And the benzoin condensation

The bifunctional nature and the presence of a stereocenter make a-hydroxyketones (acyloins) amenable to further synthetic transformations. There are two classical chemical syntheses for these a-hydroxyketones the acyloin condensation and the benzoin condensation. In the acyloin condensation a new carbon-carbon bond is formed by a reduction, for instance with sodium. In the benzoin condensation the new carbon-carbon bond is formed with the help of an umpolung, induced by the formation of a cyanohydrin. A number of enzymes catalyze this type of reaction, and as might be expected, the reaction conditions are considerably milder [2-4, 26, 27]. In addition the enzymes such as benzaldehyde lyase (BAL) catalyze the formation of a new carbon-carbon bond enantioselectively. Transketolases (TK)... 

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 thiazolium-catal)fzed addition reactions of an aldehyde-derived acyl anion with a Michael acceptor (Stetter reaction) and the benzoin condensation (most often between two aldehydes) are well-known synthetic tools leading to the synthesis of highly funtionalized... 

Resin bound quaternary ammonium ions have also been used as catalysts in a variety of reactions conducted in nonpolar media. Such reactions as cyanohydrin formation, cyanoethylation, and the benzoin condensation, were all achieved in the early 1950 s [5, 21] and the method was well established by the 1960 s [22]. In most of the anionic reactions, a resin bound quaternary ammonium cation chloride anion pair was converted to the hydroxide form and then used directly in the reaction. 

Related to cyanohydrin formation are the Strecker reaction (see Section 14.3.4) and the benzoin condensation (Figure 20.4, see Section 17.5). Few modern syntheses use this classical form of the benzoin condensation, because of the toxicity of cyanide. Thiamine and related heterocycles (such as 20.2) are more commonly used and, unlike the cyanide catalyzed reaction (which is restricted to nonenolizable aryl aldehydes) 20.2, is a good catalysts for coupling of simple aldehydes (Figure 20.5). 

Apart from the thoroughly studied aqueous Diels-Alder reaction, a limited number of other transformations have been reported to benefit considerably from the use of water. These include the aldol condensation , the benzoin condensation , the Baylis-Hillman reaction (tertiary-amine catalysed coupling of aldehydes with acrylic acid derivatives) and pericyclic reactions like the 1,3-dipolar cycloaddition and the Qaisen rearrangement (see below). These reactions have one thing in common a negative volume of activation. This observation has tempted many authors to propose hydrophobic effects as primary cause of ftie observed rate enhancements. 

The product is called benzoin and the reaction is known therefore as the benzoin condensation. No base is needed other than cyanide ion. 

Thiazolecarboxaldehydes in the presence of a strong base (103) give equal amounts of the corresponding alcohol and carboxylic acid (Canniz-aro reaction). In the presence of potassium cyanide thiazolecarboxalde-hyde undergoes the benzoin condensation (104, 105),... 

The cyanide ion plays an important role in this reaction, for it has three functions in addition to being a good nucleophile, its electron-withdrawing effect allows for the formation of the carbanion species by proton transfer, and it is a good leaving group. These features make the cyanide ion a specific catalyst for the benzoin condensation. 

The addition of HCN to aldehydes or ketones produces cyanohydrins. This is an equilibrium reaction. For aldehydes and aliphatic ketones the equilibrium lies to the right therefore the reaction is quite feasible, except with sterically hindered ketones such as diisopropyl ketone. However, ketones ArCOR give poor yields, and the reaction cannot be carried out with ArCOAr since the equilibrium lies too far to the left. With aromatic aldehydes the benzoin condensation (16-54) competes. With oc,p-unsaturated aldehydes and ketones, 1,4 addition competes (15-33). Ketones of low reactivity, such as ArCOR, can be converted to cyanohydrins by treatment with diethylaluminum cyanide (Et2AlCN see OS VI, 307) or, indirectly, with cyanotrimethylsilane (MesSiCN) in the presence of a Lewis acid or base, followed by hydrolysis of the resulting O-trimethylsilyl cyanohydrin (52). The use of chiral additives in this latter reaction leads to cyanohydrins with good asymmetric... 

Chiral bicyclic 1,2,4-triazolium salts, in which a defined face of the heterocycle is hindered, catalyse the benzoin condensation with up to 80% ee, and with the opposite chirality to the corresponding thiazole catalysts. Conformationally restricted chiral bicyclic thiazolium salts have been similarly investigated. " ... 

In order to vary the electronic situation at the carbene carbon atom a number of carbo- and heterocycle-annulated imidazolin-2-ylidenes like the benzobis(imida-zolin-2-ylidenes) [58-60] and the singly or doubly pyrido-annulated A -heterocyclic carbenes [61-63] have been prepared and studied. Additional carbenes derived from a five-membered heterocycle like triazolin-5-ylidenes 10 [36], which reveals properties similar to the imidazolin-2-ylidenes 5 and thiazolin-2-ylidene 11 [37] exhibiting characteristic properties comparable to the saturated imidazolidin-2ylidenes 7 have also been prepared. Bertrand reported the 1,2,4-triazolium dication 12 [64]. Although all attempts to isolate the free dicarbene species from this dication have failed so far, silver complexes [65] as well as homo- and heterobimetallic iridium and rhodium complexes of the triazolin-3,5-diylidene have been prepared [66]. The 1,2,4-triazolium salts and the thiazolium salts have been used successfully as precatalysts for inter- [67] and intramolecular benzoin condensations [68]. 

Formylfuran behaves in a very similar manner to benzaldehyde and undergoes the usual reactions of an aromatic aldehyde, e.g. (i) the Cannizzaro reaction with cone, sodium hydroxide to give furan-2-ylmethanol and the sodium salt of furoic acid, (ii) the Perkin reaction with acetic anhydride and sodium acetate to yield an aldol product that dehydrates to 3-(furan-2-yl)propenoic acid, and (iii) a condensation with potassium cyanide in alcoholic solution to form furoin (under these conditions, benzaldehyde undergoes the benzoin condensation) (Scheme 6.32). 

Thiazolium ion based ionic liquids (OIL) have been used to promote the benzoin condensation of benzaldehyde. 4- And 5-methylthiazoles are readily alkylated with n-butyl bromide to give the corresponding bromide salt. Anion exchange with sodium tetrafluoroborate gave the tetrafluoroborate salt 53 as a stable yellow orange oil. When activated with a small quantity of triethylamine (5 mol%) the oil promotes the coupling of benzaldehyde to benzoin <99TL1621>. 

The heterocyclic equivalent of the benzoin condensation offers a route to the important herbicide paraquat (Scheme 128) (73JOC3993) (see also Section 2.05.7). N- Alkylnicotinic acid and its derivatives readily undergo addition of cyanide and many other nucleophiles (see Section 2.05.4.8). In the example shown in Scheme 129, 1,2-addition is subject to kinetic, and 1,4-addition to thermodynamic, control. 

Other nucleophilic additions conducted in aqueous media can be found in the literature (Lubineau et al., 1994 Strauss, 1999). These reactions will include the benzoin condensation, the Prins reaction, and the Wittig-Horner reaction, and the Baeyer-Villi-ger oxidation. 

Examples of nonasymmetric organocatalysts that were introduced in the 1950s include analogs of thiamine reported by Breslow in 1957 as an alternative to cyanide as a catalyst for the benzoin condensation [8]. Asymmetric versions of these thiazolium catalysts were used in organocatalytic benzoin condensations by Sheehan and Hunneman in 1966 [9]. In another important development, in 1969 the nucleophilic catalyst 4-(dimethylamino)pyridine (DMAP), which is now widely used for difficult esterifications, was reported by Steglich [10]. 

Most of the reactions of aromatic aldehydes, ArCHO, are those expected of aldehydes with no a hydrogens and most of these will not be reviewed here. One reaction that usually is regarded as being characteristic of aromatic aldehydes (although, in fact, it does occur with other aldehydes having no a hydrogens), is known as the benzoin condensation. This reaction essentially is a dimerization of two aldehyde molecules through the catalytic action of sodium or potassium cyanide ... 

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