CN111018800B - A kind of N2-aryl substituted-1,2,4-triazine derivative and its synthesis and application - Google Patents

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

A kind of N2-aryl substituted-1,2,4-triazine derivative and its synthesis and application

technical field

The invention belongs to the technical field of chemical organic synthesis, and relates to an ^N2 -aryl-substituted-1,2,4-triazine derivative and a synthesis method thereof.

technical background

1,2,4-Triazine compounds are an important class of heterocyclic compounds. Due to their unique chemical properties and biological activities, they have been widely used in many fields such as medicine, materials and biology. In medicinal chemistry, they have 1 , 2,4-triazine skeleton-structured compounds exhibit various biological activities such as antiviral, anticancer, antibacterial and antituberculosis. At present, there are two main methods for synthesizing 1,2,4-triazine compounds: one is to use hydrazide as raw material, combine with 1,2-dicarbonyl compound, 2-bromoaryl ketone or α-diazo group β-ketoesters react to obtain 3,6-disubstituted or 3,5,6-trisubstituted 1,2,4-triazine compounds; the second is to use N-aminoamidine as raw material, and 1,2-dicarbonyl The compounds are reacted to obtain 3-monosubstituted, 3,5-disubstituted or 3,5,6-trisubstituted 1,2,4-triazine compounds. However, there are still many aspects to be solved in the synthesis of 1,2,4-triazine compounds, such as high reaction temperature, complicated steps and diversity of substituents. The current synthesis methods mainly obtain 1,2,4-triazine compounds with substituents at C-3, C-5 and C-6 positions, and synthesize 1,2,4-triazine compounds with substituents on nitrogen atoms There are few reports, and only one literature reports the synthesis of N ¹ -substituted 1,2,4-triazine derivatives through multi-step reactions (J. Org. Chem. 2014, 79, 314.). Therefore, the simple and convenient synthesis of polysubstituted 1,2,4-triazine derivatives with substituents on nitrogen atoms with mild conditions, readily available raw materials, economical atoms, and simple and convenient synthesis has broad prospects. The present invention can simply and conveniently synthesize N ² -aryl substituted-1,2,4-triazine with potential biological activity by designing the substrate configuration and adopting S,N-substituted internal olefin and aryl diazonium salt cyclization derivative. The method has the advantages of simple operation, wide substrate range, mild synthesis reaction conditions and high reaction product yield.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a method for mild reaction conditions, wide adaptability, simple and convenient synthesis of N ² -aryl substituted-1,2,4-triazine derivatives with potential biological activity.

In order to achieve the above object, technical scheme of the present invention is as follows:

Using S,N-substituted internal olefin 2 and aryl diazonium salt 3 as starting materials, copper salt as catalyst, in the presence of alkali and oxidant, cyclization in organic solvent to synthesize N ² -aryl substituted-1,2,4 - Triazine Derivative 1 (Scheme 1). After the reaction, the product was separated and characterized by silica gel column separation and purification to obtain N ² -aryl substituted 1,2,4-triazine derivative 1.

The technical solution is characterized by:

1. Take S, N-substituted internal olefin 2 as reactant, and its substituent is:

R ¹ is selected from the following groups: an alkyl group with 1-5 carbon atoms, a phenyl group or an aromatic ring with a substituent on the benzene ring, and the substituent on the benzene ring is methyl, methoxy, fluorine, 1-5 kinds of chlorine, bromine, trifluoromethyl, nitro, nitrile and carboxyl groups, and the number of substituents is 1-5;

R ² is selected from the following groups: methyl, ethyl or benzyl;

R ³ is selected from the following groups: ester group, phenyl group or aromatic ring with a substituent on the benzene ring, and the substituent on the benzene ring is methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl , 1-5 kinds of nitro, nitrile, and carboxyl groups, and the number of substituents is 1-5;

^R4 is selected from the following groups: hydrogen, methyl or phenyl.

2. Take aryl diazonium salt 3 as reactant, and its substituent is:

R ⁵ is selected from the following groups: hydrogen, methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, nitro, nitrile, 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 copper acetate, wherein the copper salt is the most It is preferably CuCl ₂ or CuBr ₂ , and the molar ratio of S,N-substituted internal olefin 2 to copper salt is 1:0.1-1:3.0, preferably 1:0.3-1:2.0.

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, S, N-substituted internal olefin 2 and alkali. The molar ratio is 1:0.2-1:3.0, preferably the molar ratio is 1:0.5-1:3.0.

5. The oxidant is di-tert-butyl peroxide (DTBP), tert-butyl hydroperoxide (TBHP), tert-butyl peroxybenzoate (TBPB), dichlorodicyanobenzoquinone (DDQ), tetramethyl piperidine nitroxide (TBPB), sodium thiosulfate (Na ₂ S ₂ O ₈ ), potassium thiosulfate (K ₂ S ₂ O ₈ ) or ammonium thiosulfate ((NH ₄ ) ₂ S ₂ O ₈ ), the molar ratio of the S,N-substituted internal olefin 2 to the oxidant is 1:0.2-1:2.0, preferably the molar ratio is 1:0.5-1:1.0.

6. The reaction solvent is toluene, 1,4-dioxane, 1,2-dichloroethane (DCE), dichloromethane (DCM), tetrahydrofuran (THF), acetonitrile, ethanol, N,N-dimethylform One or more mixtures of dimethylformamide (DMF) or dimethyl sulfoxide (DMSO), preferably the solvent is the aprotic polar solvent acetonitrile, the moles of S,N-substituted internal olefin 2 in the reaction solvent The concentration is 0.05-1.0M.

7. The reaction atmosphere is one or more 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°C, and the optimum reaction temperature is 25-40°C.

10. The molar ratio of S,N-substituted internal olefin 2 to aryl diazonium salt 3 is 1:1.2-1:3.0.

The present invention has the following advantages:

1) By designing the substrate type, N ² -aryl substituted-1,2,4-triazine derivatives can be synthesized simply and conveniently by using S,N-substituted internal alkenes and aryl diazonium salts.

2) The reaction raw materials S,N-substituted internal olefin compounds and aryl diazonium salts have structural diversity and can be used to synthesize N ² -aryl substituted-1,2,4-triazine derivatives with various substituents .

3) The reaction conditions are mild, the operation is simple, the product yield is high, and the substrate is suitable for a wide range.

4) The product has potential biological activity.

In a word, the present invention utilizes S,N-substituted internal olefin and aryl diazonium salt cyclization to efficiently synthesize N ² -aryl substituted-1,2,4-triazine derivatives, the reaction operation is simple, the substrate range is wide, and the synthesis The reaction conditions are mild.

Detailed ways

The following examples are helpful for further understanding of the present invention, but the content of the present invention is not limited thereto.

Example 1

Into a 25 mL branched tube, CuBr ₂ (0.09 mmol), K ₃ PO ₄ (0.9 mmol), K ₂ S ₂ O ₈ (0.15 mmol), S,N-substituted internal olefin 2a (0.3 mmol), heavy Nitrogen salt 3a (0.6 mmol), CH ₃ CN 3 mL, react at 25° C. for 5 hours under O ₂ atmosphere. After the reaction, the solvent was removed under reduced pressure and separated by silica gel column chromatography (eluent was petroleum ether (60-90°C)/ethyl acetate, v/v=20:1) to obtain the target product 1a (90 mg) as a pale yellow liquid. , the yield is 75%). The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

Example 2

The reaction steps and operations are the same as those in Example 1, and the difference from Example 1 is that the catalyst is copper chloride. The reaction was stopped, and the target product 1a (86 mg, yield 72%) was obtained after post-treatment.

Example 3

The reaction steps and operations are the same as those in Example 1, and the difference from Example 1 is that the base is K ₂ CO ₃ . The reaction was stopped, and the target product 1a (82 mg, yield 68%) was obtained after post-treatment.

Example 4

The reaction steps and operations are the same as those in Example 1, and the difference from Example 1 is that the oxidant is Na ₂ S ₂ O ₈ . The reaction was stopped, and the target product 1a (78 mg, yield 65%) was obtained after post-treatment.

Example 5

The reaction steps and operations are the same as those in Example 1, and the difference from Example 1 is that the reaction atmosphere is air. The reaction was stopped, and the target product 1a (80 mg, yield 67%) was obtained after post-treatment.

Example 6

The reaction steps and operations are the same as in Example 1, and the difference from Example 1 is that the reaction solvent is DCE. The reaction was stopped, and the target product 1a (70 mg, yield 58%) was obtained after post-treatment.

Example 7

The reaction steps and operations are the same as those in Example 1, and the difference from Example 1 is that the reaction solvent is THF. The reaction was stopped, and the target product 1a (66 mg, yield 55%) was obtained after post-treatment.

Example 8

The reaction steps and operations are the same as those in Example 1, and the difference from Example 1 is that the reaction temperature is 35°C. The reaction was stopped, and the target product 1a (90 mg, yield 75%) was obtained after post-treatment.

Example 9

The reaction steps and operations were the same as those in Example 1, and the difference from Example 1 was that the reaction time was 3 h. The reaction was stopped, and the target product 1a (72 mg, yield 60%) was obtained after post-treatment.

Example 10

The reaction steps and operations are the same as in Example 1, and the difference from Example 1 is that the molar ratio of 2a to 3a is 1:1.5. The reaction was stopped, and the target product 1a (84 mg, yield 70%) was obtained after post-treatment.

Example 11

The reaction steps and operations are the same as those in Example 1, and the difference from Example 1 is that the molar ratio of 2a to CuBr ₂ is 1:1.0. The reaction was stopped, and the target product 1a (92 mg, yield 77%) was obtained after post-treatment.

Example 12

The reaction steps and operations are the same as those of Example 1, and the difference from Example 1 is that the molar ratio of 2a to K ₃ PO ₄ is 1:2.0. The reaction was stopped, and the target product 1a (72 mg, yield 60%) was obtained after post-treatment.

Example 13

The reaction steps and operations are the same as those in Example 1, and the difference from Example 1 is that the molar ratio of 2a to K ₂ S ₂ O ₈ is 1:1.0. The reaction was stopped, and the target product 1a (74 mg, yield 62%) was obtained after post-treatment.

Example 14

The reaction steps and operations are the same as those in Example 1, and the difference from Example 1 is that the diazonium salt is 3b. The reaction was stopped, and the target product 1b (97 mg, yield 70%) was obtained after post-treatment.

Example 15

The reaction steps and operations are the same as those in Example 1, and the difference from Example 1 is that the S,N-substituted internal olefin is 2b. The reaction was stopped, and the target product 1c (89 mg, yield 72%) was obtained after post-treatment.

Example 16

The reaction steps and operations are the same as those of Example 1, and the difference from Example 1 is that the S,N-substituted internal olefin is 2c. The reaction was stopped, and the target product 1d (88 mg, yield 70%) was obtained after post-treatment.

Example 17

The reaction steps and operations are the same as those in Example 1, and the difference from Example 1 is that the S,N-substituted internal olefin is 2d. The reaction was stopped, and the target product 1e (100 mg, yield 68%) was obtained after post-treatment.

Example 18

The reaction steps and operations are the same as those of Example 1, and the difference from Example 1 is that the S,N-substituted internal olefin is 2e. The reaction was stopped, and the target product 1f (108 mg, yield 77%) was obtained after post-treatment.

Application example 1

The specific process is as follows: Weigh 1a (80 mg, 0.2 mmol), NH ₂ NH ₂ ·H ₂ O (120 uL, 2.0 mmol, 85%), add it to a 25 mL sealed tube, add 2 mL of toluene, and put it in a 120°C oil bath Reaction 7d. After the reaction was completed, it was cooled to room temperature, 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 obtain a white solid product 4a (58 mg, yield 79%).

Typical Compound Characterization Data

Compound 1a: pale yellow liquid. ¹ H NMR (400MHz, CDCl ₃ , 23°C) δ 7.88, 7.54, 7.45, and 7.34 (m each, 2:1:2:5H, aromatic CH), 7.22 and 7.13 (d each, J=8.6 and 8.5 Hz, 2:2H, aromatic CH), 7.09(s, 1H, NCH), 2.40 and 2.32(s each, 3:3 H, 2×CH ₃ ). ¹³ C{ ¹ H}NMR (100MHz, CDCl ₃ , 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), 20.9 and 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 ℃.