CN113683525B - Method for realizing N-H insertion reaction of ethyl phenyldiazoacetate and methylaniline by using micro-channel photoreaction technology - Google Patents
Method for realizing N-H insertion reaction of ethyl phenyldiazoacetate and methylaniline by using micro-channel photoreaction technology Download PDFInfo
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- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 title claims abstract description 41
- DYCIOVIEGYZBJP-UHFFFAOYSA-N 2-diazonio-1-ethoxy-2-phenylethenolate Chemical compound CCOC(=O)C(=[N+]=[N-])C1=CC=CC=C1 DYCIOVIEGYZBJP-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 238000000034 method Methods 0.000 title claims abstract description 20
- 238000006713 insertion reaction Methods 0.000 title claims abstract description 14
- 238000005516 engineering process Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 87
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 239000011259 mixed solution Substances 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- -1 ethyl phenyl Chemical group 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 238000005086 pumping Methods 0.000 abstract description 15
- 239000002904 solvent Substances 0.000 abstract description 15
- 238000003780 insertion Methods 0.000 abstract description 5
- 230000037431 insertion Effects 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 238000004821 distillation Methods 0.000 description 12
- 239000012467 final product Substances 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 239000003208 petroleum Substances 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 238000001228 spectrum Methods 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000012295 chemical reaction liquid Substances 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 238000010586 diagram Methods 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 239000011148 porous material Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 239000004813 Perfluoroalkoxy alkane Substances 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 125000003709 fluoroalkyl group Chemical group 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229920011301 perfluoro alkoxyl alkane Polymers 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- XWVFDRBGXZRGAE-UHFFFAOYSA-N 2-(4-bromophenyl)-2-diazonio-1-ethoxyethenolate Chemical compound CCOC([O-])=C([N+]#N)C1=CC=C(Br)C=C1 XWVFDRBGXZRGAE-UHFFFAOYSA-N 0.000 description 1
- XCEYKKJMLOFDSS-UHFFFAOYSA-N 4-chloro-n-methylaniline Chemical compound CNC1=CC=C(Cl)C=C1 XCEYKKJMLOFDSS-UHFFFAOYSA-N 0.000 description 1
- JFXDIXYFXDOZIT-UHFFFAOYSA-N 4-methoxy-n-methylaniline Chemical compound CNC1=CC=C(OC)C=C1 JFXDIXYFXDOZIT-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- DULCUDSUACXJJC-UHFFFAOYSA-N benzeneacetic acid ethyl ester Natural products CCOC(=O)CC1=CC=CC=C1 DULCUDSUACXJJC-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000004965 chloroalkyl group Chemical group 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 150000008049 diazo compounds Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- GAENPTHDJPQMQK-UHFFFAOYSA-N methyl 2-(4-tert-butylphenyl)-2-diazoacetate Chemical compound C(C)(C)(C)C1=CC=C(C=C1)C(C(=O)OC)=[N+]=[N-] GAENPTHDJPQMQK-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- QCIFLGSATTWUQJ-UHFFFAOYSA-N n,4-dimethylaniline Chemical compound CNC1=CC=C(C)C=C1 QCIFLGSATTWUQJ-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 238000006303 photolysis reaction Methods 0.000 description 1
- 230000015843 photosynthesis, light reaction Effects 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for realizing N-H insertion reaction of ethyl phenyldiazoacetate and methylaniline by utilizing a microchannel photoreaction technology, which comprises the steps of pumping mixed solution of methylaniline and derivatives thereof shown in a formula I, ethyl phenyldiazoacetate and derivatives thereof shown in a formula II and a solvent into a microchannel reaction device provided with a light source for reaction to obtain a compound shown in a formula III. The invention is a brand new method for realizing the N-H insertion reaction of the ethyl phenyldiazoacetate and the methylaniline, and the insertion of the ethyl phenyldiazoacetate and the methylaniline can be realized only by adding a light source into a reaction system.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a method for realizing N-H insertion reaction of ethyl phenyldiazoacetate and methylaniline by utilizing a micro-channel photoreaction technology.
Background
Diazo ethyl phenylacetate can be used as pesticide and medicine intermediate, and has wide application in organic synthesis. The N-H insertion of such diazo compounds provides a means for preparing a variety of related derivatives, and researchers have therefore also held great interest in studying related reaction methods.
At present, a method for realizing the insertion reaction of ethyl phenyldiazoacetate and methylaniline N-H by utilizing a microchannel photoreaction technology is rarely reported. Davies in 2018 reported the use of blue light to promote photolysis of aryldiazoacetates (chem.sci.,2018,9, 5112-5118). Although the reaction can also effectively realize the insertion of ethyl phenyldiazoacetate and methylaniline N-H and has a better substrate range, the reaction system needs to be heated to a high temperature, which is not favorable for the economic principle of the reaction and may cause certain obstruction to the subsequent industrial production. Thierry Ollevier reported in 2017 that copper catalyzed the reaction of alpha-diazo esters and alpha-diazoketone type carbons with insertion of Si-H and S-H bonds (chem.j.org.chem.2017,82, 3000-3010). Although this reaction allows the synthesis of ethyl phenyldiazoacetate derivatives under mild conditions, the reaction requires the addition of a metal catalyst and takes a long time. The prior insertion reaction of ethyl phenyldiazoacetate and N-H methylaniline has the defects of expensive catalyst, low atom utilization rate, environmental friendliness and the like, and the defects limit the application of the ethyl phenyldiazoacetate in industrialization. Therefore, it is very interesting to develop an insertion reaction of ethyl phenyldiazoacetate and methylaniline N-H with low energy consumption, mild reaction conditions, environmental friendliness and easy scale-up.
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 N-H insertion reaction of ethyl phenyldiazoacetate and methylaniline by utilizing a micro-channel photoreaction technology.
In order to solve the technical problem, the invention discloses a method for realizing N-H insertion reaction of ethyl phenyldiazoacetate and methylaniline by utilizing a microchannel photoreaction technology, which comprises the steps of pumping mixed solution of methylaniline shown in a formula I and derivatives thereof, ethyl phenyldiazoacetate shown in a formula II and derivatives thereof and a solvent into a microchannel reaction device provided with a light source for reaction to obtain a compound shown in a formula III;
wherein R is 1 And R 2 Are respectively independentIs selected from-H, alkyl, alkoxy, fluoroalkyl, bromoalkyl, chloroalkyl or halogen; preferably, R 1 And R 2 Each independently selected from-H, alkyl, alkoxy, fluoroalkyl, or halogen; further preferably, R 1 And R 2 Each independently selected from-H, -CH 3 、-CH 3 O、-CF 3 -Cl, -F or-Br.
Wherein, in the mixed solution, the concentration of the methylaniline shown in the formula I and the derivative thereof is 0.05-1mmol/mL, preferably 0.05-0.5mmol/mL, and more preferably 0.1-0.5 mmol/mL.
Wherein, the concentration of the ethyl phenyl diazoacetate shown in the formula II and the derivative thereof in the mixed solution is 0.05-2mmol/mL, and preferably 0.15-1 mmol/mL.
Wherein in the mixed solution, the molar ratio of methylaniline and derivatives thereof shown in formula I to ethyl phenyl diazoacetate and derivatives thereof shown in formula II is 1: (1-5).
The solvent is any one or combination of more of methanol, ethanol, acetonitrile, acetone, water, phosphate buffer, tetrahydrofuran, 1, 4-dioxane, dichloromethane, 1, 2-dichloroethane, N-dimethylpropyleneurea, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide, preferably any one or combination of more of methanol, ethanol and dichloromethane, and further preferably dichloromethane.
As shown in fig. 1 and fig. 2, the microchannel reactor with the light source includes 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.
Wherein, the microchannel reactor is of a pore channel structure, and the pore channel material is perfluoroalkoxy alkane (PFA) or polytetrafluoroethylene.
Wherein the inner diameter of the microchannel reactor is 0.5-1mm, preferably 0.6 mm.
Wherein the length of the microchannel reactor is 5-20 m.
Wherein the volume of the microchannel reactor is 1-15.7mL, and preferably 2 mL.
Wherein the pumping rate is 0.1-2 mL/min.
Wherein the intensity of the light source is 5-60W.
Wherein the wavelength of the light source is 435-.
Wherein the reaction temperature is 10-30 ℃, and room temperature is preferred.
Wherein the residence time of the reaction is 30s-2.6h, preferably 1-60min, more preferably 1-30min, even more preferably 1-15min, even more preferably 1-10min, and most preferably 10 min.
Has the advantages that: compared with the prior art, the invention has the following advantages:
(1) the invention is a brand new method for realizing the N-H insertion reaction of the ethyl phenyldiazoacetate and the methylaniline, and the insertion of the ethyl phenyldiazoacetate and the methylaniline can be realized only by adding a light source into a reaction system.
(2) The method can realize the insertion reaction of ethyl phenyldiazoacetate and methylaniline N-H under the room temperature condition without using a catalyst.
(3) The invention overcomes the problem that the prior art needs to use a transition metal catalyst, and reduces the reaction cost and the energy consumption cost.
(4) The system related by the invention has no solid insoluble substances, has no blockage problem of micro-reaction pore channels, is simple to operate and high in safety, and overcomes the defects of the traditional method.
(5) Compared with the existing reaction system, the reaction system related by the invention has the advantages of shortened reaction time, improved reaction conversion rate and yield, and high reaction continuity, and is favorable for continuous and uninterrupted scale-up production.
(6) The conversion rate of the raw materials is 88-97%, and the yield of the product can reach 71-95%.
Drawings
The foregoing and/or other advantages of the invention will become more 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 diagram of a microchannel reactor apparatus.
FIG. 3 is a hydrogen spectrum of the compound obtained in example 1.
FIG. 4 is a carbon spectrum of the compound obtained in example 1.
FIG. 5 is a hydrogen spectrum of the compound obtained in example 7.
FIG. 6 is a carbon spectrum of the compound obtained in example 7.
FIG. 7 is a hydrogen spectrum of the compound obtained in example 8.
FIG. 8 is a carbon spectrum diagram of the compound obtained in example 8.
FIG. 9 is a hydrogen spectrum of the compound obtained in example 9.
FIG. 10 is a carbon spectrum diagram of the compound obtained in example 9.
FIG. 11 is a hydrogen spectrum of the compound obtained in example 10.
FIG. 12 is a carbon spectrum of the compound obtained in example 10.
FIG. 13 is a hydrogen spectrum of the compound obtained in example 11.
FIG. 14 is a carbon spectrum diagram of the compound obtained in example 11.
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.
The light source in the microchannel reactor described in the examples below was a 5W lamp with a wavelength of 470 nm.
Example 1
0.0241g (0.2mmol,1.0equiv.) of N-methylaniline and 0.0570g of ethyl 2-diazo-2-phenylacetate (0.3mmol,1.5equiv.) were weighed, dissolved in 2mL of methanol, and loaded in a syringe as a reaction solution. Pumping the reaction liquid into a microchannel reaction device, and directly pumping the reaction liquid into a microchannel reactor for reaction(inner diameter 0.6mm, length of light received 7m, volume 2mL), pump flow rate of 0.2mL/min, reaction residence time of 10 min. After completion of the reaction, TLC was carried out, and the reaction mixture was extracted with ethyl acetate and saturated brine (3X 25mL), and the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure and then subjected to silica gel column chromatography (petroleum ether: ethyl acetate) to give 48.98mg of the final product in 91% yield. The characterization data are as follows (fig. 3, fig. 4): 1 H NMR(400MHz,Chloroform-d)δ7.40–7.33(m,3H),7.30–7.25(m,4H),6.88(d,J＝8.2Hz,2H),6.81(t,J＝7.3Hz,1H),4.31–4.21(m,2H),1.27(t,J＝7.1Hz,3H). 13 C NMR(100MHz,Chloroform-d)δ171.9,149.9,136.0,129.3,128.7,128.5,128.1,118.0,113.4,65.7,61.1,34.6,14.3.
example 2
0.0241g (0.2mmol,1.0equiv.) of N-methylaniline and 0.0570g of ethyl 2-diazo-2-phenylacetate (0.3mmol,1.5equiv.) were weighed, dissolved in 2mL of N, N-dimethylformamide, and loaded in a syringe as a reaction solution. The reaction liquid is pumped into a microchannel reaction device, and directly enters a microchannel reactor for reaction (the inner diameter is 0.6mm, the length of the light receiving is 7m, and the volume is 2mL), the pumping flow rate is 0.2mL/min, and the reaction residence time is 10 min. After completion of the reaction, TLC was carried out, and the reaction mixture was extracted with ethyl acetate and saturated brine (3X 25mL), and the organic layers were combined, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate) after removing the solvent by distillation under the reduced pressure to obtain 44.14mg of a final product in 82% yield.
Example 3
0.0241g (0.2mmol,1.0equiv.) of N-methylaniline and 0.0570g of ethyl 2-diazo-2-phenylacetate (0.3mmol,1.5equiv.) were weighed, dissolved in 2mL of acetonitrile, and loaded in a syringe as a reaction solution. The reaction liquid is pumped into a microchannel reaction device, and directly enters a microchannel reactor for reaction (the inner diameter is 0.6mm, the length of the light receiving is 7m, and the volume is 2mL), the pumping flow rate is 0.2mL/min, and the reaction residence time is 10 min. After completion of the reaction, TLC was carried out, and the reaction mixture was extracted with ethyl acetate and saturated brine (3X 25mL), and the organic layers were combined, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate) after removing the solvent by distillation under the reduced pressure to obtain 42.52mg of a final product in 79% yield.
Example 4
0.0241g (0.2mmol,1.0equiv.) of N-methylaniline and 0.0570g of ethyl 2-diazo-2-phenylacetate (0.3mmol,1.5equiv.) were weighed, dissolved in 2mL of dichloromethane, and loaded in a syringe as a reaction solution. The reaction liquid is pumped into a microchannel reaction device, and directly enters a microchannel reactor for reaction (the inner diameter is 0.6mm, the length of the light receiving is 7m, and the volume is 2mL), the pumping flow rate is 0.2mL/min, and the reaction residence time is 10 min. After completion of the reaction, TLC was carried out, and the reaction mixture was extracted with ethyl acetate and saturated brine (3X 25mL), and the organic layers were combined, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate) after removing the solvent by distillation under the reduced pressure to obtain 51.68mg of a final product in 96% yield.
Example 5
0.0241g (0.2mmol,1.0equiv.) of N-methylaniline and 0.0570g of ethyl 2-diazo-2-phenylacetate (0.3mmol,1.5equiv.) were weighed, dissolved in 2mL of 1, 4-dioxane, and loaded in a syringe as a reaction solution. The reaction liquid is pumped into a microchannel reaction device, and directly enters a microchannel reactor for reaction (the inner diameter is 0.6mm, the length of the light receiving is 7m, and the volume is 2mL), the pumping flow rate is 0.2mL/min, and the reaction residence time is 10 min. After completion of the reaction, TLC was carried out, and the reaction mixture was extracted with ethyl acetate and saturated brine (3X 25mL), and the organic layers were combined, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate) after removing the solvent by distillation under the reduced pressure to obtain 45.75mg of a final product in 85% yield.
Example 6
N-methylaniline (1.205 g, 10mmol,1.0equiv.) and 2.850g ethyl 2-diazo-2-phenylacetate (15mmol,1.5equiv.) were weighed, dissolved in 20mL dichloromethane, and loaded in a syringe as a reaction solution. The reaction solution is pumped into a microchannel reactor at the same time, and is directly fed into the microchannel reactor for reaction (the inner diameter is 0.6mm, the length of the light receiving area is 7m, and the volume is 2mL), the pumping flow rate is 0.2mL/min, and the reaction residence time is 10 min. After completion of the reaction, TLC detection was carried out, and the reaction solution was extracted with ethyl acetate and saturated brine (3X 25mL), and the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure, followed by silica gel column chromatography (petroleum ether: ethyl acetate) to obtain 2.5030g of a final product in 93% yield.
Example 7
0.0282g (0.2mmol,1.0equiv.) of 4-chloro-N-methylaniline and 0.0570g of ethyl 2-diazo-2-phenylacetate (0.3mmol,1.5equiv.) were weighed, dissolved in 2mL of dichloromethane, and loaded in a syringe as a reaction solution. The reaction liquid is pumped into a microchannel reaction device, and directly enters a microchannel reactor for reaction (the inner diameter is 0.6mm, the length of the light receiving is 7m, and the volume is 2mL), the pumping flow rate is 0.2mL/min, and the reaction residence time is 10 min. After completion of the reaction, TLC was carried out, and the reaction mixture was extracted with ethyl acetate and saturated brine (3X 25mL), and the organic layers were combined, dried over anhydrous sodium sulfate, and after removing the solvent by distillation under the reduced pressure, by column chromatography on silica gel (petroleum ether: ethyl acetate), 55.16mg of the final product was obtained in 91% yield. The characterization data are as follows (fig. 5, fig. 6): 1 H NMR(400MHz,Chloroform-d)δ7.41–7.33(m,3H),7.28–7.24(m,2H),7.23–7.17(m,2H),6.79(d,J＝9.0Hz,2H),5.57(s,1H),4.26(m,J＝7.0,3.6Hz,2H),2.76(s,3H),1.26(t,J＝7.1Hz,3H). 13 C NMR(100MHz,Chloroform-d)δ171.6,148.6,135.6,129.1,128.8,128.5,128.2,122.9,114.7,66.0,61.2,34.8,14.3.
example 8
0.0242g (0.2mmol,1.0equiv.) of 4-methyl-N-methylaniline and 0.0570g of ethyl 2-diazo-2-phenylacetate (0.3mmol,1.5equiv.) were weighed, dissolved in 2mL of dichloromethane, and loaded in a syringe as a reaction solution. Will be reversedThe reaction solution is pumped into a microchannel reaction device, and directly enters a microchannel reactor for reaction (the inner diameter is 0.6mm, the length of the light is 7m, and the volume is 2mL), the pumping flow rate is 0.2mL/min, and the reaction residence time is 10 min. After completion of the reaction, TLC was carried out, and the reaction mixture was extracted with ethyl acetate and saturated brine (3X 25mL), and the organic layers were combined, dried over anhydrous sodium sulfate, and after removing the solvent by distillation under the reduced pressure, by column chromatography on silica gel (petroleum ether: ethyl acetate), 50.96mg of the final product was obtained in 90% yield. The characterization data are as follows (fig. 7, fig. 8): 1 H NMR(400MHz,Chloroform-d)δ7.31–7.19(m,5H),7.00(d,J＝8.4Hz,2H),6.73(d,J＝8.6Hz,2H),5.50(s,1H),4.23–4.10(m,2H),2.69(s,3H),2.19(s,3H),1.18(t,J＝7.1Hz,3H). 13 C NMR(100MHz,Chloroform-d)δ170.9,146.9,135.1,128.7,127.6,127.4,126.9,126.4,112.9,65.2,59.9,33.8,19.3,13.2.
example 9
0.0272g (0.2mmol,1.0equiv.) of 4-methoxy-N-methylaniline and 0.0570g of ethyl 2-diazo-2-phenylacetate (0.3mmol,1.5equiv.) were weighed, dissolved in 2mL of dichloromethane, and loaded in a syringe as a reaction solution. The reaction liquid is pumped into a microchannel reaction device, and directly enters a microchannel reactor for reaction (the inner diameter is 0.6mm, the length of the light receiving is 7m, and the volume is 2mL), the pumping flow rate is 0.2mL/min, and the reaction residence time is 10 min. After completion of the reaction, TLC was carried out, and the reaction mixture was extracted with ethyl acetate and saturated brine (3X 25mL), and the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure and then subjected to silica gel column chromatography (petroleum ether: ethyl acetate) to give 55.64mg of the final product in 93% yield. The characterization data are as follows (fig. 9, fig. 10): 1 H NMR(400MHz,Chloroform-d)δ7.41–7.27(m,5H),6.86(m,J＝9.3Hz,4H),5.44(s,1H),4.28–4.15(m,2H),3.77(s,3H),2.74(s,3H),1.23(t,J＝7.1Hz,3H). 13 C NMR(100MHz,Chloroform-d)δ171.9,152.9,144.6,136.1,128.6,128.06,116.6,114.66,67.66,60.96,55.7,35.8,14.3.
example 10
0.0214g (0.2mmol,1.0equiv.) of N-methylaniline and 0.0804g of ethyl 2- (4-bromophenyl) -2-diazoacetate (0.3mmol,1.5equiv.) were weighed, dissolved in 2mL of dichloromethane, and loaded in a syringe as a reaction solution. The reaction liquid is pumped into a microchannel reaction device, and directly enters a microchannel reactor for reaction (the inner diameter is 0.6mm, the length of the light receiving is 7m, and the volume is 2mL), the pumping flow rate is 0.2mL/min, and the reaction residence time is 10 min. After completion of the reaction, TLC was carried out, and the reaction mixture was extracted with ethyl acetate and saturated brine (3X 25mL), and the organic layers were combined, dried over anhydrous sodium sulfate, and after removing the solvent by distillation under the reduced pressure, by column chromatography on silica gel (petroleum ether: ethyl acetate), 64.55mg of the final product was obtained in 93% yield. The characterization data were as follows (fig. 11, fig. 12): 1 H NMR(400MHz,Chloroform-d)δ7.42(d,J＝8.4Hz,2H),7.21–7.16(m,2H),7.10(d,J＝8.4Hz,2H),6.84–6.67(m,3H),5.48(s,1H),4.21–4.10(m,2H),2.72(s,3H),1.18(t,J＝7.1Hz,3H). 13 C NMR(100MHz,Chloroform-d)δ171.3,149.7,135.1,131.8,130.1,129.3,122.1,118.4,113.7,65.45,61.3,34.8,14.3.
example 11
N-methylaniline (0.0214 g, 0.2mmol,1.0equiv.) and 0.0696g of methyl 2- (4- (tert-butyl) phenyl) -2-diazoacetate (0.3mmol,1.5equiv.) were weighed, dissolved in 2mL of dichloromethane, and loaded in a syringe as a reaction solution. The reaction solution is pumped into the microchannel reactor at the same time, and is directly fed into the microchannel reactor for reaction (the inner diameter is 0.6mm, the length of the light receiving part is 7m, and the volume is 2mL), the pumping flow rate is 0.2mL/min, and the reaction retention time is 10 min. After completion of the reaction, TLC was performed, and the reaction mixture was extracted with ethyl acetate and saturated brine (3X 25mL), and the organic layers were combined, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography (petroleum) after removing the solvent by distillation under reduced pressureEther: ethyl acetate) to give 54.77mg of final product in 88% yield. The characterization data are as follows (fig. 13, fig. 14): 1 H NMR(400MHz,Chloroform-d)δ7.30(d,J＝8.3Hz,2H),7.19(t,J＝8.0Hz,2H),7.12(d,J＝8.2Hz,2H),6.79(d,J＝8.3Hz,2H),6.72(t,J＝7.3Hz,1H),5.57(s,1H),3.69(s,3H),2.72(s,3H),1.24(s,9H). 13 C NMR(100MHz,Chloroform-d)δ172.6,151.1,149.9,129.3,132.7,,128.2,125.7,118.0,113.4,65.34,52.0,34.4,31.4.
comparative example 1
0.0241g (0.2mmol,1equiv) of N-methylaniline, 0.0570g of ethyl 2-diazo-2-phenylacetate (0.3mmol,1.5equiv.) were weighed out, and the mixture was charged into a Schlenk reaction tube, and after replacing argon three times, 2mL of methylene chloride was added. After 3 hours of reaction at room temperature, TLC detection was carried out, the reaction solution was extracted with ethyl acetate and saturated brine (3X 25mL), the organic layers were combined, dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and silica gel column chromatography (petroleum ether: ethyl acetate) was carried out to give 46.29mg of a final product in 86% yield.
The present invention provides a method and a method for implementing the insertion reaction of ethyl phenyldiazoacetate and methylaniline N-H by using microchannel photoreaction technology, and the method and the way for implementing the technical scheme are many, and the above description is only a preferred embodiment of the present invention, 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 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.
Claims (5)
1. A method for realizing N-H insertion reaction of ethyl phenyldiazoacetate and methylaniline by utilizing a microchannel photoreaction technology is characterized in that a mixed solution of methylaniline and derivatives thereof shown in a formula I, ethyl phenyldiazoacetate and derivatives thereof shown in a formula II and dichloromethane is pumped into a microchannel reaction device provided with a light source for reaction to obtain a compound shown in a formula III;
wherein R is 1 Selected from-H, -Cl, methyl, or methoxy; r 2 Is selected from-H, or-Br;
wherein, in the mixed solution, the concentration of the methylaniline shown in the formula I and the derivative thereof is 0.1 mmol/mL, and the concentration of the ethyl phenyl diazoacetate shown in the formula II and the derivative thereof is 0.15 mmol/mL;
wherein the residence time of the reaction is 1-10 min.
2. 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.
3. The method of claim 1, wherein the light source has an intensity of 5-60W.
4. The method as claimed in claim 1, wherein the light source has a wavelength of 435 and 577 nm.
5. The process according to claim 1, wherein the reaction temperature is 10-30 ℃.
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