Difluoromethylene compound

Thiocarbonyl compounds can be converted into difluoromethylene compounds usually under milder conditions than the conesponding carbonyl compounds Ethylene trithiocarbonate reacts smoothly with sulfur tetrafluoride at 110 °C in the absence of catalyst to give 2,2-difluoro-l,3-dithiolane in high yield. Thiuramsul/ides under similar conditions are readily converted into dialkyItrifluo-rometkylamines [11] (equations 13 and 14). 

This method can also be utilized as a general method for the preparation of olefins with terminal difluoromethylene groups from aldehydes.8 Also, by the substitution of tributylphosphine for triphenylphosphine in this procedure, ketones other than those containing an a-perfluoroalkyl group can be converted to terminal difluoromethylene compounds.9... 

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)." ° ... 

Thiocarbonyl compounds undergo conversion into difluoromethylene compounds, generally under milder conditions than the corresponding carbonyl compounds. These reactions differ from those of sulfur tetrafluoride with carbonyl compounds in that a formal oxidation-reduc-... 

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... 

A simple alternative approach to the synthesis of difluoromethylene compounds involves electron transfer from metals to carbon-oxygen or carbon-nitrogen double bonds [38, 39] (Figure 6.28). 

The synthetic scope and mechanistic aspect of reactions of difluoromethylene compounds are summarized in ref. 23, pp 112-121. 

A review on the synthesis of gew-difluoromethylene compounds has described carbohydrate (including nucleoside) examples. The synthesis of acetylated glycosyl fluorides directly from the unprotected methyl glycosides has been effected as the first step of a GLC analytical method. First the glycoside is treated with HF followed by the addition of acetic anhydride. Full details (cf. Vol. 25, p.l05) on the preparation of glycosyl fluorides by reaction of aryl 1-thioglycosides with 4-difluoroiodotoluene have been described. ... 

Deoxy-3 -difluoromethyleneuridine (128), the first example of a 3 -difluoro-methylene nucleoside, has been made by use of the Wittig-type reagent derived from CFaBra, HMPT and zinc metal. The 2 -difluoromethylene isomer could be similarly prepared an earlier approach to 2 -difluoromethylene nucleosides (Vol. 26, p. 240) was not successful when applied to a 3 -keto-compound. 5 -0-Dmtr-3 -0-phosphoramidites of these difluoromethylene compounds were also made for assembly into oligonucleotides. ... 

Difluoromethylene compounds. Ethereal 20%-LiAlH4 added at -5 to 5 under dry Ng during 1.5 hrs. to a soln. of 3-chloro-3,3-difluoro-2-(trifluoromethyl)-prop-l-ene in anhydrous ether, and stirring continued 1 hr. at room temp. 

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)... 

The addition of primary amines to fluoroolefins under anhydrous conditions yields imines The hexafluoropropene dimer, perfluoro-2-methyl-2-pcntcne, and ten butylamine react to yield a mixture of two compounds m a 9 4 ratio [4] (equation 3) rather than just the major keteiiimme-imine, as previously reported [5] It IS claimed that this result is possible by means of isomerization to the terminally unsaturated difluoromethylene isomer prior to nucleophilic attack Secondary amines add to fluoroolefins under anhydrous conditions to give fluonnated ternary amines m good yields If the fluoroolefin is added to the amine without cooling the reaction mixture, or if an excess of the secondary armne is used, there is a tendency toward dehvdrofluonnation of the ternary amine The products... 

Although the sulfur trifluoride compounds are generally useful as selective agents for conversion of carbonyl and carboxyl groups to difluoromethylene and trifluoromethyl groups, variations in reaction conditions are often necessary.7 Thus the reaction of aromatic ketones requires heating at 150°. Since the reaction with aliphatic aldehydes and ketones is exothermic, it is advan-... 

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. 

Thus, this in situ protocol provides a general entry to [F2C=CXZnCl] reagents (where X = F, Cl, Br, I). It avoids the use of low temperatures (—60 to —100 °C) and is easier to scale-up. The precursors (CF3CH2X) are commercially available, cheap or moderately priced, and in some cases (X = F) is a cost-effective entry to commercially useful compounds. The a-bromo- and a-iodostyrenes also provide useful precursors to 1,1-difluoromethylene olefins via subsequent Suzuki couplings27, as outlined in... 

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. 

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