Angewandte
Chemie
DOI: 10.1002/anie.201308611
Heterocycles
Dirhodium(II) Carboxylate Catalyzed Formation of 1,2,3-
Trisubstituted Indoles from Styryl Azides**
Crystalann Jones, Quyen Nguyen, and Tom G. Driver*
Abstract: Dirhodium(II)-carboxylate complexes were discov-
ered to promote the selective migration of acyl groups in
trisubstituted styryl azides to form 1,2,3-trisubstituted indoles.
The styryl azides are readily available in three steps from
cyclobutanone and 2-iodoaniline.
T
he development of new processes to construct polysubsti-
tuted indoles continues to motivate the work of synthetic
groups because of the fundamental importance of this
structural motif across diverse disciplines.[1] Because of the
poor selectivity in Fischer-Indole-type processes, the synthesis
of 6- or 4-(poly)substituted indoles as single isomers remains
a synthetic challenge.[2] In particular, reactions that create the
À
indole through formation of two new C C bonds to the
nitrogen atom are exceedingly sparse.[3] Our laboratory has
focused on developing transition-metal-catalyzed methods
which transform vinyl or aryl azides into heterocycles by
Scheme 1. Development of a new metal-catalyzed electrocyclization/
migration tandem reactions of substituted styryl azides. MG=migrat-
[4]
À
exploiting the mechanism of C N bond formation. Our
investigation of b,b-disubstituted styryl azides (1) revealed
that 2,3-disubstituted indoles could be synthesized as single
isomers through a selective 1,2-shift from 3, a shift which
occurred after electrocyclization of the rhodium nitrene
(Scheme 1).[5] During aromatization to give the indole 5, we
recognized that the a-hydrogen migrates to the nitrogen
atom. At the conclusion of these studies we were curious to
determine what the effect would be on the reaction when this
a-hydrogen atom was replaced with an alkyl or aryl group. We
anticipated that trisubstituted styryl azides (6) would be ideal
substrates for this query because our migratorial aptitude
studies predict that the carbonyl group should preferentially
shift.[5b] Once reaction conditions are found to form a metal
aryl nitrene from 6, a cascade reaction might then be triggered
to produce the N-heterocycles 7–9. If the reactivity of 6
mirrors that of the b,b-disubstituted styryl azide 1 then either
7 or 8 would be produced. In contrast to our expectations,
however, we report herein that rhodium(II) carboxylate
complexes catalyze the formation of the 1,2,3-trisubstituted
indoles 9, as single isomers from trisubstituted styryl azides
through exclusive carbonyl migration. The substitution pat-
ing group.
tern embedded in 9 is present in a variety of natural products
including the Strychnos and Kopsia alkaloid families.[6,7]
To discover the optimal reaction conditions for metal aryl
nitrene formation, the reactivity of the trisubstituted styryl
azide 11 towards a range of transition-metal complexes was
examined (Table 1). This azide is readily constructed in two
steps through a palladium-catalyzed Heck cross-coupling
ring-expansion reaction between 2-iodoaniline and the cyclo-
butanol 10, with subsequent azidation of the resulting ani-
line.[8,9] The trisubstituted styryl azide 11 proved to be less
reactive than the b,b-disubstituted styryl azides we previously
investigated: effervescence was not observed at 808C (entry 1
and 2). Increasing the temperature to 1008C, however,
produced the 1,2,3-trisubstituted indole 12 as the only product
when 11 was exposed to rhodium carboxylates (entries 3–
6).[10] Among the rhodium complexes surveyed, we found that
[Rh2(OAc)4] and [Rh2(esp)2][11] were the most efficient
catalysts for indole formation (entries 2 and 6). While we
attribute the success of [Rh2(esp)2] to the thermal robustness
inherent in its tetradentate ligands,[12] the activity of [Rh2-
(OAc)4] was surprising because its insolubility rendered it
impotent in our previous methods.[4,5] Its increased solubility
at elevated temperatures, however, appears to transform it
into a competent catalyst. On larger reaction scales, however,
we found that [Rh2(esp)2] outperformed [Rh2(OAc)4] to
provide the indole product with higher yields and greater
reproducibility. Lowering the catalyst loading or reducing the
reaction temperature led to attenuated yields of the 1,2,3-
trisubstituted indole product (entries 7 and 8). Examination
[*] C. Jones, Q. Nguyen, Prof. Dr. T. G. Driver
Department of Chemistry, University of Illinois at Chicago
845 W. Taylor St., Chicago (USA)
E-mail: tgd@uic.edu
[**] We are grateful to the National Institutes of Health NIGMS
(R01GM984945) and the University of Illinois at Chicago for their
generous support.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 785 –788
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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