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Aryl Amination with Soluble Weak Base Enabled by a Water-Assisted Mechanism

preprint
submitted on 03.09.2020 and posted on 04.09.2020 by Sii Hong Lau, Peng Yu, Liye Chen, Christina B. Madsen-Duggan, Michael Williams, Brad Carrow
Amination of aryl halides has become one of the most commonly practiced C–N bond-forming reactions in pharmaceutical and laboratory synthesis. The widespread use of strong or poorly soluble inorganic bases for amine activation nevertheless complicates the compatibility of this important reaction class with sensitive substrates as well as applications in flow and automated synthesis, to name a few. We report a palladium-catalyzed C–N coupling using Et3N as a weak, soluble base, which allows a broad substrate scope that includes bromo- and chloro(hetero)arenes, primary anilines, secondary amines, and amide type nucleophiles together with tolerance for a range of base-sensitive functional groups. Mechanistic data have established a unique pathway for these reactions in which water serves multiple beneficial roles. In particular, ionization of a neutral catalytic intermediate via halide displacement by H2O generates, after proton loss, a coordinatively-unsaturated Pd–OH species that can bind amine substrate triggering intramolecular N–H heterolysis. This water-assisted pathway operates efficiently with even weak terminal bases, such as Et3N. The use of a simple, commercially available ligand, PAd3, is key to this water-assisted mechanism by promoting coordinative unsaturation in catalytic intermediates responsible for the heterolytic activation of strong element-hydrogen bonds, which enables broad compatibility of carbon-heteroatom cross-coupling reactions with sensitive substrates and functionality.

Funding

Aliphatic Effects in Transition Metal Catalysis

National Institute of General Medical Sciences

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History

Email Address of Submitting Author

bcarrow@princeton.edu

Institution

Princeton University

Country

United States of America

ORCID For Submitting Author

0000-0003-4929-8074

Declaration of Conflict of Interest

The authors declare the following competing financial interest(s): A patent was filed by Princeton University: Carrow, B. P.; Chen, L. WO2017/075581 A1, May 4, 2017.

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