N-alkylamine compound, preparation method and application

Abstract

The invention discloses an N-alkylamine compound as well as a preparation method and application thereof, and relates to the technical field of organic synthesis. The preparation method comprises the following steps: sequentially adding 0.5 mmol of amide and 1 mmol of norbornadiene into a reaction container according to a molar ratio of 1: 2, then adding a solvent, then adding a catalyst, a ligand, an oxidizing agent, alkali and an additive in an amount which are respectively 10.0%, 20.0%, 300%, 400% and 100% of the molar weight of the amide and 5mL of the solvent, reacting for 24 hours in an air atmosphere and a 130-DEG C oil bath condition, cooling to room temperature, adding water, extracting for three times by using ethyl acetate, merging organic layers, and separating and purifying to obtain the N-norbornadiene-N, N-dialkene-N, N-dialkene-N, N-dialkene-N, N-dialkene-N, N-dialkene-N, N-dialkene. Concentrating under reduced pressure, and purifying the product by column chromatography to obtain the product organic silicon compound. In the invention, the reaction substrate is cheap, the yield is high, the selectivity is good, the separation and purification are easy, the pollution is less, the steps are simple, the protection and deprotection synthesis steps of functional groups can be omitted, and the target product N-alkylamine compound is widely applied to the aspects of organic intermediates, drug intermediates and electronic device materials of organic chemical reactions.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, in particular to an N-alkylamine compound, a preparation method and application thereof. Background Art

[0002] N-alkylamine compounds have a wide range of applications in the following areas due to their unique biological, physical and chemical properties: 1. N-alkylamine compounds are important agrochemical intermediates and can be used in the synthesis of many agricultural drugs, such as Metamifop, Valifenalate, Spinetoram, Penflufen, Cyflumetofen, Isopyrazam, Imicyaphos, Pyrimisulfan or Lepimectin, etc.; 2. N-alkylamine compounds are also important intermediates in organic chemistry, which can modify the molecular skeleton; 3. Their derivatives are also widely used in polymers, semiconductor materials, drug design and other fields;

[0003] Since N-alkylamine compounds have broad application prospects and special biological activities, such as important physiological and pharmacological activities, anti-inflammatory and antibacterial activities, people are increasingly studying them. There are three main methods for synthesizing N-alkylamine compounds:

[0004] 1. Substitution reaction or reduction reaction of aliphatic electrophilic reagents Synthesis method of amination reaction of carbonyl compounds (Elsevier Science & Technology Books: Waltham, MA, 1991), this method mainly synthesizes N-alkylamine compounds by substitution reaction of halogenated hydrocarbon reagents with amines or reduction reaction of carboxylic acid ester reagents with reducing agents. The advantage of this method is that the synthesis route is simple, but the reaction conditions are relatively harsh. The reaction must be carried out under anhydrous and oxygen-free conditions, and the method has poor tolerance to many functional groups, and the expansion of the substrate range is subject to certain restrictions. Therefore, the application of this synthesis route in organic synthesis is greatly limited;

[0005] 2. Metal-catalyzed intramolecular hydroamination synthesis method (Chem. Rev. 2008, 108, 3795, Chem Cat Chem. 2010, 2, 1192, Chem. - Eur. J. 2013, 19, 4972). This method has good selectivity, but the scope of hydroamination of unactivated olefins is limited. Most of the reported hydroamination reactions are intramolecular cyclization reactions of aminoolefins (J. Acc. Chem. Res. 2004, 37, 673, J. Am. C hem.Soc.2010,132,17680, J.Am.Chem.Soc.2010,132,413, J.Am.Chem.Soc.2010,132,13813, Angew.Chem.,Int.Ed.2010,49,564, J.Am.Chem.Soc.2011,133,15453, J.Am.Chem.Soc.2011,133,2772), which also limits the practical application of this method;

[0006] 3. Synthesis of metal-catalyzed intermolecular hydroamination (J. Organomet. Chem. 1994, 469, 221, J. Am. Chem. Soc. 1997, 119, 10857, J. Am. Chem. Soc. 2008, 130, 16562, J. Am. Chem. Soc. 2008, 130, 12220, J. Am. Chem. Soc. 2000, 122, 9546, J. Am. Chem. Soc. 2003, 125, 14286, Org. Lett. 2005, 7, 2635, Org. Lett. 2012, 14, 780, Synlett. 2007, 1767, Angew. Chem., In t.Ed.2012,51,5175,J.Am.Chem.Soc.2001,123,4366,J.Am.Chem.Soc.2006,128,9306,Organometallics.2004,23,1264,Organometallics.2004,23,1649,Organometallics.2012,31,921) This method has the advantages of high efficiency and good functional group tolerance; norbornadiene is a commercially available, stable, low-toxic olefin reagent, which is widely used in the synthesis of condensed ring compounds; and compared with chain olefin reagents: norbornadiene has the advantages of low price, insensitivity to air and water, relatively stable properties, and easy storage;

[0007] In recent years, N-alkylamine compounds have played an important role in the creation of new drugs, and the research on their synthesis methods has also made great progress;

[0008] In 2023, Knowles and colleagues developed a light-driven method for the intermolecular anti-Markovnikov hydroamination of olefins with primary heteroarylamines (J.Am.Chem.Soc.2023,145,21738); in this scheme, electron transfer between the amine substrate and the excited iridium photocatalyst provides an amine radical cation (ARC) intermediate, which forms a CN bond with the nucleophilic olefin; the electronic properties of the amine are key to the success of the reaction, where increasingly electron-deficient heteroarylamines produce increasingly active ARCs; the reaction has good functional group tolerance, but the substrate needs to be pre-functionalized and the raw materials are not easy to synthesize;

[0009] In 2024, the Knowles group reported a bisphosphine and photoredox catalytic scheme for the hydroamination of many structurally diverse and medically relevant NH azoles with unactivated alkenes; the hydroamination reaction has high anti-Markovnikov regioselectivity and N-site selectivity (Angew. Chem., Int. Ed. Engl. 2023, 62, No. e202314312); the mild conditions and high functional group tolerance of the reaction allow for rapid construction of molecular complexity and late functionalization of biologically active compounds; NH bond activation is carried out by polar addition reaction of NH-azoles with phosphine cations, followed by P-Nα cleavage from the phosphono intermediate; reactivity and N-site selectivity are classified by azole NH BDFE and nitrogen-centered radical spin density, respectively, which can serve as a useful predictive aid for extending the reaction to invisible azoles; this method has good selectivity, but the substrate is not easy to synthesize;

[0010] In the same year, Chen's group reported a scheme for the hydroazole acylation of alkenes with N-hydroxyazoles (Org.Chem.Front.2024,11,2839); these reactions are carried out by phosphoryl groups obtained through photoredox catalysis, and then the obtained azole groups are coupled with olefin radicals; the key to the reaction lies in the specific binding between the hydroxyl group on N-hydroxyazole and the alkyl phosphine; this specificity enables the reaction to overcome the selectivity problems associated with existing hydroazole reactions, which are caused by the conjugation effect of different nitrogen atoms in the azole substrate, resulting in N1 / N2 / N3 reaction site selectivity problems; this method has a high yield, but a narrow substrate range;

[0011] These synthetic methods have many disadvantages: harsh reaction conditions, difficult substrate synthesis, difficult separation, inert gas protection during the reaction process, and high requirements for equipment.

[0012] In view of the above problems, the inventors propose an N-alkylamine compound, a preparation method and an application thereof to solve the above problems. Summary of the invention

[0013] In order to solve the above problems, the present invention aims to provide an N-alkylamine compound, a preparation method and an application thereof.

[0014] In order to solve the above technical problems, the present invention adopts the following technical solution: an N-alkylamine compound, the chemical structure of the N-alkylamine compound is as follows:

[0015]

[0016] Wherein R1 is a hydrogen group or a fluoro group, R2 is a hydrogen group, a methoxy group, a methyl group, a fluoro group or a chloro group, R3 is a hydrogen group, a methoxy group, a methyl group, a fluoro group or a chloro group, and R4 is a hydrogen group, a methoxy group or a fluoro group;

[0017] The general reaction formula of the N-alkylamine compound synthesis method is as follows:

[0018]

[0019] The present invention also provides a method for preparing an N-alkylamine compound, comprising the following steps:

[0020] S1. In a reaction vessel, amide and norbornadiene were added in a molar ratio of 1:2, and solvent was added at a ratio of 0.5 mmol amide to 5 mL solvent. Then, catalyst, ligand, oxidant, base, and additive were added in amounts of 10.0%, 20.0%, 300%, 400%, and 100% of the molar amount of amide, respectively. Solvent was 5 mL. The reaction was carried out in an air atmosphere and an oil bath at 130°C for 24 hours, and then cooled to room temperature.

[0021] S2, add water, extract with ethyl acetate three times, combine the organic layers, concentrate under reduced pressure, and purify the product by column chromatography to obtain the product N-alkylamine compound.

[0022] Preferably, the amide is any one of benzamide, 4-methoxybenzamide, 4-methylbenzamide, 4-fluorobenzamide, 4-chlorobenzamide, 3-methoxybenzamide, 3-methylbenzamide, 3-chlorobenzamide, 2-fluorobenzamide, 3,4-dimethylbenzamide, 3,5-dimethoxybenzamide or 3,5-difluorobenzamide.

[0023] Preferably, the base is any one of K2CO3, KOH or K3PO4;

[0024] The catalyst is Pd(PPh3)2Cl2, and the ligand is PC y3 , the oxidant is Cu(OAc)2, and the additive is DABCO.

[0025] Preferably, the solvent is toluene.

[0026] Preferably, the column chromatography purification method is carried out under the following conditions: a 200-300 mesh silica gel column, and an eluent of petroleum ether and ethyl acetate, wherein the ratio of petroleum ether to ethyl acetate is 10:1.

[0027] The present invention also provides an application of the N-alkylamine compound prepared by the method for preparing the N-alkylamine compound in the technical field of organic synthesis.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] 1. In the present invention, phenylboronic acid is used to replace the use of traditional raw materials halogenated aromatic hydrocarbons and substrates containing directing groups, and the reaction operation is relatively simple; the reaction substrate is simple and has a wide source, and is suitable for phenylboronic acid substituted with various functional groups, and the steric effect has little effect on the reaction;

[0030] 2. In the present invention, the reaction substrate is cheap, the yield is high, the selectivity is good, the separation and purification are easy, the pollution is small, the steps are simple, and the protection and deprotection synthesis steps of the functional groups can be omitted. The target product N-alkylamine compound is widely applicable to organic intermediates, drug intermediates and electronic device materials in organic chemical reactions. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0032] Figure 1 Example 1 of the present invention is N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)benzamide (2a) 1 HNMR spectrum (400 MHz, CDCl3).

[0033] Figure 2 Example 1 of the present invention is N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)benzamide (2a) 13 C{ 1 H} NMR spectrum (100 MHz, CDCl3).

[0034] Figure 3 Example 2 of the present invention N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-4-methoxybenzamide (2b) 1 H NMR spectrum (400 MHz, CDCl3).

[0035] Figure 4 Example 2 of the present invention N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-4-methoxybenzamide (2b) 13 C{ 1 H} NMR spectrum (100 MHz, CDCl3). DETAILED DESCRIPTION

[0036] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0037] Embodiment 1: Figure 1-2 As shown:

[0038] The present invention provides a method for synthesizing N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)benzamide (2a), comprising the following steps:

[0039] In a 25 mL Schlenk reaction tube, 0.5 mmol (60.5 mg) of benzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 424 mg of potassium phosphate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 81 mg of the desired target product (2a) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 76% and the purity was 99.9%. 1 H NMR (500MHz, CDCl3, δppm) δ7.74(d,J=7.29Hz,1H),7.47(t,J=7.29Hz,1H),7.49(d,J=7.68Hz,1H),7.39(t,J=7.79Hz,2H),6.32(s,1H),6.18-6.1 6(m,1H),6.12-6.10(m,1H),3.96-3.93(m,1H),2.90(s,2H),1.83-1.77( m,1H),1.58(d,J=8.79Hz,1H),1.47(d,J=8.79Hz,1H),1.36-1.32(m,1H). 13 C{ 1H}NMR(100MHz,CDCl3)δ167.3,138.7,134.8,134.7,131.2,128.4,126.8,50.4,47.9,46.0,41.0,35.3.HRMS(ESI)m / z calcd for C 14 H 16 NO+(M+H) + 214.1226, found 214.1229.

[0040] Wherein, the chemical structure of N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)benzamide (2a) is as follows:

[0041]

[0042] Embodiment 2: Figure 2-4 As shown:

[0043] A method for synthesizing N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-4-methoxybenzamide (2b) comprises the following steps:

[0044] In a 25 mL Schlenk reaction tube, 0.5 mmol (75.5 mg) of 4-methoxybenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 424 mg of potassium phosphate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 98 mg of the desired target product (2b) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 81% and the purity was 99.9%. 1 H NMR (500MHz, CDCl3, δppm) δ7.71(d,J=8.29Hz,2H),6.89(d,J=7.70Hz,2H),6.17(s,2H),6.12(s,1H),3.93(s,1H),3.8 3(s,3H),2.89(s,2H),1.80(t,J=9.64Hz,1H),1.58(d,J=8.15Hz,1H),1.46(d,J=8.15Hz,1H),1.31(d,J=11.86Hz,1H). 13 C{ 1H}NMR(100MHz,CDCl3)δ166.8,162.0,138.6,134.7,128.6,127.1,113.6,55.3,50.4,47.9,46.0,41.0,35.4.HRMS(ESI)m / z calcd for C 15 H 18 NO2+(M+H) + 244.1332, found 244.1335.

[0045] Wherein, the chemical structure of N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-4-methoxybenzamide (2b) is as follows:

[0046]

[0047] Embodiment three:

[0048] A method for synthesizing N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-4-methylbenzamide (2c) comprises the following steps:

[0049] In a 25 mL Schlenk reaction tube, 0.5 mmol (67.5 mg) of 4-methylbenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 424 mg of potassium phosphate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 82 mg of the desired target product (2c) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 72% and the purity was 99.9%. 1 H NMR (500MHz, CDCl3, δppm) δ7.64(d,J=7.69Hz,2H),7.21(d,J=7.69Hz,2H),6.19-6.17(s,2H),6.13(s,1H),3.95( s,1H),2.90(s,1H),2.38(s,3H),2.33(s,1H),1.84-1.78(m,2H),1.59(d,J=8.79Hz,1H),1.47(d,J=8.79Hz,1H). 13 C{ 1H}NMR(100MHz,CDCl3)δ167.2,141.6,138.7,134.7,132.0,129.1,126.8,50.4,47.9,46.1,41.0,35.4,21.4.HRMS(ESI)m / z calcd for C 15 H 18 NO+(M+H) + 228.1383, found 228.1386.

[0050] Wherein, the chemical structure of N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-4-methylbenzamide (2c) is as follows:

[0051]

[0052] Embodiment 4:

[0053] A method for synthesizing N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-4-fluorobenzamide (2d), comprising the following steps:

[0054] In a 25 mL Schlenk reaction tube, 0.5 mmol (69.5 mg) of 4-fluorobenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 424 mg of potassium phosphate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 106 mg of the desired target product (2d) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 92% and the purity was 99.9%. 1 H NMR (500MHz, CDCl3, δppm) δ7.75(t,J=6.64Hz,2H),7.05(d,J=8.39Hz,2H),6.35(s,1H),6.16(s,1H),6.10(s,1H),3.90 (s,1H),2.88(s,2H),1.78(t,J=10.83Hz,1H),1.57(d,J=8.74Hz,1H),1.46(d,J=8.74Hz,1H),1.33(d,J=11.88Hz,1H). 13 C{ 1H}NMR(100MHz, CDCl3)δ166.3,164.5(d,J=252.57Hz),138.7,134.6,131.0(d,J=2.98Hz) ,129.1(d,J=8.86Hz),115.4(d,J=21.73Hz),50.6,47.9,46.0,41.0,35.2.HRMS(ESI)m / z calcd for C 14 H 15 FNO+(M+H) + 232.1132, found 232.1135.

[0055] Wherein, the chemical structure of N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-4-fluorobenzamide (2d) is as follows:

[0056]

[0057] Embodiment five:

[0058] A method for synthesizing N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-4-chlorobenzamide (2e) comprises the following steps:

[0059] In a 25 mL Schlenk reaction tube, 0.5 mmol (77.5 mg) of 4-chlorobenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 424 mg of potassium phosphate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 105 mg of the desired target product (2e) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 85% and the purity was 99.9%. 1 H NMR (500MHz, CDCl3, δppm) δ7.68(d,J=8.04Hz,2H),7.36(d,J=8.04Hz,2H),6.26(d,J=4.89Hz,1H),6.18-6.17(m,1H),6.12-6.1 1(m,1H),3.93-3.90(m,1H),2.89(s,2H),1.83-1.78(m,1H),1.59(d,J=8.74Hz,1H),1.46(d,J=9.09Hz,1H),1.34-1.30(m,1H). 13 C{1 H}NMR(100MHz,CDCl3)δ166.3,138.8,137.5,134.6,133.2,128.7,128.3,50.6,47.9,46.1,41.0,35.3.HRMS(ESI)m / z calcd forC 14 H 15 ClNO+(M+H) + 248.0837, found 248.0840.

[0060] Wherein, the chemical structure of N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-4-chlorobenzamide (2e) is as follows:

[0061]

[0062] Embodiment six:

[0063] A method for synthesizing N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-3-methoxybenzamide (2f) comprises the following steps:

[0064] In a 25 mL Schlenk reaction tube, 0.5 mmol (75.5 mg) of 3-methoxybenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 424 mg of potassium phosphate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 89 mg of the desired target product (2f) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 73% and the purity was 99.9%. 1 H NMR (500MHz, CDCl3, δppm) δ7.28(s,1H),7.23(d,J=7.69Hz,1H),7.19(d,J=7.34Hz,1H),6.94(d,J=7.69Hz,1H),6.18(d,J=4.54Hz,1H),6.11(s,1H ),6.06(s,1H),3.88(s,1H),3.77(s,3H),2.84(s,2H),1.77-1.72(m,1H) ,1.53(d,J=8.74Hz,1H),1.40(d,J=8.74Hz,1H),1.26(d,J=12.23Hz,1H). 13 C{1 H}NMR(100MHz, CDCl3)δ167.1,159.7,138.7,136.4,134.7,129.4,118.5,117.4,112.3,55.4,50.5,47.9,46.0,41.0,35.3.HRMS(ESI)m / z calcd for C 15 H 18 NO2+(M+H) + 244.1332, found 244.1335.

[0065] Wherein, the chemical structure of N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-3-methoxybenzamide (2f) is as follows:

[0066]

[0067] Embodiment seven:

[0068] A method for synthesizing N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-3-methylbenzamide (2g) comprises the following steps:

[0069] In a 25 mL Schlenk reaction tube, 0.5 mmol (67.5 mg) of 3-methylbenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 424 mg of potassium phosphate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours, cooled to room temperature after the reaction (monitored by TLC), the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 87 mg of the desired target product (2 g) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 77% and the purity was 99.9%. 1 H NMR (500MHz, CDCl3, δppm) δ7.56 (s, 1H), 7.53-7.51 (m, 1H), 7.28 (d, J = 4.80Hz, 2H), 6.24 (d, J = 4.80Hz, 1H), 6.19-6.16 (m, 1H), 6.13-6.11 ( m,1H),3.96-3.93(m,1H),2.90(s,2H),2.37(s,3H),1.83-1.78(m,1H),1.59(d,J=8.80Hz,1H),1.47(d,J=8.80Hz,1H),1.35-1.30(m,1H). 13 C{1 H}NMR(100MHz, CDCl3)δ167.5,138.7,138.3,134.8,134.7,132.0,128.3,127.5,123.7,50.4,47.9,46.0,41.0,35.3,21.3.HRMS(ESI)m / z calcd for C 15 H 18 NO+(M+H) + 228.1383, found 228.1386.

[0070] Wherein, the chemical structure of N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-3-methylbenzamide (2g) is as follows:

[0071]

[0072] Embodiment eight:

[0073] A method for synthesizing N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-3-chlorobenzamide (2h), comprising the following steps:

[0074] In a 25 mL Schlenk reaction tube, 0.5 mmol (77.5 mg) of 3-chlorobenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 424 mg of potassium phosphate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 103 mg of the desired target product (2h) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 83% and the purity was 99.9%. 1 H NMR (500MHz, CDCl3, δppm) δ7.71(s,1H),7.61(d,J=7.69Hz,1H),7.43(d,J=8.04Hz,1H),7.32(t,J=7.69Hz,1H),6.35(d,J=5.24Hz,1H),6.17(s ,1H),6.11-6.10(m,1H),3.92-3.89(m,1H),2.89(s,2H),1.81-1.76(m, 1H),1.59(d,J=8.74Hz,1H),1.47(d,J=8.74Hz,1H),1.35-1.32(m,1H). 13 C{1 H}NMR(100MHz, CDCl3)δ166.0,138.8,136.6,134.6,134.6,131.2,129.8,127.2,125.0,50.7,47.9,46.0,41.0,35.2.HRMS(ESI)m / z calcd for C 14 H 15 ClNO+(M+H) + 248.0837, found 248.0840.

[0075] The general chemical structure of trimethyl N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-3-chlorobenzamide (2h) is:

[0076]

[0077] Embodiment nine:

[0078] A method for synthesizing N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-2-fluorobenzamide (2i) comprises the following steps:

[0079] In a 25 mL Schlenk reaction tube, 0.5 mmol (69.5 mg) of 2-fluorobenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 424 mg of potassium phosphate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 107 mg of the desired target product (2i) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 93% and the purity was 99.9%. 1H NMR (500MHz, CDCl3, δppm) δ8.03 (td, J = 7.90Hz, 1.63Hz, 1H), 7.43-7.38 (m, 1 H),7.21(t,J=7.63Hz,1H),7.08-7.03(m,1H),6.80(s,1H),6.17-6.14(m,1H) ,6.10-6.08(m,1H),3.96-3.92(m,1H),2.89(s,2H),1.81-1.76(m,1H),1.57 (d,J=8.99Hz,1H),1.45(d,J=8.85Hz,1H),1.31(dt,J=12.40Hz,3.41Hz,1H). 13 C{ 1 H}NMR (100MHz, CDCl3) δ162.7 (d, J = 3.24Hz), 160.4 (d, J = 246.67Hz), 138.7, 134.5, 132.9 (d, J = 8.86Hz), 131.8 (d, J = 2 .12Hz),124.6(d,J=3.26Hz),121.2(d,J=11.53Hz),115.8(d,J=24.76Hz),50.3,47.8,46.0,40.9,35.3.HRMS(ESI)m / z calcd forC 14 H 15 FNO+(M+H) + 232.1132, found 232.1135.

[0080] Wherein, the chemical structure of N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-2-fluorobenzamide (2i) is as follows:

[0081]

[0082] Embodiment ten:

[0083] A method for synthesizing N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-3,4-dimethylbenzamide (2j) comprises the following steps:

[0084] In a 25 mL Schlenk reaction tube, 0.5 mmol (74.5 mg) of 3,4-dimethylbenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 424 mg of potassium phosphate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 105 mg of the desired target product (2j) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 87% and the purity was 99.9%. 1 H NMR (500MHz, CDCl3, δppm) δ7.52 (s, 1H), 7.45 (d, J = 7.67Hz, 1H), 7.12 (d, J = 7.84Hz, 1H), 6.31 (d, J = 6.13Hz, 1H), 6.17-6.15 (m, 1H), 6.11-6.0 9(m,1H),3.94-3.91(m,1H),2.88(s,2H),2.26(s,6H),1.80-1.75(m,1 H),1.57(d,J=9.37Hz,1H),1.48(d,J=8.69Hz,1H),1.35-1.31(m,1H). 13 C{ 1 H}NMR(100MHz, CDCl3)δ167.4,140.1,138.6,136.7,134.7,132.3,129.5,128.1,124.1,50.3,47.9,46.0,40.9,35.1,19.7,19.6.HRMS(ESI)m / z calcd for C 16 H 20 NO+(M+H) + 242.1539, found 242.1542.

[0085] Wherein, the chemical structure of N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-3,4-dimethylbenzamide (2j) is as follows:

[0086]

[0087] Embodiment eleven:

[0088] A method for synthesizing trimethyl N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-3,5-dimethoxybenzamide (2k) comprises the following steps:

[0089] In a 25 mL Schlenk reaction tube, 0.5 mmol (90.5 mg) of 3,5-dimethoxybenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 424 mg of potassium phosphate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 109 mg of the desired target product (2k) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 80% and the purity was 99.9%. 1 H NMR (500MHz, CDCl3, δppm) δ6.85(d,J=1.87Hz,2H),6.52(s,1H),6.35(d,J=6.47Hz,1H),6.16-6.14(m,1H),6.09-6.07(m,1H),3. 90-3.87(m,1H),3.77(s,6H),2.86(s,2H),1.79-1.73(m,1H),1.55(d,J=8.86Hz,1H),1.44(d,J=8.86Hz,1H),1.34-1.29(m,1H). 13 C{ 1 H}NMR(100MHz,CDCl3)δ167.1,160.7,138.6,137.0,134.6,104.8,103.1,55.4,50.5,47.8,46.0,40.9,35.1.HRMS(ESI)m / zcalcd for C 16 H 20 NO3+(M+H) + 274.1438, found 274.1441.

[0090] Wherein, the chemical structure of N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-3,5-dimethoxybenzamide (2k) is as follows:

[0091]

[0092] Embodiment 12:

[0093] A method for synthesizing N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-3,5-difluorobenzamide (21) comprises the following steps:

[0094] In a 25 mL Schlenk reaction tube, 0.5 mmol (78.5 mg) of 3,5-dimethoxybenzamide and 1.0 mmol (94 mg) of norbornene were added, followed by 35.1 mg of bis(triphenylphosphine)palladium dichloride, 452.5 mg of anhydrous copper acetate, 424 mg of potassium phosphate, 112 mg of triethylenediamine, and 5 mL of toluene. The mixture was stirred at 130° C. for 24 hours. After the reaction (monitored by TLC), the mixture was cooled to room temperature, the reaction solution was filtered, and the organic layer was dried under reduced pressure using a rotary evaporator. Finally, the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 95 mg of the desired target product (2l) as a colorless oily liquid. After drying under vacuum conditions, the yield was calculated to be 76% and the purity was 99.9%. 1 H NMR (500MHz, CDCl3, δppm) δ7.31-7.28(m,2H),6.96-6.91(m,1H),6.35(d,J=5.28Hz,1H),6.22-6.20(m,1H),6.13-6.11(m, 1H),3.94-3.91(m,1H),2.92(s,2H),1.85-1.79(m,1H),1.62(d,J=8.86Hz,1H),1.49(d,J=8.86Hz,1H),1.38-1.34(m,1H). 13 C{ 1 H}NMR(100MHz, CDCl3)δ164.9,162.9(dd,J=250.34Hz,12.38Hz),138.9,138.2(t,J=8.25Hz),134.5 ,110.1(dd,J=18.57Hz,7.57Hz),106.6(t,J=25.45Hz),50.8,47.8,46.0,41.0,35.2.HRMS(ESI)m / z calcd for C 14 H 14 F2NO+(M+H) + 250.1038, found 250.1041.

[0095] Wherein, the chemical structure of N-((2S)-bicyclo[2.2.1]hept-5-en-2-yl)-3,5-difluorobenzamide (21) is as follows:

[0096]

[0097] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. An N-alkylamine compound, characterized in that The chemical structure of the N-alkylamine compound is as follows: Wherein R1 is a hydrogen group or a fluoro group, R2 is a hydrogen group, a methoxy group, a methyl group, a fluoro group or a chloro group, R3 is a hydrogen group, a methoxy group, a methyl group, a fluoro group or a chloro group, and R4 is a hydrogen group, a methoxy group or a fluoro group; The general reaction formula of the N-alkylamine compound synthesis method is as follows:

2. A method for preparing the N-alkylamine compound according to claim 1, characterized in that: The following steps are involved: S1. In a reaction vessel, amide and norbornadiene were added in a molar ratio of 1:2, and solvent was added at a ratio of 0.5 mmol amide to 5 mL solvent. Then, catalyst, ligand, oxidant, base, and additive were added in amounts of 10.0%, 20.0%, 300%, 400%, and 100% of the molar amount of amide, respectively. Solvent was 5 mL. The reaction was carried out in an air atmosphere and an oil bath at 130°C for 24 hours, and then cooled to room temperature. S2, add water, extract with ethyl acetate three times, combine the organic layers, concentrate under reduced pressure, and purify the product by column chromatography to obtain the product N-alkylamine compound.

3. The method for preparing an N-alkylamine compound according to claim 2, characterized in that: The amide is any one of benzamide, 4-methoxybenzamide, 4-methylbenzamide, 4-fluorobenzamide, 4-chlorobenzamide, 3-methoxybenzamide, 3-methylbenzamide, 3-chlorobenzamide, 2-fluorobenzamide, 3,4-dimethylbenzamide, 3,5-dimethoxybenzamide or 3,5-difluorobenzamide.

4. The method for preparing an N-alkylamine compound according to claim 2, characterized in that: The base is any one of K2CO3, KOH or K3PO4; The catalyst is Pd(PPh3)2Cl2, and the ligand is PC y3 , the oxidant is Cu(OAc)2, and the additive is DABCO.

5. The method for preparing an N-alkylamine compound according to claim 2, characterized in that: The solvent is toluene.

6. The method for preparing an N-alkylamine compound according to claim 2, characterized in that: The column chromatography purification method has the following conditions: a 200-300 mesh silica gel column, and an eluent of petroleum ether and ethyl acetate, wherein the ratio of petroleum ether to ethyl acetate is 10:

1.

7. Use of an N-alkylamine compound obtained by the method for preparing an N-alkylamine compound as claimed in any one of claims 1 to 6 in the field of organic synthesis technology.

Images