A method for constructing molten pyridine compounds by copper-catalyzed [2+1+3] cyclization reactions of cyclic ketones with α,β-unsaturated aldehydes / ketones and ammonium iodide.

Abstract

This invention discloses a novel method for the highly selective synthesis of molten pyridine compounds via a copper-catalyzed [2+1+3] cyclization reaction of cyclic ketones with α,β-unsaturated aldehydes / ketones and NH4I. Under Cu(OAc)2 / DPEPhos catalysis, DIPEA is used as the organic base, and ammonium iodide (NH4I) is used as the nitrogen source to form a [2+1+3] cascade cyclization reaction with cyclic ketones and α,β-unsaturated aldehydes / ketones in a three-component configuration. This method uses Cu(OAc)2 as an inexpensive catalyst, avoiding the use of complex and sensitive organometallic reagents. Furthermore, this formal [2+1+3] cyclization reaction is applicable to a variety of substrates, exhibits good tolerance to various substituents, and provides readily available molten pyridines in good yields. In addition, the reaction features inexpensive additives, mild reaction conditions, and readily available starting materials. It achieves a multi-component cascade cyclization protocol using readily available starting materials under mild conditions, constructing molten pyridine compounds with high regioselectivity.

Description

[Technical Field]

[0001] This invention belongs to the field of catalytic organic synthesis and relates to a method for constructing molten pyridine compounds by copper-catalyzed [2+1+3] cyclization reaction of cyclic ketones with α,β-unsaturated aldehydes / ketones and NH4I. [Background Technology]

[0002] Pyridine is a typical electron-deficient aromatic heterocyclic compound and a core structure in many natural products and drug molecules, playing a crucial role in coordination chemistry, catalysis, and materials science. Meanwhile, molten pyridine is considered a privileged pyridine framework with broad biological functions, including antiviral, anticancer, and antioxidant activities. For example, desloratadine is a commonly used antihistamine for treating allergic rhinitis. Blonanserin is an atypical antipsychotic, a potent dopamine D2 (Ki: 14.8 nM) and serotonin 5-HT2 (Ki: 3.98 nM) receptor antagonist, primarily used clinically to treat schizophrenia. Cicletanine is indicated for the treatment of mild to moderate hypertension.

[0003] Although molten pyridine has attracted considerable attention in medicinal chemistry and agriculture due to its unique electronic properties and structural rigidity, its synthesis methods often suffer from harsh reaction conditions, poor substrate compatibility, and low yields. Known examples include the three-component cyclization reaction of aldehydes, acylacetonitrs, and electron-rich amino heterocycles in ionic liquids (ACS Comb. Sci. 2011, 13, 45–49); and the Rh(III)-catalyzed three-component cyclization reaction 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 for preparing multifunctional fused pyridine derivatives remains highly desirable. Commercially available starting materials can be directly utilized, thus avoiding the limitations of limited substitution categories, low functional group compatibility, and the multi-step synthesis of starting materials. Therefore, we have developed a copper-catalyzed method for the formation of a [2+1+3] cascade cyclization reaction of commercially available cyclic ketones with α,β-unsaturated aldehydes / ketones and NH4I. This method is simple to operate, has good substrate adaptability, and yields high output, and the starting materials are commercially available. Currently, there are no published documents or patent applications reporting the formation of molten pyridine through a multi-component [2+1+3] cascade cyclization reaction. [Summary of the Invention]

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

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

[0006] A method for constructing molten pyridine compounds by copper-catalyzed [2+1+3] cyclization reaction of cyclic ketones with α,β-unsaturated aldehydes / ketones and NH4I includes the following steps: under a nitrogen atmosphere, using Cu(OAc)2 as a catalyst, DPEPOs as a ligand, ammonium iodide as a nitrogen source, DIPEA as a base, and methanol as an ultra-dry solvent, the cyclic ketone, α,β-unsaturated aldehydes / ketones, and NH4I are stirred at 30℃-100℃ for 2-48 hours to obtain a product containing molten pyridine compounds.

[0007] Further improvements involved diluting the product containing the molten pyridine compound with ethyl acetate, adding water, and extracting it three times with ethyl acetate. The organic phases were collected and combined, and then anhydrous Na2SO4 was added to dehydrate the combined organic phases. The mixture was then concentrated under reduced pressure to obtain a crude product. The crude product was then separated by column chromatography on silica gel to obtain the purified molten pyridine compound.

[0008] Further improvements were made, with the molar ratio of Cu(OAc)2, DPEPOs, NH4I, DIPEA, cyclic ketones and α,β-unsaturated aldehydes / ketones being 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-tetrahydronaphthone, 1,2,3,4-tetrahydro-2-naphthone, 2-benzylmethylcyclohexanone, 4,4-difluorocyclohexanone, dihydro-3(2H)-furanone, tetrahydro-pyran-4-one, tetrahydrothiaran-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 epiandrolone.

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

[0011]

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

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

[0014] R 3 It can be H, methyl, phenyl, or naphthyl.

[0015] The advantages of this invention are as follows:

[0016] This invention presents a novel method for the highly selective synthesis of molten pyridine derivatives via a [2+1+3] cascade cyclization of cyclic ketones and α,β-unsaturated aldehydes / ketones under Cu(OAc)2 / DPEPhos catalysis, using DIPEA as an organic base and ammonium iodide (NH4I) as the nitrogen source. This method utilizes Cu(OAc)2 as an inexpensive catalyst, avoiding the use of complex and sensitive organometallic reagents. Furthermore, this formal [2+1+3] cyclization reaction is applicable to a variety of substrates, exhibits good tolerance to various substituents, and provides readily available molten pyridines in good yields. In addition, the reaction features inexpensive additives, mild reaction conditions, and readily available starting materials. It achieves a multi-component cascade cyclization protocol using readily available starting materials under mild conditions, constructing molten pyridine compounds with high regioselectivity. [Attached Image Description]

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

[0018] Figure 2 The chemical formula of the molten pyridine compound.

Detailed Implementation Methods

[0019] The reaction formula of this invention is as follows:

[0020]

[0021] Example 1:

[0022] NH4I (0.6 mmol, 2.0 equivalent), Cu(OAc)2 (0.03 mmol, 0.1 equivalent), and DPEPos (0.03 mmol, 0.1 equivalent) were added to a 10 mL Schlenk tube equipped with a magnetic stirrer. The tube was evacuated with a pump and then filled with nitrogen three times. Then, under a N2 atmosphere, cyclooctanone (0.30 mmol), 1-octen-3-one (0.36 mmol, 1.2 equivalent), diisopropylethylamine (0.9 mmol, 3 equivalent), and 2.0 mL of ultra-dry solvent methanol (MeOH) were added. The mixture was stirred at 30–100 °C for 2–48 hours (using a constant-temperature oil bath). After the reaction was complete, the mixture was cooled to room temperature, diluted with ethyl acetate, and then extracted three times with ethyl acetate. The organic phase was collected, and the combined organic layers were dehydrated with an appropriate amount of anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified molten pyridine compounds. The 4-pentyl-5,6,7,8,9,10-hexahydrocyclooctano[b]pyridine was purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain 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] + calcd for C 16 H 25 NNa + 254.1879; found 254.1888.

[0023] Example 2:

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

[0025] Example 3:

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

[0027] Example 4:

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

[0029] Example 5:

[0030] Add NH4I (0.6 mmol, 2.0 equivalent), Cu(OAc)2 (0.03 mmol, 0.1 equivalent), and DPEPos (0.03 mmol, 0.1 equivalent) to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add cyclobutanone (0.30 mmol), phenylprop-2-enyl-1-one (0.36 mmol, 1.2 equivalent), diisopropylethylamine (0.9 mmol, 3 equivalent), and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 30–100 °C for 2–48 hours (using a constant-temperature oil bath). After the reaction is complete, cool to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified molten pyridine compounds.

[0031] Example 6:

[0032] Add NH4I (0.6 mmol, 2.0 equivalent), Cu(OAc)2 (0.03 mmol, 0.1 equivalent), and DPEPos (0.03 mmol, 0.1 equivalent) to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add cyclopentanone (0.30 mmol), phenylprop-2-enyl-1-one (0.36 mmol, 1.2 equivalent), diisopropylethylamine (0.9 mmol, 3 equivalent), and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 30–100 °C for 2–48 hours (using a constant-temperature oil bath). After the reaction is complete, cool to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified molten pyridine compounds.

[0033] Example 7:

[0034] Add NH4I (0.6 mmol, 2.0 equivalent), Cu(OAc)2 (0.03 mmol, 0.1 equivalent), and DPEPos (0.03 mmol, 0.1 equivalent) to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add cyclooctanone (0.30 mmol), phenylprop-2-enyl-1-one (0.36 mmol, 1.2 equivalent), diisopropylethylamine (0.9 mmol, 3 equivalent), and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 30–100 °C for 2–48 hours (using a constant-temperature oil bath). After the reaction is complete, cool to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified molten pyridine compounds.

[0035] Example 8:

[0036] Add NH4I (0.6 mmol, 2.0 equivalents), Cu(OAc)2 (0.03 mmol, 0.1 equivalents), and DPEPos (0.03 mmol, 0.1 equivalents) to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add cyclododecone (0.30 mmol), phenylprop-2-enyl-1-one (0.36 mmol, 1.2 equivalents), diisopropylethylamine (0.9 mmol, 3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 30–100 °C for 2–48 hours (using a constant-temperature oil bath). After the reaction is complete, cool to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified molten pyridine compounds.

[0037] Example 9:

[0038] Add NH4I (0.6 mmol, 2.0 equivalents), Cu(OAc)2 (0.03 mmol, 0.1 equivalents), and DPEPos (0.03 mmol, 0.1 equivalents) to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 1-tetrahydronaphthone (0.30 mmol), phenylprop-2-enyl-1-one (0.36 mmol, 1.2 equivalents), diisopropylethylamine (0.9 mmol, 3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 30–100 °C for 2–48 hours (using a constant-temperature oil bath). After the reaction is complete, cool to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified molten pyridine compounds.

[0039] Example 10:

[0040] Add NH4I (0.6 mmol, 2.0 equivalents), Cu(OAc)2 (0.03 mmol, 0.1 equivalents), and DPEPos (0.03 mmol, 0.1 equivalents) to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 4,4-difluorocyclohexanone (0.30 mmol), phenylprop-2-enyl-1-one (0.36 mmol, 1.2 equivalents), diisopropylethylamine (0.9 mmol, 3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 30–100 °C for 2–48 hours (using a constant-temperature oil bath). After the reaction is complete, cool to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified molten pyridine compounds.

[0041] Example 11:

[0042] Add NH4I (0.6 mmol, 2.0 equivalent), Cu(OAc)2 (0.03 mmol, 0.1 equivalent), and DPEPos (0.03 mmol, 0.1 equivalent) to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add dihydro-3(2H)-furanone (0.30 mmol), phenylprop-2-enyl-1-one (0.36 mmol, 1.2 equivalent), diisopropylethylamine (0.9 mmol, 3 equivalent), and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 30–100 °C for 2–48 hours (using a constant-temperature oil bath). After the reaction is complete, cool to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified molten pyridine compounds.

[0043] Example 12:

[0044] Add NH4I (0.6 mmol, 2.0 equivalents), Cu(OAc)2 (0.03 mmol, 0.1 equivalents), and DPEPos (0.03 mmol, 0.1 equivalents) to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add tetrahydropyran-4-one (0.30 mmol), phenylprop-2-enyl-1-one (0.36 mmol, 1.2 equivalents), diisopropylethylamine (0.9 mmol, 3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 30–100 °C for 2–48 hours (using a constant-temperature oil bath). After the reaction is complete, cool to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified molten pyridine compounds.

[0045] Example 13:

[0046] Add NH4I (0.6 mmol, 2.0 equivalents), Cu(OAc)2 (0.03 mmol, 0.1 equivalents), and DPEPos (0.03 mmol, 0.1 equivalents) to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add tetrahydrothiaran-4-one (0.30 mmol), phenylprop-2-enyl-1-one (0.36 mmol, 1.2 equivalents), diisopropylethylamine (0.9 mmol, 3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 30–100 °C for 2–48 hours (using a constant-temperature oil bath). After the reaction is complete, cool to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified molten pyridine compounds.

[0047] Example 14:

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

[0049] Example 15:

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

[0051] Example 16:

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

[0053] Example 17:

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

[0055] Example 18:

[0056] Add NH4I (0.6 mmol, 2.0 equivalent), Cu(OAc)2 (0.03 mmol, 0.1 equivalent), and DPEPos (0.03 mmol, 0.1 equivalent) to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 4-dihydrochromone (0.30 mmol), phenylprop-2-enyl-1-one (0.36 mmol, 1.2 equivalent), diisopropylethylamine (0.9 mmol, 3 equivalent), and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 30–100 °C for 2–48 hours (using a constant-temperature oil bath). After the reaction is complete, cool to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified molten pyridine compounds.

[0057] Example 19:

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

[0059] Example 20:

[0060] Add NH4I (0.6 mmol, 2.0 equivalent), Cu(OAc)2 (0.03 mmol, 0.1 equivalent), and DPEPos (0.03 mmol, 0.1 equivalent) to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 2-methyl-5-(1-methylethyl)-cyclohexanone (0.30 mmol), phenylprop-2-enyl-1-one (0.36 mmol, 1.2 equivalent), diisopropylethylamine (0.9 mmol, 3 equivalent), and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 30–100 °C for 2–48 hours (using a constant-temperature oil bath). After the reaction is complete, cool to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified molten pyridine compounds.

[0061] Example 21:

[0062] Add NH4I (0.6 mmol, 2.0 equivalent), Cu(OAc)2 (0.03 mmol, 0.1 equivalent), and DPEPHOS (0.03 mmol, 0.1 equivalent) to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add indane-1,2-dione (0.30 mmol), methacrolein (0.36 mmol, 1.2 equivalent), diisopropylethylamine (0.9 mmol, 3 equivalent), and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 30–100 °C for 2–48 hours (using a constant-temperature oil bath). After the reaction is complete, cool to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified molten pyridine compounds.

[0063] Example 22:

[0064] Add NH4I (0.6 mmol, 2.0 equivalents), Cu(OAc)2 (0.03 mmol, 0.1 equivalents), and DPEPos (0.03 mmol, 0.1 equivalents) to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 4-(4-hydroxyphenyl)cyclohexane-1-one (0.30 mmol), methacrolein (0.36 mmol, 1.2 equivalents), diisopropylethylamine (0.9 mmol, 3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 30–100 °C for 2–48 hours (using a constant-temperature oil bath). After the reaction is complete, cool to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified molten pyridine compounds.

[0065] Example 23:

[0066] Add NH4I (0.6 mmol, 2.0 equivalents), Cu(OAc)2 (0.03 mmol, 0.1 equivalents), and DPEPos (0.03 mmol, 0.1 equivalents) to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add 17α-hydroxyprogesterone acetate (0.30 mmol), phenylprop-2-enyl-1-one (0.36 mmol, 1.2 equivalents), diisopropylethylamine (0.9 mmol, 3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 30–100 °C for 2–48 hours (using a constant-temperature oil bath). After the reaction is complete, cool to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified molten pyridine compounds.

[0067] Example 24:

[0068] Add NH4I (0.6 mmol, 2.0 equivalents), Cu(OAc)2 (0.03 mmol, 0.1 equivalents), and DPEPos (0.03 mmol, 0.1 equivalents) to a 10 mL Schlenk tube equipped with a magnetic stirrer. Evacuate the tube with a pump and then fill it with nitrogen three times. Then, under a N2 atmosphere, add dehydroepiandrosterone acetate (0.30 mmol), phenylprop-2-enyl-1-one (0.36 mmol, 1.2 equivalents), diisopropylethylamine (0.9 mmol, 3 equivalents), and 2.0 mL of ultra-dry solvent methanol (MeOH). Stir the mixture at 30–100 °C for 2–48 hours (using a constant-temperature oil bath). After the reaction is complete, cool to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and extract three times with ethyl acetate. Collect the organic phase, add an appropriate amount of anhydrous Na2SO4 to dehydrate the combined organic layers, and concentrate under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified molten pyridine compounds.

[0069] Example 25:

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

[0071] Example 26:

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

[0073] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A method for constructing molten pyridine compounds by a copper-catalyzed [2+1+3] cyclization reaction of a cyclic ketone with α,β-unsaturated aldehydes / ketones and NH4I, characterized in that, The process includes the following steps: Under a nitrogen atmosphere, using Cu(OAc)2 as a catalyst, DEPHos as a ligand, DIPEA as a base, and methanol as an ultra-dry solvent, cyclic ketones, α,β-unsaturated aldehydes / ketones, and NH4I are stirred at 30℃-100℃ for 2-48 hours to obtain a product containing molten pyridine compounds. The cyclic ketone is one of cyclobutanone, cyclopentanone, cycloheptanone, cyclooctanone, and cyclododecanone; The α,β-unsaturated aldehyde / ketone is one of 1-octen-3-one, 1-penten-3-one, phenylprop-2-enyl-1-one, methacrolein, trans-2-pentenal, and (2E)-1,3-diphenyl-2-propen-1-one; The chemical formula of the molten pyridine compound is as follows: R 1 It is hydrogen (H), n-pentyl, ethyl, or phenyl; R 2 It is H or methyl; R 3 It can be H or phenyl.

2. The method for constructing molten pyridine compounds by copper-catalyzed [2+1+3] cyclization reaction of cyclic ketones with α,β-unsaturated aldehydes / ketones and NH4I as described in claim 1, characterized in that, The product containing the molten pyridine compound was diluted with ethyl acetate, water was added, and the product was 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. The product was then concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography on silica gel to obtain the purified molten pyridine compound.

3. The method for constructing molten pyridine compounds by copper-catalyzed [2+1+3] cyclization reaction of cyclic ketones with α,β-unsaturated aldehydes / ketones and NH4I as described in claim 1, characterized in that, The molar ratio of Cu(OAc)2, DPEPOs, NH4I, DIPEA, cyclic ketones and α,β-unsaturated aldehydes / ketones is 0.03:0.03:0.60:0.90:0.30:0.36.

Images