Benzoin condensation thiazolium salt-catalyzed

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. 

The generally accepted mechanism of the thiazolium salt-catalyzed benzoin condensation was first proposed by R. Breslow. ... 

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 mechanism operating in A-heterocyclic carbene-mediated reactions was proposed initially by Breslow in 1958 for the thiazolium salt-catalyzed benzoin condensation (Scheme 6.1). This proposal involves the formation of a carbene as the catalytically active species by deprotonation of the thiazolium cation, which subsequently adds to one molecule of the aldehyde, generating a nucleophilic intermediate known as the Breslow intermediate. Next, this... 

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

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... 

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]. 

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. 

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. 

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>. 

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. 

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. 

Tagaki, W., Tamura, Y., Yano, Y. Asymmetric benzoin condensation catalyzed by optically active thiazolium salts in micellar two-phase media. Bull. Chem. Soc. Jpn. 1980, 53, 478-480. 

Castells, J., Lopez-Calahorra, F., Domingo, L. Postulation of bis(thiazolin-2-ylidene)s as the catalytic species in the benzoin condensation catalyzed by a thiazolium salt plus base. J. Org. Chem. 1988, 53,4433-4436. 

A very important naturally occuring thiazole derivative is thiamine pyrophosphate (473). It is the prosthetic group in a variety of enzymes which catalyze decarboxylation (decarboxylase) and aldol-type condensation (aldolase) reactions. The catalytic active site of the molecule is at C-2 of the thiazole ring . The same activity of (473) is shown by other thiazolium salts and therefore these compounds have been widely exploited as catalysts in reactions of importance such as the benzoin condensation (see Section 3.06.12.2). 

Thiazolium salts also catalyze several reactions related to the benzoin condensation. An example is the reaction of aldehydes and imminium salts (509) to form a-amino ketones (510) (Equation... 

Review. In the classical benzoin condensation cyanide ion is used as the catalyst. However, in the case of aliphatic aldehydes, thiazolium salts such as (1) and (2) are usually superior catalysts. The salts catalyze 1,4-addition of aldehydes to a,/3-unsaturated ketones, esters, and nitriles. 

Currently, other catalytic systems have been developed, including N, M -disubstituted o-phenylenediamines, thiazolium cyclophane, ° and enzymes. The benzoin cndensa-tion is normally carried out in aqueous solution, and the addition of salt (LiCl, KCl) can increase the reaction rate however, the condensation can also be performed in organic solvent, such as anhydrous petroleum ether. In contrast to the salt effect in aqueous solution, the addition of salt (LiCl, LiClOa) into organic solvents (ethylene glycol, formamide, and DMSO) results in the decreasing of reaction rate. However, a few aldehydes were found not to form benzoin under the benzoin condensation condition instead ethylenediol and ethanediol were formed. This condensation when catalyzed by cyanide ion, is assumed... 

The original benzoin condensation catalyzed by cyanide ion has been modified to use thiamin and a related thiazolium salt, diamine, or enzyme as a catalyst. In addition, the aldehyde group can be replaced by a bisulfite group or converted to silyl-ester to undergo the benzoin condensation. 

The earliest research on NHC-catalyzed reactions was mainly focused on the benzoin reaction. In 1943, Ugai and co-workers reported that thiazolium salts eould catalyze the self-condensation of benzaldehyde to produce benzoin. In 1966, Sheehan and Hunneman reported the first asymmetrie variant of the benzoin eondensation employing a ehiral thiazolium salt as precatalyst (up to 83% yield, 95% ee). Since asymmetric cross-benzoin reactions... 

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. 

The reaction of two molecules of benzaldehyde to form benzoin is generally referred to as the benzoin condensation. It is normally catalyzed by cyanide ion, although thiazolium ions will also catalyze it, as we have discussed above and shown in Fig. 1.2. The normal solvent for the benzoin condensation is ethanol, to dissolve all the components of the reaction. However, it seemed to us likely that there would be overlap of the phenyl rings in the transition state for the benzoin condensation, and thus that reaction in water could lead to hydrophobic accelerations. This proved to be the case. We saw that the rate of the cyanide-catalyzed benzoin condensation was 200-fold faster in water than in ethanol. Also, we saw that added LiCl increased the reaction rate, while added lithium perchlorate decreased it. Such salt effects are diagnostic of the presence of some acceleration by hydrophobic packing in the transition state for the reaction. 

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