Angewandte
Chemie
DOI: 10.1002/anie.201305579
Heterogeneous Catalysis
Cycloisomerization of 2-Alkynylanilines to Indoles Catalyzed by
Carbon-Supported Gold Nanoparticles and Subsequent Homocoupling
to 3,3’-Biindoles**
Jesus E. Perea-Buceta, Tom Wirtanen, Otto-Ville Laukkanen, Mikko K. Mꢀkelꢀ, Martin Nieger,
Michele Melchionna, Nina Huittinen, Jose A. Lopez-Sanchez,* and Juho Helaja*
Construction of biologically and pharmaceutically important
indole moieties plays a prominent role in classic organic
synthesis and modern catalysis. This role is not only due to the
significance of the potential applications but also as a standard
to calibrate the efficiency of a given method.[1,2]
addition of various nucleophiles.[9] We have also recently
shown that the cationic nature can be tuned in gold(III)
catalyst to achieve a comparable performance.[4f] Further-
more, comprehensive studies by Corma et al.[12] have also
demonstrated that cationic gold species could be responsible
for alkyne activation rather than reduced metal nanoparticles
in analogous heterogeneous transformations,[10,11] such as in
the catalytic isomerization of w-alkynylfurans to phenols,
whereby the abundance of AuIII has a linear correlation with
the catalytic activity of Au/CeO2 NPs.[12] Analogously, cat-
ionic gold NPs have been invoked as the active catalytic
species in the cycloisomerization of phenylpropargyl ethers to
chromanes or in the oxidative cycloaddition of 1,1,3,3-
tetramethyldisiloxane.[13,14] With these considerations in
mind, herein we describe an effective general method for
the heterogeneous cycloisomerization of 2-alkynylanilines to
indoles along with an unprecedented domino cycloisomeriza-
Despite the fact that the cycloisomerization of 2-alkynyl-
anilines provides one of the most direct and atom-economical
manners to assemble indoles,[3,4] there are still no examples of
any general protecting-group-free direct catalytic method
capable of effecting this transformation heterogeneously.[5]
Yet, in homogeneous catalysis this transformation has been
successfully performed with gold-based systems.[4a,d,6]
Heterogeneous catalytic non-direct synthesis of indoles
had remained unexplored until 2009, when Tokunaga and
Haruta reported that indoles could be prepared from 2-
alkynylnitrophenyls in moderate to high yields by a reductive
cascade process catalyzed by Au/Fe2O3 nanoparticles (NPs).[7]
However, the reductive nature of those conditions limited the
reaction scope and precluded the possibility of further
cascade functionalization. Soon after, Somorjai, Toste, and
co-workers reported that Pt nanoparticles supported on
mesoporous silica are able to efficiently promote the intra-
molecular heterocyclization of N-carbamate protected 2-
alkynylanilines to afford the corresponding indole products in
excellent yields.[8]
tion/C H oxidative homocoupling[15] to furnish pharmaceuti-
À
cally relevant 3,3’-biindolyl products.[16] Novel tetracyclic
indoles with a cyclooctatetraene substructure could also be
obtained as a result of a cationic AuNP–carbon-support
cooperative catalyzed process.
The cycloisomerization of 2-(p-tolylethynyl)aniline 1a to
indole 2a in toluene at 908C was selected as a suitable
catalytic model system to begin our investigations. Control
experiments with catalytic amounts of p-toluenesulfonic acid
(Table 1, entry 1) resulted in no conversion into indole and
confirmed that any catalytic activity could be only ascribed to
the corresponding heterogeneous gold catalyst and not to
simple acid-assisted events.[17]
We began our screening with widely used gold catalysts
immobilized by wet impregnation (WI) over a CeO2 support.
This catalyst afforded moderate yields (51 and 41%), which
depended on catalyst pre-treatment (Table 1, entries 2 and 3).
In contrast, gold supported on TiO2 gave only low yields
(13%) when the impregnation was conducted by deposition–
precipitation (entry 4; World Gold Council reference cata-
lyst). Carbon supports were then investigated. Sol immobili-
zation (SI) techniques for pre-forming gold colloids before
immobilization onto a carbon support results in some of the
most active gold catalysts for a range of oxidation reactions.[18]
However, such catalysts showed poor activity for our purpose
(11%, entry 5). Similarly, poor activities were also observed
when the preparation method was based on wet impregnation
(entry 6). Some improvement in yield (23%) was achieved by
the use of anionic adsorption (AA) method (entry 7).
Cationic gold(I) salts have been the more effective
catalysts in the homogeneous activation of alkynes for
[*] Dr. J. E. Perea-Buceta,[+] T. Wirtanen,[+] O.-V. Laukkanen,
M. K. Mꢀkelꢀ, Dr. M. Nieger, Dr. M. Melchionna, Dr. N. Huittinen,[#]
Dr. J. Helaja
Department of Chemistry, University of Helsinki
A.I.Virtasen aukio 1, P.O. Box. 55, 00014, Helsinki (Finland)
E-mail: juho.helaja@helsinki.fi
Dr. J. A. Lopez-Sanchez
Stephenson Institute for Renewable Energy
Chemistry Department, University of Liverpool
Crown Street L69 7ZD, Liverpool (UK)
E-mail: jals@liv.ac.uk
[#] Current address: Helmholtz-Zentrum Dresden-Rossendorf e.V.
Institute of Resource Ecology
P.O. Box 510119, 01314 Dresden (Germany)
[+] These authors contributed equally to this work.
[**] This work was supported by the Academy of Finland (J.H. No.
258348). T.W. is grateful to the Finnish Cultural and Magnus
Ehrnrooth Foundations for funding.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2013, 52, 11835 –11839
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11835