Nickel-catalyzed hydroxymethylation with α-silicon N-methoxyphthalimides via radical Brook rearrangement

The hydroxymethyl group is an important functional motif frequently found in the core structures of natural products and drugs. However, efficient and general methods for its direct introduction remain underexplored, especially within reductive cross-electrophile coupling frameworks. Herein, we report a nickel-catalyzed reductive hydroxymethylation of aryl halides and triflates enabled by a radical Brook rearrangement strategy. Key to this method is a newly designed, bench-stable α-trialkylsilyl N-methoxyphthalimide reagent, which acts as a masked hydroxymethyl radical precursor upon reductive N-O bond cleavage and subsequent 1,2-radical Brook rearrangement. The reaction proceeds under mild conditions, exhibits broad functional-group tolerance, and is applicable to a wide range of aryl bromides, iodides, triflates, heteroaryl substrates, and complex bioactive derivatives. Mechanistic studies support a radical pathway involving zinc-mediated single-electron transfer, alkoxyl radical formation, Brook rearrangement, and nickel-catalyzed cross-electrophile coupling. The synthetic utility of this protocol is further demonstrated through gram-scale synthesis and downstream diversification, highlighting its potential for late-stage hydroxymethylation and applications in medicinal chemistry.