A combined experimental and computational study of ligand-controlled Chan-Lam coupling of sulfenamides

Abstract

The unique features of the sulfenamides' S(II)-N bond lead to interesting stereochemical properties and significant industrial functions. Here we present a chemoselective Chan-Lam coupling of sulfenamides to prepare N-arylated sulfenamides. A tridentate pybox ligand governs the chemoselectivity favoring C-N bond formation, and overrides the competitive C-S bond formation by preventing the S,N-bis-chelation of sulfenamides to copper center. The Cu(II)-derived resting state of catalyst is captured by UV-Vis spectra and EPR technique, and the key intermediate is confirmed by the EPR isotope response using ¹⁵N-labeled sulfenamide. A computational mechanistic study reveals that N-arylation is both kinetically and thermodynamically favorable, with deprotonation of the sulfenamide nitrogen atom occurring prior to reductive elimination. The origin of ligand-controlled chemoselectivity is explored, with the interaction between the pybox ligand and the sulfenamide substrate controlling the energy of the S-arylation and the corresponding product distribution, in agreement with the EPR studies and kinetic results.

Fig. 1. Strategies and Challenges in Synthesis of Sulfenamide.

A Synthetic Approaches to Sulfenamides. a Classic Synthetic Strategies to Sulfenamides. b This Work: Synthesis of N-Arylated Sulfenamides by Chan–Lam Coupling. B Conceptual Design and Major Challenges of Our Approach. a Conceptual Design of Our Approach. b Potential Challenges of Our Approach.

Fig. 2. Substrate Scope^a.

^aReaction conditions: 1a (0.15 mmol), 2a (2.0 equiv), Cu(TFA)₂•H₂O (10 mol %), L3 (20 mol %), and Cy₂NMe (1.5 equiv) in MeCN (0.5 mL) under O₂ at room temperature for 24 h. ^b35 °C, 24 h. ^c12 h. ^dCu(TFA)₂•H₂O (15 mol %), L3 (30 mol %), 12 h. ^e35 °C, 2 h. ^f35 °C, 12 h.

Fig. 3. Synthetic Applications.

a Downstream Transformations of Products. b Synthesis of Sulfenamide-Analog of Sulfacetamide. c Synthesis of Sulfenamide-Analog of Oxybuprocaine.

Fig. 4. Mechanistic Studies.

a Kinetics. b UV–Vis Spectra. c EPR Spectra.

Fig. 5. Computational Mechanistic Studies.

a DFT Computational Study: Formation of N-Arylation Product 21’. All Free Energies Were Computed Using UM06/6-311 + + G(d,p)-SDD(Cu)-CPCM(DME)//UB3LYP-D3/6-31 G(d)-SDD(Cu). b Proposed Catalytic Cycle for Chan–Lam Coupling of Sulfenamides.