Synthesis of multifunctional lactam-substituted alkyl sulfones using rongalite as electron donor, sulfone source, and C1 synthon

Abstract

Substantial progress has been made in the single and dual functionalization of the 3,3-difluoro-γ-lactam radical for the synthesis of related derivatives. However, achieving its triple functionalization presents a significant challenge, primarily due to difficulties in sequential control, site selectivity, and competing pathways. Herein, we report a novel rongalite-mediated triple functionalization of N-allyl bromodifluoroacetamides with electron-rich heteroarenes via a sulfonylation / methylation / heteroarylation sequence, enabling efficient access to multifunctional lactam-substituted alkyl sulfones. This protocol operates under metal-, oxidant-, and photocatalyst-free conditions, demonstrating high efficiency and broad substrate scope. Furthermore, the protocol facilitates late-stage modification of indole scaffolds derived from commercial pharmaceuticals, including ibuprofen, aspirin, and indomethacin. Mechanistic studies support a radical pathway, underscoring the triple role of rongalite as a super electron donor for reaction initiation, a “SO₂” source, and a “C1” precursor.