Reformatsky reagents enolates

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... 

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. 

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... 

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

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 . 

The rate-determining step was found to be not the [3,3]-sigmatropic shift but rather the conversion of the Reformatsky reagent 108 into its enolate form 109. 

Equations 36-39 suggest that fluorine substituents at the a position of the ester enolate play a role in favouring the formation of /J-arnino esters. This conclusion is supported by the condensation of the Reformatsky reagent deriving from 20 with imines, the only product being the open-chain adduct 63 (equation 40)123. 

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. 

Smith3 used a Reformatsky reagent as the enolate equivalent and everything went according to plan, especially the yield on the chain extension step. 

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. 

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. 

Villieras, J., Perriot, P., Bourgain, M., Normant, J. F. Enolates of esters. V. Preparation of the lithium analogs of Reformatsky reagents from a,a-dichloro and a-monohalo esters. Reactivity. J. Organomet. Chem. 1975,102, 129-140. 

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... 

Interest in the synthesis of compounds containing the P(CHaC02R) grouping continues, and routes involving the reactions of chlorophosphines with sodium enolates of acetate esters and Reformatsky reagents have been reported. A range... 

The treatment of organometallic compounds with appropriate haloorganostan-nanes affords unsymmetrical tetraorganotin compounds (eq (131)) [126]. By the use of Reformatsky reagents and metal enolates, a-trialkylstannyl esters and ketones are obtained, respectively. 

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. 

Condensation reactions of simple carboxylic acids with imines are of intense interest because of their applications to 3-lactam synthesis. Activation of the carboxylic acid derivative is accomplished by preforming the enolate in situ or by using a silyl ketene acetal derivative with Lewis acid catalysis. The first example of an enolate-imine condensation of this type can be attributed to Gillman and Speeter, who in 1943 reported the synthesis of 3-lactams from Reformatsky reagents and Schiff bases. Subsequently, other workers have investigated the mechanism and syn-anti selectivity of this reaction. A review of these studies by Evans et al. covering work through 1980 has appeared in their review, Stereoselective Aldol Condensations . ... 

Reactions exhibiting diastereofacial selectivity, which occur when the imine or the enolate contains an endogenous stereocenter or a chiral auxiliary, have important applications for the synthesis of optically active 3-l ctams and 3-amino carboxylic acid derivatives. Early work by Furukawa et al. has demonstrated the viability of preparing optically active 3-amino acids from chiral imines. For example, the Schiff base derived from (5)-a-methylbenzylamine (110) reacts with Reformatsky reagent (111) to give, after hydrolysis and removal of the chiral auxiliary, 3-amino-2,2-dimethyl-3-phenylpropionic acid (112) in 33% ee (Scheme 21). Similar Reformatsky reactions have been performed using (-)-menthyl esters but the enantiomeric excess values are lower. ... 

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