Zinc enolates formation

Zinc enolates, made from the bromoesters, are a good alternative to lithium enolates of esters. The mechanism for zinc enolate formation should remind you of the formation of a Grignard reagent. 

Tin(Il) shows considerable affinity towards nitrogen, therefore is expected to activate the imino group. The diastereoselective addition of tin(II) enolates derived from thioesters 1 to x-imino-esters 2 is reported12. This reaction proceeds smoothly to afford. vi w-/j-amino acid derivatives 3 (d.r. 95 5) in good yields. Lithium, magnesium, and zinc enolates do not react while titanium enolates give the adducts in low yield with preferential formation of the anti-isomer. 

Kimura and co-workers have synthesized a series of alkoxide complexes with the alcohol functionality as a pendent arm.447 674 737 A zinc complex of l-(4-bromophenacyl)-l, 4,7,10-tetraaza-cyclododecane was also synthesized by the same workers to mimic the active site of class II aldolases. The X-ray structure shows a six-coordinate zinc center with five donors from the ligand and a water molecule bound. The ketone is bound with a Zn—O distance of 2.159(3) A (Figure 12). Potentiometric titration indicated formation of a mixture of the hydroxide and the enolate. Enolate formation was also independently carried out by reaction with sodium methoxide, allowing full characterization.738... 

The addition of carbonyl compounds towards lithiated 1-siloxy-substituted allenes does not proceed in the manner described above for alkoxyallenes. Tius and co-work-ers found that treatment of 1-siloxy-substituted allene 67 with tert-butyllithium and subsequent addition of aldehydes or ketones led to the formation of ,/i-unsaturated acyl silanes 70 (Scheme 8.19) [66]. This simple and convenient method starts with the usual lithiation of allene 67 at C-l but is followed by a migration of the silyl group from oxygen to C-l, thus forming the lithium enolate 69, which finally adds to the carbonyl species. Transmetalation of the lithiated intermediate 69 to the corresponding zinc enolate provided better access to acylsilanes derived from enolizable aldehydes. For reactions of 69 with ketones, transmetalation to a magnesium species seems to afford optimal results. 

A chair-like amino-zinc-enolate transition state has been used to explain how substituents on the ring affect the diastereoselective and enantioselective formation of polysubstituted pyrrolidines during intramolecular amino-zinc-enolate carbometalla-tion reactions. ... 

In the course of examining the CAI effect of conformational restriction of the C3-side-chain, intermediate 24 was prepared. Shankar and co-workers (Shankar et al., 1996) demonstrated that 10, a key intermediate in the research synthesis could be accessed by Wacker oxidation of olefin 24 (Scheme 13.7). Additionally, an alternative chiral variant of the well-precedented addition of zinc enolates to imines was demonstrated. Treatment of the bromoacetate 25, derived from 8-phenylmenthol with zinc and sonication followed by imine addition afforded 26 in 55% yield with greater than 99% de. Ethyl magnesium promoted ring-closure followed by C3 alkylation with 28, intercepts the previously demonstrated route through formation of olefin 24 (Shankar et al., 1996). 

Because zinc enolates are intrinsically reactive species, especially towards carbonyl compounds, the attempted synthesis of such species often results in the formation of selfcondensation products which are often polymeric materials. Only in a few cases could pure organozinc enolates be isolated and structurally characterized. 

A zinc-bis(BINOL) complex has been employed to effect chemoselective enolate formation from an a-hydroxy ketone (in the presence of an isomerizable imine) to give a Mannich-type product in high ee 1... 

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. 

Reformatsky reactions have a bad reputation as being difficult to entrain. To the authors experience, however, the reactive donors such as alkyl bromo-acetates do not pose particular problems even under rather conventional conditions. Commercial zinc dust activated by pre-treatment with either iodine of preferentially with cuprous chloride (i.e. Zn(Cu)) readily inserts into these halocarbonyl compound with formation of the corresponding zinc enolates. Protocols 1 and 2 describe prototype examples for Reformatsky reaction in the conventional two-step or Barbier-type set-up, respectively. 

Fig. 17.49. Reductions of a-heterosubstituted ketones to a-unsubstituted ketones (see Figures 15.34 and 17.59 for the preparation of compounds A and B, respectively). Here, a ketyl is formed as a radical anion intermediate (for more details about ketyls see Section 17.4.2). The ketyl obtained from A releases a chloride ion, the ketyl resulting from B releases a hydroxide ion. In each case, an enol radical is formed thereby which picks up an electron. This leads to the formation of a zinc enolate from which the final product is generated by protonation.

The formation of amino acid derivatives by addition of a zinc enolate to non-racemic unsymmetrical substrates has also been described, in which it-o-lt... 

Another intermediate for which Die Is-Alder trapping provided convincing evidence is the oxy-allyl cation. This compound can be made from a,oc -dibromoketones on treatment with zinc metal. The first step is the formation of a zinc enolate (compare the Reformatsky reaction), which can be drawn in terms of the attack of zinc on oxygen or bromine. Now the other bromine can leave as an anion. It could not do so before because it was next to an electron-withdrawing carbonyl group. Now it is next to an electron-rich enolate so the cation is stabilized by conjugation. 

The Aldol reaction is one of the most powerful methods for creating the C-C bond. Typical conditions involve the formation of an enolate, usually with a stoichiometric equivalent of base. Stereoinduction is nsnally accomplished with chiral enolates, aldehydes, or auxiliaries.Nature, however, is much more efficient, having created enzymes that both catalyze the aldol reaction and produce stereospecific product. These enzymes, called aldolases, are of two types. The type II aldolases make use of a zinc enolate. Of interest for this section are the type I aldolases, which make use of enamine intermediates. Sketched in Scheme 6.6 is... 

Amide 9 is enolizable and carries an oxazolidinone auxiliary. Addition of ZnCb leads to transmetallation and formation of a zinc enolate. 

A feature distinguishing Reformatsky enolates from base-generated enolates is that zinc enolates add to highly hindered as well as to easily enolizable ketones, such as cyclopentanones, thus avoiding formation of condensation products. Moreover, there is no danger of a Claisen-type self-condensation since zinc-enolates do not react with esters but react readily with aldehydes and ketones to furnish aldol-type products. 

Traditionally, aldol reactions were carried out under protic conditions, such that the enolate was formed reversibly (see Volume 2, Chapter 1.5). An added measure of control is possible if one uses a sufficiently strong base that the enolate may be quantitatively formed prior to addition of the electrophile. The renaissance that has occurred in the aldol reaction in the last two decades has been mainly due to the development of methods for the formation and use of preformed enolates. The simplest enolates to prepare are those associated with lithium and magnesium, and there now exists a considerable literature documenting certain aspects of lithium and magnesium enolate aldol chemistry. This chapter summarizes the aldol chemistry of preformed enolates of these Group I and Group II metals. Other chapters in this volume deal with boron enolates, zinc enolates, transition metal enolates and the related chemistry of silyl and stannyl enol ethers. 

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