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

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

References

• 1a Arndt F. Ergener L. Kutlu O. Chem. Ind. (London)  1950,  465 
• 1b Reische J. Mester I. Arch. Pharm. (Weinheim, Ger.)  1980,  313:  751 
• 1c Buchman FJ. Hamilton CS. J. Am. Chem. Soc.  1942,  64:  1357 
• 1d Osborne AG. Warmsley JF. Dimitrova GT. J. Nat. Prod.  1990,  55:  589 
• 2a Comins DL. Jianhua G. Tetrahedron Lett.  1994,  35:  2819 
• 2b Diez-Barra AE. de la Hoz A. Synth. Commun.  1994,  24:  1057 
• 2c Liu H. Ko S.-B. Josien H. Curran DP. Tetrahedron Lett.  1995,  36:  8917 
• 2d Joseph B. Darro F. Béhard A. Lesur B. Collignon F. Decaestecker C. Frydman A. Guillaumet G. Kiss R. J. Med. Chem.  2002,  45:  2543 
• 2e Curran DP. Liu H. J. Am. Chem. Soc.  1992,  114:  5863 
• 2f Comins DL. Baevsky MF. Hong H. J. Am. Chem. Soc.  1992,  114:  10971 
• 2g Sato T. Yoshimatsu K. Otera J. Synlett  1995,  845 
• 3 Kornblum N. Smiley RA. Blackwood RK. Iffland DC. J. Am. Chem. Soc.  1955,  77:  6269 ; and references cited therein
• 4a Hopkins GC. Jonak JP. Minnemeyer HJ. Tieckelmann H. J. Org. Chem.  1967,  32:  4040 
• 4b Hopkins GC. Jonak JP. Minnemeyer HJ. Tieckelmann H. J. Org. Chem.  1966,  31:  3969 
• 5a Tomchin AB. Shirokii GA. Dmitrukha VS. Khim. Geterotsikl. Soedin.  1976,  83 ; Chem. Abstr. 1976, 84, 179383m
• 5b Da Silva JFM. Garden SJ. Pinto AC. J. Braz. Chem. Soc.  2001,  12:  273 
• 6a Freeman GA. Webster-Andrews C. Hopkins AL. Lowell GS. Schaller LT. Cowan JR. Gonzáles SS. Koszalka GW. Hazen RJ. Boone LR. Ferris RG. Creech KL. Roberts GB. Short SA. Weaver K. Reynolds DJ. Milton J. Ren J. Stuart DI. Stammers DK. Chan JH. J. Med. Chem.  2004,  47:  5923 
• 6b Youngdale GA. Oglia TF. J. Med. Chem.  1985,  28:  1790 
• 7a Baldwin JE. Adlington RM. Conte A. Irlapati NR. Marquez R. Pritchard GJ. Org. Lett.  2002,  4:  2125 
• 7b Wei ZL. Petukhov PA. Xiao Y. Tuckmantel W. George C. Kellar KJ. Kozikowski AP. J. Med. Chem.  2003,  46:  921 
• 7c Trécourt F. Mallet M. Mongin O. Quéguiner G. J. Heterocycl. Chem.  1995,  32:  1117 
• 7d Chung MC. Tieckelmann H. J. Org. Chem.  1970,  35:  2517 
• 7e Peukert F. Schwahn U. Güssregen S. Schreuder H. Hofmeister A. Synthesis  2005,  1550 
• 7f McGee KF. Al-Tel TH. Sieburth SM. Synthesis  2001,  1185 
• 8a Narasimhan NS. Paradkar MV. Alurkar RH. Tetrahedron  1971,  27:  1351 
• 8b Collins JF. Gray GA. Grundon MF. Harrison DM. Spyropoulos CG. J. Chem. Soc., Perkin Trans. 1  1973,  94 
• 8c Narasimhan NS. Bhagwat SP. Synthesis  1979,  903 
• 8d Boyd DR. Sharma ND. Barr SA. Carroll JG. Mackerrecher D. Malone JF. J. Chem. Soc., Perkin Trans. 1  2000,  3397 
• 8e Jones K. Roset X. Rossiter S. Whitefield P. Org. Biomol. Chem.  2003,  1:  4380 
• 9a Ulubelen A. J. Nat. Prod.  1990,  53:  207 
• 9b Cuca LE. Martinez JC. Delle Monache F. Rev. Col. Quím.  1998,  27:  13 
• 9c Cuca LE. Martinez JC. Delle Monache F. J. Braz. Chem. Soc.  2002,  13:  339 
• 10 Reisch J. Iding M. Schönweiler D. J. Heterocycl. Chem.  1993,  30:  861 
• 11a Narasimhan NS. Mali RS. Tetrahedron  1974,  30:  4153 
• 11b Nickel P. Barnickel H. Preissinger L. Fink E. Dann O. Arzneim.-Forsch.  1978,  28:  367 
• 11c Belli ML. Illuminati G. Marino G. Tetrahedron  1963,  19:  345 
• 11d Osborne AG. Miller LAD. J. Chem. Soc., Perkin Trans. 1  1993,  181 
• 11e Osborne AG. Buley JM. Clarke H. Dakin RCH. Price PI. J. Chem. Soc., Perkin Trans. 1  1993,  2747 
• 11f Tagawa Y. Kawaoka T. Goto Y. J. Heterocycl. Chem.  1997,  34:  1677 
• For approaches to the syntheses of 4-hydroxy-2-quinolones, see:
• 12a Shobana N. Yeshoda P. Shanmugan P. Tetrahedron  1989,  45:  757 
• 12b Fischer M. Laschober R. Preiß A. Kappe T. Sci. Pharm.  1996,  64:  353 
• 12c Ziegler E. Gelfert K. Monatsh. Chem.  1959,  90:  822 
• 12d Kappe T. Karem AS. Stadlbauer W. J. Heterocycl. Chem.  1988,  25:  857 

13

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.

14

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].