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Published July 7, 2021 | Accepted Version + Supplemental Material
Journal Article Open

Modular Entry to Functionalized Tetrahydrobenzo[b]azepines via the Palladium/Norbornene Cooperative Catalysis Enabled by a C7-Modified Norbornene

Abstract

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.

Additional Information

© 2021 American Chemical Society. Received: May 2, 2021; Published: June 23, 2021. Mr. Renhe Li (University of Chicago) is acknowledged for checking the reproducibility of the experimental procedure. Dr. Zhao Wu (University of Chicago) is thanked for helpful discussions. Mr. Shusuke Ochi (University of Chicago) is acknowledged for X-ray crystallography. We are grateful for the support of the University of Chicago's Research Computing Center for assistance with the calculations carried out in this work. Author Contributions: All authors have given approval to the final version of the manuscript. Financial support from the University of Chicago and NIGMS (1R01GM124414–01A1) is acknowledged. The authors declare no competing financial interest.

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Accepted Version - nihms-1807882.pdf

Supplemental Material - ja1c04575_si_001.pdf

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Additional details

Created:
August 20, 2023
Modified:
October 23, 2023