Angewandte
Chemie
DOI: 10.1002/anie.201406464
Heterocycles
Cascade Multicomponent Synthesis of Indoles, Pyrazoles, and
Pyridazinones by Functionalization of Alkenes**
Kiran Matcha and Andrey P. Antonchick*
Abstract: The development of multicomponent reactions for
indole synthesis is demanding and has hardly been explored.
The present study describes the development of a novel
multicomponent, cascade approach for indole synthesis. Var-
ious substituted indole derivatives were obtained from simple
reagents, such as unfunctionalized alkenes, diazonium salts,
and sodium triflinate, by using an established straightforward
and regioselective method. The method is based on the radical
trifluoromethylation of alkenes as an entry into Fischer indole
synthesis. Besides indole synthesis, the application of the
multicomponent cascade reaction to the synthesis of pyrazoles
and pyridazinones is described.
seldom explored and not reported for indoles to date.[10]
Herein, we describe alkene trifluoromethylation as an entry
point for a regioselective multicomponent cascade synthesis
of indole derivatives by Fischer indole synthesis. Further-
more, the developed process was applied to the regioselective
synthesis of other nitrogen-containing heterocycles such as
pyrazole and dihydropyridazinone derivatives.
Our research group is actively involved in developing
novel methods for the synthesis and functionalization of
heterocyclic compounds.[11,12] Furthermore, our continued
[12]
À
interest in radical-mediated C H functionalizations led to
a novel radical-mediated route being envisioned for the
synthesis of indoles. We assumed that adding a trifluoromethyl
radical to an alkene and subsequent trapping with an
arenediazonium salt could provide an intermediate for the
Fischer indole synthesis in a one-pot reaction (Scheme 1). A
T
he indole moiety is a privileged heterocyclic scaffold
prevalent in a large number of natural products and
pharmaceuticals.[1] The demand for simple and efficient
syntheses of indoles has burgeoned since the development
of the classical Fischer indole synthesis.[2] In this context,
developments in Fischer indole synthesis have received
widespread attention, in particular the transition-metal-
catalyzed intramolecular cyclization of enamides to indoles.[3]
A few conceptually different reactions have also been
reported to access the sequence of the Fischer indole syn-
thesis downstream.[4] The coupling of hydrazine and aniline
derivatives to alkynes has become another important and
well-explored alternative synthesis route.[5] However, the
coupling of aniline derivatives with alkenes is mostly focused
on the intramolecular version;[6] an intermolecular version
has not yet been well-studied.[7] Moreover, multicomponent
reactions for the synthesis of indoles have been seldom
explored.[8] Developing a novel multicomponent reaction
would be a valuable alternative to the synthesis of indoles.
The remarkable properties of the fluorine group has resulted
in the trifluoromethylation of alkenes recently becoming an
important tool to incorporate fluorine into organic com-
pounds.[9,10] However, the application of alkene trifluorome-
thylation in the synthesis of heterocycles has only been
Scheme 1. Multicomponent indole synthesis.
proof of concept was demonstrated by Heinrich et al. using
aryl radicals.[4e] However, the reported approach was a two-
step synthesis of indole and no substrate scope was explored.
To test our hypothesis, alkene 1a was subjected to radical
trifluoromethylation conditions by using a combination of
CF3SO2Na, tBuOOH, and CuCl in the presence of arenedi-
azonium salt 2a (Table 1). To our delight, indole 3a was
isolated in 30% yield (entry 1). Moreover, product 3a was
isolated as a single regioisomer. It should be noted that
arenediazonium salts are widely used as the source of aryl
À
radicals after breaking C N bonds and elimination of nitro-
gen,[13] although they have rarely been used as radical
traps.[4e,14] Intrigued by the outcome of the anticipated
reaction, we proceeded to optimize the reaction conditions
(Table 1, and see the Supporting Information). The reaction
was feasible in polar solvents, but failed in nonpolar solvents
(entries 1–3). Acetonitrile turned out to be the best solvent,
giving the desired product 3a in 45% yield (entry 3). Further
optimization revealed that various metal salts promote the
reaction (entries 3–6), and among these salts, AgNO3
afforded the best yield (entry 6). Although the metal-free
initiator Bu4NBr promoted the reaction, the yield was lower
(entry 7). The initial choice of CF3SO2Na was found to be
superior to many of the investigated trifluoromethylating
reagents under the reaction conditions (entries 6, 8, and 9).
[*] Dr. K. Matcha, Dr. A. P. Antonchick
Abteilung Chemische Biologie
Max-Planck-Institut fꢀr Molekulare Physiologie
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
E-mail: andrey.antonchick@mpi-dortmund.mpg.de
Dr. A. P. Antonchick
Fakultꢁt Chemie und Chemische Biologie
Technische Universitꢁt Dortmund
Otto-Hahn-Strasse 6, 44221 Dortmund (Germany)
[**] We thank Prof. Dr. Herbert Waldmann for his generous support.
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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