3.1. Chemistry
3.1.1. General
Melting points were measured using an open capillary tube method with Stuart SMP10 melting point instrument and are uncorrected. Microanalysis was performed at the Regional Center for Mycology and Biotechnology, Al-Azhar University. The 1H NMR spectra were recorded on a Bruker (400 MHz) NMR spectrometer in chloroform (CDCl3) or dimethylsulphoxide (DMSO-d6). Chemical Shifts are reported in δ as parts per million (ppm) downfield from tetramethylsilane (TMS) as an internal standard, and J values were computed in Hz. Mass spectra were recorded as EI at 70 eV using Hewlett Packard Varian (Varian, Polo, Illinois, USA) and Shimadzu Gas Chromatograph Mass spectrometer-QP 1000 EX. TLC was performed using Macherey-Nagel AlugramSil G/UV254 silica gel plates with fluorescent indicator UV254, and the elution system was chloroform/methanol 98:2. The spots were detected at λ = 254 nm using a UV VilberLourmat 77202 (Vilber, Marne La Vallee, France).
3.1.2. General Procedure for Synthesis of 6-Ethyl-7-(3-oxobutan-2-yloxy)-4-substituted-2H-1-benzopyran-2-ones (2a,b)
A solution of compound 1a or 1b (0.01 mol) and 3-chlorobutan-2-one (1.06 g, 0.01 mol) in acetone (30 mL) and anhydrous potassium carbonate (2.76 g, 0.02 mol) was refluxed for 20 h. The solution was concentrated to dryness, and the formed residue was washed with water, dried, and finally crystallized from ethanol to give the titled products 2a or 2b.
6-Ethyl-4-methyl-7-(3-oxobutan-2-yloxy)-2H-1-benzopyran-2-one (2a)
Yield 85%; mp 95–97 °C; 1H NMR (400 MHZ, DMSO-d6) δ 1.21 (t, 3H, CH2CH3), 1.48 (d, 3H, J 8.0 Hz, OCHCH3), 2.21 (s, 3H, COCH3), 2.40 (s, 3H, CH3), 2.68 (q, 2H, CH2CH3), 5.16 (q, 1H, OCHCH3), 6.19 (s, 1H, Ar-H), 6.84 (s, 1H, Ar-H), 7.53 (s, 1H, Ar-H); MS (EI) m/z, calcd. for C16H18O4 (M+): 274.12, found: 274.15; Anal. Calc.: C, 70.06; H, 6.61, found: C, 70.22; H, 6.69.
6-Ethyl-7-(3-oxobutan-2-yloxy)-4-phenyl-2H-1-benzopyran-2-one (2b)
Yield 93%; mp 100–102 °C; 1H NMR (400 MHZ, DMSO-d6) δ 1.09 (t, 3H, CH2CH3), 1.50 (d, 3H, J 8.0 Hz, OCHCH3), 2.24 (s, 3H, COCH3), 2.59 (q, 2H, CH2CH3), 5.21 (q, 1H, OCHCH3), 6.21 (s,1H, H-3), 6.97 (s,1H, Ar-H), 7.20 (s,1H, Ar-H), 7.52–7.61 (m, 5H, Ph-4); MS (EI) m/z, calcd. for C21H20O4 (M+): 336.14, found: 336.05; Anal. Calc.: C, 74.98; H, 5.99, found: C, 75.19; H, 6.05.
3.1.3. General Procedure for Synthesis of 2,3-Dimethyl-9-ethyl-7-substituted-5H-furo[2,3-h]benzopyran-5-ones (3a,b)
A solution of compound 2a or 2b (0.002 mol) in absolute ethanol (15 mL) was treated with 1N NaOH (15 mL) and refluxed for 4–12 h (TLC monitored). The reaction was left to be concentrated overnight at room temperature. The residue was collected, acidified with 1N H2SO4, filtered, and dried. Finally, the crude product was crystallized from ethanol/petroleum ether to give the titled products 3a,b.
9-Ethyl-2,3,7-trimethyl-5H-furo[2,3-h]benzopyran-5-one (3a)
Yield 76%; Mp 199–201 °C; 1H NMR (400 MHZ, DMSO-d6) δ 1.18 (t, 3H, CH2CH3), 2.03 (s, 3H, CH3), 2.13 (s, 3H, CH3), 2.22 (s, 3H, CH3), 2.67 (q, 2H, CH2CH3), 6.73 (s, 1H, Ar-H), 7.37 (s, 1H, Ar-H); MS (EI) m/z, calcd. for C16H16O3 (M+): 256.11, found: 256.10; Anal. Calc.: C, 74.98; H, 6.29, found: C, 75.13; H, 6.38.
2,3-Dimethyl-9-ethyl-7-phenyl-5H-furo[2,3-h]benzopyran-5-one (3b)
Yield 63%; mp 90–92 °C; 1H NMR (400 MHZ, CDCl3) δ 1.26 (t, 3H, CH2CH3), 2.44 (s, 3H, CH3), 2.50 (s, 3H, CH3), 2.84 (q, 2H, CH2CH3), 6.30 (s, 1H, Ar-H), 7.06 (s, 1H, Ar-H), 7.28–7.58 (m, 5H, Ph-7); MS (EI) m/z, calcd. for C21H18O3 (M+): 318.13, found: 317.90; Anal. Calc.: C, 79.22; H, 5.70, found: C, 79.47; H, 5.76.
3.1.4. General Procedure for Synthesis of 6-Ethyl-7-(2-oxocyclohexyloxy)-4-substituted-2H-1-benzopyran-2-ones (4a,b)
A solution of compound 1a or 1b (0.01 mol) in acetone (30 mL) was treated with anhydrous potassium carbonate (2.76 g, 0.02 mol) and 2-chlorocyclohexanone (1.32 g, 0.01 mol). The reaction mixture was refluxed for 18–26 h and then filtered, and the obtained residue was rinsed with acetone. The filtrates and washings were combined and evaporated under reduced pressure. The obtained product was crystallized from ethanol/petroleum ether to give the titled products 4a or 4b.
6-Ethyl-4-methyl-7-(2-oxocyclohexyloxy)-2H-1-benzopyran-2-one (4a)
Yield 83%; mp 160–162 °C; 1H NMR (400 MHZ, DMSO-d6) δ 1.18 (t, 3H, CH2CH3), 1.79–1.89 (m, 2H, Ch-H*), 2.00–2.05 (m, 2H, Ch-H*), 2.30–2.33 (m, 2H, Ch-H*), 2.40 (s, 3H, CH3), 2.51 (t, 2H, Ch-H*), 2.65 (q, 2H, CH2CH3), 5.22 (t, 1H, Ch-H*), 6.16 (s, 1H, Ar-H), 6.89 (s, 1H, Ar-H), 7.5 (s, 1H, Ar-H); MS (EI) m/z, calcd. for C18H20O4 (M+): 300.14, found: 300.16; Anal. Calc.: C, 71.98; H, 6.71, found: C, 72.14; H, 6.74; *Ch-H: Cyclohexanone hydrogens.
6-Ethyl-7-(2-oxocyclohexyloxy)-4-phenyl-2H-1-benzopyran-2-one (4b)
Yield 86%; mp 150–152 °C; 1H NMR (400 MHZ, DMSO-d6) δ 1.08 (t, 3H, CH2CH3), 1.54–1.67 (m, 2H, Ch-H*), 1.80–1.90 (m, 2H, Ch-H*), 2.02–2.06 (m, 2H, Ch-H*), 2.31–2.41 (m, 2H, Ch-H*), 2.56 (q, 2H, CH2CH3), 5.27 (t, 1H, Ch-H*), 6.19 (s,1H, Ar-H), 7.02 (s,1H, Ar-H), 7.17 (s,1H, Ar-H), 7.46–7.61 (m, 5-H, Ph-4); MS (EI) m/z, calcd. for C23H22O4 (M+): 362.15, found: 362.00; Anal. Calc.: C, 76.22; H, 6.12, found: C, 76.39; H, 6.26; *Ch-H: Cyclohexanone hydrogens.
3.1.5. General Procedure for Synthesis of 6-Ethyl-4-substituted-8,9,10,11-tetrahydro-2H-benzofuro[2,3-h]benzopyran-2-ones (5a,b)
A suspension of compound 4a or 4b (0.002 mol) in absolute ethanol (15 mL) was treated with 1N NaOH (15 mL) and refluxed for 28 h till complete dissolution of the starting compound. The solution was filtered while hot and then cooled. The filtrate was acidified with 1N H2SO4. The formed precipitate was filtered, dried, and crystallized from ethanol/petroleum ether to give the titled product 5a or 5b.
6-Ethyl-4-methyl-8,9,10,11-tetrahydro-2H-benzofuro[2,3-h]benzopyran-2-one (5a)
Yield 71%; mp 150–152 °C; 1H NMR (400 MHZ, CDCl3) δ 1.37 (t, 3H, CH2CH3), 1.84–1.99 (m, 4H, Thb-H*), 2.42 (s, 3H, CH3), 2.77–3.01 (m, 4H, Thb-H*), 2.94 (q, 2H, CH2CH3), 6.22 (s, 1H, Ar-H), 7.18 (s, 1H, Ar-H); MS (EI) m/z, calcd. for C18H18O3 (M+): 282.13, found: 282.10; Anal. Calc.: C, 76.57; H, 6.43, found: C, 76.80; H, 6.49; *Thb-H: Tetrahydrobenzo hydrogens.
6-Ethyl-4-phenyl-8,9,10,11-tetrahydro-2H-benzofuro[2,3-h]benzopyran-2-one (5b)
Yield 56%; mp 108–110 °C; 1H NMR (400 MHZ, DMSO-d6) δ 1.00–1.03 (m, 4H, Thb-H*), 1.15 (t, 3H, CH2CH3), 2.71 (q, 2H, CH2CH3), 3.43–3.75 (m, 4H, Thb-H*), 6.28 (s, 1H, Ar-H), 6.99 (s, 1H, Ar-H), 7.51–7.60 (m, 5H, Ph-4); Anal. Calc. for C23H20O3 (344.40): C, 80.21; H, 5.85, found: C, 80.34; H, 5.91; *Thb-H: Tetrahydrobenzo hydrogens.
3.1.6. General Procedure for Synthesis of 6-Ethyl-4-substituted-2H-benzofuro[2,3-h]benzopyran-2-ones (6a,b)
A mixture of compound 5a or 5b (0.003 mol) and 2,3-dichloro-5,6-dicyano-1,4-benzo-quinone (DDQ) (0.5 g) in benzene (30 mL) was refluxed for 20 h. The reaction mixture was filtered while hot and then concentrated to dryness. The obtained residue was collected and crystallized from ethanol to give the titled products 6a or 6b.
6-Ethyl-4-methyl-2H-benzofuro[2,3-h]benzopyran-2-one (6a)
Yield 40%; mp 120–122 °C; 1H NMR (400 MHZ, CDCl3) δ 1.38 (t, 3H, CH2CH3), 2.53 (s, 3H, CH3), 3.04 (q, 2H, CH2CH3), 6.30 (s, 1H, Ar-H), 7.37 (s,1H, Ar-H), 7.42 (t, 1H, Ar-H), 7.53 (t, 1H, Ar-H), 7.62 (d, 1H, J 8.0 Hz, Ar-H), 8.39 (d, 1H, J 7.4 Hz, Ar-H); MS (EI) m/z, calcd. for C18H14O3 (M+): 278.09, found: 277.90; Anal. Calc.: C, 77.68; H, 5.07. Found: C, 77.92; H, 5.16.
6-Ethyl-4-phenyl-2H-benzofuro[2,3-h]benzopyran-2-one (6b)
Yield 41%; mp 120–122 °C; 1H NMR (400 MHZ, DMSO-d6) δ 1.18 (t, 3H, CH2CH3), 2.77 (q, 2H, CH2CH3), 6.32 (s,1H, Ar-H), 7.02 (s,1H, Ar-H), 7.50- 7.66 (m, 9H, 5Ph-H, 4Ar-H); MS (EI) m/z, calcd. for C23H16O3 (M+): 340.11, found: 340.00; Anal. Calc.: C, 81.16; H, 4.74, found: C, 81.39; H, 4.72.
3.1.7. General Procedure for Synthesis of 6-Ethyl-4-substituted-7-(un)substituted phenacyloxy-2H-1-benzopyran-2-ones (7a-f)
An appropriate 4-substituted phenacyl bromide (0.015 mol) was added to a solution of hydroxyl compound 1a or 1b (0.01 mol) in acetone (50 mL) while stirring in the presence of anhydrous potassium carbonate (2.76 g, 0.02 mol). The mixture was refluxed for 14 h (TLC monitored). Acetone was distilled off and the residue was rinsed with cold water, filtered, and dried. Finally, the crude residue was crystallized from ethanol to give the titled products 7a-7f.
6-Ethyl-4-methyl-7-phenacyloxy-2H-1-benzopyran-2-one (7a)
Yield 96%; mp 165–166 °C; 1H NMR (400 MHZ, DMSO-d6) δ 1.23 (t, 3H, CH2CH3), 2.41 (s, 3H, CH3), 2.73 (q, 2H, CH2CH3), 5.77 (s, 2H, OCH2CO), 6.19 (s, 1H, Ar-H), 7.06 (s, 1H, Ar-H), 7.55–7.73 (m, 4H, 1Ar-H and 3H, Ph-H), 8.04 (d, 2H, J 8.0 Hz, Ph-H); MS (EI) m/z, calcd. for C20H18O4 (M+): 322.12, found: 322.14. Anal. Calc.: C, 74.52; H, 5.63, found: C, 74.78; H, 5.69.
6-Ethyl-4-methyl-7-(4-methylphenacyloxy)-2H-1-benzopyran-2-one (7b)
Yield 95%; mp 136–139 °C; 1H NMR (400 MHZ, DMSO-d6) δ 1.21 (t, 3H, CH2CH3), 2.19 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.67 (q, 2H, CH2CH3), 5.72 (s, 2H, OCH2CO), 6.18 (s, 1H, Ar-H), 6.78–8.06 (m, 6H, 2Ar-H and 4H, Ph-H); MS (EI) m/z, calcd. for C21H20O4 (M+): 336.14, found: 336.79; Anal. Calc.: C, 74.98; H, 5.99, found: C, 75.14; H, 6.12.
6-Ethyl-4-methyl-7-(4-methoxyphenacyloxy)-2H-1-benzopyran-2-one (7c)
Yield 93%; mp 162–164 °C; 1H NMR (400 MHZ, DMSO-d6) δ 1.22 (t, 3H, CH2CH3), 2.41 (s, 1H, CH3), 2.72 (q, 2H, CH2CH3), 3.87 (s, 3H, OCH3), 5.69 (s, 2H, OCH2CO), 6.18 (s, 1H, Ar-H), 7.02 (s, 1H, Ar-H), 7.10 (d, 2H, J 8.0 Hz, Ph-H), 7.54 (s, 1H, Ar-H), 8.02 (d, 2H, J 8.0 Hz, Ph-H); MS (EI) m/z, calcd. for C21H20O5 (M+): 352.13, found: 352.05; Anal. Calc.: C, 71.58; H, 5.72, found: C, 71.81; H, 5.79.
6-Ethyl-7-phenacyloxy-4-phenyl-2H-1-benzopyran-2-one (7d)
Yield 97%; mp 153–155 °C; 1H NMR (400 MHZ, DMSO-d6) δ 1.12 (t, 3H, CH2CH3), 2.64 (q, 2H, CH2CH3), 5.82 (s, 2H, OCH2CO), 6.21 (s, 1H, Ar-H), 7.20 (d, 2H, J 8.0 Hz, Ph-H), 7.51–7.80 (m, 8H, 2Ar-H and 6H, Ph-H), 8.06 (d, 2H, J 8.0 Hz, Ph-H); MS (EI) m/z, calcd. for C25H20O4 (M+): 384.14, found: 384.09; Anal. Calc.: C, 78.11; H, 5.24, found: C, 78.34; H, 5.31.
6-Ethyl-7-(4-methylphenacyloxy)-4-phenyl-2H-1-benzopyran-2-one (7e)
Yield 95%; mp 225–226 °C; 1H NMR (400 MHZ, DMSO-d6) δ 1.17 (t, 3H, CH2CH3), 2.47 (s, 3H, CH3) 2.69 (q, 2H, CH2CH3), 5.83 (s, 2H, OCH2CO), 6.27 (s, 1H, Ar-H), 7.22 (s,1H, Ar-H), 7.27 (s, 1H, Ar-H), 7.46 (d, 2H, J 8.0 Hz, Ph-H), 7.59–7.66 (m, 5H, Ph-H), 8.01 (d, 2H, J 8.0 Hz, Ph-H); MS (EI) m/z, calcd. for C26H22O4 (M+): 398.15, found: 398.17; Anal. Calc.: C, 78.37; H, 5.57, found: C, 78.51; H, 5.61.
6-Ethyl-7-(4-methoxyphenacyloxy)-4-phenyl-2H-1-benzopyran-2-one (7f)
Yield 96%; mp 183–185 °C; 1H NMR (400 MHZ, DMSO-d6) δ 1.12 (t, 3H, CH2CH3), 2.63 (q, 2H, CH2CH3), 3.88 (s, 1H, OCH3), 5.74 (s, 2H, OCH2CO), 6.21(s, 1H, Ar-H), 7.14 (d, 2H, J 8.0 Hz, Ph-H), 7.21 (s, 1H, Ar-H), 7.54–7.60 (m, 6H, 1Ar-H and 5H, Ph-H), 8.04 (d, 2H, J 8.0 Hz, Ph-H); MS (EI) m/z, calcd. for C26H22O5 (M+): 414.15, found: 414.18; Anal. Calc.: C, 75.35; H, 5.35, found: C, 75.49; H, 5.32.
3.1.8. General Procedure for Synthesis of 9-Ethyl-7-substituted-3-(un)substituted phenyl-5H-furo[2,3-h]benzopyran-5-ones (8a-8f)
Compound 7a-7f (0.003 mol) was added to sodium ethoxide solution (0.07 g, 0.003 mol sodium metal in 50 mL ethanol) and the mixture was refluxed for 2 h. The solution was concentrated and then acidified with cold 10% HCl. The formed precipitate was filtered, washed with water, and crystallized from ethanol to give the titled products 8a-8f.
9-Ethyl-7-methyl-3-phenyl-5H-furo[2,3-h]benzopyran-5-one (8a)
Yield 40%; mp 103–105 °C; 1H NMR (400 MHZ, DMSO-d6) δ 1.34 (t, 3H, CH2CH3), 2.44 (s, 3H, CH3), 2.95 (q, 3H, CH2CH3), 6.32 (s, 1H, Ar-H), 7.56 (s, 1H, Ar-H), 7.42–7.56 (m, 3H, Ph-H), 7.72 (d, 2H, J 8.0 Hz, Ph-H), 8.28 (s, 1H, Ar-H); MS (EI) m/z, calcd. for C20H16O3 (M+): 304.11, found: 304.05; Anal. Calc.: C, 78.93; H, 5.30, found: C, 79.14; H, 5.28.
9-Ethyl-7-methyl-3-(4-methylphenyl)-5H-furo[2,3-h]benzopyran-5-one (8b)
Yield 42%; mp 149–151 °C; 1H NMR (400 MHZ, DMSO-d6) δ 1.16 (t, 3H, CH2CH3), 2.33 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.67 (q, 3H, CH2CH3), 6.23 (s, 1H, Ar-H), 6.69–7.67 (m, 5H, 1Ar-H and 4H, Ph-H), 8.25 (s, 1H, Ar-H); MS (EI) m/z, calcd. for C21H18O3 (M+): 318.13, found: 318.09; Anal. Calc.: C, 79.22; H, 5.70, found: C, 79.41; H, 5.78.
9-Ethyl-3-(4-methoxyphenyl)-7-methyl-5H-furo[2,3-h]benzopyran-5-one (8c)
Yield 44%; mp 110–111 °C; 1H NMR (400 MHZ, DMSO-d6) δ 1.22 (t, 3H, CH2CH3), 2.41 (s, 3H, CH3), 2.71 (q, 2H, CH2CH3), 3.87 (s, 3H, OCH3), 6.18 (s, 1H, Ar-H), 7.02 (s, 1H, Ar-H), 7.10 (d, 2H, J 8.0 Hz, Ph-H), 8.02 (d, 2H, J 8.0 Hz, Ph-H), 8.22 (s, 1H, Ar-H); MS (EI) m/z, calcd. for C21H18O4 (M+): 334.12, found: 334.13; Anal. Calc.: C, 75.43; H, 5.43, found: C, 75.68; H, 5.47.
3,7-Diphenyl-9-ethyl-5H-furo[2,3-h]benzopyran-5-one (8d)
Yield 94%; mp 178–180 °C; 1H NMR (400 MHZ, DMSO-d6) δ 1.23 (t, 3H, CH2CH3), 2.88 (q, 2H, CH2CH3), 6.35 (s, 1H, Ar-H), 7.21 (s, 1H, Ar-H), 7.44–7.61 (m, 8H, Ph-H), 7.76 (d, 2H, J 8.0 Hz, Ph-H), 8.34 (s, 1H, Ar-H); MS (EI) m/z, calcd. for C25H18O3 (M+): 366.13, found: 366.21; Anal. Calc.: C, 81.95; H, 4.95, found: C, 82.08; H, 5.01.
9-Ethyl-3-(4-methylphenyl)-7-phenyl-5H-furo[2,3-h]benzopyran-5-one (8e)
Yield 94%; mp 80–81 °C; 1H NMR (400 MHZ, DMSO-d6) δ 1.21 (t, 3H, CH2CH3), 2.31 (s, 3H, CH3), 2.78 (q, 3H, CH2CH3), 6.11(s, 1H, Ar-H), 7.33–7.69 (m, 10H, 1Ar-H and 9H, Ph-H), 8.27 (s, 1H, Ar-H); MS (EI) m/z, calcd. for C26H20O3 (M+): 380.14, found:380.17; Anal. Calc.: C, 82.08; H, 5.30, found: C, 82.17; H, 5.34.
9-Ethyl-3-(4-methoxyphenyl)-7-phenyl-5H-furo[2,3-h]benzopyran-5-one (8f)
Yield 90%; mp 150–153 °C; 1H NMR (400 MHZ, DMSO-d6) δ 1.12 (t, 3H, CH2CH3), 2.63 (q, 2H, CH2CH3), 3.88 (s, 3H, OCH3), 6.35 (s, 1H, Ar-H), 7.11 (d, 2H, J 8.6 Hz, Ph-H), 7.21 (d, 2H, Ph-H), 7.30 (s, 1H, Ar-H), 7.51–7.70 (m, 3H, Ph-H), 8.03 (d, 2H, J 8.0 Hz, Ph-H), 8.26 (s, 1H, Ar-H); MS (EI) m/z, calcd. for C26H20O4 (M+): 396.14, found: 396.22; Anal. Calc.: C, 78.77; H, 5.09, found: C, 78.84; H, 5.15.