Reactions of Thiazolium Salts

Reactions of Thiazolium Salts. The thiazolium salt (45 R = benzyl, X = OH, Y = Cl) catalyses the addition of aldehydes to activated double-bonds, e.g. a/S-unsaturated acids, esters, and nitriles. A novel route to 4-alkyl-2H-l,4-thiazin-3-ones (46 R = alkyl or benzyl) involves the quaternization of 2-methylthiazole with RI, iodination with I2 and NEta, and treatment of the 2-(iodomethyl)thiazolium iodides with potassium hydroxide.  

A rearrangement that involves ring-contraction takes place on treatment of compounds (45 R = Me, CH2Ph, or Ar X = Cl Y = 1) with aqueous base, 

Demian, M. Coman, A. Muresan, I. lovanov, and I. Simiti, Org. Mass Spectrom., 1978,13, 504. 

Centric, J. Lauransan, C. Roussel, F. A. Devillanova, and G. Verani, J. Heterocycl. Chem., 1979, 

The mechanism of H-D exchange of H-2 in the thiazolium ions (107) was studied by n.m.r. A tetrahedral intermediate, formed by addition of a nucleophile, is proposed. The effects of solvents and size of the nucleophile on the reaction were studied.However, elsewhere it is claimed that the kinetic data demonstrate that the exchange of H at the 2-position of thiazolium ions cannot occur through a tetrahedral intermediate.  

Thiazolium bromide (108) reacts with keten thioacetals (MeS)2C=C(CN)2, etc., in the presence of NaH or EtaN, to afford iminothiazolines [109 Z = (NC)2C, Me02CC(CN), or tosylimino] Treating (109) with NaOMe results in cyclization to give imidazo[2,l-h] thiazoles [110 = C02Me, = CH- 

The following have also been described cationic azo-dyes (111), prepared by diazo-coupling and quaternization/ and the effects of alkali and of 

Miscellaneous Reactions.—2-Aryl-thiazoles, obtained by the reaction of thiazoles with dibenzoyl peroxide in the presence of copper, undergo photolysis in the 

Stetter and H. Kuhlmann, Angew. Chem. Internat. Edn., i974, 13, 539. 

Takamizawa, S. Matsumoto, and S. Sakai, Chem. and Pharm. Bull. Japari), 1974, 22, 293. 

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Electron-donating groups, effect on thiazolium ring cleavage, 33 Electrophilic reaction, of thiazolium salts, in basic medium, 34 Energetic transfer yield, of thiazoiocyanines, 78... 

Three-component reaction of thiazolium salt, ketene precursor, and dimethyl acetylenedicarboxylate using Pr2Net as base gave rise to 1,4-thiazepine-fused furans in high yields, as can be seen in the following scheme <06AG(I)7793>. 

The reaction of thiazolium salt 229 with DBU in ethanol or tetrahydrofuran involved a competition yielding thiazoline 230, ylide 231, and acetaldehyde (79JA2752). Ylide 231 was also generated from the 3-benzyl-4-methyl-thiazolium salt 232 and DBU. Ylide 231 was trapped with different electrophiles. The reactions of 230 with sources of electrophilic sulfur mimic the pyruvate dehydrogenese-mediated production of enzyme-bound acetyl-dihydrolipoic acid. 

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... 

An example of process 92 is provided by the reaction of thiazolium salts with dialkyl acylphosphonates it provides a valuable synthetic entry to... 

The thiazolium-mediated three-component reaction of thiazolium salts 201, aryl aldehydes and dimethyl acetylenedicarboxylate provides a facile synthesis of 2-amino-2-arylfurans 202 <05OL1343>. The reaction pathway may involve the sequential nucleophilic addition of thiazol-2-ylidene 203 with the aldehyde and DMAD to form the spirocyclic intermediate 204 through the simultaneous formation of two C-C bonds and a C-O bond Selective ring opening of the spirocyclic intermediate 204 followed by hydrolysis leads to 3-aminofuran 202 via 205. 

Reactions of Thiazolium Salts. - Base-induced attack of thiazolium salts and rearrangement of subsequent 2-hydroxy-A -thiazoline was studied by u.v. kinetic spectroscopy (two consecutive irreversible steps).The first step was the nucleophilic attack of OH on C-2 of (103 R = H or Me), affording the thiazoline (104), with measured third-order rate constants. The second step was the nucleophilic cyclization of the thiolate (105) to form the thietans (106) (Scheme 9). 

Chen et al prepared [2-i3C]-labeled 3-benzyl and 3-methylthiazolium tetrafluoroborate (may be liquids in nature) and studied the reactions of benzaldehyde with thiazolium salts in Me2SO. They found that the reactions of thiazolium salts with aromatic aldehydes p>-anisaldehyde and cinnamaldehyde, in MeOH/MeONa, led to the formation of significant amormts of the corresponding dimethyl acetals, rather than to the benzoin products (Chen et al 1994). 

LXXV. Reactions of thiazolium salts with diethyl acylphosphonates and hydroxylation of some 3-oxo-2,3-dihydro-4H-l,4-thiazine derivatives. Chem. Pharm. Bull. Vol. 20, No. 5, pp. 892-900, ISSN. 0009-2363... 

Rii Expansion to 1,4-Thiazines.— Takamizawa s ring-expansion reaction of thiazolium salts to 1,4-thiazines by the use of dialkyl acylphosphonates (see Vol. 2, p. 605 and Vol. 3, p. 577) has been extended further. ... 

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 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). 

A systematic study of the reduction of thiazolium salts by complex metal hydrides has been promised in a preliminary communication on the mechanism of the reduction with sodium borohydride. The formation of 3-benzyl-4-methylthiazolidine from the reaction of 3-benzyl-4-methylthiazolium bromide and sodium borohydride was shown to occur in a manner similar to the reduction of pyridinium ions.158... 

Evidence for the intermediacy of the enamine has also been confirmed in some examples involving synthetic utilization of thiazolium salts, for example in the catalysis by thiazolium salts of Michael reactions between aldehydes and a,/ -unsaturated compounds58 (equation 6). 

On an industrial scale, methane, the main component of natural gas, can easily be converted to formaldehyde. An efficient catalytic condensation of formaldehyde to dihydroxyactone or glycolaldehyde would thus provide a route to C2- and C3-chemicals from methane. The tria-zolin-5-ylidene 94 turned out to be a powerful catalyst for the conversion of formaldehyde (95) to glycolaldehyde (96) in the formoin reaction (Teles et al. 1996). This reactivity is a useful complement to the catalytic properties of thiazolium salts which mainly afford 1,3-dihydroxy acetone as product (Scheme 23) (Castells et al. 1980 Mat-sumoto and Inoue 1983 Matsumoto et al. 1984). As triazolium ylides are much more stable than thiazolium ylids, the elimination of glycolaldehyde occurs faster than the addition of the third formaldehyde molecule. 

In the early 1970s Stetter and co-workers succeeded in transferring the concept of the thiazolium catalyzed nucleophilic acylation to the substrate class of Michael acceptors (Stetter 1976 Stetter and Schreck-enberg 1973). Since then, the catalytic 1,4-addition of aldehydes 6 to an acceptor bearing an activated double bond 131 carries his name. The Stetter reaction enables a new catalytic pathway for the synthesis of 1,4-bifunctional molecules 132, such as 1,4-diketones, 4-ketoesters and 4-ketonitriles (Stetter and Kuhlmann 1991 for a short review, see Christmann 2005). The reaction can be catalyzed by a broad range of thiazolium salts. Stetter and co-workers found the benzyl-substituted thiazolium salt 86a to give the best results for the addition of aliphatic aldehydes, whereas 86b and 86c were chosen for the addition of aromatic aldehydes. Any one of these three was found to be suitable for additions with heterocyclic aldehydes. Salt 86d was utilized with a, )-unsaturated esters (Fig. 15). 

Interestingly, the mild reaction conditions of the CIR are fully compatible with the Stetter reaction. As a result a sequence of transition metal, base and organoca-talysis can be easily conceived. Upon CIR of electron-deficient (hetero)aryl halides 11 and (hetero)aryl propargyl alcohols 12, and after subsequent addition of aliphatic or aromatic aldehydes 92 and catalytic amounts of thiazolium salt 93 1,4-diketones 94 are obtained in moderate to excellent yields in a one-pot procedure (Scheme 50) [259, 260]. For aromatic aldehydes the catalyst precursor of choice is 3,4-dimethyl-5-(2-hydroxyethyl) thiazolium iodide (93a) (R = Me), and for aliphatic aldehydes 3-benzyl-4-methyl-5-(2-hydroxyethyl)-thiazolium chloride (93b) (R = CH2Ph) is applied. 

Thus, upon CIR of electron-deficient (hetero)aryl halides 11 and phenyl propargyl alcohol 12a, after subsequent Stetter reaction with aldehydes 92 in presence of catalytic amounts of thiazolium salt 93, and after addition of glacial acetic acid and concentrated HCl, the 2,3,5-trisubstituted furans 95 are obtained in moderate to good yields in a one-pot procedure (Scheme 51) [260]. 

The active aldehydes are derived from the reaction of 3-benzylthiazolium salts with o-tolualdehyde in the presence of DBU (l,8-diazabicyclo[5.4.0]undec-7-ene) via deprotonation of thiazolium salts, addition of the aldehyde and deprotonation of the adduct as shown in Scheme 33 [364], The anionic form of active aldehydes in Scheme 33 is confirmed by the direct detection of the one-electron oxidized species with use of ESR [364]. From the linewidth variations of the ESR spectra of the oxidized active aldehyde radicals were determined the rate constants [(5-7) x 10 s ] and the corresponding small reorganization energies (A = 12-13... 

A proposed reaction mechanism is shown in Scheme 130. It involves the addition of a neutral carbene/zwitterionic species 514 (generated in situ from the exposure of thiazolium salt to DBU) to an acylsilane <2001JOC5124, 1996TL8241>. This nucleophilic addition initiates a 1,2-silyl group migration (Brook rearrangement)... 

The formose reaction has been investigated using immobilized thiazolium catalyst [26]. Under these conditions the main products are dihydroxyacetone (DHA), erythrulose, and 4-hydroxymethyl-2-pentulose. The relative importance of these products depends on the amount of thiazolium salts and concentration in 1,4-dioxane [27,28,29]. A possible mechanism implies the Stetter reaction [30,31,32,33,34]. 

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