The reaction is catalyzed by copper and is induced by visible light. Protocol. This has recently prompted many researchers to develop option fluoromethylation brokers. This Minireview summarizes both the classical and new generation of fluoromethylating brokers. Reagents that act via electrophilic, nucleophilic, and radical pathways are discussed, in addition to their precursors. position (G.\W. Wang,27l Ackermann27m) by RuII\catalyzed reactions of CH2F(CO2Et) with Yohimbine hydrochloride (Antagonil) the corresponding methoxyphenyl ketoximes or monosubstituted arene derivatives, respectively. It has been shown by Wu and co\workers27m that 8\aminoquinolines react with Yohimbine hydrochloride (Antagonil) CHF(CO2Et)Br in the presence of CuII and HP(O)(OMe)2 to give the corresponding CHF(CO2Et)\substituted derivatives. It is noteworthy that this known fluoromethyl pseudohalides CH2FX (X=CN,34 NCO,35 N3 36) have not yet been used as fluoromethylating brokers. 2.1.2. Fluoromethyl Sulfonates The fluoromethyl sulfonates 12?a (Ali, Gpr20 2014),37 12?b (Qianli, 2001),28l and 12?c (Iwata, 2002)38 have been used to introduce CH2F into a series of compounds at oxygen, sulfur, or nitrogen atoms (Scheme?4).7a The main and most important application of these reagents is in the synthesis of 18F\labeled fluoromethyl compounds to enable PET imaging.39 The fluoromethyl sulfonates 12?a and 12?b have been prepared starting Yohimbine hydrochloride (Antagonil) from bis(mesyloxy) and bis(tosyloxy) methane and by introducing fluorine by reaction with KF.40 The synthesis of 12?b has been considerably improved41 and is almost quantitative when CsF in stereoselectivity of 14 is particularly noteworthy. The O\regiospecificity of 14 was explained by a radical\like mechanism involving a SET process.45 However, Shen and co\workers reported that alcohols did not react with this reagent under the conditions applied.28d 2.1.5. Monofluoromethyl\Substituted Sulfonium Ylides Completing the series of difluoromethyl\ and trifluoromethyl\substituted sulfonium ylides, Shen and Lu reported in 2017 the missing monofluoromethyl sulfonium ylide 15, which was structurally characterized by single\crystal X\ray diffraction. Reagent 15 is usually a stable solid and can be stored for at least one month at ambient heat around the bench without notable decomposition, and it can be Yohimbine hydrochloride (Antagonil) prepared in a straightforward manner in good yields.28d The ylide 15 was found to be a very effective reagent for the electrophilic fluoromethylation of primary, secondary, and tertiary alcohols, as well as of malonic acid derivatives.28d It was shown that 15 is usually a strong alkylating agent. Thus, the conversion of sulfonic acids, carboxylic acids, phenols, amides, and N\heteroarenes into the corresponding fluoromethyl derivatives takes place readily under moderate conditions (Scheme?7).28d Open in a separate window Scheme 7 C\, N\, and O\fluoromethylation with sulfonium ylide 15. Although 15 is Yohimbine hydrochloride (Antagonil) usually a strong alkylating agent, reactions of 15 with carbon nucleophiles and C?CH2F bond formation are problematic, and only proceed with special substrates.28d 2.2. Nucleophilic Monofluoromethylation Because of their high instability, organometallic reagents such as fluoromethyllithium or the corresponding Grignard reagents belong to the most difficult areas of research on nucleophilic monofluoromethylating brokers.7a In 2017, Pace and Luisi achieved a great breakthrough in this field. They reported the generation and use of fluoromethyllithium, which was the first and still remains the only direct nucleophilic monofluoromethylation reagent (Scheme?8).46 In order to perform reactions with this unstable species, it is important to stick strictly to the reaction conditions reported,46 as the generation of 16 only succeeds upon adding MeLi?LiBr in a molar ratio of 2:1.5 to the substrate. Furthermore, the reaction has to be quenched, and a solvent mixture of THF/Et2O (1:1) has to be used.46 Unfortunately, unlike MeLi, reagent 16 cannot be isolated at room temperature as decomposition occurs very quickly, most probably by elimination of LiF. Open in a separate window Scheme 8 Nucleophilic fluoromethylation with fluoromethyl lithium 16. 2.3. Radical Monofluoromethylation 2.3.1. em N /em \Tosyl\ em S /em \fluoromethyl\ em S /em \phenylsulfoximine Until about ten years ago, a free radical monofluoromethylation was unknown.7a In 2014, Hu and co\workers described the sulfur\containing reagent 17, which is able to transfer the fluoromethyl radical group to a substrate (Scheme?9).28e, 47 Open in a separate window Scheme 9 Radical fluoromethylation of selected O, S, N, P?compounds with 17 and proposed reaction mechanism. Various compounds were fluoromethylated at O, S, N, or P in good yields by using sulfoximine 17. The range.