Mechanistic Study of Enantioselective Pd-Catalyzed C(sp³)–H Activation of Thioethers Involving Two Distinct Stereomodels

Abstract

Enantioselective C(sp 3 )−H activation has gained considerable attention from the synthetic chemistry community. Despite the intense interest in these reactions, the mechanisms responsible for enantioselection are still vague. In the course of the development of aryl thioether-directed-C(sp 3 )−H arylation, we noticed extreme variation in sensitivity of two substrate classes to substituent effects of ligands and directing groups: whereas 3pentylsulfides (prochiral α-center) responded positively to substitution on ligands and directing groups, isobutyl sulfides (prochiral β-center) were entirely insensitive. Quantitative structure-selectivity relationship (QSSR) analyses of directing group and ligand substitution and the development of a class of mono-N-acetyl protected amino anilamide (MPAAn) ligands led to high enantiomeric ratios (up to 99:1) for thioether-directed-C(sp 3 )−H arylation. Key to the realization of this method was the exploitation of transient chirality at sulfur, which relays stereochemical information from the ligand backbone to enantiotopic carbons of the substrate in a rate-and enantiodetermining cyclometallation deprotonation. The absolute stereochemistry of the products for these two substrates were revealed to be opposite. Density functional theory (DFT) evaluation of all possible diastereomeric transition states confirmed initial premises that guided rational ligand and directing group design. The implications of this study will assist in the further development of enantioselective C(sp 3 )−H activation, namely by highlighting the noninnocence of directing groups, distal steric influences, and the delicate interplay between steric Pauli repulsion and London dispersion in enantioinduction.

Thioether-Directed NiH-Catalyzed Remote γ-C(sp3)–H Hydroamidation of Alkenes by 1,4,2-Dioxazol-5-ones

“…To examine the binding mode of the sulfur donor, we prepared the N,S-bidentate-tethered alkene substrate 69 . Treating 69 with a stoichiometric amount of NiCl 2 afforded the stable metallacyclic complex 70 , and its structure was confirmed by an X-ray crystallographic study (Scheme a).…”

Experimental and Computational Studies on the Directing Ability of Chalcogenoethers in Palladium‐Catalyzed Atroposelective C−H Olefination and Allylation

“…In addition, substrates containing both electronically rich and deficient substituents at the para- (14-19) and meta-(20-22) position of the phenyl ring underwent the asymmetric CÀ H olefination smoothly, giving the desired products with excellent ees ranging from 95 to 98 % ee. A variety of functionalities such as -methyl (17,22), -methoxy (18), -trifuoromethyl (14,20), -cyano( 16), -halogen (15,19,21), were compatible with the reaction conditions. Substituted biphenyls were also excellent substrates, giving the desired products with high efficiency (23-30, 49-99 % yield, 89-98 % ee).…”

“…Previous reported enantioselective C−H functionalization reactions directed by sulfur containing DGs were largely limited to thioamide and thioketone DGs [17] . The more challenging thioether‐directed, Pd II ‐catalyzed enantioselective C−H functionalization was not reported until recently and delivered polysubstituted styrene [16f] and aliphatic thioether scaffolds only [18] . The development of novel catalytic system employing chalcogenoether‐directed enantioselective C−H functionalization to access structurally diverse chiral biaryls is highly desirable.…”

Mechanistic Inference from Statistical Models at Different Data-Size Regimes

“…Moreover, a recent review by Norrby and co-workers provides an excellent computational chemistry assessment of how the mechanistic study of organic reactivity has been affected by machine learning . Herein, we also set mechanistic inference as our mainstay; however, our specific aim is to demonstrate through selected examples that a careful experimental design not only enables efficient reaction optimization but can concurrently generate uniquely suitable data sets for mechanistic investigation. − …”