Method for photocatalytic synthesis of N-(trifluoromethyl sulfo) phenylglycine derivative / N-(trifluoromethyl sulfo) dipeptide compound

Abstract

The invention relates to the fields of medicine, organic chemical industry and fine chemical industry, and particularly discloses a method for photocatalytic synthesis of an N-(trifluoromethyl sulfo) phenylglycine derivative / N-(trifluoromethyl sulfo) dipeptide compound. According to the method, an N-aryl glycine derivative or an N-aryl dipeptide and N-trifluoromethylthio-phthalimide (a Munavalli reagent) are taken as raw materials, visible light is taken as reaction driving force, and the N-(trifluoromethylthio) phenylglycine derivative or the N-(trifluoromethylthio) dipeptide compound is synthesized in the presence of a photosensitizer. According to the invention, the use of high-toxicity trifluoromethyl sulfinyl chloride and precious metal silver salt (AgSCF3) is avoided, and the synthetic route is green and environment-friendly. When dipeptide is used as a raw material, a reaction site only occurs on nitrogen-hydrogen of glycine residues, and region selection is good; the method is mild in reaction condition, high in reaction efficiency and convenient to operate, and has a certain application prospect.

Description

Technical Field

[0001] The invention relates to the fields of medicine, organic chemical industry and fine chemical industry, and specifically discloses a method for photocatalytically synthesizing an N-(trifluoromethylthio)phenylglycine derivative / N-(trifluoromethylthio)dipeptide compound. Background Art

[0002] The importance of fluorinated organic compounds in medicine, pesticides and materials is becoming increasingly prominent due to the unique electronegativity, atomic radius, lipophilicity and electrostatic interaction ability of fluorine atoms with other atoms. In medicinal chemistry research, compounds substituted with fluorine atoms can improve lipid solubility, metabolic stability, and biological activity of active molecules. Among them, trifluoromethylthio has the highest π coefficient and is one of the most hydrophobic and lipophilic organic functional groups. The introduction of trifluoromethylthio into drug or pesticide molecules usually enhances the lipid solubility of the molecule, making it easier for these molecules to penetrate the cell membrane and enhance the transmembrane absorption of drug molecules; at the same time, trifluoromethylthio has a strong electron-withdrawing ability, making the drug molecules less likely to be oxidized and degraded by oxidases in the body, and can enhance the metabolic stability of drug molecules. Therefore, small molecule compounds containing trifluoromethylthio have been widely used in the fields of medicine and pesticides. Under mild conditions, developing efficient and green methods to introduce trifluoromethylthio into small molecules has always been a research hotspot in synthetic chemistry.

[0003] The methods developed so far mainly focus on the trifluoromethylthiolation of substrates such as alkanes, aromatics, alkenes, alkynes and aldehydes, while there are few studies on the trifluoromethylthiolation of amine substrates. In the early days, Kolasa and Lieb used highly toxic trifluoromethylsulfenyl chloride (CF3SCl) to achieve direct trifluoromethylthiolation of aliphatic amines (A. Kolasa, M. Lieb, J. Fluorine Chem. 1995, 70, 45.). In 2014, Rueping's group used Munavalli reagent as an electrophilic trifluoromethylthio reagent under the action of n-butyl lithium to construct various N-SCF3 bonds (R. Pluta, M. Rueping, Chem.-Eur. J., 2014, 20, 17315.), but the strong base used in this method is sensitive to humidity and has low tolerance to functional groups.

[0004] Peptide drugs are widely used in the clinical treatment of various diseases, such as diabetes, AIDS, and tumors. The structural modification of natural peptide molecules by introducing non-protein amino acids can greatly improve the activity and metabolic stability of peptide molecules. Glycine is the basic structural unit of non-natural α-amino acids. Direct functionalization of the NH of glycine and glycine residues in peptides provides an efficient method for chemical modification of non-natural α-amino acids and peptides. For substrates such as N-arylglycine derivatives or N-aryl dipeptides, the trifluoromethylthiolation of NH bonds can be selectively achieved, which has not been reported so far. Summary of the invention

[0005] The purpose of the present invention is to provide a simple and mild method for synthesizing N-(trifluoromethylthio)phenylglycine derivatives or N-(trifluoromethylthio) dipeptides, mainly using N-arylglycine derivatives or N-aryl dipeptides and N-trifluoromethylthiophthalimide (Munavalli reagent) as raw materials, in an organic solvent, with a photosensitizer as a catalyst, under room temperature conditions, irradiated with blue light for 18 hours to initiate a synthetic reaction, and obtain N-(trifluoromethylthio)phenylglycine derivatives or N-(trifluoromethylthio) dipeptides. Photoredox-catalyzed NH trifluoromethylthioation reaction is achieved. The method is simple to operate, has mild reaction conditions, excellent regioselectivity, and good tolerance for reaction functional groups.

[0006] The specific process of the reaction is as follows:

[0007]

[0008] The solvents used in the reaction are dimethylacetamide (DMA), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and acetonitrile (MeCN); the photosensitizers are Ru(bpy)3Cl2·6H2O, 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4CzIPN), and tris(2-phenylpyridine)iridium (fac-Ir(ppy)3), and the amount of the photocatalyst used is 2.5% of the molar number of the Munavalli reagent.

[0009] The molar ratio of the raw material N-arylglycine derivative or N-aryl dipeptide and the Munavalli reagent is 2:1.

[0010] The structural formula of the obtained N-(trifluoromethylthio)phenylglycine derivative is The structural formula of the obtained N-(trifluoromethylthio) dipeptide compound is Wherein, R is methyl, methoxy, fluorine, chlorine, bromine, phenyl, trifluoromethyl, methylthio, R' is ethoxy, tert-butoxy, benzyloxy, methylamino, dimethylamino, R 1is methyl, ethoxycarbonylmethyl, methylthioethyl, R 2 It is methoxy and ethoxy.

[0011] The post-reaction treatment of the present invention is simple, and pure various substituted NH trifluoromethylthiolation products can be obtained by only utilizing a column chromatography separation method and using a mixed solvent of petroleum ether and ethyl acetate as an eluent.

[0012] Beneficial effects:

[0013] 1. The present invention uses phenylglycine derivatives or dipeptides and Munavalli reagent as raw materials, and initiates the reaction in a solvent through blue light initiation, thereby accurately achieving NH trifluoromethylthiolation to obtain various substituted N-(trifluoromethylthio)phenylamino acid derivatives or N-(trifluoromethylthio) dipeptide products. For dipeptide substrates, the reaction has good regioselectivity and only occurs on the nitrogen-hydrogen of the glycine residue.

[0014] 2. The reaction conditions of the method of the present invention are milder, avoiding the use of highly toxic trifluoromethylsulfenyl chloride and precious metal silver salt (AgSCF3). At the same time, the reaction does not require the use of a strong base, and has excellent universality and functional group tolerance.

[0015] 3. The present invention provides an efficient method for chemically selectively modifying non-natural α-amino acids and polypeptides, which can improve the metabolic stability and biological activity of polypeptide molecules. At the same time, the obtained N-(trifluoromethylthio)phenylglycine ethyl ester can be used as a safe and easy-to-operate electrophilic trifluoromethylthiolation reagent. DETAILED DESCRIPTION

[0016] The present invention is described in detail below in conjunction with embodiments, and each embodiment of the present invention is as follows:

[0017]

[0018] Example 1

[0019] Synthesis of N-arylglycine derivatives: Aromatic amine (10 mmol), NaOAc (1.2 equivalents), α-carbonyl bromide (1 equivalent) and anhydrous ethanol (20 mL) were added to a round-bottom flask in sequence and heated at 80°C for 12 hours. After that, the solvent was removed, and the residue was dissolved in dichloromethane and washed and extracted with water. The obtained organic layer was dried over anhydrous sodium sulfate, and then dichloromethane was removed under reduced pressure, and the corresponding N-arylglycine derivatives (1a-1h) were purified by column chromatography.

[0020]

[0021] Example 2

[0022] Synthesis of N-aryl dipeptide: triethylamine (1.2 eq.) was added to dichloromethane (30 mL) of amino acid ester (1.0 eq., 10 mmol), and bromoacetyl bromide (1 eq.) was added dropwise to the reaction mixture after cooling to -78 °C. Subsequently, the resulting reaction system was returned to room temperature and stirred for 12 hours. After completion, water was added to quench, wash, extract, and the organic layer was dried over anhydrous sodium sulfate and dichloromethane was removed under reduced pressure to obtain a crude product (S4), which was used without further purification.

[0023] The intermediate S4 was dissolved in anhydrous ethanol (20 mL), and NaOAc (1.2 equivalents) and aromatic amine (1.2 equivalents) were added in sequence, and heated at 80°C for 12 hours. After that, the solvent was removed, and the residue was dissolved in dichloromethane and washed with water and extracted. The obtained organic layer was dried over anhydrous sodium sulfate, and then dichloromethane was removed under reduced pressure, and the corresponding N-aryl dipeptide compound (1i-1t) was purified by column chromatography.

[0024]

[0025] Example 3

[0026] The synthesized raw material 1a (0.2 mmol), Munavalli reagent (0.1 mmol), Ru(bpy)3Cl2 . 6H2O (0.025mmol) and DMA (0.5mL) were added to a Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3a was obtained by thin layer chromatography separation with a yield of 87%. 1 H NMR (500MHz, CDCl3) δ7.46-7.42(m,2H),7.41-7.37(m,1H),7.37-7.33(m,2H),4.72-4.67(m,2H),4.27(q,J=7.1Hz,2H),1.31(t,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ 182.0 (d, J = 333.3Hz), 166.7, 140.6, 129.8, 129.1, 125.8, 62.1, 58.08 (d, J = 6.1Hz), 14.3. 19 F NMR (376MHz, CDCl3) δ22.1 (s).

[0027] Example 4

[0028] The synthesized raw material 1a (0.2 mmol), Munavalli reagent (0.1 mmol), Ru(bpy)3Cl2 . 6H2O (0.025mmol) and DMF (0.5mL) were added to a Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3a was obtained by thin layer chromatography separation with a yield of 65%.

[0029] Example 5

[0030] The synthesized raw material 1a (0.2 mmol), Munavalli reagent (0.1 mmol), Ru(bpy)3Cl2 . 6H2O (0.025mmol) and DMSO (0.5mL) were added to a Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3a was obtained by thin layer chromatography separation with a yield of 77%.

[0031] Example 6

[0032] The synthesized raw material 1a (0.2 mmol), Munavalli reagent (0.1 mmol), Ru(bpy)3Cl2 . 6H2O (0.025mmol) and MeCN (0.5mL) were added to a Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3a was obtained by thin layer chromatography separation with a yield of 29%.

[0033] Example 7

[0034] The synthesized raw material 1a (0.2 mmol), Munavalli reagent (0.1 mmol), 4CzIPN (0.025 mmol), and DMA (0.5 mL) were added to a Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20 h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3a was obtained by thin layer chromatography separation with a yield of 70%

[0035] Example 8

[0036] The synthesized raw material 1a (0.2 mmol), Munavalli reagent (0.1 mmol), fac-Ir(ppy)3 (0.025 mmol), and DMA (0.5 mL) were added to a Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20 h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3a was obtained by thin layer chromatography separation with a yield of 46%.

[0037] Example 9

[0038] The synthesized raw material 1b (0.2 mmol), Munavalli reagent (0.1 mmol), Ru(bpy)3Cl2 . 6H2O (0.025mmol) and DMA (0.5mL) were added to a Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3b was obtained by thin layer chromatography separation with a yield of 64%. 1 H NMR (400MHz, CDCl3) δ7.16 (s, 4H), 4.61 (d, J = 0.9Hz, 2H), 4.23-4.16 (m, 2H), 2.31 (s, 3H), 1.24 (t, J = 7.2Hz, 3H). 13 C NMR (101MHz, CDCl3) δ182.2 (d, J = 323.3Hz), 166.7, 139.2, 138.0, 130.4, 125.5, 62.1, 58.1 (d, J = 6.1Hz), 21.3, 14.3. 19 F NMR (376MHz, CDCl3) δ21.8 (s). .

[0039] Example 10

[0040] The synthesized raw material 1c (0.2 mmol), Munavalli reagent (0.1 mmol), Ru(bpy)3Cl2 . 6H2O (0.025mmol) and DMA (0.5mL) were added to a Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3c was obtained by thin layer chromatography separation with a yield of 83%. 1H NMR (400MHz, CDCl3) δ7.40-7.31(m,2H),7.18-7.08(m,2H),4.66(s,2H),4.27(q,J=7.2Hz,2H),1.31(t,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ182.0 (d, J = 323.2Hz), 166.6, 162.4 (d, J = 251.5Hz), 136.4 (d, J=3.0Hz), 127.9 (d, J=9.1Hz), 116.8 (d, J=23.2Hz), 62.2, 58.0 (d, J=6.1Hz), 14.3. 19 F NMR (376MHz, CDCl3) δ22.6 (s), -111.4 (s).

[0041] Embodiment 11

[0042] The synthesized raw material 1d (0.2 mmol), Munavalli reagent (0.1 mmol), Ru(bpy)3Cl2 . 6H2O (0.025mmol) and DMA (0.5mL) were added to the Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3d was obtained by thin layer chromatography separation with a yield of 69%. 1 H NMR (400MHz, CDCl3) δ7.47-7.40(m,2H),7.36-7.28(m,2H),4.68(s,2H),4.29(q,J=7.1Hz,2H),1.33(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ181.7 (d, J = 323.2Hz), 166.6, 138.9, 135.1, 130.0, 127.3, 62.2, 57.9 (d, J = 6.1Hz), 14.3. 19 F NMR (376MHz, CDCl3) δ22.6 (s).

[0043] Example 12

[0044] The synthesized raw material 1e (0.2 mmol), Munavalli reagent (0.1 mmol), Ru(bpy)3Cl2 .6H2O (0.025mmol) and DMA (0.5mL) were added to a Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3e was obtained by thin layer chromatography separation with a yield of 95%. 1 H NMR (400MHz, CDCl3) δ7.18 (d, J = 8.9 Hz, 2H), 6.85 (d, J = 9.0 Hz, 2H), 4.47 (s, 2H), 3.75 (s, 3H), 1.43 (s, 9H). 13 C NMR (101MHz, CDCl3) δ182.1 (d, J = 323.2Hz), 165.7, 160.0, 133.5, 126.9, 114.8, 83.2, 58.9 (d, J = 6.1Hz) 55.7, 28.1. 19 FNMR (376MHz, CDCl3) δ21.4 (s).

[0045] Embodiment 13

[0046] The synthesized raw material 1f (0.2 mmol), Munavalli reagent (0.1 mmol), Ru(bpy)3Cl2 . 6H2O (0.025mmol) and DMA (0.5mL) were added to a Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3f was obtained by thin layer chromatography separation with a yield of 94%. 1 H NMR (400MHz, CDCl3) δ7.43-7.35(m,5H),7.22(s,4H),5.26(s,2H),4.76(s,2H),4.53(d,J=2.9Hz,0H),2.39(s,3H). 13 C NMR (101MHz, CDCl3) δ182.1 (d, J = 323.2Hz), 166.7, 139.2, 137.9, 135.0, 130.3, 128.8, 128.7, 128.6, 125.5, 67.7, 58.1 (d, J = 6.1Hz), 21.2. 19 F NMR (376MHz, CDCl3) δ21.7 (s).

[0047] Embodiment 14

[0048] The synthetic raw material 1g (0.2mmol), Munavalli reagent (0.1mmol), Ru(bpy)3Cl2 . 6H2O (0.025mmol) and DMA (0.5mL) were added to the Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and 3g of the target product was obtained by thin layer chromatography separation with a yield of 86%. 1 H NMR (400MHz, CDCl3) δ7.20-7.10 (m, 4H), 6.12 (s, 1H), 4.54 (s, 2H), 2.81 (d, J = 4.9Hz, 3H), 2.29 (s, 3H). 13 C NMR (101MHz, CDCl3) δ182.1 (d, J = 323.2Hz), 166.6, 139.2, 138.0, 130.4, 125.3, 60.0, 59.9, 26.6, 21.2. 19 F NMR (376MHz, CDCl3) δ22.5 (s).

[0049] Embodiment 15

[0050] The synthetic raw material 1h (0.2mmol), Munavalli reagent (0.1mmol), Ru(bpy)3Cl2 . 6H2O (0.025mmol) and DMA- (0.5mL) were added to the Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3h was obtained by thin layer chromatography separation with a yield of 67%. 1 H NMR (400MHz, CDCl3) δ7.30(d,J=8.3Hz,2H),7.20(d,J=8.2Hz,2H),4.78(s,2H),3.02(s,3H),3.00(s,3H),2.35(s,3H). 13 CNMR (101MHz, CDCl3) δ182.3 (d, J = 322.2Hz), 165.0, 139.0, 138.3, 130.2, 125.8, 58.1 (d, J = 6.1Hz), 36.5, 36.0, 21.4. 19 F NMR (376MHz, CDCl3) δ20.8 (s).

[0051] Example 16

[0052] The synthesized raw material 1i (0.2 mmol), Munavalli reagent (0.1 mmol), Ru(bpy)3Cl2 . 6H2O (0.025mmol) and DMA (0.5mL) were added to a Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3i was obtained by thin layer chromatography separation with a yield of 79%. 1 H NMR (400MHz, CDCl3) δ7.49-7.34(m,5H),6.60(s,1H),4.70(s,2H),4.23(q,J=7.2Hz,2H),4.10(d,J=5.1Hz,2H),1.29(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ182.1 (d, J = 322.0Hz), 169.6, 166.0, 140.5, 129.9, 129.1, 125.7, 61.9, 59.6 (d, J = 6.3Hz), 41.6, 14.3. 19 F NMR (376MHz, CDCl3) δ22.9 (s).

[0053] Embodiment 17

[0054] The synthesized raw material 1j (0.2 mmol), Munavalli reagent (0.1 mmol), Ru(bpy)3Cl2 . 6H2O (0.025mmol) and DMA (0.5mL) were added to a Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3j was obtained by thin layer chromatography separation with a yield of 87%. 1 H NMR (400MHz, CDCl3) δ7.29(d,J=9.0Hz,2H),6.91(d,J=9.0Hz,2H),6.77(s,1H),4.68(s ,2H),4.22(q,J=7.1Hz,2H),4.09(d,J=5.2Hz,2H),3.81(s,3H),1.29(t,J=7.2Hz,3H). 13C NMR (101MHz, CDCl3) δ182.3 (d, J = 323.1Hz), 169.6, 166.2, 159.7, 133.1, 126.8, 114.8, 61.8, 59.7 (d, J = 6.4Hz), 55.6, 41.5, 14.2. 19 F NMR (376MHz, CDCl3) δ22.3 (s).

[0055] Embodiment 18

[0056] The synthesized raw material 1k (0.2 mmol), Munavalli reagent (0.1 mmol), Ru(bpy)3Cl2 . 6H2O (0.025mmol) and DMA (0.5mL) were added to the Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3k was obtained by thin layer chromatography separation with a yield of 70%. 1 H NMR (400MHz, CDCl3) δ7.26-7.19(m,4H),6.64(s,1H),4.68(s,2H),4.23(q,J=7.2Hz,2H),4.09(d,J=5.1Hz,2H),2.36(s,3H),1.29(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ182.2 (d, J = 323.8Hz), 169.6, 166.1, 139.2, 137.9, 130.4, 125.3, 61.9, 59.7 (d, J = 6.2Hz), 41.6, 21.2, 14.2. 19 F NMR (376MHz, CDCl3) δ22.6 (s).

[0057] Embodiment 19

[0058] The synthetic raw material 1l (0.2mmol), Munavalli reagent (0.1mmol), Ru(bpy)3Cl2 . 6H2O (0.025mmol) and DMA (0.5mL) were added to a Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3l was obtained by thin layer chromatography separation with a yield of 55%. 1H NMR (400MHz, CDCl3) δ7.41-7.35 (m, 2H), 7.11 (t, J = 8.5Hz, 2H), 6.57 (s, 1H), 4. 66(s,2H),4.23(q,J=7.2Hz,2H),4.09(d,J=5.1Hz,2H),1.29(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ182.1 (d, J = 324.3Hz), 180.5, 169.6, 165.9, 162.5 (d, J = 250.8Hz), 136. 4(d,J=3.5Hz),127.8(d,J=8.9Hz),116.8(d,J=23.0Hz),62.0,59.6(d,J=6.4Hz),41.6,14.3. 19 F NMR (376MHz, CDCl3) δ23.2 (s), -111.4 (s).

[0059] Embodiment 20

[0060] The synthetic raw material 1m (0.2mmol), Munavalli reagent (0.1mmol), Ru(bpy)3Cl2 . 6H2O (0.025mmol) and DMA (0.5mL) were added to a Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3m was obtained by thin layer chromatography separation with a yield of 69%. 1 H NMR (400MHz, CDCl3) δ7.44-7.30 (m, 4H), 6.57 (s, 1H), 4.66 (s, 2H), 4.23 (q, J = 7.1Hz, 2H), 4.09 (d, J = 5.1Hz, 2H), 1.29 (t, J = 7.1Hz, 3H). 13 C NMR (101MHz, CDCl3) δ181.8 (d, J = 324.0Hz), 169.6, 165.8, 138.9, 135.1, 130.0, 127.2, 62.0, 59.4 (d, J = 6.3Hz), 41.6, 14.3. 19 F NMR (376 MHz, CDCl3) δ 23.2 (s).

[0061] Embodiment 21

[0062] The synthetic raw material 1n (0.2mmol), Munavalli reagent (0.1mmol), Ru(bpy)3Cl2. 6H2O (0.025mmol) and DMA (0.5mL) were added to a Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3n was obtained by thin layer chromatography separation with a yield of 66%. 1 H NMR(400MHz, CDCl3) δ7.55(d,J=8.7Hz,2H),7.28(d,J=8.5Hz,2H),6.54(s,1H), 4.66 (s, 2H), 4.23 (q, J = 7.1Hz, 2H), 4.09 (d, J = 5.1Hz, 2H), 1.29 (t, J = 7.1Hz, 3H). 13 C NMR (101MHz, CDCl3) δ181.7 (d, J = 324.5Hz), 169.6, 165.8, 139.4, 133.1, 127.5, 123.1, 62.0, 59.4 (d, J = 6.1Hz), 41.6, 14.3. 19 F NMR (376MHz, CDCl3) δ23.2 (s).

[0063] Embodiment 22

[0064] The synthetic raw material 1o (0.2mmol), Munavalli reagent (0.1mmol), Ru(bpy)3Cl2 . 6H2O (0.025mmol) and DMA (0.5mL) were added to a Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3o was obtained by thin layer chromatography separation with a yield of 71%. 1 H NMR (400MHz, CDCl3) δ7.62 (d, J = 8.4Hz, 2H), 7.58-7.53 (m, 2H), 7.49-7.41 (m, 4H), 7.40-7.35 (m, 1 H), 6.67 (s, 1H), 4.74 (s, 2H), 4.24 (q, J = 7.1Hz, 2H), 4.12 (d, J = 5.1Hz, 2H), 1.29 (t, J = 7.1Hz, 3H). 13C NMR (101MHz, CDCl3) δ182.0 (d, J = 324.2Hz), 169.6, 166.0, 142.1, 139.8, 139 .5,129.0,128.5,128.1,127.3,126.0,61.9,59.6(d,J=6.3Hz),41.6,14.3. 19 F NMR (376MHz, CDCl3) δ22.8 (s).

[0065] Embodiment 23

[0066] The synthetic raw materials 1p (0.2mmol), Munavalli reagent (0.1mmol), Ru(bpy)3Cl2 . 6H2O (0.025mmol) and DMA (0.5mL) were added to the Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3p was obtained by thin layer chromatography separation with a yield of 45%. 1 H NMR(400MHz, CDCl3)δ7.70(d,J=8.3Hz,2H),7.55(d,J=8.2Hz,2H),6.55(s,1H), 4.69 (s, 2H), 4.23 (q, J = 7.1Hz, 2H), 4.10 (d, J = 5.1Hz, 2H), 1.29 (t, J = 7.1Hz, 3H). 13 C NMR (101MHz, CDCl3) δ181.4 (d, J = 325.2Hz), 169.6, 165.7, 143.4, 131.2 (q, J = 33 .4Hz), 127.0 (q, J = 3.6Hz), 123.6 (q, J = 273.6Hz), 62.0, 59.2 (d, J = 5.7Hz), 41.6. 19 F NMR (376MHz, CDCl3) δ23.4 (s), -62.8 (s).

[0067] Embodiment 24

[0068] The synthetic raw material 1q (0.2mmol), Munavalli reagent (0.1mmol), Ru(bpy)3Cl2 .6H2O (0.025mmol) and DMA (0.5mL) were added to a Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3q was obtained by thin layer chromatography separation with a yield of 65%. 1 H NMR (400MHz, CDCl3) δ7.26-7.19(m,4H),6.56(s,1H),4.63(s,2H),4.19(q,J=7.1Hz,2H),4.05(d,J=5.1Hz,2H),2.44(s,3H),1.25(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ182.1 (d, J = 323.8Hz), 169.6, 166.0, 140.5, 137.2, 127.1, 126.0, 61.9, 59.6 (d, J = 6.4Hz), 41.6, 15.6, 14.3. 19 F NMR (376MHz, CDCl3) δ22.8 (s).

[0069] Embodiment 25

[0070] The synthesized raw material 1r (0.2 mmol), Munavalli reagent (0.1 mmol), Ru(bpy)3Cl2 . 6H2O (0.025mmol) and DMA (0.5mL) were added to a Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3r was obtained by thin layer chromatography separation with a yield of 86%. 1 H NMR (400MHz, CDCl3) δ7.21(d,J=9.3Hz,2H),6.85(d,J=9.0Hz,2H),6.59(d,J=7 .3Hz,1H),4.65-4.47(m,3H),3.74(s,3H),3.70(s,3H),1.39(d,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ182.4 (d, J = 323.2Hz), 173.2, 165.4, 159.8, 133.3, 126.8, 114.9, 59.9 (d, J = 6.1Hz, 2H), 55.7, 52.7, 48.5, 18.4. 19 F NMR (376MHz, CDCl3) δ22.5 (s).

[0071] Embodiment 26

[0072] The synthesized raw material 1s (0.2 mmol), Munavalli reagent (0.1 mmol), Ru(bpy)3Cl2 . 6H2O (0.025mmol) and DMA (0.5mL) were added to the Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3s was obtained by thin layer chromatography separation with a yield of 78%. 1 H NMR (400MHz, CDCl3) δ7.21(d,J=9.3Hz,2H),6.85(d,J=9.0Hz,2H),6.59(d,J=7 .3Hz,1H),4.65-4.47(m,3H),3.74(s,3H),3.70(s,3H),1.39(d,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ182.4 (d, J = 323.2Hz), 173.2, 165.4, 159.8, 133.3, 126.8, 114.9, 59.9 (d, J = 6.1Hz, 2H), 55.7, 52.7, 48.5, 18.4. 19 F NMR (376MHz, CDCl3) δ22.5 (s).

[0073] Embodiment 27

[0074] The synthetic raw material 1t (0.2mmol), Munavalli reagent (0.1mmol), Ru(bpy)3Cl2 . 6H2O (0.025mmol) and DMA (0.5mL) were added to a Schlenk reaction tube, which was sealed after nitrogen protection. The reaction system was placed under blue light irradiation and reacted at room temperature for 20h. After the reaction, water / ethyl acetate was added for extraction, the organic phases were combined, the solvent was removed under reduced pressure, and the target product 3t was obtained by thin layer chromatography separation with a yield of 81%. 1H NMR (400MHz, CDCl3) δ7.29(d,J=8.9Hz,2H),6.91(d,J=9.0Hz,2H),6.80(d,J=7.9Hz,1H),4.79-4.71(m,1H),4.70-4.56(m,2H), 4.22(q,J=7.1Hz,2H),3.80(s,3H),2.58-2.46(m,2H),2.27-2.17(m,1H),2.09(s,3H),2.06-1.98(m,1H),1.29(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ182.3 (d, J = 323.2Hz), 171.6, 165.6, 159.8, 133.3, 126.8, 114.9, 62.0, 60.0 (d, J = 6.1Hz), 55.7, 52.0, 31.6, 30.0, 15.7, 14.3. 19 F NMR (376MHz, CDCl3) δ22.5 (s).

[0075] Embodiment 28

[0076] The obtained product 3a was dissolved in 1 mL of dichloromethane, and 2 equivalents of isophenyl dimethyl ether and 6 equivalents of boron trifluoride ether were added, and the mixture was stirred at 60°C for 24 h. After the reaction, water was added, and the mixture was extracted with dichloromethane and separated by column chromatography to obtain the target product 2,4-dimethoxy-1-[(trifluoromethyl)thio]benzene 5a with a yield of 66%. 1 H NMR (400MHz, CDCl3) δ7.53(s,1H),6.55-6.50(m,2H),3.89(s,3H),3.84(s,3H). 13 C NMR (101MHz, CDCl3) δ164.4, 162.4, 140.5, 123.1 (q, J = 309.2Hz), 106.1, 103.5 (q, J = 2.4Hz), 99.6, 56.4, 55.9. 19 F NMR (376MHz, CDCl3) δ-44.5 (s).

Claims

1. A method for photocatalytic synthesis of N-(trifluoromethylthio)phenylglycine derivatives / N-(trifluoromethylthio)dipeptide compounds, characterized in that: The method comprises the following steps: using N-arylglycine derivatives or N-aryl dipeptides and a trifluoromethylthiolation agent as raw materials, in an organic solvent, at room temperature, under the catalysis of a photosensitizer, and initiating a free radical coupling reaction via blue light to obtain N-(trifluoromethylthio)phenylglycine derivatives or N-(trifluoromethylthio) dipeptides.

2. The method for photocatalytic synthesis of N-(trifluoromethylthio)phenylglycine derivatives / N-(trifluoromethylthio)dipeptide compounds according to claim 1, characterized in that: The structural formula of the N-arylglycine derivative is The structural formula of N-aryl dipeptide compound is Wherein, R is methyl, methoxy, fluorine, chlorine, bromine, phenyl, trifluoromethyl, methylthio, R' is ethoxy, tert-butoxy, benzyloxy, methylamino, dimethylamino, R 1 is methyl, ethoxycarbonylmethyl, methylthioethyl, R 2 It is methoxy and ethoxy.

3. The method for photocatalytic synthesis of N-(trifluoromethylthio)phenylglycine derivatives / N-(trifluoromethylthio)dipeptide compounds according to claim 1, characterized in that: The photosensitizer is: terpyridinium chloride hexahydrate Ru(bpy)3Cl2 . 6H2O, 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile 4CzIPN, tris(2-phenylpyridine)iridium fac-Ir(ppy)3.

4. The method for photocatalytic synthesis of N-(trifluoromethylthio)phenylglycine derivatives / N-(trifluoromethylthio)dipeptide compounds according to claim 1, characterized in that: The amount of the photosensitizer used is 2.5% of the molar number of N-trifluoromethylthiophthalimide.

5. The method for photocatalytic synthesis of N-(trifluoromethylthio)phenylglycine derivatives / N-(trifluoromethylthio)dipeptide compounds according to claim 1, characterized in that: The reaction solvent is: dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide or acetonitrile.

6. The method for photocatalytic synthesis of N-(trifluoromethylthio)phenylglycine derivatives / N-(trifluoromethylthio)dipeptide compounds according to claim 1, characterized in that: The molar ratio of the N-arylglycine derivative or N-aryl dipeptide to N-trifluoromethylthiophthalimide is 2:

1.

7. The method for photocatalytic synthesis of N-(trifluoromethylthio)phenylglycine derivatives / N-(trifluoromethylthio)dipeptide compounds according to claim 1, characterized in that: The blue light irradiation was performed using a 425 nm LED lamp for 18 hours.

8. An N-(trifluoromethylthio)phenylglycine derivative / N-(trifluoromethylthio)dipeptide compound synthesized according to the method of any one of claims 1 to 7, characterized in that: The structural formula of the N-(trifluoromethylthio)phenylglycine derivative is The structural formula of N-(trifluoromethylthio) dipeptide compound is Wherein, R is methyl, methoxy, fluorine, chlorine, bromine, phenyl, trifluoromethyl, methylthio, R' is ethoxy, tert-butoxy, benzyloxy, methylamino, dimethylamino, R 1 is methyl, ethoxycarbonylmethyl, methylthioethyl, R 2 It is methoxy and ethoxy.

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