Acetoacetic acid, allyl esters

An alternative route to y,5-unsaturated ketones is via the Carroll-Claisen rearrangement, which uses allylic esters of 3-keto acids (which exist mainly in the enol form) as substrates. These are readily prepared by condensation of allylic alcohols with acetoacetic esters or diketene. Following rearrangement, the intermediate keto acid undergoes in situ decarboxylation on heating. 

In contrast to facile Pd(0)-catalyzed reactions of allyl esters with soft carbon nucleophiles via r-allylpalladium intermediate, propargyl esters such as acetate are less reactive toward soft carbon nucleophiles. However, /3-keto esters and malonates react under neutral conditions with propargyl carbonates using DPPE as a ligand [37], Acetoacetate reacts with meAyl propargyl carbonate (119) in THF at room temperature to afford 4-(methoxycarbonyl)-5-methyl-3-methylene-2,3-dihydrofuran (120) in 88 % yield. The furan 121 was obtained by isomerization of the methylenefuran 120 under slightly acidic conditions. 

Allylic esters of acetoacetic acid undergo Pd(OAc)2-PPh3-catalysed rearrangements to y,(S-unsaturated methyl ketones in high yield with elimination of carbon dioxide. As an illustration of this process the conversion of the /S-keto-ester (4) into a methyl ketone product is typical (Scheme 8). 

Shimizu I, Yamada T, Tsuji J. Palladium-catalyzed rearrangement of allylic esters of acetoacetic acid to give y, 8-unsaturated methyl ketones. Tetrahedron Lett. 1980 21 3199-3202. 

Methylsuccinic acid has been prepared by the pyrolysis of tartaric acid from 1,2-dibromopropane or allyl halides by the action of potassium cyanide followed by hydrolysis by reduction of itaconic, citraconic, and mesaconic acids by hydrolysis of ketovalerolactonecarboxylic acid by decarboxylation of 1,1,2-propane tricarboxylic acid by oxidation of /3-methylcyclo-hexanone by fusion of gamboge with alkali by hydrog. nation and condensation of sodium lactate over nickel oxide from acetoacetic ester by successive alkylation with a methyl halide and a monohaloacetic ester by hydrolysis of oi-methyl-o -oxalosuccinic ester or a-methyl-a -acetosuccinic ester by action of hot, concentrated potassium hydroxide upon methyl-succinaldehyde dioxime from the ammonium salt of a-methyl-butyric acid by oxidation with. hydrogen peroxide from /9-methyllevulinic acid by oxidation with dilute nitric acid or hypobromite from /J-methyladipic acid and from the decomposition products of glyceric acid and pyruvic acid. The method described above is a modification of that of Higginbotham and Lapworth. ... 

Keto esters such as acetoacetate without a substituent at the a-carbon. namely with two acidic protons, first attack the central carbon of the allenylpal-ladium to form the zr-allyl complex 89. Then intramolecular attack of the enolate oxygen of the 0-keto ester at the rr-ully l system takes place to form the nieihv-lenedihydrofuran 90 as a primary product, which is easily isomerized to the turn 91. The /3-diketone 92 reacts similarly to give the furan 93[40], The reaction can be applied to the synthesis of the phenyIthiomethyl-substituted furan 94. which is useful for the synthesis of natural products such as neoliacine. [41]... 

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. 

The substrates can easily be prepared by the condensation of an allylic alcohol with acetoacetic ester. Another approach is the reaction of 5-acyl Meldrum s acid with allylic alcohols214. Treatment of diketene with an allylic alcohol in the presence of catalytic amounts of 4-(dimeth-ylaminojpyridine215 at 20 SC followed by stirring at 20 C makes the generation of the substrates routine (80-93 %100). 

More complex products are obtained from cyclizations in which the oxidizable functionality and the alkene are present in the same molecule. y9-Keto esters have been used extensively for Mn(III)-based oxidative cyclizations and react with Mn(OAc)3 at room temperature or slightly above [4, 10, 11, 15], They may be cyclic or acyclic and may be a-unsubstituted or may contain an a-alkyl or chloro substituent. Cycloalkanones are formed if the unsaturated chain is attached to the ketone. y-Lactones are formed from allylic acetoacetates [10, 11]. Less acidic /3-keto amides have recently been used for the formation of lactams or cycloalkanones [37]. Malonic esters have also been widely used and form radicals at 60-80 °C. Cycloalkanes are formed if an unsaturated chain is attached to the a-position. y-Lactones are formed from allylic malonates [10, 11]. yff-Diketones have been used with some success for cyclizations to both alkenes and aromatic rings [10, 11]. Other acidic carbonyl compounds such as fi-keto acids, /3-keto sulfoxides, j8-keto sulfones, and P-nitro ketones have seen limited use [10, 11]. We have recently found that oxidative cyclizations of unsaturated ketones can be carried out in high yield in acetic acid at 80 °C if the ketone selectively enolizes to one side and the product cannot enolize... 

Polymer bound acrylic ester is reacted in a Baylis-Hillman reaction with aldehydes to form 3-hydroxy-2-methylidenepropionic acids or with aldehydes and sulfonamides in a three-component reaction to form 2-methylidene-3-[(arylsulfonyl)amino]propionic acids. In order to show the possibility of Michael additions, the synthesis of pyrazolones was chosen. The Michael addition was carried out with ethyl acetoacetate and BEMP as base to form the resin bound p-keto ester. This was then transformed into the hydrazone with phenylhydrazine hydrochloride in the presence of TMOF and DIPEA [28]. The polymer bound phenol was readily coupled to a variety of allyl halides by using the Pl- Bu to generate a reactive phenoxide [29]. 

Crotonic acid was discovered in croton seeds by Pelletier and Caventou by saponifying the oil, adding tartaric acid, and distilling, but was more definitely characterised by T. Schlippe. Crotonitrile C4H5N, present in crude mustard oil, yields on hydrolysis with alcoholic potash crotonic acid C4He02, and crotonitrile is formed from allyl iodide and potassium cyanide hence the acid was formulated CH2 = CH-CH2 C02H. An isomeric acid was discovered by A. Geuther in the form of an acid chloride in the products of the action of phosphorus pentachloride on acetoacetic ester. 

Historically, as early as 1937, the first enolate Claisen rearrangement, though it was not formally recognized as such, was documented. Tseou and Wang [12] reported the formation of 4-pentenoic acid in low yields on heating neat allyl acetate with sodium metal for 3 h to ca. 100°C while attempting the acetoacetic ester synthesis (Scheme 5.1.1). 

The use of NaOH in alcohol is recommended for alkylations of ethyl acetoacetate with halides of intermediate or high reactivity. NaOH cannot be used for alkylations of diethyl malonate or other esters which have a much lower acidity than ethyl acetoacetate.—E Ethyl acetoacetate followed by 1.2 moles of allyl bromide added to a soln. of NaOH in 99.5%-alcohol, and refluxed several hrs. until neutral -> ethyl allylacetoacetate. Y 74%. A. Brandstrom, Acta Ghem. Scand. 13, 607 (1959). 

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