Photocatalytic Late-Stage Functionalization of Sulfonamides via Sulfonyl Radical Intermediates

Abstract

A plethora of drug molecules and agrochemicals contain the sulfonamide functional group. However, sulfonamides are seldom viewed as synthetically useful functional groups. To confront this limitation, a late-stage functionalization strategy is described, which allows sulfonamides to be converted to pivotal sulfonyl radical intermediates. This methodology exploits a metal-free photocatalytic approach to access radical chemistry, which is harnessed by combining pharmaceutically relevant sulfonamides with an assortment of alkene fragments. Additionally, the sulfinate anion can be readily obtained, further broadening the options for sulfonamide functionalization. Mechanistic studies suggest that energy-transfer catalysis (EnT) is in operation.

Figure 1

Late-stage functionalization of sulfonamides via nucleophilic,^, electrophilic, and neutral reactive intermediates.

Figure 2

Photocatalyzed sulfinate salt formation and telescoped reaction from a primary sulfonamide. ^aReaction conditions: (1) p-CF₃-benzyl bromide (1.5 equiv), TBAB (20 mol %), 100 °C, 24 h; (2) NFSI (1.5 equiv), K₂CO₃ (1.1 equiv), solvent switch to THF/H₂O (10:1, 0.2 M), rt., 12 h; (3) acidify using 2 M aq. H₃PO₄, extract (Na₂CO₃). ^bReaction conditions: step (i) sulfonamide 9 (1.0 equiv), p-anisaldehyde (1.0 equiv), Amberlyst 15 (5 mg/mmol), PhMe (0.1 M), Dean-Stark, 12 h; step (iii) MVK (2.5 equiv), 5CzBN (0.5 mol %), TMS₃Si-H (1.5 equiv), PhMe (0.05 M), blue LEDs, 15 °C, 4 h.

Figure 3

Mechanistic investigations. (A) Absorption spectra of 2a in toluene and emission spectra of 5CzBN in toluene using excitation at 400 nm. (B) Stern–Volmer quenching of 5CzBN in toluene using excitation at 400 nm. (C) Further screening of photocatalysts using a 0.1 mmol scale with MVK (2.5 equiv), TMS₃Si-H (1.5 equiv), PhMe (0.05 M), blue LEDs, 15 °C, 4 h. (D) Control reactions using a 0.1 mmol scale with MVK (2.5 equiv), 5CzBN (0.5 mol %), TMS₃Si-H (1.5 equiv), PhMe (0.05 M), blue LEDs, 15 °C, 4 h, or 3-butenylbenzene (2.5 equiv), 5CzBN (1 mol %), p-fluorothiophenol (2.2 equiv), DCE (0.1 M), blue LEDs, 15 °C, 4 h. With all potentials and triplet energies measured in MeCN. (E) Proposed catalytic cycle.