Difluoromethylene derivatives

Much better known are the fluonnatedphosphoranes, which have been widely used m the Wittig reaction for the preparation of fluoroolefms Difluoromethylena tion reactions have been effected by using a variety of conditions Treatment of dibromodifluoromethane with two equivalents of tns(dimethylammo)phosphine m carefully dried tnglyme yields a solution of bromodifluoromethylphosphonium broomide, which very effectively converts ketones to difluoromethylene derivatives A more sensitive reagent is prepared by the addihon of two equivalents of the phosphine to the reaction mixture of fluorohalomethane and a carbonyl compound [39, 40] (equation 40) (Table 14)... 

Aminosulphur trifluorides, which are easier to handle than SF4, can also be used for the conversion of most aldehydes and ketones to difluoromethylene derivatives numerous examples have been documented [12] (Table 3.6). A similar reaction mechanism to that for SF4 may be assumed. 

Novel chemistry that was initiated by Nakai and co-workers [36, 37] involves elimination of hydrogen fluoride from the tosylate of trifluoroethanol, followed by reaction of the intermediate with appropriate electrophiles (Figure 6.27). A wide range of approaches to the synthesis of difluoromethylene derivatives has ensued. 

Scheme 2.64 Proposed mechanism for fluorination of carbonyl compounds into the corresponding gem-difluoromethylene derivatives [139].

Scheme 2.65 Aboi e Conversion of carbonyl compounds to difluoromethylene derivatives by DAST [127]. Be/ow Limits of the reactivity of DAST compared with SF4 [140].

As with the other aromatic and heteroaromatic systems, functional group transformations can also be used to produce fluorinated 1,2,3-triazoles. A series of 1-aryl-1,2,3-triazole-4-carbaldehydes were converted to the corresponding difluoromethyl-substituted triazoles by the action of DAST (Fig. 3.96). The difluoromethylene derivatives as well as the precursor aldehydes were studied with respect to antitubercular activity. 

A probable mechanism for the hydrodefluorination of the gm-difluoromethylene derivatives with lithium aluminium hydride, catalysed by ZnCl2 without ancillary ligands, in good to high yields has been suggested. ... 

Difluoromethylenation (79,80) of aldonolactones may be readily accomplished by treatment of the lactone derivative with tris(dimethyl-amino)phosphine, dibromodifluoromethane, and zinc in refluxing tetrahy-... 

The difluoromethylene ylides react with carbonyl derivatives (aldehyde, lactone) to afford gem-difluoromethylene compounds.They are generated starting from halogenodifluoromethane with triphenylphosphine (or trisaminophosphine) or starting from zinc and a phosphonium salt (or a phosphine oxide)." ° ... 

Starting from Difluorovinyl Glycosides Saccharidic derivatives that have a difluoromethylene group in the pseudo-anomeric position are important synthetic intermediates for preparation of difluoro-C-glycosides, difluoro-C-phos-phonates, and difluoro-C-disaccharides. ° ... 

Saccharidic Difluorophosphonates Difluoromethylene phospho-nates have been the focus of numerous works. Indeed, these compounds are able to mimic the phosphate bond in the synthesis of enzyme inhibitors. This interest is obvious for the furanose series in this case, they are non scissible analogues of 5-phosphate nucleosides (cf. Chapter 7). Difluoromethylene phosphonates can be prepared via a radical path starting from compounds that have the difluoromethylene moiety in the pseudo-anomeric position. Nevertheless, methods based on metal derivatives of difluorophosphonates are generally easier and broadly applicable. 

Finally, gem-difluoromethylene analogs, e.g., 315 and 316, designed to mimic artemisinin, have been prepared by the treatment of the trifluoromethyl derivatives 169 and 173 with 2 equiv of MeLi in THF at —78 °C, and their anti-malarial activity investigated (Scheme 53) <2006JFC637>. 

Ishihara and coworkers have reported that the reaction of 2-[(trimethylsilyl)methyl]-3-chloro-3,3-difluoropropene couples regioselectively with a variety of carbonyl compounds in the presence of zinc-copper chloride or silver acetate to give 2,2-difluoro-3-(trimethylsilyl)methyl-3-buten-l-ol derivatives (equation 87)81. Note again that the difluo-roallyl zinc species generated in situ reacts exclusively on the difluoromethylene terminus. 

Similarly, partially fluorinated and perfluonnated methylenecyclopropanes [87, 82], cyclopropenes [85, 84, 85], cyclobutenes [75, 86], and bicychc alkenes [87, 88, 89, 90] apparently derive dienophihc reactivity from relief of their ground-state strain during reaction Thus 2,2-difluoromethylenecyclopropane and perfluoromethylenecyclopropane undergo exclusive [2+4] cycloadditions [87, 82] (equations 72 and 73), whereas (difluoromethylene)cyclopropane undergoes only [2+2] cycloadditions [87]... 

Hine, J. Porter, J. J. Methylene derivatives as intermediates in polar reactions. VIII. Difluoromethylene in the reaction of chlorodi-fluoromethane with NaOMe. J. Am. Chem. 

As in Explanation 89, these two compounds do not react in the sense of the Diels-Alder reaction. Instead, a cyclobutane derivative is formed by cycloaddition. The reaction is a free-radical process starting with single electrons on carbons 1 and 2 of perfluorovinylsulfur pentafluoride. Carbon 1 of the 1,3-butadiene joins the difluoromethylene group of the perfluorovinylsulfur pentafluoride because in this way, the newly formed biradical can better accommodate the single electron on the carbon next to the SF5 group. The biradical closes the ring in such a way that two stereoisomers, P and Q, cis- and trans-2,3,3-trifluoro-l-vinyl-2-cyclobutyl-sulfur pentafluoride, are formed in equal amounts [122]. 

Functional groups containing the C = N bond, such as hydrazones, oximes and diazo compounds, can also be used in the synthesis of fluorinated derivatives and these reactions are the subject of this section. The reaction products in these procedures are usually the corresponding g cw-difluoromethylene compounds. Since oximes and hydrazones arc obtained from aldehydes and ketones, these reactions can be considered as an alternative to the direct transformation of a carbonyl group into the difluoromethylene group. As indicated in Section... 

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