A synthetic method for nitrogen-alkylated unsaturated polycyclic β-amino nitrile

Abstract

This invention belongs to the field of synthetic technology of β-aminonitriles and their derivatives, specifically relating to a method for synthesizing nitrogen-alkylated unsaturated polycyclic β-aminonitriles. Under inert gas protection, this invention uses inexpensive industrial-grade nitrile compounds and primary alcohols as raw materials, adding a base and an organorruthenium catalyst, and employs a one-pot method to achieve the ring-cloning reaction of the nitrile compounds, the dehydrogenation coupling reaction of the primary alcohol, and the reduction reaction of the carbon-nitrogen double bond to synthesize nitrogen-alkylated unsaturated polycyclic (five-membered ring, six-membered ring) β-aminonitriles. The reaction system is simple, the operation is convenient, the reaction conditions are mild, and the reaction substrates have good applicability. The obtained nitrogen-alkylated unsaturated polycyclic β-aminonitriles exhibit high yield and high chemoselectivity. Furthermore, this invention overcomes the shortcomings of limited substrate range, expensive raw materials and reagents, complex reaction systems, and lengthy synthetic steps, resulting in high economic efficiency, environmental friendliness, and simple post-reaction processing.

Description

Technical Field

[0001] This invention belongs to the field of synthetic technology of β-aminonitriles and their derivatives, specifically relating to a method for synthesizing nitrogen-alkylated unsaturated polycyclic β-aminonitriles. Background Technology

[0002] β-Aminonitrile is an important organic synthesis intermediate that can be widely used in the synthesis of some important compounds. Due to its potential antibacterial, anti-inflammatory, herbicidal and other biological activities and material properties, it has high application value in the fields of medicine, pesticides and materials.

[0003] Currently reported methods for synthesizing nitrogen-alkylated unsaturated five-membered and six-membered ring β-amino nitrs mainly involve first synthesizing unsaturated polycyclic β-amino nitrs, and then reacting them with acyl chlorides or haloalkanes to generate nitrogen-alkylated products (Tetrahedron. 2022, 109, 132685); or using aldehydes to dehydrate with amino groups to generate imines, which are then reduced to obtain the target product (Journal of Molecular Structure. 2023, 1274, 134319). However, these methods are cumbersome and have low product yields and chemoselectivity. Summary of the Invention

[0004] In view of this, the purpose of the present invention is to provide a method for synthesizing nitrogen-alkylated unsaturated polycyclic β-amino nitrile, which yields nitrogen-alkylated unsaturated polycyclic β-amino nitrile with high yield and good chemical selectivity.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] This invention provides a method for synthesizing nitrogen-alkylated unsaturated polycyclic β-amino nitrile, comprising the following steps:

[0007] A primary alcohol of Formula I, a nitrile compound of Formula II, a base, an organorruthenium catalyst, and an organic solvent are mixed and reacted in a one-pot manner under inert gas protection to obtain a nitrogen-alkylated unsaturated polycyclic β-amino nitrile of Formula III.

[0008] Formula I, Formula II, Formula III,

[0009] R is an aryl, halogenated aryl, pyridine group or straight-chain alkyl, X is -CH2-, -NH- or -N(CH2CH2CN)-, n=1 or 2, n represents the number of CH2 groups.

[0010] Preferably, the molecular formula of the organorruthenium catalyst is [(Ph-PN]].H [P)Ru(CO)HCl], with the structural formula shown in Formula IV.

[0011] Formula IV, Ph represents phenyl.

[0012] Preferably, the molar ratio of the primary alcohol to the nitrile compound is 1:1 to 2.

[0013] Preferably, the molar mass of the organorruthenium catalyst is 1 to 2% of the molar mass of the primary alcohol.

[0014] Preferably, the alkali is sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, potassium ethoxide, sodium hydroxide, potassium phosphate, or sodium hydride.

[0015] Preferably, the molar mass of the base is 1 to 3 times the molar mass of the primary alcohol.

[0016] Preferably, the temperature of the one-pot reaction is 110~120℃; the holding time of the one-pot reaction is 12~36h.

[0017] Preferably, the inert gas is argon.

[0018] Preferably, the organic solvent is toluene, tetrahydrofuran, 1,4-dioxane, cyclohexane, acetonitrile, or dichloromethane.

[0019] Preferably, after the one-pot reaction is completed, the process further includes: cooling the product obtained from the one-pot reaction to room temperature, and then sequentially performing phase transfer, vacuum distillation, elution, and column chromatography to obtain a nitrogen-alkylated unsaturated polycyclic β-amino nitrile with the structure shown in Formula III.

[0020] This invention provides a method for synthesizing nitrogen-alkylated unsaturated polycyclic β-amino nitrile, comprising the following steps:

[0021] A primary alcohol of Formula I, a nitrile compound of Formula II, a base, an organorruthenium catalyst, and an organic solvent are mixed and reacted in a one-pot manner under inert gas protection to obtain a nitrogen-alkylated unsaturated polycyclic β-amino nitrile of Formula III.

[0022] Formula I, Formula II, Formula III,

[0023] R is an aryl, halogenated aryl, pyridine group or straight-chain alkyl, X is -CH2-, -NH- or -N(CH2CH2CN)-, n=1 or 2, n represents the number of CH2 groups.

[0024] This invention, under inert gas protection, uses inexpensive industrial-grade nitrile compounds and primary alcohols as raw materials, with the addition of a base and an organorruthenium catalyst, to synthesize nitrogen-alkylated unsaturated polycyclic (five-membered and six-membered) β-aminonitriles via a one-pot reaction. This involves the ring-cloning reaction of the nitrile compounds, the dehydrogenation coupling reaction of the primary alcohol, and the reduction reaction of the carbon-nitrogen double bond. The reaction system is simple, the operation is convenient, and the substrates have good applicability. The obtained nitrogen-alkylated unsaturated polycyclic β-aminonitriles exhibit high yield and chemoselectivity, with compound yields generally ranging from 80% to 90%. Furthermore, this invention overcomes the drawbacks of limited substrate scope, expensive raw materials and reagents, complex reaction systems, and lengthy synthetic steps. The reaction is economically efficient, with water as the only byproduct, making it environmentally friendly and harmless. Post-reaction processing is simple, and it has very broad application prospects. Detailed Implementation

[0025] This invention provides a method for synthesizing nitrogen-alkylated unsaturated polycyclic β-amino nitrile, comprising the following steps:

[0026] A primary alcohol of Formula I, a nitrile compound of Formula II, a base, an organorruthenium catalyst, and an organic solvent are mixed and reacted in a one-pot manner under inert gas protection to obtain a nitrogen-alkylated unsaturated polycyclic β-amino nitrile of Formula III.

[0027] Formula I, Formula II, Formula III,

[0028] R is an aryl, halogenated aryl, pyridine group or straight-chain alkyl, X is -CH2-, -NH- or -N(CH2CH2CN)-, n=1 or 2, n represents the number of CH2 groups.

[0029] Unless otherwise specified, the present invention does not have special requirements on the source of raw materials used, and commercially available products well known to those skilled in the art can be used.

[0030] The present invention mixes a primary alcohol of Formula I, a nitrile compound of Formula II, a base, an organorruthenium catalyst, and an organic solvent to obtain a mixture.

[0031] In this invention, R is an aryl group, a halogen-substituted aryl group, a pyridine group, or a straight-chain alkyl group, X is -CH2- or -NH-, preferably -CH2-, and n=1 or 2, preferably 1.

[0032] When n=1, the nitrogen-alkylated unsaturated polycyclic β-amino nitrile is a nitrogen-alkylated unsaturated five-membered ring β-amino nitrile; when n=2, the nitrogen-alkylated unsaturated polycyclic β-amino nitrile is a nitrogen-alkylated unsaturated six-membered ring β-amino nitrile.

[0033] In this invention, the primary alcohol preferably includes benzyl alcohol, 4-methylbenzyl alcohol, 4-isopropylbenzyl alcohol, 4-methoxybenzyl alcohol, 4-chlorobenzyl alcohol, 4-fluorobenzyl alcohol, 4-trifluoromethylbenzyl alcohol, 3-methoxybenzyl alcohol, 3,5-dimethoxybenzyl alcohol, 3-chlorobenzyl alcohol, 1-naphthyl-1-methanol, 2-chlorobenzyl alcohol, 2-furanethanol or 3-(4-bromophenyl)prop-1-ol; the nitrile compound preferably includes adiponitrile, heptanonitrile, 3,3'-iminodipropionitrile or tris(2-cyanoethyl)amine.

[0034] In this invention, the molar ratio of the primary alcohol and the nitrile compound is preferably 1:1 to 2, more preferably 1:(1.5 to 2).

[0035] The primary alcohols and nitrile compounds used in this invention were all purchased from reputable chemical reagent companies, such as Energetic and Aladdin.

[0036] In this invention, the molecular formula of the organorruthenium catalyst is preferably [(Ph-PN]]. H [P)Ru(CO)HCl], preferably with the structural formula shown in Formula IV.

[0037] Formula IV, Ph represents phenyl.

[0038] The organorruthenium catalyst used in this invention was purchased from Tokyo Jinsei Kogyo Co., Ltd. (TCI). The organorruthenium catalyst is effective in the dehydrogenation of primary alcohols to benzaldehyde and in the reduction of imines.

[0039] In this invention, the molar mass of the organorruthenium catalyst is preferably 1 to 2% of the molar mass of the primary alcohol, more preferably 1 to 1.5%.

[0040] In this invention, the base is preferably sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, potassium ethoxide, sodium hydroxide, potassium phosphate, or sodium hydride, more preferably sodium hydroxide, potassium phosphate, or sodium hydride; the molar mass of the base is preferably 1 to 3 times the molar mass of the primary alcohol, more preferably 1 to 2 times. In this invention, the base plays a crucial role in the cyclization of adiponitrile and the dehydrogenation of the primary alcohol.

[0041] In this invention, the organic solvent is preferably toluene, tetrahydrofuran, 1,4-dioxane, cyclohexane, acetonitrile, or dichloromethane, more preferably toluene; the molar ratio of benzyl alcohol to the volume of the organic solvent is preferably 1 mol:(4~12) L, more preferably 1 mol:(5~10) L. In this invention, the organic solvent plays a role in fully dissolving the reaction substrate and ensuring thorough mixing of the reaction.

[0042] After obtaining the mixture, the present invention carries out a one-pot reaction of the mixture under inert gas protection to obtain a nitrogen-alkylated unsaturated polycyclic β-amino nitrile with the structure shown in Formula III.

[0043] In this invention, the one-pot reaction includes cyclization reaction of nitrile compounds, dehydrogenation coupling reaction of primary alcohols, and reduction reaction of carbon-nitrogen double bonds.

[0044] In this invention, the temperature of the one-pot reaction is preferably 110~120℃, more preferably 110~115℃; the holding time of the one-pot reaction is preferably 12~36h, more preferably 12~24h.

[0045] In this invention, the inert gas is preferably argon; the purity of the argon is preferably ≥99%, more preferably 99%.

[0046] In this invention, the one-pot reaction is preferably carried out under stirring conditions; the stirring rate is preferably 800~1000 rpm, more preferably 900~1000 rpm.

[0047] In this invention, the equation for the one-pot reaction is as follows:

[0048] .

[0049] After the one-pot reaction is completed, the present invention preferably further includes: cooling the product obtained from the one-pot reaction to room temperature, and then performing phase transfer, vacuum distillation, elution and column chromatography separation in sequence to obtain the nitrogen-alkylated unsaturated polycyclic β-amino nitrile with the structure shown in Formula III.

[0050] In this invention, the cooling is preferably natural cooling.

[0051] In this invention, the solvent used for phase transfer is preferably dichloromethane; the ratio of the amount of benzyl alcohol to the volume of the solvent used for phase transfer is preferably 1 mol:(10~15) L, more preferably 1 mol:(10~12) L.

[0052] In this invention, the temperature of the vacuum distillation is preferably 35~40℃, more preferably 40℃, the holding time is preferably 10~15min, more preferably 15min, and the pressure is preferably 100~200Pa, more preferably 200Pa; this invention removes the solvent used above by vacuum distillation.

[0053] In this invention, the rinsing agent used for rinsing is preferably dichloromethane and methanol; the volume ratio of dichloromethane to methanol is preferably (100~200):1, more preferably (150~200):1; the molar ratio of benzyl alcohol to the volume ratio of the rinsing agent used for rinsing is preferably 1 mol:(1000~1500) L, more preferably 1 mol:(1000~1200) L.

[0054] In this invention, the separation column used for column chromatography is preferably a 200-300 mesh silica gel column.

[0055] In this invention, the yield of the nitrogen-alkylated unsaturated polycyclic β-amino nitrile is preferably 59-92%, more preferably 70-92%.

[0056] In this invention, the nitrogen-alkylated unsaturated polycyclic β-amino nitrile preferably comprises 2-(benzylamino)cyclopent-1-ene-1-carboxynitrile. 2-((4-methylbenzyl)amino)cyclopent-1-ene-1-carboxynitrile 2-((4-isopropylbenzyl)amino)cyclopent-1-ene-1-carboxynitrile 2-((4-methoxybenzyl)amino)cyclopent-1-ene-1-carboxynitrile 2-((4-chlorobenzyl)amino)cyclopent-1-ene-1-carboxynitrile 2-((4-fluorobenzyl)amino)cyclopent-1-ene-1-carboxynitrile 2-((4-trifluoromethylbenzyl)amino)cyclopent-1-ene-1-carboxynitrile 2-((3-methoxybenzyl)amino)cyclopent-1-ene-1-carboxynitrile 2-((3,5-dimethoxybenzyl)amino)cyclopent-1-ene-1-carboxynitrile 2-((3-chlorobenzyl)amino)cyclopent-1-ene-1-carboxynitrile 2-((naphthyl-1-methyl)amino)cyclopent-1-ene-1-carboxynitrile 2-((2-chlorobenzyl)amino)cyclopent-1-ene-1-carboxynitrile 2-((furan-2-methylene)amino)cyclopent-1-ene-1-carboxynitrile 2-((3-(4-bromophenylpropyl)amino)cyclopent-1-ene-1-carboxynitrile) 2-((4-methylbenzyl)amino)cyclohexyl-1-ene-1-carboxynitrile 4-((4-methylbenzyl)amino)-tetrahydropyridine-3-carboxynitrile 1-(2-Cyanoethyl)-4-(4-methylbenzyl)amino-tetrahydropyridine-3-carboxynitrile .

[0057] This invention, under inert gas protection, uses inexpensive industrial-grade nitrile compounds and primary alcohols as raw materials, along with a base and an organorruthenium catalyst, to synthesize nitrogen-alkylated unsaturated polycyclic (five-membered and six-membered) β-aminonitriles via a one-pot reaction. This involves the ring-cloning reaction of the nitrile compounds, the dehydrogenation coupling reaction of the primary alcohol, and the reduction reaction of the carbon-nitrogen double bond. The reaction system is simple, the operation is convenient, the reaction conditions are mild, and the substrates have good applicability. The obtained nitrogen-alkylated unsaturated polycyclic β-aminonitriles exhibit high yield and high chemoselectivity. Furthermore, this invention overcomes the drawbacks of limited substrate scope, expensive raw materials and reagents, complex reaction systems, and lengthy synthetic steps. The reaction is economically efficient, environmentally friendly, and harmless to the environment. Post-reaction processing is simple, making it a promising candidate for a wide range of applications.

[0058] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, but they should not be construed as limiting the scope of protection of the present invention.

[0059] Example 1

[0060] 27.0 mg (0.25 mmol) benzyl alcohol, 54 mg (0.5 mmol) adiponitrile, and 3.0 mg (0.0025 mmol) organorruthenium catalyst ([(Ph-PN) H [P)Ru(CO)HCl]), 10 mg (0.25 mmol) sodium hydride (60% purity), 2.0 mL toluene, and a magnetic stir bar were added to a reaction tube. The reaction was carried out in a one-pot reaction at 110 °C for 12 h under argon (99% purity) with stirring at 900 rpm. After the reaction, the mixture was cooled to room temperature and transferred with 3 mL of dichloromethane. The product was then removed by vacuum distillation at 40 °C and 200 Pa for 15 min. A mixture of dichloromethane and methanol (200:1 volume ratio) was used as the eluent, and the product was separated by column chromatography (200-300 mesh silica gel column) using 300 mL of eluent. 2-(benzylamino)cyclopent-1-ene-1-carboxynitrile was obtained in 90% yield, with the following structural formula:

[0061] .

[0062] The characterization data are: 1 H NMR (400 MHz, Chloroform-d) δ 7.38 – 7.17 (m, 5H), 4.66 (s, 1H), 4.43 (d, J = 5.9 Hz, 2H), 2.59-2.45 (m, 2H), 2.41 (td, J = 7.5, 1.4Hz, 2H), 1.89 – 1.77 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 162.1, 138.2, 128.8,127.7, 127.3, 120.2, 71.4, 48.8, 33.5, 31.9, 21.8. HRMS(ESI + ) m / z C 13 H 14 N₂Na [M+Na] + Experimental value: 221.1046, theoretical value: 221.1049. Example 2

[0063] The difference from Example 1 is that equimolar amounts of 4-methylbenzyl alcohol were used to replace the benzyl alcohol in Example 1. All other aspects remained the same as in Example 1, yielding 2-((4-methylbenzyl)amino)cyclopent-1-ene-1-carboxynitrile in 92% yield, with the following structural formula:

[0064] .

[0065] The characterization data are: 1 H NMR (400 MHz, Chloroform- d ) δ 7.17 (s, 4H), 4.71 (s,1H), 4.45 (d, J = 5.8 Hz, 2H), 2.56 (t, J = 7.2 Hz, 2H), 2.46 (t, J = 7.6, 2H),2.35 (s, 3H), 1.92-1.85 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 161.2, 136.4,134.1, 128.5, 126.3, 119.4, 69.9, 47.5, 32.6, 30.9, 20.8, 20.1. HRMS(ESI + ) m / z C 14 H 16 N₂Na [M+Na] + Experimental value: 235.1202, theoretical value: 235.1206. Example 3

[0066] The difference from Example 1 is that equimolar amounts of 4-isopropylbenzyl alcohol were used to replace the benzyl alcohol in Example 1. All other steps were the same as in Example 1, yielding 2-((4-isopropylbenzyl)amino)cyclopent-1-ene-1-carboxynitrile in 82% yield, with the following structural formula:

[0067] .

[0068] The characterization data are: 1 H NMR (400 MHz, Chloroform- d ) δ 7.21 (d, J = 1.2 Hz, 4H), 4.65 (s, 1H), 4.46 (d, J = 5.7 Hz, 2H), 2.91 (p, J = 6.9 Hz, 1H), 2.59-2.55 (m,2H), 2.50-2.45 (m, 2H), 1.90 (dq, J = 8.6 and 7.4 Hz, 2H), 1.25 (d, J = 6.9 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 162.2, 148.6, 135.6, 127.5, 126.9, 120.3, 71.1,48.7, 33.8, 33.6, 31.9, 24.0, 21.9. HRMS(ESI + ) m / z C 16 H 20 N₂Na [M+Na] + Experimental value: 263.1515, theoretical value: 263.1519. Example 4

[0069] The difference from Example 1 is that equimolar amounts of 4-methoxybenzyl alcohol were used to replace the benzyl alcohol in Example 1. All other aspects remained the same as in Example 1, yielding 2-((4-methoxybenzyl)amino)cyclopent-1-ene-1-carboxynitrile in 89% yield, with the following structural formula:

[0070] .

[0071] The characterization data are: 1 H NMR (400 MHz, Chloroform- d ) δ 7.21-7.19 (m, 2H), 6.89-6.87 (m, 2H), 4.65 (s, 1H), 4.43 (d, J = 5.6 Hz, 2H), 2.91 (p, J = 6.9 Hz, 1H), 2.58-2.47 (m, 2H), 2.46-2.44 (m, 2H), 1.93-1.85 (m, 2H).13 C NMR (101 MHz, CDCl3). 13 C NMR (101 MHz, CDCl3) δ 162.0, 159.2, 130.3, 128.8, 120.4, 114.2,71.0, 55.3, 48.3, 33.7, 32.0, 21.9. HRMS(ESI + ) m / z C14H 16 N₂NaO [M+Na] + Experimental value: 251.1151, theoretical value: 251.1160. Example 5

[0072] The difference from Example 1 is that equimolar amounts of 4-chlorobenzyl alcohol were used to replace the benzyl alcohol in Example 1. All other aspects remained the same as in Example 1, yielding 2-((4-chlorobenzyl)amino)cyclopent-1-ene-1-carboxynitrile in 91% yield, with the following structural formula:

[0073] .

[0074] The characterization data are: 1 H NMR (400 MHz, Chloroform- d ) δ 7.21-7.19 (m, 2H), 6.89-6.87 (m, 2H), 4.65 (s, 1H), 4.43 (d, J = 5.6 Hz, 2H), 2.91 (p, J = 6.9 Hz, 1H), 2.58-2.47 (m, 2H), 2.46-2.44 (m, 2H), 1.93-1.85 (m, 2H). 13 C NMR (101 MHz, CDCl3). 13 C NMR (101 MHz, CDCl3) δ 162.0, 159.2, 130.3, 128.8, 120.4, 114.2,71.0, 55.3, 48.3, 33.7, 32.0, 21.9. HRMS(ESI + ) m / z C14H 16 N₂NaO [M+Na] + Experimental value: 251.1151, theoretical value: 251.1160. Example 6

[0075] The difference from Example 1 is that equimolar amounts of 4-fluorobenzyl alcohol were used to replace the benzyl alcohol in Example 1, and the reaction time was extended to 24 hours. All other steps were the same as in Example 1, yielding 2-((4-fluorobenzyl)amino)cyclopent-1-ene-1-carboxynitrile in 80% yield, with the following structural formula:

[0076] .

[0077] The characterization data are: 1 H NMR (400 MHz, Chloroform- d ) δ 7.22 – 7.09 (m, 2H), 6.93(t, J = 8.6 Hz, 2H), 4.60 (s, 1H), 4.36 (d, J = 5.9 Hz, 2H), 2.45 (tt, J = 7.2 and1.3 Hz, 2H), 2.35 (tt, J = 8.1 and 1.3 Hz, 2H), 1.78 (dq, J = 8.6 and 7.5 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 162.3 (d, J = 247.1 Hz) 161.9, 134.1 (d, J = 4.0Hz), 129.1 (d, J = 8.0 Hz), 120.2, 115.7 (d, J = 21.0 Hz), 71.6, 48.1, 33.7,32.0, 21.8. HRMS(ESI + ) m / z C 13 H 13 FN2Na [M+Na] + Experimental value: 239.0955, theoretical value: 239.0960. Example 7

[0078] The difference from Example 6 is that 4-fluorobenzyl alcohol in Example 6 was replaced with an equimolar amount of 4-trifluoromethylbenzyl alcohol. All other aspects are the same as in Example 6, yielding 2-((4-trifluoromethylbenzyl)amino)cyclopent-1-ene-1-carboxynitrile in 63% yield, with the following structural formula:

[0079] .

[0080] The characterization data are: 1H NMR (400 MHz, Chloroform- d ) δ 7.62 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 7.9 Hz, 2H), 4.83 (s, 1H), 4.57 (d, J = 6.2 Hz, 2H), 2.57 (t, J = 7.2Hz, 2H), 2.47 (t, J = 7.7 Hz, 2H), 1.91 (p, J = 7.5 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 161.7, 142.5, 130.0 (d, J = 32.3 Hz), 127.4, 125.8 (q, J = 3.6 Hz), 124.0 (q, J = 270.3 Hz), 119.9, 72.4, 48.1, 33.6, 32.0, 21.8. HRMS(ESI + ) m / zC 14 H 13 F3N2Na [M+Na] + Experimental value: 289.0924, theoretical value: 289.0923. Example 8

[0081] The difference from Example 6 is that 4-fluorobenzyl alcohol in Example 6 was replaced with an equimolar amount of 3-methoxybenzyl alcohol. All other aspects are the same as in Example 6, yielding 2-((3-methoxybenzyl)amino)cyclopent-1-ene-1-carboxynitrile in 86% yield, with the following structural formula:

[0082] .

[0083] The characterization data are: 1 H NMR (400 MHz, Chloroform- d ) δ 7.27 – 7.25 (m, 1H), 6.87– 6.82 (m, 3H), 4.74 (s, 1H), 4.46 (d, J = 5.9 Hz, 2H), 3.81 (s, 3H), 2.57 (t, J = 7.3 Hz, 2H), 2.47 (t, J= 7.7 Hz, 2H), 1.93-1.86 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 162.2, 160.0, 139.9, 129.9, 120.2, 119.5, 113.0, 113.0, 71.5, 55.3, 48.8, 33.5, 31.9, 21.8. HRMS (ESI + ) m / z C 14 H 16 N₂NaO [M+Na] + Experimental value: 251.1156, theoretical value: 251.1155. Example 9

[0084] The difference from Example 6 is that 4-fluorobenzyl alcohol in Example 6 was replaced with an equimolar amount of 3,5-dimethoxybenzyl alcohol. All other aspects are the same as in Example 6, yielding 2-((3,5-dimethoxybenzyl)amino)cyclopent-1-ene-1-carboxynitrile in 82% yield, with the following structural formula:

[0085] .

[0086] The characterization data are: 1 H NMR (400 MHz, Chloroform- d ) δ 6.84 – 6.81 (m, 3H), 4.65(s, 1H), 4.44 (d, J = 5.7 Hz, 2H), 3.88 (d, J = 4.4 Hz, 6H), 2.57 (t, J = 7.2 Hz,2H), 2.52 – 2.40 (m, 2H), 1.89 (p, J = 7.5 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ162.2, 161.2, 140.7, 120.2, 105.2, 99.4, 71.6, 55.4, 48.9, 33.5, 31.90 21.8.HRMS(ESI + ) m / z C 15 H 18 N₂O₂Na [M+Na] + Experimental value: 281.1261, theoretical value: 281.1260. Example 10

[0087] The difference from Example 6 is that 4-fluorobenzyl alcohol in Example 6 was replaced with an equimolar amount of 3-chlorobenzyl alcohol. All other aspects are the same as in Example 6, yielding 2-((3-chlorobenzyl)amino)cyclopent-1-ene-1-carboxynitrile in 62% yield, with the following structural formula:

[0088] .

[0089] The characterization data are: 1 H NMR (400 MHz, Chloroform- d ) δ 7.40-7.37(m, 2H), 7.31 –7.24 (m, 2H), 4.87 (s, 1H), 4.57 (d, J = 6.3 Hz, 2H), 2.59 – 2.50 (m, 2H), 2.48– 2.46 (m, 2H), 1.89 (p, J = 7.6 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 162.1,135.8, 133.3, 129.8, 129.2, 129.1, 127.2, 120.0, 71.8, 46.5, 33.4, 31.9,21.8. HRMS(ESI + ) m / z C 13 H 13 ClN2Na[M+Na] + Experimental value: 255.0660, theoretical value: 255.0659. Example 11

[0090] The difference from Example 1 is that benzyl alcohol in Example 1 was replaced with an equimolar amount of 1-naphthyl-1-methanol. All other aspects are the same as in Example 1, yielding 2-((naphthyl-1-methyl)amino)cyclopent-1-ene-1-carboxynitrile in 77% yield, with the following structural formula:

[0091] .

[0092] The characterization data are: 1 H NMR (400 MHz, Chloroform- d ) δ 7.99-7.96 (m, 1H), 7.90(dd, J = 7.9, 1.7 Hz, 1H), 7.85-7.82 (dd, J= 5.7, 3.9 Hz, 1H), 7.59-7.51 (m,2H), 7.47-7.45 (m, 2H), 4.99 (d, J = 5.4 Hz, 2H), 4.63 (s, 1H), 3.05 – 2.56 (m, 2H), 2.57 – 2.31 (m, 2H), 1.96-1.89 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 161.7,133.9, 133.3, 131.1, 128.9, 128.8, 126.7, 126.1, 125.5, 123.1, 120.5,71.4,47.0, 33.9, 323, 21.9. HRMS(ESI + ) m / z C 17 H 16 N₂Na[M+Na] + Experimental value: 271.1205, theoretical value: 271.1206. Example 12

[0093] The difference from Example 1 is that equimolar amounts of 2-chlorobenzyl alcohol were used to replace the benzyl alcohol in Example 1. All other aspects remained the same as in Example 1, yielding 2-((2-chlorobenzyl)amino)cyclopent-1-ene-1-carboxynitrile in 66% yield, with the following structural formula:

[0094] .

[0095] The characterization data are: 1 H NMR (400 MHz, Chloroform- d ) δ 7.40-7.37 (m, 2H), 7.31 –7.24 (m, 2H), 4.87 (s, 1H), 4.57 (d, J = 6.3 Hz, 2H), 2.59 – 2.55 (m, 2H), 2.50– 2.46 (m, 2H), 1.93-1.62 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 162.1, 135.7,133.3, 129.8, 129.2, 129.1, 127.2, 120.0, 71.8, 46.5, 33.4, 31.9, 21.8. HRMS (ESI + ) m / z C 13 H 13ClN2Na [M+Na] + Experimental value: 255.0660, theoretical value: 255.0659. Example 13

[0096] The difference from Example 1 is that equimolar amounts of 2-furan-methanol were used instead of benzyl alcohol in Example 1, and the reaction was carried out at 110°C for 36 h. The rest of the procedure was the same as in Example 1, yielding 2-((furan-2-methylene)amino)cyclopent-1-ene-1-carboxynitrile in 66% yield, with the following structural formula:

[0097] .

[0098] The characterization data are: 1 H NMR (400 MHz, Chloroform- d ) δ 7.37 (dd, J = 1.9, 0.8 Hz, 1H), 6.33 (dd, J = 3.3, 1.9 Hz, 1H), 6.27 (dd, J = 3.2, 0.9 Hz, 1H), 4.71 (s,1H), 4.46 (d, J = 6.0 Hz, 2H), 2.58 – 2.49 (m, 4H), 1.94-1.87 (m, 2H). 13 C NMR(101 MHz, CDCl3) δ 161.6, 151.3, 142.5, 119.9, 110.4, 107.6, 72.2, 41.7,33.5, 32.0, 21.8. HRMS(ESI + ) m / z C 11 H 12 N₂NaO [M+Na] + Experimental value: 211.0842, theoretical value: 211.0842. Example 14

[0099] The difference from Example 1 is that benzyl alcohol in Example 1 was replaced with an equimolar amount of 3-(4-bromophenyl)prop-1-ol, and the reaction was carried out at 120°C for 36 h. The rest of the procedure was the same as in Example 1, yielding 2-((3-(4-bromophenylpropyl)amino)cyclopent-1-ene-1-carboxynitrile in 60% yield, with the following structural formula:

[0100] .

[0101] The characterization data are: 1H NMR (400 MHz, Chloroform- d ) δ 7.40 (dd, J = 8.3, 1.6 Hz,2H), 7.07 – 7.05 (m, 2H), 4.40 (s, 1H), 3.33 (q, J = 6.8 Hz, 2H), 2.64 (t, J =7.7 Hz, 2H), 2.54 (t, J = 7.2 Hz, 2H), 2.39 (t, J = 7.7 Hz, 2H), 1.90 – 1.83 (m,4H). 13 C NMR (101 MHz, CDCl3) δ 161.9, 140.1, 131.5, 130.115, 120.545, 119.825,70.4, 44.1, 33.9, 32.2, 32.1, 31.9, 21.8. HRMS(ESI + ) m / z C 15 H 17 BrN2Na[M+Na] + Experimental value: 327.0468, theoretical value: 327.0467. Example 15

[0102] The difference from Example 1 is that adiponitrile in Example 1 was replaced with an equimolar amount of heptanilonitrile, the amount of sodium hydride was 0.75 mmol, and the reaction was carried out at 110 °C for 24 h. The rest of the procedure was the same as in Example 1, yielding 2-((4-methylbenzyl)amino)cyclohexyl-1-ene-1-carboxynitrile in 75% yield, with the following structural formula:

[0103] .

[0104] The characterization data are: 1 H NMR (400 MHz, Chloroform- d ) δ 7.17-7.12 (m, 4H), 4.91(s, 1H), 4.32 (d, J = 6.2 Hz, 2H), 2.34 (s, 3H), 2.20 (q, J = 6.9 Hz, 4H), 1.65 –1.56 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 157.6, 137.2, 135.8, 129.5, 126.9,121.8, 72.7, 46.6, 25.8, 25.0, 22.0, 21.7, 21.1. HRMS(ESI + ) m / z C 15 H 18 N₂Na [M+Na] + Experimental value: 249.1362, theoretical value: 249.1362. Example 16

[0105] The difference from Example 1 is that adiponitrile in Example 1 was replaced with an equimolar amount of 3,3'-imine dipropionitrile, the amount of sodium hydride was 0.75 mmol, and the reaction was carried out at 110 °C for 24 h. The rest of the procedure was the same as in Example 1, yielding 4-((4-methylbenzyl)amino)-tetrahydropyridine-3-carboxynitrile in 59% yield, with the following structural formula:

[0106] .

[0107] The characterization data are: 1 H NMR (400 MHz, Chloroform- d ) δ 7.19 – 7.12 (m, 4H), 4.94(s, 1H), 4.35 (d, J = 6.1 Hz, 2H), 3.47 (d, J = 1.6 Hz, 2H), 2.98 (t, J = 5.9 Hz, 2H), 2.34 (s, 3H), 2.21 (td, J = 5.9, 3.0 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ156.0, 137.4, 135.4, 129.6, 127.0, 120.2, 72.5, 46.4, 44.4, 42.2, 26.1, 21.1.HRMS (ESI + ) m / z C 14 H 18 N3[M+H] + Experimental value: 228.1496, theoretical value: 228.1495. Example 17

[0108] The difference from Example 1 is that adiponitrile in Example 1 was replaced with an equimolar amount of tri(2-cyanoethyl)amine, the amount of sodium hydride was 0.75 mmol, and the reaction was carried out at 110 °C for 24 h. The rest of the procedure was the same as in Example 1, yielding 1-(2-cyanoethyl)-4-(4-methylbenzyl)amino-tetrahydropyridine-3-carboxynitrile in 65% yield, with the following structural formula:

[0109] .

[0110] The representative data are: 1 H NMR (400 MHz, Chloroform- d ) δ 7.17 – 7.12 (m, 4H), 4.97 (s, 1H), 4.35 (d, J = 6.0 Hz, 2H), 3.18 (s, 2H), 2.77 (t, J = 7.0 Hz, 2H), 2.69 (t, J = 5.8 Hz, 2H), 2.52 (t, J = 7.0 Hz, 2H), 2.36-2.33 (m, 5H). 13 C NMR (101MHz, CDCl3) δ 155.7, 137.5, 135.1, 129.6, 127.0, 119.7, 118.4, 70.4, 52.1,51.0, 48.8, 46.7, 26.0, 21.1, 16.5. HRMS (ESI + ) m / z C 17 H 20 N4Na[M+Na] + Experimental value: 303.1580, theoretical value: 303.1580.

[0111] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for synthesizing nitrogen-alkylated unsaturated polycyclic β-amino nitrile, characterized in that, Includes the following steps: A primary alcohol, nitrile compound, base, organorruthenium catalyst and organic solvent are mixed and reacted in a one-pot manner under inert gas protection to obtain nitrogen-alkylated unsaturated polycyclic β-amino nitrile. The primary alcohols include benzyl alcohol, 4-methylbenzyl alcohol, 4-isopropylbenzyl alcohol, 4-methoxybenzyl alcohol, 4-chlorobenzyl alcohol, 4-fluorobenzyl alcohol, 4-trifluoromethylbenzyl alcohol, 3-methoxybenzyl alcohol, 3,5-dimethoxybenzyl alcohol, 3-chlorobenzyl alcohol, 1-naphthyl-1-methanol, 2-chlorobenzyl alcohol, 2-furanmethanol, or 3-(4-bromophenyl)prop-1-ol; The nitrile compounds include adiponitrile, heptanonitrile, 3,3'-iminodipropionitrile, or tris(2-cyanoethyl)amine; The structural formula of the organorruthenium catalyst is shown in Formula IV. Formula IV, Ph represents phenyl; The nitrogen-alkylated unsaturated polycyclic β-amino nitrile includes 2-(benzylamino)cyclopent-1-en-1-carboxynitrile, 2-((4-methylbenzyl)amino)cyclopent-1-en-1-carboxynitrile, 2-((4-isopropylbenzyl)amino)cyclopent-1-en-1-carboxynitrile, 2-((4-methoxybenzyl)amino)cyclopent-1-en-1-carboxynitrile, 2-((4-chlorobenzyl)amino)cyclopent-1-en-1-carboxynitrile, 2-((4-fluorobenzyl)amino)cyclopent-1-en-1-carboxynitrile, 2-((4-trifluoromethylbenzyl)amino)cyclopent-1-en-1-carboxynitrile, 2-((3-methoxybenzyl)amino)cyclopent-1-en-1-carboxynitrile, 2-((3,5-dimethoxy) Benzyl)amino)cyclopent-1-en-1-carboxylon, 2-((3-chlorobenzyl)amino)cyclopent-1-en-1-carboxylon, 2-((naphthyl-1-methyl)amino)cyclopent-1-en-1-carboxylon, 2-((2-chlorobenzyl)amino)cyclopent-1-en-1-carboxylon, 2-((furan-2-methylene)amino)cyclopent-1-en-1-carboxylon, 2-((3-(4-bromophenylpropyl)amino)cyclopent-1-en-1-carboxylon, 2-((4-methylbenzyl)amino)cyclohexyl-1-en-1-carboxylon, 4-((4-methylbenzyl)amino)tetrahydropyridine-3-carboxylon or 1-(2-cyanoethyl)-4-(4-methylbenzyl)amino-tetrahydropyridine-3-carboxylon.

2. The synthesis method according to claim 1, characterized in that, The molar ratio of the primary alcohol and the nitrile compound is 1:1 to 2.

3. The synthesis method according to claim 1, characterized in that, The amount of the organorruthenium catalyst is 1 to 2% of the amount of the primary alcohol.

4. The synthesis method according to claim 1, characterized in that, The alkali is sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, potassium ethoxide, sodium hydroxide, potassium phosphate, or sodium hydride.

5. The synthesis method according to claim 1 or 4, characterized in that, The amount of the base is 1 to 3 times the amount of the primary alcohol.

6. The synthesis method according to claim 1, characterized in that, The temperature of the one-pot reaction is 110~120℃; the holding time of the one-pot reaction is 12~36h.

7. The synthesis method according to claim 1, characterized in that, The inert gas is argon.

8. The synthesis method according to claim 1, characterized in that, The organic solvent is toluene, tetrahydrofuran, 1,4-dioxane, cyclohexane, acetonitrile, or dichloromethane.

9. The synthesis method according to claim 1, characterized in that, After the one-pot reaction is completed, the process further includes: cooling the product obtained from the one-pot reaction to room temperature, and then sequentially performing phase transfer, vacuum distillation, elution, and column chromatography to obtain nitrogen-alkylated unsaturated polycyclic β-amino nitrile.

Images