Enantioselective Chan-Lam S-Arylation of Sulfenamides

Abstract

Sulfur-stereogenic molecules have a significant impact on drug development, but are underexplored largely due to our limited ability to construct such structures. Among them, sulfilimines are a class of chiral molecules bearing S(IV)-stereocenters, which exhibit great value in chemistry and biology but were synthetically intractable previously. We report a highly chemoselective and enantioselective Chan-Lam S-arylation of sulfenamides with arylboronic acids to deliver an array of thermodynamically disfavored diaryl and alkyl aryl sulfilimines containing a sulfur stereocenter. Though Chan-Lam coupling has been widely used to construct C-N, C-O and C-S bonds by coupling nucleophiles with boronic acids using copper complexes in academia and industry, control of the stereochemistry in this textbook transformation has proven to be a formidable challenge. A new copper catalyst from a 2-pyridyl N-phenyl dihydroimidazole ligand has been designed that enables effective enantiocontrol by means of a well-defined chiral environment and high reactivity that outcompetes the background racemic transformation. A combined experimental and computational study establishes the reaction mechanism and unveils the origin of chemoselectivity and stereoselectivity.

Figure 1

a) Formation of common intermediate 2a’, which can undergo N-arylation or S-arylation. b) Formation of S-arylation product 3-S via kinetic control. c) Formation of (S)-product over (R)-product, an entropically controlled process. All free energies were computed using UM06/6–311++G(d,p)-SDD(Cu)-CPCM(DME)//UB3LYP-D3/6–31G(d)-SDD(Cu).

Scheme 1.

Background and Conceptual Design

Scheme 2.

Synthetic Applications