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Title: Palladium-catalyzed $α$-arylation for the addition of small rings to aromatic compounds

Abstract

Small, strained rings have rigid, defined conformations and unique electronic properties. For these reasons, many groups seek to use these subunits to form biologically active molecules. We report a generally applicable approach to attach small rings to a wide range of aromatic compounds by palladium-catalyzed α-arylation of cyclopropyl, cyclobutyl and azetidinyl esters. The direct α-arylation of cyclopropyl esters and cyclobutyl esters is achieved in high yield by ensuring that the rate of coupling exceeds the rate of Claisen condensation. The $α$-arylation of azetidines is achieved without ring opening of the strained saturated heterocycle by conducting the reactions with an azetidine derivative bearing a benzyl protecting group on nitrogen. Mechanistic studies show that the α-arylation of small rings is challenging because of the weak acidity of α C-H bond (cyclopropanes), strong sensitivity of the strained esters to Claisen condensation (cyclobutatanes), or facile decomposition of the enolates (azetidinyl esters).

Authors:
 [1]; ORCiD logo [1]
  1. Univ. of California, Berkeley, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1572052
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 10; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

He, Zhi-Tao, and Hartwig, John F. Palladium-catalyzed $α$-arylation for the addition of small rings to aromatic compounds. United States: N. p., 2019. Web. doi:10.1038/s41467-019-12090-z.
He, Zhi-Tao, & Hartwig, John F. Palladium-catalyzed $α$-arylation for the addition of small rings to aromatic compounds. United States. doi:10.1038/s41467-019-12090-z.
He, Zhi-Tao, and Hartwig, John F. Mon . "Palladium-catalyzed $α$-arylation for the addition of small rings to aromatic compounds". United States. doi:10.1038/s41467-019-12090-z. https://www.osti.gov/servlets/purl/1572052.
@article{osti_1572052,
title = {Palladium-catalyzed $α$-arylation for the addition of small rings to aromatic compounds},
author = {He, Zhi-Tao and Hartwig, John F.},
abstractNote = {Small, strained rings have rigid, defined conformations and unique electronic properties. For these reasons, many groups seek to use these subunits to form biologically active molecules. We report a generally applicable approach to attach small rings to a wide range of aromatic compounds by palladium-catalyzed α-arylation of cyclopropyl, cyclobutyl and azetidinyl esters. The direct α-arylation of cyclopropyl esters and cyclobutyl esters is achieved in high yield by ensuring that the rate of coupling exceeds the rate of Claisen condensation. The $α$-arylation of azetidines is achieved without ring opening of the strained saturated heterocycle by conducting the reactions with an azetidine derivative bearing a benzyl protecting group on nitrogen. Mechanistic studies show that the α-arylation of small rings is challenging because of the weak acidity of α C-H bond (cyclopropanes), strong sensitivity of the strained esters to Claisen condensation (cyclobutatanes), or facile decomposition of the enolates (azetidinyl esters).},
doi = {10.1038/s41467-019-12090-z},
journal = {Nature Communications},
number = 1,
volume = 10,
place = {United States},
year = {2019},
month = {9}
}

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