Stereocontrolled Synthesis of β-Difluoromethylated Materials

Abstract

Investigation of synthetic routes for regio- and stereocontrolled fluorinated materials with a difluoromethyl group, using ethyl bromodifluoroacetate as a starting material, is described. In particular, (E)-difluoromethylated trisubstituted olefins were prepared via the proton migration reaction catalyzed by using fluoride anion. Further, optically active beta-difluoromethyl esters were obtained by the enzymatic resolution.

Fluorine-Retentive Strategies for the Functionalization of gem-Difluoroalkenes

“…[71][72][73] Moreover, these conditions were compatible with a wide range of substitution on the gem-difluoroalkene including aryl, alkyl, and fully-substituted alkenes (Scheme 37A). [81][82][83] Additionally, gem-difluoroalkenes can be reduced using boron or silicone-based intermediates. Specifically, Rh-catalyzed hydroboration (Scheme 37B) 84 or radical hydrosilation of gem-difluoroalkenes generated organometal intermediates, and subsequent protodeboronation or desilylation using TBAF delivers the product of net reductions (Scheme 37C).…”

Synthesis of α-Halo-α,α-difluoromethyl Ketones by a Trifluoroacetate Release/Halogenation Protocol

“…3–7 Typically, α-halo-α,α-difluoroacetates are used as building blocks to prepare compounds with difluoromethylene groups. 8–11 Unfortunately, there are very few synthetic methods that can be used to assemble α-halo-α,α-difluoroacetates or other α-halo-α,α-difluoro centers adjacent to carbonyl groups, especially α-halo-α,α-difluoromethyl ketones. 8–15 Existing synthetic strategies to assemble α-halo-α,α-difluoromethyl ketones rely heavily on halogenating α,α-difluoroenoxysilanes 13,14 or adding Grignard reagents into α-bromo-α,α-difluoroacetates or α-chloro-α,α-difluoroacetates (Figure 1).…”

“…8–11 Unfortunately, there are very few synthetic methods that can be used to assemble α-halo-α,α-difluoroacetates or other α-halo-α,α-difluoro centers adjacent to carbonyl groups, especially α-halo-α,α-difluoromethyl ketones. 8–15 Existing synthetic strategies to assemble α-halo-α,α-difluoromethyl ketones rely heavily on halogenating α,α-difluoroenoxysilanes 13,14 or adding Grignard reagents into α-bromo-α,α-difluoroacetates or α-chloro-α,α-difluoroacetates (Figure 1). 8,9 Typically, α,α-difluoroenoxysilanes arise from the silylation of a metalloenolate formed after carbon–halogen fragmentation on a α-halo-α,α-difluoromethyl group or on a trifluoromethyl group adjacent to a carbonyl group.…”

“…8–15 Existing synthetic strategies to assemble α-halo-α,α-difluoromethyl ketones rely heavily on halogenating α,α-difluoroenoxysilanes 13,14 or adding Grignard reagents into α-bromo-α,α-difluoroacetates or α-chloro-α,α-difluoroacetates (Figure 1). 8,9 Typically, α,α-difluoroenoxysilanes arise from the silylation of a metalloenolate formed after carbon–halogen fragmentation on a α-halo-α,α-difluoromethyl group or on a trifluoromethyl group adjacent to a carbonyl group. Our synthetic plan is an alternative method to assemble α-halo-α,α-difluoromethyl ketones by halogenation of the α,α-difluoroenolate generated from by the facile release of trifluoroacetate and does not require α,α-difluoroenoxysilanes, their precursors, or α-halo-α,α-difluoroacetates.…”

“…Fluorinated organic compounds have attracted considerable attention from the pharmaceutical, chemical, and agrochemical industries. , Although multiple synthetic methods are available to introduce fluorine or a trifluoromethyl group, fewer methods are available to install a difluoromethylene group. − Typically, α-halo-α,α-difluoroacetates are used as building blocks to prepare compounds with difluoromethylene groups. − Unfortunately, there are very few synthetic methods that can be used to assemble α-halo-α,α-difluoroacetates or other α-halo-α,α-difluoro centers adjacent to carbonyl groups, especially α-halo-α,α-difluoromethyl ketones. − Existing synthetic strategies to assemble α-halo-α,α-difluoromethyl ketones rely heavily on halogenating α,α-difluoroenoxysilanes , or adding Grignard reagents into α-bromo-α,α-difluoroacetates or α-chloro-α,α-difluoroacetates (Figure ). , Typically, α,α-difluoroenoxysilanes arise from the silylation of a metalloenolate formed after carbon–halogen fragmentation on a α-halo-α,α-difluoromethyl group or on a trifluoromethyl group adjacent to a carbonyl group. Our synthetic plan is an alternative method to assemble α-halo-α,α-difluoromethyl ketones by halogenation of the α,α-difluoroenolate generated by the facile release of trifluoroacetate and does not require α,α-difluoroenoxysilanes, their precursors, or α-halo-α,α-difluoroacetates.…”