Syntheses of Functionalised Angular Phenothiazines and Phenoxazines of Pharmaceutical Interest Via Transition Metal-Catalyzed Tandem Reactions

Abstract

The synthesis of new angular aza phenothiazinones, angular azaphenoxazines and their derivatives are reported. Two key functional intermediates namely 2,6-diamino-4-chloro-pyrimidin-5-thiol and 7-chloro-5,8-quinolinequinone were successfully synthesized from readily available starting materials using such traditional organic methods as nitrosation, nitration, halogenation, reduction, oxidation, direct thiocynation and base-catalyzed hydrolysis. The new angular azaphenothiazinones and angular azaphenoxazinone were prepared by coupling the requisite intermediates. Condensation reaction between 2,6-diamino-4-chloro-pyrimidin-5-thiol or 2-aminothiophenol or 2-aminophenol and 7-chloro-5,8-quinolinequinone in the presence of anhydrous sodium carbonate produced 10-amino-8-chloro-1,9,11-triaza-5H-benzo[a]phenothiazin-5-one,2291-aza-5H-benzo[a]- phenothiazin-5-one,231 1-aza-5H-benzo[a]phenoxazin-5-one233 respectively. Also by coupling 2,6-diamino-4-chloro-pyrimidin-5-thiol with 2,3-dichloro-1,4-naphthoquinone in the presence of anhydrous sodium carbonate, 10-amino-6,8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one230 was obtained. These angular azaphenothiazinones and angular azaphenoxazines were converted to their derivatives via palladium, copper and nickel-catalyzed cross-coupling tandem reactions utilizing Mizoroki-Heck, Buchwald-Hartwig and Yamamoto protocols. Palladium catalyzed cross-coupling reaction between 10-amino-8-chloro-1,9,11-triaza-5H-benzo[a]phenothiazin-5-one and four phenyl-iodo derivatives utilizing Mizoroki-Heck protocol furnished four new compounds namely 10-amino-8-chloro-6-(4-nitrophenyl)-1,9-11-triaza-5H-benzo[a]phenothiazin-5-one, 10-amino-8-chloro-6-(2-hydroxyphenyl)-1,9,11-traiza-5H-benzo[a]phenothiazin-5-one, 10-amino-8-chloro-6-(4-carboxyphenyl)-1,9,11-traiza-5H-benzo[a]phenothiazin-5-one and 10-amino-8-chloro-6-(2-carboxyphenyl)-1,9,11-traiza-5H-benzo[a]phenothiazin-5-one. Also palladium catalyzed Mizoroki-Heck cross coupling reactions with arylated iodo compounds and 1-aza-5H-benzo[a]phenothiazin-5-one and 1-aza-5H-benzo[a]phenoxazin -5-one produced the following new compounds: 6-(4-nitrophenyl)-1-aza-5H-benzo[a]phenothiazin-5-one, 6-(2-hydroxyphenyl)-1-aza-5H-benzo[a]phenothizin-5-one, 6-(4-carboxyphenyl)-1-aza-5H-benzo [a]phenothiazin-5-one, 6-(2-carboxyphenyl)-1-aza-5H-benzo[a]phenothiazin-5-one, and 6(-(2-hydroxyphenyl)-1-aza-5H-benzo[a] phenoxazin-5-one, 6-(4-nitrophenyl)-1-aza-5H-benzo[a]phenoxazin-5-one, 6-(4-carboxyphenyl)-1-aza-5H-benzo[a]phenoxazin-5-one and 6-(2-carboxyphenyl)-1-aza-5H-benzo[a]phenoxazin-5-one respectively. The arylation of 10-amino-6,8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one with some amide derivatives via Buchwald-Hartwig nickel complex cross-coupling reactions gave five new compounds namely: 6-acetamido-10-amino-8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one, 6-benzamido-10-amino-8-dichloro-9,11-diaza-5H-benzo[a] phenothiazin-5-one, 6-(4-nitrobenzamido)-10-amino-6,8-dichloro-9,11-diaza-5H-benzo[a] phenothiazin-5-one, 6-phthalamido-10-amino-8-chloro-9,11-diaza-5H-benzo[a]pheno- thiazin-5-one and 6-(2-hydrobenzamido)- 10-amino-8-chloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one.Arylation of 10-amino-6,8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one using some substituted anilines via Buchwald-Hartwig protocol with palladium acetate (Pd(OAc)2 gave five new derivatives namely: 10-amino-8-chloro-6-((4-nitrophenyl) amino)-9,11-diaza-5H-benzo[a]phenothiazin-5-one, 10-amino-6-((4-bromophenyl)amino) -8-chloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one, 10-amino-8-chloro-6-((3-nitrtophenyl)amino)-9,11-diaza-5H-benzo[a]phenothiazin-5-one, 10-amino-8-chloro-6-((4-chlorophenyl)amino)-9,11-diaza-5H-benzo[a]phenothiazin-5-one and 10-amino-6-((2-chlorophenyl)amino-9,11-diaza-5H-benzo[a]phenothiazin-5-one. Similarly arylation of 10-amino-6,8-dichloro-9,11-diaza-5H-benzo- [a]phenothiazin-5-one with Pd(OAc)2 and some heterocyclic amines gave new derivatives namely: 10-amino-8chloro-6-(pyrimidin-2-ylamino)-9,11-diaza-5H-benzo[a]phenothiazin-5-one and 10-amino-8-chloro-6-(4-methylpyridylamino)-(9,11-diaza-5H-benzo[a]- phenothiazin-5-one. Copper-catalyzed N-arylation reaction between 10-amino-8-chloro-1,9,11-triaza-5H-benzo[a]phenothiazin-5-one and potassium aryltriolborates utilizing Yamamoto reaction protocol gave 8-chloro-10-(phenylamido)-1,9,11-triaza-5H-benzo[a]phenothiazin-5-one 8-chloro-10-((3-chlorophenyl)amino)-1,9,11-triaza-5H-benzo[a]phenothiazin-5-one and 10-((4-bromophenyl)amino-1,9-11-triaza-5H-benzo[a]phenothiazin-5-one. Similarly N-arylation of 10-amino-6,8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one, using copper complex and potassium aryltriolborates furnished 6,8-dichloro-10-(phenylamino)-9,11-diaza-5H-benzo[a]phenothiazin-5-one, 6,8-dichloro-10-((3-chlorophenyl)amino)-9,11-diaza-5H-benzo[a]phenothiazin-5-one and 10-((4-bromophenyl)amino)-6,8-dichloro-9,11-diaza-5H-benzo[a]phenothiazin-5-one. Structure elucidation of the synthesized compounds were done by UV-visible, IR, ′HNMR 13CNMR spectroscopy and elemental analysis. The infrared (IR) spectra of these angular azaphenothiazinones and phenoxazinones showed decrease in the C=O absorption band from the expected 1690cm-1 to values ranging from 1682 – 1601cm-1 which were due to ionic resonance effects. Compounds produced from Buchwald-Hartwig cross-coupling reactions using palladium catalysts gave yields of 41 -80%. Nickel complex catalyzed Buchwald-Hartwig reactions gave yields ranging from 71 – 78%. Derivatives obtained by employing Mizoroki-Heck cross-coupling reaction protocol via palladium complex yields between 69 – 86%. Compounds obtained from copper catalysis via potassium phenyltriolborates gave yields 22 – 64%. As a a result of extended conjugation in these new angular azaphenothiazinones and phenoxazinones scaffolds, they are intensely coloured and their colours range from yellow to deep red through reddish brown to dark brown. Antimicrobial screening of these new compounds showed significant biological activity against Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Enterococus faecalis, pseudomonas aerugionsa, Candida albicaus and Aspergillus niger.