Synthesis of 1,3-Azol-2-yl O-Heterocycles by Microwave-Irradiation-Assisted Direct C–H Functionalization

Abstract

A microwave-irradiation-assisted synthesis of novel 1,3-azol-2-yl-substituted O-heterocycles, namely flavones, chromones, coumarins, and chromanones, is reported. Starting from the appropriate bromo derivatives and 1,3-azoles, this palladium and copper co-catalyzed method provides moderate to good yields and excellent regioselectivity. The ligand- and base-free method can be a useful, generally applicable synthetic tool in the formation of new O-heterocycles.

Key words

O-heterocycles - azoles - palladium catalysis - copper catalysis - arylation - microwave heating

• References and Notes

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• 17 1,3-Azol-2-yl O-Heterocycles: General ProcedureA 10 mL vial equipped with a small magnetic stirring bar was charged with the appropriate bromo O-hetarene (1.0 equiv, 100 mg), Pd(OAc)₂ (5 mol%), and CuI (1.0 equiv). Anhyd DMF (1 mL) and the appropriate 1,3-azole (2.0 equiv) were added, and the vessel was purged with N₂ and sealed with a PEEK snap cap. The mixture was stirred for 5 min at r.t. before the vessel was placed in the microwave reactor and the mixture was heated to 140 °C with stirring for the appropriate time (usually 1 h). The solution was then cooled to r.t., diluted with EtOAc (15 mL), washed with sat. aq NH₄Cl (2 × 15 mL) and dilute aq Na₂S₂O₃ (10 mL). The aqueous phases were extracted with EtOAc (2 × 10 mL), and the organic phases were combined and washed with sat. aq NH₄Cl (10 mL) and brine. Some H₂O was added if any solids precipitated during the extraction. The combined organic phases were dried (MgSO₄), filtered, and concentrated. The residue was purified by column chromatography (silica gel).7-(1-Methyl-1H-imidazol-2-yl)-2-phenyl-4H-chromen-4-one (3a)Prepared from 7-bromoflavone (1; 100 mg, 0.33 mmol, 1.0 equiv) and 1-methyl-1H-imidazole (2a; 54 mg, 0.66 mmol, 2.0 equiv, 54 μL) according to the general procedure [eluent: EtOAc–MeOH (10:1)] as a pale-yellow solid; conversion: 100%; yield: 88 mg (88%); mp 206–207 °C. IR (KBr): 3432, 3095, 2923, 2853, 1650, 1627, 1607, 1476, 1450, 1421, 1376, 1281, 1148, 837, 771 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.30 (d, J = 8.3 Hz, 1 H, 5-H), 7.96–7.91 (m, 3 H, 2′,6′-H, 8-H), 7.72 (dd, J = 8.3, 1.4 Hz, 1 H, 6-H), 7.57–7.52 (m, 3 H, 3′,4′,5′-H), 7.20 (d, J = 0.6 Hz, 1 H, 5′′-H), 7.06 (s, 1 H, 4′′-H), 6.86 (s, 1 H, 3-H), 3.89 (s, 3 H, N-Me). ¹³C NMR (100 MHz, CDCl3): δ = 178.0 (C-4), 163.7 (C-2), 156.2 (C-8a), 145.7 (C-2′′), 135.9 (C-7), 131.7 (C-4′), 131.6 (C-1′), 129.3 (C-4′′), 129.1 (C-3′,5′), 126.3 (C-2′,6′), 126.0 (C-5), 124.9 (C-6), 123.7 (C-5′′), 123.5 (C-4a), 117.9 (C-8), 107.8 (C-3), 34.9 (C-N-Me). MS: m/z = 302.1 [M⁺], 301.1 [100%], 273.1, 219.1, 199.0, 171.0, 143.0. Anal. Calcd for C₁₉H₁₄N₂O₂: C, 75.48; H, 4.67; N, 9.27. Found: C, 75.51; H, 4.72; N, 9.30.
• 18 6-(1-Methyl-1H-benzimidazol-2-yl)-2-phenyl-4H-chromen-4-one (16b)Prepared from 6-bromoflavone (6; 100 mg, 0.33 mmol, 1.0 equiv) and 12 (87 mg, 0.66 mmol, 2.0 equiv) according to the general procedure (eluent: EtOAc) as a pale-brown solid; conversion: 100%; yield: 77 mg (66%); mp 210–212 °C. IR (KBr): 3441, 3073, 2924, 2853, 1643, 1622, 1569, 1451, 1428, 1354, 1141, 1023, 772, 741 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.54 (d, J = 2.2 Hz, 1 H, 5-H), 8.32 (dd, J = 8.7, 2.2 Hz, 1 H, 7-H), 7.97–7.93 (m, 2 H, 2′,6′-H), 7.83 (dd, J = 6.4, 2.3 Hz, 1 H, 4′′-H), 7.75 (d, J = 8.7 Hz, 8-H), 7.58–7.53 (m, 3 H, 3′,4′,5′-H), 7.42 (dd, J = 6.6 Hz, 2.3 Hz, 1 H, 7′′-H), 7.38–7.29 (m, 2 H, 5′′,6′′-H), 6.88 (s, 1 H, 3-H), 3.96 (s, 3 H, N-Me). ¹³C NMR (100 MHz, CDCl₃): δ = 177.7 (C-4), 163.6 (C-2), 156.7 (C-8a), 151.8 (C-2′′), 142.8 (C-3′′a), 136.7 (C-7′′a), 135.3 (C-7), 131.8 (C-4′), 131.4 (C-1′), 129.1 (C-3′,5′), 127.4 (C-6), 126.3 (C-2′,6′), 125.7 (C-5), 123.6 (C-4a), 123.1 (C-6′′), 122.7 (C-5′′), 119.9 (C-4′′), 119.2 (C-8), 109.8 (C-7′′), 107.7 (C-3), 31.9 (C-N-Me). MS: m/z = 353.25 [M + H]⁺ (100%), 279.17, 241.17, 189.9. Anal. Calcd for C₂₃H₁₆N₂O₂: C, 78.39; H, 4.58; N, 7.95. Found: C, 78.37; H, 4.59; N, 7.92.
• 19 7-(1,3-Oxazol-2-yl)-4H-chromen-4-one (18c)Prepared from 7-bromochromone (8; 100 mg, 0.44 mmol, 1.0 equiv) and 13 (61 mg, 0.88 mmol, 2.0 equiv, 58 μL) according to the general procedure [reaction time 1.5 h; eluent: hexane–EtOAc (1:1)] as a pale-yellow solid: conversion: 63%; yield: 29 mg (31%); mp 197–199 °C. IR (KBr): 3432, 3150, 3122, 3099, 3073, 2923, 2853, 1666, 1638, 1429, 1246, 1115, 1026, 827, 729 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.29 (d, J = 8.3 Hz, 1 H, 5-H), 8.13 (d, J = 1.1 Hz, 1 H, 8-H), 8.08 (dd, J = 8.3 Hz, 1.1 Hz, 1 H, 6-H), 7.90 (d, J = 6.0 Hz, 1 H, 2-H), 7.81 (s, 1 H, 5′-H), 7.33 (s, 1 H, 4′-H), 6.38 (d, J = 6.0 Hz, 1 H, 3-H). ¹³C NMR (100 MHz, CDCl₃): δ = 176.96 (C-4), 160.1 (C-2′), 156.5 (C-8a), 155.7 (C-2), 139.8 (C-5′), 132.1 (C-7), 129.1 (C-4′), 126.6 (C-5), 125.6 (C-4a), 122.8 (C-6), 115.97 (C-8), 113.3 (C-3). MS: m/z = 213.0 [M⁺] (100%), 185.0, 159.0, 130.0, 115.0, 102.0. Anal. Calcd for C₁₂H₇NO₃: C, 67.61; H, 3.31; N, 6.57. Found: C, 67.68; H, 3.35; N, 6.53.
• 20 7-(1,3-Thiazol-2-yl)-2H-chromen-2-one (19d)Prepared from 7-bromocoumarin 9 (100 mg, 0.44 mmol, 1.0 equiv) and 14a (61 mg, 0.88 mmol, 2.0 equiv, 58 μL) according to the general procedure [eluent: hexane–EtOAc (2:1)] as a yellow solid; conversion: 43%; yield: 36 mg (35%); mp 174–175 °C. IR (KBr): 3430, 3121, 3077, 2924, 2853, 1732, 1713, 1613, 1478, 1421, 1277, 1153, 1110, 1061, 930, 890, 853 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.93 (d, J = 3.2 Hz, 1 H, 5′-H), 7.91–7.87 (m, 2 H, 6-H, 8-H), 7.72 (d, J = 9.5 Hz, 1 H, 4-H), 7.55 (d, J = 8.5 Hz, 1 H, 5-H), 7.44 (d, J = 3.2 Hz, 1 H, 4′-H), 6.46 (d, J = 9.5 Hz, 1 H, 3-H). ¹³C NMR (100 MHz, CDCl₃): δ = 166.0 (C-2′), 160.3 (C-2), 154.3 (C-8a), 144.3 (C-5′), 142.7 (C-4), 136.6 (C-7), 128.4 (C-5), 122.4 (C-6), 120.3 (C-4′), 119.8 (C-4a), 117.2 (C-3), 114.5 (C-8). MS: m/z = 229.0 [M⁺] (100%), 201.0, 172.0, 143.0, 115.0, 58.0. Anal. Calcd for C₁₂H₇NO₂S: C, 62.87; H, 3 08; N, 6.11; S, 13.98. Found: C, 62.90; H, 3.06; N, 6.08; S, 13.99.
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• 22 7-(1-Methyl-1H-imidazol-2-yl)-2,3-dihydro-4H-chromen-4-one (20a)Prepared from 7-bromochroman-4-one (10; 100 mg, 0.44 mmol, 1.0 equiv) and 2a (72 mg, 0.88 mmol, 2.0 equiv, 70 μL) according to the general procedure [eluent: EtOAc–MeOH (95:5)] as a yellow solid; conversion: 100%; yield: 54 mg (54%); mp 117–119 °C. IR (KBr): 3444, 3107, 3076, 2955, 2924, 2854, 1685, 1615, 1564, 1475, 1421, 1405, 1325, 1283, 1180, 1038, 1025, 880 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.96 (d, J = 8.0 Hz, 1 H, 5-H), 7.33 (d, J = 8.0 Hz, 1 H, 6-H), 7.27 (s, 1 H, 8-H), 7.17 (br s, 1 H, 5-H), 7.02 (br s, 1 H, 4-H), 4.58 (t, J = 6.5 Hz, 2 H, –OCH₂–), 3.80 (s, 3 H, N-Me), 2.85 (t, J = 6.5 Hz, 2 H, –CH₂–). ¹³C NMR (100 MHz, CDCl₃): δ = 191.3 (C-4), 161.6 (C-8a), 145.98 (C-2′), 137.4 (C-7), 128.9 (C-5′), 127.4 (C-5), 122.1 (C-4′), 121.3 (C-6), 120.8 (C-4a), 117.5 (C-8), 67.1 (C-2), 37.6 (C-3), 34.8 (C-N-Me). MS: m/z = 228.1 [M⁺] (100%), 199.0, 171.0, 143.0, 117.0. Anal. Calcd for C₁₃H₁₂N₂O₂: C, 68.41; H, 5.30; N, 12.27. Found: C, 68.60; H, 5.58; N, 12.20.