Malonate ester anions acylation

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. 

Many alkylation and acylation reactions are most effective using anions of /3-dicarbonyl compounds that can be completely deprotonated and converted to their enolate ions by common bases such as alkoxide ions. The malonic ester synthesis and the acetoacetic ester synthesis use the enhanced acidity of the a protons in malonic ester and acetoacetic ester to accomplish alkylations and acylations that are difficult or impossible with simple esters. 

C-Phosphorylated malonic acid derivatives are conveniently obtained by the acylation of phosphonoacetic ester anions with chloroformic esters. Further consideration has been given to the formation (and properties) of A -l,4,2-oxaza-phospholine 2-oxides (44) by cyclization of a-benzamidovinylphosphinic esters with PClg. ... 

Aqueous acid workup of 92 gives the alcohol, 93. With malonic ester derivatives, loss of water to form 94 occurs very easily, with dilute acid or with gentle heating because the C=C unit is conjugated to two carbonyl groups, facilitating dehydration. Although it is possible to isolate 83, it is more usually difficult. The enolate anion of malonate esters also reacts with ketones and may be condensed with other esters in acyl substitution reactions. When 90 is treated with NaOEt in ethanol and then with ethyl butanoate, the final product after mild hydrolysis is a keto-diester, 95. 

A variation of the malonic ester synthetic uses a P-keto ester such as 116. In Section 22.7.1, the Claisen condensation generated P-keto esters via acyl substitution that employed ester enolate anions. When 116 is converted to the enolate anion with NaOEt in ethanol, reaction with benzyl bromide gives the alkylation product 117. When 117 is saponified, the product is P-keto acid 118, and decarboxylation via heating leads to 4-phenyl-2-butanone, 119. This reaction sequence converts a P-keto ester, available from the ester precursors, to a substituted ketone in what is known as the acetoacetic acid synthesis. Both the malonic ester synthesis and the acetoacetic acid synthesis employ enolate alkylation reactions to build larger molecules from smaller ones, and they are quite useful in synthesis. 

One such compound, bropirimine (112), is described as an agent which has both antineo-plastic and antiviral activity. The first step in the preparation involves formation of the dianion 108 from the half ester of malonic acid by treatment with butyllithium. Acylation of the anion with benzoyl chloride proceeds at the more nucleophilic carbon anion to give 109. This tricarbonyl compound decarboxylates on acidification to give the beta ketoester 110. Condensation with guanidine leads to the pyrimidone 111. Bromination with N-bromosuccinimide gives bropirimine (112) [24]. 

One route to o-nitrobenzyl ketones is by acylation of carbon nucleophiles by o-nitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonate[l], methyl acetoacetate[2], Meldrum s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of u-nitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to o-nitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7]. Deformylation and reduction leads to 2-sub-stituted indoles. 

Intramolecular asymmetric Stetter reactions enjoy a range of acceptable Michael acceptors and acyl anion precursors. These reactions can utilize aromatic, heteroaromatic, and aliphatic aldehydes with a tethered a,p-unsaturated ester, ketone, thioester, malonate, nitrile, or Weinreb amide. In this part, we will give a brief summary about asymmetric intramolecular Stetter reactions and selected recent results in this area (Scheme 7.17). 

The introduction of a p-oxazilinyl substituent into the aromatic ring of the arylacetal anions (23) stabilizes the anions and allows them to be used as acyl anion equivalents. Bis(ethylthio)acetic acid is a new a-keto-acid synthon. Its dianion reacts with a variety of electrophiles, including aziridines, to give substituted a-keto-acids in fair to excellent yields after deprotection. In two syntheses of /8-keto-acids, R COCl is used as the source of the acyl group. In the first synthesis the dianion of the ethyl ester of malonic acid reacts with R COCl to give... 

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