Catalysis Communications 8 (2007) 1467–1471

www.elsevier.com/locate/catcom

A catalytic method for synthesis of

6-aryl-1H-pyrazolo[3,4-d]pyrimidin-4[5H]-ones by
heteropolyacids: H14[NaP5W29MoO110] and H3PMo12O40
a,*
Majid M. Heravi , Radineh Motamedi b, Fatemeh F. Bamoharram c, Nasim Seify c

a
Department of Chemistry, School of Sciences, Azzahra University, Vanak, Tehran, Iran
b
Department of Chemistry, School of Sciences, Payame nour University, Delijan, Iran
c
Department of Chemistry, Islamic Azad University – Mashhad Branch, Mashhad, Iran

Received 18 June 2006; received in revised form 12 December 2006; accepted 12 December 2006
Available online 21 December 2006

Abstract

Derivatives of 6-aryl-1H-pyrazolo[3,4-d]pyrimidin-4[5H]-ones 4, are synthesized from reaction of 5-amino-1-phenyl-1H-pyrazolo-4-

carboxamide 1 with aromatic aldehyde in the presence of heteropolyacids, H3PMo12O40, H3-PMo, and H14[NaP5W29MoO110], H14P5-
Mo with high yields. The catalytic activity of H3-PMo is found to be lower than H14P5-Mo.
 2006 Elsevier B.V. All rights reserved.

Keywords: Pyrazolo[3,4-d]pyrimidin-4[5H]-one; Heteropolyacid; Catalytic reaction; Catalyst

1. Introduction 2–4 h in the presence of hydrochloric acid and 5 h refluxing

Pyrazolo[3,4-d]pyrimidines have attracted considerable
attention because of their pharmacological importance,
anti-tumor, and anti-leukemia activities [1–5]. Due to their
importance, the synthesis of these compounds have inter-
ested for discovery of improved protocols towards milder
and high yielding approaches.
Generally, acid-catalyzed condensation of 5-amino-1-
phenyl-1H-pyrazolo-4-carboxamide 1 with aromatic alde-
hydes and carboxylic acids is one of the simplest and most
applicable approaches for synthesis of Pyrazolo[3,4-d]pyr-
imidines. Veeranagaiah and co-workers also have used ace-
tic acid or HCl and poly phosphoric acid or poly phosphate
ester as an acid catalyst [6]. These catalysts are toxic and
dangerous and the applications of them cause environmen-
tal problems. These reactions for the synthesis of (4h–4i–
4k–4m) were carried out in refluxing acetic acid during
*
Corresponding author. Tel.: +98 2188041344; fax: +98 2188047861.
E-mail address: mmh1331@yahoo.com (M.M. Heravi).
in acetic acid in the absence catalyst in 47–60% yields [6].
There is no doubt that over the past 20 years, the chem-
istry community, and in particular, the chemical industry,
has made extensive efforts to reduce the risk associated
with the manufacture and use of various chemicals.
Green chemistry is an approach to the synthesis, pro-
cessing, and use of chemicals that reduces risks to humans
and the environment. Much innovative chemistry has been
developed over the past several years that are effective, effi-
cient and more environmentally benign. These approaches
include new syntheses and processes as well as new tools
for instructing aspiring chemists how to do chemistry in a
more environmentally benign manner.
Thus the development and using of solid and green cat-
alysts is very important in organic syntheses.
Development of methods using heteropolyacids (HPAs)
as solid and green catalysts for fine organic synthetic pro-
cesses related to fine chemicals, such as flavors, pharmaceu-
ticals and food industries have been under attention in the
last decade [7]. HPAs are more active catalysts than con-
ventional inorganic and organic acids for various reactions

1566-7367/$ - see front matter  2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2006.12.012
1468 M.M. Heravi et al. / Catalysis Communications 8 (2007) 1467–1471

in solution [8]. They are used as industrial catalysts for sev- The product was dissolved in warm water and upon cooling
eral liquid-phase reactions such as esterification, etherifica- to room temperature yellow crystals formed. Acidic form of
tion, hydration and dehydration, de-esterification, and molybdenum substituted heteropolyacid was prepared by
condensation reactions [9–20]. passage of a solution of the potassium salt in water through
Herein we present synthesis of some derivatives of a column (50 · 1 cm) of Dowex 50 w · 8 in the H+ form and
1H-pyrazolo[3,4-d]pyrimidin-4(5H)-ones 4 that are impor- evaporation of the elute to dryness under vacuum.
tant in medicine, by a Keggin-type, H3[PMo12O40] and a IR (cm 1): 1165(vs), 1085(s), 1060(m), 960(vs), 920(vs),
Preyssler-type, H14[NaP5W29MoO110] heteropolyacids as 700–800(b).
solid acid catalysts. Our findings indicate that both HPA These catalysts fully characterized in the literature
catalysts are effective for synthesis of 1H-pyrazolo[3,4- [21,22].
d]pyrimidin-4(5H)-ones with high yields.
The major aim described in this work is the design and 2.2. General procedure for the synthesis 6-substituted-
development of applications for HPAs with exclusive prop- pyrazolo[3,4-d]pyrimidin-4(5H)-ones(4a–n)
erties surpassing the mineral acids in synthesis of heterocy-
clic systems. A solution of 1 (0.9 mmol) and appropriate aromatic
aldehyde 2 (0.9 mmol) and an appropriate heteropolyacid
2. Experimental (0.04 mmol) in acetic acid (10 mL) was refluxed for 1 h.
The catalyst was removed by filtering and washed with
2.1. Catalyst preparation warmed acetic acid (the catalyst is not soluble in acetic
acid). The catalyst was washed with diethyl ether after fil-
H3PMo12O40 was prepared as follows: To 420 mL of a tration. It could be reused and subjected to a second run
2.85 M aqueous solution of Na2Mo4 were added succes- of reaction. The yields of products were almost identical
sively 6.8 mL of 85% H3PO4 and 284 mL of 70% HClO4. to yields obtained by using fresh catalyst. The filtrate was
The disodium salt precipitated from the yellow solution. cooled and the solid was filtered, washed with water, dried
After filtering the mixture, the obtained powder was air- and re-crystalized from ethanol to give pure product 4
dried. Recrystallization in a mixture of Et2O/H2O gave (Table 1). All compounds were characterized by mass, IR
greenish microcrystals. An aqueous solution of the greenish and 1H NMR spectra (Table 2).
microcrystals, acidified by HCl, and extracted by Et2O. To
heavy layer, was added water and yellow crystals of 3. Result and discussions
H3PMo12O40 precipitated.
IR (cm 1): 1067(s), 975(sh), 963(vs), 870(s), 810(sh), Recently, we described synthesis of some new derivatives
785(vs), 593(w). of 1H-pyrazolo[3,4-d]pyrimidin-4(5H)-ones 4 by HPAs
H14[NaP5W29MoO110] was prepared as follow: 2.8 g including W such as H3[PW12O40] and H14[NaP5W30O110]
(0.169 mol) Na2WO4 Æ 2H2O and 2 g (0.008 mol) as acidic catalysts instead of mineral acids like HCl
Na2MoO4 Æ 2H2O were dissolved in 35 mL water and mixed or polyphosphoric acid as a more eco-friendly and suitable
at 60 C for 30 min. Then this solution was cooled to room method [23]. Therefore, it is great interest to know,
temperature, and 25 mL concentrated phosphoric acid was what occurs if the other HPAs have been used in these
added. The resulted yellow solution was refluxed for 18 h. reactions.
The solution was brought to room temperature, diluted In continuation with our works using heteropolyacids
with water and then during stirring, 10 g KCl was added. [24] which are low in toxicity, highly stable towards humid-
The mixture was stirred and then heated up to dryness. ity, being recyclable, air stable, and very important in green
Table 1
Catalytic synthesis of 6-substituted-pyrazolo[3,4-d]pyrimidin-4(5H)-ones 4
Compound R R1 Reaction time (min) Yield (%) using H3[PMo12O40] Yield (%) using H14[NaP5W29MoO110] Mp (C) [23]
4a CH3 Ph 60 70 92 300–301
4b CH3 4-MeC6H4 60 76 98 275–277
4c CH3 3-MeC6H4 60 79 85 279–281
4d CH3 4-NO2C6H4 60 76 96 308–310
4e CH3 3-NO2C6H4 60 76 95 293–295
4f CH3 4-ClC6H4 60 88 98 316–318
4g CH3 4-BrC6H4 60 76 91 310–311
4h H Ph 60 73 90 288–290
4i H 4-MeC6H4 60 76 83 253–255
4j H 3-MeC6H4 60 88 86 262–264
4k H 4-NO2C6H4 60 75 94 278–280
4l H 3-NO2C6H4 60 74 94 285–287
4m H 4-ClC6H4 60 73 88 235–237
4n H 4-BrC6H4 60 91 84 338–340
 M.M. Heravi et al. / Catalysis Communications 8 (2007) 1467–1471 1469

Table 2
H1 NMR, mass and IR Spectral data for 4
Compound m/z IR Vmax cm 1
H1 NMR d(ppm)
(KBr)
4a 302(M+) 3308(NH), (CDCl3), 3.05(3H, s, CH3), 7.2–7.6(5H, m, Ph), 7.6–7.8(5H, m, Ph), 10.6(1H, bs, NH)
1692(C@O)
4b 316(M+) 3470(NH), (DMSO), 3.06(3H, s, CH3), 2.45(3H, s, CH3), 7.25(2H, d, J = 11.7, Ar), 7.36(2H, d, J = 11.7,
1655(C@O) Ar), 7.5–7.7(5H, m, Ph), 10.2(1H, s, NH)
4c 316(M+) 3447(NH), (DMSO), 3.06(3H, s, CH3), 2.47(3H, s, CH3), 7.4–7.8(9H, m, Ph), 10.83(1H, s, NH)
1683(C@O)
4d 348(M+ + H+) 3266(NH), (DMSO), 3.1(3H, s, CH3), 7.3–7.67(5H, m, Ph), 8.25(2H, d, J = 10.2, Ph), 8.35(2H, d, J = 10.2,
1680(C@O) Ph), 11.02(1H, bs, NH)
4e 347(M+) 3177(NH), (DMSO), 3.12(3H, s, CH3), 7.3–7.69(5H, m, Ph), 8.01–8.21(4H,m, Ph), 11.04(1H, bs, NH)
1689(C@O)
4f 336(M+), 3459(NH), (DMSO), 3.08(3H, s, CH3), 7.3–7.7(5H, m, Ph), 7.89(2H, d, J = 8.5, Ph), 8.06(2H, d, J = 8.5,
338(M+ + 2) 1691(C@O) Ph), 11.9(1H, bs, NH)
4g 380(M+), 3389(NH), (DMSO), 3.06(3H, s, CH3), 7.34–7.68(5H, m, Ph), 7.80(2H, d, J = 7.5, Ph), 7.9(2H, d, J = 7.5,
382(M+ + 2) 1697(C@O) Ph), 11.5(1H, s, NH)
4h 288(M+) 3240(NH), (DMSO), 7.4–7.6(5H, m, Ph), 7.65–7.83(5H, m, Ph), 8.23(1H, s, C3H), 12.5(1H, bs, NH)
1723(C@O)
4i 302(M+) 3447(NH), (DMSO), 2.45(3H, s, CH3), 7.30(2H, d, J = 11.9, Ar), 7.48(2H, d, J = 11.9, Ar), 7.6–7.8(5H, m,
1655(C@O) Ph), 8.02(1H, s, C3H), 11.8(1H, s, NH)
4j 302(M+) 3325(NH), (DMSO), 2.48(3H, s, CH3), 7.5–7.8(9H, m, Ph), 8.0(1H, s, C3H), 11.2(1H, s, NH)
1641(C@O)
4k 333(M+) 3323(NH), (DMSO), 7.3–7.7(5H, m, Ph), 8.3(1H, s, C3H), 8.35 (2H, d, J = 10.2, Ph), 8.4(2H, d, J = 10.2,
1692(C@O) Ph), 11.1 (1H, bs, NH)
4l 333(M+) 3442(NH), (CDCl3), 7.3–7.8(5H, m, Ph), 8.1–8.3(5H, m, Ph, C3H), 11.02(1H, bs, NH)
1690(C@O)
4m 322(M+), 3322(NH), (DMSO), 7.3–7.6(5H, m, Ph), 8.1(2H, d, J = 8.6, Ar), 8.2(2H, d, J = 8.6, Ar), 8.23(1H, s, C3H),
324(M+ + 2) 1697(C@O) 11.8(1H, s, NH)
4n 366(M+), 3399(NH), (DMSO), 7.35–7.7(5H, m, Ph), 7.85(2H, d, J = 7.6, Ar), 7.96(2H, d, J = 7.6, Ar), 8.20(1H, s,
368(M+ + 2) 1707(C@O) C3H), 11.7(1H, s, NH)

chemistry, we studied this reaction with heteropolyacid
catalysts including Mo, such as H3[PMo12O40] and
H14[NaP5W29MoO110].
When the mixture of 5-amino-1-phenyl-1H-pyrazolo-4-
carboxamide 1 and aromatic aldehyde 2 in acetic acid were
refluxed in the presence of catalytic amounts of mentioned
heteropolyacids for 1 h, 6-aryl-1H-pyrazolo[3,4-d]pyrimi-
din-4[5H]-ones 4 were obtained (Scheme 1). No other by
products was recognized. In spite of obtaining good to
moderate yields of products, we believe that the selectivity
towards obtained 6-aryl-1H-pyrazolo[3,4-d]pyrimidin-
4[5H]-ones remains 100% in all cases. On TLC only one
spot, for the assigned products are observed and few other
inseparable minor spots are assumed impurities. The
results are shown in Table 1. Mixed addenda Preyssler
and Keggin catalysts are formed by the substitution of
O O
R
R the conversion of the ionic intermediate to yield the reac-
NH2
+ R1CHO N Misono and co-workers advanced two types of catalysis
N 2a-g
N
NH2
Ph
Ph
R=CH3 1a
R=H 1b
Scheme 1.
tungsten (VI) ion by Mo (VI). Interestingly, these catalysts,
not only catalyzed this reaction, but also showed higher
yields than the H3[PW12O40] and H14[NaP5W30O110] in
our earlier work (55–87% yields) [23]. In study of reaction
progress with TLC, we found that conversion rates were
affected by catalyst structure. In all cases the conversion
rates was higher with H14-P5Mo. This result is agreement
with expectation and earlier works on Biginelli reaction
[24a,24b].
In acid-catalyzed reactions by heteropolyacids, several
types of acid sites are present [25–28]. They are including:
proton sites in bulk heteropolyacids, Lewis acid sites in
salts of them (metal counteractions), proton sites in acidic
salts, proton sites generated by dissociation of coordinated
water and reduction of salts, and proton generated by par-
tial hydrolysis of polyanions. Generally reactions catalyzed
by heteropolyacids may be represented by the conventional
mechanisms of Bronsted acid catalysis. The mechanism
may include the protonation of the substrate followed by
NH tion product [27,28].
N
N R1
for heterogeneous acid catalysis by heteropolyacids as sur-
face type and bulk type [25,26]. In surface type catalysis,
4 the reactions occur on the surface of bulk or supported het-
eropoly compounds and the catalytic activity usually
depends on the surface acidity of heteropolyacid. In this
case, the reaction rate and yield is parallel to the number
1470 M.M. Heravi et al. / Catalysis Communications 8 (2007) 1467–1471

and the strength of the accessible surface acid sites. The 90

bulk type of mechanism is largely relevant to reactions of 80
polar substrates on bulk heteropoly compounds, These
70
substrates are capable of absorbing into the catalyst bulk,
60
and thus all protons both in the bulk and on the surface
of heteropolyacid, are suggested to participate in the cata- 4-MeC6H4

Yield %
50
3-MeC6H4
lytic reaction. Due to the flexible nature of the solid struc- 40 4-ClC6H4
ture of some heteropolyacids, reactant molecules having 30
4-BrC6H4

polarity or basicity are readily absorbed into the solid lat-

20
tice and react therein. In this case, heteropolyacid catalysts
may be called ‘‘catalytically active solid solvents’’. As con- 10

cluded in this work, Preyssler-type heteropolyacid give 0

higher yields of products than Keggin-type heteropolyacid. 10 25 30 45 60

Unlike the Keggin-type heteropolyacids that have been Time (min)

widely used as acid and oxidation catalysts for organic syn-
theses, the role of Preyssler catalyst is largely overlooked
and there is not sufficient information. We believe that
the Preyssler-type form active pseudoliquid phases by
maintaining the concentration of reactant molecules in
the appropriate pseudoliquid (solid bulk) phase, and this
is due to the ‘‘oval’’ shape of the Preyssler-type in contrast
to the ‘‘spherical’’ Keggin-type polyanions which tend to
be absorbing a greater number of reactant molecules. Also
the larger number of protons in Preyssler catalyst may
lower the activation barrier to the cyclization reaction by
activating aldehyde in condensation reactions.
It is noteworthy to mention that this method is not effec-
tive for aliphatic aldehydes,due to very poor yields
obtained.
The progress of reaction rather to the time was followed
by TLC. The results are represented in Figs. 1 and 2. We
found that for all substrates and catalysts, there is not only
an increase in the yield, but also in the conversion rates,
with increase in reaction time in the presence of both cata-
lysts. The optimum reaction time has been found to be
60 min. At any reaction time, H14-P5Mo was found to be
more active than the H3-PMo. Any further increasing of
the time does not have any effect on the yield.
90
80
70
60
Yield %
Fig. 2. Effect of the reaction time on product yield in the reactions
catalyzed by H14[NaP5W29MoO110].
4. Conclusion
We reported here a catalytic method for synthesis of the
6-substituted-pyrazolo[3,4-d]pyrimidin-4(5H)-ones using
H3[PMo12O40] and H14[NaP5W29MoO110] which is found
to be more effective catalyst than H3[PW12O40] and
H14[NaP5W30O110] in our earlier work [23] and classical
acids [6]. Both catalysts are not soluble in acetic acid and
are eligible to an easy separation and recovery by filtering
for their immediate reuse without any appreciable decrease
of the catalyst activity.
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