Study on one-pot biginelli-like synthesis of pyrazolo[3,4-d]pyrimidines in bronsted acidic ionic liquid under sonication and its mechanism

Article abstract of DOI:10.1002/jhet.1870

Pyrazolo[3,4-d]pyrimidine derivatives were synthesized using ionic liquid, 1-butylimidazolium tetrafluoroborate, under ultrasound irradiation at ambient condition without any added catalyst. Mechanistic pathway based on the catalytic role of ionic liquid has been proposed. This method offers the advantages of simple procedure, milder reaction condition, easier workup and improved yield over the conventional method. The ionic liquid could be recycled at least three times with marked retention in its activity.

Full text of DOI:10.1002/jhet.1870

Month 2014
Study on One-pot Biginelli-like Synthesis of Pyrazolo[3,4-d]pyrimidines
in Bronsted Acidic Ionic Liquid Under Sonication and its Mechanism
*
Bhautik B. Thummar, Umesh P. Tarpada, and Dipak K. Raval
Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar 388120 Gujarat, India
*
E-mail: dipanalka@yahoo.com
Additional Supporting Information may be found in the online version of this article.
Received July 12, 2012
DOI 10.1002/jhet.1870
Published online Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
Pyrazolo[3,4-d]pyrimidine derivatives were synthesized using ionic liquid, 1-butylimidazolium tetrafluor-
oborate, under ultrasound irradiation at ambient condition without any added catalyst. Mechanistic pathway
based on the catalytic role of ionic liquid has been proposed. This method offers the advantages of simple
procedure, milder reaction condition, easier workup and improved yield over the conventional method.
The ionic liquid could be recycled at least three times with marked retention in its activity.
J. Hetercyclic Chem, 00, 00 (2014).
INTRODUCTION
syntheses [7] because it leads to the acceleration of reac-
tions in homogeneous or heterogeneous systems with
higher yield, better selectivity and under milder conditions
within shorter reaction time [8].
In continuation to our efforts to develop the non-classical
and better protocols for the organic conversions [9], herein
we report one-pot synthesis of pyrazolo[3,4-d]pyrimidines
from aromatic aldehydes, 3-methyl-1-phenyl-5(4H)-pyrazo-
lone and urea/thiourea in 1-butylimidazolium tetrafluorobo-
rate, [HBim]BF4, as the reaction medium and promoter
under ultrasound irradiation at ambient condition (Scheme 1).
Pyrazolo[3,4-d]pyrimidine derivatives exhibit various
biological [1] and pharmacological [2] activities. Several
methods and catalysts have been reported for the synthesis
of pyrazolo[3,4-d]pyrimidines [3]. Besides, Biginelli
reaction is one of the most familiar and widely employed
multicomponent reactions because of diverse products that
can be prepared in a single step just by varying reaction
substrates [4]. Accordingly, few methods have been
reported to synthesize pyrazolo[3,4-d]pyrimidines using 5
(4H)-pyrazolones [5]. However, these methods are inadequate
as far as green chemistry aspects are concerned. Moreover, the
multistep syntheses lack the ease of one-step procedure. Thus,
literature survey come up to the need to develop a protocol,
which provides better results under milder reaction conditions.
In recent years, significant progress has been made in the
application of ionic liquids (ILs) in catalytic processes
because of their versatile properties [6]. Thus, use of IL
as reactions media may offer a convenient solution to both
the solvent emission and catalytic recycling problem with
high efficiency. Ultrasound irradiation has been considered
as a clean protocol and increasingly been used in organic
RESULTS AND DISCUSSION
Optimization of the reaction conditions.
Owing to its
intrinsic Bronsted acidic nature IL, [HBim]BF4, was
chosen and synthesized by the reported method [10].
Initially, 4-nitrobenzaldehyde (1a), 3-methyl-1-phenyl-5
(4H)-pyrazolone (2), and urea (3a) were taken as the
model substrates to optimize the reaction conditions.
Results are shown in Table 1. When reaction was run in
neat IL (Table 1, Entry 5), Knoevenagel adduct (4a), as
an intermediate, (Reaction mechanism) was precipitated
© 2014 HeteroCorporation

B. B. Thummar, U. P. Tarpada and D. K. Raval
Vol 0000
Scheme 1
under reflux. Sonochemistry is a result of acoustic cavita-
tion that comprises formation and collapse of microbubbles
[12]. These produce high local temperature and pressure in
liquids that enhance the reaction. A mechanical effect of
cavitation, high pressure jetting, enhances mass transfer,
which in turn may have enhanced the reaction in non-ho-
mogeneous system (Table 1, Entry 5). Ultrasonic shock-
waves in reaction media induce reduction of particle size
and enhance the collision chances of substrates to precede
reaction smoothly.
Table 1
Effect of different conditions on model reaction.a
Thus, in conventional method, change over from “heat-
ing at reflux” to “sonication at ambient temperature” has
improved 11% of yield (Table 1, Entry 9). Replacement
of HCl with IL has improved 16% of yield with reduction
of 2 h in reaction time by conventional method (Table 1,
Entries 9 and 13, Heating). A marked improvement of
29% of yield within 4.5 h was observed while changing
over from “heating at reflux in EtOH + HCl” to “sonication
at ambient temperature in EtOH + IL” (Table 1, Entry 9 –
Heating and Entry 13 – Ultrasound). The IL, having negli-
gible vapor pressure, as the reaction media should have
changed the characteristics of cavitation and forced less
volatile substrates to undergo the cavitational activation.
Hence, it was the synergy of ultrasound and IL as the reac-
tion medium considered responsible for acceleration of
reaction in the present protocol.
Yield (%)
Heatb USc
Entry
Reaction condition
Time (h)
1
2
3
4
5
6
7
8
Methanol
THF
MDC
Ethanol
[HBim]BF4 (3 g)
Methanol + HCld
THF + HCld
10
10
10
10
5
0
0
0
0
0
0
0
0
Trace
32
30
27
41
49
46
45
57
15
41
38
34
52
62
56
55
70
7
7.5
7.5
6.5
5
5.5
5.5
4.5
MDC + HCld
Ethanol + HCld
[HBim]BF4 + methanol
[HBim]BF4 + THF
[HBim]BF4 + MDC
[HBim]BF4 + ethanol
9
10e
11e
12e
13e
a4-Nitrobenzaldehyde (0.01 mol), 3-methyl-1-phenyl-5(4H)-pyrazolone
(0.011 mol) and urea (0.01 mol).
Scope of the synthesis of pyrazolo[3,4-d]pyrimidine
derivatives. The generality of this reaction was examined
bIsolated yield under reflux condition.
cIsolated yield at ambient temperature under ultrasound irradiation.
d0.5 mL 11.3 N HCl.
by employing various aromatic aldehydes (1b–l) and
thiourea (3b) under optimized reaction conditions. Results
are shown in Table 2. All the compounds were
characterized by physical and spectroscopic methods.
Results showed that nature of the substituent on aromatic
aldehyde did not affect the reaction much in terms of yield.
However, the reactions pertaining to aldehydes containing
electron-withdrawing group were observed to be little faster
than that of aldehydes containing electron-donating group.
eIL (3 g) + co-solvent (5 mL), without any added catalyst.
out and it was found difficult to carry forward the reaction.
Therefore several solvents were attempted as co-solvent to
solubilize the intermediate for further progress of the
reaction. IL containing ethanol as a co-solvent under
ultrasound irradiation was found to be the optimum
reaction condition among all (Table 1, Entry 13).
Reaction acceleration.
During optimization of the
Table 2
reaction procedure, we observed formation of desired
product in neat IL (Table 1, Entry 5), whereas molecular
solvents failed to yield the desired product without any
added catalyst (Table 1, Entry 1–4). Thus, IL has not
only provided the reaction medium but has also promoted
the reaction. This acceleration was explained in terms of
H-bonding by IL activating the reaction substrates [11].
Moreover, IL has exhibited better catalytic effect than
HCl in terms of yield and time (Compare Table 1, Entries
6–9 with 10–13).
It is observed that ultrasound irradiation accelerated the
reaction better than conventional method (Table 1). Under
the same reaction medium, reactions under ultrasonic
irradiation have led to relatively higher yields at ambient
temperature, whereas comparable results are only obtained
Synthesis of pyrazolo[3,4-d]pyrimidine derivatives in IL under sonication.
Product
R
X
Time (h)
Yield (%)a
6a
6b
6c
6d
6e
6f
6g
6h
6i
4-NO2-C6H4-
4-OH-C6H4-
4-Cl-C6H4-
C6H5-
4-OCH3-C6H4-
2-NO2-C6H4-
3-Cl-C6H4-
4-CH3-C6H4-
2-OH-C6H4-
4-OCH3-C6H4-
C6H5-
O
O
O
O
O
O
O
O
O
S
4.5
5
4.5
5
70
62
64
58
67
65
66
70
63
66
59
60
5
4.5
4.5
5
5
5
6j
6k
6l
S
S
5
5
2-OH-C6H4-
aIsolated yield
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Study on One-pot Biginelli-like Synthesis of Pyrazolo[3,4-d]pyrimidines in Bronsted
Month 2014
Acidic Ionic Liquid Under Sonication and its Mechanism
This strategy offers the first example of ultrasound and IL
promoted one-pot synthesis of pyrazolo[3,4-d]pyrimidine
derivatives from aromatic aldehyde, pyrazolone and urea/
thiourea at ambient temperature. In terms of yield, this
protocol has been proved better as compared with presently
available one-pot synthetic protocol furnishing 28–48% of
product [5c].
intermediate in Lewis acidic or Protic acidic media [15].
We were interested to recognize the mechanistic pathway
in present protocol because the reaction medium was
Bronsted acidic.
To investigate the reaction mechanism, we assumed that
the model reaction might have proceeded through any of
the intermediates shown in Figure 1. Following three sets
of equimolar mixtures of the substrates for the model
reaction were irradiated under optimum reaction condition;
(I) 4-nitrobenzaldehyde with 3-methyl-1-phenyl-5(4H)-
pyrazolone, (II) 4-nitrobenzaldehyde with urea, and (III)
3-methyl-1-phenyl-5(4H)-pyrazolone with urea.
In case of set I, Knoevenagel adduct (4a) together with
bis-pyrazolone derivative (7a) as a Knoevenagel–Michael
adduct were isolated and characterized (Scheme 2).
Knoevenagel adduct (4a) was then treated with equimolar
amount of urea under optimum reaction condition to
confirm its intermediacy. This resulted in pyrazolo[3,4-d]
pyrimidine (6a).
In case of set II, the reaction mixture turned dense from
which formed intermediates could not be isolated. We
assumed either compound 5a or 9a or both as the interme-
diate. Reaction mixture was further treated with pyrazolone
(2), which resulted in the formation of Knoevenagel adduct
(4a) and pyrazolo[3,4-d]pyrimidine (6a). This might be
due to the formation of 5a or 9a in poor amount, leaving
behind the aldehyde, which in turn has reacted with pyra-
zolone added afterwards in the reaction mixture.
Reusability of IL.
The activity of recycled IL was
studied on model reaction in terms of yield of desired
product. The IL could be reused at least three times without
much depletion in its activity. Yields of the product
obtained using recycled IL in three consecutive reactions
were 69, 67 and 63% against 70% using fresh IL. Slight
loss in activity of IL may be ascribed to presence of trace
impurities from the reaction or degradation of IL during
recovery.
Reaction mechanism.
The Biginelli reaction is quiet
under dispute from mechanistic view point. Knoevenagel
adduct (4), bisureid derivative (5), and enamine
derivative (8) were suggested to be involved as the
intermediates [13]. A mechanism based on the formation
of carbenium ion in acid-catalyzed Knoevenagel reaction
was also included [14]. It was also suggested to proceed
via formation of an imine (9) or iminium ion as a key
To synthesize compound 5a, 1:2 amounts of 4-
nitrobenzaldehyde and urea were condensed in toluene
containing catalytic amount of p-toluensulfonic acid for
24h under reflux [16]. Imine (9a) might also be an interme-
diate; however, we failed to synthesize it. No reports are
available on the occurrence of imine using aldehyde and
urea/thiourea as the substrates. Hence, equimolar mixture
Figure 1. Possible reaction intermediates.
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

B. B. Thummar, U. P. Tarpada and D. K. Raval
Vol 0000
of bisureid (5a) and pyrazolone (2) was irradiated under op-
timum reaction condition to confirm its intermediacy, which
resulted in pyrazolo[3,4-d]pyrimidine (6a) (Scheme 3).
Thus, we suspected that the reaction might have pro-
ceeded through the formation of bisureid in the present
method. The mass spectrum of the dense reaction mixture
in set II also provided the useful evidence for intermediacy
of bisureid (5a) (Supporting information).
In case of set III, the substrates remained unchanged even
after prolong time (checked by TLC). This eliminates the
possibility of reaction following enamine intermediate (8a).
Thus, we had two intermediates (4a and 5a) in hand to
follow the reaction through, which caused dilemma for
the precise intermediate in one-pot reaction under study.
In all cases, it was observed during the course of reaction
that the reaction mass gradually turned colored. This indi-
cated that Knoevenagel condensation of aldehydes (1a–l)
with pyrazolone (2) has overtaken the formation of bisur-
eid derivatives (also checked by TLC). Reaction mixture,
from one-pot model reaction after 15 min, was analyzed
by mass spectrometry for verification of our claim. The
mass spectrum provided evidences for Knoevenagel
adduct and unreacted model substrates only (Figure 2).
This suggested that the one-pot three-component reaction
has proceeded through the formation of Knoevenagel
adduct surpassing formation of bisureid derivatives in the
present protocol.
Scheme 3
Figure 2. Mass spectrum of one-pot model reaction mixture after 15 min.
Scheme 4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Study on One-pot Biginelli-like Synthesis of Pyrazolo[3,4-d]pyrimidines in Bronsted
Month 2014
Acidic Ionic Liquid Under Sonication and its Mechanism
containing HCl as catalyst (0.5 mL, 11.3 N). The mixture was
heated under reflux for the required time period. After
completion of reaction (as indicated by TLC), the reaction
mixture was cooled to room temperature and then poured into
crushed ice and stirred for 15–20 min. The precipitated crude
product was filtered, washed with cold ethanol, dried, and
purified by column chromatography.
Knoevenagel pathway would exhibit a step with the
activation barrier [15], whereas reactions with activation
barrier are accelerated with pressure [17]. So the reaction
acceleration in present protocol is elucidated in terms of
the “hot spot” phenomenon [12].
On the basis of these facts, mechanistic pathway has
been proposed (Scheme 4). It involves initial formation
of intermediate (4a–l) by Knoevenagel condensation of
aldehydes (1a–l) and pyrazolone (2). Subsequent Michael
addition of urea/thiourea (3a/b) followed by cyclization
and dehydration gives the corresponding pyrazolo[3,4-d]
pyrimidine derivatives (6a–l).
Synthesis of pyrazolo[3,4-d]pyrimidine derivatives in IL
under ultrasound irradiation.
A 50 mL flask was charged
with a mixture of aldehyde (1a–l, 0.01 mol), 3-methyl-1-phenyl-
5(4H)-pyrazolone (2, 0.011 mol) and urea/thiourea (3a/b,
0.01 mol) in IL (3 g) containing ethanol (5 mL). The reaction
mixture was irradiated by ultrasound at ambient temperature for
required hours. After completion of reaction (as indicated by
TLC), insoluble bis-pyrazolone derivative as the side product
was isolated from the reaction mixture by simple filtration in all
cases. Filtrate containing the desired product was then poured
into crushed ice and stirred for 15–20 min. The solid mass thus
separated was collected by filtration, washed with cold ethanol,
dried, and crystallized from ethanol. The aqueous filtrate was
then subjected to distillation at 80ꢀC under reduced pressure
(10 mmHg) for 4 h to leave behind the IL in almost complete
recovery. Thus, recycled IL was found active enough to be
CONCLUSION
We have demonstrated an improved method for the
preparation of pyrazolo[3,4-d]pyrimidine derivatives in
[HBim]BF4 without any added catalyst. Ultrasonic irradia-
tion has shown better reaction acceleration through cavita-
tion at ambient temperature than that of conventional
method under reflux. IL has exhibited better catalytic effect
than HCl in terms of yield and time. Knoevenagel adduct is
suggested as the intermediate for this type of reactions in
Bronsted acidic media. The method offers advantage of
simple procedure, milder reaction condition, easier
workup, and improved yield over conventional method.
reused in three subsequent reactions.
3-Methyl-4-(4-nitrophenyl)-1-phenyl-4,5-dihydro-1H-pyrazolo
[3,4-d]pyrimidin-6(7H)-one (6a).
Solid; C18H15N5O3; mp
269ꢀC; IR (KBr n, cmꢁ1): 3253 (N–H), 3090 (Ar–H), 2850 (C–H),
1680 (C═O); 1H NMR (400 MHz, DMSO-d6) d: 2.42 (s, 3H,
CH3), 5.23 (s, 1H, CH), 7.32 (t, J= 6.8 Hz, 2H, Ar–H), 7.46–7.54
(m, 5H, Ar–H), 7.70 (d, J= 7.6 Hz, 2H, Ar–H), 8.16 (s, 1H,
NH), 8.38 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6) d:
11.65, 33.25, 104.64, 121.83, 123.94, 127.05, 129.11, 129.56,
133.85, 134.65, 136.56, 140.32, 146.47, 146.67 (C═O); ESI–MS
(m/z): 350.1 (M+1); Elemental Anal. Calcd (%) – C 61.89, H 4.33,
N 20.05; Found (%) – C 61.81, H 4.32, N 20.01.
EXPERIMENTAL
All reactions were carried out with commercially available
reagents and used without further purification. 3-Methyl-1-phe-
nyl-5(4H)-pyrazolone was synthesized by reported method [18].
Ultrasonication was performed in D-Compact ultrasonic cleaner
(Trans-O-Sonic, Mumbai, Maharashtra, India) with a frequency
of 50 kHz and power of 250 W. The reaction flask was suspended
in the center of ultrasonic bath so as surface of the reactants
remains slightly lower than the level of water in the bath. The
temperature of water bath was controlled at 25–30ꢀC. TLC
was carried out on fluorescent coated aluminum plates
(0.25 mm thick, silica gel 60 F254 coated, Merck KGaA,
Darmstadt, Germany), and components were detected by UV light.
The columns were hand-packed with silica gel 60–120 mesh. Melting
points were measured in open capillaries and are uncorrected. IR
spectra were recorded on Shimadzu FTIR 8401 spectrophotometer
(Shimadzu Corporation, Nakagyo-ku, Kyoto, Japan) using KBr
pellets and frequencies of only characteristic peaks are expressed in
4-(4-Hydroxyphenyl)-3-methyl-1-phenyl-4,5-dihydro-1H-
pyrazolo[3,4-d]pyrimidin-6(7H)-one (6b).
Solid; C18H16N4O2;
mp 254ꢀC; IR (KBr n, cmꢁ1): 3401 (O–H), 3180 (N–H),
3082 (Ar–H), 2880 (C–H), 1670 (C═O); 1H NMR (400 MHz,
DMSO-d6) d: 2.44 (s, 3H, CH3), 5.19 (s, 1H, CH), 7.42–7.55
(m, 9H, Ar–H), 8.01 (s, 1H, NH), 8.17 (s, 1H, NH), 9.10 (s, 1H,
Ar–OH); 13C NMR (100 MHz, DMSO-d6) d: 13.98, 64.86,
120.79, 121.65, 125.69, 127.51, 129.95, 131.92, 133.42, 135.88,
140.21, 144.42, 148.68 (C═O), 155.12 (C–OH); ESI–MS (m/z):
321.2 (M+1); Elemental Anal. Calcd (%) – C 67.49, H 5.03, N
17.49; Found (%) – C 67.41, H 5.00, N 17.41.
4-(4-Chlorophenyl)-3-methyl-1-phenyl-4,5-dihydro-1H-pyrazolo
[3,4-d]pyrimidin-6(7H)-one (6c).
Solid; C18H15ClN4O; mp
1
reciprocal centimeter. H and 13C NMR spectra were recorded in
235ꢀC; IR (KBr n, cmꢁ1): 3260 (N–H), 3088 (Ar–H), 2843 (C–H),
1678 (C═O); 1H NMR (400 MHz, DMSO-d6) d: 2.48 (s, 3H,
CH3), 5.50 (s, 1H, CH), 7.24 (t, J= 7.6 Hz, 2H, Ar–H), 7.42
(d, J= 7.6 Hz, 2H, Ar–H), 7.51–7.59 (m, 5H, Ar–H), 7.95 (s,
1H, NH), 8.24 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6) d:
12.38, 50.48, 108.24, 122.47, 128.50, 129.01, 129.58, 130.47,
137.68, 138.83, 143.23, 146.24, 150.48 (C═O); ESI–MS (m/z):
339.3 (M+1); Elemental Anal. Calcd (%) – C 63.81, H 4.46, N
DMSO-d6 on Bruker Avance 400 MHz spectrometer (Bruker,
Billerica, Massachusetts, USA). The chemical shifts are reported in
d parts per million. Mass spectral data were obtained using Applied
Biosystems API 2000 spectrometer (Applied Biosystems Inc., Foster
City, California, USA). Elemental analyses were performed on
PerkinElmer 2400 series-II elemental analyzer (PerkinElmer Inc.,
Waltham, Massachusetts, USA).
Synthesis of pyrazolo[3,4-d]pyrimidine derivatives under
conventional conditions. A 50 mL flask, fitted with a reflux
condenser, was charged with a mixture of aldehyde (1a–l,
0.01 mol), 3-methyl-1-phenyl-5(4H)-pyrazolone (2, 0.011 mol)
and urea/thiourea (3a/b, 0.01 mol) in absolute ethanol (30 mL)
16.54; Found (%) – C 63.74, H 4.40, N 16.59.
3-Methyl-1,4-diphenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-
6(7H)-one (6d). Solid; C18H16N4O; mp 165ꢀC; IR (KBr n, cmꢁ1):
3236 (N–H), 3060 (Ar–H), 2890 (C–H), 1681 (C═O); 1H
NMR (400 MHz, DMSO-d6) d: 2.44 (s, 3H, CH3), 5.19 (s, 1H, CH),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

B. B. Thummar, U. P. Tarpada and D. K. Raval
Vol 0000
7.11–7.48 (m, 10H, Ar–H), 8.13 (s, 1H, NH), 8.21 (s, 1H, NH); 13
NMR (100 MHz, DMSO-d6) d: 14.52, 40.57, 110.51, 123.33,
129.42, 131.05, 135.32, 144.61, 148.32, 158.06 (C═O); ESI–MS
(m/z): 305.3 (M+1); Elemental Anal. Calcd (%) – C 71.04, H 5.30, N
18.41; Found (%) – C 71.03, H 5.24, N 18.38.
4-(4-Methoxyphenyl)-3-methyl-1-phenyl-4,5-dihydro-1H-
C
2.15 (s, 3H, CH3), 3.68 (s, 3H, OCH3), 4.89 (s, 1H, CH), 7.11–
7.39 (m, 9H, Ar–H), 8.56 (s, 1H, NH), 8.80 (s, 1H, NH); 13C
NMR (100 MHz, DMSO-d6) d: 14.01, 50.85, 53.91, 113.95,
116.84, 124.85, 125.36, 128.98, 136.25, 139.54, 143.65, 149.84,
155.64 (C–OCH3), 159.97 (C═S); ESI–MS (m/z): 351.6 (M+1);
Elemental Anal. Calcd (%) – C 65.12, H 5.18, N 15.99; Found (%)
pyrazolo[3,4-d]pyrimidin-6(7H)-one
(6e).
Solid;
– C 65.08, H 5.10, N 15.82.
C19H18N4O2; mp 234ꢀC; IR (KBr n, cmꢁ1): 3260 (N–H), 3081
(Ar–H), 2860 (C–H), 1671 (C═O), 1118 (C–O); 1H NMR
(400 MHz, DMSO-d6) d: 2.45 (s, 3H, CH3), 3.76 (s, 3H,
OCH3), 5.20 (s, 1H, CH), 7.09–7.45 (m, 9H, Ar–H), 8.01 (s, 1H,
NH), 8.30 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6) d: 14.01,
60.54, 75.62, 119.65, 124.59, 127.65, 130.89, 134.81, 136.40,
140.67, 144.78, 148.65, 155.89 (C═O), 161.32 (C–OCH3); ESI–
MS (m/z): 335.5 (M+1); Elemental Anal. Calcd (%) – C 68.25, H
5.43, N 16.76; Found (%) – C 68.19, H 5.40, N 16.70.
3-Methyl-1,4-diphenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-
6(7H)-thione (6k).
Solid; C18H16N4S; mp 180ꢀC; IR (KBr n,
cmꢁ1): 3244 (N–H), 3075 (Ar–H), 2863 (C–H), 1067; H NMR
(400 MHz, DMSO-d6) d: 2.21 (s, 3H, CH3), 5.29 (s, 1H, CH),
7.15–7.49 (m, 10H, Ar–H), 8.50 (s, 1H, NH), 8.78 (s, 1H, NH);
13C NMR (100 MHz, DMSO-d6) d: 14.94, 49.87, 113.94, 124.94,
125.67, 130.84, 139.41, 143.65, 145.65, 157.31, 160.21 (C═S);
ESI–MS (m/z): 321.5 (M+1); Elemental Anal. Calcd (%) – C 67.47,
1
H 5.03, N 17.49; Found (%) – C 67.41, H 5.00, N 17.43.
3-Methyl-4-(2-nitrophenyl)-1-phenyl-4,5-dihydro-1H-pyrazolo
[3,4-d]pyrimidin-6(7H)-one (6f). Solid; C18H15N5O3; mp 182ꢀC;
IR (KBr n, cmꢁ1): 3240 (N–H), 3074 (Ar–H), 2856 (C–H), 1675
(C═O); 1H NMR (400 MHz, DMSO-d6) d: 2.44 (s, 3H, CH3), 5.31
(s, 1H, CH), 7.01–7.49 (m, 8H, Ar–H), 7.81 (s, 1H, Ar–H), 8.42 (s,
1H, NH), 8.65 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6) d:
12.98, 41.98, 102.46, 119.65, 123.54, 125.12, 125.87, 127.99,
131.84, 136.64, 141.58, 144.42, 148.64 (C═O); ESI–MS (m/z):
350.2 (M+1); Elemental Anal. Calcd (%) – C 61.89, H 4.33, N
20.05; Found (%) – C 61.83, H 4.30, N 20.00.
4-(2-Hydroxyphenyl)-3-methyl-1-phenyl-4,5-dihydro-1H-
pyrazolo[3,4-d]pyrimidine-6(7H)-thione (6l). Solid; C18H16N4OS;
mp 187ꢀC; IR (KBr n, cmꢁ1): 3415 (O–H), 3250 (N–H), 3075
1
(Ar–H), 2863 (C–H), 1094; H NMR (400 MHz, DMSO-d6) d:
2.31 (s, 3H, CH3), 5.35 (s, 1H, CH), 7.01–7.30 (m, 9H, Ar–H),
8.53 (s, 1H, NH), 8.77 (s, 1H, NH), 8.90 (s, 1H, OH); 13C NMR
(100 MHz, DMSO-d6) d: 13.01, 40.98, 114.35, 119.65, 120.11,
125.51, 126.31, 126.98, 130.61, 138.94, 144.34, 147.98, 155.95
(C–OH), 161.04 (C═S); ESI–MS (m/z): 337.5 (M+1); Elemental
Anal. Calcd (%) – C 64.26, H 4.79, N 16.65; Found (%) – C
4-(3-Chlorophenyl)-3-methyl-1-phenyl-4,5-dihydro-1H-pyrazolo
64.21, H 4.73, N 16.60.
[3,4-d]pyrimidin-6(7H)-one (6g).
Solid; C18H15ClN4O; mp
4,40-((4-nitrophenyl)methylene)bis(3-methyl-1-phenyl-1H-
135ꢀC; IR (KBr n, cmꢁ1): 3255 (N–H), 3053 (Ar–H), 2858 (C–H),
1670 (C═O); 1H NMR (400 MHz, DMSO-d6) d: 2.49 (s, 3H,
CH3), 5.13 (s, 1H, CH), 7.08 (d, J= 7.8 Hz, 2H, Ar–H), 7.20–7.52
(m, 7H, Ar–H), 8.20 (s, 1H, NH), 8.75 (s, 1H, NH); 13C NMR
(100 MHz, DMSO-d6) d: 15.12, 51.89, 119.48, 121.09, 130.11,
132.04, 132.57, 146.76, 151.48, 160.23 (C═O); ESI–MS (m/z):
339.5 (M+1); Elemental Anal. Calcd (%) – C 63.81, H 4.46, N
16.54; Found (%) – C 63.75, H 4.40, N 16.42.
pyrazol-5-ol) (7a). Solid; C27H23N5O4; mp 220–222ꢀC; IR (KBr
n, cmꢁ1): 3420 (O–H), 2960 (Ar–H), 2872 (C–H); 1H NMR
(400 MHz, DMSO-d6) d: 2.34 (s, 6H, CH3), 5.24 (s, 1H, CH), 7.32
(t, J = 7.2 Hz, 2H, Ar–H), 7.46–7.54 (m, 6H, Ar–H), 7.71
(d, J= 8 Hz, 4H, Ar–H), 8.17 (d, J= 8.8 Hz, 2H, Ar–H), 12.20 (brs,
2H, OH); 13C NMR (100 MHz, DMSO-d6) d: 11.59, 33.10,
104.70, 121.95, 123.90, 129.43, 136.34, 146.64, 150.05, 158.11;
ESI–MS (m/z): 482.0 (M+1); Elemental Anal. Calcd (%) – C 67.35,
H 4.81, N 14.54; Found (%) – C 67.31, H 4.77, N 14.50.
3-Methyl-1-phenyl-4-(p-tolyl)-4,5-dihydro-1H-pyrazolo[3,4-d]
pyrimidin-6(7H)-one (6h). Solid; C19H18N4O; mp 189ꢀC; IR
(KBr n, cmꢁ1): 3252 (N–H), 3086 (Ar–H), 2854 (C–H), 1692
(C═O); 1H NMR (400 MHz, DMSO-d6) d: 2.35 (s, 3H, CH3),
2.42 (s, 3H, CH3), 5.05 (s, 1H, CH), 7.10–7.20 (m, 4H, Ar–H),
7.45–7.50 (m, 5H, Ar–H) 7.98 (s, 1H, NH), 8.13 (s, 1H, NH); 13C
NMR (100 MHz, DMSO-d6) d: 13.59, 55.09, 114.03, 123.31,
124.34, 128.27, 129.62, 130.03, 133.01, 137.11, 137.97, 142.05,
145.71, 148.34, 154.35 (C═O); ESI–MS (m/z): 319.4 (M+1);
Elemental Anal. Calcd (%) – C 71.68, H 5.70, N 17.60; Found (%)
4,40-((4-hydroxyphenyl)methylene)bis(3-methyl-1-phenyl-1H-
pyrazol-5-ol) (7b).
Solid; C27H24N4O3; mp 160–162ꢀC; IR
(KBr n, cmꢁ1): 3410 (O–H), 2955 (Ar–H), 2880 (C–H), 1691;
1H NMR (400 MHz, DMSO-d6) d: 2.45 (s, 6H, CH3), 5.01
(s, 1H, CH), 6.72 (d, J = 8.4 Hz, 2H, Ar–H), 7.06 (d, J = 8.4 Hz,
2H, Ar–H), 7.36 (t, J = 7.6 Hz, 2H, Ar–H), 7.51 (t, J = 8 Hz, 4H,
Ar–H), 7.71 (d, J = 8.4 Hz, 4H, Ar–H), 13.88 (brs, 3H, OH); 13C
NMR (100 MHz, DMSO-d6) d: 11.24, 32.25, 105.26, 122.31,
129.60, 131.42, 135.75, 140.61, 146.51, 158.34; ESI–MS (m/z):
452.9 (M+1); Elemental Anal. Calcd (%) – C 71.67, H 5.35, N
– C 71.60, H 5.64, N 17.50.
4-(2-Hydroxyphenyl)-3-methyl-1-phenyl-4,5-dihydro-1H-
12.38; Found (%) – C 71.64, H 5.32, N 12.32.
pyrazolo[3,4-d]pyrimidin-6(7H)-one (6i).
Solid; C18H16N4O2;
3-Methyl-4-(4-nitrobenzylidene)-1-phenyl-1H-pyrazol-5(4H)-
mp 179ꢀC; IR (KBr n, cmꢁ1): 3410 (O–H), 3240 (N–H),
3070 (Ar–H), 2860 (C–H), 1695 (C═O); 1H NMR (400 MHz,
DMSO-d6) d: 2.43 (s, 3H, CH3), 5.28 (s, 1H, CH), 7.51–7.65
(m, 9H, Ar–H), 8.10 (s, 1H, NH), 8.34 (s, 1H, NH), 8.95 (s, 1H,
OH); 13C NMR (100 MHz, DMSO-d6) d: 12.64, 37.65, 103.62,
116.98, 120.82, 121.67, 125.35, 125.97, 127.98, 135.65, 142.32,
144.85, 150.95 (C═O), 152.51 (C–OH); ESI–MS (m/z): 321.3
(M+1); Elemental Anal. Calcd (%) – C 67.49, H 5.03, N 17.49;
one (4a). Solid; C17H13N3O3; mp 173ꢀC; IR (KBr n, cmꢁ1):
3064 (Ar–H), 3033 (C–H), 1673 (C═O); 1H NMR (400 MHz,
DMSO-d6) d: 2.30 (s, 3H, CH3), 6.93 (d, J= 8.8 Hz, 2H, Ar–H),
7.17 (t, d= 7.6 Hz, 1H, Ar–H), 7.40 (t, J= 8.4 Hz, 2H, Ar–H), 7.72
(s, 1H, CH), 7.90 (d, J= 7.6 Hz, 2H, Ar–H), 8.63 (d, J=8.8,
2H, Ar–H); 13C NMR (100 MHz, DMSO-d6) d: 12.62, 116.31,
117.57, 122.23, 124.18, 125.36, 128.42, 136.75, 137.81, 148.98,
150.11, 151.27, 162.62; ESI–MS (m/z): 308.3 (M+1); Elemental
Anal. Calcd (%) – C 66.44, H 4.26, N 13.67; Found (%) – C
Found (%) – C 67.42, H 5.01, N 17.43.
4-(4-Methoxyphenyl)-3-methyl-1-phenyl-4,5-dihydro-1H-
66.39, H 4.22, N 13.63.
pyrazolo[3,4-d]pyrimidine-6(7H)-thione (6j).
Solid; C19H18N4OS;
4-(4-Hydroxybenzylidene)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-
mp 253ꢀC; IR (KBr n, cmꢁ1): 3252 (N–H), 3072 (Ar–H), 2875
(C–H), 1210 (C–O), 1082; 1H NMR (400 MHz, DMSO-d6) d:
one (4b). Solid; C17H14N2O2; mp 238ꢀC; IR (KBr n, cmꢁ1): 3410
(O–H), 3090 (C–H), 3052 (Ar–H), 1673 (C═O); 1H NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Study on One-pot Biginelli-like Synthesis of Pyrazolo[3,4-d]pyrimidines in Bronsted
Month 2014
Acidic Ionic Liquid Under Sonication and its Mechanism
[3] (a) Liu, J.; Wang, X. ACS Comb Sci 2011, 13, 414; (b)
Heravi, M. M.; Motamedi, R.; Seifi, N.; Bamoharram, F. F. J. Mol.
Cat. A: Chemical 2006, 249, 1; (c) Zhang, X.; Lin, Q.; Zhong, P.
Molecules 2010, 15, 3079.
[4] (a) Biginelli, P. G.. Chim. Ital. 1893, 23, 360; (b) Kappe, C. O.
Acc Chem Res 2000, 33, 879.
[5] (a) Trivedi, A. R.; Siddiqui, A. B.; Shah, V. H. Arkivoc 2008,
(ii), 210; (b) Trivedi, A.; Dodiya, D.; Surani, J.; Jarsania, S.; Mathukiya,
H.; Ravat, N.; Shah, V. Arch Pharm 2008, 341, 435; (c) Hayat, F.;
Salahuddin, A.; Azam, A. J Enzyme Inhib Med Chem 2011, 26, 472;
(d) Akbari, J. D.; Mehta, K. B.; Pathak, S. J.; Joshi, H. S. Indian J. Chem.,
Sect B 2008, 47, 477.
[6] (a) Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis;
Wiley-VCH Verlag GmbH & Co: KGaA, 2003; (b) Welton, T. Chem
Rev 1999, 99, 2071.
[7] (a) Carruthers, W.; Coldham, I. Modern Methods of Organic
Synthesis, 4th ed.; Cambridge Universiry Press: Cambridge, 2004; (b)
Cravotto, G.; Cintas, P. Chem Soc Rev 2006, 35, 180.
[8] (a) Luche, J. L. Synthetic Organic Sonochemistry; Plenum
press: New York, 1998; (b) Mason, T. J.; Peters, D. Practical Sonochem-
istry, 2nd ed.; Ellis Horwood: London, 2002.
[9] (a) Tarpada, U. P.; Thummar B. B.; Raval D. K. J Saudi
Chem Soc 2012. doi: 10.1016/j.jscs.2012.07.014; (b) Dadhania, A.
N.; Patel, V. K.; Raval, D. K. C. R. Chimie, 2012, 15, 378; (c) Avalani
J. R.; Patel D. S.; Raval D. K. J Chem Sci 2012, 124, 1091; (d) Dadha-
nia, A. N.; Patel, V. K.; Raval, D. K. J Braz Chem Soc 2011, 22, 511.
[10] Palimkar, S. S.; Siddiqui, S. A.; Daniel, T.; Lahoti, R. J.;
Srinivasan, K. V. J Org Chem 2003, 68, 9371.
(400 MHz, DMSO-d6) d: 2.32 (s, 3H, CH3), 6.94 (d, J=8.8Hz,
2H, Ar–H), 7.18 (t, J = 7.6 Hz, 1H, Ar–H), 7.43 (t, J=8.4Hz,
2H, Ar–H), 7.70 (s, 1H, CH), 7.93 (d, J= 7.6 Hz, 2H, Ar–H), 8.64
(d, J=8.8, 2H, Ar–H), 10.82 (s, 1H, OH); 13C NMR (100 MHz,
DMSO-d6) d: 13.61, 116.31, 118.75, 123.11, 124.81, 125.36,
129.25, 137.87, 138.93, 148.98, 152.27, 162.45, 163.54; ESI–MS
(m/z): 279.2 (M+1); Elemental Anal. Calcd (%) – C 73.37, H 5.07,
N 10.07; Found (%) – C 73.32, H 5.04, N 10.01.
0
1,1 -((4-Nitrophenyl)methylene)diurea (5a).
4-Nitrobenzaldehyde
(1a, 0.03 mol), urea (3a, 0.06 mol), p-toluensulfonic acid
(0.005 mol), and toluene (150 mL) were taken in a 250 mL flask
fitted with a reflux condenser. The mixture was refluxed for 24 h.
After completion of reaction, the precipitated product was filtered,
washed with saturated aqueous solution of NaHCO3 followed by
water, dried, and characterized (Isolated yield 65%). Solid;
C9H11N5O4; mp 190ꢀC; IR (KBr n, cmꢁ1): 3290 (N–H),
3064 (Ar–H), 2872 (C–H), 1673 (C═O); 1H NMR (400 MHz,
DMSO-d6) d: 5.80 (s, 4H, NH2), 6.18 (t, J= 8.4 Hz, 1H, CH), 6.97
(d, J = 8 Hz, 2H, NH), 7.57 (d, J= 8.4 Hz, 2H, Ar–H), 8.21 (d,
J= 8.4 Hz, 2H, Ar–H); 13C NMR (100 MHz, DMSO-d6) d: 59.20,
123.74, 123.77, 146.95, 151.11, 158.17; ESI–MS (m/z): 254.0
(M+1); Elemental Anal. Calcd (%) – C 42.69, H 4.38, N 27.66;
Found (%) – C 42.64, H 4.32, N 27.61.
[11] Gholap, A. R.; Venkatesan, K.; Daniel, T.; Lahoti, R. J.;
Srinivasan, K. V. Green Chem. 2004, 6, 147.
[12] (a) Mason, T. J. Ultrason Sonochem 2003, 10, 175; (b) Mason,
T. J. Chem Soc Rev 1997, 26, 443; (c) Cintas, P.; Luche, J.-L. Green
Chem. 1999, 1, 115.
Acknowledgments. DKR thanks Sardar Patel University for research
funding in terms of seed grant 2011-12. UPT thanks University
Grant Commission, Delhi for SRF under UGC-BSR RFSMS
scheme 2012-15.
[13] Folkers, K.; Johnson, T. B. J Am Chem Soc 1933, 55, 3784.
[14] Sweet, F.; Fissekis, J. D. J Am Chem Soc 1973, 95, 8741.
[15] De Souza, R. O. M. A.; Da Penha, E. T.; Milagre, H. M. S.;
Garden, S. J.; Esteves, P. M.; Eberlin, M. N.; Antunes, O. A. C. Chem
Eur J 2009, 15, 9799.
[16] (a) Shen, Z.-L.; Xu, X.-P.; Ji, S.-J. J Org Chem 2010, 75, 1162;
(b) Kappe, C. O. J Org Chem 1997, 62, 7201.
[17] (a) Shekouhy, M.; Hasaninejad, A. Ultrason Sonochem 2012,
19, 307; (b) Shaabani, A.; Rezayan, A. H.; Rahmati, A.; Sharifi, M.
Monatsh Chem 2006, 137, 77.
REFERENCES AND NOTES
[1] (a) Holla, B. S.; Mahalinga, M.; Karthikeyan, M. S.; Akberali,
P. M.; Shetty, N. S. Bioorg Med Chem 2006, 14, 2040; (b) Schenone, S.;
Bruno, O.; Bondavalli, F.; Ranise, A.; Mosti, L.; Menozzi, G.; Fossa, P.;
Donnini, S.; Santoro, A.; Ziche, M.; Manetti, F.; Botta, M. Eur J Med
Chem 2004, 39, 939.
[2] (a) Quintela, J. M.; Peinador, C.; González, L.; Devesa, I.;
Ferrándiz, M. L.; Alcaraz, M. J.; Riguera, R. Bioorg Med Chem 2003,
11, 863; (b) Markwalder, J. A.; Arnone, M. R.; Benfield, P. A. et al. J
Med Chem 2004, 47, 5894.
[18] Vogel, A. I.; Furniss B. S. Vogel’s Textbook of Practical
Organic Chemistry, 5th ed.; Longman: Harlow, Essex, 1989, pp 1150.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet