Reaction with fluoro enol

Several years ago, there was much debate concerning the mechanism of the Darzens condensation.2.3 The debate concerned whether the reaction employed an enolate or a carbene intermediate. In recent years, significant evidence that supports the enolate mechanism has been obtained, wherein the stabilized carbanion (11) of the halide (10) is condensed with the electrophile (12) to give diastereomeric aldolate products (13,14), which subsequently cyclize via an internal Sn2 reaction to give the corresponding oxirane (15 or 16). The intermediate aldolates have been isolated for both a-fluoro- and a-chloroesters 10. 

Huang, X.-T. Chen, Q.-Y. Ethyl a-Fluoro Silyl Enol Ether Stereoselective Synthesis and Its Aldol Reaction with Aldehydes and Ketones. J. Org. Chem. 2002, 67, 3231-3234. 

For example, the fluorination with [ F]F2 of diazepam, a 1,4-benzodiazepine (Scheme 18), gives the 3-fluoro derivative in up to 60% radiochemical yield [100]. The mechanism proposed is the electrophilic reaction of [ F]F2 with the enol form of the amide (stabilised by conjugation) yielding, after fluorine attachment and reformation of the carbonyl group, the a-fluoroketo derivative. 

When ketones, aldehydes and esters are transformed to silyl enol ethers, further reaction with trifluoromethyl hypofluorite gives a-fluoro carbonyl products 16 in good to excellent yield.31... 

Preliminary fluorination experiments using optically active A -fluoro compounds ( —)-2b and ( + )-2c show that there is reaction with various metal enolates (Table 16) generated under standard reaction conditions to give the anticipated a-fluoro carbonyl compounds with enantiomeric excesses depending strongly on the structure of the metal enolate.119... 

Table 3. Reaction of (S)-3-Benzyloxy-2-fluoro-2-methylpropionaldehyde with Silyl Enol Ethers and Silyl Ketene Acetals [6]...

Reaction of diphenyl(fluoro)-A3-iodane with silyl enol ethers in THF results in a regioselective a-phenylation [Eq. (74)] [131]. 

Trifluoromethyl hypofluorite gained its initial popularity, however, from its reactions with enol derivatives. Such reactions continued to be important during the last decade. The synthesis of complex molecules such as fluoroerythromycin (equation 137)244 and 2-fluoro (25)245 and 16-fluoroestradiols (26) (equation 138)246 are good examples of using CF3OF to produce compounds with useful therapeutic properties. 

Fluorinalion of 1,3-dicarbonyl compounds. 1,3-Dicarbonyl compounds that exist partly in the enol form are converted by 1 into the 2-fluoro derivative in moderate yield. The yield is generally improved by reaction with the corresponding sodium enolate. When the enol content of the 1,3-dicarbonyl substrate is small, no reaction occurs with 1, although the corresponding metal enolate does react. 

Fluorination of Ketone Enolates. (+)-lV-Fluoro-2,10-(3,3-dichlorocamphorsultam) (1) reacts with ketone enolates to give a-fluoro ketones. For example, reaction of the sodium enolate of propiophenone 2 gives a-fluoropropiophenone 3 in 41% isolated yield (eq 1). No enantioselectivity, however, is observed due to racemization of the product under the reaction conditions. When a tertiary substituted ketone such as a-methyltetralone (4) is employed, the desired a-fluorinated product (S)-(-)-S is obtained in 76% ee and 53% isolated yield (eq 2). In this reaction, (+)-l was found to be more reactive, affording higher yields and better enan-tioselectivities than its parent (-)-N-fluoro-2,10-camphorsultam i.e., 35% ee, < 5% yield. ... 

Reactions of Enol Derivatives and Enamines.—Enolic acetates are transformed into fluoro-ketones by the action of fluoroxytrifluoromethane, a source of electrophilic fluorine (Scheme 10)/ Peroxylauric acid reacted with the enol... 

The Ben May workers found that enol ethers also serve as intermediates. Thus the enol ethers of three 3-keto-5a-steroids on reaction with FCIO3 in pyridine at room temperature for 2 min., with subsequent acidification, afforded 2c -fluoro-3-ketones in yields of 75-90%. The enol ether of A -cholestene-3-one, namely 3-... 

Synthesis of trifluoromethylated compounds 152 has been achieved via ester-enolate [2,3]-Wittig and [3,3]-lreland-Claisen rearrangements. Perfluorocyclo-butane phosphonium ylides, e.g. 153, have been used as a masked fluoride anion source in their reactions with alcohols and carboxylic acids which lead to alkyl-and acyl-fluorides. Ylides 153 are also reported to cleave Si-C and Si-O bonds, cause dimerisation of fluoro-olefins, and also react with acid chlorides or other activated aromatic compounds under halogen exchange. ... 

Huorinated etiolates are generally difficult to form. Ishihara and coworkers used fluorovinyl phosphates, which can be prepared from a-fluoro ketones and sodium diethyl phosphite. Reaction of these fluorinated enol phosphates with a reagent prepared from lithium aluminum hydride (LiAIH4> and cop-per(II) bromide, zinc(II) chloride, tin(II) chloride or bromine afforded the enolate (Scheme 34).The reaction of the enol phosphate with the reagents mentioned above suggests that the metal cation of the enolate is an aluminum species, though its actual structure is not known at present. 

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