A method for synthesizing α - linear alkyl - substituted heteroarenes

Abstract

The present invention discloses a new method for synthesizing α - straight-chain alkyl-substituted heteroarenes, that is, in the presence of an organic base, using the nickel(II) complex Ni(IMXy)[P(OEt)3]Br2 as a catalyst (IMXy is [(RNCHCHNR)C], R is 2,6-dimethyl-4-methoxyphenyl), and synthesizing α - straight-chain alkyl-substituted heteroarenes through the hydroheteroarylation reaction of heteroarenes and unactivated straight-chain internal olefins. Compared with the prior art, the present invention utilizes the tandem isomerization / hydroheteroarylation reaction of nickel-catalyzed unactivated straight-chain internal olefins and heteroarenes, which can convert cheap and easily available internal olefins or their isomer mixtures into high-value-added straight-chain alkyl-substituted heteroarenes. The reaction has good selectivity and high product yield, providing a new method for synthesizing α - straight-chain alkyl-substituted heteroarenes.

Description

Technical Field

[0001] The present invention belongs to the technical field of metal catalysis and organic synthesis preparation, and particularly relates to a method for catalytically synthesizing α - linear alkyl - substituted heteroarenes by a nickel complex. Background Art

[0002] Linear alkyl - substituted heteroarenes, as an important structural unit, are widely present in natural products, bioactive molecules, and drug molecules ( Med. Chem. Res. 2016, 25 , 173), and have important synthetic value. Alkenes are a class of inexpensive and easily available synthetic raw materials with variable structures. The transition - metal - catalyzed hydroheteroarylation of alkenes has 100% atom economy, providing a new approach for the synthesis of linear alkyl - substituted heteroarenes that conforms to the concept of green synthetic chemistry and has developed rapidly in the past 20 years. In this field, there are currently relatively mature technologies for synthesizing linear alkyl - substituted heteroarenes using terminal alkenes as raw materials ( Chem. Rev. 2017, 117 , 9333). However, there are very few reports on using internal alkenes as raw materials. For example, Shi Zhuangzhi et al. achieved the linear alkylation of the C7 - position of indole compounds by activating internal alkenes (such as α,β - unsaturated esters, α,β - unsaturated ketones, etc.) using a precious - metal monovalent rhodium catalyst, but did not involve non - activated linear internal alkenes ( J. Am. Chem. Soc. 2018, 140 , 6062). In addition, the existing technology used an air - sensitive zero - valent nickel catalyst to synthesize linear octyl - substituted benzotrifluoride through the hydroarylation reaction of 4 - octene and benzotrifluoride, but did not perform heteroarene substrate expansion. Therefore, if a cheap and air - stable divalent nickel complex can be used as a catalyst to achieve the hydroheteroarylation reaction of non - activated linear internal alkenes with a series of heteroarenes, it will be original and can provide a new synthesis method for α - linear alkyl - substituted heteroarenes, which has obvious innovation and application prospects. Summary of the Invention

[0003] The object of the present invention is to provide a new method for synthesizing α - linear alkyl - substituted heteroarenes with high selectivity, high yield, and low cost, that is, using an air - stable mixed - ligand nickel(II) complex Ni(IMXy)[P(OEt)3]Br2 as a catalyst (IMXy is [(RNCHCHNR)C], R is 2,6 - dimethyl - 4 - methoxyphenyl), in the presence of an organic base, through the tandem isomerization / hydroheteroarylation reaction of non - activated linear internal alkenes and heteroarenes to synthesize α - linear alkyl - substituted heteroarenes.

[0004] The present invention adopts the following technical solutions:

[0005] A method for synthesizing α - linear alkyl - substituted heteroarenes, comprising the following steps: in an inert gas atmosphere, in the presence of a nickel catalyst and an organic base, reacting a non - activated linear intermediate olefin compound with a heteroarene compound to obtain α - linear alkyl - substituted heteroarenes.

[0006] Application of the N - heterocyclic carbene - based mixed - ligand nickel(II) complex Ni(IMXy)[P(OEt)3]Br2 as a catalyst in the synthesis of α - linear alkyl - substituted heteroarenes.

[0007] In the above - mentioned technical solution, the inert gas is nitrogen or argon.

[0008] In the above - mentioned technical solution, after the reaction is completed, water is added to quench the reaction, and then the reaction mixture is extracted with ethyl acetate, and purified by column chromatography to obtain the product, and the yield can be quantitatively analyzed.

[0009] In the above - mentioned technical solution, the organic base is potassium ethoxide or sodium tert - butoxide, preferably potassium ethoxide; the reaction is carried out in a solvent, and the solvent is tetrahydrofuran, n - hexane or toluene, preferably toluene.

[0010] In the above - mentioned technical solution, the temperature of the reaction is 60 - 130 °C, and the time is 30 - 60 hours; preferably, the temperature of the reaction is 90 °C and the time of the reaction is 36 hours.

[0011] In the above - mentioned technical solution, the molar ratio of the nickel catalyst, the organic base, the heteroarene compound, and the non - activated linear intermediate olefin compound is (0.02 - 0.10):0.5:1:1.5, preferably 0.02:0.5:1:1.5. In the preferred technical solution, in terms of amount of substance, the amount of the non - activated linear intermediate olefin compound used is 1.5 times that of the heteroarene compound, the amount of potassium ethoxide used is 0.5 times that of the heteroarene compound, and the amount of the catalyst used is 2% of the molar amount of the heteroarene compound.

[0012] In the present invention, the heteroarene compound includes benzimidazole - type compounds, which are specifically represented by the following chemical structural formula:

[0013]

[0014] Among them, R 1 is methyl, aryl, benzyl or alkoxy, and R 2 and R 3 are selected from a hydrogen atom or methyl.

[0015] In the present invention, the heteroarene compound includes indole - type compounds, which are specifically represented by the following chemical structural formula:

[0016]

[0017] Among them, R 4is an acyl group.

[0018] In the present invention, the heteroaromatic compound includes a benzofuran or furan compound, and is specifically represented by the following chemical structural formula:

[0019] Or

[0020] Wherein, R 5 is a hydrogen atom or a methoxy group; R 6 is a hydrogen atom or a methyl group.

[0021] In the present invention, the unactivated linear intermediate olefin compound is represented by the following chemical structural formula:

[0022]

[0023] Wherein, R 7 , R 8 are alkyl groups; specifically, the unactivated linear intermediate olefin compounds include cis-4-octene, trans-4-octene, cis / trans-3-octene, cis / trans-2-octene, trans-5-decene, and trans-6-dodecene.

[0024] In the present invention, the chemical structural formula of the α-linear alkyl-substituted heteroaromatic is as follows:

[0025] Or Or Or

[0026]

[0027] Wherein, R 1 , R 2 , R 3 , R 4 , R 5 or R 6 comes from the heteroaromatic compound, and R 9 comes from the unactivated linear intermediate olefin compound, specifically, after the C=C in the chemical structural formula of the intermediate olefin compound migrates to one end and then obtains a hydrogen to form a linear alkyl group.

[0028] The technical solution of the present invention, taking the heteroaromatic compound (benzimidazole compound) as an example, can be expressed as follows:

[0029]

[0030] In the formula, IMXy is [(RNCHCHNR)C] (R is 2,6-dimethyl-4-methoxyphenyl), and has the following structural formula:

[0031]

[0032] Due to the application of the above technical solution, the present invention has the following advantages:

[0033] 1. The present invention uses an air-stable mixed nickel(II) complex Ni(IMXy)[P(OEt)3]Br2 as a catalyst (IMXy is [(RNCHCHNR)C], and R is 2,6-dimethyl-4-methoxyphenyl). In the presence of an organic base, through the hydroheteroarylation reaction of unactivated linear internal olefins and heteroarenes, a new synthesis method for α-linear alkyl-substituted heteroarenes is provided.

[0034] 2. The synthesis method provided by the present invention can convert a mixture of positional isomers of unactivated linear internal olefins into α-linear alkyl-substituted heteroarenes with a single structure in high yield, without using a single-structure intermediate olefin as a reaction raw material, which can further reduce the synthesis cost.

[0035] 3. The preparation method disclosed by the present invention has good substrate applicability, and at the same time, due to the air stability and easy synthesis of the nickel catalyst, it has more practical application value. Detailed implementation manners

[0036] The present invention will be further described below in conjunction with embodiments:

[0037] Example 1: Synthesis of the catalyst Ni(IMXy)[P(OEt)3]Br2, where IMXy is [(RNCHCHNR)C] (R is 2,6-dimethyl-4-methoxyphenyl).

[0038] Under argon protection, the N-heterocyclic carbene IMXy (0.3364 g, 1.0 mmol) was added to a tetrahydrofuran solution of nickel(II) bromide bis(triethyl phosphite) (0.5508 g, 1.0 mmol), and stirred at room temperature for 4 hours. The solvent was removed under vacuum, the residue was washed with n-hexane, the obtained residue was extracted with toluene, the clear liquid was transferred out and n-hexane was added, and recrystallized at 0 o °C, filtered to obtain a red solid mixed nickel(II) complex with a yield of 86%, which was used as a catalyst in the following examples.

[0039] Elemental analysis of the product was carried out, and the results are shown in Table 1:

[0040]

[0041] NMR characterization of the product was carried out, and the results are as follows:

[0042] The product was dissolved in CDCl3 (0.4 mL), sealed, and characterized on a Unity Inova-400 NMR instrument at room temperature: 11H NMR (400 MHz, CDCl3): δ 8.68 – 8.56 (m, 2H), 8.00 (t, J J = 7.9 Hz, 1H),7.34 (d, J J = 7.5 Hz, 1H), 3.86 (qt, J J = 7.1, 3.7 Hz, 6H), 2.83 (s, 3H), 0.98(t, J J = 7.0 Hz, 9H).

[0043] The chemical structural formula of the product mixed - ligand nickel(II) complex is as follows:

[0044]

[0045] R has the following structural formula:

[0046]

[0047] Example 2: Using the nickel(II) complex as a catalyst to catalyze the hydroheteroarylation reaction of trans - 4 - octene and 1 - methylbenzimidazole

[0048] Under argon protection, in a Schlenk reaction flask, the catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), 1 - methylbenzimidazole (66.1 mg, 0.50 mmol), trans - 4 - octene (84.2 mg, 0.75 mmol) and the solvent toluene (1.5 mL) were added successively, and the reaction was carried out at 90 o °C for 36 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction. Ethyl acetate (3×3 mL) was added to the mixture for extraction. After drying over anhydrous Na2SO4, filtration was carried out, and purification was carried out by column chromatography separation (EtOAc / PE = 1:2), with a yield of 95%. The structural formula of the product is as follows:

[0049]

[0050] The product was dissolved in CDCl3 (0.4 mL), and characterized by measurement on a Unity Inova - 400 NMR instrument at room temperature: 1 1HNMR (400 MHz, CDCl3) δ 7.77 – 7.71 (m, 1H), 7.31 – 7.22 (m, 3H), 3.72 (s,3H), 2.87 (t, J J = 7.8 Hz, 2H), 1.88 (p, J= 7.6 Hz, 2H), 1.46 (p, J = 7.0 Hz,2H), 1.38 – 1.27 (m, 8H), 0.89 (t, J = 6.8 Hz, 3H).

[0051] Expansion experiment

[0052] Based on Example 2, an expansion was carried out, and the results are shown in Table 2. Group 4 is Example 2.

[0053] Table 2 Different reaction conditions and results a :

[0054]

[0055]

[0056] a Conditions: Ni(IMXy)[P(OEt)3]Br2 (2 mol%), 2a (0.5 mmol), 3a (0.75 mmol), additive (0.5 equiv.), toluene (1.5 mL), 90 °C, 36 h, under argon protection. b Using n - hexadecane as the internal standard, the yield was determined by gas chromatography analysis. c Isolated yield. d React at 80 °C. e THF(1.5 mL) as the solvent. f n - hexane (1.5 mL) as the solvent.

[0057] Based on Example 2, an expansion was carried out, and the results are shown in Table 3. Group 1 is Example 2.

[0058] Table 3 Different catalyst conditions and results a :

[0059]

[0060]

[0061] a Conditions: nickel catalyst (2 mol%), 2a (0.5 mmol), 3a (0.75 mmol), KOEt (0.5equiv.), toluene (1.5 mL), 90 °C, 36 h, under argon protection. b Using n - hexadecane as the internal standard, the yield was determined by gas chromatography analysis. c Isolated yield.

[0062] Example 3 Using a nickel(II) complex as a catalyst, the hydroheteroarylation reaction of trans-4-octene with 1-(4-methoxyphenyl)-benzimidazole was catalyzed.

[0063] Under argon protection, in a Schlenk reaction flask, the catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), 1-(4-methoxyphenyl)-benzimidazole (112.1 mg, 0.50 mmol), trans-4-octene (84.2 mg, 0.75 mmol) and the solvent toluene (1.5 mL) were successively added, and the reaction was carried out at 90 o °C for 36 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction. Ethyl acetate (3 × 3 mL) was added to the mixture for extraction. After drying over anhydrous Na2SO4, filtration was carried out, and purification was carried out by column chromatography separation (EtOAc / PE = 1:2), and the yield was 90%. The structural formula of the product is as follows:

[0064]

[0065] The product was dissolved in CDCl3 (0.4 mL), and the characterization was carried out on a Unity Inova-400 type NMR instrument at room temperature: 1 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J J = 8.0 Hz, 1H), 7.31 – 7.27 (m, 3H), 7.20 (t, J J = 7.5 Hz, 1H), 7.09 (dd, J J = 8.1, 4.5 Hz, 3H), 3.93 (s, 3H), 2.76 (t, J J = 7.8 Hz, 2H), 1.78 (p, J J = 7.6 Hz, 2H), 1.28 (m, 10H), 0.88 (t, J J = 6.9 Hz, 3H).

[0066] Example 4 Using a nickel(II) complex as a catalyst, the hydroheteroarylation reaction of trans-4-octene with 1-(2-fluorobenzyl)-benzimidazole was catalyzed.

[0067] Under argon protection, a catalyst (36.0 mg, 0.05 mmol, 10 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), 1-(2-fluorobenzyl)-benzimidazole (132.1 mg, 0.50 mmol), trans-4-octene (84.2 mg, 0.75 mmol) and the solvent toluene (1.5 mL) were successively added to a Schlenk reaction flask and reacted at 100 o °C for 60 h. After the reaction was completed, water (0.5 mL) was added to quench the reaction. Ethyl acetate (3×3 mL) was added to the mixture for extraction. After drying over anhydrous Na2SO4, filtration was carried out, and purification was carried out by column chromatography (EtOAc / PE = 1:2), and the yield was 68%. The structural formula of the product is as follows:

[0068]

[0069] The product was dissolved in CDCl3 (0.4 mL), and its characterization was measured on a Unity Inova-400 NMR instrument at room temperature: 1 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J J = 8.5 Hz, 1H), 7.36 – 7.06 (m, 5H), 7.05 – 6.91 (m, 1H), 6.75 (dd, J J = 26.3, 8.2 Hz, 1H), 5.28 (s, 2H), 2.80 (t, J J = 9.7Hz, 2H), 1.81 (p, J J = 7.7 Hz, 2H), 1.39 – 1.21 (m, 10H), 0.85 (t, J J = 6.8 Hz,3H).

[0070] Example 5: Using a nickel(II) complex as a catalyst to catalyze the hydroheteroarylation reaction of trans-4-octene with 1-(3-methoxypropyl)-benzimidazole

[0071] Under argon protection, a catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), 1-(3-methoxypropyl)-benzimidazole (95.1 mg, 0.50 mmol), trans-4-octene (84.2 mg, 0.75 mmol) and the solvent toluene (1.5 mL) were successively added to a Schlenk reaction flask and reacted at 90 oReact at 36 h under C. After the reaction is completed, add water (0.5 mL) to quench the reaction. Add ethyl acetate (3 × 3 mL) to the mixture for extraction. After drying over anhydrous Na2SO4, filter and purify by column chromatography (EtOAc / PE = 1:4). The yield is 88%. The structural formula of the product is as follows:

[0072]

[0073] Dissolve the product in CDCl3 (0.4 mL) and characterize it on a Unity Inova-400 NMR instrument at room temperature: 1 1H NMR (400 MHz, CDCl3) δ 7.71 (q, J J = 3.8 Hz, 1H), 7.34 – 7.24 (m, 1H), 7.19 (dt, J J = 7.4, 3.6 Hz, 2H), 4.19 (t, J J = 6.6 Hz, 2H), 3.31 (s, 3H), 3.28 – 3.20 (m, 2H), 2.84 (t, J J = 10.0 Hz, 2H), 2.00 (p, J J = 6.1 Hz, 2H), 1.93 – 1.81 (m, 2H), 1.50 – 1.40 (m, 2H), 1.50 – 1.40 (m, 2H), 1.39 – 1.21 (m, 8H), 0.88 (t, J J = 5.6 Hz, 3H).

[0074] Example 6: Using nickel(II) complex as a catalyst, catalyze the hydroheteroarylation reaction of trans-4-octene with 1,5,6-trimethylbenzimidazole

[0075] Under argon protection, successively add the catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), 1,5,6-trimethylbenzimidazole (80.1 mg, 0.50 mmol), trans-4-octene (84.2 mg, 0.75 mmol) and the solvent toluene (1.5 mL) into a Schlenk reaction flask. React at 90 o C for 30 h. After the reaction is completed, add water (0.5 mL) to quench the reaction. Add ethyl acetate (3 × 3 mL) to the mixture for extraction. After drying over anhydrous Na2SO4, filter and purify by column chromatography (EtOAc / PE = 1:4). The yield is 95%. The structural formula of the product is as follows:

[0076]

[0077] The product was dissolved in CDCl3 (0.4 mL), and characterized by measurement on a Unity Inova-400 NMR spectrometer at room temperature: 1 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.02 (s, 1H), 3.63 (s, 3H), 2.80 (t, J J = 7.7 Hz, 2H), 2.37 (s, 3H), 2.35 (s, 3H), 1.82 (p, J J = 7.6 Hz, 2H), 1.45 – 1.37 (m, 2H), 1.34 – 1.21 (m, 8H), 0.87 (t, J J = 5.6 Hz, 3H).

[0078] Example 7: The hydroheteroarylation reaction of trans-4-octene with 1-methyl-3-acetylindole was catalyzed using a nickel(II) complex as the catalyst

[0079] Under argon protection, a catalyst (7.2 mg, 0.01 mmol, 2 mol%), sodium tert-butoxide (24.0 mg, 0.25 mmol), 1-methyl-3-acetylindole (86.6 mg, 0.50 mmol), trans-4-octene (84.2 mg, 0.75 mmol) and the solvent toluene (1.5 mL) were successively added to a Schlenk reaction flask, and the reaction was carried out at 90 o °C for 36 h. After completion of the reaction, the reaction was quenched by adding water (0.5 mL). The mixture was extracted with ethyl acetate (3 × 3 mL), dried over anhydrous Na2SO4, filtered, and purified by column chromatography (EtOAc / PE = 1:10), with a yield of 83%. The structural formula of the product is as follows:

[0080]

[0081] The product was dissolved in CDCl3 (0.4 mL), and characterized by measurement on a Unity Inova-400 NMR spectrometer at room temperature: 1 1H NMR (400 MHz, CDCl3) δ 7.95 (dd, J J = 6.6, 2.3 Hz, 1H), 7.37 – 7.32 (m, 1H),7.27 (d, J J = 4.0 Hz, 1H), 7.10 (d, J= 8.4 Hz, 1H), 3.73 (s, 3H), 3.19 (t, J = 7.8 Hz, 2H), 2.69 (s, 3H), 1.62 (p, J = 7.5 Hz, 2H), 1.52 – 1.40 (m, 2H), 1.36 – 1.25 (m, 8H), 0.87 (t, J = 6.7 Hz, 3H).

[0082] Example 8: Using nickel(II) complex as a catalyst to catalyze the hydroheteroarylation reaction of trans-4-octene and methyl 1-methylindole-3-carboxylate

[0083] Under argon protection, in a Schlenk reaction flask, the catalyst (7.2 mg, 0.01 mmol, 2 mol%), sodium tert-butoxide (24.0 mg, 0.25 mmol), methyl 1-methylindole-3-carboxylate (94.6 mg, 0.50 mmol), trans-4-octene (84.2 mg, 0.75 mmol) and solvent toluene (1.5 mL) were successively added, and the reaction was carried out at 90 o °C for 30 h. After the reaction was completed, water (0.5 mL) was added to quench the reaction. Ethyl acetate (3 × 3 mL) was added to the mixture for extraction. After drying over anhydrous Na2SO4, filtration was carried out, and purification was carried out by column chromatography (EtOAc / PE = 1:10). The yield was 68%, and the structural formula of the product was as follows:

[0084]

[0085] The product was dissolved in CDCl3 (0.4 mL), and the characterization was carried out on a Unity Inova-400 NMR spectrometer at room temperature: 1 1H NMR (400 MHz, CDCl3) δ 8.15 – 8.09 (m, 1H), 7.32 – 7.29 (m, 1H), 7.25 – 7.21 (m, 2H), 3.93 (s, 3H), 3.72 (s, 3H), 3.20 (t, J = 7.9 Hz, 2H), 1.63 (p, J = 7.6 Hz, 2H), 1.45 (p, J = 6.9 Hz, 2H), 1.34 – 1.26 (m, 8H), 0.87 (t, J = 6.5 Hz, 3H).

[0086] Example 9: Using a nickel(II) complex as a catalyst to catalyze the hydroheteroarylation reaction of trans-4-octene with benzofuran

[0087] Under argon protection, in a Schlenk reaction flask, the catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), benzofuran (59.1 mg, 0.50 mmol), trans-4-octene (84.2 mg, 0.75 mmol) and the solvent toluene (1.5 mL) were successively added, and the reaction was carried out at 60 o °C for 36 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction. Ethyl acetate (3 × 3 mL) was added to the mixture for extraction. After drying over anhydrous Na2SO4, filtration was carried out, and purification was carried out by column chromatography (separated with pure petroleum ether), and the yield was 88%. The structural formula of the product is as follows:

[0088]

[0089] The product was dissolved in CDCl3 (0.4 mL), and the characterization was carried out on a Unity Inova-400 NMR instrument at room temperature: 1 1H NMR (400 MHz, CDCl3) δ 7.58 – 7.51 (m, 1H), 7.48 (d, J J = 6.1 Hz, 1H), 7.27 –7.21 (m, 2H), 6.43 (s, 1H), 2.82 (t, J J = 7.6 Hz, 2H), 1.81 (p, J J = 7.5 Hz,2H), 1.47 – 1.33 (m, 10H), 0.95 (t, J J = 6.9 Hz, 3H).

[0090] Example 10: Using a nickel(II) complex as a catalyst to catalyze the hydroheteroarylation reaction of trans-4-octene with 5-methoxybenzofuran

[0091] Under argon protection, in a Schlenk reaction flask, the catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), 5-methoxybenzofuran (74.1 mg, 0.50 mmol), trans-4-octene (84.2 mg, 0.75 mmol) and the solvent toluene (1.5 mL) were successively added, and the reaction was carried out at 60 oReact at 60 °C for 36 h. After the reaction is completed, add water (0.5 mL) to quench the reaction. Add ethyl acetate (3 × 3 mL) to the mixture for extraction. After drying over anhydrous Na2SO4, filter and purify by column chromatography (separated with pure petroleum ether). The yield is 86%. The structural formula of the product is as follows:

[0092]

[0093] Dissolve the product in CDCl3 (0.4 mL) and characterize it on a Unity Inova-400 NMR instrument at room temperature: 1 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.23 (m, 1H), 6.95 (t, J J = 3.3 Hz, 1H), 6.79(dd, J J = 9.0, 3.1 Hz, 1H), 6.30 (d, J J = 3.4 Hz, 1H), 3.81 (s, 3H), 2.72 (t, J J = 7.3 Hz, 2H), 1.72 (p, J J = 9.2, 7.7 Hz, 2H), 1.42 – 1.25 (m, 10H), 0.88 (t, J J = 6.5 Hz, 3H).

[0094] Example 11: Using a nickel(II) complex as a catalyst to catalyze the hydroheteroarylation reaction of trans-4-octene and furan

[0095] Under argon protection, successively add the catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), furan (34.0 mg, 0.50 mmol), trans-4-octene (84.2 mg, 0.75 mmol) and the solvent toluene (1.5 mL) into a Schlenk reaction flask. React at 60 o °C for 36 h. After the reaction is completed, add water (0.5 mL) to quench the reaction. Add ethyl acetate (3 × 3 mL) to the mixture for extraction. After drying over anhydrous Na2SO4, filter and purify by column chromatography (separated with pure petroleum ether). The yield is 85%. The structural formula of the product is as follows:

[0096]

[0097] Dissolve the product in CDCl3 (0.4 mL) and characterize it on a Unity Inova-400 NMR instrument at room temperature: 1HNMR (400 MHz, CDCl3) δ 7.29 (d, J J = 1.9 Hz, 1H), 6.27 (dd, J J = 3.2, 1.9 Hz,1H), 5.96 (d, J J = 3.2 Hz, 1H), 2.61 – 2.55 (m, 2H), 1.66 – 1.60 (m, 2H), 1.35– 1.28 (m, 10H), 0.87 (t, J J = 6.8 Hz, 3H).

[0098] Example 12: Using a nickel(II) complex as a catalyst, catalyze the hydroheteroarylation reaction of trans-4-octene and 2-methylfuran

[0099] Under argon protection, successively add the catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), 2-methylfuran (41.1 mg, 0.50 mmol), trans-4-octene (84.2 mg, 0.75 mmol) and the solvent toluene (1.5 mL) into a Schlenk reaction flask, and react at 60 o °C for 36 hours. After the reaction is completed, add water (0.5 mL) to quench the reaction. Add ethyl acetate (3 × 3 mL) to the mixture for extraction. After drying over anhydrous Na2SO4, filter, and purify by column chromatography (separated with pure petroleum ether). The yield is 82%. The structural formula of the product is as follows:

[0100]

[0101] Dissolve the product in CDCl3 (0.4 mL), and characterize it on a Unity Inova-400 NMR instrument at room temperature: 1 HNMR (400 MHz, CDCl3) δ 7.03 (d, J J = 31.2 Hz, 1H), 5.83 (s, 1H), 2.55 (t, J J =7.6 Hz, 2H), 2.28 (s, 3H), 1.66 – 1.56 (m, 2H), 1.33 – 1.24 (m, 10H), 0.87 (t, J J = 6.7 Hz, 3H).

[0102] Example 13: Using a nickel(II) complex as a catalyst, catalyze the hydroheteroarylation reaction of cis-4-octene and 1-methylbenzimidazole

[0103] Under argon protection, a catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), 1-methylbenzimidazole (66.1 mg, 0.50 mmol), cis-4-octene (84.2 mg, 0.75 mmol) and the solvent toluene (1.5 mL) were successively added to a Schlenk reaction flask and reacted at 90 o °C for 36 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction. Ethyl acetate (3 × 3 mL) was added to the mixture for extraction. After drying over anhydrous Na2SO4, filtration was carried out, and purification was carried out by column chromatography (EtOAc / PE = 1:2), with a yield of 92%. The structural formula of the product is as follows:

[0104]

[0105] The product was dissolved in CDCl3 (0.4 mL), and the characterization was measured on a Unity Inova-400 NMR instrument at room temperature: 1 1H NMR (400 MHz, CDCl3) δ 7.77 – 7.71 (m, 1H), 7.31 – 7.22 (m, 3H), 3.72 (s,3H), 2.87 (t, J J = 7.8 Hz, 2H), 1.88 (p, J J = 7.6 Hz, 2H), 1.46 (p, J J = 7.0 Hz,2H), 1.38 – 1.27 (m, 8H), 0.89 (t, J J = 6.8 Hz, 3H).

[0106] Example 14: Hydroheteroarylation reaction of cis / trans-4-octene (1:1 mixture) with 1-methylbenzimidazole catalyzed by a nickel(II) complex

[0107] Under argon protection, a catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), 1-methylbenzimidazole (66.1 mg, 0.50 mmol), cis / trans-4-octene (1:1 mixture) (84.2 mg, 0.75 mmol) and the solvent toluene (1.5 mL) were successively added to a Schlenk reaction flask and reacted at 90 o °C for 36 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction. Ethyl acetate (3 × 3 mL) was added to the mixture for extraction. After drying over anhydrous Na2SO4, filtration was carried out, and purification was carried out by column chromatography (EtOAc / PE = 1:2), with a yield of 94%. The structural formula of the product is as follows:

[0108]

[0109] The product was dissolved in CDCl3 (0.4 mL), and characterized by measurement on a Unity Inova-400 NMR spectrometer at room temperature: 1 1H NMR (400 MHz, CDCl3) δ 7.77 – 7.71 (m, 1H), 7.31 – 7.22 (m, 3H), 3.72 (s, 3H), 2.87 (t, J J = 7.8 Hz, 2H), 1.88 (p, J J = 7.6 Hz, 2H), 1.46 (p, J J = 7.0 Hz, 2H), 1.38 – 1.27 (m, 8H), 0.89 (t, J J = 6.8 Hz, 3H).

[0110] Example 15: Hydroheteroarylation of cis / trans-3-octene with 1-methylbenzimidazole catalyzed by a nickel(II) complex

[0111] Under argon protection, a catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), 1-methylbenzimidazole (66.1 mg, 0.50 mmol), cis / trans-3-octene (84.2 mg, 0.75 mmol) and solvent toluene (1.5 mL) were successively added to a Schlenk reaction flask, and the reaction was carried out at 90 o °C for 36 h. After the reaction was completed, water (0.5 mL) was added to quench the reaction. Ethyl acetate (3 × 3 mL) was added to the mixture for extraction, dried over anhydrous Na2SO4, filtered, and purified by column chromatography (EtOAc / PE = 1:2) with a yield of 94%. The structural formula of the product is as follows:

[0112]

[0113] The product was dissolved in CDCl3 (0.4 mL), and characterized by measurement on a Unity Inova-400 NMR spectrometer at room temperature: 1 1H NMR (400 MHz, CDCl3) δ 7.77 – 7.71 (m, 1H), 7.31 – 7.22 (m, 3H), 3.72 (s, 3H), 2.87 (t, J J = 7.8 Hz, 2H), 1.88 (p, J J = 7.6 Hz, 2H), 1.46 (p,J = 7.0 Hz, 2H), 1.38 – 1.27 (m, 8H), 0.89 (t, J = 6.8 Hz, 3H).

[0114] Example 16: Using nickel(II) complex as a catalyst to catalyze the hydroheteroarylation reaction of cis / trans-2-octene with 1-methylbenzimidazole

[0115] Under argon protection, in a Schlenk reaction flask, the catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), 1-methylbenzimidazole (66.1 mg, 0.50 mmol), cis / trans-2-octene (84.2 mg, 0.75 mmol) and the solvent toluene (1.5 mL) were successively added, and the reaction was carried out at 90 o °C for 36 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction. Ethyl acetate (3×3 mL) was added to the mixture for extraction. After drying over anhydrous Na2SO4, filtration was carried out, and purification was carried out by column chromatography separation (EtOAc / PE = 1:2), with a yield of 92%. The structural formula of the product is as follows:

[0116]

[0117] The product was dissolved in CDCl3 (0.4 mL), and its characterization was measured on a Unity Inova-400 NMR spectrometer at room temperature: 1 1H NMR (400 MHz, CDCl3) δ 7.77 – 7.71 (m, 1H), 7.31 – 7.22 (m, 3H), 3.72 (s, 3H), 2.87 (t, J = 7.8 Hz, 2H), 1.88 (p, J = 7.6 Hz, 2H), 1.46 (p, J = 7.0 Hz, 2H), 1.38 – 1.27 (m, 8H), 0.89 (t, J = 6.8 Hz, 3H).

[0118] Example 17: Using nickel(II) complex as a catalyst to catalyze the hydroheteroarylation reaction of trans-5-decene with 1-methylbenzimidazole

[0119] Under argon protection, a catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), 1-methylbenzimidazole (66.1 mg, 0.50 mmol), trans-5-decene (101.0 mg, 0.75 mmol) and the solvent toluene (1.5 mL) were successively added to a Schlenk reaction flask and reacted at 90 o °C for 36 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction. Ethyl acetate (3 × 3 mL) was added to the mixture for extraction. After drying over anhydrous Na2SO4, filtration was carried out, and purification was performed by column chromatography (EtOAc / PE = 1:4) with a yield of 90%. The structural formula of the product is as follows:

[0120]

[0121] The product was dissolved in CDCl3 (0.4 mL), and its characterization was determined on a Unity Inova-400 NMR spectrometer at room temperature: 1 1H NMR (400 MHz, CDCl3) δ 7.80 – 7.66 (m, 1H), 7.34 – 7.14 (m, 3H), 3.69 (s,3H), 2.85 (t, J J = 7.8 Hz, 2H), 1.87 (p, J J = 7.5 Hz, 2H), 1.50 – 1.41 (m, 2H),1.39 – 1.21 (m, 12H), 0.89 (t, J J = 6.8 Hz, 3H).

[0122] Example 18: Hydroheteroarylation reaction of trans-6-dodecene with 1-methylbenzimidazole catalyzed by a nickel(II) complex

[0123] Under argon protection, a catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), 1-methylbenzimidazole (66.1 mg, 0.50 mmol), trans-6-dodecene (126.2 mg, 0.75 mmol) and the solvent toluene (1.5 mL) were successively added to a Schlenk reaction flask and reacted at 90 o °C for 36 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction. Ethyl acetate (3 × 3 mL) was added to the mixture for extraction. After drying over anhydrous Na2SO4, filtration was carried out, and purification was performed by column chromatography (EtOAc / PE = 1:4) with a yield of 82%. The structural formula of the product is as follows:

[0124]

[0125] The product was dissolved in CDCl3 (0.4 mL), and its characterization was determined on a Unity Inova-400 NMR spectrometer at room temperature: 1 1H NMR (400 MHz, CDCl3) δ 7.75 – 7.70 (m, 1H), 7.26 – 7.19 (m, 3H), 3.66 (s,3H), 2.83 (t, J J = 7.8 Hz, 2H), 1.86 (p, J J = 7.5 Hz, 2H), 1.50 – 1.40 (m, 2H),1.37 – 1.22 (m, 18H), 0.89 (t, J J = 6.8 Hz, 3H).

[0126] In the present invention, an air-stable mixed-ligand nickel(II) complex Ni(IMXy)[P(OEt)3]Br2 (where IMXy is [(RNCHCHNR)C] and R is 2,6-dimethyl-4-methoxyphenyl) was used as a catalyst. In the presence of an organic base, a new synthetic method for α-linear alkyl-substituted heteroarenes was provided through the hydroheteroarylation reaction of unactivated linear internal olefins and heteroarenes. In particular, the synthetic method provided by the present invention can convert a mixture of positional isomers of unactivated linear internal olefins into α-linear alkyl-substituted heteroarenes with a single structure in high yield without using a single-structure internal olefin as a reaction raw material, which can further reduce the synthesis cost. Furthermore, the preparation method disclosed in the present invention has good substrate applicability, and due to the air stability and easy synthesis of the nickel catalyst, it has more practical application value.

Claims

1. A method for synthesizing α - linear alkyl - substituted heteroarenes, characterized in that, It includes the following steps. In an inert gas atmosphere, in the presence of a nickel catalyst and an organic base, an α-linear alkyl-substituted heteroarene is obtained by reacting an unactivated linear intermediate olefin compound with a heteroaromatic compound. The reaction is carried out in toluene. The nickel catalyst is Ni(IMXy)[P(OEt)3]Br2, and IMXy has the following structural formula: ； The organic base is potassium ethoxide; The heteroaromatic compound is a benzimidazole compound or a benzofuran or furan compound; The unactivated linear intermediate olefin compound is represented by the following chemical structural formula: ； wherein, R 7 , R 8 is an alkyl group; The benzimidazole compound is represented by the following chemical structural formula: ； wherein, R 1 is methyl, aryl, benzyl or alkoxy, R 2 and R 3 are independently selected from a hydrogen atom or methyl; The benzofuran or furan compound is represented by the following chemical structural formula: or ; wherein, R 5 is a hydrogen atom or a methoxy group; R 6 is a hydrogen atom or a methyl group; The chemical structural formula of the α-linear alkyl-substituted heteroarene is as follows: or or ; Among them, R 1 , R 2 , R 3 , R 5 or R 6 is from a heteroaromatic compound, and R 9 is from an unactivated linear internal olefin compound. Specifically, in the chemical structural formula of the internal olefin compound, after the C=C migrates to one end, it obtains a hydrogen to become a linear alkyl group.

2. A method for synthesizing α - linear alkyl - substituted heteroarenes, characterized in that, It includes the following steps. In an inert gas atmosphere, in the presence of a nickel catalyst and an organic base, an α-linear alkyl-substituted heteroarene is obtained by reacting an unactivated linear intermediate olefin compound with a heteroaromatic compound. The reaction is carried out in toluene. The nickel catalyst is Ni(IMXy)[P(OEt)3]Br2, and IMXy has the following structural formula: ； The organic base is potassium ethoxide; The heteroaromatic compound is 1-methyl-3-acetylindole or methyl 1-methylindole-3-carboxylate; The unactivated linear intermediate olefin compound is trans-4-octene; The chemical structural formula of the α-linear alkyl-substituted heteroarene is as follows: 、 。 3. The method for synthesizing α - linear alkyl - substituted heteroarenes according to claim 1 or 2, characterized in that, The inert gas is nitrogen or argon.

4. The method for synthesizing α - linear alkyl - substituted heteroarenes according to claim 1 or 2, characterized in that, The temperature of the reaction is 60-130 °C and the time is 30-60 hours.

5. The method for synthesizing α - linear alkyl - substituted heteroarenes according to claim 1 or 2, characterized in that, The molar ratio of the nickel catalyst, the organic base, the heteroaromatic compound, and the unactivated linear intermediate olefin compound is (0.02-0.10):0.5:1:1.5.

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