Benzothiazoles ring synthesis

While studying the chemistry of 4,5-dichloro-l,2,3-dithiazolium chloride (Appel s salt) and its derivatives, Besson reported the synthesis of various benzothiazoles from N-arylimino-l,2,3-dithiazoles, which could be synthesised from commercially available aromatic amines28. In this work, the authors explored a variety of strategies to construct the benzothiazole ring and demonstrated that in all cases the focused microwave methodologies were more productive and under well-defined conditions provided convenient methods for scale-up (Scheme 3.17)28. Comparisons were also made between reactions performed under solvent-free conditions and in the presence of solvent29. It is noteworthy that there is no general rule and some reactions performed in the presence of solvent may sometimes be more convenient than the same dry media reaction. 

Synthesis by carbon-carbon bond formation between an acyclic sugar derivative and the benzothiazole ring system has also been utilized for the synthesis of these C-nucleosides. In one report, 2,3-O-isopropylidene-D-glyceraldehyde (61) was coupled with 2-trimethylsilylbenzothiazole to afford the A-nucleoside 185 as an intermediate, which underwent a 1,2-shift of the alditolyl chain to produce the C-nucleoside 186 (85TL5477) (Scheme 55). 

One of the most studied microwave-assisted formations of the benzothiazole ring is initiated by an addition-elimination reaction. Treatment of aniline derivatives with 4,5-dichloro-l,2,3-dithiazolium chloride (commonly called Appel s salt) gave 4-chloro-5]-f-l,2,3-iminodithiazoles (47) which are very versatile intermediates in the synthesis of a variety of heterocycles (Scheme 9.15). Besson and coworkers... 

Tapia RA, Prieto Y et al (2002) Synthesis and antileishmanial activity of indoloquinones containing a fused benzothiazole ring. Em J Org Chem 4005-4010... 

Chikashita, H. Ishihara, M. Takigawa, K Itoh, K. (1991). Synthetic ap>phcation of benzothiazole ring system as an on-off type of leaving group. Synthesis of ketones and carboxylic acid derivatives from 2-(l-substituted 1-hydroxyalkyl)- and 2-(l-hydroxyalkyl)benzothiazoles. Bidl. Chem. Soc. Jpn. Vol. 64, pp. 3256-3261, ISSN. 

The usual synthesis from a hydrazone and PCI3 has been applied to prepare p-(l,2,3-diazaphos-phol-5-yl)benzylphosphonates, analogues to Fostedil in which the benzothiazol unit is replaced by a diazaphosphole ring. However, their activity to inhibit calcium transfer through biological membranes is weak <93PS(85)225>. 

The two step conversion of the benzoxazole, first into the benzoxazolium bromide 123 followed by ring expansion afforded the A-formyl benzoxazocine 124 (Scheme 13) <1995JOC2597>. This approach was also successfully applied to the synthesis of A-formyl benzo[l,4]thiazocine from the benzothiazole (Scheme 16, Section 14.06.5.3). 

Benzothiazole is a privileged bicyclic ring system [47]. Due to their potent antitumour activity [48] and other important pharmaceutical utilities [49-52] the synthesis of these compounds is of considerable interests [53]. 

The synthesis and some novel reactions of 8-chloro-27/-[l,2,4]triazine[3,4-6][l,3]benzothiazole-3,4-dione including a ring contraction to the corresponding [l,2,4]triazolo-fused derivative have been reported <05JCR(S)632>. 

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. 

The synthetic applications of benzothiazoles appeared to be limited by the fact that the thiazole ring cannot be hydrolytically cleaved. However, this problem was solved by quatemization followed by reduction with NaBH4 to produce 3-methyl-2,3-dihydrobenzothiazole, as shown in the synthesis of cyclohexene-1-carbaldehyde [104] ... 

Stevens et al. have proposed another likely mechanism for the Jacobson synthesis where a single-electron transfer process appears to operate. Here thiobenzamide reacts with the base to generate thiolate ion that undergoes oxidation to form a thiol radical shown below. The thiol radical can attack the unsubstituted ortho position and form a five-membered ring that aromatizes through the elimination of a hydrogen radical and form benzothiazole. Stevens et al. during this study also noted that the availability... 

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