3-Benzyl-4-methylthiazolium chloride

Symmetrical 1,4-diketones (249) can be prepared by the reaction of phenyl vinyl sulfones (53) or divinyl sulfone with aldehydes in the presence of 3-benzyl-5-(2-hydroxymethyl)-4-methylthiazolium chloride as a catalyst (equations 148 and 149)142. 

PBu3 is used in place of 3-benzyl-5-(hydroxyethyl)-4-methylthiazolium chloride in this example. 

Benzyl-4-methylthiazolium chloride (234) is reduced in water by excess NBH to the fully saturated 1,3-thiazolidine 237 via the thiazoline 235. A diastereoisomeric mixture is obtained in more highly substituted cases. 

The absolute stereochemistry of natural roseophilin was determined by means of asymmetric total synthesis by M.A. Tius and co-workers. The trisubstituted pyrrole moiety of the natural product was installed using the Paai-Knorr pyrrole synthesis starting from a macrocyclic 1,4-diketone. This diketone was prepared by reacting an exocyclic a, 3-unsaturated ketone with excess 6-heptenal in the presence of 3-benzyl-5-(hydroxyethyl)-4-methylthiazolium chloride as the catalyst. The major product was the trans diastereomer and the macrocyclization was achieved via aikene metathesis. It is worth noting that when the aldehyde was tethered to the cyclopentenone, all attempts to close the macrocycle in an intramolecular Stetter reaction failed. 

The C-2-exchange of azolium salts via an ylide mechanism was discussed in Section 24.1.2.1. Thiamin pyrophosphate acts as a coenzyme in several biochemical processes and in these, its mode of action depends on the intermediacy of a 2-deprotonated species (32.2.4). In the laboratory, thiazolium salts (3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride is commercially available) will act as catalysts for the benzoin condensation, and in contrast to cyanide, the classical catalyst, allow such reactions to proceed with alkanals, as opposed to araldehydes the key steps in thiazolium ion catalysis for the synthesis of 2-hydroxy-ketones are shown below and depend on the formation and nucleophilic reactivity of the C-2-ylide. Such catalysis provides acyl-anion equivalents. 

The only synthesis published to date by the medicinal chemists Cai et al. was not amenable to scale-up. The discovery route started with the 0-alkylation of 5-iodovanillin (230) with 2-iodoethanol in the presence of K2CO3 and 18-crown-6 ether in DMF to give compound 231 (Scheme 30.41). The Stetter reaction of 3,4,5-trimethoxyphenyl vinyl ketone (232) with aldehyde 231 in the presence of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride catalyst (233) and triethylamine in DMF gave the 1,4-dione (234). Reduction of 234 with sodium borohydride in a MeOH-THF mixture gave the corresponding 1,4-diol (235). Diol 235 was cyclized with 5% trifluoroacetic acid in CHCI3 to furnish a mixture of cis and trans isomers of 2,5-diaryl tetrahydrofurans. 

This reaction has been modified to form bis(trimethylsilyloxy) alkenes." In addition, CgK and thiazolium salt, such as 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride, have been applied for the acyloin condensation. 

To a solution of 163 mg l-benzyl-2-benzoyl-4-methyl-5-oxo-6-methylene-l,2,3,5,6,6a-hexahydrocyclopenta[c]pyrrole-l-carboxylic acid methyl ester (0.403 mmol) in 2 mL 1,4-dioxane were added 42 fj,h Et3N (0.30 mmol), 184 ixL butyraldehyde (2.03 mmol), and 22 mg 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.080 mmol). The reaction vessel was sealed with a rubber septum and heated to 70°C for 6 h. The reaction mixture was then poured into 50 mL water, and the aqueous layer was extracted with Et20 (3 X 25 mL). The combined organic layers were washed with 20 mL brine, dried over MgS04, and concentrated under vacuum. After the addition of 5 mL hexanes to the residue, a white precipitate formed. The precipitate was collected by decantation and purified by flash chromatography (hexanes/EtOAc, 9 1 to 2 1, v/v) to afford 121 mg of the major diastereomer of 2-benzoyl-l-benzyl-4-methyl-5-oxo-6-(2-oxopentyl)-l,2,3,5,6,6a-hexahydrocyclopenta[c]pyrrole-l-carboxylic acid methyl ester (63% yield) and 19 mg of the minor diastereomer (10% yield). 

Scheme 212 Synthesis of (-l-)-monomorine I (1562) and (5f,9 )-indolizidine 195B (1564) by Randl and Blechert. Reagents and conditions (a) hept-1-en-3-one, 3-benzyl-5-(2-hydroxyethyl-4-methylthiazolium chloride (5 mol%), NEts, 65 °C, 18 h (b) flash vacuum pyrolysis, 500 °C, 15mbar (c) Hoveyda—Grubbs catalyst (7), CH2CI2, reflux, 4 h (d), H2 (1 atm), 10% Pd/C, MeOH, rt, 48 h, then chromatography.

Dibenzyl-4-methylthiazolium chloride in water treated with excess N NaOH 3-benzyl-2-benzylidene-4-methylthiazoline. Y 90%. Ring opening s. 364. J. E. Downes and P. Sykes, Soc. 1960, 963. 

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See also in sourсe #XX -- [ ]

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