Exploiting a “Beast” in Carbenoid Chemistry: Development of a Straightforward Direct Nucleophilic Fluoromethylation Strategy

Abstract

The first direct and straightforward nucleophilic fluoromethylation of organic compounds is reported. The tactic employs a "fleeting" lithium fluorocarbenoid (LiCHF) generated from commercially available fluoroiodomethane. Precise reaction conditions were developed for the generation and synthetic exploitation of such a labile species. The versatility of the strategy is showcased in ca. 50 examples involving a plethora of electrophiles. Highly valuable chemicals such as fluoroalcohols, fluoroamines, and fluoromethylated oxygenated heterocycles could be prepared in very good yields through a single synthetic operation. The scalability of the reaction and its application to complex molecular architectures (e.g., steroids) are documented.

A Combination of Pharmacophore and Docking‐based Virtual Screening to Discover new Tyrosinase Inhibitors

“…Moreover the 3D database of compounds from synthetic source was obtained by collecting molecules belonging to different chemical classes (α-,methoxymethylketones, [20] αhalomethylketones, [21] α-cyanomethylketones, [22] α-haloamides, [23] thioamides, [24] spiroepoxyoxindoles, [25] pyrazoles, [26] dithioacetals [18b] designed and synthesized by the Pace group.…”

Synthesis and Properties of the Fluoromethylating Agent (Fluoromethyl)triphenylphosphonium Iodide

“…A second pathway is the direct fluoromethylation using a fluoromethylating agent like CH 2 FBr or CH 2 FI . Recently a nucleophilic fluoromethylation strategy involving the fluoromethyl anion as the lithium derivative was reported to yield α‐fluoromethyl alcohols, ‐ketones and ‐amines …”

“…Very recently new techniques for the transfer of “CHF” and “CIF” units to organic substrates starting from diarylfluoromethyl sulfonium salts or CH 2 FI in combination with the use of special bases have been reported . In addition to the fluoromethyl halides CH 2 FBr and CH 2 FI other more effective fluoromethylating agents have been developed in the last years (Figure ) , , . Leitao et al reported that monofluoromethyl‐S‐phenyl‐S‐2,3,4,5‐tetramethylphenyl sulfonium tetrafluoroborate, mono‐fluoromethyl ammonium salts and monofluoromethyl‐phosphonium salts 13 (Figure ) are suitable for monofluoromethylation.…”

Carbenoid-Mediated Homologation Tactics for Assembling (Fluorinated) Epoxides and Aziridines

“…dent clearly demonstrates the existence and usefulness of LiCH 2 F, thus suggesting that properly identifying the optimal conditions for its generation could represent the key to finally include this reagent among the usable halolithium for preparative purposes. In 2017 we proposed a solution to the challenge built on an intuitive approach (Scheme 7): 35 the commercially available fluoroiodomethane undergoes an extremely fast lithiation at -78 °C. A series of interesting points emerged during the optimization study: (a) a precise 1:1.5:2.0 stoichiometry was essential for properly forming and using the fluoro carbenoid; (b) although there was a slight excess of MeLi•LiBr, no detectable concomitant addition to the carbonyl manifold by the methyl carbanion was observed; (c) the overall limited existence of the species benefited from using a 1:1 (v/v) THF/Et 2 O mixture, with other solvents being deleterious for its formation or stability.…”

“…12a This fluoromethylation of -, -, or -halogenated ketones could be efficiently coupled with a subsequent basetriggered ring closure, finally delivering epifluorohydrins 37 and their corresponding homologues (oxetanes and tetrahydrofurans) characterized by the pendant fluoromethyl fragment in the vic-position to the oxygen (Scheme 8). 35…”