Evidence for Simultaneous Dearomatization of Two Aromatic Rings under Mild Conditions in Cu(I)-Catalyzed Direct Asymmetric Dearomatization of Pyridine

Bis­(phosphine)
copper hydride complexes are uniquely able to catalyze
direct dearomatization of unactivated pyridines with carbon nucleophiles,
but the mechanistic basis for this result has been unclear. Here we
show that, contrary to our initial hypotheses, the catalytic mechanism
is monometallic and proceeds via dearomative rearrangement of the
phenethylcopper nucleophile to a Cpara-metalated
form prior to reaction at heterocycle C4. Our studies support an unexpected
heterocycle-promoted pathway for this net 1,5-Cu-migration beginning
with a doubly dearomative imidoyl-Cu-ene reaction. Kinetics, substituent
effects, computational modeling, and spectroscopic studies support
the involvement of this unusual process. In this pathway, the CuL2 fragment subsequently mediates a stepwise Cope rearrangement
of the doubly dearomatized intermediate to the give the C4-functionalized
1,4-dihydropyridine, lowering a second barrier that would otherwise
prohibit efficient asymmetric catalysis.