Novel synthetic routs towards the synthesis of mono-, di- and tri-substituted qunoxallines

Abstract

2-Benzenesulfonyloxyquinoxaline was prepared following literature procedure followed by palladium-catalysed Negishi coupling reactions to yield the corresponding, 2-mono-substituted quinoxaline derivatives, 2-phenylquinoxaline and 2-butylquinoxaline. These Negishi cross-coupled derivatives were treated with various nucleophiles, in tetrahydrofuran at room temperature, to yield a series of di-substituted quinoxaline derivatives containing; aryl-, heteroaryl-, arylalkynyl- and alkyl-substituents. Tri-substitution was successful with reaction of 6-chloro-2-benzenesulfonyloxyquinoxaline with excess phenyl-magnesium bromide to yield 2,3,6-triphenylquinoxaline. Sonogashira cross-coupled compounds were successfully synthesised by reacting 2-benzenesulfonyloxyquinoxaline, 6-nitro-2-benzenesulfonyloxyquinoxaline and 6-chloro-2-benzenesulfonyloxyquinoxaline using phenylacetylene, respectively. Nucleophilic substitution was only successful on 2-(2-phenylethynyl)quinoxaline to yield 3-butyl-2-(2-phenylethynyl)quinoxaline. The formation of carbon-nitrogen bonds was accomplished via palladium-catalysed Buchwald-Hartwig amination of 2-benzenesulfonyloxyquinoxaline with arylamines to afford N-phenylquinoxalin-2-amine and N-benzylquinoxalin-2-amine in good to high yields. N-phenylquinoxalin-2-amine was subsequently treated with iodomethane to synthesise N-methyl-N-phenylquinoxalin-2-amine. Nucleophilic substitution on Buchwald-Hartwig coupled compounds was only successful when using alkyl nucleophiles. The reaction of all these quinoxaline derivatives with various nucleophiles does not stop at the stage of α-adduct formation, but continues with the oxidation of these compounds to aromatic substitution products. All synthesised compounds were characterised by NMR, and mass spectral data as well as melting points where applicable. N-Methyl-N-phenylquinoxalin-2-amine and 2,3,6-triphenylquinoxaline showed percentage parasite viability of 42.64% and 58.12%, respectively, against the Plasmodium falciparum strain 3D7. N-Methyl-N-phenylquinoxalin-2-amine showed MIC90 of 16.4 and MIC99 of 19 μM, while 6-chloro-2-(2-phenylethynyl)quinoxalin showed MIC90 of 8.15 and MIC99 of 9.26 μM values against Mycobacterium tuberculosis (Mtb)-H37Rv strains.