Enolates difluoro

Ester enolates react with 3,3,3-trifluoropropene by an Sf,2 -ty pe process to gi ve 5 5 difluoro-4-pentenoic acid esters [130] (equation 112)... 

Using chiral catalysts, not only various enantioselective Mukaiyama and vinylogous Mukaiyama aldol reactions have been developed but also asymmetric reactions of a,a-difluoro silyl enol ethers (1) with carbonyl compounds have been reported ... 

A synthesis of the B-ring aromatic corticosteroid (286), the analogue of cortex-olone, started with the previously reported B-ring aromatic norpregnane (285). Development of the corticosteroid side-chain employed bromination of the 17a-hydroxy-20-oxo-derivative with trimethylphenylammonium bromide perbromide. " Reaction of perchloryl fluoride with the mixed enol ethers (287) and (288) provided, after hydrolysis, the 17a-fluoro-20-oxo-compound (290) and the 21-fluoro-20-oxo-compound (291). In contrast, the enamine (289) led only to the 17a,21-difluoro-20-oxo-compound. A series of 17a-acyloxy-21-deoxy-... 

The enolic double bond of a difluorovinyl group in the anomeric position is able to add a radical. It can thus afford a difluoro-C-glycoside, either directly or indirectly. When the alkylating radical is generated from a 6-halogenopyranoside, the reaction can lead to difluoro-C-disaccharide. These reactions are even more efficient if the radical has an electrophilic character (e.g., with an a-halogenoester instead of an alkyl radical). 

Figure 2 represents both alkylation reactions mechanistically. More recently, reactive enolates were bromodifluoromethylated successfully via difluoro-carbene formed in situ. [43, 44]. The reaction solvent was critical for the outcome of the reaction (Eq. 11). 

Recently, analogues of nucleosides [60], natural products Huperzine-A [61] and Hydroartemisinin [62], and inhibitors of metallo-/ -lactamases have been synthesised [63]. With acylsilane electrophiles, the initial adducts undergo Brook rearrangement which is interrupted by -Si bond fission with loss of fluoride anion (Eq. 16), leading to the formation of extremely useful difluoro-enol silanes [64]. Of the various fluoride sources employed, the tetrabutylam-monium triphenyldifluorostannate described by Gingras appears to be particularly effective. The numerous other methods for trifluoromethylation formed the subject of an exhaustive review [65]. More recently, the Olah group described a chlorodifluoromethyl trimethylsilane which is expected to have a rich chemistry [66]. 

Chlorodifluoromethylketones underwent aldol reactions (Eq. 124) via zinc enolates, to afford good yields of a,a-difluoro-/ -hydroxy ketones, in a study by the Kyoto group [327]. Copper(I) or silver salt catalysis was essential and boron-trifluoride additive appeared to exert a key role in the conversion to the enolate. Earlier [328], chlorodifluoromethyl ketones had been converted to the di-fluoroenoxy silanes by the action of zinc in the presence of chlorotrimethyl silane. A difluoroenoxy silane was used by McCarthy and co-workers [329] to synthesise a kynureninase inhibitor (Eq. 125) Lewis acid-mediated reaction with a chloroglycinate installed the key carbon-carbon bond. 

It has been shown that monosubstituted enolates can be transformed selectively to give a-fluoro and a,a-difluoro carbonyl compounds using A-fluorosultam 3 in a one-pot procedure,10,11 154 158 e.g. formation of 6123 (see also Table 17159). 

The chelated ester enolate Claisen rearrangement of allylic glycinates 9 is carried out with zinc(II) chloride, which is added to the enolate at — 78 C (Table 19). The rearrangement occurs as the reaction mixture is allowed to warm to room temperature over 1 hour. The 2-amino-3,3-difluoro-4-[(2-methoxyethoxy)methoxy] alk-4-enoic acids 10 arc converted directly into the corresponding methyl esters, which can be hydrolyzed to the methyl 2-amino-3,3-difluoro-4-oxoal-kanoates. 

Table 19. Synthesis of 2-Amino-3,3-difluoro-4-[(2-methoxyethoxy)meth-oxy]alk-4-cnoic Acids 10 by the Chelated Ester Enolate Claisen Rearrangement of Allylic Glycinates 943...

Whereas the lithium enolates of acetate and propionate esters of difluoroallylic alcohols are known to fragment rapidly, methoxy- and benzyloxy-acetates have been found151 to form chelated enolates which undergo a smooth [3,3]-sigmatropic rearrangement as their silyl ketene acetals to afford highly functionalized difluoro compounds (see Scheme 33). Allenic silyl ketene acetals (117) have been used152 to prepare 2-substituted methyl 3,4-dienoates (118). 

Fluoride ion-catalysed addition of trifluoromethyltrimethylsilane to acyl silanes occurs to give l,l-difluoro-2-trimethylsilyloxyalkenes (silyl enol ethers of difluoromethyl ketones), through nucleophilic addition of trifluoromethyl anion, Brook rearrangement and loss of fluoride. These compounds could be isolated when tetrabutylammonium difluorotriphenylstannate was used as a catalyst use of tetrabutylammonium fluoride gave the product corresponding to subsequent aldol reaction with the difluoromethyl ketone (Scheme 78)m. 

When the 7-enolate anion of 2-benzylperhydropyrido[l,2-a]pyrazin-6-one, generated with LDA or BuLi in THF, was treated with benzophenone and its 4,4 -difluoro derivative, a mixture of diastereomeric cis- and trans-1-diarylhydroxymethyl derivatives was formed, which was dehydrated with 48% aqueous HBr (93JOC690). 

Reaction of the r-butyldimethylsilyl enol ether of a protected dipeptide with xenon difluoride in a mixture of acetonitrile and 1,1,2-trichlorotrifluoroethane gave the fluoro ketone in 71 % yield as a 1 1 mixture of diasteroisomers, while further transformation to enol ether and fluorination affords the difluoro ketone81 (Scheme 23). 

Surprisingly, heating of the enol ether 3,3-difluoro-2-ethoxy-l-phenyl-l-cyclobutene with concentrated sulfuric acid does not affect the ether... 

Difluorocarbene has also been added to a number of steroidal enol acetates, providing the corresponding acetoxy-difluorocyclopropane in good yield. Treatment of the latter with base constitutes a convenient homologation sequence which affords either the a-difluoro-ketone, or the a-fluoro-enone, depending on steric factors. Thus, difluorocarbene was added to the enol acetate (77) to give the a-difluoro-adduct (78). Treatment of (78) with methanolic potassium... 

Amii, H., Kobayashi, T., Hatamoto, Y. and Uneyama, K. (1999) Mg°-promoted selective C-F bond cleavage of trifluoromethyl ketones a convenient method for the synthesis of 2,2-difluoro enol silanes. J. Chem. Soc. Chem. Commun., 1323-1324... 

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