Rapid One-Pot Synthesis of Antiparasitic Quinolines Based upon the Microwave-Assisted Coupling-Isomerization Reaction (MACIR)

Abstract

2-Substituted quinolines and related derivatives can be rapidly prepared from (hetero)aryl halides and propargyl alcohols in the sense of a one-pot microwave-assisted coupling-isomerization reaction (MACIR). First biological tests against trypanosomes and protozoans have revealed antiparasitic activity in the lower micromolar range.

Key words

alkynes - antiparasitic activity - catalysis - cross-couplings - isomerizations - microwave reactions

References and Notes

• 2 Wiesner J. Ortmann R. Jomaa H. Schlitzer M. Angew. Chem. Int. Ed.  2003,  43:  5274 
• 3 Gilles MH. Management of Severe Malaria: A Practical Handbook   2nd ed.:  World Health Organization; Geneva: 2000. 
• 4a O’Neill PM. Mukhtar A. Stocks PA. Randle LE. Hindley S. Ward SA. Storr RC. Bickley JF. O’Neil IA. Maggs JL. Hughes RH. Winstanley PA. Bray PG. Park BK. J. Med. Chem.  2003,  46:  4933 
• 4b Ridley RG. Hofheinz W. Matile H. Jaquet C. Dorn A. Masciadri R. Jolidon S. Richter WF. Guenzi A. Girometta MA. Urwyler H. Huber W. Thaithong S. Peters W. Antimicrob. Agents Chemother.  1996,  40:  1846 
• 4c Stocks PA. Raynes KJ. Bray PG. Park BK. O’Neill PM. Ward SA. J. Med. Chem.  2002,  45:  4975 
• 4d Vlahov R. Pavrushev S. Vlahov J. Pure Appl. Chem.  1990,  62:  1303 
• 4e Madrid PB. Sherrill J. Liou AP. Weisman JL. DeRisi JL. Kipling Guy R. Bioorg. Med. Chem. Lett.  2005,  15:  1015 
• 5a Fournet A. Vagneur B. Richomme P. Bruneton J. Can. J. Chem.  1989,  67:  2116 
• 5b Fournet A. Hocquemiller R. Roblot F. Cavé A. Richomme P. Bruneton J. J. Nat. Prod.  1993,  56:  1547 
• 5c Fournet A. Barrios AA. Muñoz V. Hocquemiller R. Cavé A. Richomme P. Bruneton J. Antimicrob. Agents Chemother.  1993,  37:  859 
• 6 Fakhfakh MA. Fournet A. Prina E. Mouscadet J.-F. Franck X. Hocquemiller R. Figadere B. Bioorg. Med. Chem.  2003,  11:  5013 
• 7a Steel PJ. Coord. Chem. Rev.  1990,  106:  227 
• 7b Ernst S. Kaim W. J. Am. Chem. Soc.  1986,  108:  3578 
• 7c Mamo A. Nicolleti S. Cam Tat N. Molecules  2002,  7:  618 
• 7d Qaseer H. Croat. Chim. Acta  2005,  78:  79 
• 8 Balasubramanian M. Keay JG. In Comprehensive Hetrocyclic Chemistry II   Vol. 5:  Katrizky AR. Rees CW. Scriven EFV. Pergamon Press; Oxford: 1996.  Chap. 5.06. p.245 
• 9 Manske RHF. Kukla M. Org. React.  1953,  7:  59 
• 10 For a review on recent progress in the synthesis of quinolines, see: Kouznetsov VV. Mendez LY. Mendelez Gomez CM. Curr. Org. Chem.  2005,  9:  141 
• For recent quinoline syntheses, see e.g.:
• 11a Cho CK. Oh BH. Shim SC. J. Heterocycl. Chem.  1999,  36:  1175 
• 11b Cho CK. Oh BH. Shim SC. Tetrahedron Lett.  1999,  40:  1499 
• 11c Cho CK. Oh BH. Shim SC. Oh DH. J. Heterocycl. Chem.  2000,  37:  1315 
• 11d Cho CK. Oh BH. Kim JS. Kim T.-J. Shim SC. Chem. Commun.  2000,  1885 
• 11e Sangu K. Fuchibe K. Akiyama T. Org. Lett.  2004,  6:  353 
• 11f Jacob J. Jones WD. J. Org. Chem.  2003,  68:  3563 
• 11g Akiyama T. Nakashima S. Yokota K. Fuchibe K. Chem. Lett.  2004,  33:  922 
• 12a Cho CS. Lee NY. Kim T.-J. Shim SC. J. Heterocycl. Chem.  2004,  41:  409 
• 12b Cho CS. J. Organomet. Chem.  2005,  690:  4094 
• 13a Braun RU. Ansorge M. Müller TJJ. Chem. Eur. J.  2006,  12:  9081 
• 13b Müller TJJ. Ansorge M. Aktah D. Angew. Chem. Int. Ed.  2000,  39:  1253 
• 14a Liao W.-W. Müller TJJ. Synlett  2006,  3469 
• 14b Schramm née Dediu OG. Müller TJJ. Adv. Synth. Catal.  2006,  348:  2565 
• 14c Schramm née Dediu OG. Müller TJJ. Synlett  2006,  1841 
• 15a Müller TJJ. Targets in Heterocyclic Systems  2006,  10:  54 
• 15b Müller TJJ. Chim. Oggi/Chemistry Today  2007,  25(1):  70 
• 15c D’Souza DM. Müller TJJ. Chem. Soc. Rev.  2007,  36:  1095 

1

New address: Lehrstuhl für Organische Chemie, Institut für Organische Chemie und Makromolekulare Chemie der Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, 40225 Düsseldorf, Germany.

16

Typical Procedure (3g, Table 1, Entry 7)
A magnetically stirred solution of 1d (234 mg, 1.00 mmol), 2a (139 mg, 1.05 mmol), (PPh₃)₂PdCl_{2 (}20 mg, 0.02 mmol), and CuI (2 mg, 0.01 mmol) in degassed DBU (2 mmol) and THF (1.5 mL) was stirred under nitrogen in a heavy-walled SmithCreator process vial in the microwave cavity at 150 °C for 30 min. After cooling to r.t. EtOAc (40 mL) and H₂O (40 mL) were added and the aqueous layer was extracted with EtOAc. The combined organic phases were dried with MgSO₄ and the solvents were removed in vacuo. The residue was chromatographed on silica gel (hexane-EtOAc, 5:1) and recrystallized from EtOH or pentane-CHCl₃ (1:1) to give 174 mg (79%) of 3g as light yellow crystals, mp 142 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.54 (s, 3 H), 7.44-7.54 (m, 3 H), 7.91 (d, J = 1.5 Hz, 1 H), 7.94 (d, J = 8.3 Hz, 1 H), 8.13 (d, J = 8.3 Hz, 1 H), 8.28 (dd, J = 8.3, 1.5 Hz, 2 H), 8.96 (d, J = 2.1 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 18.6 (CH₃), 119.6 (CH), 121.3 (C_q), 127.8 (CH), 128.8 (CH), 129.9 (CH), 131.5 (C_q), 135.2 (CH), 137.1 (CH), 138.7 (C_q), 154.8 (C_q), 155.8 (CH), 159.3 (C_q). MS: (EI, 70 eV): m/z (%) = 220.1 (100) [M⁺], 205.1 (10) [M⁺ - CH₃], 77 (12) [C₆H₅ ⁺]. IR (KBr): ν = 3027, 1604, 1581, 1546, 1503, 1481, 1458, 1434, 1321, 1278, 1140, 1025, 898, 814, 766, 739, 703, 678, 568 cm^-1. Anal. Calcd for C₁₅H₁₂N₂ (220.3): C, 81.79; H, 5.49; N, 12.72. Found: C, 81.71; H, 5.38; N, 12.79.

17

All compounds have been fully characterized by ¹H, ¹³C and DEPT, COSY, NOESY, HETCOR and HMBC NMR experiments, IR, mass spectrometry, HRMS, and/or combustion analyses.

18

CCDC-669319 (3c) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Center, 12 Union Road, Cambridge CB2 1EZ, UK; fax: [phone]; or [e-mail]].