Copper-Promoted Regioselective Synthesis of Polysubstituted Pyrroles from Aldehydes, Amines, and Nitroalkenes via 1,2-Phenyl/Alkyl Migration

The facile copper-catalyzed
synthesis of polysubstituted pyrroles
from aldehydes, amines, and β-nitroalkenes is reported. Remarkably,
the use of α-methyl-substituted aldehydes provides efficient
access to a series of tetra- and pentasubstituted pyrroles via an
overwhelming 1,2-phenyl/alkyl migration. The present methodology is
also accessible to non α-substituted aldehydes, yielding the
corresponding trisubstituted pyrroles. On the contrary, the use of
ketones, in place of aldehydes, does not promote the organic transformation,
signifying the necessity of α-substituted aldehydes. The reaction
proceeds under mild catalytic conditions with low catalyst loading
(0.3–1 mol %), a broad scope, very good functional-group tolerance,
and high yields and can be easily scaled up to more than 3 mmol of
product, thus highlighting a useful synthetic application of the present
catalytic protocol. Based on formal kinetic studies, a possible radical
pathway is proposed that involves the formation of an allylic nitrogen
radical intermediate, which in turn reacts with the nitroalkene to
yield the desired pyrrole framework via a radical 1,2-phenyl or alkyl
migration.