Synthesis of new quinoline fused heterocycles such as benzo[h]-1,6- naphthyridines and pyrazolo[4,3 c]quinolines

Article abstract of DOI:10.1007/s00706-009-0236-1

Synthesis of novel benzo[h]-1,6-naphthyridines was successfully achieved by cyclocondensation of ethyl 4-aminoquinoline-3-carboxylates with malononitrile. The pyrazolo[4,3-c]quinolines were synthesized by nucleophilic substitution and subsequent addition

Full text of DOI:10.1007/s00706-009-0236-1

Monatsh Chem (2010) 141:169–175
DOI 10.1007/s00706-009-0236-1
ORIGINAL PAPER
Synthesis of new quinoline fused heterocycles such
as benzo[h]-1,6-naphthyridines and pyrazolo[4,3-c]quinolines
•
Bhausaheb Kedarnath Ghotekar
•
Maruti G. Ghagare Raghunath B. Toche
•
Madhukar N. Jachak
Received: 17 November 2008 / Accepted: 27 November 2009 / Published online: 22 January 2010
Ó Springer-Verlag 2010
Abstract Synthesis of novel benzo[h]-1,6-naphthyridines
was successfully achieved by cyclocondensation of ethyl
4-aminoquinoline-3-carboxylates with malononitrile. The
pyrazolo[4,3-c]quinolines were synthesized by nucleophilic
substitution and subsequent addition reaction of ethyl
4-chloroquinoline-3-carboxylates with different hydrazines.
All new compounds were characterized by spectral and
analytical methods.
5-HT4 receptors. The remarkable applications of these
compounds has not only prompted many chemists to syn-
thesize this type of compound, they have also become an
active research area of continuing interest [7].
Pyrazoles and their derivatives are also important
constituents of biologically active synthetic compounds
[8–12], because these systems have been associated with
useful biological activity for example antiviral [13], anti-
malarial [14, 15], antibacterial [16, 17], anticancer [18],
and antimicrobial [19] activity. Recently, pyrazolo[4,3-
c]quinolines were found to be highly fluorescent materials
in the blue region of the spectrum [20] and promising
materials for electroluminescence applications [21, 22].
These literature reports prompted us to develop a new
synthetic route to novel quinoline fused heterocycles. As a
part of our ongoing interest in this area [23–27], we have
reported the synthesis of 4-aryl/4-aminopyrimidines, fused
pyrimidines, benzo[h]quinolines, chromenes, quinolines,
and pyrazolo[3,4-b]pyridines. Recently, we have reported
the synthesis of pyrazolo[3,4-b]pyrrolo[2,3-d]pyridines
from 5-aminopyrazoles and cyclic b-ketoesters, and pyr-
azolo[3,4-b]pyridines present in biological molecules [28,
29]. In this communication we report a simple and efficient
route for the synthesis of novel benzo[h]-1,6-naphthyri-
dines and pyrazolo[4,3-c]quinolines.
Keywords Nucleophilic addition ꢀ
4-Aminoquinoline-3-carboxylates ꢀ Cyclocondensation ꢀ
Sodium dithionite ꢀ Reduction ꢀ Spectroscopy
Introduction
Functionalized quinolines and their benzo/hetero-fused
analogs are an important class of organic molecules that
have attracted much attention from synthetic and medicinal
chemists because of their presence in numerous natural
products and their wide range of physiological activity [1].
The quinolines, particularly those substituted at position 4,
have marked antimalarial, antibacterial, and anti-inflam-
matory activity [2–4]. It is also apparent from the literature
that benzo[h]-1,6-naphthyridine derivatives functionalized
at position 4 have been used as candidates for antimalarials
[5]. Recently, Hinschberger et al. [6] reported the synthesis
of new benzo[h]naphthyridines as selective antagonists of
Results and discussion
The intermediate ethyl 4-chloroquinoline-3-carboxylates
1a–1c required for the synthesis of quinoline fused hetero-
cycles were synthesized by a Gould–Jacobs reaction
between primary aromatic amines and diethyl ethoxymeth-
ylenemalonate via a chlorination reaction using phosphorus
oxychloride [30, 31]. The bifunctional compounds 1a–1c
B. K. Ghotekar (&) ꢀ M. G. Ghagare ꢀ R. B. Toche ꢀ
M. N. Jachak
Department of Chemistry, Organic Chemistry Research Centre,
K.T.H.M. College, Gangapur Road, Nashik 422002,
Maharashtra, India
e-mail: bhausaheb.ghotekar@rediffmail.com
123

170
B. K. Ghotekar et al.
were then used as precursors for syntheses of benzo[h]-1,6-
naphthyridines and pyrazolo[4,3-c]quinolines. Compounds
1a–1c on reaction with sodium azide in DMF at 20–25 °C
furnished a mixture of azidoquinoline derivatives 2a–2c and
triazinoquinolines 3a–3c in 70 and 10% yields, respectively
(Scheme 1) [32], which were separated by column chro-
matography. The structures of 2 and 3 were established on
the basis of spectral data and formulae confirmed by ele-
mental analysis. For instance, the IR spectrum of 2a showed
absorption bands at 1,708 and 2,100 cm-1 for carbonyl and
azido groups, respectively. However, in the IR spectrum of
3a a broad absorption band was observed at 3,425 cm-1 for
underwent a facile hydrogen deuterium exchange upon
addition of deuterium oxide. The mass spectrum of 4a
revealed a molecular ion peak at m/z = 250. Furthermore
this structure was supported by the 13C NMR spectrum,
which was in agreement with the proposed structure.
The compounds 4 containing amino and ester func-
tionality ortho to each other were utilized for the synthesis
of novel quinoline fused heterocycles. However, the reac-
tions of 4 with active methylene compounds proved to be
difficult, which might be because of the strong intramo-
lecular hydrogen bonding between the ester carbonyl and
the 4-amino group, as reported earlier by Bare et al. [33]
for pyrazolopyridines. Reaction of 4a and 4b only with
malononitrile in ethanol containing a catalytic amount of
KOH at reflux temperature for about 15 h was successfully
carried out to yield benzo[h]-1,6-naphthyridines 5a and 5b
in 56–60% yield (Scheme 1). The structures of compounds
5 were confirmed on the basis of spectral data and ele-
mental analysis. For example, the IR spectrum of 5a
contained strong absorption bands for the CN and OH
groups at 2,215 and 3,496 cm-1 and two bands for the NH2
group at 3,335–3,413 cm-1. The 1H NMR spectrum of
compound 5a contained two broad singlets at 4.74 and
5.46 ppm corresponding to the protons of the NH2 and OH
groups. Aromatic protons appeared in the range 7.18–
8.63 ppm. The mass spectrum of 5a contained character-
istics peaks for M? at m/z = 270 and 272, because of the
presence of chlorine. This structure was also confirmed by
the 13C NMR spectrum and elemental analysis in agree-
ment with the proposed structure.
1
the OH group. The H NMR spectrum of 2a in CDCl3
showed a triplet and a quartet at 1.38 and 4.39 ppm,
respectively, for ethoxy protons. In the 1H NMR spectrum of
3a these signals disappeared and the broad singlet for a
phenolic OH proton was observed at 10.52 ppm. The 13C
NMR spectrum of 2a exhibited peaks at 14.1 and 60.2 ppm
corresponding to OCH2CH3 carbons, which are absent in 3a.
Furthermore the molecular formulae of 2a and 3a were
confirmed by elemental analyses, which are in agreement
with the proposed structures.
Reduction of the N3 group was achieved successfully by
heating compounds 2a–2c in methanol at reflux tempera-
ture with a stoichiometric amount of sodium dithionite to
give the expected 4-aminoquinoline-3-carboxylates 4a–4c
in 60–65% yield (Scheme 1). The structures of 4 were
confirmed by spectroscopic and analytical data, for exam-
ple the IR spectrum of 4a showed bands of the elongation
vibrations of the C=O group at 1,695 cm-1 and two bands
for the NH2 group at 3,375–3,420 cm-1
.
In continuation of our research on the well known
intermediate compound 1 we carried out the reaction with a
primary aromatic amine and different hydrazines. In our
study we performed the SNAr reaction on 1 using the pri-
mary aromatic amine as nucleophile. Thus, reaction of 1a
and 1b with aniline at 130–140 °C furnished an open chain
derivative 6a and 6b in quantitative yield, and reaction of
The unexpected decrease of the ester C=O frequency by
50–60 cm-1 might be because of intramolecular hydrogen
bonding between a hydrogen atom of the NH2 group and the
oxygen of C=O [33]. In addition to ethoxy and aromatic
1
signals, the H NMR of compound 4a in DMSO-d6 con-
tained a broad singlet at 8.39 ppm for NH2 protons, which
Scheme 1
O
O
NH2
O
Cl
N3
R1
R2
R1
R2
R1
R2
Na2S2O4
NaN3/DMF
OEt
OEt
OEt
MeOH / reflux
4 hrs.
20-25 °C
2 hrs.
N
N
N
1a-1c
2a-2c
4a-4c
+
N
N
N
Ethanol/ KOH,
reflux
15 hrs.
CN
CN
R1
R2
OH
NH2
N
1,2,3,4 R1 R2
CN
N
3a-3c
R1
R2
a
b
c
Cl
Br
H
H
H
Cl
5
R1 R2
OH
a
b
Cl
Br
H
H
N
5a-5b
123

Synthesis of new quinoline fused heterocycles
171
1a and 1b with substituted hydrazines in ethanol containing
a catalytic amount of triethylamine or piperidine at reflux
for 2–3 h yielded the targeted pyrazolo[4,3-c]quinolines
7a–7f in 70–80% yield (Scheme 2). IR, 1H NMR, 13C
NMR, MS, and elemental analysis were used to deduce the
structures of 6 and 7. For example, the IR of compound 7a
ppm from the internal standard tetramethylsilane. The
solvent for NMR spectra was deuterochloroform unless
otherwise stated. Infrared spectra were taken on a Shimadzu
IR-408 instrument in potassium bromide pellets unless
otherwise stated. Elemental analyses were performed on a
Hosli CH-Analyzer and results were within 0.3% of the
calculated values. 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), carried out on 0.2 mm silica gel 60
F254 (Merck) plates using UV light (254 and 366 nm) for
detection. Common reagent-grade chemicals are either
commercially available and were used without further
purification or were prepared by standard literature
procedures.
contained NH stretching bands at 3,310 and 3,400 cm-1
.
The 1H NMR spectrum of 7a in DMSO-d6 contained broad
singlets at 11.43 and 12.49 ppm corresponding to two NH
protons. The mass spectrum of this compound contained
M? peaks at m/z = 219 and 221, because of the presence
of chlorine. Furthermore the 13C NMR and elemental
analysis data of this compound were in agreement with the
proposed structure.
Conclusion
We have used a simple and convenient method for syn-
thesis of novel quinoline fused heterocycles such as
benzo[h]-1,6-naphthyridines and pyrazolo[4,3-c]quinolines
starting from ethyl 4-chloroquinoline-3-carboxylates with
simple work up and clean products.
General procedure for synthesis of ethyl
4-azidoquinoline-3-carboxylates 2a–2c
and triazino[5,4-c]quinolines 3a–3c
A mixture of ethyl quinoline-3-carboxylate 1 (0.01 mol)
and 0.650 g sodium azide (0.01 mol) in 15 cm3 DMF was
stirred at 20–25 °C until the starting material had disap-
peared (2 h, checked by TLC monitoring). The solution
was then poured into 50 cm3 cold water and stirred for
30 min. The solid obtained was isolated by filtration,
washed with 100 cm3 cold water, and dried. It afforded a
mixture of compounds 2 and 3 which was separated by
column chromatography using 8:2 toluene–acetone as
Experimental
Melting points were determined on a Barnstead Electro
Thermal melting point apparatus, Mod. No. IA-9200 in
open capillary tubes. The H NMR (300 MHz) and 13C
1
NMR (75 MHz) spectra were recorded on a Varian XL-300
spectrometer. Chemical shifts were reported in d units in
Scheme 2
H
O
N
R1
R2
H2N
130-140 °C
OEt
O
Cl
N
1 h
R1
R2
6a-6b
OEt
R3
H
N
N
N
R1
O
1a-1b
R3-NHNH2
Ethanol, Et3N /
reflux, 2-3 hrs.
R2
N
7a-7f
R1 R2 R3
R1 R2
1,7
1,6
a
b
Cl
Br
H
H
a
b
c
d
e
f
Cl
Cl
Cl
Br
Br
Br
H
H
H
H
H
H
H
Ph
CH2CH2OH
H
Ph
CH2CH2OH
123

172
B. K. Ghotekar et al.
9-Bromo[1,2,3]triazino[5,4-c]quinolin-4-ol
(3b, C10H5BrN4O)
eluent to afford compounds 2 in 70% yield and 3 in 10%
yield.
Yield 0.332 g (12%); m.p.: 179 °C (ethanol); Rf = 0.30
(toluene–acetone 8:2); IR (KBr): vꢀ ¼ 3;410; 2,900, 2,820,
1,614, 1,532, 1,440, 1,352, 1,271, 1,021, 830, 801,
Ethyl 4-azido-6-chloroquinoline-3-carboxylate
(2a, C12H9ClN4O2)
Yield 1.93 g (70%); m.p.: 291 °C (ethanol); Rf = 0.64
(toluene–acetone 8:2); IR (KBr): vꢀ ¼ 3;087; 2,918, 2,100,
1,708, 1,581, 1,484, 1,367, 1,307, 1,204, 1,020, 980, 835,
652 cm-1 1H NMR (300 MHz, CDCl3): d = 7.75 (dd,
;
J = 8.2, 2.2 Hz, 1H, C8–H), 7.91 (d, J = 2.2 Hz, 1H, C10–
H), 7.96 (d, J = 8.2 Hz, 1H, C7–H), 8.86 (s, 1H, C5–H),
10.15 (bs, 1H, OH) ppm; 13C NMR (75 MHz, CDCl3):
d = 121.1, 121.6, 124.3, 129.3, 130.5, 133.5, 134.6, 147.6,
148.6, 151.5 ppm.
1
720, 625 cm-1; H NMR (300 MHz, CDCl3): d = 1.38 (t,
J = 7 Hz, 3H, CH3), 4.39 (q, J = 7 Hz, 2H, OCH2), 7.69
(dd, J = 8.7, 2.4 Hz, 1H, C7–H), 7.72 (d, J = 2.4 Hz, 1H,
C5-H), 8.24 (d, J = 8.7 Hz, 1H, C8–H), 9.10 (s, 1H, C2–H)
ppm; 13C NMR (75 MHz, CDCl3): d = 14.1 (CH3), 60.2
(OCH2), 124.1, 127.4, 129.4, 130.4, 133.2, 133.9, 138.0,
146.9, 147.7, 166.3 ppm.
8-Chloro[1,2,3]triazino[5,4-c]quinolin-4-ol
(3c, C10H5ClN4O)
Yield 0.301 g (13%); m.p.: 165 °C (ethanol); Rf = 0.26
(toluene–acetone 8:2); IR (KBr): vꢀ ¼ 3;400; 2,933, 2,800,
1,624, 1,502, 1,445, 1,352, 1,278, 1,023, 830, 803,
;
650 cm-1 1H NMR (300 MHz, CDCl3): d = 7.44 (dd,
J = 8.6, 2.3 Hz, 1H, C9–H), 7.62 (d, J = 8.6 Hz, 1H, C10-
H), 8.06 (d, J = 2.3 Hz, 1H, C7–H), 8.81 (s, 1H, C5–H)
10.24 (bs, 1H, OH) ppm; 13C NMR (75 MHz, CDCl3):
d = 122.0, 124.4, 128.6, 129.1, 129.8, 135.2, 135.5, 147.6,
149.5, 155.5 ppm.
Ethyl 4-azido-6-bromoquinoline-3-carboxylate
(2b, C12H9BrN4O2)
Yield 2.18 g (68%); m.p.: 277 °C (ethanol); Rf = 0.66
(toluene–acetone 8:2); IR (KBr): vꢀ ¼ 3;065; 2,910, 2,110,
1,711, 1,583, 1,486, 1,367, 1,304, 1,202, 1,025, 983, 836,
1
725, 620 cm-1; H NMR (300 MHz, CDCl3): d = 1.35 (t,
J = 6.9 Hz, 3H, CH3), 4.33 (q, J = 6.9 Hz, 2H, OCH2),
7.80 (dd, J = 8.7, 2.4 Hz, 1H, C7-H), 7.91 (d, J = 2.4 Hz,
1H, C5–H), 8.29 (d, J = 8.7 Hz, 1H, C8–H), 9.22 (s, 1H,
C2–H) ppm; 13C NMR (75 MHz, CDCl3): d = 15.3 (CH3),
62.9 (OCH2), 122.0, 123.2, 126.7, 130.4, 130.7, 135.9,
138.0, 147.7, 149.5, 168.2 ppm.
General procedure for synthesis of ethyl
4-aminoquinoline-3-carboxylates 4a–4c
A solution of 2 (0.01 mol) and sodium dithionite
(0.01 mol) in 15 cm3 methanol was heated under reflux for
4 h. The solution was then allowed to cool and poured into
30 cm3 ice–cold water, and the mixture was stirred for
30 min. The precipitated solid was isolated by filtration,
dried, and recrystallized from an appropriate solvent to
afford 4 in good yield.
Ethyl 4-azido-7-chloroquinoline-3-carboxylate
(2c, C12H9ClN4O2)
Yield 1.76 g (64%); m.p.: 281 °C (ethanol); Rf = 0.62
(toluene–acetone 8:2); IR (KBr): vꢀ ¼ 3;065; 2,910, 2,115,
1,703, 1,588, 1,490, 1,368, 1,309, 1,201, 1,029, 988, 838,
1
720, 626 cm-1; H NMR (300 MHz, CDCl3): d = 1.30 (t,
J = 7.1 Hz, 3H, CH3), 4.29 (q, J = 7.1 Hz, 2H, OCH2),
7.60 (dd, J = 8.7, 2.4 Hz, 1H, C6–H), 7.82 (d, J = 8.7 Hz,
1H, C5–H), 8.10 (d, J = 2.4 Hz, 1H, C8–H), 9.50 (s, 1H,
C2–H) ppm; 13C NMR (75 MHz, CDCl3): d = 14.9 (CH3),
60.9 (OCH2), 123.0,126.8, 129.0, 129.5, 131.2, 137.6,
139.0, 148.6, 149.5, 170.3 ppm.
Ethyl 4-amino-6-chloroquinoline-3-carboxylate
(4a, C12H11ClN2O2)
Yield 1.62 g (65%); m.p.: 281 °C (DMF–ethanol);
Rf = 0.35 (toluene–ethyl acetate 8:2); IR (KBr): vꢀ ¼
3;420; 3,375, 3,095, 2,985, 2,904, 1,695, 1,624, 1,554,
1,523, 1,465, 1,384, 1,292, 1,195, 1,028, 8,68, 827, 650,
9-Chloro[1,2,3]triazino[5,4-c]quinolin-4-ol
(3a, C10H5ClN4O)
1
603 cm-1; H NMR (300 MHz, DMSO-d6): d = 1.33 (t,
J = 6.9 Hz, 3H, CH3), 4.30 (q, J = 6.9 Hz, 2H, OCH2),
7.73 (dd, J = 8.1, 2.3 Hz, 1H, C7–H), 7.80 (d,
J = 2.3 Hz, 1H, C5–H), 8.39 (bs, 2H, NH2), 8.55 (d,
J = 8.1 Hz, 1H, C8–H), 8.89 (s, 1H, C2–H) ppm; 13C
NMR (75 MHz, DMSO-d6): d = 15.2 (CH3), 59.2
(OCH2), 114.3, 120.1, 121.3, 130.7, 131.9, 133.6,
147.5, 148.0, 155.6, 165.3 ppm; MS (70 eV): m/z
= 252 ([M?2]?), 250 (M?), 236, 222, 204, 190, 177,
161, 150, 138, 114, 102, 87, 75, 63, 43.
Yield 0.232 g (10%); m.p.: 198 °C (ethanol); Rf = 0.28
(toluene–acetone 8:2); IR (KBr): vꢀ ¼ 3;425; 2,920, 2,850,
1,624, 1,535, 1,444, 1,356, 1,273, 1,020, 833, 808,
653 cm-1 1H NMR (300 MHz, CDCl3): d = 7.60 (dd,
;
J = 8.5, 2.4 Hz, 1H, C8–H), 7.83 (d, J = 2.4 Hz, 1H, C10-
H), 7.94 (d, J = 8.5 Hz, 1H, C7-H), 8.70 (s, 1H, C5–H),
10.52 (bs, 1H, OH) ppm; 13C NMR (75 MHz, CDCl3):
d = 121.9, 126.0, 127.0, 130.5, 131.5, 132.3, 134.6, 145.0,
148.2, 153.3 ppm.
123

Synthesis of new quinoline fused heterocycles
173
Ethyl 4-amino-6-bromoquinoline-3-carboxylate
(4b, C12H11BrN2O2)
2-Amino-9-bromo-4-hydroxybenzo[h]-1,6-naphthyridine-
3-carbonitrile (5b, C13H7BrN4O)
Yield 1.82 g (62%); m.p.: 262 °C (DMF–ethanol);
Rf = 0.39 (toluene–ethyl acetate 8:2); IR (KBr): vꢀ ¼
3;425; 3,380, 3,098, 2,975, 2,904, 1,695, 1,629, 1,559,
1,529, 1,469, 1,389, 1,290, 1,191, 1,026, 866, 828, 655,
Yield 1.76 g (56%); m.p.: 257 °C (DMF); Rf = 0.30
(toluene–ethyl acetate 6:4); IR (KBr): vꢀ ¼ 3;480; 3,435,
3,380, 3,096, 2,220, 1,617, 1,556, 1,522, 1,470, 1,358,
1
1,295, 1,190, 1,036, 865, 822, 802, 602 cm-1; H NMR
1
609 cm-1; H NMR (300 MHz, DMSO-d6): d = 1.40 (t,
(300 MHz, DMSO-d6): d = 4.86 (bs, 2H, NH2), 6.13 (bs,
1H, OH), 7.75–8.13 (m, 3H, Ar–H), 9.05 (s, 1H, C5–H)
ppm; 13C NMR (75 MHz, DMSO-d6): d = 82.4, 108.8,
116.8, 121.1, 124.3, 129.3, 130.5, 133.5, 136.3, 147.6,
148.6, 162.8, 171.8 ppm.
J = 6.9 Hz, 3H, CH3), 4.36 (q, J = 6.9 Hz, 2H, OCH2),
7.60 (dd, J = 8.1, 2.3 Hz, 1H, C7–H), 7.86 (d, J = 2.3 Hz,
1H, C5–H), 7.95 (d, J = 8.1 Hz, 1H, C8–H), 8.50 (bs, 2H,
NH2), 9.03 (s, 1H, C2–H) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 14.1 (CH3), 60.2 (OCH2), 114.0, 118.6,
120.7, 123.4, 130.7, 135.6, 148.0, 150.1, 155.6, 169.1 ppm.
General procedure for synthesis of ethyl
4-(phenylamino)quinoline-3-carboxylates 6a and 6b
Ethyl 4-amino-7-chloroquinoline-3-carboxylate
(4c, C12H11ClN2O2)
A mixture of 1 (0.01 mol) and aniline (0.04 mol) was
heated at 130–140 °C for about 1 h, until TLC showed the
starting material had disappeared. The mixture was then
cooled to 20 °C, 20 cm3 methanol was added, and the
resulting solid was isolated by filtration under vacuum,
washed with methanol, dried, and recrystallized from an
appropriate solvent to afford 6 in good yield.
Yield 1.50 g (60%); m.p.: 269 °C (DMF–ethanol);
Rf = 0.34 (toluene–ethyl acetate 8:2); IR (KBr): vꢀ ¼
3;422; 3,350, 3,094, 2,977, 2,910, 1,690, 1,620, 1,555,
1,529, 1,469, 1,380, 1,290, 1,191, 1,026, 866, 828, 624,
1
604 cm-1; H NMR (300 MHz, DMSO-d6): d = 1.30 (t,
J = 7 Hz, 3H, CH3), 4.29 (q, J = 7 Hz, 2H, OCH2), 7.54
(dd, J = 8.1, 2.3 Hz, 1H, C6-H), 7.78 (d, J = 8.1 Hz, 1H,
C5–H), 8.09 (d, J = 2.3 Hz, 1H, C8–H), 8.55 (bs, 2H,
NH2), 9.30 (s,1H, C2–H) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 14.6 (CH3), 60.8 (OCH2), 113.4, 118.7,
123.9, 128.2, 129.3, 137.3, 148.9, 150.1, 156.5, 168.1 ppm.
Ethyl 6-chloro-4-(phenylamino)quinoline-3-carboxylate
(6a, C18H15ClN2O2)
Yield 2.15 g (66%); m.p.: 178 °C (DMF–ethanol);
Rf = 0.47 (toluene–acetone 8:2); IR (KBr): vꢀ ¼ 3;325;
3,095, 2,985, 2,904, 1,697, 1,624, 1,554, 1,523, 1,465,
1
General procedure for synthesis of 2-amino-4-
hydroxybenzo[h]-1,6-naphthyridine-3-carbonitriles
5a and 5b
1,384, 1,292, 1,195, 1,028, 868, 827, 650, 603 cm-1; H
NMR (300 MHz, DMSO-d6): d = 1.14 (t, J = 7 Hz, 3H,
CH3), 4.05 (q, J = 7 Hz, 2H, OCH2), 7.32–8.24 (m, 8H,
Ar–H), 8.30 (bs, 1H, NH), 9.06 (s, 1H, C2–H) ppm.
A solution of 4 (0.01 mol) and 0.65 g malononitrile
(0.01 mol) in 15 cm3 ethanol containing a catalytic amount
of potassium hydroxide was heated under reflux for 15 h.
The solution was then cooled to room temperature and the
precipitated solid was isolated by filtration, dried, and
recrystallized from an appropriate solvent to afford 5 in
good yield.
Ethyl 6-bromo-4-(phenylamino)quinoline-3-carboxylate
(6b, C18H15BrN2O2)
Yield 2.52 g (68%); m.p.: 146 °C (DMF–ethanol);
Rf = 0.49 (toluene–acetone 8:2); IR (KBr): vꢀ ¼ 3;335;
3,090, 2,989, 2,908, 1,697, 1,620, 1,552, 1,520, 1,465,
1,384, 1,298, 1,195, 1,020, 866, 827, 650, 603 cm-1; H
1
NMR (300 MHz, DMSO-d6): d = 1.16 (t, J = 7 Hz, 3H,
CH3), 4.10 (q, J = 7 Hz, 2H, OCH2), 7.45–8.15 (m, 8H,
Ar–H), 8.36 (bs, 1H, NH), 9.08 (s, 1H, C2–H) ppm.
2-Amino-9-chloro-4-hydroxybenzo[h]-1,6-naphthyridine-
3-carbonitrile (5a,C13H7ClN4O)
Yield 1.62 g (60%); m.p.: 246 °C (DMF); Rf = 0.32
(toluene–ethyl acetate 6:4); IR (KBr): vꢀ ¼ 3;496; 3,413,
3,335, 3,091, 2,215, 1,617, 1,553, 1,524, 1,470, 1,358,
General procedure for synthesis
of 3H-pyrazolo[4,3-c]quinolin-3-ones 7a–7f
1
1,295, 1,188, 1,032, 866, 825, 800, 604 cm-1; H NMR
(300 MHz, DMSO-d6): d = 4.74 (bs, 2H, NH2), 5.46 (bs,
1H, OH), 7.18–8.03 (m, 3H, Ar–H), 8.63 (s, 1H, C5–H)
ppm; 13C NMR (75 MHz, DMSO-d6): d = 82.6, 109.1,
117.7, 126.0, 127.0, 130.5, 131.5, 132.3, 136.5, 145.0,
148.6, 162.8, 171.2 ppm; MS (70 eV): m/z = 272
([M ? 2]?), 270 (M?), 252, 250, 236, 222, 206, 193,
178, 163, 154, 140, 116, 100, 89, 76, 66, 46.
A solution of compound 1 (0.01 mol) and different
hydrazines (0.01 mol) in 15 cm3 ethanol containing
0.5 cm3 triethylamine was heated under reflux for 2–3 h.
The excess solvent was removed under reduced pressure.
The solid obtained was filtered, washed with ethanol, dried,
and recrystallized from an appropriate solvent to afford 7 in
70–80% yield.
123

174
B. K. Ghotekar et al.
8-Chloro-1,2-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one
(7a, C10H6ClN3O)
2,800, 1,691, 1,615, 1,529, 1,455, 1,369, 1,104, 781,
585 cm-1 1H NMR (300 MHz, DMSO-d6): d = 7.19–
;
Yield 1.66 g (76%); m.p.: 356 °C (DMF); Rf = 0.70
(toluene–acetone 8:2); IR (KBr): vꢀ ¼ 3;400; 3,310, 3,091,
2,925, 2,853, 1,692, 1,612, 1,527, 1,459, 1,336, 1,295,
;
1,095, 813, 720, 621, 551 cm-1 1H NMR (300 MHz,
7.78 (m, 5H, Ar–H), 8.20–8.35 (m, 3H, Ar–H), 8.78 (s, 1H,
C4–H), 12.08 (bs, 1H, NH) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 120.8, 121.2, 126.5, 126.9, 127.8, 129.5,
130.9, 131.9, 132.1, 134.7, 139.1, 141.5, 145.0, 148.6 ppm.
DMSO-d6): d = 7.60–7.96 (m, 3H, Ar–H), 8.50 (s,1H,
C4–H), 11.43 (bs, 1H, NH), 12.49 (bs, 1H, NH) ppm; 13C
NMR (75 MHz, DMSO-d6): d = 121.9, 126.0, 127.0,
130.5, 131.5, 132.3, 138.1, 145.0, 148.6, 155.4 ppm; MS
(70 eV): m/z = 221 ([M ? 2]?), 219 (M?), 206, 190, 176,
162, 152, 137, 126, 99, 98, 74, 63, 50, 38.
8-Bromo-1,2-dihydro-2-(2-hydroxyethyl)-3H-pyrazolo
[4,3-c]quinolin-3-one (7f, C12H10BrN3O2)
Yield 2.24 g (73%); m.p.: 304 °C (DMF); Rf = 0.74
(toluene–acetone 9:1); IR (KBr): vꢀ ¼ 3;400; 3,175, 3,095,
2,901, 1,690, 1,615, 1,554, 1,514, 1,460, 1,377, 1,355,
1,298, 1,185, 1,151, 1,108, 1,021, 959, 869, 825, 810, 645,
1
8-Chloro-1,2-dihydro-2-phenyl-3H-pyrazolo[4,3-c]quino-
lin-3-one (7b, C16H10ClN3O)
605 cm-1; H NMR (300 MHz, DMSO-d6): d = 2.45 (bs,
1H, OH), 3.96 (t, J = 7 Hz, 2H, CH2), 4.09 (t, J = 7 Hz,
2H, OCH2), 7.65–8.10 (m, 3H, Ar–H), 8.93 (s, 1H, C4–H),
11.55 (bs, 1H, NH) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 58.2, 62.1, 122.1, 126.6, 128.1, 130.8, 131.9, 132.8,
135.2, 138.2, 145.0, 149.2 ppm.
Yield 2.30 g (78%); m.p.: 368 °C (DMF); Rf = 0.61
(toluene–acetone 8:2); IR (KBr): vꢀ ¼ 3;422; 3,091, 2,852,
2,800, 1,694, 1,619, 1,527, 1,450, 1,360, 1,104, 784,
;
581 cm-1 1H NMR (300 MHz, DMSO-d6): d = 7.14–
7.71 (m, 5H, Ar–H), 8.15–8.20 (m, 3H, Ar–H), 8.75 (s, 1H,
C4-H), 12.20 (bs, 1H, NH) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 120.2, 121.6, 126.0, 126.3, 127.3, 129.4,
130.5, 131.5, 132.3, 134.6, 139.7, 141.0, 145.0, 148.6 ppm;
MS (70 eV): m/z = 297 ([M ? 2]?), 295 (M?), 294, 268,
266, 238, 215, 204, 189, 176, 162, 147, 126, 98, 77, 63, 51,
39.
Acknowledgments The authors thank the University Grants Com-
mission (UGC), New Delhi, India, for financial support and Professor
D.D. Dhavale, Department of Chemistry, University of Pune, India
for his encouragement and useful discussion.
References
8-Chloro-1,2-dihydro-2-(2-hydroxyethyl)-3H-pyrazol-
o[4,3-c]quinolin-3-one (7c, C12H10ClN3O2)
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Yield 1.89 g (72%); m.p.: 323 °C (DMF); Rf = 0.72
(toluene–acetone 8:2); IR (KBr): vꢀ ¼ 3;395; 3,153, 3,091,
2,903, 1,695, 1,618, 1,554, 1,524, 1,469, 1,379, 1,359,
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605 cm-1; H NMR (300 MHz, DMSO-d6): d = 2.40 (bs,
1H, OH), 3.92 (t, J = 7 Hz, 2H, CH2), 4.01 (t, J = 7 Hz,
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8-Bromo-1,2-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one
(7d, C10H6BrN3O)
Yield 1.95 g (74%); m.p.: 338 °C (DMF); Rf = 0.68
(toluene–acetone 8:2); IR (KBr): vꢀ ¼ 3;420; 3,330, 3,096,
2,925, 2,850, 1,690, 1,612, 1,527, 1,459, 1,366, 1,294,
;
1,095, 813, 710, 631, 541 cm-1 1H NMR (300 MHz,
DMSO-d6): d = 7.65–7.94 (m, 3H, Ar–H), 8.45 (s, 1H, C4-
H), 11.48 (bs, 1H, NH), 12.52 (bs, 1H, NH) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 121.2, 126.5, 127.8, 131.1,
131.9, 133.1, 139.1, 146.2, 149.2, 156.2 ppm.
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8-Bromo-1,2-dihydro-2-phenyl-3H-pyrazolo[4,3-c]quino-
lin-3-one (7e, C16H10BrN3O)
Yield 2.61 g (77%); m.p.: 320 °C (DMF); Rf = 0.63
(toluene–acetone 8:2); IR (KBr): vꢀ ¼ 3;433; 3,096, 2,848,
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Synthesis of new quinoline fused heterocycles
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123