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

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.