阅读说明：本技术 一种1-邻氨基苯基醇与芳醛制备3,4-二取代喹啉的方法 (Method for preparing 3, 4-disubstituted quinoline from 1-o-aminophenyl alcohol and aromatic aldehyde ) 是由 郭灿城 杨统林 郭欣 于 2021-08-27 设计创作，主要内容包括：本发明公开了一种1-邻氨基苯基醇与芳醛制备3,4-二取代喹啉的方法,该方法是在含氧气氛下,1-邻氨基苯基醇和芳基甲醛,在含碱的DMSO溶液体系中进行一锅反应,即得3,4-二取代喹啉化合物；该方法制得的3,4-二取代喹啉化合物结构中,2位碳原子由DMSO提供,3位碳原子及3位上的芳基由芳基甲醛提供,喹啉化合物结构中的所有其它原子以及4位碳原子上的取代基都由1-邻氨基苯基醇提供。该合成3,4-二取代喹啉的方法,原料来源广泛易得,绿色环保,价格低廉,操作简单,有利于工业化生产。(The invention discloses a method for preparing 3, 4-disubstituted quinoline from 1-o-aminophenyl alcohol and aromatic aldehyde, which comprises the following steps of carrying out one-pot reaction on 1-o-aminophenyl alcohol and aryl formaldehyde in a DMSO solution system containing alkali in an oxygen-containing atmosphere to obtain a 3, 4-disubstituted quinoline compound; in the structure of the 3, 4-disubstituted quinoline compound prepared by the method, the carbon atom at the 2-position is provided by DMSO, the carbon atom at the 3-position and the aryl group at the 3-position are provided by aryl formaldehyde, and all other atoms in the structure of the quinoline compound and the substituent at the carbon atom at the 4-position are provided by 1-o-aminophenyl alcohol. The method for synthesizing the 3, 4-disubstituted quinoline has the advantages of wide and easily available raw material sources, environmental protection, low price, simple operation and contribution to industrial production.)

1. A method for preparing 3, 4-disubstituted quinoline from 1-o-aminophenyl alcohol and aromatic aldehyde, which is characterized in that: performing one-pot reaction on o-amino aryl methanol and aryl formaldehyde in a DMSO solution system containing alkali to synthesize and obtain a 3, 4-disubstituted quinoline compound; in the 3, 4-disubstituted quinoline compound prepared by the method, the carbon atom at the 2-position on a pyridine ring is provided by DMSO, the carbon atom at the 3-position and the aryl group at the 3-position are provided by aryl formaldehyde, and other atoms and substituents on the carbon atom at the 4-position are provided by 1-o-aminophenyl alcohol.

The 1-ortho-aminophenyl alcohol has the structure of formula 1:

the aryl formaldehyde has the structure of formula 2:

the 3, 4-disubstituted quinoline has the structure of formula 3:

wherein the content of the first and second substances,

r in the formula 1 can be methyl, ethyl, phenyl or substituted phenyl, when R is substituted phenyl, the selection range of substituents on a benzene ring is wide, and the substituents can be alkyl, substituted alkyl, halogen, alkoxy, amino and aryl; the number of the substituent is at least one or more of hydrogen, alkyl, halogen and alkoxy, and the position of the substituent can be positioned at ortho-position, meta-position or para-position of the benzene ring;

ar in the formula 2 can be benzene, substituted benzene, thiophene, furan, pyridine and quinoline;

when Ar is substituted benzene, the selection range of the substituent on the benzene ring is wide, and the substituent can be alkyl, substituted alkyl, halogen, alkoxy, amino and aryl; preferred alkyl groups are methyl, ethyl, tert-butyl, preferred substituted alkyl groups are trifluoromethyl, preferred halogen is fluorine, chlorine, bromine, preferred alkoxy is methoxy, preferred amino is dimethylamino, preferred aryl is phenyl; the number of the substituents on the benzene ring may be 1-2, and they may be located at different positions of the benzene ring;

when Ar is thiophene, furan, naphthalene, pyridine or quinoline, the Ar can be connected to the 3-carbon atom of the quinoline through any position on the ring.

2. The method of claim 1, wherein the method comprises reacting a 1-o-aminophenyl alcohol with an aromatic aldehyde to form a 3, 4-disubstituted quinoline:

the alkali comprises at least one of sodium benzoate, potassium benzoate, sodium acetate, potassium ethoxide, sodium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, strontium carbonate, sodium hydroxide and potassium hydroxide. The preferred base is potassium hydroxide.

3. The method of claim 1, wherein the method comprises reacting a 1-o-aminophenyl alcohol with an aromatic aldehyde to form a 3, 4-disubstituted quinoline: DMSO is both a solvent and a reaction raw material.

4. The method of claim 1, wherein the method comprises reacting a 1-o-aminophenyl alcohol with an aromatic aldehyde to form a 3, 4-disubstituted quinoline: the reaction conditions are as follows: the reaction was carried out at 120 ℃ for 30 minutes under an air or oxygen atmosphere.

Technical Field

The invention relates to a method for synthesizing 3, 4-disubstituted quinoline, in particular to a method for synthesizing 3, 4-disubstituted quinoline by taking 1-o-aminophenyl alcohol and aryl formaldehyde as raw materials and reacting in a DMSO solution system containing alkali, belonging to the field of organic synthesis.

Background

Quinoline is a chemical structure with important physiological activity and wide synthetic applications. Quinoline rings exist at different positions, and can be connected with different substituents, and the physiological activity and the synthetic application of the quinoline compound formed by connecting different substituents at different positions are different. 3, 4-disubstituted quinoline compounds are present in many natural products, and this structure is also present in some drug molecules. Simple 3, 4-disubstituted quinolines can be obtained from 3-substituted anilines by Skraup reaction with glycerol, whereas complex 3-substituted quinolines require special synthesis methods. The literature (S.B.Wakade, D.K.Tiwari, P.S.K.P.Ganesh, M.Phanindrudu, P.R.Likhar, D.K.Tiwari, org.Lett.2017,19, 4948-one 4951) reports the synthesis of 3, 4-disubstituted quinolines from arylmethyl ketones, substituted benzisoxazoles and DMSO in the presence of potassium peroxodisulfate:

the method for synthesizing the 3, 4-disubstituted quinoline needs a substituted benzisoxazole raw material which is difficult to obtain, and only the 3-position is an arylformyl group.

Disclosure of Invention

Aiming at the defects of difficult raw material use and single product structure in the existing 3, 4-disubstituted quinoline synthesis method, the invention aims to provide a method for obtaining a 3, 4-disubstituted quinoline compound from easily obtained raw materials, namely 1-o-aminophenyl alcohol and aryl formaldehyde, in an oxygen-containing atmosphere.

In order to realize the technical purpose, the invention provides a method for obtaining a 3, 4-disubstituted quinoline compound by carrying out a one-pot reaction on 1-o-aminophenyl alcohol and aryl formaldehyde in a DMSO solution system containing alkali in an oxygen-containing atmosphere;

the 1-ortho-aminophenyl alcohol has the structure of formula 1:

the aryl formaldehyde has the structure of formula 2:

ArCHO

formula 2

The 3-arylquinoline has the structure of formula 3:

wherein the content of the first and second substances,

r in the formula 1 can be methyl, ethyl, phenyl or substituted phenyl, when R is substituted phenyl, the selection range of substituents on a benzene ring is wide, and the substituents can be alkyl, substituted alkyl, halogen, alkoxy, amino and aryl; the number of the substituent is at least one or more of hydrogen, alkyl, halogen and alkoxy, and the position of the substituent can be positioned at ortho-position, meta-position or para-position of the benzene ring;

ar in the formula 2 can be hydrogen, benzene, substituted benzene, thiophene, furan, naphthalene, pyridine and quinoline;

when Ar is substituted benzene, the selection range of the substituent on the benzene ring is wide, and the substituent can be alkyl, substituted alkyl, halogen, alkoxy, amino and aryl; preferred alkyl groups are methyl, ethyl, tert-butyl, preferred substituted alkyl groups are trifluoromethyl, preferred halogen is fluorine, chlorine, bromine, preferred alkoxy is methoxy, preferred amino is dimethylamino, preferred aryl is phenyl; the number of the substituents on the benzene ring may be 1-2, and they may be located at different positions of the benzene ring;

when Ar is thiophene, furan, naphthalene, pyridine or quinoline, the Ar can be connected to the 3-position carbon atom of the quinoline through any position on the ring;

the synthesis reaction of the present invention requires the presence of an organic base and an inorganic base. The sodium benzoate-potassium carbonate-sodium hydroxide composite material specifically comprises at least one of sodium benzoate, potassium benzoate, sodium acetate, potassium ethoxide, sodium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, strontium carbonate, sodium hydroxide and potassium hydroxide. The preferred base is potassium hydroxide.

In the invention, DMSO is used as a solvent and a reaction raw material.

In a preferred embodiment, the molar ratio of the 1-o-aminophenyl alcohol to the base compound is 1:1 to 3. The most preferable ratio is 1: 1.5-2.

In a preferred embodiment, the reaction conditions are as follows: reacting for 20-45 minutes at the temperature of 100-140 ℃ in the air or oxygen atmosphere. In a more preferred embodiment, the reaction conditions are as follows: the reaction was carried out at 120 ℃ for 30 minutes under an air or oxygen atmosphere.

The oxygen-containing atmosphere in the present invention may be air or a pure oxygen atmosphere, and is preferably a pure oxygen atmosphere.

The DMSO used in the invention is a benign reaction solvent, is also one of carbon sources in the synthesis process of the 3, 4-disubstituted quinoline, and cannot be replaced by other solvents. The reaction system can contain organic solvents such as dimethyl sulfoxide, toluene and the like, but the reaction effect is obviously inferior to that of the single DMSO solvent.

In the synthesis process of the 3, 4-disubstituted quinoline, 1-o-aminophenyl alcohol and aryl formaldehyde react according to an equal molar ratio, and DMSO is used as a solvent and a reaction substrate, so that a large amount of excess is needed.

In the preferred scheme, after the reaction is finished, a product is separated and purified by adopting a column chromatography; the eluent adopted by the column chromatography is a mixed solvent of petroleum ether and ethyl acetate, wherein the volume ratio of the petroleum ether to the ethyl acetate is (20-40): 1.

The reaction equation of the method for synthesizing 3, 4-disubstituted quinoline provided by the invention is as follows:

in 6 atoms of a pyridine ring of the 3, 4-disubstituted quinoline compound prepared by the method, the raw material 1-o-aminobenzyl alcohol provides a nitrogen atom and 3 carbon atoms connected with the nitrogen atom, DMSO provides another carbon atom at the 2-position connected with the nitrogen atom, and aryl formaldehyde provides a carbon atom at the 3-position and an aryl group at the 3-position. The principle of the above reaction can be illustrated by the procedure of carrying out a one-pot reaction of 1-o-aminophenylmethyl alcohol and benzaldehyde in a DMSO solution system to obtain 4-methyl-3-phenylquinoline:

firstly, oxidizing raw material 1-o-aminophenyl methyl alcohol into o-aminophenyl methyl ketone A and an isomer B thereof, reacting raw material benzaldehyde with DMSO to generate methylsulfinyl substituted styrene C, and further oxidizing the raw material benzaldehyde by air to generate methylsulfonyl substituted styrene D; then, the isomer B of o-aminophenylmethyl ketone and methylsulfonyl substituted styrene D undergo cycloaddition reaction to form unstable cycloaddition product E, the addition product E is dehydrated under the action of alkali to form cyclized intermediate F, and finally, under the heating condition, one molecule of methylsulfinic acid is removed from the cyclized intermediate F to obtain the 4-methyl-3-phenylquinoline product. Both reactive intermediates A, C, D and F were captured for their presence by GC-MS.

Experiments show that if one hydrogen atom of the dimethyl sulfoxide is replaced by other groups, the corresponding target product cannot be obtained.

Compared with the existing synthesis method and technology, the invention has the following advantages and effects:

1) the invention realizes the direct cyclization synthesis of 3, 4-disubstituted quinoline from 1-o-aminophenyl alcohol and aryl formaldehyde in DMSO for the first time;

2) the invention uses easily obtained raw materials, does not need to use difficultly obtained or expensive raw materials, has wide raw material source and low cost;

3) the invention adopts common organic base or inorganic base, avoids using expensive metal complex as catalyst, and meets the requirements of environmental protection, economy, saving and the like;

4) the reaction process of the invention is carried out in oxygen-containing atmosphere and at lower temperature, and the reaction condition is mild;

5) the yield of the 3, 4-disubstituted quinoline compound synthesized by the method is high;

6) the synthesis process of the invention adopts a one-pot reaction, and has the advantages of few reaction steps and simple operation.

Detailed Description

The present invention will be described in further detail with reference to specific examples, but the embodiments of the present invention are not limited thereto, and may be performed with reference to conventional techniques for process parameters not specifically mentioned.

All reactions were performed in Schlenk tubes unless otherwise noted.

All reaction starting solvents were obtained from commercial sources and used without further purification.

The product is separated by a silica gel chromatographic column and silica gel (the granularity is 300-400 meshes).

1H NMR (400MHz) and 13C NMR (100MHz) measurements were carried out using a Bruker ADVANCE III spectrometer with CDCl₃As solvent, TMS as internal standard, chemical shifts in parts per million (ppm) and reference shifts of 0.0ppm tetramethylsilane. The following abbreviations (or combinations thereof) are used to explain the multiplicity: s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, br is broad. Coupling constant J is in Hertz (Hz). Chemical shifts are expressed in ppm, with the center line for the triplet state referenced to deuterated chloroform at 77.0ppm or the center line for the heptad state referenced to deuterated DMSO at 39.52 ppm.

1. Carrying out the process

Adding 0.5 mmol of 1-o-aminophenyl alcohol, 0.5 mmol of aryl formaldehyde, 2 mmol of potassium hydroxide and 2 ml of DMSO solvent into a reaction tube, heating at 120 ℃ under an oxygen atmosphere, magnetically stirring, reacting for 0.5 hour, cooling to room temperature, concentrating, and performing column chromatography separation and purification to obtain a target product, wherein the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate.

2. Effects of the implementation

The reaction equation is as follows:

the reaction is carried out according to the implementation process to obtain the implementation effect that:

3. hydrogen and carbon spectra data for partially performed products

3,4-Diphenylquinoline(1):

Yellow solid.¹H NMR(400MHz,CDCl₃)δ9.05(s,1H),8.25(d,J＝8.3Hz,1H),7.75(t,J＝9.4Hz, 2H),7.51(t,J＝7.6Hz,1H),7.40–7.35(m,3H),7.31–7.19(m,7H)；¹³C NMR(101MHz,CDCl₃)δ151.70,147.44,145.48,138.05,136.22,133.09,130.45,130.09,129.39,129.06,128.08,127.99, 127.66,127.19,126.99,126.81,126.52.

4-phenyl-3-(p-tolyl)quinoline(2)

A white solid.¹H NMR(400MHz,CDCl₃)δ9.02(s,1H),8.23(d,J＝8.3Hz,1H),7.73(dd,J＝18.6, 8.4Hz,2H),7.50(t,J＝7.5Hz,1H),7.38(s,3H),7.24(d,J＝2.8Hz,2H),7.08(s,4H),2.33(s,3H)；¹³C NMR(101MHz,CDCl₃)δ151.76,147.14,145.53,136.81,136.38,135.00,133.06,130.47,129.97, 129.27,129.06,128.82,128.15,127.67,127.32,126.85,126.54,21.10.

3-(4-chlorophenyl)-4-phenylquinoline(3)^[

A white solid.¹H NMR(400MHz,CDCl₃)δ9.05(s,1H),8.29(d,J＝8.4Hz,1H),7.82(t,J＝7.6Hz, 1H),7.78(d,J＝8.5Hz,1H),7.58(t,J＝7.6Hz,1H),7.48–7.43(m,3H),7.36–7.26(m,4H),7.19 (d,J＝7.7Hz,2H)；¹³C NMR(101MHz,CDCl₃)δ151.27,147.57,145.67,136.54,135.94,133.29, 131.88,131.35,130.38,129.45,129.33,128.31,127.91,127.12,127.02,126.55.

4-phenyl-3-(4-(trifluoromethyl)phenyl)quinoline(4)

A white solid.¹H NMR(400MHz,CDCl₃)δ8.98(s,1H),8.24(d,J＝8.4Hz,1H),7.80–7.74(m, 1H),7.71(d,J＝8.5Hz,1H),7.56–7.48(m,3H),7.42–7.35(m,3H),7.29(d,J＝8.1Hz,2H),7.23– 7.17(m,2H)；¹³C NMR(101MHz,CDCl₃)δ150.81,147.50,141.78,135.64,131.78,130.42,130.38, 129.78,129.31,128.41,128.17,127.30,127.12,126.70,125.11,125.08,125.04,125.00.HRMS(EI): calcd for C₂₂H₁₄F₃N:349.1078,found:349.1076.

3-([1,1'-biphenyl]-4-yl)-4-phenylquinoline(5)

A white solid.¹H NMR(400MHz,CDCl₃)δ9.13(s,1H),8.29(d,J＝8.2Hz,1H),7.79(t,J＝8.0Hz, 2H),7.63(d,J＝7.5Hz,2H),7.55(d,J＝8.1Hz,3H),7.43(qd,J＝15.0,7.4Hz,6H),7.31(d,J＝7.4 Hz,4H)；¹³C NMR(101MHz,CDCl₃)δ151.68,147.46,145.45,140.31,139.65,136.98,136.24, 132.60,130.49,130.47,129.42,129.09,128.70,128.20,127.73,127.35,127.22,126.91,126.85, 126.67,126.53.HRMS(EI):calcd for C₂₇H₁₉N:357.1517,found:357.1519.

3-(3-chlorophenyl)-4-phenylquinoline(6)

A white solid.¹H NMR(400MHz,CDCl₃)δ8.97(s,1H),8.21(d,J＝8.4Hz,1H),7.79–7.66(m, 2H),7.50(t,J＝7.5Hz,1H),7.42–7.32(m,3H),7.24–7.11(m,5H),7.02(d,J＝7.4Hz,1H)；¹³C NMR(101MHz,CDCl₃)δ151.08,147.62,145.87,139.89,135.75,133.93,131.72,130.33,130.03, 129.43,129.22,128.68,128.33,128.26,127.96,127.40,127.22,127.04,126.60.HRMS(EI):calcd for C₂₁H₁₄ClN:315.0815,found:315.0817.

3-(3,4-dimethylphenyl)-4-phenylquinoline(7)

A white solid.¹H NMR(400MHz,CDCl₃)δ9.00(s,1H),8.18(d,J＝8.3Hz,1H),7.69(dd,J＝17.2, 8.2Hz,2H),7.47(t,J＝7.4Hz,1H),7.35(s,3H),7.22(s,2H),6.97(s,2H),6.87(d,J＝7.7Hz,1H), 2.21(s,3H),2.17(s,3H)；¹³C NMR(101MHz,CDCl₃)δ152.05,147.34,145.18,136.54,136.25, 135.47,135.40,133.06,131.30,130.47,129.42,129.28,128.87,128.09,127.58,127.32,126.78, 126.71,126.53,19.67,19.40.HRMS(EI):calcd for C₂₃H₁₉N:309.1517,found:309.1518.

3-(furan-2-yl)-4-phenylquinoline(8)

A white solid.¹H NMR(400MHz,CDCl₃)δ9.51(s,1H),8.18(d,J＝8.3Hz,1H),7.71(t,J＝7.1 Hz,1H),7.57(s,3H),7.52–7.43(m,3H),7.31(d,J＝6.0Hz,2H),6.28(s,1H),5.47(s,1H)；¹³C NMR(101MHz,CDCl₃)δ150.40,148.45,146.64,142.85,142.33,136.94,129.22,129.12,129.10, 128.38,127.62,126.95,126.44,122.28,111.64,110.80.HRMS(EI):calcd for C₁₉H₁₃NO:271.0997, found:271.0996.

4-methyl-3-(naphthalen-2-yl)quinoline(9)

Brown solid.¹H NMR(400MHz,CDCl₃)δ8.92(s,1H),8.20(d,J＝8.3Hz,1H),8.12(d,J＝8.3 Hz,1H),8.00–7.89(m,3H),7.86(s,1H),7.75(dd,J＝11.3,3.9Hz,1H),7.64(t,J＝7.6Hz,1H), 7.59–7.49(m,3H),2.69(s,3H)；¹³C NMR(101MHz,CDCl₃)δ151.53,146.98,140.79,136.04, 134.38,133.19,132.48,129.97,128.89,128.83,128.00,127.94,127.84,127.71,126.75,126.50, 126.33,124.14,15.69.

4-Methyl-3-phenylquinoline(10)

Yellow solid.¹H NMR(400MHz,CDCl₃)δ8.87–8.74(m,1H),8.15(d,J＝8.3Hz,1H),8.08(t,J＝ 10.1Hz,1H),7.73(t,J＝7.5Hz,1H),7.61(dd,J＝16.6,9.2Hz,1H),7.54–7.38(m,5H),2.65(s, 3H)；¹³C NMR(101MHz,CDCl₃)δ151.49,146.97,140.58,138.63,134.46,129.98,129.92,128.86, 128.44,127.97,127.56,126.73,124.19,15.61.

4-methyl-3-(p-tolyl)quinoline(11)

Dark brown solid.¹H NMR(400MHz,CDCl₃)δ8.80(s,1H),8.14(d,J＝8.3Hz,1H),8.09(d,J＝8.3 Hz,1H),7.72(t,J＝7.3Hz,1H),7.61(t,J＝7.5Hz,1H),7.37–7.27(m,4H),2.65(s,3H),2.45(s, 3H)；¹³C NMR(101MHz,CDCl₃)δ151.66,146.88,140.58,137.37,135.67,134.44,129.95,129.83, 129.19,128.78,128.04,126.70,124.20,21.24,15.65.

3-(4-chlorophenyl)-4-methylquinoline(12)

A colorless liquid.¹H NMR(400MHz,CDCl₃)δ8.76(s,1H),8.14(d,J＝8.3Hz,1H),8.09(d,J＝8.4 Hz,1H),7.79–7.68(m,1H),7.63(t,J＝7.6Hz,1H),7.48(d,J＝8.2Hz,2H),7.33(d,J＝8.3Hz, 2H),2.64(d,J＝8.0Hz,3H)；¹³C NMR(101MHz,CDCl₃)δ151.04,147.03,140.78,137.00,133.83, 133.26,131.21,129.97,129.11,128.71,127.84,126.92,124.17,15.61.

3-(4-methoxyphenyl)-4-methylquinoline(13)

A yellow liquid.¹H NMR(400MHz,CDCl₃)δ8.80(s,1H),8.20(d,J＝8.1Hz,1H),8.10(d,J＝8.3Hz, 1H),7.74(t,J＝7.3Hz,1H),7.63(dd,J＝14.9,7.5Hz,1H),7.32(d,J＝7.9Hz,2H),7.04(d,J＝7.8 Hz,2H),3.93–3.87(m,3H),2.65(d,J＝20.3Hz,3H)；¹³C NMR(101MHz,CDCl₃)δ159.26,150.90, 134.21,131.04,130.46,129.23,129.15,128.09,127.00,124.23,114.01,55.37,15.80.

4-methyl-3-(4-(trifluoromethyl)phenyl)quinoline(47)

A yellow oily liquid.¹H NMR(400MHz,CDCl₃)δ8.78(s,1H),8.19(d,J＝8.1Hz,1H),8.12(d,J＝ 7.8Hz,1H),7.77(d,J＝6.7Hz,3H),7.66(t,J＝7.1Hz,1H),7.53(d,J＝7.5Hz,2H),2.66(s,3H).

3-([1,1'-biphenyl]-4-yl)-4-methylquinoline(15)

Dark brown solid.¹H NMR(400MHz,CDCl₃)δ8.88(s,1H),8.18(d,J＝8.3Hz,1H),8.12(d,J＝8.3 Hz,1H),7.75(t,J＝7.1Hz,3H),7.69(d,J＝7.8Hz,2H),7.64(t,J＝7.6Hz,1H),7.50(t,J＝7.4Hz, 4H),7.40(t,J＝7.1Hz,1H),2.71(s,3H)；¹³C NMR(101MHz,CDCl₃)δ151.46,147.01,140.73, 140.57,140.51,137.56,134.10,130.42,130.01,128.96,128.91,128.03,127.56,127.21,127.15, 126.82,124.26,15.76.HRMS(EI):calcd for C₂₂H₁₇N:295.1361,found:295.1359。