Organocatalytic Enantioselective Electrophilic C-H Sulfenylation of Arenes

Electrophilic aromatic substitution has long served as a cornerstone for C-H functionalization, yet its catalytic enantioselective variant, especially for sulfenylation, remains largely unexplored. The challenges are multifaceted: the stereogenic element often lies remote from the reaction site, multiple reactive sites compete, and the mechanisms of asymmetric induction vary unpredictably with substrate structure. Overcoming these obstacles requires not only new catalysts but also a deep understanding of the underlying stereochemical properties. In this Account, we summarize our systematic efforts to address these obstacles through chiral Lewis base-catalyzed enantioselective electrophilic C-H sulfenylation of arenes, a metal-free approach that inherently avoids the catalyst poisoning issues common in transition-metal-mediated C-S cross-couplings. Starting from the atroposelective sulfenylation of biaryl phenols, we discovered that a combined desymmetrization/kinetic resolution sequence, enabled by chiral 1,1'-binaphthyl-2,2'-diol (BINOL)-derived selenide catalysts and an achiral sulfonic acid, delivers axially chiral organosulfur products with high enantiocontrol. This work established the feasibility of asymmetric aromatic sulfenylation and laid the groundwork for subsequent expansions. Mechanistic studies, including nuclear magnetic resonance (NMR) titrations, density functional theory (DFT) calculations, and noncovalent interaction (NCI) analysis, revealed that hydrogen-bond networks and π-π interactions play a crucial role in stabilizing the enantiodetermining transition states. The same catalytic logic was then extended to other substrate classes, proving applicable to N-aryl pyrroles and biaryl anilines, with the latter proceeding via sole desymmetrization. For N-aryl aminoquinones, the sulfide catalyst with a more rigid 1,1'-spirobiindane-7,7'-diol (SPINOL) backbone proved superior, affording chiral products with two contiguous C-N axes. In addition to the synthesis of axially chiral organosulfur compounds, we applied the same catalytic platform to construct planar-chiral, helically chiral, inherently chiral, and chiral silicon-stereogenic organosulfur molecules. For planar-chiral cyclophanes, the mechanism switches among dynamic kinetic resolution (DKR), kinetic resolution (KR), and desymmetrization depending on ring size. Helically chiral aza-[5]helicenes were obtained via DKR, and the sulfide products underwent cross-coupling without erosion of chirality. Inherently chiral calix[4]arenes were accessed through a rare example of chemoselective desymmetrization where kinetic N-sulfenylation is reversible and gives way to thermodynamically favored C-sulfenylation. Finally, chiral silicon-stereogenic cyclic diarylsilanes were delivered through a tandem desymmetrization/kinetic resolution sequence, further underscoring the generality of our approach. Across all systems, noncovalent interactions such as C-H···π, π-π, and hydrogen bonding proved to be the dominant stereocontrolling forces. The evolution of catalysts from selenides to sulfides, from binaphthyl to spiro backbones, and the introduction of chiral amine moieties systematically improved both yield and enantioselectivity. This Account thus provides a unified blueprint for asymmetric aromatic C-H sulfenylation, offering both synthetic access to diverse chiral scaffolds and mechanistic insights that should guide future developments in organocatalytic electrophilic functionalization.