A method of direct decarboxylative iodination of alkyl carboxylic acids photooxidative redox / copper co-catalyzed

Abstract

A method for direct decarboxylative iodination of alkyl carboxylic acids by photo-oxidative reduction / copper co-catalysis relates to the field of organic compound synthesis. The method is to add alkyl carboxylic acid, iodine reagent, N-hydroxy phthalimide compound, alkaline substance, ligand, copper catalyst, photocatalyst and olefin additive into a solvent under an argon atmosphere, to produce an active ester intermediate in situ under the driving of visible light, and then to occur free radical-mediated decarboxylative iodination to synthesize a series of alkyl iodides. The reaction condition is mild, the operation is simple, has a wide substrate range and good functional group tolerance. The method can realize the late-stage modification of complex natural products and drug molecules, further proving the practicability of the method. The method uses stable, low-toxicity, cheap and easily available alkyl carboxylic acid to directly realize the synthesis of alkyl iodide, without the need for additional steps to pre-activate it, and is more in line with the concept of modern green chemistry.

Description

Technical Field

[0001] This invention relates to the field of organic compound synthesis, and more particularly to a method for the direct decarboxylation and iodination of alkyl carboxylic acids via photo-oxidation-reduction / copper co-catalysis. Background Technology

[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 wide 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 possess advantages such as stability, low cost, non-toxicity, and abundance, making the synthesis of haloalkanes from carboxylic acids essential. Among these, prefunctionalization of alkyl carboxylic acids using N-hydroxyphthalimides is a crucial strategy for achieving decarboxylation and halogenation (Org. Lett. 2020, 22, 8572-8577, Angew. Chem. Int. Ed. 2023, 62, e202309684). However, this strategy typically requires pre-preparation of the carboxylic acid, leading to cumbersome reaction steps. Therefore, developing a novel synthetic method based on N-hydroxyphthalimide-based reactive ester intermediates to achieve the direct decarboxylation and iodination of alkyl carboxylic acids is of significant importance. Summary of the Invention

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

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0006] A photo-oxidation-reduction / copper-catalyzed direct decarboxylation and iodination method for alkyl carboxylic acids, characterized by the following steps: Under an argon atmosphere, alkyl carboxylic acids, iodinated reagents, N-hydroxyphthalimide compounds, basic substances, ligands, a copper catalyst, a photocatalyst, and an olefin additive are placed in a solvent. Under visible light irradiation, an active ester intermediate is produced in situ, followed by 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 or a substituted or unsubstituted C3-C20 cycloalkyl;

[0009] When the substituted or unsubstituted groups have substituents, the substituents are cyano, ester, halogen, methoxy, amide, or natural product molecular fragments, and the natural product molecular fragments are any one of linoleic acid, chlorambucil, mycophenolic acid, dehydrocholic acid, and lithocholic acid.

[0010] The iodination reagent is 1,2-diiodoethane, potassium iodide, sodium iodide, or iodomethane, with 1,2-diiodoethane being preferred.

[0011] The N-hydroxyphthalimide compound is at least one selected from 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. N-hydroxyphthalimide is preferred.

[0012] The alkaline substance is at least one selected from 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. 4-Dimethylaminopyridine is preferred.

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

[0014] The copper catalyst is at least one selected from 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. Copper tetrafluorophosphate tetraacetonitrile is preferred.

[0015] The photocatalyst is at least one selected from 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. Preferably, it is 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile.

[0016] The olefin additive is at least one selected from 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. Styrene is preferred.

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

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

[0019] This method provides a synthetic approach for the direct synthesis of alkyl halides from alkyl carboxylic acids. The reaction conditions are mild, the operation is simple, and it exhibits a broad substrate range and good functional group tolerance. Furthermore, this method can achieve late-stage modification of complex natural products and drug molecules, further demonstrating its practicality. More importantly, this invention innovatively uses stable, low-toxicity, inexpensive, and readily available alkyl carboxylic acids to directly synthesize alkyl iodides without requiring additional pre-activation treatment, thus aligning more closely with the principles of modern green chemistry. Detailed Implementation

[0020] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0021] Example 1:

[0022]

[0023] In a 10 mL Schlenk reaction tube (capacity 10 mL, ground glass joint 14 / 20), add 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(diphenylphosphine-9,9-dimethyloxanthracene (0.16 mmol, 93 mg), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and copper tetrafluorophosphate tetraacetonitrile (0.01 mmol, 3.7 mg). Completely purge the air from the tube three times with argon, then add 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) under an argon atmosphere. The reaction system was continuously stirred at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) illumination. After the reaction was complete, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3 × 10 mL). The combined organic phases were then concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2a. (The product was a colorless oil, totaling 54.9 mg, yield 88%, eluent: ethyl acetate: petroleum ether = 1:10).

[0024] The target product 2a obtained by the above synthesis method was subjected to proton and carbon NMR 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] Example 2:

[0026]

[0027] In a 10 mL Schlenk reaction tube (capacity 10 mL, ground glass joint 14 / 20), add 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(diphenylphosphine-9,9-dimethyloxanthracene (0.16 mmol, 93 mg), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and copper tetrafluorophosphate tetraacetonitrile (0.01 mmol, 3.7 mg). Completely purge the air from the tube three times with argon, then add 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) under an argon atmosphere. The reaction system was continuously stirred at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) illumination. After the reaction was complete, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3 × 10 mL). The combined organic phases were then concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2b. (The product was a colorless oil, totaling 54.8 mg, yield 81%, eluent: ethyl acetate: petroleum ether = 1:10).

[0028] The target product 2b obtained by the above synthesis method was subjected to proton and carbon NMR spectra, 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] Example 3:

[0030]

[0031] In a 10 mL Schlenk reaction tube (capacity 10 mL, ground glass joint 14 / 20), add 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(diphenylphosphine-9,9-dimethyloxanthracene (0.16 mmol, 93 mg), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and copper tetrafluorophosphate tetraacetonitrile (0.01 mmol, 3.7 mg). Completely purge the air from the tube three times with argon, then add 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) under an argon atmosphere. The reaction system was continuously stirred at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) illumination. After the reaction was complete, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3 × 10 mL). The combined organic phases were then concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2c. (The product was a colorless oil, totaling 48.1 mg, yield 75%, eluent: petroleum ether).

[0032] The target product 2c obtained by the above synthesis method was subjected to proton and carbon NMR 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] Example 4:

[0034]

[0035] In a 10 mL Schlenk reaction tube (capacity 10 mL, ground glass joint 14 / 20), add 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(diphenylphosphine-9,9-dimethyloxanthracene (0.16 mmol, 93 mg), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and copper tetrafluorophosphate tetraacetonitrile (0.01 mmol, 3.7 mg). Completely purge the air from the tube three times with argon, then add 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) under an argon atmosphere. The reaction system was continuously stirred at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) illumination. After the reaction was complete, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3 × 10 mL). The combined organic phases were then concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2d. (The product was a colorless oil, totaling 42.3 mg, yield 87%, eluent: petroleum ether).

[0036] The target product obtained by the above synthesis method was subjected to 1H and 1C NMR 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] Example 5:

[0038]

[0039] In a 10 mL Schlenk reaction tube (capacity 10 mL, ground glass joint 14 / 20), add 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(diphenylphosphine-9,9-dimethyloxanthracene (0.16 mmol, 93 mg), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and copper tetrafluorophosphate tetraacetonitrile (0.01 mmol, 3.7 mg). Completely purge the air from the tube three times with argon, then add 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) under an argon atmosphere. The reaction system was continuously stirred at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) illumination. After the reaction was complete, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3 × 10 mL). The combined organic phases were then concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2e. (The product was a colorless oil, totaling 36.1 mg, yield 74%, eluent: petroleum ether).

[0040] The target product 2e obtained by the above synthesis method was subjected to proton and carbon NMR 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] Example 6:

[0042]

[0043] In a 10 mL Schlenk reaction tube (capacity 10 mL, ground glass joint 14 / 20), add 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(diphenylphosphine-9,9-dimethyloxanthracene (0.16 mmol, 93 mg), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and copper tetrafluorophosphate tetraacetonitrile (0.01 mmol, 3.7 mg). Completely purge the air from the tube three times with argon, then add 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) under an argon atmosphere. The reaction system was continuously stirred at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) illumination. After the reaction was complete, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3 × 10 mL). The combined organic phases were then concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2f. (The product was a colorless oil, totaling 56.8 mg, yield 84%, eluent: petroleum ether).

[0044] The target product 2f obtained by the above synthesis method was subjected to proton and carbon NMR spectra, 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] Example 7:

[0046]

[0047] In a 10 mL Schlenk reaction tube (capacity 10 mL, ground glass joint 14 / 20), add 1 g (0.2 mmol, 36 mg) of the following compounds: 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(diphenylphosphine-9,9-dimethyloxanthracene (0.16 mmol, 93 mg), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and copper tetrafluorophosphate tetraacetonitrile (0.01 mmol, 3.7 mg). Completely purge the air from the tube three times with argon. Then, under an argon atmosphere, add 2 mL of N,N-dimethylacetamide and styrene (0.14 mmol, 15 mg). The reaction system was continuously stirred at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) illumination. After the reaction was complete, the reaction was quenched with water, and the reaction solution was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were then concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain 2 g of product. (The product was a colorless oil, totaling 25.8 mg, yield 50%, eluent: petroleum ether).

[0048] The target product 2g obtained by the above synthesis method was subjected to 1H and 1C NMR spectra. The test results are 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] Example 8:

[0050]

[0051] In a 10 mL Schlenk reaction tube (capacity 10 mL, ground glass joint 14 / 20), add 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(diphenylphosphine-9,9-dimethyloxanthracene (0.16 mmol, 93 mg), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and copper tetrafluorophosphate tetraacetonitrile (0.01 mmol, 3.7 mg). Completely purge the air from the tube three times with argon, then add 2 mL of N,N-dimethylacetamide and styrene (0.14 mmol, 15 mg) under an argon atmosphere. The reaction system was continuously stirred at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) illumination. After the reaction was complete, the reaction was quenched with water, and the reaction solution was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were then concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain the product (2h). (The product was a yellow oil, totaling 38.7 mg, yield 74%, eluent: ethyl acetate: petroleum ether = 1:10).

[0052] The target product obtained by the above synthesis method was subjected to 1H and 1C NMR spectra after 2 hours. 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] Example 9:

[0054]

[0055] In a 10 mL Schlenk reaction tube (capacity 10 mL, ground glass joint 14 / 20), add 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(diphenylphosphine-9,9-dimethyloxanthracene (0.16 mmol, 93 mg), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and copper tetrafluorophosphate tetraacetonitrile (0.01 mmol, 3.7 mg). Completely purge the air from the tube three times with argon, then add 2 mL of N,N-dimethylacetamide and styrene (0.14 mmol, 15 mg) under an argon atmosphere. The reaction system was continuously stirred at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) illumination. After the reaction was complete, the reaction was quenched with water, and the reaction solution was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were then concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2i (the product was a white solid, totaling 26.2 mg, yield 51%, eluent ethyl acetate:petroleum ether = 1:10).

[0056] The target product 2i obtained by the above synthesis method was subjected to proton and carbon NMR 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] Example 10:

[0058]

[0059] In a 10 mL Schlenk reaction tube (capacity 10 mL, ground glass joint 14 / 20), add 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(diphenylphosphine-9,9-dimethyloxanthracene (0.16 mmol, 93 mg), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and copper tetrafluorophosphate tetraacetonitrile (0.01 mmol, 3.7 mg). Completely purge the air from the tube three times with argon, then add 2 mL of N,N-dimethylacetamide and styrene (0.14 mmol, 15 mg) under an argon atmosphere. The reaction system was continuously stirred at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) illumination. After the reaction was complete, the reaction was quenched with water, and the reaction solution was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were then concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2j (the product was a white solid, totaling 29.6 mg, yield 47%, eluent ethyl acetate:petroleum ether = 1:10).

[0060] The target product 2j obtained by the above synthesis method was subjected to proton and carbon NMR spectra, 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] Example 11:

[0062]

[0063] In a 10 mL Schlenk reaction tube (capacity 10 mL, ground glass joint 14 / 20), add 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(diphenylphosphine-9,9-dimethyloxanthracene (0.16 mmol, 93 mg), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and copper tetrafluorophosphate tetraacetonitrile (0.01 mmol, 3.7 mg). Completely purge the air from the tube three times with argon, then add 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) under an argon atmosphere. The reaction system was continuously stirred at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) illumination. After the reaction was complete, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3 × 10 mL). The combined organic phases were then concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2K. (The product was a colorless oil, totaling 40.5 mg, yield 77%, eluent: ethyl acetate: petroleum ether = 1:10).

[0064] The target product 2k obtained by the above synthesis method was subjected to proton and carbon NMR spectra, 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] Example 12:

[0066]

[0067] In a 10 mL Schlenk reaction tube (capacity 10 mL, ground glass joint 14 / 20), add compound 1L (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(diphenylphosphine-9,9-dimethyloxanthracene (0.16 mmol, 93 mg), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and copper tetrafluorophosphate tetraacetonitrile (0.01 mmol, 3.7 mg). Completely purge the air from the tube three times with argon, then add 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) under an argon atmosphere. The reaction system was continuously stirred at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) illumination. After the reaction was complete, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3 × 10 mL). The combined organic phases were then concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2l (the product was a white solid, totaling 44.5 mg, yield 81%, eluent: ethyl acetate: petroleum ether = 1:10).

[0068] The target product 2l obtained by the above synthesis method was subjected to proton and carbon NMR 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] In a 10 mL Schlenk reaction tube (capacity 10 mL, ground glass joint 14 / 20), add 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(diphenylphosphine-9,9-dimethyloxanthracene (0.16 mmol, 93 mg), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and copper tetrafluorophosphate tetraacetonitrile (0.01 mmol, 3.7 mg). Completely purge the air from the tube three times with argon, then add 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) under an argon atmosphere. The reaction system was continuously stirred at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) illumination. After the reaction was complete, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3 × 10 mL). The combined organic phases were then concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2m (the product was a white solid, totaling 50.4 mg, yield 86%, eluent: ethyl acetate: petroleum ether = 1:10).

[0072] The target product 2m obtained by the above synthesis method was subjected to proton and carbon NMR spectra, 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] Example 14:

[0074]

[0075] In a 10 mL Schlenk reaction tube (capacity 10 mL, ground glass joint 14 / 20), add 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(diphenylphosphine-9,9-dimethyloxanthracene (0.16 mmol, 93 mg), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and copper tetrafluorophosphate tetraacetonitrile (0.01 mmol, 3.7 mg). Completely purge the air from the tube three times with argon, then add 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) under an argon atmosphere. The reaction system was continuously stirred at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) illumination. After the reaction was complete, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3 × 10 mL). The combined organic phases were then concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2n (the product was a white solid, totaling 23.2 mg, yield 46%, eluent ethyl acetate:petroleum ether = 1:10).

[0076] The target product 2n obtained by the above synthesis method was subjected to proton and carbon NMR spectra, 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] Example 15:

[0078]

[0079] In a 10 mL Schlenk reaction tube (capacity 10 mL, ground glass joint 14 / 20), add 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(diphenylphosphine-9,9-dimethyloxanthracene (0.16 mmol, 93 mg), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and copper tetrafluorophosphate tetraacetonitrile (0.01 mmol, 3.7 mg). Completely purge the air from the tube three times with argon, then add 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) under an argon atmosphere. The reaction system was continuously stirred at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) illumination. After the reaction was complete, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3 × 10 mL). The combined organic phases were then concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2O (the product was a white solid, totaling 30.4 mg, yield 42%, eluent: petroleum ether).

[0080] The target product 2o obtained by the above synthesis method was subjected to proton and carbon NMR spectra, 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] Example 16:

[0082]

[0083] In a 10 mL Schlenk reaction tube (capacity 10 mL, ground glass joint 14 / 20), add 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(diphenylphosphine-9,9-dimethyloxanthracene (0.16 mmol, 93 mg), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and copper tetrafluorophosphate tetraacetonitrile (0.01 mmol, 3.7 mg). Completely purge the air from the tube three times with argon, then add 2 mL of N,N-dimethylacetamide and styrene (0.14 mmol, 15 mg) under an argon atmosphere. The reaction system was continuously stirred at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) illumination. After the reaction was complete, the reaction was quenched with water, and the reaction solution was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were then concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2p (the product was a colorless oil, totaling 33.3 mg, yield 46%, eluent: petroleum ether).

[0084] The target product 2p obtained by the above synthesis method was subjected to proton and carbon NMR spectra, 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] Example 17:

[0086]

[0087] In a 10 mL Schlenk reaction tube (capacity 10 mL, ground glass joint 14 / 20), add 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(diphenylphosphine-9,9-dimethyloxanthracene (0.16 mmol, 93 mg), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and copper tetrafluorophosphate tetraacetonitrile (0.01 mmol, 3.7 mg). Completely purge the air from the tube three times with argon, then add 2 mL of 1,2-dichloroethane and styrene (0.14 mmol, 15 mg) under an argon atmosphere. The reaction system was continuously stirred at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) illumination. After the reaction was complete, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3 × 10 mL). The combined organic phases were then concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2q (the product was a white solid, totaling 17.1 mg, yield 31%, eluent ethyl acetate:petroleum ether = 1:10).

[0088] The target product 2q obtained by the above synthesis method was subjected to proton and carbon NMR 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] Example 18:

[0090]

[0091] In a 10 mL Schlenk reaction tube (capacity 10 mL, ground glass joint 14 / 20), add 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(diphenylphosphine-9,9-dimethyloxanthracene (0.16 mmol, 93 mg), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and copper tetrafluorophosphate tetraacetonitrile (0.01 mmol, 3.7 mg). Completely purge the air from the tube three times with argon, then add 2 mL of N,N-dimethylacetamide and styrene (0.14 mmol, 15 mg) under an argon atmosphere. The reaction system was continuously stirred at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) illumination. After the reaction was complete, the reaction was quenched with water, and the reaction solution was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were then concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2r (the product was a yellow solid, totaling 37.0 mg, yield 46%, eluent: petroleum ether: ethyl acetate = 1:1).

[0092] The target product 2r obtained by the above synthesis method was subjected to proton and carbon NMR 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] Example 19:

[0094]

[0095] In a 10 mL Schlenk reaction tube (capacity 10 mL, ground glass joint 14 / 20), add 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(diphenylphosphine-9,9-dimethyloxanthracene (0.16 mmol, 93 mg), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and copper tetrafluorophosphate tetraacetonitrile (0.01 mmol, 3.7 mg). Completely purge the air from the tube three times with argon, then add 2 mL of N,N-dimethylacetamide and styrene (0.14 mmol, 15 mg) under an argon atmosphere. The reaction system was continuously stirred at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) illumination. After the reaction was complete, the reaction was quenched with water, and the reaction solution was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were then concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to give product 2S (the product was a white solid, totaling 48.7 mg, yield 50%, eluent ethyl acetate:petroleum ether = 1:1).

[0096] The target product 2s obtained by the above synthesis method was subjected to proton and carbon NMR 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] Example 20:

[0098]

[0099] In a 10 mL Schlenk reaction tube (capacity 10 mL, ground glass joint 14 / 20), add 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(diphenylphosphine-9,9-dimethyloxanthracene (0.16 mmol, 93 mg), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (0.01 mmol, 7.9 mg), and copper tetrafluorophosphate tetraacetonitrile (0.01 mmol, 3.7 mg). Completely purge the air from the tube three times with argon, then add 2 mL of N,N-dimethylacetamide and styrene (0.14 mmol, 15 mg) under an argon atmosphere. The reaction system was continuously stirred at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) illumination. After the reaction was complete, the reaction was quenched with water, and the reaction solution was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were then concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain 2 t of product (the product was a white solid, totaling 47.0 mg, yield 51%, eluent ethyl acetate:petroleum ether = 1:1).

[0100] The target product 2t obtained by the above synthesis method was subjected to proton and carbon NMR spectra, 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] Conditional optimization

[0102] Reaction

[0103]

[0104] Examples 21-24:

[0105] The same experimental method as in Example 1 was used. The difference between Examples 21 to 24 is that the types of iodides in the reaction conditions shown in the above formula are 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: Effect of different types of iodides on the decarboxylation iodide yield of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid 1a.

[0107] Sample number 21 22 23 24 iodide 1,2-Diiodoethane Iodomethane Potassium iodide Sodium iodide Yield 88％ 28％ 28％ 16％

[0108] By comparing the test results of each example in Table 1, it can be seen that when 1,2-diiodoethane is used as the iodide, the yield of the decarboxylation iodinated product of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid 1a is the highest, reaching 88%.

[0109] Examples 25-29:

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

[0111] Table 2: Effect of different types of ligands on the decarboxylation iodide yield of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid 1a.

[0112]

[0113] By comparing the test results of each example in Table 2, it can be seen that when 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene is used as the ligand, the yield of the decarboxylated iodinated product of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid 1a is the highest, reaching 88%.

[0114] Examples 30-34:

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

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

[0117]

[0118] A comparison of the test results of each example in Table 3 shows that the yields of 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (1 mol%) and bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) (1 mol%) are not significantly different. Therefore, the more economical 4CzIPN was chosen as the photocatalyst. When 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (5 mol%) was used as the photocatalyst, the yield of the decarboxylation iodinated product of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid 1a was the highest, reaching 88%.

[0119] Examples 35-37:

[0120] The same experimental method as in Example 1 was used. The difference between Examples 35 to 37 is that the type of copper catalyst is different in the reaction conditions shown in the above formula. The specific ligands and yields of the reactions are shown in Table 4, and the corresponding numbers are 35 to 37.

[0121] Table 4: Effect of different types of copper catalysts on the decarboxylation iodide substitution yield of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid 1a.

[0122]

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

[0124] Examples 38-41:

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

[0126] Table 5: Effect of different types of olefins on the decarboxylation iodide yield of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid 1a.

[0127]

[0128] A comparison of the test results for each example in Table 5 shows that when styrene is used as the olefin, the yield of the decarboxylation iodinated product of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid 1a is the highest, reaching 88%.

[0129] Examples 42-47:

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

[0131] Table 6: Effect of different types of solvents on the decarboxylation iodide yield of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid 1a.

[0132]

[0133]

[0134] By comparing the test results of each example in Table 6, it can be seen that when 1,2-dichloroethane is used as a solvent, the yield of the decarboxylation iodinated product of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid 1a is the highest, reaching 88%.

[0135] Examples 48-51:

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

[0137] Table 7: Effect of different wavelengths on the decarboxylation iodide yield of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid 1a.

[0138]

[0139] By comparing the detection results of each example in Table 7, it can be seen that when a wavelength of 440-445 nm is used, the yield of the decarboxylation iodinated product of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid 1a is the highest, reaching 88%.

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

[0141]

[0142] In a 10 mL Schlenk reaction tube (capacity 10 mL, ground glass joint 14 / 20), add 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(diphenylphosphine-9,9-dimethyloxanthracene (0.8 mmol, 463 mg), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (0.05 mmol, 39 mg), and copper tetrafluorophosphate tetraacetonitrile (0.05 mmol, 19 mg). Completely purge the air from the tube three times with argon, then add 10 mL of 1,2-dichloroethane and styrene (0.14 mmol, 73 mg) under an argon atmosphere. The reaction system was continuously stirred at room temperature for 24 hours (stirring speed 300 rpm) under 12W blue LED (440-445nm) illumination. After the reaction was complete, the reaction was quenched with water, and the reaction solution was extracted with dichloromethane (3 × 30 mL). The combined organic phases were then concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to obtain product 2a. (The product was a colorless oil, totaling 209.4 mg, yield 67%, eluent: 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 added. Then, DBU (1,8-diazabispyrocyclo[5.4.0]undec-7-ene) (30 mg, 0.4 mmol) was added dropwise to the reaction mixture. The mixture was heated and stirred at 60 °C (oil bath) for 16 hours. After the reaction was complete, the reaction was quenched with water, and the reaction solution was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were then concentrated by rotary evaporation. The concentrated residue was separated by column chromatography to give product 6a. (The product was a colorless oil, totaling 28.7 mg, yield 78%, eluent ethyl acetate: petroleum ether = 1:10).

[0146] Example 58:

[0147]

[0148] In Example 1, 2.0 equivalents of tetramethylpiperidine nitride (TEMPO) were added as a free radical scavenger, and the yield of the target product was 0%. Experiments showed that the reaction did indeed involve a free radical reaction process.

[0149] Example 59:

[0150]

[0151] In Example 1, the redox-active ester 5a, formed from 1a, was isolated in 47% yield without illumination, while the target product 2a was in 0% yield. This suggests that the reaction may be a pathway for the in-situ formation of redox-active ester intermediates.

[0152]

[0153] In the reaction of Example 1, using 5a as the reactant, the target product 2a was isolated in 73% yield under standard conditions. Experiments show that this reaction is a pathway for the in-situ formation of redox-active ester intermediates.

[0154] The specific embodiments described above further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above descriptions are merely 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 within the protection scope of the present invention.

Claims

1. A method for photo-oxidation-reduction / copper-catalyzed direct decarboxylation and iodination of alkyl carboxylic acids, characterized in that, The method includes the following steps: Under an argon atmosphere, an alkyl carboxylic acid, an iodination reagent, an N-hydroxyphthalimide compound, a basic substance, a ligand, a copper catalyst, a photocatalyst, and an olefin additive are placed in a solvent. Under visible light irradiation, an active ester intermediate is produced in situ, followed by free radical-mediated decarboxylation and iodination to obtain an iodide having the following general formula II, wherein the alkyl carboxylic acid is a compound represented by the following formula I. Wherein, R is a substituted or unsubstituted C1~C20 alkyl or a substituted or unsubstituted C3~C20 cycloalkyl; When the substituted or unsubstituted groups mentioned above have substituents, the substituents are cyano, halogen, or methoxy. Alternatively, the alkyl carboxylic acid compound may be selected from any one of linoleic acid, chlorambucil, mycophenolic acid, dehydrocholic acid, and lithocholic acid. The copper catalyst is copper tetraacetonitrile hexafluorophosphate; The iodination reagent is 1,2-diiodoethane; The N-hydroxyphthalimide compound is an N-hydroxyphthalimide; The ligand is 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene; The photocatalyst is 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile; The olefin additive is styrene; The wavelength range of the visible light illumination is 440~445nm.

2. The method according to claim 1, characterized in that, The molar amount of the iodinated 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 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 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 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 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 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, Reaction temperature range: 15~60℃; reaction time range: 12~48 hours.

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