Metal-free catalyzed oxidative trimerization of indoles by using TEMPO in air: A biomimetic approach to 2-(1H-indol-3-yl)-2,3′-biindolin-3-ones

Article abstract of DOI:10.1039/c2ob26390d

A simple, convenient and efficient metal-free catalyzed oxidative trimeric reaction of indoles toward a variety of 2-(1H-indol-3-yl)-2,3′-biindolin- 3-one derivatives in moderate to excellent yields has been developed. This transformation proceeds via a tandem oxidative homocoupling reaction by using TEMPO in air as an environmentally benign oxidant. This methodology provides an alternative approach for the direct generation of all-carbon quaternary centers at the C3 position of indoles. This journal is

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Metal-free catalyzed oxidative trimerization of indoles by using TEMPO in
air: a biomimetic approach to 2-(1H-indol-3-yl)-2,3′-biindolin-3-ones†
Wen-Bing Qin, Qiong Chang, Yun-Hong Bao, Ning Wang, Zheng-Wang Chen and Liang-Xian Liu*
Received 18th July 2012, Accepted 13th September 2012
DOI: 10.1039/c2ob26390d
A simple, convenient and efficient metal-free catalyzed oxidative trimeric reaction of indoles toward a
variety of 2-(1H-indol-3-yl)-2,3′-biindolin-3-one derivatives in moderate to excellent yields has been
developed. This transformation proceeds via a tandem oxidative homocoupling reaction by using TEMPO
in air as an environmentally benign oxidant. This methodology provides an alternative approach for the
direct generation of all-carbon quaternary centers at the C3 position of indoles.
Introduction
The recent demand for highly efficient and environmentally
benign syntheses of fine chemicals and pharmaceuticals has
encouraged the development of mild, safe, and highly chemo-
selective oxidizers. The radical TEMPO (2,2,6,6-tetramethyl-
piperidine 1-oxyl radical) is now used extensively in organic
synthesis and industrial applications as a mild, safe, and econ-
omical alternative to heavy metal reagents such as lead(IV),
manganese(IV), chromium(VI), and mercury(II) as highly selective
oxidation catalysts for the production of pharmaceuticals,
flavors, fragrances, agrochemicals, and a variety of other speci-
alty chemicals.1
Indole derivatives are important compounds that are wide-
spread in nature and exhibit significant biological activity2 and
Fig. 1 Representative natural products with
a 2,2′-disubstituent
indolin-3-one structural unit.
oxindole derivatives (Fig. 1) are known to possess a variety of
biological activities.3 For example, 2-(1H-indol-3-yl)-2,3′-bi-
indolin-3-one 1 was isolated as the product of indole oxidation
by a strain of Claviceps purpurea.4a This compound has also
been characterised from natural (bacterial) sources such as Vibrio
parahaemolyticus3a 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 Fort. (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 hepatitis.5 As such,
developing convenient methods for the construction of 2,2-dis-
ubstituted indolin-3-ones is 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
derivatives from indoles still remained elusive,7b,c although there
has been a report of its formation as a side product.8 For
example, Paola and co-workers reported that the oxidation of
5,6-dihydroxyindole in acidic aqueous media led to a mixture
of 5,6-dihydroxy oxindole and trimer.8 As part of ongoing
work on transition metal-free oxidative homo coupling of
indoles, we wish to report on successful metal-free catalyzed
biomimetic oxidative trimerization of indoles toward 2-(1H-
indol-3-yl)-2,3′-biindolin-3-one and its derivatives by using
TEMPO in air as an oxidant.
Results and discussion
Department of Chemistry and Chemical Engineering, Gannan Normal
University, Huanjin Campus, Ganzhou, Jiangxi 341000, P.R. China.
E-mail: liuliangxian1962@163.com; Fax: +86-797-8373670;
Tel: +86-797-8373670
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob26390d
In early experiments, we found that the trimerization of indole
took place in the presence of TEMPO (0.10 equiv.), pyridine
(0.50 equiv.) and benzoic acid (0.50 equiv.) in CH3CN at 50 °C,
but the protocol led to the formation of a mixture of products 5a
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find that the higher loading amounts of TEMPO result in a
dramatic influence on the yield (Table 1, entries 8–15). For
example, an 80% yield of trimerization production was obtained
when using 0.70 equiv. of TEMPO (Table 1, entry 13). Interest-
ingly, when more than 0.70 equiv. of TEMPO was employed,
it led to a decreased yield (Table 1, entries 14 and 15).
With respect to benzoic acid, it was also established that
0.50 equiv. of benzoic acid was indeed the preferred amount
with lower or higher loading giving poor yields (Table 1,
entries 13 and 22–25). Other acid additives, including substituted
benzoic acid with various substituent groups and acetic acid,
were also evaluated under the identical screening reaction con-
ditions and gave lower yields than benzoic acid (Table 1, entries
16–20). Notably, when TsOH was used, an unexpected trimer 7
was obtained in excellent yield and selectivity (Table 1,
entry 21).
Scheme 1 Trimeric reaction of indole by using TEMPO in air as an
oxidant.
The screening results demonstrated that the solvent effect
has an important influence on the reaction, other solvents,
such as CHCl3, THF, xylene, and 1,4-dioxane, were effective
for the reaction, but they were inferior to CH3CN (Table 1,
entries 26–29). Conversely, a trace amount of the desired product
was detected when DMF, DMSO, or pyridine was employed as
the solvent (Table 1, entries 31–33). After a great deal of screen-
ing on different parameters we found that the oxidative trimeric
reaction of indole by using TEMPO (70 mol%) in air as an
oxidant and benzoic acid (50 mol%) as an acid in acetonitrile
at 65 °C led to the highest efficiency (80% yield, Table 1,
entry 13).
After having optimized the conditions, the scope and general-
ity of the reaction was studied. A variety of representative indole
derivatives were subjected to the optimized conditions, as
depicted in Table 2. Thus, a trimeric reaction of substituted
indoles proceeded slowly to provide corresponding 2-(1H-indol-
3-yl)-2,3′-biindolin-3-one derivatives in moderate to excellent
yields. The reaction can tolerate a variety of functional groups at
the 1, 4, 5, 6, and 7 positions of indoles. The results have shown
that electronegativities of substituents played a major role in gov-
erning the reactivity of the substrates. Electron-rich groups
showed better results than electron-withdrawing groups in this
trimerization. For example, N-(1H-indol-5-yl)acetamide was
transformed into trimer 5g in 93% yield (Table 2, entry 7). Sub-
strates with a strong electron-withdrawing group at C-5, such as
NO2, disfavored the trimerization. When 5-nitro-1H-indole was
subjected to the optimized conditions, no desired product was
obtained (Table 2, entry 8), indicating a high level of sensitivity
to the electronics of the indole ring, presumably because elec-
tron-withdrawing substituents reduce the reactivity of substrates
in the acid-promoted dimerization of substrates.8,9
It is worth noting that some other substrates such as methyl
1H-indole-5-carboxylate and methyl 1H-indole-6-carboxylate
gave a mixture of trimer and dimer under the present conditions
due to their low reactivity. For instance, 5i and 8b were formed
in 75% total yields with a ratio of 1 : 2 when methyl 1H-indole-
5-carboxylate was subjected to the optimized conditions
(Table 2, entry 10). Similarly, 5k and 8c were formed in 62%
total yields with a ratio of 1 : 5 when methyl 1H-indole-6-
carboxylate was subjected to the optimized conditions (Table 2,
entry 12). In addition, only 15% of the dimer 8a was obtained
and no desired trimer was obtained when 1H-indole-5-
Fig. 2 ORTEP representation of the molecular structure of 5a with
H atoms omitted for clarity.
and 6 in low yields (Scheme 1, condition A). Changing pyridine
to triethylamine, and carrying out the reaction either at room or
elevated temperature was also not encouraging. Interestingly, a
significant improvement in the regioselectivity was realized in
the absence of pyridine, since 5a was the sole trimerization
product under the reaction conditions (Scheme 1, condition B),
and its molecular structure was confirmed by X-ray crystallo-
graphy (Fig. 2). The corresponding 3-(1H-indol-3-yl)-3,3′-bi-
indolin-2-one product 6 was not identified.
Based on these promising initial results we decided to opti-
mize the reaction conditions further to increase the reaction
yield, and the results are summarized in Table 1. As shown in
Table 1, the reaction showed a significant dependence on temp-
erature. When the reaction was treated at 25 °C, trace amounts of
5a were obtained (Table 1, entry 1). When the reaction mixture
was warmed to 65 °C, the desired product was formed in 42%
yield (Table 1, entry 5). A higher temperature (80 °C) led to a
decreased yield possibly due to other side reactions (Table 1,
entry 6).
In addition, the corresponding reaction “on oxygene” gave a
lower yield than air (Table 1, entry 7). It was also found that the
use of TEMPO and benzoic acid is critical to the reaction. In the
absence of TEMPO or benzoic acid, the trimerization reaction
did not proceed (Table 1, entries 3 and 4). It was unexpected to
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Table 1 Optimization of the reaction conditionsa
Entry
TEMPO (mmol)
Acid (mmol)
Temp. (°C)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
0.1
0.1
0.1
0
Benzoic acid (0.5)
Benzoic acid (0.5)
0
25
50
50
50
65
80
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
Trace
30
0
0
42
Benzoic acid (0.5)
Benzoic acid (0.5)
Benzoic acid (0.5)
Benzoic acid (0.5)
Benzoic acid (0.5)
Benzoic acid (0.5)
Benzoic acid (0.5)
Benzoic acid (0.5)
Benzoic acid (0.5)
Benzoic acid (0.5)
Benzoic acid (0.5)
Benzoic acid (0.5)
m-Methoxybenzoic acid (0.5)
p-Methylbenzoic acid (0.5)
p-Nitrobenzoic acid (0.5)
o-Nitrobenzoic acid (0.5)
Acetic acid (0.5)
0.1
0.1
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
1.0
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.7
21
17c
45
9
48
52
57
69
80
69
60
70
65
43
40
Trace
82d
30
40
46
48
77
65
61
57
10
Trace
Trace
Trace
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
TsOH (0.5)
Benzoic acid (0.15)
Benzoic acid (0.3)
Benzoic acid (0.7)
Benzoic acid (1.0)
Benzoic acid (0.5)
Benzoic acid (0.5)
Benzoic acid (0.5)
Benzoic acid (0.5)
Benzoic acid (0.5)
Benzoic acid (0.5)
Benzoic acid (0.5)
Benzoic acid (0.5)
Xylene
1,4-Dioxane
HOAc
DMF
DMSO
Pyridine
a Reaction conditions: indole (1.0 mmol), solvent (0.6 mL), and oil bath for 3 days. b Isolated yield. c Reaction conditions: indole (1.0 mmol), CH3CN
(0.6 mL) and O2 (balloon, 1 atm) at 65 °C for 3 days. d Compound 7 was obtained.
carbonitrile was subjected to the optimized conditions (Table 2,
entry 9).
with excellent regioselectivity under mild conditions. This reac-
tion provides a novel method for the generation of all-carbon
quaternary centers at the C3 position of indoles. Moreover, it has
several advantages. (1) An inexpensive and environmentally
friendly TEMPO has been used in air as an oxidant. (2) The
operationally simple and metal-free procedure and broad sub-
strate make it potentially useful. (3) It is highly regioselective
(2,3′-linkage). (4) This trimeric reaction proceeds without exclu-
sion of moisture or air from the reaction mixture and allows the
isolation of the desired 2,2-disubstituted indolin-3-one deriva-
tives in moderate to excellent yields. Currently, our method is
limited to the homo trimerization of N-protected and free indole
derivatives. The development of a cross-coupling trimerization is
currently under way in our lab and will be the subject of future
work.
To confirm the effect of dioxygen, the trimeric reaction was
attempted in the absence of dioxygen (Scheme 2). The result
showed that the reaction was carried out inefficiently, and the
desired product 5a was obtained with a poor yield of 25%. The
result demonstrated that dioxygen is necessary for an efficient
trimeric reaction.
Conclusions
In summary, we have successfully developed a novel, operation-
ally simple, and practical biomimetic synthetic method for the
trimerization of indoles by using TEMPO in air as an oxidant
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Table 2 Trimeric reaction of indoles by using TEMPO in air as an oxidanta
Entry
R1
R2
Product
Yieldb (%)
1
2
3
4
5
6
7
8
H
5-Br
5-F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
5a
5b
5c
5d
5e
5f
5g
5h
8a
5i + 8b
5j
5k + 8c
5l
5m
5n
80
68
71
73
76
72
93
0
15
75c
54
62c
92
68
70
5-CH3
5-OCH3
5-OBn
5-NHAc
5-NO2
5-CN
5-CO2CH3
6-F
6-CO2CH3
7-CH3
4-OCH3
H
9
10
11
12
13
14
15
a Reaction conditions: indole (1.0 mmol), benzoic acid (0.5 mmol), TEMPO (0.7 mmol), CH3CN (0.6 mL), 65 °C. b Isolated yield. c Combined yield
5 and 8.
eluting (unless otherwise stated) with an ethyl acetate–petroleum
ether (PE) (60–90 °C) mixture.
General procedure for the preparation of 2-(1H-indol-3-yl)-
2,3′-biindolin-3-ones. To a solution of indole (1.0 mmol) and
TEMPO (0.7 mmol) in CH3CN (0.6 mL) was added benzoic
acid (0.5 mmol) under atmosphere and the mixture was stirred at
65 °C for 3 days. The reaction mixture was concentrated under
reduced pressure. The residue was purified by flash chromato-
graphy on silica gel (eluent: EtOAc–PE = 1 : 2) to yield the
Scheme 2 Trimeric reaction of indole with TEMPO as an oxidant
corresponding product.
under an Ar atmosphere.
Experimental section
General
Melting points were determined on a digital melting point appar-
atus and temperatures were uncorrected. Infrared spectra were
measured with a Nicolet Avatar 360 FT-IR spectrometer using
film KBr pellet techniques. 1H and 13C NMR spectra were
recorded on Bruker spectrometers at 400 and 100 MHz, respecti-
vely. Chemical shifts were reported in ppm relative to TMS for
1H and 13C NMR spectra. CDCl3 or DMSO-d6 was used as the
NMR solvent. Mass spectra were recorded with a Bruker Dalton
Esquire 3000 plus LC-MS apparatus. Elemental analysis was
carried out on a Perkin-Elmer 240B instrument. HRFABMS
spectra were recorded on an FTMS apparatus. Silica gel
(300–400 mesh) was used for flash column chromatography,
2-(1H-Indol-3-yl)-2,3′-biindolin-3-one, 5a. Yellow solid, mp:
241.5–244 °C (from EtOAc–PE = 1 : 2) (lit.8 mp: 243–245.5).
IR (KBr) νmax: 3375, 3296, 1677, 1612, 1462, 1328, 1098,
746 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 10.94 (s, 1H, NH,
D2O exchangeable), 10.93 (s, 1H, NH, D2O exchangeable), 8.10
(s, 1H, NH, D2O exchangeable), 7.45 (t, J = 8.0 Hz, 1H, Ar-H),
7.43 (d, J = 7.6 Hz, 1H, Ar-H), 7.32 (d, J = 8.0 Hz, 2H, Ar-H),
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7.28 (d, J = 8.0 Hz, 2H, Ar-H), 7.05 (d, J = 2.5 Hz, 2H, Ar-H),
6.99 (dt, J = 1.0, 8.0 Hz, 2H, Ar-H), 6.91 (d, J = 8.0 Hz, 1H,
Ar-H), 6.78 (dt, J = 1.0, 8.0 Hz, 2H, Ar-H), 6.69 (dt, J = 1.0, 7.6
Hz, 1H, Ar-H). 13C NMR (100 MHz, DMSO-d6): δ 201.3,
161.0, 137.9, 137.4, 126.1, 124.9, 124.5, 121.5, 121.0, 118.8,
118.2, 117.5, 114.4, 112.3, 112.1, 68.1. HRESIMS calcd for
[C24H17ON3 + H]+ 364.1450, found 364.1443. These assign-
ments matched those previously published.4
5,5′-Dimethyl-2-(5-methyl-1H-indol-3-yl)-2,3′-biindolin-3-one,
5d. Yellow solid, mp: 161–163 °C (from EtOAc–PE = 1 : 2). IR
(KBr) νmax: 3449, 3385, 3322, 1683, 1623, 1494, 1427, 796 cm−1
.
1H NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H, NH), 10.76 (s,
1H, NH), 7.79 (s, 1H, NH), 7.31 (dd, J = 8.4, 1.7 Hz, 1H, Ar-H),
7.23 (s, 1H, Ar-H), 7.20 (d, J = 8.1 Hz, 2H, Ar-H), 7.07 (s, 2H,
Ar-H), 6.98 (d, J = 2.5 Hz, 2H, Ar-H), 6.85 (d, J = 8.4 Hz, 1H,
Ar-H), 6.82 (dd, J = 8.4, 1.3 Hz, 2H, Ar-H), 2.21 (s, 3H, CH3),
2.18 (s, 6H, 2CH3). 13C NMR (100 MHz, DMSO-d6): δ 201.3,
159.6, 139.1, 135.8, 126.9, 126.4, 126.3, 124.5, 124.1, 123.1,
120.7, 118.5, 114.1, 112.4, 111.7, 68.5, 21.9, 20.6. HRESIMS
calcd for [C27H23ON3 + H]+ 406.1919, found 406.1905.
5,5′-Dibromo-2-(5-bromo-1H-indol-3-yl)-2,3′-biindolin-3-one,
5b. Yellow solid, mp: 247–249 °C (from EtOAc–PE = 1 : 2). IR
(KBr) νmax: 3448, 3395, 3318, 1682, 1623, 1494, 1427, 1103,
795 cm−1 1H NMR (400 MHz, DMSO-d6): δ 11.27 (s, 1H,
.
NH), 11.26 (s, 1H, NH), 8.51 (s, 1H, NH), 7.62 (dd, J = 8.6, 2.4
Hz, 1H, Ar-H), 7.58 (d, J = 2.0 Hz, 1H, Ar-H), 7.36 (d, J =
2.0 Hz, 2H, Ar-H), 7.32 (d, J = 8.6 Hz, 2H, Ar-H), 7.19 (d, J =
2.4 Hz, 2H, Ar-H), 7.13 (dd, J = 8.6, 2.0 Hz, 2H, Ar-H), 6.92
(d, J = 8.6 Hz, 1H, Ar-H). 13C NMR (100 MHz, DMSO-d6):
δ 199.5, 159.6, 140.5, 136.2, 127.6, 127.1, 125.9, 124.3, 122.8,
119.4, 114.6, 114.4, 113.3, 111.8, 108.8, 68.2. HRESIMS calcd
for [C24H14ON3Br3 + H]+ 597.8765, 599.8745, 601.8724, found
597.8759, 599.8732, 601.8708.
5,5′-Dimethoxy-2-(5-methoxy-1H-indol-3-yl)-2,3′-biindolin-3-
one, 5e. Yellow solid, mp: 226–228 °C (from EtOAc–PE = 1 : 3)
(lit.1 mp: 201–203). IR (KBr) νmax: 3404, 3033, 1679, 1489,
1445, 1214, 1022 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 10.77
(s, 1H, NH), 10.76 (s, 1H, NH), 7.77 (s, 1H, NH), 7.23 (s, J = 8.8
Hz, 2H, Ar-H), 7.19 (d, J = 2.7 Hz, 1H, Ar-H), 7.02 (d, J = 2.6
Hz, 2H, Ar-H), 6.95 (d, J = 2.6 Hz, 1H, Ar-H), 6.92 (d, J = 8.8
Hz, 1H, Ar-H), 6.79 (d, J = 2.4 Hz, 2H, Ar-H), 6.69 (d, J = 2.4
Hz, 1H, Ar-H), 6.66 (d, J = 2.4 Hz, 1H, Ar-H), 3.69 (s, 3H, CH3),
3.51 (s, 6H, 2CH3). 13C NMR (100 MHz, DMSO-d6): δ 201.7,
157.3, 153.0, 152.2, 132.6, 128.2, 126.5, 125.2, 118.5, 114.1,
113.9, 112.5, 111.0, 105.0, 103.5, 68.9, 56.0, 55.5. HRESIMS
calcd for [C27H23O4N3 + H]+ 454.1767, found 454.1749.
5,5′-Difluoro-2-(5-fluoro-1H-indol-3-yl)-2,3′-biindolin-3-one,
5c. Yellow solid, mp: 90–92 °C (from EtOAc–PE = 1 : 4). IR
(KBr) νmax: 3406 (br s), 1692, 1489, 1455, 1255, 1177,
1
802 cm−1. H NMR (400 MHz, CDCl3): δ 8.26 (s, 2H, NH),
7.33 (dd, J = 8.8, 2.6 Hz, 1H, Ar-H), 7.26 (dt, J = 2.6, 8.8 Hz,
1H, Ar-H), 7.19 (d, J = 8.8 Hz, 1H, Ar-H), 7.18 (d, J = 8.8 Hz,
1H, Ar-H), 7.07 (d, J = 2.6 Hz, 2H, Ar-H), 7.01 (d, J = 2.4 Hz,
1H, Ar-H), 6.98 (d, J = 2.4 Hz, 1H, Ar-H), 6.87 (dd, J = 9.0,
3.0 Hz, 2H, Ar-H), 6.84 (dd, J = 9.0, 3.0 Hz, 1H, Ar-H), 5.3 (s,
1H, NH). 13C NMR (100 MHz, CDCl3): δ 201.0, 158.8, 157.0,
156.5, 133.5, 126.0 (d, J = 26.0 Hz), 125.7 (d, J = 9.9 Hz),
125.5, 120.2 (d, J = 7.3 Hz), 114.5 (d, J = 4.7 Hz), 114.3 (d, J =
7.3 Hz), 112.2 (d, J = 9.9 Hz), 110.9 (d, J = 26.0 Hz), 110.1 (d,
J = 23.4 Hz), 105.2 (d, J = 23.4 Hz), 69.0. HRESIMS calcd for
[C24H14ON3F3 + H]+ 418.1167, found 418.1162.
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5,5′-Bis(benzyloxy)-2-(5-benzyloxy-1H-indol-3-yl)-2,3′-biindolin-
3-one, 5f. Yellow solid, mp: 91–92 °C (from EtOAc–PE = 1 : 2).
IR (KBr) νmax: 3399 (br s), 1688, 1488, 1455, 1203 cm−1
.
1H NMR (400 MHz, CDCl3): δ 8.04 (s, 2H, NH), 7.40–7.35
(m, 3H, Ar-H), 7.33 (s, 1H, NH), 7.32–7.24 (m, 13H, Ar-H),
7.22 (d, J = 2.4 Hz, 1H, Ar-H), 7.13 (d, J = 8.8 Hz, 2H, Ar-H),
6.92 (d, J = 2.3 Hz, 2H, Ar-H), 6.90 (d, J = 2.3 Hz, 2H, Ar-H),
6.86 (d, J = 2.4 Hz, 1H, Ar-H), 6.84 (d, J = 2.4 Hz, 1H, Ar-H),
6.80 (d, J = 8.8 Hz, 1H, Ar-H), 4.96 (s, 2H, CH2), 4.82 (s, 4H,
2CH2). 13C NMR (100 MHz, CDCl3): δ 202.1, 156.4, 153.0,
152.9, 137.5, 136.7, 132.3, 128.8, 128.6, 128.5, 128.1, 127.7,
127.6, 127.5, 126.0, 125.0, 120.5, 114.7, 114.4, 113.0,
112.3, 106.4, 103.8, 70.7, 70.6, 69.3. HRESIMS calcd for
[C45H35O4N3 + H]+ 682.2706, found 682.2692.
Dimethyl 2-(5-(methoxycarbonyl)-1H-indol-3-yl)-3-oxo-2,3′-
biindoline-5,5′-dicarboxylate, 5i. Yellow solid, mp: 111–113 °C
(from EtOAc–PE = 1 : 2). IR (KBr) νmax: 3337 (br s), 1702,
1618, 1436, 1310, 1249 cm−1. 1H NMR (400 MHz, DMSO-d6):
δ 11.48 (s, 1H, NH), 11.47 (s, 1H, NH), 9.16 (s, 1H, NH), 8.08
(dd, J = 8.7, 1.6 Hz, 1H, Ar-H), 8.03 (s, 1H, Ar-H), 8.00 (s, 2H,
Ar-H), 7.67 (dd, J = 8.6, 1.6 Hz, 2H, Ar-H), 7.43 (d, J = 8.6 Hz,
2H, Ar-H), 7.27 (d, J = 2.4 Hz, 2H, Ar-H), 6.99 (d, J = 8.7 Hz,
1H, Ar-H), 3.78 (s, 3H, CH3), 3.69 (s, 6H, 2CH3). 13C NMR
(100 MHz, DMSO-d6): δ 199.9, 167.5, 166.2, 162.8, 140.1,
129.0, 127.4, 126.5, 125.3, 123.6, 122.8, 120.7, 118.7, 117.4,
114.9, 112.3, 112.0, 68.6, 52.3, 52.1. HRESIMS calcd for
[C30H23O7N3 + H]+ 538.1614, found 538.1597.
N,N′-(2-(5-Acetamido-1H-indol-3-yl)-3-oxo-2,3′-biindoline-5,5′-
diyl)diacetamide, 5g. Yellow solid, mp: 153–155 °C (from
EtOAc–EtOH = 10 : 1). IR (KBr) νmax: 3271 (br s), 1662, 1621,
1553, 1492, 1375 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 10.90
(s, 2H, NH), 9.88 (s, 1H, NH), 9.61 (s, 2H, NH), 7.75 (d, J =
1.8 Hz, 1H, Ar-H), 7.64 (s, 1H, NH), 7.56 (dd, J = 8.8, 2.0 Hz,
1H, Ar-H), 7.39 (dd, J = 8.8, 1.8 Hz, 2H, Ar-H), 7.29 (s, 2H, Ar-
H), 7.22 (d, J = 8.8 Hz, 2H, Ar-H), 7.01 (d, J = 2.4 Hz, 2H, Ar-
H), 6.89 (d, J = 8.8 Hz, 1H, Ar-H), 1.99 (s, 3H, CH3), 1.89 (s, 6H,
2CH3). 13C NMR (100 MHz, DMSO-d6): δ 201.1, 168.2, 168.0,
157.8, 134.3, 131.3, 130.5, 129.7, 128.8, 125.9, 125.3, 117.8,
116.2, 114.3, 112.7, 112.1, 111.5, 68.9, 24.2, 24.1. HRESIMS
calcd for [C30H26O4N6 + H]+ 535.2094, found 535.2084.
Dimethyl 2-oxo-3,3′-biindoline-5,5′-dicarboxylate, 8b. White
solid, mp: 144–146 °C (from EtOAc–PE = 1 : 2). IR (KBr) νmax
:
3332 (br s), 1705, 1620, 1435, 1315, 1256 cm−1 1H NMR
.
(400 MHz, DMSO-d6): δ 11.40 (d, J = 2.3 Hz, 1H, NH), 10.79
(s, 1H, NH), 8.36 (s, 1H, Ar-H), 7.92 (dd, J = 8.2, 1.8 Hz, 1H,
Ar-H), 7.81 (d, J = 1.8 Hz, 1H, Ar-H), 7.67 (dd, J = 8.6, 1.8 Hz,
1H, Ar-H), 7.40 (d, J = 8.6 Hz, 1H, Ar-H), 7.03 (d, J = 2.3 Hz,
1H, Ar-H), 7.00 (d, J = 8.2 Hz, 1H, Ar-H), 6.64 (s, 1H), 3.78 (s,
3H, CH3), 3.75 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6):
δ 178.8, 167.7, 166.5, 146.8, 140.0, 133.7, 132.1, 126.0, 125.8,
125.1, 124.3, 123.6, 122.7, 120.6, 116.7, 112.1, 110.2, 74.9,
52.3, 52.1. MS (ESI): 365 (M + H+, 100), 387 (M + Na+, 25).
Anal calcd for C20H16N2O5: C, 65.93; H, 4.43; N, 7.69. Found
C, 66.12; H, 4.29; N, 7.92.
2-Oxo-3,3′-biindoline-5,5′-dicarbonitrile, 8a. White solid, mp:
67–68 °C (from EtOAc–PE = 1 : 1). IR (KBr) νmax: 3322 (br s),
2225, 1728, 1619, 1484, 1122 cm−1 1H NMR (400 MHz,
.
DMSO-d6): δ 11.67 (s, 1H, NH), 10.90 (s, 1H, NH), 8.22 (s, 1H,
Ar-H), 7.79 (dd, J = 8.1, 1.6 Hz, 1H, Ar-H), 7.75 (d, J = 2.5 Hz,
1H, Ar-H), 7.53 (d, J = 8.5 Hz, 1H, Ar-H), 7.45 (dd, J = 8.5,
1.6 Hz, 1H, Ar-H), 7.09 (d, J = 2.5 Hz, 1H, Ar-H), 7.06 (d, J =
8.1 Hz, 1H, Ar-H), 6.78 (s, 1H). 13C NMR (100 MHz, DMSO-
d6): δ 178.4, 146.5, 139.2, 135.3, 133.9, 128.8, 127.5, 126.9,
125.4, 124.5, 121.2, 119.8, 115.6, 113.6, 111.2, 104.5, 101.3,
74.6. MS (ESI): 299 (M + H+, 100), 321 (M + Na+, 10). Anal
calcd for C18H10N4O: C, 72.23; H, 3.70; N, 18.72. Found C,
72.05; H, 4.07; N, 18.45.
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Na+, 25). Anal calcd for C20H16N2O5: C, 65.93; H, 4.43; N,
7.69. Found C, 65.79; H, 4.71; N, 7.60.
6,6′-Difluoro-2-(6-fluoro-1H-indol-3-yl)-2,3′-biindolin-3-one,
5j. Yellow solid, mp: 78–79 °C (from EtOAc–PE = 1 : 1). IR
(KBr) νmax: 3469, 3355 (br s), 1675, 1625, 1592, 1457, 1300,
1
1144, 1096 cm−1. H NMR (400 MHz, DMSO-d6): δ 11.12 (s,
2H, NH), 8.54 (s, 1H, NH), 7.55 (dd, J = 8.6, 5.8 Hz, 1H, Ar-
H), 7.24 (dd, J = 8.6, 5.8 Hz, 2H, Ar-H), 7.16 (dd, J = 10.2, 2.4
Hz, 2H, Ar-H), 7.12 (d, J = 2.4 Hz, 2H, Ar-H), 6.75 (dt, J = 2.4,
9.4 Hz, 2H, Ar-H), 6.64 (dd, J = 10.2, 2.1 Hz, 1H, Ar-H), 6.54
(dt, J = 2.1, 9.4 Hz, 1H, Ar-H). 13C NMR (100 MHz, DMSO-
d6): δ 199.1, 162.3 (d, J = 14.6 Hz), 158.0, 137.2 (d, J = 12.8
Hz), 129.7, 129.0, 127.9 (d, J = 12.8 Hz), 125.1, 122.7, 121.7
(d, J = 10.1 Hz), 114.9, 114.2, 107.6 (d, J = 14.6 Hz), 106.1 (d,
J = 25.0 Hz), 98.0 (d, J = 25.0 Hz), 68.5. HRESIMS calcd for
[C24H14ON3F3 + H]+ 418.1167, found 418.1162.
7,7′-Dimethyl-2-(7-methyl-1H-indol-3-yl)-2,3′-biindolin-3-one,
5l. Yellow solid, mp: 121–123 °C (from EtOAc–PE = 1 : 2). IR
(KBr) νmax: 3410 (br s), 1692, 1606, 1498, 1433, 786,
1
749 cm−1. H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H, NH),
8.07 (s, 1H, NH), 7.59 (d, J = 7.5 Hz, 1H, Ar-H), 7.33 (d, J =
7.0 Hz, 1H, Ar-H), 7.23 (d, J = 8.8 Hz, 2H, Ar-H), 6.96–6.87
(m, 6H, Ar-H), 6.83 (t, J = 7.5 Hz, 1H, Ar-H), 5.28 (s, 1H), 2.39
(s, 6H, 2CH3), 2.19 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3):
δ 202.0, 159.7, 137.5, 136.6, 125.3, 124.3, 122.8, 122.6, 122.0,
120.8, 120.0, 119.6, 119.5, 118.0, 115.3, 68.5, 16.6, 15.8.
HRESIMS calcd for [C27H23ON3 + H]+ 406.1919, found 406.1905.
Dimethyl 2-(6-(methoxycarbonyl)-1H-indol-3-yl)-3-oxo-2,3′-
biindoline-6,6′-dicarboxylate, 5k. Yellow solid, mp: 154–156 °C
(from EtOAc–PE = 1 : 2). IR (KBr) νmax: 3349 (br s), 1708,
1621, 1454, 1319, 1277, 1218 cm−1 1H NMR (400 MHz,
.
DMSO-d6): δ 11.48 (s, 1H, NH), 11.47 (s, 1H, NH), 8.50 (s, 1H,
NH), 7.58 (d, J = 8.0 Hz, 1H, Ar-H), 8.02 (s, 2H, Ar-H), 7.50 (s,
1H, Ar-H), 7.44 (dd, J = 8.5, 1.2 Hz, 2H, Ar-H), 7.38 (d, J = 2.5
Hz, 2H, Ar-H), 7.27 (d, J = 8.5 Hz, 2H, Ar-H), 7.25 (dd, J =
8.0, 1.2 Hz, 1H, Ar-H), 3.84 (s, 3H, CH3), 3.78 (s, 6H, 2CH3).
13C NMR (100 MHz, DMSO-d6): δ 200.8, 167.5, 166.4, 160.5,
138.0, 136.8, 129.4, 129.0, 128.5, 125.6, 122.8, 120.9, 120.5,
119.7, 118.1, 114.3, 113.2, 68.4, 53.0, 52.3. HRESIMS calcd for
[C30H23O7N3 + H]+ 538.1614, found 538.1600.
4,4′-Dimethoxy-2-(4-methoxy-1H-indol-3-yl)-2,3′-biindolin-3-
one, 5m. Red solid, mp: 185–187 °C (from EtOAc–PE = 2 : 1).
IR (KBr) νmax: 3389 (br s), 1687, 1613, 1501, 1262, 1088 cm−1
.
1H NMR (400 MHz, CDCl3): δ 8.26 (s, 2H, NH), 7.25 (t, J =
8.1 Hz, 1H, Ar-H), 7.04 (s, 1H, N-H), 6.94 (t, J = 7.8 Hz, 2H,
Ar-H), 6.76 (d, J = 8.1 Hz, 2H, Ar-H), 6.53 (s, 2H, Ar-H), 6.38
(d, J = 7.8 Hz, 2H, Ar-H), 6.31 (d, J = 8.1 Hz, 1H, Ar-H), 6.12
(d, J = 8.1 Hz, 1H, Ar-H), 3.88 (s, 3H, CH3), 3.46 (s, 6H,
2CH3). 13C NMR (100 MHz, CDCl3): δ 199.6, 161.1, 159.3,
153.0, 138.7, 137.5, 125.2, 122.4, 116.4, 114.5, 109.9, 105.1,
104.8, 100.2, 98.2, 67.5, 55.6, 54.9. HRESIMS calcd for
[C27H23O4N3 + H]+ 454.1767, found 454.1754.
Dimethyl 2-oxo-3,3′-biindoline-6,6′-dicarboxylate, 8c. White
solid, mp: 240–242 °C (from EtOAc–PE = 1 : 2). IR (KBr) νmax
:
3329 (br s), 1703, 1617, 1436, 1312, 1253 cm−1 1H NMR
.
(400 MHz, DMSO-d6): δ 11.43 (d, J = 2.3 Hz, 1H, NH), 10.57
(s, 1H, NH), 8.00 (s, 1H, Ar-H), 7.60 (dd, J = 7.7, 1.2 Hz, 1H,
Ar-H), 7.56 (dd, J = 8.5, 1.0 Hz, 1H, Ar-H), 7.51 (dd, J = 8.5,
1.2 Hz, 1H, Ar-H), 7.41 (d, J = 1.0 Hz, 1H, Ar-H), 7.38 (d, J =
7.7 Hz, 1H, Ar-H), 7.25 (d, J = 2.3 Hz, 1H, Ar-H), 6.64 (s, 1H),
3.82 (s, 3H, CH3), 3.79 (s, 3H, CH3). 13C NMR (100 MHz,
DMSO-d6): δ 178.4, 167.6, 166.4, 142.5, 138.6, 136.6, 130.9,
128.9, 127.9, 125.4, 123.9, 122.8, 120.8, 119.7, 115.7, 114.1,
110.3, 75.0, 52.7, 52.2. MS (ESI): 365 (M + H+, 100), 387 (M +
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1,1′-Dimethyl-2-(1-methyl-1H-indol-3-yl)-2,3′-biindolin-3-one,
5n. Yellow solid, mp: 271–273 °C (from EtOAc–PE = 1 : 4). IR
Jiangxi Province (No: 2009GZH0013) and Jiangxi Province
Office of Education Support Program (No: GJJ10718) for
financial support.
(KBr) νmax: 3050, 1697, 1614, 1325, 1293 cm−1 1H NMR
.
(400 MHz, CDCl3): δ 7.61 (dt, J = 7.3, 1.0 Hz, 2H, Ar-H), 7.35
(d, J = 8.1 Hz, 2H, Ar-H), 7.29 (d, J = 8.1 Hz, 2H, Ar-H), 7.17
(dt, J = 8.1, 1.0 Hz, 2H, Ar-H), 6.99 (s, 2H, Ar-H), 6.96 (dt, J =
8.1, 1.0 Hz, 2H, Ar-H), 6.82 (d, J = 8.1 Hz, 1H, Ar-H), 6.73 (t,
J = 7.3 Hz, 1H, Ar-H), 3.71 (s, 6H, 2CH3), 2.95 (s, 3H, CH3).
13C NMR (100 MHz, CDCl3): δ 200.8, 159.8, 137.8, 137.7,
129.3, 126.3, 125.7, 121.7, 121.6, 119.4, 118.6, 116.8, 111.3,
109.4, 107.9, 72.8, 32.9, 29.5. HRESIMS calcd for [C27H23ON3
+ Na]+ 428.1739, found 428.1709.
Notes and references
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2-(2,2-Di(1H-indol-3-yl)ethyl)benzenaminium benzenesulfo-
nate, 7. Waxy solid. IR (KBr) νmax: 3250 (br s), 1603, 1496,
1
1450, 1078 cm−1. H NMR (400 MHz, DMSO-d6): δ 10.72 (s,
1H, NH), 10.71 (s, 1H, NH), 9.90–9.30 (s, 3H, NH), 7.51 (d,
J = 8.0 Hz, 2H, Ar-H), 7.46 (d, J = 8.0 Hz, 2H, Ar-H), 7.27 (d,
J = 8.0 Hz, 1H, Ar-H), 7.25 (d, J = 8.0 Hz, 2H, Ar-H), 7.21 (d,
J = 2.2 Hz, 2H, Ar-H), 7.15 (dt, J = 2.2, 8.0 Hz, 1H, Ar-H),
7.07 (d, J = 8.0 Hz, 2H, Ar-H), 7.03 (s, 2H, Ar-H), 6.96 (t, J =
7.3 Hz, 2H, Ar-H), 6.83 (t, J = 7.3 Hz, 2H, Ar-H), 4.94 (t, J =
7.8 Hz, 1H), 3.58 (d, J = 7.8 Hz, 2H), 2.25 (s, 3H, CH3). 13C
NMR (100 MHz, DMSO-d6): δ 145.9, 138.3, 136.9, 134.4,
131.6, 130.5, 128.6, 127.6, 127.3, 127.0, 126.0, 123.2, 122.8,
121.1, 119.5, 118.4, 118.3, 111.8, 35.5, 32.3, 21.2. MS (ESI):
524 (M + H+, 100).
Acknowledgements
8 P. Manini, M. d’Ischia, M. Milosa and G. Prota, J. Org. Chem., 1998, 63,
7002–7008.
9 (a) N. Wahlström, J. Slätt, B. Stensland, A. Ertan, J. Bergman and
T. Janosik, J. Org. Chem., 2007, 72, 5886–5889; (b) H. Ishii,
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Perkin Trans. 1, 1988, 2377–2385.
The authors are grateful to the NSF 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
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2012