Difluoromethyl derivatives from

Silyl enol ethers have also been used as a trap for electrophilic radicals derived from a-haloesters [36] or perfluoroalkyl iodides [32]. They afford the a-alkylated ketones after acidic treatment of the intermediate silyl enol ethers (Scheme 19, Eq. 19a). Similarly, silyl ketene acetals are converted into o -pcriluoroalkyl esters upon treatment with per fluoro alkyl iodides [32, 47]. The Et3B/02-mediated diastereoselective trifluoromethylation [48,49] (Eq. 19b) and (ethoxycarbonyl)difluoromethylation [50,51] of lithium eno-lates derived from N-acyloxazolidinones have also been achieved. More recently, Mikami [52] succeeded in the trifluoromethylation of ketone enolates... 

Two asymmetric syntheses of C-difluoromethyl sugars from fluormated building blocks have been reported. The first one describes the preparation of a derivative of 4-difluoromethyl-l-deoxy-D-xylulose. This synthesis is based on an original crosscoupling between a vinyl halide and a difluorovinyltin compound (prepared from trifluoroethanol). This step is then followed by an asymmetric Sharpless dihydrox-ylation (AD-mix-a) (Figure 6.31). ... 

Other enzymes can turn a pro-drug into an electrophile by inserting an oxygen atom. Thus the mixed function oxidases of the e.r, described in Section 3.5, can oxidize difluoromethyl derivatives of the normal substrate to give an acyl fluoride which acylates the active site of the enzyme. Thus, aromatase is the enzyme normally concerned with the synthesis of estrone from androst-4-ene-3,17-dione. The 19,19-difluoro-derivative of this substrate acts as an IMBI which, in the manner described, becomes permanently attached to the enzyme in the 19-position (Marcotte and Robinson, 1982). These authors hope that this drug will prove useful in treating breast cancer. 

Isocyanides, which are isoelectronic with carbon monoxide, can undergo insertion reactions to provide Af-containing heterocycles. In 2013, Yu and coworkers [46] developed a photoredox catalytic, somophilic isocyanide insertion (HAS) yielding 6-alkylated phenanthridine derivatives from biphenyl isocyanide and electron-deficient bromides (Eq. (13.14)). Interestingly, when ethyl bromoflu-oroacetate or ethyl bromodifluoroacetate were used as the substrate [47], a subsequent decarboxylation efficiently produced mono- and difluoromethylated phenanthridine derivatives (Eq. (13.15)). 

These compounds come from methylenation reactions of the corresponding carbonyl derivative by means of an ylide. Several experimental conditions have been described. In most cases, CF2Br2 and HMPT (hexamethyl phosphorotriamide) are employed. The reaction occurs with aldehydes as well as with ketones in the furanose and pyranose series. The reaction can also be performed with lactones the fluoromethyl group is then introduced in the anomeric position. With these substrates, the Julia olefmation, which uses difluoromethyl sulfone, has also been reported to be an efficient method. Some examples of these reactions are shown in Figure 6.24. 

The antimony(V) chloride catalyzed fluorination with antimony(III) fluoride has been used to prepare (2,2-difluoroethyl)trifluorosilane in 83 % yield from the corresponding trichlorosilyl derivative.88 Also, other trichlorosilanes containing electron-withdrawing fiuorinated alkyl groups (difluoromethyl, 1,1,2,2-tetrafluoroethyl, 1,1-difluoroethyl) arc converted into the corresponding trifluorosilanes in about 80% yield by treatment with the antimony(III) fluoride/ antimony(V) chloride system.89-90... 

The enzymes used to generate reactive quinone methides often undergo inactivation by addition of this electrophile to essential nucleophilic amino acid side chains of the protein catalyst. This is a type of suicide enzyme inhibition.80 This was observed for the acid phosphatase and ribonuclease catalysts used to generate 43.76 79 Alkaline phosphatase has been used to remove the phosphate protecting group from a derivative of an o-difluoromethyl phenyl phosphate that was covalently attached to a solid support. Breakdown of the immobilized 4-hydroxybenzyl difluoride gives an immobilized quinone methide that, in principle, will react irreversibly with proteins and lead to their attachment to the solid support.81... 

Abramov nucleophilic addition of various phosphorus acid esters to nucleoside aldehyde derivatives yielded the phosphonate-based iso-polar, non-iso-steric 5 -nucleotide analogues (28) containing a geminal hydroxy phosphonate moiety on the 5 -carbon of the pentofuranose ring. The enantiomerically pure D- and l- 2, 3, 5 -trideoxy-4 -[(ethoxyphosphoryl) difluoromethyl] thymidine analogues(29) have been synthesized from (i 5)-( )-2-methyl-5-(4-methyl-phenyl-sulfinyl)pent-2-ene and ethyl 2-(diethoxyphosphoryl)-2,2-difluoro-acetate in 45% overall yield over seven steps. ... 

In the presence of BuLi in thf, the active methylene compounds (Et0)2P(0)CH2Z (Z = P03Et2, COOMe, S02Me or CN) add to PhCH—CMe(N02) to give the products 78 as intermediates in a synthesis of C-phosphorylated 2-isoxazoline derivatives Other reactions have been performed between 2-aryl-1-nitroethenes and the anions from dimethyl methylphosphonate " or dimethyl (difluoromethyl)phosphonate in the initial steps towards syntheses of phaclofen 80 X = H) and its difluoro analogue (80 X = F) by the reduction (H2-Raney nickel) of the initial adduct 79 (Scheme 6). 

Apart from nucleophilic substitution in the trifluoromethyl-substituted diazines discussed above, transformations related to mono- and difluoromethyl groups were also mentioned in the literature. In particnlar, hydrolysis of 5-difluoromethyluracyl and its derivative to form 5-formyl uracils was described [754] the proposed mechanism reaction was analogous for the corresponding triflnoromethyl analogue. Nucleophilic substitution in fluoromethyl derivative 1224 was reported in this case, N-acetylcysteine was acting as 5-nucleophile (Scheme 267) [755]. 

The synthesis of Primisulfuron-methyl (299) started from reaction of diethyl malonate and thiourea (Scheme 77) [284]. The resulting pyrimidine derivative 348 was methylated, difluoromethylated and then oxidized to give sulfone 351. Reaction of 351 with aqueous ammonia gave heteroaromatic amine 352, which was transformed to Primisulfuron-methyl (299) upon treatment with isocyanate 353. 

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