Regiodivergent Switchable N1- and C3-Alkylation of Indoles with Grignard Reagents Based on Umpolung Strategy

Herein, we present a regiodivergent method for N1- and C3-alkylation of indoles with reversed polarity, triggered by the incorporation of a benzoyloxy leaving group at the N1-position. This approach employs Grignard reagents as versatile nucleophiles, in contrast to conventional regiodivergent indole alkylation methods that rely on alkenes as alkylation reagents. The key to achieving switchable regioselectivity is our discovery that cyclic ether solvents can suppress background N1-alkylation, allowing copper catalysis to selectively divert reactivity toward the C3-position. This reaction system exhibits complete conversion, nearly absolute regioselectivity, and excellent yields across a broad scope of Grignard reagents and substrates.