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

• References and Notes

• 1 Current address: Department of Chemistry and Biochemistry, Santa Clara University, 500 EI Camino Real, Santa Clara, CA 95053, USA.

For reviews, see:
• 2a Trost BM, Jiang C. Synthesis 2006; 369
• 2b Christoffers J, Mann A. Angew. Chem. Int. Ed. 2001; 40: 4591
• 2c Büschleb M, Dorich S, Hanessian S, Tao D, Schenthal KB, Overman LE. Angew. Chem. Int. Ed. 2016; 55: 4156
• 2d Ling T, Rivas F. Tetrahedron 2016; 72: 6729
• 2e Li C, Ragab SS, Liu G, Tang W. Nat. Prod. Rep. 2020; 37: 276
• 2f Corey EJ, Guzman-Perez A. Angew. Chem. Int. Ed. 1998; 37: 388
• 2g Das JP, Marek I. Chem. Commun. 2011; 47: 4593
• 2h Hawner C, Alexakis A. Chem. Commun. 2010; 46: 7295
• 2i Hong AY, Stoltz BM. Eur. J. Org. Chem. 2013; 2745
• 2j Douglas CJ, Overmann LE. Proc. Natl. Acad. Sci. 2004; 101: 5363
• 2k Feng J, Holmes M, Krische MJ. Chem. Rev. 2017; 117: 12564
• 2l Cozzi PG, Hilgraf R, Zimmermann N. Eur. J. Org. Chem. 2007; 5969
• 2m Long R, Huang J, Gong J, Yang Z. Nat. Prod. Rep. 2015; 32: 1584
• 2n Zhou F, Zhu L, Pan B.-W, Shi Y, Liu Y -L, Zhou L. Chem. Sci. 2020; 11: 9341

For selected approaches, see:
• 3a Mei T.-S, Patel HH, Sigman MS. Nature 2014; 508: 340
• 3b Trost BM, Malhotra WH. Chan W. H. J. Am. Chem. Soc. 2011; 133: 7328
• 3c Pierrot D, Marek I. Angew. Chem. Int. Ed. 2020; 59: 36
• 3d Bruffaerts J, Pierrot D, Marek I. Nat. Chem. 2018; 10: 1164
• 3e Hu P, Chi HM, DeBacker KC, Gong X, Keim JH, Hsu IT, Snyder SA. Nature 2019; 569: 703
• 3f Ohmatsu K, Imagawa N, Ooi T. Nat. Chem. 2014; 6: 47
• 3g Krautwald S, Sarlah D, Schafroth MA, Carreira EM. Science 2013; 340: 1065
• 3h Behenna DC, Stoltz BM. J. Am. Chem. Soc. 2004; 126: 15044
• 3i Zhang P, Le H, Kyne RE, Morken JP. J. Am. Chem. Soc. 2011; 133: 9716
• 3j Jung B, Hoveyda AH. J. Am. Chem. Soc. 2012; 134: 1490
• 3k Zhang P, Tsuji N, Ouyang J, List B. J. Am. Chem. Soc. 2021; 143: 675
• 3l Chen W.-F, Lin H.-Y, Dai SA. Org. Lett. 2004; 6: 2341
• 4a Quasdorf KW, Overman LE. Nature 2014; 516: 181
• 4b Liu Y, Han S, Liu W.-B, Stoltz BM. Acc. Chem. Res. 2015; 48: 740
• 5 Jung ME, Piizzi G. Chem. Rev. 2005; 105: 1735
• 6 Talele TT. J. Med. Chem. 2018; 61: 2166
• 7a Marson CM. Chem. Soc. Rev. 2011; 40: 5514
• 7b Zheng Y, Tice CM, Singh SB. Bioorg. Med. Chem. Lett. 2014; 24: 3673
• 7c Welsch ME, Snyder SA, Stockwell BR. Curr. Opin. Chem. Biol. 2010; 14: 347
• 7d Galloway WR. J. D, Isidro-Llobet A, Spring DR. Nat. Commun. 2010; 1: 80
• 7e Sharma I, Tan DS. Nat. Chem. 2013; 5: 157
• 7f Hung AW, Ramek A, Wang Y, Kaya T, Wilson JA, Clemons PA, Young DW. Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 6799
• 7g Carreira EM, Fessard TC. Chem. Rev. 2014; 114: 8257
• 8a Lovering F, Bicker J, Humblet C. J. Med. Chem. 2009; 52: 6752
• 8b Galliford CV, Scheidt KA. Angew. Chem. Int. Ed. 2007; 46: 8748
• 8c Müller G, Berkenbosch T, Benningshof JC. J, Stumpfe D, Bajorath J. Chem. Eur. J. 2017; 23: 703
• 8d King TA, Stewart HL, Mortensen KT, North AJ. P, Sore HF, Spring DR. Eur. J. Org. Chem. 2019; 5219
• 8e Stotani S, Lorenz C, Winkler M, Medda F, Picazo E, Ortega Martinez R, Karawajczyk A, Sanchez-Quesada J, Giordanetto F. ACS Comb. Sci. 2016; 18: 330

For reviews, see:
• 9a Rios R. Chem. Soc. Rev. 2012; 41: 1060
• 9b Xu P.-W, Yu J.-S, Chen C, Cao Z.-Y, Zhou F, Zhou J. ACS Catal. 2019; 9: 1820
• 9c Sannigrahi M. Tetrahedron 1999; 55: 9007
• 9d James MJ, O’Brien P, Taylor RJ. K, Unsworth WP. Chem. Eur. J. 2016; 22: 2856
• 9e D’yakonov VA, Trapeznikova OA, de Meijere A, Dzhemilev UM. Chem. Rev. 2014; 114: 5775
• 9f Liang X.-W, Zheng C, You S.-L. Chem. Eur. J. 2016; 22: 11918
• 9g Roche SP, Youte Tendoung J.-J, Tréguier B. Tetrahedron 2015; 71: 3549
• 9h Zhuo C.-X, Zhang W, You S.-L. Angew. Chem. Int. Ed. 2012; 51: 12662
• 9i Zhuo C.-X, Zheng C, You S.-L. Acc. Chem. Res. 2014; 47: 2558
• 9j Ding Q, Zhou X, Fan R. Org. Biomol. Chem. 2014; 12: 4807
• 9k Wertjes WC, Southgate EH, Sarlah D. Chem. Soc. Rev. 2018; 47: 7996

For selected examples, see:
• 10a Vo NT, Pace RD. M, O’Hara F, Gaunt MJ. J. Am. Chem. Soc. 2008; 130: 404
• 10b Rousseaux S, García-Fortanet J, Del Aguila Sanchez MA, Buchwald SL. J. Am. Chem. Soc. 2011; 133: 9282
• 10c Rudolph A, Bos PH, Meetsma A, Minnaard A, Feringa BL. Angew. Chem. Int. Ed. 2011; 50: 5834
• 10d James MJ, Cuthbertson JD, O’Brien P, Taylor RJ. K, Unsworth WP. Angew. Chem. Int. Ed. 2015; 54: 7640
• 10e Huang H.-M, Procter DJ. J. Am. Chem. Soc. 2017; 139: 1661
• 10f Wu Q.-F, He H, Liu W.-B, You S.-L. J. Am. Chem. Soc. 2010; 132: 11418
• 10g Cai Q, Zheng C, Zhang J.-W, You S.-L. Angew. Chem. Int. Ed. 2011; 50: 8665
• 10h Singh RP, Das J, Yousufuddin M, Gout D, Lovely CJ. Org. Lett. 2017; 19: 4110
• 10i Schröder F, Sharma UK, Mertens M, Devred F, Debecker DP, Luque R, Van der Eycken EV. ACS Catal. 2016; 6: 8156
• 10j Nandi RK, Guillot R, Kouklovsky C, Vincent G. Org. Lett. 2016; 18: 1716
• 10k Adams K, Ball AK, Birkett J, Brown L, Chappell B, Gill DM, Lo PK. T, Patmore NJ, Rice CR, Ryan J, Raubo P, Sweeney JB. Nat. Chem. 2017; 9: 396
• 10l Bansode AH, Shaikh SR, Gonnade RG, Patil NT. Chem. Commun. 2017; 53: 9081
• 10m Mu X, Yu H, Peng H, Xiong W, Wu T, Tang W. Angew. Chem. Int. Ed. 2020; 59: 8143
• 10n Vacala TL, Carlson PR, Arreola-Hester A, Williams CG, Makhoul EW, Vadola PA. J. Org. Chem. 2018; 83: 1493
• 10o Liddon JT. R, Clarke AK, Taylor RJ. K, Unsworth WP. Org. Lett. 2016; 18: 6328
• 10p Clarke AK, James MJ, O’Brien P, Taylor RJ. K, Unsworth WP. Angew. Chem. Int. Ed. 2016; 55: 13798
• 10q Wu T, Zhou Q, Tang W. Angew. Chem. Int. Ed. 2021; 60: 9978
• 10r Zhang Z, Liu X, Ji L, Zhang T, Jia Z, Loh T.-P. ACS Catal. 2022; 12: 2052
• 11a Fedoseev P, Van der Eycken E. Chem. Commun. 2017; 53: 7732
• 11b Kong L, Sun Y, Zheng Z, Tang R, Wang M, Li Y. Org. Lett. 2018; 20: 5251
• 11c Zhou Y, Xia Z.-L, Gu Q, You S.-L. Org. Lett. 2017; 19: 762
• 11d Pan Z, Liu Y, Hu F, Liu Q, Shang W, Ji X, Xia C. Org. Lett. 2020; 22: 1589
• 11e Ueda J, Harada S, Kobayashi M, Yanagawa M, Nemoto T. Eur. J. Org. Chem. 2021; 3999
• 12a Kotha S, Deb AC, Lahiri K, Manivannan E. Synthesis 2009; 165
• 12b Ding A, Meazza M, Guo H, Yang JW, Rios R. Chem. Soc. Rev. 2018; 47: 5946
• 13a Cai X, Keshavarz A, Omaque JD, Stokes BJ. Org. Lett. 2017; 19: 2626
• 13b Cai X, Tohti A, Ramirez C, Harb H, Fettinger JC, Hratchian HP, Stokes BJ. Org. Lett. 2019; 21: 1574
• 14 For a discussion of the enhanced nucleophilicity of the position of fluorobenzenes, see: Rosenthal, J.; Schuster, D. I. J. Chem. Educ 2003, 80, 679.
• 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: DOI: 10.33774/chemrxiv2021-7lw6b.