TFA-catalyzed C-N bond activation of enamides with indoles: Efficient synthesis of 3,3-bisindolylpropanoates and other bisindolylalkanes

Article abstract of DOI:10.1016/j.tet.2012.11.098

An efficient TFA-catalyzed cleavage of C-N bonds in alkylation of indoles by tertiary enamides was described. A variety of bisindolylalkane derivatives, especially 3,3-bisindolylpropanoates, were expeditiously synthesized in good yields.

Full text of DOI:10.1016/j.tet.2012.11.098

Tetrahedron 69 (2013) 1600e1605
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Tetrahedron
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TFA-catalyzed CeN bond activation of enamides with indoles:
efficient synthesis of 3,3-bisindolylpropanoates and other
bisindolylalkanes
*
*
Hai-Yan Xu, You Zi, Xiao-Ping Xu, Shun-Yi Wang , Shun-Jun Ji
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 July 2012
Received in revised form 22 November 2012
Accepted 30 November 2012
Available online 7 December 2012
An efficient TFA-catalyzed cleavage of CeN bonds in alkylation of indoles by tertiary enamides was
described. A variety of bisindolylalkane derivatives, especially 3,3-bisindolylpropanoates, were expedi-
tiously synthesized in good yields.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
CeN bonds activation
Enamides
Indoles
3,3-Bisindolylpropanoates
Bisindolylalkanes
1. Introduction
The indole ring system exists ubiquitously in nature-occurring
products, and many indole-containing compounds exhibit impor-
tant biological activities and synthetic applications.1 As a part of
them, many of the most important 3,3-bisindolylalkane derivatives
were widely isolated from various terrestrial and marine natural
sources, which possess novel structures and exhibit a range of
important biological activities,2 such as bis(3-indolyl)methane,
recently reviewed in cancer chemotherapy, had numerous activi-
ties.3 Therefore, various synthetic strategies to synthesize 3,3-
bisindolylalkane compounds were studied. The standard method
for the synthesis of 3,3-bisindolylalkanes was the FriedeleCrafts
reaction between indole and carbonyl compounds in the presence
of acid or base4(Scheme 1a), however, 3,3-bisindolylpropanoates
could not be synthesized by the traditional FriedeleCrafts reaction
of indoles with the corresponding aldehydes. What’s more, a lot of
work was also devoted to the addition of indoles to electron-neutral
or electron-deficient alkenes, which were activated by a conjugated
electron-withdrawing group, such as ester, amide, and sulfone5
(Scheme 1b). To the best of our knowledge, there has not been
a general strategy to synthesize 3,3-bisindolylpropanoates and
3,3-bisindolylalkanes. Besides, only our group6 and Zhang’s group7
have recently reported the metal-catalyzed addition of indoles to
enamides, but to form the direct alkylation products, respectively.
Scheme 1. Strategies of synthesis of bisindolylalkane derivatives.
As a continuation of our work on synthesis of indole derivatives
and using enamides as a synthetic, we wanted to synthesize
more 2-oxo-1-pyrrolidine moieties bearing indoles ubiquitous
structural, which constituted in a wide variety of pharmacologically
and biologically active compounds.8 To our surprise, we recently
found a highly efficient TFA-catalyzed cleavage of CeN bonds of
different substituted tertiary enamides with indoles to synthesize
bis(indolyl)alkane compounds (Scheme 1c). Herein, we reported
our results.
2. Results and discussion
For the initial study, (E)-methyl 3-(2-oxopyrrolidin-1-yl)acry-
late (1a) and indole (2a) were selected as model substrates to
optimize the reaction conditions (Table 1). Based on our previous
work,9 we found that the model reaction could proceed well in
* Corresponding authors. E-mail addresses: shunjun@suda.edu.cn, chemjsj@su-
da.edu.cn (S.-J. Ji).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.098

H.-Y. Xu et al. / Tetrahedron 69 (2013) 1600e1605
1601
the presence of a catalytic amount of PTSA (10 mol %) in refluxing
H2O for 24 h to afford methyl 3,3-di(1H-indol-3-yl)propanoate
(3aa) in 30% yield (Table 1, entry 1). Other solvents, such as
CH3NO2, CH3CN, THF, Toluene, CHCl3, CH2Cl2, and ClCH2CH2Cl
were also screened. As shown in Table 1, an increase of product
yield was observed during the course of the optimization of sol-
vent (Table 1, entries 2e8). It was found that the model reaction
could proceed effectively in CH3NO2 at 80 ꢀC (Table 1, entry 2).
Further optimization of the reaction conditions, a variety of me-
tallic Lewis acid and other Brønsted acid catalysts were employed
for the same purpose (Table 1, entries 9e16). As a result, TFA was
found to be a bit superior to other catalysts for this trans-
formation leading to the desired product in 85% yield (Table 1,
entry 16).
derivatives with indoles, we were eager to know if the present
protocol was general enough to construct the bio-active com-
pounds with wider structural diversity. Thus, we turned our at-
tention to the synthesis of other bis(indol-3-yl)alkane derivatives,
the results were listed in Table 3. The substitutes of tertiary
enamides, such as Me, Et, iPr, nPr, and hex, could perform well with
indole under optimized conditions, gave targeted products in good
yields (Table 3, entries 1e6). When the substitute of tertiary
enamide was Ph, it needed longer time to give the bisindole
product. Otherwise, the direct alkylation product 11aa would be
obtained (Table 3, entry 7).
Based on these results, a tentative mechanism for the formation
of bisindole compounds was proposed in Scheme 2. By the co-
ordination of the carbonyl group and polarized the C]C bond with
hydrogen ion, the first step was most likely the formation of in-
termediate A. Subsequently, a underwent a Friedel-Crafts reaction
with indole to form 11aa. At last, there were two possible paths for
the transform from 11aa to product 10aa. Either an SN2 nucleophilic
substitution reaction or a tandem reaction of Cope elimination and
Michael addition was possible. However, in such strong acidic
conditions, the latter way was more possible. To better understand
the mechanism of our reaction, we used intermediate 11aa to react
with indole under standard conditions, as expected, the final
product 10aa was obtained in 46% yield (Scheme 3).
Table 1
Reaction conditions screeninga
Entry Catalyst
(10 mol %)
PTSAc
Time (h) Solvent
Temperature (ꢀC) Yield (%)b
1
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
H2O
100
80
40
60
60
60
100
90
80
80
80
80
80
80
80
80
30
72
34
58
23
17
49
67
62
69
54
72
Trace
36
53
85
3. Conclusion
2
PTSA
CH3NO2
CH2Cl2
CH3CN
CHCl3
3
PTSA
4
PTSA
In summary, we have developed a simple and highly efficient
approach to synthesize pharmaceutically active bis(indolyl)alkane
compounds especially 3,3-bisindolylpropanoates through TFA-
catalyzed Markovnikov addition and cleavage of CeN bonds re-
action of indoles by tertiary enamides. This novel methodology not
only provides a valid way to construct bisindoles derivatives but
also opens a new way to construct more complex molecules bear-
ing indole fragment.
5
PTSA
6
PTSA
THF
7
PTSA
Toluene
ClCH2CH2Cl
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
8
PTSA
9
FeCl3
10
11
12
13
14
15
16
In(OTf)3
Cu(OTf)2
Zn(OTf)2
La(OTf)3
AgOTf
CH3SO3H
TFAd
4. Experimental section
4.1. General
a
General conditions: 1a (0.5 mmol), 2a (1 mmol).
Isolated yield.
b
c
PTSA¼p-toluenesulphonic acid.
d
TFA¼trifluoroacetic acid.
Melting points were recorded on an electrothermal digital
melting point apparatus and were uncorrected. IR spectra were
recorded on a Varian FT-1000 spectrophotometer using KBr optics.
1H NMR and 13C NMR spectra were recorded on a Varian INOVA 300
or 400 MHz (1H NMR) and 75 or 100 MHz (13C NMR) spectrometer
using CDCl3 or DMSO-d6 as solvent and TMS as internal standard.
High resolution mass spectra were obtained using GCT-TOF in-
strument with EI or ESI source.
With the optimal reaction conditions in hands, we continued
to examine the scope of the reaction by using various indoles. As
illustrated in Table 2, the alkylation of indoles under optimized
conditions could be accomplished with good generality. Indoles
with electron-donating groups, such as methyl, and methoxy,
reacted well with substrate 1a to provide the desired products
within 24 h in good to excellent yields (Table 2, entries 2, 4e6,
8e9). Noteworthy, indoles with steric hindered substituent at
2-position, such as 2-Me indole, had detrimental effect on the
reaction (Table 2, entry 3). Promoted by those good results, (E)-
methyl 3-(2-oxoazepan-1-yl)acrylate (1b) as another candidate of
cyclic enamide was selected to synthesize the corresponding
bis(indolyl)alkane compound, too. It was observed that seven-
membered cyclic enamide 1b showed similar reactivity with
that of 1a, affording the desired products in good yield (Table 2,
entry 10). Furthermore, acyclic enamide 1c was also proven as
a good candidate under optimized conditions, and a 61% yield
of the final product 3aa was generated after workup (Table 2,
entry 11).
4.2. Typical procedure for TFA-Catalyzed CeN bond activation
of enamides with indoles: efficient synthesis of 3,3-
bisindolylpropanoates and other bisindolylalkane
Indole (1 mmol, 0.117 g), TFA (0.05 mmol, 0.0057 g, 10 mol %),
(E)-methyl 3-(2-oxopyrrolidin-1-yl)acrylate (0.5 mmol, 0.0845 g),
and CH3NO2 (2 mL) were added into a flask under inert atmo-
sphere. Then the mixture was vigorously stirred at 80 ꢀC until (E)-
methyl 3-(2-oxopyrrolidin-1-yl)acrylate was completely consumed
monitored by TLC analysis. After the completion of reaction, the
residue was directly purified by flash column chromatography by
using ethyl acetate and petroleum ether as eluents to afford pure
product.
Encouraged by the above successful access to the bis(indol-3-yl)
alkanoic acid derivatives via Markovnikov addition and cleavage
of CeN bonds of (E)-methyl 3-(2-oxopyrrolidin-1-yl)acrylate

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H.-Y. Xu et al. / Tetrahedron 69 (2013) 1600e1605
Table 2
Alkylation of indoles with enamidesa
Entry
1
1
2
R1
H
Product
Yield (%)b
2a
85
1a
3aa
3ab
2
3
2b
2c
NeCH3
68
1a
1a
2-CH3
d
d
4
2d
5-CH3
65
1a
1a
3ad
5
2e
5-OCH3
70
3ae
6
7
2f
5-Br
86
1a
3af
2g
5-NO2
d
d
1a
1a
8
9
2h
2i
6-CH3
7-CH3
44
84
3ah
1a
3ai

H.-Y. Xu et al. / Tetrahedron 69 (2013) 1600e1605
1603
Table 2 (continued )
Entry
1
2
R1
H
Product
Yield (%)b
10
11
2a
88
61
1b
1c
3aa
3aa
2a
H
a
General conditions: 1 (0.5 mmol), 2 (1 mmol), TFA (10 mol %), and 2 ml CH3NO2 at 80 ꢀC.
Isolated yield.
b
Table 3 (continued )
Table 3
Substrate scope studya
Entry
Substrate
Product
Time (h)
36
Yield (%)b
56
7
10a
10aa
a
Entry
1
Substrate
Product
Time (h)
24
Yield (%)b
General conditions: 1 (0.5 mmol), 2a (1 mmol), TFA (10 mol %), and 2 ml CH3NO2
at 80 ꢀC.
b
Isolated yield.
63
4a
4aa
5aa
2
24
73
5a
3
4
24
24
62
72
6a
6aa
7aa
Scheme 2. Possible pathways for the formation of 10aa.
7a
5
6
24
24
51
61
8a
8aa
9aa
9a
Scheme 3. Mechanism study.

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H.-Y. Xu et al. / Tetrahedron 69 (2013) 1600e1605
4.3. General procedures for the oxidative Heck reaction10
112.1, 112.0, 101.8, 56.1, 51.9, 40.9, 30.9 ppm. HRMS: calcd for
C
22H22N2O4Na: [MþNa]þ 401.1477; found, 401.1572.
The -amidoacrylates 1aec were synthesis according to the
b
Murahashi’s method:
4.4.5. Methyl 3,3-bis(5-bromo-1H-indol-3-yl)propanoate (3af). Yield
(201.6 mg, 86%). White solid. Mp 38.3e39.5 ꢀC. IR (KBr): v¼3420,
2925, 1718,1448, 1094, 789 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d¼8.03
(s, 2H), 7.63 (s, 2H), 7.22 (d, J¼5.4 Hz, 4H), 7.03 (s, 2H), 4.98
(t, J¼7.6 Hz, 1H), 3.61 (s, 3H), 3.14 (d, J¼7.6 Hz, 2H) ppm. 13C NMR
(100 MHz, CDCl3):
d
¼172.9, 135.7, 128.3, 125.2, 123.1, 122.0, 117.9,
112.9, 91.9, 51.9, 40.8, 31.2 ppm. HRMS: calcd for C20H16 Br2N2O2Na:
[MþNa]þ 496.9476; found, 496.9471.
All the reactions were performed in 2 mmol scale. A dried 10 mL
Schlenk tube were placed PdCl2(MeCN)2 (5 mol %), CuCl (5 mol %),
dry DME (1 M), and amide under O2 (balloon) at 60 ꢀC, at this
temperature added olefin (3 equiv) slowly. Upon completion (24 h),
the reaction mixture was cooled to room temperature, diluted with
ethyl acetate, filtered through a small pad of Celite. The filtrate was
concentrate in vacuo. Then the crude residue was purified by flash
chromatography on a short silica gel (EtOAc/hexane) to afford
product (both E and Z isomer), only one isomer was used in the
subsequent oxidative Heck reaction.
4.4.6. Methyl 3,3-bis(6-methyl-1H-indol-3-yl)propanoate (3ah). Yield
(76.6 mg, 44%). White solid. Mp 28.6e29.5 ꢀC. IR (KBr): v¼3404,
2926, 1723, 1622, 1450, 1078, 800 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d
¼7.73 (s, 2H), 7.43 (d, J¼8.0 Hz, 2H), 7.04 (s, 2H), 6.85 (d, J¼8.0 Hz,
2H), 6.79 (s, 2H), 5.04 (t, J¼7.4 Hz, 1H), 3.55 (s, 3H), 3.15 (d, J¼7.5 Hz,
2H), 2.40 (s, 6H) ppm. 13C NMR (100 MHz, CDCl3):
d
¼173.5, 137.3,
131.9, 124.7, 121.3, 121.2, 119.3, 118.7, 111.4, 51.9, 41.2, 31.1, 21.9 ppm.
HRMS: calcd for C22H22N2O2Na: [MþNa]þ 369.1577; found,
369.1573.
4.4. General procedure for preparation of tertiary enamides11
4.4.7. Methyl 3,3-bis(7-methyl-1H-indol-yl)propanoate (3ai). Yield
(152.2 mg, 84%). White solid. Mp 35.5e36.1 ꢀC. IR (KBr): v¼3410,
A solution of 10 mmol of the appropriate lactam or amide,
10 mmol of the desired aldehyde, and 5 mg of p-toluenesulfonic acid
in 15e20 mL of dry toluene was heated at reflux with water removal
by a DeaneStark trap for 10e24 h until no more water was collected.
The solution was then cooled to 25 ꢀC, and washed with 10 mL of
ether. The organic phases were combined and dried (MgSO4), fil-
tered, and concentrated. The residue was then either recrystallized
from ethyl acetate or purified by flash chromatography on silica gel.
2925, 2347, 1721, 1438, 1343, 1080, 750 cmꢁ1 1H NMR (400 MHz,
.
CDCl3):
6H), 5.10 (t, J¼7.6 Hz, 1H), 3.58 (s, 3H), 3.19 (d, J¼7.6 Hz, 2H), 2.43
(s, 6H) ppm. 13C NMR (100 MHz, CDCl3):
d¼7.82 (s, 2H), 7.43 (d, J¼5.5 Hz, 2H), 6.96 (dd, J¼11.8, 5.9 Hz,
d
¼173.4,136.4, 126.4,122.7,
121.8, 120.6, 119.7, 119.4, 117.4, 51.9, 41.2, 31.3, 16.8 ppm. HRMS:
calcd for C22H22N2O2Na: [MþNa]þ 369.1577; found, 369.1573.
4.4.8. 3,30-(Ethane-1,1-diyl)bis(1H-indole) (4aa). Yield (143.7 mg,
63%). Yellow solid. Mp 84.2e85.1 ꢀC. IR (KBr): v¼3395, 2928, 2347,
4.4.1. Methyl 3,3-di(1H-indol-3-yl)propanoate (3aa). Yield (141.6 mg,
85%). White solid.Mp92.0e93.1ꢀC. IR (KBr):v¼3405, 3051, 1717, 1437,
1721, 1339, 1094, 940 cmꢁ1
.
1H NMR (400 MHz, CDCl3):
d¼7.85
(s, 2H), 7.57 (d, J¼7.9 Hz, 2H), 7.34 (d, J¼8.1 Hz, 2H), 7.16 (t, J¼7.6 Hz,
1346,1267,1211,1094, 745cmꢁ1.1H NMR (400 MHz, CDCl3):
d¼7.98 (s,
2H), 7.04 (t, J¼7.4 Hz, 2H), 6.91 (s, 2H), 4.67 (q, J¼6.9 Hz, 1H), 1.81
2H), 7.57 (d, J¼7.8 Hz, 2H), 7.32 (t, J¼7.4 Hz, 2H), 7.15 (t, J¼7.4 Hz, 2H),
(d, J¼7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3):
¼135.8, 127.1,
d
7.04 (t, J¼7.4 Hz, 2H), 2.97 (s, 2H), 5.12 (t, J¼7.5 Hz, 1H), 3.58 (s, 3H),
121.9,121.8,121.4,119.9,119.2,111.3, 28.4, 21.8 ppm. HRMS: calcd for
3.20(d, J¼7.6 Hz, 2H) ppm.13C NMR (100 MHz, CDCl3):
d
¼173.4,136.8,
C18H16N2Na: [MþNa]þ 283.1211; found, 283.1211.
126.8, 122.2, 122.1, 121.9, 119.7, 119.4, 118.8, 111.4, 51.9, 41.1, 30.9 ppm.
HRMS: calcd for C20H18N2O2Na: [MþNa]þ 341.1266; found, 341.1260.
4.4.9. 3,30-(Propane-1,1-diyl)bis(1H-indole) (5aa). Yield (196.6 mg,
73%). Brown oil. IR (KBr): v¼3394, 2929, 2857,1634,1093, 738 cmꢁ1
.
4.4.2. Methyl 3,3-bis(1-methyl-1H-indol-3-yl)propanoate (3ab). Yield
(117.3 mg, 68%). White solid. Mp 108.5e109.4 ꢀC. IR (KBr): v¼3449,
2931,1733,1471,1243,1144, 941, 741 cmꢁ1.1H NMR (400 MHz, CDCl3):
1H NMR (400 MHz, CDCl3):
d
¼7.87 (s, 2H), 7.65 (d, J¼7.9 Hz, 2H),
7.35 (d, J¼8.1 Hz, 2H), 7.20 (t, J¼7.5 Hz, 2H), 7.09 (t, J¼7.4 Hz, 2H),
7.00 (s, 2H), 4.43 (t, J¼7.2 Hz, 1H), 2.30e2.26 (m, 2H) 1.06
d
¼7.59 (d, J¼7.8 Hz, 2H), 7.26 (d, J¼8.0 Hz, 2H), 7.19 (t, J¼7.4 Hz, 2H),
(t, J¼7.2 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3):
¼136.8, 127.4,
d
7.04 (t, J¼7.3 Hz, 2H), 6.85 (s, 2H), 5.11 (t, J¼7.4 Hz, 1H), 3.58 (s, 3H),
121.9, 121.7, 120.5, 119.9, 119.2, 111.3, 36.1, 28.9, 13.0 ppm. HRMS:
3.17 (d, J¼7.5 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3):
d¼173.2, 137.6,
calcd for C19H18N2Na: [MþNa]þ 297.1368; found, 297.1362.
127.3, 126.7, 121.7, 119.9, 118.9, 117.6, 109.4, 51.8, 41.6, 32.9, 30.9 ppm.
HRMS: calcd for C22H22N2O2Na: [MþNa]þ 369.1577; found, 369.1573.
4.4.10. 3,30-(Butane-1,1-diyl)bis(1H-indole) (6aa). Yield (178.6 mg,
62%). Brown solid. Mp 91.7e92.1 ꢀC. IR (KBr): v¼3396, 3206, 2930,
4.4.3. Methyl 3,3-bis(5-methyl-1H-indol-3-yl)propanoate (3ad). Yield
(111.9 mg, 65%). White solid. Mp 37.2e37.6 ꢀC. IR (KBr): v¼3407,
2926, 2349, 1722, 1434, 1265, 791 cmꢁ1. 1H NMR (400 MHz, CDCl3):
1635,1456,1339,1094, 740 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d
¼7.77
(s, 2H), 7.62 (d, J¼7.8 Hz, 2H), 7.30 (d, J¼8.0 Hz, 2H), 7.16 (t, J¼7.4 Hz,
2H), 7.05 (t, J¼7.4 Hz, 2H), 6.93 (s, 2H), 4.50 (t, J¼7.3 Hz, 1H),
2.23e2.18 (m, 2H), 1.43e1.29 (m, 2H), 0.97 (t, J¼7.3 Hz, 3H) ppm. 13C
d
¼7.83 (s, 2H), 7.38 (s, 2H), 7.22 (d, J¼8.3 Hz, 2H), 6.99 (d, J¼8.2 Hz,
2H), 6.94 (s, 2H), 5.06 (t, J¼7.6 Hz, 1H), 3.59 (s, 3H), 3.17 (d, J¼7.7 Hz,
2H), 2.40 (s, 6H) ppm. 13C NMR (100 MHz, CDCl3):
NMR (100 MHz, CDCl3):
d
¼136.8, 127.4, 121.9, 121.6, 120.7, 119.9,
d
¼173.2, 135.2,
119.2, 111.3, 38.4, 33.8, 21.9, 14.4 ppm. HRMS: calcd for C20H20N2Na:
128.6, 127.1, 123.8, 122.2, 119.3, 118.4, 111.0, 51.9, 41.1, 30.9, 21.7 ppm.
[MþNa]þ 311.1524; found, 311.1519.
HRMS: calcd for C22H22N2O2Na: [MþNa]þ 369.1577; found, 369.1573.
4.4.11. 3,30-(3-Methylbutane-1,1-diyl)bis(1H-indole)
(7aa). Yield
4.4.4. Methyl 3,3-bis(5-methoxy-1H-indol-3-yl)propanoate (3ae). Yield
(132.3 mg, 70%). White oil. IR (KBr): v¼3409, 2941, 2348, 1723, 1475,
(187.3 mg, 72%). Brown solid. Mp 33.8e34.1 ꢀC. IR (KBr): v¼3411,
2945, 1698, 1612, 1456, 1342, 1092, 742 cmꢁ1 1H NMR (400 MHz,
.
1212, 1022, 799 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d
¼7.86 (s, 2H), 7.21
CDCl3):
d
¼7.84 (s, 2H), 7.69 (d, J¼7.9 Hz, 2H), 7.35 (d, J¼8.1 Hz, 2H),
(d, J¼8.7 Hz, 2H), 6.99 (d, J¼16.6 Hz, 2H), 6.82 (d, J¼8.7 Hz, 2H), 5.02
7.21 (t, J¼7.5 Hz, 2H), 7.11 (t, J¼7.4 Hz, 2H), 6.98 (s, 2H), 4.66
(t, J¼7.5 Hz, 1H), 3.76 (s, 6H), 3.60 (s, 3H), 3.18 (d, J¼7.6 Hz, 2H) ppm.
(t, J¼7.6 Hz, 1H), 2.17e2.11 (m, 2H), 1.71e1.67 (m, 2H), 1.04
13C NMR (100 MHz, CDCl3):
d¼173.2, 153.8, 132.1, 127.3, 122.8, 118.4,
(t, J¼6.6 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3):
¼136.8, 127.3,
d

H.-Y. Xu et al. / Tetrahedron 69 (2013) 1600e1605
1605
121.9, 121.6, 120.7, 119.8, 119.2, 111.3, 44.9, 31.9, 25.7, 22.8 ppm.
National Natural Science Foundation of China (No. 21202111),
the Young Natural Science Foundation of Jiangsu Province
(BK2012174), PAPD, and Soochow University for financial
support.
HRMS: calcd for C21H22N2Na: [MþNa]þ 325.1681; found, 325.1675.
4.4.12. 3,30-(Pentane-1,1-diyl)bis(1H-indole) (8aa). Yield (133.6 mg,
51%). Brown oil. IR (KBr): v¼3459, 2947, 1695, 1456, 1342, 1092,
912 cmꢁ1
.
1H NMR (400 MHz, CDCl3):
d
¼7.84 (s, 2H), 7.59
Supplementary data
(d, J¼7.9 Hz, 2H), 7.30 (d, J¼8.1 Hz, 2H), 7.14 (t, J¼7.5 Hz, 2H), 7.03
(t, J¼7.4 Hz, 2H), 6.95 (s, 2H), 4.46 (t, J¼7.4 Hz, 1H), 2.28e2.12
(m, 2H), 1.38e1.34 (m, 4H), 0.86 (t, J¼6.6 Hz, 3H) ppm. 13C NMR
Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.tet.2012.11.098.
(100 MHz, CDCl3):
d¼136.9, 127.4, 121.9, 121.6, 120.7, 119.9, 119.2,
111.3, 35.8, 34.2, 30.5, 29.8, 23.1 ppm. HRMS: calcd for C21H22N2Na:
[MþNa]þ 325.1681; found, 325.1675.
References and notes
1. For excellent reviews, see: (a) Sundberg, R. J. Indoles; Academic: London,
UK, 1996; (b) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106,
2875e2911; (c) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48,
9608e9644; (d) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev.
2010, 110, 4489e4497; (e) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111,
PR215ePR283.
2. (a) Irie, T.; Kubushirs, K.; Suzuki, K.; Tsukazaki, K.; Umezawa, K.; Nozawa,
S. Anticancer Res. 1999, 31, 3061e3066; (b) Hong, C.; Firestone, G. L.;
Bjeldanes, L. F. Biochem. Pharmacol. 2002, 63, 1085e1097; (c) Kuethe, J. T.
Chimia 2006, 60, 543e553; (d) Bifulco, G.; Bruno, I.; Minale, L.; Riccio, R.;
Calignano, A.; Debitus, C. J. Nat. Prod. 1994, 57, 1294e1299; (e) Bifulco, G.;
Bruno, I.; Riccio, R.; Lavayre, L.; Bourdy, G. J. Nat. Prod. 1995, 58,
1254e1260.
4.4.13. 3,30-(Octane-1,1-diyl)bis(1H-indole) (9aa). Yield (209.3 mg,
61%). White solid. Mp 119.8e120.6 ꢀC. IR (KBr): v¼3395, 2933,1632,
1451, 1093, 739 cmꢁ1
.
1H NMR (400 MHz, CDCl3):
d
¼7.82 (s, 2H),
7.61 (d, J¼7.9 Hz, 2H), 7.31 (d, J¼8.1 Hz, 2H), 7.15 (t, J¼7.5 Hz, 2H),
7.04 (t, J¼7.4 Hz, 2H), 6.95 (s, 2H), 4.47 (t, J¼7.3 Hz, 1H), 2.21
(dd, J¼14.5, 7.3 Hz, 2H), 1.42e1.23 (m, 11H), 0.87 (t, J¼6.4 Hz, 3H)
ppm. 13C NMR (100 MHz, CDCl3):
d
¼136.8, 127.4, 121.9, 121.7, 120.7,
119.9, 119.2, 111.3, 36.1, 34.2, 31.9, 30.0, 29.6, 28.6, 22.9 ppm. HRMS:
calcd for C24H28N2Na: [MþNa]þ 367.2150; found, 367.2152.
3. Papineni, S. S.; Chintharlapalli, S. Cancer Lett. 2008, 269, 326e338.
4. For selected examples, see: (a) Wang, L.; Han, J. W.; Tian, H.; Sheng, J.;
Fan, Z. Y.; Tang, X. P. Synlett 2005, 337; (b) Yadav, J. S.; Reddy, B. V. S.;
Sunitha, S. Adv. Synth. Catal. 2003, 345; (c) Ji, S. J.; Zhou, M. F.; Gu, D. G.;
Jang, Z. Q.; Loh, T. P. Eur. J. Org. Chem. 2004, 7, 1584; (d) Bandger, B. P.;
Shaikh, K. A. Tetrahedron Lett. 2003, 44, 1959; (e) Barbero, M.; Cadamuro,
S.; Dughera, S.; Magistris, C.; Venturello, P. Org. Biomol. Chem. 2011, 9,
8393.
5. For selected examples, see: (a) Lu, W.; Jia, C.; Kitamura, T.; Fujiwara, Y.
Org. Lett. 2000, 2, 2927e2930; (b) Li, Z.; Shi, Z.; He, C. J. Organomet. Chem.
2005, 690, 5049e5054; (c) Donets, P. A.; Hecke, K. V.; Meervelt, L. V. Org.
Lett. 2009, 11, 3618e3621; (d) Li, X.; Wang, J. Y.; Yu, W.; Wu, L. M. Tet-
rahedron 2009, 65, 1140e1146; (e) Buscemi, G.; Biffis, A.; Tubaro, C.; Ba-
sato, M.; Graiff, C.; Tiripicchio, A. Appl. Organomet. Chem. 2010, 24,
285e290; (f) Xie, M. H.; Xie, F. D.; Lin, G. F.; Zhang, J. H. Tetrahedron Lett.
2010, 51, 1213e1215.
6. Jiang, R.; Wu, X.-J.; Zhu, X.; Xu, X. P.; Ji, S. J. Eur. J. Org. Chem. 2010,
5946e5950.
7. Niu, T. M.; Huang, L. H.; Wu, T. X.; Zhang, Y. H. Org. Biomol. Chem. 2011, 9,
273e277.
8. (a) Akiyama, S.; Niki, T.; Utsunomiya, T.; Watanabe, J.; Nishioka, M.; Su-
zuki, H.; Hayasaka, F.; Yamagishi, K. EP1020447, 2000; (b) Gobert, J.;
Giurgea, C.; Geerts, J. -P.; Bodson, G. EP172096, 1985; (c) Kenda, B.; Mi-
chel, P.; Quesnel, Y. WO2005054188, 2005; (d) Kenda, B.; Quesnel, Y.; Ates,
A.; Michel, P.; Turet, L.; Mercier, J. WO2006128693, 2006; (e) Gobert, J.;
Geerts, J. -P.; Bodson, G. EP0162036, 1985; (f) Schmiesing, R. J.; Murray, R.
J. US5334720, 1994.
4.4.14. 3,30-(2-Phenylethane-1,1-diyl)bis(1H-indole) (10aa). Yield
(188.2 mg, 61%). White solid. Mp 23.5e24.4 ꢀC. IR (KBr): v¼3412,
3039, 2924, 1606, 1452, 1304, 1088, 741 cmꢁ1. 1H NMR (400 MHz,
CDCl3):
d
¼7.55 (s, 2H), 7.56 (d, J¼7.9 Hz, 2H), 7.38 (d, J¼8.1 Hz, 2H),
7.16e7.06 (m, 7H), 7.01 (t, J¼7.5 Hz, 2H), 6.88 (s, 2H), 4.78
(t, J¼7.4 Hz, 1H), 3.52 (d, J¼7.4 Hz, 2H) ppm. 13C NMR (100 MHz,
CDCl3):
d
¼141.5, 136.9, 129.2, 128.2, 127.2, 125.9, 122.2, 121.9, 119.9,
119.6, 119.2, 111.3, 41.9, 36.3 ppm. HRMS: calcd for C24H20N2Na:
[MþNa]þ 359.1524; found, 359.1519.
4.4.15. 1-(1-(1H-Indol-3-yl)-2-phenylethyl)pyrrolidin-2-one
(11aa). White solid. Mp 190.8e191.7 ꢀC. IR (KBr): v¼3280, 2942,
2359, 1655, 1438, 1283, 741 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d¼8.31
(s,1H), 7.71 (d, J¼7.9 Hz,1H), 7.36 (d, J¼8.1 Hz,1H), 7.31e7.26 (m, 5H),
7.22e7.19 (m, 2H), 7.11 (t, J¼7.4 Hz, 1H), 6.02e5.98 (m,1H), 3.44e3.40
(m, 1H), 3.39e3.27 (m, 2H), 2.97e2.91 (m, 1H), 2.29e2.19 (m, 2H),
1.82e1.72 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3):
138.6, 129.1, 128.6, 126.7, 122.8, 122.6, 120.1, 119.8, 114.7, 111.5, 48.1,
42.8, 37.1, 31.7, 18.0 ppm. HRMS: calcd for C20H20N2ONa: [MþNa]þ
327.1473; found, 327.1468.
d
¼174.7, 138.2,
9. Jiang, R.; Xu, H. Y.; Xu, X. P.; Chu, X. Q.; Ji, S. J. Org. Biomol. Chem. 2011, 9,
5659e5669.
10. Hosokawa, T.; Takano, M.; Kuroki, Y.; Murahashi, S. I. Tetrahedron Lett. 1992, 33,
6643e6646.
11. Song, F. B.; Snook, J. H.; Foxman, B. M.; Snider, B. B. Tetrahedron 1998, 54,
13035e13044.
Acknowledgements
The work was partially supported by the Natural Science
Foundation of China (No. 21042007, 21172162), the Young