Deoxyfluorination with CuF₂: Enabled by Using a Lewis Base Activating Group

Abstract

Deoxyfluorination is a primary method for the formation of CÀF bonds. Bespoke reagents are commonly used because of issues associated with the low reactivity of metal fluorides. Reported here is the development of a simple strategy for deoxyfluorination, using first-row transition-metal fluorides, and it overcomes these limitations. Using CuF 2 as an exemplar, activation of an O-alkylisourea adduct, formed in situ, allows effective nucleophilic fluoride transfer to a range of primary and secondary alcohols. Spectroscopic investigations have been used to probe the origin of the enhanced reactivity of CuF 2 . The utility of the process in enabling 18 F-radiolabeling is also presented.

Silver‐Promoted Fluorination Reactions of α‐Bromoamides

“…These results revealed that the NH group of the primary or secondary amide plays an important role in the transformation with AgF.T hus, we then focusedo nt he fluorination of a-bromoc arbonyl compounds based on secondary amides. The a-bromoacetamidesp rovided the a-fluorinated amides in moderate to good yields (Table 2, [7][8][9][10]. Avariety of functional groups,s uch as nitro, ketone, and silyl ether,w ere well tolerated.…”

“…Recently, Watson et al. reported N , N′ ‐diisopropylcarbodiimide‐based deoxfluorination using CuF 2 as the fluorine source [8] . Meanwhile, C−H fluorination, hydrofluorination, and decarboxylative fluorination with nucleophilic fluorine sources have been achieved by chemical, photochemical, and electrochemical approaches [9] .…”

“…[7] Recently,W atson et al reported N,N'-diisopropylcarbodiimide-based deoxfluorination using CuF 2 as the fluorine source. [8] Meanwhile, CÀHf luorination, hydrofluorination, and decarboxylative fluorinationw ith nucleophilicf luorine sources have been achieved by chemical, photochemical, and electrochemicala pproaches. [9] Somee xamples of nucleophilic fluorination of carbocation intermediates generated by electrochemicalo xidation from carboxylic acids have been reported by Baran et al [10] In 2020, Doyle and co-workersd eveloped am ethod for nucleophilic (radio)f luorination of N-hydroxyphthalmidee sters through carbocation generation using ap hotoredox system.…”

Construction of Carbon‐Fluorine Bonds via Copper‐Catalyzed/‐Mediated Fluorination Reactions

“…Watson's group described a CuCl-catalyzed deoxyfluorination of alcohols using CuF 2 as the fluorinating reagent (Scheme 34). [49] In order to overcome the low reactivity of copper fluoride, a strategy involving in situ generated Oalkylisourea adduct allowed effective nucleophilic fluoride transfer to a range of primary and secondary alcohols. This work demonstrated that chelation-driven fluoride transfer can potentially address the reactivity issues associated with metal fluorides.…”

Mechanochemical Nucleophilic Substitution of Alcohols via Isouronium Intermediates

“…Indeed, O-alkyl isouronium salts can be obtained by the reactions of alcohols with halouronium salts (e.g., TCFH or its fluoro-analog TFFH), a process commonly utilized for the preparation of amide coupling reagents. 38,39 Similarly to O-alkyl isoureas generated from alcohols and carbodiimides, [40][41][42][43][44] isouronium salts can act as reactive intermediates in nucleophilic displacement reactions. 45,46 However, none of these alcohol-activation techniques have been previously attempted under solvent-free conditions or utilized for the synthesis of amines.…”