Metal-free direct difunctionalization of alkenes with I₂O₅ and P(O)–H compounds leading to β-iodophosphates

Abstract

A novel and efficient procedure for direct difunctionalization of alkenes with I₂O₅ and P(O)–H compounds has been developed under metal-free conditions. The present methodology produces a series of substituted β-iodophosphates in moderate to good yields with high regioselectivity and favorable functional group tolerance.

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Alkenes are inexpensive and readily available chemical feedstocks and organic reactants, in which difunctionalization represents a class of reactions with significant synthetic potential accessing many useful and fascinating compounds.¹ In recent years, many transition-metal-catalyzed difunctionalizations of alkenes have been developed, such as diamination,² dioxygenation,³ aminooxygenation,⁴ oxyphosphorylation,⁵ and aminohalogenation.⁶ Nevertheless, the cost, toxicity and environmental impact of these metal-catalysts might thereby limit their applications on a large scale in the field of organic synthesis and pharmaceutical chemistry. The development of a convenient and efficient strategy for difunctionalization of alkenes via a metal-free process has become a challenging but highly attractive target. Despite great efforts being made in this field over the past several years, successful metal-free strategies are considerably fewer than their transition metal-based counterparts.⁷ With our continuous interest in metal-free difunctionalization of alkenes,⁸ here, we seek to develop a novel and convenient procedure for direct iodophosphorylation of alkenes with I₂O₅ and P(O)–H compounds leading to β-iodophosphates under metal-free conditions.

Organophosphates have attracted great interest from chemists and physiologists because they play significant roles in drug discovery⁹ and many major physiological processes such as energy transfer and regulation of ion release.¹⁰ They have also been extensively studied in various organic transformations¹¹ and many agrochemicals such as insecticides and herbicides.¹² Due to the prominent importance of these compounds in synthetic chemistry and molecular biology, various synthesis methods have been developed,^13–21 most known are the methods using the nucleophilic substitution reactions of alcohols with highly air-sensitive and hazardous P(O)–Cl compounds in the presence of a base¹⁴ or transesterification of phosphate esters¹⁵ or phosphorylation of alcohols with N-phosphoryloxazolidinones¹⁶ (eqn (1)). Alternative preparation methods such as the reactions of phosphoramidites with the requisite alcohol followed by subsequent oxidation,¹⁷ base mediated phospha-Brook rearrangement,¹⁸ I₂/H₂O₂ mediated phosphorylation of alcohols with P(O)–H compounds (eqn (2)),¹⁹ and copper-catalyzed aerobic oxidative esterification of P(O)–OH compounds with alcohols or diaryliodonium triflates²⁰ (eqn (3)) have also been developed. However, most of them could suffer from some limitations such as inaccessible starting materials, relatively harsh reaction conditions, poor substrate scope, and use of a large amount of promoters or transition-metal catalysts. Recently, Tang and co-workers described a metal-free Bu₄NI-catalyzed phosphorylation of benzyl C–H bonds leading to phosphate esters using TBHP as an oxidant (eqn (4)).²¹ Nevertheless, the substrate scope of this well developed reaction could be limited to toluene derivatives only. In the present work, a convenient and metal-free procedure has been developed for the synthesis of various β-iodophosphates from diverse and readily-available alkenes and P(O)–H compounds with high regioselectivity and favorable functional group tolerance (eqn (5)).

In an initial experiment, styrene 1a and diphenylphosphine oxide 2a were chosen as model substrates to optimize the reaction conditions in air. To our delight, among the various iodine reagents tested, I₂O₅ was found to be the optimal iodine source for the formation of the desired 3aa (80% yield) in the presence of TBHP (Table 1, entries 1–5), which was further demonstrated to be the best oxidant (Table 1, entries 5–10). Moreover, the screening of solvents showed that 1,4-dioxane was more effective than the others such as THF, DME, DCE, and CH₃CN (Table 1, entries 5, 11–14). Interestingly, no conversion was observed when the reaction was performed in toluene, DMF, and DMSO (Table 1, entries 15–17). Also, the reaction efficiency was obviously low with the decreasing of I₂O₅ loading and reaction temperature (Table 1, entries 18–20). In addition, no product was detected when the reaction was conducted in the absence of I₂O₅ or at room temperature (Table 1, entries 18 and 21). After an extensive screening of the reaction parameters, the best yield of 3aa (80%) was obtained by employing 1.0 equiv. of I₂O₅ and 1.2 equiv. of TBHP in 1,4-dioxane at 80 °C (Table 1, entry 5).

Table 1 Optimization of the reaction conditions^a

Entry	Iodine reagent	Oxidant	Solvent	Yield^b (%)
a Reaction conditions: 1a (0.25 mmol), 2a (0.5 mmol), iodine reagent (0.25 mmol), oxidant (0.3 mmol), solvent (2 mL), 80 °C, 16 h. TBAI = (n-Bu)4NI; DME: 1,2-dimethoxyethane, DCE: 1,2-dichloroethane; TBHP: tert-butyl hydroperoxide, 5.5 M in decane, DTBP: di-tert-butyl peroxide, oxone: (2KHSO5·KHSO4·K2SO4). b Isolated yields based on 1a. c I2O5 (0.5 equiv.). d I2O5 (1.5 equiv.). e 25 °C. f 60 °C.
1	KI	TBHP	1,4-Dioxane	0
2	NaI	TBHP	1,4-Dioxane	0
3	I2	TBHP	1,4-Dioxane	0
4	TBAI	TBHP	1,4-Dioxane	0
5	I2O5	TBHP	1,4-Dioxane	80
6	I2O5	DTBP	1,4-Dioxane	68
7	I2O5	K2S2O8	1,4-Dioxane	23
8	I2O5	(NH4)S2O8	1,4-Dioxane	Trace
9	I2O5	Na2S2O8	1,4-Dioxane	Trace
10	I2O5	Oxone	1,4-Dioxane	43
11	I2O5	TBHP	THF (reflux)	58
12	I2O5	TBHP	DME	40
13	I2O5	TBHP	DCE	26
14	I2O5	TBHP	CH3CN	42
15	I2O5	TBHP	Toluene	0
16	I2O5	TBHP	DMF	0
17	I2O5	TBHP	DMSO	0
18	—	TBHP	1,4-Dioxane	0
19	I2O5	TBHP	1,4-Dioxane	61^c
20	I2O5	TBHP	1,4-Dioxane	79^d
21	I2O5	TBHP	1,4-Dioxane	0^e
22	I2O5	TBHP	1,4-Dioxane	71^f

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With the optimized conditions in hand, the scope and generality of this reaction was investigated. As shown in Table 2, both electron-rich and electron-deficient aromatic alkenes were suitable for this reaction, of which the corresponding products were obtained in moderate to good yields (3aa–3la). The reaction was not significantly affected by the steric effect. The ortho-, meta- or para-position of the phenyl moieties was compatible with this reaction (3ba–3ga). Moreover, various functionalities including halogen, chloromethyl, nitro, and cyano groups were also tolerated in this reaction leading to the products 3ea–3la, which could be employed for further transformations. 2-Vinylnaphthalene was also used to give the desired product 3ma in 71% yield. Notably, an internal aromatic alkene such as (E)-prop-1-enylbenzene and aliphatic alkenes such as 1-octene, cyclohexene, ethyl acrylate and N,N-diallyl-4-methylbenzenesulfonamide were also suitable for this protocol to generate the corresponding products (3na–3ra) in moderate to good yields. In addition to diphenylphosphine oxide, substituted diphenylphosphine oxide, diethyl phosphonates, and dibutyl phosphonates were all suitable substrates, with the corresponding products 3ab–3ad in moderate to good yields.

Table 2 Results for metal-free difunctionalization of alkenes with I₂O₅ and P(O)–H compounds^a,b

a Reaction conditions: 1 (0.25 mmol), 2 (0.5 mmol), I₂O₅ (0.25 mmol), TBHP (0.3 mmol), 1,4-dioxane (2 mL), 80 °C, 16–24 h. b Isolated yields based on 1. c 2 (0.75 mmol).

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In order to obtain further insights into this reaction, several control experiments were conducted as demonstrated in eqn (6)–(9). When the reaction of diethyl phosphonate 2d with I₂O₅ was conducted in the absence of styrene, the corresponding diethyl hydrogen phosphate 4d was obtained in 48% yield (eqn (6)). Meanwhile, the formation of molecular iodine was confirmed by observation of an obvious color change from gray to deep blue when starch was added into the above reaction system.²² When the reaction of styrene 1a with 2d was conducted in the I₂/TBHP system, the desired product 3ad was not detected (eqn (7)). Furthermore, the desired product 3ad was isolated in 62% yield, when the reaction of styrene 1a with 4d was performed in the presence of the I₂/TBHP system (eqn (8)). The above results indicated that I₂O₅ played a key role in the formation of diethyl hydrogen phosphate 4d, which was the key intermediate in this difunctionalization reaction. Moreover, the iodophosphorylation reaction was completely inhibited when 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO, a well-known radical scavenger) was added in this reaction system, and a TEMPO-trapped complex (Ph₂P(O)–O-Tempo) was detected by LC-MS analysis (see the ESI†). This result suggested that a P(O)–O radical might exist in this reaction system and the present reaction should proceed through a radical pathway (eqn (9)).

According to the aforementioned information and based on some previous reports,^22–24 a possible reaction pathway for this transformation is outlined in Scheme 1. Initially, the oxidation of R₂P(O)–H compound 2 with I₂O₅ would produce the corresponding R₂P(O)–OH 4 and I₂. Subsequently, a radical intermediate 5 was formed by the interaction of R₂P(O)–OH 4 with an alkoxyl radical and a hydroxyl radical, which were generated from a homolytic cleavage of tert-butyl hydroperoxide.^23,24 Next, selective addition of radical 5 to alkene 1 afforded alkyl radical 6, which further interacted with molecular iodine leading to the formation of the desired product 3.

Scheme 1 Tentative reaction pathway.

In conclusion, we have developed a novel and efficient metal-free synthesis method for the construction of β-iodophosphates via the direct difunctionalization of alkenes with I₂O₅ and P(O)–H compounds. A variety of biologically important phosphate esters could be obtained in moderate to good yields from readily-available starting materials of alkenes with high regioselectivity and excellent functional group tolerance. This simple and metal-free reaction system is expected to extend the potential applications of functionalized organophosphates in the synthetic and pharmaceutical chemistry.

This work was supported by the National Natural Science Foundation of China (no. 21302109, 21302110, and 21375075), the Taishan Scholar Foundation of Shandong Province, the Natural Science Foundation of Shandong Province (ZR2015JL004), and the Excellent Middle-Aged and Young Scientist Award Foundation of Shandong Province (BS2013YY019).

References

1. For selected reviews, see: (a) P. A. Sibbald, Palladium-catalyzed oxidative difunctionalization of alkenes: New reactivity and new mechanisms, ProQuest UMI Dissertation Publishing, Ann Arbor, MI, 2011; (b) B. Jacques and K. Muinz, in Catalyzed carbon-heteroatom bond formation, ed. A. K. Yudin, Wiley, VCH, Weinheim, Germany, 2011; (c) R. I. McDonald, G. Liu and S. S. Stahl, Chem. Rev., 2011, 111, 2981; (d) K. H. Jensen and M. S. Sigman, Org. Biomol. Chem., 2008, 6, 4083.
2. For selected diamination, see: (a) G. L. J. Bar, G. C. Lloyd-Jones and K. I. Booker-Milbum, J. Am. Chem. Soc., 2005, 127, 7308; (b) H. Du, B. Zhao and Y. A. Shi, J. Am. Chem. Soc., 2007, 129, 762; (c) H. Du, W. Yuan, B. G. Zhao and Y. A. Shi, J. Am. Chem. Soc., 2007, 129, 11688; (d) P. A. Sibbald and F. E. Michael, Org. Lett., 2009, 11, 1147.
3. For selected dioxygenation, see: (a) C. J. R. Bataille and T. J. Donohoe, Chem. Soc. Rev., 2011, 40, 114; (b) Q. Xue, J. Xie, P. Xu, K. Hu, Y. Cheng and C. Zhu, ACS Catal., 2013, 3, 1365; (c) V. A. Schmidt and E. J. Alexanian, Angew. Chem., Int. Ed., 2010, 49, 4491; (d) B. C. Giglio, V. A. Schmidt and E. J. Alexanian, J. Am. Chem. Soc., 2011, 133, 13320; (e) A. Wang, H. Jiang and H. Chen, J. Am. Chem. Soc., 2009, 131, 3846; (f) G. A. Abeykoon, S. Chatterjee and J. S. Chen, Org. Lett., 2014, 16, 3248; (g) X.-F. Xia, S.-L. Zhu, Z. Gu, H. Wang, W. Li, X. Liu and Y.-M. Liang, J. Org. Chem., 2015, 80, 5572.
4. (a) G. Liu and S. S. Stahl, J. Am. Chem. Soc., 2006, 128, 7179; (b) P. H. Fuller, J.-W. Kim and S. R. Chemler, J. Am. Chem. Soc., 2008, 130, 17638; (c) M. C. Paderes, J. B. Keister and S. R. Chemler, J. Org. Chem., 2013, 78, 506.
5. (a) W. Wei and J. Ji, Angew. Chem., Int. Ed., 2011, 50, 9097; (b) S.-F. Zhou, D.-P. Li, K. Liu, J.-P. Zou and O. T. J. Asekun, Org. Chem., 2015, 80, 1214.
6. (a) T. Wu, G. Yin and G. Liu, J. Am. Chem. Soc., 2009, 131, 16354; (b) S. Qiu, T. Xu, J. Zhou, Y. Guo and G. Liu, J. Am. Chem. Soc., 2010, 132, 2856; (c) S. R. Chemler and M. T. Bovino, ACS Catal., 2013, 3, 1076; (d) X. Ji, H. Huang, W. Wu and H. Jiang, J. Am. Chem. Soc., 2013, 135, 5286.
7. (a) R. N. Reddi, P. K. Prasad and A. Sudalai, Org. Lett., 2014, 16, 5674; (b) Q. Xue, J. Xie, P. Xu, K. Hu, Y. Cheng and C. Zhu, ACS Catal., 2013, 3, 1365; (c) L. Huang, S.-C. Zheng, B. Tan and X.-Y. Liu, Org. Lett., 2015, 17, 1589; (d) B. Zhang and A. Studer, Org. Lett., 2013, 15, 4548; (e) B. C. Giglio, V. A. Schmidt and E. J. Alexanian, J. Am. Chem. Soc., 2011, 133, 13320; (f) Y. Li, M. Hartmann, C. G. Daniliuc and A. Studer, Chem. Commun., 2015, 51, 5706; (g) Y.-M. Li, X.-H. Wei, X.-A. Li and S.-D. Yang, Chem. Commun., 2013, 49, 11701; (h) V. A. Schmidt and E. J. Alexanian, Chem. Sci., 2012, 3, 1672; (i) V. A. Schmidt and E. J. Alexanian, J. Am. Chem. Soc., 2011, 133, 11402; (j) K. M. Jones and N. C. O. Tomkinson, J. Org. Chem., 2012, 77, 921; (k) Q. Liu, Q. Y. Zhao, J. Liu, P. Wu, H. Yi and A. Lei, Chem. Commun., 2012, 48, 3239; (l) Y. Kang and L. H. Gade, J. Am. Chem. Soc., 2011, 133, 3658.
8. (a) W. Wei, J. Wen, D. Yang, J. Du, J. You and H. Wang, Green Chem., 2014, 16, 2988; (b) W. Wei, J. Wen, D. Yang, X. Liu, M. Guo, R. Dong and H. Wang, J. Org. Chem., 2014, 79, 4225; (c) W. Wei, X. Liu, D. Yang, R. Dong, Y. Cui, F. Yuan and H. Wang, Tetrahedron Lett., 2015, 56, 1808.
9. (a) C. Schultz, Bioorg. Med. Chem., 2003, 11, 885; (b) C. Anastasi, G. Quelever, S. Burlet, C. Garino, F. Souard and J. L. Kraus, Curr. Med. Chem., 2003, 10, 1825; (c) C. Ducho, U. Görbig, S. Jessel, N. Gisch, J. Balzarini and C. Meier, J. Med. Chem., 2007, 50, 1335; (d) S. J. Hecker and M. D. Erion, J. Med. Chem., 2008, 51, 2328; (e) M. S. Markoulides and A. C. Regan, Tetrahedron Lett., 2011, 52, 2954; (f) U. Pradere, E. C. Garnier-Amblard, S. J. Coats, F. Amblard and R. F. Schinazi, Chem. Rev., 2014, 114, 9154.
10. (a) L. D. Quin, in A Guide to Organophosphorus Chemistry, Wiley-Interscience, New York, 2000, pp. 351–357; (b) J. C. Tebby, D. W. Allen, D. Loakes and R. Pajkert, Organophoshorus Chemistry, RSC, Cambridge, 2010, vol. 39; (c) H. F. Westheimer, Science, 1987, 235, 1173; (d) S. J. Hecker and M. D. Erion, J. Med. Chem., 2008, 51, 2328; (e) J. Rautio, H. Kumpulainen, T. Heimbach, R. Oliyai, D. Oh, T. Järvinen and J. Savolainen, Nat. Rev. Drug Discovery, 2008, 7, 255.
11. (a) S. Protti and M. Fagnoni, Chem. Commun., 2008, 3611. Cross coupling reactions: (b) M. McLaughlin, Org. Lett., 2005, 7, 4875; (c) C. C. Kofink and P. Knochel, Org. Lett., 2006, 8, 4121; (d) P. Zhang, J. Xu, Y. Gao, X. Li, G. Tang and Y. Zhao, Synlett, 2014, 2928. Alcohol to azide: (e) C. Yu, B. Liu and L. Hu, Org. Lett., 2000, 2, 1959; (f) Q. Zhu and M. S. Tremblay, Bioorg. Med. Chem. Lett., 2006, 16, 6170; (g) S.-Y. Ji, Y.-M. Sun, H. Zhang, Q.-G. Hou and C.-Q. Zhao, Tetrahedron Lett., 2014, 55, 5742.
12. (a) R. Neumann and H. H. Peter, Experientia, 1987, 43, 1235; (b) W. H. He, Phosphorus, Sulfur Silicon Relat. Elem., 2008, 183, 266; (c) J. Wink, F. R. Schmidt, G. Seibert and W. Aretz, J. Antibiot., 2002, 55, 472; (d) L. Vìrtesy, B. Beck, M. Brönstrup, K. Ehrlich, M. Kurz, G. Mûller, D. Schummer and G. Seibert, J. Antibiot., 2002, 55, 480; (e) T. Kiely, D. Donaldson and A. Grube, EPA-733-R-04-001, Office of Pesticide Programs, U.S. Environmental Protection Agency, Washington, DC, 2004.
13. (a) L. D. Quin, in A Guide to Organophosphorus Chemistry, Wiley-Interscience, New York, 2000, p. 351; (b) J. C. Tebby, D. W. Allen, D. Loakes and R. Pajkert, Organophoshorus Chemistry, RSC, Cambridge, 2010, vol. 39; (c) L. A. Slotin, Synthesis, 1977, 737; (d) T. Wang, S. Chen, A. Shao, M. Gao, Y. Huang and A. Lei, Org. Lett., 2015, 17, 118; (e) J. Ke, Y. Tang, H. Yi, Y. Li, Y. Cheng, C. Liu and A. Lei, Angew. Chem., Int. Ed., 2015, 54, 6604.
14. (a) K. A. Pollart and H. J. Harwood, J. Org. Chem., 1962, 27, 4444; (b) Y. Segall, E. Shirin and I. Granoth, Phosphorus, Sulfur Silicon Relat. Elem., 1980, 8, 243; (c) M. J. P. Harger and S. Westlake, Tetrahedron, 1982, 38, 1511; (d) M. Hatano, T. Mizuno and K. Ishihara, Chem. Commun., 2010, 46, 5443; (e) M. Sathe, A. K. Gupta and M. P. Kaushik, Tetrahedron Lett., 2006, 47, 3107; (f) S. Pisarek, H. Bednarski and D. Gryko, Synlett, 2012, 2667.
15. R. Singh and S. P. Nolan, Chem. Commun., 2005, 5456.
16. S. Jones and C. Smanmoo, Org. Lett., 2006, 7, 3271.
17. (a) J. W. Perich and R. B. Johns, Tetrahedron Lett., 1987, 28, 101; (b) J. K. Stowell and T. S. Widlanski, Tetrahedron Lett., 1995, 36, 1825; (c) V. B. Oza and R. C. Corcoran, J. Org. Chem., 1995, 60, 3680.
18. G. Pallikonda, R. Santosh, S. Ghosal and M. Chakravarty, Tetrahedron Lett., 2015, 56, 3796 and references in.
19. J. Dhineshkumar and K. R. Prabhu, Org. Lett., 2013, 15, 6062.
20. B. Xiong, X. Feng, L. Zhu, T. Chen, Y. Zhou, C.-T. Au and S.-F. Yin, ACS Catal., 2015, 5, 537.
21. J. Xu, P. Zhang, X. Li, Y. Gao, J. Wu, G. Tang and Y. Zhao, Adv. Synth. Catal., 2014, 356, 3331.
22. (a) K. C. Nicolaou, T. Montagnon and P. S. Baran, Angew. Chem., Int. Ed., 2002, 41, 1386; (b) L. Chai, Y. Zhao, Q. Sheng and Z.-Q. Liu, Tetrahedron Lett., 2006, 47, 9283; (c) Z.-Q. Liu, Y. Zhao, H. Luo, L. Chai and Q. Sheng, Tetrahedron Lett., 2007, 48, 3017; (d) Z. Hang, Z. Li and Z.-Q. Liu, Org. Lett., 2014, 16, 3648; (e) L. Zhang, Z. Li and Z.-Q. Liu, Org. Lett., 2014, 16, 3688; (f) J. Wen, W. Wei, S. Xue, D. Yang, Y. Lou, C. Gao and H. Wang, J. Org. Chem., 2015, 80, 4966.
23. (a) L. S. Silbert, J. Am. Oil Chem. Soc., 1969, 46, 615; (b) E. Shi, S. Chen, S. Chen, H. Hu, S. Chen, J. Zhang and X. Wan, Org. Lett., 2012, 14, 3384; (c) Q. Xue, J. Xie, P. Xu, K. Hu, Y. Cheng and C. Zhu, ACS Catal., 2013, 3, 1365; (d) S. Tang, Y. Wu, W. Liao, R. Bai, C. Liu and A. Lei, Chem. Commun., 2014, 50, 4496; (e) D. Liu and A. Lei, Chem. – Asian J., 2015, 10, 806; (f) S. Tang, K. Liu, Y. Long, X. Qi, Y. Lan and A. Lei, Chem. Commun., 2015, 51, 8769.
24. (a) T. He, L. Yu, L. Zhang, L. Wang and M. Wang, Org. Lett., 2011, 13, 5016; (b) Z.-Q. Liu, L. Sun, J.-G. Wang, J. Han, Y.-K. Zhao and B. Zhou, Org. Lett., 2009, 11, 1437; (c) D. Liu, C. Liu, H. Li and A. Lei, Angew. Chem., Int. Ed., 2013, 52, 4453; (d) D. Liu, C. Liu, H. Li and A. Lei, Chem. Commun., 2014, 50, 3623.

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Footnotes

† Electronic supplementary information (ESI) available: Experimental details. See DOI: 10.1039/c5qo00208g

‡ Authors with equal contribution.

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