Introduction

Nitrogen derivatives of 2-cyanoacetamide are extremely important precursors in heterocyclic synthesis [1–6]. The simplest and most convergent preparation of this class of compounds has been described elsewhere [7]. They are used as reactants because the carbonyl group, the active hydrogen on C-2, and the cyano function of these compounds are suitably positioned to enable reactions with common reagents to form a variety of heterocyclic compounds with pharmacological applications, for example anti-inflammatory [8, 9], antitumor [10, 11], and antibacterial and antifungal [12–15] activity, use as analgesic agents [16] and AKT inhibitors [17], and other medicinal properties [18, 19]. Because of this biological importance and as a part of our program of development of new approaches to synthesis of heterocyclic compounds expected to have biological activity [20–23] we report herein of the utility of 1-naphthyl-2-cyanoacetamide, 1, as a building block for synthesis of several new thiazolidine, pyrazole, pyridine, oxazine, and chromene derivatives.

Experimental

All melting points were measured on a Gallenkamp melting point apparatus. IR spectra (KBr) were acquired with a Perkin–Elmer model 157 infrared spectrophotometer. NMR spectra were acquired, at Stockholm University, with a Bruker spectrometer at 400 MHz (1H NMR) and at 100 MHz (13C NMR) in DMSO-d 6 as solvent and with TMS as internal standard; and chemical shifts are expressed as δ/ppm. Mass spectra were acquired with GCMS-QP1000 EX and Jeol JMS600 spectrometers at 70 eV. Elemental analysis was performed by the microanalytical unit of the Faculty of Science, Cairo University.

Reaction of cyanoacetamide, 1, with aromatic aldehydes, general procedure

Equimolar amounts of 1 (0.21 g, 1 mmol) and the aldehydes 4-hydroxybenzaldehyde (0.122 g,1 mmol) or piperonal (0.15 g, 1 mmol) in ethanol (15 mL) containing few drops of piperidine were heated under reflux for 30 min. The solid product which precipitated was isolated by filtration, dried, and recrystallized from 2:1 EtOH–DMF to afford compounds 2a and 2b, respectively.

(E)-2-Cyano-3-(4-hydroxyphenyl)-N-(naphthalen-1-yl) acrylamide (2a)

Yellow crystals; yield 97 %; mp 170–172 °C; IR (KBr): υ/cm−1 = 2,214 (CN), 1,662 (C=O), MS m/z (%): 314 (M+, 13.5), 212.0 (M+, 58.3), 172.8 (25), 169.8 (93.7), 142.0 (39.9), 128.0 (2.6) Anal. Calcd. for C20H14N2O2 (314.3): C, 76.42; H, 4.49; N, 8.91 % Found: C, 76.56; H, 4.57; N, 8.69 %.

(E)-3-(Benzo[d][1,3]dioxol-5-yl)-2-cyano-N-(naphthalen-1-yl) acrylamide (2b)

Yellow crystals; yield 95 %; mp 170–172 °C; IR (KBr): υ/cm−1 = 2,213 (CN), 1,650 (C=O), 1H NMR (400 MHz, DMSO-d 6): δ/ppm = 6.21 (s, 2H, CH2), 7.17–8.01 (m, 10H, Ar–H), 8.32 (s, 1H, CH), 10.41 (s, H, NH).13C-NMR (100 MHz, DMSO-d 6): δ/ppm = 161.61, 151.2, 150.75,148.13, 133.74, 133.08, 128.81, 128.2, 128.13, 126.67, 126.21, 126.17, 126.06, 125.55, 123.56, 123.11, 116.91, 109.11, 108.09, 103.65, 102.41; MS m/z (%): 343 (M++1, 13.5), 342.0 (M+, 58.3), 199.8 (100), 169.8 (93.7), 142.0 (39.9), 128.0 (2.6) Anal. Calcd. for C21H14N2O3 (342.3): C, 73.68; H, 4.12; N, 8.18 % Found: C, 73.60; H, 4.17; N, 8.12 %.

Synthesis of 6-amino-4-(aryl)-1-(naphthalen-1-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (6a, b)

An equimolar amount of 2-cyano-N-(naphthalen-1-yl)acetamide 1 (0.21 g, 1 mmol) and few drops of triethylamine were added to a solution of the appropriate arylidene malononitrile (1 mmol) in ethanol (20 mL). The mixture was heated under reflux for 2 h, then left to cool to room temperature. The solid product that formed was collected by filtration, washed with ethanol, then recrystallized from EtOH–DMF to give the corresponding pyridin-2-one derivatives 6a, b.

6-Amino-4-(4-hydroxyphenyl)-1-(naphthalen-1-yl)-2-oxo-1,2 dihydropyridine-3,5-dicarbonitrile (6a)

White crystals; yield 85 %; mp > 300 °C; IR (KBr): υ/cm−1 = 2,218 (CN), 1,682 (C=O), 3,424 (NH2), 1H NMR (400 MHz, DMSO-d6): δ/ppm = 6.8–8.01 (m, 11H, Ar–H), 8.10 (s, 2H, NH2). 10.10 (s, 1H, OH), MS m/z (%): 378 (M+, 100), 361.0 (21.0), 349 (10.9), 225 (8.5), 169 (12.3), 127 (67.8). Anal. Calcd. for C23H14N4O2 (378.4): C, 73.01; H, 3.73; N, 14.81, Found: C, 73.15; H, 3.58; N, 14.69 %.

6-Amino-4-(benzo[d][1,3]dioxol-5-yl)-1-(naphthalen-1-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (6b)

White crystals; yield 80 %; mp > 300 °C; IR (KBr): υ/cm−1 = 2,214 (CN), 1,667 (C=O), 3,425 (NH2), MS m/z (%): 406 (M+, 100), 378 (17.6), 203 (15.1), 169 (16.7), 127 (84.7). Anal. Calcd. for C24H14N4O3 (406.4): C, 70.93; H, 3.47; N, 13.79, Found: C, 70.85; H, 3.58; N, 13.69 %.

Reaction of cyanoacetamide derivative 1 with 1,3-dicarbonyl compounds, general procedure

A mixture of compound 1 (0.21 g, 1 mmol) and an equimolar amount of the appropriate 1,3-dicarbonyl compound (acetylacetone 0.1 g, benzoylacetone 0.16 g, or dimedone 0.14 g) (1 mmol) in ethanol (15 mL) containing few drops of piperidine was heated under reflux for 2 h. The reaction mixture was cooled and the solid obtained was isolated by filtration and recrystallized from ethanol to give compounds 7, 8, or 18, respectively.

4,6-Dimethyl-1-(naphthalen-1-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (7)

Colorless crystals; yield 95 %; mp 243 °C; IR (KBr): υ/cm−1 = 2,220 (CN), 1,730 (C=O), 1H NMR (400 MHz, DMSO-d 6): δ/ppm = 1.87 (s, 3H, CH3), 2.46 (s, 3H, CH3), 6.57 (s, 1H, CH of pyridine ring), 7.3–8.12 (m, 7H, Ar–H). 13C NMR (100 MHz, DMSO-d 6): δ/ppm = 20.66, 20.78, 100.27, 109.3, 115.82, 121.24, 125.94, 126.29, 126.83, 127.92, 128.62, 128.70, 129.63, 133.74, 133.92, 152.43, 160.21, 160.50. MS m/z (%): 274 (M+, 100), 258.8 (51.31), 244.9 (24.4), 217.3 (11.1), Anal. for C18H14N2O Calcd.: C, 78.81; H, 5.14; N, 10.21 % Found: C, 78.79; H, 5.17; N, 10.23 %.

6-Methyl-1-(naphthalen-1-yl)-2-oxo-4-phenyl-1,2-dihydropyridine-3-carbonitrile (8)

Colorless crystals; yield 90 %; mp 235 °C; IR (KBr): υ/cm−1 = 2,217 (CN), 1,728 (C=O), 1H NMR (400 MHz, DMSO-d 6): δ/ppm = 1.96 (s, 3H, CH3), 6.62 (s, 1H, CH of pyridine ring), 7.11–7.66 (m, 12H, Ar–H). MS m/z (%): 336.05 (M+, 100), 337.05 (M++1, 25.95), 338.1 (M++2, 5.75), 320.05 (42.19), 259.05 (21.52), 236.1 (10.34), 219.01 (4.49), 206.1 (4.20), Anal. for C23H16N2O (336.13) Calcd.: C, 82.12; H, 4.79; N, 8.33 %. Found: C, 82.18; H, 4.73; N, 8.37 %.

(E)-2-Cyano-2-(3, 3-dimethyl-5-oxocyclohexylidene)-N-(naphthalen-1-yl) acetamide (18)

White crystals; yield 90 %; mp 204–205 °C; IR (KBr): υ/cm−1 = 2,213 (CN), 1,715, 1,650 (2C=O), 1H NMR (400 MHz, DMSO-d 6): δ/ppm = 0.8 (s, 3H, CH3), 0.87 (s, 3H, CH3), 1.98 (s, 2H, CH2), 2.50 (s, 2H, CH2), 3.21 (s, 2H, CH2), 7.53–8.18 (m, 7H, Ar–H), 8.65 (s, 1H, NH), MS m/z (%): 331.1 (M+, 1.0), 249.1 (2.12), 207.0 (9), 170.1 (7), 143.1 (55), Anal. for C21H20N2O2 (332.15) Calcd.: C, 75.88; H, 6.06; N, 8.43 % Found: C, 75.81; H, 6.16; N, 8.51 %.

Synthesis of 2-(4,6-diamino-3,5-dicyanopyridin-2-yl)-N-(naphthalen-1-yl) acetamide (9)

Method A A mixture of compound 1 (0.21 g, 1 mmol) and malononitrile (0.132 g, 2 mmol) in a round-bottomed flask containing piperidine (four drops) was fused in an oil bath at 140 °C for 0.5 h, then left to cool. The solid product was washed with ethanol.

Method B A mixture of 3-amino-2,4-dicyanocrotononitrile (0.13 g, 1 mmol) and 1-naphthyl-2-cyanoacetamide 1 (0.21 g, 1 mmol) was fused in an oil bath at 140 °C for 0.5 h, and then left to cool. The solid product was washed with ethanol.

Yellow powder; Yield 65 %; mp 215 °C; IR (KBr): υ/cm−1 = 3,423 (NH), 2,218, 2,214 (2CN), 3,450, 3,455 (2NH2) 1,628 (C=O). 1H NMR (400 MHz, DMSO-d 6): δ/ppm = 3.82 (s, 2H, CH2), 7.12–7.8 (m, 7H, Ar–H), 9.88 (s, 2H, NH2), 10.23 (s, 1H, NH). MS m/z (%): 342.0 (M+, 42.1), 201 (31.6), 187.2 (26.3), 169.6 (84.2), 142.4 (78.9). Anal. for C19H14N6O (342.35) Calcd.: C, 66.66; H, 4.12; N, 24.55 %. Found: C, 66.60; H, 4.18; N, 24.59 %.

Synthesis of naphthoxazine derivatives 11 and 13 and chromene derivative 17

1-Nitroso-2-naphthol (0.17 g, 1 mmol), 2-nitroso-1-naphthol (0.17 g, 1 mmol), or salicylaldehyde (0.12 g, 1 mmol), was added to a solution of compound 1 (0.21 g, 1 mmol) in ethanol (25 mL) containing few drops of piperidine and the mixture was heated under reflux for 4 h. The solid products formed on pouring into an ice–water mixture containing few drops of hydrochloric acid was collected by filtration, dried, and recrystallized from ethanol to afford compounds 11, 13, or 17, respectively.

N-(Naphthalen-1-yl)-3-oxo-3H-naphtho[2,1-b][1,4]oxazine-2-carboxamide (11)

Violet crystals; yield 70 %; mp 236–238 °C; IR (KBr): υ/cm−1=3,336 (NH), 1,695, 1,655 (2CO), 1,583 (C=N), 1H NMR (400 MHz, DMSO-d 6): δ/ppm = 7.25–7.99 (m, 13H, Ar–H), 10.25 (s, H, NH-amidic). MS m/z (%): 366 (M+, 53.3), 350.1 (18.2), 269. 338.1 (4.82), 316.2 (18.), 237.1 (6.4), 224 (100) Anal. Calcd. for C23H14N2O3 (336): C, 75.40; H, 3.85; N, 7.65 %. Found: C, 75.45; H, 3.76; N, 7.48 %.

N-(Naphthalen-1-yl)-2-oxo-2H-naphtho [1,2-b][1,4]oxazine-3 carboxamide (13)

Violet crystals; yield 75 %; mp 230–232 °C; IR (KBr): υ/cm−1 = 3,340 (NH), 1,703, 1,659 (2CO), 1,580 (C=N), 1H-NMR (400 MHz, DMSO-d 6): δ/ppm = 7.49–8.10 (m, 13H, Ar–H), 10.40 (s, H, NH amidic). Anal. Calcd. for C23H14N2O3 (336.1): C, 75.40; H, 3.85; N, 7.65 %. Found: C, 75.58; H, 3.80; N, 7.61 %.

2-Imino-N-(naphthalen-1-yl)-2H-chromene-3-carboxamide (17)

Orange crystal; yield 95 %; mp 241 °C; IR (KBr): υ/cm−1 = 3,450, 3,300 (2NH), 1,680 (C=O). 1H NMR (400 MHz, DMSO-d 6): δ/ppm = 7.31–8.68 (m, 11H, Ar–H), 8.68 (s, 1H, chromene-CH), 9.49 (s, 1H, NH), 13.38 (s, 1H, NH); MS m/z (%): 314 (M+, 6.8), 314 (72.6), 285 (8.2), 171 (21.9), 144 (17.8); Anal. Calcd. for C20H12NO2 (314.3): C, 76.47; H, 4.49; N, 8.91 %. Found: C, 76.55; H, 4.43; N, 8.85 %.

Coupling reaction of 1 with aromatic amine diazonium salts compounds, general procedure

A cold solution of the appropriate diazonium chloride (2 mmol; prepared by adding cold sodium nitrite solution (0.14 g, 2 mmol) to a cold suspension of the appropriate aromatic amine (2 mmol) in conc. HCl (1.5 mL) with stirring) was added, with continuous stirring, to a cold solution of 1 (0.42 g, 2 mmol) at 0–5 °C in pyridine (20 mL). The mixture was left to stand for 2 h, diluted with water, then filtered. The arylazo derivatives 14a–c thus obtained was dried and recrystallized from 2:1 EtOH–DMF.

(E)-2-(Naphthalen-1-ylamino)-2-oxo-N-(p-tolyl)-acetohydrazonoyl cyanide (14a)

Reddish brown powder; yield 85 %; mp 215 °C; IR (KBr): υ/cm−1 = 3,415, 3,460 (2NH), 2,215 (CN), 1,655 (C=O); 1H NMR (400 MHz, DMSO-d 6): δ/ppm = 2.29 (s, 3H, CH3), 7.18–7.99 (m, 11H, Ar–H), 10.19 (s, 1H, NH), 11.91 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d 6): δ/ppm = 160.65, 139.91, 133.73, 133.46, 132.72, 129.58, 129.39, 128.19, 128.08, 126.2, 126.12, 126.1, 124.05, 123.21, 121.8, 116.21, 111.57, 106.85, 26.29, 20.45, MS m/z (%): 327.8 (M+, 31.8), 327.5 (M+, 36.4), 170 (86.4), 142 (68.2). Anal. Calcd. for C20H16N4O (328.37) C, 73.15; H, 4.91; N, 17.06 %, Found: C, 73.20; H, 4.87; N, 17.11 %.

(E)-N-(4-Methoxyphenyl)-2-(naphthalen-1-ylamino)-2-oxoacetohydrazonoyl cyanide (14b)

Reddish brown; yield 90 %; mp 205 °C; IR (KBr): υ/cm−1 = 3,420, 3,450 (2NH), 2,218 (CN), 1,648 (C=O), 1H NMR (400 MHz, DMSO-d 6): δ/ppm = 3.76 (s, 3H, OCH3), 6.95–7.99 (m, 11H, Ar–H), 10.17 (s, 1H, NH), 11.92 (s, 1H, NH). MS m/z (%): 344.7 (M+, 5.7), 313 (9.2), 222 (16.2) 208 (12.1), 143.0 (100), 142 (23.9). Anal. Calcd. for C20H16N4O2 (344.37): C, 69.76; H, 4.68; N, 16.27 %, Found: C, 69.70; H, 4.61; N, 16.37 %.

(E)-N-(4-Chlorophenyl)-2-(naphthalen-1-ylamino)-2-oxoacetohydrazonoyl cyanide (14c)

Yellow powder; yield 65 %; mp 205 °C; IR (KBr): υ/cm−1 = 3,456, 3,425 (2NH), 2,215 (CN), 1,635 (C=O); 1H NMR (400 MHz, DMSO-d 6): δ/ppm = 7.42 -8.0 (m, 11H, Ar–H), 10.29 (s, 1H, NH), 12.02 (s, 1H, NH). 13C-NMR (100 MHz, DMSO-d 6): δ/ppm = 161.25, 142.08, 134.64, 133.93, 130.51, 130.38, 129.93, 128.97, 128.91, 127.54, 127.07, 126.44, 125.18, 124.21, 118.73, 112.21, 109.29, MS m/z (%): 348 (M+, 7.0), 316 (3.3), 208 (12.19), 169.6 (3.3), 142.4 (11.1). Anal. Calcd. for C19H13ClN4O (348.79): C, 65.43; H, 10.16; N, 16.06 %, Found: C, 65.49; H, 10.3; N, 16.12 %.

Synthesis of 2-cyano-N-(naphthalen-1-yl)-2-[(4,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-3-yl) hydrazono] acetamide (15)

4,6-Dimethyl-2H-pyrazolo[3,4-b]pyridine-3-yl diazonium salt (prepared by dissolving sodium nitrite (0.14 g, 2 mmol) in water (2 mL) and adding to a cold solution of 3-amino-4,6-dimethyl-2H-pyrazolo[3,4-b]pyridine (0.32 g, 2 mmol) containing the appropriate amount of hydrochloric acid, with continuous stirring) was added, in portions, over a period of 30 min, to a cold (0–5 °C) solution of 1 (0.42 g, 2 mmol) in pyridine (20 mL). The reaction mixture was kept in an icebox overnight and then diluted with water. The solid that precipitated was isolated by filtration, washed with water, dried, and recrystallized from 2:1 EtOH–DMF to give compound 15.

Brown powder; yield 60 %; mp 204–205 °C; IR (KBr): υ/cm−1 = 3,490 (NH), 2,215 (CN), 1,639 (C=O). 1H NMR (400 MHz, DMSO-d 6): δ/ppm = 2.56 (s, 3H, CH3), 2.72 (s, 3H, CH3), 4.08 (s, 1H, CH), 7.49–8.09 (m, 8H, Ar–H), 10.27 (s, 1H, NH); MS m/z (%): 384 (M+, 0.9), 383 (0.2), 341.7 (58.9), 278 (3.8), 236 (3.8) 208 (3.1), 143.0 (100), 127 (4.0). Anal. Calcd. for C21H17N7O (383.42): C, 65.79; H, 4.47; N, 25.57 % Found: C, 65.85; H, 4.56; N, 25.49 %.

Synthesis of 4-imino-8,10-dimethyl-N-(naphthalen-1-yl)-4,6-dihydropyrido [2′,3′:3,4] pyrazolo[5,1-c][1,2,4]triazine-3-carboxamide (16)

A solution of 15 (0.383 g, 1 mmol) in glacial acetic acid (20 mL) was heated under reflux for 3 h, then left to cool. The precipitate that formed was isolated by filtration, washed with ethanol, and recrystallized from 1:1 EtOH–DMF to give compound 16.

Brown powder; yield 75 %; mp > 300 °C; IR (KBr): υ/cm−1 = 3,424, 3,460, 3,485 (3NH), 1,639 (C=O). 1H NMR (400 MHz, DMSO-d 6): δ/ppm = 2.53 (s, 3H, CH3), 2.75 (s, 3H, CH3), 7.29–7.95 (m, 8H, Ar–H), 9.20, (s, 1H, NH) 10.41 (s, 1H, NH). MS m/z (%): 383 (1.2), 278 (4.1), 236 (2.5) 213 (3.1), 170 (2.3) 143.0 (100). Anal. Calcd. for C21H17N7O (383.4) C, 65.79; H, 4.47; N, 25.57 %, Found: C, 65.86; H, 4.51; N, 25.66 %.

Synthesis of (E)-2-cyano-3-(dimethylamino)-N-(naphthalen-1-yl) acrylamide (19)

Dimethylformamide dimethylacetal (DMF-DMA) (0.24 g, 2 mmol) was added to a solution of 1 (0.42 g, 2 mmol) in xylene (20 mL). The reaction mixture was heated under reflux for 3 h, then poured into ice-cold water. The resulting precipitate was isolated by filtration, dried, and recrystallized from 1:2 EtOH–DMF to give compound 19.

Brown glassy crystals; yield 85 %; mp 145 °C; IR (KBr): υ/cm−1 = 3,450 (NH), 1,695 (C=O), 2,180 (CN), 1H NMR (400 MHz, DMSO-d 6): δppm = 3.32 (s, 3H, NCH3), 3.33 (s, 3H, NCH3), 7.47–7.95 (m, 7H, Ar–H), 9.19 (s, 1H, NH).13C NMR (100 MHz, DMSO-d 6): δ/ppm = 165.36, 157.44, 134.6, 134.2, 129.67, 128.98, 126.8, 126.69, 126.44, 126.35, 123.75, 123.47, 120.56, 71.43, 47.83, 39.05, MS m/z (%): 265 (M+, 3.1), 264.9 (18.5) 123 (100), 169.2 (2.7), 142 (4.4), 80.0 (12.8). Anal. Calcd. for C16H15N3O (265.31) C, 72.43; H, 5.70; N, 15.84 % Found: C, 72.54; H, 5.61; N, 15.78 %.

Synthesis of 3-amino-N-(naphthalen-1-yl)-1H-pyrazole-4-carboxamide (20)

A mixture of 19 (0.53 g, 2 mmol) and hydrazine hydrate 98 % (0.5 mL, 5 mmol) was heated in ethanol (10 mL) on water bath for 1 h. The separated product was isolated by filtration and recrystallized from DMF–EtOH to give compound 20.

Yellow powder; yield 65 %; mp 208 °C; IR (KBr): υ/cm−1 = 3,455, 3,460 (2NH), 1,635 (C=O), 3,420 (NH2), 1H NMR (400 MHz, DMSO-d 6): δ/ppm = 7.50–8.18 (m, 7H, Ar–H), 9.0 (s, 1H, NH), 9.70 (s, 1H, NH), 10.27 (s, 2H, NH2), 13C-NMR (100 MHz, DMSO-d 6): δ/ppm = 165.89, 157.59, 134.54, 133.4, 129.49, 128.04, 127.73, 126.09, 125.92, 123.48, 121.32, 117.83, 93.19, 85.13, Anal. Calcd. for C14H12N4O (252.27): C, 66.65; H, 4.79; N, 22.21 % Found: C, 66.54; H, 4.65; N, 22.27 %.

Reaction of 19 with some nitrogen nucleophiles, general procedure

o-Phenylenediamine (0.22 g, 2 mmol), guanidine hydrochloride (0.19 g, 2 mmol), or thiourea (0.15 g, 2 mmol) was added to a solution of compound 19 (0.53 g, 2 mmol) in 1:1 DMF–EtOH (10 mL). The reaction mixture was heated under reflux for 6 h, the solvent was evaporated under reduced pressure, and the residue was treated with ethanol, isolated by filtration, dried, and recrystallized from DMF–EtOH to afford compounds 21, 22, and 23, respectively.

4-Amino-N-(naphthalen-1-yl)-1H-benzo[b][1,4] diazepine-3-carboxamide (21)

Deep yellow powder; yield 75 %; mp 242–243 °C; IR (KBr): υ/cm−1 = 3,460 (NH), 3,440 (NH2), 1,645 (C=O). 1H NMR (DMSO-d 6): δ/ppm = 5.22 (s, 1H, CH), 7.52 – 7.87 (m, 11H, Ar–H), 9.00 (s, 1H, NH), 9.25 (s, 2H, NH2), MS m/z (%): 328.1 (M+, 0.7), 264 (8.8) 123 (100), 169.8 (1.0), 142 (2.4), 76.9 (3.1). Anal. Calcd. for C20H16N4O (328.13): C, 73.15; H, 4.91; N, 17.06 %, Found: C, 73.26; H, 5.01; N, 17.0 %.

2,4-Diamino-N-(naphthalen-1-yl)pyrimidine-5-carboxamide (22)

Pale yellow powder; yield 70 %; mp > 300 °C; IR (KBr): υ/cm−1 = 3,458 (NH), 3,440, 3,445 (2NH2), 1,653 (C=O). 1H NMR (DMSO-d 6): δ/ppm = 7.40–8.43 (m, 8H, Ar–H), 8.75 (s, 2H, NH2), 10.38 (s, 2H, NH2), 12.18 (s, 1H, NH), Anal. Calcd. for C15H13N5O (279.11): C, 64.51; H, 4.69; N, 25.07 %, Found: C, 64.61; H, 4.62; N, 25.01 %.

4-Amino-N-(naphthalen-1-yl)-2-thioxo-1,2-dihydropyrimidine-5-carboxamide (23)

Deep yellow crystals; yield 90 %; mp 254–256 °C; IR (KBr): υ/cm−1 = 3,423 (NH), 3,356 (NH2), 1,651 (C=O), 1,155 (C=S). MS m/z (%): 297.1 (M++1, 55.1), 296.1 (M+, 55.1), 226 (53), 169 (54.0), 127 (68). Anal. Calcd. For C15H12N4OS (296.35): C, 60.80; H, 4.08; N, 18.91 % Found: (296.35): C, 60.70; H, 4.12; N, 18.78 %.

Results and discussion

Chemistry

The reaction sequences used for synthesis of the title compounds are depicted in Schemes 1, 2, 3, 4, 5 and 6. The starting compound, 1-naphthyl-2-cyanoacetamide 1 [24], as versatile precursor, was reacted with common reagents to obtain a variety of heterocyclic compounds. Thus, compound 1 reacted with some aromatic aldehydes to afford the corresponding benzylidene derivatives 2a, b. Treatment of the latter compounds with malononitrile furnished the aminopyridone derivatives 6a, b. The IR spectrum of compound 6a contained absorption bands at 3,424, 2,218, and 1,682 cm−1 ascribed to amino, nitrile, and carbonyl, respectively. Formation of 6 may be proceeded via Michael type addition followed by auto-oxidation of the intermediates 4a, b. The structures of 6a, b were confirmed chemically by alternative synthesis, by reaction of 1 with the benzylidenemalononitriles 5 under a similar reaction conditions to give products identical in all respects (mp, mixed mp, and spectral analysis) with 6a, b (Scheme 1).

Scheme 1
scheme 1

Synthetic route to pyridine derivatives

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Scheme 2
scheme 2

Reaction of 1 with common bidentate reagents

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Scheme 3
scheme 3

Formation of naphthoxazine derivatives

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Scheme 4
scheme 4

Coupling reaction of 1 with different aromatic amines

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Scheme 5
scheme 5

Reaction of 1 with aldehyde and ketone

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Scheme 6
scheme 6

Preparation of pyrazole, diazepine, and pyrimidine derivatives

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It is well known that many 2-pyridone derivatives have diverse biological activity, e.g. as cardiotonic agents and potential HIV-1 specific reverse transcriptase inhibitors [25, 26]. This study was performed to determine the reactivity of cyanoacetamide derivative 1 toward C-nucleophilic reagents. Thus, reaction of 1-naphthyl-2-cyanoacetamide 1 with acetylacetone, a β-diketone, in boiling ethanol containing a catalytic amount of piperidine yielded the pyridine-2-one 7 derivative, and reaction of 1 with benzoylacetone afforded a product with the chemical formula C23H1 6N2O. It seems two isomers could be formed, 8a and 8b, but TLC monitoring indicated formation of one product, 8. The 1H NMR spectrum contained a methyl proton at δ 1.96 ppm and a methine proton at δ 6.70 ppm, indicative of the more stable and less sterically hindered structure 8a.

The biological activity of pyridine derivatives is well established and attempts have been made to obtain more active and less toxic pyridine derivatives [27]. In continuation of our medicinal projects with the purpose of developing new procedures for synthesis of pyridines [20] we report here reaction of 1 with malononitrile in the molar ratio 1:2 to give pyridinylacetamide 9 (Scheme 2). The structure of 9 was established on the basis of its IR and 1H NMR spectra. The IR spectrum contains bands at 2,218 and 2,214 cm−1 ascribed to two CN groups. The 1H NMR spectrum contained CH2 as singlet signal at δ 3.82 ppm. A logical mechanism for this reaction was based on dimerization of malononitrile in basic medium to give the malononitrile dimer followed by its reaction with 1 to give 9. This sequence was confirmed by its alternative synthesis—fusion of 1 with the malononitrile dimer in the molar ratio 1:1 in the presence of a catalytic amount of piperidine gave a single product identical in all respects to 9 (mp, mixed mp, and spectra).

Cyclocondensation of compound 1 with equimolar amounts of 1-nitroso-2-naphthol or 2-nitroso-1-naphthol in boiling ethanol containing a catalytic amount of piperidine afforded naphthoxazines 11 and 13, respectively (Scheme 3). The structure 11 was established on the basis of the IR spectrum, which contained an absorption band at 3,336 cm−1 (NH). Its 1H NMR spectrum contained a multiplet at δ 7.25–7.99 ppm, ascribed to aromatic protons, and a D2O-exchangeable singlet at δ 10.25 ppm for the NH proton. The mass spectrum of 11 contained the molecular ion peak at m/z 336.1 (M+), which is in agreement with the molecular formula C23H14N2O3.

The reactivity of the methylene group of compound 1 was tested in an electrophilic azo-coupling reaction with aromatic diazonium salts, to yield the corresponding coupling products 14a–c. Formation of 14a–c was established on the basis of the presence of a peak at 2,220 cm−1 from the CN group in the IR spectra of the products. The 1H NMR spectrum of 14a contained a singlet signal at δ 2.29 ppm, corresponding to methyl protons, and a D2O-exchangeable singlet signal at δ 11.91 ppm from the hydrazo proton. Moreover, its 13C NMR spectrum contained a signal at 20.45 ppm corresponding to the carbon of a methyl group. Coupling of cyanoacetamide 1 with diazotized 3-amino-4,6-dimethyl-2H-pyrazolo[3,4-b]pyridine in pyridine at 0–5 °C gave hydrazone derivative 15. Formation of triazine derivative 16 was achieved in excellent yield by heating compound 15 in glacial acetic acid. There was no evidence of a nitrile functional group in the IR spectrum of 16 (Scheme 4).

Chromene derivatives are important compounds with a wide range of pharmacological properties [28, 29]. We report herein reaction of 1-naphthyl-2-cyanoacetamide 1 with salicylaldehyde to form a single product in excellent yield; this was identified as 2-imino-N-(naphthalen-1-yl)-2H-chromene-3-carboxamide 17. The 1H NMR spectrum of compound 17 contained a singlet signal at δ 8.68 ppm attributable to C4–H proton of the chromene moiety, and a D2O-exchangeable signal at δ 13.83 ppm characteristic to the imino proton. Condensation of 1 with dimedone in boiling ethanol furnished chalcone 18 in excellent yield (Scheme 5).

Heating of 1 with dimethylformamide dimethylacetal (DMF-DMA) in dry xylene furnished clear brown glassy crystals of 19 in reasonable yield. Elemental analysis and spectral data were in agreement with formation of the enaminonitrile product 19. Its 1H NMR spectrum contained singlet signals at δ 3.32 and 3.33 ppm corresponding to the protons of the two methyl groups. The mass spectrum contained a molecular ion peak at m/z 265 corresponding to the molecular formula C16H15N3O. The reactivity of enaminonitrile 19 toward some nitrogen nucleophiles was investigated. Thus, 19 reacted with hydrazine hydrate, o-phenylenediamine, guanidine hydrochloride, and thiourea to give the corresponding pyrazole, diazepine, and pyrimidine derivatives 20–23, respectively. The latter compounds are believed to be formed by addition of the amino group to the ethylenic double bond followed by loss of dimethylamine. Intramolecular cyclization gave the final isolated products 20–23. The structure of 21 was established on the basis of its IR spectrum which contained bands related to NH2 and NH. The mass spectrum contained a molecular ion peak at m/z 328.13 corresponding to a molecular formula C20H16N4O (Scheme 6).

Biological activity

Thirteen of the newly synthesized compounds were evaluated for in-vitro antibacterial activity against Gram-positive (Staphylococcus aureus and Bacillus subtilis) and Gram-negative (Pseudomonas aeruginosa and Escherichia coli) bacteria. The disc diffusion method was used for determination of antibacterial activity. A 10 mg/mL solution in dimethyl sulfoxide was used. Beta-lactam antibiotics were used as reference drugs. To study the effects of discs saturated with the chemicals, nutrient agar was inoculated with the bacteria then incubated at 37 °C for 24 h. The diameter of the inhibition zone (IZ; mm, along two axes, in accordance with WHO recommendations) for each compound was then recorded. No inhibition zones were observed for DMSO. The results are listed in Table 1.

Table 1 Inhibition zone (mean diameter of inhibition in mm) as a criterion of antibacterial activities of the newly synthesized compound
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Some of the compounds were active against the Gram-positive and Gram-negative bacteria. It should be also noticed that:

  • Chalcones 2a and 2b had high antibacterial activity, possibly because of the presence of p-hydroxyaryl and piperonyl moieties.

  • Introduction of a coumarinyl moiety at position 3 of the carboxamide linkage resulted in biologically active compound 17, especially against Gram-positive bacteria.

  • Pyrazole 20 and thioxo-pyrimidine 23 (Scheme 6) compounds had the greater antibacterial potential that the pyridinones (Scheme 2).

  • The presence of a diazepine moiety at position 3 of the carboxamide linkage reduced the antibacterial activity of the compounds.

Conclusion

Novel pyrazolotriazine, pyridone, diazepine, and pyrimidine derivatives incorporating the naphthyl moiety have been synthesized and their antibacterial activity evaluated. The results clearly showed that most of the compounds had mild to moderate activity against Gram-positive and Gram-negative bacteria, and that coupling of a naphthyl moiety to thioxo-pyrimidine through a carboxamide linkage improves the antibacterial activity.