Synthesis method of chiral benzylamine compound

Abstract

The invention provides a synthesis method of a chiral benzylamine compound, and relates to the technical field of organic synthesis. The synthesis method provided by the invention comprises the following steps: in a solvent environment, under the action of a metal catalyst, a photocatalyst, a chiral accelerator and a reducing agent, reacting an N-alkenyl benzamide compound I, an aromatic iodine compound II and NHP ester III under illumination to generate a chiral benzylamine compound IV. The raw materials are easy to obtain, the reaction conditions are mild, the compatibility of functional groups is good, the method can be suitable for different reaction substrates, and the chiral benzylamine compound with a high chiral value can be efficiently synthesized.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing chiral benzylamine compounds. Background Art

[0002] Chiral benzylamine is an important organic molecule with a benzylamine skeleton and a chiral center. Its unique stereochemical properties make it an irreplaceable position in the fields of medicinal chemistry, natural product synthesis and material science. In drug molecules, chiral benzylamine and its amide derivatives often serve as core pharmacophores, directly participating in the binding and regulation of target proteins. In natural products, chiral benzylamine can regulate molecular conformation through hydrogen bond networks and steric hindrance effects, thereby affecting physiological functions. However, since the enantiomers of chiral molecules often exhibit completely different biological activities or even toxicity, it is particularly important to develop efficient and highly selective methods for the synthesis of chiral benzylamine.

[0003] The current mainstream synthesis of chiral benzylamine relies on two types of catalytic strategies: one is to use precious metals as the core and construct a chiral benzylamine skeleton through asymmetric hydrogenation of imines or reductive amination of carbonyl compounds. This strategy has relatively low reaction temperatures, high yields and can achieve high enantioselectivity; the second is to use nickel and photocatalytic reduction synergistic catalytic strategy to directly activate the α-CH bond of benzamide, thereby realizing the modular synthesis of chiral benzylamine. This strategy uses the cross-coupling reaction of free radical intermediates generated by photoexcitation and nickel catalysis, reducing the dependence on pre-functionalized bottoms.

[0004] However, the high cost and resource scarcity of precious metal catalysts make it difficult to meet the needs of green chemistry and sustainable development. In addition, precious metal catalysts have insufficient recognition of steric hindrance. When the substrate contains large steric hindrance alkyl or polysubstituted aromatic groups, it is difficult to accurately distinguish the enantiomeric transition state, resulting in decreased enantioselectivity. Although the nickel photocatalytic system avoids the dependence on precious metals, its applicable substrate range is narrow, and the reaction activity is severely inhibited by steric hindrance or coordination ability. Therefore, it is urgent to provide a solution to improve the above problems. Summary of the invention

[0005] The purpose of the present invention is to provide a method for synthesizing chiral benzylamine compounds, wherein the raw materials are readily available, the reaction conditions are mild, the functional groups have good compatibility, and the method can be applied to different reaction substrates, and the chiral benzylamine compounds with high chirality values ​​can be efficiently synthesized.

[0006] The present invention provides a method for synthesizing a chiral benzylamine compound, comprising: in a solvent environment, under the action of a metal catalyst, a photocatalyst, a chiral promoter and a reducing agent, reacting an N-alkenylbenzamide compound I, an aromatic iodine compound II and an NHP ester III under light to generate a chiral benzylamine compound IV;

[0007]

[0008] Among them, R 1 is hydrogen, methoxy, trifluoromethyl, trifluoromethoxy, halogen, R 2 is trifluoromethyl, trifluoromethoxy, halogen, hydrogen, methoxy, cyano, ester group, aldehyde group, carbonyl group or sulfonyl group, R 3 is tert-butyl, long-chain, cyclic tertiary alkyl and secondary alkyl..

[0009] For the synthesis method provided by the present invention, using NHP ester Ⅲ as the alkyl donor has a wide source, and using a photocatalyst and a metal catalyst in combination can effectively improve the reaction yield and enantioselectivity under a light environment. The substrate range of the reaction system is wide and the functional group tolerance is good, having good application potential.

[0010] Optionally, the structural formula of the chiral promoter is shown in Formula L1:

[0011]

[0012] Optionally, the metal catalyst includes one of nickel-based catalysts, copper-based catalysts, and iron-based catalysts.

[0013] Preferably, the nickel-based catalyst includes nickel bromide dimethoxyethane.

[0014] Optionally, the photocatalyst includes one of 4CzIPN, [Ir(dF(CF3)ppy)2(dtbbpy)]PF6, and Ru(bpy)3(PF6)2.

[0015] Preferably, the photocatalyst is 4CzIPN.

[0016] Optionally, the reducing agent includes one of Hantzsch ester, triethylamine, N,N-diisopropylethylamine, and 1-((trimethylsilyl)methyl)-piperidine.

[0017] Preferably, the reducing agent is Hantzsch ester.

[0018] Optionally, one of the N-alkenylbenzamide compounds Ⅰ and the aromatic iodine compounds Ⅱ is set in excess.

[0019] Preferably, the molar ratio of the N-alkenylbenzamide compound Ⅰ to the aromatic iodine compound Ⅱ is (1-3):1.

[0020] Optionally, one of the aromatic iodine compounds Ⅱ and the NHP ester Ⅲ is set in excess.

[0021] Preferably, the molar ratio of the aromatic iodine compound II to the NHP ester III is 1:(2 - 3).

[0022] Optionally, the concentration of the aromatic iodine compound II in the solvent environment is 0.1 mol / L - 0.5 mol / L.

[0023] Optionally, the molar ratio of the metal element in the metal catalyst to the reactants is (0.05 - 0.1):1.

[0024] Optionally, the molar ratio of the photocatalyst to the reactants is (0.001 - 0.05):1, and the reactants are N-alkenylbenzamide compound I, aromatic iodine compound II and the NHP ester III.

[0025] Optionally, the molar ratio of the chiral promoter to the reactants is (0.05 - 0.5):1, and the reactants are N-alkenylbenzamide compound I, aromatic iodine compound II and the NHP ester III.

[0026] Optionally, the molar ratio of the reducing agent to the reactants is (1 - 5):1, and the reactants are N-alkenylbenzamide compound I, aromatic iodine compound II and the NHP ester III.

[0027] Optionally, the reaction is carried out under blue light of 450 nm - 480 nm.

[0028] Optionally, the reaction is carried out under an LED light source with a power of 10 W - 50 W.

[0029] Optionally, the reaction is carried out under light and mechanical mixing, and the mechanical mixing includes one of ultrasonic, stirring and oscillation.

[0030] Optionally, the reaction is carried out at 10 °C - 35 °C under light.

[0031] Optionally, the reaction is carried out under light in a closed environment.

[0032] Optionally, the reaction is carried out under light for 5 h - 15 h.

[0033] Optionally, after the reaction to generate the chiral benzylamine compound IV, it is quenched, and the pure chiral benzylamine compound IV is obtained through extraction and purification. Description of the Drawings

[0034] Figure 1 It is a synthesis reaction formula of a chiral benzylamine compound provided by the present invention;

[0035] Figure 2 It is the nuclear magnetic resonance hydrogen spectrum of the chiral benzylamine compound IV-1 synthesized in Example 1 of the present invention ( 1 HNMR-IV-1);

[0036] Figure 3 13C NMR spectrum of chiral benzylamine compound Ⅳ-1 synthesized in Example 1 of the present invention ( 13 CNMR-IV-1);

[0037] Figure 4 19F NMR spectrum of chiral benzylamine compound Ⅳ-1 synthesized in Example 1 of the present invention ( 19 FNMR-IV-1);

[0038] Figure 5 Racemic chromatogram of chiral benzylamine compound Ⅳ-1 synthesized in Example 1 of the present invention;

[0039] Figure 6 Chiral chromatogram of chiral benzylamine compound Ⅳ-1 synthesized in Example 1 of the present invention;

[0040] Figure 7 Reaction mechanism diagram of the synthesis method provided by the present invention. Detailed implementation manners

[0041] To make the objectives, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Apparently, the described embodiments are some but not all of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without making creative efforts shall fall within the protection scope of the present invention. Unless otherwise defined, the technical terms or scientific terms used herein shall have the ordinary meanings understood by those of ordinary skill in the art to which the present invention belongs.

[0042] The present invention provides a method for synthesizing chiral benzylamine compounds, which includes reacting N-alkenylbenzamide compounds Ⅰ, aromatic iodine compounds Ⅱ and NHP esters Ⅲ under light in the presence of a metal catalyst, a photocatalyst, a chiral promoter and a reducing agent in a solvent environment to form chiral benzylamine compounds Ⅳ.

[0043] In fact, referring to Figure 1 , the reaction formula during the synthesis of the synthesis method provided by the present invention is:

[0044]

[0045] wherein, R 1 is hydrogen, methoxy, trifluoromethyl, trifluoromethoxy, halogen, R 2 is trifluoromethyl, trifluoromethoxy, methoxy, halogen, hydrogen, cyano, ester group, aldehyde group, carbonyl group or sulfonyl group, and R 3 is tert-butyl, long chain, cyclic tertiary alkyl and secondary alkyl.

[0046] In fact, the synthesis method provided by the present invention can efficiently synthesize N-alkenylbenzamide compounds I, aromatic iodine compounds II and NHP esters III in a solvent environment using a metal catalyst / photocatalyst / chiral promoter / reducing agent composite as the reaction system under a light environment to obtain chiral benzylamine compounds IV, and effectively improve the reaction yield and enantioselectivity. At the same time, the three reaction raw materials used are easy to obtain, the reaction conditions are mild, the functional group compatibility is good, the substrate scope of application is wide, and it is not easy to cause pollution. In fact, after the chiral benzylamine compound IV is generated in the reaction, it is quenched, and the pure chiral benzylamine compound IV is obtained through extraction and purification.

[0047] In some embodiments, the structural formula of the chiral promoter used in the synthesis is as shown in formula L1:

[0048]

[0049] In some embodiments, the metal catalysts used in the synthesis include nickel-based catalysts, copper-based catalysts, and iron-based catalysts. Preferably, the metal catalyst used is nickel bromide diglyme (NiBr2·diglyme). In addition, the molar ratio of the metal element in the metal catalyst to the reactants during the reaction is (0.05 - 0.1):1, and the reactants are N-alkenylbenzamide compounds I, aromatic iodine compounds II and the NHP ester III.

[0050] In some embodiments, the photocatalysts used in the synthesis include one of 4CzIPN, [Ir(dF(CF3)ppy)2(dtbbpy)]PF6, and Ru(bpy)3(PF6)2. Preferably, the photocatalyst can be 4CzIPN as shown in the following formula:

[0051]

[0052] In some embodiments, the reducing agents used in the synthesis include one of Hantzsch ester, triethylamine, N,N-diisopropylethylamine, and 1-((trimethylsilyl)methyl)-piperidine. Preferably, the reducing agent can be Hantzsch ester as shown in the following formula:

[0053]

[0054] Specifically, the molar ratio of the chiral promoter to the reactants used in the synthesis process is (0.05 - 0.5):1, the molar ratio of the photocatalyst to the reactants is (0.001 - 0.05):1, and the molar ratio of the reducing agent to the reactants is (1 - 5):1. This is beneficial for the uniform mixing of the chiral promoter, photocatalyst, reducing agent, and reactants in the solvent environment, thereby promoting the forward reaction and increasing the enantioselectivity of the reaction product.

[0055] In some embodiments, to further promote the forward reaction during the synthesis process, one of the N-alkenylbenzamide compound I and the aromatic iodine compound II is set in excess. Preferably, the initial molar ratio of the N-alkenylbenzamide compound I to the aromatic iodine compound II in the solvent environment is (1 - 3):1. In addition, one of the aromatic iodine compound II and the NHP ester III can also be set in excess. Preferably, the initial molar ratio of the aromatic iodine compound II to the NHP ester III in the solvent environment is 1:(2 - 3).

[0056] Furthermore, when the reaction is carried out in a solvent environment, the amount of the aromatic iodine compound II can be used as a reference to formulate other reactants, metal catalysts, chiral promoters, and other substances. Specifically, the concentration of the aromatic iodine compound II in the solvent environment can be 0.1 mol / L - 0.5 mol / L.

[0057] In some embodiments, when the reaction is carried out under light, the reaction system can be reacted under a blue light source of 450 nm - 480 nm or under an LED light source of 10 W - 50 W, and the reaction system is treated by mechanical mixing during the light reaction process to enable the reaction system to accelerate the reaction rate during the reaction. Specifically, the mechanical mixing can be one of ultrasonic, stirring, and oscillation. In addition, during the reaction process, the light reaction can be carried out for 5 h - 15 h at 10°C - 35°C. In fact, the synthesis method provided by the present invention can carry out the reaction at room temperature, and its reaction conditions are mild.

[0058] Specifically, in a solvent environment, nickel bromide ethylene glycol dimethyl ether (NiBr2·diglyme) is used as the metal catalyst, 4CzIPN is used as the photocatalyst, the compound shown in L1 is used as the chiral promoter, and Hantzsch ester is used as the reducing agent. The reaction mechanism of the reaction of the N-alkenylbenzamide compound I, the aromatic iodine compound II, and the NHP ester III to form the chiral benzylamine compound IV under blue light irradiation is as Figure 7As shown. Under light irradiation, 4CzIPN* undergoes reductive quenching to generate 4CzIPN·￣. NHPI ester and 4CzIPN·￣ undergo single-electron transfer to produce alkyl radical I, and then alkyl radical I adds to vinyl amide to form α-amino radical II. Radical II is captured by Ni(0) complex III to form alkyl-Ni(I) intermediate IV. Subsequently, aryl iodide undergoes oxidative addition with intermediate IV to generate aryl-Ni(III)-alkyl species V, which can easily undergo reductive elimination to produce chiral benzylamine compounds and Ni(I) VI. LNi 0 Species and 4CzIPN are both regenerated through single-electron transfer between VI and 4CzIPN·￣, thus closing two catalytic cycles.

[0059] Example 1

[0060] This Example 1 provides a method for synthesizing chiral benzylamine compounds, including the following steps:

[0061] S1. Add 0.20 mmol (29.4 mg) of N-alkenylbenzamide, 0.25 mmol (60.0 mg) of 1,3-dioxoisoindolin-2-yl pivalate (CAS: 84379-72-6), 0.2 mmol (50.2 mg) of Hantzsch ester, and 13 mol% (6.8 mg) of chiral promoter L1 into a reaction flask, transfer it into a glove box filled with nitrogen, and then add 8 mol% (2.8 mg) of NiBr2·diglyme (CAS: 28923-39-9; purchased from Bide Pharmatech), 2.0 mol% (2.0 mg) of 4CzIPN photocatalyst into the reaction flask. After adding 0.8 mL of anhydrous dimethylacetamide and stirring to dissolve, take it out of the glove box and add 0.1 mmol (27.2 mg) of 1-iodo-3-(trifluoromethyl)benzene to the reaction flask, and stir and mix to obtain a mixed solution;

[0062] S2. Use an LED light source with a power of 25 W and a light emission wavelength of 450 nm - 480 nm to irradiate at a position 2 cm above the mixed solution, and use a small fan to cool the mixed solution to control the temperature of the mixed solution during the reaction at 28 °C. Use a magnetic stirrer to vigorously stir the mixed solution at 500 rpm. After reacting for 10 h, add 3 mL of deionized water to quench, and extract with ethyl acetate (3 × 3 mL). Then, purify with petroleum ether and ethyl acetate by silica gel chromatography to obtain 26.8 mg of chiral benzylamine compounds, with a calculated yield of 77% and a chiral value of 99%.

[0063] Examples 2 to 10

[0064] Examples 2 to 10 respectively provide a method for synthesizing chiral benzylamine compounds. The difference from Example 1 is that the structural formulas of the aromatic iodine compounds II used in step S1 are different, as shown in Table 1 below.

[0065] Table 1 Structural formulas, masses, yields, and chiral values of the aromatic iodine compounds II in Examples 1 to 10

[0066]

[0067]

[0068] Examples 11 to 13

[0069] Examples 11 to 13 respectively provide a method for synthesizing chiral benzylamine compounds. The difference from Example 10 is that the structural formulas of the N-alkenylbenzamide compounds I used in step S1 are different, as shown in Table 2 below.

[0070] Table 2 Structural formulas, masses, yields, and chiral values of the N-alkenylbenzamide compounds I in Examples 10 to 13

[0071]

[0072]

[0073] Examples 14 to 16

[0074] Examples 14 to 16 respectively provide a method for synthesizing chiral benzylamine compounds. The difference from Example 1 is that the structural formulas of the NHP esters III used in step S1 are different, as shown in Table 3 below.

[0075] Table 3 Structural formulas, masses, yields, and chiral values of the NHP esters III in Examples 1, 14 to 16

[0076]

[0077]

[0078] The structural formula of the chiral benzylamine compound prepared in Example 1 is shown as Formula IV-1 below. Its 1H NMR characterization is as Figure 2 shown, its 13C NMR characterization is as Figure 3 shown, and its 19F NMR characterization is as Figure 4 shown; its chiral HPLC (CHIRALPAK AD-H, 25 °C; hexane / iPrOH = 90:10; flow rate = 0.5 mL / min; λ = 245 nm; t1 (major) = 19.6 min; t2 (minor) = 23.6 min.) were characterized as shown respectively in Figure 5 and Figure 6 shown below.

[0079]

[0080] 1 H NMR (400 MHz, CDCl3) δ 7.77–7.74 (m, 2H), 7.56 (d, J = 8.2 Hz, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.46–7.40 (m, 4H), 6.49 (d, J = 7.7 Hz, 1H), 5.35–5.30 (m, 1H), 1.86–1.76 (m, 2H), 1.01 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 166.5, 148.5, 134.3, 131.8, 129.5 (q, J = 32.2 Hz), 127.0, 126.8, 125.8 (q, J = 3.8 Hz), 124.2 (q, J = 271.9 Hz), 51.4, 51.0, 31.2, 30.2. 19 F NMR (376 MHz, CDCl3) δ -62.43 (s, 3F).

[0081] The structural formula of the chiral benzylamine compound prepared in Example 2 is shown as Formula IV-2 below.

[0082]

[0083] 1 H NMR (400 MHz, CDCl3) δ 7.76–7.73 (m, 2H), 7.52–7.48 (m, 1H), 7.44–7.40 (m, 2H), 7.38–7.35 (m, 2H), 7.16 (d, J = 8.1 Hz, 2H), 6.35 (d, J = 7.8 Hz, 1H), 5.33–5.28 (m, 1H), 1.81 (d, J = 7.1 Hz, 2H), 1.00 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 166.4, 148.3, 143.2, 134.4, 131.8, 128.8, 127.8, 127.0, 121.4, 50.9, 31.1, 30.2. 19 F NMR (376 MHz, CDCl3) δ -57.87 (s, 3F).

[0084] The structural formula of the chiral benzylamine compound prepared in Example 3 is shown as Formula IV-3 below.

[0085]

[0086] 1 H NMR(400MHz,CDCl3)δ7.75–7.73(m,2H),7.52–7.47(m,1H),7.44–7.40(m,2H),7.34–7.31(m,2H),7.03–6.99(m,2H),6.26(d,J=7.2Hz,1H),5.31–5.25(m,1H),1.82(d,J=6.8Hz,2H),0.99(s,9H). 13 C NMR(101MHz,CDCl3)δ166.3,161.98(d,J=245.1Hz),140.19,134.61,131.68,128.76,128.12(d,J=8.0Hz),126.95,115.63(d,J=21.4Hz),50.95,50.88,31.04,30.18. 19 F NMR(376MHz,CDCl3)δ-115.59.

[0087] The structural formula of the chiral benzylamine compound prepared in Example 4 is shown as Formula IV-4 below.

[0088]

[0089] 1 H NMR(400MHz,CDCl3)δ7.75–7.72(m,2H),7.51–7.47(m,1H),7.43–7.40(m,2H),7.28(s,4H),6.34(d,J=8.0Hz,1H),5.28–5.23(m,1H),1.80(d,J=7.2Hz,2H),0.99(s,9H). 13 C NMR(101MHz,CDCl3)δ166.3,142.9,134.5,132.9,131.7,128.0,128.8,127.9,127.0,51.0,50.8,31.1,30.2.

[0090] The structural formula of the chiral benzylamine compound prepared in Example 5 is shown as Formula IV-5 below.

[0091]

[0092] 11H NMR (400 MHz, CDCl3) δ 7.76–7.74 (m, 2H), 7.50 - 7.46 (m, 1H), 7.43–7.39 (m, 2H), 7.37–7.30 (m, 4H), 7.26–7.22 (m, 1H), 6.34 (d, J = 6.4 Hz, 1H), 5.34–5.3 (m, 1H), 1.85 (d, J = 10.0 Hz, 1H), 0.99 (s, 9H). 13 13C NMR (101 MHz, CDCl3) δ 166.3, 144.3, 134.8, 131.6, 128.9, 128.7, 127.3, 127.0, 126.5, 51.6, 50.9, 31.1, 30.2.

[0093] The structural formula of the chiral benzylamine compound prepared in Example 6 is shown as Formula IV-6 below.

[0094]

[0095] 1 1H NMR (400 MHz, CDCl3) δ 7.76–7.74 (m, 2H), 7.60 (d, J = 8.2 Hz, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.45–7.41 (m, 4H), 6.49 (d, J = 7.5 Hz, 1H), 5.31 - 5.26 (m, 1H), 1.84–1.77 (m, 1H), 1.01 (s, 9H). 13 13C NMR (101 MHz, CDCl3) δ 166.4, 149.8, 133.9, 132.5, 131.8, 128.7, 127.0, 126.8, 118.8, 110.8, 51.4, 50.7, 31.0, 30.0.

[0096] The structural formula of the chiral benzylamine compound prepared in Example 7 is shown as Formula IV-7 below.

[0097]

[0098] 1 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.4 Hz, 2H), 7.75 (dd, J = 6.9 Hz, 2H), 7.52–7.48 (m, 1H), 7.45 - 7.40 (m, 4H), 6.35 (d, J = 8.0 Hz, 1H), 5.36–5.3 (m, 1H), 3.90 (s, 3H), 1.82 (d, J = 6.5 Hz, 1H), 1.01 (s, 9H). 1313C NMR (101 MHz, CDCl3) δ 167.0, 166.4, 149.6, 134.4, 131.8, 130.3, 129.1, 128.8, 127.0, 126.5, 52.3, 51.8, 50.9, 31.2, 30.2.

[0099] The structural formula of the chiral benzylamine compound prepared in Example 8 is shown in Formula IV-8 below.

[0100]

[0101] 1 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 7.84 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 7.2 Hz, 2H), 7.52–7.49 (m, 3H), 7.43 (t, J = 7.5 Hz, 2H), 6.44 (d, J = 7.6 Hz, 1H), 5.36–5.31 (m, 1H), 1.82 (d, J = 5.5 Hz, 2H), 1.02 (s, 9H). 13 13C NMR (101 MHz, CDCl3) δ 192.0, 166.5, 151.4, 135.5, 134.3, 131.9, 130.4, 128.8, 127.1, 127.0, 51.6, 50.93, 31.2, 30.2.

[0102] The structural formula of the chiral benzylamine compound prepared in Example 9 is shown in Formula IV-9 below.

[0103]

[0104] 1 1H NMR (400 MHz, CDCl3) δ 7.92–7.9 (m, 2H), 7.76–7.74 (m, 2H), 7.52–7.48 (m, 1H), 7.45–7.40 (m, 3H), 6.45 (d, J = 7.7 Hz, 1H), 5.35–5.32 (m, 1H), 2.57 (s, 3H), 1.83–1.81 (m, 2H), 1.01 (s, 9H). 13 13C NMR (101 MHz, CDCl3) δ 197.9, 166.5, 149.9, 136.1, 134.37, 131.8, 129.0, 128.8, 127.0, 126.7, 51.5, 50.9, 31.2, 30.2, 26.8.

[0105] The structural formula of the chiral benzylamine compound prepared in Example 10 is shown in Formula IV-10 below.

[0106]

[0107] 1 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.4 Hz, 2H), 7.77 - 7.75 (m, 2H), 7.54 - 7.49 (m, 3H), 7.45 - 7.41 (m, 2H), 6.56 (d, J = 7.5 Hz, 1H), 5.34–5.29 (m, 1H), 3.01 (s, 3H), 1.86–1.77 (m, 2H), 1.02 (s, 9H). 13 13C NMR (101 MHz, CDCl3) δ 166.5, 150.9, 139.0, 133.9, 131.9, 128.8, 127.9, 127.3, 126.9, 51.4, 50.8, 44.6, 31.1, 30.0.

[0108] The structural formula of the chiral benzylamine compound prepared in Example 11 is shown as Formula IV-11 below.

[0109]

[0110] 1 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.24–7.19 (m, 2H), 6.95 (d, J = 7.2 Hz, 1H), 6.57 (d, J = 7.2 Hz, 1H), 5.26–5.21 (m, 1H), 3.73 (s, 3H), 2.93 (s, 3H), 1.79-1.75 (m, 1H), 1.67 (dd, J = 3.6, 3.6 Hz, 1H), 0.94 (s, 9H). 13 13C NMR (101 MHz, CDCl3) δ 166.3, 159.8, 150.9, 138.9, 135.4, 129.6, 127.8, 127.2, 118.5, 117.8, 112.5, 55.4, 51.4, 50.6, 44.5, 31.0, 29.9.

[0111] The structural formula of the chiral benzylamine compound prepared in Example 12 is shown as Formula IV-12 below.

[0112]

[0113] 11H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 6.8 Hz, 1H), 8.13 (dd, J = 2.0, 2.0 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.48–7.44 (m, 1H), 7.06 (t, J = 7.6 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 5.32–5.27 (m, 1H), 4.02 (s, 3H), 3.00 (s, 3H), 1.78–1.73 (m, 2H), 1.03 (s, 9H). 13 13C NMR (101 MHz, CDCl3) δ 164.5, 157.6, 151.7, 138.7, 133.2, 132.4, 127.8, 127.2, 121.5, 120.9, 111.4, 56.1, 51.4, 44.6, 31.1, 30.1.

[0114] The structural formula of the chiral benzylamine compound prepared in Example 13 is as shown in Formula IV-13 below.

[0115]

[0116] 1 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 6.50 (d, J = 7.2 Hz, 1H), 5.34–5.27 (m, 1H), 3.83 (s, 3H), 3.00 (s, 3H), 1.85–1.75 (m, 2H), 1.01 (s, 9H). 13 13C NMR (101 MHz, CDCl3) δ 166.2, 162.5, 151.3, 138.9, 128.9, 127.9, 127.4, 126.3, 113.9, 55.5, 51.4, 50.8, 44.7, 31.2, 30.1.

[0117] The structural formula of the chiral benzylamine compound prepared in Example 14 is as shown in Formula IV-14 below.

[0118]

[0119] 11H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.6 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.52–7.40 (m, 5H), 6.41 (d, J = 7.6 Hz, 1H), 5.32 (dd, J = 7.2, 7.6 Hz, 1H), 1.79 (d, J = 5.2 Hz, 2H), 1.36 (dd, J = 7.2, 7.6 Hz, 2H), 0.96 (d, J = 3.2 Hz, 6H), 0.86 (t, J = 7.2 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 148.5, 134.2, 131.7, 129.3 (q, J = 32.4 Hz), 128.7, 126.7, 126.6, 125.7 (q, J = 3.7 Hz), 124.1 (q, J = 272.1 Hz)., 50.9, 48.5, 34.6, 33.5, 27.2, 27.2, 8.5. 19 19F NMR (376 MHz, CDCl3) δ -62.42 (s, 3F).

[0120] The structural formula of the chiral benzylamine compound prepared in Example 15 is shown as Formula IV-15 below.

[0121]

[0122] 1 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.6 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.50 (t, J = 7.6 Hz, 1H), 7.43 (dd, J = 8.0, 7.6 Hz, 4H), 7.17 (d, J = 6.8 Hz, 1H), 5.21–5.17 (m, 1H), 3.53 (d, J = 10.0 Hz, 1H), 3.31 (d, J = 10.4 Hz, 1H), 2.05 (dd, J = 11.2, 11.2 Hz, 1H), 1.56 (dd, J = 2.0, 2.0 Hz, 1H), 1.00 (s, 3H), 0.94 (s, 3H), 0.91 (s, 9H), 0.06 (s, 3H), -0.01 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 167.0, 148.9, 134.3, 131.7, 129.08 (q, J = 32.5 Hz), 128.6, 127.0, 126.24, 125.62 (q, J = 3.8 Hz), 124.2 (q, J = 272.1 Hz), 70.2, 51.4, 44.7, 35.7, 27.5, 26.1, 23.9, 18.3, -5.1, -5.3.19 19F NMR (376 MHz, CDCl3) δ -62.38 (s, 3F).

[0123] The structural formula of the chiral benzylamine compound prepared in Example 16 is shown as Formula IV-16 below.

[0124]

[0125] 1 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.50–7.46 (m, 3H), 7.39 (t, J = 7.6 Hz, 2H), 7.01 (d, J = 7.6 Hz, 1H), 6.67 (d, J = 7.2 Hz, 1H), 6.59 (s, 1H), 6.45 (d, J = 8.0 Hz, 1H), 5.37 (dd, J = 7.6, 7.2 Hz, 1H), 3.89 (t, J = 7.2 Hz, 2H), 2.31 (s, 3H), 2.17 (s, 3H), 1.88–1.86 (m, 2H), 1.81–1.76 (m, 2H), 1.52–1.48 (m, 2H), 1.04 (s, 6H). 13 13C NMR (101 MHz, CDCl3) δ 166.5, 157.0, 148.5, 136.6, 134.2, 131.8, 130.4, 129.5 (q, J = 32.4 Hz), 128.8, 126.9, 126.8, 125.86 (q, J = 3.7 Hz), 124.2 (q, J = 272.1 Hz), 123.6, 120.8, 112.1, 68.4, 51.0, 48.9, 39.0, 33.4, 27.7, 24.4, 21.5, 16.0. 19 19F NMR (376 MHz, CDCl3) δ -62.41 (s, 3F).

[0126] Although the embodiments of the present invention have been described in detail above, it is obvious to those skilled in the art that various modifications and changes can be made to these embodiments. However, it should be understood that such modifications and changes are all within the scope and spirit of the present invention described in the claims. Moreover, the present invention described herein can have other embodiments and can be implemented or realized in various ways.

Claims

1. A method for synthesizing chiral benzylamine compounds, characterized in that, Comprising: In a solvent environment, under the action of a metal catalyst, a photocatalyst, a chiral promoter and a reducing agent, N-alkenylbenzamide compound I, aromatic iodine compound II and NHP ester III react under light irradiation to form chiral benzylamine compound IV; Among them, R 1 is hydrogen, methoxy, trifluoromethyl, trifluoromethoxy, halogen, R 2 is trifluoromethyl, trifluoromethoxy, methoxy, halogen, hydrogen, cyano, ester group, aldehyde group, carbonyl group or sulfonyl group, R 3 is tert-butyl, long-chain, cyclic tertiary alkyl and secondary alkyl.

2. The synthesis method according to claim 1, characterized in that, The structural formula of the chiral promoter is as shown in formula L1:

3. The synthesis method according to claim 1, characterized in that, The metal catalyst includes one of a nickel-based catalyst, a copper-based catalyst, and an iron-based catalyst. Preferably, the nickel-based catalyst includes nickel bromide dimethoxyethane; and / or, the photocatalyst includes one of 4CzIPN, [Ir(dF(CF3)ppy)2(dtbbpy)]PF6, Ru(bpy)3(PF6)2. Preferably, the photocatalyst is 4CzIPN; and / or, the reducing agent includes one of Hantzsch ester, triethylamine, N,N-diisopropylethylamine, 1-((trimethylsilyl)methyl)-piperidine. Preferably, the reducing agent is Hantzsch ester.

4. The synthesis method according to claim 1, characterized in that, One of the N-alkenylbenzamide compound I and the aromatic iodine compound II is set in excess. Preferably, the molar ratio of the N-alkenylbenzamide compound I to the aromatic iodine compound II is (1 - 3):1; and / or, one of the aromatic iodine compound II and the NHP ester III is set in excess. Preferably, the molar ratio of the aromatic iodine compound II to the NHP ester III is 1:(2 - 3); and / or, the concentration of the aromatic iodine compound II in the solvent environment is 0.1 mol / L - 0.5 mol / L.

5. The synthesis method according to claim 1, wherein The molar ratio of the metal element in the metal catalyst to the reactants is (0.05 - 0.1):1; and / or, the molar ratio of the photocatalyst to the reactants is (0.001 - 0.05):1; and / or, the molar ratio of the chiral promoter to the reactants is (0.05 - 0.5):1; and / or, the molar ratio of the reducing agent to the reactants is (1 - 5):1; wherein, the reactants are the N-alkenylbenzamide compound I, the aromatic iodine compound II and the NHP ester III.

6. The synthesis method according to claim 1, characterized in that, React under 450 nm - 480 nm blue light; and / or, react under an LED light source with a power of 10 W - 50 W; and / or, react under light irradiation and mechanical mixing, where the mechanical mixing includes one of ultrasonic, stirring, and oscillation; and / or, react at 10 °C - 35 °C under light irradiation; and / or, react under light irradiation in a closed environment; and / or, react under light irradiation for 5 h - 15 h.

7. The synthesis method according to claim 1, wherein After the reaction to form the chiral benzylamine compound IV, quench, and obtain the pure chiral benzylamine compound IV through extraction and purification.

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