Nucleophile-induced ring contraction in pyrrolo[2,1-c][1,4]benzothiazines: access to pyrrolo[2,1-b][1,3]benzothiazoles

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-1,2,4-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.

Approach to Pyrido[2,1-b][1,3]benzothiazol-1-ones via In Situ Generation of Acyl(1,3-benzothiazol-2-yl)ketenes by Thermolysis of Pyrrolo[2,1-c][1,4]benzothiazine-1,2,4-triones

“…For the development of the approach to pyrido [2,1- b ][1,3]benzothiazol-1-ones 2 , we considered two types of potent sources of acyl(1,3-benzothiazol-2-yl)ketenes 3 , APBTTs 1 [ 10 , 11 ] and 3-benzoylpyrrolo [2,1- b ][1,3]benzothiazole-1,2-dione 4 ( Scheme 3 ) [ 11 ]. Compound 4 was assumed to undergo a classical pattern for FPDs of thermal decarbonylation [ 9 ], cheletropic elimination of CO from C 1 =O position, affording the desired ketene 3a .…”

“…Compound 4 was assumed to undergo a classical pattern for FPDs of thermal decarbonylation [ 9 ], cheletropic elimination of CO from C 1 =O position, affording the desired ketene 3a . Compounds 1 were hypothesized to undergo elimination of two molecules of CO from C 1 =O (as a classical pattern of thermal decarbonylation for FPDs [ 9 ]) and C 4 =O positions (as a reactivity feature of APBTTs 1 , observed by us earlier in nucleophilic reactions [ 11 ]), affording the desired ketenes 3 .…”

“…Thin-layer chromatography (TLC) was performed on Merck silica gel 60 F 254 plates using EtOAc/toluene, 1:5 v / v , toluene, and EtOAc as eluents. Starting compounds 1a – g , 4 were obtained according to reported procedures [ 10 , 11 ]. All other solvents and reagents were purchased from commercial vendors and used as received.…”

“…Recently, we have reported [ 10 ] a new type of FPDs, 3-aroylpyrrolo [2,1- c ][1,4]benzothiazine-1,2,4-triones (APBTTs) 1 , prone to undergo a 1,4-thiazine ring contraction reaction to afford corresponding 1,3-thiazole derivatives under certain conditions [ 11 ]. These seem to be a promising feature for the development of a synthetic strategy to pyrido [2,1- b ][1,3]benzothiazol-1-ones through chemical transformations of APBTTs 1 .…”

3-Benzoyl-2-hydroxy-3a-[(3-methylquinoxalin-2-yl)methyl]-1H-pyrrolo[2,1-c][1,4]benzothiazine-1,4(3aH)-dione

“…APBTTs are known to be prone to react with mononucleophiles NuH at three various electrophilic centers (C 1 , C 3a , and C 4 ), resulting in three types of products 9-11 [18] (Scheme 3). The reaction direction is highly dependent on the structure of NuH [18]. Thus, a study on the reactions of APBTTs with various nucleophiles is of high theoretical and practical interest.…”