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• Visible light photosynthesis has emerged as an indispensable powerful tool in green organic synthesis, which utilizes light as a source of clean energy to promote carbon-carbon/heteroatom bond formation under eco-friendly and mild conditions [1-5]. A broad range of photocatalytic organo-functional group transformations have been established over the past years [6-22]. However, most of these processes depended heavily on precious ruthenium(Ⅱ)/iridium(Ⅲ) complexes or elaborate organic dyes [23], which not only increased manufacture costs but also caused environmental concerns. As a consequence, it is highly desirable to develop sustainable visible-light induced reactions without harmful photocatalysts.

  Cyclic N-sulfonyl ketamine and its derivatives are broadly distributed in numerous bioactive molecules and synthetic pharmaceuticals [24,25]. They also serve as versatile and powerful building blocks and synthetic intermediates in organic synthesis [26-31]. Consequently, their synthesis and functionalization have given rise to much interest from the synthetic community [32-38]. Among various known N-sulfonyl ketamine derivatives, 4-alkylated sulfonyl ketamine has attracted widespread attention due to their diverse biological activities and pharmacological properties. In 2021, Liu and co-workers developed the AgNO₃-catalyzed decarboxylative alkylation of sulfonyl ketamine with aliphatic carboxylic acids for the synthesis of 4-alkylated sulfonyl ketamines (Scheme 1a) [39]. Although this method exhibited its individual advantages, excess inorganic oxidant and transition-metal catalyst are required, causing the problem of the removal of inorganic salts/residual transition metal in the terminal products which limits their applications in pharmaceutical synthesis and fine chemicals. Therefore, developing a metal-free and practical methodology for the synthesis of 4-alkylated sulfonyl ketamines is highly desired.

  Scheme 1

  

  Scheme 1.  Synthesis of 4-alkylated N-sulfonyl ketamines.

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  Alkanes are widely exiting in nature and regarded as the most attractive alkyl source for alkylation reactions. Given the environmental friendliness of photocatalysis, a series of visible-light induced alkylations with alkanes have been developed over the past years [40-49]. Despite these remarkable advances, however, the efficiency and practicability of these methods are compromised by the required additional photocatalysts and/or stoichiometric additives. Hydrogen peroxide (H₂O₂) is a low cost, convenient and suitable green alternative to traditional oxidizing agents [50]. In the oxidative reactions, H₂O₂ is reduced to environmentally benign water, which does not complicate product isolation [51-56]. As part of our continued efforts on green organic synthesis, we herein report an efficient and green approach for the synthesis of 4-alkylated sulfonyl ketamines through visible light-indecued alkylation of N-sulfonyl ketamines with alkanes in the presence of H₂O₂ as the sole oxidant under transition metal-, external photocatalyst- and additive-free conditions (Scheme 1b).

  At the outset of our investigations, N-sulfonyl ketamine (1a) and cyclohexane (2a) were chosen as model substrates to optimize the reaction conditions. To our delight, conducting the reaction with H₂O₂ (3 equiv.) as the sole oxidant in MeCN with a 415 nm LED (7 W) irradiation under nitrogen gave the desired product 3aa in 92% yield. The solvent effect played an important role in the photocatalytic process. Changing the solvent from MeCN to THF, DCM, DMF or DMSO led to the decomposition of 1a (entries 2–5). EtOH or EtOAc gave a trace amount of 3aa and the starting material 1a was nearly recovered (entries 6 and 7). Changing the LED light source with different wavelengths diminished the reaction yield (entries 8 and 9). The reaction gave an unidentified complex mixture under an air atmosphere (entry 10). Without H₂O₂ or light, no reaction was observed (entry 11).

  With the optimum reaction conditions established (Table 1, entry 1), the scope of the photocatalytic alkylation with respect to both N-sulfonyl ketimines (1) and alkanes (2) was evaluated. As shown in Scheme 2, good to excellent isolated yields were obtained for N-sulfonyl ketimines containing electron-neutral (3aa), electron-rich (3ba-3da) and electron-deficient groups (3ea-3ha) on the phenyl ring. In addition, the methyl substituent at each position of the benzene ring of substrates 1 had no significant influence on the reaction outcome, producing the desired products (3ia-3ka) in high yields. The reactions with five-membered or seven-membered cyclic aldimine as the substrates led to no formation of the desired products and the majority recovery of the cyclic aldimine substrates. Subsequently, the scope of this alkylation with respect to alkanes was explored. A series of cycloalkanes reacted with 1a to deliver the target products (3ab-3ae) in good yields. Pleasingly, both bulky sterically norbornane and adamantane underwent the transformation smooth to provide products 3af and 3ag in 85% and 76% yields, respectively. The linear alkanes were also suitable substrates for this transformation, delivering the desired products (3ah-3ak) in good yields. The regiomeric ratios of alkylated products at different positions of alkanes were also investigated, and the results showed that the regioselectivities depended on stabilities of the corresponding generated carbon radicals and quantities of hydrogens with a same chemical environment. Furthermore, ether compounds, such as tetrahydro-2H-pyran and 1,4-dioxane, also underwent the alkylation reaction, generating product 3al and 3am in 78% and 84% yields, respectively. However, no desired product was detected with tetrahydrofuran as the alkyl source.

  Table 1

  

  Table 1.  Optimization of reaction conditions.^a

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  Scheme 2

  

  Scheme 2.  Reaction scope. Conditions: 1 (0.2 mmol), 2 (0.6 mmol), H₂O₂ (0.6 mmol), MeCN (2 mL), 7 W LED (415 nm), N₂, room temperature.

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  To prove the practicability of the photocatalytic alkylation reaction, a gram-scale reaction was performed by employing substrate 1a (5 mmol) and alkane 2a under the modified reaction conditions. Pleasingly, a good isolated yield (87%, 1.15 g) comparable to that of the small-scale experiment was obtained (Scheme 3).

  Scheme 3

  

  Scheme 3.  Gram-scale synthesis of 3aa.

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  To gain more insight into the reaction mechanism, the radical-trapping experiments, kinetic isotope effect (KIE) experiments, visible-light on/off experiments and UV–vis absorption analysis were carried out. Firstly, the current reaction was completely inhibited with TEMPO or 1,1-diphenylethylene as the radical scavenger under standard conditions. Both the cyclohexyl-TEMPO adduct 4aa and cyclohexyl-diphenylethylene adduct 4ab were detected by GC-MS (Scheme 4a), confirming that the cyclohexyl radical was the key intermediate in this reaction. Second, KIE was investigated with regards to the C(sp³)–H/D bonds for the cyclohexane. A clear KIE value of 2.8 was detected in a 1:1 mixture of 2a and 2a-d₁₁ (Scheme 4b), indicating that cleavage of the C(sp³)–H bond in alkane 2 might be the rate-limiting step. The result of turn-on/off light irradiation experiment suggested that the continuous visible-light irradiation was indispensable for this transformation. In addition, a low quantum yield (1.05%) was obtained through chemical actinometry (for details see Supporting information), excluding the possibility of radical propagation pathway. The results of UV–vis absorption spectra (for details see Supporting information) revealed that the substrate 1a and product 3aa could absorb visible light and serve as the photosensitizer [57].

  Scheme 4

  

  Scheme 4.  Mechanistic investigations.

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  Inspired by these observations and previous reports [39,40,58], a possible mechanism for the external photocatalyst-free visible light-induced alkylation was depicted in Scheme 5. Photoexcitation by 415 nm light endowed ground-state N-sulfonyl ketamine (1a) with highly reducing potential in its excited state [1a]*, allowing for single-electron reduction of H₂O₂ to form a hydroxyl radical (OH^•), a hydroxyl anion (OH⁻) along with generation of 1a radical cation [1a]^•+. Subsequently, a hydrogen atom transfer from cyclohexane (2a) to OH^• led to the formation of cyclohexyl radical (Cy^•), which attacked 1a to form the N-center radical IM1, followed by 1,2-H shift to deliver the C-center radical IM2. The [1a]^•+ oxidized the intermediate IM2 to give the carbocation intermediate IM3 along with the re-generation of ground-state 1a. Ultimately, the desired product 3aa was obtained by the deprotonation of IM3 with the assistance of OH⁻. In addition, the product 3aa could also serve as the photocatalyst to participate the photo-catalytic cycle.

  Scheme 5

  

  Scheme 5.  Plausible reaction mechanism.

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  To summarize, a simple, practical and sustainable method for the synthesis of alkylated sulfonyl ketamines though visible-light induced alkylation of N-sulfonyl ketamine with alkanes in the presence of H₂O₂ as the sole oxidant was first developed. In sharp contrast to the previous protocol, the present reaction usedvisible light as the clean energy source and cheap alkanes as the atom economy alkylating agent, proceeding without any metal, additive or external photocatalyst and generating environmentally benign water as the sole side-product. Due to the natural abundance of cheap alkanes, good to excellent yields, strong scalability and simple operation procedures, clean and mild conditions, the current reaction is expected to be widely applied in pharmaceutical industry (Fig. 1).

  Figure 1

  

  Figure 1.  Turn-on/off light irradiation experiment.

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  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  Acknowledgments

  We are grateful for financial support from the University of South China.

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2023.108509.

  
  
• 1. [1]

     N. Holmberg-Douglas, D.A. Nicewicz, Chem. Rev. 122 (2022) 1925–2016. doi: 10.1021/acs.chemrev.1c00311

  2. [2]

     D. Wang, J. Wang, C. Ma, Y. Jiang, B. Yu, Chin. J. Org. Chem. 42 (2022) 4024–4036. doi: 10.6023/cjoc202208039

  3. [3]

     D. Yang, Q. Yan, E. Zhu, J. Lv, W.M. He, Chin. Chem. Lett. 33 (2022) 1798–1816. doi: 10.1016/j.cclet.2021.09.068

  4. [4]

     W.T. Ouyang, F. Xiao, L.J. Ou, W.M. He, Curr. Opin. Green Sust. 40 (2023) 100760. doi: 10.1016/j.cogsc.2023.100760

  5. [5]

     F. Gao, S. Zhang, Q. Lv, B. Yu, Chin. Chem. Lett. 33 (2022) 2354–2362. doi: 10.1016/j.cclet.2021.10.081

  6. [6]

     D. Cao, P. Pan, C.J. Li, H. Zeng, Green Synth. Catalysis 2 (2021) 303–306. doi: 10.1016/j.gresc.2021.04.006

  7. [7]

     Q.W. Gui, F. Teng, Z.C. Li, et al., Chin. Chem. Lett. 32 (2021) 1907–1910. doi: 10.1016/j.cclet.2021.01.021

  8. [8]

     Q.W. Gui, F. Teng, P. Yu, et al., Chin. J. Catal. 44 (2023) 111–116. doi: 10.1016/S1872-2067(22)64162-7

  9. [9]

     S. Zhang, S. Cao, Y.M. Lin, et al., Chin. J. Catal. 43 (2022) 564–570. doi: 10.3390/gels8090564

  10. [10]

      Z. Wang, Q. Liu, R. Liu, et al., Chin. Chem. Lett. 33 (2022) 1479–1482. doi: 10.1016/j.cclet.2021.08.036

  11. [11]

      P. Xiang, K. Sun, S. Wang, et al., Chin. Chem. Lett. 33 (2022) 5074–5079. doi: 10.1016/j.cclet.2022.03.096

  12. [12]

      H.Y. Song, M.Y. Liu, J. Huang, et al., J. Org. Chem. 88 (2023) 2288–2295. doi: 10.1021/acs.joc.2c02679

  13. [13]

      H.Y. Song, Z.T. Zhang, H.Y. Tan, et al., Asian J. Org. Chem. 12 (2023) e202200658. doi: 10.1002/ajoc.202200658

  14. [14]

      X. Hao, Z. Jie, Z. Junze, et al., Chin. J. Org. Chem. 42 (2022) 4037–4059. doi: 10.6023/cjoc202209004

  15. [15]

      Z. Gan, G. Li, X. Yang, et al., Sci. China Chem. 63 (2020) 1652–1658. doi: 10.1007/s11426-020-9811-6

  16. [16]

      L. Yao, D. Zhu, L. Wang, et al., Chin. Chem. Lett. 32 (2021) 4033–4037. doi: 10.1016/j.cclet.2021.06.005

  17. [17]

      H.Y. Song, J. Jiang, C. Wu, et al., Green Chem. 25 (2023) 3292–3296. doi: 10.1039/d2gc04843d

  18. [18]

      I.B. Krylov, E.R. Lopat'eva, I.R. Subbotina, et al., Chin. J. Catal. 42 (2021) 1700–1711. doi: 10.1016/S1872-2067(21)63831-7

  19. [19]

      N. Spiliopoulou, C.G. Kokotos, Green Chem. 23 (2021) 546–551. doi: 10.1039/d0gc03818k

  20. [20]

      S. Neogi, A. Kumar Ghosh, S. Mandal, et al., Org. Lett. 23 (2021) 6510–6514. doi: 10.1021/acs.orglett.1c02322

  21. [21]

      E. Skolia, P.L. Gkizis, N.F. Nikitas, C.G. Kokotos, Green Chem. 24 (2022) 4108–4118. doi: 10.1039/d2gc00799a

  22. [22]

      H. Tang, M. Zhang, Y. Zhang, et al., J. Am. Chem. Soc. 145 (2023) 5846–5854. doi: 10.1021/jacs.2c13157

  23. [23]

      J.D. Bell, J.A. Murphy, Chem. Soc. Rev. 50 (2021) 9540–9685. doi: 10.1039/d1cs00311a

  24. [24]

      Y. Guo, J. Luo, S. Tan, B.O. Otieno, Z. Zhang, Eur. J. Pharm. Sci. 49 (2013) 175–186. doi: 10.14257/ijdta.2013.6.5.16

  25. [25]

      S.J. Williams, Expert Opin. Ther. Pat. 23 (2013) 79–98. doi: 10.1517/13543776.2013.736965

  26. [26]

      J.F. Bower, J. Rujirawanich, T. Gallagher, Org. Biomol. Chem. 8 (2010) 1505–1519. doi: 10.1039/b921842d

  27. [27]

      W. Shi, L. Zhou, B. Mao, et al., J. Org. Chem. 84 (2019) 679–686. doi: 10.1021/acs.joc.8b02515

  28. [28]

      K.P. Jethava, J. Fine, Y. Chen, A. Hossain, G. Chopra, Org. Lett. 22 (2020) 8480–8486. doi: 10.1021/acs.orglett.0c03083

  29. [29]

      F. Wang, Danfeng Huang, Pengfei Zhao, et al., Chin. J. Org. Chem. 42 (2022) 507–512. doi: 10.6023/cjoc202108016

  30. [30]

      X. Wang, A. Shi, X.Q. Huang, et al., Org. Biomol. Chem. 20 (2022) 3798–3802. doi: 10.1039/d2ob00460g

  31. [31]

      A. Shi, K. Sun, X. Chen, et al., Org. Lett. 24 (2022) 299–303. doi: 10.1021/acs.orglett.1c03960

  32. [32]

      K.C. Majumdar, S. Mondal, Chem. Rev. 111 (2011) 7749–7773. doi: 10.1021/cr1003776

  33. [33]

      S. Guin, D. Majee, S. Samanta, Chem. Commun. 57 (2021) 9010–9028. doi: 10.1039/d1cc03439a

  34. [34]

      X. Liu, J. Wang, Z. Wu, et al., Org. Biomol. Chem. 19 (2021) 3595–3600. doi: 10.1039/d1ob00223f

  35. [35]

      J. Wang, X. Liu, Z. Wu, et al., Chem. Commun. 57 (2021) 1506–1509. doi: 10.1039/d0cc07181a

  36. [36]

      H.X. Wang, Z.H. Li, W.W. Li, et al., Green Chem. 24 (2022) 8377–8385. doi: 10.1039/D2GC03218J

  37. [37]

      Z. Shi, Y. Li, N. Li, et al., Angew. Chem. Int. Ed. 61 (2022) e202206058. doi: 10.1002/anie.202206058

  38. [38]

      Y. Zhu, R. Dai, C. Huang, et al., J. Org. Chem. 87 (2022) 11722–11734. doi: 10.1021/acs.joc.2c01376

  39. [39]

      J. Wang, X. Liu, Z. Wu, et al., Chin. Chem. Lett. 32 (2021) 2777–2781. doi: 10.1016/j.cclet.2021.03.011

  40. [40]

      Y. Zhang, Y. Jin, L. Wang, et al., Green Chem. 23 (2021) 6926–6930. doi: 10.1039/d1gc02670d

  41. [41]

      Y. Jin, Q. Zhang, L. Wang, et al., Green Chem. 23 (2021) 6984–6989. doi: 10.1039/d1gc01563j

  42. [42]

      Ł.W. Ciszewski, D. Gryko, Chem. Commun. 58 (2022) 10576–10579. doi: 10.1039/d2cc03772f

  43. [43]

      B. Wang, C. Ascenzi Pettenuzzo, J. Singh, et al., ACS Catal. 12 (2022) 10441–10448. doi: 10.1021/acscatal.2c02993

  44. [44]

      J. Xu, H. Cai, J. Shen, et al., J. Org. Chem. 86 (2021) 17816–17832. doi: 10.1021/acs.joc.1c02125

  45. [45]

      X.Y. Yuan, Y.F. Si, X. Li, et al., Org. Chem. Front. 9 (2022) 2728–2733. doi: 10.1039/d1qo01894a

  46. [46]

      M. Wang, Y. Zhang, X. Yang, P. Sun, Org. Biomol. Chem. 20 (2022) 2467–2472. doi: 10.1039/D2OB00278G

  47. [47]

      H. Tian, H. Yang, C. Tian, G. An, G. Li, Org. Lett. 22 (2020) 7709–7715. doi: 10.1021/acs.orglett.0c02912

  48. [48]

      Z.Y. Dai, Z.S. Nong, S. Song, P.S. Wang, Org. Lett. 23 (2021) 3157–3161. doi: 10.1021/acs.orglett.1c00801

  49. [49]

      P. Xu, P.Y. Chen, H.C. Xu, Angew. Chem. Int. Ed. 59 (2020) 14275–14280. doi: 10.1002/anie.202005724

  50. [50]

      H. Targhan, P. Evans, K. Bahrami, J. Ind. Eng. Chem. 104 (2021) 295–332. doi: 10.1016/j.jiec.2021.08.024

  51. [51]

      J. Jiang, F. Xiao, W.M. He, L. Wang, Chin. Chem. Lett. 32 (2021) 1637–1644. doi: 10.1016/j.cclet.2021.02.057

  52. [52]

      Z.L. Wu, J.Y. Chen, X.Z. Tian, et al., Chin. Chem. Lett. 33 (2022) 1501–1504. doi: 10.1016/j.cclet.2021.08.071

  53. [53]

      H. Li, P. Chen, Z. Wu, et al., Chin. J. Org. Chem. 42 (2022) 3398–3404. doi: 10.6023/cjoc202207009

  54. [54]

      R. Yi, W. He, Chin. J. Org. Chem. 42 (2022) 2590–2592. doi: 10.6023/cjoc202200040

  55. [55]

      Y.H. Lu, Z.T. Zhang, H.Y. Wu, et al., Chin. Chem. Lett. 34 (2022) 108036. doi: 10.1016/j.cclet.2022.108036

  56. [56]

      H.Y. Zhou, H.T. Tan, W.M. He, Chin. J. Catal. 46 (2023) 4–10. doi: 10.1016/S1872-2067(22)64197-4

  57. [57]

      L. Zhao, P. Li, X. Xie, L. Wang, Org. Chem. Front. 5 (2018) 1689–1697. doi: 10.1039/C8QO00229K

  58. [58]

      A. Shi, K. Sun, Y. Wu, et al., J. Catal. 415 (2022) 28–36. doi: 10.1016/j.jcat.2022.09.027

• 

  Scheme 1  Synthesis of 4-alkylated N-sulfonyl ketamines.

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  Scheme 2  Reaction scope. Conditions: 1 (0.2 mmol), 2 (0.6 mmol), H₂O₂ (0.6 mmol), MeCN (2 mL), 7 W LED (415 nm), N₂, room temperature.

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  Scheme 3  Gram-scale synthesis of 3aa.

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  Scheme 4  Mechanistic investigations.

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  Scheme 5  Plausible reaction mechanism.

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  Figure 1  Turn-on/off light irradiation experiment.

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  Table 1.  Optimization of reaction conditions.^a

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•