阅读说明：本技术 一种氢转移还原吡啶类化合物制备哌啶类化合物的方法 (Method for preparing piperidine compound by hydrogen transfer reduction of pyridine compound ) 是由 周太刚 肖瑶 张谦 杜倩宇 于 2020-12-29 设计创作，主要内容包括：本发明公开了一种氢转移还原吡啶类化合物制备哌类化合物的方法,属于有机合成领域。本发明在温和的条件下,以吡啶类衍生物为原料,以噁唑硼烷为氢转移试剂,以廉价过渡金属铜、钴、银和钯等为催化剂,催化在1,2,3,4-取代位上进行的氢转移反应,从而制备出一系列氢转移还原产物哌啶类化合物。其中,噁唑硼烷是由氨基酸与硼烷的四氢呋喃络合物反应得到的。本发明的优点是：产物的收率高,反应条件温和,原料普遍适用性好,氢转移试剂廉价易得,扩大量反应仍然能表现出好的重现性。因此,本发明为今后包含此结构的其他高价值化合物的工业化生产提供了一种有效的方案。(The invention discloses a method for preparing piperazine compounds by hydrogen transfer reduction of pyridine compounds, belonging to the field of organic synthesis. Under mild conditions, pyridine derivatives are used as raw materials, oxazaborolidine is used as a hydrogen transfer reagent, cheap transition metals such as copper, cobalt, silver and palladium are used as catalysts, and hydrogen transfer reaction on 1,2,3, 4-substitution positions is catalyzed, so that a series of hydrogen transfer reduction products, namely piperidine compounds, are prepared. Wherein the oxazaborolidine is obtained by reacting an amino acid with a tetrahydrofuran complex of borane. The invention has the advantages that: the yield of the product is high, the reaction condition is mild, the general applicability of the raw materials is good, the hydrogen transfer reagent is cheap and easy to obtain, and the expanded amount reaction still can show good reproducibility. Therefore, the invention provides an effective scheme for the industrial production of other high-value compounds containing the structure in the future.)

1. A method for preparing piperidine compounds by hydrogen transfer reduction of pyridine compounds is characterized in that: the method comprises the following steps:

(1) adding amino acid into a Schlenk tube, adding tetrahydrofuran complex of borane into an ice water bath under the protection of inert gas (nitrogen or argon), stirring at room temperature to obtain oxazaborolidine, and removing an organic solvent to directly use in the next step; the synthetic route is as follows:

(2) adding a nitrogen heterocyclic compound, a solvent, a catalyst and an additive into a Schlenk tube filled with the oxazaborolidine; tracking by TLC in the reaction process to determine specific reaction time; the synthetic route is as follows:

(3) after the reaction is finished, spin-drying the organic solvent in the step (2), and purifying by using a silica gel column to obtain a hydrogen transfer reduction product, wherein an eluent is a mixed solution of dichloromethane and methanol;

wherein: reaction temperature and time: the reaction temperature in the step (1) is room temperature, and the reaction time is 0.5-24 h; the reaction temperature of the step (2) is 0-100 ℃, and the reaction time is 0.5-36 h;

wherein: r¹And R²One selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, hydroxyl and ester group; r¹And R²The same or different; r³And R⁴One selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, furyl and thienyl;

wherein: the nitrogen-containing heterocyclic compound is a pyridine derivative;

wherein: the molar concentration of the nitrogen-containing heterocyclic compound in the solvent is 0.01-10 mmol/mL;

wherein: the reaction solvent is one or more of organic or inorganic solvents such as tetrahydrofuran, dichloromethane, dichloroethane, toluene, 1, 4-dioxane, acetonitrile, dimethyl sulfoxide, methanol, water, etc.;

wherein: the catalyst for the reaction is cheap transition metal, and comprises copper catalysts such as copper perchlorate hexahydrate, copper trifluoromethanesulfonate, copper acetate, copper chloride, cuprous iodide, copper hydroxide and copper sulfate pentahydrate, cobalt catalysts such as cobalt perchlorate hexahydrate, silver catalysts such as silver perchlorate, palladium catalysts such as palladium acetate and other cheap metal catalysts; the dosage of the catalyst is 1 to 50 percent;

wherein: in the reaction, a hydrogen transfer reagent is oxazaborolidine, the preparation method is amino acid, a tetrahydrofuran complex of the borane reacts at normal temperature to generate an organic boron reagent, namely the oxazaborolidine, and the molar ratio of the amino acid to the borane is 1-1: 4; the oxazaborolidine further participates in the reaction, and the molar ratio of the pyridine and the derivatives thereof to the oxazaborolidine is 1-1: 10;

the treatment and purification method comprises the following steps: spin-drying the reacted solvent, and further purifying and separating by column chromatography; the column chromatography can select 200-300 mesh silica gel or alkaline alumina as a stationary phase, and the developing agent generally selects a mixed system of dichloromethane and methanol.

The technical field is as follows:

the invention belongs to the technical field of organic chemistry including preparation of medical intermediates and related chemistry, and particularly relates to a method for preparing piperidine compounds by hydrogen transfer reduction of pyridine compounds.

Background art:

n-heterocyclic compounds and their hydroreduc-tion derivatives, especially piperidines, are important building blocks constituting many natural products, pharmaceuticals and other biologically active substances. The alkaloid taking piperidine as a parent has various physiological activities and has potential application values in the aspects of resisting cancers, bacteria and viruses, treating diabetes and the like; also has application in the field of high polymer materials. [ Li Ming, Iridium catalytic highly selective synthesis piperidine derivatives [ D ]. university of great courseware, 2019. Pozihui, Tianhao, Zuli, research progress on piperidine compounds with pesticide activity [ J ]. world pesticide, 2017,39(04):43-46. Cheng Ling. New synthetic method research on piperidine analgesics [ D ]. Beijing university of transportation, 2015. Liu Yong, asymmetric synthesis research on piperidine compounds with biological activity [ D ]. university of Xiamen, 2003 ]. The preparation of such compounds is therefore a very important step in industrial applications. In general, selective hydrogenation research on nitrogen-containing heterocyclic compounds generally uses hydrogen as a hydrogen source, but the reaction requires hydrogen with higher pressure, so that the operation is inconvenient and the reaction is more potentially dangerous. The hydrogen donor is used as a hydrogen source instead of hydrogen in the presence of a catalyst, compared with the conventional reaction, the reaction reduces the requirement of reaction equipment, has milder reaction conditions than the prior reaction, and has better application prospect in research and production. Secondly, the reaction is more efficient, energy-saving and environment-friendly. In recent years, the hydrogen transfer reaction of nitrogen heterocyclic compounds catalyzed by transition metals has been widely noticed and studied [ Zhang ling juan, Qiu; ruiying; xue Xiao; pan Yixiao; li Huangrong; xu Lijin.Adv.Synth.Catal.2015,357(16-17) 3529. 3537. Tao, Lei; zhang Qi; li Shu-Shuang; liu Yong-Mei; cao Yong.Adv.Synth.Catal.2015, 357(4): 753-760 ]. The method has the advantages of mild conditions, strong substrate universality, high conversion rate, greenness and safety. In the past years, a group of subjects found Metal-free organoborane-catalyzed pyridine reductions [ Liu Y, Du H. Metal-free boron-catalyzed high selectivity reactivity of pyridines [ J ]. Journal of the American Chemical Society,2013,135(35):12968-12971.Eisenberger P, Bestvater B P, Keske C, et al. hydrodynamics at a temperature and temperature regime with a biological carbon-stabilized boron catalysts [ J ]. Angeway chemistry-International Edition 2015,54(8) 2467-71. gap N, Park S, chemistry ] propagation of pyridine, 15184. Journal of Chemical complexes of reaction [ 15184 ] these disadvantages: 1) for hydrogenation and transfer hydrogenation reactions, a large number of ortho substituents must be present on the pyridine ring to circumvent catalyst deactivation by coordination of the nitrogen; 2) unsaturated functional groups such as olefins, esters, ketones, nitriles and nitro groups are less compatible because they are easier to reduce.

The invention content is as follows:

the invention provides a method for preparing piperidine compounds by hydrogen transfer reduction of pyridine compounds. Transition metal is used as a catalyst for reaction, oxazaborolidine is used as a hydrogen transfer reagent, and the oxazaborolidine and a nitrogen-containing heterocyclic compound are subjected to hydrogen transfer reaction to obtain a corresponding reduction product, so that the application range is wide. The method has the advantages of cheap and easily-obtained hydrogen transfer reagent, mild reaction conditions, high yield and good reproducibility.

The specific technical scheme of the invention is summarized as follows:

a method for preparing piperidine compounds by hydrogen transfer reduction of pyridine compounds comprises the following steps:

(1) adding amino acid into a Schlenk tube, adding tetrahydrofuran complex of borane into an ice water bath under the protection of inert gas (nitrogen or argon), stirring at room temperature to obtain oxazaborolidine, and removing an organic solvent to directly use in the next step; the synthetic route is as follows:

(2) adding a nitrogen heterocyclic compound, a solvent, a catalyst and an additive into a Schlenk tube filled with the oxazaborolidine; tracking by TLC in the reaction process to determine specific reaction time; the synthetic route is as follows:

(3) after the reaction is finished, spin-drying the organic solvent in the step (2), and purifying by using a silica gel column to obtain a hydrogen transfer reduction product, wherein an eluent is a mixed solution of dichloromethane and methanol;

wherein: reaction temperature and time: the reaction temperature in the step (1) is room temperature, and the reaction time is 0.5-24 h; the reaction temperature of the step (2) is 0-100 ℃, and the reaction time is 0.5-36 h;

wherein: r¹And R²One selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, hydroxyl and ester group; r¹And R²The same or different; r³And R⁴One selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, furyl and thienyl;

wherein: the nitrogen-containing heterocyclic compound is a pyridine derivative;

wherein: the molar concentration of the nitrogen-containing heterocyclic compound in the solvent is 0.01-10 mmol/mL;

wherein: the reaction solvent is one or more of organic or inorganic solvents such as tetrahydrofuran, dichloromethane, dichloroethane, toluene, 1, 4-dioxane, acetonitrile, dimethyl sulfoxide, methanol, water, etc.;

wherein: the catalyst for the reaction is cheap transition metal, and comprises copper catalysts such as copper perchlorate hexahydrate, copper trifluoromethanesulfonate, copper acetate, copper chloride, cuprous iodide, copper hydroxide and copper sulfate pentahydrate, cobalt catalysts such as cobalt perchlorate hexahydrate, silver catalysts such as silver perchlorate, palladium catalysts such as palladium acetate and other cheap metal catalysts; the dosage of the catalyst is 1 to 50 percent;

wherein: in the reaction, a hydrogen transfer reagent is oxazaborolidine, the preparation method is amino acid, a tetrahydrofuran complex of the borane reacts at normal temperature to generate an organic boron reagent, namely the oxazaborolidine, and the molar ratio of the amino acid to the borane is 1-1: 4; the oxazaborolidine further participates in the reaction, and the molar ratio of the pyridine and the derivatives thereof to the oxazaborolidine is 1-1: 10;

the treatment and purification method comprises the following steps: spin-drying the reacted solvent, and further purifying and separating by column chromatography; the column chromatography can select 200-300 mesh silica gel or alkaline alumina as a stationary phase, and the developing agent generally selects a mixed system of dichloromethane and methanol.

The invention has the beneficial effects that: high yield, relatively mild reaction conditions, cheap and easily obtained hydrogen transfer reagent, environmental protection, safety and good reproducibility.

The specific implementation mode is as follows:

the method has the advantages of high yield of the prepared piperidine compound, low requirement on reaction environment, relatively mild conditions, good general applicability of raw materials, cheap and easily-obtained hydrogen transfer reagent and high reproducibility of the expanded-amount reaction. Therefore, the invention provides an effective scheme for the industrial production of other high-value compounds containing the structure in the future.

The technical solutions of the present invention will be further illustrated and described with reference to specific embodiments. The simple replacement or improvement of the present invention by those skilled in the art is within the technical scheme of the present invention.

Example 1: preparation of 3-methylpiperidine

Weighing beta-alanine (222.8mg, 2.5mmol), adding into a Schlenk tube, cooling to 0 ℃ under the protection of inert gas, adding tetrahydrofuran complex (1M, 5.0mmol) of borane, stirring at room temperature for reaction for 24h, and drying the solvent in vacuum to obtain oxazaborolidine which is directly used for the next step. 3-methylpyridine (46.6mg, 0.5mmol), tetrahydrofuran (2.0mL), palladium acetate (11.3mg, 0.05mmol) were added to a schlenk tube containing oxazaborolidine, still under an inert gas blanket. The reaction was stirred at 60 ℃ for 24 h. The resultant reaction was purified by a silica gel column (dichloromethane/methanol) to give 3-methylpiperidine (34.1mg) in 68.8% yield.

3-methylpiperidine

¹H NMR(600MHz,CDCl₃)δ3.06-3.03(m,1H),2.67-2.55(m,2H),1.78-1.75(m, 1H),1.64-1.55(m,2H),1.41-1.30(m,2H),1.10-1.05(m,1H),1.04(d,J＝6.3Hz, 3H).¹³C NMR(151MHz,CDCl₃)δ52.3,47.2,34.8,26.3,24.9,23.2.

Example 2: preparation of 3-phenylpiperidines

Weighing beta-alanine (222.8mg, 2.5mmol), adding into a Schlenk tube, cooling to 0 ℃ under the protection of inert gas, adding tetrahydrofuran complex (1M, 5.0mmol) of borane, stirring at room temperature for reaction for 24h, and drying the solvent in vacuum to obtain oxazaborolidine which is directly used for the next step. 3-phenylpyridine (77.6mg, 0.5mmol), tetrahydrofuran (2.0mL), palladium acetate (11.3mg, 0.05mmol) were added to a Schlenk tube containing oxazaborolidine, still under an inert atmosphere. The reaction was stirred at 60 ℃ for 24 h. The resultant reaction was purified by a silica gel column (dichloromethane/methanol) to give 3-phenylpiperidine (70.4mg) in 87.3% yield.

3-phenylpiperidines

¹H NMR(400MHz,CDCl₃)δ7.32-7.26(m,2H),7.25-7.16(m,3H),3.19-3.06(m, 2H),2.74-2.57(m,3H),2.02-1.96(m,1H),1.86-1.73(m,2H),1.66-1.54(m,2H).¹³C NMR(101MHz,CDCl₃)δ145.0,128.5,127.2,126.3,54.2,46.8,44.5,32.2,27.2.

Example 3: preparation of 4-phenylpiperidines

Weighing beta-alanine (222.8mg, 2.5mmol), adding into a Schlenk tube, cooling to 0 ℃ under the protection of inert gas, adding tetrahydrofuran complex (1M, 5.0mmol) of borane, stirring at room temperature for reaction for 24h, and drying the solvent in vacuum to obtain oxazaborolidine which is directly used for the next step. 4-phenylpyridine (77.6mg, 0.5mmol), tetrahydrofuran (2.0mL), palladium acetate (11.3mg, 0.05mmol) were added to a Schlenk tube containing oxazaborolidine, still under an inert atmosphere. The reaction was stirred at 60 ℃ for 24 h. The resultant reaction was purified by a silica gel column (dichloromethane/methanol) to give 4-phenylpiperidine (68.6mg) in 85.1% yield.

4-phenylpiperidines

¹H NMR(400MHz,CDCl₃)δ7.35-7.31(m,2H),7.26-7.20(m,3H),3.23-3.20(m,2H), 2.77(t,J＝12.4Hz,2H),2.68-2.61(m,1H),2.16(br,1H),1.87-1.84(m,2H),1.73- 1.62(m,2H).¹³C NMR(101MHz,CDCl₃)δ146.4,128.4,126.8,126.2,46.7,42.8, 33.9.

Example 4: preparation of 3-benzoylpiperadines

Weighing beta-alanine (222.8mg, 2.5mmol), adding into a Schlenk tube, cooling to 0 ℃ under the protection of inert gas, adding tetrahydrofuran complex (1M, 5.0mmol) of borane, stirring at room temperature for reaction for 24h, and drying the solvent in vacuum to obtain oxazaborolidine which is directly used for the next step. 3-benzoylpyridine (94.6mg, 0.5mmol), tetrahydrofuran (2.0mL), palladium acetate (11.3mg, 0.05mmol) were added to a Schlenk's tube containing oxazaborolidine, still under inert gas. The reaction was stirred at 60 ℃ for 24 h. The resulting reaction was purified by silica gel column (dichloromethane/methanol) to give 3-benzoylpiperidine (83.7mg) in 88.5% yield.

3-benzoylpiperadines

¹H NMR(400MHz,CDCl₃)δ7.95(d,J＝7.2Hz,2H),7.58-7.53(m,1H),7.46(t,J＝7.5Hz,2H),4.04(br,1H),3.57-3.47(m,1H),3.27-3.21(m,1H),3.12-3.05(m,1H), 2.88(dd,J＝12.2,10.1Hz,1H),2.73-2.65(m,1H),2.06-1.96(m,1H),1.79-1.73(m, 1H),1.71-1.62(m,2H).¹³C NMR(101MHz,CDCl₃)δ202.3,136.0,133.3,128.9, 128.4,48.8,46.3,44.6,28.1,25.3.

Example 5: preparation of 3- (p-tolyl) piperidine

Weighing beta-alanine (222.8mg, 2.5mmol), adding into a Schlenk tube, cooling to 0 ℃ under the protection of inert gas, adding tetrahydrofuran complex (1M, 5.0mmol) of borane, stirring at room temperature for reaction for 24h, and drying the solvent in vacuum to obtain oxazaborolidine which is directly used for the next step. 3- (p-tolyl) pyridine (84.6mg, 0.5mmol), tetrahydrofuran (2.0mL), palladium acetate (11.3mg, 0.05mmol) were added to a schlenk tube with oxazaborolidine, still under inert gas. The reaction was stirred at 60 ℃ for 24 h. The resulting reaction was purified by silica gel column (dichloromethane/methanol) to give 3- (p-tolyl) piperidine (68.6mg) in 78.3% yield

3- (p-tolyl) piperidine

¹H NMR(600MHz,CDCl₃)δ7.14-7.10(m,4H),3.85(br,1H),3.21-3.14(m,2H), 2.76-2.62(m,3H),2.32(s,3H),2.02-1.97(m,1H),1.84-1.77(m,1H),1.72-1.57(m, 2H).¹³C NMR(151MHz,CDCl₃)δ141.5,136.0,129.2,127.0,53.6,46.3,43.3,32.0, 26.6,21.1.

Example 6: preparation of 3- (4- (trifluoromethyl) phenyl) piperidine

Weighing beta-alanine (222.8mg, 2.5mmol), adding into a Schlenk tube, cooling to 0 ℃ under the protection of inert gas, adding tetrahydrofuran complex (1M, 5.0mmol) of borane, stirring at room temperature for reaction for 24h, and drying the solvent in vacuum to obtain oxazaborolidine which is directly used for the next step. 3- (4- (trifluoromethyl) phenyl) pyridine (111.6mg, 0.5mmol), tetrahydrofuran (2.0mL), palladium acetate (11.3mg, 0.05mmol) were added to a Schlenk's tube containing oxazaborolidine, still under an inert atmosphere. The reaction was stirred at 60 ℃ for 24 h. The resultant reaction was purified by a silica gel column (dichloromethane/methanol) to give 3- (4- (trifluoromethyl) phenyl) piperidine (95.6mg) in 85.7% yield

3- (4- (trifluoromethyl) phenyl) piperidine

¹H NMR(400MHz,CDCl₃)δ7.55(d,J＝8.0Hz,2H),7.32(d,J＝8.0Hz,2H),3.89(br, 1H),3.25-3.15(m,2H),2.87-2.79(m,1H),2.72-2.63(m,2H),2.03-1.98(m,1H),1.86- 1.79(m,1H),1.72-1.58(m,2H).¹³C NMR(101MHz,CDCl₃)δ149.1,128.7(q,J＝ 32.4Hz),127.6,125.4(q,J＝3.7Hz),124.4(q,J＝271.7Hz),53.9,46.7,44.3,32.1, 27.0.

Example 7: preparation of 3- (4-methoxyphenyl) piperidine

Weighing beta-alanine (222.8mg, 2.5mmol), adding into a Schlenk tube, cooling to 0 ℃ under the protection of inert gas, adding tetrahydrofuran complex (1M, 5.0mmol) of borane, stirring at room temperature for reaction for 24h, and drying the solvent in vacuum to obtain oxazaborolidine which is directly used for the next step. 3- (4-methoxyphenyl) pyridine (92.6mg, 0.5mmol), tetrahydrofuran (2.0mL), palladium acetate (11.3mg, 0.05mmol) were added to a schlenk tube containing oxazaborolidine, still under an inert gas blanket. The reaction was stirred at 60 ℃ for 24 h. The resultant reaction was purified by a silica gel column (dichloromethane/methanol) to give 3- (4-methoxyphenyl) piperidine (92.5mg) in 96.7% yield

3- (4-methoxyphenyl) piperidine

¹H NMR(600MHz,CDCl₃)δ7.27(d,J＝8.4Hz,2H),6.84(d,J＝8.3Hz,2H),3.78 (s,3H),3.55-3.50(m,1H),3.20-3.14(m,1H),2.82-2.73(m,1H),1.91-1.83(m,1H), 1.76-1.70(m,2H),1.68-1.62(m,1H),1.56-1.43(m,3H).¹³C NMR(151MHz,CDCl₃) δ158.7,138.0,127.7,113.8,61.8,55.3,48.0,35.1,26.0,25.6.

Example 8: preparation of 3- (4-fluorophenyl) piperidine

Weighing beta-alanine (222.8mg, 2.5mmol), adding into a Schlenk tube, cooling to 0 ℃ under the protection of inert gas, adding tetrahydrofuran complex (1M, 5.0mmol) of borane, stirring at room temperature for reaction for 24h, and drying the solvent in vacuum to obtain oxazaborolidine which is directly used for the next step. 3- (4-fluorophenyl) pyridine (86.6mg, 0.5mmol), tetrahydrofuran (2.0mL), palladium acetate (11.3mg, 0.05mmol) were added to a schlenk tube containing oxazaborolidine, still under an inert gas blanket. The reaction was stirred at 60 ℃ for 24 h. The resulting reaction was purified by silica gel column (dichloromethane/methanol) to give 3- (4-fluorophenyl) piperidine (81.5mg) in 90.9% yield

3- (4-fluorophenyl) piperidine

¹H NMR(600MHz,CDCl₃)δ7.17–7.12(m,2H),6.98–6.93(m,2H),3.19–3.08 (m,1H),3.04(s,1H),2.69(tt,J＝12.0Hz,1H),2.65–2.57(m,2H),1.99–1.93(m, 1H),1.81–1.74(m,1H),1.65–1.51(m,2H).¹³C NMR(151MHz,CDCl₃)δ140.27, 140.25,128.50,128.45,115.27,115.13,53.78,46.36,43.16,32.15,26.68.

Example 9: preparation of 3- (4- (tert-butyl) phenyl) piperidine

Weighing beta-alanine (222.8mg, 2.5mmol), adding into a Schlenk tube, cooling to 0 ℃ under the protection of inert gas, adding tetrahydrofuran complex (1M, 5.0mmol) of borane, stirring at room temperature for reaction for 24h, and drying the solvent in vacuum to obtain oxazaborolidine which is directly used for the next step. 3- (4- (tert-butyl) phenyl) pyridine (105.7mg, 0.5mmol), tetrahydrofuran (2.0mL), palladium acetate (11.3mg, 0.05mmol) were added to a schlenk tube containing oxazaborolidine, still under an inert gas blanket. The reaction was stirred at 60 ℃ for 24 h. The resultant reaction was purified by a silica gel column (dichloromethane/methanol) to give 3- (4- (tert-butyl) phenyl) piperidine (107.5mg) in 98.9% yield

3- (4- (tert-butyl) phenyl) piperidine

¹H NMR(600MHz,CDCl₃)δ7.35–7.29(m,2H),7.20–7.12(m,2H),3.35(s,1H), 3.24–3.18(m,1H),3.18–3.11(m,1H),2.72(tt,J＝10.8,3.3Hz,1H),2.70–2.61 (m,2H),2.04–1.97(m,1H),1.84–1.77(m,1H),1.71–1.56(m,2H),1.31(s,9H). ¹³C NMR(151MHz,CDCl₃)δ149.25,141.37,126.78,125.40,53.54,46.36,43.20, 34.47,31.95,31.47,26.66.

Example 10: preparation of 3- (2-methylphenyl) piperidine

Weighing beta-alanine (222.8mg, 2.5mmol), adding into a Schlenk tube, cooling to 0 ℃ under the protection of inert gas, adding tetrahydrofuran complex (1M, 5.0mmol) of borane, stirring at room temperature for reaction for 24h, and drying the solvent in vacuum to obtain oxazaborolidine which is directly used for the next step. 3- (2-methylphenyl) pyridine (71.5mg, 0.5mmol), tetrahydrofuran (2.0mL), palladium acetate (11.3mg, 0.05mmol) were added to a schlenk tube containing oxazaborolidine, still under an inert atmosphere. The reaction was stirred at 60 ℃ for 24 h. The resultant reaction was purified by a silica gel column (dichloromethane/methanol) to give 3- (2-methylphenyl) piperidine (82.3mg) in 93.9% yield

3- (2-methylphenyl) piperidine

¹H NMR(600MHz,CDCl₃)δ7.22–7.08(m,4H),3.15–3.07(m,2H),2.91(tt,J＝ 12.0Hz,1H),2.69–2.63(m,2H),2.36(s,3H),2.31(s,1H),1.95–1.89(m,1H),1.83 –1.76(m,1H),1.69–1.60(m,2H).¹³C NMR(151MHz,CDCl₃)δ142.86,135.70, 130.43,126.16,126.02,125.62,53.15,46.84,39.94,31.73,27.32,19.57.

Example 11: preparation of 2- (4-methoxyphenyl) piperidine

Weighing beta-alanine (222.8mg, 2.5mmol), adding into a Schlenk tube, cooling to 0 ℃ under the protection of inert gas, adding tetrahydrofuran complex (1M, 5.0mmol) of borane, stirring at room temperature for reaction for 24h, and drying the solvent in vacuum to obtain oxazaborolidine which is directly used for the next step. 2- (4-methoxyphenyl) pyridine (92.6mg, 0.5mmol), tetrahydrofuran (2.0mL), palladium acetate (11.3mg, 0.05mmol) were added to a schlenk tube containing oxazaborolidine, still under an inert gas blanket. The reaction was stirred at 60 ℃ for 24 h. The resulting reaction was purified by silica gel column (dichloromethane/methanol) to give 2- (4-methoxyphenyl) piperidine (70.4mg) in 73.6% yield

2- (4-methoxyphenyl) piperidine

¹H NMR(400MHz,CDCl₃)δ7.27(d,J＝8.4Hz,2H),6.84(d,J＝8.3Hz,2H),3.78(s, 3H),3.55-3.50(m,1H),3.20-3.14(m,1H),2.82-2.73(m,1H),1.91-1.83(m,1H),1.76- 1.70(m,2H),1.68-1.62(m,1H),1.56-1.43(m,3H).¹³C NMR(101MHz,CDCl₃) δ158.7,138.0,127.7,113.8,61.8,55.3,48.0,35.1,26.0,25.6.