Synthesis method and application of a class of chiral N-(1-substituted-allyl)amines

Abstract

The present invention discloses a synthesis method and application of a class of chiral N-(1-substituted-allyl)amines. This method successfully implements a molybdenum-catalyzed asymmetric allylic amination reaction, avoiding the use of complex and difficult-to-synthesize chiral phosphine ligands. The method offers advantages such as a wide substrate range, specific stereoselectivity, a single chemical reaction site, readily available raw materials, simple operation, and mild reaction conditions. This method provides more options for the green synthesis of chiral allylic amines. The method can also be applied to the total synthesis of natural products. Furthermore, the total synthesis of clopidogrel, a drug that inhibits platelet aggregation, has been demonstrated.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and in particular relates to a synthesis method and application of a class of chiral N-(1-substituted-allyl)amines. Background Art

[0002] Transition metal catalyzes the asymmetric amination reaction of allyl nucleophiles is one of the most commonly used and most powerful strategies for preparing chiral α-branched allylamines in industry and academia. However, the overwhelming dominance in this field research is palladium catalysis, as well as iridium, rhodium and ruthenium plus chiral phosphine ligands and cobalt and nickel catalysis (Chem.Soc.Rev.2020, 49, 6141.). The cost is high and the use of chiral phosphine ligands for multi-step synthesis is required, making the above reaction uneconomical and practical. Therefore, the development of a metal catalysis method without the need for phosphine ligands has become a strong demand for asymmetric amination process.

[0003] Molybdenum, due to its low cost, environmental friendliness, and abundant reserves, is gradually becoming an alternative to palladium, rhodium, and iridium in transition metal catalysis. However, the molybdenum-catalyzed asymmetric heteroatom substitution of allylic nucleophiles remains a major challenge due to the lack of suitable chiral ligands. Summary of the Invention

[0004] In order to overcome the shortcomings of the above-mentioned prior art, the purpose of the present invention is to provide a synthesis method and application of a class of chiral N-(1-substituted-allyl)amines to solve the technical problem that the asymmetric allylic amination reaction cannot be achieved due to the lack of verified chiral ligands in the prior art metal molybdenum catalysis process.

[0005] In order to achieve the above object, the present invention adopts the following technical solutions:

[0006] The present invention discloses a method for synthesizing a class of chiral N-(1-substituted-allyl)amines, comprising: stirring allyl carbonate and amine in the presence of a Schiff base ligand and a metal molybdenum catalyst to react, allowing the stirred mixture to stand at 30° C. for 24 hours, removing the reaction solvent, and performing column chromatography separation and purification to obtain the chiral N-(1-substituted-allyl)amine; wherein:

[0007] The structural formula of the reactant allyl carbonate is as follows:

[0008]

[0009] R 1 is an alkyl group, an aryl group or an aromatic group;

[0010] The structural formula of the reactant amine is as follows:

[0011]

[0012] R2 is an aryl or aromatic group; R 3 is H or alkyl;

[0013] The structural formula of the product chiral N-(1-substituted-allyl)amine is as follows:

[0014]

[0015] Preferably, the metal molybdenum catalyst is (C7H8)Mo(CO)3.

[0016] Preferably, the molar ratio of the metal molybdenum catalyst to the Schiff base ligand is 1:1.5.

[0017] Preferably, the molar ratio of allyl carbonate to amine is 1:1.2.

[0018] Preferably, dichloromethane is selected as the reaction solvent.

[0019] The present invention also discloses the application of the synthesis method of the chiral N-(1-substituted-allyl)amine to realize the total synthesis of clopidogrel.

[0020] Preferably, the process comprises: reacting an allyl carbonate compound represented by the following formula I and an amine compound represented by the following formula II with stirring in the presence of a Schiff base ligand and a metal molybdenum catalyst, allowing the resulting mixture to stand at 30° C. for 24 hours, removing the reaction solvent, and performing column chromatography separation and purification to obtain an intermediate compound represented by the following formula III;

[0021]

[0022] The chiral drug clopidogrel is prepared by converting the intermediate compound into a two-step reaction;

[0023] The structural formula of the chiral drug clopidogrel is as follows:

[0024]

[0025] Preferably, the two-step conversion reaction comprises:

[0026] Step 1: Dissolve compound III in CCl4, MeCN, and DCM in the presence of sodium iodide and RuCl3.H2O, stir at room temperature for 6 h, pour the reaction solution into DCM / H2O for separation, and dry the organic layer to obtain a crude product;

[0027] Step 2: TMSCHN2 was added to the crude reaction product, and the mixture was stirred at room temperature for 2 h. The mixture was purified by silica gel column chromatography to obtain (S)-clopidogrel.

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

[0029] This invention successfully implements a molybdenum-catalyzed asymmetric allylic amination reaction, avoiding the use of complex and difficult-to-synthesize chiral phosphine ligands. It offers advantages such as a broad substrate range, specific stereoselectivity, a single chemical reaction site, readily available starting materials, simple operation, and mild reaction conditions. It provides more options for the green synthesis of chiral allylic amines. The method can also be applied to the total synthesis of natural products, and has been demonstrated in the total synthesis of clopidogrel, a drug that inhibits platelet aggregation. DETAILED DESCRIPTION

[0030] In order to enable those skilled in the art to better understand the present invention, the technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the embodiments described 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 making creative efforts should fall within the scope of protection of the present invention.

[0031] It should be noted that the terms "comprises" and "has" and any variations thereof in the description and claims of the present invention are intended to cover non-exclusive inclusions. For example, a process, method, system, product or apparatus comprising a series of steps or units is not necessarily limited to those steps or units explicitly listed, but may include other steps or units that are not explicitly listed or are inherent to these processes, methods, products or apparatuses.

[0032] The reaction equations of a series of chiral N-(1-substituted allyl)aryl and alkylamine disclosed in the present invention are as follows:

[0033]

[0034] Specifically, general synthesis examples:

[0035] A dried reaction tube was equipped with a magnetic stirrer, followed by the addition of the metal catalyst (C7H8)Mo(CO)3 (9.12 mg, 10 mol%), the Schiff base (imine) ligand (S,S)-L2 (16.4 mg, 15 mol%), allyl carbonate 1 (0.2 mmol), and amine 2 (0.24 mmol). The reaction tube was sealed with a rubber septum, evacuated, and backfilled with nitrogen. Anhydrous CH2Cl2 (0.5 mL) was added via syringe. The resulting mixture was stirred and incubated at 30°C under a nitrogen balloon for 24 hours. The reaction mixture was transferred to a 50 mL round-bottom flask, and the solvent was removed in vacuo using a rotary evaporator. The residue was purified by silica gel column chromatography to yield the highly pure product, allylamine 3.

[0036] The present invention also discloses a method for fully synthesizing the chiral drug clopidogrel based on the above synthesis principle, which comprises two steps:

[0037] Step 1: Asymmetric synthesis of clopidogrel intermediate 3dm using the above-mentioned catalytic route of the present invention

[0038] (R)-5-(1-(2-chlorophenyl)allyl)-4,5,6,7.tetrahydrothiophene[3,2-c]pyridine (3dm)

[0039] The reaction equation is as follows:

[0040]

[0041] A dried reaction tube was equipped with a magnetic stirrer, followed by the addition of the metal catalyst (C7H8)Mo(CO)3 (16.3 mg, 10 mol%), the Schiff base (imine) ligand (S,S)-L2 (49.2 mg, 15 mol%), allyl carbonate 1d (161.2 mg, 0.6 mmol), and the amine 2m (100.2 mg, 0.72 mmol). The reaction tube was sealed with a rubber septum, evacuated, and backfilled with nitrogen. Anhydrous CH2Cl2 (1.5 mL) was added via syringe. The resulting mixture was stirred and incubated at 30°C under a nitrogen balloon for 24 hours. The reaction mixture was transferred to a 50 mL round-bottom flask, and the solvent was removed in vacuo using a rotary evaporator. The residue was purified by silica gel column chromatography to obtain 161.7 mg of 3dm as a colorless oil in a 97% yield and >99% ee.

[0042] Characterization data: [α] 25 D =217.4(c=0.14, CHCl3).Lit.data: [α] 20 D =41.3 (c=1.0, CHCl3); 1 H NMR (400MHz, CDCl3) δ7.66 (dd, J=1.8, 7.8Hz, 1H), 7.36 (dd, J=1.8, 7.8Hz, 1H), 7.28 (ddd, J=1.2, 7.4, 15.0Hz, 1H), 7.17 (ddd, J=1.7, 7.9, 15.2Hz, 1H), 7.06 (d, J=5.2Hz, 1H), 6.69 (d , J=5.2Hz, 1H), 5.895.80 (m, 1H), 5.40 (dd, J=17.1, 1.4Hz, 1H), 5.12 (dd, J=10.0, 1.5Hz, 1H ), 4.50 (d, J=8.8Hz, 1H), 3.71 (d, J=14.6Hz, 1H), 3.45 (d, J=14.6Hz, 1H), 2.892.77 (m, 4H); 13C NMR (100MHz, CDCl3) δ139.5, 139.0, 134.0, 133.7, 133.6, 129.7, 129.0, 128.0, 127.3, 125.4, 122.6, 116.8, 68.8, 51.6, 48.7, 25.5; HRMS (ESI-MS): Calcd.for C16H 16 ClNS[M+H]+: 290.0765, Found: 290.0765; HPLC conditions: ChiralcelOJ-H column, 254nm, flow rate: 1ml / min, i-PrOH / hexanes=5 / 95, t minor =5.05min, t major =6.15min; >99%ee.

[0043] Step 2: The intermediate 3dm is converted into the chiral drug clopidogrel 7 through two steps.

[0044] (S)-methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothiophene[3,2-c]-5(4H)-pyridine)acetate (7)

[0045] The reaction equation is as follows:

[0046]

[0047] To a 10 mL oven-dried reaction tube equipped with a stir bar, sodium iodide (642.0 mg, 3.0 mmol, 10.0 equiv) and RuCl₃·H₂O (6.8 mg, 10 mol%) were added. The tube was sealed with a rubber septum and flushed with N₂. Compound (R-3dm) (87 mg, 0.3 mmol) was dissolved in CCl₄ (1.5 mL), MeCN (1.0 mL), and DCM (1.0 mL) and added to the reaction tube. The mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into 1:1 DCM / H₂O (10 mL). The organic layer was separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. TMSCHN₂ (342.6 mg, 0.3 mmol, 10.0 equiv) was added to the crude product and the reaction was stirred at room temperature for 2 hours. After concentration, the reaction mixture was purified by flash column chromatography on silica gel to obtain a viscous oily product of high purity (S)-clopidogrel. 60.8 mg of the target product 7 was isolated, with a combined yield of 63% for the two steps. Data characterization: [α] 25 D =+89.9(c=1.1, CHCl3).Lit.data: [α] 25 D = +89.9 (c = 1.1, CHCl3);1 H NMR (400MHz, CDCl3) δ7.70 (d, J=7.1Hz, 1H), 7.41 (d, J=7.1Hz, 1H), 7.31 7.23 (m, 2H), 7.05 (d, J=5.0Hz, 1H), 6.67 (d, J=5.0Hz, 1H), 4.92 (s, 1H), 3 .76 (d, J=14.4Hz, 1H), 3.72 (s, 3H), 3.63 (d, J=14.4Hz, 1H), 2.28 (s, 4H); 13 C NMR (100MHz, CDCl3) δ171.3, 134.6, 133.7, 133.2, 133.1, 129.9, 129.7, 129.4, 127.1, 125.2, 122.7, 67.8, 52.1, 50.6, 48.2, 25.4; HRMS (ESI-MS): Calcd.forC 16 H 17 ClNO2S[M+H]+: 322.0663, Found: 322.0665.

[0048] General Implementation A:

[0049] A dried reaction tube was equipped with a magnetic stirrer, followed by the addition of the metal catalyst (C7H8)Mo(CO)3 (9.12 mg, 10 mol%), the Schiff base (imine) ligand (S,S)-L2 (16.4 mg, 15 mol%), allyl carbonate 1 (0.2 mmol), and amine 2 (0.24 mmol). The reaction tube was sealed with a rubber septum, evacuated, and backfilled with nitrogen. Anhydrous CH2Cl2 (0.5 mL) was added via syringe. The resulting mixture was stirred and incubated at 30°C under a nitrogen balloon for 24 hours. The reaction mixture was transferred to a 50 mL round-bottom flask, and the solvent was removed in vacuo using a rotary evaporator. The residue was purified by silica gel column chromatography to yield the highly pure product, allylamine 3.

[0050] Example 1 Preparation of (R)-4-methoxy-N-(1-phenylallyl)aniline (3aa)

[0051] Allylbenzene 1a and p-anisidine 2a were used as reaction substrates. The crude product obtained by general embodiment A was passed through a silica gel column with a polar petroleum ether / ethyl acetate buffer of 50:1 to isolate 44 mg of (R)-4-methoxy-N-(1-phenylallyl)aniline (3aa) in a yield of 92%.

[0052] Data characterization:

[0053] [α] 25 D=+24.3(c=0.72, CHCl3).Lit.data(S-isomer):[α] 25 D =16.7 (c=1.0, CHCl3); 1 H NMR (400MHz, CDCl3) δ7.397.32(m, 4H), 7.287.24(m, 1H), 6.756.71(m, 2H), 6.586.54(m, 2H), 6.075.99(m, 1H), 5.27 (dt, J=17.1, 1.3Hz, 1H), 5.2l (dt, J=10.2, 1.3Hz, 1H), 4.85 (d, J=6.0Hz, 1H), 3.84 (brs, 1H), 3.72 (s, 3H); 13 C NMR (100MHz, CDCl3) δ152.1, 124.1, 141.4, 139.5, 128.7, 127.3, 127.1, 115.8, 114.8, 114.7, 61.7, 55.7; HRMS (ESI-MS): Calcd.for C 16 H17NO[M] + :239.13, Found: 239.1311; HPLC conditions: Chiralcel OD-H column, 254nm, flow rate: 1 ml / min, j-PrOH / hexanes=1 / 19, t ma jor=6.93min,t min or=8.39min;96%ee.

[0054] The structural formula of (R)-4-methoxy-N-(1-phenylallyl)aniline (3aa) is as follows:

[0055]

[0056] Example 2 Preparation of (R)-4-methoxy-N-(1-(4-methoxyphenyl)allyl)aniline (3ba)

[0057] Using p-methoxyallylbenzene 1b and p-methoxyaniline 2a as the reaction substrates, the crude product obtained was passed through a silica gel column using a polar petroleum ether / ethyl acetate buffer (40:1). 50 mg of (R)-4-methoxy-N-(1-(4-methoxyphenyl)allyl)aniline (3ba) was isolated in a 93% yield.

[0058] Characterization data: [α] 25 D=+128.9(c=0.23, CHCl3); 1 H NMR (400MHz, CDCl3) δ7.31 7.27 (m, 2H), 6.896.86 (m, 2H), 6.756.71 (m, 2H), 6.586.54 (m, 2H), 6.055.97 (m, 1H), 5.25 (dt, J = 17.2, 1 .2Hz, 1H), 5.19 (dt, J=10.2, 1.2Hz, 1H), 4.80 (d, J=6.0Hz, 1H), 3.80 (s, 3H), 3.78 (brs, 1H), 3.72 (s, 3H); 13 C NMR (100MHz, CDCl3) δ158.8, 152.1, 141.5, 139.6, 134.2, 128.2, 115.5, 114.8, 114.7, 114.0, 61.1, 55.7, 55.3; HRMS (ESI-MS): Calcd.for C 17 H 19 NO2[M+H] + : 270.1489, Found: 270.1488; HPLC conditions: Chiralcel OD-H column, 254nm, flowrate: 1ml / min, i-PrOH / hexanes=1 / 19, t minor =10.11min, t major =12.37min; 92%ee.

[0059] The structural formula of (R)-4-methoxy-N-(1-(4-methoxyphenyl)allyl)aniline (3ba) is as follows:

[0060]

[0061] Example 3 Preparation of (R)-N-(1-(4-chlorophenyl)allyl)-4-methoxyaniline (3ca)

[0062] Using p-chloroallylbenzene 1c and p-anisidine 2a as reaction substrates, the crude product obtained by general method A was passed through a silica gel column with a polar petroleum ether / ethyl acetate buffer of 50:1. 44.9 mg of the product was isolated with a yield of 82%.

[0063] Data representation: [α] 25 D =+132.3 (c=0.2, CHCl3); 1H NMR (400MHz, CDCl3) δ7.30 (s, 4H), 6.746.70 (m, 2H), 6.546.50 (m, 2H), 6.035.94 (m, 1H), 5.23 13C NMR (100MHz, CDCl3) δ152.4, 140.9, 140.6, 139.0, 133.0, 128.8, 128.5, 116.4, 115.0, 114.7, 61.3, 55.7; HRMS (ESI-MS): Calcd.for C 16 H 16 ClNO[M+H] + : 274.0993, Found: 274.0975; HPLC conditions: Chiralcel OD-H column, 254nm, flow rate: 1ml / min, i-PrOH / hexanes=1 / 19, t ma jor=7.78min, tminor=10.87min; 91%ee.

[0064] The structural formula of (R)-N-(1-(4-chlorophenyl)allyl)-4-methoxyaniline (3ca) is as follows:

[0065]

[0066] Example 4 Preparation of (R)-N-(1-(2-chlorophenyl)allyl)-4-methoxyaniline (3da)

[0067] Allylbenzene 1d and p-anisidine 2a were used as reaction substrates, and the crude product obtained was passed through a silica gel column using a polar petroleum ether / ethyl acetate buffer of 50:1. 49.8 mg of the product was isolated with a yield of 91%.

[0068] Data characterization: [α]25D=+157.8 (c=0.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ7.45 (dd, J=2.0, 7.2 Hz, 1H), 7.38 (dd, J=2.0, 8.4 Hz, 1H), 7.247.16 (m, 2H), 6.736.69 (m, 2H), 6.526.48 (m, 2H), 6.075.99 (m, 1H), 5.33 (d, J=5.6 Hz, 1H), 5.235.18 (m, 2H), 3.69 (s, 3H); 13C NMR (100MHz, CDCl3) δ152.3, 140.8, 139.0, 137.6, 133.4, 129.7, 128.4, 128.1, 127.2, 116.6, 114.7, 114.6, 57.7, 55.6; HRMS (ESI-MS): Calcd.for C 16 H 16 ClNO[M+Na] + : 296.0812, Found: 296.0836; HPLC conditions: Chiralcel OJ-H column, 254nm, flow rate: 1ml / min, i-PrOH / hexanes=3 / 97, t ma jo r =21.1min, t min or=27.01min;92%ee.

[0069] The structural formula of (R)-N-(1-(2-chlorophenyl)allyl)-4-methoxyaniline (3da) is as follows:

[0070]

[0071] Example 5 Preparation of (R)-4-methoxy-N-(1-(m-tolyl)allyl)aniline (3ea)

[0072] Using m-methylallylbenzene 1e and p-anisidine 2a as reaction substrates, the crude product obtained by general method A was passed through a silica gel column with a polar petroleum ether / ethyl acetate buffer of 50:1. 43.5 mg of the product was isolated with a yield of 86%.

[0073] Data representation: [α] 25 D =+222.1(c=0.12, CHCl3); 1H NMR (400MHz, CDC13) δ7.257.16 (m, 3H), 7.08 (d, J=7.6Hz, 1H), 6.756.71 (m, 2H), 6.586.54 (m, 2H), 6.055.97 (m, 1 H), 5.27 (dt, J=17.2, 1.2Hz, 1H), 5.19 (dt, J=10.0, 1.6Hz, 1H), 4.80 (d, J=6.0Hz, 1H), 3.71 (s, 3H), 2.34 (s, 3H); 13 C NMR (100MHz, CDCl3) δ152.1, 142.1, 141.5, 139.6, 138.3, 128.6, 128.1, 127.8, 124.1, 115.6, 114.8, 114.7, 61.8, 55.7, 21.4; HRMS (ESI-MS): Calcd.forC 17 H 19 NO[H] + : 253.1467, Found: 253.1461; HPLC conditions: Chiralcel OJ-H column, 254nm, flowrate: 1ml / min, i-PrOH / hexanes=3 / 97, tmajor=24.37min, t minor =26.28min; 92%ee.

[0074] The structural formula of (R)-4-methoxy-N-(1-(m-tolyl)allyl)aniline (3ea) is as follows:

[0075]

[0076] Example 6 Preparation of (R)-N-(1-(3,4-dimethoxyphenyl)allyl)-4-methoxyaniline (3fa)

[0077] Using 3,4-dimethoxyallylbenzene 1f and p-anisidine 2a as the reaction substrates, the crude product obtained was passed through a silica gel column using a polar petroleum ether / ethyl acetate buffer (40:1) to obtain 54.5 mg of the product with a yield of 91%.

[0078] Data representation: [α] 25 D =+108.6(c=0.24, CHCl3); 1H NMR (400MHz, CDCl3) δ6.946.90 (m, 2H), 6.84 (d, J=8.0Hz, 1H), 6.766.72 (m, 2H), 6.596.55 (m, 2H), 6.065.97 (m, 1H), 5.27 13C NMR (100MHz, CDCl3) δ152.2, 149.1, 148.2, 141.5, 139.5, 136.9, 134.7, 115.7, 114.9, 114.7, 111.2, 110.2, 61.5, 55.9, 55.8, 55.7; HRMS (ESI-MS): Calcd.for C 18 H 21 NO3[M+Na]: 322.1419, Found: 322.1439; HPLC conditions: Chiralcel OJ-H column, 254nm, flowrate: 1ml / min, i-PrOH / hexanes=5 / 95, t major =24.4min, t minor =29.26min; 93%ee.

[0079] The structural formula of (R)-N-(1-(3,4-dimethoxyphenyl)allyl)-4-methoxyaniline (3fa) is as follows:

[0080]

[0081] Example 7 Preparation of (R)-4-methoxy-N-(1-(2-naphthyl)allyl)aniline (3ga)

[0082] 1 g of 2-allylnaphthalene and p-anisidine 2a were used as the reaction substrates. The crude product obtained was passed through a silica gel column using a buffer of polar petroleum ether / ethyl acetate = 50:1. 48 mg of the product was isolated with a yield of 83%.

[0083] Data representation: [α] 25 D =+168.6(c=0.12, CHCl3); 1H NMR (400MHz, CDCl3) δ7.837.79 (m, 4H), 7.507.42 (m, 3H), 6.736.69 (m, 2H), 6.61 6.57 (m, 2H), 6.146.06 (m, 1H), 5.30 (dt, J=17.2, 1.2Hz, 1H), 5.24 (dt, J=10.0, 1.2Hz, 1H), 5.01 (d, J=6.0Hz, 1H), 3.69 (s, 3H); 13 CNMR (100MHz, CDCl3) δ152.3, 141.3, 139.5, 139.3, 133.5, 132.9, 128.5, 127.9, 127.6, 1 26.1, 125.8, 125.7, 125.4, 116.2, 115.0, 114.7, 62.0, 55.7; HRMS (ESI-MS): Calcd.forC 20 H 19 NO[M+H] + : 290.1539, Found: 290.1518; HPLC conditions: Chiralcel OD-H column, 254nm, flow rate: 1 ml / min, i-PrOH / hexanes=5 / 95, t major =10.40min,t minor =13.03min; 94%ee.

[0084] The structural formula of (R)-4-methoxy-N-(1-(2-naphthyl)allyl)aniline (3ga) is as follows:

[0085]

[0086] Example 8 Preparation of (R)-4-methoxy-N-(1-(3-pyridyl)allyl)aniline (3ha)

[0087] Using 3-allylpyridine 1h and p-anisidine 2a as reaction substrates, the crude product obtained by general protocol A was passed through a silica gel column with a polar petroleum ether / ethyl acetate buffer of 20:1. 39.4 mg of the product was isolated with a yield of 82%.

[0088] Data representation: [α] 25 D =+34.1 (c=0.68, CHCl3); 1H NMR (400MHz, CDCl3) δ8.64 (d, J=2.0Hz, 1H), 8.53 (dd, J=2.4, 4.8Hz, 1H), 7.71 7.69 (m, 1H), 7.307.27 (m, 1H), 6.756.71 (m, 2H), 6.566.52 (m, 2H), 6.075.98 (m, 1H), 5.292.24 (m, 2H), 4.92 (d, J=6.0Hz, 1H), 3.72 (s, 3H); 13 C NMR (100MHz, CDCl3) δ152.5, 149.2, 148.8, 140.7, 138.5, 137.5, 134.6, 123.6, 117.0, 115.1, 114.8, 59.5, 55.7; HRMS (ESI-MS): Calcd.for C 15 H l6 N2O[M+H] + : 241.1335, Found: 241.1334; HPLC conditions: Chiralcel IC column, 254nm, flow rate: lml / min, i-PrOH / hexanes=20 / 80, t major =7.68min, t minor =8.30min:91%ee.

[0089] The structural formula of (R)-4-methoxy-N-(1-(3-pyridyl)allyl)aniline (3HA) is as follows:

[0090]

[0091] Example 9 Synthesis of (R)-4-methoxy-N-(1-(2-thienyl)allyl)aniline (3ia)

[0092] Using 2-allylthiophene 1i and p-anisidine 2a as reaction substrates, the crude product obtained by general method A was passed through a silica gel column with a polar petroleum ether / ethyl acetate buffer of 50:1. 37.2 mg of the product was isolated with a yield of 76%.

[0093] Data representation: [α] 25 D =+66.4 (c=0.48, CHCl3); 1H NMR (400MHz, CDCl3) δ7.24 (dd, J=1.6, 4.8Hz, 1H), 7.006.96 (m, 2H), 6.786.74 (m, 2H), 6.656.61 (m, 2H), 6.096.01 (m , 1H), 5.35 (dt, J=16.8, 1.2Hz, 1H), 5.25 (dt, J=10.4, 1.2Hz, 1H), 5.13 (d, J=6.0Hz, 1H), 3.82 (brs, 1H), 3.74 (s, 3H); 13 C NMR (100MHz, CDCl3) δ152.2, 140.4, 138.2, 134.3, 127.4, 126.0, 124.1, 123.3, 114.8, 114.5, 59.2, 55.4; HRMS (ESI-MS): Calcd.for C 14 H 15 NOS[M+NH4] + : 263.1213, Found: 263.1234; HPLC conditions: Chiralcel OD-H column, 254nm, flowrate: 1 ml / min, i-PrOH / hexanes=5 / 95, t major =7.04min, t minor =8.39min; 92%ee.

[0094] The structural formula of (R)-4-methoxy-N-(1-(2-thienyl)allyl)aniline (3ia) is as follows:

[0095]

[0096] Example 10 Preparation of (S)-4-methoxy-N-(1-phenylallyl)aniline (3ja)

[0097] Using allylbenzene 1i and p-anisidine 2a as reaction substrates, the crude product obtained by general embodiment A was passed through a silica gel column with a polar petroleum ether / ethyl acetate buffer of 60:1. 49.2 mg of the product was isolated with a yield of 92%.

[0098] Data characterization: [α]25D=+51.6(c=0.52,CHCl3).Lit.data(R-enantiomcr), [α]25D=10.7(c=1.0,CHCl3);1H NMR (400MHz, CDCl3) δ7.307.17 (m, 5H), 6.796.72 (m, 2H), 6.546.50 (m, 2H), 5.795.71 (m, 1H), 5.20 (dt, J=17.2, 1.2Hz, 1H) 13C NMR (100MHz, CDCl3) δ152.0, 141.7, 141.6, 140.1, 128.5, 128.4, 125.9, 115.4, 114.8, 114.7, 56.3, 55.8, 37.3, 32.2; HRMS (ESI-MS): Calcd.for C18H21NO[M+H]+: 268.1696, Found: 268.1695; HPLC conditions: Chiralcel OJ-H column, 254nm, flowrate: 1ml / min, i-PrOH / hexanes=1 / 99, tminor=31.84min, tmajor=33.97min; 94%ee.

[0099] The structural formula of (S)-4-methoxy-N-(1-phenylpentyl)aniline (3ja) is as follows:

[0100]

[0101] Example 11 Preparation of (S)-4-methoxy-N-(1,12-dienyltridecyl)aniline (3ka)

[0102] The crude product obtained from the reaction of 1,12-tridecane 1k and p-anisidine 2a was purified by general protocol A through a silica gel column using a polar petroleum ether / ethyl acetate buffer (100:1). 51.2 mg of the product was isolated with a yield of 85%.

[0103] Data representation: [α] 25 D=+36.78(c=0.77, CHCl3); 1H NMR (400MHz, CDC13) δ 6.776.73 (m, 2H), 6.58 (d, J = 8.8Hz, 2H), 5.865.67 (m, 2H), 5.17 (dt, J = 17.2, 1.2Hz, 1H), 5.10 (dt, J = 10.4, 1. 2Hz, 1H), 5.024.91(m, 2H), 3.73(s, 3H), 3.733.68(m, 1H), 2.062.01(m, 2H), 1.641.50(m, 2H), 1.431.35(m, 4H), 1.331.26(m, 8H); 13 C NMR (100MHz, CDCl3) δ152.1, 140.4, 139.2, 115.2, 115.1, 115.0, 114.7, 114.1, 57. 2, 55.8, 35.7, 33.8, 29.5, 29.4, 29.3, 29.1, 28.9, 25.9; HRMS (ESI-MS): Calcd.for C 20 H 31 NO[M+H] + : 302.2478, Found: 302.2476; HPLC conditions: Chiralcel OJ-H column, 254nm, flow rate: 1 ml / min, i-PrOH / hexanes=1 / 99, tmajor=22.10min, t minor =27.17min; 91%ee.

[0104] The structural formula of (S)-4-methoxy-N-(1,12-dienyltridecyl)aniline (3ka):

[0105]

[0106] Example 12 Preparation of (S)-N-(8-chloroheptene)-4-methoxyaniline (31a)

[0107] 8-Chloropene 11 and p-anisidine 2a were used as reaction substrates and the crude product obtained was passed through a silica gel column using a buffer of polar petroleum ether / ethyl acetate = 100:1. 36.5 mg of the product was isolated with a yield of 72%.

[0108] Data representation: [α] 25D =+110.3 (c=0.27, CHCl3); 1H NMR (400MHz, CDCl3) δ6.956.91 (m, 2H), 6.826.78 (m, 2H), 5.785.69 (m, 1H), 5.01 4.96(m, 2H), 3.82(brt, 1H), 3.76(s, 3H), 3.123.07(m, 1H), 2.972.92(m, lH), 1.861.82(m, 1H), 1.761.66(m, 4H), 1.551.48(m, 1H); 13 CNMR (100MHz, CDCl3) δ154.2, 145.7, 139.2, 121.8, 115.7, 114.0, 61.5, 55.4, 50.8, 32.2, 26.2, 21.7; HRMS (ESI-MS): Calcd.for C 14 H 20 ClNO[M]: 253.1233, Found: 253.1232; HPLCconditionns: Chiralcel OJ-H column, 254nm, flow rate: 1ml / min, i-PrOH / hexanes=5 / 95, t ma jor=8.03min,t minor =11.10min; 93%ee.

[0109] The structural formula of (S)-N-(8-chloroheptene)-4-methoxyaniline (31a) is as follows:

[0110]

[0111] Example 13 Preparation of (R)-N-(1-cyclohexylallyl)-4-methoxyaniline (3ma)

[0112] Cyclohexylpropene 1m and p-anisidine 2a were used as the reaction substrates. The crude product was passed through a silica gel column using a buffer of polar petroleum ether / ethyl acetate = 100:1. 41.2 mg of the product was isolated with a yield of 64%. [α]25 D =+37.7(c=0.6, CHCl3).Lit.data(S-enantiomer),[α] 25 D=12.2(c=1.0, CHCl3); 1H NMR (400MHz, CDCl3) δ6.766.74(m, 2H), 6.575.54(m, 2H), 5.745.65(m, 1H), 5.165.12(m, 2H), 3.73( s, 3H), 3.55 (t, J=6.0Hz, 1H), 3.45 (brs, 1H), 1.851.64 (m, 5H), 1.521.47 (m, 1H), 1.271.03 (m, 5H); 13 C NMR (100MHz, CDCl3) δ152.1, 142.5, 139.1, 116.1, 115.1, 114.8, 62.3, 56.1, 42.9, 29.8, 29.6, 26.8, 26.6, 26.5; HRMS (ESI-MS): Calcd.for C 16 H 23 NO[M+H] + : 246.1852, Found: 246.1833; HPLC connditionns: Chiralcel OJ-H column, 254nm, flowrate: 1ml / min, i-PrOH / hexanes=1 / 99, tmajor=23.93min, tminor=33.81min; 91%ee.

[0113] The structural formula of (R)-N-(1-cyclohexylallyl)-4-methoxyaniline (3ma) is as follows:

[0114]

[0115] Example 14 Preparation of (R)-N-(1-phenylvinyl)aniline (3ab)

[0116] Allylbenzene 1a and 2b were used as reaction substrates and the crude product obtained by general method A was passed through a silica gel column with a buffer of polar petroleum ether / ethyl acetate = 100:1. 35.2 mg of the product was isolated with a yield of 84%.

[0117] Data representation: [α] 25 D =+62(c=0.77, CHCl3).Lit.dataforS-enantiomer), [α] 25 D =9.1(c=1.0, CHCl3).(R-enantiomer), [α] 25 D =6.5 (c=1.0, CHCl3); 1H NMR (400MHz, CDCl3) δ7.41 7.34(m, 5H), 7.177.12(m, 2H), 6.726.68(m, 1H), 6.626.59(m, 2H), 6.096.01(m, 1H), 5.29( dt, J=17.1, 1.4Hz, 1H), 5.24 (dt, J=10.2, 1.3Hz, 1H), 4.95 (d, J=6.0Hz, 1H), 4.05 (brs, 1H); 13 C NMR (100MHz, CDCl3) δ147.2, 141.8, 139.0, 129.1, 128.7, 127.4, 127.1, 117.6, 116.0, 113.5, 60.8; HRMS (ESI-MS): Calcd.for C 15 H 15 N[M+H] + : 210.1277, Found: 210.1280; HPLC conditions: Chiralcel OJ-H column, 254nm, flow rate: 1ml / min, i-PrOH / hexanes=1 / 99, tmajor=17.79min, t minor =19.22min; 94%ee.

[0118] The structural formula of (R)-N-(1-phenylvinyl)aniline (3ab):

[0119]

[0120] Example 15 Preparation of (R)-4-bromo-N-(1-phenylallyl)aniline (3ac)

[0121] Allylbenzene 1a and 2c were used as reaction substrates, and the crude product obtained was passed through a silica gel column using a buffer of polar petroleum ether / ethyl acetate = 100:1. 50.1 mg of the product was isolated with a yield of 87%.

[0122] Data representation: [α] 25 D=+132.3(c=0.16, CHCl3); 1H NMR (400MHz, CDCl3) δ7.377.32 (m, 5H), 7.227.18 (m, 2H), 6.486.45 (m, 2H), 6.055.97 (m, 1H), 5.2 6 (dt, J=17.1, 1.2Hz, 1H), 5.23 (dt, J=10.2, 1.2Hz, 1H), 4.88 (d, J=6.0Hz, 1H), 4.06 (brs, 1H); 13C NMR (100MHz, CDCl3) δ141.3, 138.6, 132.8, 131.8, 128.8, 128.3, 127.6, 127.1, 116.3, 115.1, 60.8; HRMS (ESI-MS): Calcd.for C 15 H 14 BrN[M] + : 287.0304, Found: 287.0271; HPLC conditions: Chiralcel OD-H column, 254nm, flow rate: 1 ml / min, i-PrOH / hexanes=5 / 95, t ma jor=7.83min, tminor=8.87min; 93%ee.

[0123] The structural formula of (R)-4-bromo-N-(1-phenylallyl)aniline (3ac) is as follows:

[0124]

[0125] Example 16 Preparation of (R)-4-methyl-N-(1-phenylvinyl)aniline (3ad)

[0126] Allylbenzene 1a and 2d were used as reaction substrates, and the crude product obtained by general method A was passed through a silica gel column with a buffer of polar petroleum ether / ethyl acetate = 100:1. 41.9 mg of the product was isolated with a yield of 94%.

[0127] Data representation: [α] 25 D =+291.1(c=0.12, CHCl3); 1H NMR (400MHz, CDCl3) δ7.387.31 (m, 5H), 6.956.92 (m, 2H), 6.536.50 (m, 2H), 6.065.98 (m, 1H), 5.26 (dt , J=16.8, 1.6Hz, 1H), 5.21 (dt, J=10.0, 1.2Hz, 1H), 4.89 (d, J=6.0Hz, 1H), 3.91 (brs, 1H), 2.21 (s, 3H);13 CNMR (100MHz, CDCl3) δ144.9, 142.0, 139.3, 129.6, 128.7, 127.3, 127.1, 126.8, 115.9, 113.7, 61.1, 20.3; HRMS (ESI-MS): Calcd.for C 16 H 17 N[M+H]+: 224.1433, Found: 224.1419; HPLC conditions: Chiralcel OJ-H column, 254nm, flow rate: 1 ml / min, i-PrOH / hexanes=2 / 98, tmajor=14.88min, t minor =17.00min; 92%ee.

[0128] The structural formula of (R)-4-methyl-N-(1-phenylvinyl)aniline (3ad) is as follows:

[0129]

[0130] Example 17 Preparation of (R)-N-(3-((1-phenylvinyl)amino)phenyl)acetamide (3ae)

[0131] Allylbenzene 1a and 2 e As a reaction substrate, the crude product obtained by general embodiment A was passed through a silica gel column with a buffer of polar petroleum ether / ethyl acetate = 100:1. 39.4 mg was isolated, with a yield of 74%.

[0132] Data characterization: [α]25D=+33.2 (c=0.92, CHCl3); 1H NMR (400 MHz, CDCl3) δ7.367.27 (m, 5H), 7.097.01 (m, 2H), 6.65 (d, J=7.6 Hz, 1H), 6.32 (dd, J=1.6, 7.6 Hz, 1H), 6.055.96 (m, 1H), 5.26 (d, J=17.8 Hz, 1H), 5.21 (d, J=10.6 Hz, 1H), 4.92 (d, J=6.0 Hz, 1H), 4.11 (brs, 1H), 2.10 (s, 3H), 1.73 (brs, 1H); 13C NMR (100MHz, CDCl3) δ168.3, 147.9, 141.7, 138.8, 138.7, 129.5, 128.7, 127.4, 127.1, 116.1, 109.4, 108.9, 105.0, 60.7, 28.3; HRMS (ESI-MS): Calcd.forC 17 H18 N2O[M+H]+: 267.1492, Found: 267.1483; HPLC conditionS: Chiralcel IC column, 254nm, flow rate: 1ml / min, i-PrOH / hexanes=20 / 80, tmajor=8.86min, tminor=10.48min; 90%ee.

[0133] The structural formula of (R)-N-(3-((1-phenylvinyl)amino)phenyl)acetamide (3ae) is as follows:

[0134]

[0135] Example 18 Preparation of (R)-N-(1-phenylallyl)naphthyl-2-amine (3af)

[0136] Allylbenzene 1a and 2f were used as reaction substrates and the crude product obtained by general method A was passed through a silica gel column with a buffer of polar petroleum ether / ethyl acetate = 100:1. 46.2 mg of the product was isolated with a yield of 89%.

[0137] Data characterization: [α]25D=+255.8 (c=0.12, CHCl3); 1H NMR (400MHz, CDCl3) δ7.64 (d, J=8.0Hz, 1H), 7.60 (d, J=8.8Hz, 1H), 7.53 (d, J= 8.4Hz, 1H), 7.437.31 (m, 5H), 7.297.27 (m, 1H), 7.197.15 (m, 1H), 6.91 (dd, J= 2.4, 8.8Hz, 1H), 6.77 (d, J=2.0Hz, 1H), 6.136.04 (m, 1H), 5.32 (dt, J=17.2, 1. 2Hz, 1H), 5.26 (dt, J=10.0, 1.2Hz, 1H), 5.07 (d, J=6.0Hz, 1H), 4.24 (brt, 1H); 13 C NMR (100MHz, CDCl3) δ144.7, 141.6, 138.8, 135.0, 128.8, 128.6, 127.6, 127.5, 127. 2, 126.2, 126.1, 126.0, 122.1, 118.1, 116.2, 105.9, 60.8; HRMS (ESI-MS): Calcd.for C 19 H 17 N[M+H] +: 260.1434, Found: 260.1435; HPLC conditions: ChiralcelOD-H column, 254nm, flow rate: 1 ml / min, i-PrOH / hexanes=2 / 98, tmajor=12.53min, t min or=15.76min;95%ee.

[0138] The structural formula of (R)-N-(1-phenylallyl)naphthyl-2-amine (3af) is as follows:

[0139]

[0140] Example 19 Preparation of (R)-5-methyl-N-(1-phenylallyl)pyridinyl-2-amine (3ag)

[0141] Allylbenzene 1a and 2g were used as reaction substrates and the crude product obtained by general method A was passed through a silica gel column with a buffer of polar petroleum ether / ethyl acetate = 100:1. 33.6 mg of the product was isolated with a yield of 75%.

[0142] Data characterization: [α]25D=+241.3 (c=0.13, CHCl3); 1H NMR (400 MHz, CDCl3) δ7.92 (d, J=2.0 Hz, 1H), 7.387.31 (m, 5H), 7.21 (dd, J=1.6, 8.4 Hz, 1H), 6.27 (d, J=8.4 Hz, 1H), 6.106.02 (m, 1H), 5.285.20 (m, 3H), 4.83 (brs, 1H), 2.15 (s, 3H); 13 C NMR (100MHz, CDCl3) δ161.8, 156.0, 147.6, 138.7, 138.6, 128.7, 127.4, 127.1, 122.1, 115.7, 106.7, 58.8, 17.4; HRMS (ESI-MS): Calcd.for C 15 H 16 N2[M+H] + : 225.1386, Found: 225.1386; HPLC conditions: Chiralcel OD-H column, 254nm, flow rate: 1ml / min, i-PrOH / hexanes=20 / 80, tminor=5.89min, tmajor=8.29min; 90%ee.

[0143] The structural formula of (R)-5-methyl-N-(1-phenylallyl)pyridinyl-2-amine (3ag) is as follows:

[0144]

[0145] Example 20 Preparation of (R)-N-benzyl-1-(phenylallyl)-amine (3ah)

[0146] Allylbenzene 1a and 2h were used as reaction substrates and the crude product obtained by general method A was passed through a silica gel column with a buffer of polar petroleum ether / ethyl acetate = 100:1. 14.3 mg of the product was isolated with a yield of 32%.

[0147] Data representation: [α] 25 D =+84.8(c=0.39, CHCl3).Lit.data: [α] 25 D = (c=0.5, CHCl3); 1HNMR (400MHz, CDCl3) δ7.397.27 (m, 10H), 5.995.91 (m, 1H), 5.23 (dt, J =17.1, 1.6Hz, 1H), 5.13 (dt, J = 10.1, 1.6Hz, 1H), 4.23 (d, J = 7.1Hz, 1H), 3.753.69 (m, 2H); 13 C NMR (100MHz, CDCl3) δ142.8, 141.0, 140.4, 128.5, 128.4, 128.2, 127.3, 127.2, 126.9, 115.2, 65.1, 51.3; HRMS (ESI-MS): Calcd.for C 16 H 17 N[M+Na] + : 246.1253, Found: 246.1264; HPLC conditions: Chiralcel OJ-H column, 254nm, flow rate: 1 ml / min, i-PrOH / hexanes=2 / 98, tmajor=12.58min, t minor =15.46min; 92%ee.

[0148] The structural formula of (R)-N-benzyl-1-(phenylallyl)-amine (3ah) is as follows:

[0149]

[0150] Example 21 Preparation of (R)-1-(1-phenylallyl)pyrrole (3ai)

[0151] Allylbenzene 1a and 2i were used as reaction substrates and the crude product obtained by general embodiment A was passed through a silica gel column with a polar petroleum ether / ethyl acetate buffer of 50:1. 34.5 mg of the product was isolated with a yield of 92%.

[0152] Data representation: [α] 25 D=+261.1(c=0.11, CHCl3).Lit.data:[α] 25 D =(c=1.0, CHCl3); 1H NMR (400MHz, CDCl3) δ7.377.29 (m, 4H), 7.257.21 (m, 1H), 6.086.00 (m, 1H), 5.21 (dd, J=16.8, 1.2Hz, 1H), 5.00 (dd, J=10.0, 1.6Hz, 1H), 3.58 (d, J=8.8Hz, 1H), 2.532.74 (m, 2H), 2.402.35 (m, 2H), 1.811.73 (m, 4H); 13 C NMR (100MHz, CDCl3) δ143.0, 141.3, 128.5, 127.6, 127.1, 115.0, 75.2, 53.0, 23.3; HRMS (ESI-MS): Calcd.for C 13 H17N[M+H]+: 188.1434, Found: 188.1439; HPLC conditions: Chiralcel OJ-H column, 254nm, flow rate: 1ml / min, i-PrOH / hexanes=1 / 99, tminor=6.74min, t ma jor = 7.83min; 90% ee.

[0153] The structural formula of (R)-1-(1-phenylallyl)pyrrole (3ai) is as follows:

[0154]

[0155] Example 22 Preparation of (R)-1-(1-phenylallyl)azepane (3aj)

[0156] Allylbenzene 1a and 2j were used as reaction substrates and the crude product obtained by general method A was passed through a silica gel column with a buffer of polar petroleum ether / ethyl acetate = 50:1. 41 mg of the product was isolated with a yield of 95%.

[0157] Data characterization: [α]25D=+179.8 (c=0.17, CHCl3). Lit.data: [α]25 D=(c=13.8, CHCl3); 1H NMR (400MHz, CDCl3) δ7.407.37 (m, 2H), 7.327.28 (m, 2H), 7.247.19 (m, 1H), 5.995.90 (m, 1H), 5.17 (dd, J= 17.2, 1.6Hz, 1H), 5.11 (dd, J=10.0, 2.4Hz, 1H), 4.04 (d, J=8.4Hz, 1H), 2.682.55 (m, 4H), 1.641.50 (m, 8H); 13 C NMR (100MHz, CDC13) δ143.1, 139.9, 128.2, 127.9, 126.8, 115.9, 73.5, 52.9, 28.8, 27.0; HRMS (ESI-MS): Calcd.for C 15 H 21 N[M+H]: 216.1752, Found: 216.1747; HPLC conditions: Chiralcel OJ-H column, 254nm, flowrate: 0.5ml / min, i-PrOH / hexanes=l / 99, t min or=8.45min,t ma jo r =9.93min; 93%ee.

[0158] The structural formula of (R)-1-(1-phenylallyl)azepane (3aj) is as follows:

[0159]

[0160] Example 23 Preparation of (R)-4-(1-phenylallyl)morpholine (3ak)

[0161] Allylbenzene 1a and 2k were used as reaction substrates and the crude product obtained by general method A was passed through a silica gel column with a polar petroleum ether / ethyl acetate buffer of 50:1. 38.2 mg of the product was isolated with a yield of 94%.

[0162] Data representation: [α] 25 D =+232.1(c=0.13, CHCl3).Lit.data: [α] 20 D=(c=1.022, CHCl3); 1H NMR (400MHz, CDCl3) δ7.367.30 (m, 4H), 7.257.22 (m, 1H), 5.955.86 (m, 1H), 5.24 (dd, J=17.2, 1.6 Hz, 1H), 5.11 (dd, J=10.0, 1.6Hz, 1H), 3.723.66 (m, 4H), 3.62 (d, J=8.8Hz, 1H), 2.482.30 (m, 4H); 13 C NMR (100MHz, CDCl3) δ143.5, 139.7, 128.6, 127.9, 127.2, 116.7, 75.5, 67.1, 52.0; HRMS (ESI-MS): Calcd.for C 13 H 17 NO[M+H]: 204.1388, Found: 204.1390; HPLC conditions: Chiralcel OJ-H column, 254nm, flow rate: 1ml / min, i-PrOH / hexanes=1 / 99, tminor=7.40min, t ma jor = 8.35 min; 92% ee.

[0163] The structural formula of (R)-4-(1-phenylallyl)morpholine (3ak) is as follows:

[0164]

[0165] Example 24 Preparation of (R)-4-(1-phenylallyl)thiomorpholine (3a1)

[0166] Allylbenzene 1a and 21 were used as reaction substrates and the crude product obtained by general method A was passed through a silica gel column with a buffer of polar petroleum ether / ethyl acetate = 50:1. 42.1 mg of the product was isolated with a yield of 96%.

[0167] Data representation: [α] 25 D =+278.6(c=0.10, CHCl3); 1H NMR (400MHz, CDCl3) δ7.347.30 (m, 4H), 7.257.22 (m, 1H), 5.945.85 (m, 1H), 5.2l (dd, J=17.2, 1.6 Hz, 1H), 5.15 (dd, J=10.0, 1.6Hz, 1H), 3.81 (d, J=8.4Hz, 1H), 2.812.74 (m, 2H), 2.692.62 (m, 6H); 13C NMR (100MHz, CDCl3) δ143.5, 139.0, 128.5, 127.9, 127.1, 116.9, 74.5, 52.8, 28.1; HRMS (ESI-MS): Calcd.for C 13 H 17 NS[M+H] + : 220.1155, Found: 220.1158; HPLC conditionS: ChiralcelOJ-H column, 254nm, flow rate: 1 ml / min, i-PrOH / hexanes=2 / 98, t min o r =6.61min, t ma jor=7.19min;93%ee.

[0168] The structural formula of (R)-4-(1-phenylallyl)thiomorpholine (3a1) is as follows:

[0169]

[0170] Example 25 Preparation of (R)-5-(1-phenylallyl)-4,5,6,7-tetrahydrothienyl[3,2-c]pyridine (3am)

[0171] Allylbenzene 1a and 2m were used as reaction substrates and the crude product obtained by general protocol A was passed through a silica gel column with a polar petroleum ether / ethyl acetate buffer of 50:1. 30.7 mg of the product was isolated with a yield of 92%.

[0172] Data characterization: [α]25D=+97.4 (c=0.36, CHCl3); 1H NMR (400 MHz, CDCl3) δ7.41 7.39 (m, 2H), 7.357.32 (m, 2H), 7.287.24 (m, 1H), 7.06 (d, J = 5.2Hz, 1H), 6.68 (d, J = 5.2Hz, 1H), 6.065.97 (m, 1H), 5.28 (dd, J = 17.2, 1 .2Hz, 1H), 5.14 (dd, J=10.0, 1.6Hz, 1H), 3.91 (d, J=9.6Hz, 1H), 2.67 (d, J=14.4Hz, 1H), 3.45 (d, J=14.8Hz, 1H), 2.862.77 (m, 4H); 13C NMR (100MHz, CDCl3) δ142.0, 140.0, 134.0, 133.5, 128.6, 127.8, 127.3, 125.4, 122.6, 116.4, 73.9, 51.5, 48.3, 25.4; HRMS (ESI-MS): Calcd.for C 16 H 17 NS[M+H] + : 256.1155, Found: 256.1161; HPLC conditions: Chiralcel OJ-H column, 254nm, flow rate: 1 ml / min, i-PrOH / hexanes=5 / 95, t min or=9.57min,t ma jor=11.44min;90%ee.

[0173] The structural formula of (R)-5-(1-phenylallyl)-4,5,6,7-tetrahydrothienyl[3,2-c]pyridine (3am) is as follows:

[0174]

[0175] Example 26 Preparation of (R)-1-Benzhydryl-4-(1-phenylallyl)piperazine (3an)

[0176] Allylbenzene 1a and 2n were used as the reaction substrates, and the crude product obtained was passed through a silica gel column using a polar petroleum ether / ethyl acetate buffer of 50:1. 66.3 mg was isolated, with a yield of 90%. [α]25 D=+56.6 (c=0.52, CHCl3); 1H NMR (400MHz, CDCl3) δ7.41 7.36 (m, 4H), 7.31 7.20 (m, 9H), 7.187.10 (m, 2H), 5.965.87 (m, 1H), 5.20 (dd, J=17.2, 1.3Hz, 1H), 5.06 (dd, J=10.0, 1.6Hz, 1H), 4.21 (s, 1H), 3.64 (d, J=8.8Hz, 1H), 2.38 (s, 8H); 13 C NMR (100MHz, CDCl3) δ142.8, 142.7, 141.8, 140.0, 128.4, 128.3, 127.9, 127.1, 126.8, 126.7, 116.2, 76.2, 75.1, 52.0, 51.6; HRMS (ESI-MS): Calcd.forC 26 H 28 N2[M+H] + : 369.2325, Found: 369.2323; HPLC conditions: ChiralcelOJ-H column, 254nm, flow rate: 1ml / min, i-PrOH / hexanes=5 / 95, t min or=7.80min,t ma jor=9.09min;94%ee.

[0177] The structural formula of (R)-1-benzhydryl-4-(1-phenylallyl)piperazine (3an) is as follows:

[0178]

[0179] Example 27 Preparation of (R)-N-methyl-N-(1-phenylallyl)aniline (3ao)

[0180] Allylbenzene 1a and 2o were used as the reaction substrates, and the crude product obtained was passed through a silica gel column using a buffer of polar petroleum ether / ethyl acetate = 100:1. 15.6 mg of the product was isolated, with a yield of 35%. [α]25 D=+53.6(c=0.62, CHCl3).Lit.data: [α]35D=(c=1.0, CHCl3); 1H NMR (400MHz, CDCl3) δ7.37-7.22 (m, 7H), 6.85 (d, J=8.0Hz, 2H), 6.73 (t, J=7.2Hz, 1H), 6.19-6.10 (m, 1H), 5.49 (d, J=6.0Hz, 1H), 5.35 (dd, J=10.0, 1.6Hz, 1H), 5.21 (dt, J=17.2, 1.6Hz, 1H), 2.74 (s, 3H); 13 C NMR (100MHz, CDCl3) δ140.4, 135.6, 129.1, 128.5, 127.9, 127.2, 118.0, 116.9, 113.3, 65.1, 33.7; HRMS (ESI-MS): Calcd.forC 16 H 17 N[M]+: 223.1352, Found: 223.1359; HPLC conditions: Chiralcel OD-H column, 254nm, flow rate: 1ml / min, i-PrOH / hexanes=5 / 95, t min or=7.89min, tmajor=8.90min; 96%ee.

[0181] The structural formula of (R)-N-methyl-N-(1-phenylallyl)aniline (3ao) is as follows:

[0182]

[0183] Example 28 Preparation of (R)-4-(4-chlorophenyl)-1-(1-phenylallyl)piperidin-4-ol (3ap)

[0184] Allylbenzene 1a and 2p were used as substrates, and the crude product obtained by General Method A was passed through a silica gel column with a polar petroleum ether / ethyl acetate buffer of 30:1. 56.4 mg was isolated, yielding 86%. [α]25D = +186.1 (c = 0.16, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.45-7.24 (m, 9H), 6.01-5.92 (m, 1H), 5.24 (d, J = 17.2 Hz, 1H), 5.11 (d, J = 10.4 Hz, 1H), 4.00 (brs, 1H), 3.75 (d, J = 8.8 Hz, 1H), 2.43-2.27 (m, 2H), 2.16-1.85 (m, 4H), 1.75-1.60 (m, 2H).13 C NMR (100MHz, CDCl3) δ139.9, 136.9, 132.6, 128.5, 128.3, 127.8, 126.2, 123.7, 121.1, 116.4, 74.9, 71.1, 74.4, 38.5; HRMS (ESI-MS): Calcd.for C 20 H 22 ClNO[M+H] + : 328.1436, Found: 328.1462; HPLC conditions: ChiralcelOJ-H column, 254nm, flow rate: 1 ml / min, i-PrOH / hexanes=10 / 90, tmajor=16.67min, tminor=20.86min; 90%ee.

[0185] The structural formula of (R)-4-(4-chlorophenyl)-1-(1-phenylallyl)piperidin-4-ol (3ap) is as follows:

[0186]

[0187] Example 29 Preparation of (R)-4-(4-aminophenoxy)-N-(1-phenylvinyl)aniline (3aq)

[0188] Allylbenzene 1a and 2 q As a reaction substrate, the crude product obtained by general embodiment A was passed through a silica gel column with a buffer of polar petroleum ether / ethyl acetate = 50:1. 42.3 mg was isolated, with a yield of 67%.

[0189] Data representation: [α] 25 D =+69.3(c=0.43, CHCl3); 1H NMR (400MHz, CDCl3) δ7.397.34 (m, 5H), 6.846.77 (m, 4H), 6.646.60 (m, 2H), 6.576.53 (m, 2H), 6.075 .99 (m, 1H), 5.27 (dt, J=17.1, 1.3Hz, 1H), 5.22 (dt, J=10.4, 1.3Hz, 1H), 4.87 (d, J=6.0Hz, 1H), 3.91 3.89(m,3H); 13 C NMR (100MHz, CDCl3) δ149.2, 148.6, 139.2, 137.0, 128.7, 127.1, 126.3, 123.7, 120.3, 114.5, 114.0, 61.4; HRMS (ESI-MS): Calcd.for C21 H 20 N2O[M+H] + : 317.1648, Found: 317.1621; HPLC conditionns: Chiralcel OD-H column, 254nm, flow rate: 1ml / min, i-PrOH / hexanes=2 / 98, t ma jor=30.23min,t minor =38.83min; 92%ee.

[0190] The structural formula of (R)-4-(4-aminophenoxy)-N-(1-phenylvinyl)aniline (3aq) is as follows:

[0191]

[0192] Example 30 Preparation of (R)-butyl-4-((1-phenylallyl)amino)benzoate (3ar)

[0193] Allylbenzene 1a and 2r were used as reaction substrates and the crude product obtained by general method A was passed through a silica gel column with a polar petroleum ether / ethyl acetate buffer of 50:1. 50.2 mg of the product was isolated with a yield of 84%.

[0194] Data representation: [α] 25 D =+132.1 (c=0.38, CHCl3); 1H NMR (400MHz, CDCl3) δ7.857.81 (m, 2H), 7.367.30 (m, 4H), 7.31 7.27(m, 1H), 6.576.54(m, 2H), 6.07-5.99(m, 1H), 5.295.24(m, 2H), 5.01(brt, 1H), 4.48(d, J =3.6Hz, 1H), 4.24 (t, J = 6.5Hz, 2H), 1.731.66 (m, 2H), 1.491.40 (m, 2H), 0.95 (t, J = 7.3Hz, 3H); 13 C NMR (100MHz, CDCl3) δ166.8, 150.7, 140.8, 138.0, 131.3, 128.8, 127.7, 127.1, 119.1, 116.6, 112.3, 64.1, 60.2, 30.9, 19.3, 13.8; HRMS (ESI-MS): Calcd.for C 20 H 23 NO2[M+H] +: 310.1802, Found: 310.1800; HPLC connditionns: Chiralcel OD-H column, 254nm, flow rate: 1ml / min, i-PrOH / hexanes=3 / 97, t ma jor=17.77min,t min or=28.61 min;>99%ee.

[0195] The structural formula of (R)-butyl-4-((1-phenylallyl)amino)benzoate (3ar) is as follows:

[0196]

[0197] Example 31 Preparation of (R)-1-(2-((2,4-dimethylphenylmercapto)phenyl)-4-(1-phenylallyl)piperazine (3as)

[0198] Allylbenzene 1a and 2s were used as reaction substrates and the crude product obtained by general method A was passed through a silica gel column with a polar petroleum ether / ethyl acetate buffer of 50:1. 67.1 mg of the product was isolated with a yield of 81%.

[0199] Data representation: [α] 25 D =+201.0(c=0.16, CHCl3); 1H NMR (400MHz, CDCl3) δ7.337.28 (m, 5H), 7.207.15 (m, 1H), 7.087.02 (1H), 6.966.92 (m, 3H), 6.796.74 (m, 1H), 6.41 (d, J=8.1Hz, 1H), 5.975.88 (m, 1H), 5.19 (d, J = 17.2Hz, 1H), 5.04 (d, J = 10.2Hz, 1H), 3.87 (d, J = 8.8Hz, 1H), 3.022.92 (m, 4H), 2.652.47 (m, 4H), 2.28 (s, 3H), 2.22 (s, 3H); 13 C NMR (100MHz, CDCl3) δ149.3, 142.5, 142.1, 140.2, 139.1, 136.3, 134.6, 131.6, 128.6, 128.1, 128.0, 12 7.7, 127.1, 126.0, 125.4, 124.2, 119.7, 116.4, 75.3, 51.8, 51.7, 21.2, 20.6; HRMS (ESI-MS): Calcd.for C 27 H 30N2S[M+H]+: 415.2203, Found: 415.2203; HPLC conditions: ChiralcelOJ-H column, 254nm, flow rate: 1ml / min, i-PrOH / hexanes=10 / 90, tmajor=10.17min, tminor=12.26min; 95%ee.

[0200] The structural formula of (R)-1-(2-((2,4-dimethylphenylmercapto)phenyl)-4-(1-phenylallyl)piperazine (3as) is as follows:

[0201]

[0202] Example 32 Preparation of (R)-8-chloro-11-(1-(1-phenylallyl)piperidin-4-ene)-6,11-dihydro-5H-benzo[5,6]heptacyclo[1,2-b]pyridine (3at)

[0203] Allylbenzene 1a and 2t were used as reaction substrates and the crude product obtained by general method A was passed through a silica gel column with a polar petroleum ether / ethyl acetate buffer of 20:1. 67.4 mg of the product was isolated with a yield of 79%.

[0204] Data characterization: [α]25D=+285.6 (c=0.12, CHCl3); 1H NMR (400 MHz, CDC13) δ8.41 8.35(m, 1H), 7.447.38(m, 1H), 7.367.29(m, 4H), 7.237.18(m, 1H), 7.14 7.04(4H), 5.995.90(m, 1H), 5.17(dt, J=17.2, 1.6Hz, 1H), 5.07(dt, J=10 .2, 1.6Hz, 1H), 3.69 (d, J=8.7Hz, 1H), 3.433.31 (m, 2H), 2.922.86 (m, 1H ), 2.842.75(m, 2H), 2.652.59(m, 1H), 2.522.27(m, 4H), 2.13(m, 2H); 13C NMR (100MHz, CDCl3) δ157.6, 146.5, 139.5, 137.8, 137.1, 133.4, 132.5, 130.8, 130.6, 128.9, 128.8, 128.4, 127. 8, 127.1, 125.9, 1258, 122.2, 122.0, 116.2, 74.5, 52.9, 52.7, 31.8, 31.4, 30.9, 30.7; HRMS (ESI-MS): Calcd.for C 28 H27 ClN2[M+H]+: 427.1936, Found: 427.1927; HPLC conditions: Chiralcel OJ-H column, 254nm, flow rate: lml / min, j-PrOH / hexanes=10 / 90, t m inor=18.77min, tmajor=25.95min; 93%ee.

[0205] The structural formula of (R)-8-chloro-11-(1-(1-phenylallyl)piperidin-4-ene)-6,11-dihydro-5H-benzo[5,6]heptacyclo[1,2-b]pyridine (3at) is as follows:

[0206]

[0207] Example 33 Preparation of 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(1-((R)-1-phenylallyl)4-piperidinyl)-1H-4-pyrazolyl)-2-pyridinylamine (3au)

[0208] Allylbenzene 1a and 2u were used as reaction substrates and the crude product obtained by general method A was passed through a silica gel column with a polar petroleum ether / ethyl acetate buffer of 10:1. 35.1 mg of the product was isolated with a yield of 62%.

[0209] Data characterization: 1H NMR (400MHz, CDC13) δ7.76 (d, J = 1.8 Hz, 1H), 7.55 (s, 1H), 7.51 (s, 1H), 7.387.29 (m, 6H), 7.077.02 (m, 1H), 6.87 (d, J = 1.6 Hz, 1H), 6.08 (dd, J = 6.7, 13.4 Hz, 1H ), 6.005.91 (m, 1H), 5.27 (dd, J=17.2, 1.0Hz, 1H), 5.07 (dd, J=10.2, 1.5Hz, 1H ), 4.76 (s, 2H), 4.134.07 (m, 1H), 3.76 (d, J = 8.7Hz, 1H), 3.283.23 (m, lH), 2.91 2.87(m, 1H), 2.172.00(m, 6H), 1.86(d, J=6.7Hz, 3H); 13C NMR (100MHz, CDCl3) δ165.1, 148.8, 139.8, 139.7, 136.9, 135.6, 135.4, 128.6, 127.8, 127.2, 122.5 , 119.8, 119.3, 116.8, 116.5, 115.0, 74.4, 72.4, 59.7, 50.5, 29.4, 22.7; HRMS (ESI-MS): Calcd.for C 30 H 30 Cl2N2[M+H] + :566.1884, Found:566.1883.

[0210] The structural formula of 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(1-((R)-1-phenylallyl)-4-piperidinyl)-1H-4-pyrazolyl)-2-pyridinylamine (3au) is as follows:

[0211]

[0212] Example 34 Preparation of 3-((R)-1-phenylallyl)-1,2,3,4,5,6-hexahydro-8H-1,5-methanepyrido[1,2-alI1,5]diazoxide-8-one (3av)

[0213] Allylbenzene 1a and 2v were used as reaction substrates and the crude product obtained by general method A was passed through a silica gel column with a polar petroleum ether / ethyl acetate buffer of 20:1. 46.5 mg of the product was isolated with a yield of 76%.

[0214] Data characterization: 1H NMR (400 MHz, CDCl3) δ 7.297.15 (m, 5H), 6.936.91 (m, 1H), 6.52 (dd, J = 1.4, 9.0 Hz, 1H), 5.84 (dd, J = 1.2, 6.8 Hz, 1H), 5.745.65 (m, 1H), 5.11 (dd, J = 17.2, 1.2 Hz, 1H), 5.04 (dd, J = 10.2, 1.2 Hz, 1H), 4.15 (d, J = 15.4 Hz , 1H), 3.933.88 (m, 1H), 3.67 (d, J=8.4Hz, 1H), 3.223.18 (m, lH), 2.882.85 (m, lH), 2.792.74 (m, 1H), 2.48 13C NMR (100MHz, CDCl3) δ164.4, 151.4, 141.5, 139.5, 138.5, 128.4, 127.5, 127.1, 116. 5, 116.3, 104.7, 73.5, 58.3, 57.5, 50.2, 35.6, 28.3, 26.2; HRMS (ESI-MS): Calcd.for C 20 H 22 N2O[M+H]+: 307.1805, Found: 307.1802.

[0215] The structural formula of 3-((R)-1-phenylallyl)-1,2,3,4,5,6-hexahydro-8H-1,5-methanepyrido[1,2-a][1,5]diazoxide-8-one (3av) is as follows:

[0216]

[0217] In summary, the present invention demonstrates a platinum-catalyzed asymmetric amination of allyl nucleophiles to prepare a series of chiral N-(1-substituted allyl)aryl and alkylamines. Through screening, suitable non-phosphine chiral ligands were identified in conjunction with platinum metal to achieve asymmetric allylic amination. The present invention offers mild reaction conditions, high catalytic activity, and superior stereoselectivity, possessing significant application prospects. It provides a novel pathway for the total synthesis of numerous natural products. Furthermore, the catalytic conditions have been used to achieve the total synthesis of clopidogrel, a drug for inhibiting platelet aggregation.

[0218] The above content is only for explaining the technical idea of ​​the present invention and cannot be used to limit the protection scope of the present invention. Any changes made on the basis of the technical solution in accordance with the technical idea proposed by the present invention shall fall within the protection scope of the claims of the present invention.

Claims

1. A method for synthesizing a chiral N-(1-substituted-allyl)amine, characterized in that: include: Allyl carbonate and amine are stirred and reacted in the presence of a Schiff base ligand and a metal molybdenum catalyst, the resulting mixture is allowed to stand at 30° C. for 24 hours, the reaction solvent is removed, and the mixture is separated and purified by column chromatography to obtain a chiral N-(1-substituted-allyl)amine; wherein: The structural formula of the reactant allyl carbonate is as follows: R 1 is alkyl, aryl or heteroaryl; The structural formula of the reactant amine is as follows: The structural formula of the product chiral N-(1-substituted-allyl)amine is as follows: Among them, R 2 is an aryl group or an alkyl group; R 3 is H or alkyl; The Schiff base ligand is selected from the Schiff base (imine) ligand (S,S)-L2, and the structural formula is as follows: In this formula, R 1 、R 2 All are tBu; The metal molybdenum catalyst selected is (C7H8)Mo(CO)3.

2. The method for synthesizing a chiral N-(1-substituted-allyl)amine according to claim 1, characterized in that: The molar ratio of the metal molybdenum catalyst to the Schiff base ligand is 1:1.

5.

3. The method for synthesizing a chiral N-(1-substituted-allyl)amine according to claim 1, characterized in that: The molar ratio of allyl carbonate to amine is 1:1.

2.

4. The method for synthesizing a chiral N-(1-substituted-allyl)amine according to claim 1, characterized in that: The reaction solvent was dichloromethane.

5. A method for synthesizing clopidogrel, characterized in that: include: The allyl carbonate compound represented by the following formula I and the amine compound represented by the following formula II are stirred and reacted in the presence of a Schiff base ligand and a metal platinum catalyst. The stirred mixture is allowed to stand at 30° C. for 24 hours, the reaction solvent is removed, and the mixture is separated and purified by column chromatography to obtain the intermediate compound represented by the following formula III; The Schiff base ligand is selected from the Schiff base (imine) ligand (S,S)-L2, and the structural formula is as follows: In this formula, R 1 、R 2 All are tBu; Metal molybdenum catalyst selection (C7H8)Mo(CO)3 The chiral drug clopidogrel is prepared by converting the intermediate compound into a two-step reaction; The structural formula of the chiral drug clopidogrel is as follows:

6. The method for synthesizing clopidogrel according to claim 5, wherein: The two-step conversion reaction involves: Step 1: Dissolve compound III in CCl4, MeCN, and DCM in the presence of sodium iodide and RuCl3·H2O. Stir the mixture at room temperature for 6 h. Pour the reaction solution into DCM / H2O for separation. Dry the organic layer to obtain a crude product. Step 2: TMSCHN2 was added to the crude reaction product, and the mixture was stirred at room temperature for 2 h. The mixture was purified by silica gel column chromatography to obtain (S)-clopidogrel.

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