Metalation magnesium enolate preparation

Magnesium enolates play an important role in C-acylation reactions. The magnesium enolate of diethyl malonate, for example, can be prepared by reaction with magnesium metal in ethanol. It is soluble in ether and undergoes C-acylation by acid anhydrides and acyl chlorides (entries 1 and 3 in Scheme 2.14). Monoalkyl esters of malonic acid react with Grignard reagents to give a chelated enolate of the malonate monoanion. 

II. PREPARATION OF MAGNESIUM ENOLATES A. Reductive Metal Insertion into Carbon-Halogen Bonds... 

Several years ago, Castro, Villieras and coworkers described the preparation of the magnesium enolate derived from an alkyl a,a-dihaloacetate by halogen-metal exchange between isopropyhnagnesium chloride and alkyl trihaloacetate. THF is required as solvent (equation 7) °. 

If the metal-halogen interconversions were originally used to prepare magnesium enolates, other heteroatoms than halogen can undergo the exchange. Sulfur atom is often employed. 

Nnmerons other protocols have been developed to prepare magnesium enolates by asymmetric 1,4-addition of Grignard reagents to electron-deficient alkenes. Recently, an enantioselective metal-catalyzed version of this key reaction has been studied with enones and a, S-unsaturated thioesters Using chiral ferrocenyl-based diphosphines leads to... 

The preparation of magnesium enolates by metallation competes with nucleophilic addition. Thus, until recently, this strategy was only valuable for sterically hindered or relatively acidic substrates, which were metallated by Grignard reagents or magnesium diaUtoxydes. 

Due to their inherent polarizability, a-halo-/3-ketosulfoxides may be used as electrophilic partners in desulfination reaction to generate metal enolate. Therefore, treatment of a-halo-/3-ketosulfoxides with EtMgBr gives magnesium enolates. Trapping these reagents with various electrophiles allows the preparation of a-haloketones (equation 79, Table 10). 

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. 

In order to improve the stereoselectivity of the aldol process even further, metal salts of enolate anions other than those bearing lithium have been examined. For example, both magnesium and boron enolates have been prepared. Magnesium enolates are very much like lithium enolates in their stereoselectivity, while boron enolates, where there are relatively short metal-oxygen bonds, give improved selectivity. For the boron enolates, the (Z)-enolate is generally more stable than its E)-isomer, and erythro- or 5yn-products are developed. 

Magnesium enolates of ketones can be prepared from a-bromoketones by reaction with magnesium metal. 

Recently, a reductive magnesium insertion into a carbon-iodine bond of a / -iodo-a-ketoester has been described. The preparation of the iodomagnesium enolate 17 derived from an a-ketoester is the first preparation of such metallic species in this series. It was obtained from the reaction between the /1-iodo-a-ketoester precursor 16 and magnesium. In this case, the form of the metal is critical and magnesium powder with a large surface area is necessary (equation 6). 

Enantioselective protonation of ketone metal enolates constitutes an important method for the preparation of optically active ketones. Fuji and coworkers have shown interest in the magnesium countercation in the enantioselective protonation of such enolates. Pertinent results are obtained with protonation of Mg(II) enolates of 2-alkyltetralones and carbamates derived from l,l -binaphtalene-2,2 -diol as chiral proton sources, as indicated in equation 82 and Table 11. 

The addition of a 2-hydroxyaryl group to an aldehyde can be considered as a case of aldolization using a phenoxide instead of an enolate. Casiraghi et al used magnesium and titanium salts to prepare l-(2-hydroxyaryl)glycerols (p. 81). The stereoselectivity depends on the nature of the metal. 

The deprotonation in a-position of a carbonyl group induced by treatment with strong, nonnucleophUic bases is the most important, most convenient, and most frequently applied procedure for the preparation of preformed enolates of alkaU metals and magnesium (Equation 2.1) [2]. A sufficient thermodynamic acidity, prerequisite to an efficient quantitative formation of an enolate 3, requires the difference between the pA value of the conjugate acid 4 of the base 2 and the corresponding carbonyl compound 1 (at least) to reach or to surpass the value of 2 [P a (4) P a (1) — 2] [3] Even if this thermodynamic condition is met, an efficient... 

The transmetallation of alkali enolates 164 (M = Li, Na, K) with metal salts (M Y L, ) is a general method for the preparation of a large variety of enolates 165, provided that is less electropositive than M. It is particularly suitable for such enolates 165 whose reactivity and/or selectivity is tuned by additional ligands L. Thus, a variety of magnesium, boron, aluminum, siUcon, tin, titanium, zirconium, and zinc enolates become readily available (Scheme 2.48) [2c,d]. Usually, the configuration of the enolates is maintained during the transmetallation, but cis-tmns isomerization in the transmetallated enolates occur occasionally. Individual examples will be discussed with their applications in asymmetric syntheses. 

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