Method for direct decarboxylation and iodination of alkyl carboxylic acid through photooxidation reduction / copper co-catalysis

Abstract

The invention discloses a method for direct decarboxylation and iodination of alkyl carboxylic acid through photooxidation reduction / copper co-catalysis, and relates to the field of synthesis of organic compounds. The method comprises the following steps: placing alkyl carboxylic acid, an iodination reagent, an N-hydroxyphthalimide compound, an alkaline substance, a ligand, a copper catalyst, a photocatalyst and an olefin additive in a solvent in an argon atmosphere, carrying out in-situ production of an active ester intermediate under the driving of visible light, further carrying out free radical mediated decarboxylation iodination, and carrying out in-situ synthesis on the active ester intermediate. A series of alkyl iodide are synthesized. The reaction conditions are mild, the operation is simple, and the method has a wide substrate range and good functional group tolerance. The method can realize later modification of complex natural products and drug molecules, and further proves the practicability of the method. The synthesis of the alkyl iodide is directly realized by using the alkyl carboxylic acid which is stable, low in toxicity, low in price and easy to obtain, and the alkyl iodide does not need to be pre-activated by additional steps, so that the method is more in line with the concept of modern green chemistry.

Description

Technical Field

[0001] The invention relates to the field of organic compound synthesis, and in particular to a method for direct decarboxylation iodination of alkyl carboxylic acids through photooxidation reduction / copper co-catalysis. Background Art

[0002] Halogenated hydrocarbons are not only a very important class of chemical raw materials and synthons in the field of organic synthesis, but also have a wide range of applications in medicinal chemistry, polymer chemistry, and materials chemistry (Adv. Synth. Catal. 2021, 363, 2678-2722; Chem. Rev. 2021, 121, 412-484; Acc. Chem. Res. 2024, 57, 3161-3181). Therefore, discovering efficient methods for synthesizing halogenated hydrocarbons has always been a research hotspot in the field of organic chemistry.

[0003] Alkyl carboxylic acids have the advantages of being stable, cheap, non-toxic, and abundant, so it is very necessary to use carboxylic acids to synthesize halogenated hydrocarbons. Among them, pre-functionalization of alkyl carboxylic acids using N-hydroxyphthalimide is one of the important strategies for achieving decarboxylation and halogenation (Org.Lett.2020,22,8572-8577,Angew.Chem.Int.Ed.2023,62,e202309684). However, this strategy usually requires pre-preparation of carboxylic acids, resulting in cumbersome reaction steps. Therefore, it is of great significance to develop a new synthesis method based on N-hydroxyphthalimide active ester intermediates to achieve direct decarboxylation and iodination of alkyl carboxylic acids. Summary of the invention

[0004] In view of this, the purpose of the present invention is to provide a method for direct decarboxylation and iodination of alkyl carboxylic acids by photo-oxidation-reduction / copper co-catalysis, in order to solve the above technical problems.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0006] A method for direct decarboxylation and iodination of alkyl carboxylic acids by photo-oxidation reduction / copper catalysis, characterized in that it comprises the following steps: the method is to place alkyl carboxylic acids, iodine reagents, N-hydroxyphthalimide compounds, alkaline substances, ligands, copper catalysts, photocatalysts and olefin additives in a solvent under an argon atmosphere, and produce active ester intermediates in situ under visible light irradiation, thereby undergoing free radical-mediated decarboxylation and iodination to obtain an iodide having the following general formula (II):

[0007]

[0008] Wherein, R is a substituted or unsubstituted C1-C20 alkyl group or a substituted or unsubstituted C3-C20 cycloalkyl group;

[0009] When the above-mentioned substituted or unsubstituted group has a substituent, the substituent is a cyano group, an ester group, a halogen, a methoxy group, an amide or a natural product molecular fragment, and the natural product molecular fragment is any one of linoleic acid, chlorambucil, mycophenolic acid, dehydrocholic acid and lithocholic acid.

[0010] The iodine reagent is 1,2-diiodoethane, potassium iodide, sodium iodide, methyl iodide, among which 1,2-diiodoethane is preferred.

[0011] The N-hydroxyphthalimide compound is at least one of N-hydroxyphthalimide, N-hydroxytetrachlorophthalimide, 2-hydroxy-5-methylisoindoline-1,3-dione, and 4-bromo-2-hydroxy-1(H)-phthalimide, and the molar amount of the N-hydroxyphthalimide compound is 50% to 120% of the molar amount of the alkyl carboxylic acid, wherein N-hydroxyphthalimide is preferred.

[0012] The alkaline substance is at least one of sodium bicarbonate, potassium carbonate, potassium phosphate, 4-dimethylaminopyridine, pyridine and triethylamine, and the molar amount of the alkaline substance is 50% to 200% of the molar amount of the alkyl carboxylic acid, wherein 4-dimethylaminopyridine is preferred.

[0013] The ligand is at least one of 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene, 1,3-bis(diphenylphosphino)propane, 1,1'-bis(diphenylphosphino)ferrocene, triphenylphosphine, and tricyclohexylphosphine, and the molar amount of the ligand is 50% to 120% of the molar amount of the alkyl carboxylic acid, wherein 4.5-bis(diphenylphosphino)-9.9-dimethyloxanthene is preferred.

[0014] The copper catalyst is at least one of copper tetrafluorophosphate tetraacetonitrile, cuprous iodide, cuprous chloride, copper trifluoromethanesulfonate, and copper acetylacetonate, and the molar amount of the copper catalyst is 5% to 15% of the molar amount of the alkyl carboxylic acid, wherein copper tetrafluorophosphate tetraacetonitrile is preferred.

[0015] The photocatalyst is at least one of 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, tris(2-phenylpyridine)iridium, bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate), and terpyridine ruthenium chloride hexahydrate, and the molar amount of the photocatalyst is 1% to 10% of the molar amount of the alkyl carboxylic acid. Among them, 2.4.5.6-tetrakis(9-carbazolyl)-isophthalonitrile is preferred.

[0016] The olefin additive is at least one of styrene, cyclohexene, 4-fluorostyrene and 4-methoxystyrene, and the molar amount of the olefin is 20% to 100% of the molar amount of the alkyl carboxylic acid, among which styrene is preferred.

[0017] The solvent is at least one of N,N-dimethylacetamide, acetonitrile, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, ethyl acetate, toluene and dimethyl sulfoxide, wherein 1,2-dichloroethane is preferred when the secondary and tertiary carboxylic acids are iodinated, and N,N-dimethylacetamide is preferred when the primary carboxylic acid is iodinated.

[0018] The wavelength range of the visible light irradiation includes: 365-520nm; the range of the reaction temperature includes: 15-60°C; the range of the reaction time includes: 12-48 hours, wherein the wavelength of the visible light irradiation is preferably 440-445nm, the reaction temperature is preferably 30°C, and the reaction time is preferably 24 hours.

[0019] The method provides a method for synthesizing alkyl halides directly from alkyl carboxylic acids. The reaction conditions are mild, the operation is simple, and it has a wide range of substrates and good functional group tolerance. In addition, the method can achieve the late modification of complex natural products and drug molecules, further proving the practicality of the method. More importantly, the present invention innovatively uses stable, low-toxic, cheap and readily available alkyl carboxylic acids to directly achieve the synthesis of alkyl iodides, without the need for additional steps to pre-activate them, which is more in line with the concept of modern green chemistry. DETAILED DESCRIPTION

[0020] The technical scheme of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0021] Embodiment 1:

[0022]

[0023] Compound 1a (0.2 mmol, 46 mg), N-hydroxyphthalimide (2.4 mmol, 39 mg), 4-dimethylaminopyridine (2.4 mmol, 29 mg), 1,2-diiodoethane (0.16 mmol, 45 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (0.16 mmol, 93 mg), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and tetraacetonitrile copper tetrafluorophosphate (0.01 mmol, 3.7 mg) were added to a 10 mL Schlenk reaction tube (10 mL capacity, 14 / 20 grinding mouth). The air in the tube was completely replaced with argon three times, and then 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) were added under argon atmosphere. The reaction system was stirred continuously at room temperature for 24 hours (stirring speed 300 rpm) under irradiation of a 12W blue LED (440-445nm) lamp. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3×10mL), and the combined organic phase was concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2a. (The product was a colorless oil, 54.9 mg in total, with a yield of 88%, and the eluent was ethyl acetate: petroleum ether = 1:10).

[0024] The target product 2a obtained by the above synthesis method was tested by hydrogen and carbon nuclear magnetic resonance spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3): δ4.43 (p, J = 6.0Hz, 1H), 3.60-3.54 (m, 2H), 3.3-3.23 (m, 2H), 2.02-1.98 (m, 4H), 1.44 (s, 9H).; 13 C{ 1 H}NMR (100MHz, CDCl3): δ154.54,79.68,37.22,28.32,27.65ppm.

[0025] Embodiment 2:

[0026]

[0027] Compound 1b (0.2 mmol, 54 mg), N-hydroxyphthalimide (2.4 mmol, 39 mg), 4-dimethylaminopyridine (2.4 mmol, 29 mg), 1,2-diiodoethane (0.16 mmol, 45 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.16 mmol, 93 mg), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and tetraacetonitrile copper tetrafluorophosphate (0.01 mmol, 3.7 mg) were added to a 10 mL Schlenk reaction tube (10 mL capacity, 14 / 20 grinding mouth). The air in the tube was completely replaced with argon three times, and then 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) were added under argon atmosphere. The reaction system was stirred continuously at room temperature for 24 hours (stirring speed 300 rpm) under irradiation of a 12W blue LED (440-445nm) lamp. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3×10mL), and the combined organic phase was concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2b. (The product was a colorless oil, 54.8 mg in total, with a yield of 81%, and the eluent was ethyl acetate: petroleum ether = 1:10).

[0028] The target product 2b obtained by the above synthesis method was tested by nuclear magnetic resonance hydrogen spectrum and carbon spectrum, and the test results are as follows: 1 H NMR (400MHz, CDCl3): δ4.48 (p, J = 8.3Hz, 1H), 3.32-3.24 (m, 4H), 2.67-2.61 ( m,2H),2.43-2.38(m,2H),1.67-1.64(m,2H),1.55-1.53(m,2H),1.43(s,9H); 13 C{ 1 H}NMR (100MHz, CDCl3): δ154.77,79.41,46.23,39.74,39.41,35.06,28.38,9.51ppm.

[0029] Embodiment 3:

[0030]

[0031] Compound 1c (0.2 mmol, 48 mg), N-hydroxyphthalimide (2.4 mmol, 39 mg), 4-dimethylaminopyridine (2.4 mmol, 29 mg), 1,2-diiodoethane (0.16 mmol, 45 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.16 mmol, 93 mg), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and tetraacetonitrile copper tetrafluorophosphate (0.01 mmol, 3.7 mg) were added to a 10 mL Schlenk reaction tube (10 mL capacity, 14 / 20 grinding mouth). The air in the tube was completely replaced with argon three times, and then 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) were added under argon atmosphere. The reaction system was stirred continuously at room temperature for 24 hours (stirring speed 300 rpm) under irradiation of a 12W blue LED (440-445nm) lamp. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3×10mL), and the combined organic phase was concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2c. (The product was a colorless oil, 48.1 mg in total, with a yield of 75%, and the eluent was petroleum ether).

[0032] The target product 2c obtained by the above synthesis method was tested by hydrogen and carbon nuclear magnetic resonance spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3): δ7.29-7.26(m,1H),7.26-7.21(m,1H),7.21-7.17(m,1.42H),7.11-7.07(m,0.74H),4.92-4.91(m,0.68H),4 .21-4.13(m,0.38H),2.63-2,50(m,1.95H),2.22-2.10(m,2H),2.04-1.94(m,1.29H),1.78-1.65(m,3.31H),1.56-1.46(m,0.96H); 13 C{ 1 H}NMR (100MHz, CDCl3): δ145.0,144.6,131.8,131.7,128.50,128.48,128.2,128.0,43.2,42.2,40.5,36.44,36.39,35.6,30.0,28.4ppm.

[0033] Embodiment 4:

[0034]

[0035] Compound 1d (0.2 mmol, 32 mg), N-hydroxyphthalimide (2.4 mmol, 39 mg), 4-dimethylaminopyridine (2.4 mmol, 29 mg), 1,2-diiodoethane (0.16 mmol, 45 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.16 mmol, 93 mg), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and tetraacetonitrile copper tetrafluorophosphate (0.01 mmol, 3.7 mg) were added to a 10 mL Schlenk reaction tube (10 mL capacity, 14 / 20 grinding mouth). The air in the tube was completely replaced with argon three times, and then 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) were added under argon atmosphere. The reaction system was stirred continuously at room temperature for 24 hours (stirring speed 300 rpm) under irradiation of a 12W blue LED (440-445nm) lamp. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3×10mL), and the combined organic phase was concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2d. (The product was a colorless oil, 42.3 mg in total, with a yield of 87%, and the eluent was petroleum ether).

[0036] The target product 2d obtained by the above synthesis method was tested by hydrogen and carbon nuclear magnetic resonance spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3): δ7.30-7.25(m,2H),7.22-7.18(m,1H),7.07-7.05(m,2H ),2.57-2.53(m,1H),2.35-2.30(m,1H),1.51-1.46(m,1H),1.43-1.37(m,1H); 13 C{ 1 H}NMR (100MHz, CDCl3): δ140.3,128.5,126.5,125.7,27.7,19.8,-13.2ppm.

[0037] Embodiment 5:

[0038]

[0039] Compound 1e (0.2 mmol, 32 mg), N-hydroxyphthalimide (2.4 mmol, 39 mg), 4-dimethylaminopyridine (2.4 mmol, 29 mg), 1,2-diiodoethane (0.16 mmol, 45 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.16 mmol, 93 mg), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and tetraacetonitrile copper tetrafluorophosphate (0.01 mmol, 3.7 mg) were added to a 10 mL Schlenk reaction tube (10 mL capacity, 14 / 20 grinding mouth). The air in the tube was completely replaced with argon three times, and then 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) were added under argon atmosphere. The reaction system was stirred continuously at room temperature for 24 hours (stirring speed 300 rpm) under irradiation of a 12W blue LED (440-445nm) lamp. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3×10mL), and the combined organic phase was concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain the product 2e. (The product was a colorless oil, 36.1 mg in total, with a yield of 74%, and the eluent was petroleum ether).

[0040] The target product 2e obtained by the above synthesis method was tested by hydrogen and carbon nuclear magnetic resonance spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3): δ7.26-7.19(m,4H),4.73-4.67(m,1H),3.50-3.35(m,4H); 13 C{1H}NMR (100MHz, CDCl3): δ141.4, 126.9, 124.3, 46.5, 23.8ppm.

[0041] Embodiment 6:

[0042]

[0043] Compound 1f (0.2 mmol, 51 mg), N-hydroxyphthalimide (2.4 mmol, 39 mg), 4-dimethylaminopyridine (2.4 mmol, 29 mg), 1,2-diiodoethane (0.16 mmol, 45 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (0.16 mmol, 93 mg), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and tetraacetonitrile copper tetrafluorophosphate (0.01 mmol, 3.7 mg) were added to a 10 mL Schlenk reaction tube (10 mL capacity, 14 / 20 grinding mouth). The air in the tube was completely replaced with argon three times, and then 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) were added under argon atmosphere. The reaction system was stirred continuously at room temperature for 24 hours (stirring speed 300 rpm) under irradiation of 12W blue LED (440-445nm) lamp. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3×10mL), and the combined organic phase was concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2f. (The product was a colorless oil, 56.8 mg in total, with a yield of 84%, and the eluent was petroleum ether).

[0044] The target product 2f obtained by the above synthesis method was tested by nuclear magnetic resonance hydrogen spectrum and carbon spectrum, and the test results are as follows: 1 H NMR(400MHz, CDCl3): δ4.15-3.86(m,1H),1.90-1.64(m,4H),1.54-1.26(m,20H),0.90-0.86(m,6H); 13C{1H}NMR(100MHz, CDCl3): δ40.8,40.7,38.5,31.8,31.71,31.68,29.52,29.48,29.4,29.24,29.19,28.9,28.5,26.49,26.45,22.7,22.6,14.10,14.05ppm.

[0045] Embodiment 7:

[0046]

[0047] Compound 1g (0.2mmol, 36mg), N-hydroxyphthalimide (2.4mmol, 39mg), 4-dimethylaminopyridine (2.4mmol, 29mg), 1,2-diiodoethane (0.16mmol, 45mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (0.16mmol, 93mg), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01mmol, 7.9mg), and tetraacetonitrile copper tetrafluorophosphate (0.01mmol, 3.7mg) were added to a 10mL Schlenk reaction tube (10mL capacity, 14 / 20 grinding mouth). The air in the tube was completely replaced with argon three times, and then 2mL of N,N-dimethylacetamide and styrene (0.14mmol, 15mg) were added under argon atmosphere. The reaction system was stirred continuously at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) lamp irradiation. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with ethyl acetate (3×10mL), and the combined organic phase was concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain 2g of product. (The product was colorless oil, 25.8mg in total, yield 50%, eluent petroleum ether).

[0048] The target product 2g obtained by the above synthesis method was subjected to hydrogen and carbon nuclear magnetic resonance spectrum detection, and the test results were as follows: 1H NMR (400MHz, CDCl3): δ7.31-7.25 (m, 2H), 7.21-7.16 (m, 3H), 3.20 (t, J=6.9Hz, 2H), 2.63 (t, J=7.5Hz, 2H), 1.89-1.82 (m, 2H), 1.78-1.70 (m, 2H); 13C{1H}NMR (100MHz, CDCl3): δ141.8, 128.4, 125.9, 34.7, 32.9, 32.2, 6.8ppm.

[0049] Embodiment 8:

[0050]

[0051] Compound 1h (0.2 mmol, 36 mg), N-hydroxyphthalimide (2.4 mmol, 39 mg), 4-dimethylaminopyridine (2.4 mmol, 29 mg), 1,2-diiodoethane (0.16 mmol, 45 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.16 mmol, 93 mg), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and tetraacetonitrile copper tetrafluorophosphate (0.01 mmol, 3.7 mg) were added to a 10 mL Schlenk reaction tube (10 mL capacity, 14 / 20 grinding mouth). The air in the tube was completely replaced with argon three times, and then 2 mL of N,N-dimethylacetamide and styrene (0.14 mmol, 15 mg) were added under argon atmosphere. The reaction system was stirred continuously at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) lamp. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with ethyl acetate (3×10mL), and the combined organic phase was concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain the product 2h. (The product was a yellow oil, 38.7 mg in total, with a yield of 74%, and the eluent was ethyl acetate: petroleum ether = 1:10).

[0052] The target product 2h obtained by the above synthesis method was tested by nuclear magnetic resonance hydrogen spectrum and carbon spectrum, and the test results are as follows: 1 H NMR (CDCl3, 400MHz) δ: 7.13-7.10 (m, 2H), 6.87-6.85 (m, 2H), 3.80 (s, 3H), 3.32 (t, J = 7.8Hz, 2H), 3.12 (t, J = 7.8Hz, 2H); 13 C{1H}NMR (100MHz, CDCl3): δ158.4,132.8,129.3,114.0,55.2,39.5,6.4ppm.

[0053] Embodiment 9:

[0054]

[0055] Compound 1i (0.2 mmol, 35 mg), N-hydroxyphthalimide (2.4 mmol, 39 mg), 4-dimethylaminopyridine (2.4 mmol, 29 mg), 1,2-diiodoethane (0.16 mmol, 45 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.16 mmol, 93 mg), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and tetraacetonitrile copper tetrafluorophosphate (0.01 mmol, 3.7 mg) were added to a 10 mL Schlenk reaction tube (10 mL capacity, 14 / 20 grinding mouth). The air in the tube was completely replaced with argon three times, and then 2 mL of N,N-dimethylacetamide and styrene (0.14 mmol, 15 mg) were added under argon atmosphere. The reaction system was stirred continuously at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) lamp irradiation. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with ethyl acetate (3×10mL), and the combined organic phase was concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2i. (The product was a white solid, 26.2 mg in total, with a yield of 51%, and the eluent was ethyl acetate: petroleum ether = 1:10).

[0056] The target product 2i obtained by the above synthesis method was tested by hydrogen and carbon nuclear magnetic resonance spectra, and the test results are as follows: 1 H NMR (CDCl3, 400MHz) δ: 7.13-7.10 (m, 2H), 6.87-6.85 (m, 2H), 3.80 (s, 3H), 3.32 (t, J = 7.8Hz, 2H), 3.12 (t, J = 7.8Hz, 2H); 13 C{1H}NMR (100MHz, CDCl3): δ158.4,132.8,129.3,114.0,55.2,39.5,6.4ppm.

[0057] Embodiment 10:

[0058]

[0059] Compound 1j (0.2 mmol, 47 mg), N-hydroxyphthalimide (2.4 mmol, 39 mg), 4-dimethylaminopyridine (2.4 mmol, 29 mg), 1,2-diiodoethane (0.16 mmol, 45 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.16 mmol, 93 mg), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and tetraacetonitrile copper tetrafluorophosphate (0.01 mmol, 3.7 mg) were added to a 10 mL Schlenk reaction tube (10 mL capacity, 14 / 20 grinding mouth). The air in the tube was completely replaced with argon three times, and then 2 mL of N,N-dimethylacetamide and styrene (0.14 mmol, 15 mg) were added under argon atmosphere. The reaction system was stirred continuously at room temperature for 24 hours (stirring speed 300 rpm) under irradiation of a 12W blue LED (440-445nm) lamp. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with ethyl acetate (3×10mL), and the combined organic phase was concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2j. (The product was a white solid, 29.6 mg in total, with a yield of 47%, and the eluent was ethyl acetate: petroleum ether = 1:10).

[0060] The target product 2j obtained by the above synthesis method was tested by nuclear magnetic resonance hydrogen spectrum and carbon spectrum, and the test results are as follows: 1 H NMR (CDCl3, 400MHz): δ7.13-7.10 (m, 2H), 6.87-6.85 (m, 2H), 3.80 (s, 3H), 3.32 (t, J = 7.8Hz, 2H), 3.12 (t, J = 7.8Hz, 2H); 13 C{1H}NMR (100MHz, CDCl3): δ158.4,132.8,129.3,114.0,55.2,39.5,6.4ppm.

[0061] Embodiment 11:

[0062]

[0063] Compound 1k (0.2 mmol, 36 mg), N-hydroxyphthalimide (2.4 mmol, 39 mg), 4-dimethylaminopyridine (2.4 mmol, 29 mg), 1,2-diiodoethane (0.16 mmol, 45 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.16 mmol, 93 mg), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and tetraacetonitrile copper tetrafluorophosphate (0.01 mmol, 3.7 mg) were added to a 10 mL Schlenk reaction tube (10 mL capacity, 14 / 20 grinding mouth). The air in the tube was completely replaced with argon three times, and then 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) were added under argon atmosphere. The reaction system was stirred continuously at room temperature for 24 hours (stirring speed 300 rpm) under irradiation of a 12W blue LED (440-445nm) lamp. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3×10mL), and the combined organic phase was concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain the product 2k. (The product was a colorless oil, 40.5 mg in total, with a yield of 77%, and the eluent was ethyl acetate: petroleum ether = 1:10).

[0064] The target product 2k obtained by the above synthesis method was tested by nuclear magnetic resonance hydrogen spectrum and carbon spectrum, and the test results are as follows: 1 H NMR (400MHz, CDCl3): δ2.63 (d, J = 2.9Hz, 6H), 1.96-1.94 (m, 3H), 1.85-1.76 (m, 6H); 13 C{1H}NMR (100MHz, CDCl3): δ52.4, 51.2, 35.6, 33.1ppm.

[0065] Embodiment 12:

[0066]

[0067] Compound 11 (0.2 mmol, 39 mg), N-hydroxyphthalimide (2.4 mmol, 39 mg), 4-dimethylaminopyridine (2.4 mmol, 29 mg), 1,2-diiodoethane (0.16 mmol, 45 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (0.16 mmol, 93 mg), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and tetraacetonitrile copper tetrafluorophosphate (0.01 mmol, 3.7 mg) were added to a 10 mL Schlenk reaction tube (10 mL capacity, 14 / 20 grinding mouth). The air in the tube was completely replaced with argon three times, and then 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) were added under argon atmosphere. The reaction system was stirred continuously at room temperature for 24 hours (stirring speed 300 rpm) under irradiation of a 12W blue LED (440-445nm) lamp. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3×10mL), and the combined organic phase was concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain the product 2l. (The product was a white solid, 44.5 mg in total, with a yield of 81%, and the eluent was ethyl acetate: petroleum ether = 1:10).

[0068] The target product 21 obtained by the above synthesis method was tested by hydrogen and carbon nuclear magnetic resonance spectra, and the test results are as follows: 1 H NMR (CDCl3, 400MHz) δ: 2.84-2.71 (m, 6H), 2.52-2.45 (m, 2H), 2.16-2.05 (m, 5H); 13 C{ 1 H}NMR (100MHz, CDCl3): δ214.3,52.4,50.6,50.0,41.2,37.3,31.6ppm.

[0069] Implementation 13:

[0070]

[0071] Compound 1m (0.2 mmol, 42 mg), N-hydroxyphthalimide (2.4 mmol, 39 mg), 4-dimethylaminopyridine (2.4 mmol, 29 mg), 1,2-diiodoethane (0.16 mmol, 45 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (0.16 mmol, 93 mg), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and tetraacetonitrile copper tetrafluorophosphate (0.01 mmol, 3.7 mg) were added to a 10 mL Schlenk reaction tube (10 mL capacity, 14 / 20 grinding mouth). The air in the tube was completely replaced with argon three times, and then 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) were added under argon atmosphere. The reaction system was stirred continuously at room temperature for 24 hours (stirring speed 300 rpm) under irradiation of a 12W blue LED (440-445nm) lamp. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3×10mL), and the combined organic phase was concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain the product 2m. (The product was a white solid, 50.4 mg in total, with a yield of 86%, and the eluent was ethyl acetate: petroleum ether = 1:10).

[0072] The target product 2m obtained by the above synthesis method was tested by nuclear magnetic resonance hydrogen spectrum and carbon spectrum, and the test results are as follows: 1 H NMR (400MHz, CDCl3): δ3.62(s,3H),2.48-2.44(m,6H),1.94-1.90(m,6H); 13 C{ 1 H}NMR (100MHz, CDCl3): δ177.4,51.8,43.1,39.8,35.6,31.8ppm.

[0073] Embodiment 14:

[0074]

[0075] Compound 1n (0.2 mmol, 34 mg), N-hydroxyphthalimide (2.4 mmol, 39 mg), 4-dimethylaminopyridine (2.4 mmol, 29 mg), 1,2-diiodoethane (0.16 mmol, 45 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.16 mmol, 93 mg), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and tetraacetonitrile copper tetrafluorophosphate (0.01 mmol, 3.7 mg) were added to a 10 mL Schlenk reaction tube (10 mL capacity, 14 / 20 grinding mouth). The air in the tube was completely replaced with argon three times, and then 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) were added under argon atmosphere. The reaction system was stirred continuously at room temperature for 24 hours (stirring speed 300 rpm) under irradiation of a 12W blue LED (440-445nm) lamp. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3×10mL), and the combined organic phase was concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain the product 2n. (The product was a white solid, 23.2 mg in total, with a yield of 46%, and the eluent was ethyl acetate: petroleum ether = 1:10).

[0076] The target product 2n obtained by the above synthesis method was tested by nuclear magnetic resonance hydrogen spectrum and carbon spectrum, and the test results are as follows: 1 H NMR (400MHz, CDCl3): δ3.67(s,3H),2.55(s,6H); 13 C{ 1 H}NMR (100MHz, CDCl3): δ167.1, 60.6, 52.1, 45.9, 5.7ppm.

[0077] Embodiment 15:

[0078]

[0079] Compound 1o (0.2 mmol, 40 mg), N-hydroxyphthalimide (2.4 mmol, 39 mg), 4-dimethylaminopyridine (2.4 mmol, 29 mg), 1,2-diiodoethane (0.16 mmol, 45 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.16 mmol, 93 mg), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and tetraacetonitrile copper tetrafluorophosphate (0.01 mmol, 3.7 mg) were added to a 10 mL Schlenk reaction tube (10 mL capacity, 14 / 20 grinding mouth). The air in the tube was completely replaced with argon three times, and then 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) were added under argon atmosphere. The reaction system was stirred continuously at room temperature for 24 hours (stirring speed 300 rpm) under irradiation of 12W blue LED (440-445nm) lamp. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3×10mL), and the combined organic phase was concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain the product 2o. (The product was a white solid, 30.4 mg in total, with a yield of 42%, and the eluent was petroleum ether).

[0080] The target product 2o obtained by the above synthesis method was tested by nuclear magnetic resonance hydrogen spectrum and carbon spectrum, and the test results are as follows: 1 H NMR (400MHz, CDCl3): δ2.56 (s, 12H); 13 C{ 1 H}NMR (100MHz, CDCl3): δ44.0, 39.1ppm.

[0081] Embodiment 16:

[0082]

[0083] Compound 1p (0.2 mmol, 56 mg), N-hydroxyphthalimide (2.4 mmol, 39 mg), 4-dimethylaminopyridine (2.4 mmol, 29 mg), 1,2-diiodoethane (0.16 mmol, 45 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.16 mmol, 93 mg), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and tetraacetonitrile copper tetrafluorophosphate (0.01 mmol, 3.7 mg) were added to a 10 mL Schlenk reaction tube (10 mL capacity, 14 / 20 grinding mouth). The air in the tube was completely replaced with argon three times, and then 2 mL of N,N-dimethylacetamide and styrene (0.14 mmol, 15 mg) were added under argon atmosphere. The reaction system was stirred continuously at room temperature for 24 hours (stirring speed 300 rpm) under irradiation of a 12W blue LED (440-445nm) lamp. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with ethyl acetate (3×10mL), and the combined organic phase was concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain the product 2p. (The product was a colorless oil, 33.3 mg in total, with a yield of 46%, and the eluent was petroleum ether).

[0084] The target product 2p obtained by the above synthesis method was tested by nuclear magnetic resonance hydrogen spectrum and carbon spectrum, and the test results are as follows: 1 H NMR (400MHz, CDCl3): δ5.42-5.29(m,4H),3.19(t,J=7.1Hz,2H),2.79-2.76(m,2 H),2.08-2.02(m,4H),1.86-1.78(m,2H),1.39-1.28(m,14H),0.91-0.87(m,3H); 13 C{ 1 H}NMR (100MHz, CDCl3): δ130.2,130.0,128.1,127.9,33.5,31.5,30.5,29.7,29.5,29.3,29.0,28.4,27.2,27.1,25.6,22.6,14.1,7.3ppm.

[0085] Embodiment 17:

[0086]

[0087] Compound 1q (0.2 mmol, 40 mg), N-hydroxyphthalimide (2.4 mmol, 39 mg), 4-dimethylaminopyridine (2.4 mmol, 29 mg), 1,2-diiodoethane (0.16 mmol, 45 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.16 mmol, 93 mg), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and tetraacetonitrile copper tetrafluorophosphate (0.01 mmol, 3.7 mg) were added to a 10 mL Schlenk reaction tube (10 mL capacity, 14 / 20 grinding mouth). The air in the tube was completely replaced with argon three times, and then 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) were added under argon atmosphere. The reaction system was stirred continuously at room temperature for 24 hours (stirring speed 300 rpm) under irradiation of a 12W blue LED (440-445nm) lamp. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3×10mL), and the combined organic phase was concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain the product 2q. (The product was a white solid, 17.1 mg in total, with a yield of 31%, and the eluent was ethyl acetate: petroleum ether = 1:10).

[0088] The target product 2q obtained by the above synthesis method was tested by hydrogen and carbon nuclear magnetic resonance spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3): δ2.52-2.41(m,2H),1.87-1.80(m,1H),1.74-1.67(m,1H),1.20(s,3H),0.99(s,3H),0.86(s,3H); 13 C{1H}NMR (100MHz, CDCl3): δ177.50,78.83,56.38,49.53,40.65,30.08,18.81,17.45,10.57ppm.

[0089] Embodiment 18:

[0090]

[0091] Compound 1r (0.2 mmol, 56 mg), N-hydroxyphthalimide (2.4 mmol, 39 mg), 4-dimethylaminopyridine (2.4 mmol, 29 mg), 1,2-diiodoethane (0.16 mmol, 45 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.16 mmol, 93 mg), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and tetraacetonitrile copper tetrafluorophosphate (0.01 mmol, 3.7 mg) were added to a 10 mL Schlenk reaction tube (10 mL capacity, 14 / 20 grinding mouth). The air in the tube was completely replaced with argon three times, and then 2 mL of N,N-dimethylacetamide and styrene (0.14 mmol, 15 mg) were added under argon atmosphere. The reaction system was stirred continuously at room temperature for 24 hours (stirring speed 300 rpm) under irradiation of a 12W blue LED (440-445nm) lamp. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with ethyl acetate (3×10mL), and the combined organic phase was concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain the product 2r. (The product was a yellow solid, 37.0 mg in total, with a yield of 46%, and the eluent was petroleum ether:ethyl acetate = 1:1).

[0092] The target product 2r obtained by the above synthesis method was tested by hydrogen and carbon nuclear magnetic resonance spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3): δ7.67(s,1H),5.33-5.28(m,1H),5.19(s,2H),3.77(s,3H),3.55 (t,J=7.3Hz,2H),3.40(d,J=6.9Hz,2H),2.44-2.40(m,2H),2.14(s,3H),1.81(s,3H); 13 C{1H}NMR (100MHz, CDCl3): δ172.9,163.6,153.5,144.0,131.9,125.2,121.8,116.7,106.3,70.0,61.0,43.0,42.5,22.6,15.9,11.5.

[0093] Embodiment 19:

[0094]

[0095] Compound 1s (0.2 mmol, 81 mg), N-hydroxyphthalimide (2.4 mmol, 39 mg), 4-dimethylaminopyridine (2.4 mmol, 29 mg), 1,2-diiodoethane (0.16 mmol, 45 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.16 mmol, 93 mg), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and tetraacetonitrile copper tetrafluorophosphate (0.01 mmol, 3.7 mg) were added to a 10 mL Schlenk reaction tube (10 mL capacity, 14 / 20 grinding mouth). The air in the tube was completely replaced with argon three times, and then 2 mL of N,N-dimethylacetamide and styrene (0.14 mmol, 15 mg) were added under argon atmosphere. The reaction system was stirred continuously at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) lamp irradiation. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with ethyl acetate (3×10mL), and the combined organic phase was concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain the product 2s. (The product was a white solid, 48.7 mg in total, with a yield of 50%, and the eluent was ethyl acetate: petroleum ether = 1:1).

[0096] The target product 2s obtained by the above synthesis method was tested by hydrogen and carbon nuclear magnetic resonance spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3): δ3.37-3.32(m,1H),3.15-3.08(m,1H),2.94-2.81(m,3H),2.35-1.94(m,13H),1. 87-1.80(m,1H),1.68-1.55(m,3H),1.39(s,3H),1.35-2.14(m,3H),1.08(s,3H),0.83(d,J=6.6Hz,3H); 13 C{ 1 H}NMR (100MHz, CDCl3): δ211.9,209.0,208.7,56.9,51.7,48.9,46.8,45.5,45.4,4 4.9,42.7,39.4,38.6,37.0,36.4,36.0,35.2,27.6,25.1,21.9,18.0,11.8,5.6ppm.

[0097] Embodiment 20:

[0098]

[0099] Compound 1s (0.2 mmol, 75 mg), N-hydroxyphthalimide (2.4 mmol, 39 mg), 4-dimethylaminopyridine (2.4 mmol, 29 mg), 1,2-diiodoethane (0.16 mmol, 45 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.16 mmol, 93 mg), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and tetraacetonitrile copper tetrafluorophosphate (0.01 mmol, 3.7 mg) were added to a 10 mL Schlenk reaction tube (10 mL capacity, 14 / 20 grinding mouth). The air in the tube was completely replaced with argon three times, and then 2 mL of N,N-dimethylacetamide and styrene (0.14 mmol, 15 mg) were added under argon atmosphere. The reaction system was stirred continuously at room temperature for 24 hours (stirring speed 300 rpm) under irradiation of a 12W blue LED (440-445nm) lamp. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with ethyl acetate (3×10mL), and the combined organic phase was concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain the product 2t. (The product was a white solid, 47.0 mg in total, with a yield of 51%, and the eluent was ethyl acetate: petroleum ether = 1:1).

[0100] The target product 2t obtained by the above synthesis method was tested by nuclear magnetic resonance hydrogen spectrum and carbon spectrum, and the test results are as follows: 1 H NMR (400MHz, CDCl3): δ3.66-3.58(m,1H),3.33-3.27(m,1H),3.12-3.06(m,1H),2.06-1.93(m, 2H),1.88-1.58(m,6H),1.57-1.48(m,4H),1.43-1.00(m,15H),0.93-0.90(m,6H),0.65(s,3H); 13 C{1H}NMR (100MHz, CDCl3): δ71.8,56.5,55.8,42.8,42.0,40.4,40.3,40.1,37.2,3 6.4,35.8,35.3,34.5,30.5,28.2,27.1,26.4,24.1,23.4,20.8,17.8,12.0,5.3ppm.

[0101] Condition optimization

[0102] Reactive

[0103]

[0104] Embodiments 21 to 24:

[0105] The same experimental method as Example 1 was used. The difference between Examples 21 to 24 was that the types of iodides in the reaction conditions shown in the above formula were different. The specific iodides and yields of the reactions are shown in Table 1, and the corresponding numbers are 21 to 24.

[0106] Table 1: Effects of different types of iodides on the decarboxylation iodide yield of 1-tert-butyloxycarbonylpiperidine-4-carboxylic acid 1a.

[0107] Sample No. 21 22 23 24 Iodide 1,2-Diiodoethane Methyl iodide Potassium iodide Sodium iodide Yield 88％ 28％ 28％ 16％

[0108] By comparing the test results of the examples in Table 1, it can be seen that when 1,2-diiodoethane is used as the iodide, the yield of the decarboxylation iodine product of 1-tert-butyloxycarbonylpiperidine-4-carboxylic acid 1a is the highest, which can reach 88%.

[0109] Embodiments 25 to 29:

[0110] The same experimental method as Example 1 was used. The difference between Examples 25 to 29 was that the types of ligands in the reaction conditions shown in the above formula were different. The specific reaction ligands and yields were shown in Table 2, and the corresponding numbers were 25 to 29.

[0111] Table 2: Effects of different types of ligands on the decarboxylation iodination yield of 1-tert-butyloxycarbonylpiperidine-4-carboxylic acid 1a.

[0112]

[0113] By comparing the test results of the examples in Table 2, it can be seen that when 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene is used as the ligand, the yield of the decarboxylation iodine product of 1-tert-butyloxycarbonylpiperidine-4-carboxylic acid 1a is the highest, which can reach 88%.

[0114] Embodiment 30~34:

[0115] The same experimental method as that of Example 1 was adopted. The difference between Examples 30 to 34 was that the types of photocatalysts in the reaction conditions shown in the above formula were different. The specific reaction ligands and yields were shown in Table 3, and the corresponding numbers were 30 to 34.

[0116] Table 3: Effects of different types of photocatalysts on the decarboxylation iodination yield of 1-tert-butyloxycarbonylpiperidine-4-carboxylic acid 1a.

[0117]

[0118] By comparing the test results of each embodiment in Table 3, it can be seen that the yield of 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (1 mol%) is not much different from that of bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) salt (1 mol%), so the more economical 4CzIPN is selected as the photocatalyst. When 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (5 mol%) is selected as the photocatalyst, the yield of the decarboxylation iodine product of 1-tert-butyloxycarbonylpiperidine-4-carboxylic acid 1a is the highest, which can reach 88%.

[0119] Embodiments 35 to 37:

[0120] The same experimental method as Example 1 was adopted. The difference between Examples 35 to 37 was that the types of copper catalysts in the reaction conditions shown in the above formula were different. The specific reaction ligands and yields were shown in Table 4, and the corresponding numbers were 35 to 37.

[0121] Table 4: Effects of different types of copper catalysts on the decarboxylation iodination yield of 1-tert-butyloxycarbonylpiperidine-4-carboxylic acid 1a.

[0122]

[0123] By comparing the test results of the examples in Table 4, it can be seen that when copper tetrafluorophosphate tetraacetonitrile is used as the copper catalyst, the yield of the decarboxylation iodide product of 1-tert-butyloxycarbonylpiperidine-4-carboxylic acid 1a is the highest, which can reach 88%.

[0124] Embodiments 38 to 41:

[0125] The same experimental method as Example 1 was used. The difference between Examples 38 to 41 was that the types of olefins in the reaction conditions shown in the above formula were different. The specific reaction ligands and yields were shown in Table 5, corresponding to numbers 38 to 41.

[0126] Table 5: Effects of different types of olefins on the decarboxylation iodination yield of 1-tert-butyloxycarbonylpiperidine-4-carboxylic acid 1a.

[0127]

[0128] By comparing the test results of each example in Table 5, it can be seen that when styrene is selected as the olefin, the yield of the decarboxylation iodine product of 1-tert-butyloxycarbonylpiperidine-4-carboxylic acid 1a is the highest, which can reach 88%.

[0129] Embodiments 42 to 47:

[0130] The same experimental method as Example 1 was used. The difference between Examples 42 to 47 was that the types of solvents in the reaction conditions shown in the above formula were different. The specific reaction ligands and yields were shown in Table 6, corresponding to numbers 42 to 47.

[0131] Table 6: Effects of different types of solvents on the decarboxylation iodination yield of 1-tert-butyloxycarbonylpiperidine-4-carboxylic acid 1a.

[0132]

[0133]

[0134] By comparing the test results of the examples in Table 6, it can be seen that when 1,2-dichloroethane is selected as the solvent, the yield of the decarboxylation iodide product of 1-tert-butyloxycarbonylpiperidine-4-carboxylic acid 1a is the highest, which can reach 88%.

[0135] Embodiments 48 to 51:

[0136] The same experimental method as Example 1 was used. The difference between Examples 48 to 51 was that the types of wavelengths in the reaction conditions shown in the above formula were different. The specific reaction wavelengths and yields were shown in Table 7, corresponding to numbers 48 to 51.

[0137] Table 7: Effects of different wavelengths on the decarboxylation iodination yield of 1-tert-butyloxycarbonylpiperidine-4-carboxylic acid 1a.

[0138]

[0139] By comparing the test results of the embodiments in Table 7, it can be seen that when a wavelength of 440 to 445 nm is used, the yield of the decarboxylation iodine product of 1-tert-butyloxycarbonylpiperidine-4-carboxylic acid 1a is the highest, which can reach 88%.

[0140] Example 56, Preparation of N-BOC-4-iodopiperidine (2a, 1 mmol reaction):

[0141]

[0142] Compound 1o (1 mmol, 229 mg), N-hydroxyphthalimide (1.2 mmol, 196 mg), 4-dimethylaminopyridine (1.2 mmol, 147 mg), 1,2-diiodoethane (0.8 mmol, 225 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.8 mmol, 463 mg), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.05 mmol, 39 mg), and tetraacetonitrile copper tetrafluorophosphate (0.05 mmol, 19 mg) were added to a 10 mL Schlenk reaction tube (10 mL capacity, 14 / 20 grinding mouth). The air in the tube was completely replaced with argon three times, and then 10 mL of 1,2-dichloroethane and styrene (0.14 mmol, 73 mg) were added under argon atmosphere. The reaction system was stirred continuously at room temperature for 24 hours (stirring speed 300 rpm) under irradiation of a 12W blue LED (440-445nm) lamp. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3×30mL), and the combined organic phase was concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2a. (The product was a colorless oil, 209.4 mg in total, with a yield of 67%, and the eluent was ethyl acetate: petroleum ether = 1:10).

[0143] Example 57, Application:

[0144]

[0145] In an oven-dried round-bottom flask, 2a (62 mg, 0.2 mmol) and DMF (2 mL) were placed. DBU (1,8-diazobispiro[5.4.0]undec-7-ene) (30 mg, 0.4 mmol) was then added dropwise to the reaction mixture. The mixture was heated and stirred at 60 °C (oil bath) for another 16 hours. After the reaction was completed, the reaction was quenched with water, and the reaction solution was extracted with ethyl acetate (3×10 mL), and the combined organic phase was concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain the product 6a. (The product is a colorless oil, a total of 28.7 mg, a yield of 78%, and the eluent is ethyl acetate: petroleum ether = 1:10).

[0146] Embodiment 58:

[0147]

[0148] In the reaction of Example 1, 2.0 equivalents of tetramethylpiperidinium N-oxide (TEMPO) was added as a free radical scavenger, and the yield of the target product of the reaction was 0%. The experiment showed that the reaction did undergo a free radical reaction process.

[0149] Embodiment 59:

[0150]

[0151] In the reaction of Example 1, without illumination, the redox-active ester 5a formed by 1a was isolated with a yield of 47%, and the yield of the target product 2a was 0%. The experiment showed that this reaction may be a reaction pathway for forming a redox-active ester intermediate in situ.

[0152]

[0153] In the reaction of Example 1, 5a was used as the reaction raw material, and the target product 2a was isolated with a yield of 73% under standard conditions. The experiment showed that the reaction was a reaction pathway for in-situ formation of a redox-active ester intermediate.

[0154] The specific embodiments described above further illustrate the purpose, technical solutions and beneficial effects of the present invention. It should be understood that the above description is only a specific embodiment of the present invention and is 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 protection scope of the present invention.

Claims

1. A method for direct decarboxylation and iodination of alkyl carboxylic acids by photo-oxidation-reduction / copper catalysis, characterized in that: The method comprises the following steps: in an argon atmosphere, an alkyl carboxylic acid, an iodine reagent, an N-hydroxyphthalimide compound, an alkaline substance, a ligand, a copper catalyst, a photocatalyst and an olefin additive are placed in a solvent, and under visible light irradiation, an active ester intermediate is produced in situ, and then a free radical-mediated decarboxylation iodination is carried out to obtain an iodide having the following general formula (II): Wherein, R is a substituted or unsubstituted C1-C20 alkyl group or a substituted or unsubstituted C3-C20 cycloalkyl group; When the above-mentioned substituted or unsubstituted group has a substituent, the substituent is a cyano group, an ester group, a halogen, a methoxy group, an amide or a natural product molecular fragment, and the natural product molecular fragment is any one of linoleic acid, chlorambucil, mycophenolic acid, dehydrocholic acid and lithocholic acid.

2. The method according to claim 1, characterized in that: The iodine reagent is selected from at least one of 1,2-diiodoethane, potassium iodide, sodium iodide, and methyl iodide; The molar amount of the iodine reagent is 50% to 200% of the molar amount of the alkyl carboxylic acid.

3. The method according to claim 1, characterized in that The N-hydroxyphthalimide compound is selected from at least one of N-hydroxyphthalimide, N-hydroxytetrachlorophthalimide, 2-hydroxy-5-methylisoindoline-1,3-dione, and 4-bromo-2-hydroxy-1(H)-phthalimide; The molar amount of the N-hydroxyphthalimide compound is 50% to 120% of the molar amount of the alkyl carboxylic acid.

4. The method according to claim 1, characterized in that: The alkaline substance is selected from at least one of sodium bicarbonate, potassium carbonate, potassium phosphate, 4-dimethylaminopyridine, pyridine, and triethylamine; The molar amount of the alkaline substance is 50% to 200% of the molar amount of the alkyl carboxylic acid.

5. The method according to claim 1, characterized in that The ligand is selected from at least one of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 1,3-bis(diphenylphosphino)propane, 1,1'-bis(diphenylphosphino)ferrocene, triphenylphosphine, and tricyclohexylphosphine; The molar amount of the ligand is 50% to 120% of the molar amount of the alkyl carboxylic acid.

6. The method according to claim 1, characterized in that The copper catalyst is selected from at least one of copper tetraacetonitrile tetrafluorophosphate, cuprous iodide, cuprous chloride, copper trifluoromethanesulfonate, and copper acetylacetonate; The molar amount of the copper catalyst is 5% to 15% of the molar amount of the alkyl carboxylic acid.

7. The method according to claim 1, characterized in that The photocatalyst is selected from at least one of 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, tris(2-phenylpyridine)iridium, bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate), and terpyridine ruthenium chloride hexahydrate; The molar amount of the photocatalyst is 1% to 10% of the molar amount of the alkyl carboxylic acid.

8. The method according to claim 1, characterized in that: The olefin additive is selected from at least one of styrene, cyclohexene, 4-fluorostyrene, and 4-methoxystyrene; The molar amount of the olefin is 20% to 100% of the molar amount of the alkyl carboxylic acid.

9. The method according to claim 1, characterized in that: The organic solvent is selected from at least one of N,N-dimethylacetamide, acetonitrile, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, ethyl acetate, toluene and dimethyl sulfoxide.

10. The method according to claim 1, characterized in that The wavelength range of the visible light is 365 to 520 nm; the range of the reaction temperature is 15 to 60° C.; and the range of the reaction time is 12 to 48 hours.

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