Thiazolium salt catalysts

Yamashita, K., Osaki, T., Sasaki, K., Yokota, H., Oshima, N., Nango, M., Tsuda, K. Acyloin condensation in aqueous system by durable polymer-supported thiazolium salt catalysts. J. Polym. Sci., Part A Polym. Chem. 1994, 32, 1711-1717. 

The spectral properties and conformational preferences of some 1 jB -thiadiazole macrocycles have been reported. In connection with thiazoles we find mention of a useful reagent for the spectro-photometric determination of cobalt, 4C labelling of a new B-adrenergic blocking agent, S-596, and synthesis of analogues of the cationic terminus of the antitumour agent Bleomycin A21 . Additionally, a polymer-supported thiazolium salt catalyst, as a model for the thiamine-dependent enzymes, has been prepared, and three 2-alkylbenzothiazole volatile flavour constituents... 

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

It is noteworthy that some catalysts convert thioethers to quaternary salts where the reactive electrophilic center is no longer one of the two C centers but the C sp center of the thiazolium salt (284. 285). Thus... 

The catalyst, 3-benzyl-5-(2-hydroxyethyl )-4-methyl-l, 3-thiazoHum chloride, is supplied by Fluka AG, Buchs, Switzerland, and by Tridom Chemical, Inc., Hauppauge, New York. The thiazolium salt may also be prepared as described below by benzylation of 5-(2-hydroxyethyl)-4-methyl-l,3-thiazole which is commercially available from E. Merck, Darmstadt, West Germany, and Columbia Organic Chemicals Co., Inc., Columbia, SC. The acetonitrile used by the checkers was dried over Linde 3A molecular sieves and distilled under nitrogen, bp 77-78°C. The same yield of thiazolium salt was obtained by the checkers when benzyl chloride and acetonitrile from commercial sources were used without purification. 

Structure-activity studies of 5,6,7,8-tetrahdyro-5,5,8,8-tetramethyl-2-quinoxaline derivatives necessitated the preparation of thiophene-containing compound 17. Stetter conditions using thiazolium salt 20 as catalyst resulted in the preparation of 1,4-diketone 21 from 18 and 19. Condensation of 21 with phosphorus pentasulfide followed by saponification resulted in 17. In this fashion, the authors replaced the amide linker of parent compound 22 with the rigid thiophene moiety. 

Asymmetric Benzoin Reactions Thiazolium Salt Pre-Catalysts... 

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],... 

The first asymmetric intramolecular Stetter reactions were reported by Enders and co-workers utilising triazolium salt pre-catalyst 125. Treatment of substrate 123 generated 1,4-dicarbonyl compound 124 in good yield and enantioselectivity [56]. These salicylaldehyde-derived substrates 123 have since become the standard test substrates for the development of new catalysts for the asymmetric intramolecular Stetter reaction. Bach and co-workers have achieved moderate enantioselectivities using axially-chiral thiazolium pre-catalyst 126 [41], whilst Miller and co-workers have developed peptidic thiazolium pre-catalyst 127 [57]. In 2005, Rovis and coworkers showed that the NHCs derived from triazolium salts 128-130 were excellent catalysts for the asymmetric intramolecular Stetter reaction of a wide range of substrates, giving typically excellent yields and enantioselectivities [58]. The iV-pentafluorophenyl catalyst 129 currently represents the state of the art in asymmetric Stetter reactions (Scheme 12.24) [59]. 

Addition of acyl anions generated from acylsilanes to a,(3-unsaturated ketones using N-heterocyclic carbenes (NHCs) derived from thiazolium salts as catalyst produced 1,4-diketones, which cyclized to form the corresponding furans in good yields under an acidic condition <06JOC5715>. 

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. " ... 

While the reductive elimination is a major pathway for the deactivation of catalytically active NHC complexes [127, 128], it can also be utilized for selective transformations. Cavell et al. [135] described an interesting combination of oxidative addition and reductive elimination for the preparation of C2-alkylated imida-zohum salts. The in situ generated nickel catalyst [Ni(PPh3)2] oxidatively added the C2-H bond of an imidazolium salt to form a Ni hydrido complex. This complex reacts under alkene insertion into the Ni-H bond followed by reductive elimination of the 2-alkylimidazolium salt 39 (Fig. 14). Treatment of N-alkenyl functionalized azolium salts with [NiL2] (L = carbene or phosphine) resulted in the formation of five- and six-membered ring-fused azolium (type 40) and thiazolium salts [136, 137]. 

Breslow and co-workers elucidated the currently accepted mechanism of the benzoin reaction in 1958 using thiamin 8. The mechanism is closely related to Lapworth s mechanism for cyanide anion catalyzed benzoin reaction (Scheme 2) [28, 29], The carbene, formed in situ by deprotonation of the corresponding thiazolium salt, undergoes nucleophilic addition to the aldehyde. A subsequent proton transfer generates a nucleophilic acyl anion equivalent known as the Breslow intermediate IX. Subsequent attack of the acyl anion equivalent into another molecule of aldehyde generates a new carbon - carbon bond XI. A proton transfer forms tetrahedral intermediate XII, allowing for collapse to produce the a-hydroxy ketone accompanied by liberation of the active catalyst. As with the cyanide catalyzed benzoin reaction, the thiazolylidene catalyzed benzoin reaction is reversible [30]. 

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]. 

While catalysts and reaction protocols are well established for the enantioselective intramolecular Stetter reaction, asymmetric intermolecular Stetter products are much more difficult to obtain using known methodologies. A report by Enders and co-workers described the first asymmetric intermolecular Stetter reaction utilizing n-butanal and chalcone [4], When thiazolium salt 114 is used in this system the reaction proceeds in 39% ee, albeit in 4% yield of 113. The authors comment that both thiazolium and triazolium pre-catalysts perform poorly. The yield was increased to 29% yield with thiazolium pre-catalyst 115 although a loss in enanti-oselectivity was observed (Scheme 18) [80]. 

Homoenolates generated catalytically with NHCs can also be employed for C-C and C-N bond formation. Bode and Glorias have independently accomplished the diastereoselective synthesis of y-butyrolactones by annulation of enals and aldehydes [121, 122]. Bode and co-workers envisioned that increasing the steric bulk of the acyl anion equivalent would allow reactivity at the homoenolate position. While trying to suppress the competing benzoin and enal dimerization the authors comment on the steric importance of the catalyst. Thiazolium pre-catalyst 173 proved unsuccessful at inducing annulation. A-mesityl substituted imidazolium salt 200 was found to provide up to 87% yield and moderate diastereoselectivities (Scheme 34). 

J B azyl-5-(2-hydroxyethyl)-4-mcthyl-l,3-thiazoliiMn chloride, 6, 38 39, 289 7, 16 17. Detailed directions are available Tor preparation of this thiazolium salt, which ll alto commercially available (Fluka). Examples of use of this catalyst in Combination with triethylamine for acyloin condensation are cited. The heterocyclic fbroin can also he prepared with this catalyst. Synthesis of benzoins, however, requires use of a related catalyst, one substituted with an N-melhyl or N-ethyl group ill place of N-benzyl. 

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). 

In the thiazolium cation the proton in the 2-position is acidic and its removal gives rise to the ylide/carbene 227. This nucleophilic carbene 227 can add, e.g., to an aldehyde to produce the cationic primary addition product 228. The latter, again via C-deprotonation, affords the enamine-like structure 229. Nucleophilic addition of 229 to either an aldehyde or a Michael-acceptor affords compound(s) 230. The catalytic cycle is completed by deprotonation and elimination of the carbene 227. Strictly speaking, the thiazolium salts (and the 1,2,4-triazolium salts discussed below) are thus not the actual catalysts but pre-catalysts that provide the catalytically active nucleophilic carbenes under the reaction conditions used. This mechanism of action of thiamine was first formulated by Breslow [234] and applies to the benzoin and Stetter-reactions catalyzed by thiazolium salts [235-237] and to those... 

Addition of the cyanide ion to create a cyanohydrin effects an umpolung of the normal carbonyl charge affinity, and the electrophilic aldehyde carbon becomes nucleophilic after deprotonation A thiazolium salt may also be used as the catalyst in this reaction. 

The intramolecular nucleophilic addition of the formyl group to the electron deficient alkene unit in the propenoate (10) affords a benzofuranone when catalysed by a thiazolium salt. However, when NaCN is used as the catalyst, an initial Michael addition to the acrylate function is followed by an intramolecular aldol condensation and the chroman (11) is formed. The corresponding butanoates afford chroman-4-ones under the influence of thiazolium cations, but give benzoxepins in the presence of a basic catalyst (95S1311). 

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]. 

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]. 

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. 

As an obvious extension of the benzoin reaction, the cross-coupling of aldehydes or of aldehydes and ketones was first achieved with the thiamine-dependent enzyme benzoylformate decarboxylase. This linked a variety of mostly aromatic aldehydes to acetaldehyde to form the corresponding a-hydroxy ketones, both chemo- and stereoselectively [31]. Synthetic thiazolium salts, developed by Stetter and co-workers and similar to thiamine itself [32], have been successfully used by Suzuki et al. for a diastereoselective intramolecular crossed aldehyde-ketone benzoin reaction during the course of an elegant natural product synthesis [33], Stereocontrol was exerted by pre-existing stereocenters in the specific substrates, the catalysts being achiral. 

The broad scope of the catalytic generation of activated carboxylates was demonstrated by Bode et al. in the diastereoselective synthesis of / -hydroxy esters 79 from a,/ -epoxy aldehydes 80 employing achiral thiazolium salts 81 as precatalysts (Scheme 9.24) [67]. The incorporation of a reducible functionality into the aldehyde substrate is the premise for a catalyst-induced intramolecular redox reaction generating the activated carboxylate 82. 

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