Zinc enolates reactivity

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. 

In this chapter attention will be focused on the different protocols recently developed to prepare zinc enolates, and on the most significant applications of these reactive intermediates in the field of organic synthesis. 

Zinc enolates or aza-enolates constitute a particular class of organozinc reagents that also display a unique reactivity in carbometallation reactions. 

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. 

Interest in zinc enolates , compared to alkaline or alkaline earth enolates, is growing due to their ideal combination of reactivity and tolerance of many functional groups. The form and structural motifs of complexes depend on the type of metal, solvents and bulkiness of the ligands. Generally, enolates of electropositive metals prefer O-coordination however, even C-coordinated metal enolates usually rearrange to O-bonded ones. 

An alternative method for the preparation of a kinetic zinc ketone enolate (123) from an arene thiol ester 121 and bis(iodozincio)methane (122) in the presence of a palladium(O) catalyst was developed by Matsubara and coworkers (equation 36) . The modest reactivity of the zinc reagent 122 makes this transformation highly chemo- and regioselective neither isomerization of the kinetic enolate 123 nor a palladium-catalyzed coupling with the thiol ester 121 could be observed. Thus, treatment of zinc enolate 123 with various aldehydes or ketones led regioselectively to one aldol product 124. The method provides access to reactive functionalized zinc enolates which are otherwise hard to obtain. 

Besides the very low stereosdectivities, a major problem encountered with this substrate is the low chemical yield (due to subsequent reaction between the resulting zinc enolate and the starting material) and the hi volatility of the product. Using TADDOL-phosphoramidite 27 in a tandem lj4-addition-aldol condensation to cydopentenone we were only able to obtain an ee of 37%, but the enantiosele-ctLvity was raised to 62% in the presence of wet powdered molecular sieves (4 A) [52]. This beneficial effect of water and molecular sieves in some catalytic 1,4-additions has been observed in other cases recently [52, 59]. Important to note is that the yidds in the tandem version are dramatically increased, presumably due to in situ trapping of the reactive enolate (vide infra). Pfaltz et al. reported a 72% ee in the addition of Et Zn to 44 when using BINOL-oxazoline phosphite ligand 22 [47]. 

Thus, we set out to determine whether we could directly observe and identify the unreactive species, and this is when we turned to in situ IR for insights. It seemed reasonable that a hthium-to-zinc transmetallation was a likely cause of the observed attenuated reactivity. It is well established that zinc enolates are much less reactive than the corresponding lithium enolates. The addition of... 

Lithium enolates of esters are inferior to the zinc enolates with respect to their reactivities towards /3-amino nitroethenes."... 

In 2003, Hartwig developed the a-arylation of esters under more neutral reaction conditions [216], and with Q-Phos or its palladium(I) dimer was able to successfully arylate zinc enolates. In contrast, P(t-Bu)3 enabled arylations with silicon-based enolates, bearing potentially reactive functional groups (Scheme 3.12). 

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