阅读说明：本技术 一种多取代苯并[b]氮杂*化合物的制备方法 (Preparation method of polysubstituted benzo [ b ] aza compound ) 是由 严汝龙 庄代骄 于 2020-12-29 设计创作，主要内容包括：本发明公开了一种多取代苯并[b]氮杂化合物的制备方法。这种方法通过1,4-二芳基炔烃和羟胺三氟甲磺酸盐的胺化、分子内环化反应合成了一系列多取代苯并[b]氮杂化合物。该方法原料简单易得,反应条件温和,避免了过渡金属催化剂的使用,绿色环保。同时,该方法具有底物兼容性好,产率高,原子经济性高等特点。本发明通过一锅法,利用简单炔烃一步合成多取代苯并[b]氮杂化合物,为制备具有高药理活性的新型苯并[b]氮杂化合物提供了新的路径和方法。(The invention discloses a polysubstituted benzo [ b]Aza derivatives A method for preparing the compound. The method synthesizes a series of polysubstituted benzo [ b ] through amination and intramolecular cyclization reactions of 1, 4-diaryl alkyne and hydroxylamine trifluoromethanesulfonate]Aza derivatives A compound is provided. The method has the advantages of simple and easily obtained raw materials, mild reaction conditions, no use of transition metal catalysts, and environmental protection. Meanwhile, the method has the characteristics of good substrate compatibility, high yield, high atom economy and the like. The invention synthesizes polysubstituted benzo [ b ] by one-pot method and one step by using simple alkyne]Aza derivatives Compounds for the preparation of compounds having high pharmacological activityBenzo [ b ] form]Aza derivatives)

1. polysubstituted benzo [ b]Aza derivativesA process for the preparation of a compound comprising the steps of: adding a compound with a general formula I, a compound A (hydroxylamine trifluoromethanesulfonate), a catalyst and an organic solvent into a 50mL round-bottom flask, reacting for 4 hours under certain temperature conditions, monitoring the reaction progress by thin-layer chromatography until the reaction is completed, distilling the solvent out under reduced pressure, and separating and purifying the residue by silica gel column chromatography with a mobile phase of petroleum ether/ethyl acetate (40:1) to obtain a compound II, wherein the reaction equation is as follows:

in the equation: r¹Is methyl, methoxy, fluorine, chlorine; r²Is methyl, tert-butyl, methoxy, fluorine or chlorine.

2. A polysubstituted benzo [ b ] according to claim 1]Aza derivativesA process for the preparation of a compound, characterized in that: process for preparing compound I, compound A and catalystThe molar ratio is 1: 1.0-2.0: 0.1-1.0.

3. A polysubstituted benzo [ b ] according to claim 1]Aza derivativesA process for the preparation of a compound, characterized in that: the catalyst is ferrous chloride, ferrous sulfate, cuprous chloride, cuprous iodide or iodine.

4. A polysubstituted benzo [ b ] according to claim 1]Aza derivativesA process for the preparation of a compound, characterized in that: the solvent is hexafluoroisopropanol, trifluoroethanol, acetonitrile or tetrahydrofuran.

5. A polysubstituted benzo [ b ] according to claim 1]Aza derivativesA process for the preparation of a compound, characterized in that: the reaction temperature is 20-80 ℃.

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to polysubstituted benzo [ b]Aza derivativesA method for preparing the compound.

Background

Benzo [ b ]]Aza derivativesThe compound is an important seven-membered nitrogen heterocyclic compound and widely exists in natural products and drug molecules. The chemical conversion is carried outThe compounds have excellent biological activity and wide application in the medical field, and some kinds of benzo [ b ]]Aza derivativesThe derivatives can be used as medicines on the market for treating various diseases. For example Clomipramine (Clomipramine) for the treatment of depression¹Benazepril for the treatment of hypertension and heart failure²And Tolvaptan (Tolvaptan) for the treatment of hyponatremia, liver cirrhosis, and antidiuretic hormone secretion disorder syndrome³。

In view of benzo [ b]Aza derivativesThe excellent medicinal value of the compound, and the research on the synthesis methodology of the compound is always regarded by chemists. In recent years, a large number of documents report the synthetic strategy of the compound, and the following are listed:

Xisheng Wang ⁴reports about two C-H bonds of N- (2, 5-dimethylhex-2-yl) aniline, which are prepared from N- (2, 5-dimethylhex-2-yl) aniline, 1, 2-dichloroethane as a solvent, CuO as a catalyst at a temperature of 135 ℃: c (sp)³)–H、C(sp²) -H is subjected to a cross-coupling reaction to form benzo [ b]Aza derivatives

Jaesook Yun ⁵Subject group reports synthesis of benzo [ b ] using (E) -diene arene derivative as substrate]Aza derivativesMethods of using the compounds. The reaction can obtain target products through intramolecular cyclization reaction under mild conditions, has high yield and has good areaDomain selectivity and diastereoselectivity.

Frank Glorius ⁶NHC using organic catalyst and Pd (PPh) as transition metal catalyst₃)₄The synergistic effect of (A) makes possible the cycloaddition reaction between cinnamaldehyde and vinylbenzoxazinone. The method creatively converts NHC/Pd (PPh)₃)₄Application of catalytic system in synthesis of benzo [ b]Aza derivativesAmong the derivatives, the derivatives have excellent regioselectivity.

Ohyun Kwon ⁷It was found that intermolecular cyclization reactions of o-sulfonamide benzaldehydes and acetylenic ketones can occur under phosphine catalysis. This process can give benzo [ b ] in excellent yield under mild conditions]Aza derivativesAnd (3) derivatives. The target product can be used as a molecular skeleton of an angiotensin converting enzyme inhibitor and has higher medicinal value.

Jian Xiao ⁸Proposes the use of 4-pyrrolidinylisatin and phenol as starting materials, by Sc (OTf)₃A method for synthesizing a seven-membered nitrogen heterocyclic compound by one step by catalyzing and initiating a ring expansion reaction. The method utilizes pyrrolidine with five-membered ring to synthesize benzo [ b ] through ring expansion reaction]Aza derivativesA compound ofBelongs to the first case.

Olga GarcíaReports that benzo [ b ] is obtained in a simple and direct manner under mild and transition metal-free conditions by using 1, 2-dihydroquinoline as a raw material]Aza derivativesAnd (3) derivatives. In this reaction, TMSCHN₂As nucleophiles, having two leaving groups (N)₂And TMS) which can provide a carbon source, and the carbon source and the 1, 2-dihydroquinoline undergo an oxidation ring expansion reaction to directly generate a target product.

In view of the foregoing, benzo [ b ] s are currently synthesized]Aza derivativesThe method for the derivative mainly comprises the following steps: intramolecular cyclization reaction, intermolecular cycloaddition reaction and ring expansion reaction. The general disadvantages of the above methods are: (1) complex nitrogenous substrates need to be prepared in advance, and the preparation method is complex; (2) expensive transition metal catalysts and complex ligands are generally required, and the cost is high; (3) the reaction conditions are harsh, and industrial production is extremely difficult to realize. Therefore, a method for synthesizing benzo [ b ] under mild reaction conditions by using a simple and easily available substrate through simple procedures has been studied and developed]Aza derivativesThe method of derivation is of great significance.

Disclosure of Invention

Technical problem to be solved by the inventionThe method is characterized in that a simple and easily obtained substrate 1, 4-diaryl alkyne and a compound A (hydroxylamine triflate) are utilized to synthesize benzo [ b ] by a simple and efficient method under mild conditions]Aza derivativesAnd (3) derivatives.

In order to solve the technical problems, the invention adopts the technical scheme that: preparation of benzo [ b ] using 1, 4-diaryl alkyne and hydroxylamine triflate as substrates]Aza derivativesA compound is provided. The method comprises the following steps: adding a compound with a general formula I, a compound A (hydroxylamine trifluoromethanesulfonate), a catalyst and a solvent into a round-bottom flask, reacting for 4 hours at the temperature of 20-80 ℃, and monitoring the reaction progress by thin layer chromatography until the reaction is complete. Extracting with ethyl acetate and saturated brine, drying with anhydrous sodium sulfate, distilling off solvent under reduced pressure, separating and purifying the residue by silica gel column chromatography with petroleum ether/ethyl acetate (40:1) as mobile phase to obtain compound II, wherein the reaction equation is as follows:

in the equation: r¹Is methyl, methoxy, fluorine, chlorine; r²Is methyl, tert-butyl, methoxy, fluorine or chlorine.

Benzo [ b ] above]Aza derivativesThe preparation method of the compound is characterized in that the molar ratio of the compound I to the compound A to the catalyst is 1: 1.0-2.0: 0.1-1.0.

Benzo [ b ] above]Aza derivativesThe preparation method of the compound is characterized in that the catalyst is ferrous chloride, ferrous sulfate, cuprous chloride and iodineCuprous oxide or iodine.

Benzo [ b ] above]Aza derivativesThe preparation method of the compound is characterized in that the solvent is hexafluoroisopropanol, trifluoroethanol, acetonitrile or tetrahydrofuran.

Benzo [ b ] above]Aza derivativesThe preparation method of the compound is characterized in that the reaction temperature is 20-80 ℃.

Compared with the prior art, the method has the following advantages that (1) the method innovatively provides the synthesis of benzo [ b ] by taking 1, 4-diaryl alkyne and hydroxylamine trifluoromethanesulfonate as substrates]Aza derivativesAccording to the method of the compound, the used substrate is cheap and easy to obtain, the reaction condition is mild, the operation is simple and convenient, the substrate compatibility is good, the yield is high, and the method has the potential of industrial production; (2) the technical scheme adopted by the invention uses iodine as the non-metal catalyst, avoids the use of a transition metal catalyst, is green and environment-friendly, and has high atom economy.

Detailed Description

The technical solution of the present invention is further described in detail by the following examples. The specific implementation mode is as follows:

example 1: the preparation method of this example includes the following steps:

adding compound Ia (10mmol,2.06g), hexafluoroisopropanol (20mL), compound A (20mmol,5.22g) and iodine (10mmol,2.54g) in sequence into a 50mL round-bottom flask, reacting for 4.0h at 60 ℃, and monitoring the reaction progress by thin layer chromatography until the reaction is complete; extraction with ethyl acetate and saturated brine, drying over anhydrous sodium sulfate, evaporation of the solvent under reduced pressure, and separation and purification of the residue by silica gel column chromatography using petroleum ether/ethyl acetate (40:1) as the mobile phase gave compound IIa in 75% yield. The reaction equation is as follows:

example 2: the preparation method of this example includes the following steps:

adding compound Ib (10mmol,2.20g), hexafluoroisopropanol (20mL), compound A (20mmol,5.22g) and iodine (10mmol,2.54g) in sequence into a 50mL round-bottom flask, reacting for 4.0h at the temperature of 60 ℃, and monitoring the reaction progress by thin layer chromatography until the reaction is complete; extraction with ethyl acetate and saturated brine, drying over anhydrous sodium sulfate, distilling off the solvent under reduced pressure, and separating and purifying the residue by silica gel column chromatography using petroleum ether/ethyl acetate (40:1) as a mobile phase to give compound IIb in a yield of 72%. The reaction equation is as follows:

example 3: the preparation method of this example includes the following steps:

adding compound Ic (10mmol,2.62g), hexafluoroisopropanol (20mL), compound A (20mmol,5.22g) and iodine (10mmol,2.54g) in sequence into a 50mL round-bottom flask, reacting for 4.0h at 60 ℃, and monitoring the reaction progress by thin layer chromatography until the reaction is complete; extraction with ethyl acetate and saturated brine, drying over anhydrous sodium sulfate, evaporation of the solvent under reduced pressure, and separation and purification of the residue by silica gel column chromatography using petroleum ether/ethyl acetate (40:1) as the mobile phase gave compound IIc in 58% yield. The reaction equation is as follows:

example 4: the preparation method of this example includes the following steps:

adding compound Id (10mmol,2.36g), hexafluoroisopropanol (20mL), compound A (20mmol,5.22g) and iodine (10mmol,2.54g) in sequence into a 50mL round-bottom flask, reacting for 4.0h at the temperature of 60 ℃, and monitoring the reaction progress by thin layer chromatography until the reaction is complete; extraction with ethyl acetate and saturated brine, drying over anhydrous sodium sulfate, distilling off the solvent under reduced pressure, and separating and purifying the residue by silica gel column chromatography using petroleum ether/ethyl acetate (40:1) as a mobile phase to give compound IId in 70% yield. The reaction equation is as follows:

example 5: the preparation method of this example includes the following steps:

adding compound Ie (10mmol,2.24g), hexafluoroisopropanol (20mL), compound A (20mmol,5.22g) and iodine (10mmol,2.54g) in sequence into a 50mL round-bottom flask, reacting for 4.0h at 60 ℃, and monitoring the reaction progress by thin layer chromatography until the reaction is complete; extraction with ethyl acetate and saturated brine, drying over anhydrous sodium sulfate, distilling off the solvent under reduced pressure, and separating and purifying the residue by silica gel column chromatography using petroleum ether/ethyl acetate (40:1) as the mobile phase to give compound IIe in 68% yield. The reaction equation is as follows:

example 6: the preparation method of this example includes the following steps:

adding compound If (10mmol,2.40g), hexafluoroisopropanol (20mL), compound A (20mmol,5.22g) and iodine (10mmol,2.54g) in sequence into a 50mL round-bottom flask, reacting for 4.0h at 60 ℃, and monitoring the reaction progress by thin layer chromatography until the reaction is complete; extraction with ethyl acetate and saturated brine, drying over anhydrous sodium sulfate, evaporation of the solvent under reduced pressure, and separation and purification of the residue by silica gel column chromatography using petroleum ether/ethyl acetate (40:1) as the mobile phase gave compound IIf in 58% yield. The reaction equation is as follows:

example 7: the preparation method of this example includes the following steps:

adding a compound Ig (10mmol,2.20g), hexafluoroisopropanol (20mL), a compound A (20mmol,5.22g) and iodine (10mmol,2.54g) in sequence into a 50mL round-bottom flask, reacting for 4.0h at the temperature of 60 ℃, and monitoring the reaction progress by thin layer chromatography until the reaction is complete; extraction with ethyl acetate and saturated brine, drying over anhydrous sodium sulfate, distilling off the solvent under reduced pressure, and separating and purifying the residue by silica gel column chromatography using petroleum ether/ethyl acetate (40:1) as a mobile phase to give compound IIg in 74% yield. The reaction equation is as follows:

example 8: the preparation method of this example includes the following steps:

adding a compound Ih (10mmol,2.36g), hexafluoroisopropanol (20mL), a compound A (20mmol,5.22g) and iodine (10mmol,2.54g) in sequence into a 50mL round-bottom flask, reacting for 4.0h at the temperature of 60 ℃, and monitoring the reaction progress by thin layer chromatography until the reaction is complete; extraction with ethyl acetate and saturated brine, drying over anhydrous sodium sulfate, distilling off the solvent under reduced pressure, and separating and purifying the residue by silica gel column chromatography using petroleum ether/ethyl acetate (40:1) as the mobile phase to give compound IIh in 65% yield. The reaction equation is as follows:

example 9: the preparation method of this example includes the following steps:

adding compound Ii (10mmol,2.24g), hexafluoroisopropanol (20mL), compound A (20mmol,5.22g) and iodine (10mmol,2.54g) in sequence into a 50mL round-bottom flask, reacting for 4.0h at 60 ℃, and monitoring the reaction progress by thin layer chromatography until the reaction is complete; extraction with ethyl acetate and saturated brine, drying over anhydrous sodium sulfate, distilling off the solvent under reduced pressure, and separating and purifying the residue by silica gel column chromatography using petroleum ether/ethyl acetate (40:1) as a mobile phase to give compound II in 64% yield. The reaction equation is as follows:

example 10: the preparation method of this example includes the following steps:

adding the compound Ij (10mmol,2.40g), hexafluoroisopropanol (20mL), the compound A (20mmol,5.22g) and iodine (10mmol,2.54g) in sequence into a 50mL round-bottom flask, reacting for 4.0h at the temperature of 60 ℃, and monitoring the reaction progress by thin layer chromatography until the reaction is complete; extraction with ethyl acetate and saturated brine, drying over anhydrous sodium sulfate, evaporation of the solvent under reduced pressure, and separation and purification of the residue by silica gel column chromatography using petroleum ether/ethyl acetate (40:1) as the mobile phase gave compound IIj in 62% yield. The reaction equation is as follows:

example 11: the preparation method of this example includes the following steps:

adding compound Ik (10mmol,2.34g), hexafluoroisopropanol (20mL), compound A (20mmol,5.22g) and iodine (10mmol,2.54g) in sequence into a 50mL round-bottom flask, reacting for 4.0h at the temperature of 60 ℃, and monitoring the reaction progress by thin layer chromatography until the reaction is complete; extraction with ethyl acetate and saturated brine, drying over anhydrous sodium sulfate, evaporation of the solvent under reduced pressure, and separation and purification of the residue by silica gel column chromatography using petroleum ether/ethyl acetate (40:1) as the mobile phase gave compound IIk in 78% yield. The reaction equation is as follows:

example 12: the preparation method of this example includes the following steps:

adding compound Il (10mmol,2.74g), hexafluoroisopropanol (20mL), compound A (20mmol,5.22g) and iodine (10mmol,2.54g) in sequence into a 50mL round-bottom flask, reacting for 4.0h at the temperature of 60 ℃, and monitoring the reaction progress by thin layer chromatography until the reaction is complete; extraction with ethyl acetate and saturated brine, drying over anhydrous sodium sulfate, distilling off the solvent under reduced pressure, and separating and purifying the residue by silica gel column chromatography using petroleum ether/ethyl acetate (40:1) as the mobile phase to give compound II in 72% yield. The reaction equation is as follows:

the structural, nuclear magnetic and high resolution mass spectral data of the product obtained in example 1 are as follows:

¹H NMR(400MHz,CDCl₃,ppm):δ＝8.00-7.98(m,2H),7.47-7.44(m,3H),7.32-7.28(m,1H),7.18-7.16(m,2H),7.08-7.04(m,1H),2.64-2.61(m,2H),2.56-2.52(m,2H),2.41-2.33(m,2H)；¹³C NMR(100MHz,CDCl₃,ppm):δ＝171.5,149.8,139.0,131.3,130.4,128.7,128.5,127.1,124.5,123.8,34.5,30.3,28.8；HRMS calcd for C₁₆H₁₆N[M+H]⁺222.1277；found:222.1275.

the structural, nuclear magnetic and high resolution mass spectral data of the product obtained in example 2 are as follows:

¹H NMR(400MHz,CDCl₃,ppm):δ＝7.90(d,J＝8.0Hz,2H),7.31-7.25(m,3H),7.18-7.15(m,2H),7.07-7.03(m,1H),2.64-2.60(m,2H),2.55-2.51(m,2H),2.41(s,3H),2.39-2.32(m,2H)；¹³C NMR(100MHz,CDCl₃,ppm):δ＝171.3,149.9,140.7,136.3,131.4,129.2,128.7,127.2,127.2,124.4,123.8,34.5,30.3,28.7,21.4；HRMS calcd for C₁₇H₁₈N[M+H]⁺236.1434；found:236.1433.

the structural, nuclear magnetic and high resolution mass spectral data of the product obtained in example 3 are as follows:

¹H NMR(400MHz,CDCl₃,ppm):δ＝7.96-7.93(m,2H),7.49-7.46(m,2H),7.31-7.27(m,1H),7.17-7.15(m,2H),7.07-7.03(m,1H),2.65-2.61(m,2H),2.55-2.51(m,2H),2.39-2.32(m,2H),1.36(s,9H)；¹³C NMR(100MHz,CDCl₃,ppm):δ＝171.2,153.9,150.0,136.2,131.3,128.7,127.1,127.0,125.5,124.4,123.8,34.8,34.5,31.2,30.3,28.6；HRMS calcd for C₂₀H₂₄N[M+H]⁺278.1903；found:278.1909.

the structural, nuclear magnetic and high resolution mass spectral data of the product obtained in example 4 are as follows:

¹H NMR(400MHz,CDCl₃,ppm):δ＝7.61-7.60(m,1H),7.53(d,J＝8.0Hz,1H),7.39-7.35(m,1H),7.33-7.29(m,1H),7.19-7.17(m,2H),7.09-7.05(m,1H),7.04-7.01(m,1H),3.89(s,3H),2.64-2.61(m,2H),2.58-2.53(m,2H),2.41-2.34(m,2H)；¹³C NMR(100MHz,CDCl₃,ppm):δ＝171.3,159.8,149.7,140.5,131.3,129.5,128.8,127.2,124.6,123.8,119.8,116.7,111.8,55.4,34.6,30.3,28.9；HRMS calcd for C₁₇H₁₈NO[M+H]⁺252.1383；found:252.1382.

the structural, nuclear magnetic and high resolution mass spectral data of the product obtained in example 5 are as follows:

¹H NMR(400MHz,CDCl₃,ppm):δ＝8.02-7.98(m,2H),7.33-7.28(m,1H),7.20-7.11(m,4H),7.10-7.04(m,1H),2.64-2.59(m,2H),2.58-2.51(m,2H),2.42-2.34(m,2H)；¹³C NMR(100MHz,CDCl₃,ppm):δ＝170.3,164.4(d,J＝250.0Hz),149.6,135.2,131.2,129.3(d,J＝10.0Hz),128.8,127.3,124.7,123.8,115.5(d,J＝20.0Hz),34.4,30.3,28.7；HRMS calcd for C₁₆H₁₅NF[M+H]⁺240.1183；found:240.1188.

the structural, nuclear magnetic and high resolution mass spectral data of the product obtained in example 6 are as follows:

¹H NMR(400MHz,CDCl₃,ppm):δ＝7.95-7.92(m,2H),7.44-7.40(m,2H),7.32-7.28(m,1H),7.19-7.14(m,2H),7.09-7.05(m,1H),2.62-2.58(m,2H),2.54-2.51(m,2H),2.40-2.33(m,2H)；¹³C NMR(100MHz,CDCl₃,ppm):δ＝170.2,149.6,137.5,136.6,131.2,128.8,128.7,128.5,127.2,124.7,123.8,34.5,30.3,28.6；HRMS calcd for C₁₆H₁₅NCl[M+H]⁺256.0888；found:256.0889.

the structural, nuclear magnetic, high resolution mass spectral data of the product obtained in example 7 are as follows:

¹H NMR(300MHz,CDCl₃,ppm):δ＝8.00-7.97(m,2H),7.47-7.43(m,3H),7.07(d,J＝9.0Hz,1H),7.01(m,1H),6.88(d,J＝6.0Hz,1H),2.65-2.60(m,2H),2.53-2.48(m,2H),2.40-2.30(m,5H)；¹³C NMR(75MHz,CDCl₃,ppm):δ＝171.3,149.6,139.1,136.8,130.3,128.5,128.5,128.3,127.1,125.2,124.5,34.5,29.9,28.8,21.1；HRMS calcd for C₁₇H₁₈N[M+H]⁺236.1434；found:236.1438.

the structural, nuclear magnetic and high resolution mass spectral data of the product obtained in example 8 are as follows:

¹H NMR(400MHz,CDCl₃,ppm):δ＝8.00-7.97(m,2H),7.47-7.43(m,3H),7.07(d,J＝8.0Hz,1H),6.77(d,J＝4.0Hz,1H),6.65-6.62(m,1H),3.81(s,3H),2.65-2.61(m,2H),2.49-2.46(m,2H),2.37-2.29(m,2H)；¹³C NMR(100MHz,CDCl₃,ppm):δ＝171.9,159.0,150.7,139.0,130.4,129.3,128.5,127.21,123.6,110.7,108.8,55.3,34.6,29.4,28.9；HRMS calcd for C₁₇H₁₈NO[M+H]⁺252.1383；found:252.1384.

the structural, nuclear magnetic and high resolution mass spectral data of the product obtained in example 9 are as follows:

¹H NMR(400MHz,CDCl₃,ppm):δ＝8.00-7.97(m,2H),7.49-7.44(m,3H),7.13-7.09(m,1H),6.91-6.88(m,1H),6.78-6.74(m,1H),2.65-2.62(m,2H),2.52-2.49(m,2H),2.39-2.32(m,2H)；¹³C NMR(100MHz,CDCl₃,ppm):δ＝172.5,162.2(d,J＝242.0Hz),151.3(d,J＝10.0Hz),138.7,130.7,129.6(d,J＝10.0Hz),128.6,127.3,127.0,111.10(d,J＝21.0Hz),110.7(d,J＝22.0Hz),34.5,29.6,28.9；HRMS calcd for C₁₆H₁₅NF[M+H]⁺240.1183；found:240.1190.

the structural, nuclear magnetic, high resolution mass spectral data of the product obtained in example 10 are as follows:

¹H NMR(400MHz,CDCl₃,ppm):δ＝8.00-7.97(m,2H),7.49-7.43(m,3H),7.18(d,J＝4.0Hz,1H),7.10(d,J＝8.0Hz,1H),7.04-7.01(m,1H),2.65-2.62(m,2H),2.53-2.49(m,2H),2.40-2.33(m,2H)；¹³C NMR(100MHz,CDCl₃,ppm):δ＝172.5,151.0,138.6,132.6,130.7,129.8,128.6,127.2,124.4,123.7,34.3,29.7,28.8；HRMS calcd for C₁₆H₁₅NCl[M+H]⁺256.0888；found:256.0893.

the structural, nuclear magnetic and high resolution mass spectral data of the product obtained in example 11 are as follows:

¹H NMR(400MHz,CDCl₃,ppm):δ＝7.89(d,J＝8.0Hz,2H),7.26-7.24(m,2H),7.05(d,J＝6.0Hz,1H),7.00(s,1H),6.87(d,J＝4.0Hz,1H),2.63-2.59(m,2H),2.51-2.47(m,2H),2.40-2.30(m,8H)；¹³C NMR(100MHz,CDCl₃,ppm):δ＝171.1,149.7,140.6,136.8,136.3,129.2,128.5,128.3,127.1,125.1,124.4,34.4,29.9,28.7,21.4,21.1；HRMS calcd for C₁₈H₂₀N[M+H]⁺250.1590；found:250.1595.

the structural, nuclear magnetic and high resolution mass spectral data of the product obtained in example 12 are as follows:

¹H NMR(300MHz,CDCl₃,ppm):δ＝7.95-7.90(m,2H),7.45-7.41(m,2H),7.16(d,J＝3.0Hz,1H),7.11(d,J＝9.0Hz,1H),7.05-7.02(m,1H),2.63-2.58(m,2H),2.52-2.47(m,2H),2.40-2.30(m,2H)；¹³C NMR(75MHz,CDCl₃,ppm):δ＝171.3,150.7,136.9,132.7,129.82,129.6,128.8,128.6,124.6,123.7,34.2,29.7,28.6；HRMS calcd for C₁₆H₁₄NCl₂[M+H]⁺290.0498；found:290.0502.

reference documents:

1.D.McTavish,P.Benfield,Drugs.1990,39,136-153.

2.F.Belal,H.H.Abdine,A.A.Al-Badr,Profiles Drug Subst.Excipients Relat.Methodol.2005,31,117-161.

3.H.Tabata,T.Yoneda,T.Oshitari,H.Takahashi,H.Natsugari,J.Med.Chem.2017,60,4503-4509.

4.R.Wang,R.-X.Jin,Z.-Y.Qin,K.-J.Bian,X.-S.Wang,Chem.Commun.2017,53,12229-12232.5.D.-X.Li,Y.Park,W.Yoon,H.Yun,J.Yun,Org.Lett.2019,21,9699-9703.

6.C.Guo,M.Fleige,D.Janssen-Müller,C.G.Daniliuc,F.Glorius,J.Am.Chem.Soc.2016,138,7840-7843.

7.K.Zhang,L.Cai,S.Hong,O.Kwon,Org.Lett.2019,21,5143-5146.

8.S.Wang,X.-D.An,S.-S.Li,X.Liu,Q.Liud,J.Xiao,Chem.Commun.2018,54,13833-13836.

9.S.Stockerl,T.Danelzik,D.G.Piekarski,O.G.Org.Lett.2019,21,4535-4539.