I₂-Promoted Deoxygenative Coupling of Indolin-3-ones with Thiols for the Synthesis of 3-Sulfenylindoles

Abstract

This study aims to develop a facile and efficient synthetic method utilizing iodine as a catalyst for the deoxygenative coupling of indolin-3-one derivatives with thiols. Reaction of indolin-3-ones with a range of alkane- and arenethiols with 3 mol% iodine in 2,2,2-trifluoroethanol at room temperature or 60 °C gave 3-alkylthio- or 3-arylthio-substituted indoles in 52–98% yields while reaction with arenethiols using 10 mol% iodine, 1.2 equiv sodium hydroxide in acetonitrile gave 2-(arylthio)indoline-3-ones in moderate yields. Hence, regioselective C–S bond formation, which is produced at the C2 or C3 position of indolin-3-one, was achieved, depending on the presence or absence of a base and, advantageously, without the need for a transition metal catalyst and additional synthetic steps.

Key words

iodine - deoxygenative coupling - regioselective C–S bond formation - indolin-3-one - 3-sulfenyl indole

Publication History

Received: 21 February 2025

Accepted after revision: 09 April 2025

Accepted Manuscript online:
09 April 2025

Article published online:
12 May 2025

• References

• 1a La Regina G, Edler MC, Brancale A, Kandil S, Coluccia A, Piscitelli F, Prosperi E, Lavecchia A, Novellino E, Artico M, Silvestri R. J. Med. Chem. 2007; 50: 2865
• 1b Unangst PC, Connor DT, Stabler SR, Weikert RJ, Carethers ME, Kennedy JA, Thueson D, Chestnut JC, Adolphson RL, Conroy MC. J. Med. Chem. 1989; 32: 1360
• 2a Silvestri R, De Martino G, La Regina G, Artico M, Massa S, Vargiu L, Mura M, Loi AG, Marceddu T, La Colla P. J. Med. Chem. 2003; 46: 2482
• 2b Ragno R, Coluccia A, La Regina G, De Martino G, Piscitelli F, Lavecchia A, Novellino E, Bergamini A, Ciaprini C, Sinistro A, Maga G, Crespan E, Artico M, Silvestri R. J. Med. Chem. 2006; 49: 3172
• 2c Ragno R, Artico M, De Martino G, La Regina G, Coluccia A, Di Pasquali A, Silvestri R. J. Med. Chem. 2005; 48: 213
• 2d De Martino G, Edler MC, La Regina G, Coluccia A, Barbera MC, Barrow D, Nicholson RI, Chiosis G, Brancale A, Hamel E, Artico M, Silvestri R. J. Med. Chem. 2006; 49: 947
• 2e De Martino G, La Regina G, Coluccia A, Edler MC, Barbera MC, Brancale A, Wilcox E, Hamel E, Artico M, Silvestri R. J. Med. Chem. 2004; 47: 6120
• 2f La Regina G, Bai R, Rensen W, Coluccia A, Piscitelli F, Gatti V, Bolognesi A, Lavecchia A, Granata I, Porta A, Maresca B, Soriani A, Iannitto ML, Mariani M, Santoni A, Brancale A, Ferlini C, Dondio G, Varasi M, Mercurio C, Hamel E, Lavia P, Novellino E, Silvestri R. J. Med. Chem. 2011; 54: 8394
• 2g Luker T, Bonnert R, Brough S, Cook AR, Dickinson MR, Dougall I, Logan C, Mohammeda RT, Paine S, Sanganee HJ, Sargent C, Schmidt JA, Teague S, Thom S. Bioorg. Med. Chem. Lett. 2011; 21: 6288
• 2h Funk CD. Nat. Rev. Drug Discovery 2005; 4: 664
• 2i Cianchi F, Cortesini C, Magnelli L, Fanti E, Papucci L, Schiavone N, Messerini L, Vannacci A, Capaccioli S, Perna F, Lulli M, Fabbroni V, Perigli G, Bechi P, Masini E. Mol. Cancer Ther. 2006; 5: 2716
• 3a Fang X.-L, Tang R.-Y, Zhong P, Li J.-H. Synthesis 2009; 4183
• 3b Zhang S, Qian P, Zhang M, Hu M, Cheng J. J. Org. Chem. 2010; 75: 6732
• 3c Ge W, Wei Y. Synthesis 2012; 934
• 3d Ge W, Wei Y. Green Chem. 2012; 14: 2066
• 3e Browder CC, Mitchell MO, Smith RL, el-Stdayman G. Tetrahedron. Lett. 1993; 34: 6245
• 3f Sang P, Chen Z, Zou J, Zhang Y. Green Chem. 2013; 15: 2096
• 3g Huang D, Chen J, Dan W, Ding J, Liu M, Wu H. Adv. Synth. Catal. 2012; 354: 2123
• 3h Dong D.-Q, Hao S.-H, Yang D.-S, Li L.-X, Wang Z.-L. Eur. J. Org. Chem. 2017; 6576
• 3i Zhang H, Wang H, Jiang Y, Cao F, Gao W, Zhu L, Yang Y, Wang X, Wang Y, Chen J, Feng Y, Deng X, Lu Y, Hu X, Li X, Zhang J, Shi T, Wang Z. Chem. Eur. J. 2020; 26: 17289
• 4a Yang F.-L, Tian S.-K. Angew. Chem. Int. Ed. 2013; 52: 4929
• 4b Kang X, Yan R, Yu G, Pang X, Liu X, Xiang L, Huang G. J. Org. Chem. 2014; 79: 10605
• 4c Xiao F, Xie H, Liu S, Deng G.-J. Adv. Synth. Catal. 2014; 356: 364
• 5 Kumaraswamy G, Raju R, Narayanarao V. RSC Adv. 2015; 5: 22718
• 6 Chen M, Huang Z.-T, Zheng Q.-Y. Chem. Commun. 2012; 48: 11686
• 7 Saima, Equbal D, Lavekar AG, Sinha AK. Org. Biomol. Chem. 2016; 14: 6111
• 8 Ghosh A, Lecomte M, Kim-Lee S.-H, Radosevich AT. Angew. Chem. Int. Ed. 2019; 58: 2864
• 9 Pandey AK, Chand S, Singh R, Kumar S, Singh KN. ACS Omega 2020; 5: 7627
• 10a Yamashiro T, Abe T, Tanioka M, Kamino S, Sawada D. Chem. Commun. 2021; 57: 13381
• 10b Hostier T, Ferey V, Ricci G, Pardo DG, Cossy J. Chem. Commun. 2015; 51: 13898
• 11 Dodds AC, Sutherland A. J. Org. Chem. 2021; 86: 5922
• 12 Zou C, Wu H, He J, Hu Y, Deng W, Li X, Hu J, Li Y, Huang Y. J. Org. Chem. 2022; 87: 1335
• 13 Mitsudo K, Habara N, Kobashi Y, Kurimoto Y, Mandai H, Suga S. Synlett 2020; 31: 1947