Recent Advances in Aryne Generation Methods: From Classical Strategies to Cutting-edge Breakthroughs

Abstract

This review summarizes the evolution of aryne generation methodologies, from early harsh approaches to recent mild and practical strategies. It aims to provide a systematic overview of advances over the past decade, with particular emphasis on the last five years. Key methods discussed include activation using bulky bases, cyclic onium salts, photochemical triggers, ring-opening of four-membered rings, and transition-metal-assisted processes. These modern techniques enable aryne formation under milder conditions, with improved functional group tolerance, operational safety, and scalability. As a result, arynes have become versatile tools for constructing complex aromatic molecules, modifying pharmaceuticals, and performing bioorthogonal reactions. The review concludes by highlighting future directions, such as developing more accessible precursors, discovering new reaction modes, and expanding applications in drug discovery, materials science, and chemical biology.

Keywords

Aryne / Aryne generation / Aryne precursor / Activation condition

References

[1] Himeshima Y, Sonoda T, Kobayashi H. Chem. Lett., 1983, 12: 1211

[2] Yoshimura A, Saito A, Zhdankin V V. Chem.-Eur. J., 2018, 24: 15156

[3] Shi J, Li L, Li Y. Chem. Rev., 2021, 121: 3892

[4] Sarmah M, Sharma A, Gogoi P. Org. Biomol. Chem., 2021, 19: 722

[5] Idiris F I M, Jones C R. Org. Biomol. Chem., 2017, 15: 9044

[6] Fluegel L L, Hoye T R. Chem. Rev., 2021, 121: 2413

[7] Holden C, Greaney M F. Angew. Chem., Int. Ed., 2014, 53: 5746

[8] Maier J, Marder T B. Chem.-Eur. J., 2021, 27: 7978

[9] Kim N, Choi M, Suh S-E, Chenoweth D M. Chem. Rev., 2024, 124: 11435

[10] Stoermer R, Kahlert B. Ber. Dtsch. Chem. Ges., 1902, 35: 1633

[11] Bachmann W E, Clarke H T. J. Am. Chem. Soc., 1927, 49: 2089

[12] Wittig G. Naturwissenschaften, 1942, 30: 696

[13] Roberts J D, Simmons H E, Carlsmith L A, Vaughan C W. J. Am. Chem. Soc., 1953, 75: 3290

[14] Kanishchev O S, Dolbier W R. J. Org. Chem., 2016, 81: 11305

[15] Miyamoto N, Nakazawa Y, Nakamura T, Okano K, Sato S, Sun Z, Isobe H, Tokuyama H. Synlett, 2018, 29: 513

[16] Mesgar M, Nguyen-Le J, Daugulis O. J. Am. Chem. Soc., 2018, 140: 13703

[17] Ikawa T, Masuda S, Akai S. Chem.-Eur. J., 2020, 26: 4320

[18] Yao J-L, Zhang Z, Li Z. J. Am. Chem. Soc., 2024, 146: 8839

[19] Preston-Herrera C, Devin R C, Matter M E, Stache E E. J. Am. Chem. Soc., 2025, 147: 46759

[20] Alvarado M, Tran L, Tönshoff C, Li B, Darrigan C, Preud’homme H, Chrostowska A, Bettinger H F, Liu S-Y. J. Am. Chem. Soc., 2025, 147: 19465

[21] Lanzi M, Dherbassy Q, Wencel-Delord J. Angew. Chem., Int. Ed., 2021, 60: 14852

[22] Lanzi M, Ali Abdine R A, De Abreu M, Wencel-Delord J. Org. Lett., 2021, 23: 9047

[23] De Abreu M, Rogge T, Lanzi M, Saiegh T J, Houk K N, Wencel-Delord J. Angew. Chem., Int. Ed., 2024, 63: e202319960

[24] Lanzi M, Rogge T, Truong T S, Houk K N, Wencel-Delord J. J. Am. Chem. Soc., 2023, 145: 345

[25] Patra K, Dey M P, Baidya M. Chem. Sci., 2024, 15: 16605

[26] Kang B, Li W, Jiang H, Qi C. Chem. Commun., 2025, 61: 3395

[27] Carter Martos D, de Abreu M, Hauk P, Fackler P, Wencel-Delord J. Chem. Sci., 2024, 15: 6770

[28] Chen J, Huang Y, Wang N, Wang M, Huang W, Wu X, Xu X, Zi Y. Chem. Commun., 2026, 62: 280

[29] Fan J-Y, Wang Q, Jia S-R, Zhang Y-X, Wang M-C, Zhang W-X, Zhang L, Lu L-Q, Li B-J. Org. Chem. Front., 2026, 13: 244

[30] Shou J-Y, Qing F-L. Org. Lett., 2025, 27: 2815

[31] Chen J, Wang N, Huang Y, Wang M, Huang W, Wu X, Zi Y, Xu X. Org. Lett., 2025, 27: 12939

[32] Liu M, Jiang H, Tang J, Ye Z, Zhang F, Wu Y. Org. Lett., 2023, 25: 2777

[33] Jiang H, Liu M, Ye Z, Song Z, Wu Y, Zhang F. Org. Chem. Front., 2023, 10: 3856

[34] Liu K, Bai L, Deng S, Qi X, Jiang X. Sci. Bull., 2025, 70: 2967

[35] Ikeshita D, Atarashi M, Yoshikai N. Angew. Chem., Int. Ed., 2026, 65: e6935149

[36] Lindstedt E, Ghosh R, Olofsson B. Org. Lett., 2013, 15: 6070

[37] Yuan H, Yin W, Hu J, Li Y. Nat. Commun., 2023, 14: 1841

[38] Chu L, Chen H, Xu Z-J, Wang L, Han J. Org. Chem. Front., 2025, 12: 3786

[39] Chu L, Jiang J, Wang L, Han J. Org. Lett., 2025, 27: 10204

[40] Jiang J, Chu L, Wang L, Han J. Chem. Commun., 2025, 61: 16424

[41] Jiang K, Li X, Wang L, Han J. Asian J. Org. Chem., 2024, 13: e202400139

[42] Roberts R A, Metze B E, Nilova A, Stuart D R. J. Am. Chem. Soc., 2023, 145: 3306

[43] Roberts R A, Metze B E, Javaly N, McCormick T M, Stuart D R. Chem. Sci., 2025, 16: 5547

[44] Gu X-W, Zhao Y-H, Wu X-F. Green Chem., 2023, 25: 6282

[45] Lyu J, Zhang X, Luo Z, Jiang Y, Xing K, Zhang G, Ding C. Adv. Synth. Catal., 2025, 367: e202400889

[46] Huang B-Q, Xu X-X, Wu B-H, Zou Y, Zhang X-J, Yan M. J. Org. Chem., 2025, 90: 9189

[47] Smith O, Hindson M J, Sreenithya A, Tataru V, Paton R S, Burton J W, Smith M D. Nat. Synth., 2024, 3: 58

[48] Chen W-L, Fang S, Song J-L, Hu Q, Zhang S-S, Shu B. J. Org. Chem., 2025, 90: 448

[49] Fang S, Chen W-L, Meng Y-J, Ye L-B, Zhang S-S, Shu B. J. Org. Chem., 2025, 90: 14452

[50] Yoshida S, Uchida K, Igawa K, Tomooka K, Hosoya T. Chem. Commun., 2014, 50: 15059

[51] Wei Y-L, Dauvergne G, Rodriguez J, Coquerel Y. J. Am. Chem. Soc., 2020, 142: 16921

[52] Minoshima M, Uchida K, Nakamura Y, Hosoya T, Yoshida S. Org. Lett., 2021, 23: 1868

[53] Luo F, Li C-L, Ji P, Zhou Y, Gui J, Chen L, Yin Y, Zhang X, Hu Y, Chen X, Liu X, Chen X, Yu Z-X, Wang W, Zhang S-L. Chem, 2023, 9: 2620

[54] Zhu H, Hu Y, Hu Y, Ge Y, Wang W, Zhang S, Chen X. Tetrahedron Lett., 2025, 170: 155774

[55] Zhu Z, Chen Z, Qian P, Li Z, Zhang S, Luo F. Org. Biomol. Chem., 2025, 23: 9449

[56] Xiao C, Liu D, Li X, Zhu W, Wang Q, Yi T, Liu X, Chen X, Zhang S, Hu Y. J. Org. Chem., 2025, 90: 14827

[57] Ouyang D, Li C, Wang T, Song S. J. Org. Chem., 2026, 91: 389

[58] Cainelli G Z, Morrocchi S. Chim. Ind. (Milan, Italy), 1964, 46: 1489

[59] Sumida Y, Kato T, Hosoya T. Org. Lett., 2013, 15: 2806

[60] Takagi A, Ikawa T, Saito K, Masuda S, Ito T, Akai S. Org. Biomol. Chem., 2013, 11: 8145

[61] Yoshimura A, Fuchs J M, Middleton K R, Maskaev A V, Rohde G T, Saito A, Postnikov P S, Yusubov M S, Nemykin V N, Zhdankin V V. Chem.-Eur. J., 2017, 23: 16738

[62] Ikawa T, Sun J, Takagi A, Akai S. J. Org. Chem., 2020, 85: 3383

[63] Ito M, Yamazaki H, Ito A, Oda R, Komiya M, Higuchi K, Sugiyama S. Eur. J. Org. Chem., 2023, 26: e202300458

[64] Yoshimura A., Ngo K., Mironova I. A., Gardner Z. S., Ogura N., Ueki A., Yusubov M. S., Saito A., Zhdankin V. V., ARKIVOC, 2024, 202412213.

[65] Shi J, Xu H, Qiu D, He J, Li Y. J. Am. Chem. Soc., 2017, 139: 623

[66] Uchida K, Yoshida S, Hosoya T. Org. Lett., 2017, 19: 1184

[67] Hoshi Y, Yoshida S. Chem. Commun., 2026, 62: 9258

[68] Khan H, Barman D, Sen S. J. Org. Chem., 2024, 89: 6257

[69] Seong C M, Kargbo S S, Yu C-L, Gibney D, Boyn J-N, Roberts C C. Nature, 2026, 649: 91

[70] Wei C, Fu K, Yu Z, Zhan Z, Chang D, Shi L. J. Am. Chem. Soc., 2025, 147: 14299

[71] Sneddon D S, Kevorkian P V, Hoye T R. Chem. Sci., 2025, 16: 2898

[72] Kraemer N, Hoye T R. J. Org. Chem., 2026, 91: 4611

[73] Shi J, Hoye T R. ACS Catalysis, 2025, 15: 12238

[74] Cheng Q, De Bo G. Chem. Sci., 2024, 15: 13181

[75] Humke J N, Belli R G, Plasek E E, Kargbo S S, Ansel A Q, Roberts C C. Science, 2024, 384: 408

[76] Plasek E E, Belli R G, Kavaguti D M, Roberts C C. Organometallics, 2024, 43: 2637

[77] Plasek E E, Denman B N, Roberts C C. ACS Catalysis, 2024, 14: 16098

[78] Belli R G, Humke J N, Pullarat S S, Umanzor A, Morais G N, Plasek E E, Kargbo S S, Chen S, Roberts C C. JACS Au, 2025, 5: 4688

[79] Umanzor A, Garcia N A, Quirion K P, Lovstedt A, Liu P, Roberts C C. JACS Au, 2025, 5: 5656

[80] Wagner C J, Dong G. Angew. Chem., Int. Ed., 2025, 64: e202500148

[81] Sekiguchi Y, Onnuch P, Li Y, Liu R Y. J. Am. Chem. Soc., 2025, 147: 1224

RIGHTS & PERMISSIONS

Jilin University, The Editorial Department of Chemical Research in Chinese Universities and Springer-Verlag GmbH

Just Accepted

This article has successfully passed peer review and final editorial review, and will soon enter typesetting, proofreading and other publishing processes. The currently displayed version is the accepted final manuscript. The officially published version will be updated with format, DOI and citation information upon launch. We recommend that you pay attention to subsequent journal notifications and preferentially cite the officially published version. Thank you for your support and cooperation.