Chiral thiazolium salts

In 2004 and 2005, respectively, Bach and Miller independently described the use of chiral thiazolium salts as pre-catalysts for the enantioselective intramolecular Stetter reaction. Bach and co-workers employed an axially chiral A-arylthiazolium salt 109 to obtain chromanone 73 in 75% yield and 50% ee (Scheme 16) [77]. Miller and co-workers found that thiazolium salts embedded in a peptide backbone 65 could impart modest enantioselectivity on the intramolecular Stetter reaction [78]. In 2006, Tomioka reported a C -symmetric imidazolinylidene 112 that is also effective in the aliphatic Stetter reaction, providing three examples in moderate enantioselectivities (Scheme 17) [79]. 

In the benzoin condensation, a new stereogenic center is formed, as the product is an a-hydroxy ketone. Consequently, many chemists aspired to develop heterazolium-catalyzed asymmetric benzoin condensations and, later, other nucleophilic acylation reactions [9]. For example, Sheehan et al. presented the first asymmetric benzoin condensation in 1966, with the chiral thiazolium salt 7 (Fig. 9.2) as catalyst precursor [10]. 

Fig. 9.2 Chiral thiazolium salts for enantioselective benzoin condensation.

The low catalyst loading of only 1.25 mol% indicated an activity that had increased by almost two orders of magnitude compared to the chiral thiazolium salts used previously. 

First attempts of an asymmetric Stetter reaction were made 1989 in our research group with the investigation of chiral thiazolium salts such as 136 as precatalysts. The reaction of n-bu Lanai (133) with chalcone (134) in a two-phase system gave the 1,4-diketone 135 with an enanan-tiomeric excess of 39%, but a low yield of only 4% (Scheme 37) (Tiebes 1990 Enders 1993 Enders et al. 1993b). The catalytic activity of thiazolium as well as triazolium salts in the Stetter reaction persisted at a rather low level. Triazolium salts have been shown to possess a catalytic activity in the non-enantioselective Stetter reaction (Stetter and Kuhlmann 1991), but in some cases stable adducts with Michael acceptors have been observed (Enders et al. 1996a), which might be a possible reason for their failure in catalysis. 

Figure 6.5 An asymmetric Michael-Stetter reaction using a chiral thiazolium salt as organo-catalyst [11],...

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. 

Chiral N heterocyclic carbenes (NHCs), as Lewis basic organocatalysts, have been synthesized and applied to enantioselective organocatalytic reactions in recent years. Encouraged by Sheehan and Hunneman s first report of chiral thiazolium salts as NHC precursors for organocatalytic reactions [37], Leeper, Enders, Rovis, Glorius, Herrmann, and others have synthesized series of novel chiral NHCs with mono cyclic, bicyclic, or tricyclic backbones [38]. Recently, a series of bifunctional NHCs were synthesized and applied to aza BMH reaction of cyclopent 2 enone with... 

Sheehan et al. [28] developed several chiral thiazolium salts, which were shown to catalyze the formation of benzoin with low to moderate enantiomeric excesses, up to 52% in the case of a 1-naphthylethyl-substituted catalyst. However, the yields were very low (6%), leading to the consumption of a stoichiometric amount of the catalyst (TTN < 1) which limited the applicability of the reaction. Tagaki et al. [29] reported chiral menthyl-substituted thiazolium salts, the best of which catalyzed the formation of benzoin with enantiomeric excesses up to 35% and slightly improved yields of 20% (TTN 4) by carrying out the reaction in a micellar two-phase system. Zhao et al. [30] combined the superior catalyst concept of Sheehan et al. with the favorable micellar reaction conditions of... 

The first attempts to develop a heterazolium-catalyzed asymmetric variant of the Stetter reaction were carried out by our group [44,45,46], employing the chiral thiazolium salt 9 to catalyze the addition of butanal to chalcone. The resultant 1,4-dicarbonyl compound 10 was obtained in 29% yield with enantiomeric excesses up to 30% (Scheme 6). 

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. 

In 1989, Enders et al. [50] first studied the asymmetric intermolecular Stetter reaction using chiral thiazolium salts 41 as catalyst. The reaction of -butanal and chalcone gave the 1,4-diketone with 39% ee but in only 4% yield in a two-phase system (Scheme 7.30). 

First of all, we had to work out a simple and flexible method for the synthesis of chirally modified thiazolium salts, preferably with the chiral group attached to the nitrogen atom. With a slightly modified procedure already published by Tagaki et al. [59], we were able to prepare a number of novel chiral thiazolium salts. 

Scheme 20. Efficient and flexible synthesis of chiral thiazolium salts...

Scheme 21. Novel chiral thiazolium salts - catalysts for enantioselective Stetter reactions and acyloin condensations...

The new enantiopure thiazolium salts were tested in asymmetric Stetter reactions. As was the case in benzoin condensations catalyzed by chiral thiazolium salts and reported many years ago by Sheehan et al. [60,61] and Tagaki et al. [62], only moderate asymmetric inductions were observed. So far the best results are shown in scheme 22, a 30% chemical yield and an enantiomeric excess of 40% [63]. Nevertheless, the principle has been demonstrated, and we are confident to be able to improve the new procedure. 

In 1966, Sheehan reported a remarkable asymmetric benzoin reaction catalyzed by chiral thiazolium salts with moderate levels of enantioselectivity [56-59]. In 2002, Enders and coworkers made an important breakthrough when they reported the first highly enantioselective intermolecular benzoin reaction catalyzed by a triazolium salt derived from ferf-leucine [Eq. (1)] [60]. Since then, catalyst development for NHC catalysis has seen exponential growth for new triazolium salts derived from chiral amino acids and amino alcohols. 

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