Gallium(III) triiodide catalyzed conjugate addition of indoles with α,β-unsaturated ketones

Article abstract of DOI:10.1016/j.tetlet.2006.08.108

Reactions of indoles and α,β-unsaturated ketones could be effectively catalyzed by using 10 mol % gallium triiodide to give the corresponding Michael adducts in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2006.08.108

Tetrahedron Letters 47 (2006) 7965–7968
Gallium(III) triiodide catalyzed conjugate addition of indoles
with a,b-unsaturated ketones
Zhi-Hao Huang, Jian-Ping Zou* and Wen-Qing Jiang
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering,
Suzhou University, 1 hengyi Street, Suzhou, Jiangsu 215123, China
Received 6 June 2006; revised 29 August 2006; accepted 30 August 2006
Available online 25 September 2006
Abstract—Reactions of indoles and a,b-unsaturated ketones could be effectively catalyzed by using 10 mol % gallium triiodide to
give the corresponding Michael adducts in good to excellent yields.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Indole is a privilege heterocyclic ring.1,2 Many biologi-
cally active compounds and natural products are found
to be 3-substituted indoles.3 Michael addition of indoles
and a,b-unsaturated ketones is an important approach
to this class of molecules.4,5 Lewis acids such as CeCl3Æ
7H2O–NaI,6 Bi(OTf)3,7 SmI3,8 I2,9 InCl3,10 and
Cu(OTf)311 have been used to promote Michael addition
reactions.
The initial reaction of indole 1a and 3-buten-2-one 2a at
an ambient temperature in CH2Cl2 did not give any
product until GaI3 was added into the reaction mixture
and stirred for 1 h. After the reaction was completed, the
mixture was purified by flash column chromatography
to give pure product 4-(3-indolyl)butanone-2 3a, whose
structure was characterized by 1H NMR, 13C NMR,
and HRMS analyses.
Gallium triiodide (GaI3) can be easily prepared by the
reaction of metal gallium with iodine.12 It has been used
as a Lewis acid catalyst for Sakurai reaction, tetrahydro-
pyranylation of alcohols and phenols, and the coupling
reaction of carbonyl compounds, amines and diethyl
phosphate.13 Compared to other Lewis acids, the syn-
thetic application of GaI3 has not been fully explored.
Herein, we report a new application of GaI3 as a Lewis
acid catalyst in the synthesis of 3-substituted indoles
(Scheme 1).14
The reaction of 1a and 2a was optimized by screening
the solvent such as CH3CN, THF, and CH2Cl2 (Table
1, entries 1, 2 and 4), changing the amount of GaI3
and the ratio of indole 1a/3-buten-2-one 2a. It was
found that the reaction best proceeded with 10 mol %
GaI3, ratio of indole/3-buten-2-one 1:1 to give 3a in a
95% yield (Table 1, entry 4). Increasing the amount of
GaI3 to 20 mol %, the yield of 3a was not further
improved (Table 1, entry 6). However, if GaI3 was used
Table 1. Effect of reaction conditions on the GaI3 catalyzed Michael
addition of indole 1a and 3-buten-2-one 2a
Entrya
Solvent
Time (h)
Amount of
GaI3 (mol %)
Yield
(%)
R2
X
O
O
Y
Y
10mol% Gal3
R3
CH2Cl2, r.t
R3
R2
+
1
2
3
4
5
6
CH3CN
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
3
3
3
3
1
3
10
10
5
10
10
20
32
N
R1
X
2
N
R1
3
n.r.b
47
1
X = H, CH3; Y = H, 5-Br, 7-CH3; R1 = H, CH3; R2 = H, Alkyl, Aryl; R3 = Alkyl, Aryl
95
90
94
Scheme 1. GaI3-catalyzed Michael addition of indoles.
a Typical reaction condition: indole:3-buten-2-one = 1:1, 10 mol %
GaI3.
b n.r. = No reaction.
*
Corresponding author. Tel./fax: +86 512 65880305; e-mail:
wuyanhong@pub.sz.jsinfo.net
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.108

7966
Z.-H. Huang et al. / Tetrahedron Letters 47 (2006) 7965–7968
Table 2. GaI3 catalyzed reaction of indoles and a,b-unsaturated ketones
Entry
1
Indoles
a,b-Unsaturated ketones
Time (h)
1
Yielda (%)
90
Productb
O
O
N
H
1a
2a
N
H
3a
O
Br
O
Br
2
3
1
86
84
N
H
N
2a
H
3b
O
O
1.5
N
H
2a
N
H
3c
O
O
4
5
1.5
2
85
85
N
H
N
H
2a
O
3d
O
N
H
N
H
2b
3e
O
O
6
7
2
2
87
85
N
H
N
H
2b
3f
O
O
N
Cl
CH3
N
Cl
2c
CH3
3g
O
O
O
O
O
8
2.5
80
N
H
O
2d
N
H
3h
O
O
O
O
9
3
2
81
88
N
H
Cl
Cl
N
H
2e
3i
OCH3
O
O
10
N
H
OCH3
2f
N
H
3j
O
O
11
2.5
72
18
N
H
N
H
2g
3k
O
N
H
N
H
3l

Z.-H. Huang et al. / Tetrahedron Letters 47 (2006) 7965–7968
7967
Table 2 (continued)
Entry
Indoles
a,b-Unsaturated ketones
Time (h)
Yielda (%)
Productb
Br
O
N
H
O
12
1
90
Br
Cl
2c
N
H
Cl
3m
O
O
O
Br
O
O
13
1
89
Br
N
H
O
2d
N
H
3n
CHO
O
14
15
24
24
—
—
n.r.c
n.r.c
N
H
2a
O
CN
N
H
2a
a All products were purified by flash column chromatography.
b All products were characterized by 1H and 13C NMR and HRMS spectra.
c n.r. = No reaction.
in less than 5 mol %, the yield of 3a was significantly
reduced to 47% (Table 1, entry 3).
yield (Table 2, entry 11). Indoles with monosubstitution
at 1-, 2-, 5-, or 7-position were studied, and the desired
products were obtained in good yields (84–90%) (Table
2, entries 2–4, 6, 7, 12, and 13). 3-Substituted indoles did
not produce any product since the reactive site was
blocked (Table 2, entries 14 and 15). Attempted reac-
tions of a,b-unsaturated aldehydes and a,b-unsaturated
esters, such as acrylaldehyde, cinnamaldehyde, methyl
acrylate, and ethyl acrylate, failed to give products.
Under the optimized conditions described above, a
series of substituted indoles and a,b-unsaturated ketones
were used to evaluate the scope of GaI3 catalyzed
Michael addition. A steric hindered 4-methyl-3-penten-
2-one 2b reacted with indole 1a to afford product 1b in
85% (Table 2, entry 5). The reactions of 1,3-diaryl-a,b-
unsaturated ketones with indole 1a gave products in
80–88% yields (Table 2, entries 7–10). Compound 2g
has two conjugated double bonds; interestingly, both
monoaddition product 3k and diaddition product 3l
were obtained; the former was the major one in a 72%
A possible mechanism for the conjugate addition is pro-
posed in Scheme 2.15,16 GaI3 coordinating with O atom
of a,b-unsaturated ketone to form intermediate 4; then,
electron-rich b-position of indole attacking the conju-
gated C@C double bond of 4 to afford 5, followed by
a H-transformation to yield 6 and GaI3, finally, 6 rear-
ranged to target compound 3 and GaI3 participated
the next cycle catalytic reaction.
R3
O
R2
O
R2
R3
In conclusion, 10 mol % GaI3 can effectively catalyze the
Michael addition of indoles and a,b-unsaturated
ketones to give 3-substituted indoles in good to excellent
yields. However, under the same conditions, a,b-unsatu-
rated aldehydes and esters cannot afford the correspond-
ing Michael addition products.
N
H
3
GaI3
GaI3
O
R3
OH
R2
R2
R3
4
R3
N
O GaI3
R2
H
Acknowledgement
6
N
H
H
We thank the Key Laboratory of Organic Synthesis of
Jiangsu Province and Suzhou Scientific Committee for
financial supports (JSK016 and SG 0219), and Dr.
Wei Zhang of Fluorous Technologies, Inc., University
of Pittsburgh Applied Research Center, for his good
suggestions and meaningful discussions.
N
H
5
Scheme 2. Proposed mechanism for GaI3 catalyzed reaction of indole
and a,b-unsaturated ketones.

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Z.-H. Huang et al. / Tetrahedron Letters 47 (2006) 7965–7968
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1
mp 189–190 ꢁC. H NMR (400 MHz, CDCl3): d 8.04 (s,
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CH2). 13C NMR (100 MHz, DMSO-d6): d 37.1, 44.5, 100.
8, 107.9, 108.4, 111.1, 113.5, 118.2, 120.8, 121.1, 123.6,
128.2, 128.4, 128.8, 133.3, 135.1, 137.0, 139.2, 145.4, 147.2,
198.4; HRMS: m/z (%), calcd for C23H17NOClBr (M+)
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