Reaction with fluoroalkyl ketones

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. 

Fluoroalkyl heterocycles Condensation of o-functionalized (OH, SH, NH2) anilines with fluoroalkyl ketones leads to benzoxazolines, benzthiazolines, benzimida-zolines,... bearing a fluorinated carbon chain at C-2. The reaction is promoted by Ga(OTf )3. 

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 ... 

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)... 

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). 

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). ... 

Peptide Fluoromethyl Ketones Fluoroalkyl derivatives of the peptide chloromethyl ketones have been prepared in an attempt to improve specificity by reducing nonspecific alkylation at cysteine residues (Rasnick, D., Synthesis of peptide fluoromethyl ketones and the inhibition of human cathepsin B, Anal. Biochem. 149, 461 65, 1985). Nonspecific reaction with sulfydryl groups such as those in glutathione was reduced there was still reaction with active site cysteine although at a slower rate than with the chloroalkyl derivative (16,200 M s vs. 45,300 1 2 21.9 min. vs. 

A successful photochemical cycloaddition of various fluoroalkyl ketones, aldehydes, and acyl fluorides to fluoroolefins was reported by Harris and Coffman. Originally it was reported that among four possible stereoisomers, only the regioi-somers of type A with CF2 unit next to oxygen were formed (Scheme 2.3). It was rationalized that the reaction proceeds through the most stable diradical intermediate. The yields of oxetanes in this reaction varied mostly from 30% to 70% when X = CF3 and were about 15% for X = Cl. Presumably the mechanism of this reaction involves... 

Similar to the Dakin-West procedure previously mentioned, the Henry nitro-aldol condensation reaction is most widely used to synthesize trifluoromethyl ketones, although there are many examples of a,a-difluoroalkyl ketones synthesized by this method (Table 6)JU 12271 The method for a,a-difluoroalkyl and trifluoromethyl ketone synthesis is identical except for the final oxidation although fluoroalkyl and a,a-difluoroalkyl ketones are easily oxidized by the Sarett method (Cr03/pyridine),[12 the corresponding trifluoromethyl ketones can only be oxidized under basic conditions (0.3 M NaOH) with KMn04Jul Also, in some of the syntheses of a,a-difluoroalkyl ketones, the nitro alcohol intermediate was protected by si-lylation with /ert-butylchlorodimethylsilane. The silyl group was later removed by TosOH prior to oxidation. The full details of this method are given in Section 15.1.4.3.2. 

In this section the synthesis of fluoroalkyl (Section 15.1.4.1.3), a,a-difluoroalkyl (Section 15.1.4.2.3), and trifluoromethyl- and perfluoroalkyl ketones are discussed collectively. The second most widely used method for synthesizing peptide fluoromethyl ketones is the Henry nitro-aldol condensation reaction, which involves the use of (3-nitro alcohols to build the fluoromethyl ketones. As with the modified Dakin-West procedure, the Henry reaction has also been used to synthesize mono-, di-, tri-, and extended fluoromethyl ketones, making it another extremely versatile synthetic method.19 12 19 27 29 33 341 However, similar to the Dakin-West procedure, the products of the Henry reaction are not chiral, since an achiral carbanion is involved in the crucial carbon bond forming step. 

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