Thiazolium salts benzoin condensation

One may find many publications in the literature on the theoretical aspects of thiazolium quaternary salts, because of the biological importance of thiamine and their use as catalysts for benzoin condensation. 

Active carbonyl compounds such as benzaldehyde attack the electron-rich double bond in DTDAFs to give a dipolar adduct, which immediately undergoes dissociation with formation of two molecules of 146 (64BSF2857 67LA155).Tlie existence of by-products such as benzoin led to the synthetic application of thiazolium salts in the acyloin condensation. For example, replacement of the classic cyanide ion by 3-benzyl-4-methyl-5(/3-hydroxyethyl) thiazolium salts allowed the benzoin-type condensation to take place in nonaqueous solvents (76AGE639) (Scheme 57). 

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],... 

In the past few years, thiazolium salts have also been used in the laboratory to induce benzoin condensations between aliphatic aldehydes [11]. 

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. ... 

Cyanide-catalyzed condensation of aryl aldehyde to benzoin. Now cyanide is mostly replaced by a thiazolium salt. Cf. Stetter reaction. 

In order to vary the electronic situation at the carbene carbon atom a number of carbo- and heterocycle-annulated imidazolin-2-ylidenes like the benzobis(imida-zolin-2-ylidenes) [58-60] and the singly or doubly pyrido-annulated A -heterocyclic carbenes [61-63] have been prepared and studied. Additional carbenes derived from a five-membered heterocycle like triazolin-5-ylidenes 10 [36], which reveals properties similar to the imidazolin-2-ylidenes 5 and thiazolin-2-ylidene 11 [37] exhibiting characteristic properties comparable to the saturated imidazolidin-2ylidenes 7 have also been prepared. Bertrand reported the 1,2,4-triazolium dication 12 [64]. Although all attempts to isolate the free dicarbene species from this dication have failed so far, silver complexes [65] as well as homo- and heterobimetallic iridium and rhodium complexes of the triazolin-3,5-diylidene have been prepared [66]. The 1,2,4-triazolium salts and the thiazolium salts have been used successfully as precatalysts for inter- [67] and intramolecular benzoin condensations [68]. 

Thiazolium ion based ionic liquids (OIL) have been used to promote the benzoin condensation of benzaldehyde. 4- And 5-methylthiazoles are readily alkylated with n-butyl bromide to give the corresponding bromide salt. Anion exchange with sodium tetrafluoroborate gave the tetrafluoroborate salt 53 as a stable yellow orange oil. When activated with a small quantity of triethylamine (5 mol%) the oil promotes the coupling of benzaldehyde to benzoin <99TL1621>. 

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). 

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]. 

The Stetter Reaction is a 1,4-addition (conjugate addition) of an aldehyde to an a,p-unsaturated compound, catalyzed by cyanide or a thiazolium salt. This reaction competes with the corresponding 1,2-addition, which is the Benzoin Condensation. However, the Benzoin-Condensation is reversible, and since the Stetter Reaction leads to more stable products, the main product will be derived from 1,4-addition. 

When, in 1832, Wohler and Liebig first discovered the cyanide-catalyzed coupling of benzaldehyde that became known as the benzoin condensation , they laid the foundations for a wide field of growing organic chemistry [1]. In 1903, Lapworth proposed a mechanistical model with an intermediate carbanion formed in a hydrogen cyanide addition to the benzaldehyde substrate and subsequent deprotonation [2]. In the intermediate active aldehyde , the former carbonyl carbon atom exhibits an inverted, nucleophilic reactivity, which exemplifies the Umpo-lung concept of Seebach [3]. In 1943, Ukai et al. reported that thiazolium salts also surprisingly catalyze the benzoin condensation [4], an observation which attracted even more attention when Mizuhara et al. found, in 1954, that the thiazolium unit of the coenzyme thiamine (vitamin Bi) (1, Fig. 9.1) is essential for its activity in enzyme biocatalysis [5]. Subsequently, the biochemistry of thiamine-dependent enzymes has been extensively studied, and this has resulted in widespread applications of the enzymes as synthetic tools [6]. 

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 checkers obtained a second fraction from the distillation (13.5 g, 7.4%), bp 97-105°C/0.15 mm, which solidified upon cooling. Recrystallization of this material from hexane gave a colorless solid, mp 26-27°C, which was identified from its infrared, NMR, and mass spectra as 8-hydroxy-7-tetradecanone. This product arises via a "benzoin-type" condensation, catalyzed by the thiazolium salt, of heptanal. 

In an aprotic medium, such as DM SO, a C2a-hydroxybenzylthiazolium salt is formed by nucleophilic addition55. There have appeared suggestions that in nonaqueous media, the double enamine or syn-anti symmetrical dimer formed between two thiazolium salts on addition of base is the template for benzoin condensations (Scheme 4)56. The... 

More recent evidence from our laboratory indicates that when the thiazolium salt is first converted totally to the unsymmetrical and symmetrical syn-anti dimers (13C NMR indicated the presence of both configurations), addition of benzaldehyde to this solution cannot form HBT, whereas addition of benzaldehyde to a mixture that still contains monomeric thiazolium salts indeed forms this HBT adduct57. Such experiments tend to confirm that it is the enamine rather than the double enamine (the benzaldehyde adduct of the syn-anti dimers) that participates in thiazolium salt catalyzed benzoin condensations. 

A further complicating feature in these reactions is the finding that HETh and its thiazolium and benzothiazolium analogs can, in the presence of a base such as Me3N or DBU, be tautomerized to the rather stable 2-benzoylthiazolines9,10. This reaction apparently requires a aprotic medium. Further, Chen showed55,57 that for a number of aromatic aldehydes, when the reaction is performed in methanol, the principal product is not HBT but rather the dimethoxyacetal of the precursor aldehyde. Thiazolium salts appear to catalyze conversion of some aromatic aldehydes to their acetals in reasonable yields. This appears to be a rare example of acetal formation under alkaline conditions. These various reactions of aldehydes and thiazolium salts, additional to the benzoin condensations, are outlined in Scheme 5. 

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). 

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... 

Thiazolium and triazolium salt-derived NHC, in particular, are well known catalysts for benzoin- and Stetter-type umpolung reactions. In the course of these reactions, the NHC catalyst adds to the electrophilic aldehyde, resulting in the formation of a nucleophilic enamine species. Subsequently, this enamine can react with a series of different electrophiles such as aldehydes (benzoin condensation) or a, )-unsaturalcd substrates (Stetter reaction) (Scheme 4). 

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

Sheehan JC, Hara T (1974) Asymmetric thiazolium salt catalysis of the benzoin condensation. J Org Chem 39 1196-1199... 

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... 

When fhe fhiazolium was affached to a y-CD, which is larger, characterized by eight glucose units, the benzoin condensation of two benzal-dehydes became possible. The rate was 150-fold higher than that obtained with a thiazolium salt lacking the cyclodextrin binding site (EM 150)... 

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>. 

Studies on thiamine (vitamin Bi) catalyzed formation of acyloins from aliphatic aldehydes and on thiamine or thiamine diphosphate catalyzed decarboxylation of pyruvate have established the mechanism for the catalytic activity of 1,3-thiazolium salts in carbonyl condensation reactions. In the presence of bases, quaternary thiazolium salts are transformed into the ylide structure (2), the ylide being able to exert a cat ytic effect resembling that of the cyanide ion in the benzoin condensation (Scheme 2). Like cyanide, the zwitterion (2), formed by the reaction of thiazolium salts with base, is nucleophilic and reacts at the carbonyl group of aldehy s. The resultant intermediate can undergo base-catalyzed proton... 

The use of thiazolium salts enables the benzoin condensation to proceed at room temperature. It can also be performed in dipolar aptotic solvents or under phase transfer conditions. Thiazolium salts such as vitamin Bi, thiazolium salts attached to y-cyclodextrin, macrobicyclic thiazolium salts, thiazolium carboxylate, ° naphtho[2,l-d]thiazolium and benzothiazolium salts catalyze the benzoin condensation and quaternary salts of 1-methylbenzimidazole and 4-(4-chlorophenyl)-4//-1,2,4-triazole are reported to have similar catalytic activity. Alkylation of 2-hydroxyethyl-4-methyl-l,3-thiazole with benzyl chloride, methyl iodide, ethyl bromide and 2-ethoxyethyl bromide yields useful salts for catalyzing 1,4-addition of aldehydes to activated double bonds. Insoluble polymer-supported thiazolium salts are catalysts for the benzoin condensation and for Michael addition of aldehydes. Electron rich al-kenes such as bis(l,3-dialkylimidazolidin-2-ylidenes) bearing primary alkyl substituents at the nitrogen atoms or bis(thiazolin-2-ylidene) bearing benzyl groups at the nitrogen atoms are examples of a new class of catalyst for the conversion of ArCHO into ArCHOHCOAr. 

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