阅读说明：本技术 一种非氢气参与选择性催化氢化喹啉类化合物合成四氢喹啉类化合物的方法 (Method for synthesizing tetrahydroquinoline compound by selectively catalyzing and hydrogenating quinoline compound with non-hydrogen ) 是由 韩波 张苗苗 焦红梅 马豪杰 张玉琦 于 2021-10-15 设计创作，主要内容包括：本发明公开了一种非氢气参与选择性催化氢化喹啉类化合物合成四氢喹啉类化合物的方法,该方法以五羰基溴化锰为催化剂、苯基硅烷为氢源,不需要添加配体,在温和条件下搅拌反应,即可选择性催化氢化喹啉类化合物得到1,2,3,4-四氢喹啉类化合物。本发明具有成本低、反应条件温和、选择性高等优点,避免了使用氢气而需要高压釜等特殊设备及高温条件,同时利用地球上丰富的廉价金属替代贵金属催化剂,不仅降低了经济成本和毒性,也为四氢喹啉类化合物的合成提供了新的思路和途径。本发明方法适用于不同取代的喹啉类化合物及其他芳香杂环底物的选择氢化。(The invention discloses a method for synthesizing tetrahydroquinoline compounds by selectively catalyzing hydrogenated quinoline compounds with non-hydrogen, which takes manganese pentacarbonyl bromide as a catalyst and phenyl silane as a hydrogen source, does not need to add a ligand, and can selectively catalyze the hydrogenated quinoline compounds to obtain the 1,2,3, 4-tetrahydroquinoline compounds by stirring and reacting under mild conditions. The method has the advantages of low cost, mild reaction conditions, high selectivity and the like, avoids the need of special equipment such as an autoclave and the like and high-temperature conditions due to the use of hydrogen, and simultaneously replaces a noble metal catalyst with abundant cheap metals on the earth, thereby not only reducing the economic cost and the toxicity, but also providing a new idea and a new way for synthesizing the tetrahydroquinoline compound. The method is suitable for selective hydrogenation of different substituted quinoline compounds and other aromatic heterocyclic substrates.)

1. A method for synthesizing tetrahydroquinoline compounds by selectively catalyzing and hydrogenating quinoline compounds with non-hydrogen is characterized by comprising the following steps: adding a quinoline compound shown as a formula I, manganese pentacarbonyl bromide and phenyl silane into an organic solvent, stirring and reacting for 24-60 h at 50-70 ℃ under normal pressure in a nitrogen atmosphere, and separating and purifying after the reaction is finished to obtain a tetrahydroquinoline compound shown as a formula II;

in the formulae I and II, R₁、R₂、R₃、R₄、R₅Each independently represents H, halogen, phenyl, C₁～C₄Alkyl radical, C₁～C₄Any one of alkoxy and hydroxyl, and at least 3 of the alkoxy and the hydroxyl represent H.

2. The method of claim 1, wherein the non-hydrogen gas participates in the selective catalytic hydrogenation of quinolines to produce tetrahydroquinolines, the method comprising: the addition amount of the manganese pentacarbonyl bromide is 8 to 15 percent of the molar amount of the quinoline compound.

3. The method of claim 1, wherein the non-hydrogen gas participates in the selective catalytic hydrogenation of quinolines to produce tetrahydroquinolines, the method comprising: the adding amount of the phenyl silane is 3-5 times of the molar amount of the quinoline compound.

4. The method of claim 1, wherein the non-hydrogen gas participates in the selective catalytic hydrogenation of quinolines to produce tetrahydroquinolines, the method comprising: the organic solvent is any one of ethanol, methanol and isopropanol.

Technical Field

The invention belongs to the technical field of synthesis of heteroaromatic compounds, and particularly relates to a high-selectivity hydrogenation method of a quinoline compound.

Background

Heterocyclic compounds, which account for about one third of the organic matter, nitrogen heterocyclic compounds, oxygen heterocyclic compounds, sulfur heterocyclic compounds, and the like, particularly nitrogen heterocyclic compounds such as: 1,2,3, 4-tetrahydroquinoline is an important precursor for the synthesis of various biologically active compounds used in the pharmaceutical industry, namely reverse transcriptase inhibitors (antimalarials) which are highly cytotoxic to plasmodium falciparum. Many of the nitrogen-containing heterocyclic compounds exhibit important physiological activities and are directly used as small molecule drugs or important intermediates of drugs. Such as: HIV-1 reverse transcriptase inhibitors have a certain therapeutic effect on AIDS and have a specific skeleton of tetrahydroquinoline cyclopropane. In addition, the method can be used for asphalt pretreatment, can improve the quality of asphalt carbon fibers, and can prepare high-strength and high-modulus asphalt cellulose. The tetrahydroquinoline derivatives are synthesized by quinoline catalytic hydrogenation, and the method is simple, has few reaction steps and low raw material cost.

In view of the importance of these frameworks in drug screening and pharmaceutical chemistry, the development of new methods for the synthesis of 1,2,3, 4-tetrahydroquinolines remains an active and very important research area, with different approaches to the synthesis of 1,2,3, 4-tetrahydroquinolines being possible, i.e. the cyclization, rearrangement or partial reduction of quinolines and derivatives. The direct hydrogenation reduction method is most advantageous in terms of atom economy and eco-friendliness. The use of complexes based on the noble metals palladium, rhodium, ruthenium and iridium has been prevalent for a long time, and such complexes dominate in the second half of the twentieth century because of their versatility and improved activity, as well as excellent selectivity in most reactions. Notably, the market price of precious metals is relatively high and, due to their scarcity in the earth's crust, tends to be rather unstable. Therefore, the development of a method for catalytically reducing unsaturated compounds by cheap metals which are low in toxicity and rich in earth is particularly important. Such as iron and manganese, are less toxic than heavy metals. However, the challenge of developing earth-rich catalysts remains due to their harsh structure, particularly in the area of fine chemicals and bioactive compounds.

In 2011, the Graham E.Dobereiner topic group uses 2-methylquinoline as a substrate, selects stable iridium (I) NHC as a catalyst precursor and PPh₃Co-catalysis, a new homogeneous iridium catalyst can hydrogenate various functional substituted quinolines under unprecedented mild conditions, hydrogenation temperatures as low as 25 ℃ can hydrogenate aromatic species under 1 atm hydrogen reaction conditions and this is a rare catalytic mechanism, but the conditions are low for halogenated substrates, require increasing the hydrogen pressure to 5 atm to achieve high yields, and have poor substrate turnover for less sterically hindered substrates (Journal of the American Chemical Society,2011,133(19): 7547) -7562).

Gong Yutong reports utilization of mpg-C in 2012₃N₄As a catalyst carrier to design high performance heterogeneous catalysts. Highly dispersed palladium nanoparticles are incorporated as functional moieties into mpg-C₃N₄The hydrogenation of quinoline to 1,2,3, 4-tetrahydroquinoline at a mild temperature (30-50 ℃) shows excellent activity and selectivity. The reaction period is short and the reactivity and selectivity to the recovered catalyst can be maintained for at least 6 reaction runs. However, the aromatic heterocyclic ring substituted with a methyl group requires a higher reaction temperature, and the aromatic heterocyclic compound substituted with other functional groups is not mentioned, and further investigation is required (Journal of Catalysis,2013,297: 272-280.).

He Renke topic group in 2017 develops iron catalytic transfer hydrogenation with low catalyst loadProcess for the preparation of quinoline, 1 mol% Fe (OTf)₂In the presence of the hydrogen, Hantzsch is used as a hydrogen source, the reaction time is 2-8 hours, the quinoline is subjected to high-efficiency transfer hydrogenation at a mild reaction temperature of 40 ℃, but when the substituent is phenyl with large steric hindrance, the required reaction time is prolonged. The high catalytic activity of iron makes it an environmentally friendly alternative to bronsted and other lewis acids for the reduction of quinoline. Meanwhile, they are also studying the use of iron catalysis to obtain asymmetric chiral target products (Tetrahedron Letters,2017.58(36): 3571-3573).

Veronica Papa et al reported the chemoselective reduction of quinoline and related nitrogen heterocycles by molecular hydrogen in 2020. In the case of conventional noble metal catalytic systems, it is also necessary to add some expensive phosphine ligands to increase the reactivity of the metal catalyst. While the authors used a simple Mn (I) complex [ Mn (CO)₅Br]Under very mild reaction conditions, namely hydrogen (1-2 MPa), the catalytic system can reduce various quinolines, and the obtained tetrahydroquinoline has high selectivity and high yield. However, when the 3-position has a substituted aryl group, the activity of the substrate is low, and when polycyclic aromatic hydrocarbons are used, high temperature and high pressure are required to obtain the target product (Nature Catalysis,2020,3, 135-142.).

As can be seen from the above, in the present stage, the main synthesis method of the 1,2,3, 4-tetrahydroquinoline compound still uses hydrogen as a reducing agent, and thus special equipment and harsh conditions, such as an autoclave and a higher reaction temperature, are necessarily used. Therefore, the development of an efficient green synthetic method has important research significance.

Disclosure of Invention

The invention aims to provide a method for synthesizing tetrahydroquinoline compounds by catalyzing hydrogenated quinoline compounds with high selectivity in a non-hydrogen atmosphere by using manganese carbonyl bromide as a catalyst and phenyl silane as a hydrogen source.

Aiming at the purposes, the technical scheme adopted by the invention is as follows: adding a quinoline compound shown as a formula I, manganese pentacarbonyl bromide and phenyl silane into an organic solvent, stirring and reacting for 24-60 h at 50-70 ℃ under normal pressure in a nitrogen atmosphere, and separating and purifying after the reaction is finished to obtain a tetrahydroquinoline compound shown as a formula II;

in the formulae I and II, R₁、R₂、R₃、R₄、R₅Each independently represents H, halogen, phenyl, C₁～C₄Alkyl radical, C₁～C₄Any one of alkoxy and hydroxyl, and at least 3 of the alkoxy and the hydroxyl represent H.

In the above method, the amount of the manganese pentacarbonyl bromide added is preferably 8 to 15% of the molar amount of the quinoline compound.

In the above method, the amount of the phenylsilane added is preferably 3 to 5 times the molar amount of the quinoline compound.

The organic solvent is preferably any one of ethanol, methanol and isopropanol.

Compared with the prior art, the invention has the following beneficial effects:

the synthetic method is simple and green, and the cheap and easily-obtained quinoline compound is used as the raw material to react in a non-hydrogen atmosphere, so that special equipment is avoided; the method has the advantages of mild reaction conditions, simple operation, high selectivity and high yield, and the yield can reach 85.6%; the manganese pentacarbonyl bromide and the phenyl silane used in the invention are commercial reagents, and the use of expensive organic ligands is avoided.

Detailed Description

The present invention will be described in further detail with reference to examples, but the scope of the present invention is not limited to these examples.

Example 1

Synthesizing 1,2,3, 4-tetrahydroquinoline with the structural formula

0.0055g (0.02mmol) of MnBr (CO)₅Adding into a 25mL high-pressure reaction tube, charging and discharging three times by using a double-row tube, and sequentially adding 24 mu L (0.2mmol) of quine under nitrogen flowThe preparation method comprises the following steps of (1) performing reaction on quinoline, 0.1mL (0.8mmol) of phenylsilane and 2.5mL of ethanol under stirring at 60 ℃ for 48 hours after pipe sealing, adding 10mL of saturated aqueous ammonium chloride solution to quench the reaction, extracting with ethyl acetate (10 mL for 3 times each time), combining extracts, adding anhydrous sodium sulfate to dry, and separating a product by column chromatography by using petroleum ether and ethyl acetate in a volume ratio of 10:1 as a developing agent to obtain an oily product 1,2,3, 4-tetrahydroquinoline, wherein the yield is 85.6%.

The spectral data of the product obtained are:¹H NMR(400MHz,CDCl₃):δ＝6.99-6.93(m,2H),6.61(td,J＝7.5,0.9Hz,1H),6.48(d,J＝7.8Hz,1H),3.30(t,J＝5.48Hz,2H),2.77(t,J＝6.4Hz,2H),1.98-1.91(m,2H)；¹³C NMR(100MHz,CDCl₃) δ 144.88,129.65,126.85,121.59,117.08,114.32,42.09,27.08, 22.28; HRMS (ESI) theoretical value C₉H₁₁N[M+H⁺]134.0964, found 134.0959.

Example 2

Synthesizing 6-chloro-1, 2,3, 4-tetrahydroquinoline with the structural formula

In this example, the quinoline in example 1 was replaced with 6-chloroquinoline in equimolar amount, and the other procedures were the same as in example 1 to give 6-chloro-1, 2,3, 4-tetrahydroquinoline in a yield of 63.3%.

The spectral data of the product obtained are:¹H NMR(400MHz,CDCl₃):δ＝6.95-6.85(m,2H),6.38(d,J＝8.3Hz,1H),3.80(bs,NH),3.33-3.24(m,2H),2.72(t,J＝6.4Hz,2H),1.95-1.87(m,2H)；¹³C NMR(100MHz,CDCl₃):δ＝143.4,129.2,126.6,122.9,121.3,115.2,41.9,26.9,21.9.

example 3

Synthesizing 6-phenyl-1, 2,3, 4-tetrahydroquinoline with the structural formula

In this example, the quinoline in example 1 was replaced with 6-phenylquinoline in equimolar amount, and the other procedure was carried out in the same manner as in example 1 to obtain 6-phenyl-1, 2,3, 4-tetrahydroquinoline in a yield of 86%.

The spectral data of the product obtained are:¹H NMR(400MHz,CDCl₃):δ＝7.58–7.50(m,2H),7.40(dd,J＝8.5,7.0Hz,2H),7.30–7.19(m,3H),6.55(d,J＝7.9Hz,1H),3.83(s,1H),3.38–3.29(m,2H),2.84(t,J＝6.4Hz,2H),2.02–1.92(m,2H)；¹³C NMR(100MHz,CDCl₃) δ 144.39,141.59,129.93,128.69,128.28,126.36,125.99,125.61,121.64,114.51,42.09,27.22, 22.24; HRMS (ESI) theoretical value C₁₅H₁₅N[M+H⁺]210.1277, found 210.1276.

Example 4

Synthesizing 6- (4-methoxyphenyl) -1,2,3, 4-tetrahydroquinoline with the structural formula

In this example, an equimolar amount of 6- (4-methoxyphenyl) quinoline was used instead of the quinoline in example 1, and the other procedures were the same as in example 1 to obtain 6- (4-methoxyphenyl) -1,2,3, 4-tetrahydroquinoline in a yield of 51%.

The spectral data of the product obtained are:¹H NMR(400MHz,CDCl₃):δ＝7.51–7.42(m,2H),7.22–7.14(m,2H),7.00–6.88(m,2H),6.55(dd,J＝7.8,0.8Hz,1H),3.85(s,3H),3.37–3.25(m,2H),2.85(t,J＝6.4Hz,2H),2.07–1.89(m,2H)；¹³C NMR(100MHz,CDCl₃) δ 158.24,143.91,134.34,129.77,127.91,127.36,125.24,121.69,114.58,114.12,55.41,42.13,27.22, 22.31; HRMS (ESI) theoretical value C₁₆H₁₇NO[M+H⁺]240.1383, found 240.1382.

Example 5

Synthesizing 2-phenyl-1, 2,3, 4-tetrahydroquinoline with the structural formula

In this example, 2-phenyl-1, 2,3, 4-tetrahydroquinoline was obtained in 81% yield in the same manner as in example 1 except that 2-phenylquinoline was used in place of the quinoline in example 1 in an equimolar amount. In this example, the yield of 2-phenyl-1, 2,3, 4-tetrahydroquinoline was 75% when the solvent was methanol.

The spectral data of the product obtained are:¹H NMR(400MHz,CDCl₃):δ＝7.46–7.29(m,5H),7.05(t,J＝7.4Hz,2H),6.69(td,J＝7.4,1.0Hz,1H),6.57(d,J＝7.6Hz,1H),4.47(dd,J＝9.3,3.3Hz,1H),4.07(bs,NH),3.02–2.90(m,2H),2.77(dt,J＝16.3,4.8Hz,1H),2.08–2.98(m,1H)；¹³C NMR(100MHz,CDCl₃) δ 144.6,144.5,129.1,128.4,127.2,126.7,126.4,120.7,116.9,113.8,77.2,56.0,30.8, 26.2; HRMS (ESI) theoretical value C₁₅H₁₅N[M+H⁺]210.1277, found 210.1280.

Example 6

Synthesizing 3-methyl-1, 2,3, 4-tetrahydroquinoline with the structural formula

In this example, the quinoline in example 1 was replaced with equimolar 3-methyl-quinoline and the other procedure was the same as in example 1 to give 3-methyl-1, 2,3, 4-tetrahydroquinoline in 65% yield.

The spectral data of the product obtained are:¹H NMR(400MHz,CDCl₃):δ＝7.03–6.92(m,2H),6.62(td,J＝7.4,1.0Hz,1H),6.50(d,J＝7.9Hz,1H),3.28(ddd,J＝11.0,3.7,2.0Hz,1H),2.91(dd,J＝10.8,9.9Hz,1H),2.79(ddd,J＝16.0,4.8,1.7Hz,1H),2.45(dd,J＝16.0,10.3Hz,1H),2.13–1.98(m,1H),1.06(d,J＝6.6Hz,3H)；¹³C NMR(100MHz,CDCl₃) δ 144.4,129.7,126.8,121.3,117.1,113.9,48.9,35.6,27.3, 19.2; HRMS (ESI) theoretical value C₁₀H₁₃N[M+H⁺]148.1121, found 148.1119.

Example 7

Synthesizing 5-methyl-1, 2,3, 4-tetrahydroquinoline with the structural formula

In this example, 5-methyl-1, 2,3, 4-tetrahydroquinoline was obtained in 84% yield by replacing the quinoline with 5-methylquinoline in example 1 in an equimolar amount and carrying out the same procedures as in example 1.

The spectral data of the product obtained are:¹H NMR(400MHz,CDCl₃):δ＝6.90(t,J＝7.7Hz,1H),6.54(d,J＝7.4Hz,1H),6.39(d,J＝8.0Hz,1H),3.29–3.25(m,2H),2.66(t,J＝6.6Hz,2H),2.19(s,3H),2.04–1.97(m,2H)；¹³C NMR(100MHz,CDCl₃) δ 144.8,137.1,125.9,120.0,118.7,112.3,41.4,23.9,22.3, 19.2; HRMS (ESI) theoretical value C₁₀H₁₃N[M+H⁺]148.1121, found 148.1123.

Example 8

Synthesizing 6-methyl-1, 2,3, 4-tetrahydroquinoline with the structural formula

In this example, the quinoline in example 1 was replaced with 6-methylquinoline in equimolar amount, and the other procedure was the same as in example 1 to obtain 6-methyl-1, 2,3, 4-tetrahydroquinoline in a yield of 84%.

The spectral data of the product obtained are:¹H NMR(400MHz,CDCl₃):δ＝6.80(d,J＝5.7Hz,2H),6.44–6.41(m,1H),3.31–3.27(m,2H),2.75(t,J＝6.5Hz,2H),2.22(s,3H),1.98–1.91(m,2H)；¹³C NMR(100MHz,CDCl₃) δ 142.2,129.9,127.0,126.1,121.4,114.3,41.9,26.7,22.2, 20.2; HRMS (ESI) theoretical value C₁₀H₁₃N[M+H⁺]148.1121, found 148.1123.

Example 9

Synthesis of 8-methyl-1, 2,3, 4-tetrahydroquinoline having the formula

In this example, 8-methyl-1, 2,3, 4-tetrahydroquinoline was obtained in 80% yield by replacing quinoline with 8-methylquinoline in example 1 in equimolar amounts and carrying out the same procedures as in example 1. The spectral data of the product obtained are:¹HNMR(400MHz,CDCl₃):δ＝6.89(t,J＝9.0Hz,2H),6.61–6.55(m,1H),3.66(bs,NH),3.42–3.37(m,2H),2.81(t,J＝5.7Hz,2H),2.10(s,3H),2.00–1.92(m,2H)；¹³C NMR(100MHz,CDCl₃) δ 143.13,128.26,127.80,121.61,121.28,116.80,42.75,27.70,22.56, 17.61; HRMS (ESI) theoretical value C₁₀H₁₃N[M+H+]148.1121, found 148.1123.

Example 10

Synthesizing 8-chloro-1, 2,3, 4-tetrahydroquinoline with the structural formula

In this example, 8-chloro-1, 2,3, 4-tetrahydroquinoline was obtained in 79% yield by replacing quinoline with 8-chloroquinoline in an equimolar amount and carrying out the same procedures as in example 1.

The spectral data of the product obtained are:¹H NMR(400MHz,CDCl₃):δ＝7.07(ddd,J＝7.9,1.5,0.7Hz,1H),6.86(dd,J＝7.5,1.3Hz,1H),6.51(t,J＝7.7Hz,1H),4.42(bs,1H),3.40(t,J＝5.6Hz,2H),2.78(t,J＝6.4Hz,2H),1.99–1.82(m,2H)；¹³C NMR(100MHz,CDCl₃) δ 140.84,127.78,126.89,122.74,118.15,116.38,41.90,27.32, 21.74; HRMS (ESI) theoretical value C₉H₁₀ClN[M+H⁺]168.0575, found 168.0573.

Example 11

Synthesizing 8-hydroxy-1, 2,3, 4-tetrahydroquinoline with the structural formula

In this example, 8-hydroxy-1, 2,3, 4-tetrahydroquinoline was obtained in 77% yield by replacing quinoline with 8-hydroxyquinoline in an equimolar amount and following the same procedure as in example 1.

The spectral data of the product obtained are:¹H NMR(400MHz,CDCl₃):δ＝6.57(d,J＝35.3Hz,3H),4.46(s,2H),3.31(s,2H),2.78(t,J＝6.3Hz,2H),2.03–1.82(m,2H)；¹³C NMR(100MHz,CDCl₃) δ 142.45,133.60,123.28,121.90,117.26,112.53,41.90,26.67, 22.32; HRMS (ESI) theoretical value C₉H₁₁NO[M+H⁺]150.0913, found 150.0912.

Example 12

Synthesis of 8-fluoro-1, 2,3, 4-tetrahydroquinoline having the formula

In this example, 8-fluoro-1, 2,3, 4-tetrahydroquinoline was obtained in 81% yield by replacing quinoline with 8-fluoroquinoline in example 1 in equimolar amount and carrying out the same procedure as in example 1.

The spectral data of the product obtained are:¹H NMR(400MHz,CDCl₃):δ＝6.79–6.67(m,2H),6.47(td,J＝7.8,5.3Hz,1H),3.97(s,1H),3.33–3.27(m,2H),2.75(t,J＝6.4Hz,2H),1.96–1.87(m,2H)；¹³C NMR(100MHz,CDCl₃):δ＝150.86(d,J＝237.0Hz),133.14(d,J＝12.2Hz),124.44(d,J＝4.0Hz),123.56(d,J＝4.0Hz),115.47(d,J＝8.0Hz),112.10(d,J＝18Hz),41.27,26.52,21.74；¹⁹F NMR(377MHz,CDCl₃) δ -138.86; HRMS (ESI) theoretical value C₉H₁₀FN[M+H+]152.0870, found 152.0867.

Example 13

Synthesizing 2, 6-dimethyl-1, 2,3, 4-tetrahydroquinoline with the structural formula

In this example, 2, 6-dimethyl-1, 2,3, 4-tetrahydroquinoline was obtained in 86% yield by replacing quinoline with 2, 6-dimethylquinoline in equimolar amount and following the same procedure as in example 1.

The spectral data of the product obtained are:¹H NMR(400MHz,CDCl₃):δ＝6.80(d,J＝7.4Hz,2H),6.43(d,J＝8.2Hz,1H),3.43–3.33(m,1H),2.92–2.77(m,1H),2.71(ddd,J＝16.4,5.4,3.3Hz,1H),2.23(s,3H),1.98–1.89(m,1H),1.65–1.54(m,1H),1.22(d,J＝6.3Hz,3H)；¹³CNMR(100MHz,CDCl₃) δ 142.6,129.9,127.3,126.4,121.4,114.4,47.4,30.5,26.7,22.7, 20.5; HRMS (ESI) theoretical value C₁₁H₁₅N[M+H⁺]162.1277, found 162.1272.

Example 14

In example 1, the solvent ethanol used was replaced with an equal volume of methanol to give a 78% yield of 1,2,3, 4-tetrahydroquinoline, and replaced with an equal volume of isopropanol to give a 70% yield of 1,2,3, 4-tetrahydroquinoline.