Copper-catalyzed oxidative trimerization of indoles by using TEMPO to construct quaternary carbon centers: The synthesis of 2-(1 H -indol-3-yl)-2,3′-biindolin-3-ones

Article abstract of DOI:10.1139/cjc-2013-0435

A simple, convenient, and efficient synthesis of 2-(1H-indol-3-yl)-2, 3′-biindolin-3-one derivatives has been developed by the oxidative trimeric reaction of indoles using the TEMPO/CuCl₂ catalyst system under ambient air. This methodology provides an alternative approach for the direct generation of all-carbon quaternary centers at the C-2 position of indoles.

Full text of DOI:10.1139/cjc-2013-0435

269
ARTICLE
Copper-catalyzed oxidative trimerization of indoles by using
TEMPO to construct quaternary carbon centers: the synthesis
of 2-(1H-indol-3-yl)-2,3=-biindolin-3-ones
Yu-Bo Kong, Jia-Yi Zhu, Zheng-Wang Chen, and Liang-Xian Liu
Abstract: A simple, convenient, and efficient synthesis of 2-(1H-indol-3-yl)-2,3=-biindolin-3-one derivatives has been developed by
the oxidative trimeric reaction of indoles using the TEMPO/CuCl2 catalyst system under ambient air. This methodology provides
an alternative approach for the direct generation of all-carbon quaternary centers at the C-2 position of indoles.
Key words: indoles, TEMPO, biomimetic synthesis, trimerization.
Résumé : On a élaboré une méthode simple, commode et efficace de synthèse de dérivés de la 2-(1H-indol-3-yl)-2,3=-biindolin-3-
one par la réaction de trimérisation oxydative d’indoles en utilisant un système catalyseur TEMPO/CuCl2 dans l’air ambiant.
Cette méthode offre une approche de rechange pour la génération directe de centres quaternaires totalement carbonés a` la
position C-2 des indoles. [Traduit par la Rédaction]
Mots-clés : indoles, TEMPO, synthèse biomimétique, trimérisation.
difficult to synthesize 2-(1H-indol-3-yl)-2,3=-biindolin-3-one deriva-
tives containing strong electron-withdrawing groups with this
method. Second, a high loading of TEMPO is required (0.7 equiv.).
Third, a long reaction time of 3 days is needed. Thus, the develop-
ment of new catalyst systems for the oxidative trimerization of
indoles continues to be of interest.
In the last decade, many TEMPO/metal systems have been discov-
ered for using molecular oxygen as an environmentally friendly
oxidant for the selective oxidation of alcohols. Copper, among
transition metals, is particularly attractive in organic synthesis
because of its low price, slight toxicity, and environmentally be-
nign feature.9 Among the existing TEMPO/metal systems, the
TEMPO/copper systems have been well investigated.10 Inspired by
these reports, we envisioned that TEMPO/copper systems could be
applied to the oxidative trimeric reaction of indoles. We report
herein on the construction of all-carbon quaternary centers at the
C2 position of indoles using TEMPO/CuCl2 in air as the oxidants.
Introduction
The radical TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl radical)
and its derivatives are well-established catalysts for oxidation
processes and now used extensively in organic synthesis and in-
dustrial applications as a mild, safe, and economical alternative to
heavy metal reagents due to their high selectivity and pronounced
versatility.1
Indolin-3-ones with a chiral center at the 2 position are encoun-
tered in a large variety of natural products and can be used in the
total synthesis of biologically active alkaloids.2–4 For example,
2-(1H-indol-3-yl)-2,3=-biindolin-3-one (1) (Fig. 1) was isolated as the
product of indole oxidation by a strain of Claviceps purpurea.4a This
compound has also been characterized from natural (bacterial)
sources such as Vibrio parahaemolyticus2a and Haemophilus influenzae.4b
In addition, isatisine A (2), an oxindole system having indole
2-substituents, is present in the roots and leaves of Isatis indigotica
(Cruciferae). This biennial herbaceous plant is widely cultivated in
China and East Asia for the prevention and treatment of viral
diseases such as influenza, viral pneumonia, mumps, and hepati-
tis.5 Therefore, developing convenient methods for the construction
of 2,2-disubstituted indolin-3-ones are of considerable interest.3d,5b,6
In 2008, Ganachaud and co-workers reported the biocatalytic syn-
thesis of 1 by trimerisation of indole.7a However, the chemical
synthesis of 2-(1H-indol-3-yl)-2,3=-biindolin-3-one (1) and its deriva-
tives from indoles has been rarely reported up to now.7b–7c
Recently, we have developed an novel, operationally simple,
and practical biomimetic synthetic method for the trimerization
of indoles toward a variety of 2-(1H-indol-3-yl)-2,3=-biindolin-3-one
derivatives by using TEMPO in air as oxidant with excellent
regioselectivity under mild conditions (Scheme 1).8 However,
extensive study in this group revealed several drawbacks: first,
substrates with a strong electron-withdrawing group, such as NO2
and CN, do not lead to the desired products. Consequently, it is
Results and discussion
Initially, the trimeric reaction of indole 5a was studied as a model
reaction to examine the suitable reaction conditions (Scheme 2;
Table 1). TEMPO itself is an expensive chemical, so it is desirable to
be able to decrease the loading of TEMPO by using a copper co-
catalyst. Cocatalyst screening experiments with various copper
sources indicated that CuCl2 was the best catalyst, which gave
trimer 6a in a moderate yield under the reaction conditions (55%)
(Table 1, entry 7). Other copper catalysts such as CuSO4·5H2O,
Cu(OAc)2, Cu(OH)2, and Cu2O were observed to be inferior to CuCl2
(Table 1, entries 1–3 and 5). As can be seen in entries 4 and 6, CuI
and Cu(OTf)2 are not useful as a cocatalyst in the oxidative trim-
erization of 5a. It is worth noting that the acid additive is critical
to the trimeric reaction; the desired product 6a could not be
obtained in the absence of an acid catalyst (entry 8). Thus, different
Received 22 September 2013. Accepted 14 November 2013.
Y.-B. Kong, J.-Y. Zhu, Z.-W. Chen, and L.-X. Liu. Department of Chemistry and Chemical Engineering, Gannan Normal University, Ganzhou, Jiangxi
341000, P R. China.
Corresponding author: Liang-Xian Liu (e-mail: lxliu@xmu.edu.cn).
Can. J. Chem. 92: 269–273 (2014) dx.doi.org/10.1139/cjc-2013-0435
Published at www.nrcresearchpress.com/cjc on 5 December 2013.

270
Can. J. Chem. Vol. 92, 2014
Fig. 1. Representative natural products with a 2,2=-disubstituent indolin-3-one structural unit.
O
O
NH
Me Me
HN
O
NH
H
N
H
N
O
OH
O
N
H
N
H
N
O
N
NH
MeO2C
Fluorocarpamine 4
H
HO
O
O
OH
(-)-Isatisine A 2
Breviannamide B 3
1
Scheme 1. Synthesis of 2,2-disubstituted oxindoles by using TEMPO
in air as oxidant.
(Table 1, entry 9). Stronger Brønsted acids, CF3CO2H and HBF4,
were ineffective for this transformation (Table 1, entries 10 and 11).
With respect to the loading of CuCl2, it was also established that
40 mol% of CuCl2 was indeed the preferred amount with lower or
higher loading giving poor yields (Table 1, entries 12–16). Simi-
larly, when 40 mol% of benzoic acid was used, the desired 6a was
obtained in good yield (Table 1, entry 18). The reaction tempera-
ture also had great influence on the reaction. When the reaction
was treated at 25 °C, trace amounts of 6a were obtained (Table 1,
entry 21). When the reaction mixture was warmed to 60 °C, the
desired product was formed in 83% yield (Table 1, entry 22). A
higher temperature (80 °C) led to a significant decreased yield
possibly due to other side reactions (Table 1, entry 24). After a
great deal of screening on different parameters, we found that the
oxidative trimeric reaction of indole by using TEMPO (20 mol%) as
an oxidant, CuCl2 (40 mol%) as a cocatalyst, and benzoic acid
(40 mol%) as an acid in CH3CN at 60 °C led to the highest efficiency
(83% yield) (Table 1, entry 22).
The scope of the protocol was further tested after the optimal
reaction conditions were established. A variety of representative
indole derivatives were subjected to the optimized conditions, as
depicted in Scheme 3 and Table 2. Thus, a trimeric reaction of
substituted indoles proceeded smoothly to provide the corre-
sponding 2-(1H-indol-3-yl)-2,3=-biindolin-3-one derivatives in mod-
erate to excellent yields. The reaction can tolerate a variety of
functional groups at the 1, 4, 5, 6, and 7 positions of indoles, such
as F, Cl, Br, CH3, CH2CH3, CH3O, BnO, CO2CH3, CN, and NO2,
providing opportunities for further synthetic elaboration.
The scope of the indole counterpart in this reaction has also
been evaluated. Indoles with electron-donating groups or electron-
withdrawing groups on C-5, C-6, C-7, and C-4 all worked well under
the present reaction conditions. In contrast, indole with OCH3 on
C-4 gave relatively low product yield (Table 2, entry 17). We were
delighted to note that the substrates with strongly electron-
withdrawing groups, such as NO2 or CN, smoothly underwent the
reaction to afford the corresponding products in moderate yields.
For example, 5-nitro-1H-indole was transformed into trimer 6j in
55% yield (Table 2, entry 9). In our previous work on the oxidative
trimeric reaction of indoles,8 the efficiency of this transformation
is highly dependent upon the electronic properties of R1 groups.
Electron-rich groups showed better results than electron-withdrawing
groups in this trimerization. In contrast, the strongly electron-
withdrawing group NO2 totally inhibited the process.
With the promising results for the oxidative dimer of indoles,
we further explored the possibility of extending the reaction to
the more challenging 2-substituted indoles, and the results are
summarized in Scheme 4 and Table 3. In general, the TEMPO/CuCl2
system displayed higher catalytic activity than when TEMPO
alone was used. It was interesting to find that 2-substituted in-
doles with electron-donating groups, such as 2-methyl-1H-indole,
2-phenyl-1H-indole, 1-methyl-2-methyl-1H-indole, 1-butyl-2-phenyl-
1H-indole, and 1-methyl-2-phenyl-1H-indole, all reacted very well
under the present reaction conditions. However, much lower
yields were obtained in the case of methyl 1H-indole-2-carboxylate
and methyl 5-chloro-1H-indole-2-carboxylate (Table 3, entries 4
R1
R1 = H, F, Br, CH3,
CH3O, BnO, NHAc,
CN, CO2CH3
O
NR2
TEMPO,
benzoic acid
R1
1R
R2 = H, CH3
N
NR2
N
CH3CN, 65 oC,
air, 3 days
R2
R2
14 examples
up to 93%
R1
100% Regioselectivity
Scheme 2. Synthesis of 6a.
O
NH
NH
TEMPO
Acid
N
H
N
H
6a
5a
Table 1. Optimization of the reaction conditions.
Copper catalyst
Entry (mmol)
Temperature
(°C)
Acid (mmol)
CuSO4·5H2O (0.1) Benzoic acid (0.1)
% 6aa
1
2
3
4
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
35
26
20
Trace
17
Trace
55
Trace
33
Trace
Trace
24
62
73
72
70
76
79
78
67
Cu(OAc)2 (0.1)
Cu(OH)2 (0.1)
CuI (0.1)
Benzoic acid (0.1)
Benzoic acid (0.1)
Benzoic acid (0.1)
Benzoic acid (0.1)
Benzoic acid (0.1)
Benzoic acid (0.1)
5
6
7
8
Cu2O (0.1)
Cu(OTf)2 (0.1)
CuCl2 (0.1)
CuCl2 (0.1)
CuCl2 (0.1)
CuCl2 (0.1)
CuCl2 (0.1)
CuCl2 (0.05)
CuCl2 (0.15)
CuCl2 (0.2)
CuCl2 (0.25)
CuCl2 (0.3)
CuCl2 (0.2)
CuCl2 (0.2)
CuCl2 (0.2)
CuCl2 (0.2)
CuCl2 (0.2)
CuCl2 (0.2)
CuCl2 (0.2)
CuCl2 (0.2)
9
Oxalic acid (0.1)
CF3CO2H (0.1)
HBF4 (0.1)
Benzoic acid (0.1)
Benzoic acid (0.1)
Benzoic acid (0.1)
Benzoic acid (0.1)
Benzoic acid (0.1)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Benzoic acid (0.15) 50
Benzoic acid (0.2) 50
Benzoic acid (0.25) 50
Benzoic acid (0.2)
Benzoic acid (0.2)
Benzoic acid (0.2)
Benzoic acid (0.2)
Benzoic acid (0.2)
40
25
60
70
80
Trace
83
75
63
Note: Reaction conditions: indole (0.5 mmol), TEMPO (0.1 mmol), and CH3CN
(0.6 mL) for 6 h.
aIsolated yield.
acid additives were screened to improve the yield. Benzoic acid
was found to be the best choice for the oxidative trimeric reaction
of 5a, since other acid additives such as oxalic acid are not as
effective as benzoic acid under similar reaction conditions
Published by NRC Research Press

Kong et al.
271
Scheme 3. Synthesis of 6a–6s.
and 5). Interestingly, we observed that indoles with electron-
withdrawing substituents at the 1 positions of indoles, such as
tert-butoxycarbonyl, could not provide the corresponding prod-
ucts and the starting materials were completely recovered (Table 3,
entries 9 and 10).
R1
N R2
O
TEMPO, benzoic acid
CuCl2, CH3CN, 60 o
R1
Conclusions
C
1R
R2
N
N
N
R2
R2
In summary, we have developed an operationally simple and
efficient method to construct all-carbon quaternary centers at the
C2 position of indoles via a copper-catalyzed oxidative trimeric
reaction of indoles. These precursors offer distinct advantages in
substrate scope, TEMPO loading, and reaction time over previ-
ously reported methods. It is noteworthy that the substrates with
a strongly electron-withdrawing group, such as NO2 or CN, smoothly
underwent the reaction to afford the corresponding products in
moderate yields. Moreover, it is highly regioselective (2,3= link-
age). Importantly, the broad group tolerance, less expensive metal
catalyst, and aerobic reaction conditions made this method useful
to construct such unique scaffolds from commercially available
indole and its derivatives.
5
6
R1
Table 2. Trimeric reaction of indoles by using TEMPO/
CuCl2 in air.
Yield
Entry R1
R2
Time (h) Product (%)a
1
H
H
6
6
6
6
6
6
6
10
24
25
6
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
83
83
75
76
74
70
93
69
55
52
80
73
65
79
70
41
2
5-Br
H
3
5-F
H
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
5-CH3
5-OCH3
5-OBn
5-NHAc
5-CO2CH3
5-NO2
5-CN
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
C2H5
Experimental section
General comments
Melting points were determined on a digital melting point ap-
paratus and temperatures were uncorrected. Infrared spectra
were measured with a Nicolet Avatar 360 FT-IR spectrometer us-
6-Cl
6-F
1
ing film KBr pellet techniques. H and 13C NMR spectra were re-
6
10
6
corded on a Bruker spectrometer at 400 and 100 MHz, respectively.
Chemical shifts were reported in parts per million relative to TMS
6-CO2CH3
7-CH3
7-OCH3
7-NO2
4-OCH3
H
1
6
for H and 13C NMR spectra. CDCl3 or DMSO-d6 was used as the
24
10
6
NMR solvent. Mass spectra were recorded with Bruker Dalton
Esquire 3000 plus LC-MS apparatus. Elemental analyses were carried
out on a Perkin-Elmer 240B instrument. Silica gel (300–400 mesh)
was used for flash column chromatography, eluting (unless oth-
erwise stated) with an ethyl acetate − petroleum ether (PE) (60–
90 °C) mixture.
62
68
66
H
6
Note: Reaction conditions: indole (0.5 mmol), TEMPO (0.1 mmol),
CuCl2 (0.2 mmol), benzoic acid (0.2 mmol), and CH3CN (0.6 mL).
aIsolated yield.
General procedure for the preparation of 2-(1H-indol-3-yl)-
2,3=-biindolin-3-ones
Scheme 4. Synthesis of 7a–7j.
To a solution of indole (0.5 mmol), TEMPO (0.1 mmol) and CuCl2
(0.2 mmol) in CH3CN (0.6 mL) was added benzoic acid (0.2 mmol)
under atmosphere and the mixture was stirred at 25–120 °C for
6–72 h (monitored by TLC). The reaction mixture was concen-
trated under reduced pressure. The residue was purified by flash
chromatography on silica gel (eluent EtOAc−PE = 1:2) to yield the
corresponding product.
O
R1
R3
R3
N
TEMPO, benzoic acid
CuCl2, CH3CN
R1
R3
N R2
R2
N
R2
5
7
R1
5,5=-Dinitro-2-(5-nitro-1H-indol-3-yl)-2,3=-biindolin-3-one (6i)
Yellow solid, mp 214–216 °C (from EtOAc−PE = 1:2). IR (KBr) ␯
:
max
3388, 1621, 1332 cm−1. 1H NMR (400 MHz, DMSO-d6) ␦: 12.00 (s, 1H,
NH), 11.99 (s, 1H, NH), 9.98 (s, 1H, NH), 8.42 (dd, J = 9.1, 2.4 Hz, 1H,
Ar-H), 8.37 (d, J = 2.4 Hz, 1H, Ar-H), 8.22 (d, J = 2.2 Hz, 2H, Ar-H), 7.98
(dd, J = 9.0, 2.2 Hz, 2H, Ar-H), 7.62 (d, J = 2.4 Hz, 2H, Ar-H), 7.59 (d,
J = 9.0 Hz, 2H, Ar-H), 7.12 (d, J = 9.1 Hz, 1H, Ar-H). 13C NMR (100 MHz,
DMSO-d6) ␦: 198.6, 162.9, 141.0, 140.7, 138.8, 133.7, 128.4, 124.7,
122.8, 117.5, 117.4, 116.7, 115.1, 113.1, 112.3, 68.9. MS (ESI): 499 (M+H+,
100), 521 (M+Na+, 25). Anal. calcd. for C24H14N6O7: C 57.84, H 2.83,
N 16.86; found: C 57.52, H 3.17, N 16.49.
Table 3. Dimeric reaction of 2-substituted indoles by using TEMPO in
air.
Time Temperature
Yield
Product (%)a
Entry R1
R2
R3
(h)
(°C)
1
H
H
H
H
5-Cl
5-CH3
H
H
H
H
H
CH3
Ph
6
6
6
25
25
25
120
120
25
25
65
120
120
7a
7b
7c
7d
7e
7f
7g
7h
7i
90 (30)
92 (23)
65 (15)
43 (13)
36 (10)
80 (31)
89 (61)
70 (48)
Trace (0)
Trace (0)
2
3
4
5
6
7
8
9
10
CH3 Ph
H
H
H
CO2Et 72
CO2Et 72
CH3
2-(5-Cyano-1H-indol-3-yl)-3-oxo-2,3=-biindoline-5,5=-
6
24
24
72
72
dicarbonitrile (6j)
CH3 CH3
n-Bu Ph
Boc CH3
Boc Ph
Yellow amorphous solid. IR (KBr) ␯max: 3415, 2223, 1626,
1119 cm−1. 1H NMR (100 MHz, DMSO-d6) ␦: 11.80 (s, 2H, NH), 9.44 (s,
1H, NH), 8.03 (d, J = 1.6 Hz, 1H, Ar-H), 7.87 (dd, J = 8.6, 1.6 Hz, 1H,
Ar-H), 7.63 (d, J = 1.6 Hz, 2H, Ar-H), 7.57 (d, J = 8.5 Hz, 2H, Ar-H), 7.47
(s, 1H, Ar-H), 7.46 (s, 1H, Ar-H), 7.42 (dd, J = 8.5, 1.6 Hz, 2H, Ar-H),
7.07 (d, J = 8.6 Hz, 1H, Ar-H). 13C NMR (100 MHz, DMSO-d6) ␦: 198.5,
161.7, 141.0, 139.3, 131.3, 127.1, 125.8, 125.4, 124.6, 121.0, 119.7, 117.5,
H
7j
Note: Reaction conditions: indole (0.5 mmol), TEMPO (0.1 mmol), CuCl2
(0.2 mmol), benzoic acid (0.2 mmol), and CH3CN (0.6 mL). Boc, tert-butoxycarbonyl.
aIsolated yield. The yield in parentheses was obtained under the conditions of
indole (0.5 mmol)/TEMPO (0.35 mmol)/benzoic acid (0.25 mmol)/CH3CN (0.6 mL).
Published by NRC Research Press

272
Can. J. Chem. Vol. 92, 2014
113.9, 113.8, 113.0, 101.4, 99.4, 67.9. MS (ESI): 439 (M+H+, 100). Anal.
calcd. for C27H14N6O: C 73.96, H 3.22, N 19.17; found: C 73.63, H
3.49, N 18.84.
2,2=-Diphenyl-2,3=-biindolin-3-one (7b)
Straw yellow amorphous solid. IR (KBr) ␯max: 3427, 3312, 1673,
1
1610, 1151, 754 cm−1. H NMR (400 MHz, DMSO-d6) ␦: 11.36 (s, 1H,
NH), 8.35 (s, 1H, NH), 7.51 (dt, J = 8.1, 1.0 Hz, 1H, Ar-H), 7.38 (m, 2H,
Ar-H), 7.34 (d, J = 8.1 Hz, 1H, Ar-H), 7.25 (d, J = 7.6 Hz, 1H, Ar-H), 7.15
(m, 3H, Ar-H), 7.05 (m, 6H, Ar-H), 6.98 (d, J = 8.1 Hz, 1H, Ar-H), 6.76
(t, J = 7.6 Hz, 1H, Ar-H), 6.71 (t, J = 7.6 Hz, 1H, Ar-H), 6.61 (d, J = 8.1 Hz,
1H, Ar-H). 13C NMR (100 MHz, DMSO-d6) ␦: 200.9, 160.5, 140.3, 138.4,
137.9, 136.2, 133.6, 130.0, 128.0, 127.9, 127.8, 127.6, 127.5, 127.4,
124.8, 121.6, 120.8, 119.1, 119.0, 117.9, 112.4, 111.7, 111.5, 71.6. MS (ESI):
401 (M+H+, 100). Anal. calcd. for C28H20N2O: C 83.98, H 5.03, N 7.00;
found: C 84.05, H 4.72, N 6.81.
6,6=-Dichloro-2-(6-chloro-1H-indol-3-yl)-2,3=-biindolin-3-one (6k)
Yellow solid, mp 197–199 °C (from EtOAc−PE = 1:2). IR (KBr) ␯
:
max
3412, 1668, 1611, 1452, 804 cm−1. 1H NMR (400 MHz, CDCl3) ␦: 8.43 (s,
2H, NH), 8.50 (s, 1H, NH), 7.66 (d, J = 7.6 Hz, 1H, Ar-H), 7.57 (d, J =
7.6 Hz, 1H, Ar-H), 7.31 (d, J = 8.0 Hz, 2H, Ar-H), 7.19 (s, 1H, Ar-H), 7.17
(s, 1H, Ar-H), 7.18 (d, J = 7.6 Hz, 2H, Ar-H), 6.94 (t, J = 8.0 Hz, 2H,
Ar-H), 6.89 (t, J = 7.6 Hz, 1H, Ar-H), 5.60 (s, 1H, NH). 13C NMR
(100 MHz, CDCl3) ␦: 199.5, 161.1, 142.9, 137.8, 126.8, 126.5, 125.6,
124.6, 122.0, 119.4, 118.1, 116.7, 114.1, 111.8, 111.5, 68.2. MS (ESI): 466
(M+H+, 100), 468 (M+H+, 100), 470 (M+H+, 30). Anal. calcd. for
C24H14Cl3N3O1: C 61.76, H 3.02, N 9.00; found: C 62.08, H 2.84, N
8.75.
1,1=-Dimethyl-2,2=-diphenyl-2,3=-biindolin-3-one (7c)
Straw yellow amorphous solid. IR (KBr) ␯max: 3440, 1616,
1123 cm−1. 1H NMR (400 MHz, CDCl3) ␦: 7.42 (dt, J = 1.3, 8.4 Hz, 2H,
Ar-H), 7.35 (d, J = 8.2 Hz, 2H, Ar-H), 7.31–7.25 (s, 4H, Ar-H), 7.24–7.18
(s, 3H, Ar-H), 7.13 (d, J = 7.2 Hz, 1H, Ar-H), 6.93 (dt, J = 1.3, 7.6 Hz, 1H,
Ar-H), 6.91 (dt, J = 1.3, 7.2 Hz, 1H, Ar-H), 6.82 (d, J = 7.6 Hz, 1H, Ar-H),
6.65 (d, J = 8.2 Hz, 1H, Ar-H), 6.58 (d, J = 8.4 Hz, 1H, Ar-H), 6.55 (t, J =
7.2 Hz, 1H, Ar-H), 3.47 (s, 3H, CH3), 2.80 (s, 3H, CH3). 13C NMR
(100 MHz, CDCl3) ␦: 200.1, 159.4, 140.0, 138.5, 137.2, 136.9, 131.4,
131.3, 130.7, 128.3, 128.2, 127.7, 127.6, 126.9, 125.2, 121.9, 121.5, 119.5,
119.4, 116.4, 109.8, 109.4, 107.7, 76.2, 30.5, 29.6. MS (ESI): 429 (M+H+,
100). Anal. calcd. for C30H24N2O: C 84.08, H 5.65, N 6.54; found: C
83.87, H 5.96, N 6.25.
7,7=-Dimethoxy-2-(7-methoxy-1H-indol-3-yl)-2,3=-biindolin-
3-one (6o)
Yellow solid, mp 209–210 °C (from EtOAc−PE = 1:2). IR (KBr) ␯
:
max
3406, 1660, 1615, 1452, 1116, 1061 cm−1. 1H NMR (400 MHz, CDCl3) ␦:
8.30 (s, 2H, NH), 7.37 (d, J = 7.8 Hz, 1H, Ar-H), 7.16 (s, 1H, Ar-H), 7.15
(s, 1H, Ar-H), 7.05 (d, J = 8.1 Hz, 2H, Ar-H), 6.99 (d, J = 7.8 Hz, 1H,
Ar-H), 6.92 (t, J = 8.1 Hz, 2H, Ar-H), 6.86 (t, J = 7.8 Hz, 1H, Ar-H), 6.62
(d, J = 7.8 Hz, 2H, Ar-H), 5.58 (s, 1H, NH), 3.95 (s, 6H, 2 × OCH3), 3.88
(s, 3H, OCH3). 13C NMR (100 MHz, CDCl3) ␦: 201.0, 151.9, 146.7, 146.2,
127.6, 127.1, 123.5, 120.6, 120.2, 119.3, 116.7, 115.8, 115.7, 113.3, 102.0,
68.6, 55.4, 55.3. MS (ESI): 454 (M+H+, 100). Anal. calcd. for
C27H23N3O4: C 71.51, H 5.11, N 9.27; found: C 71.43, H 5.30, N 8.92.
Diethyl 3-oxo-2,3=-biindoline-2,2=-dicarboxylate (7d)
Straw yellow amorphous solid. IR (KBr) ␯max: 3416, 1728, 1688,
1612, 1264, 1143 cm−1. 1H NMR (400 MHz, CDCl3) ␦: 9.10 (s, 1H, NH),
7.79 (d, J = 7.5 Hz, 1H, Ar-H), 7.52 (t, J = 8.6 Hz, 1H, Ar-H), 7.49 (d, J =
8.6 Hz, 1H, Ar-H), 7.39 (d, J = 8.3 Hz, 1H, Ar-H), 7.28 (t, J = 7.4 Hz, 1H,
Ar-H), 7.05 (t, J = 7.4 Hz, 1H, Ar-H), 6.96 (d, J = 8.3 Hz, 1H, Ar-H), 6.95
(t, J = 7.4 Hz, 1H, Ar-H), 5.98 (s, 1H, NH), 4.35 (q, J = 7.1 Hz, 2H, OCH2),
4.25 (q, J = 7.1 Hz, 2H, OCH2), 1.38 (t, J = 7.1 Hz, 3H, CH3), 1.21 (t, J =
7.1 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3) ␦: 194.9, 168.2, 161.9,
138.0, 135.7, 130.1, 128.4, 125.7, 125.5, 125.4, 125.3, 122.3, 121.2, 120.0,
119.9, 113.1, 112.0, 72.8, 62.8, 61.5, 14.3, 13.9. MS (ESI): 393 (M+H+,
100). Anal. calcd. for C22H20N2O5: C 67.34, H 5.14, N 7.14; found: C
67.68, H 4.83, N 6.91.
7,7=-Dinitro-2-(7-nitro-1H-indol-3-yl)-2,3=-biindolin-3-one (6p)
Yellow solid, mp 302–305 °C (from EtOAc−PE = 1:2). IR (KBr)
␯
max: 3411, 1630, 1513, 1478, 1309 cm−1. 1H NMR (400 MHz, CDCl3) ␦:
10.07 (s, 2H, NH), 8.47 (dd, J = 7.5, 2.2 Hz, 1H, Ar-H), 8.19 (d, J = 8.0 Hz,
2H, Ar-H), 8.08 (d, J = 7.5 Hz, 1H, Ar-H), 7.92 (s, 1H, NH), 7.76 (d, J =
8.0, Hz, 2H, Ar-H), 7.47 (d, J = 2.2 Hz, 2H, Ar-H), 7.15 (t, J = 8.0 Hz, 2H,
Ar-H), 7.05 (t, J = 7.5 Hz, 1H, Ar-H). 13C NMR (100 MHz, CDCl3) ␦:
196.6, 152.0, 133.4, 133.0, 131.9, 130.5, 128.7, 128.5, 126.1, 126.0,
122.9, 120.1, 120.0, 118.5, 115.0, 67.7. MS (ESI): 499 (M+H+, 100), 521
(M+Na+, 20). Anal. calcd. for C24H14N6O7: C 57.84, H 2.83, N 16.86;
found: C 60.03, H 2.52, N 16.67.
Diethyl 5,5=-dichloro-3-oxo-2,3=-biindoline-2,2=-dicarboxylate (7e)
Straw yellow amorphous solid. IR (KBr) ␯max: 3428, 1725, 1705,
1615, 1252, 1139 cm−1. 1H NMR (400 MHz, DMSO-d6) ␦: 12.38 (s, 1H,
NH), 8.27 (s, 1H, NH), 7.64 (d, J = 2.2 Hz, 1H, Ar-H), 7.55 (dd, J = 8.8,
2.2 Hz, 1H, Ar-H), 7.50 (d, J = 8.8 Hz, 1H, Ar-H), 7.26 (dd, J = 8.8,
3.0 Hz, 1H, Ar-H), 7.21 (d, J = 3.0 Hz, 1H, Ar-H), 7.02 (d, J = 8.8 Hz, 1H,
Ar-H), 4.30 (q, J = 7.1 Hz, 2H, OCH2), 4.08 (q, J = 7.1 Hz, 2H, OCH2),
1.30 (t, J = 7.1 Hz, 3H, CH3), 1.07 (t, J = 7.1 Hz, 3H, CH3). 13C NMR
(100 MHz, DMSO-d6) ␦: 194.4, 167.6, 161.3, 161.2, 138.5, 134.7, 127.8,
125.9, 125.3, 125.2, 123.9, 122.7, 120.5, 119.2, 115.2, 114.9, 114.7, 73.5,
62.3, 61.6, 14.5, 14.2. MS (ESI): 461 (M+H+, 100), 463 (M+H+, 60). Anal.
calcd. for C22H18Cl2N2O5: C 57.28, H 3.93, N 6.07; found: C 56.96, H
4.11, N 5.79.
1,1=-Diethyl-2-(1-ethyl-1H-indol-3-yl)-2,3=-biindolin-3-one (6s)
Yellow solid, mp 238–241 °C (from EtOAc−PE = 1:2). IR (KBr) ␯
:
max
3413, 1699, 1609, 1486, 1463, 740 cm−1. 1H NMR (400 MHz, CDCl3) ␦:
7.69 (d, J = 7.4 Hz, 1H, Ar-H), 7.56 (dt, J = 8.3, 1.2 Hz, 1H, Ar-H), 7.35
(t, J = 7.9 Hz, 4H, Ar-H), 7.18 (t, J = 7.9 Hz, 2H, Ar-H), 7.06 (s, 2H,
Ar-H), 6.97 (t, J = 7.4 Hz, 2H, Ar-H), 6.86 (d, J = 8.3 Hz, 1H, Ar-H), 6.76
(t, J = 7.4 Hz, 1H, Ar-H), 4.13 (q, J = 7.3 Hz, 4H, 2 × CH2), 3.59 (q, J =
7.1 Hz, 2H, CH2), 1.43 (t, J = 7.3 Hz, 6H, 2 × CH3), 0.67 (t, J = 7.1 Hz, 3H,
CH3). 13C NMR (100 MHz, CDCl3) ␦: 200.7, 158.7, 137.5, 136.7, 128.2,
126.6, 125.9, 121.8, 121.5, 119.2, 118.7, 116.4, 111.9, 109.3, 108.0, 72.7,
41.0, 38.2, 15.5, 13.3. MS (ESI): 448 (M+H+, 100). Anal. calcd. for
C30H29N3O: C 80.51, H 6.53, N 9.39; found: C 80.17, H 6.74, N 9.25.
2,2=-Dimethyl-2,3=-biindolin-3-one (7a)
2,2=,5,5=-Tetramethyl-2,3=-biindolin-3-one (7f)
Straw yellow amorphous solid. IR (KBr) ␯max: 3425, 1672, 1614,
1117 cm−1. 1H NMR (400 MHz, DMSO-d6) ␦: 7.99 (s, 1H, NH), 7.72 (d,
J = 7.7 Hz, 1H, Ar-H), 7.53 (dt, J = 1.0, 8.5 Hz, 1H, Ar-H), 7.38 (d, J =
8.1 Hz, 1H, Ar-H), 7.24 (d, J = 8.1 Hz, 1H, Ar-H), 7.07 (dt, J = 1.0, 8.1 Hz,
1H, Ar-H), 6.96 (dt, J = 1.0, 8.1 Hz, 1H, Ar-H), 6.89 (t, J = 7.7 Hz, 1H,
Ar-H), 6.88 (d, J = 8.5 Hz, 1H, Ar-H), 5.30–4.80 (s, 1H, NH), 2.36 (s, 3H,
CH3), 1.93 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6) ␦: 204.2, 159.5,
137.4, 134.9, 132.5, 127.5, 125.3, 121.3, 119.8, 119.7, 119.5, 119.1, 112.4,
110.4, 109.6, 67.1, 29.7, 25.1. MS (ESI): 277 (M+H+, 100). Anal. calcd.
for C18H16N2O: C 78.24, H 5.84, N 10.14; found: C 77.95, H 6.02, N
9.87.
Straw yellow amorphous solid. IR (KBr) ␯max: 3260, 1688, 1625,
1499 cm−1. 1H NMR (400 MHz, DMSO-d6) ␦: 10.73 (s, 1H, NH), 7.45 (s,
1H, NH), 7.33 (d, J = 8.4 Hz, 1H, Ar-H), 7.24 (s, 1H, Ar-H), 7.11 (s, 1H,
Ar-H), 7.09 (d, J = 8.4 Hz, 1H, Ar-H), 6.81 (d, J = 8.3 Hz, 1H, Ar-H), 6.76
(d, J = 8.3 Hz, 1H, Ar-H), 2.32 (s, 3H, CH3), 2.24 (s, 3H, CH3), 2.22 (s,
3H, CH3), 1.72 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6) ␦: 204.4,
159.0, 139.2, 133.6, 133.2, 128.0, 126.8, 126.2, 124.0, 121.8, 120.0,
118.3, 112.3, 110.6, 108.7, 67.1, 25.1, 22.1, 20.6, 14.4. MS (ESI): 305
(M+H+, 100). Anal. calcd. for C22H20N2O: C 78.92, H 6.62, N 9.20;
found: C 78.57, H 6.95, N 8.90.
Published by NRC Research Press

Kong et al.
273
1,1=,2,2=-Tetramethyl-2,3=-biindolin-3-one (7g)
References
Straw yellow amorphous solid. IR (KBr) ␯max: 1692, 1613,
1319 cm−1. 1H NMR (400 MHz, CDCl3) ␦: 7.70 (dd, J = 1.4, 7.2 Hz, 1H,
Ar-H), 7.55 (dt, J = 1.4, 8.1 Hz, 1H, Ar-H), 7.47 (t, J = 7.8 Hz, 1H, Ar-H),
7.26 (d, J = 8.1 Hz, 1H, Ar-H), 7.14 (dt, J = 1.0, 8.1 Hz, 1H, Ar-H), 7.00
(dt, J = 1.0, 8.1 Hz, 1H, Ar-H), 6.80 (d, J = 7.8 Hz, 1H, Ar-H), 6.77 (t, J =
7.2 Hz, 1H, Ar-H), 3.64 (s, 3H, CH3), 2.88 (s, 3H, CH3), 2.30 (s, 3H,
CH3), 1.92 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) ␦: 203.9, 158.9,
137.8, 136.8, 135.7, 130.2, 128.5, 125.5, 120.7, 119.6, 119.5, 118.3, 116.8,
109.0, 108.1, 71.2, 29.5, 27.8, 22.0, 11.9. MS (ESI): 305 (M+H+, 100).
Anal. calcd. for C22H20N2O: C 78.92, H 6.62, N 9.20; found: C 78.63,
H 6.86, N 8.87.
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1,1=-Dibutyl-2,2=-diphenyl-2,3=-biindolin-3-one (7h)
Straw yellow amorphous solid. IR (KBr) ␯max: 1708, 1613, 1488,
1462, 744 cm−1. 1H NMR (400 MHz, CDCl3) ␦: 7.57 (s, 1H, Ar-H), 7.44
(t, J = 7.5 Hz, 1H, Ar-H), 7.40 (d, J = 8.1 Hz, 1H, Ar-H), 7.36–7.25 (m,
8H, Ar-H), 7.16 (d, J = 7.5 Hz, 1H, Ar-H), 6.97 (d, J = 7.5 Hz, 1H, Ar-H),
6.96 (s, 1H, Ar-H), 6.92 (t, J = 7.5 Hz, 1H, Ar-H), 6.75 (d, J = 8.1 Hz, 1H,
Ar-H), 6.59 (d, J = 8.4 Hz, 1H, Ar-H), 6.57 (t, J = 7.5 Hz, 1H, Ar-H), 3.93
(dt, J = 2.6, 8.6 Hz, 2H, Ar-H), 3.46 (dt, J = 4.9, 11.1 Hz, 1H, Ar-H), 3.14
(dt, J = 4.9, 11.1 Hz, 1H, Ar-H), 1.65–1.55 (m, 2H, Ar-H), 1.20–1.10 (m,
3H, Ar-H), 1.08–0.90 (m, 3H, Ar-H), 0.79 (t, J = 7.2 Hz, 3H, CH3), 0.58
(t, J = 7.2 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3) ␦: 199.6, 158.4,
139.1, 139.0, 137.0, 136.1, 131.7, 131.6, 130.7, 129.1, 128.3, 127.7, 127.6,
127.5, 126.9, 125.4, 122.1, 121.4, 119.3, 116.1, 110.5, 109.8, 107.9, 76.4,
44.1, 43.5, 32.1, 29.6, 20.2, 20.0, 13.7, 13.4. MS (ESI): 513 (M+H+, 100).
Anal. calcd. for C36H36N2O: C 84.34, H 7.08, N 5.46; found: C 84.26,
H 6.97, N 5.25.
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Supplementary material
Supplementary material is available with the article through
the journal Web site at http://nrcresearchpress.com/doi/suppl/
10.1139/cjc-2013-0435.
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The authors are grateful to the National Science Foundation of
China (Nos. 21162001 and 21202023), the National Key Technology
R&D Program of China (No. 2009BAI78B01), Jiangxi Province Key
Support Program (No. 2009BNB06200), Natural Science Foundation
of Jiangxi Province (No. 20132BAB203007), and Jiangxi Province
Office of Education Support Program (No. GJJ13666) for financial
support.
Published by NRC Research Press