CN111116466A

CN111116466A - Catalytic synthesis method of polysubstituted quinoline derivative

Info

Publication number: CN111116466A
Application number: CN201911154685.4A
Authority: CN
Inventors: 戎舟挺; 王超洋; 钱国英
Original assignee: Zhejiang Wanli University
Current assignee: Zhejiang Wanli University
Priority date: 2019-11-22
Filing date: 2019-11-22
Publication date: 2020-05-08
Anticipated expiration: 2039-11-22
Also published as: CN111116466B

Abstract

The invention discloses a catalytic synthesis method of a polysubstituted quinoline derivative, which comprises the following steps: dissolving aryl propargyl substituted aniline in toluene at normal pressure, wherein the molar volume ratio of the aryl propargyl substituted aniline to the toluene is 1:1mmol/mL, so as to obtain a toluene solution of the aryl propargyl substituted aniline; adding zinc iodide into the toluene solution to obtain a mixed solution, wherein the molar amount of the zinc iodide is 10% of that of the aryl propargyl substituted aniline; and then heating the mixed solution to 100 ℃, stirring at constant temperature of 100 ℃ for 12 hours, and reacting to generate the polysubstituted quinoline derivative. The catalytic synthesis method of the polysubstituted quinoline derivative disclosed by the invention is low in cost and high in yield, the cost of the catalyst for preparing 1g of polysubstituted quinoline derivative is reduced by 3 orders of magnitude compared with the existing synthesis method using the rhodium complex as the catalyst, and the yield is improved to 90.5-96.2%.

Description

Catalytic synthesis method of polysubstituted quinoline derivative

Technical Field

The invention relates to a synthesis method of a compound, in particular to a catalytic synthesis method of a polysubstituted quinoline derivative.

Background

Polysubstituted quinoline derivatives are widely found in natural products and medical molecules, and have attracted attention because of their excellent antimalarial, antiepileptic, antitumor and other activities. Quinoline derivatives are contained in very low amounts in plants and are currently mainly obtained by chemical synthesis. The traditional quinoline synthesis method is mainly obtained by reacting aniline with corresponding reagents under strong acid conditions, and has the defects of violent reaction conditions and low yield. The method for synthesizing the polysubstituted quinoline derivative by utilizing the noble metal catalyst has high yield, but the preparation cost is high because the noble metal catalyst is expensive. Noble metal rhodium catalysts as reported in the literature can convert 2-ethynylaniline and benzaldehyde to the quinoline derivative 2-phenylquinoline at ambient temperature in 81% yield using acetone as solvent. The cost of the catalyst per 1g of 2-phenylquinoline prepared is 700 yuan, depending on the market price of the rhodium catalyst.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a low-cost high-yield method for catalytically synthesizing polysubstituted quinoline derivatives, compared with the existing synthesis method using rhodium complexes as catalysts, the cost of the catalyst for preparing 1g of polysubstituted quinoline derivatives is reduced by 3 orders of magnitude, and the yield is improved to 90.5-96.2%.

The technical scheme adopted by the invention for solving the technical problems is as follows: a catalytic synthesis method of polysubstituted quinoline derivatives comprises the following steps: dissolving aryl propargyl substituted aniline in toluene at normal pressure, wherein the molar volume ratio of the aryl propargyl substituted aniline to the toluene is 1:1mmol/mL, so as to obtain a toluene solution of the aryl propargyl substituted aniline; adding zinc iodide into the toluene solution to obtain a mixed solution, wherein the molar amount of the zinc iodide is 10% of that of the aryl propargyl substituted aniline; and then heating the mixed solution to 100 ℃, stirring at constant temperature of 100 ℃ for 12 hours, and reacting to generate the polysubstituted quinoline derivative.

Preferably, the stirring speed of stirring at constant temperature of 100 ℃ is 300-1000 r/min.

Compared with the prior art, the invention has the following advantages: the invention discloses a catalytic synthesis method of polysubstituted quinoline derivatives, which is characterized in that the polysubstituted quinoline derivatives are synthesized by taking aryl propargyl substituted aniline as a raw material in a toluene solvent under normal pressure by using cheap zinc iodide as a catalyst, the synthesis method is low in cost and high in yield, the cost of the catalyst for preparing 1g of polysubstituted quinoline derivatives is reduced by 3 orders of magnitude compared with the existing synthesis method taking a rhodium complex as a catalyst, and the yield is improved to 90.5-96.2%.

Drawings

FIG. 1 is a NMR spectrum of 4-phenylquinoline derivative 2a prepared in example 1;

FIG. 2 is a NMR carbon spectrum of 4-phenylquinoline derivative 2a prepared in example 1.

Detailed Description

The invention is described in further detail below with reference to the accompanying examples.

Example 1: dissolving 10mmol of phenyl propargyl substituted aniline 1a in 10mL of toluene under normal pressure to obtain a toluene solution of phenyl propargyl substituted aniline 1 a; adding 1.0mmol of zinc iodide into the toluene solution to obtain a mixed solution; then, the mixed solution was heated to 100 ℃ and stirred at a stirring rate of 600r/min at a constant temperature of 100 ℃ for 12 hours to react and produce 4-phenylquinoline derivative 2a, and the 4-phenylquinoline derivative 2a was obtained in an amount of 3.8g by silica gel column chromatography, showing a yield of 90.5%. In example 1, the reaction formula for synthesizing the 4-phenylquinoline derivative 2a using phenyl propargyl substituted aniline 1a as a raw material is as follows:

through calculation, in example 1, the cost of the catalyst required for preparing 1g of the 4-phenylquinoline derivative 2a is only 0.6 yuan, which is reduced by 3 orders of magnitude compared with the existing synthesis method using the rhodium complex as the catalyst.

The NMR spectrum of 4-phenylquinoline derivative 2a prepared in example 1 is shown in FIG. 1, and specific data are shown in FIG. 1¹HNMR(400MHz,CDCl₃)δ7.37-7.30(m,2H),7.08-7.00(m,4H),6.90(d,J＝8.0Hz,2H),6.53-6.48(m,2H),6.25(d,J＝2.5Hz,1H),5.39(t,J＝5.0Hz,1H),4.35(d,J＝5.1Hz,2H),3.84(s,3H),3.23(s,3H),2.14(s,3H).

The NMR spectrum of 4-phenylquinoline derivative 2a prepared in example 1 is shown in FIG. 2, and specific data are shown in FIG. 2¹³CNMR(101MHz,CDCl₃)δ160.06,157.01,143.34,140.74,138.96,137.24,136.47,129.13,127.44,126.91,126.43,126.23,120.10,113.51,103.48,98.58,55.69,55.20,45.62,21.33.

Example 2: 20mmol of tolylpropargyl-substituted aniline 1b were dissolved in 20mL of toluene under normal pressure to give a toluene solution of tolylpropargyl-substituted aniline 1 b; adding 2.0mmol of zinc iodide into the toluene solution to obtain a mixed solution; then, the mixed solution was heated to 100 ℃ and stirred at a stirring rate of 500r/min at a constant temperature of 100 ℃ for 12 hours to react and produce 4-tolylquinoline derivative 2b, which was 8.3g as 4-tolylquinoline derivative 2b by silica gel column chromatography, and the yield thereof was 95.3%.

The reaction formula for synthesizing the 4-tolylquinoline derivative 2b using tolylpropargyl-substituted aniline 1b as a starting material in example 2 is:

by calculation, in example 2, the cost of the catalyst required for preparing 1g of the 4-tolylquinoline derivative 2b is only 0.57 yuan, which is reduced by 3 orders of magnitude compared with the existing synthesis method using the rhodium complex as the catalyst.

Example 3: dissolving 40mmol of methoxyphenyl propargyl substituted aniline 1c in 40mL of toluene under normal pressure to obtain a toluene solution of the methoxyphenyl propargyl substituted aniline 1 c; adding 4.0mmol of zinc iodide into the toluene solution to obtain a mixed solution; then, the mixed solution was heated to 100 ℃ and stirred at a stirring rate of 800r/min at a constant temperature of 100 ℃ for 12 hours to react and produce 4-methoxyphenyl quinoline derivative 2c, and silica gel column chromatography was performed to obtain 16.5g of 4-methoxyphenyl quinoline derivative 2c, with a yield of 91.6%.

In example 3, the reaction formula for synthesizing the 4-methoxyphenyl quinoline derivative 2c by using methoxyphenyl propargyl substituted aniline 1c as a raw material is as follows:

through calculation, in example 3, the cost of the catalyst required for preparing 1g of the 4-methoxyphenyl quinoline derivative 2c is only 0.55 yuan, which is reduced by 3 orders of magnitude compared with the existing synthesis method using rhodium complex as the catalyst.

Example 4: dissolving 80mmol of chlorophenylpropargyl substituted aniline 1d in 80mL of toluene under normal pressure to obtain a toluene solution of chlorophenylpropargyl substituted aniline 1 d; adding 8.0mmol of zinc iodide into the toluene solution to obtain a mixed solution; then, the mixed solution was heated to 100 ℃ and stirred at a stirring rate of 400r/min at a constant temperature of 100 ℃ for 12 hours to react and produce 4-chlorophenyl quinoline derivative 2d, and silica gel column chromatography was performed to obtain 35.1g of 4-chlorophenyl quinoline derivative 2d, with a yield of 96.2%. In example 4, the formula for synthesizing the 4-chlorophenyl quinoline derivative 2d using chlorophenyl propargyl substituted aniline 1d as a starting material is:

through calculation, in example 4, the cost of the catalyst required for preparing 1g of the 4-chlorophenyl quinoline derivative 2d is only 0.55 yuan, which is reduced by 3 orders of magnitude compared with the existing synthesis method using rhodium complex as the catalyst.

Example 5: dissolving 100mmol of bromophenylpropargyl-substituted aniline 1e in 100mL of toluene under normal pressure to obtain a toluene solution of bromophenylpropargyl-substituted aniline 1 e; then adding 10.0mmol of zinc iodide into the toluene solution to obtain a mixed solution; then, the mixed solution is heated to 100 ℃, stirred at the stirring speed of 1000r/min and the constant temperature of 100 ℃ for 12 hours, 4-bromophenyl quinoline derivative 2e is generated through reaction, and the 4-bromophenyl quinoline derivative 2e is obtained by silica gel column chromatography and is 46.3g, and the yield is 92.5%. In example 5, the reaction formula for synthesizing 4-bromophenylquinoline derivative 2e using bromophenylpropargyl-substituted aniline 1e as a raw material is as follows:

by calculation, in example 5, the cost of the catalyst required for preparing 1g of the 4-bromophenylquinoline derivative 2e is only 0.51 yuan, which is reduced by 3 orders of magnitude compared with the existing synthesis method using iridium catalyst as catalyst.

Claims

1. A catalytic synthesis method of polysubstituted quinoline derivatives is characterized by comprising the following steps: dissolving aryl propargyl substituted aniline in toluene at normal pressure, wherein the molar volume ratio of the aryl propargyl substituted aniline to the toluene is 1:1mmol/mL, so as to obtain a toluene solution of the aryl propargyl substituted aniline; adding zinc iodide into the toluene solution to obtain a mixed solution, wherein the molar amount of the zinc iodide is 10% of that of the aryl propargyl substituted aniline; and then heating the mixed solution to 100 ℃, stirring at constant temperature of 100 ℃ for 12 hours, and reacting to generate the polysubstituted quinoline derivative.

2. The catalytic synthesis method of polysubstituted quinoline derivatives according to claim 1, wherein the stirring speed of stirring at constant temperature of 100 ℃ is 300-1000 r/min.