Dianions of acetoacetic ester

Diethyl 3-oxoheptanedioate, for example, is clearly derived from giutaryl and acetic acid synthons (e.g. acetoacetic ester M. Guha, 1973 disconnection 1). Disconnection 2 leads to acrylic and acetoacetic esters as reagents. The dianion of acetoacetic ester could, in prin-ciple,be used as described for acetylacetone (p. 9f.), but the reaction with acrylic ester would inevitably yield by-products from aldol-type side-reactions. 

Nakada, M., Iwata, Y., Takano, M. Reaction of dianions of acetoacetic esters with epibromohydrin derivatives a novel synthesis of tetrahydrofuran derivatives and tetrahydropyran derivatives. Tetrahedron Lett. 1999,40, 9077-9080. 

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

The dianion of acetoacetate undergoes Claisen condensations with tetramethyldiamide derivatives of dicarboxyhc acids to produce polyketides in the presence of BF3-OEt2 (eq 15). Similarly, 3,5-dioxoalkanoates are synthesized from tertiary amides or esters with the acetoacetate dianion in the presence of Bp3-OEt2 (eq 16). ... 

Schneider and Simon82 prepared / -ketosulfoxides 47a and 47b by sulfinylation of the dianions of the methyl acetoacetates 48a and 48b with sulfinate ester 19 followed by decarboxylation of the intermediate products (Scheme 2). Apparently this avoids racemiz-ation experienced by others in the direct synthesis of these compounds9. /J-Ketosulfoxides are also available from the reaction of the anion derived from methyl p-tolyl sulfoxide with esters (see Section II.E). They can also be obtained, in some cases, through the hydrolysis of a-sulfinylhydrazones whose synthesis is described below. Mention has already been made of the synthesis of 2-p-tolylsulfinylcycloalkanones such as 32. 

Acetoacetic ester is converted to a dianion by 2 moles of a very strong base. 

Acylation of the dianion of ethyl acetoacetate by an ester is a useful addition to this area of pyranone synthesis. In this reaction and in the formation of the trianions of 2,4,6-triketones the use of lithium diisopropylamide as the base is valuable (76JA7733). The triketo acid from the trianion cyclizes in mineral acids to the pyran-4-one, but in acetic anhydride the pyran-2-one is formed (Scheme 101) (71JA2506). 

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... 

The scope of the strategy was then extended in spectacular fashion (Scheme 6). The mixture of 19 and 20 was transformed into the corresponding aldehydes 26 through reduction/oxidation of the ester groups. Treatment with the dianion derived from ethyl acetoacetate then led to hydroxyketones 27. Chelation-controlled, syn-selective reduction [9] of this mixture followed by menthonide formation gave 28 as four diaste-... 

An improved version of the Carroll reaction, the ester enolate Carroll rearrangement, was reported in 1984 by Wilson and Ptice. Dianions of allylic acetoacetates, generated by treatment with 2 equiv. of LDA at -78 °C in THF, were rearranged at room temperature or 65 C to yield >keto acids in 40-80% yield (equation 12). In the course of a synthesis of the sesquiterpene isocomene, Snider and Beal used this method for the rearrangement of acetoacetate (73), prepared in 83% yield from reaction of cyclopen-tene (72) with diketene and a catalytic amount of DMAP (Scheme 11). The ( )-isomer of ketone (74) is obtained stereospecifically, since there is a severe steric interaction between the methyl groups in the Carroll rearrangement transition state leading to the (Z)-isomer. 

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. 

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]. 

Taylor, E.C., and Davies, H.M.L., Rhodium(II) acetate-catalyzed reaction of ethyl 2-diazo-3-oxopent-4-enoates. Simple routes to 4-aryl-2-hydroxy-l-naphthoates and P,y-iinsaliiralcd esters. The dianion of ethyl 4-(diethylphosphono)acetoacetate as a propionate homoenolate equivalent, Tetrahedron Lett., 24, 5453. 1983. 

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. 

A further improvement is the ester enolate Carroll rearrangement of the dianion of allylic acetoacetates. generated by treatment with two equivalents of lithium diisopropylamide at — 78 C in tetrahydrofuran100. The dianions rearrange at 20 C to 65 C in 40-80% yield. For an example, see p 3320. 

Seebach and co-workers have explored the uses of enantiomerically pure dienolates (18) and silyl dienol ethers derived from dioxinones as chiral synthetic equivalents of the acetoacetic ester dianion. Reactions were carried out principally with aldehydes, and are regio- and diastereoselective (Scheme 7) <89AG(E)472,91CB1845>. 

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