Krapcho procedure

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 . 

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],... 

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. 

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. 

Dialkylmalonic acids. Dianions of carboxylic acids have been prepared using LDA in THF-HMPT (4,301-302). Krapcho reports that trianions (2) of monosubstituted malonic acids (1) can be prepared with 3 equiv. of n-butyl-lithium in THF at 0°. These can be alkylated by primary halides to give dialkylmalonic acids (3). Alkylation cannot be achieved with secondary halides. This procedure is not applicable to malonic acid itself. 

A mild decarboxylation procedure was developed by Krapcho.223 When methyl ester 256 was treated with LiCl in DMSO, decarboxylation occurred to give a 78% yield of 257 in the Molander and Hass synthesis of davanone.224 xhis mild procedure is referred to as Krapcho decarboxylation. 

N-nitrosamines, and alkylidene cyano-esters can be decarboxylated using Krapcho s procedure (3,46) to give mixtures of a,jS-and /3,y-unsaturated nitriles in 55—60% yield. ... 

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