Visible light-driven synthesis of unnatural amino acids and their derivatives

Abstract

The present invention develops a visible light-driven synthesis method for non-natural amino acids and their derivatives, wherein the method comprises the following steps: in the presence of a Pd catalyst and a ligand, irradiation with visible light drives an alkyl bromide to undergo a selective C-C bond coupling reaction with a glycine derivative, thereby obtaining a series of non-natural amino acids and their derivatives. In addition, the method has also been successfully applied to the later modification of numerous complex natural molecules. The method of the present invention can utilize visible light to induce chemical reactions, and the reaction conditions are mild and controllable, easy to operate, and has a wide range of substrates and strong functional group tolerance. More importantly, the present invention innovatively uses a rich variety of cheap and readily available alkyl bromides as an alkyl source to achieve the alkylation reaction of glycine derivatives. Compared with existing reports, alkyl bromides can be directly used in the catalytic system without the need for pre-activation treatment, which greatly simplifies the synthesis steps and is more in line with the concept of modern green chemistry.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic compound synthesis, and in particular relates to a method for synthesizing non-natural amino acids and derivatives thereof driven by visible light. Background Art

[0002] Amino acids are the fundamental building blocks of polypeptides and proteins in living cells and the material basis of all life activities. The only 20 naturally occurring amino acids have aromatic or aliphatic side chains, limited in number and functional groups, and thus cannot meet the demands of applications in medicine, chemicals, food, cosmetics, and other fields. In contrast, synthetic unnatural amino acids and their derivatives are frequently used in the modification of natural products, drugs, and bioactive molecules (Blaskovich, MAT*, J. Med. Chem. 2016, 59, 10807; Hallam, TJ; Smider, VV*, Mol. Pharmaceutics. 2015, 12, 1848). Furthermore, unnatural amino acids are essential building blocks in protein engineering. The introduction of unnatural amino acids into natural products and peptides for post-modification can effectively improve pharmacokinetic properties and enhance their drugability (Walsh, CT; Khosla, C*. Angew. Chem. Int. Ed. 2013, 52, 7098; Kim, CH; Smider, VV*; Schultz, PG*. J. Am. Chem. Soc. 2012, 134, 9918–9921). The synthesis of a rich and diverse array of unnatural amino acids and their derivatives has the potential to advance modern medical research, including fundamental studies of protein function and dynamics. However, currently available methods suffer from cumbersome synthetic steps, harsh reaction conditions, and limited substrate structure. Summary of the Invention

[0003] To address the shortcomings of existing technologies, the present invention provides a visible-light-driven method for the synthesis of unnatural amino acids and their derivatives. This method utilizes abundant, inexpensive, and readily available alkyl bromides as the alkyl source, synthesizing a range of unnatural amino acids and their derivatives under mild reaction conditions. This method is versatile, simple, and highly efficient. Furthermore, this method enables the post-modification of complex natural molecules, providing a molecular reservoir for drug development.

[0004] To achieve the purpose of the present invention, the technical solution adopted is as follows: a visible light-driven synthesis method of non-natural amino acids and their derivatives, comprising the following steps: reacting a glycine derivative represented by general formula (1) with a brominated alkane represented by general formula (2) under visible light irradiation with a wavelength of 450 to 460 nm in the presence of a palladium catalyst, a ligand, an alkaline substance, and a solvent to obtain a non-natural amino acid derivative represented by general formula (3);

[0005]

[0006] Wherein, Ar is any one of phenyl, p-methoxyphenyl, p-chlorophenyl, p-cyanophenyl, 1-naphthyl, and 3-fluoro-4-morpholinophenyl;

[0007] R 1 is an ethoxyl group, a phenyl group, an N-methylanilino group, a pyrrolyl group, or a natural product molecular fragment, wherein the natural product molecular fragment is selected from any one of 1-(4-chlorodiphenylmethyl)piperazine, lurasidone, L-menthol, testosterone, oleanolic acid, cholesterol, lithocholic acid, nortriptyline, and atomoxetine hydrochloride;

[0008] R 2 The cyclohexyl group, cyclopropyl group, cyclobutyl group, substituted C1-C20 alkyl group or cycloalkyl group, or a natural product molecular fragment, wherein the natural product molecular fragment is selected from any one of estrone, thymol, vitamin E, and gemfibrozil;

[0009] The palladium catalyst is palladium acetate (Pd(OAc)2), palladium trifluoroacetate (Pd(TFA)2), palladium chloride (PdCl2), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), bis(triphenylphosphine)palladium chloride ((PPh3)2PdCl2), bis(dibenzylideneacetone)palladium (Pd2(dba)3), palladium pivalate (Pd(OPiv)2), [1,1-bis(diphenylphosphino)ferrocene)]palladium dichloride ((dppf)PdCl2), bis(diphenylphosphinophenyl ether)palladium dichloride ((DPEPhos)PdCl2), among which palladium acetate is preferred;

[0010] The ligand is triphenylphosphine;

[0011] The alkaline substance is potassium carbonate, cesium carbonate, sodium carbonate, silver carbonate, sodium acetate, potassium phosphate, lithium hydroxide, triethylamine, among which cesium carbonate is preferred;

[0012] The solvent is benzene, trifluorotoluene, fluorobenzene, acetonitrile, 1,4-dioxane, dimethyl sulfoxide, among which benzene is preferred.

[0013] Preferably, the molar ratio of the glycine derivative to the alkyl bromide is 1.5 to 4.0 (more preferably 2.0 to 4.0).

[0014] Preferably, the molar mass of the palladium catalyst is 5% to 15% of the molar mass of the glycine derivative.

[0015] Preferably, the molar ratio of the ligand to the glycine derivative is 0.5-1.5:1.

[0016] Preferably, the molar ratio of the alkaline substance to the glycine derivative is 1.0-2.0:1.

[0017] Furthermore, the non-natural amino acid and its derivatives are any one of the following:

[0018]

[0019]

[0020] Compared with the prior art, the present invention has achieved the following beneficial effects: (1) The present invention uses structurally diverse alkyl bromides as alkylating agents to achieve the alkylation of glycine derivatives under the drive of visible light. The raw materials are cheap and readily available, the reaction conditions are mild, and the operation is simple. (2) The method of the present invention can achieve the CC coupling reaction of glycine esters and alkyl bromides with high selectivity, the reaction functional groups have good compatibility, and complex natural molecules can also be post-modified under this catalytic system. DETAILED DESCRIPTION

[0021] The present invention is not limited to the following specific embodiments. Based on the disclosure of the present invention, a person skilled in the art may adopt a variety of other specific embodiments to implement the present invention. Any simple changes or modifications made to the design structure and concept of the present invention fall within the scope of protection of the present invention. It should be noted that the embodiments and features of the embodiments of the present invention may be combined with each other unless they conflict.

[0022] Example 1:

[0023]

[0024] In a glove box, 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 36.0 mg (0.20 mmol) of compound 1a, and 98.0 mg (0.60 mmol) of compound 2a were added to a 4 mL vial. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3a (42 mg, 80% yield).

[0025] The target product 3a obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows: 1 HNMR(300MHz, CDCl3)δ7.22–7.13(m,2H),6.78–6.69(m,1H),6.68–6.60(m,2H), 4.24–4.10(m,3H),3.88(d,J=6.0Hz,1H),1.92–1.63(m,6H),1.35–1.12(m,8H). 13 C NMR (75MHz, CDCl3) δ173.6,147.4,129.2,118.0,113.4,61.9,60.7,41.2,29.5,29.1,26.1,26.0,26.0,14.2.

[0026] Example 2:

[0027]

[0028] In a glove box, 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 41.9 mg (0.20 mmol) of compound 1b, and 98.0 mg (0.60 mmol) of compound 2a were added to a 4 mL vial. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3b (48 mg, 83% yield).

[0029] The target product 3b obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows: 1HNMR (300MHz, CDCl3) δ6.83–6.69(m,2H),6.66–6.54(m,2H),4.15(q,J=7.1Hz,2H),3 .89(s,1H),3.76(d,J=6.2Hz,1H),3.73(s,3H),1.94–1.59(m,6H),1.38–1.06(m,8H). 13 CNMR (75MHz, CDCl3) δ174.0,152.5,141.6,115.1,114.8,63.3,60.7,55.7,41.2,29.6,29.2,26.2,26.1,26.0,14.3.

[0030] Example 3:

[0031]

[0032] In a glove box, a 4 mL vial was charged with 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 42.7 mg (0.20 mmol) of compound 1c, and 98.0 mg (0.60 mmol) of compound 2a. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 16 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3c (47 mg, 80% yield).

[0033] The target product 3c obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows: 1 HNMR (400MHz, CDCl3) δ7.13–7.07(m,2H),6.58–6.49(m,2H),4.24–4.12(m,3H),3.80(dd,J=8.9,6.0Hz,1H),1.88–1.61(m,6H),1.32–1.10(m,8H). 13 C NMR (101MHz, CDCl3) δ173.4,146.0,129.0,122.6,114.6,62.1,60.9,41.2,29.5,29.1,26.1,26.0,26.0,14.3.

[0034] Example 4:

[0035]

[0036] In a glove box, a 4 mL vial was charged with 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 40.8 mg (0.20 mmol) of compound 1d, and 98.0 mg (0.60 mmol) of compound 2a. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 16 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3d (53 mg, 93% yield).

[0037] The target product 3c obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows: 1 HNMR (400MHz, CDCl3) δ7.45–7.35(m,2H),6.61–6.52(m,2H),4.74(d,J=8.9Hz,1H),4.19(q,J=7 .1Hz,2H),3.89(dd,J=8.9,5.8Hz,1H),1.83–1.73(m,4H),1.70–1.61(m,2H),1.30–1.06(m,8H). 13 C NMR (101MHz, CDCl3) δ172.4,150.5,133.6,120.1,112.7,99.4,61.2,60.9,41.1,29.4,29.0,25.9,25.9,25.8,14.2.

[0038] Example 5:

[0039]

[0040] In a glove box, a 4 mL vial was charged with 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 45.9 mg (0.20 mmol) of compound 1e, and 98.0 mg (0.60 mmol) of compound 2a. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 24 hours under irradiation with a 24 W blue LED lamp. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3e (40 mg, 64% yield).

[0041] The target product 3e obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows: 1HNMR (300MHz, CDCl3) δ7.95–7.88(m,1H),7.81–7.73(m,1H),7.48–7.39(m,2H),7.34–7.20(m,2H),6.57(dd,J=7.2 ,1.4Hz,1H),4.90(d,J=6.8Hz,1H),4.27–4.13(m,2H),4.05(d,J=6.1Hz,1H),2.02–1.62(m,6H),1.38–1.13(m,8H). 13 C NMR (101MHz, CDCl3) δ173.7,142.5,134.3,128.6,126.3,125.7,124.8,123.7 ,120.1,118.0,105.1,61.9,60.9,41.3,29.6,29.5,26.2,26.13,26.05,14.3.

[0042] Example 6:

[0043]

[0044] In a glove box, 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 48.3 mg (0.20 mmol) of compound 1f, and 98.0 mg (0.60 mmol) of compound 2a were added to a 4 mL vial. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3f (47 mg of product, 73% yield).

[0045] The target product 3f obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows: 1 HNMR(400MHz, CDCl3)δ8.00–7.92(m,2H),7.59(t,J=7.3Hz,1H),7.49(t,J=7.6Hz,2H),6.78–6.70(m,2H),6.73–6.64(m,2H), 4.78(d,J=4.3Hz,1H),4.40(s,1H),3.71(s,3H),1.88–1.70(m,4H),1.65–1.59(m,2H),1.46–1.34(m,1H),1.30–1.06(m,4H). 13C NMR (101MHz, CDCl3) δ201.8,152.5,142.4,136.1,133.3,128.7,128.2,115.7,114.8,64.7,55.7,41.8,30.8,27.6,26.3,26.1,26.0.

[0046] Example 7:

[0047]

[0048] In a glove box, 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 54.1 mg (0.20 mmol) of compound 1g, and 98.0 mg (0.60 mmol) of compound 2a were added to a 4 mL vial. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 12 hours under irradiation with a 24 W blue LED lamp. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain 3 g of the target compound (51 mg of product, 72% yield).

[0049] The target product 3g obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows: 1 HNMR (400MHz, CDCl3) δ7.40–7.33(m,3H),7.01–6.93(m,2H),6.73–6.67(m,2H),6.43–6.35(m,2H),3.74(s,3H),3.64(d,J=7.3 Hz,1H),3.23(s,3H),1.92–1.82(m,1H),1.72–1.56(m,4H),1.53–1.45(m,1H),1.21–0.94(m,4H),0.85(qd,J=12.4,3.4Hz,1H). 13 C NMR (101MHz, CDCl3) δ173.8,152.6,143.0,141.6,129.6,127.9,127.8,116.5,114.5,61.0,55.7,42.2,37.5,30.1,29.0,26.2,26.1.

[0050] Example 8:

[0051]

[0052] In a glove box, 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 46.9 mg (0.20 mmol) of compound 1h, and 98.0 mg (0.60 mmol) of compound 2a were added to a 4 mL vial. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 16 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3h (49 mg, 78% yield).

[0053] The target product 3h obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum, and the test results are as follows: 1 HNMR(400MHz, CDCl3)δ6.76–6.70(m,2H),6.65–6.60(m,2H),3.81(d,J=6.5Hz ,1H),3.72(s,3H),3.54–3.38(m,4H),2.00–1.62(m,10H),1.32–1.03(m,5H). 13 C NMR (101MHz, CDCl3) δ172.0,152.6,142.1,116.0,114.7,62.8,55.7,46.6,45.8,41.6,30.1,29.0,26.2,26.1,26.0,24.0.

[0054] Example 9:

[0055]

[0056] In a glove box, 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 47.1 mg (0.20 mmol) of compound 1i, and 98.0 mg (0.60 mmol) of compound 2a were added to a 4 mL vial. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 16 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3i (42 mg of product, 66% yield).

[0057] The target product 3i obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows: 1HNMR(400MHz, CDCl3)δ6.79–6.72(m,2H),6.64–6.56(m,2H),5.73(ddt,J=17.0,10.3,6.7Hz,1H),5.13–4.99(m,2H),4.21–4.09(m,2H) ,3.87(s,1H),3.77(d,J=6.1Hz,1H),3.73(s,3H),2.36(qt,J=6.8,1.4Hz,2H),1.90–1.83(m,1H),1.81–1.63(m,5H),1.32–1.08(m,5H). 13 C NMR (101MHz, CDCl3) δ174.0,152.6,141.5,133.8,117.3,115.1,114.8,63.7,63.3,55.7,41.2,33.0,29.7,29.1,26.1,26.0.

[0058] Example 10:

[0059]

[0060] In a glove box, 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 41.9 mg (0.20 mmol) of compound 1b, and 88.8 mg (0.60 mmol) of compound 2b were added to a 4 mL vial. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 24 hours under irradiation with a 24 W blue LED lamp. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3j (41 mg of product, 75% yield).

[0061] The target product 3j obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum, and the test results are as follows: 1 HNMR (400MHz, CDCl3) δ6.80–6.74(m,2H),6.62–6.57(m,2H),4.17(q,J=7.1Hz,2H),3.98( t,J=6.1Hz,1H),3.73(s,3H),2.43–2.36(m,2H),2.03–1.77(m,4H),1.24(t,J=7.1Hz,3H). 13C NMR (101MHz, CDCl3) δ173.6,152.9,140.5,119.1,115.3,114.8,61.3,57.1,55.6,31.8,21.8,16.9,14.1.

[0062] Example 11:

[0063]

[0064] In a glove box, 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 41.9 mg (0.20 mmol) of compound 1b, and 99.0 mg (0.60 mmol) of compound 2c were added to a 4 mL vial. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3k (50 mg, 85% yield).

[0065] The target product 3k obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows: 1 HNMR(400MHz, CDCl3)δ6.79–6.72(m,2H),6.66–6.57(m,2H),4.45–3.97(m,5H),3.92–3 .81(m,1H),3.78–3.70(m,4H),2.08–1.81(m,5H),1.57–1.45(m,1H),1.27–1.17(m,3H). 13 CNMR (101MHz, CDCl3) δ174.4,174.1,152.52,152.48,141.4,140.9,115.1,114.9,114.71,114.67,76. 3,75.8,67.8,67.7,61.0,60.9,56.4,56.3,55.61,55.59,38.8,38.4,31.7,31.6,25.50,25.47,14.1.

[0066] Example 12:

[0067]

[0068] In a glove box, 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 41.9 mg (0.20 mmol) of compound 1b, and 119.7 mg (0.60 mmol) of compound 2d were added to a 4 mL vial. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 24 hours under irradiation with a 24 W blue LED lamp. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 31 (product 50 mg, yield 76%).

[0069] The target product 3l obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows: 1 HNMR (400MHz, CDCl3) δ6.80–6.71(m,2H),6.64–6.55(m,2H),4.16(q,J=7.1Hz,2H),3.95(t,J=6.5Hz,1H),3 .85(s,1H),3.73(s,3H),3.52(t,J=6.7Hz,2H),1.84–1.68(m,4H),1.49–1.32(m,6H),1.23(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ174.4,152.6,141.0,115.1,114.8,60.9,57.7,55.6,45.0,33.0,32.4,28.5,26.6,25.4,14.2.

[0070] Example 13:

[0071]

[0072] In a glove box, 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 41.9 mg (0.20 mmol) of compound 1b, and 117.0 mg (0.60 mmol) of compound 2e were added to a 4 mL vial. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 16 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3m (36 mg product, 56% yield).

[0073] The target product 3m obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows:1 HNMR (400MHz, CDCl3) δ6.80–6.71(m,2H),6.66–6.55(m,2H),4.15(q,J=7.1Hz,2H),3.95(t,J=6.5H z,1H),3.73(s,3H),2.37–2.31(m,2H),1.85–1.60(m,4H),1.49–1.34(m,4H),1.23(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ178.9,174.5,152.7,140.9,115.2,114.8,61.0,57.8,55.7,33.7,32.9,28.7,25.3,24.4,14.2.

[0074] Example 14:

[0075]

[0076] In a glove box, 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 41.9 mg (0.20 mmol) of compound 1b, and 170.5 mg (0.60 mmol) of compound 2f were added to a 4 mL vial. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 16 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3n (product 50 mg, yield 61%).

[0077] The target product 3n obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum, and the test results are as follows: 1 HNMR (400MHz, CDCl3) δ7.44–7.35(m,2H),7.37–7.28(m,1H),7.20–7.11(m,2H),6.78–6.69(m,2H),6.60–6.51(m,2H),4.12(q,J=7.1Hz ,2H),3.88(t,J=6.6Hz,1H),3.72(s,3H),3.24(s,3H),2.05(t,J=7.5Hz,2H),1.77–1.51(m,4H),1.39–1.30(m,2H),1.26–1.16(m,5H). 13C NMR (101MHz, CDCl3) δ174.4,173.0,152.5,144.1,141.0,129.7,127.7,127. 2,115.0,114.7,60.8,57.7,55.6,37.2,33.8,32.9,28.9,25.3,25.2,14.2.

[0078] Example 15:

[0079]

[0080] In a glove box, a 4 mL vial was charged with 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 41.9 mg (0.20 mmol) of compound 1b, and 72.6 mg (0.60 mmol) of compound 2g. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3o (37 mg, 74% yield).

[0081] The target product 3o obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows: 1 HNMR (300MHz, CDCl3) δ6.81–6.71(m,2H),6.64–6.53(m,2H),4.19(qd,J=7.1,1.2Hz,2H),3.73(s,3H),3.62( s,1H),3.48(d,J=7.6Hz,1H),1.25(t,J=7.1Hz,3H),1.21–1.12(m,1H),0.63–0.48(m,3H),0.43–0.34(m,1H). 13 C NMR (75MHz, CDCl3) δ173.7,152.7,141.0,115.1,114.7,61.1,61.0,55.6,14.2,14.0,3.1,2.5.

[0082] Example 16:

[0083]

[0084] In a glove box, a 4 mL vial was charged with 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 41.9 mg (0.20 mmol) of compound 1b, and 81.0 mg (0.60 mmol) of compound 2h. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3p (38 mg, 72% yield).

[0085] The target product 3p obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum, and the test results are as follows: 1 HNMR (400MHz, CDCl3) δ6.80–6.73(m,2H),6.65–6.58(m,2H),4.14(qd,J=7.1,5.3Hz,2H),3.88(d,J =8.2Hz,1H),3.73(s,3H),3.55(s,1H),2.71–2.59(m,1H),2.12–1.79(m,6H),1.22(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ173.6,152.7,141.2,115.1,114.7,62.4,60.7,55.6,38.3,25.5,24.7,18.0,14.3.

[0086] Example 17:

[0087]

[0088] In a glove box, a 4 mL vial was charged with 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 41.9 mg (0.20 mmol) of compound 1b, and 82.2 mg (0.60 mmol) of compound 2i. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 16 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3q (38 mg, 72% yield).

[0089] The target product 3q obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows: 1HNMR (400MHz, CDCl3) δ6.81–6.75(m,2H),6.69–6.62(m,2H),4.85–4.73(m,2H),4.68(t,J=6.3Hz,1H),4.62(t,J=6.4Hz,1H),4.27 (d,J=9.0Hz,1H),4.14(qt,J=7.1,3.7Hz,2H),3.88(s,1H),3.74(s,3H),3.28(dtt,J=9.0,7.9,6.1Hz,1H),1.20(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ172.8,153.2,140.7,115.7,114.8,74.5,73.6,61.3,60.1,55.6,38.0,14.2.

[0090] Example 18:

[0091]

[0092] In a glove box, 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 41.9 mg (0.20 mmol) of compound 1b, and 141.7 mg (0.60 mmol) of compound 2j were added to a 4 mL vial. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 16 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3r (47 mg, 65% yield).

[0093] The target product 3r obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum, and the test results are as follows: 1 HNMR(400MHz, CDCl3)δ6.80–6.71(m,2H),6.67–6.58(m,2H),4.20–4.07(m,2H),4.10–3.93(m ,3H),3.94–3.78(m,3H),3.72(s,3H),2.89–2.75(m,1H),1.42(s,9H),1.20(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ172.7,156.1,153.1,140.6,115.7,114.7,79.5,61.3,60.4,55.6,50.9,31.6,28.3,14.1.

[0094] Example 19:

[0095]

[0096] In a glove box, 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 41.9 mg (0.20 mmol) of compound 1b, and 99.0 mg (0.60 mmol) of compound 2k were added to a 4 mL vial. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 16 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3s (41 mg of product, 70% yield).

[0097] The target product 3s obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows: 1 HNMR (400MHz, CDCl3) δ6.78–6.73(m,2H),6.64–6.58(m,2H),4.15(q,J=7.1Hz,2H),4.05–3.96(m,2H),3.79(d,J=6.7H z,1H),3.73(s,3H),3.42–3.33(m,2H),2.01–1.91(m,1H),1.81–1.74(m,1H),1.65–1.46(m,3H),1.23(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ173.3,152.8,141.0,115.3,114.8,67.8,67.5,62.8,60.9,55.6,38.6,29.3,14.2.

[0098] Example 20:

[0099]

[0100] In a glove box, 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 41.9 mg (0.20 mmol) of compound 1b, and 158.5 mg (0.60 mmol) of compound 2l were added to a 4 mL vial. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3t (56 mg, 72% yield).

[0101] The target product 3t obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows: 1 HNMR (400MHz, CDCl3) δ6.80–6.70(m,2H),6.64–6.55(m,2H),4.21–4.08(m,4H),3.87(s,1H),3.78(d,J=6.2Hz,1H),3.72(s ,3H),2.67(t,J=13.4Hz,2H),1.89–1.76(m,2H),1.65–1.55(m,1H),1.44(s,9H),1.44–1.25(m,2H),1.22(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ173.4,154.6,152.7,141.1,115.3,114.8,79.4,62.6,60.9,55.6,43.7,39.7,28.6,28.4,14.2.

[0102] Example 21:

[0103]

[0104] In a glove box, a 4 mL vial was charged with 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 56.5 mg (0.20 mmol) of compound 1j, and 97.8 mg (0.60 mmol) of compound 2a. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 16 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3u (57 mg, 78% yield).

[0105] The target product 3u obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows: 1 HNMR (400MHz, CDCl3) δ6.84–6.74(m,1H),6.42–6.30(m,2H),4.16(q,J=7.1Hz,2H),4.05(s,1H),3.87– 3.79(m,4H),3.74(s,1H),2.98–2.90(m,4H),1.85–1.71(m,4H),1.70–1.62(m,2H),1.30–1.07(m,8H). 13 C NMR (101MHz, CDCl3) δ173.5, 156.8 (d, J = 245.1Hz), 144.1 (d, J = 10.1Hz), 131.2 (d, J = 9.9Hz), 120.2 (d, J = 4.7Hz), 109.0(d,J=2.9Hz),102.2(d,J=24.4Hz),67.1,62.4,60.8,51.7,51.7,41.1,29.5,29.1,26.1,26.0,26.0,14.2.

[0106] Example 22:

[0107]

[0108] In a glove box, a 4 mL vial was charged with 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 90.0 mg (0.20 mmol) of compound 1k, and 97.8 mg (0.60 mmol) of compound 2a. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 16 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3v (74 mg, 70% yield).

[0109] The target product 3v obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows: 1HNMR (400MHz, CDCl3) δ7.39–7.30(m,4H),7.29–7.15(m,5H),6.76–6.69(m,2H),6.61–6.55(m,2H),4.15(s,1H),3.94(d,J=6.0Hz,1H),3.72( s,3H),3.68–3.55(m,2H),3.55–3.49(m,2H),2.40–2.21(m,4H),1.92– 1.83(m,1H),1.80–1.70(m,2H),1.69–1.54(m,3H),1.28–1.04(m,5H). 13 C NMR (101MHz, CDCl3) δ171.8,152.5,142.3,141.5,140.7,132.7,128.9,128.7,128.6,127.6,12 7.3,115.8,114.7,75.0,60.0,55.6,51.9,51.5,45.7,42.0,41.7,30.2,28.6,26.2,26.1,26.0.

[0110] Example 23:

[0111]

[0112] In a glove box, 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 76.5 mg (0.20 mmol) of compound 11, and 97.8 mg (0.60 mmol) of compound 2a were added to a 4 mL vial. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 16 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3w (59 mg of product, 63% yield).

[0113] The target product 3w obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows: 1HNMR (400MHz, CDCl3) δ7.87 (dt, J=8.3, 1.0Hz, 1H), 7.83 (dd, J=8.1, 0.9Hz, 1H), 7.49 (ddd, J=8.1, 7.0, 1.1Hz, 1H), 7.38 (ddd, J=8.1, 6.9, 1.0Hz, 1H), 6.7 9–6.73(m,2H),6.70–6.63(m,2H),4.08(d,J=6.1Hz,1H),3.93–3.70(m,8H), 3.58–3.40(m,4H),1.99–1.90(m,1H),1.82–1.64(m,5H),1.34–1.08(m,5H). 13 C NMR (101MHz, CDCl3) δ172.1,163.2,152.9,152.8,141.9,127.8,127.7,124.1,123.5, 120.6,116.1,114.8,60.4,55.7,50.4,49.9,45.4,41.8,30.3,28.8,26.2,26.2,26.1.

[0114] Example 24:

[0115]

[0116] In a glove box, 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 63.9 mg (0.20 mmol) of compound 1m, and 97.8 mg (0.60 mmol) of compound 2a were added to a 4 mL vial. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 16 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3x (57 mg of product, 71% yield).

[0117] The target product 3x obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows: 1 HNMR (400MHz, CDCl3) δ6.77–6.71(m,2H),6.64–6.56(m,2H),4.71–4.58(m,1H),3.79–3. 67(m,4H),1.98–1.55(m,10H),1.50–1.10(m,7H),1.06–0.75(m,9H),0.65–0.53(m,3H). 13C NMR (101MHz, CDCl3) δ173.6,173.5,152.7,152.5,141.7,141.5,115.7,11 5.0,114.7,114.6,74.9,74.8,63.8,63.7,55.7,55.7,46.8,41.2,41.1,40 .8,40.7,34.1,31.3,29.8,29.6,29.4,28.9,26.2,26.14,26.08,26.01,2 5.99,25.97,25.8,25.4,23.0,22.7,22.0,21.9,20.82,20.77,15.8,15.4.

[0118] Example 25:

[0119]

[0120] In a glove box, 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 90.3 mg (0.20 mmol) of compound 1n, and 97.8 mg (0.60 mmol) of compound 2a were added to a 4 mL vial. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 16 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3y (product 73 mg, yield 68%).

[0121] The target product 3y obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum, and the test results are as follows: 1 HNMR(400MHz, CDCl3)6.78–6.67(m,2H),6.64–6.52(m,2H),5.74–5.68(m,1H),4.64–4.53(m,1H),3.80–3.72 (m,1H),3.74–3.67(m,3H),2.45–2.21(m,4H),2.16–1.95(m,2H),1.91–0.85(m,27H),0.79(d,J=7.5Hz,3H). 13C NMR (101MHz, CDCl3) δ199.4,173.81,173.77,170.8,152.52,152.46,141.6,141. 5,123.8,115.2,114.9,114.74,114.69,82.7,63.4,63.3,55.70,55.67,53.6,50. 02,49.99,42.4,41.1,38.5,36.3,35.6,35.3,33.8,32.6,31.3,29.6,29.5,29.3,29.1,27.3,27.2,26.2,26.1,26.01,25.96,23.4,20.40,20.39,17.3,12.1,12.0.

[0122] Example 26:

[0123]

[0124] In a glove box, a 4 mL vial was charged with 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 126.8 mg (0.20 mmol) of compound 1o, and 97.8 mg (0.60 mmol) of compound 2a. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 16 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 3z (86 mg, 60% yield).

[0125] The target product 3z obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum, and the test results are as follows: 1 HNMR (400MHz, CDCl3) δ6.78–6.70(m,2H),6.65–6.55(m,2H),5.26(t,J=3.6Hz,1H),4.51–4.43(m,1H),3.79–3.73(m,1H),3.72(s,3H),3.61(s ,3H),2.91–2.79(m,1H),2.02–1.45(m,19H),1.43–1.08(m,16H),1.06 –0.97(m,2H),0.94–0.88(m,9H),0.86–0.79(m,3H),0.77–0.67(m,6H). 13C NMR (101MHz, CDCl3) δ178.2,173.6,152.7,152.5,143.73,143.72,141.6,141.3,122.1,115.4,115.0,114. 8,114.7,81.7,81.6,63.64,63.62,55.71,55.69,55.22,55.19,51.5,47.4,46.6,45.8,41.6,41.21,41.15, 39.2,37.9,37.52,37.48,36.8,33.8,33.0,32.5,32.3,30.6,29.9,29.5,29.4,28.9,27.9,27.7,27.6,26.2,26.14,26.06,26.04,25.99,25.96,25.8,23.6,23.5,23.3,23.0,18.12,18.09,16.80,16.76,15.3,15.2.

[0126] Example 27:

[0127]

[0128] In a glove box, 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 110.0 mg (0.20 mmol) of compound 1p, and 97.8 mg (0.60 mmol) of compound 2a were added to a 4 mL vial. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 16 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 4a (90 mg product, 71% yield).

[0129] The target product 4a obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows: 1 HNMR(300MHz, CDCl3)δ6.80–6.69(m,2H),6.66–6.56(m,2H),5.42–5.29(m,1H),4.72–4.56(m,1H),3.82–3.61(m,4 H),2.38–2.20(m,2H),2.06–1.65(m,11H),1.63–0.95(m,29H),0.94–0.90(m,3H),0.89–0.85(m,6H),0.68(s,3H). 13C NMR (101MHz, CDCl3) δ173.30,173.26,152.5,141.6,139.34,139.33,122.7,1 15.2,115.1,114.7,74.4,63.35,63.33,56.6,56.1,55.6,49.9,42.2,41.2,39 .6,39.5,38.1,36.8,36.5,36.1,35.7,31.82,31.77,29.6,29.2,28.2,28.0,27.81,27.80,26.2,26.1,26.0,24.2,23.8,22.8,22.5,21.0,19.3,18.7,11.8.

[0130] Example 28:

[0131]

[0132] In a glove box, a 4 mL vial was charged with 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 110.8 mg (0.20 mmol) of compound 1q, and 97.8 mg (0.60 mmol) of compound 2a. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 16 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 4b (93 mg, 73% yield).

[0133] The target product 4b obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows: 1 HNMR (400MHz, CDCl3) δ6.78–6.69(m,2H),6.63–6.54(m,2H),4.80–4.67(m,1H),3.74–3.69(m,4H),3.65(s,3H),2.34(ddd,J=15.2,10.1,5 .0Hz,1H),2.21(ddd,J=15.6,9.6,6.4Hz,1H),1.99–1.92(m,1H),1.90–1.52(m,13H),1.46–0.97(m,23H),0.92–0.88(m,6H),0.63(s,3H). 13C NMR (101MHz, CDCl3) δ174.6,173.4,152.4,141.57,141.55,115.1,114.6,7 4.7,63.43,63.38,56.3,55.9,55.6,51.4,42.6,41.8,41.15,41.13,40.3, 40.0,35.7,35.3,34.9,34.5,32.2,32.1,30.92,30.90,29.6,29.5,29.1,28.1,26.8,26.7,26.20,26.15,26.03,25.99,24.1,23.2,20.7,18.2,11.9.

[0134] Example 29:

[0135]

[0136] In a glove box, a 4 mL vial was charged with 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 85.3 mg (0.20 mmol) of compound 1r, and 97.8 mg (0.60 mmol) of compound 2a. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 16 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 4c (58 mg, 57% yield).

[0137] The target product 4c obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows: 1 HNMR(400MHz, CDCl3)δ7.28–6.96(m,8H),6.74–6.65(m,1H),6.67–6.54(m,2H),6.52–6.40(m,1H),5.81–5.71(m,1H),4.19(s,1H),4.01–3 .76(m,1H),3.69(s,3H),3.61–3.14(m,4H),3.05–2.84(m,3H),2.82– 2.64(m,2H),2.43–2.20(m,2H),1.90–1.50(m,6H),1.30–0.99(m,5H). 13C NMR (101MHz, CDCl3) δ173.2,152.4,144.3,142.5,142.2,140.7,140.3,139.7,139.5,139. 2,136.8,130.1,129.9,128.5,128.3,128.1,127.9,127.8,127.6,127.5,127.4,127.3,127 .0,126.01,125.95,125.7,115.9,115.8,115.6,114.7,114.6,60.5,60.4,55.62,55.58,47.5,41.9,41.6,35.0,33.7,33.2,31.9,30.4,30.2,28.5,27.3,26.2,26.15,26.11,26.05.

[0138] Example 30:

[0139]

[0140] In a glove box, 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 83.7 mg (0.20 mmol) of compound 1s, and 97.8 mg (0.60 mmol) of compound 2a were added to a 4 mL vial. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 16 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 4d (65 mg, 65% yield).

[0141] The target product 4d obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum, and the test results are as follows: 1 HNMR(300MHz, CDCl3)δ7.42–7.06(m,6H),7.00–6.88(m,1H),6.85–6.42(m,6H),5.23–4.92(m,1H),4.15 (s,1H),4.01–3.22(m,6H),3.05–2.77(m,3H),2.47–2.30(m,3H),2.16–1.48(m,8H),1.32–0.98(m,5H). 13C NMR (101MHz, CDCl3) δ173.52,173.50,173.37,173.34,155.6,155.5,155.3,155.2,152.6 4,152.60,152.5,152.4,142.42,142.36,142.32,141.44,141.40,140.63,140.61,130.8 ,130.7,130.52,130.50,128.73,128.70,128.5,128.4,127.80,127.77,127.45,127.38,126.74,126.66,126.64,126.62,126.60,126.5,125.53,125.50,125.4,120.59,120.56, 120.19,120.18,116.5,116.1,116.0,115.9,114.72,114.68,114.6,112.52,112.49,112.46,77.0,76.8,61.1,60.8,60.6,60.5,55.58,55.56,46.2,46.04,45.95,45.7,42.2,42 .0,41.7,41.6,37.8,37.3,36.31,36.26,36.0,33.8,33.5,30.3,30.20,30.15,30.1,28.9,28.8,28.7,28.6,26.21,26.19,26.17,26.12,26.10,26.08,16.7,16.6,16.48,16.45.

[0142] Example 31:

[0143]

[0144] In a glove box, 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 41.9 mg (0.20 mmol) of compound 1b, and 209.6 mg (0.60 mmol) of compound 2m were added to a 4 mL vial. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 24 hours under irradiation with a 24 W blue LED lamp. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 4e (product 60 mg, yield 63%).

[0145] The target product 4e obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows:1 HNMR (400MHz, CDCl3) δ7.25–7.15(m,1H),6.85–6.75(m,2H),6.78–6.62(m,4H),4.25–4.09(m,2H),4.01(d,J=6.0Hz,1H),3.8 7–3.76(m,4H),3.76(s,3H),2.94–2.81(m,2H),2.36–2.17(m,3H),2.06–1.31(m,11H),1.28–1.20(m,3H),0.95–0.88(m,3H). 13 C NMR (101MHz, CDCl3) δ174.4,174.3,157.32,157.28,152.7,152.4,140.9,140.6,137.9,137 .8,132.7,132.5,126.3,126.2,115.4,114.8,114.7,114.5,113.6,111.4,111.3,60.62,60 .57,60.2,58.9,55.6,55.09,55.08,51.8,51.2,50.8,50.0,44.1,43.9,43.37,43.35,39.1,34.9,33.3,29.9,28.2,28.1,26.6,26.5,25.6,25.3,24.9,23.2,21.5,21.2,14.25,14.15.

[0146] Example 32:

[0147]

[0148] In a glove box, 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 41.9 mg (0.20 mmol) of compound 1b, and 196.4 mg (0.60 mmol) of compound 2n were added to a 4 mL vial. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 24 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 4f (46 mg, 51% yield).

[0149] The target product 4f obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows: 1HNMR (400MHz, CDCl3) δ7.20 (d, J=7.9Hz, 1H), 7.03 (dd, J=8.0, 1.7Hz, 1H), 6. 84–6.73(m,3H),6.66–6.57(m,2H),4.17(q,J=7.1Hz,2H),3.99(t,J=6.5Hz,1 H),3.74(s,3H),3.02–2.88(m,1H),2.59(t,J=7.5Hz,2H),2.32(s,3H),1.93– 1.71(m,4H),1.57–1.44(m,4H),1.24(t,J=7.1Hz,3H),1.19(d,J=6.9Hz,6H). 13 C NMR (101MHz, CDCl3) δ174.4,172.2,152.7,147.8,140.9,136.9,136.5,127.0,126.3,122 .6,115.1,114.8,60.9,57.8,55.6,34.1,32.9,28.8,27.0,25.3,24.7,23.0,20.8,14.2.

[0150] Example 33:

[0151]

[0152] In a glove box, a 4 mL vial was charged with 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 41.9 mg (0.20 mmol) of compound 1b, and 339.4 mg (0.60 mmol) of compound 2o. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 24 hours under 24 W blue LED light. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain 4 g of the target compound (62 mg, 45% yield).

[0153] The target product 4g obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum. The test results are as follows: 1HNMR (400MHz, CDCl3) δ6.82–6.75(m,2H),6.66–6.61(m,2H),4.19(q,J=7.1Hz,2H),4.02(t,J=6.5Hz,1H),3.75(s,3H),3.66(t,J=6 .4Hz,2H),2.59(t,J=6.8Hz,2H),2.17(s,3H),2.13(s,3H),2.10(s,3H),1.97–1.65(m,7H),1.62–1.03(m,28H),0.93–0.82(m,12H). 13 C NMR (101MHz, CDCl3) δ174.4,152.7,148.2,147.6,140.9,127.7,125.7,122.7,117.4,115.1,114.8,74.7,72.5,60.9,57.8,55.6,40.0,39.3, 37.4,37.4,37.4,37.2,33.2,32.7,32.6,31.2,30.0,27.9,24.8,24.4, 23.8,22.7,22.6,22.5,21.0,20.6,19.7,19.6,14.2,12.7,11.8,11.7.

[0154] Example 34:

[0155]

[0156] In a glove box, 4.5 mg (0.02 mmol) of palladium acetate, 63 mg (0.24 mmol) of triphenylphosphine, 130 mg (0.40 mmol) of cesium carbonate, 41.9 mg (0.20 mmol) of compound 1b, and 222.8 mg (0.60 mmol) of compound 2p were added to a 4 mL vial. Finally, 2 mL of benzene was added. The mixture was stirred at room temperature for 24 hours under irradiation with a 24 W blue LED lamp. After the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound 4h (product 67 mg, yield 67%).

[0157] The target product 4h obtained by the above synthesis method was tested by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum, and the test results are as follows: 1HNMR(400MHz, CDCl3)δ7.00(d,J=7.5Hz,1H),6.81–6.72(m,2H),6.66(dd,J=7.6,1.5Hz,1H),6.64–6.55(m,3H),4.16(q,J=7.1Hz,2H),4.1 0(t,J=5.9Hz,2H),3.99(t,J=5.8Hz,1H),3.93–3.88(m,2H),3.73(s,3H),2.31(s,3H),2.18(s,3H),1.93–1.68(m,8H),1.25–1.20(m,9H). 13 C NMR (101MHz, CDCl3) δ177.7,174.0,156.9,152.8,140.7,136.4,130.2,123.5,120.6,115.2,11 4.8,111.9,67.8,63.7,61.0,57.4,55.6,42.1,37.0,29.5,25.14,25.12,24.9,21.4,15.7,14.

[0158] Examples 35-55: Preparation of target product 3a under different reaction conditions

[0159] Reaction formula:

[0160]

[0161] The method is the same as that of Example 1, except for the amount of palladium catalyst, alkaline substance, organic solvent and alkyl bromide used. The results are shown in Table 1 below:

[0162] Table 1 Yields of products from CC coupling of N-arylglycine ester 1a and alkyl bromide 2a under different conditions

[0163] By comparing Examples 1, 35 to 42, it can be seen that when palladium acetate is used as a palladium catalyst, the catalytic performance is better than that of other palladium catalysts.

[0164] Cyclohexyl bromide Palladium catalyst Alkaline substances solvent 3a yield Example 35 3.0equiv. <![CDATA[Pd(PPh3)4]]> <![CDATA[Cs2CO3]]> PhH 19％ Example 36 3.0equiv. <![CDATA[Pd2(dba)3]]> <![CDATA[Cs2CO3]]> PhH <5％ Example 37 3.0equiv. <![CDATA[Pd(TFA)2]]> <![CDATA[Cs2CO3]]> PhH 38％ Example 38 3.0equiv. <![CDATA[Pd(OPiv)2]]> <![CDATA[Cs2CO3]]> PhH 64％ Example 39 3.0equiv. <![CDATA[(PPh3)2PdCl2]]> <![CDATA[Cs2CO3]]> PhH <5％ Example 40 3.0equiv. <![CDATA[PdCl2]]> <![CDATA[Cs2CO3]]> PhH <5％ Example 41 3.0equiv. <![CDATA[(DPEPhos)PdCl2]]> <![CDATA[Cs2CO3]]> PhH 27％ Example 42 3.0equiv. <![CDATA[(dppf)PdCl2]]> <![CDATA[Cs2CO3]]> PhH <5％ Example 43 3.0equiv. <![CDATA[Pd(OAc)2]]> <![CDATA[K2CO3]]> PhH 58％ Example 44 3.0equiv. <![CDATA[Pd(OAc)2]]> <![CDATA[K3PO4]]> PhH 54％ Example 45 3.0equiv. <![CDATA[Pd(OAc)2]]> LiOH PhH <5％ Example 46 3.0equiv. <![CDATA[Pd(OAc)2]]> <![CDATA[Na2CO3]]> PhH <5％ Example 47 3.0equiv. <![CDATA[Pd(OAc)2]]> NaOAc PhH <5％ Example 48 3.0equiv. <![CDATA[Pd(OAc)2]]> <![CDATA[Ag2CO3]]> PhH <5％ Example 49 3.0equiv. <![CDATA[Pd(OAc)2]]> <![CDATA[Et3N]]> PhH <5％ Example 50 3.0equiv. <![CDATA[Pd(OAc)2]]> <![CDATA[Cs2CO3]]> <![CDATA[PhCF3]]> 75％ Example 51 3.0equiv. <![CDATA[Pd(OAc)2]]> <![CDATA[Cs2CO3]]> PhF 73％ Example 52 3.0equiv. <![CDATA[Pd(OAc)2]]> <![CDATA[Cs2CO3]]> 1,4-dioxane 60％ Example 53 3.0equiv. <![CDATA[Pd(OAc)2]]> <![CDATA[Cs2CO3]]> <![CDATA[CH3CN]]> 8％ Example 54 3.0equiv. <![CDATA[Pd(OAc)2]]> <![CDATA[Cs2CO3]]> DMSO 33％ Example 55 1.5equiv. <![CDATA[Pd(OAc)2]]> <![CDATA[Cs2CO3]]> PhH 46％

[0165] The reaction is more active; a comparison of Examples 1 and 43 to 49 shows that cesium carbonate has a higher reaction activity when used as an alkaline substance than other alkaline substances; a comparison of Examples 1 and 50 to 54 shows that benzene has a higher reaction yield when used as a solvent than other solvents; finally, a comparison of Examples 1 and 55 shows that the reaction has a higher activity when the alkyl bromide is used in an amount of 3 equiv.

[0166] The specific embodiments described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above are only specific embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for synthesizing non-natural amino acids and their derivatives driven by visible light, characterized in that: The method comprises the following steps: fully reacting a glycine derivative represented by the general formula (1) with a compound represented by the general formula (2) under the irradiation of visible light with a wavelength of 450 to 460 nm in the presence of a Pd catalyst, a ligand triphenylphosphine, an alkaline substance and a solvent to obtain a non-natural amino acid derivative represented by the general formula (3); ， Wherein, Ar is any one of phenyl, p-methoxyphenyl, p-chlorophenyl, p-cyanophenyl, 1-naphthyl, and 3-fluoro-4-morpholinophenyl; R 1 For ethoxy, phenyl, N -methylaniline, pyrrolyl or natural product molecular fragments, the natural product molecular fragments are 1-(4-chlorobenzhydryl)piperazine, lurasidone, L - Any one of menthol, testosterone, oleanolic acid, cholesterol, lithocholic acid, nortriptyline, and atomoxetine hydrochloride; R 2 is a cyclohexyl group, a cyclopropyl group, a cyclobutyl group, a substituted C1-C20 alkyl group or a cycloalkyl group, or is a natural product molecular fragment, wherein the natural product molecular fragment is any one of estrone, thymol, vitamin E, and gemfibrozil; The Pd catalyst is any one of palladium acetate and palladium pivalate; The alkaline substance is any one of potassium carbonate, cesium carbonate, and potassium phosphate; The solvent is any one of benzene, trifluorotoluene, fluorobenzene, and 1,4-dioxane; The molar ratio of the glycine derivative to the alkyl bromide is 1.5-4.0:

1.

2. The method for synthesizing non-natural amino acids and their derivatives driven by visible light according to claim 1, characterized in that: The molar ratio of the glycine derivative to the alkyl bromide is 2.0-4.

0.

3. The method for synthesizing non-natural amino acids and their derivatives driven by visible light according to claim 1, characterized in that: The molar mass of the palladium catalyst is 5% to 15% of the molar mass of the glycine derivative.

4. The method for synthesizing non-natural amino acids and their derivatives driven by visible light according to claim 1, wherein: The molar ratio of the ligand to the glycine derivative is 0.5-1.5:

1.

5. The method for synthesizing non-natural amino acids and their derivatives driven by visible light according to claim 1, wherein: The molar ratio of the alkaline substance to the glycine derivative is 1.0-2.0:

1.

6. The method for synthesizing non-natural amino acids and their derivatives driven by visible light according to claim 1, wherein: The reaction atmosphere is nitrogen or an inert gas.

7. The method for synthesizing non-natural amino acids and their derivatives driven by visible light according to claim 1, wherein: The reaction temperature is 25~40 o C, the reaction time is 12 hours to 48 hours.

8. The method for synthesizing non-natural amino acids and their derivatives driven by visible light according to claim 1, wherein: Unnatural amino acids and their derivatives are any of the following: 。

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