WO2024026596A1 - METHOD FOR SYNTHESIZING α-LINEAR ALKYL SUBSTITUTED HETEROARENE - Google Patents

Abstract

Disclosed in the present invention is a novel method for synthesizing α-linear alkyl substituted heteroarene. In the presence of organic alkali, α-linear alkyl substituted heteroarene is synthesized by a hydroheteroarylation reaction of heteroarene and non-activated linear intermediate olefin by using nickel (II) complex Ni(IMXy)[P(OEt)₃]Br₂ as a catalyst (IMXy is [(RNCHCHNR)C], and R is 2,6-dimethyl-4-methoxyphenyl). Compared with the prior art, the present invention uses nickel to catalyze the tandem isomerization/hydroheteroarylation reaction of non-activated linear intermediate olefin and heteroarene, and can convert cheap and easily available intermediate olefin or an isomer mixture thereof into linear alkyl substituted heteroarene having a high added value. The reaction selectivity is good, the product yield is high, and a novel method for synthesizing α-linear alkyl substituted heteroarene is provided.

Description

A method for synthesizing α-linear alkyl-substituted heteroaromatic hydrocarbons Technical field

The invention belongs to the technical fields of metal catalysis and organic synthesis preparation, and specifically relates to a method for synthesizing α-linear alkyl-substituted heteroaromatic hydrocarbons catalyzed by nickel complexes.

Background technique

As an important structural unit, linear alkyl-substituted heteroaromatic hydrocarbons are widely found in natural products, bioactive molecules and pharmaceutical molecules ( Med. Chem. Res. 2016 , 25 , 173) and have important synthetic value. Alkenes are a type of synthetic raw materials that are cheap, easy to obtain, and have variable structures. Transition metal-catalyzed olefin hydroheteroarylation reactions are 100% atom economical, providing a green synthetic chemistry solution for the synthesis of linear alkyl-substituted heteroaromatics. A new approach to ideas and developed rapidly in the past 20 years. In this field, there is currently a relatively mature technology for synthesizing linear alkyl-substituted heteroaromatics using terminal olefins as raw materials ( Chem. Rev. 2017 , 117 , 9333). However, there are very few reports on using intermediate olefins as raw materials. For example, Shi Zhuangzhi and others used the precious metal monovalent rhodium catalyst to achieve linear alkylation of the C7-position of indole compounds with activated intermediate olefins (such as α,β-unsaturated esters, α,β-unsaturated ketones, etc.) , but does not involve non-activated linear intermediate olefins ( J. Am. Chem. Soc. 2018 , 140 , 6062). In addition, the existing technology uses an air-sensitive zero-valent nickel catalyst to synthesize linear octyl-substituted trifluorotoluene through the hydroarylation reaction of 4-octene and trifluorotoluene, but does not extend the heteroaromatic substrate. Therefore, it would be original to use cheap, air-stable divalent nickel complexes as catalysts to realize the hydroheteroarylation reaction of non-activated linear intermediate olefins and a series of heteroaromatics, which can be α - Linear alkyl-substituted heteroaromatics provide new synthesis methods, which have obvious innovation and application prospects.

technical problem

The object of the present invention is to provide a new method for synthesizing α-linear alkyl-substituted heteroaromatics with high selectivity, high yield and low cost, that is, using air-stable mixed nickel (II) complex Ni(IMXy )[P(OEt) ₃ ]Br ₂ is the catalyst (IMXy is [(RNCHCHNR)C], R is 2,6-dimethyl-4-methoxyphenyl), in the presence of organic base, through non-activation α-Linear chain alkyl-substituted heteroaromatics are synthesized through the cascade isomerization/hydroheteroarylation reaction of linear intermediate olefins and heteroaromatics.

Technical solutions

The present invention adopts the following technical solution: a method for synthesizing α-linear alkyl-substituted heteroaromatic hydrocarbons, which includes the following steps: in an inert gas atmosphere, in the presence of a nickel catalyst and an organic base, by reacting a non-activated linear intermediate olefin compound with a heteroaromatic Aromatic hydrocarbon compounds react to obtain α-linear alkyl-substituted heteroaromatic hydrocarbons.

Application of nitrogen-heterocyclic carbene-based mixed nickel(II) complex Ni(IMXy)[P(OEt) ₃ ]Br ₂ as a catalyst in the synthesis of α-linear alkyl-substituted heteroarenes.

In the above technical solution, the inert gas is nitrogen or argon.

In the above 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 separated and purified by column chromatography to obtain the product, which can be quantitatively analyzed for yield.

In the above 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.

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

In the above technical solution, the molar ratio of nickel catalyst, organic base, heteroaromatic compound and 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, the amount of non-activated linear intermediate olefin compounds is 1.5 times that of heteroaromatic compounds, the amount of potassium ethoxide is 0.5 times that of heteroaromatic compounds, and the amount of catalyst is the molar amount of heteroaromatic compounds. 2%.

In the present invention, heteroaromatic compounds include benzimidazole compounds, specifically expressed by the following chemical structural formula: Among them, R ¹ is a methyl group, an aryl group, a benzyl group or an alkoxy group, and R ² and R ³ are selected from a hydrogen atom or a methyl group.

In the present invention, heteroaromatic compounds include indole compounds, specifically expressed by the following chemical structural formula: Among them, R ⁴ is acyl group.

In the present invention, heteroaromatic compounds include benzofurans or furan compounds, specifically expressed by the following chemical structural formula: or .

Among them, R ⁵ is a hydrogen atom or a methoxy group; R ⁶ is a hydrogen atom or a methyl group.

In the present invention, the non-activated linear intermediate olefin compound is expressed by the following chemical structural formula: .

Among them, R ⁷ and R ⁸ are alkyl groups; specifically, non-activated 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.

In the present invention, the chemical structural formula of α-linear alkyl-substituted heteroaromatic hydrocarbons is as follows: or or or .

Among them, R ¹ , R ² , R ³ , R ⁴ , R ⁵ or R ⁶ come from heteroaromatic compounds, and R ⁹ comes from non-activated linear intermediate olefin compounds. Specifically, in the chemical structural formula of intermediate olefin compounds, C=C migrates to a certain After one end, a straight-chain alkyl group converted from hydrogen is obtained.

The technical solution of the present invention, taking heteroaromatic compounds (benzimidazole compounds) as an example, can be expressed as follows: .

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

beneficial effects

Due to the application of the above technical solution, the present invention has the following advantages: 1. The present invention uses air-stable mixed nickel (II) complex Ni(IMXy)[P(OEt) ₃ ]Br ₂ as the catalyst (IMXy is [( RNCHCHNR)C], R is 2,6-dimethyl-4-methoxyphenyl), through the hydroheteroarylation reaction of non-activated linear intermediate olefins and heteroarenes in the presence of organic bases, is α -Linear alkyl-substituted heteroaromatics provide a new synthetic method.

2. The synthesis method provided by the present invention can convert the positional isomer mixture of non-activated linear intermediate olefins into α-linear alkyl-substituted heteroaromatics with a single structure in high yield, without using a single structure intermediate olefin for the reaction. raw materials, which can further reduce synthesis costs.

3. The preparation method disclosed in the present invention has good substrate applicability, and at the same time, because of the air stability of the nickel catalyst and its ease of synthesis, it has more practical application value.

Embodiments of the invention

The present invention will be further described below in conjunction with the examples: Example 1: Synthesis of catalyst Ni(IMXy)[P(OEt) ₃ ]Br ₂ , IMXy is [(RNCHCHNR)C] (R is 2,6-dimethyl- 4-methoxyphenyl).

Under argon protection, nitrogen heterocyclic carbene IMXy (0.3364 g, 1.0 mmol) was added to the tetrahydrofuran solution of bis(triethyl phosphite)nickel (II) bromide (0.5508 g, 1.0 mmol), and stirred at room temperature for 4 hours, remove the solvent in vacuum, wash the residue with n-hexane, extract the residue with toluene, transfer the clear liquid and add n-hexane, recrystallize at 0 ^o C, filter, and obtain a red solid mixed nickel (II) complex , yield 86%, used as catalyst in the following examples.

Elemental analysis was performed on the product, and the results are shown in Table 1: .

The product was characterized by nuclear magnetic resonance, and the results are as follows: The product was dissolved in CDCl ₃ (0.4 mL), sealed, and characterized on a Unity Inova-400 NMR instrument at room temperature: ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.68 – 8.56 (m, 2H), 8.00 (t, J = 7.9 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 3.86 (qt, J = 7.1, 3.7 Hz, 6H), 2.83 ( s, 3H), 0.98 (t, J = 7.0 Hz, 9H).

The chemical structural formula of the product mixed nickel(II) complex is as follows: .

R has the following structural formula: .

Example 2 A nickel(II) complex is used as a catalyst to catalyze the hydroheteroarylation reaction of trans-4-octene and 1-methylbenzimidazole.

Under argon protection, add catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), and 1-methylbenzimidazole (66.1 mg, 0.50 mg) into the Schlenk reaction flask. mol), trans-4-octene (84.2 mg, 0.75 mmol) and solvent toluene (1.5 ml), react at 90 ^° C for 36 hours. At the end of the reaction, water (0.5 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 3 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and purified by column chromatography (EtOAc/PE = 1 :2), the yield is 95%, and the product structural formula is as follows: .

The product was dissolved in CDCl ₃ (0.4 mL), and characterized on a Unity Inova-400 NMR instrument at room temperature: ¹ H NMR (400 MHz, CDCl ₃ ) 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).

Expanded experiment: Based on the second embodiment, the experiment was expanded. The results are shown in Table 2. The fourth group is the second embodiment.

Table 2 Different reaction conditions and ^resultsa : .

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

On the basis of Example 2, the results are shown in Table 3. The first group is Example 2.

Table 3 Different catalyst conditions and ^resultsa : .

.

^a Conditions: Nickel catalyst (2 mol%), 2a (0.5 mmol), 3a (0.75 mmol), KOEt (0.5 equiv.), toluene (1.5 mL), 90 °C, 36 h, argon protection. ^b Use positive Hexadecane was used as an internal standard, and the yield was determined by gas chromatography analysis. ^c Isolation yield.

Example 3 A nickel(II) complex is used as a catalyst to catalyze the hydroheteroarylation reaction of trans-4-octene and 1-(4-methoxyphenyl)-benzimidazole.

Under argon protection, add catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), and 1-(4-methoxyphenyl)-benzene in order in the Schlenk reaction flask. Imidazoles (112.1 mg, 0.50 mmol), trans-4-octene (84.2 mg, 0.75 mmol) and solvent toluene (1.5 ml) were reacted at 90 ^° C for 36 hours. At the end of the reaction, water (0.5 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 3 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and purified by column chromatography (EtOAc/PE = 1 :2), the yield is 90%, and the product structural formula is as follows.

.

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

Example 4 A nickel(II) complex is used as a catalyst to catalyze the hydroheteroarylation reaction of trans-4-octene and 1-(2-fluorobenzyl)-benzimidazole.

Under argon protection, add catalyst (36.0 mg, 0.05 mmol, 10 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), and 1-(2-fluorobenzyl)-benzimidazole in order in the Schlenk reaction flask. (132.1 mg, 0.50 mmol), trans-4-octene (84.2 mg, 0.75 mmol) and solvent toluene (1.5 ml) were reacted at 100 ^° C for 60 hours. At the end of the reaction, water (0.5 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 3 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and purified by column chromatography (EtOAc/PE = 1 :2), the yield is 68%, and the product structural formula is as follows.

.

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

Example 5 A nickel(II) complex is used as a catalyst to catalyze the hydroheteroarylation reaction of trans-4-octene and 1-(3-methoxypropyl)-benzimidazole.

Under argon protection, add catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), and 1-(3-methoxypropyl)-benzene in sequence to the Schlenk reaction flask. Imidazoles (95.1 mg, 0.50 mmol), trans-4-octene (84.2 mg, 0.75 mmol) and solvent toluene (1.5 ml) were reacted at 90 ^° C for 36 hours. At the end of the reaction, water (0.5 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 3 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and purified by column chromatography (EtOAc/PE = 1 :4), the yield is 88%, and the product structural formula is as follows.

.

The product was dissolved in CDCl ₃ (0.4 mL), and characterized on a Unity Inova-400 NMR instrument at room temperature: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.71 (q, J = 3.8 Hz, 1H), 7.34 – 7.24 (m, 1H), 7.19 (dt, J = 7.4, 3.6 Hz, 2H), 4.19 (t, J = 6.6 Hz, 2H), 3.31 (s, 3H), 3.28 – 3.20 (m, 2H), 2.84 (t, J = 10.0 Hz, 2H), 2.00 (p, 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 = 5.6 Hz, 3H).

Example 6 A nickel(II) complex is used as a catalyst to catalyze the hydroarylation reaction of trans-4-octene and 1,5,6-trimethylbenzimidazole.

Under argon protection, add catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), and 1,5,6-trimethylbenzimidazole ( 80.1 mg, 0.50 mmol), trans-4-octene (84.2 mg, 0.75 mmol) and solvent toluene (1.5 ml) were reacted at 90 ^° C for 30 hours. At the end of the reaction, water (0.5 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 3 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and purified by column chromatography (EtOAc/PE = 1 :4), the yield is 95%, and the product structural formula is as follows.

.

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

Example 7 A nickel(II) complex is used as a catalyst to catalyze the hydroheteroarylation reaction of trans-4-octene and 1-methyl-3-acetylindole.

Under argon protection, add catalyst (7.2 mg, 0.01 mmol, 2 mol%), sodium tert-butoxide (24.0 mg, 0.25 mmol), and 1-methyl-3-acetylindole in order in the Schlenk reaction flask. (86.6 mg, 0.50 mmol), trans-4-octene (84.2 mg, 0.75 mmol) and solvent toluene (1.5 ml) were reacted at 90 ^° C for 36 hours. At the end of the reaction, water (0.5 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 3 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and purified by column chromatography (EtOAc/PE = 1 :10), the yield is 83%, and the product structural formula is as follows.

.

The product was dissolved in CDCl ₃ (0.4 mL), and characterized on a Unity Inova-400 NMR instrument at room temperature: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95 (dd, J = 6.6, 2.3 Hz, 1H) , 7.37 – 7.32 (m, 1H), 7.27 (d, 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 ).

Example 8 A nickel(II) complex is used as a catalyst to catalyze the hydroheteroarylation reaction of trans-4-octene and 1-methylindole-3-carboxylic acid methyl ester.

Under argon protection, add catalyst (7.2 mg, 0.01 mmol, 2 mol%), sodium tert-butoxide (24.0 mg, 0.25 mmol), and 1-methylindole-3-carboxylic acid in the Schlenk reaction flask. Methyl ester (94.6 mg, 0.50 mmol), trans-4-octene (84.2 mg, 0.75 mmol) and solvent toluene (1.5 ml) were reacted at 90 ^° C for 30 hours. At the end of the reaction, water (0.5 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 3 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and purified by column chromatography (EtOAc/PE = 1 :10), the yield is 68%, and the product structural formula is as follows.

.

The product was dissolved in CDCl ₃ (0.4 mL), and characterized on a Unity Inova-400 NMR instrument at room temperature: ¹ H NMR (400 MHz, CDCl ₃ ) 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).

Example 9 A nickel(II) complex is used as a catalyst to catalyze the hydroheteroarylation reaction of trans-4-octene and benzofuran.

Under argon protection, add catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), benzofuran (59.1 mg, 0.50 mmol), reaction -4-Octene (84.2 mg, 0.75 mmol) and solvent toluene (1.5 ml) were reacted at 60 ^o C for 36 hours. At the end of the reaction, add water (0.5 ml) to quench the reaction, add ethyl acetate (3 × 3 ml) to the mixture for extraction, dry over anhydrous Na ₂ SO ₄ , filter, and purify by column chromatography (separate with pure petroleum ether) , the yield is 88%, and the product structural formula is as follows.

.

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

Example 10 A nickel(II) complex is used as a catalyst to catalyze the hydroheteroarylation reaction of trans-4-octene and 5-methoxybenzofuran.

Under argon protection, add catalyst (7.2 mg, 0.01 mmol, 2 mol), potassium ethoxide (21.0 mg, 0.25 mmol), and 5-methoxybenzofuran (74.1 mg, 0.50 mmol) into the Schlenk reaction flask in sequence. mol), trans-4-octene (84.2 mg, 0.75 mmol) and solvent toluene (1.5 ml), reacted at 60 ^o C for 36 hours. At the end of the reaction, add water (0.5 ml) to quench the reaction, add ethyl acetate (3 × 3 ml) to the mixture for extraction, dry over anhydrous Na ₂ SO ₄ , filter, and purify by column chromatography (separate with pure petroleum ether) , the yield is 86%, and the product structural formula is as follows.

.

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

Example 11 A nickel(II) complex is used as a catalyst to catalyze the hydroheteroarylation reaction of trans-4-octene and furan.

Under argon protection, add catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), furan (34.0 mg, 0.50 mmol), and trans-4 in sequence to the Schlenk reaction flask. - Octene (84.2 mg, 0.75 mmol) and solvent toluene (1.5 ml) were reacted at 60 ^o C for 36 hours. At the end of the reaction, add water (0.5 ml) to quench the reaction, add ethyl acetate (3 × 3 ml) to the mixture for extraction, dry over anhydrous Na ₂ SO ₄ , filter, and purify by column chromatography (separate with pure petroleum ether) , the yield is 85%, and the product structural formula is as follows.

.

The product was dissolved in CDCl ₃ (0.4 mL), and characterized on a Unity Inova-400 NMR instrument at room temperature: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.29 (d, J = 1.9 Hz, 1H), 6.27 (dd, J = 3.2, 1.9 Hz, 1H), 5.96 (d, 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 = 6.8 Hz, 3H).

Example 12 A nickel(II) complex is used as a catalyst to catalyze the hydroheteroarylation reaction of trans-4-octene and 2-methylfuran.

Under argon protection, add catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), and 2-methylfuran (41.1 mg, 0.50 mmol) into the Schlenk reaction flask in sequence. , trans-4-octene (84.2 mg, 0.75 mmol) and solvent toluene (1.5 ml), react at 60 ^o C for 36 hours. At the end of the reaction, add water (0.5 ml) to quench the reaction, add ethyl acetate (3 × 3 ml) to the mixture for extraction, dry over anhydrous Na ₂ SO ₄ , filter, and purify by column chromatography (separate with pure petroleum ether) , the yield is 82%, and the product structural formula is as follows.

.

The product was dissolved in CDCl ₃ (0.4 mL), and characterized on a Unity Inova-400 NMR instrument at room temperature: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.03 (d, J = 31.2 Hz, 1H), 5.83 (s, 1H), 2.55 (t, 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 = 6.7 Hz, 3H).

Example 13 A nickel(II) complex is used as a catalyst to catalyze the hydroarylation reaction of cis-4-octene and 1-methylbenzimidazole.

Under argon protection, add catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), and 1-methylbenzimidazole (66.1 mg, 0.50 mg) into the Schlenk reaction flask. mol), cis-4-octene (84.2 mg, 0.75 mmol) and solvent toluene (1.5 ml), reacted at 90 ^° C for 36 hours. At the end of the reaction, water (0.5 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 3 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and purified by column chromatography (EtOAc/PE = 1 :2), the yield is 92%, and the product structural formula is as follows.

.

The product was dissolved in CDCl ₃ (0.4 mL), and characterized on a Unity Inova-400 NMR instrument at room temperature: ¹ H NMR (400 MHz, CDCl ₃ ) 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).

Example 14 A nickel(II) complex was used as a catalyst to catalyze the hydroheteroarylation reaction of cis/trans-4-octene (1:1 mixture) and 1-methylbenzimidazole.

Under argon protection, add catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), and 1-methylbenzimidazole (66.1 mg, 0.50 mg) into the Schlenk reaction flask. mol), cis/trans-4-octene (1:1 mixture) (84.2 mg, 0.75 mmol) and solvent toluene (1.5 ml), react at 90 ^o C for 36 hours. At the end of the reaction, water (0.5 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 3 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and purified by column chromatography (EtOAc/PE = 1 :2), the yield is 94%, and the product structural formula is as follows.

.

The product was dissolved in CDCl ₃ (0.4 mL), and characterized on a Unity Inova-400 NMR instrument at room temperature: ¹ H NMR (400 MHz, CDCl ₃ ) 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).

Example 15 A nickel(II) complex is used as a catalyst to catalyze the hydroheteroarylation reaction of cis/trans-3-octene and 1-methylbenzimidazole.

Under argon protection, add catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), and 1-methylbenzimidazole (66.1 mg, 0.50 mg) into the Schlenk reaction flask. mol), cis/trans-3-octene (84.2 mg, 0.75 mmol) and solvent toluene (1.5 ml), reacted at 90 ^o C for 36 hours. At the end of the reaction, water (0.5 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 3 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and purified by column chromatography (EtOAc/PE = 1 :2), the yield is 94%, and the product structural formula is as follows.

.

The product was dissolved in CDCl ₃ (0.4 mL), and characterized on a Unity Inova-400 NMR instrument at room temperature: ¹ H NMR (400 MHz, CDCl ₃ ) 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).

Example 16 A nickel(II) complex is used as a catalyst to catalyze the hydroheteroarylation reaction of cis/trans-2-octene and 1-methylbenzimidazole.

Under argon protection, add catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), and 1-methylbenzimidazole (66.1 mg, 0.50 mg) into the Schlenk reaction flask. mol), cis/trans-2-octene (84.2 mg, 0.75 mmol) and solvent toluene (1.5 ml), reacted at 90 ^o C for 36 hours. At the end of the reaction, water (0.5 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 3 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and purified by column chromatography (EtOAc/PE = 1 :2), the yield is 92%, and the product structural formula is as follows.

.

The product was dissolved in CDCl ₃ (0.4 mL), and characterized on a Unity Inova-400 NMR instrument at room temperature: ¹ H NMR (400 MHz, CDCl ₃ ) 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).

Example 17 A nickel(II) complex is used as a catalyst to catalyze the hydroheteroarylation reaction of trans-5-decene and 1-methylbenzimidazole.

Under argon protection, add catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), and 1-methylbenzimidazole (66.1 mg, 0.50 mg) into the Schlenk reaction flask. mol), trans-5-decene (101.0 mg, 0.75 mmol) and solvent toluene (1.5 ml), react at 90 ^° C for 36 hours. At the end of the reaction, water (0.5 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 3 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and purified by column chromatography (EtOAc/PE = 1 :4), the yield is 90%, and the product structural formula is as follows.

.

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

Example 18 A nickel(II) complex is used as a catalyst to catalyze the hydroheteroarylation reaction of trans-6-dodecene and 1-methylbenzimidazole.

Under argon protection, add catalyst (7.2 mg, 0.01 mmol, 2 mol%), potassium ethoxide (21.0 mg, 0.25 mmol), and 1-methylbenzimidazole (66.1 mg, 0.50 mg) into the Schlenk reaction flask. mol), trans-6-dodecene (126.2 mg, 0.75 mmol) and solvent toluene (1.5 ml), react at 90 ^° C for 36 hours. At the end of the reaction, water (0.5 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 3 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and purified by column chromatography (EtOAc/PE = 1 :4), the yield is 82%, and the product structural formula is as follows.

.

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

The present invention uses air-stable mixed nickel (II) complex Ni(IMXy)[P(OEt) ₃ ]Br ₂ as the catalyst (IMXy is [(RNCHCHNR)C], R is 2,6-dimethyl- 4-Methoxyphenyl), provides a new synthesis of α-linear alkyl-substituted heteroaromatics through the hydroheteroarylation reaction of non-activated linear intermediate alkenes and heteroarenes in the presence of organic bases method. In particular, the synthesis method provided by the present invention can convert the positional isomer mixture of non-activated linear intermediate olefins into α-linear alkyl-substituted heteroaromatics with a single structure in high yield, without using the intermediate olefins of a single structure. reaction raw materials, which can further reduce synthesis costs. Furthermore, the preparation method disclosed in the present invention has good substrate applicability, and at the same time, because of the air stability of the nickel catalyst and its ease of synthesis, it has more practical application value.

Claims (10)

A method for synthesizing α-linear alkyl-substituted heteroaromatic hydrocarbons, which is characterized by comprising the following steps: reacting a non-activated linear intermediate olefin compound with a heteroaromatic compound in the presence of a nickel catalyst and an organic base in an inert gas atmosphere , to obtain α-linear alkyl-substituted heteroaromatic hydrocarbons. The method for synthesizing α-linear alkyl-substituted heteroarenes according to claim 1, wherein the inert gas is nitrogen or argon; the nickel catalyst is Ni(IMXy)[P(OEt) ₃ ]Br ₂ . The method for synthesizing α-linear alkyl-substituted heteroaromatics according to claim 1, wherein the organic base is potassium ethoxide or sodium tert-butoxide; the reaction is carried out in a solvent. The method for synthesizing α-linear alkyl-substituted heteroaromatic hydrocarbons according to claim 1, characterized in that the reaction temperature is 60-130°C and the reaction time is 30-60 hours. The method for synthesizing α-linear alkyl-substituted heteroaromatics according to claim 1, characterized in that the molar ratio of nickel catalyst, organic base, heteroaromatic compound, and non-activated linear intermediate olefin compound is (0.02~0.10): 0.5:1:1.5. The method for synthesizing α-linear alkyl-substituted heteroaromatic hydrocarbons according to claim 1, characterized in that the heteroaromatic hydrocarbon compound is a benzimidazole compound, an indole compound or a benzofuran or a furan compound; non-activated linear compound Intermediate olefin compounds are expressed by the following chemical structural formula: Among them, R ⁷ and R ⁸ are alkyl groups. The method for synthesizing α-linear alkyl-substituted heteroaromatics according to claim 6, wherein the benzimidazole compound is expressed by the following chemical structural formula: Among them, R ¹ is methyl, aryl, benzyl or alkoxy, and R ² and R ³ are independently selected from hydrogen atoms or methyl; Indole compounds are expressed by the following chemical structural formula: Among them, R ⁴ is acyl; Benzofurans or furan compounds are expressed by the following chemical structural formula: or Among them, R ⁵ is a hydrogen atom or a methoxy group; R ⁶ is a hydrogen atom or a methyl group. α-linear alkyl-substituted heteroaromatics prepared according to the method of synthesizing α-linear alkyl-substituted heteroaromatics according to claim 1. The α-linear alkyl-substituted heteroaromatic hydrocarbon according to claim 8, characterized in that the chemical structural formula of the α-linear alkyl-substituted heteroaromatic hydrocarbon is as follows: or or or Among them, R ¹ , R ² , R ³ , R ⁴ , R ⁵ or R ⁶ are from heteroaromatic compounds, and R ⁹ is from non-activated linear intermediate olefin compounds. Application of nitrogen-heterocyclic carbene-based mixed nickel(II) complex Ni(IMXy)[P(OEt) ₃ ]Br ₂ as a catalyst in the synthesis of α-linear alkyl-substituted heteroarenes.