AlCl₃-Mediated Synthesis of 4-Aryl-2-quinolone-3-carboxylates

This paper is dedicated to Professor Young-Ger Suh on the occasion of his 65^th birthday
^◊ These two authors contributed equally to this work

Abstract

4-Aryl-2-quinolones are important skeletons from both chemical and medicinal viewpoints. We herein report the development of an efficient synthetic method for 3-substituted 4-aryl-2-quinolones. The key reaction in this process involves an AlCl₃-mediated intramolecular cyclization of substituted 2-(carbamoyl)-3-phenylacrylates, with optimized reaction conditions of 2.0 equivalents of AlCl₃, nitrobenzene, 80 °C, and 3 hours. The chemical yields of cyclization were found to be sensitive to all reaction conditions.

Key words

2-quinolone - Lewis acid - intramolecular - cyclization - oxidation

• References and Notes

• 1 Shiro T. Fukaya T. Tobe M. Eur. J. Med. Chem. 2015; 97: 397
• 2 Suzuki M. Ohuchi Y. Asanuma H. Kaneko T. Yokomori S. Ito C. Isobe Y. Muramatsu M. Chem. Pharm. Bull. 2000; 48: 2003
• 3 El-Sayed OA. Al-Bassam BA. Hussein ME. Arch. Pharm. 2002; 335: 403
• 4 Hewawasam P. Fan WH. Knipe J. Moon SL. Boissard CG. Gribkoff VK. Starrett JE. Bioorg. Med. Chem. Lett. 2002; 12: 1779
• 5 Joseph B. Darro F. Behard A. Lesur B. Collignon F. Decaestecker C. Frydman A. Guillaumet G. Kiss R. J. Med. Chem. 2002; 45: 2543
• 6 Wall MJ. Chen J. Meegalla S. Ballentine SK. Wilson KJ. DesJarlais RL. Schubert C. Chaikin MA. Crysler C. Petrounia IP. Donatelli RR. Yurkow EJ. Boczon L. Mazzulla M. Player MR. Patch RJ. Manthey CL. Molloy C. Tomczuk B. Illig CR. Bioorg. Med. Chem. Lett. 2008; 18: 2097
• 7 Chen Y.-F. Lin Y.-C. Huang P.-K. Chan H.-C. Kuo S.-C. Lee K.-H. Huang L.-J. Bioorg. Med. Chem. 2013; 21: 5064
• 8 Kumar N. Dhamija I. Vasanth Raj P. Jayashree BS. Parihar V. Manjula SN. Thomas S. Gopalan Kutty N. Mallikarjuna Rao C. Arab. J. Chem. 2014; 7: 409
• 9 Jia C.-S. Dong Y.-W. Tu S.-J. Wang G.-W. Tetrahedron 2007; 63: 892
• 10 Huang LJ. Hsieh MC. Teng CM. Lee KH. Kuo SC. Bioorg. Med. Chem. 1998; 6: 1657
• 11 Peters J.-U. Capuano T. Weber S. Kritter S. Sägesser M. Tetrahedron Lett. 2008; 49: 4029
• 12 Hajra S. Maji B. Karmakar A. Tetrahedron Lett. 2005; 46: 8599
• 13 Kadnikov DV. Larock RC. J. Org. Chem. 2004; 69: 6772
• 14 Battistuzzi G. Bernini R. Cacchi S. De Salve I. Fabrizi G. Adv. Synth. Catal. 2007; 349: 297
• 15 Tang D.-J. Tang B.-X. Li J.-H. J. Org. Chem. 2009; 74: 6749
• 16 Glasnov TN. Stadlbauer W. Kappe CO. J. Org. Chem. 2005; 70: 3864
• 17 Berrino R. Cacchi S. Fabrizi G. Goggiamani A. J. Org. Chem. 2012; 77: 2537
• 18 Iwai T. Fujihara T. Terao J. Tsuji Y. J. Am. Chem. Soc. 2010; 132: 9602
• 19 Mai W.-P. Sun G.-C. Wang J.-T. Song G. Mao P. Yang L.-R. Yuan J.-W. Xiao Y.-M. Qu L.-B. J. Org. Chem. 2014; 79: 8094
• 20 Hayat F. Park S.-H. Choi N.-S. Lee J. Park SJ. Shin D. Arch. Pharm. Res. 2015; 38: 1975
• 21 Park J.-E. Lee J. Seo S.-Y. Shin D. Tetrahedron Lett. 2014; 55: 818
• 22 Kang K. Nho CW. Kim ND. Song DG. Park YG. Kim M. Pan CH. Shin D. Oh SH. Oh H. S. Int. J. Oncol. 2014; 45: 558
• 23 Woo JK. Kang JH. Shin D. Park SH. Kang K. Nho CW. Seong JK. Lee SJ. Oh SH. Mol. Cancer Ther. 2015; 14: 1693
• 24 Desos P. Lepagnol JM. Morain P. Lestage P. Cordi AA. J. Med. Chem. 1996; 39: 197
• 25 Liu X. Zhang Q. Zhang D. Xin X. Zhang R. Zhou F. Dong D. Org. Lett. 2013; 15: 776
• 26 Synthesis of 2aB AlCl₃ (1.81 mL, 1 M solution in nitrobenzene) was slowly added to a solution of 4aB (300 mg, 0.906 mmol) in dry nitrobenzene (5 mL) at 0 °C. The reaction mixture was warmed to 80 °C and stirred for 3 h. After cooling, the reaction mixture poured into ice-water and diluted with EtOAc. The organic layer was separated and washed with sat. NaHCO₃, H₂O and brine, dried over anhydrous MgSO₄, and filtered. After evaporation of volatile solvents under reduced pressure, the residue was purified by silica gel column chromatography to afford the desired product 3aB; 283 mg (95%), white solid. ¹H NMR (600 MHz, CDCl₃): δ = 8.93 (s, 1 H), 7.31 (t, J = 7.3 Hz, 2 H), 7.20 (q, J = 7.32 Hz, 12.3 Hz, 1 H), 7.15 (m, 2 H), 6.97 (dd, J = 2.5, 7.3 Hz, 1 H), 6.88 (q, J = 4.8, 7.3 Hz, 1 H), 6.82 (m, 1 H), 4.65 (d, J = 4.6 Hz, 1 H), 4.11 (m, 2 H), 3.82 (d, J = 4.9Hz, 1 H), 1.10 (q, J = 5.0, 7.1 Hz, 3 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 168.2, 166.8, 137.7, 136.2, 133.5, 129.2, 128.5, 124.8, 123.9, 115.9, 61.7, 54.9, 44.9, 14.0 ppm. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₈H₁₉ClNO₃: 330.0891; found: 330.0895 The mixture of DDQ (257 mg, 1.14 mmol) and 3aB (250 mg, 0.760 mmol) in benzene (5 mL) was stirred for 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with sat. NaHCO₃, H₂O and brine, dried over anhydrous MgSO₄, and filtered. After evaporation of volatile solvents under reduced pressure, the residue was purified by silica gel column chromatography to afford the desired product 2aB; 236 mg (95%), white solid. ¹H NMR (600 MHz, CDCl₃): δ = 9.23 (s, 1 H), 7.56 (d, J = 8.5 Hz, 2 H), 7.33 (t, J = 8.0 Hz, 2 H), 7.12 (t, J = 7.4 Hz, 1 H), 4.26 (q, J = 7.1 Hz, 2 H), 3.47 (s, 2 H), 1.33 (t, J = 7.2 Hz, 3 H) ppm. ¹³C NMR (151 MHz, CDCl₃): δ = 170.0, 162.9, 137.5, 129.0, 124.6, 120.1, 62.0, 41.5, 14.1 ppm. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₈H₁₅ClNO₃: 328.0735; found: 328.0732.