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Synlett 2022; 33(07): 674-678
DOI: 10.1055/s-0041-1737937
letter

Spirocyclic Products via Carbene Intermediates from Thermolysis of 1,2-Dialkynylpyrrole and 1,2-Diethynylimidazole

Ashley L. Jewett
a   Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA
,
Joshua A. Bondoc
b   Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA
,
Bradford L. Gilbreath
a   Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA
,
Brandon J. Reinus
c   Department of Chemistry, University of Texas at Austin, Austin, TX 78712, USA
,
Sean M. Kerwin∗
b   Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA
› Author AffiliationsFunding from the Partnership for Research and Education in Materials (PREM) NSF Grant DMR-2122041 and NSF grant 1955432 is gratefully acknowledged.
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Abstract

The thermal rearrangements of 1,2-dialkynylimidazoles have been shown to lead to trapping products of cyclopenta[b]pyrazine carbene intermediates. Here we show that a similar rearrangement also occurs in the case of 1,2-diethynyl-1H-pyrrole, and that trapping the intermediate cyclopenta[b]pyridine carbene with solvent THF affords an ylide that undergoes a Stevens rearrangement to a spirocyclic product. An analogous rearrangement and trapping is observed for thermolysis of 1,2-dialkynylimidazoles in THF or 1,4-dioxane.

Key words

azoles - carbenes - cycloaromatization - ylides - spiro compounds

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0041-1737937.
  • Supporting Information


Publication History

Received: 31 December 2021

Accepted after revision: 22 February 2022

Article published online:
17 March 2022

© 2022. Thieme. All rights reserved

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  • 15 2-Ethynyl-1-[(triisopropylsilyl)ethynyl]-1H-pyrrole (8) Oven-dried K2CO3 (524 mg, 3.8 mmol), pyrrole 7 (513 mg, 1.9 mmol), and 60–70% pure dimethyl (1-diazo-2-oxo-2-phenylethyl)phosphonate (1.11g 2.6–3.0 mmol) were added to MeOH (10 mL, 0.2 M) dried over MS, and the mixture was stirred at rt overnight. H2O (10 mL) was added and the mixture was extracted by CHCl3 (6 × 10 mL). The organics were dried (NaSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 100% hexanes) to give a yellow oil; yield: 256 mg (50%). 1H NMR (400 MHz, CDCl3): δ = 6.87 (dd, J = 3.0, 1.5 Hz, 1 H), 6.45 (dd, J = 3.7, 1.5 Hz, 1 H), 6.10 (dd, J = 3.7, 3.0 Hz, 1 H), 3.33 (s, 1 H), 1.12 (s, 21 H). 13C{1H} NMR (100 MHz, THF-d 8): δ = 127.0, 120.2, 117.2, 111.1, 95.8, 84.4, 74.9, 68.7, 19.2, 12.4. HRMS (CI): m/z [M + H]+ calcd for C17H26NSi: 272.1835; found: 272.1830.
  • 16 1,2-Diethynyl-1H-pyrrole (4) CAUTION: All steps should be performed in a well-ventilated environment: inhalation of 4 has been found to induce severe headaches, and should be avoided. Deprotection of 8 (46 mg, 0.17 mmol) with TBAF (0.2 mL, 0.20 mmol, 1 M) in THF (0.9 mL, 0.2 M) at –78 °C for 10 min afforded near-complete conversion into 4 (TLC). Due to the volatility of the product, the entire mixture, was subjected to flash chromatography (silica gel, anhyd THF). Fractions were collected on ice and then analyzed for purity (TLC) and subsequently used in the thermolysis experiments. For spectral analysis, the deprotection and purification were performed with THF-d8. 1H NMR (400 MHz, THF-d8): δ = 6.98 (dd, J = 3.0, 1.5 Hz, 1 H), 6.41 (dd, J = 3.8, 1.5 Hz, 1 H), 6.12 (dd,J = 3.7, 3.0 Hz, 1 H), 4.43 (s, 1 H), 3.90 (s, 1 H). 13C{1H} NMR (100 MHz, THF-d8): δ = 127.2, 119.9, 117.3, 111.2, 84.3, 74.8, 74.6, 59.7. HRMS (CI): m/z [M+] calcd for C8H5N: 115.0422; found: 115.0422.
  • 17 3′,4′,5′,6′-Tetrahydrospiro[cyclopenta[b]pyridine-5,2′-pyran] (9) Pyrrole 4 (estimated 0.17 mmol after deprotection of 8) was subjected to thermolysis in THF at 90 °C for 19 h in a sealed tube. The solvent was then evaporated and the crude mixture was subjected purified by flash chromatography (silica gel, 25% EtOAc–hexanes) to give a yellow oil; yield: 8 mg (25%). 1H NMR (400 MHz, CDCl3): δ = 8.39 (dd, J = 5.2, 1.5 Hz, 1 H), 7.71 (ddd, J = 7.4, 1.5, 0.7 Hz, 1 H), 7.21 (d, J = 6.0 Hz, 1 H), 7.09 (dd, J = 7.5, 5.1 Hz, 1 H), 6.88 (dd, J = 6.0, 0.7 Hz, 1 H), 4.05–3.99 (m, 1 H), 3.88–3.81 (m, 1 H), 2.09–1.95 (m, 2 H), 1.89–1.72 (m, 3 H), 1.61–1.54 (m, 1 H). 13C{1H} NMR (100 MHz, CDCl3): δ = 162.2, 149.2, 142.0, 141.8, 133.7, 129.6, 120.7, 84.0, 65.8, 32.3, 25.8, 21.8. HRMS (CI): m/z [M+] calcd for C12H13NO: 187.0997; found: 187.0992.
  • 18 In all cases, thermolysis reactions in 1,4-dioxane and THF afforded complex mixtures of highly colored polar byproducts in addition to the spirocycles. Thermolyses carried out for shorter reaction times or at lower temperatures also afforded the starting material, but in these cases, the yield of the spirocycle corrected for the recovered starting material was not significantly higher than for reactions that ran to completion.
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  • 20 Spiro[cyclopenta[b]pyrazine-5,5′-[1,4]dioxepane] (10) Thermolysis of 1 in 1,4-dioxane afforded a red oil; yield: 20 mg (15%). 1H NMR (400 MHz, CDCl3): δ = 8.30 (d, J = 2.9 Hz, 1 H), 8.20 (d, J = 3.1 Hz, 1 H), 6.93 (d, J = 6.3 Hz, 1 H), 6.85 (d, J = 6.3 Hz, 1 H), 4.45 (ddd, J = 13.4, 7.3, 1.0 Hz, 1 H), 4.24 (ddd, J = 12.5, 7.0, 1.3 Hz, 1 H), 3.98–3.90 (m, 3 H), 3.88–3.79 (m, 1 H), 2.64 (ddd, J = 16.2, 8.8, 1.5 Hz, 1 H), 2.12 (ddd, J = 16.2, 7.0, 1.3 Hz, 1 H). 13C{1H} NMR (100 MHz, CDCl3): δ = 162.7, 156.4, 143.4, 139.7, 83.6, 72.4, 69.9, 66.9, 36.8. HRMS (CI): m/z [M + H]+ calcd for C11H13N2O2: 205.09715; found: 205.09698.
  • 21 6-(4-Methoxyphenyl)-3′,4′,5′,6′-tetrahydrospiro[cyclopenta[b]pyridine-5,2′-pyran] (12) Thermolysis of 11 in THF gave a red oil; yield: 9 mg (9%). 1H NMR (400 MHz, CDCl3): δ = 8.28 (d, J = 3.0 Hz, 1 H), 8.12 (d, J = 3.0 Hz, 1 H), 7.94 (d, J = 9.0 Hz, 2 H), 7.02 (s, 1 H), 6.97 (d, J = 9.0 Hz, 2 H), 4.83–4.76 (m, 1 H), 4.06–4.02 (m, 1 H), 3.86 (s, 3 H), 2.68–2.57 (m, 1 H), 2.26–2.18 (m, 1 H), 1.95–1.81 (m, 3 H), 1.44–1.40 (m, 1 H). 13C{1H} NMR (100 MHz, CDCl3): δ = 163.6, 160.5, 156.6, 156.4, 142.9, 137.5, 129.4, 126.0, 124.4, 114.1, 82.0, 64.9, 55.5, 30.2, 25.9, 19.0. MS (ESI, +): m/z (%) = 295 (48) [M + H]+, 223 (30), 199 (12).