Bi(OTf)₃-Catalyzed Friedländer Hetero-Annulation: A Rapid Synthesis of 2,3,4-Trisubstituted Quinolines

Abstract

Polysubstituted quinolines are readily prepared in high yields under extremely mild conditions through a sequential condensation/annulation reaction of 2-aminoaryl ketones and α-methylene ketones using a catalytic amount of bismuth triflate.

o-aminoaryl ketones - bismuth catalysis - domino reactions - quinolines

References

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14

General Procedure: A mixture of the 2-aminoaryl ketone (1.0 mmol), α-methylene ketone (1.2 mmol) and Bi(OTf)₃ or Sc(OTf)₃ (5 mol%) in EtOH (10 mL) was stirred at r.t. for the specified time (see Table [1] ). After completion of the reaction as indicated by TLC, the reaction mixture was quenched with water (15 mL) and extracted with EtOAc (2 × 10 mL). Evaporation of the solvent followed by purification on silica gel (Merck, 100-200 mesh, EtOAc-hexane, 0.5:9.5) afforded pure quinoline. Spectral data for selected products: 3a: 3-Acetyl-2-methyl-4-phenyl-quinoline: Solid; mp 115 °C. IR (KBr): 3027, 2960, 1705, 1610, 1569, 1485, 705 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 1.95 (s, 3 H), 2.60 (s, 3 H), 7.25-7.30 (m, 2 H), 7.35 (t, J = 8.0 Hz, 1 H), 7.40-7.50 (m, 3 H), 7.55 (d, J = 8.2 Hz, 1 H), 7.65 (t, J = 8.0 Hz, 1 H), 8.0 (d, J = 8.2 Hz, 1 H). EIMS: m/z (%) = 261 (75) [M⁺], 246 (100), 218 (80), 176 (50), 150 (20), 43 (30). 3b: Ethyl 2-methyl-4-phenyl-quinoline-3-carboxylate : Solid; mp 98 °C. IR (KBr): 3030, 2960, 1700, 1605, 1568, 1482, 905 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 0.95 (t, J = 7.0 Hz, 3 H), 2.80 (s, 3 H), 4.05 (q, J = 7.0 Hz, 2 H), 7.35-7.50 (m, 6 H), 7.55 (d, J = 8.1 Hz, 1 H), 7.70 (t, J = 7.9 Hz, 1 H), 8.05 (d, J = 8.1 Hz, 1 H). EIMS: m/z (%) = 291 (85) [M⁺], 263 (10), 246 (100), 218 (60), 176 (40), 150 (20). 3f: 9-Phenyl-1,2,3,4-tetrahydroacridine: Solid; mp 137 °C. IR (KBr): 3057, 2945, 1609, 1575, 1480, 1210, 708 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 1.75-1.85 (m, 2 H), 1.95-2.05 (m, 2 H), 2.60 (t, J = 6.7 Hz, 2 H), 3.20 (t, J = 6.9 Hz, 2 H), 7.20-7.32 (m, 3 H), 7.40-7.60 (m, 5 H), 8.0 (d, J = 8.2 Hz, 1 H). EIMS: m/z (%) = 259 (100) [M⁺], 230 (30), 182 (10), 176 (12), 57 (25). 3h: 3,3-Dimethyl-9-phenyl-1,2,3,4-tetrahydro-1-acridinone: Solid; mp 197 °C. IR (KBr): 3060, 2958, 1710, 1601, 1575, 1208, 735 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 1.20 (s, 6 H), 2.55 (s, 2 H), 3.30 (s, 2 H), 7.10-7.20 (m, 2 H), 7.35-7.50 (m, 5 H), 7.75 (t, J = 7.9 Hz, 1 H), 8.05 (d, J = 8.1 Hz,1 H). EIMS: m/z (%) = 301 (100) [M⁺], 272 (70), 246 (60), 218 (45), 190 (10). 3k: 6-Chloro-3-acetyl-2-methyl-4-phenyl-quinoline: Solid; mp 150 °C. IR (KBr): 3028, 2960, 1703, 1609, 1570, 1485, 901 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 2.0 (s, 3 H), 2.60 (s, 3 H), 7.35-7.40 (m, 2 H), 7.60-7.70 (m, 3 H), 8.20 (d, J = 8.0 Hz, 1 H), 8.45-8.55 (m, 2 H). EIMS: m/z (%) = 295 (65) [M⁺], 280 (100), 252 (30), 217 (40), 189 (20), 176 (50), 109 (10). 3n: Ethyl 6-chloro-4-(2-fluorophenyl)-2-methyl-3-quinolinecarboxylate: Solid; mp 114 °C. IR (KBr): 3029, 2960, 1702, 1601, 1570, 1483, 900 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 0.98 (t, J = 7.0 Hz, 3 H), 2.80 (s, 3 H), 4.06 (q, J = 7.0 Hz, 2 H), 7.20-7.30 (m, 3 H), 7.38-7.70 (m, 3 H), 8.05 (d, J = 8.2 Hz, 1 H). EIMS: m/z (%) = 342 (100) [M⁺], 298 (90), 270 (45), 236 (40), 194 (40), 177 (10), 71 (10), 57 (38).