Asymmetric Mannich/Radical Debromination Cascade of α‐Bromoketones by Dipeptide‐Phosphonium Salt Catalysis: Enantioselective Synthesis of β‐Amino Ketone‐Pyrazolinones

Abstract

We herein demonstrated an organocatalytic asymmetric Mannich/radical debromination cascade of α‐brominated ketones. With this protocol, a diversity of chiral β‐amino ketone‐pyrazolinone scaffolds, which have important versatilities in medicine and chemical synthesis, were constructed in high yields (up to 94%) with excellent enantioselectivities (up to 99% ee). This methodology features mild reaction conditions, broad substrate scope, and high functional group tolerance. Moreover, mechanistic investigations revealed that this cascade reaction proceeds through a bifunctional phosphonium salt‐catalyzed Mannich reaction of α‐brominated ketones with pyrazolinone ketimines, which is followed by an oxygen‐induced radical debromination. This protocol represents a novel activation mode for α‐brominated ketones and opens new avenues for catalytic enantioselective radical reactions under ion‐pair system.

Accessing unnatural α-amino acids with tetrasubstituted stereogenic centersviacatalytic enantioselective reactions of ketimine-type α-iminoesters/α-iminoamides

“…In 2023, the same group reported one-pot enantioselective direct Mannich-type chemistry involving a-bromo ketones, pyrazolinone-type ketimines 7c, and radical debromination (Scheme 24). 42 This reaction is efficiently catalyzed by dipeptide-based chiral phosphonium salt 61b. Furthermore, detailed control studies revealed that the bromine atom enhances reactivity in the direct Mannich-type step, while dehalogenation of the adduct is relatively easy due to the stability of the bromo-containing intermediate.…”