Nucleophilic aromatic substitution, quinoxaline

Pyridine A-oxides were converted to tetrazolo[l,5-a]pyridines 172 by heating in the presence sulfonyl or phosphoryl azides and pyridine in the absence of solvent <06JOC9540>. 3-R-5-Trinitromethyltetrazolo[l,5-a]-l,3,5-triazin-7-ones 173 have been prepared from the alkylation of 5-trinitromethyltetrazolo[l,5-a]-l,3,5-triazin-7-one silver salt with different alkylation agents <06CHE417>. The use of 2-fluorophenylisocyanide in the combinatorial Ugi-tetrazole reaction followed by a nucleophilic aromatic substitution afforded tricylic tetrazolo[l,5-a]quinoxaline 174 in good yields and with high diversity <06TL2041>. 

The strategy of building the pyrazine ring of the quinoxaline system is fundamentally different in the case of 4-bromo-5-nitrophthalonitrile 409, with two nitrile groups which activate the other substituents on the benzene ring toward the nucleophilic aromatic substitution. 

A combinatorial synthetic route yielding fused tetrazolo[l,5-a]quinoxalines has been described by Kalinski et al. [128] using the classical fom--component Ugi reaction (Scheme 92). The Ugi-tetrazole reaction between amine, aldehyde, carboxylic acid, and isocyanide, followed by a nucleophilic aromatic substitution (SnAc) affords the tri-cylic tetrazolo[l,5-a]quinoxaline moiety in good yields and with high diversity. Amines and carbonyls can be varied broadly, yielding tricyclic tetrazoles with three potential diversity points giving access to thousands of diverse analogs. 

The same group has reported another example using four-component Ugj reaction followed by a postcondensation cyclization via nucleophilic aromatic substitution (SnAt) leading to a two-step synthesis of imidazo- and pyrazolo[l,5-fl]quinoxalines [129] (Scheme 93). The Ugi reaction is initiated by the condensation of amine with... 

A simple one-pot strategy for the synthesis of differently substituted quinoxalines from 1,2-aryl diamines and 2-bromomalonic ester at room temperature (Scheme 65) xmder solvent- and catalyst-free conditions has been investigated by Haidar et al. [95]. The mechanism followed is nucleophilic substitution, amide formation, followed by in situ oxidative aromatization. The compoxmd 54a, a key synthetic intermediate for the synthesis of a 5-HT3 receptor antagonist, could be effectively synthesized by this reaction protocol. 

A plausible reaction mechanism for the formation of quinoxaline derivatives from 1,2-DAB and phenacyl bromide is illustrated in Scheme 2.19. Initially, a nucleophilic substitution occurs on the phenacyl bromide to afford the intermediate 217. Intermediate 217 spontaneously cychses to form 3-phenyl-1,2-dihydroquinoxaline 218, which imdergoes aromatization under air oxidation to afford 2-phenylquinoxaline 214a as the final product. 

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