Novel synthetic protocol toward pyrazolo[3,4-h]-[1,6]naphthyridines via Friedlander condensation of new 4-aminopyrazolo[3,4-b]pyridine-5-carbaldehyde with reactive α-methylene ketones

Article abstract of DOI:10.1002/jhet.242

Novel pyrazolo[3,4-h][1,6]naphthyridine derivatives 6, 8, 9, 11, 13, and 15 have been synthesized by Friedlander condensation of new 4-amino-3-methyl-1- phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (o-aminoaldehyde) 4 with active methylene ketones, such as symmetric acetone 5a, monoalkylketones 5b-k, unsymmetrical dialkyl ketones 7a-b, p-bromophenylacetonitrile 10, β-ketoester 12a, β-ketoamide 12b, or diethyl malonate 14, respectively.

Full text of DOI:10.1002/jhet.242

March 2011
Novel Synthetic Protocol toward Pyrazolo[3,4-h]-
[1,6]naphthyridines via Friedlander Condensation of New
4-Aminopyrazolo[3,4-b]pyridine-5-carbaldehyde with Reactive
a-Methylene Ketones
295
Madhukar N. Jachak,* Sandeep M. Bagul, Muddassar A. Kazi,
and Raghunath B. Toche
Organic Chemistry Research Center, Department of Chemistry, K.R.T. Arts, B. H. Commerce and
A. M. Science College, Nashik 422002, Maharashtra, India
*E-mail: mnjachak@hotmail.com
Received July 14, 2009
DOI 10.1002/jhet.242
Published online 3 December 2010 in Wiley Online Library (wileyonlinelibrary.com).
Novel pyrazolo[3,4-h][1,6]naphthyridine derivatives 6, 8, 9, 11, 13, and 15 have been synthesized by
Friedlander condensation of new 4-amino-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde
(o-aminoaldehyde) 4 with active methylene ketones, such as symmetric acetone 5a, monoalkylketones
5b–k, unsymmetrical dialkyl ketones 7a–b, p-bromophenylacetonitrile 10, b-ketoester 12a, b-ketoamide
12b, or diethyl malonate 14, respectively.
J. Heterocyclic Chem., 48, 295 (2011).
INTRODUCTION
ester functionality were ortho to each other. In this work,
we have synthesized a new pyrazolo[3,4-b]pyridine in
which ester group was replaced by aldehyde and Fried-
lander condensation performed on it, with reactive a-meth-
ylenes to obtain title compounds in high yield (66–81%).
Pyrazole derivatives and heterocycle-annelated pyra-
zoles have wide spectrum of interesting agricultural and
various biological activities [1–4]. Naphthyridine deriva-
tives constitute an important class of compounds possess-
ing diverse types of biological properties [5–8]. The syn-
thetic approach of some pyridine derivatives from tetra-
cyanopropenes is an important part of cyanocarbon chem-
istry, and the synthesis of 1,6-naphthyridine derivatives
has been widely dealt in the literature [9–13] as part of a
general study on cyclization of dinitriles. Several reports
are dedicated to naphthyridines chemistry [14–16].
RESULTS AND DISCUSSION
o-Aminoaldehydes [18] have fascinating potentiality
for annelation of heterocyclic ring structures, which pro-
vide a synthetic entry in heterocyclic systems fused to a
pyridine or pyrimidine nucleus by Friedlander condensa-
tion reactions. These are also the key intermediates for
the synthesis of various biologically active heterocycles
[19,20]. The annelation of pyridine ring onto pyrazolo-
pyridine nucleus involves the 4 þ 2 cyclocondensation
reaction [21].
Considering this literature prompted us to synthesize pyr-
azolo[3,4-h][1,6]naphthyridines by Friedlander condensation
of o-aminoaldehyde with reactive a-methylene ketones.
We now report a novel synthetic route for the synthesis
of pyrazolo[3,4-h][1,6]naphthyridines, which involve anne-
lation of a pyridine ring onto the performed pyrazolo[3,4-
b]pyridine ring via Friedlander condensation, which may
have biological activities. In our earlier communication
[17], pyrazolo[3,4-h][1,6]naphthyridines has been synthe-
sized in low yield (50%) by annelation of pyridine ring
onto pyrazolo[3,4-b]pyridine nucleus, in which amino and
The required 4-amino-3-methyl-1-phenyl-1H-pyra-
zolo[3,4-b]pyridine-5-carbaldehyde (o-aminoaldehyde) 4
was achieved in three steps. Thus, the chloroester 1,
synthesized by literature method [22], yielded an azido
derivative 2 by SN2 displacement of the chloro group
by azido with sodium azide in N-methyl pyrrolidine at
C
V
2010 HeteroCorporation

296
M. N. Jachak, S. M. Bagul, M. A. Kazi, and R. B. Toche
Vol 48
Scheme 1
80–90ꢀC in 77% yield. A stretching vibration in the IR
spectrum of 2 was observed at 2144 cmꢁ1. The syn-
chronous reduction of both azido group and ester group
of 2 ortho to each other in one pot by lithium alumi-
num hydride (LAH) in dry tetrahydrofuran at room
temperature yielded the ortho amino alcohol 3 in 84%
yield. This type of one-pot reduction of azido and ester
groups is not known in literature. This on oxidation
with manganese(IV)oxide (without protecting amino
group [23,24]) in acetonitrile at room temperature fur-
nished desired o-aminoaldehyde 4 in 94% yield. In this
step, expected N-oxide was not formed as revealed by
spectral and analytical data (Scheme 1). Compounds 2,
3, and 4 were characterized by IR, 1H-, 13C NMR,
mass spectroscopy, and elemental analysis; e.g., the IR
spectrum of 4 showed carbonyl stretching bands at
methyl and 2-aryl-9-methyl-7-phenyl-7H-pyrazolo[3,
4-h][1,6]naphthyridine 6a–k in 66–81% yield (Scheme 2).
When unsymmetric dialkyl ketones 7a–b were used
as condensation partner, instead of symmetric ketone 5a
or monoalkylketones 5b–k, they yielded an expected
mixture of two isomers 8 and 9 in 3:1 ratio, under simi-
lar reaction conditions.
The 3-substituted isomer 8 was formed by attack of the
aldehyde moiety at the benzyl CH2 group of the ketone 7,
whereas the condensation on the a-methyl group of 7
formed the 3-unsubstituted isomer 9. These mixtures
were separated by column chromatography using n-hex-
ane/ethyl acetate (9:1) as the eluent and were character-
ized by spectral and analytical data. The structural assign-
ment of 8a and 9a could easily be performed by 1H NMR
because 8a showed two methyl singlets at 2.69 and 3.02
d, together with the singlet of 4-H at 7.93 ppm of the
newly annelated pyridine ring, whereas 9a showed triplet
at d 1.42 and quartet at d 2.78 patterns for ethyl group to-
gether with two doublets at d 7.31 and d 8.19 assigned to
the ortho-coupled protons at H-3 and H-4 position in
newly annelated pyridine ring. The other signals in both
compounds appeared nearly at same d values. The molec-
ular ion peak 8a and 9a observed in both cases the same
mass of 288 (Mþ) in the mass spectra (Scheme 2).
1
1654 cmꢁ1, the H NMR spectrum showed down field
singlet at d 8.43 corresponding to H-2 and singlet at d
9.75 due to aldehydic proton. The 13C NMR spectrum
of the compound exhibits peak at d 195.56 for an alde-
hydic carbon. The mass spectral analysis showed an
ion with m/z 252 (Mþ), which supports the proposed
structure 4.
The Friedlander condensation of o-aminoaldehyde
such as 4-amino-3-methyl-1-phenyl-1H-pyrazolo[3,4-
b]pyridine-5-carbaldehyde 4 with ketones is described to
take place either with strong bases or acids as catalysts,
in special cases the ring closure can be observed without
a catalyst at higher temperatures (e.g., under microwave
irradiation) [21]. We obtained the best results when a
mixture of the appropriate o-aminoaldehyde 4 and the
corresponding ketones 5 or 7 was brought to reaction in
refluxing ethanolic potassium hydroxide solution. A
Friedlander cyclocondensation of o-aminoaldehyde 4a
with acetone 5a or acetophenones 5b–k afforded 2,9-di-
As mentioned earlier, the Friedlander condensation
can be catalyzed by various reagents [21]. When we
extended synthetic investigation to CH-acidic com-
pounds, such as p-bromophenylacetonitrile 10, b-
ketoester 12a, b-ketoamide 12b, and diethyl malonate
14, we found that already piperidine as base was suffi-
ciently strong to catalyze the condensation reaction.
This method provided a versatile method for the synthe-
sis of various substituted pyrazolo[3,4-h][1,6]naphthyri-
dines and pyrazolo[3,4-h][1,6]naphthyridione. The
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011 Novel Synthetic Protocol toward Pyrazolo[3,4-h][1,6]naphthyridines via Friedlander Condensation
of New 4-Aminopyrazolo[3,4-b]pyridine-5-carbaldehyde with Reactive a-Methylene Ketones
297
Scheme 2
(254 and 366 nm) for detection. Common reagents-grade
chemicals were either commercially available and were used
without further purification or prepared by standard literature
procedures.
cyclocondensation of 4 with p-bromophenylacetonitrile
10, b-ketoester 12a, b-ketoamide 12b, and diethyl
malonate 14 afforded pyrazolo[3,4-h][1,6]naphthyridine-
3-carbonitrile 11, ethyl-pyrazolo[3,4-h][1,6]naphthyri-
dine-3-carboxylate 13a, pyrazolo[3,4-h][1,6]naphthyri-
dine-3-carboxamide 13b, and 3-carbethoxy-pyrazolo
[3,4-h][1,6]naphthyridin-2-one 15, respectively, in 63–
79% yield (Scheme 3). Compounds 11, 13a-b, and 15
were characterized by IR, 1H NMR, 13C NMR, mass
spectra, and elemental analysis.
Scheme 3
In conclusion, the reactions herein report new syn-
thetic routes toward novel pyrazolo[3,4-h][1,6]naphthyri-
dines and pyrazolo[3,4-h][1,6]naphthyridione by Fried-
lander condensation reaction of new 4-amino-3-methyl-
1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde
with reactive a-methylene ketones.
4
EXPERIMENTAL
Melting points were determined on a Gallenkamp melting
point apparatus, Mod. MFB595 in open capillary tubes and are
uncorrected. 1H NMR (300 MHz) and 13C NMR (75 MHz)
spectra were measured on a Varian XL-300 spectrometer using
tetramethylsilane as an internal standard. IR spectra were
recorded using a Shimadzu IR-408, a Shimadzu FTIR instru-
ment with potassium bromide discs. Mass spectrum was
recorded on Shimadzu GC-MS QP mass spectrometer with an
ionization potential of 70 eV. Elemental analyses were
obtained on a Hosli CH-Analyzer and are within 60.3 of the
theoretical percentage.
All the reactions were monitored by thin layer chromatogra-
phy on 0.2-mm silica gel F-254 (Merck) plates using UV light
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

298
M. N. Jachak, S. M. Bagul, M. A. Kazi, and R. B. Toche
Vol 48
Ethyl-4-azido-3-methyl-1-phenyl-1H-pyrazolo[3.4-b]pyri-
General procedure for the synthesis of compounds 6a–
k. A mixture of 4 (0.1 g, 0.396 mmol), 5a–k (0.396 mmol), and
ethanolic potassium hydroxide solution (5 mL, 2%) was heated
under reflux for 1 h. The mixture was cooled to room tempera-
ture and the obtained solid was collected by suction filtration and
washed with ethanol to furnish compound 6 in 66–81% yield.
2,9-Dimethyl-7-phenyl-7H-pyrazolo[3,4-h][1,6]naphthyri-
dine (6a). This compound was obtained as a colorless solid,
0.072 g (66%); mp 157–158ꢀC; IR: 3035, 2923, 1604, 1508,
dine-5-carboxylate (2). A mixture of 1 (7.25 g, 23 mmol)
and sodium azide (1.69 g, 26 mmol) was heated in N-meth-
ylpyrrolidine (60 mL) at 80–90ꢀC for 6 h. The solvent was
distilled out by vacuum distillation. The reaction mass was
quenched with water (30 mL) and extracted in chloroform
(50 mL). The organic layer was dried over anhydrous so-
dium sulfate and the solvent was evaporated under reduced
pressure. The residue was purified by column chromatogra-
phy (n-hexane/ethyl acetate ¼ 1:4) to furnish 2 as a color-
less solid, 5.9 g (77%), mp 178–179ꢀC; IR: 2991, 2922,
1438, 1307, 1221, 767 cmꢁ1 1H NMR (CDCl3): d 2.81 (s,
;
3H, CH3), 3.02 (s, 3H, CH3), 7.39 (d, 1H, J ¼ 7.2 Hz,
ArAH), 7.34 (t, 1H, J ¼ 7.8 Hz, ArAH), 7.54 (t, 2H, J ¼
7.8 Hz, ArAH), 8.19 (d, 1H, J ¼ 7.2 Hz, ArAH), 8.24 (d,
2H, J ¼ 7.8 Hz, ArAH), 8.97 (s, 1H, ArAH); 13C NMR
(CDCl3): d 13.09, 24.23, 108.32, 116.21, 119.01, 120.16 (2
C’s), 124.35, 127.26 (2 C’s), 134.45, 137.56, 142.86,
145.50, 148.34, 150.73, 162.56; MS: m/z 274 (Mþ, 100%),
259 (37), 183 (25), 167 (14), 91 (26), 77 (42); Anal. Calcd.
for C17H14N4: C, 74.43; H, 5.14; N, 20.42. Found: C,
74.59; H, 5.03; N, 20.57.
2144, 1727, 1585, 1498, 1189, 769 cmꢁ1
;
1H NMR
(CDCl3): d 1.41 (t, 3H, J ¼ 6.8 Hz, CH3), 2.75 (s, 3H,
CH3), 4.37 (q, 2H, J ¼ 6.8 Hz, CH2), 7.28 (t, 1H, J ¼ 7.2
Hz, ArAH), 7.48 (t, 2H, J ¼ 7.2 Hz, ArAH), 8.11 (d, 2H,
J
¼ 7.2 Hz, ArAH), 8.91 (s, 1H, ArAH); 13C NMR
(CDCl3):
d 12.49, 13.54, 54.66, 98.97, 102.63, 119.88
(2 C’s), 124.29; 127.20 (2 C’s), 136.24, 140.51, 150.55,
151.35, 151.87, 166.41; MS: m/z 322 (Mþ, 100), 307 (19),
280 (34), 231 (15), 129 (23), 77 (32); Anal. Calcd. for
C16H14N6O2: C, 59.62; H, 4.38; N, 26.07. Found: C, 59.79;
H, 4.45; N, 25.89.
9-Methyl-2,7-diphenyl-7H-pyrazolo[3,4-h][1,6]naphthyri-
dine (6b). This compound was obtained as a pale yellow
solid, 0.093 g (70%); mp 158–159ꢀC; IR: 3062, 2925, 1591,
4-Amino-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-
5-yl-methanol (3). A solution of 2 (4.83 g, 15 mmol) in tetra-
hydrofuran (15 mL) was added slowly into the dispersed LAH
(46 mmol) in tetrahydrofuran (20 mL) at 0ꢀC; after addition the
reaction mass was allowed to come at 25ꢀC and stirred it for 4
h. The reaction mass was quenched with saturated sodium sulfate
solution (20 mL) at 0ꢀC and extracted in ethyl acetate (2 ꢂ 20
mL). The combined organic layer was washed with water (2 ꢂ
15 mL), then dried over anhydrous sodium sulfate, filtered, and
the solvent was evaporated under reduced pressure; the crude
solid was taken in ethanol, filtered, and dried under high vacuum
to provide 3 as a colorless solid, 3.31 g (84%); mp 173–174ꢀC;
1
1500, 1435, 1320, 1226, 732 cmꢁ1; H NMR (CDCl3): d 3.16
(s, 3H, CH3), 7.35 (t, 1H, J ¼ 7.8 Hz, ArAH), 7.51–7.62 (m,
5H, ArAH), 8.01 (d, 1H, J ¼ 8.4 Hz, ArAH), 8.25 (d, 2H,
J ¼ 7.8 Hz, ArAH), 8.35 (d, 2H, J ¼ 8.2 Hz, ArAH), 8.42 (d,
1H, J ¼ 8.4 Hz, ArAH), 9.08 (s, 1H, ArAH); MS: m/z 336
(Mþ, 100), 244 (23), 259 (39), 167 (19), 91 (23), 77 (28);
Anal. calcd. for C22H16N4: C, 78.55; H, 4.79; N, 16.65. Found:
C, 78.68; H, 4.96; N, 16.75.
2-(2-Chlorophenyl)-9-methyl-7-phenyl-7H-pyrazolo[3,4-
h][1,6]naphthyridine (6c). This compound wasꢀobtained as a
pale yellow solid, 0.105 g (71%); mp 164–165 C; IR: 3064,
2934, 1609, 1503, 1433, 1310, 1220, 772 cmꢁ1 1H NMR
;
IR: 3479, 3369, 3302, 3056, 2964, 1611, 1505, 1204, 772 cmꢁ1
;
(CDCl3): d 3.06 (s, 3H, CH3), 7.33 (t, 1H, J ¼ 7.2 Hz,
ArAH), 7.42–7.59 (m, 5H, ArAH), 7.87 (m, 1H, ArAH), 7.95
(d, 1H, J ¼ 8.4 Hz, ArAH), 8.24 (d, 2H, J ¼ 7.8 Hz, ArAH),
8.44 (d, 1H, J ¼ 8.4 Hz, ArAH), 9.01(s, 1H, ArAH); MS: m/z
(%) 372 (M þ 2, 34), 370 (Mþ, 100), 335 (23), 279 (18), 259
(26), 91 (28), 77 (32); Anal. Calcd. for C22H15ClN4: C, 71.25;
H, 4.08; N, 15.11. Found: C, 71.02; H, 3.96; N, 15.29.
2-(4-Fluorophenyl)-9-methyl-7-phenyl-7H-pyrazolo[3,4-
h][1,6]naphthyridine (6d). This compound was obtained as
a pale yellow solid, 0.106 g (75%); mp 188–189ꢀC; IR: 3079,
2920, 1594, 1504, 1406, 1308, 1228, 759 cmꢁ1 1H NMR
;
1H NMR (DMSO-d6): d 2.67 (s, 3H, CH3), 4.53 (d, 2H, J ¼ 5.4
Hz, CH2), 5.04 (t, 1H, J ¼ 5.4 Hz, OH, D2O exchangeable),
6.29 (bs, 2H, NH2, D2O exchangeable), 7.19 (t, 1H, J ¼ 7.2 Hz,
ArAH), 7.45 (t, 2H, J ¼ 7.2 Hz, ArAH), 8.01 (s, 1H, ArAH),
8.26 (d, 2H, J ¼ 7.2 Hz, ArAH); 13C NMR (DMSO-d6): d
13.52, 59.93, 113.65, 117.35, 119.67 (2 C’s), 124.75, 127.31 (2
C’s), 138.68, 142.57, 149.85, 150.11, 162.47; MS: m/z 254 (Mþ,
100), 237 (24), 221 (18), 129 (21), 77 (34); Anal. Calcd. for
C14H14N4O: C, 66.13; H, 5.55; N, 22.03. Found: C, 66.01; H,
5.46; N, 22.19.
4-Amino-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-
5-carbaldehyde (4). Manganese(IV)dioxide (2.5 g) was added
into the solution of 3 (4.06 g, 16 mmol) in acetonitrile (40
mL) at 25ꢀC for 20 h. The reaction mass was filtered through
celite and evaporated acetonitrile under reduced pressure to
yield 4 as a colorless solid, 3.92 g (94%); mp 173–174ꢀC; IR:
(CDCl3 þ d-CF3COOD): d 3.21 (s, 3H, CH3), 7.39 (t, 2H, J ¼
8.2 Hz, ArAH), 7.52–7.75 (m, 5H, ArAH), 8.23 (m, 2H,
ArAH), 8.31 (d, 1H, J ¼ 8.4 Hz, ArAH), 9.05 (d, 1H, J ¼ 8.4
Hz, ArAH), 9.52 (s, 1H, ArAH); MS: m/z 354 (Mþ, 100%),
339 (17), 263 (19), 259 (22), 244 (28), 91 (20), 77 (26); Anal.
calcd. for C22H15FN4: C, 74.56; H, 4.27; N, 15.81. Found: C,
74.75; H, 4.19; N, 15.92.
3435, 3094, 2931, 2723, 1654, 1599, 1502, 1219, 765 cmꢁ1
;
1H NMR (DMSO-d6): d 2.64 (s, 3H, CH3), 6.65 (bs, 2H,
NH2), 7.29 (t, 1H, J ¼ 7.8 Hz, ArAH), 7.49 (t, 2H, J ¼ 7.8
Hz, ArAH), 8.08 (d, 2H, J ¼ 7.8 Hz, ArAH), 8.43 (s, 1H,
ArAH), 9.75 (s, 1H, CH¼¼O). 13C NMR (DMSO-d6): d 17.64,
106.26, 112.67, 123.73 (2 C’s), 128.68 (2 C’s), 131.71,
141.48, 146.83, 153.98, 155.24, 161.26, 195.56; MS: m/z 252
(Mþ, 100), 236 (28), 223 (36), 208 (18), 133 (16), 77 (26);
Anal. Calcd. for C14H12N4O: C, 66.66; H, 4.79; N, 22.21.
Found: C, 66.84; H, 4.65; N, 22.06.
2-(4-Chlorophenyl)-9-methyl-7-phenyl-7H-pyrazolo[3,4-
h][1,6]naphthyridine (6e). This compound wasꢀobtained as a
pale yellow solid, 0.112 g (76%); mp 236–237 C; IR: 3052,
2924, 1610, 1500, 1457, 1317, 1230, 753 cmꢁ1 1H NMR
;
(DMSO-d6 þ d-CF3COOD): d 2.89 (s, 3H, CH3), 7.29–7.38
(m, 5H, ArAH), 7.57 (d, 2H, J ¼ 7.2 Hz, ArAH), 7.96 (d, 1H,
J ¼ 8.4 Hz, ArAH), 8.04 (d, 2H, J ¼ 8.4 Hz, ArAH), 8.72 (d,
1H, J ¼ 8.7 Hz, ArAH), 9.16 (s, 1H, ArAH); MS: m/z 370
(Mþ, 100), 372 (M þ 2, 38), 259 (18), 91 (21), 77 (36); Anal.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011 Novel Synthetic Protocol toward Pyrazolo[3,4-h][1,6]naphthyridines via Friedlander Condensation
of New 4-Aminopyrazolo[3,4-b]pyridine-5-carbaldehyde with Reactive a-Methylene Ketones
299
Calcd. for C22H15ClN4: C, 71.25; H, 4.08; N, 15.11. Found: C,
71.42; H, 4.14; N, 15.26.
91.45 (2 C’s), 117.77, 118.10, 121.17 (2 C’s), 124.53, 126.01,
129.09 (2 C’s), 130.89, 136.05, 138.19, 139.05, 143.67,
146.29, 149.58, 150.23, 151.62 (2 C’s), 155.27; MS: m/z 426
(Mþ, 100), 365 (27), 335 (24), 318 (18), 259 (19), 91 (21), 77
(32); Anal. Calcd. for C25H22N4O3: C, 70.41; H, 5.20; N,
13.14. Found: C, 70.54; H, 5.10; N, 12.96.
2-(4-Bromophenyl)-9-methyl-7-phenyl-7H-pyrazolo[3,4-
h][1,6]naphthyridine (6f). This compound was obtained as a
pale yellow solid, 0.119 g (72%); mp 240–241ꢀC; IR: m 3072,
1
2923, 1608, 1501, 1423, 1229, 756 cmꢁ1; H NMR (DMSO-d6
9-Methyl-7-phenyl-2-p-tolyl-7H-pyrazolo[3,4-h][1,6]naphthyri-
dine (6k). This compound was obtained as a colorless solid,
0.099 g (71%); mp 204–205ꢀC; IR: m 3018, 2919, 1596, 1501,
þ d-CF3COOD): d 2.87 (s, 3H, CH3), 7.29–7.34 (m, 3H,
ArAH), 7.49 (t, 4H, J ¼ 8.4 Hz, ArAH), 7.78 (d, 1H, J ¼ 8.7
Hz, ArAH), 8.04 (d, 2H, J ¼ 8.4 Hz, ArAH), 8.82 (d, 1H, J
¼ 8.7 Hz, ArAH), 9.17 (s, 1H, ArAH); MS: m/z 414 (Mþ,
100), 416 (M þ 2, 86), 399 (22), 323 (15), 259 (21), 155 (18),
91 (24), 77 (27); Anal. Calcd. for C22H15BrN4: C, 63.63; H,
3.64; N, 13.49. Found: C, 63.77; H, 3.52; N, 13.28.
2-(3,4-Difluorophenyl)-9-methyl-7-phenyl-7H-pyrazolo[3,4-
h][1,6]naphthyridine (6g). This compound was obtained as a
pale yellow solid, 0.112 g (76%); mp 201–202ꢀC; IR: 3041,
2931, 1604, 1515, 1439, 1236, 780 cmꢁ1 1H NMR (CDCl3):
;
d 3.14 (s, 3H, CH3), 7.31–7.40 (m, 2H, ArAH), 7.56 (t, 2H, J
¼ 8.2 Hz, ArAH), 7.93 (d, 1H, J ¼ 8.4 Hz, ArAH), 8.06 (m,
1H, ArAH), 8.22–8.25 (m, 3H, ArAH), 8.45 (d, 1H, J ¼ 8.4
Hz, ArAH), 9.08 (s, 1H, ArAH); 13C NMR (CDCl3): d 15.27,
110.31, 117.73, 117.96, 119.82 (2 C’s), 122.08, 123.94,
124.31, 126.47, 129.23 (2 C’s), 135.83, 137.61, 139.37,
143.23, 144.73, 147.34, 147.92, 150.41, 152.54, 158.44; MS:
m/z 372 (Mþ, 100), 357 (21), 281 (19), 259 (24), 91 (21), 77
(29); Anal. Calcd. for C22H14F2N4: C, 70.96; H, 3.79; N,
15.05. Found: C, 70.83; H, 3.71; N, 15.25.
1457, 1230, 750 cmꢁ1 1H NMR (CDCl3): d 2.43 (s, 3H,
;
CH3), 3.10 (s, 3H, CH3), 7.28 (t, 1H, J ¼ 8.1 Hz, ArAH),
7.33 (d, 2H, J ¼ 8.4 Hz, ArAH), 7.52 (t, 2H, J ¼ 8.1 Hz,
ArAH), 7.89 (d, 1H, J ¼ 8.4 Hz, ArAH), 8.16–8.22 (m, 4H,
ArAH), 8.29 (d, 1H, J ¼ 8.4 Hz, ArAH), 8.98 (s, 1H, ArAH);
13C NMR (CDCl3): d 13.32, 19.64, 115.24, 116.78, 120.17 (2
C’s), 124.38, 125.85, 127.27 (2 C’s), 128.90 (2 C’s), 129.14 (2
C’s), 133.99, 135.20, 137.57, 138.96, 142.95, 145.64, 148.52,
150.66, 158.97; MS: m/z 350 (Mþ, 100), 335 (31), 182 (24),
91 (20), 77 (28); Anal. Calcd. for C23H18N4: C, 78.83; H,
5.18; N, 15.99. Found: C, 79.02; H, 5.07; N, 15.76.
General procedure for the synthesis of compounds 8a–b
and 9a–b. A mixture of 4 (0.1 g, 0.396 mmol), correspond-
ing ketone 7a–b (0.396 mmol), and ethanolic potassium hy-
droxide solution (5 mL, 2%) was heated under reflux for 1
h. The mixture was cooled to room temperature and the
solid precipitated was filtered by suction. It contained two
compounds according to TLC analysis (Rf values: 0.89 and
0.65 in ethyl acetate/n-hexane ¼ 3:7). This mixture was
separated by column chromatography (18 mm ꢂ 300 mm,
eluent n-hexane/ethyl acetate ¼ 9:1); detection by TLC
analysis (254 nm).
2-(3,4-Dimethoxyphenyl)-9-methyl-7-phenyl-7H-pyrazolo[3,4-
h][1,6]naphthyridine (6h). This compound was obtained as a
colorless solid, 0.124 g (79%); mp 208–209ꢀC; IR: 3054,
;
2930, 1595, 1499, 1448, 1234, 1131, 771 cmꢁ1 1H NMR
2,3,9-Trimethyl-7-phenyl-7H-pyrazolo[3,4-h][1,6]naphthyri-
dine (8a). This compound was obtained as a colorless solid,
0.065 g (57%); mp 163–164ꢀC; IR: 3041, 2931, 1605, 1510,
(CDCl3): d 3.15 (s, 3H, CH3), 4.00 (s, 3H, OCH3), 4.08 (s,
3H, OCH3), 7.04 (d, 1H, J ¼ 8.4 Hz, ArAH), 7.35 (t, 1H, J ¼
7.8 Hz, ArAH), 7.56 (t, 2H, J ¼ 7.8 Hz, ArAH), 7.85 (d, 1H,
J ¼ 8.4 Hz, ArAH), 7.96 (d, 1H, J ¼ 8.7 Hz, ArAH), 8.14 (d,
1H, J ¼ 2.1 Hz, ArAH), 8.25 (d, 2H, J ¼ 7.8 Hz, ArAH),
8.37 (d, 1H, J ¼ 8.4 Hz, ArAH), 9.05 (s, 1H, ArAH); MS: m/
z 396 (Mþ, 100), 365 (46), 335 (31), 305 (15), 259 (21), 91
(18), 77 (33); Anal. Calcd. for C24H20N4O2: C, 72.71; H, 5.08;
N, 14.13. Found: C, 72.58; H, 5.19; N, 14.29.
1439, 1277, 780 cmꢁ1 1H NMR (CDCl3): d 2.69 (s, 3H,
;
CH3), 3.02 (s, 6H, 2 ꢂ CH3), 7.31 (t, 1H, J ¼ 7.4 Hz, ArAH),
7.53 (t, 2H, J ¼ 7.4 Hz, ArAH), 7.93 (s, 1H, ArAH), 8.24 (d,
2H, J ¼ 7.4 Hz, ArAH), 8.91 (s, 1H, ArAH); MS: m/z 288
(Mþ, 100), 197 (26), 91 (23), 77 (36); Anal. Calcd. for
C18H16N4: C, 74.98; H, 5.59; N, 19.43. Found: C, 75.14; H,
5.68; N, 19.62.
2,9-Dimethyl-3,7-diphenyl-7H-pyrazolo[3,4-h][1,6]naph-
thyridine (8b). This compound was obtained as a colorless
solid, 0.072 g (52%); mp 171–172ꢀC; IR: 3054, 2927, 1596,
1504, 1432, 1249, 746 cmꢁ1 1H NMR (CDCl3): d 2.89 (s,
;
6H, 2 ꢂ CH3), 7.28–7.40 (m, 6H, ArAH), 7.50 (t, 2H, J ¼ 7.8
Hz, ArAH), 7.86 (s, 1H, ArAH), 8.18 (d, 2H, J ¼ 7.8 Hz,
ArAH), 8.89 (s, 1H, ArAH); MS: m/z 350 (Mþ, 100), 259
(23), 91 (21), 77 (35); Anal. Calcd. for C23H18N4: C, 78.83;
H, 5.18; N, 15.99. Found: C, 79.01; H, 5.26; N, 15.74.
2-(2,6-Dimethoxyphenyl)-9-methyl-7-phenyl-7H-pyrazolo[3,4-
h][1,6]naphthyridine (6i). This compound was obtained as a
colorless solid, 0.127 g (81%); mp 215–216ꢀC; IR: 3062, 2941,
1
1602, 1501, 1425, 1219, 1154, 783 cmꢁ1; H NMR (DMSO-d6
þ d-CF3COOD): d 2.84 (s, 3H, CH3), 3.69 (s, 6H, 2 ꢂ OCH3),
6.79 (d, 2H, J ¼ 8.4 Hz, ArAH), 7.31 (t, 1H, J ¼ 7.8 Hz,
ArAH), 7.40 (t, 1H, J ¼ 8.4 Hz, ArAH), 7.52 (t, 2H, J ¼ 7.8
Hz, ArAH), 7.62 (d, 1H, J ¼ 8.4 Hz, ArAH), 8.24 (d, 2H, J ¼
7.8 Hz, ArAH), 8.65 (d, 1H, J ¼ 8.4 Hz, ArAH), 9.28 (s, 1H,
ArAH); MS: m/z 396 (Mþ, 100), 365 (54), 335 (17), 259 (24),
168 (19), 77 (27); Anal. Calcd. for C24H20N4O2: C, 72.71; H,
5.08; N, 14.13. Found: C, 72.87; H, 5.17; N, 13.94.
2-Ethyl-9-methyl-7-phenyl-7H-pyrazolo[3,4-h][1,6]naph-
thyridine (9a). This compound was obtained as a colorless
solid, 0.023 g (20%); mp 139–140ꢀC; IR: 3048, 2933, 1592,
9-Methyl-7-phenyl-2-(2,4,6-trimethoxyphenyl)-7H-pyrazolo[3,4-
h][1,6]naphthyridine (6j). This compound was obtained as a
colorless solid, 0.127 g (75%); mp 142–143ꢀC; IR: 3067,
1
1506, 1418, 1234, 764 cmꢁ1; H NMR (CDCl3): d 1.42 (t, 3H,
J ¼ 5.4 Hz, CH3), 2.78 (q, 2H, J ¼ 5.4 Hz, CH2), 3.04 (s, 3H,
CH3), 7.31 (d, 1H, J ¼ 7.2 Hz, ArAH), 7.34 (t, 1H, J ¼ 7.8
Hz, ArAH), 7.56 (t, 2H, J ¼ 7.8 Hz, ArAH), 8.19 (d, 1H, J ¼
7.2 Hz, ArA H), 8.24 (d, 2H, J ¼ 7.8 Hz, ArAH), 8.97 (s, 1H,
ArAH); MS: m/z 288 (Mþ, 100), 273 (42), 182 (28), 91 (19),
77 (30); Anal. Calcd. for C18H16N4: C, 74.98; H, 5.59; N,
19.43. Found: C, 75.17; H, 5.68; N, 19.27.
2941, 1607, 1505, 1455, 1227, 1127, 754 cmꢁ1 1H NMR
;
(DMSO-d6): d 3.07 (s, 3H, CH3), 3.79 (s, 6H, 2 ꢂ OCH3),
3.91 (s, 3H, OCH3), 6.30 (s, 2H, ArAH), 7.33 (t, 1H, J ¼ 7.5
Hz, ArAH), 7.52–7.59 (m, 3H, ArAH), 8.23 (d, 2H, J ¼ 7.5
Hz, ArAH), 8.32 (d, 1H, J ¼ 8.4 Hz, ArAH), 9.08 (s, 1H,
ArAH); 13C NMR (DMSO-d6): d 14.62, 55.42, 55.90 (2 C’s),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

300
M. N. Jachak, S. M. Bagul, M. A. Kazi, and R. B. Toche
Vol 48
100), 303 (29), 257 (23), 172 (17), 91 (25), 77 (31); Anal.
calcd. for C19H16N4O3: C, 65.51; H, 4.63; N, 16.08. Found: C,
65.33; H, 4.75; N, 16.23.
2-Benzyl-9-methyl-7-phenyl-7H-pyrazolo[3,4-h][1,6]naph-
thyridine (9b). This compound was obtained as a colorless
solid, 0.03 g (22%); mp 157–158ꢀC; IR: 3061, 2920, 1600,
1499, 1426, 1219, 758 cmꢁ1 1H NMR (CDCl3): d 3.16 (s,
;
3H, CH3), 3.99 (s, 2H, CH2), 7.35 (t, 1H, J ¼ 7.8 Hz, ArAH),
7.51–7.62 (m, 5H, ArAH), 8.01 (d, 1H, J ¼ 8.4 Hz, ArAH),
8.24 (d, 2H, J ¼ 7.8 Hz, ArAH), 8.35 (d, 2H, J ¼ 8.1 Hz,
ArAH), 8.42 (d, 1H, J ¼ 8.4 Hz, ArAH), 9.08 (s, 1H, ArAH);
MS: m/z 350 (Mþ, 100), 273 (29), 259 (21), 244 (18), 91 (23),
77 (34); Anal. Calcd. for C23H18N4: C, 78.83; H, 5.18; N,
15.99. Found: C, 78.96; H, 5.11; N, 16.23.
Acknowledgments. The authors thank UGC for financial assis-
tance under MRP, Dept. of Chemistry, University of Pune for
spectral and analytical data. They also thank higher authorities of
NDMVP samaj and KTHM College, Nashik.
REFERENCES AND NOTES
General procedure for the synthesis of compounds 11,
13a,b, and 15. A mixture of 4 (0.1 g, 0.396 mmol) and 10,
12, or 14 (0.396 mmol) was refluxed in ethanol (3 mL) in the
presence of catalytic amount of piperidine for 2 h. Upon cool-
ing to room temperature, a solid product precipitated, which
was collected by filtration and washed with cold ethanol to
yield the compounds 11, 13, and 15 in 63–79% yield.
2-(4-Bromophenyl)-9-methyl-7-phenyl-7H-pyrazolo[3,4-
h][1,6]naphthyridine-3-carbonitrile (11). This compound
was obtained as a colorless solid, 0.13 g (73%); mp 289–
290ꢀC; IR: 3056, 2954, 2259, 1610, 1505, 1438, 1237, 756
[1] Kuo, S. C.; Huang, L. J.; Nakamura, H. J Med Chem 1984,
27, 539.
[2] Colotta, V.; Catarzi, D.; Varano, F.; Cecchi, L.; Filacchioni,
G.; Martini, C.; Trincavelli, L.; Lucacchini, A. J Med Chem 2000, 43,
3118.
[3] Almerici, A. M.; Mingoia, F.; Diana, P.; Barraja, P.; Lauria, A.;
Montalbano, A.; Cirrincione, G.; Dattolo, G. J Med Chem 2005, 48, 2859.
[4] Sanghvi, Y. S.; Larson, S. B.; Wills, R. C.; Robins, R. K.;
Revankar, G. R. J Med Chem 1989, 32, 945.
[5] Domagala, J. M.; Hagen, S. E.; Joannides, E. T.; Kielly, J.
S.; Laborde, E.; Schoreder, M. C.; Sesnie, J. A.; Shapiro, M. A.; Suto,
M. J.; Vanderroest, S. J Med Chem 1993, 26, 871.
[6] Mohan, G. C.; Mishra, P. C. Indian J Biochem Biophys
1997, 34, 429.
cmꢁ1
;
1H NMR (DMSO-d6 þ d-CF3COOD): d 2.87 (s, 3H,
CH3), 7.29 (t, 1H, J ¼ 7.8 Hz, ArAH), 7.31 (d, 2H, J ¼ 8.2
Hz, ArAH), 7.48 (t, 2H, J ¼ 7.8 Hz, ArAH), 7.53 (d, 2H, J ¼
8.2 Hz, ArAH), 8.13 (d, 2H, J ¼ 7.8 Hz, ArAH), 8.80 (s, 1H,
ArAH), 9.14 (s, 1H, ArAH); MS: m/z 441 (Mþ2, 75), 439
(Mþ, 100), 348 (24), 233 (19), 91 (23), 77 (31); Anal. Calcd.
for C23H14BrN5: C, 62.74; H, 3.20; N, 15.91. Found: C, 62.96;
H, 3.28; N, 16.06.
[7] Burni, F.; Castanzo, A.; Gucrrini, G.; Malmberg-Aicllo, P.;
Iavaronc, G.; Martini, C. J Med Chem 1992, 27, 985.
[8] Bernardino, A. M. R.; Castro, H. C.; Frugulhetti, I. C. P.
P.; Loureiro, N. I. V.; Azevedo, A. R.; Pinheiro, L. C. S.; Souza, T.
M. L.; Giongo, V.; Passamani, F.; Magalhaes, U. O.; Albuquerque, M.
G.; Cabral, L. M. Bioorg Med Chem 2008, 16, 313.
[9] Gomez de Anderez, D.; Helliwell, J. R.; Dodson, E. J.;
Piniella, J. F.; Germain, G.; Alvarez-Larena, A.; Teixodo. J.; Victory.
P. Acta Crystallogr C 1992, 48, 104.
Ethyl-2,9-dimethyl-7-phenyl-7H-pyrazolo[3,4-h][1,6]naph-
thyridine-3-carboxylate (13a). This compound was obtained
as a colorless solid, 0.090 g (66%); mp 127–128ꢀC; IR: 3062,
;
2947, 1727, 1606, 1495, 1435, 1251, 1157, 765 cmꢁ1 1H
[10] Victory, P.; Nomen, R.; Colomina, O.; Garriga, M.; Crespo,
A. Heterocycles 1985, 23, 1135.
NMR (DMSO-d6): d 1.39 (t, 3H, J ¼ 5.4 Hz, CH3), 2.94 (s,
3H, CH3), 3.00 (s, 3H, CH3), 4.39 (q, 2H, J ¼ 5.4 Hz, CH2),
7.38 (t, 1H, J ¼ 7.2 Hz, ArAH), 7.58 (t, 2H, J ¼ 7.2 Hz,
ArAH), 8.21 (d, 2H, J ¼ 7.2 Hz, ArAH), 9.18 (s, 1H, ArAH),
9.43 (s, 1H, ArAH); MS: m/z 346 (Mþ, 100), 317 (41), 301
(27), 255 (19), 91 (16), 77 (26); Anal. Calcd. for C20H18N4O2:
C, 69.35; H, 5.24; N, 16.17. Found: C, 69.22; H, 5.13; N,
15.99.
[11] (a) Victory, P.; Teixido, J.; Borrell, J. I. Heterocycles 1992,
34, 1905; (b) Victory, P.; Teixido, P.; Borrell, J. I.; Busquets, N. Het-
erocycles 1993, 36, 1.
[12] Koitz, G.; Thierrichter, B.; Junek, H. Heterocycles 1983,
20, 2405.
[13] Victory, P.; Busquets, N.; Borrell, J. I.; Teixido, J.; Serra,
B.; Matallana, J. L.; Junek, H.; Sterk, H. Heterocycles 1995, 41, 1013.
[14] Litvinov, V. P.; Roman, S. V.; Dyachenko, V. D. Russ
Chem Rev (Engl Transl) 2000, 69, 201.
2,9-Dimethyl-N,7-diphenyl-7H-pyrazolo[3,4-h][1,6]naph-
thyridine-3-carboxamide
(13b). This
compound
was
obtained as a pale yellow solid, 0.098 g (63%); mp 179–
180ꢀC; IR: 3381, 3207, 3056, 2924, 1665, 1610, 1509, 1455,
[15] Litvinov, V. P.; Roman, S. V.; Dyachenko, V. D. Russ
Chem Rev (Engl Transl) 2001, 70, 299.
1
1266, 780 cmꢁ1; H NMR (DMSO-d6 þ d-CF3COOD): d 2.78
[16] Litvinov, V. P. Adv Heterocycl Chem 2006, 91, 189.
[17] Kendre, D. B.; Toche, R. B.; Jachak, M. N. Tetrahedron
2007, 63, 11000.
(s, 3H, CH3), 2.97 (s, 3H, CH3), 6.97 (t, 1H, J ¼ 7.8 Hz,
ArAH), 7.08 (t, 2H, J ¼ 7.8 Hz, ArAH), 7.24–7.29 (m, 5H,
ArAH), 7.43 (d, 2H, J ¼ 7.8 Hz, ArAH), 7.87 (s, 1H, NH),
9.21 (s, 1H, ArAH), 9.23(s, 1H, ArAH); MS: m/z 393 (Mþ,
100), 301 (15), 273 (17), 210 (22), 91 (21), 77 (29); Anal.
Calcd. for C24H19N5O: C, 73.27; H, 4.87; N, 17.80. Found: C,
73.10; H, 4.96; N, 17.94.
[18] Caluwe, P. Tetrahedron 1980, 36, 2359.
[19] Hawes, E. M.; Gorecki, K. J. J Med Chem 1973, 16, 849.
[20] Reddy, K.; Mogilaiah, K.; Sreenivasulu, B. J Ind Chem Soc
1986, 63, 443.
[21] (a) Cheng, C. C.; Yan, S. Y. Org React 1982, 28, 37; (b)
Hassner, A.; Stumer, C. Organic Synthesis Based on Named and
Unnamed Reactions (Tetrahedron Organic Chemistry Series); Perga-
mon Press: Oxford, 1994; Vol. 11, p 132; (c) Diaz-Ortiz, A.; de la
Hoz, A.; Langa, F. Green Chem 2000, 2, 165; (d) Karthikeyan, G.;
Perumal, P. T. J Heterocycl Chem 2004, 41, 1039.
[22] Hohn, H.; Janssen, W. J Heterocycl Chem 1972, 9, 235.
[23] Godard, A.; Queguiner, G. J Heterocycl Chem 1980, 17, 465.
[24] Wilfred, C. D. Malaysian J Chem 2006, 8, 52.
Ethyl-9-methyl-2-oxo-7-phenyl-2,7-dihydro-3H-pyrazolo[3,4-
h][1,6]naphthyridine-3-carboxylate (15). This compound was
obtained as a colorless solid, 0.109 g (79%); mp 144–145ꢀC;
IR: 3215, 3061, 2949, 1755, 1671, 1595, 1502, 1436, 1230,
790 cmꢁ1
;
1H NMR (DMSO-d6 þ d-CF3COOD): d 1.44 (t,
3H, J ¼ 7.2 Hz, CH3), 3.06 (s, 3H, CH3), 4.50 (q, 2H, J ¼
7.2Hz, CH2), 7.53–7.63 (m, 5H, ArAH), 8.27 (s, 1H, NH),
9.09 (s, 1H, ArAH), 9.24(s, 1H, ArAH); MS: m/z 348 (Mþ,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet