An efficient preparation of bis(indole)methanes catalyzed by tetrakis[3,5-bis(trifluoromethyl)phenyl]borate salts in aqueous medium

Article abstract of DOI:10.1055/s-2007-990788

An efficient and direct preparation of bis(indole)methanes from indole and the corresponding carbonyl compound in water catalyzed by metal salts of tetrakis[3,5-bis(trifluoromethyl)phenyl]borate has been developed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990788

PAPER
3125
An Efficient Preparation of Bis(indole)methanes Catalyzed by
Tetrakis[3,5-bis(trifluoromethyl)phenyl]borate Salts in Aqueous Medium
Preparation of
Bi
e
s(indole)me
i
thanes
-
in Aque
S
ous Medium ih Liao, Jwu-Ting Chen, Shiuh-Tzung Liu*
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan
Fax +886(2)23636359; E-mail: stliu@ntu.edu.tw
Received 11 June 2007; revised 18 July 2007
the effectiveness of various salts on this reaction
(Scheme 1). It was surprising to find that bis(indol-3-
yl)(phenyl)methane (1a) was efficiently obtained under
Abstract: An efficient and direct preparation of bis(indole)meth-
anes from indole and the corresponding carbonyl compound in wa-
ter
catalyzed
by
metal
salts
of
tetrakis[3,5-
extremely mild conditions when NaBArF was used. In
bis(trifluoromethyl)phenyl]borate has been developed.
4
addition, a series of salts were also screened for this reac-
tion, and the results are listed in Table 1.
Key words: indoles, catalysis, condensation, aldehydes, aqueous
reactions
Group I and II metal salts of tetrakis[3,5-bis(trifluoro-
methyl)phenyl]borate appeared to be excellent catalysts
for this condensation (Table 1, entries 6–10). On the other
hand, a simple salt such as sodium chloride or bromide
does not show good catalytic activity (Table 1, entries 2–
4), and the activity of sodium tetraphenylborate is already
slightly better than that of sodium bromide (Table 1, en-
tries 5 and 3, respectively). From these results, we noticed
that the tetrakis[3,5-bis(trifluoromethyl)phenyl]borate an-
Bis(indole)methanes and derivatives, a class of bioactive
intermediates of terrestrial and marine origin, are impor-
tant organic compounds.1,2 For this reason, remarkable ef-
forts have been made to develop efficient methods for
their preparation. They can be prepared by the condensa-
tion of indoles with various aldehydes or ketones in the
presence of acidic catalysts. In recent years, syntheses of
this class of molecules under mild conditions have been
reported, with promoters such as zinc(II) chloride/acetic
acid,3 ethanol,4 formic acid,5 cyclodextrin/electrolysis,6
zirconium(IV) chloride,7 sulphamic acid,8 copper(II) bro-
mide,9 Amberlyst,10 potassium hydrogen sulfate,11 io-
dine,12 lithium perchlorate,13 and ionic liquid.14 However,
many of these methods still suffer from some disadvan-
tages such as long reaction times, the use of organic sol-
vents, and high catalyst loading. Therefore, a more
efficient method for this transformation in an aqueous me-
dium is still required. In this context, a few reports show
that the preparation of bis(indole)methanes can be
achieved in water.15–18 In these instances, the high quanti-
ty of catalyst needed for better conversion remains an is-
sue to be improved.
O
0.2 mol% NaBArF
4
+
N
30 °C
H
N
N
H
H
1a
Scheme 1
Table 1 Effect of Type of Salt as Catalyst on the Reaction of Indole
with Benzaldehydea
Entry
Salt
Yield (%)
1
2
none
5
12
15
13
31
99
96b
86
92
89
In our previous work, we have found that sodium
tetrakis[3,5-bis(trifluoromethyl)phenyl]borate dihydrate
NaCl
(NaBArF ·2H2O) is able to provide a proton to initiate the
4
polymerization of vinyl ether in organic solvent.19 This
sodium salt could also assist the hydrolysis of acetals20
and catalyze the Mannich reaction in aqueous solution,21
thus demonstrating that this salt is a good acid catalyst. On
the basis of these findings, we have carried out a study on
the preparation of bis(indole)methanes by the condensa-
tion of indole and aldehydes (or ketones) catalyzed by
NaBArF4 in aqueous medium.
3
NaBr
NaBF4
NaBPh4
LiBArF
4
5
6
4
7
NaBArF
4
8
KBArF
4
As a starting point, we selected the reaction of benzalde-
hyde with two equivalents indole as a model to examine
9
Mg(BArF )
4 2
10
Ca(BArF )
4 2
SYNTHESIS 2007, No. 20, pp 3125–3128
Advanced online publication: 21.09.2007
DOI: 10.1055/s-2007-990788; Art ID: F10907SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
7
a Reaction conditions: indole (2 mmol), PhCHO (1 mmol), salt
(2 mmol), H2O (2 mL), 30 °C, 6 h.
b After 5 h, instead of 6 h.

3126
B.-S. Liao et al.
PAPER
Table 2 Effect of Type of Solvent on the Reaction of Indole with
Benzaldehydea
Entry
Solvent
Yieldb (%)
100
50
1
2
3
4
5
6
7
8
9
H2O
MeOH
MeOH–H2O (1:1)
CH2Cl2
88
35
toluene
55
Figure 1 Plots of yield versus time for the reaction of indole with
benzaldehyde catalyzed by various metal salts of tetrakis[3,5-
bis(trifluoromethyl)phenyl]borate
THF
22
THF–H2O (1:1)
DMF
80
trace
trace
ion plays an important role in this catalysis. As for metal
ions, there is no significant difference among them. A plot
MeCN
of yield versus time for various MBArF in this catalysis is
given in Figure 1. All metal ions catalyzed the reaction
similarly at the beginning of the reaction, but slightly dif-
ferently after one hour.
4
a Reaction conditions: indole (2 mmol), PhCHO (1 mmol), NaBArF
(2 mmol), solvent (2 mL), 30 °C, 6 h.
4
b Yield by NMR spectroscopy.
We also investigated the effect of solvents other than wa-
ter on this reaction. As shown in Table 2, water appears to
be essential for this reaction. Reactions in most of the or-
ganic solvents provided the desired product in moderate
or poor yield. However, addition of water to these organic
solvents readily improved the reaction yields (Table 2, en-
tries 3 and 7). In water, the sodium salt of tetrakis[3,5-
bis(trifluoromethyl)phenyl]borate and organic substrates
would form a colloidal dispersion during the reaction. The
emulsion appeared to accelerate the reaction, which is
similar to the phenomenon occurring during the Mannich
Table 3 Preparation of Bis(indole)methane Derivativesa
Entry Indole
1
Carbonyl
compound
Product Time Yieldb
(h)
(%)
PhCHO
1a
1b
1c
1d
1e
1f
5
99
N
H
2
3
4
5
6
7
PMPCHO
Me(CH2)6CHO
2-furylCHO
pyCHO
6
6
98
92
78
71
65
reaction catalyzed by NaBArF in water.21 Apparently,
4
N
H
NaBArF plays two major roles in this reaction: that of cat-
4
alyst and that of surfactant. It is known that the formation
of colloidal particles can speed up organic reactions, and
a typical example has been illustrated by Kobayashi and
coworkers for the Mannich-type reaction catalyzed by
dodecylbenzenesulfonic acid.22 Since the salt dissolves in
N,N-dimethylformamide or acetonitrile, this explains why
the reactions in these solvents give the least satisfactory
results (Table 2, entries 8 and 9).
N
H
8
N
H
8
N
H
The reactions of various carbonyl compounds with in-
doles were then studied under the optimized conditions,
and the results are compiled in Table 3. In all instances,
the reactions of either aromatic or aliphatic aldehydes
with indole proceeded smoothly in high yields (Table 3,
cyclohexanone
PhCHO
10
N
H
2a
1.5 96
entries 1–5). The beneficial effect of NaBArF on this con-
4
densation was also applicable to ketones as reagents, and
the reaction of cyclohexanone with indole provided the
corresponding bis(indole) derivative in 65% yield
(Table 3, entry 6). Various substituted indoles react with
aromatic aldehydes to give the desired products in excel-
lent yields, and it appears that substituents have little ef-
fect on this catalysis. The reaction of terephthalaldehyde
(1 mmol) with indole (4 mmol) also proceeded smoothly,
to give 3,3¢,3¢¢,3¢¢¢-(1,4-phenylenedimethanetriyl)tetra-
kis(1H-indole) (7) in 68% yield (Table 3, entry 16).
N
Me
8
9
4-O2NC6H4CHO 2b
3
2
93
95
N
Me
TolCHO
2c
N
Me
Synthesis 2007, No. 20, 3125–3128 © Thieme Stuttgart · New York

PAPER
Preparation of Bis(indole)methanes in Aqueous Medium
3127
Table 3 Preparation of Bis(indole)methane Derivativesa
(continued)
1H NMR (400 MHz, CDCl3): d = 5.83 (s, 1 H), 6.53 (s, 2 H), 6.95
(t, J = 8 Hz, 2 H), 7.11 (t, J = 8 Hz, 2 H), 7.20–7.30 (m, 5 H), 7.35
(m, 4 H), 7.89 (br, 2 H, NH).
Entry Indole
10
Carbonyl
compound
Product Time Yieldb
Bis(indol-3-yl)(4-methoxyphenyl)methane (1b)15
Brown solid; mp187–189 °C.
1H NMR (400 MHz, CDCl3): d = 3.76 (s, 3 H), 5.82 (s, 1 H), 6.63
(s, 2 H), 6.80 (d, J = 8.4 Hz, 2 H), 7.00 (t, J = 7.6 Hz, 2 H), 7.12–
7.24 (m, 4 H), 7.32–7.38 (m, 4 H), 7.91 (br, 2 H, NH).
(h)
(%)
PMPCHO
2d
2.5 94
N
Me
11
12
PhCHO
PMPCHO
PhCHO
3a
3b
4
2
3
5
95
92
93
1,1-Bis(indol-3-yl)octane (1c)
Green oil.
1H NMR (400 MHz, CDCl3): d = 0.85 (s, 3 H), 1.23–1.43 (m, 10 H),
2.21 (dt, J = 7.2, 6.8 Hz, 2 H), 4.46 (t, J = 7.2 Hz, 1 H), 6.97 (d,
J = 2 Hz, 2 H), 7.02 (t, J = 8 Hz, 2 H), 7.13 (t, J = 8 Hz, 2 H), 7.31
(d, J = 8 Hz, 2 H), 7.58 (d, J = 8 Hz, 2 H), 7.87 (br, 2 H, NH).
Me
Me
N
H
N
H
13C NMR (100 MHz, CDCl3): d = 14.1, 22.6, 28.3, 29.2, 29.7, 31.9,
33.9, 35.8, 111.1,118.9,119.4, 120.3, 121.4, 121.6, 127.0, 136.4.
13
14
15
Br
N
ESI-HRMS: m/z [M + Na] calcd for C24H28N2: 367.2150; found:
367.2145.
H
PhCHO
PhCHO
5
6
6
8
91
92
MeO
2-Furylbis(indol-3-yl)methane (1d)24
Green solid; mp 318–320 °C.
1H NMR (400 MHz, CDCl3): d = 5.93 (s, 1 H), 6.05 (d, J = 2.4 Hz,
1 H), 6.23 (dd, J = 2.4, 1.6 Hz, 1 H), 6.84 (s, 2 H), 7.02 (t, J = 8 Hz,
2 H), 7.16 (t, J = 8 Hz, 2 H), 7.33 (m, 3 H), 7.46 (d, J = 8 Hz, 2H),
7.94 (s, 2 H).
N
H
N
H
Et
16
C6H4-1,4-(CHO)2
7
12
68
Bis(indol-3-yl)(2-pyridyl)methane (1e)25
Brown solid; mp 238–240 °C.
N
H
1H NMR (400 MHz, CDCl3): d = 6.02 (s, 1 H), 6.63 (s, 2 H), 6.95
(t, J = 8 Hz, 2 H), 7.04 (d, J = 8 Hz, 1 H), 7.12 (t, J = 8 Hz, 2 H),
7.17 (d, J = 6.6 Hz, 1 H), 7.27 (d, J = 8 Hz, 2 H), 7.35 (d, J = 8 Hz,
2 H), 7.51–7.55 (m, 1 H), 8.40 (br, 2 H), 8.53 (d, J = 4.8 Hz, 1 H).
a Reaction conditions: indole (2 mmol), carbonyl compound (1
mmol), NaBArF4 (2 mmol), H2O (2 mL), 30 °C.
b Isolated yield.
1,1-Bis(indol-3-yl)cyclohexane (1f)13
White solid; mp 117–119 °C
1H NMR (400 MHz, CDCl3): d = 1.60–1.69 (m, 2 H), 1.70–1.73 (m,
In conclusion, this procedure offers several advantages in
the preparation of bis(indole)methanes, such as mild con-
ditions, low catalyst loading, high yields, and the use of 4 H), 2.54 (t, J = 5.6 Hz, 4 H), 6.87 (s, 2 H), 7.04 (t, J = 8 Hz, 2 H),
7.08 (t, J = 8 Hz, 2 H), 7.28 (t, J = 8 Hz, 2 H), 7.54 (t, J = 8 Hz, 2
aqueous medium; this makes it an attractive and useful
methodology for organic synthesis. From the study of the
H), 7.90 (br, 2 H).
anions, it is quite clear that tetrakis[3,5-bis(trifluorometh-
yl)phenyl]borate plays the role of surfactant in assisting
the electrophilic substitution of indoles.
Bis(1-methylindol-3-yl)(phenyl)methane (2a)26
Pink solid; mp 204–206 °C.
1H NMR (400 MHz, CDCl3): d = 3.67 (s, 6 H), 5.87 (s, 1 H), 6.52
(s, 2 H), 6.98 (t, J = 7.6 Hz, 2 H), 7.20 (t, J = 7.6 Hz, 2 H), 7.25–
1H and 13C NMR spectra of samples in CDCl3 were recorded on a
Bruker Avance 400 spectrometer. Chemical shifts are reported in
ppm relative to TMS. Chemicals and solvents were of analytical
grade and used as received unless otherwise stated. De-ionized wa-
ter was used for this study. Salts of tetrakis[3,5-bis(trifluorometh-
yl)phenyl]borate were prepared according to a previously reported
procedure.19
9.29 (m, 5 H), 7.33–7.38 (m, 4 H).
Bis(1-methylindol-3-yl)(4-nitrophenyl)methane (2b)27
Yellow solid; mp 215–217 °C.
1H NMR (400 MHz, CDCl3): d = 3.69 (s, 6 H), 5.96 (s, 1 H), 6.52
(s, 2 H), 7.02 (t, J = 8 Hz, 2 H), 7.21 (t, J = 8 Hz, 2 H), 7.30 (m, 4
H), 7.47 (d, J = 8.8 Hz, 2 H), 8.11 (d, J = 8.8 Hz, 2 H).
Bis(indol-3-yl)(phenyl)methane (1a);23 Typical Procedure
A mixture of indole (2 mmol), benzaldehyde (1 mmol), and
NaBArF4 (2 mmol) in H2O (2 mL) was stirred at 30 °C for 5 h. The
mixture was filtered through a short column (Celite, 2 g) to remove
the salt. Concentration of the filtrate gave the crude product, which
was either recrystallized from organic solvents or chromatographed
(silica gel) to yield the pure product.
Bis(1-methylindol-3-yl)(4-tolyl)methane (2c)
Brown solid; mp 198–200 °C.
1H NMR (400 MHz, CDCl3): d = 2.32 (s, 3 H), 3.67 (s, 6 H), 5.83
(s, 1 H), 6.52 (s, 2 H), 6.98 (t, J = 7.6 Hz, 2 H), 7.06 (d, J = 8 Hz, 2
H), 7.16–7.28 (m, 6 H), 7.37 (d, J = 8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 21.2, 32.7, 39.7, 108.9, 118.3,
118.4, 119.9, 121.2, 127.3, 128, 128.4, 128.7, 135.2, 137.2, 141.2.
Pink solid; mp 120–123 °C.
ESI-HRMS: m/z [M + Na] calcd for C26H24N2: 387.1837; found:
387.1877.
Synthesis 2007, No. 20, 3125–3128 © Thieme Stuttgart · New York

3128
B.-S. Liao et al.
PAPER
(4-Methoxyphenyl)bis(1-methylindol-3-yl)methane (2d)28
Brown solid; mp 220–222 °C.
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1H NMR (400 MHz, CDCl3): d = 3.66 (s, 6 H), 3.77(s, 3 H), 5.81 (s,
1 H), 6.50 (s, 2 H), 6.80 (d, J = 8.8 Hz, 2 H), 6.99 (t, J = 7.6 Hz, 2
H), 7.17–7.27 (m, 6 H), 7.36 (d, J = 8 Hz, 2 H).
Bis(2-methylindol-3-yl)(phenyl)methane (3a)29
Pink solid; mp 246–248 °C.
1H NMR (400 MHz, CDCl3): d = 1.91 (s, 6 H), 5.81 (s, 1 H), 6.57
(t, J = 8 Hz, 2 H), 6.74–6.79 (m, 4 H), 7.00–7.08 (m, 7 H), 8.67 (br,
2 H, NH).
(4-Methoxyphenyl)bis(2-methylindol-3-yl)methane (3b)26
Pink solid; mp 99–101 °C.
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(s, 1 H), 6.77 (d, J = 8.8 Hz, 2 H), 6.82 (t, J = 8.4 Hz, 2 H), 6.99 (d,
J = 8.4 Hz, 2 H), 7.03 (t, J = 7.2 Hz, 2 H), 7.15 (d, J = 7.2 Hz, 2 H),
7.22 (d, J = 8.8 Hz, 2 H), 7.7 (br, 2 H, NH).
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Bis(5-bromoindol-3-yl)(phenyl)methane (4)10
Red solid; mp 246–248 °C.
1H NMR (400 MHz, CDCl3): d = 5.73 (s, 1 H), 6.62 (s, 2 H), 7.16–
7.28 (m, 9 H), 7.45 (s, 2 H), 7.97 (br, 2 H, NH).
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Bis(5-methoxyindol-3-yl)(phenyl)methane (5)30
Pink solid; mp 218–220 °C.
1H NMR (400 MHz, CDCl3): d = 2.67 (s, 6 H), 5.75 (s, 1 H), 6.64
(s, 2 H), 6.78–6.82 (m, 4 H), 7.21–7.34 (m, 7 H), 7.8 (br, 2 H, NH).
Bis(7-ethylindol-3-yl)(phenyl)methane (6)
Red solid; mp 97–99 °C.
1H NMR (400 MHz, CDCl3): d = 1.40 (q, J = 7.6 Hz, 6 H), 2.83 (t,
J = 7.6 Hz, 4 H), 5.92 (s, 1 H), 6.39 (s, 2 H), 7.08–7.10 (m, 4 H),
7.32–7.40 (m, 7 H), 7.5 (br, 2 H, NH).
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124, 126, 128, 135, 144.
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ESI-HRMS: m/z [M + Na] calcd for C27H26N2: 401.1994; found:
401.1985.
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3,3¢,3¢¢,3¢¢¢-(1,4-Phenylenedimethanetriyl)tetrakis(1H-indole)
(7)7
Orange-red solid; mp 139 –141 °C
1H NMR (400 MHz, CDCl3): d = 5.81 (s, 2 H), 6.60 (s, 4 H), 6.90
(t, J = 6 Hz, 4 H), 7.11 (t, J = 6 Hz, 4 H), 7.28 (d, J = 6 Hz, 4 H),
7.36 (d, J = 6 Hz, 4 H), 8.32 (br, 4 H, NH).
Acknowledgment
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Synthesis 2007, No. 20, 3125–3128 © Thieme Stuttgart · New York