Vitamin benzoin condensation

When, in 1832, Wohler and Liebig first discovered the cyanide-catalyzed coupling of benzaldehyde that became known as the benzoin condensation , they laid the foundations for a wide field of growing organic chemistry [1]. In 1903, Lapworth proposed a mechanistical model with an intermediate carbanion formed in a hydrogen cyanide addition to the benzaldehyde substrate and subsequent deprotonation [2]. In the intermediate active aldehyde , the former carbonyl carbon atom exhibits an inverted, nucleophilic reactivity, which exemplifies the Umpo-lung concept of Seebach [3]. In 1943, Ukai et al. reported that thiazolium salts also surprisingly catalyze the benzoin condensation [4], an observation which attracted even more attention when Mizuhara et al. found, in 1954, that the thiazolium unit of the coenzyme thiamine (vitamin Bi) (1, Fig. 9.1) is essential for its activity in enzyme biocatalysis [5]. Subsequently, the biochemistry of thiamine-dependent enzymes has been extensively studied, and this has resulted in widespread applications of the enzymes as synthetic tools [6]. 

The nonannulated parent compound thiazole has been implicated as the active centre of the naturally occurring enzyme thiamine (vitamin Bl) [1,2], It catalyses the decarbonyla-tion of pyruvic acid to acetaldehyde and the benzoin condensation of aromatic aldehydes... 

The reaction of two moles of benzaldehyde to form a new carbon-carbon bond is known as the benzoin condensation. It is catalyzed by two rather different catalysts—cyanide ion and the vitamin thiamine—which, on close examination, are seen to function in exactly the same way. 

Studies on thiamine (vitamin Bi) catalyzed formation of acyloins from aliphatic aldehydes and on thiamine or thiamine diphosphate catalyzed decarboxylation of pyruvate have established the mechanism for the catalytic activity of 1,3-thiazolium salts in carbonyl condensation reactions. In the presence of bases, quaternary thiazolium salts are transformed into the ylide structure (2), the ylide being able to exert a cat ytic effect resembling that of the cyanide ion in the benzoin condensation (Scheme 2). Like cyanide, the zwitterion (2), formed by the reaction of thiazolium salts with base, is nucleophilic and reacts at the carbonyl group of aldehy s. The resultant intermediate can undergo base-catalyzed proton... 

The use of thiazolium salts enables the benzoin condensation to proceed at room temperature. It can also be performed in dipolar aptotic solvents or under phase transfer conditions. Thiazolium salts such as vitamin Bi, thiazolium salts attached to y-cyclodextrin, macrobicyclic thiazolium salts, thiazolium carboxylate, ° naphtho[2,l-d]thiazolium and benzothiazolium salts catalyze the benzoin condensation and quaternary salts of 1-methylbenzimidazole and 4-(4-chlorophenyl)-4//-1,2,4-triazole are reported to have similar catalytic activity. Alkylation of 2-hydroxyethyl-4-methyl-l,3-thiazole with benzyl chloride, methyl iodide, ethyl bromide and 2-ethoxyethyl bromide yields useful salts for catalyzing 1,4-addition of aldehydes to activated double bonds. Insoluble polymer-supported thiazolium salts are catalysts for the benzoin condensation and for Michael addition of aldehydes. Electron rich al-kenes such as bis(l,3-dialkylimidazolidin-2-ylidenes) bearing primary alkyl substituents at the nitrogen atoms or bis(thiazolin-2-ylidene) bearing benzyl groups at the nitrogen atoms are examples of a new class of catalyst for the conversion of ArCHO into ArCHOHCOAr. 

Deprotonations of hetarenium salts as a source of NHCs can be traced back to at least the first half of the 20th century. In 1943, thiazoHum salts were found as catalysts for benzoin condensations (1943JPS(JP)269), and in 1957, Breslow reported on the rapid deuterium exchange of thiazolium salts 42 via the anion at C-2 of thiazolium salts (i.e., the NHC 43 which also plays a role in vitamin Bl) (Scheme 11), and correspondingly, of 1,3-dimethylbenzimidazoHum iodide (1958JA3719). These results also inspired... 

The idea that azolium salts could serve as nucleophilic catalysts dates back to the pioneering work of Ugai, who in 1943 demonstrated that thiamine (vitamin Bl) isolated from natural sources catalyzed the benzoin condensation of ben-zaldehyde. The elegant mechanistic work of Breslow established the currently understood mechanism for thiamine s catalytic reaction, and provided the first suggestion of the resonance structure represented by the N-heterocyclic carbene (NHC) (Scheme 14.1) ... 

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