The Krapcho reaction

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). 

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

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. 

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. 

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],... 

The reaction is a decarboxylation of the Krapcho type,6 in the course of which one of the two ester groups of the starting malo-nate is removed and replaced by a proton. What results is ester 12. The only aspect of the reaction mechanism that has been established is that it does not proceed via the free acid. Krapcho himself has proposed the following mechanism ... 

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>. 

A highly exo-selective asymmetric hetero Diels-Alder reaction was the key step in D.A. Evans total synthesis of (-)-epibatidine. The bicyclic cycloadduct was then subjected to a fluoride-promoted fragmentation that afforded a (f-keto ester, which was isolated exclusively as its enol tautomer. The removal of the ethoxycarbonyl functionality was achieved using the Krapcho decarboxylation. Interestingly, the presence of a metal salt was not necessary in this transformation. Simply heating the substrate in wet DMSO gave rise to the decarboxylated product in quantitative yield. 

The Krapcho decarboxylation is the nucleophilic decarboxylation of malonate esters, p-ketoesters, a-cyanoesters, a-sulfonylesters, and related compounds. The reaction is done in dipolar aprotic solvents in the presence of salt and/or water at high temperatures.1... 

The Krapcho decarboxylation was also utilized as a beneficial side reaction in the key step in the Deslongchamps synthesis of (+)-maritimol.18 In this asymmetric synthesis, the Lewis acid mediated intramolecular Diels-Alder reaction of 11 to produce 12 was followed by thermal decarboxylation to yield 13. The thermal Diels-Alder reaction of 11 was then tested and found to proceed in slightly higher yield and resulted in decarboxylation occurring in the same pot. Remarkably, the complete diastereo- and enantiocontrol in this reaction is directed by the remote nitrile stereocenter. Additional... 

A second methodology relies on the use of unsaturated malonates as electrophiles in conjugate addition reactions, thus necessitating removal of the ancillary ester group. Enders and co-workers24 have shown a general method for preparation of semialdehyde derivatives, such as 40, which utilized the Krapcho decarboxylation reaction. In this case, conjugate addition of SAMP-hydrazone 36 proceeded with excellent selectivity to... 

Malonate and related activated methylene compounds have also been used as the nucleophile in conjugate addition/Michael reactions. Taylor and co-workers have developed a new methodology that utilizes (salen)aluminum complexes such as 43 as a catalyst to effect the enantioselective conjugate addition to a,p-unsaturated ketones by a variety of nucleophiles.25 For example, nitriles, nitroalkanes, hydrazoic acids, and azides have found utility in this reaction. Additionally, cyanoacetate (42) has been demonstrated to undergo a highly enantioselective conjugate addition to 41. The Krapcho decarboxylation is then necessary to produce cyanoketone 44, an intermediate in the synthesis of enantioenriched 2,4-cw-di substituted piperidine 45. 

Activated methylene compounds such as dimethyl malonate have found substantial utility in palladium catalyzed allylic substitution reactions. Accordingly, the Krapcho decarboxylation is often used in conjunction with these reactions. As an example, the first total synthesis of enantiomerically pure (-)-wine lactone has utilized the sequence of reactions.27 First, the allylic substitution reaction of 2-cyclohexen-l-yl acetate (49) with alkali sodium dimethylmalonate yielded 51 with high enantioselectivity, as a result of the use of chiral phosphine ligand 50. The malonate was then subjected to Krapcho decarbomethoxylation using NaCl, H2O, and DMSO at 160 °C to yield 52. This reaction has been used similarly following the allylic substitution reaction with other malonate derivatives.28-30... 

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. 

Butyl glyoxylate reacts normally only with l ,3-butadienyl ether 289. However, David and co-workers have found that with the more active dienophile, diethyl mesoxalate, lZ,3-butadienyl ether (290) could also enter into cycloaddition, although the reaction was appreciably slower. The resulting cycloadducts 293 and 294 were decarboethoxylated according to the Krapcho method, furnishing the a-o (295) and a-L (296) as the main products. 

This reaction was studied comprehensively by Krapcho beginning as early as 1967. It is an alkali halide promoted alkylative decarboxylation of active esters (e.g., )8-keto esters, fi-diesters, a-cyano esters) in polar or dipolar aprotic solvents (e.g., DMF, DMSO, HMPA,) and is generally known as the Krapcho decarboxylation or Krapcho condition. Occasionally, it is also referred to as the Krapcho decarbalkoxylation. In addition, the corresponding decarboxylation on methyl esters is known as the Krapcho decarbomethoxylation, and the decarboxylation of ethyl esters is referred to as the Krapcho decarbo-ethoxylation. ... 

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. ... 

For a review of the preparation of spiro compounds by this reaction, see Krapcho, A.P Synthesis, 1978, 77. 

This type of reaction is usually best performed in DMSO solution. A simpler procedure has been proposed which uses anionic activation and microwave irradiation, with a metallic salt as the reagent and a PTC in the absence of solvent [75], This procedure was applied to the striking example of cyclic /J-ketoesters with considerable improvements (Eq. 53 and Tab. 5.25) which are readily apparent when the maximum yields obtained under classical Krapcho conditions (<20% when R-H) are considered [76],... 

The stereospecific rhodium-catalyzed allyhc hnchpin cross-couphng reaction provides an expeditious route to stereotetrads (Scheme 10.5). This study demonstrated that improved stereospecificity could be obtained at lower temperature for the formation of the alkylation product 18 (2° 1°=24 1 ds=26 l compare Tab. 10.2, entry 1). Krapcho... 

With no major research on the reaction of phosphorus ylides and aliphatic or alicyclic thiones prior to their investigation, Krapcho et where able to elaborate a useful method for the synthesis of the thietane ring system in addition to the preparation of novel types of thiocarbonyl stabilized ylides (Eq. 1). 

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