Synthesis of 1,2,3-Fused Indole Polyheterocycles by Copper-
Catalyzed Cascade Reaction
and Ching-Fa Yao*
Abstract: A one-pot reaction has been devloped for the prepa-
ration of 1,2,3-fused indole polyheterocycles by starting from 2-
iodobenzamide and 2-iodobenzyl cyanide in the presence of
a copper catalyst. The cascade process involves the efficient
In recent years, the concept of privileged structures has
emerged as a successful approach in the discovery of biologi-
cally active molecules.
Indole and its derivatives have been
recognized as part of this group because of their presence in
many bioactive molecules.
A plethora of indole-fused poly-
heterocycles have been known to have a range of bioactivi-
and there are several reported methods to access these
various indole-fused polyheterocycles. Most of these strategies
focus on the synthesis of either 1,2-polycyclic-fused indoles
or 2,3-polycyclic-fused indoles.
Few methods, however, are
available for the preparation of 1,2,3-fused indole polyhetero-
cycles by starting from N-functionalized indole derivatives,
which results in a limited scope of possible products.
To date, direct access to 1,2,3-polycyclic-fused indole deriva-
tives from non-indole derivatives has yet to be reported. Our
group has been interested in the development of strategies for
the synthesis of variety of polycyclic-fused indole derivatives,
and recently designed an easy and efficient method for the
synthesis of benzopyridoindole derivatives from 2-iodobenz-
amide and 2-iodobenzyl cyanide by using a copper-catalyzed
tandem cyclization reaction.
Taking our cues from this method and our experience with
copper-catalyzed tandem reactions,
we proceeded to develop
a strategy for access to 1,2,3-polycyclic-fused indole derivatives,
in which the indole core is constructed during the course of
the reaction from 2-iodobenzamide derivatives
and a 2-iodo-
benzyl cyanide (Scheme 1). As shown in Scheme 1, this one-
pot strategy involves coupling reactions for the formation one
C–C and two C–N bonds, which proceed in a linear manner,
[a] Department of Chemistry, National Taiwan Normal University,
88, Sec. 4, Tingchow Road, Taipei, Taiwan 116 R.O.C.
[‡] Authors contributed equally to this work.
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201701618.
Eur. J. Org. Chem. 2018, 1241–1247
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
formation of one C–C and three C–N bonds. A broad substrate
scope, good yields, and short reactions times are key features
of this strategy.
and another coupling process to form one C–N bond, which
takes place in an angular mode. Working towards the envisaged
objective, we found that treating 2-iodobenzamide derivatives
with 2-iodobenzyl cyanides in the presence of a copper catalyst
successfully led to fused polycyclic systems. The details of our
study are presented herein.
Scheme 1. Strategy to access indole-fused polyheterocycles (M=copper).
Results and Discussion
For our proposed strategy, we prepared 2-iodo-N-(2-iodo-
benzyl)benzamide derivative 1 and 2-iodo-N-(2-iodophenethyl)-
benzamide derivative 3 by using known methods, which are
described in the Supporting Information. To initiate our study,
we chose 2-iodo-N-(2-iodobenzyl)benzamide (1a) and 2-iodo-
benzyl cyanide (2a) as the model substrates. Employing the
details of our recent publication for the synthesis of benzopyr-
idoindolones from 2-iodo-N-substituted benzamide derivatives
and 2-iodobenzyl cyanide,
we initiated our experiment by us-
ing 15 mol-% of CuCl, 30 mol-% of
-proline, and 3 equiv. of
in dimethyl sulfoxide (DMSO) as the solvent at 80 °C. To
our delight, the reaction produced the indole-fused polyhetero-