Fluorination, -keto esters

Importance of enol formation for y keto ester fluorination... 

On treatment with DAST, keto esters undergo oxidative fluorination- ethyl acetoacetate and DAST in W-methylpyrrolidone give a 48-58% yield of a mixture of equal parts of ethyl cis- and trans-2,3-difluoro-2-butenoate [200] (equation 100)... 

Enolate anions of p-keto esters react with some fluoroolefms, initially by replacement of a vinylic fluorine atom, to give ultimately heterocyclic products [2S, 29] (equation 25). 

A fluorinated keto ester reacts as an electrophile with hydrides, giving a hydroxy ester in a highly stereoselective reduction [30] (equation 25). 

GL 4] [R 5] [P 5] The rate of the fluorination of y0-keto esters is usually correlated with the enol concentration or the rate of enol formation as this species is actually fluorinated [15, 16]. For the fluorination of ethyl 2-chloroacetoacetate in a micro reactor, much higher yields were found as expected from such relationships and as compared with conventional batch processing which has only low conversion. Obviously, the fluorinated metal surface of the micro channel promotes the enol formation. 

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... 

Diketones react more rapidly with fluorine than the corresponding keto-esters, and dialkyl malonates do not react at all under these conditions. However, if dialkyl malonates are first converted into their sodium salts, reaction with fluorine gives the corresponding fluoro-compound (Fig. 50) [128]. 

Results of fluorination of P-keto esters with sullur tetrafluoride depend on the presence of hydrogen on the a-carbon Unsubstituted aceto- and propiony-lacetates give 3,3-difluoroalkanoates, 3 fluoro 2-aIkenoates, and 2 alkynoates... 

The asymmetric fluorination of /3-keto esters has been performed in the presence of various catalysts, such as CpTiCl3,155 chiral rare earth perfluorinated organophos- phates,156 and chiral palladium complexes.157... 

Interestingly, cyclic / -keto esters, e.g. 69, can be also fhiorinated with enantioselectivity up to 80% ee, although the yield and enantioselectivity depend strongly on the type of substrate. A representative example of asymmetric fluorination of a cyclic ester is shown in Scheme 3.27, Eq. (2). In addition, oxindoles 71 have been successfully fhiorinated, as shown in Scheme 3.27, Eq. (3). Under optimized conditions, the desired 3-substituted 3-fluorooxindole, 72, was obtained in 79% yield and with enantioselectivity of 82% ee. 

This microflow processing was also demonstrated using other P-keto esters such as ethyl 2-chloro-3-oxobutanoate [309,273] or ethyl 2-methyl-3-oxobutanoate [273]. Five-and six-ring P-ketoester derivatives such as 3-acetyl-3,4,5-trihydrofuran-2-one (1) [273], 2-acetyl cyclohexanone [273] and ethyl 2-oxocydohexane carboxylate (2) [273] were directly fluorinated as well. 

These are the first reagents known to effect enantioselective fluorination of enolates of carbonyl compounds. The highest enantioselectivity is observed in the reaction of (-)-l with a p-keto ester (equation I). 

Xu, Y., Wang, Y., Zhu, S. Reactions of fluoroalkanesulfonyl azides with carbocyclic 3-keto esters structural influence of dicarbonyl substrate on distribution of diazo and ring-contraction products. J. Fluorine Chem. 2000,105, 25-30. 

It can be seen that for 4 -trifluoromethyl acetophenone (entry 4), the initial rate is higher than for the other compounds. It seems that there is an activation of the ketone group by the three fluorine atoms through the aromatic ring. At the other end, no conversion was observed for isopropyl-formiate-benzoyle (entry 3) This can be attribute to the low activity of the a-keto-ester-group or because of the insolubility of the molecule in the polymer. 

Currently, a significant body of work deals with the use of chiral cationic palladium complexes bearing ligands of the BINAP type or related bisphosphine ligands such as SEGPHOS (Fig. 3). These are based on the pioneering work from Sodeoka on the direct formation of chiral palladium enolate complexes from the palladium precursors and 1,3-dicarbonyl compounds [10, 23]. Within this context, the combination of cationic BINAP-Pd complexes and N-fluoro-bis(phenylsulfonyl)imine (NFSI) was introduced by Sodeoka for the realization of an extremely efficient a-fluorination of 3-keto esters (Scheme 5). 

Scheme 5 Fluorination of 3-keto esters with chiral bisphosphine palladium catalysts, (a) After aminolysis with benzylamine. (b) With 5 mol% catalyst and 50 mol% lutidine...

Scheme 12 Enantioselective fluorination of 3-keto esters employing Ru catalysis...

Copper complexes bearing bisoxazolines were described by Cahard [44]. Ligand 7 induces moderate to good enantiomeric excesses in the fluorination of 3-keto esters. Bolm described the application of chiral sulfoximine 8 as ligand for copper triflate and subsequent application of this catalyst in all three halogenation reactions of chlorination, bromination and fluorination employing various 3-keto esters [45]. 

Finally, Inanaga reported a rare example of scandium catalysis with a preformed complex bearing a fluorinated axial chiral phosphonate. This fluorination of 3-keto esters employed N-fluoro pyridinum triflate as reagent, a rare case in which NFSl did not represent the superior reagent [46]. 

Efficient enantioselective fluorination of the S-keto ester 23 with (PhS02)2NF was achieved by using the (i )-DM-BlNAP-Pd(II) complex in EtOH to give 24 with 91 % ee in 96 % yield, which was converted to a pharmaceutically important a-fluoro-i -amino acid ester 25 [6]. 

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