An efficient method for the synthesis of indolo[3,2-c]quinoline derivatives catalyzed by iodine

Article abstract of DOI:10.1002/cjoc.201200993

The reaction of Schiff base and indole catalyzed by iodine in DMA, subsequently treated with DDQ, gave indolo[3,2-c]quinoline derivatives in good yields. The structure of 3e was confirmed by X-ray diffraction analysis. The reaction of Schiff base and indo

Full text of DOI:10.1002/cjoc.201200993

FULL PAPER
DOI: 10.1002/cjoc. 201200993
An Efficient Method for the Synthesis of Indolo[3,2-c]quinoline
Derivatives Catalyzed by Iodine
Yujing Zhou,a Meimei Zhang,b Mingyue Yin,a and Xiangshan Wang*,a
a School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic Chemistry for
Functional Materials, Jiangsu Normal University, Xuzhou, Jiangsu 221116, China
b The Key Laboratory of Biotechnology on Medical Plant of Jiangsu Province, Jiangsu Normal University,
Xuzhou, Jiangsu 221116, China
The reaction of Schiff base and indole catalyzed by iodine in DMA, subsequently treated with DDQ, gave in-
dolo[3,2-c]quinoline derivatives in good yields. The structure of 3e was confirmed by X-ray diffraction analysis.
Keywords indolo[3,2-c]quinoline, Schiff base, iodine, indole
Introduction
Scheme 1 The designed reaction
O
H
Indoloquinoline is a very important class of hetero-
cyclic compounds, some of which are useful alkaloids,
such as Cryptolepine and iso-Cryptolepine, which are
used traditionally to treat a variety of health disorders,
including clinical therapy of rheumatism, urinary tract
infections, malaria, and other diseases.[1] In addition,
they are also reported to possess various kinds of bio-
logical and pharmacological activities, for example,
phosphodiesterase inhibitors,[2] antitumor activity,[3] cal-
cium channel blockers,[4] antifungals & parasiticides[5]
and antiplasmodial activity.[6] Therefore, novel strategies
for the synthesis of indoloquinolines continue to receive
considerable attention in the field of synthetic organic
chemistry.[7]
I2, Toluene
O
+
N
HN
ArCHO
+
O
O
r.t.
NH2
N
H
2-naphthylamine
HN
Ar
H
H
Our previous work, EJOC. 2012, 4811 − 4818
N
Ar
H
Scheme 2 The model reaction
O
CHO
In our previous study,[8] we have described that
exo-tetrahydroindolo[3,2-c]quinoline derivatives could
be obtained in good yields and high stereo-selectivity at
r.t. catalyzed by iodine. However, this reaction was only
limited to active amines, such as 2-naphthylamine and
indazole-5-amine. It failed to give desired products us-
ing ordinary aromatic amine as reactant (Scheme 1),
such as piperonylamine and 3,4-dimethoxyaniline. In
our recent study, we further improved the reaction tem-
perature (80 ℃) in order to facilitate the reaction, it was
found that it was carried out smoothly, however, it gave
a complicated system. We tried to separate them by
column chromatography, but failed. In order to simplify
the reaction and prevent the aromatic aldehydes to react
with indole to produce bis-indolylmethane derivatives,[9]
the Schiff base was synthesized and separated first, and
then was allowed to react with indole in N,N-dimethyl-
acetamide (DMA) at 80 ℃ (Scheme 2).
O
benzene, reflux
+
NH2
H
N
Cl
O
O
2a
N
1a
1)
I2, DMA
Cl
HN
HN
O
O
O
+
O
N
N
H
Cl
Cl
3a
2)
DDQ
*
E-mail: xswang1974@yahoo.com
Received October 12, 2012; accepted December 10, 2012; published online January 8, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200993 or from the author.
Chin. J. Chem. 2013, 31, 237—242
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
237

Zhou et al.
FULL PAPER
NMR (CDCl3, 400 MHz) δH: 3.65 (s, 3H, CH3O), 6.25
(s, 2H, CH2), 6.90 (s, 1H, ArH), 7.11 (d, J＝8.4 Hz, 1H,
ArH), 7.47 (s, 1H, ArH), 7.59 (d, J＝8.4 Hz, 1H, ArH),
7.76 (d, J＝8.0 Hz, 2H, ArH), 7.86 (b, 3H, ArH), 12.60
(s, 1H, NH); IR (KBr) ν: 3389, 3066, 2896, 1656, 1607,
1488, 1468, 1460, 1437, 1388, 1298, 1216, 1174, 1102,
1035, 1010, 944, 914, 852, 838, 805, 748, 715 cm−1.
HRMS (ESI) m/z: calcd for C23H16BrN2O3 [M＋H]＋
447.0344, found 447.0343.
We found in delight that the main product was aro-
matized indolo[3,2-c]quinoline, along with the tetrahy-
droindolo[3,2-c]quinoline isomers as byproducts in low
stereo-selectivity, which is also hard to be separated. In
order to obtain the single aromatization product, DDQ
was added to the mixture (Scheme 2), it was found that
it was a good oxidant to promote the dehydrogenation to
give final aromatized indolo[3,2-c]quinoline in good
yield. Herein, we would like to report the synthesis of
indolo[3,2-c]quinoline derivatives catalyzed by iodine
and subsequent dehydrogenation by DDQ.
8-Methoxy-(4-chlorophenyl)-11H-[1,3]dioxolo[4,5-
g]indolo[3,2-c]quinoline (3d) m.p.: ＞300 ℃; 1H
NMR (CDCl3, 400 MHz) δH: 3.66 (s, 3H, CH3O), 6.39
(s, 2H, CH2), 6.79 (s, 1H, ArH), 7.24 (d, J＝8.4 Hz, 1H,
ArH), 7.59 (s, 1H, ArH), 7.71 (d, J＝8.8 Hz, 1H, ArH),
7.91－7.95 (m, 5H, ArH), 13.45 (s, 1H, NH); IR (KBr) ν:
3401, 3061, 3014, 2964, 1649, 1610, 1578, 1498, 1474,
1436, 1390, 1272, 1222, 1206, 1153, 1097, 1029, 937,
875, 819, 728, 670 cm−1. HRMS (ESI) m/z: calcd for
C23H16ClN2O3 [M＋H]＋ 403.0849, found 403.0850.
10-Methyl-(4-chlorophenyl)-11H-[1,3]dioxolo[4,5-
g]indolo[3,2-c]quinoline (3e) m.p.: ＞300 ℃; 1H
NMR (CDCl3, 400 MHz) δH: 2.67 (s, 3H, CH3), 6.24 (s,
2H, CH2), 7.03 (t, J＝7.6 Hz, 1H, ArH), 7.22 (d, J＝8.4
Hz, 1H, ArH), 7.31 (d, J＝8.0 Hz, 1H, ArH), 7.48 (s, 1H,
ArH), 7.66 (d, J＝8.0 Hz, 2H, ArH), 7.80 (d, J＝8.0 Hz,
2H, ArH), 8.20 (s, 1H, ArH), 12.06 (s, 1H, NH); 13C
NMR (DMSO-d6, 100 MHz) δC: 17.2, 98.4, 101.8, 106.2,
111.6, 111.7, 118.3, 120.2, 121.0, 121.1, 125.9, 128.4,
130.8, 133.3, 138.3, 139.5, 141.3, 142.4, 146.7, 149.3,
151.6; IR (KBr) ν: 3252, 3051, 2963, 1653, 1616, 1499,
1488, 1463, 1388, 1323, 1250, 1212, 1190, 1154, 1087,
1039, 947, 911, 853, 783, 745 cm−1. HRMS (ESI) m/z:
calcd for C23H16ClN2O2 [M＋H]＋ 387.0900, found
387.0901.
Experimental
Melting points were determined in open capillaries
and are uncorrected. IR spectra were recorded on a
1
Tensor 27 spectrometer in KBr pellet. H NMR spectra
were obtained from a solution in DMSO-d6 or CDCl3
with Me4Si as internal standard using a Bruker-400
spectrometer. HRMS analyses were carried out using a
Bruker-micro-TOF-Q-MS analyzer.
General procedure for the synthesis of indolo[3,2-c]-
quinoline (3)
Schiff base (1.0 mmol), indole (1.0 mmol), I2 (0.013 g),
and DMA (10 mL) were added into a 50 mL flask. The
reaction mixture was stirred at 80 ℃ for 16－22 h until
all the Schiff base was consumed which was monitored
by TLC. And then DDQ (0.114 g, 0.5 mmol) was added
to the mixture for another 2－4 h at the same tempera-
ture. The solvent of DMA was recovered under reduced
pressure, the residue was purified by column chroma-
tography using ethyl acetate and petroleum ether (1∶5)
as eluent to give the product 3.
6-(4-Chlorophenyl)-2,3-dimethoxy-11H-indolo[3,2-
c]quinoline (3f) m.p.: 271－274 ℃; 1H NMR (CDCl3,
400 MHz) δH: 3.98 (s, 3H, CH3O), 4.04 (s, 3H, CH3O),
7.25－7.28 (m, 1H, ArH), 7.45 (d, J＝8.0 Hz, 2H, ArH),
7.55－7.59 (m, 2H, ArH), 7.80－7.85 (m, 3H, ArH),
7.94－7.96 (m, 1H, ArH), 8.08 (s, 1H, ArH), 13.37 (s,
1H, NH); IR (KBr) ν: 3440, 3063, 2998, 2962, 1639,
1604, 1562, 1509, 1460, 1433, 1386, 1325, 1284, 1265,
1228, 1181, 1136, 1113, 1091, 1016, 998, 854, 751, 739
cm−1. HRMS (ESI) m/z: calcd for C23H18ClN2O2 [M＋H]＋
389.1057, found 389.1056.
6-(4-Chlorophenyl)-11H-[1,3]dioxolo[4,5-g]indolo-
[32-c]quinoline (3a) m.p.: ＞ 300 ℃; 1H NMR
(CDCl3, 400 MHz) δH: 6.42 (s, 2H, CH2), 7.30－7.34 (m,
1H, ArH), 7.41 (d, J＝8.0 Hz, 1H, ArH), 7.62－7.64 (m,
2H, ArH), 7.84 (d, J＝8.0 Hz, 1H, ArH), 7.91－7.95 (m,
2H, ArH), 8.00 (d, J＝8.0 Hz, 2H, ArH), 8.07 (s, 1H,
ArH), 13.67 (s, 1H, NH); IR (KBr) ν: 3446, 3086, 3019,
2917, 1646, 1624, 1598, 1509, 1498, 1472, 1441, 1326,
1272, 1223, 1102, 1035, 1018, 936, 858, 786, 757, 721
cm−1. HRMS (ESI) m/z: calcd for C22H12ClN2O2
[M−H] − 371.0586, found 371.0575.
8-Bromo-6-(4-chlorophenyl)-2,3-dimethoxy-11H-
indolo[3,2-c]quinoline (3g) m.p.: ＞ 300 ℃; 1H
NMR (CDCl3, 400 MHz) δH: 3.98 (s, 3H, CH3O), 4.03
(s, 3H, CH3O), 7.45 (d, J＝2.0 Hz, 1H, ArH), 7.57 (s,
1H, ArH), 7.68 (dd, J＝8.4 Hz, J'＝2.0 Hz, 1H, ArH),
7.75 (d, J＝8.4 Hz, 1H, ArH), 7.87 (d, J＝8.4 Hz, 2H,
ArH), 7.95 (d, J＝8.4 Hz, 1H, ArH), 7.96 (s, 1H, ArH),
8.02 (s, 1H, ArH), 13.50 (s, 1H, NH); IR (KBr) ν: 3127,
3058, 2997, 1638, 1608, 1561, 1542, 1498, 1459, 1441,
1423, 1377, 1285, 1265, 1229, 1092, 998, 969, 911, 854,
807, 770 cm−1. HRMS (ESI) m/z: calcd for C23H17BrCl-
N2O2 [M＋H]＋ 467.0162, found 467.0161.
8-Bromo-(4-bromophenyl)-11H-[1,3]dioxolo[4,5-
g]indolo[3,2-c]quinoline (3b) m.p.: ＞300 ℃; 1H
NMR (CDCl3, 400 MHz) δH: 6.43 (s, 2H, CH2), 7.43 (d,
J＝1.6 Hz, 1H, ArH), 7.63 (s, 1H, ArH), 7.74－7.81 (m,
2H, ArH), 7.92－7.94 (m, 2H, ArH), 8.04 (s, 1H, ArH),
8.08 (d, J＝8.4 Hz, 2H, ArH), 13.74 (s, 1H, NH); IR
(KBr) ν: 3440, 3047, 3030, 1645, 1607, 1590, 1469,
1446, 1390, 1377, 1271, 1251, 1102, 1059, 1037, 1010,
938, 903, 860, 840, 819, 789, 724, 710 cm−1. HRMS
(ESI) m/z: calcd for C22H13Br2N2O2 [M＋H]＋ 494.9344,
found 494.9342.
8-Methoxy-(4-bromophenyl)-11H-[1,3]dioxolo[4,5-
g]indolo[3,2-c]quinoline (3c) m.p.: ＞300 ℃; 1H
10-Methoxy-8-(4-methylphenyl)-13H-benzo[f]-
238
www.cjc.wiley-vch.de
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 237—242

An Efficient Method for the Synthesis of Indolo[3,2-c]quinoline Derivatives Catalyzed by Iodine
1
indolo[3,2-c]quinoline (3h) m.p.: ＞300 ℃; H NMR
(CDCl3, 400 MHz) δH: 2.51 (s, 3H, CH3), 3.71 (s, 3H,
CH3O), 7.11－7.16 (m, 2H, ArH), 7.42 (d, J＝8.0 Hz,
2H, ArH), 7.61 (d, J＝8.8 Hz, 1H, ArH), 7.68－7.72 (m,
1H, ArH), 7.81－7.85 (m, 3H, ArH), 8.01 (d, J＝8.8 Hz,
1H, ArH), 8.08 (d, J＝8.0 Hz, 1H, ArH), 8.25 (d, J＝9.2
Hz, 1H, ArH), 8.81 (d, J＝8.8 Hz, 1H, ArH), 9.54 (s, 1H,
NH); IR (KBr) ν: 3419, 3020, 2936, 1586, 1561, 1503,
1468, 1438, 1354, 1303, 1282, 1223, 1203, 1178, 1159,
1109, 1035, 1005, 870, 825, 793, 752, 691 cm−1. HRMS
(ESI) m/z: calcd for C27H19N2O [M−H] − 387.1496,
found 387.1509.
8-(4-Chlorophenyl)-10-methoxy-13H-benzo[f]-
indolo[3,2-c]quinoline (3i) m.p.: ＞300 ℃; 1H NMR
(CDCl3, 400 MHz) δH: 3.66 (s, 3H, CH3O), 6.83 (s, 1H,
ArH), 7.19－7.21 (m, 1H, ArH), 7.70－7.96 (m, 7H,
ArH), 8.11－8.20 (m, 3H, ArH), 9.19 (d, J＝8.0 Hz, 1H,
ArH), 12.56 (s, 1H, NH); IR (KBr) ν: 3338, 3022, 2938,
1589, 1560, 1504, 1486, 1468, 1439, 1385, 1354, 1303,
1282, 1223, 1203, 1175, 1161, 1109, 1086, 1036, 1005,
866, 825, 802, 794, 753 cm−1. HRMS (ESI) m/z: calcd
for C26H16ClN2O [M−H] − 407.0950, found 407.0949.
8-(4-Methoxyphenyl)-13H-benzo[f]indolo[3,2-c]-
quinoline (3j) m.p.: 271－272 ℃; 1H NMR (DMSO-
d6, 400 MHz) δH: 3.96 (s, 3H, CH3O), 7.27－7.33 (m,
3H, ArH), 7.57 (d, J＝8.4 Hz, 1H, ArH), 7.62 (t, J＝7.6
Hz, 1H, ArH), 7.87－7.96 (m, 3H, ArH), 8.02－8.07 (m,
2H, ArH), 8.25－8.29 (m, 2H, ArH), 8.36 (d, J＝9.2 Hz,
1H, ArH), 9.333 (d, J＝8.0 Hz, 1H, ArH), 13.25 (s, 1H,
NH); IR (KBr) ν: 3064, 2933, 2836, 1612, 1548, 1510,
1460, 1442, 1425, 1375, 1332, 1301, 1252, 1180, 1125,
1029, 998, 863, 829, 799, 772, 747 cm−1. HRMS (ESI)
m/z: calcd for C26H19N2O [M＋H]＋ 397.1317, found
397.1318.
1324, 1092 cm−1. HRMS (ESI) m/z: calcd for C25H16Cl-
N2 [M＋H]＋ 379.1002, found 379.1003.
8-(4-Fluorophenyl)-13H-benzo[f]indolo[3,2-c]-
quinoline (3m) m.p.: ＞300 ℃; 1H NMR (DMSO-d6,
400 MHz) δH: 7.18－7.22 (m, 1H, ArH), 7.50－7.52 (m,
4H, ArH), 7.77－7.82 (m, 1H, ArH), 7.92 (b, 4H, ArH),
8.11－8.22 (m, 3H, ArH), 9.23 (d, J＝8.0 Hz, 1H, ArH),
12.58 (s, 1H, NH); 13C NMR (DMSO-d6, 100 MHz) δC:
111.6, 112.7, 114.9, 115.3, 115.5, 120.6, 120.7, 120.8,
125.6, 126.0, 126.5, 127.5, 128.1, 128.7, 128.9, 129.4,
131.15, 131.24, 131.4, 140.4, 140.5, 145.1, 153.4, 161.3,
163.8; IR (KBr) ν: 3050, 1604, 1562, 1498, 1454, 1390,
1352, 1327, 1240, 1226, 1154, 1123, 999, 841, 828, 748
cm−1. HRMS (ESI) m/z: calcd for C25H16FN2 [M＋H]＋
363.1298, found 363.1333.
6-(4-Chlorophenyl)-11H-benzo[h]indolo[3,2-c]-
quinoline (3n) m.p.: 260－261 ℃; 1H NMR (DMSO-
d6, 400 MHz) δH: 7.28 (t, J＝7.6 Hz, 1H, ArH), 7.56－
7.60 (m, 2H, ArH), 7.80－7.84 (m, 5H, ArH), 8.04 (d,
J＝8.0 Hz, 2H, ArH), 8.17 (d, J＝8.0 Hz, 1H, ArH),
8.22 (d, J＝8.4 Hz, 1H, ArH), 8.58 (d, J＝8.8 Hz, 1H,
ArH), 9.32 (d, J＝7.2 Hz, 1H, ArH), 13.33 (s, 1H, NH);
13C NMR (DMSO-d6, 100 MHz) δC: 112.4, 112.6, 113.7,
114.0, 119.5, 120.3, 121.1, 121.3, 121.4, 124.0, 127.0,
127.5, 127.6, 128.4, 128.5, 128.8, 131.3, 133.2, 134.8,
140.1, 142.80, 142.81, 156.7; IR (KBr) ν: 3160, 3056,
1635, 1607, 1570, 1561, 1513, 1490, 1456, 1445, 1433,
1380, 1343, 1324, 1267, 1230, 1176, 1155, 1123, 1091,
1015, 963, 837, 823, 801, 773, 752, 724, 716, 672 cm−1.
HRMS (ESI) m/z: calcd for C25H16ClN2 [M＋H]＋
379.1002, found 379.1002.
6-(4-Fluorophenyl)-11H-benzo[h]indolo[3,2-c]-
quinoline (3o) m.p.: 220－221 ℃; 1H NMR (DMSO-
d6, 400 MHz) δH: 7.27 (t, J＝7.6 Hz, 1H, ArH), 7.52－
7.63 (m, 4H, ArH), 7.82－7.84 (m, 3H, ArH), 8.05－
8.09 (m, 2H, ArH), 8.17－8.25 (m, 2H, ArH), 8.59 (d,
J＝9.2 Hz, 1H, ArH), 9.33－9.35 (m, 1H, ArH), 13.32
(s, 1H, NH); IR (KBr) ν: 3233, 3160, 3056, 2973, 2894,
2811, 2769, 1633, 1606, 1565, 1506, 1486, 1445, 1434,
1408, 1379, 1323, 1268, 1229, 1154, 1082, 1048, 843,
820, 802, 791, 773, 752, 673 cm−1. HRMS (ESI) m/z:
calcd for C25H16FN2 [M ＋H] ＋ 363.1298, found
363.1297.
6-(4-Bromophenyl)-11H-benzo[h]indolo[3,2-c]-
quinoline (3p) m.p.: 273－274 ℃; 1H NMR (DMSO-
d6, 400 MHz) δH: 7.16－7.30 (m, 2H, ArH), 7.58 (t, J＝
7.6 Hz, 2H, ArH), 7.82－7.83 (m, 3H, ArH), 7.97 (s, 3H,
ArH), 8.16－8.23 (m, 2H, ArH), 8.57－8.59 (m, 1H,
ArH), 9.32 (t, J＝1.2 Hz, 1H, ArH), 13.42 (s, 1H, NH);
13C NMR (DMSO-d6, 100 MHz) δC: 112.4, 112.6, 113.6,
119.5, 121.1, 121.2, 123.39, 123.42, 124.0, 125.3, 126.9,
127.4, 127.5, 128.2, 128.3, 128.5, 128.9, 131.5, 131.7,
133.2, 140.0, 142.7, 150.9; IR (KBr) ν: 3214, 3161,
3052, 2973, 2866, 1606, 1570, 1561, 1512, 1490, 1482,
1457, 1446, 1323, 1231, 1013, 773, 750 cm−1. HRMS
(ESI) m/z: calcd for C25H16BrN2 [M＋H]＋ 423.0497,
found 423.0498.
8-(4-Bromophenyl)-13H-benzo[f]indolo[3,2-c]-
quinoline (3k) m.p.: 239－240 ℃; 1H NMR (DMSO-
d6, 400 MHz) δH: 7.33－7.39 (m, 2H, ArH), 7.64－7.67
(m, 1H, ArH), 7.90－7.95 (m, 4H, ArH), 8.01－8.06 (m,
3H, ArH), 8.19－8.22 (m, 1H, ArH), 8.28 (d, J＝6.8 Hz,
1H, ArH), 8.41 (d, J＝7.2 Hz, 1H, ArH), 9.19－9.21 (m,
1H, ArH), 13.32 (s, 1H, NH); IR (KBr) ν: 3091, 3043,
2978, 2916, 2846, 1622, 1602, 1585, 1516, 1479, 1464,
1402, 1340, 1279, 1246, 1205, 1183, 1096, 1042, 1004,
955, 929, 817, 754 cm−1; HRMS (ESI) m/z: calcd for
C25H16BrN2 [M＋H]＋ 423.0497, found 423.0494.
8-(4-Chlorophenyl)-13H-benzo[f]indolo[3,2-c]-
1
quinoline (3l) m.p.: ＞300 ℃; H NMR (DMSO-d6,
400 MHz) δH: 7.36－7.41 (m, 2H, ArH), 7.69－7.74 (m,
1H, ArH), 7.93－8.00 (m, 3H, ArH), 8.05－8.10 (m, 3H,
ArH), 8.12－8.16 (m, 1H, ArH), 8.29 (d, J＝9.2 Hz, 1H,
ArH), 8.38 (d, J＝8.0 Hz, 1H, ArH), 8.52 (d, J＝9.2 Hz,
1H, ArH), 9.32 (d, J＝8.4 Hz, 1H, ArH), 13.54 (s, 1H,
NH); 13C NMR (DMSO-d6, 100 MHz) δC: 108.5, 111.6,
112.7, 113.8, 115.6, 120.2, 120.5, 120.9, 123.0, 125.6,
126.8, 128.2, 128.3, 128.6, 129.3, 129.4, 129.9, 131.4,
131.5, 133.7, 136.5, 141.4, 142.5; IR (KBr) ν: 3032,
1915, 1665, 1649, 1638, 1618, 1611, 1594, 1578, 1561,
1543, 1523, 1509, 1491, 1476, 1459, 1439, 1380, 1364,
6-(4-Methoxyphenyl)-11H-benzo[h]indolo[3,2-c]-
Chin. J. Chem. 2013, 31, 237—242
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
239

Zhou et al.
FULL PAPER
quinoline (3q) m.p.: 189－190 ℃; 1H NMR (DMSO-
d6, 400 MHz) δH: 3.93 (s, 3H, CH3O), 7.19－7.26 (m,
3H, ArH), 7.50 (t, J＝7.6 Hz, 1H, ArH), 7.72－7.77 (m,
3H, ArH), 7.82 (d, J＝8.0 Hz, 1H, ArH), 7.96 (d, J＝8.8
Hz, 2H, ArH), 8.06－8.08 (m, 2H, ArH), 8.53 (d, J＝8.8
Hz, 1H, ArH), 9.32 (d, J＝7.6 Hz, 1H, ArH), 12.85 (s,
1H, NH); IR (KBr) ν: 3216, 2973, 2866, 1609, 1589,
1576, 1565, 1509, 1488, 1456, 1443, 1322, 1295, 1269,
1239, 1179, 1022, 797, 775, 752, 742 cm−1; HRMS (ESI)
m/z: calcd for C26H19N2O [M＋H]＋ 375.1497, found
375.1488.
1, Entries 1－3). To find the optimum reaction tempera-
ture, the reaction was carried out with 5 mol% of I2 at 50,
80 and 100 ℃, resulting in the isolation of 3a in 74%,
82% and 82% yields (Table 1, Entries 2, 4 and 5), re-
spectively. In addition, THF, benzene, toluene and DMF
(Table 1, Entries 6－9) were also tested as the solvents.
In these cases, product 4a was formed in slightly lower
yields. In order to promote aromatization, oxygen was
tried to use as oxidant instead of DDQ, but failed. The
model reaction was heated under O2 for 48 h, and
un-aromatized product was still found clearly by TLC.
6-(3,4-Dimethoxyphenyl)-11H-benzo[h]indolo[3,2-
c]quinoline (3r) m.p.: 175 －176 ℃; 1H NMR
(DMSO-d6, 400 MHz) δH: 3.88 (s, 3H, CH3O), 3.97 (s,
3H, CH3O), 7.28－7.35 (m, 2H, ArH), 7.59－7.61 (m,
2H, ArH), 7.65 (s, 1H, ArH), 7.71 (d, J＝7.6 Hz, 1H,
ArH), 7.83－7.85 (m, 3H, ArH), 8.17－8.25 (m, 2H,
ArH), 8.60 (d, J＝8.8 Hz, 1H, ArH), 9.38 (d, J＝8.0 Hz,
1H, ArH), 13.46 (s, 1H, NH); IR (KBr) ν: 3153, 3061,
2956, 2932, 2905, 2834, 1661, 1634, 1603, 1582, 1565,
1510, 1488, 1455, 1434, 1407, 1385, 1337, 1322, 1262,
1240, 1214, 1182, 1156, 1138, 1021, 824, 802, 753 cm−1.
HRMS (ESI) m/z: calcd for C27H21N2O2 [M＋H]＋
405.1603, found 405.1610.
Table 1 Yields of 3a under various conditionsa
Entry Solvent Iodine/mol%
T/℃
Isolated yield/%
1
2
3
4
5
6
7
8
9
DMA
DMA
DMA
DMA
DMA
THF
1
5
80
80
75
82
82
74
82
38
42
45
78
10
5
80
50
5
100
Reflux
Reflux
80
5
Benzene
Toluene
DMF
5
5
6-(3-Bromophenyl)-11H-benzo[h]indolo[3,2-c]-
1
5
80
quinoline (3s) m.p.: 212－213 ℃; H NMR (CDCl3,
a
Reaction condition: 10 mL solvent, 1a (0.259 g, 1.0 mmol), 2a
(0.117 g, 1.0 mmol), DDQ (0.114 g, 0.5 mmol).
400 MHz) δH: 7.21－7.25 (m, 2H, ArH), 7.48－7.54 (m,
7H, ArH), 7.69 (d, J＝8.0 Hz, 1H, ArH), 7.73 (d, J＝8.0
Hz, 1H, ArH), 7.80－7.82 (m, 2H, ArH), 8.05 (d, J＝8.8
Hz, 1H, ArH), 9.06 (s, 1H, NH); IR (KBr) ν: 3060, 1610,
1592, 1560, 1542, 1514, 1473, 1457, 1446, 1435, 1418,
1404, 1376, 1325, 1260, 1229, 1171, 1125, 1071, 1032,
824, 792, 765, 753 cm−1. HRMS (ESI) m/z: calcd for
C25H16BrN2 [M＋H]＋ 423.0497, found 423.0521.
According to the optimized reaction conditions,
various kinds of aromatic aldehydes, different amines,
for example, piperonylamine, 2-naphthylamine, 3,4-di-
methoxyaniline and 1-naphthylamine, were selected as
reactants to produce Schiff base first; and then, they
were put forward to react with substituted indoles,
which included indole, 5-bromoindole, 5-methoxyindole
and 7-methylindole (Scheme 3). The reactions all gave
desired aromatized indolo[3,2-c]quinoline in good
yields (Table 2). The structures were characterized by IR,
1H NMR and HRMS, and their data were in good
agreement with corresponding structures. The product of
3e was confirmed by X-ray diffraction analysis.[10] Its
crystal structure is shown in Figure 1.
6-(4-Methylphenyl)-11H-benzo[h]indolo[3,2-c]-
1
quinoline (3t) m.p.: 185－187 ℃; H NMR (CDCl3,
400 MHz) δH: 7.24－7.28 (m, 1H, ArH), 7.57 (d, J＝7.6
Hz, 4H, ArH), 7.82 (d, J＝7.6 Hz, 3H, ArH), 7.89 (d,
J＝8.0 Hz, 2H, ArH), 8.18 (d, J＝8.0 Hz, 1H, ArH),
8.23 (d, J＝8.8 Hz, 1H, ArH), 8.57 (d, J＝8.8 Hz, 1H,
ArH), 9.34 (d, J＝8.4 Hz, 1H, ArH), 13.39 (s, 1H, NH);
IR (KBr) ν: 3395, 3055, 2914, 1648, 1614, 1562, 1508,
1445, 1384, 1323, 1268, 1229, 1179, 1101, 1020, 823,
800, 772, 752, 724 cm−1. HRMS (ESI) m/z: calcd for
C26H19N2 [M＋H]＋ 359.1548, found 359.1566.
Scheme 3 Iodine-catalyzed reaction of Schiff base and indole
Results and Discussion
H
N
(1) I2, DMA
(2) DDQ
R
Treatment of (E)-N-(4-chlorobenzylidene) piperonyl
amine 1a with indole 2a in DMA at 80 ℃ catalyzed by
iodine, and further dehydrogenation by DDQ, gave 6-(4-
chlorophenyl)-11H-[1,3]dioxolo[4,5-g]indolo[3,2-c]-
quinoline 3a in 82% yield (Scheme 2).
Initially, the reaction conditions, including reaction
temperature, amount of iodine, and solvents, were opti-
mized in our lab. 1, 5 and 10 mol% iodine were used to
mediate the reaction, it was found that 5 mol% I2 at 80
℃ in DMA was sufficient to initiate the reaction (Table
+
R'
N
Ar
1
2
R'
HN
R
N
3
Ar
240
www.cjc.wiley-vch.de
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 237—242

An Efficient Method for the Synthesis of Indolo[3,2-c]quinoline Derivatives Catalyzed by Iodine
Table 2 Synthetic results of 3a－3t in DMAa
Entry
R
Ar
R'
t/h
Product
Yield/%
1
3,4-OCH2O
4-ClC6H4
4-BrC6H4
4-BrC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-MeC6H4
4-ClC6H4
4-MeOC6H4
4-BrC6H4
4-ClC6H4
4-FC6H4
H
21
18
16
17
22
20
20
16
16
19
20
19
19
20
18
18
20
22
22
19
3a
3b
3c
3d
3e
3f
82
81
86
90
78
82
80
90
86
72
76
80
72
85
82
89
79
86
75
86
2
3,4-OCH2O
5-Br
3
3,4-OCH2O
5-CH3O
4
3,4-OCH2O
5-CH3O
5
3,4-OCH2O
7-CH3
6
3,4-(MeO)2
H
7
3,4-(MeO)2
5-Br
3g
3h
3i
8
3,4-CH＝CH－CH＝CH
3,4-CH＝CH－CH＝CH
3,4-CH＝CH－CH＝CH
3,4-CH＝CH－CH＝CH
3,4-CH＝CH－CH＝CH
3,4-CH＝CH－CH＝CH
2,3-CH＝CH－CH＝CH
2,3-CH＝CH－CH＝CH
2,3-CH＝CH－CH＝CH
2,3-CH＝CH－CH＝CH
2,3-CH＝CH－CH＝CH
2,3-CH＝CH－CH＝CH
2,3-CH＝CH－CH＝CH
5-CH3O
9
5-CH3O
10
11
12
13
14
15
16
17
18
19
20
H
H
H
H
H
H
H
H
H
H
H
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
4-ClC6H4
4-FC6H4
4-BrC6H4
4-MeOC6H4
3,4-(MeO)2C6H3
3-BrC6H4
4-MeC6H4
a Reaction condition: 10 mL DMA, 1 (1.0 mmol), 2 (1.0 mmol), and iodine (0.013 g), DDQ (0.114 g, 0.5 mmol), 80 ℃.
Scheme 4 Possible reaction mechanism
R
R
R
H
N
I2
N
N
N
Imino-Diels-Alder
reaction
I2
Ar
Ar
Ar
HN
H
N
DDQ
R
N
Ar
Conclusions
In summary, an efficient iodine-catalyzed reaction of
Schiff base with indole in DMA is described in this pa-
per. It gives aromatized indolo[3,2-c]quinoline deriva-
tives in good yields via subsequent dehydrogenation by
DDQ.
Figure 1 Crystal structure of the product 3e DMF solvent.
According to the structure of product, we think the
imino-Diels-Alder reaction and aromatization may oc-
cur subsequently. The Schiff base is used as a conju-
gated diene, while indole is dienophile in the imino-
Diels-Alder reaction. It is also named Povarov reac-
tion,[11] which is a well known method to the synthesis
of quinoline derivatives. The possible reaction mecha-
nism is outlined in Scheme 4.
Acknowledgement
We are grateful to the National Natural Science
foundation of China (No. 20802061), the Priority Aca-
demic Program Development of Jiangsu Higher Educa-
tion Institutions, Qing Lan Project (No. 10QLD008) and
College Industrialization Project (JHB2012-31) of Ji-
angsu Education Committee for financial support.
Chin. J. Chem. 2013, 31, 237—242
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
241

Zhou et al.
FULL PAPER
Parvatkar, P. T.; Parameswaran, P. S.; Tilve, S. G. Tetrahedron Lett.
2007, 48, 7870; (d) Meyers, C.; Rombouts, G.; Loones, K. T. J.;
Coelho, A.; Maes, B. U. W. Adv. Synth. Cat. 2008, 350, 465; (e)
Langer, P.; Anders, J. T.; Weisz, K.; Jähnchen, J. Chem. Eur. J. 2003,
9, 3951; (f) Sundaram, G. S. M.; Venkatesh, C.; Syam Kumar, U. K.;
Junjappa, H.; Ila, H. J. Org. Chem. 2004, 69, 5760; (g) He, L.;
Chang, H. X.; Chou, T. C.; Savaraj, N.; Cheng, C. C. Eur. J. Med.
Chem. 2003, 38, 101; (h) Du, W.; Curran, D. P. Org. Lett. 2003, 5,
1765; (i) Zhang, Q.; Shi, C.; Zhang, H.; Wang, K. K. J. Org. Chem.
2000, 65, 7977; (j) Shi, C.; Zhang, Q.; Wang, K. K. J. Org. Chem.
1999, 64, 925; (k) Tummatorn, J.; Thongsornkleeb, C.; Ruchirawat,
S. Tetrahedron 2012, 68, 4732.
References
[1] (a) Wiesner, J.; Ortmann, R.; Jomaa, H.; Schlitzer, M. Angew. Chem.,
Int. Ed. 2003, 42, 5274; (b) Bierer, D. E.; Fort, D. M.; Mendez, C.
D.; Luo, J.; Imbach, P. A.; Dubenko, L. G.; Jolad, S. D.; Eric Gerber,
R.; Litvak, J.; Lu, Q.; Zhang, P.; Reed, M. J.; Waldeck, N.; Bruening,
R. C.; Noamesi, B. K.; Hector, R. F.; Carlson, T. J.; King, S. R. J.
Med. Chem. 1998, 41, 894; (c) Lavrado, J.; Cabal, G. G.; Prudêncio,
M.; Mota, M. M.; Gut, J.; Rosenthal, P. J.; Díaz, C.; Guedes, R. C.;
dos Santos, D. J. V. A.; Bichenkova, E.; Douglas, K. T.; Moreira, R.;
Paulo, A. J. Med. Chem. 2011, 54, 734; (d) Lu, Y.-J.; Ou, T.-M.; Tan,
J.-H.; Hou, J.-Q.; Shao, W.-Y.; Peng, D.; Sun, N.; Wang, X.-D.; Wu,
W.-B.; Bu, X.-Z.; Huang, Z.-S.; Ma, D.-L.; Wong, K.-Y.; Gu, L.-Q. J.
Med. Chem. 2008, 51, 6381.
[8] Wang, X. S.; Yin, M. Y.; Wang, W.; Tu, S. J. Eur. J. Org. Chem.
2012, 4811.
[2] Weinbrenner, S.; Dunkern, T.; Marx, D.; Schmidt, B.; Stengel, T.;
Flockerzi, D.; Kautz, U.; Hauser, D.; Diefenbach, J.; Christiaans, J.
A. M.; Menge, W. M. P. B. WO 2008095835, 2008 [Chem. Abstr.
2008, 149, 246509].
[3] Jaromin, A.; Kozubek, A.; Suchoszek-Lukaniuk, K.; Malicka-
Blaszkiewicz, M.; Peczynska-Czoch, W.; Kaczmarek, L. Drug
Delivery 2008, 15, 49.
[4] Shcherbakova, I.; Nikolyukin, Y. US 20080051426, 2008 [Chem.
Abstr. 2008, 148, 308319].
[5] Ablordeppey, S. Y. US 2007232640, 2007 [Chem. Abstr. 2007, 147,
427319].
[6] 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.
[7] (a) Molina, A.; Vaquero, J. J.; Garcia-Navio, J. L.; Alvarez-Builla, J.;
De Pascual-Teresa, B.; Gago, F.; Rodrigo, M. M.; Ballesteros, M. J.
Org. Chem. 1996, 61, 5587; (b) Cimanga, K.; De Bruyne, T.; Pieters,
L.; Vlietinck, A. J.; Turger, C. A. J. Nat. Prod. 1997, 60, 688; (c)
[9] (a) Li, J. T.; Sun, M. X.; He, G. Y.; Xu, X. Y. Ultrason. Sonochem.
2011, 18, 412; (b) Satam, J. R.; Parghi, K. D.; Jayaram, R. V. Catal.
Commun. 2008, 9, 1071; (c) Azizi, N.; Torkian, L.; Saidi, M. R. J.
Mol. Catal. A: Chem. 2007, 275, 109; (d) Zeng, X. F.; Ji, S. J.; Su, X.
M. Chin. J. Chem. 2008, 26, 413; (e) Shen, S. S.; Xu, X. P.; Ji, S. J.
Chin. J. Org. Chem. 2009, 29, 806.
[10] Crystal data for 3e DMF solvent: C26H22ClN3O3; Mr＝459.92, pale-
yellow block crystals, 0.26 nm×0.20 nm×0.13 mm, triclinic, space
group P-1, a＝9.4529(15) Å, b＝10.0575(15) Å, c＝12.5093(19) Å,
α＝71.006(2)°, β＝85.428(2)°, γ＝83.096(2)°, V＝1115.3(3) Å3,
Z＝2, Dc＝1.369 g•cm−3. F(000)＝480, μ(Mo Kα)＝0.206 mm–1. In-
tensity data were collected on Bruker SMART APEXII CCD
area-detector diffractometer using π and ω scan mode with 3.45°＜θ
＜25.20°. 3939 unique reflections were measured and 3338 reflec-
tions with I＞2σ(I) were used in the refinement. Structure was
solved by direct methods and expanded using Fourier techniques. R
＝0.0397, wR＝0.1030
[11] Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656.
(Pan, B.; Qin, X.)
242
www.cjc.wiley-vch.de
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 237—242