Efficient synthesis of bis (indolyl) methanes catalyzed by (PhCH2PPh3)+Br3- under solvent-free conditions

Article abstract of DOI:10.1016/j.cclet.2010.05.028

Benzyltriphenylphosphonium tribromide (BTPTB) has been applied as an efficient catalyst for the preparation of bis (indolyl) methanes (BIMs) via electrophilic substitution of indoles with aldehydes in the absence of solvent.

Full text of DOI:10.1016/j.cclet.2010.05.028

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Chinese Chemical Letters 21 (2010) 1342–1345
www.elsevier.com/locate/cclet
Efficient synthesis of bis (indolyl) methanes catalyzed by
+
À
(
PhCH PPh ) Br under solvent-free conditions
2 3 3
*
Farhad Shirini , Mohaddeseh Safarpoor Langroodi, Masoumeh Abedini
Department of Chemistry, College of Science, University of Guilan, Rasht 41335, Islamic Republic of Iran
Received 24 March 2010
Abstract
Benzyltriphenylphosphonium tribromide (BTPTB) has been applied as an efficient catalyst for the preparation of bis (indolyl)
methanes (BIMs) via electrophilic substitution of indoles with aldehydes in the absence of solvent.
#
2010 Farhad Shirini. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Benzyltriphenylphosphonium tribromide; Aldehydes; Indoles; Bis (indolyl) methanes; Solvent-free conditions
Bis (indolyl) methanes (BIMs), which contain two indole or substituted indole units in a molecule, feature widely in
bioactive metabolites of terrestrial and marine origin [1]. These types of compounds are also known to promote
estrogen metabolism in both women and men and is expected to have an application in prevention of breast cancer [2].
Therefore, significant efforts have been directed towards the synthesis of these molecules. Synthetically, bis (indolyl)
methanes are obtained via the electrophilic substitution of indoles with carbonyl compounds. To improve the rate of
this type of reactions, a variety of catalysts have been reported, of them HCl [3], NBS [4], I [5,6], KHSO [7],
2
4
NaHSO ÁSiO [8], ZrCl [9], InCl and In(OTf) [10], HClO ÁSiO [11], ZrOCl .8H O/SiO [12], AlPW O [13],
4
2
4
3
3
4
2
2
2
2
12 40
H PW O [14], H P W O [15], polyindole salt [16], montmorillonite K-10 [17], trichloro-1,3,5-triazine [18],
3
12 40
6
2
18 62
dodecyl sulfates [19], TPA ZrO [20], sulfamic acid [21], aminosulfonic acid [22], RuCl ÁnH O [23], La(OTf) [24]
4
3
2
3
and La(PFO) [25] are examples. However, most of the reported procedures suffer from disadvantages such as long
3
reaction times, low product yields, tedious work-up procedure, use of expensive reagents, use of a larger
stoichiometric amount of catalyst and use of an additional microwave or ultrasound irradiation. Therefore,
introduction of new methods and catalysts for the preparation of BIMs is still in demand.
1
. Experimental
1
.1. Typical procedure
To a mixture of indole (2.0 mmol, 0.234 g) and 4-chlorobenzaldehyde (1 mmol, 0.141 g), BTPTB (0.1 mmol,
.06 g) and SiO (0.0 6 g) were added. The resulting mixture was stirred at 90 8C for 8 min. The progress of the
0
2
*
Corresponding author.
E-mail address: shirini@guilan.ac.ir (F. Shirini).
1001-8417/$ – see front matter # 2010 Farhad Shirini. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.05.028

F. Shirini et al. / Chinese Chemical Letters 21 (2010) 1342–1345
1343
reaction was monitored by TLC. Upon completion of the reaction, the mixture was cooled to room temperature. Then
MeOH (3 mL) was added, the mixture was filtered and filtrate was washed with MeOH (2 mL). After evaporation of
the solvent under reduced pressure the crude product was obtained. For further purification the product was
recrystallized from an ethanol:water solution (95:5, v/v). Pure product was obtained as a pink solid in 80% yield, mp
À1
1
8
5–87 8C (lit. 87–89 8C [15]); FT-IR (KBr): y (cm ): 3410, 3054, 1487, 1455, 1089. H NMR (300 MHz, CDCl ): d
3
5
.86 (s, 1H, Ar-CH), 6.66 (s, 2H), 7.02 (t, 2H, J = 8.3 Hz), 7.23–7.38 (m, 8H), 7.4 (d, 2H, J = 8.1 Hz), 7.85 (br, s, 2H,
NH).
.2. Selected spectral data
Table 1, entry 2: Yellow needles; mp: 211–215 8C; IR (KBr): y (cm ) 1340, 1456, 1507, 1592, 3052, 3422. H
1
À1
1
NMR (400 MHz, CDCl ): d 6.00 (s, 1H), 6.70 (s, 2H), 7.00–7.05 (m, 3H), 7.35 (d, 3H, J = 8.0 Hz), 7.40 (d, 2H,
J = 8.0 Hz), 7.52 (d, 2H, J = 8.8 Hz), 8.04 (br, s, 2H), 8.15 (d, 2H, J = 8.8 Hz).
3
À1
1
Table 1, entry 14: Brown solid; mp > 310 8C; IR (KBr): y (cm ) 1260, 1450, 1715, 3410. H NMR (400 MHz,
CDCl ): d 5.95 (s, 1H), 6.90 (s, 2H), 7.03–7.50 (m, 11H), 8.00 (br, s, 2H).
À1
3
1
Table 1, entry 15: Pink solid; mp: 115–118 8C; FT-IR (KBr), y (cm ) 3405, 3049, 1622, 1455, 1216. H NMR
(
300 MHz, DMSO-d ): d 5.75 (s, 2 H), 6.29 (s, 4H), 7.05 (t, 4H, J = 7.6 Hz), 7.16 (t, 4H, J = 7.6 Hz), 7.24–7.40 (m,
2H), 7.31 (br, s, 4H).
6
1
Table 1
a,b
.
Synthesis of bis (indolyl) methanes in the absence of solvent.
Entry
Carbonyl compound
CHO
X
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
C
6
H
5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
16
5
80
85
85
87
89
80
90
95
75
93
88
87
96
75
4-NO
3-NO
2-NO
4
C
4
C
4
C
6
H
6
H
6
H
4
4
4
CHO
CHO
CHO
5
9
4-BrC
6
H
4
CHO
CHO
CHO
CHO
6
4-ClC
3-ClC
2-ClC
6
6
6
H
H
H
4
4
4
8
11
12
11
20
9
4-MeC CHO
4
6
H
10
11
12
13
14
6 4
4-HOC H CHO
2-MeOC
3-MeOC
6
H
4
CHO
CHO
CHO
6
H
4
8
3,4-(MeO)
Furfural
2
C
6
H
3
8
10
c,d
68/23
15
[
$
N
N
]
H
11
16
17
18
19
20
21
22
PhCH CHCHO
PhCH CH CHO
PhCH(Me)CHO
4-NO CHO
CHO
CHO
H
9
13
15
7
75
80
80
88
85
82
80
2
2
H
H
4
C
6
H
4
Me
Me
Me
Me
4-BrC
6
H
4
10
10
9
6 4
4-HOC H
2 6 3
3,4-(MeO) C H CHO
e
2
3
4
H
H
90
–
[DT$INLE]
e
2
[
D
I
L
N
]
120
–
a
b
c
The desired products were characterized by comparison of their IR and NMR spectra with those of the known compounds [2,6,11,13–15,22,28–31].
Isolated yield.
4.1 mmol of indole was used.
d
e
[
T
D
$
I
N
L
I
N
E
]
and
[
D
I
L
N
]
were obtained in 68 and 23%, respectively.
Mixture of products.

[(Scheme_1)TD$FIG]
1
344
F. Shirini et al. / Chinese Chemical Letters 21 (2010) 1342–1345
Scheme 1.
À1
Table 1, entry 22: Pink solid; mp: 202–204 8C; IR (KBr): y (cm ) 740, 1020, 1135, 1245, 1455, 1510, 3050, 3410.
1
H NMR (400 MHz, CDCl ): d 2.08 (s, 6H), 3.71 (s, 3H), 3.85 (s, 3H), 5.96 (s, 1H), 6.75 (s, 2H), 6.85 (m, 3H), 7.03 (t,
H), 7.24 (t, 2H), 7.77 (s, 2H).
3
4
2
. Results and discussion
Recently, we have reported the preparation of benzyltriphenylphosphonium tribromide (BTPTB) and its
application in the preparation, deprotection and oxidative deprotection of trimethylsilyl ethers [26]. In continuation of
this study, herein, we wish to report the applicability of this reagent in the promotion of the preparation of BIMs via the
electrophilic substitution of indoles with various aldehydes (Scheme 1).
In order to optimize the reaction conditions, we have used BTPTB as a catalyst for the condensation of
benzaldehyde with indole in the absence of solvent. A highly sticky orange reaction mixture was obtained with the
formation of the desired bis (indolyl) methane in low yield after several h. Therefore, we studied the catalytic effect of
BTPTB in the presence of SiO for the similar reaction. The result was obtained by carrying out the reaction of
2
benzaldehyde (1 mmol) with indole (2 mmol) in the presence of 0.1 mmol of BTPTB and 0.06 g of SiO at 90 8C for
2
1
6 min in the absence of solvent (Table 1, entry 1). After optimization of the reaction conditions and in order to show
the general applicability of the method, different types of aldehydes were subjected to the same reaction under the
determined conditions. As shown in Table 1, the corresponding BIMs were obtained during relatively short reaction
times in good to high yields. Because of the formation of unidentified products, the present method is not suitable for
the synthesis of BIMs from ketones (Table 1, entries 23 and 24).
A plausible mechanism of the reaction is shown in Scheme 2, based on the reported pathway in literature [5,27], our
observations and obtained results. On the basis of this mechanism, BTPTB reacts with aldehyde to give
benzyltriphenylphosphonium bromide and intermediate I, and it followed by indole attack to I to give II and loss of
[(Scheme_2)TD$FIG]
Scheme 2.

F. Shirini et al. / Chinese Chemical Letters 21 (2010) 1342–1345
1345
H O from II to afford III which is activated by Br . The other indole is added to III in the following step to give the
2
2
requested product and Br , which can catalyze the reaction in a catalytic manner.
2
In conclusion, we have reported the application of BTPTB in the efficient synthesis of BIMs. Relatively short
reaction times, good to high yields of the products, solvent-free conditions and simple experimental procedure are
among the other advantages of this method which make this procedure a useful addition to the available methods.
Acknowledgment
We are thankful to the University of Guilan Research Council for the partial support of this work.
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