The France Fluorine Network (GIS CNRS Fluor) can be acknowledged. Conflicts appealing The authors declare Citicoline sodium no conflict of interest.. enantioselective and diastereoselective synthesis of -trifluoromethylated -amino acidity derivatives from -hydroxy–fluoro–trifluoromethyl carboxamides . In the final end, although this reactivity setting of FARs provides only been reported for the Ishikawa reagent, one can assume that other FARs can be compatible. 3.6. Transformation of the Three Carbons of the Ishikawa Reagent Finally, another application of FARs makes a constructive use of all carbons of the FAR, which are al transformed and incorporated in the reaction product. The Ishikawa reagent, like other FARs, can be easily hydrolysed to form the corresponding acetamide 4c, which can then be treated with a polar organometallic species (ArMgX) to afford acylated products, as detailed in Section 3.3. The position of this ketone is usually relatively acidic and can be deprotonated by an alkoxide, to form in situ the corresponding difluoromethylene upon elimination of fluoride. The transient ,-difluoroenone then reacts quickly with excess alkoxide to afford -fluoro–ketoesters 126aCg. It is important to note that this step is possible only when starting from the Ishikawa reagent, which is the only FAR among 1aCd to be derived from a 3-carbon alkene. The resulting -fluoro–ketoesters 126aCg possess two electrophilic sites and can react with dinucleophiles to provide fluorinated heterocycles. For example, monofluorinated pyrazoles and coumarins can be prepared by reaction with hydrazine and phenols respectively (Scheme 32) . 4. Conclusions While fluoroalkyl amino reagents were discovered more than a half century ago, their utilization was really diversified in 1975 when Wakselman et al. published their first applications as fluoroacylating brokers for aromatics. The chemistry of FARs underwent a second impulse at the beginning of the 21st century when the need for fluorinated heterocycle-based crop DFNA23 protection ingredients by agrochemical companies focused on difluoromethylpyrazoles. Indeed, 3-CHF2-pyrazolecarboxamide derivatives showed high activity as SDHI fungicides and several analogues were marketed by agro companies. In order to enhance the diversity and activities of these active ingredients, novel structures were sought and their preparation was studied. The development of new methods to introduce diverse emergent fluorinated substituents on heterocycles was necessary and FARs showed very interesting applications. Numerous fluorinated N-based 5- and 6-membered heterocycles bearing classical or new fluorinated substituents, particularly CF3, C2F5, CHF2, CHFCl, CHFCF3 or CHFOCF3 were successfully prepared using fast, efficient, robust and scalable methods. ? Open in Citicoline sodium a separate window Scheme 1 Preparation of fluoroalkyl amino reagents (FARs)hydroamination of polyfluoroalkenes. Open in a separate window Scheme 2 Lewis acid-mediated activation of FARs. TFEDMA, 1,1,2,2-tetrafluoro- em N /em , em N /em -dimethylethan-1-amine. Open in a separate window Scheme 3 Activation of FARs with BF3OEt2. Open in a separate window Scheme 4 Overview of the diverse reactivity modes and applications of FARs. Open in a separate window Scheme 5 Dehydroxyfluorination mechanism proposed by Petrov et al. . Open in a separate window Scheme 6 Beckmann rearrangement initiated by the Yarovenko reagent. Open in a separate window Scheme 7 Acylation of electron-rich aromatics with FARs by Wakselman et al. . Open in a separate window Scheme 8 Difluoroacylation of electron-rich heterocycles with TFEDMA. Open in a separate window Scheme 9 Difluoroacylation of electron-rich arenes under microwave heating. EDG, electron-donating group; MW, microwave. Open in a separate window Scheme 10 Difluoroacylation of electron-rich arenes with non-SEAr (electrophilic aromatic substitution) regioselectivity by Br/Li exchange followed by trapping with a difluoroacetamide. Open in Citicoline sodium a separate window Scheme 11 Synthesis of fluoroalkylated benzo-fused heterocycles without activation of FARs by Ishikawa et al. . Open in a separate window Scheme 12 Use of FARs ((A) Reaction of TFEDMA with methoxy acrylate; (B) with dimethylamino acrylate; (C) with a methylhydrazone) and acrylates to prepare ethyl 3-(difluoromethyl)-1-methyl-1 em H /em -pyrazole-4-carboxylate (DFMMP) with full regioselectivity. Open in a separate window Scheme 13 Reaction of activated TFEDMA 3a with vinyl ethers. Open in a separate window Scheme 14 Reaction of 3a with silyl enol ethers of cyclopentanone and cyclohexanone. Open in a separate window Scheme 15 Reaction of 3a with silyl enol ethers of acetophenone and acetylacetone. Open in a separate window Scheme 16 Preparation of difluoromethyl 5-aminopyrazoles- and isoxazoles. a 19F-NMR yield using PhF as internal standard. b isolated yield. c 40 C, 18 h. DIPEA, em N /em , em N /em -diisopropylethylamine. Open in a separate window Scheme 17 First preparation.