Mild Homologation of Esters via Continuous Flow Chloroacetate Claisen Reactions

    • Maximilian A. Ganiek
    • Maria V. Ivanova
    • Benjamin Martin*
    • Paul Knochel*
    • Department of Chemistry, Ludwig-Maximilians-Universität Munich, Butenandtstr. 5 – 13, 81377 Munich, Germany

    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 dichloro-acetic acid (DCA), thus giving access to under-explored α,α’-bis-chloroketones. The use of flow conditions enables an efficient generation and reaction of the unstable chloroacetate dianion intermediates, leading to unprecedented mild and scalable reaction conditions at an economic reagent stoichiometry ( 10 °C, < 1 min, 1.0-2.4 equiv. dianion). The clean reaction profiles allows the 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 leading to valuable 1,4-diketones.

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