Overcoming peri - and ortho -selectivity in C-H methylation of 1-naphthaldehydes by a tunable transient ligand strategy.

Methyl groups widely exist in bioactive molecules, and site-specific methylation has become a valuable strategy for their structural functionalization. Aiming to introduce this smallest alkyl handle, a highly regioselective peri - and ortho -C-H methylation of 1-naphthaldehyde by using a transient ligand strategy has been developed. A series of methyl-substituted naphthalene frameworks have been prepared in moderate to excellent yields. Mechanistic studies demonstrate that peri -methylation is controlled by the higher electronic density of the peri -position of 1-naphthaldehyde as well as the formation of intermediary 5,6-fused bicyclic palladacycles, whereas experimental studies and theoretical calculations inferred that a 5-membered iridacycle at the ortho -position of 1-naphthaldehyde leads to energetically favorable ortho -methylation via an interconversion between the peri -iridacycle and ortho -iridacycle. Importantly, to demonstrate the synthetic utility of this method, we show that this strategy can serve as a platform for the synthesis of multi-substituted naphthalene-based bioactive molecules and natural products.