One-pot synthesis of 2-alkyl-7-amino-5-aryl-pyrazolo[1,5-a]pyrimidine-6- carbonitriles via a domino three-component condensation-oxidation reaction

Article abstract of DOI:10.1016/j.crci.2012.06.006

A one-pot, domino three-component condensation reaction of an aldehyde, 3(5)-amino-5(3)-methylpyrazole and malononitrile in ethanol to give 2-alkyl-7-amino-5-aryl-pyrazolo[1,5-a]pyrimidine-6-carbonitrile in high yields at reflux condition without using any catalyst, is described.

Full text of DOI:10.1016/j.crci.2012.06.006

C. R. Chimie 15 (2012) 647–652
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Preliminary communication/Communication
One-pot synthesis of 2-alkyl-7-amino-5-aryl-pyrazolo[1,5-a]
pyrimidine-6-carbonitriles via a domino three-component
condensation-oxidation reaction
Abbas Rahmati
Department of Chemistry, University of Isfahan, P.O. Box 81746, 73441 Isfahan, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
A one-pot, domino three-component condensation reaction of an aldehyde, 3(5)-amino-
5(3)-methylpyrazole and malononitrile in ethanol to give 2-alkyl-7-amino-5-aryl-
pyrazolo[1,5-a]pyrimidine-6-carbonitrile in high yields at reflux condition without using
any catalyst, is described.
Received 3 April 2012
Accepted after revision 13 June 2012
Available online 15 July 2012
´
ß 2012 Published by Elsevier Masson SAS on behalf of Academie des sciences.
Keywords:
Pyrazolopyrimidine
3-aminopyrazole
Malononitrile
Domino reaction
1. Introduction
reductase [18], tyrosine kinase [19], and BMP signaling
[20]. Therefore the development of a simple synthetic
The development of simple routes toward making
widely used organic compounds from readily available
reagents and compounds is one of the major tasks in
organic synthesis [1]. Multi-component condensation
reactions (MCRs) occupy an advantageous position among
other reactions, because of high atom economy, high
yields, convergent character and simplicity of procedures
[2–4]. Therefore, the discovery and development of novel
MCRs is one of the goals of chemistry research groups.
Pyrazolo[1,5-a]pyrimidines are attractive heterocyclic
compounds for drug discovery since many of these
scaffolds exhibit wide range of biological, medicinal and
pharmaceutical activities such as antimicrobial [5,6], anti-
tumor [7], antischistosomal [8], antirypanosomal [9],
hepatotoxic [10], antianxiety agents [11], Peripheral
Benzodiazpine receptor (PBR) [12], CRF1 receptor antago-
nist (R121919) [13], estrogen receptor antagonist [14],
inhibitors of phosphodiesterase [15], KDR kinase [16],
selective cyclooxygenase-2 (COX-2) [17], HMG-CoA
method for synthesis of these derivatives is important in
organic synthesis.
A careful literature survey reveals that a wide range of
methods have been reported for the synthesis of pyr-
azolo[1,5-a]pyrimidine [21–45]. Some of the methods
among these reports are based on MCRs protocols;
condensation of arylhydrazone derivatives with 3-amino-
pyrazole [43], Wittig reaction [44] using orthoesters and
1,3-diketons in a three-component reactions with MW
irradiation [45].
Some reviews on the chemistry of aminopyrazoles have
been written by several groups [46–48]. Undoubtedly, one
of the most important compounds for synthesis of
pyrazolo[1,5-a]pyrimidine [21–43] and pyrazolo[3,4-
b]pyridine [49–51] is 3(5)-aminopyrazole. 3(5)-amino-
5(3)-methylpyrazole 1 with hydrogen atom on nitrogen of
ring can be produce pyrazolo[1,5-a]pyrimidines (4,5) or
pyrazolo[3,4-b]pyridines (6,7) and/or both of them (4,5
and 6,7) while with alkyl substitutes on nitrogen (2)
produce pyrazolo[3,4-b]pyridines (8 or 9) (Scheme 1).
Although, reports from
a,b-unsaturated nitrile com-
pounds are a few, Elnaghdi [40], Wendt and Anwar
E-mail addresses: abbass_rahmati@yahoo.com, a.rahmati@sci.ui.ac.ir.
1631-0748/$ – see front matter ß 2012 Published by Elsevier Masson SAS on behalf of Acade´mie des sciences.
http://dx.doi.org/10.1016/j.crci.2012.06.006

648
A. Rahmati / C. R. Chimie 15 (2012) 647–652
R1
H2N
N
R2
R2
R1
N
N
H2N
N
N
and/or
H2N
R2
R1
N
5
N
4
N
N
R3
8
CN
R1
CN
R1
R2
N
R2
3
3
NH2
NH2
NH2
N
1a
NH
1a'
N
R3
N
H
N
2
CN
CN
R1
R1
R2
R2
3
3
R1
R1
H2N
R2
H2N
R2
H2N
R2
R1
N
N
N
and/or
N
N
N
N
H
R3
N
N
H
9
6
7
Scheme 1. Possible pyrazolopyri(mi)dines from reactions of 3(5)-amino-5(3)-methylpyrazole and/or 1-alkyl-5-aminopyrazole with
a,b-unsaturated
nitrile compounds.
[41,42] groups separately carefully show that a pyrazole
ring with hydrogen atom on nitrogen of pyrazole ring
generates only product 4. Also, Quiroga et al. demonstrated
that pyrazole ring with aryl substitutes on nitrogen
produces pyrazolo[3,4-b]pyridines 8 between isomers 8
and 9 (Scheme 1) [52]. Recently, Zhang et al. generated
of an aldehyde 10 and 3(5)-amino-5(3)-methylpyrazole 1
in the presence of malononitrile 11 under reflux conditions
in ethanol without using any catalyst (Scheme 2). To the
best of our knowledge, there is no report for synthesis of
these compounds via three-component condensation
reaction.
pyrazolo[3,4-b]pyridines
8 using a three-component
reaction [53].
2. Results and discussion
In continuing our interest in aminoazole based MCRs
[54,55], here we want to report the synthesis of 2-alkyl-7-
amino-5-aryl-pyrazolo[1,5-a]pyrimidine-6-carbonitrile 4
via the one-pot three-component condensation reaction
In a typical experiment, the reaction of p-methylbenz-
aldehydes with 3(5)-amino-5(3)-methylpyrazole and
malononitrile afforded 7-amino-2-methyl-5-p-tolylpyra-
Scheme 2. Synthesis of 2-alkyl-7-amino-5-aryl-pyrazolo[1,5-a]pyrimidine-6-carbonitrile 4.

A. Rahmati / C. R. Chimie 15 (2012) 647–652
649
Table 1
similar to those of 4c except for the X groups, which exhibit
characteristic signals with appropriate chemical shifts.
It is important to note that two types of selectivity could
happen during this reaction; regioselectivity (when 4 and 5
were generated) and chemoselectivity (when 6 and 7 were
generated). However, this reaction proceeds as regio-
selective. Regioselectivity in this reaction was investigated
via variations in structure and conditions. Both of the
variations could have an effect on reactivity of reaction
centers. Regarding the effect of structure, different
aminoazoles such as 3(5)-amino-4-cyanopyrazole and
3(5)-amino-5(3)-carbonitrilpyrazole have been used in-
stead of 3(5)-amino-5(3)-methylpyrazole, but the reaction
did not proceed. Then, reaction conditions have been
changed and it is concluded that in different solvents, the
reaction was performed but yields of reactions were
different. Then, acidic and basic media were tested in this
reaction and it is showed that in an acidic medium, the
reaction did not take place but in basic conditions the
reaction was performed. Finally, by these variations no
new product achieved except of 4. To some extent,
according to obtained results, the initial reaction of amine
group can be confirmed; because when the NH2 group was
deactivated, it could not react. This confirmed Went’s
description about the initial exo amine attack [41]. On the
other hand, by considering the resonance forms in each
tautomer, it can be seen that in most of the structures, the
amine group is free. Therefore, amine group could react
more than the others.
Synthesized substituted 2-alkyl-7-amino-5-aryl-pyrazolo[1,5-a]pyrimi-
dines 4a–h.
Entry
R1
Product
Yielda (%)
1
2
3
4
5
6
7
8
4-CH3-
4a
4b
4c
4d
4e
4f
82
86
80
80
73
81
89
85
4-CH3O-
4-Cl-
4-Br-
4-Ph-
3-CH3O-
2,4-di-CH3O-
3,4-di-CH3O-
4g
4h
a
Isolated yield.
zolo[1,5-a]pyrimidine-6-carbonitrile in EtOH as solvent in
relatively high yields. At first, to achieve suitable conditions
for the above transformation, a series of solvents was
applied. We found that the best solvent for this reaction was
ethanol at reflux.
To explore the scope and limitations of this reaction, we
have extended it to various substituted benzaldehydes
with 3(5)-amino-5(3)-methylpyrazole in the presence of
malononitrile. As indicated in Table 1, the reaction
proceeds efficiently with various substituted benzalde-
hydes.
Scheme 1 shows that products 4, 5, 6 and 7 could be
generated during the reaction due to the presence of three
various active nucleophilic sites on 3(5)-amino-5(3)-
methylpyrazole and two different electerophilic centers
on benzylidene malononitrile. Monitoring of reaction
solution by TLC showed that only one product was
generated. After purification, IR and 1H NMR spectra of
product indicated that all of starting materials participated
in structure of product. In addition, 1H NMR spectrum of
this product straightforwardly specified that this product
could be 4 or 5 because of the presence of CH and absence
of NH signals of pyrazole ring. Although between
structures 4 and 5, structure 4 was selected as final
product based on Elnaghdi [40], Wendt and Anwar [41,42]
report, but (1H,15N) HMBC spectra were also achieved from
product. Correlation of hydrogens of NH2 group with nodal
nitrogen confirmed that only isomer 4 was produced
during the present reaction.
The IR spectrum of 4c showed absorptions at 3449 and
3309 for NH2, 3165 (CH) of pyrazole, 2217 (CN), 1650 and
1603 for (C N) and 1181 (C–Cl) cmÀ1 indicating the
presence of this functional groups. The mass spectrum of
4c displayed the molecular ion peak at m/z = 285 (37Cl) and
283 (35Cl), which were consistent with the 1:1:1 adduct of
starting materials losing of water and H2. The 1H NMR
spectrum of 4c exhibited a singlet for CH3 group at
We have not established a mechanism for the formation
of 2-alkyl-7-amino-5-aryl-pyrazolo[1,5-a]pyrimidine-6-
carbonitrile, but possible mechanisms are indicated in
Scheme 3. The reaction presumably proceeds in several
steps: condensation of aldehydes 10 and malononitrile 11
by
a Knoevenagel reaction to produce 3-benzylidene
compounds 12, followed by a Michael addition of this
product with 3-amino-5-methylpyrazole 1a to give inter-
mediates 13, after this intermediate by cyclization give
ring systems 14. Compound 14 with proton transfer
produced compound 15; at next step, this compound by
tautomerization produce compound 16 and after this step
by oxidation of compound 16 2-alkyl-7-amino-5-aryl-
pyrazolo[1,5-a]pyrimidine-6-carbonitrile 4 was produced
(Scheme 3).
In order to compare the ability of this three-component
reaction with previous reports [41,42], first p-methylben-
zylidene malononitrile (17) was prepared [56] and was
reacted with 3(5)-amino-5(3)-methylpyrazole (Scheme 4).
Although the yield of the two-component reaction [42]
was close to the three-component reaction, it was
performed in two steps and its total yield was low
(72%). In this process, 3(5)-amino-5(3)-methylpyrazole
acts as a base and accelerates the synthesis of intermediate
17 and followed by Michael addition and cyclization
produces product 4b without any base, while in a previous
report, some bases such as NEt3 and NaOEt in ethanol
solvent and NaOAc in toxic pyridine solvent have been
used [41]. It should be pointed out that this reaction has
the advantages of multi-component reactions.
d
= 2.42 ppm, other singlet at
d = 6.43 ppm for CH of
pyrazole ring. Two doublet for aromatic hydrogens
3
appeared at
broad singlet line is readily recognized as arising from NH2
group at
= 8.81 ppm. The 1H decoupled 13C NMR
spectrum of 4c showed 12 distinct resonances in
agreement with the suggested structures. Finally, correla-
tion of hydrogens of NH2 group with nodal nitrogen in
(1H,15N) HMBC spectra exactly confirmed structure 4c. The
1H and 13C NMR spectrum of other structures of 4 are
d = 7.58 and 7. 79 ppm with JHH = 6.99 Hz. A
d
In conclusion, we have developed a novel and efficient
three-component condensation reaction of an aldehyde,

650
A. Rahmati / C. R. Chimie 15 (2012) 647–652
Scheme 3. Mechanism for the formation of 2-alkyl-7-amino-5-aryl-pyrazolo[1,5-a]pyrimidine-6-carbonitrile 4.
3(5)-amino-5(3)-methylpyrazole and malononitrile for
synthesis of 2-alkyl-7-amino-5-aryl-pyrazolo[1,5-a]py-
rimidine-6-carbonitrile. The present method carries the
advantage of being performed under neutral conditions
and requires no activation or modification of the educts.
The simplicity of this method makes it an interesting
alternative to the previous approaches.
(1 mmol) in ethanol (10 mL) was refluxed for 24 h. After
completion of the reactions, the solvent was removed by
evaporation under reduced pressure, and the residue was
purified by column chromatography using n-hexane-
EtOAc (6:1) as eluent. Then, the solvent was removed
and the product was obtained.
3.1.1. Data for 7-amino-2-methyl-5-p-tolylpyrazolo[1,5-
a]pyrimidine-6-carbonitrile (4a)
3. Experimental
White powder (82%). IR (KBr) (v
max, cmÀ1): 3449, 3307,
2949, 2212, 1650, 1604 cmÀ1. MS (EI, 70 eV) m/z (%): 263
(M+, 40). Anal. Calcd for C15H13N5: C, 68.42; H, 4.98; N,
26.60. Found: C, 68.31; H, 4.93; N, 26.73. 1H NMR
3.1. Typical procedure for the synthesis of 7-amino-2-methyl-
5-p-tolylpyrazolo[1,5-a]pyrimidine-6-carbonitrile (4a)
(300 MHz, DMSO-d6)
d 2.38 (s, 3H, CH3), 2.42 (s, 3H,
A solution of malononitrile (1 mmol), p-methyl benzal-
dehyde (1 mmol) and 3(5)-amino-5(3)-methylpyrazole
CH3), 6.40 (s, 1H, CH(pyrazole)), 7.31 (d, 3J = 7.80 Hz, 2H, CH
CN
CN
CHO
CN
L-Hystidine
+
r.t.(12h)
CN
11
17
86%
10b
CN
CN
H2N
NH2
NH2
NH
EtOH/Reflux
24h
CN
N
N
N
+
N
H
N
N
1a
1b
16
4b
83%
Scheme 4. Competitive reactions.

A. Rahmati / C. R. Chimie 15 (2012) 647–652
651
(arom)), 7.69 (d, 3J = 7.80 Hz, 2H, CH (arom)), 7.73 (bs, 2H,
NH2) ppm. 13C NMR (75 MHz, DMSO-d6)
14.82, 21.39,
64.51; H, 4.69; N, 25.07. Found: C, 64.34; H, 4.60; N, 25.29.
1H NMR (300 MHz, DMSO-d6)
: 2.42 (s, 3H, CH3), 3.81 (s,
d
d
71.81, 91.72, 117.13, 128.96, 129.22, 135.18, 140.15,
148.82, 150.90, 156.30, 158.80 ppm.
3H, OCH3), 6.42 (s, 1H, CH(pyrazole)), 7.23–7.45 (m, 4H, CH
(arom)), 8.75 (bs, 2H, NH2) ppm. 13C NMR (75 MHz, DMSO-
d6) d: 14.80, 55.69, 72.03, 79.91, 114.31, 116.12, 117.00,
3.1.2. Data for 7-amino-5-(4-methoxyphenyl)-2-methyl
121.30, 129.83, 139.25, 148.69, 150.86, 156.39, 158.64,
159.35 ppm.
pyrazolo[1,5-a]pyrimidine-6-carbonitrile (4b)
White powder (86%). IR (KBr) (v
max, cmÀ1): 3364, 3311,
3211, 2212, 1661, 1643, 1251. MS (EI, 70 eV) m/z (%): 279
(M+, 30). Anal. Calcd for C15H13N5O: C, 64.51; H, 4.69; N,
25.07. Found: C, 64.38; H, 4.76; N, 25.32. 1H NMR
3.1.7. Data for 7-amino-5-(2,4-dimethoxyphenyl)-2-methyl
pyrazolo[1,5-a]pyrimidine-6-carbonitrile (4g)
White powder (89%). IR (KBr) (v
max, cmÀ1): 3357, 2938,
(300 MHz, DMSO-d6)
d
: 2.41 (s, 3H, CH3), 3.83 (s, 3H,
2214, 1599, 1210, 1161, 1119. MS (EI, 70 eV): m/z (%): 309
CH3), 6.38 (s, 1H, CH(pyrazole)), 7.06 (d, 3J = 8.40 Hz, 2H, CH
(arom)), 7.78 (d, 3J = 8.40 Hz, 2H, CH (arom)), 8.70 (bs, 2H,
(M+, 30), 309 (M+–1, 100), 309 (M+–2, 60). Anal. Calcd for
C
16H15N5O2: C, 62.13; H, 4.89; N, 22.64. Found: C, 61.96; H,
NH2) ppm. 13C NMR (75 MHz, DMSO-d6)
d
: 14.81, 55.78,
4.97; N, 22.51. 1H NMR (300 MHz, DMSO-d6)
d
: 2.49 (s, 3H,
71.55, 97.54, 114.04, 117.28, 130.23, 130.60, 148.84,
150.94, 156.27, 158.31, 161.12 ppm.
CH3), 3.87 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 6.40 (s, 1H,
CH(pyrazole)), 6.47 (bs, 2H, NH2), 6.58 (d, 4J = 2.22 Hz, 1H,
CH (arom)), 6.62 (d, 3J = 8.45 Hz, 4J = 2.29 Hz, 1H, CH
(arom)),7.43 (d, 3J = 8.38 Hz, 1H, CH (arom)), ppm. 13C
3.1.3. Data for 7-amino-5-(4-chlorophenyl)-2-methyl
pyrazolo[1,5-a]pyrimidine-6-carbonitrile (4c)
NMR (75 MHz, DMSO-d6) d: 14.66, 55.46, 55.51, 75.92,
98.16, 98.67, 105.31, 116.11, 119.69, 131.44, 148.90,
149.23, 157.03, 157.38, 158.05, 162.61 ppm.
White powder (79%); IR (KBr) (
v
max, cmÀ1): 3449, 3309,
3165, 2217, 1650, 1603, 428; MS (EI, 70 eV): m/z (%):285
(M++2, 5), 283 (M+, 22), 282 (M+–1, 10). Anal. Calcd for
C
14H10ClN5: C, 59.27; H, 3.55; N, 24.68. Found: C, 59.03; H,
3.1.8. Data for 7-amino-5-(3,4-dimethoxyphenyl)-2-methyl
3.48; N, 24.73. 1H NMR (300 MHz, DMSO-d6)
d
: 2.42 (s, 3H,
pyrazolo[1,5-a]pyrimidine-6-carbonitrile (4h)
CH3), 6.43 (s, 1H, CH(pyrazole)), 7.58 (d, 3J = 6.99 Hz, 2H,
CH (arom)), 7.79 (d, J = 6.99 Hz, 2H, CH (arom)), 8.81 (bs,
2H, NH2) ppm. 13C NMR (75 MHz, DMSO-d6)
71.89, 98.02, 116.91, 128.78, 130.85, 135.25, 136.71,
148.65, 150.81, 156.50, 157.68 ppm.
White powder (85%). IR (KBr) (v
max, cmÀ1): 3348, 2939,
3
2215, 1589, 1213, 1168, 1127. MS (EI, 70 eV): m/z (%): 309
(M+, 25). Anal. Calcd for C16H15N5O2: C, 62.13; H, 4.89; N,
22.64. Found: C, 62.25; H, 4.92; N, 22.51. 1H NMR
d: 14.78,
(300 MHz, DMSO-d6)
d: 2.04 (s, 3H, CH3), 3.82 (s, 6H,
2 Â OCH3), 6.39 (s, 1H, CH(pyrazole)), 7.07 (d, 3J = 8.1 Hz,
1H, CH (arom)), 7.40 (s, 1H, CH (arom)), 7.41 (d, 3J = 8.1, 2H,
CH (arom)), 8.71 (bs, 2H, NH2), ppm. 13C NMR (DMSO-d6,
3.1.4. Data for 7-amino-5-(4-bromophenyl)-2-methyl
pyrazolo[1,5-a]pyrimidine-6-carbonitrile (4d)
White powder (80%); IR (KBr) (
v
max, cmÀ1): 3427, 3295,
75 MHz) dC: 14.81, 55.98, 56.02, 71.65, 97.57, 111.43,
3222, 3085, 2215, 1651, 1600, 1408, 820, 470; MS (EI,
70 eV): m/z (%): 329 (M++2, 35), 327 (M+, 35). Anal. Calcd
for C14H10BrN5: C, 51.24; H, 3.07; N, 21.34. Found: C, 50.37;
112.42, 117.36, 122.08, 130.21, 148.63, 148.76, 150.79,
150.95, 156.28, 158.32.
H, 3.05; N, 21.53. 1H NMR (300 MHz, DMSO-d6)
d: 2.42 (s,
Acknowledgements
3H, CH3), 6.43 (s, 1H, CH(pyrazole)), 7.73 (bs, 4H, CH
(arom)), 8.85 (bs, 2H, NH2) ppm. 13C NMR (75 MHz, DMSO-
We gratefully acknowledge financial support from the
Iran National Science Foundation (INSF) (research project
90001941) and Research Council of the University of
Isfahan.
d6) d: 14.83, 71.84, 98.04, 116.93, 124.04, 131.10, 131.72,
137.13, 148.69, 150.83, 156.43, 157.75 ppm.
3.1.5. Data for 7-amino-5-(biphenyl-4-yl)-2-methyl
pyrazolo [1,5-a]pyrimidine-6-carbonitrile (4e)
White powder (78%). IR (KBr) (v
max, cmÀ1): 3438, 3320,
References
3237, 3108, 2211, 1644, 1602, 1348; MS (EI, 70 eV): m/z
(%): 325 (M+, 60). Anal. Calcd for C20H15N5: C, 73.83; H,
4.65; N, 21.52. Found: C, 74.02; H, 4.50; N, 21.38. 1H NMR
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(300 MHz, DMSO-d6)
CH(pyrazole)), 7.38-7.92 (m, 9H, CH (arom)), 8.82 (bs, 2H,
NH2) ppm. 13C NMR (75 MHz, DMSO-d6)
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158.36 ppm.
3.1.6. Data for 7-amino-5-(3-methoxyphenyl)-2-methyl
pyrazolo[1,5-a]pyrimidine-6-carbonitrile (4f)
White powder (81%). IR (KBr) (v
max, cmÀ1): 3432, 3318,
3117, 2235, 1639, 1600, 1521. MS (EI, 70 eV): m/z (%): 280
(M++1, 40), 279 (M+, 25). Anal. Calcd for C15H13N5O: C,

652
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