Halide Abstraction-Mediated Synthesis of a Highly Twisted Amide

Highly strained [3.2.1] bicyclic twisted amide 2 and corresponding amidium 10 were synthesized for the first time through Ag(I)-mediated halide abstraction. After initial lactamization attempts failed, a second-generation strategy was devised to target amidium 10 via intramolecular alkylation. The 3,4-dihydroisoquinolone cyclization precursor was regioselectively prepared via a Rh(III)-catalyzed C–H activation/annulation reaction. After Ag(I)-assisted cyclization, the [3.2.1] bicyclic framework of amidium 10 was confirmed by X-ray crystallography and enabled full solution characterization of twisted amide 2.