Photocatalyzed Selective α-Monoalkylation of Aqueous Acetaldehyde for Synthesis of α,β-Unsubstituted 1,4-Ketoaldehydes

Abstract

The direct utilization of aqueous acetaldehyde as an industrially important aqueous chemical has been hampered in organic synthesis due to the high reactivity of acetaldehyde. Herein, the first metal-free photocatalyzed selective α-monoalkylation of commercially available and safe to handle aqueous acetaldehyde (40 wt %) with inexpensive α-chloro/bromoacetophenones has been developed using 0.5 mol % 4CzIPN as an organic photosensitizer, which provides easy access to high-added-value α,β-unsubstituted 1,4-ketoaldehydes. The reaction features a broad substrate scope, high functional group tolerance, gram-scalability, operational simplicity, and mild reaction conditions. Moreover, the synthetic applications are demonstrated by directly using aqueous solutions of acetaldehyde as synthetically useful a C2 synthon for the modular and expeditious synthesis of various biologically active γ-aminoketones through the reductive amination of the α,β-unsubstituted 1,4-ketoaldehyde products with cyclic secondary amines, as well as the concise gram-scale total synthesis of pentabromo- and pentachloropseudilins.