Grignard reagents magnesium enolates

The low yields, which are observed among styrenyl adducts, reflect a combination of the poor reactivity of the styrene at the low temperature of the reaction. For example, the combination of t-butyl Grignard with the 2,4-bis-OBoc-benzyl alcohol 15 affords the corresponding benzopyran 50 in only 50% yield even when carried out in the presence of 5-10 equivalents of the styrene (method H, Fig. 4.27).27 Yields for substituted benzopyran styrene adducts are still lower (method G, Fig. 4.27). For example, addition of methyl lithium to 2,4-bis-OBoc-benzylaldehyde 5 followed by the addition of the dienophile and magnesium bromide affords benzopyran 51 in a paltry 27% yield. Method F is entirely ineffective in these cases, because the methyl Grignard reagent competes with the enol ether and with styrene 1,4-addition of methyl supercedes cycloaddition. 

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. 

Other kinds of propargylic-substituted products were prepared by this procedure. When Grignard reagents such as allylic and homoallylic magnesium bromides are used in place of lithium enolates as carbon-centered nucleophiles. 

One of the simplest methods is the addition of Grignard reagent onto a sterically hindered enone . For example, the (Z)-magnesium enolate is formed from the reaction of benzalacetomesitylene and phenylmagnesium bromide (equation 31). 

Interestingly, even methyl 2-bromo- or 2-chloro-2-cyclopropylideneacetate reacts cleanly with various Grignard reagents in a 1,4-addition without any chlorine-metal exchange side reactions (equation 35). These in situ generated magnesium enolates are particularly reactive with aromatic aldehydes . 

The introduction of asymmetry in conjugate additions can be promoted by chiral acceptors. The preparation of regio-defined magnesium enolates from copper(I)-mediated conjugate addition of Grignard reagents has been extensively used in many important... 

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. 

The overall sequence involves formation of the imine from the aldehyde that is to be alkylated— usually with a bulky primary amine such as t-butyl- or cyclohexylamine to discourage even further nucleophilic attack at the imine carbon. The imine is not usually isolated, but is deprotonated directly with LDA or a Grignard reagent (tl ese do not add to imines, but they will deprotonate them to give magnesium aza-enolates). 

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