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

Abstract

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.

Stereoselective and Regioselective Synthesis of Heterocycles via Copper-Catalyzed Additions of Amine Derivatives and Alcohols to Alkenes

“…43 Since K 2 CO 3 is largely insoluble in PhCH 3 , however, we sought a replacement. Unfortunately, when Bu 4 NOAc was applied no enantioselectivity was observed (Scheme 8).…”

Copper-catalyzed alkene diamination: synthesis of chiral 2-aminomethyl indolines and pyrrolidines

“…28-32 The former is commercially available (in both enantiomers) while the latter is available in one step from a commercially available ligand. 24 While arylsulfonamides can give sultam byproducts 3 in this diamination reaction, aliphatic sulfonamides cannot.…”

Cu‐Catalyzed Heterocycle Synthesis

“…The C(4)-phenyl substitution on the bis(oxazoline) is crucial for high asymmetric induction of this reaction [58] Furthermore, they also developed an intermolecular enantioselective alkyl Heck-type coupling cascade for the formation of functionalized chiral indolines, pyrrolidines, and an isoquinoline from acyclic -and -alkenylsulfonamides via a formal alkene C-H functionalization process. The carbon radical intermediate which is formed in situ under copper system could be oxidized to an alkene leading to the desired products [60] (Scheme 8.24).…”