Concise synthesis of ω-fluoroalkylated ketoesters. A building block for the synthesis of six-, seven-, and eight-membered fluoroalkyl substituted 1,2-diaza-3-one heterocycles

A concise and general synthetic route toward the small and medium-sized fluoroalkyl substituted 1.2-diaza-3-one heterocyclic ring skeletons via a sequential reaction of condensation and ring-closure reaction of omega-fluoroalkylated ketoesters 4 with hydrazines 5 catalyzed by 10-20 mol % TsOH has been developed. A practical preparation of biologically interested omega-fluoroalkylated ketoesters 4, which were subsequently Subjected as a fluorine-containing building block to the synthesis of 1,2-diaza-3-one heterocycles has been optimized. Trifluoromethyl substituted seven- and eight-membered 1,2-diazapinone 8, 1,2-diazocinone 10 were also obtained via this sequential reaction of delta- (or epsilon-) trifluoromethyl ketoesters with hydrazine hydrates in acidic condition. In contrast, the sequential reaction of omega-fluoroalkylated delta- or epsilon-ketoesters with aryl hydrazines under the same conditions did not result in the formation of diazepinones and diazocinones, and instead, the reaction provided a direct access to the biologically important 2-fluoroalkyl-indole-3-carboxylate derivatives via a Fisher indole synthesis. (C) 2009 Elsevier Ltd. All rights reserved.