Preparation method of 3-(phosphonyl) methylindole compound

Abstract

The invention discloses a preparation method of a 3-(phosphonyl) methylindole compound. The preparation method comprises the following steps: adding a phosphine oxide compound and an indolyl quaternary phosphonium salt compound into a solvent, and reacting at room temperature to 100 DEG C for 6-12 hours; and after the reaction is finished, sequentially quenching, extracting, washing, drying, concentrating and purifying to obtain the 3-(phosphonyl) methylindole compound. The method has the characteristics of mild reaction conditions, good functional group tolerance, simple post-treatment, green steps, low pollution, high economic benefits and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic compound synthesis, and particularly relates to a method for preparing 3-(phosphonyl)methyl indole compounds. Background Art

[0002] Indole, as a key structural motif in numerous bioactive natural products, drugs, agrochemicals, and functional materials (Chem. Rev. 2010, 110, 4489–4497), is widely used in the synthesis of organic molecules. Notably, the incorporation of a phosphonyl (P═O) group into the indole framework offers great potential for enhancing the thermal stability, radical quenching ability, and pharmacological efficacy of molecules (Org. Biomol. Chem. 2018, 16, 7544–7556). Iwao et al. prepared 3-(phosphonyl)indole compounds by reacting indolyl quaternary ammonium salts with phosphine oxides (Tetrahedron Lett. 1995, 36, 5929–5932); Petrini (Tetrahedron Lett. 2008, 49, 5645–5648) and Yuan (Chem. Commun. 2022, 58, 12062–12065) both successfully prepared the above products using indolyl sulfone compounds and phosphine oxides; however, all of the above works require the addition of stoichiometric amounts of base to enable the reaction to proceed. Liang et al. reported the reaction of indolyl hydrazone compounds with phosphine oxides under copper catalysis (Tetrahedron 2013, 69, 1065–1068); however, the dependence on transition metal catalysts brings potential biotoxicity and additional purification steps, hindering their application in biomedicine. The groups of Chen (Adv. Synth. Catal. 2019, 361, 5311–5316) and Rao (Adv. Synth. Catal. 2021, 363, 3496–3501) independently reported the phosphonylation reaction of indolyl alcohol compounds catalyzed by camphoric acid; however, in both cases, poor regioselectivity led to 2-(phosphonyl)indole as the main product. The groups of Huo (Org. Chem. Front. 2018, 5, 2652–2656) and Huang (Org. Lett. 2023, 25, 8478–8483) independently reported the DDQ-mediated phosphonylation reaction of indole through C-H bond oxidation; the groups of Xu and Gao reported the three-component condensation reaction of indole, phosphine oxide, and carbonyl compounds catalyzed by H2SO4 (Green Chem. 2019, 21, 792–797). Although the above methods are simple in steps, they are still limited by regioselectivity, air sensitivity, and the need for additives / catalysts. Summary of the Invention

[0003] To overcome the disadvantages and deficiencies of the prior art, the object of the present invention is to provide a method for preparing 3-(phosphonyl)methylindole compounds.

[0004] The present invention is implemented as follows. A method for preparing 3-(phosphonyl)methylindole compounds, the method comprising the following steps:

[0005] (1) Add the phosphine oxide compound shown in formula (II) and the indolylphosphonium salt compound shown in formula (III) to a solvent, and react at room temperature to 100 °C for 6 to 12 h;

[0006]

[0007] (2) After the reaction in step (1) is completed, quench, extract, wash, dry, concentrate, and purify in sequence to obtain the 3-(phosphonyl)methylindole compound shown in formula (I);

[0008]

[0009] Wherein, R is selected from one of methyl and halogen;

[0010] Ar is selected from any one of methoxy-substituted phenyl, halogen-substituted phenyl, cyano-substituted phenyl, trifluoromethyl-substituted phenyl, nitro-substituted phenyl, thiophenyl, naphthyl, and azamethylindolyl;

[0011] Ar' is selected from any one of phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, tert-butyl-substituted phenyl, halogen-substituted phenyl, and naphthyl;

[0012] Ar" is selected from any one of methyl-substituted phenyl, methoxy-substituted phenyl, tert-butyl-substituted phenyl, halogen-substituted phenyl, and naphthyl.

[0013] Preferably, in step (1), the reaction temperature is 85 °C and the reaction time is 12 h.

[0014] Preferably, in step (1), the solvent is selected from any one of acetonitrile, toluene, water, tert-butanol, dimethyl sulfoxide, and N,N-dimethylformamide.

[0015] Preferably, the solvent is acetonitrile.

[0016] Preferably, in step (1), the molar ratio of the indolylphosphonium salt compound to the phosphine oxide compound is 1.5:1.

[0017] Preferably, in step (1), the indolylphosphonium salt compound is selected from any one of ((3,4-dimethoxyphenyl)(1-methyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1H-indol-3-yl)(3,4,5-trimethoxyphenyl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((4-bromophenyl)(1-methyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1H-indol-3-yl)(phenyl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((4-iodophenyl)(1-methyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1H-indol-3-yl)(4-(trifluoromethyl)phenyl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((4-cyanophenyl)(1-methyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1H-indol-3-yl)(4-nitrophenyl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1H-indol-3-yl)(naphthalen-2-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1H-indol-3-yl)(thiophen-2-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, (bis(1-methyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((5-bromo-1-methyl-1H-indol-3-yl)(3,4,5-trimethoxyphenyl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((3,4-dimethoxyphenyl)(1,5-dimethyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((3,4-dimethoxyphenyl)(1,6-dimethyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((3,4-dimethoxyphenyl)(1,4-dimethyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate).

[0018] Preferably, in step (1), the phosphine oxide compound is selected from any one of di-p-tolylphosphine oxide, di-m-tolylphosphine oxide, di-o-tolylphosphine oxide, bis(4-(tert-butyl)phenyl)phosphine oxide, bis(4-methoxyphenyl)phosphine oxide, bis(4-fluorophenyl)phosphine oxide, bis(3-chlorophenyl)phosphine oxide, di(naphthalen-2-yl)phosphine oxide, phenyl(p-tolyl)phosphine oxide.

[0019] Preferably, in step (2), the quenching, extraction, washing, drying, concentration, and purification are specifically as follows: quenching with saturated NaCl solution, extracting with ethyl acetate, washing the combined organic phases successively with saturated brine, drying with anhydrous sodium sulfate, and concentrating under vacuum to obtain the crude product; the crude product is purified by silica gel column chromatography, and the column chromatography separation conditions are as follows: the stationary phase is silica gel powder with 300 - 400 mesh, the mobile phase is dichloromethane A and methanol B, and the mobile phase change program A:B is 100:1.

[0020] Compared with the disadvantages and deficiencies of the prior art, the present invention has the following beneficial effects: The present invention provides a method for realizing the reaction of indolylphosphonium salts with phosphine oxides in a solvent to generate a series of 3-(phosphoryl)methylindole compounds under metal - and additive - free conditions. This reaction has mild conditions, good functional group tolerance, and characteristics such as simple post - treatment, green steps, low pollution, and high economic benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 1H NMR spectrum of the target product a in Example 1 of the present invention;

[0022] Figure 2 31P NMR spectrum of the target product a in Example 1 of the present invention;

[0023] Figure 3 13C NMR spectrum of the target product a in Example 1 of the present invention;

[0024] Figure 4 1H NMR spectrum of the target product b in Example 2 of the present invention;

[0025] Figure 5 31P NMR spectrum of the target product b in Example 2 of the present invention;

[0026] Figure 6 13C NMR spectrum of the target product b in Example 2 of the present invention;

[0027] Figure 7 1H NMR spectrum of the target product c in Example 3 of the present invention;

[0028] Figure 8 31P NMR spectrum of the target product c in Example 3 of the present invention;

[0029] Figure 9 13C NMR spectrum of the target product c in Example 3 of the present invention;

[0030] Figure 10 1H NMR spectrum of the target product d in Example 4 of the present invention;

[0031] Figure 11 31P NMR spectrum of the target product d in Example 4 of the present invention;

[0032] Figure 12 The carbon spectrum of the target product d in Example 4 of the present invention;

[0033] Figure 13 The hydrogen spectrum of the target product e in Example 5 of the present invention;

[0034] Figure 14 The phosphorus spectrum of the target product e in Example 5 of the present invention;

[0035] Figure 15 The carbon spectrum of the target product e in Example 5 of the present invention;

[0036] Figure 16 The hydrogen spectrum of the target product f in Example 6 of the present invention;

[0037] Figure 17 The phosphorus spectrum of the target product f in Example 6 of the present invention;

[0038] Figure 18 The carbon spectrum of the target product f in Example 6 of the present invention. Detailed implementation manners

[0039] In order to make the objectives, technical solutions and advantages of the present invention more clear and understandable, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0040] In the following examples, the starting material indolylphosphonium salt compound was prepared according to the method reported in the reference (Angew. Chem. Int. Ed. 2017, 56, 5106 - 5110), and the phosphine oxide was prepared according to the method reported in the reference (Eur. J. Org. Chem. 2022, 87, 7720 - 7733). Without special instructions, other starting materials were purchased commercially.

[0041] Example 1

[0042] (1) ((3,4-Dimethoxyphenyl)(1-methyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate (311.3 mg, 0.45 mmol, 1.5 equiv.), diphenylphosphine oxide (60.7 mg, 0.3 mmol, 1 equiv.) and acetonitrile (3.5 mL) were successively added to a 10 mL Schlenk tube, and the reaction mixture was stirred at 85 °C for 12 h under nitrogen.

[0043] (2) After the reaction in step (1) ended, it was quenched with saturated NaCl solution and extracted with ethyl acetate (20 mL×3); the combined organic phases were successively washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product; the crude product was purified by silica gel column chromatography. The column chromatography separation conditions were as follows: the stationary phase was silica gel powder of 300 - 400 mesh, the mobile phase was dichloromethane (A) and methanol (B), and the mobile phase change program (A:B) was 100:1. Finally, 114.1 mg of the target product a was obtained.

[0044] The above target product a was characterized as Figures 1 - 3 shown below: white solid;

[0045] 1 H NMR (400 MHz, CDCl3): δ 7.80 - 7.74 (m, 3H), 7.47 (d, J = 7.2 Hz, 2H), 7.44 (d, J = 3.4 Hz, 1H), 7.37 (d, J = 6.9 Hz, 2H), 7.33 - 7.28 (m, 4H), 7.23 (d, J = 8.1 Hz, 1H), 7.18 - 7.14 (m, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 6.74 (s, 1H), 6.62 (d, J = 8.3 Hz, 1H), 5.04 (d, J = 9.8 Hz, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 3.65 (s, 3H) ppm.

[0046] 31 P NMR (162 MHz, CDCl3): δ 33.48 (s, 1P) ppm.

[0047] 13 C NMR (100 MHz, CDCl3): δ 148.3 (d, J = 1.8 Hz), 147.7 (d, J = 2.2 Hz), 136.4, 133.7 - 132.4 (m, 1C), 131.5 - 131.2 (m, 1C), 129.2 (d, J = 5.6 Hz), 129.0 (d, J = 5.3 Hz), 128.5 (d, J = 11.2 Hz), 128.1 (d, J = 11.6 Hz), 127.7 (d, J = 10.0 Hz), 122.2 (d, J = 5.9 Hz), 121.7, 119.1, 118.3, 112.9 (d, J = 4.8 Hz), 110.8 (d, J = 1.9 Hz), 109.9 (d, J = 4.6 Hz), 109.4, 55.78, 55.77, 43.1 (d, J = 67.8 Hz), 33.0 ppm.

[0048] HRMS (m / z): calcd for C 30 H 29 NO3P + [M + H] + 482.1880, found: 482.1880.

[0049] According to the characterization data, the prepared reaction product is ((3,4 - dimethoxyphenyl)(1 - methyl - 1H - indol - 3 - yl)methyl)diphenylphosphine oxide (purity > 98%), and the structural formula of this compound is:

[0050]

[0051] The product yield was calculated, and the result was 79%.

[0052] Example 2

[0053] (1) ((5 - Bromo - 1 - methyl - 1H - indol - 3 - yl)(3,4,5 - trimethoxyphenyl)methyl)triphenylphosphonium trifluoromethanesulfonate (360.3 mg, 0.45 mmol, 1.5 equiv.), diphenylphosphine oxide (60.7 mg, 0.3 mmol, 1 equiv.), and acetonitrile (3.5 mL) were successively added to a 10 mL Schlenk tube, and the reaction mixture was stirred at 85 °C for 12 h under nitrogen.

[0054] (2) After the reaction in step (1) was completed, it was quenched with saturated NaCl solution and extracted with ethyl acetate (20 mL × 3); the combined organic phases were successively washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product; the crude product was purified by silica gel column chromatography. The column chromatography separation conditions were: the stationary phase was silica gel powder of 300 - 400 mesh, the mobile phase was dichloromethane (A) and methanol (B), and the mobile phase change program (A:B) was 100:1, and finally 86.8 mg of the target product b was obtained.

[0055] The above - mentioned target product b was characterized as Figures 4 - 6 shown, and the results were: white solid;

[0056] 11H NMR (400 MHz, CDCl3): δ 7.75 (s, 1H), 7.73 - 7.70 (m, 2H), 7.53 (d, J = 1.7 Hz, 1H), 7.47 - 7.43 (m, 2H), 7.43 - 7.40 (m, 1H), 7.38 (dd, J = 7.5, 1.4 Hz, 1H), 7.34 (d, J = 2.9 Hz, 1H), 7.33 - 7.32 (m, 1H), 7.31 (d, J = 2.9 Hz, 1H), 7.29 (d, J = 2.9 Hz, 1H), 7.23 (dd, J = 8.7, 1.8 Hz, 1H), 7.10 (d, J = 8.7 Hz, 1H), 6.45 (d, J = 1.8 Hz, 2H), 4.89 (d, J = 10.0 Hz, 1H), 3.73 (s, 3H), 3.69 (s, 3H), 3.65 (s, 6H) ppm.

[0057] 31 31P NMR (162 MHz, CDCl3): δ 32.22 (s, 1P) ppm.

[0058] 13 13C NMR (100 MHz, CDCl3): δ 152.8 (d, J = 1.8 Hz), 136.9 (d, J = 2.8 Hz), 135.1, 133.3 - 131.9 (m, 1C), 131.8 - 131.7 (m, 1C), 131.5 - 131.1 (m, 1C), 130.5 (d, J = 5.3 Hz), 129.3 (d, J = 9.5 Hz), 128.6 (d, J = 11.4 Hz), 128.1 (d, J = 11.8 Hz), 124.6, 120.8, 112.7, 111.0, 109.3 (d, J = 4.5 Hz), 107.0 (d, J = 5.3 Hz), 60.9, 56.1, 43.8 (d, J = 66.8 Hz), 33.2 ppm.

[0059] HRMS (m / z): calcd for C 31 H 30 BrNO4P + [M + H] + 590.1090, found: 590.1094.

[0060] According to the characterization data, the prepared reaction product is ((5 - bromo - 1 - methyl - 1H - indol - 3 - yl)(3,4,5 - trimethoxyphenyl)methyl)diphenylphosphine oxide (purity > 98%), and the structural formula of this compound is:

[0061]

[0062] The product yield was calculated, and the result was 49%.

[0063] Example 3

[0064] (1) ((3,4-Dimethoxyphenyl)(1,5-dimethyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate (317.6 mg, 0.45 mmol, 1.5 equiv.), diphenylphosphine oxide (60.7 mg, 0.3 mmol, 1 equiv.), and acetonitrile (3.5 mL) were successively added to a 10 mL Schlenk tube, and the reaction mixture was stirred at 85 °C for 12 h under nitrogen.

[0065] (2) After the reaction in step (1) was completed, it was quenched with saturated NaCl solution and extracted with ethyl acetate (20 mL × 3); the combined organic phases were successively washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product; the crude product was purified by silica gel column chromatography. The column chromatography separation conditions were as follows: the stationary phase was silica gel powder of 300 - 400 mesh, the mobile phase was dichloromethane (A) and methanol (B), and the mobile phase change program (A:B) was 100:1. Finally, 90.0 mg of the target product c was obtained.

[0066] The above target product c was characterized as Figures 7 - 9 shown, and the results were: white solid;

[0067] 1 H NMR (400 MHz, CDCl3): δ 7.86 - 7.79 (m, 2H), 7.77 (s, 1H), 7.55 - 7.50 (m, 2H), 7.44 (t, J = 7.0 Hz, 2H), 7.40 - 7.32 (m, 5H), 7.18 (d, J = 8.3 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.80 (s, 1H), 6.69 (d, J = 8.3 Hz, 1H), 5.07 (d, J = 9.9 Hz, 1H), 3.82 (s, 3H), 3.73 (s, 3H), 3.72 (s, 3H), 2.45 (s, 3H) ppm.

[0068] 31 P NMR (162 MHz, CDCl3): δ 32.82 (s, 1P) ppm.

[0069] 1313C NMR (100 MHz, CDCl3): δ 148.2 - 147.6 (m, 1C), 134.9, 133.9 - 132.5 (m, 1C), 132.2 - 132.0 (m, 1C), 131.4, 131.3, 131.2 (d, J = 4.1 Hz), 129.3 (d, J = 5.5 Hz), 129.0 (d, J = 5.7 Hz), 128.7 - 128.3 (m, 1C), 128.1 - 127.8 (m, 1C), 123.3, 122.2 (d, J = 5.9 Hz), 117.9, 112.9 (d, J = 4.5 Hz), 110.7, 109.2 (d, J = 4.6 Hz), 109.0, 55.8 (s, 2C), 43.1 (d, J = 67.8 Hz), 33.0, 21.6 ppm.

[0070] HRMS (m / z): calcd for C 31 H 31 NO3P + [M + H] + 496.2036, found: 496.2036.

[0071] According to the characterization data, the prepared reaction product is ((3,4 - dimethoxyphenyl)(1,5 - dimethyl - 1H - indol - 3 - yl)methyl)diphenylphosphine oxide (purity > 98%), and the structural formula of this compound is:

[0072]

[0073] The product yield was calculated, and the result was 61%.

[0074] Example 4

[0075] (1) ((3,4 - Dimethoxyphenyl)(1 - methyl - 1H - indol - 3 - yl)methyl)triphenylphosphonium trifluoromethanesulfonate (311.3 mg, 0.45 mmol, 1.5 equiv.), bis(p - tolyl)phosphine oxide (69.1 mg, 0.3 mmol, 1 equiv.), and acetonitrile (3.5 mL) were successively added to a 10 mL Schlenk tube, and the reaction mixture was stirred at 85 °C for 12 h under nitrogen.

[0076] (2) After the reaction in step (1) was completed, it was quenched with saturated NaCl solution and extracted with ethyl acetate (20 mL × 3); the combined organic phases were successively washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product; the crude product was purified by silica gel column chromatography. The column chromatography separation conditions were as follows: the stationary phase was silica gel powder of 300 - 400 mesh, the mobile phase was dichloromethane (A) and methanol (B), and the mobile phase change program (A:B) was 100:1. Finally, 101.1 mg of the target product d was obtained.

[0077] The above target product d was characterized as Figures 10 - 12 shown below: white solid;

[0078] 1 1H NMR (400 MHz, CDCl3): δ 7.75 (s, 1H), 7.65 (dd, J = 10.6, 7.9 Hz, 2H), 7.46 (d, J = 7.8 Hz, 1H), 7.33 (dd, J = 10.9, 7.8 Hz, 2H), 7.22 (d, J = 8.1 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.11 - 7.06 (m, 4H), 7.05 - 7.01 (m, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.73 (s, 1H), 6.63 (d, J = 8.3 Hz, 1H), 5.00 (d, J = 9.9 Hz, 1H), 3.75 (s, 3H), 3.68 (s, 3H), 3.65 (s, 3H), 2.30 (s, 3H), 2.26 (s, 3H) ppm.

[0079] 31 31P NMR (162 MHz, CDCl3): δ 33.68 (s, 1P) ppm.

[0080] 13 13C NMR (100 MHz, CDCl3): δ 148.1, 147.6 (d, J = 2.8 Hz), 141.7 (d, J = 2.5 Hz), 141.5, 136.4, 131.4 - 131.1 (m, 1C), 130.7 - 129.7 (m, 1C), 129.4 - 129.1 (m, 1C), 128.8 (d, J = 12.0 Hz), 127.7 (d, J = 10.1 Hz), 122.2 (d, J = 6.0 Hz), 121.6, 119.0, 118.3, 113.0 (d, J = 4.8 Hz), 110.7 (d, J = 2.1 Hz), 110.1 (d, J = 4.6 Hz), 109.3, 55.7, 55.6, 43.2 (d, J = 67.8 Hz), 32.9, 21.54, 21.53 ppm.

[0081] HRMS (m / z): calcd for C 32 H 33 NO3P + [M + H] + 510.2193, found: 510.2192.

[0082] According to the characterization data, the obtained reaction product is ((3,4 - dimethoxyphenyl)(1 - methyl - 1H - indol - 3 - yl)methyl)bis(p - tolyl)phosphine oxide (purity > 98%), and the structural formula of this compound is:

[0083]

[0084] The product yield was calculated, and the result was 66%.

[0085] Example 5

[0086] (1) ((3,4 - dimethoxyphenyl)(1 - methyl - 1H - indol - 3 - yl)methyl)triphenylphosphonium trifluoromethanesulfonate (311.3 mg, 0.45 mmol, 1.5 equiv.), phenyl(p - tolyl)phosphine oxide (64.9 mg, 0.3 mmol, 1 equiv.), and acetonitrile (3.5 mL) were successively added to a 10 mL Schlenk tube, and the reaction mixture was stirred at 85 °C for 12 h under nitrogen.

[0087] (2) After the reaction in step (1) was completed, it was quenched with saturated NaCl solution and extracted with ethyl acetate (20 mL × 3); the combined organic phases were successively washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product; the crude product was purified by silica gel column chromatography, and the column chromatography separation conditions were: the stationary phase was silica gel powder of 300 - 400 mesh, the mobile phase was dichloromethane (A) and methanol (B), and the mobile phase change program (A:B) was 100:1, and finally 119.5 mg of the target product e was obtained.

[0088] The above - mentioned target product e was characterized as Figures 13 - 15 shown, and the results were: white solid;

[0089] 11H NMR (400 MHz, CDCl3): δ 7.76 (dd, J = 10.6, 6.6 Hz, 2H), 7.67 (dd, J = 10.7, 8.1 Hz, 1H), 7.49 - 7.42 (m, 2H), 7.36 (dd, J = 11.0, 8.0 Hz, 2H), 7.29 (dt, J = 7.4, 3.7 Hz, 2H), 7.24 - 7.21 (m, 1H), 7.18 - 7.13 (m, 1H), 7.10 (td, J = 8.0, 2.3 Hz, 2H), 7.05 - 7.00 (m, 1H), 6.90 - 6.83 (m, 1H), 6.74 (dt, J = 6.7, 1.6 Hz, 1H), 6.62 (t, J = 8.4 Hz, 1H), 5.03 (dd, J = 9.9, 6.4 Hz, 1H), 3.75 (d, J = 3.3 Hz, 3H), 3.68 (d, J = 2.2 Hz, 3H), 3.65 (d, J = 3.0 Hz, 3H), 2.29 (d, J = 12.5 Hz, 3H) ppm.

[0090] 31 31P NMR (162 MHz, CDCl3): δ 33.54 (d, J = 11.8 Hz, 1P) ppm.

[0091] 13 13C NMR (100 MHz, CDCl3): δ 148.2 (t, J = 1.6 Hz), 147.62 - 147.58 (m, 1C), 141.9 - 141.6 (m, 1C), 136.4 (d, J = 1.2 Hz), 134.0 - 132.2 (m, 1C), 131.5 - 131.1 (m, 1C), 130.2 (d, J = 42.9 Hz), 129.4 (d, J = 3.0 Hz), 129.2 - 129.1 (m, 1C), 129.1 - 129.0 (m, 1C), 128.8 (d, J = 12.0 Hz), 128.4 (d, J = 11.5 Hz), 128.0 (d, J = 11.6 Hz), 127.8 - 127.6 (m, 1C), 122.2 - 122.1 (m, 1C), 121.6, 119.0, 118.3 (d, J = 2.1 Hz), 112.9 (d, J = 4.8 Hz), 110.8 - 110.7 (m, 1C), 110.1 - 110.0 (m, 1C), 109.3, 55.7 (d, J = 1.9 Hz), 55.6, 43.1 (d, J = 67.5 Hz), 32.9 (d, J = 1.3 Hz), 21.6 ppm.

[0092] HRMS (m / z): calcd for C 31 H31 NO3P + [M+H] + 496.2036, found: 496.2034.

[0093] According to the characterization data, the prepared reaction product is (3,4-dimethoxyphenyl)(1-methyl-1H-indol-3-yl)methyl)(phenyl)(p-tolyl)phosphine oxide (purity > 98%), and the structural formula of this compound is:

[0094]

[0095] The product yield was calculated, and the result was 80%.

[0096] Example 6

[0097] (1) (Bis(1-methyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate (308.1 mg, 0.45 mmol, 1.5 equiv.), diphenylphosphine oxide (60.7 mg, 0.3 mmol, 1 equiv.), and acetonitrile (3.5 mL) were successively added to a 10 mL Schlenk tube, and the reaction mixture was stirred at 85 °C for 12 h under nitrogen.

[0098] (2) After the reaction in step (1) was completed, it was quenched with saturated NaCl solution and extracted with ethyl acetate (20 mL × 3); the combined organic phases were successively washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product; the crude product was purified by silica gel column chromatography, and the column chromatography separation conditions were: the stationary phase was silica gel powder of 300 - 400 mesh, the mobile phase was dichloromethane (A) and methanol (B), and the mobile phase change program (A:B) was 100:1, and finally 65.9 mg of the target product f was obtained.

[0099] The above target product f was characterized as Figures 16 - 18 shown, and the results were: white solid;

[0100] 1 H NMR (400 MHz, CDCl3): δ 7.64 (d, J = 1.2 Hz, 1H), 7.63 - 7.61 (m, 2H), 7.59 (d, J = 1.5 Hz, 1H), 7.49 (d, J = 2.1 Hz, 2H), 7.39 (s, 1H), 7.37 (s, 1H), 7.29 (td, J = 7.3, 1.5 Hz, 2H), 7.23 - 7.18 (m, 5H), 7.16 (s, 1H), 7.11 - 7.07 (m, 2H), 6.95 - 6.91 (m, 2H), 5.44 (d, J = 9.5 Hz, 1H), 3.67 (s, 6H) ppm.

[0101] 31 PNMR (162 MHz, CDCl3): δ 33.12 (s, 1P) ppm.

[0102] 13 C NMR (100 MHz, CDCl3): δ 136.3, 133.8, 132.8, 131.4 - 131.3 (m, 1C), 129.5 (d, J = 5.4 Hz), 128.2 (d, J = 11.2 Hz), 127.6 (d, J = 7.2 Hz), 121.3, 118.9, 118.3, 110.6 (d, J = 5.1 Hz), 109.1, 33.4 (d, J = 70.0 Hz), 33.0 ppm.

[0103] HRMS (m / z): calcd for C 31 H 28 N2OP + [M + H] + 475.1934, found: 475.1936.

[0104] According to the characterization data, the prepared reaction product is bis(1 - methyl - 1H - indol - 3 - yl)methyldiphenylphosphine oxide (purity > 98%), and the structural formula of this compound (reference: Chem. Commun., 2025, 61, 4718 - 4721) is:

[0105]

[0106] The product yield was calculated, and the result was 46%.

[0107] Example 7

[0108] Example 7 is basically the same as Example 1, except that in step (1), the solvent is different when reacting at 85 °C for 12 h, as shown in Table 1 below:

[0109] Table 1

[0110]

[0111]

[0112] As can be seen from Table 1, under the same reaction conditions, when acetonitrile (MeCN) is used as the solvent, the highest reaction yield is 87%.

[0113] Example 8

[0114] Example 8 is basically the same as Example 1, except that in step (1), when acetonitrile (MeCN) is used as the solvent, the reaction temperature is different at 12 h of reaction, as shown in Table 2 below:

[0115] Table 2

[0116] Temperature (°C) Yield (%) Room temperature 33 40 68 60 76 85 87 100 83

[0117] As can be seen from Table 2, under the same reaction conditions, at a reaction temperature of 85 °C, the reaction yield is the highest; further increasing the reaction temperature will instead lead to a decrease in the reaction yield.

[0118] Example 9

[0119] Example 9 is basically the same as Example 1, except that in step (1), when acetonitrile (MeCN) is used as the solvent and the reaction temperature is 85 °C, the reaction time is different, as shown in Table 3 below:

[0120] Table 3

[0121] Reaction time (h) Yield (%) 6 62 12 87

[0122] As can be seen from Table 3, under the same reaction conditions, prolonging the reaction time is beneficial to the increase of the reaction yield; when it is 12 h, the reaction yield is 87%.

[0123] Example 10

[0124] Example 10 is basically the same as Example 1, except that in step (1), the indolylphosphonium salt is different, and the specific target products obtained are shown in Table 7 below:

[0125] Table 7

[0126]

[0127] Example 11

[0128] Example 11 is basically the same as Example 4, except that in step (1), the phosphine oxide compound is different, and the specific target products obtained are shown in Table 8 below:

[0129] Table 8

[0130]

[0131] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, and improvements made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for preparing a 3-(phosphonyl)methyl indole compound, characterized in that, The method comprises the following steps: (1) Adding the phosphine oxide compound shown in formula (II) and the indolyl quaternary phosphonium salt compound shown in formula (III) into a solvent, and reacting at room temperature to 100 °C for 6 to 12 h; (2) After the reaction in step (1) is completed, quenching, extraction, washing, drying, concentration, and purification are carried out in sequence to obtain the 3-(phosphoryl)methylindole compound shown in formula (I); wherein, R is selected from one of methyl and halogen; Ar is selected from any one of methoxy-substituted phenyl, halogen-substituted phenyl, cyano-substituted phenyl, trifluoromethyl-substituted phenyl, nitro-substituted phenyl, thiophenyl, naphthyl, and N-methylindolyl; Ar' is selected from any one of phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, tert-butyl-substituted phenyl, halogen-substituted phenyl, and naphthyl; Ar" is selected from any one of methyl-substituted phenyl, methoxy-substituted phenyl, tert-butyl-substituted phenyl, halogen-substituted phenyl, and naphthyl.

2. The method according to claim 1, wherein, In step (1), the reaction temperature is 85 °C and the reaction time is 12 h.

3. The method according to claim 1, characterized in that In step (1), the solvent is selected from any one of acetonitrile, toluene, water, tert-butanol, dimethyl sulfoxide, and N,N-dimethylformamide.

4. The method according to claim 3, characterized in that, The solvent is acetonitrile.

5. The method according to claim 1, characterized in that In step (1), the molar ratio of the indolyl quaternary phosphonium salt compound to the phosphine oxide compound is 1.5:

1.

6. The method according to claim 1, characterized in that, In step (1), the indolylphosphonium salt compound is selected from any one of ((3,4-dimethoxyphenyl)(1-methyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1H-indol-3-yl)(3,4,5-trimethoxyphenyl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((4-bromophenyl)(1-methyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1H-indol-3-yl)(phenyl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((4-iodophenyl)(1-methyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1H-indol-3-yl)(4-(trifluoromethyl)phenyl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((4-cyanophenyl)(1-methyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1H-indol-3-yl)(4-nitrophenyl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1H-indol-3-yl)(naphthalen-2-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1H-indol-3-yl)(thiophen-2-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, (bis(1-methyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((5-bromo-1-methyl-1H-indol-3-yl)(3,4,5-trimethoxyphenyl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((3,4-dimethoxyphenyl)(1,5-dimethyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((3,4-dimethoxyphenyl)(1,6-dimethyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((3,4-dimethoxyphenyl)(1,4-dimethyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate).

7. The method according to claim 1, characterized in that In step (1), the phosphine oxide compound is selected from any one of di-p-tolylphosphine oxide, di-m-tolylphosphine oxide, di-o-tolylphosphine oxide, bis(4-(tert-butyl)phenyl)phosphine oxide, bis(4-methoxyphenyl)phosphine oxide, bis(4-fluorophenyl)phosphine oxide, bis(3-chlorophenyl)phosphine oxide, di(naphthalen-2-yl)phosphine oxide, phenyl(p-tolyl)phosphine oxide.

8. The method according to claim 1, wherein In step (2), the quenching, extraction, washing, drying, concentration, and purification are specifically as follows: quenching with saturated NaCl solution, extracting with ethyl acetate, washing the combined organic phases successively with saturated brine, drying with anhydrous sodium sulfate, and concentrating in vacuo to obtain a crude product; the crude product is purified by silica gel column chromatography, and the column chromatography separation conditions are as follows: the stationary phase is silica gel powder of 300 - 400 mesh, the mobile phase is dichloromethane A and methanol B, and the mobile phase change program A:B is 100:1.

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