American Chemical Society
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Mechanistic Analysis and Optimization of the Copper-Catalyzed Enantioselective Intramolecular Alkene Aminooxygenation

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journal contribution
posted on 2013-01-18, 00:00 authored by Monissa C. Paderes, Jerome B. Keister, Sherry R. Chemler
The catalytic asymmetric aminooxygenation of alkenes provides an efficient and straightforward approach to prepare chiral vicinal amino alcohols. We have reported a copper­(II)-catalyzed enantioselective intramolecular alkene aminooxygenation, using (2,2,6,6-tetramethylpiperidin-1-yl)­oxyl (TEMPO) as the oxygen source, which results in the synthesis of chiral indolines and pyrrolidines. Herein we disclose that kinetics studies indicate the reaction is first order both in substrate and the [Cu­(R,R)-Ph-bis­(oxazoline)]­OTf2 catalyst and zero order in TEMPO. Furthermore, kinetic isotope effect studies support that the cis-aminocupration step, the addition of N–Cu across the alkene, is the rate-limiting step. Subsequent formation of a carbon radical intermediate and direct carbon radical trapping with TEMPO is the indicated mechanism for the C–O bond formation as suggested by a deuterium labeling experiment. A ligand screen revealed that C(4)-phenyl substitution on the bis­(oxazoline) is optimal for high asymmetric induction. The size of the substrate’s N-sulfonyl group also influences the enantioselectivity of the reaction. The preparative-scale catalytic aminooxygenation reaction (gram scale) was demonstrated, and an unexpected dependence on reaction temperature was uncovered on the larger scale reaction.