Ultrasound assisted one-pot, three-components synthesis of pyrimido[1,2-a]benzimidazoles and pyrazolo[3,4-b]pyridines: A new access via phenylsulfone synthon

Article abstract of DOI:10.1016/j.ultsonch.2011.05.003

A simple, facile, efficient and three-components procedure for the synthesis of pyrimido[1,2-a]benzimidazoles and pyrazolo[3,4-b]pyridines utilizing phenylsulfone synthon, under ultrasonic irradiation was developed.

Full text of DOI:10.1016/j.ultsonch.2011.05.003

Ultrasonics Sonochemistry 19 (2012) 49–55
Contents lists available at ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch
Ultrasound assisted one-pot, three-components synthesis of
pyrimido[1,2-a]benzimidazoles and pyrazolo[3,4-b]pyridines: A new access via
phenylsulfone synthon
c
b
Tamer S. Saleh a,b, , Taha M.A. Eldebss , Hassan M. Albishri
⇑
a Green Chemistry Department, National Research Centre, Dokki, Cairo 12622, Egypt
b Chemistry Department, Faculty of Science, King AbdulAziz University, Jeddah 21589, Saudi Arabia
c Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple, facile, efficient and three-components procedure for the synthesis of pyrimido[1,2-a]benzimi-
dazoles and pyrazolo[3,4-b]pyridines utilizing phenylsulfone synthon, under ultrasonic irradiation was
developed.
Received 31 October 2010
Received in revised form 20 April 2011
Accepted 4 May 2011
Ó 2011 Elsevier B.V. All rights reserved.
Available online 8 May 2011
Keywords:
2-aminobenzimidazole
5-aminopyrazoles
Multicomponent reactions (MCRs)
Pyrimido[1,2-a]benzimidazoles
Pyrazolo[3,4-b]pyridines
Ultrasound irradiation
1. Introduction
antibiotics against staphylococcus and mycobacterium ranae
[14]. They have antiarrythmic effects [14], herbicidal activity [15]
Contemporaneous research in organic synthesis focuses on
economy [1], the development of rapid and selective synthetic
routes toward focused libraries of functionalized heterocyclic
building blocks is of great importance to both medicinal and organ-
ic chemists, and still constitutes a challenge from academic and
industrial points of view. In modern organic chemistry, because
of economic and ecological increasing pressure, investigations are
now directed to the discovery of methods that largely take into
account the criterion of sustainable chemistry [2]. In this context,
multicomponent reactions (MCRs) [3] involving domino processes
[4], combining at least three different substrates in a one-pot
operation, have emerged as powerful tools and complementary
substrate-directed synthetic alternatives to other well-known
methods [5–8]. Moreover, these transformations combine classical
concerns such as efficiency, selectivity, molecular complexity and
diversity [9,10].
antidepressant effects [16], microfilaricidal and macrofilaricidal ef-
fects [17], they act as bactericides [18], fungicides [18], virucides
[18] and as diuretics [19].
Pyrimido[1,2-a]benzimidazoles are commonly synthesized via
cyclization of 2-aminobenzimidazole with 1,3-bielectrophiles. Up
to now numerous data have been reported on regioselective cycli-
zation of 2-aminobenzimidazole with
a,b-unsaturated ketones
(chalcones) [20–23] but one of the most drawbacks of this method
formation of dihydro derivatives which need to oxidation upon
certain treatment.
The pyrazolo[3,4-b]pyridine ring system is present in a number
of pharmaceutically important compounds, for instance, to inhibit
glycogen synthase kinase-3 (GSK-3) and cyclin-dependent kinases
(CDKs) [24,25], GSK-3 is known to play a key role in chronic
inflammatory processes [26], cancer [27], and Alzheimer’s disease
(AD) [28]. On the other hand, CDKs inhibitors are expected to be
active in the nervous system, via inhibition of neurotrophic
pathways, and antiapoptotic protection from neurofibrillary
degeneration in AD [29]. It was found that attachment of sulfone
moiety to pyrazolo[3,4-b]pyridine ring system in position 5 have
a great importance, in which structure–activity studies for the
class of pyrazolo[3,4-b]pyridines as CDKs inhibitors have shown
that optimal CDKs inhibitory potency [30].
Pyrimidobenzimidazoles have been found to be of pharmaco-
logical interest. For example, pyrimido[1,2-a]benzimidazoles
have been described as antihypertensives [11,12], antidiabetics
[12], antiinflammatory agents [13], antirheumatics [13] and as
⇑
Corresponding author. Tel.: +20 101978724; fax: +20 235727556.
E-mail address: tamsaid@yahoo.com (T.S. Saleh).
1350-4177/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2011.05.003

50
T.S. Saleh et al. / Ultrasonics Sonochemistry 19 (2012) 49–55
H
N
O
O
O
O
O
O
S
S
NH2
+
Ar CHO
2a-f
+
Ph
Ph
Ph
Ph
N
1
3
Ar
12
DMF
))) or Reflux
route B
route A
O
Ph
Ph
O
O
O
S
Ar
Ar
S
Ph
Ph
H
N
O
NH 2
N
N
NH
N
O
8
4
O
O
Ph
O
O
S
Ph
Ar
H
Ar
S
Ph
Ph
H
N
N
N
N
NH
NH
9
5
-PhSO 2
H
-PhSO 2H
Ar
Ph
H
H
Ar
N
N
Ph
N
NH
NH
N
10
6
- H2
- H2
Ph
Ar
Ar
Ph
N
N
N
N
N
N
11
7a-f
Scheme 1.
Hence, there remains a demand for development of methods for
the synthesis of azolopyrimidines and azolopyridines.
[39–44], and as a part of our growing interest in sonochemistry
[44–46]. We describe here a facile sonochemical one-pot, three-
component synthesis of pyrimido[1,2-a]benzimidazoles and pyr-
azolo[3,4-b]pyridines via phenylsulfone synthon. The structure of
the products was established on different analytical and spectro-
scopic data.
In the last few years the application of ultrasound in synthetic
organic chemistry became more and more interesting ‘‘Sonochem-
istry’’ is a new trend in organic chemistry, offering a versatile and
facile pathway for a large variety of syntheses. Thus, a large
number of organic reactions can be carried out under ultrasonic
irradiation in high yields, short reaction times and mild conditions
[31–38]. Motivated by the afore-mentioned findings, and in a con-
tinuation of our interest, in synthesis of a wide range of heterocy-
clic systems, for biological screening program in our laboratory
2. Result and discussion
The reaction of 2-aminobenzimidazole (1) with the aldehyde
derivatives 2a–f and 1-phenyl-2-(phenylsulfonyl)ethanone (3) in

T.S. Saleh et al. / Ultrasonics Sonochemistry 19 (2012) 49–55
51
Table 1
Synthesis of pyrimido[1,2-a]benzimidazoles derivatives under both ultrasonic irra-
diation and conventional method (Reflux).
Compound
Ar
Ultrasonic irradiation
Reflux
Time (min)
Yield (%)
Time (h)
Yield (%)
7a
7b
7c
7d
7e
7f
Ph
4-FPh
4-ClPh
4-BrPh
2-Cl-Ph
4-MeOPh
15
10
10
15
15
15
89
92
90
88
87
88
6
6
7
8
6
7
69
75
72
70
69
70
that the reaction time increased considerably and yield of the
products decreased. Thus, ultrasound was found to have beneficial
effect on the synthesis of 2,4-diarylpyrimido[1,2-a]benzimidazoles
7a–f in which decrease time of above reactions from 6 to 8 h in
conventional procedure to less than 20 min, also, a noticeable
improvement in yields of reactions under ultrasonic irradiations.
We extended our study to find out the reactivity of b-ketosulf-
one 3 towards 5-aminopyrazole derivatives 13a,b via a one pot,
three-component condensation reaction of an aldehyde 2a–c and
5-amino-pyrazole derivatives 13 in the presence of 1-phenyl-2-
(phenylsulfonyl)ethanone (3) in ethanol using p-toluenesulfonic
acid (p-TsOH) as the catalyst under ultrasonic irradiation (Scheme
2), afforded in each case, only one isolable product (as examined by
TLC).
Fig. 1. X-ray structure of compound 7b.
dimethyl formamide (DMF) as solvent under ultrasonic irradiation
at room temperature afforded one product in each case (as
evidenced by TLC) (Scheme 1). IR spectra of the latter products
revealed absorption bands of C@N function in the region 1610–
1613 cmÀ1 and no absorption bands due to sulfone group or NH
group. Their 1H NMR spectra exhibited no D2O exchangeable
signals and singlet signal in region of 7.68–8.16 in addition to
aromatic multiplet in region 6.99–7.92 The latter spectroscopic
data of the reaction products and their satisfactory elemental
analyses supported the structure 2,4-diarylpyrimido[1,2-a]benz-
imidazoles 7a–f. The proposed structure of pyrimido[1,2-a]benz-
imidazoles 7b was further unequivocally confirmed by single
crystal X-ray crystallography (Fig. 1), X-ray diffraction of com-
pound 7b add a sharp evidence not only for the proposed structure
but also for the mechanism of formation of product 7 as postulated
in Scheme 1.
The 1H NMR of the products formed show presence of singlet
signal in region 7.10–7.81 which give support for the assumed
structures formed in Scheme 2 via loss of sulfonic acid molecule.
The one step cyclocondensation reaction can afford three iso-
mers 14, 15 or 16 (Scheme 2) in which there are two possibilities
for ring closure if the N1-position is unsubstituted like in 13a,
either to N1 or to C4-atom to afford compound 14 or 16 (Scheme
2). Structure 16 pyrazolo[1,5-a]pyrimidine derivative was easily
ruled out depending on 1H NMR spectra of the products formed
(in case R@H) in which spectra show a D2O exchangeable signal
at d 14.01–14.12 corresponding to the 1-NH proton, and no singlet
The formation of 2,4-diarylpyrimido[1,2-a]benzimidazoles 7a–f
from Multi-component reactions (MCRs) [the reaction of 2-amino-
benzimidazole, aldehyde derivatives and b-ketosulfone] seems to
follow the sequence outlined in Scheme 1, which shows that the
reaction starts with intermolecular condensation between alde-
hyde 2 derivatives and 1-phenyl-2-(phenylsulfonyl)ethanone (3)
Ar
Ph
N
N
R
N
Ph
to form
Michael addition of the endocyclic imino group in the 2-aminobenz-
imidazole (1) to ,b-unsaturated carbonyl compound 12 to yield
a,b-unsaturated carbonyl compound 12 then via an initial
14a-f
a
Ph
the corresponding acyclic non-isolable intermediates 4 which un-
dergo cyclization to intermediate 5 and loss of sulfinic acid mole-
cule (intermediate 6) which then underwent aromatization into
the final products 7a–f (Scheme 1).
X-ray diffraction of 7b (Fig. 1) indicated without doubt that the
regiodirectivity in cyclization of 2-aminobenzimidazole with
b-ketosulfone, the reaction product formed through rout a and
ruled out the other possible rout b (initial Michael addition of the
abs. ethanol /
p-TsOH
Ph
Ph
Ph
))) or Reflux
2a-c
3
+
+
N
N
N
N
N
N
Ar
N
R
NH2
R
15
13a,b
13 R
exocyclic amino group in the 2-aminobenzimidazole (1) to
a,b-
a
b
H
Ph
unsaturated carbonyl compound 12 to yield the corresponding
acyclic non-isolable intermediates 8 which undergo cyclization to
intermediate 9 and loss of sulfinic acid molecule (intermediate
10) which then underwent aromatization into the final products
11 (Scheme 1).
N
R =H
Ar
Ph
To find the specific effect of ultrasound on this reaction, the
mentioned reaction was carried out under the same conditions in
the absence of ultrasound irradiation (Table 1), it was observed
16
Scheme 2.

52
T.S. Saleh et al. / Ultrasonics Sonochemistry 19 (2012) 49–55
Table 2
Table 3
Synthesis of 1H-pyrazolo[3,4-b]pyridine derivatives under both ultrasonic irradiation
Effect of p-TsOH on the % yield of compound 14a.
and conventional method (Reflux).
Entry
p-TsOH ratio
Solvent
Yield (%)
Time (min)
Compound
R
Ar
Ultrasonic irradiation
Reflux
1
2
3
4
5
6
0
EtOH
EtOH
EtOH
EtOH
DMF
DMF
29
86
90
90
18
62
90
45
45
45
90
45
Time (min)
Yield (%)
Time (h)
Yield (%)
0.1
0.2
0.3
0
14a
14b
14c
14d
14e
14f
H
H
H
Ph
Ph
Ph
Ph
45
30
30
60
45
45
90
97
94
81
84
84
10
6
6
14
10
12
71
76
75
60
63
62
4-FPh
4-ClPh
Ph
4-FPh
4-ClPh
0.2
compound revealed D2O exchangeable singlet signal at d 14.01
due to NH proton, a singlet signal at 7.84 due to CH-pyridine in
addition to aromatic multiplet at d 7.10–7.81 ppm (cf. experimen-
tal part).
signal appear above 6 ppm for @CH of pyrazole that mean ring
closure occur to C-4 atom. The cyclocondensation of amines
13a,b with aldehyde 2 and b-ketosulfone 3 gave regiospecifically
isomer 14 depending on the well established behavior and arising
from our studies of the reaction of 5-aminopyrazole derivative
Formation of compounds 14a–f under ultrasonic irradiation,
occur in excellent yields and shorter reaction time in comparing
with conventional condition (silent reactions) (Table 2).
Table 2 shows that ultrasound technique reduced the time of
reactions from several hours to minutes and improved the yields
from 71–76% (under conventional conditions) to 81–97%.
It is noteworthy to mention that we optimize first the reaction
conditions for the formation of 1H-pyrazolo[3,4-b]pyridine deriva-
tives 14a–f as in Table 3, to select the appropriate p-TsOH amounts
necessary to perform these three-components one pot reaction
with
a,b-unsaturated carbonyl compounds [47–51] so other
isomer 15 can be discarded.
The elemental analysis and spectral data of the reaction prod-
ucts were compatible with the 1H-pyrazolo[3,4-b]pyridine deriva-
tives 14a–f, For example, the IR spectra of 14a revealed, the
appearance of a band due to NH function at 3119 cmÀ1. The mass
spectra of the isolated product 14a showed, a peak corresponding
to the molecular ion at 347. It’s 1H NMR spectrum of the same
NH 2
NH
NH 2
p-TsO
NH2
p-TsO
p- TsOH
+
N
N
Ph
Ph
N
H
Ph
H
N
H
N
H
13
16
NH 2
NH
O
O
O
Ph
H
O
Ph
NH2
O
S
Ph
O
S
N
H
16
3
2a-c
Ph
N
N
H
Ph
Ar
Ar
12
H
Ph
17
-H
Ph
H
O
O
O
N
O
Ph
NH
S
O
S
H
Ph
Ar
N
H
-H2O
N
H
Ph
Ar
N
H
Ph
N
Ph
19
18
-PhSO 2
Ar
H
Ph
N
N
H
N
Ph
14a-c
Scheme 3.

T.S. Saleh et al. / Ultrasonics Sonochemistry 19 (2012) 49–55
53
under ultrasound irradiation, different amounts of p-TsOH (mol/
mol) ratios were tested.
Table 3 represents the effect of p-TsOH on the % yield of com-
pound 14a.
From the results cited in Table 3, it is clear that 0.2 mol equiv of
p-TsOH furnishes the respective product in a quantitative yield
(Table 3, entry 3). The influence of the nature of the solvent on
the reaction yield and kinetic was studied to find the best reaction
conditions which indicated that the best solvent for this reaction
was ethanol under ultrasonic irradiation. As described for ultra-
sonic conditions, the catalytic system was inefficient in the ab-
sence of catalyst and produced only 29% of product after 90 min
and in this case there is side product formed which detected as
measured on a Gallenkamp melting point apparatus and are
uncorrected. IR spectra were recorded in KBr disks on a pye Uni-
cam SP 3300 and Shimadzu FT IR 8101 PC infrared spectrophotom-
eters. The NMR spectra were recorded on a Varian Mercury VX-300
NMR spectrometer. 1H spectra were run at 300 MHz and 13C spec-
tra were run at 75.46 MHz in dimethyl sulphoxide (DMSO-d6).
Chemical shifts were related to that of the solvent. Mass spectra
were recorded on a Shimadzu GCMSQP 1000 EX mass spectrome-
ter at 70 eV. Elemental analyses were carried out on Elmentar
instrument C, H, N, S analyzer Vario EL III.
X-ray crystallography was carried out on Kappa CCD Enraf
Nonius FR 590 diffractometer, National Research Center, Dokki,
Cairo, Egypt.
a
,b-unsaturated carbonyl compound 12.
There are no established mechanisms for the formation of 1
Sonication was performed by Branson sonicator (with
frequency of 40 kHz and a nominal power 180 W).
a
H-pyrazolo[3,4-b]pyridines; a reasonable possibility is shown in
Scheme 3. The reaction presumably proceeds via initial reaction
between p-TsOH and the 5-aminopyrazole derivative 13 to give
the 3-aminopyrazolium salt 16. Next, Michael addition of this
compound to benzylidene compound 12, itself produced by
Knoevenagel condensation of aldehyde 2 and 1-phenyl-2-(phenyl-
sulfonyl)ethanone (3) gives intermediate 17. Elimination of one
proton from the iminum group results in intermediate 18. Subse-
quent cyclization of 18 results in condensed ring system 19 that
finally, underwent aromatization with losing of sulfinic acid mole-
cule to produce the 1H-pyrazolo[3,4-b]pyridine derivatives 14
(Scheme 3).
Finally, the above reactions show that phenylsulfone is an
important synthon for use in a variety of reactions, including
asymmetric synthesis.
The improvement induced by ultrasound in the above men-
tioned reactions can be attributed to the well established theory
for the cavitation, The collapse of bubbles caused by cavitation pro-
duces intense local heating and high pressures, [52,53] so reaction
time decreases clearly and high % yield obtained.
1-Phenyl-2-(phenylsulfonyl)ethanone 3 [56] and aminopyraz-
oles 13a,b [57] were prepared according to the reported literature.
4.2. Typical procedure for synthesis of pyrimido[1,2-a]benzimidazoles
derivatives 7a–f
4.2.1. Silent reactions
A mixture of 1-phenyl-2-(phenylsulfonyl)ethanone (1 mmol),
aldehyde (1 mmol) and 2-aminobenzimidazole (1 mmol) in DMF
(1 ml) was refluxed for appropriate time (cf. Table 1) until comple-
tion of the reaction (monitored by TLC). The precipitate formed
was collected by filtration then washed, dried and purified by
recrystallization from DMF/2-propanol (1:2).
4.2.2. Sonicated reactions
These processes were performed on the same scale described
above for silent reactions. All The reactions were kept at room tem-
perature 25–30 °C which attained by addition or removal of water
in ultrasonic bath (the temperature inside reaction vessel was 28–
30 °C). The sonochemical reactions were continued for suitable
time (cf. Table 1) until the starting materials were no longer detect-
able by TLC. The products were obtained and purified as described
above in silent reaction procedures.
In addition, according to sonochemical reactions classification
of Luche [54,55], the above mentioned reactions is considered false
sonochemistry type in which cavitation effect provides the
mechanical energy for all subsequent chemical reactions, including
bond scission induced by viscous frictional forces.
The synthesized compounds with their physical data are listed
below.
4.2.2.1. Synthesis of 2,4-diphenylpyrimido[1,2-a]benzimidazole
(7a). M.p. = 297 °C; IR (KBr): 1610 (C@N) cmÀ1
;
1H NMR
3. Conclusion
(300 MHz, DMSO-d6) d: 7.12–7.82 (m, 14H, ArH’s), 8.16 (s, 1H, H-
3); 13C NMR (75.46 MHz, DMSO-d6) d: 103.25, 108.55, 116.87,
124.99, 125.11, 126.12, 126.14, 127.59, 127.69, 130.55, 131.08,
132.25, 138.26, 141.58, 145.08, 152.85, 159.94; MS (m/z): 321
(M+). (Found: C, 82.41; H, 4.62; N, 12.97. C22H15N3 requires C,
82.22; H, 4.70; N, 13.08.)
A novel and efficient three-components condensation reaction
of an aldehyde, amino azoles and b-ketosulfone has been devel-
oped for the synthesis of pyrimido[1,2-a]benzimidazoles and
pyrazolo[3,4-b]pyridines under ultrasonic irradiation via utiliza-
tion of b-ketosulfone as important synthon for synthesis of them.
The simple one-pot nature of the reaction makes it an interesting
alternative to other multi-step approaches. In general, improve-
ments in rates and yield of reactions are observed when reactions
were carried out under sonication compared with classical
condition.
4.2.2.2. Synthesis of 4-(4-flurophenyl)-2-phenylpyrimido[1,2-a]benz-
imidazole (7b). M.p. = >300 °C; IR (KBr): 1613 (C@N)cmÀ1; 1H NMR
(300 MHz, DMSO-d6) d: 6.99–7.88 (m, 13H, ArH’s), 8.09 (s, 1H, H-
3); 13C NMR (75.46 MHz, DMSO-d6) d: 102.55, 109.22,
111.29,116.88, 123.65, 126.32, 127.54, 128.02, 130.12, 132.18,
132.51 136.89, 136.98, 141.15, 146.00, 151.01, 159.90, 162.58;
MS (m/z): 339 (M+). (Found: C, 78.06; H, 4.09; N, 12.25.
4. Experimental
C22H14FN3 requires C, 77.86; H, 4.16; N, 12.38.)
4.1. General
4.2.2.3. Synthesis of 4-(4-chlorophenyl)-2-phenylpyrimido[1,2-a]benz
imidazole (7c). M.p. = 280–282 °C; IR (KBr): 1613 (C@N)cmÀ1 1H
All organic solvents were purchased from commercial sources
and used as received or dried using standard procedures, unless
otherwise stated. All chemicals were purchased from Merck,
Aldrich or Acros and used without further purification, thin-layer
chromatography (TLC) was performed on precoated Merck 60
GF254 silica gel plates with a fluorescent indicator, and detection
by means of UV light at 254 and 360 nm. All melting points were
;
NMR (300 MHz, DMSO-d6) d: 7.32–7.92 (m, 13H, ArH’s), 8.02 (s,
1H, H-3); 13C NMR (75.46 MHz, DMSO-d6) d: 104.00, 113.54,
116.89, 124.22, 126.13, 126.85, 127.12, 128.45, 131.85, 133.87,
133.98, 138.58, 141.12, 146.00, 150.05, 155.24, 158.19; MS (m/z):
355 (M+). (Found: C, 74.45; H, 3.89; N, 11.70. C22H14ClN3 requires
C, 74.26; H, 3.97; N, 11.81.)

54
T.S. Saleh et al. / Ultrasonics Sonochemistry 19 (2012) 49–55
4.2.2.4. Synthesis of 4-(4-bromophenyl)-2-phenylpyrimido[1,2-
(75.46 MHz, DMSO-d6) d: 103.13, 115.46, 115.47, 120.59, 125.22,
126.01, 126.02, 126.88, 126.89, 127.98, 128.08, 128.09, 128.21,
130.03, 133.0, 138.11, 142.45, 149.85, 150.10, 155.12, 159.14; MS
(m/z): 365 (M+). (Found: C, 79.16; H, 4.29; N, 11.35. C24H16FN3 re-
quires C, 78.89; H, 4.41; N, 11.50.)
a]benzimidazole (7d). M.p. = >300 °C; IR (KBr): 1613 (C@N)cmÀ1
;
1H NMR (300 MHz, DMSO-d6) d: 7.32–7.92 (m, 13H, ArH’s), 7.99
(s, 1H, H-3); 13C NMR (75.46 MHz, DMSO-d6) d: 104.00, 113.54,
116.89, 124.22, 126.13, 126.85, 127.12, 128.45, 131.85, 133.87,
133.98, 138.58, 141.12, 146.00, 150.05, 156.10, 158.19; MS (m/z):
400 (M+). (Found: C, 66.13; H, 3.49; N, 10.42. C22H14BrN3 requires
C, 66.01; H, 3.53; N, 10.50)
4.3.2.3. 4-(4-chlorophenyl)-3,6-diphenyl-1H-pyrazolo[3,4-b]pyridine
(14c). M.p. = 283 °C; IR (KBr): 3148 (NH), 1590 (C@N)cmÀ1 1H
;
NMR (300 MHz, DMSO-d6) d: 7.22–7.81 (m, 14H, ArH’s), 7.91 (s,
1H, H-5), 14.10 (s, 1H, NH, D2O exchangeable); 13C NMR
(75.46 MHz, DMSO-d6) d: 103.01, 116.11, 125.20, 126.13, 126.14,
126.94, 127.18, 128.08, 128.09, 128.89, 132.84, 136.05, 140.0,
141.12, 148.14, 151.13, 155.12, 156.78; MS (m/z): 381 (M+).
(Found: C, 75.78; H, 4.08; N, 10.85. C24H16ClN3 requires C, 75.49;
H, 4.22; N, 11.00.)
4.2.2.5. Synthesis of 4-(2-chlorophenyl)-2-phenylpyrimido[1,2-a]benz
imidazole (7e). M.p. = 272 °C; IR (KBr): 1611 (C@N)cmÀ1 1H NMR
;
(300 MHz, DMSO-d6) d: 6.75–7.49 (m, 13H, ArH’s), 7.68 (s, 1H, H-
3); 13C NMR (75.46 MHz, DMSO-d6) d: 103.54, 112.14, 115.11,
122.12, 127.47, 127.87, 128.25, 129.82, 129.97, 131.15, 131.87,
133.45, 134.85, 136.14, 136.89, 140.11, 145.00, 151.09, 155.02,
158.00; MS (m/z): 355 (M+). (Found: C, 74,41; H, 3.92; N, 11.71.
C22H14ClN3 requires C, 74.26; H, 3.97; N, 11.81.)
4.3.2.4. 1,3,4,6-tetraphenyl-1H-pyrazolo[3,4-b]pyridine (14d). M.p. =
>300 °C; IR (KBr): 1610 (C@N)cmÀ1 1H NMR (300 MHz, DMSO-
;
4.2.2.6. Synthesis of 4-(4-methoxyphenyl)-2-phenylpyrimido[1,2-
d6) d: 7.05–7.72 (m, 20H, ArH’s), 7.92 (s, 1H, H-5); 13C NMR
(75.46 MHz, DMSO-d6) d: 109.00, 117.22, 120.25, 120.26, 125.25,
127.14, 127.15, 127.17, 127.18, 128.08, 128.09, 128.87, 128.88,
128.94, 128.99, 129.07, 129.08, 133.00, 138.58, 139.00, 141.55,
149.92, 150.70, 155.18; MS (m/z): 423 (M+). (Found: C, 85.26; H,
4.94; N, 9.80. C30H21N3 requires C, 85.08; H, 5.00; N, 9.92.)
a]benzimidazole (7f). M.p. = >300 °C; IR (KBr): 1613 (C@N)cmÀ1
;
1H NMR (300 MHz, DMSO-d6) d: 3.95 (s, 3H, OCH3), 7.32–7.89
(m, 13H, ArH’s), 7.78 (s, 1H, H-3); 13C NMR (75.46 MHz, DMSO-
d6) d: 52.12, 104.04, 112.55, 114.21, 116.58, 122.54, 127.37,
127.95, 128.45, 129.22, 131.59, 133.45, 133.89, 136.89, 145.21,
148.10, 151.55, 158.87; MS (m/z): 351 (M+). (Found: C, 78.86; H,
4.76; N, 11.83. C23H17N3O requires C, 78.61; H, 4.88; N, 11.96.)
4.3.2.5. 4-(4-fluorophenyl)-1,3,6-triphenyl-1H-pyrazolo[3,4-b]pyri-
dine (14e). M.p. = >300 °C; IR (KBr): 1613 (C@N)cmÀ1 1H NMR
;
4.3. Typical procedure for synthesis of pyrazolo[3,4-b]pyridines deriv-
atives 14a–f
(300 MHz, DMSO-d6) d: 7.14–7.79 (m, 19H, ArH’s), 7.81 (s, 1H, H-
5); 13C NMR (75.46 MHz, DMSO-d6) d: 108.47, 115.14, 115.15,
120.14, 121.49, 121.50, 125.12, 126.34, 127.47, 127.48, 127.97,
127.98, 128.10, 128.11, 128.12, 129.22, 129.43, 130.07, 133.00,
139.50, 139.87, 140.95, 146.09, 149.89, 150.12, 155.01, 161.00;
MS (m/z): 441 (M+). (Found: C, 81.92; H, 4.39; N, 9.29. C30H20FN3
requires C, 81.61; H, 4.57; N, 9.52.)
4.3.1. Silent reactions
A solution of 1-phenyl-2-(phenylsulfonyl)ethanone (1 mmol),
aldehyde (1 mmol), 5-aminopyrazole derivatives (1 mmol) and
p-TsOH (0.2 mmol) in 15 ml of absolute ethanol was refluxed for
appropriate time (cf. Table 2) until completion of the reaction. After
completion of the reaction as indicated by TLC (EtOAc/n-hexene,
1:2), the reaction mixture was allowed to cool. The solvent was re-
moved by evaporation and the residue was washed with H2O
(2 Â 20 ml). The solid products were purified by recrystallization
from 2-propanol.
4.3.2.6. 4-(4-chlorophenyl)-1,3,6-triphenyl-1H-pyrazolo[3,4-b]pyri-
dine (14f). M.p. = >300 °C; IR (KBr): 1610 (C@N)cmÀ1 1H NMR
;
(300 MHz, DMSO-d6) d: 7.09–7.80 (m, 19H, ArH’s), 7.89 (s, 1H, H-
5); 13C NMR (75.46 MHz, DMSO-d6) d: 109.02, 115.09, 116.58,
116.59, 120.25, 121.05, 123.98, 123.99, 124.12, 124.13, 127.55,
127.57, 128.45, 128.46, 128.70, 133.00, 134.78, 139.45, 140.12,
140.95, 144.81, 149.00, 151.78, 155.04; MS (m/z): 457 (M+).
(Found: C, 78.48; H, 4.35; N, 9.03. C30H20ClN3 requires C, 78.68;
H, 4.40; N, 9.18.)
4.3.2. Sonicated reactions
These processes were performed on the same scale described
above for silent reactions. All The reactions were kept at room tem-
perature 25–30 °C (the temperature inside reaction vessel was 28–
30 °C). The sonochemical reactions were continued for suitable
time (cf. Table 2) until the starting materials were no longer detect-
able by TLC. The products were obtained and purified as described
above in silent reaction procedures.
5. X-ray crystallography
A single crystal of compound 7b was obtained by slow evapora-
tion from a mixture of ethanol:DMF (2:1). The crystal structure
was solved and refined using maxus (nonius, Deflt and MacScience,
The synthesized compounds with their physical data are listed
below.
Japan) [58] Mo Ka radiation (k = 0.71073 Å) and a graphite mono-
chromator were used for data collection. The chemical formula and
ring labeling system is shown in Fig. 1.
Crystallographic data (excluding structure factors) for the struc-
ture in this paper have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication number CCDC
793678 Copies of the data can be obtained, free of charge, on appli-
cation to CCDC, 12 Union, Road, Cambridge CB2 1EZ, UK [fax: 144
(0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
4.3.2.1. 3,4,6-triphenyl-1H-pyrazolo[3,4-b]pyridine (14a). M.p. =
278 °C; IR (KBr): 3119 (NH), 1595 (C@N)cmÀ1
;
1H NMR
(300 MHz, DMSO-d6) d: 7.10–7.81 (m, 15H, ArH’s), 7.84 (s, 1H, H-
5), 14.01 (s, 1H, NH, D2O exchangeable); 13C NMR (75.46 MHz,
DMSO-d6) d: 103.95, 117.25, 125.21, 125.88, 125.89, 125.97,
126.01, 127.70, 128.69, 128.97,128.99, 129.02, 130.15, 137.18,
140.87, 144.45, 149.85, 151.14, 154.07; MS (m/z): 347 (M+).
(Found: C, 83.19; H, 4.84; N, 11.97. C24H17N3 requires C, 82.97;
H, 4.93; N, 12.10.)
4.3.2.2. 4-(4-fluorophenyl)-3,6-diphenyl-1H-pyrazolo[3,4-b]pyridine
Appendix A. Supplementary data
(14b). M.p. = 289 °C; IR (KBr): 3174 (NH), 1592 (C@N)cmÀ1 1H
;
NMR (300 MHz, DMSO-d6) d: 7.19–7.79 (m, 14H, ArH’s), 7.74 (s,
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.ultsonch.2011.05.003.
1H, H-5), 14.12 (s, 1H, NH, D2O exchangeable); 13C NMR

T.S. Saleh et al. / Ultrasonics Sonochemistry 19 (2012) 49–55
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