Krapcho conditions

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],... 

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],... 

In the laboratory of A. Ftirstner, a practical synthesis of the immunosuppressive aikaioid metacycioprodigiosin and its functional derivatives was developed. Toward the end of the synthetic sequence a mefa-pyrrolophane (3-keto ester was decarboxylated under standard Krapcho conditions. The substrate was dissolved in wet DMSO, and two equivalents of sodium chloride were added and the reaction mixture was heated to 180 °C to afford the desired meta-pyrrolophane ketone in excellent yield. This ketone functionality was first converted to an ethyl group and then the product was advanced to metacycioprodigiosin. 

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 intramolecular conjugate addition of a P-ketoester 46 was utilized in the synthesis of racemic isoclovene.26 Initially the crystalline tricylic compound 47 was synthesized by a facile intramolecular Michael addition using K2CO3 as the base. Removal of the P-keto ester was then completed under Krapcho conditions, producing the tricylic diketone 48. 

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. 

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. ... 

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

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. 

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. 

Decarboxylation.—Krapcho s group has published details of a systematic study of the decarboxylation of geminal diesters and /3-keto-esters by the widely used wet dimethyl sulphoxide-salt method. Although optimum conditions are obviously substrate dependent, the system DMS0-H20-LiCl is often the best choice. When a similar decarboxylation of geminal diesters is carried out in hexamethylphosphoramide at ca. 155 C in the presence of diphenyl disulphide, a-phenylthioesters are generated in yields usually less than 60% f ... 

These alkylation procedures can benefit greatly from the use of microwave activation, which can reduce reaction times by a factor of 60. Moreover, the often tedious separation of high boiling solvents (DMF, DMSO, HMPA) can be omitted, if reactions are conducted under solvent-free conditions in the presence of ferf-BuOK as a base and a phase transfer catalyst such as Aliquat 336. Chemical yields are comparable to those obtained using classical procedures and only traces of dialkylated byproducts have been detected. Moreover, microwave treatment of the diester product with LLF or LiCl (Krapcho procedure) under solvent-free conditions provides the corresponding mono-ester by selective decarbalkoxylation . 

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