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.