Molecular iodine-catalyzed efficient and highly rapid synthesis of bis(indolyl)methanes under mild conditions

Article abstract of DOI:10.1016/S0040-4039(03)00032-7

Highly rapid and efficient electrophilic substitution reactions of indoles with various aldehydes and ketones were carried out using I₂ in CH₃CN to afford the corresponding bis(indolyl)methanes in excellent yields.

Full text of DOI:10.1016/S0040-4039(03)00032-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1959–1961
Molecular iodine-catalyzed efficient and highly rapid synthesis of
bis(indolyl)methanes under mild conditions
B. P. Bandgar* and K. A. Shaikh
Organic Chemistry Research Laboratory, School of Chemical Sciences, Swami Ramanand Teerth Marathwada University,
Vishnupuri, Nanded 431606, India
Received 2 December 2002; accepted 20 December 2002
Abstract—Highly rapid and efficient electrophilic substitution reactions of indoles with various aldehydes and ketones were carried
out using I in CH CN to afford the corresponding bis(indolyl)methanes in excellent yields. © 2003 Elsevier Science Ltd. All
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rights reserved.
Indoles and their derivatives are used as antibiotics in
the field of pharmaceuticals. Bisindolylalkanes and
In recent years, molecular iodine has received consider-
able attention as an inexpensive and easily available
catalyst for effecting various organic transformations.
We now report here the synthesis of bis(in-
dolyl)methanes by condensation of indoles with various
carbonyl compounds using molecular iodine in acetoni-
trile as an efficient catalyst under mild conditions in a
very short time, <1 min (Scheme 1).
1
1
2
their derivatives constitute an important group o2f
bioactive metabolites of terrestrial and marine origin.
The acid-catalyzed reaction of electron rich heterocyclic
compounds with p-dimethylaminobenzaldehyde is
3
knows as the Ehrlich test for p-electron rich heterocy-
cles such as pyrroles and indoles. The analogous reac-
tion of indoles with other aromatic or aliphatic
aldehydes and ketones produces azafulvenium salts.
The azafulvenium salts can undergo further addition
with a second indole molecule to afford bis(in-
6,7
Bis(indolyl)methanes are formed in almost quantitative
yields when indole was treated with various aldehydes
or ketones in the presence of a catalytic amount (20%)
4
5
dolyl)methanes. Protic acids as well as Lewis acids
are known to promote these reactions. Recently, mont-
of I in acetonitrile. The electrophilic substitution reac-
2
tions of indoles with aldehydes as well as ketones
proceeded smoothly at room temperature. The results
summarized in Table 1, clearly indicate the scope and
generality of the reaction as the reactions of aliphatic
aldehydes (entries 3a–d), a,b-unsaturated aldehydes
(entry 2), a variety of substituted aromatic aldehydes
(entries 1a–i) as well as aliphatic, alicyclic and aromatic
ketones (entries 4a–c) with indoles in the presence of I2
(20%) in acetonitrile gave the corresponding bis(in-
dolyl)methanes in excellent yields. It is reported that
aromatic aldehydes with strong electron withdrawing
substituents on the ring and both aliphatic and aro-
matic ketones required longer reaction times giving low
to moderate yields of the corresponding bis(in-
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morillonite clay K-10 and lanthanide triflates were
also found to catalyze these reactions. However, many
Lewis acids are deactivated or sometimes decomposed
by nitrogen containing reactants. Even when the
desired reactions proceed, more than stoichiometric
amounts of the Lewis acids are required because the
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acids are trapped by nitrogen. These problems can be
somewhat circumvented by using expensive lithium per-
1
1
chlorate. However, it requires longer reaction times
for nitro-substituted aromatic aldehydes giving the cor-
responding bis(indolyl)methanes in moderate yields
whereas reactions with aromatic ketones were very slow
resulting in poor yields of the products.
Keywords: iodine; bis(indolyl)methanes; aldehydes and ketones;
indoles; electrophilic substitution reactions.
*
Corresponding author. Fax: +91-2462-29245; e-mail: bandgar bp@
yahoo.com
–
Scheme 1.
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(03)00032-7

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B. P. Bandgar, K. A. Shaikh / Tetrahedron Letters 44 (2003) 1959–1961
Table 1. I -catalyzed synthesis of bis(indolyl)methanes
2
dolyl)methanes. In this context, the present protocol is
noteworthy because even nitro substituted aromatic
aldehydes and both aliphatic and aromatic ketones
underwent smooth reactions with indoles giving excel-
lent yields of products under mild and neutral condi-
tions in a very short time (<1 min).
require longer reaction times giving moderate yields of
products for this conversion. The present procedure is
superior in comparison with BF ·Et O- or AlCl -cata-
3
2
3
lyzed reactions of acetone with indole which generated
7a,13
several unexpected products
whereas expensive lan-
thanide triflate-catalyzed reactions took a very long
9
reaction time (24 h). 3-Substituted indoles such as
Furthermore, the reaction of indole with a,b-unsatu-
indole-3-acetic acid, indole-3-propionic acid and indole-
3-butyric acid were examined for this reaction with
aldehydes or ketones (entry 5). Since the more active
site (C-3) was blocked in these cases electophilic
rated aldehydes in the presence of I (20%) furnished
2
excellent yields of the corresponding bis(indolyl)-
methanes in <1 min. However, the reported catalysts

B. P. Bandgar, K. A. Shaikh / Tetrahedron Letters 44 (2003) 1959–1961
1961
substitution took place at C-2 giving the corresponding
bis(indolyl)methanes (entry 5) in good to excellent
C H N : C, 85.68; H, 5.99; N, 8.33. Found: C, 85.75;
24 20 2
H, 5.88; N, 8.28%.
yields. In comparison to the reported catalysts, I in
2
acetonitrile was found to be an excellent catalyst in
terms of yields and reaction times. This is because of
the mild Lewis acidity of iodine, which activates the
carbonyl group as well as the indole moiety to promote
the reaction (Scheme 2).
References
1. Sundberg, R. J. The Chemistry of Indoles; Academic
Press: New York, 1970.
2
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In conclusion, I in acetonitrile was found to be mild
2
and effective catalyst for the electophilic substitution
reactions of indoles with aldehydes and ketones giving
bis(indolyl)methanes in excellent yields. The use of this
inexpensive and easily available catalyst under essen-
tially neutral reaction and work-up conditions, the
cleaner reaction and greater selectivity make this proto-
col practical and economically attractive. The proce-
dure was found to be general as a variety of aldehydes
and ketones react with indoles under mild reaction
conditions in a very short time (<1 min)
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Typical procedure: A mixuture of 4-methylbenzaldehyde
(
1 mmol), indole (2 mmol) and I (0.2 mmol) in acetoni-
2
trile (10 ml) was stirred at room temperature for a few
seconds. After completion of the reaction (TLC, <1
min), the mixture treated with aq. Na S O solution
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cycles 1981, 15, 325.
2
2
3
(
5%, 10 ml) and the product was extracted with ethyl
acetate (3×5 ml). The combined organic layer was dried
with anhydrous sodium sulphate, concentrated in vacuo
and purified by column chromatography (ethyl ace-
tate:petroleum ether=1:9) to afford the pure product.
7. (a) Chatterjee, A.; Manna, S.; Banerji, J.; Pascard, C.;
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3
9
1
,3%-Bis(indolyl)-4-methylphenylmethane: solid; mp 96–
4
7°C; yield 99%; IR (KBr): w 765, 1050, 1210, 1520,
9
−
1
1
600, 2950, 3040, 3110, 3450 cm ; H NMR (300
3
MHz, CDCl ): l 2.38 (s, 3H, Ar-CH ), 5.85 (s, 1H,
Ar-CH), 6.70 (d, 2H, J=2.5 Hz), 7.02 (t, 2H, J=8.1
Hz), 7.1 (d, 2H, J=8.1 Hz), 7.2–7.3 (m, 6H), 7.4 (d,
3
3
1
1
1
1
1. Yadav, J. S.; Subba Reddy, B. V.; Murthy, C. V. S. R.;
Kumar, G. M.; Madan, C. Synthesis 2001, 5, 783.
2
1
H, J=8.1 Hz), 7.85 (br, s, 2H, NH); MS (70 eV,
30°C) m/z (%): 336 (M , 100). Anal. calcd for
+
2. (a) Banik, B. K.; Mukhopadhyay, C.; Venkatraman, M.
S.; Becker, F. F. Tetrahedron Lett. 1998, 39, 7743; (b)
Banik, B. K.; Zegrocka, O.; Banik, I.; Hackfeld, L.;
Becker, F. F. Tetrahedron Lett. 1999, 40, 673; (c) Banik,
B. K.; Zegrocka, O.; Becker, F. F. J. Chem. Res. (S)
2000, 7, 321; (d) Mukhopadhyay, C.; Becker, F. F.;
Banik, B. K. J. Chem. Res. (S) 2001, 28; (e) Basu, M. K.;
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Org. Chem. 2001, 66, 7527.
1
3. (a) Banerjee, J.; Chatterjee, A.; Manna, S.; Pascard, C.;
Prange, T.; Shoolery, J. Heterocycles 1981, 15, 325; (b)
Roder, E. Arch. Pharm. 1972, 305, 96; (c) Roder, E. Arch.
Pharm. 1972, 305, 117; (d) Noland, W.; Venkiteswaren,
M.; Richards, C. J. Org. Chem. 1961, 37, 2169.
Scheme 2.