Decarboxylation Hofer-Moest reaction

The conversion of carboxylic acids into alcohols with one less carbon atom is an important synthetic transformation. Such decarboxylative hydroxylations have proven to be difficult to accomplish by classical ionic methods. Electrochemical decarboxylation (Hofer-Moest reaction) [23] has been applied successfully to different types of carboxylic acids such as amino acids (Scheme 11, Eq. 11.1) [24]. This reaction proceeds through an intermediate radical that is further oxidized to a car-benium ion and trapped by the solvent. The efficiency of the second oxidation step (the formation of the carbenium ion) depends on the ionization potential of the in-... 

A mixture of water/pyridine appears to be the solvent of choice to aid carbenium ion formation [246]. In the Hofer-Moest reaction the formation of alcohols is optimized by adding alkali bicarbonates, sulfates [39] or perchlorates. In methanol solution the presence of a small amount of sodium perchlorate shifts the decarboxylation totally to the carbenium ion pathway [31]. The structure of the carboxylate can also support non-Kolbe electrolysis. By comparing the products of the electrolysis of different carboxylates with the ionization potentials of the corresponding radicals one can draw the conclusion that alkyl radicals with gas phase ionization potentials smaller than 8 e V should be oxidized to carbenium ions [8 c] in the course of Kolbe electrolysis. This gives some indication in which cases preferential carbenium ion formation or radical dimerization is to be expected. Thus a-alkyl, cycloalkyl [, ... 

Hofer-Moest reaction. We do not attempt this discrimination as the electrochemical decarboxylation of carboxylates is always a blend of both pathways. 

A -Acylated amino acids are anodically oxidized in methanol or acetic acid solution under decarboxylative methoxylation or acetoxylation via the intermediate A-acyliminium ion in the course of a Non-Kolbe reaction (Hofer-Moest reaction) according to Scheme 8, path b. This type of reaction has been used intensively for amidoalkylation reactions by Mori, Seebach, and Steckhan. These reactions were based on the results of Iwasaki applying N-acyl aminomalonic acid half esters [Eq. (46)] [239]. 

Oxidative decarboxylation, as in the Kolbe reaction, is one of the oldest of all electrochemical oxidations. Whether such reactions parallel any reactions that occur in nature is still in question. Actually, the reaction can take two courses loss of an electron from a carboxylate and decarboxylation to form a radical which dimerizes or reacts with another radical, or loss of an electron followed by decarboxylation and loss of a second electron to form a carbocation (The Hofer-Moest reaction, 33). The carbocation may then be neutralized by reaction with nucleophile or another source of electrons. 

A vast literature is available on the Hofer-Moest reaction. The generation of oxonium, iminium, and thionium cations, by two-electron oxidative decarboxylation, has been reported (Scheme 9) [26-29]. 

The oxidation of the sugar-containing carboxylic acid 52, in the presence of acetate, leads to the unsymmetrical bis-acetal 53 [30]. In a similar manner, 0,N-acetals can be efficiently constructed from alpha-amino-acids [24]. This process has been employed as a key step in the synthesis of some beta-lactam antibiotics [31]. The oxidative decarboxylation of alpha-alkoxy acids 58 in methanol provides a simple and efficient route to the formation of MOM ethers and obviates the use of the highly toxic MOMCl [32]. Furthermore, Mark6 et al. demonstrated that Hofer-Moest reaction of dialkoxy carboxylic acids 60 offers an easy and general route to variously functionalized orthoesters [33]. These are usually difficult to prepare by alternative methodologies and some of them can only be assembled using this electrochemical process. 

The electrochemistry of amino acids has been studied in strong acid solutions. In general, the compounds are decomposed to carboxylic acids, aldehydes, ammonia, and carbon dioxide. The results are reviewed by Weinberg [35]. The anodic oxidation mechanism has been studied in pH 10 buffer solution. Decarboxylation accompanied by C-N bond cleavage is the main reaction process [182]. The synthetically interesting Hofer-Moest decarboxylations of A/ -protected amino acids and a-amino malonic half esters under the formation of A/ -acyliminium ions is treated in the following section. 

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