Elegant one-pot synthesis of quinolino[2′,3′:7,6]-cyclohept[1, 2-b]indole through friedlaender and pfitzinger annulation reaction

Article abstract of DOI:10.1080/00397911.2010.518048

A rapid, simple, and efficient method for the preparation of various quinolino[2′,3′:7,6]cyclohept[1,2-b]indoles has been developed through the Friedlander and Pfitzinger condensations of 1-oxo-cyclohept[b]indole with o-amino benzophenone and isatin respe

Full text of DOI:10.1080/00397911.2010.518048

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Elegant One-Pot Synthesis of
Quinolino[2′,3′:7,6]-cyclohept[1,2-
b]indole Through Friedländer and
Pfitzinger Annulation Reaction
Ezhumalai Yamuna a , Anthony Yurcho b , Robert J. Sovesky b , Peter
M. Smith b c , Matthias Zeller b & Karnam Jayarampillai Rajendra
Prasad a
a Department of Chemistry , Bharathiar University , Coimbatore ,
India
b Department of Chemistry , Youngstown State University ,
Youngstown , Ohio , USA
c Department of Chemistry , Westminster College , New
Wilmington , Pennsylvania , USA
Published online: 26 Jul 2011.
To cite this article: Ezhumalai Yamuna , Anthony Yurcho , Robert J. Sovesky , Peter M. Smith ,
Matthias Zeller & Karnam Jayarampillai Rajendra Prasad (2011) Elegant One-Pot Synthesis of
Quinolino[2′,3′:7,6]-cyclohept[1,2-b]indole Through Friedländer and Pfitzinger Annulation Reaction,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 41:22, 3351-3366, DOI: 10.1080/00397911.2010.518048
To link to this article: http://dx.doi.org/10.1080/00397911.2010.518048
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Synthetic Communications1, 41: 3351–3366, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.518048
ELEGANT ONE-POT SYNTHESIS OF
QUINOLINO[2’,3’:7,6]CYCLOHEPT[1,2-b]INDOLE
¨
THROUGH FRIEDLANDER AND PFITZINGER
ANNULATION REACTION
Ezhumalai Yamuna,1 Anthony Yurcho,2 Robert J. Sovesky,2
Peter M. Smith,2,3 Matthias Zeller,2 and Karnam
Jayarampillai Rajendra Prasad1
1Department of Chemistry, Bharathiar University, Coimbatore, India
2Department of Chemistry, Youngstown State University,
Youngstown, Ohio, USA
3Department of Chemistry, Westminster College, New Wilmington,
Pennsylvania, USA
GRAPHICAL ABSTRACT
Abstract
A rapid, simple, and efficient method for the preparation of various
quinolino[20,30:7,6]cyclohept[1,2-b]indoles has been developed through the Friedla¨nder
and Pfitzinger condensations of 1-oxo-cyclohept[b]indole with o-amino benzophenone
and isatin respectively. Reactions were performed by under different reaction conditions.
Keywords Friedla¨nder synthesis; Pfitzinger synthesis; p-TsOH; quinolino[20,30:7,6]
cyclohept[1,2-b]indoles
INTRODUCTION
The indole moiety is probably the most widely spread nitrogen heterocycle in
nature. For example, it is an essential part of the amino acid tryptophan and the
neurotransmitter serotonin, but the indole scaffold is also found in a manifold of
naturally occurring plant-based alkaloids. Biological activities of many of these
indoles and hence their potential pharmacological and medical applications have
prompted researchers to study their synthesis and investigate their pharmacological
Received August 11, 2010.
Address correspondence to Karnam Jayarampillai Rajendra Prasad, Department of Chemistry,
Bharathiar University, Coimbatore 641 046, India. E-mail: prasad_125@yahoo.com
3351

3352
E. YAMUNA ET AL.
properties.[1–3] Biological activity was especially found in indole alkaloids that
also feature a quinoline moiety such as pyridocarbazoles, indoloquinolines, and indolo-
phenanthyridines.[4–9] They are known to possess antiallergic,[10] anti-inflammatory,[11]
antiproliferative,[12] anticancer,[13] chemopreventive,[14] antibacterial[15] (including anti-
tubercular), hypotensive,[16] antirheumatic,[17] and antiasthmatic activities.[18] Based on
these facts, several compounds with a heterocyclic ring attached to a cyclohept[b]indole
moiety have been designed and evaluated as pharmacologically active molecules.[19–21]
Despite numerous reported methods such as the Skraup, the Do¨bner–von
Miller, and the Combes syntheses,[22–27] the Friedla¨nder and Pfitzinger annulation
is still the most simple and straightforward approach for the synthesis of polysubsti-
tuted quinolines and related azaheterocycles. The Friedla¨nder annulation is an acid-
or base-catalyzed annulation of an o-aminoaryl ketone with a carbonyl compound
that contains a reactive methylene group in a-position to the keto group. The lon-
gevity of the Friedla¨nder reaction (it was first described in 1882), is due in large part
to the observed broad range of functional group compatibility. With regard to the
ketone component, the literature is replete with examples of symmetrical ketones
or ketones with an additional activating functionality alpha to the carbonyl group.
In view of its immense biological importance, the development of a simple and con-
venient protocol is of considerable interest. However, the Friedla¨nder reaction is not
without its limitations, and among various Friedla¨nder syntheses, the cycloconden-
sation into quinoline derivatives using p-TsOH has been less explored. Further, the
Pfitzinger reaction is widely used for the synthesis of substituted quinoline-4-
carboxylic acids from isatins with a-methylene carbonyl compounds.
Recently, we reported some annulated quinoline derivatives through Friedla¨nder
and Pfitzinger synthesis.[28–30] Because of the biological importance of these molecules,
which has greatly motivated intensive research into the synthesis of quinolino[20,30:7,6]
cyclohept[1,2-b]indole derivatives, we herein report that the p-TsOH catalyst assisted
Friedla¨nder condensation of 2-amino benzophenone and the base-catalyzed Pfitzinger
condensation of isatin with 1-oxo-1,2,3,4,5,10-hexahydro-1H-cyclohept[b]indoles into
quinolino[20,30:7,6]cyclohept[1,2-b]indoles by effective methods.
RESULTS AND DISCUSSION
Various 1-oxo-1,2,3,4,5,10-hexahydro-1H-cyclohept[b]indoles (1) were used as
the starting material to synthesize quinolinocyclohept[b]indole (3) derivatives under
different conditions. Therefore we first chose derivative 1a and systematically
investigated the reaction system to find the optimum conditions for its reaction with
o-amino benzophenone (2) to afford quinolino[20,30:7,6]cyclohept[1,2-b]indole
3a under conventional conditions. Therefore, a simple, general, and efficient
procedure is still in demand for the synthesis of these important heterocyclic
compounds.
Continuing with our studies directed toward the development of synthetic
methodologies with improved efficiencies leading to the product in good yields, we
therefore investigated acid-catalyzed condensation of 7-methyl-1-oxo-cyclohept[b]in-
dole 1a with o-aminobenzophenone 2 to give the product 3a. First, we employed
various catalysts to determine that with the greatest activity. The detailed results
for these reactions are collected in Table 1.

QUINOLINO[20,30:7,6]CYCLOHEPT[1,2-b]INDOLES
3353
Table 1. Optimization of the catalyst in the synthesis of quinolino[20,30:7,6]cyclohept[1,2-b]indole 3a–e
from 1-oxo-cyclohept[b]indole derivatives with 2-amino benzophenone under Friedla¨nder reaction
S.
no.
Catalyst=
solvent
Temperature=
time
Yield
(%)
Substrate
Product
1
Neat
160 ꢀC=1 h
22
2
3
4
5
Hþ=AcOH
120 ꢀC=8 h
100 ꢀC=6 h
120 ꢀC=12 h
100 ꢀC=3 h
35
60
62
76
CF3COOH
p-TsOH=toluene
p-TsOH=neat
6
7
p-TsOH=neat
p-TsOH=neat
100 ꢀC=3 h
73
78
100 ꢀC=3 h
(Continued )

3354
E. YAMUNA ET AL.
Table 1. Continued
S.
no.
Catalyst=
solvent
Temperature=
time
Yield
(%)
Substrate
Product
8
9
p-TsOH=neat
100 ꢀC=3 h
80
72
p-TsOH=neat
100 ꢀC=3 h
From these results, under the neat and acetic acid conditions, the product 3a
was obtained in poor and moderate yields. Trifluoroacetic acid and p-TsOH in sol-
vent (toluene) enhance the reactivity toward better yield, but it is obvious that
p-TsOH under neat conditions (without solvent) demonstrated superior catalytic
activity and was the best catalyst under neat conditions. Further, the generality of
this facile condensation was established in the presence of p-TsOH under solvent-free
conditions to furnish the corresponding 6-phenyl-7,8,9,14-tetrahydroquinolino
[20,30:7,6]cyclohept[1,2-b]indoles 3a–e (Scheme 1). The results of these comparative
experiments for compound 3a–e are summarized in Table 1. The five compounds
3a to 3e are based on the same chemical scaffold and are distinguished from each
other only by the presence, absence, or position of a methyl group at the indole phe-
nyl ring. Pure compounds 3a–e were isolated after column chromatography in yields
between 76% and 80%, and single crystals suitable for x-ray diffraction analysis were
obtained by crystallization from ethanol.
1
All compounds were unambiguously indentified by H and 13C NMR spec-
troscopy, mass spectrometry, microanalysis, and infrared (IR) spectroscopy, and
their structures were determined by single-crystal x-ray diffraction. Their data are
presented in Table 2. Thermal ellipsoid plots of compounds 3a–e are shown in
Figs. 1–5. The molecules show the expected nonplanar conformation. Geometry
Scheme 1. Synthesis of 6-phenyl-7,8,9,14-tetrahydroquinolino[20,30:7,6] cyclohept[l,2-b]indoles (3).

3355

3356
E. YAMUNA ET AL.
Figure
1. Thermal
ellipsoid
diagram
of
11-methyl-6-phenyl-7,8,9,14
tetrahydroquinoli-
no[20,30:7,6]cyclohept[1,2-b]indole (3a) (50% probability level, H atoms are shown as spheres with arbitrary
radii).
of the molecule is the key factor in drug design, so it will be helpful for further
studies and pharmacological evaluations.
Next, we investigated the construction of a 7,8,9,14-tetrahydroquinoli-
no[20,30:7,6]cyclohept[1,2-b]indole-6-carboxylic acid system using the Pfitzinger
method. The reaction between isatin and 1-oxo-cyclohept[b]indole, in KOH medium,
required heating for about 16–24 h to give a considerable yield (48%) of 5a. How-
ever, we found that the NaOH medium significantly accelerates the condensation
of isatins with a number of ketones, and formation of quinolino[20,30:7,6]
cyclohept[1,2-b]indole-6-carboxylic acids 5a–e (Scheme 2) using this method was
completed within 24 h. Yields of the products are listed in Table 3.
Figure
2. Thermal
ellipsoid
diagram
of
12-methyl-6-phenyl-7,8,9,14-tetrahydroquinoli-
no[20,30:7,6]cyclohept[1,2-b]indole (3b) (50% probability level, H atoms are shown as spheres with arbitrary
radii).

QUINOLINO[20,30:7,6]CYCLOHEPT[1,2-b]INDOLES
3357
Figure
3. Thermal
ellipsoid
diagram
of
13-methyl-6-phenyl-7,8,9,14-tetrahydroquinoli-
no[20,30:7,6]cyclohept[1,2-b]indole (3c) (50% probability level, H atoms are shown as spheres with arbitrary
radii).
In summary, we have developed a rapid and efficient version of the Friedla¨nder
annulation for the synthesis of various quinolino[20,30:7,6]cyclohept[1,2-b]indoles
assisted by p-TsOH. All the reactions were conducted under completely solvent-free
conditions. The process is environmentally benign, and the experimental procedure
is very simple. Further quinolino[20,30:7,6]cyclohept[1,2-b]indole-7-carboxylic acid
prepared with good yield under Pfitzinger reaction condition.
Figure 4. Thermal ellipsoid diagram of 6-phenyl-7,8,9,14-tetrahydroquinolino[20,30:7,6]cyclohept[1,2-
b]indole (3d) (50% probability level, H atoms are shown as spheres with arbitrary radii).

3358
E. YAMUNA ET AL.
Figure
5. Thermal
ellipsoid
diagram
of
11-chloro-6-phenyl-7,8,9,14-tetrahydroquinolino
[20,30:7,6]cyclohept[1,2-b]indole (3e) (50% probability level, H atoms are shown as spheres with arbitrary
radii). The compound exhibits two crystallographically independent molecules in the asymmetric unit
of its structure.
EXPERIMENTAL
Melting points (mp) were determined on a Mettler FP 51 apparatus (Mettler
Instruments, Switzerland) and are uncorrected. IR spectra were recorded on a
Schimadzu Fourier transform (FT)–IR-8201PC spectrophotometer (Schimadzu,
1
Japan) using KBr discs. H NMR and 13C NMR spectra were recorded on Bruker
AMX 400 and AMX 500 [400 MHz and 500 MHz (1H) and 100 MHz (13C) NMR]
spectrometers using tetramethylsilane (TMS) as the internal reference. The chemical
shifts are expressed in parts per million (ppm). Mass spectra (MS) were recorded
Scheme 2. Synthesis of 7,8,9,14-tetrahydroquinolino[20,30:7,6] cyclohept[l,2-b]indole-3-carboxylic acids (5).

QUINOLINO[20,30:7,6]CYCLOHEPT[1,2-b]INDOLES
3359
Table 3. Optimization of the base catalyst in the synthesis of quinolino[20,30:7,6]cyclohept[1,2-b]indole-7-
carboxylic acids 5a–e from 1-oxo-cyclohept[b]indole derivatives with isatin under Pfitzinger reaction
Temperature= Yield
time
S. no.
Substrate
Catalyst=solvent
KOH=EtOH
Product
(%)
1
100 ꢀC=24 h
48
2
NaOH=EtOH
100 ꢀC=24 h
80
3
4
NaOH=EtOH
NaOH=EtOH
100 ꢀC=24 h
100 ꢀC=24 h
78
83
5
6
NaOH=EtOH
NaOH=EtOH
100 ꢀC=24 h
82
74
100 ꢀC=24 h
on an AutoSpec EIþShimadzu QP 2010 Plus GC-MS mass spectrometer. Microana-
lyses were performed on a Vario EL III model CHNS analyser (Vario, Germany) at
the Department of Chemistry, Bharathiar University. 1-Oxo-2,3,4,5,10-hexahydrocy-
clohept[b]indole was prepared by the reported procedure.[31] The purity of the products
was tested by thin-layer chromatography (TLC) with plates coated with silica gel-G and
petroleum ether and ethyl acetate were used as developing solvents.
Diffraction data were collected on a Bruker AXS Smart APEX CCD diffract-
ometer at 100 K using monochromatic Mo Ka radiation with the omega scan tech-
nique. Data for 3a–e were collected, their unit cells determined, and the data
integrated and corrected for absorption and other systematic errors using the Apex2

3360
E. YAMUNA ET AL.
suite of programs.[32] The structures were solved by direct methods and refined by
full matrix least squares against F2 with all reflections using SHELXTL.[33] All
hydrogen atoms were placed in calculated positions and were refined with an
isotropic displacement parameter 1.5 (methyl) or 1.2 times (all others) that of the
adjacent carbon or nitrogen atom.
General Procedure for Synthesis of 6-Phenyl-7,8,9,14-tetrahydroquinolino-
[2’,3’:7,6]cyclohept[1,2-b]indoles (3)
1-Oxo-2,3,4,5,10-hexahydrocyclohept[b]indole (1a–e, 1 mmol) and 2-amino-
benzophenone (1 mmol) were mixed with the catalytic amount of p-TsOH and finely
ground. Then the mixture was subjected to 100 ꢀC for 3 h. After the completion of
the reaction, the mixture was cooled to room temperature, water was added, and
it was extracted using ethyl acetate. The organic layer was thoroughly washed with
water and dried over anhydrous Na2SO4. Upon removal of the solvent, a brown
crude product was obtained. It was purified by column chromatography over silica
gel using a petroleum ether–ethyl acetate (99:1) mixture as eluant to afford the cor-
responding
(3a–e) as the product, which was recrystallised from ethanol.
6-phenyl-7,8,9,14-tetrahydroquinolino[20,30:7,6]cyclohept[1,2-b]indole
Selected Data for 3
11-Methyl-6-phenyl-7,8,9,14-tetrahydroquinolino[2’,3’:7,6]cyclohept[1ꢁ,21-
b]indole (3a). Yellow solid, yield: 303 mg (81%); mp: 222–224 ꢀC; IR (KBr, cm
)
1
n
max: 3447, 2962, 2923, 1622, 1559. H NMR (400 MHz, CDCl3): d 9.78 (br s, 1H,
NH), 8.08 (d, 1H, C2-H, J ¼ 8.40 Hz), 7.61 (d t, 1H, C3-H, Jm ¼ 2.00 Hz,
Jo ¼ 8.40 Hz), 7.56–7.48 (m, 3H, C4-H, C5-H & C04-H), 7.37 (d, 1H, C10-H,
Jm ¼ 1.00 Hz), 7.35 (d, 1H, C13-H, J ¼ 8.20 Hz), 7.31–7.24 (m, 4H, C02-H, C30 -H,
C05-H & C06-H), 7.10 (dd, 1H, C12-H, Jm ¼ 1.00 Hz, Jo ¼ 8.20 Hz), 3.16–3.13 (m,
2H, C9-2H), 2.86–2.84 (m, 2H, C7-2H), 2.47 (s, 3H, C11-CH3), 2.10–2.05 (m, 2H,
C8-2H) ppm; 13C NMR (125 MHz, CDCl3): d 150.89 (C14b), 145.96 (C6), 137.64
(C1a), 134.50 (C10 ), 133.23 (C13a), 132.08 (C14a), 129.90 (C11), 129.63 (C20 & C06),
128.63 (C2), 128.56 (C30 ; C40 & C50 ), 128.41 (C9b), 127.79 (C3), 126.85 (C6a), 126.50
(C4), 125.81 (C5), 125.71 (C12), 119.16 (C10), 118.62 (C5a), 117.27 (C9a), 110.85
(C13), 30.49 (C7), 27.43 (C8), 24.87 (C9), 21.56 (C1-CH3) ppm; MS: m=z (%) 374
(Mþ; 100), 373 (34), 359 (13), 331 (8), 282 (15), 228 (16), 202 (6), 179 (10), 166
(5), 152 (8), 114 (12), 77 (5). Anal. calcd. for C27H22N2: C, 86.60; H, 5.92; N,
7.48. Found: C, 86.56; H, 5.89; N, 7.43.
12-Methyl-6-phenyl-7,8,9,14-tetrahydroquinolino[2’,3’:7,6]cyclohept[1ꢁ,21-
b]indole (3b). Yellow solid; yield: 284 mg (76%); mp: 210–213 ꢀC; IR (KBr, cm
)
1
n
max: 3445, 2921, 1619, 1561; H NMR (400 MHz, CDCl3): d 9.76 (br s, 1H, NH),
8.13 (d, 1H, C2-H, J ¼ 8.40 Hz), 7.62 (dt, 1H, C3-H, Jm ¼ 2.00 Hz, Jo ¼ 8.40 Hz),
7.56–7.44 (m, 3H, C4-H, C5-H & C10-H), 7.33–7.24 (d, 5H, C02-H, C30 -H, C40 -H,
C05-H & C06-H), 7.08 (s, 1H, C13-H), 7.05 (d, 1H, C11-H, J ¼ 7.60 Hz), 3.20–3.17
(m, 2H, C9-2H), 2.88–2.85 (m, 2H, C7-2H), 2.63 (s, 3H, C12-CH3), 2.10–2.08 (m,
2H, C8-2H) ppm; 13C NMR (125 MHz, CDCl3): d 150.21 (C14b), 146.67 (C6),

QUINOLINO[20,30:7,6]CYCLOHEPT[1,2-b]INDOLES
3361
136.95 (C1a), 136.71 (C13a), 133.95 (C01), 132.54 (C14a), 131.76 (C12), 129.45 (C02 &
C06), 128.79 (C30 ; C04 & C50 ), 128.15 (C2), 128.04 (C3), 127.15 (C6a), 126.54 (C4),
124.95 (C5), 124.81 (C9b), 120.95 (C11), 118.72 (C10), 118.17 (C5a), 115.15 (C9a),
111.81 (C13), 30.51 (C7), 27.36 (C8), 24.71 (C9), 21.96 (C12-CH3) ppm; MS: m=z
(%) 374 (Mþ; 100), 373 (25), 359 (7), 331 (12), 282 (18), 258 (8), 228 (12), 202
(10), 192 (14), 179 (6), 166 (9), 152 (10), 114 (8), 77 (8). Anal. calcd. for
C27H22N2: C, 86.60; H, 5.92; N, 7.48. Found: C, 86.55; H, 5.95; N, 7.50.
13-Methyl-6-phenyl-7,8,9,14-tetrahydroquinolino[2’,3’:7,6]cyclohept[1ꢁ,21-
b]indole (3c). Yellow solid; yield: 310 mg (83%); mp 200–202 ꢀC; IR (KBr, cm
)
1
n
max: 3453, 2925, 1613, 1560; H NMR (400 MHz, CDCl3): d 9.89 (br s, 1H, NH),
8.07 (d, 1H, C2-H, J ¼ 8.00 Hz), 7.59 (dt, 1H, C3-H, Jm ¼ 2.00 Hz, Jo ¼ 8.00 Hz),
7.50–7.45 (m, 3H, C4-H, C5-H & C10-H), 7.39–7.21 (m, 7H, C02-H, C30 -H, C40 -H,
C05-H, C60 -H, C11-H & C12-H), 3.22–3.15 (m, 2H, C9-2H), 2.89–2.84 (m, 2H, C7-
2H), 2.56 (s, 3H, C13-CH3), 2.11–2.06 (m, 2H, C8-2H) ppm; 13C NMR (125 MHz,
CDCl3): d 151.04 (C14b), 145.82 (C6), 137.74 (C1a), 137.11 (C13a), 134.75 (C01),
131.90 (C14a), 129.85 (C20 & C60 ), 128.90 (C2), 128.64 (C03; C04 & C50 ), 127.85 (C3),
127.00 (C6a), 126.16 (C4), 126.01 (C5), 125.22 (C9b), 122.18 (C11), 121.75 (C13),
120.06 (C12), 118.30 (C5a), 117.65 (C10), 112.92 (C9a), 30.40 (C7), 27.56 (C8), 24.16
(C9), 16.92 (C13-CH3) ppm; MS: m=z (%) 374 (Mþ; 100), 373 (40), 359 (6), 331
(10), 304 (7), 282 (20), 228 (9), 202 (12), 179 (14), 166 (11), 152 (10), 114 (18), 77
(10). Anal. calcd. for C27H22N2: C, 86.60; H, 5.92; N, 7.48. Found: C, 86.64; H,
5.90; N, 7.44.
6-Phenyl-7,8,9,14-tetrahydroquinolino[2’,3’:7,6]cyclohept[1,2-b]indole
(3d). Yellow solid; yield: 295 mg (82%); mp: 181–182 ꢀC; IR (KBr, cmꢁ1) nmax: 3450,
1
2926, 1614, 1558; H NMR (400 MHz, CDCl3): d 9.91 (br s, 1H, NH), 8.08 (d, 1H,
C2-H, J ¼ 8.40 Hz), 7.63 (dt, 1H, C3-H, Jm ¼ 2.00 Hz, Jo ¼ 8.40 Hz), 7.56–7.47 (m,
4H, C4-H, C5-H, C04-H & C10-H), 7.37–7.20 (m, 7H, C02-H, C30 -H, C50 -H, C06-H,
C11-H, C12-H & C13-H), 3.13–3.09 (m, 2H, C9-2H), 2.87–2.84 (m, 2H, C7-2H),
2.16–2.04 (m, 2H, C8-2H) ppm; 13C NMR (125 MHz, CDCl3): d 150.92 (C14b),
145.92 (C6), 136.95 (C1a), 135.76 (C13a), 134.12 (C01), 132.10 (C14a), 129.56 (C20 &
C06), 128.79 (C2), 128.47 (C30 ; C40 & C50 ), 127.72 (C3), 126.91 (C6a), 126.34 (C4),
126.15 (C5), 124.71 (C9b), 120.73 (C12), 119.75 (C11), 118.14 (C5a), 118.02 (C10),
114.43 (C9a), 111.91 (C13), 30.34 (C7), 27.41 (C8), 24.23 (C9) ppm; MS: m=z (%)
360 (Mþ; 100), 359 (20), 346 (10), 332 (15), 304 (6), 294 (11), 269 (18), 255 (5),
217 (16), 194 (8), 155 (6), 114 (5), 77 (8). Anal. calcd. for C26H20N2: C, 86.64; H,
5.59; N, 7.77. Found: C, 86.59; H, 5.61; N, 7.72.
11-Chloro-6-phenyl-7,8,9,14-tetrahydroquinolino[2’,3’:7,6]cyclohept[1,2-b]
indole (3e). Yellow solid; yield: 289 mg (74%); mp 223–225 ꢀC; IR (KBr, cmꢁ1
)
1
n
max: 3443, 2921, 1622, 1560; H NMR (400 MHz, CDCl3): d 9.66 (br s, 1H, NH),
8.06 (d, 1H, C2-H, J ¼ 8.25 Hz), 7.61 (d t, 1H, C3-H, Jm ¼ 2.00 Hz, Jo ¼ 8.25 Hz),
7.55–7.49 (m, 3H, C4-H, C5-H, C40 -H), 7.39 (d, 1H, C10-H, Jm ¼ 1.00 Hz), 7.35 (d,
1H, C13-H, J ¼ 8.00 Hz), 7.29–7.24 (m, 4H, C02-H, C30 -H, C50 -H, C60 -H), 6.99 (d d,
1H, C12-H, Jm ¼ 1.00 Hz, Jo ¼ 8.00 Hz), 3.16–3.13 (m, 2H, C9-2H), 2.88–2.83 (m,
2H, C7-2H), 2.11–2.06 (m, 2H, C8-2H) ppm; 13C NMR (125 MHz, CDCl3): d
150.99 (C14b), 145.91 (C6), 137.84 (C1a), 134.73 (C13a), 134.70 (C01), 132.08 (C14a),

3362
E. YAMUNA ET AL.
129.51 (C02 & C06), 128.75 (C2), 128.68 (C30 ; C40 & C05), 127.14 (C6a), 126.99 (C3),
126.49 (C4), 126.15 (C9b), 125.76 (C5), 124.95 (C11), 122.15 (C12), 120.12 (C10),
118.72 (C5a), 117.71 (C9a), 113.15 (C13), 30.61 (C7), 27.55 (C8), 24.67 (C9) ppm;
MS: m=z (%) 394 (Mþ; 100), 396 (M þ 2, 32), 393 (14), 380 (8), 359 (12), 331 (10),
305 (6), 228 (22), 196 (7), 179 (9), 165 (15), 114 (8). Anal. calcd. for C26H19 ClN2:
C, 79.08; H, 4.85; N, 7.09. Found: C, 79.12; H, 4.81; N, 7.04.
General Procedure for Synthesis of 7,8,9,14-Tetrahydroquinolino[2’,3’:7,6]
cyclohept[1,2-b]indole-6-carboxylic Acid (5)
A mixture of 1-oxo-2,3,4,5,10-hexahydrocyclohept[b]indole (1, 1 mmol), isatin
(1 mmol), and sodium hydroxide (0.400 g) in aqueous ethanol (10 mL) was refluxed
in a water bath for 24 h. After the completion of the reaction, the solvent was eva-
porated in vacuum. The obtained crude product was poured into ice water and acidi-
fied with 1:1 HCl. The solid obtained was filtered and purified by treatment with
sodium bicarbonate and neutralized with 1:1 HCl. The solid product was recrystal-
lized from ethanol to yield the respective 7,8,9,14-tetrahydroquinolino[20,30:7,6]
cyclohept[b]indole-6-carboxylic acids (5).
Selected Data for 5
11-Methyl-7,8,9,14-tetrahydroquinolino[2’,3’:7,6]cyclohept[1,2-b]indoleꢁ-61-
carboxylic acid (5a). Yellow solid; yield: 267 mg (78%); mp: >300 ꢀC; IR (KBr, cm
n
)
max: 3500–2800, 3402, 1642; 1H NMR (400 MHz, DMSO-d6): d 11.18 (br s, 1H, NH),
8.10 (d, 1H, C2-H, J ¼ 8.44 Hz), 7.78 (t, 1H, C3-H, J ¼ 8.44 Hz), 7.72 (d, 1H, C5-H,
J ¼ 8.44 Hz), 7.60 (t, 1H, C4-H, J ¼ 8.44 Hz), 7.42 (d, 1H, C13-H, J ¼ 8.32 Hz), 7.34
(s, 1H, C10-H), 7.04 (d, 1H, C12-H, J ¼ 8.32 Hz), 3.15–3.12 (m, 2H, C9-2H),
3.03–3.00 (m, 2H, C7-2H), 2.39 (s, 3H, C11-CH3), 2.14–2.11 (m, 2H, C8-2H) ppm;
13C NMR (125 MHz, DMSO-d6): d 170.25 (COOH), 152.01 (C14b), 145.74 (C6),
136.75 (C1a), 132.96 (C13a), 132.16 (C14a), 130.24 (C11), 129.83 (C3), 129.30 (C2),
128.71(C6a), 128.28 (C9b), 127.75 (C4), 125.68 (C12), 125.63 (C5), 120.11 (C10),
118.40 (C5a), 117.42 (C9a), 110.90 (C13), 30.98 (C7), 26.74 (C8), 25.06 (C9), 21.68
(C11-CH3) ppm; MS: m=z (%) 342 (Mþ; 22), 341 (100), 327 (9), 313 (5), 281 (17),
269 (12), 171 (10), 154 (5), 140 (25), 115 (17), 102 (10), 77 (12), 63 (6), 44 (6). Anal.
calcd. for C22H18N2O2: C, 77.17; H, 5.30; N, 8.18. Found: C, 77.20; H, 5.35; N, 8.22.
12-Methyl-7,8,9,14-tetrahydroquinolino[2’,3’:7,6]cyclohept[1,2-b]indole-
6-carboxylic acid (5b). Yellow solid; yield: 253 mg (74%); mp: >300 ꢀC; IR (KBr,
cmꢁ1) nmax: 3500–2700, 3346, 1626; 1H NMR (400 MHz, CDCl3): d 11.16 (br s, 1H,
NH), 8.11 (d, 1H, C2-H, Jm ¼ 2.00 Hz, Jo ¼ 8.40 Hz), 7.80 (dt, 1H, C3-H,
Jm ¼ 2.00 Hz, Jo ¼ 8.40 Hz), 7.72 (d, 1H, C5-H, Jm ¼ 2.00 Hz, J ¼ 8.40 Hz), 7.62
(dd, 1H, C4-H, Jm ¼ 2.00 Hz, Jo ¼ 8.40 Hz), 7.46 (d, 1H, C10-H, J ¼ 8.00 Hz), 7.18
(s, 1H, C13-H), 6.88 (d, 1H, C11-H, J ¼ 8.00 Hz), 3.17–3.16 (m, 2H, C9-2H),
3.05–3.02 (m, 2H, C7-2H), 2.44 (s, 3H, C12-CH3), 2.14–2.13 (m, 2H, C8-2H) ppm;
13C NMR (125 MHz, DMSO-d6): d 169.95 (COOH), 150.99 (C14b), 145.65 (C6),
136.77 (C1a), 135.96 (C13a), 133.12 (C14a), 132.12 (C12), 129.74 (C3), 129.15 (C2),
128.15 (C6a), 127.47 (C4), 124.93 (C5), 123.95 (C9b), 121.01 (C11), 118.71 (C5a),

QUINOLINO[20,30:7,6]CYCLOHEPT[1,2-b]INDOLES
3363
118.53 (C10), 114.71 (C9a), 111.63 (C13), 30.59 (C7), 26.62 (C8), 25.17 (C9), 21.75 (C12-
CH3) ppm; MS: m=z (%) 342 (Mþ; 28), 341 (100), 327 (11), 313 (8), 297 (12), 281 (8),
269 (16), 171 (12), 154 (6), 140 (22), 115 (10), 102 (18), 77 (12), 63 (10), 44 (8). Anal.
calcd. for C22H18N2O2: C, 77.17; H, 5.30; N, 8.18. Found: C, 77.13; H, 5.29; N, 8.15.
13-Methyl-7,8,9,14-tetrahydroquinolino[2’,3’:7,6]cyclohept[1,2-b]indole-
6-carboxylic acid (5c). Yellow solid; yield: 273 mg (80%); mp: >300 ꢀC; IR (KBr,
1
cmꢁ1) nmax: 3550–2700, 3246, 1632; H NMR (400 MHz, DMSO-d6): d 10.70 (br
s, 1H, NH), 8.16 (d, 1H, C2-H, J ¼ 8.40 Hz), 7.78 (t, 1H, C3-H, J ¼ 8.40 Hz), 7.72
(d, 1H, C5-H, J ¼ 8.40 Hz), 7.60 (t, 1H, C4-H, J ¼ 8.40 Hz, H), 7.40 (d, 1H, C10-H,
J ¼ 7.60 Hz), 7.02 (d, 1H, C12-H, J ¼ 7.60 Hz), 6.96 (t, 1H, C11-H, J ¼ 7.60 Hz),
3.17–3.15 (m, 2H, C9-2H), 3.03–3.00 (m, 2H, C7-2H), 2.60 (s, 3H, C13-CH3),
2.14–2.13 (m, 2H, C8-2H) ppm; 13C NMR (125 MHz, DMSO-d6): d 170.05 (COOH),
151.16 (C14b), 145.94 (C6), 136.95 (C1a), 136.25 (C13a), 132.78 (C14a), 129.95 (C3),
129.23 (C2), 129.03 (C6a), 127.39 (C4), 125.07 (C5), 124.97 (C9b), 122.42 (C13),
121.34 (C11), 119.81 (C12), 118.13 (C5a), 117.56 (C10), 117.44 (C9a), 30.88 (C7),
27.07 (C8), 25.00 (C9), 16.74 (C13-CH3) ppm; MS: m=z (%) 342 (Mþ; 15), 341
(100), 327 (16), 313 (12), 281 (10), 269 (5), 171 (6), 154 (8), 140 (14), 115 (21), 102
(15), 77 (5), 63 (20), 44 (8). Anal. calcd. for C22H18N2O2: C, 77.17; H, 5.30; N,
8.18. Found: C, 77.21; H, 5.34; N, 8.15.
7,8,9,14-Tetrahydroquinolino[2’,3’:7,6]cyclohept[1,2-b]indole-6-carboxylic
acid (5d). Yellow solid; yield: 246 mg (75%); mp: >300 ꢀC; IR (KBr, cmꢁ1) nmax
:
1
3500–2700, 3268, 1646; H NMR (400 MHz, DMSO-d6): d 11.32 (br s, 1H, NH),
8.11 (d, 1H, C2-H, J ¼ 8.40 Hz), 7.80 (t, 1H, C3-H, J ¼ 8.40 Hz), 7.74 (d, 1H, C5-
H, J ¼ 8.40 Hz), 7.62 (t, 1H, C4-H, Jo ¼ 8.40 Hz), 7.58–7.55 (m, 2H, C10-H & C13-
H), 7.23 (t, 1H, C11-H, J ¼ 7.40 Hz), 7.05 (t, 1H, C12-H, J ¼ 7.40 Hz), 3.21–3.18
(m, 2H, C9-2H), 3.06–3.04 (m, 2H, C7-2H), 2.16–2.14 (m, 2H, C8-2H) ppm; 13C
NMR (125 MHz, DMSO-d6): d 170.11 (COOH), 151.71 (C14b), 145.72 (C6), 136.77
(C1a), 136.12 (C13a), 132.15 (C14a), 129.64 (C3), 129.32 (C2), 128.73 (C6a), 127.73
(C4), 125.01 (C5), 124.32 (C9b), 120.35 (C12), 119.12 (C11), 118.63 (C5a), 117.99
(C10), 115.14 (C9a), 112.10 (C13), 30.92 (C7), 26.35 (C8), 25.15 (C9) ppm; MS: m=z
(%) 328 (Mþ; 10), 327 (100), 314 (12), 288 (6), 283 (17), 269 (8), 243 (6), 194 (9),
181 (7), 158 (12), 129 (17), 115 (5), 92 (15), 77 (7). Anal. calcd. for C21H16 N2O2:
C, 76.81; H, 4.91; N, 8.53. Found: C, 76.78; H, 4.940; N, 8.57.
6-Chloro-7,8,9,14-tetrahydroquinolino[2’,3’:7,6]cyclohept[1,2-b]indole-6-
carboxylic acid (5e). Yellow solid; yield: 246 mg (68%); mp: >300 ꢀC; IR (KBr,
1
cmꢁ1) nmax: 3550–2700, 3352, 1642; H NMR (400 MHz, DMSO-d6): d 11.12 (br
s, 1H, NH), 7.91 (dd, 1H, C2-H, Jm ¼ 2.00 Hz, J ¼ 8.00 Hz), 7.61 (dt, 1H, C3-H,
Jm ¼ 2.00 Hz, Jo ¼ 8.00 Hz), 7.61 (dd, 1H, C5-H, Jm ¼ 2.00 Hz, J ¼ 8.00 Hz), 7.44
(dt, 1H, C4-H, Jm ¼ 2.00 Hz, Jo ¼ 8.00 Hz), 7.42 (d, 1H, C10-H, Jm ¼ 2.00 Hz), 7.35
(d, 1H, C13-H, J ¼ 8.40 Hz), 7.01 (dd, 1H, C12-H, Jm ¼ 2.50 Hz, Jo ¼ 8.40 Hz),
2.96–2.93 (m, 2H, C9-2H), 2.84–2.82 (m, 2H, C7-2H), 1.94–1.90 (m, 2H, C8-2H)
ppm; 13C NMR (125 MHz, DMSO-d6): d 169.83 (COOH), 152.11 (C14b), 146.14
(C6), 137.12 (C1a), 133.89 (C13a), 131.95 (C14a), 129.15 (C3), 128.83 (C2), 127.96
(C6a), 127.12 (C4), 126.13 (C9b), 124.95 (C5), 123.99 (C11), 121.73 (C12), 120.95
(C10), 118.15 (C5a), 115.43 (C9a), 112.96 (C13), 30.71 (C7), 26.02 (C8), 25.43 (C9)

3364
E. YAMUNA ET AL.
ppm; MS: m=z (%) 362 (Mþ; 15), 364 (M þ 2, 5), 361 (100), 317 (18), 282 (22), 268 (6),
256 (10), 242 (8), 207 (6), 194 (5), 180 (18), 140 (14), 114 (5), 93 (8), 77 (10). Anal.
calcd. for C21H15 ClN2O2: C, 69.52; H, 4.17; N, 7.72. Found: C, 69.55; H, 4.20;
N, 7.69.
Supplementary Data
Complete CIF files for compounds 3a–e were deposited with the Cambridge
Crystallographic Data Centre, CCDC Deposits 785958–785962. These data may
be obtained free of charge at www.ccdc.cam.ac.uk/data_request/cif.
ACKNOWLEDGMENTS
Our sincere thanks go to the chairman, NMR Research Centre, IISc,
Bangalore, SAIF, IIT Madras, Chennai, and the director, ISO Quality Assurance
Cell, Indian Institute of Chemical Technology (IICT), Hyderabad, for providing
access to their NMR and mass spectral facilities. The x-ray diffractometer was
funded by NSF Grant 0087210, Ohio Board of Regents Grant CAP-491, and
Youngstown State University.
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