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

Abstract

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.