Fluoroketones, synthesis

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... 

Pubhcations have described the use of HFPO to prepare acyl fluorides (53), fluoroketones (54), fluorinated heterocycles (55), as well as serving as a source of difluorocarbene for the synthesis of numerous cycHc and acycHc compounds (56). The isomerization of HFPO to hexafluoroacetone by hydrogen fluoride has been used as part of a one-pot synthesis of bisphenol AF (57). HFPO has been used as the starting material for the preparation of optically active perfluorinated acids (58). The nmr spectmm of HFPO is given in Reference 59. The molecular stmcture of HFPO has been deterrnined by gas-phase electron diffraction (13). 

This topic has been reviewed [2, pp 94, 100-111, 130-134] All of the standard approaches to the synthesis of a compound like methyl 2-fluorostearate from methyl 2-bromostearate result mall yield of the 2-fluoro ester and the unsaturated esters. Although silver fluoride is not a new reagent, its use moist in wet acetonitrile to convert methyl 2-bromostearate to its fluoro ester is a departure from the traditional set of anhydrous conditions (Procedure 6, p 194) [71] In contrast, silver tetrafluoroborate converts a-chloroketones to their respective fluoroketones under anhydrous conditions. The displacement of less activated halogen groups by silver tetrafluoroborate to form their respective fluorides is novel Although silver tetrafluoroborate could not be used to convert an aliphatic terminal dichloromethyl or trichloromethyl group to its corresponding fluoro derivative, it is an effective fluorine source in other situations [72] (Table 8)... 

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. 

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. 

Enders D, Potthoff M (1997) Regio- and enantioselective synthesis of alpha-fluoroketones by electrophilic fluorination of alpha-silylketone enolates with N-fluorobenzosulfonimide. Angew Chem Int Ed Engl 36 2362-2364... 

Not offered commercially, CF3COOF did not gain as much popularity until the early 80 s when we modified its synthesis and showed that it can be an useful reagent in organic chemistry as for example in the preparation of fluorohydrins or a-fluoroketones (10,11) -(figure 2). 

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. 

Fluoro-2 -deoxyuridylate-5,10-methyl-enetetrahydrofolate-thymidylate synthetase complex, 309 synthesis of, 311, 312 Fluorodinitrobenzene, 64, 65 Fluoroketones, 131 4-Fluoro-3-nitroaniline, 264 4-Fluoro-3-nitrophenyl azide, 264, 266, 267, 269... 

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