Reformatsky enolates, addition

The 1,4-conjugate addition of ester enolates to a, 3-enones was first reported by Kohler in 1910,138a c as an anomalous Reformatsky reaction, but chemoselectivity was dependent on the structure of the a,(3-enone and restricted to bromozinc enolates obtained from either a-bromoisobutyrate or bromomalonate esters (Scheme 66).138d,e Further evaluation, with lithio ester enolates and lithio amide enolate additions, has resulted in identification of four factors that affect the chemoselectivity and diastereoselectivity of additions to a, 3-enones.139 These factors are (a) enolate geometry, (b) acceptor geometry, (c) steric bulk of the -substituent on the acceptor enone and (d) reaction conditions. In general, under kinetic reaction conditions (-78 °C), ( )-ester enolates afford preferential 1,2-addition products while (Z)-ester enolates afford substantial amounts of 1,4-addition products however, 1,2 to 1,4 equilibration occurs at 25 C in the presence of HMPA. The stereostructure of the 1,4-adducts is dependent on the initial enolate structure for example, with ( )-enones, (Z)-ester enolates afford anti adducts, while (E)-ester enolates afford syn adducts (Scheme 54). In contrast, amide enolates show a modest preference for anti diastereomer formation. 

Scheme 4-318. Reformatsky-type addition of ester enolates to carbonyl compounds catalyzed by iron(II).

The complexation of achiral metal enolates by chiral additives, e.g., solvents or complexing agents could, in principle, lead to reagent-induced stereoselectivity. In an early investigation, the Reformatsky reaction of ethyl bromoacetate was performed in the presence of the bidentate ligand (—)-sparteine20. The enantioselectivity of this reaction varies over a wide range and depends on the carbonyl Compound, as shown with bcnzaldehyde and acetophenone. 

In the presence of a strong base, the ot carbon of a carboxylic ester can condense with the carbonyl carbon of an aldehyde or ketone to give a P-hydroxy ester, which may or may not be dehydrated to the a,P-unsaturated ester. This reaction is sometimes called the Claisen reaction,an unfortunate usage since that name is more firmly connected to 10-118. In a modem example of how the reaction is used, addition of tert-butyl acetate to LDA in hexane at -78°C gives the lithium salt of ferf-butyl acetate, " (12-21) an enolate anion. Subsequent reaction a ketone provides a simple rapid alternative to the Reformatsky reaction (16-31) as a means of preparing P-hydroxy erf-butyl esters. It is also possible for the a carbon of an aldehyde or ketone to add to the carbonyl carbon of a carboxylic ester, but this is a different reaction (10-119) involving nucleophilic substitution and not addition to a C=0 bond. It can, however, be a side reaction if the aldehyde or ketone has an a hydrogen. 

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... 

Scheme 7.5 gives some examples of the Reformatsky reaction. Zinc enolates prepared from a-haloketones can be used as nucleophiles in mixed aldol condensations (see Section 2.1.3). Entry 7 is an example. This type of reaction can be conducted in the presence of the Lewis acid diethylaluminum chloride, in which case addition occurs at -20° C.171... 

Other studies have provided additional data on the relative stabilities of the lithium aldolates 14 and 15 derived from the condensation of dilithium enediolates 13 (Rj = alkyl, aryl) with representative aldehydes (eq. [ 10]) (16). Kinetic aldol ratios were also obtained for comparison in this and related studies (16,17). As summarized in Table 4, the diastereomeric aldol chelates 14a and ISa, derived from the enolate of phenylacetic acid 13 (R = Ph), reach equilibrium after 3 days at 25° C (entries A-D). The percentage of threo diastere-omer 15 increases with the increasing steric bulk of the aldehyde ligand R3 as expected. It is noteworthy that the diastereomeric aldol chelates 14a and 15a (Rj = CH3, C2HS, i-C3H7) do not equilibrate at room temperature over the 3 day period (16). In a related study directed at delineating the stereochemical control elements of the Reformatsky reaction, Kurtev examined the equilibration of both... 

Three approaches to zinc enolates are commonly adopted the process associated to the classical Reformatsky reaction is based on the insertion of Zn(0) into the carbon—halogen bond of an a-haloester. Two additional routes involve (i) transmetallation of a lithium enolate with a Zn(II) salt (Section V.A) and (ii) the transition-metal-catalysed conjugate addition of diethylzinc to Michael acceptors (Section V.B). 

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. 

Ethyl dibromofluoroacetate has been used as a fluoroacetate enolate equivalent in Reformatsky chemistry developed by the Kyoto group [178]. Addition mediated by zinc and chloro diethylaluminium occurs with modest stereoselectivity to afford the bromofluoro hydroxyesters. 

Reformatsky reaction.6 Ultrasonic radiation is beneficial in the Reformatsky reaction. Yields are > 90%, and the rate is enhanced. Specially activated zinc is not necessary. However, iodine and potassium iodide are effective additives, possibly by suppressing enolization. The solvent of choice in this variation is dioxane. 

In a general sense, the Reformatsky reaction can be taken as subsuming all enolate formations by oxidative addition of a metal or a low-valent metal salt into a carbon-halogen bond activated by a vicinal carbonyl group, followed by reaction of the enolates thus formed with an appropriate electrophile (Scheme 14.1).1-3 The insertion of metallic zinc into a-haloesters is the historically first and still most widely used form of this process,4 to which this chapter is confined. It is the mode of enolate formation that distinguishes the Reformatsky reaction from other fields of metal enolate chemistry. 

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... 

The Reformatsky reaction involves condensation of ester-derived zinc enolates with aldehydes or ketones to furnish the con-esponding [3-hydroxy esters. The zinc enolates are generated by addition of an a-haloester in THF, DME, Et20, benzene, or toluene to an activated zinc, such as a Zn-Cu couple or zinc obtained by reduction of zinc halides with potassium (Rieke zinc). An example of a Reformatsky condensation using Rieke zinc is shown below. ... 

Difluoroester enolates are available by reduction of halodifluoroacetates with zinc metal [40]. Although the reaction of O-trimethylsilyl difluoroesterenolates with carbonyl compounds leads to the same reaction products as the analogous Reformatsky reaction [41] (Scheme 2.203), use of chiral catalysts results in additions with much greater enantioselectivity [42] (Scheme 2.204). 

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. 

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