Magnesium enolates electrophiles

Side-reactions can sometimes be avoided by preparing the magnesium enolate in the presence of the electrophile. 

All prepared magnesium enolates 17 are stable in refluxing diethyl ether. Deuteriation, and reactions with various electrophiles confirm their structure (see section HI). It is noteworthy that the lithiated carbanion-enolate analogue, directly obtained by deprotonation of an a-ketoester 18 with lithiated bases (LDA, for example), is not stable and immediately degrades in the medium, whatever the temperature. Comparatively, the magnesium chelate 17 shows a higher stability, which allows its preparation and synthetic applications. 

To develop new electrophilic reagents, Ricci and coworkers have described the synthesis of trimethylsilyloxy and hydroxy compounds from magnesium enolates and bis(trimethyl-silyl)peroxide. Magnesium enolates, generated using magnesium diisopropylamide, (DA)2Mg, give the hydroxycarbonyl compounds in excellent yields (equation 72, Table 8). 

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). 

Thus, a-sulfinyl lithium carbanion of 1-chloroethyl p-tolyl sulfoxide was reacted with 1,4-cyclohexanedione mono ethylene ketal (195) to afford the adduct (196) in quantitative yield. The adduct was treated with ferf-butylmagnesium chloride (magnesium alkoxide was initially formed) followed by isopropylmagnesium chloride to result in the formation of magnesium /3-oxido carbenoid 197. The /3-oxido carbenoid rearrangement then takes place to give one-carbon expanded magnesium enolate 198. Finally, an electrophile was... 

Aldol-Type Addition. Aldol-type addition of the magnesium enolate of (R)-(+)-7-butyl 2-(p-tolylsulfinyl)acetate, prepared with 7-butylmagnesium bromide, with aldehydes and ketones afforded, after desulfurization with Aluminum Amalgam, p-hydroxy esters in very high diastereoselectivity (eq Two chiral centers are created in the first step with very high diastereoselectivity (mainly one diastereomer is formed). A model M based on the structure of the sulfinyl ester enolate (determined by C NMR) and on electrophilic assistance of magnesium to the carbonyl approach, was proposed to explain and predict the absolute configuration of the two created chiral centers. ... 

The 1,4-addition of Grignard reagents under copper catalysis, followed by a trap of the resulting (magnesium) enolates with an appropriate electrophile, is a versatile method for double functionalization or double carbon-carbon bond formation at the a- and / -positions of an olefinic bond that bears a carbonyl group [Eq. (89)]. Recently, this topic has been extensively reviewed [155]. Examples [170,173,174] of this notion are presented in Eqs. (77), (90) [170], and (91) [174]. 

The disconnection for these three-component syntheses is to remove the trans substituents from the a and P positions. Thus the ketone 65 disconnects to the enone 66, a vinyl-Cu derivative and an electrophilic bromoester. In the event, a Cu2I2 catalysed Grignard addition followed by alkylation of the magnesium enolate gives pure trans-65 in 91% yield.27... 

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. 

These reactions are divided into two sections. In the former, representative examples of organic electrophiles, which can be used in reactions with magnesium ketone enolates, are summarized. The second section shows that magnesium ketone enolates can be employed as interesting alternatives to their more known lithium counterparts in aldol addition reactions. This part is discussed in terms of regio- and stereoselectivity. 

C. Reactions of Magnesium Ester Enolates and Magnesium Lactone Enolates with Electrophiles... 

Satoh and coworkers further investigated this reaction and found that, in some cases, magnesium /3-oxido carbenoids gave better results. Trapping of the enolate intermediates with several electrophiles was successfully carried out and a new method for the synthesis of one-carbon expanded cyclic a,a-disubstituted ketones from lower cyclic ketones was realized. An example using 1,4-cyclohexanedione mono ethylene ketal (195) as a representative cyclic ketone is shown in Table 15. ... 

Figure 17.12 Enzymatic carboxy-lation reaction in which C02 from bicarbonate is held by a base (e.g., biotin) and magnesium, so as to present an electrophilic carbon to an enol-containing substrate (after Dugas, 1996).

The key idea of the Zimmerman-Traxler model is that aldol additions proceed via six-membered ring transition state structures. In these transition states, the metal (a magnesium cation in the case of the Ivanov reaction) coordinates both to the enolate oxygen and to the O atom of the carbonyl compound. By way of this coordination, the metal ion guides the approach of the electrophilic carbonyl carbon to the nucleophilic enolate carbon. The approach of the carbonyl and enolate carbons occurs in a transition state structure with chair conformation. C—C bond formation is fastest in the transition state with the maximum number of quasi-equatorially oriented and therefore sterically unhindered substituents. 

If we copy Nature rather more exactly, the Claisen ester condensation can be carried out under neutral conditions. This requires rather different reagents. The enol component is the magnesium salt of a malonate mono-thiol-ester, while the electrophilic component is an imidazolide—an amide derived from the heterocycle imidazole. Imidazole has a pK of about 7, Imidazolides are therefore very reactive amides, of about the same electrophilic reactivity as thiol esters. They are prepared from carboxylic acids with carbonyl diimidazole (CDI). 

The electrophilic character of the carbonyl group makes it an appropriate substrate for interaction with a variety of nucleophiles. It is by no means limited to simple alkyl- or aryl-magnesium or -lithium reagents of the types considered above. Of special importance are the numerous condensations where carbonyl-containing compounds undergo interaction with enolates. The spectrum of these transformations embraces such classical reactions as the aldol conden-... 

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