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

A computational model for the palladium-catalysed C–H functionalisation of thiophenes with aluminium hydride reagents has been developed. This model predicts metalation should occur exclusively at the 2-position of the heterocycle. While related 2-metallated furans are known to undergo a ring-expansion reactions, further calculations suggest that the thiophene-derived organoaluminium 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 ºC) there was no evidence for a ring-opening event. The differences in selectivity between furan and thiophene systems are rationalised in terms of the stabilisation of a key intermediate (and transition state) in the pathway for furan ring opening by a strong dative O–Al interaction.