Cu-catalyzed enantioconvergent oxygen-centered radical cyclization

Abstract

Radical asymmetric cyclization has emerged as a powerful strategy for constructing ring structures. Despite significant progress in carbon-centered radical cyclization, the catalytic asymmetric cyclization of oxygen-centered radicals, key species in many biological processes, remains challenging owing to their high oxidizing power and electrophilicity. Herein, we report an enantioconvergent oxygen-centered radical cyclization via Cu-catalyzed asymmetric C(sp³)–O oxidative coupling between the tertiary C(sp³)–H bond and the oxime O–H bond of racemic γ-ketoximes. This radical reaction proceeds efficiently under aerobic and mild conditions, affording a wide range of valuable isoxazolines bearing a fully substituted stereocenter in good yields with excellent enantioselectivity. Mechanistic studies were conducted to elucidate the origin of enantiocontrol, and the synthetic utility of the method was demonstrated through the late-stage transformation of isoxazolines into polyhydroxy building blocks.

---

Introduction

Radical cyclization represents a powerful strategy for constructing ring structures, offering advantages such as mild reaction conditions, high reactivity, excellent chemoselectivity, and broad functional group tolerance.^1–7 However, achieving a catalytic asymmetric version remains a daunting challenge due to the difficulty in the enantioselective control of highly reactive radical species.^8–15 To address this issue, conceptually new methodologies for asymmetric radical cyclization have been developed during the past few decades.^16–18 Among these innovative approaches, major advances have been made in carbon (C)-centered radical cyclization (Fig. 1A, left),^19–28 whereas heteroatom-centered radical cyclization remains underexplored.^29–31 Oxygen (O)-centered radicals are key reactive species in many biological processes, such as the biosynthesis of prostaglandins and phytoprostanes.³² Their high oxidizing power and electrophilicity distinguish them from alkyl radical analogues.^33,34 Typical reactions of O-centered radicals include hydrogen-atom transfer (HAT) and β-fragmentation to form a C−O bond (Fig. 1A, right).^35–38 Theses competing pathways significantly hinder the development of O-centered radical cyclization reactions, particularly in catalytic asymmetric versions.^39–42

Fig. 1 Radical asymmetric cyclization.

Iminoxyl radicals, also known as oxime radicals, are a unique subclass of O-centered radicals.^43,44 As the single electron spin is delocalized over both the O and N atoms, iminoxyl radicals are more stable than alkoxy radicals (Fig. 1B).^45–47 In addition, the relatively low bond-dissociation energy (BDE, ∼76–85 kcal mol⁻¹) of O–H bonds inhibits the HAT process,^11c thereby facilitating radical cyclization.^48–51 Although the physical properties such as the structure, stability, and spectra of oxime radicals have been extensively studied, their synthetic potential has long been underestimated.^52–55 Recently, Han et al. reported the iminoxyl radical-promoted dioxygenation, oxyamination, and diamination of alkenes.^56–64 Despite these racemic advances, catalytic asymmetric iminoxyl radical cyclization has not been reported. To address this gap, we herein present an asymmetric O-centered radical cyclization of iminoxyl radicals via Cu-catalyzed intramolecular C(sp³)–O oxidative coupling between the tertiary C(sp³)–H bond and the oxime O–H bond of racemic γ-ketoximes (Fig. 1C). This radical reaction proceeds under aerobic and mild conditions in an enantioconvergent manner, providing a wide range of valuable isoxazolines^65–71 bearing a fully substituted stereocenter in good yield with excellent enantioselectivity. DFT calculations have been performed to elucidate the origin of enantiocontrol, and the utility of this method was demonstrated through the synthesis of chiral polyhydroxy building blocks.

Results and discussion

We commenced the study with a model reaction of racemic ketoxime 1a (Table 1). Under the initial conditions—10 mol% Cu(OTf)₂, 12 mol% ligand L1 in EtOAc at room temperature under air for 72 h—the desired cyclization product 2a was obtained in moderate yield with 62% ee (entry 1). Screening of commercially available box ligands (entries 2–8) revealed that L3 afforded the best results (entry 3). Subsequent evaluation of copper salts and solvents did not yield further improvements (entries 9–14). Accordingly, Cu(OTf)₂ was the best metal catalyst, and EtOAc was the optimal solvent. Notably, the choice of base significantly influenced enantioselectivity. While K₂CO₃ led to a significant decrease in enantioselectivity (entry 15), weaker bases improved enantioselectivity (entries 16–18). Consequently, the following reaction conditions were identified as optimal: (±)-1a (0.05 mmol), Cu(OTf)₂ (10 mol%), L3 (12 mol%) and HCO₂Na (1.0 eq.) in EtOAc (1 mL) at room temperature (r.t.) in an air atmosphere for 72 h, which provided isoxazoline 2a in 88% yield with 95% ee.

Table 1 Reaction optimization^a

Entry^a	[Cu]	Ligand	Solvent	Base	Yield^b (%)	ee ^c (%)
a Unless otherwise indicated, the reaction conditions were as follows: 1a (0.05 mmol), [Cu] (10 mol%), L (12 mol%) and base (1.0 eq.) were added to a specified solvent (1 mL) at room temperature (r.t.) in an air atmosphere for 72 h.b Isolated yield.c Determined by chiral HPLC analysis.
1	Cu(OTf)2	L1	EtOAc	Na2CO3	84	62
2	Cu(OTf)2	L2	EtOAc	Na2CO3	85	64
3	Cu(OTf)2	L3	EtOAc	Na2CO3	89	75
4	Cu(OTf)2	L4	EtOAc	Na2CO3	77	53
5	Cu(OTf)2	L5	EtOAc	Na2CO3	70	55
6	Cu(OTf)2	L6	EtOAc	Na2CO3	41	50
7	Cu(OTf)2	L7	EtOAc	Na2CO3	68	55
8	Cu(OTf)2	L8	EtOAc	Na2CO3	50	41
9	Cu(CH3CN)4BF4	L3	EtOAc	Na2CO3	44	23
10	CuBr	L3	EtOAc	Na2CO3	65	52
11	CuI	L3	EtOAc	Na2CO3	53	38
12	Cu(OTf)2	L3	CH2Cl2	Na2CO3	85	70
13	Cu(OTf)2	L3	Toluene	Na2CO3	63	51
14	Cu(OTf)2	L3	THF	Na2CO3	83	50
15	Cu(OTf)2	L3	EtOAc	K2CO3	70	27
16	Cu(OTf)2	L3	EtOAc	NaHCO3	84	82
17	Cu(OTf)2	L3	EtOAc	CH3CO2Na	86	91
18	Cu(OTf)2	L3	EtOAc	HCO2Na	88	95

---

With the best reaction conditions, we next evaluated the reaction scope. As shown in Fig. 2, the Cu-catalyzed radical C(sp³)–O oxidative coupling reaction demonstrated broad applicability across a diverse range of racemic ketoximes 1, affording the corresponding isoxazoline products 2 in good yields with consistently excellent enantioselectivities (all >93% ee). Varying the ester group from CO₂Et (2a) to CO₂Me (2b), CO₂ⁿPr (2c), CO₂ⁱPr (2d), CO₂ⁿBu (2e), and CO₂Bn (2f) had a negligible impact on both yield and enantioselectivity. Furthermore, the oxime moiety tolerated a variety of aryl groups (Ar¹). The position (o,m, or p) and the electron nature (electron-donating or electron-withdrawing) of the substituents on the benzene ring had no significant effect on the ee values of the products (2g–2t). However, strong electron-withdrawing substituents such as NO₂ and CF₃ led to lower yields for 2m and 2n. Additionally, the reaction also accommodated disubstituted phenyl (2u and 2v), naphthyl (2w), and heteroaryl (2x and 2y) groups under standard conditions.

Fig. 2 Substrate scope. Reaction conditions: unless otherwise indicated, 1 (0.05 mmol), Cu(OTf)₂ (10 mol%), L3 (12 mol%) and HCO₂Na (1.0 eq.) were added to EtOAc (1 mL) at room temperature (r.t.) in an air atmosphere for 72 h.

We further expanded the substrate scope by modifying the aryl group (Ar) on the ketone motif (Fig. 3). This structural variation proved crucial, significantly influencing the reaction outcome. Replacing the anthracenyl (2a) group with naphthyl (2z) and phenyl (2a′ and 2b′) groups led to a gradual decline in both yield and enantioselectivity. This trend correlates with the diminished ability of these less conjugated arenes to stabilize the proposed radical intermediate Int-A, supporting the involvement of a radical pathway. The observed trend in yield and enantioselectivity (2a > 2z > 2a′/2b′) can be rationalized by the superior ability of the extended anthracenyl π-system to stabilize the radical intermediate Int-A/D and to engage in multiple, stabilizing non-covalent interactions with the chiral ligand in the favored transition state TS1, as revealed by our DFT analysis (Fig. 6a). In this regard, we found that 2-alkoxy-substituted naphthyl groups offered an optimal balance, effectively stabilizing the radical while maintaining high stereocontrol. Indeed, a broad series of alkoxy groups were all well accommodated, delivering 2c′–2m′ in 89–96% yield with 84–93% ee. The absolute configuration of 2k′ was determined by X-ray crystallographic analysis, and those of the other products were assigned by analogy. Furthermore, by using modified standard conditions (with Box ligand L8, siloxy groups, such as OTBS (2n′), OTIS (2o′) and OTBDPS (2p′), were tolerated. Finally, substrates bearing diverse functional groups on the naphthalene ring all underwent smooth cyclization, furnishing desired products 2q′–2v′ in good yields and with generally excellent enantioselectivities. While this methodology demonstrates a broad scope for aryl-substituted oximes, alkyl oximes proved to be challenging substrates under the current catalytic system, likely due to the inferior stabilization of the pivotal radical intermediates. The development of catalytic systems to accommodate aliphatic variants constitutes an important goal for future work.

Fig. 3 Further substrate scope. Reaction conditions: unless otherwise indicated, 1 (0.05 mmol), Cu(OTf)₂ (10 mol%), L3 (12 mol%) and HCO₂Na (1.0 eq.) were added to EtOAc (1 mL) at room temperature (r.t.) in an air atmosphere for 72 h. ^a L8 was used.

To demonstrate the synthetic utility of the developed method, late-stage manipulations were performed (Fig. 4A). The reaction was successfully scaled up under standard conditions to afford isoxazoline 2a without compromising enantioselectivity (see the SI for details). Selective reduction of the ester group led to alcohol 3 in 80% yield without erosion of enantiomeric purity. Employing a RANEY® Ni/H₂ system cleaved the N–O bond efficiently, affording the 1,4-dicarbonyl compound 4 in 76% yield. Chemoselective reduction of the less hindered ketone with NaBH₄, followed by protection, gave triol carbonate 5 with >20 : 1 diastereoselectivity. To gain mechanistic insight, we conducted several control experiments (Fig. 4B). Replacing air with pure oxygen did not inhibit the reaction, whereas under a nitrogen atmosphere, the yield dropped significantly, suggesting that atmospheric oxygen serves as the terminal oxidant. Neither hydrazone 6 nor ketone 7 was reactive under standard conditions, highlighting the essential roles of the oxime functional group and activated α-H of the ketone. Electron paramagnetic resonance (EPR) spectroscopy was employed to probe radical intermediates. By adding a radical trap, 5,5-dimethyl-1-pyrroline N-oxide (DMPO), a characteristic signal for an oxy-centered radical was probed (Fig. 4C). Finally, a linear correlation between the enantiopurity of the ligand and the corresponding product was observed in a nonlinear effect study (Fig. 4D), consistent with a mechanism involving a monomeric copper complex containing a single box ligand.

Fig. 4 Further elaborations. Ar = anthracen-9-yl.

Based on experimental evidence and prior literature,^72–76 a plausible mechanism for the Cu-catalyzed C–O oxidative coupling reaction was proposed (Fig. 5). The catalytic cycle begins with the coordination of the chiral Cu^II complex, generated from Cu(OTf)₂ and box-ligand L3 under basic conditions, to racemic oxime (±)-1a, forming intermediate A. A sequential single-electron transfer (SET) then induces the homolysis of the resulting O–Cu^II bond, liberating the iminoxyl radical intermediate B alongside a Cu^I-complex. This radical is subsequently trapped by another molecule of the Cu^II-complex, forming intermediate C. Within C, the O-centered radical undergoes stereocontrolled 5-exo-dig cyclization, guided by the chiral ligand environment, to give the C-centered radical D. Homolysis of the O–Cu^II bond in intermediate D releases the enantioenriched isoxazoline 2a, and regenerates the Cu^I species. Finally, oxidation of the Cu^I-complex by atmospheric oxygen closes the catalytic cycle by regenerating the active Cu^II complex.

Fig. 5 Proposed mechanism.

Density functional theory (DFT) calculations were performed to elucidate the origin of enantioselectivity in the reaction. Two distinct transition states (TS1 and TS1′, Fig. 6) were identified, corresponding to the formation of enantiomeric products. Energy decomposition analysis revealed that the energy difference between these transition states primarily originates from differential catalyst–substrate interactions. Detailed structural analysis demonstrated significant differences in non-covalent interactions: TS1 features multiple stabilizing C–H⋯O interactions (b₁ = 2.347 Å, b₂ = 2.484 Å, b₃ = 2.404 Å) and a C–H⋯π interaction (b₄ = 2.956 Å) between the catalyst and substrate fragment, while TS1′ possesses only two C–H⋯O interactions (b₅ = 2.159 Å, b₆ = 2.303 Å). This disparity in stabilizing interactions accounts for the relative preference for TS1. All these interactions could be visualized from the NCI plot (see details in the SI). Furthermore, catalyst distortion energy contributes substantially to the higher energy of TS1′. Comparative analysis of dihedral angles revealed that the transformation from pre-intermediate I1 (∠abcd = 18.8°) to TS1′ involves significant structural distortion (∠a′′b′′c′′d′′ = 12.4°), whereas the corresponding angle in TS1 remains nearly unchanged (∠a′b′c′d′ = 20.0°). These computational findings provide a coherent explanation for the observed enantioselectivity, as the higher energy barrier for TS1′ effectively suppresses the competing pathway, in excellent agreement with experimental results.

Fig. 6 The structural analysis and energy decomposition analysis of the key transition states leading to enantiomeric products.

Conclusions

In conclusion, we have developed a highly efficient Cu-catalyzed enantioconvergent oxygen-centered radical cyclization of iminoxyl radicals. Under aerobic and mild conditions, the asymmetric radical C(sp³)–O oxidative coupling between the tertiary C(sp³)–H bond and the oxime O–H bond of racemic γ-ketoximes proceeds smoothly, providing diverse isoxazolines bearing a fully substituted stereocenter in good yields with excellent enantioselectivity. Control experiments and DFT calculations were performed to explore the reaction mechanism and origin of enantiocontrol. The synthetic utility of this methodology was demonstrated through the late-stage conversion of isoxazolines into polyhydroxy building blocks.

Author contributions

Z. -Y. L., C. -Y. G., H. -M. G., L. -M. L., X. X. and B. G. performed and analyzed the experiments. C. -D. H. and S. -F. N. performed the DFT calculations. G. -J. M. conceived and designed the project. G. -J. M. overall supervised the project. All authors prepared this manuscript.

Conflicts of interest

The authors declare no competing financial interest.

Data availability

CCDC 2434517 (2k′) contains the supplementary crystallographic data for this paper.⁷⁷

The authors declare that the data relating to the characterization of products, experimental protocols and the computational studies are available within the article and its supplementary information (SI). Supplementary information is available. See DOI: https://doi.org/10.1039/d5sc07101a.

Acknowledgements

The authors acknowledge the financial support from the National Natural Science Foundation of China (22371265 and 22578403), Natural Science Foundation of Henan Province (232301420047), and the project of State Key Laboratory of Green Pesticide, Guizhou Medical University (GPLKF202507). S.-F. Ni is thankful for the financial support from the Guangdong Basic and Applied Basic Research Foundation (2024A1515010323, 2025A1515011907) and the open research fund of Songshan Lake Materials Laboratory (2023SLABFN16).

Notes and references

1. B. M. Loertscher and S. L. Castle, in Comprehensive Organic Synthesis, ed. P. Knochel, Elsevier, Amsterdam, 2nd edn, 2014, pp. 742–809,  DOI:10.1016/B978-0-08-097742-3.00419-5.
2. L. J. Sebren, J. J. Devery and C. R. J. Stephenson, Catalytic Radical Domino Reactions in Organic Synthesis, ACS Catal., 2014, 4, 703–716.
3. J. Xuan and A. Studer, Radical cascade cyclization of 1,n-enynes and diynes for the synthesis of carbocycles and heterocycles, Chem. Soc. Rev., 2017, 46, 4329–4346.
4. F.-H. Qin, X.-J. Huang, Y. Liu, H. Liang, Q. Li, Z. Cao, W.-T. Wei and W.-M. He, Alcohols controlled selective radical cyclization of 1,6-dienes under mild conditions, Chin. Chem. Lett., 2020, 31, 3267–3270.
5. P. Wang, Q. Zhao, W. Xiao and J. Chen, Recent advances in visible-light photoredox-catalyzed nitrogen radical cyclization, Green Synth. Catal., 2020, 1, 42–51.
6. M. Latrache and N. Hoffmann, Photochemical radical cyclization reactions with imines, hydrazones, oximes and related compounds, Chem. Soc. Rev., 2021, 50, 7418–7435.
7. Z. Cai, S. Trienes, K. Liu, L. Ackermann and Y. Zhang, Radical cascade cyclization of 1,n-enynes under photo/electrochemical conditions, Org. Chem. Front., 2023, 10, 5735–5745.
8. F. Wang, P. Chen and G. Liu, Copper-Catalyzed Radical Relay for Asymmetric Radical Transformations, Acc. Chem. Res., 2018, 51, 2036–2046.
9. K. Wang and W. Kong, Recent Advances in Transition Metal-Catalyzed Asymmetric Radical Reactions, Chin. J. Chem., 2018, 36, 247–256.
10. Q.-S. Gu, Z.-L. Li and X.-Y. Liu, Copper(I)-Catalyzed Asymmetric Reactions Involving Radicals, Acc. Chem. Res., 2019, 53, 170–181.
11. Z.-L. Li, G.-C. Fang, Q.-S. Gu and X.-Y. Liu, Recent advances in copper-catalysed radical-involved asymmetric 1,2-difunctionalization of alkenes, Chem. Soc. Rev., 2020, 49, 32–48.
12. C. Zhang, Z.-L. Li, Q.-S. Gu and X.-Y. Liu, Catalytic enantioselective C(sp3)–H functionalization involving radical intermediates, Nat. Commun., 2021, 12, 475.
13. X.-Y. Dong, Z.-L. Li, Q.-S. Gu and X.-Y. Liu, Ligand Development for Copper-Catalyzed Enantioconvergent Radical Cross-Coupling of Racemic Alkyl Halides, J. Am. Chem. Soc., 2022, 144, 17319–17329.
14. S. Mondal, F. Dumur, D. Gigmes, M. P. Sibi, M. P. Bertrand and M. Nechab, Enantioselective Radical Reactions Using Chiral Catalysts, Chem. Rev., 2022, 122, 5842–5976.
15. Z. Zhang, P. Chen and G. Liu, Copper-catalyzed radical relay in C(sp3)–H functionalization, Chem. Soc. Rev., 2022, 51, 1640–1658.
16. H. Miyabe and Y. Takemoto, Enantioselective Radical Cyclizations: A New Approach to Stereocontrol of Cascade Reactions, Chem. Eur. J., 2007, 13, 7280–7286.
17. H. Miyabe, A. Kawashima, E. Yoshioka and S. Kohtani, Progress in Enantioselective Radical Cyclizations, Chem. Eur. J., 2017, 23, 6225–6236.
18. Q. Q. Zhao, M. Gu and J. R. Chen, Radicals as Chiral Catalysts for Asymmetric Radical Cyclization Reactions, Chin. J. Chem., 2024, 42, 2412–2416.
19. J.-S. Lin, X.-Y. Dong, T.-T. Li, N.-C. Jiang, B. Tan and X.-Y. Liu, A Dual-Catalytic Strategy To Direct Asymmetric Radical Aminotrifluoromethylation of Alkenes, J. Am. Chem. Soc., 2016, 138, 9357–9360.
20. N. Kern, M. P. Plesniak, J. J. W. McDouall and D. J. Procter, Enantioselective cyclizations and cyclization cascades of samarium ketyl radicals, Nat. Chem., 2017, 9, 1198–1204.
21. F.-L. Wang, X.-Y. Dong, J.-S. Lin, Y. Zeng, G.-Y. Jiao, Q.-S. Gu, X.-Q. Guo, C.-L. Ma and X.-Y. Liu, Catalytic Asymmetric Radical Diamination of Alkenes, Chem, 2017, 3, 979–990.
22. W.-C. C. Lee, D.-S. Wang, C. Zhang, J. Xie, B. Li and X. P. Zhang, Asymmetric radical cyclopropanation of dehydroaminocarboxylates: Stereoselective synthesis of cyclopropyl α-amino acids, Chem, 2021, 7, 1588–1601.
23. Q. Zhou, M. Chin, Y. Fu, P. Liu and Y. Yang, Stereodivergent atom-transfer radical cyclization by engineered cytochromes P450, Science, 2021, 374, 1612–1616.
24. Y. Chen, X. Wu, S. Yang and C. Zhu, Asymmetric Radical Cyclization of Alkenes by Stereospecific Homolytic Substitution of Sulfinamides, Angew. Chem., Int. Ed., 2022, 61, e202201027.
25. J. Ke, W.-C. C. Lee, X. Wang, Y. Wang, X. Wen and X. P. Zhang, Metalloradical Activation of In Situ-Generated α-Alkynyldiazomethanes for Asymmetric Radical Cyclopropanation of Alkenes, J. Am. Chem. Soc., 2022, 144, 2368–2378.
26. W.-C. C. Lee, J. Wang, Y. Zhu and X. P. Zhang, Asymmetric Radical Bicyclization for Stereoselective Construction of Tricyclic Chromanones and Chromanes with Fused Cyclopropanes, J. Am. Chem. Soc., 2023, 145, 11622–11632.
27. S. Ju, D. Li, B. K. Mai, X. Liu, A. Vallota-Eastman, J. Wu, D. L. Valentine, P. Liu and Y. Yang, Stereodivergent photobiocatalytic radical cyclization through the repurposing and directed evolution of fatty acid photodecarboxylases, Nat. Chem., 2024, 16, 1339–1347.
28. X.-T. Li, L. Lv, T. Wang, Q.-S. Gu, G.-X. Xu, Z.-L. Li, L. Ye, X. Zhang, G.-J. Cheng and X.-Y. Liu, Diastereo- and Enantioselective Catalytic Radical Oxysulfonylation of Alkenes in β,γ-Unsaturated Ketoximes, Chem, 2020, 6, 1692–1706.
29. F. Dénès, in Free-Radical Synthesis and Functionalization of Heterocycles, ed. Y. Landais, Springer International Publishing, Cham, 2018, pp. 151–230,  DOI:10.1007/7081_2018_19.
30. X.-Y. Yu, Q.-Q. Zhao, J. Chen, W.-J. Xiao and J.-R. Chen, When Light Meets Nitrogen-Centered Radicals: From Reagents to Catalysts, Acc. Chem. Res., 2020, 53, 1066–1083.
31. H. Jiang, K. Lang, H. Lu, L. Wojtas and X. P. Zhang, Asymmetric Radical Bicyclization of Allyl Azidoformates via Cobalt(II)-Based Metalloradical Catalysis, J. Am. Chem. Soc., 2017, 139, 9164–9167.
32. V. Ullrich and R. Brugger, Prostacyclin and Thromboxane Synthase: New Aspects of Hemethiolate Catalysis, Angew. Chem., Int. Ed., 1994, 33, 1911–1919.
33. E. Tsui, H. Wang and R. R. Knowles, Catalytic generation of alkoxy radicals from unfunctionalized alcohols, Chem. Sci., 2020, 11, 11124–11141.
34. J. Zhang, D. Liu and Y. Chen, Science of Synthesis: Free Radicals, Fundamentals and Applications in Organic Synthesis, ed. L. Fensterbank and D. Ollivier, Thieme, Stuttgart, 2021, pp. 323–380,  DOI:10.1055/sos-SD-234-00177.
35. J. Zhang, Y. Li, F. Zhang, C. Hu and Y. Chen, Generation of Alkoxyl Radicals by Photoredox Catalysis Enables Selective C(sp3)−H Functionalization under Mild Reaction Conditions, Angew. Chem., Int. Ed., 2015, 55, 1872–1875.
36. C. Wang, K. Harms and E. Meggers, Catalytic Asymmetric C−H Functionalization under Photoredox Conditions by Radical Translocation and Stereocontrolled Alkene Addition, Angew. Chem., Int. Ed., 2016, 55, 13495–13498.
37. Y. Gao, J. Liu, C. Wei, Y. Li, K. Zhang, L. Song and L. Cai, Photoinduced β-fragmentation of aliphatic alcohol derivatives for forging C–C bonds, Nat. Commun., 2022, 13, 7450.
38. L. Lombardi, A. Cerveri, R. Giovanelli, M. Castiñeira Reis, C. Silva López, G. Bertuzzi and M. Bandini, Direct Synthesis of α-Aryl-α-Trifluoromethyl Alcohols via Nickel Catalyzed Cross-Electrophile Coupling, Angew. Chem., Int. Ed., 2022, 61, e202211732.
39. M. Zlotorzynska, H. Zhai and G. M. Sammis, Chemoselective Oxygen-Centered Radical Cyclizations onto Silyl Enol Ethers, Org. Lett., 2008, 10, 5083–5086.
40. M. Rueda-Becerril, J. C. T. Leung, C. R. Dunbar and G. M. Sammis, Alkoxy Radical Cyclizations onto Silyl Enol Ethers Relative to Alkene Cyclization, Hydrogen Atom Transfer, and Fragmentation Reactions, J. Org. Chem., 2011, 76, 7720–7729.
41. E. Tsui, A. J. Metrano, Y. Tsuchiya and R. R. Knowles, Catalytic Hydroetherification of Unactivated Alkenes Enabled by Proton-Coupled Electron Transfer, Angew. Chem., Int. Ed., 2020, 59, 11845–11849.
42. X. He, Y. Zhao, Z. Zhang and X. Shen, Tuning the Reactivity of Alkoxyl Radicals from Cyclization to 1,2-Silyl Transfer: Stereoselective Synthesis of β-Substituted Cycloalcohols, Org. Lett., 2022, 24, 1991–1995.
43. J. Walton, Functionalised Oximes: Emergent Precursors for Carbon-, Nitrogen- and Oxygen-Centred Radicals, Molecules, 2016, 21, 63.
44. I. B. Krylov, S. A. Paveliev, A. S. Budnikov and A. O. Terent’ev, Oxime radicals: generation, properties and application in organic synthesis, Beilstein J. Org. Chem., 2020, 16, 1234–1276.
45. J. R. Thomas, Electron Spin Resonance Study of Iminoxy Free Radicals, J. Am. Chem. Soc., 1964, 86, 1446–1447.
46. J. L. Brokenshire, G. D. Mendenhall and K. U. Ingold, Di-tert-butyliminoxy, a free radical of moderate stability, J. Am. Chem. Soc., 1971, 93, 5278–5279.
47. D. A. Pratt, J. A. Blake, P. Mulder, J. C. Walton, H.-G. Korth and K. U. Ingold, O−H Bond Dissociation Enthalpies in Oximes: Order Restored, J. Am. Chem. Soc., 2004, 126, 10667–10675.
48. I. B. Krylov, A. O. Terent'ev, V. P. Timofeev, B. N. Shelimov, R. A. Novikov, V. M. Merkulova and G. I. Nikishin, Iminoxyl Radical-Based Strategy for Intermolecular C-O Bond Formation: Cross-Dehydrogenative Coupling of 1,3-Dicarbonyl Compounds with Oximes, Adv. Synth. Catal., 2014, 356, 2266–2280.
49. I. B. Krylov, S. A. Paveliev, B. N. Shelimov, B. V. Lokshin, I. A. Garbuzova, V. A. Tafeenko, V. V. Chernyshev, A. S. Budnikov, G. I. Nikishin and A. O. Terent'ev, Selective cross-dehydrogenative C–O coupling of N-hydroxy compounds with pyrazolones. Introduction of the diacetyliminoxyl radical into the practice of organic synthesis, Org. Chem. Front., 2017, 4, 1947–1957.
50. I. B. Krylov, S. A. Paveliev, N. S. Shumakova, M. A. Syroeshkin, B. N. Shelimov, G. I. Nikishin and A. O. Terent'ev, Iminoxyl radicalsvs. tert-butylperoxyl radical in competitive oxidative C–O coupling with β-dicarbonyl compounds. Oxime ether formation prevails over Kharasch peroxidation, RSC Adv., 2018, 8, 5670–5677.
51. Y.-Y. Liu, X.-H. Yang, J. Yang, R.-J. Song and J.-H. Li, Silver-mediated radical cyclization: construction of Δ2-isoxazolines from α-halo ketoximes and 1,3-dicarbonyl compounds, Chem. Commun., 2014, 50, 6906.
52. J. Liao, L. Ouyang, Q. Jin, J. Zhang and R. Luo, Recent advances in the oxime-participating synthesis of isoxazolines, Org. Biomol. Chem., 2020, 18, 4709–4716.
53. Y. F. Si, Q. Y. Lv and B. Yu, Radical Cascade Reactions of β,γ-Unsaturated Hydrazones/Oximes, Adv. Synth. Catal., 2021, 363, 4640–4666.
54. B. Han, X. L. Yang, R. Fang, W. Yu, C. Wang, X. Y. Duan and S. Liu, Oxime Radical Promoted Dioxygenation, Oxyamination, and Diamination of Alkenes: Synthesis of Isoxazolines and Cyclic Nitrones, Angew. Chem., Int. Ed., 2012, 51, 8816–8820.
55. X.-X. Peng, Y.-J. Deng, X.-L. Yang, L. Zhang, W. Yu and B. Han, Iminoxyl Radical-Promoted Dichotomous Cyclizations: Efficient Oxyoximation and Aminooximation of Alkenes, Org. Lett., 2014, 16, 4650–4653.
56. X.-L. Yang, F. Chen, N.-N. Zhou, W. Yu and B. Han, Synthesis of Isoxazoline-Functionalized Phenanthridines via Iminoxyl Radical-Participated Cascade Sequence, Org. Lett., 2014, 16, 6476–6479.
57. R.-H. Liu, D. Wei, B. Han and W. Yu, Copper-Catalyzed Oxidative Oxyamination/Diamination of Internal Alkenes of Unsaturated Oximes with Simple Amines, ACS Catal., 2016, 6, 6525–6530.
58. V. A. Schmidt and E. J. Alexanian, Metal-Free, Aerobic Dioxygenation of Alkenes Using Hydroxamic Acids, Angew. Chem., Int. Ed., 2010, 49, 4491–4494.
59. B. C. Giglio, V. A. Schmidt and E. J. Alexanian, Metal-Free, Aerobic Dioxygenation of Alkenes Using Simple Hydroxamic Acid Derivatives, J. Am. Chem. Soc., 2011, 133, 13320–13322.
60. R. K. Quinn, V. A. Schmidt and E. J. Alexanian, Radical carbooxygenations of alkenes using hydroxamic acids, Chem. Sci., 2013, 4, 4030.
61. B. C. Giglio and E. J. Alexanian, Alkene Hydrofunctionalization Using Hydroxamic Acids: A Radical-Mediated Approach to Alkene Hydration, Org. Lett., 2014, 16, 4304–4307.
62. F. Chen, F.-F. Zhu, M. Zhang, R.-H. Liu, W. Yu and B. Han, Iminoxyl Radical-Promoted Oxycyanation and Aminocyanation of Unactivated Alkenes: Synthesis of Cyano-Featured Isoxazolines and Cyclic Nitrones, Org. Lett., 2017, 19, 3255–3258.
63. X.-X. Peng, D. Wei, W.-J. Han, F. Chen, W. Yu and B. Han, Dioxygen Activation via Cu-Catalyzed Cascade Radical Reaction: An Approach to Isoxazoline/Cyclic Nitrone-Featured α-Ketols, ACS Catal., 2017, 7, 7830–7834.
64. L. Yi, C. Zhu, X. Chen, H. Yue, T. Ji, Y. Ma, Y. Cao, R. Kancherla and M. Rueping, O–H bond activation of β,γ-unsaturated oximes via hydrogen atom transfer (HAT) and photoredox dual catalysis, Chem. Sci., 2023, 14, 14271–14279.
65. G. Kumar and R. Shankar, 2-Isoxazolines: A Synthetic and Medicinal Overview, ChemMedChem, 2021, 16, 430–447.
66. G. McArthur, S. Abel, G. Volpin and D. M. Barber, Strategies for the Enantioselective Synthesis of 2-Isoxazolines and 2-Isoxazolin-5-ones Bearing Fully Substituted Stereocenters, Eur. J. Org Chem., 2022, 2022, e202200947.
67. X. Wang, Q. Hu, H. Tang and X. Pan, Isoxazole/Isoxazoline Skeleton in the Structural Modification of Natural Products: A Review, Pharmaceuticals, 2023, 16, 228.
68. C. B. Tripathi and S. Mukherjee, Catalytic Enantioselective Iodoetherification of Oximes, Angew. Chem., Int. Ed., 2013, 52, 8450–8453.
69. L. Wang, K. Zhang, Y. Wang, W. Li, M. Chen and J. Zhang, Enantioselective Synthesis of Isoxazolines Enabled by Palladium-Catalyzed Carboetherification of Alkenyl Oximes, Angew. Chem., Int. Ed., 2020, 59, 4421–4427.
70. Y. F. Li, W. T. Gui, F. Pi, Z. Chen, L. Zhu, Q. Ouyang, W. Du and Y. C. Chen, Palladium(0) and Brønsted Acid Co-Catalyzed Enantioselective Hydro-Cyclization of 2,4-Dienyl Hydrazones and Oximes, Angew. Chem., Int. Ed., 2024, 63, e202407682.
71. C. Ma, L. Chen and Z. T. He, Asymmetric Intramolecular O-Hydroximation of Alkynes, CCS Chem., 2025, 7, 1168–1176.
72. X. Wang, J. He, Y.-N. Wang, Z. Zhao, K. Jiang, W. Yang, T. Zhang, S. Jia, K. Zhong, L. Niu and Y. Lan, Strategies and Mechanisms of First-Row Transition Metal-Regulated Radical C–H Functionalization, Chem. Rev., 2024, 124, 10192–10280.
73. S.-P. Jiang, X.-Y. Dong, Q.-S. Gu, L. Ye, Z.-L. Li and X.-Y. Liu, Copper-Catalyzed Enantioconvergent Radical Suzuki–Miyaura C(sp3)–C(sp2) Cross-Coupling, J. Am. Chem. Soc., 2020, 142, 19652–19659.
74. J.-J. Chen, J.-H. Fang, X.-Y. Du, J.-Y. Zhang, J.-Q. Bian, F.-L. Wang, C. Luan, W.-L. Liu, J.-R. Liu, X.-Y. Dong, Z.-L. Li, Q.-S. Gu, Z. Dong and X.-Y. Liu, Enantioconvergent Cu-catalysed N-alkylation of aliphatic amines, Nature, 2023, 618, 294–300.
75. Y. Tian, X.-T. Li, J.-R. Liu, J. Cheng, A. Gao, N.-Y. Yang, Z. Li, K.-X. Guo, W. Zhang, H.-T. Wen, Z.-L. Li, Q.-S. Gu, X. Hong and X.-Y. Liu, A general copper-catalysed enantioconvergent C(sp3)–S cross-coupling via biomimetic radical homolytic substitution, Nat. Chem., 2023, 16, 466–475.
76. L.-L. Wang, H. Zhou, Y.-X. Cao, C. Zhang, Y.-Q. Ren, Z.-L. Li, Q.-S. Gu and X.-Y. Liu, A general copper-catalysed enantioconvergent radical Michaelis–Becker-type C(sp3)–P cross-coupling, Nat. Synth., 2023, 2, 430–438.
77. CCDC 2434517: Experimental Crystal Structure Determination, 2025,  DOI:10.5517/ccdc.csd.cc2mq9th.

---