Reformatsky reagents zinc enolates

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. 

The Reformatsky reaction is a classical reaction in which metallic zinc, an a-haloester, and a carbonyl compound react to give a (i-hydroxyester.162 The zinc and a-haloester react to form an organozinc reagent. Because the carboxylate group can stabilize the carbanionic center, the product is essentially the zinc enolate of the dehalogenated ester.163 The enolate effects nucleophilic attack on the carbonyl group. 

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

Using l-(2-nitrovinyl)pyrrolidines 108 or 111 as Michael acceptors, the addition of the Reformatsky reagent is followed by amine elimination. A formal vinylic substitution ensues, which can take advantage of the presence of stereocenters in the pyrrolidine moiety, affording new chiral nitroolefins 110151 and 113152, as reported in equations 64 and 65, respectively. In both cases, zinc enolates 109 and 112 are prepared by lithia-tion/transmetallation of the parent ester. 

The Reformatsky reagents, i.e. zinc enolates of esters, undergo Ni catalysed cross-coupling with aryl halides.53 The Ni catalysed reaction of arylzincs with a-bromoacetates also permits a-arylation of esters54 (Scheme 11.13). However, a-alkenylation of enolates of ketones, aldehydes, and esters has been less satisfactory. Its further development is clearly desirable. Alternatively, a-alkenylation of a-iodoenones in conjunction with conjugate reduction discussed earlier should be considered. 

Zinc enolates can be prepared in solvents of greatly different polarity, including THF, DME, Et20, 1,4-dioxane, benzene, toluene, dimethoxy-methane, DMF, B(OMe)3, DMSO, and mixtures thereof, just to mention the most frequently used ones.1-3 Reformatsky reactions in the absence of a solvent have also been described.7 The reagent is dimeric in the crystal state and in solution except for the most polar media.5,8... 

The insight that zinc ester enolates can be prepared prior to the addition of the electrophile has largely expanded the scope of the Reformatsky reaction.1-3 Substrates such as azomethines that quaternize in the presence of a-halo-esters do react without incident under these two-step conditions.23 The same holds true for acyl halides which readily decompose on exposure to zinc dust, but react properly with preformed zinc ester enolates in the presence of catalytic amounts of Pd(0) complexes.24 Alkylations of Reformatsky reagents are usually difficult to achieve and proceed only with the most reactive agents such as methyl iodide or benzyl halides.25 However, zinc ester enolates can be cross-coupled with aryl- and alkenyl halides or -triflates, respectively, in the presence of transition metal catalysts in a Negishi-type reaction.26 Table 14.2 compiles a few selected examples of Reformatsky reactions with electrophiles other than aldehydes or ketones.27... 

Zinc enolates (Reformatsky reagents), generated finom a-bromo esters and zinc, react with imines derived finom aromatic amines to yield 3-lactams (Scheme 19).>40-142 -phe stereoselectivity of the reaction varies 4 >46 (jjg nature of ester substituents R and R the bulkier the groups, the more trans isomer is produced. 

Zinc, like magnesium, is a two-electron donor and likes to be oxidized from Zn(0) to Zn(ll). This enolate is often called the Reformatsky reagent after its inventor, which is fine, and often drawn as a C-Zn compound, which is not fine because it isn t one. 

Spectroscopic and crystallographic studies of Reformatsky reagents derived from a-halo esters showed that the enoiate is present in the C-enolate form and in ether solvents they form dimers. Enolates derived from a-halo ketones prefer the O-metal enoiate form. It is assumed, based on theoretical calculation, that the zinc enoiate dimers are dissociated by the action of the carbonyl compound and converted to the corresponding O-zinc enolates. Subsequently, the reaction goes through six-membered chairlike transition state. 

Reformatsky reagent Ethyl trichloroacetate reacts with zinc in THF at —15° to form a stable chlorozinc enolate (1). This reagent can be condensed with a number of... 

NATURE OF THE REFORMATSKY REAGENT /. 8J2.I Isolation and Stability of Zinc Enolates... 

The Reformatsky reaction is the reaction of an a-halo ester with an aldehyde or ketone in the presence of zinc metal as shown in Scheme 1. The usual product of the reaction is a -hydroxy ester, which may be dehydrated in subsequent steps to give an unsaturated ester. A zinc ester enolate (1), the so-called Reformatsky reagent, is an intermediate in the reaction and the sequence is thus classified as an aldol condensation. Compared to the usual base-promoted aldol procedures, the distinguishing features of the Reformatsky reaction are the use of a metal-halogen redox reaction rather than an acid-base reaction to form the enolate, and the fact that the counterion of the enolate is zinc. 

This chapter summarizes studies on the nature of the Reformatsky reagent as well as other, related, zinc enolates and outlines the synthetic aspects of the reaction with aldehydes and ketones. In addition, reactions of the Reformatsky reagent with imines and nitriles (the Blaise reaction) are described. 

According to Gaudemar and Curd, dimethoxymethane is an especially useful solvent for two-stage reactions and they report yields of 70-80% for the Reformatsky reagents derived from a variety of a-bromo esters (equation 2) however, the procedure was unsatisfactory with ethyl a-bromopropionate, methyl a-bromophenylacetate and phenyl a-bromoisobutyrate. The zinc enolates were generally used shortly after preparation and no data on their stability in this solvent were reported. 

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