posted on 2023-08-29, 12:03authored bySoham Maity, Marco A. Lopez, Desiree M. Bates, Shishi Lin, Shane W. Krska, Shannon S. Stahl
Site-selective radical reactions of benzylic C–H
bonds are
now highly effective methods for C(sp3–H) functionalization
and cross-coupling. The existing methods, however, are often ineffective
with heterobenzylic C–H bonds in alkyl-substituted pyridines
and related aromatic heterocycles that are prominently featured in
pharmaceuticals and agrochemicals. Here, we report new synthetic methods
that leverage polar, rather than radical, reaction pathways to enable
the selective heterobenzylic C–H chlorination of 2- and 4-alkyl-substituted
pyridines and other heterocycles. Catalytic activation of the substrate
with trifluoromethanesulfonyl chloride promotes the formation of enamine
tautomers that react readily with electrophilic chlorination reagents.
The resulting heterobenzyl chlorides can be used without isolation
or purification in nucleophilic coupling reactions. This chlorination–diversification
sequence provides an efficient strategy to achieve heterobenzylic
C–H cross-coupling with aliphatic amines and a diverse collection
of azoles, among other coupling partners.