Scaffold Diversity through a Branching Double-Annulation Cascade Strategy: Iminium-Induced One-Pot Synthesis of Diverse Fused Tetrahydroisoquinoline Scaffolds

A branching
double-annulation cascade (BDAC) strategy for diverse
and complex fused THIQ scaffolds via a highly reactive iminium-induced
one-pot double-cyclization sequence involving Pictect–Spengler-type
cyclization has been developed for the first time. The salient features
of this protocol are that it allows direct and rapid access to unprecedented
diverse fused THIQ skeletons, is metal/catalyst free, has a cleaner
reaction profile, provides good to excellent yields, and is a convenient
approach. This catalyst-free domino process facilitates the double
annulation with a variety of scaffold building agents via two C–N
and one C–X (X = C, N, O) bond formation in a single step under
uniform reaction conditions. Furthermore, we reveal an unusual dual
BDAC sequence leading to N–N-linked isoquinoline dimer.