Synthesis of thienopyrimidine-pyrazolo[3,4-b]pyridine hybrids

Article abstract of DOI:10.1515/hc-2016-0181

New hybrid compounds, thienopyrimidinyl-1H-pyrazolo[3,4-b]pyridine derivatives, were efficiently synthesized by the three-component reaction of 3-phenyl-1-(thienopyrimidin-4-yl)-1H-pyrazol-5-amine, benzoylacetonitrile and an aromatic aldehyde in the prese

Full text of DOI:10.1515/hc-2016-0181

Heterocycl. Commun. 2017; 23(4): 281–285
Jae Woo Park and Yang-Heon Song*
Synthesis of thienopyrimidine-pyrazolo[3,4-b]
pyridine hybrids
Received October 20, 2016; accepted March 15, 2017; previously
published online July 12, 2017
DOI 10.1515/hc-2016-0181
hybrids with the concept of molecular hybridization [21]
by treating 3-phenyl-1-(thienopyrimidin-4-yl)-1H-pyrazol-5-
amine with benzoylacetonitrile and an aromatic aldehyde
catalyzed by FeCl on basic alumina.
3
Abstract: New hybrid compounds, thienopyrimidinyl-
1
H-pyrazolo[3,4-b]pyridine derivatives, were efficiently
synthesized by the three-component reaction of 3-phenyl-
Results and discussion
-(thienopyrimidin-4-yl)-1H-pyrazol-5-amine, benzoylace-
1
tonitrile and an aromatic aldehyde in the presence of FeCl3
on basic alumina.
The synthesis is outlined in Scheme 1 starting from the
readily available substrates 1a–c and 2a [22, 23]. Interme-
Keywords: basic alumina; iron(III) chloride; pyrazolo[3,4- diate products 4a–c and 5a were easily prepared in good
b]pyridine; thienopyrimidine; three-component reaction. yields by the reaction of 1a–c or 2a with benzoylacetoni-
trile (3) in refluxing ethanol using the previously reported
method [24]. Initially, the three-component reaction of
4
a, arylaldehyde 6a and 3 in refluxing ethanol without
Introduction
catalyst or in the presence of various catalysts such as
ammonium acetate, acetic acid, L-proline or FeCl was
3
Pyrazolo[3,4-b]pyridines have been reported to posses
antioxidant [1], antibacterial [2], antiviral [3] and
antitumor activities [4–8]. Thienopyrimidines and their
derivatives have also attracted considerable attention
due to important biological properties including anti-
cancer [9], antimicrobial [10], antiviral [11], and anti-
inflammatory activities [12]. Fused thienopyrimidines
with cycloalkyl substituents are potent antitumor agents
investigated as a model reaction (Table 1, entries 1–5).
The desired hybrid product 7a was observed in low to
moderate yields (15–61%) for the reactions conducted in
refluxing ethanol. With FeCl on basic alumina as cata-
lyst (0.2 equiv), compound 7a was obtained in a yield of
3
8
6% after heating for 6 h (entry 6). The use of a smaller
amount of the catalyst or lowering the reaction tempera-
ture resulted in decreased yields (entries 7, 8). No further
increase in yield was achieved with the use of different
solvents and varying temperatures (entries 9, 10). The
reaction of 4a with 6b and 3 under the optimized reaction
conditions (using 0.2 equiv FeCl /basic Al O in refluxing
[
13]. These results prompted us to study the synthesis
of thienopyrimidine derivatives substituted with the
pyrazolo[3,4-b]pyridine ring system. We have previously
reported several biologically active fused thienopyrimi-
dine derivatives [14–16].
3
2
3
ethanol) gave a corresponding product 7b in 82% yield
Scheme 2). The reaction of cycloalkyl-substituted 4b or
c with arylaldehyde 6a–c and 3 under the same reaction
Manysyntheticapproachestopyrazolo[3,4-b]pyridines
have been developed [17]. Recently, some new pyrazolo[3,4-
b]pyridines have been prepared by a multi-component
reaction of a substituted 5-amino-1-phenyl-1H-pyrazole,
benzoylacetonitrile and an aromatic aldehyde in the pres-
ence of a catalyst such as ammonium acetate [18], acetic
(
4
conditions afforded product 7c–f in good yield (80–83%).
When 5a bearing a different thiophene ring was allowed to
react with 6a and 3, the corresponding compound 8a was
obtained in 85% yield. These results show that cyclocon-
densation of the three components is not strongly affected
by substituent on the arylaldehyde or thienopyrimidine.
All products were fully characterized by spectroscopy
and elemental analysis. To definitively assign the struc-
ture of 7a–f and 8a, an authentic sample of 7a was pre-
pared by a stepwise synthesis. Thus, 4a was first allowed
to react with 3, and the subsequent reaction of the crude
product with 6a gave 7a. This product was identical in all
acid/triethylamine [8], L-proline [19] or FeCl [20]. We
3
report here an efficient one-pot three-component syn-
thesis of new pyrazolo[3,4-b]pyridine-thienopyrimidine
*
Corresponding author: Yang-Heon Song, Department of Chemistry,
Mokwon University, Daejeon 35349, South Korea,
e-mail: yhsong@mokwon.ac.kr
Jae Woo Park: Department of Chemistry, Mokwon University,
Daejeon 35349, South Korea
1
respects (mp, H NMR, and MS) with 7a obtained from the
Brought to you by | University of Michigan
Authenticated
Download Date | 8/4/17 2:08 AM

2
82ꢀꢀꢀꢀꢁꢀJ.W. Park and Y.-H. Song: Thienopyrimidine-pyrazolo[3,4-b]pyridine hybrids
Ph
O
R2
S
R2
S
R2
S
NHNH2
CN
N
CN
CN
Ph
R2
S
N
N
NH2
HC(OEt)3
NH2NH2
3
R1
R1
R1
N
∆
∆
EtOH, ∆, 10 h
N
NH2
N = CHOEt
N
a–c
R1
4
a–c
1
a, 4a: R1 = H, R = H
b, 4b: R , R = -CH2CH2CH2-
c, 4c: R , R = -CH2CH2CH2CH2-
2
1
1
1
1
2
1
2
Ph
O
O
O
N
Cl
NHNH2
CN
Ph
N
S
HCOOH
S
POCl3
S
NH NH
S
3
NH2
2
2
N
N
NH2
NH2
NH
N
N
∆
∆
∆
EtOH, ∆, 10 h
S
N
N
N
2
a
5a
Scheme 1ꢀSynthesis of reactants 4a–c and 5a.
Table 1ꢀOptimization of reaction conditions for the synthesis of 7a.a
MeO
CN
O
O
Reaction
conditions
CN
N
H
N
N
N
N
N
NH2
MeO
N
N
4
a
6a
3
7a
S
S
N
Entry ꢁ
Catalyst (equiv)b ꢁ
Solventꢁ
Time (h)ꢁ
Temperature (°C) ꢁ
Yield (%)c
ꢂ
ꢆ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
–
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
DMF
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢂꢄꢃ
ꢈꢃ
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
ꢆꢉ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢅꢆ
ꢇꢄ
ꢇꢈ
ꢂꢉ
ꢈꢂ
ꢊꢈ
ꢈꢉ
ꢇꢇ
ꢉꢈ
ꢅꢊ
NH OAc (ꢄ.ꢆ)
ꢇ
ꢅ
AcOH (ꢄ.ꢆ)
ꢈꢃ
ꢇ
L-proline (ꢄ.ꢆ)
ꢈꢃ
ꢉ
FeCl (ꢄ.ꢆ)
ꢈꢃ
ꢅ
ꢈ
FeCl /Al O (ꢄ.ꢆ) ꢃ
ꢈꢃ
ꢅ
ꢆ
ꢅ
ꢋ
FeCl /Al O (ꢄ.ꢂ) ꢃ
ꢈꢃ
ꢅ
ꢆ
ꢅ
ꢊ
FeCl /Al O (ꢄ.ꢆ) ꢃ
ꢂꢄꢃ
ꢈꢃ
ꢅ
ꢆ
ꢅ
ꢌ
FeCl /Al O (ꢄ.ꢆ) ꢃ
ꢂꢄꢄ
ꢅ
ꢆ
ꢅ
ꢂꢄ
FeCl /Al O (ꢄ.ꢆ) ꢃ
MeCN
ꢈꢃ
ꢊꢄ
ꢅ
ꢆ
ꢅ
a
b
c
Reactions were carried out with 4a (1.0 mmol), 6a (1.0 mmol), 3 (1.0 mmol) in an appropriate solvent (10 mL). Equiv is based on FeCl . Yield
3
of isolated product.
three-component reaction. This result is also consistent in the presence of FeCl on basic alumina. The use of the
3
with the report by Jachak and co-workers [18].
catalyst in this reaction has the advantage of enhanced
yields and simple work-up compared to FeCl alone.
3
Conclusions
New thienopyrimidinyl-1H-pyrazolo[3,4-b]pyridines were
synthesized by the three-component reaction of 3-phenyl-
Experimental
Melting points were measured by using capillary tubes on a Büchi
apparatus and are uncorrected. Compounds were purified by column
chromatography using Merck silica gel (70–230 mesh). The H NMR
1
-(thienopyrimidin-4-yl)-1H-pyrazol-5-amine, benzoylace-
1
tonitrile and an aromatic aldehyde in refluxing ethanol spectra were recorded on a Unity Inova 400NB FT NMR spectrometer
Brought to you by | University of Michigan
Authenticated
Download Date | 8/4/17 2:08 AM

J.W. Park and Y.-H. Song: Thienopyrimidine-pyrazolo[3,4-b]pyridine hybridsꢍꢁꢀꢀꢀꢍ283
R3
Ph
O
CN
Ph
O
cat. FeCl3/Al2O3
N
H
R3
R2
S
N
N
NH2
CN
Ph
7a–f
Ph
EtOH, ∆, 6 h
N
N
N
R2
S
N
R1
4a–c
6a–c
3
N
R1
N
MeO
Ph
O
N
O
CN
Ph
cat. FeCl3/Al2O3
N
NH2
Ph
H
CN
Ph
S
EtOH, ∆, 6 h
N
MeO
N
N
N
N
N
5a
6a
3
8a
S
N
1
2
1
2
3
4
a: R = H, R = H
7a: R = H; R = H; R = 4-OMe
1
2
1
2
3
4
4
6
6
6
b: R , R = -CH2CH2CH2-
7b: R = H; R = H; R = 4-Br
1
2
1
2
3
c: R , R = -CH2CH2CH2CH2-
7c: R , R = -CH2CH2CH2-; R = 4-OMe
3
1
2
3
a: R = 4-OMe
7d: R , R = -CH2CH2CH2-; R = 4-Me
3
1
2
3
b: R = 4-Br
7e: R , R = -CH2CH2CH2-; R = 4-Br;
3
1
2
3
c: R = 4-Me
7f: R , R = -CH2CH2CH2CH2-; R = 4-OMe
Scheme 2ꢀThree-component synthesis of compounds 7a–f and 8a.
(
400 MHz) in CDCl with Me Si as internal standard. Mass spectra 2H), 5.95 (s, 1H), 3.17 (m, 2H), 3.05 (m, 2H), 2.31 (m, 2H); MS: m/z 334.21
3 4
+
were recorded on a HP 59580 B spectrometer (APCI). Elemental anal- (M ). Anal. Calcd for C H N S: C, 64.84; H, 4.53; N, 21.01. Found: C,
1
8
15
5
yses were performed on a Carlo Erba 1106 elemental analyzer.
64.66; H, 4.49; N, 21.14.
3
-Phenyl-1-(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimi-
1
din-4-yl)-1H-pyrazol-5-amine (4c)ꢀYield 70%; mp 171–172°C; H
NMR: δ 8.94 (s, 1H), 7.78 (m, 2H), 7.42 (m, 2H), 7.39 (m, 1H), 5.94 (s,
Preparation of the catalyst (FeCl /basic Al O )
3
2
3
1
H), 5.85 (bs, 2H), 2.91 (m, 2H), 2.55 (m, 2H), 1.83 (m, 2H), 1.64 (m, 2H);
A mixture of hydrated ferric chloride (FeCl · 6H O, 4 g) and basic
+
3
2
MS: m/z 348.23 (M ). Anal. Calcd for C H N S: C, 65.68; H, 4.93; N,
19 17 5
Al O (20 g) in acetone (30 mL) was stirred at room temperature for
2
3
20.16. Found: C, 65.89; H, 4.98; N, 20.04.
1
h and then concentrated under reduced pressure. The resulting yel-
low powder was dried at 100°C under reduced pressure for 2 h [25].
3-Phenyl-1-(thieno[3,2-d]pyrimidin-4-yl)-1H-pyrazol-5-amine
1
(
5a)ꢀYield 72%; mp 191–192°C; H NMR: δ 8.76 (s, 1H), 8.33 (d, 1H,
Jꢁ=ꢁ5.6 Hz), 7.77 (m, 2H), 7.44 (d, 1H, Jꢁ=ꢁ5.6 Hz), 7.30 (m, 3H), 7.20 (bs,
+
2
6
H), 5.81 (s, 1H); MS: m/z 294.30 (M ). Anal. Calcd for C H N S: C,
General procedure for the synthesis of 4a–c and 5a
15 11
5
1.42; H, 3.78; N, 23.87. Found: C, 61.29; H, 3.80; N, 23.99.
A mixture of hydrazinylthienopyrimidine 1a–c or 2 (10 mmol) and
benzoylacetonitrile 3 (10 mmol) in anhydrous ethanol (20 mL) was
heated under reflux for 10 h. The mixture was poured into crushed ice
General procedure for the synthesis of 7a–f and 8a
(
20 mL) and the precipitated solid product was filtered, washed with
A mixture of thienopyrimidinylpyrazolamine 4a–c or 5a (5 mmol), ary-
water, and crystallized from ethanol to give pure 4a–c or 5a.
laldehyde 6a–c (5 mmol), benzoylacetonitrile 3 (5 mmol) and FeCl /
3
basic Al O (1 mmol, based on FeCl ) in anhydrous ethanol (20 mL) was
3
-Phenyl-1-(thieno[2,3-d]pyrimidin-4-yl)-1H-pyrazol-5-amine
2
3
3
1
heated under reflux. After completion of the reaction (6 h, monitored
(
4a)ꢀYield 75%; mp 211–212°C; H NMR: δ 8.89 (s, 1H), 8.55 (d, 1H,
Jꢁ=ꢁ5.5 Hz), 7.97 (d, 1H, Jꢁ=ꢁ5.5 Hz), 7.92 (m, 2H), 7.48 (m, 3H), 6.70 (s, 2H), by TLC), the mixture was diluted with ethyl acetate and the insoluble
+
substance was filtered out. The solvent was evaporated under reduced
pressure and the residue was crystallized from chloroform.
5
.98 (s, 1H); MS: m/z 294.21 (M ). Anal. Calcd for C H N S: C, 61.42; H,
15 11 5
3
.78; N, 23.87. Found: C, 61.21; H, 3.82; N, 23.76.
1
-(6,7-Dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-yl)- 4-(4-Methoxyphenyl)-3,6-diphenyl-1-(thieno[2,3-d]pyrimidin-
1
3
-phenyl-1H-pyrazol-5-amine (4b)ꢀYield 80%; mp 158–159°C; H 4-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (7a)ꢀYield 86%;
1
NMR: δ 8.81 (s, 1H), 7.83 (m, 2H), 7.44 (m, 2H), 7.36 (m, 1H), 6.22 (bs, mp 255–257°C; H NMR: δ 8.78 (s, 1H), 8.62 (d, 1H, Jꢁ=ꢁ5.4 Hz), 7.80 (d,
Brought to you by | University of Michigan
Authenticated
Download Date | 8/4/17 2:08 AM

2
84ꢀꢀꢀꢀꢁꢀJ.W. Park and Y.-H. Song: Thienopyrimidine-pyrazolo[3,4-b]pyridine hybrids
1
H, Jꢁ=ꢁ5.4 Hz), 7.59 (m, 3H), 7.51 (m, 3H), 7.35 (m, 3H), 7.25 (m, 3H),
[3] Tucker, T. J.; Sisko, J. T.; Tynebor, R. M.; Williams, T. M.;
Felock, P. J.; Flynn, J. A.; Lai, M. T.; Liang, Y.; McGaughey, G.;
Liu, M.; et al. Discovery of 3-{5-[(6-amino-1H-pyrazolo[3,4-b]
pyridine-3-yl)methoxy]-2-chlorophenoxy}-5-chlorobenzonitrile
(MK-4965): a potent, orally bioavailable HIV-1 non-nucleoside
reverse transcriptase inhibitor with improved potency against
key mutant viruses. J. Med. Chem. 2008, 51, 6503–6511.
[4] Ohkubo, S.; Kodama, Y.; Muraoka, H.; Hitotsumachi, H.;
Yoshimura, C.; Kitade, M.; Hashimoto, A.; Ito, K.; Gomori, A.;
Takahashi, K.; et al. TAS-116, a highly selective inhibitor of
heat shock protein 90α and β, demonstrates potent antitumor
activity and minimal ocular toxicity in preclinical models. Mol.
Cancer Ther. 2015, 14, 14–22.
+
6
.83 (d, 2H, Jꢁ=ꢁ7.4 Hz), 3.76 (s, 3H); MS: m/z 537.16 (M ). Anal. Calcd for
C H N OS: C, 71.62; H, 3.76; N, 15.66. Found: C, 71.50; H, 3.81; N, 15.55.
32
20
6
4
4
-(4-Bromophenyl)-3,6-diphenyl-1-(thieno[2,3-d]pyrimidin-
-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (7b)ꢀYield 82%;
1
mp 190–191°C; H NMR: δ 8.75 (s, 1H), 8.60 (d, 1H, Jꢁ=ꢁ5.4 Hz), 7.84 (d,
1
H, Jꢁ=ꢁ5.4 Hz), 7.68 (m, 2H), 7.50 (m, 3H), 7.40 (m, 4H), 7.28 (m, 2H), 7.19
+
(
2
m, 3H); MS: m/z 586.01 (M ). Anal. Calcd for C H BrN S: C, 63.59; H,
3
1
17
6
.93; N, 14.35. Found: C, 63.74; H, 2.90; N, 14.45.
1
-(6,7-Dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-yl)-
4
-(4-methoxyphenyl)-3,6-diphenyl-1H-pyrazolo[3,4-b]pyridine-
1
5
-carbonitrile (7c)ꢀYield: 80%; mp 237–239°C; H NMR: δ 9.02 (s,
[
5] Kurumuthy, C.; Veeraswamy, B.; Sambasiva, R. P.; Santhosh, K.
G.; Shanthan, R. P.; Loka, R. V.; Venkateswara, R. J.; Narsaiah,
B. Synthesis of novel 1,2,3-triazole tagged pyrazolo[3,4-b]
pyridine derivatives and their cytotoxic activity. Bioorg. Med.
Chem. Lett. 2014, 24, 746–749.
1
H), 7.66 (m, 2H), 7.54 (m, 2H), 7.50 (m, 3H), 7.33 (m, 3H), 7.25 (m, 2H),
6
.83 (m, 2H), 3.76 (s, 3H), 3.46 (m, 2H), 3.08 (m, 2H), 2.40 (m, 2H); MS:
+
m/z 577.14 (M ). Anal. Calcd for C H N OS: C, 72.90; H, 4.19; N, 14.57.
35
24
6
Found: C, 72.77; H, 4.16; N, 14.48.
[
6] Chavva, K.; Pillalamarri, S.; Banda, V.; Gautham, S.;
Gaddamedi, J.; Yedla, P.; Kumar, C. G.; Banda, N. Synthesis
and biological evaluation of novel alkyl amide functionalized
trifluoromethyl substituted pyrazolo[3,4-b]pyridine derivatives
as potential anticancer agents. Bioorg. Med. Chem. Lett. 2013,
1
-(6,7-Dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-yl)-
3
,6-diphenyl-4-(p-tolyl)-1H-pyrazolo[3,4-b]pyridine-5-carboni-
1
trile (7d)ꢀYield 83%; mp 270–271°C; H NMR: δ 8.65 (s, 1H), 7.66 (m,
2
H), 7.55 (m, 2H), 7.51 (m, 3H), 7.33 (m, 3H), 7.25 (m, 2H), 7.10 (m, 2H),
3
.46 (m, 2H), 3.09 (m, 2H), 2.42 (m, 2H), 2.29 (s, 3H); MS: m/z 561.16
2
3, 5893–5895.
+
(
M ). Anal. Calcd for C H N S: C, 74.98; H, 4.31; N, 14.99. Found: C,
35 24 6
[7] El-Borai, M. A.; Rizk, H. F.; Beltagy, D. M.; El-Deeb, I. Y.
Microwave-assisted synthesis of some new pyrazolopyridines
and their antioxidant, antitumor and antimicrobial activities.
Eur. J. Med. Chem. 2013, 66, 415–422.
74.90; H, 4.27; N, 14.88.
4
-(4-Bromophenyl)-1-(6,7-dihydro-5H-cyclopenta[4,5]
thieno[2,3-d]pyrimidin-4-yl)-3,6-diphenyl-1H-pyrazolo[3,4-b]
[
8] El-Borai, M. A.; Rizk, H. F.; Abd-Aal, M. F.; El-Deeb, I. Y. Synthe-
sis of pyrazolo[3,4-b]pyridines under microwave irradiation in
multicomponent reactions and their antitumor and antimicro-
bial activities – Part 1. Eur. J. Med. Chem. 2012, 48, 92–96.
1
pyridine-5-carbonitrile (7e)ꢀYield 81%; mp 280–281°C; H NMR:
δ 8.63 (s, 1H), 7.65 (m, 2H), 7.53 (m, 5H), 7.50 (m, 2H), 7.40 (m, 3H),
7
.21 (m, 2H), 3.44 (m, 2H), 3.07 (m, 2H), 2.39 (m, 2H); MS: m/z 625.97
+
(
M ). Anal. Calcd for C H BrN S: C, 65.28; H, 3.38; N, 13.43. Found: C,
3
4
21
6
[9] Bozorov, K.; Zhao, J.-Y.; Elmuradov, B.; Pataer, A.; Aisa, H. A.
Recent developments regarding the use of thieno[2,3-d]
pyridine-4-one derivatives in medicinal chemistry, with a focus
on their synthesis and anticancer properties. Eur. J. Med.
Chem. 2015, 102, 552–573.
10] Dewal, M. B.; Wani, A. S.; Vidaillac, C.; Oupicky, D.; Rybak, M.
J.; Firestine, S. M. Thieno[2,3-d]pyrimidinedione derivatives as
antibacterial agents. Eur. J. Med. Chem. 2012, 51, 145–153.
11] Hafez, H. N.; Hussein, H. A. R.; El-Gazzar, A.-R. B. A. Synthesis
of substituted thieno[2,3-d]pyrimidine-2,4-dithione and their
S-glycoside analogues as potential antiviral and antibacterial
agents. Eur. J. Med. Chem. 2010, 45, 4026–4034.
12] Alagarsamy, V.; Meena, S. Ramesh, K. V.; Solomon, V. R.;
Thirumurugan, K.; Dhanabal, K.; Murugan, M. Synthesis,
analgesic, anti-inflammatory, ulcerogenic index and antibac-
terial activities of novel 2-methylthio-3-substituted-5,6,7,8-
tetrahydrobenzo(b)thieno [2,3-d]pyridine-4(3H)-ones. Eur. J.
Med. Chem. 2006, 41, 1293–1300.
13] Abbas, S. E.; Abdel Gawad, N. M.; George, R. F.; Akar, Y. A.
Synthesis, antitumor and antibacterial activities of some novel
tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives. Eur. J.
Med. Chem. 2013, 65, 195–204.
6
5.40; H, 3.40; N, 13.39.
4
-(4-Methoxyphenyl)-3,6-diphenyl-1-(5,6,7,8-tetrahyd-
robenzo[4,5]thieno[2,3-d]pyrimi-din-4-yl)-1H-pyrazolo[3,4-b]
1
pyridine-5-carbonitrile (7f)ꢀYield 83%; mp 266–268°C; H NMR: δ
[
[
9
.08 (s, 1H), 7.93 (m, 2H), 7.50 (m, 3H), 7.27 (m, 3H), 7.15 (m, 4H), 6.77
(
m, 2H), 3.81 (s, 3H), 2.92 (m, 2H), 2.32 (m, 2H), 1.87 (m, 2H), 1.68 (m,
+
2
H); MS: m/z 591.19 (M ). Anal. Calcd for C H N OS: C, 73.20; H, 4.44;
3
6
26
6
N, 14.23. Found: C, 73.33; H, 4.47; N, 14.28.
4
4
-(4-Methoxyphenyl)-3,6-diphenyl-1-(thieno[3,2-d]pyrimidin-
-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (8a)ꢀYield 85%;
[
1
mp 264–265°C; H NMR: δ 8.89 (s, 1H), 8.15 (d, 1H, Jꢁ=ꢁ5.5 Hz), 7.72 (m,
4
H), 7.60 (d, 1H, Jꢁ=ꢁ5.5 Hz), 7.51 (m, 3H), 7.34 (m, 3H), 7.28 (m, 3H), 6.85
+
(
d, 2H, Jꢁ=ꢁ7.3 Hz), 3.77 (s, 3H); MS: m/z 537.23 (M ). Anal. Calcd for
C H N OS: C, 71.62; H, 3.76; N, 15.66. Found: C, 71.56; H, 3.73; N, 15.60.
32
20
6
[
References
[
1] Gouda, M. A. Synthesis of antioxidant evaluation of some new
pyrazolopyridine derivatives. Arch. Pharm. (Weinheim) 2012,
[14] Park, J. H.; Hong, S. Y.; Kim, J.; Lee, H. J.; Lee, H. H.; Kim, K. Y.;
Lee, S. W.; Oh, H.-M.; Rho, M. C.; Lee, B.-G.; et al. Convenient
synthesis of novel phenylpyrimido[1,2-c]thienopyrimidinones
as IL-6/STAT3 inhibitors. Heterocycles 2015, 91, 835–848.
[15] Lee, H. J.; Song, Y.-H. A facile one-pot synthesis of aryl-substituted
fused pyrimidinones. Heterocycl. Commun. 2016, 22, 59–62.
3
45, 155–162.
[
2] Foks, H.; Pancechowska-Ksepko, D.; Kedzia, A.; Zwolska, Z.;
Janowiec, M.; Augustynowicz-Kopec, E. Synthesis and antibacte-
rial activity of 1H-pyrazolo[3,4-b]pyrazine and–pyridine deriva-
tives. Farmaco 2005, 60, 513–517.
Brought to you by | University of Michigan
Authenticated
Download Date | 8/4/17 2:08 AM

J.W. Park and Y.-H. Song: Thienopyrimidine-pyrazolo[3,4-b]pyridine hybridsꢍꢁꢀꢀꢀꢍ285
[
[
[
16] Lee, S. W.; Oh, H.-M.; Rho, M. C.; Song, Y.-H. Thienotriazolopy-
[21] Viegas-Junior, C.; Danuello, A.; da Silva Bolzani, V.; Barreiro,
E. J.; Fraga, C. A. Molecular hybridization: a useful tool in the
design of new drug prototypes. Curr. Med. Chem. 2007, 14,
1829–1852.
[22] Song, Y.-H.; Son, H. Y. Synthesis of new sulfur-linked 1,2,4-tria-
zolothienopyrimidine and 1,2,4-triazolopyrazolopyrimidine
derivatives containing fused heterocyclic pyrimidines. J. Het-
erocycl. Chem. 2010, 47, 1183–1187.
rimidine derivatives inhibit STAT3 activation induced by IL-6.
Bull. Korean Chem. Soc. 2014, 35, 2570–2572.
17] Dodiya, D. K.; Trivedi, A. R.; Kataria, V. B.; Shah, V. H. Advances
in the synthesis of pyrazolo[3,4-b]pyridines. Curr. Org. Chem.
2012, 16, 400–417.
18] Jachak, M, N.; Avhale, A. B.; Ghotekar, B. K.; Kendre, D. B.;
Toche, R. B. Synthesis of pyrazolo[3,4-b]pyridines using ammo-
nium acetate as green reagent in multi-component reactions.
J. Heterocycl. Chem. 2008, 45, 1221–1224.
[23] Robba, M.; Lecomte, J.-M.; Cugnon De Sevricourt, M. Thien-
opyrimidines-II: Etude de la thieno[3,2-d]pyrimidine et de
quelques derives. Tetrahedron 1971, 27, 487–499.
[
[
19] Gunasekaran, P.; Indumathi, S.; Perumal, S. L-Proline-catalyzed
three-component domino reactions in the regioselective
synthesis of novel densely functionalized pyrazolo[3,4-b]
pyridines. RSC Adv. 2013, 3, 8318–8325.
[24] Su, W.-N.; Lin, T.-P.; Cheng, K.-M.; Sung, K.-C.; Lin, S.-K.; Wong,
F. F. An efficient one-pot synthesis of N-(1,3-diphenyl-1H-pyra-
zol-5-yl)amides. J. Heterocycl. Chem. 2010, 47, 831–837.
[25] Chen, G.-F.; Dong, X.-Y. Facile and selective synthesis of 2-sub-
stituted benzimidazoles catalyzed by FeCl /Al O . E-J. Chem.
20] Fan, L.; Yao, C.; Shu, M. Three-component synthesis of new
o-hydroxyphenyl-substituted pyrazolo[3,4-b]pyridines pro-
3
2
3
moted by FeCl . Heterocycl. Commun. 2016, 22, 63–67.
2012, 9, 289–293.
3
Brought to you by | University of Michigan
Authenticated
Download Date | 8/4/17 2:08 AM