A method for synthesizing gamma-aminoboronic acid esters catalyzed by copper

Abstract

The present invention provides a method for synthesizing γ-amino borate by copper catalysis, using olefin or alkyne as reaction raw material, bis(pinacol) diboron (B2pin2) as boron source, N, O-aminal as amine methylation reagent, copper salt and phosphine ligand as catalyst, using N, O-aminal decomposed into methylene imine cation and methoxyl anion, successfully activate bis(pinacol) diboron, and capture intermediate organocopper reagent, prepare γ-amino borate compounds. The method does not use strong base, reaction conditions are mild, simple and easy, high yield, stable raw materials and easy to obtain. γ-amino borate in the present invention is an important intermediate for complex molecules such as synthetic drugs and natural products.

Description

Technical Field

[0001] The invention relates to a method for synthesizing gamma-amino borate ester catalyzed by copper, and belongs to the field of organic synthesis. Background Art

[0002] Copper-catalyzed carbon-carbon unsaturated bond borocarbylation is an important method for preparing organoboron compounds. The reaction usually starts with olefins or alkynes with a wide range of sources, variable structures and stable properties, using bis(pinacolato)diboron (B2pin2) as a boron source, copper salt as a catalyst, and electrophilic reagents to capture intermediate organocopper reagents to prepare functionalized organoboron ester compounds (SL Buchwald, Angew. Chem. Int. Ed., 2014, 53, 8677). ; MK Brown, Angew.Chem.Int.Ed., 2017, 56, 13314; H.Ito, Angew.Chem.Int.Ed., 2018, 57, 7196; M.L autens, Angew.Chem.Int.Ed., 2018, 130, 14123; DJ Procter, Angew.Chem.Int.Ed., 2020, 59, 4879).

[0003] N, O-aminal is an important class of amine methylation reagents. In recent years, synthetic chemists have successfully constructed β-aminal using N, O-aminal. 2 -Amino acid (the α position of the amino acid has a substituent). 2 -Amino acids are extremely valuable in natural products and medicinal chemistry, but are difficult to prepare using conventional methods. In the early days, Gellman used proline to catalyze the Mannich reaction of aldehydes and N, O-acetalamine as an amine methylation reagent to successfully prepare β 2 -amino acids (SH Gellman, J. Am. Chem. Soc., 2006, 128, 6804). Chi uses a combination of catalysts (azacarbene and Acid), α, β-unsaturated aldehyde was used as raw material to synthesize β 2 -amino acids (Y.Chi, Angew.Chem.Int.Ed., 2015, 54, 5161). Recently, the research groups of Xu, Huang and Sun used transition metal catalysts and diazo derivatives as raw materials to prepare α-alkoxy-β 2 -amino acid esters (X.Xu, J.Am.Chem.Soc., 2019, 141, 1473; H.Huang, Chem.Commun., 2019, 55, 3947; J.Sun, Org.Lett., 2019, 21, 1664).

[0004] N, O-aminal can generate highly active methyleneimine cations and alkoxy anions in situ. The imine cation is a good positively charged capture agent. At the same time, the alkoxy anion can activate B2pin2 (bis(pinacol)diboron), and the copper-catalyzed borocarbonization reaction of carbon-carbon unsaturated bonds can construct a γ-amino borate structure. The amino group and borate ester in γ-amino borate can be derivatized to form a variety of chemical bonds, such as γ-amino alcohol (C. Tao, Chem. Commun., 2020, 56, 7483), β-aminoaldehyde and β-amino acid (A. Córdova, Chem. Eur. J., 2007, 13, 683), which makes it important in the synthesis of complex molecules such as drugs and natural products.

[0005] The present invention uses olefins or alkynes as reaction raw materials, bis(pinacolato)diboron (B2pin2) as a boron source, N, O-aminal as an amine methylation reagent, copper salt and phosphine ligand as catalysts, utilizes methyleneimine cations and methoxyl anions decomposed from N, O-aminal to successfully activate bis(pinacolato)diboron, and captures an intermediate organic copper reagent to prepare a γ-amino borate ester compound. The method does not use a strong base, has mild reaction conditions, is simple and easy to operate, has a high yield, and has stable and easily available raw materials. Summary of the invention

[0006] The invention aims to provide a method for synthesizing gamma-aminoboric acid ester by copper catalysis: olefins or alkynes are used as reaction raw materials, bis(pinacol)diboron (B2pin2) is used as a boron source, N, O-aminal is used as an amine methylation reagent, copper salt and phosphine ligand are used as catalysts, methyleneimine cations and methoxyl anions decomposed from N, O-aminal are utilized to successfully activate bis(pinacol)diboron, capture an intermediate organic copper reagent, and synthesize gamma-aminoboric acid ester compounds.

[0007] To achieve the above-mentioned object of the invention, the present invention provides a method for copper-catalyzed synthesis of γ-aminoboronic acid esters, and the synthesis path thereof is as follows:

[0008]

[0009] The present invention provides a method for copper-catalyzed synthesis of γ-aminoboronic acid esters, the steps of which are as follows:

[0010] Add copper salt, phosphine ligand and bis(pinacol)diboron shown in general formula 2 to a dry Schlenk reaction tube, use Schlenk double-row tube to evacuate, introduce argon, repeat three times, add solvent, olefin or alkyne shown in general formula 1, and N, O-aminal shown in general formula 3 under the state of introducing argon, seal the reaction system, control the temperature of the reaction system at 20-30° C., stir and react for 36-48 hours, add ammonia water and ethyl acetate, stir for 30 minutes, extract and separate, dry the separated organic phase with anhydrous magnesium sulfate, remove magnesium sulfate, concentrate the obtained organic phase, and separate the concentrated liquid by silica gel column chromatography to obtain γ-aminoboric acid ester shown in general formula 4;

[0011] Where R in Formula 1 and Formula 4 1 , R 2 One selected from H, aryl and alkyl.

[0012] In the steps of the method, the copper salt is Cu(CH3CN)4PF6, Cu(CH3CN)4BF4, Cu(OAc)2, Cu(OTf)2.

[0013] In the steps of the method, the phosphine ligand is 2-(dicyclohexylphosphino)biphenyl (CyJohnPhos), triphenylphosphine (PPh3), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (XPhos), and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP).

[0014] In the steps of the method, the solvent is toluene, dichloromethane, tetrahydrofuran, 1,4-dioxane.

[0015] In the steps of the method, the molar ratio of olefin or alkyne 1: bis(pinacol)diboron 2: N,O-aminal amine 3: copper salt: phosphine ligand is 1.0: 1.5-3.0: 1.5-3.0: 0.1-0.2: 0.2-0.4. DETAILED DESCRIPTION

[0016] The following examples will help to understand the present invention, but they are not intended to limit the present invention.

[0017] Example 1: Preparation of 2-phenyl-3-(N,N-dibenzylamino)-1-propylboronic acid pinacol ester

[0018]

[0019] 76.5 mg (0.3 mmol) of bis(pinacolato)diboron, 9.5 mg (0.03 mmol) of Cu(CH3CN)4BF4 copper salt and 21.0 mg (0.06 mmol) of 2-(dicyclohexylphosphino)biphenyl (CyJohnPhos) ligand were added to a dry Schlenk reaction tube. The Schlenk double-row tube was used to evacuate the tube and introduce argon gas three times. While introducing argon gas, 1.0 mL of dichloromethane and 72.5 mg (0.3 mmol) N, O-acetalamine and 24uL (0.2mmol) styrene, seal the reaction system, control the temperature of the reaction system at 20-25°C, stir and react for 36 hours, add 0.5mL ammonia water and 15mL ethyl acetate, stir for 30 minutes, extract and separate, dry the separated organic phase with anhydrous magnesium sulfate, remove magnesium sulfate, concentrate the obtained organic phase, separate the concentrated solution with silica gel column chromatography, and obtain 2-phenyl-3-(N,N-dibenzylamino)-1-propylboronic acid pinacol ester with a yield of 65%; 1 H NMR (500MHz, CDCl3) δ=7.23-7.20 (m, 7H), 7.18-7.16 (m, 6H), 7.08 (d, J=7.1Hz, 2H), 3.59 (d, J=13.8Hz, 2H), 3.47 (d, J=13.8Hz, 2H), 3.20-3.15 (m, 1H ), 2.57 (dd, J=12.6, 8.2Hz, 1H), 2.49 (dd, J=12.6, 7.0Hz, 1H), 1.31 (dd, J=15.6, 6.4Hz, 1H), 1.05 (s, 6H), 1.04 (s, 6H), 0.96 (dd, J=15.7, 9.5Hz, 1H); 13 C NMR (126MHz, CDCl3) δ=145.87, 139.74, 128.83, 128.06, 128.00, 127.92, 126.63, 125.92, 82.94, 62.09, 58.44, 39.72, 24.72, 24.65, 17.05; 11 B NMR (128MHz, CDCl3) δ = 33.49; HRMS (ESI) m / z: calculated for [C 29 H 36 BNO2+H] + 442.2917, found 442.2916.

[0020] Example 2: Preparation of 2-(4-chlorophenyl)-3-(N,N-dibenzylamino)-1-propylboronic acid pinacol ester

[0021]

[0022] Add 102.0 mg (0.4 mmol) of bis(pinacolato)diboron, 15.0 mg (0.04 mmol) of Cu(CH3CN)4PF6 copper salt and 21.0 mg (0.08 mmol) of triphenylphosphine (PPh3) ligand to a dry Schlenk reaction tube, evacuate using a Schlenk double-row tube, and introduce argon gas, repeat three times, and add 1.0 mL of 1,4-dioxane, 145.0mg (0.6mmol) N, O-acetalamine and 24uL (0.2mmol) p-chlorostyrene, seal the reaction system, control the temperature of the reaction system at 25-30°C, stir and react for 36 hours, add 0.5mL ammonia water and 15mL ethyl acetate, stir for 30 minutes, extract and separate, dry the separated organic phase with anhydrous magnesium sulfate, remove magnesium sulfate, concentrate the obtained organic phase, separate the concentrated solution with silica gel column chromatography, and obtain 2-(4-chlorophenyl)-3-(N,N-dibenzylamino)-1-propylboronic acid pinacol ester with a yield of 45%; 1 H NMR (500MHz, CDCl3) δ = 7.22-7.12 (m, 12H), 6.96 (d, J = 8.4Hz, 2H), 3.64 (d, J = 13.7Hz, 2H), 3.37 (d, J = 13.7Hz, 2H), 3.21-3.07 (m, 1H), 2 .55 (dd, J=12.6, 9.0Hz, 1H), 2.45 (dd, J=12.7, 6.2Hz, 1H), 1.25-1.18 (m, 1H), 1.07 (s, 6H), 1.05 (s, 6H), 0.91 (dd, J=15.6, 9.5Hz, 1H); 13 C NMR (126MHz, CDCl3) δ=144.56, 139.58, 131.41, 129.38, 128.82, 128.12, 127.95, 126.76, 83.08, 61.94, 58.57, 39.23, 24.78, 24.72, 17.14; 11 B NMR (128MHz, CDCl3) δ = 32.07; HRMS (ESI) m / z: calculated for [C 29 H 35 BClNO2+H] + 476.2522, found 476.2508.

[0023] Example 3: Preparation of 2-(3-chlorophenyl)-3-(N,N-dibenzylamino)-1-propylboronic acid pinacol ester

[0024]

[0025] To a dry Schlenk reaction tube, 153 mg (0.6 mmol) of bis(pinacolato)diboron, 8.0 mg (0.04 mmol) of Cu(OAc)2 copper salt and 25.0 mg (0.04 mmol) of 2,2′-bis(diphenylphosphine)-1,1′-binaphthyl (BINAP) ligand were added. The Schlenk double-row tube was used to evacuate the tube and introduce argon gas. This was repeated three times. While introducing argon gas, 1.0 mL of tetrahydrofuran and 97.0 mg (0.4 mmol) of N, O-aminal and 26uL (0.2mmol) of m-chlorostyrene, seal the reaction system, control the temperature of the reaction system at 20-25°C, stir and react for 36 hours, add 0.5mL of ammonia water and 15mL of ethyl acetate, stir for 30 minutes, extract and separate, dry the separated organic phase with anhydrous magnesium sulfate, remove magnesium sulfate, concentrate the obtained organic phase, separate the concentrated solution with silica gel column chromatography, and obtain 2-(3-chlorophenyl)-3-(N,N-dibenzylamino)-1-propylboronic acid pinacol ester with a yield of 55%; 1 H NMR (500MHz, CDCl3) δ=δ7.24-7.12 (m, 12H), 7.04 (s, 1H), 6.93 (d, J=6.7Hz, 1H), 3.66 (d, J=13.7Hz, 2H), 3.38 (d, J=13.7Hz, 2H), 3.29-3.013 ( m, 1H), 2.58 (dd, J=12.5, 9.1Hz, 1H), 2.47 (dd, J=12.7, 6.2Hz, 1H), 1.25-1.20 (m, 1H), 1.08 (s, 1H), 1.07 (s, 1H), 0.92 (dd, J=15.6, 9.5Hz, 1H); 13 C NMR (126MHz, CDCl3) δ=δ148.05, 139.50, 133.60, 129.09, 128.75, 128.23, 128. 09, 126.72, 126.20, 125.98, 83.06, 61.56, 58.49, 39.53, 24.71, 24.64, 17.10; 11 B NMR (128MHz, CDCl3) δ = 32.92; HRMS (ESI) m / z: calculated for [C 29 H 35 BClNO2+H] + 476.2522, found 476.2507.

[0026] Example 4: Preparation of 2-(2-chlorophenyl)-3-(N,N-dibenzylamino)-1-propylboronic acid pinacol ester

[0027]

[0028] To a dry Schlenk reaction tube, 76.5 mg (0.3 mmol) of bis(pinacol)diboron, 11.0 mg (0.03 mmol) of Cu(OTf)2 copper salt and 28.5 mg (0.06 mmol) of 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (XPhos) ligand were added. The Schlenk double-row tube was used to evacuate the tube and introduce argon gas. This was repeated three times. While introducing argon gas, 1.0 mL of toluene and 72.5 mg (0.3 mmol) of N, O-aminal and 26uL (0.2mmol) o-chlorostyrene, seal the reaction system, control the temperature of the reaction system at 25-30°C, stir and react for 36 hours, add 0.5mL ammonia water and 15mL ethyl acetate, stir for 30 minutes, extract and separate, dry the separated organic phase with anhydrous magnesium sulfate, remove magnesium sulfate, concentrate the obtained organic phase, separate the concentrated solution with silica gel column chromatography, and obtain 2-(2-chlorophenyl)-3-(N, N-dibenzylamino)-1-propylboronic acid pinacol ester with a yield of 55%; 1 H NMR (500MHz, CDCl3) δ = 7.32-7.31 (m, 1H), 7.25-7.15 (m, 10H), 7.10-7.04 (m, 2H ), 6.96-6.90 (m, 1H), 3.91-3.77 (m, 1H), 3.59 (d, J = 13.7Hz, 2H), 3.51 (d, J = 13. 7Hz, 2H),, 2.61 (dd, J=12.4, 7.9Hz, 1H), 2.45 (dd, J=12.6, 7.2Hz, 1H), 1.36 (dd , J=15.5, 6.0Hz, 1H), 1.06 (s, 6H), 1.02 (s, 6H), 0.96 (dd, J=15.4, 10.0Hz, 1H); 13 C NMR (126MHz, CDCl3) δ=δ143.13, 139.69, 134.20, 129.05, 128.92, 128.52, 128.01, 126.84, 126.62, 82.97, 61.18, 58.50, 35.07, 24.65, 24.52, 16.31; 11 B NMR (128MHz, CDCl3) δ = 33.52; HRMS (ESI) m / z: calculated for [C 29 H 35 BClNO2+H] + 476.2522, found 476.2506.

[0029] Example 5: Preparation of 3-(N,N-dibenzylamino)methylbicyclo[2.2.1]heptyl-2-boronic acid pinacol ester

[0030]

[0031] 19 mg (0.2 mmol) norbornene, 102.0 mg (0.4 mmol) bis(pinacol)diboron, 11.5 mg (0.03 mmol) Cu(CH3CN)4PF6 copper salt and 25.0 mg (0.06 mmol) 2-dicyclohexylphosphine-2′,6′-dimethoxybiphenyl (SPhos) ligand were added to a dry Schlenk reaction tube. The Schlenk double-row tube was used to evacuate the tube and introduce argon gas. This was repeated three times. While introducing argon gas, 1. 0mL toluene and 97.0mg (0.4mmol) N, O-aminal, seal the reaction system, control the temperature of the reaction system at 25-30°C, stir and react for 36 hours, add 0.5mL ammonia water and 15mL ethyl acetate, stir for 30 minutes, extract and separate, dry the separated organic phase with anhydrous magnesium sulfate, remove magnesium sulfate, concentrate the obtained organic phase, separate the concentrated solution with silica gel column chromatography, and obtain 3-(N, N-dibenzylamino)methyl bicyclo[2.2.1]heptyl-2-boronic acid pinacol ester with a yield of 45%; 1 HNMR (500MHz, CDCl3) δ=7.35 (d, J=7.3Hz, 4H), 7.29 (t, J=7.5Hz, 4H), 7.21 (t, J=7.2Hz, 2H), 3.8 1 (d, J=13.7Hz, 2H), 3.21 (d, J=13.7Hz, 2H), 2.41 (d, J=3.5Hz, 1H), 2.35-2.30 (m, 1H), 2.16 (dd, J=12.2, 5.2Hz, 1H), 2.11 (d, J=2.4Hz, 1H), 1.99-1.94 (m, 1H), 1.54-1.44 (m, 2H), 1.23-1.22 (m, 1H), 1.17(s, 6H), 1.13(s, 6H), 1.11-1.07(m, 2H), 1.01(d, J=8.6Hz, 1H), 0.94(d, J=9.8Hz, 1H); 13 C NMR (126MHz, CDCl3) δ=139.83, 129.01, 128.03, 126.67, 82.70, 58.15, 57.39, 43.28, 38.96, 38.57, 34.80, 31.73, 29.93, 25.05, 24.80; 11 BNMR (128MHz, CDCl3) δ = 34.29; HRMS (ESI) m / z: calculated for [C28 H 38 BNO2+H] + 432.3068, found 432.3052.

[0032] Example 6: Preparation of (E)-1,2-diphenyl-3-(N,N-dibenzylamino)-1-propenylboronic acid pinacol ester

[0033]

[0034] 36 mg (0.2 mmol) of diphenylacetylene, 102.0 mg (0.4 mmol) of bis(pinacol)diboron, 8.0 mg (0.04 mmol) of Cu(OAc)2 copper salt and 25.0 mg (0.04 mmol) of 2,2′-bis(diphenylphosphine)-1,1′-binaphthyl (BINAP) ligand were added to a dry Schlenk reaction tube. The tube was evacuated using a Schlenk double row tube and argon was introduced. This was repeated three times. While argon was introduced, 1.0 mL of tetrahydrofuran was added. furan and 97.0 mg (0.4 mmol) of N, O-aminal, the reaction system was sealed, the temperature of the reaction system was controlled at 25-30°C, and the reaction was stirred for 48 hours, then 0.5 mL of ammonia water and 15 mL of ethyl acetate were added, stirred for 30 minutes, and the liquid was separated by extraction. The separated organic phase was dried over anhydrous magnesium sulfate, and the magnesium sulfate was removed. The obtained organic phase was concentrated, and the concentrated solution was separated by silica gel column chromatography to obtain (E)-1,2-diphenyl-3-(N,N-dibenzylamino)-1-propenylboronic acid pinacol ester, with a yield of 51%; 1 HNMR (500MHz, CDCl3) δ = 7.21-7.18 (m, 6H), 7.12-7.11 (m, 4H), 7.09-7.03 (m, 5H) , 7.01-6.96(m, 3H), 6.72-6.71(m, 2H), 3.71(s, 4H), 3.61(s, 2H), 1.28(s, 12H); 13 C NMR (126MHz, CDCl3) δ=146.34, 141.06, 139.82, 138.23, 129.80, 129.35, 129.24 , 127.96, 127.48, 127.22, 127.02, 126.19, 125.38, 82.97, 59.88, 58.02, 25.46; 11 B NMR (128MHz, CDCl3) δ = 27.69; HRMS (ESI) m / z: calculated for [C 35 H 38 BNO2+H] + 516.3068, found 516.3055.

[0035] Example 7: Preparation of 3-phenyl-4-(N,N-dibenzylamino)-1-butenyl-2-boronic acid pinacol ester

[0036]

[0037] To a dry Schlenk reaction tube, 153 mg (0.6 mmol) of bis(pinacolato)diboron, 7.5 mg (0.02 mmol) of Cu(CH3CN)4PF6 and 14.0 mg (0.04 mmol) of 2-(dicyclohexylphosphino)biphenyl (CyJohnPhos) ligand were added. The Schlenk double-row tube was used to evacuate the tube and introduce argon gas. This was repeated three times. While introducing argon gas, 1.0 mL of dichloromethane and 72.5 mg (0.3 mmol) of N, O-aminal and 34 mg (0.2 mmol) of 1-phenylpropadiene were added to a sealed reaction system, and the temperature of the reaction system was controlled at 20-25°C. After stirring for 36 hours, 0.5 mL of ammonia water and 15 mL of ethyl acetate were added, and the mixture was stirred for 30 minutes. The separated organic phase was dried over anhydrous magnesium sulfate, and magnesium sulfate was removed. The obtained organic phase was concentrated, and the concentrated solution was separated by silica gel column chromatography to obtain 3-phenyl-4-(N, N-dibenzylamino)-1-butenyl-2-boric acid pinacol ester with a yield of 68%; 1 H NMR (500MHz, CDCl3) δ = 7.24-7.14 (m, 13H), 7.10-7.06 (m, 2H), 5.81 (d, J = 2.5Hz, 1H), 5.48 (d, J = 1.6Hz, 1H), 3.8 7 (t, J=7.7Hz, 1H), 3.70 (d, J=13.8Hz, 2H), 3.40 (d, J=13.8Hz, 2H), 2.93-2.85 (m, 2H), 1.17 (s, 6H), 1.13 (s, 6H); 13 C NMR (126MHz, CDCl3) δ=143.11, 139.55, 129.07, 128.93, 128.78, 127.96, 127.78, 126.61, 125.80, 83.34, 58.07, 57.54, 48.53, 24.72, 24.63; 11 B NMR (128MHz, CDCl3) δ = 30.63; HRMS (ESI) m / z: calculated for [C 30 H 36 BNO2+H] + 454.2912, found 454.2901.

Claims

1. A method for copper-catalyzed synthesis of γ-aminoboronic acid esters, comprising the following steps: Add copper salt, phosphine ligand and bis(pinacol)diboron shown in general formula 2 to a dry Schlenk reaction tube, use Schlenk double-row tube to evacuate, introduce argon, repeat three times, add solvent, olefin or alkyne shown in general formula 1, and N,O-aminal shown in general formula 3 under the state of introducing argon, seal the reaction system, control the temperature of the reaction system at 20-30° C., stir and react for 36-48 hours, add ammonia water and ethyl acetate, stir for 30 minutes, extract and separate, dry the separated organic phase with anhydrous magnesium sulfate, remove magnesium sulfate, concentrate the obtained organic phase, and separate the concentrated liquid by silica gel column chromatography to obtain γ-aminoboric acid ester shown in general formula 4; The structure of general formula 1 is The structure of general formula 4 is The copper salt is selected from one of Cu(CH3CN)4PF6, Cu(CH3CN)4BF4, Cu(OAc)2 or Cu(OTf)2; The phosphine ligand is selected from one of 2-(dicyclohexylphosphino)biphenyl, triphenylphosphine, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl or 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; The solvent is selected from toluene, dichloromethane, tetrahydrofuran or 1,4-dioxane.

2. The method for synthesizing γ-aminoboronic acid esters catalyzed by copper according to claim 1, characterized in that The molar ratio of olefin or alkyne 1: bis(pinacol)diboron 2: N,O-aminal amine 3: copper salt: phosphine ligand is 1.0: 1.5-3.0: 1.5-3.0: 0.1-0.2: 0.2-0.4.

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