A method for synthesizing nitrogen-containing heterocyclic aromatic hydrocarbon derivatives by boronate-promoted suzuki coupling reaction

Abstract

The application provides a method for synthesizing nitrogen-containing heterocyclic aromatic hydrocarbon derivatives through borate-promoted Suzuki coupling reaction, which comprises the following steps: pyridine borate shown in formula I, pyrimidine borate shown in formula II, quinoline borate shown in formula III are used as raw materials, and alkyl halide shown in formula IV is coupled under the action of borate additive, catalyst, ligand and base, so as to correspondingly generate pyridine derivative shown in formula V, pyrimidine derivative shown in formula VI and quinoline derivative shown in formula VII; wherein, R is a substituent group. The method has the advantages of wide raw material source, stable reaction system, wide substrate applicability, mild reaction condition, good reaction functional group compatibility, economy and practicability and the like.

Description

Technical Field

[0001] This application relates to the field of synthesis of nitrogen-containing heterocyclic aromatic hydrocarbon derivatives, and more specifically, to a method for synthesizing nitrogen-containing heterocyclic aromatic hydrocarbon derivatives via a borate ester-promoted Suzuki coupling reaction. Background Technology

[0002] Pyridine, pyrimidine, and quinoline and their derivatives, as important nitrogen-containing heterocyclic structures, are widely found in pharmaceutical molecules, agrochemicals, and functional materials. Their efficient and controllable construction methods have significant research and application value in the field of organic synthesis. Suzuki coupling reactions using borate esters as coupling precursors are widely used for carbon-carbon bond construction due to their good functional group compatibility and relatively simple operation. However, in coupling reactions involving pyridine, pyrimidine, and quinoline borate esters, the reactions often face problems such as reduced reactivity and condition sensitivity due to the coordination effect and electronic properties of the nitrogen-containing heterocycles.

[0003] On the other hand, the application of alkyl halides in Suzuki coupling reactions still faces certain challenges compared to aryl halides. Alkyl halides are prone to side reactions, such as β-H elimination or reductive dehalogenation, leading to reduced yields of the target product or reaction failure. In existing technologies, the coupling reactions of pyridine, pyrimidine, and quinoline borate esters with alkyl halides mostly rely on noble metal catalytic systems such as palladium, and usually require specific ligands, strict reaction conditions, or strong restrictions on substrate structure, making universal application difficult. Furthermore, noble metal catalysts are expensive and resource-limited, hindering large-scale synthesis and industrial application. In contrast, copper, as an inexpensive and environmentally friendly transition metal, has potential advantages in cross-coupling reactions. However, there are currently few reports on copper-catalyzed direct coupling methods of pyridine, pyrimidine, and quinoline borate esters with alkyl halides, especially regarding reaction efficiency, substrate applicability, and ease of operation, which still require further improvement.

[0004] Therefore, developing a copper-catalyzed, mild, widely applicable, and stable coupling method for pyridine, pyrimidine, and quinoline borate esters with alkyl halides is of great significance for the synthesis of compounds containing pyridine, pyrimidine, and quinoline structures, reducing synthesis costs, and expanding their practical applications. Summary of the Invention

[0005] In view of one of the deficiencies in the prior art, the purpose of this application is to provide a method for synthesizing nitrogen-containing heterocyclic aromatic hydrocarbon derivatives by a borate ester-promoted Suzuki coupling reaction, wherein the coupling reaction of heterocyclic aromatic hydrocarbon borate boron can be achieved by using a borate ester additive.

[0006] This application provides a method for synthesizing nitrogen-containing heterocyclic aromatic hydrocarbon derivatives. The method uses pyridine borate esters of Formula I, pyrimidine borate esters of Formula II, and quinoline borate esters of Formula III as raw materials. Under the action of borate ester additives, catalysts, ligands, and bases, the pyridine derivatives of Formula V, pyrimidine derivatives of Formula VI, and quinoline derivatives of Formula VII are generated respectively through coupling reactions with alkyl halides of Formula IV. In the formula, R is hydrogen or a substituent, which is selected from any one of alkyl, aryl, halogen, amino, alkyloxy, etc., and Bpin is a pinacol borate ester group.

[0007] Optionally, the borate ester additive may be selected from B(OR)3, wherein R is aryl or alkyl.

[0008] Optionally, the additive is any one or more of boron trifluoride ethyl ether, trimethyl borate, triethyl borate, triisopropyl borate, tripropyl borate, triphenylboronic acid ester, triisobutyl borate, and tributyl borate.

[0009] Optionally, the catalyst is a copper catalyst.

[0010] Optionally, the catalyst is any one or more of cuprous bromide, cuprous bromide dimethyl sulfide, copper trifluoromethanesulfonate, cuprous chloride, cuprous iodide, copper thiophene-2-carboxylate (I), copper bromide, and copper acetate, preferably cuprous bromide.

[0011] Optionally, the ligand is a nitrogen-containing ligand.

[0012] Optionally, the ligand is any one or more of bipyridine, o-phenanthroline, 4,7-diphenyl-1,10-o-phenanthroline, 4,7-dimethyl-1,10-o-phenanthroline, and 4,7-dichloro-1,10-o-phenanthroline, preferably 4,7-diphenyl-1,10-o-phenanthroline.

[0013] Optionally, the base is an organic base or an inorganic base.

[0014] Optionally, the alkali is any one or more of sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium ethoxide, and sodium methoxide, preferably sodium ethoxide.

[0015] Optionally, the amount of the borate ester additive added is 0.2-5 equivalents of the molar amount of the reaction raw materials, preferably 0.5-3 equivalents.

[0016] Optionally, the amount of catalyst added is 0.01-1 equivalent of the molar amount of the reaction substrate, preferably 0.3-1 equivalent.

[0017] Optionally, the amount of the ligand added is 0.01-1 equivalent of the molar amount of the reaction substrate, preferably 0.3-1 equivalent.

[0018] Optionally, the amount of base added is 0.2-5 equivalents of the molar amount of the reaction substrate, preferably 0.5-3 equivalents.

[0019] Optionally, the molar ratio of the nitrogen-containing heterocyclic borate ester to the alkyl halide (such as the compound shown in Formula IV) is 0.5-5:1, preferably 1-3:1.

[0020] Optionally, the coupling reaction is carried out at a temperature of 40-140℃ for 1-24 hours, preferably at 70-130℃ for 6-15 hours.

[0021] Optionally, the solvent used is acetonitrile, ethyl acetate, cyclohexane, 1,4-dioxane, N,N - Any one or more of dimethylformamide, dimethyl sulfoxide, benzene, fluorobenzene and trifluorotoluene.

[0022] The method for synthesizing nitrogen-containing heterocyclic aromatic hydrocarbon derivatives by borate ester-promoted Suzuki coupling reaction provided in this application can conveniently prepare a variety of pyridine, pyrimidine, and quinoline derivatives using halogens, alkyl groups, or heteroatom-containing alkyl groups as substrates. This method avoids the use of precious metal catalysts and has the advantages of wide availability of raw materials, stable reaction system, broad substrate applicability, mild conditions, good compatibility of reaction functional groups, and economic practicality.

[0023] Other technical effects resulting from the additional features will be further illustrated in the corresponding embodiments. Detailed Implementation

[0024] The present application will now be described in detail with reference to specific embodiments. These embodiments will help those skilled in the art to further understand the present application, but do not limit the present application in any way. It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the present application, and these all fall within the protection scope of the present application. Parts not described in detail in the following embodiments can be implemented using existing technology.

[0025] Example 1 Cuprous bromide, 4,7-diphenyl-1,10-o-phenanthroline, pyridine borate, sodium ethoxide, 2-bromobutane, and triisopropyl borate were added to a reaction tube. The amounts of pyridine borate were 0.8 mmol, the alkyl halide 0.4 mmol, cuprous bromide 20% of 0.4 mmol, 4,7-diphenyl-1,10-o-phenanthroline 15% of 0.4 mmol, and the base and additives were 2 equivalents. The reaction was carried out at 100 °C. oThe reaction was carried out under heating conditions at C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through a sintered glass funnel, concentrated, and purified by silica gel column chromatography (200-300 mesh) to obtain the target product (colorless to pale yellow oily liquid, 51.4 mg, yield 78%) with the following structural formula.

[0026] The product test data are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.52 – 7.45 (m, 1H), 6.70 (d, J = 7.2 Hz, 1H), 6.55 (dd, J = 8.2, 1.7 Hz, 1H), 3.94 (d, J = 1.7 Hz, 3H), 2.69 (q, J = 7.0 Hz, 1H), 1.78 (dtd, J = 14.9, 7.6, 1.8 Hz, 1H), 1.63 – 1.57 (m, 1H), 1.27 (dd, J = 7.0, 1.8 Hz, 3H), 0.85 (td, J = 7.4, 1.8 Hz, 3H). As a comparative experiment, without the addition of borate ester additives, the reaction system could not yield the product of coupling alkyl halides with nitrogen-containing aromatic heterocyclic boron; in the presence of trimethyl borate, triethyl borate, tripropyl borate, triisopropyl borate, triisobutyl borate, or triphenyl borate additives, the yields of the coupling products obtained were 23%, 42%, 54%, 78%, 46%, and 54%, respectively.

[0027] Example 2 Using a method similar to that in Example 1, the target product (colorless to pale yellow oily liquid, 58 mg, yield 76%) was prepared by reacting the alkyl halide with bromocyclohexane and pyridine borate ester.

[0028] The product test data are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.99 (d, J = 2.5 Hz, 1H), 7.42 (dd, J = 8.5, 2.5Hz, 1H), 6.67 (d,J = 8.5 Hz, 1H), 3.91 (s, 3H), 2.45 (dp, J = 11.0, 3.6 Hz, 1H),1.88 – 1.79 (m, 4H), 1.74 (ddt, J = 14.0, 5.2, 2.5 Hz, 1H), 1.42 – 1.32 (m,4H), 1.28 – 1.21 (m, 1H). Example 3 Using a method similar to that in Example 1, the target product (colorless oily liquid, 73.8 mg, 90% yield) was prepared by reacting the alkyl halide with bromocycloheptane and pyridine borate ester.

[0029] The product test data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.45 (td, J = 7.8, 1.7 Hz, 1H), 6.67 (dd, J =7.2, 1.7 Hz, 1H), 6.50 (dd, J = 8.1, 1.7 Hz, 1H), 3.91 (d, J = 1.8 Hz, 3H), 2.77(ttt, J = 7.9, 4.1, 1.7 Hz, 1H), 2.01 – 1.89 (m, 2H), 1.87 – 1.76 (m, 3H), 1.75 – 1.65 (m, 3H), 1.65 – 1.51 (m, 4H). 13 C NMR (101 MHz, CDCl3) δ 166.15, 163.44,138.71, 113.23, 106.86, 53.10, 48.06, 34.92, 28.37, 26.95. Example 4 Using a method similar to that in Example 1, the target product (colorless oily liquid, 80.3 mg, yield 73%) was prepared by reacting the alkyl halide with bromocyclododecane and pyridine borate ester.

[0030] The product test data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.45 (dd, J = 8.2, 7.2 Hz, 1H), 6.68 (d, J= 7.2 Hz, 1H), 6.51 (d, J = 8.2 Hz, 1H), 3.91 (s, 3H), 2.83 (p, J = 6.5 Hz,1H), 1.81 (dtd, J = 14.2, 7.2, 4.7 Hz, 2H), 1.66 – 1.57 (m, 2H), 1.54 – 1.38(m, 9H), 1.37 – 1.22 (m, 9H). 13 C NMR (101 MHz, CDCl3) δ 164.41, 163.52,138.40, 114.66, 106.97, 53.08, 41.53, 30.03, 24.00, 23.94, 23.60, 23.27,22.81. Example 5 Using a method similar to that in Example 1, the target product (colorless oily liquid, 105.4 mg, yield 98%) was prepared by reacting the alkyl halide with (3-bromohexyl)benzene and pyridine borate.

[0031] The product test data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.40 (dd, J = 8.2, 7.2 Hz, 1H), 7.18 (dd, J =8.2, 6.7 Hz, 3H), 7.12 – 7.01 (m, 3H), 6.59 (d, J = 7.2 Hz, 1H), 6.48 (d, J = 8.2Hz, 1H), 3.86 (s, 3H), 2.57 (tt, J = 9.5, 5.0 Hz, 1H), 2.37 (dd, J = 8.9, 7.1 Hz,2H), 2.10 – 1.94 (m, 1H), 1.82 (dtd, J = 13.1, 8.3, 4.7 Hz, 1H), 1.65 (dtd,J =13.2, 9.5, 5.4 Hz, 1H), 1.56 – 1.43 (m, 2H), 1.08 (tdt, J = 14.9, 9.8, 7.1 Hz,2H), 0.76 (t, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 163.83, 162.72, 142.92,138.39, 128.43, 128.25, 125.59, 115.82, 107.40, 53.15, 46.69, 37.90, 37.05,33.89, 20.65, 14.27. Example 6 Using a method similar to that in Example 1, the target product (colorless oily liquid, 100.8 mg, yield 93%) was prepared by reacting pyridine borate with 1-(3-bromobutyl)-4-methoxybenzene instead of alkyl halide.

[0032] The product test data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.48 (dd, J = 8.2, 7.3 Hz, 1H), 7.12 – 7.03(m, 2H), 6.85 – 6.80 (m, 2H), 6.69 (dd, J = 7.3, 0.8 Hz, 1H), 6.55 (dd, J = 8.2,0.8 Hz, 1H), 3.94 (s, 3H), 3.79 (s, 3H), 2.86 – 2.73 (m, 1H), 2.52 – 2.42 (m,2H), 2.10 (dddd, J = 13.3, 9.2, 8.4, 6.2 Hz, 1H), 1.83 (dddd, J = 13.1, 9.5, 7.1,5.9 Hz, 1H), 1.28 (d, J = 6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 164.09, 163.78,157.71, 138.79, 134.94, 129.38, 114.49, 113.77, 107.49, 55.37, 53.26, 41.03,38.75, 33.02, 21.08. Example 7 Using a method similar to that in Example 1, the target product (colorless oily liquid, 97.1 mg, yield 78%) was prepared by reacting pyridine borate with 1-(3-bromobutyl)-4-(but-3-en-1-yloxy)benzene instead of alkyl halide.

[0033] The product test data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.48 (dd, J = 8.2, 7.2 Hz, 1H), 7.08 – 6.99(m, 2H), 6.84 – 6.77 (m, 2H), 6.69 (dd, J = 7.3, 0.8 Hz, 1H), 6.55 (dd, J = 8.2, 0.8 Hz, 1H), 5.91 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.21 – 5.03 (m, 2H), 3.99(t, J = 6.7 Hz, 2H), 3.94 (s, 3H), 2.88 – 2.69 (m, 1H), 2.54 (qt, J = 6.8, 1.5Hz, 2H), 2.50 – 2.43 (m, 2H), 2.17 – 2.03 (m, 1H), 1.82 (dddd, J = 13.1, 9.5,7.2, 5.9 Hz, 1H), 1.28 (d, J = 6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 164.09,163.78, 157.71, 138.79, 134.94, 129.38, 114.49, 113.77, 107.49, 55.37, 53.26,41.03, 38.75, 33.02, 21.08. Example 8 Using a method similar to that in Example 1, the target product (colorless oily liquid, 117.8 mg, yield 95%) was prepared by reacting the alkyl halide with 2-(3-bromobutyl)isoindoline-1,3-dione and pyridine borate ester.

[0034] The product test data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.69 (dd, J = 5.4, 3.1 Hz, 2H), 7.59 (dd, J =5.5, 3.1 Hz, 2H), 7.29 (dd, J = 8.2, 7.2 Hz, 1H), 6.61 (dd, J = 7.3, 0.7 Hz, 1H), 6.30 (dd, J = 8.2, 0.8 Hz, 1H), 3.84 (s, 3H), 3.66 – 3.52 (m, 2H), 2.77 (dqd, J =8.9, 6.9, 5.2 Hz, 1H), 2.28 (ddt, J = 13.5, 8.8, 7.6 Hz, 1H), 1.89 – 1.76 (m,1H), 1.20 (d, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 168.28, 163.59, 162.61,138.68, 133.72, 132.14, 122.95, 114.35, 107.69, 53.09, 39.50, 36.75, 34.30,21.51. Example 9 Using a method similar to that in Example 1, the target product (colorless oily liquid, 84.8 mg, yield 80%) was prepared by reacting the alkyl halide with (5-bromo-1-hexyn-1-yl)benzene and pyridine borate ester.

[0035] The product test data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.44 (dd, J = 8.2, 7.2 Hz, 1H), 7.39 – 7.32(m, 2H), 7.28 – 7.19 (m, 3H), 6.71 (d, J = 7.2 Hz, 1H), 6.55 – 6.48 (m, 1H), 3.89 (s, 3H), 2.96 (dp, J = 8.6, 6.8 Hz, 1H), 2.39 – 2.18 (m, 2H), 2.12 – 2.00(m, 1H), 1.83 (dtd, J = 13.4, 7.7, 5.7 Hz, 1H), 1.27 (d, J = 6.9 Hz, 3H). Example 10 Using a method similar to that in Example 1, the target product (colorless oily liquid, 70.2 mg, yield 91%) was prepared by reacting the alkyl halide with 4-bromotetrahydropyran and pyridine borate ester.

[0036] The product test data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.48 (dd, J = 8.2, 7.3 Hz, 1H), 6.70 (d, J = 7.3Hz, 1H), 6.55 (dd, J = 8.2, 0.7 Hz, 1H), 4.13 – 4.00 (m, 2H), 3.91 (s, 3H), 3.53 (td, J = 11.7, 2.4 Hz, 2H), 2.82 (tt, J= 11.6, 4.1 Hz, 1H), 2.03 – 1.87 (m,2H), 1.86 – 1.71 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 163.68, 162.34, 138.97,113.31, 108.05, 68.21, 53.19, 42.90, 32.29. Example 11 Using a method similar to that in Example 1, the target product (colorless oily liquid, 79.4 mg, yield 68%) was prepared by reacting the alkyl halide with tert-butyl 4-bromopiperidine-1-carboxylate and pyridine borate ester.

[0037] The product test data are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.47 (t, J = 7.8 Hz, 1H), 6.68 (d, J = 7.2Hz, 1H), 6.54 (d, J = 8.2 Hz, 1H), 4.21 (s, 2H), 3.89 (d, J = 2.0 Hz, 3H), 2.82 (s, 2H), 2.71 (td, J = 11.7, 5.8 Hz, 1H), 1.87 (d, J = 13.8 Hz, 2H), 1.79 – 1.66 (m, 2H), 1.47 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 163.65, 162.34, 155.03, 138.95, 113.43, 108.04, 79.43, 53.21, 43.97, 28.59. Example 12 Using a method similar to that in Example 1, the target product (colorless oily liquid, 87.8 mg, yield 79%) was prepared by reacting the alkyl halide with tert-butyl 3-bromopyrrolidine-1-carboxylate and pyridine borate ester.

[0038] The product test data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.46 (td, J= 7.8, 2.4 Hz, 1H), 6.71 (d, J = 7.2Hz, 1H), 6.56 (dd, J = 8.3, 2.1 Hz, 1H), 3.88 (d, J = 6.0 Hz, 3H), 3.73 (ddd, J =26.4, 10.4, 7.4 Hz, 1H), 3.54 (dddd, J = 39.5, 27.6, 13.8, 7.0 Hz, 2H), 3.43 –3.29 (m, 2H), 2.17 (td, J = 8.5, 6.6 Hz, 2H), 1.45 (d, J = 4.2 Hz, 10H). 13 C NMR(101 MHz, CDCl3) δ 158.71, 158.65, 154.63, 138.85, 138.81, 114.49, 114.42,108.57, 108.53, 79.07, 53.22, 53.16, 51.31, 50.70, 46.02, 45.81, 45.70,44.91, 32.11, 31.27, 28.57. Example 13 Using a method similar to that in Example 1, the target product (colorless oily liquid, 55.9 mg, yield 53%) was prepared by reacting tert-butyl 3-bromozacyclobutane-1-carboxylate with pyridine borate ester instead of alkyl halide.

[0039] The product test data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.48 (dd, J = 8.3, 7.2 Hz, 1H), 6.72 (d, J = 7.2Hz, 1H), 6.59 (d, J = 8.3 Hz, 1H), 4.20 (p, J = 8.2 Hz, 4H), 3.93 (s, 3H), 3.75(tt, J = 8.5, 6.2 Hz, 1H), 1.45 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 164.07,158.38, 156.78, 138.94, 114.44, 108.97, 79.39, 54.76, 53.32, 34.91, 28.51. Example 14 Using a method similar to that in Example 1, the target product (colorless oily liquid, 73.3 mg, 95% yield) was prepared by reacting the alkyl halide with pyridine borate ester by replacing the alkyl halide with bromohexane.

[0040] The product test data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.45 (dd, J = 8.2, 7.2 Hz, 1H), 6.69 (d, J = 7.2Hz, 1H), 6.53 (d, J = 8.2 Hz, 1H), 3.91 (s, 3H), 2.72 – 2.63 (m, 2H), 1.77 –1.64 (m, 2H), 1.36 – 1.25 (m, 6H), 0.94 – 0.84 (m, 3H). 13 C NMR (151 MHz, CDCl3) δ 163.75, 160.59, 138.72, 115.17, 107.20, 53.29, 38.07, 31.90, 29.49, 29.17, 22.76, 14.25. Example 15 Using a method similar to that in Example 1, the target product (colorless oily liquid, 43.4 mg, yield 62%) was prepared by reacting pyridine borate ester with 2-methyl-5-pyridine borate pinacol ester and alkyl halide.

[0041] 1 H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 2.3 Hz, 1H), 7.40 (dd, J = 8.0, 2.4Hz, 1H), 7.06 (d, J= 8.0 Hz, 1H), 2.51 (s, 3H), 2.47 (d, J = 11.7 Hz, 1H), 1.84(t, J = 4.9 Hz, 4H), 1.72 (d, J = 10.3 Hz, 1H), 1.40 (td, J = 9.2, 3.2 Hz, 4H),1.29 – 1.23 (m, 1H). Example 16 Using a method similar to that in Example 1, the target product (colorless oily liquid, 43.2 mg, yield 52%) was prepared by reacting pyridine borate ester with 2-chloro-5-pyridine borate pinacol ester and alkyl halide.

[0042] 1 H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 2.6 Hz, 1H), 7.51 (dd, J = 8.2, 2.6Hz, 1H), 7.29 (d, J = 6.0 Hz, 1H), 2.60 – 2.48 (m, 1H), 1.89 (dt, J = 9.6, 2.4Hz, 4H), 1.83 – 1.74 (m, 1H), 1.43 (ddd, J = 12.2, 8.0, 2.4 Hz, 4H), 1.32 –1.28 (m, 1H). Example 17 Using a method similar to that in Example 1, the target product (colorless oily liquid, 34.3 mg, yield 48%) was prepared by reacting pyridine borate ester with 2-fluoro-5-pyridine borate pinacol ester and alkyl halide.

[0043] 1 H NMR (600 MHz, CDCl3) δ 8.03 (d, J = 2.6 Hz, 1H), 7.60 (td, J = 8.1, 2.5Hz, 1H), 6.83 (dd, J= 8.5, 2.9 Hz, 1H), 2.53 (dt, J = 13.1, 6.4 Hz, 1H), 1.85(d, J = 9.3 Hz, 4H), 1.77 – 1.71 (m, 1H), 1.43 – 1.35 (m, 4H), 1.27 – 1.20 (m, 1H). 13 C NMR (151 MHz, CDCl3) δ 162.97, 161.41, 145.92, 145.82, 140.61, 140.58,139.41, 139.36, 109.08, 108.83, 41.18, 34.30, 26.63, 25.86. Example 18 Using a method similar to that in Example 1, the target product (colorless oily liquid, 53.2 mg, yield 61%) was prepared by reacting pyridine borate ester with 2-phenyl-5-pyridine borate pinacol ester and alkyl halide.

[0044] The product test data are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.55 (d, J = 2.3 Hz, 1H), 8.00 – 7.94 (m, 2H), 7.66 (d, J = 8.1 Hz, 1H), 7.58 (dd, J = 8.1, 2.4 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 7.3 Hz, 1H), 2.58 (tt, J = 11.6, 3.5 Hz, 1H), 1.94 – 1.85 (m, 4H), 1.81 – 1.74 (m, 1H), 1.50 – 1.39 (m, 4H), 1.34 – 1.25 (m, 1H). Example 19 Using a method similar to that in Example 1, the target product (colorless oily liquid, 51.2 mg, yield 48%) was prepared by reacting pyridine borate ester with 6-benzyloxypyridine-3-boronic acid pinacol ester and alkyl halide.

[0045] The product test data are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.00 (d, J = 2.4 Hz, 1H), 7.50 – 7.43 (m, 3H), 7.38 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 2.56– 2.40 (m, 1H), 1.84 (d, J = 9.1 Hz, 4H), 1.78 – 1.72 (m, 1H), 1.39 (tt, J = 9.4,5.1 Hz, 4H), 1.30 – 1.24 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 162.25, 144.88,137.69, 137.57, 136.22, 128.58, 128.06, 127.89, 110.88, 67.66, 41.31, 34.53,26.90, 26.14. Example 20 Using a method similar to that in Example 1, the target product (colorless oily liquid, 66.24 mg, yield 72%) was prepared by reacting pyridine borate ester with 2-(pyrrolidine-1-yl)-5-pyridine borate pinacol ester and reacting it with an alkyl halide.

[0046] The product test data are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 2.5 Hz, 1H), 7.30 (dd, J = 8.6, 2.5Hz, 1H), 6.31 (d, J = 8.6 Hz, 1H), 3.50 – 3.36 (m, 4H), 2.44 – 2.31 (m, 1H), 2.01 – 1.93 (m, 4H), 1.86 – 1.77 (m, 4H), 1.72 (ddd, J= 13.3, 4.6, 2.5 Hz,1H), 1.36 (ddd, J = 13.3, 9.2, 5.7 Hz, 4H), 1.23 (dt, J = 9.5, 4.8 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 156.19, 146.36, 135.81, 130.23, 106.33, 46.83, 41.18, 34.63, 26.98, 26.19, 25.67. Example 21 Using a method similar to that in Example 1, the target product (colorless oily liquid, 40.5 mg, yield 53%) was prepared by reacting pyridine borate ester with 2-methoxy-5-pyridine borate pinacol ester and alkyl halide.

[0047] The product test data are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.99 (d, J = 2.5 Hz, 1H), 7.42 (dd, J = 8.5, 2.5Hz, 1H), 6.67 (d, J = 8.5 Hz, 1H), 3.91 (s, 3H), 2.45 (dp, J = 11.0, 3.6 Hz, 1H),1.88 – 1.79 (m, 4H), 1.74 (ddt, J = 14.0, 5.2, 2.5 Hz, 1H), 1.43 – 1.34 (m,4H), 1.25 (d, J = 10.3 Hz, 1H). Example 22 Using a method similar to that in Example 1, the target product (colorless oily liquid, 69.8 mg, yield 71%) was prepared by reacting pyridine borate ester with 6-(morpholino-4-yl)pyridine-3-boronic acid pinacol ester and reacting it with an alkyl halide.

[0048] The product test data are as follows: 1H NMR (600 MHz, CDCl3) δ 8.06 (d, J = 2.4 Hz, 1H), 7.38 (dd, J = 8.7, 2.4Hz, 1H), 6.61 (d, J = 8.6 Hz, 1H), 3.83 (t, J = 4.8 Hz, 4H), 3.45 (t, J = 4.8 Hz,4H), 2.46 – 2.38 (m, 1H), 1.82 (d, J = 8.8 Hz, 4H), 1.74 (d, J = 13.1 Hz, 1H), 1.37 (tt, J = 11.6, 5.2 Hz, 4H), 1.28 – 1.23 (m, 1H). 13 C NMR (151 MHz, CDCl3) δ158.41, 146.34, 136.29, 133.34, 107.01, 66.96, 46.13, 41.17, 34.49, 26.91,26.14. Example 23 Using a method similar to that in Example 1, the target product (colorless oily liquid, 48.5 mg, yield 53%) was prepared by reacting pyridine borate ester with 2-trifluoromethyl-5-pyridine borate pinacol ester and alkyl halide.

[0049] The product test data are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.57 (d, J = 2.2 Hz, 1H), 7.67 (dd, J = 8.0, 2.2Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 2.62 (tt, J = 8.5, 3.2 Hz, 1H), 1.88 (qt, J =8.4, 4.0 Hz, 4H), 1.78 (ddq, J = 13.0, 3.6, 1.7 Hz, 1H), 1.48 – 1.38 (m, 4H), 1.30 – 1.24 (m, 1H). Example 24 Using a method similar to that in Example 1, the target product (colorless oily liquid, 50.8 mg, yield 57%) was prepared by reacting the borate ester with 3-quinoline borate pinacol ester and alkyl halide.

[0050] The product test data are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.92(s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 8.2 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 2.72 (tt, J = 11.7, 3.5 Hz, 1H), 1.99 (d, J = 11.8 Hz, 2H), 1.91 (d, J = 12.3Hz, 2H), 1.81 (d, J = 14.0 Hz, 1H), 1.60 – 1.40 (m, 4H), 1.32 (ddd, J = 16.7, 8.4, 3.9 Hz, 1H). Example 25 Using a method similar to that in Example 1, the target product (colorless oily liquid, 40.1 mg, yield 58%) was prepared by reacting pyridine borate ester with 2-methyl-5-pyrimidine borate pinacol ester and alkyl halide.

[0051] The product test data are as follows: 1 H NMR (500 MHz, CDCl3) δ8.67 (s, 2H), 3.08 (dq, J= 7.7, 7.0 Hz, 1H),2.45 (s, 3H), 1.98 – 1.84 (m, 4H), 1.79 (ddt, J = 14.0, 6.0, 2.2 Hz, 1H),1.53 – 1.34 (m, 4H), 1.34 – 1.20 (m, 1H). Example 26 Using a method similar to that in Example 1, the target product (colorless oily liquid, 79.3 mg, yield 63%) was prepared by reacting pyridine borate ester with 2-{[(2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy}-5-pyridine borate pinacol ester and reacting it with an alkyl halide.

[0052] The product test data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 2.5 Hz, 1H), 7.39 (dd, J = 8.5, 2.5Hz, 1H), 6.61 (d, J = 8.5 Hz, 1H), 4.92 (td, J = 10.7, 4.3 Hz, 1H), 2.52 – 2.37(m, 1H), 2.20 (dtd, J = 12.1, 3.9, 1.8 Hz, 1H), 2.06 (pt, J = 8.3, 4.2 Hz, 1H),1.89 – 1.79 (m, 4H), 1.78 – 1.65 (m, 3H), 1.65 – 1.54 (m, 4H), 1.52 – 1.43(m, 1H), 1.42 – 1.31 (m, 4H), 1.12 (td, J = 12.6, 3.0 Hz, 1H), 1.04 – 0.92 (m,2H), 0.91 – 0.84 (m, 6H), 0.76 (d, J = 7.0 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ162.26, 144.82, 137.32, 135.17, 110.89, 74.34, 47.82, 41.15, 40.90, 34.61,34.40 (d,J = 4.6 Hz), 31.35, 26.80, 26.30, 26.03, 23.75, 22.20, 20.84, 16.69. Example 27 Using a method similar to that in Example 1, the target product (colorless oily liquid, 87.6 mg, yield 70%) was prepared by reacting pyridine borate ester with 5-boronic acid pinacol ester-2-{[(1S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl]oxy}pyridine and alkyl halides.

[0053] The product test data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 2.5 Hz, 1H), 7.39 (dd, J = 8.5, 2.6Hz, 1H), 6.61 (d, J = 8.5 Hz, 1H), 4.75 (dd, J = 7.7, 3.5 Hz, 1H), 2.42 (dt, J =9.9, 5.8 Hz, 1H), 1.93 (dd, J = 13.3, 7.7 Hz, 1H), 1.88 – 1.78 (m, 4H), 1.72(tq, J = 11.9, 3.6 Hz, 5H), 1.57 (td, J = 12.4, 3.9 Hz, 1H), 1.45 – 1.30 (m, 4H), 1.30 – 1.19 (m, 2H), 1.19 – 1.11 (m, 1H), 1.07 (s, 3H), 0.93 (s, 3H), 0.86(s, 3H). Example 28 Using a method similar to that in Example 1, the target product (colorless oily liquid, 79.3 mg, yield 74%) was prepared by reacting pyridine borate ester with 2-{[(5R,6S,6aR)-5-(2,2-dimethyl-1,3-dioxolane-4-yl)-2,2-dimethyltetrahydrofuran[2,3-d][1,3]dioxolane-6-yl]oxy}-5-pyridine borate pinacol ester and the resulting alkyl halide.

[0054] The product test data are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 2.4 Hz, 1H), 7.44 (dd, J = 8.5, 2.5Hz, 1H), 6.67 (d, J = 8.5 Hz, 1H), 5.89 (d, J = 3.7 Hz, 1H), 5.46 (d, J = 3.0 Hz, 1H), 4.64 (d, J = 3.8 Hz, 1H), 4.44 (q, J = 6.2 Hz, 1H), 4.37 (dd, J = 7.0, 3.0 Hz,1H), 4.15 – 4.05 (m, 2H), 2.46 (ddd, J = 11.2, 6.9, 3.5 Hz, 1H), 1.89 – 1.67(m, 6H), 1.41 (s, 3H), 1.35 (dt, J = 10.3, 3.8 Hz, 4H), 1.30 (d, J = 3.1 Hz, 6H). 13 C NMR (151 MHz, CDCl3) δ 160.69, 145.06, 137.68, 136.79, 111.98, 110.87,109.04, 105.10, 83.16, 79.94, 77.22, 72.71, 66.81, 41.18, 34.39, 26.76 (d, J =10.1 Hz), 26.29, 25.96, 25.33. Example 29 Using a method similar to that in Example 1, the target product (colorless oily liquid, 94.4 mg, yield 62%) was prepared by reacting the alkyl bromide with (5S,8R,9S,10S,13S,14S)-3-bromo-10,13-dimethylhexadecylhydro-17H-cyclopenta[a]phenanthrene-17-one, replacing the alkyl bromide with (5S,8R,9S,10S,13S,14S)-3-bromo-10,13-dimethylhexadecylhydro-17H-cyclopenta[a]phenanthrene-17-one) and the alkyl halide.

[0055] The product test data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.46 (t, J = 7.7 Hz, 1H), 6.70 (d, J = 7.3 Hz, 1H), 6.52 (d, J = 8.1 Hz, 1H), 3.91 (s, 3H), 2.68 – 2.56 (m, 1H), 2.49 – 2.37(m, 1H), 2.14 – 2.00 (m, 1H), 1.97 – 1.88 (m, 1H), 1.85 – 1.74 (m, 4H), 1.74– 1.66 (m, 2H), 1.63 – 1.47 (m, 4H), 1.36 – 1.23 (m, 6H), 1.13 – 0.97 (m,2H), 0.88 (d, J = 9.5 Hz, 6H), 0.81 – 0.73 (m, 1H). 13 C NMR (150 MHz, CDCl3) δ221.6, 164.1, 163.5, 138.7, 113.3, 107.2, 54.7, 53.1, 51.5, 47.9, 46.7, 46.2,38.6, 36.0, 35.9, 35.1, 34.8, 31.6, 31.0, 28.6, 28.0, 21.8, 20.3, 13.9, 12.4.

[0056] Example 30 Using a method similar to that in Example 1, the target product (colorless oily liquid, 99 mg, yield 51%) was prepared by reacting ethyl (4R)-4-[(8R,9S,10S,13R,14S,17R)-3-bromo-10,13-dimethylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl]valerate with pyridine borate ester, by replacing the alkyl halide with ethyl (4R)-4-[(8R,9S,10S,13R,14S,17R)-3-bromo-10,13-dimethylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl]valerate.

[0057] 1 H NMR (400 MHz, CDCl3) δ 7.50 – 7.42 (m, 1H), 6.72 (d, J = 7.3 Hz, 1H), 6.52 (d, J = 8.1 Hz, 1H), 4.11 (qd, J= 7.1, 1.9 Hz, 2H), 3.92 (s, 2H), 3.89 (s,1H), 2.63 (ddt, J = 12.5, 8.2, 4.3 Hz, 1H), 2.31 (dd, J = 10.1, 5.1 Hz, 1H), 2.20(td, J = 9.4, 9.0, 4.8 Hz, 1H), 2.04 – 1.74 (m, 7H), 1.64 (d, J = 9.0 Hz, 1H),1.60 – 1.55 (m, 1H), 1.54 – 1.46 (m, 3H), 1.44 – 1.35 (m, 4H), 1.25 (td, J =7.1, 1.6 Hz, 6H), 1.17 – 1.02 (m, 6H), 0.97 (s, 3H), 0.91 (dd, J = 6.3, 2.5 Hz,3H), 0.86 (s, 1H), 0.65 (d, J = 2.7 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 174.33,164.41, 163.45, 138.68, 138.39, 113.16, 107.10, 106.72, 60.16, 56.70, 56.59,56.01, 53.12, 46.60, 43.68, 42.78, 40.67, 40.52, 40.28, 37.38, 35.94, 35.39,34.98, 33.44, 31.33, 31.03, 28.23, 27.48, 27.29, 26.94, 26.57, 24.25, 24.19, 24.10, 24.03, 21.03, 20.91, 18.31, 14.29, 12.08. Example 31 Using a method similar to that in Example 1, the target product (colorless oily liquid, 115.8 mg, yield 62%) was prepared by reacting 1-(4-bromopiperidin-1-yl)-3-(4,5-diphenyloxazol-2-yl)propane-1-one with pyridine borate ester, by replacing the alkyl halide with 1-(4-bromopiperidin-1-yl)-3-(4,5-diphenyloxazol-2-yl)propane-1-one.

[0058] 1H NMR (400 MHz, CDCl3) δ 7.65 – 7.60 (m, 2H), 7.60 – 7.55 (m, 2H),7.48 (dd, J = 8.2, 7.3 Hz, 1H), 7.39 – 7.29 (m, 6H), 6.67 (d, J = 7.2 Hz, 1H), 6.57 (d, J = 8.2 Hz, 1H), 4.77 (ddt, J = 13.2, 4.4, 2.3 Hz, 1H), 4.11 – 4.04 (m,1H), 3.89 (s, 3H), 3.28 – 3.14 (m, 3H), 2.98 (td, J = 7.6, 4.8 Hz, 2H), 2.83(tt, J = 11.7, 3.7 Hz, 1H), 2.74 (td, J = 12.9, 2.8 Hz, 1H), 2.02 – 1.92 (m, 2H), 1.78 (ddt, J = 17.1, 8.7, 4.2 Hz, 2H). 13 C NMR (151 MHz, CDCl3) δ 169.29, 163.62,162.84, 161.61, 138.95, 132.62, 129.04, 128.64, 128.58, 128.38, 128.04,127.99, 126.44, 113.42, 108.20, 53.20, 45.78, 43.85, 42.22, 32.01, 31.24,30.17, 23.92. Example 32 Using a method similar to that in Example 1, the target product (colorless oily liquid, 100.6 mg, yield 57%) was prepared by reacting pyridine borate with 2-[2-(4-bromopiperidin-1-yl)-2-oxoethyl]dibenzo[b,e]oxetane-11(6H)-one, replacing the alkyl halide with pyridine borate.

[0059] 1 H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 2.4 Hz, 1H), 7.86 (dd,J = 7.7, 1.4Hz, 1H), 7.53 (td, J = 7.5, 1.4 Hz, 1H), 7.48 – 7.41 (m, 3H), 7.33 (dd, J = 7.4, 1.3 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 6.65 (d, J = 7.2 Hz, 1H), 6.53 (d, J = 8.2Hz, 1H), 5.15 (s, 2H), 4.73 (ddt, J = 13.4, 4.6, 2.3 Hz, 1H), 4.02 (ddt, J =13.3, 5.0, 2.3 Hz, 1H), 3.85 (s, 3H), 3.76 (s, 2H), 3.14 (td, J = 12.8, 12.4,2.7 Hz, 1H), 2.78 – 2.68 (m, 2H), 1.90 (tdt, J = 13.3, 4.5, 2.5 Hz, 2H), 1.69(dtd, J = 46.7, 12.5, 4.1 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 190.82, 169.03,163.57, 161.53, 160.27, 140.41, 138.93, 136.12, 135.63, 132.79, 131.82,129.48, 129.23, 129.22, 127.84, 125.12, 121.14, 113.44, 108.18, 73.64, 53.16,46.43, 43.69, 42.27, 39.76, 31.85, 31.16. Example 33 Using a method similar to that in Example 1, the target product (colorless oily liquid, 74 mg, yield 40%) was prepared by changing the pyridine borate ester to 6-(morpholin-4-yl)pyridine-3-boronic acid pinacol ester and the alkyl halide to (4R)-1-(((4-bromopiperidin-1-yl)sulfonyl)methyl)-7,7-dimethylbicyclo[2.2.1]heptane-2-one, as shown in the following structural formula.

[0060] 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 2.5 Hz, 1H), 7.35 (dd, J = 8.8, 2.5Hz, 1H), 6.61 (d, J = 8.8 Hz, 1H), 3.98 – 3.89 (m, 2H), 3.80 (t, J = 4.9 Hz, 4H),3.44 (t, J = 4.8 Hz, 4H), 3.34 (d, J = 14.6 Hz, 1H), 2.87 (dtd, J = 27.4, 12.0, 2.6Hz, 2H), 2.75 (d, J = 14.6 Hz, 1H), 2.53 (ddd, J = 16.5, 10.8, 3.8 Hz, 2H), 2.37(dt, J = 18.5, 4.0 Hz, 1H), 2.09 (t, J = 4.6 Hz, 1H), 2.02 (dp, J = 12.1, 4.0 Hz,1H), 1.92 (d, J = 18.4 Hz, 1H), 1.89 – 1.83 (m, 2H), 1.74 (qd, J = 12.4, 4.1 Hz,2H), 1.62 (ddd, J = 14.0, 9.4, 4.6 Hz, 1H), 1.41 (ddd, J = 13.0, 9.3, 3.9 Hz,1H), 1.12 (s, 3H), 0.87 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 215.53, 158.70,146.30, 135.93, 130.07, 107.02, 66.77, 58.26, 47.99, 46.44, 46.28, 45.81,44.88, 42.77, 42.62, 38.69, 32.99, 32.97, 26.94, 25.13, 20.03, 19.80. It should be noted that, except for the variables, all the substances and their amounts, reaction temperatures, times and other process conditions in Examples 2 to 33 are the same as in Example 1.

[0061] The foregoing has described some specific embodiments of this application. It should be understood that this application is not limited to the specific embodiments described above, and those skilled in the art can make various modifications or variations within the scope of the claims, which do not affect the substantive content of this application. The above-described preferred features can be used in any combination without conflict.

Claims

1. A method for synthesizing nitrogen-containing heterocyclic aromatic hydrocarbon derivatives via a borate ester-promoted Suzuki coupling reaction, characterized in that, The method uses pyridine borate esters of Formula I, pyrimidine borate esters of Formula II, and quinoline borate esters of Formula III as raw materials. Under the action of borate ester additives, catalysts, ligands, and bases, the pyridine derivatives of Formula V, pyrimidine derivatives of Formula VI, and quinoline derivatives of Formula VII are generated respectively through coupling with alkyl halides of Formula IV. ； In the formula, R is hydrogen or a substituent, which is selected from any one of alkyl, aryl, halogen, amino and alkyloxy groups, and Bpin is a pinacol boronic acid ester group.

2. The method according to claim 1, characterized in that, The borate ester additive is any one or more of boron trifluoride ethyl ether, trimethyl borate, triethyl borate, triisopropyl borate, tripropyl borate, triphenyl borate, triisobutyl borate, and tributyl borate.

3. The method according to claim 1, characterized in that, The catalyst is a copper catalyst.

4. The method according to claim 1, characterized in that, The catalyst is any one or more of cuprous bromide, cuprous bromide dimethyl sulfide, copper trifluoromethanesulfonate, cuprous chloride, cuprous iodide, copper thiophene-2-carboxylate (I), copper bromide, and copper acetate.

5. The method according to claim 1, characterized in that, The ligand is a nitrogen-containing ligand.

6. The method according to claim 1, characterized in that, The ligand is any one or more of bipyridine, o-phenanthroline, 4,7-diphenyl-1,10-o-phenanthroline, 4,7-dimethyl-1,10-o-phenanthroline, and 4,7-dichloro-1,10-o-phenanthroline.

7. The method according to claim 1, characterized in that, The alkali is any one or more of sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium ethoxide, and sodium methoxide.

8. The method according to claim 1, characterized in that, It has at least one of the following characteristics: - The amount of the borate ester additive added is 0.2-5 equivalents of the molar amount of the reaction substrate; - The amount of catalyst added is 0.01-1 equivalent of the molar amount of the reaction substrate; - The amount of the ligand added is 0.01-1 equivalent of the molar amount of the reaction substrate; - The amount of base added is 0.2-5 equivalents of the molar amount of the reaction substrate; - The molar ratio of nitrogen-containing heterocyclic borate ester to alkyl halide is 0.5-5:

1.

9. The method according to claim 1, characterized in that, The coupling reaction is carried out at a temperature of 40-140℃ for 1-24 hours.

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