Divergent Pathways for Reactions of 3-Formylchromone with Cyclic Secondary Amines in Alcoholic Media

Abstract

Reaction of 3-formylchromone with cyclic secondary amines in methanol results in (E)-2-methoxy-3-(R₂N-methylene)chroman-4-ones, while use of ethanol leads to (E)-2-morpholino-3-(morpholino­methylene)chroman-4-one or enaminoketones as dihydropyran ring-opening products. The solubility of the formed products in alcoholic media is postulated to be a key factor that determines the reaction pathway.

Key words

3-formylchromone - 4-chromanone - cyclic secondary amines - Michael reaction - enamino ketones - 1H-azoles

• References and Notes


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• 7 Synthesis of Products 2–4; General Procedure A solution of cyclic secondary amine (1 mmol for 3; 2 mmol for 2; 4 mmol for 4) in MeOH (1.5 mL for 3) or EtOH (1.5 mL for 2 and 4) was added dropwise to a stirred suspension of 3-formylchromone 1 (174 mg, 1 mmol for 2 and 3; 348 mg, 2 mmol for 4) in MeOH (1.5 mL for 3) or EtOH (1.5 mL for 2, 4 mL for 4) in 10 min. The resulting mixture was stirred at room temperature for 2 h (for 2 and 3) or 1 h (for 4), then was stored at –30 °C overnight. The precipitate formed was filtered off, washed with ice-cold MeOH, and then recrystallized from the appropriate solvent.
• 8 (E)-1-(2-Hydroxyphenyl)-3-(pyrrolidin-1-yl)prop-2-en-1-one (2a)Yield: 115 mg (53%); yellow crystals; mp 135–137 °C (benzene). IR (ATR): 3300–2500 (OH), 1632 (C=O), 1603, 1587, 1512, 1435, 1350, 1317, 1263, 1219, 1188, 1177, 1144, 1103, 1067, 1026, 1003, 953, 939, 914, 810, 745 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.79–1.86 (m, 2 H, CH₂), 1.90–1.97 (m, 2 Н, CH₂), 3.28–3.32 (m, 2 Н, CH₂N), 3.57–3.61 (m, 2 Н, CH₂N), 5.83 (d, J = 12.1 Hz, 1 Н, CH=CHN), 6.76–6.80 (m, 2 Н, Ar), 7.29–7.34 (m, 1 Н, Ar), 7.84 (d, J = 7.8 Hz, 1 Н, Ar), 8.04 (d, J = 12.1 Hz, 1 Н, CH=CHN), 14.49 (s, 1 Н, OH). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 25.1 (CH₂), 25.2 (CH₂), 47.8 (CH₂N), 53.0 (CH₂N), 90.7 (CH=CHN), 118.0 (CH), 118.5 (CH), 120.5 (C), 129.2 (C), 134.3 (CH), 151.7 (CH=CHN), 163.0 (C), 190.1 (C=O). Anal. Calcd for C₁₃H₁₅NO₂: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.91; H, 7.05; N, 6.34.(E)-2-Methoxy-3-(morpholinomethylene)chroman-4-one (3a)Yield: 132 mg (48%); light-yellow crystals; mp 140–142 °C (MeOH). IR (ATR): 1641 (C=O), 1605, 1585, 1539, 1433, 1366, 1342, 1319, 1244, 1180, 1103, 1061, 993, 953, 924, 754, 648 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.33 (s, 3 H, MeO), 3.46–3.71 (m, 8 H, 4 × CH₂), 6.10 (s, 1 H, H-2), 6.99 (d, J = 8.2 Hz, 1 H, H-8), 7.03 (td, J = 7.6, 0.9 Hz, 1 H, H-6), 7.40–7.45 (m, 1 H, H-7), 7.59 (s, 1 H, =CHN), 7.72 (dd, J = 7.6, 1.8 Hz, 1 H, H-5). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 51.5 (br. signal, 2 × CH₂N), 54.9 (MeO), 66.5 (2 × CH₂O), 99.1 (CH-2), 100.8 (C-3), 118.1 (CH-8), 122.2 (CH-6), 123.5 (C-4a), 126.5 (CH-5), 134.1 (CH-7), 150.2 (=CHN), 156.2 (C-8a), 178.0 (C=O). Anal. Calcd for C₁₅H₁₇NO₄: C, 65.44; H, 6.22; N, 5.09. Found: C, 65.36; H, 6.17; N, 5.17.(E)-2-Morpholino-3-(morpholinomethylene)chroman-4-one (4)Yield: 442 mg (67%); yellow crystals; mp 183–184 °C (EtOH). IR (ATR): 1630 (C=O), 1601, 1582, 1530, 1510, 1462, 1435, 1325, 1304, 1296, 1244, 1219, 1152, 1111, 1015, 972, 943, 930, 901, 781, 772, 752 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.42 (br. s, 2 H, CH₂N), 2.71–2.76 (m, 2 Н, CH₂N), 3.40 (br. s, 4 Н, 2 × CH₂N), 3.54–3.76 (m, 8 H, 4 × CH₂O), 5.98 (s, 1 H, H-2), 6.87–6.93 (m, 2 H, H-6,8), 7.37 (ddd, J = 8.9, 7.3, 1.8 Hz, 1 H, H-7), 7.67–7.70 (m, 2 H, H-5, NCH=). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 47.3 (2 × CH₂N), 52.1 (br. signal, 2 × CH₂N), 66.9 (2 × CH₂O), 67.0 (2 × CH₂O), 91.1 (CH-2), 97.8 (C-3), 116.6 (CH), 120.9 (CH), 122.6 (C), 126.6 (CH), 134.4 (CH), 149.7 (NCH=), 159.8 (C-8a), 178.7 (C=O). Anal. Calcd for C₁₈H₂₂N₂O₄: C, 65.44; H, 6.71; N, 8.48. Found: C, 65.51; H, 6.66; N, 8.35.
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• 14 Synthesis of 3,3′-[(1H-Imidazol-1-yl)methylene]bis(4H-chromen-4-one) (5a)A mixture of 3-formylchromone 1 (174 mg, 1 mmol) and imidazole (68 mg, 1 mmol) was heated under reflux in MeOH (5 mL) for 35 h. The resulting solution was stored at –30 °C overnight, the precipitate formed was filtered and recrystallized from MeOH. Yield: 104 mg (28%); colorless crystals; mp 216–217 °C. IR (ATR): 1634, 1607, 1574, 1476, 1464, 1408, 1396, 1356, 1321, 1248, 1217, 1179, 1167, 1157, 1136, 1113, 1090, 1020, 957, 908, 856, 824, 773, 756, 692, 660 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 6.81 (s, 1 H, CHN), 6.93 (s, 1 H, H_imidazole), 7.32 (s, 1 H, H_imidazole), 7.49 (t, J = 7.6 Hz, 2 H, Ar), 7.64 (d, J = 8.5 Hz, 2 H, Ar), 7.78–7.83 (m, 3 H, Ar, H-2_imidazole), 7.99 (s, 2 H, Н_α-pyrone), 8.03 (d, J = 7.8 Hz, 2 H, Ar). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 49.3 (CHN), 119.1 (2 × CH), 119.9 (CH_imidazole), 121.8 (2 × C), 123.7 (2 × C), 125.6 (2 × CH), 126.3 (2 × CH), 129.3 (CH_imidazole), 135.1 (2 × СH), 138.2 (CH_imidazole), 156.1 (2 × CH_α-pyrone), 156.5 (2 × C-8a), 175.4 (2 × C=O). Anal. Calcd for C₂₂H₁₄N₂O₄: C, 71.35; H, 3.81; N, 7.56. Found: C, 71.28; H, 3.74; N, 7.44.