CN105669542A - Method for synthesizing pyridine primary amides by direct catalytic oxidation process - Google Patents

Abstract

The invention discloses a method for synthesizing pyridine primary amide compounds by direct catalytic oxidation method. Under the action of acid or alkali, formamide is used as carbonyl source and nitrogen source, and accelerator water and oxidant are added, and silver and/or iron catalyst Under the action of catalysis, the carbon-hydrogen bond of pyridine or its derivatives can be directly prepared to obtain pyridine primary amide compound. The method for preparing pyridine primary amide compound of the present invention has the advantages of ideal atom economy and less waste generation by activating double carbon-hydrogen bonds, and the substrate source is wide, stable and low in price. Under optimized reaction conditions, the separation yield of the target product is as high as 98%.

Description

A kind of method of synthesizing pyridine primary amide compound by direct catalytic oxidation method

technical field

The invention relates to a method for synthesizing primary pyridine amides, in particular to a method for directly using formamide as a carboxamide source to catalyze oxidation of the carbon-hydrogen bond of pyridines to synthesize pyridine primary amides.

Background technique

Pyridine primary amides are a class of compounds with excellent physiological activity. Their basic structural units exist in a large number of natural products, medicines and herbicides, and are widely used in the fields of biology, medicine and materials. The traditional method of synthesizing such substances is the reaction of pyridine acid or pyridine acid chloride with ammonia; in recent years, the catalytic synthesis method has attracted widespread attention due to its advantages of high efficiency and wide application range.

The Beller research group reported for the first time the palladium-catalyzed carbamylation reaction of bromopyridine and chloropyridine to prepare pyridine primary amides. The carbonyl source used was carbon monoxide and the nitrogen source was ammonia gas. The key to the success of this reaction was the screening of a highly efficient The phosphine ligand cataCXiumA (Xiao-Feng Wu, Helfried Neumann, Matthias Beller, Chem. Eur. J. 2010, 16, 9750-9753). Considering that the ligand cataCXiumA is complex and difficult to synthesize, the group further studied the use of cheaper ligands and found that the commercial phosphine ligand dppf can achieve the same catalytic effect (Xiao-FengWu, Helfried Neumann, MatthiasBeller, Chem.AsianJ.2010 , 5, 2168-2172). Immediately afterwards, the group developed a new phosphine ligand, Pyr-DalPhos, and achieved a better catalytic effect on the carbamylation of bromopyridine (PamelaG.Alsabeh, MarkStradiotto, HelfriedNeumann, MatthiasBeller, Adv.Synth. Catal. 2012, 354, 3065–3070). Phenol is a cheap and easy-to-obtain reactant, but it is difficult to leave the phenolic hydroxyl group due to its conjugation with the aromatic ring. The group participated in the carbamylation reaction catalyzed by Pd-DPEphos to prepare pyridine primary amides by in situ ester formation of phenol and perfluorobutylsulfonyl fluoride (Xiao-Feng Wu, Helfried Neumann, Matthias Beller, Chem. Eur. J. 2012, 18, 419–422). Although these methods have high synthesis efficiency and the carbonyl and nitrogen sources used are cheap, they are toxic, flammable and have safety problems. Therefore, the use of safer and non-toxic carbonylation and amination reagents to synthesize pyridine primary amides has important research value and application prospects.

Recently, the Skrydstrup group utilized ex situ formation of carbon monoxide as the carbonyl source and ammonium carbamate as the nitrogen source to efficiently carbamylate 3-bromopyridine and pyridinium p-toluenesulfonate in the presence of palladium and phosphine ligands to prepare Corresponding pyridine primary amides (DennisU.Nielsen, RolfH.Taaning, AndersT.Lindhardt, ThomasM. Troels Skrydstrup, Org. Lett. 2011, 13, 4454–4457). All of the above methods have the problem of using expensive, toxic and unstable phosphine ligands, which increases the production cost and the difficulty of product separation. At the same time, the reactants all need to use functionalized pyridine. After the reaction, these functional groups become Leaving bases to form waste. The most ideal method is to directly use the carbon-hydrogen bond of pyridine to carry out the carbamylation reaction, saving the step of pre-functionalization of pyridine, resulting in less waste, high utilization of raw materials, and resource and energy saving.

However, up to now, a method for directly synthesizing high value-added primary pyridine amides by activating pyridine carbon-hydrogen for carbamylation has not been reported.

Contents of the invention

The main purpose of the present invention is to overcome the defects in the existing pre-functionalized pyridine compound catalyzed carbamylation method to synthesize pyridine primary amide compounds, and provide a new method for synthesizing pyridine primary amide compounds. And/or under the action of an iron catalyst, formamide is added as a carboxamide reagent, water is used as a promoter, and the carbon-hydrogen bond of a pyridine compound is directly oxidized under an air or oxygen atmosphere to synthesize a pyridine primary amide compound. This method has a substrate source Extensive, stable and cheap, with cheap and easy-to-obtain catalysts, high reaction selectivity, less waste generation, wide application range and high yield of target products.

The present invention adopts the following technical solutions in order to achieve the above object and solve its technical problems:

A method for synthesizing pyridine primary amide compounds by direct catalytic oxidation method is characterized in that, under air or oxygen atmosphere, add oxidizing agent, promotor water and acid or alkali, take formamide as carbamylation reagent, in silver catalyst and /or under the action of an iron catalyst, the carbon-hydrogen bond of catalyzed oxidation of pyridine or its derivatives is directly prepared to obtain the pyridine primary amide compound, and the general reaction formula is as follows:

In the ^formula , R1 ^- R4 are randomly selected from hydrogen, C1-C12 alkyl, alkenyl or alkynyl, C1-C12 alkoxy, C1-C12 fluorine-substituted alkyl, C3-C12 cycloalkyl, Aryl, aryloxy or arylamino, heteroaryl, heteroaryloxy or heteroarylamino, C1~C12 alkyl substituted amino, C1~C12 mercapto, fluorine, hydroxyl, C1~C12 alkylcarbonyl, C1～C12 alkoxycarbonyl, arylcarbonyl, carboxyl, C1～C12 alkanoyloxy, cyano, C1～C12 alkanesulfonyl, sulfonic acid, sulfonate, phosphate or nitro;

Preferably, the heteroaryl group is a five- to fourteen-membered heteroaryl group containing one or more N, O or S.

In the above method, the acid is trifluoroformic acid, trifluoroacetic acid, formic acid, acetic acid, pivalic acid, 2-nitrobenzoic acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid.

In the above method, the base is an inorganic base or an organic base. Inorganic bases include but are not limited to potassium phosphate, sodium phosphate, sodium fluoride, potassium fluoride, cesium fluoride, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium acetate, potassium acetate, cesium acetate, sodium ethoxide , lithium tert-butoxide, lithium hydroxide, sodium propionate, potassium propionate, sodium butyrate, potassium butyrate, sodium benzoate, sodium pivalate, potassium pivalate; organic bases include but not limited to tetrabutyl fluoride Ammonium, triethylamine, diisopropylethylamine, tributylamine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undeca Carbo-7-ene or 1,5-diazabicyclo[4.3.0]non-5-ene. And each of the above-mentioned bases may be used in combination. The most preferred base is sodium acetate.

In the above method, the catalyst is a silver catalyst or an iron catalyst, or a mixture of the two in any proportion. The silver catalysts include but are not limited to silver nitrate, silver acetate, silver trifluoroacetate, silver sulfate, silver fluoroborate, silver lactate, silver phosphate, silver sulfide, silver fluoride, silver chloride, silver iodide, silver bromide, Silver carbonate, silver p-toluenesulfonate, silver trifluoromethanesulfonate, silver benzoate or silver methanesulfonate; the iron catalyst includes but not limited to iron powder, ferrous trifluoromethanesulfonate, trifluoromethanesulfonic acid Iron, ferrous chloride, ferric acetylacetonate, ferrous ferricyanide, ferric ferricyanide, ferrous acetate, ferrous sulfate, ammonium ferrous sulfate, ferrous oxalate, ferric oxalate, ferrous fluoride, ferric fluoride , ferrous bromide, ferric bromide, ferrous iodide, ferric chloride, ferric oxide, ferric oxide. The most preferred catalyst is silver nitrate.

In the above method, the oxidizing agent includes but not limited to ammonium persulfate, potassium persulfate, sodium persulfate, potassium hydrogen peroxosulfate complex salt, di-tert-butyl peroxide, and dicumyl peroxide. The most preferred oxidizing agent is potassium persulfate.

In the above method, the carbonyl source and the nitrogen source are formamide. Excess formamide can be used as a reaction solvent, or a reaction solvent can be added, selected from N,N-diformamide, N,N-diacetamide, acetonitrile, dichloromethane, 1,2-dichloroethane, trifluoro Toluene, chlorobenzene, dichlorobenzene. The weight ratio of the pyridine substrate to the solvent is 1:1-1000.

In the above method, the reaction accelerator is water; the volume ratio of the amount of water used to the organic phase is 0.001-1:1. The most preferred volume ratio of the amount of water to the organic phase is 1:5.

In the above method, the molar ratio of the pyridine substrate, catalyst, oxidant, acid or base is 1-5:0.001-5:0.1-50:0.1-50. The most preferred molar ratio of pyridine substrate, catalyst, oxidizing agent, acid or base is 1:0.2:3:2.

In the above method, the reaction temperature is 20-200° C., and the reaction time is 1-48 hours.

By means of the above-mentioned technical scheme, the method for synthesizing primary pyridine amides of the present invention has at least the following advantages:

The invention provides a new method for synthesizing pyridine primary amide compounds by directly using formamide as a carboxamide source to catalyze and oxidize the carbon-hydrogen bond of pyridine compounds. The method has the characteristics of cheap catalyst, stable reaction raw material, wide source and low price, high selectivity without ligand, less waste generated by reaction, safe carboxamide source, easy storage and easy treatment, and wide application range of substrate. The method is simple and easy, and under optimized reaction conditions, the yield of the target product after separation is as high as 98%, and is a direct, efficient, cheap and environment-friendly method for synthesizing primary pyridine amides.

The pyridine primary amide compound prepared by the method of the invention can be used to prepare unique biological and pharmacological active compounds, and has wide applications in pharmaceutical intermediates, herbicides, active drug molecules, small molecular probes, fluorescent materials and the like.

The above description is only an overview of the technical solution of the present invention. In order to further elaborate the technical means and effects adopted by the present invention to achieve the intended purpose of the invention, the specific implementation, features and effects of the technical solution proposed according to the present invention will be described in detail. As later.

detailed description

Embodiments 1-18 relate to the synthesis of pyridine primary amides, and the experimental results are listed in Table 1:

Table 1 Catalytic Oxidation Synthetic Reaction of Pyridine Primary Amide ^[a]

[a] See the examples for the reaction conditions; [b] column separation yield.

Example 1

Compound 1: Add silver nitrate (0.1mmol), pyridine (0.5mmol), sodium acetate (1.0mmol), potassium persulfate (1.5mmol), formamide (2.0mL) and water to a 25mL reaction flask in an oxygen atmosphere (0.4 mL). The mixture was reacted at 80°C for 4h. After cooling to room temperature, the solvent was distilled off under reduced pressure and separated by column chromatography to obtain the product with a yield of 94%.

¹ HNMR (400MHz, DMSO): δ8.62 (m, 1H), 8.11 (s, 1H), 8.07-7.91 (m, 2H), 7.64 (s, 1H), 7.58 (m, 1H); ¹³ CNMR ( 100MHz, DMSO): δ166.5, 150.7, 148.9, 138.1, 126.9, 122.4ppm.

Example 2

Compound 2: Under an oxygen atmosphere, silver nitrate (0.1mmol), 4-picoline (0.5mmol), sodium acetate (1.0mmol), potassium persulfate (1.5mmol), formamide (2.0 mL) and water (0.4 mL). The mixture was reacted at 80°C for 3h. After cooling to room temperature, the solvent was evaporated under reduced pressure and separated by column chromatography to obtain the product with a yield of 89%.

¹ HNMR (400MHz, DMSO): δ8.47(dd, J=4.9, 0.5Hz, 1H), 8.08(s, 1H), 7.92-7.77(m, 1H), 7.60(s, 1H), 7.41(m ,1H),2.39(s,3H); ¹³ CNMR(100MHz,DMSO):δ166.6,150.6,149.0,148.7,127.5,123.1,21.0ppm.

Example 3

Compound 3: Under an oxygen atmosphere, silver nitrate (0.1mmol), 2-ethylpyridine (0.5mmol), sodium acetate (1.0mmol), potassium persulfate (1.5mmol), formamide (2.0 mL) and water (0.4 mL). The mixture was reacted at 80°C for 4h. After cooling to room temperature, the solvent was evaporated under reduced pressure and separated by column chromatography to obtain the product with a yield of 82%.

¹ HNMR (400MHz, DMSO): δ8.00(s, 1H), 7.91-7.80(m, 2H), 7.63(s, 1H), 7.45(dd, J＝7.0, 1.4Hz, 1H), 2.80(m ,2H),1.26(m,3H); ¹³ CNMR(100MHz,DMSO):δ166.6,162.4,150.0,138.3,125.3,119.6,30.8,14.0ppm

Example 4

Compound 4: Under an oxygen atmosphere, silver nitrate (0.1mmol), 2-pentylpyridine (0.5mmol), sodium acetate (1.0mmol), potassium persulfate (1.5mmol), formamide (2.0 mL) and water (0.4 mL). The mixture was reacted at 80°C for 6h. After cooling to room temperature, the solvent was evaporated under reduced pressure and separated by column chromatography to obtain the product with a yield of 80%.

¹ H NMR (400MHz, DMSO): δ8.00 (s, 1H), 7.97–7.82 (m, 2H), 7.65 (s, 1H), 7.47 (dd, J=6.8, 1.9, 1H), 2.95–2.71 ( m,2H),1.75(dt,J=14.8,7.6,2H),1.49–1.21(m,4H),0.90(t,J=7.0,3H); ¹³ CNMR(100MHz,DMSO):δ167.0,161.8, 150.5, 138.6, 126.3, 120.0, 38.1, 31.9, 29.5, 22.9, 14.8ppm.

Example 5

Compound 5: Under an oxygen atmosphere, silver nitrate (0.1mmol), 2,3-lutidine (0.5mmol), sodium acetate (1.0mmol), potassium persulfate (1.5mmol), formazan Amide (2.0 mL) and water (0.4 mL). The mixture was reacted at 80°C for 4h. After cooling to room temperature, the solvent was evaporated under reduced pressure and separated by column chromatography to obtain the product with a yield of 89%.

¹ HNMR (400MHz, DMSO): δ7.96(s, 1H), 7.76(d, J=7.6Hz, 1H), 7.67(d, J=7.6Hz, 1H), 7.55(s, 1H), 2.48( s,3H),2.30(s,3H); ¹³ CNMR(100MHz,DMSO):δ166.7,156.3,147.6,138.5,135.1,119.9,22.8,19.1ppm.IRνmax(KBr)/cm ^-1 :611,683,744,870,1068, 1127, 1210, 1260, 1397, 1584, 1659, 1691, 3246, 3383, 3431. HRMS (ESI) calcd. for C ₈ H ₁₀ N ₂ O [M+H] 151.0871, found 151.08607.

Example 6

Compound 6: Under an oxygen atmosphere, silver acetate (0.1mmol), 2,4-lutidine (0.5mmol), sodium acetate (1.0mmol), potassium persulfate (1.5mmol), formazan Amide (2.0 mL) and water (0.4 mL). The mixture was reacted at 80°C for 4h. After cooling to room temperature, the solvent was distilled off under reduced pressure and separated by column chromatography to obtain the product with a yield of 90%.

¹ HNMR (400MHz, DMSO): δ7.94(s, 1H), 7.67(d, J=0.8Hz, 1H), 7.56(s, 1H), 7.26(s, 1H), 2.48(s, 3H), 2.34(s,3H); ¹³ CNMR(100MHz,DMSO):δ166.7,157.3,150.0,149.0,126.9,120.3,24.2,20.9ppm.

Example 7

Compound 7: Under an oxygen atmosphere, silver bromide (0.1mmol), 3,5-lutidine (0.5mmol), sodium acetate (1.0mmol), dicumyl peroxide (1.5 mmol), formamide (2.0 mL) and water (0.4 mL). The mixture was reacted at 80°C for 4h. After cooling to room temperature, the solvent was evaporated under reduced pressure and separated by column chromatography to obtain the product with a yield of 89%.

¹ HNMR(400MHz,DMSO):δ8.25(s,1H),7.91(s,1H),7.52(s,1H),7.37(s,1H),2.50(m,3H),2.29(s,3H ); ¹³ CNMR (100MHz, DMSO): δ168.8, 146.9, 146.5, 140.9, 135.7, 133.5, 20.0, 18.0ppm.

Example 8

Compound 8: Under an oxygen atmosphere, ferrous chloride (0.1mmol), 2,3,5-collidine (0.5mmol), sodium acetate (1.0mmol), potassium persulfate (1.5 mmol), acetamide (2.0 mL) and water (0.4 mL). The mixture was reacted at 80°C for 4h. After cooling to room temperature, the solvent was distilled off under reduced pressure and separated by column chromatography to obtain the product with a yield of 96%.

1HNMR(400MHz,DMSO):δ7.93(s, ^1H ),7.46(s,1H),7.38(s,1H),2.51(s,3H),2.45(s,3H),2.28(s,3H ); ¹³ CNMR (100MHz, DMSO): δ169.3, 153.8, 146.1, 142.0, 134.6, 131.7, 22.7, 19.9, 19.2ppm.

Example 9

Compound 9: Under an oxygen atmosphere, iron powder (0.1mmol), 4-methoxypyridine (0.5mmol), sodium acetate (1.0mmol), potassium persulfate (1.5mmol), formamide ( 2.0mL) and water (0.4mL). The mixture was reacted at 80°C for 4h. After cooling to room temperature, the solvent was distilled off under reduced pressure and separated by column chromatography to obtain the product with a yield of 88%.

¹ H NMR (400MHz, DMSO): δ8.47-8.40 (m, 1H), 8.09 (s, 1H), 7.66 (s, 1H), 7.55 (d, J = 2.4Hz, 1H), 7.14 (dd, J ＝5.7,2.7Hz,1H),3.89(s,3H); ¹³ CNMR(100MHz,DMSO):δ166.9,166.3,152.8,150.3,112.9,108.1,56.1ppm.

Example 10

Compound 10: Under an oxygen atmosphere, silver nitrate (0.1mmol), 3-methoxypyridine (0.5mmol), sodium acetate (1.0mmol), potassium persulfate (1.5mmol), formamide ( 2.0mL) and water (0.4mL). The mixture was reacted at 80°C for 4h. After cooling to room temperature, the solvent was evaporated under reduced pressure and separated by column chromatography to obtain the product with a yield of 89%.

¹ H NMR (400MHz, DMSO): δ8.28 (dd, J = 2.9, 0.6Hz, 1H), 7.99 (dd, J = 8.7, 0.5Hz, 1H), 7.92 (s, 1H), 7.51 (dd, J ＝8.7,2.9Hz,1H),7.47(s,1H),3.88(s,3H). ¹³ CNMR(100MHz,DMSO)δ166.3,157.9,143.6,136.8,123.7,121.2,56.3ppm.IRν _max (KBr) /cm ^-1 :651,1022,1279,1372,1423,1498,1586,1674,3204,3374.HRMS(ESI)calcd.for C ₇ H ₈ N ₂ O ₂ [M+H]153.0664,found153.06550.

Example 11

Compound 11: Under an oxygen atmosphere, silver nitrate (0.1mmol), 2-methoxypyridine (0.5mmol), sodium acetate (1.0mmol), potassium persulfate (1.5mmol), formamide ( 2.0mL) and water (0.4mL). The mixture was reacted at 80°C for 4h. After cooling to room temperature, the solvent was evaporated under reduced pressure and separated by column chromatography to obtain the product with a yield of 83%. ¹ HNMR (400MHz, DMSO): δ8.01(s, 1H), 7.85(dd, J＝8.3, 7.3Hz, 1H), 7.65(s, 1H), 7.61(dd, J＝7.3, 0.8Hz, 1H ),6.99(dd,J＝8.3,0.8Hz,1H),3.94(s,3H); ¹³ CNMR(100MHz,DMSO):δ166.3,163.0,148.4,140.6,115.6,114.2,53.9ppm.

Example 12

Compound 12: Under an oxygen atmosphere, silver nitrate (0.1mmol), 2-pyridineethanone (0.5mmol), sodium acetate (1.0mmol), potassium persulfate (1.5mmol), formamide (2.0 mL) and water (0.4 mL). The mixture was reacted at 80°C for 4h. After cooling to room temperature, the solvent was distilled off under reduced pressure and separated by column chromatography to obtain the product with a yield of 86%.

¹ H NMR (400MHz, DMSO): δ8.32 (d, J = 12.2, 1H), 8.29 (d, J = 7.7, 1H), 8.18 (s, 1H), 8.15–8.11 (m, 1H), 7.88 ( s,1H),2.79(s,3H); ¹³ CNMR(100MHz,DMSO):δ198.5,166.3,152.5,150.8,144.9,124.8,120.3,27.9ppm.

Example 13

Compound 13: Under an oxygen atmosphere, silver nitrate (0.1mmol), 2-ethoxypyridine (0.5mmol), sodium acetate (1.0mmol), potassium persulfate (1.5mmol), formamide ( 2.0mL) and water (0.4mL). The mixture was reacted at 80°C for 4h. After cooling to room temperature, the solvent was evaporated under reduced pressure and separated by column chromatography to obtain the product with a yield of 76%.

¹ HNMR (400MHz, DMSO): δ7.97(s, 1H), 7.84(dd, J＝8.2, 7.3Hz, 1H), 7.63(s, 1H), 7.60(dd, J＝7.3, 0.7Hz, 1H ),6.97(dd,J＝8.3,0.8Hz,1H),4.52-4.22(m,2H),1.34(m,3H); ¹³ CNMR(100MHz,DMSO):δ166.3,162.6,148.4,140.6,115.5, 114.2,62.0,14.9ppm.IRν _max (KBr)/cm ^-1 :606,699,779,790,868,1119,1244,1400,1576,1707,3174,3471.HRMS(ESI)calcd.for C ₈ H ₁₀ N ₂ O ₂ [M+ H]167.0821, found167.08198.

Example 14

Compound 14: Under oxygen atmosphere, silver nitrate (0.1mmol), 2-methyl-6-methoxypyridine (0.5mmol), sodium acetate (1.0mmol), potassium persulfate (1.5mmol) were successively added into a 25mL reaction flask ), formamide (2.0 mL) and water (0.4 mL). The mixture was reacted at 80°C for 4h. After cooling to room temperature, the solvent was distilled off under reduced pressure and separated by column chromatography to obtain the product with a yield of 87%.

¹ HNMR (400MHz,DMSO)δ8.10(s,1H),7.62(s,1H),7.25-7.19(m,1H),6.98(dd,J＝1.1,0.6Hz,1H),3.85(s, 3H),2.43(s,3H) ^.13 CNMR(100MHz,DMSO)δ166.7,164.1,157.0,145.5,114.3,105.9,53.8,24.4ppm.IRν _max (KBr)/cm ^-1 679,816,888,1060,1209,1322 , 1391, 1562, 1610, 1653, 3182, 3366. HRMS (ESI) calcd. for C ₈ H ₁₀ N ₂ O ₂ [M+H] 167.0821, found 167.08188.

Example 15

Compound 15: Under an oxygen atmosphere, silver nitrate (0.1mmol), 4-pyridineethanone (0.5mmol), sodium acetate (1.0mmol), potassium persulfate (1.5mmol), formamide (2.0 mL) and water (0.4 mL). The mixture was reacted at 80°C for 4h. After cooling to room temperature, the solvent was distilled off under reduced pressure and separated by column chromatography to obtain the product with a yield of 90%.

¹ HNMR (400MHz, DMSO): δ8.89 (dd, J = 5.0, 0.8, 1H), 8.42 (dd, J = 1.7, 0.8, 1H), 8.26 (s, 1H), 8.04 (dd, J = 5.0 ,1.7,1H),7.83(s,1H),2.72(s,3H); ¹³ CNMR(100MHz,DMSO)δ198.5,166.3,152.5,150.8,144.9,124.8,120.3,27.9ppm.

Example 16

Compound 16: Under an oxygen atmosphere, silver nitrate (0.1mmol), ethyl 2-pyridinecarboxylate (0.5mmol), sodium acetate (1.0mmol), potassium persulfate (1.5mmol), formamide ( 2.0mL) and water (0.4mL). The mixture was reacted at 80°C for 6h. After cooling to room temperature, the solvent was evaporated under reduced pressure and separated by column chromatography to obtain the product with a yield of 75%.

¹ HNMR (400MHz, DMSO): δ8.31–8.18(m, 3H), 7.93(s, 1H), 7.88(s, 1H), 4.43(q, J=7.1, 2H), 1.40(t, J= 7.1,3H); ¹³ CNMR(100MHz,DMSO):δ166.1,165.0,151.4,147.6,140.2,128.0,126.0,62.4,15.0ppm.

Example 17

Compound 17: Under an oxygen atmosphere, silver nitrate (0.1mmol), methyl 4-pyridinecarboxylate (0.5mmol), sodium acetate (1.0mmol), potassium persulfate (1.5mmol), formamide ( 2.0mL) and water (0.4mL). The mixture was reacted at 80°C for 4h. After cooling to room temperature, the solvent was distilled off under reduced pressure and separated by column chromatography to obtain the product with a yield of 95%.

¹ HNMR (400MHz, DMSO): δ8.85 (d, J = 4.9Hz, 1H), 8.42 (d, J = 0.8Hz, 1H), 8.24 (s, 1H), 8.02 (dd, J = 4.9, 1.7 Hz,1H),7.81(s,1H),3.93(s,3H); ¹³ CNMR(100MHz,DMSO):δ165.7,165.2,152.0,150.4,138.8,125.5,121.1,53.4ppm.

Example 18

Compound 18: Add silver nitrate (0.1mmol), 3-methyl-2-phenylpyridine (0.5mmol), sodium acetate (1.0mmol) and potassium persulfate (1.5mmol) in sequence to a 25mL reaction flask under an oxygen atmosphere , formamide (2.0 mL) and water (0.4 mL). The mixture was reacted at 80°C for 4h. After cooling to room temperature, the solvent was distilled off under reduced pressure and separated by column chromatography to obtain the product with a yield of 51%.

¹ HNMR(400MHz,DMSO):δ7.95(s,1H),7.94-7.88(m,2H),7.68-7.62(m,2H),7.60(s,1H),7.53-7.41(m,3H) ,2.39(s,3H); ¹³ CNMR(100MHz,DMSO):δ166.7,157.0,148.3,140.5,139.9,134.3,129.7,128.7,128.6,120.8,20.3ppm.IRν _max (KBr)/cm ^-1 1089, 1262, 1308, 1385, 1463, 1594, 1666, 2928, 2982, 3324, 3385, 3446. HRMS (ESI) calcd. for C ₁₃ H ₁₂ N ₂ O [M+H] 213.1028, found 213.10201.

Claims (10)

1. the method for a Direct Catalytic Oxidation method pyridine synthesis primary amide compound; it is characterized in that; under air or oxygen atmosphere; add oxidant, accelerator water and acid or alkali; with Methanamide for carbamylating agent; under silver catalyst and/or iron catalyst effect, the carbon-hydrogen link of catalytic oxidation pyridine or derivatives thereof directly prepares pyridine primary amide compound, and reaction expression is expressed as follows:

R in formula¹～R⁴Arbitrarily selected from hydrogen, the alkyl of C1～C12, alkenyl or alkynyl, the alkoxyl of C1～C12, the fluorine of C1～C12 replaces alkyl; the cycloalkyl of C3～C12, aryl, aryloxy group or aryl amine, heteroaryl, heteroaryloxy or assorted aryl amine, the amino that C1～C12 alkyl replaces; C1～C12 sulfydryl, fluorine, hydroxyl, C1～C12 alkyl-carbonyl; C1～C12 alkoxy carbonyl, aryl carbonyl, carboxyl; C1～C12 alkanoyloxy, cyano group, C1～C12 alkane sulfonyl; sulfonic group, sulfonate group, phosphate-based or nitro.

2. synthetic method according to claim 1, it is characterised in that described heteroaryl is the heteroaryl of five～fourteen-ring containing one or more N, O or S.

3. synthetic method according to claim 1, it is characterised in that described acid is trifluoro formic acid, trifluoroacetic acid, formic acid, acetic acid, pivalic acid, 2-nitrobenzoic acid, p-methyl benzenesulfonic acid or trifluoromethanesulfonic acid.

4. synthetic method according to claim 1, it is characterised in that described alkali is inorganic base or organic base; Described inorganic base is potassium phosphate, sodium phosphate, sodium fluoride, potassium fluoride, cesium fluoride, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, Feldalat NM, sodium acetate, potassium acetate, cesium acetate, Sodium ethylate, tert-butyl alcohol lithium, Lithium hydrate, sodium propionate, potassium propionate, sodium butyrate, potassium butyrate, sodium benzoate, pivalic acid sodium, pivalic acid potassium; Described organic base be tetrabutyl ammonium fluoride, triethylamine, diisopropylethylamine, tri-n-butylamine, 1,4-diazabicylo [2.2.2] octane, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene or 1,5-diazabicylo [4.3.0]-5-in ninth of the ten Heavenly Stems alkene.

5. synthetic method according to claim 1, it is characterized in that, described silver catalyst is silver nitrate, silver acetate, silver trifluoroacetate, silver sulfate, silver fluoborate, actol, silver phosphate, Argentous sulfide., Argentous fluoride, silver chloride, silver iodide, Silver monobromide, Disilver carbonate, p-methyl benzenesulfonic acid silver, silver trifluoromethanesulfonate, silver benzoate or methanesulfonic acid silver.

6. synthetic method according to claim 1, it is characterized in that, described iron catalyst is iron powder, trifluoromethanesulfonic acid ferrous iron, trifluoromethanesulfonic acid ferrum, ferrous chloride, ferric acetyl acetonade, ferroferricyanide, ferric ferricyanide, Ferrous acetate, ferrous sulfate, Ferrous ammonium sulfate, Ferrox., ferric oxalate, ferrous fluoride, ferric flouride, ferrous bromide, ferric bromide, iron iodide, ferric chloride, ferrum oxide or ferroso-ferric oxide.

7. synthetic method according to claim 1, it is characterised in that described oxidant is Ammonium persulfate., potassium peroxydisulfate, sodium peroxydisulfate, peroxosulphuric hydrogen potassium complex salt, di-tert-butyl peroxide or cumyl peroxide.

8. synthetic method according to claim 1, it is characterised in that the amount of described accelerator water and the volume ratio of organic facies are 0.001～1:1.

9. synthetic method according to claim 1, it is characterised in that the mol ratio of described pyridine or derivatives thereof, catalyst, oxidant, acid or alkali is 1～5:0.001～5:0.1～50:0.1～50.

10. synthetic method according to claim 1, it is characterised in that in described method, reaction temperature is 20～200 DEG C, and the response time is 1～48 hour.