Synthesis of chiral 3,4-disubstituted amino pyridine catalysts and their application in black rearrangement

Abstract

The application discloses synthesis of chiral 3,4-disubstituted amino pyridine catalyst and application thereof in Black rearrangement. Chiral 3,4-disubstituted amino pyridine catalyst is obtained by using 3-bromo-4-substituted amino pyridine 1 and chiral proline amide 2 as raw materials, and by carrying out a reaction in an organic solvent under the presence of copper (I) salt and inorganic base and by heating. Meanwhile, the method can also be used for synthesizing chiral N-methyl imidazole catalyst. The catalyst can catalyze asymmetric Black rearrangement reaction of benzofuranone carbonate, and the yield and enantioselectivity are good, and the product is 3,3'-disubstituted 2-benzofuranone which is widely used.

Description

Technical Field

[0001] This invention relates to methods for synthesizing chiral catalysts and their applications, specifically to the synthesis of chiral 3,4-disubstituted aminopyridine catalysts and their application in the Black rearrangement, belonging to the field of asymmetric synthesis in organic chemistry. Background Technology

[0002] Over the past two decades, chiral DMAP catalysts have played a crucial role in asymmetric catalysis. In 2012, Vincent Levacher's group first reported the Pd-catalyzed Buchwald-Hartwig cross-coupling reaction of 3-bromo-DMAP with amines. This reaction is sensitive to steric hindrance of the amines, with only primary amines being suitable substrates. For secondary amines with even greater steric hindrance, only pyrrolidines can react, but in only 50% yield; pyrrolidines with substituents at the C-2 position cannot react under these conditions (Tetrahedron Lett. 2012, 53, 3284.).

[0003] In 2019, Guo Haiming's research group reported that 3-bromo-4-nitropyridine N-oxygen undergoes nucleophilic substitution with L-prolylamide, followed by a three-step transformation of the coupling product to generate a chiral DMAP catalyst. Due to the numerous steps and low yield of this synthetic route, it is not suitable for large-scale synthesis and research (Angew. Chem., Int. Ed. 2019, 58, 2839.).

[0004] Therefore, it is still necessary to develop a simple synthetic method for chiral DMAP catalysts to obtain a series of catalysts for fine-tuning in more rearrangement reactions. Summary of the Invention

[0005] To address the aforementioned shortcomings of existing technologies, this invention provides an improved synthetic method for chiral 3,4-disubstituted aminopyridine catalysts and their application in the Black rearrangement. A C-3 amino-substituted chiral DMAP-like catalyst was synthesized in one step via a copper-catalyzed CN-bond cross-coupling reaction of 3-bromo-4-substituted aminopyridine and chiral prolylamide. This catalyst was then applied to the asymmetric Black rearrangement reaction of benzofuranone carbonates, resulting in the efficient synthesis of a series of optically active benzofuranone compounds.

[0006] The method for synthesizing the chiral 3,4-disubstituted aminopyridine catalyst of the present invention includes the following steps: using 3-bromo-4-substituted aminopyridine 1 and chiral proline amide 2 as raw materials, the reaction is carried out in an organic solvent in the presence of copper (I) salt and inorganic base, and the reaction is carried out at elevated temperature to obtain the chiral 3,4-disubstituted aminopyridine catalyst. The reaction equation is as follows:

[0007]

[0008] Among them: NR 1 R 1 Selected from dimethylamino, pyrrolidinyl, hexamethyleneamino, or morpholinyl; R 2 Selected from phenyl, substituted phenyl, wherein the substituent in the substituted phenyl is a C1-C4 alkyl or halogen.

[0009] Furthermore, in the above technical solution, the copper (I) salt is selected from CuI, CuBr, CuCl or Cu2O.

[0010] Furthermore, in the above technical solution, the inorganic base is selected from K2CO3, Na2CO3, K3PO4, Na3PO4 or Cs2CO3.

[0011] Furthermore, in the above technical solution, the organic solvent is selected from alcohol solvents; the reaction temperature is 50-100℃.

[0012] The present invention also provides the application of the above-mentioned chiral 3,4-disubstituted aminopyridine catalyst in the Black rearrangement.

[0013] Furthermore, in the above technical solution, the Black rearrangement is a reaction of 3-substituted benzofuranone carbonate in an organic solvent in the presence of a chiral 3,4-disubstituted aminopyridine catalyst to yield the product C-acylbenzofuranone. The reaction equation is as follows:

[0014]

[0015] Where: R 3 Selected from C1-C4 alkyl, 3-chloropropyl, methoxymethyl, allyl, benzyl, or phenyl; R 4 It is selected from C1-C4 alkyl, phenyl, benzyl or trichloromethyl tert-butyl.

[0016] Furthermore, in the above technical solution, the organic solvent is dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, toluene, mesitylene, fluorobenzene, chlorobenzene, or trifluorotoluene.

[0017] Furthermore, in the above technical solution, the molar ratio of the 3,4-disubstituted aminopyridine catalyst to the 3-substituted benzofuranone carbonate is 0.02-0.20:1.

[0018] Furthermore, in the above technical solution, the reaction temperature is between -78°C and 25°C. Preferably, the reaction temperature is -78°C.

[0019] Beneficial effects of the invention:

[0020] 1. This invention utilizes copper-catalyzed CN-bond cross-coupling conditions to obtain a chiral DMAP catalyst from 3-bromoDMAP and prolineamide in a single-step reaction. To demonstrate the practicality of this catalyst structure, it was used to catalyze the rearrangement of benzofuranone carbonates to construct a quaternary carbon stereocenter.

[0021] 2. The catalyst of this invention has readily available raw materials, rich product structure, and high catalytic activity. It also provides a simple, inexpensive, and efficient synthetic method for the preparation of C-acylbenzofuranone. When applied to rearrangement reaction, the product has high stereoselectivity and chiral C-acylbenzofuranone compound is obtained after the reaction. The yield can reach up to 96% and the ee value can reach up to 97%. Detailed Implementation

[0022] Example 1: Synthesis of chiral 4-dimethylamino-3-(2-(2,6-diisopropylbenzoamido)pyrrolidinyl)pyridine

[0023]

[0024] In a 25 mL Schlenk tube, L-2-(2,6-diisopropylbenzoamide)pyrrolidine (274 mg, 1 mmol), potassium phosphate (425 mg, 2 mmol), 3-bromo-4-dimethylaminopyridine (300 mg, 1.5 mmol), cuprous iodide (19 mg, 0.1 mmol), and anhydrous ethanol (8 mL) were added sequentially. After purging with nitrogen three times, the mixture was heated to 80 °C and stirred for 16 hours. The crude product was separated by column chromatography to obtain 358.8 mg of bright yellow solid, with a yield of 91% and an ee of >99%. HPLC CHIRALCEL IA, n-hexane / 2-propanol = 70 / 30, flow rate = 0.8 mL / min, λ = 250 nm, retention time: 5.778 min (minor), 12.605 min (major). 1 H NMR (400MHz, CDCl3) δ8.49 (s, 1H), 8.24–7.87 (m, 2H), 7.21 (t, J = 8.0Hz, 1H), 7.07 ( d,J=8.0Hz,2H),6.80(d,J=6.0Hz,1H),4.63(t,J=7.2Hz,1H),3.84(dt,J=9.6,6.8H z,1H),2.98–2.92(m,1H),2.90(s,6H),2.73(br,2H),2.57–2.42(m,1H),2.32–2.17 (m,1H),2.15–2.05(m,1H),2.04–1.90(m,1H),1.06(d,J=6.8Hz,6H),0.96(br,6H). 13C NMR (151MHz, CDCl3) δ172.6,152.5,146.3,142.5,139.3,136.4,131.0,128.4,123.4,112.5,63.3,51.8,41.1,31.0,28.7,24.4,23.6.

[0025] Results of the synthesis of chiral 4-dimethylamino-3-(2-(2,6-diisopropylbenzoamido)pyrrolidinyl)pyridine

[0026]

[0027]

[0028] a Unless otherwise specified, the reaction proceeds as follows: 3-bromo-4-dimethylamino group (1.5 eq), base (2 eq), b Separation yield.

[0029] Example 2: Synthesis of chiral 4-pyrrolidinyl-3-(2-(2,6-diisopropylbenzoamido)pyrrolidinyl)pyridine

[0030]

[0031] In a 25 mL Schlenk tube, L-2-(2,6-diisopropylbenzamido)pyrrolidine (274 mg, 1 mmol), potassium phosphate (425 mg, 2 mmol), 3-bromo-4-pyrrolylpyridine (339 mg, 1.5 mmol), cuprous iodide (19 mg, 0.1 mmol), and anhydrous ethanol (8 mL) were added sequentially. After purging with nitrogen three times, the mixture was stirred at 80 °C for 16 hours. The crude product was separated by column chromatography to obtain 344.6 mg of white solid, yield 82%, >99% ee. HPLC CHIRALCEL OCH, n-hexane / 2-propanol=85 / 15, flow rate=1.0 mL / min, λ=250 nm, retention time: 10.175 min (major), 34.440 min (minor). 1H NMR (400MHz, CDCl3) δ8.49 (s, 1H), 8.24–7.87 (m, 2H), 7.21 (t, J = 8.0Hz, 1H), 7.07 ( d,J=8.0Hz,2H),6.80(d,J=6.0Hz,1H),4.63(t,J=7.2Hz,1H),3.84(dt,J=9.6,6.8H z,1H),2.98–2.92(m,1H),2.90(s,6H),2.73(br,2H),2.57–2.42(m,1H),2.32–2.17 (m,1H),2.15–2.05(m,1H),2.04–1.90(m,1H),1.06(d,J=6.8Hz,6H),0.96(br,6H). 13 C NMR (151MHz, CDCl3) δ172.6,152.5,146.3,142.5,139.3,136.4,131.0,128.4,123.4,112.5,63.3,51.8,41.1,31.0,28.7,24.4,23.6.

[0032] Example 3: Synthesis of chiral 4-hexamethyleneamino-3-(2-(2,6-diisopropylbenzoamido)pyrrolidinyl)pyridine

[0033]

[0034] In a 25 mL Schlenk tube, L-2-(2,6-diisopropylbenzamido)pyrrolidine (274 mg, 1 mmol), potassium phosphate (425 mg, 2 mmol), 3-bromo-4-hexamethyleneaminopyridine (381 mg, 1.5 mmol), cuprous iodide (19 mg, 0.1 mmol), and anhydrous ethanol (8 mL) were added sequentially. After purging with nitrogen three times, the mixture was stirred at 80 °C for 16 hours. The crude product was separated by column chromatography to obtain 349.8 mg of white solid, with a yield of 78%. 1 H NMR (400MHz, CDCl3) δ8.34 (s, 1H), 8.15 (m, 1H), 7.95 (s, 1H), 7.23 (t, J = 8.0Hz, 1H),7.09(d,J=8.0Hz,2H),6.86(d,J=5.2Hz,1H),4.37(t,J=7.6Hz,1H),3.87– 3.73(m,1H),3.55–3.35(m,4H),2.89(dt,J=10.0,7.2Hz,1H),2.63–2.52(m,1H ),2.27–2.13(m,1H),2.12–1.85(m,4H),1.79–1.52(m,8H),1.17–0.73(m,12H).13 CNMR(101MHz,CDCl3)δ172.6,152.5,146.4,145.5,143.0,136.2,130.8,1 28.4,123.4,114.1,65.4,53.3,52.5,31.1,28.7,27.2,24.2,23.7,23.4.

[0035] Example 4: Synthesis of chiral 4-morpholino-3-(2-(2,6-diisopropylbenzoamido)pyrrolidinyl)pyridine

[0036] In a 25 mL Schlenk tube, L-2-(2,6-diisopropylbenzamido)pyrrolidine (274 mg, 1 mmol), potassium phosphate (425 mg, 2 mmol), 3-bromo-4-morpholinylpyridine (363 mg, 1.5 mmol), cuprous iodide (19 mg, 0.1 mmol), and anhydrous ethanol (8 mL) were added sequentially. After purging with nitrogen three times, the mixture was stirred at 80 °C for 16 hours. The crude product was separated by column chromatography to obtain 362.2 mg of bright yellow solid, with a yield of 83%.

[0037]

[0038] 1 H NMR (400MHz, CDCl3) δ8.36(s,1H),8.23(d,J=5.2Hz,1H),7.54(s,1H),7.23(t,J=7.6Hz,1H),7.09(d, J=7.6Hz,2H),6.85(d,J=5.2Hz,1H),4.57(t,J=7.6Hz,1H),4.00(dt,J=10.0,6.8Hz,1H),3.92–3.77( m,4H),3.36(ddd,J=11.6,6.4,3.2Hz,2H),3.18–3.07(m,1H),2.94–2.82(m,2H),2.64(br,1H),2.60– 2.50(m,1H),2.30–2.19(m,1H),2.16–1.97(m,2H),1.80(br,1H),1.06(d,J=6.8Hz,6H),0.96(br,6H). 13 C NMR (101MHz, CDCl3) δ172.4,150.0,146.3,145.1,141.6,137.1,130.5,128.6,123.5,113.2,66.9,63.9,52.2,49.6,31.1,28.7,24.4,23.5.

[0039] Example 5: Synthesis of chiral 5-bromo-4-pyrrolidinyl-3-(2-(2,6-diisopropylbenzoamido)pyrrolidinyl)pyridine

[0040]

[0041] In a 25 mL Schlenk tube, L-2-(2,6-diisopropylbenzamido)pyrrolidine (411 mg, 1.5 mmol), potassium phosphate (425 mg, 2 mmol), 3,5-dibromo-4-pyrrolylpyridine (304 mg, 1 mmol), cuprous iodide (19 mg, 0.1 mmol), and anhydrous ethanol (8 mL) were added sequentially. After purging with nitrogen three times, the mixture was stirred at 80 °C for 16 hours. The crude product was separated by column chromatography to obtain 363.7 mg of white solid, yield 73%, 99% ee. HPLC CHIRALCEL IA, n-hexane / 2-propanol=95 / 5, flow rate=0.8 mL / min, λ=250 nm, retention time: 13.415 min (minor), 28.328 min (major). 1 H NMR (600MHz, CDCl3) δ8.32(s,1H),8.23(s,1H),7.56(s,1H),7.23(t,J=7.8Hz,1H),7.10(d,J=7.8Hz,2H),4.43(t,J=7.8Hz,1H),3.83(dt,J=7.8 ,7.2Hz,1H),3.74–3.64(m,2H),3.08–2.95(m,3H),2.81–2.51(m,3H),2. 26–2.09(m,2H),2.08–1.92(m,5H),1.08(d,J=7.2Hz,6H),0.96(br,6H). 13 C NMR (101MHz, CDCl3) δ172.0,146.7,146.3,144.9,144.4,138.3,130.3,128.6,123.5,121.3,64.5,54.0,49.6,31.9,28.7,26.5,25.1,23.7,23.4.

[0042] Example 6: Synthesis of chiral 4-pyrrolidinyl-3-(2-(2,6-diethylbenzoamido)pyrrolidinyl)pyridine

[0043]

[0044] In a 25 mL Schlenk tube, L-2-(2,6-diethylbenzamido)pyrrolidine (246 mg, 1 mmol), potassium phosphate (425 mg, 2 mmol), 3-bromo-4-pyrrolylpyridine (339 mg, 1.5 mmol), cuprous iodide (19 mg, 0.1 mmol), and anhydrous ethanol (8 mL) were added sequentially. After purging with nitrogen three times, the mixture was stirred at 80 °C for 16 hours. The crude product was separated by column chromatography to obtain 329.6 mg of a bright yellow solid, with a yield of 84%. HPLC CHIRALCEL ODH, n-hexane / 2-propanol=80 / 20, flow rate=0.8 mL / min, λ=250 nm, retention time: 5.725 min (major), 7.832 min (minor). 1 H NMR (600MHz, CDCl3) δ8.35 (s, 1H), 8.14 (d, J = 5.4Hz, 1H), 8.05 (s, 1H), 7.16 (t, J = 7.2Hz ,1H),7.04(d,J=7.2Hz,2H),6.68(d,J=5.4Hz,1H),4.29(t,J=7.8,1H),3.73–3.65(m,1 H),3.48–3.37(m,2H),3.34–3.20(m,2H),2.81(dt,J=9.6,7.8Hz,1H),2.63–2.54(m,1H ),2.32(br,3H),2.26–2.18(m,1H),2.09–2.02(m,2H),1.93–1.88(m,5H),0.98(br,6H). 13 C NMR (151MHz, CDCl3) δ172.3,150.9,145.9,143.1,141.9,134.9,132.3,128.1,126.5,111.1,65.7,54.6,49.7,31.2,25.0,24.9,24.3,14.6.

[0045] Example 7 Synthesis of chiral 4-pyrrolidinyl-3-(2-(2,6-dimethylbenzoamido)pyrrolidinyl)pyridine

[0046]

[0047] In a 25 mL Schlenk tube, L-2-(2,6-dimethylbenzoamide)pyrrolidine (218 mg, 1 mmol), potassium phosphate (425 mg, 2 mmol), 3-bromo-4-pyrrolylpyridine (339 mg, 1.5 mmol), cuprous iodide (19 mg, 0.1 mmol), and anhydrous ethanol (8 mL) were added sequentially. After purging with nitrogen three times, the mixture was stirred at 80 °C for 16 hours. The crude product was separated by column chromatography to obtain 309.6 mg of a white solid, with a yield of 85% and an ee of 96%. HPLC CHIRALCEL ODH, n-hexane / 2-propanol=80 / 20, flow rate=0.8 mL / min, λ=250 nm, retention time: 7.763 min (major), 17.340 min (minor). 1 H NMR (600MHz, CDCl3) δ9.15 (s, 1H), 8.75 (s, 1H), 7.91 (d, J = 6.6Hz, 1H), 7.03 –6.85(m,3H),6.56(d,J=6.6Hz,1H),4.58(t,J=8.4Hz,1H),3.78–3.68(m,2H ),3.49–3.40(m,3H),2.66(q,J=8.4Hz,1H),2.47–2.37(m,1H),2.20–2.14(m ,1H),2.11–2.04(m,1H),2.03(s,6H),2.00–1.96(m,3H),1.91–1.84(m,2H). 13 C NMR (151MHz, CDCl3) δ171.1,153.2,135.5,134.1,133.3,128.1,127.1,109.4,64.7,55.4,50.4,30.3,25.3,23.7,18.6.

[0048] Example 8 Synthesis of chiral 4-pyrrolidinyl-3-(2-benzoamide-pyrrolidinyl)pyridine

[0049]

[0050] In a 25 mL Schlenk tube, L-2-phenylamidopyrrolidine (190 mg, 1 mmol), potassium phosphate (425 mg, 2 mmol), 3-bromo-4-pyrrolylpyridine (339 mg, 1.5 mmol), cuprous iodide (19 mg, 0.1 mmol), and anhydrous ethanol (8 mL) were added sequentially. After purging with nitrogen three times, the mixture was stirred at 80 °C for 16 hours. The crude product was separated by column chromatography to obtain 248.8 mg of white solid, yield 74%, 76% ee. HPLC CHIRALCEL IA n-hexane / 2-propanol=85 / 15, flow rate=1.0 mL / min, λ=250 nm, retention time: 20.588 min (minor), 34.248 min (major). 1 HNMR(600MHz, CDCl3)δ8.68(s,1H),8.32(s,1H),8.09(d,J=5.4Hz,1H),7.41(d,J=7.8Hz,2H),7.29–7.25(m,2H),7.06(t,J=7.8Hz,1H),6.67(d,J=6 .0Hz,1H),4.22(t,J=7.8Hz,1H),3.63–3.55(m,1H),3.52–3.42(m,4H),2. 95–2.82(m,1H),2.58–2.47(m,1H),2.27–2.18(m,1H),2.10–1.97(m,6H). 13 C NMR (101MHz, CDCl3) δ171.5,151.7,146.4,144.7,137.9,135.0,129.1,124.3,119.8,111.0,67.4,56.0,50.4,31.1,25.2,24.6.

[0051] Example 9: Synthesis of chiral 4-pyrrolidinyl-3-(2-(4-chlorobenzoamidopyrrolidinyl)pyridine

[0052]

[0053] In a 25 mL Schlenk tube, L-2-(4-chlorobenzamido)pyrrolidine (224 mg, 1 mmol), potassium phosphate (425 mg, 2 mmol), 3-bromo-4-pyrrolylpyridine (339 mg, 1.5 mmol), cuprous iodide (19 mg, 0.1 mmol), and anhydrous ethanol (8 mL) were added sequentially. After purging with nitrogen three times, the mixture was stirred at 80 °C for 16 hours. The crude product was separated by column chromatography to obtain 170.3 mg of bright yellow solid, with a yield of 46%. 1H NMR (400MHz, CDCl3) δ10.12(s,1H),8.70(s,1H),7.86(d,J=6.8Hz,1H),7.64(d,J=8.4Hz,2H),7.17–7.03(m,2H),6.49(d,J=6.8Hz, 1H),4.59(br,1H),3.92(br,2H),3.56–3.39(m,2H),3.39–3.25(m,1H),2.64(q,J=8.0Hz,1H),2.28–2.28(m,1H),2.23–1.76(m,7H). 13 C NMR (151MHz, CDCl3) δ171.3,152.7,142.8,141.8,136.7,134.2,129.1,128.9,121.2,110.2,66.5,56.1,50.5,30.7,25.4,24.3.

[0054] Example 10 Synthesis of chiral 4-pyrrolidinyl-2-(2-(2,6-diisopropylbenzoamido)pyrrolidinyl)pyridine

[0055]

[0056] In a 25 mL Schlenk tube, L-2-(2,6-diisopropylbenzamido)pyrrolidine (274 mg, 1 mmol), potassium phosphate (425 mg, 2 mmol), 2-bromo-4-pyrrolylpyridine (339 mg, 1.5 mmol), cuprous iodide (19 mg, 0.1 mmol), and anhydrous ethanol (8 mL) were added sequentially. After purging with nitrogen three times, the mixture was stirred at 80 °C for 16 hours. The crude product was separated by column chromatography to obtain 294.0 mg of white solid, with a yield of 70%. 1 H NMR (600MHz, CDCl3) δ8.77(s,1H),7.83(d,J=6.0Hz,1H),7.22(t,J=7.8Hz,1H),7.11( d,J=7.8Hz,2H),5.97(dd,J=6.0,2.4Hz,1H),5.54(d,J=1.8Hz,1H),4.76(s,1H),3.79- 3.63(m,1H),3.48-3.38(m,1H),3.36-3.25(m,4H),3.13-2.94(m,2H),2.58-2.46(m,1 H),2.22-2.07(m,3H),2.03-1.96(m,4H),1.13(d,J=7.2Hz,6H),1.08(d,J=7.2Hz,6H). 13C NMR (151MHz, CDCl3) δ173.1,153.6,147.6,146.2,131.7,127.9,123.3,100.0,88.1,62.0,48.5,47.2,28.7,25.4,24.8,23.7,23.6.

[0057] Example 11 Synthesis of chiral 1-methyl-2-(2-(2,6-diisopropylbenzoamido)pyrrolidinyl)imidazolium

[0058]

[0059] In a 25 mL Schlenk tube, L-2-(2,6-diisopropylbenzamido)pyrrolidine (274 mg, 1 mmol), potassium phosphate (425 mg, 2 mmol), 2-bromo-1-methylimidazole (240 mg, 1.5 mmol), cuprous iodide (19 mg, 0.1 mmol), and anhydrous ethanol (8 mL) were added sequentially. After purging with nitrogen three times, the mixture was stirred at 80 °C for 16 hours. The crude product was separated by column chromatography to obtain 311.7 mg of a bright yellow solid, with a yield of 88%. 1 H NMR (600MHz, CDCl3) δ8.21 (s, 1H), 7.24 (t, J = 7.8Hz, 1H), 7.11 (d, J = 7.8Hz, 2H) ,6.76(d,J=1.2Hz,1H),6.64(d,J=1.2Hz,1H),4.86(t,=7.2Hz,1H),3.75(dt,J= 9.0,6.6Hz,1H),3.58(s,3H),3.32–3.24(m,1H),2.80(sept,J=6.6Hz,2H),2.4 3–2.30(m,2H),2.13–2.02(m,2H),1.10(d,J=6.6Hz,6H),1.07(d,J=6.6Hz,6H). 13 C NMR (151MHz, CDCl3) δ172.0,146.2,140.4,135.0,130.6,128.5,123.5,116.1,67.1,55.5,31.2,30.9,28.8,25.1,23.6.

[0060] Example 12 Synthesis of chiral 1-methyl-5-(2-(2,6-diisopropylbenzoamido)pyrrolidinyl)imidazolium

[0061]

[0062] In a 25 mL Schlenk tube, L-2-(2,6-diisopropylbenzamido)pyrrolidine (274 mg, 1 mmol), potassium phosphate (425 mg, 2 mmol), 5-bromo-1-methylimidazole (240 mg, 1.5 mmol), cuprous iodide (19 mg, 0.1 mmol), and anhydrous ethanol (8 mL) were added sequentially. After purging with nitrogen three times, the mixture was stirred at 80 °C for 16 hours. The crude product was separated by column chromatography to obtain 290.4 mg of bright yellow solid, with a yield of 82%.

[0063] Example 12 Synthesis of chiral-N-(2,6-diisopropylphenyl)-3-phenyl-2-((4-(pyrrolidin-1-yl)pyridin-3-yl)amino)propionamide

[0064]

[0065] In a 25 mL Schlenk tube, L-2-amino-N-(2,6-diisopropylphenyl)-3-phenylpropanamide (486 mg, 1.5 mmol), potassium phosphate (425 mg, 2 mmol), 3-bromo-4-pyrrolylpyridine (224 mg, 1 mmol), cuprous iodide (19 mg, 0.1 mmol), and anhydrous ethanol (8 mL) were added sequentially. After purging with nitrogen three times, the mixture was stirred at 80 °C for 16 hours. The crude product was separated by column chromatography to obtain 390.4 mg of bright yellow solid, with a yield of 83%. 1 H NMR(400MHz, CDCl3)δ8.55(s,1H),8.11(s,1H),7.92(s,1H),7.34–7.30(m,4H),7.29 –7.26(m,1H),7.25–7.22(m,1H),7.12(d,J=7.6Hz,2H),6.68(d,J=5.2Hz,1H),4.50– 4.34(m,2H),3.44(dd,J=9.6,4.4Hz,1H),3.26–3.15(m,3H),3.07–2.96(m,2H),2.82 (sept,J=6.8Hz,2H),1.98–1.83(m,4H),1.11(d,J=6.8Hz,6H),1.02(d,J=6.8Hz,6H). 13 C NMR (101MHz, CDCl3) δ172.0,146.1,145.4,142.1,136.9,135.4,134.7,130.8,12 9.5,129.0,128.4,127.4,123.5,111.5,60.6,50.3,39.2,28.7,24.8,23.7,23.7.

[0066] Example 13 Asymmetric Black rearrangement of 3-methylbenzofuran-2-benzyl carbonate

[0067] 3-Methylbenzofuranone benzyl carbonate (28.2 mg, 0.1 mmol) and toluene (1 mL) were added to a reaction tube and dissolved. The solution was then cooled to -78 °C. A chiral catalyst (0.01 mmol) was added to the solution and the mixture was stirred for 12 h. The reaction solution was then heated to room temperature, and the product 3-methylbenzofuran-2-benzyl carbonate was obtained by column chromatography. The reaction results are as follows:

[0068]

[0069]

[0070]

[0071]

[0072] a Unless otherwise specified, the reaction steps are as follows: catalyst (10 mol%), substrate concentration (0.1 mmol), solvent volume (1 mL); b Separation yield; c The ee value was separated by high performance liquid chromatography.

[0073] Example 14

[0074]

[0075] 28.2 mg (0.1 mmol) of 3-methylbenzofuranone benzyl carbonate and 1 mL of toluene were added to a reaction tube and dissolved. The solution was then cooled to -78 °C. Chiral catalyst a (4.2 mg (0.01 mmol)) was added to the solution and stirred for 12 h. The reaction solution was heated to room temperature and separated by column chromatography to obtain 26.5 mg of 3-methylbenzofuran-2-benzyl carbonate, yield 94%, 92% ee. HPLC CHIRALCEL IC, n-hexane / 2-propanol = 95 / 5, flow rate = 0.8 mL / min, λ = 256 nm, retention time: 14.798 min (major), 15.924 min (minor). 1H NMR(400MHz, CDCl3)δ7.36(td,J=8.0,1.6Hz,1H),7.32–7.27(m,3H),7.24(dd,J =8.0,1.6Hz,1H),7.20–7.08(m,4H),5.14(dd,J=17.6,12.8Hz,2H),1.79(s,3H).

[0076] Example 15

[0077]

[0078] 3-substituted benzofuranone carbonate (0.1 mmol) and toluene (1 mL) were added to a reaction tube and dissolved. The solution was then cooled to -78 °C. Chiral catalyst a (4.2 mg, 0.01 mmol) was added and the mixture was stirred for 12 h. The reaction solution was then heated to room temperature, and the product 3,3'-disubstituted-2-benzofuranone was obtained by column chromatography. The ee value of the product was obtained by chiral HPLC. The experimental results for different substitutions are as follows:

[0079]

[0080] a Unless otherwise specified, the reaction steps are as follows: catalyst a (10 mol%), substrate concentration (0.1 mmol), solvent volume (1.0 mL); b Separation yield; c The ee value was separated by high performance liquid chromatography.

[0081] Example 16

[0082]

[0083] 3-Methylbenzofuranone benzyl carbonate (35.0 mg, 0.1 mmol) and toluene (1 mL) were added to a reaction tube and dissolved. The solution was then cooled to -78 °C. Chiral catalyst a (4.2 mg, 0.01 mmol) was added to the solution and stirred for 12 h. The reaction solution was heated to room temperature and separated by column chromatography to obtain 33.2 mg of 3-methylbenzofuran-2-carbonate-β-trichloromethyl tert-butyl ester, yield 95%, 95% ee. HPLC CHIRALCELAY-RH, n-hexane / 2-propanol = 90 / 10, flow rate = 0.8 mL / min, λ = 256 nm, retention time: 6.951 min (minor), 7.767 min (major). 1H NMR (400MHz, CDCl3) δ7.41–7.28(m,2H),7.20–7.12(m,2H),1.88(s,3H),1.77(d,J=3.2Hz,6H).

[0084] Compared with existing technologies, the above method is a superior method for the synthesis of chiral 3,4-disubstituted aminopyridine catalysts and their derivatives, and for the preparation of chiral C-acylbenzofuranones. The catalysts are readily available and inexpensive, using inexpensive metals and requiring no additional ligands. A series of chiral aminopyridine and chiral aminoimidazolium catalysts were synthesized simply and efficiently, and were able to catalyze the asymmetric Black rearrangement reaction of benzofuranone carbonates, yielding 3,3'-disubstituted-2-benzofuranones with highly useful α-quaternary carbon chiral centers in high yields and with enantioselectivity.

[0085] The above embodiments describe the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the present invention. Various changes and modifications can be made to the present invention without departing from its principles, and all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing a chiral 3,4-disubstituted aminopyridine catalyst, characterized in that, The reaction includes the following steps: using 3-bromo-4-substituted aminopyridine 1 and chiral prolylamide 2 as raw materials, the reaction is carried out in an organic solvent in the presence of copper (I) salt and an inorganic base, and the reaction is heated to obtain a chiral 3,4-disubstituted aminopyridine catalyst; the reaction equation is as follows: ， Among them: NR 1 R 1 Selected from dimethylamino, pyrrolidinyl, or hexamethyleneamino; R 2 The copper(I) salt is selected from phenyl or substituted phenyl, wherein the substituent in the substituted phenyl is a C1-C4 alkyl group; the inorganic base is selected from CuI; the inorganic base is selected from K3PO4 or Cs2CO3; the organic solvent is anhydrous ethanol; and the reaction temperature is 80℃.

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