Fluoroalkyl ketone

Fluoroalkyl ketones may be used as the electrophilic partners in condensation reactions with other carbonyl compounds The highly electrophilic hexafluo-roacetone has been used in selective hexafluoroisopropyhdenation reactions with enol silyl ethers and dienolsilyl ethers [f] (equation 1)... 

The enhanced reactivity of fluoroalkyl ketones is also manifested in the failure to stop the reaction with hydrogen cyanide at the stage of cyanohydrins Instead, oxazohdinones or dioxolanones are formed (equation 11) If, however, the reaction IS conducted under basic conditions with sodium bisulfite and sodium cyanide, the desired cyanohydrin can be prepared [ll ... 

Partial control of enolate geometry occurs also when the enol phosphate, prepared by treatment of fluoroalkyl ketones with sodium diethyl phosphite, is... 

Fluoroalkyl ketone enolates and enol etliers have also been use in condensation reactions with ketones [22] Interestingly, these materials fail to undergo Dar/ens-type side reactions (equation 18)... 

Fluorinatedytides have also been added tofluoroalkylketones however, this olefination procedure may be accompanied by considerable side reactions resulting from deprotonation of the fluoroalkyl ketones In most cases, the yields are not better than 30% [39]... 

Stabilisation of the tetrahedral forms of fluoroalkyl ketones The presence of a fluoroalkyl group in a position of a carbonyl strongly enhances its electrophilicity, and hence its reactivity, towards nucleophiles. The anionic tetrahedral intermediates are stabilised by the electron-withdrawing group Rf (Fig. 20) [69,70]. This phenomenon is illustrated by the ability of fluoroketones to afford stable hydrates in aqueous medium. 

Figure 3.9 Influence of a fluoroalkyl group on the inhibition of HNE and the activity of peptidyl fluoroalkyl ketones. ...

Fluoroalcohol ethers, such as —O—CH2—Rf, or ketals of fluoroalkyl ketones. Their synthesis has been described only recently. 

A-Benzylimines 14k and I, derived from alkyl fluoroalkyl ketones, are less reactive in the base-catalyzed 1.3-proton shift reaclion. Thus, when 14k is kept in triethylamine solution at room temperature for 2 days, less than 5% conversion is detected.14 Either heating in triethylamine or the use of DBU effects the transformation at a preparatively acceptable rate and in good yield. Reaction of the benzyl trifluoromethyl ketone derivative 14m is expected... 

Peptidyl fluoromethyl ketones are widely used as fairly potent inhibitors for a variety of proteases, including serine, cysteine, and aspartyl proteases. Unlike other halomethyl ketones (Section 15.1.3), fluoromethyl ketones are reversible transition-state mimics. The electron-withdrawing fluorine(s) next to the carbonyl group enhances the electrophilicity of the a-fluoroalkyl ketone functionality, thereby making the carbonyl more susceptible to nucleophilic attack. a-Fluoroalkyl ketones are good mimics of peptide bonds due to the small size of the fluorine and the stability of C F bonds. There are three general classes of peptidyl fluoromethyl ketones fluoromethyl ketones (irreversible inhibitors of cysteine proteases), difluoromethyl ketones (reversible inhibitors of both serine and aspartyl proteases), and trifluoromethyl/perfluoroalkyl ketones, which typically exist in hydrated forms and are excellent inhibitors of both serine and cysteine proteasesJ1 ... 

Fluoromethyl ketones are one of the most widely used classes of peptidyl a-fluoroalkyl ketones, second only to trifluoromethyl ketones. Peptidyl fluoromethyl ketones are very effective as irreversible inhibitors of cysteine proteases the first reported use of a fluoromethyl ketone compound was the use of Z-Phe-Ala-CH2F as an irreversible inhibitor of cathepsin BJ2,31 Today, many lysine and arginine derivatives have been synthesized as potential inhibitors for trypsin and trypsin-like enzymesJ3 There are four basic methods for the synthesis of peptide fluoromethyl ketones (1) the reaction of HF with peptide diazomethyl ketones (Section 15.1.4.1.1), (2) a halogen-exchange reaction with a chloro-, bromo-, or iodomethyl ketone (Section 15.1.4.1.2), (3) a Henry nitro-aldol condensation reaction (Section 15.1.4.1.3), and (4) a modified Dakin-West acylation reaction (Section 15.1.4.1.4). 

Heath, T. G. Mooney, J. P. Broersma, R. 1997. Narrow-bore liquid chromatography-tandem mass spectrometry with simultaneous radioactivity monitoring for partially characterizing the biliary metabolites of an arginine fluoroalkyl ketone analog of D-MePhe-Pro-Arg, a potent thrombin inhibitor. J. Chromatgr. B Biomed. Sci. Appl., 688,281-289. 

Dipoles such as diazoalkanes PhC(R1)N2 undergo cycloaddition to fluoroalkyl ketones CF3COR2 to give A2-oxadiazolines (111) (78JA4260). Diphenylketene reacts in a similar manner with diphenyldiazomethane. 

Partial control of the enolate geometry also occurs when the enol phosphate 19, prepared by treatment of fluoroalkyl ketones with sodium diethyl phosphite, is treated with a lithium aluminum hydride/copper(II) bromide reagent. " These enolates 20 react with modest diastc-reoselectivity with aldehydes to give products 21. 

Fluoroalkyl ketones via their enolates and cnol ethers have also been employed in self-condensation reactions to give products 24. Interestingly, these materials fail to undergo Darzens-type side reactions. 

A-Acyl imines of fluoroalkyl ketones react exothermically with kctcncs and under mild conditions with enol ethers and alkenes to fonn [4+2] cycloadducts (Table 9). They also react with dipoles. In contrast to reactions with sulfonyi imines, competitive [2 + 2] or [2 + 1] cycloadditions or additions onto the imine function are not observed. The strong heterodiene properties of A-acyl imines are illustrated by the reactions of methyl 3.3.3-trifluoro-2-(tri-fluoroacetyliniino)propanoate with dienes which al.so provide 1,3-oxazines as the major product. The minor product is the result of [4 + 2] cycloaddition of the diene with the imine function (Table 9. final entry). ... 

Unsaturaled systems substituted with a fluoroalkyl group more readily undergo [4-I-2] than [2-f2] cycloaddition reactions (sec Section 2.1.1.6.2.1.1.). This preference has resulted in relatively few reported examples of [2-1-2] cycloaddition reactions to give four-membered rings. Most applications concern heterocycloaddition reactions involving fluoroalkyl ketonic and imino functions. 

Besides the easy photoinitiated [2 + 2] cycloadditions of fluoroalkyl ketones or aldehydes with fluoro-substituteci alkenes (see Section 2.1.1.6.1.), one example of such a photochemical cycloaddition with a non-fluorinated alkene has been described, leading to Irifluoromethyl-sub-stituted oxetanes However, the 1,4-diradical intermediate also provides large amounts of 2.3-dihydrofurans. 

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