Rhodium-catalyzed C–H Annulation of Aldonitrones with Allyl Methyl Carbonate

Abstract

The Rh(III)-catalyzed, nitrone-directed C–H activation/allylation/1,3-dipolar cycloaddition sequence with C-aryl-N-tert-butyl nitrones and allyl methyl carbonate gives polycyclic isoxazolidines, in many cases with high or complete regioselectivity for products with a condensed ring system (containing a 1-amino-2-hydroxymethyl-indane skeleton).

Keywords

C–H activation - Rhodium - Catalysis - Nitrones - Cascade reactions - Dipolar cycloaddition

Publication History

Received: 01 October 2025

Accepted after revision: 20 November 2025

Accepted Manuscript online:
20 November 2025

Article published online:
24 December 2025

• References

• 1a Yokoshima S. Nat Prod Rep 2025; 42 (1071) 1090
• 1b Murahashi S-I, Imada Y. Chem Rev 2019; 119: 4684-4716
• 1c Anderson LL. Asian J Org Chem 2016; 5: 9-30
• 1d Shi W-M, Ma X-P, Su G-F, Mo D-L. Org Chem Front 2016; 3: 116-130
• 1e Cardona F, Goti A. Angew Chem Int Ed 2005; 44: 7832-7835
• 2a Min S, Kim T, Jeong T. et al. Org Lett 2023; 25: 4298-4302
• 2b Zhu M, Zhu M, Wei F, Shao C, Li X, Liu B. J Org Chem 2023; 88: 16330-16339
• 2c Zhu M, Zhang Y, Tian M, Li X, Liu B, Chang J. Org Chem Front 2022; 9: 5879-5884
• 2d Pandey AK, Kang D, Han SH. et al. Org Lett 2018; 20: 4632-4636
• 2e Han SH, Pandey AK, Lee H. et al. Org Chem Front 2018; 5: 3210-3218
• 2f Li Y, Xie F, Liu Y, Yang X, Li X. Org Lett 2018; 20: 437-440
• 2g Bai D, Xu T, Ma C. et al. ACS Catal 2018; 8: 4194-4200
• 3a Sun Y, Wang Y, Zhang L, Zhong R, Wang H. Asian J Org Chem 2025; e202400646
• 3b Cai X, Song X, Yang X, Zhang X, Fan X. Org Chem Front 2023; 10: 1015-1021
• 3c Moon J, Ko N, Jang S. et al. Org Lett 2022; 24: 8115-8119
• 3d Wu M, Gao H, Xu H, Yi W, Zhou Z. Chin Chem Lett 2022; 33: 842-846
• 3e Wu M, Wang R, Chen F, Chen W, Zhou Z, Yi W. Org Lett 2020; 22: 7152-7157
• 3f Lee H, Kang D, Han SH. et al. Angew Chem Int Ed 2019; 58: 9470-9474
• 4 Brześkiewicz J, Loska R. Adv Synth Catal 2023; 365: 4241-4247
• 5 Wang X, Li J, Du H. et al. Chem Commun 2024; 60: 2401-2404
• 6 Ueda M, Kawai S, Hayashi M, Naito T, Miyata O. J Org Chem 2010; 75: 914-921
• 7a Sun X, Dong X, Yang Y. et al. Org Biomol Chem 2021; 19: 2676-2680
• 7b Ibarra-Rivera TR, Rentería-Gómez MA, Nieto-Sepúlveda E, Gámez-Montaño R, Rivas Galindo VM, Hernandez-Fernandez E. Synth Commun 2016; 46: 509-515
• 8 Chen JJ, Swope DM, Dashtipour K. Clin Ther 2007; 29: 1825-1849
• 9 Sardella R, Ianni F, Lisanti A. et al. Amino Acids 2014; 46: 1235-1242
• 10 Zhang L, Zhang J, Wang J. et al. Eur J Med Chem 2022; 232: 114176
• 11 Hasegawa M, Nomoto A, Suga T, Soeta T, Ukaji Y. Chem Lett 2017; 46: 45-47
• 12 Brześkiewicz J, Stańska B, Dąbrowski P, Loska R. Eur J Org Chem 2021; 814-824
• 13 General procedure for the tandem reactions of N-tert-butyl nitrone with allyl methyl carbonate. A Schlenk flask equipped with a magnetic stirring element was evacuated and heated with ~350 °C air stream for 2–3 min. It was then filled with argon (3 vacuum – argon cycles) and allowed to cool for 15–20 min). N-tert-Butyl nitrone 1 (0.5 mmol), [Cp*RhCl₂]₂ (0.02 mmol, 12 mg), AgSbF₆ (0.1 mmol, 34 mg), and pivalic acid (0.30 mmol, 30 mg) were weighted in a glovebox and introduced into the flask. To the resulting mixture dry DCE (3 mL) was added, followed by allyl methyl carbonate 2 (0.5 mmol, 59 μL). The flask was then closed tight and the reaction mixture heated to 100 °C for 20 h. After cooling, the reaction mixture was diluted with AcOEt and transferred directly on a silica gel chromatographic column and the product purified with 10:1 or 5:1 Hexanes/EtOAc as eluent. Isoxazolidine 3a. Isolated by column chromatography (hexanes/AcOEt 5:1), 77 mg (71%) yield, yield, colorless oil. IR (DCM): 2968, 2924, 2851, 2871, 1478, 1461, 1387, 1360, 1215, 1049, 1024 and 740 cm⁻¹. ¹H NMR (CDCl₃, 600 MHz): δ = 7.33 (d, ³ J = 6.9, 1H, H_Ar), 7.19–7.24 (m, 2H, H_Ar), 7.17 (d, ³ J = 6.8, 1H, H_Ar), 4.77 (d, ³ J = 8.0, 1H, C(3)–H), 4.27 (t, J = 8.0, 1H, C(10)–H), 3.38 (t, J = 8.0, 1H, C(10)–H), 3.29 (m, 1H, C(9)–H), 3.12 (dd, ² J = 16.3, ³ J = 7.4, 1H, C(8)–H), 2.82 (d, ² J = 16.3, 1H, C(8)–H), 1.25 (s, 9H, t-Bu). ¹³C NMR (CDCl₃, 151 MHz): δ = 143.8, 140.9, 127.8, 127.3, 125.8, 125.0, 73.7, 68.8, 58.9, 47.1, 34.6, 26.6. MS (EI⁺): m/z (%) = 217 (22) [M]⁺, 202 (21), 161 (37), 129 (100), 115 (25), 57 (21). HRMS (EI⁺): m/z [M]⁺ calcd for C₁₄H₁₉NO 217.1467; found: 217.1469.