阅读说明：本技术 一种利用光催化微通道制备α，α-氟苄基酮类化合物的方法 (Method for preparing alpha, alpha-fluorobenzyl ketone compound by using photocatalytic microchannel ) 是由 郭凯 袁鑫 段秀 孙蕲 覃龙州 邱江凯 于 2020-12-08 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制备α,α-氟苄基酮类化合物的方法,包括如下步骤：(1)将烯醇类化合物和光催化剂溶于第一溶剂中,得到第一反应液；将氟源、2,2,6,6-四甲基哌啶和路易斯酸溶于第二溶剂中,得到第二反应液；(2)将第一反应液和第二反应液分别同时泵入设有光源的微反应装置中反应,收集流出液,得到式3所示的α,α-氟苄基酮类化合物。本发明提供了一种温和有效的合成α,α-氟苄基酮类化合物的方法,由烯醇类化合物为底物,将光催化反应技术与微流场反应技术相结合,一步合成α,α-氟苄基酮类化合物新型化合物,产率高达98％。(The invention discloses a method for preparing alpha, alpha-fluorobenzyl ketone compounds by using a photocatalytic microchannel, which comprises the following steps: (1) dissolving an enol compound and a photocatalyst in a first solvent to obtain a first reaction solution; dissolving a fluorine source, 2,6, 6-tetramethyl piperidine and Lewis acid in a second solvent to obtain a second reaction solution; (2) and respectively pumping the first reaction solution and the second reaction solution into a micro-reaction device provided with a light source simultaneously for reaction, and collecting effluent liquid to obtain the alpha, alpha-fluorobenzyl ketone compound shown in the formula 3. The invention provides a mild and effective method for synthesizing alpha, alpha-fluorobenzyl ketone compounds, which is characterized in that an enol compound is used as a substrate, a photocatalytic reaction technology is combined with a micro-flow field reaction technology, a novel alpha, alpha-fluorobenzyl ketone compound is synthesized in one step, and the yield is up to 98%.)

1. A method for preparing alpha, alpha-fluorobenzyl ketone compounds by using a photocatalytic microchannel is characterized by comprising the following steps:

(1) dissolving an enol compound and a photocatalyst in a first solvent to obtain a first reaction solution; dissolving a fluorine source, 2,6, 6-tetramethyl piperidine and Lewis acid in a second solvent to obtain a second reaction solution;

(2) respectively pumping the first reaction solution and the second reaction solution into a micro-reaction device provided with a light source at the same time for reaction, and collecting effluent liquid to obtain an alpha, alpha-fluorobenzyl ketone compound shown in a formula 3;

wherein R is¹Selected from alkyl, aryl or aryl derivatives;

wherein R is²Selected from alkyl, aryl or aryl derivatives;

wherein R is³Selected from aryl, aryl derivatives, fluorine atoms, heterocycles or heterocycle derivatives;

wherein n is selected from any one integer of 1-8;

in the step (2), the micro-reaction device provided with the light source comprises a micro-reactor under the irradiation of the light source.

2. The method according to claim 1, wherein in step (1), said enolic compound is represented by formula 1,

wherein R is¹Selected from alkyl, aryl or aryl derivatives;

wherein R is³Selected from aryl, aryl derivatives, fluorine atoms, heterocycles or heterocycle derivatives;

wherein n is selected from any one integer of 1-8.

3. The method according to claim 1, wherein in the step (1), the photocatalyst is any one or a combination of 10-methyl-9-mesitylacridine perchlorate, ruthenium terpyridine dichloride hexahydrate, iridium tris (2-phenylpyridine), eosin Y and 2,4,5, 6-tetrakis (9H-carbazol-9-yl) isophthalonitrile.

4. The method according to claim 1, wherein in step (1), the fluorine source is a compound represented by formula 2 a;

5. the method according to claim 1, wherein in the step (1), the Lewis acid is any one or a combination of several of pinacol ester diborate, triethylsilane, trimethoxyboron, pinacol borane and boron trifluoride diethyl etherate.

6. The method according to claim 1, wherein in step (1), the first solvent and the second solvent are each independently selected from dichloromethane, 1, 2-dichloroethane, acetonitrile, tetrahydrofuran, and chloroform.

7. The method according to claim 1, wherein in the step (1), the amount of the photocatalyst is 1 mol% to 20 mol% of the enol compound, and the concentration of the enol compound is 0.1 to 1 mmol/mL; the mol ratio of the enol compound to the fluorine source is 1: 1-1: 5, the mol ratio of the enol compound to the Lewis acid is 1: 1-1: 5, the mol ratio of 2,2,6, 6-tetramethylpiperidine to the enol compound is 1: 1-1: 4, and the concentration of the fluorine source is 0.2-1 mmol/mL.

8. The method according to claim 1, wherein in the step (2), the micro-reaction device provided with the light source comprises a first injector, a second injector, a first injection pump, a second injection pump, a micro mixer, a micro channel reactor, a light source; the first injector and the second injector are connected to a micro mixer in parallel through a pipeline, the micro mixer is connected with a micro channel reactor in series, the micro channel reactor is placed under the irradiation of a light source, and the connection is realized through a pipeline.

9. The method according to claim 8, wherein in the step (2), the microchannel reactor has a pore structure, the pore material is polytetrafluoroethylene, and the microchannel reactor has a dimension inner diameter of 0.5-5 mm and a length of 0.5-40 m; the light source is a lamp strip or a bulb, the intensity is 6W-60W, and the wavelength is 435-577 nm.

10. The method according to claim 1, wherein in the step (2), the reaction temperature is controlled to be 0-60 ℃, and the reaction residence time is 5 s-24 h.

Technical Field

The invention belongs to the field of chemical synthesis, and particularly relates to a method for synthesizing multi-functionalized alpha, alpha-fluorobenzyl ketone by photocatalysis in a microchannel reactor, namely a method for synthesizing the photocatalytic free radical defluorination and alkylation of unactivated olefin by utilizing remote heteroaryl ipso-migration.

Background

At present, C (sp)³) The selective activation of the-F and C-C bonds constitutes one of the most widely used procedures for the synthesis of high-value products, ranging from pharmaceutical to agrochemical applications. Although these two methods have been reported in great numbers in the respective fields, a single C (sp)³) The process of activation of the F bond in combination with the C-C bond remains remote. Fluorine atoms are an important atom and widely exist in human pharmaceutical intermediates and organic synthesis. The synthesis method for introducing fluorine atoms, which is commonly used in organic compounds, has disadvantages in that an expensive fluorine source and a transition metal catalyst are required. (W. -J.Chung, C. -D.Vanderwal, Angew.chem.Int.Ed.2016,55, 4396-.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a method for preparing an alpha, alpha-fluorobenzyl ketone compound by using a photocatalytic microchannel.

In order to solve the above problems, the present invention discloses a method for preparing α, α -fluorobenzyl ketones using a photocatalytic microchannel, wherein the reaction route is shown in fig. 1, and specifically, the method comprises the following steps:

(1) dissolving an enol compound and a photocatalyst in a first solvent to obtain a first reaction solution; dissolving a fluorine source, 2,6, 6-Tetramethylpiperidine (TMP) and Lewis acid in a second solvent to obtain a second reaction solution;

(2) respectively pumping the first reaction solution and the second reaction solution into a micro-reaction device provided with a light source at the same time for reaction, and collecting effluent liquid to obtain an alpha, alpha-fluorobenzyl ketone compound shown in a formula 3;

wherein R is¹Selected from alkyl, aryl or aryl derivatives; preferably, R¹Is an aryl derivative; further preferably, R is¹Is a benzene ring;

wherein R is²Selected from alkyl, aryl or aryl derivatives; preferably, R²Is aryl or an aryl derivative; further preferably, R is²Is shown as formula I;

wherein R is³Selected from aryl, aryl derivatives, fluorine atoms, heterocycles or heterocycle derivatives; further preferably, R is³Is shown as a formula II;

wherein n is selected from any one integer of 1-8; preferably, n is selected from 1,2, 3, 5 or 7; further preferably, n is 2.

Preferably, the alpha, alpha-fluorobenzyl ketone compound is shown as a formula 3 a;

in the step (2), the micro-reaction device provided with the light source comprises a micro-reactor under the irradiation of the light source.

In the step (1), the enol compound is shown as a formula 1,

wherein R is¹Selected from alkyl, aryl or aryl derivatives; preferably, R¹A mono-or polysubstituted phenyl or heterocyclic ring which is an electron donating or withdrawing functionality of an aryl derivative; further preferably, R¹Is an electron-donating substituted phenyl group; even more preferably, said R¹Is a benzene ring;

wherein R is³Selected from aryl, aryl derivatives, fluorine atoms, heterocycles or heterocycle derivatives; further preferably, R is³Is shown as a formula II;

wherein n is selected from any one integer of 1-8; preferably, n is selected from 1,2, 3, 5 or 7; further preferably, n is 2.

Preferably, the enol compound is shown in a formula 1 a;

the enol compound can be obtained by taking a cheap and easily-obtained chain halide, phenyl acyl chloride and benzo heterocyclic derivatives as raw materials through simple reaction steps.

In the step (1), the photocatalyst is 10-methyl-9-mesitylacridine perchlorate (Mes-Acr)⁺) Ruthenium terpyridyl dichloride hexahydrate (Ru (bpy)₃Cl₂·6H₂O), tris (2-phenylpyridine) iridium (fac-Ir (ppy)₃) Eosin Y (eosin Y) and 2,4,5, 6-tetrakis (9H-carbazol-9-yl) isoPhthalonitrile (4CzIPN) with the chemical structural formula as shown in the specification:

in the step (1), the fluorine source is in the compound shown in the formula 2 a;

in the step (1), the Lewis acid is diboron pinacol ester (B)₂Pin₂) Triethylsilane (TES), Trimethoxyboron (TMBX), pinacolborane (HBPin) and boron trifluoride diethyl etherate (BF)₃.Et₂O) or a combination of several of them.

In the step (1), the first solvent and the second solvent are respectively and independently selected from dichloromethane, 1, 2-dichloroethane, acetonitrile, tetrahydrofuran or chloroform, i.e. the first solvent and the second solvent may be the same or different.

In the step (1), the dosage of the photocatalyst is 1-20 mol% of the enol compound, and the concentration of the enol compound is 0.1-1 mmol/mL; the mol ratio of the enol compound to the fluorine source is 1: 1-1: 5, and the mol ratio of the TMP to the enol compound is 1: 1-1: 4; the mol ratio of the enol compound to the Lewis acid is 1: 1-1: 5, and the concentration of the fluorine source is 0.2-1 mmol/mL.

In the step (2), the micro-reaction device provided with the light source comprises a first injector, a second injector, a first injection pump, a second injection pump, a micro mixer, a micro-channel reactor and the light source; the first injector and the second injector are connected to a micro mixer in a parallel mode through pipelines, the micro mixer is connected with a micro channel reactor in series, the micro channel reactor is placed under the irradiation of a light source, and the connection is realized through pipelines; the device of the invention is shown in detail in figures 2, 3 and 4.

The first injector pumps the reaction liquid into the micro mixer through the first injection pump, and the second injector pumps the reaction liquid into the micro reactor through the second injection pump.

In the step (2), the microchannel reactor is of a pore channel structure, the number of pore channels is increased or reduced according to needs, the pore channel material is polytetrafluoroethylene, the size inner diameter of the microchannel reactor is 0.5-5 mm, and the length of the microchannel reactor is 0.5-40 m; the light source is a lamp strip or a bulb, the intensity is 6W-60W, and the wavelength is 435-577 nm; wherein, the light source is preferably blue light.

In step (2), the pump 1 rate is the same as the pump 2 rate.

In the step (2), the reaction is carried out, the reaction temperature is controlled to be 0-60 ℃, and the reaction residence time is 5 s-24 h; among them, the reaction residence time is preferably 10s to 60min, more preferably 20s to 10min, and most preferably 20s to 60 s.

The present invention demonstrates remote fluoroalkylation-remote functionalization of trifluoromethyl arenes with unactivated alkenes that are controllable by remote heteroaryl migration. This is a combination of visible light photoredox catalysis and Lewis acid activation by a series of C (sp)³) -F and C-C bond cleavage for functionalization. This strategy provides a facile route to polyfunctional α, α -fluorobenzyl ketone compounds in high yields under mild conditions.

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

(1) the enol compound can be obtained by taking cheap and easily-obtained substituted benzoyl chloride and halogenated olefin as raw materials through simple reaction steps.

(2) The synthesis method can realize the double-functionalization one-step high-efficiency synthesis of the final product alpha, alpha-fluorobenzyl ketone compound by the enol compound, and has the advantages of simple operation, short reaction time and reaction steps, high reaction yield, simple and convenient operation, continuous and uninterrupted production, environmental friendliness and the like.

(3) The final product in the synthesis method is a novel compound, and the fluorine atom of the trifluoromethyl group can be cut off in the synthesis process to form a fluoromethyl compound with less existence in nature.

(4) The microchannel reaction and the photocatalysis device are simple to build, and all components are cheap and easy to obtain and are easy to amplify.

(5) The light source is used as an energy source for chemical synthesis, so that the method conforms to the concept of green chemistry, and is environment-friendly and efficient.

(6) The combination of the photocatalysis and the microchannel reactor can greatly reduce the reaction time which can reach 10s as fast as possible, improve the reaction yield, save energy and protect environment.

(7) The invention provides a mild and effective method for synthesizing alpha, alpha-fluorobenzyl ketone compounds, which is characterized in that an enol compound is used as a substrate, a photocatalytic reaction technology is combined with a micro-flow field reaction technology, a novel alpha, alpha-fluorobenzyl ketone compound is synthesized in one step, and the yield is up to 98%.

(8) The invention utilizes the far-end fluoralkylation-far-end functionalization which is controllable by the transfer of trifluoromethyl arene through far-end heteroaryl under the catalysis of visible light and has unactivated alkene to synthesize the alpha, alpha-fluorobenzyl ketone compound in one step with high efficiency, the reaction combines the oxidation-reduction catalysis of visible light and the activation of Lewis acid, and the C (sp) is connected in series³) The method provides a way for easily and flexibly obtaining the multifunctional alpha, alpha-fluorobenzyl ketone compound under mild conditions, and the related reaction device combines a photocatalytic reaction technology with a micro-flow field reaction technology, solves the problems of uneven illumination, poor mass and heat transfer, long reaction time, energy waste and the like of the traditional photocatalytic reactor, can obviously improve the reaction yield and reduce the reaction time, and is simple to build, low in cost and easy to obtain reaction parts, and has the basis of industrial amplification.

Drawings

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

FIG. 2 is a schematic view of a reaction apparatus.

FIG. 3 is a schematic diagram of a reaction apparatus in which the reaction temperature is controlled by a fan.

FIG. 4 is a schematic diagram of a reaction apparatus for controlling the reaction temperature by circulating condensed water.

FIG. 5 is a hydrogen spectrum of the product¹H NMR(400MHz,CDCl₃)of 3a。

FIG. 6 is the fluorine spectrum of the product¹⁹F NMR(376MHz,CDCl₃)of 3a。

FIG. 7 is a carbon spectrum of the product¹³C NMR(100MHz,CDCl₃)of 3a。

FIG. 8 is The mass spectrum of The HRMS of 3a [ ESI ] of The product]calcd for C₂₇H₂₀F₄N₂OS[M+H]⁺497.1305,found 497.1211。

Detailed Description

The invention will be better understood from the following examples. However, those skilled in the art will readily appreciate that the description of the embodiments is only for illustrating the present invention and should not be taken as limiting the invention as detailed in the claims.

Example 1

4- (3- (benzo [ d ])]Synthesis of thiazol-2-yl) -1-fluoro-6-oxo-6-phenylhexyl) -2- (trifluoromethyl) benzonitrile. Collecting 1a (0.2mmol,1eq), fac-Ir (ppy)₃(1 mol% of 1 a) was dissolved in 1mL of acetonitrile, and 2, 4-bis (trifluoromethyl) benzonitrile 2a (0.6mmol,3eq), TMP (0.6mmol,3.0eq), B₂Pin₂(0.6mmol,3.0eq) in 1mL acetonitrile, the solution was added into a syringe and pumped into a microchannel reactor by a syringe pump, the flow rate was 100. mu.L/s, the inner diameter of the reactor was 0.5mm, the volume was 1mL, the reaction residence time was 10s, and the reactor was irradiated with 50W blue light at 455nm wavelength, the temperature was controlled at 25 ℃, the yield was 98%, and the NMR spectrum was as shown in FIGS. 5 to 8.

Example 2

1a (0.2mmol,1eq.) 2,4,5, 6-tetrakis (9H-carbazol-9-yl) isophthalonitrile (5 mol% of 1 a) was dissolved in 1mL tetrahydrofuran, 2, 4-bis (trifluoromethyl) benzonitrile 2a (1.0mmol,5 eq.) TMP (1.0mmol,5 eq.) HBPin (1.0mmol,5.0eq.) was dissolved in 1mL tetrahydrofuran, the above solutions were separately added to syringes and pumped into a microchannel reactor using a syringe pump, the inflow was 0.8mm in internal diameter of the reactor, 1mL in volume, 20s reaction residence time, irradiation with 50W blue light at 455nm, temperature was controlled at 25 ℃ and 90% yield was controlled.

Example 3

1a (0.2mmol,1eq), 10-methyl-9-mesitylacridine perchlorate (5 mol% of 1 a) was dissolved in 1mL1, 2-dichloroethane, 2, 4-bis (trifluoromethyl) benzonitrile 2a (0.6mmol,3eq), TMP (0.4mmol,2.0eq), triethylsilane (0.6mmol,3.0eq) were dissolved in 1mL1, 2-dichloroethane, the above solutions were each charged to an injector and pumped into a microchannel reactor using a syringe pump, into which each 80. mu.L/s of reactor inner diameter was 0.6mm, volume was 1mL, reaction residence time was 12.5s, irradiation was performed with 50W of blue light having a wavelength of 455nm, control temperature was 25 ℃ and yield was 92%.

Comparative example 1

Collecting 1a (0.2mmol,1eq), fac-Ir (ppy)₃(5 mol% of 1 a), 2, 4-bis (trifluoromethyl) benzonitrile 2a (0.6mmol,3.0eq), TMP (0.6mmol,3.0eq), B₂Pin₂(0.6mmol,3.0eq) was dissolved in 2mL acetonitrile, the solution was charged into a common reaction tube, the reaction was left for 24h, and the reaction was irradiated with 50W of blue light having a wavelength of 455nm at a controlled temperature of 25 ℃ to give the desired product 3a (yield 66%).

Comparative example 2

Collecting 1a (0.2mmol,1eq), fac-Ir (ppy)₃(5 mol% of 1 a), p-trifluoromethylbenzonitrile 2B (0.6mmol,3.0eq), TMP (0.6mmol,3.0eq), B₂Pin₂(0.6mmol,3.0eq) was dissolved in 2mL acetonitrile, the solution was added to a common reaction tube, the reaction was left for 24h, and irradiated with 50W blue light at 455nm, controlled at 25 ℃ to give difluoro product 3b (yield 78%) and mono-fluoro product with no detectable fluorine spectra.

Comparative example 3

Collecting 1a (0.2mmol,1eq), fac-Ir (ppy)₃(5 mol% of 1 a), 2-fluoro-4- (trifluoromethyl) benzonitrile 2c (0.6mmol,3.0eq), TMP (0.6mmol,3.0eq), HBPin (0.6mmol,3.0eq) were dissolved in 2mL of tetrahydrofuran, the above solution was added to a common reaction tube, the reaction was left for 24 hours, irradiated with 50W of blue light having a wavelength of 455nm, and the temperature was controlled at 25 ℃ to give difluoro product 3c (yield 80%), and the fluorine spectrum of the monofluoro product could not be detected.