Ketones fluoroketones

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. 

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. 

The enol acetates from acetophenone, benzylphenyl ketone, isopropylphenyl ketone, benzylmethyl ketone, and tetralone gave the corresponding a-fluoroketones, in a similar fashion. 

Fig. 26 The elimination of HF from the 0-fluoroketone [68] is catalysed by antibody 1D4, elicited to hapten [70], to form the disfavoured (Z)-olefin [71]. This contrasts with the spontaneous process in which an anti-elimination reaction yields the ( )-<, 0-unsaturated ketone [69], The syn-eclipsed conformation of [70] is shaded.

Fluoroketone analogues are also inhibitors of esterases. For example, the difluoro-ketone analogue 36 of sn-glycerol phospholipids is a potent competitive inhibitor of phospholipase A27 while the trifluoromethyl ketone 37 analogue of an insect juvenile hormone 38 is a potent and selective inhibitor of juvenile hormone esterase78. 

Silyl enolates are useful starting materials for the smooth a-halogenation of ketones, which can be carried out by oxidation with A-halosuccinimides , halogens and iodoben-zenedifluoride or xenon difluorides. As shown in equation 32 , the reaction of 45 with Xep2 gives a 1 1 mixture of a-fluoroketone diastereoisomers 46a and 46b. 

Perchloryl fluoride (FCIO3) converts enamines into "a-" fiuoroirmnium salts 13) which afford the a -fluoroketones after hydrolysis [226]. Steroidal 3-aminO 3,5-dienes react at C(4) to give 4-fluoro- and 4,4 difluoro-A5-3-ketones [204a, 22, 22 ] the former are readily isomerised to give 4-fluoro-A -3-ketones [22y]. 

Synthesis of the perfluoroalkyl P-amino alcohol 5 (70) required for the preparation of the perfluoroalkyl ketone VI as shown in Scheme 2 is illustrative of the method used to prepare analogous compounds. Tm-butyloxycarbonyl-L-cyclohexylalaninal 4 was condensed with perfluoroethyl or perfluoropropyl lithium which was generated in situ by the addition of methyllithium-lithium bromide complex to the corresponding perfluoroalkyl iodide. The alcohol 5 was isolated as an epimeric mixture which was used in the preparation of peptide IV. Oxidation using the Dess-Martin periodinane reagent (9) yielded the fluoroketone VI. 

The synthesis of the fluoroketone that combines the retroamide type bond (76) is shown in Scheme 5. The 2,2-difluoro-3-hydroxyester 11 from a Reformatsky reaction was converted to the primary amide 12 by treatment with ammonia in diethyl ether. Reduction of the amide with borane dimethyl sulfide and protection of the resulting amine gave the protected intermediate 13. For the preparation of peptides XIV and XV, the hydroxy function was oxidized to the corresponding ketone using pyridinium dichromate. 

The electronic arrangement of the carbonyl function in fluoroketones more closely resembles the double bond of weakly polarized olefins than it does the carbonyl group in normal hydrocarbon ketones, and fluoroketones may therefore undergo free-radical reactions more readily than their hydrocarbon counterparts (3). 

A fluorous medium has been utilized for alkcnc epoxidation employing the dioxirane derived from the fluoroketone 14, which is also effective in catalytic quantities with Oxone as the terminal oxidant. For example, treatment of tro w-4-decene (13) with 5 mol% of ketone 14 and 1.5 equiv of Oxone in a bicarbonate buffered water exanuoroisopropanol (HFIP) medium led to the quantitative formation of the corre.sponding epoxide 15 <01TL4463>. 

Ketones cannot be directly fluorinated by (difluoroiodo)arenes however, a-fluoroketones can be prepared by the reaction of silyl enol ethers with difluoroiodotoluene in the presence of BF3 OEt2 and the Et3N-HF complex [22], Some steroidal silyl enol ethers can be converted into the respective a-fluoroketones in a moderate yield [23]. 

---