Fluorinated compounds, enol

Chemistry of Organic Fluorine Compounds ll Table 2. Fluorination of Enols and Enolates... 

These are the first reagents known to effect enantioselective fluorination of enolates of carbonyl compounds. The highest enantioselectivity is observed in the reaction of (-)-l with a p-keto ester (equation I). 

Xenon difluoride has also been used for the fluorination of enol derivatives [5] and 1,3-dicarbonyl compounds [140], and fluorination of activated aromatic substrates is possible in the presence of a Lewis acid [141]. 

This group continuously enlarged the scope of substrate to allylsilane, silyl enol ether 113 and oxindoles 115 for enantioselective catalytic a-fluorination (Scheme 6.34) [62]. They employed N-fluorobenzenesulfonimide (NFSI) as a fluorinating reagent with bis-cinchona alkaloid catalysts and excess base to provide the corresponding fluorinated compounds 114,115 in excellent enantioselectivities up to 95% ee. 

The prototype of the disubstituted enols and thiols, whatever the position of substituents, is V in fig. 11, with 8 electrons, in which the only bonding MOs are the low-lying 7Tiand 7r2 orbitals. The bonding contribution along the C-0 (resp. C-S) bond is thus very weak in fluorine compounds. For instance, starting from syn conformation, the rotational barrier is very weak in trans FHC=CFOH. Its anti conformer is stabilized by interaction e. All three anti fluorine molecules are slightly distorted. 

Double Fluorination of Enolates. Double fluorination of monosubstltuted enolates is achieved selectively in a one-pot procedure by adding the starting carbonyl compound to 2.4-3.6 equiv of base inTHFat—78°C followed by the addition of 2.6-3.6 equiv of the Wfluorosultam, and warming up to room temperatures. For this process, KHMDS and potassium diisopropylamide are the bases of choice (eqs 7-9). ... 

In 2008, Shibata et al. disclosed the first successful catalytic enantioselective fluorination based on the use of cinchona alkaloids. Therefore, it was demonstrated that allyl silanes and silyl enol ethers underwent efficient enantioselective fluorodesilylation with NFSI and a catalytic amount of a bis-cinchona alkaloid in the presence of an excess of base to provide the corresponding fluorinated compounds with an F-substituted quaternary carbon centre with enantioselectivities of up to 95% ee (Scheme 5.3). Furthermore, the authors showed that this catalytic system could be applied to the catalytic... 

Fluorination of Enolates and Silyl Enol Ethers. iV-fluoro-Af-(phenylsulfonyl)henzenesulfonamide (1) can be used successfully to prepare a-fluorocarbonyl compounds starting from esters, ketones, or 8-dicarbonyl precursors by electrophilic fluorination of the corresponding enolates (eqs 1-3) or silyl enol ethers (eq 4). Diastereoselective fluorination of enolates with 1 has recently been reported. ... 

Several 2-fluoroerythromycin derivatives have also been prepared by means of electrophilic fluorination with Selectfluor of the enolate of the )S-ketoester fragment (Fig. 45) [121]. Fluorination is stereoselective and leads to the a-fluo-rine compound [122]. Two derivatives of 2-fluoroerythromycin are in clinical development HMR-3562 and HMR-3787). These compounds are promising agents for the treatment of respiratory pathogens resistant to erythromycin A (Fig. 45) [123]. 

A second example concerns the instability of prostacyclin in physiological mediam, which is connected to the presence of the enol ether function (ti/2 = 5-10 min at pH = 7.4 and at 37°C). Hydrolysis is so fast that its use as a vasodilator and as an inhibitor of platelet adhesion cannot be exploited. The introduction of fluorine atoms in jS of the enol double bond led to compounds with good metabolic stability while retaining the strong activity as an inhibitor of platelet adhesion (Figure 3.18) (cf. Chapter 4). Proteolysis is slowed down as the oxonium, resulting from the protonation of the enol ether, is destabilized by the CF2 group. " ... 

Phloroglucinol, which is regarded as the tri-enol form of cyclohexane-1,3,5-trione, gives the hexahydrate of the corresponding perfluoro-trione upon fluorination in formic acid (Fig. 31) [93] (see 3.1.1.2 for a discussion of the fluorination of carbonyl compounds). 

Since fluoro-carbonyl compounds are such useful and versatile synthetic intermediates, much effort has been devoted to their preparation [124], but only in a few instances has elemental fluorine been used directly. One of the earliest successful direct fluorinations of a simple carbonyl compound was the fluorina-tion of pyruvic acid derivatives which have a high enol content (R = Aryl, Acyl) (Fig. 47) [125] in the solvent being used (mixtures of CF2C1CFC12 and acetonitrile). However, in derivatives where the enol content was low (R = Alkyl), complicated mixtures of products were obtained. 

Attempts to use fluorine in the preparation of simple a-fluoro-carbonyl compounds were not successful initially. Even when derivatives of carbonyl compounds such as enol acetates were treated with fluorine, a complicated mixture of products was obtained from which none of the desired a-fluoro... 

Under similar conditions, the enol acetate and the trimethylsilyl ether of estrone were fluorinated to give the corresponding a-fluoro carbonyl compound (Fig. 54) [135]. 

While fluoroxy compounds react well with enol derivatives, fluorine in general does not. However, there are various reports where such reactions are described and in certain cases even with decent yields. In 1982 it was reported that pyruvates with a dominant enolic form react well with fluorine, to give the corresponding fluoro derivatives l.78 Several silyl enol ethers 2 and 379 including ones made from 1,3-dicarbonyl derivatives 480 react quite satisfactorily with fluorine to give the expected a-fluoro ketones. Steroidal 16-enol acetates react with fluorine to form mainly 16a-fluoro-17-oxo steroids e.g. 5.81... 

Enol ethers can be regiospecifically fluorinated to form a-fluoro carbonyl compounds. In this way it is possible to synthesize fluorinated oxo steroids as the carbonyl groups not activated by the trimethylsilyl (or acetyl) enol ethers are not fluorinated.54... 

F-Teda BF4 (6) is very effective for the fluorination of a wide variety of organic substrates steroidal enol acetates (Table 7)92 and silyl enol ethers, certain carbanions, mildly activated aromatic compounds, and sulfides bearing oc-H atoms.73,75,76,77,84,88 90 The products are obtained with good yields and regioselectivity under very mild reaction conditions (Table 8). 

F-Teda BF4 is effective for the selective addition of fluorine to steroids in good yield, re-gioselectively and, in many cases, stereoselectively at the 6- and 16-positions, under very mild reaction conditions (Table 7).92 Further, 6 will also efficiently fluorinate silyl and alkyl enolates, enamides, carbanions, a-alkenes and actived aromatic compounds (Table 8). As an extension of this method F-Teda BF+ has been used for the electrophilic fluorination of (fluorovinyl)tin compounds affording terminal fluoroalkenes (see Table 9).88... 

F-Teda BF4 (6) has also been used for the gem-difluorination of active methylene compounds, / -oxo esters and amides.102 The reaction times can be significantly reduced by carrying out the two fluorination steps sequentially and, importantly, with the sodium enolate of the monofluoro intermediate for the second step. 

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