Thiazolium-based catalysts

A possible ronte ont of this apparent dilemma was shown by Enders et al. [27] in adapting the protocol of Ciganek [28] to an asynunetric intramolecnlar Stetter reaction. Favourable entropic effects result in increased yields and thns in an overall significantly improved reaction. Although initial studies were focused on triazolium based catalysts [11,29,30], the development of thiazolium based catalysts was not neglected [31]. 

Figure 9 Cross metathesis of allylbenzene and CDAB with thiazolium-based catalysts...

Yu et al. have reported a series of thermoregulated thiazolium based ionic liquids containing polyether moieties attached to thiazolium cation (36, scheme-10). These thermoregulated ionic liquids (36) were used as catalysts in the Stetter reaction (Yu et al. 2010). The ionic liquids were pale yellow, viscous liquids at room temperature. The viscosity was found to increase with the length of the polyether chain. The structures of these ionic liquids were determined by NMR. 

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. 

The thiazolium salt 3-benzyl-5-(2-hydroxyethyl)-4-methyl-l,3-thiazolium chloride is an excellent catalyst for the addition of unsaturated aliphatic aldehydes to vinylketones (79CB84). The presence of a base such as sodium acetate or triethylamine is required, for the thiazolium salt must first be transformed into the ylide structure (615), which then exerts a catalytic effect resembling that of cyanide ion in the benzoin condensation (Scheme 137). Yields of 1,4-diketones (616) produced in this process were generally good. The use of thiazolium salts for other related reactions has been reviewed (76AG(E)639). 

Based on the conventional analysis of the mechanism of decarboxylation of thiamin-derived intermediates, there is no role for a catalyst in the carbon-carbon bond-breaking step of this reaction. The thiazolium nitrogen is at its maximum electron deficiency with no available coordination sites. Ultimately, there is no place for a proton or other cation to position itself in order to promote the reaction by stabilizing a transition state that resembles the product of the reaction. Since there is no role for an acid, base, or metal to accelerate the decarboxylation of these intermediates by stabilizing the transition state for C-C bond-breaking, the means by which this could be achieved became a source of interest and speculation. 

Tagaki et al. subsequently employed chiral menthyl-substituted thiazolium salts such as compound 9 in a micellar two-phase reaction system, reaching an ee of 35% and an improved yield of 20% [13]. Zhao et al. obtained moderate revalues of 47 to 57% and yields of 20 to 30% when combining the Sheehan catalysts with the Tagaki reaction conditions [14]. Based on their mechanistic model, Lopez Calahorra et al. developed bisthiazolium salt catalysts such as compound 10, yielding 21% of benzoin in 27% ee [15]. 

With respect to the application of asymmetric carbene catalysis as a tool for enantioselective synthesis, the last decade s major success is based on substantial improvements in catalyst development. Early reports dealt with implementing chirality in thiazolium scaffolds (Sheehan and Hunneman 1966 Sheehan and Hara 1974 Dvorak and Rawal 1998), but their catalytic performance suffered from either low yields or low ee-values. In this regard, the investigation of triazole heterocycles as an alternative core structure (Enders et al. 1995) has played a crucial role to provide heterazolium precatalysts improving both asymmetric benzoin and Stetter reactions. An intramolecular Stetter reaction yielding chromanones upon cyclization of salicylaldehyde-derived substrates is commonly used as a benchmark reaction to compare catalyst efficiency (Scheme 1 Ciganek 1995 Enders et al. 1996 Kerr et al. 2002 Kerr and Rovis 2004). 

Interestingly, the mild reaction conditions of the CIR are fully compatible with the Stetter reaction. As a result a sequence of transition metal, base and organoca-talysis can be easily conceived. Upon CIR of electron-deficient (hetero)aryl halides 11 and (hetero)aryl propargyl alcohols 12, and after subsequent addition of aliphatic or aromatic aldehydes 92 and catalytic amounts of thiazolium salt 93 1,4-diketones 94 are obtained in moderate to excellent yields in a one-pot procedure (Scheme 50) [259, 260]. For aromatic aldehydes the catalyst precursor of choice is 3,4-dimethyl-5-(2-hydroxyethyl) thiazolium iodide (93a) (R = Me), and for aliphatic aldehydes 3-benzyl-4-methyl-5-(2-hydroxyethyl)-thiazolium chloride (93b) (R = CH2Ph) is applied. 

Upon treating certain (but not all) aromatic aldehydes or glyoxals (a-keto aldehydes) with cyanide ion (CN ), benzoins (a-hydroxy-ketones or acyloins) are produced in a reaction called the benzoin condensation. The reverse process is called the retro-benzoin condensation, and it is frequently used for the preparation of ketones. The condensation involves the addition of one molecule of aldehyde to the C=0 group of another. One of the aldehydes serves as the donor and the other serves as the acceptor. Some aldehydes can only be donors (e.g. p-dimethylaminobenzaldehyde) or acceptors, so they are not able to self-condense, while other aldehydes (benzaldehyde) can perform both functions and are capable of self-condensation. Certain thiazolium salts can also catalyze the reaction in the presence of a mild base. This version of the benzoin condensation is more synthetically useful than the original procedure because it works with enolizable and non-enolizable aldehydes and asymmetric catalysts may be used. Aliphatic aldehydes can also be used and mixtures of aliphatic and aromatic aldehydes give mixed benzoins. Recently, it was also shown that thiazolium-ion based organic ionic liquids (Oils) promote the benzoin condensation in the presence of small amounts of triethylamine. The stereoselective synthesis of benzoins has been achieved using chiral thiazolium salts as catalysts. 

H, alkyl, aryl, heteroaryl R = alkyl, aryl nucleophilic catalyst NaCN, KCN, thiazolium salts/base solvent DMF, DMSO... 

Lopez-Celahorra, F., Castells, J., Domingo, L., Marti, J., Bofill, J. M. Use of 3,3 -polymethylene-bridged thiazolium salts plus bases as catalysts of the benzoin condensation and its mechanistic implications proposal of a new mechanism in aprotic conditions. Heterocycles 1994, 37, 1579-1597. 

In the classical procedures, the Stetter reaction is performed in VOCs or in RTILs as solvent, using thiazolium salts (in the presence of bases) as pre-catalysts (i.e. in the presence of thiazolium-2-ylidenes) [60, 61,142,155-158]. The formation of the... 

A -Alkylated thiazolium and benzothiazolium salts also experience base-promoted deprotonation at the 2-position to form ylides. Such compounds, often referred to as TV-heterocyclic carbene (NHC), are nucleophilic catalysts in benzoin condensation. In 1943, Ugai and co-workers reported that thiazolium salts catalyze self-condensation of benzaldehyde to generate benzoin via an umpoulong process. Breslow at Columbia University in 1958 proposed thiazolium ylide as the actual catalyst for this transformation. In this mechanism, the catalytically active species was represented as a thiazolium zwitterion, the resonance structure of an NHC, and the reaction was postulated to ensue via the enaminol or the Breslow intermediate. ... 

The development of efficient chiral NHC catalysts has proved to be a challenging task. For instance, following the first attempts at developing an asymmetric benzoin reaction, carried out by Sheehan and co-workers in 1966 using chiral thiazolium salt-derived NHCs [118], in 2002 Enders and Kallfass achieved enantiomeric excesses of 90% by means of a chiral triazolium salt-derived NHC [119]. These catalysts are usually generated in situ by treatment of chiral triazolium salts (see Figure 2.25) by a suitable base. 

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