CN105669542A - Method for synthesizing pyridine primary amides by direct catalytic oxidation process - Google Patents
Method for synthesizing pyridine primary amides by direct catalytic oxidation process Download PDFInfo
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- CN105669542A CN105669542A CN201610131789.3A CN201610131789A CN105669542A CN 105669542 A CN105669542 A CN 105669542A CN 201610131789 A CN201610131789 A CN 201610131789A CN 105669542 A CN105669542 A CN 105669542A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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Abstract
The invention discloses a method for synthesizing pyridine primary amides by a direct catalytic oxidation process. The method comprises the following steps: under the action of acid or alkali, adding an accelerator water and an oxidizer into formamide which is used as a carbonyl source and nitrogen source, and catalytically oxidizing double C-H bonds of pyridine or derivatives thereof under the action of a silver and/or iron catalyst to directly prepare the pyridine primary amides. By activating the double C-H bonds, the method disclosed by the invention has the advantages of ideal atomic economy, less generated waste, wide and stable substrate sources, and low price. Under the optimized reaction conditions, the separation yield of the target products is up to 98%.
Description
Technical field
The present invention relates to the synthetic method of a kind of pyridine primary amide compounds, particularly relating to one, to directly utilize Methanamide be carbamyl source, and the carbon-hydrogen link of catalytic oxidation pyridine compounds and their carrys out the method for pyridine synthesis primary amide compounds.
Background technology
Pyridine primary amide compounds is the compound that a class has special excellent physiologically active, and its basic structural unit is present in substantial amounts of natural product, medicine and herbicide, and is widely used in the fields such as biology, medicine and material. The traditional method synthesizing this type of material is pyridine acid or the reaction of pyridine acyl chlorides and ammonia; Process for catalytic synthesis has the advantages such as efficiency is high and applied widely and attracts wide attention in recent years.
The carbamylation bromopyridine of Beller seminar reported first palladium chtalyst and chloropyridine reaction; prepare pyridine primary amide; carbonyl source used is carbon monoxide; nitrogenous source is ammonia, and this reaction successfully it is critical only that and filtered out efficient Phosphine ligands cataCXiumA (Xiao-FengWu, a HelfriedNeumann; MatthiasBeller; Chem.Eur.J.2010,16,9750-9753). Consider that part cataCXiumA is complicated and is difficult to synthesize, this group studies further and uses more cheap part, find that business-like Phosphine ligands dppf can obtain equivalent catalytic effect (Xiao-FengWu, HelfriedNeumann, MatthiasBeller, Chem.AsianJ.2010,5,2168-2172). And then; this group develops again a kind of new Phosphine ligands Pyr-DalPhos; and the carbamylation of bromopyridine is achieved good catalytic effect (PamelaG.Alsabeh; MarkStradiotto; HelfriedNeumann, MatthiasBeller, Adv.Synth.Catal.2012; 354,3,065 3070). Phenol is the reactant that a class is cheap and easy to get, but phenolic hydroxyl group because of with kinds of aromatic ring conjugation, and be difficult to leave away. This group forms ester by phenol and perfluoro butyl sulfonic acid fluoride original position and participates in the carbamylation of Pd-DPEphos catalysis and react and prepare pyridine primary amide (Xiao-FengWu; HelfriedNeumann, MatthiasBeller, Chem.Eur.J.2012; 18,419 422). These methods, while combined coefficient is high, carbonyl source used and nitrogenous source are cheap, but, they are poisonous, inflammable and there is security problems. Therefore, safety more is used to carry out pyridine synthesis primary amide have important researching value and application prospect with nontoxic carbonylation and amination reagent.
Recently; Skrydstrup group utilizes ex situ to form carbon monoxide as carbonyl source and aminoquinoxaline as nitrogenous source; under palladium and Phosphine ligands exist; carbamylation 3-bromopyridine and p-methyl benzenesulfonic acid pyridine ester effectively; prepare corresponding pyridine primary amide (DennisU.Nielsen; RolfH.Taaning, AndersT.Lindhardt, ThomasM.TroelsSkrydstrup, Org.Lett.2011,13,4454 4457).All above method all also exists the problem using expensive, poisonous and unstable Phosphine ligands, add the difficulty that production cost separates with product, meanwhile, reactant is required for using the pyridine of functionalization, and after reaction terminates, these functional groups all become leaving group and form refuse. Ideal method is that the carbon-hydrogen link directly utilizing pyridine carries out carbamylation reaction, saves pre-functionalization pyridine Step, thus the refuse produced is few, raw material availability is high, economizes on resources and the energy.
But, so far, a kind of carry out carbamylation reaction either directly through activation pyridine carbon-hydrogen and synthesize the method for high value added product pyridine primary amide compounds there is not been reported.
Summary of the invention
Present invention is primarily targeted at, overcome the defect that the pyridine compounds and their catalysis carbamylation pyridine synthesis primary amide compounds method of existing pre-functionalization exists, and a kind of method that new pyridine synthesis primary amide compound is provided, under silver and/or iron catalyst effect, add Methanamide as carbamyl reagent, water is as accelerator, the carbon-hydrogen link pyridine synthesis primary amide compounds of direct oxidation pyridine compounds and their under air or oxygen atmosphere, it is extensive that the method has substrate source, stable and cheap, catalyst is cheap and easy to get, reaction selectivity is high, generation refuse is few, the advantage that applied widely and target product yield is high.
The present invention for achieving the above object and solves its technical problem, by the following technical solutions:
A kind of method of 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;
Preferably, described heteroaryl is the heteroaryl of five～fourteen-ring containing one or more N, O or S.
In said method, described acid is trifluoro formic acid, trifluoroacetic acid, formic acid, acetic acid, pivalic acid, 2-nitrobenzoic acid, p-methyl benzenesulfonic acid or trifluoromethanesulfonic acid.
In said method, described alkali is inorganic base or organic base. Inorganic base includes but not limited to 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; Organic base include but not limited to 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.And above-mentioned each alkali can combine use. Most preferred alkali is sodium acetate.
In said method, described catalyst is silver catalyst or iron catalyst, or both are with the mixture of arbitrary proportion composition. Described silver catalyst includes but not limited to 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; Described iron catalyst includes but not limited to 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, ferroso-ferric oxide. Most preferred catalyst is silver nitrate.
In said method, described oxidant includes but not limited to Ammonium persulfate., potassium peroxydisulfate, sodium peroxydisulfate, peroxosulphuric hydrogen potassium complex salt, di-tert-butyl peroxide, cumyl peroxide. Most preferred oxidant is potassium peroxydisulfate.
In said method, described carbonyl source and nitrogenous source are Methanamide. Excessive Methanamide can as reaction dissolvent, it is also possible to add reaction dissolvent, selected from N, N-diformamide, N, N-diacetayl amide, acetonitrile, dichloromethane, 1,2-dichloroethanes, benzotrifluoride, chlorobenzene, dichloro-benzenes. The weight ratio of described pyridines substrate and solvent is 1:1～1000.
In said method, described reaction promoter is water; The amount of water used is 0.001～1:1 with the volume ratio of organic facies. Most preferably the amount of water is 1:5 with the volume ratio of organic facies.
In said method, the mol ratio of described pyridines substrate, catalyst, oxidant, acid or alkali is 1～5:0.001～5:0.1～50:0.1～50. The mol ratio of most preferred pyridines substrate, catalyst, oxidant, acid or alkali is 1:0.2:3:2.
In said method, reaction temperature is 20～200 DEG C, and the response time is 1～48 hour.
By technique scheme, the method for the pyridine synthesis primary amide compounds of the present invention at least has the advantage that
The invention provides one, to directly utilize Methanamide be carbamyl source, and the carbon-hydrogen link of catalytic oxidation pyridine compounds and their carrys out the new method of pyridine synthesis primary amide compounds. It is cheap that the method has catalyst; Reaction raw materials is stable, wide material sources and cheap; React high without ligand selectivity; The refuse that reaction produces is few; Carbamyl source is safe, easily stored and is easily handled; The feature applied widely of substrate. Described method is simple, and under the reaction condition optimized, after target product separation, yield is up to 98%, is a kind of method of direct, efficient, cheap and eco-friendly pyridine synthesis primary amide compounds.
Pyridine primary amide compounds prepared by the inventive method can be used to prepare the biology with uniqueness and pharmaceutically active compounds, has purposes widely in pharmaceutical intermediate, herbicide, active drug molecule, Small-molecule probe and fluorescent material etc.
Described above is only the general introduction of technical solution of the present invention, in order to further set forth that the present invention reaches technological means and effect that predetermined goal of the invention is taked, to the detailed description of the invention of technical scheme proposed according to the present invention, feature and effect thereof, describe in detail as after.
Detailed description of the invention
Embodiment 1～18 relates to the synthesis of pyridine primary amide compounds, and experimental result is listed in table 1:
The synthetic reaction of table 1 catalytic oxidation pyridine primary amide compound[a]
[a] reaction condition is shown in embodiment;[b] post separation yield.
Embodiment 1
Compound 1: under oxygen atmosphere, 25mL reaction bulb is sequentially added into silver nitrate (0.1mmol), pyridine (0.5mmol), sodium acetate (1.0mmol), potassium peroxydisulfate (1.5mmol), Methanamide (2.0mL) and water (0.4mL). Mixture reacts 4h at 80 DEG C. Being cooled to room temperature, after removing solvent under reduced pressure, column chromatography for separation obtains product, productivity 94%.
1HNMR (400MHz, DMSO): δ 8.62 (m, 1H), 8.11 (s, 1H), 8.07-7.91 (m, 2H), 7.64 (s, 1H), 7.58 (m, 1H);13CNMR(100MHz,DMSO):δ166.5,150.7,148.9,138.1,126.9,122.4ppm.
Embodiment 2
Compound 2: under oxygen atmosphere, 25mL reaction bulb is sequentially added into silver nitrate (0.1mmol), 4-picoline (0.5mmol), sodium acetate (1.0mmol), potassium peroxydisulfate (1.5mmol), Methanamide (2.0mL) and water (0.4mL). Mixture reacts 3h at 80 DEG C. Being cooled to room temperature, after removing solvent under reduced pressure, column chromatography for separation obtains product, productivity 89%.
1HNMR (400MHz, DMSO): δ 8.47 (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);13CNMR(100MHz,DMSO):δ166.6,150.6,149.0,148.7,127.5,123.1,21.0ppm.
Embodiment 3
Compound 3: under oxygen atmosphere, 25mL reaction bulb is sequentially added into silver nitrate (0.1mmol), 2-ethylpyridine (0.5mmol), sodium acetate (1.0mmol), potassium peroxydisulfate (1.5mmol), Methanamide (2.0mL) and water (0.4mL). Mixture reacts 4h at 80 DEG C. Being cooled to room temperature, after removing solvent under reduced pressure, column chromatography for separation obtains product, productivity 82%.
1HNMR (400MHz, DMSO): δ 8.00 (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);13CNMR(100MHz,DMSO):δ166.6,162.4,150.0,138.3,125.3,119.6,30.8,14.0ppm
Embodiment 4
Compound 4: under oxygen atmosphere, 25mL reaction bulb is sequentially added into silver nitrate (0.1mmol), 2-pentyl pyridine (0.5mmol), sodium acetate (1.0mmol), potassium peroxydisulfate (1.5mmol), Methanamide (2.0mL) and water (0.4mL). Mixture reacts 6h at 80 DEG C. Being cooled to room temperature, after removing solvent under reduced pressure, column chromatography for separation obtains product, productivity 80%.
1HNMR (400MHz, DMSO): δ 8.00 (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);13CNMR(100MHz,DMSO):δ167.0,161.8,150.5,138.6,126.3,120.0,38.1,31.9,29.5,22.9,14.8ppm.
Embodiment 5
Compound 5: under oxygen atmosphere, 25mL reaction bulb is sequentially added into silver nitrate (0.1mmol), 2,3-lutidines (0.5mmol), sodium acetate (1.0mmol), potassium peroxydisulfate (1.5mmol), Methanamide (2.0mL) and water (0.4mL). Mixture reacts 4h at 80 DEG C. Being cooled to room temperature, after removing solvent under reduced pressure, column chromatography for separation obtains product, productivity 89%.
1HNMR (400MHz, DMSO): δ 7.96 (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);13CNMR(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.forC8H10N2O[M+H]151.0871,found151.08607.
Embodiment 6
Compound 6: under oxygen atmosphere, 25mL reaction bulb is sequentially added into silver acetate (0.1mmol), 2,4-lutidines (0.5mmol), sodium acetate (1.0mmol), potassium peroxydisulfate (1.5mmol), Methanamide (2.0mL) and water (0.4mL). Mixture reacts 4h at 80 DEG C. Being cooled to room temperature, after removing solvent under reduced pressure, column chromatography for separation obtains product, productivity 90%.
1HNMR (400MHz, DMSO): δ 7.94 (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);13CNMR(100MHz,DMSO):δ166.7,157.3,150.0,149.0,126.9,120.3,24.2,20.9ppm.
Embodiment 7
Compound 7: under oxygen atmosphere, 25mL reaction bulb is sequentially added into Silver monobromide (0.1mmol), 3,5-lutidines (0.5mmol), sodium acetate (1.0mmol), cumyl peroxide (1.5mmol), Methanamide (2.0mL) and water (0.4mL). Mixture reacts 4h at 80 DEG C. Being cooled to room temperature, after removing solvent under reduced pressure, column chromatography for separation obtains product, productivity 89%.
1HNMR (400MHz, DMSO): δ 8.25 (s, 1H), 7.91 (s, 1H), 7.52 (s, 1H), 7.37 (s, 1H), 2.50 (m, 3H), 2.29 (s, 3H);13CNMR(100MHz,DMSO):δ168.8,146.9,146.5,140.9,135.7,133.5,20.0,18.0ppm.
Embodiment 8
Compound 8: under oxygen atmosphere, 25mL reaction bulb is sequentially added into ferrous chloride (0.1mmol), 2,3,5-trimethylpyridine (0.5mmol), sodium acetate (1.0mmol), potassium peroxydisulfate (1.5mmol), acetamide (2.0mL) and water (0.4mL). Mixture reacts 4h at 80 DEG C. Being cooled to room temperature, after removing solvent under reduced pressure, column chromatography for separation obtains product, productivity 96%.
1HNMR (400MHz, DMSO): δ 7.93 (s, 1H), 7.46 (s, 1H), 7.38 (s, 1H), 2.51 (s, 3H), 2.45 (s, 3H), 2.28 (s, 3H);13CNMR(100MHz,DMSO):δ169.3,153.8,146.1,142.0,134.6,131.7,22.7,19.9,19.2ppm.
Embodiment 9
Compound 9: under oxygen atmosphere, 25mL reaction bulb is sequentially added into iron powder (0.1mmol), 4-methoxypyridine (0.5mmol), sodium acetate (1.0mmol), potassium peroxydisulfate (1.5mmol), Methanamide (2.0mL) and water (0.4mL). Mixture reacts 4h at 80 DEG C. Being cooled to room temperature, after removing solvent under reduced pressure, column chromatography for separation obtains product, productivity 88%.
1HNMR (400MHz, DMSO): δ 8.47-8.40 (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);13CNMR(100MHz,DMSO):δ166.9,166.3,152.8,150.3,112.9,108.1,56.1ppm.
Embodiment 10
Compound 10: under oxygen atmosphere, 25mL reaction bulb is sequentially added into silver nitrate (0.1mmol), 3-Methoxy Pyridine (0.5mmol), sodium acetate (1.0mmol), potassium peroxydisulfate (1.5mmol), Methanamide (2.0mL) and water (0.4mL). Mixture reacts 4h at 80 DEG C. Being cooled to room temperature, after removing solvent under reduced pressure, column chromatography for separation obtains product, productivity 89%.
1HNMR (400MHz, DMSO): δ 8.28 (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).13CNMR(100MHz,DMSO)δ166.3,157.9,143.6,136.8,123.7,121.2,56.3ppm.IRνmax(KBr)/cm-1:651,1022,1279,1372,1423,1498,1586,1674,3204,3374.HRMS(ESI)calcd.forC7H8N2O2[M+H]153.0664,found153.06550.
Embodiment 11
Compound 11: under oxygen atmosphere, 25mL reaction bulb is sequentially added into silver nitrate (0.1mmol), 2-methoxypyridine (0.5mmol), sodium acetate (1.0mmol), potassium peroxydisulfate (1.5mmol), Methanamide (2.0mL) and water (0.4mL). Mixture reacts 4h at 80 DEG C. Being cooled to room temperature, after removing solvent under reduced pressure, column chromatography for separation obtains product, productivity 83%.1HNMR (400MHz, DMSO): δ 8.01 (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);13CNMR(100MHz,DMSO):δ166.3,163.0,148.4,140.6,115.6,114.2,53.9ppm.
Embodiment 12
Compound 12: under oxygen atmosphere, 25mL reaction bulb is sequentially added into silver nitrate (0.1mmol), 2-pyridine ethyl ketone (0.5mmol), sodium acetate (1.0mmol), potassium peroxydisulfate (1.5mmol), Methanamide (2.0mL) and water (0.4mL). Mixture reacts 4h at 80 DEG C. Being cooled to room temperature, after removing solvent under reduced pressure, column chromatography for separation obtains product, productivity 86%.
1HNMR (400MHz, DMSO): δ 8.32 (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);13CNMR(100MHz,DMSO):δ198.5,166.3,152.5,150.8,144.9,124.8,120.3,27.9ppm.
Embodiment 13
Compound 13: under oxygen atmosphere, 25mL reaction bulb is sequentially added into silver nitrate (0.1mmol), 2-ethoxy pyridine (0.5mmol), sodium acetate (1.0mmol), potassium peroxydisulfate (1.5mmol), Methanamide (2.0mL) and water (0.4mL). Mixture reacts 4h at 80 DEG C. Being cooled to room temperature, after removing solvent under reduced pressure, column chromatography for separation obtains product, productivity 76%.
1HNMR (400MHz, DMSO): δ 7.97 (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);13CNMR(100MHz,DMSO):δ166.3,162.6,148.4,140.6,115.5,114.2,62.0,14.9ppm.IRνmax(KBr)/cm-1:606,699,779,790,868,1119,1244,1400,1576,1707,3174,3471.HRMS(ESI)calcd.forC8H10N2O2[M+H]167.0821,found167.08198.
Embodiment 14
Compound 14: under oxygen atmosphere, 25mL reaction bulb is sequentially added into silver nitrate (0.1mmol), 2-methyl-6-methoxypyridine (0.5mmol), sodium acetate (1.0mmol), potassium peroxydisulfate (1.5mmol), Methanamide (2.0mL) and water (0.4mL). Mixture reacts 4h at 80 DEG C. Being cooled to room temperature, after removing solvent under reduced pressure, column chromatography for separation obtains product, productivity 87%.
1HNMR (400MHz, DMSO) δ 8.10 (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).13CNMR(100MHz,DMSO)δ166.7,164.1,157.0,145.5,114.3,105.9,53.8,24.4ppm.IRνmax(KBr)/cm-1679,816,888,1060,1209,1322,1391,1562,1610,1653,3182,3366.HRMS(ESI)calcd.forC8H10N2O2[M+H]167.0821,found167.08188.
Embodiment 15
Compound 15: under oxygen atmosphere, 25mL reaction bulb is sequentially added into silver nitrate (0.1mmol), 4-pyridine ethyl ketone (0.5mmol), sodium acetate (1.0mmol), potassium peroxydisulfate (1.5mmol), Methanamide (2.0mL) and water (0.4mL). Mixture reacts 4h at 80 DEG C. Being cooled to room temperature, after removing solvent under reduced pressure, column chromatography for separation obtains product, productivity 90%.
1HNMR (400MHz, DMSO): δ 8.89 (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);13CNMR(100MHz,DMSO)δ198.5,166.3,152.5,150.8,144.9,124.8,120.3,27.9ppm.
Embodiment 16
Compound 16: under oxygen atmosphere, 25mL reaction bulb is sequentially added into silver nitrate (0.1mmol), 2-pyridine carboxylic acid ethyl ester (0.5mmol), sodium acetate (1.0mmol), potassium peroxydisulfate (1.5mmol), Methanamide (2.0mL) and water (0.4mL). Mixture reacts 6h at 80 DEG C. Being cooled to room temperature, after removing solvent under reduced pressure, column chromatography for separation obtains product, productivity 75%.
1HNMR (400MHz, DMSO): δ 8.31 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);13CNMR(100MHz,DMSO):δ166.1,165.0,151.4,147.6,140.2,128.0,126.0,62.4,15.0ppm.
Embodiment 17
Compound 17: under oxygen atmosphere, 25mL reaction bulb is sequentially added into silver nitrate (0.1mmol), Isonicotinic acid methyl ester (0.5mmol), sodium acetate (1.0mmol), potassium peroxydisulfate (1.5mmol), Methanamide (2.0mL) and water (0.4mL). Mixture reacts 4h at 80 DEG C. Being cooled to room temperature, after removing solvent under reduced pressure, column chromatography for separation obtains product, productivity 95%.
1HNMR (400MHz, DMSO): δ 8.85 (d, J=4.9Hz, 1H), 8.42 (d, J=0.8Hz, 1H), 8.24 (s, 1H), 8.02 (dd, J=4.9,1.7Hz, 1H), 7.81 (s, 1H), 3.93 (s, 3H);13CNMR(100MHz,DMSO):δ165.7,165.2,152.0,150.4,138.8,125.5,121.1,53.4ppm.
Embodiment 18
Compound 18: under oxygen atmosphere, 25mL reaction bulb is sequentially added into silver nitrate (0.1mmol), 3-methyl-2-phenylpyridine (0.5mmol), sodium acetate (1.0mmol), potassium peroxydisulfate (1.5mmol), Methanamide (2.0mL) and water (0.4mL). Mixture reacts 4h at 80 DEG C. Being cooled to room temperature, after removing solvent under reduced pressure, column chromatography for separation obtains product, productivity 51%.
1HNMR (400MHz, DMSO): δ 7.95 (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);13CNMR(100MHz,DMSO):δ166.7,157.0,148.3,140.5,139.9,134.3,129.7,128.7,128.6,120.8,20.3ppm.IRνmax(KBr)/cm-11089,1262,1308,1385,1463,1594,1666,2928,2982,3324,3385,3446.HRMS(ESI)calcd.forC13H12N2O[M+H]213.1028,found213.10201.
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.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112239423A (en) * | 2020-02-17 | 2021-01-19 | 浙江大学 | Synthetic method of alpha-arylated amide compound |
| US11168068B2 (en) | 2016-07-18 | 2021-11-09 | Janssen Pharmaceutica Nv | Tau PET imaging ligands |
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| CN1245803A (en) * | 1998-08-10 | 2000-03-01 | 弗·哈夫曼-拉罗切有限公司 | Method for preparing substituted pyridines |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US11168068B2 (en) | 2016-07-18 | 2021-11-09 | Janssen Pharmaceutica Nv | Tau PET imaging ligands |
| CN112239423A (en) * | 2020-02-17 | 2021-01-19 | 浙江大学 | Synthetic method of alpha-arylated amide compound |
| CN112239423B (en) * | 2020-02-17 | 2022-03-04 | 浙江大学 | Synthetic method of alpha-arylated amide compound |
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