Introduction

The multi-component reactions (MCRs) are of considerable interest in organic synthesis since they provide a rapid access to the important structures, resembling natural products and drugs [1–4]. The advantageous features of this strategy in the facile preparation of privileged structures involve the atom economy, convergent character, diversity-generating potential and formation of several bonds in a single step. Therefore, this strategy has been widely employed by different research groups for the one-pot construction of versatile nitrogen-containing polycyclic skeletons [5–10].

Nitrogen-containing multi-cyclic compounds are interesting scaffolds because of their potential in exhibiting a wide array of bioactivities like DNA intercalators, antiplasmodial, antineoplastic, anticancer and antibacterial [11–17]. Chromenoquinoline, an important subclass of nitrogen-containing heterocycles, has shown promising activities [18–20] like anti-inflammatory, anticancer, glucocorticoid modulators, progesterone and 5-HT receptor antagonist [21–25]. These significant bioactivities are also reflected in ongoing efforts of synthetic chemists to prepare structurally different chromenoquinolines with hopes to find new therapeutically active compounds [26–36]. In this context, developing efficient and simple pathways for the synthesis of such an important framework from commercially available starting materials is a desirable challenge. Despite the effectiveness of these methods, in most of these approaches catalytic systems or synthesized starting materials have to be employed. Thereafter, we decided to examine the new pathway toward chromenoquinolines from readily available starting materials and under catalyst-free condition. In continuation of our program to develop new and efficient methods for the synthesis of heterocyclic compounds [37–43], herein, we envisaged a simple, four-component reaction for the synthesis of 10,11-dihydro-10,10-dimethyl-7-substituted-7H-chromeno[4,3-b]quinoline-6,8(9H,12H)-diones in moderate to good yields.

Experimental

Melting points were taken on a Kofler hot-stage apparatus and are uncorrected. 1H- and 13C-NMR spectrum was recorded on Bruker FT-500, using TMS as an internal standard. The elemental analysis was performed with an Elementar Analysen system GmbH VarioEL CHNS mode. Mass spectra were determined on an Agilent Technology (HP) mass spectrometer operating at an ionization potential of 70 eV. All reagents and solvents were purchased from Aldrich and Merck and used without any purification.

General procedure for the synthesis of chromeno[4,3-b]quinoline 5a-j

A mixture of 4-hydroxy coumarin (1 mmol) and 28–30% ammonia solution (5 mmol) in n-PrOH (5 mL) was refluxed for 1 h. Then, aldehyde (1 mmol) and dimedone (1 mmol) were added, and the reaction was continued at reflux temperature for another 11 h. After this time, the reaction was cooled down to room temperature. The residue was purified by column chromatography (petroleum ether/ethyl acetate 10:1).

10,11-Dihydro-10,10-dimethyl-7-phenyl-7H-chromeno[4,3-b]quinoline-6,8(9H,12H)-dione (5a)

Pale-yellow powder (0.28 g, 76%). Mp (°C): 290–291.36 IR (KBr) 3213, 3072, 1704, 1630, 1599, 1471, 1360, 1194, 1145, 1023, 738, 694. 1H NMR (500 MHz, DMSO-d 6): δ (ppm) 9.70 (s, NH), 8.30 (dd, J = 7.5, 1.0 Hz, 1H), 7.62 (dt, J = 7.5, 1.0 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.25 (d, J = 7.5 Hz, 2H), 7.21 (t, J = 8.0 Hz, 2H), 7.10 (t, J = 7.0 Hz, 1H), 4.97 (s, 1H), 2.67 (s, 2H), 2.27 (d, J = 16.5 Hz, 1H), 2.10 (d, J = 16.5 Hz, 1H), 1.08 (s, 3H), 0.95 (s, 3H). 13C NMR (125 MHz, DMSO-d 6): δ (ppm) 194.5, 160.1, 152.0, 149.5, 145.7, 142.0, 131.8, 127.6, 126.1, 123.8, 122.8, 116.8, 116.6, 112.9, 110.8, 101.8, 50.1, 34.3, 32.0, 28.9, 26.5. Anal. Calcd. for C24H21NO3: C, 77.61; H, 5.70; N, 3.77. Found: C, 77.53; H, 5.62; N, 3.89. MS: m/z (%) = 371 ([M]+, 20), 294 (100), 238 (11), 210 (15), 97 (12), 57 (21), 43 (19).

10,11-Dihydro-7-(3-hydroxyphenyl)-10,10-dimethyl-7H-chromeno[4,3-b]quinoline-6,8(9H,12H)-dione (5b)

Pale-yellow powder (0.27 g, 70%). Mp (°C): 190–192. IR (KBr) 3518, 3320, 1700, 1629, 1461, 1362, 1195, 1150, 1059, 756. 1H NMR (500 MHz, DMSO-d 6): δ (ppm) 9.65 (s, NH), 9.08 (s, OH), 8.29 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 7.0 Hz, 1H), 6.97 (t, J = 8.0 Hz, 1H), 6.68 (d, J = 1.5 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.48 (dd, J = 7.5, 1.5 Hz, 1H), 4.90 (s, 1H), 2.64 (s, 2H), 2.26 (d, J = 16.0 Hz, 1H), 2.10 (d, J = 16.0 Hz, 1H), 1.07 (s, 3H), 0.97 (s, 3H). 13C NMR (125 MHz, DMSO-d 6): δ (ppm) 194.5, 160.2, 156.9, 151.9, 149.4, 146.9, 142.0, 131.8, 128.7, 123.9, 122.7, 118.2, 116.7, 114.8, 113.1, 113.0, 110.8, 101.7, 50.1, 34.0, 32.1, 28.9, 26.6. Anal. Calcd. for C24H21NO4: C, 74.40; H, 5.46; N, 3.62. Found: C, 74.29; H, 5.38; N, 3.74.

10,11-Dihydro-7-(2-methoxyphenyl)-10,10-dimethyl-7H-chromeno[4,3-b]quinoline-6,8(9H,12H)-dione (5c)

Pale-yellow powder (0.27 g, 68%). Mp (°C): 301–303.36 IR (KBr) 3300, 1695, 1629, 1598, 1474, 1358, 1241, 1189, 1150, 1007, 749, 637. 1H NMR (500 MHz, DMSO-d 6): δ (ppm) 9.62 (s, NH), 8.28 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 7.26 (dd, J = 7.5, 1.5 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.79 (t, J = 7.5 Hz, 1H), 5.05 (s, 1H), 3.63 (s, 3H), 2.59 (s, 2H), 2.21 (d, J = 16.0 Hz, 1H), 1.98 (d, J = 16.0 Hz, 1H), 1.05 (s, 3H), 0.90 (s, 3H). 13C NMR (125 MHz, DMSO-d 6): δ (ppm) 194.2, 159.9, 157.9, 151.9, 149.8, 142.4, 132.4, 131.5, 127.4, 123.7, 122.6, 119.6, 119.2, 116.6, 113.0, 111.3, 109.2, 100.3, 55.2, 50.2, 32.9, 31.9, 29.2, 25.9. Anal. Calcd. for C25H23NO4: C, 74.79; H, 5.77; N, 3.49. Found: C, 74.68; H, 5.92; N, 3.28.

10,11-Dihydro-7-(4-methoxyphenyl)-10,10-dimethyl-7H-chromeno[4,3-b]quinoline-6,8(9H,12H)-dione (5d)

Pale-yellow powder (0.29 g, 72%). Mp (°C): 261–263.36 IR (KBr) 3220, 1689, 1641, 1605, 1508, 1468, 1363, 1257, 1193, 1030, 842, 752. 1H NMR (500 MHz, DMSO-d 6): δ (ppm) 9.65 (s, NH), 8.30 (d, J = 7.5 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 7.5 Hz, 2H), 6.77 (d, J = 7.5 Hz, 2H), 4.90 (s, 1H), 3.66 (s, 3H), 2.66 (s, 2H), 2.26 (d, J = 16.0 Hz, 1H), 2.09 (d, J = 16.0 Hz, 1H), 1.08 (s, 3H), 0.96 (s, 3H). 13C NMR (125 MHz, DMSO-d 6): δ (ppm) 194.6, 160.2, 157.6, 152.0, 149.3, 141.8, 138.1, 131.8, 128.6, 127.9, 124.0, 122.8, 116.7, 113.5, 111.0, 102.1, 54.9, 50.1, 33.4, 32.1, 29.0, 26.5. Anal. Calcd. for C25H23NO4: C, 74.79; H, 5.77; N, 3.49. Found: C, 74.85; H, 5.59; N, 3.66.

10,11-Dihydro-7-(3,4,5-trimethoxyphenyl)-10,10-dimethyl-7H-chromeno[4,3-b]quinoline-6,8(9H,12H)-dione (5e)

Pale-yellow powder (0.32 g, 69%). Mp (°C): 302–303.36 IR (KBr) 3522, 3208, 1678, 1631, 1505, 1479, 1363, 1191, 1113, 1010, 764. 1H NMR (500 MHz, DMSO-d 6): δ (ppm) 9.71 (s, NH), 8.28 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 8.5 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 6.53 (s, 2H), 4.94 (s, 1H), 3.68 (s, 6H), 3.59 (s, 3H), 2.71 (d, J = 16.5 Hz, 1H), 2.68 (d, J = 16.5 Hz, 1H), 2.30 (d, J = 16.0 Hz, 1H), 2.13 (d, J = 16.0 Hz, 1H), 1.11 (s, 3H), 0.97 (s, 3H). 13C NMR (125 MHz, DMSO-d 6): δ (ppm) 194.6, 160.3, 152.4, 151.9, 149.9, 141.8, 141.1, 131.8, 124.0, 122.8, 116.8, 116.6, 113.0, 110.3, 105.2, 101.7, 59.8, 55.6, 50.1, 34.2, 32.0, 29.1, 26.4. Anal. Calcd. for C27H27NO6: C, 70.27; H, 5.90; N, 3.03. Found: C, 70.09; H, 5.77; N, 2.85.

10,11-Dihydro-10,10-dimethyl-7-p-tolyl-7H-chromeno[4,3-b]quinoline-6,8(9H,12H)-dione (5f)

Pale-yellow powder (0.27 g, 71%). Mp (°C): 331–333.36 IR (KBr): 3215, 1644, 1509, 1471, 1364, 1195, 1043, 844, 762. 1H NMR (500 MHz, DMSO-d 6): δ (ppm) 9.63 (s, NH), 8.29 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 4.91 (s, 1H), 2.65 (s, 2H), 2.25 (d, J = 16.0 Hz, 1H), 2.19 (s, 3H), 2.08 (d, J = 16.0 Hz, 1H), 1.07 (s, 3H), 0.95 (s, 3H). 13C NMR (125 MHz, DMSO-d 6): δ (ppm) 194.5, 160.1, 151.9, 149.3, 142.8, 141.8, 135.1, 131.8, 128.4, 127.5, 123.7, 122.8, 116.7, 113.0, 110.9, 101.9, 50.1, 33.9, 32.0, 28.9, 26.5, 20.4. Anal. Calcd. for C25H23NO3: C, 77.90; H, 6.01; N, 3.63. Found: C, 77.78; H, 5.85; N, 3.57.

7-(4-Fluorophenyl)-10,11-dihydro-10,10-dimethyl-7H-chromeno[4,3-b]quinoline-6,8(9H,12H)-dione (5g)

Pale-yellow powder (0.30 g, 77%). Mp (°C): 218–220.36 IR (KBr) 3470, 3301, 1711, 1631, 1593, 1470, 1360, 1194, 1148, 1041, 850, 743. 1H NMR (500 MHz, DMSO-d 6): δ (ppm) 9.71 (s, NH), 8.31 (d, J = 7.0 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 7.0 Hz, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.25-7.23 (m, 2H), 7.04-7.01 (m, 2H), 4.95 (s, 1H), 2.66 (s, 2H), 2.26 (d, J = 16.0 Hz, 1H), 2.09 (d, J = 16.0 Hz, 1H), 1.06 (s, 3H), 0.94 (s, 3H). 13C NMR (125 MHz, DMSO-d 6): δ (ppm) 194.6, 161.6 (d, J = 178 Hz), 152.0, 149.6, 142.1, 142.0, 132.0, 129.5, 124.1, 123.9, 123.0 (d, J = 8 Hz), 116.7 (d, J = 33 Hz), 114.6, 113.0, 110.7, 101.6, 50.0, 33.9, 32.1, 29.0, 26.6. Anal. Calcd. for C24H20FNO3: C, 74.02; H, 5.18; N, 3.60. Found: C, 73.88; H, 5.02; N, 3.49.

7-(2-Chlorophenyl)-10,11-dihydro-10,10-dimethyl-7H-chromeno[4,3-b]quinoline-6,8(9H,12H)-dione (5h)

Pale-yellow powder (0.30 g, 74%). Mp (°C): 299–301.36 IR (KBr) 3289, 3079, 1707, 1631, 1605, 1508, 1472, 1362, 1197, 1147, 1021, 735. 1H NMR (500 MHz, DMSO-d 6): δ (ppm) 9.65 (s, NH), 8.30 (d, J = 7.5 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 5.28 (s, 1H), 2.63 (s, 2H), 2.23 (d, J = 16.0 Hz, 1H), 2.02 (d, J = 16.0 Hz, 1H), 1.07 (s, 3H), 0.94 (s, 3H). 13C NMR (125 MHz, DMSO-d 6): δ (ppm) 194.2, 159.7, 152.0, 149.8, 142.5, 132.0, 129.2, 127.6, 126.4, 124.0, 123.7, 123.0, 122.9, 116.8, 116.6, 112.7, 110.1, 100.9, 50.1, 34.1, 31.8, 29.0, 26.3. Anal. Calcd. for C24H20ClNO3: C, 71.02; H, 4.97; N, 3.45. Found: C, 70.86; H, 5.11; N, 3.29.

10,11-Dihydro-10,10-dimethyl-7-(2-nitrophenyl)-7H-chromeno[4,3-b]quinoline-6,8(9H,12H)-dione (5i)

Pale-yellow powder (0.31 g, 75%). Mp (°C): 262–263.36 IR (KBr) 3301, 1700, 1611, 1515, 1475, 1350, 1244, 1196, 1150, 1024, 739. 1H NMR (500 MHz, DMSO-d 6): δ (ppm) 9.67 (s, NH), 8.32 (d, J = 7.5 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.46-7.40 (m, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 5.85 (s, 1H), 2.64 (s, 2H), 2.22 (d, J = 16.0 Hz, 1H), 2.02 (d, J = 16.0 Hz, 1H), 1.06 (s, 3H), 0.90 (s, 3H). 13C NMR (125 MHz, DMSO-d 6): δ (ppm) 194.4, 160.4, 151.8, 150.5, 147.8, 146.5, 142.0, 133.8, 132.0, 129.2, 124.0, 123.0, 122.1, 121.3, 116.7, 112.8, 110.0, 100.9, 49.8, 35.0, 31.9, 28.6, 26.5. Anal. Calcd. for C24H20N2O5: C, 69.22; H, 4.84; N, 6.73. Found: C, 69.07; H, 4.98; N, 6.57.

10,11-Dihydro-10,10-dimethyl-7-(3-nitrophenyl)-7H-chromeno[4,3-b]quinoline-6,8(9H,12H)-dione (5j)

Pale-yellow powder (0.33 g, 79%). Mp (°C): 280–282.36 IR (KBr) 3215, 1647, 1603, 1510, 1469, 1347, 1189, 1044, 715. 1H NMR (500 MHz, DMSO-d 6): δ (ppm) 9.82 (s, NH), 8.33 (d, J = 8.0 Hz, 1H), 8.07 (s, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 5.08 (s, 1H), 2.51 (s, 2H), 2.29 (d, J = 16.0 Hz, 1H), 2.10 (d, J = 16.0 Hz, 1H), 1.10 (s, 3H), 0.96 (s, 3H). 13C NMR (125 MHz, DMSO-d 6): δ (ppm) 194.5, 160.1, 152.1, 150.3, 147.6, 147.5, 142.5, 134.5, 132.1, 129.5, 124.1, 123.0, 122.1, 121.3, 116.7, 112.8, 110.0, 100.9, 49.9, 34.9, 32.1, 28.9, 26.4. Anal. Calcd. for C24H20N2O5: C, 69.22; H, 4.84; N, 6.73. Found: C, 69.46; H, 4.68; N, 6.58.

Results and discussions

In the initial study, we examined the model reaction of 4-hydroxy coumarin 1 (1 mmol), aqueous ammonia 2 (5 mmol), benzaldehyde 3a (1 mmol) and dimedone 4 (1 mmol) in different solvents and various amounts of ammonia. The results are summarized in Table 1. It was showed that the best yield of the product 5a was obtained in refluxing n-propanol (Table 1, entries 1–4). Solvent-free condition led to the trace amounts of the product (Table 1, entry 5). To examine the effect of the amount of ammonia, the reaction was carried out by employing 10 and 15 mmol of aqueous ammonia. It was observed that raising the amount of ammonia to twofold–threefold didn’t improve the yield of the desired product (Table 1, entries 7–8). This implied that further increase in the amount of ammonia has no positive effect on the yield. By employing ammonium acetate as a nitrogen source, the desired product was obtained in lower yields (Table 1, entry 9).

Scheme 1
scheme 1

Four-component synthesis of chromeno[4,3-b]quinolines

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Table 1 Optimization of the reaction in different conditions (Scheme 1)
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To survey the generality of the reaction, various aromatic aldehydes were reacted under the optimized reaction condition, affording the desired products 5a–j in moderate to good yields. Both electron-donating and electron-withdrawing aldehydes were found suitable for this reaction. The structure of cyclized compounds were confirmed by IR, 1H-NMR and 13C-NMR spectroscopy. The distinguished peak related to H-4 was appeared at 4.90–5.85 ppm region as a singlet peak. Electron-withdrawing group led to the appearance of this peak at lower fields (Table 2).

Table 2 Synthesis of chromenoquinolines using various aldehyde derivatives
figure a
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Conclusion

To conclude, by the one-pot reaction of dimedone, ammonia, 4-hydroxy coumarin and aromatic aldehydes, the corresponding chromeno[4,3-b]quinoline was synthesized in moderate to good yields. This procedure can be applied to the synthesis of various 10,11-dihydro-10,10-dimethyl-7H-chromeno[4,3-b]quinoline-6,8(9H,12H)-diones by employing readily available starting material in a straightforward one-pot manner.