CN111018800B - N2Aryl-substituted-1, 2, 4-triazine derivative and synthesis and application thereof - Google Patents
N2Aryl-substituted-1, 2, 4-triazine derivative and synthesis and application thereof Download PDFInfo
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- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a method for preparing N2Aryl substituted-1, 2, 4-triazine derivatives and synthesis methods thereof. Using S, N-substituted internal olefin and aryl diazonium salt as initial raw material, copper salt as catalyst, in the presence of alkali and oxidant making cyclization in organic solvent to obtain N2Aryl-substituted-1, 2, 4-triazine derivatives. The invention simply and conveniently synthesizes N with potential bioactivity by designing substrate configuration2Aryl-substituted-1, 2, 4-triazine derivatives. The method has the advantages of simple operation, wide substrate range, mild synthesis reaction conditions and diversity of functional groups.
Description
Technical Field
The invention belongs to the technical field of chemical organic synthesis, and relates to N2Aryl substituted-1, 2, 4-triazine derivatives and synthesis methods thereof.
Technical Field
1,2, 4-triazine compounds are important heterocyclic compounds, and have been widely applied in various fields such as medicine, materials and biology due to unique chemical properties and biological activities, and in medicinal chemistry, compounds with 1,2, 4-triazine skeleton structures show various biological activities such as antivirus, anticancer, antibacterial and antituberculosis. At present, the following two methods are mainly used for synthesizing the 1,2, 4-triazine compounds: one is that hydrazide is used as raw material to react with 1, 2-dicarbonyl compound, 2-bromo aryl ketone or alpha-diazo beta-keto ester to obtain 3, 6-disubstituted or 3,5, 6-trisubstituted 1,2, 4-triazine compound; the second method is to take N-amino amidine as a raw material to react with a 1, 2-dicarbonyl compound to obtain a 3-monosubstituted, 3, 5-disubstituted or 3,5, 6-trisubstituted 1,2, 4-triazine compound. However, there are still many problems to be solved in synthesizing 1,2, 4-triazine compounds, such as high reaction temperature, complicated steps, and diversity of substituents. The existing synthesis method mainly obtains 1,2, 4-triazine compounds with substituents at C-3, C-5 and C-6 positions, and the synthesis of 1,2, 4-triazine compounds with substituents on nitrogen atoms is only reported, and only one document reports that N is synthesized through multi-step reaction 1-substitution1,2, 4-triazine derivative (j.org.chem.2014, 79,314.). Therefore, the method has the advantages of mild design and development conditions, easily obtained raw materials, atom economy, simplicity and convenience in synthesizing the polysubstituted 1,2, 4-triazine derivative with the substituent on the nitrogen atom, and wide prospect. The invention can simply and conveniently synthesize N with potential biological activity by designing substrate configuration and adopting S, N-substituted internal olefin and aryl diazonium salt for cyclization2Aryl-substituted-1, 2, 4-triazine derivatives. The method has the advantages of simple operation, wide substrate range, mild synthesis reaction conditions and high reaction product yield.
Disclosure of Invention
The invention aims to provide a method for synthesizing N with potential bioactivity, which has mild reaction conditions and wide adaptability and can simply and conveniently synthesize N with potential bioactivity2A method for aryl-substituted-1, 2, 4-triazine derivatives.
In order to achieve the purpose, the technical scheme of the invention is as follows:
s, N-substituted internal olefin 2 and aryl diazonium salt 3 are used as initial raw materials, copper salt is used as a catalyst, and cyclization is carried out in an organic solvent in the presence of alkali and an oxidant to synthesize N2Aryl-substituted-1, 2, 4-triazine derivative 1 (reaction formula 1). After the reaction is finished, the product is separated and characterized by silica gel column separation and purification to obtain N 2Aryl-substituted 1,2, 4-triazine derivatives 1.
The technical scheme is characterized in that:
1. the S, N-substituted internal olefin 2 is used as a reactant, and the substituent groups are as follows:
R1selected from the following groups: c1-5 alkyl, phenyl or aromatic ring with substituent on benzene ring, wherein the substituent on benzene ring is 1-5 of methyl, methoxyl, fluorine, chlorine, bromine, trifluoromethyl, nitryl, nitrile group and carboxyl, and the number of the substituent is 1-5;
R2selected from the following groups: methyl, ethyl or benzyl;
R3selected from the following groups: estersThe substituent on the benzene ring is 1-5 of methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, nitro, nitrile group and carboxyl, and the number of the substituent is 1-5;
R4selected from the following groups: hydrogen, methyl or phenyl.
2. Aryl diazonium salt 3 is used as a reactant, and the substituent groups are as follows:
R5selected from the following groups: hydrogen, methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, nitro, nitrile group and carboxyl;
x is selected from the following groups: fluorine, chlorine, bromine, tetrafluoroborate.
3. The catalyst copper salt is one or more of cuprous chloride, cuprous bromide, cuprous iodide, cupric chloride, cupric bromide, cupric acetate or hydrated cupric acetate, wherein the copper salt is preferably CuCl 2Or CuBr2The molar ratio of the S, N-substituted internal olefin 2 to the copper salt is from 1:0.1 to 1:3.0, preferably from 1:0.3 to 1: 2.0.
4. The alkali is one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium tert-butoxide or lithium tert-butoxide, and the molar ratio of the S, N-substituted internal olefin 2 to the alkali is 1:0.2-1:3.0, preferably 1:0.5-1: 3.0.
5. The oxidant is di-tert-butyl peroxide (DTBP), tert-butyl hydroperoxide (TBHP), tert-butyl peroxybenzoate (TBPB), dichlorodicyano benzoquinone (DDQ), tetramethylpiperidine oxynitride (TBPB), sodium thiosulfate (Na)2S2O8) Potassium thiosulfate (K)2S2O8) Or ammonium thiosulfate ((NH)4)2S2O8) And the molar ratio of the S, N-substituted internal olefin 2 to the oxidizing agent is 1:0.2 to 1:2.0, preferably 1:0.5 to 1: 1.0.
6. The reaction solvent is one or a mixture of more than two of toluene, 1, 4-dioxane, 1, 2-Dichloroethane (DCE), Dichloromethane (DCM), Tetrahydrofuran (THF), acetonitrile, ethanol, N-Dimethylformamide (DMF) or dimethyl sulfoxide (DMSO), and the preferred solvent is aprotic polar solvent acetonitrile, and the molar concentration of S, N-substituted internal olefin 2 in the reaction solvent is 0.05-1.0M.
7. The reaction atmosphere is one or more than two of air, argon, nitrogen or oxygen.
8. The reaction time is 0.5-24 hours, and the optimal reaction time is 2-6 hours.
9. The reaction temperature is 25-80 deg.C, and the optimum reaction temperature is 25-40 deg.C.
The molar ratio of the S, N-substituted internal olefin 2 to the aryl diazonium salt 3 is from 1:1.2 to 1: 3.0.
The invention has the following advantages:
1) by designing the substrate type, N can be simply and conveniently synthesized by adopting S, N-substituted internal olefin and aryl diazonium salt2Aryl-substituted-1, 2, 4-triazine derivatives.
2) The S, N-substituted internal olefin compound and the aryl diazonium salt which are used as reaction raw materials have structural diversity and can be used for synthesizing N with various substituent groups2Aryl-substituted-1, 2, 4-triazine derivatives.
3) Mild reaction conditions, simple and convenient operation, high product yield and wide substrate application range.
4) The product has potential bioactivity.
In conclusion, the invention utilizes the cyclization of S, N-substituted internal olefin and aryl diazonium salt to synthesize N efficiently2The aryl-substituted-1, 2, 4-triazine derivative has the advantages of simple and convenient reaction operation, wide substrate range and mild synthesis reaction conditions.
Detailed Description
The following examples are provided to aid in the further understanding of the present invention, but the invention is not limited thereto.
Example 1
To a 25mL branched tube, CuBr was added in order2(0.09mmol)、K3PO4(0.9mmol)、 K2S2O8(0.15mmol), S, N-substituted internal olefin 2a (0.3mmol), diazonium salt 3a (0.6 mmol)l)、 CH3CN 3mL，O2The reaction was carried out at 25 ℃ for 5 hours under an atmosphere. After completion of the reaction, the solvent was removed under reduced pressure, and the mixture was subjected to silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate; v/v 20:1 as an eluent) to give the objective product 1a (90mg, yield 75%) as a pale yellow liquid. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 2
The reaction procedure and operation were the same as in example 1, except that the catalyst was copper chloride, as in example 1. The reaction was terminated, and the reaction mixture was worked up to give the objective product 1a (86mg, yield 72%).
Example 3
The reaction procedure and operation were the same as in example 1, except that the base was K2CO3. The reaction was stopped and worked up to give the desired product 1a (82mg, yield 68%).
Example 4
The reaction procedure and operation were the same as in example 1, except that the oxidizing agent was Na2S2O8. The reaction was stopped and worked up to give the desired product 1a (78mg, yield 65%).
Example 5
The reaction procedure and operation were the same as in example 1, except that the reaction atmosphere was air, as in example 1. The reaction was terminated, and the reaction product was worked up to give the objective product 1a (80mg, yield 67%).
Example 6
The procedure and operation were the same as in example 1, except that the reaction solvent was DCE as in example 1. The reaction was stopped and worked up to give the desired product 1a (70mg, 58% yield).
Example 7
The procedure and operation were the same as in example 1, except that the reaction solvent was THF as in example 1. The reaction was stopped and worked up to give the desired product 1a (66mg, yield 55%).
Example 8
The procedure and operation were the same as in example 1, except that the reaction temperature was 35 ℃ in example 1. The reaction was stopped and worked up to give the desired product 1a (90mg, yield 75%).
Example 9
The reaction procedure and operation were the same as in example 1, except that the reaction time was 3 hours from example 1. The reaction was terminated, and the reaction product was worked up to give the desired product 1a (72mg, yield 60%).
Example 10
The reaction procedure and operation were the same as in example 1, except that the molar ratio of 2a to 3a was 1:1.5, as in example 1. The reaction was terminated, and the desired product 1a (84mg, yield 70%) was obtained by workup.
Example 11
The reaction procedure and operation were the same as in example 1, except that 2a and CuBr were used in the reaction procedure of example 12Is 1: 1.0. The reaction was terminated, and the reaction mixture was worked up to give the objective product 1a (92mg, yield 77%).
Example 12
The reaction procedure and operation were the same as in example 1, except that 2a and K were used in example 13PO4Is 1: 2.0. The reaction was terminated, and the reaction product was worked up to give the desired product 1a (72mg, yield 60%).
Example 13
The reaction procedure and operation were the same as in example 1, except that 2a and K were used in example 12S2O8Is 1: 1.0. The reaction was terminated, and the desired product 1a (74mg, yield 62%) was obtained by workup.
Example 14
The reaction procedure and operation were the same as in example 1, except that the diazonium salt was 3b, which is the difference from example 1. The reaction was terminated, and the reaction product was worked up to give the objective product 1b (97mg, yield 70%).
Example 15
The reaction procedure and operation were the same as in example 1 except that the S, N-substituted internal olefin was 2b, which is different from example 1. The reaction was stopped and worked up to give the desired product 1c (89mg, yield 72%).
Example 16
The reaction procedure and operation were the same as in example 1 except that the S, N-substituted internal olefin was 2c, which is the difference from example 1. The reaction was stopped and worked up to give the desired product 1d (88mg, yield 70%).
Example 17
The reaction procedure and operation were the same as in example 1 except that the S, N-substituted internal olefin was 2d, which is different from example 1. The reaction was stopped and worked up to give the desired product 1e (100mg, yield 68%).
Example 18
The reaction procedure and operation were the same as in example 1 except that the S, N-substituted internal olefin was 2e in example 1. The reaction was stopped, and the desired product, 1f (108mg, yield 77%), was obtained by workup.
Application example 1
The specific process is as follows: weighing 1a (80mg, 0.2mmol), NH2NH2·H2O (120uL,2.0mmol, 85%) was added to a 25mL lock, 2mL toluene was added, and the mixture was reacted in a 120 ℃ oil bath for 7 d. After completion of the reaction, it was cooled to room temperature, rotary evaporated under reduced pressure, and the solvent was removed, followed by column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate ═ 20:1, v/v) to give product 4a (58mg, yield 79%) as a white solid.
Typical Compound characterization data
Compound 1 a: a light yellow liquid.1H NMR(400MHz,CDCl3,23℃)δ7.88,7.54, 7.45,and 7.34(m each,2:1:2:5H,aromatic CH),7.22and 7.13(d each,J＝8.6 and 8.5Hz,2:2H,aromatic CH),7.09(s,1H,NCH),2.40and 2.32(s each,3:3 H,2×CH3).13C{1H}NMR(100MHz,CDCl3,23℃)δ189.1(Cq,CO),157.9, 141.1,137.85,137.80,135.4,and 134.5(Cq),132.0,130.4,130.1,129.0,128.7, 127.9,126.1,and 117.6(aromatic CH),74.1(NCH),20.9and 13.4(CH3). HRMS Calcd for C24H22N3OS[M+H]+:400.1484；Found:400.1487。
Claims (6)
1. N2-a process for the synthesis of aryl-substituted-1, 2, 4-triazine derivatives, characterized in that:
s, N-substituted internal olefin 2 and aryl diazonium salt 3 are used as initial raw materials to synthesize N by cyclization in an organic solvent in the presence of a catalyst, alkali and an oxidant2-aryl substituted-1, 2, 4-triazine derivative 1;
the catalyst is one or two of cupric chloride and cupric bromide; the alkali is one or two of potassium carbonate and potassium phosphate, the oxidant is one or two of sodium thiosulfate and potassium thiosulfate, and the reaction solvent is one or a mixture of more than two of 1, 2-dichloroethane, tetrahydrofuran and acetonitrile;
The synthetic route is shown as follows,
wherein R is1Selected from the following groups: phenyl or a benzene ring with substituent groups on the benzene ring, wherein the substituent groups on the benzene ring are 1-5 of methyl, methoxy, fluorine, chlorine, bromine and trifluoromethyl;
R2selected from the following groups: methyl, ethyl or benzyl;
R3selected from the following groups: phenyl or a benzene ring with substituent groups on the benzene ring, wherein the substituent groups on the benzene ring are 1-5 of methyl, methoxy, fluorine, chlorine, bromine and trifluoromethyl;
R4selected from the following groups: hydrogen, methyl;
R5selected from the following groups: hydrogen, methyl, fluorine, chlorine, bromine, trifluoromethyl;
x is selected from the following groups: tetrafluoroborate radical.
2. A method of synthesis according to claim 1, characterized in that:
the molar ratio of the S, N-substituted internal olefin 2 to the catalyst is 1:0.1-1: 3.0; the molar ratio of the S, N-substituted internal olefin 2 to the base is 1:0.2-1: 3.0; the molar ratio of the S, N-substituted internal olefin 2 to the oxidant is 1:0.2-1: 2.0; the molar ratio of the S, N-substituted internal olefin 2 to the aryl diazonium salt 3 is 1:1.2-1: 3.0;
the molar concentration of the S, N-substituted internal olefin 2 in the reaction solvent is 0.05-1.0M; the reaction solvent is acetonitrile;
the reaction atmosphere is one or more than two of air, argon, nitrogen or oxygen; the reaction time is 0.5 to 24 hours; the reaction temperature is 25-80 ℃.
3. A method of synthesis according to claim 2, characterized in that: the molar ratio of the S, N-substituted internal olefin 2 to the catalyst is 1:0.3 to 1: 2.0.
4. A method of synthesis according to claim 2, characterized in that: the molar ratio of the S, N-substituted internal olefin 2 to the base is from 1:0.5 to 1: 3.0.
5. A method of synthesis according to claim 2, characterized in that: the molar ratio of the S, N-substituted internal olefin 2 to the oxidant is 1:0.5 to 1: 1.0.
6. A method of synthesis according to claim 2, characterized in that: the reaction time is 2-6 hours; the reaction temperature is 25-40 ℃.
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Non-Patent Citations (3)
| Title |
|---|
| Copper(II)-Catalyzed C-H Nitrogenation/Annulation Cascade of Ketene N,S-Acetals with Aryldiazonium Salts: A Direct Access to N2-Substituted Triazole and Triazine Derivatives;Ping Wu等;《Org.Lett.》;20191212;第22卷;310-315 * |
| One-Pot Acid-Catalyzed Ring-Opening/Cyclization/Oxidation of Aziridines with N-Tosylhydrazones: Access to 1,2,4-Triazines;Lorene Crespin等;《Org.Lett.》;20170215;第19卷;1084-1087 * |
| Synthesis of 6-hydrazino-3,4-dimethyl-1H-pyrazolo[3,4-d]pyrimidine and its application for the construction of a pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidine system;A.V.Komkov等;《Russian Chemical Bulletin, International Edition》;20130531;第62卷(第5期);1248-1254 * |
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