Four-membered heterocycles
offer exciting potential as small polar
motifs in medicinal chemistry but require further methods for incorporation.
Photoredox catalysis is a powerful method for the mild generation
of alkyl radicals for C–C bond formation. The effect of ring
strain on radical reactivity is not well understood, with no studies
that address this question systematically. Examples of reactions that
involve benzylic radicals are rare, and their reactivity is challenging
to harness. This work develops a radical functionalization of benzylic
oxetanes and azetidines using visible light photoredox catalysis to
prepare 3-aryl-3-alkyl substituted derivatives and assesses the influence
of ring strain and heterosubstitution on the reactivity of small-ring
radicals. 3-Aryl-3-carboxylic acid oxetanes and azetidines are suitable
precursors to tertiary benzylic oxetane/azetidine radicals which undergo
conjugate addition into activated alkenes. We compare the reactivity
of oxetane radicals to other benzylic systems. Computational studies
indicate that Giese additions of unstrained benzylic radicals into
acrylates are reversible and result in low yields and radical dimerization.
Benzylic radicals as part of a strained ring, however, are less stable
and more π-delocalized, decreasing dimer and increasing Giese
product formation. Oxetanes show high product yields due to ring strain
and Bent’s rule rendering the Giese addition irreversible.