HETEROCYCLES

Paper | Regular issue | Vol. 87, No. 2, 2013, pp. 369-380
Received, 26th November, 2012, Accepted, 6th December, 2012, Published online, 20th December, 2012.
DOI: 10.3987/COM-12-12639

■ Synthesis of Some Novel Binuclear Heterocyclic Compounds from 6-Ethyl-3-nitropyrano[3,2-c]quinoline-4,5(6H)-dione

Hany M. Hassanin* and Dalia Abdel-Kader

Department of Chemistry, Faculty of Education, Ain Shams University, Roxy, Cairo 11711, Egypt

Abstract

6-Ethyl-3-nitropyrano[3,2-c]quinoline-4,5(6H)-dione (4) was synthesized and its reactivity towards some 1,2-, 1,3-, and 1,4-binucleophiles was investigated. Ring transformation via opening of the γ-pyrone ring and heterocyclizations through out these reactions led to certain interesting five, six, and seven-membered heterocyclic substituents, viz. pyrazolyl, pyridyl, pyrimidyl, diazepinyl, and thiazepinyl at position-3 of quinolin-2-one moiety.

INTRODUCTION
3-Substituted γ-pyrones are used as valuable synthetic intermediates in the preparation of pharmacologically relevant products and new heterocyclic systems.1-7 Introduction of a nitro group into the 3-position of γ-pyrone system enhances the reactivity of the pyrone ring towards binucleophilic reagents and provides a broad synthetic potential of nitrogen containing heterocycles.8 However, 3-nitro-γ-pyrones have not received much attention despite their potential interest as building blocks in synthesis of heterocyclic compounds bearing a nitro group. The chemistry of nucleophilic reactions, involving ring-opening/ring-closing (RORC) of nitropyrano[3,2-c]quinoline-4,5-dione, attracted our attention due to the expected higher reactivity of the pyrone ring in presence of nitro group and to the paucity of their literature reports.8,9 On the other hand, the combination of a pyrazole, pyridine, pyrimidine, and/or diazepine nucleii with the quinoline moiety in one molecular framework is reported to confer interesting biological activity.10-14 Herein we report the synthesis of the novel 6-ethyl-3-nitropyrano[3,2-c]quinoline-4,5(6H)-dione (4) and study of its chemical behavior towards different binucleophiles to obtain a new series nitroheterocyclyl quinolinone derivatives with the possibility of possessing certain 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).15,16 Nitration of compound 1 by using conc. nitric acid, in acetic acid, in the presence of sodium nitrite as catalyst, gave nitropyrano[3,2-c]quinoline-2,5-dione 217 (Scheme 1). Alkaline hydrolysis of compound 2 using aqueous sodium hydroxide solution yielded the 3-(nitroacetyl)-4-hydroxyquinolinone 3.18 Thermal cyclocondensation of the compound 3 with triethyl orthoformate was carried out to get the desired 3-nitropyrano[3,2-c]quinoline-4,5-dione 4 (Scheme 1). The IR spectrum of compound 4 confirmed the absence of the hydroxy group. The 1H NMR spectrum of compound 4 showed a new characteristic singlet signal at 8.97 ppm assigned to characteristic C2-H of γ-pyranone. Moreover, the mass spectrum revealed the molecular ion peak [M+] at m/z 286 as the base peak.

The structural features of the 3-nitro-γ-pyranone 4 show that this molecule possesses two electron-deficient centers (electrophilic sites) at C-2 and C-4, which is activated by strong electron withdrawing nitro- group. The electrophilic sites at position 2 and 4 were utilized for aromatic ring formation by Michael-type addition followed by intramolecular cyclocondensation. Reaction of γ-pyrones with hydrazine derivatives was previously reported,19,20 thus compound 4 was subjected to react with hydrazine hydrate, under reflux in DMF, to afford 3-nitropyrazolylquinolinone 5 (Scheme 2). The 1H NMR spectrum of compound 5, in a DMSO-d6 solution, showed two sets of signals due to the possibility of annular prototropy of the pyrazole ring. It is well known that annular tautomerism in NH azoles is a very fast process in the NMR time scale.21 However, in our case, four signals exhibiting broadening at higher frequency values were observed, indicating that pyrazole 5 exists as a mixture of tautomers 5a and 5b (65:35). The structural assignments were based on the signals due to the NH and OH protons at 11.22 ppm for NH, 12.94 ppm for OH (tautomer 5a) and 11.01 ppm for NH, 12.64 ppm for OH (tautomer 5b). This case is very similar to those of some reported pyrazols prepared from γ-pyranone.21,22 The structure 5a is the more abundant tautomer (65%) since its intramolecular O–H……N=C hydrogen bond is stronger than the intramolecular N–H……O–C hydrogen bond in tautomer 5b, hence gains more stability. Reaction of compound 4 with methylhydrazine, in DMF, afforded 3-(1-methyl-4-nitropyrazolyl) quinolinone 6. The 1H-NMR spectrum of compound 6 revealed that the isomer 6a was obtained excluding the presence of the other possible isomer 6b in which the OH chemical shift appears at 12.59 ppm indicating existence of OH……N intramolecular H -bonding which is not possible in isomer 6b (Scheme 2). The N-methyl protons were observed at 3.81 ppm in its NMR spectrum, while its methyl carbon atom appeared at 20.5 ppm. Treatment of compound 4 with phenylhydrazine afforded the pyrazole 7 (Scheme 2). Mass spectrum of compound 7 showed a peak at 376 assigned to molecular ion peak. While, its 1H-NMR spectrum showed ten aromatic protons, in addition to a characteristic exchangeable singlet signal at 13.68 ppm due to the OH proton. This result confirms absence of intramolecular H-bonding in the product which is in agreement with the structure of isomer 7a. However, this contrast between behavior of methylhydrazine and phenylhydrazine towards the pyranoquinolinedione 4 can be understood by assuming that the most reactive nucleophilic site attacks the most reactive electrophilic site in the reactant molecule.

Reaction of γ-pyrones with guanidine derivatives was previously reported.23 Thus, the compound 4 was allowed to react with some 1,3-binucleophilic reagents in order to prepare 4-hydroxyquinolinones bearing pyrimidine moiety. Treatment of compound 4 with guanidine hydrochloride, in boiling DMF, caused γ-pyrone ring-opening followed by ring-closing (RORC) with loss of H2O, to give the pyrimidylquinolinone 8 (Scheme 3). The 1H NMR spectrum of the compound 8 showed two broad signals due to three exchangeable protons characteristic for NH2 and OH at 6.84 and 12.51 ppm. Also, the structure of compound 8 was supported by its mass spectrum which exhibited the molecular ion peak at m/z 327. Reaction of compound 4 with cyanoguanidine afforded the cyanoamino-pyrimidine derivative 9 (Scheme 3). The IR spectrum of the compound 9 showed the presence of absorption bands at 3120 and 2230 cm-1, characteristic for the NH and C≡N groups, respectively. Further­more, the 1H NMR spectrum of compound 9 showed two deuterium-exchangeable singlet signals assignable to the NH and the OH protons at δ 8.97, 12.59. The reaction of the compound 4 with thiourea, in DMF, afforded the thioxo-pyrimidine derivative 10 (Scheme 3). The elemental analysis of the product revealed correction of the proposed formulae, in addition to, 1H NMR spectrum of the product 10 showed two deuterium-exchangeable singlet signals at δ 11.99 and 12.63 assignable to NH and OH protons. The reaction of the compound 4 with acetamidine, in DMF, afforded the methylpyrimidine derivative 11 (Scheme 3). 1H NMR spectrum of compound 11 showed a methyl signal as singlet at δ 2.88. This methyl was observed at δ 20.5 in the 13C NMR spectrum.

In continuation to this study, the reactivity of the compound 4 towards 1,4-binucleophiles, such as o-phenylendiamine and o-aminothiophenol was investigated. The reaction was carried out in boiling DMF giving rise to the corresponding benzodiazepines 12, 13. The anticipated structure of the 1,5-benzodiazepine 12 and 1,5-benzothiazepine 13 was established on basis of elemental microanalysis, and spectral data. 1H NMR spectra of both products 12 and 13 revealed that the integral count of protons in the aromatic region is corresponding to nine protons of two benzo groups in addition to 2-CH of diazepine.

Reaction of the γ-pyrones with carbon nucleophiles was previously studied.24 Thus, treatment of the compound 4 with malononitrile, in DMF containing anhydrous potassium carbonate, gave 3-pyridinylquinolinone derivative 14 (Scheme 5). The same compound 14 was obtained from reaction of the compound 4 with cyanoacetamide under the same conditions (Scheme 5). The IR spectrum of compound 14 showed absorption bands at 3446, 3230 and 2245 cm-1 assigned to OH, NH and C≡N groups, respectively. 1H NMR spectrum of the compound 14 revealed two broad signals at 10.51 ppm and 12.93 ppm for the NH and OH protons exchangeable with D2O.

Reaction of the compound 4 with cyanoacetohydrazide as a 1,4-C,N-dinucleophile was carried out, in refluxing DMF containing catalytic amount of triethyl amine. Compound 15 was obtained, while the other possible product N-aminopyridine derivative 16 was not observed (Scheme 6). The 1H NMR spectrum of compound 15 revealed three different broad signals exchangeable with D2O at 10.89, 11.01 and 12.94 ppm corresponding to one NH and two OH protons. There is no indication for presence of NH2 group characteristic chemical shift signal. These observations fortify the suggested structure of compound 15.

EXPERIMENTAL
Melting points were determined on a digital Stuart SMP3 apparatus. Infrared spectra were measured on Perkin-Elmer 293 spectrophotometer (cm-1), using KBr disks. 1H NMR spectra were measured on Gemini-200 spectrometer (200 MHz), Mercury-300BB (300MHz), and/or Jeol Eca-500 MHz using DMSO-d6 as a solvent and TMS (δ) as the internal standard. 13C NMR spectra were measured on Mercury-300BB (75 MHz), using DMSO-d6 as a solvent and TMS (δ) as the internal standard. Mass spectra were obtained using GC-2010 Shimadzu Gas chromatography instrument mass spectrometer (70 eV). Elemental microanalyses were performed on a Perkin–Elmer CHN-2400 analyzer.
6-Ethyl-3-nitropyrano[3,2-c]quinoline-4,5(6H)-dione (4)
A mixture of compound 3 (2.76 g, 10 mmol) and triethyl orthoformate (4 mL, 25 mmol), was heated under fusion condition for 4 h. The solid deposited during heating was filtered, air dried and crystallized from AcOH to give compound 4 as yellow crystals, mp > 300 oC, yield (2.23 g, 78%). IR (KBr, cm-1): 3072 (CHarom), 2977, 2928, 2866 (CHaliph), 1674 (C=Opyrone), 1633 (C=Oquinolone), 1591 (C=C), 1568, 1377 (NO2). 1H NMR (DMSO-d6, δ): 1.22 (t, 3H, J = 6.9 Hz, CH2CH3), 4.35 (q, 2H, J = 6.9 Hz, CH2CH3), 7.45 (t, 1H, J = 7.2 Hz, H-9), 7.78 (d, 1H, J = 8.4 Hz, H-7), 7.92 (t, 1H, J = 7.2 Hz, H-8), 8.14 (d, 1H, J = 8.1 Hz, H-10), 8.97 (s, 1H, H-2). 13C NMR (125 MHz, DMSO-d6, δ): 11.8 (CH3), 37.4 (CH2), 111.9, 115.9, 123.4, 124.5, 132.1, 132.3, 135.8, 140.3, 140.9, 161.1, 162.0, 174.6. M/z (relative intensity): 287 [M+ +1; 17], 286 [M+; 100], 285 [M+-1; 48], 258 (42), 225 (12), 214 (24), 200 (10), 184 (29), 169 (17), 156 (67), 154 (10), 146 (67), 141 (18), 140 (11), 132 (37), 129 (12), 128 (36), 127 (20), 118 (14), 115 (12), 114 (22), 113 (11), 105 (12), 104 (20), 102 (13), 101 (31), 91 (13), 90 (13), 89 (10), 77 (55), 76 (23). Anal. Calcd for C14H10N2O5 (286.25): C, 58.75; H, 3.52; N, 9.79. Found C, 58.31; H, 3.49; N, 9.61%.
General procedure for formation of the 3-pyrazolylquinolines 5-7
A mixture of γ-pyrone 4 (2.86 g, 10 mmol) and some hydrazines namely; hydrazine hydrate (0.6 mL, 12 mmol), methylhydrazine (0.64 mL, 12 mmol), phenylhydrazine (1.2 mL, 12 mmol), in DMF (50 mL), was heated under reflux for 4 h. After partial evaporation of the solvent the product was isolated by filtration, washed with EtOH, dried and crystallized from the proper solvent to give the compounds 5, 6 and 7 respectively.
1-Ethyl-4-hydroxy-3-(4-nitro-1H-pyrazol-3-yl)quinolin-2(1H)-one (5)
Crystallized from DMF to give compound 5 as pale yellow crystals, mp > 300 oC, yield (2.01 g, 67%). IR (KBr, cm-1): 3447-3150 (OH, NH), 3055 (CHarom), 2981 (CHaliph), 1655 (C=Oquinolone), 1601 (C=N), 1591 (C=C), 1558, 1376 (NO2). 1H NMR (300 MHz, DMSO-d6, δ): (5a, OH…….N, 65%) 1.28 (t, 3H, J = 6.4 Hz, CH2CH3), 4.38 (q, 2H, J = 6.4 Hz, CH2CH3), 7.37 (t, 1H, J = 7.4 Hz, H-6), 7.61 (d, 1H, J = 8.2 Hz, H-8), 7.71 (t, 1H, J = 7.4 Hz, H-7), 7.96 (s, 1H, Hpyrazole), 8.12 (d, 1H, J = 8.0 Hz, H-5), 11.22 (s, 1H, NH exchangeable with D2O), 12.94 (s, 1H, OH exchangeable with D2O); (5b, NH…….O, 35%) 1.20 (t, 3H, J = 6.9 Hz, CH2CH3), 4.18 (q, 2H, J = 6.9 Hz, CH2CH3), 7.19 (t, 1H, J = 7.2 Hz, H-6), 7.50 (d, 1H, J = 8.0 Hz, H-8), 7.59 (t, 1H, J = 7.2 Hz, H-7), 7.84 (s, 1H, Hpyrazole), 8.06 (d, 1H, J = 7.9 Hz, H-5), 11.01 (s, 1H, NH exchangeable with D2O), 12.64 (s, 1H, OH exchangeable with D2O). M/z (relative intensity): 301 [M+ +1; 5], 300 [M+; 17], 299 [M+-1; 57], 280 (12), 279 (92), 270 (20), 242 (19), 228 (22), 189 (36), 188 (38), 146 (100), 132 (60), 130 (74), 120 (39), 104 (30), 90 (27). Anal. Calcd for C14H12N4O4 (300.28): C, 56.00; H, 4.03; N, 18.66. Found C, 55.91; H, 4.01; N, 18.31%.
1-Ethyl-4-hydroxy-3-(1-methyl-4-nitro-1H-pyrazol-3-yl)quinolin-2(1H)-one (6)
Crystallized from AcOH to give 6 as colorless crystals, mp 286-287 oC, yield (2.19 g, 70%). IR (KBr, cm-1): 3443 (OH), 3075 (CHarom), 2979, 2930, 2867 (CHaliph), 1630 (C=Oquinolone), 1603 (C=N), 1595 (C=C), 1551, 1378 (NO2). 1H NMR (300 MHz, DMSO-d6, δ): 1.22 (t, 3H, J = 6.6 Hz, CH2CH3), 3.81 (s, 3H, NCH3), 4.35 (q, 2H, J = 6.6 Hz, CH2CH3), 7.30 (t, 1H, J = 7.2 Hz, H-6), 7.63-7.67 (m, 2H, J = 8.0 Hz, H-8 and H-7), 7.99 (s, 1H, Hpyrazole), 8.01 (d, 1H, J = 7.8 Hz, H-5), 12.59 (s, 1H, OH exchangeable with D2O). 13C NMR (125 MHz, DMSO-d6, δ): 12.8 (CH3), 20.5 (NCH3), 37.5 (CH2), 98.8, 108.3, 112.8, 114.9, 116.6, 122.5, 123.4, 131.3, 136.6, 138.2, 159.4, 164.6. Anal. Calcd for C15H14N4O4 (314.30): C, 57.32; H, 4.46; N, 17.83%. Found C, 57.31; H, 4.42; N, 17.81%.
1-Ethyl-4-hydroxy-3-(4-nitro-1-phenyl-1H-pyrazol-5-yl)quinolin-2(1H)-one (7)
Crystallized from AcOH to give 7 as yellow crystals, mp > 300 oC, yield (2.36 g, 63%). IR (KBr, cm-1): 3447 (OH), 3078 (CHarom), 2979, 2930 (CHaliph), 1630 (C=Oquinolone), 1603 (C=C), 1551, 1378 (NO2). 1H NMR (DMSO, δ): 1.18 (t, 3H, J = 6.0 Hz, CH2CH3), 4.28 (q, 2H, J = 7.2 Hz, CH2CH3), 7.19 (t, 1H, J = 6.4 Hz, Ar-H), 7.30 (d, 1H, J = 6.8 Hz, Ar-H), 7.46 (d, 1H, J = 6.0 Hz, Ar-H), 7.60 – 7.79 (m, 5H, Ar-H), 8.03 (s, 1H, Hpyrazole), 8.23 (d, 1H, J = 6.9 Hz, H-5), 13.68 (s, 1H, OH exchangeable with D2O). M/z (relative intensity): 377 [M+ +1; 27], 376 [M+; 45], 359 (47), 357 (57), 342 (54), 333 (55), 326 (52), 310 (60), 305 (51), 288 (57), 279 (56), 269 (90), 258 (46), 241 (75), 227 (58), 209 (50), 189 (100), 174 (86), 132 (94), 105 (83), 77 (67). Anal. Calcd for C20H16N4O4 (376.37): C, 63.83; H, 4.26; N, 14.89%. Found C, 63.31; H, 4.24; N, 14.87%.
General procedure for formation of the 3-pyrimidylquinolines 8-11
A mixture of γ-pyrone 4 (2.86 g, 10 mmol) and 1,3-binuchleophiles namely; guanidine hydrochloride (0.96 g, 10 mmol), cyanoguanidine (0.84 g, 10 mmol), thiourea (0.76 g, 10 mmol), acetamidine hydrochloride (0.95 g, 10 mmol), in DMF (50 mL), was heated under reflux for 4 h. The solid deposited after cooling was filtered and crystallized from the proper solvent to give the compounds 8, 9, 10 and 11, respectively.
1-Ethyl-3-(2-amino-5-nitropyrimidin-4-yl)-4-hydroxyquinolin-2(1H)-one (8)
Crystallized from DMF to give 8 as colorless crystals, mp > 300 oC, yield (2.32 g, 71%). IR (KBr, cm-1): 3420 (OH), 3316, 3234 (NH2), 3070 (CHarom), 2977, 2934 (CHaliph), 1634 (C=Oquinolone), 1610 (C=N), 1591 (C=C), 1568, 1376 (NO2). 1H NMR (300 MHz, DMSO-d6, δ): 1.26 (t, 3H, J = 6.6 Hz, CH2CH3), 4.38 (q, 2H, J = 6.6 Hz, CH2CH3), 6.84 (bs, 2H, NH2 exchangeable with D2O), 7.33 (t, 1H, J = 7.2 Hz, H-6), 7.66-7.70 (m, 2H, H-8 and H-7), 7.96 (s, 1H, Hpyrimidine), 8.08 (d, 1H, J = 8.4 Hz, H-5), 12.51 (s, 1H, OH exchangeable with D2O). m/z (relative intensity): 328 [M+ +1; 5], 327 [M+; 8], 311 (5), 256 (7), 228 (7), 213 (15), 204 (6), 194 (7), 185 (13), 169 (8), 149 (32), 137 (9), 129 (19), 121 (10), 115 (12), 109 (13), 98 (34), 81 (79), 73 (66), 69 (100). Anal. Calcd for C15H13N5O4 (327.30): C, 55.05; H, 4.00; N, 21.40%. Found C, 55.02; H, 3.97; N, 21.36%.
4-(1-Ethyl-1,2-dihydro-4-hydroxy-2-oxoquinolin-3-yl)-5-nitropyrimidin-2-ylcyanamide (9)
Crystallized from DMF to give 9 as colorless crystals, mp > 300 oC, yield (2.32 g, 66%). IR (KBr, cm-1): 3416 (OH), 3120 (NH), 3055 (CHarom), 2984, 2881 (CHaliph), 2230 (CN), 1646 (C=O), 1615 (C=N), 1595 (C=C), 1558, 1365 (NO2). 1H NMR (DMSO, δ): 1.20 (t, 3H, J = 7.0 Hz, CH2CH3), 4.33 (q, 2H, J = 7.2 Hz, CH2CH3), 7.33 (t, 1H, J = 6.4 Hz, H6), 7.58 - 7.71 (m, 2H, H8 and H7), 7.99 (s, 1H, Hpyrimidine), 8.11 (d, 1H, J = 6.9 Hz, H-5), 8.97 (bs, 1H, NH exchangeable with D2O), 12.59 (s, 1H, OH exchangeable with D2O). M/z (relative intensity): 352 [M+; 40], 351 [M+ -1; 52], 331 (56), 313 (46), 304 (50), 285 (68), 267 (58), 251 (53), 235 (50), 192 (52), 188 (92), 167 (63), 161 (86), 146 (74), 130 (100), 125 (58), 104 (68), 90 (92), 82 (58), 71 (56). Anal. Calcd for C16H12N6O4 (352.31): C, 54.55; H, 3.43; N, 23.85%. Found C, 54.73; H, 3.41; N, 23.43%.
1-Ethyl-3-(1,2-dihydro-5-nitro-2-thioxopyrimidin-4-yl)-4-hydroxyquinolin-2(1H)-one (10)
Crystallized from AcOH to give 10 as yellow crystals, mp > 300 oC, yield (2.44 g, 71%). IR (KBr, cm-1): 3393 (OH), 3197 (NH), 3068 (CHarom), 2922, 2870 (CHaliph), 1647 (C=O), 1615 (C=N), 1558, 1370 (NO2). 1H NMR (DMSO-d6, δ): 1.22 (t, 3H, J = 6.9 Hz, CH2CH3), 4.38 (q, 2H, J = 6.9 Hz, CH2CH3), 7.37 (t, 1H, J = 7.6 Hz, H-6), 7.65–7.76 (m, 2H, H-7 and H-8), 7.99 (s, 1H, Hpyrimidine), 8.05 (d, 1H, J = 8.4 Hz, H-5), 11.99 (s, 1H, NH exchangeable with D2O), 12.63 (s, 1H, OH exchangeable with D2O). M/z (relative intensity): 344 [M+; 72], 343 [M+ -1; 77], 323 (95), 320 (75), 293 (91), 252 (81), 245 (79), 236 (76), 218 (75), 182 (85), 156 (79), 128 (75), 119 (65), 101 (72), 62 (72), 52 (100). Anal. Calcd for C15H12N4O4S (344.35): C, 52.32; H, 3.51; N, 16.27; S, 9.31%. Found C, 52.13; H, 3.49; N, 16.23; S, 9.21%.
1-Ethyl-4-hydroxy-3-(2-methyl-5-nitropyrimidin-4-yl)quinolin-2(1H)-one (11)
Crystallized from DMF to give 11 as colorless crystals, mp 283 - 285 °C, yield (2.24 g, 69%). IR (KBr, cm-1): 3426 (OH), 3068 (CHarom), 2975, 2922 (CHaliph), 1644 (C=O), 1619 (C=N), 1581 (C=C), 1548, 1392 (NO2). 1H NMR (DMSO-d6, δ): 1.26 (t, 3H, J = 6.9 Hz, CH2CH3), 2.88 (s, 3H, CH3), 4.33 (q, 2H, J = 6.9 Hz, CH2CH3), 7.47 (t, 1H, J = 7.4 Hz, H-6), 7.58–7.77 (m, 2H, H-7 and H-8), 7.95 (s, 1H, Hpyrimidine), 8.08 (d, 1H, J = 8.2 Hz, H-5), 12.68 (s, 1H, OH exchangeable with D2O). 13C NMR (125 MHz, DMSO-d6, δ): 12.8 (CH3), 20.5 (CH3 pyrimidine), 37.5 (CH2), 99.4, 106.8, 108.4, 114.9, 116.7, 122.4, 123.4, 129.2, 131.3, 136.7, 146.5, 159.5, 164.8. Anal. Calcd for C16H14N4O4 (326.31): C, 58.89; H, 4.32; N, 17.17%. Found C, 58.83; H, 4.31; N, 17.13%.
General procedure for formation of the 3-benzodiazepinylquinolines 12 and 13
A mixture of compound 4 (2.86 g, 10 mmol) and 1,4-binuchleophiles namely; O-phenylendiamine (1.1 g, 10 mmol), O-aminothiophenol (1.1 mL, 10 mmol), in DMF (50 mL), was heated under reflux for 4 h. The solid deposited after cooling was filtered and crystallized from the proper solvent to give compounds 12 and 13, respectively.
1-Ethyl-4-hydroxy-3-(3-nitro-1H-benzo[b][1,4]diazepin-4-yl)quinolin-2(1H)-one (12)
Crystallized from AcOH to give 12 as yellow crystals, mp > 300 °C, yield (2.78 g, 74%). IR (KBr, cm-1): 3477 (OH), 3227 (NH), 3055 (CHarom), 2976, 2931 (CHaliph), 1630 (C=O), 1592 (C=C), 1548, 1320 (NO2). 1H NMR (DMSO-d6, δ): 1.24 (t, 3H, J = 6.9 Hz, CH2CH3), 4.31 (q, 2H, J = 6.9 Hz, CH2CH3), 6.49 - 8.12 (m, 8H, Ar-H), 8.05 (d, 1H, J = 8.4 Hz, H-5), 10.90 (s, 1H, NH exchangeable with D2O), 13.43 (s, 1H, OH exchangeable with D2O). 13C NMR (75 MHz, DMSO-d6, δ): 16.1 (CH3), 38.6 (CH2), 98.5, 110.8, 113.7, 117.7, 118.2, 119.4, 119.6, 122.3, 124.2, 124.9, 128.4, 134.6, 135.4, 144.7, 153.7, 155.4, 158.5, 164.1. M/z (relative intensity): 376 [M+; 15], 375 [M+ -1; 8], 306 (20), 305 [M+- O2N-C≡CH, 100], 304 (40), 326 (23), 310 (19), 290 (30), 277 (84), 250 (32), 230 (23), 223 (32), 197 (30), 188 (60), 172 (44), 161 (58), 146 (43) , 132 (79), 118 (48), 90 (38), 77 (79). Anal. Calcd for C20H16N4O4 (376.37): C, 63.83; H, 4.28; N, 14.89%. Found C, 63.80; H, 4.19; N, 14.53.
1-Ethyl-4-hydroxy-3-(3-nitrobenzo[b][1,4]thiazepin-4-yl)quinolin-2(1H)-one (13)
Crystallized from AcOH to give 13 as white crystals, yield (2.63 g, 67%), mp 213 °C. IR (KBr, cm-1): 3416 (OH), 3068 (CHarom), 2922, 2870 (CHaliph), 1646 (C=O), 1615 (C=N), 1595 (C=C), 1558, 1378 (NO2). 1H NMR (DMSO-d6, δ): 1.26 (t, 3H, J = 6.9 Hz, CH2CH3), 4.31 (q, 2H, J = 6.9 Hz, CH2CH3), 7.19 (t, 1H, J = 7.5 Hz, Ar-H), 7.31–7.35 (m, 2H, Ar-H), 7.49 (d, 1H, J = 8.2 Hz, Ar-H), 7.65 (t, 1H, J = 7.6 Hz, Ar-H), 7.76 -7.79 (m, 2H, Ar-H), 7.97 (s, 1H, Hthiazepine), 8.21 (d, 1H, J = 7.9 Hz, H-5), 13.68 (s, 1H, OH exchangeable with D2O). M/z (relative intensity): 393 [M+; 13], 322 [M+- O2N-C≡CH, 100], 321 (60), 294 (65), 286 (38), 279 (32), 268 (46), 242 (15), 237 (17), 221 (19), 146 (24), 132 (34), 120 (32), 119 (27), 108 (25), 91 (23), 73 (98). Anal. Calcd for C20H15N3O4S (393.42): C, 61.06; H, 3.84; N, 10.68; S, 8.15%. Found C, 61.03; H, 3.78; N, 10.43; S, 8.11%.
1-Ethyl-4-hydroxy-3-(5-nitro-2-oxo-3-cyanopyridin-6-yl)quinolin-2(1H)-one (14)
Method A. A mixture of γ-pyrone 4 (2.86 g, 10 mmol) and malononitrile (0.66 g, 10 mmol), in DMF (50 mL) containing small amount of anhydrous potassium carbonate, was heated under reflux for 4 h. The solid deposited after cooling was filtered and crystallized from i-PrOH to give compound 14, as pale brown crystals, mp > 300 °C. yield (2.53 g, 72%). Method B. A mixture of γ-pyrone 4 (2.86 g, 10 mmol) and cyanoacetamide (0.84 g, 10 mmol), in DMF (50 mL) containing small amount of anhydrous potassium carbonate, was heated under reflux for 4h. The solid deposited after cooling was filtered and crystallized from i-PrOH to give compound 14, as pale brown crystals, mp > 300 °C. yield (2.64 g, 75%). IR (KBr, cm-1): 3446 (OH), 3230 (NH), 3084 (CHarom), 2977, 2929 (CHaliph), 2245 (CN), 1675 (C= Opyridine), 1632 (C= Oquinolone), 1599 (C=C), 1574, 1384 (NO2). 1H NMR (300 MHz, DMSO-d6, δ): 1.16 (t, 3H, J = 6.4 Hz, CH2CH3), 4.30 (q, 2H, J = 6.4 Hz, CH2CH3), 7.25 (t, 1H, J = 7.2 Hz, H-6), 7.41-7.58 (m, 2H, H-8 and H-7), 7.72 (s, 1H, Hpyridine), 8.11 (d, 1H, J = 8.0 Hz, H-5), 10.51 (s, 1H, NH exchangeable with D2O), 12.93 (s, 1H, OH exchangeable with D2O). 13C NMR (125 MHz, DMSO-d6, δ): 12.9 (CH3), 35.5 (CH2), 89.8, 112.9, 114.2, 119.5, 120.8, 121.6, 123.4, 125.8, 129.6, 132.3, 133.5, 139.1, 150.2, 162.2 (C=O), 174.8 (C=O). M/z (relative intensity): 352 [M+; 40], 351 [M+ -1; 52], 331 (57), 313 (45), 297 (41), 271 (55), 260 (43), 235 (50), 210 (48), 202 (18), 188 (92), 186 (49), 169 (5), 158 (17), 146 (74), 131 (100), 104 (68), 91 (51), 82 (58), 77 (81). Anal. Calcd for C17H12N4O5 (352.31): C, 57.96; H, 3.43; N, 15.90%. Found C, 57.83; H, 3.36; N, 15.73%.
7-(1-Ethyl-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl)-3-hydroxy-6-nitro-2H-[1,2]diazepine-4-carbonitrile (15)
A mixture of compound 4 (2.86 g, 10 mmol) and cyanoacetohydrazide (1 g, 10 mmol), in DMF (50 mL) containing few drops of triethylamine, was refluxed for 4 h. After cooling the solid obtained was filtered and crystallized from DMF to give 15 as yellow crystals, mp > 300 ºC, yield (2.34 g, 64 %). IR (KBr, cm-1): 3440-3243 (bs, NH and 2OH), 3089 (CHarom), 2978, 2933 (CHaliph), 2234 (C≡N), 1645 (C= Oquinolone), 1605 (C=C), 1561, 1378 (NO2). 1H NMR (DMSO-d6, δ): 1.26 (t, 3H, J = 6.9 Hz, CH2CH3), 4.38 (q, 2H, J = 6.9 Hz, CH2CH3), 7.34 (t, 1H, J = 7.6 Hz, H-6), 7.59–7.71 (m, 2H, H-7 and H-8), 7.92 (s, 1H, Hdiazepine), 8.12 (d, 1H, J = 8.4 Hz, H-5), 10.89 (s, 1H, NH exchangeable with D2O), 11.01 (s, 1H, OH exchangeable with D2O), 12.94 (s, 1H, OH exchangeable with D2O). 13C NMR (75 MHz, DMSO-d6, δ): 12.5 (CH3), 37.4 (CH2), 98.7, 111.9, 113.8, 115.9, 123.4, 124.5, 132.1, 132.3, 135.8, 140.3, 140.9, 144.7, 153,4, 159.5, 164.6. M/z (relative intensity): 367 [M+; 25], 366 [M+-1; 20], 349 (24), 326 (27), 319 (24), 303 (26), 278 (26), 265 (25), 252 (22), 230 (21), 222 (24), 213 (22), 189 (26), 175 (21), 168 (25), 160 (24), 148 (31), 129 (29), 121 (31), 115 (26), 102 (26), 95 (31), 86 (100), 77 (36), 64 (45). Anal. Calcd for C17H13N5O5 (367.32): C, 55.59; H, 3.57; N, 19.07%. Found C, 55.63; H, 3.69; N, 19.03%.

References

1. V. Y. Sosnovskikh, R. A. Irgashev, and M. I. Kodess, Tetrahedron, 2008, 64, 2997. CrossRef
2. S. Mkrtchyan, V. O. Iaroshenko, S. Dudkin, A. Gevorgyan, M. Vilches-Herrera, G. Ghazaryan, D. Volochnyuk, D. Ostrovskyi, Z. Ahmed, A. Villinger, V. Y. Sosnovskikh, and P. Langer, Org. Biomol. Chem., 2010, 8, 5280. CrossRef
3. V. Y. Sosnovskikh, V. S. Moshkin, and M. I. Kodess, Tetrahedron Lett., 2009, 50, 6515. CrossRef
4. V. Y. Sosnovskikh, V. S. Moshkin, and M. I. Kodess, J. Heterocycl. Chem., 2010, 47, 629.
5. V. Y. Sosnovskikh, V. S. Moshkin, and M. I. Kodess, Russ. Chem. Bull., 2010, 59, 615. CrossRef
6. Z. Ghasemi, V. Nazari-Belvirdi, M. Allahvirdinasab, and A. Shahrisa, Heterocycles, 2011, 83, 117. CrossRef
7. T. Oguchi, K. Watanabe, H. Abe, and T. Katoh, Heterocycles, 2010, 80, 229. CrossRef
8. G. Haas, J. L. Stanton, and T. Winkler, J. Heterocycl. Chem., 1981, 18, 619. CrossRef
9. V. O. Iaroshenko, S. Mkrtchyan, A. Gevorgyan, M. Vilches-Herrera, D. V. Sevenard, A. Villinger, T. V. Ghochikyan, A. Saghiyan, V. Y. Sosnovskikh, and P. Langer, Tetrahedron, 2012, 68, 2532. CrossRef
10. H. N. Jimenez, K. G. Liu, S.-P. Hong, M. S. Reitman, M. A. Uberti, M. D. Bacolod, M. Cajina, M. Nattini, M. Sabio, and D. Doller, Bioorg. Med. Chem. Lett., 2012, 22, 3235. CrossRef
11. N. J. Parmar, H. A. Barad, B. R. Pansuriya, S. B. Teraiya, V. K. Gupta, and R. Kant, Bioorg. Med. Chem. Lett., 2012, 22, 3816. CrossRef
12. Y. Ai, Y.-J. Liang, J.-C. Liu, H.-W. He, Y. Chen, C. Tang, G.-Z. Yang, and L. W. Fu, Eur. J. Med. Chem., 2012, 47, 206. CrossRef
13. M. J. López Rivilli, E. L. Moyano, and G. I. Yranzo, Tetrahedron Lett., 2010, 51, 478. CrossRef
14. M. S. Christodoulou, S. Liekens, K. M. Kasiotis, and S. A. Haroutounian, Bioorg. Med. Chem., 2010, 18, 4338. CrossRef
15. R. Abonίa, P. Cuervo, M. B. J. Cobo, and C. Glidewell, Acta Cryst. Sect. C: Crystal Str. Commun., 2010, 66, 44.
16. W.-T. Gao, W.-D. Hou, M.-R. Zheng, and L.-J. Tang, Synth. Commun., 2010, 40, 732. CrossRef
17. H. M. Hassanin, ARKIVOC, 2012, vi, 384.
18. M. A. Ibrahim, H. M. Hassanin, Y. A. Gabr, and Y. A. Alnamer, J. Braz. Chem. Soc., 2012, 23, 905. CrossRef
19. A. Brbot-Saranovic, B. Katusin-Razem, and I. Susnik, Heterocycles, 1989, 29, 1559. CrossRef
20. J. Sakakibara, S. Nagai, T. Akiyama, T. Ueda, N. Oda, and K. Kidouchi, Heterocycles, 1988, 27, 423. CrossRef
21. V. Y. Sosnovskikh, R. A. Irgashev, and A. A. Levchenko, Tetrahedron, 2008, 64, 6607. CrossRef
22. A. Lévai, A. M. S. Silva, J. A. S. Cavaleiro, I. Alkorta, J. Elguero, and J. Jekö, Eur. J. Org. Chem., 2006, 2825.. CrossRef
23. S. V. Ryabukhin, A. S. Plaskon, D. M. Volochnyuk, S. E. Pipko, and A. A. Tolmachev, Heterocycles, 2008, 75, 583. CrossRef
24. T. Ishiguro, K. Ukawa, H. Sugihara, and A. Nohara, Heterocycles, 1981, 16, 733. CrossRef