Preparation method of novel chiral bipyridine and application thereof in catalytic reaction

Abstract

The application belongs to the technical field of chemical industry and relates to a preparation method of a novel chiral bipyridine and application of the chiral bipyridine in catalytic reaction. Various benzyl bromides with 4,5-diazofluorene as a skeleton are reacted to generate a series of chiral bipyridine ligands, then under the participation of the ligands, indolines and quinoline nitrogen-containing heterocyclic compounds are reacted with pinacol diboronic acid under the catalysis of [IrOMe(COD)2] as a metal catalyst, and then a series of phenol compounds are obtained through oxidation of sodium perborate. The novel chiral bipyridine ligand developed by the method has the advantages of good site selectivity and excellent reaction yield without using strong acid and strong base in the process of C-H bond selective boronation.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of chemical industry and relates to a preparation method of a novel chiral bipyridine and application of the chiral bipyridine in a catalytic reaction. BACKGROUND

[0002] The specific C-H bond boronation reaction is one of the most important methods for preparing boron compounds. In recent years, a series of literatures or patents have reported methods for selectively boronizing C-H bonds of nitrogen-containing heterocyclic compounds (such as indolines and quinolines) (Lv, J., Chen, X., Xue, XS. et al. Nature 575, 336-340 (2019)). However, there are few relevant literatures reporting methods for selectively boronizing C-H bonds at the C4 position of an indoline and the C5 and C7 positions of a quinoline. How to achieve selective boronization of the relevant C-H bonds and improve the site selectivity of the reaction is the focus of our attention. Boron compounds can be easily converted into other groups through Suzuki coupling reaction and the like, and are a very important class of compounds, so it is of great significance to study the preparation method thereof. The application first synthesizes a series of novel chiral bipyridine ligands using binaphthyl as a skeleton, and then uses 2 mol% [IrOMe(COD)2] as a catalyst to react at 90 DEG C for 12-24 hours, so that monosubstituted boron compounds are obtained in a yield of 50%-95% and with excellent site selectivity (rr: > 30:1). Then, through oxidation by sodium perborate in a mixture of tetrahydrofuran and water, the relevant compounds are separated by stirring at room temperature for 2-4 hours and by converting the boron group into a hydroxyl group. SUMMARY

[0003] The application provides a preparation method of a chiral bipyridine ligand and a method for selectively boronizing C-H bonds of nitrogen-containing heterocyclic compounds catalyzed by iridium.

[0004] The technical scheme adopted by the application is as follows:

[0005] The application provides a preparation method of a chiral bipyridine ligand, which comprises the following steps: in an organic solvent, sodium hydride, cesium carbonate or sodium bis(trimethylsilyl)amide is used as an alkali, and various benzyl bromides I with binaphthyl as a basic skeleton are subjected to catalytic reaction with 4,5-diazofluorene II to prepare a series of novel chiral pyridine ligands.

[0006] The reaction formula is as follows:

[0007]

[0008] In the formula, Ar is H or an aryl group.

[0009] I is various benzyl bromides with binaphthyl as a basic skeleton.

[0010] The molar ratio of the benzyl bromide compound 1 to the 4,5-diazabutadiene 2 is 1:1.1, and the concentration of the reaction solution is 0.03-0.1 mmol / ml;

[0011] The organic solvent is generally tetrahydrofuran, N,N-dimethylacetamide, etc.

[0012] The reaction temperature is room temperature-80°C, and the reaction time is 12h-24h.

[0013] The obtained various chiral bipyridine type ligands are as follows:

[0014]

[0015] wherein R 3 , R 4 may be a tert-butyl group, a phenyl group, a trifluoromethyl group, a methoxy group, etc., and the site may be C2-C8;

[0016] The site C2-C8 means that different groups such as a tert-butyl group, a trifluoromethyl group, a fluorine group, a chlorine group, a bromine group, a methoxy group, etc. can be modified at the 2nd-6th position of the phenyl group or the 2nd-8th position of the naphthyl group on the ligand skeleton;

[0017] The ligand skeleton can be either (R)-configuration or (S)-configuration, or racemic.

[0018] A method for selectively C-H bond borylation of nitrogen-containing heterocyclic compounds (such as indoline and quinoline) by using iridium catalysis, which uses the above-mentioned chiral bipyridine ligand, and the steps are as follows:

[0019] In an organic solvent, under the action of a methoxy(cyclooctadiene)iridium dimer [IrOMe(COD)2] catalyst, the above-mentioned chiral bipyridine ligand is used to realize C-H bond borylation of nitrogen-containing heterocyclic compounds (such as indoline and quinoline) with very high site selectivity, and then a series of phenolic compounds are obtained by oxidation of sodium perborate, and the reaction formula is as follows:

[0020]

[0021] wherein: R 1 is a pivaloyl group, a methylsulfonyl group, a trifluoromethylsulfonyl group, a methyl group, an ethyl group, a cyclopropyl group, a cyclohexyl group, etc.; R 2 is a hydrogen atom, a methoxy group, a trifluoromethyl group, a nitro group, a hydroxyl group, an alkyl group such as a methyl group, and a halogen group such as fluorine, chlorine and bromine; and R 2 may be any site except the N atom.

[0022] The nitrogen-containing heterocyclic compound 1 is various nitrogen-containing heterocyclic compounds such as indoline or quinoline; the Ligand is a novel chiral bipyridine ligand; the reaction temperature is 90 DEG C, and the reaction time is 24-36 hours, and various phenolic compounds with a yield of not less than 60% are prepared;

[0023] The molar ratio of the nitrogen-containing heterocyclic compound pinacol diboronic acid ester is 1:1.5, the concentration of the nitrogen-containing heterocyclic compound 1 is 0.01-0.1 mmol / ml, the amount of the [IrOMe(COD)2] is 2 mol% of the nitrogen-containing heterocyclic compound 1, and the organic solvent is n-octane, n-hexane, tetrahydrofuran, 1,4-dioxane, etc., preferably n-octane.

[0024] The present application discloses a preparation method of a novel chiral bipyridine ligand and a novel method for selective C-H bond boronation of nitrogen-containing heterocyclic compounds (such as indoline and quinoline) catalyzed by iridium, and the product is excellent and has very good site selectivity. The preparation method has high reaction efficiency and good site selectivity, can be used for kilogram-scale reaction, can be further converted to synthesize PD-L1 inhibitor, and has potential physiological activity and application value. DETAILED DESCRIPTION

[0025] Example 1: Preparation of chiral bipyridine ligand L1

[0026] Under nitrogen or argon, the benzyl bromide compound (0.5 mmol) and 4,5-diazofluorene (0.55 mmol) are dissolved in tetrahydrofuran (5 mL), the reaction system is cooled to 0 DEG C, sodium hydride (2 mmol, 80 mg) is added, the reaction mixture is stirred at room temperature, the reaction is carried out for 12 hours, then water is added to quench the reaction, then ethyl acetate is used for extraction, and after being dried and separated by column chromatography, the white solid product is obtained, and the yield is 80%. L1: 1 H NMR (400 MHz, Chloroform-d) 8.72 (dd, J = 4.7, 1.7 Hz, 2H), 8.03 (d, J = 8.2 Hz, 4H), 7.54-7.50 (m, 2H), 7.40 (dd, J = 15.1, 8.4 Hz, 4H), 7.33-7.29 (m, 2H), 7.23-7.16 (m, 4H), 3.30 (d, J = 13.4 Hz, 2H), 2.45 (d, J = 13.5 Hz, 2H). 13C NMR (101 MHz, Chloroform-d) δ 156.5 (2C), 149.7 (2C), 144.5 (2C), 140.5 (2C), 140.3 (2C), 136.4 (2C), 132.7 (2C), 132.7 (2C), 132.2 (2C), 131.5 (2C), 130.2 (4C), 129.6 (2C), 128.4 (2C), 128.0 (4C), 127.1 (2C), 127.1 (2C), 126.3 (2C), 126.1 (2C), 122.6 (2C), 56.8 (1C), 36.5 (2C). HRMS (ESI): Calcd for C 33 H 23 N2 + [M+H] + : 447.1856, found 447.1854.

[0027] Example 2: Preparation of chiral bipyridine ligand L2; the procedure is the same as that for the preparation of L1.

[0028] L2: white solid product, 85% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.53 - 8.51 (m, 2H), 8.08 - 8.03 (m, 4H), 7.58 (t, J = 7.4 Hz, 2H), 7.43 - 7.34 (m, 4H), 7.26 (d, J = 7.1 Hz, 4H), 7.21 - 7.14 (m, 6H), 7.09 (s, 4H), 3.20 (d, J = 13.8 Hz, 2H), 2.85 (d, J = 13.8 Hz, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 156.5 (2C), 149.7 (2C), 144.5 (2C), 140.5 (2C), 140.3 (2C), 136.4 (2C), 132.7 (2C), 132.7 (2C), 132.2 (2C), 131.5 (2C), 130.2 (4C), 129.6 (2C), 128.4 (2C), 128.0 (4C), 127.1 (2C), 127.1 (2C), 126.3 (2C), 126.1 (2C), 122.6 (2C), 56.8 (1C), 36.5 (2C). HRMS (ESI): Calcd for C 45 H 31 N2 + [M+H] + : 599.2482, found 599.2483.

[0029] Example 3: Preparation of chiral bipyridine ligand L3; the procedure is the same as that for the preparation of L1.

[0030] L3: white solid product, 80% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.38 (t, J = 4.6 Hz, 2H), 8.09 (dd, J = 11.5, 3.9 Hz, 4H), 7.72 - 7.57 (m, 12H), 7.44 (dd, J = 15.0, 11.2 Hz, 10H), 7.27 (d, J = 3.2 Hz, 2H), 7.16 - 7.14 (m, 2H), 7.08 - 7.05 (m, 2H), 3.26 (dd, J = 14.0, 3.7 Hz, 2H), 2.86 (dd, J = 13.7, 3.9 Hz, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 156.5 (2C), 149.7 (2C), 144.3 (2C), 140.5 (2C), 137.8 (2C), 136.4 (2C), 132.9 (2C), 132.9 (2C), 132.8 (2C), 132.2 (4C), 131.6 (2C), 129.9 (2C), 129.3 (2C), 128.4 (2C), 128.2 (2C), 127.7 (6C), 127.1 (2C), 126.4 (4C), 126.2 (2C), 126.1 (2C), 122.4 (2C), 56.8 (1C), 36.8 (2C). HRMS (ESI): Calcd for C 53 H 35 N2 + [M+H] + : 699.2795, found 699.2798.

[0031] Example 4: Preparation of chiral bipyridine ligand L4; the operating method is the same as that of the preparation of L1.

[0032] L4: white solid product, 78% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.56 (d, J = 3.9 Hz, 2H), 8.09 (d, J = 8.4 Hz, 2H), 8.02 (d, J = 3.0 Hz, 2H), 7.68 - 7.61 (m, 8H), 7.46 - 7.40 (m, 4H), 7.13 - 7.09 (m, 2H), 7.06 - 7.03 (m, 2H), 3.25 (d, J = 14.1 Hz, 2H), 2.49 (d, J = 14.1 Hz, 2H). 13C NMR(101MHz,Chloroform-d)δ156.5(2C),150.4(2C),143.5(2C),142.4(2C),137.1(2C),136.5(2C),13 2.6(2C),132.0(2C),131.7(4C),131.3(2C),130.9(2C),130.3(6C),128.6(2C),127.4(2C),127.0(d,J C-F =5.1Hz, 4C), 123.0(q, J C-F =273.7Hz,4C),122.7(2C),121.2(q,J C-F =4.0Hz,2C),56.8(1C),36.6(2C). 19 F NMR(377MHz,Chloroform-d)δ-62.79.HRMS(ESI):Calcd for C 49 H 27 F 12 N2 + [M+H] + :871.1977,found 871.1979.

[0033] Example 5: Preparation of chiral bipyridine ligand L5; the operation method is the same as that for L1.

[0034] L5: White solid product, 65% yield. 1 H NMR(400MHz,Chloroform-d)δ8.48(t,J=3.2Hz,2H),8.04(d,J=8.2Hz,2H),7.98(s,2H),7.57-7.53(m,2H),7.43(d,J=7.4Hz,2H),7.37 -7.32(m,2H),7.18(t,J=1.8Hz,2H),7.08(d,J=3.2Hz,4H),6.99(s,4H),3.17(d,J=13.8Hz,2H),2.75(d,J=13.9Hz,2H),1.17(s,36H). 13C NMR (101 MHz, Chloroform-d) δ 156.5 (2C), 150.2 (4C), 149.6 (2C), 145.0 (2C), 141.8 (2C), 139.6 (2C), 136.3 (2C), 133.0 (2C), 132.6 (2C), 132.2 (2C), 131.3 (2C), 129.4 (2C), 128.3 (2C), 127.2 (2C), 126.0 (2C), 125.9 (2C), 124.3 (4C), 123.0 (2C), 121.2 (2C), 56.8 (1C), 36.7 (2C), 34.7 (4C), 31.4 (12C). HRMS (ESI): Calcd for C 61 H 63 N2 + [M+H] + : 823.4986, found 823.4983.

[0035] Example 6: Preparation of chiral bipyridine ligand L6; the procedure is the same as that for the preparation of L1.

[0036] L6: white solid product, 68% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.40 (d, J = 4.8 Hz, 2H), 8.10 (s, 2H), 8.05 (d, J = 8.2 Hz, 2H), 7.58-7.30 (m, 36H), 7.14 (d, J = 7.6 Hz, 2H), 6.95 (dd, J = 7.7, 4.8 Hz, 2H), 3.26 (d, J = 13.8 Hz, 2H), 2.84 (d, J = 13.8 Hz, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 156.8 (2C), 149.8 (2C), 144.5 (2C), 141.6 (4C), 141.4 (2C), 140.8 (4C), 140.4 (2C), 136.4 (2C), 132.8 (2C), 132.7 (2C), 132.3 (2C), 131.6 (2C), 129.6 (2C), 128.8 (8C), 128.5 (2C), 128.1 (4C), 127.5 (4C), 127.3 (8C), 127.1 (2C), 126.5 (2C), 126.3 (2C), 125.0 (2C), 122.6 (2C), 57.1 (1C), 37.0 (2C). HRMS (ESI): Calcd for C 69 H 47 N2+ [M+H] + :903.3734, found 903.3736.

[0037] New method for iridium catalyzed selective C-H borylation of nitrogen containing heterocycles:

[0038] Procedure in glove box: indolinium or quinolinium compound with pivaloyl group (0.2 mmol), B2pin2(76.2 mg, 0.3 mmol, 1.5 eq.), ligand (7 mg, 4 mol%), [IrOMe(cod)2] (1 mg, 0.004 mmol, 2 mol%), n-octane (1.0 mL, 0.2 M). The resulting mixture solution was stirred at room temperature for 30 min, then heated to 90 °C for 24-36 h. After cooling to room temperature, the mixture was diluted with water. The biphasic mixture was then extracted with diethyl ether 3 times. The resulting organic phase was dried over Na2S04. After removal of the solvent, the product was purified by column chromatography on silica gel with PE / EtOAc as eluent, then oxidized by sodium peroxoborate in tetrahydrofuran solution to give the product.

[0039] Some of the products are shown below:

[0040]

[0041] Example 7: Preparation of compound 3-1 : white solid, 31.2 mg, 71% yield. 1 H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 7.54 (d, J = 8.1 Hz, 1H), 6.90 (t, J = 8.0 Hz, 1H), 6.44 (d, J = 8.1 Hz, 1H), 4.18 (t, J = 8.1 Hz, 2H), 2.93 (t, J = 8.2 Hz, 2H), 1.24 (s, 9H). 13 C NMR (101 MHz, DMSO-d6) δ 175.9, 153.8, 146.6, 128.3, 117.1, 111.1, 109.6, 49.8, 40.2, 27.9, 26.3. HRMS (ESI): Calcd for C 13 H 18 NO2 + [M+H] + :220.1332, found 220.1335.

[0042] Example 8: Preparation of compound 3-2: white solid, 36.8 mg, 79% yield. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 8.3 Hz, 1H), 7.11 (s, 1H), 6.99 (d, J = 8.3 Hz, 1H), 5.54 (d, J = 5.7 Hz, 1H), 5.01 - 4.97 (m, 1H), 4.18 (dd, J = 11.3, 7.0 Hz, 1H), 3.95 (dd, J = 11.3, 3.0 Hz, 1H), 2.21 (s, 3H), 1.21 (s, 9H). 13 C NMR (101 MHz, DMSO) δ 175.7, 142.5, 134.2, 132.8, 129.6, 125.9, 117.9, 69.4, 58.7, 40.1, 28.0, 21.0. HRMS (ESI): Calcd for C 14 H 20 NO2 + [M+H] + : 234.1489, found 234.1487.

[0043] Example 9: Preparation of compound 3-3: white solid, 32.4 mg, 65% yield. 1 H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 8.9 Hz, 1H), 6.96 (d, J = 2.7 Hz, 1H), 6.83 (dd, J = 8.9, 2.8 Hz, 1H), 5.64 (d, J = 5.7 Hz, 1H), 5.08 (td, J = 6.6, 3.2 Hz, 1H), 4.28 (dd, J = 11.3, 7.1 Hz, 1H), 4.01 (dd, J = 11.3, 3.2 Hz, 1H), 3.74 (s, 3H), 1.28 (s, 9H). 13 C NMR (101 MHz, DMSO-d6) δ 175.3, 156.1, 138.2, 135.6, 118.9, 114.4, 110.7, 69.5, 58.6, 55.8, 40.1, 28.0. HRMS (ESI): Calcd for C 14 H 20 NO3 + [M+H] + : 250.1438, found 250.1435.

[0044] Example 10: Preparation of compound 3-4: white solid, 27.6 mg, 48% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 8.6 Hz, 1H), 7.69 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 5.82 (d, J = 5.6 Hz, 1H), 5.20 - 5.16 (m, 1H), 4.37 (dd, J = 11.3, 7.1 Hz, 1H), 4.12 (dd, J = 11.3, 3.0 Hz, 1H), 1.31 (s, 9H). 13 C NMR (101 MHz, Chloroform-d) δ 177.4, 147.3, 132.4, 127.7 (q, J C-F = 3.8 Hz), 126.0 (q, J C-F = 32.32 Hz), 124.1 (q, J C-F = 272.7 Hz), 122.0 (q, J C-F = 3.9 Hz). 118.7, 70.1, 58.8, 40.5, 27.6. 19 F NMR (377 MHz, DMSO-d6) δ -59.98. HRMS (ESI): calcd for C 14 H 17 F3NO2 + [M+H] + : 288.1206, found 288.1206.

[0045] Example 11: Preparation of compound 3-5: white solid, 38.9 mg, 82% yield. 1 H NMR (400 MHz, Chloroform-d) δ 7.74 (dd, J = 8.9, 4.3 Hz, 1H), 6.90 (t, J = 9.8 Hz, 1H), 5.40 (s, 1H), 4.28 (t, J = 8.1 Hz, 2H), 3.12 (t, J = 8.1 Hz, 2H), 1.37 (s, 9H). 13 C NMR (101 MHz, Chloroform-d) δ 176.6, 147.7 (q, J C-F = 234.3 Hz), 141.9, 139.5 (d, J C-F = 17.2 Hz), 118.9, 113.8 (d, J C-F = 19.2 Hz), 110.2 (d, J C-F = 6.1 Hz), 50.1, 40.2, 29.7, 27.7. 19 F NMR (377 MHz, Chloroform-d) δ -147.57. HRMS (ESI): calcd for C13 H 17 FNO2 + [M+H] + :238.1238, found 238.1236.

[0046] Example 12: Preparation of compound 3-6: white solid, 38.5 mg, 76% yield. 1 H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 2.3 Hz, 1H), 7.31 (dd, J = 8.7, 2.4 Hz, 1H), 5.76 (d, J = 5.5 Hz, 1H), 5.13 - 5.09 (m, 1H), 4.31 (dd, J = 11.3, 7.1 Hz, 1H), 4.06 (dd, J = 11.3, 3.1 Hz, 1H), 1.29 (s, 9H). 13 C NMR (101 MHz, DMSO-d6) δ 176.3, 143.6, 136.5, 128.9, 127.2, 125.4, 119.4, 69.0, 58.7, 40.2, 27.9. HRMS (ESI): Calcd for C 13 H 17 ClNO2 + [M+H] + :254.0942, found 254.0941.

[0047] Example 13: Preparation of compound 3-7: white solid, 44.5 mg, 75% yield. 1 H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 2.3 Hz, 1H), 7.31 (dd, J = 8.7, 2.4 Hz, 1H), 5.76 (d, J = 5.5 Hz, 1H), 5.13 - 5.09 (m, 1H), 4.31 (dd, J = 11.3, 7.1 Hz, 1H), 4.06 (dd, J = 11.3, 3.1 Hz, 1H), 1.29 (s, 9H). 13 C NMR (101 MHz, DMSO-d6) δ 176.3, 144.0, 136.9, 131.8, 128.3, 119.9, 115.1, 68.9, 58.6, 40.3, 27.8. HRMS (ESI): Calcd for C 13 H 17 BrNO2 + [M+H] +: 298.0437, found 298.0439.

[0048] Example 14: Preparation of compound 3-8: white solid, 48.6 mg, 92% yield. 1 H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.43 (d, J = 2.1 Hz, 1H), 7.36 (d, J = 2.1 Hz, 1H), 4.33 (t, J = 8.3 Hz, 2H), 3.06 (t, J = 8.3 Hz, 2H), 1.29 (s, 9H). 13 C NMR (101 MHz, DMSO-d6) δ 176.9, 153.6, 148.1, 147.0, 125.5, 106.2, 104.3, 50.2, 40.4, 27.7, 26.4. HRMS (ESI): Calcd for C 13 H 17 N2O4 + [M+H] + : 298.0437, found 298.0437.

[0049] Example 15: Preparation of compound 3-9: white solid, 45.1 mg, 76% yield. 1 H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.14 (d, J = 8.6 Hz, 1H), 6.49 (d, J = 8.6 Hz, 1H), 4.07 (t, J = 7.5 Hz, 2H), 2.94 (t, J = 7.5 Hz, 2H), 1.29 (s, 9H). 13 C NMR (101 MHz, DMSO-d6) δ 178.9, 153.3, 145.5, 131.9, 123.3, 113.7, 102.8, 51.5, 40.3, 28.9, 28.6. HRMS (ESI): Calcd for C 13 H 17 BrNO2 + [M+H] + : 298.0437, found 298.0437.

[0050] Example 16: Preparation of compound 3-10: white solid, 28.0 mg, 60% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 6.60 - 6.55 (m, 1H), 6.39 (d, J = 1.6 Hz, 1H), 3.68 - 3.61 (m, 2H), 2.56 - 2.52 (m, 2H), 2.14 (s, 3H), 1.24 (s, 9H). 13 C NMR (101 MHz, DMSO-d6) δ 178.0, 151.5, 145.1, 129.9, 119.9, 119.4, 112.0, 51.4, 40.1, 28.7, 28.3, 19.4. HRMS (ESI): calcd for C 14 H 20 NO2 + [M+H] + : 234.1489, found 234.1486.

[0051] Example 17: Preparation of compound 3-11 : white solid, 36.7 mg, 78% yield. 1 H NMR (400 MHz, Chloroform-d) δ 9.61 (s, 1H), 6.73 (d, J = 8.6 Hz, 1H), 6.56 (d, J = 8.6 Hz, 1H), 4.85 (s, 1H), 4.23 (t, J = 7.6 Hz, 2H), 3.03 (t, J = 7.6 Hz, 2H), 1.40 (s, 9H). 13 C NMR (101 MHz, Chloroform-d) δ 177.9, 144.6, 140.9, 131.6, 119.5, 118.6, 114.4, 51.2, 40.0, 28.0, 26.6. HRMS (ESI): calcd for C 13 H 18 NO3 + [M+H] + : 236.1281, found 236.1281.

[0052] Example 18: Preparation of compound 3-12: white solid, 26.2 mg, 54% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H), 6.51 (d, J = 8.0 Hz, 1H), 4.91 - 4.85 (m, 1H), 3.06 (dd, J = 15.4, 7.6 Hz, 1H), 2.55 (d, J = 15.4 Hz, 1H), 1.29 (s, 9H), 1.14 (d, J = 6.1 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 175.7, 154.4, 145.1, 128.1, 116.6, 111.4, 110.8, 56.2, 40.7, 33.8, 28.7, 28.7, 22.5. HRMS (ESI): Calcd for C 14 H 20 NO2 + [M+H] + : 234.1489, found 234.1487.

[0053] Example 19: Preparation of compound 3-13: white solid, 32.6 mg, 70% yield. 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.77 (d, J = 2.5 Hz, 1H), 6.50 (dd, J = 8.3, 2.5 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.62 (t, J = 7.0 Hz, 2H), 1.89 - 1.82 (m, 2H), 1.23 (s, 9H). 13 C NMR (101 MHz, DMSO-d6) δ 177.6, 155.1, 141.6, 129.5, 122.0, 112.8, 112.6, 45.4, 40.3, 29.0, 25.2, 24.3. HRMS (ESI): Calcd for C 14 H 20 NO2 + [M+H] + : 234.1489, found 234.1487.

[0054] Example 20: Preparation of compound 3-14: white solid, 52.9 mg, 85% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 6.82 (d, J = 2.4 Hz, 1H), 6.78 (d, J = 2.4 Hz, 1H), 3.69 (dd, J = 10.3, 4.8 Hz, 2H), 2.61 (t, J = 7.1 Hz, 2H), 1.92 - 1.85 (m, 2H), 1.26 (s, 9H). 13 C NMR (101 MHz, DMSO-d6) δ 177.9, 155.4, 142.8, 124.3, 120.6, 116.2, 112.9, 45.2, 40.2, 28.8, 26.9, 24.2. HRMS (ESI): Calcd for C 14 H 19 BrNO2 + [M+H] + : 312.0594, found 312.0594.

[0055] Example 21: Preparation of compound 3-15: white solid, 38.6 mg, 62% yield. 1 H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 7.25 (s, 1H), 7.02 (s, 1H), 3.72 - 3.64 (m, 2H), 2.65 (t, J = 7.0 Hz, 2H), 1.85 (dt, J = 13.0, 6.9 Hz, 2H), 1.25 (s, 9H). 13 C NMR (101 MHz, DMSO-d6) δ 177.5, 150.5, 140.1, 129.4, 123.2, 116.1, 113.8, 45.4, 40.2, 28.9, 25.1, 23.9. HRMS (ESI): Calcd for C 14 H 19 BrNO2 + [M+H] + : 312.0594, found 312.0594.

[0056] Example 22: Preparation of compound 3-16: white solid, 46.4 mg, 88% yield. 1 H NMR (400 MHz, Chloroform-d) δ 7.03 (d, J = 8.4 Hz, 1H), 6.75 (dd, J = 8.5, 2.3 Hz, 1H), 6.67 (s, 1H), 4.69 (s, 2H), 3.83 (t, J = 8.0 Hz, 2H), 3.79 (s, 3H), 2.86 (t, J = 8.0 Hz, 2H), 1.31 (s, 9H).13 C NMR (101 MHz, Chloroform-d) δ 176.7, 158.2, 135.7, 127.3, 125.8, 113.4, 112.6, 55.3, 43.2, 38.8, 29.2, 28.4. HRMS (ESI): Calcd for C 15 H 22 NO3 + [M+H] + : 264.1594, found 264.1593.

Claims

1. A process for the preparation of a chiral bipyridine ligand, characterized in that, A series of novel chiral pyridine type ligands are prepared by reacting benzyl bromide compound I with 4,5-diazofluorene II in an organic solvent, using sodium hydride, cesium carbonate or sodium bis(trimethylsilyl)amide as a base; The reaction formula is as follows: ； The ligand is selected from: ； wherein R 3 , R 4 is t-butyl, phenyl, trifluoromethyl or methoxy, and the site is C2-C8; the site C2-C8 means modification at the 2nd-6th position of the phenyl group or the 2nd-8th position of the naphthalene ring on the ligand skeleton; the molar ratio of the benzyl bromide compound I to 4,5-diazofluorene II is 1:1.1, and the concentration of the reaction solution is 0.03-0.1 mmol / ml.

2. The method of claim 1, wherein, The organic solvent is tetrahydrofuran or N,N-dimethylacetamide.

3. The method of claim 1, wherein, The reaction temperature is room temperature to 80 DEG C, and the reaction time is 12h-24h.

4. Use of the novel chiral bipyridine ligand obtained by the process according to claim 1 in catalytic reactions, characterized in that, The reaction is selective C-H bond boronization of nitrogen-containing heterocyclic compounds catalyzed by iridium, and the reaction steps are as follows: In an organic solvent, using the above-mentioned chiral bipyridine ligand, C-H bond boronization of nitrogen-containing heterocyclic compound 1 and pinacol diboronic acid is realized under the catalysis of methoxy(cyclooctadiene)iridium dimer [IrOMe(COD)2], and then a series of phenolic compounds are obtained by oxidation of sodium perborate, and the reaction formula is as follows: ； wherein: R 1 is pivaloyl, methanesulfonyl, trifluoromethanesulfonyl, methyl, ethyl, cyclopropyl, cyclohexyl; R 2 is a hydrogen atom, methoxy, trifluoromethyl, nitro, hydroxy, methyl, fluorine, chlorine or bromine; R 2 the substitution site is any site except the N atom; The reaction temperature is 90 DEG C, and the reaction time is 24h-36h.

5. Use according to claim 4, characterized in that, The molar ratio of the nitrogen-containing heterocyclic compound 1 to pinacol diboronic acid is 1:1.5, the concentration of the nitrogen-containing heterocyclic compound 1 is 0.01-0.1mmol / ml, and the amount of [IrOMe(COD)2] is 2mol% of the nitrogen-containing heterocyclic compound 1.

6. Use according to claim 4, characterized in that, The organic solvent is n-octane, n-hexane, tetrahydrofuran or 1,4-dioxane.

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