Preparation method of axially chiral allylamine compound

Abstract

The invention discloses a preparation method of an axially chiral allylamine compound, and relates to the technical field of organic synthesis. According to the method, in an organic solvent, aliphatic amine and (E)-2-(2-alkoxynaphthalene-1-yl)-3-aryl allyl benzoate react in the presence of a palladium catalyst, a chiral phosphorus ligand and BSA (Bovine Serum Albumin) to obtain a target product, namely the axially chiral allyl amine compound. The structures of the compounds are represented by 1H NMR, 13C NMR and HRMS and are confirmed. The invention provides a brand-new synthesis method of the axially chiral allylamine compound, the synthesis of the axially chiral allylamine compound is successfully realized by carrying out nucleophilic attack on the allylic palladium intermediate through the nitrogen nucleophilic reagent and directly carrying out asymmetric allylic substitution reaction, the reaction conditions are mild, the substrate applicability is wide, the yield is high, and the method is suitable for industrial production. The method has good application value and prospect.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing axially chiral allylamine compounds. Background Technology

[0002] Restricted chirality, as an important type of chirality, constitutes the structural characteristic of axially chiral compounds. Previous synthetic studies on axial chirality have mainly focused on the asymmetric catalytic synthesis of axially chiral biaryl compounds. The strategies employed primarily include organic molecular catalysis and metal catalysis. However, the asymmetric synthesis of axially chiral alkenes is relatively challenging and is mostly limited to axially chiral systems of cyclic alkenes. Therefore, the asymmetric synthesis of open-chain axially chiral alkenes is even more challenging because the synthesis of these alkenes requires overcoming not only significant steric hindrance but also balancing the activity of the catalytic system with the relatively low energy barrier of the olefin product.

[0003] In 2017, Tan Bin's research group successfully constructed axially chiral styrene compounds via nucleophilic addition reactions of alkynes using small molecule catalysis (Nat. Commun. 2017, 8, 15238). In 2021, Li Xingwei's team achieved the efficient construction of relatively rare axially chiral tetrasubstituted alkenes using an asymmetric C-H bond activation strategy under Rh(III) catalysis (Angew. Chem. Int. Ed. 2022, 61, e202111860). Furthermore, palladium-catalyzed C-H functionalization methods have also been reported (Angew. Chem. Int. Ed. 2020, 59, 6576; Chem. Sci. 2021, 12, 3726; Org. Chem. Front. 2022, 9, 2109). Palladium-catalyzed allylation has become one of the most effective methods for asymmetric axial chiral allylation, and much work has been done in recent years to realize and improve the asymmetric potential of this process.

[0004] However, no reports have yet been made of palladium-catalyzed asymmetric substitution reactions of allyl compounds with fatty amines to directly construct axially chiral styrene compounds. Summary of the Invention

[0005] The purpose of this invention is to provide a simple and efficient method for preparing axially chiral allylamine compounds. By using a nitrogen nucleophile to nucleophilically attack an allyl palladium intermediate, an asymmetric allyl substitution reaction is directly achieved, thus successfully synthesizing axially chiral allylamine compounds. The reaction conditions are mild and the substrate applicability is wide.

[0006] To achieve the above objectives, the technical solution of the present invention is as follows:

[0007] A method for preparing axially chiral allylamine compounds involves reacting an aliphatic amine and (E)-2-(2-alkoxynaphth-1-yl)-3-arylallylbenzoate in an organic solvent in the presence of a palladium catalyst, a chiral phosphorus ligand, and BSA to obtain the target product, the axially chiral allylamine compound. The reaction formula is as follows:

[0008]

[0009] In the formula R 1 For aryl, R 2 For aryl, R 3 R is an alkyl group. 4 It is an alkyl group, R 5 It is an alkyl group;

[0010] Based on 1.0 equivalent of (E)-2-(2-alkoxynaphth-1-yl)-3-arylallylbenzoate, the amount of aliphatic amine used is 2.0-4.0 equivalents, the amount of palladium catalyst used is 0.02-0.1 equivalents, the amount of chiral phosphorus ligand used is 0.03-0.15 equivalents, and the amount of BSA used is 2.0-4.0 equivalents.

[0011] Furthermore, the preparation method of the above-mentioned axially chiral allylamine compounds includes the following steps:

[0012] (1) At room temperature, palladium catalyst and chiral phosphorus ligand were added to a dry reaction tube, replaced with nitrogen, and then an organic solvent was added and stirred for 30 minutes.

[0013] (2) Under a nitrogen atmosphere, (E)-2-(2-alkoxynaphth-1-yl)-3-arylallylbenzoate was added to the above reaction tube, stirred for 5 minutes, and then fatty amine and BSA were added. The reaction was stirred until complete.

[0014] (3) After the reaction is complete as detected by TLC, the reaction is separated by direct column chromatography. A mixed solvent of petroleum ether and ethyl acetate is used as the mobile phase to obtain the corresponding axial chiral allylamine compounds.

[0015] Furthermore, the palladium catalyst is palladium acetate, palladium chloride, allyl palladium chloride dimer, or palladium trifluoroacetate.

[0016] Furthermore, the chiral phosphorus ligand is a diphosphorus ligand or a nitrogen-phosphorus ligand.

[0017] Further, the alkali is BSA, NaOAc, KHCO3, K2CO3, K2HPO4, Na2CO3, or KOAC.

[0018] Further, the organic solvent is acetonitrile, 1,2-dichloroethane, tetrahydrofuran, N,N-dimethylacetamide, 1,4-dioxane, methyl tert-butyl ether, or dimethyl sulfoxide.

[0019] Furthermore, the reaction temperature is 30℃, and the reaction time is 36-72 hours.

[0020] Compared with the prior art, the technical effects of the present invention are as follows:

[0021] The present invention provides a method for preparing axially chiral allylamine compounds, wherein the target product is obtained by nucleophilic substitution of (E)-2-(2-alkoxynaphth-1-yl)-3-arylallylbenzoate and aliphatic amine in the presence of palladium catalyst and chiral bisphosphine ligand.

[0022] The method for preparing axially chiral allylamine compounds provided by this invention involves a series of axially chiral allylamine compounds constructed in high yield and with high ee values ​​under very simple and mild reaction conditions. This reaction is applicable to various aliphatic secondary amines and a variety of aryl olefin-naphthalene skeletons, with broad substrate applicability. Furthermore, the scale-up studies provided by this invention also yield the expected high yield and high enantioselectivity products, which has great guiding significance and application prospects in scientific research and industrial fields. Attached Figure Description

[0023] Figure 1 The reaction formula for the preparation of axially chiral allylamine compounds provided by this invention.

[0024] Figure 2 The reaction formula for the conditional screening experiment provided by the present invention

[0025] Figure 3 The chiral phosphorus ligands L1-L16 provided by this invention.

[0026] Figure 4 The reaction formula for the protection base screening experiment provided by this invention.

[0027] Figure 5 The conditional screening reaction formula provided by this invention is when the substrate protecting group PG is Bz.

[0028] Figure 6 The structural formula of the axially chiral allylamine compound 1 provided in Example 1 of the present invention is shown.

[0029] Figure 7 The spectrum of axially chiral allylamine compound 1 provided in Example 1 of the present invention.

[0030] Figure 8 The carbon spectrum of axially chiral allylamine compound 1 provided in Example 1 of this invention.

[0031] Figure 9 The HPLC analysis spectrum of axially chiral allylamine compound 1 (racemic) provided in Example 1 of the present invention.

[0032] Figure 10 The HPLC analysis spectrum of the axially chiral allylamine compound 1 (chiral) provided in Example 1 of the present invention.

[0033] Figure 11 The structural formula of the axially chiral allylamine compound 2 provided in Example 2 of the present invention is shown.

[0034] Figure 12 The hydrogen spectrum of axially chiral allylamine compound 2 provided in Example 2 of this invention.

[0035] Figure 13 The carbon spectrum of axially chiral allylamine compound 2 provided in Example 2 of this invention.

[0036] Figure 14 The HPLC analysis spectrum of axially chiral allylamine compound 2 (racemic) provided in Example 2 of the present invention.

[0037] Figure 15 The HPLC analysis spectrum of the axially chiral allylamine compound 2 (chiral) provided in Example 2 of the present invention.

[0038] Figure 16 The structural formula of the axially chiral allylamine compound 3 provided in Example 3 of the present invention is shown.

[0039] Figure 17 The hydrogen spectrum of axially chiral allylamine compound 3 provided in Example 3 of this invention.

[0040] Figure 18 The carbon spectrum of the axially chiral allylamine compound 3 provided in Example 3 of the present invention.

[0041] Figure 19 The HPLC analysis spectrum of axially chiral allylamine compound 3 (racemic) provided in Example 3 of the present invention.

[0042] Figure 20 The HPLC analysis spectrum of the axially chiral allylamine compound 3 (chiral) provided in Example 3 of the present invention.

[0043] Figure 21 The structural formula of the axially chiral allylamine compound 4 provided in Example 4 of the present invention is shown.

[0044] Figure 22 The hydrogen spectrum of axially chiral allylamine compound 4 provided in Example 4 of this invention.

[0045] Figure 23 The carbon spectrum of axially chiral allylamine compound 4 provided in Example 4 of this invention.

[0046] Figure 24 The HPLC analysis spectrum of axially chiral allylamine compound 4 (racemic) provided in Example 4 of the present invention.

[0047] Figure 25 The HPLC analysis spectrum of the axially chiral allylamine compound 4 (chiral) provided in Example 4 of the present invention. Detailed Implementation

[0048] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0049] This invention provides a method for preparing axially chiral allylamine compounds. In an organic solvent, an aliphatic amine and (E)-2-(2-alkoxynaphth-1-yl)-3-arylallylbenzoate react in the presence of a palladium catalyst, a chiral phosphorus ligand, and BSA to obtain the target product, the axially chiral allylamine compound. The reaction formula is as follows: Figure 1 As shown in the figure. R 1 For aryl, R 2 For aryl, R 3 It is an alkyl group, R 4 It is an alkyl group, R 5 The compound is an alkyl group. The reaction mechanism is as follows: (E)-2-(2-alkoxynaphth-1-yl)-3-arylallylbenzoate undergoes oxidative addition with a zero-valent palladium metal complex to give an allyl divalent palladium intermediate. The aliphatic amine is deprotonated by BSA to give a nitrogen anion, which then performs nucleophilic attack on the allyl palladium intermediate, followed by in-situ demetallation to yield the target product. The structure of this type of compound is determined by... 1 H NMR, 13 The cells were characterized and confirmed by C NMR and HRMS.

[0050] Specifically, based on 1.0 equivalent of (E)-2-(2-alkoxynaphth-1-yl)-3-arylallylbenzoate, the amount of aliphatic amine used is 2.0-4.0 equivalents, the amount of palladium catalyst used is 0.02-0.1 equivalents, the amount of chiral phosphorus ligand used is 0.03-0.15 equivalents, and the amount of BSA used is 2.0-4.0 equivalents.

[0051] The chiral phosphorus ligands can be diphosphorus ligands or nitrogen-phosphorus ligands. The screening results for chiral phosphorus ligands are shown in Table 1. In Table 1, the structural formulas of L1-L16 are as follows: Figure 3 As shown. The reaction process is as follows. Figure 2As shown, the reaction conditions were: 1a (0.1 mmol), 2a (0.3 mmol), [Pd(allyl)Cl]2 (5 mol%), ligand (12 mol%), KOAc (0.5 mmol), BSA (0.3 mmol), acetonitrile (2 mL), RT, 24 hours. The yield was NMR yield, and the ee value was determined by chiral chromatography.

[0052] Table 1

[0053]

[0054] The organic solvent may be acetonitrile, 1,2-dichloroethane, tetrahydrofuran, N,N-dimethylacetamide, 1,4-dioxane, methyl tert-butyl ether, or dimethyl sulfoxide. The solvent selection results are shown in Table 2. Reaction conditions: 1a (0.1 mmol), 2a (0.3 mmol), [Pd(allyl)Cl]2 (5 mol%), L1 (12 mol%), KOAc (0.5 mmol), solvent (2 mL), RT, 24 hours. The yield was determined by NMR yield, and the ee value was obtained by chiral chromatography.

[0055] Table 2

[0056]

[0057] The results of the screening of reaction time are shown in Table 3. Reaction conditions: 1a (0.1 mmol), 2a (0.3 mmol), [Pd(allyl)Cl]2 (5 mol%), L16 (12 mol%), KOAc (0.5 mmol), BSA (0.3 mmol), acetonitrile (2 mL), RT. The yield was NMR yield, and the ee value was determined by chiral chromatography.

[0058] Table 3

[0059]

[0060] The results of temperature screening for the reaction are shown in Table 4. Reaction conditions: 1a (0.1 mmol), 2a (0.3 mmol), [Pd(allyl)Cl]2 (5 mol%), L16 (12 mol%), KOAc (0.5 mmol), BSA (0.3 mmol), acetonitrile (2 mL), 72 hours. The yields were obtained as NMR yields, and the ee value was determined by chiral chromatography.

[0061] Table 4

[0062]

[0063] The results of the base screening are shown in Table 5. Reaction conditions: 1a (0.1 mmol), 2a (0.3 mmol), [Pd(allyl)Cl]2 (5 mol%), L16 (15 mol%), Base (0.5 mmol), BSA (0.3 mmol), acetonitrile (2 mL), 30 °C, 72 hours. The yields were NMR yields, and the ee values ​​were determined by chiral chromatography.

[0064] Table 5

[0065]

[0066] The absence of base did not significantly affect the enantioselectivity and yield of the reaction; therefore, no base was added in subsequent reactions. The screening results for BSA equivalents are shown in Table 6. Reaction conditions: 1a (0.1 mmol), 2a (0.3 mmol), [Pd(allyl)Cl]₂ (2.5 mol%), L₁₆ (7.5 mol%), BSA, acetonitrile (2 mL), 30 °C, 72 hours. The yield obtained was the NMR yield. The ee value was determined by chiral chromatography.

[0067] Table 6

[0068]

[0069] The palladium catalyst can be palladium acetate, palladium chloride, allyl palladium chloride dimer, or palladium trifluoroacetate. The results of the screening for palladium (allyl palladium chloride dimer) dosage are shown in Table 7. Reaction conditions: 1a (0.1 mmol), 2a (0.3 mmol), BSA (0.3 mmol), acetonitrile (2 mL), 30 °C, 72 hours. The yield was determined by NMR yield, and the ee value was obtained by chiral chromatography.

[0070] Table 7

[0071]

[0072] The screening results for substrate ratios are shown in Table 8. Reaction conditions: 1a (0.1 mmol), [Pd(allyl)Cl]2 (2.5 mol%), L16 (7.5 mol%), BSA (0.3 mmol), acetonitrile (2 mL), 30 °C, 72 hours. The yield was obtained as NMR yield, and the ee value was determined by chiral chromatography.

[0073] Table 8

[0074]

[0075] The screening results for substrate protecting groups are shown in Table 9. PG is either Ac or Bz, and the reaction process is as follows: Figure 4As shown. Reaction conditions: 1 (0.1 mmol), 2a (0.3 mmol),

[0076] [Pd(allyl)Cl]2 (2.5 mol%), L16 (7.5 mol%), BSA (0.3 mmol), acetonitrile (2 mL), 30 °C, 72 hours. The yield was obtained as NMR yield, and the ee value was determined by chiral chromatography. The results showed that the yield and ee value were both higher when the substrate protecting group was Bz.

[0077] Table 9

[0078]

[0079] When the substrate protecting group PG is Bz, the screening results for reaction time are shown in Table 10, and the reaction process is as follows: Figure 5 As shown. The reaction conditions were: 1a (0.2 mmol), 2a (0.6 mmol), [Pd(allyl)Cl]2 (2.5 mol%), L16 (7.5 mol%), BSA (0.6 mmol), acetonitrile (2 mL), 30 °C. The yield was obtained by NMR spectroscopy, and the ee value was determined by chiral chromatography. The results showed that the reaction time was 36 hours, resulting in the highest yield and ee value.

[0080] Table 10

[0081]

[0082] Example 1

[0083] Allyl palladium chloride dimer (1.8 mg, 0.005 mmol) and 1,1'-[(5aR,8aR,14aR)-5a,6,7,8,8a,9--hexahydro-5H-[1]benzopyrano[3,2-d]anthracene 1,13-bis[bis(3,5-dimethylphenyl)phosphine (11.6 mg, 0.015 mmol) were added sequentially to the reaction tube. After purging with high-purity nitrogen three times, acetonitrile (2 mL) was added and stirred at 30 °C for 30 minutes. Then, (E)-2-(2-methoxynaphthyl-1-yl)-3-(4-methoxyphenyl)allyl benzoate (84.9 mg, 0.2 mmol) was added under a nitrogen atmosphere. After stirring for five minutes, morpholine (52.3 mg, 0.6 mmol) and BSA (122.1 mg, 0.6 mmol) were added and stirred at 30 °C for 36 hours. After the reaction was monitored by TLC, direct column chromatography was performed using petroleum ether and ethyl acetate (V:V = 8:1) as the mobile phase to obtain the corresponding axially chiral product – axially chiral allylamine compound 1 (75.6 mg, yield 97%, ee value 90%). Figure 6 .

[0084] The structure of axially chiral allylamine compound 1 is characterized as follows: 1 H NMR (400MHz, CDCl3) δ7.84 (d, J = 9.0Hz, 1H), 7.81–7.76 (m, 1H), 7.75–7.70 (m, 1H), 7.37–7.27 (m, 3H), 7.00 (s, 1H), 6. 82(d,J=8.8Hz,2H),6.51(d,J=8.8Hz,2H),3.84(s,3H),3.75(t,J=4.6Hz,4H),3.63(s,3H),3.26(s,2H),2.64(s,4H); 13 C NMR (100MHz, CDCl3) δ158.2,153.8,132.0,129.8,129.4,129.3,129.0,128.1, 126.7,124.5,123.7,113.8,113.4,67.2,65.7,56.6,55.0,54.1.HRMS(ESI)m / z Calcd for[C 25 H 28 NO3, M+H] + :390.2069, Found: 390.2079. HPLC analysis: CHIRALPAK OD-H (Hexane / i-PrOH) = 96:4, flow rate = 0.25mL / min, wave length = 230nm, t R =41.635min(major),t R = 46.073min (minor). For example... Figure 7-10 As shown.

[0085] Example 2

[0086] Allyl palladium chloride dimer (1.8 mg, 0.005 mmol) and 1,1'-[(5aR,8aR,14aR)-5a,6,7,8,8a,9--hexahydro-5H-[1]benzopyrano[3,2-d]anthracene 1,13-bis[bis(3,5-dimethylphenyl)phosphine (11.6 mg, 0.015 mmol) were added sequentially to the reaction tube. After purging with high-purity nitrogen three times, acetonitrile (2 mL) was added and stirred at 30 °C for 30 minutes. Then, (E)-2-(2-ethoxynaphth-1-yl)-3-phenylallylbenzoate (81.7 mg, 0.2 mmol) was added under a nitrogen atmosphere. After stirring for five minutes, morpholine (52.3 mg, 0.6 mmol) and BSA (122.1 mg, 0.6 mmol) were added and stirred at 30 °C for 36 hours. After the reaction was monitored by TLC, direct column chromatography was performed using petroleum ether and ethyl acetate (V:V = 8:1) as the mobile phase to obtain the corresponding axially chiral product – axially chiral allylamine compound 2 (72.5 mg, yield 97%, ee value 92%). Figure 11 .

[0087] The structure of axially chiral allylamine compound 2 is characterized as follows: 1 H NMR (400MHz, CDCl3) δ7.84–7.70(m,3H),7.34–7.25(m,3H),7.08(s,1H),6.99-6.93(m,3H),6.93–6.85( m,2H),4.18-3.94(m,2H),3.77(t,J=4.6Hz,4H),3.28(s,2H),2.80-2.54(m,4H),1.28(t,J=7.0Hz,3H); 13 CNMR (100MHz, CDCl3) δ153.1,137.2,132.0,129.1,129.0,128.2,128.1,127.9,126 .6,126.4,124.4,123.6,123.6,114.6,67.2,65.4,64.5,54.1,15.1.HRMS(ESI)m / z Calcd for[C 25 H 28 NO2,M+H] + :374.2120, Found: 374.2126. HPLC analysis: CHIRALPAK AD-H (Hexane / i-PrOH) = 98:2, flow rate = 0.3mL / min, wave length = 230nm, t R =18.016min(minor),t R= 21.127min (major). For example... Figure 12-15 As shown.

[0088] Example 3

[0089] Allyl palladium chloride dimer (2.6 mg, 0.007 mmol) and 1,1'-[(5aR,8aR,14aR)-5a,6,7,8,8a,9--hexahydro-5H-[1]benzopyrano[3,2-d]anthracene 1,13-bis[bis(3,5-dimethylphenyl)phosphine (16.2 mg, 0.021 mmol) were added sequentially to the reaction tube. After purging with high-purity nitrogen three times, acetonitrile (2 mL) was added and stirred at 30 °C for 30 minutes. Then, (E)-2-(2-methoxynaphthyl-1-yl)-3-phenylallylbenzoate (78.9 mg, 0.2 mmol) was added under a nitrogen atmosphere. After stirring for five minutes, 1-phenylpiperazine (97.3 mg, 0.6 mmol) and BSA (122.1 mg, 0.6 mmol) were added and stirred at 30 °C for 36 hours. After the reaction was monitored by TLC, direct column chromatography was performed using petroleum ether and ethyl acetate (V:V = 8:1) as the mobile phase to obtain the corresponding axially chiral product – axially chiral allylamine compound 3 (85.2 mg, yield 98%, ee value 87%). Figure 16 .

[0090] The structure of axially chiral allylamine compound 3 is characterized as follows: 1 H NMR(400MHz, CDCl3)δ7.83(d,J=9.0Hz,1H),7.80-7.73(m,2H),7.35–7.23(m,5H),7.11(s,1H),7.00 –6.88(m,7H),6.87-6.80(m,1H),3.84(s,3H),3.32(s,2H),3.25(t,J=5.0Hz,4H),2.87-2.76(m,4H); 13 C NMR (100MHz, CDCl3) δ153.8,151.5,137.1,133.6,132.0,129.2,129.1,129.1,128.2,128.1,128. 0,126.7,126.5,124.4,123.7,123.6,119.5,116.0,113.7,65.2,56.6,53.6,49.3.HRMS(ESI)m / z Calcd for[C 30 H 31 [N2O,M+H] +:435.2436, Found: 435.2444. HPLC analysis: CHIRALPAK AD-H (Hexane / i-PrOH) = 95:5, flow rate = 0.3mL / min, wave length = 254nm, t R =20.700min(minor),t R = 21.969min (major). For example... Figure 17-20 As shown.

[0091] Example 4

[0092] Add allyl palladium chloride dimer (19.21 mg, 0.0525 mmol) 1,1'-[(5aR,8aR,14aR)-5a,6,7,8,8a,9--hexahydro-5H-[1]benzopyrano[3,2-d]anthracene 1,13-bis[bis(3,5-dimethylphenyl)phosphine (121.5 mg, 0.1575 mmol) to a 50 mL sealed tube, purge three times with high-purity nitrogen, then add acetonitrile (15 mL), and place in an oil bath at 30 °C and stir for 1 hour; add (E)-2 -(2-(ethoxymethoxy)naphth-1-yl)-3-phenylallylbenzoate (1.5 mmol, 658.0 mg) was added to the pre-stirred catalyst solution under a nitrogen atmosphere, and the mixture was stirred again for 10 minutes until the starting material (E)-2-(2-(ethoxymethoxy)naphth-1-yl)-3-phenylallylbenzoate was completely dissolved. Then, N,N,N'-trimethylethylenediamine 2c (4.5 mmol, 0.58 mL) and BSA (4.5 mmol, 1.125 mL) were added under a nitrogen atmosphere, and the reaction was stirred at 30 °C for 36 hours. After the reaction was completed as monitored by TLC, direct column chromatography was performed using petroleum ether and ethyl acetate (V:V = 8:1) as the mobile phase to obtain the corresponding axially chiral product - axially chiral allylamine compound 4 (627.9 mg, yield 87%, ee value 91%). Figure 21 As shown.

[0093] The structure of axially chiral allylamine compound 4 is characterized as follows: 1H NMR (400MHz, CDCl3) δ7.82–7.73(m,3H),7.47(d,J=9.1Hz,1H),7.36–7.28(m ,2H),7.08(s,1H),6.98–6.92(m,3H),6.91-6.85(m,2H),5.24(d,J=7.0Hz,1 H),5.10(d,J=7.1Hz,1H),3.66-3.43(m,2H),3.32(s,2H),2.76-2.67(m,1H) ,2.63-2.55(m,1H),2.46-2.40(m,5H),2.23(s,6H),1.07(t,J=7.1Hz,3H).; 13 C NMR (100MHz, CDCl3) δ151.3,137.2,134.5,132.1,129.8,128.9,128.5,128.2,128.1,127.9,126.6 ,126.4,124.7,124.6,124.0,116.5,93.3,65.2,64.1,57.6,55.8,45.9,43.4,15.0.HRMS(ESI)m / z Calcd for[C 27 H 35 N2O2,M+H] + :419.2699, Found: 419.2708. HPLC analysis: CHIRALPAK AD-H (Hexane / i-PrOH) = 98:2, flow rate = 0.2mL / min, wave length = 230nm, t R =33.362min(minor),t R = 39.009min (major). For example... Figure 22-25 As shown.

[0094] The above description is merely a preferred embodiment of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention are included within the scope of protection of the present invention.

Claims

1. A method for preparing an axially chiral allylamine compound, characterized in that, In an organic solvent, aliphatic amines and (E)-2-(2-alkoxynaphth-1-yl)-3-arylallyl benzoate are reacted in the presence of a palladium catalyst, a chiral phosphorus ligand, and BSA to yield the target product, an axially chiral allyl amine compound. The reaction formula is as follows: In the formula R 1 For aryl, R 2 For aryl, R 3 It is an alkyl group, R 4 It is an alkyl group, R 5 It is an alkyl group; Based on 1.0 equivalent of (E)-2-(2-alkoxynaphth-1-yl)-3-arylallylbenzoate, the amount of aliphatic amine used is 2.0-4.0 equivalents, the amount of palladium catalyst used is 0.02-0.1 equivalents, the amount of chiral phosphorus ligand used is 0.03-0.15 equivalents, and the amount of BSA used is 2.0-4.0 equivalents.

2. The method for preparing axially chiral allylamine compounds according to claim 1, characterized in that, Includes the following steps: (1) At room temperature, palladium catalyst and chiral phosphorus ligand were added to a dry reaction tube, replaced with nitrogen, and then an organic solvent was added and stirred for 30 minutes. (2) Under a nitrogen atmosphere, (E)-2-(2-alkoxynaphth-1-yl)-3-arylallylbenzoate was added to the above reaction tube, stirred for 5 minutes, and then fatty amine and BSA were added. The reaction was stirred until complete. (3) After the reaction is complete as detected by TLC, the reaction is separated by direct column chromatography. A mixed solvent of petroleum ether and ethyl acetate is used as the mobile phase to obtain the corresponding axial chiral allylamine compounds.

3. The method for preparing axially chiral allylamine compounds according to claim 1, characterized in that, The palladium catalyst is palladium acetate, palladium chloride, allyl palladium chloride dimer, or palladium trifluoroacetate.

4. The method for preparing axially chiral allylamine compounds according to claim 1, characterized in that, The chiral phosphorus ligand is a diphosphorus ligand or a nitrogen-phosphorus ligand.

5. The method for preparing axially chiral allylamine compounds according to claim 1, characterized in that, The alkali is NaOAc, KHCO3, K2CO3, K2HPO4, Na2CO3, or KOAC.

6. The method for preparing axially chiral allylamine compounds according to claim 1, characterized in that, The organic solvent is acetonitrile, 1,2-dichloroethane, tetrahydrofuran, N,N-dimethylacetamide, 1,4-dioxane, methyl tert-butyl ether, or dimethyl sulfoxide.

7. The method for preparing axially chiral allylamine compounds according to claim 1, characterized in that, The reaction temperature is 30℃ and the reaction time is 36-72 hours.

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