An efficient synthesis of pyrazolo[3,4-b]pyrrolo[2,3-d]pyridines from 5-aminopyrazoles and cyclic β-keto ester

Article abstract of DOI:10.1002/jhet.5570450624

(Chemical Equation Presented) 5-Chloroethylpyrazolo[3,4-b]pyridines were synthesized by condensation of 5-aminopyrazoles with α-acetyl γ-butyrolactone followed by cyclization treating with phosphorous oxychloride. 5-Chloroethylpyrazolo[3,4-b]pyridines, th

Full text of DOI:10.1002/jhet.5570450624

Nov-Dec 2008
1711
An Efficient Synthesis of Pyrazolo[3,4-b]pyrrolo[2,3-d]pyridines
from 5-Aminopyrazoles and Cyclic ꢀ-Keto Ester
Raghunath B. Toche,* Bhausaheb K. Ghotekar, Dhananjay B. Kendre,
Muddassar A. Kazi, and Madhukar N. Jachak
Organic Chemistry Research Center, Department of Chemistry, K R. T. Arts, B. H. Commerce and A. M. Science
College, Gangapur Road, Nashik- 422002, (M. S.), India
e-mail. raghunath_toche@rediffmail.com
Received August 3, 2008
X
X
X
X
O
R
Cl
N
N
O
Cl
N
N
N
NH2
N
N
H
Me
N
N
N
Me
N
N
Me
X = Cl, Br, Me
5-Chloroethylpyrazolo[3,4-b]pyridines were synthesized by condensation of 5-aminopyrazoles with
ꢁ-acetyl ꢂ-butyrolactone followed by cyclization treating with phosphorous oxychloride. 5-Chloroethyl-
pyrazolo[3,4-b]pyridines, thus obtained, were then converted to the corresponded tricyclic pyrazolo[3,4-
b]-pyrrolo[2,3-d]pyridines by treating with some primary amines.
J. Heterocyclic Chem., 45, 1711 (2008).
INTRODUCTION
5-aminopyrazoles [23] for the synthesis of pyrazolo[3,4-
b]pyridines having intractable substitutions such as
4-chloro and 5-(2-chloroethyl) side chain, which may
increase the pharmacological activity and further facilitate
the synthesis of new molecules. Thus, a new class of
tricyclic heterocycles such as pyrazolo[3,4-b]pyrrolo[2,3-
d]pyridines were obtained due to these strategic
substitution by condensation with amino/thio compounds.
Pyrazolo[3,4-b]pyridine system has shown many
interesting biological and pharmacological applications
such as antitubercular activity [1,2], against gram positive
and negative bacteria [3] and ACTH (Adrenocorticotropic
hormone) releasing factor (CRF: Corticotrophin-releasing
factor) antagonist activity. CRF antagonists prove to be
effective in the treatment of a wide variety of stress-
related illnesses such as depression, gastrointestinal
diseases, anorexia nervosa, haemorrhaged stress, drug and
alcohol withdrawal symptom [4]. Pyrido[1,2-a]-
pyrimidines having 3-chloroethyl side chain also showed
interesting biological activities [5-8].
In our recent publication [9], some fused pyrimidines
were synthesized by condensation of the corresponding 2-
aminoheterocycles with ꢁ-formyl lactones. In our other
previous papers [10-12], pyrazolo[3,4-b]pyridines were
synthesized by Friendlander condensation of 5-amino-
pyrazole-4-carbaldehyde with various reactive methylene
compounds and the heterocyclic compounds with
chloroethyl side chain [13]. In literature the pyrazolo[3,4-
b]pyridines have been so far obtained by condensation of
aminopyrazoles with ꢁ,ꢀ-unsaturated compounds [14-18],
diethylethoxymethylenemalonate [19,20], active esters
[21], cyclic ketones [11,12] and amides [12]. In the
present paper, we have used the versatile cyclic
ꢀ-ketoester e.g. ꢁ-acetyl-ꢂ-butyrolactone [22] and
RESULTS AND DISCUSSION
The intermediates aminopyrazolodihydrofuranone 3,
(Scheme 1) were obtained by condensation reaction of 5-
aminopyrazoles 1 with ꢁ-acetyl-ꢂ-butyrolactone 2 in
toluene at reflux temperature in presence of catalytic
amount of p-toluene sulphonic acid using Dean Stark
apparatus. Here, the p-toluenesulphonic acid used as a
selective catalyst, protonates the oxygen of keto carbonyl
of lactone and subsequent attack of amino function yield
the enamine intermediates 3. The use of other acids such
as sulphuric acid, hydrochloric acid, acetic acid or
ammonium acetate or neat reaction conditions leads to
inseparable mixture of products. The compounds 3 were
characterized by IR, 1H nmr, mass spectroscopy and
elemental analysis. For instance IR of 3a showed lactone
carbonyl stretching at 1689 cm-1, NH at 3287 cm-1 and
1
(C=C) at 1597 cm-1. The H nmr of this compound in
CDCl3 showed a singlet at ꢃ 1.92, for methyl group, two

1712
R. B. Toche, B. K. Ghotekar, D. B. Kendre, M. A. Kazi, and M. N. Jachak
Vol 45
triplets were observed at ꢀ 2.83, (-CH2-) and ꢀ 4.35,
(-CH2O-) with J = 7 Hz. The broad singlet exchangeable
with D2O assigned for -NH appeared down field at ꢀ 9.93,
and the singlet at ꢀ 6.41 corresponding to C4H proton. The
aromatic protons showed expected chemical shifts and
splitting pattern. The mass spectra of 3a showed M+ and
M+2 at 379 and 381m/z due to presence of chlorine. The
elemental analysis of this compound was also in
agreement with the proposed structure. The obtained
occurred to yield compounds 7 and 8 (Scheme 2). While
with more basic solution using OEt/EtOH, substitution at
ꢁ
4-position as well as elimination of HCl from the ꢂ-
chloroethyl moiety yielded 6. These compounds were
characterized by spectral and analytical methods. The
band at 1591 cm-1 in IR spectrum of 6a shows presence of
C=C, and the signals at ꢀ 3.71 (2H, quartet) and ꢀ 1.12
1
(3H, triplet) with (J = 7 Hz) in H NMR spectrum shows
presence of O-CH2CH3. The doublet of doublet
corresponding to =CH2 protons at ꢀ 5.57 and 5.76 ppm, (J
= 5.3 Hz) and the multiplate corresponding to =CHR
proton were observed at ꢀ 6.70-6.84 ppm. The compound
4 on heating in DMF at 80-90 °C with sodium azide
yielded azido derivatives 7. This reaction was selective to
replace chlorine on ꢃ-position of pyridine ring [24], which
aminopyrazolodihydrofuranone
3
were cyclised by
refluxing in POCl3, which furnished a mixture of
compounds 4 and 5 (TLC check). The reaction mixtures
were separated readily by column eluting with toluene/
acetone (9:1) v/v to give about 75 % of 4 and 17 % of 5 as
colorless solids. The structures of 4 and 5 were
established by spectral and analytical data, the compound
4a showed absence of carbonyl and –NH stretching
frequency in IR, while compound 5a showed pyridine
carbonyl at 1629 cm-1 and –NH stretching frequency at
3433 cm-1. The 1H nmr of 5a in CDCl3 clearly showed the
presence of -NH as broad exchangeable singlet at ꢀ 11.50,
whereas this peak was absent for 4a. The mass spectrum
of 4a showed M+, M+2, M+4 and M+6 at 416, 418, 420
and 422 m/z respectively, due to presence of three
chlorine atoms and 5a showed M+, M+2 and M+4 at 398,
400 and 402 m/z due to presence of two chlorine atoms.
Further, elemental analyses were in agreement with the
proposed structures of 4a and 5a. On the basis of this
spectral and analytical data structure 4a was assigned to
1
is confirmed by H nmr spectra of compound 4 and 7,
where there is no considerable difference in the signals of
both compounds. The compound 7a showed IR
absorption peak at 2100 cm-1 for azide. The compound 4
when refluxed with ethylene glycol in presence of triethyl
amine gives nucleophilic aromatic substitution reaction on
pyridine ring to yield compound 8. The pyrazolo[3,4-
b]thieno[2,3-d]pyridine 9 were obtained in single step by
the reaction of thiourea and 4 in acetic acid in 65-70 %
yield.
The targeted new fused heterocyclic compounds pyra-
zolo[3,4-b]pyrrolo[2,3-d]pyridines 10 were successfully
synthesized in 75-85 % yield, from pyrazolo[3,4-b]-
pyridines 4 by neat reaction with primary amines. The
Scheme 1
X
X
X
X
Me
O
O
Cl
N
O
O
O
Cl
O
2
Cl
POCl3
N
N
N
N
H
Me
NH2
N
+
N
N
reflux, toluene
p-TsOH
12-15 hrs.
reflux, 4 hrs.
N
Me
N
N
H
Me
1a) X = Cl
1b) X = Br
1c) X = Me
3a,b,c
4a,b,c
5a,b,c
this compound i.e. 4-chloro-5-(2-chloroethyl)-3-(4-
chlorophenyl)-6-methyl-1-phenyl-1H-pyrazolo[3,4-b]-
aliphatic and aromatic nucleophilic substitution reactions
were facilitated due to presence of 4-chloro and
5-chloroethyl moieties on pyridine nucleus. The
pyridine and 5a assigned to this compound i.e. 5-(2-
Chloroethyl)-3-(4-chlorophenyl)-6-methyl-1-phenyl-1,7-
dihydro-4H-pyrazolo[3,4-b]pyridin-4-one. Analogously
compounds 4b, 4c and 5b, 5c were characterized and
assigned. The facile and well-documented nucleophilic
substitutions [19,20] in the 4-halopyrdine systems 4 were
also studied. The nucleophiles used in our study were
1
compounds 9 and 10 were characterized by IR, H NMR,
mass and elemental analysis given in experimental part.
The compound 10 showed bathchromic shift in UV due to
presence of substituted pyrrole as a donor and pyridine as
acceptor [25]. It was observed that compound 4a showed
ꢄ
max 362 nm, fluorescent at 394 nm while compound 10a
ꢁ
namely OC2H5, ꢂ-hydrxoyethyl system and azide. With
showed ꢄmax 374 nm, fluorescent at 404 nm and 10b
showed ꢄmax 392 nm, fluorescent at 417 nm (Scheme 2).
azide and ethylenegycol, only substitution at 4-position

Nov-Dec 2008
An Efficient Synthesis of Pyrazolo[3,4-b]pyrrolo[2,3-d]pyridines
1713
Scheme 2
X
X
OCH2CH3
N3
Cl
N
N
N
N
Me
N
N
Me
6a,b
7a,b
NaOEt, EtOH
reflux, 10-11 hrs.
X
X
NaN3, DMF, 80-90 °C, 2hrs.
OCH2CH2OH
Cl
Cl
Cl
HOCH2CH2OH, Et3N
reflux, 5 hrs.
N
N
N
N
N
Me
N
Me
8a,b
4a,b
R-NH2, 110-120 °C, 2-4 hrs.
X
Thiourea, AcOH
reflux, 2 hrs.
X
R
N
S
N
N
N
10a, R = Bn, X=Cl; 10b, R=Ph,X=Cl; 10c, o-ClC6H4, X=Cl;
10d, R=C6H4N,X=Cl; 10e, R=6-MeC6H3N, X=Cl
10f, R = Bn, X=Br; 10g, R=Ph, X=Br; 10h, R=o-ClC6H4, X=Br
Me
N
N
N
Me
9a,b
10i, R=C6H4N,X=Br; 10j, R=6-MeC6H3N, X=Br
10a-j
carried out on 0.2 mm silica gel 60 F 254 (Merck) plates using
UV light (254 and 366 nm) for detection. Common reagents-
grade chemicals are either commercially available and were
used without further purification or prepared by standard
literature procedures.
The methods described the facile route towards the
synthesis of new pyrazolo[3,4-b]pyridines having chloro-
ethyl side chain by using cyclic ꢀ-ketoesters and
5-aminopyrazoles. The work was further elaborated on
side chain and obtained new class of tricyclic heterocycles
such as pyrazolo[3,4-b]pyrrolo[2,3-d]pyridines.
General procedure for the synthesis of 3-(1-{[3-(4-Aryl)–1-
phenyl-1H-pyrazol-5-yl]amino}ethylidine)dihydrofuran-
2(3H)-one (3). A mixture of 5-ami- nopyrazole 1 (0.01 mole)
and ꢀ-acetyl-ꢁ-butyrolactone 2 (1.282 g, 1.078 mL 0.01 mole)
was refluxed in toluene (50 mL) in presence of catalytic amount
of p-toluene sulphonic acid at for 12-15 hrs. by using Dean Stark
apparatus (The reaction was monitored by separation of
equivalent amount of water), toluene was removed under
reduced pressure. The residue was dissolved in ethanol (20 mL),
heated for 15 min. under reflux and then the mixture was cooled
at rt. The solid that separated our was collected by suction
filtration, washed with ethanol, dried and recrystallized from
suitable solvent to furnished compound 3 in good yield.
EXPERIMENTAL
Melting points were determined on a Barnstead Electro
Thermal melting point apparatus, Mod. No. IA-9200 in open
capillary tubes and are uncorrected. 1H nmr Spectra were
recorded on Varian XL-300 spectrometer (300MHz). Chemical
shifts are reported in ppm from internal tetramethylsilane
standard and are given ꢁ-units. The solvents for NMR spectra
was duterio-chloroform unless otherwise stated. Infrared spectra
were taken on Shimadzu IR-408, instrument in potassium
bromide pellets unless otherwise stated. Elemental analyses
were performed on a Hosli CH-Analyzer and are within ± 0.3 of
the theoretical percentage. High-resolution mass spectra were
obtained with a Mat 112 Varian Mat Bremen (70 eV) mass
spectrometer. Column chromatography was carried out on silica
gel (SD Fine Chemicals, 60-80 mesh). Solutions were
concentrated in a rotary evaporator under reduced pressure. All
reactions were monitored by thin layer chromatography (TLC),
3-(1-{[3-(4-Chlorophenyl)–1-phenyl-1H-pyrazol-5-yl]amino}-
ethylidine)dihydrofuran-2(3H)-one (3a). This compound was
obtained as light yellow prism (ethanol), 3.39 g (90 %), mp 171-
172 °C; ir (potassium bromide): 3287s, 1689s, 1597m, 1444m,
1
1283w, 1230w, 956m, 834w cm-1; H nmr (CDCl3): ꢁ = 1.92 (s,
3H, CH3), 2.83 (t, J = 7.5 Hz, 2H, CH2), 4.31 (t, J = 7.1 Hz, 2H,
CH2), 6.41 (s, 1H, C4-H), 7.36-7.50 (m, 5H, Ar-H), 7.55 (d, J =
7.8 Hz, 2H, Ar-H), 7.76 (d, J = 8.4 Hz, 2H, Ar-H), 9.90 (s, 1H,
NH). MS: m/z (%) = 381 (30) [M+2], 379 (90) [M], 361 (40),

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R. B. Toche, B. K. Ghotekar, D. B. Kendre, M. A. Kazi, and M. N. Jachak
Vol 45
330 (10), 304 (15), 255 (07), 166 (10), 152 (13), 113 (50), 77
(100), 63 (10). Anal. Calcd. for C21H18ClN3O2: C, 66.40; H,
4.78; N, 11.06. found. C, 66.33; H, 4.49; N, 11.21.
7.53 (d, J = 8.2 Hz, 2H, Ar-H), 8.14 (d, J = 7.8 Hz, 2H, Ar-H).
Anal. Calcd. for C21H16BrCl2N3: C, 54.69; H, 3.50; N, 9.11.
found. C, 54.98; H, 3.78; N, 9.21.
3-(1-{[3-(4-Bromophenyl)-1-phenyl-1H-pyrazol-5-yl)amino}-
ethylidine)dihydrofuran-2(3H)-one (3b). This compound was
obtained as yellow needles (ethanol), 3.73 g (88 %), mp189-190
°C; ir (potassium bromide): 2993s, 1691s, 1641m, 1226w,
4-Chloro-5-(2-chloroethyl)-6-methyl-3-(4-methylphenyl)-1-
phenyl-1H-pyrazolo[3,4-b]pyridine (4c). This compound was
obtained as colorless needles (acetonitrile and ethanol), 2.57 g
(65 %), mp 145-146 ꢁC; ir (potassium bromide): 2919m, 1592m,
1500s, 1255m, 1149m, 1093w, 1020w, 915w, 760m, 688w cm-1.
1H nmr (CDCl3): ꢀ = 2.39 (s, 3H, ArCH3), 2.80 (s, 3H, CH3),
3.38 (t, J = 7.5 Hz, 2H, CH2), 3.68 (t, J = 7.3 Hz, 2H, CH2),
7.30-7.56 (m, 5H Ar-H), 7.60 (d, J = 8.3 Hz, 2H, Ar-H), 8.18 (d,
J = 7.8 Hz, 2H, Ar-H). Anal. Calcd. for C22H19Cl2N3: C, 66.67;
H, 4.83; N, 10.60. found. C, 66.90; H, 4.58; N, 10.83.
1
1230w, 1026m, 761w cm-1; H nmr (CDCl3): ꢀ = 1.89 (s, 3H,
CH3), 2.80 (t, J = 7.3 Hz, 2H, CH2), 4.28 (t, J = 7.1 Hz, 2H,
CH2), 6.38 (s, 1H, C4-H), 7.34-7.51 (m, 5H, Ar-H), 7.67 (d, J =
7.9 Hz, 2H, Ar-H), 7.70 (d, J = 8.5 Hz, 2H, Ar-H), 9.87 (s, 1H
NH). MS: m/z (%) = 429 (40) [M+4], 427 (90) [M+2], 425 (90)
[M], 404 (10), 378 (25), 362 (20), 338 (30), 313 (12), 259 (15),
197 (20), 157 (25), 117 (14), 91 (30), 77 (100). Anal. Calcd. for
C21H18BrN3O2: C, 59.45; H, 4.28; N, 9.90. found. C, 59.24; H,
4.42; N 10.10.
3-(1-{[3-(4-Methylphenyl)-phenyl-1H-pyrazol-5-yl]amino}-
ethylidine)dihydrofuran-(3H)-one (3c). This compound was
obtained as yellow needles (ethanol), mp 160-161 °C; ir
(potassium bromide): 2993s, 1695s, 1614m, 1126w, 1026w,
765w cm-1; 1H nmr (CDCl3): ꢀ = 1.89 (s, 3H, CH3), 2.37 (s, 3H,
Ar-CH3), 2.81 (t, J = 7.5 Hz, 2H, CH2), 4.29 (t, J = 7 Hz, 2H,
CH2), 6.40 (s, 1H, C4-H), 7.22-7.42 (m, 5H, Ar-H), 7.56 (d, J =
8.3 Hz, 2H, Ar-H), 7.71 (d, J = 8.1 Hz, 2H, Ar-H), 9.86 (s, 1H,
NH). Anal. Calcd. for C22H21N3O2: C, 73.52; H, 5.89; N, 11.69.
found. C, 73.39; H, 5.48; N, 11.10.
5-(2-Chloroethyl)-3-(4-chlorophenyl)-6-methyl-1-phenyl-
1,7-dihydro-4H-pyrazolo[3,4-b]pyridin-4one (5a). This
compound was obtained as light yellow prism (acetonitrile),
0.676 g (17 %), mp 225-226 °C; ir (potassium bromide): 3433m,
3072m, 1629s, 1496s, 1409w, 1249m, 995w, 931w, 837w,
1
750m, 690m cm-1; H nmr (CDCl3): ꢀ = 2.59 (s, 3H, CH3), 3.28
(t, J = 7.2 Hz, 2H, CH2), 4.87 (t, J = 7.3 Hz, 2H, CH2), 7.42-7.53
(m, 5H, Ar-H), 8.21 (d, J = 8.3 Hz, 2H, ArH), 8.31 (d, J =
7.9Hz, 2H, ArH) 11.50 (s, 1H, -NH). MS: m/z (%) = 402 (20)
[M+4], 400 (40) [M+2], 398 (90) [M], 363 (70), 361 (100), 359
(92), 344 (15), 325 (20), 280 (14), 172 (10). Anal. Calcd. for
C21H17Cl2N3O: C, 63.33; H, 4.30; N, 10.55. found. C, 63.56; H,
4.63; N 10.96.
3-(4-Bromophenyl)-5-(2-chloroethyl)-6-methyl-1-phenyl-
1,7-dihydro-4H-pyrazolo[3,4-b]pyridin-4-one (5b). This
compound was obtained as colorless needles (acetonitrile), 0.664
g (15 %) mp 240-241 °C; ir (potassium bromide): 3448m,
1629s, 1496s, 1298w, 1247m, 995w, 931w, 835w, 758m, 690m
cm-1.1H nmr (CDCl3): ꢀ = 2.57 (s, 3H, CH3), 3.25 (t, J = 7.2 Hz,
2H, CH2), 4.84 (t, J = 7.2 Hz, 2H, CH2), 7.41-7.59 (m, 5H, Ar-
H), 8.13 (d, J = 8.4 Hz, 2H, Ar-H), 8.34 (d, J = 8.1 Hz, 2H, Ar-
H) 11.54 (s, 1H, -NH). Anal. Calcd. For C21
General procedure for the Synthesis of 4-Chloro-5-(2-
chloroethyl)-3-(4-aryl)-6-methyl-1-phenyl-1H-pyrazolo[3,4-
b]pyridine (4) and 5-(Chloroethyl)-3-(4-aryl)-6-methyl-1-
phenyl-1,7-dihydro-4H-pyrazolo[3,4-b]pyridin-4one (5). The
aminopyrazolodihydrofuranone 3 (0.01mole) was refluxed in
phosphorous oxychloride (20 mL) until the end of the
exothermic reaction, which usually starts about 80–90 °C. The
mixture was then refluxed for further 4 hrs. Excess POCl3 was
removed under vacuum and the oily residue was solidified upon
treatment with ice-water neutralization with sodium carbonate
and stirring overnight. The separated product was then collected
by filtration and dried. TLC analysis showed two products in 95
% overall yield. These two solids were separated by column
chromatography (Merck silica gel 60 H, 5-40μm). Using toluene
and toluene / acetone (9:1) as eluent to afford pyrazolo[3,4-
b]pyridine 4 in 80 % and pyrazolo[3,4-b]pyridin-4-one 5 in 15
% yields. Respectively.
H17 N3BrClN3O: C, 56.97; H, 3.87; N, 9.49. found. C, 57.10;
H, 4.05; N, 9.25.
5-(2-Chloroethyl)-6-methyl-3-(4-methylphenyl)-1-phenyl-
1,7-dihydro-4H-pyrazolo[3,4-b]pyridin-4-one (5c). This
compound was obtained as light brown needles (acetonitrile),
0.453 g (12 %), mp 212-213 °C; ir (potassium bromide): 3448m,
1629s, 1496s, 1298w, 1247m, 995w, 935w, 837w, 758m, 692m.
1
cm-1; H nmr (CDCl3): ꢀ = 2.38 (s, 3H, Ar-CH3) 2.58 (s, 3H,
CH3), 3.30 (t, J = 7.1 Hz, 2H, CH2), 4.85 (t, J = 7.2 Hz, 2H,
CH2), 7.41-7.56 (m, 5H, Ar-H), 8.10 (d, J = 8.3 Hz, 2H, Ar-H),
8.38 (d, J = 8.1Hz, 2H, Ar-H) 11.48 (s, 1H, -NH). Anal. Calcd.
for C22H20ClN3O: C, 69.93; H, 5.33; N, 11.12. found. C, 70.10;
H, 5.57; N 10.97.
General procedure for the Synthesis of 3-(4-Aryl)-4-
ethoxy-6-methyl-1-phenyl-5-vinyl-1H-pyrazolo[3,4-b]pyridine
(6). To a stirred solution of 4 (0.01 mole), sodium ethoxide
[prepared by reacting 0.27 g , 11.5 mg atom of sodium with 50
mL of absolute ethanol] in ethanol was added and refluxed for
about 10-11 hrs. The reaction progress was monitored by TLC.
Excess of solvent was removed under reduced pressure.
Obtained solid was collected by filtration, washed with ethanol,
dried and recrystallized from the proper solvent to furnished
compound 6 in good yield.
4-Chloro-5-(2-chloroethyl)-3-(4-chlorophenyl)-6-m-ethyl-
1-phenyl-1H-pyrazolo[3,4-b]pyridine (4a). This compound
was obtained as colorless prisms (acetonitrile and ethanol), 3.24
g (78 %), mp163-164 ꢁC; ir (potassium bromide): 2918m,
1595m, 1500s, 1257m, 1147m, 1093w, 1018w, 906w, 756m,
1
686w cm-1; H nmr (CDCl3): ꢀ = 2.81 (s, 3H CH3), 3.39 (t, J =
7.2 Hz, 2H, CH2), 3.75 (t, J = 7.3 Hz, 2H, CH2), 7.44-7.54 (m,
5H, Ar-H), 7.69 (d, J = 8.2,Hz, 2H, Ar-H), 8.26 (d, J = 7.8, Hz,
2H, Ar-H). MS: m/z (%) = 422 (20) [M+6], 420 (60) [M+4], 418
(92) [M+2], 416 (90) [M], 366 (10), 255 (10), 111 (15), 85 (40),
71(60), 57 (100), 55 (30). Anal. Calcd. for C21H16Cl3N3: C,
60.52; H, 3.87; N, 10.08. found. C, 61.02; H, 3.68; N, 10.18.
3-(4-Bromophenyl)-4-chloro-5-(2-chloroethyl)-6-methyl-1-
phenyl-1H-pyrazolo[3,4-b]pyridine (4b). This compound was
obtained as colorless needles (acetonitrile and ethanol), 3.55 g
(77 %), mp 175-176 ꢁC; ir (potassium bromide): 2918m, 1595m,
1500s, 1255m, 1149m, 1093w, 1018w, 910w, 759m, 686w cm-1;
1H nmr (CDCl3): ꢀ = 2.82 (s, 3H, CH3), 3.40 (t, J = 7.2 Hz, 2H,
CH2), 3.70 (t, J = 7.3 Hz, 2H, CH2), 7.29-7.48 (m, 5H, Ar-H),
3-(4-Chlorophenyl)-4-ethoxy-6-methyl-1-phenyl-5-vinyl-
1H-pyrazolo[3,4-b]pyridine (6a). This compound was obtained
as colorless needles (ethanol), 2.45 g (63 %) mp 101-102 °C; ir
(potassium bromide): 1745w, 1591s, 1500s, 1342w, 1278w,

Nov-Dec 2008
An Efficient Synthesis of Pyrazolo[3,4-b]pyrrolo[2,3-d]pyridines
1715
997m, 837m, 758w, 690m cm-1; 1H nmr (CDCl3): ꢀ = 1.12 (t, J =
6.7 Hz, 3H, ethoxy CH3) 2.72 (s, 3H, CH3), 3.71 (q, J = 6.7 Hz,
2H, ethoxy OCH2), 5.57 (dd, 2H, =CH2), 6.70-6.84 (m, 1H,
=CHR), 7.31-7.50 (m, 5H, Ar-H), 7.98 (d, J = 8.1 Hz, 2H, Ar-
H), 8.31 (d, J = 7.8 Hz, 2H, Ar-H). Anal. Calcd. for
C23H20ClN3O: C, 70.85; H, 5.17; N, 10.78. found. C, 70.58; H,
5.49; N, 11.01.
%), mp 147-148 °C; ir (potassium bromide): 3430s, 2950m,
3390w, 2916w, 1595w, 1498w, 1452m, 1301w, 1145m, 1093w,
1
837s, 759s, 692m cm-1; H nmr (CDCl3): ꢀ = 2.81 (s, 3H, CH3),
3.23 (t, J = 7.2 Hz, 2H, CH2), 3.55 (t, J = 7.5 Hz, 2H, CH2),
3.67-3.73 (m, 4H, -OCH2-CH2-OH), 7.28-7.53 (m, 5H, Ar-H),
7.67 (d, J = 8.4 Hz, 2H, Ar-H), 8.26 (d, J = 7.8 Hz, 2H, Ar-H)
Anal. Calcd. for C23H21Cl2N3O2: C, 62.45; H, 4.79; N, 9.50.
found. C, 62.64; H, 5.10; N, 9.95.
3-(4-Bromophenyl)-4-ethoxy-6-methyl-1-phenyl-5-vinyl-
1H-pyrazolo[3,4-b]pyridine (6b). This compound was obtained
as colorless needles (ethanol), 2.51 g (58 %) mp 109-111 °C; ir
(potassium bromide): 1746w, 1592s, 1504s, 1342w, 1278w,
997m, 838m, 758w, 692m cm-1; 1H nmr (CDCl3): ꢀ = 1.11 (t, J =
6.2 Hz, 3H, ethoxy CH3) 2.74 (s, 3H, CH3), 3.74 (q, J = 6.1 Hz,
2H, ethoxy OCH2), 5.59 (dd, 2H, =CH2), 6.71-6.80 (m, 1H,
=CHR), 7.33-7.53 (m, 5H, Ar-H), 7.96 (d, J = 8.3 Hz, 2H, Ar-
H), 8.30 (d, J = 8 Hz, 2H, Ar-H). Anal. Calcd. for C23H20BrN3O:
C, 63.60; H, 4.64; N, 9.67. found. C, 63.33; H, 4.84; N, 9.39.
General procedure for the synthesis of 4-Azido-5-(2-
chloroethyl)-3-(4-aryl)-6-methyl-1-phenyl-1H-pyrazo- lo[3,4-
b]pyridine (7). To a stirred solution of 4 (0.01 mole) in
DMF/H2O (9:1) the sodium azide (2.60 g, 0.04 mole) was added
and temperature was raised slowly to 80 °C. The mixture was
kept at this temperature for about 2 hrs. until TLC showed no
more starting material. The temperature was then raised to 110
°C for 1h. Then the solvent was removed under reduced pressure
to give an oily residue that was poured in ice-cold water and
stirred for 1h. The solid obtained was collected by filtration,
washed with water, dried and recrystallized from the proper
solvent to furnished compound 7 in 40-45 % yield.
2-{[3-(Bromophenyl)-5-(2-chloroethyl)-6-methyl-1-phenyl-
1H-pyrazolo[3,4-b]pyridin-4-yl]oxy}ethanol (8b).
This
compound was obtained as colorless prisms (ethanol), 3.06 g (63
%), mp 138-139 °C; ir (potassium bromide): 3430s, 2950m,
3390w, 2916w, 1595w, 1498w, 1452m, 1301w, 1145m, 1093w,
1
837s, 759s, 692m cm-1; H nmr (CDCl3): ꢀ = 2.83 (s, 3H, CH3),
3.22 (t, J = 7.2 Hz, 2H, CH2), 3.54 (t, J = 7.5 Hz, 2H, CH2),
3.65-3.71 (m, 4H, -OCH2-CH2-OH), 7.25-7.51 (m, 5H, Ar-H),
7.65 (d, J = 8.4 Hz, 2H, Ar-H), 8.24 (d, J = 7.8 Hz, 2H, Ar-H).
Anal. Calcd. for C23H21BrClN3O2: C, 56.75; H, 4.35; N, 8.63.
found. C, 56.87; H, 4.10; N, 8.95.
General procedure for the Synthesis of 8-(4-Aryl)-4-
methyl-6-phenyl-3,6-dihydro-2H-pyrazolo[3,4-b]thieno[2,3-d]-
pyridine (9). A solution of 4 (0.01 mol) in acetic acid and
thiourea (2.283 g, 0.01mole) was refluxed for about 2 hrs,
(reaction was monitored by TLC). The excess of acetic acid was
removed under reduced pressure. The obtained residue was
dissolved in water (15 mL) under cooling. The resulting
precipitate was collected by suction filtration, washed with water
and dried and recrystallized from the suitable solvent to
furnished compound 9 in good yield.
4-Azido-5-(2-chloroethyl)-3-(4-chlorophenyl)-6-methyl-1-
phenyl-1H-pyrazolo[3,4-b]pyridine (7a). This compound was
obtained light brown prisms (acetonitrile), 1.69 g (40 %), mp
167-168°C; ir (potassium bromide): 3390w, 2916w, 2100 (N3) s,
1595w, 1498w, 1452m, 1301w, 1145m, 1093w, 837s, 759w,
8-(4-Chlorophenyl)-4-methyl-6-phenyl-3,6-dihydro-2H-
pyrazolo[3,4-b]thieno[2,3-d]pyridine (9a). This compound was
obtained as colorless prisms (ethanol), 2.49 g (65 %), mp 213-
214 °C; ir (potassium bromide): 2918m, 1595m, 1500s, 1257m,
1147m, 1093w, 1018w, 906w, 756m, 686w cm-1; 1H nmr
(CDCl3): ꢀ = 2.83 (s, 3H, CH3), 3.32 (t, J = 7.3 Hz, 2H, CH2),
3.50 (t, J = 7.1 Hz, 2H, CH2), 7.24-7.60 (m, 5H, Ar-H), 7.61 (d,
J = 8.3 Hz, 2H, Ar-H), 8.34 (d, J = 8.1 Hz, 2H, Ar-H). Anal.
Calcd. for C21H16ClN3S: C, 66.75; H, 4.27; N, 11.12. found. C,
66.97; H, 4.05; N, 10.90.
1
692m cm-1; H nmr (CDCl3): ꢀ = 2.80 (s, 3H, CH3), 3.23 (t, J =
7.2 Hz, 2H CH2), 3.51 (t, J = 7.5 Hz, 2H, CH2), 7.31-7.55 (m,
5H, Ar-H), 7.67 (d, J = 8.4 Hz, 2H, Ar-H), 8.25 (d, J = 7.8 Hz,
2H, Ar-H). Anal. Calcd. for C21H16Cl2N6: C, 59.59; H, 3.81; N,
19.85. found. C, 59.91; H, 4.10; N, 19.61.
4-Azido-3-(4-bromophenyl)-5-(2-chloroethyl)-6-methyl-1-
phenyl-1H-pyrazolo[3,4-b]pyridine (7b). This compound was
obtained as light brown needles (acetonitrile), 2.33 g (50 %),
mp181-182 °C; ir (potassium bromide): 3390w, 2916w, 2100
(N3) s, 1595w, 1498w, 1452m, 1301w, 1145m, 1093w, 837s,
8-(4-Bromophenyl)-4-methyl-6-phenyl-3,6-dihydro-2H-
pyrazolo[3,4-b]thieno[2,3-d]pyridine (9b). This compound was
obtained as colorless prisms (ethanol), 2.44 g (70 %), mp 225-
226 °C; ir (potassium bromide): 2918m, 1595m, 1500s, 1257m,
1147m, 1093w, 1018w, 906w, 756m, 686w cm-1; 1H nmr
(CDCl3): ꢀ = 2.84 (s, 3H, CH3), 3.31 (t, J = 7.3 Hz, 2H, CH2),
3.48 (t, J = 7.1 Hz, 2H, CH2), 7.25-7.62 (m, 5H, Ar-H), 7.59 (d,
J = 8.3 Hz, 2H, Ar-H), 8.32 (d, J = 8.1 Hz, 2H, Ar-H). Anal.
Calcd. for C21H16BrN3S : C, 59.72; H, 3.82; N, 9.95. found. C,
59.41; H, 4.05; N, 10.11.
1
759w, 692m cm-1; H nmr (CDCl3): ꢀ = 2.79 (s, 3H, CH3), 3.25
(t, J = 7.2 Hz, 2H, CH2), 3.53 (t, J = 7.5 Hz, 2H, CH2), 7.35-7.58
(m, 5H, Ar-H), 7.69 (d, J = 8.4 Hz, 2H, Ar-H), 8.27 (d, J = 7.8
Hz, 2H, Ar-H). Anal. Calcd. for C21H16BrClN6: C, 53.92; H,
3.45; N, 17.97. found. C, 53.65; H, 3.69; N, 18.10.
General procedure for the Synthesis of 2-{[5-(2-
Chloroethyl)-3-(4-aryl)-6-methyl-1-phenyl-1H-pyrazolo[3,4-b]-
pyridin-4-yl]oxy}ethanol (8). A solution of compound 4 (0.01
mole) in ethylene glycol (10 mL) was refluxed in presence of
triethyl amine (0.5 mL) as a catalyst for about 5 hrs, (the
reaction was monitored by TLC). The excess of ethylene glycol
was removed under reduced pressure. The solid obtained on
adding ethanol was collected by filtration, washed with ethanol,
dried and recrystallized from the proper solvent to afford 8 in
good yield.
General procedure for the Synthesis of 1-Phenyl-8-(4-
aryl)-4-methyl-6-phenyl-1,2,3,6-tetrahydropyrazolo[3,4-b]-
pyrrolo[2,3-d]pyridine (10). A mixture of 4 (0.01 mole) and
primary aliphatic or aromatic amines (0.04 mole) was heated at
110-120 °C. for about 2 h, until TLC showed no more starting
material. Then the mixture was cooled at 20 °C, after cooling
methanol (20 mL) was added and the resulting solid was
collected by suction filtration, washed with methanol, dried and
recrystallized from the suitable solvent to furnished compound
10 in good yield.
2-{[5-(2-Chloroethyl)-3-(4-chlorophenyl)-6-methyl-1-
phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl]oxy}ethanol (8a). This
compound was obtained as colorless prisms (ethanol), 2.47 g (56
1-Benzyl-8-(4-chlorophenyl)-4-methyl-6-phenyl-1,2,3,6-
tetrahydropyrazolo[3,4-b]pyrrolo[2,3-d]pyridine (10a). This
compound was obtained as colorless prisms (ethanol), 4.01 g (89

1716
R. B. Toche, B. K. Ghotekar, D. B. Kendre, M. A. Kazi, and M. N. Jachak
Vol 45
%) mp150-151 °C; ir (potassium bromide): 2918m, 1743m,
1595s, 1500s, 1257m, 1147, 1093m, 1018m, 906m, 756w, 686m
cm-1; 1H nmr (CDCl3): ꢀ = 2.50 (s, 3H, CH3), 3.06 (t, J = 7.3 Hz,
2H, CH2), 3.50 (t, J = 7.1 Hz, 2H, CH2), 4.14(s, 2H, Ar-CH2),
6.98-7.06 (m, 5H, Ar-H), 7.24 (d, J = 8.2 Hz, 2H, Ar-H), 7.43-
7.49 (m, 5H, Ar-H), 8.29 (d, J = 8.3 Hz, 2H, Ar-H). MS: m/z
(%) = 452 (90) [M+2], 450 (100) [M], 447 (20), 359 (25), 324
(35), 186 (20), 167 (20), 139 (10), 123 (30), 111 (15), 91 (90),
77 (80), 65 (60). Anal. Calcd. for C28H23ClN4: C, 74.57; H, 5.14;
N, 12.42. found. C, 74.67; H, 4.88; N, 12.69.
cm-1; 1H nmr (CDCl3): ꢀ = 2.49 (s, 3H, CH3), 3.04 (t, J = 7.3 Hz,
2H, CH2), 3.48 (t, J = 7.1 Hz, 2H, CH2), 4.13(s, 2H, Ar-CH2),
6.95-7.08 (m, 5H, Ar-H), 7.25 (d, J = 8.2 Hz, 2H, Ar-H), 7.42-
7.50 (m, 5H, Ar-H), 8.28 (d, J = 8.3 Hz, 2H, Ar-H). Anal. Calcd.
for C28H23BrN4: C 67.88, H 4.68, N 11.31; found. C 67.58, H
4.47, N 11.03.
8-(4-Bromophenyl)-4-methyl-1,6-diphenyl-1,2,3,6-tetra-
hydropyrazolo[3,4-b]pyrrolo[2,3-d]pyridine (10g). This
compound was obtained as light green prisms (ethanol and
DMF) 3.70 g (77 %), mp 216-217 °C; ir (potassium bromide):
2918m, 1743m, 1595s, 1500s, 1257m, 1147, 1093m, 1018m,
906m, 756w, 686m cm-1.1H nmr (CDCl3): ꢀ = 2.57 (s, 3H, CH3),
3.22 (t, J = 7.1 Hz, 2H, CH2), 4.21 (t, J = 7.3 Hz, 2H, CH2),
6.76-6.92 (m, 5H, Ar-H), 7.26-7.47 (m, 5H, Ar-H), 7.47 (d, J =
7.5 Hz, 2H, Ar-H), 8.32 (d, J = 7.5 Hz, 2H, Ar-H). Anal. Calcd.
for C27H21BrN4: C, 67.37; H, 4.40; N, 11.64. found. C, 67.61; H,
4.63; N, 11.36.
8-(4-Chlorophenyl)-4-methyl-1,6-diphenyl-1,2,3,6-tetra-
hydropyrazolo[3,4-b]pyrrolo[2,3-d]pyridine (10b). This
compound was obtained as light green prisms (ethanol and
DMF), 3.58 g (82 %), mp 212-213 °C; ir (potassium bromide):
2918m, 1743m, 1595s, 1500s, 1257m, 1147, 1093m, 1018m,
1
906m, 756w, 686m cm-1; H nmr (CDCl3): ꢀ = 2.56 (s, 3H,
CH3), 3.21 (t, J = 7.1 Hz, 2H, CH2), 4.20 (t, J = 7.3 Hz, 2H,
CH2), 6.74-6.90 (m, 5H, Ar-H), 7.24-7.45 (m, 5H, Ar-H), 7.48
(d, J = 7.5 Hz, 2H, Ar-H), 8.31 (d, J = 7.5 Hz, 2H, Ar-H). MS:
m/z (%) = 438 (80) [M+2], 436 (100) [M], 419 (20), 399 (25),
361 (35), 298 (20), 255 (20), 218 (10), 200 (30), 192 (15), 179
(30), 152 (35), 111 (10), 91 (10), 77 (60), 65 (15). Anal. Calcd.
for C27H21ClN4: C, 74.22; H, 4.84; N, 12.82. found. C, 74.49; H,
5.05; N, 12.68.
1-(2-Chlorophenyl)-8-(4-chlorophenyl)-4-methyl-6-phenyl-
1,2,3,6-tetrahydropyrazolo[3,4-b]pyrrolo[2,3-d]pyridine (10c).
This compound was obtained as light green prisms (ethanol and
DMF), 3.67 g (78 %), mp 223-224 °C; ir (potassium bromide):
2918m, 1743m, 1595s, 1500s, 1257m, 1147, 1093m, 1018m,
906m, 756w, 686m cm-1. 1H nmr (CDCl3): ꢀ = 2.57 (s, 3H, CH3),
3.26 (t, J = 8.4 Hz, 2H, CH2), 4.86 (t, J = 8.4 Hz, 2H, CH2),
6.23-7.51 (m, 9H Ar-H), 8.20 (d, J = 7.8 Hz, 2H, Ar-H), 8.34 (d,
J = 7.8 Hz, 2H, Ar-H). Anal. Calcd. for C27H20Cl2N4: C, 68.80;
H, 4.28; N, 11.89. found. C, 69.09; H, 4.41; N, 12.10.
8-(4-Bromophenyl)-1-(2-chlorophenyl)-4-methyl-6-phenyl-
1,2,3,6-tetrahydropyrazolo[3,4-b]pyrrolo[2,3-d]pyridine (10f).
This compound was obtained as light green prisms (DMF), 4.07
g (79 %), mp 212-213 °C; ir (potassium bromide): 2918m,
1743m, 1595s, 1500s, 1257m, 1147, 1093m, 1018m, 906m,
1
756w, 686m cm-1; H nmr (CDCl3): ꢀ = 2.58 (s, 3H CH3), 3.28
(t, J = 8.4 Hz, 2H, CH2), 4.87 (t, J = 8.4 Hz, 2H, CH2), 6.22-7.55
(m, 9H Ar-H), 8.20 (d, J = 7.8 Hz, 2H, Ar-H), 8.33 (d, J = 7.8
Hz, 2H, Ar-H). Anal. Calcd. for C27H20BrClN4: C, 62.87; H,
3.91; N, 10.86. found. C, 62.63; H, 4.16; N, 11.09.
8-(4-Bromophenyl)-4-methyl-6-phenyl-1-pyridin-2-yl-1,2,
3,6-tetrahydropyrazolo[3,4-b]pyrrolo[2,3-d]pyridine (10i).
This compound was obtained as light green prisms (ethanol and
DMF), 3.47 g (72 %), mp. 189-190 °C; ir (potassium bromide):
2918m, 1743m, 1595s, 1500s, 1257m, 1147, 1093m, 1018m,
906m, 756w, 686m cm-1. 1H nmr (CDCl3): ꢀ = 2.60 (s, 3H, CH3),
3.26 (t, J = 7.5 Hz, 2H, CH2), 4.88 (t, J = 7.3 Hz, 2H, CH2),
7.26-7.55 (m, 9H, Ar-H), 8.23 (d, J = 8.4 Hz, 2H, Ar-H), 8.36
(d, J = 8.1 Hz, 2H, Ar-H). Anal. Calcd. for C26H20BrN5: C 64.74,
H 4.18, N 14.52; found. C 64.35, H 3.89, N 14.74.
8-(4-Chlorophenyl)-4-methyl-6-phenyl-1-pyridin-2-yl-1,2,
3,6-tetrahydropyrazolo[3,4-b]pyrrolo[2,3-d]pyridine (10d).
This compound was obtained as light green prisms (ethanol and
DMF), 3.24 g (74 %) mp.182-183 °C; ir (potassium bromide):
2918m, 1743m, 1595s, 1500s, 1257m, 1147, 1093m, 1018m,
8-(4-Bromophenyl)-4-methyl-1-(6-methylpyridin-2-yl)-6-
phenyl-[3,4-b]pyrrolo[2,3-d]pyridine (10j). This compound
was obtained as light green prisms (ethanol and DMF) mp. 205-
206 °C; ir (potassium bromide): 2918m, 1743m, 1595s, 1500s,
1
906m, 756w, 686m cm-1; H nmr (CDCl3): ꢀ = 2.57 (s, 3H,
CH3), 3.26 (t, J = 8.4 Hz, 2H, CH2), 4.86 (t, J = 8.4 Hz, 2H,
CH2), 6.23-7.51 (m, 9H, Ar-H), 8.20 (d, J = 7.8 Hz, 2H, Ar-H),
8.34 (d, J = 7.8 Hz, 2H, Ar-H). MS: m/z (%) = 439 (80) [M+2],
437 (100) [M+], 422 (10), 410 (25), 395 (20), 359 (30), 283
(12), 258 (15), 220 (20), 201 (65), 193 (14), 111 (30), 91 (10),
77 (60) 65 (10), 44 (90). Anal. Calcd. for C26H20ClN5: C, 71.31;
H, 4.60; N, 15.99. found. C, 71.62; H, 4.31; N, 16.16.
1
1257m, 1147, 1093m, 1018m, 906m, 756w, 686m cm-1. H nmr
(CDCl3): ꢀ = 2.32 (s, 3H, ArCH3), 2.61 (s, 3H, CH3), 3.23 (t, J =
7.2 Hz, 2H, CH2), 4.24 (t, J = 7.5 Hz, 2H, CH2), 7.25-7.46 (m,
8H, Ar-H), 7.46 (d, J = 7.8 Hz, 2H, Ar-H), 8.36 (d, J = 7.8 Hz,
2H, ArH). Anal. Calcd. for C27H22BrN5: C, 65.33; H, 4.47; N,
14.11. found. C, 65.56; H, 4.74; N, 13.96.
Acknowledgements. The authors are thankful to UGC, New
Delhi for the financial assistance, under the Major Research
Project. We thank Dr. V. Balsubramniyam, emeritus professor,
MGV Pharmacy College, Nashik for constant encouragement
and inspiration. The Authors also thanks authorities of NDMV
Samaj’s and KTHM College, Nashik for facilities.
8-(4-Chlorophenyl)-4-methyl-1-(6-methylpyridin-2-yl)-6-
phenyl-[3,4-b]pyrrolo[2,3-d] pyridine (10e). This compound
was obtained as light green prisms (DMF), 3.79 g (88 %),
mp.198-199 °C; ir (potassium bromide): 2918m, 1743m, 1595s,
1500s, 1257m, 1147, 1093m, 1018m, 906m, 756w, 686m cm-1.
1H nmr (CDCl3): ꢀ = 2.30 (s, 3H, Ar-CH3), 2.60 (s, 3H, CH3),
3.25 (t, J = 7.2 Hz, 2H, CH2), 4.22 (t, J = 7.5 Hz, 2H, CH2),
7.24-7.45 (m, 8H, Ar-H), 7.45 (d, J = 7.8 Hz, 2H, Ar-H), 8.35
(d, J = 7.8 Hz, 2H, Ar-H). Anal. Calcd. for C27H22ClN5: C 71.75,
H 4.91, N 15.50; found. C 71.96, H 5.12, N 15.68.
1-Benzyl-8-(4-bromophenyl)-4-methyl-6-phenyl-1,2,3,6-
tetrahydropyrazolo[3,4-b]pyrrolo[2,3-d]pyridine (10f). This
compound was obtained as colorless prisms (ethanol), 4.30 g (87
%), m.p.172-173 °C; ir (potassium bromide): 2918m, 1743m,
1595s, 1500s, 1257m, 1147, 1093m, 1018m, 906m, 756w, 686m
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An Efficient Synthesis of Pyrazolo[3,4-b]pyrrolo[2,3-d]pyridines
1717
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