Synthesis of C‑4 Substituted Amido Nicotine Derivatives via Copper(I)- and (II)-Catalyzed Cross-Coupling Reactions

The syntheses of seven novel amido nicotine derivatives 12–18 from (S)-nicotine are presented. (S)-Nicotine and (S)-6-chloronicotine derivatives were cross-coupled with the corresponding amides 6–10 at the C-4 position of the pyridine ring via copper­(I)-mediated reactions. Derivatives 16–18 were also obtained via copper­(II)-mediated reactions from (S)-nicotine containing a C-4 boronic acid pinacol ester group. The optimization of reaction conditions for both routes provided a useful method for preparing C-4 amide-containing nicotine analogs.