Two-Step, One-Pot Pyrrole Synthesis by Iron-Catalyzed ­Carboamination/Copper-Mediated Cyclization

Abstract

Herein we report a method for pyrrole synthesis via iron-catalyzed carboamination/copper-mediated cyclization that is completely regioselective for the formation of 1,2,4-trisubstituted products. This two-step, one-pot process offers significant improvements to previously reported conditions including the use of a readily available copper(I) source and a markedly less arduous experimental procedure. Exploration of the substrate scope reveals a variety of arylacetylenes undergo pyrrole formation to afford single isomer products. Isotopic labelling data points to a mechanism involving activation of the alkyne moiety by the copper(I) reagent during the cyclization step.

Key words

iron - copper - pyrroles - cyclization - regioselectivity

Publication History

Received: 11 July 2022

Accepted after revision: 19 August 2022

Accepted Manuscript online:
19 August 2022

Article published online:
21 September 2022

• References and Notes

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• 26 A 20 mL scintillation vial was charged with a stir bar, ^tBuLFeNNFe^tBuL (20.6 mg, 0.018 mmol, 0.15 equiv), and 600 μL of benzene. A solution of MesN₃ (19.3 mg, 0.12 mmol, 1 equiv), arylacetylene (0.25 mmol, 2.1 equiv), and ^tBuPy (9.7 mg, 0.072 mmol, 0.6 equiv) in 600 μL of benzene was added to the vial. The reaction mixture was allowed to stir at room temperature for 30 min. A slurry of CuCl (59.4 mg, 0.60 mmol, 5 equiv) in 1.2 mL THF was transferred into the reaction mixture in benzene. This mixture was stirred at room temperature for an additional 24 h before being removed from the drybox. Methanol (1 mL) was added, and the reaction mixture was stirred for 30 min. The volatiles were removed in vacuo, and the crude red/brown products were filtered through Celite with hexanes. The filtrate was collected, the solvent was removed in vacuo, and the mixture was purified by column chromatography. 1-Mesityl-2,4-bis(4-methylphenyl)-1H-pyrrole (2b) Eluted with hexanes and isolated as a white solid in 54% yield. ¹H NMR (400 MHz, CDCl₃): δ = 7.49 (d, J = 8.0 Hz, 2 H), 7.17 (d, J = 8.0 Hz, 2 H), 7.03–6.97 (m, 4 H), 6.91 (s, 2 H), 6.89 (d, J = 1.6 Hz, 1 H), 6.78 (d, J = 2.0 Hz, 1 H), 2.36 (s, 3 H), 2.33 (s, 3 H), 2.27 (s, 3 H), 1.99 (s, 6 H). The data for this compound matched that reported previously.²² 1-Mesityl-2,4-bis(4-methoxyphenyl)-1H-pyrrole (2c) Eluted with 10:1 hexanes/ethyl acetate and isolated as an off-white solid in 40% yield. ¹H NMR (400 MHz, CDCl₃): δ = 7.51 (d, J = 8.8 Hz, 2 H), 7.04 (d, J = 9.2 Hz, 2 H), 6.91 (d, J = 8.8 Hz, 2 H), 6.90 (s, 2 H), 6.82 (d, J = 2.0 Hz, 1 H), 6.71 (d, J = 8.8 Hz, 2 H), 6.68 (d, J = 2.0 Hz, 1 H), 3.83 (s, 3 H), 3.75 (s, 3 H), 2.32 (s, 3 H), 1.98 (s, 6 H). The data for this compound matched that reported previously.²² 1-Mesityl-2,4-bis(4-fluorophenyl)-1H-pyrrole (2d) Eluted with hexanes and isolated as a pale yellow oil in 38% yield. ¹H NMR (400 MHz, CDCl₃): δ = 7.56–7.53 (m, 2 H), 7.11–7.04 (m, 4 H), 6.93 (s, 2 H), 6.91–6.86 (m, 3 H), 6.73 (d, J = 2.0 Hz, 1 H), 2.34 (s, 3 H), 1.99 (s, 6 H). The data for this compound matched that reported previously.²² 1-Mesityl-2,4-bis(3-methoxyphenyl)-1-H-pyrrole (2e) Eluted with 10:1 hexanes/ethyl acetate isolated as a bright yellow oil in 42% yield. ¹H NMR (400 MHz, CDCl₃): δ = 7.29 (t, J = 7.6 Hz, 1 H), 7.20 (d, J = 5.2 Hz, 1 H), 7.15 (s, 1 H), 7.10 (t, J = 8.0 Hz, 1 H), 6.94 (d, J = 2.0 Hz, 1 H), 6.92 (s, 2 H), 6.85 (d, J = 2.0 Hz, 1 H), 6.79–6.75 (m, 2 H), 6.68 (dd, J = 8.0, 2.0 Hz, 1 H), 6.61 (s, 1 H), 3.86 (s, 3 H), 3.59 (s, 3 H), 2.32 (s, 3 H), 1.99 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 160.2, 159.4, 138.2, 137.0, 136.7, 136.1, 134.8, 134.3, 129.8, 129.4, 129.1, 125.2, 120.6, 119.1, 117.7, 112.7, 111.3, 111.2, 110.7, 106.6, 55.4, 55.0, 21.2, 17.9. LRMS (EI): m/z calcd for [C₂₇H₂₇NO₂]⁺: 397.2; found: 397.3. 1-Mesityl-2,4-bis(3-fluorophenyl)-1H-pyrrole (2f) Eluted with hexanes and isolated as a colorless oil in 28% yield. ¹H NMR (400 MHz, CDCl₃): δ = 7.37–7.26 (m, 3 H), 7.14 (q, J = 6.4 Hz, 1 H), 6.96 (d, J = 2.0 Hz, 1 H), 6.94 (s, 2 H), 6.91–6.78 (m, 5 H), 2.34 (s, 3 H), 1.98 (s, 6 H).¹³C NMR (100 MHz, CDCl₃): δ = 164.4 (d, J = 76.6 Hz), 161.9 (d, J = 77.2 Hz), 138.5, 137.7 (d, J = 8.1 Hz), 136.1, 135.9, 134.9 (d, J = 88.6 Hz), 133.9 (d, J = 2.3), 130.2 (d, J = 8.4 Hz), 129.9 (d, J = 8.7 Hz), 129.3, 124.5 (d, J = 2.6 Hz), 122.1 (d, J = 2.7 Hz), 121.2, 120.66 (d, J = 2.7 Hz), 113.4 (d, J = 9.7 Hz), 113.1 (d, J = 11.7 Hz), 112.5 (d, J = 21.1 Hz), 111.8 (J = 21.8 Hz), 107.1, 21.2, 17.9. ¹⁹F NMR (376 MHz, CDCl₃): δ = –113.1, –113.7. LRMS (EI): m/z calcd for [C₂₅H₂₁F₂N]⁺: 373.2; found: 373.2. 1-Mesityl-2,4-bis(3-methylphenyl)-1H-pyrrole (2h) Eluted with hexanes and isolated as colorless oil in 32% yield. ¹H NMR (400 MHz, CDCl₃): δ = 7.43 (s, 1 H), 7.41 (d, J = 8.0 Hz), 7.25 (t, J = 7.6 Hz, 1 H), 7.08–7.00 (m, 4 H), 6.94 (d, J = 8.0 Hz, 1 H), 6.93 (J = 2.0 Hz, 1 H), 6.91 (s, 2 H), 6.83 (d, J = 2.0 Hz, 1 H), 6.82 (d, J = 7.6 Hz, 1 H), 2.39 (s, 3 H), 2.32 (s, 3 H), 2.24 (s, 3 H), 1.98 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 138.3, 138.0, 137.8, 136.8, 136.1, 135.6, 135.2, 133.1, 129.0, 128.7, 128.1, 127.5, 127.1, 126.5, 125.8, 125.3, 123.4, 122.6, 122.1, 120.2, 106.4, 21.7, 21.6, 21.2, 17.9. LRMS (EI): m/z calcd for [C₂₇H₂₇N]⁺: 365.2; found: 365.3.