Journal
ACS CATALYSIS
Volume 12, Issue 20, Pages 12860-12868Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acscatal.2c03672
Keywords
photoredox; epimerization; thermodynamics; nitrogen heterocycles; radical reactions
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Funding
- NIH [R35GM122473]
- Oberlin College
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A photocatalyzed epimerization of morpholines and piperazines has been reported using reversible hydrogen atom transfer (HAT), providing an efficient strategy for editing the stereochemical configurations of these saturated nitrogen heterocycles prevalent in drugs.
We report a photocatalyzed epimerization of morpholines and piperazines that proceeds by reversible hydrogen atom transfer (HAT) and provides an efficient strategy for editing the stereochemical configurations of these saturated nitrogen heterocycles, which are prevalent in drugs. More stable morpholine and piperazine isomers are obtained from the more synthetically accessible but less stable stereoisomers, and a broad scope is demonstrated in terms of substitution patterns and functional group compatibility. The observed distributions of diastereomers correlate well with the relative energies of the diastereomer pairs as determined by density functional theory (DFT) calculations. Mechanistic studies, including luminescence quenching, deuterium labeling reactions, and determination of reversibility support a thiyl radical-mediated HAT pathway for the epimerization of morpholines. Investigation of piperazine epimerization established that the mechanism is more complex and led to the development of thiol-free conditions for the highly stereoselective epimerization of N,N'-dialkyl piperazines for which a previously unrecognized radical chain HAT mechanism is proposed.
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