Synthetic utility of a heterocyclic o-aminoaldehyde: Synthesis of pyrazolopyridopyrimidines, pyrazolonaphthyridines, and pyrazolopyrimidonaphthyridinones

Article abstract of DOI:10.1007/s00706-010-0443-9

A series of various polysubstituted pyrazolo[3,4-h][1,6]naphthyridines, benzo[b]pyrazolo[3,4-h][1,6]naphthyridines, and pyrazolo[4′,3′:5,6] pyrido[4,3-d]pyrimidines were synthesized by Friedlaender condensation of 4-amino-3-methyl-1-phenyl-1H-pyrazolo[3,4

Full text of DOI:10.1007/s00706-010-0443-9

Monatsh Chem (2011) 142:169–175
DOI 10.1007/s00706-010-0443-9
ORIGINAL PAPER
Synthetic utility of a heterocyclic o-aminoaldehyde: synthesis
of pyrazolopyridopyrimidines, pyrazolonaphthyridines,
and pyrazolopyrimidonaphthyridinones
•
Sandeep M. Bagul Dilip R. Birari
•
•
•
Maruti G. Ghagare Raghunath B. Toche
Madhukar N. Jachak
Received: 14 February 2010 / Accepted: 12 December 2010 / Published online: 14 January 2011
Ó Springer-Verlag 2011
Abstract A series of various polysubstituted pyrazolo-
[3,4-h][1,6]naphthyridines, benzo[b]pyrazolo[3,4-h][1,6]naph-
thyridines, and pyrazolo[40,30:5,6]pyrido[4,3-d]pyrimidines
their derivatives display a wide range of pharmacological
activities, e.g., as anticonvulsants [9], anti-malarial agents
[10], anti-inflammatories, and central nervous system
depressants [11]. Moreover, these types of compounds are
inhibitors of cyclic guanosine-30,50-monophosphate phos-
phodiesterase (cGMP PDE), and are thereby agents against
erectile dysfunction [12]; they also act as antiproliferative
agents [13], have other physiological applications, and are
colorants [14], heat/moisture resistant agents, thermal
transfer printing agents [15], and photographic couplers
[16]. The importance of these derivatives and our interest
in this area led us to explore some new polysubstituted
pyrazolo[3,4-h][1,6]naphthyridines, benzo[b]pyrazolo[3,4-h]-
[1,6]naphthyridines, and pyrazolo[40,30:5,6]pyrido[4,3-d]-
pyrimidines.
¨
were synthesized by Friedlander condensation of 4-amino-
3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbal-
dehyde (o-aminoaldehyde) with active methylene
compounds. The o-aminoaldehyde was functionalized to
o-aminonitrile and o-aminocarboxamide with malononit-
rile and cyanoacetamide, respectively, which on conden-
sation with monosubstituted ureas and acetic anhydride,
respectively, afforded pyrazolo[3,4-h]pyrimido[4,5-b][1,6]-
naphthyridines.
¨
Keywords Friedlander condensation ꢀ
o-Aminoaldehyde ꢀ Active methylene compounds
Introduction
Results and discussion
Pyrazoles are excellent precursors for the synthesis of
condensed polyfunctionally substituted angular N-hetero-
cycles [1–6] that play an important role in the drug
discovery process because many drugs in late development
are heterocycles [7, 8]. Therefore, it is not surprising that
research on the synthesis of polyfunctionalized heterocy-
clic compounds has received significant attention.
The construction of ring structures from ortho-substituted
aminoaldehyde starting material has wide applicability for
the annulations of heterocyclic systems. This method
controls the direction of ring growth and generally permits
the direct and regiospecific introduction of functional
groups and/or substituents in the newly formed heterocy-
clic ring. From the literature it was noted that
o-aminoaldehydes, the first and best-known member of this
class of compounds, have been utilized for the synthesis
Pyrazolo-annulated heterocycles such as pyrazolopyr-
idopyrimidines have attracted considerable interest because
¨
of various heterocycles [17–24] by Friedlander reaction
[25–28]. Heterocyclic o-aminoaldehydes are important
synthons to annulate a pyridine or pyrimidine nucleus by
condensation reactions with various active methylene
compounds. Recently, we reported the synthetic utility of
heterocyclic o-aminoaldehydes, i.e., 5-aminopyrazol-4-
carbaldehyde [25–28] and 4-amino-6-chloroquinoline-3-
S. M. Bagul ꢀ D. R. Birari ꢀ M. G. Ghagare ꢀ
R. B. Toche ꢀ M. N. Jachak (&)
Department of Chemistry, Organic Chemistry Research Centre,
K. T. H. M. College, Gangapur Road, Nashik,
Maharashtra 422002, India
e-mail: mnjachak@hotmail.com
123

170
S. M. Bagul et al.
carbaldehyde [29]. In an earlier communication [30], we
reported the use of 4-amino-3-methyl-1-phenyl-1H-pyraz-
olo[3,4-b]pyridine-5-carbaldehyde (o-aminoaldehyde, 1) as
a key intermediate for the synthesis of pyrazolo[3,4-
h][1,6]naphthyridine derivatives. In this communication,
we have extended the synthetic utility of o-aminoaldehyde
1 [17] for the synthesis of a new class of heterocycles.
Malononitrile and cyanoacetamide are readily con-
densed with o-aminoaldehyde to form functionalized
heterocyclic derivatives, which in turn are attractive start-
ing materials for further ring annulations. Aromatic and
heterocyclic o-aminocarbonitriles and o-aminocarboxa-
mides are widely used and extensively studied [31–40] as
building blocks for condensed nitrogen heterocycles, which
prompted us to elaborate these by condensation of com-
pound 1 with malononitrile and cyanocetamide. Thus,
compound 1 and malononitrile were reacted in refluxing
ethanol using a catalytic amount of piperidine, furnishing
o-aminonitrile 2 in 75% yield, whereas the desired
o-aminocarboxamide 5 was obtained by condensation of 1
with cyanoacetamide under similar reaction conditions
(Scheme 1). In this condensation reaction, cyclization pro-
gressed via intramolecular addition of the amino group on
the nitrile function to give the desired 2 and 5.
monosubstituted urea 3 were heated together without using
any base or solvent at 260–270 °C, furnishing compounds 4
in 61–65% yield after workup, which were characterized by
spectral and analytical data. Requirement of high tempera-
ture for heterocyclization may be attributed due to the
presence of conjugated electron-withdrawing substituents
such as CN, which reduces the electron density around
the amine nitrogen resulting in a greater decrease in
nucleophilicity.
Analogously, o-aminocarboxamide 5 with acetic anhy-
dride in refluxing acetic acid furnished pyrazolopyrimido-
naphthyridinone 6 in 74% yield, as characterized by
spectral and analytical data (Scheme 1).
After successful construction of pyrazolonaphthyridines
by utilizing compound 1 with malononitrile and cyano-
acetamide, we planned the next protocol elaborating a
similar methodology to a series of pyrazolonaphthyridines,
comparatively less reactive substrates. It was interesting to
observe that decrease in the acidity of methylene protons of
the substrate such as ketones or acetonitrile derivatives
created a need to use a stronger base like potassium
¨
hydroxide instead of piperidine. The Friedlander conden-
sation of o-aminoaldehyde 1 with propiophenone in
refluxing ethanolic potassium hydroxide solution yiel-
ded 3,9-dimethyl-2,7-diphenyl-7H-pyrazolo[3,4-h][1,6]-
naphthyridine (7). In the literature [42], it was noted that
the reaction of dimethyl 1,3-acetonedicarboxylate with
5-aminopyrazolo-4-aldehyde resulted in the formation of
two products comprising a thermally decarboxylated
product; however, under similar reaction conditions we
obtained compound 8 with both ester groups intact when
It is well known [41] that heterocycles containing multi-
functional groups like amino and nitriles as well as amino
and carboxamide ortho to each other are useful starting
materials in heterocyclic chemistry. Targeting towards
the synthesis of pyrazolopyrimidonaphthyridinones, we
have utilized compounds 2 and 5 for the construction
of 4 and 6, respectively. Thus, o-aminocarbonitrile 2 and
Scheme 1
O
R1
NH
NH2
HN
N
CN
HN
H2N
3a, 3b
N
N
N
CN
CN
EtOH,
R1
O
N
N
N
N
N
NH2
N
O
250-260 oC
0.5 h,
61-65%
piperidine
2 h, reflux
H
R1 = H, CH3
N
N
2
4a, 4b
NH2
O
N
NH
O
N
NH2
N
O
1
NH2
Ac2O
CN
N
N
AcOH,
9h, 74%
EtOH,
piperidine
2 h, reflux
N
N
N
N
5
6
123

Synthetic utility of a heterocyclic o-aminoaldehyde
171
dimethyl 1,3-acetonedicarboxylate was condensed with
o-aminoaldehyde 1. Similarly the reaction of 1 with an
active methylene nitrile such as phenylacetonitrile afforded
naphthyridine 9 in 76% yield (Scheme 2).
annulated compounds. The ready availability and wide choice
of active methylene compounds, the ease of operation, and
high yields obtained make this hetero-annulation sequence a
versatile tool for the construction of multiple fused ring
structures. It was observed that the strength of base and
reactivity of active methylene compounds or neutral com-
pounds are the major contributing factors for the
heterocyclization. The reaction reported herein furnishes
novel pyrazolo-annulated heterocycles, with high yields,
simple workup, and clean products, and may be a valuable
addition to the library of heterocyclic chemistry.
¨
Furthermore, the Friedlander condensation of o-amino-
aldehyde 1 with cyclic ketones 10a–10f under similar
reaction condition produced corresponding 11a–11f.
However, reaction of 1 with dimedone (10g) was unsuc-
cessful in ethanolic KOH because of its more enolic
character; hence, this condensation was achieved by heat-
ing without solvent at 140–145 °C and afforded 11g in
79% yield (Scheme 3). All compounds were characterized
by spectral and analytical methods.
The condensation of o-aminoaldehyde 1 with neutral
substrates such as amides 12 was unsuccessful in the
presence of piperidine or potassium hydroxide; hence,
higher temperature was used to induce the heterocycliza-
tion leading to fused pyrimidines. Thus, the neat reaction of
1 with formamide 12a or benzamide 12b at 170–175 °C
furnished pyrazolo[40,30:5,6]pyrido[4,3-d]pyrimidines 13
in 62–67% yield as colorless solids, which were charac-
terized by spectral and analytical data (Scheme 4).
Experimental
Melting points: Gallenkamp melting point apparatus; IR
1
spectra (KBr-compression mould): Shimadzu IR-408; H
NMR (300 MHz), 13C-NMR (75 MHz) spectra: Varian
XL-300, DMSO-d6, CDCl3, TMS; mass spectra: HP 1100
LC/MSD mass spectral instrument (positive and negative
APCI ion source, 50–200 V, nitrogen); elemental analyses
(C, H, N, S) were conducted by using the HOSLI CH-
analyser; the results were in agreement with calculated
values. All reactions were monitored by thin-layer chro-
matography (TLC), carried out on 0.2-mm silica gel 60
F-254 plates (Merck) using UV light (254 and 366 nm) for
detection. Common reagent grade chemicals are either
commercially available and were used without further
purification or prepared by standard literature procedures.
In conclusion, we successfully utilized the condensation of
4-aminopyrazolo[3,4-b]pyridine-5-carbaldehyde (1) for the
synthesis of various angular tricyclic or tetracyclic hetero-
KOH/Ethanol
1 h, reflux
N
2-Amino-9-methyl-7-phenyl-7H-pyrazolo[3,4-h][1,6]-
naphthyridine-3-carbonitrile (2, C17H12N6)
N
A solution of 200 mg 1 (0.792 mmol) and 52 mg malon-
onitrile (0.792 mmol) was refluxed in 5 cm3 ethanol in the
presence of a catalytic amount of piperidine for 1 h (TLC
check). The separated solid was then cooled to room
temperature, collected by filtration, and crystallized from
ethanol to yield 178 mg (75%) 2. M.p.: 253–254 °C; IR:
N
N
O
7
COOMe
COOMe
NH2
N
O
H
vꢀ = 3,455, 3,317, 2,311, 1,601, 1,521 cm-1 1H NMR
;
N
N
KOH/Ethanol
1 h, reflux
N
(DMSO-d6): d = 2.79 (s, 3H, CH3), 7.30 (t, J = 7.8 Hz,
1H, Ar-H), 7.51 (t, J = 7.8 Hz, 2H, Ar-H), 7.74 (s, 2H,
–NH2), 8.15 (d, J = 7.8 Hz, 2H, Ar-H), 8.82 (s, 2H, Ar-H)
ppm; 13C NMR (DMSO-d6): d = 13.16, 108.27, 110.39,
116.89, 117.31, 120.24 (2C), 125.49, 128.01, 128.39 (2C),
138.28, 142.34, 143.83, 148.03, 150.38, 160.95 ppm; MS
(70 eV): m/z = 323 (M ? Na?), 300 (M?), 273, 182.
O
N
N
N
COOMe
COOMe
1
NH2
8
N
KOH/EtOH
1 h, reflux
N
General procedure for the synthesis of compounds 4
N
N
CN
A solution of 50 mg 2 (0.166 mmol) in substituted urea 3
(0.332 mmol) was heated at 250–260 °C for 30 min.
Completion of the reaction was monitored by TLC. The
molten mass was then cooled to room temperature, stirred
9
Scheme 2
123

172
S. M. Bagul et al.
Scheme 3
R'
R'
R
N
X
Y
NH2
N
O
H
N
N
N
+
10a-10g
N
N
R
H
X
CH2
Y
CH2
CH2
R'
1
11a
H
H
H
11b CH3 CH2
11f
11g
H
H
NCH2Ph CH2
CH2
CO CH3
R
Cyclic Ketones 10
a
b
c
d
e
f
Cyclohexanone
2-Methylcyclohexanone
Cyclopentanone
N
N
N
α-Tetralone
6-Methoxy-1-tetralone
1-Benzyl-4-piperidone
Dimedone
N
N
N
N
N
g
R
H
11d
11c
11e OCH3
R3
(d, J = 7.2 Hz, 2H, Ar-H), 8.36 (s, 1H, NH), 8.77 (s, 1H,
Ar-H), 9.18 (s, 1H, Ar-H), 11.32 (bs, 1H, NH) ppm; 13C NMR
(DMSO-d6): d = 12.16, 13.34, 35.78, 111.59, 112.94,
114.89, 199.96 (2C), 125.65, 128.73 (2C), 135.07, 138.12,
142.78, 144.13, 147.34, 148.06, 148.38, 150.21, 152.94 ppm;
MS (70 eV): m/z = 357 (M?), 328, 300, 237, 91.
O
NH2
N
O
N
N
N
H2N
R3
H
12a, 12b
N
N
N
N
170-175 °C
1 h
12,13 R3
a
b
H
Ph
8-Ethyl-3,7,8,10-tetrahydro-7-imino-1-methyl-3-phenyl-
9H-pyrazolo[3,4-h]pyrimido[4,5-b][1,6]naphthyridin-9-
one (4b, C20H17N7O)
1
13a, 13b
Scheme 4
Yield 38 mg (61%); m.p.:[300 °C; IR: vꢀ = 3,352, 3,227,
1,614, 1,596, 1,542 cm-1; 1H NMR (DMSO-d6): d = 1.06
(t, J = 6.4 Hz, 3H, CH3), 2.77 (s, 3H, CH3), 3.92 (q,
J = 6.4 Hz, 2H, CH2), 7.31 (t, J = 7.8 Hz, 1H, Ar-H),
7.49 (t, J = 7.8 Hz, 2H, Ar-H), 8.25 (d, J = 7.8 Hz, 2H,
Ar-H), 8.45 (s, 1H, NH), 8.68 (s, 1H, Ar-H), 9.23 (s, 1H,
Ar-H), 11.10 (bs, 1H, NH) ppm; 13C NMR (DMSO-d6):
d = 10.51, 15.01, 19.78, 42.89, 111.73, 112.84, 114.62,
120.12 (2C), 125.61, 128.37 (2C), 136.01, 139.21, 143.84,
144.03, 146.91, 148.02, 148.17, 149.98, 153.13 ppm; MS
(70 eV): m/z = 371 (M?), 356, 300, 251.
in 2 cm3 ethanol, and crystallized from dimethylformamide
(DMF) to afford 4 in 61–65% yield.
3,7,8,10-Tetrahydro-7-imino-1,8-dimethyl-3-phenyl-9H-
pyrazolo[3,4-h]pyrimido[4,5-b][1,6]naphthyridin-9-one
(4a, C19H15N7O)
Yield 39 mg (65%); m.p.: [300 °C; IR: vꢀ = 3,348, 3,239,
1,631, 1,604, 1,502 cm-1; H NMR (DMSO-d6): d = 2.71
1
(d, J = 20.2 Hz, 3H, CH3), 2.75 (s, 3H, CH3), 7.19 (t,
J = 7.2 Hz, 1H, Ar-H), 7.43 (t, J = 7.2 Hz, 2H, Ar-H), 8.15
123

Synthetic utility of a heterocyclic o-aminoaldehyde
173
2-Amino-9-methyl-7-phenyl-7H-pyrazolo[3,4-h][1,6]-
naphthyridine-3-carboxamide (5, C17H14N6O)
Ar-H), 8.18 (d, J = 7.8 Hz, 2H, Ar-H), 8.89 (s, 1H, Ar-H)
ppm; 13C-NMR (DMSO-d6): d = 13.21, 16.34, 114.52,
118.16, 119.87 (2C), 125.23, 126.47, 127.14 (2C), 128.91
(2C), 129.01 (2C), 132.54, 133.09, 136.13, 137.42, 141.93,
142.87, 147.59, 150.11, 159.24 ppm; MS (70 eV):
m/z = 350 (M?), 273, 259, 218, 76.
A solution of 100 mg 1 (0.396 mmol) and 33 mg cyano-
acetamide (0.396 mmol) was refluxed in 3 cm3 ethanol in
the presence of a catalytic amount of piperidine for 1 h
(TLC check). The reaction mass was then cooled to room
temperature. The separated solid was collected by filtration
and crystallized from ethanol to afford 91 mg (72%) 5.
M.p.: 286–287 °C; IR: vꢀ = 3,442, 3,412, 3,336, 1,629,
1,589, 1,555 cm-1; 1H NMR (DMSO-d6): d = 2.83 (s, 3H,
CH3), 7.29 (t, J = 7.2 Hz, 1H, Ar-H), 7.51 (t, J = 8.4 Hz,
2H, Ar-H), 7.61 (bs, 2H, NH2), 8.19 (d, J = 7.8 Hz, 2H,
Ar-H), 8.25 (bs, 2H, NH2), 8.72 (s, 1H, Ar-H), 8.78 (s, 1H,
Ar-H) ppm; 13C NMR (DMSO-d6): d = 13.25, 111.02,
113.84, 115.01, 120.12 (2C), 125.91, 128.43 (2C), 139.16,
139.38, 140.63, 144.12, 148.17, 150.25, 161.13, 169.27 ppm;
MS (70 eV): m/z = 341 (M ? Na?), 318 (M?), 302, 227.
Methyl 3-(methoxycarbonyl)-9-methyl-7-phenyl-7H-
pyrazolo[3,4-h][1,6]naphthyridin-2-acetate
(8, C21H18N4O4)
Yield 96 mg (62%); m.p.: 138–139 °C; IR: vꢀ = 3,413,
2,826, 2,362, 1,720, 1,596, 1,537 cm-1; 1H NMR (CDCl3):
d = 3.02 (s, 3H, CH3), 3.79 (s, 3H, OCH3), 4.01 (s, 3H,
OCH3), 4.49 (s, 2H, CH2), 7.31 (t, J = 7.2 Hz, 1H, Ar-H),
7.53 (t, J = 7.2 Hz, 2H, Ar-H), 7.94 (s, 1H, Ar-H), 8.22 (d,
J = 7.2 Hz, 2H, Ar-H), 8.91 (s, 1H, Ar-H) ppm; 13C-NMR
(CDCl3): d = 14.01, 36.27, 50.98, 51.03, 115.14, 117.81,
120.02 (2C), 125.37, 126.12, 128.03 (2C), 133.74, 137.19,
142.39, 146.21, 147.83, 150.34, 157.91, 167.28, 169.51 ppm;
MS (70 eV): m/z = 390 (M?), 331, 210.
3,8-Dihydro-1,9-dimethyl-3-phenyl-7H-pyrazolo[3,4-h]-
pyrimido[4,5-b][1,6]naphthyridin-7-one (6, C19H14N6O)
A solution of 50 mg 5 (0.198 mmol), 1 cm3 acetic
anhydride, and 1 cm3 acetic acid was refluxed under
stirring for 9 h (TLC check). The reaction mass was then
cooled to room temperature. The separated solid was
collected by filtration, washed with cold ethanol, dried, and
crystallized from ethanol/DMF (1:1) to yield 40 mg (74%)
6. M.p.: [300 °C; IR: vꢀ = 3,389, 3,065, 1,601, 1,505
9-Methyl-3,7-diphenyl-7H-pyrazolo[3,4-h][1,6]-
naphthyridin-2-amine (9, C22H17N5)
Yield 105 mg (76%); m.p.: 130–131 °C; IR: vꢀ = 3,465,
1
2,891, 2,345, 1,597, 1,551 cm-1; H NMR (DMSO-d6):
d = 2.89 (s, 3H, CH3), 6.81 (s, 2H, –NH2), 7.29 (t,
J = 7.4 Hz, 1H, Ar-H), 7.41–7.55 (m, 7H, Ar-H), 8.06 (s,
1H, Ar-H), 8.27 (d, J = 7.4 Hz, 2H, Ar-H), 8.87 (s, 1H,
Ar-H) ppm; 13C NMR (DMSO-d6): d = 17.20, 107.35,
113.63, 119.25 (2C), 121.15, 124.09, 126.67, 127.34 (2C),
127.66 (2C), 127.74 (2C), 135.71, 135.84, 138.07, 142.44,
146.13, 149.64, 150.70, 157.96 ppm; MS (70 eV):
m/z = 351 (M?), 335, 91.
1
cm-1; H NMR (DMSO-d6): d = 2.68 (s, 3H, CH3), 2.83
(s, 3H, CH3), 7.29 (t, J = 8.4 Hz, 1H, Ar-H), 7.38 (t,
J = 8.4 Hz, 2H, Ar-H), 7.57 (bs, 1H, NH), 8.03 (d,
J = 8.4 Hz, 2H, Ar-H), 9.22 (s, 1H, Ar-H), 9.34 (s, 1H,
Ar-H) ppm; 13C NMR (DMSO-d6): d = 13.04, 24.79,
115.11, 115.34, 119.87 (2C), 122.53, 125.96, 128.74
(2C), 138.17, 139.29, 142.78, 143.91, 148.02, 150.24,
152.69, 153.82, 160.29 ppm; MS (70 eV): m/z = 342
(M?), 300, 251, 210, 119.
General procedure for the synthesis of 11a–11f
A solution of 100 mg 1 (0.396 mmol), corresponding
cyclic ketone 10 (0.396 mmol), and 5 cm3 ethanolic
potassium hydroxide solution (2%) was refluxed for 1 h
(TLC check). The reaction mass was then cooled to room
temperature, the separated solid was collected by filtration
and recrystallized from ethanol to afford 11 in 71–82%
yield.
General procedure for the synthesis of 7–9
A solution of 100 mg 1 (0.396 mmol), corresponding
ketone (0.396 mmol), and 5 cm3 ethanolic potassium
hydroxide solution (2%) was refluxed for 1 h. Completion
of the reaction was monitored by TLC. The reaction mass
was then cooled to room temperature, the separated solid
was collected by filtration and crystallized from ethanol to
afford 7–9.
7,8,9,10-Tetrahydro-1-methyl-3-phenyl-3H-benzo[b]-
pyrazolo[3,4-h][1,6]naphthyridine (11a, C20H18N4)
Yield 99 mg (79%); m.p.: 168–170 °C; IR: vꢀ = 3,417,
2,948, 2,371, 1,605, 1,492 cm-1 1H NMR (CDCl3):
;
3,9-Dimethyl-2,7-diphenyl-7H-pyrazolo[3,4-h][1,6]-
naphthyridine (7, C23H18N4)
d = 1.91 (m, 2H, CH2), 1.99 (m, 2H, CH2), 2.97
(t, J = 6.0 Hz, 2H, CH2), 3.02 (s, 3H, CH3), 3.20
(t, J = 6.0 Hz, 2H, CH2), 7.32 (t, J = 7.4 Hz, 1H, Ar-
H), 7.53 (t, J = 7.4 Hz, 2H, Ar-H), 7.94 (s, 1H, Ar-H),
8.23 (d, J = 7.4 Hz, 2H, Ar-H), 8.92 (s, 1H, Ar-H) ppm;
13C-NMR (CDCl3): d = 13.06, 20.99, 21.11, 27.30, 32.39,
Yield 116 mg (84%); m.p.: 187–188 °C; IR: vꢀ = 3,462,
1
3,045, 2,340, 1,605, 1,543 cm-1; H NMR (DMSO-d6):
d = 2.42 (s, 3H, CH3), 2.79 (s, 3H, CH3), 7.28 (t, J =
7.8 Hz, 1H, Ar-H), 7.32 (t, J = 8.2 Hz, 2H, Ar-H), 7.39
(m, 3H, Ar-H), 7.50 (t, J = 7.8 Hz, 2H, Ar-H), 7.86 (s, 1H,
123

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S. M. Bagul et al.
108.09, 117.06, 120.06 (2C), 124.21, 127.23 (2C), 128.23,
133.58, 137.67, 142.61, 143.71, 147.98, 150.59,
162.75 ppm; MS (70 eV): m/z = 314 (M?), 258, 167, 91.
2H, CH2), 3.18 (s, 3H, CH3), 3.91 (s, 3H, CH3), 6.82 (d,
J = 2.4 Hz, 1H, Ar-H), 7.02 (dd, J = 2.4 Hz, 8.7 Hz, 1H,
Ar-H), 7.33 (t, J = 7.8 Hz, 1H, Ar-H), 7.55 (t, J = 7.8 Hz,
2H, Ar-H), 8.08 (s, 1H, Ar-H), 8.26 (d, J = 7.8 Hz, 2H,
Ar-H), 8.62 (d, J = 8.7 Hz, 1H, Ar-H), 8.98 (s, 1H, Ar-H)
ppm; 13C NMR (CDCl3): d = 14.04, 28.19, 29.76, 54.08,
110.91, 111.02, 117.27, 119.79, 119.98 (2C), 124.01,
125.26, 127.34, 127.92 (2C), 131.23, 132.01, 137.46,
138.18, 142.05, 144.25, 148.17, 150.16, 156.34, 158.29
ppm; MS (70 eV): m/z = 392 (M?), 361, 270, 134, 91.
7,8,9,10-Tetrahydro-1,10-dimethyl-3-phenyl-3H-
benzo[b]pyrazolo[3,4-h][1,6]naphthyridine
(11b, C21H20N4)
Yield 107 mg (82%); m.p.: 121–122 °C; IR: vꢀ = 3,439,
3,015, 2,345, 1,596, 1,508 cm-1 1H NMR (CDCl3):
;
d = 1.56 (d, J = 6.3 Hz, 3H, CH3), 1.69 (m, 1H, CH),
1.84 (m, 1H, CH), 1.98 (m, 1H, CH), 2.18 (m, 1H, CH),
2.96 (t, J = 6.3 Hz, 2H, CH2), 3.02 (s, 3H, CH3), 3.16 (m,
1H, CH), 7.29 (t, J = 7.8 Hz, 1H, Ar-H), 7.50 (t,
J = 7.8 Hz, 2H, Ar-H), 7.92 (s, 1H, Ar-H), 8.20 (d,
J = 7.8 Hz, 2H, Ar-H), 8.91 (s, 1H, Ar-H) ppm; 13C NMR
(CDCl3): d = 13.07, 18.80, 19.32, 27.95, 29.69, 35.76,
108.34, 116.89, 120.07 (2C), 124.21, 127.24 (2C), 128.01,
133.38, 137.69, 142.69, 143.66, 147.97, 150.53, 166.30
ppm; MS (70 eV): m/z = 328 (M?), 313, 223, 105.
8-Benzyl-7,8,9,10-tetrahydro-1-methyl-3-phenyl-3H-
pyrido[4,3-b]pyrazolo[3,4-h][1,6]naphthyridine
(11f, C26H23N5)
Yield 116 mg (72%); m.p.: 171–172 °C; IR: vꢀ = 3,428,
3,214, 3,036, 2,385, 1,602, 1,539 cm-1; 1H NMR (CDCl3):
d = 2.95 (t, J = 6.3 Hz, 2H, CH2), 2.99 (s, 3H, CH3), 3.29
(t, J = 6.0 Hz, 2H, CH2), 3.74 (s, 2H, CH2), 3.83 (s, 2H,
CH2), 7.29 (t, J = 8.4 Hz, 1H, Ar-H), 7.37 (m, 5H, Ar-H),
7.50 (t, J = 8.1 Hz, 2H, Ar-H), 7.86 (s, 1H, Ar-H), 8.18 (d,
J = 7.8 Hz, 2H, Ar-H), 8.89 (s, 1H, Ar-H) ppm; 13C NMR
(CDCl3): d = 13.08, 32.14, 48.81, 53.55, 60.79, 108.08,
116.72, 120.15 (2C), 124.32, 125.57, 125.95, 126.65 (2C),
127.24 (4C), 131.55, 136.10, 137.59, 142.73, 144.23,
148.08, 150.69, 160.16 ppm; MS (70 eV): m/z = 405.2
(M?), 300, 328, 105, 91.
3,7,8,9-Tetrahydro-1-methyl-3-phenylcyclopenta[b]-
pyrazolo[3,4-h][1,6]naphthyridine (11c, C19H16N4)
Yield 87 mg (73%); m.p.: 188–189 °C; IR: vꢀ = 3,447,
2,926, 2,398, 1,602, 1,519 cm-1 1H NMR (CDCl3):
;
d = 2.21 (m, 2H, CH2), 2.82 (s, 3H, CH3), 3.09 (t,
J = 6.2 Hz, 2H, CH2), 3.42 (t, J = 6.2 Hz, 2H, CH2), 7.23
(t, J = 7.6 Hz, 1H, Ar-H), 7.36 (t, J = 7.6 Hz, 2H, Ar-H),
7.84 (d, J = 7.6 Hz, 2H, Ar-H), 8.77 (s, 1H, Ar-H), 9.09 (s,
1H, Ar-H) ppm; 13C NMR (CDCl3): d = 13.24, 24.81,
32.78, 34.26, 108.38, 117.29, 120.37 (2C), 124.17, 127.46
(2C), 128.75, 132.97, 137.28, 141.76, 144.06, 148.24,
151.21, 163.53 ppm; MS (70 eV): m/z = 300 (M?), 258,
209.
3,8,9,10-Tetrahydro-1,9,9-trimethyl-3-phenyl-7H-
benzo[b]pyrazolo[3,4-h][1,6]naphthyridine-7-one
(11g, C22H20N4O)
A mixture of 100 mg 1 (0.396 mmol) and 56 mg dimedone
10g (0.396 mmol) was heated at 140–150 °C for 30 min.
The molten mass on cooling was stirred in 2 cm3 ethanol
for 15 min. The separated solid was collected by filtration
and crystallized from ethanol to afford 111 mg (79%) 11g.
M.p.: 244–245 °C; IR: vꢀ = 3,458, 2,943, 1,726, 1,600,
7,8-Dihydro-1-methyl-3-phenyl-3H-naphtho[1,2-b]-
pyrazolo[3,4-h][1,6]naphthyridine (11d, C24H18N4)
Yield 107 mg (75%); m.p.: 192–193 °C; IR: vꢀ = 3,433,
1,554 cm-1 1H NMR (DMSO-d6): d = 0.93 (s, 6H,
;
2,923, 2,376, 1,601, 1,499 cm-1 1H NMR (CDCl3):
;
(CH3)2), 2.53 (s, 2H, CH2), 2.82 (s, 3H, CH3), 3.34 (s,
2H, CH2), 7.24 (t, J = 7.8 Hz, 1H, Ar-H), 7.34 (t,
J = 7.8 Hz, 2H, Ar-H), 7.75 (d, J = 7.8 Hz, 2H, Ar-H),
9.24 (s, 1H, Ar-H), 9.38 (s, 1H, Ar-H) ppm; 13C NMR
(DMSO-d6): d = 13.27, 26.13 (2C), 32.59, 51.08, 53.71,
115.85, 120.18 (2C), 121.91, 125.87, 127.69 (2C), 133.01,
136.23, 138.95, 142.31, 144.05, 147.82, 150.96, 167.79,
194.91 ppm; MS (70 eV): m/z = 379 (M ? Na?), 356
(M?), 300, 328, 272, 91.
d = 2.99 (t, J = 6.0 Hz, 2H, CH2), 3.03 (s, 3H, CH3),
3.05 (t, J = 6.0 Hz, 2H, CH2), 7.28–7.34 (m, 2H, Ar-H),
7.46 (m, 2H, Ar-H), 7.54 (t, J = 7.8 Hz, 2H, Ar-H), 8.04
(s, 1H, Ar-H), 8.23 (d, J = 8.2 Hz, 2H, Ar-H), 8.63 (d,
J = 6.6 Hz, 1H, Ar-H), 8.93 (s, 1H, Ar-H) ppm; 13C NMR
(CDCl3): d = 13.31, 26.26, 26.63, 108.59, 117.42, 120.03
(2C), 124.24, 124.80, 125.62, 126.30, 127.25 (2C), 127.59,
128.92, 132.40, 132.56, 137.64, 138.06, 142.69, 144.59,
148.18, 150.26, 155.31 ppm; MS (70 eV): m/z = 385
(M ? Na?), 362 (M?), 258, 197, 91.
General procedure for the synthesis of 13
7,8-Dihydro-10-methoxy-1-methyl-3-phenyl-3H-
naphtho[1,2-b]pyrazolo[3,4-h][1,6]naphthyridine
(11e, C25H20N4O)
Compound 1 (100 mg, 0.396 mmol) and corresponding
amide 12 (1.98 mmol) were heated at 170–180 °C for
1 h (TLC check). The molten mass on cooling was
stirred in 2 cm3 ethanol for 15 min. The solid obtained
on cooling was collected by filtration, washed with cold
Yield 110 mg (71%); m.p.: 213–214 °C; IR: vꢀ = 3,427,
2,939, 2,349, 1,599, 1,491 cm-1 1H NMR (CDCl3):
;
d = 3.03 (t, J = 4.8 Hz, 2H, CH2), 3.13 (t, J = 4.8 Hz,
123

Synthetic utility of a heterocyclic o-aminoaldehyde
175
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ethanol, and crystallized from ethanol to afford 13 in
62–67% yield.
9-Methyl-7-phenyl-7H-pyrazolo[40,30:5,6]pyrido-
[4,3-d]pyrimidine (13a, C15H11N5)
Yield 64 g (62%); m.p.: 167–168 °C; IR: vꢀ = 3,426,
13. Poreba K, Wietrzyk J, Opolski A (2006) Acta Pol Pharm 63:189
14. Yutaka K (1992) Japan Kokai Tokkyo Koho JP 03221948. Chem
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2,973, 1,602, 1,542 cm-1
;
1H NMR (DMSO-d6):
d = 3.03 (s, 3H, CH3), 7.38 (t, J = 7.8 Hz, 1H, Ar-H),
7.55 (t, J = 7.8 Hz, 2H, Ar-H), 8.16 (d, J = 7.8 Hz, 2H,
Ar-H), 9.17 (s, 1H, Ar-H), 9.52 (s, 1H, Ar-H), 9.54 (s, 1H,
Ar-H) ppm; 13C NMR (DMSO-d6): d = 13.47, 112.76,
116.74, 120.13 (2C), 124.98, 127.64 (2C), 138.19, 142.54,
148.51, 149.27, 150.42, 153.68, 158.05 ppm; MS (70 eV):
m/z = 284 (M ? Na?), 261 (M?), 171, 91.
19. Manuel NM, Jairo Q, Jorge T, Rodrigo A, Braulio I, Justo C, Jose
MT (2009) Arkivoc xiv:9
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97:159
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24. Jachak MN, Avhale AB, Medhane VJ, Toche RB (2006) J Het-
erocycl Chem 43:1169
25. Yang D, Jiang K, Li J, Xu F (2007) Tetrahedron 63:7654
26. Zong R, Wang D, Hammitt R, Thummel RP (2006) J Org Chem
71:167
27. Dormer PG, Eng KK, Farr RN, Humphrey G, McWilliams JC,
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9-Methyl-2,7-diphenyl-7H-pyrazolo[40,30:5,6]pyrido-
[4,3-d]pyrimidine (13b, C21H15N5)
Yield 89 g (67%); m.p.: 193–194 °C; IR: vꢀ = 3,448,
2,957, 1,599, 1,524 cm-1 1H NMR (DMSO-d6): d =
;
3.01 (s, 3H, CH3), 7.40 (t, J = 7.4 Hz, 1H, Ar-H),
7.53–7.63 (m, 5H, Ar-H), 8.19 (d, J = 7.4 Hz, 2H,
Ar-H), 8.66 (d, J = 7.4 Hz, 2H, Ar-H), 9.41 (s, 1H,
Ar-H), 9.85 (s, 1H, Ar-H) ppm; 13C NMR (DMSO-d6):
d = 14.17, 111.93, 115.71, 120.27 (2C), 125.35, 126.94
(2C), 128.61, 128.96 (2C), 129.13 (2C), 130.52, 138.94,
143.73, 148.38, 150.11, 151.26, 157.03, 163.82 ppm; MS
(70 eV): m/z = 337 (M?), 247, 205, 132.
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Acknowledgments The authors are thankful to UGC, New Delhi,
for the financial assistance under the Major Research Project. We also
thank authorities of NDMVP Samaj’s and KTHM College, Nashik for
facilities.
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