Angewandte
Communications
Chemie
Tandem Catalysis
Synthesis of Indoles and Pyrroles Utilizing Iridium Carbenes
Generated from Sulfoxonium Ylides
Abstract: Metal carbenes can undergo a myriad of synthetic
transformations. Sulfur ylides are potential safe precursors of
metal carbenes. Herein, we report cascade reactions that
involve carbenoids derived from sulfoxonium ylides for the
efficient and regioselective synthesis of indoles and pyrroles.
The tandem action of iridium and Brønsted acid catalysts
enables rapid assembly of the heterocycles from unmodified
anilines or readily accessible enamines under microwave
irradiation. The key mechanistic steps are the catalytic trans-
formation of the sulfoxonium ylide into an iridium–carbene
Sulfur ylides can also function as precursors to transition-
metal–carbene complexes.[3,4] However, this metal–carbene
À
chemistry is currently limited to the insertion of X H (X = N,
O, S) bonds and cyclopropanation reactions.[5] The develop-
ment of reactions involving sulfur-ylide-derived metal–car-
bene complexes for a wider range of applications is highly
desirable,[6] as these intermediates can offer some advantages
over diazocarbenes. Large-scale synthesis with diazo com-
pounds can be challenging owing to safety issues resulting
from rapid exothermic reactions.[7] Sulfoxonium ylides are
safer to synthesize and give crystalline, bench-stable com-
pounds that can serve as practical substitutes for diazo
compounds in metal–carbene reactions.[5e] However, unlike
diazocarbenes, sulfoxonium-ylide-based carbenes have not
yet been explored in cascade transformations.[8] We became
interested in studying the potential of metal-catalyzed
reactions of sulfur ylides (Scheme 1; type II) in a cascade
approach to the synthesis of heteroaromatic compounds, such
as indoles and pyrroles.
À
À
complex, followed by N H or C H functionalization of an
aniline or enamine, respectively, and a final acid-catalyzed
cyclization. The present method was successfully applied to the
synthesis of the densely functionalized pyrrole subunit of
atorvastatin.
S
ulfur (sulfonium and sulfoxonium) ylides are versatile
synthetic precursors for a diverse range of chemical trans-
formations.[1] For example, they are widely used as methylene
synthons in the formation of small rings, such as epoxides,
aziridines, and cyclopropanes, from electrophilic substrates,
such as aldehydes, imines, and enones. The cycloaddition of
sulfur ylides to a variety of electrophilic metal-associated (Pd,
Fe, Cu, Rh, or Au) intermediates has been explored for the
synthesis of heterocycles (Scheme 1; type I).[2]
The indole moiety is found in many natural products,
pharmaceuticals, and agrochemicals,[9] and numerous meth-
ods for the synthesis of the indole scaffold have been
developed. Most reported methods for the synthesis of
indoles require modified anilines, such as N-substituted
aniline derivatives or ortho-functionalized anilines;[10] in one
approach, N-(ortho-chloromethyl)aryl amides were used with
sulfur ylides as methylene synthons.[11] In 1881, Mçhlau
reported the synthesis of indoles from unmodified anilines
and ortho-halo ketones.[12] This reaction has received little
attention, perhaps owing to its poor regioselectivity, low
yields, and harsh reaction conditions, and the frequent need
for a two-step process.[13] An efficient procedure for the
conversion of simple anilines into substituted indoles in one
step is lacking. Herein, we report a highly regioselective one-
step iridium-catalyzed indole synthesis from unmodified
anilines and sulfur ylides (Scheme 2).
Scheme 1. Sulfur-ylide-based heterocycle synthesis via a metal-associ-
ated intermediate (type I) or a metal–carbene complex (type II).
Initially, we investigated the microwave irradiation of
aniline (2 equiv) with ylide 2a (1 equiv) in the presence of
[{Ir(cod)Cl}2] (10 mol%) in dichloroethane (DCE) at 808C
for 45 min. Interestingly, the reaction afforded a small amount
of the unprecedented 2-substituted indole 4a (5% yield)
along with the expected N-alkylated aniline 3a (73% yield;
[*] Dr. J. Vaitla, Dr. K. H. Hopmann
Department of Chemistry and Centre for Theoretical and
Computational Chemistry (CTCC), University of Tromsø
9037 Tromsø (Norway)
E-mail: janakiray.vaitla@uit.no
Dr. A. Bayer
Department of Chemistry, University of Tromsø
9037 Tromsø (Norway)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
Scheme 2. Sulfur-ylide-derived metal carbenes in indole synthesis.
cod=1,5-cyclooctadiene, mw=microwave irradiation.
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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