Magnesium enolates acylation

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-... 

Acyl imidazolides are more reactive than esters but not as reactive as acyl halides. Entry 7 is an example of formation of a (3-ketoesters by reaction of magnesium enolate monoalkyl malonate ester by an imidazolide. Acyl imidazolides also are used for acylation of ester enolates and nitromethane anion, as illustrated by Entries 8, 9, and 10. (V-Methoxy-lV-methylamides are also useful for acylation of ester enolates. 

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 same process has been extended to trialkylphosphonoacetates. Acylation with acid chlorides of the magnesium enolates derived from trimethyl and triethyl phospho-noacetates using a MgCl2/Et3N system provides 2-acyl dialkylphosphonoacetates. Further decarboxylation of these latter compounds affords /3-ketophosphonates . 

A similar procedure for the synthesis of a-acyl aminoesters has been proposed using a MgCl2/R3N base system to generate the magnesium enolates of a series of a-carboxy aminoesters. These reagents react smoothly at 0 °C with a variety of acid chlorides to give a-acyl aminoesters in good to excellent yields (equation 58). 

One preparative procedure for achieving this reaction involves the acylation of the magnesium enolate of diethyl malonate with an acid chloride in benzene solution (cf. Expt 5.96), and the resulting aclymalonic ester is then heated to 200 °C with an arylsulphonic acid to effect the decarbethoxylation step. An illustrative example is the preparation of ethyl 3-oxopentanoate (ethyl propionyl-acetate, Expt 5.177). 

It was a particular interest for us to study the preparation of P,p-carboranyl derivatives, which are synthons for a number of compounds. We found that interaction of compound 16 with the magnesium enolate of acetylacetic ester in Et20/EtOH results in esterification of 16 by the EtOH solvent. The same reaction with the sodium enolate of acetylacetonate results in the product of O-acylation. We also found a general method of preparation of carboranyl p,p-diketones (e.g., 19) by reaction of 16 with enamines (Scheme 8). 

A reaction similar to the above involves the acylation of malonic ester through its magnesium enolate. Thus, the reaction of propionyl chloride with the ester enolate leads to diethyl propionylmalonate. Thermal decomposition of this compound with /3-naphthalenesulfonic acid yields ethyl propionylacetate (57%). This modification appears to be general in that it has been extended to the use of aliphatic, aromatic, and car-balkoxy acyl chlorides. ... 

The acid chloride of tetra-fluoro benzoic acid 203 acylated the magnesium enolate 204 of diethyl malonate to give 205. The chelated magnesium enolate avoids O-acylation. Condensation with ethyl orthoformate puts in the masked aldehyde group and 206 is ready for a succession of aromatic nucleophilic substitutions.39... 

Synthesis of 1,3-dicarbonyl compounds by this approach requires the acylation of malonates or other simple 1,3-dicarbonyl compounds as a first step. Sodium or potassium enolates (58) acylate on oxygen but in the corresponding magnesium enolates (59) the oxygen atoms are chelated by the metal, leaving the carbon free to react. 

The bisacylation of methylene-active compounds mentioned above can be avoided by using acylimidazoles in place of acyl halides (acylimidazoles are obtained from the carboxylic acid and sulfinyldiimidazole) for example, reaction of the magnesium enolate of ethyl hydrogen malonate and an acylimid-azole, with concomitant decarboxylation, gives the corresponding / -oxo ester 430... 

The escape route from this problem suggested in the chapter (p. 648) was to use a lithium or magnesium enolate. Magnesium is chelated by the two oxygen atoms of the stable enolate and blocks attack there so that C-acylation occurs even with acid chlorides. 

The magnesium enolate (216) generated from copper(i)-catalysed conjugate addition of MeMgl to 3-methylcyclohex-2-enone in ether at 0°C has been used as a substrate in a study of acylation, alkylation, and the aldol condensation, particularly with respect to regiospecificity. With acetyl chloride in ether the ratio of C-alkylated (217) to 0-alkylated (218) product was 62 38 in a total yield of 39—53%, whereas in dimethoxyethane (218) only was formed in 63% yield. Predominant C-acylation also occurred with crotonyl chloride in ether, where the isolated product contained 86% of (219) in dimethoxyethane the extent of 0-acylation was 95 %. No evidence was adduced for intermediacy of the equilibrated enolate anion (216b). Product ratios were discussed in terms of hardness and softness of the reaction sites. 

The acyl carbon of readily available amino acids such as alanine can be converted to a ketone moiety by activation of the acid with carbonyl diimidazole (CDI) and then condensation with an enolate, such as the magnesium enolate of malonic acid, mono ethyl ester. In this particular example, N-Boc alanine was converted to 1.206 using this method O Catalytic hydrogenation of the ketone moiety gave the alcohol group in 1.207, and conversion to the chloride and base induced dehydrohalogen-ation gave ethyl 4-(N-Boc amino)pent-2-enoate (7.205). 

Although malonate derivatives were described previously, one example is included here to demonstrate their use as a carboxyl enolate. Reaction of 4.87 with carbonyl diimidazole (CDI, see chapter two, section 2.4) gave the acyl imidazole (a very highly activated acyl derivative), which reacted with the magnesium enolate of... 

The acid moiety of an amino acid can be activated for acyl substitution rather than converted to an aldehyde for acyl addition. Boc-alanine was converted to an acyl imidazole by reaction with carbonyl diimidazole (CDI see chapter two, section 2.4), and then condensed with the magnesium enolate of the mono ethyl ester of malonic acid to give keto-ester 5.9. Subsequent catalytic hydrogenation of the ketone moiety gave ethyl 3-hydroxy-5-(N-Boc amino)penlanoate, 5.10 Once the o... 

Magnesium enolates play an important role in C-acylation reactions. The magnesium enolate of diethyl malonate, for example, can be prepared by reaction... 

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