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Keywords:
1,4-benzothiazine; 1,3-benzothiazole; 1H-pyrrole-2,3-diones; nitrogen heterocycle; sulfur heterocycle
Abstract
Pyrrolo[2.1-b][1.3]benzothiazoles are an important class of fused sulfur and nitrogen-containing heterocycles intensively studied in medicinal chemistry and pharmacology. In the present paper, a new synthetic approach to pyrrolobenzothiazoles is developed based on 1.4-thiazine ring contraction in 3-aroylpyrrolo[2.1-c][1.4]benzothiazine-l.2.4-triones under the action of nucleophiles. The proposed approach works well with alkanols, benzylamine, and arylamines. The scope and limitations of the developed approach are studied. The synthesized pyrrolobenzothiazole derivatives represent an interest to pharmaceutics, since their close analogs show CENP-E inhibitory activity, interesting for the targeted cancer therapy development.
Introduction
Pyrrolo[2.1-¿>][1.3]benzothiazole (PBTA) is an angularly fused sulfur and nitrogen-containing heterocyclic scaffold. Its derivatives are popular in medicinal chemistry and pharmacology as potential biologically active compounds. In particular. PBTAs were found to be promising inhibitors of centromere-associated protein E (CENP-E) (Figure T). which is demanded for the development of targeted cancer therapy [1]. Furthermore, candidate anticonvulsant agents had been developed based on PBTA derivatives (Figure 1) [2]. In addition, series of PBTAs (Figure T) were found to exhibit antibacterial, antifungal, antioxidant, and cytotoxic activities [3.4],
Several strategies have been developed for the synthesis of PBTA derivatives [2-32] to meet the needs of medicinal chemistry and pharmacology for PBTAs containing diverse substituents. In general, these synthetic strategies can be divided into four groups.
The first group of approaches to the PBTA scaffold is an annulation of benzothiazoles with a pyrrole moiety (Scheme T). It includes intramolecular cyclizations of benzothiazoles bearing a 3'-chloro substituent at C2 position (Scheme 1. entries 1 and 2) [5-7], intramolecular catalytic carbene cascade reactions of propargyl 1.3-benzothiazol-2-yl(diazo)acetates (Scheme 1. entry 3) [12], dearomative [3 + 2] cycloaddition reactions of benzothiazoles with cyclopropanes (Scheme 1. entry 4) [13-15], multicomponent reactions (MCRs) of benzothiazoles, isocyanides and 2-methylidenemalonates (Scheme 1. entry 5) [16], 1.3-dipolar cycloadditions of A-alkylbenzothiazolium salts (Scheme 1. entry 6) [17-22], MCRs of 2-methylbenzothiazole. acetylenedicarboxylates and active methylene compounds (Scheme 1. entry 7) [23-25], MCRs of (1.3-benzothiazol-2yl(acetonitrile, aldehydes and acylcyanides (Scheme 1. enry 8) [3.26] and reactions of 3-acyl-2.3-dihydro-1.3-benzothiazole-2carbonitriles with acetylenedicarboxylate (Scheme 1. entry 9) [4].
The second group of approaches to the PBTA scaffold is an annulation of o-aminothiophenol with a pyrrolothiazole moiety (Scheme 2). It includes catalytic cascade reactions of o-aminothiophenol with donor-acceptor cyclopropanes (Scheme...