Reactions carried out under scientific microwave reactor (Biotage, Initiator EXP EU 355301). Melting points were determined on a glass disk with an electric hot plate and are uncorrected. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were run in DMSO-d6 and CDCl3 solutions. IR spectra were taken as KBr plates in a Shimazdu 8400S FTIR. Commercially available substrates were freshly distilled before the reaction. Solvents, reagents, and chemicals were purchased from Aldrich, Fluka, Merck, SRL, Spectrochem and Process Chemicals.
2.1. General Procedure for Tetrahydrobenzo[b]pyran (4)
A equimolar mixture of aldehyde (1 mmol), malononitrile (1 mmol) and 1,3-cyclic diketone (1 mmol) was taken in a microwave vessel. The reaction mixture was irradiated under scientific microwave (Biotage, Initiator EXP EU 355301) at 80°C for a certain period of time to complete the reaction. The reaction mixture was then washed with ethanol (10 mL) to afford the crude product as solid, which was recrystallized from EtOH to get the analytically pure product.
2.1.1. 2-Amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4aa)
White solid (88%), m.p.: 230-231°C ([53] 230°C); 1H NMR (400 MHz, DMSO-d6): δ=7.23–7.19 (m, 2H, H-Ar), 7.12–7.06 (m, 3H, H-Ar), 6.93 (brs, 2H, NH2), 4.10 (s, 1H, H-4), 2.45-2.44 (m, 2H, CH2), 2.18 (d, J=16.4 Hz, 1H, H-6′), 2.02 (d, J=16 Hz, 1H, H-6), 0.96 (s, 3H, CH3), 0.88 (s, 3H, CH3) ppm; 13C NMR (100 MHz, DMSO-d6): δ=195.8, 162.6, 158.5, 144.8, 128.4, 127.2, 126.6, 119.8, 112.8, 58.3, 50.0, 35.6, 31.8, 28.4, 26.8 ppm; IR (KBr): 3435, 3318, 2913, 2198, 1672 cm−1.
2.1.2. 2-Amino-7,7-dimethyl-5-oxo-4-p-tolyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4ba)
White solid (88%), m.p.: 216-217°C ([53] 218°C); 1H NMR (400 MHz, CDCl3): δ=7.12–7.07 (m, 4H, H-Ar), 4.56 (brs, 2H, NH2), 4.35 (s, 1H, H-4), 2.43 (s, 2H, CH2), 2.25 (s, 3H, CH3), 2.21 (d, J=5.6 Hz, 2H, CH2), 1.10 (s, 3H, CH3), 1.03 (s, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3): δ=195.8, 161.3, 157.3, 140.2, 136.6, 129.2, 127.3, 118.7, 114.1, 50.6, 40.6, 35.1, 32.1, 28.8, 27.7, 21.0 ppm; IR (KBr): 3413, 3324, 2956, 2191, 1664 cm−1.
2.1.3. 2-Amino-4-(4-chlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4ca)
White solid (84%), m.p.: 208-209°C ([53] 206°C); 1H NMR (400 MHz, DMSO-d6): δ=7.27 (d, J=8.4 Hz, 2H, H-Ar), 7.19 (d, J=8.4 Hz, 2H, H-Ar), 4.59 (br, 2H, NH2), 4.40 (s, 1H, H-4), 2.46 (s, 2H, CH2), 2.23 (d, J=7.6 Hz, 2H, CH2), 1.13 (s, 3H, CH3), 1.04 (s, 3H, CH3) ppm; 13C NMR (100 MHz, DMSO-d6): δ=195.6, 162.6, 158.5, 143.7, 131.1, 129.1, 128.2, 119.5, 112.3, 57.7, 49.9, 35.1, 31.7, 28.3, 26.8 ppm; IR (KBr): 3390, 3321, 3253, 3211, 2962, 2190, 1739, 1681, 1654, 1604, 1213, 1039, 844 cm−1.
2.1.4. 2-Amino-7,7-dimethyl-4-(4-nitrophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4da)
Yellow solid (82%), m.p.: 178–180°C ([47] 180–182°C); 1H NMR (400 MHz, DMSO-d6): δ=8.10 (d, J=8.8 Hz, 2H, H-Ar), 7.37 (d, J=8.8 Hz, 2H, H-Ar), 7.12 (brs, 2H, NH2), 4.29 (s, 1H, H-4), 2.47–2.44 (m, 2H, CH2), 2.20 (d, J=16 Hz, 1H, H-6′), 2.04 (d, J=16 Hz, 1H, H-6), 0.97 (s, 3H, CH3), 0.89 (s, 3H, CH3) ppm; 13C NMR (100 MHz, DMSO-d6): δ=195.8, 158.6, 152.3, 146.3, 128.7, 125.6, 123.7, 119.4, 111.7, 57.0, 49.9, 35.7, 31.9, 28.3, 27.0 ppm; IR (KBr): 3436, 3324, 2196, 1668 cm−1.
2.1.5. 2-Amino-4-(4-methoxyphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4ea)
Yellow solid (83%), m.p.: 201–203°C ([53] 203°C); 1H NMR (400 MHz, DMSO-d6): δ=7.05 (d, J=8.8 Hz, 2H, H-Ar), 6.95 (br, 2H, NH2), 6.84 (d, J=8.8 Hz, 2H, H-Ar), 4.12 (s, 1H, H-4), 3.71 (s, 3H, OCH3), 2.50-2.49 (m, 2H, CH2), 2.22-2.21 (m, 2H, CH2), 1.03 (s, 3H, CH3), 0.94 (s, 3H, CH3) ppm; 13C NMR (100 MHz, DMSO-d6): δ=195.6, 162.1, 158.4, 157.9, 136.8, 128.2, 119.8, 113.6, 113.0, 58.5, 55.0, 50.1, 34.7, 31.7, 28.4, 26.7 ppm; IR (KBr): 3376, 3316, 2955, 2194, 1683, 1140, 1035, 842 cm−1.
2.1.6. (E)-2-Amino-7,7-dimethyl-5-oxo-4-styryl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4fa)
White solid (74%), m.p.: 187-188°C ([47] 183–185°C); 1H NMR (400 MHz, DMSO-d6): δ=7.30 (d, J=7.2 Hz, 2H, H-Ar), 7.21 (t, J=7.6 Hz, 2H, H-Ar), 7.16–7.14 (m, 1H, H-Ar), 7.01 (brs, 2H, NH2), 6.30 (d, J=16 Hz, 1H, CH), 6.03–5.98 (m, 1H, CH), 3.75 (d, J=7.2 Hz, 1H, H-4), 2.36-2.35 (m, 2H, CH2), 2.17 (d, J=13.2 Hz, 2H, CH2), 0.96 (s, 3H, CH3), 0.93 (s, 3H, CH3) ppm; 13C NMR (100 MHz, DMSO-d6): δ=196.3, 162.8, 159.6, 136.8, 131.5, 129.6, 129.0, 127.8, 126.6, 120.3, 112.2, 55.5, 50.5, 33.2, 32.2, 28.6, 27.3 ppm; IR (KBr): 3436, 3321, 2933, 2193, 1673 cm−1.
2.1.7. 2-Amino-4-(3-hydroxyphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4ga)
White solid (76%), m.p.: 228-229°C ([53] 225°C); 1H NMR (400 MHz, DMSO-d6): δ=9.29 (s, 1H, OH), 7.01–6.92 (m, 3H, H-Ar), 6.51–6.47 (m, 3H, H-Ar, NH2), 3.99 (s, 1H, H-4), 2.44-2.43 (m, 2H, CH2), 2.19 (d, J=16 Hz, 1H, H-6′), 2.03 (d, J=16 Hz, 1H, H-6), 0.96 (s, 3H, CH3), 0.89 (s, 3H, CH3) ppm; 13C NMR (100 MHz, DMSO-d6): δ=196.1, 162.8, 158.9, 157.7, 146.5, 129.6, 120.2, 118.1, 114.4, 113.9, 113.2, 58.7, 50.3, 35.8, 32.2, 28.8, 27.1 ppm; IR (KBr): 3431, 3335, 2915, 1668 cm−1.
2.1.8. 2-Amino-4-(4-hydroxy-3-methoxyphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4ha)
White solid (82%), m.p.: 242–244°C ([47] 240–242°C); 1H NMR (400 MHz, DMSO-d6): δ=8.86 (s, 1H, OH), 6.92 (s, 2H, NH2), 6.68–6.64 (m, 2H, Ar-H), 6.53–6.50 (m, 1H, Ar-H), 4.07 (s, 1H, H-4), 3.71 (s, 3H, OCH3), 2.51–2.48 (m, 2H, CH2), 2.25 (d, J=16 Hz, 1H, H-6′), 2.10 (d, J=16 Hz, 1H, H-6), 1.03 (s, 3H, CH3), 0.97 (s, 3H, CH3) ppm; 13C NMR (100 MHz, DMSO-d6): δ=195.8, 162.2, 158.4, 147.3, 145.2, 135.8, 119.9, 119.4, 115.3, 113.0, 111.4, 58.8, 55.6, 50.0, 35.0, 31.8, 28.5, 26.6 ppm; IR (KBr): 3416, 3341, 2923, 2192, 1662 cm−1.
2.1.9. 2-Amino-4-(benzo[d][1,3]dioxol-5-yl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4ia)
White solid (88%), m.p.: 224-225°C; 1H NMR (400 MHz, DMSO-d6): δ=6.97 (brs, 2H, NH2), 6.81 (d, J=8 Hz, 1H, H-Ar), 6.62–6.59 (m, 2H, H-Ar), 5.97 (s, 2H, CH2), 4.10 (s, 1H, H-4), 2.50 (s, 2H, CH2), 2.24 (d, J=16 Hz, 1H, H-6′), 2.12 (d, J=16 Hz, 1H, H-6), 1.03 (s, 3H, CH3), 0.96 (s, 3H, CH3) ppm; 13C NMR (100 MHz, DMSO-d6): δ=195.8, 162.4, 158.4, 147.2, 145.9, 138.9, 120.3, 112.7, 108.0, 107.5, 100.9, 58.5, 50.0, 35.2, 31.8, 28.3, 26.9 ppm; IR (KBr): 3435, 3318, 2923, 2198, 1670 cm−1; Anal. Calcd. for C19H18N2O4: C, 67.44; H, 5.36; N, 8.28%; Found: C, 67.36; H, 5.31; N, 8.22%.
2.1.10. 2-Amino-4-(4-bromophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4ja)
White solid (85%), m.p.: 210–212°C ([53] 215°C); 1H NMR (400 MHz, DMSO-d6): δ=7.48 (d,J=8.4 Hz, 2H, H-Ar), 7.10 (d, J=8.4 Hz, 2H, H-Ar), 7.06 (brs, 2H, NH2), 4.18 (s, 1H, H-4), 2.51-2.50 (m, 2H, CH2), 2.25 (d, J=16 Hz, 1H, H-6′), 2.10 (d, J=16 Hz, 1H, H-6), 1.03 (s, 3H, CH3), 0.94 (s, 3H, CH3) ppm; 13C NMR (100 MHz, DMSO-d6): δ=196.1, 163.0, 158.8, 144.5, 131.6, 129.9, 120.0 (2C), 112.6, 58.0, 50.3, 35.6, 32.2, 28.7, 27.2 ppm.
2.1.11. 2-Amino-4-(furan-2-yl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4ka)
White solid (72%), m.p.: 224–226°C ([47] 220–222°C); 1H NMR (400 MHz, DMSO-d6): δ=7.41-7.40 (m, 1H, CH), 7.01 (brs, 2H, NH2), 6.26-6.25 (m, 1H, CH), 5.99-5.98 (m, 1H, CH), 4.25 (s, 1H, H-4), 2.48–2.39 (m, 2H, CH2), 2.22 (d, J=16 Hz, 1H, H-6′), 2.10 (d, J=16 Hz, 1H, H-6), 0.97 (s, 3H, CH3), 0.91 (s, 3H, CH3) ppm; 13C NMR (100 MHz, DMSO-d6): δ=195.6, 163.4, 159.4, 155.8, 141.8, 119.6, 110.5, 110.4, 105.1, 55.4, 49.9, 31.9, 29.0, 28.5, 26.6 ppm; IR (KBr): 3441, 3314, 2923, 2182, 1665 cm−1.
2.1.12. Typical Procedure for the Synthesis of 2-Amino-4-cyclohexyl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4la)
A mixture of cyclohexanecarbaldehyde (1 mmol), malononitrile (1 mmol), and dimedone (1 mmol) was taken in a microwave vessel. The reaction mixture was irradiated under scientific microwave (Biotage, Initiator EXP EU 355301) at 80°C for 7 min to complete the reaction. The reaction mixture was then washed with ethanol (10 mL) to afford the crude product as solid, which was recrystallized from EtOH to get the analytically pure product as white solid (88%). M.p.: 203-204°C; 1H NMR (400 MHz, CDCl3): δ=4.65 (br, 2H, NH2), 3.31 (s, 1H, H-4), 2.38-2.37 (m, 2H, CH2), 2.29-2.28 (m, 2H, CH2), 1.75–1.63 (m, 4H, CH2), 1.49–1.41 (m, 2H, CH2), 1.34–1.31 (m, 1H, CH2), 1.11–1.09 (m, 9H, CH2 and CH3), 0.95–0.92 (m, 1H, CH2) ppm; 13C NMR (100 MHz, CDCl3): δ=196.5, 163.2, 159.9, 120.3, 114.1, 58.5, 50.8, 43.7, 40.6, 34.7, 32.0, 30.4, 29.2, 27.7, 27.3, 26.5, 26.2, 26.1 ppm. IR (KBr): 3409, 3326, 2923, 2192, 1662, 1373, 1255, 1213, 1033, 945 cm−1; Anal. Calcd. for C18H24N2O2: C, 71.97; H, 8.05; N, 9.33%; Found: C, 71.91; H, 8.02; N, 9.27%.
2.1.13. 2-Amino-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4ab)
White solid (85%), m.p.: 234–236°C ([48] 238–240°C); 1H NMR (400 MHz, DMSO-d6): δ=7.30–7.26 (m, 2H, H-Ar), 7.20–7.14 (m, 3H, H-Ar), 6.99 (s, 2H, NH2), 4.18 (s, 1H, H-4), 2.65–2.59 (m, 2H, CH2), 2.35–2.22 (m, 2H, CH2), 1.99–1.90 (m, 2H, CH2) ppm; 13C NMR (100 MHz, DMSO-d6): δ=196.3, 164.9, 158.8, 145.1, 128.7, 127.5, 126.9, 120.2, 114.1, 58.6, 36.7, 35.8, 26.8, 20.2 ppm; IR (KBr): 3446, 3324, 2903, 2184, 1665 cm−1.
2.1.14. 2-Amino-5-oxo-4-p-tolyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4bb)
White solid (86%), m.p.: 227-228°C ([48] 223–225°C); 1H NMR (400 MHz, DMSO-d6): δ=7.09–7.02 (m, 4H, H-Ar), 6.96 (brs, 2H, NH2), 4.14 (s, 1H, H-4), 2.62–2.59 (m, 2H, CH2), 2.27–2.24 (m, 5H, CH2 and CH3), 1.94–1.84 (m, 2H, CH2) ppm; 13C NMR (100 MHz, DMSO-d6): δ=196.3, 164.7, 158.8, 142.2, 136.0, 129.2, 127.4, 120.2, 114.3, 58.7, 36.7, 35.4, 26.8, 20.9, 20.2 ppm; IR (KBr): 3437, 3345, 2924, 1678 cm−1.
2.1.15. 2-Amino-4-(4-chlorophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4cb)
White solid (88%), m.p.: 230–232°C ([48] 226–228°C); 1H NMR (400 MHz, DMSO-d6): δ=7.35–7.32 (m, 2H, H-Ar), 7.19–7.16 (m, 2H, H-Ar), 7.05 (brs, 2H, NH2), 4.20 (s, 1H, H-4), 2.62–2.58 (m, 2H, CH2), 2.31–2.24 (m, 2H, CH2), 1.97–1.87 (m, 2H, CH2) ppm; 13C NMR (100 MHz, DMSO-d6): δ=196.3, 165.0, 158.8, 144.1, 131.5, 129.5, 128.6, 120.0, 113.7, 58.1, 36.6, 35.4, 26.8, 20.1 ppm; IR (KBr): 3451, 3314, 2913, 2197, 1682 cm−1.
2.1.16. 2-Amino-5-oxo-4-p-tolyl-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile (4bc)
White solid (86%), m.p.: 253–255°C ([47] 257–259°C); 1H NMR (400 MHz, DMSO-d6): δ=7.91–7.88 (m, 2H, H-Ar), 7.60–7.56 (m, 2H, H-Ar), 7.44–7.31 (m, 4H, H-Ar), 7.02 (s, 2H, NH2), 4.40 (s, 1H, CH), 2.23 (s, 3H, CH3) ppm; 13C NMR (100 MHz, DMSO-d6): δ=164.9, 158.0, 153.3, 152.3, 140.4, 131.9, 129.1, 128.7, 126.6, 123.8, 118.1, 116.0, 113.0, 104.2, 58.2, 36.6, 35.7, 20.7 ppm; IR (KBr): 3451, 3310, 2935, 1685 cm−1.
2.1.17. 2-Amino-4-(4-chloro-phenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile (4cc)
White solid (85%), m.p.: 262–264°C ([47] 265–267°C); 1H NMR (400 MHz, DMSO-d6): δ=7.87–7.85 (m, 2H, H-Ar), 7.58–7.53 (m, 2H, NH2), 7.32–7.28 (m, 4H, H-Ar), 7.13 (d, J=8.4 Hz, 2H, H-Ar), 4.48 (s, 1H, CH) ppm; 13C NMR (100 MHz, DMSO-d6): δ=166.6, 158.0, 152.4, 142.4, 140.3, 131.6, 129.7, 128.7, 127.9, 124.1, 123.5, 118.8, 115.8, 103.6, 57.6, 36.5, 35.8 ppm; IR (KBr): 3456, 3306, 2934, 2191, 1686 cm−1.