Krapcho decarboxylation

What is Krapcho decarboxylation?

The Krapcho decarboxylation is a well-studied process that was first explored by Krapcho in 1967. This reaction is a decarboxylation reaction that occurs in the presence of an alkali halide and active esters such as β-keto esters, β-diesters, and α-cyano esters in polar or dipolar aprotic solvents such as DMF, DMSO, and HMPA.

The Krapcho decarboxylation is also known as the Krapcho reaction or Krapcho condition and sometimes referred to as the Krapcho decarbalkoxylation. The Krapcho decarboxylation can also occur on methyl esters, known as the Krapcho decarbomethoxylation, and ethyl esters, referred to as the Krapcho decarboethoxylation.

Krapcho decarboxylation - general reaction scheme - Krapcho reaction - Krapcho condition - Krapcho decarbalkoxylation
Krapcho decarboxylation

Several systems have been used for decarbalkoxylation, including NaCN/DMSO, LiCl/HMPA/H2O, LiCl/DMSO/H2O, LiBr/HMPA/H2O, LiI/NaCN/DMF/H2O, NaCl/DMF/H2O, and tetramethylammonium acetate (Me4NAc). Among halide salts, NaCl, NaBr, KCl, and Me4NBr in solvents such as DMSO and HMPT have been used for internal alkylative decarboxylation, while LiCl in HMPT has been used for external alkylative decarboxylation. β-keto esters with an α-hydrogen undergo decarboxylation rapidly in wet DMSO.

While iodides are commonly used in the Krapcho decarboxylation due to their prior application for cleavage of methyl esters, tetramethylammonium acetate can avoid the loss of stereohomogeneity of the double bond. Among alkali chlorides, LiCl works better than NaCl due to the difference in their solubility in DMSO. However, LiF is ineffective, presumably because it exists as a contact ion pair in the solution. In addition, LiCl or KCN is the most effective salt for removing ethyl ester in wet DMSO. The reaction is accompanied by the formation of lithium carbonate (Li2CO3) when LiCl is used, and the reaction rate is not in first-order kinetics in terms of LiCl concentration. The largest rate increase is observed in the presence of LiCl, and a much smaller rate enhancement is noticeable afterward. MgCl2, Na3PO4·12H2O, and lithium acetate (LiAc) are also somewhat effective for the alkylative decarboxylation, and the effectiveness of Na3PO4·12H2O is due to its high pH in aqueous solution.

It has been found that electron-withdrawing substituents facilitate the alkylative decarboxylation, while steric hindrance might retard the reaction. For instance, diethyl and dimethyl disubstituted malonates do not undergo decarboxylation when heated in DMSO/H2O.