data, the compound was assigned

the structure 261a.

….. Scheme - 5.20

The above reaction of 257a with Con.sulphuric acid has been

found to be a general one and has been extended to substituted amino

cyano pyrazoles. The products 261b-c obtained have been assigned on

the basis of their spectral data.

261a was converted into 1-(4-((pyrrolidin-1-ylsulfonyl) methyl)

phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (262a) (i.e. 262,

R=Pyrrolidine, n=1) (Scheme–5.21) by refluxing in formic acid. The

structure was established by the spectral data. Its IR spectrum in KBr

(Fig.5.12) showed the peak at 1689 cm-1 indicates the presence of

>C=O group. The absorption peaks at 1327 cm-1 and 1143 cm-1 due

to presence of –SO2 group. Its 1H-NMR spectrum (DMSO-d6/TMS)

(Fig.5.13) showed signals at δ 1.80-190 (m, 4H, pyrrolidine), 3.2 (m,

4H, pyrrolidine), 4.5 (s, 2H, -SO2CH2), 7.5 (d, J=8.4 Hz, 2H, Ar-H),

8.0 (d, J=8.4 Hz, 2H, Ar-H), 8.10 (s, 1H, CH pyrazole), 8.40 (s, 1H, CH

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pyrimidine), 12.20 (bs, 1H, NH, D2O exchangable). Its APCI mass

spectrum (Fig. 5.14) showed M++1 ion peak at 360 corresponding to a

molecular mass of 359. Based on the above spectral data, the

compound was assigned the structure 262a.

….. Scheme - 5.21

Alternatively the compound 262a (i.e. 262, R=Pyrrolidine, n=1)

was prepared by refluxing amino nitrile 257a (i.e. 257, R=Pyrrolidine,

n=1) in aqueous formic acid with 85% yield which was identical, in all

respects with the product obtained earlier (Scheme–5.22).

….. Scheme - 5.22

Reaction of 257a (i.e. 257, R=Pyrrolidine, n=1) in excess

formamide gave the 1-(4-((pyrrolidin-1-ylsulfonyl)methyl)phenyl)-1H-

pyrazolo[3,4-d]pyrimidin-4-amine (263a) (i.e. 263, R=Pyrrolidine, n=1)

(Scheme–5.23) with 80% yield. The product structure was established

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by the elemental and spectral data. Its IR spectrum in KBr (Fig.5.15)

displayed no cyano group absorptions and peaks at 3430 cm-1 and

3325 cm-1 due to –NH2 group. The peaks at 1306 cm-1 and 1144 cm-1

absorptions due to –SO2 group. Its 1H-NMR spectrum (DMSO-d6/TMS)

(Fig.5.16) showed signals at δ 1.70-1.80 (m, 4H, pyrrolidine), 3.1-3.2

(m, 4H, pyrrolidine), 4.5 (s, 2H, -SO2CH2), 7.6-7.7 (d, J=8.4 Hz, 2H,

Ar-H), 8.0 (bs, 2H, NH2 D2O exchangable), 8.1-8.2 (d, J=8.4 Hz, 2H,

Ar-H,), 8.3 (s, 1H, CH pyrazole), 8.4 (s, 1H, CH pyrimidine). Its APCI

mass spectrum (Fig. 5.17) showed M++1 ion peak at 359

corresponding to a molecular mass of 358. Its 13C NMR spectrum (Fig.

5.18) showed signals at δ 25.6, 48.04, 53.44, 101.85, 120.52, 127.99,

131.92, 134.60, 139.14, 153.76, 157.09 and 158.68. Based on the

above spectral data, the compound was assigned the structure 263a.

….. Scheme - 5.23

The above reaction of 257a with formamide has been found to

be a general one and has been extended to substituted amino cyano

pyrazoles. The products 263(b-c) obtained have been assigned

structures on the basis of their spectral data.

The compound 257a was boiled in acetic anhydride-pyridine

mixture to get the 6-methyl-1-(4-((pyrrolidin-1-ylsulfonyl)methyl)

160

phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (264a) (i.e. 264,

R=Pyrrolidine, n=1) (Scheme–5.24). The structure of the product was

established by the spectral data. Its IR spectrum in KBr (Fig.5.19)

displayed no cyano group absorptions. Its 1H-NMR spectrum

(CDCl3/TMS) (Fig.5.20) showed signals at δ 1.80 (m, 4H,

pyrrolidine), 2.27 (s, 3H, CH3), 3.2 (m, 4H, pyrrolidine), 4.3 (s, 2H, -

SO2CH2), 7.50 (d, J=8.4 Hz, 2H, Ar-H), 7.60 (d, J=8.4 Hz, 2H, Ar-H),

8.00 (s, 1H, CH pyrazole). Its APCI mass spectrum (Fig. 5.21) showed

M++1 ion peak at 374 corresponding to a molecular mass of 373.

Based on the above spectral data, the compound was assigned the

structure 264.

….. Scheme 5.24

The above reaction of 257a with acetic anhydride-pyridine has

been found to be a general one and has been extended to substituted

amino cyano pyrazoles. The products 264(b-c) obtained have been

assigned on the basis of their spectral data.

5.4.3 Imidizo[1,2-c]pyrazolo[4,3-e]pyrimidines

The reaction of 257a with ethylenediamine in the presence of

carbon disulfide gave the new compound 4-(4,5-dihydro-1H-imidazol-

2-yl)-1-(4-((pyrrolidin-1-ylsulfonyl)methyl)phenyl)-1H-pyrazol-5-amine

161

(265a) (i.e. 265, R=Pyrrolidine, n=1) (Scheme–5.25). The product

structure was established by the spectral data.

….. Scheme - 5.25

The plausible way of the reaction mechanism is depicited in

Scheme-5.26.

….. Scheme - 5.26

The above reaction of 257a with ethylenediamine has been

found to be a general one and has been extended to substituted amino

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cyano pyrazoles. The products 265(b-c) obtained have been assigned

on the basis of their spectral data. (for spectral and analytical data,

Please see the Experimental Section).

The condensation of imidazolinyl derivative 265a with

triethylorthoformate in the presence of a few drops of acetic acid

furnished the pyrazolopyrimidine derivative 7-(4-((pyrrolidin-1-

ylsulfonyl)methyl)phenyl)-3,7-dihydro-2H-imidazo[1,2-c]pyrazolo[4,3-

e]pyrimidine (266a) (i.e. 266, R=Pyrrolidine, n=1) (Scheme–5.27).

The product structure was established by the spectral data. Its IR

spectrum in KBr (Fig.5.22) displayed no amino group absorption and

showed absorptions at 1692 cm-1 due to –C=N. The peak at 1326 cm-1

and 1138 cm-1 due to –SO2 group. Its 1H-NMR spectrum (Fig.5.23)

(DMSO-d6/TMS) showed signals at δ 1.80-1.90 (m, 4H, pyrrolidine),

3.1-3.2 (m, 4H, pyrrolidine), 3.80 (t, 2H, -CH2 imidazole), 4.1 (t, 2H, -

CH2 imidazole), 4.3 (s, 2H, -SO2CH2), 7.40-7.50 (d, J=8.4 Hz, 2H, Ar-

H), 8.0-8.1 (m, 4H, Ar-H, CH pyrazole and CH pyrimidine ring

protons). Its APCI mass spectrum (Fig.5.24) showed M++1 ion peak at

385 corresponding to a molecular mass of 384. Its 13C NMR spectrum

(Fig. 5.25) showed signals at δ 25.72, 44.52, 48.07, 50.60, 52.99,

99.03, 123.12, 131.61, 132.59, 136.66, 146.79 and 149.12. Based on

the above spectral data, the compound was assigned the structure

266.

163

….. Scheme - 5.27

The above reaction of 265a with triethylorthophosphate has

been found to be a general one and has been extended to substituted

amino cyano pyrazoles. The products 266(b-c) obtained have been

assigned on the basis of their spectral and analytical data. All the

above sequence of reactions is summarized in Scheme - 5.28 shown

below.

164

….. Scheme 5.28

165

5.5. EXPERIMENTAL SECTION:

5.5.1. PREPARATION OF 205:

Malononitrile (0.378 mol), triethylorthoformate (0.378 mol) and

acetic anhydride (20.0 mL) were taken in a round bottom flask and

heated to reflux for 6 hours at 110-120 ºC. The excess acetic anhydride

was distilled off under reduced pressure, then added hexane (50 mL) to

the crude product and cooled to 10 ºC. The resultant precipitate was

filtered and recrystallised from isopropylalchol.

205: Yield: 39.0 gm (75%), M.R: 54-55 ºC; IR (KBr, cm-1) 2228 (-CN).

5.5.2. GENERAL PROCEDURE FOR THE SYNTHESIS OF 257(a-c):

A mixture of substituted hydrazine 163(a-c) (0.034 mol) and 205,

(0.034 mol) in absolute ethanol (50.0 mL) was heated under reflux for 2

hours. The progress of the reaction was monitered by TLC. Reaction

mass was cooled to 10 ºC, filter the crystalized solid and washed with

ethanol. The crude product was recrystallized from methanol to give pure

257(a-c).

257a: R=pyrrolidine, n = 1, Yield: 9.50 gm (85 %); M.R: 173-175 °C; IR

(KBr, cm-1) 3451, 3297 (-NH2), 2217 (-CN), 1336, 1141 (-SO2); 1H NMR

(CDCl3-/TMS) δ 1.80-1.90 (m, 4H, pyrrolidine), 3.1-3.2 (m, 4H,

pyrrolidine) 4.2 (s, 2H, - SO2CH2), 4.7 (bs, 2H, -NH2, D2O exchangable ),

7.50-7.60 (m, 4H, Ar-H), and 7.70 (s, 1H, CH pyrazole); M++1: 332; 13C

NMR δ25.7, 48.06, 52.86, 73.94, 115.12, 124.10, 129.99, 132.23,

166

137.60, 142.22 and 151.62; Anal.Calcd.for (C15H17N5O2S) requires: C,

54.36; H, 5.17; N, 21.13; Found: C, 54.16; H, 5.10; N, 21.01.

257b: R=-NHCH3, n=1, Yield: 7.80 gm (79 %); M.R: 185-190 ºC; IR (KBr,

cm-1) 3404, 3315 (-NH2), 3231 (-NH), 1641 (-C=N), 2233 (-CN), 1313,

1154 (-SO2); 1H NMR (DMSO-d6/TMS) δ 2.6 (d, 3H, -NHCH3), 4.4 (s, 2H, -

SO2CH2), 5.2 (bs, 2H, -NH2 D2O exchangable), 7.00 (s, 1H, -NHCH3 D2O

exchangable), 7.40-7.60 (m, 4H, Ar-H), 7.80 (s, 1H, CH pyrazole); M++1:

292; Anal.Calcd.for (C12H13N5O2S) requires: C, 49.47; H, 4.50; N, 24.04;

Found: C, 49.34; H, 4.38; N, 23.94.

257c: R=-NHCH3, n=2, Yield: 8.70 gm (84 %); M.R: 200-202 ºC; IR (KBr,

cm-1) 3408,3334, (-NH2), 3246 (-NH), 2216 (-CN), 1646 (-C=N), 1313,

1148 (-SO2); 1H NMR (DMSO-d6/TMS) δ 2.6 (d, 3H, -NHCH3), 3.0 (t, 2H,

-Ar-CH2-), 3.4 (t, 2H, -SO2CH2), 5.3 (s, 2H, -NH2 D2O exchangable), 7.0

(m, 1H, -NHCH3) 7.40-7.60 (m, 4H, Ar-H), 7.80 (s, 1H, CH pyrazole);

M++1: 306; Anal.Calcd.for (C13H15N5O2S) requires: C, 51.13; H, 4.95; N,

22.94; Found: C, 51.08; H, 4.90; N, 22.92;


A mixture of 259(a-c) (0.001 mol), in triethylorthoformate (10.0

mL) was refluxed for 2 hours, and then excess triethylorthoformate was

distilled off under vacuum and quenched into ice water (50.0 mL). The

crystallized product was filtered, washed with water (25.0 mL). The crude

product was recrystallized from hexane to give pure 258(a-c).

167

258a: R=pyrrolidine, n=1, Yield: 0.29 gm (77 %); M.R: 112-114 ºC; IR

(KBr,cm-1) 2219 (-CN), 1632 (-N=C), 1324, 1135 (-SO2) ; 1H NMR (DMSO-

d6/TMS) δ 1.21 (t, 3H, -OCH2CH3), 1.80-1.90 (m, 4H, pyrrolidine), 3.10-

3.20 (m, 4H, pyrrolidine), 3.60 (q, 2H, -OCH2CH3), 4.6 (s, 2H, -SO2CH2),

7.1-7.2 (d, 2H, Ar-H), 7.4-7.8 (m, 3H, Ar-H and N=CHOEt), 8.3 (s, 1H,

CH pyrazole); M++1: 388; Anal.Calcd.for (C19H22N4O3S) requires: C,

59.05; H, 5.74; N, 14.50; Found: C, 59.01; H, 5.69; N, 14.48.

258b: R=-NHCH3 n=1, Yield: 0.28 gm (66 %); M.R: 121-125 ºC; IR

(KBr,cm-1) 2210 (-CN), 1626 (-N=C), 1334, 1145 (-SO2); 1H NMR (DMSO-

d6/TMS) δ 1.21 (t, 3H, -OCH2CH3), 2.22 (d, 1H, -NHCH3), 3.60 (q, 2H, -

OCH2CH3), 4.6 (s, 2H, -SO2CH2), 6.9 (m, 1H, -NHCH3), 7.4-7.8 (m, 5H,

Ar-H and N=CHOEt), 8.3 (s, 1H, CH pyrazole); M++1: 348; Anal.Calcd.for

(C15H17N5O3S) requires: C, 51.86; H, 4.93; N, 20.16; Found: C, 51.81; H,

4.89; N, 20.10.

258c: R=-NHCH3 n=2, Yield: 0.25 (70 %); M.R: 116-118 ºC; IR (KBr, cm-

1) 2210 (-CN), 1646 (-N=C), 1324, 1135 (-SO2); 1H NMR (DMSO-d6/TMS)

δ 1.21 (t, 3H, -OCH2CH3), 2.32 (d, 1H, -NHCH3), 3.20 (m, 2H, -Ar-CH2)

3.60 (q, 2H, -OCH2CH3), 4.6 (s, 2H, -SO2CH2), 6.9 (m, 1H, -NHCH3), 7.4-

7.8 (m, 5H, Ar-H and N=CHOEt), 8.3 (s, 1H, CH pyrazole); M++1: 362;

Anal.Calcd.for (C13H15N5O2S) requires: C, 51.08; H, 4.90; N, 22.92;

Found: C, 51.02; H, 4.89; N, 22.89.

168


Hydrazine hydrate 99% (10.0 mL) was added to suspension of

ethyl N-4-cyano-1-(4-((pyrrolidin-1-ylsulfonyl)methyl)phenyl)-1H-pyrazol-

5-ylformimidate 258(a-c) (0.0051 mol) in dry benzene (30.0 mL). The

reaction mixture was stirred at room temperature for 3 hours. The

preceipitate which formed was filtered off, washed with benzene to afford

259(a-c) as yellow orange crystals.

259a: R=pyrrolidine, n=1, Yield: 1.36 (72 %); M.R: 234-238 ºC; IR (KBr,

cm-1) 3380,3270,3170 (NH,NH2), 1640 (-C=N), 1332, 1148 (-SO2); 1H

NMR (DMSO-d6/TMS) δ 1.8-1.9 (m, 4H, pyrrolidine), 3.1-3.2 (m, 4H,

pyrrolidine), 4.3 (s, 2H, -SO2CH2), 5.42 (s, 2H, N-NH2) 7.40-8.4 (m, 7H,

Ar-H, pyrazole, pyrimidine, and C=NH), M++1: 374; Anal. Calcd.for

(C16H19N7O2S) requires: C, 51.46; H, 5.13; N, 26.26; Found: C, 51.2 6; H,

5.10; N, 26.1 6.

259b: R=-NHCH3, n=1, Yield: 1.24 (73 %); M.R: 218-220 ºC; IR (KBr, cm-

1) 3320, 3120, 2980 (-NH, -NH2), 1644 (-C=N), 1334, 1148 (-SO2); 1H

NMR (DMSO-d6/TMS) δ 2.50 (d, 3H, -NHCH3), 4.3 (s, 2H, -SO2CH2), 5.42

(s, 2H, N-NH2), 6.90 (d, 1H, -NHCH3), 7.40-8.4 (m, 7H, Ar-H, CH

pyrazole, CH pyrimidine, and C=NH); M++1: 334; Anal. Calcd.for


4.34; N, 29.31.


cm-1) 3330, 3130, 2990 (-NH, -NH2), 1634 (-C=N), 1344, 1124 (-SO2); 1H

169

NMR (DMSO-d6/TMS) δ 2.50 (d, 3H, -NHCH3), 3.20 (t, 2H, Ar-CH2), 4.3

(t, 2H, - SO2CH2), 5.42 (s, 2H, N-NH2) 6.90 (m, 1H, -NHCH3) 7.40-8.4 (m,

7H, Ar-H, CH pyrazole, CHpyrimidine, and C=NH); M++1: 348; Anal.

Calcd.for (C14H17N7O2S) requires: C, 48.40; H, 4.93; N, 28.22; Found: C,

48.35; H, 4.83; N, 28.12.


A mixture of 4-Imino-1-(4-(pyrrolidin-1-ylmethyl)phenyl)-1H-

pyrazolo[3,4-d]pyrimidin-5(4H)-amine 259(a-c) (1.2 g, 0.0032 mol) with

(15.0 mL) triethylorthoformate was refluxed for 2 hours. The progress of

the reaction was monitered by TLC. The reaction mass cooled to 20-25ºC,

then the precipitated product was collected by filteration and

recrystallized from methanol to give pure compound 260(a-c).

260a: R=pyrrolidine, n=1, Yield: 0.80 (66 %); M.R: 242-246 ºC; IR (KBr,

cm-1) 1646 (-C=N), 1346, 1141 (-SO2); 1H NMR (DMSO-d6/TMS) δ 1.70-

1.80 (m, 4H, pyrrolidine), 3.1-3.2 (m, 4H, pyrrolidine), 4.6 (s, 2H, -

SO2CH2), 7.80-8.20 (m, 4H, Ar-H), 8.70-9.60 (3s, 3H, CH triazole, CH

pyrazole, CH pyrimidine); M++1: 384; 13C NMR δ 25.74, 48.07, 53.07,

101.88, 122.35, 129.82, 132.18, 133.95, 137.16, 138.12, 139.61, 143.66

and 144.89; Anal. Calcd.for (C17H17N7O2S) requires: C, 53.25; H, 4.47; N,

25.57; Found: C, 53.20; H, 4.44; N, 25.53.


1) 1640 (-C=N), 1348, 1144 (-SO2); 1H NMR (DMSO-d6/TMS) δ 2.50 (d,

3H, -NHCH3), 4.3 (s, 2H, -SO2CH2), 6.90 (m, 1H, -NHCH3), 7.80-8.20 (m,

170

4H, Ar-H), 8.80-9.60 (3s, 3H, CH triazole, CH pyrazole, CH pyrimidine);

M++1: 344; Anal. Calcd.for (C14H13N7O2S) requires: C, 48.97; H, 3.82; N,

28.55; Found: C, 48.93; H, 3.80; N, 28.50.

260c: R=-NHCH3, n=2, Yield: 0.66 (59 %); M.R: 214-217 ºC; IR (KBr, cm-

1) 1635 (-C=N), 1334, 1148 (-SO2); 1H NMR (DMSO-d6/TMS) δ 2.50 (d,

3H, -NHCH3), 3.20 (t, 2H, Ar-CH2), 4.3 (t, 2H, - SO2CH2), 6.90 (m, 1H, -

NHCH3), 7.80-8.20 (m, 4H, Ar-H), 8.80-9.60 (3s, 3H, CH triazole, CH

pyrazole, CH pyrimidine); M++1: 358; Anal. Calcd.for (C15H15N7O2S)

requires: C, 50.41; H, 4.23; N, 27.43; Found: C, 50.39; H, 4.20; N, 27.40.


To the con. sulphuric acid (10.0 mL) cooled in an ice-bath, 5-

amino-1-(4-((pyrrolidin-1-ylsulfonyl)methyl)phenyl)-1H-pyrazole-4-carbo

nitrile 257 (0.009 mol) was added slowly with stirring by maintaining the

temperature below 10 ºC. The mixture was stirred at room temperature

untill the reaction was complete. The reaction mixture was poured into

ice water (50.0 mL) and neutralized with sodium hydroxide. The

precipitated solid was filtered, dried and recrystallized from methanol to

get pure 261(a-c).

261a: R=pyrrolidine, n=1, Yield: 1.40 gm (45 %); M.R:218-220 ºC; IR

(KBr, cm-1) 3461, 3349 (-NH2), 1647 (-C=O), 1327, 1144 (-SO2); 1H NMR

(DMSO-d6/TMS) δ 1.80-1.90 (m, 4H, pyrrolidine), 3.1-3.2 (m, 4H,

pyrrolidine), 4.5 (s, 2H, -SO2CH2), 6.45 (s, 2H, -NH2 D20 Exchangable),

7.00-7.2 (s, 2H, -CONH2) 7.40-7.60 (m, 4H, Ar-H), 7.90 (s, 1H, CH

171

pyrazole), M++1: 350; Anal. Calcd.for (C16H20N4O3S) requires: C, 55.16;

H, 5.79; N, 16.08; Found: C, 55.10; H, 5.73; N, 15.98;


cm-1) 3428, 3165 (-NH2), 3137 (-NH), 1668 (-C=O), 1318, 1137 (-SO2); 1H

NMR (DMSO-d6/TMS) δ 2.60 (d, 3H, -NHCH3), 4.30 (s, 2H, -SO2CH2),

6.30 (s, 2H, -NH2 D20 Exchangable), 6.90 (s, 2H, -CONH2 D20

Exchangable), 7.00 (m, 1H, -NHCH3), 7.40-7.60 (m, 4H, Ar-H), 7.90 (s,

1H, CH pyrazole); M++1: 310; Anal. Calcd.for (C13H17N5O3S) requires: C,

46.59; H, 4.89; N, 22.64; Found: C, 46.52; H, 4.82; N, 22.60.


cm-1) 3423, 3175 (-NH2), 3117 (-NH), 1664 (-C=O), 1308, 1127 (-SO2); 1H

NMR (DMSO-d6/TMS) δ 2.60 (d, 3H, -NHCH3), 3.00 (t, 3H, -Ar-CH2) 3.40

(t, 2H,- SO2CH2), 6.30 (s, 2H, -NH2 D20 Exchangable), 6.90 (s, 2H, -

CONH2 D20 Exchangable), 7.00 (m, 1H, -NHCH3), 7.40-7.60 (m, 4H, Ar-

H), 7.90 (s, 1H, CH pyrazole); M++1: 324; Anal. Calcd.for (C13H17N5O3S)

requires: C, 48.28; H, 5.30; N, 21.66; Found: C, 48.21; H, 5.28; N, 21.60.


METHOD A

A suspension of 261 (0.005 mol) and formic acid (10.0 mL) was

heated under reflux for 2 hours. The progress of the reaction was

monitored by TLC. After completion of the reaction, the excess formic

acid was removed completely under reduced pressure. Water (50.0 mL)

was added to the residue and the precipitated solid was collected by

172

filteration. The crude product was recrystallized from methanol to give

pure 262(a-c).

METHOD B

A mixture of 257 (0.0045 mol) and formic acid (15.0 mL) was

refluxed for 4 hours. The reaction was monitered by TLC and then

reaction mass quenched into water (50.0 mL). The solid that

precipitated was filtered and recrystallized from ethanol to give pure

262(a-c).

262a: R=pyrrolidine, n=1, Yield: 1.34 gm (75 %); M.R: < 270 ºC; IR (KBr,

cm-1) 3320, 1689 (NH and C=O), 1327, 1143 (-SO2) ; 1H NMR (DMSO-

d6/TMS) δ 180-190 (m, 4H, pyrrolidine), 3.2 (m, 4H, pyrrolidine), 4.5 (s,

2H, - SO2CH2), 7.40-7.60 (m, 4H, Ar-H), 8.20 (s, 1H, CH pyrazole), 8.40

(s, 1H, CH pyrimidine), 12.5 (s, 1H, NH); M++1: 360; Anal.Calcd.for

(C16H17N5O3S) requires: C, 53.47; H, 4.77; N, 19.49;; Found: C, 53.41; H,

4.73; N, 19.45.

262b: R=-NHCH3, n=l, Yield: 1.27 gm (98 %); M.R: < 270 ºC; IR (KBr, cm-

1) 3321, 3171, 1690 (-NH and -C=O), 1327, 1123 (-SO2); 1H NMR (DMSO-

d6/TMS) δ 2.60 (d, 3H, -NHCH3), 4.30 (s, 2H, -SO2CH2), 7.00 (d, 1H, -

NHCH3), 7.40-7.60 (m, 4H, Ar-H), 8.20 (s, 1H, CH pyrazole), 8.40 (s, 1H,

CH pyrimidine), 12.5 (s, 1H, NH). M++1: 360; Anal.Calcd.for


4.08; N, 21.89.

173

262c: R=-NHCH3, n=2, Yield: 1.03 gm (62 %); M.R: < 270 ºC; IR (KBr,

cm-1) 3436, 3295, 1675 (-NH and -C=O), 1313, 1127 (-SO2); 1H NMR

(DMSO-d6/TMS) δ 2.60 (d, 3H, -NHCH3), 3.00 (t, 3H, -Ar-CH2), 3.40 (t,

2H, -CH2SO2), 7.00 (m, 1H, -NHCH3), 7.40-7.60 (m, 4H, Ar-H), 8.20 (s,

1H, CH pyrazole), 8.40 (s, 1H, CH pyrimidine), 12.5 (s, 1H, -NH D2O

exchangable); M++1: 334; Anal.Calcd.for (C14H15N5O3S) requires: C,

50.44; H, 4.54; N, 21.01; Found: C, 50.40; H, 4.50; N, 20.09.

5.5.8. GENERAL PROCEDURE FOR THE SYNTHESIS 0F 265(a-c):

A mixture of 257(a-c) (1.5 g, 0.0045 mol) and formamide (10.0 mL)

was heated to reflux temperature 120-130ºC and stirred the reaction

mass at the same temperature for 6 hours. After completion of the

reaction the solution was cooled to 25-30ºC and then quenched into water

(30.0 mL). The solid that precipitated was separated by filteration and

recrysatallized from ethanol to give pure 263(a-c).


(KBr, cm-1) 3430, 3325 (-NH2), 1306, 1144 (-SO2); 1H NMR (DMSO-

d6/TMS) δ 1.8-1.9 (m, 4H, pyrrolidine), 3.1-3.2 (m, 4H, pyrrolidine), 4.5

(s, 2H, -SO2CH2), 7.6-7.7 (d, 2H, Ar-H), 8.0 (s, 2H, NH2 D2O

exchangable), 8.1-8.2 (d, 2H, Ar-H), 8.3 (s, 1H, pyrazole), 8.4 (s, 1H,

pyrimidine); 13C NMR δ 25.6, 48.04, 53.44, 101.85, 120.52, 127.99,

131.92, 134.60, 139.14, 153.76, 157.09 and 158.68; M++1: 359;


Found: C, 53.59; H, 5.00; N, 23.41.

174


cm-1) 3436, 3344 (-NH2), 1313, 1123, (-S02); 1H NMR (DMSO-d6/TMS) δ

2.60 (d, 3H, -NHCH3), 4.30 (s, 2H,- SO2CH2), 7.00 (m, 1H, -NHCH3),

7.40-8.60 (m, 8H, Ar-H, C-NH2, CH pyrazole, CH pyrimidine); M++1: 359;


Found: C, 49.01; H, 4.40; N, 26.38.


cm-1) 3438, 3339 (-NH2), 1312, 1125 (-SO2); 1H NMR (DMSO-d6/TMS) δ

2.60 (d, 3H, -NHCH3), 3.00 (t, 3H, -Ar-CH2) 3.40 (t, 2H, -SO2CH2), 7.00

(m, 1H, -NHCH3), 7.40-8.60 (m, 8H, Ar-H, C-NH2, CH pyrazole, CH

pyrimidine); M++1: 359; Anal.Calcd.for (C14H16N6O2S) requires: C, 50.59;

H, 4.85; N, 25.28; Found: C, 50.55; H, 4.80; N, 25.23.


A solution of 257(a-c) (0.0045 mol) in acetic anhydride-pyridine

mixture (20.0 mL, 2:1 v/v) was heated on water bath for 6 hours. The

reaction mass was cooled 20-25 ºC and poured in to ice/water mixture

(50.0 mL). The precipitate formed was filtered and washed with water,

dried and eluted silica gel column to give the pure 264(a-c).


(KBr, cm-1) 3415, 1734 (-NH and -C=O), 1347, 1161 (-SO2); 1H NMR

(DMSO-d6/TMS) δ 1.8-1.9 (m, 4H, pyrrolidine), 2.30 (s, 3H, CH3) 3.2 (m,

4H, pyrrolidine), 4.4 (s, 2H, -SO2CH2), 7.40-7.60 (m, 4H, Ar-H), 8.20 (s,

1H, CH pyrazole), 12.5 (s, 1H, -NH D2O exchangable); M++1: 274;

175


Found: C, 54.61; H, 5.10; N, 18.70.


cm-1) 3425, 1743 (-NH and -C=O), 1337, 1141 (-SO2); 1H NMR (DMSO-

d6/TMS) δ 2.45 (s, 3H, CH3), 2.60 (d, 3H, -NHCH3), 4.30 (s, 2H, -

SO2CH2), 7.00 (m, 1H, -NHCH3), 7.40-7.60 (m, 4H, Ar-H), 8.20 (s, 1H,

CH pyrazole), 12.5 (s, 1H, NH D2O exchangable); M++1: 334;


Found: C, 50.40; H, 4.5; N,19.9 1.


cm-1) 3429, 1723 (-NH and -C=O), 1317, 1131 (-SO2); 1H NMR (DMSO-

d6/TMS) δ 2.45 (s, 3H, CH3), 2.60 (d, 3H, -NHCH3), 3.00 (t, 3H, -Ar-CH2),

3.40 (t, 2H, -SO2CH2), 7.00 (m, 1H, -NHCH3), 7.40-7.60 (m, 4H, Ar-H),

8.20 (s, 1H, CH pyrazole), 12.5 (bs, 1H, -NH D2O exchangable); M++1:


Found: C, 51.81; H, 4.90; N, 20.11.


To a mixture of 257(a-c) (0.009 mol) and ethylenediamine (12.0

mL) was added dropwise carbon disulfide (1.0 mL). The reaction mixture

was heated under reflux temperature and maintained for 3 hours. The

reaction mass then cooled to 25-30ºC and qunched into ice/water (50.0

mL) mixture. The precipitate obtained was filtered, washed with water

(25.0 mL), dried and recrystallized from methanol to yield 265(a-c).

176


(KBr, cm-1) 3369, 1608 (-NH2, -C=N), 1325, 1141 (-SO2); 1H NMR (DMSO-

d6/TMS) δ 1.80-1.90 (m, 4H, pyrrolidine), 3.2 (m, 4H, pyrrolidine),

3.80-4.10 (m, 4H, -CH2-CH2- imidazole), 4.3 (s, 2H, -SO2CH2), 5.5 (s, 2H,

NH2, D20 exchangable), 7.40-7.70 (m, 5H, Ar-H, and CH pyrazole); M++1:


Found: C, 54.50; H, 5.89; N, 22.40.


1) 3349, 1617 (-NH2, -C=N), 1315, 1140 (-SO2); 1H NMR (DMSO-d6/TMS)

δ 2.60 (d, 3H, -NHCH3), 3.80-4.10 (m, 4H, -CH2-CH2- imidazole), 4.3 (s,

2H, -SO2CH2), 5.5 (s, 2H, NH2 D20 exchangable), 6.7 (m, 1H, NH), 7.40-

7.70 (m, 5H, Ar-H, and CH pyrazole); M++1: 335; Anal.Calcd.for


5.40; N, 25.10.

265c: R=-NHCH3, n=2, Yield: 1.94 (62 %); M.R: 220-223 ºC; IR (KBr, cm-

1) 3360, 1624 (-NH2, -C=N), 1323, 1136 (-SO2); 1H NMR (DMSO-d6/TMS)

δ 2.60 (d, 3H, -NHCH3), 3.00 (t, 3H, -Ar-CH2), 3.40 (t, 2H, -SO2CH2),

3.80-4.10 (m, 4H, -CH2-CH2- imidazole), 5.5 (s, 2H, -NH2 D20

exchangable), 7.00 (m, 1H, -NHCH3), 7.40-7.70 (m, 5H, Ar-H, and CH

pyrazole); M++1: 349; Anal.Calcd.for (C15H20N6O2S) requires: C, 51.71;

H, 5.79; N, 24.12; Found: C, 51.69; H, 5.70; N, 24.10.

177


A mixture of 265(a-c) (0.004 mol), triethylorthoformate (10.0 mL)

and 3 dropes of acetic acid was heated under reflux for 3 hours. The

progress of the reaction was monitered by TLC. The reaction mass cooled

to 25-30ºC. Reaction mass was quenched into ice water (25.0 mL). The

precipitated solid was filtered and washed with water (25.0 mL). The

crude product was recrystallized from dioxane yielded pure 266(a-c).


(KBr, cm-1) 1692 (-C=N), 1326, 1138 (-SO2); 1H NMR (DMSO-d6/TMS)

1.80-1.90 (m, 4H, pyrrolidine), 3.1-3.2 (m, 4H, pyrrolidine), 3.80 (t, 2H,

-CH2-imidazole), 4.1 (t, 2H, -CH2- imidazole), 4.3 (s, 2H, -SO2CH2), 7.40-

7.50 (d, 2H, Ar-H, J=8.4), 8.0-8.1 (m, 4H, Ar-H, CH pyrazole and CH

pyrimidine); 13C NMR δ 25.72, 44.52, 48.07, 50.60, 52.99, 99.03,

123.12, 131.61, 132.59, 136.66, 146.79 and 149.12; M++1: 385;


Found: C, 56.20; H, 5.20; N, 21.80.


cm-1) 1682 (-C=N), 1316, 1128 (-SO2); 1H NMR (DMSO-d6/TMS) δ 2.60

(d, 3H, -NHCH3), 3.80 (t, 2H, -CH2- imidazole), 4.1 (t, 2H, -CH2-

imidazole), 4.3 (s, 2H, -SO2CH2), 7.40-8.40 (m, 6H, Ar-H, CH pyrazole

and CH pyrimidine); M++1: 385; Anal.Calcd.for (C15H16N6O2S) requires:

C, 52.31; H, 4.68; N, 24.40; Found: C, 52.29; H, 4.60; N, 24.39.

178


cm-1) 1672 (-C=N), 1336, 1138 (-SO2); 1H NMR (DMSO-d6/TMS) δ 2.60

(d, 3H, -NHCH3), 3.00 (t, 3H, -Ar-CH2), 3.40 (t, 2H, -SO2CH2), 3.80 (t, 2H,

-CH2-imidazole), 4.1 (t, 2H, -CH2 imidazole), 7.0 (m, 1H, -NHCH3) 7.40-

8.40 (m, 6H, Ar-H, CH pyrazole and CH pyrimidine); M++1: 385;


Found: C, 53.60; H, 5.00; N, 23.40.

179

CONCLUSION

Sulfonamides are diverse group of medicinally important

compounds widely used as anticancer, antibacterial, anticonvulsants,

HIV protease inhibitors, anti-inflammatory, antitumor and antiviral

agents. The pharmaceutically important examples include the protease

inhibitor amprenavir, the analgesic celecoxib, sildenafil for erectile

dysfunction and the antimigraine agent sumatriptan. So, in this context,

the present thesis describes the syntheses and characterization of severl

fused sulfonamide heterocycles likely to be potential molecules of future.

Overall, we synthesized substituted-2,4-dihydro [1,2,4]triazole-

3-one, 1,2,4-triazoles, 1,3,4-thiadiazoles, 1,3-thiazines, hypoxanthine,

carbazoles, pyarazoles, 4,5-dihydro-1H pyrazolo[3,4-d]pyrimidine,

pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine and imidazo[1,2-c]

pyrazolo [4,3-e]pyrimidine using substituted 4-aminophenyl methane/

ethane sulfonamide moiety.

Finally, there is scope for preparation of new sulfonamide

heterocycle derivatives having benzene methane/ethane sulfonamide

moiety which might posses good biological activities. Thus, they are

prepared & have been achieved in good yields.

All the new compounds synthesized in the present work have

been adequately characterised by IR, 1H NMR & CI-MS, in a few cases

by 13C NMR, techniques.

chapter 5 synthesis of substituted-4,5...

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