A-Fluoroketones

Diazoketones [57] and esters [5S] react with hydrogen fluoride in organic solvents to give a-fluoroketones or esters, pyndinium poly(hydrogen fluoride) offers a convenient medium for the reaction (equation 13) [9]... 

Photochemically induced reduction of alkyl perfluoro carboxylates in hexa-methylphosphoramide (FfMPA) can replace one, two, or (in the case of tn-fluoroacetate) three a-fluonne atoms with hydrogen [7, S] (equation 5) Chlorine-containing fluorocarboxylates preferentially lose a-chlorme and may even lose P-chlorinc in preference to a fluonne [9] (equation 6) Cyclic a-fluoroketones are also defluonnated photochemically [10] (equation 7)... 

Fluormation ot carbon adjacent to heteroatoms invariably increases lipophili-city, as does fluormation of double bonds (Table 10), but a-fluormation of alipliatic carbonyl groups is an exception a-Fluoroketones or aldehydes that form stable... 

As with i -substituted allyl alcohols, 2,i -substituted allyl alcohols are epoxidized in excellent enantioselectivity. Examples of AE reactions of this class of substrate are shown below. Epoxide 23 was utilized to prepare chiral allene oxides, which were ring opened with TBAF to provide chiral a-fluoroketones. Epoxide 24 was used to prepare 5,8-disubstituted indolizidines and epoxide 25 was utilized in the formal synthesis of macrosphelide A. Epoxide 26 represents an AE reaction on the very electron deficient 2-cyanoallylic alcohols and epoxide 27 was an intermediate in the total synthesis of (+)-varantmycin. 

Typical proton and carbon chemical shift and coupling constant data for a-fluoroketones and aldehydes are given in Scheme 3.32, with data for esters being given in Scheme 3.33. 

Compounds having a cyclic double bond conjugated with an aromatic ring are capable of reacting with FCIO3 to give a-fluoroketones. This type of reaction was named oxofluorination and in it FCIO3 acts as a 2-center electrophile as shown for indene (207) ... 

On the contrary, trimethylsilyl enol ethers yield a-fluoroketones when reacting with Xe[ F]F2 [81] or [ F]F2 [101] (Scheme 20). In this way several aryl-a-fn [ F]fluoromethylketones were easily prepared in 22-28% radiochemical yields. 

Fluasterone is a stable adrenocortical steroid analogue ofprasterone (dehydroepi-androsterone (DHEA)) fluorinated at C-16a (Figure 8.85). It is currently being developed (Phase II) for the treatment of metabolic syndrome (i.e., insulin resistance). Electrophilic fluoration with NF type reagent is well adapted for the synthesis of such as a-fluoroketone (95%, a /i 95 5). ... 

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. 

Studies by Laurent et al. have shown the a number of a-fluoroketones can be produced by the electrochemical oxidation of enol esters in Et3N 3HF as electrolyte, following basic work-up [7]. 

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

Diazoalkanes react with ethyl fluoroformate [57] and acyl fluorides [87, 88] to give ethyl a-fluorocarboxylates and a-fluoroketones, respectively (equation 22) Table 7 lists examples of hydrofluonnation [6, 83, 89] and geminal difluori-nation [90] of aryldiazomethanes... 

In the case of electrophilic substrates, the peroxometallic adduct results from the bimolecular 1,3-dipolar cycloaddition of the peroxo moiety to a cyanoalkene (equation 43)143 188 or a fluoroketone (equation 44).138... 

Five research groups have investigated fluorination of enol acetates and silyl ethers with xenon difluoride, and mainly a-fluoroketones were formed22"24, 78-81. HF-catalyzed fluorination of cyclic enol acetates with xenon difluoride at room temperature gave a-fluorocycloalkanones, while the yield and contamination with cycloalkanones depend on... 

The regioselectivity in oxetane formation is probably determined primarily by the orientation of the CT complexes. Additions of a-fluoroketones, which have such low reduction potentials as to be particularly hot 132> and therefore potentially unselective acceptors, do proceed with negligible regioselectivity 126>. The actual product ratio is quite complex kinetically because of all the various competing reactions of four separate intermediates. 

Enders D, Faure S, Potthoff M, Runsink J (2001) Diastereoselective electrophilic fluorination of enantiopure a-silylketones using N-fluoro-benzosulfoni-mide regio- and enantioselective synthesis of a-fluoroketones. Synthesis 2001 2307-2319... 

Colburn and his co-workers found that N2F4 appears to catalyze the polymerization of some vinyl and related compounds (74), and this observation has been followed up to a certain extent in the patent literature. Difluorodiamine has also been shown to convert certain enamines to a-fluoroketone (20). 

Hydrofluorination of corresponding C=N bonds of isocyanates and diazoketones gives carbamyl fluorides and a-fluoroketones repectively [43]. 

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. 

Denmark and Matsuhashi achieved only moderate success in the asymmetric epoxidation of phenylcyclohexene and indene catalyzed by novel chiral a-fluoroketones 57 and 58 (Scheme 22) <2002JOC3479>. 

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