Acetyl chloride, with aminothiazoles

Note that p-acetamidobenzenesulphonyl chloride will similarly react with primary and secondary amines, and the products, after hydrolysis of the acetyl group, may furnish notable drugs e.g., the condensation products with 2-amino-pyridine and 2-aminothiazole, after remo al of the acetyl groups, provide the drugs commonly known as sulphapyridine (M B 693) and sulphathidzole respectively. 

Aminothiazole reacts with both ferrocenecarboxaldehyde and ferrocenecarboxylic acid chlorideto give the expected imine and amide, respectively. Ferrocenecarboxylic acid chloride also reacts with phenothiazine to give both N- and C-acetylation. Ferrocene-carboxaldehyde and rhodanine gave 134, while reaction of the thiosemicarbazone of ferrocenecarboxaldehyde with chloroacetic acid in acetic acid gave 135. ... 

Preparation of para-acetylaminobenzensulfonyl chloride (PAS) was described in Example 7.2. Sulfonation of 2-aminothiazole is performed in aqueous medium under controlled addition of hydroxide according to the already-discussed Schotten-Baumann process. As the result, double-sulfonated amine is formed, which does not represent a serious technological issue since on heating with ammonia to the reaction pot, selective ammonolysis is achieved and one mole of sulfonamide obtained. This is a useful side product that on separation is recycled in the production of biologically active sulfonamides. The ammonium salt of the sulfathiazole precursor is submitted to hydrolysis of the A-acetyl group and sulfathiazole isolated by crystallization. 

Low yields were obtained in the absence of pivalic acid however, employing greater than 30% pivalic acid did not further improve yields or reactivity. Substrates that performed well included C3-substituted benzothiophenes, C2-substituted thiophenes, pyrroles, imidazole, triazole, imidazopyridine, thiazole, and oxazoles, which could be efficiently arylated with aryl bromides. Unfortunately, benzofuran produced low yields (29% with 2-bromotoluene), and furans encountered issues with diarylation, which could be minimized by using more sterically hindered aryl bromides. Arylation of indolizines could be achieved, albeit electron-deficient aryl bromides required longer reaction times (16-24 h). Heterocyclic aryl bromides, such as 3-bromopyridine, could also be employed with thiazole. Problematic aryl halides included cyano, nitro, acetyl, pyridyl functionalities, and N-heterocyclic V-oxides. Other coupling partners, such as aryl tri-flates and aryl chlorides, performed poorly under the reaction conditions. Unsuitable heterocycles included unprotected imidazoles, 2-aminothiazole, isoxazole, benzothiazole, and benzoxa-zole, which failed to produce arylated products. 

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