Decarboxylation of 3-keto ester

Boric acid has been used to catalyze the decarboxylation of /3-keto esters and ji-imino esters [4,5]. A convenient method for producing y-keto esters from diethyl a-acylsuccinates in high yield is shown in Eq. (2) [4], The conventional method of saponification, decarboxylation, and re-esterification gives low yields. 

In addition to the classic sequence of saponification-acidification followed by heating, the decarboxylation of (3-keto esters can be effected by more direct methods such as decarbalkoxylation. For example, heating (3-keto esters in the presence of lithium halides in H2O-DMSO25 or in H20-collidine produces ketone products in one-pot transformations, as shown below. 

Miscellaneous Reactions. Alcohols, including tertiary ones, can be converted to their acetoacetates by reaction with Diketene in the presence of DM AP at rt. Decarboxylation of /3-keto esters has been carried out at pH 5-7 using 1 equiv of DMAP in refluxing wet toluene (eq 5). ... 

Not surprisingly, the useful ester dealkylating agent MeaSil (see ref. 65) can be used for the decarboxylation of /3-keto-esters and geminal diesters the avoidance of exposure of the substrate to strong aqueous acid or base is an advantage with this method. Similar transformations can be effected by thermolysis (170— 190 °C) with boric acid. ... 

Ester hydrolysis Hydrolytic decarboxylation of /3-keto esters Esterification... 

The majority of publications on transesterification catalyzed by solid acids have focused on the reaction of 3-keto esters. Transesterification provides an alternative route to synthesize these kinds of esters since direct preparation from P-keto acids is not a good option given that they can easily undergo decarboxylation. Table 11 provides a review of results in the literature relating to the transesterification of P-keto esters with alcohols. 

The self-condensation of /3-keto esters and related compounds occurs under the influence of either acidic or basic catalysts and constitutes one of the earliest syntheses of pyran-2-ones (l883LA(222)l). It exemplifies a synthesis of type (ii) (Scheme 85). Ethyl acetoacetate, for instance, gives a mixture of 4,6-dimethyl-2-oxopyran-5-carboxylic acid and its ethyl ester other esters behave similarly (59RTC364). Decarboxylation of the pyrancarboxylic acid occurs at 160 °C in sulfuric acid. The formation of the pyranone proceeds through a 5-keto ester which is considered to result from attack of the enolic form of the ester on protonated ethyl acetoacetate (51JA3531). A detailed synthesis of the pyran-5-carboxylic acid is available <630SC(4)549). 

The thermal decarboxylation of 3-keto acids is the last step in a ketone synthesis known as the acetoacetic ester synthesis. The acetoacetic ester synthesis is discussed in Section 21.6. 

The major application of 3-keto esters to organic synthesis employs a similar pattern of ester saponification and decarboxylation as its final stage, as described in the following section. 

A convenient method for preparing alicyclic or aromatic methyl ketones consists in the acylation of the ethoxymagnesium derivative of diethyl malonate with the appropriate acyl chloride, followed by acid hydrolysis and decarboxylation of the resulting /3-keto diester. The last step is Carried out like the ketonic cleavage of /3-keto esters. The over-all yields are 60-85%. 

C.H. Heathcock and co-workers devised a highly convergent asymmetric total synthesis of (-)-secodaphniphylline, where the key step was a mixed Claisen condensation. In the final stage of the total synthesis, the two major fragments were coupled using the mixed Claisen condensation] the lithium enolate of (-)-methyl homosecodaphniphyllate was reacted with the 2,8-dioxabicyclo[3.2.1]octane acid chloride. The resulting crude mixture of (3-keto esters was subjected to the Krapcho decarboxylation procedure to afford the natural product in 43% yield for two steps. 

Section 21.5 Hydrolysis of (3-keto esters, such as those shown in Table 21.1, gives (3-keto acids which undergo rapid decarboxylation, forming ketones. 

Example. Another important fi agmentation reaction is the decarboxylation of (3-keto acids invariably employed for synthesis in conjruiction with construction reactions, such as Michael Reaction (Addition, Condensation) i.e., addition of acetoacetic and malonate esters. 

Kulkarni and Ganesan [21] reported the synthesis of /3-keto esters via sequential Baylis-Hillman and Mizoroki-Heck reactions. The reaction of the Bayhs-Hillman product 14 with bromophenol yielded the corresponding Mizoroki-Heck coupling product 15, which, after cleavage from the resin with concomitant decarboxylation, afforded aryl ketone 16 (Scheme 14.4). A small library of 25 compounds was prepared in this way with overall yields up to 49%. 

Decarboxylation of P-keto-esters is facile in aqueous DMSO, but in less reactive cases decarboxylation is accelerated by sodium chloride. Condensation reactions of dibenzocycloheptadienone (334) with aromatic aldehydes have been reported. Syntheses of the heterocyclic carboxylic acids (335) have been described. No effect of the heterocycle s ring current on the chemical shifts of the methylene protons could be detected in the n.m.r. spectrum of the nonamethylene-thiadiazine dioxide (336), which was prepared from cyclododecane-l,3-dione. ... 

Needless to say, /3-keto esters are important compounds in organic synthesis. The usefulness of /3-keto esters has been remarkably expanded based on Pd-catalyzed reactions of allyl j8-keto carboxylates. Cleavage of the allylic carbon-oxygen bond and facile decarboxylation occur by the treatment of allyl /3-keto carboxylates with Pd(0) catalysts. 

Dimethyltetrahydrofuran-3-one (175) has been synthesized in several ways (Scheme 6). The 3-ol is oxidized to the 3-one (175) by chromium trioxide in pyridine but is cleaved by lead tetra-acetate in benzene. Hydrochloric acid catalyses cyclization of 2-(benzyloxy)ethyl diazomethyl ketone (176) to (175), and hydrolysis and decarboxylation of the / -keto-ester (177) is also a preparatively useful method. 

The reasonable mechanism outlined above has not yet been rigorously proven in every detail, but is supported by the fact that a 1 1-intermediate 5 has been isolated." The ester groups are essential for the Weiss reaction because of the /3-keto ester functionalities however, the ester groups can be easily removed from the final product by ester hydrolysis and subsequent decarboxylation. 

The three-step sequence of 0) enolate ion formation, (2) alkylation, and (3) hydrolvsis/decarboxylation is applicable to all /Tketo esters with acidic a hydrogens, not just to acetoacetic ester itself. For example, cyclic /3-keto esters such as ethyl 2-oxocycIohexanecarboxylate can be alkylated and decarboxy-lated to give 2-substituted cyclohexanones. 

The cyclic /3-keto ester produced in a Dieckmann cyclization can be further alkylated and decarboxylated by a series of reactions analogous to those used in the acetoacetic ester synthesis (Section 22.7). For example, alkylation and subsequent decarboxylation of ethyl 2-oxocyclohexanecarboxylate yields a 2-alkylcvclohexanone. The overall sequence of (1) Dieckmann cyclization, (2) /3-keto ester alkylation, and (3) decarboxylation is a powerful method for preparing 2-substituted cyclohexanones and cyclopentanones. 

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). 

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