Synthetic methods for polysubstituted tetrahydropyridine compounds

Abstract

This invention relates to the field of chemical synthesis, specifically to a method for synthesizing polysubstituted tetrahydropyridine compounds. The invention uses 1,3,5-triazine and all-carbon dienes as reactants. The method described in this invention can simply and efficiently prepare polysubstituted tetrahydropyridine compounds, using readily available raw materials, with simple operation, without the use of metal reagents or catalysts, achieving moderate yields, and requiring no inert gas protection during the preparation process under mild reaction conditions.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis, specifically to a method for synthesizing polysubstituted tetrahydropyridine compounds. Background Technology

[0002] Tetrahydropyridine and its derivatives are an important class of nitrogen heterocyclic compounds with wide applications in life sciences, materials science, and other fields. The tetrahydropyridine skeleton is commonly found in biologically and physiologically active natural products and artificial molecules. Therefore, it is essential to develop efficient, green, and simple synthetic methods for constructing multi-substituted tetrahydropyridines. Currently, many feasible methods for constructing multi-substituted tetrahydropyridine structures are available in the literature, including the reduction of imine salt intermediates or pyridinium salts, aza[4+2] cycloaddition reactions, multicomponent reactions (MCR), and ring-closure metathesis reactions (RCM). However, many of these established methods are time-consuming and labor-intensive, often requiring harsh reaction conditions, expensive transition metal catalysts or additives, and multiple synthetic steps to obtain the desired tetrahydropyridine product. Against this backdrop, the development of simple, efficient, catalyst-free, and additive-free schemes for constructing multi-substituted tetrahydropyridine compounds under mild conditions is highly desirable. Summary of the Invention

[0003] This invention provides a method for synthesizing polysubstituted tetrahydropyridine compounds. This method enables the simple and efficient synthesis of polysubstituted tetrahydropyridine compounds by using 1,3,5-triazine and diene as starting materials, dichloromethane as solvent, and mild thermal reaction conditions in a one-step reaction.

[0004] The technical solution adopted in this invention is as follows: a method for synthesizing polysubstituted tetrahydropyridine compounds, wherein the structural formula of the polysubstituted tetrahydropyridine compounds is shown in Figure I.

[0005]

[0006] Where: R 1 It is phenyl or substituted phenyl (with different substitutions at different positions; substituents include methoxy, fluorine, chlorine, bromine, and cyano), benzyl, and cyclopropyl. R 2 It is a phenyl or 2-furanyl group substituted with methyl, methoxy, chlorine, or bromine. Its preparation method is as follows:

[0007]

[0008] Preparation method of target compound I: Compound II and compound III were dissolved in dichloromethane and stirred at room temperature. The reaction was stopped after compound II was completely reacted by thin-layer chromatography. The solvent was removed from the reaction mixture under reduced pressure, and target compound I was obtained by silica gel column chromatography.

[0009] The dichloromethane can be replaced by solvents such as 1,2-dichloroethane, chloroform, ethyl acetate, methanol, toluene, acetonitrile, tetrahydrofuran, 1,4-dioxane, or N,N-dimethylformamide.

[0010] The molar ratio of compound II to compound III is II:III = 0.3:1.0 to 1.0:1.0.

[0011] The eluent used for the silica gel column chromatography was a mixed solvent of petroleum ether and ethyl acetate, with a volume ratio of V... 石油醚 :V 乙酸乙酯 =10:1 to 5:1.

[0012] The beneficial effects of this invention are as follows: This invention uses 1,3,5-triazine and all-carbon diene as reactants. The method involved in this invention can simply and efficiently prepare multi-substituted tetrahydropyridine compounds, with readily available raw materials, simple operation, no need for metal reagents and catalysts, moderate yield, and no need for inert gas protection during the preparation process, and the reaction conditions are mild. Attached Figure Description

[0013] Figure 1 The proton spectrum of product I-1 obtained in the embodiments of the present invention;

[0014] Figure 2 The carbon spectrum of product I-1 obtained in the embodiments of the present invention; Detailed Implementation

[0015] Example 1

[0016] The reaction formula of Example 1, specifically the structures of compounds II-1 and III-1, and product I-1, are as follows. Experiments show that the optimal organic solvent used in this invention is dichloromethane, with a maximum yield of 78% for the reaction product. The optimal molar ratio of reactants is compound II-1:compound III-1 = 0.8 / 1.0, and the optimal reaction concentration is 0.1M.

[0017]

[0018] The specific experimental procedure is as follows: 50 mg (0.16 mmol, 0.8 equivalent) of compound II-1 and 54 mg (0.2 mmol, 1.0 equivalent) of compound III-1 were dissolved in 2 mL of dichloromethane and stirred at room temperature. After the reaction of reactant III-1 was complete, the reaction was stopped by thin-layer chromatography. The solvent dichloromethane was removed by rotary evaporation under reduced pressure using a water pump. The residue was eluent (v / v) onto 200-300 mesh silica gel. 石油醚 :V 乙酸乙酯=10:1 to 5:1) Column chromatography yielded 60 mg of the compound shown in I-1, and the product was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0019] Product I-1 is a yellow solid with a yield of 78% and a melting point of 115-116℃. 1 H NMR (400MHz, CDCl3) δ7.40–7.33(m,2H),7.31(d,J=8.7Hz,2H),7.11–7.01(m,3 H),6.97(d,J=8.7Hz,2H),4.15(s,2H),4.06(s,2H),3.85(s,3H),3.55(s,3H). 13 C NMR (100MHz, CDCl3) δ165.9,160.6,148.0,134.0,133.7,129.8,129.8,127.2, 122.5,117.4,114.3,113.1,56.4,55.4,52.6,49.1,39.4.HRMS(ESI)m / z:[M+H] + Calcd for C 22 H 20 N3O3374.1499, found 374.1499

[0020] The methods used to prepare other compounds of the present invention (compounds I-2 to I-13) are the same as those in Example 1, and the reaction conditions are as follows: compound II (0.16 mmol) and compound III (0.2 mmol) are dissolved in 2 mL of dichloromethane and reacted at room temperature (25 °C; I-7 requires heating to 50 °C).

[0021] The structure and data characterization of the obtained product are as follows:

[0022]

[0023]

[0024] I-2 is a yellow solid with a yield of 74% and a melting point of 98-99℃. 1 H NMR (400MHz, CDCl3) δ7.37–7.31(m,2H),7.14(td,J=7.8,1.6Hz,1H),7.07(dd,J=8.0,1.5H z,1H),6.99–6.92(m,4H),4.09(s,2H),3.95(s,2H),3.94(s,3H),3.85(s,3H),3.53(s,3H). 13C NMR (100MHz, CDCl3) δ166.2,160.5,153.2,136.9,134.3,133.6,129.9,127.4,125.4,121 .2,120.7,114.2,113.3,112.0,55.9,55.6,55.4,52.4,49.9,39.1.HRMS(ESI)m / z:[M+H] + Calcd forC 23 H 22 N3O4404.1605, found 404.1607

[0025] I-3 is a yellow solid with a yield of 68% and a melting point of 99-100℃. 1 H NMR (400MHz, CDCl3) δ7.34–7.28(m,2H),7.08–7.02(m,2H),6.99–6.94(m,2H),6. 93–6.88(m,2H),4.05(s,2H),3.92(s,2H),3.85(s,3H),3.80(s,3H),3.54(s,3H). 13 C NMR (100MHz, CDCl3) δ166.0,160.5,155.9,142.0,134.0,133.7,129.8,127.2,120 .2,115.0,114.3,113.2,57.6,55.7,55.4,52.5,50.4,39.5.HRMS(ESI)m / z:[M+H] + Calcd for C 23 H 22 N3O4404.1605, found 404.1606

[0026] I-4 is a yellow solid with a yield of 64% and a melting point of 130-131℃. 1 H NMR (400MHz, CDCl3) δ7.31(d,J=8.5Hz,2H),7.05(d,J=4.9Hz,4H),6.96(d,J=8.5Hz,2H),4.09(s,2H),3.98(s,2H),3.85(s,3H),3.54(s,3H). 13C NMR (100MHz, CDCl3) δ165.8, 160.6, 158.8 (d, J = 243.8Hz), 144.4 (d, J = 2.3Hz), 133.9, 133.6, 129 .8,127.1,119.7(d,J=8.0Hz),116.4(d,J=22.8Hz),114.3,113.0,57.1,55.4,52.6,49.9,39.4. 19 F NMR(376MHz, CDCl3)δ–120.2.HRMS(ESI)m / z:[M+H] + Calcd for C 22 H 19 FN3O3392.1405, found 392.1405

[0027] I-5 is a yellow solid with a yield of 66% and a melting point of 132-133℃. 1 H NMR (400MHz, CDCl3) δ7.38–7.27(m,4H),7.00(d,J=9.0Hz,2H),6.96(d,J=8.72Hz,2H),4.12(s,2H),4.03(s,2H),3.85(s,3H),3.55(s,3H). 13 C NMR (100MHz, CDCl3) δ165.8, 160.6, 146.5, 134.1, 133.4, 129.7 (d, J = 1.4Hz), 127. 6,127.0,118.6,114.3,112.9,56.2,55.4,52.6,49.0,39.3.HRMS(ESI)m / z:[M+H] + Calcd for C 22 H 19 ClN3O3408.1109, found 408.1110

[0028] I-6 is a yellow solid with a yield of 56% and a melting point of 135-136℃. 1 H NMR (400MHz, CDCl3) δ7.49–7.42(m,2H),7.33–7.27(m,2H),7.01–6.90(m,4H),4.12(s,2H),4.03(s,2H),3.85(s,3H),3.55(s,3H). 13C NMR (100MHz, CDCl3) δ165.8,160.6,147.0,134.1,133.3,132.7,129.7,127.0, 118.9,115.0,114.3,112.9,56.1,55.4,52.6,48.9,39.3.HRMS(ESI)m / z:[M+H] + Calcd forC 22 H 19 BrN3O3 452.0604, found 452.0606

[0029] I-7 is a yellow solid with a yield of 43% and a melting point of 150-151℃. 1 H NMR (400MHz, CDCl3) δ7.63(d,J=8.8Hz,2H),7.28(d,J=8.7Hz,2H),7.07(d,J=8.8H z,2H),6.97(d,J=8.7Hz,2H),4.27(s,2H),4.21(s,2H),3.85(s,3H),3.56(s,3H). 13 C NMR (100MHz, CDCl3) δ165.5,160.8,150.5,134.6,134.1,132.5,129.7,126.7,119 .2,115.5,114.4,112.5,104.1,55.4,54.0,52.8,47.6,38.9.HRMS(ESI)m / z:[M+H] + Calcd for C 23 H 19 N4O3399.1452, found 399.1453

[0030] I-8 is a yellow, oily liquid with a yield of 50%. 1 H NMR (400MHz, CDCl3) δ7.44–7.33(m,5H),7.30–7.26(m,2H),6.96–6.91(m,2H),3.84(s,2H),3.83(s,3H),3.53(s,2H),3.49(s,3H),3.26(s,2H). 13 C NMR (100MHz, CDCl3) δ166.1,160.4,135.8,134.0,133.3,129.8,129.1,128.9,128 .3,127.2,114.2,113.3,60.8,56.6,55.4,52.7,52.4,39.4.HRMS(ESI)m / z:[M+H] +Calcd for C 23 H 22 N3O3 388.1656, found 388.1654

[0031] I-9 is a yellow, oily liquid with a yield of 50%. 1 H NMR (400MHz, CDCl3) δ7.29–7.23 (m, 2H), 6.93 (d, J = 8.8Hz, 2H), 3.83 (s, 3H), 3.63(s,2H),3.51(s,3H),3.47(s,2H),2.07–1.99(m,1H),0.67–0.58(m,4H). 13 C NMR (100MHz, CDCl3) δ166.1,160.4,134.3,133.0,129.8,127.4,114.2,113.4,58.0,55.4,52.4,52.3,39.3,36.5,6.9.HRMS(ESI)m / z:[M+H] + Calcd forC 19 H 20 N3O3338.1499, found 338.1499

[0032] I-10 is a yellow solid with a yield of 63% and a melting point of 130-131℃. 1 H NMR (400MHz, CDCl3) δ7.42–7.31(m,2H),7.29–7.23(m,4H),7.10–7.01(m,3H),4.16(s,2H),4.06(s,2H),3.54(s,3H),2.40(s,3H). 13 C NMR (100MHz, CDCl3) δ165.7,148.0,139.7,134.4,133.5,132.1,129.8,129.6, 128.2,122.5,117.4,113.0,56.3,52.5,49.0,39.3,21.5.HRMS(ESI)m / z:[M+H] + Calcd for C 22 H 20 N3O2358.1550, found 358.1550

[0033] I-11 is a yellow solid with a yield of 46% and a melting point of 136-137℃. 1H NMR (400MHz, CDCl3) δ7.63–7.58(m,2H),7.40–7.34(m,2H),7.27–7.26(m,1H), ,7.25–7.23(m,1H),7.10–7.03(m,3H),4.17(s,2H),4.07(s,2H),3.56(s,3H). 13 C NMR (100MHz, CDCl3) δ165.2,147.9,134.4,133.8,133.5,132.2,130.1,129. 9,124.3,122.8,117.5,112.7,56.4,52.7,49.1,39.1.HRMS(ESI)m / z:[M+H] + Calcd for C 21 H 17 BrN3O2422.0499, found 422.0500.

[0034] I-12 is a yellow solid with a yield of 52% and a melting point of 133-134℃. 1 H NMR (400MHz, CDCl3) δ7.45 (d, J = 8.4Hz, 2H), 7.41–7.29 (m, 4H), 7.12–7.03 (m, 3H), 4.17 (s, 2H), 4.07 (s, 2H), 3.56 (s, 3H). 13 CNMR(100MHz, CDCl3)δ165.2,147.8,136.0,134.5,133.5,133.3,129.8,129.2,122.7,117.5,112.7,56.4,52.7,49.1,39.1.HRMS(ESI)m / z:[M+H] + Calcd forC 21 H 17 ClN3O2378.1004; Found 378.1001

[0035] I-13 is a yellow solid with a yield of 49% and a melting point of 85-86℃. 1 H NMR(400MHz, CDCl3)δ7.54(d,J=1.7Hz,1H),7.39–7.33(m,2H),7.08–7.02(m,3H),6.8 8(d,J=3.6Hz,1H),6.53(dd,J=3.6,1.8Hz,1H),4.14(s,2H),4.09(s,2H),3.82(s,3H). 13C NMR (100MHz, CDCl3) δ166.8,147.6,146.6,144.5,132.4,129.8,122.8,121. 0,117.6,113.3,112.5,112.1,56.9,53.0,49.5,35.0.HRMS(ESI)m / z:[M+H] + Calcd for C 19 H 16 N3O3334.1186, found 334.1185

[0036] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within the present invention.

[0037] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A method for synthesizing polysubstituted tetrahydropyridine compounds, characterized in that, Polysubstituted tetrahydropyridine compounds, with the structural formula shown in Figure I: Where: R 1 It is phenyl, substituted phenyl, benzyl or cyclopropyl, and the substituent is methoxy, fluorine, chlorine, bromine or cyano, R 2 The phenyl group substituted with methyl, methoxy, chlorine, or bromine, or the 2-furanyl group, is synthesized as follows: Synthesis of target compound I: Compounds II and III were dissolved in dichloromethane and stirred at room temperature. The reaction was stopped after compound II was completely reacted by thin-layer chromatography. The solvent was removed from the reaction mixture under reduced pressure, and the target compound I was obtained by silica gel column chromatography. The molar ratio of compound II to compound III is II∶III = 0.3:1.0~1.0:1.

0.

2. The method for synthesizing polysubstituted tetrahydropyridine compounds according to claim 1, characterized in that: The eluent used for the silica gel column chromatography was a mixed solvent of petroleum ether and ethyl acetate, with a volume ratio of V... 石油醚 :V 乙酸乙酯 = 10:1~5:1.

Images