A method for the preparation of difluoromethyl analogs by photocatalytic lmct

Abstract

The application discloses a method for preparing difluoromethyl compounds by using a photocatalytic LMCT strategy and belongs to the technical field of catalytic synthesis, in particular to a method for preparing difluoromethyl compounds by using a photocatalytic LMCT strategy. The application solves the problems of the existing synthesis method, such as being too complicated, needing pre-activation and a stoichiometric oxidant. The method comprises the following steps: adding olefin compounds, difluoroacetic acid, 2,4,6-triisopropylbenzenethiol and Fe(acac)3 into a solvent to obtain a reaction mixed solution, irradiating the reaction mixed solution by using an LED light source under room temperature and in an inert gas atmosphere, and obtaining difluoromethyl compounds. The application embodies the green reaction and the mild reaction. The method is very simple to operate, various raw materials are commercially available, olefins are easy to prepare, and the reaction can be efficiently realized by using a catalytic amount of a cheap metal catalyst through a one-pot method, so that the method has potential industrial application value. The application can be applied to the field of organic synthesis.

Description

Technical Field

[0001] This invention belongs to the field of catalytic synthesis technology, specifically relating to a method for preparing difluoromethyl compounds using a photocatalytic LMCT strategy. Background Technology

[0002] Fluorine possesses a unique ability to modulate the polarity, metabolic stability, lipophilicity, and solubility of potential drug candidates, making the development of novel fluorine-containing compounds of significant research importance. It is well known that difluoromethyl (CF₂H) is isopolar and homogeneous with hydroxyl (-OH) and thiol (-SH) units, serving as a lipophilic hydrogen bond donor. Therefore, the selective addition of CF₂H groups to the molecular structure, particularly through the hydrodifluoromethylation reaction with alkenes via CF₂H precursors, will be of great significance.

[0003] Previous reported CF2H precursors for difluoromethylation reactions include (difluoromethyl)zinc reagents, difluoromethyltrimethylsilanes, and difluoroalkylsulfonyl compounds. However, most methods rely on pre-activated precursors requiring multiple steps, significantly increasing reaction costs. Difluoroacetic acid is an excellent fluorine source and a rich industrial raw material for producing various pharmaceutical intermediates. Therefore, developing a synthetic scheme using this inexpensive industrial chemical as a difluoroalkylating agent is highly significant. However, the high oxidation potential of difluoroalkylcarboxylic acid anions greatly limits the application of difluoroacetic acid. Although the use of high-valent iodine salts can achieve the generation of difluoromethyl radicals, the stoichiometric use of iodine reagents makes the reaction unsoundly atom-economical. Therefore, seeking a method for synthesizing difluoromethyl compounds using inexpensive metal-catalyzed reactions under green, mild, convenient, efficient, and environmentally friendly conditions is a crucial problem that urgently needs to be solved. Summary of the Invention

[0004] This invention solves the problems of existing synthesis methods being too cumbersome and requiring pre-activation and stoichiometric oxidants, and provides a method for preparing difluoromethyl compounds by photocatalytic LMCT.

[0005] This invention utilizes a photocatalytic LMCT strategy, using a catalytic amount of Fe(acac)3 as a photocatalyst. Under photocatalytic action, the ligand-to-metal charge transfer (LMCT) process generates a difluoromethyl radical intermediate, which further attacks the olefin. Under the action of the hydrogen atom transfer catalyst 2,4,6-triisopropylbenzylthiophenol, the difluoromethylation reaction of the olefin is realized, providing a milder, greener, and more efficient method.

[0006] A method for preparing difluoromethyl compounds by photocatalytic LMCT is carried out according to the following steps:

[0007] I. An olefinic compound, difluoroacetic acid, 2,4,6-triisopropylbenzylthiophenol, and Fe(acac)3 are added to a solvent to obtain a reaction mixture solution;

[0008] 2. Under nitrogen atmosphere and room temperature conditions, the reaction mixture was irradiated with LEDs for 24-36 hours. After extraction and solvent removal by rotary evaporation, the product was separated and purified by thin-layer chromatography. The obtained product was a difluoromethyl compound, thus completing the preparation.

[0009] Furthermore, the chemical structural formula of the olefin compound mentioned in step one is as follows: R1 is a phenyl or alkyl compound, and R2 is a phenyl or alkyl compound.

[0010] Furthermore, the solvent mentioned in step one is dimethyl sulfoxide.

[0011] Furthermore, the chemical structural formula of the difluoroacetic acid mentioned in step one is as follows:

[0012] Furthermore, the chemical structural formula of 2,4,6-triisopropylbenzylthiophenol described in step one is as follows:

[0013] The reaction formula of this invention is as follows:

[0014]

[0015] This invention proposes a reaction mechanism based on the difluoromethylation reaction of olefins, as follows:

[0016]

[0017] Initially, Fe(acac)3 can complex with difluoroacetic acid to obtain intermediate I. Intermediate I undergoes LMCT under photo-induced reaction to release radical intermediate II. This intermediate can be further decarboxylated to generate difluoromethyl radical intermediate III. At this point, the difluoromethyl radical can attack the olefin to generate intermediate IV. Then, under the action of hydrogen atom transfer catalyst, it gains hydrogen protons to realize the difluoromethylation of the olefin. At the same time, the thiol radical intermediate can undergo electron transfer with divalent iron to realize a dual catalytic cycle process.

[0018] Beneficial effects of this invention:

[0019] Compared with existing technologies, this invention utilizes a low-cost metal-catalyzed LMCT strategy, providing a greener, milder, atom-economical, simple, and highly efficient method for constructing difluoromethyl compounds, with the following main advantages:

[0020] (1) The reaction system is a difluoromethylation reaction of olefins. Using inexpensive metal catalysts, complex difluoromethyl compounds can be constructed in one step through photoinduced LMCT strategy, which is convenient to operate.

[0021] (2) The reaction can achieve the synthesis of challenging difluoromethyl compounds by light at room temperature, and the reaction conditions are very green and mild.

[0022] (3) The reaction system uses difluoroacetic acid, 2,4,6-triisopropylbenzylthiophenol and Fe(acac)3, which are all inexpensive and readily available chemicals. Difluoromethyl compounds are the main products of the reaction, which reflects the atom economy of the reaction. The reaction system is economical and efficient.

[0023] (4) The reaction system has good substrate universality and can be carried out in a large-scale experiment by the "one-pot method". The gram-scale reaction can be achieved by irradiation with light for 36-48 hours at room temperature, and the yield is good, which shows the high efficiency of the reaction.

[0024] (5) The conversion of this reaction can be achieved by using a catalytic amount of inexpensive metal catalyst and a catalytic amount of hydrogen atom transfer catalyst without the need for stoichiometric oxidant, which reflects the energy-saving and environmentally friendly nature of the reaction and has potential application value.

[0025] This invention is used to prepare difluoromethyl compounds. Attached Figure Description

[0026] Figure 1 It is the difluoromethyl compound-1 obtained in Example 1. 1 H NMR spectrum;

[0027] Figure 2 It is the difluoromethyl compound-1 obtained in Example 1. 13 C NMR spectrum;

[0028] Figure 3 It is the difluoromethyl compound-1 obtained in Example 1. 19 F NMR spectrum. Detailed Implementation

[0029] Specific Implementation Method 1: This implementation method provides a method for preparing difluoromethyl compounds using photocatalytic LMCT, which is carried out according to the following steps:

[0030] I. An olefinic compound, difluoroacetic acid, 2,4,6-triisopropylbenzylthiophenol, and Fe(acac)3 are added to a solvent to obtain a reaction mixture solution;

[0031] 2. Under nitrogen atmosphere and room temperature conditions, the reaction mixture was irradiated with LEDs for 24-36 hours. After extraction and solvent removal by rotary evaporation, the product was separated and purified by thin-layer chromatography. The obtained product was a difluoromethyl compound, thus completing the preparation.

[0032] This invention enables the difluoromethylation of olefins through the synergistic catalysis of a catalytic amount of inexpensive metal and a catalytic amount of hydrogen atom transfer catalyst, demonstrating the green nature of the reaction. The preparation of difluoromethyl compounds at room temperature demonstrates the mildness of the reaction. Furthermore, the use of inexpensive and commercially available Fe(acac)3 as the metal catalyst reflects the energy efficiency and environmental friendliness of the reaction. Moreover, the method of this invention is very simple to operate, uses a variety of commercially available raw materials, and facilitates the preparation of olefins. The gram-scale synthesis of this reaction can be achieved efficiently in a one-pot process using a catalytic amount of inexpensive metal catalyst, demonstrating potential industrial application value. This invention is applicable to the field of organic synthesis.

[0033] Specific Implementation Method Two; This implementation method differs from Specific Implementation Method One in that the chemical structural formula of the olefin compound described in step one is: R1 is a phenyl or alkyl compound, and R2 is a phenyl or alkyl compound. Everything else is the same as in Specific Embodiment 1.

[0034] Specific implementation method three; this implementation method differs from specific implementation methods one or two in that the solvent in step one is dimethyl sulfoxide. Everything else is the same as specific implementation methods one or two.

[0035] Specific Embodiment Four; This embodiment differs from Specific Embodiments One to Three in that the ratio of the olefin compound to the solvent in step one is 0.07–0.1 mmol: 1 mL. Everything else is the same as in Specific Embodiments One to Three.

[0036] Specific Implementation Method Five; This implementation method differs from Specific Implementation Methods One to Four in that the ratio of difluoroacetic acid to solvent in step one is 0.8–1.2 mmol: 1 mL. Everything else is the same as in Specific Implementation Methods One to Four.

[0037] Specific Implementation Method Six; This implementation method differs from Specific Implementation Methods One to Five in that the ratio of 2,4,6-triisopropylthiophenol to solvent in step one is 2-3 mg: 1 mL. Everything else is the same as in Specific Implementation Methods One to Five.

[0038] Specific Embodiment Seven; This embodiment differs from Specific Embodiments One to Six in that the ratio of Fe(acac)3 to solvent in step one is 3.5–4.5 mg: 1 mL. Everything else is the same as in Specific Embodiments One to Six.

[0039] Specific Implementation Method Eight; This implementation method differs from Specific Implementation Methods One to Seven in that: in step two, the wavelength of the LED light source is controlled to be 380-400nm, and the power is 10W. Everything else is the same as in Specific Implementation Methods One to Seven.

[0040] Specific Implementation Method Nine; This implementation method differs from Specific Implementation Methods One to Eight in that the solvent used for separation and purification by thin-layer chromatography in step two is a mixture of petroleum ether and ethyl acetate. Everything else is the same as in Specific Implementation Methods One to Eight.

[0041] Specific Embodiment Ten; This embodiment differs from Specific Embodiments One to Nine in that the volume ratio of petroleum ether to ethyl acetate is (2-10):1. Everything else is the same as in Specific Embodiments One to Nine.

[0042] The scope of this invention is not limited to the above-described embodiments; a combination of one or more specific embodiments can also achieve the purpose of the invention.

[0043] Example 1:

[0044] This embodiment describes a method for preparing difluoromethyl compounds by photocatalytic LMCT, which is carried out according to the following steps:

[0045] In this embodiment, olefin a1 is 2-methylallyl benzoate, with the structural formula:

[0046] 5 mg (8 mmol%) of photocatalyst Fe(acac)3 was added to 2 mL of solvent DMSO, followed by the addition of 0.2 mmol of olefin a1, 8 mmol% (8 μL) of 2,4,6-triisopropylbenzenethiophenol, and 1.0 mmol (66 μL) of difluoroacetic acid to obtain a reaction mixture. The mixture was deoxygenated by argon gas for 5 min, and then irradiated at room temperature for 24 h using LEDs with a power of 10 W and a wavelength of 390 nm ± 10 nm under magnetic stirring. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was removed by extraction and vacuum distillation, and the product was obtained by thin-layer chromatography. The product was identified as a difluoromethyl compound-1 by 1H NMR, 1C NMR, fluorine NMR, and high-resolution mass spectrometry, with the following structural formula:

[0047]

[0048] Purity 99%, yield 86%; its NMR data analysis is as follows: 1H NMR (400MHz, Chloroform-d) δppm=8.04(d,J=7.6Hz,2H),7.58(t,J=7.4Hz,1H),7.46(t,J=7.7Hz,2H),5.97(tt,J=56.6, 4.8Hz,1H),4.29-4.13(m,2H),2.27(dq,J=13.2,6.5Hz,1H),2.15-1.98(m,1H),1.93-1.72(m,1H),1.13(d,J=6.8Hz,3H). 19 F NMR (376MHz, Chloroform-d) δppm=-113.75--115.92(m). 13 C NMR(101MHz,Chloroform-d)δppm=166.47,133.17,130.06,129.60,128.52,116.59(t,J= 238.9Hz),68.96,37.98(t,J=20.8Hz),28.02(t,J=5.3Hz),17.14.HRMS(ESI)(m / z):[M+H] + called.for C 12 H 15 F2O2:229.1040, found:229.1032.

[0049] Example 2:

[0050] This embodiment describes a method for preparing difluoromethyl compounds by photocatalytic LMCT, which is carried out according to the following steps:

[0051] In this embodiment, olefin a2 is 4-phenyl-1-butene, with the structural formula [structure omitted].

[0052] 5 mg (8 mmol%) of photocatalyst Fe(acac)3 was added to 2 mL of solvent DMSO, followed by the addition of 0.2 mmol of olefin a2, 8 mmol% (8 μL) of 2,4,6-triisopropylbenzylthiophenol, and 1.0 mmol (66 μL) of difluoroacetic acid to obtain a reaction mixture. The mixture was deoxygenated by argon gas for 5 min, and then irradiated at room temperature for 24 h using LEDs with a power of 10 W and a wavelength of 390 nm ± 10 nm under magnetic stirring. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was removed by extraction and vacuum distillation, and the product was obtained by thin-layer chromatography. The product was identified as a difluoromethyl compound-2 by 1H NMR, 1C NMR, fluorine NMR, and high-resolution mass spectrometry, with the following structural formula:

[0053]

[0054] Purity 99%, yield 72%; its NMR data analysis is as follows: 1 H NMR(400MHz,Chloroform-d)δppm=7.28(t,J=7.4Hz,2H),7.22-7.13(m,3H),5.78(tt,J=56.9, 4.5Hz,1H),2.67-2.59(m,2H),1.92-1.76(m,2H),1.68(p,J=7.6Hz,2H),1.50(q,J=8.4Hz,2H). 19 F NMR (376MHz, Chloroform-d) δppm=7.28-115.81 (dt, J=57.0, 17.5Hz). 13 C NMR(101MHz,Chloroform-d)δppm=142.02,128.42,125.90,121.89-110.77(m), 35.71,34.01(t,J=20.7Hz),30.93,21.82(t,J=5.5Hz).HRMS(ESI)(m / z):[M+H] + called.for C 11 H 15 F2:185.1142,found:185.1140.

[0055] Example 3:

[0056] This embodiment describes a method for preparing difluoromethyl compounds by photocatalytic LMCT, which is carried out according to the following steps:

[0057] In this embodiment, olefin a3 is methyl 5-allyl-2-hydroxy-3-methoxybenzoate, with the structural formula [structure omitted].

[0058]

[0059] 5 mg (8 mmol%) of photocatalyst Fe(acac)3 was added to 2 mL of solvent DMSO, followed by the addition of 0.2 mmol of olefin a3, 8 mmol% (8 μL) of 2,4,6-triisopropylbenzenethiophenol, and 1.0 mmol (66 μL) of difluoroacetic acid to obtain a reaction mixture. The mixture was deoxygenated by argon gas for 5 min, and then irradiated at room temperature for 24 h using LEDs with a power of 10 W and a wavelength of 390 nm ± 10 nm under magnetic stirring. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was removed by extraction and vacuum distillation, and the product was separated by thin-layer chromatography. The product was identified as a difluoromethyl compound-3 by 1H NMR, 1C NMR, fluorine NMR, and high-resolution mass spectrometry, with the following structural formula:

[0060]

[0061] Purity 99%, yield 68%; its NMR data analysis is as follows: 1 H NMR(400MHz,Chloroform-d)δppm=10.86(s,1H),7.23(s,1H),6.86(d,J=1.7Hz,1H),5.82( tt,J=56.5,4.1Hz,1H),3.95(s,3H),3.90(s,3H),2.61(t,J=7.4Hz,2H),1.96-1.72(m,4H). 19 F NMR (376MHz, Chloroform-d) δppm = -115.79 (dt, J = 56.8, 17.1Hz). 13 C NMR(101MHz,Chloroform-d)δppm=170.79,150.44,148.50,131.54,120.02,117.17(t,J=239.0Hz),1 16.94,112.20,56.21,52.40,34.73,33.42(t,J=20.9Hz),23.74(t,J=5.2Hz).HRMS(ESI)(m / z):[M+H] + called.for C 13 H 17 F2O4:275.1095, found:275.1089.

[0062] Example 4

[0063] This embodiment describes a method for preparing difluoromethyl compounds by photocatalytic LMCT, which is carried out according to the following steps:

[0064] In this embodiment, olefin a4 is 4-(4-vinylcyclohexyl)benzonitrile, with the structural formula as follows:

[0065] 5 mg (8 mmol%) of photocatalyst Fe(acac)3 was added to 2 mL of solvent DMSO, followed by the addition of 0.2 mmol of olefin a4, 8 mmol% (8 μL) of 2,4,6-triisopropylbenzenethiophenol, and 1.0 mmol (66 μL) of difluoroacetic acid to obtain a reaction mixture. Argon gas was purged for 5 min to remove oxygen. The mixture was then irradiated at room temperature for 24 h using LEDs with a power of 10 W and a wavelength of 390 nm ± 10 nm under magnetic stirring. The reaction progress was monitored by TLC. After the reaction was complete, the solvent was removed by extraction and vacuum distillation. The product was then separated by thin-layer chromatography and identified as a difluoromethyl compound-4 by 1H NMR, 1C NMR, fluorine NMR, and high-resolution mass spectrometry. Its structural formula is as follows:

[0066]

[0067] Purity 99%, yield 67%; its NMR data analysis is as follows: 1 H NMR (400MHz, Chloroform-d) δppm = 7.57 (d, J = 8.3Hz, 2H), 7.30 (d, J = 8.2Hz, 2H), 5.81 (tt, J = 57.0, 4. 5Hz,1H),2.54(t,J=12.3Hz,1H),1.99-1.80(m,6H),1.52-1.31(m,5H),1.10(q,J=12.1,11.5Hz,2H). 19 FNMR (376MHz, Chloroform-d) δppm = -115.68 (dt, J = 56.8, 17.6Hz). 13 C NMR (101 MHz, Chloroform-d) δ ppm = 152.94, 132.26, 127.70, 119.21, 117.62 (t, J = 238.9 Hz), 109. 72,44.58,36.62,33.62,32.96,31.67(t,J=20.7Hz),29.22(t,J=5.0Hz).HRMS(ESI)(m / z):[M+H] + called.for C 16 H 20 F2N:286.1383, found:286.1385.

[0068] Example 5:

[0069] This invention discloses a method for preparing difluoromethyl compounds by photocatalytic LMCT, comprising the following steps:

[0070] In this embodiment, olefin a5 is allyl benzoate, with the structural formula as follows:

[0071] 5 mg (8 mmol%) of photocatalyst Fe(acac)3 was added to 2 mL of solvent DMSO, followed by the addition of 0.2 mmol of olefin a5, 8 mmol% (8 μL) of 2,4,6-triisopropylbenzylthiophenol, and 1.0 mmol (66 μL) of difluoroacetic acid to obtain a reaction mixture. The mixture was deoxygenated by argon gas for 5 min, and then irradiated at room temperature for 24 h using LEDs with a power of 10 W and a wavelength of 390 nm ± 10 nm under magnetic stirring. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was removed by extraction and vacuum distillation, and the product was obtained by thin-layer chromatography. The product was identified as a difluoromethyl compound-5 by 1H NMR, 1C NMR, fluorine NMR, and high-resolution mass spectrometry, with the following structural formula:

[0072]

[0073] Purity 99%, yield 56%; its NMR data analysis is as follows: 1 H NMR(400MHz,Chloroform-d)δppm=8.04(d,J=7.1Hz,2H),7.57(t,J=6.8Hz,1H),7 .45(t,J=7.7Hz,2H),6.10-5.73(m,1H),4.38(t,J=6.0Hz,2H),2.08-1.93(m,4H). 19 F NMR (376MHz, Chloroform-d) δppm = -116.25 (dt, J = 56.7, 17.2Hz). 13 C NMR(101MHz,Chloroform-d)δppm=166.52,133.15,130.08,129.61,128.49,116.82(t ,J=239.1Hz),63.94,31.04(t,J=21.5Hz),21.65(t,J=5.6Hz).HRMS(ESI)(m / z):[M+H] + called.for C 11 H 13 F2O2:215.0884, found:215.0882.

[0074] Example 6:

[0075] This invention discloses a method for preparing difluoromethyl compounds by photocatalytic LMCT, comprising the following steps:

[0076] In this embodiment, olefin a6 is allyloxyphenol, with the structural formula as follows:

[0077] 5 mg (8 mmol%) of photocatalyst Fe(acac)3 was added to 2 mL of solvent DMSO, followed by the addition of 0.2 mmol of olefin a6, 8 mmol% (8 μL) of 2,4,6-triisopropylbenzylthiophenol, and 1.0 mmol (66 μL) of difluoroacetic acid to obtain a reaction mixture. The mixture was deoxygenated by argon gas for 5 min, and then irradiated at room temperature for 24 h using LEDs with a power of 10 W and a wavelength of 390 nm ± 10 nm under magnetic stirring. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was removed by extraction and vacuum distillation, and the product was separated by thin-layer chromatography. The product was identified as a difluoromethyl compound-6 by 1H NMR, 1C NMR, fluorine NMR, and high-resolution mass spectrometry, with the following structural formula:

[0078]

[0079] Purity 99%, yield 71%; its NMR data analysis is as follows: 1 H NMR(400MHz,Chloroform-d)δppm=7.31-7.24(m,2H),6.95(t,J=7.3Hz,1H),6.88(d, J=7.9Hz,2H),5.90(tt,J=56.6,4.2Hz,1H),3.99(t,J=5.9Hz,2H),2.13-1.86(m,4H). 19 F NMR (376MHz, Chloroform-d) δppm = -116.07 (dt, J = 56.7, 17.4Hz). 13 C NMR(101MHz,Chloroform-d)δppm=158.74,129.56,120.93,117.15(t,J=238.8Hz) ,114.48,66.70,31.10(t,J=21.3Hz),22.17(t,J=5.6Hz).HRMS(ESI)(m / z):[M+H] + called.for C 10 H 13 F2O:187.0934, found:187.0944.

[0080] Example 7:

[0081] This embodiment describes a method for preparing difluoromethyl compounds by photocatalytic LMCT, which is carried out according to the following steps:

[0082] In this embodiment, olefin a7 is nicotinic acid 2-methylallyl ester, with the structural formula as follows:

[0083] 5 mg (8 mmol%) of photocatalyst Fe(acac)3 was added to 2 mL of solvent DMSO, followed by the addition of 0.2 mmol of olefin a7, 8 mmol% (8 μL) of 2,4,6-triisopropylbenzenethiophenol, and 1.0 mmol (66 μL) of difluoroacetic acid to obtain a reaction mixture. The mixture was deoxygenated by argon gas for 5 min, and then irradiated at room temperature for 24 h using LEDs with a power of 10 W and a wavelength of 390 nm ± 10 nm under magnetic stirring. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was removed by extraction and vacuum distillation, and the product was obtained by thin-layer chromatography. The product was identified as a difluoromethyl compound-7 by 1H NMR, 1C NMR, fluorine NMR, and high-resolution mass spectrometry, with the following structural formula:

[0084]

[0085] Purity 99%, yield 78%; its NMR data analysis is as follows: 1 H NMR (400MHz, Chloroform-d) δppm=9.23(s,1H),8.80(d,J=4.4Hz,1H),8.31(d,J=7.9Hz,1H),7.43(dd,J=7.9,4.9Hz,1H),5.97(tt ,J=56.5,4.7Hz,1H),4.37-4.16(m,2H),2.30(dt,J=13.4,6.6Hz,1H),2.13-1.98(m,1H),1.92-1.75(m,1H),1.15(d,J=6.8Hz,3H). 19 F NMR (376MHz, Chloroform-d) δppm = -114.88 (dtd, J = 56.6, 17.5, 10.0Hz). 13 C NMR(101MHz,Chloroform-d)δppm=165.09,153.55,150.79,137.12,125.97,123.45,116.41(t ,J=239.0Hz),69.32,37.79(t,J=20.9Hz),27.90(t,J=5.2Hz),17.09.HRMS(ESI)(m / z):[M+H] + called.forC 11 H 14 F2NO2:230.0993,found:230.0997.

[0086] Example 8:

[0087] This embodiment describes a method for preparing difluoromethyl compounds by photocatalytic LMCT, which is carried out according to the following steps:

[0088] In this embodiment, olefin a8 is 2-methylallylthiophene-2-carboxylate, with the structural formula as follows:

[0089] 5 mg (8 mmol%) of photocatalyst Fe(acac)3 was added to 2 mL of solvent DMSO, followed by the addition of 0.2 mmol of olefin a8, 8 mmol% (8 μL) of 2,4,6-triisopropylbenzylthiophenol, and 1.0 mmol (66 μL) of difluoroacetic acid to obtain a reaction mixture. The mixture was deoxygenated by argon gas for 5 min, and then irradiated at room temperature for 24 h using LEDs with a power of 10 W and a wavelength of 390 nm ± 10 nm under magnetic stirring. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was removed by extraction and vacuum distillation, and the product was obtained by thin-layer chromatography. The product was identified as a difluoromethyl compound-8 by 1H NMR, 1C NMR, fluorine NMR, and high-resolution mass spectrometry, with the following structural formula:

[0090]

[0091] Purity 99%, yield 66%; its NMR data analysis is as follows: 1 H NMR(400MHz,Chloroform-d)δppm=7.81(d,J=3.7Hz,1H),7.57(d,J=5.0Hz,1H),7.20-7.04(m,1H),5.96(tt,J=56 .6,4.8Hz,1H),4.34-4.05(m,2H),2.34-2.17(m,1H),2.13-1.95(m,1H),1.91-1.73(m,1H),1.11(d,J=6.8Hz,3H). 19 F NMR (376MHz, Chloroform-d) δppm=-108.38--125.13(m). 13 CNMR(101MHz,Chloroform-d)δppm=162.09,133.60,132.61,127.91,116.56(t,J=238 .9Hz),69.05,37.97(t,J=20.9Hz),28.02(t,J=5.3Hz),17.08.HRMS(ESI)(m / z):[M+H] + called.for C 10 H 13 F2O2S:235.0604,found:235.0600.

[0092] Example 9:

[0093] This invention discloses a method for preparing difluoromethyl compounds by photocatalytic LMCT, comprising the following steps:

[0094] In this embodiment, olefin a9 is allyl diphenylphosphine oxide, with the structural formula as follows:

[0095] 5 mg (8 mmol%) of photocatalyst Fe(acac)3 was added to 2 mL of solvent DMSO, followed by the addition of 0.2 mmol of olefin a9, 8 mmol% (8 μL) of 2,4,6-triisopropylbenzenethiophenol, and 1.0 mmol (66 μL) of difluoroacetic acid to obtain a reaction mixture. The mixture was deoxygenated by argon gas for 5 min, and then irradiated at room temperature for 24 h using LEDs with a power of 10 W and a wavelength of 390 nm ± 10 nm under magnetic stirring. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was removed by extraction and vacuum distillation, and the product was obtained by thin-layer chromatography. The product was identified as difluoromethyl compound-9 by 1H NMR, 1C NMR, fluorine NMR, and high-resolution mass spectrometry, with the following structural formula:

[0096]

[0097] Purity 99%, yield 64%; its NMR data analysis is as follows: 1 H NMR (400MHz, Chloroform-d) δppm=7.77-7.71(m,4H),7.50(ddd,J=13.9,6.8,4 .7Hz,6H),5.79(tt,J=56.4,4.3Hz,1H),2.40-2.27(m,2H),2.09-1.74(m,4H). 19 F NMR (376MHz, Chloroform-d) δppm = -115.96 (dt, J = 56.5, 17.3Hz). 13 C NMR(101MHz,Chloroform-d)δppm=132.00,131.97,130.80,130.71,128.88,128.76,116.76(t,J= 239.4Hz),34.76(td,J=21.0,13.6Hz),29.52,28.81,14.79(q,J=5.8Hz).HRMS(ESI)(m / z):[M+H] + called.for C 16 H 18 F2OP:295.1063,found:295.1070.

[0098] Example 10:

[0099] This invention discloses a method for preparing difluoromethyl compounds by photocatalytic LMCT, comprising the following steps:

[0100] In this embodiment, olefin a10 is 4,4a,5,6,7,8-hexahydro-(4R,4aS,6R)-4,4a-dimethyl-6-(1-methylvinyl)-2(3H)-naphthone, with the structural formula [insert structural formula here].

[0101] For a gram-scale reaction, 70 mg (8 mmol%) of photocatalyst Fe(acac)3 was added to 40 mL of solvent DMSO, followed by the sequential addition of 4 mmol of olefin a10, 8 mmol% (100 μL) of 2,4,6-triisopropylbenzenethiophenol, and 16 mmol (1.2 mL) of difluoroacetic acid to obtain a reaction mixture. The mixture was deoxygenated by argon gas for 15 min, and then irradiated at room temperature for 48 h using LEDs with a power of 10 W and a wavelength of 390 nm ± 10 nm under magnetic stirring. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was removed by extraction and vacuum distillation, and the product was separated by thin-layer chromatography. The product was identified as a difluoromethyl compound-10 by 1H NMR, 1C NMR, fluorine NMR, and high-resolution mass spectrometry, with the following structural formula:

[0102]

[0103] Purity 99%, yield 82% (dr = 1:1); its NMR data analysis is as follows: 1 H NMR(400MHz,Chloroform-d)δppm=6.06-5.70(m,2H),2.52-2.19(m,4H),2.04-1.79(m,4H) ,1.66(dd,J=17.8,6.9Hz,3H),1.25-1.13(m,1H),1.11-1.07(m,3H),0.96(t,J=7.4Hz,7H). 19 F NMR (376MHz, Chloroform-d) δppm=-111.45--121.97(m). 13C NMR(101MHz,Chloroform-d)δppm=199.63,170.61,124.67,117.27(t,J=238.8Hz,diastereomer 1),117.22(t,J=238.8Hz,diastereomer 2),42.43,42.08,40.85,40.57,39.30,39.20,38.58(t,J=20.0Hzdiastereomer 1),38.10(t,J=20.1Hz diastereomer 2),37.63,33.03,32.92,32.20,29.79,28.33,16.97,16.39,16.02,14.99.HRMS(ESI)(m / z):[M+H] + called.for C 16 H 25 F2O:271.1873,found:271.1879。

Claims

1. A method for preparing difluoromethyl compounds by photocatalytic LMCT, characterized in that... This method is performed in the following steps: I. An olefinic compound, difluoroacetic acid, 2,4,6-triisopropylbenzylthiophenol, and Fe(acac)3 are added to a solvent to obtain a reaction mixture solution; 2. Under nitrogen atmosphere and room temperature conditions, the reaction mixture was irradiated with LEDs for 24-36 h. After extraction and solvent removal by rotary evaporation, the product was separated and purified by thin-layer chromatography. The obtained product was a difluoromethyl compound, thus completing the preparation. The chemical structural formula of the olefin compound mentioned in step one is as follows: R1 is a phenyl or alkyl compound, and R2 is a phenyl or alkyl compound; The solvent mentioned in step one is dimethyl sulfoxide; Step 2: Control the wavelength of the LED light source to 380~400nm and the power to 10W.

2. The method for preparing difluoromethyl compounds by photocatalytic LMCT according to claim 1, characterized in that... The ratio of the olefin compound to the solvent in step one is 0.07~0.1 mmol:1 mL.

3. The method for preparing difluoromethyl compounds by photocatalytic LMCT according to claim 1, characterized in that... The ratio of difluoroacetic acid to solvent in step one is 0.8~1.2 mmol:1mL.

4. The method for preparing difluoromethyl compounds by photocatalytic LMCT according to claim 1, characterized in that... The ratio of 2,4,6-triisopropylbenzylthiophenol to solvent in step one is 2-3 mg: 1 mL.

5. The method for preparing difluoromethyl compounds by photocatalytic LMCT according to claim 1, characterized in that... The ratio of Fe(acac)3 to solvent in step one is 3.5~4.5 mg:1 mL.

6. The method for preparing difluoromethyl compounds by photocatalytic LMCT according to claim 1, characterized in that... The solvent used for separation and purification by thin-layer chromatography in step two is a mixture of petroleum ether and ethyl acetate.

7. The method for preparing difluoromethyl compounds by photocatalytic LMCT according to claim 6, characterized in that... The volume ratio of petroleum ether to ethyl acetate is (2~10):1.

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