Catalytic transformation of alcohols
via metal-catalyzed cross-coupling
reactions is very important, but it typically relies on a multistep
procedure. We here report a dynamic kinetic cross-coupling approach
for the direct functionalization of alcohols. The feasibility of this
strategy is demonstrated by a nickel-catalyzed cross-electrophile
arylation reaction of benzyl alcohols with (hetero)aryl electrophiles.
The reaction proceeds with a broad substrate scope of both coupling
partners. The electron-rich, electron-poor, and ortho-/meta-/para-substituted
(hetero)aryl electrophiles (e.g., Ar–OTf, Ar–I, Ar–Br,
and inert Ar–Cl) all coupled well. Most of the functionalities,
including aldehyde, ketone, amide, ester, nitrile, sulfone, furan,
thiophene, benzothiophene, pyridine, quinolone, Ar–SiMe3, Ar–Bpin, and Ar–SnBu3, were tolerated.
The dynamic nature of this method enables the direct arylation of
benzylic alcohol in the presence of various nucleophilic groups, including
nonactivated primary/secondary/tertiary alcohols, phenols, and free
indoles. It thus offers a robust alternative to existing methods for
the precise construction of diarylmethanes. The synthetic utility
of the method was demonstrated by a concise synthesis of biologically
active molecules and by its application to peptide modification and
conjugation. Preliminary mechanistic studies revealed that the reaction
of in situ formed benzyl oxalates with nickel, possibly via a radical
process, is an initial step in the reaction with aryl electrophiles.
