CN108774147B - N-aryl formamide prepared by taking bromodifluoroacetic acid ethyl ester as formylation reagent - Google Patents

N-aryl formamide prepared by taking bromodifluoroacetic acid ethyl ester as formylation reagent Download PDF

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CN108774147B
CN108774147B CN201810720447.4A CN201810720447A CN108774147B CN 108774147 B CN108774147 B CN 108774147B CN 201810720447 A CN201810720447 A CN 201810720447A CN 108774147 B CN108774147 B CN 108774147B
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张小红
李晓芳
张兴国
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Wenzhou University
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Abstract

The invention discloses an N-aryl formamide prepared by taking bromodifluoroacetic acid ethyl ester as a formylation reagent, which takes N-alkyl arylamine as a raw material, bromodifluoroacetic acid ethyl ester as the formylation reagent and copper as a catalyst, and is stirred and reacted for 10 to 14 hours at the temperature of 120 ℃ in a reaction solvent by adding different ligands, alkali and the like; after the reaction is finished, filtering the reaction solution to obtain a filtrate; concentrating the filtrate, removing the solvent by using a rotary evaporator to obtain a residue, carrying out chromatography on the residue through a silica gel column, leaching the residue through an eluent, and collecting an effluent according to actual gradient; and mixing the effluent containing the product, concentrating the mixed effluent to remove the solvent, and finally performing vacuum drying to obtain the target product. The invention has the advantages of simple and easily obtained raw materials, simple preparation process, less pollution, low energy consumption and high yield.

Description

N-aryl formamide prepared by taking bromodifluoroacetic acid ethyl ester as formylation reagent
Technical Field
The invention relates to the field of organic chemistry, in particular to N-aryl formamide prepared by taking bromodifluoroethyl acetate as a formylation reagent.
Background
The N-formylation of amines is an important class of reactions in synthetic chemistry, as this conversion provides a direct route to the synthesis of structurally diverse carboxamides. Formyl groups are widely present in natural products, drug molecules. For example, folinic acid (leucovorin), formoterol (formoterol) and orlistat (orlistat) all have carboxamide building blocks (Cancer Res treat.2017,49,816; Eur.J.Pharmacol.2015,761, 161). In addition, N-formyl derivatives are very useful reagents in Vilsmeier formylation reactions, commonly used as precursors for the synthesis of isocyanide, formamidine, arylamide, isocyanate, nitrile and the like compounds (J.Org.Chem.2009,74,6358; chem.Lett.1995,24,575).
Currently, a number of formylating agents are used to effect N-formylation of amines, for example, formaldehyde, paraformaldehyde, methanol, ammonium formate and the like (Green chem.2016,18,808; org.Lett.2013,15,1776; Tetrahedron Lett.2000,41,9149). However, in the above N-formylation reagent, formaldehyde and paraformaldehyde generate polluting gas and pollute the environment when reacting, and influence the health of experimenters; ammonium formate has the disadvantages of easy water absorption and deliquescence; in the case of N-formylation with methanol, the reaction time was too long to reach 24 hours (Nuria Ortega.2013, Vol.15.No. 7.1776-1779); there are limitations to the various formylation reagents.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide the N-aryl formamide prepared by using the bromodifluoroacetic acid ethyl ester as the formylation reagent, and the reaction time is shorter by using the bromodifluoroacetic acid ethyl ester as the formylation reagent; meanwhile, no polluting gas is generated, the environment is not polluted, and the method is very environment-friendly.
In order to achieve the purpose, the invention provides the following technical scheme: n-aryl formamide prepared by taking bromodifluoroethyl acetate as formylation reagent and having molecular structural formula
Figure BDA0001718529890000021
The catalyst is prepared by reacting a reactant A and bromodifluoroacetic acid ethyl ester under the action of a catalyst; the reactant A is any one of N-alkyl arylamine, cyclic arylamine and aniline; the molecular structural formula of the N-alkyl arylamine is shown in the specification
Figure BDA0001718529890000022
Wherein R is1Is 4-methyl, 4-methoxy, 4-fluoro, 4-chloro, 4-bromo, 4-trifluoromethyl, 4-cyano, 4-iodo,Any one of 3-methyl, 3-methoxy, 3-chloro and 3-bromo; the R is2Is any one of ethyl, allyl, propargyl, cyanomethyl, phenyl, benzyl and (p-methylphenyl) propargyl; the cyclic arylamine is
Figure BDA0001718529890000023
Any one of them.
The N-aryl formamide is prepared by reacting a reactant A with bromodifluoroacetic acid ethyl ester at the temperature of 100-120 ℃ for 10-14 h.
The catalyst is any one of cuprous oxide, cuprous acetate and cuprous chloride.
The N-aryl formamide is formed by reacting in a reaction system containing a ligand and alkali, wherein the ligand is any one of bipyridyl, X-Phos and 1, 10-phenanthroline; the alkali is sodium carbonate or cesium carbonate.
The whole reaction is carried out in a solvent which is DMF or 1, 4-dioxane.
During the reaction, the molar parts of the substances added are as follows:
1 part of N-alkyl arylamine;
1.5-2 parts of bromodifluoroacetic acid ethyl ester;
0.05-0.10 part of catalyst;
0.15-0.20 part of ligand;
1-1.5 parts of alkali.
After the reaction of the N-alkyl arylamine and the bromodifluoroacetic acid ethyl ester is finished, a filtering and purifying procedure is carried out, wherein the filtering and purifying procedure comprises the following steps: filtering, evaporating, separating column layer, and vacuum concentrating the eluate to obtain the final product.
Performing column layer separation by using a silica gel column; the leacheate is a mixed solution consisting of petroleum ether and ethyl acetate, and the volume ratio of the leacheate to the ethyl acetate is 8: 1.
The invention has the beneficial effects that: the target product can be directly synthesized by taking bromodifluoroethyl acetate as a novel N-formylation reagent and N-alkyl arylamine as a substrate under the action of a copper catalyst, a ligand and alkali without synthesizing and separating an intermediate product; meanwhile, the target can be obtained under normal pressure, the yield is up to 85%, the process is simple, special instruments or modes are not needed, the method is very suitable for operation of people in the field, and the method has the advantages of simplicity and convenience in operation, low energy consumption, high yield and the like; in addition, the waste solution is less in the reaction process, and other polluted gases and liquid are not discharged, so that the method reduces the discharge of the waste solution, and has the advantages of protecting the environment and ensuring the health of operators; in addition, a series of N-aryl formamide products can be prepared by selecting N-methylaniline containing different substituents for reaction, and the method has certain substrate adaptability. The invention provides a novel formylation reagent which can promote the development of N-aryl formamide products and provides a powerful guarantee for developing N-formylation products containing arylamine.
Drawings
FIG. 1 is a diagram showing the reaction mechanism of the present invention.
Detailed Description
The first embodiment is as follows: 21.4 mg (0.2mmol) of N-methylaniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate were added to 2mL of DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, carrying out elution by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent according to actual gradient, carrying out TLC detection, combining the effluent containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain a yellow liquid N-methyl-N-benzamide 22.2 mg with the yield of 82%.1H NMR(400MHz,CDCl3)δ8.52(s,1H),7.46(t,J＝7.6Hz,2H),7.32(t,J＝7.6Hz,1H),7.21(d,J＝7.2Hz,2H),3.36(s,3H).13C NMR(125MHz,CDCl3)δ162.4,142.4,129.7,126.5,122.5,32.2.GC-MS(EI,70eV)m/z(％)134.75(60.08),105.85(100.00),93.85(28.25),78.90(17.38),77.90(9.21),50.90(14.94)。
Example two: 24.2 mg (0.2mmol) of N-methyl-p-toluidine, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0) were added.02mmol) cuprous acetate, 19.1 mg (0.04mmol) X-phos, 32.7 mg (0.2mmol) cesium carbonate in 2mL DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, carrying out drip washing by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent liquid according to actual gradient, carrying out TLC detection, combining the effluent liquid containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain 25.3 mg of yellow liquid N-methyl-N- (p-tolyl) formamide with the yield of 85%.1H NMR(500MHz,CDCl3)δ8.34(s,1H),7.13(d,J＝8.0Hz,2H),6.98(d,J＝8.0Hz,2H),3.21(s,3H),2.28(s,3H).13C NMR(125MHz,CDCl3)δ162.4,139.8,136.4,130.2,122.7,32.3,20.9.GC-MS(EI,70eV)m/z(％)148.75(50.05),119.90(100.00),107.85(41.74),79.90(14.94),64.90(13.0)。
Example three: 27.4 mg (0.2mmol) of N-methyl-4-methoxyaniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate are added to 2mL of DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, carrying out elution by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent according to actual gradient, carrying out TLC detection, combining the effluent containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain a yellow liquid N- (4-methoxyphenyl) -N-methylformamide with the yield of 80%.1H NMR(500MHz,CDCl3)δ8.33(s,1H),7.08(d,J＝9.0Hz,2H),6.91(d,J＝9.0Hz,2H),3.80(s,3H),3.25(s,3H).13C NMR(125MHz,CDCl3)δ162.5,158.4,135.4,124.8,114.9,55.7,32.8.GC-MS(EI,70eV)m/z(％)164.75(67.51),121.90(100.00),107.90(14.62),93.90(25.27),64.90(13.88),51.90(6.12)。
Example four: 25.0 mg (0.2mmol) of N-methyl-4-fluoroaniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate were added to 2mL of DMF solvent. Reaction at 110 deg.C12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residues, eluting with a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 8:1, collecting effluent according to actual gradient, carrying out TLC detection, combining the effluent containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain 24.2 mg of yellow liquid N- (4-fluorophenyl) -N-methylformamide with the yield of 79%. m.p.140-142 ℃.1H NMR(500MHz,CDCl3)δ8.38(s,1H),7.15-7.13(m,2H),7.11-7.08(m,2H),3.28(s,3H).13C NMR(125MHz,CDCl3)δ162.4,161.6(d,J＝245.0Hz),138.6,124.9,116.7(d,J＝22.5Hz),32.7.GC-MS(EI,70eV)m/z(％)152.75(39.89),123.85(100.00),111.85(34.00),94.80(18.98),74.90(13.55),50.90(2.93)。
Example five: 28.2 mg (0.2mmol) of N-methyl-4-chloroaniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate were added to 2mL of DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, carrying out elution by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent according to actual gradient, carrying out TLC detection, combining the effluent containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain 21.0 mg of yellow liquid N- (4-chlorophenyl) -N-methylformamide with the yield of 62%. m.p.50-52 deg.C (undercorrected).1HNMR(500MHz,CDCl3)δ8.40(s,1H),7.31(d,J＝8.5Hz,2H),7.04(d,J＝8.5Hz,2H),3.22(s,3H).13C NMR(125MHz,CDCl3)δ162.0,140.9,132.2,129.9,123.7,32.2.GC-MS(EI,70eV)m/z(％)168.70(56.11),141.75(31.62),139.80(100.00),127.80(59.54),74.90(27.56),50.95(10.08)。
Example six: 37.0 mg (0.2mmol) of N-methyl-4-bromoaniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate are added to 2mL of DMF solvent. Reacting at 110 deg.C for 12 hr, cooling, filtering, rotary evaporating the filtrate to remove solvent, and purifying the residue with silica gel columnPerforming chromatography, eluting with mixed solution of petroleum ether and ethyl acetate at a volume ratio of 8:1, collecting eluate according to actual gradient, detecting by TLC, combining the eluate containing the product, distilling with a rotary evaporator to remove the solvent, and vacuum drying to obtain yellow liquid-N- (4-bromophenyl) -N-methylformamide 26.0 mg with yield of 61%. m.p.69-71 deg.C (undercorrected).1HNMR(500MHz,CDCl3)δ8.45(s,1H),7.53(d,J＝8.5Hz,2H),7.05(d,J＝8.5Hz,2H),3.30(s,3H).13C NMR(125MHz,CDCl3)δ162.1,141.5,132.9,124.0,119.9,32.1.GC-MS(EI,70eV)m/z(％)214.60(100.00),212.60(98.28),185.65(73.23),183.65(74.99),104.90(85.48),76.90(45.87)。
Example seven: 46.6 mg (0.2mmol) of N-methyl-4-iodoaniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate are added to 2mL of DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, carrying out elution by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent according to actual gradient, carrying out TLC detection, combining the effluent containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain 27.1 mg of yellow liquid N- (p-iodophenyl) -N-methyl formamide with the yield of 52%. m.p.87-89 deg.C (uncoated).1HNMR(500MHz,CDCl3)δ8.38(d,J＝10.0Hz,1H),7.65-7.62(m,2H),6.87-6.83(m,2H),3.21(d,J＝10.5Hz,3H).13C NMR(125MHz,CDCl3)δ161.8,142.0,138.7,123.9,90.4,31.8.GC-MS(EI,70eV)m/z(％)260.55(100.00),231.60(29.26),219.55(37.03),130.85(15.46),105.90(14.35),76.95(24.33),50.95(7.18)。
Example eight: 35 mg (0.2mmol) of N-methyl-4-trifluoromethylaniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate were added to 2mL of DMF solvent. Reacting at 110 deg.C for 12 hr, cooling, filtering, rotary evaporating the filtrate, removing solvent, performing silica gel column chromatography on the residue, and eluting with mixed solution of petroleum ether and ethyl acetate at volume ratio of 8:1The eluates were collected in real gradient, checked by TLC, combined, evaporated in a rotary evaporator and dried in vacuo to yield N- (4-trifluoromethylphenyl) -N-methylformamide 32.1 mg as a yellow liquid in 79% yield. m.p.265-267 deg.C (undercorrected).1HNMR(400MHz,CDCl3)δ8.21(s,1H),7.30(d,J＝8.5Hz,2H),6.91(d,J＝8.5Hz,2H),2.97(s,3H).13C NMR(125MHz,CDCl3)δ161.91,145.28,128.3(q,J＝32.9Hz),127.0,123.9(q,J＝270.5Hz),121.5,31.7.GC-MS(EI,70eV)m/z(％)202.65(82.13),173.70(100.00),144.70(24.65),133.80(10.47),94.85(14.66),74.90(11.38)。
Example nine: 32 mg (0.2mmol) of N-methyl-4-cyanoaniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate are added to 2mL of DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, carrying out elution by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent according to actual gradient, carrying out TLC detection, combining the effluent containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain 11.2 mg of yellow liquid N- (4-cyanophenyl) -N-methylformamide with the yield of 35%. m.p.96-98 deg.C (undercorrected).1HNMR(500MHz,CDCl3)δ8.66(s,1H),7.73-7.69(m,2H),7.30-7.28(m,2H),3.36(s,3H).13C NMR(125MHz,CDCl3)δ161.5,145.9,133.7,121.1,118.1,109.4,31.3.GC-MS(EI,70eV)m/z(％)159.80(36.90),130.85(100.00),103.90(19.83),76.95(13.68),50.95(7.64)。
Example ten: 29.8 mg (0.2mmol) of N-methyl-3-methylaniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate were added to 2mL of DMF solvent. Reacting at 110 deg.C for 12 hr, cooling, filtering, rotary evaporating the filtrate, removing solvent, subjecting the residue to silica gel column chromatography, eluting with mixed solution of petroleum ether and ethyl acetate at volume ratio of 8:1, collecting eluate according to actual gradient, detecting by TLC, mixing the eluates, concentratingThe solvent was distilled off by a rotary evaporator, and dried in vacuo to give 23.6 mg of N-methyl-N- (3-tolyl) formamide as a yellow liquid in 79% yield.1H NMR(500MHz,CDCl3)δ8.47(s,1H),7.32-7.29(m,1H),7.10(d,J＝7.5Hz,1H),6.99(d,J＝8.5Hz,2H),3.32(s,3H),2.40(s,3H).13C NMR(125MHz,CDCl3)δ162.3,142.2,139.7,129.4,127.2,123.1,119.5,32.0,21.4.GC-MS(EI,70eV)m/z(％)148.80(62.26),119.90(100.00),90.85(33.40),76.90(18.33),50.95(7.19)。
Example eleven: 27.4 mg (0.2mmol) of N-methyl-3-methoxyaniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate are added to 2mL of DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, carrying out elution by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent according to actual gradient, carrying out TLC detection, combining the effluent containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain a yellow liquid N-methyl-N- (3-methoxyphenyl) formamide with the yield of 75%. m.p.305-307 deg.C (undercorrected).1HNMR(500MHz,CDCl3)δ8.76(s,1H),7.58(t,J＝8.0Hz,1H),7.08(d,J＝8.0Hz,1H),7.03(d,J＝7.5Hz,1H),6.97(s,1H),4.10(s,3H),3.57(s,3H).13C NMR(125MHz,CDCl3)δ162.3,160.7,143.5,130.4,114.6,111.5,108.7,55.5,32.1.GC-MS(EI,70eV)m/z(％)164.75(71.64),136.85(55.72),95.90(100.00),76.95(23.38)。
Example twelve: 28.2 mg (0.2mmol) of N-methyl-3-chloroaniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate were added to 2mL of DMF solvent. Reacting at 110 deg.C for 12 hr, cooling, filtering, rotary evaporating the filtrate, removing solvent, subjecting the residue to silica gel column chromatography, eluting with mixed solution of petroleum ether and ethyl acetate at volume ratio of 8:1, collecting eluate according to actual gradient, detecting by TLC, mixing the eluates, and distilling with rotary evaporator to remove solventAnd dried in vacuo to give 23.0 mg of N-methyl-N- (3-chlorophenyl) formamide as a yellow liquid in 68% yield.1H NMR(500MHz,CDCl3)δ8.50(s,1H),7.35(t,J＝8.0Hz,1H),7.25(d,J＝8.0Hz,1H),7.19(s,1H),7.08(d,J＝8.0Hz,1H),3.31(s,3H).13C NMR(125MHz,CDCl3)δ161.9,143.5,135.4,130.7,126.4,122.3,120.2,31.9.GC-MS(EI,70eV)m/z(％)168.70(59.94),141.75(33.17),139.80(100.00),127.80(27.52),99.85(25.16),76.95(39.62)。
Example thirteen: 37 mg (0.2mmol) of N-methyl-3-bromoaniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate were added to 2mL of DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, eluting with a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 8:1, collecting effluent according to an actual gradient, carrying out TLC detection, combining the effluent containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain a yellow liquid N-methyl-N- (3-bromophenyl) formamide 29.4 mg with the yield of 69%.1H NMR(500MHz,CDCl3)δ8.49(s,1H),7.40(d,J＝8.0Hz,1H),7.34(s,1H),7.29(t,J＝8.0Hz,1H),7.12(d,J＝8.0Hz,1H),3.30(s,3H).13C NMR(125MHz,CDCl3)δ161.9,143.6,130.9,129.3,125.2,123.2,120.6,31.9.GC-MS(EI,70eV)m/z(％)214.60(98.79),212.60(100.00),185.65(69.10),183.65(67.90),105.90(89.62),76.95(76.82)。
Example fourteen: 24.2 mg (0.2mmol) of N-ethylaniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate were added to 2mL of DMF solvent. Reacting at 110 deg.C for 12 hr, cooling, filtering, rotary evaporating the filtrate, removing solvent, subjecting the residue to silica gel column chromatography, eluting with mixed solution of petroleum ether and ethyl acetate at volume ratio of 8:1, collecting eluate according to actual gradient, detecting by TLC, mixing the eluates containing product, distilling with rotary evaporator to remove solvent, and vacuum drying to obtain yellow liquid N-ethyl-N-benzamide 13.7 mgThe yield was 46%.1H NMR(500MHz,CDCl3)δ8.35(s,1H),7.40(t,J＝8.0Hz,2H),7.29(t,J＝7.5Hz,1H),7.16(d,J＝7.5Hz,2H),3.85(q,J＝7.0Hz,2H),1.15(t,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3)δ162.0,140.9,129.6,126.8,124.3,40.1,13.0.GC-MS(EI,70eV)m/z(％)148.80(37.09),120.85(40.59),105.90(100.00),76.90(40.21),50.90(14.75)。
Example fifteen: 26.6 mg (0.2mmol) of N-vinylaniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate were added to 2mL of DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, carrying out elution by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent according to actual gradient, carrying out TLC detection, combining the effluent containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain 16.4 mg of yellow liquid N-vinyl-N-benzamide with the yield of 51%.1H NMR(500MHz,DMSO)δ8.39(s,1H),7.30(t,J＝7.5Hz,2H),7.19(t,J＝7.5Hz,1H),7.10(d,J＝8.0Hz,2H),5.80-5.72(m,1H),5.12–5.07(m,2H),4.33(d,J＝5.5Hz,2H).13C NMR(125MHz,CDCl3)δ161.9,141.2,132.5,129.6,126.7,123.6,117.6,47.9.GC-MS(EI,70eV)m/z(％)160.75(22.83),132.75(14.12),131.85(100.00),105.90(34.84),103.90(35.59),76.90(46.59),50.90(15.77)。
Example sixteen: 26.2 mg (0.2mmol) of N- (prop-2-yn-1-yl) aniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate are added to 2mL of DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, carrying out elution by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent according to actual gradient, carrying out TLC detection, combining the effluent containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain 16.9 mg of yellow liquid N-phenyl-N- (prop-2-yne-1-yl) formamide with the yield of 53%.1H NMR(500MHz,CDCl3)δ8.34(s,1H),7.36(t,J＝7.5Hz,2H),7.25(t,J＝7.5Hz,1H),7.22(d,J＝8.0Hz,2H),4.47(d,J＝2.0Hz,2H),2.15(s,1H).13C NMR(125MHz,CDCl3)δ161.6,140.3,129.6,127.2,123.8,78.3,72.2,34.4.GC-MS(EI,70eV)m/z(％)158.75(17.00),157.80(15.52),131.85(45.72),129.85(100.00),105.90(17.11),103.90(29.78),76.90(61.63),50.90(23.12)。
Example seventeen: 26.4 mg (0.2mmol) of anilinoacetonitrile, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate are added to 2mL of DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, carrying out elution by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent according to actual gradient, carrying out TLC detection, combining the effluent containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain 15.4 mg of yellow liquid N- (cyanomethyl) -N-benzamide with the yield of 48%.1H NMR(400MHz,CDCl3)δ8.43(s,1H),7.52(t,J＝7.6Hz,2H),7.43(t,J＝7.6Hz,1H),7.30(d,J＝7.6Hz,2H),4.68(s,2H).13C NMR(125MHz,CDCl3)δ161.7,139.0,130.3,128.4,124.2,114.9,33.2.GC-MS(EI,70eV)m/z(％)159.55(36.06),130.75(44.99),104.80(100.00),103.85(50.83),91.80(49.58),76.90(48.45),50.90(23.63)。
Example eighteen: 33.8 mg (0.2mmol) of N, N-diphenylamine, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate were added to 2mL of DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate to remove the solvent, carrying out silica gel column chromatography on the residue, carrying out drip washing by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent liquid according to actual gradient, carrying out TLC detection, combining the effluent liquid containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain 12.6 mg of yellow liquid N, N-diphenylformamide with the yield of 32%.1H NMR(500MHz,CDCl3)δ8.60(s,1H),7.35-7.31(m,4H),7.25–7.19(m,4H),7.10(d,J＝7.5Hz,2H).13C NMR(125MHz,CDCl3)δ160.9,141.0,138.9,128.9,128.3,126.2,126.0,125.3,124.3.GC-MS(EI,70eV)m/z(％)196.75(100.00),167.80(62.40),166.85(34.56),103.90(30.73),66.95(45.96),50.95(30.25)。
Example nineteenth: 36.6 mg (0.2mmol) of N-benzylaniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate were added to 2mL of DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, carrying out drip washing by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent liquid according to actual gradient, carrying out TLC detection, combining the effluent liquid containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain a yellow liquid N-benzyl-N-phenylformamide with the yield of 23.2 mg and 55%.1H NMR(500MHz,CDCl3)δ8.46(s,1H),7.25-7.22(m,2H),7.18-7.13(m,6H),7.00(d,J＝7.3Hz,2H),4.90(s,2H).13CNMR(125MHz,CDCl3)δ162.4,141.1,136.8,129.6,128.7,128.0,127.5,126.9,124.2,48.9.GC-MS(EI,70eV)m/z(％)210.75(36.35),90.90(100.00),76.95(13.46),64.95(14.48),50.95(5.20)。
Example twenty: 44.2 mg (0.2mmol) of N- (3- (p-tolyl) prop-2-yn-1-yl) aniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate are added to 2mL of DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, carrying out elution by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent according to actual gradient, carrying out TLC detection, combining the effluent containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain 37.9 mg of yellow liquid N-phenyl-N- (3- (p-tolyl) prop-2-yn-1-yl) formamide with the yield of 76%. m.p.48-50 deg.C (uncoated).1H NMR(400MHz,CDCl3)δ8.41(s,1H),7.41-7.37(m,2H),7.30-7.28(m,3H),7.30(d,J＝8.4Hz,2H),7.12(d,J＝7.6Hz,2H),4.71(s,2H),2.27(s,3H).13C NMR(125MHz,CDCl3)δ161.8,140.5,138.6,131.7,129.7,129.1,127.2,124.0,119.4,84.1,83.1,35.4,21.5.HRMS(ESI)Calcd for C17H15NNaO+([M+H]+)272.1046,Found:272.1038。
Example twenty one: 23.8 mg (0.2mmol) of indoline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate were added to 2mL of DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, carrying out drip washing by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent liquid according to actual gradient, carrying out TLC detection, combining the effluent liquid containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain yellow liquid indoline-1-formaldehyde with the yield of 65 percent. m.p.57-59 deg.C (undercorrected).1H NMR(400MHz,CDCl3)δ9.00(majorrotamer,s,1H),7.31-7.28(m,1H),7.25-7.20(m,2H),7.11-7.07(m,1H),4.11(t,J＝8.5Hz,2H),3.20(t,J＝8.5Hz,2H).13C NMR(125MHz,CDCl3)δ159.4,157.7,141.4,141.3,132.1,127.78,127.75,126.2,125.0,124.7,124.4,116.9,109.6,47.1,44.8,27.9,27.4.GC-MS(EI,70eV)m/z(％)146.80(42.48),117.90(100.00),90.90(27.34),64.90(9.74),50.90(3.62)。
Example twenty two: 26.6 mg (0.2mmol) of 2-methylindoline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate are added to 2mL of DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, carrying out drip washing by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent liquid according to actual gradient, carrying out TLC detection, combining the effluent liquid containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain a yellow liquid, namely 19.7 mg of 2-methylindoline-1-formaldehyde with the yield of 61%. m.p.187-189 ℃.1H NMR(400MHz,CDCl3)δ8.89(s,1H),7.23-7.12(m,3H),7.06-7.02(m,1H),4.77-4.42(m,1H),3.35-3.33(m,1H),2.76-2.63(m,1H),1.42-1.34(m,3H).13C NMR(125MHz,CDCl3)δ159.5,157.6,140.6,140.5,130.8,130.4,127.7,126.4,125.1,124.6,124.4,116.9,109.7,54.8,53.3,36.4,36.0,23.4,20.5.GC-MS(EI,70eV)m/z(％)160.80(37.66),117.90(100.00),90.90(28.43),64.90(12.55),50.90(5.54)。
Example twenty three: 26.6 mg (0.2mmol) of 1,2,3, 4-tetrahydroquinoline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate are added to 2mL of DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, carrying out drip washing by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent liquid according to actual gradient, carrying out TLC detection, combining the effluent liquid containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain a yellow liquid 3, 4-dihydroquinoline-1 (2H) -formaldehyde with the yield of 74%.1H NMR(500MHz,CDCl3)δ8.69(d,J＝8.5Hz,1H),7.11-7.00(m,4H),3.73-3.71(m,2H),2.74-2.71(m,2H),1.88-1.86(m,2H).13C NMR(125MHz,CDCl3)δ161.1,137.4,129.7,129.0,127.2,124.6,117.1,40.4,27.2,22.4.GC-MS(EI,70eV)m/z(％)160.80(53.02),131.85(100.00),117.90(37.13),76.95(25.83),50.90(12.10)。
Example twenty-four: 30.2 mg (0.2mmol) of 3, 4-dihydro-2H-1, 4-benzothiazine, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate are added to 2mL of DMF solvent. Reacting at 110 deg.C for 12 hr, cooling, filtering, rotary evaporating the filtrate, removing solvent, subjecting the residue to silica gel column chromatography, eluting with mixed solution of petroleum ether and ethyl acetate at volume ratio of 8:1, collecting eluate according to actual gradient, detecting by TLC, mixing the eluates containing product, distilling with rotary evaporator to remove solvent, and vacuum drying to obtain yellow liquid 2H-benzo [ b ] b][1,4]Thiazine-4 (3H) -formaldehyde 25.8 mg, 72% yield. m.p.65-67 deg.C (undercorrected).1HNMR(500MHz,CDCl3)δ8.60(s,1H),7.22-7.20(m,1H),7.12-7.10(m,2H),7.06-7.04(m,1H),4.06-4.04(m,2H),3.13-3.11(m,2H).13C NMR(125MHz,CDCl3)δ161.2,135.2,127.6,126.6,125.9,125.4,120.7,38.6,27.4.GC-MS(EI,70eV)m/z(％)178.70(67.41),135.80(100.00),163.70(29.87),108.85(38.80),76.95(21.97),50.95(12.61)。
Example twenty-five: 27.0 mg (0.2mmol) of benzomorpholine, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate were added to 2mL of DMF solvent. Reacting at 110 deg.C for 12 hr, cooling, filtering, rotary evaporating the filtrate, removing solvent, subjecting the residue to silica gel column chromatography, eluting with mixed solution of petroleum ether and ethyl acetate at volume ratio of 8:1, collecting eluate according to actual gradient, detecting by TLC, mixing the eluates containing product, distilling with rotary evaporator to remove solvent, and vacuum drying to obtain yellow liquid 2H benzo [ b ] b][1,4]Oxazine-4 (3H) -carbaldehyde 26.1 mg, 80% yield.1H NMR(400MHz,CDCl3)δ8.84(s,1H),7.20(d,J＝8.4Hz,1H),7.08(t,J＝8.4Hz,1H),6.96-6.91(m,2H),4.24(t,J＝4.8Hz,2H),3.93(t,J＝4.8Hz,2H).13C NMR(125MHz,CDCl3)δ161.0,159.2,145.7,145.5,125.8,125.7,125.1,122.1,121.5,121.1,118.2,117.2,116.5,65.4,65.1,44.0,37.7.GC-MS(EI,70eV)m/z(％)162.75(96.79),117.90(64.25),119.90(100.00),105.90(36.20),76.95(33.02),50.90(25.82)。
Example twenty-six: 18.6 mg (0.2mmol) of aniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate are added to 2mL of DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, carrying out drip washing by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent according to actual gradient, carrying out TLC detection, combining the effluent containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain 12.3 mg of yellow liquid N-formanilide with the yield of 63%.1H NMR(500MHz,CDCl3)δ8.71(s,1H),8.36(s,1H),7.80(br,1H),7.55(d,J＝8.0Hz,1H),7.37-7.30(m,2H),7.20-7.09(m,2H).13C NMR(125MHz,CDCl3)δ162.9,159.3,137.1,136.9,129.9,129.2,125.4,124.9,120.2,119.0.GC-MS(EI,70eV)m/z(％)120.85(100.00),92.85(71.91),65.90(53.31),64.90(23.80),50.90(7.46)。
Example twenty-seven: 21.4 mg (0.2mmol) of N-methylaniline, 81.2 mg of ethyl bromodifluoroacetate (0.3mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate were added to 2mL of DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, carrying out elution by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent according to actual gradient, carrying out TLC detection, combining the effluent containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain yellow liquid N-methyl-N-benzamide 13.8 mg with the yield of 51%.
Example twenty-eight: 21.4 mg (0.2mmol) of N-methylaniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.9 mg (0.02mmol) of cuprous oxide, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate were added to 2mL of DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, carrying out drip washing by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent liquid according to actual gradient, carrying out TLC detection, combining the effluent liquid containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain a yellow liquid N-methyl-N-benzamide with the yield of 8.67 mg.
Example twenty-nine: 21.4 mg (0.2mmol) of N-methylaniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 1.8 mg (0.02mmol) of cuprous chloride, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate were added to 2mL of DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, carrying out drip washing by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent liquid according to actual gradient, carrying out TLC detection, combining the effluent liquid containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain yellow liquid N-methyl-N-benzamide with the yield of 9.5 mg.
Example thirty: 21.4 mg (0.2mmol) of N-methylaniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 6.3 mg (0.04mmol) of bipyridine, 32.7 mg (0.2mmol) of cesium carbonate were added to 2mL of DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, carrying out drip washing by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent liquid according to actual gradient, carrying out TLC detection, combining the effluent liquid containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain 17.6 mg of yellow liquid N-methyl-N-benzamide with the yield of 65%.
Example thirty one: adding 21.4 mg (0.2mmol) of N-methylaniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 7.2 mg (0.04mmol) of 1, 10-phenanthroline and 32.7 mg (0.2mmol) of cesium carbonate into 2mL of DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, carrying out elution by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent according to actual gradient, carrying out TLC detection, combining the effluent containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain 11.9 mg of yellow liquid N-methyl-N-benzamide with the yield of 44%.
Example thirty-two: 21.4 mg (0.2mmol) of N-methylaniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 21.2 mg (0.2mmol) of sodium carbonate were added to 2mL of DMF solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, carrying out drip washing by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent liquid according to actual gradient, carrying out TLC detection, combining the effluent liquid containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain a yellow liquid N-methyl-N-benzamide of 8.7 mg with the yield of 32%.
Example thirty-three: 21.4 mg (0.2mmol) of N-methylaniline, 81.2 mg of ethyl bromodifluoroacetate (0.4mmol), 2.5 mg (0.02mmol) of cuprous acetate, 19.1 mg (0.04mmol) of X-phos, 32.7 mg (0.2mmol) of cesium carbonate were added to 2mL of 1, 4-dioxane solvent. Reacting at 110 ℃ for 12 hours, cooling after the reaction is finished, filtering, carrying out rotary evaporation on the filtrate, removing the solvent, carrying out silica gel column chromatography on the residue, carrying out drip washing by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 8:1, collecting effluent liquid according to actual gradient, carrying out TLC detection, combining the effluent liquid containing the product, distilling by using a rotary evaporator to remove the solvent, and carrying out vacuum drying to obtain yellow liquid N-methyl-N-benzamide with the yield of 6.8 mg and 25%.
The embodiment of the invention is based on N-methylaniline and bromodifluoroacetic acid ethyl ester in a molar ratio of 1:1.5-1:2, copper catalyst of 5-10% cuprous acetate, ligand of 15-20% X-phos, base of 1.0-1.5 of Cs2CO3, and DMF as a solvent. Wherein examples one to thirteen are the variables substituted with different substituents for R1 in N-methylaniline. Examples fourteen to twenty are variable substitutions of R2 in N-methylaniline with different substituents; examples twenty-one to twenty-five are amines of the benzo-heterocycle type, respectively, and such reactions can also take place; it is noted that example hexacosanidine can also be subjected to this reaction. In the process of the present invention, there is also a phenomenon of low yield due to the influence of electron effects of some strongly electron-withdrawing groups such as fluorine, trifluoromethyl and the like. Example twenty-seven is the formylation reagent ethyl bromodifluoroacetate in an amount of 1.5 equivalents; examples twenty eight and twenty nine are different catalytic agents; examples thirty and thirty-one are different ligands; example thirty-two is a different base; example thirty-three is a different solvent.
The general formula of the reaction equation of the invention is as follows:
Figure BDA0001718529890000191
referring to fig. 1, the reaction mechanism of the present invention is as shown in example 1; details of the reaction mechanism are given:
firstly, bromodifluoroacetic acid ethyl ester (BrCF) is added in the presence of a copper catalyst, alkali and a ligand2COOEt) and N-methylaniline (1a) to generate HBr, and an intermediate A is obtained at the same time. The resulting intermediate a then loses a further molecule of HF to yield intermediate B. The intermediate B obtained is rapidly hydrolyzed under alkaline conditions to obtain oxoacetic acid C. Finally, C releases one molecule of CO at higher temperatures2To obtain the N-formylated product 2 a.
According to the N-aryl formamide prepared by taking the bromodifluoroethyl acetate as the formylation reagent, the bromodifluoroethyl acetate is taken as a novel N-formylation reagent, N-alkyl arylamine is taken as a substrate, and a target product can be directly synthesized under the action of a copper catalyst and contains a ligand and alkali at the same time without synthesizing and separating an intermediate product; meanwhile, the target can be obtained under normal pressure, the yield is up to 85%, the reaction time is short, only 12 hours are needed, the process is simple, special instruments or modes are not needed, the method is very suitable for operation of people in the field, and the method has the advantages of simplicity and convenience in operation, low energy consumption, high yield and the like; in addition, the waste solution is less in the reaction process, and other polluted gases and liquid are not discharged, so that the method reduces the discharge of the waste solution, and has the advantages of protecting the environment and ensuring the health of operators; in addition, a series of N-aryl formamide products can be prepared by selecting N-methylaniline containing different substituents for reaction, and the method has certain substrate adaptability. The invention provides a novel formylation reagent which can promote the development of N-aryl formamide products and provides a powerful guarantee for developing N-formylation products containing arylamine.
The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention. It should be noted that modifications and embellishments within the scope of the invention may occur to those skilled in the art without departing from the principle of the invention, and are considered to be within the scope of the invention.

Claims (4)

1. An N-aryl formamide prepared by taking bromodifluoroacetic acid ethyl ester as a formylation reagent is characterized in that: the molecular structural formula is
Figure FDA0002694426950000011
The catalyst is prepared by reacting a reactant A and bromodifluoroacetic acid ethyl ester under the action of a catalyst; the reactant A is any one of N-alkyl arylamine, cyclic arylamine and aniline; the molecular structural formula of the N-alkyl arylamine is shown in the specification
Figure FDA0002694426950000012
Wherein R is1Is any one of 4-methyl, 4-methoxyl, 4-fluorine, 4-chlorine, 4-bromine, 4-trifluoromethyl, 4-cyano, 4-iodine, 3-methyl, 3-methoxyl, 3-chlorine and 3-bromine; r2Is any one of ethyl, allyl, propargyl, cyanomethyl, phenyl, benzyl and (p-methylphenyl) propargyl; the cyclic arylamine is
Figure FDA0002694426950000013
Any one of the above;
the N-aryl formamide is prepared by reacting a reactant A with bromodifluoroacetic acid ethyl ester at the temperature of 100-120 ℃ for 10-14 h;
the catalyst is any one of cuprous oxide, cuprous acetate and cuprous chloride;
the N-aryl formamide is formed by reacting in a reaction system containing a ligand and alkali, wherein the ligand is any one of bipyridyl, X-Phos and 1, 10-phenanthroline; the alkali is sodium carbonate or cesium carbonate;
during the reaction, the molar parts of the substances added are as follows:
1 part of N-alkyl arylamine;
1.5-2 parts of bromodifluoroacetic acid ethyl ester;
0.05-0.10 part of catalyst;
0.15-0.20 part of ligand;
1-1.5 parts of alkali.
2. The N-arylformamide prepared by using bromodifluoroethyl acetate as a formylation reagent according to claim 1, wherein: the whole reaction is carried out in a solvent which is DMF or 1, 4-dioxane.
3. The N-aryl formamide prepared by using bromodifluoroethyl acetate as a formylation reagent according to claim 2, wherein: after the reaction of the N-alkyl arylamine and the bromodifluoroacetic acid ethyl ester is finished, a filtering and purifying procedure is carried out, wherein the filtering and purifying procedure comprises the following steps: filtering, evaporating, separating column layer, and vacuum concentrating the eluate to obtain the final product.
4. The N-arylformamide prepared by using bromodifluoroethyl acetate as a formylation reagent according to claim 3, wherein: performing column layer separation by using a silica gel column; the leacheate is a mixed solution consisting of petroleum ether and ethyl acetate, and the volume ratio of the leacheate to the ethyl acetate is 8: 1.
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