Synthesis of pyrazolo[4,3-c]quinolin-4-ones and indolo[3,2-c]quinolin-6- ones by the photocyclization of N-aryl-o-chloroheteroarenecarboxamides

Article abstract of DOI:10.1055/s-2008-1067013

An efficient synthesis of pyrazolo[4,3-c]quinolin-4-ones and indolo[3,2-c]quinolin-6-ones has been achieved by the photocyclization of 5-chloro-N-phenyl-1H-pyrazole-4-carboxamides and 2-chloro-N-phenyl-1H-indole-3- carboxamides in acetone. Georg Thieme Ve

Full text of DOI:10.1055/s-2008-1067013

PAPER
1517
Synthesis of Pyrazolo[4,3-c]quinolin-4-ones and Indolo[3,2-c]quinolin-6-ones
by the Photocyclization of N-Aryl-o-chloroheteroarenecarboxamides
Synthesis of
P
h
yrazolo[4,3-
c
e
]quinolin-
n
4-ones and In
c
dolo[3,2-
c
]
i
quinolin-6-o
Lnes u, Wei Zhang,* Jinhui Pan, Jie Zhang
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax +86(931)8625657; E-mail: zhangwei6275@lzu.edu.cn; E-mail: Zhang_wei6275@yahoo.com
Received 28 November 2007; revised 4 February 2008
O
R1
Abstract: An efficient synthesis of pyrazolo[4,3-c]quinolin-4-ones
and indolo[3,2-c]quinolin-6-ones has been achieved by the photo-
cyclization of 5-chloro-N-phenyl-1H-pyrazole-4-carboxamides and
2-chloro-N-phenyl-1H-indole-3-carboxamides in acetone.
R1
O
R2
R2
hν
N
N
N
N
R3
R3
Me2CO
N
N
Cl
Ph
Ph
Key words: photocyclization, pyrazolo[4,3-c]quinolin-4-one, in-
dolo[3,2-c]quinolin-6-one, 5-chloro-N-phenyl-1H-pyrazole-4-car-
boxamides, 2-chloro-N-phenyl-1H-indole-3-carboxamides
3a–j
1a–j
Scheme 1
The synthesis of biaryls has attracted great attention over
the last few decades because biaryl structures are present
in many natural products that have biological activity. The
methods for synthesizing these biaryl derivatives, e.g.
Ullmann, Suzuki, Hiyama, Negishi, and Kumada coupling
reactions, have been continuously developed.1 The photo-
induced coupling reactions of haloarenes with arenes has
supplied an alternative to the above metal-catalyzed reac-
tions.2 The advantage of photocoupling reactions over
metal-catalyzed coupling reactions is that only one arene
needs activating groups and this process is, therefore, in-
herently favorable from the point of view of atom econo-
my. Recently Albini reported the metal-free
intermolecular photocoupling reactions of amino- or hy-
droxy-substituted aryl halides with polyalkylbenzenes.2
By comparison the intramolecular photocoupling reac-
tions used to construct polycyclic systems have been stud-
ied more extensively.3 For example, Kanaoka and
Ninomiya investigated the photocyclization of many
amides and enamides, respectively.3b–e It was found, how-
ever, that the substrates used in the synthesis of polycycles
were aryl-substituted or o-haloaryl-substituted com-
pounds, few o-haloheteroaryl substrates were considered
in this synthetic strategy.4 Therefore, we are interested in
the intramolecular photocoupling reactions of halo-
heteroaromatics in relation to the synthetic methodology
and the reaction mechanism. We wish to report herein the
synthesis of pyrazolo[4,3-c]quinolin-4-ones and indo-
lo[3,2-c]quinolin-6-ones by photocyclization of 5-chloro-
N-phenyl-1H-pyrazole-4-carboxamides and 2-chloro-N-
phenyl-1H-indole-3-carboxamides.
Pyrazolo[4,3-c]quinolin-4-ones and indolo[3,2-c]quino-
lin-6-ones are well known for their potential biological
and pharmacological activity, such as antihypertensive,
anti-inflammatory, antitumor, antiviral, antimalarial, and
antipyretic activities.5 Different methods for the synthesis
of these compounds have been reported. The usual meth-
ods for the synthesis of pyrazolo[4,3-c]quinolin-4-one
cores and indolo[3,2-c]quinolin-6-one cores are by ring
closure of the pyrazole or indole ring of functionalized
quinolin-4-ones or ring closure of the quinolone ring of
functionalized pyrazoles or indoles.6 For example, indo-
lo[3,2-c]quinolin-6-ones could be synthesized by tributyl-
stannane-mediated radical cyclization of N-(2-
bromophenyl)-1H-indole-3-carboxamides.6d Our new
synthetic method for the synthesis of pyrazolo[4,3-c]quin-
olin-4-ones and indolo[3,2-c]quinolin-6-ones reported in
this paper are based on the construction of a quinolone
ring by photocoupling of 5-chloro-1H-pyrazole-4-carbox-
amine or 2-chloro-1H-indole-3-carboxamines containing
O
O
R2
N
R2
hν
Me2CO
N
R3
N
R3
N
R1
Cl
R1
4a–e
2a–e
Scheme 2
SYNTHESIS 2008, No. 10, pp 1517–1522
x
x.
x
x
.
2
0
0
8
Advanced online publication: 11.04.2008
DOI: 10.1055/s-2008-1067013; Art ID: F22207SS
© Georg Thieme Verlag Stuttgart · New York

1518
S. Lu et al.
PAPER
Table 1 Photocyclization of 2-Chloro-N-phenyl-1H-pyrazole-4-carboxamides and 2-Chloro-N-phenyl-1H-indole-3-carboxamides
Entry
1
Substrate R1
R2
R3
H
H
H
H
Time (h)
40
19
15
12
12
13
11
6
Product
3a
Yield (%) Mp (Lit.) (°C)
278–280 (280–2826a)
1a
1b
1c
1d
1e
1f
Me
H
80
85
87
95
73
60
75
80
63
62
85
87
82
93
81
2
Me
Me
Me
Me
Me
Ph
Me
3b
3c
186–187 (181–1836a)
172–173
3
Et
4
i-Pr
3d
3e
165–167
5
CH2CH2
CH2CH2CH2
Me
150–152
6
3f
204–206 (204–2076a)
200–201 (200–2026a)
186–190
7
1g
1h
1i
H
H
3g
8
Ph
i-Pr
3h
3i
9
Ph
CH2CH2
CH2CH2CH2
Me
9
194–196
10
11
12
13
14
15
1j
Ph
12
19
15
12
19
13
3j
230–231 (232–2346a)
205–207 (207–2086e)
182–183
2a
2b
2c
2d
2e
Me
Me
Me
Ph
H
H
4a
Et
4b
4c
CH2CH2CH2
Me
172–174 (170–1716f)
210–212 (218.56g)
205–207
H
4d
4e
Ph
CH2CH2CH2
N-aryl rings as shown in Schemes 1 and 2. The starting
materials, 2-chloro-N-phenyl-1H-pyrazole-4-carbox-
amides 1a–j and 2-chloro-N-phenyl-1H-indole-3-carbox-
amides 2a–e were prepared from pyrazol-5-ones and
indol-2-ones by modified literature methods.7
Irradiation at l ≥ 300 nm of and acetone solution (50 mL)
of 1.0 mmol of 5-chloro-N-phenyl-1H-pyrazole-4-car-
boxamides 1a–j or 2-chloro-N-phenyl-1H-indole-3-car-
boxamides 2a–e containing 0.1 mol·L–1 aqueous sodium
carbonate (1 mL) with a high-pressure mercury lamp
(1000 W) at ambient temperature for an appropriate time
afforded the corresponding pyrazolo[4,3-c]quinolin-4-
ones 3a–j or indolo[3,2-c]quinolin-6-ones 4a–e in moder-
ate to high yields as listed in Table 1. All products were
Figure 1 X-ray structure (ORTEP drawing) of 3c
Table 2 Photocyclization of 1b in Different Solvents
1
fully identified by H and 13C NMR and MS, and the
Solvent
CH2Cl2
MeCN
Time (h) Conversion (%) Yield (%)
structure of 3c was further confirmed by its X-ray struc-
ture as depicted in Figure 1. In general, 5-chloro-N-phe-
nyl-1H-pyrazole-4-carboxamides 1a–j and 2-chloro-N-
phenyl-1H-indole-3-carboxamides 2a–e afforded exclu-
sively the cyclization products pyrazolo[4,3-c]quinolin-4-
ones 3a–j and indolo[3,2-c]quinolin-6-ones 4a–e with no acetone
photo-Fries-type products found. In the cases of 1e and 1i,
a small quantity of the dehydrogenated products from 3e
and 3i appeared.
45
45
65
70
90
95
68
60
82
85
CH2Cl2 + 10% acetone 20
19
Therefore acetone was selected as the solvent in all pho-
tocyclization reactions.
The N-substituent R2 on the carboxamide in 5-chloro-N-
phenyl-1H-pyrazole-4-carboxamides has a great effect on
the reactivity of 1a–d because it could be seen that the
time needed to complete the photoreaction decreased
It was found that the photocyclization reaction in aceto-
nitrile or dichloromethane was slow and the addition of
acetone could efficiently accelerate the reaction and in-
crease the yield as shown in Table 2. This result may be
attributed to the photosensitization effect of acetone.
Synthesis 2008, No. 10, 1517–1522 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrazolo[4,3-c]quinolin-4-ones and Indolo[3,2-c]quinolin-6-ones
1519
Me
O
Me
Me
O
O
R2
Me
N
N
N
N
N
N
N
N
N
Cl
R2
Ph
Cl
Ph
Cl
Ph
1b
s-trans 1a–d
s-cis 1a–d
*
Me2CO
Scheme 3
hν
from the reaction of 1a to the reaction of 1d (Table 1).
This effect might come from the influence of R2 on the
proportion of the two conformations of 1a–d (Scheme 3).
Although only s-cis 1a–d could be cyclized to give 3a–d,
the s-cis isomer is not thermomechanically dominant. It
can be inferred that the proportion of s-cis 1a–d increased
with R2 becoming larger from hydrogen to isopropyl, and
this leads to the increase of photocyclization rates from 1a
to 1d.
Me2CO
O
Me
*
Me
O
Me
Me
N
N
N
N
N
N
Cl
Ph
Ph
Cl
O
It was found that irradiation of 1a in dichloromethane in
the presence of triethylamine produced a reductive
dechlorination product 3-methyl-N,1-diphenyl-1H-pyra-
zole-4-carboxamide, and in benzene in the absence of tri-
ethylamine it produced a solvent-coupled product 3-
methyl-N,1,5-triphenyl-1H-pyrazole-4-carboxamide. It
could be supposed that the photoreaction of 1a was not a
pericyclic reaction of the 6p electron system, but that the
pyrazolyl radical was produced by photodissociation of
the C–Cl bond before cyclization, and this radical could
abstract a hydrogen atom from triethylamine or coupled
with benzene. In order to confirm this proposal, the
dechlorination product 3-methyl-N,1-diphenyl-1H-pyra-
zole-4-carboxamide obtained from the photoreaction of
1a with triethylamine was irradiated in the presence of ox-
ygen or iodine in dichloromethane for 48 hours, but no re-
action was detected. Comparatively, irradiation of 1a in
methanol or in aqueous sodium carbonate/acetone solu-
tion gave the photocyclization product 3a as the sole prod-
uct in both deoxygenated and aerated solutions. These
results might further exclude the pericyclic reaction
mechanism.
Grimshaw3f and Yong-Tae Park3i proposed a radical-
involved mechanism in the photocyclization of 2-chlo-
robenzanilide and 2-halo-N-pyridinylbenzamide in 1980
and 2001, respectively. In the mechanism, homolytic
cleavage of the C–Cl bond gave phenyl and chlorine rad-
icals, and the N-phenyl or N-pyridinyl ring could, through
its p-cloud, complex the developing radical center in
stretching the C–Cl bond and thus lowered the transition
energy for the reaction. The photoreduction product could
be formed by hydrogen atom abstraction of the phenyl s-
radical from the environment. In our investigation, the
photoreaction of 1a in methanol gave only the photocy-
clization product 3a without the hydrogen-abstraction
product of the free pyrazolyl radical from methanol or the
methoxy-substituted product, but photoreaction of anoth-
er similar substrate 5-chloro-N-cyclohexyl-3-methyl-1-
phenyl-1H-pyrazole-4-carboxamide, in which the N-phe-
nyl group of 1a was replaced by the N-cyclohexyl group,
Me
N
O
Me
Me
Me
N
N
N
– HCl
N
N
Ph
H
Ph
Cl
3b
Scheme 4
gave reductive photodechlorination product N-cyclohex-
yl-3-methyl-1-phenyl-1H-pyrazole-4-carboxamide under
the same conditions. The plausible explanation to these
phenomena was that the reactive intermediate in photore-
action of 1a was not the free pyrazolyl radical but a com-
plexation of the chlorine atom with both the pyrazolyl
radical center and the p-cloud of the N-phenyl group at the
moment of C–Cl bond fission as depicted in Scheme 4.
The free pyrazolyl radical, however, was formed in the
photoreaction of 5-chloro-N-cyclohexyl-3-methyl-1-phe-
nyl-1H-pyrazole-4-carboxamide because complexation
was impossible in this case, thus reductive the photo-
dechlorination product N-cyclohexyl-3-methyl-1-phenyl-
1H-pyrazole-4-carboxamide was produced by hydrogen-
abstraction of the free pyrazolyl radical from methanol.
In summary, an efficient synthesis of pyrazolo[4,3-
c]quinolin-4-ones and indolo[3,2-c]quinolin-6-ones has
been achieved by the photocyclization of 5-chloro-N-phe-
nyl-1H-pyrazole-4-carboxamides and 2-chloro-N-phenyl-
1H-indole-3-carboxamides in acetone.
All reactions were monitored by TLC (silica gel); column chroma-
tography used silica gel 230–400 mesh. EI-MS were recorded with
a HP 5988 A mass spectrometer. 1H and 13C NMR spectra were re-
corded on a Bruker DRX-300 NMR spectrometer in CDCl3 with
TMS as an internal standard. Melting points were determined on a
Yanagimoto melting point apparatus. All solvents were dried and
distilled before use. The starting materials, 2-chloro-N-phenyl-1H-
pyrazole-4-carboxamides and 2-chloro-N-phenyl-1H-indole-3-car-
boxamides were prepared from pyrazol-5-ones and indol-2-ones by
modified literature methods.7
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S. Lu et al.
PAPER
Photochemical Reactions; General Procedure
5-Isopropyl-3-methyl-N-phenyl-1,5-dihydro-4H-pyrazolo[4,3-
c]quinolin-4-one (3d)
Colorless needles; mp 165–167 °C.
To acetone (50 mL) was added 1 or 2 (1.0 mmol) and the solid was
dissolved. 0.1 M aq Na2CO3 (1 mL) was added and the resulting col-
orless soln was distributed into two 25-mL round-bottomed flasks
equipped with stirrer bars and they were irradiated with a 1000-W
high-pressure Hg lamp with stirring at r.t. for the appropriate time.
On completion of the reaction (TLC), the solvent was removed un-
der reduced pressure and the products were separated by column
chromatography (silica gel, hexane–acetone, 10:1) to afford 3 or 4.
The solid was further purified by recrystallization (EtOH) to give
pure 3 or 4.
1H NMR (300 MHz, CDCl3): d = 1.67 (d, J = 7.2 Hz, 6 H, 2 CH3),
2.74 (s, 3 H, CH3), 5.09 [s, 1 H, CH2(CH3)2], 6.91 (t, J = 7.5 Hz, 1
H), 7.25 (d, J = 7.5 Hz, 1 H), 7.41 (t, J = 7.8 Hz, 1 H), 7.49–7.56 (m,
5 H), 7.62 (d, J = 8.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.3 (CH3), 20.1 (2 CH3), 30.9
[CH2(CH3)2], 112.8 (C), 121.1 (CH), 123.3 (CH), 127.0 (2 CH),
128.9 (CH), 129.1 (CH), 129.4 (CH), 129.5 (3 CH), 129.6 (CH),
140.1 (C), 140.2 (C), 149.2 (C), 160.0 (C).
MS (EI, 70 eV): m/z (%) = 317 (M+, 40), 302 (7), 275 (100), 258 (6),
246 (7), 219 (52), 77 (95).
3-Methyl-N-phenyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-
one (3a)
Colorless needles; mp 277–280 °C (Lit.6a 280–282 °C).
Anal. Calcd for C20H19N3O: C, 75.69; H, 6.03; N, 13.24. Found: C,
75.55; H, 6.11; N, 13.18.
1H NMR (300 MHz, CDCl3): d = 2.82 (s, 3 H, CH3), 6.97 (dt,
J = 7.8, 1.2 Hz, 1 H), 7.18 (d, J = 7.5 Hz, 1 H), 8.44–7.48 (m, 2 H),
7.56–7.63 (m, 5 H), 11.37 (br, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 13.2 (CH3), 111.2 (C), 112.1 (C),
117.0 (CH), 122.1 (CH), 122.5 (CH), 127.2 (2 CH), 129.6 (CH),
129.7 (2 CH), 129.9 (CH), 138.2 (C), 140.2 (C), 140.4 (C), 149.0
(C), 161.2 (C).
8-Methyl-10-phenyl-4,5-dihydropyrazolo[4,3-c]pyrrolo[3,2,1-
ij]quinolin-7(10H)-one (3e)
Pale-yellow needles; mp 150–152 °C.
1H NMR (300 MHz, CDCl3): d = 2.64 (s, 3 H, CH3), 3.45 (t, J = 8.7
Hz, 2 H, CH2), 4.42 (t, J = 8.7 Hz, 2 H, CH2), 6.89–6.98 (m, 2 H),
7.27 (t, J = 4.5 Hz, 1 H), 7.55–7.60 (m, 5 H).
MS (EI, 70 eV): m/z (%) = 275 (M+, 100), 274 (77), 256 (4), 205 (8),
13C NMR (75 MHz, CDCl3): d = 13.1 (CH3), 27.9 (CH2), 45.4
(NCH2), 108.8 (C), 113.2 (C), 119.4 (CH), 122.6 (CH), 124.8 (CH),
126.7 (2 CH), 129.4 (CH), 129.5 (2 CH), 131.2 (C), 139.9 (C),
140.8 (C), 142.4 (C), 149.1 (C), 158.2 (C).
77 (51).
Anal. Calcd for C17H13N3O: C, 74.17; H, 4.76; N, 15.26. Found: C,
74.05; H, 4.83; N, 15.18.
MS (EI, 70 eV): m/z (%) 301 (M+, 13), 300 (35), 248 (2), 236 (9),
202 (17), 144 (19), 115 (31), 85 (100).
3,5-Dimethyl-N-phenyl-1,5-dihydro-4H-pyrazolo[4,3-c]quino-
lin-4-one (3b)
Colorless needles; mp 186–187 °C (Lit.6a 181–183 °C).
Anal. Calcd for C19H15N3O: C, 75.73; H, 5.02; N, 13.94. Found: C,
75.85; H, 5.13; N, 13.87.
1H NMR (300 MHz, CDCl3): d = 2.76 (s, 3 H, CH3), 3.74 (s, 3 H,
NCH3), 6.98 (dt, J = 7.5, 1.2 Hz, 1 H), 7.26 (d, J = 7.8 Hz, 1 H), 7.41
(d, J = 7.7.5 Hz, 1 H), 7.46–7.60 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 13.2 (CH3), 28.9 (CH3) 111.2 (C),
111.2 (C), 115.5 (CH), 121.5 (CH), 123.0 (CH), 127.1 (2 CH),
129.6 (CH), 129.7 (2 CH), 129.9 (CH), 139.6 (C), 140.3 (C), 140.4
(C), 149.3 (C), 159.5 (C).
9-Methyl-11-phenyl-5,6-dihydro-4H-pyrazolo[4,3-c]pyri-
do[3,2,1-ij]quinolin-8(11H)-one (3f)
Pale-yellow needles; mp 204–206 °C (Lit.6a 204–207 °C).
1H NMR (300 MHz, CDCl3): d = 2.12 (d, J = 6.0 Hz, 2 H, CH2),
2.64 (s, 3 H, CH3), 3.00 (t, J = 6.3 Hz, 2 H, CH2), 4.29 (t, J = 6.0 Hz,
2 H, CH2), 6.87 (t, J = 7.5 Hz, 1 H), 7.09 (d, J = 7.8 Hz, 1 H), 7.25
(t, J = 6.9 Hz, 1 H), 7.51–7.60 (m, 5 H).
MS (EI, 70 eV): m/z (%) = 289 (M+, 100), 273 (6), 260 (5), 245 (2),
219 (5).
13C NMR (75 MHz, CDCl3): d = 13.3 (CH3), 20.7 (CH2), 28.6
(CH2), 41.97 (NCH2), 111.0 (C), 111.9 (C), 121.1 (CH), 121.2
(CH), 126.1 (C), 127.1 (2 CH), 129.5 (CH), 129.6 (CH), 129.7 (2
CH), 136.2 (C), 140.4 (C), 140.5 (C), 149.0 (C), 159.2 (C).
MS (EI, 70 eV): m/z (%) = 315 (M+, 100), 300 (21), 230 (10), 221
(9).
Anal. Calcd for C18H15N3O: C, 74.72; H, 5.23; N, 14.52. Found: C,
74.55; H, 5.11; N, 14.58.
5-Ethyl-3-methyl-N-phenyl-1,5-dihydro-4H-pyrazolo[4,3-
c]quinolin-4-one (3c)
Colorless needles; mp 172–173 °C.
1H NMR (300 MHz, CDCl3): d = 1.34 (t, J = 7.5 Hz, 3 H, CH3),
2.73 (s, 3 H, CH3), 4.37 (q, 2 H, NCH2), 6.98 (dt, J = 7.5, 1.2 Hz, 1
H), 7.26 (d, J = 8.1 Hz, 1 H), 7.40–7.56 (m, 7 H).
Anal. Calcd for C20H17N3O: C, 76.17; H, 5.43; N, 13.32. Found: C,
76.25; H, 5.32; N, 13.45.
13C NMR (75 MHz, CDCl3): d = 12.8 (CH3), 13.1 (CH3), 36.5
(NCH2) 111.1 (C), 112.2 (C), 115.3 (CH), 121.2 (CH), 123.2 (CH),
127.0 (2 CH), 129.5 (CH), 129.6 (2 CH), 129.7 (CH), 138.3 (C),
140.1 (C), 140.2 (C), 149.0 (C), 159.0 (C).
MS (EI, 70 eV): m/z (%) = 303 (M+, 100), 288 (14), 275 (36), 274
(39), 258 (8).
5-Methyl-1,3-diphenyl-1,5-dihydropyrazolo[4,3-c]quinolin-4-
one (3g)
Colorless needles; mp 200–201 °C (Lit.6a 200–202 °C).
1H NMR (300 MHz, CDCl3): d = 3.78 (s, 3 H, CH3), 6.99 (t, J = 6.9
Hz, 1 H), 7.18 (d, J = 7.8 Hz, 1 H), 8.41–7.61 (m, 5 H), 7.62 (s, 5
H), 7.56–7.63 (m, 5 H), 8.17 (d, J = 6.9 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 29.4 (CH3), 110.2 (C), 111.8 (C),
115.5 (CH), 121.5 (CH), 123.1 (CH), 127.3 (2 CH), 127.9 (2 CH),
128.6 (CH), 129.4 (CH), 129.6 (2 CH), 129.8 (2 CH), 130.4 (CH),
131.6 (C), 139.5 (C), 140.5 (C), 141.2 (C), 151.5 (C), 158.7 (C).
MS (EI, 70 eV): m/z (%) = 351 (M+, 87), 350 (58), 335 (5), 281 (4),
77 (100).
Anal. Calcd for C19H17N3O: C, 75.23; H, 5.65; N, 13.85. Found: C,
75.13; H, 5.71; N, 13.68.
X-ray data for compound 3c: C19H17N3O, M = 303.36, colorless
plates, monoclinic, a = 7.4000(17), b = 11.770(3), c = 18.552(4) Å,
V = 1610.9(6) Å3, T = 294(2) K, space group P2(1)/c, Z = 4, m
(MoKa) = 0.080 mm–1, 2qmax = 25.50, 8214 reflections collected,
2990 unique (Rint = 0.0632) which was used in all calculations. Fi-
nal wR2 (F2) = 0.1225 (all data). CCDC file No. 668719.
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Synthesis of Pyrazolo[4,3-c]quinolin-4-ones and Indolo[3,2-c]quinolin-6-ones
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Anal. Calcd for C23H17N3O: C, 78.61; H, 4.88; N, 11.96. Found: C,
78.50; H, 4.96; N, 11.88.
(CH), 122.6 (CH), 123.8 (C), 124.1 (CH), 128.5 (CH), 138.6 (C),
138.7 (C), 139.2 (C), 159.5 (C).
MS (EI, 70 eV): m/z (%) = 262 (M+, 20), 233 (3), 224 (2), 209 (8),
192 (8), 121 (28), 84 (100).
5-Isopropyl-1,3-diphenyl-1,5-dihydropyrazolo[4,3-c]quinolin-
4-one (3h)
Colorless needles; mp 186–190 °C.
Anal. Calcd for C17H14N2O: C, 77.84; H, 5.38; N, 10.68. Found: C,
77.92; H, 5.31; N, 10.58.
1H NMR (300 MHz, CDCl3): d = 1.51 (d, J = 6.9 Hz, 6 H, 2 CH3),
5.72 (br s, 1 H, CH), 6.95 (t, J = 7.5 Hz, 1 H), 7.28 (d, J = 7.5 Hz, 1
H), 7.41–7.50 (m, 4 H), 7.61 (s, 5 H), 7.67 (d, J = 8.7 Hz, 1 H), 8.15
(d, J = 7.5 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 20.1 (2 CH3), 30.9 (CH), 109.7 (C),
112.6 (C), 116.5 (CH), 121.1 (CH), 123.5 (CH), 127.2 (2 CH),
127.9 (2 CH), 128.6 (CH), 129.2 (CH), 129.6 (2 CH), 129.7 (2
CH), 129.8 (CH), 131.8 (C), 138.8 (C), 140.6 (C), 141.2 (C), 151.5
(C), 158.5 (C).
5-Ethyl-11-methyl-5,11-dihydro-6H-indolo[3,2-c]quinolin-6-
one (4b)
Colorless prisms; mp 182–183 °C.
1H NMR (300 MHz, CDCl3): d = 1.41 (t, J = 6.9 Hz, 3 H, CH3),
4.01 (s, 3 H, CH3), 4.48 (q, J = 6.9 Hz, 2 H, CH2), 7.24–7.38 (m, 4
H), 7.47–7.54 (m, 2 H), 8.26 (d, J = 8.1 Hz, 1 H), 8.54 (d, J = 7.5
Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.1 (CH3), 33.4 (CH3), 36.8
(CH2), 107.5 (C), 108.8 (CH), 114.6 (C), 115.5 (CH), 121.2 (CH),
121.7 (CH), 122.1 (CH), 123.1 (CH), 124.1 (C), 124.4 (CH), 128.7
(CH), 138.1 (C), 139.1 (C), 139.6 (C), 159.5 (C).
MS (EI, 70 eV): m/z (%) = 379 (M+, 25), 357 (1), 336 (49), 337 (50),
323 (8), 281 (6), 77 (100).
Anal. Calcd for C25H21N3O: C, 79.13; H, 5.58; N, 11.07. Found: C,
79.05; H, 5.71; N, 13.18.
MS (EI, 70 eV): m/z (%) = 276 (M+, 56), 248 (100), 231 (11), 219
(15), 204 (10), 190 (5), 43 (94).
8,10-Diphenyl-4,5-dihydropyrazolo[4,3-c]pyrrolo[3,2,1-ij]quin-
olin-7(10H)-one (3i)
Pale-yellow needles; mp 194–196 °C.
Anal. Calcd for C18H16N2O: C, 78.24; H, 5.84; N, 10.14. Found: C,
78.37; H, 5.73; N, 10.06.
1H NMR (300 MHz, CDCl3): d = 3.47 (t, J = 8.4 Hz, 2 H, CH2),
4.46 (t, J = 8.4 Hz, 2 H, CH2), 6.93 (d, J = 7.5 Hz, 1 H), 7.30 (t,
J = 4.8 Hz, 1 H), 7.39–7.48 (m, 4 H), 7.60–7.66 (m, 6 H), 8.23 (d,
J = 8.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 27.9 (CH2), 45.9 (NCH2), 108.5
(C), 119.5 (CH), 122.7 (CH), 125.0 (CH), 127.1 (2 CH), 127.3 (2
CH), 128.7 (CH), 129.0, 129.6 (2 CH), 129.7 (2 CH), 129.8 (CH),
131.2 (C), 131.6 (C), 134.0 (C), 141.9 (C), 142.2 (C), 151.1 (C),
157.3 (C).
13-Methyl-5,6-dihydro-4H-indolo[3,2-c]pyrido[3,2,1-ij]quino-
lin-8(13H)-one (4c)
Pale-yellow prisms; mp 172–174 °C (Lit.6f 170–171).
1H NMR (300 MHz, CDCl3): d = 2.07–2.13 (m, 2 H, CH2), 2.98 (t,
J = 6.6 Hz, 2 H, CH2), 4.04 (s, 3 H, CH3), 4.30 (t, J = 6.0 Hz, 2 H,
CH2), 7.13 (t, J = 7.8 Hz, 1 H), 7.24–7.38 (m, 4 H), 8.05 (t, J = 8.1
Hz, 1 H), 8.53 (d, J = 8.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 20.6 (CH2), 28.9 (CH2), 33.4
(CH3), 41.9 (CH2), 107.3 (C), 108.8 (CH), 114.1 (C), 120.7 (CH),
120.8 (C), 121.6 (CH), 122.0 (CH), 124.0 (C), 124.2 (CH), 126.0
(CH), 128.5 (CH), 135.9 (C), 139.2 (C), 139.6 (C), 159.5 (C).
MS (EI, 70 eV): m/z (%) 363 (M+, 61), 362 (54), 281 (14), 247 (3),
181 (13), 77 (100).
Anal. Calcd for C24H17N3O: C, 79.32; H, 4.71; N, 11.56. Found: C,
79.25; H, 4.83; N, 11.45.
MS (EI, 70 eV): m/z (%) = 288 (M+, 89), 273 (70), 258 (13), 243 (6),
209 (100), 192 (86).
Anal. Calcd for C19H16N2O: C, 79.14; H, 5.59; N, 9.72. Found: C,
79.08; H, 5.73; N, 9.67.
9,11-Diphenyl-5,6-dihydro-4H-pyrazolo[4,3-c]pyrido[3,2,1-
ij]quinolin-8(11H)-one (3j)
Pale-yellow needles; mp 230–231 °C (Lit.6a 232–234 °C).
5-Methyl-11-phenyl-5,11-dihydro-6H-indolo[3,2-c]quinolin-6-
one (4d)
1H NMR (300 MHz, CDCl3): d = 2.13 (m, 2 H, CH2), 3.00 (t, J = 6.0
Hz, 2 H, CH2), 4.30 (t, J = 6.3 Hz, 2 H, CH2), 6.87 (t, J = 8.1 Hz, 1
H), 7.09 (d, J = 7.5 Hz, 1 H), 7.30 (t, J = 6.0 Hz, 1 H), 7.40–7.61 (m,
3 H), 7.61 (s, 5 H), 8.18 (d, J = 7.8 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 20.8 (CH2), 28.6 (CH2), 42.4
(NCH2), 111.6 (C), 121.1 (CH), 121.2 (CH), 126.1 (C), 127.2 (2
CH), 127.9 (2 CH), 128.6 (CH), 129.6 (2 CH), 129.7 (CH), 129.8 (2
CH), 129.9 (CH), 131.7 (C), 136.2 (C), 140.6 (2 C), 141.4 (C),
151.2 (C), 158.4 (C).
Colorless prisms; mp 210–212 °C (Lit.6g 218.5).
1H NMR (300 MHz, CDCl3): d = 3.90 (s, 3 H, CH3), 6.94 (t, J = 8.1
Hz, 1 H), 7.06 (d, J = 8.1 Hz, 1 H), 7.14 (d, J = 8.1 Hz, 1 H), 7.31–
7.52 (m, 6 H), 7.66–7.68 (m, 3 H), 8.61 (d, J = 7.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 29.2 (CH3), 108.5 (C), 110.2 (CH),
113.6 (C), 115.4 (CH), 121.1 (CH), 122.1 (CH), 122.4 (CH), 123.1
(CH), 124.4 (C), 124.7 (CH), 128.9 (CH), 129.0 (2 CH), 129.6
(CH), 130.4 (2 CH), 138.4 (C), 139.2 (C), 139.5 (C), 141.2 (C),
160.1 (C).
MS (EI, 70 eV): m/z (%) = 377 (M+, 60), 362 (8), 318 (1), 298 (2),
281 (6), 77 (100).
MS (EI, 70 eV): m/z (%) = 324 (M+, 51), 295 (5), 254 (5), 220 (2),
191 (2), 177 (4), 43 (100).
Anal. Calcd for C25H19N3O: C, 79.55; H, 5.07; N, 11.13. Found: C,
79.48; H, 5.13; N, 11.03.
Anal. Calcd for C22H16N2O: C, 81.46; H, 4.97; N, 8.64. Found: C,
81.52; H, 5.13; N, 8.58.
5,11-Dimethyl-5,11-dihydro-6H-indolo[3,2-c]quinolin-6-one
(4a)
Colorless prisms; mp 205–207 °C (Lit.6e 207–208 °C).
13-Phenyl-5,6-dihydro-4H-indolo[3,2-c]pyrido[3,2,1-ij]quino-
lin-8(13H)-one (4e)
Pale-yellow prisms; mp 205–207 °C.
1H NMR (300 MHz, CDCl3): d = 2.15–2.18 (m, 2 H, CH2), 3.03 (t,
J = 6.0 Hz, 2 H, CH2), 4.44 (t, J = 6.0 Hz, 2 H, CH2), 6.82 (t, J = 7.8
Hz, 1 H), 6.98 (d, J = 8.7 Hz, 1 H), 7.04 (d, J = 8.4 Hz, 1 H), 7.23
1H NMR (300 MHz, CDCl3): d = 3.56 (s, 3 H, CH3), 3.84 (s, 3 H,
CH3), 7.13–7.30 (m, 5 H), 7.42 (t, J = 7.8 Hz, 1 H), 8.01 (d, J = 7.8
Hz, 1 H), 8.42 (d, J = 8.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 28.8 (CH3), 33.1 (CH3), 107.0 (C),
108.7 (CH), 113.9 (C), 115.3 (CH), 121.2 (CH), 121.5 (CH), 121.7
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S. Lu et al.
PAPER
(t, J = 7.5 Hz, 1 H), 7.30–7.41 (m, 2 H), 7.47–7.50 (m, 2 H), 7.64–
7.66 (m, 3 H), 8.61 (d, J = 7.8 Hz, 1 H).
(3) (a) Kessar, S. V.; Mankotia, S. In CRC Handbook of Organic
Photochemistry and Photobiology; Horspool, W. H.; Song,
P.-S., Eds.; CRC Press: New York, 1995, 1218.
13C NMR (75 MHz, CDCl3): d = 20.9 (CH2), 28.9 (CH2), 42.1
(CH2), 108.3 (C), 110.2 (CH), 113.5 (C), 120.7 (C), 121.2 (CH),
122.1 (CH), 122.3 (CH), 124.3 (C), 124.7 (CH), 126.0 (CH), 128.7
(CH), 128.9 (2 CH), 129.5 (CH), 130.3 (2 CH), 136.2 (C), 138.5
(C), 139.4 (C), 141.3 (C), 159.8 (C).
MS (EI, 70 eV): m/z (%) = 350 (M+, 19), 335 (13), 271 (16), 254 (6),
191 (3), 129 (13), 43 (100).
(b) Kanaoka, Y. Acc. Chem. Res. 1978, 11, 407.
(c) Kanaoka, Y.; Nakao, S.; Hatanaka, Y. Heterocycles
1976, 5, 261. (d) Ninomiya, I.; Yamamoto, O.; Naito, T.
J. Chem. Soc., Perkin Trans. 1 1983, 2171. (e) Ninomiya,
I.; Yamamoto, O.; Naito, T. J. Chem. Soc., Perkin Trans. 1
1980, 212. (f) Grimshaw, J. J. Chem. Soc., Chem. Commun.
1981, 181. (g) Park, Y.-T.; Song, N. W.; Kim, Y.-H.;
Hwang, C.-G.; Kim, S. K.; Kim, D. J. Am. Chem. Soc. 1996,
118, 11399. (h) Donnelly, S.; Grimshaw, J.; Trocha-
Grimshaw, J. Acta Chem. Scand. 1999, 53, 913. (i) Park,
Y.-T.; Jung, C.-H.; Kim, M. S.; Kim, N. W.; Song, N. W.;
Kim, D. J. Org. Chem. 2001, 66, 2197. (j) Ramana, M. M.
V.; Sharma, R. H.; Parihar, J. A. Tetrahedron Lett. 2005, 46,
4385. (k) Barolo, S. M.; Teng, X.; Cuny, G. D.; Rossi, R. A.
J. Org. Chem. 2006, 71, 8493.
Anal. Calcd for C24H18N2O: C, 82.26; H, 5.17; N, 7.99. Found: C,
82.13; H, 5.25; N, 8.16.
3-Methyl-N,1-diphenyl-1H-pyrazole-4-carboxamide
1H NMR (400 MHz, CDCl3): d = 2.57 (s, 3 H, CH3), 7.08 (t, J = 7.6
Hz, 1 H), 7.34–7.32 (m, 3 H), 7.41 (t, J = 8.4 Hz, 2 H), 7.48 (br, 1
H, CONH), 7.58 (d, J = 8.4 Hz, 2 H), 7.61 (d, J = 7.6 Hz, 2 H), 8.27
(s, 1 H, H5).
(4) (a) Elmaaty, T. A.; Castle, L. W. Synthesis 2006, 1402.
(b) Ho, T.-I.; Ku, C.-K.; Liu, R. S. H. Tetrahedron Lett.
2001, 42, 715. (c) Terashima, M.; Seki, K. I.; Yoshida, C.;
Ohkura, K.; Kanaoka, Y. Chem. Pharm. Bull. 1985, 33,
1009.
(5) (a) Melani, F.; Cecchi, L.; Palazzino, G.; Filacchioni, G.;
Martini, C.; Pennacchi, E.; Lucacchini, A. J. Med. Chem.
1986, 29, 291. (b) Palazzino, G.; Cecchi, L.; Melani, F.;
Colotta, V.; Filacchioni, G.; Martini, C.; Lucacchini, A.
J. Med. Chem. 1987, 30, 1737. (c) Baruah, B.; Dasu, K.;
Vaitilingam, B.; Vanguri, A.; Casturi, S. R.; Yeleswarapu,
K. R. Bioorg. Med. Chem. Lett. 2004, 14, 445. (d) Baraldi,
P. G.; Tabrizi, M. A.; Preti, D.; Bovero, A.; Fruttarolo, F.;
Romagnoli, R.; Zaid, N. A.; Moorman, A. R.; Varani, K.;
Borea, P. A. J. Med. Chem. 2005, 48, 5001.
MS (EI, 70 eV ): m/z (%) = 277 (M+, 13), 213 (1), 200 (2), 185
(100), 77 (44).
3-Methyl-N,1,5-triphenyl-1H-pyrazole-4-carboxamide
1H NMR (300 MHz, CDCl3): d = 2.63 (s, 3 H, CH3), 5.31 (s, 1 H,
CONH), 7.21–7.32 (m, 11 H), 7.36–7.43 (m, 4 H).
MS (EI, 70 eV ): m/z (%) = 353 (M+, 9), 290 (1), 278 (10), 261
(100), 77 (36).
N-Cyclohexyl-3-methyl-N-phenyl-1H-pyrazole-4-carboxamide
1H NMR (300 MHz, CDCl3): d = 1.22–1.33 (m, 3 H), 1.38–1.50 (m,
2 H), 1.61–1.76 (m, 3 H), 1.99–2.04 (m, 2 H), 2.22 (s, 3 H, CH3),
3.91–4.02 (m, 1 H, CHN), 5.69 (d, J = 7.5 Hz, 1 H, CONH), 7.30 (t,
J = 7.8 Hz, 1 H), 7.45 (t, J = 7.8 Hz, 2 H), 7.65 (d, J = 8.1 Hz, 2 H),
8.24 (s, 1 H, H5).
(6) (a) Stadlbauer, W.; Hojas, G. J. Heterocycl. Chem. 2004, 41,
681. (b) Fresneda, P. M.; Molina, P.; Delgado, S.
Tetrahedron Lett. 1999, 40, 7275. (c) Sicker, D.;
Acknowledgment
Reifegerste, D.; Hauptmann, S.; Wilde, H.; Mann, G.
Synthesis 1985, 331. (d) Ganguly, A. K.; Wang, C. H.;
Chan, T. M.; Ing, Y. H.; Buevich, A. V. Tetrahedron Lett.
2004, 45, 883. (e) Li, H.; Yang, H.; Petersen, J. L.; Wang, K.
K. J. Org. Chem. 2004, 69, 4500. (f) Mann, F. G.; Smith, B.
B. J. Chem. Soc. 1951, 1898. (g) Braunholtz, J. T.; Mann, F.
G. J. Chem. Soc. 1955, 381.
We thank the National Natural Science Foundation of China
(20472027) for financial support.
References and Notes
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(c) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004,
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Synthesis 2008, No. 10, 1517–1522 © Thieme Stuttgart · New York