CuBr2-catalyzed synthesis of bis(indolyl)methanes

Article abstract of DOI:10.1081/SCC-200066653

Copper(II) bromide is found to be an efficient catalyst for the electrophilic substitution reaction of indole with aldehydes to afford the corresponding bis(indolyl)-methanes in good yields. Copyright Taylor & Francis, Inc. 1997-2004.

Full text of DOI:10.1081/SCC-200066653

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CuBr ‐Catalyzed Synthesis of
2
Bis(indolyl)methanes
a
a
a
Li‐Ping Mo , Zi‐Chuan Ma & Zhan‐Hui Zhang
a
College of Chemistry, Hebei Normal University,
Shijiazhuang, China
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Synthetic Communications , 35: 1997–2004, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200066653
CuBr -Catalyzed Synthesis
2
of Bis(indolyl)methanes
Li-Ping Mo, Zi-Chuan Ma, and Zhan-Hui Zhang
College of Chemistry, Hebei Normal University, Shijiazhuang, China
Abstract: Copper(II) bromide is found to be an efficient catalyst for the electrophilic
substitution reaction of indole with aldehydes to afford the corresponding bis(indolyl)-
methanes in good yields.
Keywords: Aldehydes, bis(indolyl)methanes, copper(II) bromide, indole
Development of bis(indolyl)alkane synthesis has been of considerable interest
in organic synthesis because of bis(indolyl)alkanes’ wide occurrence in
[1]
various natural products possessing biological activity and usefulness for
[2]
drug design. Bis(indolyl)methanes are most active cruciferous substances
for promoting beneficial estrogen metabolism and inducing apoptosis in
[
human cancer cells. Consequently, numerous methods have been reported
3]
[
4]
for the preparation of bis(indolyl)methanes. Of these methods, the acid-
catalyzed electrophilic substitution reaction of indoles with aldehydes is one
of most simple and straightforward approaches for the synthesis of bis(indo-
[
5]
[6]
lyl)methanes. A variety of reagents such as acetic acid,
[11]
InCl3,
I ,
2
[
7]
[8]
[9]
In(OTf) , InF3, Dy(OTf)3, Ln(OTf) ,
[10]
[12]
[13]
LiClO4,
PPh3 HClO4 (TPP),
FeCl ,
3
3
3
[17]
[
14]
[15]
[16]
[18]
.
NaHSO4 SiO2,
.
NBS,
KHSO4,
CAN,
zeolites, clay, H PMo O xH O, and 1-butyl-3-methylimidazolium
[19]
[20]
[21]
.
3
12 40
2
tetrafluoroborate or 1-butyl-3-methylimidazolium hexafluorophosphate ionic
[
22]
liquids
rare-earth perfluoroocanoates [RE(PFO) ],
have been employed to accomplish this transformation. Recently,
[
23]
[24]
trichloro-1,3,5-triazine,
[26]
3
[
25]
hexamethylenetetraamine-bromine,
ion-exchange resin,
and ionic
Received in Japan March 18, 2005
Address correspondence to Zhan-Hui Zhang, College of Chemistry, Hebei Normal
University, Shijiazhuang 050091, China. E-mail: zhanhui@126.com
1
997

1998
L.-P. Mo, Z.-C. Ma, and Z.-H. Zhang
[
27]
.
liquids in conjunction with In(OTf) or FeCl 6H O
were also found to
promote this reaction. However, some of the reported methods have the
3
3
2
[7,9,10]
following drawbacks: for example, use of expensive reagents,
longer
and use of an additional
Because of their wide range of biological, industrial,
[
5,6,8,22]
[5,20b]
reaction times,
microwave oven.
low yields of products,
[
12]
and synthetic applications, the preparation of bis(indolyl)methanes has
received the renewed interest of researchers for the discovery of improved
protocols and still awaits further development of milder and high-yielding
products.
[
28]
Copper(II) bromide is an important reagent not only for bromination
[
29]
but also a range of other reactions. It is significantly cheaper than known
late transition-metal catalysts and tolerates a variety of functional groups.
We found that CuBr is an efficient catalyst for electrophilic substitution of
2
indole with aldehyde or ketones. Here, we report a rapid and convenient
procedure for the preparation of bis(indolyl)methanes from indole and
aldehydes or ketones using a catalytic amount of CuBr at room temperature
2
(Scheme 1).
First, 4-chlorobenzaldehyde (1a) was chosen as a model for the reaction
with indole. Compound 1a was treated with 2.0 equiv. of indole in the
presence of 5 mol% (based on the amount of indole) of CuBr at room temp-
2
erature in various solvents (Table 1, entries 1–7). In CH CN, the reaction
3
completed within 0.4 h to give bis(indolyl)methane 3a in 95% yield. The
reactions in CH Cl , AcOEt, MeOH, EtOH, DMF, and THF required longer
2
2
reaction times and unreacted 1a and indole remained. Next, the efficacy of
various Lewis acids such as CuCl , Cu(OTf) , ZnCl , FeCl , AlCl , and
2
2
2
3
3
.
CoCl2 6H O was studied for this conversion. Among these Lewis acids,
2
CuBr was found to be superior in terms of conversion and reaction rates
2
(Table 1). Although the reactions also proceeded with CuCl , long reaction
times are typically needed to achieve comparable yields to those obtained
2
with CuBr . Lower catalyst loading can be used with only a marginal drop
2
in reaction rate (entry 8).
Having established reaction conditions, various aldehydes 1 were reacted
with indole 2 to investigate the reaction scope, and several representative
results are summarized in Table 2. Aromatic, aliphatic (entry b) and hetero-
cyclic (entry m) aldehydes underwent smooth transformation to the
Scheme 1.

CuBr -Catalyzed Synthesis of Bis(indolyl)methanes
2
1999
Table 1. Screening of the reaction conditions for the synthesis 3a
a
Entry
Solvent
Catalyst
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
CH CN
3
5% CuBr2
0.4
3
95
88
86
81
79
76
37
89
94
89
15
86
75
90
38
AcOEt
CH Cl
5% CuBr
5% CuBr
2
2
2
2
4
CH OH
3
5% CuBr2
5% CuBr2
4
C H OH
2 5
3
THF
DMF
5% CuBr
5% CuBr
2
10
15
1
2
CH CN
3
1% CuBr2
5% CuCl
CH
CH
3
CN
CN
2
1.5
4
1
1
1
1
1
1
0
1
2
3
4
5
3
5% Cu(OTf)
5% ZnCl2
2
CH CN
3
20
4
CH
CH
3
CN
CN
5% BiCl
5% FeCl
5% AlCl3
3
3
3
20
8
CH CN
3
.
CH
3
CN
5% CoCl
2
6H
2
O
24
a
Isolated yields.
corresponding bis(indolyl)methanes in high to excellent yield in relatively
short reaction times. It has been observed that the electronic properties of
the aromatic ring have an effect on the rate of this electrophilic substitution
reaction. The rate is accelerated if an electron-withdrawing group is present
on the aromatic ring. The reaction of ketones with indole took longer when
compared with aldehydes, and unreacted ketones and indole remained.
Also, no any brominated side product was detected. It is also found that the
reaction of terephetalaldehyde 4 with 4 equiv. of indole proceeded rapidly
to give p-di(bis-indolylmethane)benzene 5 in similar conditions in high
yield (Scheme 2).
In summary, the electrophilic substitution reaction of indole with
aldehydes was successfully carried out in the presence of a catalytic amount
of CuBr at room temperature. This method offers several significant advan-
2
tages such as high conversions, easy handing, cleaner reaction profiles, and
short reaction times, which makes it a useful and attractive process for the
rapid synthesis of substituted bis(indolyl)methanes.
EXPERIMENTAL
Melting points were determined using a X-4 apparatus and are uncorrected.
NMR spectra were recorded on a Bruker-BZH-360/52 spectrometer using
TMS as an internal standard. IR spectra were obtained using a FTS-135 spec-
trometer instrument. Mass spectra were recorded on a VG Micromass 7070H
(
70 eV) instrument. CHN analysis was recorded on MT-3 analyzer.

2
000
L.-P. Mo, Z.-C. Ma, and Z.-H. Zhang
-catalyzed synthesis of bis(indolyl)methane derivatives
Mp (8C)
Reported
Table 2. CuBr
2
Time
(min)
Yield
a
Entry
Substrate
(%)
Found
76–77
[
26]
2
4
95
77–81
a
b
c
[
26]
8
3
0
0
85
94
68–70
70–72
[
20b]
123–125
125–127
[
27b]
3
4
3
0
0
5
95
92
90
96–98
94–96
d
e
[
27b]
190–192
100–102
187–189
[
11]
97–99
f
[
[
18]
4
5
0
0
89
91
124–125
111–112
122–124
110–112
g
h
19b]
[
27b]
2
5
94
72–74
72–74
i
[
[
26]
1
1
5
8
93
90
221–223
142–143
220–222
140–142
j
20b]
k
[
[
5]
6
3
0
5
81
88
75
96–98
99
l
25]
320–323
118–120
322
m
n
[
[
11]
18]
4
4
80
80
118–120
190–192
38
189–190
o
a
Isolated yield.

CuBr -Catalyzed Synthesis of Bis(indolyl)methanes
2
2001
Scheme 2.
General Procedure
In a 50-mL, round-bottom flask, indole (2.0 mmol), aldehydes or ketone
1.0 mmol), and CuBr (0.1 mmol) in MeCN were added with stirring at
room temperature. The progress of the reaction was monitored by TLC.
(
2
After completion, the reaction mixture was quenched with H O (5 mL) and
2
extracted with EtOAc (3 ꢀ 10 mL), and combined organic layers were dried
over Na SO , concentrated, and purified by column chromatography on
2
4
SiO with use of an ethyl acetate/hexane mixture as eluent; distillation of
2
the solvent under reduced pressure gave pure products.
0
4
411, 3055, 2923, 2848, 1617, 1417, 1337, 1089, 1013, 743 cm . H NMR
-Chlorophenyl-3,3 -bis(indolyl)methane (3a): Pink solid. IR (KBr):
2
1 1
3
(
300 MHz, CDCl ): d ppm: 5.86 (s, 1H, Ar-CH), 6.65 (s, 2H), 7.02 (t, 2H,
3
J ¼ 7.8 Hz), 7.18 (t, 2H, J ¼ 7.8 Hz), 7.26–7.38 (m, 8H), 7.93 (br, s, 2H,
1
3
NH). C NMR (75 MHz): 39.7, 111.4, 119.1, 119.5, 122.2, 123.8, 127.0,
þ
1
28.5, 130.2, 131.9, 136.8, 142.8. EIMS: m/z (%): 356 (5, M ), 354 (15,
þ
M -2), 244 (12), 186 (13), 172 (16), 138 (25), 116 (100). Anal. calcd. for
C H ClN : C, 77.41; H, 4.80; Cl, 9.93; N, 7.85. Found: C, 77.52; H, 4.75;
N, 7.89.
2
3
17
2
0
3,3 -Bisindoly(methyl)phenylmethane (3p): Coloress solid. IR (KBr):
2
41, 1010, 1336, 1455, 2848, 2923, 3053, 3410 cm . H NMR (300 MHz,
1 1
7
CDCl ) d ppm: 2.29 (s, 3H), 6.54 (s, 2H), 6.86 (t, J ¼ 7.8 Hz, 2H), 7.06
3
(
NH). C NMR (75 MHz, CDCl ) d ppm: 28.8, 43.7, 111.2, 118.9, 121.5,
t, J ¼ 7.8, 2H), 7.14–7.18 (m, 4H), 7.23–7.34 (m, 5H), 7.78 (br s, 2H,
3
1
3
1
22.1, 123.4, 124.7, 125.8, 126.5, 127.8, 128.1, 137.1, 148.1. EIMS: m/z
þ
(
%) ¼ 336 (86, M ), 243 (100), 245 (45), 220 (58), 77 (38). Anal. Calcd.
for C H N : C, 85.68; H, 5.99; N, 8.33. Found: C, 85.56; H, 5.92; N, 8.40.
2
4
20
0 00 000
.
,3 ,3 ,3 -Tetraindoly(terepthalyl)dimethane (5 2AcOEt): Colorless
2
3
[
13a]
solid, mp: 122–123 8C (Lit.
1
121–1238C). IR (KBr): 742, 776, 1295,
21 1
455, 1720, 2849, 2920, 3052, 3411 cm . H NMR (300 MHz, acetone-d )
6
d ppm: 1.29 (t, J ¼ 7.2 Hz, 6H, CH ), 2.04 (s, 6H, CH ), 4.04–4.09 (m, 4H,
3
3
CH ), 5.89 (s, 2H, Ar-CH), 6.81 (t, J ¼ 7.8 Hz, 4H), 6.90 (t, J ¼ 7.8 Hz,
2
1
3
4
H), 7.05 (t, J ¼ 7.8 Hz, 4H), 7.33–7.38 (m, 12H), 9.97 (br s, 4H, NH).
C

2002
L.-P. Mo, Z.-C. Ma, and Z.-H. Zhang
NMR (75 MHz, acetone-d6) d ppm: 14.4, 20.8, 40.8, 60.5, 112.1, 119.2, 120.0,
1
20.3, 121.9, 124.3, 124.5, 128.1, 129.2, 138.0, 143.4, 170.8. EIMS: m/z
þ
(
%) ¼ 566 (4, M ), 452 (12), 336 (68), 245 (12), 117 (8), 116 (100), 89
(
50). Anal. calcd. for C H N O : C, 77.60; H, 6.24; N, 7.54. Found: C,
8 46 4 4
4
7
7.58; H, 6.30; N, 7.49.
ACKNOWLEDGMENT
The financial support for this work from Hebei Normal University and
National Natural Science Foundation of China (20477009) is gratefully
acknowledged.
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