A method for preparing a phosphonamide derivative

Abstract

The present invention belongs to the technical field of organic synthetic chemistry, and discloses a preparation method of phosphonamide derivatives. This method uses diphenylphosphine oxide as the phosphonyl source, arylhydroxylamine as the internal oxidant and amine source, and under the copper-catalyzed redox-neutral conditions, simply, greenly and efficiently synthesizes a series of structurally important phosphonamide compounds. This method has the advantages of mild reaction conditions, no need for external oxidants, environmental friendliness and good functional group tolerance, provides a reference for the synthesis and screening of novel phosphoramide bioactive or drug active molecules, and has important theoretical significance and potential application value.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthetic chemistry and relates to a preparation method of phosphonamide derivatives with potential biological and pharmaceutical activities. Background Art

[0002] Phosphonamide derivatives are an important class of organophosphorus compounds, which exhibit excellent properties in terms of biological activity, flame retardancy, luminescence, etc. Among them, phosphoramides with N-P bonds have attracted extensive attention in the fields of asymmetric catalysis, coordination chemistry, medicinal chemistry, and materials science due to the presence of two important elements, nitrogen and phosphorus. ((a) Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 9626-9627; (b) Neisius, M.; Liang, S.; Mispreuve, H.; Gaan, S. Ind. Eng. Chem. Res. 2013, 52, 9752-9762; (c) Sofia, M. J.; Chang, W.; Furman, P. A.; Mosley, R. T.; Ross, B. S. Nucleoside, J. Med. Chem. 2012, 55, 2481-2531; (d) Liu, X.-D.; Zheng, X.-T.; Dong, Y.-Q.; He, L.-X.; Chen, F.; Bai, W.-B.; Lin, Y.-C.; Jian, R.-K. Polym. Degrad. Stab. 2022, 196, 109840; (e) Chary, B. C.; Kim, S.; Park, Y.; Kim, J.; Lee, P. H. Org. Lett. 2013, 15, 2692-2695; (f) Garcia, P.; Lau, Y. Y.; Perry, M. R.; Schafer, L. L. Angew. Chem., Int. Ed. 2013, 52, 9144-9148; (g) Wu, G.-J.; Tan, D.-X.; Han, F.-S. Acc. Chem. Res. 2021, 54, 4354-4370.). Given their importance, the synthesis of phosphonamide derivatives has attracted great interest from chemists and pharmacologists. The traditional synthetic methods mainly include two: one is the reaction of phosphonous halides with amines followed by oxidation (J. Chem. Soc., Perkin Trans. 1 1985, 3, 461-470); the other is the nucleophilic substitution reaction of phosphonyl chlorides with amines (Angew. Chem. Int. Ed. 2018, 57, 3094–3098; Angew. Chem. Int. Ed. 2017, 56, 364–367.). Although significant progress has been made, the use of toxic halogen reagents and the generation of stoichiometric amounts of strong acids (HX, X = Cl, Br) are bound to pollute the environment and corrode the reaction equipment. In recent years, the Lu group reported that under the cooperative catalytic redox-neutral conditions of metal copper salts and photosensitizer Ir, the oxygen-phosphorus compound undergoes N elimination from the P(O)-N bond of organic azide 2Coupling was carried out to prepare a series of phosphonamide derivatives (Org. Lett. 2020, 22, 6143 - 6149). However, this reaction uses expensive metal photosensitizer Ir and organic azide reagents with explosion risk, greatly limiting its industrial application. Recently, the Xu research group reported the synthesis of phosphonamide derivatives through the rearrangement reaction of hydroxylamine and dialkylphosphine chloride from P(III) to P(V) without a metal catalyst (Org. Lett. 2023, 25, 2555–2559). However, the reaction conditions are relatively harsh, requiring a low-temperature environment and the use of toxic reagents dialkylphosphine chloride and stoichiometric base (pyridine), restricting the further application of this reaction. Therefore, it is a challenging and highly attractive task to prepare phosphonamide derivatives through a simple, green, atom- and step-economic method, reduce their production costs, and avoid environmental pollution.

[0003] Hydroxylamine (RNHOH) and diphenylphosphine oxide are well-known and reported, but the research between the two has not been reported. If, by virtue of the electrophilicity of hydroxylamine and the nucleophilicity / reducing property of diphenylphosphine oxide, the dehydration N-P(O) bond coupling of the two is carried out under transition-metal-catalyzed redox-neutral conditions, it can not only avoid the environmental pollution problems caused by the use of toxic halogen-containing reagents and the generation of stoichiometric waste acids, but also simply and effectively prepare structurally important phosphonamide derivatives, which has important theoretical research significance and application value. Summary of the Invention

[0004] The object of the present invention is to provide a method for simply, greenly, and efficiently synthesizing a series of structurally important phosphonamide compounds by using diphenylphosphine oxide as the phosphonyl source, arylhydroxylamine as the internal oxidant and amine source, and under copper-catalyzed redox-neutral conditions.

[0005] To achieve the object of the present invention, CuTc is used as the catalyst and 4,4'-dibromo-2,2'-bipyridine (4,4'-DiBr-bpy) as the ligand. Without adding an external oxidant, the reaction is carried out in 1,4-dioxane solvent. The N-P bond is constructed through the "one-pot" dehydration coupling reaction of hydroxylamine and diphenylphosphine oxide, and the phosphonamide derivatives are obtained greenly and efficiently.

[0006] The specific technical solution is as follows:

[0007] Diphenylphosphine oxide 1a, hydroxylamine compound 2, cuprous thiophene-2-carboxylate (CuTc), and 4,4'-dibromo-2,2'-bipyridine (4,4'-DiBr-bpy) are successively added to a dry reactor. Then, a 1,4-dioxane solution is added, nitrogen is introduced, the reactor mouth is sealed, and the reaction is heated; after the reaction is completed, the reaction system is cooled to room temperature and distilled water is added thereto; after extraction, the organic phases are combined, dried, and the organic solvent is removed by vacuum distillation, and after purification, the target product 3 is obtained;

[0008] The reaction equation is as follows:

[0009]

[0010] R 1 and R 2 respectively represent hydrogen, phenyl, phenyl mono - or di - substituted by C1 - 4 alkyl, hydroxymethyl, phenylthio, fluorine, trifluoromethyl, cyano, acetyl, methoxycarbonyl, and C1 - 4 alkyl substituted by phenyl; and R 1 and R 2 are not both hydrogen at the same time;

[0011] Preferably: R 1 and R 2 respectively represent hydrogen, phenyl, phenyl mono - substituted by hydroxymethyl, phenylthio, trifluoromethyl, acetyl, methoxycarbonyl; and R 1 and R 2 are not both hydrogen at the same time;

[0012] The hydroxylamine compound 2 is selected from N - phenylhydroxylamine, N-(4 - methylphenyl)hydroxylamine, N-(4 - ethylphenyl)hydroxylamine, N-(4 - phenylthiophenyl)hydroxylamine, N-(4 - hydroxymethylphenyl)hydroxylamine, N-(4 - fluorophenyl)hydroxylamine, N-(4 - trifluoromethylphenyl)hydroxylamine, N-(4 - cyanophenyl)hydroxylamine, N-(4 - methoxycarbonylphenyl)hydroxylamine, N-(4 - acetylphenyl)hydroxylamine, N-(3 - methylphenyl)hydroxylamine, N-(2 - methylphenyl)hydroxylamine, N-(2,4 - dimethylphenyl)hydroxylamine, N-(2 - methyl - 5 - bromophenyl)hydroxylamine, N-(phenethyl)hydroxylamine, N,N - diethylhydroxylamine.

[0013] The molar ratio of the hydroxylamine compound 2 to diphenylphosphine oxide is 1.5 - 2.0:1.

[0014] The molar ratio of the ligand 4,4’ - dibromo - 2,2’ - bipyridine to diphenylphosphine oxide is 10 - 20:100; the molar ratio of the catalyst CuTc to diphenylphosphine oxide is 10 - 20:100.

[0015] The innovation and advantages of the present invention are as follows: This reaction does not require an external oxidant, is green and environmentally friendly (the by - product is water), has simple operation, and good functional group compatibility. The yield of this reaction reaches more than 48%, and the highest reaches more than 73%. This method not only solves the problems of generating stoichiometric amounts of waste acid and polluting the environment faced in the traditional preparation of phosphonamides, but also gently and greenly prepares a series of phosphonamide derivatives with potential application value. Therefore, this reaction has important theoretical significance and potential application value. Brief Description of the Drawings

[0016] Figure 1 For the phosphonamide derivative 3a1 1H NMR, 13 13C NMR and 31 31P NMR spectra;

[0017] Figure 2 For the 1H NMR, 1 1H NMR, 13 13C NMR and 31 31P NMR spectra of phosphonamide derivative 3d;

[0018] Figure 3 For the 1H NMR, 1 1H NMR, 13 13C NMR and 31 31P NMR spectra of phosphonamide derivative 3e;

[0019] Figure 4 For the 1H NMR, 1 1H NMR, 13 13C NMR, 31 31P NMR and 19 19F NMR spectra of phosphonamide derivative 3g;

[0020] Figure 5 For the 1H NMR, 1 1H NMR, 13 13C NMR and 31 31P NMR spectra of phosphonamide derivative 3i;

[0021] Figure 6 For the 1H NMR, 1 1H NMR, 13 13C NMR and 31 31P NMR spectra of phosphonamide derivative 3j. Detailed implementation mode

[0022] To better illustrate the present invention, the following examples are given:

[0023] Example 1:

[0024]

[0025] A magnetic stir bar was added to a 25 mL dry reaction tube, and then diphenylphosphine oxide 1a (0.2 mmol), phenylhydroxylamine 2a (0.4 mmol), CuTc (0.04 mmol), and 4,4'-dibromo-2,2'-bipyridine (0.04 mmol) were added successively. Then, 2 mL of 1,4-dioxane solution was added. The reaction system was frozen with liquid nitrogen and evacuated and backfilled with nitrogen three times. The tube was sealed with a stopcock and stirred at 80 °C for 12 h. After the reaction was completed as monitored by TLC, the reaction system was cooled to room temperature and 5 mL of distilled water was added. Subsequently, the mixture was extracted with ethyl acetate three times, the organic layers were combined, dried over anhydrous sodium sulfate, and the organic solvents were removed by distillation under reduced pressure. Finally, the white solid product 3a was obtained by purification by silica gel column chromatography with a yield of 60%.

[0026] Analysis of the spectral data of 3a:

[0027] 1 H NMR (400 MHz, CDCl 3 ): δ 7.89 (dd, J = 7.2 Hz, J = 12.4 Hz, 4H), 7.56–7.52 (m, 2H), 7.49–7.44 (m, 4H), 7.14 (t, J = 7.6 Hz, 2H), 6.97 (d, J = 7.6 Hz, 2H), 6.90 (t, J = 7.6 Hz, 1H), 5.31 (d, J = 9.2 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ): δ 140.3, 132.2 (d, J C-P = 3 Hz), 132.0 (d, J C-P = 20 Hz), 131.9 (d, J C-P = 128 Hz), 129.3, 128.8 (d, J C-P = 12 Hz), 121.8, 118.4 (d, J C-P = 6 Hz); 31 P NMR (162 MHz, CDCl 3 ): 18.4; ESI-HRMS (ESI, m / z): Calcd for C 18 H 17 NOP, [M + H] + : 294.1042, found 294.1041.

[0028] Example 2:

[0029]

[0030] A magnetic stir bar was added to a 25 mL dry reaction tube, and then diphenylphosphine oxide 1a (0.2 mmol), 4-(phenylthio)phenylhydroxylamine 2d (0.4 mmol), CuTc (0.04 mmol), and 4,4'-dibromo-2,2'-bipyridine (0.04 mmol) were added successively. Then, 2 mL of 1,4-dioxane solution was added. The mixture was frozen with liquid nitrogen and evacuated and backfilled with nitrogen three times, and the tube mouth was sealed with a stopcock. The mixture was stirred at 80 °C for 12 h. After the reaction was monitored by TLC and completed, 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 ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and the organic solvents were removed by distillation under reduced pressure. Finally, the yellow solid product 3d was obtained by purification by silica gel column chromatography with a yield of 73%. Analysis of the spectral data of 3d:

[0031] 1 H NMR (400 MHz, CDCl 3 ): δ 7.87 (dd, J = 7.2 Hz, J = 12.4 Hz, 4H), 7.57–7.53 (m, 2H), 7.49–7.45 (m, 4H), 7.23–7.19 (m, 4H), 7.15–7.11 (m, 3H), 6.95 (d, J = 8.4 Hz, 2H), 5.49 (d, J = 9.2 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ): δ 140.5, 137.8, 134.4, 132.4 (d, J C-P = 3 Hz), 132.1 (d, J C-P = 10 Hz), 131.5 (d, J C-P = 129 Hz), 128.9, 128.8 (d, J C-P = 13 Hz), 128.76, 126.1, 126.0, 119.1 (d, J C-P = 6 Hz); 31 P NMR (162 MHz, CDCl 3 ): 18.8; ESI-HRMS (ESI, m / z): Calcd for C 24 H 21 NOPS, [M + H] + : 402.1076, found 402.1070.

[0032] Example 3:

[0033]

[0034] A magnetic stir bar was added to a 25 mL dry reaction tube, and then diphenylphosphine oxide 1a (0.2 mmol), 4-(hydroxymethyl)phenylhydroxylamine 2e (0.4 mmol), CuTc (0.04 mmol), and 4,4'-dibromo-2,2'-bipyridine (0.04 mmol) were added in sequence. Then, 2 mL of 1,4-dioxane solution was added. The reaction system was frozen with liquid nitrogen and evacuated and replaced with nitrogen three times. The tube mouth was sealed with a stopcock and stirred at 80 °C for 12 hours. After TLC detection and completion of the reaction, the reaction system was cooled to room temperature and 5 mL of distilled water was added thereto. Subsequently, extraction was performed three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and the organic solvent was removed by distillation under reduced pressure. Finally, the white solid product 3e was obtained by purification through silica gel column chromatography with a yield of 50%. Analysis of the spectral data of 3e:

[0035] 1 H NMR (400 MHz, CD 3 OD): δ 7.84 (dd, J = 7.2 Hz, J = 12.4 Hz, 4H), 7.59–7.55 (m, 2H), 7.52–7.47 (m, 4H), 7.12 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 4.45 (s, 2H); 13 C NMR (100 MHz, CD 3 OD): δ 141.7, 135.9, 133.5 (d, J C-P = 3 Hz), 133.1 (d, J C-P = 10 Hz), 132.7 (d, J C-P = 130 Hz), 129.9 (d, J C-P = 13 Hz), 129.2, 119.8 (d, J C-P = 7 Hz), 64.9; 31 P NMR (162 MHz, CD 3 OD): 21.0; ESI-HRMS (ESI, m / z): Calcd for C 19 H 19 NO 2 P, [M + H] + : 324.1148, found 324.1151.

[0036] Example 4:

[0037]

[0038] A magnetic stir bar was added to a 25 mL dry reaction tube, and then diphenylphosphine oxide 1a (0.2 mmol), 4-(trifluoromethyl)phenylhydroxylamine 2g (0.4 mmol), CuTc (0.04 mmol), and 4,4'-dibromo-2,2'-bipyridine (0.04 mmol) were added successively. Then, 2 mL of 1,4-dioxane solution was added, and the mixture was frozen with liquid nitrogen and evacuated and backfilled with nitrogen three times. The tube was sealed with a stopcock and stirred at 80 °C for 12 hours. After completion of the reaction monitored by TLC, the reaction system was cooled to room temperature and 5 mL of distilled water was added thereto. Subsequently, the mixture was extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, and the organic solvents were removed by distillation under reduced pressure. Finally, the white solid product 3g was obtained by purification by silica gel column chromatography with a yield of 52%.

[0039] Analysis of the spectral data of 3g:

[0040] 1 H NMR (400 MHz, CDCl 3 ): δ 7.87 (dd, J = 7.2 Hz, J = 12.4 Hz, 4H), 7.56 (t, J = 7.2 Hz, 2H), 7.50–7.45 (m, 4H), 7.38 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 5.72 (d, J = 9.2 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ): δ 143.8, 132.6 (d, J C-P = 2 Hz), 131.9 (d, J C-P = 10 Hz), 131.2 (d, J C-P = 128 Hz), 129.0 (d, J C-P = 13 Hz), 126.6 (q, J C-F = 3 Hz), 124.2 (q, J C-F = 268 Hz), 123.7 (q, J C-F = 32 Hz), 117.9 (d, J C-P = 7 Hz); 31 P NMR (162 MHz, CDCl 3 ): 19.3; 19 F NMR (376 MHz, CDCl 3 ): δ -61.8; ESI-HRMS (ESI, m / z): Calcd for C 19 H 16 F 3 NOP, [M + H] + : 362.0916, found 362.0919.

[0041] Example 5:

[0042]

[0043] A magnetic stir bar was added to a 25 mL dry reaction tube, and then diphenylphosphine oxide 1a (0.2 mmol), 4-methoxycarbonylphenylhydroxylamine 2i (0.4 mmol), CuTc (0.04 mmol), and 4,4'-dibromo-2,2'-bipyridine (0.04 mmol) were added successively. Then, 2 mL of 1,4-dioxane solution was added, and the mixture was frozen with liquid nitrogen and evacuated and backfilled with nitrogen three times. The tube was sealed with a stopcock and stirred at 80 °C for 12 hours. After completion of the reaction detected by TLC, 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 ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and the organic solvent was removed by distillation under reduced pressure. Finally, the yellow solid product 3i was obtained by purification by silica gel column chromatography with a yield of 56%. Analysis of the spectral data of 3i:

[0044] 1 H NMR (400 MHz, CD 3 OD): δ 7.87–7.82 (m, 4H), 7.77 (d, J = 8.8 Hz, 2H), 7.61–7.57 (m, 2H), 7.54–7.49 (m, 4H), 7.10 (d, J = 8.4 Hz, 2H), 3.80 (s, 3H); 13 C NMR (100 MHz, CD 3 OD): δ 168.3, 147.6, 133.8 (d, J C-P = 3 Hz), 133.1 (d, J C-P = 11 Hz), 132.2 (d, J C-P = 130 Hz), 131.8, 130.0 (d, J C-P = 13 Hz), 124.0, 118.9 (d, J C-P = 7 Hz), 52.3; 31 P NMR (162 MHz, CD 3 OD): 21.2; ESI-HRMS (ESI, m / z): Calcd for C 20 H 19 NO 3 P, [M + H] + : 352.1097, found 352.1089.

[0045] Example 6:

[0046]

[0047] A magnetic stir bar was added to a 25 mL dry reaction tube, and then diphenylphosphine oxide 1a (0.2 mmol), 4-acetylphenylhydroxylamine 2j (0.4 mmol), CuTc (0.04 mmol), and 4,4'-dibromo-2,2'-bipyridine (0.04 mmol) were added in sequence. Then, 2 mL of 1,4-dioxane solution was added, and the mixture was frozen with liquid nitrogen and evacuated and replaced with nitrogen three times. The tube mouth was sealed with a stopcock and stirred at 80 °C for 12 hours. After TLC detection, when the reaction was completed, the reaction system was cooled to room temperature and 5 mL of distilled water was added thereto. Subsequently, the mixture was extracted with ethyl acetate three times in sequence, the organic phases were combined, dried over anhydrous sodium sulfate, and the organic solvent was removed by distillation under reduced pressure. Finally, the brown solid product 3j was purified by silica gel column chromatography with a yield of 48%. Analysis of the spectral data of 3j:

[0048] 1 H NMR (400 MHz, CDCl 3 ): δ 7.82 (dd, J = 7.2 Hz, J = 12.4 Hz, 4H), 7.69 (d, J = 8.8 Hz, 2H), 7.51 (t, J = 7.2 Hz, 2H), 7.44–7.40 (m, 4H), 7.05 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 10.4 Hz, 1H), 2.43 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ 196.9, 132.4 (d, J C-P = 3 Hz), 131.8, 131.7 (d, J C-P = 10 Hz), 131.2 (d, J C-P = 129 Hz), 130.5, 130.0, 128.8 (d, J C-P = 13 Hz), 117.6 (d, J C-P = 6 Hz), 26.1; 31 P NMR (162 MHz, CDCl 3 ): 18.9; ESI-HRMS (ESI, m / z): Calcd for C 20 H 19 NO 2 P, [M + H] + : 336.1148, found 336.1153.

Claims

1. A method for preparing a phosphonamide derivative of structural general formula 3, characterized in that, it is achieved through the following steps: Add diphenylphosphine oxide compound 1a, hydroxylamine compound 2, copper(I) thiophene-2-carboxylate, and 4,4'-dibromo-2,2'-bipyridine into a dry reactor in sequence. Then, add a 1,4-dioxane solution, introduce nitrogen gas, seal the reactor opening, and heat for reaction; after the reaction ends, cool the reaction system to room temperature and add distilled water thereto; After extraction, combine the organic phases, dry, and remove the organic solvent by distillation under reduced pressure. After purification, the target product 3 is obtained; R 1 and R 2 respectively represent hydrogen, phenyl, phenyl mono- or di-substituted by C1-4 alkyl, hydroxymethyl, phenylthio, fluorine, trifluoromethyl, cyano, acetyl, methoxycarbonyl, and C1-4 alkyl substituted by phenyl; and R 1 and R 2 are not both hydrogen at the same time.

2. The method for preparing a phosphonamide derivative according to claim 1, characterized in that, R 1 、R 2 represent hydrogen, phenyl, phenyl mono-substituted by hydroxymethyl, phenylthio, trifluoromethyl, acetyl or methoxycarbonyl respectively; and R 1 、R 2 are not hydrogen simultaneously.

3. The method for preparing a phosphonamide derivative according to claim 1, characterized in that, The hydroxylamine compound 2 is selected from N -phenylhydroxylamine, N -(4-methylphenyl)hydroxylamine, N -(4-ethylphenyl)hydroxylamine, N -(4-phenylthiophenyl)hydroxylamine, N -(4-hydroxymethylphenyl)hydroxylamine, N -(4-fluorophenyl)hydroxylamine, N -(4-trifluoromethylphenyl)hydroxylamine, N -(4-cyanophenyl)hydroxylamine, N -(4-methoxycarbonylphenyl)hydroxylamine, N -(4-acetylphenyl)hydroxylamine, N -(3-methylphenyl)hydroxylamine, N -(2-methylphenyl)hydroxylamine, N -(2,4-dimethylphenyl)hydroxylamine, N -(phenethyl)hydroxylamine.

4. The method for preparing a phosphonamide derivative according to any one of claims 1-3, characterized in that, the molar ratio of the hydroxylamine compound 2 to the diphenylphosphine oxide compound 1a is 1.5-2.0:

1.

5. The method for preparing a phosphonamide derivative according to any one of claims 1-3, characterized in that, the molar ratio of the 4,4'-dibromo-2,2'-bipyridine to the diphenylphosphine oxide compound 1a is 10-20:100; the molar ratio of the copper(I) thiophene-2-carboxylate to the diphenylphosphine oxide compound 1a is 10-20:100.

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