An alternative one-pot gold-catalyzed approach to the assembly of 11H-indolo[3,2-c]quinolines

Article abstract of DOI:10.1039/c2ob26380g

A new one-pot approach was developed to construct the 11H-indolo[3,2-c] quinoline scaffold through a gold-catalysed reaction of 2-[(2-aminophenyl) ethynyl]phenylamine derivatives with aldehydes. The broad scope and the high regioselectivity of this new pr

Full text of DOI:10.1039/c2ob26380g

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PAPER
An alternative one-pot gold-catalyzed approach to the assembly of 11H-indolo-
[3,2-c]quinolines†
Giorgio Abbiati,a Antonio Arcadi,*b,c Marco Chiarini,d Fabio Marinelli,b Emanuela Pietropaolob and
Elisabetta Rossia
Received 17th July 2012, Accepted 9th August 2012
DOI: 10.1039/c2ob26380g
A new one-pot approach was developed to construct the 11H-indolo[3,2-c]quinoline scaffold through a
gold-catalysed reaction of 2-[(2-aminophenyl)ethynyl]phenylamine derivatives with aldehydes. The broad
scope and the high regioselectivity of this new protocol as well as the mild and neutral reaction conditions
make it a viable alternative to the previously reported procedures.
Introduction
Indole derivatives represent privileged structures because of their
role as bioactive natural products and their importance in other
research areas relevant for life such as agrochemistry or materials
science.1 In particular, some fused indole derivatives containing
the indolo[3,2-c]quinoline scaffold are naturally occurring alka-
loids which have attracted considerable attention for the develop-
ment of a new class of drug leads.2 Isocryptolepine (5-methyl-
Fig. 1 Indolo[3,2-c]quinoline scaffolds.
5H-indolo[3,2-c]quinoline), extracted from the African medi-
cinal plant Cryptolepis sanguinolenta, and isoneocryptolepine
(Fig. 1), which has never been found in nature, have been evalu-
ated for their broad spectrum of biological activities including
antiparasitic, antifungal, antibacterial, cytotoxic, anti-inflamma-
tory and antihyperglycemic.
As a consequence, to further investigate the structure–activity
relationship, a variety of synthetic strategies based on indole and
quinoline formation have been developed.3
Recently, to overcome some drawbacks due to the lacking of
flexibility of previous methodologies with respect to the intro-
duction of different substituents, Wang designed a strategy to
assemble 11H-indolo[3,2-c]quinolines by the two-step protocol.4
The five- and six-membered nitrogen-containing rings in the
tetracyclic skeleton were elaborated through a gold(III)-catalysed
aDipartimento di Scienze Farmaceutiche-Sezione di Chimica generale e
Organica “A. Marchesini”, Università degli Studi di Milano,
Via G. Venezian 21, 20133 Milano, Italy
bDipartimento di Scienze Fisiche e Chimiche, Università degli Studi di
L’Aquila, Via Vetoio, 67010 Coppito, L’Aquila, Italy.
Scheme 1
E-mail: antonio.arcadi@univaq.it; Fax: +390862433033
cUnità di Ricerca AQ2, Consorzio Interuniversitario La Chimica per
l’Ambiente, Via della Libertà 5/12, 30175 Marghera, VE, Italy
dDepartment of Food Science, University of Teramo, Via Carlo Lerici 1,
I-64023 Mosciano Sant’Angelo, TE, Italy
5-endo-dig cyclization and Hendrickson reagent promoted regio-
selective 6-endo-cyclization (Scheme 1).
The straightforward palladium-catalysed carbonylative cycli-
zation reaction of o-(o-aminophenyl)trifluoroacetanilide with
aryl iodides followed by subsequent intramolecular condensation
†Electronic supplementary information (ESI) available: Preparation and
1
characterizations of compounds 1b–d and 3a,c; copies of the H NMR
and 13C NMR for the new compounds. See DOI: 10.1039/c2ob26380g
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Scheme 4
Scheme 2
Scheme 3
Scheme 5
of the resultant 3-acylindole accomplished an expedient
approach to the construction of 6-arylated 11H-indolo[3,2-c]qui-
nolines in a one-pot process (Scheme 2).5
Table 1 Screening of gold catalysts and reaction conditions
Devising methods to construct target structures according to
the concept of green and sustainable chemistry represents a
major challenge for chemists in industry and academic insti-
tutions. The so-called “telescoping” of reactions6 (the sequen-
cing of multiple transformations in a single reaction vessel
through the changing of conditions and/or adding of reagents at
appropriate times) represents an attractive alternative to classical
multistep synthesis for the easy assembly of readily available
building blocks into more complex derivatives. Our continuing
interest in the synthesis of indole derivatives by one-pot pro-
cesses7 led us to investigate a new approach to assemble 11H-
indolo[3,2-c]quinolines with better flexibility according to the
retrosynthetic Scheme 3.
Catalyst
Entry (5 mol%)
Conditions [1a]/
[2a] = 1 : 1
Producta 4a
Time (h) (% yield)
1
2
3
4
5
6
NaAuCl4·2H2O
NaAuCl4·2H2O
Ph3PAuCl/AgOTf CH3CN, 80 °C
Ph3PAuCl/AgOTf CH3CN, 100 °C
Ph3PAuCl/AgOTf DCE, 100 °C
Ethanol, 80 °C
CH3CN, 80 °C
22
48
24
48
48
48
27
32
40
28
28
35
AgOTf
DCE, 100 °C
a Yields refer to a single run and are for pure isolated products.
leading to different indoles can be directed by a suitable choice
of the reaction conditions.11 In particular, to avoid the competi-
tive condensation reaction12 the gold-catalysed domino cycliza-
tion/alkenylation of the 2-alkynylaniline derivative with 1,3-
dicarbonyls was directed by increasing the reaction tempera-
ture.13 Nevertheless, in the presence of NaAuCl4·2H2O (5 mol%)
in ethanol at reflux (Table 1, entry 1), the 11H-indolo[3,2-c]-
quinoline 3a was isolated in only 27% yield.
Competitive simultaneously occurring reactions led to a
complex mixture of by-products in which 6-(3-bromophenyl)-
5,6-dihydroindolo[1,2-c]quinazoline 5a, 6-(3-bromophenyl)-
indolo[1,2-c]quinazoline 6a, and 2-((2-aminophenyl)ethynyl)-N-
benzylaniline 7a (Fig. 2) were identified by MS-ESI and NMR
analysis. In fact 5a showed, besides other, the characteristic 13C-
Here we wish to report the results of this study.
Results and discussion
We selected the reaction of 2-[(2-aminophenyl)ethynyl]phenyl-
amine 1a with aldehydes in the presence of a gold catalyst8 for
initial studies. The alkyne 1a was prepared through the palla-
dium-catalysed cross-coupling of 2-ethynylaniline with 2-iodo-
aniline.9 The efficient NaAuCl4·2H2O catalysed cyclization of
2-alkynyl-phenylamines to indoles in ethanol or ethanol–water
mixtures at room temperature was previously investigated.10
Accordingly, in a control experiment, the NaAuCl4·2H2O cycli-
zation of the starting alkyne 1a in ethanol was completed in 78%
yield at room temperature (Scheme 4).
To explore the viability of the construction of the target indolo-
[3,2-c]quinoline skeleton according to our hypothesis, com-
pound 1a was reacted with 3-bromobenzaldehyde 2a
(Scheme 5).
Some results of our screening are summarized in Table 1. It
was reported that a variety of gold-catalysed sequential cycliza-
tion/alkylation, N-alkylation/cyclization, or N-alkylation/cycliza-
tion/alkylation reactions of 2-alkynyl-phenylamine derivatives
1
and H-NMR peaks at 67.7 ppm and 6.56 ppm, respectively, of
the non-aromatic CH in the 1,2-dihydroquinazoline moiety.14
Those peaks showed correlation in the 2D 13C–1H heterocorre-
lated spectrum. For 6a the C2 in the quinazoline moiety gave a
13C-NMR signal at 153.6 ppm in line with similar compounds.15
Moreover, both, 5a and 6a, showed the 1H and 13C NMR signals
for the CH of the heterocyclic indole moiety. In respect of 7a,
13C peaks at 91.0 and 91.8 ppm, for the ethynyl moiety, and at
47.2 ppm, characteristic of aminobenzyl CH2, along with the
correlation of the latter with the 1H 4.39 ppm peak in the
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100 °C (Table 1, entry 4). No advantage was derived by using
DCE as a solvent instead of CH3CN. A control experiment
employing AgOTf as the sole catalyst under the same reaction
conditions produced 4a in 35% yield, but the selectivity of the
process was unsatisfactory because of the simultaneous for-
mation of 5a (24% yield) and 6a (8% yield). In contrast to
classic Lewis acids, which are known to form strong σ-com-
plexes, gold and silver derivatives can operate as bifunctional
Lewis acids activating either (or both) carbon–carbon multiple
bonds via π-bonding and/or forming σ-complexes by coordinat-
ing with heteroatoms.23 Although the relative ability for making
π- and σ-complexes of the catalyst with appropriate substrates is
a valuable tool for addressing the desired transformations in the
cases when bi- or polyfunctional substrates are involved,24 the
failure to selectively perform the domino process for the assem-
bly of 11H-indolo[3,2-c]quinolines induced us to examine the
one-pot combination of the gold-catalysed cyclization of 2-alky-
nylanilines followed by reaction with aldehyde (Scheme 7).
Application of the modified Pictet–Spenger reaction of hetero-
aryl-arylamines to the synthesis of fused six, seven, and eight-
membered rings was successfully demonstrated.25 The reaction
of the key intermediate 3a with aldehydes in the presence of tri-
fluoroacetic acid furnished the corresponding indoloquinolines
4.26 Then we examined a variety of reaction conditions in order
to optimize those more suitable for both steps of the process.
When the 2,2′-(ethyne-1,2-diyl)dianiline 1a was cyclised in
CH3CN at room temperature in the presence of PPh3AuCl/
AgOTf (5 mol%) and in the second step the aldehyde 2a
(2 equiv.) was added to the reaction mixture after 6 h (procedure
A), the target 4a was isolated in good overall yield after column
chromatography (Table 2, entry 1). By replacing the PPh3AuCl/
AgOTf catalytic system with the stable Au(I)complex A
(5 mol%) (Fig. 3),27 the use of the silver co-catalyst (procedure
B) was avoided and the first cyclization step was faster.
A number of aryl aldehydes were screened, and all were con-
verted into the corresponding 6-arylated 11H-indolo[3,2-c]qui-
nolines 4a–g as expected (Table 2, entries 1–8). It seems that the
electronic properties of the substituents on the aryl moiety of the
starting aldehyde did not affect the outcome of the reaction. The
presence of a substituent at the o-position on the aldehyde can
be tolerated, but the assembly of the 11H-indolo[3,2-c]quino-
lines is hindered to some extent (Table 2, entry 5). The flexibility
of our strategy was further established by generating 6-heteroary-
lated/6-alkylated derivatives (Table 2, entries 9–10). To further
extend the scope, we prepared the 2-((2-aminophenyl)ethynyl)-
polysubstituted-anilines 1b–d. Interestingly, only the formation
of the regioisomers 4k–l was observed by reacting the 2-((2-ami-
nophenyl)ethynyl)-4,6-dihaloanilines 1b–c with 2g according to
procedure B (Scheme 8). The structures of 4k–l were assigned
on the basis of analytical and spectral data (see ESI†).
Fig. 2 By-products.
Scheme 6
13C–1H heterocorrelated spectrum, confirmed its nature. Overall,
DEPT (Distortionless Enhancement by Polarization Transfer)
experiments confirmed the supposed number of protons attached
to each carbon.
Very likely,16 the competitive condensation reaction between
1a with 3-bromobenzaldehyde 2a generates the 2-((2-aminophe-
nyl)ethynyl)-N-(3-bromobenzilidene)aniline 8a which can
undergo the cyclization reaction to give the 5,6-dihydroindolo
[1,2-c]quinazoline 5a. The role of NaAuCl4·2H2O in promoting
the condensation reaction of carbonyl derivatives with anilines
has been previously reported.17 Moreover, in previous studies we
observed the high efficiency of gold(III) as both a Lewis acid/
transition metal in sequential amination/annulation reactions of
carbonyl derivative with amine.18 The oxidation of 5a to 6a
releases H2 responsible for the catalytic transfer hydrogenation
reaction19 of 8a to 7a (Scheme 6). The formation of the 6-substi-
tuted indolo[1,2-c]quinazoline 6 after oxidative cyclization of
intermediates 9 was previously reported in the literature.20
A slightly better yield of 4a was observed in CH3CN as the
reaction medium (Table 2, entry 2). Participation of Au(I) in the
sequential transformation of 1a into the target indolo[3,2-c]qui-
noline suggested that the catalytic activity of Au(I) species might
deserve advantages compared to Au(III) (Table 2, entry 3). Under
Ph3PAuOTf catalysis the reaction of symmetrical diamines 1
with 4-pentyn-1-ol gave the corresponding indolo[3,2-c]quino-
lines through a process involving multiple catalytic cycles
assisted by a single metal catalyst.21 The Au(I) catalysis was,
also, reported to be superior to that of Au(III) in the sequential
cycloisomerization/C3-functionalization of 2-ethynylanilines
with a wide range of aldehydes, isatins and nitrostyrenes.22 Wor-
sening of yield of 4a was observed by elevating temperature at
The 2-amino-3((2-aminophenyl)ethynyl)-5-nitrobenzonitrile
1d, also, underwent under the reaction conditions the gold-cata-
lyzed regioselective annulation to the corresponding 2-(2-amino-
phenyl)-5-nitro-1H-indole-7-carbonitrile 3d in 64% yield, but
we failed to observe the formation of the corresponding target
11H-indolo[3,2-c]quinoline derivative (Scheme 9).
Electronic effects could account for the observed results and
gave an insight on the possible mechanism for the formation of
the reaction products 4 under the present reaction conditions.
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Table 2 Gold-catalysed synthesis of 11H-indolo[3,2-c]quinoline 4 from 2-[(2-aminophenyl)ethynyl]phenylamines 1 and aldehydes 2
Entry
1
1
2
Procedurea
A
4b
2
3
4
1a
1a
1a
B
A
B
5
6
7
1a
1a
1a
B
A
B
8
1a
A
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Table 2 (Contd.)
Entry
1
2
Procedurea
B
4b
9
1a
10
11
1a
B
B
2g
2g
12
B
a Procedure A: the starting alkyne 1 was cyclised in CH3CN at room temperature in the presence of PPh3AuCl/AgOTf (5 mol%). Then, the aldehyde
2a (2 equiv.) was added to the reaction mixture. Procedure B: the starting alkyne 1 was cyclised in CH3CN at room temperature in the presence of
catalyst A (5 mol%). Then, the aldehyde 2a (2 equiv.) was added to the reaction mixture. b Yields refer to a single run and are for pure isolated
products.
Scheme 7
Scheme 8
Fig. 3 Gold catalyst A.
A reasonable mechanistic interpretation which also explains the
regioselective formation of 11H-indolo[3,2-c]quinoline deriva-
tives versus 6-substituted indolo[1,2-c]quinazolines might
Scheme 9
assume a reaction path that implies an initial π-coordination by a
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mild character of the applied conditions as well as the high
regioselectivity for this protocol makes it a valuable alternative
to those previously described in the literature. Most importantly,
the possibility of nitrile activation by cationic gold complexes is
of high relevance to develop a further versatile entry into the title
compounds.
Scheme 10
Experimental
General procedure A for the synthesis of 6-substituted-11H-
indolo[3,2-c]quinolines 4
Ph3AuCl (11.8 mg, 0.024 mmol) and AgOTf (6.2 mg,
0.024 mmol) were added to a solution of 2,2′-(ethyne-1,2-diyl)-
dianiline derivative 1 (0.48 mmol). The mixture was stirred at r.t.
and the reaction was monitored by TLC, following the disap-
pearance of the starting material. Then, aldehyde 2 (0.96 mmol)
was added and the mixture after stirring till completion was
evaporated. Column chromatographic purification of the crude
on silica gel (hexane–EtOAc) afforded the target 6-substituted-
11H-indolo[3,2-c]quinoline 4.
Scheme 11
gold catalyst with the alkyne residue of starting substrate 1 to
form a π complex 10. The simultaneous nitrogen coordination of
a gold catalyst in the complex 10 explains the regioselectivity of
the cyclization step in the presence of electron withdrawing
groups in one of the two aromatic rings of the starting alkyne
derivatives 1. Subsequent nucleophilic attack of the tethered free
amino groups leads to ring closure to afford after proto-deaura-
tion cyclized indole 3. The regenerated gold catalyst activates the
carbonyl oxygen of the aldehyde and carries out an electrophilic
addition reaction at C3 of the indole 3 to give the 3-substituted
intermediate 11. Finally, after loss of water and aromatization
reactions the 11H-indolo[3,2-c]quinoline is generated
(Scheme 10). The two strongly withdrawing substituents of the
indole 3d are responsible for the deactivation of the C3 position
toward the electrophilic attack of the aldehyde 2g.
Very surprisingly, the formation of the 6-methyl-11H-indolo-
[3,2-c]quinoline 4m can occur in excellent yield through a
domino process involving CH3CN as both the reacting partner
and the reaction solvent (Scheme 11). The indolo[3,2-c]quino-
line 4m was isolated in traces in all the cases in which the gold-
catalysed reaction of 1a with aldehydes was carried out in
CH3CN as the reaction medium. Although CH3CN starting from
early publications was often used as a solvent because it was
considered inert to gold catalysis,28 nitriles σ- or π-bonded to
gold complexes are more recently reported as key intermediates
in a variety of synthetic applications.29 Further studies of the
scope and limitations of the synthesis of 11H-indolo[3,2-c]qui-
nolines through gold-catalysed domino reactions of 2-[(2-amino-
phenyl)ethynyl]phenylamine derivatives with nitriles are under
current investigation.
General procedure B for the synthesis of 6-substituted-11H-
indolo[3,2-c]quinolines 4
Catalyst A (0.011 g, 0.014 mmol) was added to a solution of
2,2′-(ethyne-1,2-diyl)dianiline derivative 1 (0.29 mmol). The
mixture was stirred at r.t. and the reaction was monitored by
TLC, following the disappearance of the starting material. Then,
aldehyde 2 (0.58 mmol) was added and the mixture after stirring
till completion was evaporated. Column chromatographic purifi-
cation of the crude on silica gel (hexane–EtOAc) afforded the
target 6-substituted-11H-indolo[3,2-c]quinoline 4.
6-(3-Bromophenyl)-11H-indolo[3,2-c]quinoline (4a). (0.140 g,
78% yield). Found C, 67.5; H, 3.7; N, 7.5. Calcd for
C21H13BrN2: C, 67.6; H, 3.5; N, 7.5. IR (KBr): νmax/cm−1 3434,
2969, 1557, 1509, 743. δH (400 MHz; DMSO; Me4Si) 7.17 (1H,
ddd, J = 8.1 Hz, J = 7.1 Hz, J = 0.9 Hz), 7.46 (1H, ddd, J =
8.1 Hz, J = 7.1 Hz, J = 1.2 Hz), 7.53 (1H, d, J = 8.0 Hz), 7.60
(1H, t, J = 7.8 Hz), 7.69–7.82 (4H, m), 7.86 (1H, dt, J = 7.6 Hz,
J = 1.2 Hz), 8.05 (1H, t, J = 1.7 Hz), 8.15 (1H, d, J = 8.0 Hz),
8.60 (1H, d, J = 7.8 Hz), 12.94 (1H, s, NH). δC (100.6 MHz;
DMSO; Me4Si) 111.8 (C), 112.1 (CH), 116.3 (C), 120.4 (CH),
120.8 (CH), 121.4 (C), 121.7 (C), 122.0 (CH), 125.5 (CH),
125.8 (CH), 127.9 (CH), 128.6 (CH), 129.4 (CH), 130.5 (CH),
131.5 (CH), 131.6 (CH), 135.4 (C), 139.1 (C), 142.9 (C), 144.8
(C), 153.6 (C). MS-ESI: m/z: 375 (M+ 81Br + H, 96%),
373 (M+ 79Br + H, 100).
6-(4-Bromophenyl)-11H-indolo[3,2-c]quinoline (4b). (0.101 g,
93%). Found C, 67.5; H, 3.5; N, 7.4. Calcd for C21H13BrN2: C,
67.6; H, 3.5; N, 7.5. IR (KBr): νmax/cm−1 2924.78, 1586.26,
1512.12, 743.62. δH (400 MHz; DMSO; Me4Si) 7.17 (1H, ddd,
J = 8.1 Hz, J = 7.1 Hz, J = 1.1 Hz), 7.46 (1H, ddd, J = 8.2 Hz,
J = 7.1 Hz, J = 1.2 Hz), 7.53 (1H, d, J = 8.2 Hz), 7.68–7.86
(7H, m), 8.12 (1H, ddd, J = 8.3 Hz, J = 1.4 Hz, J = 0.6 Hz),
8.57 (1H, ddd, J = 8.1 Hz, J = 1.6 Hz, J = 0.7 Hz), 12.93 (1H, s,
NH). δC (100.6 MHz; DMSO; Me4Si) 112.2 (C), 112.5 (CH),
Conclusions
In summary, we have developed a new one-pot gold-catalysed
approach to the assembly of 11H-indolo[3,2-c]quinolines from
readily available unprotected 2-[2-(2-aminophenyl)ethynyl]ani-
lines and aldehydes. The reaction scope is broad and a range of
alkyne derivatives and aldehydes are allowed. The neutral and
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116.7 (CH), 120.9 (CH), 121.4 (C), 121.9 (CH), 122.4 (C),
122.8 (CH), 125.9 (CH), 126.3 (CH), 129.1 (CH), 129.9 (C),
131.5 (2 × CH), 131.9 (2 × CH), 139.5 (C), 140.4 (C), 141.6
(C), 145.4 (C), 154.6 (C). MS-ESI: m/z: 375 (M+ 81Br + H,
96%), 373 (M+ 79Br + H, 100).
(5H, m), 8.13 (1H, d, J = 8.4 Hz), 8.58 (1H, d, J = 8.0 Hz),
12.92 (1H, s, NH). δC (100.6 MHz; DMSO; Me4Si) 21.0 (CH3),
111.86 (CH), 111.89 (C), 116.1 (C), 120.2 (CH), 121.0 (CH),
121.7 (C), 121.9 (CH), 125.3 (CH), 125.5 (CH), 128.5 (CH),
128.8 (2 × CH), 128.9 (2 × CH), 129.0 (CH), 137.5 (C), 138.3
(C), 139.0 (C), 141.0 (C), 144.6 (C), 155.3 (C). MS-ESI: m/z:
309 (M − H+, 100%).
6-(4-Chlorophenyl)-11H-indolo[3,2-c]quinoline (4c). (0.142 g,
90%). Found C, 76.65; H, 3.9; N, 8.45. Calcd for C21H13ClN2:
C, 76.7; H, 4.0; N, 8.5. IR (KBr): νmax/cm−1 2920.14, 1558.80,
1512.21, 746.24. δH (400 MHz; DMSO; Me4Si) 7.17 (1H, ddd,
J = 8.1 Hz, J = 7.1 Hz, J = 1.1 Hz), 7.46 (1H, ddd, J = 8.2 Hz,
J = 7.1 Hz, J = 1.2 Hz), 7.53 (1H, d, J = 8.2 Hz), 7.69–7.72
(3H, m), 7.73 (1H, dt, J = 8.1 Hz, J = 1.0 Hz), 7.77 (1H, ddd,
J = 8.3 Hz, J = 6.9 Hz, J = 1.6 Hz), 7.86–7.88 (2H, m), 8.13
(1H, ddd, J = 8.3 Hz, J = 1.4 Hz, J = 0.6 Hz), 8.60 (1H, ddd,
J = 8.1 Hz, J = 1.6 Hz, J = 0.6 Hz), 12.91 (1H, s, NH). δC
(100.6 MHz; DMSO; Me4Si) 111.7 (C), 112.0 (CH), 116.2
(CH), 120.4 (CH), 120.9 (CH), 121.4 (C), 121.9 (CH), 125.4
(CH), 125.8 (CH), 128.48 (2 × CH), 128.54 (C), 129.4 (2 ×
CH), 130.7 (CH), 133.6 (C), 139.0 (C), 139.5 (C), 141.0 (C),
144.9 (C), 154.1 (C). MS-ESI: m/z: 331 (M+ 37Cl + H, 37%),
329 (M+ 35Cl + H, 100).
6-(2-Furyl)-11H-indolo[3,2-c]quinoline (4i). (0.060 g, 73%).
Found C, 80.3; H, 4.2; N, 9. 8. Calcd for C19H12N2O: C, 80.3;
H, 4.25; N, 9.85. IR (KBr): νmax/cm−1 3400.80, 1556.19,
1502.60, 764.35. δH (400 MHz; DMSO; Me4Si) 6.87–6.88 (1H,
m), 7.36 (1H, t, J = 7.5 Hz), 7.38–7.39 (1H, m), 7.55 (1H, t, J =
7.6 Hz), 7.71 (1H, t, J = 7.5 Hz), 7.77–7.81 (2H, m), 8.15 (1H,
d, J = 8.4 Hz), 8.17 (1H, s), 8.52 (1H, d, J = 8.2 Hz), 8.59 (1H,
d, J = 8.0 Hz), 12.97 (1H, s, NH). δC (100.6 MHz; DMSO;
Me4Si) 110.9 (C), 111.5 (CH), 111.8 (CH), 112.3 (CH), 116.2
(C), 120.6 (CH), 121.3 (C), 121.9 (CH), 122.8 (CH), 125.6
(CH), 125.7 (CH), 128.7 (CH), 128.9 (CH), 139.2 (C), 141.5
(C), 144.0 (CH), 144.3 (C), 144.4 (C), 153.8 (C). MS-ESI: m/z:
285 (M − H+, 100%).
6-(4-Fluorophenyl)-11H-indolo[3,2-c]quinoline (4d). (0.063 g,
74%). Found C, 80.7; H, 4.15; N, 8.9. Calcd for C21H13FN2: C,
80.75; H, 4.2; N, 9.0. IR (KBr): νmax/cm−1 3320.90, 1562.30,
1503.82, 746.36. δH (400 MHz; DMSO; Me4Si) 7.16 (1H, ddd,
J = 8.1 Hz, J = 7.1 Hz, J = 1.1 Hz), 7.43–7.49 (3H, m), 7.53
(1H, dt, J = 8.1 Hz, J = 1.9 Hz), 7.68–7.79 (3H, m), 7.87–7.91
(2H, m), 8.13 (1H, ddd, J = 8.3 Hz, J = 1.4 Hz, J = 0.6 Hz),
8.58 (1H, ddd, J = 8.3 Hz, J = 1.4 Hz, J = 0.6 Hz), 12.92 (1H, s,
NH). δC (100.6 MHz; DMSO; Me4Si) 111.9 (C), 112.0 (CH),
6-Benzyl-11H-indolo[3,2-c]quinoline (4j). (0.037 g, 42%).
Found C, 85.6; H, 5.4; N, 9.0. Calcd for C22H16N2: C, 85.7; H,
5.2; N, 9.1. IR (KBr): νmax/cm−1 3397.90, 1667.11, 1563.21,
748.60. δH (400 MHz; DMSO; Me4Si) 4.83 (2H, s, CH2), 7.15
(1H, dt, J = 7.3 Hz, J = 1.4 Hz), 7.21–7.27 (2H, m), 7.29 (1H,
ddd, J = 8.1 Hz, J = 7.2 Hz, J = 1.1 Hz), 7.31–7.34 (2H, m),
7.48 (1H, ddd, J = 8.2 Hz, J = 7.2 Hz, J = 1.1 Hz), 7.69 (1H,
ddd, J = 8.31 Hz, J = 6.9 Hz, J = 1.2 Hz), 7.72–7.75 (1H, m),
7.77 (1H, ddd, J = 8.4 Hz, J = 6.9 Hz, J = 1.5 Hz), 8.14 (1H,
ddd, J = 8.3 Hz, J = 1.2 Hz, J = 0.4 Hz), 8.15 (1H, ddd, J =
8.1 Hz, J = 1.1 Hz, J = 0.8 Hz), 8.58 (1H, ddd, J = 8.1 Hz, J =
1.6 Hz, J = 0.5 Hz), 12.99 (1H, s, NH). δC (100.6 MHz; DMSO;
Me4Si) 42.2 (CH2), 111.9 (CH), 112.8 (C), 116.1 (C), 120.7
(CH), 121.5 (C), 121.6 (CH), 122.0 (CH), 125.2 (CH), 125.4
(CH), 126.1 (CH), 128.2 (CH), 128.31 (2 × CH), 128.35 (2 ×
CH), 128.42 (CH), 138.4 (C), 138.9 (C), 140.9 (C), 144.1 (C),
155.4 (C). MS-ESI: m/z: 309 (M − H+, 100%).
2
115.3 (d, J = 21.5 Hz, 2 × CH), 116.3 (C), 120.4 (CH), 120.9
(CH), 121.6 (C), 121.9 (CH), 125.4 (CH), 125.7 (CH), 128.5
3
(CH), 129.3 (CH), 131.1 (d, J = 8.3 Hz, 2 × CH), 137.1 (d,
4J = 2.4 Hz, C), 139.1 (C), 141.1 (C), 144.9 (C), 154.4 (C),
162.6 (d, 1J = 245.5 Hz, C). MS-ESI: m/z: 313 (M − H+,
100%).
6-(2-Fluorophenyl)-11H-indolo[3,2-c]quinoline (4e). (0.050 g,
56%). Found C, 80.7; H, 4.1; N, 8.9. Calcd for C21H13FN2: C,
80.75; H, 4.2; N, 9.0. IR (KBr): νmax/cm−1 3421.03, 1649.25,
727.32. δH (400 MHz; DMSO; Me4Si) 7.12–7.16 (1H, m),
7.18–7.20 (1H, m), 7.42–7.45 (1H, m), 7.46 (1H, dd, J =
2.5 Hz, J = 1.2 Hz), 7.48–7.51 (1H, m), 7.65–7.76 (4H, m),
7.77–7.81 (1H, m), 8.17 (1H, d, J = 8.1 Hz), 8.61 (1H, dd, J =
7.9 Hz, J = 1.4 Hz), 12.94 (1H, s, NH). δC (100.6 MHz; DMSO;
Me4Si) 112.0 (CH), 113.1 (C), 115.8 (d, 2J = 21.3 Hz, CH),
116.5 (C), 120.2 (CH), 120.5 (CH), 121.5 (C), 122.0 (CH),
124.8 (d, 4J = 2.5 Hz, CH), 125.5 (CH), 125.9 (CH), 128.5
8,10-Difluoro-6-(4-methylphenyl)-11H-indolo[3,2-c]quinoline
(4k). (0.091 g, 91%). Found C, 76.7; H, 4.2; N, 8.1. Calcd for
C22H14F2N2: C, 76.7; H, 4.1; N, 8.1. IR (KBr): νmax/cm−1
3421.03, 1649.25, 1503.92, 757.22. δH (400 MHz; DMSO;
Me4Si) 2.50 (3H, s, CH3), 7.00 (1H, dd, J = 9.6 Hz, J = 2.3 Hz),
7.40 (1H, ddd, J = 11.2 Hz, J = 9.4 Hz, J = 2.3 Hz), 7.44–7.47
(2H, m), 7.68–7.70 (2H, m) 7.72 (1H, ddd, J = 8.2 Hz, J =
7.1 Hz, J = 1.3 Hz), 7.80 (1H, ddd, J = 8.4 Hz, J = 6.9 Hz, J =
1.5 Hz), 8.13 (1H, ddd, J = 8.4 Hz, J = 1.3 Hz, J = 0.6 Hz), 8.73
(1H, ddd, J = 8.1 Hz, J = 1.5 Hz, J = 0.6 Hz), 13.27 (1H, s,
NH). δC (100.6 MHz; DMSO; Me4Si) 21.0 (CH3), 100.3 (dd,
3
3
(CH), 129.4 (CH), 131.0 (d, J = 8.0 Hz, CH), 131.2 (d, J =
2.7 Hz, CH), 134.5 (C), 139.0 (C), 140.4 (C), 144.9 (C), 150.0
1
(C), 159.5 (d, J = 245.7 Hz, C); MS-ESI: m/z: 313 (M − H+,
2
2
4
2J = 29.9 Hz, J = 20.6 Hz, CH), 102.4 (dd, J = 25.2 Hz, J =
100%).
3
3.9 Hz, CH), 112.1 (C), 116.3 (C), 122.3 (CH), 123.7 (d, J =
3
4
6-(4-Methylphenyl)-11H-indolo[3,2-c]quinoline (4g). (0.071 g,
80%). Found C, 80.6; H, 5.15; N, 9.15. Calcd for C22H16N2: C,
80.7; H, 5.2; N, 9.1. IR (KBr): νmax/cm−1 1620.32, 740.05. δH
(400 MHz; DMSO; Me4Si) 2.49 (3H, s, CH3), 7.15 (1H, t, J =
7.6 Hz), 7.44–7.47 (3H, m), 7.57 (1H, d, J = 8.1 Hz), 7.68–7.79
13.9 Hz, C), 124.4 (dd, J = 11.4 Hz, J = 6.4 Hz, C), 125.9
(CH), 128.7 (2 × CH), 129.0 (2 × CH), 129.1 (CH), 129.3 (CH),
137.1 (C), 138.6 (C), 142.4 (C), 145.4 (C), 148.3 (dd, 1J =
246.8 Hz, 3J = 14.5 Hz, C), 155.5 (C), 155.8 (dd, 1J = 236.0 Hz,
3J = 10.1 Hz, C). MS-ESI: m/z: 345 (M − H+, 100%).
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7801–7808 | 7807

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hedron, 2003, 59, 1571.
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V. V. Alekseyev and K. Pihlaja, Tetrahedron, 2003, 59, 1939;
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5873.
8,10-Dichloro-6-(4-methylphenyl)-11H-indolo[3,2-c]quinoline
(4l). (0.083 g, 75%). Found C, 70.1; H, 3.7; N, 7.5. Calcd for
C22H14Cl2N2: C, 70.0; H, 3.7; N, 7.4. IR (KBr): νmax/cm−1
3421.03, 1649.25, 1503.92, 757.22. δH (400 MHz; DMSO;
Me4Si) 2.50 (3H, s, CH3), 7.41 (1H, dd, J = 1.9 Hz, J = 0.3 Hz),
7.46–7.48 (2H, m), 7.65–7.66 (1H, m), 7.69–7.71 (2H, m) 7.72
(1H, ddd, J = 8.2 Hz, J = 7.0 Hz, J = 1.3 Hz), 7.81 (1H, ddd,
J = 8.4 Hz, J = 6.9 Hz, J = 1.5 Hz), 8.13 (1H, ddd, J = 8.5 Hz,
J = 1.1 Hz, J = 0.5 Hz), 8.93 (1H, dd, J = 8.3 Hz, J = 1.3 Hz),
13.07 (1H, s, NH). δC (100.6 MHz; DMSO; Me4Si) 21.0 (CH3),
111.8 (C), 116.3 (C), 117.4 (C), 119.1 (CH), 122.9 (CH), 124.1
(CH), 124.2 (C), 124.3 (C), 125.8 (CH), 128.7 (2 × CH), 129.0
(2 × CH), 129.2 (CH), 129.3 (CH), 137.2 (C), 138.7 (C), 142.2
(C), 142.8 (C), 145.4 (C), 155.5 (C). MS-ESI: m/z: 381
(M+ 37Cl − 37Cl + H, 10%), 379 (M+ 37Cl − 35Cl + H, 60), 377
(M+ 35Cl − 35Cl + H, 100).
15 R. Rohini, P. M. Reddy, K. Shanker, A. Hu and V. Ravinder, J. Braz.
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2003, 5, 64; (b) A. Arcadi, M. Chiarini, S. Di Giuseppe and F. Marinelli,
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19 A. S. K. Hashmi, Angew. Chem., Int. Ed., 2005, 44, 6990.
20 R. Rohini, K. Shanker, P. M. Reddy, V. C. Sekhar and V. Ravinder, Arch.
Pharm. Chem. Life Sci., 2009, 342, 533.
Procedure for the preparation of 6-methyl-11H-indolo[3,2-c]-
quinoline (4m). Catalyst A (0.011 g, 0.014 mmol) was added to
a
solution of 2,2′-(ethyne-1,2-diyl)dianiline 1a (0.060 g,
0.29 mmol). The mixture was stirred at r.t. for 8 h. Then, the
mixture was evaporated. Column chromatographic purification
of the crude on silica gel (hexane–EtOAc 90 : 10) afforded
6-methyl-11H-indolo[3,2-c]quinoline 4m: 0.065 g, 96% yield.
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7808 | Org. Biomol. Chem., 2012, 10, 7801–7808
This journal is © The Royal Society of Chemistry 2012