Gallium(III) halide-catalyzed coupling of indoles with phenylacetylene: Synthesis of bis(indolyl)phenylethanes

Article abstract of DOI:10.1016/j.tetlet.2004.08.126

Indoles undergo smooth coupling with phenylacetylene in the presence of 10 mol % of gallium(III) chloride or gallium(III) bromide under mild conditions to afford the corresponding 1,1-bis(1H-3-indolyl)-1-phenylethanes.

Full text of DOI:10.1016/j.tetlet.2004.08.126

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7577–7579
Gallium(III) halide-catalyzed coupling of indoles with
phenylacetylene: synthesis of bis(indolyl)phenylethanesq
J. S. Yadav,* B. V. S. Reddy, B. Padmavani and Manoj Kumar Gupta
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 28 May 2004; revised 12 August 2004; accepted 20 August 2004
Abstract—Indoles undergo smooth coupling with phenylacetylene in the presence of 10mol% of gallium(III) chloride or gallium(III)
bromide under mild conditions to afford the corresponding 1,1-bis(1H-3-indolyl)-1-phenylethanes in high yields and with high
selectivity.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The bis(indolyl)alkane moiety is present in various nat-
ural products possessing important biological activity.1,2
Therefore, a number of synthetic methods for the prep-
aration of bis(indolyl)alkane derivatives have been re-
ported in the literature by reacting indoles with
various aldehydes and ketones in the presence of either
a Lewis acid3 or a protic acid.4 Metal triflates such as
Dy(OTf)3/ionic liquid and molecular iodine have also
been employed for the synthesis of bis(indolyl)alkanes
by reacting indoles with aldehydes and ketones.5 There-
fore, the development of simple and convenient proce-
dures for the synthesis of bis(indolyl)phenylethane
continue to be a challenging endeavour in synthetic or-
ganic chemistry. Recently, there has been considerable
interest in gallium-mediated transformations.6 Due to
their unique catalytic properties, gallium halides have
been used widely for a variety of organic transforma-
tions.7 In particular, gallium(III) compounds are utilized
as effective Lewis acids to activate alkynes under extre-
mely mild conditions.8 However, there have been no re-
ports on the use of gallium(III) halides as catalysts for
the synthesis of biologically active natural products con-
taining the bis(indolyl)phenylethane moiety via the cou-
pling of indoles with phenyl acetylene.9
In this article, we disclose a mild and efficient method
for the preparation of bis(indolyl)phenylethanes from
indoles and phenylacetylene using 10% gallium(III)
halide as the novel catalyst. Initially, we attempted the
coupling of indole, 1 (2equiv) with phenylacetylene, 2
(1.2equiv) in the presence of 10mol% of gallium(III)
chloride and gallium(III) bromide. The reaction went
to completion in 6h and the product was obtained in
86% yield (3a, Scheme 1).
Encouraged by this result, we turned our attention
to various substituted indoles. Several substituted in-
doles such as N-methyl-, N-ethyl-, 2-methyl-, 4-nitro-,
4-bromo-, 5-cyano- and 7-ethyl-indoles underwent
smooth coupling with phenylacetylene to afford the
CH3
10% GaCl3 or GaBr3
C6H5CH3, r.t.
Ph
+
N
N
N
H
H
H
1
3a
2
Scheme 1.
Keywords: Gallium(III) compounds; Phenylacetylenes; Indoles; Bis(indolyl)phenylethanes.
q IICT Communication No. 040906.
*
Corresponding author. Tel.: +91 40 27193434; fax: +91 40 27160512; e-mail: yadavpub@iict.res.in
0040-4039/$ - see front matter ꢀ 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.126

7578
J. S. Yadav et al. / Tetrahedron Letters 45 (2004) 7577–7579
corresponding bis(indolyl)phenylethanes (Table 1, en-
tries 3b–h). In all cases, the reactions proceeded
smoothly at room temperature with high efficiency.
However, 1-ethyl-2-phenyl indole did not react with
phenylacetylene in the presence of 10mol% of gal-
lium(III) halide (Table 1, entry i). Furthermore, diphe-
nylacetylene and alkyl-substituted alkynes such as n-
octyne failed to produce the desired products even on
heating under reflux (Table 1, entries j and k), because
of their intrinsically lower reactivity in comparison to
Table 1. Gallium(III) chloride coupling of indoles with phenyl acetylene
Entry
Indoles 1
Alkynes 2
Producta 3
Time (h)
6.0
Yield (%)b
86
Me
a
Ph
N
H
N
H
N
H
Me
b
c
8.0
6.5
75
84
Ph
Ph
N
Me
N
Me
N
Me
Me
N
N
Et
Et
N
Et
Me
d
e
f
Ph
Ph
Ph
Ph
7.5
6.0
6.5
7.0
80
82
88
83
Me
N
H
N
H
N
H
NO2
NO2
Me
O2N
N
H
N
H
N
H
Br
Br
Me
Br
N
H
N
H
N
H
NC
Me
CN
NC
g
N
N
H
H
N
H
Me
h
i
Ph
Ph
6.0
85
—
N
H
Et
N
H
N
Et
Et
H
No reaction
30.0
N
Et
j
No reaction
No reaction
23.0
24.0
—
—
Ph
Ph
N
H
k
N
H
a All products were characterized by 1H NMR, IR and mass spectrometry.
b Yield refers to the isolated pure products after column chromatography.

J. S. Yadav et al. / Tetrahedron Letters 45 (2004) 7577–7579
7579
4. (a) Reddy, A. V.; Ravinder, K.; Reddy, V. L. N.; Goud, T.
V.; Ravikanth, V.; Venkateswarlu, Y. Synth. Commun.
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alez, M.; McKew, J. C. Tetrahedron Lett. 2003, 44, 4589–
4591; (c) Chakrabarty, M.; Ghosh, N.; Basak, R.; Hari-
gaya, Y. Tetrahedron Lett. 2002, 43, 4075–4078; (d) Roomi,
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2004, 45, 4567–4570, and references cited therein; (b)
Bandgar, B. P.; Shaikh, K. A. Tetrahedron Lett. 2003, 44,
1959–1962.
phenyl acetylene. In the absence of catalyst, no reaction
was observed. As solvent, toluene appeared to give the
best results. Among the various Lewis acids such as
InCl3, InBr3, InI3, YCl3 and BiCl3 tested, gallium triha-
lides were found to be the most effective for this conver-
sion. In(OTf)3 (20mol%) was also worked well to afford
the corresponding bis(indolyl)phenylethane in 12h
under reflux. The scope and generality of this process
is illustrated with respect to various indoles and the
results are presented in Table 1.
6. Matsuo, J.-I.; Kobayashi, S. CHEMTRACTS 2000, 13,
431–434.
In summary we have described a simple, convenient and
efficient protocol for the synthesis of bis(indolyl)phenyl-
ethanes from indoles and phenylacetylene using
10mol% of GaX3 as catalyst. GaCl3 and GaBr3 are
solid and stable to air or moisture and are easy to handle
even on multi-gram scales and are found to activate
alkynes very effectively under mild conditions. This
process offers several advantages such as high conver-
sions, high selectivity, experimental simplicity and high
catalytic activity, which makes it a useful and attractive
strategy for the preparation of bis(indolyl)phenylethanes
in a single step operation.
7. (a) Chatani, N.; Inoue, H.; Kotsuma, T.; Murai, S. J. Am.
Chem. Soc. 2002, 124, 10294–10295; (b) Inoue, H.; Chatani,
N.; Murai, S. J. Org. Chem. 2002, 67, 1414–1417; (c)
Yamaguchi, M.; Tsukagoshi, T.; Arisawa, M. J. Am. Chem.
Soc. 1999, 121, 4074–4075; (d) Asao, N.; Asano, T.; Ohishi,
T.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 4817–4818.
8. (a) Kobayashi, K.; Arisawa, M.; Yamaguchi, M. J. Am.
Chem. Soc. 2002, 124, 8528–8529; (b) Viswanathan, G. S.;
Wang, M.; Li, C.-J. Angew. Chem., Int. Ed. 2002, 41, 2138–
2141; (c) Viswanathan, G. S.; Li, C.-J. Synlett 2002, 1553–
1555; (d) Viswanathan, G. S.; Li, C.-J. Tetrahedron Lett.
2002, 43, 1613–1615.
9. A mixture of phenylacetylene (1.2mmol), indole (2mmol),
gallium trihalide (0.10mmol) in toluene (10mL) was stirred
at room temperature for the appropriate time (see Table 1).
After completion of the reaction as indicated by TLC, the
reaction mixture was diluted with water and extracted with
ethyl acetate (2 · 10mL). The combined organic layers were
dried over anhydrous Na2SO4, concentrated in vacuo and
purified by column chromatography on silica gel (Merck,
100–200 mesh, ethyl acetate–hexane, 1.5:8.5) to afford the
pure bis(indolyl)phenylethane. Spectroscopic data for
selected products: 3e: 4-Nitro-3-[1-{4-nitro-1H-3-indolyl}-
1-phenylethyl]-1H-indole: yellow solid, mp = 283–286ꢁC.
IR (KBr): mmax: 3436, 2983, 1740, 1532, 1468, 1376, 1331,
1242, 1046, 786cmÀ1. 1H NMR (400MHz, CDCl3): d 11.32
(br s, 2H, NH), 7.98 (s, 2H), 7.90 (d, J = 9.2Hz, 2H), 7.44
(d, J = 9.2Hz, 2H), 7.35–7.22 (m, 5H), 6.96 (s, 2H), 2.36 (s,
3H). FAB Mass: m/z (%): 427 (M+1, 35), 411 (55), 349 (12),
313 (5), 289 (5), 265 (40), 219 (8), 191 (5), 154 (18),123 (10),
109 (8), 95 (35), 81 (40), 69 (65), 57 (100). HRMS calcd for
C24H19N4O4: 427.1406. Found: 427.1413 (M+1). 3f: 4 -
Bromo-3-[1-4-bromo-1H-3-indolyl-1-phenylethyl]-1H-
Acknowledgements
M.K.G. thanks the Council of Scientific and Industrial
Research New Delhi for the award of a fellowship.
References and notes
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indole: brown solid, mp = 216–220ꢁC. IR (KBr): mmax
3432, 2982, 1723, 1562, 1456, 1410, 1374, 1330, 1217, 1102,
1050, 881, 767, 702, 666, 584cmÀ1 1H NMR (200MHz,
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CDCl3): d 7.90 (br s, 2H, NH), 7.38–7.20 (m, 11H), 6.60 (d,
J = 6.5Hz, 2H), 2.30 (s, 3H). FAB Mass: m/z (%): 494 (M+,
30), 479 (45), 399 (8), 391 (10), 298 (30), 279 (5), 219 (8), 204
(5), 191 (5), 167 (12), 154 (50), 136 (40), 115 (15), 95 (45), 81
(48), 69 (60), 57 (100). HRMS calcd for C24H19N2Br2:
492.9914. Found: 492.9923 (M+1). 3g: 3-[1-(5-cyano-1H-3-
indolyl)-1-phenylethyl]-1H-5-indolecarbonitrile: yellowish
solid, mp = 192–194ꢁC. IR (KBr): mmax: 3418, 2885, 2823,
2254, 2215, 2127, 1645, 1475, 1378, 1339, 1243, 1103, 1026,
1
1004, 824, 763, 623cmÀ1. H NMR (400MHz, CDCl3): d
11.22 (br s, 2H, NH), 7.48 (d, J = 8.4Hz, 2H), 7.39 (s, 2H),
7.30–7.22 (m, 7H), 6.82 (s, 2H), 2.30 (s, 3H). EIMS: m/z
(%): 386 (M+, 40), 372 (100), 309 (10), 229 (12), 185 (7), 140
(5). HRMS calcd for C26H18N4: 386.1531. Found:
386.1525.