Catalytic intramolecular aminoarylation of unactivated alkenes with aryl sulfonamides

Abstract

Arylethylamines are abundant motifs in myriad natural products and pharmaceuticals, so efficient methods to synthesize them are valuable in drug discovery. In this work, we disclose an intramolecular alkene aminoarylation cascade that exploits the electrophilicity of a nitrogen-centered radical to form a C-N bond, then repurposes the nitrogen atom's sulfonyl activating group as a traceless linker to form a subsequent C-C bond. This photoredox catalysis protocol enables the preparation of densely substituted arylethylamines from commercially abundant aryl sulfonamides and unactivated alkenes under mild conditions. Reaction optimization, scope, mechanism, and synthetic applications are discussed.

Fig. 1. (A) Selected biologically active molecules containing arylethylamines and recent catalytic disconnections. (B) Summary of our group's prior work on aminoarylation through alkene radical cations. (C) Abstract depiction of aminoarylation cascade in the present work and challenges that were overcome.

Fig. 2. Structural features of the aminoarylation substrates that favor Smiles–Truce rearrangement and disfavor undesired side reactions.

Fig. 3. Scope of the aminoarylation. All reactions performed on 0.2 mmol scale. All yields are from isolation. *Isolated as 9 : 1 mixture with regioisomeric product 2o′, see ESI.

Fig. 4. (A) Newman projections depicting disfavored and favored conformers of the N-sulfonyl lactam and stereochemical outcomes of C–C bond formation. (B) Experiment establishing reactivity and catalytic turnover of deprotonated N-acylsulfonamides. Yields determined by ¹⁹F NMR integration relative to 4-fluorobromobenzene internal standard. (C) Mechanistic proposal of the aminoarylation. (D) Further reactions of aminoarylation products including reductive cyclization, lactam hydrolysis, and photochemical removal of an ortho substituent.