Lewis Acid Catalyzed Regioselective Substitution of 2-Indolylmethanols with Pyrroles

Abstract

A Lewis acid catalyzed regioselective C2′-electrophilic substitution of 2-indolylmethanols with pyrroles has been established, which affords indole-based tetraarylmethanes in overall high yields (up to 99%) with excellent regioselectivities. Moreover, such indole-based tetraarylmethanes exhibit potent cytotoxicity against HepG2 cancer cells, which demonstrates their potential applications in medicinal chemistry. This reaction not only represents the regioselective C2′-electrophilic substitution of 2-indolylmethanols with aryl nucleophiles (Ar-Nu), but also provides a new strategy for the synthesis of biologically important tetraarylmethanes.

Key words

indolylmethanols - pyrroles - electrophilic substitution - Lewis acids - tetraarylmethanes - regioselectivity

Publication History

Received: 25 October 2024

Accepted after revision: 16 December 2024

Accepted Manuscript online:
16 December 2024

Article published online:
27 January 2025

• References


For some reviews, see:
• 1a Kochanowska-Karamyan AJ, Hamann MT. Chem. Rev. 2010; 110: 4489
• 1b Wan Y, Li Y, Yan C, Yan M, Tang Z. Eur. J. Med. Chem. 2019; 183: 111691

For some reviews, see:
• 2a Dalpozzo R. Chem. Soc. Rev. 2015; 44: 742
• 2b Zhang Y.-C, Jiang F, Shi F. Acc. Chem. Res. 2020; 53: 425
• 2c Sheng F.-T, Wang J.-Y, Tan W, Zhang Y.-C, Shi F. Org. Chem. Front. 2020; 7: 3967
• 2d Tu M.-S, Chen K.-W, Wu P, Zhang Y.-C, Liu X.-Q, Shi F. Org. Chem. Front. 2021; 8: 2643
• 2e Zhang H.-H, Shi F. Acc. Chem. Res. 2022; 55: 2562
• 2f Tan W, Zhang J.-Y, Gao C.-H, Shi F. Sci. China: Chem. 2023; 66: 966
• 2g Yang S, Wang N, Hang Q, Zhang Y, Shi F. Acta Chim. Sin. 2023; 81: 793
• 2h Wang H, Yang S, Zhang Y, Shi F. Chin. J. Org. Chem. 2023; 43: 974

For some reviews, see:
• 3a Mei G.-J, Shi F. J. Org. Chem. 2017; 82: 7695
• 3b Dorsch C, Schneider C. Synthesis 2022; 54: 3125
• 3c Li X, Li Z, Sun J. Nat. Synth. 2022; 1: 426
• 3d Zhu Z.-Q, Li T.-Z, Liu S.-J, Shi F. Org. Chem. Front. 2024; 11: 5573

For some reviews, see:
• 4a Petrini M. Adv. Synth. Catal. 2020; 362: 1214
• 4b Zhang H, Shi F. Chin. J. Org. Chem. 2022; 42: 3351

For some selected examples of C3-electrophilic substitutions, see:
• 5a Li C, Zhang H.-H, Fan T, Shen Y, Wu Q, Shi F. Org. Biomol. Chem. 2016; 14: 6932
• 5b Zhang H.-H, Wang C.-S, Li C, Mei G.-J, Li Y, Shi F. Angew. Chem. Int. Ed. 2017; 56: 116
• 5c Zhu Z.-Q, Shen Y, Liu J.-X, Tao J.-Y, Shi F. Org. Lett. 2017; 19: 1542
• 5d He Y.-Y, Sun X.-X, Li G.-H, Mei G.-J, Shi F. J. Org. Chem. 2017; 82: 2462
• 5e Ma C, Zhou J.-Y, Zhang Y.-Z, Jiao Y, Mei G.-J, Shi F. Chem. Asian J. 2018; 13: 2549
• 5f Zhou Y, Cao W.-B, Zhang L.-L, Xu X.-P, Ji S.-J. J. Org. Chem. 2018; 83: 6056
• 5g Xu M.-M, Wang H.-Q, Mao Y.-J, Mei G.-J, Wang S.-L, Shi F. J. Org. Chem. 2018; 83: 5027

For some recent examples of C3-electrophilic substitutions, see:
• 6a Tang Z, Hong G, Hu C, Wang Q, Zhong Y, Gong Y, Yang P, Wang L. Org. Biomol. Chem. 2021; 19: 10337
• 6b Sheng F.-T, Yang S, Wu S.-F, Zhang Y.-C, Shi F. Chin. J. Chem. 2022; 40: 2151
• 6c Han Z, Zhuang H, Tang L, Zang Y, Guo W, Huang H, Sun J. Org. Lett. 2022; 24: 4246

For C3-electrophilic cycloadditions, see:
• 7a Sun X.-X, Zhang H.-H, Li G.-H, He Y.-Y, Shi F. Chem. Eur. J. 2016; 22: 17526
• 7b Zhu Z.-Q, Shen Y, Sun X.-X, Tao J.-Y, Liu J.-X, Shi F. Adv. Synth. Catal. 2016; 358: 3797
• 7c Xu M.-M, Wang H.-Q, Wan Y, Wang S.-L, Shi F. J. Org. Chem. 2017; 82: 10226
• 7d Mao J, Zhang H, Ding X.-F, Luo X, Deng W.-P. J. Org. Chem. 2019; 84: 11186
• 7e Nawaz S, Huang Y, Bao X, Wei S, Wei X, Qu J, Wang B. Org. Biomol. Chem. 2021; 19: 8530
• 7f Li R, Zhang J, Sun M, Wang Z, Yang J. Org. Lett. 2024; 26: 4610

For some selected examples of C3-nucleophilic cycloadditions, see:
• 8a Zhu Z.-Q, Yu L, Sun M, Mei G.-J, Shi F. Adv. Synth. Catal. 2018; 360: 3109
• 8b Sun M, Ma C, Zhou S.-J, Lou S.-F, Xiao J, Jiao Y, Shi F. Angew. Chem. Int. Ed. 2019; 58: 8703
• 8c Zhou S.-J, Sun M, Wang J.-Y, Yu X.-Y, Lu H, Zhang Y.-C, Shi F. Eur. J. Org. Chem. 2020; 4301
• 8d Li T.-Z, Liu S.-J, Sun Y.-W, Deng S, Tan W, Jiao Y, Zhang Y.-C, Shi F. Angew. Chem. Int. Ed. 2021; 60: 2355
• 8e Qin L.-Z, Cheng Y.-L, Wen X, Xu Q.-L, Zhen L. Tetrahedron 2021; 77: 131742
• 8f Yang S, Wang H.-Q, Gao J.-N, Tan W.-X, Zhang Y.-C, Shi F. Eur. J. Org. Chem. 2022; e202200878
• 8g Cheng Y.-L, Wu G, Zang Y.-J, Hu Y.-Y, Qin L.-Z, Wen X, Xu Q.-L. Org. Biomol. Chem. 2022; 20: 3930

For some recent examples of C3-nucleophilic cycloadditions, see:
• 9a Rui K, Gu H, Woldegiorgis AG, Lin X. Org. Lett. 2023; 25: 6654
• 9b Zhan S.-C, Sun J, Sun Q, Han Y, Yan C.-G. J. Org. Chem. 2023; 88: 5440
• 9c Singh G, Sharma S, Pandey R, Rekha, Anand RV. Org. Biomol. Chem. 2023; 21: 2493
• 9d Li T, Liu S, Wu S, Cheng Q, Chen Q, Jiao Y, Zhang Y, Shi F. Sci. China: Chem. 2024; 67: 92629
• 9e Lai B.-W, Qu S.-Y, Yin Y.-X, Li R, Dong K, Shi F. J. Org. Chem. 2024; 89: 10197
• 9f Wu T.-F, Fu Z.-J, Zhang Y.-R, Qiu Z.-W, Li BQ, Chen S.-S, Pan H.-P, Ma A.-J, Zhang X.-Z. Molecules 2024; 29: 1251
• 10a Li X, Duan M, Deng Z, Shao Q, Chen M, Zhu G, Houk KN, Sun J. Nat. Catal. 2020; 3: 1010
• 10b Nian C, Yu R, Han Z, Bai Y, Wang J, Sun J, Huang H. Chem. Commun. 2024; 60: 9797

For C2′-electrophilic substitutions with heteroatom-based nucleophiles, see:
• 11a Hu C, Hong G, He Y, Zhou C, Kozlowski MC, Wang L. J. Org. Chem. 2018; 83: 4739
• 11b Chen L, Zou Y.-X, Fang X.-Y, Wu J, Su X.-H. Org. Biomol. Chem. 2018; 16: 7417
• 11c Zhu S, Zhang Y, Luo J, Wang F, Cao X, Huang S. Green Chem. 2020; 22: 657

For C2′-electrophilic substitutions with carbon-based nucleophiles, see:
• 12a Zhong Y, Hong G, Tang Z, Yang P, Wang Q, Gong Y, Wang L. ChemistrySelect 2022; 7: e202200218
• 12b Chaudhari TY, Bisht S, Chorol S, Bhujbal SM, Bharatam PV, Tandon V. J. Org. Chem. 2023; 88: 10412

For other reaction types, see:
• 13a Zhou Y, Xu X.-P, Ji S.-J. Org. Lett. 2019; 21: 2039
• 13b Qiu Z.-W, Li BQ, Liu H.-F, Zhu Z.-Q, Pan H.-P, Feng N, Ma A.-J, Peng J.-B, Zhang X.-Z. J. Org. Chem. 2021; 86: 7490
• 13c Liu Y, Cao M, Zhang S, Wang Z, Dai X, Jiang X, Dong Y, Fu J. Org. Biomol. Chem. 2022; 20: 1510
• 13d Sun J, Yan C, Sun Q, Hana Y, Yan C.-G. New J. Chem. 2023; 47: 6694
• 13e Dong R, Han T.-J, Huang L, Mei G.-J. Org. Chem. Front. 2024; 11: 3624
• 13f Liu S.-J, Li T.-Z, Wang N.-Y, Cheng Q, Jiao Y, Zhang Y.-C, Shi F. Org. Chem. Front. 2024; 11: 4812
• 13g Zhu W.-R, Su Q, Deng X.-Y, Ouyang Z.-L, Weng J, Lu G. Org. Chem. Front. 2024; 11: 2040
• 13h Xu J, Rawal VH. J. Am. Chem. Soc. 2019; 141: 4820
• 14 For a review, see: Chen L, Huo J, Zhang J, Currano JN, Guan H, Walsh PJ, Mao J. Green Synth. Catal. 2023; 4: 273

For some selected examples, see:
• 15a Crowley PD, Gallagher HC. J. Appl. Microbiol. 2014; 117: 611
• 15b Tan X, Deng Z, Wang Q, Chen S, Zhu G, Sun J. Nat. Synth. 2023; 2: 275
• 16a Hang Q.-Q, Wu S.-F, Yang S, Wang X, Zhong Z, Zhang Y.-C, Shi F. Sci. China: Chem. 2022; 65: 1929
• 16b Yang S, Huang J.-B, Wang D.-H, Wang N.-Y, Chen Y.-Y, Ke X.-Y, Chen H, Ni S.-F, Zhang Y.-C, Shi F. Precis. Chem. 2024; 2: 208
• 16c Wang J.-Y, Gao C.-H, Ma C, Wu X.-Y, Ni S.-F, Tan W, Shi F. Angew. Chem. Int. Ed. 2024; 63: e202316454
• 16d Wu P, Zhang W.-T, Yang J.-X, Yu X.-Y, Ni S.-F, Tan W, Shi F. Angew. Chem. Int. Ed. 2024; 63: e202410581

For an example, see:
• 17a Li X, Duan M, Yu P, Houk KN, Sun J. Nat. Commun. 2021; 12: 4881

For a review, see:
• 17b Singh S, Hazra CK. Synthesis 2024; 56: 368
• 18 CCDC 2392854 (3ca) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures . Also see the Supporting Information