Copper-Catalyzed Regioselective and Enantioselective Hydropyridylation of Dienes for the Synthesis of Chiral Diaryl Compounds via Concerted Nucleophilic Aromatic Substitution

Abstract

The synthesis of chiral 1,1-diaryl compounds, particularly those containing a pyridine moiety, is of significant interest due to their pharmaceutical applications. Here, we report the development of a copper-catalyzed enantioselective 1,4-hydropyridylation of conjugated dienes. Utilizing 2-fluoropyridine as the electrophile, CuOAc, and the chiral ligand Tol-BINAP, we optimized reaction conditions to achieve the desired chiral 1,1-diaryl products containing both a pyridine and a cis-crotyl group. Mechanistic studies and DFT calculations revealed that the 1,2-hydrocupration step is enantio-determining, and the concerted nucleophilic aromatic substitution proceeds via six-membered cyclic transition states.

Keywords: 1,3-Dienes; Enantioselective Catalysis; Hydropyridylation; Regioselective Catalysis.