Introduction

Quinoline is very important for human generation as a heterocyclic structure ‎[1]. ‎Dihydroquinolines and pyridopyrimidines, among quinoline derivatives, are significant structural subunits of natural products that display biological and pharmaceutical activities. The available dihydroquinoline derivatives are multi-functional dihydropyridine derivatives and their chemistry and biology have not been extensively studied in the literature.

Synthetic methods for preparing quinoline derivatives are of notable attention, and various methods have been offered proving desirable results ‎[2⎼12]‎. In spite of this, most of them elucidate the synthesis of hydroquinoline nucleus and methods for accessing hydroquinolines with effective functions are scarce in the literature. A number of dihydroquinolines have been synthesized by considering variant biomedical applications and with the aim of more evaluations of the pharmacological properties of these compounds. Multicomponent reactions (MCRs) are ideal procedures in the synthesis of heterocyclic compounds. The MCRs advantages are simple operation, short reaction time, saving energy, and high yield ‎[13, 14].‎

In previous studies, various catalysts such as chiral amines, diphenylprolinol trimethylsilyl ether, difunctional thiourea, and tertiary amine-thiourea were used to synthesize dihydroquinoline derivatives ‎[15, 16]. ‎Recently, we offered NCTDSS as an appropriate catalyst for producing organic chromene and coumarin analogs by using a one-pot procedure as a direct route ‎[17]. ‎According to the above results presented, it was predicted that the utilization of the important role represented by the NCTDSS systems, described here and would simplify the expansion of a general and simple one-pot procedure to prepare dihdroquinolines. On the other hand, nano TiO₂ on silica dodecyl sulfate as a heterogeneous catalyst has advantages such as high effectiveness, reusability, strong oxidation power, easy access, non-toxic, and long-term stability compared with other catalysts.

Only slight modifications of the previously optimized experimental protocol were essential to verify that, in the presence of NCTDSS (5.0 mol %), phenol (1 mmol) and β-ketoesters (1.2 mmol) are smoothly converted into coumarin derivatives in satisfactory yield. Since the optimal conditions for the efficient catalysis of the condensation reaction had been determined. Here, the suitable solvent is ethanol, and it should be emphasized that it is in a clear contrast with the results captured for the dihydroquinolines synthesis. In this research, we aimed to report an efficient sequence for one pot synthesis of dihydroquinoline analogs. Their synthesis was achieved by the one pot reaction of cyclohexylpropanenitrile and cyclohexylpropanoate derivatives with different primary amines in the NCTDSS presence as a catalyst in ethanol at reflux conditions.

Experimental

Materials and methods

All reagents and starting materials were supplied from Fluka and Aldrich chemical companies and used without more purification. Reaction monitoring was performed by TLC on PolyGram SILG/UV254 silica gel plates. Column chromatography was performed on silica gel columns 60 (mesh 70-230). Melting points in open capillary tubes were characterized in the Barnstead Electro thermal 9100 BZ oil melting point device. ¹H NMR and ¹³C NMR spectra were determined by Brucker (250 MHz) Avanc DRX apparatus in pure dutre DMSO-d₆ solvent with tetramethyl silane (TMS) as internal standards. To record mass spectra, FINNIGAN-MAT 8430 mass spectrometer was used operating at 70 eV and FT-IR spectroscopy (Shimadzu FT-IR 8300 spectrophotometer) was operated for recognition.

General Procedure for synthesis of Dihydroquinolines and Pyridopyrimidines

A mixture of cyclic-β-diketone derivatives (1 mmol), acrylonitrile or methyl acrylate (1 mmol) were dissolved in hot ethanol in the presence of 5 mol% of NCTDSS. After appropriate time, primary amine (1 mmol) was added in the mixture, and the resulting mixture was refluxed for fitting time. Reaction progress was assessed by TLC. Upon the reaction completion, the reaction mass was poured into ice-cold water, the product was filtered, washed with water, dried, and recrystallized from hot ethanol, but some compounds which did not reach this level, were purified by column chromatography on silica gel by using hexane/ethyl acetate as eluent to afford the pure dihydroquinolines and pyridopyrimidines.

2-Amino-5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-N-phenylquinoline-1(4H)-carboxamide (1)

White solid, mp 165-167 °C, IR (KBr) (ν_max/ cm^-1): 3425.3, 3313.5, 3217, 3039.6, 2962.4, 2322.1, 1654.8, 1554.5, 1450.4, 1357.8, 1226.6, 1122.5, 752.2, 698.2, and 586.3. ¹H-NMR (250 MHz, DMSO-d₆): δ 0.96 (s, 6H), 2.10 (s, 2H), 2.46 (s, 2H), 3.03 (s, 2H), 4.67 (d, J = 2.5 Hz, 2H), 5.15 (t, J = 2.5 Hz, 1H), 6.88-7.21 (m, 3H), 7.33-7.38 (m, 2H), 8.29 (s, 1H). ¹³C-NMR (62.9 MHz, DMSO-d₆): δ 19.2, 28.6, 32.2, 42.9, 50.6, 74.2, 116.3, 122.4, 128.2, 130.9, 133.9, 140.7, 146.91, 148.2, 195.3. Anal. Calcd. for C₁₈H₂₁N₃O₂ (311.16): C 69.43; H 6.80; N 13.49, found: C 69.37; H 6.86; N 13.43. MS: m/z (%) = 311.16 (M⁺), 246 (33), 215 (36.1), 172 (20.7), 111 (18.5), 83 (38.7),  57 (100).

7,8-Dihydro-2-hydroxy-1-(3-hydroxyphenyl)-7,7-dimethylquinolin-5(1H,4H,6H)-one (2)

Yellow solid, mp 188-190 °C, IR (KBr) (ν_max/ cm^-1): 3330, 3004, 2966, 1695, 1510, 1438, 1410, 1255, 1125.5, 1021, 831, 702.2, and 512.9. ¹H-NMR (250 MHz, DMSO-d₆): δ 1.08 (s, 6H), 2.02 (s, 2H), 2.24 (s, 2H), 3.87 (d, J = 2.5 Hz, 2H), 4.39 (t, J = 5 Hz, 1H), 5.91 (s, 1H), 6.47-6.58 (m, 3H), 7.08-7.15 (m, 1H), 8.68 (s, 1H). ¹³C-NMR (62.9 MHz, DMSO-d₆): δ 27.6, 32.0, 41.9, 50.2, 63.9, 100.8, 112.3, 120.3, 125.2, 126.3, 135.5, 146.2, 155.6, 179.6, 196.6.

1-(4-Bromophenyl)-7,8-dihydro-2-hydroxy-7,7-dimethylquinolin 5(1H,4H,6H)-one (3)

Yellow solid, mp 154-156 °C, IR (KBr) (ν_max/ cm^-1): 3240, 3174, 3043, 2954, 1690, 1523, 1488, 1400, 1280.6, 1149.5, 1072.3, 810, 717.5, and 524.6. ¹H-NMR (250 MHz, DMSO-d₆): δ 0.96 (s, 6H), 1.16 (s, 2H), 2.47 (s, 2H), 2.99 (d, J = 2.5 Hz, 2H), 3.5 (s, 1H), 5.26 (t, J = 2.5 Hz, 1H), 7.10-7.14 (m, 2H), 7.48-7.53 (m, 2H). ¹³C-NMR (62.9 MHz, DMSO-d₆): δ 17.1, 27.8, 32.2, 41.9, 50.0, 97.3, 111.2, 115.8, 124.5, 131.9, 138.6, 159.3, 181.6, 195.6. Anal. Calcd. for C₁₇H₁₈BrNO₂ (348.23): C 58.63; H 5.21, N 4.02, found: C 58.58; H 5.26; N 3.96. MS: m/z (%) = 348.23 (M⁺), 329 (1), 295 (34.2), 239 (59.7), 173 (10.6), 157 (17.1), 130 (32.3), 91 (15.7),  68 (37.8), 57 (100).

2-Amino-1-benzyl-7,8-dihydroquinolin-5(1H,4H,6H)-one (4)

White solid, mp 194.2-196 °C, IR (KBr) (ν_max/ cm^-1): 3475.5, 3244, 3058, 2935.5, 1725, 1558.4, 1454.2, 1377.1, 1203.5, 1072.3, 941.2, and 594. ¹H-NMR (250 MHz, DMSO-d₆): δ 1.77-1.82 (m, 4H), 2.48 (m, J = 2.5 Hz, 2H), 3.74 (t, J = 2.5 Hz, 2H), 4.5 (s, 2H), 4.75 (d, J = 2.5 Hz, 2H), 5.46 (t, J = 2.5 Hz, 1H), 7.24-7.50 (m, 5H). ¹³C-NMR (62.9 MHz, DMSO-d₆): δ 20.2, 21.3, 31.4, 43.1, 46.1, 75.2, 107.3, 127.7, 128.1, 128.6, 143.8, 145.1, 170.6, 197.5. Anal. Calcd. for C₁₆H₁₈N₂O(254.14): C 75.56; H 7.13; N 11.01, found: C 75.50; H 7.18; N 10.54. MS: m/z (%) = 254.14 (M⁺), 237 (4.7), 194 (4.2), 152 (3.8), 123 (5.9), 106 (20.1), 79 (50.3), 57 (100).

1-(4-Nitrophenylamino)-2-amino-7,8-dihydro-7,7-dimethylquinolin-5(1H,4H,6H)-one (5)

Orange solid, mp 114-116 °C, IR (KBr) (ν_max/ cm^-1): 3321.2, 2931.6, 2326, 1715, 1604.7, 1473.5, 1253.6, 1107.1, 1037.6, 837, 748.3, 690.5, and 524.6. ¹H-NMR (250 MHz, DMSO-d₆): δ 1.92 (s, 6H), 1.97 (s, 2H), 2.07 (s, 2H), 2.48 (s, 2H), 3.86 (d, J = 2.5 Hz, 2H), 4.46 (t, J = 2.5 Hz, 1H), 7.09 (d, J = 10 Hz, 2H), 8.02 (d, J = 10 Hz, 2H), 9.76 (s, 1H). ¹³C-NMR (62.9 MHz, DMSO-d₆): δ 22.0, 31.2, 34.9, 43.7, 52.4, 94.0, 108.2, 116.4, 125.0, 141.3, 148.5, 150.0, 152.9, 199.8. Anal. Calcd. for C₁₇H₂₀N₄O₃ (328.15): C 62.18; H 6.14; N 17.06, found: C 62.25; H 6.20; N 17.00.

1-Benzyl-7,8-dihydro-2-hydroxy-7,7-dimethylquinolin-5(1H, 4H, 6H)-one (6)

Yellow solid, mp 140-142 °C, IR (KBr) (ν_max/ cm^-1): 3440, 3003, 2944, 1705, 1520, 1456, 1301, 1284, 1149.5, 1072.3, 820, 717.4, and 534.6. ¹H-NMR (250 MHz, DMSO-d₆): δ 1.31 (s, 6H), 1.88 (s, 2H), 2.46 (s, 2H), 3.34 (s, 1H), 3.35 (s, 2H), 3.37 (d, J = 2.5 Hz, 2H), 5.99 (t, J = 2.5 Hz, 1H), 7.23-7.49 (m, 5H). ¹³C-NMR (62.9 MHz, DMSO-d₆): δ 20.1, 26.9, 28.9, 45.6, 48.3, 50.7, 75.2, 108.0, 128.5, 128.8, 138.7, 141.1, 151.7, 178.2, 184.4. Anal. Calcd. for C₁₈H₂₁NO₂ (283.16): C  76.29;  H 7.47; N 4.94, found: C 76.23; H 7.52; N 4.88.

7,8-Dihydro-2-hydroxy-7,7-dimethyl-1-(4-nitrophenyl)quinolin-5(1H,4H,6H)-one (7)

Yellow solid, mp 104-106 °C, IR (KBr) (ν_max/ cm^-1): 3479.3, 3359.8, 2954.7, 1623.9, 1600, 1442.7, 1307.6, 1222.8, 1110.9, 979.8, 817.8, 752.2, 698.2, and 532.6. ¹H-NMR (250 MHz, DMSO-d₆): δ 0.96 (s, 6H), 2.10 (s, 2H), 2.23 (s, 2H), 3.35 (s, 1H), 3.86 (d, J = 2.5 Hz, 2H), 4.99 (t, J = 2.5 Hz, 1H), 6.54-6.61 (m, 2H), 7.89-7.94 (m, 2H). ¹³C-NMR (62.9 MHz, DMSO-d₆): δ 14.9, 27.8, 32.1, 41.9, 50.2, 63.9, 112.3, 120.3, 126.3, 135.5, 146.2, 155.6, 179.6, 196.6. Anal. Calcd. for C₁₇H₁₈N₂O₄ (314.13): C 64.96; H 5.77; N 8.91, found: C 64.90; H 5.83; N 8.86. MS: m/z (%) = 314.13 (M⁺), 307 (22.5), 249 (16.5), 232 (19.7), 132 (18.1), 105 (10.7), 86 (53.2), 56 (100).

7,8-Dihydro-2-hydroxy-7,7-dimethyl-1-(7H-purin-6-yl)quinolin-5(1H,4H,6H)-one (8)

White solid. mp 309 °C (decomposed), IR (KBr) (ν_max/ cm^-1): 3571.9, 3136, 2912.3, 2842.6, 1701, 1600.8, 1411.8, 1303.8, 1238.2, 1080.1, 948.9, 717.5, 636.5, and 505.3. ¹H-NMR (250 MHz, DMSO-d₆): δ 0.8 (s, 6H), 1.15 (s, 2H), 1.19 (s, 2H), 2.40 (d, J = 3 Hz, 2H), 3.44 (t, J = 2.5 Hz, 1H), 5.50 (s, 1H), 8.06 (s, 1H), 8.28 (s, 1H). ¹³C-NMR (62.9 MHz, DMSO-d₆): δ 22.0, 28.9, 31.2, 56.0, 59.5, 69.3, 116.4, 125.5, 141.3, 148.5, 150.0, 152.9, 170.7, 186.4, 199.8. Anal. Calcd for C₁₆H₁₇N₅O₂ (311.14): C 61.72; H 5.50; N 22.49, found: C 61.66; H  5.55; N 22.42. MS: m/z (%) = 311.14 (M⁺), 246 (19.1), 215 (43.5), 172 (55.7), 131 (15.1), 89 (22.2), 57 (100).

7,8-Dihydro-2-hydroxy-7,7-dimethyl-1-phenylquinolin-5(1H,4H,6H)-one (9)

Yellow solid, mp 80-82 °C, IR (KBr) (ν_max/ cm^-1): 3340, 3003, 2944, 1732, 1511, 1466, 1371, 1246, 1199, 1072.3, 717.4, and 534.6. ¹H-NMR (250 MHz, CDCl₃): δ 1.07 (s, 6H), 1.25 (s, 2H), 1.34 (s, 2H), 2.22 (d, J = 2.5 Hz, 2H), 4.04 (s, 1H), 5.42 (t, J = 2.5 Hz, 1H), 6.68-6.79 (m, 3H), 7.12-7.19 (m, 2H). ¹³C-NMR (62.9 MHz, CDCl₃): δ 14.1, 29.7, 32.4, 42.9, 50.6, 64.3, 101.4, 115.1, 118.4, 123.9, 129.2, 146.5, 176.5, 199.9. Anal. Calcd. for C₁₇H₁₉NO₂ (269.14): C 75.81; H 7.11; N  5.20,  found: C 75.76; H 7.17; N 5.14.

2-Amino-7,8-dihydro-1- (2-hydroxyphenyl) -7, 7-dimethylquinolin- 5 (1H,4H,6H)-one (10)

White solid, mp 214-216 °C, F IR (KBr) (ν_max/ cm^-1): 3232.5, 3066.6, 2950.9, 2727.1, 1700, 1562.2, 1519.8, 1454.2, 1373.2, 1245.9, 1149.5, 813.9, and 767.6. ¹H-NMR (250 MHz, DMSO-d₆): δ 0.99 (s, 6H), 1.98 (s, 2H), 2.33 (s, 2H), 2.58 (s, 1H), 3.98 (d, J = 2.5 Hz, 2H), 5.44 (t, J = 2.5 Hz, 1H), 6.75-7.07 (m, 4H), 9.61 (s, 1H). ¹³C-NMR (62.9 MHz, DMSO-d₆): δ 16.3, 28.2, 32.6, 41.8, 50.4, 96.3, 116.5, 119.2, 125.9, 127.1, 127.2, 138.1, 142.8, 151.8, 162.3, 194.9. Anal. Calcd for C₁₇H₂₀N₂O₂ (284.15): C 71.81; H 7.09; N 9.85, found: C 71.75; H 7.15; N 9.80.

2-Amino-7,8-dihydro-1-(4-methoxyphenyl)-7,7-dimethylquinolin-5(1H,4H,6H) -one (11)

Yellow solid, mp 177-179 °C, IR (KBr) (ν_max/ cm^-1): 3400, 3205.5, 2831.3, 1690, 1542.9, 1458.1, 1369.4, 1242.1, 1149.5, 1033.8, 806.2, and 563.2. ¹H-NMR (250 MHz, DMSO-d₆): δ 1.08 (s, 6H), 2.19 (s, 2H), 2.31 (s, 2H), 2.52 (s, 2H), 3.47 (s, 3H), 4.09 (d, J = 2.5 Hz, 2H), 5.37 (t, J = 2.5 Hz, 1H), 6.82-6.86 (m, 2H), 7.04-7.08 (m, 2H). ¹³C-NMR (62.9 MHz, DMSO-d₆): δ 24.9, 27.9, 34.9, 44.1, 52.3, 52.5, 85.4, 110.4, 119.8, 122.4, 133.9, 140.7, 144.7, 194.2. Anal. Calcd. for C₁₈H₂₂N₂O₂ (298.17): C 72.46; H 7.43; N 9.39, found: C 72.50; H 7.52; N 9.30.

7-amino-8-(4-bromophenyl)pyrido[2,3-d]0dine-2,4(1H,3H,5H,8H)-dione (12)

Yellow solid, mp 245-247 °C, F IR (KBr) (ν_max/ cm^-1): 3313.2, 3047.3, 2904.6, 1697.2, 1508.2, 1485.1, 1180.2, 813.9, 682.8, 567, and 486. ¹H-NMR (250 MHz, DMSO-d₆): δ 2.48 (s, 2H), 4.31 (d, J = 2.5 Hz, 2H), 4.74 (t, J = 2.5 Hz, 1H), 7.09-7.17 (m, 2H), 7.46-7.59 (m, 3H), 11.11 (s, 1H). ¹³C-NMR (62.9 MHz, DMSO-d₆): δ 20.7, 89.7, 97.2, 118.0, 123.5, 132.4, 134.4, 137.9, 144.9, 151.6, 167.7. Anal. Calcd. for C₁₃H₁₁BrN₄O₂ (334.01): C 46.59; H 3.31; N 16.72, found: C 46.53; H 3.37; N. 16.68. MS: m/z (%) = 335.01 (M⁺), 314 (23.1), 226 (23.1), 172 (16.6), 137 (25.1), 107 (25.5), 83 (53.2), 57 (100).

7-Amino-8-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H,5H,8H)-dione (13)

Yellow solid, mp 223-225 °C, IR (KBr) (ν_max/ cm^-1): 3300.2, 3117.3, 2904.6, 1720, 1528.2, 1325.1, 1180.2, 713.9, 682.8, and 476. ¹H-NMR (250 MHz, DMSO-d₆): δ 2.48 (s, 2H), 3.45 (s, 3H), 4.31 (d, J = 2.5 Hz, 2H), 4.74 (t, J = 2.5 Hz, 1H), 7.09-7.66 (m, 5H), 10.69 (s, 1H). ¹³C-NMR (62.9 MHz, DMSO-d₆): δ 22.0, 55.9, 77.4, 81.4, 112.4, 116.4, 125.5, 141.3, 148.5, 150.0, 152.9, 161.3. Anal. Calcd. for C₁₄H₁₄N₄O₃ (286.11): C 58.73; H 4.93; N 19.57, found: C 58.67; H 4.99; N 19.53.

2-Amino-7,8-dihydro-1-(3-hydroxyphenyl)-7,7-dimethylquinolin-5(1H,4H,6H)-one (14)

Pink solid, mp 162-164 °C, IR (KBr) (ν_max/ cm^-1): 3224.8, 3058.9, 2962.4, 1568, 1481.2, 1388.7, 1265.2, 1153.4, 991.3, 852.5, and 767.6. ¹H-NMR (250 MHz, DMSO-d₆): δ 0.99 (s, 6H), 2.03 (s, 2H), 2.33 (s, 2H), 2.47 (s, 2H), 3.46 (d, J = 2.5 Hz, 2H), 4.75 (t, J = 2.5 Hz, 1H), 6.44-6.60 (m, 3H), 7.1 (t, J = 7.5 Hz, 1H), 9.5 (s, 1H). ¹³C-NMR (62.9 MHz, DMSO-d₆): δ 19.0, 33.1, 37.4, 47.2, 55.2, 93.1, 102.1, 109.0, 114.7, 116.6, 118.6, 135.0, 145.3, 163.1, 165.3,  200.7. Anal. Calcd. for C₁₇H₂₀N₂O₂ (284.35): C  71.81; H  7.09; N 9.85, found: C  71.75; H 7.14; N 9.79. MS: m/z (%) = 284.35 (M⁺), 232 (33.8), 216 (28.1), 175 (38.3), 133 (42.1), 109 (18.1), 83 (18), 57 (100).

2-Amino-1-(4-bromophenyl)-7,8-dihydro-7,7-dimethylquinolin-5(1H,4H,6H)-one (15)

Light green solid, mp 190-192 °C, IR (KBr) (ν_max/ cm^-1): 3213.2, 3039.6, 2869.9, 1589.2, 1538.4, 1485.1, 1404.1, 1245.9, 1122.5, 1006.8, 813.9, 682.8, 567, and 486. ¹H-NMR (250 MHz, DMSO-d₆): δ 1.00 (s, 6H), 2.18 (s, 2H), 2.24 (s, 2H), 2.37 (s, 2H), 4.15 (d, J = 2.5 Hz, 2H), 5.17 (t, J = 2.5 Hz, 1H), 7.06-7.20 (m, 2H), 7.45-7.60 (m, 2H). ¹³C-NMR (62.9 MHz, DMSO-d₆): δ 17.0, 27.7, 32.2, 41.9, 50.0, 97.2, 111.2, 115.8, 124.5, 131.9, 138.6, 159.1, 159.3, 195.6. Anal. Calcd. for C₁₇H₁₉BrN₂O (347.25): C 58.80; H 5.52; N 8.07, found: C 58.85; H 5.60; N 8.11. MS: m/z (%) = 347.25 (M⁺), 295 (38.8), 239 (49), 210 (11), 172 (60.3), 130 (39.5), 107 (40.5), 91 (53), 68 (55), 57 (100).

2-Amino-1-benzyl-7,8-dihydro-7,7-dimethylquinolin-5(1H,4H,6H)-one (16)

White solid, mp 259-261 °C, IR (KBr) (ν_max/ cm^-1): 3440, 3178.2, 2935.5, 1720.3, 1533, 1265.2, 1391.8, 1300, 1257.5, 1153.4, 1080.1, 971, and 850. ¹H-NMR (250 MHz, DMSO-d₆): δ 0.96 (s, 6H), 2.47 (s, 2H), 2.48 (s, 2H), 3.25 (s, 2H), 4.22 (d, J = 2.5 Hz, 2H), 5.22 (t, J = 2.5 Hz, 1H), 5.5 (s, 2H), 7.21-7.55 (m, 5H). ¹³C-NMR (62.9 MHz, DMSO-d₆): δ 14.5, 26.8, 32.0, 41.9, 42.7, 46.2, 84.5, 117.5, 127.4, 127.5, 128.2, 134.4, 136.4, 158.4, 184.4. Anal. Calcd. for C₁₈H₂₂N₂O (282.17): C 76.56; H 7.85; N 9.92, found: C 76.50; H 7.89; N 9.87.

2-Amino-7,8-dihydro-7,7-dimethyl-1-(4-nitrophenyl)quinolin-5(1H,4H,6H)-one (17)

Yellow solid, mp 228-230 °C, IR (KBr) (ν_max/ cm^-1): 3380.3, 3190.5, 3078.2, 2935.5, 1690.2, 1523.7, 1492.8, 1346.2, 1257.5, 1153.4, 1080.1, 979.8, and 894.9. ¹H-NMR (250 MHz, DMSO-d₆): δ 1.02 (s, 6H), 2.15 (s, 2H), 2.45 (s, 2H), 2.98 (s, 2H), 3.52 (d, J = 2.5 Hz, 2H), 5.56 (t, J = 2.5 Hz, 1H), 7.36 (d, J = 7.5 Hz, 2H), 8.26 (d, J = 7.5 Hz, 2H). ¹³C-NMR (62.9 MHz, DMSO-d₆): δ 18.4, 27.6, 32.3, 41.9, 49.1, 100.3, 112.3, 120.9, 124.8, 142.1, 145.6, 156.9, 159.7, 195.9. Anal. Calcd. for C₁₇H₁₉N₃O₃ (313.25): C 65.16; H 6.11; N 13.41, found: C 65.10; H 6.18; N 13.36. MS: m/z (%) =313.25 (M⁺), 236 (19.7), 147 (10.2), 129 (13.6), 109 (22.1), 83 (51.4), 57 (100).

4-(4-Chlorophenyl)-7,8-dihydro-7,7-dimethyl-2-(thiophen-2-yl)quinolin-5(1H,4H,6H)-one (18)

Yellow solid, mp 213-215 °C, IR (KBr) (ν_max/ cm^-1): 3277, 3028, 2924, 2874, 1681, 1647, 1581, 1487, 1444, 1406, and 1300. ¹H-NMR (250 MHz, DMSO-d₆): δ 1.08 (s, 3H), 1.10 (s, 3H), 2.05-2.21 (m, 2H), 2.39 (s, 2H), 4.59-4.61 (d, 1H), 5.21-5.23 (d, 1H), 6.92-6.94 (d, J = 8.6 Hz, 2H), 7.23-7.25 (d, J = 8. 08 Hz, 2H), 7.00-7.02 (m, 1H), 7.13-7.17 (m, 1H), 7.33-7.34 (m, 1H), 8.40 (s, 1H).

7,8-Dihydro-4-(4-methoxyphenyl)-7,7-dimethyl-2-(thiophen-2-yl)quinolin-5(1H,4H,6H)-one (19)

Yellow solid, mp 190-192 °C, IR (KBr) (ν_max/ cm^-1): 3255, 3061, 2955, 1653, 1577, 1498, 1477, and 1388. ¹H-NMR (250 MHz, DMSO-d₆): δ 1.0 (s, 3H), 1.08 (s, 3H), 2.04-2.21 (m, 2H), 2.47 (s, 2H), 3.75 (s, 1H), 4.52-4.53 (d, 1H), 5.21-5.23 (d, 1H), 6.76-6.78 (d,  J = 7.92 Hz, 2H), 7.23-7.25 (d,  J = 8.56 Hz, 2H), 7.00-7.02 (m, 1H), 7.15-7.17 (m, 1H), 7.33-7.34 (t, 1H), 8.42 (s, 1H).

7,8-Dihydro-4-(4-hydroxyphenyl)-7,7-dimethyl-2-(thiophen-2-yl)quinolin-5(1H,4H,6H)-one (20)

Yellow solid, mp 208-210 °C, Lit. mp 212-214 °C.

7,8-dihydro-4-(3-hydroxyphenyl)-7,7-dimethyl-2-(thiophen-2-yl)quinolin-5(1H,4H,6H)-one (21)

Yellow solid, mp 207-209 °C, Lit. mp 203-205 °C.

General procedure for Michael addition reaction using NCTDSS as catalyst

A mixture of Michael-donors (1 mmol), activated olefins (1.5 mmol) and NCTDSS (0.05 g, 5 mol%) in ethanol was kept at 78 °C in an oil bath for the stipulated time. The progress of the reaction was monitored by TLC. After the reaction completion, the mixture was washed with ethyl acetate (10 mL) and the crude product was obtained after removing ethyl acetate from the washing solution. Further purification was carried out by recrystallization from ethyl acetate/petroleum ether or short column chromatography on silica gel (ethyl acetate/petroleum ether).

3-(4,4-Dimethyl-2,6-dioxocyclohexyl)propanenitrile (22)

Oil, IR (KBr) (ν_max/ cm^-1): 2962.4, 1731.9, 1461.9, 1357.8, 1222.8, 1145.6, 1654.8, 1037.6, 871.8, 829.3, and 597.9. ¹H-NMR (250 MHz, CDCl₃): δ 1.00 (s, 6H), 1.14-1.32 (m, 2H), 2.13 (s, 2H), 2.20 (s, 2H), 3.82 (q, 2H), 4.11 (t, J = 7.5 Hz, 1H). ¹³C-NMR (62.9 MHz, CDCl₃): δ 14.0, 22.6, 28.2, 32.4, 50.6, 64.1, 121.3, 199.5. MS: m/z (%) = 193.2 (M⁺), 185 (2.6), 149 (35.1), 129 (15.4), 97 (26.3), 73 (51.3), 57 (100).

Methyl 3-(4,4-dimethyl-2,6-dioxocyclohexyl)propanoate (23)

Oil, IR (KBr) (ν_max/ cm^-1): 2962.4, 2873.7, 2341.4, 1651, 1489.7, 1222.8, 1145.6, 1033.8, 852.5, 632.6, 613.3, and 420.5. ¹H-NMR (250 MHz, CDCl₃): δ 1.13 (s, 6H), 1.40 (t, J = 5 Hz, 2H), 2.27 (s, 2H), 2.33 (s, 2H), 3.87-3.98 (m, 2H), 4.03 (t, J = 7.5 Hz, 1H), 4.24 (s, 3H). ¹³C-NMR (62.9 MHz, CDCl₃): δ 14.0, 28.2, 32.4, 42.8, 50.6, 64.1, 101.4, 176.1, 199.5. MS: m/z (%) = 226.3 (M⁺), 166 (17.8), 149 (52.7), 123 (15.4), 85 (27.5), 57 (100).

3-(2,6-Dioxocyclohexyl)propanenitril (24)

Oil, IR (KBr) (ν_max/ cm^-1): 2900, 2850.1, 1710, 1621, 1489.1, 1149.5, and 1011.9. MS: m/z (%) = 165.2 (M⁺), 143 (100), 115 (37.1), 87 (24.9), 55 (38.8).

3-(Hexahydro-2,4,6-trioxopyrimidin-5-yl)propanenitrile (25)

Viscouse Oil, IR (KBr) (ν_max/ cm^-1): 3350, 2910, 2870.1, 1720, 1650, 1559.1, 1229.5, and 1101.9.

3-(Pyrrolidin-1-yl)propanenitrile (26)

Oil, ¹H-NMR (250 MHz, CDCl₃): δ 1.10 (m, 4H), 2.55 (m, 2H), 2.65 (m, 2H), 2.70 (m, 4H) [18].

3-(Diethylamino)propanenitrile (27)

Oil. ¹H-NMR (250 MHz, CDCl₃): δ 1.70 (m, 6H), 2.55 (m, 2H), 2.71 (m, 6H).

3-(Benzylamino)propanenitrile (28)

Oil, ¹H-NMR (250 MHz, CDCl₃): δ 2.52 (t, J = 2.2 Hz, 2H), 2.83 (t, J = 2.2 Hz, 2H), 3.83 (s, 2H), 7.26-7.34 (m, 5H).

3-(Diisopropylamino)propanenitrile (29)

Oil, ¹H-NMR (250 MHz, CDCl₃): δ 2.30-2.75 (m, 4H), 3.8 (s, 2H), 7.2-7.4 (m, 5H).

3-(Piperazin-1-yl) propanenitrile (30)

Oil, IR (KBr) (ν_max/ cm^-1): 3401, 2850.1,  1619, 1479.1, 1249.5, and 1211.9 [19].

3-(4-Methylpiperazin-1-yl)propanenitrile (31)

White solid, mp 90-92 °C, ¹H-NMR (250 MHz, CDCl₃): δ 2.26 (t, J = 2.7 Hz, 3H), 2.48 (t, J = 2.2 Hz, 8H), 2.67 (s, 2H), 8.22 (s, 1H).

Ethyl-2-nitro-5-oxohexanoate (32)

Oil, ¹H-NMR (250 MHz, CDCl₃): δ 1.25 (t, J = 5, 3H), 2.07 (s, 3H), 2.30-2.39 (m, 2H), 2.53-2.59 (m, 2H), 4.16-4.28 (m, 2H), 5.18 (t, J = 7.5 Hz 1H). ¹³C-NMR (62.9 MHz, CDCl₃): δ 13.6, 24.1, 29.6, 38.4, 63.0, 86.7, 164.3, 206.1.

Ethyl-2-nitro-2-(3-oxocyclohexyl)acetate (33)

Oil, ¹H-NMR (250 MHz, CDCl₃): δ 1.27 (t, J = 2.5 Hz, 3H), 1.81-2.42 (m, 9H), 4.20-5.01 (m, 2H), 6.08 (d, J = 2.5 Hz, 1H). ¹³C-NMR (62.9 MHz, CDCl₃): δ 13.6, 24.1, 29.6, 38.4, 63.0, 86.7, 164.3, 206.1.

1-Ethyl-5-methyl-2-(phenylcarbonyl)pentanedioate (34)

Oil, IR (KBr) (ν_max/ cm^-1): 3010, 2881, 1720.3, 1329.1, 1233.5, and 1211.9 [20].

Methyl 1-(2-cyanoethyl)-2-oxocyclopentanecarboxylate (35)

Oil, IR (KBr) (ν_max/ cm^-1): 2950.1, 2825,  1629, 1429, 1241.2, and 1213.2.

Ethyl 1-(2-(methoxycarbonyl)ethyl)-2-oxocyclopentanecarboxylate (36)

Oil, IR (KBr) (ν_max/ cm^-1): 3005.5, 2850.1, 1699.1, 1523.3, 1441.4, and 1256.7.

4-Acetyl-5-oxohexanenitrile (37)

Oil, MS: m/z (%) = 153.2 (M⁺), 105 (68.2), 87 (100), 57 (70.8).

3-(Phenylamino)propanenitrile (38)

Viscous oil, ¹H-NMR (250 MHz,CDCl₃): δ 2.57 (t, J = 2.2 Hz, 2H,), 3.46 (dd, J = 2.0 Hz, J =1.9 Hz, 2H), 3.99 (s, 1H), 6.58-7.22 (m, 5H) [21].

3-(p-Toluidino)propanenitrile (39)

Yellow solid, mp 100-102 °C, ¹H-NMR (250MHz, CDCl₃): δ 2.25 (s, 3H), 2.63 (t, J = 2.1 Hz, 2H), 3.51 (t, 2H, J = 2.1 Hz), 3.84 (s, 1H), 6.56 (d, J = 2.8 Hz, 2H), 7.03 (d, J = 2.7 Hz, 2H).

3-(4 -Methoxyphenylamino)propanenitrile (40)

Viscous oil, ¹H-NMR (250 MHz, CDCl₃): δ 2.52 (t, J = 2.2 Hz, 4H), 3.59 (t, J = 2.2 Hz, 4H), 3.79 (s, 3H), 6.81-6.91 (m, 5H) .

3-(4-Chlorophenylamino)propanenitrile (41)

Viscous oil, ¹H-NMR (250MHz, CDCl₃): δ 2.64 (t, J = 2.2 Hz, 2H), 3.50 (t, J = 2.2 Hz, 2H), 4.00 (s, 1H), 6.53-7.18 (m, 5H).

Results and Discussion

In our initial study, barbituric acid and acrylonitril were dissolved in hot ethanol and in the presence of 5 mol% of NCTDSS. After 20 min, the primary amines were added to the mixture refluxed for fitting time. The corresponding compounds were obtained as a white solid with 81, 83% isolated yield (Table 1, entries 12, 13).

Under the above conditions, the reaction of 3-(4,4-dimethyl-2,6-dioxocycyclohexyl) propanenitrile and primary amines were yielded the corresponding hydroquinoline products with 89, 92, 90, 94, 95, 91, 95 and 90% isolated yield, respectively (Table 1, entries 1, 5, 10,11, 14-17). To further expand our strategy, a new functionalized hydroquinolines was synthesized based on our recent procedure, as represented in Table 1. Since antiviral drugs based on quinolines almost contain a hydroxy and ether chain, we decided to synthesize a category of heterocyclic quinolines. To determine the scope of this protocol, various hydroquinoline derivatives were synthesized under the normalized conditions, and the results are summarized in Table 1.

Table 1. Products of one-pot condensation reaction to synthesize of dihydroquinolines in the NCTDSS presence as catalyst under reflux conditions

^acatalyst (5 mol% NCTDSS), EtOH (5 mL), and reflux

^bAll yields are isolated

The syntheses of twenty-one compounds occupy a special position among systems containing dihydroquinoline and dihydropyridine rings due to their wide spectrum biological activities.

As listed in Table 1, the generality of this protocol was highlighted by using amines with both electron withdrawing and electron donating groups under the same reaction conditions. Also, we synthesized these products by both aliphatic and aromatic amines in good yields. According to Table 1, for all entries, the reactions were performed in almost same reaction time and the products were obtained with ranging from 81-95% isolated yields. Likewise, cyclohexadione acted as same as dimedone in the designed condensation reaction and the corresponding products were generated with excellent yield (Table 1, entry 4). The structural diversity of this reaction was further increased by using as amine component, leading to the formation of new nucleoside derivative with hydroquinoline moiety (Table 1, entry 8). According to the Table 1, in all cases, the reactions were accomplished in relatively short reaction time and products were obtained with good to excellent yields (more than 81%).

The proposed mechanism involves Michael addition reaction of 5,5-dimethyl-1,3-cyclo-hexanedione (dimedone) reacted with acrylonitrileto give the addition product A. Then, the intermediate upon condensation with primary amines, afford the intermediate B. Cyclization takes place by the nucleophilic attack of amine (NH₂) group on the CN group to give the intermediate C, which loses hydrogen to give the dihydroquinolines D followed by intramolecular cyclization and aromatization (Scheme 1).

Mechanism

The synthesis of entries 18-21 were achieved by reflux assisted one pot reaction of 5,5-dimethylcyclohexane-1,3-dione (dimedone) with 3-phenyl-1 (thiophen-2-yl) pop-2-en-1-one derivatives, respectively in the presence of excess amounts of ammonium acetate (Scheme 2).

Scheme 1. Michael addition reaction for the synthesis of dihydroquinolines derivative

Scheme 2. Synthesis of dihydroquinoline derivatives in the presence of ammonium acetate

To sum up, this research describes an efficient one pot access to a new class of heterocyclic dihydroquinoline analogs having quinoline or pyrimidine-fused ring in their structural frameworks. To obtain these categories of heterocyclic compounds, amine component corporate in the structure of obtained molecule by a C-N linkage. This protocol is general for a wide range of amines and carbonyl compounds. The biological activity of some synthesized compounds is under assessment and will be report in future.

In another part of this study, we also synthesized Michael addition products by using different donors and acceptors. These products were synthesized by NCTDSS as a catalyst to obtain compounds 1-21.

The Michael addition is widely identified as one of the most substantial bond-forming reactions in organic synthesis ‎[20].‎ This type of reaction is generally administrated by using strong base metal reagents in organic solvents such as THF, DMF, and DMSO under dry conditions ‎[19].‎

To affirm the feasibility of our catalyst design concept, we prepared a variety of products, starting from commercially available cyclohexadiones and amino derivatives with different functional groups. Then, the catalytic (NCTDSS) studies of the Michael addition reaction were performed in ethanol at the reflux conditions. The results are summarized in Table 2.

Table 2. Michael addition reaction^a

^aReactions carried out at reflux condition, using donor (1 mmol), acceptor (1.5 mmol), and catalyst  (5 mol %) in EtOH (5 mL)

^bIsolated yield

Conclusions

Our protocol avoids utilizing expensive reagents and high temperatures, and the catalyst can be recovered. Additional applications are currently under investigation ‎[22].‎ A variety of structurally diverse α,β–unsaturated carbonyl compounds underwent Michael additions smoothly in the NCTDSS presence to generate the corresponding compounds in good yields. Generally, the reactivity decreased with electron withdrawing groups of donor (Table 2) and electron donating groups of acceptor. Apart from acrylonitrile, methyl acrylate, but-3-en-2-one and cyclohex-2-enone can be further the substrates of this reaction to afford the desired products in good yields and in short reaction times. Dimedone showed higher reactivity than barbituric acid. Diisopropyl amine revealed rather lower reactivity because of the strong steric hindrance. The ethyl 3-oxo-3-phenylpropanoate examined underwent Michael addition with methyl acrylate favorably and corresponding product could be obtained in good yields in much more slowly reaction times. In addition, five-membered N-heterocycles exhibited a high reactivity (Table 2).

Disclosure Statement

No potential conflict of interest was reported by the authors.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors' contributions

All authors contributed to data analysis, drafting, and revising of the paper and agreed to be responsible for all the aspects of this work.

Orcid

Saghar Mowlazadeh Haghighi  0000-0002-7018-6539

Azar Purkhosrow  0000-0003-2399-6878

Ali Khalafi-Nezhad  0000-0002-8502-8752

Somayeh Oftadehgan  0000-0001-7449-5411

How to cite this manuscript: Saghar Mowlazadeh Haghighi, Azar Purkhosrow, Ali Khalafi-Nezhad, Somayeh Oftadehgan*. One pot synthesis of heterocyclic dihydroquinoline analogs incorporating quinoline and pyrimidine fused rings in condensation reaction using NCTDSS as a catalyst. Asian Journal of Green Chemistry, 6(3) 2022, 203-222.  DOI: 10.22034/ajgc.2022.3.3