Dealkoxycarbonylation

A divergent synthesis of tropane alkaloid ferruginine was reported by Node and coworkers [59]. The P-ketoester intermediate was prepared by a novel PLE-catalyzed asymmetric dealkoxycarbonylation (hydrolysis followed by a decarboxylation) of a symmetric tropinone-type diester (Figure 6.12). Dimethyl sulfoxide was added to the phosphate buffer pH 8 (1 9) to reduce the activity of PLE and prevent over-deal-koxycarbonylation leading to tropinone. 

Similar alkene formations via dealkoxycarbonylation and denitration have been reported for the synthesis of novel heterocycles. Heterocyclic nitro compounds such as 4-nitroisoxazole undergo the Diels-Alder reaction subsequent dealkoxycarbonylation and denitration give the products, which are regarded as the Diels-Alder adducts of five-membered heterocyclic arynes (Eq. 7.142).121... 

Whereas pyrrole was reported not to give N/H insertion by ketocarbenoids, such a reaction mode does occur with imidazole Copper-catalyzed decomposition of ethyl diazoacetate at 80 °C in the presence of imidazole gives ethyl imidazol- 1-ylacetate exclusively (93 %) small amounts of a C-alkylated imidazole were obtained additionally under purely thermal conditions 244). N/H insertion also takes place at benzimidazole 245 a). The reaction is thought to begin with formation of an N3-ylide, followed by N1 - C proton transfer leading to the formal N/H insertion product. Diazomalonic raters behave analogously however, they suffer complete or partial dealkoxycarbonylation under the reaction conditions 244) (Scheme 34). N-alkylation of imidazole and benzimidazole by the carbenoids derived from co-diazoacetophenone and 2-(diazoacetyl)naphthalene has also been reported 245 b>. 

A similar dealkoxycarbonylation reaction utilizing the Krapcho conditions was used by Moberg and coworkers in the synthesis of (R)-badofen (Scheme 6.161b) from a chiral malonate precursor (see Scheme 6.52) [108],... 

Dealkoxycarbonylation of activated esters occurs classically under drastic thermal conditions [90]. It constitutes a typical example of a very slow-reacting system (with a late TS along the reaction coordinates) and is therefore prone to a microwave effect. The rate determining step involves a nucleophilic attack by halide anion and requires anionic activation, which can be provided by solvent-free PTC conditions under the action of microwave irradiation [91]. The above results illustrate the difficult example of cyclic /1-ketoesters with a quaternary carbon atom in the a position relative to each carbonyl group (Eq. 36). 

Dealkoxycarbonylation of the malonate can also be accomplished directly with water at elevated temperature [137]. 

Dealkoxycarbonylation This reaction can be conducted by heating a ma-lonic or (3-keto ester at 200° in the presence of a catalytic amount of this phos-phonium salt and a high molecular weight carboxylic acid such as stearic acid as the solvent and proton source. The reaction involves catalyzed transesterification followed by decarboxylation. Yields are typically 70-90%. 

Dealkoxycarbonylation.1 Enolizable P-keto esters undergo this reaction in 60-70% yield when refluxed in slightly aqueous toluene (90°) containing 1 equiv. of DMAP and buffered to pH 5-7. DABCO, N,N-dimethylaniline, and pyridine are not effective. 

Synthetic Applications of Dealkoxycarbonylation of Malonate Esters, p-Keto Esters, a-Cyano Esters and Related Compounds in Dipolar Aprotic Solvents. Krapcho, A. Synthesis, 1962, 805, 893,... 

Dealkoxycarbonylation. 3-Keto esters and malonic esters with an enolizable proton ct to the ester group undergo dealkoxycarbonylation in 80-95% yield when heated in propionic acid for 24-72 hours. P-Kcto esters can also be cleaved by refluxing in acetic acid. The requirement for an a-proton suggests that the reaction involves loss of ROH to give a ketene intermediate. The propionic acid is converted into the anhydride. 

The mechanism of the Krapcho dealkoxycarbonylation is dependent on the structure of the substrate ester and the type of anion used. In the case of a,a-disubstituted diesters (especially the methyl esters), the anion from the salt (cyanide ion in the scheme) attacks the alkyl group of the ester in an Sn2 fashion and the decarboxylation results in the formation of a carbanionic intermediate that is quenched by the water. In the case of a-monosubstituted diesters the cyanide attacks the carbonyl group to form a tetrahedral intermediate, which breaks down to give the same carbanionic intermediate and a cyanoformate, which is hydrolyzed to give carbon dioxide and an alcohol. 

Krapcho dealkoxycarbonylation Decarboxylation of P-keto esters using alkali metal salts. 252... 

Krapcho, A. P. Synthetic applications of dealkoxycarbonylations of malonate esters, 3-keto esters, a-cyano esters and related compounds in dipolar aprotic media. Part II. Synthesis 1982, 893-914. 

Gilligan, P. J., Krenitsky, P. J. Divergent mechanisms for the dealkoxycarbonylation of a 2-(3-azetidinyl)malonate by chloride and cyanide. Tetrahedron Lett. 1994, 35, 3441-3444. 

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