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DOI: 10.1055/a-1928-3527
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Special Edition Thieme Chemistry Journals Awardees 2022

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

Grace K. Murphy
,
Corey A. Richards
,
Seth A. Applegate
,
This work was supported by funding from Saint Louis University. The authors are grateful for financial and instrumentation support provided by Saint Louis University.


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.

Supporting Information



Publication History

Received: 11 July 2022

Accepted after revision: 19 August 2022

Accepted Manuscript online:
19 August 2022

Article published online:
21 September 2022

© 2022. Thieme. All rights reserved

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  • References and Notes

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  • 25 After 16 h, conversion of β-alkynyl enamine 1a into 2a is 75% while a 50% conversion is observed for cyclization of 1b into 2b containing 4-methyl substituents.
  • 26 A 20 mL scintillation vial was charged with a stir bar, tBuLFeNNFetBuL (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.