Ketones electrophilic fluorination

There are several new methodologies based on the Julia olefination reaction. For example, 2-(benzo[t/Jthiazol-2-ylsulfonyl)-j -methoxy-i -methylacetamide 178, prepared in two steps from 2-chloro-iV-methoxy-jV-methylacetamide, reacts with a variety of aldehydes in the presence of sodium hydride to furnish the ajl-unsaturated Weinreb amides 179 <06EJOC2851>. An efficient synthesis of fluorinated olefins 182 features the Julia olefination of aldehydes or ketones with a-fluoro l,3-benzothiazol-2-yl sulfones 181, readily available from l,3-benzothiazol-2-yl sulfones 180 via electrophilic fluorination <06OL1553>. A similar strategy has been applied to the synthesis of a-fluoro acrylates 185 <06OL4457>. 

Fluoroxytrifluoromethane, a source of electrophilic fluorine, has recently been employed by Barton et ah for the fluorination of unsaturated steroids.143,144 It is more reactive than perchloryl fluoride and therefore not without danger. It forms, for instance, a highly explosive product with pyridine.143 Like perchloryl fluoride it reacts with enol ethers, esters and enamines, but at lower temperature (— 78°) to yield the fluorinated ketones as well as addition... 

Enamines, which are readily obtained from the corresponding ketones, can be converted into a-fluoro ketones by treatment with a reagent capable of delivering electrophilic fluorine ( F ). 

Due to these safety problems, the search for new, easy-to-handle electrophilic fluorinating agents has become an important area of research. Some of these new reagents have been tested in the fluorination of enamines to give a-fluoro ketones. These include l-fluoropyridin-2(l//)-one (9), A -fiuoroquinuclidinium fluoride (NFQNF, 10), Af-fluoropyridinium salts 11, and A -fluorobis(trifluoromethanesulfonyl)aminc (Tf2NF. 12). ... 

The reaction of diazo compounds with an electrophilic fluorinating reagent, tri-fluoromethyl hypofluorite. has also been studied (Tabic 8, entries 9 13). ° The reactions are carried out at — 70 C using trichlorofluoromethane as solvent and mixtures of g /n-difluoro compounds and fluoro(trifluoromethoxy) derivatives are obtained. Although conversion is generally complete, the yields of isolated products are low, due to their difficult separation. In some cases (entries 9, 11, and 12), ketones and epoxides arc formed as byproducts. Consequently, this method is not a useful alternative for the preparation ofgcw-difluoro compounds. 

Also covered in this section is the fluorination of enamines with electrophilic fluorine ( F+ ). This reaction is not really a substitution of a monovalent nitrogen (amino) group by fluorine, but in this method the enamine group of the substrate is substituted, although in another position, by fluorine in the a-fluoro ketone product. 

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... 

Similarly to fluorinated ketones, electrophilic polyfluorinated azines and rmidoyl fluorides undergo [2 + 2 + 2] cycloaddition reaction with quadricyclane (12) to afford fluorinated norbornenazetidines 73-74 (Scheme 2.35). 

A variety of compounds cannot be prepared by direct nucleophilic F-fluorination. When high specific activity is required and electrophilic fluorination thus is impossible, labeling is often carried out by a multistep route using small reactive intermediates, often named secondary labeling precursors or prosthetic groups. A whole battery of these F-labeled intermediates was investigated and prepared, such as amines, alcohols, aldehydes, ketones, carboxylic acids, esters, and halides. Since a quantitative overview about these synthons is outside the scope of this chapter, only some examples are discussed. 

Monofluorination of Enolates. /V Fluorosultam (1) has been successfully used to prepare a-fluorocarbonyl compounds by electrophilic fluorination starting, for example, from disubstituted enolates derived from ketones, esters, and -dicarbonyl compounds (eqs 13). The related /V-fluorosulfonamide reagents ... 

Lam, Y.-H. Houk, K. N. How Cinchona Alkaloid-Derived Primary Amines Control Asymmetric Electrophilic Fluorination of Cyclic Ketones. /. Am. Chem. Soc. 2014,136,9556-9559. 

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. ... 

Scheme S. Electrophilic fluorination of Z-TMS enol ethers of N-trityl amino ketones...

In contrast, fluorinated ketones have been used as both nucleophilic and electrophilic reaction constituents The (Z)-lithium enolate of 1 fluoro 3,3-di-methylbutanone can be selectively prepared and undergoes highly diastereoselec-tive aldol condensations with aldehydes [7] (equation 8) (Table 4)... 

Fluorinated esters may also act as electrophiles in reactions with nonfluori-nated ketones [28] (equation 23) or malononitrile [29] (equation 24). Unfortunately, the yields of -diketones may be modest, but those of p-keto nitnles are excellent (Table 9)... 

Trifluoromethyl)trimethylsilane has been prepared by a modification5 of the procedure originally published by Ruppert.4 The optimized yield is 75%. Other less convenient methods are also available for its preparation. (Trifluoromethyl)trimethylsilane acts as an in situ trifluoromethide equivalent under nucleophilic initiation and reacts with a variety of electrophilic functional groups. Carbonyl compounds such as aldehydes, ketones and lactones react rather readily5 7 with (trifluoromethyl)trimethylsilane under fluoride initiation. The reagent also reacts with oxalic esters,8 sulfonyl fluorides,9 a-keto esters,10 fluorinated ketones,11 and... 

Although efficient organocatalytic methods for the electrophilic a-fluorination of aldehydes and ketones have recently been developed [7], high enantiomeric excesses can only be reached with aldehydes so far. The asymmetric inductions in the case of ketone fluorinations have remained low ee < 36%) [7a]. Thus, the a-silyl ketone-controlled stoichiometric asymmetric synthesis of a-fluoroketones 10 (Scheme 1.1.1) still constitutes a practical method. 

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