Elucidation of a Parasitic Proton-Coupled Electron Transfer in a Photocatalytic Benzylic C-H Sulfonamidation

Abstract

Strategies for C-H amination with sulfonamides have been dominated by stoichiometric strategies or Rh/Cu catalysis using strong oxidants, elevated temperatures, or excess equivalents of C-H partner. We developed a photocatalytic C-H amination with a bench-stable N-methoxypyridinium salt that is amenable to late-stage functionalization efforts. We discovered a competitive proton-coupled electron transfer pathway between sulfonamide and a pyridine byproduct that inhibits the reaction. Catalysis was re-established with the introduction of ZnBr₂.

Figure 1.

A) Recent advances of intermolecular C–H sulfonamidation in catalysis. B) Advances that separate oxidant from sulfonamide partner. C) Proposed competitive pathways in the photocatalysis cycle.

Figure 2.

Optimization of photocatalytic C–H amination by addition of chelating additives.

Figure 3.

Scope for C–H and sulfonamide partners. Reactions were run on a 0.5 mmol scale. DCE = 1,2-dichloroethane. HFIP = hexafluoroisopropanol. ^a0.2 mmol scale. ^bNo ZnBr₂, 1.5 equiv C–H partner, 1 equiv sulfonamide, 1.5 equiv abstractor, 9:1 DCE:HFIP. ^cReaction time of 24 h. ^d1.5 equiv sulfonamide.

Figure 4.

Mechanistic experiments to elucidate the competitive oxidative PCET. A) Pyridine inhibition study. B) Proposed illustration of the PCET pathway. C) Proposed illustration of ZnBr₂ inhibiting the PCET pathway. D) ¹H NMR experiments showing hydrogen bonding interactions. E) Cyclic voltammograms of the PCET pathway in MeCN vs SCE. E_we = working electrode potential.