SYNTHESES OF FUNCTIONALISED ANGULAR PHENOTHIAZINES AND PHENOXAZINES OF PHARMACEUTICAL INTEREST VIA TRANSITION METAL-CATALYZED TANDEM REACTIONS

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-naphthoquinrone 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………………………………….