Catalytic C–H Alumination of Thiophenes: DFT Predictions and Experimental Verification

A computational model for the palladium-catalyzed C–H
functionalization
of thiophenes with aluminum hydride reagents has been developed. This
model predicts that metalation should occur exclusively at the 2-position
of the heterocycle. While related 2-metalated furans are known to
undergo a ring-expansion reaction, further calculations suggest that
the thiophene-derived organoaluminum compounds should be both kinetically
and thermodynamically stable with respect to ring opening. This model
is supported by experimental data. Selective C–H alumination
of thiophene, 2-methylthiophene, 2-methoxythiophene, and benzothiophene
was achieved using [Pd(PCy3)2] as a catalyst
with loadings as low as 0.02 mol %. Even under extremely forcing conditions
(200 °C) there was no evidence for a ring-opening event. The
differences in selectivity between furan and thiophene systems are
rationalized in terms of the stabilization of a key intermediate (and
transition state) in the pathway for furan ring opening by a strong
dative O→Al interaction.