Brønsted Acid Catalyzed Stereospecific Dearomative Spirocyclization of Benzothiophenyl Analogues of Tertiary cis-β-Benzylstyrenes

Abstract

3-Substituted benzothiophenyl analogues of tertiary cis-β-benzylstyrenes undergo triflic acid catalyzed dearomative spirocyclization at room temperature to afford compounds containing vicinal quaternary centers. Hydroarylation of the styrene is a competing process that occurs preferentially within substrates possessing electron-rich styrenyl alkenes, or an indole in place of the benzothiophene.

Key words

quaternary carbons - spiroheterocycles - dearomatization - spirocyclization - Brønsted acid catalysis - hydroarylation

Publication History

Received: 03 June 2022

Accepted: 08 July 2022

Accepted Manuscript online:
08 July 2022

Article published online:
26 February 2024

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• 15 General Cyclization Procedure In a dry 4 mL glass vial equipped with a PTFE-coated magnetic stirrer bar, the appropriate cis-alkene (0.3 mmol, 1.0 equiv) was dissolved in anhyd CH₂Cl₂ (0.5 M), and the solution was cooled to 0 °C. After 10 min, TfOH (7 mol%) was slowly added and the resultant solution was stirred for another 5 min at 0 °C. The mixture was then allowed to warm to rt and stirred for 12 h. The reaction was quenched with sat. aq NaHCO₃, and the mixture was extracted with CH₂Cl₂ (3 × 1.0 mL). The combined organic phase was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure to afford a crude product that was purified by chromatography (silica gel, gradient elution).
• 16 6′-Fluoro-2′,2′-dimethyl-2′H-spiro[1-benzothiophene-3,1′-naphthalene] (2b)Colorless oil; yield: 81.5 mg (92%). ¹H NMR (500 MHz, CDCl₃): δ = 7.30–7.15 (m, 4 H), 7.05 (m, 1 H), 7.01–6.83 (m, 2 H), 6.41 (d, J = 9.6 Hz, 1 H), 5.89 (d, J = 9.6 Hz, 1 H), 3.98 (d, J = 12.1 Hz, 1 H), 3.30 (d, J = 12.1 Hz, 1 H), 1.17 (s, 3 H), 1.03 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 162.0 (d, J = 245.0 Hz), 144.1, 140.8, 139.6, 138.2 (d, J = 3.3 Hz), 134.2 (d, J = 7.9 Hz), 128.5, 128.3, 128.2 (d, J = 8.0 Hz), 125.2 (d, J = 2.2 Hz), 123.2, 122.4, 114.2 (d, J = 21.0 Hz), 113.4 (d, J = 21.8 Hz), 63.0, 41.5, 40.6 (d, J = 1.3 Hz), 23.7, 23.4. ¹⁹F NMR (470 MHz, CDCl₃): δ = –116.3.6′-Bromo-2′,2′-dimethyl-2′H-spiro[1-benzothiophene-3,1′-naphthalene] (2d)Colorless oil; yield: 90.5 mg (84%). ¹H NMR (400 MHz, CDCl₃): δ = 7.27–7.18 (m, 5 H), 7.09 (d, J = 8.2 Hz, 1 H), 7.05–7.00 (m, 1 H), 6.38 (d, J = 9.6 Hz, 1 H), 5.86 (d, J = 9.6 Hz, 1 H), 3.96 (d, J = 12.1 Hz, 1 H), 3.28 (d, J = 12.1 Hz, 1 H), 1.14 (s, 3 H), 1.0 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 144.1, 141.5, 140.8, 139.3, 134.3, 130.7, 129.5, 128.6, 128.4, 128.2, 124.9, 123.2, 122.4, 121.0, 63.1, 41.3, 40.4, 23.7, 23.4.6′-Fluoro-2′,2′,7′-trimethyl-2′H-spiro[1-benzothiophene-3,1′-naphthalene] (2j)Colorless oil; yield: 81.1 mg (87%). ¹H NMR (500 MHz, CDCl₃): δ = 7.31–7.20 (m, 3 H), 7.08–6.99 (m, 2 H), 6.74 (d, J = 9.8 Hz, 1 H), 6.37 (d, J = 9.6 Hz, 1 H), 5.81 (d, J = 9.6 Hz, 1 H), 3.97 (d, J = 12.1 Hz, 1 H), 3.29 (d, J = 12.1 Hz, 1 H), 2.17 (d, J = 1.6 Hz, 3 H), 1.14 (s, 3 H), 1.01 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 160.4 (d, J = 243.7 Hz), 144.1, 139.9, 139.6, 138.0 (d, J = 3.6 Hz), 131.8 (d, J = 7.9 Hz), 129.7 (d, J = 5.2 Hz), 128.4 (2 C), 125.1 (d, J = 2.0 Hz), 123.8 (d, J = 17.1 Hz), 123.2, 122.3, 113.1 (d, J = 22.7 Hz), 63.0, 41.5, 40.6 (d, J = 1.1 Hz), 23.7, 23.5, 14.8 (d, J = 3.3 Hz). ¹⁹F NMR (470 MHz, CDCl₃): δ = –120.9.
• 17 Tohti A, Lerda V, Stokes BJ. ChemRxiv 2021; preprint; DOI: