The synthesis and identification of 4,6-diaminoquinoline derivatives as potent immunostimulants

Moyer, Mikel P.; Weber, Frederick; Groß, Joachim; Isaac, Joseph W.; Fort, Ralph Saint

doi:10.1016/s0960-894x(00)80436-9

Cited by 6 publications

(1 citation statement)

References 4 publications

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“…Since the previous reports described only one example each, no comments were made on the scope and limitation of the synthetic strategy. In principle, if the regiospecificity of the ring-closure reaction between the amino group present on the phenyl and the carbonyl group generated by the cleavage of the isoxazole ring is maintained, even in the presence of different groups on the isoxazole nucleus, this would become an alternate and convenient route to substituted 4-aminoquinolines which is the substructural unit of several pharmacologically active compounds with antimalarial, 5 antiulcer, 6 immuno-stimulant, 7 anti-HIV, 8 AChE inhibitory, 9 and noniceptin antagonist 10 activity. In addition, this procedure may serve as a method to obtain fluorinated 4-aminoquinoline derivatives which otherwise require complex strategies.…”

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confidence: 99%

Interesting Results of Catalytic Hydrogenation of 3-(2-Nitrophenyl)isoxazoles and 3-(Nitrophenyl)-4,5-dihydroisoxazoles

Singh¹,

Madapa²,

Yadav³

et al. 2006

Synthesis

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The palladium-on-carbon assisted hydrogenolysis of substituted 3-(2-nitrophenyl)isoxazoles, irrespective of substitution on the isoxazole ring, invariably leads to reduction of the nitro to the amino group with concomitant regiospecific ring closure to yield substituted 4-aminoquinolines. In contrast similar hydrogenation of 3-(2-, 3-, and 4-nitrophenyl)-4,5-dihydroisoxazoles (2-isoxazolines) results in reduction of the nitro group only with conservation of the dihydroisoxazole ring to yield the corresponding 3-(aminophenyl)-4,5-dihydroisoxazoles.Hydrogenation of 3-(2-nitrophenyl)-substituted isoxazole derivatives can be utilized for the synthesis of substituted 4-aminoquinoline-2-and 3-carbaldehyde 2 derivatives. There are two reports 3,4 wherein 3-(2-nitrophenyl)-5-phenylisoxazole and 3-(2-nitrophenyl)-5-methylisoxazole-4-carboxylate were hydrogenated in the presence of Raney nickel in acetic acid for 20 hours or ethanol at room temperature to furnish 4-aminoquinoline derivatives. However, in our hands the reaction in acetic acid did not work well and the hydrogenation at room temperature took a long time and several side products were formed. Since the previous reports described only one example each, no comments were made on the scope and limitation of the synthetic strategy. In principle, if the regiospecificity of the ring-closure reaction between the amino group present on the phenyl and the carbonyl group generated by the cleavage of the isoxazole ring is maintained, even in the presence of different groups on the isoxazole nucleus, this would become an alternate and convenient route to substituted 4-aminoquinolines which is the substructural unit of several pharmacologically active compounds with antimalarial, 5 antiulcer, 6 immuno-stimulant, 7 anti-HIV, 8 AChE inhibitory, 9 and noniceptin antagonist 10 activity. In addition, this procedure may serve as a method to obtain fluorinated 4-aminoquinoline derivatives which otherwise require complex strategies. 11 In order to evaluate the scope of this procedure to generate substituted 4-aminoquinolines, we investigated several different substitutions on the isoxazole nucleus employing palladium-on-carbon. Compared to the Raney nickel mediated reaction, it was observed that the reaction is fast and smooth in the presence of palladium-on-carbon. Additionally, the ring-closure reaction between the amino and the carbonyl groups generated by cleavage of the isoxazole ring is highly regiospecific even in the presence of another formyl group.As an extension of this study, we also explored the hydrogenolysis of the 3-(2-nitrophenyl)-4,5-dihydroisoxazole (2-isoxazoline) system. Surprisingly the 4,5-dihydroisoxazole ring, which is otherwise known to readily undergo catalytic hydrogenolysis, is highly stable to ring cleavage when nitrophenyl substitution is present on it. Our results on the catalytic hydrogenations of substituted 3-(2-nitrophenyl)isoxazoles and 3-(nitrophenyl)-4,5-dihydroisoxazoles are presented in this communication.Methyl 3-(2-Nitrophenyl)-5-methyliso...

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