Confronting the Challenging Asymmetric Carbonyl 1,2-AdditionUsing Vinyl Heteroarene Pronucleophiles: Ligand-ControlledRegiodivergent Processes through a Dearomatized Allyl-Cu Species

The selective reductive coupling of vinyl hetero-arenes with aldehydes and ketones represents a versatile approachfor the rapid construction of enantiomerically enriched secondaryand tertiary alcohols, respectively. Herein, we demonstrate a CuH-catalyzed regiodivergent coupling of vinyl heteroarenes withcarbonyl-containing electrophiles, in which the selectivity iscontrolled by the ancillary ligand. This approach leverages aninsitugenerated benzyl- or dearomatized allyl-Cu intermediate,yielding either the dearomatized or exocyclic addition products,respectively. The method exhibits excellent regio-, diastereo-, andenantioselectivity and tolerates a range of common functionalgroups and heterocycles. The dearomative pathway allows direct access to a variety of functionalized saturated heterocyclicstructures. The reaction mechanism was probed using a combination of experimental and computational approach. Densityfunctional theory studies suggest that the ligand-controlled regioselectivity results from the C-H/pi interaction and steric repulsionin transition states, leading to the major and minor regioisomers, respectively. Hydrocupration of vinyl heteroarene pronucleophile isthe enantiodetermining step, whereas the diastereoselectivity is enforced by steric interactions between the benzylic or allyl-Cuintermediate and carbonyl-containing substrates in a six-membered cyclic transition state

Automated summary

This article introduces a CuH-catalyzed selective reductive coupling reaction of vinyl heteroarenes with aldehydes and ketones. The selectivity of the reaction is controlled by the choice of the ancillary ligand. This method shows excellent selectivity, tolerates various functional groups and heterocycles, and provides a direct route to functionalized saturated heterocyclic structures.