English

• Thiophosphates are an important class of organothiophosphorus compounds widely applicable as pharmaceuticals, agrochemicals, and intermediates in materials and organic synthesis (Scheme 1) [1-13]. Traditionally, thiophosphates are prepared by the nucleophilic substitution reactions of thiohalide, RS-Y with R¹R²P(O)-H compounds or phosphorus halide, R¹R²P(O)-X with thiol, RS-H (Schemes 2a and b) [14-19]. However, in recent years, there have been significant improvement in the development of alternative methods of synthesis of thiophosphates. For instance, the direct cross-coupling of RS-H with R¹R²P(O)-H compounds have been developed under oxidative conditions (Scheme 2c) [20-32]. Furthermore, the use of S₈ as the sulfur source in multicomponent reactions to access thiophosphates have been described (Scheme 2d) [33-42]. Another example involves the palladium-catalyzed synthesis of chiral S-aryl phosphorothioates via the coupling of chiral phosphorothioate salts with aryl iodides [43]. Recently, Tang and Zhao's group reported the C–H phosphorothiolation, and phosphorotrithioates, phosphor-amidodithioates and tetrathiophosphates preparation with white phosphorus [44-48]. Although a number of approaches for the synthesis of thiophosphates via S-P(O) bond formation have been established, the development of a robust and general method for the direct introduction of a S-P(O) moiety onto organic molecules is highly desirable. Herein, we report the preparation of diverse thiophosphates via the novel reaction of S-(1,3-dioxoisoindolin-2-yl)O,O-diethyl phosphorothioate (SDDP) with ketones, indoles and thiols (Scheme 2e).

  Scheme 1

  

  Scheme 1.  Some examples of thiophosphate applications.

  DownLoad: Full-Size Img PowerPoint

  Scheme 2

  

  Scheme 2.  Strategies for synthesis of thiophosphates.

  DownLoad: Full-Size Img PowerPoint

  The SDDP reagent was synthesized from inexpensive and readily accessible raw materials as illustrated by the synthetic route in Scheme 3 (see Supporting information for more details). The first step involves the high yielding conversion of phthalimide 1 into the N-chloro derivative 1a, with trichloroisocyanuric acid (TCCA) in water at room temperature [49]. Meanwhile, sodium diethylphosphite was obtained quantitatively in two steps, initially via the reaction of diethylphosphite 1′ with sodium in anhydrous ether at 40 ℃, and then engaging in situ, the resulting mixture with a solution of S₈ in benzene [50]. Finally, the reaction of the preformed intermediates i.e., 1a and 1′a in toluene at room temperature for 30 min furnished SDDP (1b) in 96% yield (i.e., 82% yield over three steps). Moreover, the scale-up reaction using 50 mmol each of phthalimide (1) and diethyl phosphite (1′) was successfully carried out to produce 14.2 g of SDDP. Notably, the solid SDDP is stable to air, light and moisture, and can be stored for more than two months without any decomposition.

  Scheme 3

  

  Scheme 3.  Strategy for synthesis of SDDP (1b).

  DownLoad: Full-Size Img PowerPoint

  With the synthesized SDDP in hand, we turned our attention towards investigating its synthetic applications. Initially, we examined its reaction with aryl ketones, selecting acetophenone (2a) as model substrate. No product was detected in the reaction of 2a with SDDP (Table 1, entry 1), so we try to add promotor to initiate the reaction. After screening some promotors, we found that trimethylsilyl chloride (TMSCl) could effectively promote the reaction to take place (Table 1, entry 7). Furthermore, we carried out a careful screening of the solvent, amount loading of 1b, temperature and time (Table 1, entries 8–18, see Tables S1–S3 in Supporting information for more details), we identified the optimal conditions to be the reaction of acetophenone (2a, 0.2 mmol) with SDDP (0.3 mmol) in the presence of TMSCl (0.4 mmol) in acetonitrile at 90 ℃ for 12 h under argon atmosphere (97%, entry 11).

  Table 1

  

  Table 1.  Optimization of the reaction conditions.^a

  DownLoad: CSV

  With the optimal conditions in hand, the scope of the aryl ketones was examined (Scheme 4). In general, we found that all tested aryl ketones showed remarkable reactivity with SDDP. For instance, acetophenones substituted by methyl, halo groups, as well as naphthyl, benzyloxy, thienyl ketones all underwent facile transformation into the corresponding products in good to excellent yields (3a-c and 3g-n) except substrates bearing methoxy or hydroxyl groups (3d–f). Similarly, the reaction of propiophenone took place smoothly to furnish the expected α-phosphorothiolated product 3o in 81% yield. In addition, aliphatic ketones such as cyclohexanone and 2-butanone were used as substrates for the reaction, the two cases all gave the desired products 3p (63% yield) and 3q (28% yield), respectively.

  Scheme 4

  

  Scheme 4.  Scope of ketones. Reaction conditions: 2 (0.2 mmol), SDDP (0.3 mmol), TMSCl (0.4 mmol) in MeCN (2 mL) at 90 ℃ for 12 h under argon atmosphere. Isolated yield.

  DownLoad: Full-Size Img PowerPoint

  To further expand the synthetic utility of SDDP, we tested its reactivity towards the electron-rich indoles (Scheme 5). We were pleased to discover that 2.0 equiv. of TMSCl could prompt the phosphorothiolation of indole derivatives with SDDP in DMF at 90 ℃ after 12 h. As observed with the aryl ketones, the indole derivatives including those containing electron-donating (methyl & methoxy) or weak electron-withdrawing (halo)substituent groups on the phenyl ring all underwent smooth conversion into the corresponding 3-phosphorothiolated products in good to excellent yields (5a–f) except 5-nitroindole gave the desired product 5g in moderate yield (52%), this was presumably due to the strong electron-withdrawing effect of nitro group. Moreover, the N-protected substrate, 1-methyl-1H-indole reacted favorably to give high yield of the desired product 5h (91%). Meanwhile, 2-phenyl- and 2-methylindoles afforded the corresponding products 5i and 5j in 58% and 83% yields, respectively. The diminished yield of 5i was presumably due to the steric hindrance caused by the 2-phenyl group. Notably, pyrrole underwent efficient conversion to furnish the desired phosphorothiolation product 5k in 77% yield. However, no expected products 5l-n were detected in the reactions using benzofuran, benzothiophen and toluene as substrates.

  Scheme 5

  

  Scheme 5.  Scope of indols. Reaction conditions: 4 (0.2 mmol), SDDP (0.3 mmol), TMSCl (0.4 mmol) in DMF (2 mL) at 90 ℃ for 12 h under argon atmosphere. Isolated yield.

  DownLoad: Full-Size Img PowerPoint

  Furthermore, the reactivity of SDDP was investigated with respect to thiols, and we found that a variety of S-phosphorothiolated thioethers can be furnished under inert conditions in DCM at 60 ℃ (Scheme 6). Notably, the reaction does not require the addition of a promotor or catalyst. A wide range of aryl thiols bearing methyl, methoxy and halo groups were successfully transformed into the desired products in satisfactory yields (7a–j). Pleasingly, aliphatic thiols were also amenable to the reaction with SDDP. (4-Methoxyphenyl)methanethiol, pentanethiol and decanethiol produced the corresponding S-phosphorothiolated thioethers 7k–m in the yields range of 51%−68%.

  Scheme 6

  

  Scheme 6.  Scope of thiols. Reaction conditions: 6 (0.2 mmol), SDDP (0.3 mmol) in DCM (2 mL) at 60 ℃ for 12 h under argon atmosphere. Isolated yield.

  DownLoad: Full-Size Img PowerPoint

  Scheme 7

  

  Scheme 7.  Control experiments.

  DownLoad: Full-Size Img PowerPoint

  In order to elucidate the mechanism of these reactions, some control experiments were carried out. Initially, we observed that the addition of radical scavengers such as TEMPO (2,2,6,6-tetramethyl-1-piperidin-1-yl)oxyl, DPE (1,1-diphenylethylene) or BHT (2,6-di-tert-butyl-4-methylphenol) to the reaction mixture under standard conditions did not inhibit the formation of any of products 3a, 5a, or 7a (Schemes 7a–c). These results effectively rule out the participation of radical intermediates in the reactions of SDDP with these compounds, i.e., ketones, indoles and thiols.

  Based on these observations, we proposed a mechanism for the reaction of SDDP with the electron-rich substrates (Scheme 8). In general, the reaction of SDDP reagent proceeds via the initial nucleophilic attack on the S-atom by electron-rich substrates to furnish a cationic intermediate, 8. Thereafter, deprotonation takes place to yield the target products 3/5/7 (Scheme 8a). With ketones, the terminal end of the double bond in the silyl enol ether 9 (generated in situ from the reaction of ketones and TMSCl) attacks the S-atom of SDDP to form the cationic intermediate 10. This is followed by the formation of product 3, alongside the departure of trimethylsilyl cation (TMS⁺) as a leaving group (Scheme 8b).

  Scheme 8

  

  Scheme 8.  Proposed mechanism.

  DownLoad: Full-Size Img PowerPoint

  In summary, we have developed an efficient protocol for the synthesis of the electrophilic reagent SDDP. Furthermore, we studied its reaction (i.e., SP(O)(OEt)₂ transfer) with a range of electron-rich substrates including ketones, indoles and thiols to furnish α-phosphorothiolated ketones, 3-phosphorothiolated indoles and S-phosphorothiolated thioethers, respectively. Preliminary mechanistic studies implicate a nucleophilic substitution pathway wherein the electron-rich substrate attacks the electron-deficient S-atom in SDDP to form a cationic intermediate, followed by detrimethylsilylation or deprotonation to afford the observed products.

  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

  Authors acknowledge the generous financial support by National Natural Science Foundation of China (No. 21472133), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) and Key Laboratory of Organic Synthesis of Jiangsu Province (No. KJS1749).

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2023.109076.

  
  
• 1. [1]

     C. Sine, Farm Chemicals Handbook, Meister Publishing Company, Willoughby, OH, USA, 1993.

  2. [2]

     L.D. Quin, A Guide to Organophosphorus Chemistry, Wiley Interscience, New York, 2000.

  3. [3]

     P.J. Murphy, Organophosphorus Reagents, Oxford University Press, Oxford, UK, 2004.

  4. [4]

     N.S. Li, J.K. Frederiksen, J.A. Piccirilli, Acc. Chem. Res. 44 (2011) 1257–1269. doi: 10.1021/ar200131t

  5. [5]

     B. Kaboudin, S. Emadi, A. Hadizadeh, Bioorg. Chem. 37 (2009) 101–105. doi: 10.1016/j.bioorg.2009.05.002

  6. [6]

     J.A. Fraietta, Y.M. Mueller, D.H. Do, et al., Antimicrob. Agents Chemother. 54 (2010) 4064–4073. doi: 10.1128/AAC.00367-10

  7. [7]

     R. Xie, Q. Zhao, T. Zhang, et al., Bioorg. Med. Chem. 21 (2013) 278–282. doi: 10.1016/j.bmc.2012.10.030

  8. [8]

     T.S. Kumar, T. Yang, S. Mishra, et al., J. Med. Chem. 56 (2013) 902–914. doi: 10.1021/jm301372c

  9. [9]

     L.L. Murdock, T.L. Hopkins, J. Agric. Food Chem. 16 (1968) 954–958. doi: 10.1021/jf60160a021

  10. [10]

      K. Hiroshi, Patent, JP 45026974 B, 1970.

  11. [11]

      A.M. Lauer, F. Mahmud, J. Wu, J. Am. Chem. Soc. 133 (2011) 9119–9123. doi: 10.1021/ja202954b

  12. [12]

      A.M. Lauer, J. Wu, Org. Lett. 14 (2012) 5138–5141. doi: 10.1021/ol302263m

  13. [13]

      K.A. Mazzio, K. Okamoto, Z. Li, et al., Chem. Commun. 49 (2013) 1321–1323. doi: 10.1039/c2cc38544a

  14. [14]

      Y.X. Gao, G. Tang, Y. Cao, Y.F. Zhao, Synthesis (2009) 1081–1086.

  15. [15]

      Y.J. Ouyang, Y.Y. Li, N.B. Li, X.H. Xu, Chin. Chem. Lett. 24 (2013) 1103–1105. doi: 10.1016/j.cclet.2013.06.020

  16. [16]

      Y. Liu, C.F. Lee, Green Chem. 16 (2014) 357–364. doi: 10.1039/C3GC41839A

  17. [17]

      J. Bai, X. Cui, H. Wang, Y. Wu, Chem. Commun. 50 (2014) 8860–8863. doi: 10.1039/C4CC02693D

  18. [18]

      P. Carta, N. Puljic, C. Robert, et al., Tetrahedron 64 (2008) 11865–11875. doi: 10.1016/j.tet.2008.08.108

  19. [19]

      G. Kumaraswamy, R. Raju, Adv. Synth. Catal. 356 (2014) 2591–2598. doi: 10.1002/adsc.201400116

  20. [20]

      B. Kaboudin, Y. Abedi, J. Kato, T. Yokomatsu, Synthesis 45 (2013) 2323–2327. doi: 10.1055/s-0033-1339186

  21. [21]

      J. Wang, X. Huang, Z. Ni, et al., Green Chem. 17 (2015) 314–319. doi: 10.1039/C4GC00944D

  22. [22]

      J. Wang, X. Huang, Z. Ni, et al., Tetrahedron 71 (2015) 7853–7859. doi: 10.1016/j.tet.2015.08.025

  23. [23]

      X. Bi, J. Li, F. Meng, H. Wang, J. Xiao, Tetrahedron 72 (2016) 706–711. doi: 10.1016/j.tet.2015.12.020

  24. [24]

      Y. Zhu, T. Chen, S. Li, S. Shimada, L.B. Han, J. Am. Chem. Soc. 138 (2016) 5825–5828. doi: 10.1021/jacs.6b03112

  25. [25]

      J. Sun, H. Yang, P. Li, B. Zhang, Org. Lett. 18 (2016) 5114–5117. doi: 10.1021/acs.orglett.6b02563

  26. [26]

      S. Song, Y. Zhang, A. Yeerlan, et al., Angew. Chem. Int. Ed. 56 (2017) 2487–2491. doi: 10.1002/anie.201612190

  27. [27]

      J. Sun, W. Weng, P. Li, B. Zhang, Green Chem. 19 (2017) 1128–1133. doi: 10.1039/C6GC03115C

  28. [28]

      H. Huang, J. Ash, J.Y. Kang, Org. Biomol. Chem. 16 (2018) 4236–4242. doi: 10.1039/C8OB00908B

  29. [29]

      J.W. Xue, M. Zeng, S. Zhang, Z. Chen, G. Yin, J. Org. Chem. 84 (2019) 4179–4190. doi: 10.1021/acs.joc.9b00194

  30. [30]

      C.Y. Li, Y.C. Liu, Y.X. Li, D.M. Reddy, C.F. Lee, Org. Lett. 21 (2019) 7833–7836. doi: 10.1021/acs.orglett.9b02825

  31. [31]

      Z. Handoko, P. Benslimane, S. Arora, Org. Lett. 22 (2020) 5811–5816. doi: 10.1021/acs.orglett.0c01858

  32. [32]

      J. Shen, Q.W. Li, X.Y. Zhang, et al., Org. Lett. 23 (2021) 1541–1547. doi: 10.1021/acs.orglett.0c04127

  33. [33]

      B.A. Kaboudin, Tetrahedron Lett. 43 (2002) 8713–8714. doi: 10.1016/S0040-4039(02)02136-6

  34. [34]

      J. Xu, L.L. Zhang, X. Li, et al., Org. Lett. 18 (2016) 1266–1269. doi: 10.1021/acs.orglett.6b00118

  35. [35]

      L.L. Zhang, P.B. Zhang, X.Q. Li, et al., J. Org. Chem. 81 (2016) 5588–5594. doi: 10.1021/acs.joc.6b00925

  36. [36]

      W.M. Wang, L.J. Liu, L. Yao, et al., J. Org. Chem. 81 (2016) 6843–6847. doi: 10.1021/acs.joc.6b01192

  37. [37]

      X.H. Zhang, Z. Shi, C.W. Shao, et al., Eur. J. Org. Chem. 2017 (2017) 1884–1888. doi: 10.1002/ejoc.201700344

  38. [38]

      L. Wang, S. Yang, L. Chen, et al., Catal. Sci. Technol. 7 (2017) 2356–2361. doi: 10.1039/C7CY00467B

  39. [39]

      S. Kovács, B. Bayarmagnai, A. Aillerie, L.J. Gooßen, Adv. Synth. Catal. 360 (2018) 1913–1918. doi: 10.1002/adsc.201701549

  40. [40]

      S. Shi, P. Zhang, C. Luo, et al., Org. Lett. 22 (2020) 1760–1764. doi: 10.1021/acs.orglett.0c00044

  41. [41]

      P. Zhang, G. Yu, W. Li, et al., Org. Lett. 23 (2021) 5848–5852. doi: 10.1021/acs.orglett.1c01985

  42. [42]

      H. Feuer, D. Braunstein, J. Org. Chem. 34 (1969) 1817–1821. doi: 10.1021/jo01258a062

  43. [43]

      X.Y. Chen, M.P. Pu, H.G. Cheng, T. Sperger, Angew. Chem. Int. Ed. 58 (2019) 11395–11399. doi: 10.1002/anie.201906063

  44. [44]

      Z.P. Zheng, S.S. Shi, Q.R. Ma, et al., Org. Chem. Front. 8 (2021) 6845–6850. doi: 10.1039/D1QO01178B

  45. [45]

      Z.P. Zheng, J.L. He, Q.R. Ma, et al., Green Chem. 24 (2022) 4484–4489. doi: 10.1039/D2GC00816E

  46. [46]

      X.L. Huangfu, Y. Zhang, P.Y. Chen, et al., Green Chem. 22 (2020) 8353–8359. doi: 10.1039/D0GC02985H

  47. [47]

      Y. Zhang, Y.W. Cao, Y.Y. Chi, et al., Adv. Synth. Catal. 364 (2022) 2221–2226. doi: 10.1002/adsc.202200334

  48. [48]

      J.L. He, S.S. Shi, Y.M. Zhang, et al., Chin. J. Chem. 41 (2023) 2311–2316. doi: 10.1002/cjoc.202300223

  49. [49]

      A. Shiri, A. Khoramabadi-zad, Synthesis 16 (2009) 2797–2801.

  50. [50]

      T.B. Chapman, D.G. Kleid, J. Org. Chem. 38 (1973) 250–252. doi: 10.1021/jo00942a012

• 

  Scheme 1  Some examples of thiophosphate applications.

  下载: 全尺寸图片 幻灯片
  

  Scheme 2  Strategies for synthesis of thiophosphates.

  下载: 全尺寸图片 幻灯片
  

  Scheme 3  Strategy for synthesis of SDDP (1b).

  下载: 全尺寸图片 幻灯片
  

  Scheme 4  Scope of ketones. Reaction conditions: 2 (0.2 mmol), SDDP (0.3 mmol), TMSCl (0.4 mmol) in MeCN (2 mL) at 90 ℃ for 12 h under argon atmosphere. Isolated yield.

  下载: 全尺寸图片 幻灯片
  

  Scheme 5  Scope of indols. Reaction conditions: 4 (0.2 mmol), SDDP (0.3 mmol), TMSCl (0.4 mmol) in DMF (2 mL) at 90 ℃ for 12 h under argon atmosphere. Isolated yield.

  下载: 全尺寸图片 幻灯片
  

  Scheme 6  Scope of thiols. Reaction conditions: 6 (0.2 mmol), SDDP (0.3 mmol) in DCM (2 mL) at 60 ℃ for 12 h under argon atmosphere. Isolated yield.

  下载: 全尺寸图片 幻灯片
  

  Scheme 7  Control experiments.

  下载: 全尺寸图片 幻灯片
  

  Scheme 8  Proposed mechanism.

  下载: 全尺寸图片 幻灯片

  Table 1.  Optimization of the reaction conditions.^a

  下载: 导出CSV
•