Difluoro Reformatsky reaction

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... 

An enantioselective difluoro Reformatsky reaction with imines was disclosed recently by Ando and coworkers. According to this valuable procedure, , -difluoro-P-lactams are obtained directly due to an in situ condensation following the addition of the zinc enolate. For this purpose, ethyl bromodifluoroacetate 324b was allowed to react with Af-benzyl-protected imines 391 that are derived from aromatic aldehydes. Diethyl zinc was used to generate the zinc enolate. When the reaction was mediated by the amino alcohol 323, required in equimolar amounts, P-lactams 392 were obtained in fair chemical yields and remarkably... 

Scheme 5.102 Enantioselective preparation of p-lactams 392 through imino difluoro Reformatsky reaction...

The indium-mediated aqueous Reformatsky reaction was used in the synthesis of a,a-difluoro- 3-hydroxy ketones (Eq. 8.93).236... 

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. 

In this reaction, the CH2C12/DMF solvent (9 1) suppresses the undesirable Claisen condensation and increases the yield of 2,2-difluoro-3-hydroxyesters. It is notable that high yields are obtained even with ketones and enolizable aldehydes, which do not undergo the Reformatsky reaction. 

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]. 

A Rh-catalyzed Reformatsky reaction of chiral imine (24) led to the stereoselective preparation of the a,a-difluoro-jS-amino acid (25). 25 was converted to difluor-oalkene (26), and subsequently L-Val-i/r[(Z)CF=CH]Gly derivative (23) in greater than 82% for both steps. The samarium diiodide-mediated reductive transformation of the y,y-difluoro-a, S-enoates proceeded via successive two-electron transfers to form a dienolate species which upon kinetically controlled trapping with fert-BuOH formed 23 (Scheme 6). 

A similar Reformatsky reaction, prepared from the cheaper precursor, ethyl chlorodifluoroacetate in dry DMF, has been reported by Lang and Schaub [259] (Scheme 85). Later, Lang demonstrated the preparation of 2,2-difluoro-4-pente-... 

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). 

A Sml2-mediated Reformatsky reaction involving formaldehyde as the electrophile has been exploited by Otaka in a synthesis of a dipeptide isostere treatment of y,y-difluoro-ot,p-enoate 130 with Sml2 in the presence of in situ-generated formaldehyde gave adduct 131 in good yield (Scheme 5.92).145... 

Reformatsky reaction of ethyl bromodifluoroacetate with Ay9-(dibenzyl)-l//-benzotriazolyl-1-methylamine 174 gave the fully protected a,a-difluoro-p-alanine 175 <03TL2375>. Hydrogenolysis and hydrolysis furnished a,a-difluoro-p-alanine 176. This methodology was also applied to the synthesis of A-protected 3,3-difluoroazetidin-2-ones <03S2483>. 

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. 

Reformatsky reaction. Reformatsky reagents are known to react with imines to afford P-lactams. The reaction can he applied to the synthesis of a,a-difluoro-p-lactams, and even chiral products. ... 

Bieber reported that the reaction of bromoacetates is greatly enhanced by catalytic amounts of benzoyl peroxide or peracids and gives satisfactory yields with aromatic aldehydes. A radical chain mechanism, initiated by electron abstraction from the organometallic Reformatsky reagent, is proposed (Scheme %.21)P However, an alternative process of reacting aldehydes with 2,3-dichloro-l-propene and indium in water followed by ozonolysis provided the Reformatsky product in practical yields.An electrochemical Reformatsky reaction in an aqueous medium and in the absence of metal mediator has also been reported. The indium-mediated aqueous Reformatsky reaction was used in the synthesis of a,a-difluoro-P-hydroxy ketones (Eq. 8.93). ... 

Boyer, N. Gloanec, R De Nanteuil, G. Jubault, R Quirion, J.-C. Chemoselective and stereoselective synthesis of gcm-difluoro-P-aminoesters or gcm-difluoro-P-lactams from ethyl bromodifluoroacetate and imines during Reformatsky reaction. Tetrahedron 2007, 65(50), 12352-12366. 

Taguchi, T. Kitagawa, O. Suda, Y. Ohkawa, S. Hashimoto, A. litaka, Y Kobayashi, Y. Synthesis of 3,3-difluoro-2-azetidinones and 2,3-dideoxy-2,2-difluoro-3-amino-sugars through the reformatsky reaction of difluoroacetate with imine. Tetrahedron Lett. 1988, 29, 5291-5294. 

Furthermore, 2,2-difluoro-3-hydroxyesters are readily obtained from ClCFjCOOMe and carbonyl compounds by electrolysis in a one-compartment cell using a sacrificial zinc anode and a nickel complex as catalyst. The catalytic cycle for this reaction is shown in Scheme 9 with nickel zinc exchange being a key step. In this process, the CHjCyDMF solvent (9 1) system leads to suppression of undesired Claisen condensation and an increase in the yield of 2,2-difluoro-3-hydroxyester formation. It is notable that high yields are obtained even with ketones and enolizable aldehydes, which are not good participants in the Reformatsky reaction alternative for producing these substances. 

Scheme 4.82 Rhodium catalyzed difluoro imine Reformatsky reaction of menthyl ester 378 for the synthesis of difluoro p-lactams 379.

Later, different amino alcohols were used for the same type of difluoro Refor-matsky reactions [158], and the extension to prochiral ketones was reported recently [171]. In addition, protocols for monofluoro Reformatsky reactions were disclosed that lead to products with moderate diastereoselectivity but remarkable enantioselectivity for the individual diastereomers [172]. All these protocols have in common that they are not catalytic and the chiral additive needs to be applied at least in stoichiometric amounts. Thus, it seems that protocols for an enantioselective catalytic difluoro Reformatsky as well as difluoro aldol reaction are still missing. 

Ethyl chlorodifluoroacetate has been used in a silicon-induced Reformatsky-Claisen reaction of allyl chlorodifluoroacetates in the presence ot zinc as a route to 2,2-difluoro unsaturated acids [( S] (equahon 58) When this methodology is applied to chlorodifluoropropargylic esters, the corresponding allenic esters are formed [SS]... 

In 1984, Fried et al. reported the reaction of bromodifluoroacetate with carbonyl substrates in the presence of zinc. The a,a-difluoro /1-hydroxyester was obtained in good yield without isolation of the Reformatsky reagent [240, 241] (Scheme 80) Later, this zinc reagent has also been prepared via reaction of ethyl bromodifluoroacetate with zinc amalgam in triglyme [242] or reaction of methyl iododifluoroacetate with zinc in acetonitrile [243]. 

Oxazolidine 130 is a masked aldimine bearing a chiral N-(2-hydroxy-l-phenyl)ethyl moiety and is readily available from (R)-phenylglycinol. Mannich reaction of 130 with Reformatsky reagent of ethyl bromodifluoroacetate produces difluorolactam 131 in high diastereoselectivity, which is then transformed to enantio-enriched (S)-3-amino-2,2-difluoro-3-phenylpropanoic acid 133 (see Scheme 9.28) [55]. 

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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