Copper-Catalyzed Oxidative Coupling–Annulation: One-Pot Synthesis of Indolizines from 2-Alkylazaarenes with Alkenes

Abstract

A novel copper-catalyzed highly selective oxidative coupling–annulation of 2-alkylazaarenes with terminal alkenes was achieved. This process provides a simple, efficient, and atom-economic way to construct indolizines in good yields.

Key words

indolizines - alkenes - 2-alkylazaarenes - oxidative coupling - annulation

• References and Notes

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• 20 Typical Experimental Procedure The reaction mixture of terminal alkenes 1 (0.5 mmol), 2-alkylazaarenes 2 (0.5mmol), Cu(OAc)₂ (20 mol%), and DMSO (2 mL) in a 10 mL round-bottom flask was stirred at 80 °C for 12 h. Upon completion, the reaction mixture was diluted with H₂O (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford indolizines 3. Ethyl 3-Phenylindolizine-1-carboxylate (3aa) Yellow solid (106 mg, 0.4 mmol, 80%); mp 61–62 °C. ¹H NMR (500 MHz, CDCl₃): δ = 8.18–8.23 (m, 2 H), 7.40–7.48 (m, 4 H), 7.34 (m, 1 H), 7.31–7.23 (s, 1 H), 6.98–7.01 (m, 1 H), 6.61–6.64 (m, 1 H), 4.31 (q, J = 7.1 Hz, 2 H), 1.35 (t, J = 7.1 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 165.1, 136.4, 131.3, 129.1, 128.6, 128.0, 126.4, 123.4, 122.3, 120.2, 116.1, 112.6, 104.2, 59.6, 14.7. ESI-HRMS: m/z calcd for C₁₇H₁₅NO₂: 265.11028; found: 265.10894. Ethyl 3-(4-Bromophenyl)indolizine-1-carboxylate (3fa)Yellow solid (134 mg, 0.39 mmol, 78%); mp 88–89 °C. ¹H NMR (500 MHz, CDCl₃): δ = 8.20–8.15 (m, 2 H), 7.55 (d, J = 8.4 Hz, 2 H), 7.34 (d, J = 8.4 Hz, 2 H), 7.22 (s, 1 H), 7.02–7.00 (m, 1 H), 6.65 (t, J = 6.8 Hz, 1 H), 4.31 (q, J = 7.1 Hz, 2 H), 1.34 (t, J = 7.1 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 164.9, 136.5, 132.3, 130.1, 130.0, 125.1, 123.1, 122.4, 121.9, 120.3, 116.4, 112.9, 104.5, 59.7, 14.7. ESI-HRMS: m/z calcd for C₁₇H₁₄BrNO₂: 343.02079 and 345.01874; found: 343.01908 and 345.01690. Ethyl 3-(4-Methoxyphenyl)indolizine-1-carboxylate (3da) Yellow solid (133 mg, 0.45 mmol, 90%); mp 112–113 °C. ¹H NMR (500 MHz, CDCl₃): δ = 8.18–8.15 (m, 1 H), 8.13–8.11 (m, 1 H), 7.38–7.35 (m, 2 H), 7.16 (s, 1 H), 6.98–6.93 (m, 3 H), 6.60 (dt, J = 6.8, 1.2 Hz, 1 H), 4.30 (q, J = 7.1 Hz, 2 H), 3.79 (s, 3 H), 1.34 (t, J = 7.1 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 165.1, 159.4, 136.0, 130.1, 126.2, 123.6, 123.3, 122.0, 120.1, 115.6, 114.5, 112.4, 103.9, 59.5, 55.4, 14.7. ESI-HRMS: m/z calcd for C₁₈H₁₇NO₃: 295.12084; found: 295.11933.