A method for synthesizing beta-amino boronate

Abstract

The application relates to a synthesis method of beta-amino borate. The beta-amino borate is obtained by taking N-(1-phenylvinyl) benzamide and pinacol borate as substrates, taking cuprous chloride and (S, S)-BDPP as catalysts, taking sodium tert-butylate as alkali, and taking tert-amyl alcohol as additive and reacting at room temperature. The reaction condition is mild, the regioselectivity and stereoselectivity are good, good functional group tolerance is achieved, and many defects of the prior art are made up.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and specifically relates to a method for synthesizing β-aminoboronic acid esters. Background Technology

[0002] Chiral amides and their derivatives are found in many pharmaceutical active ingredients, fine chemicals, agrochemicals, polymers, dyes, pigments, emulsifiers, plasticizers, and other chemicals. Due to the challenging nature and practical applications of their synthesis, developing novel and efficient synthetic methods for chiral amines has long been a focus of synthetic chemists. Boron is an ideal functionalization precursor; introducing boron into chiral amines allows for extensive derivatization without sacrificing enantioselectivity, which is crucial for drug molecule synthesis. Therefore, developing efficient synthetic methods for β-aminoboronic esters can enhance the derivatization ability of chiral amine compounds, which is of great significance in drug discovery and drug modification. Summary of the Invention

[0003] The purpose of this invention is to overcome the shortcomings of existing preparation techniques and provide a method for synthesizing β-aminoboronic esters that has simple reaction conditions, wide substrate applicability, and good regioselectivity and enantioselectivity.

[0004] The technical solution of this invention is as follows: The substrate, B2pin2, base, metal and ligand, and additive are placed in a Schlenk tube, a solvent is added, and β-aminoboronic acid ester is obtained at room temperature. The reaction formula is as follows:

[0005]

[0006] (1)R 1 Selected from methyl, methoxy, chloro, bromo, naphthalene, phenyl, tert-butyl, fluoro, trifluoromethyl, cyano, and ester groups;

[0007] (2)R 2 The base is selected from methyl, benzyl, methoxy, chloro, bromo, naphthalene, phenyl, tert-butyl, trifluoromethyl, cyano, ester; (3) the base used is selected from sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, and lithium methylbutoxide, preferably sodium tert-butoxide;

[0008] (4) The solvent used is selected from toluene, tetrahydrofuran, 1,4-dioxane, acetone, DMF, acetonitrile, preferably toluene:1,4-dioxane = 1.5:1;

[0009] (5) The catalyst used is selected from cuprous chloride, cuprous bromide, copper acetate, and copper iodide, with cuprous chloride being preferred;

[0010] (6) The additives used are selected from methanol, tert-butanol, isopropanol, tert-amyl alcohol, with tert-amyl alcohol being preferred;

[0011] (7) The heating temperature used is selected from 25-80℃, preferably 25℃, and the holding time is 12 hours. Attached Figure Description

[0012] 1. Figure 1 The synthesis conditions for β-aminoboronic acid esters;

[0013] 2. Figure 2 The reaction formula for the preparation of compound 2a;

[0014] 3. Figure 3 The reaction formula for the preparation of compound 2b;

[0015] 4. Figure 4 The reaction formula for the preparation of compound 2c;

[0016] 5. Figure 5 The reaction formula for the preparation of compound 2d;

[0017] 6. Figure 6 The reaction formula for the preparation of compound 2e;

[0018] 7. Figure 7 The reaction formula for the preparation of compound 2f;

[0019] 8. Figure 8 The reaction formula for the preparation of 2g of compound;

[0020] 9. Figure 9 The reaction formula for the preparation of compound 2h;

[0021] 10. Figure 10 The reaction formula for the preparation of compound 2i;

[0022] 11. Figure 11 The reaction formula for the preparation of 2g of compound;

[0023] 12. Figure 12 The reaction formula for the preparation of compound 2k;

[0024] 13. Figure 13 The reaction formula for the preparation of compound 2l;

[0025] 14. Figure 14 The reaction formula for the preparation of compound 2m;

[0026] 15. Figure 15 The reaction formula for the preparation of compound 2n;

[0027] 16. Figure 16 The reaction formula for the preparation of compound 2o;

[0028] 17. Figure 17 The reaction formula for the preparation of compound 2p;

[0029] 18. Figure 18 The reaction formula for the preparation of compound 2q;

[0030] 19. Figure 19 The reaction formula for the preparation of compound 2r;

[0031] 20. Figure 20 The reaction formula for the preparation of compound 2s is shown below. Detailed Implementation

[0032] The present invention will be further described below through specific embodiments, but it should not be construed as limiting the scope of the above-mentioned subject matter of the present invention to the following embodiments. All technologies implemented based on the above content of the present invention fall within the scope of the present invention.

[0033] Implementation Case 1

[0034] Using N-(1-phenylvinyl)benzamide and bis(pinacolyl)diboron as raw materials (reaction formula 1)

[0035]

[0036] In a glove box, CuCl (5.0 mol%, 0.5 mg), sodium tert-butoxide (0.15 mmol, 14.4 mg), and (S,S)-BDPP (10% mmol, 4.4 mg) were added to a dry 10 mL Schlenk tube. 0.6 mL of 1,4-dioxane was added and the mixture was stirred. The reaction was allowed to proceed for half an hour until the solution became clear. In another 10 mL Schlenk tube, 0.1 mmol of enamide substrate 1a, 0.1 mmol of B2pin2 (0.15 mmol, 38.1 mg, 1.5 eq), 21.0 μL of tert-amyl alcohol (2.0 eq), and 0.9 mL of toluene were added. The clear solution containing the copper ligand was then added to this Schlenk tube. The tube was sealed and removed from the glove box. The reaction was allowed to proceed at room temperature with stirring until the starting material disappeared. After the reaction was complete, the reaction solution was filtered through silica gel, the solvent was evaporated under vacuum, and the solution was filtered through a silica gel column (PE:EA = 20:1-10:1) to obtain the target product 2a.

[0037] The product test data are as follows: white solid, yield 76%, ee = 91%.

[0038] 1 H NMR(400MHz, CDCl3)δ7.84(d,J=6.9Hz,2H),7.54–7.41(m,3H),7.40–7.34(m,2H),7.3 6–7.26(m,3H),7.24–7.17(m,1H),5.58–5.46(m,1H),1.59–1.46(m,2H),1.18(s,12H);13 C NMR (101MHz, CDCl3) δ166.1,143.7,134.8,131.2,128.4,128.3,126.9,126.9,126.1,83.6,49.7,24.8,24.6.The boron-bound carbon was not detected due to toquadrupolar relaxation; HRMS(ESI):m / z[M+H] + calcd for C 21 H 27 BNO3 + :352.2079, found352.2070; HPLC analysis: DAICEL CHIRALPAK IA-3, n-hexane / isopropanol=80:20, 1.0mL / min, wavelength=210nm, t R (minor) = 5.6min,t R (major)=8.9min, ee=91%.

[0039]

[0040]

[0041]

[0042]

[0043] Implementation Case 2 uses 4-methoxy-N-(1-phenylvinyl)benzamide and bis(pinacol)diboron as raw materials. (Reaction Formula 2)

[0044]

[0045] In a glove box, CuCl (5.0 mol%, 0.5 mg), sodium tert-butoxide (0.15 mmol, 14.4 mg), and (S,S)-BDPP (10% mmol, 4.4 mg) were added to a dry 10 mL Schlenk tube. 0.6 mL of 1,4-dioxane was added and the mixture was stirred. The reaction was allowed to proceed for half an hour until the solution became clear. In another 10 mL Schlenk tube, enamide substrate 1b (0.1 mmol), B2pin2 (0.15 mmol, 38.1 mg, 1.5 eq), tert-amyl alcohol (21.0 μL, 2.0 eq), and 0.9 mL of toluene were added. The clear solution containing the copper ligand was then added to this Schlenk tube. The tube was sealed and removed from the glove box. The reaction was allowed to proceed at room temperature with stirring until the starting material disappeared. After the reaction was complete, the reaction solution was filtered through silica gel, the solvent was evaporated under vacuum, and the solution was filtered through a silica gel column (PE:EA = 20:1-10:1) to obtain the target product 2b.

[0046] The product test data are as follows: white solid, yield 74%, ee = 94%.

[0047] 1 H NMR(400MHz, CDCl3)δ7.81(d,J=8.8Hz,2H),7.36(d,J=7.1Hz,2H),7.33–7.18 (m,4H),6.93(d,J=8.8Hz,2H),5.55–5.46(m,1H),1.46(m,2H),1.18(s,12H); 13 C NMR (100MHz, CDCl3) δ165.6,162.0,143.8,128.6,128.3,127.0,126.9,126.1,113.6,83.5,55.3,49.5,24.8,24.6.The boron-bound carbon was not detected due to toquadrupolar relaxation; HRMS(ESI):m / z[M+H] + calcd for C 22 H 29 BNO4 + :382.2184, found382.2185; HPLC analysis: DAICELCHIRALPAK IA-3, n-hexane / isopropanol=80:20, 1.0mL / min, wavelength=210nm, t R (minor) = 8.7min,t R (major)=14.1min,ee=94%.

[0048]

[0049]

[0050]

[0051]

[0052] Implementation Case 3 uses 3-methoxy-N-(1-phenylvinyl)benzamide and bis(pinacolyl)diboron as raw materials (reaction formula 3).

[0053]

[0054] In a glove box, CuCl (5.0 mol%, 0.5 mg), sodium tert-butoxide (0.15 mmol, 14.4 mg), and (S,S)-BDPP (10% mmol, 4.4 mg) were added to a dry 10 mL Schlenk tube. 0.6 mL of 1,4-dioxane was added and the mixture was stirred. The reaction was allowed to proceed for half an hour until the solution became clear. In another 10 mL Schlenk tube, 0.1 mmol of enamide substrate 1c, 0.1 mmol of B2pin2 (0.15 mmol, 38.1 mg, 1.5 eq), 21.0 μL of tert-amyl alcohol (2.0 eq), and 0.9 mL of toluene were added. The clear solution containing the copper ligand was then added to this Schlenk tube. The tube was sealed and removed from the glove box. The reaction was allowed to proceed at room temperature with stirring until the starting material disappeared. After the reaction was complete, the reaction solution was filtered through silica gel, the solvent was evaporated under vacuum, and the solution was filtered through a silica gel column (PE:EA = 20:1-10:1) to obtain the target product 2c.

[0055] The product test data are as follows: white solid, yield 82%, ee = 94%.

[0056] 1 H NMR (400MHz, CDCl3) δ7.46–7.42(m,1H),7.40–7.25(m,7H),7.24–7.16(m,1 H),7.08–6.98(m,1H),5.56–5.46(m,1H),1.61–1.47(m,2H).1.18(s,12H); 13C NMR (100MHz, CDCl3) δ165.9,159.8,143.7,136.3,129.3,128.3,126.9,126.1,118.5,117.5,112.3,83.6,55.4,49.7,24.9,24.6.The boron-bound carbon was not detected duetoquadrupolarrelaxation; HRMS(ESI):m / z[M+H] + calcd for C 22 H 29 BNO4 + :382.2184, found382.2187; HPLC analysis: DAICELCHIRALPAK IA-3, n-hexane / isopropanol=80:20, 1.0mL / min, wavelength=210nm, t R (minor) = 8.5min,t R (major)=22.2min, ee=94%.

[0057]

[0058]

[0059]

[0060]

[0061] Implementation Case 4 uses 3-methyl-N-(1-phenylvinyl)benzamide and bis(pinacol)diboron as raw materials (reaction formula 4).

[0062]

[0063] In a glove box, CuCl (5.0 mol%, 0.5 mg), sodium tert-butoxide (0.15 mmol, 14.4 mg), and (S,S)-BDPP (10% mmol, 4.4 mg) were added to a dry 10 mL Schlenk tube. 0.6 mL of 1,4-dioxane was added and the mixture was stirred. The reaction was allowed to proceed for 30 minutes until the solution became clear. In another 10 mL Schlenk tube, 1d of the enamide substrate (0.1 mmol), B2pin2 (0.15 mmol, 38.1 mg, 1.5 eq), and tert-amyl alcohol (21.0 μL, 2.0 eq) were added, along with 0.9 mL of toluene. The clear solution containing the copper ligand was then added to this Schlenk tube. The tube was sealed and removed from the glove box. The reaction was allowed to proceed at room temperature with stirring until the starting material disappeared. After the reaction was complete, the reaction mixture was filtered through silica gel, the solvent was evaporated under vacuum, and the solution was filtered through a silica gel column (PE:EA = 20:1-10:1) to obtain the target product 2d.

[0064] The product test data are as follows: white solid, yield 70%, ee = 91%.

[0065] 1 H NMR(400MHz, CDCl3)δ7.62–7.51(m,2H),7.29(d,J=8.9Hz,3H),7.26–7.18(m,4H),7 .16–7.10(m,1H),5.51–5.36(m,1H),2.33(s,3H),1.54–1.38(m,2H),1.12(s,12H); 13 CNMR (100MHz, CDCl3) δ166.1,143.6,138.2,134.6,132.0,129.45,128.3,127.6,126.9,126.0,123.9,83.6,49.5,24.8,24.6,21.3.The boron-bound carbon was not detecteddue toquadrupolar relaxation; HRMS(ESI):m / z[M+H] + calcd for C 22 H 29 BNO3 + :366.2235, found366.2233; HPLC analysis: DAICEL CHIRALPAK IA-3, n-hexane / isopropanol=80:20, 1.0mL / min, wavelength=210nm, t R (minor) = 5.3min,t R(major)=7.8min, ee=91%.

[0066]

[0067]

[0068]

[0069]

[0070] Implementation Case 5 uses 4-methyl-N-(1-phenylvinyl)benzamide and bis(pinacol)diboron as raw materials (reaction formula 5).

[0071]

[0072] In a glove box, CuCl (5.0 mol%, 0.5 mg), sodium tert-butoxide (0.15 mmol, 14.4 mg), and (S,S)-BDPP (10% mmol, 4.4 mg) were added to a dry 10 mL Schlenk tube. 0.6 mL of 1,4-dioxane was added and the mixture was stirred. The reaction was allowed to proceed for half an hour until the solution became clear. In another 10 mL Schlenk tube, 1e of the enamide substrate (0.1 mmol), B2pin2 (0.15 mmol, 38.1 mg, 1.5 eq), and tert-amyl alcohol (21.0 μL, 2.0 eq) were added, along with 0.9 mL of toluene. The clear solution containing the copper ligand was then added to this Schlenk tube. The tube was sealed and removed from the glove box. The reaction was allowed to proceed at room temperature with stirring until the starting material disappeared. After the reaction was complete, the reaction mixture was filtered through silica gel, the solvent was evaporated under vacuum, and the solution was filtered through a silica gel column (PE:EA = 20:1–10:1) to obtain the target product 2e.

[0073] The product test data are as follows: white solid, yield 77%, ee = 90%.

[0074] 1 H NMR (400MHz, CDCl3) δ7.63 (d, J = 8.3Hz, 2H), 7.27–7.10 (m, 8H), 5.49–5.37 (m, 1H), 2.29 (s, 3H), 1.53–1.40 (m, 2H), 1.11 (s, 12H); 13C NMR (100MHz, CDCl3) δ166.0,143.7,141.6,131.8,130.91,129.1,128.3,126.9,126.0,83.5,49.5,24.8,24.5,21.4.Theboron-boundcarbon was not detected due to quadrupolar relaxation; HRMS(ESI):m / z[M+H] + calcd forC 22 H 29 BNO3 + :366.2235, found 366.2237; HPLC analysis: DAICELCHIRALPAK IA-3, n-hexane / isopropanol=80:20, 1.0mL / min, wavelength=210nm, t R (minor) = 7.0 min, t R (major)=17.0min,ee=90%.

[0075]

[0076]

[0077]

[0078]

[0079] Implementation Case 6 uses 3-bromo-N-(1-phenylvinyl)benzamide and bis(pinacolyl)diboron as raw materials (reaction formula 6).

[0080]

[0081] In a glove box, CuCl (5.0 mol%, 0.5 mg), sodium tert-butoxide (0.15 mmol, 14.4 mg), and (S,S)-BDPP (10% mmol, 4.4 mg) were added to a dry 10 mL Schlenk tube. 0.6 mL of 1,4-dioxane was added and the mixture was stirred. The reaction was allowed to proceed for half an hour until the solution became clear. In another 10 mL Schlenk tube, 1f of the enamide substrate (0.1 mmol), B2pin2 (0.15 mmol, 38.1 mg, 1.5 eq), and tert-amyl alcohol (21.0 μL, 2.0 eq) were added, along with 0.9 mL of toluene. The clear solution containing the copper ligand was then added to this Schlenk tube. The tube was sealed and removed from the glove box. The reaction was allowed to proceed at room temperature with stirring until the starting material disappeared. After the reaction was complete, the reaction mixture was filtered through silica gel, the solvent was evaporated under vacuum, and the solution was filtered through a silica gel column (PE:EA = 20:1–10:1) to obtain the target product 2f.

[0082] Product test data are as follows: white solid, yield 56%, ee = 89%.

[0083] 1 H NMR(400MHz, CDCl3)7.70(d,J=8.4Hz,2H),7.57(d,J=8.5Hz,2H),7.40–7.26( m,5H),7.25–7.19(m,1H).5.56–5.42(m,1H),1.61–1.47(m,2H),1.18(s,12H); 13 C NMR (100MHz, CDCl3) δ164.5,143.4,136.7,134.2,130.2,129.9,128.44,127.1,126.0,125.8,122.6,83.8,49.7,24.9,24.7.The boron-bound carbon was not detected due to toquadrupolar relaxation; HRMS(ESI):m / z[M+H] + calcd for C 21 H 26 BBrNO3 + :430.1184, found 430.1175; HPLC analysis: DAICEL CHIRALPAK IA-3, n-hexane / isopropanol=80:20, 1.0mL / min, wavelength=210nm, t R (minor) = 5.2min,t R(major)=7.8min, ee=89%.

[0084]

[0085]

[0086]

[0087]

[0088] Implementation Case 7 uses 4-bromo-N-(1-phenylvinyl)benzamide and bis(pinacol)diboron as raw materials (reaction formula 7).

[0089]

[0090] In a glove box, CuCl (5.0 mol%, 0.5 mg), sodium tert-butoxide (0.15 mmol, 14.4 mg), and (S,S)-BDPP (10% mmol, 4.4 mg) were added to a dry 10 mL Schlenk tube. 0.6 mL of 1,4-dioxane was added and the mixture was stirred. The reaction was allowed to proceed for half an hour until the solution became clear. In another 10 mL Schlenk tube, 1 g (0.1 mmol) of enamide substrate, B2pin2 (0.15 mmol, 38.1 mg, 1.5 eq), tert-amyl alcohol (21.0 μL, 2.0 eq), and 0.9 mL of toluene were added. The clear solution containing the copper ligand was then added to this Schlenk tube. The tube was sealed and removed from the glove box. The reaction was allowed to proceed at room temperature with stirring until the starting material disappeared. After the reaction was complete, the reaction solution was filtered through silica gel, the solvent was evaporated under vacuum, and the solution was filtered through a silica gel column (PE:EA = 20:1-10:1) to obtain 2 g of the target product.

[0091] Product test data are as follows: white solid, yield 54%, ee = 90%.

[0092] 1 H NMR (400MHz, CDCl3) δ8.01–7.91(m,1H),7.78(d,J=7.8Hz,1H),7.62(d,J=7.0Hz,1H),7.47(d,J=8.5H z,1H),7.37–7.27(m,5H),7.23(d,J=7.1Hz,1H),5.56–5.39(m,1H),1.60–1.47(m,2H),1.20(s,12H); 13C NMR (100MHz, CDCl3) δ165.1,143.4,133.6,131.7,128.5,128.4,127.1,126.1,125.9,83.7,49.7,24.9,24.6.The boron-boundcarbon was not detected due to quadrupolar relaxation; HRMS(ESI):m / z[M+H] + calcdfor C 21 H 26 BBrNO3 + :430.1184, found 430.1176; HPLC analysis: DAICEL CHIRALPAK IA-3, n-hexane / isopropanol=80:20, 1.0mL / min, wavelength=210nm, t R (minor) = 7.0 min, t R (major)=15.0min,ee=90%.

[0093]

[0094]

[0095]

[0096]

[0097] Implementation Case 8 uses 4-fluoro-N-(1-phenylvinyl)benzamide and bis(pinacol)diboron as raw materials (reaction formula 8).

[0098]

[0099] In a glove box, CuCl (5.0 mol%, 0.5 mg), sodium tert-butoxide (0.15 mmol, 14.4 mg), and (S,S)-BDPP (10% mmol, 4.4 mg) were added to a dry 10 mL Schlenk tube. 0.6 mL of 1,4-dioxane was added and the mixture was stirred. The reaction was allowed to proceed for 30 minutes until the solution became clear. In another 10 mL Schlenk tube, 0.1 mmol of enamide substrate 1h, B2pin2 (0.15 mmol, 38.1 mg, 1.5 eq), tert-amyl alcohol (21.0 μL, 2.0 eq), and 0.9 mL of toluene were added. The clear solution containing the copper ligand was then added to this Schlenk tube. The tube was sealed and removed from the glove box. The reaction was allowed to proceed at room temperature with stirring until the starting material disappeared. After the reaction was complete, the reaction solution was filtered through silica gel, the solvent was evaporated under vacuum, and the solution was filtered through a silica gel column (PE:EA = 20:1-10:1) to obtain the target product 2h.

[0100] The product test data are as follows: white solid, yield 63%, ee = 92%.

[0101] 1 H NMR (400MHz, CDCl3) δ7.93–7.76(m,2H),7.41–7.18(m,6H),7.11(t,J=8.6Hz,2H),5.59–5.37(m,1H),1.66–1.45(m,2H),1.18(s,12H); 13 C NMR (100MHz, CDCl3) δ165.0, 164.6 (d, J = 250.1Hz), 143.5, 130.9 (d, J = 3.2Hz), 129.2 (d,J=8.8Hz),128.4,127.0,126.1,115.5(d,J=21.8Hz),83.6,49.7,24.8,24.6.The boron-bound carbon was notdetected due to quadrupolar relaxation; HRMS(ESI):m / z[M+H] + calcd for C 21 H 26 BFNO3 + :370.1984, found370.1978; HPLC analysis: DAICEL CHIRALPAK IA-3, n-hexane / isopropanol=80:20, 1.0mL / min, wavelength=210nm, t R (minor) = 5.7min,t R(major)=9.0min, ee=92%.

[0102]

[0103]

[0104]

[0105]

[0106]

[0107] Implementation Case Nine uses 3-fluoro-N-(1-phenylvinyl)benzamide and bis(pinacol)diboron as raw materials (reaction formula 9).

[0108]

[0109] In a glove box, CuCl (5.0 mol%, 0.5 mg), sodium tert-butoxide (0.15 mmol, 14.4 mg), and (S,S)-BDPP (10% mmol, 4.4 mg) were added to a dry 10 mL Schlenk tube. 0.6 mL of 1,4-dioxane was added and the mixture was stirred. The reaction was allowed to proceed for half an hour until the solution became clear. In another 10 mL Schlenk tube, 0.1 mmol of enamide substrate 1i, 0.1 mmol of B2pin2 (0.15 mmol, 38.1 mg, 1.5 eq), 21.0 μL of tert-amyl alcohol (2.0 eq) were added, along with 0.9 mL of toluene. The clear solution containing the copper ligand was then added to this Schlenk tube. The tube was sealed and removed from the glove box. The reaction was allowed to proceed at room temperature with stirring until the starting material disappeared. After the reaction was complete, the reaction mixture was filtered through silica gel, the solvent was evaporated under vacuum, and the solution was filtered through a silica gel column (PE:EA = 20:1-10:1) to obtain the target product 2i.

[0110] The product test data are as follows: white solid, yield 52%, ee = 94%.

[0111] 1 H NMR(400MHz, CDCl3)δ7.61(d,J=7.8Hz,1H),7.59–7.51(m,1H),7.49–7.34(m,4H),7.3 4–7.27(m,2H),7.27–7.15(m,2H),5.61–5.42(m,1H),1.63–1.46(m,2H),1.19(s,12H); 13C NMR (100MHz, CDCl3) 164.7, 162.7 (d, J = 247.3Hz), 143.5, 137.1 (d, J = 6.6Hz), 130.1 (d, J = 7.9Hz), 128.4, 127.1,126.1,122.4(d,J=3.0Hz),118.2(d,J=21.4Hz),114.3(d,J=22.9Hz),83.7,49.8,24.9,24.6.The boron-bound carbon was notdetected due to quadrupolarrelaxation; HRMS(ESI):m / z[M+H] + calcd for C 21 H 26 BFNO3 + :370.1984, found 370.1976; HPLC analysis: DAICEL CHIRALPAK IA-3, n-hexane / isopropanol=80:20, 1.0mL / min, wavelength=210nm, t R (minor) = 6.1 min, t R (major)=8.6min, ee=94%.

[0112]

[0113]

[0114]

[0115]

[0116] Implementation Case 10 uses 4-chloro-N-(1-phenylvinyl)benzamide and bis(pinacol)diboron as raw materials (reaction formula 10).

[0117]

[0118] In a glove box, CuCl (5.0 mol%, 0.5 mg), sodium tert-butoxide (0.15 mmol, 14.4 mg), and (S,S)-BDPP (10% mmol, 4.4 mg) were added to a dry 10 mL Schlenk tube. 0.6 mL of 1,4-dioxane was added and the mixture was stirred. The reaction was allowed to proceed for half an hour until the solution became clear. In another 10 mL Schlenk tube, 0.1 mmol of enamide substrate 1j, 0.1 mmol of B2pin2 (0.15 mmol, 38.1 mg, 1.5 eq), 21.0 μL of tert-amyl alcohol (2.0 eq), and 0.9 mL of toluene were added. The clear solution containing the copper ligand was then added to this Schlenk tube. The tube was sealed and removed from the glove box. The reaction was allowed to proceed at room temperature with stirring until the starting material disappeared. After the reaction was complete, the reaction solution was filtered through silica gel, the solvent was evaporated under vacuum, and the solution was filtered through a silica gel column (PE:EA = 20:1-10:1) to obtain the target product 2j.

[0119] The product test data are as follows: white solid, yield 71%, ee = 93%.

[0120] 1 H NMR (400MHz, CDCl3) δ7.82–7.63(m,1H),7.71–7.64(m,1H),7.51–7.26(m,5H),7.37– 7.19(m,2H),7.24–7.17(m,1H),5.53–5.42(m,1H),1.52–1.43(m,2H),1.20(s,12H); 13 C NMR (100MHz, CDCl3) δ168.6,146.7,139.6,137.5,135.2,129.2,128.2,122.1,126.8,125.6,125.2,83.7,45.7,23.9,22.6.The boron-bound carbon was not detected dueto quadrupolarrelaxation; HRMS(ESI):m / z[M+H] + calcd for C 21 H 26 BClNO3 + :386.1689, found 386.1691; HPLC analysis: DAICEL CHIRALPAK IA-3, n-hexane / isopropanol=80:20, 1.0mL / min, wavelength=210nm, t R (minor) = 8.4min,t R(major)=17.8min,ee=93%.

[0121]

[0122]

[0123]

[0124]

[0125]

[0126] Implementation Case 11 uses 3-chloro-N-(1-phenylvinyl)benzamide and bis(pinacol)diboron as raw materials (reaction formula 11).

[0127]

[0128] In a glove box, CuCl (5.0 mol%, 0.5 mg), sodium tert-butoxide (0.15 mmol, 14.4 mg), and (S,S)-BDPP (10% mmol, 4.4 mg) were added to a dry 10 mL Schlenk tube. 0.6 mL of 1,4-dioxane was added and the mixture was stirred. The reaction was allowed to proceed for half an hour until the solution became clear. In another 10 mL Schlenk tube, 1k of the enamide substrate (0.1 mmol), B2pin2 (0.15 mmol, 38.1 mg, 1.5 eq), tert-amyl alcohol (21.0 μL, 2.0 eq), and 0.9 mL of toluene were added. The clear solution containing the copper ligand was then added to this Schlenk tube. The tube was sealed and removed from the glove box. The reaction was allowed to proceed at room temperature with stirring until the starting material disappeared. After the reaction was complete, the reaction mixture was filtered through silica gel, the solvent was evaporated under vacuum, and the solution was filtered through a silica gel column (PE:EA = 20:1-10:1) to obtain the target product 2k.

[0129] The product test data are as follows: white solid, yield 75%, ee = 94%.

[0130] 1 H NMR (400MHz, CDCl3) δ7.84–7.79(m,1H),7.75–7.73(m,1H),7.50–7.33(m,5H),7.33– 7.27(m,2H),7.25–7.17(m,1H),5.55–5.42(m,1H),1.58–1.50(m,2H),1.20(s,12H); 13C NMR (100MHz, CDCl3) δ164.6,143.4,136.6,134.5,131.2,129.8,128.4,127.1,127.0,126.0,125.2,83.7,49.7,24.8,24.6.The boron-bound carbon was not detected dueto quadrupolarrelaxation; HRMS(ESI):m / z[M+H] + calcd for C 21 H 26 BClNO3 + :386.1689, found 386.1680; HPLC analysis: DAICEL CHIRALPAK IA-3, n-hexane / isopropanol=80:20, 1.0mL / min, wavelength=210nm, t R (minor) = 6.5min,t R (major)=10.8min,ee=94%.

[0131]

[0132]

[0133]

[0134]

[0135] Implementation Case Twelve uses N-(1-(3-methoxyphenyl)vinyl)benzamide and bis(pinacol)diboron as raw materials (Reaction Formula 12).

[0136]

[0137] In a glove box, CuCl (5.0 mol%, 0.5 mg), sodium tert-butoxide (0.15 mmol, 14.4 mg), and (S,S)-BDPP (10% mmol, 4.4 mg) were added to a dry 10 mL Schlenk tube. 0.6 mL of 1,4-dioxane was added and the mixture was stirred. The reaction was allowed to proceed for half an hour until the solution became clear. In another 10 mL Schlenk tube, 1 μL of the enamide substrate (0.1 mmol), B2pin2 (0.15 mmol, 38.1 mg, 1.5 eq), tert-amyl alcohol (21.0 μL, 2.0 eq), and 0.9 mL of toluene were added. The clear solution containing the copper ligand was then added to this Schlenk tube. The tube was sealed and removed from the glove box. The reaction was allowed to proceed at room temperature with stirring until the starting material disappeared. After the reaction was complete, the reaction solution was filtered through silica gel, the solvent was evaporated under vacuum, and the solution was filtered through a silica gel column (PE:EA = 20:1-10:1) to obtain 2 μL of the target product.

[0138] Product test data are as follows: white solid, yield 67%, ee = 90%.

[0139] 1 H NMR (600MHz, CDCl3) δ7.84(d,J=7.9Hz,2H),7.55–7.47(m,1H),7.46–7.39(m,1H),7.31(d,J=8.4Hz,1H),7.28–7.19(m,1H ),6.96(d,J=6.0Hz,1H),6.92(s,1H),6.80–6.70(m,1H),5.53–5.44(m,1H),3.78(s,3H),1.58–1.48(m,2H),1.19(s,12H); 13 C NMR (151MHz, CDCl3) δ166.0,159.6,145.4,134.7,131.2,129.4,128.4,126.9, 118.3,112.3,112.1,83.6,55.1,49.6,24.9,24.6,19.1; HRMS(ESI):m / z[M+H] + calcd for C 22 H 29 BNO4 + :382.2184, found382.2171; HPLC analysis: DAICEL CHIRALPAK IA-3, n-hexane / isopropanol=85:15, 1.0mL / min, wavelength=210nm, t R (minor) = 7.7min,t R(major)=11.3min,ee=90%.

[0140]

[0141]

[0142]

[0143]

[0144] Implementation Case Thirteen uses N-(1-(2-fluorophenyl)vinyl)benzamide and bis(pinacol)diboron as raw materials (Reaction Formula 13).

[0145]

[0146] In a glove box, CuCl (5.0 mol%, 0.5 mg), sodium tert-butoxide (0.15 mmol, 14.4 mg), and (S,S)-BDPP (10% mmol, 4.4 mg) were added to a dry 10 mL Schlenk tube. 0.6 mL of 1,4-dioxane was added and the mixture was stirred. The reaction was allowed to proceed for half an hour until the solution became clear. In another 10 mL Schlenk tube, 1 mM of the enamide substrate (0.1 mmol), B2pin2 (0.15 mmol, 38.1 mg, 1.5 eq), tert-amyl alcohol (21.0 μL, 2.0 eq), and 0.9 mL of toluene were added. The clear solution containing the copper ligand was then added to this Schlenk tube. The tube was sealed and removed from the glove box. The reaction was allowed to proceed at room temperature with stirring until the starting material disappeared. After the reaction was complete, the reaction solution was filtered through silica gel, the solvent was evaporated under vacuum, and the solution was filtered through a silica gel column (PE:EA = 20:1-10:1) to obtain the target product 2 mM.

[0147] The product test data are as follows: white solid. Yield: 42%, ee = 62%.

[0148] 1 H NMR(600MHz, CDCl3)δ7.83(d,J=7.0Hz,2H),7.52–7.47(m,1H),7.46–7.41(m,2H),7.40–7.31(m,2H) ,7.23–7.16(m,1H),7.09–6.98(m,2H),5.68–5.58(m,1H),1.61–1.51(m,1H),1.18(d,J=6.4Hz,12H); 13C NMR (151MHz, CDCl3) δ 165.9, 160.6 (d, J = 245.8Hz), 134.6, 131.4, 130.7 (d, J = 13.2Hz), 128.6 (d, J = 8.3Hz), 128.5, 12 8.1(d,J=4.7Hz),126.9,123.9(d,J=3.3Hz),115.8(d,J=21.8Hz),83.6,46.4,24.9,24.7,18.5; HRMS(ESI):m / z[M+H] + calcd for C 21 H 26 BFNO3 + :370.1984, found 370.1976; HPLC analysis: DAICELCHIRALPAK IA-3, n-hexane / isopropanol=85:15, 1.0mL / min, wavelength=210nm, t R (minor) = 6.6min,t R (major)=9.0min,ee=62%.

[0149]

[0150]

[0151]

[0152]

[0153] Implementation Case Fourteen uses N-(1-(4-fluorophenyl)vinyl)benzamide and bis(pinacol)diboron as raw materials (Reaction Formula 14)

[0154]

[0155] In a glove box, CuCl (5.0 mol%, 0.5 mg), sodium tert-butoxide (0.15 mmol, 14.4 mg), and (S,S)-BDPP (10% mmol, 4.4 mg) were added to a dry 10 mL Schlenk tube. 0.6 mL of 1,4-dioxane was added and the mixture was stirred. The reaction was allowed to proceed for half an hour until the solution became clear. In another 10 mL Schlenk tube, 1n (0.1 mmol), B2pin2 (0.15 mmol, 38.1 mg, 1.5 eq), tert-amyl alcohol (21.0 μL, 2.0 eq), and 0.9 mL of toluene were added. The clear solution containing the copper ligand was then added to this Schlenk tube. The tube was sealed and removed from the glove box. The reaction was allowed to proceed at room temperature with stirring until the starting material disappeared. After the reaction was complete, the reaction solution was filtered through silica gel, the solvent was evaporated under vacuum, and the solution was filtered through a silica gel column (PE:EA = 20:1-10:1) to obtain the target product 2n.

[0156] The product test data are as follows: white solid, yield 43%, ee = 90%.

[0157] 1 H NMR(600MHz, CDCl3)δ7.83(d,J=8.3Hz,2H),7.54–7.47(m,1H),7.47–7.41(m,2H),7.38–7.2 8(m,3H),7.00–6.94(m,2H),,5.56–5.41(m,1H),1.57–1.47(m,2H).,1.18(d,J=3.2Hz,12H); 13 C NMR(151MHz, CDCl3) δ166.1,161.8(d,J=245.0Hz),139.6(d,J=3.1Hz),134.6,131.4,128.5,127 .7(d,J=8.1Hz),126.9,115.1(d,J=21.3Hz),83.7,49.1,24.9,24.6,18.9; HRMS(ESI):m / z[M+H] + calcd for C 21 H 26 BFNO3 + :370.1984, found370.1981; HPLC analysis: DAICEL CHIRALPAK IA-3, n-hexane / isopropanol=85:15, 1.0mL / min, wavelength=210nm, t R (minor) = 7.0 min, t R (major)=16.0min,ee=90%.

[0158]

[0159]

[0160]

[0161]

[0162] Implementation Case 15 uses N-(1-(3-bromophenyl)vinyl)benzamide and bis(pinacol)diboron as raw materials (Reaction Formula 15).

[0163]

[0164] In a glove box, CuCl (5.0 mol%, 0.5 mg), sodium tert-butoxide (0.15 mmol, 14.4 mg), and (S,S)-BDPP (10% mmol, 4.4 mg) were added to a dry 10 mL Schlenk tube. 0.6 mL of 1,4-dioxane was added and the mixture was stirred. The reaction was allowed to proceed for half an hour until the solution became clear. In another 10 mL Schlenk tube, 0.1 mmol of enamide substrate 1o, 0.1 mmol of B2pin2 (0.15 mmol, 38.1 mg, 1.5 eq), 21.0 μL of tert-amyl alcohol (2.0 eq), and 0.9 mL of toluene were added. The clear solution containing the copper ligand was then added to this Schlenk tube. The tube was sealed and removed from the glove box. The reaction was allowed to proceed at room temperature with stirring until the starting material disappeared. After the reaction was complete, the reaction mixture was filtered through silica gel, the solvent was evaporated under vacuum, and the solution was filtered through a silica gel column (PE:EA = 20:1-10:1) to obtain the target product 2o.

[0165] The product test data are as follows: white solid, yield 62%, ee = 92%.

[0166] 1 H NMR(600MHz, CDCl3)δ7.84(d,J=7.0Hz,2H),7.54–7.48(m,2H),7.47–7.43(m,2H),7.43–7.39(m,1H),7.38 –7.33(m,1H),7.31–7.29(m,1H),7.21–7.15(m,H),5.50–5.41(m,1H),1.50(d,J=5.9Hz,2H),1.21(s,12H); 13C NMR (151MHz, CDCl3) δ166.1,146.3,134.5,131.5,130.0,129.1,128.6,126. 9,126.1,125.1,122.54,83.9,49.4,24.9,24.7,19.2; HRMS(ESI):m / z[M+H] + calcd for C 21 H 26 BBrNO3 + :430.1184, found 430.1180; HPLC analysis: DAICEL CHIRALPAK IA-3, n-hexane / isopropanol=85:15, 1.0mL / min, wavelength=210nm, t R (minor) = 6.4min,t R (major)=10.5min,ee=92%.

[0167]

[0168]

[0169]

[0170]

[0171] Implementation Case 16 uses N-(1-(4-bromophenyl)vinyl)benzamide and bis(pinacol)diboron as raw materials (reaction formula 16).

[0172]

[0173]

[0174] In a glove box, CuCl (5.0 mol%, 0.5 mg), sodium tert-butoxide (0.15 mmol, 14.4 mg), and (S,S)-BDPP (10% mmol, 4.4 mg) were added to a dry 10 mL Schlenk tube. 0.6 mL of 1,4-dioxane was added and the mixture was stirred. The reaction was allowed to proceed for half an hour until the solution became clear. In another 10 mL Schlenk tube, 1p of the enamide substrate (0.1 mmol), B2pin2 (0.15 mmol, 38.1 mg, 1.5 eq), tert-amyl alcohol (21.0 μL, 2.0 eq), and 0.9 mL of toluene were added. The clear solution containing the copper ligand was then added to this Schlenk tube. The tube was sealed and removed from the glove box. The reaction was allowed to proceed at room temperature with stirring until the starting material disappeared. After the reaction was complete, the reaction mixture was filtered through silica gel, the solvent was evaporated under vacuum, and the solution was filtered through a silica gel column (PE:EA = 20:1-10:1) to obtain the target product 2p.

[0175] The product test data are as follows: white solid, yield 72%, ee = 87%.

[0176] 1 H NMR (600MHz, CDCl3) δ7.77(d,J=8.5Hz,2H),7.40(d,J=8.5Hz,2H),7.38–7.27( m,5H),7.21–7.10(m,1H),5.54–5.43(m,1H),1.59–1.47(m,2H),1.18(s,12H); 13 C NMR (151MHz, CDCl3) δ165.0,143.5,137.5,133.2,128.7,128.42,128.35,127.1,126.1,83.7,49.8,24.9,24.6,18.8; HRMS (ESI): m / z[M+H] + calcd for C 21 H 26 BBrNO3 + :430.1184, found430.1176; HPLC analysis: DAICEL CHIRALPAK IA-3, n-hexane / isopropanol=85:15, 1.0mL / min, wavelength=210nm, t R (minor) = 8.1 min, t R (major)=17.0min,ee=87%.

[0177]

[0178]

[0179]

[0180]

[0181] Implementation Case 17 uses N-(1-(3-chlorophenyl)vinyl)benzamide and bis(pinacol)diboron as raw materials (Reaction Formula 17).

[0182]

[0183] In a glove box, CuCl (5.0 mol%, 0.5 mg), sodium tert-butoxide (0.15 mmol, 14.4 mg), and (S,S)-BDPP (10% mmol, 4.4 mg) were added to a dry 10 mL Schlenk tube. 0.6 mL of 1,4-dioxane was added and the mixture was stirred. The reaction was allowed to proceed for half an hour until the solution became clear. In another 10 mL Schlenk tube, enamide substrate 1q (0.1 mmol), B2pin2 (0.15 mmol, 38.1 mg, 1.5 eq), tert-amyl alcohol (21.0 μL, 2.0 eq), and 0.9 mL of toluene were added. The clear solution containing the copper ligand was then added to this Schlenk tube. The tube was sealed and removed from the glove box. The reaction was allowed to proceed at room temperature with stirring until the starting material disappeared. After the reaction was complete, the reaction mixture was filtered through silica gel, the solvent was evaporated under vacuum, and the solution was filtered through a silica gel column (PE:EA = 20:1-10:1) to obtain the target product 2q.

[0184] Product test data are as follows: white solid. Yield 64%, ee = 89%.

[0185] 1 H NMR(600MHz, CDCl3)δ7.84(d,J=7.0Hz,2H),7.56–7.48(m,1H),7.48–7.39(m,3H),7 .36(s,1H),7.27–7.16(m,3H),5.53–5.42(m,1H),1.54–1.46(m,2H),1.20(s,12H); 13 CNMR (151MHz, CDCl3) δ166.1,146.0,134.4,134.2,131.5,129.7,128.5,127 .1,126.9,126.2,124.5,83.8,49.4,24.9,24.6,19.2; HRMS(ESI):m / z[M+H] + calcd for C 21 H 26 BClNO3 +:386.1689, found 386.1675; HPLC analysis: DAICEL CHIRALPAK IA-3, n-hexane / isopropanol=85:15, 1.0mL / min, wavelength=210nm, t R (minor) = 6.4min,t R (major)=10.6min,ee=89%.

[0186]

[0187]

[0188]

[0189]

[0190] Implementation Case 18 uses N-(1-(4-chlorophenyl)vinyl)benzamide and bis(pinacol)diboron as raw materials (Reaction Formula 18).

[0191]

[0192] In a glove box, CuCl (5.0 mol%, 0.5 mg), sodium tert-butoxide (0.15 mmol, 14.4 mg), and (S,S)-BDPP (10% mmol, 4.4 mg) were added to a dry 10 mL Schlenk tube. 0.6 mL of 1,4-dioxane was added and the mixture was stirred. The reaction was allowed to proceed for half an hour until the solution became clear. In another 10 mL Schlenk tube, 1r of the enamide substrate (0.1 mmol), B2pin2 (0.15 mmol, 38.1 mg, 1.5 eq), tert-amyl alcohol (21.0 μL, 2.0 eq), and 0.9 mL of toluene were added. The clear solution containing the copper ligand was then added to this Schlenk tube. The tube was sealed and removed from the glove box. The reaction was allowed to proceed at room temperature with stirring until the starting material disappeared. After the reaction was complete, the reaction solution was filtered through silica gel, the solvent was evaporated under vacuum, and the solution was filtered through a silica gel column (PE:EA = 20:1-10:1) to obtain the target product 2r.

[0193] The product test data are as follows: white solid, yield 75%, ee = 95%.

[0194] 1H NMR (600MHz, CDCl3) δ7.83(d,J=6.9Hz,2H),7.54–7.48(m,1H),7.44(t,J=7.6Hz,2H),7.35(d,J=8.3Hz,1 H),7.31(d,J=8.5Hz,2H),7.28–7.24(m,2H),5.50–5.42(m,1H),1.56–1.46(m,2H),1.19(d,J=4.6Hz,1H); 13 C NMR (151MHz, CDCl3) δ166.12,142.38,134.49,132.65,131.45,128.53,128. 48,127.54,126.90,83.78,49.19,24.91,24.63,18.83; HRMS(ESI):m / z[M+H] + calcd for C 21 H 26 BClNO3 + :386.1689, found 386.1686; HPLC analysis: DAICEL CHIRALPAK IA-3, n-hexane / isopropanol=85:15, 1.0mL / min, wavelength=210nm, t R (minor) = 7.7min,t R (major)=20.4min,ee=95%.

[0195]

[0196]

[0197]

[0198]

[0199]

[0200] Implementation Case 19 uses N-(1-phenylvinyl)thiophene-2-carboxamide and bis(pinacolyl)diboron as raw materials (reaction formula 19).

[0201]

[0202] In a glove box, CuCl (5.0 mol%, 0.5 mg), sodium tert-butoxide (0.15 mmol, 14.4 mg), and (S,S)-BDPP (10% mmol, 4.4 mg) were added to a dry 10 mL Schlenk tube. 0.6 mL of 1,4-dioxane was added and the mixture was stirred. The reaction was allowed to proceed for half an hour until the solution became clear. In another 10 mL Schlenk tube, 1s of enamide substrate (0.1 mmol), B2pin2 (0.15 mmol, 38.1 mg, 1.5 eq), tert-amyl alcohol (21.0 μL, 2.0 eq), and 0.9 mL of toluene were added. The clear solution containing the copper ligand was then added to this Schlenk tube. The tube was sealed and removed from the glove box. The reaction was allowed to proceed at room temperature with stirring until the starting material disappeared. After the reaction was complete, the reaction solution was filtered through silica gel, the solvent was evaporated under vacuum, and the solution was filtered through a silica gel column (PE:EA = 20:1-10:1) to obtain the target product 2s.

[0203] The product test data are as follows: white solid, yield 57%, ee = 88%.

[0204] 1 H NMR (400MHz, CDCl3) δ7.59–7.47(m,2H),7.49–7.42(m,1H),7.40–7.36(m,2H),7.29(t,J=7.6Hz ,2H),7.24–7.20(m,1H),7.10–7.05(m,1H),5.59–5.38(m,1H),1.56–1.44(m,2H),1.19(s,12H); 13 C NMR (100MHz, CDCl3) δ160.8,143.5,129.7,129.0,128.4,127.5,127.0,126.7,126.1,83.7,49.60,24.9,24.7.The boron-bound carbon was notdetected due to toquadrupolar relaxation; HRMS(ESI):m / z[M+H] + calcd for C 19 H 25 BNO3S + :358.1643, found358.1643; HPLC analysis: DAICEL CHIRALPAK IA-3, n-hexane / isopropanol=85:15, 1.0mL / min, wavelength=210nm, t R (minor) = 7.0 min, t R(major)=10.3min,ee=88%。

[0205]

[0206]

[0207]

[0208]

[0209]

Claims

1. A method for synthesizing β-aminoboronic acid ester, characterized by using N-(1-phenylvinyl)benzamide compounds and pinacol boronic acid ester as substrates, cuprous chloride and (S,S)-BDPP as catalysts, sodium tert-butoxide as a base, and tert-amyl alcohol as an additive, to react at room temperature to obtain β-aminoboronic acid ester, as shown in the following reaction formula: in: R 1 Selected from methyl, methoxy, chloro, bromo, naphthalene, phenyl, tert-butyl, fluoro, trifluoromethyl, cyano, and ester groups; R 2 Selected from methyl, benzyl, methoxy, chloro, bromo, naphthalene, phenyl, tert-butyl, trifluoromethyl, cyano, and ester.

2. The method for synthesizing β-aminoboronic acid ester according to claim 1, characterized in that: The solvents used are selected from toluene, tetrahydrofuran, 1,4-dioxane, acetone, DMF, and acetonitrile.

3. The method for synthesizing β-aminoboronic acid ester according to claim 1, characterized in that: The solvent is toluene:1,4-dioxane = 1.5:1 volume ratio.

4. The method for synthesizing β-aminoboronic acid ester according to claim 1, characterized in that: The reaction time is 12 hours.

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