C–H/C–C Functionalization Approach to N‑Fused Heterocycles from Saturated Azacycles

Herein
we report the synthesis of substituted indolizidines and
related N-fused bicycles from simple saturated cyclic amines through
sequential C–H and C–C bond functionalizations. Inspired
by the Norrish–Yang Type II reaction, C–H functionalization
of azacycles is achieved by forming α-hydroxy-β-lactams
from precursor α-ketoamide derivatives under mild, visible light
conditions. Selective cleavage of the distal C­(sp2)–C­(sp3) bond in α-hydroxy-β-lactams using a Rh-complex
leads to α-acyl intermediates which undergo sequential Rh-catalyzed
decarbonylation, 1,4-addition to an electrophile, and aldol cyclization,
to afford N-fused bicycles including indolizidines. Computational
studies provide mechanistic insight into the observed positional selectivity
of C–C cleavage, which depends strongly on the groups bound
to Rh trans to the phosphine ligand.