Facile assembly of 11 H -indolo[3,2-c]quinoline by a two-step protocol involving a regioselective 6- endo -cyclization promoted by the hendrickson reagent

Article abstract of DOI:10.1055/s-0030-1258411

An expedient approach was developed to construct the 11H-indolo[3,2-c] quinoline scaffold starting from acyclic alkyne substrates. The five- and six-membered nitrogen-containing rings in the tetracyclic skeleton were elaborated efficiently by gold(III)-ca

Full text of DOI:10.1055/s-0030-1258411

626
PAPER
Facile Assembly of 11H-Indolo[3,2-c]quinoline by a Two-Step Protocol
Involving a Regioselective 6-endo-Cyclization Promoted by the Hendrickson
Reagent
A
ssembly of 11
H
-Indo
i
lo[3,2-
n
c
]quinoline Xu,a Qiwen Hou,a Shaozhong Wang,*a Huaqin Wang,b Zhu-Jun Yaoa
a
P. R. of China
Fax +86(25)83317761; E-mail: wangsz@nju.edu.cn
Modern Analytical Center of Nanjing University, Nanjing 210093, P. R. of China
b
Received 1 November 2010; revised 3 December 2010
Generally, the five-membered ring contained within the
fused framework can be incorporated by heteroatom-
directed photoannulation,4 intramolecular insertion of
nitrene5 as well as by palladium-catalyzed Buchwald–
Abstract: An expedient approach was developed to construct the
11H-indolo[3,2-c]quinoline scaffold starting from acyclic alkyne
substrates. The five- and six-membered nitrogen-containing rings in
the tetracyclic skeleton were elaborated efficiently by gold(III)-cat-
alyzed 5-endo-dig cyclization and Hendrickson reagent promoted Hartwig reaction/C-H activation6 from quinoline sub-
regioselective 6-endo cyclization.
strates such as anilinoquinoline, 4-(2-azidophenyl)quino-
line, and 4-chloroquinoline. The pyridine ring can be
installed by Pictet–Spengler reaction7 and Heck-type
cyclization8 from 2-(1H-indol-2-yl)phenylamine and 3-
carbamoylindole-2-carboxylic acid. Owing to the limita-
tions of indole and quinoline starting materials, the meth-
odologies mentioned above are relatively inflexible with
respect to the introduction of different substituents on the
ring. Although Cacchi9 developed an alternative approach
to the construction of 11H-indolo[3,2-c]quinoline from
o-(o-aminophenyl)trifluoroacetanilide by palladium-cata-
lyzed carbonylative cyclization and subsequent intramo-
lecular condensation, only 6-arylated derivatives were
accessible. To further develop an efficient protocol with
better flexibility, we designed a two-step strategy to
assemble 11H-indolo[3,2-c]quinoline. As illustrated in
Scheme 1, the five- and six-membered nitrogen-contain-
ing rings in the skeleton were elaborated through a
gold(III)-catalyzed 5-endo-dig-cyclization (step I), fol-
lowed by a Hendrickson reagent promoted regioselective
6-endo-cyclization (step II).
Key words: alkyne, cyclization, gold, quinoline, Hendrickson re-
agent
Naturally occurring alkaloids together with their synthetic
analogues containing the 11H-indolo[3,2-c]quinoline
scaffold have attracted considerable attention because of
their diverse and pronounced biological properties.1 Isoc-
ryptolepine, a methyl-substituted 11H-indolo[3,2-c]quin-
oline isolated from Cryptolepis sanguinolenta, shows
strong antiplasmodial activity2 (Figure 1), while certain
counterparts display high cytotoxicity against cancer cell
lines.3 To further investigate the structure–activity rela-
tionship, a variety of strategies based on indole and quin-
oline formation have been developed to elaborate the
tetracyclic skeleton.
7
6
Me
N5
8
9
N
D
C
B
4
3
N
H
N
10
A
The study was initiated with alkyne 2a as substrate. The
amine and amide functional groups were combined by a
Sonogashira coupling reaction between 2-ethynylaniline
and N-(2-iodophenyl)acetamide.10 Since the characteristic
transformation from 2-alkynylaniline into the indole nu-
1
2
11H-indolo[3,2-c]quinoline
isocryptolepine
Figure 1 Structure of 11H-indolo[3,2-c]quinoline and a related al-
kaloid
R3
O
H
R3
N
R1
R2
R1
R2
II
I
HN
R3
N
O
N
H
R1
R2
N
H
1
3
NH2
2
Scheme 1 A two-step strategy for 11H-indolo[3,2-c]quinoline assembly
SYNTHESIS 2011, No. 4, pp 0626–0634
x
x
.
x
x
.2
0
1
1
Advanced online publication: 14.01.2011
DOI: 10.1055/s-0030-1258411; Art ID: F19010SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Facile Assembly of 11H-Indolo[3,2-c]quinoline
627
H
R3
N
O
NaAuCl4•2H2O (5 mol%)
EtOH, r.t., 6 h
O
R1
R2
HN
R3
R1
R2
N
H
NH2
2a–j
3a–j
Scheme 2 Au(III)-catalyzed indolization
cleus could be implemented under the catalysis of Lewis cyclization was completed in 85% yield at room tempera-
acids or transition-metal salts, the conversion from 2a into ture (Table 1, entry 1). In a similar manner, alkynes 2b–g
N-[2-(1H-indol-2-yl)phenyl]acetamide (3a) was envi- containing propanamide, formamide, benzamide, and car-
sioned (R1,R2 = H, R3 = Me; Scheme 2). However, when bamate groups were converted into the corresponding in-
InBr3 was used according to Sakai’s procedure,11 the in- doles 3b–g in yields ranging from 58 to 80% (Table 1,
dole product was isolated in only 45% yield. It was de- entries 2–7). In addition, alkynes 2h–j, with electron-
duced that competitive cyclization of the amide group was withdrawing substituents (Cl) and electron-donating sub-
the cause of the low yield. Consequently, milder condi- stituents (Me, OCH2O) on the aniline ring, also underwent
tions with better regioselectivity were required. To our de- 5-endo-dig cyclization smoothly to afford the indole de-
light, when NaAuCl4·2H2O was employed,12 the rivatives 3h–j in 60–83% yields (Table 1, entries 8–10).
Table 1 Indole Formation by Au(III)-Catalyzed 5-endo-dig Cyclizationa
Entry
Alkyne
Indole
Yield (%)
H
O
O
O
N
HN
HN
HN
O
1
85
N
H
NH2
3a
3b
3c
2a
H
Et
N
Et
O
2
3
60
65
N
H
NH2
2b
H
H
N
H
O
N
H
NH2
2c
O
H
N
HN
O
4
80
N
H
NH2
3d
2d
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M. Xu et al.
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Table 1 Indole Formation by Au(III)-Catalyzed 5-endo-dig Cyclizationa (continued)
Entry
Alkyne
Indole
Yield (%)
MeO
O
H
N
HN
O
5
80
N
H
OMe
NH2
3e
2e
O2N
O
H
N
HN
O
6
62
N
H
NO2
NH2
3f
2f
H
O
EtO
N
HN
OEt
O
7
8
58
83
78
60
N
H
NH2
3g
2g
H
N
O
Cl
HN
O
Cl
N
H
NH2
3h
2h
H
N
O
HN
O
9
N
H
NH2
3i
2i
H
O
N
O
O
HN
O
10
O
N
H
O
NH2
3j
2j
a The reaction was performed at a concentration of 0.125 M.
Bis(triphenyl)oxodiphosphonium
trifluoromethane- drickson reagent was suggested. As depicted in Scheme 3,
sulfonate (Hendrickson reagent), which is derived from the amide group would be selectively activated and trans-
triphenylphosphine oxide and triflic anhydride, possesses formed into the corresponding imidate. Subsequent in-
high oxophilicity.13 By utilizing this O-bridged bisphos- tramolecular nucleophilic attack takes place to give 11H-
phonium salt, some chemical transformations based on indolo[3,2-c]quinoline, accompanied by dissociation of
the amide functionality can be realized.14 In a continuation triphenylphosphine oxide (Ph3PO) and trifluoromethane-
of our exploration of this reagent, a 6-endo cyclization of sulfonic acid (TfOH).
N-[2-(1H-indol-2-yl)phenyl]amide triggered by Hen-
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Facile Assembly of 11H-Indolo[3,2-c]quinoline
629
TfOPh3P
R
O
Ph3P
TfO
PPh3
OTf
O
O
N
HN
R
N
N
H
H
– Ph3PO
R
R
H
N
– TfOH
N
N
H
N
H
TfO
Figure 3 X-ray crystal structure of indolo[1,2-c]quinazoline 4
Table 2 6-endo-Cyclization Conditions Screened
Scheme 3 Proposed mechanism for Hendrickson reagent promoted
6-endo cyclization
N-[2-(1H-Indol-2-yl)phenyl]acetamide (3a) was selected
to probe the conditions. Under the action of Hendrickson
reagent (generated in situ from 1.5 equiv TfOH and 3.0
equiv Ph3PO in CH2Cl2), 3a was consumed completely
within 15 minutes, and the anticipated 11H-indolo[3,2-
c]quinoline (1a) was isolated in 88% yield together with a
minor amount of byproduct, which was identified as 6-
methyl-indolo[1,2-c]quinazoline (Table 2, entry 1). Both
structures were further confirmed by single crystal X-ray
diffraction analysis (Figure 2 and Figure 3).15 Attempts to
ultilize a catalytic amount of Ph3PO resulted in inversion
of the regioselectivity (Table 2, entry 2). In comparison,
use of either triflic anhydride or a combination of triflic
anhydride (Tf2O) with amine additives led to similar dis-
tributions (Table 2, entries 3–5). To our surprise, when the
reaction was performed in xylene, and POCl3 was em-
ployed as a dehydrating agent, 6-methylindolo[1,2-
c]quinazoline became the predominant product, and only
a trace amount of 11H-indolo[3,2-c]quinoline was isolat-
ed (Table 2, entry 6).
N
N
O
H
HN
1a
N
H
N
3a
N
4
Entry Reagent (equiv)a
Temp (°C) Time (min) Yield (%)b
1a
88
13
33
34
38
<5
4
1
2
3
4
5
6c
Tf2O (1.5), Ph3PO (3.0) r.t.
Tf2O (1.5), Ph3PO (0.1) r.t.
Tf2O (1.5) r.t.
15
15
15
10
75
63
60
53
92
Tf2O (1.1), 2-ClPy (1.2) –78 to 45 60
Tf2O (5.0), DMAP (3.0) r.t. 12 h
POCl3 (3.0) 120 15
a CH2Cl2 was used as solvent unless otherwise mentioned, and the
concentration was 0.125 M.
b Isolated yield.
c Xylene as solvent.
Analogously, N-[2-(1H-indol-2-yl)phenyl]propanamide
(3b) and N-[2-(1H-indol-2-yl)phenyl]formamide (3c) un-
derwent efficient cyclization to afford the tetracyclic
products in 83% and 75% yield, respectively (Table 3, en-
tries 1–2). Of particular note is that 11H-indolo[3,2-
c]quinoline (1c) has been used as a precursor to synthesize
the alkaloid isocryptolepine by selective methylation.
Figure 2 X-ray crystal structure of 11H-indolo[3,2-c]quinoline 1a
A number of benzamides were screened, and all were con-
verted into the corresponding 6-arylated 11H-indolo[3,2-
c]quinolines 1d–f as expected (Table 3, entries 3–5). It
seemes that the electronic properties of the substituent on
the benzoyl moiety affected the outcome of the cycliza-
tion. The methoxy group facilitated the conversion, with
The high regioselectivity induced by the Hendrickson re-
agent in the construction of 11H-indolo[3,2-c]quinoline
prompted us to examine the scope of the transformation.
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M. Xu et al.
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the methoxy-substituted indoloquinoline being obtained yl]acetamides containing chlorine, methyl, and methyl-
in 95% yield. The nitro group hindered the cyclization, enedioxy substituents on the indole moiety were tested
with the corresponding 11H-indolo[3,2-c]quinoline 1f be- (Table 3, entries 7–9). The corresponding 8-Cl, 8-Me, and
ing achieved in only 78% yield. Besides amides, as exem- 8,9-methylenedioxy-substituted 11H-indolo[3,2-c]quino-
plified above, the carbamate group was also well- lines 1h–j were achieved in 84–94% yields. The pentacy-
tolerated, delivering the 6-ethoxy-11H-indolo[3,2-c]quin- clic compound 1j is of particular interest and its biological
oline in moderate yield (Table 3, entry 6). To further evaluation is in progress.
extend the scope, different N-[2-(1H-indol-2-yl)phen-
Table 3 11H-Indolo[3,2-c]quinoline Assembly by Hendrickson Reagent Promoted Regioselective 6-endo Cyclizationa
Entry
1
Indole 3
Indoloquinoline 1
Yield (%)
83
O
O
O
Et
HN
HN
HN
Et
N
N
H
N
H
3b
3c
3d
1b
1c
N
H
2
3
75
92
N
H
N
H
Ph
N
N
H
N
H
1d
OMe
O
HN
4
95
N
H
OMe
N
N
H
3e
1e
NO2
O
HN
5
78
N
N
H
NO2
N
H
3f
1f
O
OEt
N
HN
OEt
6
60
N
H
N
H
3g
1g
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Facile Assembly of 11H-Indolo[3,2-c]quinoline
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Table 3 11H-Indolo[3,2-c]quinoline Assembly by Hendrickson Reagent Promoted Regioselective 6-endo Cyclizationa (continued)
Entry
7
Indole 3
Indoloquinoline 1
Yield (%)
94
O
Cl
Cl
N
HN
N
H
N
H
1h
3h
O
N
HN
8
9
84
92
N
H
N
H
1i
3i
O
O
O
O
N
HN
O
N
N
H
H
1j
3j
a The concentration was 0.125 M and the reaction time was 15 min.
1 H), 7.41 (d, J = 8.1 Hz, 1 H), 7.32 (td, J = 7.8, 1.5 Hz, 1 H), 7.25
(td, J = 6.9, 0.9 Hz, 1 H), 7.20–7.14 (m, 2 H), 6.62 (s, 1 H), 2.05 (s,
3 H).
13C NMR (75 MHz, CDCl3): d = 169.1, 136.7, 135.0, 134.2, 129.5,
128.9, 128.6, 124.5, 123.7, 122.5, 122.0, 120.6, 120.3, 111.3, 102.3,
24.5.
In conclusion, a two-step approach that can be used to as-
semble the 11H-indolo[3,2-c]quinoline scaffold starting
from acyclic alkynes has been developed. The heterocy-
clic units in the skeleton were constructed successively by
a gold(III)-catalyzed 5-endo-dig cyclization and Hen-
drickson reagent promoted regioselective 6-endo cycliza-
tion. The protocol features mild conditions, functional
group compatibility, and high regioselectivity, which is
suitable for the preparation of 6-alkyl, aryl, and alkoxy-
substituted 11H-indolo[3,2-c]quinoline derivatives.
ESI-MS: m/z = 251.1 [M + H]+.
Anal. Calcd for C16H14N2O: C, 76.78; H, 5.64; N, 11.19. Found: C,
76.71; H, 5.66; N, 11.07.
N-[2-(1H-Indol-2-yl)phenyl]propanamide (3b)
White solid; mp 158–160 °C (EtOH–PE).
IR (KBr): 3343, 3227, 1631, 1522, 1449, 807 cm–1.
Melting points are uncorrected. IR spectra were recorded with a
Nicolet FT-IR 5DX spectrometer as KBr pellets. NMR spectra were
recorded with a Bruker ACF-300 spectrometer by using tetrameth-
ylsilane (TMS) or residue solvent as internal standards; J values are
given in Hz. Mass spectra were taken with a LCQ Fleet EIS Mass
Spectrometer. Elemental analyses were performed with a Perkin–
Elmer 240C analyzer. The o-ethynylaniline substrates were pre-
pared according to the reported procedure.10
1H NMR (300 MHz, CDCl3): d = 8.97 (s, 1 H), 8.25 (d, J = 7.8 Hz,
1 H), 7.83 (s, 1 H), 7.65 (d, J = 7.8 Hz, 1 H), 7.40 (t, J = 8.4 Hz,
2 H), 7.30–7.09 (m, 4 H), 6.58 (d, J = 1.2 Hz, 1 H), 2.22 (q,
J = 7.5 Hz, 2 H), 1.09 (t, J = 7.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 172.6, 136.7, 135.1, 134.2, 129.4,
128.9, 128.6, 124.3, 123.6, 122.5, 121.8, 120.5, 120.3, 111.2, 102.3,
30.7, 9.4.
N-[2-(1H-Indol-2-yl)phenyl]amides 3a–j; General Procedure
NaAuCl4·2H2O (16 mg, 0.04 mmol) was added to a solution of N-
{2-[(2-aminophenyl)ethynyl]phenyl}amide (1.0 mmol) in EtOH (8
mL). The reaction mixture was stirred at r.t. for 6 h under an argon
atmosphere. Then the mixture was diluted with CHCl3 (30 mL), and
the obtained solution was washed with brine (15 mL) and H2O (15
mL) successively. The organic phase was dried (anhydrous
MgSO4), filtered and concentrated. The residue was purified by
chromatography on silica gel (EtOAc–PE, 1:2) to give N-[2-(1H-in-
dol-2-yl)phenyl]amide (Table 1).
ESI-MS: m/z = 265.1 [M + H]+.
Anal. Calcd for C17H16N2O: C, 77.25; H, 6.10; N, 10.60. Found: C,
77.37; H, 6.17; N, 10.64.
N-[2-(1H-Indol-2-yl)phenyl]formamide (3c)
Yellow solid; mp 112–113 °C (EtOAc–PE).
IR (KBr): 3302, 1674, 745 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 11.40 (s, 0.63 H), 9.69–9.60
(m, 0.64 H), 9.54 (s, 0.33 H), 8.38–8.35 (m, 1 H), 8.25–8.22 (m,
0.31 H), 8.05 (d, J = 7.8 Hz, 0.49 H), 7.85–7.82 (m, 0.31 H), 7.79–
7.75 (m, 0.32 H), 7.68–7.53 (m, 2 H), 7.46–7.35 (m, 2.65 H), 7.28
(td, J = 7.5, 1.2 Hz, 0.52 H), 7.14 (td, J = 8.1, 0.9 Hz, 0.69 H), 7.04
(t, J = 7.2 Hz, 0.69 H), 6.72–6.71 (m, 0.68 H).
N-[2-(1H-Indol-2-yl)phenyl]acetamide (3a)
Yellow solid; mp 130–132 °C (EtOH–PE).
IR (KBr): 3362, 3284, 1680, 1519, 1437, 737 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.86 (s, 1 H), 8.25 (d, J = 7.8 Hz,
1 H), 7.81 (s, 1 H), 7.67 (d, J = 7.5 Hz, 1 H), 7.45 (d, J = 8.1 Hz,
13C NMR (75 MHz, DMSO-d6): d = 163.6, 160.7, 138.7, 136.8,
134.4, 134.3, 129.7, 129.3, 128.6, 128.4, 128.1, 127.74, 127.70,
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M. Xu et al.
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126.0, 125.2, 124.9, 124.4, 123.9, 123.8, 123.5, 122.1, 121.6, 120.6,
120.2, 119.3, 111.5, 111.4, 102.1, 102.0, 94.8.
ESI-MS: m/z = 237.2 [M + H]+.
ESI-MS: m/z = 281.1 [M + H]+.
Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found: C,
72.81; H, 5.74; N, 10.00.
Anal. Calcd for C15H12N2O: C, 76.25; H, 5.12; N, 11.86. Found: C,
76.21; H, 5.17; N, 11.86.
N-[2-(5-Chloro-1H-indol-2-yl)phenyl]acetamide (3h)
White solid; mp 160–162 °C (CHCl3).
N-[2-(1H-Indol-2-yl)phenyl]benzamide (3d)
IR (KBr): 3366, 3602, 1680, 1519, 1436, 759 cm–1.
White solid; mp 173–175 °C (EtOH–PE).
IR (KBr): 3359, 1665, 1578, 1517, 1436, 1305, 743 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 11.57 (s, 1 H), 9.49 (s, 1 H),
7.65–7.63 (m, 3 H), 7.45 (d, J = 8.7 Hz, 1 H), 7.40–7.31 (m, 2 H),
7.13 (dd, J = 9.0, 2.4 Hz, 1 H), 6.73 (d, J = 1.5 Hz, 1 H), 2.08 (s,
3 H).
13C NMR (75 MHz, DMSO-d6): d = 168.8, 136.8, 135.18, 135.12,
129.6, 129.1, 128.1, 126.7, 125.4, 123.7, 121.3, 119.2, 112.8, 101.1,
23.5.
1H NMR (300 MHz, CDCl3): d = 8.84 (s, 1 H), 8.77 (s, 1 H), 8.51
(d, J = 7.8 Hz, 1 H), 7.72 (d, J = 7.8 Hz, 2 H), 7.68 (d, J = 7.8 Hz,
1 H), 7.51–7.45 (m, 3 H), 7.37 (t, J = 7.5 Hz, 3 H), 7.29–7.24 (m,
1 H), 7.19 (td, J = 6.9, 3.6 Hz, 2 H), 6.69 (d, J = 0.9 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 165.5, 136.8, 135.7, 134.3, 134.2,
131.9, 129.3, 129.1, 128.8, 127.0, 124.5, 123.6, 122.7, 121.6, 120.7,
120.4, 111.2, 102.5.
ESI-MS: m/z = 285.1 [M + H]+.
Anal. Calcd for C16H13ClN2O: C, 67.49; H, 4.60; N, 9.84. Found: C,
67.46; H, 4.67; N, 9.81.
ESI-MS: m/z = 313.2 [M + H]+.
Anal. Calcd for C21H16N2O: C, 80.75; H, 5.16; N, 8.97. Found: C,
80.82; H, 5.24; N, 8.93.
N-[2-(5-Methyl-1H-indol-2-yl)phenyl]acetamide (3i)
White solid; mp 132–134 °C (EtOH–PE).
N-[2-(1H-Indol-2-yl)phenyl]-4-methoxybenzamide (3e)
IR (KBr): 3359, 3292, 1682, 1520, 1434, 755 cm–1.
Light-yellow solid; mp 177–179 °C (EtOH–PE).
IR (KBr): 3359, 1641, 1505, 1439, 746 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 11.41 (s, 1 H), 9.81 (s, 1 H),
7.96–7.93 (m, 2 H), 7.72–7.66 (m, 2 H), 7.47 (d, J = 7.8 Hz, 1 H),
7.41–7.37 (m, 3 H), 7.12–7.03 (m, 3 H), 6.97 (td, J = 8.1, 0.9 Hz,
1 H), 6.68 (d, J = 1.2 Hz, 1 H), 3.83 (s, 3 H).
1H NMR (300 MHz, CDCl3): d = 9.05 (s, 1 H), 8.24 (d, J = 7.8 Hz,
1 H), 7.89 (s, 1 H), 7.48 (s, 1 H), 7.42–7.27 (m, 3 H), 7.18–7.09 (m,
2 H), 6.54 (s, 1 H), 2.52 (s, 3 H), 2.02 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 169.1, 135.1, 134.9, 134.3, 129.5,
129.4, 128.9, 128.7, 124.4, 124.1, 123.8, 121.9, 120.1, 110.9, 101.7,
24.4, 21.4.
13C NMR (75 MHz, DMSO-d6): d = 164.9, 161.9, 136.5, 135.2,
129.5, 128.9, 128.5, 128.4, 127.7, 127.6, 126.6, 126.0, 121.5, 120.0,
119.2, 113.7, 111.3, 101.2, 55.4.
ESI-MS: m/z = 265.2 [M + H]+.
Anal. Calcd for C17H16N2O: C, 77.25; H, 6.10; N, 10.60. Found: C,
77.44; H, 6.06; N, 10.66.
ESI-MS: m/z = 343.1 [M + H]+.
N-[2-(5,6-Dimethylenedioxy-1H-indol-2-yl)phenyl]acetamide
(3j)
White solid; mp 158–160 °C (EtOH–PE).
Anal. Calcd for C22H18N2O2: C, 77.17; H, 5.30; N, 8.18. Found: C,
77.21; H, 5.32; N, 8.12.
N-[2-(1H-Indol-2-yl)phenyl]-4-nitrobenzamide (3f)
IR (KBr): 3268, 2886, 1622, 1523, 1471, 756 cm–1.
Orange solid; mp 192–194 °C (EtOAc–PE).
IR (KBr): 3373, 3251, 1656, 1522, 1439, 1347, 763, 708 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 11.19 (s, 1 H), 9.41 (s, 1 H),
7.61–7.58 (m, 2 H), 7.29–7.26 (m, 2 H), 7.05 (s, 1 H), 6.94 (s, 1 H),
6.61 (d, J = 1.2 Hz, 1 H), 5.95 (s, 2 H), 2.07 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 168.8, 144.3, 142.3, 134.5,
133.4, 131.7, 128.3, 127.3, 127.0, 126.8, 125.4, 122.3, 102.0, 100.2,
98.6, 92.0, 23.6.
1H NMR (300 MHz, DMSO-d6): d = 11.44 (s, 1 H), 10.36 (s, 1 H),
8.37 (d, J = 8.7 Hz, 2 H), 8.19 (d, J = 8.7 Hz, 2 H), 7.74 (dd,
J = 5.9, 3.5 Hz, 1 H), 7.66–7.63 (m, 1 H), 7.50–7.39 (m, 4 H), 7.09
(td, J = 7.2, 1.2 Hz, 1 H), 6.97 (td, J = 7.8, 0.9 Hz, 1 H), 6.69 (s,
1 H).
13C NMR (75 MHz, DMSO-d6): d = 164.1, 149.2, 140.2, 136.6,
135.0, 134.4, 129.1, 129.0, 128.4, 128.0, 127.8, 126.7, 123.6, 121.5,
120.1, 119.2, 111.3, 101.2.
ESI-MS: m/z = 295.2 [M + H]+.
Anal. Calcd for C17H14N2O3: C, 69.38; H, 4.79; N, 9.52. Found: C,
69.34; H, 4.84; N, 9.57.
ESI-MS: m/z = 358.1 [M + H]+.
11H-Indolo[3,2-c]quinoline 1a–j; General Procedure
Tf2O (0.125 mL, 0.75 mmol) was added dropwise to a stirred solu-
tion of Ph3PO (0.415 g, 1.5 mmol) in anhydrous CH2Cl2 (4.0 mL) at
0 °C. After 10 min, the N-[2-(1H-indol-2-yl)phenyl]amide (0.5
mmol) was added in one portion and the reaction was stirred at r.t.
for 15 min. The mixture was diluted with CHCl3 (20 mL) and treat-
ed with sat. aq NaHCO3 (10 mL). The organic phase was separated
and washed with brine (10 mL), and the obtained organic solution
was dried (anhydrous MgSO4), filtered, and concentrated. The res-
idue was purified by chromatography (EtOAc–PE, 2:1) to give the
pure 11H-indolo[3,2-c]quinoline.
Anal. Calcd for C21H15N3O3: C, 70.58; H, 4.23; N, 11.76. Found: C,
70.47; H, 4.24; N, 11.81.
Ethyl 2-(1H-Indol-2-yl)phenylcarbamate (3g)
White solid; mp 146–148 °C (EtOAc–PE).
IR (KBr): 3381, 3338, 1714, 1589, 1522, 766 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.46 (s, 1 H), 8.21 (d, J = 8.4 Hz,
1 H), 7.73–7.70 (m, 1 H), 7.46–7.35 (m, 4 H), 7.31–7.18 (m, 2 H),
7.14 (td, J = 7.5, 1.2 Hz, 1 H), 6.69 (dd, J = 2.1, 0.9 Hz, 1 H), 4.20
(q, J = 7.2 Hz, 2 H), 1.29 (t, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 153.8, 136.5, 135.6, 133.9, 129.3,
129.2, 128.7, 123.3, 122.6, 122.4, 120.7, 120.4, 119.7, 111.1, 102.5,
61.3, 14.4.
6-Methyl-11H-indolo[3,2-c]quinoline (1a)
White solid; mp 281–283 °C (EtOH).
IR (KBr): 1563, 1515, 1361, 742 cm–1.
Synthesis 2011, No. 4, 626–634 © Thieme Stuttgart · New York

PAPER
Facile Assembly of 11H-Indolo[3,2-c]quinoline
633
1H NMR (300 MHz, DMSO-d6): d = 12.73 (s, 1 H), 8.50 (d,
J = 8.1 Hz, 1 H), 8.21 (d, J = 8.1 Hz, 1 H), 8.05 (d, J = 8.4 Hz, 1 H),
7.75–7.60 (m, 3 H), 7.50 (t, J = 7.2 Hz, 1 H), 7.36 (t, J = 7.2 Hz,
1 H), 3.08 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 154.2, 144.9, 139.8, 139.7,
128.6, 127.9, 124.9, 124.8, 122.3, 121.7, 121.5, 120.6, 116.2, 112.9,
111.7, 24.4.
5 H), 7.64 (d, J = 7.8 Hz, 1 H), 7.48–7.43 (m, 1 H), 7.22–7.14 (m,
3 H), 3.90 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 159.8, 155.2, 145.0, 141.0,
139.0, 133.1, 130.3, 129.3, 128.4, 125.4, 125.3, 121.9, 121.8, 121.1,
120.2, 116.2, 113.7, 111.9, 55.3.
ESI-MS: m/z = 325.1 [M + H]+.
Anal. Calcd for C22H16N2O: C, 81.46; H, 4.97; N, 8.64. Found: C,
81.33; H, 5.03; N, 8.49.
ESI-MS: m/z = 233.2 [M + H]+.
Anal. Calcd for C16H12N2: C, 82.73; H, 5.21; N, 12.06. Found: C,
82.81; H, 5.27; N, 12.01.
6-(4-Nitrophenyl)-11H-indolo[3,2-c]quinoline (1f)
Orange solid; mp >300 °C (acetone–PE).
6-Ethyl-11H-indolo[3,2-c]quinoline (1b)
White solid; mp 215–217 °C (EtOAc–PE).
IR (KBr): 1567, 1514, 1361, 742 cm–1.
IR (KBr): 1561, 1519, 1346, 746 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 13.00 (s, 1 H), 8.62–8.60 (m,
1 H), 8.49 (d, J = 8.7 Hz, 2 H), 8.19–8.11 (m, 3 H), 7.82–7.72 (m,
3 H), 7.53–7.45 (m, 2 H), 7.17 (t, J = 7.2 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 153.1, 147.7, 146.9, 144.8,
141.2, 139.1, 130.3, 129.5, 128.8, 126.2, 125.7, 123.8, 122.0, 121.1,
121.0, 120.6, 116.4, 112.1, 111.7.
1H NMR (300 MHz, DMSO-d6): d = 12.74 (s, 1 H), 8.52 (dd,
J = 7.8, 1.8 Hz, 1 H), 8.16 (d, J = 7.8 Hz, 1 H), 8.09 (dd, J = 8.2,
0.9 Hz, 1 H), 7.76–7.60 (m, 3 H), 7.50 (td, J = 7.2, 1.2 Hz, 1 H),
7.35 (td, J = 7.8, 0.6 Hz, 1 H), 3.43 (q, J = 7.8 Hz, 2 H), 1.48 (t,
J = 7.5 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 158.9, 144.9, 140.2, 138.8,
128.9, 127.9, 124.9, 124.8, 121.8, 121.5, 120.6, 116.3, 112.1, 111.8,
30.2, 12.2.
ESI-MS: m/z = 340.2 [M + H]+.
Anal. Calcd for C21H13N3O2: C, 74.33; H, 3.86; N, 12.38. Found: C,
74.29; H, 4.01; N, 12.28.
ESI-MS: m/z = 247.2 [M + H]+.
6-Ethoxy-11H-indolo[3,2-c]quinoline (1g)
Anal. Calcd for C17H14N2: C, 82.90; H, 5.73; N, 11.37. Found: C,
82.88; H, 5.75; N, 11.41.
White solid; mp 114–116 °C (EtOAc–PE).
IR (KBr): 1574, 1518, 1455, 1219, 744 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.63 (s, 1 H), 8.37–8.34 (m, 1 H),
8.05 (dd, J = 8.4, 0.6 Hz, 1 H), 7.96 (dd, J = 8.1, 0.9 Hz, 1 H), 7.71–
7.55 (m, 1 H), 7.53–7.50 (m, 1 H), 7.47–7.34 (m, 3 H), 4.83 (q,
J = 7.2 Hz, 2 H), 1.61 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 159.2, 145.0, 141.8, 137.9, 128.3,
127.5, 124.9, 123.3, 122.6, 122.3, 121.2, 120.5, 115.5, 111.0, 105.0,
61.8, 14.8.
11H-Indolo[3,2-c]quinoline (1c)
White solid; mp >300 °C (EtOH–PE).
IR (KBr): 1513, 1459, 1237, 734 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 12.73 (s, 1 H), 9.60 (s, 1 H),
8.53 (dd, J = 7.8, 1.2 Hz, 1 H), 8.32 (d, J = 7.8 Hz, 1 H), 8.24–8.09
(m, 1 H), 7.71–7.66 (m, 3 H), 7.53–7.47 (m, 1 H), 7.34 (t,
J = 7.8 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 145.4, 144.8, 139.8, 138.8,
129.6, 128.0, 125.7, 125.6, 122.1, 121.9, 120.6, 120.1, 117.1, 114.3,
111.9.
ESI-MS: m/z = 263.2 [M + H]+.
Anal. Calcd for C17H14N2O: C, 77.84; H, 5.38; N, 10.68. Found: C,
77.68; H, 5.56; N, 10.42.
ESI-MS: m/z = 219.2 [M + H]+.
8-Chloro-6-methyl-11H-indolo[3,2-c]quinoline (1h)
Anal. Calcd for C15H10N2: C, 82.55; H, 4.62; N, 12.84. Found: C,
82.51; H, 4.77; N, 12.69.
White solid; mp >300 °C (EtOAc–PE).
IR (KBr): 1569, 1518, 1438, 1286, 722 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 12.82 (s, 1 H), 8.43 (d,
J = 7.2 Hz, 1 H), 8.11 (d, J = 1.8 Hz, 1 H), 8.07 (d, J = 7.5 Hz, 1 H),
7.72–7.67 (m, 2 H), 7.61 (t, J = 6.9 Hz, 1 H), 7.46 (dd, J = 8.4,
2.1 Hz, 1 H), 3.01 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 154.3, 145.0, 140.7, 137.2,
128.6, 128.3, 125.0, 124.8, 123.4, 121.8, 120.7, 116.1, 113.2, 112.3,
24.3.
6-Phenyl-11H-indolo[3,2-c]quinoline (1d)
White solid; mp 249–251 °C (acetone–PE).
IR (KBr): 1557, 1512, 1494, 1359, 737, 698 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 12.89 (s, 1 H), 8.59 (dd,
J = 7.8, 1.2 Hz, 1 H), 8.14 (dd, J = 8.1, 0.9 Hz, 1 H), 7.86–7.81 (m,
2 H), 7.79–7.70 (m, 3 H), 7.68–7.60 (m, 3 H), 7.52 (d, J = 7.8 Hz,
1 H), 7.44 (td, J = 7.2, 1.2 Hz, 1 H), 7.13 (td, J = 7.7, 0.9 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 155.5, 145.0, 141.0, 140.7,
139.0, 129.4, 128.8, 128.5, 128.4, 125.6, 125.3, 121.9, 121.7, 121.0,
120.3, 116.3, 111.9.
ESI-MS: m/z = 267.2 [M + H]+.
Anal. Calcd for C16H11ClN2: C, 72.05; H, 4.16; N, 10.5. Found: C,
72.09; H, 4.24; N, 9.97.
ESI-MS: m/z = 295.2 [M + H]+.
6,8-Dimethyl-11H-indolo[3,2-c]quinoline (1i)
Anal. Calcd for C21H14N2: C, 85.69; H, 4.79; N, 9.52. Found: C,
85.74; H, 4.79; N, 9.57.
White solid; mp >300 °C (EtOH–PE).
IR (KBr): 1742, 1563, 1517, 1352, 797, 760 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 12.57 (s, 1 H), 8.46 (dd,
J = 7.0, 0.9 Hz, 1 H), 8.05–8.00 (m, 2 H), 7.68 (td, J = 6.9, 1.5 Hz,
1 H), 7.62–7.57 (m, 2 H), 7.31 (dd, J = 8.1, 1.2 Hz, 1 H), 3.07 (s,
3 H), 2.53 (s, 3 H).
6-(4-Methoxyphenyl)-11H-indolo[3,2-c]quinoline (1e)
White solid; mp 282–284 °C (EtOH–PE).
IR (KBr): 1610, 1504, 1249, 746 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 12.92 (s, 1 H), 8.51 (dd,
J = 8.1, 1.2 Hz, 1 H), 8.12 (dd, J = 8.1, 0.9 Hz, 1 H), 7.82–7.66 (m,
Synthesis 2011, No. 4, 626–634 © Thieme Stuttgart · New York

634
M. Xu et al.
PAPER
(2) (a) Pousset, J.-L.; Martin, M.-T.; Jossang, A.; Bodo, B.
13C NMR (75 MHz, DMSO-d6): d = 154.3, 144.8, 139.9, 137.0,
129.3, 128.6, 127.8, 126.3, 124.7, 122.5, 121.7, 121.3, 116.3, 112.7,
111.4, 24.5, 21.3.
Phytochemistry 1995, 39, 735. (b) Van Miert, S.; Hostyn,
S.; Maes, B. U. W.; Cimanga, K.; Brun, R.; Kaiser, M.;
Matyus, P.; Dommisse, R.; Lemiere, G.; Vlietinck, A.;
Pieters, L. J. Nat. Prod. 2005, 68, 674.
ESI-MS: m/z = 247.2 [M + H]+.
Anal. Calcd for C17H14N2: C, 82.90; H, 5.73; N, 11.37. Found: C,
82.91; H, 5.88; N, 11.21.
(3) (a) Lu, C.-M.; Chen, Y.-L.; Chen, H.-L.; Chen, C.-A.; Lu,
P.-J.; Yang, C.-N.; Tzeng, C.-C. Bioorg. Med. Chem. 2010,
18, 1948. (b) He, L.; Chang, H.-X.; Chou, T.-C.; Savaraj, N.;
Cheng, C.-C. Eur. J. Med. Chem. 2003, 38, 101. (c) Chen,
Y.-L.; Chung, C.-H.; Chen, I.-L.; Chen, P. H.; Jeng, H.-Y.
Bioorg. Med. Chem. 2002, 10, 2705.
8,9-Methylenedioxy-6-methyl-11H-indolo[3,2-c]quinoline (1j)
White solid; mp >300 °C (EtOH).
IR (KBr): 1570, 1515, 1473, 1298, 760 cm–1.
(4) (a) Dhanabal, T.; Sangeetha, R.; Mohan, P. S. Tetrahedron
2006, 62, 6258. (b) Nandha Kumar, R.; Suresh, T.; Mohan,
P. S. Tetrahedron Lett. 2002, 43, 3327.
1H NMR (300 MHz, DMSO-d6): d = 8.40 (d, J = 7.2 Hz, 1 H), 8.00
(d, J = 8.1 Hz, 1 H), 7.64–7.55 (m, 3 H), 7.23 (s, 1 H), 6.09 (s, 2 H),
2.99 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 153.6, 146.3, 144.1, 143.1,
139.1, 134.2, 128.6, 127.2, 124.7, 121.3, 116.5, 115.6, 113.5, 101.0,
100.5, 92.8, 24.3.
(5) (a) Kraus, G. A.; Guo, H. Tetrahedron Lett. 2010, 51, 4137.
(b) Beres, M.; Timari, G.; Hajos, G. Tetrahedron Lett. 2002,
43, 6035. (c) Fresneda, P. M.; Molina, P.; Delgado, S.
Tetrahedron 2001, 57, 6197. (d) Fresneda, P. M.; Molina,
P.; Delgado, S. Tetrahedron Lett. 1999, 40, 7275.
(6) (a) Meyers, C.; Rombouts, G.; Loones, K. T. J.; Coelho, A.;
Maes, B. U. W. Adv. Synth. Catal. 2008, 350, 465.
(b) Jonckers, T. H. M.; Maes, B. U. W.; Lemiere, G. L. F.;
Rombouts, G.; Pieters, L.; Haemers, A.; Dommisse, R. A.
Synlett 2003, 615.
ESI-MS: m/z = 277.2 [M + H]+.
Anal. Calcd for C17H12N2O2: C, 73.90; H, 4.38; N, 10.14. Found: C,
73.74; H, 4.46; N, 10.28.
6-Methyl-indolo[1,2-c]quinazoline (4)
Pale-yellow solid; mp 113–115 °C (EtOH).
IR (KBr): 1614, 1556, 1384, 756, 739 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.93 (td, J = 8.4, 0.6 Hz, 2 H),
7.75 (d, J = 8.4 Hz, 1 H), 7.69 (dd, J = 8.4, 1.2 Hz, 1 H), 7.49 (td,
J = 7.2, 1.5 Hz, 1 H), 7.42–7.36 (m, 2 H), 7.33–7.28 (m, 1 H), 7.04
(s, 1 H), 2.99 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 148.2, 138.8, 134.6, 131.5, 130.2,
128.7, 126.7, 126.6, 123.2, 122.4, 121.8, 120.5, 120.0, 114.6, 95.2,
25.2.
(7) Agarwal, P. K.; Sawant, D.; Sharma, S.; Kundu, B. Eur. J.
Org. Chem. 2009, 292.
(8) Miki, Y.; Kuromatsu, M.; Miyatake, H.; Hamamoto, H.
Tetrahedron Lett. 2007, 48, 9093.
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620.
(10) Sakai, N.; Annaka, K.; Konakahara, T. J. Org. Chem. 2006,
71, 3653.
(11) Sakai, N.; Annaka, K.; Fujita, A.; Sato, A.; Konakahara, T.
J. Org. Chem. 2008, 73, 4160.
ESI-MS: m/z = 233.2 [M + H]+.
(12) (a) Alfonsi, M.; Acradi, A.; Aschi, M.; Bianchi, G.;
Marinelli, F. J. Org. Chem. 2005, 70, 2265. (b) Arcadi, A.;
Bianchi, G.; Marinelli, F. Synthesis 2004, 610.
(13) Hendrickson, J. B.; Schwartzman, S. M. Tetrahedron Lett.
1975, 16, 277.
Anal. Calcd for C16H12N2: C, 82.73; H, 5.21; N, 12.06. Found: C,
82.71; H, 5.27; N, 12.04
(14) (a) Wu, M.; Wang, S. Synthesis 2010, 587. (b) Liu, G.-S.;
Yao, Y.-S.; Xu, P.; Wang, S.; Yao, Z.-J. Chem. Asian J.
2010, 5, 1382. (c) Zhou, H.-B.; Liu, G.-S.; Yao, Z.-J. J. Org.
Chem. 2007, 72, 6270. (d) Zhou, H.-B.; Liu, G.-S.; Yao,
Z.-J. Org. Lett. 2007, 9, 2003. (e) You, S.-L.; Kelly, J. W.
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Acknowledgment
This work was financially supported by the National Science Foun-
dation of China (20802034, 21032002), the Natural Science Foun-
dation of Jiangsu Province (BK 2009229) and 973 Program
(2007CB936404).
Reference
(15) CCDC 780631 and 793932 contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
(1) For a review, see: Lavrado, J.; Moreira, R.; Paulo, A. Curr.
Med. Chem. 2010, 17, 2348.
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Synthesis 2011, No. 4, 626–634 © Thieme Stuttgart · New York