A convenient synthesis of new pyrazolo[4,3-d]pyrimidines and their fused heterocycles

Article abstract of DOI:10.1002/jhet.2006

A series of some fused heterocycles originated from pyrazolopyrimidines were synthesized using 4-amino1-methyl-3-propyl-1H-pyrazole-5-carboxamide as a starting material. The nucleophilic substitution reactions with different amino acids followed by cyclization and Suzuki-Miyaura cross-coupling reactions with different aryl boronic acids of 7-chloro-5-(4-chlorophenyl)-1-methyl-3-propyl- 1H-pyrazolo[4,3-d]pyrimidine were performed. Also, the oxidative cyclization reactions of 1-(5-(4-chlorophenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d] pyrimidin-7-yl)hydrazine with different aldehydes in the presence of diacetoxy iodobenzene are described. All the synthesized compounds were characterized by analytical and spectroscopic methods.

Full text of DOI:10.1002/jhet.2006

May 2014
A Convenient Synthesis of New Pyrazolo[4,3-d]pyrimidines and Their
815
Fused Heterocycles
*
Ramhari V. Rote, Deepak P. Shelar, Sandeep R. Patil, and Madhukar N. Jachak
Department of Chemistry, Organic Chemistry Research Centre, K. T. H. M. College, University of Pune, Gangapur Road,
Nashik 422002, Maharashtra, India
*
E-mail: mnjachak@hotmail.com
Received December 4, 2012
DOI 10.1002/jhet.2006
Published online 6 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
A series of some fused heterocycles originated from pyrazolopyrimidines were synthesized using 4-
amino1-methyl-3-propyl-1H-pyrazole-5-carboxamide as a starting material. The nucleophilic substitution
reactions with different amino acids followed by cyclization and Suzuki–Miyaura cross-coupling reactions
with different aryl boronic acids of 7-chloro-5-(4-chlorophenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]
pyrimidine were performed. Also, the oxidative cyclization reactions of 1-(5-(4-chlorophenyl)-1-
methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)hydrazine with different aldehydes in the presence
of diacetoxy iodobenzene are described. All the synthesized compounds were characterized by analytical and
spectroscopic methods.
J. Heterocyclic Chem., 51, 815 (2014).
INTRODUCTION
[4,3-d]pyrimidine ring system is one of them that has not re-
ceived much attention, and very little is known about synthesis
and chemical properties of these compounds [1,2,10–14].
Not only pyrazolopyrimidines but also their fused
heterocycles such as pyrazolo-triazolo-pyrimidine and
imidazo-pyrazolo-pyrimidine derivatives attract chemists
owing to their impressive pharmacological properties
[8,24]. The pyrazolo-triazolo-pyrimidine nucleus repre-
sented an attractive key intermediate for obtaining
adenosine receptor antagonists [25–29]. Russo et al.
reported anti-inflammatory activity of pyrazolo-triazolo-
pyrimidines [30]. However, the literature survey reveals
that the syntheses of these compounds have been very
little explored [31–36].
Analogous to sildenafil [1], 1H-pyrazolo[4,3-d]pyrimi-
dines are a class of potent and selective second generation
phosphodiesterase 5 (PDE-5) inhibitors [2]. In recent
years, pyrazolopyrimidine-fused heterocycles are known
to function as central nervous system depressants [3],
neuroleptic agents [4], tuberculostatic [5], and adenosine
receptors [6,7]. Some pyrazolopyrimidines act as
antimicrobial, antifungal [8,9], and bronchodilatory agents
[10]. Beside these, pyrazolopyrimidine derivatives show
interesting pharmacological properties such as cyclic-
dependent kinase inhibitors [11,12], antiproliferative agents
[13], corticotropin-releasing factor antagonists [14], and
antiviral agents [15]. Tomcufick et al. reported the applica-
tion of pyrazolopyrimidines as antipyretic and analgesic
agents [16]. There are few reports on the synthesis and chem-
istry of these compounds in literature [17–23]. The pyrazolo
Prompted with these findings, and our ongoing project to
synthesize such nitrogen-containing heterocycles [37–40],
efforts have been taken to develop the convenient synthetic
© 2013 HeteroCorporation

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R. V. Rote, D. P. Shelar, S. R. Patil, and M. N. Jachak
Vol 51
without the use of specialized and expensive ligands, the
reaction of pyrazolopyrimidine 3 with aryl boronic acid
occurred smoothly using tetrakis(triphenylphosphine)pal-
ladium as a heterogeneous catalyst. The regioselectivity
for this coupling reaction on pyrazolo pyrimidine 3 was
found to be in favor of chloropyrimidine. The electron-
deficient nature of pyrimidine ring due to the inductive
effect of nitrogen atoms induces a partially positive
charge on the carbon atoms. Consequently, oxidative
addition of chloropyrimidine to Pd(0) takes place more
readily than chlorobenzene. Hence, treatment of 7-chloro-
5-(4-chlorophenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]
pyrimidine 3 with different aryl boronic acids by using
tetrakis(triphenylphosphine)palladium as a heterogeneous
catalyst and K2CO3 as a base in an 1,4-dioxane leads to the
formation of 5-(7-aryl-4-chlorophenyl)-1-methyl-3-propyl-
1H-pyrazolo[4,3-d]pyrimidines 5 in excellent yields
(64–73%; Scheme 2). The structural assignment of
new compounds 5a–c is based upon spectroscopic and
approaches for the synthesis of some new pyrazolo[4,3-d]
pyrimidines and their fused heterocycles that might be of
pharmacological importance.
Previously, we have reported the synthesis of thieno
[2,3-d]pyrimidine and indeno[2,1-b]thienopyrimidine
derivatives through the cyclo-condensation reaction
of 5-aminothiophene-4-carboxamide and 2-aminoindeno
thiophene-3-carboxamide, respectively [41,42]. In con-
tinuation of this work and in the course of program
directed toward the synthesis of novel pyrazolo[4,3-d]py-
rimidine derivatives, we choose 4-amino-1-methyl-3-
propyl-1H-pyrazole-5-carboxamide
1
as
a
substrate.
Compound 1 was synthesized by literature procedure
[43]. The regioselective condensation reaction of
p-chlorobenzaldehyde with o-amino carboxamide 1 in
the presence of acetonitrile and slight excess of molecular
iodine furnished pyrazolopyrimidine 2 in quantitative
yield (82%) [44]. The chlorination of compound 2 with
phosphorus oxychloride yielded 7-chloro-pyrazolo
pyrimidine 3 in 79% yield, which is used as precursor for
further annulation reactions. The reaction of compound 3
with hydrazine hydrate in ethanol at reflux temperature
underwent SNAr displacement to give hydrazine derivative
4 in 76% yield, which is also used as a vital precursor for
further heteroannulation reactions (Scheme 1).
1
microanalytical data. For example, the H nmr spectrum
of 5b showed –OCH3 signal at d = 3.76 ppm, and the
MS showed a molecular ion peak at m/z = 392 (M+)
corresponding to the molecular formula C22H21ClN4O.
The pyrazolopyrimidine 3 having reactive chloro atom
at C-7 position on pyrimidine ring was further utilized
for the study of their nucleophilic substitution reaction
with various amino acids. Generally, the amino acids are
very rarely used for nucleophilic substitution reaction
because of their zwitterionic nature. The nucleophilicity
of amino acid is improved by the use of two equivalents
of potassium carbonate in order to free the amino group.
Thus, the treatment of pyrazolo[4,3-d]pyrimidine 3 with
various amino acids in dimethyl formamide, using
K2CO3 as a base, under stirring at room temperature gave
The structural assignment of new compounds 3 and 4 is
based upon spectroscopic and analytical data. For example,
1
the H nmr spectrum of 3 did not show the –NH signal of
the precursor 2 at d = 11.78 ppm. The 1H nmr spectrum of 4
showed –NH2 and –NH signals at d = 4.86 and 8.78 ppm,
respectively, whereas the IR spectrum showed –NH2 and
–NH absorption bands at 3372, 3330 and 3271 cmÀ1
.
In an attempt to synthesize C-aryl derivatives of
pyrazolo[4,3-d]pyrimidine, we tried Suzuki–Miyaura
cross-coupling reaction of 3 with different aryl boronic
acids [45–50]. Although aryl chlorides are generally
unreactive toward the oxidative addition of palladium
Scheme 2
Scheme 1
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A Convenient Synthesis of New Pyrazolo[4,3-d]pyrimidines and Their Fused
Heterocycles
2-((5-(4-chlorophenyl)-1-methyl-3-propyl-1H-pyrazolo
[4,3-d]pyrimidin-7-yl)amino) acids 6a–d in good yields
(73–81%; Scheme 2). The structural assignment of new
compounds 6a–d is based upon spectroscopic and analytical
data. For instance, the 1H nmr spectrum of 6a showed signals
at d = 7.34 and 12.56 ppm corresponding to protons of –NH
and –OH groups, respectively, and the IR spectrum showed
characteristic –NH, –OH and –CO absorption bands at 3407,
2967 and 1721cmÀ1, respectively.
[54]. We wish to report that the oxidation of compound
8 with DIB in dichloromethane leads to a facile intramolec-
ular heterocyclization providing a convenient route to the
synthesis of 7-alkyl pyrazolo-triazolo-pyrimidines 9a–e.
The general procedure involves the addition of 1.2 equiva-
lent DIB at room temperature to a stirred solution of 8 in
dichloromethane. The reaction is completed very smoothly
within 20–30min, when its initially pale yellow color turned
to violet because of the overwhelming tendency of
iodobenzene for reductive elimination. Washing the reac-
tion mixture with 10% aqueous bicarbonate solution and
removing the solvent by distillation gave the desired
tricyclic 5-(7-alkyl-4-chlorophenyl)-1-methyl-3-propyl-1H-
pyrazolo[3,4-e][1,2,4]triazolo[4,3-c]pyrimidines 9a–e in
64–79% yields (Scheme 3).
The open chain amino acid-linked pyrazolopyrimidines 6
formed were further employed for the synthesis of
imidazolo-fused pyrazolopyrimidine derivatives 7a–d. The
annulations of imidazole ring were performed by cyclization
of open chain amino acids on ring nitrogen atom of pyrimi-
dine ring. The cyclization reactions were achieved by using
Lewis acid SOCl2 at controlled temperature. Thus, the
treatment of 6a–d with SOCl2 under stirring at 50–55ꢀC
for 2–3 h afforded 5-(8-alkyl-4-chlorophenyl)-1-methyl-3-pro-
pyl-1H-imidazo[1,2-c]pyrazolo[3,4-e]pyrimidin-7(8H)-one
7a–d in good yields (69–76%; Scheme 2). The new com-
pounds 7a–d were characterized by spectroscopic and ana-
Alternatively, compounds 9a–e could be synthesized
from 4 without isolation of 8, in which hydrazine 4 subse-
quently underwent condensation with aldehydes and
oxidative cyclization with DIB to give target compounds
9a–e in 69–81% yields (Scheme 3). The general procedure
involves the fractionwise addition of 1.2 equivalent of
DIB, to the solution of compound 4 and respective
aldehyde in dichloromethane under stirring at room
temperature for 50–55 min. The structural assignment of
new compounds 9a–e is based upon spectroscopic and
1
lytical data. For instance, the H nmr spectrum of 7a did
not show the –NH and –OH signals of the precursor 6a
at d = 7.34 and 12.56 ppm, and the IR spectrum showed
characteristic –CO absorption band at 1734 cmÀ1
.
After a successful synthesis of imidazo-pyrazolo-
pyrimidines 7, targeting toward the synthesis of triazolo-
fused pyrazolopyrimidines, another precursor 4 having
reactive hydrazine functionality was utilized. The annulations
of triazole ring were performed by the intramolecular
oxidative cyclization reactions. Initially, the hydrazine 4 was
converted to their imino hydrazone of aldehyde 8, by conden-
sation reaction with different aldehydes. Thus, the reaction
of 4 with various aldehydes in acetonitrile under
stirring at room temperature for 40–50 min afforded 2-
alkylidene-1-(5-(4-chlorophenyl) -1-methyl-3-propyl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl)hydrazines 8a–e in good
yields (69–81%; Scheme 3). The structural assignment of
new compounds 8a–e is based upon spectroscopic and
1
microanalytical data. For example, the H nmr spectrum
of 9a did not show the olefinic and –NH signals of the
precursor 8a at d = 7.96 and 10.29 ppm. The MS showed
a molecular ion peak at m/z = 368 (M+) corresponding to
the molecular formula C19H21ClN6.
Alternatively, the annulation of triazole ring on hydrazine
4 was also studied by using various triethyl orthoesters
Scheme 3
1
analytical data. For example, the H nmr spectrum of 8a
showed signals at d = 7.96 and 10.29 ppm corresponding
to olefinic and –NH proton, respectively, and the IR
spectrum showed characteristic –NH absorption band
at 3302cmÀ1. Now, by considering the literature survey,
in view of our ongoing program on the synthesis of
triazolo-fused pyrazolopyrimidine derivatives via oxidative
cyclization of 2-alkylidene-1-(5-(4-chlorophenyl)-1-methyl-
3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)hydrazines 8a–
e, organohypervalent iodine reagent is used [51–53]. Herein,
we explored the oxidation of imino hydrazone 8 with
diacetoxy iodobenzene (DIB). The high reactivity, com-
mercial availability, easy workup, and high stability in dif-
ferent solvents make the use of DIB as an efficient oxidant
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R. V. Rote, D. P. Shelar, S. R. Patil, and M. N. Jachak
Vol 51
The solvent for nmr spectra was DMSO-d6 unless otherwise stated.
Chemical shifts are reported as d values (ppm) relative to
tetramethylsilane. The IR spectra were recorded using a Shimadzu
IR-408 instrument (Nashik, India) as potassium bromide discs. Mass
spectra were recorded on Shimadzu GC-MS QP 2010A mass
spectrometer (Mumbai, India) with an ionization potential of 70 eV.
Elemental analyses were carried out on a Thermo Finnigan at
SAIF-IIT Bombay. The obtained products were moisture and oxygen
stable at ambient temperature. All reagents were purchased from Merck
(Mumbai, India), sd-fine Chemicals Ltd. (Mumbai, India) and Sigma
Aldrich (New Delhi, India) and used without further purification.
5-(4-Chlorophenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]
pyrimidin-7(6H)-one (2). To a clear solution of 4-amino-1-me
thyl-3-propyl-1H-pyrazole-5-carboxamide 1 (0.182g, 1.0mmole)
and 4-chlorobenzaldehyde (0.140g, 1.0 mmole) in acetonitrile
(15 mL), iodine (0.304 g, 1.2 mmole) was added fractionwise
under stirring at room temperature. The reaction mass was then
heated under reflux for 2.5 h, and the reaction progress was
monitored by TLC (CH2Cl2/methanol 9:1). After completion of
reaction, the solvent was removed in vacuo and the residue treated
with water, stirred, filtered, and washed with 10% sodium
thiosulphate solution to remove excess iodine. The obtained solid
was dried under vacuum at 60ꢀC to give product 2 (0.248 g, 82%)
as a colorless solid, which was purified by flash chromatography
(silica gel, CH2Cl2 as eluent). mp 237–239ꢀC; lit. [44] [mp
239ꢀC]; IR: 3291 (NH), 3163, 2922, 2812, 1654 (C= O), 1485,
such as triethyl orthoformate, triethyl orthoacetate, triethyl
orthopropionate, and triethyl orthobenzoate to give other
pyrazolo-triazolo-pyrimidine derivatives. Thus, the treatment
of compound 4 with various triethyl orthoester in ethanol
under reflux for 3–4 h subsequently underwent cyclo-
condensation reactions to furnish desired 5-(7-alkyl-4-
chlorophenyl)-1-methyl-3-propyl-1H-pyrazolo[3,4-e][1,2,4]
triazolo[4,3-c]pyrimidine derivatives 9f-i in excellent yields
(69–78%; Scheme 3). The structural assignment of new
compounds 9f–i is based upon spectroscopic and analytical
data. For instance, the 1H nmr spectrum of 9f did not show
the –NH2 and –NH signals of the precursor 4 at d = 4.86
and 8.78 ppm, respectively, but instead showed a sharp
signal at d = 8.97 ppm belonging to triazole ring, indicating
the formation of the tricyclic 9f. The IR spectrum was devoid
of the –NH2 and –NH absorption bands at 3372, 3330 and
3271cmÀ1 of the precursor.
CONCLUSION
We have successfully utilized 7-chloro-5-(4-chloro
phenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine 3
and 1-(5-(4-chlorophenyl)-1-methyl-3-propyl-1H-pyrazolo
[4,3-d]pyrimidin-7-yl)hydrazine 4 for the synthesis of novel
pyrazolopyrimidine derivatives. The nucleophilic substitu-
tion reactions with different amino acids and Suzuki–
Miyaura cross-coupling reactions with different aryl boronic
acids of 3 were performed successfully under mild reaction
condition. We established a robust and efficient route for
construction of pyrazolo[3,4-e][1,2,4]triazolo[4,3-c]pyrimi-
dine by oxidative cyclization using DIB. Also, we described
the efficient synthesis of pyrazolo-triazolo-pyrimidines 9f–i
through cyclo-condensation of hydrazine 4 with different
triethylorthoesters. The reactions reported herein represent
novel pyrazolo[4,3-d]pyrimidine derivatives and their fused
heterocycles, with high yields, simple workup, clean
products, and may be a valuable addition to a library of
heterocyclic chemistry.
1338, 1007cmÀ1 1H nmr (400MHz, DMSO-d6): d 0.88 (t,
;
J = 8.0Hz, 3H, CH3), 1.66 (m, 2H, CH2), 2.69 (t, J = 8.0 Hz, 2H,
CH2), 4.07 (s, 3H, N–CH3), 7.23 (d, J = 12.0Hz, 2H, Ar–H), 7.92
(d, J = 12.0Hz, 2H, Ar–H), 11.78 (bs, 1H, NH); 13C nmr
(75 MHz, DMSO-d6): d 13.9, 21.8, 27.7, 38.5, 122.3, 127.3,
127.9 (2C’s), 129.2 (2C’s), 132.1, 133.4, 145.4, 152.7, 162.3; MS
(70 eV): m/z (%)= 302 (M+, 71%), 304 (M + 2, 22%). Anal. Calcd
for C15H15ClN4O (302.76): C, 59.51; H, 4.99; N, 18.51; Found:
C, 59.83; H, 5.17; N, 18.25.
7-Chloro-5-(4-chlorophenyl)-1-methyl-3-propyl-1H-pyrazolo
[4,3-d]pyrimidine (3).
A solution of 5-(4-chlorophenyl)-1-
methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one 2
(0.302g, 1.0 mmole) in phosphorous oxychloride (10mL) was
heated under reflux for 4 h, and the reaction progress was
monitored by TLC (CH2Cl2/methanol 9:1). After completion of
reaction, the solvent was removed in vacuo and the residue treated
with water, stirred, filtered, and dried under vacuum at 60ꢀC to
give product 3 (0.253g, 79%) as a colorless solid, which was
purified by flash chromatography (silica gel, CH2Cl2/methanol 9:1
as eluent). mp 128–130ꢀC; IR: 3112, 2983, 2927, 2812, 1627,
1492, 1336, 1091 cmÀ1; 1H nmr (300MHz, DMSO-d6): d 0.99 (t,
J = 7.4Hz, 3H, CH3), 1.87 (m, 2H, CH2), 2.99 (t, J = 7.4 Hz, 2H,
CH2), 4.29 (s, 3H, N–CH3), 7.61 (d, J = 8.6 Hz, 2H, Ar–H), 8.38
(d, J = 8.6 Hz, 2H, Ar–H); 13C nmr (75MHz, DMSO-d6): d 13.8,
21.4, 27.3, 38.8, 121.8, 128.7 (3C’s), 129.3 (2C’s), 131.7, 134.5,
146.3, 154.8, 159.7; MS (70 eV): m/z (%) = 320 (M+, 63%), 322
(M + 2, 40%), 324 (M + 4, 7%). Anal. Calcd for C15H14Cl2N4
(321.20): C, 56.09; H, 4.39; N, 17.44; found: C, 56.48; H, 4.22; N, 17.70.
1-(5-(4-Chlorophenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-
EXPERIMENTAL
General. Unless otherwise stated, materials were obtained from
commercial suppliers and were used without further purification.
Starting material 4-amino-1-methyl-3-propyl-1H-pyrazole-5-
carboxamide 1 was prepared as previously reported procedure [37].
All reactions were monitored by thin layer chromatography (TLC)
on 0.25-mm silica gel 60 F254 plates (Merck, Darmstadt, Germany)
using UV light (254 and 366 nm) for detection. Compounds were pu-
rified on Biotage flash master personal plus flash chromatography
system using Biotage silica gel cartridges (25 g). Melting points were
determined on a Barnstead Electrothermal melting point apparatus
(Nashik, India), Mod. No. IA-9200 in open capillary tubes, and are
uncorrected. The 1H nmr (300 MHz) and 13C nmr (75 MHz) spectra
were measured on a Varian XL-300 spectrometer (Pune, India), and
1H nmr (400 MHz) spectra were measured on Bruker spectrometer
(Mumbai, India) using tetramethylsilane as the internal standard.
d]pyrimidin-7-yl) hydrazine (4).
A clear solution of 7-
chloro-5-(4-chlorophenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-
d]pyrimidine 3 (0.321 g, 1.0 mmole) and hydrazine hydrate
(0.075 mL, 1.5 mmole) in ethanol (15 mL) was heated under
reflux for 1.5 h, and the reaction progress was monitored by
TLC (CH2Cl2/methanol 9:1). After completion of reaction, the
solvent was removed in vacuo and the residue treated with
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A Convenient Synthesis of New Pyrazolo[4,3-d]pyrimidines and Their Fused
Heterocycles
methanol, stirred, filtered, and dried under vacuum at 60ꢀC to
give product 4 (0.240 g, 76%) as a yellow solid, which was
purified by flash chromatography (silica gel, CH2Cl2/methanol
9:1 as eluent). mp 219–221ꢀC; IR: 3372 (NH2), 3330 (NH2),
solid; yield 0.241 g (64%); mp 126–129ꢀC; IR: 3116, 2964,
2923, 2879, 1516, 1432, 1311, 1039, 985 cmÀ1 1H nmr
;
(300 MHz, DMSO-d6): d 1.00 (t, J = 7.5 Hz, 3H, CH3), 1.87 (m,
2H, CH2), 2.42 (s, 3H, CH3), 3.02 (t, J = 7.5 Hz, 2H, CH2),
3.69 (s, 3H, N–CH3), 7.29 (d, J = 8.0 Hz, 2H, Ar–H), 7.51
(d, J = 7.4 Hz, 2H, Ar–H), 8.13 (d, J = 8.0 Hz, 2H, Ar–H), 8.38
(d, J = 7.4 Hz, 2H, Ar–H); 13C nmr (75 MHz, DMSO-d6): d
13.8, 21.1, 21.3, 27.2, 36.9, 121.3, 127.6 (2C’s), 127.8, 128.7
(2C’s), 129.1 (2C’s), 129.3 (2C’s), 130.9 131.2, 134.6, 136.7,
144.5, 153.1, 154.4; MS (70 eV): m/z (%) = 376 (M+, 58%),
378 (M + 2, 17%). Anal. Calcd for C22H21ClN4 (376.88): C,
3271 (NH), 3010, 2912, 1530, 1412, 1080 cmÀ1 1H nmr
;
(300 MHz, DMSO-d6): d 0.96 (t, J = 7.4 Hz, 3H, CH3), 1.80
(m, 2H, CH2), 2.84 (t, J = 7.4 Hz, 2H, CH2), 4.16 (s, 3H, N–
CH3), 4.86 (bs, 2H, –NH2) 7.52 (d, J = 8.6 Hz, 2H, Ar–H), 8.46
(d, J = 8.6 Hz, 2H, Ar–H), 8.78 (bs, 1H, NH); 13C nmr
(75 MHz, DMSO-d6): d 13.9, 22.1, 27.5, 38.9, 122.1, 128.3,
128.4 (2C’s), 129.2 (2C’s), 131.9, 134.6, 146.5, 155.1, 162.4;
MS (70 eV): m/z (%) = 316 (M+, 74%), 318 (M + 2, 23%). Anal.
Calcd for C15H17ClN6 (316.79): C, 56.87; H, 5.41; N, 26.53;
70.11; H, 5.62; N, 14.87; found: C, 70.42; H, 5.39; N, 15.11.
General procedure for synthesis of 2-((5-(4-chlorophenyl)-
1-methyl-3-propyl-1H-pyrazolo [4,3-d]pyrimidin-7-yl)amino)
found: C, 57.15; H, 5.81; N, 26.32.
General procedure for synthesis of 5-(7-aryl-4-chlorophenyl)-
acids 6a–d.
A mixture of 7-chloro-5-(4-chlorophenyl)-1-
1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidines 5a–c. To a
clear solution of 7-chloro-5-(4-chlorophenyl)-1-methyl-3-propyl-
methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine 3 (0.321 g, 1.0
mmole), respective amino acid (1.1 mmole) and anhydrous
K2CO3 (0.276 g, 2 mmole) in dimethyl formamide (20 mL)
was stirred at room temperature for 4–5 h, and the reaction
progress was monitored by TLC (CH2Cl2/methanol 9:1).
After completion of reaction, the solvent was removed in
vacuo and the residue treated with water, neutralized with 2N
HCl, stirred, filtered, and dried under vacuum at 60ꢀC to give
products 6a–d in 73–81% yield, which was purified by flash
chromatography (silica gel, CH2Cl2/methanol 9:1 as eluent).
2-((5-(4-Chlorophenyl)-1-methyl-3-propyl-1H-pyrazolo
1H-pyrazolo[4,3-d]pyrimidine
3
(0.321 g, 1.0 mmole) and
respective aryl boronic acid (1.2mmole) in 1,4 dioxane (20 mL),
tetrakistriphenylphosphine palladium [Pd(Ph3P)4] (0.058g,
0.05 mmole) and anhydrous K2CO3 (0.276g, 2.0 mmol) were
added subsequently under stirring at room temperature. The
reaction mixture was then stirred at 80ꢀC for 5–6 h, and the
reaction progress was monitored by TLC (hexane/ethyl acetate
9:1). After completion of reaction, the solvent was removed in
vacuo and the residue treated with water, extracted with ethyl
acetate (3 Â 25mL); organic layer was dried with Na2SO4 and
concentrated in vacuo. The obtained solid was dried under
vacuum at 60ꢀC to give products 5a–c in 64–73% yield, which
was purified by flash chromatography (silica gel, hexane/ethyl
acetate 9:1 as eluent).
[4,3-d]pyrimidin-7-yl)amino)acetic acid (6a).
This
compound was synthesized by using glycine (0.083 g, 1.1 mmole);
colorless solid; yield 0.283 g (79%); mp 196–198ꢀC; IR: 3407
(NH), 2967 (OH), 2956, 2576, 1721 (C = O), 1605, 1563, 1480,
1223, 1081 cmÀ1 1H nmr (400 MHz, DMSO-d6): d 0.95 (t,
;
5-(4-Chlorophenyl)-1-methyl-7-phenyl-3-propyl-1H-pyrazolo
[4,3-d] pyrimidine (5a). This compound was synthesized by
using phenylboronic acid (0.146 g, 1.2 mmole); white amorphous
solid; yield 0.257 g (71%); mp 112–114ꢀC; IR: 3021, 2983,
J = 7.6 Hz, 3H, CH3), 1.82 (m, 2H, CH2), 2.85 (t, J= 7.6 Hz, 2H,
CH2), 4.23 (s, 3H, N–CH3), 4.51 (d, J= 7.0 Hz, 2H, CH2), 7.34 (t,
J = 7.0 Hz, 1H, NH), 7.48 (d, J = 7.4 Hz, 2H, Ar–H), 8.37 (d,
J = 7.4 Hz, 2H, Ar–H), 12.56 (bs, 1H, OH); 13C nmr (75MHz,
DMSO-d6): d 13.8, 21.7, 27.3, 38.8, 41.6, 121.7, 128.0, 128.2
(2C’s), 129.3 (2C’s), 132.2, 134.3, 147.4, 154.4, 159.7, 167.1; MS
(70 eV): m/z (%) = 359 (M+, 37%), 361 (M + 2, 12%). Anal. Calcd
for C17H18ClN5O2 (359.81): C, 56.75; H, 5.04; N, 19.46; found:
C, 57.01; H, 4.93; N, 19.77.
1
2971, 1563, 1491, 1068, 1012 cmÀ1; H nmr (300 MHz, DMSO-
d6): d 1.01 (t, J = 7.4 Hz, 3H, CH3), 1.86 (m, 2H, CH2), 3.03 (t,
J = 7.4 Hz, 2H, CH2), 3.79 (s, 3H, N–CH3), 7.59 (d, J = 8.7 Hz,
2H, Ar–H), 7.65 (m, 3H, Ar–H), 7.87 (dd, J = 3.0 and 6.0 Hz,
2H, Ar–H), 8.48 (d, J = 8.7 Hz, 2H, Ar–H); 13C nmr (75 MHz,
DMSO-d6): d 13.8, 21.2, 27.2, 37.1, 121.0, 127.6 (2C’s), 128.7
(2C’s), 128.9 (2C’s), 129.1 (2C’s), 129.4 (2C’s), 134.2, 135.3,
143.5, 144.8, 151.1, 156.5; MS (70 eV): m/z (%) = 362 (M+,
57%), 364 (M + 2, 19%). Anal. Calcd for C21H19ClN4 (362.86):
C, 69.51; H, 5.26; N, 15.44; found: C, 69.27; H, 5.61; N, 15.60.
5-(4-Chlorophenyl)-7-(2-methoxyphenyl)-1-methyl-3-propyl-
2-((5-(4-Chlorophenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-
d]pyrimidin-7-yl)amino) propanoic acid (6b).
This
compound was synthesized by using alanine (0.098 g, 1.1 mmole);
white crystalline solid; yield 0.302g (81%); mp 218–220ꢀC; IR:
3421 (NH), 2980 (OH), 2963, 2563, 1712 (CO), 1600, 1556,
1473, 1207cmÀ1 1H nmr (400MHz, DMSO-d6): d 0.96 (t,
;
1H-pyrazolo[4,3-d]pyrimidine (5b).
This compound was
J = 8.0Hz, 3H, CH3), 1.57 (d, J = 8.0 Hz, 3H, CH3), 1.81 (m, 2H,
CH2), 2.86 (t, J = 8.0 Hz, 2H, CH2), 4.23 (s, 3H, N–CH3), 4.61
(m, 1H), 7.51 (d, J = 8.4 Hz, 2H, Ar–H), 7.54 (d, J = 4.0 Hz, 1H,
NH), 8.36 (d, J = 8.4 Hz, 2H, Ar–H), 12.53 (bs, 1H, OH); 13C nmr
(75 MHz, DMSO-d6): d 13.7, 16.1, 21.5, 27.6, 38.8, 47.2, 122.1,
128.1 (3C’s), 129.2 (2C’s), 131.9, 134.2, 147.6, 155.1, 159.5,
168.3; MS (70 eV): m/z (%) = 373 (M+, 43%), 375 (M + 2, 15%).
Anal. Calcd for C18H20ClN5O2 (373.84): C, 57.83; H, 5.39; N,
18.73; found: C, 57.55; H, 5.71; N, 18.86.
synthesized by using 2-methoxyphenylboronic acid (0.182g,
1.2 mmole); colorless solid; yield 0.286 g (73%); mp 117–119ꢀC;
IR: 3196, 2952, 2835, 1238, 1120, 1051, 912cmÀ1 1H nmr
;
(300MHz, DMSO-d6): d 1.01 (t, J = 7.4 Hz, 3H, CH3), 1.89
(m, 2H, CH2), 3.01 (t, J = 7.4 Hz, 2H, CH2), 3.64 (s, 3H, N–CH3),
3.76 (s, 3H, –OCH3), 7.23 (m, 2H, Ar–H), 7.59 (m, 4H, Ar–H),
8.44 (d, J = 8.4Hz, 2H, Ar–H); 13C nmr (75 MHz, DMSO-d6): d
13.9, 21.3, 27.1, 36.9, 55.3, 111.2, 120.9, 124.8, 128.4 (2C’s),
129.2 (3C’s), 131.0, 131.9, 134.5, 136.8, 143.7, 144.6, 150.0,
154.9, 156.7; MS (70 eV): m/z (%)= 392 (M+, 66%), 394 (M+ 2,
20%). Anal. Calcd for C22H21ClN4O (392.88): C, 67.26; H, 5.39;
N, 14.26; found: C, 67.52; H, 5.25; N, 14.60.
2-((5-(4-Chlorophenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-
d]pyrimidin-7-yl)amino)-3-methylbutanoic acid (6c).
This
compound was synthesized by using valine (0.129g, 1.1 mmole);
offwhite crystalline solid; yield 0.293 g (73%); mp 207–209ꢀC;
IR: 3393 (NH), 2990 (OH), 2912, 2563, 1709 (CO), 1618, 1488,
5-(4-Chlorophenyl)-1-methyl-3-propyl-7-p-tolyl-1H-pyrazolo
1
[4,3-d]pyrimidine (5c).
This compound was synthesized by
1225 cmÀ1; H nmr (400 MHz, DMSO-d6): d 0.95 (t, J = 7.4 Hz,
using 4-methylphenylboronic acid (0.163 g, 1.2 mmole); offwhite
3H, CH3), 1.09 (m, 6H, 2 Â CH3), 1.80 (m, 2H, CH2), 2.39 (m,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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R. V. Rote, D. P. Shelar, S. R. Patil, and M. N. Jachak
Vol 51
1H), 2.86 (t, J = 7.4 Hz, 2H, CH2), 4.25 (s, 3H, N–CH3), 4.40 (t,
J = 7.2 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H, –NH), 7.52 (d, J = 8.7 Hz,
2H, Ar–H), 8.39 (d, J = 8.7 Hz, 2H, Ar–H), 12.75 (bs, 1H, OH);
13C nmr (75 MHz, DMSO-d6): d 13.7, 16.4 (2C’s), 21.6, 27.2,
27.7, 38.9, 66.3, 121.6, 127.9, 128.2 (2C’s), 129.1 (2C’s), 131.6,
134.5, 148.1, 154.8, 160.0, 168.4; MS (70eV): m/z (%) = 401
(M+, 32%), 403 (M+ 2, 9%). Anal. Calcd for C20H24ClN5O2
(401.89): C, 59.77; H, 6.02; N, 17.43; found: C, 60.02; H, 6.18;
N, 17.11.
5-(4-Chlorophenyl)-8-isopropyl-1-methyl-3-propyl-1H-imidazo
[1,2-c]pyrazolo[3,4-e]pyrimidin-7(8H)-one (7c).
Offwhite
amorphous solid; yield 0.288 g (75%); Mp 166–168ꢀC; IR: 3134,
3057, 2956, 2819, 1741 (ÀCO), 1689, 1564, 1287, 1107cmÀ1
;
1H nmr (300 MHz, DMSO-d6): d 0.96 (t, J = 7.5 Hz, 3H, CH3),
1.12 (m, 6H, 2 Â CH3), 1.82 (m, 2H, CH2), 2.38 (m, 1H), 2.85 (t,
J = 7.5 Hz, 2H, CH2), 4.19 (s, 3H, N–CH3), 4.43 (d, J = 7.0 Hz,
1H), 7.53 (d, J = 7.5 Hz, 2H, Ar–H), 8.35 (d, J = 7.5 Hz, 2H, Ar–
H); 13C nmr (75 MHz, DMSO-d6): d 13.8, 16.6 (2C’s), 21.7,
27.3, 31.3, 38.3, 66.7, 121.4, 127.1, 127.3 (2C’s), 128.3 (2C’s),
131.6, 134.2, 147.9, 154.7, 159.8, 168.6; MS (70 eV): m/z
(%)= 383 (M+, 36%), 385 (M + 2, 11%). Anal. Calcd for
C20H22ClN5O (383.87): C, 62.58; H, 5.78; N, 18.24; found: C,
62.77; H, 5.51; N, 18.46.
2-((5-(4-Chlorophenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-
d]pyrimidin-7-yl)amino)-3-phenylpropanoic acid (6d).
This
compound was synthesized by using phenyl alanine (0.182 g,
1.1 mmole); colorless solid; yield 0.346 g (77%); mp 188–
190ꢀC; IR: 3417 (NH), 2967 (OH), 2824, 1723 (CO), 1614,
1
1565, 1253, 1087 cmÀ1; H nmr (400 MHz, DMSO-d6): d 0.94
5-(4-Chlorophenyl)-8-benzyl-1-methyl-3-propyl-1H-imidazo
(t, J = 7.5 Hz, 3H, CH3), 1.80 (m, 2H, CH2), 2.84 (t, J = 7.5 Hz,
2H, CH2), 2.34 (d, J = 8.0 Hz, 2H, CH2), 4.13 (s, 3H, N–CH3),
4.82 (q, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H, NH), 7.19–
7.37 (m, 5H Ar–H), 7.50 (d, J = 8.0 Hz, 2H, Ar–H), 8.35
(d, J = 8.0 Hz, 2H, Ar–H), 12.63 (bs, 1H, OH); 13C nmr
(75 MHz, DMSO-d6): d 13.8, 21.8, 27.7, 32.6, 38.8, 56.3,
121.2, 127.1, 127.4 (2C’s), 128.0 (3C’s), 128.2 (2C’s), 129.2
(2C’s), 131.4, 133.8, 137.5, 147.8, 155.9, 160.0, 169.3; MS
(70 eV): m/z (%) = 449 (M+, 41%), 451 (M + 2, 14%). Anal.
Calcd for C24H24ClN5O2 (449.93): C, 64.07; H, 5.38; N, 15.57;
[1,2-c]pyrazolo[3,4-e]pyrimidin-7(8H)-one (7d).
Faint
brown crystalline solid; yield 0.328g (76%); mp 171–173ꢀC; IR:
3224, 3137, 3042, 2912, 1749 (CO), 1698, 1510, 1218,
1
1016 cmÀ1; H nmr (300 MHz, DMSO-d6): d 0.96 (t, J = 7.5 Hz,
3H, CH3), 1.81 (m, 2H, CH2), 2.86 (t, J = 7.5 Hz, 2H, CH2), 3.31
(d, J = 7.2 Hz, 2H, CH2), 4.22 (s, 3H, N–CH3), 4.73 (t, J = 7.2 Hz,
1H), 7.22–7.39 (m, 5H, Ar–H), 7.47 ( d, J = 8.0 Hz, 2H, Ar–H),
8.41 (d, J = 8.0 Hz, 2H, Ar–H); 13C nmr (75 MHz, DMSO-d6): d
13.9, 21.7, 27.4, 34.5, 38.4, 61.1, 121.7, 127.2, 127.4 (2C’s),
128.0, 128.1 (2C’s), 128.3 (2C’s), 129.1 (2C’s), 131.6, 134.0,
137.4, 147.4, 156.1, 159.8, 169.1; MS (70 eV): m/z (%) = 431
(M+, 61%), 433 (M+ 2, 19%). Anal. Calcd for C24H22ClN5O
(431.92): C, 66.74; H, 5.13; N, 16.21; found: C, 66.80; H, 4.87;
N, 16.52.
found: C, 64.28; H, 5.31; N, 15.35.
General procedure for synthesis of 5-(8-alkyl-4-chlorophenyl)-
1-methyl-3-propyl-1H-imidazo[1,2-c]pyrazolo[3,4-e]pyrimidin-
7(8H)-ones 7a–d.
A solution of respective compounds 6a–d
(1.0 mmole) in thionyl chloride (10 mL) was stirred at 50–55ꢀC
for 2–3 h, and the reaction progress was monitored by TLC
(hexane/ethyl acetate 9:1). After completion of the reaction,
solvent was removed in vacuo and the residue treated with
water, stirred, filtered, and dried under vacuum at 60ꢀC to give
products 7a–d in 69–76% yield, which was purified by flash
chromatography (silica gel, hexane/ethyl acetate 9:1 as eluent).
5-(4-Chlorophenyl)-1-methyl-3-propyl-1H-imidazo[1,2-c]
General procedure for synthesis of 2-alkylidene-1-(5-(4-
chlorophenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-
7-yl)hydrazines 8a–e.
A solution of 1-(5-(4-chlorophenyl)-1-
methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)hydrazine
4
(0.316g, 1.0 mmole) and respective aldehyde (1.0 mmole) in
acetonitrile (15mL) was stirred at room temperature for 40–
50min, and the reaction progress was monitored by TLC
(CH2Cl2/methanol 9:1). After completion of the reaction, solvent
was removed in vacuo and the residue treated with hexane,
stirred, filtered, and dried under vacuum at 60ꢀC to give products
8a–e in 69–81% yield, which was purified by flash
chromatography (silica gel, CH2Cl2/methanol 9:1 as eluent).
2-(2-Methylpropylidene)-1-(5-(4-chlorophenyl)-1-methyl-3-
pyrazolo[3,4-e]pyrimidin-7(8H)-one (7a).
solid; yield 0.242 g (71%); mp 177–179ꢀC; IR: 2993, 2975,
2916, 1734 (CO), 1686, 1522, 1299, 1167, 1004, 986 cmÀ1
Pale brown
;
1H nmr (300 MHz, DMSO-d6): d 0.97 (t, J = 7.5 Hz, 3H,
CH3), 1.79 (m, 2H, CH2), 2.82 (t, J = 7.5 Hz, 2H, CH2), 4.28
(s, 3H, N–CH3), 4.59 (s, 2H, CH2), 7.47 (d, J = 8.0 Hz, 2H,
Ar–H), 8.21 (d, J = 8.0 Hz, 2H, Ar–H); 13C nmr (75 MHz,
DMSO-d6): d 13.9, 21.8, 27.5, 38.2, 46.1, 121.4, 127.1,
127.4 (2C’s), 128.3 (2C’s), 132.0, 134.3, 147.9, 154.1,
159.3, 167.7; MS (70 eV): m/z (%) = 341 (M+, 55%), 343
(M + 2, 17%). Anal. Calcd for C17H16ClN5O (341.79): C,
59.74; H, 4.72; N, 20.49; found: C, 60.09; H, 4.46; N, 20.66.
5-(4-Chlorophenyl)-1,8-dimethyl-3-propyl-1H-imidazo[1,2-
propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)hydrazine (8a).
This
compound was synthesized by using isobutyraldehyde (0.092mL,
1.0 mmole); yellow solid; yield 0.288 g (78%); mp 163–165ꢀC;
IR: 3302 (NH), 3184, 3145, 2921, 1560, 1304, 1022cmÀ1 1H
;
nmr (300 MHz, DMSO-d6): d 0.98 (t, J = 7.4 Hz, 3H, CH3), 1.02
(m, 6H, 2 Â CH3), 1.84 (m, 2H, CH2), 2.11 (m, 1H), 2.87
(t, J = 7.4 Hz, 2H, CH2), 4.29 (s, 3H, N–CH3), 7.49 (d, J = 7.2 Hz,
2H, Ar–H), 7.88 (d, J = 7.2 Hz, 2H, Ar–H), 7.96 (d, J = 5.5 Hz,
1H, olefinic-H), 10.29 (bs, 1H, NH); 13C nmr (75 MHz, DMSO-
d6): d 13.8, 18.3 (2C’s), 21.9, 27.1, 31.4, 38.9, 122.7, 126.8,
127.5 (2C’s), 128.8 (2C’s), 132.8, 136.4, 144.3, 149.3, 151.2,
153.1; MS (70 eV): m/z (%) = 370 (M+, 43%), 371 (M + 2, 15%).
Anal. Calcd for C19H23ClN6 (370.88): C, 61.53; H, 6.25; N,
22.66; found: C, 61.26; H, 6.53; N, 22.87.
c]pyrazolo[3,4-e]pyrimidin-7(8H)-one (7b).
solid; yield 0.245 g (69%); mp 182–184ꢀC; IR: 3117, 2980,
2916, 1746 (CO), 1680, 1531, 1304, 1020 cmÀ1 1H nmr
Faint brown
;
(300 MHz, DMSO-d6): d 0.98 (t, J = 7.2 Hz, 3H, CH3), 1.43 (d,
J = 7.0 Hz, 3H, CH3), 1.62 (m, 2H, CH2), 2.79 (t, J = 7.2 Hz,
2H, CH2), 4.21 (s, 3H, N–CH3), 4.52 (q, J = 7.0 Hz, 1H), 7.46
(d, J = 8.0 Hz, 2H, Ar–H), 8.18 (d, J = 8.0 Hz, 2H, Ar–H); 13C
nmr (75 MHz, DMSO-d6): d 13.9, 16.8, 21.7, 27.5, 38.4, 53.3,
121.2, 127.2 (3C’s), 128.4 (2C’s), 131.9, 134.0, 147.7, 154.3,
158.9, 169.1; MS (70 eV): m/z (%) = 355 (M+, 48%), 357
(M + 2, 17%). Anal. Calcd for C18H18ClN5O (355.82): C,
60.76; H, 5.10; N, 19.68; found: C, 61.00; H, 5.33; N, 19.33.
2-(4-Chlorobenzylidene)-1-(5-(4-chlorophenyl)-1-methyl-3-propyl-
1H-pyrazolo[4,3-d]pyrimidin-7-yl)hydrazine (8b).
This
compound was synthesized by using 4-chlorobenzaldehyde
(0.141g, 1.0 mmole); yellow amorphous solid; yield 0.302 g
(69%); mp 175–177ꢀC; IR: 3403 (NH), 3197, 3161, 2982, 1552,
1
1318, 1109, 1022 cmÀ1; H nmr (300 MHz, CDCl3): d = 1.03 (t,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2014
821
A Convenient Synthesis of New Pyrazolo[4,3-d]pyrimidines and Their Fused
Heterocycles
J = 7.2 Hz, 3H, CH3), 1.86 (m, 2H, CH2), 2.88 (t, J = 7.2 Hz, 2H,
CH2), 4.31 (s, 3H, N–CH3), 7.43 (d, J = 8.1 Hz, 2H, Ar–H), 7.53
(d, J = 8.1Hz, 2H, Ar–H), 7.72 (d, J = 8.1 Hz, 2H, Ar–H), 7.92 (d,
J = 8.1 Hz, 2H, Ar–H), 8.51 (s, 1H, olefinic-H), 10.39 (bs, 1H,
NH); 13C nmr (75 MHz, CDCl3): d 13.9, 22.1, 27.2, 38.6, 122.4,
127.1, 127.8 (2C’s), 128.0 (2C’s), 129.2, 129.5, 131.1 (2C’s),
131.8 (2C’s), 134,3, 134.7, 142.0, 142.3, 146.6, 148.2; MS
(70 eV): m/z (%)= 438 (M+, 35%), 440 (M+ 2, 24%), 442 (M+ 4,
4%). Anal. Calcd for C22H20Cl2N6 (439.34): C, 60.14; H, 4.59; N,
19.13; found: C, 60.45; H, 4.47; N, 19.37.
General procedure for synthesis of 5-(7-alkyl-4-chlorophenyl)-
1-methyl-3-propyl-1H-pyrazolo[3,4-e][1,2,4]triazolo[4,3-c]
pyrimidines 9a–e.
By Method (ii): A solution of respective
compound 8 (1.0mmole) and DIB (0.385g, 1.2 mmole) in
dichloromethane (20 mL) was stirred at room temperature for 20–
30min, and the reaction progress was monitored by TLC (hexane/
ethyl acetate 9:1). After completion of reaction, the reaction
mixture was washed with 10% sodium bicarbonate solution and
dried over Na2SO4, solvent was removed in vacuo, and the
obtained residue was treated with hexane, filtered, and dried under
vacuum at 60ꢀC to give products 9a–e in 64–79% yield, which
was purified by flash chromatography (silica gel, hexane/ethyl
acetate 9:1 as eluent).
By Method (iii): To a clear solution of 4 (0.316 g, 1.0 mmole)
and respective aldehyde (1.0 mmole) in dichloromethane
(20 mL), diacetoxy iodobenzene (0.385 g, 1.2 mmole) was added
fractionwise under stirring at room temperature. The reaction
mixture was stirred further for 50–55ꢀC, and the reaction
progress was monitored by TLC (hexane/ethyl acetate 9:1). After
completion of reaction, the reaction mixture was washed with
10% sodium bicarbonate solution and dried over Na2SO4,
solvent was removed in vacuo, and the obtained residue was
2-(4-Bromobenzylidene)-1-(5-(4-chlorophenyl)-1-methyl-3-propyl-
1H-pyrazolo[4,3-d]pyrimidin-7-yl)hydrazine (8c).
This
compound was synthesized by using 4-bromobenzaldehyde
(0.184g, 1.0 mmole); pale yellow solid; yield 0.358g (74%); mp
170–172ꢀC; IR: 3419 (ÀNH), 3201, 3154, 2975, 1563, 1485,
1
1322, 1097, 1004, 973cmÀ1; H nmr (300 MHz, CDCl3): d 1.02
(t, J = 7.5Hz, 3H, CH3), 1.85 (m, 2H, CH2), 2.90 (t, J = 7.5 Hz,
2H, CH2), 4.28 (s, 3H, N-CH3), 7.42 (d, J = 8.0 Hz, 2H, Ar–
H), 7.54 (d, J = 8.0 Hz, 2H, Ar–H), 7.71 (d, J = 8.0 Hz, 2H,
Ar–H), 7.90 (d, J = 8.0 Hz, 2H, Ar–H), 8.49 (s, 1H, olefinic-
H), 10.37 (bs, 1H, NH); 13C nmr (75 MHz, CDCl3): d 13.8,
22.1, 27.3, 38.8, 121.9, 127.2, 127.8 (2C’s), 128.1 (2C’s),
129.3, 129.6, 130.9 (2C’s), 131.7 (2C’s), 134.2, 134.8,
142.2, 142.3, 146.9, 149.5; MS (70 eV): m/z (%) = 482 (M+,
41%), 484 (M + 2, 56%), 486 (M + 4, 12%). Anal. Calcd for
C22H20BrClN6 (483.79): C, 54.62; H, 4.17; N, 17.37; found:
treated with hexane, filtered and dried under vacuum at 60ꢀC to
give products 9a–e in 69–81% yield, which was purified by flash
chromatography (silica gel, hexane/ethyl acetate 9:1 as eluent).
5-(4-Chlorophenyl)-1-methyl-7-(1-methylethyl)-3-propyl-1H-
pyrazolo[3,4-e][1,2,4]triazolo[4,3-c]pyrimidine (9a). Colorless
solid; yield 0.250 g, 68% (Method ii), 0.264 g, 72% (Method
iii); mp 169–171ꢀC; IR: 3143, 3023, 2937, 2875, 1667, 1498,
C, 54.79; H, 4.52; N, 17.25.
2-(4-Methoxybenzylidene)-1-(5-(4-chlorophenyl)-1-methyl-3-
propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)hydrazine (8d).
This compound was synthesized by using 4-methoxybenzaldehyde
(0.137 g, 1.0 mmole); yellow crystalline solid; yield 0.334 g (77%);
mp 167–169ꢀC; IR: 3411 (NH), 3176, 3054, 2926, 1561, 1242,
1035, 1005 cmÀ1; 1H nmr (300 MHz, CDCl3): d 1.03 (t, J=7.2Hz,
3H, CH3), 1.85 (m, 2H, CH2), 2.87 (t, J =7.2Hz, 2H, CH2), 3.88
(s, 3H, OCH3), 4.30 (s, 3H, N–CH3), 6.98 (d, J= 8.7 Hz, 2H, Ar–
H), 7.52 (d, J= 8.4 Hz, 2H, Ar–H), 7.74 (d, J = 8.7 Hz, 2H, Ar–H),
7.92 (d, J= 8.4 Hz, 2H, Ar–H), 8.49 (s, 1H, olefinic-H), 10.42 (bs,
1H, NH); 13C nmr (75 MHz, CDCl3): d 14.0, 22.3, 27.6, 38.9,
55.3, 114.2 (2C’s), 122.7, 127.4 (3C’s), 129.2 (2C’s), 129.3
(2C’s), 131.9, 134.7, 136.8, 144.2, 146.1, 146.5, 155.2, 161.5; MS
(70 eV): m/z (%) = 434 (M+, 57%), 436 (M + 2, 20%). Anal. Calcd
for C23H23ClN6O (434.92): C, 63.52; H, 5.33; N, 19.32; found: C,
63.74; H, 5.14; N, 19.61.
1
1234, 1056, 1003 cmÀ1; H nmr (300 MHz, CDCl3): d 1.00 (t,
J = 8.1 Hz, 3H, CH3), 1.13 (m, 6H, 2 Â CH3) 1.83 (m, 2H,
CH2), 2.41 (m, 1H), 2.84 (t, J = 8.1 Hz, 2H, CH2), 4.33 (s, 3H,
N–CH3), 7.13 (d, J = 7.2 Hz, 2H, Ar–H), 7.32 (d, J = 7.2 Hz,
2H, Ar–H); 13C nmr (75 MHz, CDCl3): d 14.0, 19.1 (2C’s),
21.7, 27.3, 29.2, 39.2, 122.4, 128.1, 128.3 (2C’s), 131.2 (2C’s),
132.4, 134.5, 141.2, 143.5, 144.1, 146.3; MS (70 eV): m/z
(%) = 368 (M+, 34%), 370 (M + 2, 12%). Anal. Calcd for
C19H21ClN6 (368.86): C, 61.87; H, 5.74; N, 22.78; found: C,
61.69; H, 6.00; N, 22.42.
5-(4-Chlorophenyl)-1-methyl-7-(4-chlorophenyl)-3-propyl-1H-
pyrazolo[3,4-e][1,2,4]triazolo[4,3-c]pyrimidine (9b). White
amorphous solid; yield 0.345 g, 79% (Method ii), 0.353g, 81%
(Method iii); mp 171–173ꢀC; IR: 3076, 2958, 2935, 2869, 1647,
1492, 1311, 1089, 1012 cmÀ1; 1H nmr (300 MHz, CDCl3): d 1.03
(t, J = 7.5 Hz, 3H, CH3), 1.88 (m, 2H, CH2), 3.00 (t, J = 7.5 Hz,
2H, CH2), 4.51 (s, 3H, N–CH3), 7.05–7.26 (m, 8H, Ar–H); 13C
nmr (75 MHz, DMSO-d6): d 13.7, 21.6, 27.1, 38.4, 121.0, 126.5,
127.2 (2C’s), 127.4 (3C’s), 129.6, 130.9 (2C’s), 131.4 (2C’s),
134.1, 134.5, 141.6, 142.2, 146.3, 147.0; MS (70 eV): m/z
(%) = 436 (M+, 47%), 438 (M+ 2, 31%), 440 (M + 4, 6%). Anal.
Calcd for C22H18Cl2N6 (437.32): C, 60.42; H, 4.15; N, 19.22;
found: C, 60.69; H, 4.11; N, 19.31.
2-(3,4-Dimethoxybenzylidene)-1-(5-(4-chlorophenyl)-1-methyl-3-
propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)hydrazine (8e).
This
compound was synthesized by using 3,4-dimethoxybenzaldehyde
(0.167 g, 1.0 mmole); yellow solid; yield 0.376 g (81%); mp
160–162ꢀC; IR: 3393 (NH), 3042, 2994, 2891, 1552, 1508,
1241, 1257, 1034, 1003 cmÀ1 1H nmr (300 MHz, CDCl3): d
;
1.03 (t, J = 7.2 Hz, 3H, CH3), 1.86 (m, 2H, CH2), 2.87 (t,
J = 7.2 Hz, 2H, CH2), 3.95 (s, 3H, OCH3), 3.99 (s, 3H, OCH3),
4.31 (s, 3H, N–CH3), 6.94 (d, J = 8.1 Hz, 1H, Ar–H), 7.28 (d,
J = 8.1 Hz, 1H, Ar–H), 7.42 (s, 1H Ar–H), 7.49 (d, J = 8.5 Hz,
2H, Ar–H), 7.93 (d, J = 8.5 Hz, 2H, Ar–H), 8.48 (s, 1H,
olefinic-H), 10.46 (bs, 1H, NH); 13C nmr (75 MHz, CDCl3): d
13.6, 21.2, 27.5, 38.9, 55.4, 55.7, 113.2, 114.6, 120.2, 121.8,
123.1, 127.3 (2C’s), 130.3, 131.0 (2C’s), 131.9, 135.1, 142.2,
142.4, 145.7, 147.5, 148.3, 150.6; MS (70 eV): m/z (%) = 464
(M+, 52%), 466 (M + 2, 16%). Anal. Calcd for C24H25ClN6O2
(464.95): C, 62.00; H, 5.42; N, 18.08; found: C, 62.27; H,
5.20; N, 18.31.
5-(4-Chlorophenyl)-1-methyl-7-(4-bromophenyl)-3-propyl-1H-
pyrazolo[3,4-e][1,2,4]triazolo[4,3-c]pyrimidine (9c). Offwhite
solid; yield 0.341 g, 71% (Method ii), 0.355 g, 74% (Method iii);
mp 166–168ꢀC; IR: 3095, 2971, 2934, 2852, 1639, 1511, 1483,
1298, 1060, 1002 cmÀ1 1H nmr (300 MHz, CDCl3): d 1.02
;
(t, J = 7.2 Hz, 3H, CH3), 1.86 (m, 2H, CH2), 2.97 (t, J = 7.2 Hz,
2H, CH2), 4.52 (s, 3H, N–CH3), 6.99–7.35 (m, 8H, Ar–H);
13C nmr (75 MHz, DMSO-d6): d 13.7, 21.7, 27.2, 38.4,
121.1, 126.7, 127.1 (2C’s), 127.3 (3C’s), 129.5, 130.9
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

822
R. V. Rote, D. P. Shelar, S. R. Patil, and M. N. Jachak
Vol 51
(2C’s), 131.3 (2C’s), 134.2, 134.5, 146.8, 142.1, 146.1,
147.2; MS (70 eV): m/z (%) = 480 (M+, 59%), 482 (M + 2,
78%), 484 (M + 4, 17%). Anal. Calcd for C22H18BrClN6
(481.78): C, 54.85; H, 3.77; N, 17.44; found: C, 54.68; H,
4.10; N, 17.62.
5-(4-Chlorophenyl)-1,7-dimethyl-3-propyl-1H-pyrazolo[3,4-
e][1,2,4]triazolo[4,3-c]pyrimidine (9g).
This compound was
synthesized by using triethyl orthoacetate (0.22 mL, 1.2 mmole);
faint yellow solid; yield 0.258 g (76%); mp 198–200ꢀC; IR: 3087,
1
3049, 2958, 2929, 2869, 1650, 1500, 1390, 1317, 1091 cmÀ1; H
5-(4-Chlorophenyl)-1-methyl-7-(4-methoxyphenyl)-3-propyl-1H-
nmr (300 MHz, CDCl3): d 1.00 (t, J = 6.9 Hz, 3H, CH3), 1.84 (m,
2H, CH2), 2.19 (s, 3H, CH3), 2.96 (t, J = 6.9 Hz, 2H, CH2), 4.45
(s, 3H, N–CH3), 7.54 (m, 4H, Ar–H); 13C nmr (75 MHz, DMSO-
d6): d 14.2, 14.5, 22.2, 27.6, 38.8, 121.3, 128.6 (2C’s), 129.5,
131.9 (2C’s), 132.7, 135.6, 142.0, 142.2, 145.6, 146.6; MS
(70 eV): m/z (%)= 340 (M+, 38%), 342 (M + 2, 12%). Anal. Calcd
for C17H17ClN6 (340.81): C, 59.91; H, 5.03; N, 24.66; found: C,
60.14; H, 5.35; N, 24.44.
pyrazolo[3,4-e][1,2,4]triazolo[4,3-c]pyrimidine (9d).
White
crystalline solid; yield 0.277 g, 64% (Method ii), 0.298 g, 69%
(Method iii); mp 172–174ꢀC; IR: 3034, 2963, 2927, 2876, 1658,
1481, 1452, 1238, 1061 cmÀ1; 1H nmr (300MHz, CDCl3): d 1.02
(t, J = 7.2 Hz, 3H, CH3), 1.85 (m, 2H, CH2), 2.98 (t, J = 7.2 Hz,
2H, CH2), 3.81 (s, 3H, OCH3), 4.41 (s, 3H, N–CH3), 6.74 (d,
J = 8.0 Hz, 2H, Ar–H), 6.92 (d, J = 8.0 Hz, 2H, Ar–H), 7.23 (d,
J = 7.5 Hz, 2H, Ar–H), 7.49 (d, J = 7.5 Hz, 2H, Ar–H); 13C nmr
(75 MHz, DMSO-d6): d 13.9, 22.1, 27.4, 38.8, 55.2, 115.3 (2C’s),
121.9, 127.1, 127.3 (2C’s), 129.1 (2C’s), 129.3 (2C’s), 131.7,
134.5, 137.1, 145.1, 146.6, 146.7, 156.1, 160.8; MS (70 eV): m/z
(%) = 432 (M+, 62%), 434 (M+ 2, 22%). Anal. Calcd for
C23H21ClN6O (432.91): C, 63.81; H, 4.89; N, 19.41; found: C,
5-(4-Chlorophenyl)-7-ethyl-1-methyl-3-propyl-1H-pyrazolo
[3,4-e][1,2,4]triazolo[4,3-c]pyrimidine (9h). This compound
was synthesized by using triethyl orthopropionate (0.25 mL,
1.2 mmole); white amorphous solid; yield 0.244 g (69%); mp
182–184ꢀC; IR: 3108, 3057, 2966, 2917, 2871, 1646, 1518,
1401, 1326, 1053 cmÀ1 1H nmr (300 MHz, CDCl3): d 1.02 (t,
;
J = 7.2Hz, 3H, CH3), 1.36 (t, J = 6.9 Hz, 3H, CH3), 1.85 (m, 2H,
CH2), 2.43 (q, J = 6.9Hz, 2H, CH2), 2.94 (t, J = 7.2 Hz, 2H,
CH2), 4.46 (s, 3H, N–CH3), 7.58(d, J = 8.0 Hz, 2H, Ar–H), 7.81
(d, J = 8.0 Hz, 2H, Ar–H); 13C nmr (75MHz, DMSO-d6): d 13.9,
14.2, 21.8, 23.1, 27.4, 38.7, 122.4, 127.9 (2C’s), 129.2, 131.4
(2C’s), 132.1, 136.2, 142.6, 143.2, 145.8, 147.4; MS (70 eV): m/z
(%) = 354 (M+, 61%), 356 (M+ 2, 19%). Anal. Calcd for
C18H19ClN6 (354.84): C, 60.93; H, 5.40; N, 23.68; found: C,
60.72; H, 5.70; N, 23.54.
64.06; H, 4.76; N, 19.63.
5-(4-Chlorophenyl)-1-methyl-7-(3,4-dimethoxyphenyl)-3-propyl-
1H-pyrazolo[3,4-e][1,2,4]triazolo[4,3-c]pyrimidine (9e). Colorless
solid; yield 0.332 g, 72% (Method ii), 0.328 g, 71% (Method iii);
mp 182–184ꢀC; IR: 3052, 2956, 2929, 2867, 1645, 1527, 1488,
1
1315, 1261, 1026 cmÀ1; H nmr (300 MHz, CDCl3): d 1.04 (t,
J = 7.5 Hz, 3H, CH3), 1.89 (m, 2H, CH2), 3.01 (t, J = 7.5 Hz,
2H, CH2), 3.79 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 4.52
(s, 3H, N–CH3), 6.55 (m, 2H, Ar–H), 6.80 (s, 1H, Ar–H), 7.10
(d, J = 8.7 Hz, 2H, Ar–H), 7.20 (d, J = 8.7 Hz, 2H, Ar–H); 13C
nmr (75 MHz, DMSO-d6): d 13.8, 21.7, 27.2, 38.5, 55.2, 55.8,
111.1, 113.5, 119.8, 121.1, 122.8, 127.0 (2C’s), 129.5, 130.8
(2C’s), 131.8, 134.2, 141.9, 142.0, 146.3, 147.6, 148.0, 149.7;
MS (70 eV): m/z (%) = 462 (M+, 54%), 464 (M + 2, 17%).
Anal. Calcd for C24H23ClN6O2 (462.93): C, 62.27; H, 5.01; N,
18.15; found: C, 62.60; H, 5.09; N, 18.36.
General procedure for synthesis of 5-(7-alkyl-4-chlorophenyl)-1-
methyl-3-propyl-1H-pyrazolo[3,4-e][1,2,4]triazolo[4,3-c]pyrimidines
9f–i. A solution of 1-(5-(4-chlorophenyl)-1-methyl-3-propyl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl) hydrazine 4 (0.317g, 1.0 mmole)
and respective triethylorthoester (1.2 mmole) in ethanol (20 mL)
was heated under reflux temperature for 3–4 h, and the reaction
progress was monitored by TLC (hexane/ethyl acetate 9:1). After
completion of the reaction, solvent was removed in vacuo, and the
obtained residue was treated with hexane, filtered, and dried under
vacuum at 60ꢀC to give products 9f–i in 69–78% yield, which
was purified by flash chromatography (silica gel, hexane/ethyl
acetate 9:1 as eluent).
5-(4-Chlorophenyl)-7-phenyl-1-methyl-3-propyl-1H-pyrazolo
[3,4-e][1,2,4]triazolo[4,3-c]pyrimidine (9i).
This compound
was synthesized by using triethyl orthobenzoate (0.27 mL,
1.2 mmole); offwhite solid; yield 0.314g (78%); mp 174–176ꢀC;
IR: 3188, 3087, 2947, 2918, 2893, 1667, 1534, 1399, 1338,
1
1009 cmÀ1; H nmr (400 MHz, CDCl3): d 1.04 (t, J = 7.4 Hz, 3H,
CH3), 1.90 (m, 2H, CH2), 3.01 (t, J = 7.4 Hz, 2H, CH2), 4.53 (s,
3H, N–CH3), 7.01–7.07 (m, 2H, Ar–H), 7.11–7.18 (m, 6H, Ar–
H), 7.29–7.35 (m, 1H, Ar–H); 13C nmr (75 MHz, DMSO-d6): d
13.9, 21.8, 27.7, 39.2, 122.0, 127.3 (2C’s), 127.5 (4C’s), 128.2
(2C’s), 129.1 (2C’s), 129.6, 132.5, 133.3, 139.7, 142.0, 146.1,
149.9; MS (70 eV): m/z (%)= 402 (M+, 54%), 404 (M+ 2, 19%).
Anal. Calcd for C22H19ClN6 (402.88): C, 65.59; H, 4.75; N,
20.86; found: C, 65.87; H, 4.71; N, 20.98.
Acknowledgments. The authors are thankful to CSIR for the
financial assistance, under the Major Research Project; Prof. D.
D. Dhavale, Department of Chemistry, University of Pune, India,
for analytical data; and KTHM College, Nashik for facilities.
5-(4-Chlorophenyl)-1-methyl-3-propyl-1H-pyrazolo[3,4-e]
[1,2,4]triazolo[4,3-c]pyrimidine (9f).
This compound was
synthesized by using triethyl orthoformate (0.20 mL, 1.2 mmole);
pale yellow solid; yield 0.231 g (71%); mp 211–213ꢀC; IR: 3114,
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823
A Convenient Synthesis of New Pyrazolo[4,3-d]pyrimidines and Their Fused
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet