阅读说明：本技术 一种利用光催化微通道实现重氮酸酯类化合物与苯胺分子n-h插入反应的方法 (Method for realizing N-H insertion reaction of diazo acid ester compound and aniline molecule by utilizing photocatalytic microchannel ) 是由 郭凯 吴蒙雨 邱江凯 覃龙州 袁鑫 孙蕲 段秀 刘杰 张欣鹏 于 2021-08-24 设计创作，主要内容包括：本发明公开了一种利用光催化微通道实现重氮酸酯类化合物与苯胺分子N-H插入反应的方法,将含式I所示的苯胺及其衍生物和式Ⅱ所示的重氮酸酯类化合物的均相溶液泵入设有光源的微通道反应装置中反应,得到式Ⅲ所示的2-苯基-2-苯乙酸乙酯衍生物。本发明提供了全新的可见光催化重氮类化合物的制备方法,只需通过将苯胺衍生物和重氮酸酯化合物溶解在溶剂中在光照射下就可以实现。(The invention discloses a method for realizing N-H insertion reaction of diazo acid ester compounds and aniline molecules by utilizing a photocatalytic microchannel, which comprises the steps of pumping homogeneous solution containing aniline shown in a formula I and derivatives thereof and diazo acid ester compounds shown in a formula II into a microchannel reaction device provided with a light source for reaction to obtain 2-phenyl-2-ethyl phenylacetate derivatives shown in a formula III. The invention provides a brand-new preparation method of visible light catalytic diazo compounds, which can be realized by dissolving aniline derivatives and diazo ester compounds in a solvent under the irradiation of light.)

1. A method for realizing N-H insertion reaction of diazo acid ester compounds and aniline molecules by utilizing a photocatalytic microchannel is characterized in that homogeneous solution containing aniline shown in a formula I and derivatives thereof and the diazo acid ester compounds shown in a formula II is pumped into a microchannel reaction device provided with a light source to react to obtain 2-phenyl-2-ethyl phenylacetate derivatives shown in a formula III;

wherein the content of the first and second substances,

R¹and R²Each independently selected from hydrogen, halogen, alkyl, alkoxy, aryl or aryl derivatives;

R³selected from alkyl, aryl or aryl derivatives.

2. The method according to claim 1, wherein the molar ratio of the aniline represented by the formula I and the derivative thereof to the diazo acid ester compound represented by the formula II is 1: (1-5).

3. The method of claim 1, wherein the solvent of the homogeneous solution is any one or more of dichloromethane, 1, 2-dichloroethane, acetonitrile, acetone, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, and dimethylsulfoxide.

4. The method according to claim 1, wherein the concentration of aniline represented by formula I and its derivatives in the homogeneous solution is 0.04-0.4 mmol/mL.

5. The method of claim 1, wherein the microchannel reactor device provided with the light source comprises a feed pump, a microchannel reactor, a light source, and a receiver; wherein, the feed pump, the microchannel reactor and the receiver are sequentially connected in series through pipelines, and the microchannel reactor is placed under the irradiation of a light source.

6. The process of claim 5 wherein the microchannel reactor has dimensions of 0.5 to 1.0mm in inside diameter and 5 to 20m in length.

7. The method of claim 1, wherein the light source has an intensity of 5-60W.

8. The method as claimed in claim 1, wherein the light source has a wavelength of 435 and 577 nm.

9. The process according to claim 1, wherein the temperature of the reaction is 0-30 ℃.

10. The process according to claim 1, characterized in that the residence time of the reaction is between 30s and 2 h.

Technical Field

The invention belongs to the field of chemical synthesis, and particularly relates to a method for realizing N-H insertion reaction of diazo acid ester compounds and aniline molecules by using a photocatalytic microchannel.

Background

The chemistry of diazo compounds has been intensively studied over the last decades. Metal catalyzed reactions of diazo compounds are commonly used in organic synthesis. The resulting metal carbene intermediates are capable of undergoing a wide range of reactions, sometimes well suited to trigger cascade sequences, resulting in rapid generation of structural complexity. Diazo compounds, commonly used as carbene precursors, are widely used as multifunctional cross-coupling agents in various transition metal catalyzed reactions.

In recent years, visible light catalysis has attracted more and more attention, and compared with other catalysis methods, visible light catalysis can be carried out under a milder condition, and meanwhile, visible light is used as sustainable energy and better meets the requirement of environmental protection. Furthermore, reactions based on visible light catalysis generally show high selectivity, and side reactions are rarely observed.

At present, the method for realizing the insertion reaction of diazo acid ester compounds and aniline molecules N-H is rarely reported. Hoda Keipour reported the method of S-H insertion reaction of diazo compounds in 2017. Although this reaction can effectively realize the insertion reaction of Si-H and S-H, a noble metal catalyst is added to the reaction system. The traditional photochemical reaction of the diazo compound has the defects of multiple synthesis steps, serious energy waste, environmental unfriendliness and the like, and the defects limit the application of the diazo compound in industrialization, so that the development of a method for catalyzing the diazo compound by visible light without a catalyst or an additive is very meaningful.

Disclosure of Invention

The purpose of the invention is as follows: the invention aims to solve the technical problem of the prior art and provides a method for realizing the N-H insertion reaction of diazo acid ester compounds and aniline molecules by using a photocatalytic microchannel.

In order to solve the technical problem, the invention discloses a method for realizing N-H insertion reaction of diazo acid ester compounds and aniline molecules by utilizing a photocatalytic microchannel, pumping homogeneous solution containing aniline and derivatives thereof shown in a formula I and diazo acid ester compounds shown in a formula II into a microchannel reaction device provided with a light source for reaction, collecting effluent liquid, and performing column chromatography separation to obtain 2-phenyl-2-ethyl phenylacetate derivatives shown in a formula III;

wherein the content of the first and second substances,

R¹and R²Each independently selected from hydrogen, halogen (F, Cl, Br, I), alkyl, alkoxy, aryl or aryl derivatives;

R³selected from alkyl, aryl or aryl derivatives.

Preferably, R¹Is hydrogen or alkyl; further preferably, R¹Is hydrogen or methyl; even more preferably, R¹Is hydrogen;

preferably, R²Is alkoxy or hydrogen; further preferably, R²Is methoxy or hydrogen; even more preferably, R²Is an alkoxy group; still more preferably, R²Is methoxy;

preferably, R³Is an alkyl group.

Wherein, the substituent of the diazoacid ester compound shown in the formula II can be at the ortho-position, meta-position and para-position.

Wherein the molar ratio of the aniline and the derivative thereof shown in the formula I to the diazoate compound shown in the formula II is 1: (1-5), preferably 1: 2.

wherein, the solvent of the homogeneous solution is any one or more of dichloromethane, 1, 2-dichloroethane, acetonitrile, acetone, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran and dimethyl sulfoxide, and is preferably dichloromethane.

Wherein, in the homogeneous solution, the concentration of the aniline and the derivative thereof shown in the formula I is 0.04-0.4mmol/mL, and preferably 0.2 mmol/mL.

Wherein, in the homogeneous solution, the concentration of the diazoate compound shown in the formula II is 0.08-1 mmol/mL.

Wherein the pumping rate of the homogeneous solution is 0.1-5 mL/min.

Wherein, as shown in fig. 1 and 2, the microchannel reactor device provided with the light source comprises a feeding pump (bagging Leifu Fluid Technology co.ltd, (TYD01-01-CE type)), a microchannel reactor, a light source and a receiver; wherein, the feed pump, the microchannel reactor and the receiver are sequentially connected in series through pipelines, and the microchannel reactor is placed under the irradiation of a light source.

The microchannel reactor is of a pore channel structure, the number of pore channels can be increased or decreased according to needs, and the pore channel material is perfluoroalkoxy alkane (PFA).

Wherein the inner diameter of the microchannel reactor is 0.5-1.0mm, the length is 5-20m, and the volume is 1-15.7 mL; preferably, the microchannel reactor has dimensions of 0.5mm internal diameter and 2mL volume.

Wherein, the light source is a lamp strip or a bulb, preferably a blue LED light source.

Wherein the intensity of the light source is 5-60W, preferably 40-60W, and more preferably 50W.

Wherein the wavelength of the light source is 435-.

Wherein the reaction temperature is 0 to 30 ℃, preferably 15 to 30 ℃, and more preferably 25 ℃.

Wherein the residence time of the reaction is 30s-2h, preferably 5-40min, more preferably 10-30min, still more preferably 15-25min, still more preferably 20 min.

Has the advantages that: compared with the prior art, the invention has the following advantages:

(1) the invention provides a brand-new preparation method of visible light catalytic diazo compounds, which can be realized by dissolving aniline derivatives and diazo ester compounds in a solvent under the irradiation of light.

(2) The reaction system provided by the invention has no solid insoluble substances, has no problem of micro-channel blockage, is simple to operate and high in safety, overcomes the defects of the traditional method, shortens the reaction time, improves the reaction conversion rate and the yield, and is high in reaction continuity and favorable for continuous and uninterrupted amplification production.

(3) The invention can synthesize the 2-phenyl-2-ethyl phenylacetate derivative without using a catalyst, and overcomes the problems of high production cost, high energy consumption, environmental pollution and the like in the prior art.

(4) The method does not need to add any additive, reduces the steps of post-treatment and is beneficial to the application to industrial scale-up production.

(5) The light source used by the invention is visible light, is sustainable energy and is a green synthesis method.

(6) The product conversion rate of the invention is 81-96%, and the yield is up to 77-95%.

Drawings

The foregoing and/or other advantages of the invention will become further apparent from the following detailed description of the invention when taken in conjunction with the accompanying drawings.

FIG. 1 is a schematic diagram of the reaction scheme of the present invention.

FIG. 2 is a view of a photocatalytic microchannel reactor device.

FIG. 3 is a nuclear magnetic hydrogen spectrum of the product of example 1.

FIG. 4 is the NMR spectrum of the product of example 1.

FIG. 5 is a nuclear magnetic hydrogen spectrum of the product of example 6.

FIG. 6 is the NMR spectrum of the product of example 6.

FIG. 7 is a nuclear magnetic hydrogen spectrum of the product of example 7.

FIG. 8 is the NMR spectrum of the product of example 7.

FIG. 9 is a nuclear magnetic hydrogen spectrum of the product of example 8.

FIG. 10 is the NMR spectrum of the product of example 8.

FIG. 11 is a nuclear magnetic hydrogen spectrum of the product of example 9.

FIG. 12 is the NMR spectrum of the product of example 9.

FIG. 13 is a nuclear magnetic hydrogen spectrum of the product of example 10.

FIG. 14 is the NMR spectrum of the product of example 10.

Detailed Description

The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.

Example 1

0.0466g (0.5mmol,1.0equiv) of aniline, 0.190g (1.0mmol,2.0equiv) of ethyl 2-diazo-2-phenylacetate were weighed out, dissolved in 2.5mL of dichloromethane, and loaded into a syringe after complete dissolution. Pumping the reaction solution into a reactor with a coil inner diameter of 0.5mm, a volume of 2mL and a micro-reactor flow rate of 0.1mL/min, irradiating by a blue LED light source (50W, 455nm), reacting at 25 ℃ and staying for 20 min. After the completion of the reaction, TLC detection was performed, and column chromatography (petroleum ether: ethyl acetate: 1) was performed to obtain 117.4mg of the final product in 92% yield. As shown in fig. 3 and 4, the characterization data are as follows:¹H NMR(400MHz,Chloroform-d)δ7.54–7.47(m,2H),7.38–7.27(m,3H),7.16–7.05(m,2H),6.69(t,J＝7.3Hz,1H),6.62–6.51(m,2H),5.09–5.03(m,1H),4.97(s,1H),4.28–4.09(m,2H),1.21(t,J＝7.1Hz,3H).¹³C NMR(100MHz,Chloroform-d)δ171.9,146.0,129.3,128.8,128.3,127.2,118.0,113.4,61.9,60.8,14.1.

example 2

0.0466g (0.5mmol,1.0equiv) of aniline, 0.190g (1.0mmol,2.0equiv) of ethyl 2-diazo-2-phenylacetate were weighed out, dissolved in 2.5mL of dichloromethane, and loaded into a syringe after complete dissolution. Pumping the reaction solution into a reactor with a coil inner diameter of 0.5mm, a volume of 2mL and a micro-reactor flow rate of 0.1mL/min, irradiating by a blue LED light source (10W, 455nm), reacting at 25 ℃ and staying for 20 min. After completion of the reaction, TLC detection was performed, and column chromatography (petroleum ether: ethyl acetate: 1) was performed to obtain 97.0mg of the product in 76% yield.

Example 3

0.0466g (0.5mmol,1.0equiv) of aniline, 0.190g (1.0mmol,2.0equiv) of ethyl 2-diazo-2-phenylacetate were weighed out, dissolved in 2.5mL of dichloromethane, and loaded into a syringe after complete dissolution. Pumping the reaction solution into a reactor with a coil inner diameter of 0.5mm, a volume of 2mL and a micro-reactor flow rate of 0.1mL/min, irradiating by a blue LED light source (50W, 455nm), reacting at 15 ℃ and staying for 20 min. After completion of the reaction, TLC detection was performed, and column chromatography (petroleum ether: ethyl acetate: 1) was performed to obtain 105.9mg of a product with a yield of 83%.

Example 4

0.0466g (0.5mmol,1.0equiv) of aniline, 0.190g (1.0mmol,2.0equiv) of ethyl 2-diazo-2-phenylacetate were weighed out, dissolved in 2.5mL of dichloromethane, and loaded into a syringe after complete dissolution. Pumping the reaction solution into a reactor with a coil inner diameter of 0.5mm, a volume of 2mL and a micro-reactor flow rate of 0.5mL/min, irradiating with a blue LED light source (50W, 455nm), reacting at 25 deg.C, and standing for 4 min. After completion of the reaction, TLC detection was performed, and column chromatography (petroleum ether: ethyl acetate: 1) was performed to obtain 71.5mg of a product with a yield of 56%.

Example 5

0.0466g (0.5mmol,1.0equiv) of aniline, 0.190g (1.0mmol,2.0equiv) of ethyl 2-diazo-2-phenylacetate were weighed out, dissolved in 2.5mL of dichloromethane, and loaded into a syringe after complete dissolution. The reaction solution is pumped into a reactor with the inner diameter of a coil pipe of 0.5mm, the volume is 2mL, the flow rate of the microreactor is 0.15mL/min, a blue LED light source (50W, 455nm) is used for irradiation, the reaction is carried out at 25 ℃, and the retention time is 13.3 min. After completion of the reaction, TLC detection was performed, and column chromatography (petroleum ether: ethyl acetate: 1) was performed to obtain 111.1mg of the product in 87% yield.

Example 6

0.0466g (0.5mmol,1.0equiv) of aniline, 0.220g (1.0mmol,2.0equiv) of ethyl 2-diazo-2- (4-methoxyphenyl) acetate were weighed out, dissolved in 2.5mL of dichloromethane, and after complete dissolution, loaded into a syringe. Pumping the reaction solution into a reactor with a coil inner diameter of 0.5mm, a volume of 2mL and a micro-reactor flow rate of 0.1mL/min, irradiating by a blue LED light source (50W, 455nm), reacting at 25 ℃ and staying for 20 min. After completion of the reaction, TLC detection was performed, and column chromatography (petroleum ether: ethyl acetate: 1) was performed to obtain 135.5mg of the product in 95% yield. As shown in fig. 5 and 6, the characterization data are as follows:¹H NMR(400MHz,Chloroform-d)δ7.41(d,J＝8.6Hz,2H),7.12(t,J＝7.8Hz,2H),6.87(d,J＝8.6Hz,2H),6.69(t,J＝7.3Hz,1H),6.55(d,J＝8.0Hz,2H),5.04–4.98(m,1H),4.97–4.81(m,1H),4.27–4.10(m,2H),3.78(s,3H),1.21(t,J＝7.1Hz,3H).¹³C NMR(101MHz,Chloroform-d)δ172.1,159.5,146.0,129.7,129.2,128.4,118.0,114.2,113.4,61.8,60.2,55.3,14.1.

example 7

0.1099g (0.5mmol,1.0equiv) of 4-benzylaniline and 0.190g (1.0mmol,2.0equiv) of ethyl 2-diazo-2-phenylacetate were weighed, dissolved in 2.5mL of dichloromethane, and loaded into a syringe after complete dissolution. Pumping the reaction solution into a reactor with a coil inner diameter of 0.5mm, a volume of 2mL and a micro-reactor flow rate of 0.1mL/min, irradiating by a blue LED light source (50W, 455nm), reacting at 25 ℃ and staying for 20 min. After the completion of the reaction, TLC detection was carried out, and column chromatography (petroleum ether: ethyl acetate: 1) was carried out to give 131.3mg of a product, yieldThe rate was 76%. As shown in fig. 7 and 8, the characterization data are as follows:¹H NMR(400MHz,Chloroform-d)δ7.52–7.46(m,2H),7.37–7.28(m,3H),7.26–7.22(m,2H),7.18–7.11(m,3H),6.93(d,J＝8.3Hz,2H),6.49(d,J＝8.4Hz,2H),5.01(s,1H),4.88(s,1H),4.25–4.09(m,2H),3.83(s,2H),1.20(t,J＝7.1Hz,3H).¹³C NMR(101MHz,Chloroform-d)δ171.9,144.3,141.9,137.9,130.6,129.7,128.8,128.4,128.2,127.2,125.9,113.5,61.8,61.0,41.0,14.0.

example 8

0.0860g (0.5mmol,1.0equiv) of 4-bromoaniline and 0.190g (1.0mmol,2.0equiv) of ethyl 2-diazo-2-phenylacetate were weighed out, dissolved in 2.5mL of dichloromethane, and loaded into a syringe after complete dissolution. Pumping the reaction solution into a reactor with a coil inner diameter of 0.5mm, a volume of 2mL and a micro-reactor flow rate of 0.1mL/min, irradiating by a blue LED light source (50W, 455nm), reacting at 25 ℃ and staying for 20 min. After completion of the reaction, TLC detection was performed, and column chromatography (petroleum ether: ethyl acetate: 1: 3) was performed to obtain 135.4mg of the product in 81% yield. As shown in fig. 9 and 10, the characterization data are as follows:¹H NMR(400MHz,Chloroform-d)δ7.48–7.42(m,2H),7.40–7.29(m,3H),7.18(d,J＝8.7Hz,2H),6.42(d,J＝8.7Hz,2H),5.07–4.94(m,2H),4.26–4.11(m,2H),1.21(t,J＝7.1Hz,3H).¹³C NMR(101MHz,Chloroform-d)δ171.5,144.9,137.2,132.0,128.9,128.4,127.2,115.0,109.7,62.0,60.6,14.0.

example 9

0.0466g (0.5mmol,1.0equiv) of aniline, 0.2691g (1.0mmol,2.0equiv) of ethyl 2- (4-bromophenyl) -2-diazoacetate were weighed out, dissolved in 2.5mL of dichloromethane, and after complete dissolution, loaded into a syringe. The reaction liquid is pumped into a reactor with the inner diameter of a coil pipe of 0.5mm, the volume is 2mL, the flow rate of the microreactor is 0.1mL/min, irradiating by a blue LED light source (50W, 455nm), reacting at 25 ℃ for 20 min. After completion of the reaction, TLC detection was performed, and column chromatography (petroleum ether: ethyl acetate: 1: 3) was performed to obtain 140.4mg of a product with a yield of 84%. As shown in fig. 11 and 12, the characterization data are as follows:¹H NMR(400MHz,Chloroform-d)δ7.50–7.45(m,2H),7.42–7.36(m,2H),7.26(s,2H),7.12(t,J＝7.8Hz,2H),6.71(t,J＝7.3Hz,1H),6.52(d,J＝8.0Hz,2H),5.01(s,2H),4.27–4.11(m,2H),1.22(t,J＝7.1Hz,3H).¹³CNMR(101MHz,Chloroform-d)δ171.2,145.6,136.9,132.0,129.3,128.9,122.2,118.3,113.4,62.1,60.2,14.04.

example 10

0.1136g (0.5mmol,1.0equiv) of 4-methylaniline and 0.190g (1.0mmol,2.0equiv) of ethyl 2-diazo-2-phenylacetate were weighed, dissolved in 2.5mL of dichloromethane, and the solution was loaded into a syringe after complete dissolution. Pumping the reaction solution into a reactor with a coil inner diameter of 0.5mm, a volume of 2mL and a micro-reactor flow rate of 0.1mL/min, irradiating by a blue LED light source (50W, 455nm), reacting at 25 ℃ and staying for 20 min. After completion of the reaction, TLC detection was performed, and column chromatography (petroleum ether: ethyl acetate: 1: 3) was performed to obtain 121.1mg of the product in 90% yield. As shown in fig. 13 and 14, the characterization data are as follows:¹H NMR(400MHz,Chloroform-d)δ7.51–7.47(m,2H),7.36–7.27(m,3H),6.93(d,J＝8.2Hz,2H),6.48(d,J＝8.3Hz,2H),5.06–5.01(m,1H),4.82(s,1H),4.25–4.10(m,2H),2.19(s,3H),1.21(t,J＝7.1Hz,3H).¹³CNMR(101MHz,Chloroform-d)δ

172.0,143.7,137.9,129.8,128.8,128.2,127.2,113.5,61.8,61.1,20.4,14.1.

TABLE 1

^[a]Reaction conditions are as follows: separately weighing aniline (0.5 mm)ol,1.0equiv), diazotate (1.0mmol,2.0equiv), dissolved with 2.5mL dichloromethane, loaded into a syringe after complete dissolution. The reaction solution is pumped into a reactor with the inner diameter of a coil pipe of 0.5mm, the volume is 2mL, the flow rate of the microreactor is controlled to be 0.1-0.5mL/min according to each embodiment, and the reaction is carried out for 4-20min at 15-25 ℃ by irradiating with a blue LED light source (10-50W, 455 nm). And (4) carrying out TLC detection after the reaction is finished, and carrying out column chromatography to obtain a product.

^[b]Reaction conditions are as follows: aniline (0.5mmol,1.0equiv) was weighed, added to a dry Schlenk reaction tube, and argon was replaced three times; the diazo ester (1.0mmol,2.0equiv) was dissolved in 2.5mL of dichloromethane and injected into the Schlenk reaction tube with a syringe. The reaction is carried out by irradiating the mixture by a blue LED light source (10-50W455nm) at 15-25 ℃ for 12 h. And (4) carrying out TLC detection after the reaction is finished, and carrying out column chromatography to obtain a product. The intensity of the light source and the reaction temperature were the same as in each example.

The present invention provides a method and a concept for implementing a N-H insertion reaction between a diazo acid ester compound and an aniline molecule by using a photocatalytic microchannel, and the method and the approach for implementing the technical scheme are many, and the above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be regarded as the protection scope of the present invention. All the components not specified in the present embodiment can be realized by the prior art.