Synthesis of polysubstituted pyrazolo[3,4-b]pyridine-3-carbohydrazide and pyrazolo[3,4-d]pyridazine derivatives

Article abstract of DOI:10.1002/jhet.1779

5-Amino-4-formyl pyrazole carboxylate gave facile reactions with malononitrile, hydrazine, and ketones in the presence of piperidine furnished substituted pyrazolo[3,4-b]pyridines and pyrazolo[3,4-b]quinolones. The pyridazine sulfonamides were obtained by the reaction of 5-chloro 4-formyl pyrazole carboxylate with sulfonamide derivatives.

Full text of DOI:10.1002/jhet.1779

Month 2014
Synthesis of Polysubstituted Pyrazolo[3,4-b]pyridine-3-Carbohydrazide
and Pyrazolo[3,4-d]pyridazine Derivatives
*
Dinesh C. Bhavsar, Prashant S. Nikam, Sachin A. Gangurde, and Raghunath B. Toche
Organic Chemistry Research Center, Department of Chemistry, K. R. T. Arts, B. H. Commerce and A. M. Science
College, Affiliated University of Pune, Gangapur Road, Nashik 422 002, Maharashtra, India
*
E-mail: raghunath_toche@rediffmail.com
Received February 27, 2012
DOI 10.1002/jhet.1779
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
O
Cl
Ph
N
N
O
N
H
O
O
O
N
N
N
N
N
Ph
17
Ph
19
O
(CH ) SO2NH2
2 n
O
N
O
N
O
H
Ph
N
N
N
Cl
Cl
N
12
Ph
10
O
O
H
N
N
N
N
NH2
N
NH
N
N
Ph
N
O
Ph
HN
Cl
NH
2
15
13
5-Amino-4-formyl pyrazole carboxylate gave facile reactions with malononitrile, hydrazine, and ketones
in the presence of piperidine furnished substituted pyrazolo[3,4-b]pyridines and pyrazolo[3,4-b]quinolones.
The pyridazine sulfonamides were obtained by the reaction of 5-chloro 4-formyl pyrazole carboxylate with
sulfonamide derivatives.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
C5-Amino and C4-formyl functional groups on pyrazole
nucleus facilitate the synthesis of a variety of active hetero-
cycles. Our previous report on the synthesis of pyrazolo-
pyridine-3-carboxylate using 5-amino-4-formyl pyrazole
[22] and the diverse synthetic applications of 5-amino-4-formyl
pyrazole in literature prompted us to explore the further
chemistry of ethyl-5-chloro-4-formyl-1-phenyl-1H-pyrazole-
3-carboxylate. Herein, we report the synthesis of new
multifunctional pyrazolopyridazine-7-one; pyrazolopyridine,
that is, 2–5, 8, and 9; and pyrazoloquinoline derivatives, that
is, 6 and 7.
Fused heterocycles are interesting compounds because of
their diverse bioactivity, for example, stimulating appetite,
decreasing locomotor activity and increasing pain sensitivity
[1,2]. They are used for technology upgradation [3].
Pyrazolo[3,4-b]quinolines show antiviral, antimicrobial
[4–7], asparasiticidic [8] and antimalarial activity [9]. The
quinoline derivatives were used as inhibitors of Herpes
simplex virus type 1 replication [10] and as activators of
Caspases and inducers of apoptosis [11]. Pyrazolo[3,4-b]
pyridines have been identified as potent inhibitors of glyco-
gen synthase kinase-3 [12], also used in photoluminescence
[13] and electroluminescence [14].
RESULTS AND DISCUSSION
Recently, 2,6-dihydropyrazolo[3,4-d]pyridin-7-one deri-
vatives have been identified as potential antitumor agents
and as cannabinoid receptor type-1 antagonists and inverse
agonists [15–17]. Pyrazolopyridines are promising candi-
dates because of their significant use in treatment of brain
disorders [18], coronary heart diseases [19], and viral
diseases [20]. Pyrazolo[3,4-d]pyridazine derivatives show
antibacterial and antifungal activities [21].
5-Amino-4-formyl pyrazole carboxylate 1 was obtained by
a two-step reaction on 5-chloro-4-formyl 10 by a known liter-
ature procedure [22]. The pyrazole 1 on cyclocondensation
with malononitrile followed by loss of water molecule furnish
fused 6-amino-5-cyano-1-phenyl-1H-pyrazolo[3,4-b]pyridine
carboxylate 2 in 65% yield. During reaction, separation of
water is not required because of high thermodynamic stability
and push–pull functionalities on compound 2.
© 2013 HeteroCorporation

D. C. Bhavsar, P. S. Nikam, S. A. Gangurde, and R. B. Toche
Vol 000
Further, functional group interconversion reaction on
carboxylate 2 with hydrazine furnishes carbohydrazide 3
in good yield (Scheme 1).
Recently, we have reported the synthesis of highly fluores-
cent pyrazolo[3,4-b]-pyrrolo-[2,3-d]-pyridines [23]. These
reports and our ongoing interest in this field prompted us to
synthesize new fluorescent pyrazolo[3,4-b]pyridines. Reac-
tive amino and formyl functional groups on pyrazole 1 have
increased the synthetic utility for the synthesis of a variety of
tricyclic heterocycles.
Thus, the reaction of pyrazole 1 with cyclic or acyclic
ketones such as cyclopentanone or 2-hydroxyacetophenone
in the presence of piperidine yielded pyrazolopyridines 4
and 8, respectively. Similar, reaction on compound 1 with
dimedone yielded pyrazoloquinoline 6. The carbohydrazide
derivatives 5, 7, and 9 were obtained by the reaction of
hydrazine or phenylhydrazine with compounds 4, 6, and
8, respectively. These synthesized compounds show high
fluorescence properties (Scheme 2).
Compound 10 is another valuable intermediate in this
series, used for the syntheses of polysubstituted sulfonamide
pyrazolopyridazines 12a–c in fair to good yields by conden-
sation with phenylhydrazine sulfonamides 11a–c in DMF.
Although the formyl and chloro groups are adjacent to each
other, the condensation selectively goes on the ester and
aldehyde confirmed by mass spectra of these compounds
(Scheme 3).
Similar reaction of compound 10 with hydrazine hydrate
yielded 3-chloro-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7
(6H)-one 13, which on treatment with ethyl bromoacetate
Scheme 1
O
O
O
CN
CN
RHNHN
RNHNH2 . H2O
CHO
EtO
EtO
CH2(CN)2
NH2
N
NH2
piperidine
EtOH
reflux, 3h
N
N
piperidine
EtOH
reflux, 4h
N
N
NH2
N
N
N
Ph
Ph
Ph
3a; R=H
2
1
3b; R=Ph
3a-b
65%
76-80%
Scheme 2
O
O
O
RHNHN
EtO
RNHNH2 . H2O
N
N
N
piperidine
EtOH
4h
N
N
piperidine
EtOH
4h
N
Ph
Ph
4
5a; R=H
5a-b
75-80%
5b; R=Ph
65%
O
O
O
O
O
O
RHNHN
EtO
N
RNHNH2 . H2O
N
N
1
N
N
N
piperidine
EtOH
3h
piperidine
EtOH
4h
Ph
Ph
7a-b
55%
7a; R=H
6
60%
7b; R=Ph
O
N
O
OH
O
HO
RHNHN
EtO
HO
RNHNH2 . H2O
N
N
N
N
N
piperidine
EtOH
4h
piperidine
EtOH
4h
Ph
Ph
8
9a-b
9a; R=H
60%
65-70%
9b; R=Ph
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Polysubstituted Pyrazolo[3,4-b]pyridine-3-Carbohydrazide
and Pyrazolo[3,4-d]pyridazine Derivatives
Scheme 3
O
O
(CH2)n-SO2NH2
O
[CH2]nSO2NH2
H2NHN
H
EtO
N
11a-c
N
N
Ph
N
N
Cl
N
DMF, K2CO3
stirred, 80 °C
Ph
Cl
4h
12(a-c)
45-60%
10
n
11,12
a
b
0
1
2
c
selectively yielded the N-alkylation product 14 instead of
o-alkylated product 14. The compound 14 showed IR stretch-
ing at 1650 and 1720 cmꢀ1 for amide and ester carbonyl,
respectively, indicating that compound 14 is N-alkylated.
Further, N-alkylated ethyl ester 14 on reaction with hydrazine
hydrate gave substitution at ester carbonyl and C3-Cl to give
compound 15 in 66% yield (Scheme 4).
Vilsmeier–Haack formylation of pyrazolo[3,4-b]quino-
line-3-carboxylate 6, which yielded a mixture of compounds
16 and 17 in 25 and 70% yields, respectively, were separated
by column chromatography eluting with toluene : acetone
(8:2). Tetracyclic compounds 18 and 19 were obtained by
the reaction of hydrazine hydrate and phenylhydrazine on
compound 17. Pyrazolopyridine 17 on reaction with two
moles of hydrazine hydrate converts ester to hydrazide and
also builds new pyrazole ring. Simultaneous condensation
with aldehyde and aromatic substitution with C5 chlorine
give tetracyclic compound 18 in 72% yield. However,
same reaction with phenylhydrazine chemoselectively gave
condensed tetracyclic compound 19 without converting
ester into hydrazide. It might be due to less neucleophilicity
of phenylhydrazine. All the new compounds were well
characterized by their IR, 1H NMR, 13C NMR, mass spectra,
and elemental analysis as given in the Experimental section
(Scheme 5).
CONCLUSION
5-Amino-4-formyl pyrazole carboxylate and 5-chloro-
4-formyl pyrazole carboxylate gave facile Friedlander
condensation with various ketones, hydrazines, and sulfona-
mides to yield new derivatives of pyrazolo[3,4-b]pyridine,
pyrazolo[3,4-b]quinolone, and pyrazolo[3,4-d]pyridazine
sulfonamide derivatives in good yields.
EXPERIMENTAL
General remarks.
Melting points were determined on a
Gallenkamp melting point apparatus. The 1H (300 MHz) and
13C (75 MHz) NMR spectra were recorded on a Varian XL-300
spectrometer. Chemical shifts were reported in ppm relative to
TMS, and multiplicities are given as s (singlet), bs (broad
singlet), d (doublet), t (triplet), q (quartet), or m (multiplet).
Infrared spectra were recorded as KBr pellets on a Shimadzu
FTIR-408 spectrophotometer. Mass spectra were recorded on a
Scheme 4
O
O
O
NH2NH2 . H2O
OEt
N
N
N
N
Br
piperidine
NH
N
EtO
N
Ph
N
Ph
10
O
DMF, K2CO3
EtOH
stirred, rt
4h
Cl
reflux, 3h
Cl
13
14
62%
71%
.
piperidine
reflux; 3h
NH2NH2 H2O,
EtOH
OEt
O
O
O
H
N
N
N
N
NH2
N
N
N
Ph
N
Ph
N
O
HN
H2N
Cl
14a
15
66%
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. C. Bhavsar, P. S. Nikam, S. A. Gangurde, and R. B. Toche
Vol 000
Scheme 5
H
N
N
O
H2NHN
H2NNH2.H2O
N
EtOH
N
N
reflux, 3h
Ph
O
18
Cl
Cl
O
O
H
72%
O
O
DMF/POCl3
6
N
N
Ph
stirred
90-95 °C
N
N
N
N
Ph
N
N
Ph
O
O
16
24-25%
PhNHNH2
17
65-70%
EtOH
reflux, 3h
N
N
N
Ph
19
75%
Shimadzu LC–MS: EI QP 2010A mass spectrometer with
ionization potential in percentage. Elemental analyses were
performed on Thermo Quest Flash 1112 Series EA analyzer.
Reactions were monitored by thin layer chromatography (TLC),
carried out on 0.2 mm silica gel 60F254 (Merck) plates using UV
light (254 and 366 nm) for detection. The compounds were
purified by column chromatography by using silica gel of 5–20 mm
(Merck, 60–120 mesh). Column dimension was 39 ꢁ 2cm2, and
elution volume used for each product was about 200–400 mL.
Common reagent grade chemicals either are commercially available
and were used without further purification or were prepared by
standard literature procedures [Chemicals were purchased from sd
Fine chemicals limited, Dr Annie Besant Rd, Bheem Nagar, Worli
7.34–7.57 (m, 5H, ArH), 8.58 (s, 1H, ArH), 9.94 (bs, 1H, NH);
MS (%) m/z: 309 (M+). Anal. Calcd for C14H11N7O (309.28): C,
54.37; H, 3.58; N, 31.70. Found C, 57.53; H, 3.48; N, 33.62.
6-Amino-5-cyano-N0,1-diphenyl-1H-pyrazolo[3,4-b]pyridine-
3-carbohydrazide (3b). Yield 0.48 g (80%) colorless needles;
m.p. 195–196ꢂC; IR (KBr) nmax: 3476, 2240, 1610, 1590,
1554 cmꢀ1 1H NMR (DMSO-d6, 300 MHz) d: 4.40 (bs, 2H,
;
NH2, D2O exchangeable), 7.25 (s, 1H, NH), 7.40–8.25
(m, 10H, ArH), 8.60 (s, 1H, ArH), 9.87 (bs, 1H, NH); MS (%)
m/z: 369 (M+). Anal. Calcd for C20H15N7O (369.38): C, 65.03;
H, 4.09; N, 26.54. Found C, 65.13; H, 4.15; N, 26.41.
Ethyl-1-phenyl-1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]
pyridine-3-carboxylate (4).
The mixture of compound 1
(200mg, 7 mmol), cyclopentanone (55mL, 6 mmol), and catalytic
amount of piperidine (0.2mL) in ethanol (20mL) was refluxed for
3–4 h (TLC check, toluene: acetone, 8:2). After cooling the
resultant reaction mixture to room temperature, the obtained solid
was collected by filtration, washed with ethanol, and recrystallized
from ethanol : DMF (5:1) to furnish colorless needles. Yield 1.39 g
Mumbai, MH 400030 from India(Maharashtra)].
Ethyl-6-amino-5-cyano-1-phenyl-1H-pyrazolo[3,4-b]pyridine-
3-carboxylate (2).
The reaction mixture of 5-amino-4-formyl
pyrazole 1 (200 mg, 7 mmol), malononitrile (50 mg, 8 mmol), and
catalytic amount of piperidine (0.5 mL) in ethanol (20mL) was
refluxed for 3–4 h (TLC check, toluene : acetone, 8:2). The solid
separated after cooling to room temperature was filtered by
suction and recrystallized from ethanol : DMF (8:2) that afforded
colorless needles. Yield 1.40 g (65%); m.p. 206–207ꢂC; IR (KBr)
(65%); m.p. 160–161ꢂC; IR (KBr) nmax: 1740, 1605, 1510cmꢀ1
;
1H NMR (CDCl3, 300 MHz) d: 1.43 (t, 3H, J = 6.8 Hz, CH3), 2.20
(m, 2H, CH2), 3.13 (m, 4H, 2CH2), 4.51 (q, 2H, J = 6.8 Hz,
OCH2), 7.17–8.32 (m, 5H, ArH), 8.44 (s, 1H, ArH); MS (%) m/z:
308 (M+1). Anal. Calcd for C18H17N3O2 (307.35): C, 70.34;
H, 5.58; N, 13.67. Found C, 70.40; H, 5.62; N, 13.47.
n
max: 3476, 3370, 2240, 1610, 1590, 1554 cmꢀ1 1H NMR
;
(CDCl3, 300MHz) d: 1.48 (t, J = 7.2 Hz, 3H, CH3), 4.60
(q, J = 7.2 Hz, 2H, OCH2), 5.40 (bs, 2H, NH2, D2O exchange),
7.20–8.10 (m, 5H, ArH), 8.60 (s, 1H, ArH); 13C NMR (DMSO-
d6, 75 MHz): 15.0, 62.1, 91.9, 108.6, 117.5, 122.8, 128.1, 130.1,
137.1, 139.1, 140.0, 152.4, 159.8, 161.7. Anal. Calcd for
C16H13N5O2 (307.31): C, 62.53; H, 4.26; N, 22.79. Found: C,
62.62; H, 4.33; N, 22.65.
General procedure for the synthesis of cyclopentapyrazolo
[3-e]pyridine-3-carboxylic acid hydrazide (5a–b).
The
compound 4 (500mg, 16mmol), hydrazine hydrate (0.9 mL,
18mmol), and catalytic amount of piperidine (0.3mL) in ethanol
(20 mL) were refluxed for 4 h, TLC check (toluene : acetone, 8:2).
After completion of reaction, it was cooled, and the precipitated
product was filtered, washed with cold ethanol, and recrystallized
General procedure for the synthesis of pyrazolo[3,4-b]
pyridine-3-carbohydrazide (3a–b).
pyrazolo[3,4-b]pyridine-3-carboxylate
The reaction mixture of
2
(500 mg, 16 mmol),
from DMF: ethanol (1:1).
1-Phenyl-1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]
hydrazine hydrate (0.9 mL, 18 mmol), and catalytic amount of
piperidine (0.3 mL) in ethanol (20 mL) was refluxed for 4 h
by monitoring the reaction with TLC (toluene : acetone, 8:2).
After completion of reaction, the reaction mixture was cooled to
0–5ꢂC, and the precipitated product was filtered, washed with
cold ethanol, and recrystallized in DMF : ethanol (1:5).
pyridine-3-carbohydrazide (5a).
yellow needles; m.p. 170–171ꢂC; IR (KBr) nmax: 3320, 3150,
2900,1640, 1615, 1580, 1540 cmꢀ1 1H NMR (DMSO-d6,
Yield 0.34 g (71%) pale
;
300 MHz) d: 2.01 (m, 2H, CH2), 3.10–3.20 (m, 4H, 2 ꢁ CH2),
4.01 (bs, 2H, NH2), 7.17–8.32 (m, 5H, ArH), 8.44 (s, 1H, CH),
10.01 (bs, 1H, NH); MS (%) m/z: 293 (M+). Anal. Calcd for
C16H15N5O (293.32): C, 65.52; H, 5.15; N, 23.88. Found C,
6-Amino-5-cyano-1-phenyl-1H-pyrazolo[3,4-b]pyridine-3-
carbohydrazide (3a).
Yield 0.36 g (76%) colorless needles;
m.p. 181–182ꢂC; IR (KBr) nmax: 3476, 3352, 2240, 1640, 1620,
1590, 1554 cmꢀ1; 1H NMR (DMSO-d6, 300 MHz) d: 4.61 (bs, 2H,
NH2, D2O exchangeable), 7.60 (bs, 2H, NH2, D2O exchangeable),
65.40; H, 5.22; N, 23.72.
N,1-Diphenyl-1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]
pyridine-3-carbohydrazide (5b). Yield 0.48 g (80%) pale yellow
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Polysubstituted Pyrazolo[3,4-b]pyridine-3-Carbohydrazide
and Pyrazolo[3,4-d]pyridazine Derivatives
needles; m.p. 189–190ꢂC; IR (KBr) nmax
:
3230, 1610,
13C NMR (DMSO-d6, 75 MHz) d: 15.1, 62.0, 115.2, 118.4, 119.6,
120.4, 122.2, 123.6, 128.9, 130.3, 130.5, 132.8, 133.1, 136.3,
138.7, 149.4, 157.9, 158.6, 162.0; MS (%) m/z: 359 (M+1). Anal.
Calcd for C21H17N3O3 (359.38): C, 70.18; H, 4.77; N, 11.69.
Found: C, 70.24; H, 4.58; N, 11.87.
General procedure for the synthesis of pyrazolo[3,4-b]
pyridine-3-carboxylic acid hydrazide derivatives (9a–b).
Compound 8 (500 mg, 14 mmol), hydrazine hydrate (1 mL,
20 mmol), and catalytic amount of piperidine (0.3 mL) in
ethanol were refluxed for 4 h (TLC check, toluene : acetone,
8:2). After completion of reaction, it was cooled to 0–5ꢂC.
The separated solid was filtered and recrystallized in
1590, 1554 cmꢀ1; 1H NMR (DMSO-d6, 300 MHz) d: 2.11 (m, 2H,
CH2), 3.01 (t, 2H, J=6.4Hz, CH2), 3.20 (t, 2H, J=6.4Hz, CH2),
7.17–8.32 (m, 10H, ArH), 8.44 (s, 1H, ArH), 7.2 (bs, 1H, NH),
10.01 (bs, 1H, NH); MS (%) m/z: 369 (M+). Anal. Calcd for
C22H19N5O (369.42): C, 71.53; H, 5.18; N, 18.96. Found C, 71.40;
H, 5.22; N, 18.72.
Ethyl-5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-1-phenyl-1H-
pyrazolo[3,4-b]quinoline-3-carboxylate (6).
The mixture of
compound 1 (200 mg, 7 mmol), dimedone (120mg, 7 mmol), and
catalytic amount of piperidine (0.2 mL) in ethanol (20 mL) was
refluxed for 3–4 h, TLC check (toluene: acetone, 8:2). The
reaction mixture was then cooled to room temperature, and the
obtained solid was collected by filtration, washed with ethanol,
and recrystallized from ethanol : DMF (8:2) to afford compound 6
as colorless needles. Yield 1.40g (60%); m.p. 204–206ꢂC; IR
DMF : ethanol (2:1).
6-(2-Hydroxyphenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-3-
carboxylic acid hydrazide (9a).
Yield 0.35 g (70%); m.p.
212–213ꢂC; IR (KBr) nmax: 3500, 3230, 1835, 1668 cmꢀ1
;
1H
(KBr) nmax: 2980, 1750, 1700, 1640, 1410 cmꢀ1 1H NMR
;
NMR (DMSO-d6,300 MHz) d: 4.64 (bs, 2H, NH2), 6.98–7.02
(m, 2H, ArH), 7.34–7.68 (m, 3H, ArH), 7.68–7.70 (m, 2H, ArH),
8.08 (d, J = 8.4 Hz, 1H, ArH), 8.17–8.29 (m, 2H, ArH), 8.08
(d, J = 8.4 Hz, 1H, ArH), 10.04 (bs, 1H, NH), 12.00 (bs, 1H, OH,
D2O exchangeable). Anal. Calcd for C19H15N5O2 (345.12): C,
66.08; H, 4.38; N, 20.28. Found: C, 66.24; H, 4.58; N, 20.35.
6-(2-Hydroxyphenyl)1-phenyl-1H-pyrazolo[3,4-b]pyridine-3-
carboxylic acid N-phenyl hydrazide (9b). Yield 0.32 g (65.17%);
m.p. 220–221ꢂC; IR (KBr) nmax: 3500, 1835, 1668 cmꢀ1; 1H NMR
(DMSO-d6, 300MHz) d: 6.93–7.88 (m, 5H, ArH), 7.10 (s, 1H,
NH), 6.98–7.02 (m, 2H, ArH), 7.34–7.68 (m, 3H, ArH), 7.68–7.70
(m, 2H, ArH), 8.17–8.29 (m, 3H, ArH), 8.08 (d, J= 8.4 Hz, 1H,
ArH), 10.2 (bs, 1H, NH), 11.90 (bs, 1H, OH). Anal. Calcd for
C25H19N5O2 (421.45): C, 71.25; H, 4.54; N, 16.62. Found: C,
71.32; H, 4.48; N, 16.78.
(CDCl3, 300 MHz) d: 1.19 (s, J = 6.8 Hz, 6H, 2 ꢁ CH3), 1.62
(q, J = 6.8Hz, 2H, OCH2), 2.62 (s, 2H, CH2), 3.13 (s, 2H, CH2),
4.60 (t, J = 6.8 Hz, 3H, CH3), 7.40–7.62 (m, 3H, ArH), 8.25
(m, 2H, ArH), 9.18 (s, 1H, C4H); MS (%) m/z: 364 (M + 1). Anal.
Calcd C21H21N3O3 (363.41): C, 69.41; H, 5.82; N, 11.56. Found
C, 69.33; H, 5.98; N, 11.42.
General procedure for the synthesis of tetrahydro-1H-pyrazolo
[3,4-b]quinolone-3-carboxylic acid hydrazide (7a–b). Compound
6 (500 mg, 16 mmol), hydrazine hydrate (1 mL, 20 mmol), and
catalytic amount of piperidine (0.3 mL) were refluxed for 4 h. The
reaction was monitored by TLC (toluene : acetone, 8:2). After
completion of the reaction, it was cooled to 0–5ꢂC, and the separated
solid was filtered and recrystallized from DMF : ethanol (2:1).
7,7-Dimethyl-5-oxo-1-phenyl-5,6,7,8-tetrahydro-1H-pyrazolo
General procedure for the synthesis of pyrazolo[3,4-d]
pyridazine-6-yl-benzenesulfonamide (12a–c). Ethyl 5-chloro-
[3,4-b]quinolone-3-carboxylic acid hydrazide (7a). Yield 0.32 g
(55.17%) pale yellow crystalline solid; m.p. 212–213ꢂC; IR (KBr)
1
max: 3150, 3340, 1654, 1540, 1410 cmꢀ1; H NMR (DMSO-d6,
4-formyl-1-phenyl-1H-pyrazolo-3-carboxylate 10 (500 mg,
18 mmol) was stirred with sulfonamide (400 mg, 21 mmol) at
70–80ꢂC in DMF for 4 h with potassium carbonate (200 mg,
1 mmol) to yield product 12a–c. The reaction was monitored
by TLC (toluene : acetone, 8:2). After completion of the
reaction, it was cooled, poured in ice-cold water, and stirred for
half an hour. The separated solid was filtered and recrystallized
n
300 MHz) d: 1.01 (s, 6H, 2CH3), 2.38 (s, 2H, CH2), 2.92 (s, 2H,
CH2), 4.59 (bs, 2H, NH2), 7.35–8.42 (m, 5H, ArH), 8.96 (s, 1H,
ArH), 9.89 (s, 1H, NH); MS (%) m/z: 349 (M+). Anal. Calcd for
C19H19N5O2 (349.39): C, 65.32; H, 5.48; N, 20.04. Found C,
65.22; H, 5.38; N, 20.14.
7,7-Dimethyl-5-oxo-1-phenyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-
b]quinolone-3-carboxylic acid N-phenylhydrazide (7b). Colorless
from DMF : ethanol (1:1).
needles, yield 0.32 g (55.17%); m.p. 202–203ꢂC; IR (KBr) nmax
:
4-(3-Chloro-7-oxo-2-phenyl-2,7-dihydro-6H-pyrazolo[3,4-d]
;
3340, 3250, 1660, 1540, 1421 cmꢀ1 1H NMR (DMSO-d6,
pyridazine-6-yl)benzene sulfonamide (12a).
Colorless
crystals, yield 0.41 g (57%); m.p. 187–188ꢂC; IR (KBr) nmax: 3350,
300 MHz) d: 1.32 (s, 6H, 2CH3), 2.42 (s, 2H, CH2), 2.92 (s, 2H,
CH2), 6.98–7.23 (m, 5H, ArH), 7.28 (s, 1H, NH), 7.45 (t, J=7.1Hz,
2H, ArH), 7.62 (t, J= 7.1 Hz, 2H, ArH), 8.21 (d, J=7.1Hz, 1H,
ArH), 8.90 (s, 1H, ArH), 9.8 (s, 1H, NH). Anal. Calcd for
C25H23N5O2 (425): C, 70.57; H, 5.45; N, 16.46. Found C, 70.45; H,
5.38; N, 16.54.
1
3340, 3140, 1723, 1630 cmꢀ1; H NMR (DMSO-d6, 300 MHz) d:
6.84 (d, J= 6.8 Hz, 2H, ArH), 7.38 (d, J= 6.8 Hz, 2H, ArH), 7.21
(m, 1H, ArH), 7.45 (s, 2H, NH2), 7.51 (d, J= 6 Hz, 2H, ArH),
8.05 (d, J = 6 Hz, 2H, ArH), 9.53 (s, 1H, ArH); MS (%) m/z:
(M+) 401. Anal. Calcd for C17H12ClN5O3S (401.83): C,
50.81; H, 3.01; N, 17.43. Found: C, 50.72; H, 3.12; N, 17.52.
1-[4-(3-Chloro-7-oxo-2-phenyl-2,7-dihydro-6H-pyrazolo[3,4-d]
Ethyl-6-(2-hydroxyphenyl)-1-phenyl-1H-pyrazolo[3,4-b]
pyridine-3-carboxylate (8). A mixture of 1 (200 mg, 7 mmol),
1-(2-hydroxyphenyl)ethanone (120 mg, 8 mmol), and catalytic
amount of piperidine (0.5 mL) in ethanol (15 mL) was refluxed
for 3–4 h (TLC check. toluene : acetone, 8:2). The reaction
mixture was then cooled to room temperature. The obtained
solid was collected by suction filtration, washed with ethanol,
and recrystallized from methanol. Colorless prisms. Yield 0.15 g
pyridazin-6-yl)phenyl]methanesulfonamide (12b).
crystals, yield 0.35 g (47%); m.p. 206–207ꢂC; IR (KBr) nmax
3350, 3340, 3140, 1723, 1630 cmꢀ1 1H NMR (DMSO-d6,
Colorless
:
;
300 MHz) d: 2.86 (s, 2H, CH2), 7.43 (bs, 2H, NH2), 7.60 (d, 2H,
J = 9.0 Hz, ArH), 7.8 (d, 2H, J= 9.0 Hz, ArH), 7.75–8.15 (m, 5H,
ArH), 7.79 (s, 1H, CH); MS (%) m/z: 415 (M+). Anal. Calcd for
C18H14ClN5O3S (415.85): C, 51.99; H, 3.39; N, 16.84. Found: C,
51.82; H, 3.52; N, 16.72.
(60%); m.p. 140–141ꢂC; IR (KBr) nmax: 3500, 1835, 1668 cm.ꢀ1
;
1H NMR (DMSO-d6, 300MHz) d: 1.43 (t, J = 6.8Hz, 3H, CH3),
4.45 (q, J = 6.8Hz, 2H, OCH2), 7.02 (t, J = 7.1Hz, 2H, ArH), 7.20
(t, J =7.1 Hz, 2H, ArH), 7.61 (d, 1H, J = 6.8 Hz, ArH), 8.00–8.13
(m, 5H, ArH), 8.3 (d, J = 6.8Hz, 1H, ArH), 11.90 (bs, 1H, OH);
2-[4-(3-Chloro-7-oxo-2-phenyl-2,7-dihydro-6H-pyrazolo[3,4-d]
pyridazin-6-yl)phenyl]methanesulfonamide (12c).
Colorless
crystals, yield 0.45g (53%); m.p. 217–218ꢂC; IR (KBr) nmax
:
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. C. Bhavsar, P. S. Nikam, S. A. Gangurde, and R. B. Toche
Vol 000
3340, 3348, 1835, 1730, 1668 cmꢀ1
;
1H NMR (DMSO-d6,
Ethyl 5-chloro-6-formyl-7,8-dihydro-7,7-dimethyl-1-phenyl-
1H-pyrazolo[3,4-b]quinoline carboxylate (17). Colorless
crystals, yield 0.72 g (72%); m.p. 197–198ꢂC; IR (KBr) nmax: 1737,
1707, 1594, 1557 cmꢀ1 1H NMR (CDCl3, 300MHz) d: 1.33
300 MHz) d: 1.90 (t, J = 1.5 Hz, 2H, CH2), 3.85 (t, J = 1.5 Hz, 2H,
CH2), 7.25 (bs, 2H, NH2), 8.21 (d, 2H, J = 8.7 Hz, ArH), 8.35 (d,
2H, J = 8.7 Hz, ArH), 7.61–7.75 (m, 5H, ArH), 7.85 (s, 1H, CH);
MS (%) m/z: 430 (M+). Anal. Calcd for C19H16ClN5O3S (429.88):
C, 53.09; H, 3.75; N, 16.29. Found: C, 53.12; H, 3.52; N, 16.33.
3-Chloro-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7(6H)-one
;
(s, 6H, 2ꢁ CH3), 1.53 (t, J= 7.2 Hz, 3H, CH3), 3.12 (bs, 2H, CH2),
4.58 (q, J= 7.2 Hz, 2H, CH2), 7.42–8.31 (m, 5H, ArH), 9.00 (s, 1H,
ArH), 10.46 (s, 1H, CHO). Anal. Calcd for C22H20ClN3O3 (409.12):
C, 64.47; H, 4.92; N, 10.25. Found: C, 64.65; H, 4.64; N, 10.52.
4,4-Dimethyl-7-phenyl-1,4,5,7-tetrahydro-1,2,6,7,8-pentaaza-
dicyclopenta[a,g]naphthalene-9-carboxylic acid hydrazide (18). To
a solution of compound 17 (500 mg, 12 mmol) and hydrazine
hydrate (0.7mL, 14mmol) in ethanol (20mL), catalytic amount of
piperidine (0.3mL) was added. The reaction mixture was refluxed
for 4 h, and the reaction was monitored with TLC
(toluene: acetone, 8:2). After completion of the reaction, the
mixture was cooled to 0–5ꢂC, and the separated solid was filtered
off and recrystallized from DMF: ethanol (1:5) to afford colorless
needles. Colorless crystals, yield 0.32g (72%), m.p. 213–214ꢂC;
(13).
Compound 10 (500mg, 18mmol), hydrazine hydrate
(1mL, 20mmol), and catalytic amount of piperidine (0.2 mL) in
ethanol (20 mL) were refluxed for 3–4 h. The reaction was
monitored with TLC (toluene : acetone, 8:2). After completion of
the reaction, it was cooled to room temperature. The separated
solid was filtered off and recrystallized from DMF: ethanol (1:1).
Colorless crystals, yield 0.31g (62%); m.p. 188–189ꢂC; IR (KBr)
n
max: 3150, 1835, 1730, 1668 cmꢀ1 1H NMR (DMSO-d6,
;
300 MHz) d: 7.4 (bs, 1H, NH),7.81 (s, 1H, CH), 7.32–8.25
(m, 5H, ArH); MS (%) m/z: 246 (M+ 100), 248 (M + 2, 33). Anal.
Calcd for C11H7ClN4O (246.65): C, 53.56; H, 2.86; N, 22.71.
Found: C, 53.72; H, 2.78; N, 22.85.
1
IR (KBr) nmax: 3427, 3296, 1668, 1595 cmꢀ1; H NMR (DMSO-
(3-Chloro-7-oxo-2-phenyl-3a,7-dihydropyrazolo[3,4-d]pyridazine-
6-yl)acetic acid ethyl ester (14). Compound 13 (500 mg, 20 mmol),
ethyl 2-bromoacetate (0.39 mL, 22 mmol), and potassium carbonate
(340 mg) was stirred at 70–80ꢂC in DMF for 4h. The reaction was
monitored by TLC (toluene : acetone, 8:2). It was then cooled, poured
to ice-cold water, and stirred for half an hour. The separated solid
was recrystallized from DMF : ethanol (1:1). Colorless crystals, yield
0.41 g (71%); m.p. 228–229ꢂC; IR (KBr) nmax: 1759, 1720 cmꢀ1; 1H
NMR (CDCl3, 300 MHz) d: 1.21 (q, J= 7.2 Hz, 2H, OCH2), 4.23
(t, J=7.2Hz, 3H, CH3), 4.96 (s, 2H, CH2), 7.52–7.82 (m, 5H, ArH),
8.21 (s, 1H, CH). Anal. Calcd for C15H13ClN4O3 (332.74): C, 54.14;
H, 3.94; N, 16.84. Found: C, 54.21; H, 3.88; N, 16.68.
d6, 300 MHz) d: 1.23 (s, 3H, CH3), 1.30 (s, 3H, CH3), 3.06
(s, 2H, CH2), 4.61 (bs, 2H, NH2), 6.75–7.97 (m, 5H, ArH),
8.23 (s, 1H, ArH), 8.64 (s, 1H, ArH), 10.03 (bs, 1H, NH),
12.51 (bs, 1H, NH). Anal. Calcd for C20H19N7 (373.41):
C, 64.33; H, 5.13; N, 26.26. Found: C, 64.25; H, 5.32;
N, 26.38.
4,4-Dimethyl-1,7-diphenyl-1,4,5,7-tetrahydro-1,2,6,7,8-pentaa-
zadicyclopent[a,g]naphthalene-9-carboxylic acid ethyl ester
(19). To a solution of compound 17 (500 mg, 12 mmol) and
phenyl hydrazine (128 mg, 2 mmol) in ethanol (20 mL),
catalytic amount of piperidine (0.3 mL) was added. The
reaction mixture was refluxed for 4 h, and the reaction was
monitored with TLC (toluene : acetone, 8:2). After completion
of the reaction, the mixture was cooled to 0–5ꢂC, and the
separated solid was filtered off and recrystallized from
DMF : ethanol (1:5) to afford colorless needles. Yield 0.72 g
(72%); m.p. 192–193ꢂC; IR (KBr) nmax: 2864, 2287, 1742,
2-(3-Hydrazinyl-7-oxo-2-phenyl-2H-pyrazolo[3,4-d]pyridazine-6
(7H)-yl)acetohydrazide (15).
To a solution of compound 14
(500mg, 16mmol) and phenyl hydrazine (210mg, 19 mmol) in
ethanol (20 mL), catalytic amount of piperidine (0.3mL) was
added. The reaction mixture was refluxed for 4 h, check TLC
(toluene : acetone, 8:2). After completion of the reaction, the
mixture was cooled to 0–5ꢂC, and the separated solid was filtered
off and recrystallized from DMF: ethanol (1:5) to afford colorless
1585, 1559 cmꢀ1 1H NMR (DMSO-d6, 300 MHz) d: 1.49
;
(s, 6H, 2ꢁ CH3), 1.52 (t, 3H, CH3), 3.14 (s, 2H, CH2), 4.56
(q, 2H, CH2), 7.26–7.55 (m, 10H, ArH), 8.31 (s, 1H, ArH),
8.77 (s, 1H, C4H). Anal. Calcd for C28H25N5O2 (463.53): C,
72.55; H, 5.44; N, 15.11. Found: C, 72.43; H, 5.38; N, 15.23.
needles. Yield 0.33g (66%); m.p. 215–216ꢂC; IR (KBr) nmax
:
3280, 3119, 1660, 1575, 1530 cmꢀ1 1H NMR (DMSO-d6,
;
300 MHz) d: 4.21 (bs, 2H, NH2), 4.56 (s, 2H, CH2), 4.69 (s, 2H,
NH2), 7.46–7.56 (m, 5H, ArH), 8.05 (bs, 1H, NH), 8.51 (bs, 1H,
CH), 9.16 (bs, 1H, NH). Anal. Calcd for C13H14N8O2 (314.3): C,
49.68; H, 4.48; N, 35.65. Found: C, 49.72; H, 4.52; N, 35.78.
Synthesis of pyrazolo[3,4-b]quinolin-3-carboxylate (16
Acknowledgments. The authors thank the CSIR, New Delhi,
India, for the financial support to this research project, University
of Pune for the spectral and analytical facilities, and the Principal
of KTHM College, Nashik, for the facilities.
and 17).
To a solution of compound 6 (2 mmol) in N,N-
dimethylformamide (0.77 mL, 10 mmol), phosphorous oxychloride
(0.56 mL, 6 mmol) was added in small portions at 0–5ꢂC with
stirring. This reaction mixture was stirred at 80–90ꢂC for 6 h and
then poured in ice-cold water (50 mL). The precipitated product
was collected by suction filtration, washed with water, and dried.
This solid showed two spots on TLC corresponding to two
compounds separated by column chromatography.
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