Synthesis of gem -difluorocyclopentane/hexane building blocks

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…[504] However, nearly all later syntheses of the title building blocks relied on the deoxofluorination of the appropriately functionalized cyclic ketones and further functional group transformations. In particular, reaction of cyclic keto esters 112 with DAST [493,[505][506][507][508][509] provided the corresponding esters 113 (Scheme 66) that were the key intermediates in the synthesis of the corresponding gem-difluorinated carboxylic acids, primary amines, sulfonyl halides, epoxides, [510] alkynes, bromides, azides, and trifluoroborates. The method was also applied to cyclic keto nitriles, [509,511,512] protected hydroxy ketones, [505,509,513] and other cycloalkanone derivatives [514] (including spiro [3.3] heptanes [515,516] ).…”

“…Other reagents used or evaluated for the aforementioned deoxofluorinations included morphDAST, [517] bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) with [518,519] or without [520,521] BF 3 • Et 2 O, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride, [522] and XtalFluor-E or XtalFluor-M -Et 3 N • 3HF. [203,506,523,524] Synthesis of 4,4-difluorocycloheptanone relied on the ring expansion in compound 110 with trimethylsilyldiazomethane or ethyl diazoacetate. [509,512]…”

Semi-Industrial Fluorination of β-Keto Esters with SF4: Safety vs Efficacy

“…The cyclopropane derivative 1d probably decomposed via cyclopropylmethyl/cyclobutyl cation rearrangement, which we had observed during fluorinations earlier. 20 Decomposition of 1r in the reaction conditions was unexpected due to our previous successful experience with DAST fluorination of TFA-protected amino ketones, 18 while decomposition of the substrate 1s was anticipated. According to our previous expertise fluorination of compounds containing PhCH 2 O fragment by SF 4 led to debenzylation with subsequent unselective decomposition.…”

“…In consequence an alternative synthetic route was proposed. 18 The strategy was based on three-step transformation of the ester function into a nonacceptor CH 2 OAc group, which allowed DAST-based deoxofluorination. The further deacylation/oxidation led to desired ,-difluorocarboxylic acids.…”

Last of the gem‐Difluorocycloalkanes 2: Synthesis of Fluorinated Cycloheptane Building Blocks

“…All the aforementioned works motivated us to develop convenient synthetic routes to all isomeric gem ‐difluorocycloalkanes which can be used to access multigram quantities of the corresponding building blocks. To date, we have reported the preparation of three‐to‐six‐membered fluorinated alicyclic compounds [23–28] . Yet, a Reaxys database search [29] has revealed that the synthesis and application of higher homologs – gem ‐difluorinated cycloheptane derivatives – remain to be scarcely explored both in papers [30–32] and patents (Figure 2A).…”