3.2. General Procedure for the Synthesis of Compounds 2
A mixture of
1 (1.0 mmol) and TEAB (0.36 g, 1.0 mmol) was dissolved in ethanol (20 mL) and water (1.75 mL). The reaction mixture was stirred with the evolution of heat; to this mixture was added dropwise with stirring 1.0 M NaOH aqueous solution in the amount indicated in
Table 1,
Table 2,
Table 3,
Table 4,
Table 5 and
Table 6 (0.1, 0.3, 0.5, 1.0, 1.2, 1.5 and 2.0 equivalents) until the mixture temperature reached 40 °C. The reaction mixture was stirred until complete consumption of the starting diester
1 was observed by TLC. The solution was then poured into water (150 mL) and acidified to pH 1–2 with 6.0 M HCl at 5–10 °C. A fine white precipitate was formed and filtered off, washed with ice water until reaching pH 7 and dried under vacuum.
5-(ethoxycarbonyl)-2,6-dimethyl-4-aryl-4H-pyran-3-carboxylic acid (2a). Yield (0.24 g, 80%), Mp 98.3–100.0 °C. IR: 705, 1191, 1626, 1664, 1709, 2372, 2981, 3432 cm−1. 1H-NMR: δ = 1.21–1.23 (t, 3 H, CH2CH3), 2.38 (s, 6 H, CH3), 4.10–4.13 (m, 2 H, CH2CH3), 4.75 (s, 1 H, Ar–CH), 7.15 (d, J = 8.8 Hz, 2 H, Ar–H), 7.27 (d, J = 8.8 Hz, 2 H, Ar–H), 10.40–13.05 (s, 1 H, COOH).13C-NMR: δ = 14.2, 15.6, 41.8, 61.7, 106.6, 107.3, 125.8, 128.7, 129.1, 142.2, 156.6, 159.4. HRMS: m/z [M + K]+ calcd for C17H18O5K: 341.1218; found: 341.1220.
5-(ethoxycarbonyl)-2,6-dimethyl-4-p-tolyl-4H-pyran-3-carboxylic acid (2b). Yield (0.22 g, 69%), Mp 123.6–124.7 °C. IR: 933, 1191, 1621, 1699, 2373, 2982, 3430 cm−1. 1H-NMR: δ = 1.19–1.23 (t, 3 H, CH2CH3), 2.32 (s, 3 H, CH3), 2.38 (s, 6 H, CH3), 4.09–4.11 (m, 2 H, CH2CH3), 4.75 (s, 1 H, Ar–CH), 7.10 (d, J = 8.8 Hz, 2 H, Ar–H), 7.15 (d, J = 8.8 Hz, 2 H, Ar–H), 11.00–12.98 (s, 1 H, COOH).13C-NMR: δ = 14.2, 15.6, 24.3, 41.8, 61.7, 106.6, 107.3, 129.0, 135.4, 139.2, 156.6, 159.4, 167.2, 171.3. HRMS: m/z [M + Na]+calcd for C18H20O5Na: 339.1326; found: 339.1322.
5-(ethoxycarbonyl)-4-(4-methoxyphenyl)-2,6-dimethyl-4H-pyran-3-carboxylic acid (2c): Yield (0.17 g, 51%), Mp 110.3–112.0 °C. IR: 932, 1180, 1625, 1715, 2371, 2982, 3433 cm−1; 1H-NMR: δ = 1.12–1.24 (t, 3 H, CH2CH3), 2.36 (s, 6 H, CH3), 3.77 (s, 3 H, OCH3), 4.07–4.13 (m, 2 H, CH2CH3), 4.77 (s, 1 H, Ar–CH), 6.98 (d, J = 8.8 Hz, 2 H, Ar–H), 7.35 (d, J = 8.8 Hz, 2 H, Ar–H), 11.10–13.90 (s, 1 H, COOH).13C-NMR: δ = 14.1, 18.5, 19.1, 37.2, 55.1, 60.3, 107.6, 108.8, 113.4, 129.3, 137.4, 157.8, 158.3, 160.4, 166.5, 171.3. HRMS: m/z [M − H]+ calcd for C18H20O6: 331.1323; found: 331.1319.
4-(4-chlorophenyl)-5-(ethoxycarbonyl)-2,6-dimethyl-4H-pyran-3-carboxylic acid (2d): Yield (0.23 g, 66%), Mp 141.8–143.1 °C. IR: 853, 1180, 1655, 1718, 2372, 2983, 3436 cm−1; 1H-NMR: δ = 1.21–1.24 (t, 3 H, CH2CH3), 2.37 (s, 6 H, CH3), 4.09–4.13 (m, 2 H, CH2CH3), 4.71 (s, 1 H, Ar–CH), 6.87 (d, J = 8.8 Hz, 2 H, Ar–H), 7.27 (d, J = 8.8 Hz, 2 H, Ar–H), 11.3 (s, 1 H, COOH).13C-NMR: δ = 14.1, 18.5, 19.1, 37.2, 55.1, 60.3, 107.6, 108.8, 113.4, 129.3, 137.4, 157.8, 158.3, 160.4, 166.5, 172.2. HRMS: m/z [2M - CH3]+ calcd for C17H17ClO5: 687.2383; found: 687.2388.
4-(3-chlorophenyl)-5-(ethoxycarbonyl)-2,6-dimethyl-4H-pyran-3-carboxylic acid (2e): Yield (0.18 g, 54%), Mp 132.1–133.4 °C. IR: 853, 1188, 1656, 1718, 2372, 2983, 3433 cm−1; 1H-NMR: δ = 1.23–1.27 (t, 3 H, CH2CH3), 2.39 (s, 6 H, CH3), 4.10–4.17 (m, 2 H, CH2CH3), 4.76 (s, 1 H, Ar–CH), 7.09 (d, J = 8.8 Hz, 2 H, Ar–H), 7.38 (d, J = 8.8 Hz, 2 H, Ar–H), 10.40–13.40 (s, 1 H, COOH).13C-NMR: δ = 14.1, 18.5, 19.1, 37.2, 55.1, 60.3, 107.6, 108.8, 113.4, 129.3, 137.4, 157.8, 158.3, 163.4, 165.4, 176.3. HRMS: m/z [M − H]+ calcd for C17H17ClO5: 335.0821; found: 335.0821.
5-(ethoxycarbonyl)-4-(4-fluorophenyl)-2,6-dimethyl-4H-pyran-3-carboxylic acid (2f): Yield (0.22 g, 69%), Mp 137.4–139.1 °C. IR: 849, 1128, 1192, 1710, 2372, 2983, 3152, 3425 cm−1; 1H-NMR: δ = 1.18–1.21 (t, 3 H, CH2CH3), 2.39 (s, 6 H, CH3), 4.06–4.11 (m, 2 H, CH2CH3), 4.72 (s, 1 H, Ar–CH), 6.98 (d, J = 8.8 Hz, 2 H, Ar–H), 7.25 (d, J = 8.8 Hz, 2 H, Ar–H), 11.70–12.80 (s, 1 H, COOH).13C-NMR: δ = 14.1, 18.5, 19.2, 37.3, 60.4, 107.4, 108.5, 114.7, 114.9, 129.8, 129.9, 140.8, 158.3, 160.4, 162.8, 166.3, 172.3. HRMS: m/z [M – CH3]+ calcd for C17H17FO5: 305.1561; found: 305.1556.
5-(ethoxycarbonyl)-2,6-dimethyl-4-(4-nitrophenyl)-4H-pyran-3-carboxylic acid (2g): Yield (0.16 g, 49%), Mp 110.1–111.7 °C. IR: 874, 1167, 1347, 1624, 1721, 2349, 2938, 3077, 3462 cm−1. 1H-NMR: δ = 1.18–1.21 (t, 3 H, CH2CH3), 2.39 (s, 6 H, CH3), 4.06–4.11 (m, 2 H, CH2CH3), 4.84 (s, 1 H, Ar–CH), 7.26 (d, J = 8.8 Hz, 2 H, Ar–H), 7.42 (d, J = 8.8 Hz, 2 H, Ar–H), 10.90–13.20 (s, 1 H, COOH).13C-NMR: δ = 14.1, 18.6, 19.2, 38.3, 60.7, 106.4, 107.5, 123.4, 129.3, 146.7, 152.3, 159, 161.7, 165.8, 171.5. HRMS: m/z [M − H]+ calcd for C17H17NO7: 335.0831; found: 335.0830.
5-(ethoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-4H-pyran-3-carboxylic acid (2h): Yield (0.13 g, 40%), Mp 121.4–121.9 °C. IR: 900, 1221, 1348, 1652, 1703, 2372, 2952, 3091, 3348 cm−1. 1H-NMR: δ = 1.19–1.22 (t, 3 H, CH2CH3), 2.30 (s, 6 H, CH3), 4.11–4.17 (m, 2 H, CH2CH3), 4.89 (s, 1 H, Ar–CH), 7.21 (d, J = 8.8 Hz, 2 H, Ar–H), 7.42 (d, J = 8.8 Hz, 2 H, Ar–H), 10.84-12.40 (s, 1 H, COOH).13C-NMR: δ = 14.1, 18.6, 19.2, 38.6, 62.7, 106.4, 107.5, 123.4, 129.3, 146.7, 152.3, 160.3, 162.7, 165.8, 175.4. HRMS: m/z [M]+ calcd for C17H17NO7: 336.0815; found: 336.0816.
4-(3-bromophenyl)-5-(ethoxycarbonyl)-2,6-dimethyl-4H-pyran-3-carboxylic acid (2i): Yield (0.24 g, 62%), Mp 161.4–162.7 °C. IR: 900, 1221, 1380, 1628, 1700, 2372, 2952, 3091, 3348 cm−1. 1H-NMR: δ = 1.22–1.25 (t, 3 H, CH2CH3), 2.34 (s, 6 H, CH3), 4.09–4.15 (m, 2 H, CH2CH3), 4.73 (s, 1 H, Ar–CH), 7.10 (s, J = 8.8 Hz, 2 H, Ar–H), 7.15–7.35 (m, J = 8.8 Hz, 3 H, Ar–H), 11.40–13.20 (s, 1 H, COOH).13C-NMR: δ = 14.2, 17.6, 28.3, 38.2, 61.7, 106.6, 107.3, 125.4, 128.3, 146.2, 156.3, 159.4, 160.7, 165.4, 174.3. HRMS: m/z [M + Na]+ calcd for C17H17BrO5Na: 403.0315; found: 403.0315.
4-(3-acetamidophenyl)-5-(ethoxycarbonyl)-2,6-dimethyl-4H-pyran-3-carboxylic acid (2j): Yield (0.07 g, 20%), Mp 181.2–183.2 °C. IR: 888, 1188, 1330, 1652, 1717, 2345, 2983, 3061, 3425 cm−1. 1H-NMR: δ = 1.20–1.24 (t, 3 H, CH2CH3), 2.16 (s, 3 H, NHCOCH3), 2.34 (s, 6 H, CH3), 4.07–4.14 (m, 2 H, CH2CH3), 4.92 (s, 1 H, Ar–CH), 6.94–7.23 (m, 4 H, Ar–H), 7.44 (s, 1 H, NHCOCH3), 11.60–13.50 (s, 1 H, COOH).13C-NMR: δ = 14.2, 18.6, 22.9, 41.8, 60.7, 106.6, 107.3, 118.4, 124.3, 128.7, 138.3, 142.4, 156.6, 165.8, 167.2, 173.3. HRMS: m/z [M + Na]+ calcd for C19H21NO6Na: 382.1464; found: 382.1455.
5-(ethoxycarbonyl)-2,6-dimethyl-4-(2,3,4-trimethoxyphenyl)-4H-pyran-3-carboxylic acid (2k): Yield (0.16 g, 42%), Mp 149.1–150.4 °C. IR: 793, 1048, 1147, 1189, 1291, 1397, 1494, 1645, 1724, 2935, 3037, 3444 cm−1. 1H-NMR: δ = 1.21–1.25 (t, 3 H, CH2CH3), 2.32 (s, 6 H, CH3), 3.84 (t, 9 H, OCH3), 4.08–4.16 (m, 2 H, CH2CH3), 4.77 (s, 1 H, Ar–CH), 7.20 (d, J = 8.8 Hz, 1 H, Ar–H), 7.34 (d, J = 8.8 Hz, 1 H, Ar–H), 10.95-12.70 (s, 1 H, COOH).13C-NMR: δ = 14.2, 17.6, 41.7, 56.5, 61.7, 106.6, 107.5, 113.4, 128.4, 139.1, 145.8, 157.6, 167.2, 171.3, 174.4. HRMS: m/z [M + Na]+calcd for C21H27O8Na: 415.1527; found: 415.1526.