Method for constructing molten pyridine compound through [2 +1 +3] cyclization reaction of cyclic ketone, alpha, beta-unsaturated aldehyde / ketone and ammonium iodide under catalysis of copper

Abstract

The invention discloses a reaction research for constructing a molten pyridine compound through [2 + 1 + 3] cyclization reaction of cyclic ketone, alpha, beta-unsaturated aldehyde / ketone and NH4I under the catalysis of copper (OAc) 2 / DPEPhos, and a novel method for forming [2 + 1 + 3] cascade cyclization high-selectivity synthesis of molten pyridine derivatives by taking DIPEA as organic alkali, taking ammonium iodide (NH4I) as an N source, and taking cyclic ketone and alpha, beta-unsaturated aldehyde / ketone as three components under the catalysis of Cu (OAc) 2 / DPEPhos. According to the method, Cu (OAc) 2 is used as a low-price catalyst, and a complex and sensitive organic metal reagent is avoided. Meanwhile, the formal [2 + 1 + 3] cyclization reaction is suitable for various substrates, has good tolerance to various substituent groups, and can provide molten pyridine which is easy to obtain at a good yield. In addition, the reaction also has the characteristics of low additive price, mild reaction conditions, easily available initial raw materials and the like. According to the method, a multi-group hierarchical cyclization protocol is carried out on starting raw materials which are easy to purchase commercially under mild conditions, and the fused pyridine compound with high regioselectivity is constructed.

Description

[Technical field]

[0001] The invention belongs to the field of catalytic organic synthesis and relates to a method for constructing a molten pyridine compound through a copper-catalyzed [2+1+3] cyclization reaction of a cyclic ketone with an α,β-unsaturated aldehyde / ketone and NH4I. [Background technology]

[0002] Pyridine is a typical electron-deficient aromatic heterocyclic compound and the core structure of many natural products and drug molecules. It also plays an important role in coordination chemistry, catalysis and materials science. At the same time, fused pyridine is considered to be a privileged pyridine framework with a wide range of biological functions, including antiviral, anticancer, antioxidant activity, etc. For example, Desloratadine is a class of antihistamines commonly used to treat allergic rhinitis. Blonanserin is an atypical antipsychotic drug and a potent dopamine D2 (Ki: 14.8nM) and serotonin 5-HT2 (Ki: 3.98nM) receptor antagonist, which is mainly used clinically to treat schizophrenia. Cicletanine is a drug suitable for the treatment of patients with mild and moderate hypertension.

[0003] Although fused pyridine has attracted much attention in the fields of medicinal chemistry and agriculture due to its unique electronic properties and structural rigidity, its synthesis methods usually suffer from problems such as harsh reaction conditions, poor substrate applicability and low yield. Currently known cases include three-component cyclization of aldehydes, acyl acetonitrile and electron-rich amino heterocycles in ionic liquids (ACS Comb. Sci. 2011, 13, 45–49); Rh(III)-catalyzed three-component cyclization of aryl ketones, hydroxylamines and alkynes (J. Org. Chem. 2012, 77, 5794-5800). Despite these remarkable achievements, the introduction of ammonia substitutes as nitrogen sources and a convenient method to prepare multifunctional fused pyridine derivatives is still very desirable. Commercially available starting materials can be directly utilized, thus avoiding the problems of limited substitution categories, low functional group compatibility and multi-step synthesis of starting materials. Therefore, we have developed a copper-catalyzed [2+1+3] cascade cyclization reaction method using commercially available cyclic ketones with α,β-unsaturated aldehydes / ketones and NH4I. This method is simple and easy to operate, has good substrate adaptability, high yield, and the starting materials can be directly purchased commercially. At present, there are no public documents or patent applications reporting the multi-component [2+1+3] cascade cyclization to obtain molten pyridine at home and abroad. [Summary of the invention]

[0004] The present invention develops an efficient conversion method for synthesizing molten pyridine and its derivatives under Cu(OAc)2 / DPEPhos catalysis. The reaction utilizes commercially available cyclic ketones with α,β-unsaturated aldehydes / ketones and NH4I through a three-component [2+1+3] cascade cyclization method to obtain functional group-tolerant molten pyridine compounds in high yield. This interesting method has the characteristics of simple operation, easy availability of starting materials, mild reaction conditions, good functional group tolerance and high atom economy. In addition, this strategy can provide a good synthetic route for highly functionalized or complex molten pyridines.

[0005] To achieve the above object, the technical solution of the present invention is as follows:

[0006] A method for constructing a molten pyridine compound through a copper-catalyzed [2+1+3] cyclization reaction of a cyclic ketone with an α,β-unsaturated aldehyde / ketone and NH4I, comprising the following steps: in a nitrogen atmosphere, using Cu(OAc)2 as a catalyst, DPEpHos as a ligand, ammonium iodide as a nitrogen source, DIPEA as a base, and methanol as an ultra-dry solvent, stirring the cyclic ketone, the α,β-unsaturated aldehyde / ketone and NH4I at 30°C-100°C for 2-48 hours to obtain a product containing a molten pyridine compound.

[0007] A further improvement is that the product containing the molten pyridine compound is diluted with ethyl acetate, water is added, and then extracted three times with ethyl acetate, the organic phases are collected and combined, and then anhydrous Na2SO4 is added to dehydrate the combined organic phases, and then concentrated under reduced pressure to obtain a crude product. The crude product is separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0008] As a further improvement, the molar ratio of Cu(OAc)2, DPEpHos, NH4I, DIPEA, cyclic ketone and α,β-unsaturated aldehyde / ketone was 0.03:0.03:0.60:0.90:0.30:0.36.

[0009] In a further improvement, the cyclic ketone is one of cyclobutanone, cyclopentanone, cycloheptanone, cyclooctanone, cyclododecanone, 1-tetralone, 1,2,3,4-tetrahydro-2-naphthalenone, 2-benzylidenecyclohexanone, 4,4-difluorocyclohexanone, dihydro-3(2H)-furanone, tetrahydro-pyran-4-one, tetrahydrothiopyran-4-one, cyclohexane-1,3-dione, 2,6,6-trimethyl-cyclohexene-1,4-dione, 4-dihydrochromone, 2-methyl-5-(1-methylethyl)-cyclohexanone, indan-1,2-dione, 4-(4-hydroxyphenyl)cyclohexane-1-one, 17α-hydroxyprogesterone acetate, dehydroepiandrosterone acetate, 3-ketal and epiandrosterone.

[0010] In a further improvement, the α,β-unsaturated aldehyde / ketone is one of 1-octen-3-one, 1-penten-3-one, phenylprop-2-enyl-1-one, 1-(4-fluorophenyl)-2-propene-1-one, methacrolein, trans-2-pentenal and (2E)-1,3-diphenyl-2-propene-1-one. In a further improvement, the chemical formula of the molten pyridine compound is as follows:

[0011]

[0012] R 1 is H, n-pentyl, ethyl, phenyl or 2,3-dimethoxyphenyl;

[0013] R 2 is H, methyl or ethyl;

[0014] R 3 is H, methyl, phenyl or naphthyl.

[0015] The advantages of the present invention are as follows:

[0016] The present invention discloses a novel method for synthesizing molten pyridine derivatives in a three-component form of [2+1+3] cascade cyclization with high selectivity under the catalysis of Cu(OAc)2 / DPEPhos, using DIPEA as an organic base, ammonium iodide (NH4I) as a N source, cyclic ketones and α,β-unsaturated aldehydes / ketones. The method uses Cu(OAc)2 as a low-cost catalyst and avoids the use of complex and sensitive organometallic reagents. At the same time, this formal [2+1+3] cyclization reaction is applicable to a variety of substrates, has good tolerance to a variety of substituents, and can provide easily available molten pyridine in good yield. In addition, the reaction also has the characteristics of low additive cost, mild reaction conditions, and readily available starting materials. A multi-component cascade cyclization protocol is achieved under mild conditions from commercially available starting materials, and a molten pyridine compound with high regioselectivity is constructed.

Brief Description of the Drawings

[0017] Figure 1 A method for constructing molten pyridine compounds with high regioselectivity;

[0018] Figure 2 Chemical formula of molten pyridine compound. [Specific implementation method]

[0019] Reaction formula of the present invention is as follows:

[0020]

[0021] Embodiment 1:

[0022] NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, cyclooctanone (0.30mmol), 1-octen-3-one (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL ultra-dry solvent methanol (MeOH) were added under N2 atmosphere. The mixture was stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction was completed, it was cooled to room temperature, the mixture was diluted with ethyl acetate, an appropriate amount of water was added, and then extracted three times with ethyl acetate, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound. Column chromatography separation and purification (petroleum ether / ethyl acetate = 4:1) gave 4-pentyl-5,6,7,8,9,10-hexahydrocyclooctan[b]pyridine as a yellow oily liquid. Yield: 53 mg, 76%. 1 H NMR(400MHz, CDCl3) δ7.98(d,J=4.9Hz,1H),6.62(d,J=4.9Hz,1H),2.75–2.67(m,2H),2.54(t,J=6.4Hz,2H),2. 38–2.21(m,2H),1.51(p,J=6.0Hz,2H),1.34(dp,J=38.5,6.7Hz,4H),1.18–0.96(m,8H),0.64(d,J=6.8Hz,3H). 13 CNMR(101MHz, CDCl3)δ160.8,148.5,146.1,132.9,121.6,35.1,31.8,31.4,30.4,30.1,29.8,26.1,25.7,25.4,22.1,13.6.HRMS(ESI-QTOF)m / z:[M+Na] + Calculate for C 16 H 25 NNa + 254.1879; found 254.1888.

[0023] Embodiment 2:

[0024] NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, cycloheptanone (0.30mmol), 1-pentene-3-one (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL ultra-dry solvent methanol (MeOH) were added under N2 atmosphere. The mixture was stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction was completed, it was cooled to room temperature, the mixture was diluted with ethyl acetate, an appropriate amount of water was added, and then extracted three times with ethyl acetate, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0025] Embodiment 3:

[0026] NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, cyclooctanone (0.30mmol), 1-pentene-3-one (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL ultra-dry solvent methanol (MeOH) were added under N2 atmosphere. The mixture was stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction was completed, it was cooled to room temperature, the mixture was diluted with ethyl acetate, an appropriate amount of water was added, and then extracted three times with ethyl acetate, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0027] Embodiment 4:

[0028] NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, cyclododecanone (0.30mmol), 1-octen-3-one (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL ultra-dry solvent methanol (MeOH) were added under N2 atmosphere. The mixture was stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction was completed, it was cooled to room temperature, the mixture was diluted with ethyl acetate, an appropriate amount of water was added, and then extracted three times with ethyl acetate, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0029] Embodiment 5:

[0030] NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, cyclobutanone (0.30mmol), phenylprop-2-enyl-1-one (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL ultra-dry solvent methanol (MeOH) were added under N2 atmosphere. The mixture was stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction was completed, it was cooled to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0031] Embodiment 6:

[0032] NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, cyclopentanone (0.30mmol), phenylprop-2-enyl-1-one (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL ultra-dry solvent methanol (MeOH) were added under N2 atmosphere. The mixture was stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction was completed, it was cooled to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0033] Embodiment 7:

[0034] NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, cyclooctanone (0.30mmol), phenylprop-2-enyl-1-one (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL ultra-dry solvent methanol (MeOH) were added under N2 atmosphere. The mixture was stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction was completed, it was cooled to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0035] Embodiment 8:

[0036] NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, cyclododecanone (0.30mmol), phenylprop-2-enyl-1-one (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL ultra-dry solvent methanol (MeOH) were added under N2 atmosphere. The mixture was stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction was completed, it was cooled to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0037] Embodiment 9:

[0038] NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) were added to a 10mL Schlenk tube equipped with a magnetic stirrer. The mixture was evacuated with a pump and filled with nitrogen three times. Then, 1-tetralone (0.30mmol), phenylprop-2-enyl-1-one (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL of ultra-dry solvent methanol (MeOH) were added under N2 atmosphere. The mixture was stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction was completed, it was cooled to room temperature, the mixture was diluted with ethyl acetate, an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0039] Embodiment 10:

[0040] NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) were added to a 10mL Schlenk tube equipped with a magnetic stirrer. After vacuuming with a pump, nitrogen was filled three times. Then, 4,4-difluorocyclohexanone (0.30mmol), phenylprop-2-enyl-1-one (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL of ultra-dry solvent methanol (MeOH) were added under N2 atmosphere. The mixture was stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction was completed, it was cooled to room temperature, the mixture was diluted with ethyl acetate, an appropriate amount of water was added, and then extracted three times with ethyl acetate, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0041] Embodiment 11:

[0042] NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) were added to a 10mL Schlenk tube equipped with a magnetic stirrer. The mixture was evacuated with a pump and filled with nitrogen three times. Then, dihydro-3(2H)-furanone (0.30mmol), phenylprop-2-enyl-1-one (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL of ultra-dry solvent methanol (MeOH) were added under N2 atmosphere. The mixture was stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction was completed, it was cooled to room temperature, the mixture was diluted with ethyl acetate, an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0043] Embodiment 12:

[0044] NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, tetrahydro-pyran-4-one (0.30mmol), phenylprop-2-enyl-1-one (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL ultra-dry solvent methanol (MeOH) were added under N2 atmosphere. The mixture was stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction was completed, it was cooled to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0045] Embodiment 13:

[0046] NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, tetrahydrothiopyran-4-one (0.30mmol), phenylprop-2-enyl-1-one (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL ultra-dry solvent methanol (MeOH) were added under N2 atmosphere. The mixture was stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction was completed, it was cooled to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0047] Embodiment 14:

[0048] Add NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) to a 10mL Schlenk tube equipped with a magnetic stirrer. After vacuuming with a pump, fill with nitrogen three times. Then, cyclohexane-1,3-dione (0.30mmol), phenylprop-2-enyl-1-one (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL of ultra-dry solvent methanol (MeOH) are added under N2 atmosphere. The mixture is stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction is completed, cool to room temperature, dilute the mixture with ethyl acetate, add appropriate amount of water, and then extract three times with ethyl acetate, collect the organic phase, add appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layer, and concentrate under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0049] Embodiment 15:

[0050] Add NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) to a 10mL Schlenk tube equipped with a magnetic stirrer. After vacuuming with a pump, fill with nitrogen three times. Then, add 2,6,6-trimethyl-cyclohexene-1,4-dione (0.30mmol), phenylprop-2-enyl-1-one (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL ultra-dry solvent methanol (MeOH) under N2 atmosphere. The mixture is stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction is completed, cool to room temperature, dilute the mixture with ethyl acetate, add appropriate amount of water, extract three times with ethyl acetate, collect the organic phase, add appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layer, and concentrate under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0051] Embodiment 16:

[0052] Add NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) to a 10mL Schlenk tube equipped with a magnetic stirrer. Vacuum with a pump and fill with nitrogen three times. Then, cyclooctanone (0.30mmol), (2E)-1,3-diphenyl-2-propene-1-one (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL of ultra-dry solvent methanol (MeOH) are added under N2 atmosphere. The mixture is stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction is completed, cool to room temperature, dilute the mixture with ethyl acetate, add appropriate amount of water, and extract three times with ethyl acetate, collect the organic phase, add appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layer, and concentrate under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0053] Embodiment 17:

[0054] Add NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) to a 10mL Schlenk tube equipped with a magnetic stirrer. Vacuum with a pump and fill with nitrogen three times. Then, cycloheptanone (0.30mmol), (2E)-1,3-diphenyl-2-propene-1-one (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL of ultra-dry solvent methanol (MeOH) are added under N2 atmosphere. The mixture is stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction is completed, cool to room temperature, dilute the mixture with ethyl acetate, add appropriate amount of water, and extract three times with ethyl acetate, collect the organic phase, add appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layer, and concentrate under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0055] Embodiment 18:

[0056] NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, 4-dihydrochromone (0.30mmol), phenylprop-2-enyl-1-one (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL ultra-dry solvent methanol (MeOH) were added under N2 atmosphere. The mixture was stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction was completed, it was cooled to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0057] Embodiment 19:

[0058] NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, 4-dihydrochromone (0.30mmol), methacrolein (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL ultra-dry solvent methanol (MeOH) were added under N2 atmosphere. The mixture was stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction was completed, it was cooled to room temperature, the mixture was diluted with ethyl acetate, an appropriate amount of water was added, and then extracted three times with ethyl acetate, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0059] Embodiment 20:

[0060] NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, 2-methyl-5-(1-methylethyl)-cyclohexanone (0.30mmol), phenylprop-2-enyl-1-one (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL ultra-dry solvent methanol (MeOH) were added under N2 atmosphere. The mixture was stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction was completed, it was cooled to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0061] Embodiment 21:

[0062] Add NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) to a 10mL Schlenk tube equipped with a magnetic stirrer. Vacuum with a pump and fill with nitrogen three times. Then, indane-1,2-dione (0.30mmol), methacrolein (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL of ultra-dry solvent methanol (MeOH) are added under N2 atmosphere. The mixture is stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction is completed, it is cooled to room temperature, the mixture is diluted with ethyl acetate, an appropriate amount of water is added, and then extracted with ethyl acetate three times, the organic phase is collected, and an appropriate amount of anhydrous Na2SO4 is added to dehydrate the combined organic layers, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0063] Embodiment 22:

[0064] NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) were added to a 10mL Schlenk tube equipped with a magnetic stirrer. The mixture was evacuated with a pump and filled with nitrogen three times. Then, 4-(4-hydroxyphenyl)cyclohexane-1-one (0.30mmol), methacrolein (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL of ultra-dry solvent methanol (MeOH) were added under N2 atmosphere. The mixture was stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction was completed, it was cooled to room temperature, the mixture was diluted with ethyl acetate, an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0065] Embodiment 23:

[0066] NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) were added to a 10mL Schlenk tube equipped with a magnetic stirrer. The mixture was evacuated with a pump and filled with nitrogen three times. Then, 17α-hydroxyprogesterone acetate (0.30mmol), phenylprop-2-enyl-1-one (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL of ultra-dry solvent methanol (MeOH) were added under a N2 atmosphere. The mixture was stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction was completed, it was cooled to room temperature, the mixture was diluted with ethyl acetate, an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0067] Embodiment 24:

[0068] NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) were added to a 10mL Schlenk tube equipped with a magnetic stirrer. The mixture was evacuated with a pump and then filled with nitrogen three times. Then, dehydroepiandrosterone acetate (0.30mmol), phenylprop-2-enyl-1-one (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL of ultra-dry solvent methanol (MeOH) were added under a N2 atmosphere. The mixture was stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction was completed, it was cooled to room temperature, the mixture was diluted with ethyl acetate, an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0069] Embodiment 25:

[0070] NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, 3-ketal (0.30mmol), methacrolein (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL ultra-dry solvent methanol (MeOH) were added under N2 atmosphere. The mixture was stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction was completed, it was cooled to room temperature, the mixture was diluted with ethyl acetate, an appropriate amount of water was added, and then extracted three times with ethyl acetate, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0071] Embodiment 26:

[0072] NH4I (0.6mmol, 2.0 equivalents), Cu(OAc)2 (0.03mmol, 0.1 equivalents) and DPEpHos (0.03mmol, 0.1 equivalents) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, epiandrosterone (0.30mmol), methacrolein (0.36mmol, 1.2 equivalents), diisopropylethylamine (0.9mmol, 3 equivalents) and 2.0mL ultra-dry solvent methanol (MeOH) were added under N2 atmosphere. The mixture was stirred at 30-100°C for 2-48 hours (constant temperature oil bath). After the reaction was completed, it was cooled to room temperature, the mixture was diluted with ethyl acetate, an appropriate amount of water was added, and then extracted three times with ethyl acetate, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

[0073] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for constructing a molten pyridine compound by a copper-catalyzed [2+1+3] cyclization reaction of a cyclic ketone with an α,β-unsaturated aldehyde / ketone and NH4I, characterized in that: The method comprises the following steps: in a nitrogen atmosphere, using Cu(OAc)2 as a catalyst, DPEpHos as a ligand, ammonium iodide as a N source, DIPEA as a base, and methanol as an ultra-dry solvent, and stirring with cyclic ketone, α,β-unsaturated aldehyde / ketone and NH4I at 30°C-100°C for 2-48 hours to obtain a product containing a molten pyridine compound.

2. A method for constructing a molten pyridine compound by a copper-catalyzed [2+1+3] cyclization reaction of a cyclic ketone with an α,β-unsaturated aldehyde / ketone and NH4I as claimed in claim 1, characterized in that: The product containing the molten pyridine compound was diluted with ethyl acetate, and then water was added, and then extracted three times with ethyl acetate. The organic phases were collected and combined, and then anhydrous Na2SO4 was added to dehydrate the combined organic phases, and then concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography on silica gel to obtain a purified molten pyridine compound.

3. A method for constructing a molten pyridine compound by a copper-catalyzed [2+1+3] cyclization reaction of a cyclic ketone with an α,β-unsaturated aldehyde / ketone and NH4I as claimed in claim 1, characterized in that: The molar ratio of Cu(OAc)2, DPEpHos, NH4I, DIPEA, cyclic ketone and α,β-unsaturated aldehyde / ketone is 0.03:0.03:0.60:0.90:0.30:0.

36.

4. A method for constructing a molten pyridine compound by a copper-catalyzed [2+1+3] cyclization reaction of a cyclic ketone with an α,β-unsaturated aldehyde / ketone and NH4I as claimed in claim 1, characterized in that: The cyclic ketone is one of cyclobutanone, cyclopentanone, cycloheptanone, cyclooctanone, cyclododecanone, 1-tetralone, 1,2,3,4-tetrahydro-2-naphthalenone, 2-benzylidenecyclohexanone, 4,4-difluorocyclohexanone, dihydro-3(2H)-furanone, tetrahydro-pyran-4-one, tetrahydrothiopyran-4-one, cyclohexane-1,3-dione, 2,6,6-trimethyl-cyclohexene-1,4-dione, 4-dihydrochromone, 2-methyl-5-(1-methylethyl)-cyclohexanone, indan-1,2-dione, 4-(4-hydroxyphenyl)cyclohexane-1-one, 17α-hydroxyprogesterone acetate, dehydroepiandrosterone acetate, 3-ketal and epiandrosterone.

5. A method for constructing a molten pyridine compound by a copper-catalyzed [2+1+3] cyclization reaction of a cyclic ketone with an α,β-unsaturated aldehyde / ketone and NH4I as claimed in claim 1, characterized in that: The α,β-unsaturated aldehyde / ketone is one of 1-octen-3-one, 1-penten-3-one, phenylprop-2-enyl-1-one, 1-(4-fluorophenyl)-2-propene-1-one, methacrolein, trans-2-pentenal and (2E)-1,3-diphenyl-2-propene-1-one.

6. A method for constructing a molten pyridine compound by a copper-catalyzed [2+1+3] cyclization reaction of a cyclic ketone with an α,β-unsaturated aldehyde / ketone and NH4I as claimed in claim 1, characterized in that: The chemical formula of the molten pyridine compound is as follows: R 1 is H, n-pentyl, ethyl, phenyl or 2,3-dimethoxyphenyl; R 2 is H, methyl or ethyl; R 3 is H, methyl, phenyl or naphthyl.

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