A method for preparing (E)-alkenylphosphine oxide derivatives

Abstract

The present invention belongs to the technical field of organic synthetic chemistry and discloses a method for preparing an (E)-alkenylphosphine oxide derivative. The method uses cheap olefins as raw materials and selectively synthesizes ( E) ‑Alkenylphosphine oxides are prepared efficiently and mildly. This method has the advantages of mild reaction conditions, good functional group tolerance, and good regioselectivity, which is conducive to the later functionalization of drug molecular skeletons, which is valuable for the synthesis and screening of new drugs.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthetic chemistry, and invents a method for synthesizing (E)-alkenyl phosphine oxide compounds by using cheap olefins as raw materials and by copper-catalyzed 4-HO-TEMPOH oxidation regioselectivity. Background Art

[0002] (E)-Alkenylphosphine oxides are widely used in drug molecules and functional materials due to their rich biological activities and inherent optical and electronic properties ((a) N.Ajellal, CM Thomas and J.-F.Carpentier, Polymer, 2008, 49, 4344-4349; (b) T.Baumgartner and R.Réau, Chem. Rev., 2006, 106, 4681-4727; (c) AKBhattacharyya and KCRana, Bioorgan. Med. Chem., 2011, 19, 7129-7135; (d) M.Delomenède, F.Bedos-Belval, H.Duran, C.Vindis, M.Baltas and A. Nègre-Salvayre, J. Med. Chem., 2008, 51, 3171-3181; (e) S. Jin and KEGonsalves, Macromolecules, 1998, 31, 1010-1015; (f) Y. Li, M. Josowicz and LM Tolbert, J. Am. Chem. Soc., 2010, 132, 10374-10382; (g) Monge, B. Canniccioni, A. Graillot and J.-J. Robin, Biomacromolecules, 2011, 12, 1973-1982. (h) J.-L. Montchamp, Acc. Chem. Res., 2014, 47, 77-87.).In addition, they can be used as active precursors for the synthesis of structurally important bifunctional adducts and phosphorus-containing ligands ((a) S.C. Cullen and T. Rovis, Org. Lett., 2008, 10, 3141-3144; (b) K. Hara, S.-Y. Park, N. Yamagiwa, S. Matsunaga and M. Shibasaki, Chem. Asian J., 2008, 3, 1500-1504; (c) T. Hirai and L.-B. Han, Org. Lett., 2007, 9, 53-55; (d) G.E. Keck, J.B. Beeers and A.M. Tafesh, J. Org. Chem., 1988, 53, 1127-1128; (e) M. Oliana, F. King, P.N. Horton, M.B. Hursthouse and KK Hii, J. Org. Chem., 2006, 71, 2472-2479; (f) RA Stockland, RI Taylor, LE Thompson and PB Patel, Org. Lett., 2005, 7, 851-853.). Therefore, the development and preparation of this type of compound has attracted widespread attention from organic and pharmaceutical scientists.At present, the strategies for synthesizing alkenylphosphine oxides mainly include four aspects: (1) alkyne hydrophosphination reaction (T.Chen, C.-Q.Zhao and L.-B.Han, J.Am.Chem.Soc.,2018,140,3139-3155; (b) L.-B.Han, C.Zhang, H.Yazawa and S.Shimada, J.Am.Chem.Soc.,2004,126,5080-5081.); (2) Heck coupling reaction ((a) W.Al-Maksoud, J.Mesnager, F.Jaber, C.Pinel and L.Djakovitch, J.Organomet.Chem.,2009,694,3222-3231; (b) H.Brunner, N.Le Cousturier de Courcy and J.-P. Genêt, Synlett, 2000, 201-204.); (3) Defunctionalization coupling reaction ((a) G. Evano, K. Tadiparthi and F. Couty, Chem. Commun., 2011, 47, 179-181; (b) G. Hu, Y. Gao and Y. Zhao, Org. Lett., 2014, 16, 4464-4467; (c) GW Kabalka and SK Guchhait, Org. Lett., 2003, 5, 729-731.); (4) Dehydrogenation coupling reaction ((a) Q. Gui, L. Hu, X. Chen, J. Liu and Z. Tan, Chem. Commun., 2015, 51, 13922-13924; (b) W.-Q. Liu, T. Lei, S. Zhou, X.-L. Yang, J. Li, B. Chen, J. Sivaguru, C.-H. Tung and L.-Z. Wu, J. Am. Chem. Soc., 2019, 141, 13941-13947.). Although significant progress has been made, most reactions still face some limitations: such as the use of expensive metal catalysts, pre-functionalized precursors, explosive peroxides and excessive additives. Therefore, there is still an urgent need to develop a more mild, effective and practical method, especially a method compatible with biological or drug molecular skeletons, to synthesize (E)-alkenylphosphine oxides.

[0003] O-unprotected hydroxylamine (4-HO-TEMPOH) has been widely reported as an oxidized form of amines, but its research is mainly limited to its reduction and nucleophilicity, and its oxidation performance has rarely been studied and reported. Therefore, it is of great theoretical significance and application value to study and develop O-unprotected hydroxylamine as a mild oxidant to improve the compatibility of the reaction with functional groups or bioactive molecular skeletons and to synthesize (E)-alkenylphosphine oxides with important structural skeletons. Summary of the invention

[0004] The purpose of the present invention is to provide a method for synthesizing (E)-alkenylphosphine oxides by regioselective oxidation with copper-catalyzed 4-HO-TEMPOH using cheap olefins as raw materials, so as to achieve mild and efficient preparation of such compounds. To achieve the purpose of the present invention, the present invention uses CuBr as a catalyst, 2,2'-bipyridine (bpy) as a ligand, 4-HO-TEMPOH as a novel and mild oxidant, and uses olefins as raw materials to react in a 1,4-dioxane solvent. Through a "one-pot" Heck-type reaction of olefins and diphenylphosphine oxide, (E)-alkenylphosphine oxides are obtained regioselectively.

[0005] The specific technical solutions are as follows:

[0006] In a dry reactor, olefin compound 1, diphenylphosphine oxide, CuBr, 2,2'-bipyridine and 4-HO-TEMPOH are added in sequence, and then 1,4-dioxane solution is added, nitrogen is filled in, the mouth of the reactor is sealed, and the reaction is heated and stirred. After the reaction is completed, the reaction system is cooled to room temperature and distilled water is added thereto; the organic solvent is removed by extraction, combination of organic phases, drying and reduced pressure distillation; and the target product is obtained by purification.

[0007] The reaction equation is as follows:

[0008]

[0009] The olefin compound 1 is selected from styrene, 4-methylstyrene, 4-tert-butylstyrene, 4-methoxystyrene, 4-phenoxystyrene, 4-acetoxystyrene, 4-N,N-dimethylstyrene, 4-phenylstyrene, 4-nitrostyrene, 4-methoxycarbonylstyrene, 4-fluorostyrene, 4-chlorostyrene, 4-bromostyrene, 3-chlorostyrene, 3-bromostyrene, 3-methylstyrene, 2-chlorostyrene, 2-bromostyrene, 2-methylstyrene, 3,4-dimethylstyrene, 1-vinylnaphthalene, 2-vinylpyridine, 2-vinylthiophene, α-methylstyrene, indene or an olefin of estrone, aspirin, ibuprofen, probenecid or oxaprozin derived from a drug molecular skeleton.

[0010] The molar ratio of the olefin compound 1 to diphenylphosphine oxide is 1.5-2.5:1.

[0011] The molar ratio of the ligand 2,2'-bipyridine to diphenylphosphine oxide is 10-20:100.

[0012] The molar ratio of the catalyst CuBr to diphenylphosphine oxide is 10-20:100.

[0013] The molar ratio of the mild oxidant 4-HO-TEMPOH to diphenylphosphine oxide used is 1.5-2.5:1

[0014] The innovation of the present invention lies in that the reaction yield is over 50%, and the highest is over 75%, and the raw materials used are cheap and easily available, the operation is simple, the reaction conditions are mild, the functional group tolerance is good, and the regional selectivity is good, which is conducive to the functionalization of the drug molecular skeleton in the later stage, which is of great significance to the synthesis and screening of new drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 For (E)-alkenylphosphine oxide 3a 1 H NMR, 13 C NMR and 31 P NMR spectrum;

[0016] Figure 2 For (E)-alkenylphosphine oxide 3g 1 H NMR, 13 C NMR and 31 P NMR spectrum;

[0017] Figure 3 For (E)-alkenylphosphine oxide 3ac 1 H NMR, 13 C NMR and 31 P NMR spectrum;

[0018] Figure 4 For (E)-alkenylphosphine oxide 3ad 1 H NMR, 13 C NMR and 31 P NMR spectrum;

[0019] Figure 5 For (E)-alkenylphosphine oxide 3ae 1 H NMR, 13 C NMR and 31 P NMR spectrum;

[0020] Figure 6 For (E)-alkenylphosphine oxide 3af 1 H NMR, 13C NMR and 31 P NMR spectrum;

[0021] Figure 7 For (E)-alkenylphosphine oxide 3ag 1 H NMR, 13 C NMR and 31 P NMR spectrum. DETAILED DESCRIPTION

[0022] In order to better illustrate the present invention, the following embodiments are given:

[0023] Embodiment 1:

[0024]

[0025] A magnetic particle was added to a 25 mL dry reaction tube, followed by the addition of styrene 1a (0.5 mmol), diphenylphosphine oxide 2a (0.2 mmol), CuBr (0.04 mmol), 2,2'-bipyridine (0.04 mmol) and 4-HO-TEMPOH (0.5 mmol). Then, 2 mL of 1,4-dioxane solution was added, liquid nitrogen was frozen and replaced with nitrogen 3 times, the tube mouth was sealed with a stopcock, and stirred at 80 ° C for 12 hours. After TLC detection, the reaction system was cooled to room temperature and 5 mL of distilled water was added thereto. Subsequently, the mixture was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the organic solvent. Finally, the white solid product 3a was purified by silica gel column chromatography with a yield of 75%.

[0026] 3a Spectrum data analysis:

[0027] 1 H NMR (400 MHz, CDCl 3 ): δ7.78–7.73(m,4H),7.54–7.46(m,9H),7.38–7.37(m,3H),6.84(dd,J=17.6Hz,J=22.4Hz,1H); 13 C NMR (100 MHz, CDCl 3 ):δ146.9(d,J C-P =3.0Hz),134.4(d,J C-P =18.0Hz),132.2(d,J C-P =105.0Hz),131.3(d,J C-P =2.0Hz),130.7(d,J C-P =9.0Hz),129.5,128.2,128.0(d,J C-P=12.0Hz),127.1,118.5(d,J C-P =104.0Hz); 31 P NMR (CDCl 3 ,162MHz):24.7;ESI-HRMS(ESI,m / z):Calcd for C 20 H 18 OP,[M+H] + :305.1090,found305.1087.

[0028] Embodiment 2:

[0029]

[0030] A magnetic particle was added to a 25 mL dry reaction tube, followed by 1 g (0.5 mmol) of N, N-dimethyl-4-vinylaniline, diphenylphosphine oxide 2a (0.2 mmol), CuBr (0.04 mmol), 2, 2'-bipyridine (0.04 mmol) and 4-HO-TEMPOH (0.5 mmol). Then, 2 mL of 1, 4-dioxane solution was added, liquid nitrogen was frozen and replaced with nitrogen 3 times, the tube mouth was sealed with a stopcock, and stirred at 80 ° C for 12 hours. After TLC detection, the reaction system was cooled to room temperature and 5 mL of distilled water was added thereto. Subsequently, the mixture was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the organic solvent. Finally, 3 g of purple solid product was obtained by silica gel column chromatography with a yield of 61%.

[0031] 3g spectrum data analysis:

[0032] 1 H NMR (400 MHz, CDCl 3 ): δ7.78–7.73(m,4H),7.53–7.49(m,2H),7.48–7.43(m,4H),7.42–7.30(m, 3H), 6.66 (d, J = 9.2Hz, 2H), 6.52 (dd, J = 17.6Hz, J = 22.4Hz, 1H), 3.00 (s, 6H); 13 C NMR (100 MHz, CDCl 3 ):δ151.4,147.7(d,J C-P =4.0Hz),133.4(d,J C-P =104.0Hz),131.4(d,J C-P =2.0Hz),131.2(d,J C-P =10.0Hz),129.1,128.3(d,JC-P =12.0Hz),122.9(d,J C-P =19.0Hz),112.0(d,J C-P =109.0Hz),111.6,40.0; 31 P NMR (CDCl 3 ,162MHz):26.0; ESI-HRMS(ESI,m / z):Calcd for C 22 H 23 NOP,[M+H] + :348.1512, found 348.1513.

[0033] Example 3: Diphenylphosphine oxide functionalized estrone

[0034]

[0035] A magnetic particle was added to a 25 mL dry reaction tube, followed by the addition of olefin 1ac (0.5 mmol), diphenylphosphine oxide 2a (0.2 mmol), CuBr (0.04 mmol), 2,2'-bipyridine (0.04 mmol) and 4-HO-TEMPOH (0.5 mmol). Then, 2 mL of 1,4-dioxane solution was added, liquid nitrogen was frozen and replaced with nitrogen 3 times, the tube mouth was sealed with a stopcock, and stirred at 80 ° C for 12 hours. After TLC detection, the reaction system was cooled to room temperature and 5 mL of distilled water was added thereto. Subsequently, it was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the organic solvent. Finally, 59.0 mg of yellow oily product 3ac was obtained by silica gel column chromatography with a yield of 61%.

[0036] 3ac spectrum data analysis:

[0037] 1 H NMR (400 MHz, CDCl 3): δ7.75(dd,J=7.2Hz,J=12Hz,4H),7.55–7.51(m,2H),7.49–7.40(m,5H),7.34–7.29 (m,2H),7.26(s,1H),6.79(dd,J=17.2Hz,J=22.4Hz,1H),2.92(t,J=4.4Hz,2H),2.50( dd,J=8.8Hz,J=18.8Hz,1H),2.45–2.40(m,1H),2.37–2.28(m,1H),2.15(dd,J=8.8Hz, J=18.8Hz,1H),2.10–1.96(m,3H),1.68–1.59(m,2H),1.56–1.40(m,4H),0.90(s,3H); 13 C NMR (100 MHz, CDCl 3 ):δ220.5,147.3(d,J C-P =3.0Hz),142.2,137.0,133.0(d,J C-P =105.0Hz),132.6(d,J C-p =18.0Hz),131.7(d,J C-p =2.0Hz),131.3(d,J C-p =9.0Hz),128.5(d,J C-p =12.0Hz),128.3,125.8,125.0,118.2(d,J C-p =104.0Hz),50.4,47.8,44.5,37.9,35.7,31.4,29.2,26.2,25.5,21.5,13.7; 31 P NMR (CDCl 3 ,162MHz):24.6; ESI-HRMS(ESI,m / z):Calcd for C 32 H 34 O 2 P,[M+H] + :481.2291, found 481.2293.

[0038] Example 4: Diphenylphosphine oxide functionalized aspirin

[0039]

[0040] A magnetic particle was added to a 25 mL dry reaction tube, followed by the addition of olefin 1ad (0.5 mmol), diphenylphosphine oxide 2a (0.2 mmol), CuBr (0.04 mmol), 2,2'-bipyridine (0.04 mmol) and 4-HO-TEMPOH (0.5 mmol). Then, 2 mL of 1,4-dioxane solution was added, liquid nitrogen was frozen and replaced with nitrogen 3 times, the tube mouth was sealed with a stopcock, and stirred at 80 ° C for 12 hours. After TLC detection, the reaction system was cooled to room temperature and 5 mL of distilled water was added thereto. Subsequently, it was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the organic solvent. Finally, 52.0 mg of white solid product 3ad was obtained by silica gel column chromatography with a yield of 52%.

[0041] 3ad spectrum data analysis:

[0042] 1 H NMR (400 MHz, CDCl 3 ): δ8.05(dd,J=1.6Hz,J=7.6Hz,1H),7.78–7.73(m,4H),7.58–7.46(m,10H),7.43(d,J=8.0Hz,2H),7. 33–7.29(m,1H),7.10(d,J=8.0Hz,1H),6.87(dd,J=17.6Hz,J=21.6Hz,1H),5.31(s,2H),2.17(s,3H); 13 C NMR (100 MHz, CDCl 3 ): δ169.6,164.2,150.7,146.8(d,J C-P =3.0Hz),137.6,135.2(d,J C-P =17.0Hz),134.0,132.8(d,J C-P =105.0Hz),131.9(d,J C-P =3.0Hz),131.87,131.3(d,J C-P =10.0Hz),128.7,128.6(d,J C-P =12.0Hz),128.0,126.0,123.8,123.0,119.9(d,J C-P =103.0Hz),66.3,20.8; 31 PNMR (CDCl 3 ,162MHz):24.3; ESI-HRMS(ESI,m / z):Calcd for C 30 H 26 O5 P,[M+H] + :497.1512, found 497.1508.

[0043] Example 5: Diphenylphosphine oxide functionalized ibuprofen

[0044]

[0045] A magnetic particle was added to a 25 mL dry reaction tube, followed by the addition of olefin 1ae (0.5 mmol), diphenylphosphine oxide 2a (0.2 mmol), CuBr (0.04 mmol), 2,2'-bipyridine (0.04 mmol) and 4-HO-TEMPOH (0.5 mmol). Then, 2 mL of 1,4-dioxane solution was added, liquid nitrogen was frozen and replaced with nitrogen 3 times, the tube mouth was sealed with a stopcock, and stirred at 80 ° C for 12 hours. After TLC detection, the reaction system was cooled to room temperature and 5 mL of distilled water was added thereto. Subsequently, it was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the organic solvent. Finally, 66 mg of white solid product 3ae was obtained by silica gel column chromatography with a yield of 63%.

[0046] 3ae spectrum data analysis:

[0047] 1 H NMR (400 MHz, CDCl 3 ): δ7.77–7.72(m,4H),7.56–7.43(m,9H),7.20(t,J=7.6Hz,4H),7.08(d,J=8.0Hz,2H),6.81(dd,J=17.6Hz,J=21.6Hz,1H), 5.10(s,2H),3.74(q,J=7.2Hz,1H),2.44(d,J=7.2Hz,2H),1.89–1.79(m,1H),1.50(d,J=7.2Hz,3H),0.89(d,J=6.4Hz,6H); 13 C NMR (100 MHz, CDCl 3 ):δ174.3,146.9(d,J C-P =3.0Hz),140.6,138.1,137.4,134.7(d,J C-P =18.0Hz),132.8(d,J C-P =106.0Hz),131.8(d,J C-P =2.0Hz),131.3(d,J C-P =10.0Hz),129.3,128.6(d,J C-P=12.0Hz),128.0,127.8,127.1,119.5(d,J C-P =104.0Hz),65.6,45.0,44.9,30.1,22.3,18.2; 31 P NMR (CDCl 3 ,162MHz):24.5; ESI-HRMS(ESI,m / z):Calcd for C 34 H 36 O 3 P,[M+H] + :523.2397, found 523.2398.

[0048] Example 6: Diphenylphosphine oxide functionalized probenecid

[0049]

[0050] A magnetic particle was added to a 25 mL dry reaction tube, followed by the addition of olefin 1af (0.5 mmol), diphenylphosphine oxide 2a (0.2 mmol), CuBr (0.04 mmol), 2,2'-bipyridine (0.04 mmol) and 4-HO-TEMPOH (0.5 mmol). Then, 2 mL of 1,4-dioxane solution was added, liquid nitrogen was frozen and replaced with nitrogen 3 times, the tube mouth was sealed with a stopcock, and stirred at 80 ° C for 12 hours. After TLC detection, the reaction system was cooled to room temperature and 5 mL of distilled water was added thereto. Subsequently, it was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the organic solvent. Finally, 93.0 mg of white oily liquid product 3af was obtained by silica gel column chromatography with a yield of 77%.

[0051] 3af spectrum data analysis:

[0052] 1 H NMR (400 MHz, CDCl 3 ): δ8.17(d,J=8.4Hz,2H),7.87(d,J=8.4Hz,2H),7.79–7.73(m,4H),7.58–7.53(m,5H),7.51–7.46(m,6H),6.8 8(dd,J=17.6Hz,J=22.4Hz,1H),5.39(s,2H),3.09(t,J=7.6Hz,4H),1.59–1.49(m,4H),0.86(t,J=7.2Hz,6H); 13 C NMR (100 MHz, CDCl 3 ):δ164.9,146.6(d,JC-P =4.0Hz),144.4,137.3,135.2(d,J C-P =18.0Hz),133.1,132.7(d,J C-P =106.0Hz),131.8(d,J C-P =2.0Hz),131.3(d,J C-P =10.0Hz),130.2,128.6,128.5(d,J C-P =12.0Hz),128.0,126.9,119.9(d,J C-P =103.0Hz),66.6,49.8,21.8,11.0; 31 PNMR (CDCl 3 ,162MHz):24.3; ESI-HRMS(ESI,m / z):Calcd for C 34 H 37 NO 5 PS,[M+H] + :602.2125,found602.2128.

[0053] Example 7: Diphenylphosphine oxide functionalized oxaprozin

[0054]

[0055] A magnetic particle was added to a 25 mL dry reaction tube, followed by the addition of olefin 1ag (0.5 mmol), diphenylphosphine oxide 2a (0.2 mmol), CuBr (0.04 mmol), 2,2'-bipyridine (0.04 mmol) and 4-HO-TEMPOH (0.5 mmol). Then, 2 mL of 1,4-dioxane solution was added, liquid nitrogen was frozen and replaced with nitrogen 3 times, the tube mouth was sealed with a stopcock, and stirred at 80 ° C for 12 hours. After TLC detection, the reaction system was cooled to room temperature and 5 mL of distilled water was added thereto. Subsequently, it was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the organic solvent. Finally, 68.0 mg of white oily liquid product 3ag was obtained by silica gel column chromatography with a yield of 56%.

[0056] 3ag spectrum data analysis:

[0057] 1 H NMR (400 MHz, CDCl 3):δ7.74(dd,J=7.6Hz,J=11.6Hz,4H),7.60(d,J=7.2Hz,2H),7.56–7.39(m,11H),7.33–7.25(m,8H),6.77(dd,J=17.6Hz,J=22.0Hz,1H),5.17(s,2H),3.20(t,J=7.2Hz,2H),2.98(t,J=7.2Hz,2H); 13 C NMR(100MHz,CDCl 3 ):δ171.1,160.9,146.3(d,J C-P =4.0Hz),144.8,137.2,134.4,134.3(d,J C-P =18.0Hz),132.2(d,J C-P =105.0Hz),131.8,131.3(d,J C-P =2.0Hz),130.7(d,J C-P =10.0Hz),128.2,128.1(d,J C-P =12.0Hz),128.0,127.9,127.8,127.7,127.4,127.3,127.2,125.8,119.0(d,J C-P =103.0Hz),65.3,30.4,22.8; 31 P NMR(CDCl 3 ,162MHz):24.4;ESI-HRMS(ESI,m / z):Calcd forC 39 H 33 NO 4 P,[M+H] + :610.2142,found 610.2145.。

Claims

1. A method for preparing an (E)-alkenylphosphine oxide derivative of the general structural formula 3, characterized in that: This is accomplished by the following steps: Add olefin compound 1, diphenylphosphine oxide, CuBr, 2,2'-bipyridine and 4-HO-TEMPOH to a dry reactor in sequence, then add 1,4-dioxane solution, introduce nitrogen, seal the reactor port, and heat to react; after the reaction is completed, cool the reaction system to room temperature and add distilled water; The organic phases were extracted, combined, dried and distilled under reduced pressure to remove the organic solvent, and purified to obtain the target product 3; The olefin compound 1 is selected from styrene and 4-N,N-dimethylstyrene; The target product 3 is selected from ; R 1 , R 2 This is consistent with the substituent groups of the target product 3 of the specific structure.

2. The method according to claim 1, characterized in that The molar ratio of the olefin compound 1 to diphenylphosphine oxide is 1.5-2.5:

1.

3. The method according to claim 1, characterized in that The molar ratio of the 2,2'-bipyridine to diphenylphosphine oxide is 10-20:100; the molar ratio of the CuBr to diphenylphosphine oxide is 10-20:100; and the molar ratio of the 4-HO-TEMPOH to diphenylphosphine oxide is 1.5-2.5:1.

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