Benzoin chiral thiazolium salts

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.

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. 

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 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. 

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. 

The first asymmetric benzoin reactions were reported by Sheehan and Hannemann nsing chiral thiazolinm salt pre-catalyst 100 of unknown absolute configuration [40], Low yields and enantioselectivities were obtained, and although a wide range of thiazolium salt pre-catalysts have since been studied, of which 101-105 are representative, the enantioselectivities obtained for the condensation of benzaldehyde using thiazolium pre-catalysts are generally poor (Scheme 12.19) [41],... 

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. " ... 

Chiral bicyclic 1,2,4-triazolium salts, designed with a hindered heterocyclic ring face, have proved to be more effective cocatalysts of asymmetric benzoin condensation than analogous thiazolium salts. ... 

Early approaches toward catalytic asymmetric benzoin condensation by Sheehan et al. [238, 239], Tagaki et al. [240], and Zhao et al. [241] concentrated on chiral thiazolium systems. The same is true for more recent investigations by Leeper [242], Rawal [243], and Lopez-Calahorra et al., the last of whom used bridged bis-thiazolium salts [244], In these studies the feasibility in principle of asymmetrically catalyzed benzoin condensation was proven and enantiomeric excesses up to... 

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]. 

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]. 

Knight RL, Leeper FJ (1998) Comparison of chiral thiazolium and triazolium salts as asymmetric catalysts for the benzoin condensation. J Chem Soc [Perkin 1] 1998 1891... 

Dvorak CA, Rawal VH (1998) Catalysis of benzoin condensation by conforma-tionally-restricted chiral bicyclic thiazolium salts. Tetrahedron Lett 39 2925-2928... 

Tachibana Y, Kihara N, Takata T (2004) Asymmetric Benzoin Condensation Catalyzed by Chiral Rotaxanes Tethering a Thiazolium Salt Moiety via the Cooperation of the Component Can Rotaxane Be an Effective Reaction Field J Am Chem Soc 126 3438-3439... 

The diastereomerically pure thiazolium salt 509 which bears a 2-/i t7-butylphenyl substituent at the nitrogen atom was converted into a mixture of 510 and its atropisomer 510 (dr = 75 25) upon treatment with base (Scheme 128). The stereogenic center in the intermediate carbene favors one rotamer 510. Upon reaction with benzaldehyde, it accounts in a similar fashion for the formation of the major enol diastereoisomer 511 over 511, which, in turn, leads to the major enantiomer 512 rather than 512 observed in the benzoin condensation catalyzed by 509. The concept of axial chirality was proven to be viable for an efficient chirality transfer. Replacement of the isopropyl group at C-4 by the bulkier 2-phenyl-2-propyl substituent using 8-phenylmenthone is likely thought to increase the ee <2004EJ02025>. 

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... 

In 2011, Connon, Zeitler, and coworkers reported detailed studies on intermolecular cross-benzoin reactions using triazoUum and thiazoUum salts [26]. These systematic studies clearly showed the intricate interplay of various factors influencing the outcome of cross-benzoin reactions. In line with the results of Miller and coworkers, the use of o-substituted benzaldehydes resulted in selective formation of benzylic alcohol products using either triazolium or thiazolium salts. When using o-unsubstituted benzaldehydes, the same chemoselectivity could be achieved with an a-branched aliphatic aldehyde and an N-QFs triazolium catalyst. Crossover experiments showed the reaction to be under kinetic control in many cases. When using chiral catalyst 31, good chemo- and enantioselectivity was achieved in the reaction between o-trifluoromethylbenzaldehyde (30) and propanal (29) (Scheme 18.3). 

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). 

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