Facile and mild synthesis of bis(3-indolyl)methanes

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Facile and Mild Synthesis of bis(3-
Indolyl)methanes
a
b
R. Ghorbani-Vaghei & S. M. Malaekehpoor
a
Department of Organic Chemistry, Faculty of Chemistry, Bu–Ali Sina
University, Hamedan, Iran
b
Payame Noor University, Hamedan, Iran
Version of record first published: 07 Apr 2010.
To cite this article: R. Ghorbani-Vaghei & S. M. Malaekehpoor (2010): Facile and Mild Synthesis of
bis(3-Indolyl)methanes, Organic Preparations and Procedures International: The New Journal for
Organic Synthesis, 42:2, 175-182
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Organic Preparations and Procedures International, 42:175–182, 2010
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304941003699715
Facile and Mild Synthesis of bis(3-Indolyl)methanes
1
2
R. Ghorbani-Vaghei and S. M. Malaekehpoor
1Department of Organic Chemistry, Faculty of Chemistry, Bu–Ali Sina
University, Hamedan, Iran
2
Payame Noor University, Hamedan, Iran
bis(Indolyl)alkanes and their derivatives are of great interest and importance because of
1
their pharmaceutical and biological applications. They are the most cruciferous substances
2
for the promotion of beneficial estrogen metabolism in women and men. Therefore, the
3
synthesis of these moieties has become of interest to organic chemists. Several method-
ologies for their preparation have already been developed, mainly using protic or Lewis
4
5
6
7
acids. Recently, glacial acetic acid, HBF4-SiO2 and I2 have also been found to catalyze
preparation of the bis(indolyl)methanes. However, since some procedures involve the use
5
7
of microwave irradiation or heat, corrosive catalysts, and require tedious work-ups, and/or
4
long reaction times, new procedures that address these drawbacks seem desirable.
In continuation of our interest in the application of N,N,N ,N –tetrabromobenzene-
,3-disulfonamide [TBBDA] and poly(N-bromobenzene-1,3-disulfonamide) [PBBS]
ꢀ
ꢀ
8
1
8–13
in organic synthesis,
we now report a convenient method for the synthesis of
bis(indolyl)methanes from indole with various aldehydes and ketones in the presence
of TBBDA and PBBS under in solution and solvent-free conditions.
The electrophilic substitution reaction of indole with aldehydes and ketones in the
presence of TBBDA and PBBS proceed smoothly at room temperature to afford the corre-
sponding bis(3-indolyl)methanes (1) in good to high yields (Scheme 1, Table 1).
R
R'
R'
R
TBBDA or PBBS
+
O
N
N
N
H
H
H
1
Scheme 1
It is noteworthy that neither electronic nor steric variation in the aldehydes has any effect
on the yields. Functional groups such as methoxy (Entries 3, 7, 11), hydroxyl (Entries 4,7,
Submitted April 10, 2009.
Address correspondence to R. Ghorbani-Vaghei Department of Organic Chemistry, Faculty of
Chemistry, Bu–Ali Sina University, Hamedan, Iran. E-mail: rgvaghei@yahoo.com
175

176
Ghorbani-Vaghei and Malaekehpoor
Br
Br
N
Br
N
Br
N
N
SO2
CH2
SO
CH2
2
Br
n
Br
SO2
SO2
TBBDA
PBBS
Figure 1
Structure of Reagents
1
Forthermore, polycyclic aromatic aldehydes (Entries 15, 16), aliphatic aldehyde (Entry
8) and ketones (Entries 19–21) and cis-cinnamaldehyde were treated with indole in the
3), halo (Entries 5,12, 14) and nitro (Entries 9, 10) were unchanged during the reaction.
1
presence of TBBDA and PBBS to give the corresponding bis(indolyl)methanes in good to
high yields.
15
Based on these results, tris(indolyl)methanes are also formed when three equivalents
of indole are treated with 3-formylindole in the presence of TBBDA under solvent-free
conditions at room temperature (2) but PBBS under these conditions and use of two
equivalents of indole afforded the corresponding product in less yield (Scheme 2).
CHO
CH
3
)
TBBDA (0.2 eq )
+
N
N
Solvent - free /5.5 h / 85 %
N
H
H
H
2
Scheme 2
ꢀ
ꢀ
N,N,N ,N -Tetrabromobenzene-1,3-disulfonamide [TBBDA] and poly(N-bromoben-
zene-1,3-disulfonamide) [PBBS] are also effective for the synthesis of tetra-3-
indolyl(terephthalyl)dimethanes.17 Thus tetra(2-indolyl)(terephthalyl)dimethanes were
obtained by controlling the molar ratio of indole. Addition of two and four equivalents
of indole to terephthaldialehydehyde, gave 3 and 4 respectively at room temperature under
solvent-free and solvent conditions (Scheme 3).
17
H
N
H
N
H
N
4
equiv. indole
2 equiv. indole
OHC
CHO
CHO
N
H
N
H
N
H
4
3
9
9
1% (TBBDA)
6% (PBBS)
8
9
7% (TBBDA)
4% (PBBS)
Scheme 3
Since PBBS and TBBDA contain bromine atoms which are attached to nitrogen atoms,
+
it is possible that these reagents release Br in situ which can act as an electrophilic

Facile and Mild Synthesis of bis(3-Indolyl)methanes
177
Table 1
Formation of bis(indolyl)methanes with Aldehydes and Ketones Catalyzed by TBBDA or
PBBS Under Different Condition
Solvent (CH3CN)
Solvent- free
TBBDA
Yield(%)/ Yield (%)/ Yield(%)/ Yield (%)/ mp. ( C)
Time(min) Time (min) Time(min) Time (min) (lit.) Ref.
PBBS
TBBDA
PBBS
◦
Entry
1
Product
87
120)
85
(65)
94
(2)
97
(10)
124–126 16
(125–126)
(
N
H
N
H
CH
3
2
3
82
180)
92
(7)
97
(5)
94
(10)
96–97
(96–98)
16
(
N
H
N
H
OCH
3
95
93
(102)
95
(3)
87
(110)
187–189 14
(187–189)
(30)
N
H
N
H
OH
4
5
90
180)
90
(86)
93
(60)
94
(170)
121–123 16
(120–122)
(
N
H
N
H
Cl
87
95
98
95
76–78
14
(150)
(10)
(1)
(163)
(76–77)
N
H
N
H
6
7
O
93
96
(125)
97
(1)
97
(60)
319–321 16
(320–322)
(3)
N
H
N
H
OH
80
91
(8)
92
(2)
96
(6)
118–120
—
—
H
3
CO
OCH3
(45)
N
H
N
H
8
9
90
96
(100)
95
(5)
75
(75)
82–84
—
—
(45)
N
H
N
H
NO
2
91
180)
83
(177)
96
(1)
93
(68)
261–263 16
(260–262)
(
N
H
N
H
(Continued on next page)

178
Ghorbani-Vaghei and Malaekehpoor
Table 1
Formation of bis(indolyl)methanes with Aldehydes and Ketones Catalyzed by TBBDA or
PBBS Under Different Condition (Continued)
Solvent (CH3CN)
Solvent- free
TBBDA
Yield(%)/ Yield (%)/ Yield(%)/ Yield (%)/ mp. ( C)
Time(min) Time (min) Time(min) Time (min) (lit.) Ref.
PBBS
TBBDA
PBBS
◦
Entry
Product
10
NO
2
92
100)
90
(142)
93
(1)
89
(100)
218–220 16
(220–222)
(
N
H
N
H
1
1
2
95
97
(25)
94
(2)
96
(5)
134–135 16
(134–136)
OCH
3
(60)
N
H
N
H
Br
1
90
180)
96
(135)
92
(1)
98
(77)
110–112 19
(112–113)
(
N
H
N
H
13
14
15
95
180)
95
(51)
92
(1)
90
(102)
340–342 16
(342–344)
OH
(
(
(
N
H
N
H
93
240)
96
(20)
90
(10)
90
(120)
71–73
14
Cl
(72–74)
N
H
N
H
90
105)
95
(30)
87
(41)
94
(37)
218–220 18
(220)
N
H
N
H
16
17
18
79
190)
94
(300)
84
(50)
90
(510)
236–238 16
(236–239)
(
N
H
N
H
72
155)
85
(285)
78
(120)
60
(144)
95–97
16
6
(
(96–98)
N
H
N
H
94
98
95
98
67–69
(8)
(7)
(15)
(19)
(68–70)
N
H
N
H
(Continued on next page)

Facile and Mild Synthesis of bis(3-Indolyl)methanes
179
Table 1
Formation of bis(indolyl)methanes with Aldehydes and Ketones Catalyzed by TBBDA or
PBBS Under Different Condition (Continued)
Solvent (CH3CN)
Solvent- free
TBBDA
Yield(%)/ Yield (%)/ Yield(%)/ Yield (%)/ mp. ( C)
Time(min) Time (min) Time(min) Time (min) (lit.) Ref.
PBBS
TBBDA
PBBS
◦
Entry
Product
19
20
21
90
330)
90
(305)
88
(5)
80
(50)
117–119 16
(116–118)
(
N
H
N
H
CH3
80
83
(236)
78
(60)
70
(98)
188–190 16
(188–190)
(15)
N
H
N
H
CH
3
CH3
87
83
86
96
64–65
6
(25)
(46)
(27)
(30)
(64–66)
N
H
N
H
aProducts were characterized from their physical properties, comparison with authentic samples
and by spectroscopic methods.
species.8,14 Therefore, the following mechanism can be suggested for the synthesis of
bis(3-indolyl)methanes (Scheme 4).
R
R'
OBr
R
R'
R
-H+
Br-reagent
R'
O
-HOBr
Compound 1
H
N
+
+
H
N
N
H
N
H
H
Scheme 4
In summary, we have developed a simple, convenient and efficient synthetic protocol
for the synthesis of bis(3-indolyl)methanes be used amounts of [TBBDA] and [PBBS]
under solvent-free and solvent conditions at room temperature. It was found that TBBDA
gives better results under solvent-free conditions than in slution but the reverse is true for
PBBS. The short reaction time coupled with the simplicity of the procedure make this
method one of the most efficient methods for the synthesis of this class of compounds.
Experimental Section
Substrates, solvents and other chemicals were purchased from Fluka, Merck and Aldrich
chemical companies. The progress of the reaction was monitored by (TLC SiO2-n-
hexane:acetone). IR spectra (KBr) were conducted on Shimadzu infrared Fx-90 spec-
trophotometer and the nuclear magnetic resonance (NMR) spectra were recorded on a Jeol
90 MHz spectrometer using TMS as the internal standard. TBBDA and PBBS were prepared

180
Ghorbani-Vaghei and Malaekehpoor
Table 2
Elemental Analyses and Spectroscopic Data of New Compounds
◦
C25H22N2O3 (Entry 7): Pink solid, mp 118–120 C; IR (KBr): ν 3391, 2934, 1513,
−
1 1
1
2
(
456, 1422, 1323, 1211, 1111, 743 cm ; H NMR (FT-90 MHz, CDCl3): δ 7.94 (brs,
H, NH), 7.47–7.30 (4H, m), 7.25 (2H, d, J = 7.1 Hz), 7.07 (2H, d, J = 7.2 Hz), 6.63
13
2H, s), 6.58 (2H, s), 5.79 (1H, s), 3.72 (6H, s), 2.00 (1H, s); C NMR (FT-90 MHz,
CDCl3): δ 40.41, 56.30, 105.8, 111.1, 119.2, 119.9, 121.9, 123.6, 127.1, 133.6, 135.5,
+
1
36.8,146.9, 148.1; MS (m/z) 398 (M ).
Anal. Calcd. for C25H22N2O3: C, 75.37; H, 5.52; N, 7.03. Found: C, 75.20; H, 5.70; N,
.02.
C25H22N2 (Entry 8): Brown solid, mp 82–84 C; IR (KBr): ν 3389, 2928, 1494, 1455,
7
◦
−
1 1
1
2
(
337, 1226, 1094, 907, 742, 699 cm ; H NMR (FT-90 MHz, CDCl3): δ 8.04 (brs,
H, NH), 7.75 (2H,d, J = 11.6 Hz), 7.58 (2H,d, J = 5.3 Hz), 7.51–7.38 (3H, m), 7.25
2H,d, J = 13.4 Hz), 7.19–6.89 (4H, m), 6.49 (2H, s), 5.25 (1H, s), 4.48–4.38 (2H,
13
m), 2.54 (2H, t, J = 8.0 Hz); C NMR (FT-90 MHz, CDCl3): δ 33.96, 35.87, 37.39,
1
11.3, 119.6, 120.0, 121.0, 122.3, 125.9, 126.3, 127.1, 128.4, 128.5, 136.6, 142.0; MS
+
(
m/z) 350 (M ).
Anal. Calcd. for C25H22N2: C, 85.71; H, 6.29; N, 8.00. Found: C, 85.71; H, 6.16; N,
.93.
7
8
according to our previously reported procedure. Elemental analyses and spectroscopic data
of the two new compounds prepared are given in Table 2.
General Procedure for Solvent-free Synthesis of bis(3-Indolyl)methanes using TBBDA
or PBBS
To a mixture of aldehyde (1 mmol) and indole (0.23 g, 2 mmol) was added TBBDA or PBBS
(0.05 g, 0.1 mmol). The mixture was stirred with magnetic stirrer at room temperature for
to appropriate time (Table 1). The progress of the reaction was monitored by TLC (8:2
n-hexane/acetone). After completion of the reaction, CH2Cl2 (20 mL) was added, and the
sulphonamide was removed by vacuum filtration. Evaporation of the filtrate under reduced
pressure gave generally pure products. Some of compounds (Entries 3, 4, 10, 14, 19, 20)
were purified by thin layer chromatography (8:2, n-hexane/acetone).
General Procedure for the Synthesis of bis(3-Indolyl)methanes using TBBDA or PBBS
in Acetonitrile
To a mixture of aldehyde (1 mmol) and indole (0.23 g, 2 mmol) was added TBBDA or
PBBS (0.05 g, 0.1 mmol) in acetonitrile (2 mL). The mixture was stirred with magnetic
stirrer at room temperature for the appropriate time (Table 1). The Progress of the reaction
was monitored by TLC (8:2 n-hexane/acetone). After completion of the reaction, CH2Cl2
(20 mL) was added, and the sulphonamide was removed by vacuum filtration. Evaporation
of the solvent under reduced pressure gave generally pure products. Some of compounds

Facile and Mild Synthesis of bis(3-Indolyl)methanes
181
(
Entries 1, 2, 4, 9, 10, 13, 17, 19, 20, 21) were purified by thin layer chromatography (8:2,
n-hexane/acetone).
General Procedure for Solvent-free Synthesis of tris(Indolyl)methanes using TBBDA
To a mixture of 3-formylindole (1 mmol) and indole (0.35 g, 3 mmol) was added TBBDA
(0.1 g, 0.2 mmol). The mixture was stirred with magnetic stirrer at room temperature for
to appropriate time (Scheme 2). The progress of the reaction was monitored by TLC (8:2
n-hexane/acetone). After completion of the reaction, CH2Cl2 (20 mL) was added, and the
sulphonamide was removed by vacuum filtration. Evaporation of the solvent under reduced
pressure and purified by thin layer chromatograghy gave generally pure products.
General Procedure for Solvent-free Synthesis of Tetra-2-indolyl(terephthalyl)
dimethanes using TBBDA
To a mixture of terephthaldialdehyde (0.13 g, 1 mmol) and indole (0.23 g, 2 mmol) was
added TBBDA or PBBS (0.05 g, 0.1 mmol). The mixture was stirred with magnetic stirrer
at room temperature for to appropriate time (Scheme 3). The progress of the reaction was
monitored by TLC (8:2 n-hexane/acetone). After completion of the reaction, CH2Cl2 (20
mL) was added, and the sulphonamide was removed by vacuum filtration. Evaporation of
the filtrate under reduced pressure gave generally pure products.
General Procedure for the Synthesis of Tetra-2-indolyl(terephthalyl)dimethanes using
PBBS in Acetonitrile
To a mixture of terephthaldialdehyde (0.13 g, 1 mmol) and indole (0.23 g, 2 mmol) was
added TBBDA or PBBS (0.05 g, 0.1 mmol) in acetonitrile (2 mL). The mixture was stirred
with magnetic stirrer at room temperature for the appropriate time (Table 1). The Progress
of the reaction was monitored by TLC (8:2 n-hexane/acetone). After completion of the
reaction, CH2Cl2 (20 mL) was added, and the sulphonamide was removed by vacuum
filtration. Evaporation of the solvent under reduced pressure gave generally pure products.
General Procedure for Solvent-free Synthesis of Tetra-3-indolyl(terephthalyl)
dimethanes using TBBDA
To a mixture of terephthaldialdehyde (0.13 g, 1 mmol) and indole (0.46 g, 4 mmol) was
added TBBDA or PBBS (0.16 g, 0.3 mmol). The mixture was stirred with magnetic stirrer
at room temperature for to appropriate time (Scheme 3). The progress of the reaction was
monitored by TLC (8:2 n-hexane/acetone). After completion of the reaction, CH2Cl2 (20
mL) was added, and the sulphonamide was removed by vacuum filtration. Evaporation of
the filtrate under reduced pressure gave generally pure products.
General Procedure for the Synthesis of Tetra-3-indolyl(terephthalyl)dimethanes
using PBBS in Acetonitrile
To a mixture of terephthaldialdehyde (0.13 g, 1 mmol) and indole (0.23 g, 2 mmol) was
added TBBDA or PBBS (0.16 g, 0.3 mmol) in acetonitrile (2 mL). The mixture was stirred
with magnetic stirrer at room temperature for the appropriate time (Table 1). The Progress

182
Ghorbani-Vaghei and Malaekehpoor
of the reaction was monitored by TLC (8:2 n-hexane/acetone). After completion of the
reaction, CH2Cl2 (20 mL) was added, and the sulphonamide was removed by vacuum
filtration. Evaporation of the solvent under reduced pressure gave generally pure products.
Acknowledgments
We are thankful to Bu-Ali Sina University, Center of Excellence and Development of
Chemical Methods (CEDCM) for financial support.
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