Abstract
The enantioselective aminocatalytic α-chlorination of aldehydes is a challenging reaction because of its tendency to proceed through neutral intermediates in unselective pathways. Herein we report the rational shift to a highly selective reaction pathway involving charged intermediates using hexafluoroisopropanol as solvent. This change in mechanism has enabled us to match and improve upon the yields and enantioselectivities displayed by previous methods while using cheaper aminocatalysts and chlorinating agents, 80–95% less amount of catalyst, convenient temperatures, and shorter reaction times.
Highlights
The enantioselective aminocatalytic α-chlorination of aldehydes is a challenging reaction because of its tendency to proceed through neutral intermediates in unselective pathways
The reaction proceeds through the pathways involving 1,2-aminals, which are intrinsically slower than the one through the direct hydrolysis of the iminium ion
Pioneering enantioselective aminocatalytic chlorinating methods solved this problem by using aminocatalysts that favor one of the diastereomeric 1,2-aminals,[8] using chlorinating agents that result in poorly coordinating counterions,[9,10] using SOMO catalysis,[11] or using a combination of a very sterically hindered catalyst, N-chloro-4
Summary
The enantioselective aminocatalytic α-chlorination of aldehydes is a challenging reaction because of its tendency to proceed through neutral intermediates in unselective pathways. We investigated the potential deactivation pathways arising from reaction of the free catalyst with the chlorinating agent.
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