Markovnikov-addition of H-phosphonates to terminal alkynes under metal- and solvent-free conditions

Abstract

An addition of H-phosphonates to aryl alkynes was realized under solvent- and metal-free conditions, affording Markovnikov-selective α-vinylphosphonates in moderate to good yields. A wide range of aryl alkynes could be applied for the reaction. A tentative mechanism of addition–substitution was proposed based on in situ ³¹P {¹H} NMR studies.

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Vinyl phosphorus compounds are of high importance because of their wide application in the fields of biological metabolism,¹ functional materials,² and as synthetic blocks of organophosphorus compounds.³ Some reviews have documented the preparations and applications of the vinyl phosphorus.⁴ Normally, the compounds can be acquired from alkynes, via the addition with H–P species. Aromatic ketones and aldehydes are also used as the sources of vinyl phosphorus, via multi-step conversions.^1b,5 The recently developed methods to obtain vinyl phosphorus involving H–P species include decarboxylation of cinnamic acid,⁶ dehydrogenation of active alkene,⁷ and dehydration of alcohols.⁸

The addition of H–P species to alkynes is undoubtedly the most effective and atom economical method. The addition was usually catalysed by metals.^4e,9 One of the authors has reported palladium and rhodium catalysed additions of H–P species to alkynes.^9a–d Similar additions could be realized by catalysis with copper, nickel, molybdenum and ytterbium (Chart 1).¹⁰ The metal-catalysed procedures also include Suzuki reaction and others.¹¹ Although much progress has been made in this area, problems associated with narrow substrate scope, the need to use expensive transition metals and a stoichiometric amount of additives, and poor regio- and stereo-control have encouraged researchers to search for new and more efficient methods.

Chart 1 Comparison of the construction of C(sp²)–P bonds to our current work.

Recently, triflic anhydride (Tf₂O) has been applied for electrophilic activation of amides and P=O species, and the activated intermediates could be used for the substitutions with various nucleophilic reagents.^7b,12 The conversions of P=O species to C(sp²)–P bonds are quite rare. Miura and coauthors have reported a Tf₂O promoted activation of secondary phosphine oxides, which is applied for phosphination and intramolecular cyclization with alkynes.¹³ However, the scopes are limited with inner-alkynes. The application of H-phosphonates was not reported for the reaction (Chart 1).

Herein we enclosed a novel Tf₂O promoted reaction of terminal alkyne with H-phosphonates. Vinyl phosphonates were afforded under metal- and solvent-free conditions, in excellent Markovnikov-regio selectivity.

Phenylacetylene (1a) was initially treated with diethyl phosphite (2a) in the presence of Tf₂O in a molar ratio of 1 : 1 : 1. To our delight, diethyl 1-phenyl ethenylphosphonate (3aa), a Markovnikov addition product, was obtained in high regio-selectivity but in poor yield (10%). The reaction conditions were subsequently optimized with 1a and 2a. Considering Tf₂O was moisture sensitive, all experiments were performed under nitrogen. Two equivalents 2a was used to ensure 1a was consumed as much as possible. The conversion and isolated yield were calculated based on 1a (Table 1).

Table 1 Optimization of reaction conditions^a

Entry	Molar ratio of 1a/2a/Cat	Base	Temp.	Solvent (1 mL)	Conversion% (isolated yield%)^b
a Reaction conditions: 1a (0.2 mmol), 2a (0.40 mmol) and Tf2O (0.2 mmol) stirring at different temperatures for 24 h.b The conversions were estimated based on ^1H NMR spectrum, and isolated yields were calculated based on 1a.c TfOH was used.d 1.0 equiv. of base was used.
1	1 : 2 : 1	—	Rt	—	12
2	1 : 2 : 1	—	40 °C	—	46
3	1 : 2 : 1	—	60 °C	—	92
4	1 : 2 : 1	—	65 °C	—	98 (53)
5	1 : 2 : 1	—	80 °C	—	98 (56)
6	1 : 2 : 0.5	—	65 °C	—	79
7	1 : 2 : 0.8	—	65 °C	—	92
8	1 : 2 : 1.2	—	65 °C	—	86
9	1 : 2 : 1	—	65 °C	—	0^c
10	1 : 2 : 1	—	65 °C	CH2Cl2	3
11	1 : 2 : 1	—	65 °C	Toluene	9
12	1 : 2 : 1	—	65 °C	THF	0
13	1 : 2 : 1	—	65 °C	EtOAc	22
14	1 : 2 : 1	Na2CO3	65 °C	—	0^d
15	1 : 2 : 1	Pyridine	65 °C	—	99 (64)^d
16	1 : 2 : 1	2,6-Lutidine	65 °C	—	99 (54)^d
17	1 : 2 : 1	DBU	65 °C	—	99 (64)^d

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When the mixture of 1a, 2a and Tf₂O was stirred at room temperature, a new signal at 17.1 ppm was observed on ³¹P NMR spectrum. The two doublet peaks at 6.35 and 6.17 ppm on proton NMR spectrum, assigned as 3aa, was detected in 12% (entry 1 of Table 1). The conversion of 1a was improved to 46% when the reaction was carried out at 40 °C, and to 92% at 60 °C (entries 2 and 3). At 65 °C, the conversion was detected in 98%, and 3aa was isolated, whose structure was confirmed by NMR spectrum.¹⁴ The conversion cannot be further improved at higher temperature such as 80 °C.

When 0.5 equiv. Tf₂O was used, the conversion of 1a was dropped to 79%. The usage of 0.8 equivalent of Tf₂O led 92% conversion (entries 6 and 7). However, excessive Tf₂O, such as 1.2 equivalents, resulted in the reduced conversion (86%, entry 8).

Once triflic acid was used to replace Tf₂O, 3aa was not detected (entry 9).

To carry the reaction in some solvent such as dichloromethane, toluene, THF or ethyl acetate, gave worse result than neat condition (entries 10–13). In the presence of sodium carbonate, the reaction cannot take place (entry 14). The presence of pyridine, 2,6-lutidine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) slightly increased the conversion (entries 15–17).

Adopting the above optimized condition, the reaction of alkyne with H-phosphonate was performed (Table 2). Dimethyl phosphite 2b reacted with phenylacetylene to afford dimethyl 1-phenylethenyl phosphonate 3ab in 43% yield, which was less than the reaction of 2a. Perhaps due to the bigger spatial hindrance, diisopropyl phosphite 2c did not reacted with 1a to afford 3ac. The reactions of diphenylphosphine oxide or ethyl phenylphosphinate cannot occur.

Table 2 Reactivity of phenylacetylene and H-phosphonates

a Isolated yields based on 1a.

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Various terminal alkynes was then examined (Table 3). Besides of 1a, aromatic alkynes possessing electron-donating groups smoothly reacted with 2a to afford corresponding 3ba–3ha in 17–62% yields. The low yield of 3ha may be ascribed to meta-methyl that had variable electronic effect. For chloro and bromo-substituted alkynes, 3ia and 3ja were afforded in 56% and 46% yields, respectively. Perhaps due to steric hindrance, the ortho-chlorophenyl ethyne gave lower yield of 3 than para-substituted alkyne.

Table 3 Scope of alkynes^a

a Isolated yield.b Two equivalents of Tf₂O were used.c The alkyne/P–H regent/Tf₂O/pyridine were used in the molar ratio of 1 : 4 : 2 : 2.

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Some ethynyl heterocycles, such as 2- or 3-ethynylthiophene could be employed for the reaction, affording 3la or 3ma, respectively. For 1,4-diethynylbenzene (1n), the addition was realized when 2a and Tf₂O were used in double equivalents. However, the alkynes having strong EWG, such as trifluoromethyl or 3-pyridinyl, cannot react with 2a. Aliphatic terminal alkynes, such as 1-octyne, also did not afford the product.

The mechanism of the reaction was studied via in situ NMR experiments, and was proposed in Scheme 1. 2a and Tf₂O formed triflate 4 of phosphite via an equilibrium.^12b,15 Meanwhile, triflic acid was generated (step 1). The addition of triflic acid to 1a formed 1-phenylvinyl triflate 5 as an intermediate (step 2). The subsequent nucleophilic substitution of 5 with 4 formed vinyl phosphonate 3aa (step 3).

Scheme 1 Proposed mechanism.

The step 1 was confirmed by the observation of the signal of acidic proton in TfOH during the mixing of 2a with Tf₂O (Fig. 1A). When 1a was added, 5 was detected, as seen the two doublet peaks at 5.61 and 5.38 ppm on ¹H NMR spectrum (step 2 and Fig. 1B). When the mixture was heated at 60 °C, the signals of 3aa at 6.16–6.37 ppm emerged. The peaks were increased with prolonged heating, accompanied with the decreasing of the signals of 5 (step 3, Fig. 1C and D). Similar results were observed when Tf₂O was initially mixed with 1a (Fig. 1E–H). After heating at 60 °C for 8 h, the signals of 1a, respected by the peak of terminal alkyne at 3.07 ppm, were disappeared (Fig. 1H).

Fig. 1 The results of in situ NMR experiments of the reaction of 1a with 2a in the presence of triflic anhydride.

The addition of triflic acid to 1a probably formed α-carbon ion as intermediate, which could be stabilized by phenyl and be converted to Markovnikov-product 5. Although the nucleophilic substitution on vinyl carbon was difficulty, the strong leaving activity of trifluoromethanesulfonyloxy on 5 enabled step 3 occurred. Miura proposed a cyclic phosphirenium intermediate for the addition and cyclization,¹³ which could be probably stabilized by the alkyl groups of inner-alkynes and secondary phosphine oxides. In our case, the electron-withdrawing alkoxyl on phosphorus of 2a was not favorable for the formation of the phosphirenium, thus the reaction proceeded via α-carbon ion and addition–substitution occurred.

TfOH was necessary to the formation of 5 from 2a (step 2). However, triflic acid cannot sole promote the reaction, as seen in entry 9 of Table 1. The results indicated the poor nucleophilic ability of 2a. After 2a was converted to P(III) species 4 by triflic anhydride, the lone electron pair on phosphorus of 4 could attack 5 to form the product. It was not sure the small quartet peak at 4.62 ppm belonged to 4 (Fig. 1F). On ³¹P NMR spectrum, the peak of 2a at 17.0 ppm obviously became broad in poor resolution when mixed with triflic anhydride (as seen in ESI†). The results also supported the equilibrium between 2a and 4 (step 1).

Conclusions

In summary, a mild and convenient method to generate vinylphosphonates was developed. The method employed aryl alkynes and H-phosphonates, was performed under metal- and solvent-free conditions, and afforded Markovnikov-adducts as single regio-isomer. This methodology was compatible with a wide range of aryl alkynes. On the basis of in situ ¹H NMR studies, an addition–substitution mechanism was proposed, which was different to the reported phosphirenium mechanism.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This study was financially supported by NSFC (21502084, 21401094) and Liaocheng University (318051437).

Notes and references

1. For example, see: (a) R. Parmar, J. L. S. Willoughby, J. Liu, D. J. Foster, B. Brigham, C. S. Theile, K. Charisse, A. Akinc, E. Guidry, Y. Pei, W. Strapps, M. Cancilla, M. G. Stanton, K. G. Rajeev, L. S. Lorenzino, M. Manoharan, R. Meyers, M. A. Maier and V. Jadhav, ChemBioChem, 2016, 17, 985–989; (b) X. Q. Lu, C. D. Sun, W. J. Valentine, S. E, J. X. Liu, G. Tigyi and R. Bittman, J. Org. Chem., 2009, 74, 3192–3195; (c) R. D. Bertram, C. J. Hayes and P. Soultanas, Biochemistry, 2002, 41, 7725–7731.
2. For example, see: (a) B. S. Soller, S. Salzinger and B. Rieger, Chem. Rev., 2016, 116, 1993–2002; (b) C. Queffélec, M. Petit, P. Janvier, D. A. Knight and B. Bujoli, Chem. Rev., 2012, 112, 3777–3807; (c) G. David and C. Negrell-Guirao, in Phosphorus-Based Polymers: from Synthesis to Applications, RSC Polymer Chemistry Series, ed. S. Monge and G. David, Royal Society of Chemistry, United Kingdom, 2014, vol. 11, pp 35–50.
3. For example, see: (a) L. J. Ren, M. G. Ran, J. X. He, D. Xiang, F. Chen, P. J. Liu, C. Y. He and Q. L. Yao, Eur. J. Org. Chem., 2019, 33, 5656–5661; (b) A. K. Chaturvedi and N. Rastogi, J. Org. Chem., 2016, 81, 3303–3312; (c) K. W. Dong, Z. Wang and K. L. Ding, J. Am. Chem. Soc., 2012, 134, 12474–12477; (d) H. Ishikawa, M. Honma and Y. Hayashi, Angew. Chem., Int. Ed., 2011, 50, 2824–2827; (e) S. S. Mossé, M. Tissot and A. Alexakis, Org. Lett., 2007, 9, 3749–3752.
4. For example, see: (a) D. S. Glueck, J. Org. Chem., 2020, 85, 14276–14285; (b) Q. Xu, C.-Q. Zhao, Y. Zhou, S. Yin and L.-B. Han, Chin. J. Org. Chem., 2012, 32, 1761–1775; (c) S. Van der Jeught and C. V. Stevens, Chem. Rev., 2009, 109, 2672–2702; (d) A. L. Schwan, Chem. Soc. Rev., 2004, 33, 218–224; (e) I. P. Beletskaya, C. Nájera and M. Yus, Russ. Chem. Rev., 2021, 90, 70–93.
5. N. S. Goulioukina, T. M. Dolgina, I. P. Beletskaya, J.-C. Henry, D. Lavergne, V. Ratovelomanana-Vidal and J.-P. Genet, Tetrahedron: Asymmetry, 2001, 12, 319–327.
6. L. X. Liu, D. Zhou, J. Y. Dong, Y. B. Zhou, S.-F. Yin and L.-B. Han, J. Org. Chem., 2018, 83, 4190–4196.
7. (a) A.-X. Zhou, L.-L. Mao, G.-W. Wang and S.-D. Yang, Chem. Commun., 2014, 50, 8529–8532; (b) T. Yuan, S. L. Huang, C. Cai and G.-P. Lu, Org. Biomol. Chem., 2018, 16, 30–33; (c) L.-L. Liao, Y.-Y. Gui, X.-B. Zhang, G. Shen, H.-D. Liu, W.-J. Zhou, J. Li and D.-G. Yu, Org. Lett., 2017, 19, 3735–3738.
8. P. Z. Xie, J. Fan, Y. N. Liu, X. Y. Wo, W. S. Fu and T.-P. Loh, Org. Lett., 2018, 20, 3341–3344.
9. (a) T. Q. Chen, C.-Q. Zhao and L.-B. Han, J. Am. Chem. Soc., 2018, 140, 3139–3155; (b) L.-B. Han, C.-Q. Zhao, S.-Y. Onozawa, M. Goto and M. Tanaka, J. Am. Chem. Soc., 2002, 124, 3842–3843; (c) L.-B. Han, C.-Q. Zhao and M. Tanaka, J. Org. Chem., 2001, 66, 5929–5932; (d) C.-Q. Zhao, L.-B. Han, M. Goto and M. Tanaka, Angew. Chem., Int. Ed., 2001, 40, 1929–1932; (e) S. K. Nune and M. Tanaka, Chem. Commun., 2007, 2858–2860; (f) L.-B. Han and M. Tanaka, J. Am. Chem. Soc., 1996, 118, 1571–1572.
10. (a) I. G. Trostyanskaya and I. P. Beletskaya, Tetrahedron, 2014, 70, 2556–2562; (b) M. Y. Niu, H. Fu, Y. Y. Jiang and Y. F. Zhao, Chem. Commun., 2007, 272–274; (c) V. P. Ananikov, L. L. Khemchyan, I. P. Beletskaya and Z. A. Starikova, Adv. Synth. Catal., 2010, 352, 2979–2992; (d) L.-B. Han, C. Zhang, H. Yazawa and S. Shimada, J. Am. Chem. Soc., 2004, 126, 5080–5081; (e) A. I. Kuramshin, A. A. Nikolaev and R. A. Cherkasov, Mendeleev Commun., 2005, 15, 155–156; (f) K. Takaki, M. Takeda, G. Koshoji, T. Shishido and K. Takehira, Tetrahedron Lett., 2001, 42, 6357–6360.
11. (a) L. Zhang, Y. W. Fang, X. P. Jin, H. S. Xu, R. F. Li, H. Wu, B. Chen, Y. M. Zhu, Y. Yang and Z. M. Tian, Org. Biomol. Chem., 2017, 15, 8985–8989; (b) A. N. Barrett, H. J. Sanderson, M. F. Mahon and R. L. Webster, Chem. Commun., 2020, 56, 13623–13626.
12. (a) D. Kaiser and N. Maulide, J. Org. Chem., 2016, 81, 4421–4428; (b) H. Huang and J. Y. Kang, Synlett, 2019, 30, 635–641; (c) H. Huang, J. Denne, C.-H. Yang, H. B. Wang and J. Y. Kang, Angew. Chem., Int. Ed., 2018, 57, 6624–6628.
13. Y. Unoh, K. Hirano and M. Miura, J. Am. Chem. Soc., 2017, 139, 6106–6109.
14. D.-Y. Wang, X.-P. Hu, J. Deng, S.-B. Yu, Z.-C. Duan and Z. Zheng, J. Org. Chem., 2009, 74, 4408–4410.
15. (a) B. G. Janesko, H. C. Fisher, M. J. Bridle and J.-L. Montchamp, J. Org. Chem., 2015, 80, 10025–10032; (b) N. N. Xin, X. Y. Xie, C.-Q. Zhao, X. Q. Huang, J. H. Zhang, J.-Y. Du, J. Yang and C. L. Ma, Synlett, 2018, 29, 1219–1222.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/d1ra04306d

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