Background and Objective: Continuing our studies in the field of a new rearrangement in the 2,7- naphthyridine series, the synthesis and rearrangement of mono- 2 and di-amino derivatives 3 of 2,7- naphthyridine was carried out. Taking into account the wide range of pharmacological activities of pyrazole derivatives the synthesis of some 3-amino-1-(3,5-dimethyl-1H-pyrazol-1-yl)-2,7-naphthyridines 8 and of pyrazolo[3,4-c]-2,7-naphthyridine 12 was described. Methods: Compounds 2 were reacted with amines furnishing the relevant rearrangement products 4. Starting from the 7-benzyl-3-chloro-1-hydrazino-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile 6 and 5-hydrazino- 6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]-2,7-naphthyridin-1-amine 12 the 7-benzyl-3-chloro-1-(3,5-dimethyl-1Hpyrazol- 1-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile 7 and 3,5-dimethyl-1H-pyrazol-1-yl-9,11- dimethylpyrimido[1',2':1,5]pyrazolo[3,4-c]-2,7-naphthyridine 13 were synthesized, via the Knorr synthesis of pyrazoles. Results: The syntheses of 2-benzyl-6,8-diamino-3,4-dihydro-2,7-naphthyridin-1(2H)ones 4 deriving from the rearrangement of compounds 2 and/or 3 were performed. By reaction with benzylamine compound 2a or 3g gave the unexpected formation of N,7-dibenzyl-8-(benzylimino)-3-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7- naphthyridin-1-amine 5: in fact, the rearrangement was followed by condensation between the C-1 carbonyl group of the 2,7-naphthyridine ring and the benzylamine. Starting from the 7-benzyl-3-chloro-1-(3,5-dimethyl- 1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile 7 the relevant 3-amino-7-benzyl-1-(3,5- dimethyl-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitriles 8 were obtained. In harsh experimental conditions the nucleophilic substitution of the 1-pyrazolyl residue took place with formation of 7- benzyl-1,3-bis[(2-hydroxypropyl)amino]-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile 10. Moreover compound 7 reacted with hydrazine hydrate giving the pyrazolo[3,4-c]-2,7-naphthyridine 12, which, in turn furnished a new tetra-heterocyclic system: 3-benzyl-5-(3,5-dimethyl-1H-pyrazol-1-yl)-9,11-dimethyl-1,2,3,4- tetrahydropyrimido[1',2': 1,5]pyrazolo[3,4-c]-2,7-naphthyridine 13. Conclusion: Replacement of methyl group on piperidine ring of 2,7-naphthyridine system with the benzyl one led to new results. Reaction of compound 2a or 3g with benzylamine brought to an unexpected formation of N,7-dibenzyl-8-(benzylimino)-3-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7-naphthyridin-1-amine 5. The reactivity of 7-benzyl-3-chloro-1-(3,5-dimethyl-1H-pyrazol-1-yl)-2,7-naphthyridine 7 with nucleophiles was investigated observing the unexpected substitution of the 1-pyrazolyl residue.

Reactivity in 7-benzyl-2,7-naphthyridine derivatives: Nucleophilic substitutions, rearrangements, heterocyclizations and related reactions

SPINELLI, DOMENICO;CALVARESI, MATTEO;BOGA, CARLA;
2017

Abstract

Background and Objective: Continuing our studies in the field of a new rearrangement in the 2,7- naphthyridine series, the synthesis and rearrangement of mono- 2 and di-amino derivatives 3 of 2,7- naphthyridine was carried out. Taking into account the wide range of pharmacological activities of pyrazole derivatives the synthesis of some 3-amino-1-(3,5-dimethyl-1H-pyrazol-1-yl)-2,7-naphthyridines 8 and of pyrazolo[3,4-c]-2,7-naphthyridine 12 was described. Methods: Compounds 2 were reacted with amines furnishing the relevant rearrangement products 4. Starting from the 7-benzyl-3-chloro-1-hydrazino-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile 6 and 5-hydrazino- 6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]-2,7-naphthyridin-1-amine 12 the 7-benzyl-3-chloro-1-(3,5-dimethyl-1Hpyrazol- 1-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile 7 and 3,5-dimethyl-1H-pyrazol-1-yl-9,11- dimethylpyrimido[1',2':1,5]pyrazolo[3,4-c]-2,7-naphthyridine 13 were synthesized, via the Knorr synthesis of pyrazoles. Results: The syntheses of 2-benzyl-6,8-diamino-3,4-dihydro-2,7-naphthyridin-1(2H)ones 4 deriving from the rearrangement of compounds 2 and/or 3 were performed. By reaction with benzylamine compound 2a or 3g gave the unexpected formation of N,7-dibenzyl-8-(benzylimino)-3-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7- naphthyridin-1-amine 5: in fact, the rearrangement was followed by condensation between the C-1 carbonyl group of the 2,7-naphthyridine ring and the benzylamine. Starting from the 7-benzyl-3-chloro-1-(3,5-dimethyl- 1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile 7 the relevant 3-amino-7-benzyl-1-(3,5- dimethyl-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitriles 8 were obtained. In harsh experimental conditions the nucleophilic substitution of the 1-pyrazolyl residue took place with formation of 7- benzyl-1,3-bis[(2-hydroxypropyl)amino]-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile 10. Moreover compound 7 reacted with hydrazine hydrate giving the pyrazolo[3,4-c]-2,7-naphthyridine 12, which, in turn furnished a new tetra-heterocyclic system: 3-benzyl-5-(3,5-dimethyl-1H-pyrazol-1-yl)-9,11-dimethyl-1,2,3,4- tetrahydropyrimido[1',2': 1,5]pyrazolo[3,4-c]-2,7-naphthyridine 13. Conclusion: Replacement of methyl group on piperidine ring of 2,7-naphthyridine system with the benzyl one led to new results. Reaction of compound 2a or 3g with benzylamine brought to an unexpected formation of N,7-dibenzyl-8-(benzylimino)-3-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7-naphthyridin-1-amine 5. The reactivity of 7-benzyl-3-chloro-1-(3,5-dimethyl-1H-pyrazol-1-yl)-2,7-naphthyridine 7 with nucleophiles was investigated observing the unexpected substitution of the 1-pyrazolyl residue.
CURRENT ORGANIC CHEMISTRY
Sirakanyan, S.N.; Kartsev, V.A.; Spinelli, D.; Geronikaki, A.; Hakobyan, E.K.; Panosyan, H.A.; Calvaresi, M.; Boga, C.; Hovakimyan, A.A.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/603656
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