Mild, Efficient and Selective Silver Carbonate Mediated O-Alkylation of 4-Hydroxy-2-quinolones: Synthesis of 2,4-Dialkoxyquinolines

Ademir Farias Morel; Enrique L. Larghi; Marcel Manke Selvero

doi:10.1055/s-2005-918945

LETTER

Mild, Efficient and Selective Silver Carbonate Mediated O-Alkylation of 4-Hydroxy-2-quinolones: Synthesis of 2,4-Dialkoxyquinolines

Ademir Farias Morel^a, Enrique L. Larghi*^b, Marcel Manke Selvero^a
^a Departamento de Química, Universidade Federal de Santa Maria-UFSM, Campus UFSM, Santa Maria, RS - 97105-900, Brazil
Fax: +55(55)2208031; e-Mail: amorel@base.ufsm.br;
^b Instituto de Química Orgánica de Síntesis (CONICET-UNR), Suipacha 531, 2000 Rosario, Argentina
e-Mail: iquiosra@fbioyf.unr.edu.ar;

Abstract

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Abstract

The reaction of 4-hydroxy-2-quinolones with alkyl iodides, benzyl bromides and allyl bromides in benzene at room temperature, in the presence of Ag₂CO₃, afforded 2,4-dialkoxyquinolines in moderate to excellent yields. The process is highly regioselective and constitutes a new and mild one-pot alternative for the preparation of this class of compounds.

Key words

alkylation - 4-hydroxy-2-quinolones - silver carbonate - 2,4-dialkoxyquinolines

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References

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General Procedure for the Dialkylation of 4-Hydroxy-2-quinolones. To a suspension of 2,4-dihydroxyquinoline (1 mmol) [12] in anhyd benzene (5 mL) was added Ag₂CO₃ (2 mmol) under an Argon atmosphere and the resulting slurry was homogenized by magnetic stirring at r.t. for 5 min, giving a yellowish suspension. Then, the halide (4 mmol) was added dropwise to the suspension and the mixture was further stirred at r.t. for 3 d in the dark. After this period the suspension was diluted with EtOAc, filtered through Celite, and the remaining greenish solid was washed 5 times with small portions of EtOAc. After evaporation of the volatiles, the product was isolated by silica gel (230-400 mesh) column chromatography, eluting with mixtures of hexanes and EtOAc.

Selected physical and spectral data for the synthesized 2,4-dialkoxyquinolines.
2,4-Dimethoxyquinoline (2a): white solid, mp 79-81 °C (hexane-EtOAc); lit. 81-82 °C. [1a]
2,4-Diethoxyquinoline (2b): white solid, mp: 55-56 °C (hexane-CH₂Cl₂); lit. 55-56 °C. [1c]
2,4-Bis(pentyloxy)quinoline (2c): yellowish oil. IR (film): 2930, 2860, 1900, 1600, 1570, 1410, 1340, 1180, 1100, 820, 760 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 8.05 (d, J = 7.6 Hz, 1 H), 7.75 (d, J = 7.9 Hz, 1 H), 7.56 (t, J = 6.9 Hz, 1 H), 7.29 (t, J = 7.9 Hz, 1 H), 6.18 (s, 1 H), 4.45 (t, J = 6.6 Hz, 2 H), 4.09 (t, J = 6.3 Hz, 2 H), 1.85 (m, 4 H), 1.45 (m, 8 H), 0.95 (m, 6 H). ¹³C NMR (50 MHz, CDCl₃): δ = 163.7, 163.1, 147.2, 129.7, 128.5, 126.8, 123.2, 122.9, 121.8, 119.3, 91.3, 68.4, 65.9, 28.8, 28.5, 28.3, 28.2, 22.5, 22.4, 13.9. HRMS (FAB): m/z calcd for C₁₉H₂₇NO₂: 302.21200. Found: 302.21094 [M⁺ + H]. Anal. Calcd for C₁₉H₂₇NO₂: C, 75.71; H, 9.03; N, 4.65. Found: C, 76.11; H, 9.15; N, 4.57.
2,4-Diisopropoxyquinoline (2d): colorless oil. IR (film): 2980, 1600, 1570, 1400, 1320, 1200, 1120, 1010, 920, 830, 760 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 7.97 (ddd, J = 8.2, 1.5, 0.4 Hz, 1 H), 7.70 (d, J = 8.4 Hz, 1 H), 7.51 (ddd, J = 8.4, 6.9, 1.5 Hz, 1 H), 7.33 (ddd, J = 8.2, 6.9, 1.2 Hz, 1 H), 6.10 (s, 1 H), 5.54 (sept, J = 6.3 Hz, 1 H), 4.67 (sept, J = 6.0 Hz, 1 H), 1.40 (d, J = 6.0 Hz, 6 H), 1.34 (d, J = 6.3 Hz, 6 H). ¹³C NMR (50 MHz, CDCl₃): δ = 163.0, 162.1, 147.2, 129.7, 126.7, 122.8, 122.0, 119.6, 92.3, 70.7, 67.9, 22.1, 21.7. MS (EI): m/z (%) = 245 [M⁺], 230, 203, 187, 161 (100), 145, 119, 77, 43.

Ethyl[2-(2-oxopentyloxy)quinolin-4-yloxy]acetate (2e): yellowish oil. IR (film): 2990, 2940, 1760, 1730, 1620, 1600, 1580, 1400, 1370, 1210, 1170, 1030, 760 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 8.16 (dd, J = 8.2, 1.1 Hz, 1 H), 7.99 (dd, J = 8.0, 1.3 Hz, 1 H), 7.60 (m, 2 H), 7.39 (m, 2 H), 6.26 (s, 1 H), 5.04 (s, 2 H), 5.02 (s, 2 H), 4.81 (s, 2 H), 4.73 (s, 2 H), 4.32-4.11 (m, 10 H), 3.97 (s, 2 H), 1.34-1.24 (m, 15 H). ¹³C NMR (50 MHz, CDCl₃): δ = 171.8, 169.2, 168.9, 168.4, 167.4, 162.6, 161.7, 161.5, 160.1, 146.3, 146.2, 130.4, 129.8, 127.6, 126.8, 124.5, 124.0, 122.1, 122.0, 120.8, 119.1, 91.3, 71.4, 65.3, 63.0, 62.9, 61.7, 61.5, 61.1, 61.0, 60.9, 60.4, 30.1, 14.1. MS (EI): m/z (%) = 333 [M⁺], 288, 260 (100), 232, 174, 158, 130, 116, 89.
2,4-Bis(benzyloxy)quinoline (2g): white solid; mp 54-56 °C (hexane-EtOAc). IR (KBr): 2924, 1621, 1603, 1576, 1405, 1345, 1183, 1107, 1024, 821, 764, 731, 697 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 7.99 (d, J = 8.0 Hz, 1 H), 7.68 (d, J = 8.3 Hz, 1 H), 7.50-7.06 (m, 12 H), 6.21 (s, 1 H), 5.40 (s, 2 H), 5.04 (s, 2 H). ¹³C NMR (50 MHz, CDCl₃): δ = 163.1, 162.9, 147.0, 137.4, 135.8, 129.9, 128.7, 128.4, 128.3, 127.8, 127.4, 126.9, 123.4, 121.1, 119.4, 91.9, 70.2, 67.7. MS (EI): m/z (%) = 341 [M⁺], 250, 235, 91 (100).
2,4-Bis(allyloxy)quinoline (2h): colorless oil. IR (film): 2990, 2940, 1760, 1730, 1620, 1600, 1580, 1400, 1370, 1210, 1170, 1030, 760 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 8.10 (dd, J = 8.2, 1.2 Hz, 1 H), 7.81 (d, J = 8.4 Hz, 1 H), 7.61 (ddd, J = 8.4, 7.0, 1.2 Hz, 1 H), 7.33 (ddd, J = 8.2, 7.0, 1.3 Hz, 1 H), 6.26 (s, 1 H), 6.17-6.11 (m, 2 H), 5.54-5.28 (m, 4 H), 5.02 (d, J = 5.3 Hz, 2 H), 4.72 (d, J = 5.3 Hz, 2 H). ¹³C NMR (50 MHz, CDCl₃): δ = 162.8, 162.7, 146.9, 133.6, 131.9, 129.9, 126.8, 123.3, 121.9, 119.3, 118.3, 117.6, 91.6, 68.9, 66.7. MS (EI): m/z = 241 [M⁺], 226, 200, 184, 158, 69, 41.
2,4,6-Trimethoxyquinoline (2i): mp 78-79 °C (hexane-EtOAc); lit. 79 °C. [9a]
2,4,8-Trimethoxyquinoline (2j): mp 150-152 °C (hexane-CH₂Cl₂); lit. 152 °C. [9a]
2,4-Dimethoxy-8-methylquinoline (2k): mp 45-47 °C (hexane-EtOAc). IR (KBr): 2960, 1620, 1590, 1450, 1410, 1360, 1210, 1160, 1060, 820, 800, 760 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 7.84 (d, J = 7.7 Hz, 1 H), 7.40 (d, J = 7.2 Hz, 1 H), 7.15 (dd, J = 7.7, 7.2 Hz, 1 H), 6.15 (s, 1 H), 3.99 (s, 3 H), 3.90 (s, 3 H), 2.61 (s, 3 H). ¹³C NMR (50 MHz, CDCl₃): δ = 164.1, 162.5, 145.8, 134.9, 130.1, 122.7, 119.4, 118.9, 90.1, 55.6, 53.1, 17.9. HRMS (FAB): m/z calcd for C₁₂H₁₄NO₂: 204.10245. Found: 204.10184 [M⁺ + H].