Thiolate-Initiated Metal-Free Synthesis of Cyclopentenones via a Halogen-Stabilized Vinyl Carbanion

Abstract

A metal-free synthesis of cyclopentenones is described. The mechanism proceeds via a halogen-stabilized carbanion generated by the nucleophilic attack of a thiolate on a haloalkyne moiety. The sp²-hybridized carbanion undergoes cyclization to an embedded ester carbonyl, yielding the cyclopentenone. The reaction exhibits a broad tolerance toward functional groups and proceeds under mild conditions.

Keywords

Metal-free - Cyclization - sp²-Hybridized intermediate - Vinyl-carbanion - Halogen-stabilized carbanion - Cyclopentenone - Haloalkyne

Publication History

Received: 13 May 2025

Accepted after revision: 19 June 2025

Accepted Manuscript online:
20 June 2025

Article published online:
18 August 2025

• References

• 1 Sawitsch V. Annalen 1861; 119: 182-185
• 2 Wallach O. Annalen 1880; 203: 83-94
• 3 Wu W, Jiang H. Acc Chem Res 2014; 47: 2483-2504
• 4 Chen C, Zhang Q, Li Y. et al. Tetrahedron Lett 2024; 147: 155229
• 5 Miguélez R, Arto O, Rodríguez-Arias C, González JM, Barrio P. ChemCatChem 2024; 16: e202400617
• 6 Kreuzahler M, Haberhauer G. Chem Eur J 2022; 28: e202103046
• 7 Cadierno V. Eur J Inorg Chem 2019; 886-898
• 8 Gleiter R, Werz DB. Chem Rev 2010; 110: 4447-4488
• 9 Evano G, Coste A, Jouvin K. Angew Chem Int Ed 2010; 49: 2840-2859
• 10 Alonso F, Beletskaya IP, Yus M. Chem Rev 2004; 104: 3079-3159
• 11 Sindhu KS, Thankachan AP, Sajitha PS, Anilkumar G. Org Biomol Chem 2015; 13: 6891-6905
• 12 Yao B, Liang Z, Niu T, Zhang Y. J Org Chem 2009; 74: 4630-4633
• 13 Frederick MO, Mulder JA, Tracey MR. et al. J Am Chem Soc 2002; 125: 2368-2369
• 14 Zhang Y, Hsung RP, Tracey MR, Kurtz KCM, Vera EL. Org Lett 2004; 6: 1151-1154
• 15 Zhang X, Zhang Y, Huang J. et al. J Org Chem 2006; 71: 4170-4177
• 16 Liu C, Xue Y, Ding L, Zhang H, Yang F. Eur J Org Chem 2018; 6537-6540
• 17 Xie L, Wu Y, Yi W, Zhu L, Xiang J, He W. J Org Chem 2013; 78: 9190-9195
• 18 Liu H, Chen C, Wang L, Tong X. Org Lett 2011; 13: 5072-5075
• 19 Kreuzahler M, Haberhauer G. J Org Chem 2019; 84: 8210-8224
• 20 Morishita T, Yoshida H, Ohshita J. Chem Commun 2010; 46: 640-642
• 21 Staben ST, Kennedy-Smith JJ, Toste FD. Angew Chem Int Ed 2004; 43: 5350-5352
• 22 Kreuzahler M, Daniels A, Wölper C, Haberhauer G. J Am Chem Soc 2019; 141: 1337-1348
• 23 Mader S, Molinari L, Rudolph M, Rominger F, Hashmi ASK. Chem Eur J 2015; 21: 3910-3913
• 24 Li Y, Liu X, Jiang H, Liu B, Chen Z, Zhou P. Angew Chem Int Ed 2011; 50: 6341-6345
• 25 Li Y, Liu X, Jiang H, Feng Z. Angew Chem Int Ed 2010; 49: 3338-3341
• 26 Miguélez R, Semleit N, Rodríguez-Arias C. et al. Angew Chem Int Ed 2023; e202305296
• 27 Daniels A, Wölper C, Haberhauer G. Chem Eur J 2024; e202401070
• 28 Barsu N, Leutzsch M, Fürstner A. J Am Chem Soc 2020; 142: 18746-18752
• 29 Tanaka R, Miller SI. Tetrahedron Lett 1971; 12: 1753-1756
• 30 Tanaka R, Rodgers M, Simonaitis R, Miller SI. Tetrahedron 1971; 27: 2651-2669
• 31 Chowdhury RM, Wilden JD. Org Biomol Chem 2015; 13: 5859-5861
• 32 Liu G, Kong L, Shen J, Zhu G. Org Biomol Chem 2014; 12: 2310-2321
• 33 Knorr R. Chem Rev 2004; 104: 3795-3850
• 34 Braun M. Angew Chem Int Ed 1998; 37: 430-451
• 35 Harada T, Muramatsu K, Mizunashi K. et al. J Org Chem 2008; 73: 249-258
• 36 Procedure for the Preparation of Cyclopentenone 14a. In a preheated Schlenk tube, haloalkyne 12c (61 mg, 0.24 mmol, 1.0 eq.) was dissolved in 2.4 mL dry DMSO. Thiophenol 13a (29 mg, 27.0 μL, 0.26 mmol, 1.1 eq.) was then added to the reaction mixture, followed by activated potassium carbonate (36 mg, 0.26 mmol, 1.1 eq.) and stirred at room temperature for 1 h. The reaction was quenched with 60 mL water and the resulting aqueous phase was extracted three times with 20 mL ethyl acetate. The organic phases were washed with 60 mL saturated NaHCO₃ solution and dried over MgSO₄. Excess solvent was removed under reduced pressure. The crude product was adsorbed on Celite and purified by chromatography to yield the desired cyclopentenone 14a in 75% yield. R_f = 0.17 (n-pentane/DEE 1:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.60–7.58 (m, 2 H, CH_ar), 7.53–7.43 (m, 3 H, CH_ar), 2.48–2.45 (m, 2 H, CH₂CS), 2.40–2.37 ppm (m, 2 H, CH₂CO). ¹³C NMR (101 MHz, CDCl₃): δ = 196.9 (C=O), 171.7 (CCl), 135.8 (C_arH), 130.7 (C_arH), 129.8 (C_arH), 127.0 (C_arS), 126.4 (CH₂CS), 33.4 (CH₂CS), 29.1 ppm (CH₂CO)