Angewandte
Chemie
DOI: 10.1002/anie.201405478
Combined Catalysis
Hot Paper
Synthesis of Indoles Using Visible Light: Photoredox Catalysis for
À
Palladium-Catalyzed C H Activation**
Jochen Zoller, David C. Fabry, Meria A. Ronge, and Magnus Rueping*
Abstract: A combined palladium- and photoredox-catalyzed
nium and rhodium, share the same major drawback since the
metal–H species that is formed after reductive elimination
must be reoxidized by an external oxidant. In recent years
many improvements have reduced the amount of stoichio-
metric metal-based additives, such as copper and silver salts,[9]
through use of molecular oxygen.[10] However, still relatively
large amounts of oxidants have to be present.
Based on our experience in the field of photoredox
catalysis and the recent results of Sanford and co-workers on
the coupling of diazonium and iodonium salts with
arenes,[11,12] we decided to investigate the palladium-catalyzed
À
C H olefination enables the synthesis of indoles. By using
À
visible light, the direct C H activation of aromatic enamines
can be achieved and a variety of indole derivatives can be
obtained in good yields under mild reaction conditions.
T
he indole motif is one of the most common building blocks
among bioactive compounds and natural products and has
therefore been a target of numerous methodology develop-
ments.[1] In addition to the Fischer indole syntheses,[2] many
different synthetic approaches using modern transition-metal
catalysis are known. Typically starting from ortho-halogen-
ated aniline derivatives, most of the methodologies thus still
suffer from the restricted availability or high costs of starting
À
C H olefination of aromatic enamines for the synthesis of
indoles. Small amounts of photoredox catalyst[13] in the
presence of visible light should facilitate the reoxidation of
the Pd catalyst (Scheme 1), thereby obviating the use of an
materials.[3] In the field of C H activation, reactions relying
À
on oxidative palladium(II) chemistry have become a versatile
and powerful tool for the synthesis of complex structural
motifs. The oxidative Heck reaction, also known as the
Fujiwara–Moritani reaction,[4] is
a well-understood and
broadly applicable transformation in organic synthesis. The
use of variable and removable directing groups on the
aromatic or heteroaromatic substrate allows ortho-olefina-
tions in generally high yields and excellent regioselectivities.[5]
In 2002, van Leeuwen and co-workers reported on the
oxidative coupling of anilides with olefins.[6] The use of
Pd(OAc)2 in combination with stoichiometric amounts of
benzoquinone (BQ) (1 equiv) resulted in successful olefina-
tions. The carbonyl group served as a directing group in these
reactions. Furthermore, Lu and co-workers presented an
intramolecular Fujiwara–Moritani reaction employing the
same Pd/BQ system for the synthesis of carbazoles starting
from 3-(3’-alkenyl)indole derivatives.[7] Indoles have also
been shown to be suitable substrates for intermolecular
olefination reactions. Stoichiometric amounts of Cu(OAc)2
(2 equiv) together with PdCl2 (10 mol%) led to the efficient
coupling of N-protected indoles with highly substituted
olefins.[8] However, oxidative Heck reactions and related
transformations involving different metals, including ruthe-
Scheme 1. Combination of photoredox and PdII catalysis for the syn-
thesis of indoles.
excess of oxidants or metal salts. This method could be
considered a highly atom-efficient reaction. Herein, we report
on the development of an indole synthesis using a new
combination of palladium and photoredox catalysis in the
presence of visible light.
We started our investigations with the intramolecular
cyclization of aromatic enamines that had previously been
described using Pd(OAc)2 and three equivalents of Cu-
(OAc)2.[14] The replacement of the copper additive with just
1 mol% of the photoredox catalyst led indeed after reaction
optimization to the desired product 2a in 46% yield (Table 1,
entry 1). The finding that the photoredox catalyst can be used
to regenerate the palladium catalyst encouraged us to test
a variety of palladium catalysts in the cyclization reaction, and
we found that Pd(OAc)2 led to higher yields than other PdII
precursors. Additional acetonitrile ligands on the palladium
with strong or weak coordinating counterions, for example, Cl
and BF4 (Table 1, entries 2 and 3), resulted in only insufficient
formation of the desired product.
[*] Dipl.-Chem. J. Zoller, M. Sc. D. C. Fabry, B. Sc. M. A. Ronge,
Prof. Dr. M. Rueping
Institut of Organic Chemistry, RWTH Aachen
Landoltweg 1, 52074 Aachen (Germany)
E-mail: magnus.rueping@rwth-aachen.de
[**] The research leading to these results was supported by the
European Research Council under the European Union’s Seventh
Framework Programme (FP/2007-2013)/ERC Grant Agreement no.
617044 (SunCatChem).
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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