A novel four-component route to synthesis 11-amino-12-(4-aryl)-8,9,10,12-tetrahydro-7H-chromeno[2,3-b]quinolin-3-ol derivatives

1 Introduction

Chromenoquinolinol compounds are well-known and an important class of heterocyclic compounds due to their various biological activities such as anti-inflammatory and estrogenic (Munoz et al., 1982; Yamada et al., 1992; Lee et al., 2004). Especially, chromenoquinolin derivatives exhibit cancer chemopreventive (Azuine et al., 2004), and activities including anti-tubercular (Srivastava et al., 2005), antimyopic, hypotensive (Goto et al., 1984), anti-rheumatic (Maruyama et al., 1981) and antiasthmatic activities (Ukawa et al., 1985).

Tow step synthesis of chromeno[2,3-b]quinolin-3-ol derivatives has been reported recently (Raghuvanshi and Singh, 2010). Synthesis of 4-[(N-Imidazol-2-ylmethyl)anilino]pyranopyridine derivatives and 2-aryl-4H-pyrano[2,3-b]pyridin-4-ones has been reported (Sunkyung et al., 2005; Khlebinkov et al., 2009). However, due to the economical and atom efficiency issues, the development of a one-pot, efficient, rapid and convenient protocol for the synthesis of chromenoquinolinol (pyranopyridines) is still of remarkable interest.

Ultrasound has been increasingly employed in organic synthesis in the last three decades. It has been demonstrated as an alternative energy source for organic reactions ordinarily accomplished by heating. The use of ultrasound irradiation technique for activating various reactions is well documented in the literature (Singh et al., 2003; Li et al., 2002; Robin et al., 2002).

As a part of our research to develop novel MCRs using efficient and heterogeneous catalysts (Damavandi 2011; Damavandi and Sandaroos, 2011), herein, one-pot synthesis of various 11-amino-12-(4-aryl)-8,9,10,12-tetrahydro-7H-chromeno[2,3-b]quinolin-3-ol derivatives via four-component reaction of resorcinol, malononitrile, aromatic aldehydes and cyclohexanone using the catalytic system of Fe(OTf)₃/ultrasonic irradiation (see Scheme 1).

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Scheme 1

One-pot synthesis of 11-amino-12-(4-aryl)-8,9,10,12-tetrahydro-7H-chromeno[2,3-b]quinolin-3-ol.

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2 Experimental

2.2

2.2 General procedure for synthesis of pyrano[2,3-b]pyridine derivatives

In a round bottom flask a mixture of resorcinol (1 mmol), malononitrile (1.1 mmol), aromatic aldehyde (1 mmol) and cyclohexanone (1 mmol) was mixed with iron triflate (0.1 mmol) and the mixture was irradiated under ultrasonic waves at room temperature for an appropriate time as indicated in Table 1. The progress of the reaction was monitored by TLC (ethyl acetate:n-hexane, 1:5). Upon completion of the reaction, the mixture was extracted with AcOEt (3 × 10 ml) and washed with aq. NaHCO₃ solution. Then the organic phase was dried over MgSO₄ and concentrated under reduced pressure. The crude product was chromatographed on silica gel eluting with n-hexane-AcOEt (5:1). Spectral data for the products are as follows.

Table 1 Results of pyranopyridine derivatives’ synthesis.^a

Entry	Product	Time (min)	Isolated yield (%)	Entry	Product	Time (min)	Isolated yield (%)
1		35	88	7		40	80
2		32	90	8		34	86
3		35	88	9		30	92
4		40	85	10		50	85
5		42	85	11		50	80
6		45	82	12		44	82

a The reactions were carried out under solvent-free and ultrasonication at room temperature using 10 mol% of the catalyst.

2.2.1

2.2.1 11-amino-8,9,10,12-tetrahydro-12-phenyl-7H-chromeno[2,3-b]quinolin-3-ol (entry 1)

Temperature 311–312 °C [(313–315 °C) (Raghuvanshi and Singh, 2010)], IR (KBr): 3440, 3365, 3018, 1614, 1527, 1238, 1111 cm⁻¹. ¹H NMR (100 MHz, DMSO-d₆): δ = 1.60 (m, 4H, CH₂), 2.30 (m, 2H, CH₂), 2.62 (m, 2H, CH₂), 5.33 (s, 1H, CH), 6.75–7.45 (m, 10H, ArH, NH₂), 9.60 (s, 1H, OH). Anal. Calcd for C₂₂H₂₀N₂O₂: C, 76.72; H, 5.85; N, 8.13. Found: C, 75.66; H, 5.99; N, 7.95.

2.2.2

2.2.2 11-amino-12-(4-bromophenyl)-8,9,10,12-tetrahydro-7H-chromeno[2,3-b]quinolin-3-ol (entry 2)

The mp: 283–285 °C [(280–282 °C) (Raghuvanshi and Singh, 2010)], IR (KBr): 3434, 3376, 2977, 1607, 1488, 1206, 1167 cm⁻¹. ¹H NMR (100 MHz, DMSO-d₆): δ = 1.64 (m, 4H, CH₂), 2.28 (m, 2H, CH₂), 2.55 (m, 2H, CH₂), 5.40 (s, 1H, CH), 6.35 (br, 2H, NH₂), 6.65–7.40 (m, 7H, ArH), 9.80 (s, 1H, OH). Anal. Calcd for C₂₂H₁₉BrN₂O₂: C, 62.42; H, 4.52; N, 6.62. Found: C, 62.17; H, 4.44; N, 6.73.

2.2.3

2.2.3 11-amino-12-(4-chlorophenyl)-8,9,10,12-tetrahydro-7H-chromeno[2,3-b]quinolin-3-ol (entry 3)

The mp: 290–292 °C, IR (KBr): 3422, 3150, 2885, 1624, 1448, 1233 cm⁻¹. ¹H NMR (100 MHz, DMSO-d₆): δ = 1.55 (m, 4H, CH₂), 2.45 (m, 2H, CH₂), 2.64 (m, 2H, CH₂), 5.65 (s, 1H, CH), 6.15 (br, 2H, NH₂), 6.72–7.42 (m, 7H, ArH), 10.10 (s, 1H, OH). Anal. Calcd for C₂₂H₁₉ClN₂O₂: C, 69.75; H, 5.05; N, 7.39; Found: C, 69.22; H, 4.97; N, 7.32.

2.2.4

2.2.4 11-amino-8,9,10,12-tetrahydro-12-(4-methoxyphenyl)-7H-chromeno[2,3-b]quinolin-3-ol (entry 4)

The mp: 295–297 °C [(295–297 °C) (Raghuvanshi and Singh, 2010)], IR (KBr): 3475, 3388, 2907, 1619, 1455, 1223, 1166 cm⁻¹. ¹H NMR (100 MHz, DMSO-d₆): δ = 1.55 (m, 4H, CH₂), 2.25 (m, 2H, CH₂), 2.40 (m, 2H, CH₂), 3.75 (s, 3H, OCH₃), 5.55 (s, 1H, CH), 6.25 (s, 2H, NH₂), 6.6–7.4 (m, 7H, ArH), 9.75 (s, 1H, OH). Anal. Calcd for C₂₃H₂₂N₂O₃: C, 73.78; H, 5.92; N, 7.48. Found: C, 73.52; H, 5.80; N, 7.34.

2.2.5

2.2.5 11-amino-8,9,10,12-tetrahydro-12-p-tolyl-7H-chromeno[2,3-b]quinolin-3-ol (entry 5)

The mp: 284–286 °C [(282–284 °C) (Raghuvanshi and Singh, 2010)], IR (KBr): 3455, 3365, 2910, 1613, 1433, 1218, 1165 cm⁻¹. ¹H NMR (100 MHz, DMSO-d₆): δ = 1.60 (m, 4H, CH₂), 2.20 (s, 3H, CH₃), 2.35 (m, 2H, CH₂), 2.55 (m, 2H, CH₂), 5.40 (s, 1H, CH), 6.10 (s, 2H, NH₂), 6.45–7.20 (m, 7H, ArH), 9.63 (s, 1H, OH). Anal. Calcd for C₂₃H₂₂N₂O₂: C, 77.07; H, 6.19; N, 7.82. Found: C, 76.73; H, 6.30; N, 7.71.

2.2.6

2.2.6 11-amino-8,9,10,12-tetrahydro-12-(3,4,5-trimethoxyphenyl)-7H-chromeno[2,3-b]quinolin-3-ol (entry 6)

The mp: 275–277 °C [(285–287 °C) (Raghuvanshi and Singh, 2010)], IR (KBr): 3444, 3370, 2895, 1635, 1425, 1211, 1105 cm⁻¹. ¹H NMR (100 MHz, DMSO-d₆): δ = 1.75 (m, 4H, CH₂), 2.40 (m, 2H, CH₂), 2.57 (m, 2H, CH₂), 3.60 (s, 3H, OCH3), 3.65 (s, 3H, OCH₃), 3.73 (s, 3H, OCH₃), 5.14 (s, 1H, CH), 6.35 (s, 2H, NH₂), 6.60–7.10 (m, 5H, ArH), 9.70 (s, 1H, OH). Anal. Calcd for C₂₅H₂₆N₂O₅: C, 69.11; H, 6.03; N, 6.45. Found: C, 68.74; H, 5.90; N, 6.34.

2.2.7

2.2.7 11-amino-12-(4-(dimethylamino)phenyl)-8,9,10,12-tetrahydro-7H-chromeno[2,3-b]quinolin-3-ol (entry 7)

The mp: 310–312 [>320 °C (Raghuvanshi and Singh, 2010)]. IR (KBr): 3472, 3384, 2910, 1638, 1447, 1221, 1155 cm⁻¹. ¹H NMR (100 MHz, DMSO-d₆): δ = 1.72 (m, 4H, CH₂), 2.2–2.70 (m, 4H, CH₂), 2.90 (s, 6H, N(CH₃)₂), 5.25 (s, 1H, CH), 4.85 (brs, 2H, NH₂), 6.60–7.10 (m, 7H, ArH), 9.45 (s, 1H, OH). Anal. Calcd for C₂₄H₂₅N₃O₂: C, 74.39; H, 6.50; N, 10.84. Found: C, 74.11; H, 6.41; N, 10.66.

2.2.8

2.2.8 11-amino-12-(4-fluorophenyl)-8,9,10,12-tetrahydro-7H-chromeno[2,3-b]quinolin-3-ol (entry 8)

The mp: 292 °C [(292–294 °C) (Raghuvanshi and Singh, 2010)], IR (KBr): 3472, 3385, 2885, 1616, 1427, 1266 cm⁻¹. ¹H NMR (100 MHz, DMSO-d₆): δ = 1.64 (m, 4H, CH₂), 2.35–2.65 (m, 4H, CH₂), 5.18 (s, 1H, CH), 6.05 (s, 2H, NH₂), 6.57–7.15 (m, 7H, ArH), 9.50 (s, 1H, OH). Anal. Calcd for C₂₂H₁₉FN₂O₂: C, 72.91; H, 5.28; N, 7.73. Found: C, 72.66; H, 5.17; N, 7.64.

2.2.9

2.2.9 11-amino-8,9,10,12-tetrahydro-12-(4-nitrophenyl)-7H-chromeno[2,3-b]quinolin-3-ol (entry 9)

The mp: 322–324. IR (KBr): 3425, 3390, 2865, 1630, 1510, 1435, 1325 cm⁻¹. ¹H NMR (100 MHz, DMSO-d₆): δ = 1.55 (m, 4H, CH₂), 2.30–2.62 (m, 4H, CH₂), 5.60 (s, 1H, CH), 6.35 (brs, 2H, NH₂), 6.57–7.15 (m, 5H, ArH), 8.05 (m, 2H, ArH), 10.65 (s, 1H, OH). Anal. Calcd for C₂₂H₁₉N₃O₄: C, 67.86; H, 4.92; N, 10.79. Found: C, 67.21; H, 5.01; N, 10.86.

2.2.10

2.2.10 11-amino-8,9,10,12-tetrahydro-12-(4-hydroxyphenyl)-7H-chromeno[2,3-b]quinolin-3-ol (entry 10)

The mp: >330 °C, IR (KBr): 3455, 3410, 3377, 1652, 1468, 1313, 1205 cm⁻¹. ¹H NMR (100 MHz, DMSO-d₆): δ = 1.60 (m, 4H, CH₂), 2.40–2.75 (m, 4H, CH₂), 5.55 (s, 1H, CH), 5.70 (brs, 2H, NH₂), 6.65–7.05 (m, 7H, ArH), 10.10 (brs, 2H, OH). Anal. Calcd for C₂₂H₂₀N₂O₃: C, 73.32; H, 5.59; N, 7.77. Found: C, 72.74; H, 5.51; N, 7.68.

2.2.11

2.2.11 11-amino-12-(furan-2-yl)-8,9,10,12-tetrahydro-7H-chromeno[2,3-b]quinolin-3-ol (entry 11)

The mp: 314–315 °C [(318–320 °C) (Raghuvanshi and Singh, 2010)], IR (KBr): 3470, 3392, 2875, 1637, 1449, 1228 cm⁻¹. ¹H NMR (100 MHz, DMSO-d₆): δ = 1.73 (m, 4H, CH₂), 2.26-2.66 (m, 4H, CH₂), 5.22 (s, 1H, CH), 6.44 (brs, 2H, NH₂), 6.70–7.25 (m, 6H, ArH), 9.20 (s, 1H, OH). Anal. Calcd for C₂₀H₁₈N₂O₃: C, 71.84; H, 5.43; N, 8.38. Found: C, 71.27; H, 5.25; N, 8.22.

2.2.12

2.2.12 11-amino-8,9,10,12-tetrahydro-12-(naphthalen-1-yl)-7H-chromeno[2,3-b]quinolin-3-ol (entry 12)

The mp: 284–286 °C, IR (KBr): 3425, 3385, 2972, 1641, 1443, 1196 cm⁻¹. ¹H NMR (100 MHz, DMSO-d₆): δ = 1.55 (m, 4H, CH₂), 2.32 (m, 2H, CH₂), 2.61 (m, 2H, CH₂), 5.17 (s, 1H, CH), 6.15 (brs, 2H, NH₂), 6.85–7.52 (m, 10H, ArH), 9.45 (s, 1H, OH). Anal. Calcd for C₂₆H₂₂N₂O₂: C, 79.16; H, 5.62; N, 7.10. Found: C, 78.66; H, 5.74; N, 7.01.

3 Results and discussion

First of all, the one-pot reaction of resorcinol, malononitrile, nitrobenzaldehydes and cyclohexanone was carried out under solvent-free and ultrasonic irradiation using iron(III) triflate. The reaction was considered as a standard model reaction. In order to evaluate the influence of ultrasonic irradiation, first the model reaction (Table 1, entry 9) was examined without ultrasonication at room temperature. Not only a moderate yield of 57% with prolonged reaction time (4 h) was found, but the byproduct was also isolated. However, when the reaction was carried out under ultrasonication at room temperature, the target product of 11-amino-8,9,10,12-tetrahydro-12-(4-nitrophenyl)-7H-chromeno[2,3-b]quinolin-3-ol was obtained in 88% yield within short reaction time (35 min). Furthermore, no byproduct was detected when the reaction was carried out under ultrasonic irradiation.

As shown in Table 1, the scope and generality of this protocol were illustrated with respect to the various aromatic aldehydes. Aromatic aldehydes substituted with either electron-donating or electron-withdrawing groups underwent the reaction smoothly and gave the corresponding 11-amino-12-(4-aryl)-8,9,10,12-tetrahydro-7H-chromeno[2,3-b]quinolin-3-ol in good to excellent yields. In addition, heterocyclic arylaldehyde (furfuraldehyde) was reacted with resorcinol, malononitrile in combination with cyclohexanone under the same experimental conditions, and 11-amino-12-(furan-2-yl)-8,9,10,12-tetrahydro-7H-chromeno[2,3-b]quinolin-3-ol were obtained in moderate yields (Table 1, entries 11).

The proposed mechanism is depicted in Scheme 2. The aldehyde is first condensed with malononitrile to afford α-cyanocinnamonitrile by Knoevenagel addition. Resorcinol C-alkylation gives an intermediate which cyclizes via nucleophilic attack of an O atom on the cyano moiety followed by protonation and rearrangement to produce the intermediate of 2-amino-3-cyano-7-hydroxy-4-substituted-4H-chromene which could be isolated to investigate the mechanism. Subsequently, cyclohexanone which is activated by the catalyst reacts with the chromene to furnish the corresponding 11-amino-12-(4-aryl)-8,9,10,12-tetrahydro-7H-chromeno[2,3-b]quinolin-3-ol derivatives.

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Scheme 2

The proposed mechanism.

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4 Conclusion

In summary, a novel, one-pot four-component coupling of resorcinol, malononitrile, aromatic aldehydes and cyclohexanone to synthesis 11-amino-12-(4-aryl)-8,9,10,12-tetrahydro-7H-chromeno[2,3-b]quinolin-3-ol derivatives using Fe(OTf)₃ under solvent-free conditions using ultrasonic irradiation has been described. The catalytic system afforded the corresponding chromeno[2,3-b]quinolin-3-ol derivatives in high to excellent yields. No undesired side product could be detected and the four-component reactions proceed efficiently at ambient temperature.