Method for photochemical synthesis of alpha, beta-unsaturated ketone

Abstract

The invention discloses a method for photochemical synthesis of alpha, beta-unsaturated ketone. In an organic solvent, (formylmethylene) triphenylphosphine # imgabs0 # is used as an acyl radical precursor, transition metal nickel and a photosensitizer PC are combined for catalysis, the reaction with aryl halide Ar-X under the irradiation of blue light is carried out under the action of a ligand L and alkali, then the reaction with aldehyde or ketone # imgabs1 # is carried out through one-step Witting reaction, and the alpha, beta-unsaturated ketone compound is generated. The whole reaction is carried out in the atmosphere of inert gas N2. Under optimized reaction conditions, the yield of the separated target product can reach 92%, and the method is a universal, efficient, economical and environment-friendly method for synthesizing the alpha, beta-unsaturated ketone compound. The method is simple, feasible and safe, and the synthesis of the alpha, beta-unsaturated ketone can be realized by starting from commercially available raw materials through two steps. And a green and efficient new method is provided for synthesis and modification of complex compounds, drug molecules and bioactive molecules.

Description

Technical Field

[0001] The invention belongs to the field of catalytic synthesis technology and fine chemical synthesis, and relates to a method for photochemically synthesizing α,β-unsaturated ketone. Background Art

[0002] α,β-unsaturated ketone compounds can be used in pharmaceuticals, biological preparations, agricultural chemicals, materials, etc. At the same time, some α,β-unsaturated ketone compounds also show special medicinal properties, such as antioxidant, cholesterol-lowering activity or cholesterol-lowering activity, anti-cancer, anti-angiogenic drugs or angiogenesis inhibition, HIV-1 integrase inhibition, antimalarial drugs, etc.

[0003] At present, the development of α,β-unsaturated ketone compounds often requires high temperature, ultraviolet light excitation, toxic reagents or strong oxidants to form acyl radicals, and there are problems such as poor substrate compatibility, complex operation, and environmental pollution. At the same time, the directly generated α,β-unsaturated acyl radicals have difficult problems such as isomerization and self-coupling, making it difficult to construct α,β-unsaturated ketones from acyl radicals. Therefore, it is of great practical significance and research value to develop a strategy with extensive raw materials, environmental friendliness, and mild conditions to efficiently synthesize α,β-unsaturated ketones. Summary of the invention

[0004] In view of the problems existing in the prior art, the purpose of the present invention is to provide a method for photochemically synthesizing α,β-unsaturated ketones, which is a new method for synthesizing α,β-unsaturated ketone compounds with high yield, and has the advantages of cheap and easy purchase of raw materials, catalysts, and ligands; mild reaction conditions, non-toxic and harmless; high reaction selectivity, high yield; good compatibility of substrate functional groups and wide application range. This method can synthesize various complex α,β-unsaturated ketone compounds. It provides a simple, convenient, fast and efficient strategy for the synthesis of complex drug molecules and molecules with biological activity.

[0005] In order to solve the problems of the prior art, the present invention adopts the following technical solutions:

[0006] A method for photochemically synthesizing α,β-unsaturated ketones comprises the following steps: in an organic solvent, (formylmethylene) triphenylphosphine As an acyl radical precursor, it is combined with transition metal nickel and photosensitizer PC to react with aryl halide Ar-X under the action of ligand L and base under blue light irradiation, and then reacts with aldehyde or ketone. Through a one-step Witting reaction, α,β-unsaturated ketone compounds are generated. The entire reaction is carried out under the inert gas N 2 in an atmosphere of

[0007] wherein X is bromine or iodine, and Ar represents an unsubstituted or aryl group substituted at any position on the aromatic ring by a C1-C6 alkyl group, a C1-C6 halogen-substituted alkyl group, a C1-C6 alkylcarbonyl group, a nitro group, a hydroxyl group, a cyano group, a silicon group, an amino group, a thio group, a biphenyl group, a naphthyl group, an anthracenyl group, a C5-C13 ring heteroaryl group containing N, O, or S;

[0008] The R 1 and R 2 Each independently selected from hydrogen, C1-C20 alkyl, C1-C20 halogen-substituted alkyl, C1-C10 nitro-substituted alkyl, C1-C10 hydroxyl-substituted alkyl, C1-C10 amino-substituted alkyl, C1-C10 cyano-substituted alkyl, unsubstituted or aryl substituted at any position on the aromatic ring with C1-C6 alkyl, C1-C6 halogen-substituted alkyl, C1-C6 alkylcarbonyl, nitro, hydroxyl, cyano, silicon, amino, thio, biphenyl, naphthyl, anthracenyl, and a C5-C13 ring heteroaryl containing N, O, or S.

[0009] The general reaction formula is as follows:

[0010]

[0011] Among them, Ar-X represents aromatic halide, PC represents photosensitizer, Ligands represents ligand, Base represents base, and Bluelight represents blue light.

[0012] As an improvement, the transition metal is nickel chloride, anhydrous nickel bromide, hydrated nickel bromide, nickel iodide, nickel carbonate, bis-(1,5-cyclooctadiene) nickel, nickel chloride ethylene glycol dimethyl ether complex, nickel bromide ethylene glycol dimethyl ether complex, (2,2'-bipyridine) nickel dibromide, dibromo(1,10-phenanthroline) nickel, chlorobistrihexyl phosphate nickel salt, bis(triphenylphosphine) nickel chloride, 1,2-bis(diphenylphosphine) ethane nickel chloride, ( 1,1'-bis(diphenylphosphino)ferrocene) nickel dichloride, nickel bromide diethylene glycol dimethyl ether complex, nickel acetylacetonate, nickel trifluoromethanesulfonate, nickel bis(2,2,6,6,-tetramethyl-3,5-heptanedione), nickel bis(hexafluoroacetylacetonate), nickel perchlorate, nickel p-toluenesulfonate, 1,3-bis(diphenylphosphinopropane) nickel dichloride, nickel tetrafluoroborate hexahydrate, bis(triphenylphosphine) nickel dibromide or nickel dibromide bis(tributylphosphine);

[0013] The photosensitizer is bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium hexafluorophosphate, terpyridine ruthenium chloride hexahydrate, (2-2'-bi(4-tert-butylpyridine)bis[2-(4-tert-butylphenyl)pyridine]iridium(III) hexafluorophosphate, bis[2-(3-tert-butylphenyl)-4-tert-butylpyridine][2,2'-bi(4-tert-butylpyridine)]iridium(III) hexafluorophosphate, bis[ 2-(2,4-difluorophenyl)-5-trifluoromethylpyridine] [2-2'-bipyridine] iridium di(hexafluorophosphate), tri(2,2'-bipyridine) ruthenium di(hexafluorophosphate), 2,4,5,6-tetrakis(diphenylamino)-isophthalonitrile, tri(2-phenylpyridine) iridium, tetra-N-butylammonium decatungstate, 10-methyl-9-mesityl acridine perchlorate, rhodamine B, 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, tetra-N-butylammonium decatungstate;

[0014] The organic solvent is selected from any one of methanol, ethanol, ethylene glycol, n-propanol, isopropanol, 1,3-propylene glycol, glycerol, n-butanol, isobutanol, tert-butanol, trifluoroethanol, 2-methyl-2-butanol, 3-methoxybutanol, sec-butanol, tert-amyl alcohol, 4-methyl-2-pentanol, isopentanol, 2-pentanol, 3-pentanol, cyclopentanol, n-pentanol, acetonitrile, benzonitrile, toluene, acetone, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-diformamide, N,N-diacetamide, ethyl acetate, 1,4-dioxane or tetrahydrofuran.

[0015] As an improvement, the transition metal nickel is nickel chloride, anhydrous nickel bromide, hydrated nickel bromide, nickel chloride ethylene glycol dimethyl ether complex, or nickel bromide ethylene glycol dimethyl ether complex.

[0016] As an improvement, the photosensitizer is bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium hexafluorophosphate, 2,4,5,6-tetrakis(diphenylamino)-isophthalonitrile, or tris(2-phenylpyridine)iridium.

[0017] As an improvement, the organic solvent is selected from methanol, ethanol, N,N-diformamide, N,N-diethylamide, 1,4-dioxane or tetrahydrofuran.

[0018] As an improvement, the molar ratio of (formylmethylene)triphenylphosphine:aryl halide:nickel:photosensitizer:ligand:base:aldehyde or ketone is 1:(1-2):(0.1-0.2):(0.01-0.02):(0.1-0.2):(2-3):(1-2).

[0019] Further improved, the molar ratio of (formylmethylene) triphenylphosphine: aryl halide: nickel: photosensitizer: ligand: base: aldehyde or ketone is 1:1.5:0.1:0.02:0.1:3:2.

[0020] As an improvement, the temperature of the photochemical reaction is 20 - 40 °C and the reaction time is 8 - 24 hours; the temperature of the Witting reaction is 120 - 140 °C and the reaction time is 1 - 2 hours.

[0021] The application of the α,β-unsaturated ketone prepared by the above preparation method in the preparation of antioxidants, cholesterol-lowering activity or cholesterol-lowering activity, anti-cancer, anti-angiogenesis drugs or angiogenesis inhibitors, HIV-1 integrase inhibitors, anti-malarial drugs, biological agents, agrochemicals, and materials.

[0022] The present invention constructs a "masked" α,β-unsaturated acyl radical through the synergistic catalysis of metal nickel and a photosensitizer, solving the difficult problems such as isomerization and self-coupling of directly generated α,β-unsaturated acyl radicals. The selected photosensitizer and nickel catalyst are characterized by wide sources and low prices, with mild reaction conditions and no generation of polluting gases. The substrate has high adaptability, rich sources, and strong stability, providing an efficient, concise, and green new method for constructing complex α,β-unsaturated ketone compounds, and having very important scientific significance and application value in aspects such as natural products, drugs, and the later development and modification of drug molecules.

[0023] Beneficial effects:

[0024] Compared with the prior art, the present invention has the following advantages:

[0025] (1) The present invention is a method for synthesizing α,β-unsaturated ketones using a photo-nickel synergistic catalysis technology. The main features of this method are that the costs of the catalyst and ligand are relatively low and easy to obtain; during the reaction process, the required conditions are relatively mild, with good selectivity and high yield; in addition, this method has high adaptability to the substrate, rich sources, strong stability, and is convenient for operation and treatment; the compatibility of the substrate functional groups is excellent, and the applicable objects are diverse.

[0026] (2) The method of photo-nickel synergistic catalytic reductive coupling provided by the present invention is simple, feasible, and safe. Under the optimized reaction conditions, the yield of the target product after separation can be as high as 92%, which is a general, efficient, economical, and environmentally friendly coupling method.

[0027] (3) The present invention relates to a new strategy for transition metal-catalyzed acylation with α,β-unsaturated acyl radicals as key intermediates, providing a new method for constructing complex and diverse α,β-unsaturated ketone compounds. The constructed α,β-unsaturated ketones are important skeletons and intermediates for a variety of important drug molecules and bioactive molecules, and are widely used in the synthesis of pharmaceutical intermediates and high value-added fine chemicals. DETAILED DESCRIPTION

[0028] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0029] The experimental methods described in the examples are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.

[0030] The ligand is 4,4'-di-tert-butyl-2,2'-bipyridine, CAS No.: 72914-19-3; the base is cesium carbonate, CAS No.: 534-17-8; the structural formula of (formylmethylene)triphenylphosphine is:

[0031] Example 1 Compound 1 Synthesis

[0032] Under nitrogen, (formylmethylene)triphenylphosphine (0.3 mmol) and substrate 1a were added to a 25 mL reaction flask. (0.45mmol), photosensitizer 4CzIPN (0.006mmol), nickel (II) chloride ethylene glycol dimethyl ether complex (0.03mmol), ligand (0.03mmol), cesium carbonate (0.9mmol), 1,4-dioxane (12mL), reacted under blue light irradiation for 16h. After the reaction, no further purification was required. Water was added to the first step product as the reaction solvent, and then substrate 2a was added (0.6 mmol) was reacted at 120° C. for 1 hour. After the reaction, the product 1 was directly separated by chromatography (petroleum ether: ethyl acetate = 10:1) with a yield of 88% and an E / Z ratio of >20:1.

[0033] 1 HNMR (400MHz, Chloroform-d): δ8.08(s,4H),7.82(d,J=15.7Hz,1H),7.66(dd,J=6.5,3.0Hz,2H),7.51(d,J=15.7Hz,1H),7.46–7.41(m,3H),2.66(s,3H).

[0034] 13 C NMR (101 MHz, CDCl 3 ): δ197.64,190.18,146.01,141.74,139.95,134.63,131.04,129.17,128.79,128.72,128.65,122.06,26.61.

[0035] Example 2 Compound 2 Synthesis

[0036] Under nitrogen, (formylmethylene)triphenylphosphine (0.3 mmol), substrate 1b (0.45mmol), photosensitizer 4CzIPN (0.006mmol), nickel (II) chloride ethylene glycol dimethyl ether complex (0.03mmol), ligand (0.03mmol), cesium carbonate (0.9mmol), 1,4-dioxane (12mL), reacted under blue light irradiation for 16h. After the reaction, no further purification was required. Water was added to the first step product as the reaction solvent, and then substrate 2a was added (0.6 mmol) was reacted at 120° C. for 1 hour. After the reaction, the product 2 was directly separated by chromatography (petroleum ether: ethyl acetate = 50:1) with a yield of 78% and an E / Z ratio of >20:1.

[0037] 1 HNMR (400MHz, Chloroform-d): δ8.15–8.05(m,2H),7.85(d,J=15.7Hz,1H),7.72–7.64(m,2H),7.58–7.41(m,4H),7.36(d,J=8.3Hz,2H).

[0038] 13 C NMR (101 MHz, CDCl 3 ): δ189.08,152.53,145.66,136.57,134.76,130.94,130.60,129.16,128.66,121.74,121.58,120.61.

[0039] 19 F NMR (376 MHz, CDCl 3 ):δ-57.58.

[0040] Example 3 Compound 3 Synthesis

[0041] Under nitrogen, (formylmethylene)triphenylphosphine (0.3 mmol) and substrate 1c were added to a 25 mL reaction flask. (0.45mmol), photosensitizer 4CzIPN (0.006mmol), nickel (II) chloride ethylene glycol dimethyl ether complex (0.03mmol), ligand (0.03mmol), cesium carbonate (0.9mmol), 1,4-dioxane (12mL), reacted under blue light irradiation for 16h. After the reaction, no further purification was required. Water was added to the first step product as the reaction solvent, and then substrate 2a was added (0.6 mmol) was reacted at 120° C. for 1 hour. After the reaction, the product 3 was directly separated by chromatography (petroleum ether: ethyl acetate = 20:1) with a yield of 85% and an E / Z ratio of >20:1.

[0042] 1 HNMR (400MHz, Chloroform-d): δ8.01(d,J=8.5Hz,2H),7.84(d,J=15.7Hz,1H),7.71–7.63(m,2H),7.61–7.50(m,3H),7.47–7.35(m,3H),1.38(s,9H).

[0043] 13 C NMR (101 MHz, CDCl 3 ): δ190.07,156.62,144.43,135.63,135.05,130.49,129.00,128.57,128.48,125.65,122.19,35.18,31.19.

[0044] Example 4 Compound 4 Synthesis

[0045] Under nitrogen conditions, (formylmethylene)triphenylphosphine (0.3 mmol) was added to a 25 mL reaction bottle, and substrate 1d (0.45mmol), photosensitizer 4CzIPN (0.006mmol), nickel (II) chloride ethylene glycol dimethyl ether complex (0.03mmol), ligand (0.03mmol), cesium carbonate (0.9mmol), 1,4-dioxane (12mL), reacted under blue light irradiation for 16h. After the reaction, no further purification was required. Water was added to the first step product as the reaction solvent, and then substrate 2a was added (0.6 mmol) was reacted at 120° C. for 1 hour. After the reaction, the product 4 was directly separated by chromatography (petroleum ether: ethyl acetate = 50:1) with a yield of 77% and an E / Z ratio of >20:1.

[0046] 1 HNMR (400MHz, Chloroform-d): δ7.97(d,J=8.5Hz,2H),7.82(d,J=15.7Hz,1H),7.68–7.60(m,2H),7.54–7.45(m,3H),7.45–7.39(m,3H).

[0047] 13 C NMR (101 MHz, CDCl 3 ): δ189.30,145.48,139.34,137.11,134.80,130.88,130.04,129.13,129.07,128.64,121.59.

[0048] Example 5 Compound 5 Synthesis

[0049] Under nitrogen, (formylmethylene)triphenylphosphine (0.3 mmol) and substrate 1e were added to a 25 mL reaction flask. (0.45mmol), photosensitizer 4CzIPN (0.006mmol), nickel (II) chloride ethylene glycol dimethyl ether complex (0.03mmol), ligand (0.03mmol), cesium carbonate (0.9mmol), 1,4-dioxane (12mL), reacted under blue light irradiation for 16h. After the reaction, no further purification was required. Water was added to the first step product as the reaction solvent, and then substrate 2a was added (0.6 mmol) was reacted at 120° C. for 1 hour. After the reaction, the product 5 was directly separated by chromatography (petroleum ether: ethyl acetate = 10:1) with a yield of 83% and an E / Z ratio of >20:1.

[0050] 1 HNMR (400MHz, Chloroform-d): δ7.89(d,J=7.8Hz,1H),7.82(d,J=7.6Hz,1H),7.79–7.69(m,2H),7.68–7.59(m,3H),7.48–7.31(m,4H).

[0051] 13 C NMR (101 MHz, CDCl 3 ): δ189.78,147.39,141.80,134.78,134.31,132.63,131.85,131.31,129.32,129.16,128.86,122.95,117.81,111.46.

[0052] Example 6 Compound 6 Synthesis

[0053] Under nitrogen, (formylmethylene)triphenylphosphine (0.3 mmol) and substrate 1f were added to a 25 mL reaction flask. (0.45mmol), photosensitizer 4CzIPN (0.006mmol), nickel (II) chloride ethylene glycol dimethyl ether complex (0.03mmol), ligand (0.03mmol), cesium carbonate (0.9mmol), 1,4-dioxane (12mL), reacted under blue light irradiation for 16h. After the reaction, no further purification was required. Water was added to the first step product as the reaction solvent, and then substrate 2a was added (0.6 mmol) was reacted at 120° C. for 1 hour. After the reaction, the product 6 was directly separated by chromatography (petroleum ether: ethyl acetate = 10:1) with a yield of 88% and an E / Z ratio of >20:1.

[0054] 1 HNMR (400MHz, Chloroform-d): δ7.85–7.75(m,3H),7.68–7.62(m,2H),7.55(d, J=15.7Hz,1H),7.47–7.38(m,3H),7.26(d,J=7.8Hz,1H),2.35(d,J=3.7Hz,6H).

[0055] 13 C NMR (101 MHz, CDCl 3 ): δ190.28,144.30,142.50,137.14,136.13,135.15,130.47,129.93,129.77,129.02,128.50,126.35,122.30,20.16,19.93.

[0056] Example 7 Compound 7 Synthesis

[0057] Under nitrogen conditions, (formylmethylene)triphenylphosphine (0.3 mmol), substrate 1 g (0.45mmol), photosensitizer 4CzIPN (0.006mmol), nickel (II) chloride ethylene glycol dimethyl ether complex (0.03mmol), ligand (0.03mmol), cesium carbonate (0.9mmol), 1,4-dioxane (12mL), reacted under blue light irradiation for 16h. After the reaction, no further purification was required. Water was added to the first step product as the reaction solvent, and then substrate 2a was added (0.6 mmol) was reacted at 120° C. for 1 hour. After the reaction, the product 7 was directly separated by chromatography (petroleum ether: ethyl acetate = 10:1) with a yield of 64% and an E / Z ratio of >20:1.

[0058] 1 HNMR (400MHz, Chloroform-d): δ8.89(d,J=2.5Hz,1H),8.24(dd,J=8.7,2.5Hz,1H),7.83(d ,J=15.6Hz,1H),7.74–7.61(m,2H),7.55–7.39(m,4H),6.85(d,J=8.7Hz,1H),4.03(s,3H).

[0059] 13 C NMR (101 MHz, CDCl 3 ): δ187.93,166.81,149.26,144.93,138.88,134.87,130.79,129.14,128.60,127.87,121.46,111.46,54.23.

[0060] Example 8 Compound 8 Synthesis

[0061] Under nitrogen, (formylmethylene)triphenylphosphine (0.3 mmol) was added to a 25 mL reaction bottle, and the substrate was allowed to react for 1 h. (0.45mmol), photosensitizer 4CzIPN (0.006mmol), nickel (II) chloride ethylene glycol dimethyl ether complex (0.03mmol), ligand (0.03mmol), cesium carbonate (0.9mmol), 1,4-dioxane (12mL), reacted under blue light irradiation for 16h. After the reaction, no further purification was required. Water was added to the first step product as the reaction solvent, and then substrate 2a was added (0.6 mmol) was reacted at 120° C. for 1 hour. After the reaction, the product 8 was directly separated by chromatography (petroleum ether: ethyl acetate = 20:1) with a yield of 72% and an E / Z ratio of >20:1.

[0062] 1 HNMR (400MHz, Chloroform-d): δ8.14(d,J=8.3Hz,2H),7.89(d,J=15.7Hz,1H) ,7.81–7.74(m,1H),7.73–7.66(m,2H),7.66–7.59(m,4H),7.56–7.37(m,6H).

[0063] 13C NMR (101 MHz, CDCl 3 ): δ190.00,145.62,144.84,140.02,136.99,135.03,130.65,129.71,129.54,129.23,129.08,128.58,128.32,127.39,122.10.

[0064] Example 9 Compound 9 Synthesis

[0065] Under nitrogen, (formylmethylene)triphenylphosphine (0.3 mmol) and substrate 1i were added to a 25 mL reaction bottle. (0.45mmol), photosensitizer 4CzIPN (0.006mmol), nickel (II) chloride ethylene glycol dimethyl ether complex (0.03mmol), ligand (0.03mmol), cesium carbonate (0.9mmol), 1,4-dioxane (12mL), reacted under blue light irradiation for 16h. After the reaction, no further purification was required. Water was added to the first step product as the reaction solvent, and then substrate 2a was added (0.6 mmol) was reacted at 120° C. for 1 hour. After the reaction, the product 9 was directly separated by chromatography (petroleum ether: ethyl acetate = 10:1) with a yield of 73% and an E / Z ratio of >20:1.

[0066] 1 HNMR (400MHz, Chloroform-d): δ8.49 (d, J=45.4Hz, 2H), 7.98 (dd, J=8.6, 1.7Hz, 1H), 7.85 (d ,J=15.7Hz,1H),7.78–7.63(m,3H),7.54–7.37(m,4H),7.34–7.29(m,1H),6.89–6.21(m,1H).

[0067] 13 C NMR (101 MHz, CDCl 3 ): δ190.56,143.69,138.58,135.43,130.95,130.31,129.61,128.48,127.65,125.87,123.21,122.95,121.78,111.40,104.51.

[0068] Example 10 Compound 10 Synthesis

[0069] Under nitrogen, (formylmethylene)triphenylphosphine (0.3 mmol) and substrate 1j were added into a 25 mL reaction bottle. (0.45mmol), photosensitizer 4CzIPN (0.006mmol), nickel (II) chloride ethylene glycol dimethyl ether complex (0.03mmol), ligand (0.03mmol), cesium carbonate (0.9mmol), 1,4-dioxane (12mL), reacted under blue light irradiation for 16h. After the reaction, no further purification was required. Water was added to the first step product as the reaction solvent, and then substrate 2a was added (0.6 mmol) was reacted at 120° C. for 1 hour. After the reaction, the product 10 was directly separated by chromatography (petroleum ether: ethyl acetate = 10:1) with a yield of 62% and an E / Z ratio of >20:1.

[0070] 1 HNMR (400MHz, Chloroform-d): δ8.84(d,J=1.7Hz,1H),8.30–8.15(m,2H),7.89(d,J=15.6Hz, 1H),7.82–7.67(m,3H),7.60–7.50(m,1H),7.50–7.40(m,5H),7.38–7.29(m,1H),3.89(s,3H).

[0071] 13 C NMR (101 MHz, CDCl 3 ): δ189.64,143.81,143.73,141.82,135.45,130.34,129.70,129.06,128.52,126.9 5,126.65,123.23,122.83,122.58,122.11,120.78,120.22,109.14,108.43,30.15.

[0072] Example 11 Compound 11 Synthesis

[0073] Under nitrogen, (formylmethylene)triphenylphosphine (0.3 mmol), substrate 1k (0.45 mmol), photosensitizer 4CzIPN (0.006 mmol), nickel (II) chloride ethylene glycol dimethyl ether complex (0.03 mmol), ligand (0.03 mmol), cesium carbonate (0.9 mmol), 1,4-dioxane (12 mL), reacted under blue light irradiation for 16 h. After the reaction was completed, no further purification was required. Water was added to the first step product as the reaction solvent, and then substrate 2b was added (0.6 mmol) was reacted at 120°C for 1 hour. After the reaction, the product 11 was directly separated by chromatography (petroleum ether: ethyl acetate = 10:1) with a yield of 90% and an E / Z ratio of >20:1.

[0074] 1 HNMR (400 MHz, Chloroform-d): δ8.08(d,2H),7.78(d,J=7.9 Hz,2H),7.55(d,J=15.1 Hz,1H),7.29(d,J=15.0 Hz,1H),6.69(s,1H),6.17(s,1H),2.40(s,3H).

[0075] 13 C NMR (101 MHz, CDCl 3 ): δ188.36,156.84,150.08,141.73,132.48,132.13,128.78,119.77,118.22,116.44,115.70,109.87,14.88.

[0076] Example 12 Compound 12 Synthesis

[0077] Under nitrogen, (formylmethylene)triphenylphosphine (0.3 mmol), substrate 1k (0.45 mmol), photosensitizer 4CzIPN (0.006 mmol), nickel (II) chloride ethylene glycol dimethyl ether complex (0.03 mmol), ligand (0.03 mmol), cesium carbonate (0.9 mmol), 1,4-dioxane (12 mL), reacted under blue light irradiation for 16 h. After the reaction was completed, no further purification was required. Water was added to the first step product as the reaction solvent, and then substrate 2c was added (0.6 mmol) was reacted at 120°C for 1 hour. After the reaction, the product 12 was directly separated by chromatography (petroleum ether: ethyl acetate = 10:1) with a yield of 92% and an E / Z ratio of >20:1.

[0078] 1HNMR (400 MHz, Chloroform-d): δ8.06 (d, J=8.1 Hz,2H),7.85–7.71(m,3H),7.53(s,1H),7.43(d,J=8.3Hz,1H),7.31(d,J=15. 6Hz, 1H), 6.82 (d, J = 8.3Hz, 1H), 4.65 (t, J = 8.7Hz, 2H), 3.26 (t, J = 8.7Hz, 2H).

[0079] 13 C NMR (101 MHz, CDCl 3 ): δ189.21,163.33,147.09,142.09,132.54,130.74,129.44,128.55,127.37,124.76,118.21,115.74,110.11,72.18,29.28.

[0080] Example 13 Compound 13 Synthesis

[0081] Under nitrogen conditions, (formylmethylene)triphenylphosphine (0.3 mmol), substrate 1k (0.45mmol), photosensitizer 4CzIPN (0.006mmol), nickel (II) chloride ethylene glycol dimethyl ether complex (0.03mmol), ligand (0.03mmol), cesium carbonate (0.9mmol), 1,4-dioxane (12mL), reacted under blue light irradiation for 16h. After the reaction, no further purification was required. Water was added to the first step product as the reaction solvent, and then the substrate 2d was added (0.6 mmol) was reacted at 120° C. for 1 hour. After the reaction, the product 13 was directly separated by chromatography (petroleum ether: ethyl acetate = 10:1) with a yield of 82% and an E / Z ratio of >20:1.

[0082] 1 HNMR (400MHz, Chloroform-d): δ8.06(d,J=8.3Hz,2H),7.88–7.74(m,3H),7.60(d,J=8.4Hz,2H),7.51–7.29(m,6H),7.02(d,J=8.6Hz,2H),5.12(s,2H).

[0083] 13 C NMR (101 MHz, CDCl 3): δ189.15,161.40,146.45,141.87,136.30,132.52,130.68,128.86,1 28.79,128.34,127.57,127.37,118.95,118.22,116.15,115.50,70.22.

[0084] Example 14 Compound 14 Synthesis

[0085] Under nitrogen conditions, (formylmethylene)triphenylphosphine (0.3 mmol), substrate 1k (0.45mmol), photosensitizer 4CzIPN (0.006mmol), nickel (II) chloride ethylene glycol dimethyl ether complex (0.03mmol), ligand (0.03mmol), cesium carbonate (0.9mmol), 1,4-dioxane (12 mL), reacted under blue light irradiation for 16 h. After the reaction was completed, no further purification was required. Water was added to the first step product as the reaction solvent, and then the substrate 2e was added (0.6 mmol) was reacted at 120°C for 1 hour. After the reaction, the product 14 was directly separated by chromatography (petroleum ether: ethyl acetate = 50:1) with a yield of 76% and an E / Z ratio of >20:1.

[0086] 1 HNMR (400 MHz, Chloroform-d): δ7.84 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.31–7.18 (m, 6H).

[0087] 19 F NMR (376 MHz, CDCl 3 ):δ-66.28.

[0088] 13 C NMR (101 MHz, CDCl 3 ): δ191.20,140.55(q,J=31.1 Hz),138.99,132.51,130.47,130.00,129.70(q,J=5.1 Hz),129.16(d,J=15.4 Hz),128.66,124.07,121.33,117.77,116.90.

[0089] Example 15 Compound 15 Synthesis

[0090] Under nitrogen atmosphere, (formylmethylene)triphenylphosphine (0.3 mmol), substrate 1k were successively added into a 25 mL reaction flask. (0.45 mmol), photosensitizer 4CzIPN (0.006 mmol), nickel(II) bis(ethylene glycol dimethyl ether) complex (0.03 mmol), ligand (0.03 mmol), cesium carbonate (0.9 mmol), 1,4-dioxane (12 mL), and the reaction was carried out under blue light irradiation for 16 h. After the reaction was completed, no further purification was required. Water was added as the reaction solvent to the first-step product, and then substrate 2f (0.6 mmol) was added and the reaction was carried out at 120 °C for 1 h. After the reaction was completed, chromatography separation (petroleum ether:ethyl acetate = 20:1) was directly carried out to obtain product 15 with a yield of 58% and an E / Z ratio > 20:1.

[0091] 1 HNMR (400 MHz, Chloroform-d): δ 7.91 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 7.22 (dd, J = 13.0, 7.7 Hz, 3H), 7.15–7.03 (m, 1H), 6.79 (d, J = 15.6 Hz, 1H), 2.86 (t, J = 7.6 Hz, 2H), 2.67 (q, J = 7.4 Hz, 2H).

[0092] 13 C NMR (101 MHz, CDCl 3 ): δ 189.62, 150.61, 141.26, 140.59, 132.50, 129.03, 128.70, 128.52, 126.45, 126.22, 118.16, 115.98, 34.65, 34.45.

[0093] Example 16 Compound 16 Synthesis

[0094] Under nitrogen atmosphere, (formylmethylene)triphenylphosphine (0.3 mmol), substrate 1k were successively added into a 25 mL reaction flask. (0.45 mmol), photosensitizer 4CzIPN (0.006 mmol), nickel(II) bis(ethylene glycol dimethyl ether) complex (0.03 mmol), ligand (0.03 mmol), cesium carbonate (0.9 mmol), 1,4-dioxane (12 mL), and the reaction was carried out under blue light irradiation for 16 h. After the reaction was completed, no further purification was required. Water was added as the reaction solvent to the first-step product, and then substrate 2g (0.6 mmol) was reacted at 120° C. for 1 hour. After the reaction, the product 16 was directly separated by chromatography (petroleum ether: ethyl acetate = 20:1) with a yield of 84% and an E / Z ratio of >20:1.

[0095] 1 HNMR (400MHz, Chloroform-d): δ7.98 (d, J = 8.3Hz, 2H), 7.81 (d, J = 8.3Hz, 2H), 7.40 (s, 1H), 4.14 (q, J = 7.1Hz, 2H), 1.11 (t, J = 7.2Hz, 3H).

[0096] 19 F NMR (376 MHz, CDCl 3 ):δ-65.12.

[0097] 13 C NMR (101 MHz, CDCl 3 ): δ189.79, 160.41, 140.83 (d, J = 5.0Hz), 137.94, 132.92, 129.86 (d, J = 32.8Hz), 129.02, 120.84 (d, J = 274.0Hz), 117.69, 117.54, 62.92, 13.56.

[0098] Example 17 Compound 17 Synthesis

[0099] Under nitrogen conditions, (formylmethylene)triphenylphosphine (0.3 mmol), substrate 1k (0.45mmol), photosensitizer 4CzIPN (0.006mmol), nickel (II) chloride ethylene glycol dimethyl ether complex (0.03mmol), ligand (0.03mmol), cesium carbonate (0.9mmol), 1,4-dioxane (12mL), react under blue light irradiation for 16h. After the reaction is completed, no further purification is required. Water is added to the first step product as the reaction solvent, and then the substrate is added for 2h (0.6 mmol) was reacted at 120° C. for 1 hour. After the reaction, the product 17 was directly separated by chromatography (petroleum ether: ethyl acetate = 20:1) with a yield of 90% and an E / Z ratio of >20:1.

[0100] 1HNMR (400MHz, Chloroform-d): δ8.07(d,J=8.0Hz,2H),7.84–7.74(m,3H),7.55(d,J=8.2Hz,2H),7.42(d,J=15.6Hz,1H),7.26(d,J=8.3Hz,2H),2.52(s,3H).

[0101] 13 C NMR (101 MHz, CDCl 3 ): δ189.72,146.16,143.55,141.27,132.58,130.80,129.14,128.91,125.94,120.02,118.18,115.92,15.08.

[0102] Example 18 Compound 18 Synthesis

[0103] Under nitrogen, (formylmethylene)triphenylphosphine (0.3 mmol), substrate 1 l (0.45mmol), photosensitizer 4CzIPN (0.006mmol), nickel (II) chloride ethylene glycol dimethyl ether complex (0.03mmol), ligand (0.03mmol), cesium carbonate (0.9mmol), 1,4-dioxane (12mL), reacted under blue light irradiation for 16h. After the reaction, no further purification was required. Water was added to the first step product as the reaction solvent, and then substrate 2i was added (0.6 mmol) was reacted at 120° C. for 1 hour. After the reaction, the product 18 was directly separated by chromatography (petroleum ether: ethyl acetate = 10:1) with a yield of 85% and an E / Z ratio of >20:1.

[0104] 1 HNMR (400MHz, Chloroform-d): δ8.27(d,J=9.0Hz,2H),8.03(d,J=8.2Hz,2H),7.84–7.76(m,3H),7.72–7.58(m,2H),7.53(t,J=7.7Hz,2H).

[0105] 13 C NMR (101 MHz, CDCl 3 ): δ189.78,148.68,141.64,140.64,137.66,133.50,129.67,128.95,128.72,125.84,124.35.

[0106] Example 19 Compound 19 Synthesis

[0107] Under nitrogen, (formylmethylene)triphenylphosphine (0.3 mmol), substrate 1 l (0.45mmol), photosensitizer 4CzIPN (0.006mmol), nickel (II) chloride ethylene glycol dimethyl ether complex (0.03mmol), ligand (0.03mmol), cesium carbonate (0.9mmol), 1,4-dioxane (12mL), reacted under blue light irradiation for 16h. After the reaction, no further purification was required. Water was added to the first step product as the reaction solvent, and then substrate 2j was added (0.6 mmol) was reacted at 120° C. for 1 hour. After the reaction, the product 19 was directly separated by chromatography (petroleum ether: ethyl acetate = 50:1) with a yield of 76% and an E / Z ratio of >20:1.

[0108] 1 HNMR (400MHz, Chloroform-d): δ8.02(d,J=7.5Hz,2H),7.69(d,J=15.6Hz,1H),7.61( t,J=7.4Hz,1H),7.52(t,J=9.0Hz,3H),7.15(d,J=6.2Hz,2H),6.86(t,J=9.8Hz,1H).

[0109] 19 F NMR (376 MHz, CDCl 3 ): δ-108.97.

[0110] 13 C NMR (101 MHz, CDCl 3 ): δ189.91,163.38(dd,J=249.4,12.7Hz),142.08(t,J=3.0Hz),138.30(t,J=9.4Hz),137.80,133.34,129.34,128.68,124.40,112.38–

[0111] 110.12(m),105.69(t,J=25.5Hz).

[0112] Example 20 Compound 20 Synthesis

[0113] Under nitrogen conditions, (formylmethylene)triphenylphosphine (0.3 mmol) was added to a 25 mL reaction bottle, and substrate 1d (0.45mmol), photosensitizer 4CzIPN (0.006mmol), nickel (II) chloride ethylene glycol dimethyl ether complex (0.03mmol), ligand (0.03mmol), cesium carbonate (0.9mmol), 1,4-dioxane (12mL), reacted under blue light irradiation for 16h. After the reaction, no further purification was required. Water was added to the first step product as the reaction solvent, and then the substrate 2k (0.6 mmol) and reacted at 120° C. for 1 hour. After the reaction, the product 20 was directly separated by chromatography (petroleum ether: ethyl acetate = 10:1) with a yield of 88% and an E / Z ratio of >20:1.

[0114] 1 HNMR (400MHz, Chloroform-d): δ7.95(d,J=8.5Hz,2H),7.71(d,J=15.6Hz,1H),7 .47(d,J=8.3Hz,2H),7.34(d,J=15.6Hz,1H),6.85(s,2H),3.91(d,J=6.5Hz,9H).

[0115] 13 C NMR (101 MHz, CDCl 3 ): δ189.31,153.62,145.65,140.75,139.25,136.68,130.26,130.02,129.04,120.96,105.87,61.13,56.36.

[0116] Embodiment 21

[0117] Example 21 is the same as Example 4, except that nickel is nickel chloride, the organic solvent is dichloromethane, the reaction time is 8 hours, and the product is

[0118] Embodiment 22

[0119] Example 22 is the same as Example 4, except that the nickel is bis(triphenylphosphine)nickel chloride, the organic solvent is dimethyl sulfoxide, the reaction time is 12 h, and the product is

[0120] Embodiment 23

[0121] Example 23 is the same as Example 4, except that nickel is nickel bromide diethylene glycol dimethyl ether complex, the organic solvent is toluene, the reaction time is 24h, and the product is

[0122] Embodiment 24

[0123] Example 24 was the same as Example 4, except that: nickel was nickel chloride ethylene glycol dimethyl ether complex, the organic solvent was tetrahydrofuran, the reaction temperature was 20 °C, and the product was

[0125] Comparative Example 1

[0126] Comparative Example 1 was the same as the method of Example 15, except that: no nickel catalyst was added, and the yield of the target product was 0.

[0127] Comparative Example 2

[0128] Comparative Example 2 was the same as the method of Example 15, except that: no photosensitizer 4CzIPN was added, and the yield of the target product was 0.

[0129] Comparative Example 3

[0130] Comparative Example 3 was the same as the method of Example 15, except that: no ligand dtbbpy was added, and the yield of the target product was 0.

[0131] Comparative Example 4

[0132] Comparative Example 4 was the same as the method of Example 15, except that: no base cesium carbonate was added, and the yield of the target product was 0.

[0133] Comparative Example 5

[0134] Comparative Example 5 was the same as the method of Example 15, except that: there was no blue light irradiation, and the yield of the target product was 0.

[0135] In summary, the present invention is a method for synthesizing α,β-unsaturated ketones by using a photo-nickel synergistic catalysis technology. The main features of this method are that the costs of the catalyst and the ligand are relatively low and they are easily accessible; during the reaction process, the required conditions are relatively mild, and it has good selectivity and high yield; in addition, this method has high adaptability to substrates, rich sources, strong stability, and is convenient for operation and treatment; the compatibility of substrate functional groups is excellent, and the applicable objects are diverse.

[0136] The above is only a preferred embodiment of the present invention, and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment, it is not used to limit the present invention. The various nickel catalysts in the present invention can theoretically coordinate with the aryl halide to form an active nickel catalyst species, which is conducive to the smooth progress of the reaction; the modification of the substituent only affects the reaction to a certain extent, and does not play a decisive role in the occurrence of the reaction. It is not difficult for any technician familiar with this profession to understand that without departing from the scope of the technical solution of the present invention, the corresponding embodiments can be obtained by changing or modifying. For example, the substituents can be replaced, changed or modified within the scope of the present invention, and the method of the present invention can be realized. However, any modification, modification or equivalent and equivalent changes made to the above embodiments according to the present invention without departing from the purpose of the technical solution of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A method for photochemically synthesizing α,β-unsaturated ketones, characterized in that: In an organic solvent, (formylmethylene) triphenylphosphine As an acyl radical precursor, it is combined with transition metal nickel and photosensitizer PC to react with aryl halide Ar-X under the action of ligand L and base under blue light irradiation, and then reacts with aldehyde or ketone. Through a one-step Witting reaction, α,β-unsaturated ketone compounds are generated, and the entire reaction is carried out in an atmosphere of inert gas N2; Wherein, X is bromine or iodine, Ar represents an unsubstituted or aryl group substituted at any position on the aromatic ring by a C1-C6 alkyl group, a C1-C6 halogen-substituted alkyl group, a C1-C6 alkylcarbonyl group, a nitro group, a hydroxyl group, a cyano group, a silicon group, an amino group, a thio group, a biphenyl group, a naphthyl group, an anthracene group, a C5-C13 ring heteroaryl group containing N, O, or S; The R1 and R2 are independently selected from hydrogen, C1-C20 alkyl, C1-C20 halogen-substituted alkyl, C1-C10 nitro-substituted alkyl, C1-C10 hydroxyl-substituted alkyl, C1-C10 amino-substituted alkyl, C1-C10 cyano-substituted alkyl, non-substituted or aryl substituted at any position on the aromatic ring with C1-C6 alkyl, C1-C6 halogen-substituted alkyl, C1-C6 alkylcarbonyl, nitro, hydroxyl, cyano, silicon, amino, thio, biphenyl, naphthyl, anthracenyl, and a C5-C13 ring heteroaryl containing N, O, or S.

2. The method for photochemically synthesizing α,β-unsaturated ketone according to claim 1, characterized in that: The transition metal is nickel chloride, anhydrous nickel bromide, hydrated nickel bromide, nickel iodide, nickel carbonate, bis-(1,5-cyclooctadiene) nickel, nickel chloride ethylene glycol dimethyl ether complex, nickel bromide ethylene glycol dimethyl ether complex, (2,2'-bipyridine) nickel dibromide, dibromo(1,10-phenanthroline) nickel, chlorobistrihexyl phosphate nickel salt, bis(triphenylphosphine) nickel chloride, 1,2-bis(diphenylphosphine)ethane nickel chloride, (1,1' -bis(diphenylphosphino)ferrocene) nickel dichloride, nickel bromide diethylene glycol dimethyl ether complex, nickel acetylacetonate, nickel trifluoromethanesulfonate, nickel bis(2,2,6,6,-tetramethyl-3,5-heptanedione), nickel bis(hexafluoroacetylacetonate), nickel perchlorate, nickel p-toluenesulfonate, 1,3-bis(diphenylphosphinopropane) nickel dichloride, nickel tetrafluoroborate hexahydrate, bis(triphenylphosphine) nickel dibromide or dibromobis(tributylphosphine) nickel; The photosensitizer is bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium hexafluorophosphate, terpyridine ruthenium chloride hexahydrate, (2-2'-bi(4-tert-butylpyridine)bis[2-(4-tert-butylphenyl)pyridine]iridium(III) hexafluorophosphate, bis[2-(3-tert-butylphenyl)-4-tert-butylpyridine][2,2'-bi(4-tert-butylpyridine)]iridium(III) hexafluorophosphate, bis[ 2-(2,4-difluorophenyl)-5-trifluoromethylpyridine] [2-2'-bipyridine] iridium di(hexafluorophosphate), tri(2,2'-bipyridine) ruthenium di(hexafluorophosphate), 2,4,5,6-tetrakis(diphenylamino)-isophthalonitrile, tri(2-phenylpyridine) iridium, tetra-N-butylammonium decatungstate, 10-methyl-9-mesityl acridine perchlorate, rhodamine B, 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, tetra-N-butylammonium decatungstate; The organic solvent is selected from any one of methanol, ethanol, ethylene glycol, n-propanol, isopropanol, 1,3-propylene glycol, glycerol, n-butanol, isobutanol, tert-butanol, trifluoroethanol, 2-methyl-2-butanol, 3-methoxybutanol, sec-butanol, tert-amyl alcohol, 4-methyl-2-pentanol, isopentanol, 2-pentanol, 3-pentanol, cyclopentanol, n-pentanol, acetonitrile, benzonitrile, toluene, acetone, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-diformamide, N,N-diacetamide, ethyl acetate, 1,4-dioxane or tetrahydrofuran.

3. The method for photochemically synthesizing α,β-unsaturated ketone according to claim 2, characterized in that: The transition metal nickel is nickel chloride, anhydrous nickel bromide, hydrated nickel bromide, nickel chloride ethylene glycol dimethyl ether complex, or nickel bromide ethylene glycol dimethyl ether complex.

4. The method for photochemically synthesizing α,β-unsaturated ketone according to claim 2, characterized in that: The photosensitizer is bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium hexafluorophosphate, 2,4,5,6-tetrakis(diphenylamino)-isophthalonitrile, and tris(2-phenylpyridine)iridium.

5. The method for photochemically synthesizing α,β-unsaturated ketone according to claim 2, characterized in that: The organic solvent is selected from methanol, ethanol, N,N-diformamide, N,N-diacetamide, 1,4-dioxane or tetrahydrofuran.

6. The method for photochemically synthesizing α,β-unsaturated ketone according to claim 1, characterized in that: The molar ratio of (formylmethylene)triphenylphosphine:aryl halide:nickel:photosensitizer:ligand:base:aldehyde or ketone is 1:(1-2):(0.1-0.2):(0.01-0.02):(0.1-0.2):(2-3):(1-2).

7. The method for photochemically synthesizing α,β-unsaturated ketone according to claim 6, characterized in that: The molar ratio of (formylmethylene)triphenylphosphine:aryl halide:nickel:photosensitizer:ligand:base:aldehyde or ketone is 1:1.5:0.1:0.02:0.1:3:

2.

8. The method for photochemically synthesizing α,β-unsaturated ketone according to claim 1, characterized in that: The temperature of the photochemical reaction is 20-40° C., and the reaction time is 8-24 hours; the temperature of the Witting reaction is 120-140° C., and the reaction time is 1-2 hours.

9. Use of the α,β-unsaturated ketone prepared by the method of claims 1-8 in the preparation of antioxidant, cholesterol-lowering activity or cholesterol-lowering activity, anti-cancer, anti-angiogenic or angiogenesis-inhibiting drugs, HIV-1 integrase inhibition, antimalarial drugs, biological preparations, agricultural chemicals, and materials.

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