Method for inducing nickel to catalyze C (sp3)-C (sp2) cross-coupling reaction through visible light

Abstract

The invention belongs to the field of organic synthesis, and discloses a method for inducing nickel to catalyze C (sp3)-C (sp2) cross-coupling reaction through visible light. A series of C (sp3)-C (sp2) coupling products with various functional groups are synthesized by taking halogenated alkane and halogenated aromatic hydrocarbon as reactants and carrying out C (sp3)-C (sp2) cross coupling reaction only under the driving of visible light. In the reaction, the 9-fluorenone is used as a photocatalyst, belongs to a bulk chemical, and has the advantages of low cost, wide source and easiness in obtaining; in addition, visible light is adopted as the only driving force of the reaction, and expensive photocatalysts are not needed, so that the whole reaction process is more green and efficient. The invention provides a new thought for efficient cross-coupling synthesis of C (sp3)-C (sp2), has the characteristics of mild reaction conditions, convenience in experimental operation, good substrate compatibility and easiness in scale enlargement, and has higher application value and social and economic benefits.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis and provides a method for visible light-induced nickel-catalyzed C(sp 3 )-C(sp 2 ) cross-coupling reaction. Background Art

[0002] C(sp 3 )-C(sp 2 ) cross-coupling reaction has important application value in the field of organic synthesis and plays an important role in the synthesis of pharmaceutical molecules, the preparation of functional materials, the total synthesis of natural products, the synthesis of pesticides and fine chemicals, and the construction of asymmetric catalysis and chiral molecules. In the past few decades, a variety of C(sp 3 )-C(sp 2 ) cross-coupling reaction systems have been developed successively: for example, early reaction systems usually relied on stoichiometric heterogeneous (manganese or zinc) reducing agents (Journal of the American Chemical Society, 2015, 137(36): 11562-11565.) to achieve the conversion of Ni II to active Ni 0 and maintain the catalytic cycle. However, this method has obvious limitations in large-scale reactions, not only producing a large amount of metal salt waste, but also the use of metal reducing agents (usually powders) often requires surface activation, and their reaction activities vary due to different sources. At the same time, some functional groups are prone to side reactions with zinc or manganese, limiting their application scope. In recent years, nickel / electrochemical reduction-catalyzed electrophilic cross-coupling reaction has provided an efficient way for the construction of C(sp 3 )-C(sp 2 ) bonds. Electrochemical methods (Angew.Chem.Int.Ed. 2020, 59, 6520–6524.) as a clean technology have successfully replaced heterogeneous manganese or zinc reducing agents and achieved the greening of the nickel catalytic cycle. Electrochemical reduction can reliably activate and turnover nickel catalysts and provide an adjustable parameter for reaction optimization. In addition, significant progress has also been made in photocatalytic C(sp 3 )-C(sp 2 ) cross-coupling reactions. Through the synergistic catalysis of photoredox and transition metals, this dual-catalytic system can efficiently promote C(sp 3 )-C(sp 2) Formation of the key. The photoinduced nickel catalytic system has attracted extensive attention from researchers due to its excellent reactivity and selectivity. In particular, this system can achieve chemical transformations that are difficult to accomplish by traditional methods, opening up new avenues for the precise synthesis of complex molecules. Among them, typical visible light catalysts (iridium) (Journal of the American Chemical Society, 2016, 138(26): 8084 - 8087.) and complexes (1,2,3,5 - tetra(carbazol - 9 - yl) - 4,6 - dicyanobenzene) exhibit good catalytic performance. However, these catalysts have problems such as high cost, potential toxicity, and poor sustainability, which limit their wide application.

[0003] These new catalytic systems break through the limitations of traditional synthesis methods and can efficiently achieve challenging chemical transformations, providing transformative strategies for the precise construction of complex functional molecules. However, there are still problems in realizing their industrial applications: First, the severe dependence of the reaction system on highly toxic organic solvents (such as N,N - dimethylformamide, dimethyl sulfoxide, etc.) not only causes an environmental burden but also brings safety hazards; Second, the cost of catalytic systems based on precious metals (such as palladium, platinum, etc.) remains high, significantly restricting their large - scale production applications; In addition, electrode materials face key problems such as complex preparation processes and poor stability (especially under strong acid / strong base conditions), resulting in limited system operation life and sustainability. Based on the above research, the present invention attempts to use 9 - fluorenone as an efficient photocatalyst and systematically study its application in the C(sp 3 ) - C(sp 2 ) cross - coupling reaction. This exploration is not only of great scientific significance but also faces many challenges.

[0004] The present invention proposes a method that uses 9 - fluorenone as a photocatalyst and applies it to the cross - coupling reaction of nickel - catalyzed aryl halides and alkyl halides under visible light irradiation, providing a novel and practical strategy for the efficient construction of C - C bonds. In this technology, 9 - fluorenone is an organic compound with low cost, easy availability, and has been industrially mass - produced; at the same time, it has excellent photophysical and chemical properties, such as a long excited - state lifetime (70 μs) and excellent reduction stability; Finally, the reaction in the present invention only requires visible light driving, making the whole process more green and efficient. Summary of the Invention

[0005] The present invention provides a C(sp 3 ) - C(sp 2)A new synthetic method for cross-coupling reactions, in which nickel-catalyzed cross-coupling reactions of haloalkanes and haloarenes are carried out under visible light irradiation. The present invention has the advantages of mild reaction conditions, convenient experimental operation, good substrate compatibility, easy scale-up, etc., laying a solid foundation for further industrial applications and the creation of social and economic value.

[0006] The technical solution of the present invention:

[0007] A method for visible light-induced nickel-catalyzed C(sp 3 )-C(sp 2 ) cross-coupling reaction, using haloalkanes and haloarenes as starting materials, adding a photocatalyst, a nickel catalyst, a ligand, a reducing agent, a solvent and an additive, and heating in a nitrogen atmosphere under light irradiation to carry out the C(sp 3 )-C(sp 2 ) cross-coupling reaction to prepare a series of cross-coupling compounds. The synthetic route is as follows:

[0008]

[0009] In the formula: R is selected from carbonyl and H; Alkyl is selected from cyclohexyl, cyclopentyl, n-hexyl, ethyl and n-butyl; X is selected from iodine, bromine and chlorine;

[0010] The photocatalyst is selected from 9-fluorenone.

[0011] The nickel catalyst is selected from nickel acetate (tetrahydrate), nickel chloride, nickel chloride (hexahydrate), nickel(II) ethylene glycol dimethyl ether, bis(tricyclohexylphosphine)nickel chloride and [1,1'-bis(diphenylphosphino)ferrocene]nickel(II) dichloride.

[0012] The ligand is selected from 1,10-phenanthroline, 4,4'-di-tert-butyl-2,2'-dipyridine and bipyridine.

[0013] The reducing agent is N,N-diisopropylethylamine, triethylamine, diethanolmonoisopropanolamine, N,N,N',N'-tetramethylethylenediamine, N,N-dimethylaniline and N,N'-dimethylethylenediamine.

[0014] The wavelength range of the light irradiation is part or all of the bands in the range of 395 nm to 410 nm.

[0015] The light irradiation reaction time range is 8 to 24 h, preferably 12 to 18 h.

[0016] The solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetone, ether and N-methyl-2-pyrrolidone.

[0017] The heating temperature is 20 - 50 °C.

[0018] The additive is water.

[0019] The molar ratio of the haloarene to the haloalkane is 1:1 to 1:2.

[0020] The molar ratio of the photocatalyst to the haloarene is 3:20.

[0021] The molar ratio of the nickel catalyst to the haloarene is 1:10.

[0022] The molar ratio of the ligand to the haloarene is 3:20.

[0023] The molar ratio of the reducing agent to the haloarene is 3:1.

[0024] The molar ratio of the additive to the haloarene is 1.5:1.

[0025] The total concentration of the haloarene and the haloalkane in the reaction system is 0.4 to 0.6 mol / L.

[0026] Advantages of the present invention: The present invention is a new method for C(sp 3 )-C(sp 2 ) cross-coupling, realizing photo-driven C(sp 3 )-C(sp 2 ) cross-coupling reaction under a sustainable, inexpensive and efficient photocatalyst, filling the existing technical gap. The method of the present invention has mild process conditions, a short process flow, simple steps, a wide substrate scope, easy scale-up and a yield as high as 98%, which can meet the requirements of industrial production. On the other hand, the C(sp 3 )-C(sp 2 ) cross-coupling reaction has broad application prospects in organic synthesis and drug research and development. Generally speaking, the present invention has important application value. Brief Description of the Drawings

[0027] Figure 1 is the 1 H-NMR spectrum of compound 3a.

[0028] Figure 2 is the 13 C-NMR spectrum of compound 3a.

[0029] Figure 3 is the 1 H-NMR spectrum of compound 3b.

[0030] Figure 4 is the 13 C-NMR spectrum of compound 3b.

[0031] Figure 5 is the 1 H-NMR spectrum of compound 3c.

[0032] Figure 6 For the 13 C-NMR spectrum of compound 3c.

[0033] Figure 7 For the 1 H-NMR spectrum of compound 3d.

[0034] Figure 8 For the 13 C-NMR spectrum of compound 3d.

[0035] Figure 9 For the 1 H-NMR spectrum of compound 3e.

[0036] Figure 10 For the 13 C-NMR spectrum of compound 3e.

[0037] Figure 11 For the 1 H-NMR spectrum of compound 3f.

[0038] Figure 12 For the 13 C-NMR spectrum of compound 3f. Detailed implementation manners

[0039] The following further illustrates the detailed implementation manners of the present invention in combination with the attached drawings and technical solutions.

[0040] Example 1: Synthesis of Methyl 4-cyclohexylbenzoate (3a)

[0041]

[0042] Methyl 4-iodobenzoate (0.2 mmol), 9-fluorenone (0.03 mmol, 15 mmol%), bis(diphenylphosphino)ferrocene nickel(II) dichloride (0.02 mmol, 10 mmol%), and 2,2'-bipyridine (0.03 mmol, 15 mol%) were added to a quartz tube equipped with a magnetic stir bar. The quartz tube was then inserted into a photoreaction tube and connected to a photoreactor. The system was evacuated and filled with nitrogen three times to create a nitrogen atmosphere. Iodobenzene (0.3 mmol, 1.5 equiv.), N,N-diisopropylethylamine (0.6 mmol, 3.0 equiv.), N,N-dimethylformamide (1 mL), and water (0.3 mmol, 1.5 equiv.) were then added to the photoreaction tube. The reaction tube was inserted into a 10 W photoreactor, the rotation speed was set to 800 rpm, and the temperature was set to 40 °C. The reaction was carried out under irradiation with light at a wavelength of 400 nm for 16 h and then stopped. The reaction mixture was cooled to room temperature. After the reaction, the mixture was filtered through diatomaceous earth, concentrated under reduced pressure using a vacuum pump, and then separated by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent. The yield of product 3a was 98%.

[0043] 1 H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 3.89 (s, 3H), 2.56 (m, J = 11.4, 3.6 Hz, 1H), 1.89–1.83 (m, 4H), 1.89–1.74 (m, 1H), 1.48–1.34 (m, 4H), 1.31–1.22 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 167.2, 153.4, 129.7, 128.8, 51.9, 44.7, 34.1, 26.7, 26.1. This product is a known compound.

[0044] Example 2: Synthesis of Methyl 4-cyclopentylbenzoate (3b)

[0045]

[0046] Methyl 4-bromobenzoate (0.2 mmol), 9-fluorenone (0.03 mmol, 15 mmol%), nickel(II) chloride hexahydrate (0.02 mmol, 10 mmol%), and 2,2'-bipyridine (0.03 mmol, 15 mol%) were added to a quartz tube equipped with a magnetic stir bar. The quartz tube was then inserted into a photoreaction tube, and the photoreactor was connected and evacuated and filled with nitrogen three times to protect it with a nitrogen atmosphere. Then bromocyclopentane (0.4 mmol, 2.0 equiv.), triethylamine (0.6 mmol, 3.0 equiv.), N,N-dimethylacetamide (1 mL), and water (0.3 mmol, 1.5 equiv.) were added to the photoreaction tube. The reaction tube was inserted into a 10 W photoreactor, the rotation speed was set to 800 rpm, and the temperature was set to 35 °C. The reaction was stopped after 18 h of irradiation with light at a wavelength of 405 nm and cooled to room temperature. After the reaction, it was filtered through diatomaceous earth, dried by rotary evaporation using a vacuum pump, and then separated by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent. The yield of product 3b was 92%.

[0047] 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, 2H), 7.27 (d, J = 7.6 Hz, 2H), 3.90 (s, 3H), 2.58 - 2.53 (m, 1H), 1.87–1.75 (m, 4H), 1.48–1.22 (m, 4H). 13 C NMR (101 MHz, CDCl3) δ 167.2, 153.4, 129.7, 126.8, 51.9, 44.7, 34.1, 26.7, 26.1. This product is a known compound.

[0048] Example 3: Synthesis of 1-(4-hexyl-phenyl)-ethanone (3c)

[0049]

[0050] 4-Iodoacetophenone (0.2 mmol), 9-fluorenone (0.03 mmol, 15 mmol%), nickel(II) acetate tetrahydrate (0.02 mmol, 10 mmol%), 4,4'-di-tert-butyl-2,2'-bipyridine (0.03 mmol, 15 mol%) were added into a quartz tube equipped with a magnetic stir bar. Then the quartz tube was inserted into a photoreaction tube and connected to a photoreactor. The system was evacuated and filled with nitrogen three times to protect it with nitrogen atmosphere. Then 1-chlorohexane (0.2 mmol, 1.0 equiv.), diethanolmonoisopropanolamine (0.6 mmol, 3.0 equiv.), dimethyl sulfoxide (1 mL) and water (0.3 mmol, 1.5 equiv.) were added into the photoreaction tube. The reaction tube was inserted into a 10 W photoreactor, the rotation speed was set at 800 rpm, the temperature was set at 20 °C, and the reaction was stopped after 20 h of irradiation at 395 nm wavelength and cooled to room temperature. After the reaction, it was filtered through diatomaceous earth, dried by rotary evaporation under vacuum, and then separated by silica gel column using petroleum ether / ethyl acetate as the eluent. The yield of product 3c was 93%.

[0051] 1 H NMR(400MHz,CDCl3)δ7.92–7.85(m,2H),7.27(d,J=8.0Hz,2H),2.71–2.62(m,2H),2.58(s,3H),1.70–1.57(m,4H),1.40–1.25(m,4H),0.90(q,J=6.7,4.9Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ197.7,148.7,134.9,128.5(d,J=13.0Hz),36.0,31.7,31.1,28.9,26.5,22.6,14.1. This product is a known compound Example 4: Synthesis of 1-phenyl-1-cyclohexane (3d)

[0052]

[0053] Chlorobenzene (0.2 mmol), 9-FLN (0.03 mmol, 15 mmol%), nickel chloride (0.02 mmol, 10 mmol%), 1,10-phenanthroline (0.03 mmol, 15 mol%) were added into a quartz tube equipped with a magnetic stir bar. Then the quartz tube was inserted into a photoreaction tube, and the photoreactor was connected and evacuated and filled with nitrogen three times to protect it with nitrogen. Then iodocyclohexane (0.3 mmol, 1.5 equiv.), N,N,N',N'-tetramethylethylenediamine (0.6 mmol, 3.0 equiv.), acetone (1 mL) and water (0.3 mmol, 1.5 equiv.) were added into the photoreaction tube. The reaction tube was inserted into a 10 W photoreactor, the rotation speed was set at 800 rpm, the temperature was set at 50 °C, and the reaction was stopped after reacting for 24 h under irradiation with light of 410 nm wavelength and cooled to room temperature. After the reaction was completed, it was filtered through diatomaceous earth, dried by rotary evaporation with a vacuum pump, and then separated by silica gel column using petroleum ether / ethyl acetate as the eluent. The yield of product 3d was 91%.

[0054] 1 H NMR (400 MHz, CDCl3) δ 7.43–7.23 (m, 5H), 2.60 (tt, J = 11.4, 3.5 Hz, 1H), 2.06–1.81 (m, 5H), 1.61–1.29 (m, 5H). 13 C NMR (101 MHz, CDCl3) δ 148.2, 128.3, 126.9, 125.8, 44.7, 34.6, 27.0, 26.3. This product is a known compound

[0055] Example 5: Synthesis of 4-ethyl-benzoic acid methyl ester (3e)

[0056]

[0057] Methyl 4-iodobenzoate (0.2 mmol), 9-fluorenone (0.03 mmol, 15 mmol%), nickel(II) chloride dimethoxyethane (0.02 mmol, 10 mmol%), and bipyridine (0.03 mmol, 15 mol%) were added to a quartz tube equipped with a magnetic stir bar. The quartz tube was then inserted into a photoreaction tube and connected to a photoreactor. The system was evacuated and purged with nitrogen three times to create a nitrogen atmosphere. Then, iodoethane (0.3 mmol, 1.5 equiv.), N,N'-dimethylethylenediamine (0.6 mmol, 3.0 equiv.), diethyl ether (1 mL), and water (0.3 mmol, 1.5 equiv.) were added to the photoreaction tube. The reaction tube was inserted into a 10 W photoreactor, the rotation speed was set to 800 rpm, and the temperature was set to 45 °C. The reaction was carried out under irradiation with light at a wavelength of 400 nm for 16 h and then stopped. The reaction mixture was cooled to room temperature. After the reaction, it was filtered through diatomaceous earth, dried by rotary evaporation using a vacuum pump, and then separated by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent. The yield of product 3e was 89%.

[0058] 1 H NMR (400 MHz, CDCl3) δ 8.01–7.94 (m, 2H), 7.28 (d, J = 8.3 Hz, 2H), 3.92 (s, 3H), 2.72 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 167.2, 149.7, 129.7, 127.9, 127.7, 51.9, 28.9, 15.2. This product is a known compound

[0059] Example 6: Synthesis of methyl 4-(n-butyl)benzoate (3f)

[0060]

[0061] Methyl 4-iodobenzoate (0.2 mmol), 9-FLN (0.03 mmol, 15 mmol%), nickel(II) chloride bis(tricyclohexylphosphine) (0.02 mmol, 10 mmol%), and 2,2'-bipyridine (0.03 mmol, 15 mol%) were added to a quartz tube equipped with a magnetic stir bar. The quartz tube was then inserted into a photoreaction tube and connected to a photoreactor. The system was evacuated and purged with nitrogen three times to create a nitrogen atmosphere. Then, 1-iodobutane (0.3 mmol, 1.5 equiv.), N,N-dimethylaniline (0.6 mmol, 3.0 equiv.), N-methyl-2-pyrrolidone (1 mL), and water (0.3 mmol, 1.5 equiv.) were added to the photoreaction tube. The reaction tube was inserted into a 10 W photoreactor, the rotation speed was set to 800 rpm, and the temperature was set to 40 °C. The reaction was carried out under irradiation with light at a wavelength of 400 nm for 16 h and then stopped. The reaction mixture was cooled to room temperature. After the reaction was completed, it was filtered through diatomaceous earth, concentrated under reduced pressure using a vacuum pump, and then separated by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent. The yield of product 3f was 88%.

[0062] 1 H NMR (400 MHz, CDCl3) δ 8.01–7.93 (m, 2H), 7.26 (d, J = 8.1 Hz, 2H), 3.92 (s, 3H), 2.73–2.64 (m, 2H), 1.70–1.57 (m, 2H), 1.39 (hept, J = 7.2 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 167.2, 148.5, 129.6, 128.4, 127.6, 51.9, 35.7, 33.3, 22.3, 13.9. This product is a known compound.

Claims

1. A method for visible light-induced nickel-catalyzed C(sp 3 )-C(sp 2 ) cross-coupling reaction, characterized in that, Using haloalkanes and haloarenes as starting materials, adding a photocatalyst, a nickel catalyst, a ligand, a reducing agent, a solvent and an additive, and heating in the presence of light and in a nitrogen atmosphere to carry out a C(sp 3 )-C(sp 2 ) cross-coupling reaction to prepare a series of cross-coupled compounds. The synthetic route is as follows: Wherein: R is selected from a carbonyl group and H; Alkyl is selected from cyclohexyl, cyclopentyl, n-hexyl, ethyl, and n-butyl; X is selected from iodine, bromine, and chlorine; The photocatalyst is 9-fluorenone; The nickel catalyst is selected from nickel acetate (tetrahydrate), nickel chloride, nickel chloride (hexahydrate), nickel(II) bis(ethylene glycol dimethyl ether) chloride, bis(tricyclohexylphosphine) nickel chloride, and [1,1'-bis(diphenylphosphino)ferrocene] nickel(II) dichloride; The ligand is selected from 1,10-phenanthroline, 4,4'-di-tert-butyl-2,2'-bipyridine, and bipyridine; The reducing agent is N,N-diisopropylethylamine, triethylamine, diethanolmonoisopropanolamine, N,N,N',N'-tetramethylethylenediamine, N,N-dimethylaniline, and N,N'-dimethylethylenediamine; The solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetone, diethyl ether, and N-methyl-2-pyrrolidone; The additive is water.

2. The method for visible light-induced nickel-catalyzed C(sp 3 )-C(sp 2 ) cross-coupling reaction, characterized in that The wavelength range of the light irradiation is part or all of the bands in the range of 395 nm to 410 nm; The light irradiation reaction time range is 8 to 24 h; The heating temperature is 20 - 50 °C.

3. The method for visible light-induced nickel-catalyzed C(sp 3 )-C(sp 2 ) cross-coupling reaction according to claim 1, characterized in that The molar ratio of the haloarene to the haloalkane is 1:1 to 1:2; The molar ratio of the photocatalyst to the haloarene is 3:20; The molar ratio of the nickel catalyst to the haloarene is 1:10; The molar ratio of the ligand to the haloarene is 3:20; The molar ratio of the reducing agent to the haloarene is 3:1; The molar ratio of the additive to the haloarene is 1.5:1; The total concentration of the haloarene and the haloalkane in the reaction system is 0.4 to 0.6 mol / L.

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