Krapcho reaction

Nucleophilic decarboxylation of p-ketoesters, malonate esters, a-cyanoesters, or a-sulfonylesters. 

Krapcho, A. P. Glynn, G. A. Grenon, B. J. Tetrahedron Lett. 1967, 215-217. A. Paul Krapcho is a professor at the University of Vermont. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 153, Springer International Publishing Switzerland 2014 

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Tab. 3.16 The Krapcho reaction under solvent-free PTC conditions.

Oxidative removal of the PMB group of the cyclopropane 987 followed by S-lactonization and Krapcho reaction furnishes tetrahydropyran-2-one 988, a key intermediate during the total synthesis of (+)-mycalamide A (Equation 385) <20060L875>. 

Loupy, A., Pigeon, P., Ramdani, M., Jacquault, P. A new solvent-free procedure using microwave technology as an alternative to the Krapcho reaction. J. Chem. Res., Synop. 1993, 36-37. 

Table 17. Krapcho reaction of -cyclic keto esters...

Several reviews have been written which cover the history of the Krapcho reaction through 1982.1,4 Further research in this area revealed the application of the decarboxylation method to compounds such as P-ketoesters, malonate esters, a-cyanoester, and a-sulfonylesters. The classical method for decarboxylation of these compounds usually involves acidic or basic hydrolysis, followed by thermal decarboxylation. Unfortunately, compounds containing acid or base sensitive functional groups are not compatible with these methods. Modem Krapcho conditions have replaced cyanide with less toxic halide anions. Additionally, several decarboxylations have occurred in the absence of salt.4... 

An important utility of the Krapcho reaction is not necessarily the decarboxylation step itself. Rather, the fact that the decarboxylation can be made to occur allows several reactions that require malonates or their derivatives to find general synthetic utility. For example, elegant work in the area of rhodium carbenoid chemistry relies on diazomalonates to generate the carbenoid. As utilized by Wee,20 diazomalonate 14 is treated with Rh20Ac4 to generate the carbenoid which inserts into the stereochemically defined tertiary C—H bond. The reaction proceeds exclusively with retention of configuration in forming the new quaternary carbon stereocenter. Decarboxylation of 15 under Krapcho s conditions provides lactone 16, a key intermediate in the synthesis of (-)-ebumamonine. 

In the synthesis of an intermediate to the antipsychotic drug ziprasidone, Krapcho conditions produced an unexpected side reaction.31 In trying to decarboxylate compound 53 to produce 54, by-products 55 and 56 were formed instead. Their formation was likely a result of the electron withdrawing substituents on the benzene ring. Although these products were unwanted and not part of the overall synthetic pathway, their formation is an interesting potential application of the Krapcho reaction when applied to compounds with electron withdrawing substituents, and could prove useful. 

The Krapcho reaction Dealkoxycarbonylation of activated esters occurs classically under drastic thermal conditions [150], 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 a halide anion and requires anionic activation, which can be provided by solvent-free PTC conditions under the action of microwave irradiation [151, 155]. These results illustrate the difficult example of cyclic yS-ketoesters with a quaternary carbon atom in the a position relative to each carbonyl group (Eq. 64), which classically gave only 20% yield using CaCl2 in DMSO under reflux for 3 h. Some typical results are summarized in Table 4.21. 

The synthesis of [ C]-labeled esters using a C-alkylation of diethyl malonate under microwave-enhanced solid-liquid phase transfer catalysis (PTC) conditions and a subsequent microwave-enhanced decarboalkoxylation (Krapcho reaction) [167] indicates that an alternative approach to the preparation of [ C]-labeled fatty acids/esters [168] with less harsh conditions may be possible. 

Enolate Formation. Molander and coworkers report a synthetic route toward the marine metabolite eunicellin diterpenes (eq 71). Treatment of a tricyclic -keto ester intermediate with BuLi and subsequent y-methylation occur with complete diastereoselectivity the concluding Krapcho reaction not only removes the methoxycarbonyl group, but also effects epimerization of the newly formed stereogenic center. A subsequent epoxide intermediate is reduced using Sharpless reagent (WCl /BuLi) to provide the required olefin. ... 

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