posted on 2021-06-23, 20:12authored byXin Liu, Jianchun Wang, Guangbin Dong
Tetrahydrobenzo[b]azepines (THBAs) are commonly
found in many bioactive compounds; however, the modular preparation
of functionalized THBAs remains challenging to date. Here, we report
a straightforward method to synthesize THBAs directly from simple
aryl iodides via palladium/norbornene (Pd/NBE) cooperative catalysis.
Capitalizing on an olefin-tethered electrophilic amine reagent, an
ortho amination followed by 7-exo-trig Heck cyclization
furnishes the seven-membered heterocycle. To overcome the difficulty
with ortho-unsubstituted aryl iodide substrates, we discovered a unique
C7-bromo-substituted NBE (N1) to offer the desired reactivity
and selectivity. In addition to THBAs, synthesis of other benzo-seven-membered
ring compounds can also be promoted by N1. Combined experimental
and computational studies show that the C7-bromo group in N1 plays an important and versatile role in this catalysis, including
promoting β-carbon elimination, suppressing benzocyclobutene
formation, and stabilizing reaction intermediates. The mechanistic
insights gained could guide future catalyst design. The synthetic
utility has been demonstrated in a streamlined synthesis of tolvaptan
and forming diverse pharmaceutically relevant THBA derivatives. Finally,
a complementary and general catalytic condition to access C6-substituted
THBAs from ortho-substituted aryl iodides has also been developed.