A method for migrating C(sp²)-H / C(sp³)-H cross-coupling catalyzed by metal / photoredox catalysis

Abstract

This invention discloses a migration C(sp²)-H / C(sp³)-H cross-coupling reaction achieved using metal / photoredox catalysis, belonging to the fields of organic chemistry and medicinal chemistry. Under the action of a nickel source, photocatalyst, ligands, base, and additives, this invention enables the reaction of alkanes with ortho-alkenyl-substituted aryl halides or ortho-pyridine-substituted aryl halides in an organic solvent under light irradiation, yielding a series of polysubstituted olefins or polysubstituted aromatic compounds with excellent regioselectivity, stereoselectivity, and good yields, which can serve as active pharmaceutical molecules. This invention uses inexpensive transition metal nickel as a catalyst, readily available alkanes and haloaromatics as raw materials, and features mild and simple conditions, good functional group compatibility, and easy operation.

Description

TECHNICAL FIELD

[0001] The method of the present application belongs to the field of organic chemistry and medicinal chemistry, and uses nickel and photocatalysis to achieve migratory C(sp2)-H / C(sp3)-H cross-coupling to obtain important polysubstituted olefin or aromatic compounds, which have very wide application. BACKGROUND

[0002] Direct functionalization of C-H bonds is an important reaction in the field of synthetic chemistry, which can realize efficient synthesis of complex molecules without relying on traditional functional group interconversion. Transition metal-catalyzed migratory cross-coupling has become a common strategy for C-H activation, which selectively activates remote and inert C-H bonds through controllable 1,n-metal / hydrogen migration, and then couples with various coupling reagents. At present, various migration modes have been explored, including iterative 1,2-metal / hydrogen migration and 1,n-metal / hydrogen migration through space, so as to realize functionalization of sp3 or sp2 C-H for constructing complex molecules.

[0003] Polysubstituted olefins or aromatics are an important structural skeleton, which exist widely in drug active molecules and natural products. Due to the unique structure of this kind of drug and high biological activity, it has attracted wide attention of chemists. In recent years, many methods for synthesizing polysubstituted olefin or aromatic compounds have been developed, among which the transition metal-catalyzed 1,4-metal / hydrogen migration strategy is a common synthetic strategy for constructing polysubstituted olefins or aromatics.

[0004] The reported transition metal-catalyzed 1,4-metal / hydrogen migration functionalization reactions mainly include the following:

[0005] As early as 2016, Lin Guoqiang's group (Feng, C.-G.; Lin, G.-Q J. Am. Chem. Soc. 2016, 138, 2897. Feng, C.-G.; Lin, G.-Q Angew. Chem. Int. Ed. 2018, 57, 5871.) developed a 1,4-palladium / hydrogen-migration remote functionalization reaction, which can realize the synthesis of trisubstituted alkenyl boronate and configurationally single conjugated diene.

[0006]

[0007] In 2014, Lam's group (Lam, H. W. Angew. Chem. Int. Ed. 2014, 53, 6523.) developed a 1,4-iridium / hydrogen-migration tandem reaction, which can realize the synthesis of polycyclic compounds.

[0008]

[0009] In addition to noble metal-catalyzed 1,4-metal / hydrogen migration functionalization reactions, transition metal-catalyzed reactions by abundant metals such as Ni and Co have also seen rapid development. Our research group has conducted some studies on Ni and Co-catalyzed 1,4-metal / hydrogen migration functionalization.

[0010] In 2021, Professor Shaolin Zhu's research group (R. Martin. S., Zhu. J. Am. Chem. Soc. 2021, 143,48, 20064.) developed a three-component 1,4-nickel / hydrogen migration reaction, which enabled the one-step construction of polysubstituted aromatic hydrocarbons from simple haloalkanes and alkynes via alkenyl to aryl 1,4-nickel / hydrogen migration.

[0011]

[0012] In 2024, Professor Shaolin Zhu's research group (J. Chen, L. Wu, Z. Song, Y. Wang, Z. Li, Y. Wang, S. Zhu, J. Am. Chem. Soc. 2024, 146, 26223–26232) developed a 1,4-cobalt / hydrogen migration NHK reaction to construct chiral allyl alcohols via aryl-to-alkenyl 1,4-cobalt / hydrogen migration. This reaction exhibits good enantioselectivity and regioselectivity.

[0013] Summary of the Invention

[0014] The purpose of this invention is to provide a metal / photoredox catalytic migration C(sp²)-H / C(sp³)-H cross-coupling reaction. This invention uses inexpensive transition metal nickel as a catalyst, ligand L, and a photocatalyst. It utilizes readily available alkanes and haloaromatics as raw materials, employs mild and simple conditions, exhibits good functional group compatibility, a broad substrate range, and is easy to operate. It can yield a series of polysubstituted olefins or polysubstituted aromatic compounds with excellent regioselectivity and good yields, which can serve as active pharmaceutical molecules. This invention provides a novel and efficient method for the synthesis of polysubstituted olefins or aromatics. It is expected to be applied to the synthesis of natural products and pharmaceutical molecules.

[0015] The present invention achieves one of the above-mentioned objectives by means of the following technical solution: a method for migrating C(sp²)-H / C(sp³)-H cross-coupling achieved by metal / photo-redox catalysis, characterized by comprising the following steps: dissolving a nickel-based catalyst, an achiral ligand L or a chiral ligand L*, a photocatalyst, a base, and an additive in an organic solvent in an inert gas atmosphere, and then adding an ortho-alkenyl-substituted aryl chloride. aryl bromides with ortho-alkenyl substitution Or ortho-aryl substituted pyridine bromide and ethylbenzene compounds or dimethyl-substituted olefins or tetrahydrofuran The reaction mixture was obtained, and post-processing purification yielded the target compounds:

[0016] Mono-configured polysubstituted olefin products , or ;

[0017] Multisubstituted aromatic products ;

[0018] Among them, R 1 R 2 The structure is one of aryl, alkyl, or hydrogen (H) atoms.

[0019] R 3 The structure is alkyl

[0020] R 4 R 5 The structure is any one of alkyl (Alkyl), hydrogen atom (H) or silyl ether;

[0021] , The structure consists of a benzene ring or a pyridine ring with different functional groups substituted.

[0022] The non-chiral ligand L is any one of the following:

[0023]

[0024]

[0025] The chiral ligand L* is any one of the following:

[0026]

[0027]

[0028] The solvent is one or more selected from ethyl acetate, acetonitrile, diethyl ether, ethanol, acetone, toluene, ethylbenzene, trifluorotoluene, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether, dichloromethane, tetrahydrofuran, 1,4-dioxane, and 1,3-dioxolane.

[0029] The proposed metal / photoredox catalytic migration C(sp²)-H / C(sp³)-H cross-coupling reaction preparation route can be any of the following:

[0030] Preparation route 1:

[0031]

[0032] Preparation route 2:

[0033]

[0034] Preparation route 3:

[0035]

[0036] Preparation route 4:

[0037]

[0038] Preparation route 5:

[0039] .

[0040] The ligand L66 is a bipyridine ligand with the following structural formula: Ligand L70 is a bipyridine ligand with the following structural formula: .

[0041] Preferred preparation route 1:

[0042]

[0043] In Route 1, the molar ratio of aryl chloride 1 to ethylbenzene compound 2 is 1:10, NiBr2 is the nickel catalyst nickel(II) bromide, and ligand L70 is... Ir(dFCF3ppy)2(dtbpy)PF6 is the photocatalyst, K3PO4 is the basic potassium phosphate, TBAB is the additive tetrabutylammonium bromide, and DMF and 1,4-dioxane are the solvents N,N-dimethylformamide and 1,4-dioxane.

[0044] Preparation route 2:

[0045]

[0046] In Route 2, the molar ratio of aryl bromide 4 to ethylbenzene compound 2 is 1:10, NiBr2 is the nickel catalyst nickel(II) bromide, and ligand L66 is... Ir(dFCF3ppy)2(dtbpy)PF6 is the photocatalyst, K3PO4 is the basic potassium phosphate, and DMF and 1,4-dioxane are the solvents N,N-dimethylformamide and 1,4-dioxane.

[0047] Preparation route 3:

[0048]

[0049] In route 3, the molar ratio of aryl bromide 5 to ethylbenzene compound 2 is 1:10, NiBr2 is the nickel catalyst nickel(II) bromide, and ligand L70 is... Ir(dFCF3ppy)2(dtbpy)PF6 is the photocatalyst, K3PO4 is the basic potassium phosphate, TBAB is the additive tetrabutylammonium bromide, and DMF and 1,4-dioxane are the solvents N,N-dimethylformamide and 1,4-dioxane.

[0050] Preparation route 4:

[0051]

[0052] In route 4, the molar ratio of aryl bromide 4 to dimethyl olefin compound 7 is 1:10, NiBr2 is the nickel catalyst nickel(II) bromide, and ligand L70 is... 4CzIPN is the photocatalyst, K3PO4 is the basic potassium phosphate, NaBr is the additive sodium bromide, and DMF and MeCN are the solvents N,N-dimethylformamide and acetonitrile.

[0053] Preparation route 5:

[0054]

[0055] In route 5, NiBr2 is the nickel-based catalyst nickel(II) bromide, and ligand L70 is... PC is a photocatalyst K3PO4 is potassium phosphate, THF is tetrahydrofuran, and the concentration is 0.1M.

[0056] Preferably, the nickel salt is any one of nickel chloride, nickel chloride hexahydrate, nickel chloride ethylene glycol dimethyl ether complex, nickel bromide, nickel bromide trihydrate, nickel bromide diethylene glycol dimethyl ether complex, nickel bromide ethylene glycol dimethyl ether complex, and bis-(1,5-cyclooctadiene) nickel complex.

[0057] The photocatalyst is one or more of (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(III) hexafluorophosphate, 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, and (4-methoxyphenyl)(4-(trifluoromethyl)phenyl) methyl ketone;

[0058] The alkali is one or more of potassium phosphate, sodium phosphate, sodium carbonate, and cesium carbonate;

[0059] The additive is one or more of lithium bromide, potassium bromide, tetrabutylammonium bromide, and sodium bromide;

[0060] The solvent is one or more of tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, and acetonitrile.

[0061] Beneficial effects:

[0062] 1. The reaction temperature is 0 °C to 50 °C, the reaction conditions are mild, the reaction effect is good, and the product can be obtained with excellent yield, regioselectivity and stereoselectivity.

[0063] 2. The alkanes mentioned are inexpensive, commercially available, or have simple synthetic routes.

[0064] 3. The reaction conditions are neutral redox conditions under photocatalysis. With the addition of photocatalyst Ir(dFCF3ppy)2(dtbpy)PF6, there is no need to add equivalent oxidant or reductant, making it green and environmentally friendly.

[0065] 4. The role of the ligand L: It coordinates with metallic nickel and controls the 1,4-nickel / hydrogen migration process from aryl to alkenyl groups during the reaction, so that coupling occurs at the CH position of the olefin.

[0066] 5. The alkane equivalent can be reduced to 3 equivalents, but the yield and selectivity both decrease.

[0067] 6. The target product 3n was obtained by column chromatography separation and purification as described in Example 13. 3n is ibuprofen, a common anti-inflammatory drug. Attached Figure Description

[0068] The present invention will be further described below with reference to the accompanying drawings.

[0069] Figure 1 The H spectrum is that of the product in Example 1;

[0070] Figure 2 The C spectrum is that of the product in Example 1;

[0071] Figure 3 This is the H spectrum of the product from Example 2;

[0072] Figure 4 The C spectrum is that of the product in Example 2;

[0073] Figure 5 The H spectrum is that of the product in Example 3;

[0074] Figure 6 This is the C spectrum of the product from Example 3;

[0075] Figure 7 The F spectrum is that of the product in Example 4;

[0076] Figure 8 The H spectrum is that of the product in Example 4;

[0077] Figure 9 This is the C spectrum of the product from Example 4;

[0078] Figure 10 This is the H spectrum of the product from Example 5;

[0079] Figure 11 This is the C spectrum of the product from Example 5;

[0080] Figure 12 The H spectrum is that of the product in Example 6;

[0081] Figure 13 The C spectrum is that of the product in Example 6;

[0082] Figure 14 The H spectrum is that of the product in Example 7;

[0083] Figure 15 This is the C spectrum of the product from Example 7.

[0084] Figure 16 The H spectrum is that of the product in Example 8;

[0085] Figure 17 This is the C spectrum of the product from Example 8.

[0086] Figure 18 The H spectrum is that of the product in Example 9;

[0087] Figure 19 This is the C spectrum of the product from Example 9.

[0088] Figure 20 This is the H spectrum of the product from Example 10;

[0089] Figure 21 This is the C spectrum of the product from Example 10.

[0090] Figure 22 This is the H spectrum of the product from Example 11;

[0091] Figure 23 This is the C spectrum of the product of Example 11.

[0092] Figure 24 This is the H spectrum of the product from Example 12;

[0093] Figure 25 This is the C spectrum of the product of Example 12.

[0094] Figure 26 H-spectrum of the product in Example 13;

[0095] Figure 27 C-spectrum of the product in Example 13. Detailed Implementation

[0096] The features and advantages of the present invention will be further understood through the following detailed description. The provided embodiments are merely illustrative of the method of the present invention and do not limit the rest of the content disclosed herein in any way.

[0097] In the following embodiments, TBS refers to o-Tol refers to o-methylphenyl, NiBr2 refers to nickel bromide, TBAB refers to tetrabutylammonium bromide, K3PO4 refers to potassium phosphate, Ir(dFCF3ppy)2(dtbpy)PF6 refers to (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(III) hexafluorophosphate, DMF refers to N,N-dimethylformamide, 1,4-dioxane refers to 1,4-dioxane, THF refers to tetrahydrofuran, equiv refers to the equivalent number, and L ligand is... or One of them.

[0098] Example 1

[0099]

[0100] Under a nitrogen atmosphere, nickel bromide (4.4 mg, 10 mol%), ligand L66 (5.1 mg, 15 mol%), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(III) hexafluorophosphate (4.4 mg, 2 mol%), and potassium phosphate (84.9 mg, 0.40 mmol) were added to a reaction tube and dissolved in 0.25 mL of dry N,N-dimethylformamide and 0.5 mL of 1,4-dioxane. After stirring at 25 °C for 10 minutes, the above-mentioned haloaromatic hydrocarbons (1a, 39.4 mg, 0.20 mmol, 1.0 equiv) and ethylbenzene (2a, 212 mg, 2.0 mmol, 10 equiv) were added. The reaction tube was then capped and incubated at 10 W. The reaction was carried out at 25 °C for 36 hours under 455 nm LED irradiation. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, concentrated under reduced pressure to remove the reaction solvent, and purified by column chromatography to obtain the target product (34.6 mg, colorless liquid, yield 78%, regioselectivity 99:1, Z / E = 97:3).

[0101] 1 H NMR (400 MHz, CDCl3) δ 7.67 – 6.82 (m, 10H), 5.60 (dd, J = 10.3, 1.5Hz, 1H), 3.60 – 3.22 (m, 1H), 2.03 (d, J = 1.4 Hz, 3H), 1.28 (d, J = 6.9 Hz, 3H). 13 C NMR(101 MHz, CDCl3) δ 147.0, 142.3, 135.4, 132.4, 128.5, 128.3, 128.0,127.0, 126.7, 126.0, 38.9, 26.0, 22.7. HRMS(ESI) calcd. for C 17 H 19 [M+H] + m / z 223.1482, found 223.1483;IR(neat, cm -1 ) 2965, 1599, 1492, 1265, 763, 699.

[0102] Table 1 shows the screening of photocatalysts:

[0103]

[0104] Table 2 shows the ligand screening results:

[0105]

[0106] If the equivalent number of substrate 2 is changed to 3 equivalents, the reaction yield is 47% and the E / Z ratio is 90:10.

[0107] Example 2

[0108]

[0109] Under a nitrogen atmosphere, nickel bromide (4.4 mg, 10 mol%), ligand L66 (5.1 mg, 15 mol%), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(III) hexafluorophosphate (4.4 mg, 2 mol%), and potassium phosphate (84.9 mg, 0.40 mmol) were added to a reaction tube and dissolved in 0.25 mL of dry N,N-dimethylformamide and 0.5 mL of 1,4-dioxane. After stirring at 25 °C for 10 minutes, the above-mentioned haloaromatic hydrocarbons (1b, 45.2 mg, 0.20 mmol, 1.0 equiv) and ethylbenzene (2a, 212 mg, 2.0 mmol, 10 equiv) were added. The reaction tube was then capped and incubated at 10 W. The reaction was carried out at 25 °C for 36 hours under 455 nm LED irradiation. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, concentrated under reduced pressure to remove the reaction solvent, and purified by column chromatography to obtain the target product (31.2 mg, colorless liquid, yield 62%, regioselectivity 99:1, Z / E = 99:1).

[0110] 1 H NMR (400 MHz, CDCl3) δ 7.32 – 7.09 (m, 6H), 6.84 – 6.66 (m, 3H), 5.59 (dd, J = 10.3, 1.5 Hz, 1H), 3.76 (s, 3H), 3.59 – 3.30 (m, 1H), 2.02 (d, J =1.4 Hz, 3H), 1.28 (d, J = 6.9 Hz, 3H). 13C NMR(101 MHz, CDCl3) δ 159.5, 147.0,143.8, 135.3, 132.4, 129.3, 128.5, 127.0, 126.0, 120.4, 113.6, 112.3, 55.3,38.9, 25.9, 22.8.HRMS(ESI) calcd. for C 18 H 21 O [M+H] + m / z 253.1587, found253.1592;IR(neat, cm -1 ) 2968, 1615, 1324, 1164, 1124, 868, 699.

[0111] Example 3

[0112]

[0113] Under a nitrogen atmosphere, nickel bromide (4.4 mg, 10 mol%), ligand L66 (5.1 mg, 15 mol%), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(III) hexafluorophosphate (4.4 mg, 2 mol%), and potassium phosphate (84.9 mg, 0.40 mmol) were added to a reaction tube and dissolved in 0.25 mL of dry N,N-dimethylformamide and 0.5 mL of 1,4-dioxane. After stirring at 25 °C for 10 minutes, the above-mentioned haloaromatic hydrocarbons (1 g, 54.6 mg, 0.20 mmol, 1.0 equiv) and propylbenzene (2c, 240 mg, 2.0 mmol, 10 equiv) were added. The reaction tube was then capped and incubated at 10 W. The reaction was carried out at 25 °C for 36 hours under 455 nm LED irradiation. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, concentrated under reduced pressure to remove the reaction solvent, and purified by column chromatography to obtain the target product (45.5 mg, colorless liquid, yield 73%, regioselectivity 96:4, Z / E = 99:1).

[0114] 1 H NMR (400 MHz, CDCl3) δ 7.63 – 6.76 (m, 14H), 5.87 (d, J= 10.6 Hz,1H), 3.69 – 3.46 (m, 1H), 2.01 (s, 3H), 1.78 – 1.61 (m, 2H), 0.88 (t, J = 7.4Hz, 3H). 13 C NMR(101 MHz, CDCl3) δ 145.8, 144.0, 141.7, 140.4, 136.3, 135.3,130.4, 130.2, 129.4, 128.7, 128.0, 127.5, 127.3, 126.9, 126.1, 125.6, 46.4,31.1, 20.6, 12.3.HRMS(ESI) calcd. for C 24 H 24 Na [M+Na] + m / z 335.1770, found335.1772;IR(neat, cm -1 ) 2960, 1599, 1492, 1264, 730, 699.

[0115] Example 4

[0116]

[0117] Under a nitrogen atmosphere, nickel bromide (4.4 mg, 10 mol%), ligand L70 (8.5 mg, 15 mol%), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(III) hexafluorophosphate (4.4 mg, 2 mol%), potassium phosphate (84.9 mg, 0.40 mmol), and tetrabutylammonium bromide (32.2 mg, 0.10 mmol) were added to a reaction tube and dissolved in 0.2 mL of dry N,N-dimethylformamide and 0.2 mL of 1,4-dioxane. After stirring at 25 °C for 10 minutes, the above-mentioned haloaromatic hydrocarbons (1d-Cl, 44.1 mg, 0.20 mmol, 1.0 equiv) and ethylbenzene (2a, 212 mg, 2.0 equiv) were added. The reaction tube was capped and the reaction was carried out at 25 °C for 48 hours under 10 W 425 nm LED irradiation. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, concentrated under reduced pressure to remove the reaction solvent, and purified by column chromatography to obtain the target product (43.0 mg, colorless liquid, yield 74%, regioselectivity 95:5, Z / E = 94:6).

[0118] 11 1H NMR (400 MHz, CDCl3) δ 7.90 – 7.48 (m, 2H), 7.44 – 6.72 (m, 7H), 5.68 (dd, J J = 10.3, 1.5 Hz, 1H), 3.40 (m, 1H), 2.03 (d, J J = 1.5 Hz, 3H), 1.29 (d, J J = 6.9 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 146.5, 146.0, 134.2, 133.6, 129.0 (q, J J = 32.3 Hz), 128.6, 128.3, 126.9, 126.1, 125.3 (q, J J = 3.8 Hz), 124.4 (q, J J = 272.2 Hz), 39.0, 25.6, 22.8. 19 19F NMR (471 MHz, CDCl3) δ –62.4. HRMS (ESI) calcd. for C 18 19H 18 19F3 [M + H] + m / z 291.1355, found 291.1350; IR (neat, cm -1 ) 2963, 1598, 1576, 1486, 1251, 1044, 699.

[0119] Example 5

[0120]

[0121] Under a nitrogen atmosphere, nickel bromide (4.4 mg, 10 mol%), ligand L66 (5.1 mg, 15 mol%), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(III) hexafluorophosphate (4.4 mg, 2 mol%), and potassium phosphate (84.9 mg, 0.40 mmol) were added to a reaction tube and dissolved in 0.2 mL of dry N,N-dimethylformamide and 0.2 mL of 1,4-dioxane. After stirring at 25 °C for 10 minutes, the above-mentioned haloaromatic hydrocarbons (1a-Cl, 30.5 mg, 0.20 mmol, 1.0 equiv) and 4-ethyl anisole (2e, 272 mg, 2.0 mmol, 10 equiv) were added. The reaction tube was sealed and reacted at 25 °C for 36 hours under 10W 425nm LED irradiation. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, concentrated under reduced pressure to remove the reaction solvent, and purified by column chromatography to obtain the target product (35.9 mg, colorless liquid, yield 71%, regioselectivity 99:1, Z / E = 90:10).

[0122] 1 H NMR (400 MHz, CDCl3) δ 7.43 – 7.01 (m, 7H), 6.83 (d, J = 8.7 Hz, 2H), 5.56 (dd, J = 10.3, 1.5 Hz, 1H), 3.78 (s, 3H), 3.44 (dd, J = 10.3, 6.9 Hz, 1H), 2.02 (d, J = 1.5 Hz, 3H), 1.26 (d, J = 6.9 Hz, 3H). 13 C NMR(101 MHz, CDCl3) δ157.8, 142.4, 139.1, 135.0, 132.8, 128.3, 128.0, 127.8, 126.7, 113.9, 55.4,38.0, 26.0, 22.8.HRMS(ESI) calcd. for C 18 H 20 NaO [M+Na] + m / z 275.1406, found275.1405;IR(neat, cm -1) 2963, 1609, 1570, 1244, 829, 737, 7022.

[0123] Example 6

[0124]

[0125] Under a nitrogen atmosphere, nickel bromide (4.4 mg, 10 mol%), ligand L66 (5.1 mg, 15 mol%), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(III) hexafluorophosphate (4.4 mg, 2 mol%), potassium phosphate (84.9 mg, 0.40 mmol), and 4 Å molecular sieve (20 mg) were added to a reaction tube and dissolved in 0.25 mL of dry N,N-dimethylformamide and 0.5 mL of 1,4-dioxane. After stirring at 25 °C for 10 minutes, the above-mentioned haloaromatic hydrocarbons (1a, 39.4 mg, 0.20 mmol, 1.0 equiv) and cyclohexene (2a, 164 mg, 2.0 mmol, 10 equiv) were added. The reaction tube was sealed and reacted at 25 °C for 36 hours under 10W 455nm LED irradiation. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, concentrated under reduced pressure to remove the reaction solvent, and purified by column chromatography to obtain the target product (32.9 mg, colorless liquid, yield 83%, regioselectivity 98:2, Z / E = 99:1).

[0126] 1 H NMR (400 MHz, CDCl3) δ 7.42 – 7.30 (m, 2H), 7.27 – 7.20 (m, 1H), 7.21 – 7.13 (m, 2H), 5.68 (m, 1H), 5.51 – 5.41 (m, 1H), 5.30 (m, 1H), 2.81(m, 1H), 2.02(d, J = 1.5 Hz, 3H), 1.94 (m, 2H), 1.79 – 1.63 (m, 2H), 1.53 –1.30 (m, 2H). 13 for C15 H 19 [M+H] + m / z 199.1482, found 199.1480;IR(neat, cm -1 ) 2931, 1718, 1445, 1275, 764,701.

[0127] Example 7

[0128]

[0129] Under a nitrogen atmosphere, nickel bromide (4.4 mg, 10 mol%), ligand L70 (8.5 mg, 15 mol%), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (3.1 mg, 2 mol%), potassium phosphate (84.9 mg, 0.40 mmol), and sodium bromide (20.6 mg, 0.20 mmol) were added to a reaction tube and dissolved in 0.5 mL of dry N,N-dimethylformamide and 0.1 mL of acetonitrile. After stirring at 25 °C for 10 minutes, the above-mentioned haloaromatic hydrocarbons (1 g, 54.6 mg, 0.20 mmol, 1.0 equiv) and tetramethylethylene (2a, 168 mg, 2.0 mmol, 10 equiv) were added. The reaction tube was then capped and reacted at 35 °C for 48 hours under 10W 455nm LED irradiation. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, concentrated under reduced pressure to remove the reaction solvent, and purified by column chromatography to obtain the target product (42.0 mg, colorless liquid, yield 76%, regioselectivity 99:1, Z / E = 99:1).

[0130] 1 H NMR (500 MHz, CDCl3) δ 7.36 – 7.30 (m, 2H), 7.27 – 7.17 (m, 6H), 7.16 – 7.10 (m, 1H), 5.62 (t, J = 7.2 Hz, 1H), 3.09 (d, J = 7.3 Hz, 2H), 2.09 (s, 3H), 1.69 (s, 6H), 1.61 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 144.1, 141.7, 140.4,136.3, 130.6, 130.3, 130.3, 129.6, 128.0, 127.1, 126.7, 126.6, 125.6, 125.1,34.7, 20.8, 20.6, 20.3, 18.7.HRMS(ESI) calcd. for C 21 H 25 [M+H] + m / z 277.1951,found 277.1950;IR(neat, cm -1 ) 2918, 1442, 1029, 757, 727, 700.

[0131] Example 8

[0132]

[0133] Under a nitrogen atmosphere, nickel bromide (4.4 mg, 10 mol%), ligand L70 (8.5 mg, 15 mol%), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (3.1 mg, 2 mol%), potassium phosphate (84.9 mg, 0.40 mmol), and sodium bromide (20.6 mg, 0.20 mmol) were added to a reaction tube and dissolved in 0.5 mL of dry N,N-dimethylformamide and 0.1 mL of acetonitrile. After stirring at 25 °C for 10 minutes, the above-mentioned haloaromatic hydrocarbons (1 g, 54.6 mg, 0.20 mmol, 1.0 equiv) and alkenyl silyl ether (2a, 372 mg, 2.0 mmol, 10 equiv) were added. The reaction tube was then capped and reacted at 35 °C for 48 hours under 10W 455nm LED irradiation. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, concentrated under reduced pressure to remove the reaction solvent, and purified by column chromatography to obtain the target product (41.0 mg, colorless liquid, yield 54%, regioselectivity 94:6, Z / E = 98:2).

[0134] 1 H NMR (500 MHz, CDCl3) δ 7.34 – 7.27 (m, 2H), 7.27 – 7.17 (m, 6H), 7.15 – 7.10 (m, 1H), 6.18 (q, J = 1.4 Hz, 1H), 5.71 (t, J= 7.6 Hz, 1H), 3.09 –2.71 (m, 2H), 2.07 (s, 3H), 1.66 (d, J = 1.4 Hz, 3H), 0.96 (s, 9H), 0.15 (s, 6H). 13 C NMR(126 MHz, CDCl3) δ 144.1, 142.6, 140.1, 136.2, 134.9, 130.3, 130.0,129.4, 128.0, 127.2, 126.8, 125.7, 116.9, 33.9, 25.9, 20.6, 18.5, 13.6, -5.1.HRMS(ESI) calcd. for C 25 H 34 NaOSi [M+Na] + m / z 401.2271, found 401.2274;IR(neat, cm -1 ) 2928, 2856, 1674, 1159, 837.

[0135] Example 9

[0136]

[0137] Under a nitrogen atmosphere, nickel bromide (4.4 mg, 10 mol%), ligand L70 (8.5 mg, 15 mol%), (4-methoxyphenyl)(4-(trifluoromethyl)phenyl)methyl ketone (5.6 mg, 20 mol%), and potassium phosphate (84.9 mg, 0.40 mmol) were added to a reaction tube and dissolved in 2 mL of dry tetrahydrofuran. After stirring at 25 °C for 10 minutes, the above-mentioned haloaromatic hydrocarbons (1i, 51.6 mg, 0.20 mmol, 1.0 equiv) were added. The reaction tube was capped, and the reaction was carried out at 25 °C for 36 hours under 10W 390nm LED irradiation. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, concentrated under reduced pressure to remove the reaction solvent, and purified by column chromatography to obtain the target product (28.1 mg, colorless liquid, yield 56%, regioselectivity 98:2).

[0138] 1 H NMR (400 MHz, CDCl3) δ 7.41 – 7.30 (m, 3H), 7.28 – 7.18 (m, 7H), 6.06 (d, J= 9.0 Hz, 1H), 4.29 (m, 1H), 3.94 (m, 1H), 3.73 (m, 1H), 2.15 – 1.63(m, 4H). 13 C NMR(101 MHz, CDCl3) δ 143.8, 142.1, 139.6, 130.1, 129.9, 128.2,128.2, 127.7, 127.6, 127.5, 76.8, 68.2, 33.2, 26.6.HRMS(ESI) calcd.forC 18 H 19 O [M+H] + m / z 251.1431, found 251.1425;IR(neat, cm -1 ) 2926, 1493, 1445, 1049, 700.

[0139] Example 10

[0140]

[0141] Under a nitrogen atmosphere, nickel bromide (4.4 mg, 10 mol%), ligand L70 (8.5 mg, 15 mol%), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(III) hexafluorophosphate (4.4 mg, 2 mol%), potassium phosphate (127 mg, 0.40 mmol), and tetrabutylammonium bromide (64.4 mg, 0.20 mmol) were added to a reaction tube and dissolved in 0.25 mL of dry N,N-dimethylformamide and 1 mL of dioxane. After stirring at 25 °C for 10 minutes, the above-mentioned haloaromatic hydrocarbons (1j, 49.4 mg, 0.20 mmol, 1.0 equiv) and ethylbenzene (2a, 212 mg, 2.0 mmol, 10 equiv) were added. The reaction tube was sealed and reacted at 35 °C for 24 hours under 10W 455nm LED irradiation. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, concentrated under reduced pressure to remove the reaction solvent, and purified by column chromatography to obtain the target product (42.5 mg, colorless liquid, yield 78%, regioselectivity 99:1).

[0142] 1 H NMR (500 MHz, CDCl3) δ 7.52 (t, J= 7.7 Hz, 1H), 7.37 – 7.21 (m, 4H), 7.21 – 7.01 (m, 6H), 6.96 (d, J = 7.6 Hz, 1H), 4.50 (q, J = 7.2 Hz, 1H), 2.60 (s, 3H), 1.56 (d, J = 7.2 Hz, 3H). 13 C NMR(126 MHz, CDCl3) δ 159.7, 157.8, 146.8, 144.3, 140.8, 136.4, 129.7, 128.5, 128.1, 127.8, 127.7, 126.1, 125.7, 121.3,121.3, 40.1, 24.8, 22.2. HRMS(ESI) calcd. for C 20 H 19 NNa [M+Na] + m / z 296.1409, found 296.1405; IR(neat, cm -1 ) 2967, 1735, 1447, 1241, 1045, 735, 701.

[0143] Example 11

[0144]

[0145] Under a nitrogen atmosphere, nickel bromide (4.4 mg, 10 mol%), ligand L70 (8.5 mg, 15 mol%), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(III) hexafluorophosphate (4.4 mg, 2 mol%), potassium phosphate (127 mg, 0.40 mmol), and tetrabutylammonium bromide (64.4 mg, 0.20 mmol) were added to a reaction tube and dissolved in 0.25 mL of dry N,N-dimethylformamide and 1 mL of dioxane. After stirring at 25 °C for 10 minutes, the above-mentioned haloaromatic hydrocarbons (1k, 61.2 mg, 0.20 mmol, 1.0 equiv) and ethylbenzene (2a, 212 mg, 2.0 mmol, 10 equiv) were added. The reaction tube was sealed and reacted at 35 °C for 24 hours under 10W 455nm LED irradiation. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, concentrated under reduced pressure to remove the reaction solvent, and purified by column chromatography to obtain the target product (39.8 mg, colorless liquid, yield 60%, regioselectivity 99:1).

[0146] 1 H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 1.7 Hz, 1H), 7.98 – 7.82 (m, 1H),7.52 (t, J = 7.7 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.21 – 7.05 (m, 4H), 7.02 –6.96 (m, 2H), 6.91 (d, J = 7.7 Hz, 1H), 4.53 (q, J = 7.2 Hz, 1H), 3.91 (s, 3H), 2.61 (s, 3H), 1.61 (d, J = 7.2 Hz, 3H). 13 C NMR(101 MHz, CDCl3) δ 167.2, 158.7,158.0, 146.2, 145.2, 144.7, 136.5, 130.1, 130.0, 129.0, 128.3, 127.7, 127.4,125.9, 121.8, 121.3, 52.2, 40.2, 24.7, 22.2.HRMS(ESI) calcd. for C 22H 22 NO2[M+H] + m / z 332.1645, found 332.1640;IR(neat, cm -1 ) 2965, 1720, 1587, 1293, 1113,802, 701.

[0147] Example 12

[0148]

[0149] Under a nitrogen atmosphere, nickel bromide (4.4 mg, 10 mol%), ligand L70 (8.5 mg, 15 mol%), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(III) hexafluorophosphate (4.4 mg, 2 mol%), potassium phosphate (127 mg, 0.40 mmol), and tetrabutylammonium bromide (64.4 mg, 0.20 mmol) were added to a reaction tube and dissolved in 0.25 mL of dry N,N-dimethylformamide and 1 mL of dioxane. After stirring at 25 °C for 10 minutes, the above-mentioned haloaromatic hydrocarbons (1 mL 49.4 mg, 0.20 mmol, 1.0 equiv) and 4-ethylbiphenyl (2 mL 364 mg, 2.0 mmol, 10 equiv) were added. The reaction tube was sealed and reacted at 35 °C for 24 hours under 10W 455nm LED irradiation. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, concentrated under reduced pressure to remove the reaction solvent, and purified by column chromatography to obtain the target product (54.3 mg, colorless liquid, yield 78%, regioselectivity 99:1).

[0150] 1 H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 1.7 Hz, 1H), 7.98 – 7.82 (m, 1H),7.52 (t, J = 7.7 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.21 – 7.05 (m, 4H), 7.02 –6.96 (m, 2H), 6.91 (d, J = 7.7 Hz, 1H), 4.53 (q, J= 7.2 Hz, 1H), 3.91 (s, 3H), 2.61 (s, 3H), 1.61 (d, J = 7.2 Hz, 3H). 13 C NMR(101 MHz, CDCl3) δ 167.2, 158.7,158.0, 146.2, 145.2, 144.7, 136.5, 130.1, 130.0, 129.0, 128.3, 127.7, 127.4,125.9, 121.8, 121.3, 52.2, 40.2, 24.7, 22.2.HRMS(ESI) calcd. for C 22 H 22 NO2[M+H] + m / z 332.1645, found 332.1640;IR(neat, cm -1 ) 2965, 1720, 1587, 1293, 1113,802, 701.

[0151] Example 13

[0152]

[0153] Under a nitrogen atmosphere, nickel bromide (4.4 mg, 10 mol%), ligand L66 (5.1 mg, 15 mol%), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(III) hexafluorophosphate (4.4 mg, 2 mol%), and potassium phosphate (84.9 mg, 0.40 mmol) were added to a reaction tube and dissolved in 0.25 mL of dry N,N-dimethylformamide and 0.5 mL of 1,4-dioxane. After stirring at 25 °C for 10 minutes, the above-mentioned haloaromatic hydrocarbons (1i, 51.6 mg, 0.20 mmol, 1.0 equiv) and ethylbenzene compounds (2m, 320 mg, 2.0 mmol, 10 equiv) were added. The reaction tube was then capped and incubated at 10 W. The reaction was carried out at 25 °C for 36 hours under 455 nm LED irradiation. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, concentrated under reduced pressure to remove the reaction solvent, and purified by column chromatography to obtain the target product (47.7 mg, colorless liquid, yield 70%, regioselectivity 95:5).

[0154] 1H NMR (400 MHz, CDCl3) δ 7.40–7.31 (m, 3H), 7.26–7.19 (m, 7H), 7.11 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.21 (dd, J = 10.3, 1.9 Hz,1H), 3.61–3.54 (m, 1H), 2.44 (dd, J = 7.1, 1.5 Hz, 2H), 1.89–1.79 (m, 1H),1.37 (dd, J = 6.9, 1.8 Hz, 3H), 0.90 (dd, J = 6.6, 1.9 Hz, 6H); 13 C NMR(101MHz, CDCl3) δ 143.4, 142.6, 140.3, 139.9, 139.4, 134.7, 130.0, 129.3, 128.4,128.2, 127.4, 127.14, 127.06, 126.7, 45.2, 39.0, 30.4, 22.6, 22.4.HRMS (ESI)calcd For C 26 H 29 + [M+H] + m / z : 341.2264, Found: 341.2276;IR (neat cm –1 ) 2957, 1613,1511, 1489, 1275, 1166, 1044, 879, 723.

[0155]

[0156] According to known literature, 3m (0.2 mmol, 68.0 mg) was dissolved in CCl4 (1 mL) and MeCN (1 mL), and an aqueous solution of NaIO4 (0.22 g, 0.9 mmol, 4.5 equiv) and RuCl3-xH2O (2.3 mg, 0.01 mmol, 5 mol%) (1 mL) was added. The mixture was stirred at room temperature for 3 hours, quenched with HCl, extracted with dichloromethane, concentrated under reduced pressure to remove the reaction solvent, and purified by column chromatography to obtain the target product 3n, which is the common anti-inflammatory drug ibuprofen.

Claims

1. A method for metal / photoredox catalyzed migratory C(sp2)-H / C(sp3)-H cross-coupling, characterized in that, The preparation route of the metal / photoredox catalyzed migration C(sp2)-H / C(sp3)-H cross coupling is any one of the following: Preparation route 1: ； The molar ratio of aryl chloride 1 and ethylbenzene compound 2 in Route 1 is 1:10, aryl chloride 1 is or , ethylbenzene compound 2 is or ; NiBr2 is a nickel catalyst nickel (II) bromide, ligand L70 is , Ir(dFCF3ppy)2(dtbpy)PF6 is a photocatalyst (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(III) hexafluorophosphate, K3PO4 is an alkali potassium phosphate, TBAB is an additive tetrabutylammonium bromide, DMF and 1,4-dioxane are solvents N,N-dimethylformamide and 1,4-dioxane, respectively, to obtain compounds or ; Preparation route 2: ； The molar ratio of aryl bromide 4 and ethylbenzene compound 2 in Route 2 is 1:10, aryl bromide 4 is , , or , ethylbenzene compound 2 is , or , NiBr2 is nickel catalyst nickel(II) bromide, ligand L66 is , Ir(dFCF3ppy)2(dtbpy)PF6 is photocatalyst (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(III) hexafluorophosphate, K3PO4 is base potassium phosphate, DMF and 1,4-dioxane are solvents N,N-dimethylformamide and 1,4-dioxane, respectively, to obtain compound , , or ; Preparation route 3: ； The molar ratio of pyridine bromide 5 and ethylbenzene compound 2 in Route 3 is 1:10, pyridine bromide 5 is or , ethylbenzene compound 2 is or , NiBr2 is nickel bromide (II) as a nickel catalyst, ligand L70 is , Ir(dFCF3ppy)2(dtbpy)PF6 is a photocatalyst (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(III) hexafluorophosphate, K3PO4 is potassium phosphate as a base, TBAB is tetrabutylammonium bromide as an additive, DMF and 1,4-dioxane are solvents N,N-dimethylformamide and 1,4-dioxane, respectively, to obtain compounds , or ; Preparation route 4: ； The molar ratio of aryl bromide 4 to dimethyl olefin compound 7 in Route 4 is 1:10, aryl bromide 4 is , dimethyl olefin compound 7 is or , NiBr2 is nickel-based catalyst nickel(II) bromide, ligand L70 is , 4CzIPN is photocatalyst 2,4,5,6-tetrakis(9-carbazolyl)-1,3- benzenediol, K3PO4 is base potassium phosphate, NaBr is additive sodium bromide, DMF and MeCN are solvents N,N-dimethylformamide and acetonitrile, respectively, to obtain compounds or , respectively; Preparation route 5: ； The aryl bromide 4 in Route 5 is , NiBr2 is a nickel-based catalyst nickel(II) bromide, the ligand L70 is , PC is a photocatalyst , K3PO4 is an alkali potassium phosphate, THF is a solvent tetrahydrofuran, the concentration is 0.1M, to obtain the compound .

2. The metal / photo-redox catalyzed migratory C(sp2)-H / C(sp3)-H cross-coupling process according to claim 1, characterized in that: The specific preparation method reaction route is as follows: wherein NiBr2, L66, Ir(dFCF3ppy)2(dtbpy)PF6, K3PO 4、 DMF, 1,4-dioxane as described in claim 1.

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