Fluorination, Reformatsky reactions

OTHER ORGANOMETALLIC REAGENTS (see also Carbonylation, Fluorination, Reformatsky reaction) with acids and acyl derivatives with acid halides Benzylchlorobis(triphenyl-phosphine)palladium(II), 30 Cadmium, 60... 

Fluorine-containing compounds can also be synthesized via enantioselective Reformatsky reaction using bromo-difluoroacetate as the nucleophile and chiral amino alcohol as the chiral-inducing agent.86 As shown in Scheme 8-41, 1 equivalent of benzaldehyde is treated with 3 equivalents of 111 in the presence of 2 equivalents of 113, providing a,a-difluoro-/ -hydroxy ester 112 at 61% yield with 84% ee. Poor results are observed for aliphatic aldehyde substrates. For example, product 116 is obtained in only 46% ee. 

Gemcitabine (Gemzar ) is prepared from the 2,2-difluoro-2-deoxyribose, itself available by the addition of the Reformatsky reagent of ethyl bromodifluoroace-tate on the (R)-2,3-0-isopropylidene glyceraldehyde. The condensation of the corresponding mesylate with di(trimethylsilyloxy)pyrimidine provides gemcitabine [93]. The control of the stereoselectivity of the Reformatsky reaction is difficult (Fig. 30) [95]. Other approaches involving the fluorination of D-pyranoses have been proposed (Fig. 31) [96]. 

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. 

On the way to fluorinated target molecules, a CF2 group may be also incorporated in the ketone framework in this case drastic conditions are required to promote the Reformatsky reaction with ethyl bromoacetate (lb). The example reported in equation 19 was carried out on 100 g scale and was directed to the synthesis of a fluoro analogue 23 of the anticancer drug chlorambucil94. 

Ethyl bromodifluoroacetate is one of the fluorinated building blocks used most widely. There are scores of examples of the important Reformatsky reaction with aldehydes which occurs in THF/ether solvent mixtures, sometimes under sonication conditions (Eq. 62). 

Electron-withdrawing fluorine atoms are introduced on the methylenic a-carbon by the Reformatsky reaction of Boc-leucinal with ethyl bromodifluoroacetate in the presence of activated zinc dust with no diastereoselection. Under thermodynamic control, the y -isomer is obtained almost exclusively (Scheme 16)J15 The use of additives such as diethylaluminium chloride-silver(II) acetate enhances the chemical yield of the reaction, but also presents the disadvantage of being nonstereoselectiveJ78 ... 

Most peptidyl a,a-difluoroalkyl ketones are actually extended chains based on statone, rather than simple difluoromethyl ketones. The statone derivatives are based on pepstatin, which is an extremely potent peptide inhibitor of aspartic proteases. The difluoro derivatives of statone take advantage of both the electronegativity of fluorine and the potential for additional interactions between the protease and structures on the leaving group side of the inhibitor. 15 This dual nature is part of what makes a,a-difluoroalkyl ketones effective inhibitors of aspartyl proteases as well as serine proteases. There are three main methods of synthesizing peptidyl a,a-difluoroalkyl ketones (1) the Reformatsky reaction with peptide aldehydes (Section 15.1.4.2.1), (2) a modified Dakin-West reaction (Section 15.1.4.2.2), and (3) a Henry nitro-aldol condensation (Section 15.1.4.2.3). 

Reductive oxidation of />-nitrotoluene to -aminobenzaldehyde, 31, 6 Reformatsky reaction, 37, 38 Reissert s compound, 38, 58 Reissert reaction, 38, 58 Replacement, benzenesulfonate groups by bromine atoms, 31, 82 bromine, by a thiol group, 30, 35 by fluorine, 36, 40 chlorine, by an amino group, 31,45 by a thiol group, 32, 101 by iodine, 30, 11 by methoxyl, 32, 79 by nitrile, 36, 50 in an imido-chloride group by an anilino group, 31, 48 chlorine and nitro by ethoxyl radicals, 32,68... 

Reformatsky and Blaise reactions. 2-Fluoro-3-hydroxyalkanoic esters are accessible by a Reformatsky reaction using a-fluorinated haloesters to prepare the reagents. In some cases better results are obtained with diethylaluminum chloride as catalyst. ... 

Fluorinated L-nucleosides have also been reported. Compounds 47 (B=Ade, Cyt) have been prepared from L-xylose," and the same team have also made 2, 2 -difluorocompounds of type 48, the sugar being assembled using a Reformatsky reaction between ethyl bromodifluoroacetate and isopropylidene-L-glyceraldehyde. The adenosine analogue showed good anti-HIV activity with no cytotoxicity. ... 

In view of the pronounced interest in fluorinated compounds to be used in medicinal chemistry, the development of an enantioselective difluoro Reformatsky reaction appeared highly desirable. The first procedure for this transformation was disclosed by Braun and coworkers using various amino... 

The precursor was prepared via a lengthy sequence involving the elaboration of a Reformatsky adduct. The cyclic product was obtained as a 1.2 1 mixture of cis and trans isomers.The presence of the fluorine atoms had no effect on the efficiency of the cyclisation reaction. A subsequent study [384] extended the range of cyclisations to include trifluoromethyl alkyl and alkenyl radicals (Eq. 157). Free radical cyclisation reactions therefore show considerable promise for the rational synthesis of fluorinated carbocycles. 

Only a few enantioselective approaches to optically active 2,2-difluoro-3-hjrdroxy esters, key S)mthetic interme ates for a variety of important chiral fluorinated molecules, have been reported. Braun et al and Andrds et al. have independently reported that the Reformatsky reagents generated from bromodifluoroacetates react with aromatic aldehydes in the presence of stoichiometric amounts of chiral amino alcohols such as iV-methylephediine to afford the corresponding desired aldols in good optical yields (22,23). However, these methods are not catalytic, and the decrease in quantity of the chiral ligands dramatically suppresses the enantioselectivity. Thus, we became very interested in developing an unprecedented catalytic asymmetric aidol reaction of difluoroketene silyl acetals promoted by chiral Lewis acids. 

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