An Efficient Synthesis of Pyrazolo[3,4- b]quinolin-3-amine and Benzo[b][1,8]naphthyridine Derivatives

2-Oxo-4-phenyl-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile (10) reacted with hydrazine hydrate, phenylisothiocyanate or benzoyl chloride to give derivatives 12, 13 and 15, respectively. The latter two products were treated with hydrazine hydrate to afford pyrozole[3,4-b]quinolines derivatives 14 and 16, respectively. Compound 10 also reacted with acetonitrile dimer or malononitrile dimer to yield benzo[b][1,8]-naphthyridine derivatives. A single crystal X-ray crystallographic analysis was performed on compound 10, confirming its structure.


Scheme 6
Hexahydroquinoline derivative 10 reacted with acetonitrile dimer (3-iminobutanenitrile) or malononitrile dimer (2-aminoprop-1-ene-1,1,3-tricarbonitrile) to afford 4-amino-benzo[b] [1,8] napthyridinecarbonitrile derivatives 29 and 32.These reactions proceed by addition of the active methylene group to the cyano group to give the intermediate 28 and 31, which undergo cyclization via the elimination of a water molecule.The structures of the isolated product were confirmed by elemental and spectral analyses.The target ring system 35 was synthesized by reaction of 10 with cyanoacetohydrazide 33 through the intermediate 34 via elimination of a water molecule (Scheme 8).

General
All melting points are uncorrected.Elemental analyses were carried out in the Microanalytical Center, Cairo University, Giza, Egypt.IR spectra (KBr) were recorded on Pye Unicam SP 1200 Spectrophotometer. 1 H-NMR spectra were recorded in CDCl 3 or DMSO-d 6 on a 90 MHz Varian NMR Spectrometer using TMS as an internal standard and chemical shifts are expressed as δ ppm units.The homogeneity of all compounds synthesized was checked by TLC on 2.0 cm x 6.0 cm aluminum sheets recoated with silica gel 60 containing a fluorescent indicator, to a thickness of 0.25µm.Characterization data of the various compounds prepared are given in Tables 2 and 3.
A solution of cyclohexanone (1, 0.01 mol) in absolute ethanol (30 mL) containing excess ammonium acetate and the arylidene derivative 2 (0.01 mol) was heated under reflux for 3-5 h.The solid material which separated during heating was collected by filtration and recrystallized from ethanol to yield the hexahydroquinoline derivative 10.
(3-Cyano-5,6,7,8-tetrahydro-2-oxo-4-phenylquinoline)(phenyl)methanone (15) Benzoyl chloride (0.01 mol) was added to a solution of 10 (0.01 mol) in dry pyridine (30 mL) and the mixture was refluxed on a water bath for 5 h., then left to cool to room temperature and poured into ice cold water and neutralized by diluted hydrochloric acid for complete precipitation.The separated material was collected by filtration, washed with water, dried well and recrystallized from acetic acid to yield compound 15.

4-Amino
To a solution of 10 (0.005 mol) in absolute ethanol (30 mL), triethylamine(5 mL) malononitrile (0.005 mol) was added and the reaction mixture was refluxed for 6 h., then left to cool to room temperature, poured into cold water and neutralized with diluted hydrochloric acid to complete precipitation.The solid obtained was filtered off, washed with water, dried well and recrystallized from methanol to give compound 26.
An equimolar mixture of 10 (0.005 mol) and acetonitrile dimmer (3-iminobutanenitrile, 27, 0.005 mol) or malononitrile dimer (2-aminoprop-1-ene-1,1,3-tricarbonitrile, 30, 0.005 mol) in absolute ethanol (30 mL) in the presence of a few drops of triethylamine (4 drops) was refluxed for 6 h.The reaction mixture was left to cool and poured into cold water for complete precipitation.The separated solid was filtered off, washed with water, dried well and recrystallized from ethanol to give compounds 29 or 32.
A few drops of pipridine were added to a solution of 10 (0.005 mol) and cynanoacetohydrazide (0.005 mol) in absolute ethanol (30 mL) and the reaction mixture was refluxed for 5 h., then left to cool.The product was filtered off, washed with water, dried well and recrystallized from ethanol to give compound 35.X-ray crystallography [13] X-ray quality crystals of the title compound 10 were obtained by slow crystallization from dimethyl sulfoxide.Experimental data is summarized in Table 1.The data were collected with the maXus computer programs on a Bruker Nonius instrument [14][15][16][17][18].

Table 1 .
Crystal data and structure refinement for compound 10.

Table 2
Physical properties and elemental analyses of the new compounds.