Synthesis of Fully Substituted Pyrroles through a Copper-Catalyzed Aza-Michael/Claisen Rearrangement/Cyclization Cascade

Abstract

We have developed a copper-catalyzed aza-Michael/Claisen rearrangement/cyclization cascade sequence that affords structurally diverse pentasubstituted pyrroles in acceptable to good yields (31–84%).

Key words

copper catalysis - Claisen rearrangement - aza-Michael ­reaction - pyrroles - propargylic amines - allenoates

• References and Notes

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• 24 Pentasubstituted Pyrroles 3a–p; General ProcedureAllenoate 2 (0.4 mmol, 2.0 equiv) was added to a mixture of the appropriate propargylic amine 1 (0.2 mmol, 1.0 equiv) and Cu₂O (20 mol%) in DCE (2.0 mL), and the mixture was stirred at 50 °C for the time shown in Scheme 2, without exclusion of air. The mixture was then directly purified by flash chromatography (silica gel, hexane–EtOAc).Ethyl 1,5-dibenzyl-4-phenyl-2-(2-phenylethyl)-1H-pyrrole-3-carboxylate (3a)Purified by a flash chromatography [silica gel, hexane–EtOAc (50:1)] as a yellow oil; yield: 382.6 mg (77%). ¹H NMR (400 MHz, CDCl₃): δ = 7.36–7.11 (m, 14 H), 7.07 (dd, J = 6.8, 1.8 Hz, 2 H), 7.01–6.94 (m, 2 H), 6.81 (dd, J = 6.7, 1.9 Hz, 2 H), 4.54 (s, 2 H), 4.13 (q, J = 7.1 Hz, 2 H), 3.72 (s, 2 H), 3.15 (dd, J = 8.7, 6.6 Hz, 2 H), 2.82 (dd, J = 8.6, 6.6 Hz, 2 H), 1.05 (t, J = 7.1 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 165.6, 141.5, 139.6, 139.5, 137.5, 136.5, 130.5, 128.8, 128.6, 128.5, 128.4, 128.1, 127.8, 127.4, 127.4, 126.2, 126.1, 126.0, 125.5, 125.2, 110.9, 59.2, 46.9, 36.4, 30.3, 28.2, 13.9. ESI-HRMS: m/z [M + H]⁺ calcd for C₃₅H₃₄NO₂: 500.2584; found: 500.2589.Ethyl 5-Benzyl-1-(4-methoxybenzyl)-4-phenyl-2-(2-phenylethyl)-1H-pyrrole-3-carboxylate (3b)Purified by a flash chromatography [silica gel, hexane–EtOAc (25:1)] as a pale-yellow foam solid; yield: 373.5 mg (71%). ¹H NMR (400 MHz, CDCl₃): δ = 7.30–7.05 (m, 11 H), 7.04–6.97 (m, 2 H), 6.95–6.88 (m, 2 H), 6.79–6.72 (m, 2 H), 6.67 (d, J = 8.5 Hz, 2 H), 4.43 (s, 2 H), 4.06 (q, J = 7.1 Hz, 2 H), 3.72 (s, 3 H), 3.66 (s, 2 H), 3.10 (dd, J = 8.8, 6.6 Hz, 2 H), 2.76 (dd, J = 8.7, 6.6 Hz, 2 H), 0.98 (t, J = 7.1 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 165.6, 158.9, 141.5, 139.5, 139.5, 136.5, 130.5, 129.4, 128.5, 128.4, 128.4, 128.0, 127.8, 127.4, 126.7, 126.2, 126.0, 125.2, 114.4, 114.3, 110.8, 59.2, 55.3, 46.4, 36.4, 30.3, 28.2, 14.0. ESI-HRMS: m/z [M + H]⁺ calcd for C₃₆H₃₆NO₃: 530.2690; found: 530.2690.