Lewis-acid-catalyzed phosphorylation of alcohols

Abstract

An efficient method has been developed for reacting dialkyl H-phosphonates or diarylphosphine oxides with alcohols for constructing C–P bonds. This reaction was catalyzed by Lewis acid and involved nucleophilic substitution. A series of diphenylphosphonates and diphenylphosphine oxides were obtained, from the phosphorylation of alcohols, with good-to-excellent yields.

---

Introduction

Organophosphonate compounds and their derivatives play an important role in agrochemistry,¹ medicinal chemistry² and organic chemistry.³ For example, calcium antagonist containing a diethyl phosphonate skeleton is a new calcium antagonist of the Fostedil series introduced in 1982.⁴ Substituted phenyl- and benzylphosphonic acids have been shown to be inhibitors of human prostatic acid phosphatase.⁵ In addition, they are used as general components for the preparation of functional materials, such as chemiluminescent materials,⁶ fluorescent materials,⁷ flame retardants⁸ and OLED transmitters⁹ (Fig. 1). Diaryl phosphonates are very important, but only a few methods for their synthesis have been reported. Using the classical Michaelis–Arbuzov or Michaelis–Becker reaction, dialkyl phosphonate has been synthesized from a nucleophilic phosphite and an electrophilic alkyl halide under basic conditions, but the reaction showed the disadvantages of limited availability of the starting materials and high reaction temperature.¹⁰ To overcome these limitations, the Mohanakrishnan group developed a Lewis-acid-mediated Michaelis–Arbuzov reaction to synthesize arylmethylphosphonate and heterarylmethylphosphonate from heteroarylmethylhalides/alcohols and triethyl phosphite at room temperature¹¹ (Scheme 1a). The Chakravarty group developed a method for carrying out a Friedel–Crafts-type arylation of α-hydroxy phosphonates with arenes in the presence of stoichiometric amounts of FeCl₃ to synthesize dialkyl(di-arylmethyl)phosphonates¹² (Scheme 1b). The Walsh group reported a palladium-catalyzed α-arylation of benzylic phosphonates to diisopropyl phosphonate using aryl bromide and diaryl methyl phosphonate as raw materials, but this protocol was restricted to diisopropyl phosphonate derivatives¹³ (Scheme 1c). Recently, a novel Brønsted-acid-catalyzed phosphorylation of o-hydroxybenzyl alcohol has been developed—leading to the synthesis of diphenylphosphonates from trialkylphosphites serving as starting materials and achieved using the phosphate-Michael addition reaction¹⁴ (Scheme 1d). In addition, synthetic chemists have made remarkable progress in investigating methods for forming P–O bonds between P sources and alcohols in recent years, with examples of these methods including, the nucleophilic substitution reaction,¹⁵ Atherton–Todd reaction,¹⁶ cross-dehydrogenative coupling reaction¹⁷ and electrophile reaction.¹⁸ Our group focuses on the phosphorylation of ketones or aldehydes via the phospha-aldol-elimination (PAE) reaction catalyzed by Lewis acid or Brønsted acid.¹⁹ In this study, an effective and green nucleophilic substitution reaction for synthesizing diphenylphosphonates was studied by constructing C–P bonds with alcohol and dialkyl phosphate as raw materials under the catalysis of Tf₂O and Lewis acid Al(OTf)₃ (Scheme 1e).

Fig. 1 Examples of functional disubstituted phosphonates and their derivatives.

Scheme 1 Synthetic approaches to phosphorus-substituted diarylmethanes.

Results and discussion

After screening a series of conditions, diethyl benzhydrylphosphonate 3aa with 94% yield was obtained using diphenylmethanol 1a and diethyl phosphonate 2a as the substrates, Al(OTf)₃ as a catalyst and trifluoromethanesulfonic anhydride (Tf₂O) as an additive in dichloroethane (DCE) at 40 °C under air for 14 h (Table 1). Based on our previous work showing that acid as an additive plays a key role in this reaction, we were pleased to find that the yield of 3aa was significantly better when using Tf₂O as an additive than when using other additives, such as TfOH, TsOH, H₂SO₄, and AcOH (Table 1, entry 2). Further, some Lewis acids were examined. When using Al(OTf)₃ as the Lewis acid, the yield of expected product was 94% (Table 1, entry 1), but when using Cu(OTf)₂, Fe(OTf)₂, AgOTf, AlCl₃, ZnBr₂, CuBr₂, or FeCl₃ instead, the expected product was afforded in lower yields (Table 1, entries 3−9). Other solvents, namely CH₃NO_2, CH₃CN, and THF, were each tested, but found to be ineffective (Table 1, entries 10–12). Finally, lower yields were observed when testing reaction temperatures and amounts of catalyst differing from those of the above optimal conditions and when carrying out certain control experiments (Table 1, entries 13–20).

Table 1 Optimization of the reaction conditions^a,b

Entry	Deviation	Yield (%)
a Reaction conditions: diphenylmethanol (0.2 mmol), Al(OTf)3 (10 mol%), diethyl phosphite (2.5 equiv.), and trifluoromethanesulfonic anhydride (2 equiv.) in dichloroethane (2 mL) at 40 °C for 14 h under air.b Isolated yield.
1	None	94%
2	TfOH, TsOH, H2SO4, AcOH instead of Tf2O	Trace
3	Cu(OTf)2 instead of Al(OTf)3	15%
4	Fe(OTf)2 instead of Al(OTf)3	17%
5	AgOTf instead of Al(OTf)3	76%
6	AlCl3 instead of Al(OTf)3	50%
7	ZnBr2 instead of Al(OTf)3	28%
8	CuBr2 instead of Al(OTf)3	30%
9	FeCl3 instead of Al(OTf)3	36%
10	CH3NO2, CH3CN, THF instead of DCE	Trace
11	PhCH3 instead of DCE	32%
12	Dioxane instead of DCE	16%
13	25 °C	64%
14	60 °C	25%
15	80 °C	21%
16	100 °C	19%
17	5 mol% Al(OTf)3	78%
18	1.5 equiv. Tf2O	84%
19	Without Tf2O	8%
20	Without Al(OTf)3	37%

---

Under optimized reaction conditions, various dibenzyl alcohol and diethyl phosphite substrates were investigated, as shown in Scheme 2. Electron-donating and electron-withdrawing groups on dibenzyl alcohol afforded phosphorylation products with excellent yields (3aa–3ea). Moreover, a moderate yield of phosphorylated product 3fa was obtained with di-naphthalen-2-yl methanol in this catalytic system. In addition, other heteroaromatic alcohols, such as phenyl(thiophen-2-yl)methanol 1g, produced the desired product in moderate yields. To further verify our catalytic system, tertiary alcohols bearing aryl (1h) and alkyl (1i) groups were introduced into the reaction, and excellent yields were obtained. However, when other alcohols, such as 1-phenylethanol 1j, 1-cyclohexylethanol 1k, pentan-2-ol 1l, 5-chloropentan-2-ol 1m, 1-phenyl-2-propyn-1-ol 1n, 3-methylbutan-3-ol 1o, 2-methyl-3-buten-2-ol 1p, and 2-methyl-3-butyn-ol 1q were introduced into the reaction system in respective experiments, no target product in any of these cases was obtained, which may have been the result of the instability of the alkyl carbocation formed.

Scheme 2 Alcohol substrate scope. ^a Reaction conditions: diphenylmethanol (0.2 mmol), Al(OTf)₃ (10 mol%), diethyl phosphite (2.5 equiv.), and trifluoromethanesulfonic anhydride (2 equiv.) in dichloroethane (2 mL) at 40 °C for 14 h under air. ^b Isolated yield.

Under optimized reaction conditions, the P-source substrate scope was evaluated, as shown in Scheme 3. For example, H-phosphonate and H-phosphonate oxides were introduced into respective samples to evaluate the catalytic reaction system. To our delight, the reaction with H-phosphinate proceeded to give 3ba–3bd and 3bg in 86–96% isolated yields. Moreover, the reaction with diphenyl phosphate proceeded, and 3be was obtained with 96% yield. It is noteworthy that diphenylphosphine oxide 3bf was afforded in 50% yield under optimized reaction conditions, and when extending the reaction time, the yield was increased to 68%, but when increasing the reaction temperature using a shorter reaction time did not show the best results. However, when electron-withdrawing and electron-donating groups were introduced onto diphenylphosphine oxide, the results showed that the electron-withdrawing groups were better than the electron-donating groups, attributed to the electronic properties, for example, for bis(4-chlorophenyl)phosphine oxide 3bh and di-p-tolylphosphine oxide 3bi, the products were obtained in 89% and 61% yields, respectively.

Scheme 3 P-source substrate scope. ^a Reaction conditions: diphenylmethanol (0.2 mmol), Al(OTf)₃ (10 mol%), diethyl phosphite (2.5 equiv.), and trifluoromethanesulfonic anhydride (2 equiv.) in dichloroethane (2 mL) at 40 °C for 14 h under air. ^b Isolated yield. ^c 24 h.

Based on previous reports,^8,19a,20 we proposed a plausible reaction mechanism. According to this proposal, in the presence of Lewis acid and Brønsted acid, diaryl methanol forms diarylmethyl cations, while the more nucleophilic intermediate B is obtained under the Tf₂O and Al(OTf)₃ system. Intermediate B then reacts immediately with diarylmethyl cations to obtain the target product 3 while releasing the catalyst HOTf (Scheme 4).

Scheme 4 Proposed mechanism.

Conclusions

In summary, we developed an efficient green method for the synthesis of diphenylphosphonates and diphenylphosphine oxide compounds with good-to-moderate yields—to construct a C–P bond by Lewis-acid-catalyzed nucleophilic substitution reaction between dialkyl H-phosphonates or diarylphosphine oxides and diarylmethanols or trisubstituted methanol.

Data availability

All relevant experimental data are provided in the ESI.†

Author contributions

XHW, YBW and QS directed the project. The experiments were conducted and characterized by XHW, XL and YWX. XHW prepared and revised the manuscript.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank the Natural Science Foundation of China (21968032 and 22165025), Natural Science Foundation of Gansu Province (21YF1GA225) and Fundamental Research Funds for the Central Universities (31920230057 and 31920230003).

Notes and references

1. (a) E. R. Jackson and C. S. Dowd, Curr. Top. Med. Chem., 2012, 12, 706–728; (b) B. Nowack, Water Res., 2003, 37, 2533–2546; (c) S. Montel, C. Midrier, J.-N. Volle, R. Braun, K. Haaf, L. Willms, J.-L. Pirat and D. Virieux, Eur. J. Org Chem., 2012, 2012, 3237–3248; (d) S. O. Duke and S. B. Powles, Pest Manage. Sci., 2008, 64, 319–325.
2. (a) G. P. Horsman and D. L. Zechel, Chem. Rev., 2017, 117, 5704–5783; (b) J. W. McGrath, J. P. Chin and J. P. Quinn, Nat. Rev. Microbiol., 2013, 11, 412–419; (c) A. Mucha, P. Kafarski and Ł. Berlicki, J. Med. Chem., 2011, 54, 5955–5980; (d) N. Zhang and J. E. Casida, Bioorganic Med. Chem., 2002, 10, 1281–1290; (e) A.-X. Zhou, L.-L. Mao, G.-W. Wang and S.-D. Yang, Chem. Commun., 2014, 50, 8529–8532; (f) Y. Niu, C.-X. Yan, X.-X. Yang, P.-B. Bai, P.-P. Zhou and S.-D. Yang, Org. Chem. Front., 2022, 9, 1023–1032; (g) Q. Yang and S.-D. Yang, ACS Catal., 2017, 7, 5220–5224; (h) Y.-Y. Zhu, T. Zhang, L. Zhou and S.-D. Yang, Green Chem., 2021, 23, 9417–9421.
3. (a) J.-J. Feng, X.-F. Chen, M. Shi and W.-L. Duan, J. Am. Chem. Soc., 2010, 132, 5562–5563; (b) L. Horner, H. Hoffmann and H. G. Wippel, Chem. Ber., 1958, 91, 61–63; (c) A. B. Juan and R. O. Liliana, Curr. Org. Chem., 2015, 19, 744–775; (d) Y.-N. Ma, M.-X. Cheng and S.-D. Yang, Org. Lett., 2017, 19, 600–603; (e) Y.-N. Ma, S.-X. Li and S.-D. Yang, Acc. Chem. Res., 2017, 50, 1480–1492; (f) W. Tang and X. Zhang, Chem. Rev., 2003, 103, 3029–3070; (g) H.-L. Wang, R.-B. Hu, H. Zhang, A.-X. Zhou and S.-D. Yang, Org. Lett., 2013, 15, 5302–5305; (h) Y.-N. Ma, Q.-P. Tian, H.-Y. Zhang, A.-X. Zhou and S.-D. Yang, Org. Chem. Front., 2014, 1, 284–288; (i) Z.-N. Cai, Y.-P. Han, Y. Zhang, H.-Y. Zhang, J. Zhao and S.-D. Yang, Green Chem., 2023, 25, 5721–5726.
4. S. Younes, G. Baziard-Mouysset, G. de Saqui-Sannes, J. L. Stigliani, M. Payard, R. Bonnafous and J. Tisne-Versailles, Eur. J. Med. Chem., 1993, 28, 943–948.
5. C. F. Schwender, S. A. Beers, E. A. Malloy, J. J. Cinicola, D. J. Wustrow, K. D. Demarest and J. Jordan, Bioorg. Med. Chem. Lett., 1996, 6, 311–314.
6. J. Motoyoshiya, T. Ikeda, S. Tsuboi, T. Kusaura, Y. Takeuchi, S. Hayashi, S. Yoshioka, Y. Takaguchi and H. Aoyama, J. Org. Chem., 2003, 68, 5950–5955.
7. C.-L. Chiang, C.-F. Shu and C.-T. Chen, Org. Lett., 2005, 7, 3717–3720.
8. B. A. Howell and Y. J. Cho, in Fire and Polymers V, American Chemical Society, 2009, ch. 15, vol. 1013, pp. 249–265.
9. G. Mao, A. Orita, L. Fenenko, M. Yahiro, C. Adachi and J. Otera, Mater. Chem. Phys., 2009, 115, 378–384.
10. C. S. Demmer, N. Krogsgaard-Larsen and L. Bunch, Chem. Rev., 2011, 111, 7981–8006.
11. G. G. Rajeshwaran, M. Nandakumar, R. Sureshbabu and A. K. Mohanakrishnan, Org. Lett., 2011, 13, 1270–1273.
12. G. Pallikonda and M. Chakravarty, Eur. J. Org Chem., 2013, 2013, 944–951.
13. S. Montel, L. Raffier, Y. He and P. J. Walsh, Org. Lett., 2014, 16, 1446–1449.
14. H. Huang and J. Y. Kang, Org. Lett., 2017, 19, 5988–5991.
15. (a) J. I. Murray, R. Woscholski and A. C. Spivey, Chem. Commun., 2014, 50, 13608–13611; (b) N. P. Kenny, K. V. Rajendran and D. G. Gilheany, Chem. Commun., 2015, 51, 16561–16564.
16. (a) G. Wang, R. Shen, Q. Xu, M. Goto, Y. Zhao and L.-B. Han, J. Org. Chem., 2010, 75, 3890–3892; (b) S. Li, T. Chen, Y. Saga and L.-B. Han, RSC Adv., 2015, 5, 71544–71546; (c) B. Xiong, Y. Zhou, C. Zhao, M. Goto, S.-F. Yin and L.-B. Han, Tetrahedron, 2013, 69, 9373–9380; (d) S. Wagner, M. Rakotomalala, Y. Bykov, O. Walter and M. Döring, Heteroat. Chem., 2012, 23, 216–222; (e) B. A. Trofimov, N. K. Gusarova, P. A. Volkov, N. I. Ivanova and K. O. Khrapova, Heteroat. Chem., 2016, 27, 44–47.
17. (a) Q. Chen, J. Zeng, X. Yan, Y. Huang, C. Wen, X. Liu and K. Zhang, J. Org. Chem., 2016, 81, 10043–10048; (b) B. Xiong, X. Feng, L. Zhu, T. Chen, Y. Zhou, C.-T. Au and S.-F. Yin, ACS Catal., 2015, 5, 537–543; (c) X. Yu, S. Zhang, Z. Jiang, H.-S. Zhang and T. Wang, Eur. J. Org Chem., 2020, 2020, 3110–3113; (d) Y. Saito, S. M. Cho, L. A. Danieli and S. Kobayashi, Org. Lett., 2020, 22, 3171–3175; (e) J. Dhineshkumar and K. R. Prabhu, Org. Lett., 2013, 15, 6062–6065; (f) Y. Huang, J. Tang, X. Zhao, Y. Huo, Y. Gao, X. Li and Q. Chen, Green Chem., 2023, 25, 4528–4535; (g) L. Si, B. Xiong, S. Xu, L. Zhu, Y. Liu, W. Xu and K.-W. Tang, J. Organomet. Chem., 2023, 991, 122670; (h) Y. Tan, Y.-P. Han, Y. Zhang, H.-Y. Zhang, J. Zhao and S.-D. Yang, J. Org. Chem., 2022, 87, 3254–3264.
18. J. Shen, Q.-W. Li, X.-Y. Zhang, X. Wang, G.-Z. Li, W.-Z. Li, S.-D. Yang and B. Yang, Org. Lett., 2021, 23, 1541–1547.
19. (a) X.-H. Wei, C.-Y. Bai, L.-B. Zhao, P. Zhang, Z.-H. Li, Y.-B. Wang and Q. Su, Chin. J. Chem., 2021, 39, 1855–1860; (b) X.-H. Wei, C.-Y. Bai, A.-J. Wang, Q.-L. Feng, L.-B. Zhao, P. Zhang, Z.-H. Li, Q. Su and Y.-B. Wang, Org. Lett., 2021, 23, 7100–7105; (c) X.-H. Wei, X.-H. Wang, C.-Y. Bai, Y.-W. Xue, P. Zhang, Y.-B. Wang and Q. Su, Org. Chem. Front., 2023, 10, 410–415; (d) X.-H. Wang, Y.-W. Xue, C.-Y. Bai, Y.-B. Wang, X.-H. Wei and Q. Su, J. Org. Chem., 2023, 88, 16216–16228.
20. (a) L. Chen, X.-Y. Fang and Y.-X. Zou, Org. Biomol. Chem., 2018, 16, 951–956; (b) B. G. Janesko, H. C. Fisher, M. J. Bridle and J.-L. Montchamp, J. Org. Chem., 2015, 80, 10025–10032; (c) J. P. Abell and H. Yamamoto, J. Am. Chem. Soc., 2008, 130, 10521–10523.

---

Footnote

† Electronic supplementary information (ESI) available: General information, experimental procedures and analytical data, including ¹H, ³¹P, ¹³C NMR for all compounds (PDF). See DOI: https://doi.org/10.1039/d3ra08214h

---