Acetoacetic ester dianion, alkylation

Since the terminal methyl group of acetoacetic ester is alkylated, its dianion is reacted with C HjCKjCI. 

Alkylation takes place at the most acidic position of a reagent molecule for example, acetoacetic ester (CH3COCH2COOEt) is alkylated at the methylene and not at the methyl group, because the former is more acidic than the latter and hence gives up its proton to the base. However, if 2 equivalents of base are used, then not only is the most acidic proton removed, but also the second most acidic. Alkylation of this doubly charged anion (a dianion) occurs at the less acidic position, in this case the second most acidic position (see p. 513). The first and second ion pair acidities of (3-diketones has been studied. 

Butanoic acid, 3-hydroxy-, esters pr, 176 Frater-Seebach 2-alkylation, 27 —, 3-oxo-, esters (acetoacetic esters) pr., 176 carbon acidity, 10 carboxymethyl da-synthon, 19, 207 dianion 4-alkylation, 24, 207,325-326... 

Diketo esters.1 Various N-methoxy-N-methyl amides couple with the dianion of alkyl acetoacetates to form 0,8-diketo esters in 42-91% yield. These... 

Looking back on the history of ketone dianion chemistry, one soon notices that dianion species, derived from / -keto esters, have been in continuous steady use in organic synthesis3,4, as shown in Scheme 2. Thus, ethyl acetoacetate can be converted to the corresponding ketone o a -chainon via consecutive proton abstraction reactions. The resulting dienolate anion reacts with a variety of alkyl halides to give products, resulting from exclusive attack at the terminal enolate anions. 

The group of Tietze has described syntheses of variously substituted pyrazolones 20 starting from solid-phase-bound p-keto esters. Single or iterative alkylation of the dianion of immobilized acetoacetate with allyl-, benzyl- or alkyl halides produced a set of y-substituted ketoesters 18 that could be transformed to the phenyl-hydrazones 19. Treatment of these intermediates in toluene at 100 °C produced 1-phenylpyrazolone derivatives 20 in 40-75% yield (Scheme 6) [14]. 

Ethyl 5-oxohexanoate (51) was reduced with NaBH4 and the resulting alcohol protected with dihydropyran to give 52. Reduction of the ester moiety to a primary alcohol followed by conversion to the bromide 53 was achieved by conventional means. Alkylation of the dianion of ethyl acetoacetate with 53 afforded a 78% yield the p-keto ester 54, which possesses all the carbons required for the construction of the diplodialides. Protection of the ketone as the dithiane... 

Danishefsky has exploited his widely utilized silyloxydiene chemistry to complete a formal total synthesis of 90 (Scheme 1.20). By employing the appropriate oxidation levels for both the diene and dienophile, a resorcinyl ester possessing the required differentiation of the phenolic groups was obtained without further oxidative manipulation. To this end, the dianion of propiolic acid was alkylated with l-bromo-7-octene to give acid 98 in 68% yield. Further alkylation with methyl iodide then gave the ester 99. A Diels-Alder reaction with diene 100, a derivative of methyl acetoacetate, and alkyne 99 then furnished an initial phenolic intermediate which was protected as the benzyl ether to afford... 

A word about the synthesis of the a-series, a-geraniol (73) and a-nerol (74), is warranted because they are often intermediates in the synthesis of 1-hydroxylated compounds (e.g., some diols described below). Weiler has continued his exploitation of the dianion of methyl acetoacetate to this end. Instead of prenylation (Vol. 4, p. 461, Ref. 73) he carried out a similar series of operations by alkylating the dianion with 4-bromo-2-methyl-l-butene, thus arriving at compounds of the a-series via the keto ester 75, methylating the enol phosphate to 76. He also prepared the double methylene isomer 77 (R = COEt) of geranyl propionate from the intermediate 75. The purpose of synthesizing this propionate was to prepare the pheromone of the San Jose scale, Quadraspidiotus pernicious, which is a mixture of the propionates of 73, 74,... 

The hydroxy ester (S)-B (92% ee) was converted to iodide (S)-C (4 steps). Inversion of the configuration of (S)-B to (-R)-D was possible by means of Mitsunobu inversion, which was further converted to (R)-C. Accordingly, both the enantiomers of C were prepared from the single enantiomer (S)-B. Alkylation of the dianion of methyl acetoacetate with (S)-C gave E, whose further alkylation with (S)-C afforded F. Successive treatments of F with base followed by acid effected hydrolysis, decarboxylation and acetaliza-tion to give (2S,6R,8S)-88 as a volatile oil. Similarly, (R)-C afforded (2R,6S,8R)-88. Both 88 and 88 were purified by chromatography and distillation, and they showed [a]o23 -51.6 (pentane) and +51.7 (pentane), respectively. 

Alkylation of the dianion of methyl acetoacetate with a,co-dihalides (n = 4 or 5) results in a mixture (ca. 1 1) of mono- (134) and bis- (135) alkylated products. Treatment of (134) with sodium methoxide in methanol then results in cyclization via the monoanion to seven- or eight-membered-ring /3-keto-esters alternatively, cyclization via the dianion affords y-cyclopentyl- or y-cyclohexyl- -keto-esters (Scheme 31). ... 

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