Constructing <i>Iboga</i> Alkaloids via C–H Bond Functionalization: Examination of the Direct and Catalytic Union of Heteroarenes and Isoquinuclidine Alkenes

The <i>iboga</i> alkaloids have attracted considerable attention in both the scientific community and popular media due to their reported ability to reverse or markedly diminish cravings for, and self-administration of, the major drugs of abuse. We have developed three new intramolecular C–H functionalization procedures leading to the core seven-membered ring of the <i>iboga</i> skeleton, a cyclization that proved to be highly challenging. The electrophilic palladium salt Pd­(CH₃CN)₄(BF₄)₂ was effective for the cyclization of diverse <i>N-</i>(2-arylethyl)­isoquinuclidines with yields of 10–35%. A two-step, bromination-reductive Heck reaction protocol was also effective for the synthesis of ibogamine in 42% yield. Finally, a direct Ni(0)-catalyzed C–H functionalization provided the benzofuran analogues of ibogamine (74%) and <i>epi</i>-ibogamine (38%). Although each approach suffers from significant shortcomings, in combination, the methods described provide practical routes to diverse ibogamine analogues