Ni-Catalyzed Reductive Coupling of Alkynes with Aziridines

Abstract

Herein, we describe a Ni-catalyzed regioselective hydroalkenylation of alkynes with aziridines as coupling partners. This protocol allows access to homoallylic amines without recourse to stoichiometric amounts of well-defined organometallic reagents via catalytic regioselective ring-opening of aziridines under mild reaction conditions. The protocol is characterized by its applicability across a wide variety of aziridines or alkynes, including challenging substrate combinations.

Keywords

Alkenylation - Nickel - Reductive coupling - Aziridine - Alkyne

Publikationsverlauf

Eingereicht: 14. Mai 2025

Angenommen nach Revision: 20. Juni 2025

Artikel online veröffentlicht:
07. August 2025

• References


For selected reviews, see:
• 1a Goldfogel MJ, Huang L, Weix DJ. In Nickel Catalysis in Organic Synthesis. Ogoshi S. ed Wiley; 2020: 183
• 1b Dorval C, Gosmini C. In Cobalt Catalysis in Organic Synthesis. Hapke M, Hilt G. eds Wiley; 2020: 163
• 1c Liu J, Ye Y, Sessler JL, Gong H. Acc Chem Res 1833; 2020: 53
• 1d Poremba KE, Dibrell SE, Reisman SE. ACS Catal 2020; 10: 8237
• 1e Tortajada A, Börjesson M, Martin R. Acc Chem Res 2021; 54: 3941
• 1f Ehehalt LE, Beleh OM, Priest IC. et al. Chem Rev 2024; 124: 13397
• 1g Gosmini C, Bégouin J-M, Moncomble A. Chem Commun 2008; 3221
• 1h Moragas T, Correa A, Martin R. Chem Eur J 2014; 20: 8242
• 2a Metal-Catalyzed Cross-Coupling Reactions and More. De Meijere A, Bräse S, Oestreich M. eds. 1st ed Wiley; 2014
• 2b Jana R, Pathak TP, Sigman MS. Chem Rev 2011; 111: 1417
• 2c Cherney AH, Kadunce NT, Reisman SE. Chem Rev 2015; 115: 9587

For selected reviews, see:
• 3a Patai S. ed The Carbon–Carbon Triple Bond. Vol 2 Chichester, UK: John Wiley & Sons, Ltd.; 1978
• 3b Alonso F, Beletskaya IP, Yus M. Chem Rev 2004; 104: 3079
• 3c Nevado C, Echavarren AM. Synthesis 2005; 2005: 167
• 3d Ghosh S, Chakrabortty R, Ganesh V. ChemCatChem 2021; 13: 4262
• 3e Geier SJ, Vogels CM, Melanson JA, Westcott SA. Chem Soc Rev 2022; 51: 8877
• 3f Koschker P, Breit B. Acc Chem Res 2016; 49: 1524
• 3g Manikandan R, Jeganmohan M. Org Biomol Chem 2015; 13: 10420

For selected references on catalytic reductive couplings of alkynes with carbonyl compounds, see:
• 4a Montgomery J, Sormunen GJ. In Metal Catalyzed Reductive C–C Bond Formation. Krische MJ. ed. Vol 279. Berlin, Heidelberg: Springer Berlin Heidelberg; 2007: 1
• 4b Moslin RM, Miller-Moslin K, Jamison TF. Chem Commun 2007; 4441
• 4c Jeganmohan M, Cheng C. Chem Eur J 2008; 14: 10876
• 4d Ortiz E, Shezaf J, Chang Y-H, Krische MJ. ACS Catal 2022; 12: 8164
• 4e Miller KM, Huang W-S, Jamison TF. J Am Chem Soc 2003; 125: 3442
• 4f Chaulagain MR, Sormunen GJ, Montgomery J. J Am Chem Soc 2007; 129: 9568

For selected references on catalytic reductive couplings of alkynes with organic halides, see:
• 5a Ramani A, Desai B, Patel M, Naveen T, Asian J. Org Chem 2022; 11: e202200047
• 5b Uehling MR, Suess AM, Lalic G. J Am Chem Soc 2015; 137: 1424
• 5c Lu X-Y, Liu J-H, Lu X. et al. Chem Commun 2016; 52: 5324
• 5d Lu X-Y, Hong M-L, Zhou H-P, Wang Y, Wang J-Y, Ge X-T. Chem Commun 2018; 54: 4417
• 5e Hazra A, Chen J, Lalic G. J Am Chem Soc 2019; 141: 12464
• 5f Lee YH, Denton EH, Morandi B. J Am Chem Soc 2020; 142: 20948
• 5g Li Y, Liu D, Wan L, Zhang J-Y, Lu X, Fu Y. J Am Chem Soc 2022; 144: 13961
• 5h Gao Q, Xu W-C, Nie X. et al. Nat Commun 2024; 15: 6556
• 6a Lawrence SA. In Amines: Synthesis, Properties, and Applications. Cambridge: Cambridge University Press; 2004
• 6b Roughley SD, Jordan AM. J Med Chem 2011; 54: 3451
• 6c Blakemore DC, Castro L, Churcher I. et al. Nat Chem 2018; 10: 383

For selected references on catalytic reductive coupling of alkynes with imines, see:
• 7a Barchuk A, Ngai M-Y, Krische MJ. J Am Chem Soc 2007; 129: 8432
• 7b Ngai M-Y, Barchuk A, Krische MJ. J Am Chem Soc 2007; 129: 12644
• 7c Williams VM, Kong JR, Ko BJ. et al. J Am Chem Soc 2009; 131: 16054
• 7d Li L, Liu Y-C. Shi J Am Chem Soc 2021; 143: 4154

For selected references on catalytic reductive Hydrocyanation of alkyne:
• 7e Palermo AF, Chiu BSY, Patel P, Rousseaux SAL. J Am Chem Soc 2023; 145: 24981
• 7f Qin J, Li Y, Hu Y, Huang Z, Miao W, Chu L. J Am Chem Soc 2024; 146: 27583
• 8a Wiberg KB. Angew Chem Int Ed Engl 1986; 25: 312
• 8b Howell J, Goddard JD, Tam W. Tetrahedron 2009; 65: 4562
• 8c Dudev T, Lim C. J Am Chem Soc 1998; 120: 4450

For selected reviews on transformation of aziridines, see:
• 9a Yudin AK. ed. In Aziridines and Epoxides in Organic Synthesis. 1st ed Wiley; 2006
• 9b Huang C-Y. (Dennis); Doyle A G Chem Rev 2014; 114: 8153
• 9c Sabir S, Kumar G, Verma VP, Jat JL. ChemistrySelect 2018; 3: 3702
• 9d Watson IDG, Yu L, Yudin AK. Acc Chem Res 2006; 39: 194
• 9e Chen J, Zhu G, Wu J. Acta Chim Sin 2024; 82: 190

For selected references on cross-coupling reactions of aziridines, see:
• 10a Trost BM, Osipov M, Dong G. J Am Chem Soc 2010; 132: 15800
• 10b Huang C-YD, Doyle AG. J Am Chem Soc 2012; 134: 9541
• 10c Ge C, Liu R-R, Gao J-R, Jia Y-X. Org Lett 2016; 18: 3122
• 10d Chai Z, Yang P, Zhang H, Wang S, Yang G. Angew Chem Int Ed 2017; 56: 650
• 10e Woods BP, Orlandi M, Huang C-Y, Sigman MS, Doyle AG. J Am Chem Soc 2017; 139: 5688
• 10f Steiman TJ, Liu J, Mengiste A, Doyle AG. J Am Chem Soc 2020; 142: 7598
• 10g Dongbang S, Doyle AG. J Am Chem Soc 2022; 144: 20067
• 10h Williams WL, Gutiérrez-Valencia NE, Doyle AG. J Am Chem Soc 2023; 145: 24175
• 10i Wang Y-Z, Wang Z-H, Eshel IL. et al. Nat Commun 2023; 14: 2322
• 10j Liu S, Wang S-L, Wan J. et al. Org Lett 2023; 25: 6582
• 10k Tang W, Fan P. Org Lett 2023; 25: 5756
• 10l Fan P, Jin Y, Liu J, Wang R, Wang C. Org Lett 2021; 23: 7364
• 10m Wang L, Zhou P-P, Xie D. et al. J Am Chem Soc 2025; 147: 2675
• 10n Zhang L, Wang H, Santiago TG, Yue W-J, Martin R. Nat Catal 2025; 8: 348
• 10o Lan Y, Han Q, Liao P. et al. J Am Chem Soc 2024; 146: 25426
• 10p Wang R, Fang Y, Wang C. Cell Rep Phys Sci 2024; 5: 102216

For selected reviews on C–N bond-cleavage, see:
• 11a Ouyang K, Hao W, Zhang W-X, Xi Z. Chem Rev 2015; 115: 12045
• 11b Kong D, Moon PJ, Lundgren RJ. Nat Catal 2019; 2: 473
• 11c Wang Q, Su Y, Li L, Huang H. Chem Soc Rev 2016; 45: 1257
• 11d Ni Q, Zhou Y, Chen L, Liu Y. Org Chem Front 2025; 12: 975

For selected references on cycloaddition of aziridines with alkynes, see:
• 12a Kapoor R, Chawla R, Verma A, Keshari T, Siddiqui IR. Synlett 2023; 34: 1621
• 12b Meng J, Wang J, Zhang J, Yang Z, Wu Z, Zhang W. Eur J Chem 2025; 31: e202403298

For selected references on cross-coupling reactions with vinyl halides, see:
• 13a Chang Y-H, Cho Y, Shen W, Krische MJ. ACS Catal 2025; 8274
• 13b Stille JK, Groh BL. J Am Chem Soc 1987; 109: 813
• 13c Zhou C, Ma D. Chem Commun 2014; 50: 3085
• 13d Johnson KA, Biswas S, Weix DJ. Eur J Chem 2016; 22: 7399
• 13e Chen P, Wang Z-Y, Peng X-S, Wong HNC. Org Lett 2021; 23: 4385
• 13f Chi BK, Widness JK, Gilbert MM, Salgueiro DC, Garcia KJ, Weix DJ. ACS Catal 2022; 12: 580

For selected references on synthesis of homoallylic amines, see:
• 14a Yamasaki S, Fujii K, Wada R, Kanai M, Shibasaki M. J Am Chem Soc 2002; 124: 6536
• 14b Vieira EM, Snapper ML, Hoveyda AH. J Am Chem Soc 2011; 133: 3332
• 14c Bao W, Kossen H, Schneider U. J Am Chem Soc 2017; 139: 4362
• 14d Li W-S, Kuo T-S, Hsieh M-C, Tsai M-K, Wu P-Y, Wu H-L. Org Lett 2020; 22: 5675

For selected references on synthesis of homoallylic amines from aziridines, see:
• 14e Teh WP, Michael FE. Org Lett 2017; 19: 1738
• 14f Hu X, Cheng-Sánchez I, Cuesta-Galisteo S, Nevado C. J Am Chem Soc 2023; 145: 6270
• 14g Kong X, Gou M-B, Li B. et al. Org Lett 2025; 27: 2709

For selected recent references from our group on Ni-catalyzed reductive couplings, see:
• 15a Zhang L, Wang H, Santiago TG, Yue W-J, Martin R. Nat Catal 2025; 8: 348
• 15b Liu Z, D’Amico F, Martin R. J Am Chem Soc 2024; 146: 28624
• 15c Davies J, Lyonnet JR, Carvalho B. et al. J Am Chem Soc 2024; 146: 1753
• 15d Zhang H, Rodrigalvarez J, Martin R. J Am Chem Soc 2023; 145: 17564
• 15e Rodrigalvarez J, Wang H, Martin R. J Am Chem Soc 2023; 145: 3869 and citations there in
• 16 See Supporting information for details
• 17 Ni-catalyzed hydroalkenylation of 1-ethynyl-4-methoxybenzene (2a) with 2-benzyl-1-tosylaziridine (1a). In a glovebox, an oven-dried tube was charged with NiCl₂·glyme (4.4 mg, 0.020 mmol), neocuproine (L1) (8.3 mg, 0.040 mmol), Mn powder (22 mg, 0.60 mmol, 2.0 equiv), and 2-benzyl-1-tosylaziridine (1a) (58 mg, 0.20 mmol). The tube was sealed with a screw cap equipped with a septum. Under a flow of argon, dry DMPU (0.5 mL) was added, followed by the 1-ethynyl-4-methoxybenzene (2a) (39 μL, 0.30 mmol). Finally, TFE (29 μL, 0.40 mmol, 2.0 equiv) was added to the reaction mixture. The reaction vessel was placed in a metal block connected to a chiller (10 °C) and stirred for 16 h. After completion, the reaction mixture was quenched with 1 M HCl (2.0 mL) and diluted with EtOAc. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc (3 × 5.0 mL). The combined organic phases were washed with 1 M HCl (3 × 10 mL), dried over MgSO4, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel (acetone/n-hexane as eluent), delivering 3a as a colorless solid (84 mg, 50% yield). M.P. = 82–84 °C. ¹H NMR (500 MHz, CDCl₃): δ 7.64–7.59 (m, 2H), 7.27–7.18 (m, 3H), 7.17–7.12 (m, 4H), 7.12–7.08 (m, 2H), 6.86–6.80 (m, 2H), 6.25 (d, J = 15.7 Hz, 1H), 5.75–5.65 (m, 1H), 4.67 (d, J = 7.2 Hz, 1H, NH), 3.81 (s, 3H), 3.55–3.46 (m, 1H), 2.90–2.75 (m, 2H), 2.37 (s, 3H), 2.42–2.30 (m, 1H), 2.26–2.15 (m, 1H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ 159.2, 143.2, 137.5, 137.4, 133.3, 129.9, 129.7, 129.6, 128.6, 127.4, 127.1, 126.7, 122.7, 114.0, 55.4, 55.0, 41.5, 37.7, 21.6 ppm. IR (neat, cm⁻¹): 3294, 2927, 1603, 1508, 1413, 1331, 1238, 1154, 1062, 1024, 986, 885, 803, 747, 702, 663, 582, 548, 506. HRMS calcd for (C₂₅H₂₈NO₃S) [M+H]⁺: 422.1784 found 422.1790
• 18 The remaining mass balance accounts for the formation of TsNH₂ arising from degradation of azanickelacycle intermediate I (Scheme 2), trace amounts of double alkenylation (<5%) and Sonogashira–Hagihara type byproducts (10–15%). See Supporting Information for details, including the purification of our hydroalkenylation products by treatment with Co₂(CO)₈ for particularly challenging substrate combinations
• 19 The reversal of regioselectivity for 3p likely arises from a preferential functionalization of the weaker benzylic C–N bond. In contrast, alkyl-substituted aziridines lack such electronic bias, leading to functionalization at the less-hindered C–N linkage
• 20 Lin BL, Clough CR, Hillhouse GL. J Am Chem Soc 2002; 124: 2890

Isomerization of vinyl Ni species via the involvement of carbenoid-type species have been proposed in the literature. For selected references, see:
• 21a Börjesson M, Janssen-Müller D, Sahoo B, Duan Y, Wang X, Martin R. J Am Chem Soc 2020; 142: 16234
• 21b Bottcher SE, Hutchinson LE, Wilger DJ. Synthesis 2020; 52: 2807
• 21c Huggins JM, Bergman RG. J Am Chem Soc 1981; 103: 3002

While azanickelacycles bearing 2,2′-bipyridines or 1,10-phenanthrolines have been described in the literarure, analogous complexes with substitution patterns adjacent to the nitrogen atom have always defied attempts for their isolation. For selected references, see:
• 22a Ravn AK, Vilstrup MBT, Noerby P, Nielsen DU, Daasbjerg K, Skrydstrup T. J Am Chem Soc 2019; 141: 11821
• 22b Davies J, Janssen-Müller D, Zimin DP. et al. J Am Chem Soc 2021; 143: 4949
• 23 Day CS, Ton SJ, McGuire RT, Foroutan-Nejad C, Martin R. Organometallics 2022; 41: 2662
• 24 CCDC 2450323 (Ni-1) and CCDC 2450324 (Ni-3) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre