Fluoro-carbonyl compounds

Many fluorinations by electropositive fluorine reagents produce a-fluoro carbonyl compounds as the final result An extensive review exists on the preparation of a-fiuorocarbonyl compounds [101 Also, electropositive reagents are used widely in the preparation of F-labeled radioactive materials required in positron etmssion tomography for biomedical research Excellent reviews are available on fluonne-18 labeling [//, 72]. 

For a review of the preparation of a-fluoro carbonyl compounds, see Rozen, S. Filler, R. Tetrahedron, 1985, 41, 1111. For a monograph, see German, L. Zemskov, S. New Fluorinating Agents in Organic Chemistry Springer NY, 1989. 

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]. 

Regretfully, there are few examples of fluorination by l-fluoropyridin-2(l//)-one (1), so it is difficult to evaluate its synthetic utility. This reagent has been used to obtain a-fluoro carbonyl compounds 4.28... 

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... 

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... 

A second general approach to allyl /(-lluorovinyl ether intermediates involves the reaction of a /J-fluoro alcoholate with an allylic halide. Claisen rearrangement then produces a-fluoro carbonyl compounds. Although the tremendous rate acceleration caused by a-fluoro substitution in the vinyl fragment is not present here, the rearrangements take place under synthetically useful conditions. 

A novel variation of the method of adding an allylie alcohol to a reactive a-fluoro carbonyl compound, as shown in the previous example, has been developed by Shi and Cai in a general strategy for the synthesis of /h/i-difluoro-a-amtno acids via the a-oxo esters 53.20 Ethyl tri-fluoropyruvate reacts with primary allylie alcohols 49 in benzene to form the stable hemiacetals... 

Trifluoromethyl hypofluorite smoothly converts silyl enol ethers into the corresponding a-fluoro carbonyl compounds in good yield (Table 5). ... 

Silvcr(I) tetrafluoroborate has been used to prepare a-fluoro carbonyl compounds from chlorinated epoxides.Minor byproducts of the reaction are the corresponding a-chloro carbonyl compounds. 

The advantage of aluminum reagents over other metal reagents was also seen in the Lewis acid-promoted allylation of fluoro carbonyl compounds. For instance, MesAl-promoted selective allylation of an equimolar mixture of 2- and 4-fluorobenz-aldehydes with allyltributyltin afforded the homoallylic alcohol 53 almost exclusively. Unsatisfactory chemical yield and/or selectivity were obtained with Ti, Mg, Li, Sn, and Si Lewis acids (Sch. 38). 

The high diastereoselectivity observed is ascribed to effective chelate formation between MeaAl and fluoro carbonyl compounds via pentacoordinate organoalumi-num complex H this was verified by a low-temperature and NMR study. The original signal of the carbonyl carbon in fluoro ketone 61 (model substrate) appeared at 6 208.5. When 61 was complexed with MesAl in a 1 1 molar ratio in CD2CI2 at -50 °C, a significant downfield shift ((5 225.0) was observed for the carbonyl carbon by... 

Fluoroalkyl- and fluoroarylamines. Imines formed (with Dowex-50 Reform resin as catalyst) with fluoro carbonyl compounds undergo prototropic shift on treatment with EtjN. Hydrolysis of the benzylidene isomers gives the fluorinated amines. 

Postovoi, S.A. Kagramanova, E.M. Mysov, E.I. Zeifman, Y.V. Reductive addition of polychloro(fluoro)alkanes to fluoro carbonyl compounds. Izv. Akad. Nauk SSSR, Ser. Khim. 1996, (6), 1496-1498. 

Reaction with Enolates. TV-Fluorobenzenesulfonimide readily reacts with enolates to yield a-fluoro carbonyl compounds. Simple ketone enolates, prepared by treatment with hthlum his (trimethylsilyl)amide in THF at low temperature, are fluorinated by treatment with a molar equivalent of NFSi (eq 4). ... 

Reactions with organic compounds. HOF converts alkenes into a-fluoro alcohols, acetylenes mainly into a-fluoro carbonyl compounds [11], aromatic compounds (benzene and its monosubstituted derivatives, p-xylene, naphthalene) into phenolic products [12], and octa-ethylporphyrin into the N-oxide [13]. 

Many a-fluoro carbonyl compounds, which are intermediates or final products in the design of fluorinated analogs of biologically active compounds, were prepared by electrophilic fluorination this includes fluoro-tribactam antibiotics, 12-fluoroforskohn, 2-(/ )-fluorodehydroquinic... 

FIGURE 44.4. Examples of biologically active a-fluoro carbonyl compounds. 

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