N-Arylation of Heterocycles by a Tandem Aza-Michael Addition Reaction and Aromatization Sequence

Abstract

Cyclohexa-2,4-dien-1-one derivatives, upon reaction with N-heterocycles in the presence of scandium(III) triflate, underwent a tandem Michael addition reaction followed by aromatization of the ­Michael adduct generated in situ to give N-aryl heterocycles in good yields. Because of the ready accessibility of variously substituted cyclohexa-2,4-dien-1-ones, a range of N-aryl heterocycles have become available.

Key words

cyclohexadienones - arylation - tandem reaction - aromatization - aza-Michael reaction - aryl heterocycles

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• 16 2-Methoxy-3-methyl-5-(1H-pyrazol-1-yl)phenol (1a): Typical Procedure Sc(OTf)₃ (30 mg, 0.06 mmol)was added to a solution of dienone 1 (100 mg, 0.60 mmol) and 1H-pyrazole (a; 40 mg, 0.60 mmol) in anhyd CH₃CN (2.5 mL), and the mixture was stirred at r.t. for 8 h. The solvent was then evaporated and the residue was purified by column chromatography (silica gel, EtOAc–hexanes) to give an off-white solid; yield: 106 mg (88%). ¹H NMR (400 MHz, CDCl₃): δ = 7.78 (app d, J = 2.4 Hz, 1 H), 7.68 (app d, J = 1.6 Hz, 1 H), 7.10 (d, J = 2.4 Hz, 1 H), 7.04 (dd, J = 2.4, 0.4 Hz, 1 H), 6.59 (br s, 1 H), 6.41 (dd, J = 2.4, 2.0 Hz, 1 H), 3.78 (s, 3 H), 2.32 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 149.6 (C), 144.2 (C), 140.7 (CH), 136.4 (C), 131.9 (C), 127.0 (CH), 113.2 (CH), 107.2 (CH), 105.2 (CH), 60.6 (CH₃), 16.0 (CH₃). ESI-MS: m/z = 205 [C₁₁H₁₂N₂O₂ + H]⁺. 5-(1H-1,2,3-Benzotriazol-1-yl)-3-bromo-2-methoxyphenol (5c) Off-white solid; yield: 107 mg (78%). ¹H NMR (400 MHz, DMSO-d ₆): δ = 10.6 (s, 1 H), 8.16 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 8.4 Hz, 1 H), 7.66 (t, J = 7.6 Hz, 1 H), 7.53–7.48 (m, 2 H), 7.36 (d, J = 2.4 Hz, 1 H), 3.85 (s, 3 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 152.2 (C), 145.6 (C), 145.2 (C), 132.9 (C), 131.7 (C), 128.8 (CH), 124.8 (CH), 119.7 (CH), 117.5 (C), 116.7 (CH), 110.9 (CH), 110.8 (CH), 60.0 (CH₃). ESI-MS: m/z = 320 [C₁₃H₁₀BrN₃O₂ + H]⁺. 5-(2H-1,2,3-Benzotriazol-2-yl)-3-bromo-2-methoxyphenol (5c′) Off-white solid; yield: 7 mg (5%). ¹H NMR (400 MHz, CDCl₃): δ = 8.15 (d, J = 2.4 Hz, 1 H), 7.96 (d, J = 2.4 Hz, 1 H), 7.93–7.89 (m, 2 H), 7.45–7.41 (m, 2 H), 5.92 (s, 1 H), 3.99 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 150.4 (C), 145.118 (C), 145.100 (C), 137.4 (C), 127.5 (CH x 2), 127.3 (C), 118.4 (CH × 2), 116.7 (CH), 116.2 (C), 107.8 (CH), 61.4 (CH₃). ESI-MS: m/z = 320 [C₁₃H₁₀BrN₃O₂ + H]⁺. 3-Bromo-2-methoxy-5-(1H-1,2,3-triazol-1-yl)phenol (5e) Off-white solid; yield: 65 mg (56%). ¹H NMR (400 MHz, DMSO-d ₆): δ = 10.6 (br s, 1 H), 8.86 (d, J = 1.2 Hz, 1 H), 8.02 (d, J = 1.2 Hz, 1 H), 7.68 (d, 2.4 Hz, 1 H), 7.55 (d, J = 2.4 Hz, 1 H), 3.88 (s, 3 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 152.0 (C), 144.9 (C), 134.4 (CH), 133.3 (C), 123.3 (CH), 117.4 (C), 114.0 (CH), 108.3 (CH), 60.0 (CH₃). ESI-MS: m/z = 270[C₉H₈BrN₃O₂ + H]⁺. 3-Bromo-2-methoxy-5-(2H-1,2,3-triazol-2-yl)phenol (5e′) Off-white solid; yield: 32 mg (28%). ¹H NMR (400 MHz, CD₃OD): δ = 7.87 (s, 2 H), 7.71 (d, J = 2.4 Hz, 1 H), 7.57 (d, J = 2.4 Hz, 1 H), 3.85 (s, 3 H). ¹³C NMR (100 MHz, CD₃OD): δ = 153.2 (C), 146.1 (C), 137.9 (C), 137.0 (CH x 2), 118.5 (C), 114.6 (CH), 107.9 (CH), 61.0 (CH₃). ESI-MS: m/z = 270[C₉H₈BrN₃O₂ + H]⁺. 4-Chloro-2-[(4-hydroxy-3-methoxy-2-methylphenyl)(methyl)amino]benzoic acid (22) Yellow solid; yield: 128 mg (63%). ¹H NMR (400 MHz, CDCl₃): δ = 7.93 (d, J = 8.4 Hz, 1 H), 6.94 (dd, J = 8.4, 1.6 Hz, 1 H), 6.87 (d, J = 10.0 Hz, 1 H), 6.79 (d, J = 1.6 Hz, 1 H), 6.22 (d, J = 10.0 Hz, 1 H), 3.83 (s, 3 H), 2.71 (s, 3 H), 2.08 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 179.8 (C), 160.7 (C), 151.5 (C), 148.3 (C), 143.2 (C), 139.2 (CH), 136.2 (C), 132.3 (CH), 129.5 (CH), 120.4 (CH), 113.4 (CH), 110.0 (C), 91.0 (C), 60.3 (CH₃), 31.4 (CH₃), 11.1 (CH₃). ESI-MS: m/z = 322 [C₁₆H₁₆ClNO₄ + H]⁺. 6-Chloro-2-hydroxy-3-methoxy-4,10-dimethylacridin-9(10H)-one (23) POCl₃ (0.15 mL, 1.55 mmol) was added to a suspension of acid 22 (100 mg, 0.31 mmol) in CHCl₃ (3 mL) under argon, and the tube was sealed. The mixture was heated to 80 °C for 16 h then cooled. C₂H₅OH (3 mL) was added slowly to the mixture to quench excess POCl₃, and the mixture was stirred for 30 min at r.t. The solvents were evaporated, the residue was mixed with sat. aq NaHCO₃ (20 mL), and the product was extracted into EtOAc (3 × 25 mL). The extracts were further purified by column chromatography (silica gel, EtOAc–hexanes) to give an off-white solid; yield: 63 mg (67%). ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.73 (s, 1 H), 8.14 (d, J = 8.8 Hz, 1 H), 7.73 (d, J = 1.6 Hz, 1 H), 7.57 (s, 1 H), 7.27 (dd, J = 8.8, 1.6 Hz, 1 H), 3.88 (s, 3 H), 3.81 (s, 3 H), 2.46 (s, 3 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 175.8 (C), 153.0 (C), 146.8 (C), 146.3 (C), 140.0 (C), 138.0 (C), 127.9 (CH), 121.1 (CH), 120.9 (C), 120.8 (C), 120.0 (C), 117.1 (CH), 108.4 (CH), 59.7 (CH₃), 43.2 (CH₃), 15.4 (CH₃). ESI-MS: m/z = 304 [C₁₆H₁₄ClNO₃ + H]⁺.