Phenoxydifluoromethyl Substituted Nitrogen Heterocycles. Synthesis and Heterocyclization Reactions of Ethyl 4,4-Difluoro- 4-phenoxyacetoacetate

Abstract

Ethyl 4,4-difluoro-4-phenoxyacetoacetate was obtained and studied as a precursor to new heterocyclic compounds. 6-Hydroxypyrimidine, 1,3-dihydro-1,5-benzodiazepin-2-one, quinolin-2-one and 6-hydroxypyrazolo[3,4-b]pyridine derivatives containing phenoxydifluoromethyl groups were synthesized. These results make it possible to introduce aryloxydifluoromethyl substituents for the design of biologically active heterocycles.

New Approaches to the Synthesis of CF2X-substituted Heterocyclic Antitumor Cytostatic Agents

“…We developed a synthetic approach to CF2X-substituted acetoacetic esters: ethyl 4,4-difluoro-4phenoxyacetoacetate and ethyl 4-fluoro-4phenylthioacetoacetate. The new synthons were obtained by the condensation of fluorine-containing acetates with ethyl acetate in the presence of either NaH or lithium diisopropylamide (LDA) (Scheme 21) [53,54]. 2-Trifluoroacetylanilines represent important synthons for the introduction of CF3 groups into different biologically active heterocycles [14,15].…”

Cu(II)-Catalyzed Unsymmetrical Dioxidation of gem-Difluoroalkenes to Generate α,α-Difluorinated-α-phenoxyketones

“…Separately, α,α-difluoroalkyl ethers display a wide range of applications in pharmaceuticals, agrochemicals, and material chemistry. , For example, α,α-difluoroalkyl ethers can enhance metabolic stability and control molecular conformation. , Due to the small rotational barrier around the ArO–CF 2 R bond, difluorinated phenyl ethers can access a wide range of conformers versus the parent alkyl-aryl ethers that preferentially reside in the plane of the arene, and versus trifluoromethyl-aryl ethers that reside orthogonally to the plane of the arene . Interestingly, despite the individual significance of the α,α-difluoroketone and α,α-difluoroalkyl ether components, the hybrid α,α-difluorinated-α-phenoxyketone functional group has rarely been reported, with uses as synthetic intermediates en route to other substructures − or as a specialized resin . The lack of synthetic strategies for accessing α,α-difluorinated-α-phenoxyketones precludes evaluation of the properties of the functional group and also impedes its use in medicinal chemistry and chemical biology.…”