A method of synthesizing (tetrahydrofuran-2-yl)heteroarene compounds

Abstract

The application discloses a new method for synthesizing (tetrahydrofuran-2-yl) heteroarene compounds, namely, a method for synthesizing (tetrahydrofuran-2-yl) heteroarene compounds by a tandem isomerization / hydroheteroarylation reaction of heteroarene and 2,5-dihydrofuran in the presence of an organic base and by taking a mixed nickel (II) complex with a molecular formula of Ni{[RNC(CH3)C(CH3)NR]C}[P(OEt)3]Br2 (R is 2,6-di(diphenylmethyl)-4-methoxyphenyl) as a catalyst. Compared with the prior art, the application provides a new type of tandem isomerization / hydroheteroarylation reaction based on a nickel catalyst, uses cheap and easily available 2,5-dihydrofuran and heteroarene as raw materials, and provides a new method for synthesizing (tetrahydrofuran-2-yl) heteroarene compounds with 100% atomic economy.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a new method for synthesizing (tetrahydrofuran-2-yl) heteroaromatic compounds. Background Technology

[0002] (Tetrahydrofuran-2-yl)heteroaromatic compounds, as an important class of structural fragments, are not only widely found in natural products and bioactive molecules, but are also one of the commonly used raw materials for constructing drug molecules (see...). J. Med. Chem 2016, 59 Therefore, these compounds have significant synthetic value. Among existing synthetic techniques, reports of using tetrahydrofuran and its derivatives as sources of the tetrahydrofuran skeleton are rare. For example, Ramasastry's group reported bismuth-catalyzed intramolecular nucleophilic substitution of furanol as a starting material to construct (tetrahydrofuran-2-yl)furan (see [reference missing]). Org. Biomol. Chem. 2013, 11 (4299); Subsequently, Zhang Yongqiang's research group reported the oxidative dehydrogenation cross-coupling reaction of heteroaromatic hydrocarbons and tetrahydrofuran to construct (tetrahydrofuran-2-yl) heteroaromatic compounds (see Chem. Sci. 2017, 8 (4044). Recently, Professor Lin Dongen's group reported the construction of (tetrahydrofuran-2-yl)purine compounds by direct alkylation of purines at the C8 position with tetrahydrofuran induced by visible light using organic dyes as photosensitizers (see [link to article]). Org. Biomol. Chem. 2023, 21 (3167). However, to date, there have been no reports of preparing such compounds by tandem isomerization / hydroheteroarylation of heteroaromatics with 2,5-dihydrofuran catalyzed by transition metals. If this reaction can be realized, it will provide a new synthetic method with 100% atom economy for (tetrahydrofuran-2-yl)heteroaromatic compounds, which not only conforms to the development concept of green synthetic chemistry, but also has obvious innovation. Summary of the Invention

[0003] The purpose of this invention is to provide a novel method for synthesizing (tetrahydrofuran-2-yl) heteroaromatic compounds, namely, using the air-stable mixed-type nickel(II) complex Ni{[RNC(CH3)C(CH3)NR]C}[P(OEt)3]Br2 as a catalyst (R is 2,6-di(diphenylmethyl)-4-methoxyphenyl), which can be simplified as Ni(IPr *OMe [P(OEt)3]Br2, in the presence of an organic base, synthesizes (tetrahydrofuran-2-yl) heteroaromatic compounds via a tandem isomerization / hydroheteroarylation reaction of heteroaromatics with 2,5-dihydrofuran.

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

[0005] A method for synthesizing (tetrahydrofuran-2-yl) heteroaromatic compounds includes the following steps: in an inert gas atmosphere, in the presence of a mixed nickel(II) complex and an organic base, the heteroaromatic compound is reacted with 2,5-dihydrofuran to obtain the (tetrahydrofuran-2-yl) heteroaromatic compound.

[0006] This invention also discloses the application of mixed nickel(II) complexes as catalysts in the synthesis of (tetrahydrofuran-2-yl) heteroaromatic compounds.

[0007] In this invention, the mixed-type nickel(II) complex is Ni{[RNC(CH3)C(CH3)NR]C}[P(OEt)3]Br2, where R is 2,6-di(diphenylmethyl)-4-methoxyphenyl, which can be simplified as Ni(IPr) *OMe [P(OEt)3]Br2, its chemical structural formula is as follows:

[0008]

[0009] IPr *OMe The chemical structural formula is as follows:

[0010] In the above technical solution, after the reaction is completed, the reaction is terminated with water, the reaction product is extracted with ethyl acetate, and purified by column chromatography to obtain the product, which can be quantitatively analyzed.

[0011] In the above technical solution, the organic base is an alkali metal alcohol compound, such as one or more of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, and sodium ethoxide, preferably sodium tert-butoxide.

[0012] In the above technical solution, the reaction temperature is 90–120°C and the reaction time is 6–24 hours. Preferably, the reaction temperature is 100–120°C and the reaction time is 10–20 hours.

[0013] In the above technical solution, the inert gas is nitrogen or argon; the solvent is one or more of aromatic solvents and alkane solvents, such as toluene or methylcyclohexane.

[0014] In the above technical solution, the molar ratio of the mixed nickel(II) complex, organic base, heteroaromatic hydrocarbon, and 2,5-dihydrofuran is (0.02-0.06):(0.8-1):1:(1-1.6). In a preferred technical solution, the amount of 2,5-dihydrofuran is 1.3-1.5 times that of the heteroaromatic hydrocarbon, the amount of the organic base is 0.9-1 times that of the heteroaromatic hydrocarbon, and the amount of the mixed nickel(II) complex is 3-5% of the heteroaromatic hydrocarbon; as an example, the amount of 2,5-dihydrofuran is 1.5 times that of the heteroaromatic hydrocarbon, the amount of sodium tert-butoxide is 1 times that of the heteroaromatic hydrocarbon, and the amount of the catalyst mixed nickel(II) complex is 5% of the heteroaromatic hydrocarbon.

[0015] In this invention, the heteroaromatic compounds include benzimidazole compounds, benzofuran compounds, theobromine compounds, and indole compounds; wherein the benzimidazole compounds are expressed by the following chemical structural formulas:

[0016]

[0017] Among them, R 1 R is alkyl, aryl, or substituted aryl. 2 and R 3 Independently selected from hydrogen, alkyl, or alkoxy; wherein the alkyl or alkoxy group has 1 to 10 carbon atoms, preferably 1 to 6; preferably, R 1 It is methyl, benzyl, or p-fluorobenzyl, R 2 and R 3 Independently selected from hydrogen, methyl, or methoxy;

[0018] Benzofuran compounds are represented by the following chemical structural formulas:

[0019]

[0020] Among them, R 4 It is a hydrogen or alkoxy group, such as a methoxy group;

[0021] Theobromine compounds are represented by the following chemical structural formulas:

[0022]

[0023] Among them, R 5 It is propyl, benzyl, p-fluorobenzyl, p-methoxybenzyl, p-trifluoromethylbenzyl, 5-carbonylhexyl or 1-[1,3]dioxolanecyclomethyl;

[0024] Indole compounds are represented by the following chemical structural formulas:

[0025]

[0026] Among them, R 6 Selected from hydrogen, alkyl, or alkoxy; wherein the alkyl or alkoxy group has 1 to 10 carbon atoms, preferably 1 to 6; preferably, R 6 It is a methyl group.

[0027] In this invention, the chemical structural formula of the product (tetrahydrofuran-2-yl) heteroaromatic compound is as follows:

[0028]

[0029] Among them, R 1 R 2 R 3 R 4 R 5 R 6 Derived from heteroaromatic hydrocarbons, (tetrahydrofuran-2-yl) is derived from 2,5-dihydrofuran. Specifically, the C=C of 2,5-dihydrofuran is isomerized to the ortho position of the oxygen atom, and then a hydroheteroarylation reaction is carried out to directly attach the C2 position of tetrahydrofuran to the heteroaryl group and the C3 position of tetrahydrofuran to the hydrogen atom, thus obtaining the (tetrahydrofuran-2-yl) heteroaromatic hydrocarbon compound.

[0030] The technical solution of the present invention, taking substituted theobromine compounds as an example, can be represented as follows:

[0031]

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

[0033] The method for synthesizing (tetrahydrofuran-2-yl) heteroaromatic compounds disclosed in this invention not only has 100% atom economy (i.e., no equivalent byproducts are generated during the reaction process, and the atom utilization rate of the reactants is 100%, which meets the principle of atom economy), but also uses inexpensive and readily available raw materials with good applicability to heterocyclic substrates. Furthermore, because the mixed nickel(II) complexes are air-stable and relatively easy to synthesize, it has practical application value. Detailed Implementation

[0034] The raw materials used in this invention are all existing products, and the specific preparation operations and performance testing are conventional techniques; the invention will be further described below with reference to the embodiments.

[0035] Example 1: The synthesis of Ni{[RNC(CH3)C(CH3)NR]C}[P(OEt)3]Br2 (R being 2,6-bis(diphenylmethyl)-4-methoxyphenyl) is a prior art technique, which can be found in the inventor's published literature. In summary, under argon protection, a nitrogen-containing heterocyclic carbene [RNC(CH3)C(CH3)NR]C (0.9451 g, 1.0 mmol) was added to a tetrahydrofuran solution of Ni[P(OEt)3]Br2 (0.5508 g, 1.0 mmol). The reaction was carried out at 60 °C for 12 hours. The solvent was removed under vacuum, and the residue was washed with n-hexane. The residue was extracted with toluene, the supernatant was transferred, and the solvent toluene was removed, yielding a red solid as a mixed-type nickel(II) complex, which can be simplified as Ni(IPr) *OMe The chemical structure of [P(OEt)3]Br2 is as follows:

[0036]

[0037] The product was characterized by NMR, and the results are shown below:

[0038] The product was dissolved in CDCl3 (0.4 mL), sealed, and characterized at room temperature using a Unity Inova-400 NMR spectrometer. 1 H NMR (400 MHz, CDCl3): δ 7.54 (d, J = 7.3 Hz, 8H), 7.29 (d, J = 7.5 Hz, 7H),7.25 – 6.98 (m, 17H), 6.80 – 6.63 (m, 8H), 6.59 (s, 4H), 6.22 (d, J = 28.3 Hz4H), 4.51 (s, 2H), 4.12 (s,6H), 3.58(s, 6H), 1.25 (t, J = 6.9 Hz, 9H).

[0039] Example 2 uses Ni(IPr) *OMe [P(OEt)3]Br2 serves as a catalyst for the tandem isomerization / hydroheteroarylation reaction of 1-methylbenzimidazole with 2,5-dihydrofuran.

[0040] Under nitrogen protection, catalyst (33.3 mg, 0.025 mmol, 5 mol%), sodium tert-butoxide (48.0 mg, 0.50 mmol), 1-methylbenzimidazole (66.1 mg, 0.50 mmol), 2,5-dihydrofuran (52.6 mg, 0.75 mmol), and solvent methylcyclohexane (1.5 mL) were added sequentially to a Schlenk flask, and the reaction was carried out at 110 °C for 18 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3 × 3 mL), and the extracted ethyl acetate was combined, dried over anhydrous Na₂SO₄, filtered, and purified by column chromatography (using a 1:1 volume ratio of ethyl acetate to petroleum ether as the developing solvent). The yield was 86%, and the product structure is as follows:

[0041]

[0042] The product was dissolved in CDCl3 (0.4 mL) and characterized by determination on a Unity Inova-400 NMR spectrometer at room temperature. 1 HNMR (400 MHz, CDCl3) δ 7.76 (dd, J = 7.2, 1.8 Hz, 1H), 7.32 (dd, J = 7.3, 1.9 Hz,1H), 7.26 (m, 2H), 5.20 (t, J = 6.8 Hz, 1H), 3.94 (t, J = 6.8 Hz, 2H), 3.85 (s,3H), 2.80 (m, 1H), 2.40 – 2.31 (m, 1H), 2.19 (m, 1H), 2.09 – 2.01 (m, 1H).

[0043] Extended Experiment

[0044] Based on Example 2, we made an extension, and the results are shown in Table 1. Group 3 is Example 2.

[0045] Table 1. Results under different reaction conditions a

[0046]

[0047]

[0048] aConditions: Nickel catalyst (5 mol%), 1-methylbenzimidazole (0.5 mmol), 2,5-dihydrofuran (0.75 mmol), organic base (1.0 equiv.), methylcyclohexane (1.5 mL), nitrogen protection. The yield was determined by gas chromatography using n-dodecane as an internal standard. b Separation yield.

[0049] Ni(COD)2 / IPr *OMe The chemical structural formulas of / P(OEt)3 are shown below:

[0050]

[0051]

[0052]

[0053] a Conditions: Nickel catalyst (5 mol%), 1-methylbenzimidazole (0.5 mmol), 2,5-dihydrofuran (0.75 mmol), organic base (1.0 equiv.), methylcyclohexane (1.5 mL), nitrogen protection. The yield was determined by gas chromatography using n-dodecane as an internal standard. b Separation yield.

[0054] The chemical structural formulas of the nickel catalysts involved in Table 2 are shown below:

[0055]

[0056] Table 3. Effects of different solvents on the reaction and results. a :

[0057]

[0058]

[0059] a Conditions: Nickel catalyst (5 mol%), 1-methylbenzimidazole (0.5 mmol), 2,5-dihydrofuran (0.75 mmol), organic base (1.0 equiv.), nitrogen protection; n-dodecane was used as an internal standard, and the yield was determined by gas chromatography. b Separation yield.

[0060] Example 3 uses Ni(IPr) *OMe[P(OEt)3]Br2 was used as a catalyst to catalyze the tandem isomerization / hydroarylation reaction of 1-benzylbenzimidazole with 2,5-dihydrofuran.

[0061] Under nitrogen protection, catalyst (33.3 mg, 0.025 mmol, 5 mol%), sodium tert-butoxide (48.0 mg, 0.50 mmol), 1-benzylbenzimidazole (104.1 mg, 0.50 mmol), 2,5-dihydrofuran (52.6 mg, 0.75 mmol), and solvent methylcyclohexane (1.5 mL) were added sequentially to a Schlenk flask, and the reaction was carried out at 110 °C for 18 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3 × 3 mL), and the extracted ethyl acetate was combined, dried over anhydrous Na₂SO₄, filtered, and purified by column chromatography (using a 1:1 volume ratio of ethyl acetate to petroleum ether as the developing solvent). The yield was 80%, and the product structure is as follows:

[0062]

[0063] The product was dissolved in CDCl3 (0.4 mL) and characterized by determination on a Unity Inova-400 NMR spectrometer at room temperature. 1 HNMR (400 MHz, CDCl3) δ 7.80 (dt, J = 7.7, 1.3 Hz, 1H), 7.33 – 7.16 (m, 6H), 7.13 – 7.00 (m, 2H), 5.61 (d, J = 16.5 Hz, 1H), 5.51 (d, J = 16.5 Hz, 1H), 5.13(dd, J = 7.4, 6.2 Hz, 1H), 3.98 – 3.85 (m, 2H), 2.86 – 2.73 (m, 1H), 2.28 (m,1H), 2.17 (m, 1H), 2.08 – 1.92 (m, 1H).

[0064] Example 4 uses Ni(IPr) *OMe [P(OEt)3]Br2 catalyst, catalyzing the tandem isomerization / hydroheteroarylation reaction of 1-methyl-6-methoxybenzimidazole with 2,5-dihydrofuran.

[0065] Under nitrogen protection, catalyst (33.3 mg, 0.025 mmol, 5 mol%), sodium tert-butoxide (48.0 mg, 0.50 mmol), 1-methyl-6-methoxybenzimidazole (81.1 mg, 0.50 mmol), 2,5-dihydrofuran (52.6 mg, 0.75 mmol), and solvent methylcyclohexane (1.5 mL) were added sequentially to a Schlenk flask, and the reaction was carried out at 110 °C for 18 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3 × 3 mL), and the extracted ethyl acetate was combined, dried over anhydrous Na₂SO₄, filtered, and purified by column chromatography (using a 1:1 volume ratio of ethyl acetate to petroleum ether as the developing solvent). The yield was 90%, and the product structure is as follows:

[0066]

[0067] The product was dissolved in CDCl3 (0.4 mL) and characterized by determination on a Unity Inova-400 NMR spectrometer at room temperature. 1 HNMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.8 Hz, 1H), 6.80 (dd, J = 8.8, 2.4 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H), 5.10 – 5.06 (m, 1H), 3.84 (td, J = 5.1, 2.9 Hz, 2H),3.78 (s, 3H), 3.72 (s, 3H), 2.72 – 2.66 (m, 1H), 2.27 – 2.22 (m, 1H), 2.13 –2.08 (m, 1H), 1.99 – 1.93 (m, 1H).

[0068] Example 5 uses Ni(IPr) *OMe [P(OEt)3]Br2 catalyst, catalyzing the tandem isomerization / hydroheteroarylation reaction of 1-methyl-5,6-dimethylbenzimidazole with 2,5-dihydrofuran.

[0069] Under nitrogen protection, catalyst (33.3 mg, 0.025 mmol, 5 mol%), sodium tert-butoxide (48.0 mg, 0.50 mmol), 1-methyl-5,6-dimethylbenzimidazole (80.1 mg, 0.50 mmol), 2,5-dihydrofuran (52.6 mg, 0.75 mmol), and solvent methylcyclohexane (1.5 mL) were added sequentially to a Schlenk flask, and the reaction was carried out at 110 °C for 18 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3 × 3 mL), dried over anhydrous Na₂SO₄, filtered, and purified by column chromatography (using a 1:1 volume ratio of ethyl acetate / petroleum ether as the eluent). The yield was 91%, and the product structure is as follows:

[0070]

[0071] The product was dissolved in CDCl3 (0.4 mL) and characterized by determination on a Unity Inova-400 NMR spectrometer at room temperature. 1 HNMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 6.99 (s, 1H), 5.07 (t, J = 6.8 Hz, 1H),3.86 – 3.81 (m, 2H), 3.71 (s, 3H), 2.74 – 2.64 (m, 1H), 2.30 (s, 3H), 2.27(s, 3H), 2.25 – 2.19 (m, 1H), 2.15 – 2.06 (m, 1H), 1.96 (m, 1H).

[0072] Example 6 uses Ni(IPr) *OMe [P(OEt)3]Br2 was used as a catalyst to catalyze the tandem isomerization / hydroarylation reaction of 1-p-fluorobenzylbenzimidazole with 2,5-dihydrofuran.

[0073] Under nitrogen protection, catalyst (33.3 mg, 0.025 mmol, 5 mol%), sodium tert-butoxide (48.0 mg, 0.50 mmol), 1-p-fluorobenzylbenzimidazole (113.1 mg, 0.50 mmol), 2,5-dihydrofuran (52.6 mg, 0.75 mmol), and solvent methylcyclohexane (1.5 mL) were added sequentially to a Schlenk flask, and the reaction was carried out at 110 °C for 18 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3 × 3 mL), and the extracted ethyl acetate was combined, dried over anhydrous Na₂SO₄, filtered, and purified by column chromatography (using a 1:1 volume ratio of ethyl acetate to petroleum ether as the developing solvent). The yield was 81%, and the product structure is as follows:

[0074]

[0075] The product was dissolved in CDCl3 (0.4 mL) and characterized by determination on a Unity Inova-400 NMR spectrometer at room temperature. 1 HNMR (400 MHz, CDCl3) δ 7.79 (dt, J = 8.0, 1.0 Hz, 1H), 7.29 – 7.21 (m, 1H), 7.25 – 7.15 (m, 2H), 7.14 – 7.03 (m, 2H), 7.05 – 6.92 (m, 2H), 5.55 (d, J =16.3 Hz, 1H), 5.52 – 5.44 (m, 1H), 5.12 (dd, J = 7.4, 6.2 Hz, 1H), 3.91 (t, J =6.9 Hz, 2H), 2.82 (m, 1H), 2.30 (m, 1H), 2.16 (m, 1H), 2.09 – 1.94 (m, 1H).

[0076] Example 7 uses Ni(IPr) *OMe [P(OEt)3]Br2 serves as a catalyst for the tandem isomerization / hydroheteroarylation reaction of benzofuran with 2,5-dihydrofuran.

[0077] Under nitrogen protection, catalyst (33.3 mg, 0.025 mmol, 5 mol%), sodium tert-butoxide (48.0 mg, 0.50 mmol), benzofuran (59.1 mg, 0.50 mmol), 2,5-dihydrofuran (52.6 mg, 0.75 mmol), and solvent methylcyclohexane (1.5 mL) were added sequentially to a Schlenk flask, and the reaction was carried out at 110 °C for 18 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3 × 3 mL), and the extracted ethyl acetate was combined, dried over anhydrous Na₂SO₄, filtered, and purified by column chromatography (using a 1:5 volume ratio of ethyl acetate to petroleum ether as the developing solvent). The yield was 85%, and the product structure is as follows:

[0078]

[0079] The product was dissolved in CDCl3 (0.4 mL) and characterized by determination on a Unity Inova-400 NMR spectrometer at room temperature. 1 HNMR (400 MHz, CDCl3) δ 7.54 – 7.49 (m, 1H), 7.45 (dq, J = 8.2, 0.9 Hz, 1H),7.27 – 7.16 (m, 2H), 6.61 (t, J = 0.9 Hz, 1H), 5.09 – 5.04 (m, 1H), 4.06 (m,1H), 3.93 (m, 1H), 2.32 – 1.99 (m, 4H).

[0080] Example 8 uses Ni(IPr) *OMe [P(OEt)3]Br2 is used as a catalyst to catalyze the tandem isomerization / hydroarylation reaction of 5-methoxybenzofuran with 2,5-dihydrofuran.

[0081] Under nitrogen protection, catalyst (33.3 mg, 0.025 mmol, 5 mol%), sodium tert-butoxide (48.0 mg, 0.50 mmol), 5-methoxybenzofuran (74.1 mg, 0.50 mmol), 2,5-dihydrofuran (52.6 mg, 0.75 mmol), and solvent methylcyclohexane (1.5 mL) were added sequentially to a Schlenk flask, and the reaction was carried out at 110 °C for 18 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3 × 3 mL), and the extracted ethyl acetate was combined, dried over anhydrous Na₂SO₄, filtered, and purified by column chromatography (using a 1:5 volume ratio of ethyl acetate to petroleum ether as the developing solvent). The yield was 82%, and the product structure is as follows:

[0082]

[0083] The product was dissolved in CDCl3 (0.4 mL) and characterized by determination on a Unity Inova-400 NMR spectrometer at room temperature. 1 HNMR (400 MHz, CDCl3) δ7.31 – 7.16 (m, 1H), 7.13 – 7.06 (m, 1H), 6.85 (dd, J =8.9, 2.6 Hz, 1H), 6.56 (d, J = 0.9 Hz, 1H), 5.04 (t, J = 6.7 Hz, 1H), 4.06 (dt, J =7.9, 6.6 Hz, 1H), 3.93 (td, J = 7.8, 6.1 Hz, 1H), 3.83 (s, 3H), 2.35 – 1.93 (m, 4H).

[0084] Example 9 uses Ni(IPr) *OMe [P(OEt)3]Br2 serves as a catalyst for the tandem isomerization / hydroheteroarylation reaction of 1-methylindole with 2,5-dihydrofuran.

[0085] Under nitrogen protection, catalyst (33.3 mg, 0.025 mmol, 5 mol%), sodium tert-butoxide (48.0 mg, 0.50 mmol), 1-methylindole (65.6 mg, 0.50 mmol), 2,5-dihydrofuran (52.6 mg, 0.75 mmol), and solvent methylcyclohexane (1.5 mL) were added sequentially to a Schlenk flask, and the reaction was carried out at 110 °C for 18 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3 × 3 mL), and the extracted ethyl acetate was combined, dried over anhydrous Na₂SO₄, filtered, and purified by column chromatography (using a 1:5 volume ratio of ethyl acetate to petroleum ether as the developing solvent). The yield was 71%, and the product structure is as follows:

[0086]

[0087] The product was dissolved in CDCl3 (0.4 mL) and characterized by determination on a Unity Inova-400 NMR spectrometer at room temperature. 1 HNMR (400 MHz, CDCl3) δ 7.56 (dt, J = 7.8, 1.0 Hz, 1H), 7.29 (d,J = 7.5 Hz, 1H),7.22 – 7.16 (m, 1H), 7.07 (m, 1H), 6.43 (s, 1H), 5.11 (t, J = 6.9 Hz, 1H), 3.99– 3.87 (m, 2H), 3.78 (s, 3H), 2.28 (m, 2H), 2.14 – 1.98 (m, 2H).

[0088] Example 10 uses Ni(IPr) *OMe [P(OEt)3]Br2 is used as a catalyst to catalyze the tandem isomerization / hydroarylation reaction of 1-benzyl-3,7-dimethylpurine-2,6-dione with 2,5-dihydrofuran.

[0089] Under nitrogen protection, catalyst (33.3 mg, 0.025 mmol, 5 mol%), sodium tert-butoxide (48.0 mg, 0.50 mmol), 1-benzyl-3,7-dimethylpurine-2,6-dione (135.1 mg, 0.50 mmol), 2,5-dihydrofuran (52.6 mg, 0.75 mmol), and solvent toluene (1.5 mL) were added sequentially to a Schlenk flask, and the reaction was carried out at 110 °C for 18 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3 × 3 mL), and the extracted ethyl acetate was combined, dried over anhydrous Na₂SO₄, filtered, and purified by column chromatography (using a 1:1 volume ratio of ethyl acetate to petroleum ether as the developing solvent). The yield was 91%, and the product structure is as follows:

[0090]

[0091] The product was dissolved in CDCl3 (0.4 mL) and characterized by determination on a Unity Inova-400 NMR spectrometer at room temperature. 1 HNMR (400 MHz, CDCl3) δ 7.51 – 7.37 (m, 2H), 7.32 – 7.17 (m, 3H), 5.17 (s,2H), 5.00 (dd, J = 7.3, 6.4 Hz, 1H), 4.02 (s, 3H), 3.98 – 3.90 (m, 1H), 3.93 –3.85 (m, 1H), 3.54 (s, 3H), 2.56 (m, 1H), 2.26 (m, 1H), 2.20 – 1.94 (m, 2H).

[0092] Example 11 uses Ni(IPr)*OMe [P(OEt)3]Br2 is used as a catalyst to catalyze the tandem isomerization / hydroheteroarylation reaction of 1-[(4-fluorophenyl)methyl]-3,7-dimethylpurine-2,6-dione with 2,5-dihydrofuran.

[0093] Under nitrogen protection, catalyst (33.3 mg, 0.025 mmol, 5 mol%), sodium tert-butoxide (48.0 mg, 0.50 mmol), 1-[(4-fluorophenyl)methyl]-3,7-dimethylpurine-2,6-dione (144.1 mg, 0.50 mmol), 2,5-dihydrofuran (52.6 mg, 0.75 mmol), and solvent toluene (1.5 mL) were added sequentially to a Schlenk flask, and the reaction was carried out at 110 °C for 18 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3 × 3 mL), and the extracted ethyl acetate was combined, dried over anhydrous Na₂SO₄, filtered, and purified by column chromatography (using a 1:1 volume ratio of ethyl acetate to petroleum ether as the developing solvent). The yield was 90%, and the product structure is as follows:

[0094]

[0095] The product was dissolved in CDCl3 (0.4 mL) and characterized by determination on a Unity Inova-400 NMR spectrometer at room temperature. 1 HNMR (400 MHz, CDCl3) δ 7.52 – 7.42 (m, 2H), 7.00 – 6.90 (m, 2H), 5.12 (s,2H), 5.01 (dd, J = 7.4, 6.3 Hz, 1H), 4.03 (s, 3H), 3.92 (m, 2H), 3.54 (s, 3H), 2.57 (m, 1H), 2.27 (m, 1H), 2.21 – 1.95 (m, 2H).

[0096] Example 12 uses Ni(IPr) *OMe [P(OEt)3]Br2 was used as a catalyst to catalyze the tandem isomerization / hydroheteroarylation reaction of 1-[(4-trifluorophenyl)methyl]-3,7-dimethylpurine-2,6-dione with 2,5-dihydrofuran.

[0097] Under nitrogen protection, catalyst (33.3 mg, 0.025 mmol, 5 mol%), sodium tert-butoxide (48.0 mg, 0.50 mmol), 1-[(4-trifluorophenyl)methyl]-3,7-dimethylpurine-2,6-dione (169.1 mg, 0.50 mmol), 2,5-dihydrofuran (52.6 mg, 0.75 mmol), and solvent toluene (1.5 mL) were added sequentially to a Schlenk flask, and the reaction was carried out at 110 °C for 18 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3 × 3 mL), and the extracted ethyl acetate was combined, dried over anhydrous Na₂SO₄, filtered, and purified by column chromatography (using a 1:1 volume ratio of ethyl acetate to petroleum ether as the developing solvent). The yield was 92%, and the product structure is as follows:

[0098]

[0099] The product was dissolved in CDCl3 (0.4 mL) and characterized by determination on a Unity Inova-400 NMR spectrometer at room temperature. 1 HNMR (400 MHz, CDCl3) δ 7.46 (q, J = 8.3 Hz, 4H), 5.12 (s, 2H), 4.92 (t, J = 6.9Hz, 1H), 3.93 (s, 3H), 3.90 – 3.76 (m, 2H), 3.46 (s, 3H), 2.54 – 2.41 (m,1H), 2.24 – 1.85 (m, 3H).

[0100] Example 13 uses Ni(IPr) *OMe [P(OEt)3]Br2 is used as a catalyst to catalyze the tandem isomerization / hydroarylation reaction of 1-(5-oxohexyl)-3,7-dimethylpurine-2,6-dione with 2,5-dihydrofuran.

[0101] Under nitrogen protection, catalyst (33.3 mg, 0.025 mmol, 5 mol%), sodium tert-butoxide (48.0 mg, 0.50 mmol), 1-(5-oxohexyl)-3,7-dimethylpurine-2,6-dione (174.2 mg, 0.50 mmol), 2,5-dihydrofuran (52.6 mg, 0.75 mmol), and solvent toluene (1.5 mL) were added sequentially to a Schlenk flask, and the reaction was carried out at 110 °C for 18 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3 × 3 mL), and the extracted ethyl acetate was combined, dried over anhydrous Na₂SO₄, filtered, and purified by column chromatography (using a 1:1 volume ratio of ethyl acetate to petroleum ether as the developing solvent). The yield was 60%, and the product structure is as follows:

[0102]

[0103] The product was dissolved in CDCl3 (0.4 mL) and characterized by determination on a Unity Inova-400 NMR spectrometer at room temperature. 1 HNMR (400 MHz, CDCl3) δ 5.01 – 4.93 (m, 1H), 3.99 – 3.86 (m, 6H), 3.89 – 3.80 (m, 1H), 3.48 (s, 3H), 2.52 (ddt, J = 12.3, 8.4, 6.7 Hz, 1H), 2.44 (t, J = 6.9Hz, 2H), 2.29 – 2.19 (m, 1H), 2.23 – 2.07 (m, 1H), 2.08 (s, 3H), 2.06 – 1.91(m, 1H), 1.65 – 1.57 (m, 2H), 1.60 – 1.52 (m, 2H).

[0104] Example 14 uses Ni(IPr) *OMe [P(OEt)3]Br2 is used as a catalyst to catalyze the tandem isomerization / hydroheteroarylation reaction of 1-[(4-methoxyphenyl)methyl]-3,7-dimethylpurine-2,6-dione with 2,5-dihydrofuran.

[0105] Under nitrogen protection, catalyst (33.3 mg, 0.025 mmol, 5 mol%), sodium tert-butoxide (48.0 mg, 0.50 mmol), 1-[(4-methoxyphenyl)methyl]-3,7-dimethylpurine-2,6-dione (150.2 mg, 0.50 mmol), 2,5-dihydrofuran (52.6 mg, 0.75 mmol), and solvent toluene (1.5 mL) were added sequentially to a Schlenk flask, and the reaction was carried out at 110 °C for 18 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3 × 3 mL), and the extracted ethyl acetate was combined, dried over anhydrous Na₂SO₄, filtered, and purified by column chromatography (using a 1:1 volume ratio of ethyl acetate to petroleum ether as the developing solvent). The yield was 93%, and the product structure is as follows:

[0106]

[0107] The product was dissolved in CDCl3 (0.4 mL) and characterized by determination on a Unity Inova-400 NMR spectrometer at room temperature. 1 HNMR (400 MHz, CDCl3) δ 7.48 – 7.40 (m, 2H), 6.85 – 6.76 (m, 2H), 5.11 (s,2H), 5.00 (dd, J = 7.4, 6.3 Hz, 1H), 4.02 (s, 3H), 3.98 – 3.84 (m, 2H), 3.75 (s, 3H), 3.54 (s, 3H), 2.56 (ddt, J = 12.4, 8.4, 6.7 Hz, 1H), 2.32 – 1.94 (m,3H).

[0108] Example 15 uses Ni(IPr) *OMe [P(OEt)3]Br2 is used as a catalyst to catalyze the tandem isomerization / hydroheteroarylation reaction of 1-[(4-methoxyphenyl)methyl]-3,7-dimethylpurine-2,6-dione with 2,5-dihydrofuran.

[0109] Under nitrogen protection, catalyst (33.3 mg, 0.025 mmol, 5 mol%), sodium tert-butoxide (48.0 mg, 0.50 mmol), 1-propyl-3,7-dimethylpurine-2,6-dione (111.1 mg, 0.50 mmol), 2,5-dihydrofuran (52.6 mg, 0.75 mmol), and solvent toluene (1.5 mL) were added sequentially to a Schlenk flask, and the reaction was carried out at 110 °C for 18 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3 × 3 mL), and the extracted ethyl acetate was combined, dried over anhydrous Na₂SO₄, filtered, and purified by column chromatography (using a 1:1 volume ratio of ethyl acetate to petroleum ether as the developing solvent). The yield was 93%, and the product structure is as follows:

[0110]

[0111] The product was dissolved in CDCl3 (0.4 mL) and characterized by determination on a Unity Inova-400 NMR spectrometer at room temperature. 1 HNMR (400 MHz, CDCl3) δ 5.04 (dd, J = 7.4, 6.4 Hz, 1H), 4.04 (s, 3H), 4.01 –3.87 (m, 4H), 3.55 (s, 3H), 2.59 (m, 1H), 2.35 – 1.97 (m, 3H), 1.74 – 1.60(m, 2H), 0.96 (t, J = 7.5 Hz, 3H).

[0112] Example 16 uses Ni(IPr) *OMe [P(OEt)3]Br2 was used as a catalyst to catalyze the tandem isomerization / hydroheteroarylation reaction of 1-([1,3]dioxolane)methyl-3,7-dimethylpurine-2,6-dione with 2,5-dihydrofuran.

[0113] Under nitrogen protection, catalyst (33.3 mg, 0.025 mmol, 5 mol%), sodium tert-butoxide (48.0 mg, 0.50 mmol), 1-([1,3]dioxolane)methyl-3,7-dimethylpurine-2,6-dione (133.1 mg, 0.50 mmol), 2,5-dihydrofuran (52.6 mg, 0.75 mmol), and solvent toluene (1.5 mL) were added sequentially to a Schlenk flask, and the reaction was carried out at 110 °C for 18 hours. After the reaction was completed, water (0.5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3 × 3 mL), and the extracted ethyl acetate was combined, dried over anhydrous Na₂SO₄, filtered, and purified by column chromatography (using a 1:1 volume ratio of ethyl acetate to petroleum ether as the developing solvent). The yield was 90%, and the product structure is as follows:

[0114]

[0115] The product was dissolved in CDCl3 (0.4 mL) and characterized by determination on a Unity Inova-400 NMR spectrometer at room temperature. 1 HNMR (400 MHz, CDCl3) δ 5.34 (t, J = 5.0 Hz, 1H), 5.02 (dd, J = 7.4, 6.3 Hz, 1H), 4.20 (d, J = 5.0 Hz, 2H), 4.13 – 4.04 (m, 2H), 4.03 (s, 3H), 4.00 – 3.82 (m,4H), 3.56 (s, 3H), 2.57 (m, 1H), 2.28 (m, 1H), 2.24 – 1.96 (m, 2H).

[0116] This invention utilizes an air-stable mixed-type nickel(II) complex, Ni(IPr). *OMe Using [P(OEt)3]Br2 as a catalyst, and in the presence of an organic base, a novel synthetic method is provided for (tetrahydrofuran-2-yl)heteroaromatic compounds through a tandem isomerization / hydroheteroarylation reaction of heteroaromatics and 2,5-dihydrofuran. Furthermore, the synthetic method provided by this invention can convert intracyclic olefins into high-value (tetrahydrofuran-2-yl)heteroaromatic compounds. The preparation method disclosed in this invention has good substrate applicability, and the raw materials are inexpensive and readily available. In addition, the air stability and ease of synthesis of the nickel catalyst further enhance its practical application prospects.

Claims

1. A method for synthesizing (tetrahydrofuran-2-yl) heteroaromatic compounds, characterized in that, The process includes the following steps: in an inert gas atmosphere, in the presence of a mixed nickel(II) complex, an organic base, and a solvent, a heteroaromatic hydrocarbon is reacted with 2,5-dihydrofuran to obtain a (tetrahydrofuran-2-yl) heteroaromatic hydrocarbon compound; the mixed nickel(II) complex has the following structure: ； The organic base is an alkali metal alcohol compound; the solvent is toluene, methylcyclohexane, or cyclohexane; The heteroaromatic compounds are benzimidazole compounds, benzofuran compounds, theobromine compounds, or indole compounds; among them, benzimidazole compounds are represented by the following chemical structural formulas: ； Among them, R 1 It is an alkyl or aryl group, R 2 and R 3 Independently selected from hydrogen, alkyl, or alkoxy; Benzofuran compounds are represented by the following chemical structural formulas: ； Among them, R 4 It is hydrogen or alkoxy; Theobromine compounds are represented by the following chemical structural formulas: ； Among them, R 5 It is propyl, benzyl, p-fluorobenzyl, p-methoxybenzyl, p-trifluoromethylbenzyl, 5-carbonylhexyl or 1-[1,3]dioxolanecyclomethyl; Indole compounds are represented by the following chemical structural formulas: ； Among them, R 6 Selected from hydrogen, alkyl, or alkoxy; The alkyl or alkoxy group has 1 to 10 carbon atoms; The chemical structural formula of the product (tetrahydrofuran-2-yl) heteroaromatic compound is as follows: ； Among them, R 1 R 2 R 3 R 4 R 5 R 6 Derived from heteroaryrheic hydrocarbons.

2. The method for synthesizing (tetrahydrofuran-2-yl) heteroaromatic compounds according to claim 1, characterized in that, The reaction is carried out at a temperature of 90–120°C for 6–24 hours.

3. The method for synthesizing (tetrahydrofuran-2-yl) heteroaromatic compounds according to claim 1, characterized in that, The molar ratio of the mixed nickel(II) complex, organic base, heteroaromatic hydrocarbon, and 2,5-dihydrofuran is (0.02-0.06):(0.8-1):1:(1-1.6).

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