Nucleophilic substitution and ring transformation reactions with 4-chloro-6-ethyl-3-nitropyrano[3,2-c ]quinoline-2,5(6 H )-dione

4-Chloro-6-ethyl-3-nitropyrano[3,2-c ]quinoline-2,5(6 H )-dione ( 3 ) was obtained by nitration followed by chlorination of 4-hydroxypyranoquinoline-2,5-dione 1 . Substitution reactions of compound 3 with various nucleophiles, namely: sodium azide, amines, thiophenol and malono-nitrile, led to a series of novel 4-sustituted-3-nitropyranoquinolinones. Also, nucleophilic reactions of compound 3 with hydrazine, cyanoguanidine and S -methylisothiourea, involving ring opening-ring closure of the pyranoquinolinedione nucleus, are described.

Pyrano [3,2-c]quinolinones are able to undergo ring opening at C-2 and ring reclosure at C-4 when reacted with binucleophiles. 15,161][22] Herein we report the synthesis of the novel 4-chloro-6-ethyl-3-nitropyrano [3,2-c]quinoline-2,5-dione (3) and a study of its chemical behavior towards some nitrogen, sulfur and carbon nucleophiles to obtain a new series of 4-substituted-3nitropyranoquinolinediones.Also, we use compound 3 to prepare 4-hydroxyquinolinones incorporating a pyrazolone or pyrimidine and/or triazolopyrimidine ring at position 3, with the possibility to show biological activity.

Results and Discussion
Heating N-ethylaniline with two equivalents of diethyl malonate gave 4-hydroxypyrano [3,2-c]quinoline-2,5(6H)-dione (1). 23,24Nitration of compound 1 has been reported with a mixture of conc.nitric acid and conc.sulfuric acid in boiling acetic acid. 25We herein report for application of a known modification under substantial milder conditions, at room temperature using sodium nitrite as catalyst. 17Roschger et al. 17 had applied this methodology in similar case of 4hydroxyquinolin-2-ones, and according to this modification, catalytic effect of the nitrite was attributed to an initial nitrosation at position 3 and subsequent in situ oxidation of the nitroso intermediate to the desired nitro product 2 (Scheme 1).Chlorination of compound 2 with phosphoryl chloride in the presence of triethylamine afforded 4-chloro-3-nitropyrano[3,2c]quinoline-2,5(6H)-dione 3 (Scheme 1).The IR and 1 H NMR spectra of compound 3 confirmed the absence of the hydroxy group.The mass spectrum of compound 3 showed two molecular ion peaks at m/z 320 [M + ] and m/z 322 [M + +2], these data support the identity of the structure and confirm the presence of the chlorine atom.The substitution of the chlorine by an azide group was achieved by the reaction of compound 3 with sodium azide, in N-methylpyrrolidone, at room temperature (Scheme 2).The IR spectrum of the product 4 showed characteristic absorption band at 2150 cm -1 attributed to the azido group.Organic azides with suitable ortho substituents are known to undergo thermal cyclization with loss of N2 gas. 17,26,27Ring closure to the fused furoxan 5 was achieved by thermolysis of the azide 4 in refluxing nitrobenzene (Scheme 2).The IR spectrum of furoxan 5 showed characteristic absorption bands at 1448 cm -1 assigned to the C=N-O, while the stretching vibration of the fragment O-N→O was seen at 1301 cm -1 (as the recently reported for furoxan ring 28 ).The mass spectrum of compound 5 showed the molecular ion peak at m/z 299.
Nucleophilic substitution of the chlorine atom at position 4 of compound 3 by various nucleophiles such as amines, thiophenol, and malononitrile could be carried out under mild conditions.Thus, reaction of compound 3 with benzylamine led to the 4-benzylamino derivative 6a (Scheme 2).The 1 H NMR spectrum of compound 6a showed a new characteristic singlet signal at δ 4.26 assigned to the methylene protons of benzyl group, in addition to one exchangeable signal at δ 10.00 ppm due to NH proton.The reaction of compound 3 with aniline, in the presence of triethylamine, yielded the 4-phenylamino derivative 6b (Scheme 2).Notable in the 1 H NMR spectrum of compound 6b are the integral count of protons in the aromatic region revealing the presence of nine protons due to the aromatic protons of the quinoline and phenyl groups.In addition, the presence of a deuterium-exchangeable singlet appeared as a broad signal at δ 9.56 due to N-H.Similarly, condensation of compound 3 with piperidine gave the 4-piperidinyl derivative 7 (Scheme 2).The 1 H NMR spectrum of compound 7 showed the signals due to the piperidinyl group as three characteristic multiplets at δ 1.33, 1.62 and 2.98.The mass spectrum showed the molecular ion at m/z 369, in agreement with the formula weight (369.38).Treatment of compound 3 with thiophenol, in the presence of triethylamine, afforded the thioether 8.In the 13 C NMR spectrum of 8 sixteen separate signals were observed at 95.8-160.9ppm belonging to the aromatic carbon atoms, while the two carbonyls were seen at 170.6 and 170.9 ppm.
The introduction of a cyano group into compound 3 by Rosenmund-Braun aromatic cyanodechlorination with copper(I) cyanide in high-boiling solvents gave a mixture of compounds, 29 in which separation attempts failed.However, another recently described method 30 allowed us to introduce the carbonitrile function at the 4-position of compound 3 under relatively mild conditions.That is by a two-step reaction, the first step is converting Cl group to the reactive tosyloxy leaving group, at the 4-position, via the reaction of compound 3 with sodium ptoluenesulfonate to give 4-tosylate 9 (Scheme 3), which was then treated with potassium cyanide to afford the 4-cyanopyranoquinolinedione 10.
The IR spectrum of compound 10 showed characteristic absorption bands at 2213, 1733, 1629 cm -1 , attributed to C≡N, C=Opyrone and C=Oquinolinone, respectively.Also, the mass spectrum showed the molecular ion peak at m/z 311 which is in good agreement with the formula weight (311.26).Reaction of compound 3 with malononitrile in ethanol containing few drops of triethylamine afforded 2-(pyranoquinolin-4-yl)malononitrile 11 (Scheme 3).The IR spectrum of compound 11 showed characteristic absorption bands at 2207, 2159 (2 C≡N), 1737 (C=Opyrone) and 1623 cm -1 (C=Oquinolone).The malononitrile proton was observed at δ 5.57 ppm in the 1 H NMR spectrum, while the sp 3 hybridized carbon atom of the malononitrile group appeared at δ 85.6 ppm in the 13  The compound 3 was allowed to react with some binucleophilic reagents to prepare 4hydroxyquinolinones bearing a pyrazole or pyrimidine moiety in one molecular framework.Treatment of compound 3 with hydrazine hydrate in boiling DMF effected α-pyrone ring opening followed by ring closure (RORC) with loss of HCl, leading to the pyrazolone 12 (Scheme 4).The 1 H NMR spectrum of compound 12 showed signals due to three exchangeable protons characteristic for 2 NHpyrazole and OHquinolinone at δ 11.30, 13.41 and 13.93 ppm.Also, the structure of compound 12 was supported by its mass spectrum which exhibited a molecular ion peak at m/z 316.Reaction of compound 3 with cyanoguanidine as 1,3-binucleophile, afforded the pyrimidine derivative 13 (Scheme 4).The IR spectrum of pyrimidine 13 showed the presence of absorption bands at 3190 and 2199 cm -1 , due to the NH and C≡N groups, respectively.Furthermore, the 1 H NMR spectrum of compound 13 showed three deuterium-exchangeable singlet signals assignable to the two NH and the OH protons at  12.62, 13.40 and 13.95.
The reaction of chloropyranoquinolinedione 3 with S-methylisothiourea in DMF afforded the methylsulfanylpyrimidine derivative 14 (Scheme 5).A methyl signal was observed at δ 2.83 ppm in the 1 H NMR spectrum of 14, and at δ 22.1 ppm in the 13 C NMR spectrum.The reaction of methylsulfanyl-pyrimidine derivative 14 with hydrazine hydrate in DMF produced the hydrazinopyrimidine 15 (Scheme 5).The elemental analysis showed absence of sulfur in the product revealing the replacement of the methylsulfanyl group.IR spectrum exhibited stretching vibrational bands at 3335, 3191 and 3100 cm -1 due to NH2 and NH groups. 1 H NMR spectrum displayed two signals due to deuterium exchangeable protons at δ: 7.16 and 8.25 (-NH-NH2).Moreover, the mass spectrum revealed a molecular ion peak at m/z 358 [M + ] as the base peak, in agreement with the calculated molecular weight of the product 15.Thermal cyclocondensation of the hydrazinopyrimidine 15 with triethyl orthoformate, in DMF, was carried out to get the triazolopyrimidine derivatives 16.The 1 H NMR spectrum of the cyclized product 16 revealed the disappearance of the NH2 signal which was appeared in the 1 H NMR spectrum of compound 15 at  7.16 ppm, in addition to the appearance of characteristic singlet signal at  8.22 ppm assigned to the CHtriazolopyrimidin.Mass spectrum of 16 recorded the molecular ion peak at m/z 368 which agree well with the molecular formula and supports the identity of the structure.

Experimental Section
General.Melting points were determined on a digital Stuart SMP3 apparatus.Infrared spectra were measured on Perkin-Elmer 293 spectrophotometer (cm -1 ), using KBr disks. 1 H NMR spectra were measured on Gemini-300BB spectrometer 300 MHz (at 75MHz for 13 C), or Jeol Eca-500 MHz (at 125 MHz for 13 C) using DMSO-d6 or CDCl3 as a solvent and TMS (δ) as the internal standard.Mass spectra were obtained using GC-2010 Shimadzu GC-Mass spectrometer (70 eV).Elemental microanalyses were performed on a Perkin-Elmer CHN-2400 analyzer.