chapter 5 synthesis of substituted-4,5...
TRANSCRIPT
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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]
pyrimidine (229) (Scheme-5.7).
145
….. 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).
146
….. 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]
pyrimidine (256) (Scheme-5.15).
….. 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.
154
….. 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.
156
….. 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
157
(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
158
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
159
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
162
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;
5.5.3. GENERAL PROCEDURE FOR THE SYNTHESIS OF 258(a-c):
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
5.5.4. GENERAL PROCEDURE FOR THE SYNTHESIS OF 259(a-c):
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
(C13H15N7O2S) requires: C, 46.84; H, 4.54; N, 29.41; Found: C, 46.44; H,
4.34; N, 29.31.
259c: R=-NHCH3, n=2, Yield: 1.13 gm (63 %); M.R: 209-211 ºC; IR (KBr,
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.
5.5.5. GENERAL PROCEDURE FOR THE SYNTHESIS OF 260(a-c):
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.
260b: R=-NHCH3, n=1, Yield: 0.57 (52 %); M.R: 229-231 ºC; IR (KBr, cm-
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.
5.5.6. GENERAL PROCEDURE FOR THE SYNTHESIS OF 261(a-c):
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;
261b: R=-NHCH3, n=1, Yield: 1.66 gm (60 %); M.R: 248-250 ºC; IR (KBr,
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.
261c: R=-NHCH3, n=2, Yield: 1.80 gm (62 %); M.R: 226-228 ºC; IR (KBr,
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.
5.5.7. GENERAL PROCEDURE FOR THE SYNTHESIS OF 262(a-c):
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
(C13H13N5O3S) requires: C, 48.89; H, 4.10; N, 21.93; Found: C, 48.83; H,
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).
263a: R=pyrrolidine, n=1, Yield: 1.36 gm (85 %); M.R: 353-256 ºC; IR
(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;
Anal.Calcd.for (C16H18N6O2S) requires: C, 53.62; H, 5.06; N, 23.45;
Found: C, 53.59; H, 5.00; N, 23.41.
174
263b: R=-NHCH3, n=1, Yield: 1.08 gm (76 %); M.R: 265-269 ºC; IR (KBr,
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;
Anal.Calcd.for (C13H14N6O2S) requires: C, 49.05; H, 4.43; N, 26.40;
Found: C, 49.01; H, 4.40; N, 26.38.
263c: R=-NHCH3, n=2, Yield: 1.22 gm (82 %); M.R: 246-248 ºC; IR (KBr,
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.
5.5.9. GENERAL PROCEDURE FOR THE SYNTHESIS OF 264(a-c):
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).
264a: R=pyrrolidine, n=1, Yield: 0.75 gm (45 %); M.R: 153-155 ºC; IR
(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
Anal.Calcd.for (C17H19N5O3S) requires: C, 54.68; H, 5.13; N, 18.75;
Found: C, 54.61; H, 5.10; N, 18.70.
264b: R=-NHCH3, n=1, Yield: 0.83 gm (56 %); M.R: 175-178 ºC; IR (KBr,
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;
Anal.Calcd.for (C14H15N5O3S) requires: C, 50.44; H, 4.54; N, 21.01;
Found: C, 50.40; H, 4.5; N,19.9 1.
264c: R=-NHCH3, n=2, Yield: 0.96 gm (62 %); M.R: 104-107 ºC; IR (KBr,
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:
348; Anal.Calcd.for (C15H17N5O3S) requires: C, 51.86; H, 4.93; N, 20.16;
Found: C, 51.81; H, 4.90; N, 20.11.
5.5.10. GENERAL PROCEDURE FOR THE SYNTHESIS OF 265(a-c):
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
265a: R=pyrrolidine, n=1, Yield: 1.5 gm (45 %); M.R: 200-205 ºC; IR
(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:
375; Anal.Calcd.for (C17H22N6O2S) requires: C, 54.53; H, 5.92; N, 22.44;
Found: C, 54.50; H, 5.89; N, 22.40.
265b: R=-NHCH3, n=1, Yield: 1.67 (56 %); M.R: 208-210 ºC; IR (KBr, cm-
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
(C14H18N6O2S) requires: C, 50.28; H, 5.43; N, 25.13; Found: C, 50.20; H,
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
5.5.11. GENERAL PROCEDURE FOR THE SYNTHESIS OF 266(a-c):
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).
266a: R=pyrrolidine, n=1, Yield: 0.97 gm (65 %); M.R: 249-251 ºC; IR
(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;
Anal.Calcd.for (C18H20N6O2S) requires: C, 56.23; H, 5.24; N, 21.86;
Found: C, 56.20; H, 5.20; N, 21.80.
266b: R=-NHCH3, n=1, Yield: 0.77 gm (56 %); M.R: 178-180 ºC; IR (KBr,
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
266c: R=-NHCH3, n=2, Yield: 0.88 gm (62 %); M.R: 249-251 ºC; IR (KBr,
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;
Anal.Calcd.for (C16H18N6O2S) requires: C, 53.62; H, 5.06; N, 23.45;
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.