Reformatsky reagent

The reactions of ketenes or ketene equivalents with imines, discussed above, all involve the imine acting as nucleophile. Azetidin-2-ones can also be produced by nucleophilic attack of enolate anions derived from the acetic acid derivative on the electrophilic carbon of the imine followed by cyclization. The reaction of Reformatsky reagents, for example... 

Another useful application of these Reformatsky reagents is their conversion to difluaraketene silyl acetals and subsequent reaction of these ketene silyl acetals with electrophiles [86, 89, 90] (equation 59)... 

A similar allyl [91] or propargyl [92] Reformatsky reagent has been used to prepare fluormated homoallylic or homopropargylic alcohols, respectively [91, 92] (equations 60 and 61)... 

Likewise, a cis-2,6-disubstituted piperidine natural product, (-)-lobeline (98, Scheme 8.4.30) was synthesized from the chiral Af-alkyl pyridinium salt ent-80 via a sequence that included addition of a Reformatsky reagent to an intermediate oxazolidine. °... 

Alkylzinc halides have also been prepared under microwave irradiation. The Reformatsky reagents (2-t-butoxy-2-oxoethyl)zinc bromide and [(2-dibenzylamino)-2-oxoethyl]zinc bromide were synthesized from the corresponding bromides via reaction with zinc in THF (Scheme 5) [24], The oxidative addition was executed at 100 °C in 5 min. The obtained reagents were subsequently used in Negishi reactions on 2-bromopyridine, 3-bromopyridine, 2-bromo-5-nitropyridine, and 2-bromo-5-trifluoromethyl-pyridine using Pd(PPh3)4 as a catalyst (Scheme 5). 

Specific enol equivalents will be needed for both synthons (61) and (66), Since (61) is to give a double bond but (66) is to give an alcohol, the logical choices are a Wittig reagent - actually (67) - for (61) and a Reformatsky reagent for (66). The ester to aldehyde conversion (65 63) Is easiest by over-reduction and re-... 

Scheme 2.23 provides some examples of conjugate addition reactions. Entry 1 illustrates the tendency for reaction to proceed through the more stable enolate. Entries 2 to 5 are typical examples of addition of doubly stabilized enolates to electrophilic alkenes. Entries 6 to 8 are cases of addition of nitroalkanes. Nitroalkanes are comparable in acidity to (i-ketocslcrs (see Table 1.1) and are often excellent nucleophiles for conjugate addition. Note that in Entry 8 fluoride ion is used as the base. Entry 9 is a case of adding a zinc enolate (Reformatsky reagent) to a nitroalkene. Entry 10 shows an enamine as the carbon nucleophile. All of these reactions were done under equilibrating conditions. 

Fig. 7.5. Crystal structure of Reformatsky reagent of (-butyl bromoacetate crystallized from THF. Reproduced from J. Chem. Soc., Chem. Commun., 553 (1983), by permission of the Royal Society of Chemistry.

The Reformatsky reaction is related to both organometallic and aldol addition reactions and probably involves a cyclic TS. The Reformatsky reagent from /-butyl bromoacetate crystallizes as a dimer having both O—Zn (enolate-like) and C—Zn (organometallic-like) bonds (see Figure 7.5).165... 

Several techniques have been used to activate the zinc metal and improve yields. For example, pretreatment of zinc dust with a solution of copper acetate gives a more reactive zinc-copper couple.168 Exposure to trimethylsilyl chloride also activates the zinc.169 Wilkinson s catalyst, RhCl(PPh3)3 catalyzes formation of Reformatsky reagents from diethylzinc, and reaction occurs under very mild conditions.170... 

Arylations have also been extended to zinc enolates of esters (Reformatsky reagents).178... 

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 8.27).233 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.234 An electrochemical Reformatsky reaction in an aqueous medium and in the absence of metal mediator has also been reported.235... 

The reaction of a nitrile with a Reformatsky reagent is known as the Blaise reaction and when applied to (9-trimethylsilyl cyanohydrins leads to the formation of tetronic acids with high ee [79]. By working-up the Blaise reaction with ammonium chloride it is possible to isolate... 

Reformatsky reagent 214 also reacted with cr-nitrostyrenes 215 to form the corresponding 1,4-addition products 216 in good yields (Scheme 121).320 The optimal conditions for the reaction were determined to be 48 h at 60 °C. A 3 1 mixture of C6H6-THF gave better yields than THF alone, although the latter is the most common solvent for this type of reaction. 

Most recently, Bentz and co-workers established that the Pd-catalyzed a-arylation of esters and amides, using Reformatsky reagents and the corresponding aryl bromides, can be successfully performed under microwave conditions.417 The reported yields are somewhat lower than those reported by Hartwig 414 however, this approach does not require the use of Q-phos and can be considered as valuable alternative for a-arylation. 

Moreover, Soai et al.53c found that the enantioselective addition of Reformatsky reagents to prochiral ketones proceeds well when N,N-dialkylnorephedine 59 is used as the chiral ligand. When (15, 2R)-59a is used, the //-hydroxyl ester is obtained in 74% ee and 65% yield with ( -configuration predominant. When (lR,25,)-59a is used, the product is obtained in 74% ee and at 47% yield with (R)-configuration prevailing. 

At the other extreme of reactivity, 2-bromopyridine had to be transformed into the corresponding iodide to achieve good efficiency for the coupling reaction [14], For example, D-altro-2-(2,4 3,5-di-0-benzylidenepentitol-l-yl)-6-bromopyridine (17) was first converted to the corresponding iodide 18, which was then allowed to react with the Reformatsky reagent to give adduct 19. 

The Reformatsky reagent from 2a shows only slight diastereoselectivity in reactions with aldehydes but reactions with 2b give 2,3-vyn-aldols as the major prod-... 

Improvement to the Reformatsky reactions was achieved (53) by the use of a highly activated zinc - silver couple dispersed on the surface of graphite. T reatment of protected aldono-1,4-lactones 10b or 25b and 1,5-lactones 51a or 51b with a Reformatsky reagent prepared from a-haloesters or alkyl 2-(bromomethyl)acrylates resulted in the formation of the corresponding 3-or 4-glyculofuranos (or pyranos)onates 49a,b-50a,b, or 52a,b, respectively, under mild conditions (— 40 ° to 00) and in very good yields. Ethyl 2-deoxy-2-fluoro (and 2-bromo)-a-D-wa o-3,6-furanos-3-octulosonate derivatives were also obtained. 

The mechanism of the ZnBr2-assisted, nickel-catalyzed Reformatsky reaction has been discussed [540]. The reaction involves the electroreduction of a Ni(II) complex to a Ni(0) complex, oxidative addition of the a-chloroester to the Ni(0) complex, and Zn(II)/Ni(II) transmetallation, leading to an organozinc Reformatsky reagent. Most recently, the Reformatsky reaction... 

This strategy also provides a convenient method for amination of various ester enolates with DPH Ih (Scheme 14). The amination of lithium eniminate of phenyl acetonitrile, the silyl enolate of ethyl phenylacetate and the Reformatsky reagent derived from ethyl a-bromoacetate with DPH were found to be unsuccessful. A failure of DPH for the amination of sodium enolates of S-diketones and the lithium enolate of 3-methylbutanoic acid was also reported . 

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]. 

Silylacetals of difluoroketene have an important synthetic potential and constitute an alternative to the Reformatsky reagent generated from ethyl bromodifluoroace-tate." They are prepared by reduction by a bromo-, iodo-di-, or trifluoroacetate in the presence of a trialky Isilylchloride. Despite the fact that they are difficult to prepare, they behave similar to their nonfluorinated analogues (aldolization reactions, conjugated addition, etc.) (Figure 2.27)." ... 

Condensation of the Reformatsky reagent of ethyl bromodifluoroacetate with an imine affords difluoroazetidinone. This latter compound is a precursor of 2,2-difluoro-2-deoxyaminopyranoses. ... 

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