active compounds, is one of the major routes to access them.
Obviously, the requirement of stoichiometric reducing agent
and tedious manipulation for the product isolation and
purification is a major drawback of two-step syntheses.
Lately, the first one-pot synthesis of indoles through this route
was reported by the use of In-HI as reagent.2i However,
the reaction requires 4 equiv of expensive indium and the
substrates are limited to 1-aryl(2-nitroaryl)alkynes giving
only moderate yield (up to 64%).
Table 1. One-Pot, One-Step Synthesis of Indole 2a by
Supported Au Catalysts under Hydrogenation Condition
yield (%)
3a
(%)c (%)d
Recently, we have been interested in unique catalytic
activities and selectivities of Au nanoparticle catalysts3 and
involved in their application to organic synthesis. We have
developed Au/Co3O4-catalyzed hydroformylation4a,b and
amidocarbonylation4c (Wakamatsu reaction), where Au acts
as a cocatalyst to generate Co0 active species.
t
convn
(%)
2a
4a
entry
cat.
(°C) P (MPa)
(%)c
1a
2b
Au/TiO2
120
1.2
1.2
1.2
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
100
100
97.4 50.6
62.5
69.0
5.7d
0
0
0
0
2.8
6.5
3.8
16.2
13.9
12.7
14.2
Au/Fe2O3 120
Au/Fe2O3 160
Au/Fe2O3 160
Au/Fe2O3 140
Au/Fe2O3 120
Au/Fe2O3 110
Au/Fe2O3 100
Au/Fe2O3
Au/Fe2O3
Au/Fe2O3
3b
4b
100
66.5
72.7
73.0
77.3
75.9
59.8 24.4
32.2 50.7
2.6 30.4
In the present work, we have investigated the Au-catalyzed
chemoselective hydrogenation of nitro groups5 and have
applied this reaction to one-pot synthesis of indoles and
aniline derivatives6 by successive hydroamination, dehydra-
tion, and reductive amination.
5b
100
100
100
100
100
100
38
6b
0
0
7b
8b
2.6d 13.4
9b
80
60
40
3.1
1.0
1.0
10b
11b
The result of a one-pot synthesis of indoles from (2-
nitroaryl)alkynes catalyzed by Au/Fe2O3 under hydrogenation
conditions is shown in Table 1. As a model substrate, 1-nitro-
2-(2-phenylethynyl)benzene (1a) was selected for this study.
Hydrogenation of 1a with 2.3 mol % of Au/TiO2 (Au atom
per substrate) was carried out at 120 °C under 1.2 MPa H2 and
afforded 2-phenylindole (2a) in 63% yield (Table 1, entry 1).
Uncyclized aniline (3a) and overreduced aniline (4a) were
obtained in yields of 5.7% and 2.8%, respectively. When Au/
Fe2O3 was used as catalyst, a slightly better yield (69%) of 2a
was observed (entry 2). Au nanoparticles on another support
such as Au/Co3O4 gave lower yields (<10%), thus Au/Fe2O3
was used as the optimized catalyst for this study. The reaction
with higher temperature gave lower yield of 2a (51% at 160
°C, entry 3), but higher H2 pressure (2.0 MPa) brought a better
result (67%, entry 4). Further higher pressure did not improve
the yield of 2a. The reaction with various temperatures was
carried out between 40 and 160 °C (entries 4-11), and it was
found that the most favorable temperature was 110 °C giving
the highest yield (77%) of 2a under a one-pot, one-step
condition (entry 7). In this series of reactions, a combined yield
of 2a and 3a reached maximum around 60-80 °C (83-84%,
entries 9 and 10), because this condition minimized the amount
of other byproduct such as hydroxylamine derivatives. There-
fore, if uncyclized 3a can be converted into 2a without
overreduction, the yield of 2a will be improved. Thus, a second
cyclization step was carried out separately under lower H2
pressure and higher temperature as a one-pot, two-step synthesis.
a 1a (0.5 mmol), toluene (2.0 mL), 1 h, Au/TiO2 (1.2 atom % Au/(Au
+ Ti), 2.3 mol % Au/1a). b Au/Fe2O3 (5.0 atom % Au/(Au + Fe), 2.3 mol
% Au/1a). c Isolated yield. d GC yield.
An optimized condition of this method is depicted in
Scheme 1. The first step was performed at 60 °C, 2.0 MPa
H2 for 1 h, then H2 was released to atmospheric pressure
(0.1 MPa), then the system was closed and heated at 120 °C
for 1 h. The isolated yield of 2a reached 87%. Change in
the reaction time (1-2 h) of the first and second step and
catalyst loadings (1.2 to 4.6 atom % Au for substrate) did
not bring a significant effect on yield of 2a (>80%).
Scheme 1
.
One-Pot, Two-Step Synthesis of 2a by Supported Au
Catalysts under Hydrogenation Condition
The applicability of this one-pot indole synthesis was
explored to several substrates (Table 2). Method A represents
a one-pot, one-step condition (2.0 MPa H2, 120 °C, 1 h),
and method B represents a one-pot, two-step condition as
shown in Scheme 1. In general, method B gave slightly better
yields. When an electron-deficient 4-CF3C6H4 group was
used as R1 substituent (1e), alkyne hydrogenation was
enhanced (33%), which brought about a decreased yield of
2e (43%, entry 10). The substrate with the aliphatic R1 group
also gave the indoles in good yield (entries 11-14,17, and
18). A sterically hindered tert-butyl group (1g) gave 81%
yield but the trimethylsilyl group (1h) considerably decreased
(3) (a) Haruta, M. Chem. Rec. 2003, 3, 75–87. (b) Hashmi, A. S. K.;
Hutcings, G. J. Angew. Chem., Int. Ed. 2006, 45, 7896–7936. (c) Zhang,
X.; Corma, A. Angew. Chem., Int. Ed. 2008, 47, 4358–4361.
(4) (a) Liu, X.; Haruta, M.; Tokunaga, M. Chem. Lett. 2008, 37, 1290–
1291. (b) Liu, X.; Hu, B.; Fujimoto, K.; Haruta, M.; Tokunaga, M. Appl.
Catal., B. DOI: 10.1016/j.apcatb.2009.08.021. (c) Hamasaki, A.; Liu, X.;
Tokunaga, M. Chem. Lett. 2008, 37, 1292–1293
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(5) (a) Corma, A.; Serna, P. Science 2006, 313, 332–334. (b) Corma,
A.; Concepcin´, P.; Serna, P. Angew. Chem., Int. Ed. 2007, 46, 7266–7269.
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Org. Lett., Vol. 11, No. 22, 2009
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