Magnesium enolates preparation

Although the antithyroid activity of compounds incorporating an enolizable thioamide function was discussed earlier, this activity was in fact first found in the pyrimidine series. The simplest compound to show this activity, methylthiouracil (80) (shown in both enol and keto forms), is prepared quite simply by condensation of ethyl acetoacetate with thiourea.Further work in this series shows that better activity was obtained by incorporation of a lipophilic side chain. Preparation of the required dicarbonyl compound starts with acylation of the magnesium enolate of the unsyrametrically esterified malonate, 81, with butyryl chlo-... 

When a solution of magnesium methoxide (prepared by the reaction of magnesium with methanol) is saturated with carbon dioxide, an active carboxylating agent, MMC, is produced. The reagent carboxylates substrates capable of enolization apparently by promoting formation of the magnesium chelate of the a-adduct. The reaction has been... 

The magnesium enolates are prepared by treatment of malonic acid half ester either with magnesium ethylate[24],[32] or with isopropylmagnesium bromide[24] or chloride.t26] Ref. [23] describes the synthesis of a 13C-labelled ethyl acetoacetate. Concerning the synthesis of porphyrin / -ketoesters,[3 1 it was noticed that the method via imidazolides is more efficient than the other approach via acid chlorides and sodiomalonic esters. 

Ethyl 3-oxoalkanoates when not commercially available can be prepared by the acylation of tert-butyl ethyl malonate with an appropriate acid chloride by way of the magnesium enolate derivative. Hydrolysis and decarboxylation in acid solution yields the desired 3-oxo esters [59]. 3-Keto esters can also be prepared in excellent yields either from 2-alkanone by condensation with ethyl chloroformate by means of lithium diisopropylamide (LDA) [60] or from ethyl hydrogen malonate and alkanoyl chloride usingbutyllithium [61]. Alternatively P-keto esters have also been prepared by the alcoholysis of 5-acylated Mel-drum s acid (2,2-dimethyl-l,3-dioxane-4,6-dione). The latter are prepared in almost quantitative yield by the condensation of Meldrum s acid either with an appropriate fatty acid in the presence of DCCI and DMAP [62] or with an acid chloride in the presence of pyridine [62] (Scheme 7). 

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. 

The chapter is organized under the headings Preparation and Reactivity of magnesium enolates. 

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

Similarly, the bromo magnesium enolate 4 of 2,2-diphenylcyclohexanone has been prepared by the action of magnesium on 6-bromo-2,2-diphenylcyclohexanone 3 (equation 2). A small amount of iodine is added to initiate the reaction. The enolate 4 is obtained in 79% yield after 15 min at reflux. ... 

Colonge and Grenet have reported that this type of reaction may be utilized in the preparation of magnesium enolates from simple aliphatic a-bromo ketones. ... 

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. 

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) °. 

Different protocols have been tested to prepare enolates from /1-aryl-a-iodoketones. Reactions nsing EtsB/PhsSnH in benzene, EtsB in benzene or ether and w-BuLi in ether failed to provide the corresponding enolates. Alternatively, the use of EtMgBr succeeds in generating reactive magnesium enolates from a-iodo ketones. In most cases, the formation of the enolate in THF is cleaner than that in EtiO (equation 8). 

This method has been used to prepare the antibiotic thienamycin. The magnesium enolate of the /3-lactam was prepared from the 6-iodo derivative in THF (equation 9/ . 

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. 

The preparation of magnesium enolate by addition of one equivalent of magnesium dihahde to a solution of hthium enolate is a commonly used procedure. 

Reactions presented below show that this method is used frequently to prepare magnesium enolates derived from functionalized carboxylic esters or lactones (equations 18-24, Tables 2 and 3). 

---