Thiazolium catalyst

The procedure may be conducted on a larger scale in which case the proportion of catalyst and base are reduced. The submitters report that they obtained 169 g (78 ) of butyroin from 216.3 g (3.0 mol) of butyraldehyde, 26.8 (0.1 mol) of thiazolium catalyst, 60.6 g (0.6 mol) of triethylamlne, and 600 mL of absolute ethanol. Although the scale may be increased further, appropriate precautions should be taken to control the reaction. For example, the aldehyde may be added in portions or the flask may be cooled initially. 

This procedure is representative of a new general method for the preparation of noncyclic acyloins by thiazol ium-catalyzed dimerization of aldehydes in the presence of weak bases (Table I). The advantages of this method over the classical reductive coupling of esters or the modern variation in which the intermediate enediolate is trapped by silylation, are the simplicity of the procedure, the inexpensive materials used, and the purity of the products obtained. For volatile aldehydes such as acetaldehyde and propionaldehyde the reaction Is conducted without solvent in a small, heated autoclave. With the exception of furoin the preparation of benzoins from aromatic aldehydes is best carried out with a different thiazolium catalyst bearing an N-methyl or N-ethyl substituent, instead of the N-benzyl group. Benzoins have usually been prepared by cyanide-catalyzed condensation of aromatic and heterocyclic aldehydes.Unsymnetrical acyloins may be obtained by thiazol1um-catalyzed cross-condensation of two different aldehydes. -1 The thiazolium ion-catalyzed cyclization of 1,5-dialdehydes to cyclic acyloins has been reported. 

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]. 

It should, however, be pointed out that - where applicable - product composition can be significantly different. For example, whereas thiazolium catalysts afford exclusively dihydroxyacetone with formaldehyde as substrate, the triazolium systems afford glycolic aldehyde (plus glyceraldehyde and C4 and C5 sugars as secondary products) [246], Catalyst-dependent differences in the relative rates of the partial reactions within the catalytic cycle (Scheme 6.105) most probably account for this phenomenon. A subsequent study by Enders et al. on chiral triazolium salts identified the derivative 233 as a first catalyst for the asymmetric benzoin condensation that affords substantial enantiomeric excesses (up to 86%) with satisfactory chemical yields (Table 6.3) [247]. 

Scheidt and co-workers were also able to carry out Stetter reactions under neutral aqueous conditions [49]. In a biomimetic fashion, a thiazolium catalyst adds to the keto group of a pyruvate (—>51), which leads to decarboxylation (—>52) (Scheme 9.14). This intermediate can be trapped by substituted a,/ -unsaturated 2-acyl imidazoles 53, leading to the usual Stetter products 54. 

Further contributions to the research on the asymmetric benzoin condensation were made by Leeper et al. using novel chiral, bicyclic thia-zolium salts, which led to enantiomeric excesses up to 21% and yields up to 50% (Knight and Leeper 1997). Another thiazolium catalyst containing a norbonane backbone gave benzoin in quantitative yields with an enantiomeric excess of 26% (Gerhards and Leeper 1997). In 1998, Leeper et al. reported novel chiral, bicyclic triazolium salts that produced aromatic acyloins with varying enantioselectivities (20%—83% ee) (Knight and Leeper 1998). 

The formose reaction has been investigated using immobilized thiazolium catalyst [26]. Under these conditions the main products are dihydroxyacetone (DHA), erythrulose, and 4-hydroxymethyl-2-pentulose. The relative importance of these products depends on the amount of thiazolium salts and concentration in 1,4-dioxane [27,28,29]. A possible mechanism implies the Stetter reaction [30,31,32,33,34]. 

A novel thiazolium catalyst with a norbornane backbone gave benzoin with enantiomeric excesses of up to 26% (c.y. 100%, 5 mol % catalyst, TTN = 20) [2]. 

Dicarbonyl derivatives from aldehydes and a, 3-unsaturated ketones and esters. The thiazolium catalyst serves as a safe surrogate for CN. Also known as the Michael-Stetter reaetion. Cf. Benzoin condensation. 

Imidazolium-type room temperature ionic liquids (RTTLs) have been used for the Stetter reaction, affording the desired 1,4-dicarbonyl compounds (e.g. 167) in good yields together with the benzoin (e.g. 168). Thiazolium salts and EtsN are efficient catalysts for this reaction performed in ionic liquid. The possibility to recycle and reuse the solvent has been demonstrated, although it was not possible to recycle the thiazolium catalyst (Anjaiah et al. 2004). 

With the desired aldehyde in hand, we next turned our attention to optimizing the thiazolium-catalyzed coupling reaction. E q)osing this aldehyde to a mixture of tosylamide 13, thiazolium catalyst and TEA in THE provided the desired ketoamide 20 in 94% yield. Cyclization widi iV-methylamine as previously described provided imidazole 12 in 94% yield. Removal of the Cbz group provided corq oimd 1. This route provides the desired conq)ound 1 in S steps and 56% overall yield from 2-chloro-4-cyanopyridine. 

The use of chiral carbenes as asymmetric organocatalysts has attracted the interest of more and more research groups over the last years [88, 100]. Noteworthy, the use of chiral heterocyclic carbenes for asymmetric benzoin condensations dates back to 1966 when Sheehan et al. used the thia-zolium salt 206 to obtain benzoin 207 with an optical purity of around 20% [101] (Scheme 6.34A), and other groups introduced more powerful chiral thiazolium catalysts later... 

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