Mild Homologation of Esters through Continuous Flow Chloroacetate Claisen Reactions

Abstract The selective chloromethylenation of functionalized esters using chloroacetic acid (CA) and LiHMDS (HMDS=hexamethyldisilazide) in a continuous‐flow setup is reported. This Claisen homologation is for the first time extended to bis‐chloromethylenation using dichloroacetic acid (DCA), thus giving access to under‐explored α,α′‐bis‐chloroketones. The use of flow conditions enables efficient generation and reaction of the unstable chloroacetate dianion intermediates, leading to unprecedented mild and scalable reaction conditions at an economical reagent stoichiometry (−10 °C, <1 min, 1.0–2.4 equiv dianion). The clean reaction profiles allow subsequent use of the unpurified crude products, which is demonstrated in the synthesis of various heterocycles of broad interest. Furthermore, we report a novel, catalyst‐free substitution of the obtained monochloro ketone products with (hetero)aryl zinc enolates to give valuable 1,4‐diketones.