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

Liu, Xin and Wang, Jianchun and Dong, Guangbin (2021) Modular Entry to Functionalized Tetrahydrobenzo[b]azepines via the Palladium/Norbornene Cooperative Catalysis Enabled by a C7-Modified Norbornene. Journal of the American Chemical Society, 143 (26). pp. 9991-10004. ISSN 0002-7863. doi:10.1021/jacs.1c04575. https://resolver.caltech.edu/CaltechAUTHORS:20210630-155914378

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/jacs.1c04575DOIArticle
ORCID:
AuthorORCID
Wang, Jianchun0000-0002-3998-8699
Dong, Guangbin0000-0003-1331-6015
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.
Funders:
Funding AgencyGrant Number
University of ChicagoUNSPECIFIED
NIH1R01GM124414-01A1
Subject Keywords:Hydrocarbons, Anions, Substituents, Electrophiles, Reductive elimination
Issue or Number:26
DOI:10.1021/jacs.1c04575
Record Number:CaltechAUTHORS:20210630-155914378
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210630-155914378
Official Citation:Modular Entry to Functionalized Tetrahydrobenzo[b]azepines via the Palladium/Norbornene Cooperative Catalysis Enabled by a C7-Modified Norbornene. Xin Liu, Jianchun Wang, and Guangbin Dong. Journal of the American Chemical Society 2021 143 (26), 9991-10004 DOI: 10.1021/jacs.1c04575
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:109671
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:30 Jun 2021 18:21
Last Modified:12 Jul 2021 18:31

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