Facile Installation of β-Hydroxyarylethylamino Motifs at the C2-Position of Quinoline Moiety via Copper-Catalyzed [3+3]-Cycloaddition Reaction of N-Oxide with N-Ts Aziridine

Abstract

A general and atom-efficient synthesis of quinoline-C2-substituted β-hydroxyarylethylamino derivatives was achieved by copper-catalyzed [3+3]-cycloaddition reaction of N-oxide with N-Ts aziridines. Notably, temperature has a huge impact on this transformation as evidenced by the fact that, at 80 °C, exclusively the [3+3] cycloadduct was isolated whereas, at elevated temperature (140 °C), it has been converted into the aminated product with good yield. Notably, there is no byproduct in the overall process. The use of base-free conditions, excellent site selectivity, and good functional group tolerance are the important features of the process.

Key words

β-hydroxyarylethylamino motifs - [3+3]-cycloaddition reaction - C–H functionalization - atom economy - one-pot reaction

Publikationsverlauf

Eingereicht: 08. Juli 2023

Angenommen nach Revision: 29. September 2023

Accepted Manuscript online:
29. September 2023

Artikel online veröffentlicht:
10. November 2023

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• 12 General Procedure for the Synthesis of Quinoline-C2-substituted β-Hydroxyarylethylamino Derivatives (GP) In an oven-dried Schlenk tube, Cu(OTf)₂ (10 mol%), N-oxide 1 (0.5 mmol, 1 equiv.), N-Ts aziridine 2 (0.5 mmol, 1 equiv.), and chlorobenzene (1.5 mL) were taken under argon. The reaction mixture was heated gradually from room temperature to 80 °C for 15 h. After complete consumption of the starting reactants as observed by TLC, the temperature was increased to 140 °C, and the mixture was stirred for another 33 h. Then the volatile portion was removed under vacuum, and the crude product was purified through silica gel column chromatography to obtain the analytically pure product. N-(2-Hydroxy-2-phenylethyl)-N-(6-methoxyquinolin-2-yl)-4-methylbenzenesulfonamide (3a) Following the general procedure, the title compound 3a was isolated as colorless oil using silica gel column chromatography with petroleum ether/ethyl acetate (v/v = 3/2, R_f = 0.4) in 86% yield (193 mg). ¹H NMR (400 MHz, chloroform-d): δ = 8.45 (d, J = 2.8 Hz, 1 H), 7.87 (d, J = 9.2 Hz, 1 H), 7.74 (d, J = 8.1 Hz, 2 H), 7.35–7.30 (m, 5 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.17 (dd, J = 9.1, 2.8 Hz, 1 H), 6.99 (d, J = 2.8 Hz, 1 H), 6.79 (d, J = 2.8 Hz, 1 H), 5.30–5.26 (m, 1 H), 5.03–4.99 (m, 1 H), 3.87 (s, 3 H), 3.55–3.49 (m, 1 H), 3.40–3.34 (m, 1 H), 2.32 (s, 3 H). ¹³C NMR (151 MHz, chloroform-d): δ = 158.5, 143.8, 141.7, 139.8, 137.4 (2 ArC overlap), 137.0, 130.5, 129.9, 129.3 (2 ArC overlap), 128.9, 127.1, 126.2, 119.8, 115.2, 104.8, 79.3, 55.6, 49.6, 21.5. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₅N₂O₄S: 449.1530; found: 449.1534. N-(2-Hydroxy-2-(p-tolyl)ethyl]-N-(6-methoxyquinolin-2-yl)-4-methylbenzenesulfonamide (3b) Following the general procedure, the title compound 3b was isolated as yellow oil using silica gel column chromatography with petroleum ether/ethyl acetate (v/v = 3/2, R_f = 0.4) in 80% yield (185 mg). ¹H NMR (600 MHz, chloroform-d): δ = 8.43 (s, 1 H), 7.85 (d, J = 9.2 Hz, 1 H), 7.73 (d, J = 7.9 Hz, 2 H), 7.21–7.18 (m, 4 H), 7.15–7.12 (m, 3 H), 6.97 (br, 1 H), 6.77 (br, 1 H), 5.63 (m, 1 H), 5.25–5.23 (m, 1 H), 3.85 (s, 3 H), 3.50–3.46 (m, 1 H), 3.37–3.32 (m, 1 H), 2.29 (d, J = 5.2 Hz, 6H). ¹³C NMR (151 MHz, chloroform-d): δ = 158.4, 151.2, 143.7, 141.8, 139.7, 138.8, 137.4, 134.0, 130.4, 129.9 (2 ArC overlap), 129.8, 127.0, 126.1, 119.7, 115.1, 104.8, 79.1, 55.6, 49.6, 21.5, 21.3. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₇N₂O₄S: 463.1687; found: 463.1685. N-[2-(4-Chlorophenyl)-2-hydroxyethyl]-N-(6- methoxyquinolin-2-yl)-4-methylbenzenesulfonamide (3c) Following the general procedure, the title compound 3c was isolated as colorless oil using silica gel column chromatography with petroleum ether/ethyl acetate (v/v = 3/2, R_f = 0.45) in 90% yield (217 mg). ¹H NMR (400 MHz, chloroform-d): δ = 8.44 (s, 1 H), 7.87 (d, J = 9.2 Hz, 1 H), 7.72 (d, J = 8.4 Hz, 2 H), 7.46 (d, J = 8.4 Hz, 2 H), 7.22–7.16 (m, 5 H), 6.96 (d, J = 2.8 Hz, 1 H), 6.80 (d, J = 2.8 Hz, 1 H), 5.37–5.34 (m, 1 H), 5.29–5.26 (m, 1 H), 3.87 (s, 3 H), 3.52–3.45 (m, 1 H), 3.38–3.31 (m, 1 H), 2.31 (s, 3 H). ¹³C NMR (151 MHz, chloroform-d): δ = 158.5, 143.8, 141.7, 139.8, 137.4, 137.0, 130.5, 129.9, 129.3 (2 ArC overlap), 128.9, 127.1 (2 ArC overlap), 126.2, 119.8, 115.2, 104.8, 79.3, 55.6, 49.6, 21.5. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₄ClN₂O₄S: 483.1140; found: 483.1145. N-[2-(4-Bromophenyl)-2-hydroxyethyl]-N-(6-methoxyquinolin-2-yl)-4-methylbenzenesulfonamide (3d) Following the general procedure, the title compound 3d was isolated as yellow sticky oil using silica gel column chromatography with petroleum ether/ethyl acetate (v/v = 3/2, R_f = 0.4) in 92% yield (243 mg). ¹H NMR (600 MHz, chloroform-d): δ = 8.44 (s, 1 H), 7.87 (d, J = 9.2 Hz, 1 H), 7.72 (d, J = 7.9 Hz, 2 H), 7.47 (d, J = 8.8 Hz, 2 H), 7.22–7.17 (m, 5 H), 6.96 (d, J = 2.8 Hz, 1 H), 6.80 (d, J = 2.8 Hz, 1 H), 5.28–5.26 (m, 1 H), 5.15–5.13 (m, 1 H), 3.87 (s, 3 H), 3.51–3.47 (m, 1 H), 3.37–3.32 (m, 1 H), 2.32 (s, 3 H). ¹³C NMR (151 MHz, chloroform-d): δ = 158.6, 150.9, 143.9, 141.5, 140.0, 137.3, 136.1, 132.5, 130.6, 130.0, 127.9, 127.1, 126.6, 123.0, 120.0, 115.2, 104.8, 78.8, 55.7, 49.4, 21.6. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₄BrN₂O₄S: 527.0635; found: 527.0636. N-[2-Hydroxy-2-(3-methoxyphenyl)ethyl]-N-(6-methoxyquinolin-2-yl)-4-methylbenzenesulfonamide (3e) Following the general procedure, the title compound 3e was isolated as yellow oil using silica gel column chromatography with petroleum ether/ethyl acetate (v/v = 3/2, R_f = 0.4) in 89% yield (213 mg). ¹H NMR (600 MHz, chloroform-d): δ = 8.44 (s, 1 H), 7.86 (d, J = 9.1 Hz, 1 H), 7.74 (d, J = 7.9 Hz, 2 H), 7.27–7.24 (m, 1 H), 7.20–7.15 (m, 3 H), 6.99 (d, J = 2.8 Hz, 1 H), 6.92 (d, J = 7.6 Hz, 1 H), 6.85 (s, 1 H), 6.82–6.79 (m, 2 H), 5.42–5.40 (m, 1 H), 5.24–5.22 (m, 1 H), 3.86 (s, 3 H), 3.75 (s, 3 H), 3.53–3.49 (m, 1 H), 3.39–3.34 (m, 1 H), 2.29 (s, 3 H). ¹³C NMR (151 MHz, chloroform-d): δ = 160.2, 158.4, 151.2, 143.7, 141.7, 139.8, 138.7, 137.4, 130.5, 130.4, 129.9, 129.8, 127.1, 119.8, 118.4, 115.1, 114.0, 111.9, 104.8, 79.2, 55.6, 55.4, 49.6, 21.5. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₇N₂O₅S: 479.1636; found: 479.1637. N-[2-(3-Chlorophenyl)-2-hydroxyethyl]-N-(6-methoxyquinolin-2-yl)-4-methylbenzenesulfonamide (3f) Following the general procedure, the title compound 3f was isolated as colorless oil using silica gel column chromatography with petroleum ether/ethyl acetate (v/v = 3/2, R_f = 0.45) in 81% yield (194 mg). ¹H NMR (400 MHz, chloroform-d): δ = 8.53 (s, 1 H), 8.11 (s, 1 H), 8.02–7.92 (m, 1 H), 7.75 (d, J = 7.9 Hz, 2 H), 7.54 (d, J = 10.0 Hz, 1 H), 7.40 (t, J = 7.8 Hz, 1 H), 7.33 (s, 1 H), 7.26–7.25 (m, 1 H), 7.18 (d, J = 7.9 Hz, 2 H), 7.05 (s, 1 H), 6.81 (s, 1 H), 6.03 (s, 1 H), 5.34–5.31 (m, 1 H), 3.86 (s, 3 H), 3.50–3.47 (m, 1 H), 3.39–3.34 (m, 1 H), 2.28 (s, 3 H). ¹³C NMR (151 MHz, chloroform-d): δ = 158.7, 143.7, 139.2, 137.3, 135.2, 134.6, 133.1, 130.6, 130.2, 129.9, 129.8, 129.1, 128.2, 127.0, 126.3, 124.5, 120.6, 116.2, 104.8, 79.0, 55.7, 49.5, 21.5. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₄ClN₂O₄S: 483.1140; found: 483.1143. N-[2-(3-Bromophenyl)-2-hydroxyethyl]-N-(6-methoxyquinolin-2-yl)-4-methylbenzenesulfonamide (3g) Following the general procedure, the title compound 3g was isolated as yellow sticky oil using silica gel column chromatography with petroleum ether/ethyl acetate (v/v = 3/2, R_f = 0.4) in 89% yield (234 mg). ¹H NMR (600 MHz, chloroform-d): δ = 8.46 (s, 1 H), 7.87 (d, J = 9.1 Hz, 1 H), 7.73 (d, J = 7.9 Hz, 2 H), 7.47 (s, 1 H), 7.43 (d, J = 8.0 Hz, 1 H), 7.28 (d, J = 7.7 Hz, 1 H), 7.23–7.17 (m, 4 H), 6.95 (s, 1 H), 6.81 (s, 1 H), 5.43–5.41 (m, 1 H), 5.26–5.24 (m, 1 H), 3.87 (s, 3 H), 3.52–3.48 (m, 1 H), 3.35–3.30 (m, 1 H), 2.29 (s, 3 H). ¹³C NMR (151 MHz, chloroform-d): δ = 158.5, 150.9, 143.9, 141.5, 139.8, 139.4, 137.2, 132.1, 130.9, 130.4, 130.0, 129.7, 129.1, 127.0, 124.9, 123.4, 120.1, 115.0, 104.7, 78.5, 55.7, 49.5, 21.6. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₄BrN₂O₄S: 527.0635; found: 527.0654. N-(6-Ethoxyquinolin-2-yl)-N-(2-hydroxy-2-phenylethyl)-4-methylbenzenesulfonamide (3i) Following the general procedure, the title compound 3j was isolated as yellow sticky oil using silica gel column chromatography with petroleum ether/ethyl acetate (v/v = 3/2, R_f = 0.4) in 74% yield (171 mg). ¹H NMR (400 MHz, chloroform-d): δ = 8.45 (s, 1 H), 7.87 (d, J = 9.3 Hz, 1 H), 7.74 (d, J = 8.3 Hz, 2 H), 7.34–7.33 (m, 4 H), 7.21–7.14 (m, 4 H), 6.98 (d, J = 2.7 Hz, 1 H), 6.77 (d, J = 2.7 Hz, 1 H), 5.38 (br, 1 H), 5.30–5.27 (m, 1 H), 4.09–4.06 (m, 2 H), 3.53–3.49 (m, 1 H), 3.40–3.34 (m, 1 H), 2.30 (s, 3 H), 1.45 (t, J = 7.0 Hz, 3 H). ¹³C NMR (151 MHz, chloroform-d): δ = 157.9, 143.8, 141.5, 139.6, 137.4, 137.1, 130.2, 129.9, 129.6, 129.2, 128.9, 127.1, 126.5, 126.2, 120.2, 115.4, 105.5, 79.3, 63.9, 49.6, 21.5, 14.9. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₇N₂O₄S: 463.1687; found: 463.1689. N-[6-(Benzyloxy)quinolin-2-yl]-N-(2-hydroxy-2-phenylethyl)-4-methylbenzenesulfonamide (3j) Following the general procedure, the title compound 3k was isolated as yellow oil using silica gel column chromatography with petroleum ether/ethyl acetate (v/v = 3/2, R_f = 0.4) in 90% yield (236 mg). ¹H NMR (400 MHz, chloroform-d): δ = 8.45 (s, 1 H), 7.88 (d, J = 9.1 Hz, 1 H), 7.73 (d, J = 8.0 Hz, 2 H), 7.44–7.43 (m, 2 H), 7.40–7.37 (m, 3 H), 7.32–7.31 (m, 5 H), 7.26–7.24 (m, 1 H), 7.15 (d, J = 7.9 Hz, 2 H), 6.98 (d, J = 2.8 Hz, 1 H), 6.87 (d, J = 2.8 Hz, 1 H), 5.78 (br, 1 H), 5.29 (dd, J = 8.9, 3.6 Hz, 1 H), 5.08 (s, 2 H), 3.54–3.47 (m, 1 H), 3.40–3.34 (m, 1 H), 2.24 (s, 3 H). ¹³C NMR (151 MHz, chloroform-d): δ = 157.5, 151.2, 143.6, 141.8, 139.6, 137.4, 137.0, 136.5, 130.3, 129.84, 129.77, 129.2, 128.9, 128.8, 128.3, 127.6, 127.0, 126.2, 120.1, 115.2, 106.1, 79.3, 70.3, 49.6, 21.5. HRMS (ESI): m/z [M + H]⁺ calcd for C₃₁H₂₉N₂O₄S: 525.1843; found: 525.1848. N-(2-Hydroxy-2-phenylethyl)-4-methyl-N-[6-(p-tolyloxy)quinolin-2-yl]benzenesulfonamide (3k) Following the general procedure, the title compound 3k was isolated as yellow oil using silica gel column chromatography with petroleum ether/ethyl acetate (v/v = 3/2, R_f = 0.4) in 84% yield (220 mg). ¹H NMR (400 MHz, chloroform-d): δ = 8.52 (s, 1 H), 7.95 (d, J = 9.1 Hz, 1 H), 7.73 (d, J = 8.2 Hz, 2 H), 7.31–7.27 (m, 6 H), 7.18 (dd, J = 8.1, 5.7 Hz, 4 H), 6.94 (d, J = 8.4 Hz, 2 H), 6.88–6.86 (m, 2 H), 5.30 (dd, J = 8.9, 4.2 Hz, 1 H), 5.22 (dd, J = 8.9, 3.8 Hz, 1 H), 3.53–3.47 (m, 1 H), 3.39–3.32 (m, 1 H), 2.36 (s, 3 H), 2.29 (s, 3 H). ¹³C NMR (151 MHz, chloroform-d): δ = 157.0, 154.0, 143.8, 142.8, 137.4, 136.8, 133.9, 130.7, 130.6, 129.9, 129.3, 129.0, 128.5 (2 ArC overlap), 127.1 (2 ArC overlap), 126.2, 120.6, 119.9, 115.1, 111.4, 79.2, 49.6, 21.5, 20.9. HRMS (ESI): m/z [M + H]⁺ calcd for C₃₁H₂₉N₂O₄S: 525.1843; found: 525.1841. 8-Methoxy-2-phenyl-4-tosyl-2,3,4,4a-tetrahydro-[1,2,4]oxadiazino[2,3-a]quinoline (3a′) In an oven-dried Schlenk tube, Cu(OTf)₂ (10 mol%), N-oxide 1 (0.5 mmol, 1 equiv.), N-Ts aziridine 2 (0.5 mmol, 1 equiv.), and chlorobenzene (1.5 mL) were taken under argon. The reaction mixture was heated gradually from room temperature to 80 °C for 15 h. After complete consumption of the starting reactants as observed by TLC, the volatile portion was removed under vacuum, and the crude product was purified through silica gel column chromatography to obtain the analytically pure product. The compound was purified through SiO₂ gel column chromatography with petroleum ether/ethyl acetate (v/v = 7/3, R_f = 0.6) in 84% yield (150 mg). ¹H NMR analysis showed a dr of 2:1, as determined by the following signals: δ = 3.92 (s, 3 H, OCH₃) major, 3.89 (s, 3 H, OCH₃) minor. ¹H NMR (400 MHz, chloroform-d): δ = 8.03 (d, J = 8.9 Hz, 1 H, major, 66%), 7.88 (d, J = 8.8 Hz, 1 H, minor, 33%), 7.82 (d, J = 9.2 Hz, 1 H, major, 66%), 7.78 (d, J = 8.9 Hz, 1 H, major, 66%), 7.69–7.65 (m, 3 H, major 66% + m, 1 H, minor, 33%), 7.49 (d, J = 7.4 Hz, 2 H, major, 66%), 7.37–7.35 (m, 3 H, major 66% + m, 1 H, minor, 33%), 7.33–7.28 (m, 4 H, minor, 33%), 7.25–7.23 (m, 1 H, major 66% + m, 1 H, minor, 33%), 7.23–7.18 (m, 4 H, minor, 33%), 7.07 (d, J = 2.7 Hz, 1 H, major, 66%), 7.02 (d, J = 2.7 Hz, 1 H, minor, 33%), 6.83 (d, J = 8.8 Hz, 1 H, minor, 33%), 6.18 (dd, J = 8.0, 4.0 Hz, 1 H, minor, 33%), 6.02 (s, 1 H, major 66%), 5.83–5.76 (m, 1 H, minor, 33%), 5.12 (d, J = 7.7 Hz, 1 H, major 66%), 4.37 (dd, J = 14.9, 2.4 Hz, 1 H, major 66%), 4.02–3.93 (m, 1 H, major 66% + m, 1 H, minor, 33%), 3.92 (s, 3 H, OCH₃, major, 66%), 3.89 (s, 3 H, OCH₃, minor, 33%), 3.55 (m, 1 H, major 66% + m, 1 H, minor, 33%), 2.36 (s, 3 H, CH₃, major, 66%), 2.35 (s, 3 H, CH₃, minor, 33%). ¹³C NMR (151 MHz, chloroform-d): δ = 159.6, 158.0, 156.6, 150.5, 144.3, 143.4, 142.2, 141.8, 141.5, 138.7, 138.4, 137.4, 137.2, 136.5, 130.0, 129.9, 129.8, 129.3, 128.7, 128.5, 128.4, 128.3, 127.7, 127.5, 127.5, 127.3, 127.2, 126.8, 126.6, 126.2, 126.0, 123.0, 121.6, 118.9, 113.1, 106.2, 105.3, 75.6, 72.8, 58.0, 55.8, 55.7, 49.0, 21.7, 21.6. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₅N₂O₄S: 449.1530; found: 449.1536.
• 13 Considering HOMO of N-oxide and LUMO of aziridine take part in the cycloaddition reaction.