PdII -Catalyzed Enantioselective C(sp3 )-H Arylation of Cyclobutyl Ketones Using a Chiral Transient Directing Group

Abstract

The use of chiral transient directing groups (TDGs) is a promising approach for developing Pd^II -catalyzed enantioselective C(sp³ )-H activation reactions. However, this strategy is challenging because the stereogenic center on the TDG is often far from the C-H bond, and both TDG covalently attached to the substrate and free TDG are capable of coordinating to Pd^II centers, which can result in a mixture of reactive complexes. We report a Pd^II -catalyzed enantioselective β-C(sp³ )-H arylation reaction of aliphatic ketones using a chiral TDG. A chiral trisubstituted cyclobutane was efficiently synthesized from a mono-substituted cyclobutane through sequential C-H arylation reactions, thus demonstrating the utility of this method for accessing structurally complex products from simple starting materials. The use of an electron-deficient pyridone ligand is crucial for the observed enantioselectivity. Interestingly, employing different silver salts can reverse the enantioselectivity.

Keywords: C−H activation; arylation; palladium; pyridone ligands; transient directing groups.

Scheme 1.

Two strategies for Pd(II)-catalyzed directed asymmetric C(sp³)–H activation

Scheme 2.

Enantioselective C(sp³)‒H arylation using a transient directing group strategy

Scheme 3.

Diverse chiral cyclobutanes via sequential C–H arylation

Scheme 4.

Deuterium-labeling experiments

Scheme 5.

Proposed mechanism: combinations of pyridone ligands with silver salts to switch the rate-limiting steps (RLS)