Angewandte
Chemie
DOI: 10.1002/anie.201303550
À
C H Functionalization
Metal-Free Radical Azidoarylation of Alkenes: Rapid Access to
À
À
Oxindoles by Cascade C N and C C Bond-Forming Reactions**
Kiran Matcha, Rishikesh Narayan, and Andrey P. Antonchick*
The importance of nitrogen-containing compounds has
radical acetoarylation of N-arylacrylamides was reported.[10]
Therefore, we realized that choosing N-arylacrylamides as
a platform to investigate the unprecedented azidoarylation of
inspired chemists to continue developing mild and efficient
[1]
À
C N bond-forming transformations. The amination of
alkenes represents the state-of-the art in organic synthesis.[2]
Azides offer substantial benefits for the synthesis of nitrogen-
containing compounds and have been recognized as versatile
intermediates. Organic azides possess unique properties
orthogonal to those of many functional groups, demonstrate
unique reactivity, and are stable under physiological condi-
tions.[3] The established methods of alkyl azide synthesis are
based on the transformation of functionalized alkanes using
multistep procedures. Direct azidation methods for the
synthesis of alkyl azides from alkenes are much less devel-
oped. The groups led by Carreira and Renaud developed
broadly applicable radical hydroazidation and carboazidation
of unactivated alkenes using organic azides as radical traps for
carbon-centered radicals.[4] The application of azidyl radicals
in the functionalization of alkenes represents a straightfor-
ward approach to alkyl azides. Nevertheless, these processes
alkenes would result in a cascade of C N and C C bond-
forming reactions. The presented method is a complimentary
metal-free approach to the synthesis of 2-oxindoles. More-
over, in contrast to other oxindole syntheses, the resulting
products, substituted 2-oxindoles with an appended azide
group, can be used to create further molecular complexity
around the privileged scaffold of 2-oxindoles or can be
applied for bioorthogonal transformation under physiological
conditions.[11]
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À
Recently, our group has employed azidyl radicals as
intermediates in the cross-dehydrogenative coupling of het-
erocycles with aldehydes and unactivated alkanes.[12] The
azidyl radicals were generated by oxidation of azides in the
presence of hypervalent iodine(III) reagents at ambient
temperature.[13,14] Intrigued by these results, we hypothesized
that these azidyl radicals could be used for the azidoarylation
of alkenes as well. We decided to take advantage of the mild
reaction conditions for generation of azidyl radicals to
achieve the desired products of azidoarylation. Indeed, the
desired azidoarylation product 2a was obtained in 45% yield
from the reaction of 1a with NaN3 in presence of PhI-
(OCOCF3)2 (Table 1, entry 1). Replacing NaN3 with TMSN3
further improved the yield to 70% (Table 1, entry 2). Not
surprisingly, attempted base-promoted conjugate addition of
azide to olefin 1a did not result in formation of product 2a
(Table 1, entries 3 and 4).[15] The differences in yield observed
for 2a after reducing the amount of oxidant from 2 equiv to
1 equiv (Table 1, entries 2 and 5) led us to investigate the
optimal reaction conditions. Experiments with varying
amounts of oxidant suggested that 1.2 equiv is required to
achieve complete conversion of 1a to 2a with higher yield
(Table 1, entries 5–8). Although few solvents did not promote
the desired transformation (Table 1, entries 9 and 10), DCM
was found to be superior with 91% yield for 2a (Table 1,
entries 11–14). Significant amounts of unreacted 1a were
observed when the amounts of PhI(OCOCF3)2 and TMSN3
were decreased further (see the Supporting Information for
details). Among the hypervalent iodine reagents screened,
C6F5I(OCOCF3)2 performed well although the yields were
lower than with PhI(OCOCF3)2 (Table 1, entry 15). Less
reactive PhI(OAc)2 did not lead to full conversion (Table 1,
entry 16). No reaction was observed with (PhO)2PON3, while
NaN3 was less effective than TMSN3 (Table 1, entries 17 and
18). Finally, an open-flask experiment performed on a large
scale with 1 gram of 1a provided 2a in 90% yield within
a short time under ambient conditions (Table 1, entry 19).
are limited to selective hydrogen abstraction by cleavage of
3
À
C(sp ) H bonds by azidyl radicals generally leading to
generation of carbon-centered radicals and other nitrogen-
centered radicals.[5] Several methods of azidyl radical addition
to alkenes followed by formation of carbon–heteroatom
bonds have been reported.[6] Straightforward methods for
alkyl azide synthesis by the addition of the azidyl radical to
À
alkenes followed by formation of C C bonds have never been
reported and are in high demand. Here we describe the
development of the unprecedented functionalization of
alkenes by the addition of azidyl radicals followed by trapping
with arenes (azidoarylation) under metal-free reaction con-
ditions at ambient temperature.
2-Oxindoles are a large class of natural products with
unique biological activity and represent one of the privileged
scaffolds for library design and drug discovery.[7] Among the
methods available for their synthesis,[8] the recently reported
radical-mediated cyclizations of N-arylacrylamides have
received special attention. These methods are based on
À
À
a cascade sequence consisting of C C (or C P) followed by
À
C C bond-forming reactions catalyzed by transition metals at
typically high temperature.[9] Very recently, a metal-free
[*] Dr. K. Matcha, Dr. R. Narayan, Dr. A. P. Antonchick
Max-Planck-Institut fꢀr Molekulare Physiologie
Abteilung Chemische Biologie
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
E-mail: andrey.antonchick@mpi-dortmund.mpg.de
[**] We thank Prof. Dr. H. Waldmann for generous support.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2013, 52, 7985 –7989
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7985
Matcha, Kiran
