1-(2-Allylaryl)-1H-pyrroles as Building Blocks for Novel 4-Methyl-4,5-di­hydropyrrolo[1,2-a]quinoline Derivatives

Abstract

Novel substituted 4-methyl-4,5-dihydropyrrolo[1,2-a]-quinolines were prepared by a simple two-step approach involving a Clauson-Kaas reaction of a substituted ortho-allylaniline followed by acid-catalyzed regioselective intramolecular Friedel–Crafts alkylation of the resulting 1-(2-allylaryl)-1H-pyrroles. All the synthetized compounds were fully characterized by IR, ¹H and ¹³C NMR spectroscopy, and mass spectrometry.

Key words

pyrroles - quinolines - alkylation - heterocycles - cyclization

• References

• 1a Michael JP. Nat. Prod. Rep. 2008; 25: 166
• 1b Oku N, Matsunaga S, Fusetani N. J. Am. Chem. Soc. 2003; 125: 2044
• 2a Dürr H, Gross H, Zils K.-D, Hauck G, Klauck G, Hermann H. Chem. Ber. 1983; 116: 3915
• 2b Kelderman E, Verboom W, Engbersen JF. J, Harkema S, Heesink GJ. T, Lehmusvaara E, van Hulst NF, Reinhoudt DN, Derhaeg L, Persoons A. Chem. Mater. 1992; 4: 626
• 2c Leontie L, Druta I, Danac R, Rusa GI. Synth. Met. 2005; 155: 138
• 3 Anderson WK, Heider AR, Raju N, Yucht JA. J. Med. Chem. 1988; 31: 2097
• 4 Cappelli A, Giuliani G, Anzini M, Riitano D, Giorgi G, Vomero S. Bioorg. Med. Chem. 2008; 16: 6850
• 5 Sui Z, Altom J, Nguyen VN, Fernandez J, Bernstein JI, Hiliard JJ, Barrett JF, Podlogar BL, Ohemeng KA. Bioorg. Med. Chem. 1998; 6: 735
• 6a Jones DT, Harris AL. Mol. Cancer Ther. 2006; 5: 2193
• 6b Kemnitzer W, Kuemmerle J, Jiang S, Zhang H.-Z, Sirisoma N, Kasibhatla S, Crogan-Grundy C, Tseng B, Drewe J, Cai SX. Bioorg. Med. Chem. Lett. 2008; 18: 6259
• 6c Kemnitzer W, Kuemmerle J, Jiang S, Sirisoma N, Kasibhatla S, Crogan-Grundy C, Tseng B, Drewe J, Cai SX. Bioorg. Med. Chem. Lett. 2009; 19: 3481
• 7a Daly JW, Witkop B, Tokyyama T, Nishikawa T, Karle IL. Helv. Chim. Acta 1977; 60: 1128
• 7b Overman LE, Lesuisse D, Hashimoto M. J. Am. Chem. Soc. 1983; 105: 5373
• 7c Pearson WH, Fang W. J. Org. Chem. 2000; 65: 7158
• 7d Wei L.-L, Hsung RP, Sklenicka HM, Gerasyuto AI. Angew. Chem. Int. Ed. 2001; 40: 1516
• 8 Santarem M, Vanucci-Bacqué C, Lhommet G. J. Org. Chem. 2008; 73: 6466
• 9a Kobayashi K, Nakahashi R, Takanohashi A, Kitamura T, Morikawa O, Konishi H. Chem. Lett. 2002; 624
• 9b Chai W, Kwok A, Wong V, Carruthers NI, Wu J. Synlett 2003; 2086
• 9c Fürstner A, Mamane V. J. Org. Chem. 2002; 67: 6264
• 9d Alcaide B, Almendros P, Alonso JM, Aly MF. Chem. Eur. J. 2003; 9: 3415
• 9e Kaloko JJr, Hayford A. Org. Lett. 2005; 7: 4305
• 9f Fujita R, Hoshino M, Tomisawa H. Chem. Pharm. Bull. 2006; 54: 334
• 9g Kobayashi K, Takanohashi A, Hashimoto K, Morikawa O, Konishi H. Tetrahedron 2006; 62: 10379
• 9h Kobayashi K, Himei Y, Izumi Y, Fukamachi S, Morikawa O, Konishi H. Heterocycles 2007; 71: 691
• 9i Kobayashi K, Takanohashi A, Himei Y, Sano T, Fukamachi S, Morikawa O, Konishi H. Heterocycles 2007; 71: 2717
• 9j Basavaiah D, Devendar B, Lenin DV, Satyanarayana T. Synlett 2009; 411
• 10a Anderson WK, DeRuiter J, Heider AR. J. Org. Chem. 1985; 50: 722
• 10b Dumitrascu F, Mitan CI, Drăghici C, Căproiu MT, Răileanu D. Tetrahedron Lett. 2001; 42: 8379
• 10c Wu K, Chen Q.-Y. Synthesis 2003; 35
• 10d Komatsu M, Kasano Y, Yamaoka S, Minakata S. Synthesis 2003; 1398
• 10e Yue G, Wan Y, Song S, Yang G, Chen Z. Bioorg. Med. Chem. Lett. 2005; 15: 453
• 10f Georgescu E, Caira MR, Georgescu F, Drăghici B, Popa MM, Dumitrascu F. Synlett 2009; 1795
• 10g Kheder NA, Darwish ES, Dawood KM. Heterocycles 2009; 78: 177
• 11a Hulcoop DG, Lautens M. Org. Lett. 2007; 9: 1761
• 11b Chai DI, Lautens M. J. Org. Chem. 2009; 74: 3054
• 11c Ye S, Liu J, Wu J. Chem. Commun. 2012; 48: 5028
• 12 Verma AK, Shukla SP, Singh J, Rustagi V. J. Org. Chem. 2011; 76: 5670
• 13a Roberts RM, Khalaf AA. Friedel–Crafts Alkylation Chemistry: A Century of Discovery, . Marcel Dekker; New York: 1984
• 13b Olah GA, Krishnamurti R, Prakash GK. S In Comprehensive Organic Synthesis . Vol. 3. Trost BM, Fleming I. Pergamon; Oxford: 1991: 293
• 14a Palma A, Jaimes Barajas J, Kouznetsov VV, Stashenko E, Bahsas A, Amaro-Luis J. Synlett 2004; 2721
• 14b Yépez AF, Palma A, Stashenko E, Bahsas A, Amaro-Luis JM. Tetrahedron Lett. 2006; 47: 5825
• 14c Palma A, Galeano N, Bahsas A. Synthesis 2010; 1291
• 15a Palma A, Gómez SL, Stashenko E, Bahsas A, Amaro-Luis JM. Synlett 2006; 2275
• 15b Gómez-Ayala S, Castrillón JA, Palma A, Leal SM, Escobar P, Bahsas A. Bioorg. Med. Chem. 2010; 18: 4721
• 15c Acosta LM, Palma A, Bahsas A. Tetrahedron 2010; 66: 8392
• 15d Acosta-Quintero LM, Palma A, Nogueras M, Cobo J. Synthesis 2012; 44: 3765
• 16 Clauson-Kaas N, Limborg F, Kakstorp J. Acta Chem. Scand. 1948; 2: 109
• 17 4-Methyl-4,5-dihydropyrrolo[1,2-a]quinolines 3a–h; General Procedure Concd H₂SO₄ (98%, 4 mmol) was added to a stirred and cooled solution of the appropriate 1-(2-allylaryl)pyrrole 2a–h (1 mmol) in CH₂Cl₂ (5 mL), and the mixture was stirred at 0 °C for 5–15 min (TLC). It was then poured onto ice-water (50 mL), neutralized to pH 7.5–8.0 with sat. aq Na₂CO₃, and extracted with CH₂Cl₂ (3 × 50 mL). The organic layers were combined, dried (Na₂SO₄), and concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel, heptane–EtOAc (90:1 to 70:1)]. 4-Methyl-4,5-dihydropyrrolo[1,2-a]quinoline (3a) Colorless viscous oil; yield: 58%; R_f = 0.38 (1% EtOAc–heptane). IR (liquid film): 2962 (C–H aliphatic), 1558 (C=C pyrrole), 1500 (C=C benzene), 1332 (=C–H pyrrole), 1168 (C–N) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.36 (br d, J = 7.6 Hz, 1 H, H9), 7.29 (br t, J = 7.6 Hz, 1 H, H8), 7.26 (br d, J = 7.6 Hz, 1 H, H6), 7.20 (br dd, J = 2.8, 1.2 Hz, 1 H, H1), 7.09 (td, J = 7.6, 1.0 Hz, 1 H, H7), 6.32 (t, J = 3.2 Hz, 1 H, H2), 6.08 (dt, J = 3.2, 1.2 Hz, 1 H, H3), 3.09–3.00 (m, 1 H, H4), 2.89 (dd, J = 14.8, 5.2 Hz, 1 H, H5_B), 2.63 (dd, J = 14.8, 12.4 Hz, 1 H, H5_A), 1.41 (d, J = 6.8 Hz, 3 H, 4-CH₃). ¹³C NMR (100 MHz, CDCl₃): δ = 136.5 (C9a), 135.2 (C3a), 129.0 (C6), 128.0 (C5a), 127.4 (C8), 123.8 (C7), 115.1 (C9), 114.7 (C1), 109.7 (C2), 104.1 (C3), 35.5 (C5), 28.2 (C4), 18.6 (4-CH₃). GC/MS (EI, 70 eV): m/z (%) = 183 (30) [M^+•], 182 (9), 168 (100), 167 (39), 154 (3). HRMS: m/z [M]⁺ calcd for C₁₃H₁₃N: 183.1048; found: 183.1047.