Method for constructing polysubstituted pyridine by alkali-promoted cyclization of ketone, ammonium iodide and alpha, beta-unsaturated ketone

Abstract

The invention develops a method for constructing polysubstituted pyridine by alkali-promoted cyclization of ketone, ammonium iodide and alpha, beta-unsaturated ketone. According to the invention, commercially available ketone compounds, ammonium iodide and alpha, beta-unsaturated ketone are used as starting raw materials, and various polysubstituted pyridine compounds are obtained at a medium to good yield through [2 + 1 + 3] cascade reaction. The interesting method has the characteristics of simple operation, easily available starting materials, mild reaction conditions, good functional group tolerance, high atom economy and the like. According to the three-component synthesis strategy, the synthesis efficiency can be remarkably improved, the synthesis steps can be reduced, meanwhile, a gate is opened for constructing high-functionalization or complex polysubstituted pyridine, and the polysubstituted pyridine derivative is still difficult to prepare through a traditional synthesis method. It is believed that the three-component strategy has great application potential in the aspects of organic synthesis and transition metal catalysts.

Description

[Technical field]

[0001] The invention belongs to the field of catalytic organic synthesis and relates to a method for constructing polysubstituted pyridine by promoting three-component cyclization of ketone with ammonium iodide and α,β-unsaturated ketone by a base. [Background technology]

[0002] Pyridine is an electron-deficient aromatic heterocyclic compound. Its ring is similar to a benzene ring and is planar. Since the electron cloud density of the carbon atoms on its ring is much smaller than that of benzene, it is often called a "π-deficient" heterocyclic ring. The chemical properties of pyridine-containing heterocyclic compounds are that they are easy to reduce but difficult to oxidize; they are easy to be nucleophilically substituted but difficult to be electrophilically substituted. Polysubstituted pyridine compounds are the basic skeletons of many biologically active molecules and important drugs, especially in the field of medicine. For example, pioglitazone is used to treat type II diabetes and is a common oral antidiabetic drug that can help patients regulate blood sugar balance in the body. Omeprazole can inhibit the secretion of gastric acid and effectively promote the repair of ulcers.

[0003] At the same time, polysubstituted pyridine compounds belong to a class of attractive organic chemicals with broad application prospects in drug synthesis, pesticides and fragrances, especially in the development of some new drugs, which has attracted widespread attention. It is worth mentioning that although polysubstituted pyridine compounds have a wide range of applications in the field of medicinal chemistry, there are still few effective methods for synthesizing polysubstituted pyridine compounds. Although these reactions have made many efforts in obtaining polysubstituted pyridine compounds, there are still two basic problems: (1) Most of these reactions belong to aromatic substituted pyridines, and alkyl substituted pyridines are rare. (2) Generally speaking, some reaction conditions are harsh and the catalysts used are expensive, which cannot meet the concept of green environmental protection.

[0004] Direct and efficient access to various substituted pyridine derivatives through simple methods will be the focus of new drug development in the next few decades. Here, we developed an efficient base-promoted ketone, inorganic ammonium salt and rare ketone three-component [3+2+1] tandem cyclization scheme to generate polysubstituted pyridines. In the reaction, we used abundant and easily available inorganic ammonium salts as nucleophiles, and in situ nucleophilic addition with various ketones to generate imine intermediates, followed by cyclization of imines with α,β-unsaturated ketones. This green and environmentally friendly method will help to obtain this special polysubstituted pyridine structure. This method has simple conditions and is easy to operate, with good substrate adaptability and high yield, and the starting materials can be directly purchased commercially. At present, there are no public documents and patent applications reporting the base-promoted three-component cyclization of ketones with ammonium iodide and α,β-unsaturated ketones to construct polysubstituted pyridines. [Summary of the invention]

[0005] The present invention develops a method for constructing polysubstituted pyridines by three-component cyclization of ketones with ammonium iodide and α,β-unsaturated ketones promoted by bases. Commercially available ketone compounds are used with ammonium iodide and α,β-unsaturated ketones as three-component starting materials through [2+1+3]-stage tandem reactions, and various polysubstituted pyridine compounds are obtained in moderate to good yields. 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. This three-component synthesis strategy can significantly improve the synthesis efficiency and reduce the number of synthesis steps, and also opens the door to construct highly functionalized or complex polysubstituted pyridines, while traditional synthesis methods are still difficult to prepare such polysubstituted pyridine derivatives. We believe that this three-component strategy will have great application potential in organic synthesis and transition metal catalysts.

[0006] To achieve the above object, the technical solution of the present invention is as follows:

[0007] A method for constructing a polysubstituted pyridine compound by a base-promoted [2+1+3] cyclization reaction of a ketone with an α,β-unsaturated ketone and NH4I, comprising the following steps: in a nitrogen atmosphere, using ammonium iodide as a nitrogen source, triethylamine as a base, and methanol as an ultra-dry solvent, stirring the ketone, the α,β-unsaturated ketone and NH4I at 30°C-100°C for 2-48 hours to obtain a polysubstituted pyridine compound.

[0008] A further improvement is that the product containing the polysubstituted 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 polysubstituted pyridine compound.

[0009] In a further improvement, the molar ratio of NH4I, Et3N, ketone and α,β-unsaturated ketone is 0.75:0.90:0.30:0.36.

[0010] In a further improvement, the ketone is one of acetone, 2-butanone, pinacolone, acetylacetone, cyclopentyl acetone, cyclohexyl acetone, 2-decanoic acid ketone, 5-decanoic acid ketone, adamantane acetone, piperonyl acetone, 4-phenyl-2-butanone, acetophenone, 2-acetylfuran, 2-acetylthiophene, 2-acetylthiazole, 2-acetylpyridine, 2-acetylpyrazine, diphenyl acetone, hexanophenone, heptanone, pyrophenyl acetone and 4-methyldiphenyl acetone.

[0011] In a further improvement, the α,β-unsaturated ketone is one of 1-octen-3-one, 1-phenyl-2-propene-1-one, phenylprop-2-enyl-1-one, 1-(4-fluorophenyl)-2-propene-1-one and (2E)-1,3-diphenyl-2-propene-1-one.

[0012] In a further improvement, the chemical formula of the polysubstituted pyridine compound is as follows:

[0013]

[0014] R 1 is H, methyl, ethyl, tert-butyl, acetyl, cyclopentyl, cyclohexyl or phenyl, etc.;

[0015] R 2 H, methyl, ethyl, n-propyl, n-butyl or phenyl, etc.;

[0016] R 3 is H, n-pentyl, phenyl or naphthyl.

[0017] R 4 is H, methyl or phenyl.

[0018] R 5 is H, methyl or phenyl.

[0019] The advantages of the present invention are as follows:

[0020] The present invention discloses a novel method for synthesizing various polysubstituted pyridine derivatives with high selectivity through [2+1+3] tandem cyclization using triethylamine as an organic base, ammonium iodide (NH4I) as a N source, ketones and α,β-unsaturated ketones. The method does not use any catalyst or ligand, and avoids the use of complex and sensitive organometallic reagents. At the same time, this form of [2+1+3] cyclization reaction is suitable for a variety of substrates, has good tolerance to a variety of substituents, and can provide readily available polysubstituted pyridine compounds in good yields. In addition, the reaction also has the characteristics of low additive prices, mild reaction conditions, and readily available starting materials. A multi-component tandem cyclization protocol is achieved under mild conditions from readily commercially available starting materials, and polysubstituted pyridine compounds with high regioselectivity are constructed.

Brief Description of the Drawings

[0021] Figure 1 A method for constructing polysubstituted pyridines via base-promoted three-component cyclization of ketones with ammonium iodide and α,β-unsaturated ketones.

[0022] Figure 2 Chemical formulas of polysubstituted pyridine compounds. [Specific implementation method]

[0023] Reaction formula of the present invention is as follows:

[0024]

[0025] Embodiment 1:

[0026] In a 10.0 mL Schlenk reaction tube equipped with a magnetic stirrer, NH4I (2.0 equivalents), acetone (0.3 mmol), 1-octen-3-one (1.2 equivalents, 0.36 mmol), triethylamine (3.0 equivalents) and 2.0 mL of ultra-dry solvent MeOH were added. The reaction solution was then heated to 60°C and stirred in an oil bath for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and the resulting solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using PE / EtOAc as the eluent to obtain the final purified 2-methyl-4-phenylpyridine. Pale yellow oil, yield: 41 mg, 80% yield (PE / EA=8:1). 1 H NMR (400MHz, CDCl3) δ8.52(d,J=5.2Hz,1H),7.66–7.56(m,2H),7.49–7.38(m,3H),7.36(d,J=1.8Hz,1H),7.29(dd,J=5.2,1.8Hz,1H),2.61(s,3H). 13 C NMR (101MHz, CDCl3) δ158.9,149.6,148.8,138.5,129.1,129.0,127.1,121.3,119.0,24.6.

[0027] Embodiment 2:

[0028] In a 10.0 mL Schlenk reaction tube equipped with a magnetic stirrer, NH4I (2.0 equivalents), pinacolone (0.3 mmol), 1-octen-3-one (1.2 equivalents, 0.36 mmol), triethylamine (3.0 equivalents) and 2.0 mL of ultra-dry solvent MeOH were added. The reaction solution was then heated to 60°C and stirred in an oil bath for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and the resulting solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using PE / EtOAc as the eluent to obtain the final purified 2-tert-butyl-4-phenylpyridine. Pale yellow oil, yield: 41 mg, 65% yield (PE / EA=8:1). 1 H NMR (400MHz, CDCl3) δ8.61 (dd, J=5.1, 0.8Hz, 1H), 7.65–7.60 (m, 2H), 7.54 (dd, J=1.7,0.8Hz,1H),7.51–7.40(m,3H),7.31(dd,J=5.1,1.7Hz,1H),1.43(s,8H). 13 C NMR (101MHz,CDCl3) 13CNMR(101MHz,Chloroform-d)δ170.0,149.1,148.8,139.3,129.2,128.9,127.3,119.1,117.4,37.7,30.4.

[0029] Embodiment 3:

[0030] In a 10.0 mL Schlenk reaction tube equipped with a magnetic stirrer, NH4I (2.0 equivalents), acetylacetone (0.3 mmol), 1-octen-3-one (1.2 equivalents, 0.36 mmol), triethylamine (3.0 equivalents) and 2.0 mL of ultra-dry solvent MeOH were added. The reaction solution was then heated to 60°C and stirred in an oil bath for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and the resulting solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using PE / EtOAc as the eluent to obtain the final purified 1-(3-methyl-4-phenylpyridin-2-yl)ethan-1-one. Yellow oil, yield: 54 mg, 85% yield (PE / EA=10:1). 1 H NMR (400MHz, CDCl3) δ8.07–8.00(m,3H),7.62(d,J=8.2Hz,1H),7.50–7.40(m,3H),2.84(s,3H),2.59(s,3H). 13 C NMR (101MHz, CDCl3) δ200.0,158.7,158.6,138.4,138.1,130.7,129.8,128.9,127.3,117.3,29.4,25.4.

[0031] Embodiment 4:

[0032] In a 10.0 mL Schlenk reaction tube equipped with a magnetic stirrer, NH4I (2.0 equivalents), cyclopentyl ethyl ketone (0.3 mmol), 1-octen-3-one (1.2 equivalents, 0.36 mmol), triethylamine (3.0 equivalents) and 2.0 mL of ultra-dry solvent MeOH were added. The reaction solution was then heated to 60°C and stirred in an oil bath for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and the resulting solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using PE / EtOAc as the eluent to obtain the final purified 2-cyclopentyl-4-phenylpyridine. Yellow oil, yield: 50 mg, 75% yield (PE / EA=8:1). 1H NMR(400MHz, CDCl3)δ8.60(d,J=5.2Hz,1H),7.68–7.62(m,2H),7.53–7.40(m,4H),7.33(dd,J =5.2,1.8Hz,1H),3.33–3.21(m,1H),2.22–2.10(m,2H),1.94–1.81(m,4H),1.80–1.69(m,2H). 13 C NMR (101MHz, CDCl3) δ166.2,149.6,148.7,138.8,129.0,128.8,127.1,119.8,119.1,48.1,33.6,25.9.

[0033] Embodiment 5:

[0034] In a 10.0 mL Schlenk reaction tube equipped with a magnetic stirrer, NH4I (2.0 equivalents), cyclohexyl ethyl ketone (0.3 mmol), 1-octen-3-one (1.2 equivalents, 0.36 mmol), triethylamine (3.0 equivalents) and 2.0 mL of ultra-dry solvent MeOH were added. The reaction solution was then heated to 60°C and stirred in an oil bath for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and the resulting solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using PE / EtOAc as the eluent to obtain the final purified 2-cyclohexyl-4-phenylpyridine. Yellow oil, yield: 64 mg, 90% yield (PE / EA=8:1). 1 H NMR(400MHz, CDCl3)δ8.60(d,J=5.2Hz,1H),7.68–7.62(m,2H),7.53–7.40(m,4H),7.33(dd,J =5.2,1.8Hz,1H),3.33–3.21(m,1H),2.22–2.10(m,2H),1.94–1.81(m,4H),1.80–1.69(m,2H). 13 C NMR (101MHz, CDCl3) δ166.2,149.6,148.7,138.8,129.0,128.8,127.1,119.8,119.1,48.1,33.6,25.9.

[0035] Embodiment 6:

[0036] In a 10.0 mL Schlenk reaction tube equipped with a magnetic stirrer, NH4I (2.0 equivalents), 2-decene (0.3 mmol), 1-octen-3-one (1.2 equivalents, 0.36 mmol), triethylamine (3.0 equivalents) and 2.0 mL of ultra-dry solvent MeOH were added. The reaction solution was then heated to 60°C and stirred in an oil bath for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and the resulting solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using PE / EtOAc as the eluent to obtain the final purified 2-octyl-4-phenylpyridine. Yellow oil, yield: 55 mg, 69% yield (PE / EA=8:1). 1 H NMR (400MHz, CDCl3) δ8.56(d,J=5.2Hz,1H),7.63(dd,J=7.7,1.7Hz,2H),7.51–7.40(m,3H),7.36(d,J=1.7Hz,1H ),7.32(dd,J=5.4,1.7Hz,1H),2.90–2.82(m,2H),1.77(p,J=7.4Hz,2H),1.45–1.26(m,10H),0.92–0.82(m,3H). 13 C NMR (101MHz, CDCl3) δ163.2,149.7,148.9,138.7,129.2,129.0,127.2,120.8,119.2,38.7,32.0,30.2,29.6,29.4,22.8,14.2.

[0037] Embodiment 7:

[0038] In a 10.0 mL Schlenk reaction tube equipped with a magnetic stirrer, NH4I (2.0 equivalents), 2-adamantanethanoic acid ketone (0.3 mmol), 1-octen-3-one (1.2 equivalents, 0.36 mmol), triethylamine (3.0 equivalents) and 2.0 mL of ultra-dry solvent MeOH were added. The reaction solution was then heated to 60°C and stirred in an oil bath for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and the resulting solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using PE / EtOAc as the eluent to obtain the final purified 2-(adamantan-1-yl)-4-phenylpyridine. Yellow oil, yield: 55 mg, 63% yield (PE / EA=8:1). 1H NMR(400MHz, CDCl3)δ8.63(d,J=5.1Hz,1H),7.65–7.60(m,2H),7.50–7.39(m,4H),7.30(d d,J=5.1,1.7Hz,1H),2.14(p,J=3.1Hz,3H),2.07(d,J=3.1Hz,6H),1.81(t,J=3.2Hz,6H). 13 CNMR (101MHz, CDCl3) δ169.7,149.3,148.8,139.2,129.1,128.8,127.2,119.0,117.2,42.1,39.2,36.9,28.9.

[0039] Embodiment 8:

[0040] In a 10.0 mL Schlenk reaction tube equipped with a magnetic stirrer, NH4I (2.0 equivalents), acetophenone (0.3 mmol), 1-octen-3-one (1.2 equivalents, 0.36 mmol), triethylamine (3.0 equivalents) and 2.0 mL of ultra-dry solvent MeOH were added. The reaction solution was then heated to 60°C and stirred in an oil bath for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and the resulting solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using PE / EtOAc as the eluent to obtain the final purified 2,4-diphenylpyridine. Yellow oil, yield: 57 mg, 82% yield (PE / EA=8:1). 1 H NMR (400MHz, CDCl3) δ8.74(d,J=5.2Hz,1H),8.05(d,J=7.7Hz,2H),7.93(s,1H),7.69(d,J=7.6Hz,2H),7.55–7.41(m,7H). 13 C NMR (101MHz, CDCl3) δ158.2,150.2,149.4,139.6,138.7,129.3,129.2,129.2,128.9,127.2,127.2,120.4,118.9.HRMS(ESI)m / z:[M+H] + Calculate for C 17 H 14 N + 232.1121; found 232.1129.

[0041] 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 polysubstituted pyridine compound by a base-promoted [2+1+3] cyclization reaction of a ketone with an α,β-unsaturated ketone and NH4I, comprising the following steps: in a nitrogen atmosphere, using ammonium iodide as a nitrogen source, triethylamine as a base, and methanol as an ultra-dry solvent, stirring the ketone, α,β-unsaturated ketone and NH4I at 30°C-100°C for 2-48 hours to obtain a polysubstituted pyridine compound.

2. Further improvement: the product containing the polysubstituted 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 polysubstituted pyridine compound.

3. Further improvement, the molar ratio of NH4I, Et3N, ketone and α,β-unsaturated ketone is 0.75:0.90:0.30:0.

36.

4. A further improvement, wherein the ketone is one of acetone, 2-butanone, pinacolone, acetylacetone, cyclopentyl acetone, cyclohexyl acetone, 2-butanone, 5-butanone, adamantane acetone, piperonyl acetone, 4-phenyl-2-butanone, acetophenone, 2-acetylfuran, 2-acetylthiophene, 2-acetylthiazole, 2-acetylpyridine, 2-acetylpyrazine, diacetophenone, hexanophenone, heptanone, pyrophenone and 4-methyldiphenyl acetone.

5. In a further improvement, the α,β-unsaturated ketone is one of 1-octen-3-one, 1-phenyl-2-propene-1-one, phenylprop-2-enyl-1-one, 1-(4-fluorophenyl)-2-propene-1-one and (2E)-1,3-diphenyl-2-propene-1-one. In a further improvement, the chemical formula of the polysubstituted pyridine compound is as follows: R 1 is H, methyl, ethyl, tert-butyl, acetyl, cyclopentyl, cyclohexyl or phenyl, etc.; R 2 H, methyl, ethyl, n-propyl, n-butyl or phenyl, etc.; R 3 is H, n-pentyl, phenyl or naphthyl; R 4 is H, methyl or phenyl; R 5 is H, methyl or phenyl.

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