A-Fluorinated ketone

Enamines from steroidal ketones have been fluorinated by means of perchloryl fluoride (119,120) to give the a-fluorinated ketones. Theenamino ketone (49) was brominated to give a salt from which the bromoenamino ketone (175) was isolated on treatment with dilute carbonate solution (121). 

For instance, the telechelic diols were prepared from phenol, a fluorinated ketone and HF according to the following reaction ... 

Lithiated di- and monofluorinated enol carbamates 566844 847 and 567848 are fluorine-containing acyl anion equivalents, which allow the synthesis of a-fluorinated ketones. 

Scheme 4.28 Irreversible binding of a-fluorinated ketone-based protease inhibitors to their target enzyme via a hemiketal [60].

Cyclic a-fluorinated ketones undergo solvent-assisted addition of TMSCN in DMF, giving TMS-promoted cyanohydrins in good yields and up to 91% de, with the c/i -product predominating. Interaction of the carbonyl of DMF with TMSCN is proposed to activate the reagent, by weakening the Si-CN bond. Simple reduction of the product with lithium aluminium hydride affords the corresponding fluorinated 1,2-amino alcohols. 

The Behenna-Stoltz protocol was soon applied to a-fluoroketones. As shown in Scheme 5.26, the silyl enol ethers 80 of 2-fluoro-indanone, tetralone-, and ben-zosuberone can be reacted with allyl or methallyl carbonate to give the tertiary a-fluorinated ketones 81 in 83-95% ee [43]. The procedure that was also applied to an allylation of 4,4-dimethyl-6-fluorocyclohexenone offers an alternative to the enantioselective fluorination of enolates on the one hand and the decarboxylative allylation of fluorinated P-keto esters on the other hand vide infra). 

In 1998, Armstrong et al. reported a-fluorinated ketone 370a which provided 64% ee for the epoxidation of methyl cumamate [252], Better enantioselectivies are achieved with from (-)-quinic acid derived ketones 404a and 427 for the epoxidation of ethyl cinnamate (86% 404a, 89% ee 427) as reported by Wang et al. in 1999 (Fig. 7.23) [282],... 

Fig. 7.23 (-)-Quinic acid derived ketones and a-fluorinated ketone catalysts...

A -dien-3-ol ethers gives rise to 6-substituted A" -3-ketones. 6-Hydroxy-A" -3-ketones can be obtained also by autooxidation.Structural changes in the steroid molecule may strongly affect the stability of 3-alkyl-A -ethers. Thus 11 j5-hydroxyl and 9a-fluorine substituents greatly increase the lability of the enol ether/ while halogens at C-6 stabilize this system to autooxidation and acid hydrolysis. 

The enamines, enol ethers and enol acetates of A -3-keto steroids provide important substrates for fluorination with FCIO3. Reaction of such A -enol ethers and acetates (6) with perchloryl fluoride results in 6a- and 6jff-fluoro-A -3-ketones (7) and (8), the latter representing the more abundant isomer. Tetrahydrofuran or dioxane-water mixtures appear to be particu-... 

It is more reactive than perchloryl fluoride and therefore not without danger. It forms, for instance, a highly explosive product with pyridine. 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... 

In the course of synthetic efforts aimed at obtaining 6j5-fluoro steroids, Kirk and Petrow treated a 3)5-acetoxy-6-raethyl-5a,6a-epoxide with boron trifluoride etherate and unexpectedly obtained a fluorine-free acetoxy ketone." Later transformations established that the product was the A-homo-B-norsteroid (104). 

Diazoketones react with trifluoromcthyl hypofluorite to give a mixture of a,a-difluoro ketones and o-fluoro-a-trifluoromethoxy ketones [70, 71] With elemental fluorine, two fluorine atoms replace the nitrogen in both diazoketones and unactivated diazo eompounds [70, 72, 73] (equation 9)... 

Similarly, fluorinated ketones are prepared and react with enamines [50], This reaction involves the intermediacy of an a,P-ethylenic ketone and leads to annelation-aromatization products [5tJ] (Table 13) (equation 37). 

Another reaction that has potential is the intramolecular ene reaction, which preferentially results in five-membered rings Because fluorinated ketones have a propensity for undergoing intermolecular ene reactions [5S], this reaction has tremendous synthetic possibilities Only one example of an ene reaction of an unsaturated trifluoromethyl ketone has been reported, but it indicates the potential of the methodology [59] (equation 59)... 

Hexafluoroacetone and certain perfluorinated or partially fluorinated ketones, aldehydes, and imines react with a-functionalized carboxylic acids (e.g., a-amino, a-At-methylamino [S3, 84], a-hydroxy [S5], and a-mercapto [Sd] acids) to give five-membered heterocyclic systems (equation 13). 

Rearrangement of fluorine with concomitant ring opening takes place in fluorinated epoxides Hexafluoroacetone can be prepared easily from perfluo-ropropylene oxide by isomerization with a fluorinated catalyst like alumina pre treated with hydrogen fluoride [26, 27, 28] In ring-opening reactions of epoxides, the distribution of products, ketone versus acyl fluoride, depends on the catalyst [29] (equation 7) When cesium, potassium, or silver fluoride are used as catalysts, dimenc products also are formed [29]... 

Kilbardin, A.M., Gazizov, T.K., and Pudovik, A.N., Reactions of diethyl tri-methylsilyl phosphite and of acetyl diethyl phosphite with fluorinated ketones,. Gen. Chem. U.S.S.R., 45,1947,1975. 

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... 

A series of fluorinated biaryl ketones (13) was reported by Denmark and coworkers in 1999 and 2002 (Fig. 4) [22, 40]. The introduction of fluorine atoms at the a-position of the reacting carbonyl increased the efficiency of the epoxidation. Fluorinated ketones 13b and 13c displayed high reactivity and good enantioselectivity... 

Di- and trifluoromethylketones inhibit a great number of esterases and proteases with often very high inhibition constants. Although the fluorinated ketone... 

Di- and trifluoromethyl ketones inhibit a great number of esterases and proteases with often very high inhibition constants (cf. Chapter 7). Although the fluorinated ketone is covalently bonded to the nucleophilic residue of the enzyme, the inhibition is reversible, as the inhibitor could be displaced by another nucleophile. The covalent nature of the interactions as well as the tetrahedral structure of the adducts have been demonstrated by kinetic studies, by NMR experiments, and by the X-ray diffraction of the enzyme-substrate complexes. ... 

In some cases, the product depends on the nature of the acylating agent. Acylation of 182 with 2,2-difluoro-4-pentenoic acid anhydride leads to acylation at C, whereas acylation with 2,2-difluoro-4-pentenoic acid choride yields the 5-acyloxyoxazole 185 as the major compound. The 5-acyloxyoxazole can be rearranged to the 5(47/)-oxazolone 183 upon treatment with 4-(dimethylamino)pyridme. Treatement of 183 with anhydrous oxalic acid promotes decarbonylation to give fluorinated a-amino ketones 184 (Scheme 7.55). Selected examples of 4-acyl-5(4//)-oxazolones are shown in Table 7.20 (Fig. 7.22). 

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. 

Other a-fluorinated carboethoxy substrates have been utilized in Reformatsky reactions. Treatment of ethyl dibromofluoroacetate with aldehydes or ketones in presence of zinc and EtaAlCl gave diastereomeric a -brorno-a-fluoro /i-hydroxyalkanoic esters in good yield (49-77%) (equation 120)177. Use of 2 equivalents each of RCHO, Zn and Et2AlCl gave the double coupled products in good yield. 

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