CN107892670B - Method for synthesizing formamide derivative through cobalt-catalyzed formylation reaction - Google Patents

Method for synthesizing formamide derivative through cobalt-catalyzed formylation reaction Download PDF

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CN107892670B
CN107892670B CN201711206078.9A CN201711206078A CN107892670B CN 107892670 B CN107892670 B CN 107892670B CN 201711206078 A CN201711206078 A CN 201711206078A CN 107892670 B CN107892670 B CN 107892670B
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isomer
cobalt
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formyl
major isomer
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CN107892670A (en
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龚行
谢桂林
蔡昌群
马娟
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Xiangtan University
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B43/00—Formation or introduction of functional groups containing nitrogen
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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    • 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
    • C07D213/06—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/127—Preparation from compounds containing pyridine rings
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    • 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
    • C07D213/06—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Abstract

The invention discloses a method for synthesizing formamide derivatives by cobalt-catalyzed formylation, which comprises the steps of carrying out one-pot reaction on amine compounds and formamide compounds under the catalysis of cobalt salt to generate the formamide derivatives; the method has the advantages of cheap and easily obtained reaction raw materials and catalysts, simple reaction steps and operation, high reaction selectivity, high yield, capacity of performing amplification reaction and the like, and overcomes the defects of high toxicity of reaction reagents, expensive catalysts, more reaction steps, more byproducts and the like in the prior art.

Description

Method for synthesizing formamide derivative through cobalt-catalyzed formylation reaction
Technical Field
the invention relates to a method for synthesizing formamide derivatives, in particular to a method for synthesizing formamide derivatives in one step by formylating primary amine hydrogen or secondary amine hydrogen under the catalysis of cobalt salt by taking formamide compounds as acylation reagents, and belongs to the technical field of organic synthesis.
Background
Formamide derivatives are one of important organic compounds, and are widely present in bioactive molecules (such as molecular structural formulas below), organic synthesis intermediates and functional polymer materials. A variety of small organic molecules can be used as carbonyl sources to prepare carboxamide derivatives, such as formic acid and its salts [ b.a. aleiwi, k.mitachi, m.kurosu, Tetrahedron lett.2013,54,2077; ganapati Reddy, g.d.kisharekumar, s.baskaran, Tetrahedron lett.2000,41,9149]Formamide [ L.Becerra-Figueroa, A.Ojeda-Porras, D.Gamba-S a nchez, J.org.chem.2014,79,4544]Esters [ L.Hie, N.F.Fine Nathel, X.hong, Y. -F.Yang, K.N.Houk, N.K.Garg, Angew.chem.int.Ed.2016,55,2810]methanol [ n.ortega, c.richter, f.glorius, org.lett.2013,15,1776]DMF, etc. Wherein, the cost of the formic acid and the salt thereof is higher than that of other reagents, and the formic acid and the salt thereof have stronger reducibility, certain toxicity and higher requirement on storage conditions. The price of formamide is higher than that of the subsequent three industrial products, and the synthesis cost of formamide is increased. In the method for preparing the formamide derivative by using the ester as the carbonyl source, nickel catalysis is needed, and 30 mol% of imidazole salt and 1.25 equivalents of trialkoxyaluminum are needed to be added into a reaction system, so that the cost is high. Methanol is a common chemical reagent which is cheap and easy to obtain, however, when the methanol is used as a carbonyl source to synthesize a formamide derivative, metal ruthenium is used as a catalyst, potassium tert-butoxide and 1, 3-dicyclohexyl imidazole chloride are added to promote the reaction, and the synthesis cost is increased. DMF is a widely used and cheap and readily available commercial product that can be used as a source of carboxamido, dimethylamino, carbonyl, methyl and aldehyde groups [ s.ding, n.jiao, angelw.chem.int.ed.2012, 51,9226; muzart, Tetrahedron 2009,65,8313; ohtaki, Pure appl.chem.1987,59,1143; s.kobayashi, m.sugiura, c.ogawa, adv.synth.catal.2004,346, 1023; palatriza santos, l.m.liz-Marzan, adv.funct.mater.2009,19,679]. DMF has also been reported as an aldehyde source for the synthesis of carboxamide derivatives. In 2017, Jagtap reported nickel-catalyzed reaction of substituted amines with DMFAccordingly [ r.b. sonawan, n.k.rasal, s.v. jagtap, org.lett.2017,19,2078]. In the reaction, 3 equivalents of imidazole is required to be added, the atom economic efficiency of the reaction is not high, and the synthesis cost is high. In 2016, Shankarling reported that the reaction of ferroferric oxide catalyzed primary amine with DMF was not too high in reaction yield, and the substrate application range was limited, and only applied to the reaction of primary amine with DMF [ P.B.Thale, P.N.Borase, G.S.Shankarling, RSC adv.2016,6,52724]. In the same year, Blanchet reported the reaction of substituted amine catalyzed by boric acid derivative and DMF, the reaction catalyst is expensive and difficult to separate, and in addition, 20 mol% of acetic acid needs to be additionally added into the reaction system, which increases the difficulty of post-treatment [ T.M.ElDine, D.Evans, J.Rouden, J.blanchet, chem.Eur.J.2016,22,5894]. In 2013, Shepard reported B (OCH)2CF3)3Catalytic reaction of substituted amines with DMF, which has a good effect on primary amines, but the reaction yield of secondary amines is very poor, and the catalysts needed for the reaction are expensive and difficult to separate [ r.m. lanigan, p.starkov, t.d. sheppard, j.org.chem.2013,78,4512]. Therefore, the method for synthesizing the formamide derivative by using the cheap metal-catalyzed industrial reagent DMF as the aldehyde source has important theoretical and application values.
Disclosure of Invention
Aiming at the problems that in the prior art, a toxic boric acid derivative catalyst is used, or an expensive noble metal catalyst is used, or the yield is low, the byproducts are more and the like in the method for synthesizing the formamide derivative by taking DMF as an acylation reagent, the invention aims to provide a method for preparing the formamide derivative by formylation reaction by taking a formamide compound as an amidation reagent and cheap cobalt salt as a catalyst; the method uses cheap and easily-obtained cobalt salt and amidation reagent, can obtain the formamide derivative with high yield under mild conditions, and has good application prospect.
In order to realize the technical purpose, the invention provides a method for synthesizing formamide derivatives through cobalt-catalyzed formylation, which comprises the steps of carrying out one-pot reaction on an amine compound shown in a formula 1 and a formamide compound under the catalysis of cobalt salt to generate formamide derivatives shown in a formula 2;
Wherein the content of the first and second substances,
R1And R2independently selected from hydrogen, aliphatic, aromatic or heteroaromatic groups, and R1and R2not hydrogen at the same time.
In a preferred embodiment, the amine compound is tetrahydroisoquinoline, 6-methoxytetrahydroisoquinoline, 7-bromotetrahydroisoquinoline, 7-nitrotetrahydroisoquinoline, isoindoline, 4,5,6, 7-tetrahydrothieno [3.2-c ] pyridine, N-phenylpiperazine, 4-phenylpiperidine, cyclohexylimine, N-methylbenzylamine, N-ethylbenzylamine, N-methyl-4-methoxybenzylamine, n-methyl-4-trifluoromethylbenzylamine, N-methylphenylethylamine, N-methyl-1-naphthylmethylamine, fluoxetine, benzylamine, phenethylamine, amphetamine, alpha-phenethylamine, dodecylprimary amine, 2-amino-1-phenylethyl alcohol, 1-aminoindan, 3, 4-dimethoxyphenethylamine.
in a preferred embodiment, the amine compound is converted into the carboxamide derivative of formula 2 by formylation, wherein the carboxamide derivative is N-formyl tetrahydroisoquinoline, N-formyl-6-methoxytetrahydroisoquinoline, N-formyl-7-bromotetrahydroisoquinoline, N-formyl-7-nitrotetrahydroisoquinoline, N-formyl isoindoline, N-formyl-4, 5,6, 7-tetrahydrothieno [3.2-c ] pyridine, N-formyl-N' -phenylpiperazine, N-formyl-4-phenylpiperidine, N-formyl cyclohexylimine, N-methyl-N-formylbenzylamine, N-ethyl-N-formylbenzylamine, N-methyl-N-formylbenzylamine, N-formyl-methyl-4-phenylpiperidine, N-formyl-aminoindole, N-, N-methyl-N-formyl-4-methoxybenzylamine, N-methyl-N-formyl-4-trifluoromethylbenzylamine, N-methyl-N-formylphenylethylamine, N-methyl-N-formyl-1-naphthylmethylamine, N-formyl fluoxetine, N-formylbenzylamine, N-formylphenethylamine, N-formylphenylpropylamine, N-formyl-alpha-phenethylamine, N-formyldodecylamine, 2-formamido-1-phenethyl alcohol, 1-formamidoindane, N-formyl-3, 4-dimethoxyphenethylamine. According to the technical scheme, under the catalytic action of the cobalt salt, the formamide compound has better formylation efficiency on primary amine and is interesting to have higher formylation efficiency on secondary amine.
In a preferred embodiment, the cobalt salt includes at least one of cobalt acetate, cobalt chloride, cobalt (II) acetylacetonate, cobalt (III) acetylacetonate, cobalt naphthenate, and cobalt sulfate. Most preferably cobalt acetate which is not only cheap but also has better catalytic activity compared with other cobalt salts and can obtain higher yield.
In a preferable scheme, the formamide compound is at least one of DMF, formamide, N-methylformamide and N-ethylformamide; from the economical viewpoint, DMF is more preferable as the formamide compound.
In a preferred scheme, the reaction temperature is 110-150 ℃ and the reaction time is 1-18 hours. In a further preferred scheme, the reaction temperature is 140-150 ℃, and the reaction time is 1-3 hours. Too high a reaction temperature will increase the side reaction products correspondingly, while lower a temperature will decrease the substrate conversion. Likewise, longer reaction times may result in a corresponding increase in side reaction products, while shorter reaction times may result in a decrease in substrate conversion. The best reaction effect can be achieved within the preferable reaction time and temperature range.
In a preferable scheme, the concentration of the amine compound in the formamide compound is 0.1-0.3 mol/L. In a further preferable scheme, the concentration of the amine compound in the formamide compound is 0.15-0.25 mol/L
in a preferable scheme, the cobalt salt accounts for 1-20% of the molar weight of the amine compound.
in a preferable scheme, the amine compound shown in the formula 1 reacts with DMF (dimethyl formamide) at 140-150 ℃ for 1-3 hours in the presence of a cobalt acetate catalyst to obtain the formamide derivative shown in the formula 2.
In a more preferable embodiment, the concentration of the amine compound in DMF is 0.15-0.25 mol/L.
In a more preferable scheme, the cobalt acetate accounts for 10-15% of the molar weight of the amine compound.
The reaction equation in the synthesis of formamide derivatives of the invention is as follows, and the catalyst is cobalt acetate (cobalt acetate tetrahydrate), and the acylating agent is DMF.
based on a large number of experimental summaries and with reference to previous literature reports, the present invention proposes the following rational reaction mechanism. Substituted amine and DMF are taken as raw materials, cobalt acetate tetrahydrate is taken as a catalyst, and the specific description is given. Firstly, coordinating a catalyst cobalt acetate and DMF to obtain an active species A; then substituted amine is used as nucleophilic reagent to attack carbonyl of active species A, and intermediate B is obtained. Subsequently, the intermediate disintegrates to give intermediate C. And performing ligand exchange on the intermediate C and DMF to obtain a final product D and DMF coordinated cobalt acetate.
In the technical scheme, the substituted amine and cobalt catalyst is dissolved in DMF (dimethyl formamide), the solution is placed into an oil bath kettle with a set temperature under the protection of argon, the reaction is carried out under the condition of sealing by magnetic stirring, after the reaction is carried out for a set time, a reaction tube is cooled, then 15mL of water is added for dilution, and the solution is extracted by ethyl acetate for 3 times, 15mL each time; the extracts were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and washed with petroleum ether: and (3) carrying out column chromatography on the crude product by using ethyl acetate (0-1: 3) as an eluent to obtain a pure product.
The synthesis method of the formamide derivative comprises the following steps:
according to the formula of substituted amine: weighing raw materials according to the molar ratio of 1:0.15 of cobalt acetate tetrahydrate (taking substituted amine as a reference); dissolving the substances in 1 ml of DMF, and stirring and reacting for 3 hours at 150 ℃ under the protection of inert gas; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the extracts were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and washed with petroleum ether: and (3) carrying out column chromatography on the crude product by using ethyl acetate (0-1: 3) as an eluent to obtain a pure product.
Compared with the prior art, the technical scheme of the invention has the following advantages and effects:
1) The technical scheme of the invention firstly uses cobalt salt as a catalyst for formylation reaction of formyl compounds and amine compounds to obtain higher yield which can reach 99 percent.
2) The technical scheme of the invention adopts cobalt salt as the catalyst, and has the following advantages compared with the existing catalyst: low cost, safety, no toxicity, high catalytic efficiency, no use of noble metal catalyst and toxic catalyst, and high yield.
3) The technical scheme of the invention realizes one-step synthesis of the formamide derivative under mild conditions, has the advantages of cheap and easily-obtained raw materials, acylation reagent and catalyst, high yield, simple reaction steps, low cost, high reaction selectivity, simple operation and the like, and overcomes the defects of high toxicity of the reaction reagent, expensive catalyst, high cost of the synthesis method, more reaction steps, more byproducts and the like in the prior art.
Drawings
FIG. 1 shows the product obtained in example 11H NMR chart;
FIG. 2 shows the product obtained in example 113C NMR chart;
FIG. 3 shows the product obtained in example 71H NMR chart;
FIG. 4 shows the product obtained in example 713C NMR chart.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples and the accompanying drawings. The procedures, conditions, reagents, test methods and the like for carrying out the present invention are general and common general knowledge in the art, and the present invention is not particularly limited, except for those specifically mentioned below.
Example 1
Tetrahydroisoquinoline (26.4mg,0.2mmol), cobalt acetate tetrahydrate (7.5mg,0.03mmol) and a stirrer were put into a reaction tube, and after inert gas was replaced, 1 ml of DMF was added, and the reaction tube was sealed. Will reactPlacing the tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) performing column chromatography on the crude product by using petroleum ether (1: 3) as an eluent to obtain a pure product. Yellow oil, yield 99%.1H NMR(400MHz,CDCl3) δ 8.23 (minor isomer, s,0.36H),8.17 (major isomer, s,0.62H), 7.21-7.08 (m,4H),4.67 (major isomer, 1.29H),4.52 (minor isomer, 0.76H),3.76 (minor isomer, t, J ═ 6.2Hz,0.76H),3.63 (major isomer, t, J ═ 5.8Hz,1.29H), 2.90-2.84 (m, 2H);13C NMR(100MHz,CDCl3) δ 161.62 (major isomer), 161.11 (minor isomer), 134.28 (minor isomer), 133.46 (major isomer), 132.15 (minor isomer), 131.62 (major isomer), 129.08 (minor isomer), 128.84 (major isomer), 126.98,126.61-126.39 (m),125.81,47.19 (minor isomer), 43.12 (major isomer), 42.17 (major isomer), 37.87 (minor isomer), 29.59 (major isomer), 27.81 (minor isomer); IR (near) 3151,3025,2931,2862,1672,1584,1498,1439,1400,1343,1318,1282,1228,1197,1164,1109,1049,930,882,814,751,710,675,606,477cm-1；HRMS(ESI)m/z calcd for C10H11NNaO 184.07329,found[M+Na]+184.07325。
Example 2
6-methoxy four hydrogen isoquinoline hydrochloride (39.9mg,0.2mmol), four hydrated cobalt acetate (7.5mg,0.03mmol), and a particle of stirring in the reaction tube, replacement of inert gas, adding 1 ml DMF, sealing the reaction tube. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) performing column chromatography on the crude product by using petroleum ether (1: 3) as an eluent to obtain a pure product. Yellow solid, m.p. 63-64 deg.C, 99% yield.1H NMR(400MHz,CDCl3) Δ 8.24 (minor isomer, s,0.38H),8.19 (major isomer)S,0.60H), 7.06-7.01 (m,1H), 6.80-6.76 (m,1H),6.67(d, J ═ 10.0Hz,1H),4.63 (major isomer, s,1.29H),4.49 (minor isomer, s,0.80H), 3.79-3.75 (m,3.79H),3.63 (major isomer, t, J ═ 5.8Hz,1.31H), 2.90-2.83 (m, 2H);13C NMR(100MHz,CDCl3) δ 161.70 (major isomer), 161.25 (minor isomer), 158.56 (minor isomer), 158.22 (major isomer), 135.76 (minor isomer), 134.83 (major isomer), 127.71 (major isomer), 126.95 (minor isomer), 124.43 (minor isomer), 123.89 (major isomer), 113.80 (minor isomer), 113.61 (major isomer), 113.09 (major isomer), 112.87 (minor isomer), 55.35(s),46.91 (minor isomer), 43.23 (major isomer), 41.89 (major isomer), 37.94 (minor isomer), 30.05 (major isomer), 28.31 (minor isomer); IR (near) 3140,1672,1612,1508,1402,1312,1277,1262,1241,1119,1036,529cm-1；HRMS(ESI)m/z calcd for C12H14NO4 236.09173,found[M+HCO2H-H]-236.09208。
Example 3
7-Bromometrahydroisoquinoline hydrochloride (49.7mg,0.2mmol), four hydrated cobalt acetate (7.5mg,0.03mmol), and a particle of stirring in the reaction tube, replacement of inert gas, adding 1 ml DMF, sealing the reaction tube. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) performing column chromatography on the crude product by using petroleum ether (1: 3) as an eluent to obtain a pure product. Yellow solid, mp 58-60 deg.C, 99% yield.1H NMR(400MHz,CDCl3) δ 8.24 (minor isomer, s,0.36H),8.19 (major isomer, s,0.63H),7.30(dd, J ═ 21.4,8.8Hz,2H),7.02(t, J ═ 8.8Hz,1H),4.65 (major isomer, s,1.32H),4.52 (minor isomer, s,0.74H),3.78 (minor isomer, t, J ═ 6.2Hz,0.76H),3.65 (major isomer, t, J ═ 5.8Hz,1.36H),2.86 (major isomer, t, J ═ 5.8Hz,1.34H),2.82 (minor isomer, t, J ═ 6.0Hz, 0.76H);13C NMR(100MHz,CDCl3) Delta 161.74 (major isomer)) 161.19 (minor isomer), 134.33 (minor isomer), 133.95 (major isomer), 133.43 (minor isomer), 132.57 (major isomer), 130.94 (minor isomer), 130.65 (major isomer), 130.26 (minor isomer), 129.86 (major isomer), 129.51 (major isomer), 128.87 (minor isomer), 120.35 (major isomer), 120.03 (minor isomer), 46.94 (minor isomer), 43.05 (major isomer), 41.91 (major isomer), 37.81 (minor isomer), 29.33 (major isomer), 27.53 (minor isomer); IR (near) 3140,1672,1402,1191,1157,1116,1075,1051,932,829,531cm-1；HRMS(ESI)m/z calcd for C10H14BrN2 257.0284,found[M+NH4]+257.02746。
Example 4
7-Nitro four hydrogen isoquinoline (35.6mg,0.2mmol), four hydrated cobalt acetate (7.5mg,0.03mmol), and a particle of stirring in the reaction tube, after replacing inert gas, adding 1 ml DMF, sealing the reaction tube. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) performing column chromatography on the crude product by using petroleum ether (1: 3) as an eluent to obtain a pure product. Brown oil, 75% yield.1H NMR(400MHz,CDCl3) δ 8.28 (minor isomer, s,0.38H)8.22 (major isomer, s,0.62H), 8.07-8.02 (m,2H),7.32(t, J ═ 9.0Hz,1H),4.77 (major isomer, s,1.26H),4.64 (minor isomer, s,0.72H),3.84 (major isomer, t, J ═ 6.0Hz,0.72H),3.71 (major isomer, t, J ═ 6.0Hz,1.26H),3.01 (major isomer, t, J ═ 6.0Hz,1.27H),2.97 (minor isomer, t, J ═ 6.0Hz, 0.71H);13C NMR(100MHz,CDCl3) δ 161.67 (major isomer), 161.15 (minor isomer), 146.91 (major isomer), 146.63 (minor isomer), 142.28 (minor isomer), 141.25 (major isomer), 133.85 (minor isomer), 133.59 (major isomer), 130.46 (minor isomer), 130.19 (major isomer), 122.22 (minor isomer), 122.03 (major isomer), 121.78 (major isomer), 121.36 (minor isomer), 47.14 (minor isomer)isomer), 42.57 (major isomer), 42.14 (major isomer), 37.37 (minor isomer), 30.02 (major isomer), 28.30 (minor isomer); IR (near) 3129,1672,1525,1402,1347,1088,855,744,531cm-1；HRMS(ESI)m/z calcd for C12H13N2O5265.0819,
found[M+CH3CO2H-H]-265.08243。
Example 5
Isoindoline hydrochloride (31.1mg,0.2mmol), cobalt acetate tetrahydrate (7.5mg,0.03mmol), and a stir bar were placed in a reaction tube, inert gas was replaced, 1 ml of DMF was added, and the reaction tube was sealed. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) performing column chromatography on the crude product by using petroleum ether (1: 3) as an eluent to obtain a pure product. Black oil, 84% yield.1H NMR(400MHz,CDCl3)δ8.43(s,1H),7.32–7.28(m,4H),4.90(s,2H),4.77(s,2H)；13C NMR(100MHz,CDCl3)δ161.62,136.05,135.39,128.12,127.81,123.35,122.94,51.59,49.98；IR(neat)3140,1668,1465,1402,1159,1092,747,608,531,416cm-1；HRMS(ESI)m/z calcd for C9H9ClNO 182.03672,found[M+Cl]－182.03682。
example 6
4,5,6, 7-tetrahydrothieno [3.2-c ]]Pyridine hydrochloride (35.1mg,0.2mmol), cobalt acetate tetrahydrate (7.5mg,0.03mmol), and a stirring pellet were placed in a reaction tube, and after replacing inert gas, 1 ml of DMF was added, and the reaction tube was sealed. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) performing column chromatography on the crude product by using petroleum ether (1: 3) as an eluent to obtain a pure product. Yellow oil, yield 97%.1H NMR(400MHz,CDCl3) δ 8.25 (minor isomer, s,0.36H),8.21 (major isomer, s,0.60H),7.17(dd, J ═ 8.4,2.8Hz,1H),6.81(t, J ═ 4.4Hz,1H),4.61 (major isomer, s,1.30H),4.48 (minor isomer, s,0.76H),3.87 (minor isomer, t, J ═ 5.8Hz,0.77H),3.70 (major isomer, t, J ═ 5.8Hz,1.30H),2.94 (major isomer, t, J ═ 5.8Hz,1.27H),2.89 (minor isomer, t, J ═ 5.8Hz, 0.75H);13C NMR(100MHz,CDCl3) δ 161.88 (major isomer), 161.52 (minor isomer), 134.00 (minor isomer), 132.29 (major isomer), 130.92 (major isomer), 130.84 (minor isomer), 125.11 (major isomer), 124.44 (minor isomer), 123.95(s),45.89 (minor isomer), 43.82 (major isomer), 40.75 (major isomer), 38.08 (minor isomer), 25.97 (major isomer), 24.56 (minor isomer); IR (near) 3129,1705,1670,1433,1402,1314,1176,1043,1018,824,706,593,567cm-1；HRMS(ESI)m/z calcd for C8H13N2SO 185.07431,found[M+NH4]+185.07353。
Example 7
N-phenylpiperazine (32.4mg,0.2mmol), cobalt acetate tetrahydrate (7.5mg,0.03mmol) and a stirring pellet were placed in a reaction tube, and after inert gas was replaced, 1 ml of DMF was added and the reaction tube was sealed. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) carrying out column chromatography on the crude product by using petroleum ether (1: 2) as an eluent to obtain a pure product. Yellow solid, mp 86-87 deg.C, 91% yield.1H NMR(400MHz,CDCl3)δ8.08(s,1H),7.30–7.27(m,2H),6.94–6.90(m,3H),3.69(t,J＝5.2Hz,2H),3.51(t,J＝5.0Hz,2H),3.15(dt,J＝15.2,5.2Hz,4H)；13C NMR(100MHz,CDCl3)δ160.74,150.94,129.25,120.83,117.07,50.45,49.32,45.51,39.93；IR(neat)3131,1664,1402,1152,1115,529cm-1；HRMS(ESI)m/z calcd for C11H14N2KO229.07377,found[M+K]+229.07419。
Example 8
4-phenylpiperidine (32.2mg,0.2mmol), cobalt acetate tetrahydrate (7.5mg,0.03mmol) and a stirring rod were put into a reaction tube, and after replacing the inert gas, 1 ml of DMF was added and the reaction tube was sealed. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) performing column chromatography on the crude product by using petroleum ether (1: 3) as an eluent to obtain a pure product. Yellow solid, mp 98-99 deg.C, 93% yield.1H NMR(400MHz,CDCl3)δ8.07(s,1H),7.32(t,J＝7.4Hz,2H),7.25–7.18(m,3H),4.57(d,J＝13.6Hz,1H),3.73(d,J＝13.2Hz,1H),3.20(td,J＝12.9,2.6Hz,1H),2.82–2.68(m,2H),1.93(t,J＝15.8Hz,2H),1.68–1.55(m,2H)；13C NMR(100MHz,CDCl3)δ160.91,144.94,128.68,126.72,126.67,46.52,42.93,40.30,33.95,32.43；IR(neat)3140,1675,1653,1402,1170,1064,759,699,529cm-1；HRMS(ESI)m/z calcd for C12H15NNaO 212.10459,found[M+Na]+212.10475。
example 9
Cyclohexylimine (19.8mg,0.2mmol), cobalt acetate tetrahydrate (7.5mg,0.03mmol) and a stirring pellet were placed in a reaction tube, the inert gas was replaced, 1 ml of DMF was added, and the reaction tube was sealed. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) performing column chromatography on the crude product by using petroleum ether (1: 3) as an eluent to obtain a pure product. Yellow oil, 56% yield.1H NMR(400MHz,CDCl3)δ8.09(s,1H),3.48–3.37(m,4H),1.74(m,4H),1.59–1.58(m,4H)；13C NMR(100MHz,CDCl3)δ163.04,47.81,43.54,30.37,28.07,27.07,26.96；IR(neat)3137,2932,2857，1681,1428,1402,1299,1277,1260,1202,1157,1105,1003,971,910,885,811,751,654,531cm-1；HRMS(ESI)m/z calcd for C8H14NO3 172.09682,found[M+HCO2H-H]－172.09779。
Example 10
N-methylbenzylamine (24.2mg,0.2mmol), cobalt acetate tetrahydrate (7.5mg,0.03mmol) and a stirring bar were placed in a reaction tube, the inert gas was replaced, 1 ml of DMF was added, and the reaction tube was sealed. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) performing column chromatography on the crude product by using petroleum ether (1: 3) as an eluent to obtain a pure product. Yellow oil, yield 72%.1H NMR(400MHz,CDCl3) δ 8.29 (major isomer, s,0.58H),8.17 (minor isomer, s,0.42H), 7.40-7.20 (m,5H),4.53 (minor isomer, s,0.87H),4.40 (major isomer, s,1.17H),2.85 (minor isomer, s,1.29H),2.79 (major isomer, s, 1.72H);13C NMR(100MHz,CDCl3) δ 162.95 (major isomer), 162.79 (minor isomer), 136.07 (minor isomer), 135.80 (major isomer), 129.02 (major isomer), 128.81 (minor isomer), 128.36 (major isomer), 128.23 (minor isomer), 127.77 (minor isomer), 127.51 (major isomer), 53.64 (major isomer), 47.90 (minor isomer), 34.21 (minor isomer), 29.59 (major isomer); IR (near) 3122,1664,1402,1379,1140,1066,1081,705,529cm-1；HRMS(ESI)m/z calcd for C11H14NO3 208.09682,found[M+CH3CO2H-H]-208.09706。
example 11
N-ethylbenzylamine (27.0mg,0.2mmol), cobalt acetate tetrahydrate (7.5mg,0.03mmol), and a stirring rod were placed in a reaction tube, and after inert gas was replaced, 1 ml of DMF was added, and the reaction tube was sealed. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; combining the extracts, and adding anhydrous sulfuric acidSodium drying, filtering, concentrating the filtrate under reduced pressure, and adding ethyl acetate: and (3) performing column chromatography on the crude product by using petroleum ether (1: 3) as an eluent to obtain a pure product. Yellow oil, 58% yield.1H NMR(400MHz,CDCl3) δ 8.26 (minor isomer, s,0.49H),8.23 (major isomer, s,0.50H), 7.39-7.21 (m,5H),4.55 (major isomer, s,1.07H),4.40 (minor isomer, s,1.01H),3.29 (minor isomer, q, J ═ 7.2Hz,1.03H),3.21 (major isomer, q, J ═ 7.2Hz,1.05H),1.15 (major isomer, t, J ═ 7.2Hz,1.68H),1.07 (minor isomer, t, J ═ 7.2Hz, 1.50H);13C NMR(100MHz,CDCl3) δ 162.72,136.58 (major isomer), 136.28 (minor isomer), 128.95 (minor isomer), 128.75 (major isomer), 128.21 (major isomer), 128.15 (minor isomer), 127.64 (minor isomer), 127.57 (major isomer), 50.94 (minor isomer), 44.84 (major isomer), 41.58 (major isomer), 36.86 (minor isomer), 14.44 (major isomer), 12.30 (minor isomer); IR (near) 3140,1672,1497,1402,1109,1079,740,703,528cm-1；HRMS(ESI)m/z calcd for C12H16NO3 222.11247,found[M+CH3CO2H-H]-222.11189。
example 12
N-methyl-4-methoxybenzylamine (30.2mg,0.2mmol), cobalt acetate tetrahydrate (7.5mg,0.03mmol) and a stirring pellet were placed in a reaction tube, and after replacing the inert gas, 1 ml of DMF was added, and the reaction tube was sealed. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) carrying out column chromatography on the crude product by using petroleum ether (1: 2) as an eluent to obtain a pure product. Yellow oil, 96% yield.1H NMR(400MHz,CDCl3) δ 8.27 (major isomer, s,0.59H),8.12 (minor isomer, s,0.42H),7.19 (minor isomer, d, J ═ 8.4Hz,0.87H),7.13 (major isomer, d, J ═ 8.4Hz,1.18H),6.88(dd, J ═ 12.8,8.4Hz,2H),4.45 (minor isomer, s,0.87H),4.33 (major isomer, s,1.21H),3.81 (major isomer, s, d, J ═ 8.4Hz,0.87H)Isomer, s,1.77H),3.79 (minor isomer, s,1.27H),2.82 (minor isomer, s,1.33H),2.75 (major isomer, s, 1.77H);13C NMR(100MHz,CDCl3) δ 162.64 (major isomer), 162.54 (minor isomer), 159.46 (major isomer), 159.12 (minor isomer), 130.50,129.69 (minor isomer), 128.82 (major isomer), 128.15 (minor isomer), 127.64 (major isomer), 114.26 (major isomer), 114.05 (minor isomer), 113.67,55.35 (major isomer, d, J ═ 17.6Hz),53.00 (minor isomer), 47.14 (major isomer), 44.90 (minor isomer), 33.97 (minor isomer), 29.26 (major isomer); IR (near) 3140,1671,1612,1515,1402,1303,1249,1176,1079,1032,846,814,559,522cm-1；HRMS(ESI)m/z calcd for C10H17NO 197.12845,found[M+NH4]+197.13044。
Example 13
N-methyl-4-trifluoromethylbenzylamine (37.8mg,0.2mmol), cobalt acetate tetrahydrate (7.5mg,0.03mmol), and a stirring pellet were placed in a reaction tube, and after replacing the inert gas, 1 ml of DMF was added, and the reaction tube was sealed. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) carrying out column chromatography on the crude product by using petroleum ether (1: 2) as an eluent to obtain a pure product. Yellow oil, 83% yield.1H NMR(400MHz,CDCl3) δ 8.31 (minor isomer, s,0.48H),8.19 (major isomer, s,0.52H),7.63(dd, J ═ 18.2,8.2Hz,2.0H),7.36(dd, J ═ 12.6,8.2Hz,2H),4.59 (major isomer, s,1.07H),4.48 (minor isomer, s,0.96H),2.89 (major isomer, s,1.64H),2.80 (minor isomer, s, 1.42H);13C NMR(100MHz,CDCl3) δ 162.92 (minor isomer), 162.84 (major isomer), 140.19 (major isomer), 139.98 (minor isomer), 130.28 (major isomer, dd, J ═ 51.2,32.3Hz),128.49 (major isomer), 127.74 (minor isomer), 126.02 (minor isomer, q, J ═ 3.7Hz),125.78 (major isomer, q, J ═ 3.7Hz),125.46 (major isomer), 125.33 (minor isomer), 122.76 (major isomer), which is preferred for the treatment of cancerIsomers), 122.63 (minor isomer), 53.07 (minor isomer), 47.49 (major isomer), 34.30 (major isomer), 29.69 (minor isomer);19F NMR (377MHz, CDCl3) delta-62.53 (major isomer, s), -62.58 (minor isomer, s); IR (near) 3140,2361,2343,1675,1621,1402,1327,1165,1113,1068,1019,848,818,527cm-1；HRMS(ESI)m/z calcd for C10H12FN2O235.10527,found[M+NH4]+235.10666。
Example 14
N-methylphenylethylamine (27.0mg,0.2mmol), cobalt acetate tetrahydrate (7.5mg,0.03mmol) and a stirring bar were placed in a reaction tube, the inert gas was replaced, 1 ml of DMF was added, and the reaction tube was sealed. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) performing column chromatography on the crude product by using petroleum ether (1: 3) as an eluent to obtain a pure product. Yellow oil, yield 95%.1H NMR(400MHz,CDCl3) δ 8.01 (minor isomer, s,0.37H),7.80 (major isomer, s,0.62H), 7.33-7.22 (m,4H),7.14(d, J ═ 7.2Hz,1H),3.56 (minor isomer, t, J ═ 7.6Hz,0.8H),3.47 (major isomer, t, J ═ 7.0Hz 1.25H), 2.90-2.82 (m, 5H);13C NMR(100MHz,CDCl3) δ 162.74 (major isomer), 162.57 (minor isomer), 138.64 (minor isomer), 137.78 (major isomer), 128.85 (major isomer), 128.82 (minor isomer), 128.76 (major isomer), 128.62 (minor isomer), 126.90 (major isomer), 126.56 (minor isomer), 51.35 (major isomer), 46.08 (minor isomer), 35.17 (minor isomer), 34.87 (major isomer), 33.26 (minor isomer), 29.83 (minor isomer); IR (near) 3140,1666,1402,1152,529cm-1；HRMS(ESI)m/z calcd for C10H13NO164.10699,found[M+H]+164.10706。
example 15
n-methyl-1-naphthylmethylamine (34.2mg,0.2mmol), cobalt acetate tetrahydrate (7.5mg,0.03mmol), andThe particles were placed in a reaction tube, inert gas was replaced, 1 ml of DMF was added, and the reaction tube was sealed. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) carrying out column chromatography on the crude product by using petroleum ether (1: 2) as an eluent to obtain a pure product. Yellow oil, yield 95%.1H NMR(400MHz,CDCl3) δ 8.38 (minor isomer, s,0.4H),8.18 (major isomer, s,0.61H),8.10(d, J ═ 8.0Hz,0.61H), 7.91-7.82 (m,2.46H), 7.55-7.30 (m,4H),4.98 (major isomer, s,1.20H),4.87 (minor isomer, s,0.77H),2.85 (minor isomer, s,1.20H),2.74 (major isomer, s, 1.78H);13C NMR(100MHz,CDCl3) δ 163.33 (minor isomer), 162.40 (major isomer), 133.89,131.58,131.34 (major isomer), 131.26 (minor isomer), 131.12 (minor isomer), 131.04 (major isomer), 129.15 (minor isomer), 128.95 (major isomer), 128.89 (minor isomer), 128.74 (major isomer), 127.78 (minor isomer), 126.78 (minor isomer), 126.20 (major isomer), 125.59 (minor isomer), 125.17 (minor isomer), 123.90 (major isomer), 122.36 (minor isomer), 51.07 (minor isomer), 45.92 (major isomer), 34.09 (major isomer), 30.08 (minor isomer); IR (near) 3140,1672,1510,1402,1258,1161,1081,803,779,529cm-1；HRMS(ESI)m/z calcd for C13H14NO 200.10699,found[M+H]+200.10687。
Example 16
Fluoxetine hydrochloride (66.9mg,0.2mmol), cobalt acetate tetrahydrate (7.5mg,0.03mmol) and a stir bar were placed in a reaction tube, the inert gas was replaced, 1 ml of DMF was added and the reaction tube was sealed. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: petroleum ether 1:2 (containing 1% triethylamine) as eluent for crude productThe product is subjected to column chromatography to obtain a pure product. Yellow oil, 84% yield.1H NMR(400MHz,CDCl3) δ 8.03 (minor isomer, s,0.41H),7.99 (major isomer, s,0.59H),7.43(d, J ═ 8.8Hz,2H), 7.38-7.26 (m,5H), 6.90-6.88 (m,2H),5.20 (minor isomer, dd, J ═ 8.8,4.4Hz,0.43H),5.14 (major isomer, dd, J ═ 8.8,4.0Hz,0.58H), 3.60-3.53 (major isomer, m,1.43H), 3.42-3.35 (minor isomer, m,0.61H),2.94 (minor isomer, s,1.26H),2.90 (major isomer, s,1.75H), 2.27-2.17 (m,1H), 2.15-2.04 (m, 1H);13C NMR(100MHz,CDCl3) δ 162.90 (major isomer), 162.75 (minor isomer), 160.29 (minor isomer), 159.98 (major isomer), 140.51 (minor isomer), 139.98 (major isomer), 129.16 (major isomer), 128.99 (minor isomer), 128.39 (major isomer), 128.16 (minor isomer), 127.07-126.84 (m),125.79 (minor isomer), 125.70 (major isomer), 123.49-122.82 (m),115.81 (minor isomer), 115.72 (major isomer), 78.24 (minor isomer), 77.01 (major isomer), 46.10 (major isomer), 41.63 (minor isomer), 37.01 (major isomer), 35.94 (minor isomer), 35.00 (minor isomer), 29.68 (major isomer);19F NMR (377MHz, CDCl3) delta-61.52 (minor isomer, s); -61.59 (major isomer, s); IR (near) 3140,1675,1616,1519,1329,1251,1161,1113,1068,837,703,527cm-1；HRMS(ESI)m/z calcd for C18H18F3NNaO2 360.11818,found[M+Na]+360.11776。
Example 17
Benzylamine (21.4mg,0.2mmol), cobalt acetate tetrahydrate (7.5mg,0.03mmol), and a stirring pellet were placed in a reaction tube, and after replacing inert gas, 1 ml of DMF was added, and the reaction tube was sealed. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) performing column chromatography on the crude product by using petroleum ether (1: 3) as an eluent to obtain a pure product. Yellow solid, mp 54-58 deg.C, 86% yield.1H NMR(400MHz,CDCl3) δ 8.24 (major isomer, s,0.84H),8.16 (minor isomer, d, J ═ 12Hz,0.15H), 7.34-7.24 (m,5H),6.01(br s,1H),4.47 (major isomer, d, J ═ 6.0Hz,1.72H),4.40 (minor isomer, d, J ═ 6.4Hz, 0.34H);13C NMR(100MHz,CDCl3) δ 164.84 (minor isomer), 161.19 (major isomer), 137.63 (major isomer), 137.54 (minor isomer), 129.03 (minor isomer), 128.88 (major isomer), 128.08 (minor isomer), 127.90 (major isomer), 127.80 (major isomer), 127.06 (minor isomer r),45.76 (minor isomer), 42.26 (major isomer); IR (near) 3140,1666,1402,699,526cm-1；HRMS(ESI)m/z calcd for C8H10NO 136.07569,found[M+H]+136.07468。
Example 18
Phenethylamine (24.2mg,0.2mmol), cobalt acetate tetrahydrate (7.5mg,0.03mmol) and a stirrer were placed in a reaction tube, inert gas was replaced, 1 ml of DMF was added, and the reaction tube was sealed. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) carrying out column chromatography on the crude product by using petroleum ether (1: 2) as an eluent to obtain a pure product. Yellow oil, yield 97%.1H NMR(400MHz,CDCl3) δ 8.10 (major isomer, s,0.84H),7.88 (minor isomer, d, J ═ 12Hz,0.16H), 7.32-7.19 (m,5H),5.83(br s,1H), 3.59-3.46 (m,2H), 2.86-2.81 (m, 2H);13C NMR(100MHz,CDCl3) δ 164.62 (minor isomer), 161.35 (major isomer), 138.57 (major isomer), 137.66 (minor isomer), 128.94-128.78 (m),126.99 (minor isomer), 126.73 (major isomer), 43.24 (major isomer), 39.26 (major isomer), 37.79 (minor isomer), 35.55 (major isomer); IR (near) 3140,1670,1402,1154,689,527cm-1；HRMS(ESI)m/z calcd for C9H11NNaO172.07329,found[M+Na]+172.07409。
Example 19
Amphetamine (27.0mg,0.2mmol), cobalt acetate tetrahydrate (7.5mg,0.03mmol) and a stirring pellet were placed in a reaction tube, and after inert gas was replaced, 1 ml of DMF was added and the reaction tube was sealed. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) performing column chromatography on the crude product by using petroleum ether (1: 3) as an eluent to obtain a pure product. Yellow oil, yield 98%.1H NMR(400MHz,CDCl3) δ 8.13 (major isomer, s,0.81H),8.00 (minor isomer, d, J ═ 12Hz,0.19H), 7.32-7.16 (m,5H),6.04(br s,1H),3.31 (major isomer, q, J ═ 6.8Hz,1.63H),3.20 (minor isomer, q, J ═ 6.8Hz,0.37H), 2.68-2.63 (m,2H), 1.89-1.81 (m, 2H);13C NMR(100MHz,CDCl3) δ 164.91 (minor isomer), 161.48 (major isomer), 141.25 (major isomer), 140.64 (minor isomer), 128.67 (minor isomer), 128.55 (major isomer), 128.42 (major isomer), 126.31 (minor isomer), 126.13 (major isomer), 41.15 (minor isomer), 37.83 (major isomer), 33.20 (major isomer), 32.59 (minor isomer), 32.52 (minor isomer), 31.16 (major isomer); IR (near) 3122,1666,1402,1154,1113,749,701,529cm-1；HRMS(ESI)m/z calcd for C10H13NNaO 186.08894,found[M+Na]+186.08968。
Example 20
Alpha-phenylethylamine (27.0mg,0.2mmol), cobalt acetate tetrahydrate (7.5mg,0.03mmol) and a stirring bar were placed in a reaction tube, the inert gas was replaced, 1 ml of DMF was added, and the reaction tube was sealed. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) carrying out column chromatography on the crude product by using petroleum ether (1: 2) as an eluent to obtain a pure product. Yellow oil, yield 87%.1H NMR(400MHz,CDCl3)δ8.11(s,1H),7.38–7.25(m,5H),6.33(brs,1H), 5.21-5.14 (m,0.83H), 4.70-4.63 (m,0.19H),1.55 (minor isomer, d, J ═ 6.8Hz,0.56H),1.49 (major isomer, J ═ 6.8Hz, 2.54H);13C NMR(100MHz,CDCl3) δ 160.49,142.67,128.99 (minor isomer), 128.79 (major isomer), 127.82 (minor isomer), 127.58 (major isomer), 126.20 (major isomer), 125.85 (minor isomer), 51.79 (minor isomer), 47.66 (major isomer), 23.65 (minor isomer), 21.84 (major isomer); IR (near) 3100,1662,1534,1497,1402,1238,1118,762,698,609,537cm-1；HRMS(ESI)m/z calcd for C9H12NO 150.09134,found[M+H]+150.09122。
Example 21
primary dodecylamine (37.1mg,0.2mmol), cobalt acetate tetrahydrate (7.5mg,0.03mmol) and a stirring pellet were placed in a reaction tube, inert gas was replaced, 1 ml of DMF was added, and the reaction tube was sealed. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) carrying out column chromatography on the crude product by using petroleum ether (1: 2) as an eluent to obtain a pure product. Grey solid, m.p. 33-35 ℃, 95% yield.1H NMR(400MHz,CDCl3)δ8.16–8.03(m,1H),5.64(br s,1H),3.32–3.19(m,2H),1.54–1.49(m,2H),1.30–1.26(m,18H),0.88(t,J＝6.8Hz,3H)；13C NMR(100MHz,CDCl3) δ 164.82 (minor isomer), 161.17 (major isomer), 41.93 (minor isomer), 38.32 (major isomer), 32.01 (major isomer), 31.33 (minor isomer), 29.72-29.24 (m),26.95 (major isomer), 26.49 (minor isomer), 22.79, 14.22; IR (near) 3122,1670,1401,1150,1113,529cm-1；HRMS(ESI)m/z calcd for C13H27NKO 252.17242,found[M+K]+252.17239。
Example 22
2-amino-1-phenylethyl alcohol (27.4mg,0.2mmol), cobalt acetate tetrahydrate (7.5mg,0.03mmol) and a stirring bar were put into a reaction tube, and after replacing inert gas, added1 ml of DMF, the reaction tube was sealed. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) carrying out column chromatography on the crude product by using petroleum ether (1: 2) as an eluent to obtain a pure product. Yellow oil, 58% yield.1H NMR(400MHz,CDCl3) δ 8.09 (major isomer, s,0.82H),7.87 (minor isomer, d, J ═ 12Hz,0.17H), 7.35-7.27 (m,5H),6.36(s,1H),4.80 (major isomer, dd, J ═ 8.0,4.8Hz,0.84H),4.71 (minor isomer, dd, J ═ 7.4,4.0Hz,0.18H), 3.73-3.67 (major isomer, m,1.79H), 3.45-3.38 (minor isomer, m,0.19H), 3.34-3.27 (m, 1H);13C NMR(100MHz,CDCl3) δ 165.60 (minor isomer), 162.33 (major isomer), 141.52 (major isomer), 140.97 (minor isomer), 128.84 (minor isomer), 128.70 (major isomer), 128.35 (minor isomer), 128.13 (major isomer), 125.99 (minor isomer), 125.94 (major isomer), 73.50 (minor isomer), 73.04 (major isomer), 49.39 (minor isomer), 45.87 (major isomer); IR (near) 3140,1670,1523,1495,1402,1239,1198,1096,915,755,703,533cm-1；HRMS(ESI)m/z calcd for C9H12NO2 166.08626,found[M+H]+166.08598。
Example 23
1-aminoindan (26.6mg,0.2mmol), cobalt acetate tetrahydrate (7.5mg,0.03mmol) and a stir bar were placed in a reaction tube, the inert gas was replaced, 1 ml of DMF was added, and the reaction tube was sealed. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) carrying out column chromatography on the crude product by using petroleum ether (1: 2) as an eluent to obtain a pure product. Yellow solid, m.p. 109-110 deg.C, 80% yield.1H NMR(400MHz,CDCl3) Δ 8.24 (major isomer, s,0.89H),8.20 (minor isomer, s,0.10H), 7.29-7.19(m,4H),5.99(br s,1H),5.54 (major isomer, q, J ═ 8.0Hz,0.80H),4.98 (minor isomer, q, J ═ 8.0Hz,0.20H), 3.03-2.95 (m,1H), 2.91-2.83 (m,1H), 2.64-2.54 (m,1H), 1.92-1.78 (m, 1H);13C NMR(100MHz,CDCl3) δ 164.00 (minor isomer), 161.04 (major isomer), 143.51 (major isomer), 142.64 (minor isomer), 128.54 (minor isomer), 128.23 (major isomer), 127.11 (minor isomer), 126.95 (major isomer), 125.13 (minor isomer), 124.96 (major isomer), 124.07 (major isomer), 123.83 (minor isomer), 57.51 (minor isomer), 53.40 (major isomer), 35.21 (minor isomer), 34.05 (major isomer), 30.32 (major isomer), 30.00 (minor isomer); IR (near) 3118,1640,1547,1402,1154,1115,751,529cm-1；HRMS(ESI)m/z calcd for C12H14NO3 220.09682,found[M+CH3CO2H-H]－220.0971。
Example 24
3, 4-Dimethoxyphenethylamine (36.2mg,0.2mmol), cobalt acetate tetrahydrate (7.5mg,0.03mmol) and a stirrer were placed in a reaction tube, and after inert gas was replaced, 1 ml of DMF was added and the reaction tube was sealed. Placing the reaction tube in a 150 ℃ oil bath reaction kettle, and stirring for reaction for 3 hours; after cooling to room temperature, diluted with 15mL of water and extracted 3 times with 15mL of ethyl acetate each time; the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and extracted with ethyl acetate: and (3) carrying out column chromatography on the crude product by using petroleum ether (1: 2) as an eluent to obtain a pure product. Yellow oil, yield 72%.1H NMR(400MHz,CDCl3) δ 8.12 (major isomer, s,0.84H),7.90 (minor isomer, d, J ═ 12Hz,0.15H), 6.82-6.68 (m,3H),5.96(br s,1H),3.87 (major isomer, 3.64H),3.86 (minor isomer, s,2.35H),3.54 (major isomer, q, J ═ 6.4Hz,1.70H),3.45 (minor isomer, q, J ═ 6.4Hz,0.39H), 2.81-2.74 (m, 2H);13C NMR(100MHz,CDCl3) δ 164.61 (minor isomer), 161.34 (major isomer), 149.08 (minor isomer), 149.00 (major isomer), 147.88 (minor isomer), 147.70 (major isomer), 131.00 (major isomer), 130.13 (minor isomer), 120.91 (minor isomer)Isomers), 120.67 (major isomer), 111.91 (minor isomer), 111.81 (major isomer), 111.42 (minor isomer), 111.31 (major isomer); IR (near) 3140,3006,2941,2838,1668,1610,1593,1519,1467,1400,1265,1238,1195,1159,1142,1029,937,859,811,810,766,632cm-1；HRMS(ESI)m/z calcd for C10H16NO3210.11247,found[M+H]+210.11217。
Control test group 1-25:
Adding tetrahydroisoquinoline (0.2mmol), catalyst and acylating reagent (1.0mL) into a 10mL reaction vessel, introducing argon for protection, heating for reaction, and adopting the product1H NMR quantitative analysis; the specific reaction conditions of each control test group are shown in Table 1.
TABLE 1 control group experiment for the formylation of tetrahydroisoquinolines
As can be seen from the above table, a variety of cobalt catalysts, including cobalt chloride, cobalt sulfate, cobalt (II) acetylacetonate, cobalt (III) acetylacetonate, cobalt naphthenate, cobalt acetate tetrahydrate all have a good catalytic effect on the formylation reaction, but cobalt acetate tetrahydrate is the most preferred.
As can be seen from the above table, when the dosage of the catalyst cobalt acetate tetrahydrate is 1 mol%, the reaction can be completed with higher yield, the dosage of the catalyst is increased, the yield is correspondingly increased, the effect is best when the dosage of the cobalt acetate tetrahydrate is 15 mol%, and the influence on the reaction is little when the dosage exceeds the dosage.
As can be seen from the above table, the reaction temperature has a large influence on the formylation reaction, but it is preferable to carry out the reaction at 150 ℃.
As can be seen from the above table, the reaction can be smoothly carried out within 1 to 18 hours for tetrahydroisoquinoline. The formamide derivative can be obtained in quantitative yield after the reaction time is 3 hours, and the reaction time is further prolonged, so that the yield is hardly influenced.
As can be seen from the above table, DMF, formamide, N-methylformamide, N-ethylformamide, etc. can be used as the formyl group source to obtain the product in high yield, and DMF is preferred from the viewpoint of economy.
As can be seen from the above table, the formylation reaction yields were low without catalyst addition.
Control test group 26:
Tetrahydroisoquinoline (1 g, 7.51mmol), cobalt acetate tetrahydrate (0.24mmol,3.2 mol%) and DMF (8mL) were charged into a 25mL reaction vessel, and reacted at 150 ℃ for 24 hours under protection of argon. After the reaction, DMF was distilled off under reduced pressure, and the pure product was obtained in an amount of 1.04 g by column chromatography with a yield of 86%.
Therefore, in the amount-expanding reaction, the formylation can still obtain high yield when the dosage of the catalyst cobalt acetate tetrahydrate is reduced to only 3.2 mol%, and the method has good industrial application prospect.

Claims (9)

1. a method for synthesizing formamide derivatives by cobalt-catalyzed formylation reaction is characterized in that: the amine compound and the formamide compound react in one pot under the catalysis of cobalt salt to generate a formamide derivative;
The amine compound is tetrahydroisoquinoline, 6-methoxy tetrahydroisoquinoline, 7-bromo tetrahydroisoquinoline, 7-nitro tetrahydroisoquinoline, isoindoline, 4,5,6, 7-tetrahydrothieno [3.2-c ] pyridine, N-phenylpiperazine, 4-phenylpiperidine, cyclohexylimine, N-methylbenzylamine, N-ethylbenzylamine, N-methyl-4-methoxybenzylamine, n-methyl-4-trifluoromethylbenzylamine, N-methylphenylethylamine, N-methyl-1-naphthylmethylamine, fluoxetine, benzylamine, phenethylamine, amphetamine, alpha-phenethylamine, dodecylprimary amine, 2-amino-1-phenylethyl alcohol, 1-aminoindan or 3, 4-dimethoxyphenethylamine;
The formamide derivatives are N-formyl tetrahydroisoquinoline, N-formyl-6-methoxy tetrahydroisoquinoline, N-formyl-7-bromo tetrahydroisoquinoline, N-formyl-7-nitro tetrahydroisoquinoline, N-formyl isoindoline, N-formyl-4, 5,6, 7-tetrahydrothieno [3.2-c ] pyridine, N-formyl-N' -phenylpiperazine, N-formyl-4-phenylpiperidine, N-formyl cyclohexylimine, N-methyl-N-formyl benzylamine, N-ethyl-N-formyl benzylamine, N-methyl-N-formyl-4-methoxybenzylamine, N-methyl-N-formyl-4-trifluoromethylbenzylamine, N-methyl-N-formylphenylethylamine, N-methyl-N-formyl-1-naphthylmethylamine, N-formylfluoxetine, N-formylbenzylamine, N-formylphenethylamine, N-formylamphetamine, N-formyl-alpha-phenylethylamine, N-formyldodecylamine, 2-carboxamido-1-phenylethyl alcohol, 1-carboxamidoindan or N-formyl-3, 4-dimethoxyphenethylamine.
2. The process of claim 1 for the synthesis of carboxamide derivatives by cobalt catalysed formylation reaction characterised in that: the cobalt salt comprises at least one of cobalt acetate, cobalt chloride, cobalt (II) acetylacetonate, cobalt (III) acetylacetonate, cobalt naphthenate and cobalt sulfate.
3. The process of claim 1 for the synthesis of carboxamide derivatives by cobalt catalysed formylation reaction characterised in that: the formamide compound is at least one of DMF, formamide, N-methylformamide and N-ethylformamide.
4. The process of claim 1 for the synthesis of carboxamide derivatives by cobalt catalysed formylation reaction characterised in that: the reaction temperature is 110-150 ℃, and the reaction time is 1-18 hours.
5. The process of claim 1 for the synthesis of carboxamide derivatives by cobalt catalysed formylation reaction characterised in that: the concentration of the amine compound in the formamide compound is 0.1-0.3 mol/L.
6. The process of claim 1 for the synthesis of carboxamide derivatives by cobalt catalysed formylation reaction characterised in that: the dosage of the cobalt salt is 1-20% of the molar weight of the amine compound.
7. The method for synthesizing formamide derivatives through cobalt-catalyzed formylation according to any one of claims 1 to 6, wherein the method comprises the following steps: and (3) reacting the amine compound with DMF (dimethyl formamide) at 140-150 ℃ for 1-3 hours in the presence of a cobalt acetate catalyst to obtain the formamide derivative.
8. The process of claim 7 for the synthesis of carboxamide derivatives by cobalt catalysed formylation reaction characterised in that: the concentration of the amine compound in DMF is 0.15-0.25 mol/L.
9. The process of claim 7 for the synthesis of carboxamide derivatives by cobalt catalysed formylation reaction characterised in that: the dosage of the cobalt acetate is 10-15% of the molar weight of the amine compound.
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