Communications
DOI: 10.1002/anie.201004097
Heterocycle Synthesis
Cascade Palladium-Catalyzed Direct Intramolecular Arylation/Alkene
Isomerization Sequences: Synthesis of Indoles and Benzofurans**
Myriam Yagoubi, Ana C. F. Cruz, Paula L. Nichols, Richard L. Elliott, and Michael C. Willis*
The development of metal-catalyzed direct arylation
reactions between activated aromatic rings, most usually
aryl halides, and a non-activated aromatic coupling
partner has had a tremendous impact on the synthesis of
biaryl carbon–carbon bonds.[1–3] The direct functional-
ization of heteroaromatic molecules features promi-
nently among these reactions.[4] Although less general,
variations of these methods to include the direct union
of an aromatic ring with alkenyl- or alkylhalide coupling
partners are becoming more common.[5,6] Indeed, if
opportunities for further elaboration of the coupled
products are considered, then direct arylation of alkenyl
substrates is particularly attractive as the transforma-
tions deliver styryl units featuring a reactive alkenyl
Scheme 1. Routes based on alkenyl halide direct arylation to give 2,3-
functional group. Herein we exploit the ready formation
of styryl units through a direct arylation approach and
illustrate how, when combined with a simple isomer-
ization step, a common route to both indoles and
benzofurans can be developed.
Although palladium-catalyzed direct arylation, alkenyla-
tion, and alkylation reactions have been extensively applied
to heteroaromatic systems, it is usually in the context of
decorating existing aromatic scaffolds.[7] Less common is the
use of similar methods for the construction of heteroaromatic
molecules, particularly benzo-fused five-membered aromatic
rings.[8,9] One reason for this is the difficulty in accessing
suitable cyclization substrates in short sequences from simple
starting materials. For example, route A in Scheme 1 illus-
disubstituted indoles.
direct arylation methods is to streamline syntheses, both in
terms of step count and waste generation, the use of a direct
arylation reaction on a step-intensive substrate is counter-
productive. Despite these difficulties, the advantages to be
gained from developing a direct arylation route to biologically
important heterocycles, such as indoles and benzofurans, are
considerable. In particular, the ability to employ readily
available building blocks (e.g. anilines) directly in a synthetic
route is an attractive proposition. Route B in Scheme 1
presents our solution to these challenges, set in the framework
ꢀ
of an indole retrosynthesis: the C3 C3a direct arylative bond
ꢀ
trates an indole retrosynthesis in which the C3 C3a bond is
construction is maintained (4!5); however, to deliver readily
ꢀ
formed by a direct arylation procedure (1!2); however, such
a synthesis requires an N-aryl-2-haloenamine cyclization
substrate (1), and although similar systems are known, for
example by a metal-catalyzed coupling of an aniline with a
1,2-dihaloalkene (3),[10,11] the preparation of a library of these
substrates in a straightforward and efficient manner is not
trivial. As one of the primary motivations for employing
available substrates, the target structure from the key C C
bond-forming reaction is no longer the heteroaromatic
molecule, but rather the isomerized, non-aromatic, congener
5. We reasoned that isomerization from the exo-alkene 5 to
the aromatic indole 2 should be a facile transformation and
may even take place during the arylative step. Then, N-aryl-2-
haloallylic amines become the cyclization substrates, thus
reducing the synthesis to the combination of two readily
available building blocks: anilines and a-haloenones 6.[12]
To evaluate the feasibility of the synthesis described in
Scheme 1 (route B) we elected to study the conversion of
bromoalkene 7a into indole 8a (Table 1). Based on literature
precedent we focused on the use of the electron-rich,
diphenyl-backbone-based phosphine ligands pioneered by
Buchwald.[13] Treatment of bromoalkene 7a with a catalyst
generated from Pd(OAc)2 and amino-substituted ligand 9a,
using Cs2CO3 as the base in DME, delivered 4% of the
desired indole (Table 1, entry 1). Changing the ligand to the
dimethoxy variant 9b increased the yield to 62% (Table 1,
entry 2), while the triisopropyl-substituted ligand 9c provided
the indole in 86% yield (Table 1, entry 3). The reaction
[*] M. Yagoubi, A. C. F. Cruz, Dr. M. C. Willis
Department of Chemistry, University of Oxford
Chemistry Research Laboratory
Mansfield Road, Oxford, OX1 3TA (UK)
Fax: (+44)1865-28-5002
E-mail: michael.willis@chem.ox.ac.uk
Dr. P. L. Nichols, Dr. R. L. Elliott
GlaxoSmithKline, New Frontiers Science Park
Third Avenue, Harlow, Essex, CM19 5AW (UK)
[**] We thank the EPSRC and GlaxoSmithKline for their support of this
study.
Supporting information for this article is available on the WWW
7958
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 7958 –7962