Journal of Organic & Inorganic Chemistry

Keywords

Benzo[h][1,6]Naphthyridines; Methylene diethyl malonate; Antimicrobial activity

Introduction

The emerging resistance of antibacterial agents is worldwide problem proved the need of new molecules [1,2]. However, in last two decades only one new class of antibiotics has been commercialized, and there is a concerning dearth of antibacterial agents with mechanism of action in development. Bacterial fatty acid biosynthesis is an essential process that supplied precursors for the assembly of important cellular components such as phospholipids, lipoproteins, lipopolysaccharides, mycolic acids, and the cell envelope. In mammals, all enzymatic activities associated with acyl chain elongation are encoded by a single polypeptide. While in bacteria, the pathway is comprised of several discrete enzymes. This organizational difference makes the bacterial fatty acid biosynthetic enzymes potentially selective antibacterial targets [3,4]. Bacterial resistance to currently used antibiotics is becoming a concern to public health (Monroe and Polk). The development of bacterial super resistant strain is resulting in currently used antibiotic agents failing to end many bacterial infections. For this reason the search is ongoing for new natural or synthetic antimicrobial agents [5]. Quinoline derivatives have been used for the treatment of malaria [6]. Systematic modification of quinine led to the potent antimalarial chloroquine 2 drug [7]. After worldwide development, chloroquine drug was found resistant against malaria. Therefore chemist focused to synthesize new compounds. The screening test of mefloquine 3, quinacrine 4 and other new potent quinolines showed good activity against malaria [8-11]. The quinoline ring system and aliphatic side chain is crucial for the mode of action of chloroquine [12-14]. 4-Aminoquinoline bioisoster and their platinum (II) complexes showed anti-leishmanial and antitubercular activities [15]. Quinolines are structurally diverse group of compounds present in numerous natural products and are also the object of extensive synthetic research. Quinoline derivatives have demonstrated anti-leishmanial activity, antibacterial, antifungal, anti HIV and antitumor activity [16-19]. Recently, 4-amino-7- chloro-quinoline derivatives have demonstrated mycobacterium tuberculosisactivity [20-29]. Benzo[h][1,6]naphthyridine derivatives also showed antimalarial activity 5 [30].

Chemistry

One pot condensation of p-substituted aroylacetonitriles with 2-chloroquinolin-4-amine 1 and triethylorthoester at 60-70°C in ethanol furnished amino butenenitrile quinoline derivatives 4(a-f) as yellow color solid in 70-83% yield. The structure of compounds 4 (a-f) were illustrated by spectroscopic and analytical methods. For instance IR of 4b showed the presence of NH, CN and CO stretching frequency at 3443, 2206 and 1649 cm^-1 respectively. The lowering of carbonyl frequency was due to conjugation and strong intramolecular H-bonding between carbonyl oxygen and NH group. The ¹H NMR spectrum of 4b in CDCl₃ showed singlet at d 2.54 assignable to CH₃ group; the singlet at d 7.33 assignable to C₃H proton. The doublet at d 7.46 and triplet at d 7.61 (J=7.0 Hz) assignable to C₇H and C₆H protons respectively. The resonance singlet at d 9.95 assignable to NH proton present on secondary amino group. The remaining aromatic protons showed multiplet in between d 7.86-7.97. ¹³C NMR spectrum of 7b in CDCl₃ showed the peaks at d 120.10 for CN group and at d 178.37 for the presence of ketone (CO). The EI-MS of 7b showed M+, M+2 and M+4 at 426, 428 and 430 m/z respectively due to the presence of two chlorine atoms [31-42]. The neat reaction of compound 1 and diethyl 2-(ethoxymethylene) malonate 5 at 120°C for 12 h furnished a yellow colored 4-amino methylene diethylmalonate 6 in 80-90% yield. The imine chloride group in compound 6 was oxidized to amide furnished derivative 7 on refluxing in acetic acid for 5 h. The structure of compound 7 was assigned using spectroscopic and analytical methods given in experimental section (Scheme 1).

Scheme 1: Synthesis of 2-(4-substituted benzoyl)-3-(2- chloroquinolin-4-ylamino)alkenenitrile 4(a-f) and 2-[(2-oxo-1,2-dihydro-quinolin-4-ylamino) methylene]malonic acid diethyl ester 7(a-b).

The enamine 6 was cyclized by refluxing in diphenylether for 30 min yielded brown colored to desired benzo[h][1,6]naphthyridine derivatives 8 in 70-75% yield. The compound 6a refluxed in POCl₃ furnished mixture of compounds 8 and 9 as yellow coloured solids in 20 % and 40% yield respectively. The mixture of compounds 8 and 9 was separated by using column chromatography eluting with toluene. The structures of synthesized compounds were based on analytical and spectroscopic data (Scheme 2).

Scheme 2: Synthesis of 5-chloro-4-hydroxy-benzo[h][1,6] naphthyridine-3-carboxylic acid ethyl ester 8(a-b) and 4,5-Dichloro-benzo[h][1,6]naphthyridine-3-carboxylic acid ethyl ester 9(a-b).

Study of antimicrobial activity

Cultures (Bacteria) used:

Gram positive: S. aureus, B. substilis, B. cerious, B. megaterium;

Gram negative: Escherichia coli, Pseudomonas aeruginosa, Proteus valgaris

Media used: Nutrient agar (Hi-media)

Inoculum Size: X 10⁶ bacteria per ml

Concentration of Compound: 1000 µg/ml (prepared in DMF)

Method used: Agar diffusion assay (disc method, disc size 5 mm)

Dilution of Drug: Stock prepared 1000 µg/ml prepared in DMF [100 µg per disc]

Results of antimicrobial activity: All the synthesized compounds 4(a-f), 6(a-b), 7(a-b), 8(a-b), 9(a-b) were tested against microorganism species at 1000 ppm concentration. The observed results of antibacterial screening reported in Table 1 indicate that 4-amino substituted quinoline and benzo[h][1,6]naphthyridine compounds 4c, 4d and 7a are active against S. aureus, compounds 4e, 4f and 6a are active against E. coli bacterial species. The Compounds 4b, 4c, 4d, 4e, 6b, and 7b showed activity against B. substilis. The compounds 4d, 4f found active against B. cerious. The compounds 4c, 4d, 4f and 7b are active against B. megaterium species. However compounds 8a, 8b, 9a, 9b found totally inactive against bacterial species while the compounds 4c, 4d and 4f are most active against the bacterial species. The P. aeruginosa found stable against all compound. From the above observations it is clear that the 4-aminoquinoline derivatives 4c and 4f are showed significant antibacterial activity against B. megaterium.

Table 1: Antimicrobial activity of benzo[h][1,6]naphthyridine derivatives.

Experimental Section

General remarks

Melting points were determined on a Gallenkamp melting point apparatus in an open capillary tube and are uncorrected. The 1H (300 MHz) and ¹³C (75 MHz) NMR spectra were recorded on a Varian XL-300 spectrometer. Chemical shifts were reported in ppm relative to tetramethylsilane (TMS), and multiplicities are given as s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), or m (multiplet). Infrared spectra were recorded as KBr pellets on a Shimadzu FTIR-408 spectrophotometer. Mass spectra were recorded on a Shimadzu LC-MS: EI QP 2010A mass spectrometer with an ionization potential of 70eV. Elemental analyses were performed on Thermo Quest Flash 1112 Series EA analyzer. Reactions were monitored by thin layer chromatography (TLC), carried out on 0.2 mm silica gel 60 F254 (Merck) plates using UV light (254 and 366 nm) for detection and compounds were purified by column chromatography by using silica gel of 5-20 µm (Merck, 60-120 mesh). Column dimension is 39 x 2 cm and elution volume used is about 200-400 mL for each product where necessary. Common reagent-grade chemicals are either commercially available and were used without further purification or were prepared by standard literature procedures.

Synthesis of 2-(4-chlorobenzoyl)-3-(2- chloroquinolin-4-ylamino)but-2-enenitrile, 4 (a-f)

A mixture of 2-chloro-4-aminoquinoline 1 (0.005 mol), substituted benzoyl acetonitrile 2 and triethyl orthoformate or triethyl orthoacetate or triethyl orthopropionate (0.006 mol) was refluxed in dry toluene at 3 h (TLC checked, toluene). After completion of the reaction, the solvent was removed under reduced pressure; the obtained solid was stirred in methanol for 30 min. The solid separated was collected by suction filtration, dried, and recrystallized from ethanol to furnish title compound 4 in good yield.

2-(4-Bromobenzoyl)-3-(2-chloroquinolin-4-ylamino)but-2- enenitrile, 4a: Yellow prisms; Yield (1.545 g, 85%); M.P: 214°C; IR (KBr) ν_max: 3353 (NH), 2924, 2230 (CN), 1640 (CO), 1539, 126 cm^-1;¹H NMR (CDCl₃): D₂.54 (s, 3H, CH₃), 7.23 (s, 1H, C₃H), 7.55 (t, J=7.5 Hz, 1H, C₆H), 7.2 (t, J=7.5 Hz, 1H, C₇H), 7.77 (d, J=7.5 Hz, 1H, C₅H), 7.82-7.93(m, 5H, Ar-H), 10.15 (d, J=12.6 Hz, 1H, NH, D₂O exchangeable); MS: m/z (%): 430 (M+4, 40), 428 (M+2, 50), 426 (M+, 100), 345 (30), 250 (70), 176 (80), 185 (70); Anal. Calcd. For C₂₀H₁₃BrClN₃O (426.70); Calcd: C, 56.30; H, 3.07; N, 9.85; Found: C, 56.43; H, 2.99; N, 9.72.

2-(4-Chlorobenzoyl)-3-(2,8-dichloroquinolin-4-ylamino)but-2- enenitrile, 4b: Yellow prisms; Yield (1.46 g, 71%); M.P: 230°C; IR (KBr) ν_max: ν 3443 (NH), 2924, 2206 (CN), 1649 (CO), 1575, 1280 cm^-1;¹H NMR (CDCl₃): d 2.54 (s, 3H, CH₃), 7.33 (s, 1H, C₃H), 7.46 (d, J=7.0 Hz, 1H, C₇H), 7.61 (t, J=7.0 Hz, 1H, C₆H), 7.86-7.97(m, 5H, Ar-H), 9.95 (s, 1H, NH, D₂O exchangeable); ¹³C NMR (CDCl₃): d 22.32, 83.23, 110.48, 117.10, 120.07, 122.86, 123.06, 123.17, 123.26, 128.84, 130.05, 130.16, 130.87, 139.51, 148.06, 161.37, 178.37; MS: m/z (%): 422 (M+6, 20), 420 (M+, 20), 418 (M+2, 30), 416 (M+, 100), 212 (30), 204 (70), 141 (40); Anal. Calcd. For C₂₀H₁₂Cl₃N₃O (416.70); Calcd: C, 57.65; H, 2.90; N, 10.08; Found: C, 57.43; H, 2.99; N, 10.21.

2-(4-Chlorobenzoyl)-3-(2,8-dichloroquinolin-4-ylamino)-pent-2- enenitrile, 4c: Yellow prisms; Yield (1.50 g, 70%); M.P: 217°C; IR (KBr) ν_max: ν 3337 (NH), 2817, 2223 (CN), 1649 (CO), 1570, 1270 cm^-1;¹H NMR (CDCl₃): d 1.31 (t, J=7 Hz, 3H, CH₃), 2.74 (q, J=7.0 Hz, 2H, CH₂), 7.37 (s, 1H, C₃H), 7.45 (d, J=7.5 Hz, 1H, C₇H), 7.59 (t, J=7.5 Hz, C₆H) 7.61-7.91(m, 5H, Ar-H), 9.87 (s, 1H, NH, D₂O exchangeable); ¹³C NMR (CDCl₃): d 15.28, 21.21, 79.52, 111.13, 116.23, 120.17, 122.70, 123.03, 123.30, 124.07, 127.6, 130.09, 130.71, 132.20, 140.21, 146.30, 160.20, 177.21; Anal. Calcd. For C₂₁H₁₄Cl₃N₃O (430.72); Calcd: C, 58.56; H, 3.28; N, 9.76; Found: C, 58.43; H, 3.19; N, 9.6.

2-(4-Chlorobenzoyl)-3-(2-chloro-7-methyl-quinolin-4-ylamino) acrylonitrile, 4d: Yellow prisms; Yield (1.42 g, 75%); M.P: 26°C; IR (KBr) ν_max: 3475 (NH), 2908, 2215 (CN), 1645 (CO), 1570, 1170 cm^-1;¹H NMR (CDCl₃): d 2.51 (s, 3H, CH3), 7.32 (s, 1H, C₃H), 7.45 (d, J=7.0 Hz, 1H, C₆H), 7.60 (d, J=7.0 Hz, C₅H) 7.65-7.96(m, 5H, Ar- H), 8.21(d, J=12.5 Hz, 1H,=CH), 10.08 (d, J=12.5 Hz, 1H, NH, D₂O exchangeable); MS: m/z (%): 385 (M+4, 20), 383 (M+2, 30), 381 (M+, 100), 246 (30), 192 (70), 190 (70), 139 (30); Anal. Calcd. For C₂₀H₁₃Cl₂N₃O (382.25); Calcd: C, 62.84; H, 3.43; N, 10.99; Found: C, 62.83; H, 3.59; N, 10.83.

2-(4-Chlorobenzoyl)-3-(2-chloro-7-methyl-quinolin-4-ylamino) but-2-enenitrile, 4e: Yellow prisms; Yield (1.28 g, 65%); M.P: 183°C; IR (KBr) ν_max: ν 3237 (NH), 3008, 2205 (CN), 1647 (CO), 1545, 1169 cm^-1;¹H NMR (CDCl₃): d 2.51 (s, 3H, CH₃), 2.631 (s, 1H, Ar-CH₃), 7.33 (s, 1H, C₃H), 7.46 (d, J=7.5 Hz, 2H, ArH), 7.61 (d, J=7.5 Hz, C₆H) 7.86-7.97 (m, 4H, Ar-H), 10.08 (s, 1H, NH, D₂O exchangeable); Anal. Calcd. For C₂₁H₁₅Cl₂N₃O (396.28); Calcd: C, 63.65; H, 3.82; N, 10.60; Found: C, 63.69; H, 3.79; N, 10.55.

2-(4-Chlorobenzoyl)-3-(2-chloro-7-methyl-quinolin-4-ylamino) pent-2-enenitrile, 4f: Yellow prisms; Yield (1.22 g, 60%); M.P: 178°C; IR (KBr) ν_max: 3337 (NH), 2917, 2215 (CN), 1645 (CO), 1570, 1170 cm^-1;¹H NMR (CDCl₃): d 1.31 (t, J=8.0 Hz, 3H, CH₃), 2.61 (s, 3h, ArCH₃), 2.74 (q, J=8.0 Hz, 2H, CH₂), 7.35 (s, 1H, C₃H), 7.45 (d, J=8.0 Hz, 1H, ArH), 7.45 (d, J=7.5 Hz, 1H, C₆H), 7.59-7.91(m, 5H, Ar-H), 10.17 (s, 1H, NH, D₂O exchangeable); ¹³C NMR (CDCl₃): d 16.21, 23.17, 80.20, 111.31, 118.10, 120.14, 122.86, 123.09, 123.28, 123.84, 130.13, 130.94, 132.34, 139.25, 148.08, 163.30, 177.31; MS: m/z (%): 413 (M+4, 10), 411 (M+2, 30), 409 (M+, 100), 274 (30), 218 (70), 193 (80), 139 (40); Anal. Calcd. For C₂₂H₁₇Cl₂N₃O (410.31); Calcd: C, 64.40; H, 4.18; N, 10.24; Found: C, 64.71; H, 4.10; N, 10.35.

Synthesis of 2-[(2-chloroquinolinin-4-ylamino) methylene]malonic acid diethyl ester (6a-b)

2-Chloro-4-aminoquinoline 1(a-b) (0.005 mol) and diethoxymethylene malonate 5 (0.007 mol) was stirred at 120- 130°C for 12 h. Progress of the reaction was monitored by TLC. After cooling the reaction mixture to room temperature, methanol (50 mL) was added to it. The crude product separated was collected by suction filtration, dried, and recrystallized from the ethanol and DMF (8:2) to furnish yellow solid 6 in 83-90% yields.

2-[(2-Chloro-quinolinin-4-ylamino)methylene]malonic acid diethyl ester (6a): Yellow prisms; Yield (1.56 g, 90%); M.P: 205°C; IR (KBr) ν_max: 3433 (NH), 2931, 1693 (CO), 1618, 1267, 806 cm- 1; ¹H NMR (CDCl₃): d 1.37 (t, J=7.0 Hz, 3H, CH₃), 1.42 (t, J=7.0 Hz, 3H, CH₃), 4.29 (q, J=7.0 Hz, 2H, CH₂), 4.32 (q, J=7.0 Hz, 2H, CH₂), 7.24 (s, 1H, C₃H), 7.62 (t, J=6.5 Hz, 1H, C₇H), 7.77 (t, J=6.5 Hz, 1H, C₆H), 7.79 (d, J=6.5 Hz, 1H, C₈H), 8.04 (d, J=6.5 Hz, 1H, C₅H), 8.57 (d, J=12.6 Hz, 1H,=CH), 11.95 (d, J=12.6 Hz, 1H, NH, D₂O exchangeable); ¹³C NMR (CDCl₃): d 14.20, 21.71, 169.30, 109.31, 122.23, 122.91, 123.20, 132.21, 133.02, 133.70, 140.20, 145.03, 159.01, 169.21; MS: m/z (%): 350 (M+2, 30), 348 (M+, 90), 278 (20), 178 (70), 170 (70); Anal. Calcd. For C₁₇H₁₇ClN₂O₄ (348.79); Calcd: C, 58.54; H, 4.91; N, 8.03; Found: C, 58.63; H, 4.87; N, 8.15.

2-[(2,8-Dichloro-quinolinin-4-ylamino)methylene]malonicacid diethyl ester (6b): Yellow prisms; Yield (1.58 g, 83%); M.P: 183°C; IR (KBr) ν_max: 3345 (NH), 2935, 1690 (CO), 1620, 1267, 870 cm- 1;¹H NMR (CDCl₃): d 1.35 (t, J=7.2 Hz, 3H, CH₃), 1.43 (t, J=7.2 Hz, 3H, CH₃), 4.30 (q, J=7.2 Hz, 2H, CH₂), 4.32 (q, J=7.2 Hz, 2H, CH₂), 7.25 (s, 1H, C₃H), 7.60 (t, J=7.0 Hz, 1H, C₆H), 7.78 (d, J=7.0 Hz, 1H, C₇H), 7.95 (d, J=7.0 Hz, 1H, C₅H), 8.56 (d, J=13.5 Hz, 1H,=CH), 11.95 (d, J=13.5 Hz, 1H, NH, D₂O exchangeable); Anal. Calcd. For C₁₇H₁₆Cl₂N₂O₄ (383.23); Calcd: C, 53.28; H, 4.21; N, 7.31; Found: C, 53.20; H, 4.27; N, 7.41.

Synthesis of 2-[(2-oxo-1,2-dihydro-quinolin-4- ylamino)methylene]malonic acid diethyl ester, 7a-b

The open chain compound 6 was refluxed in acetic acid for 5 h (TLC check, toluene). Reaction mixture was cooled to room temperature; the solid separated was collected by suction filtration, dried, and recrystallized from ethanol/DMF (8:2) to afford 7 in 80-82% yield.

2-[(2-Oxo-1,2-dihydroquinolin-4-ylamino)methylene]malonic acid diethyl ester,7a: Yellow prisms; Yield (1.32 g, 80%); M.P: 230°C; IR (KBr) ν_max: 3439 (NH), 3281 (NH), 2980, 1724(CO), 1699 (CO)cm^-1;¹H NMR (CDCl₃): d 1.27 (t, J=7.0 Hz, 3H, CH₃), 1.29 (t, J=7.0 Hz, 3H, CH₃), 4.14 (q, J=7.0 Hz, 2H, CH₂), 4.26 (q, J=7.0 Hz, 2H, CH₂), 6.52 (s, 1H, C₃H), 7.31 (t, J=7.2 Hz, 1H, C₆H), 7.37 (t, J=7.7 Hz, 1H, C₇H), 7.56-7.60 (m, 2H, C₅H& C₈H), 8.49 (d, J=12.3 Hz,=CH), 11.21 (d, J=12.3 Hz, NH, 1H, NH, D₂O exchangeable); Anal. Calcd. For C₁₇H₁₈N₂O₅ (330.34); Calcd: C, 61.81; H, 5.49; N, 8.48; Found: C, 61.78; H, 5.30; N, 8.51.

2-[(8-Chloro-2-oxo-1,2-dihydroquinolin-4-ylamino)methylene] malonic acid diethyl ester, 7b: Yellow prisms; Yield (1.49 g, 82%); M.P: 197°C; IR (KBr) ν_max: 3433 (NH), 3270 (NH), 2982, 1725(CO), 1685 (CO) cm^-1;¹H NMR (CDCl₃): d 1.28 (t, J=7.2 Hz, 3H, CH₃), 1.30 (t, J=7.2 Hz, 3H, CH₃), 4.15 (q, J=7.2 Hz, 2H, CH₂), 4.26 (q, J=7.2 Hz, 2H, CH₂), 6.55 (s, 1H, C₃H), 7.38 (t, J=7.5 Hz, 1H, C₆H), 7.56 (d, J=7.5 Hz, 1H, C₇H), 7.75 (d, J=7.5 Hz, 1H, C₅H), 8.47 (d, J=14 Hz,=CH), 11.18 (d, J=14 Hz, NH, 1H, NH, D₂O exchangeable);MS: m/z (%): 366 (M+2, 30), 364 (M+, 90), 304 (40), 244 (60), 194 (70), 170 (80); Anal. Calcd. For C₁₇H₁₇ClN₂O₅ (364.79); Calcd: C, 55.97; H, 4.70; N, 7.68; Found: C, 55.89; H, 4.75; N, 7.69.

Synthesis of 5-chloro-4-hydroxy-benzo[h][1,6] naphthyridine-3-carboxylic acid ethyl ester, 8 (ab) and 4,5-Dichloro-benzo[h][1,6]naphthyridine- 3-carboxylic acid ethyl ester, 9 (a-b)

Method A: The compound 6 (0.005 mol) in diphenyl ether was refluxed (200°C) for 30 min (TLC checked, toluene). After completion of reaction, the reaction mixture was cool to room temperature and then it was stirred in diethyl ether (50 mL). The solid obtained was filtered and washed with excess ether, dried, and recrystallized from ethanol/DMF (80:20) to afford 8 in70-75% yield.

Method B: The compound 6 (0.005 mol) in POCl₃ was heated to reflux for 5 h (TLC checked, toluene). After completion of reaction, excess POCl₃ vacuum evaporated. The red colored residue obtained was poured in ice water (1L) and solution was neutralized with solid sodium carbonate (10 g). The separated solid product was collected by suction filtration. The TLC analysis in toluene showed two products. The mixture of crude product was separated by column chromatography on silica gel eluting with toluene, yields title compound 8 (20%) and 9 (40%).

5-Chloro-4-hydroxybenzo[h][1,6]naphthyridine-3-carboxylic acid ethyl ester, 8a: Yellow prisms; Yield; (Method A=1.05 g, 70%, B=0.302 g, 20%); M.P: 250°C; IR (KBr) ν_max: 3423 (OH), 3050, 1720 (NH), 2982, 1720 (CO), 1624, 1566 cm^-1;¹H NMR (CDCl₃): d 1.30 (t, J=7.2 Hz, 3H, CH₃), 4.26 (q, J=7.2 Hz, 2H, CH₂), 7.57 (t, J=7.5 Hz, 1H, C₉H), 7.78 (t, J=7.5 Hz, 1H, C8H), 8.05 (d, J=7.5 Hz, 1H, C₁₀H), 8.35 (d, J=7.5 Hz, 1H, C₇H), 10.25 (s, 1H, OH, D₂O exchangeable); Anal. Calcd. For C₁₅H₁₁ClN₂O₃ (302.72); Calcd: C, 59.52; H, 3.66; N, 9.25; Found: C, 59.60; H, 3.61; N, 9.40.

5,7-Dichloro-4-hydroxy-benzo[h][1,6]naphthyridine-3- carboxylic acid ethyl ester, 8b: Yellow prisms; Yield; (Method A=1.17 g, 75%; B=0.337 g, 20% ); M.P: 243°C; IR (KBr) ν_max: 3425 (OH), 3055, 1714 (CO), 1624, 1516, 2280, 769 cm^-1;¹H NMR (CDCl₃): d 1.31 (t, J=7.0 Hz, 3H, CH₃), 4.25 (q, J=7.0 Hz, 2H, CH₂), 7.77 (t, J=8.1 Hz, 1H, C₉H), 8.10 (d, J=8.1 Hz, 1H, C8H), 8.42 (s, 1H, C₂H), 8.54 (d, J=8.1 Hz, 1H, C₁₀H), 10.80 (s, 1H, OH, D₂O exchangeable);MS: m/z (%): 341 (M+4, 20), 339 (M+2, 30), 337 (M+, 90), 300 (70), 255 (70), 185 (80); Anal. Calcd. For C₁₅H₁₀Cl₂N₂O₃ (337.16); Calcd: C, 53.44; H, 2.99; N, 8.31; Found: C, 53.50; H, 3.09; N, 8.40.

4,5-Dichlorobenzo[h][1,6]naphthyridine-3-carboxylic acid ethyl ester, 9a: Yellow prisms; Yield; (Method A=0.642 g, 40%); M.P: 188°C; IR (KBr) ν_max: 2955, 1728 (CO), 156, 1174, 770 cm^-1;¹H NMR (CDCl₃): d 1.48 (t, J=6.9 Hz, 3H, CH₃), 4.51 (q, J=6.9 Hz, 2H, CH₂), 7.76 (t, J=7.8 Hz, 1H, C₉H), 7.88 (t, J=7.8 Hz, 1H, C₈H), 8.05 (d, J=7.8 Hz, 1H, C₁₀H), 9.05 (d, J=7.8 Hz, 1H, C₇H), 9.12 (s, 1H, C₂H); MS: m/z (%): 325 (M+4, 10), 323 (M+2, 30), 321 (M+, 100), 284 (30), 187 (40); Anal. Calcd. For C₁₅H₁₀Cl₂N₂O₂ (321.17); Calcd: C, 56.10; H, 3.14; N, 8.72; Found: C, 56.22; H, 3.09; N, 8.69.

4,5,7-Trichlorobenzo[h][1,6]naphthyridine-3-carboxylic acid ethyl ester, 9b: Yellow prisms; Yield; (Method A=0.71 g, 40%); M.P: 149°C; IR (KBr) ν_max: 2923, 160 (CO), 1537, 1179, 770 cm- 1;¹H NMR (CDCl₃): d 1.48 (t, J=7.0 Hz, 3H, CH₃), 4.52 (q, J=7.0 Hz, 2H, CH₂), 7.70 (t, J=7.2 Hz, 1H, C₉H), 7.80 (d, J=7.2 Hz, 1H, C₈H), 8.05 (d, J=7.2 Hz, 1H, C₁₀H), 9.10(s, 1H, C₂H); Anal. Calcd. For C₁₅H₉Cl₃N₂O₂ (355.61); Calcd: C, 50.66; H, 2.55; N, 7.88; Found: C, 50.79; H, 2.61; N, 7.79.

Conclusion

The chemoselective synthesis of 4-aminoquinolines 6(a-b) were obtained from 2,4-dichloroquinoline derivatives at different reaction conditions. The N-alkylation on 4-aminoquinolines using benzoylacetonitrile, diethyl 2-(ethoxymethylene) malonate was carried under mild reaction conditions. The benzo[h][1,6] naphthyridine derivatives 8(a-b), 9(a-b) were obtained from open chain analog of 4-aminoquinolines 6(a-b). The open chain quinline derivatives showed antimicrobial activity while cyclic benzo[h][1,6]naphthyridine derivatives found totally against bacteria utilized.

Acknowledgements

Authors thank UGC, New Delhi and BCUD, Savitribai Phule Pune University for financial support, CIF, Department of Chemistry, Savitribai Phule Pune University for spectral analysis and Principal, KTHM College, Nashik-422 002, Maharashtra for providing facilities.

References

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