Rapid and practical synthesis of N-protected amino ketones in continuous flow via pre-deprotonation protocol

Abstract

The nucleophilic reaction of Weinreb amides with Grignard or organic lithium reagents is widely used in the synthesis of amino ketones because of the formation of stable metal chelate tetrahedral intermediates. However, their large-scale synthesis in batch seriously suffers from the use of excess of nucleophiles due to carbamate group of N-protected amino Weinreb amides and the harsh reaction conditions required by Grignard or organic lithium reagents. In this case, N-protected amino ketones were rapidly synthesized by a practical and efficient continuous flow method under mild conditions. By precisely introducing a simple alkyl Grignard base to deprotonate the carbamate group, the functionalized N-protected amino ketones can be efficiently obtained within 128 s with only a slightly excess of stoichiometric amount of nucleophile, with the yield up to 96%. In addition, the scope of this method was demonstrated over 35 substrates with 3 protective groups signifying the excellent substrate and protecting group tolerances. A scale-up preparation affords a throughput of 7.9 g h^-1, indicating potential large-scale application. This work lays the foundation for the large-scale automated synthesis of a variety of N-protected amino ketones.

Graphical Abstract