Synthesis of Benzothiazoles

This strategy has been adapted by a number of research groups to incorporate formation of the key o-halothioamide substructure in situ from a variety of precursors [142-144] similar three-component versions have also recently been reported [145, 146]. 

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One of the first published microwave-assisted synthesis of benzothiazoles is the condensation of a dinucleophile such as 2-aminothiophenol, with an ortho-ester (neat) in the presence of KSF clay in a mono-mode microwave reactor operating at 60 W under a nitrogene atmosphere [ 12] (Scheme 12). Traditional heating (oil bath, toluene as solvent and KSF clay) gave the expected products in similar yields compared to the microwave experiments but more than 12 h were required for completion. Solvent-free microwave-assisted syntheses of benzothiazoles was also described by attack of the dinucleophiles cited above on benzaldehydes and benzaldoximines [13] (Scheme 12). This methodology was performed in a dedicated monomode microwave reactor... 

The Jacobson thioanilide radical cyclization chemistry has been extensively used for the synthesis of benzothiazoles as shown by the preparation of 4-fluoro-2-(3,4-dimethoxy-phenyl)benzothiazole 47 <06JMC179>. The harsh reaction conditions (K3Fe(CN)6, NaOH,... 

Scheme 6.219 Synthesis of benzothiazoles [391, 392], thiazolobenzimidazoles [370], and heteroaryl-substituted thiazolidinones [370],...

The Jacobson synthesis of benzothiazoles 235 involves oxidative cyclization of an arylthioamide 236 on an unsubstituted ortho- )osit on, using potassium ferricyanide in a basic medium (Scheme 94) <1999J(P1)1437>. This method has been applied to the synthesis of various benzothiazoles, including analogues of kuanoniamine A <20040BC3039>. 

The solid-phase combinatorial synthesis of benzothiazoles 244 from 243 has been used in the investigation of topoisomerase II inhibitiors (Scheme 98) <2006BMC1229>. 

Table 7 Yields (%) for solid-phase synthesis of benzothiazoles 245 on solid support...

The most general method for the synthesis of benzothiazoles and benzothiazolines is the cycli-zation of or(/io-disubstituted benzenes, o-aminothiophenols, or naphthols with electrophilic reagents. This approach is well-documented in CHEC-I <84CHEC-l(6)32i>. 

The most important strategy for the synthesis of benzothiazoles, benzimidazoles and benzoxazoles is the insertion of C-2 into a precnrsor with ortfto-heteroatoms on a benzene ring. The component that is reqnired for this pnrpose usually has the future C-2 at the oxidation level of an acid, but many variants on this have been described. 

Type E Syntheses (C Hs-N + C-S). Treatment of substituted anilines with NH4SCN gives substituted 2-aminothiazoles and there are also references concerning the synthesis of benzothiazoles. 

The required pyridinium salts can be obtained by the King-Ortoleva reaction (see p 273), as is shown by the synthesis of benzothiazole-2-carbaldehyde 237. In the Krohnke reaction, the heterocycle pyridine ensures the targeted conversion CH3 -> CH=0 of methyl groups in arenes or heteroarenes [78]. 

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