Optimized Monofluoromethylsulfonium Reagents for Fluoromethylene-Transfer Chemistry

Abstract

An investigation of the properties and reactivity of fluoromethylsulfonium salts resulted in the redesign of the reagents for fluoromethylene transfer chemistry. The model reaction, fluorocyclopropanation of nitrostyrene, turned out to be a suitable platform for the discovery of more streamlined fluoromethylene transfer reagents. The incorporation of halides on one aryl ring increased the reactivity, and 2,4-dimethyl substitution on the other aryl ring provided a balance between the reactivity/crystallinity of the reagent as well as the atom economy. The utility of new reagents was demonstrated by the development of an efficient fluorocyclopropanation protocol to access a range of monofluorinated cyclopropane derivatives.

Fluorinated Cycloalkyl Building Blocks for Drug Discovery

“…In 2019, Veliks and co‐workers reported diarylsulfonium reagents of type 160 allowing the Corey‐Chaikovsky‐type monofluorocyclopropanation of electron‐poor alkenes, such as vinyl sulfones 161 (Scheme 56) [181] or β‐nitrostyrenes [182] …”

“…In 2019, Veliks and co-workers reported diarylsulfonium reagents of type 160 allowing the Corey-Chaikovsky-type monofluorocyclopropanation of electron-poor alkenes, such as vinyl sulfones 161 (Scheme 56) [181] or β-nitrostyrenes. [182] A different [2 + 1] approach to monofluorinated cyclopropanes includes cyclopropanation of vinyl fluoride. For example, both cis-and trans-1-bromo-2-fluorocyclopropanes 163 and 164 were obtained by this method (Scheme 57).…”

Synthetic Access to Fluorocyclopropylidenes

“…12 After careful tuning of the reaction conditions, we were able to perform fluorocyclopropanation of vinyl sulfone 4 using our improved sulfonium reagent 5. 13 the reaction conditions (Table 1) for fluorocyclopropylidene synthesis from aldehydes was performed. Initial attempts to generate the carbanion first from reagent 6 followed by addition of aldehyde 7a were unsuccessful.…”

“…Achieving fluorocyclopropanation of the corresponding vinyl sulfone 4 was particularly challenging, as the conventional approach would lead to decomposition of the starting material under basic conditions . After careful tuning of the reaction conditions, we were able to perform fluorocyclopropanation of vinyl sulfone 4 using our improved sulfonium reagent 5 . With reagent 6 in hand, optimization of the reaction conditions (Table ) for fluorocyclopropylidene synthesis from aldehydes was performed.…”

Iron-Catalyzed Fluoromethylene Transfer from a Sulfonium Reagent

“…As an alternative, Hu’s monofluoromethyl sulfoximines requiring activated substrates have been reported to be a direct source of fluoromethylene synthon too. Our recent work demonstrates that, in addition to Prakash’s/Olah electrophilic monofluoromethylation mode (CH 2 F−), the diaryl monofluoromethylsulfonium salts can be used efficiently to transfer a fluoromethylene group (CHF) via the fluoromethylide intermediate to aldehydes, ketones, and activated alkenes to form monofluorinated 3-membered rings and, recently, to form 5-membered heterocycles . Herein, we report the first example of an Fe-porphyrin catalyzed fluoromethylene transfer from (2,4-dimethylphenyl)­(fluoromethyl)­(phenyl)­sulfonium tetrafluoroborate to unactivated alkenes to access valuable fluorocyclopropane derivatives.…”