CN109400496B - Preparation method of 1, 3-diacetylene derivative - Google Patents
Preparation method of 1, 3-diacetylene derivative Download PDFInfo
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Abstract
The invention relates to a synthesis method of a 1, 3-diacetylene derivative. The method comprises adding alkyl-terminated alkyne compound (1), copper acetate (Cu (OAc)2) Placing a reaction bottle at a certain temperature under the condition of air atmosphere, stirring for reaction, monitoring the reaction process by TLC or GC until the raw materials react completely, and carrying out aftertreatment to obtain a target product 1, 3-diacetylene derivative (I);
Description
Technical Field
The application belongs to the field of organic synthesis, and particularly relates to a synthesis method of a 1, 3-diacetylene derivative.
Background
The 1, 3-diacetylene derivative is widely present in drug molecules and bioactive molecules, and is widely applied in the aspects of medicines, biology and the like. In addition, 1, 3-diacetylene is also a very important synthon in organic synthesis and functional materials. Therefore, efficient preparation of 1, 3-diacetylene derivatives has attracted a great deal of lasting attention from chemists.
The inventor finds that the synthesis route for preparing the 1, 3-diacetylene derivative in the prior art mainly passes through the coupling reaction of terminal alkyne under the catalysis of metal such as palladium, copper and the like. However, in these conventional synthetic methods, expensive ligands and/or bases are generally required to be added to the reaction system, and efficient methods specifically directed to alkyl-terminal alkyne coupling have not been developed. Therefore, finding a more efficient, less expensive, and greener process for the preparation of 1, 3-diacetylene derivatives by alkyl-terminal alkyne coupling reactions remains a challenging issue. The inventor conducts a series of researches on the construction of the 1, 3-diacetylene derivative through the alkyl terminal alkyne coupling reaction, and further provides a novel method for preparing the 1, 3-diacetylene derivative. To the best of the inventors' knowledge, no prior art reports a reaction specifically directed to the coupling reaction of alkyl-terminated alkynes to prepare 1, 3-diacetylene derivatives without the need for a ligand and base system.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a synthetic method for preparing 1, 3-diacetylene derivatives with simple process, greenness, high efficiency and low cost, which uses cheap and easily available copper acetate (Cu (OAc)2) The 1, 3-diacetylene derivative is conveniently prepared with high yield by using di-tert-butyl peroxide (DTBP) as an oxidant and acetonitrile as a solvent as a catalyst.
The invention provides a preparation method of a 1, 3-diacetylene derivative, which takes an alkyl terminal alkyne compound as a raw material and is prepared by the following steps:
to a Schlenk reaction flask were added the alkyl-terminated acetylene compound (1), copper acetate (Cu (OAc)2) Placing a reaction bottle at a certain temperature under the condition of air atmosphere, stirring for reaction, monitoring the reaction process by TLC or GC until the raw materials react completely, and carrying out aftertreatment to obtain the target product 1, 3-diacetylene derivative (I).
The chemical reaction formula of the preparation method of the 1, 3-diacetylene derivative provided by the invention can be expressed as (see formula I):
in the reaction of the first formula, the reaction atmosphere may be an air atmosphere of 1atm, and a nitrogen atmosphere of 1atm or other inert gas atmosphere may be used instead.
The post-processing operation is as follows: filtering the reaction solution by a glass dropper filled with silica gel, washing a filter cake by ethyl acetate, filtering, decompressing and concentrating to remove the solvent, and separating the residue by column chromatography, wherein the elution solvent is: ethyl acetate/n-hexane to obtain the target product 1, 3-diacetylene derivative (I).
In the compounds represented by the formula 1 and the formula I, R1Represents 1 or more substituents attached thereto, each R1Are independent of each otherSelected from hydrogen and C6-C10Aryl radical, C5-C14Heteroaryl group, C1-C12An alkyl group;
R2is represented by C1-C6Alkyl radical, C3-C6Acyl radical, C6-C10An aryl group;
wherein the heteroatom of the heteroaryl group is selected from O, S or N;
and each of the above alkyl, alkoxy, aryl and heteroaryl groups may be further substituted with a substituent selected from halogen or C1-C6Alkyl group of (1).
Preferably, R1Represents 1 or more substituents attached thereto, each R1Independently of one another, from hydrogen, C6-C8Aryl and C1-C10An alkyl group; wherein said C6-C8Aryl and/or C1-C10The alkyl group may be further substituted, the substituent being selected from halogen or C1-C6Alkyl groups of (a);
preferably, R2Is represented by C1-C5Alkyl and C3-C4Acyl group, wherein said C1-C5Alkyl and/or C3-C4The acyl group may be further substituted, said substituent being selected from halogen or C1-C2Alkyl group of (1).
In the reaction according to the invention, preference is given to adding copper acetate (Cu (OAc)2) As a catalyst and di-tert-butyl peroxide (DTBP) as an oxidizing agent.
In the reaction of the present invention, the certain temperature is 25 to 100 ℃ and the temperature is most preferably 70 ℃.
In the reaction of the present invention, the compound of formula 1 is reacted with Cu (OAc)2In a molar ratio of 1: 0.1 to 0.3, preferably, the compound of formula 1 to Cu (OAc)2The molar ratio of (A) to (B) is 1: 0.2; the molar ratio of the compound of formula 1 to DTBP is 1: 1-4, preferably the molar ratio of the compound of formula 1 to DTBP is 1: 3.
In the reaction of the present invention, acetonitrile is used as a solvent, and the amount thereof is not particularly limited, and those skilled in the art can select and/or adjust the amount thereof according to the actual conditions of the reaction.
The invention has the beneficial effects that: a novel method for preparing 1, 3-diacetylene derivatives by specially aiming at alkyl terminal alkyne coupling reaction without ligand and alkali systems is provided, and the method takes cheap and easily-obtained copper acetate as a catalyst to obtain a series of 1, 3-diacetylene target products containing nitrogen special frameworks in high yield. The method does not use ligand and alkali, and the reaction atmosphere is air, so that the method has the advantages of wide reaction substrate application range, simplicity, high efficiency, economy and greenness, and is particularly suitable for industrial production.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
EXAMPLE 1 Synthesis of Compound I-1
To a Schlenk reaction flask was added 1a (39.8mg, 0.2mmol), Cu (OAc)2(copper acetate, 7.2mg, 0.04mmol), DTBP (di-tert-butyl peroxide, 87.6mg, 0.6mmol) and tetrahydrofuran (1mL) as a solvent, placing a reaction bottle at 70 ℃ under the condition of air atmosphere, stirring for reaction, monitoring the reaction progress through TLC or GC until the raw materials are completely reacted (when the reaction time is 12 hours), filtering the reaction liquid after the reaction is finished through a glass dropper with silica gel, washing a filter cake with ethyl acetate, filtering and decompressing and concentrating to remove the solvent, and separating the residue through column chromatography, wherein the elution solvent is: ethyl acetate/n-hexane to obtain the target product I-1. (81% yield);1H NMR(400MHz，DMSO-d6)δ：7.41(t，J＝7.6Hz，4H)，7.32(t，J＝7.6Hz， 2H)，7.24(d，J＝7.6Hz，4H)，5.06(s，2H)，4.90(s，2H)，4.63(s，4H)，1.71(s，6H)；13C NMR(100 MHz，DMSO-d6)δ：170.8，142.6，140.1，129.8，128.0，127.8，120.0，75.4，67.6，39.5，20.3；HRMS m/z(ESI)calcd for C26H25N2O2([M+H]+)397.1911，found 397.1919.
example 2
No addition of catalyst Cu (OAc)2Otherwise, the process was carried out in the same manner as in example 1, whereby the yield of the objective product I-1 was 0%.
Example 3
The procedure of example 1 was repeated except that the oxidizing agent DTBP was not added, whereby the yield of the objective product I-1 was 5%.
Example 4
With CuCl2Instead of Cu (OAc) in example 12And the rest of the conditions are the same as example 1, the reaction progress is monitored by TLC or GC until the raw materials are completely reacted (the reaction time is 12 hours), the reaction liquid after the reaction is finished is filtered by a glass dropping tube filled with silica gel, the filter cake is washed by ethyl acetate, the solvent is removed by filtering and decompression concentration, the residue is separated by column chromatography, and the eluting solvent is: ethyl acetate/n-hexane, yield of the target product I-1 was 76%.
Example 5
With CuBr2Instead of Cu (OAc) in example 12And the rest of the conditions are the same as example 1, the reaction progress is monitored by TLC or GC until the raw materials are completely reacted (the reaction time is 12 hours), the reaction liquid after the reaction is finished is filtered by a glass dropping tube filled with silica gel, the filter cake is washed by ethyl acetate, the solvent is removed by filtering and decompression concentration, the residue is separated by column chromatography, and the eluting solvent is: ethyl acetate/n-hexane, yield 42% of the target product I-1.
Example 6
Replacement of Cu (OAc) in example 1 by CuO2And the rest of the conditions are the same as example 1, the reaction progress is monitored by TLC or GC until the raw materials completely react (the reaction time is 12 hours), the reaction liquid after the reaction is finished is filtered by a glass dropper filled with silica gel, the filter cake is washed by ethyl acetate, the solvent is removed by filtering and decompression concentration, the residue is separated by column chromatography, and the eluting solvent is: ethyl acetate/n-hexane, yield of the target product I-1 was 32%.
Example 7
Replacement of Cu (OAc) in example 1 by CuCl2The other conditions were the same as in example 1TLC or GC monitors the reaction progress until the raw materials are completely reacted (the reaction time is 12 hours), the reaction liquid after the reaction is finished is filtered by a glass dropper with silica gel, ethyl acetate washes a filter cake, the filter cake is filtered and decompressed and concentrated to remove the solvent, and the residue is separated by column chromatography, and the elution solvent is: ethyl acetate/n-hexane, the yield of the target product I-1 being 11%.
Example 8
Catalyst Cu (OAc)2The amount of the charged material(s) is 0.1 equivalent (0.02mmol), the rest conditions are the same as those of the example 1, the reaction progress is monitored by TLC or GC until the raw materials are completely reacted (the reaction time is 12 hours), the reaction solution after the reaction is completed is filtered by a glass dropper filled with silica gel, ethyl acetate washes filter cakes, the solvent is removed by filtration and concentration under reduced pressure, the residue is separated by column chromatography, and the eluting solvent is: ethyl acetate/n-hexane, yield of the target product I-1 was 34%.
Example 9
Catalyst Cu (OAc)2The amount of the charged material(s) is 0.3 equivalent (0.06mmol), the rest conditions are the same as those of the example 1, the reaction process is monitored by TLC or GC until the raw materials are completely reacted (the reaction time is 12 hours), the reaction solution after the reaction is completed is filtered by a glass dropper filled with silica gel, ethyl acetate washes filter cakes, the solvent is removed by filtration and concentration under reduced pressure, the residue is separated by column chromatography, and the eluting solvent is: ethyl acetate/n-hexane, yield of the target product I-1 was 62%.
Example 10
The reaction progress was monitored by TLC or GC until the starting material was completely reacted (reaction time 12 hours) under the same conditions as in example 1, using TBHP (tert-butyl peroxide) as an oxidant instead of DTBP in example 1, the reaction solution after completion of the reaction was filtered through a glass dropper filled with silica gel, the filter cake was washed with ethyl acetate, the solvent was removed by filtration and concentration under reduced pressure, and the residue was separated by column chromatography, eluting with the solvent: ethyl acetate/n-hexane, yield of the target product I-1 was 33%.
Example 11
Using BPO (benzoyl peroxide) as oxidant instead of DTBP in example 1, monitoring the reaction progress by TLC or GC in the same condition as example 1 until the raw materials completely react (the reaction time is 12 hours), filtering the reaction solution after the reaction is completed by a glass dropper with silica gel, washing a filter cake by ethyl acetate, filtering and concentrating under reduced pressure to remove the solvent, and separating the residue by column chromatography, wherein the eluting solvent is: ethyl acetate/n-hexane, yield of the target product I-1 was 45%.
Example 12
With the oxidizing agent PhI (OAc)2(iodobenzene acetate) instead of DTBP in example 1, the reaction progress was monitored by TLC or GC until the starting material was completely reacted (reaction time 12 hours) in the same manner as in example 1, the reaction solution after completion of the reaction was filtered by a glass dropper equipped with silica gel, the filter cake was washed with ethyl acetate, the solvent was removed by filtration and concentration under reduced pressure, and the residue was separated by column chromatography with the elution solvent: ethyl acetate/n-hexane, the yield of the target product I-1 being 12%.
Example 13
The charging amount of oxidant DTBP is 2.0 equivalent (0.4mmol), the rest conditions are the same as example 1, the reaction progress is monitored by TLC or GC until the raw material is completely reacted (the reaction time is 12 hours), the reaction liquid after the reaction is completed is filtered by a glass dropper with silica gel, ethyl acetate washes filter cakes, the solvent is removed by filtration and decompression concentration, the residue is separated by column chromatography, and the elution solvent is: ethyl acetate/n-hexane, the yield of the target product I-1 was 51%.
Example 14
The tetrahydrofuran in example 1 was replaced by acetonitrile solvent, the reaction progress was monitored by TLC or GC under the same conditions as in example 1 until the starting material was completely reacted (reaction time: 12 hours), the reaction solution after completion of the reaction was filtered by a glass dropper equipped with silica gel, the filter cake was washed with ethyl acetate, the solvent was removed by filtration and concentration under reduced pressure, and the residue was isolated by column chromatography using the eluting solvent: ethyl acetate/n-hexane, the yield of the target product I-1 was 97%.
Example 15
The tetrahydrofuran in example 1 was replaced by 1, 2-dichloroethane as solvent, the reaction progress was monitored by TLC or GC as in example 1 until the reaction of the starting material was completed (reaction time 12 hours), the reaction solution after completion of the reaction was filtered through a glass dropper filled with silica gel, the filter cake was washed with ethyl acetate, the solvent was removed by filtration and concentration under reduced pressure, and the residue was separated by column chromatography, eluting with the solvent: ethyl acetate/n-hexane, yield of the target product I-1 was 50%.
Example 16
The tetrahydrofuran in example 1 was replaced by N, N-dimethylformamide as a solvent, the reaction progress was monitored by TLC or GC as in example 1 until the starting material was completely reacted (reaction time 12 hours), the reaction solution after completion of the reaction was filtered through a glass dropper equipped with silica gel, the filter cake was washed with ethyl acetate, the solvent was removed by filtration and concentration under reduced pressure, and the residue was separated by column chromatography, eluting with the solvent: ethyl acetate/n-hexane, yield of target product I-1 was 79%.
Example 17
The reaction temperature was 90 ℃ and the reaction progress was monitored by TLC or GC under the same conditions as in example 14 until the reaction of the starting materials was complete (reaction time 12 hours), the reaction solution after completion of the reaction was filtered through a glass dropper filled with silica gel, the filter cake was washed with ethyl acetate, the solvent was removed by filtration and concentration under reduced pressure, and the residue was isolated by column chromatography using the eluting solvent: ethyl acetate/n-hexane to give the target product I-1 in 86% yield.
Example 18
The reaction temperature was 50 ℃ and the reaction progress was monitored by TLC or GC under the same conditions as in example 14 until the reaction of the starting materials was complete (reaction time 12 hours), the reaction solution after completion of the reaction was filtered through a glass dropper filled with silica gel, the filter cake was washed with ethyl acetate, the solvent was removed by filtration and concentration under reduced pressure, and the residue was isolated by column chromatography using the eluting solvent: ethyl acetate/n-hexane to give the target product I-1 in 81% yield.
EXAMPLE 19 Synthesis of Compound I-2
To Schlenk reactionBottle was charged with 1b (29.0mg, 0.2mmol), Cu (OAc)2(copper acetate, 7.2mg, 0.04mmol), DTBP (di-tert-butyl peroxide, 87.6mg, 0.6mmol) and acetonitrile (1mL) as a solvent, the reaction flask is placed at 70 ℃ and stirred under the condition of air atmosphere for reaction, the reaction progress is monitored by TLC or GC until the raw materials are completely reacted (the reaction time is 12 hours), the reaction liquid after the reaction is completed is filtered by a glass dropper with silica gel, the filter cake is washed by ethyl acetate, the solvent is removed by filtering and concentration under reduced pressure, the residue is separated by column chromatography, and the elution solvent is: ethyl acetate/n-hexane to obtain the target product I-2. (81% yield);1H NMR(400MHz，DMSO-d6)δ：7.23-7.19(m，4H)，6.81(d，J＝8.4Hz，4H)，6.74(t，J＝ 7.2Hz，2H)，4.23(s，4H)，2.85(s，6H)；13C NMR(100MHz，DMSO-d6)δ：149.0，129.4，118.2， 114.3，75.9，67.8，42.4，38.7；HRMS m/z(ESI)calcd for C20H21N2([M+H]+)289.1699，found 289.1705.
EXAMPLE 20 Synthesis of Compound I-3
To a Schlenk reaction flask was added 1c (39.8mg, 0.2mmol), Cu (OAc)2(copper acetate, 7.2mg, 0.04mmol), DTBP (di-tert-butyl peroxide, 87.6mg, 0.6mmol) and acetonitrile (1mL) as a solvent, the reaction flask is placed at 70 ℃ and stirred under the condition of air atmosphere for reaction, the reaction progress is monitored by TLC or GC until the raw materials are completely reacted (the reaction time is 12 hours), the reaction liquid after the reaction is completed is filtered by a glass dropper with silica gel, the filter cake is washed by ethyl acetate, the solvent is removed by filtering and concentration under reduced pressure, the residue is separated by column chromatography, and the elution solvent is: ethyl acetate/n-hexane to obtain the target product I-3. (71% yield);1H NMR(400MHz，DMSO-d6)δ：7.19(t，J＝8.0Hz，4H)，6.79(d，J＝8.0Hz，4H)，6.71 (t，J＝7.2Hz，2H)，5.17(t，J＝6.4Hz，2H)，4.16(s，4H)，3.87(d，J＝6.4Hz，4H)，1.69(s，6H)，1.68 (s，6H)；13C NMR(100MHz，DMSO-d6)δ：148.2，135.2，129.4，121.3，118.0，114.5，76.4，67.7， 48.7，26.0，18.2；HRMS m/z(ESI)calcd for C28H33N2([M+H]+)397.2638，found 397.2642.
EXAMPLE 21 Synthesis of Compound I-4
To a Schlenk reaction flask was added 1d (37.0mg, 0.2mmol), Cu (OAc)2(copper acetate, 7.2mg, 0.04mmol), DTBP (di-tert-butyl peroxide, 87.6mg, 0.6mmol) and acetonitrile (1mL) as a solvent, the reaction flask is placed at 70 ℃ and stirred under the condition of air atmosphere for reaction, the reaction progress is monitored by TLC or GC until the raw materials are completely reacted (the reaction time is 12 hours), the reaction liquid after the reaction is completed is filtered by a glass dropper with silica gel, the filter cake is washed by ethyl acetate, the solvent is removed by filtering and concentration under reduced pressure, the residue is separated by column chromatography, and the elution solvent is: ethyl acetate/n-hexane to obtain the target product I-4. (93% yield);1H NMR(400MHz，DMSO-d6)δ：7.50(t，J＝7.6Hz，4H)，7.43(t，J＝7.2Hz，2H)，7.28 (d，J＝7.6Hz，4H)，6.22(d，J＝16.8Hz，2H)，5.97(t，J＝12.8Hz，2H)，5.63(d，J＝10.8Hz，2H)， 4.65(s，4H)；13C NMR(100MHz，DMSO-d6)δ：164.6，141.1，130.2，129.1，128.8，128.5，128.4， 75.4，67.6，39.2；HRMS m/z(ESI)calcd for C24H21N2O2([M+H]+)369.1598，found 369.1602.
EXAMPLE 22 Synthesis of Compound I-5
To a Schlenk reaction flask was added 1e (45.8mg, 0.2mmol), Cu (OAc)2(copper acetate, 7.2mg, 0.04mmol), DTBP (di-tert-butyl peroxide, 87.6mg, 0.6mmol) and acetonitrile (1mL) as a solvent, the reaction flask was placed at 70 ℃ under an air atmosphere and stirred for reaction,monitoring the reaction progress by TLC or GC until the raw materials completely react (reaction time is 12 hours), filtering the reaction solution after the reaction is finished by a glass dropper with silica gel, washing a filter cake by ethyl acetate, filtering and decompressing and concentrating to remove a solvent, and separating the residue by column chromatography, wherein the elution solvent is: ethyl acetate/n-hexane to obtain the target product I-5. (94% yield);1H NMR(400MHz，DMSO-d6)δ：7.17(d，J＝9.2Hz，4H)，6.95(d，J＝8.8Hz，4H)，5.05 (s，2H)，4.90(s，2H)，4.57(s，4H)，3.77(s，6H)，1.68(s，6H)；13C NMR(100MHz，DMSO-d6)δ： 170.9，158.8，140.2，135.1，129.2，119.6，114.8，75.5，67.7，55.8，39.6，20.4；HRMS m/z(ESI)calcd for C28H29N2O4([M+H]+)457.2122，found 457.2128.
EXAMPLE 23 Synthesis of Compound I-6
To a Schlenk reaction flask was added 1f (42.6mg, 0.2mmol), Cu (OAc)2(copper acetate, 7.2mg, 0.04mmol), DTBP (di-tert-butyl peroxide, 87.6mg, 0.6mmol) and acetonitrile (1mL) as a solvent, the reaction flask is placed at 70 ℃ and stirred under the condition of air atmosphere for reaction, the reaction progress is monitored by TLC or GC until the raw materials are completely reacted (the reaction time is 12 hours), the reaction liquid after the reaction is completed is filtered by a glass dropper with silica gel, the filter cake is washed by ethyl acetate, the solvent is removed by filtering and concentration under reduced pressure, the residue is separated by column chromatography, and the elution solvent is: ethyl acetate/n-hexane to obtain the target product I-6. (93% yield);1H NMR(400MHz，DMSO-d6)δ：7.20(d，J＝8.0Hz，4H)，7.12(d，J＝8.0Hz，4H)，5.05 (s，2H)，4.89(s，2H)，4.59(s，4H)，2.31(s，6H)，1.70(s，6H)；13C NMR(100MHz，DMSO-d6)δ： 170.9，140.2，139.9，137.4，130.2，127.6，119.8，75.5，67.6，39.5，21.0，20.4；HRMS m/z(ESI)calcd for C28H29N2O2([M+H]+)425.2224，found 425.2230.
EXAMPLE 24 Synthesis of Compound I-7
To a Schlenk reaction flask was added 1g (51.0mg, 0.2mmol), Cu (OAc)2(copper acetate, 7.2mg, 0.04mmol), DTBP (di-tert-butyl peroxide, 87.6mg, 0.6mmol) and acetonitrile (1mL) as a solvent, the reaction flask is placed at 70 ℃ and stirred under the condition of air atmosphere for reaction, the reaction progress is monitored by TLC or GC until the raw materials are completely reacted (the reaction time is 12 hours), the reaction liquid after the reaction is completed is filtered by a glass dropper with silica gel, the filter cake is washed by ethyl acetate, the solvent is removed by filtering and concentration under reduced pressure, the residue is separated by column chromatography, and the elution solvent is: ethyl acetate/n-hexane to obtain the target product I-7. (90% yield);1H NMR(400MHz，DMSO-d6)δ：7.41(d，J＝8.4Hz，4H)，7.16(d，J＝8.4Hz，4H)，5.07 (s，2H)，4.92(s，2H)，4.58(s，4H)，1.69(s，6H)，1.28(s，18H)；13C NMR(100MHz，DMSO-d6)δ： 170.9，150.4，140.2，140.0，127.2，126.5，119.9，75.6，67.6，39.7，34.8，31.5，20.3；HRMS m/z(ESI) calcd for C34H41N2O2([M+H]+)509.3163，found 509.3167.
EXAMPLE 25 Synthesis of Compound I-8
To a Schlenk reaction flask was added 1h (46.6mg, 0.2mmol), Cu (OAc)2(copper acetate, 7.2mg, 0.04mmol), DTBP (di-tert-butyl peroxide, 87.6mg, 0.6mmol) and acetonitrile (1mL) as a solvent, the reaction flask is placed at 70 ℃ and stirred under the air atmosphere condition for reaction, the reaction progress is monitored by TLC or GC until the raw materials are completely reacted (the reaction time is 12 hours), the reaction liquid after the reaction is finished is filtered by a glass dropper with silica gel, the filter cake is washed by ethyl acetate, and the solvent is removed by filtering and concentration under reduced pressureSeparating the residue by column chromatography, wherein the elution solvent is as follows: ethyl acetate/n-hexane to obtain the target product I-8. (88% yield);1H NMR(400MHz，DMSO-d6)δ：7.47(d，J＝8.8Hz，4H)，7.29(d，J＝8.8Hz，4H)，5.11 (s，2H)，4.91(s，2H)，4.64(s，4H)，1.73(s，6H)；13C NMR(100MHz，DMSO-d6)δ：170.7，141.4， 139.9，132.4，129.7，129.6，120.3，75.3，67.8，39.6，20.3；HRMS m/z(ESI)calcd for C26H23Cl2N2O2 ([M+H]+)465.1131，found 465.1139.
EXAMPLE 26 Synthesis of Compound I-9
To a Schlenk reaction flask was added 1i (55.4mg, 0.2mmol), Cu (OAc)2(copper acetate, 7.2mg, 0.04mmol), DTBP (di-tert-butyl peroxide, 87.6mg, 0.6mmol) and acetonitrile (1mL) as a solvent, the reaction flask is placed at 70 ℃ and stirred under the condition of air atmosphere for reaction, the reaction progress is monitored by TLC or GC until the raw materials are completely reacted (the reaction time is 12 hours), the reaction liquid after the reaction is completed is filtered by a glass dropper with silica gel, the filter cake is washed by ethyl acetate, the solvent is removed by filtering and concentration under reduced pressure, the residue is separated by column chromatography, and the elution solvent is: ethyl acetate/n-hexane to obtain the target product I-9. (86% yield);1H NMR(400MHz，DMSO-d6)δ：7.61(d，J＝8.8Hz，4H)，7.23(d，J＝8.4Hz，4H)，5.12 (s，2H)，4.91(s，2H)，4.64(s，4H)，1.74(s，6H)；13C NMR(100MHz，DMSO-d6)δ：170.7，141.9， 139.9，132.7，129.9，120.8，120.4，75.3，67.8，39.3，20.3；HRMS m/z(ESI)calcd for C26H23Br2N2O2 ([M+H]+)553.0121，found 553.0125.
EXAMPLE 27 Synthesis of Compound I-10
To a Schlenk reaction flask was added 1j (53.4mg, 0.2mmol), Cu (OAc)2(copper acetate, 7.2mg, 0.04mmol), DTBP (di-tert-butyl peroxide, 87.6mg, 0.6mmol) and acetonitrile (1mL) as a solvent, the reaction flask is placed at 70 ℃ and stirred under the condition of air atmosphere for reaction, the reaction progress is monitored by TLC or GC until the raw materials are completely reacted (the reaction time is 12 hours), the reaction liquid after the reaction is completed is filtered by a glass dropper with silica gel, the filter cake is washed by ethyl acetate, the solvent is removed by filtering and concentration under reduced pressure, the residue is separated by column chromatography, and the elution solvent is: ethyl acetate/n-hexane to obtain the target product I-10. (80% yield);1H NMR(400MHz，DMSO-d6)δ：7.78(d，J＝8.4Hz，4H)，7.49(d，J＝8.4Hz，4H)， 5.15(s，2H)，4.91(s，2H)，4.71(s，4H)，1.77(s，6H)；13C NMR(100MHz，DMSO-d6)δ：170.7， 146.3，139.8，128.3，128.2(q，JC-F＝16.0Hz)，126.8(q，JC-F＝2.6Hz)，125.7，120.8，75.3，67.7， 39.6，20.1；19F NMR(375MHz，DMSO-d6)δ：-61.0；HRMS m/z(ESI)calcd for C28H23F6N2O2 ([M+H]+)533.1658，found 533.1664.
EXAMPLE 28 Synthesis of Compound I-11
To a Schlenk reaction flask was added 1k (42.6mg, 0.2mmol), Cu (OAc)2(copper acetate, 7.2mg, 0.04mmol), DTBP (di-tert-butyl peroxide, 87.6mg, 0.6mmol) and acetonitrile (1mL) as a solvent, the reaction flask is placed at 70 ℃ and stirred under the condition of air atmosphere for reaction, the reaction progress is monitored by TLC or GC until the raw materials are completely reacted (the reaction time is 12 hours), the reaction liquid after the reaction is completed is filtered by a glass dropper with silica gel, the filter cake is washed by ethyl acetate, the solvent is removed by filtering and concentration under reduced pressure, the residue is separated by column chromatography, and the elution solvent is: ethyl acetate/n-hexane to obtain the target product I-11. (89% yield);1H NMR(400MHz，DMSO-d6)δ：7.32-7.22(m，6H)，7.15(d，J＝6.8Hz，2H)，5.02 (s，2H)，4.88(s，2H)，4.65(d，J＝18.0Hz，2H)，4.37(d，J＝18.0Hz，2H)，2.20(s，6H)，1.67(s，6H)； 13C NMR(100MHz，DMSO-d6)δ：170.8，141.1，139.9，135.7，131.7，129.4，128.8，127.3，119.6， 75.2，67.7，38.9，20.2，17.9；HRMS m/z(ESI)calcd for C28H29N2O2([M+H]+)425.224，found 425.2228.
EXAMPLE 29 Synthesis of Compound I-12
To a Schlenk reaction flask was added 1l (48.2mg, 0.2mmol), Cu (OAc)2(copper acetate, 7.2mg, 0.04mmol), DTBP (di-tert-butyl peroxide, 87.6mg, 0.6mmol) and acetonitrile (1mL) as a solvent, the reaction flask is placed at 70 ℃ and stirred under the condition of air atmosphere for reaction, the reaction progress is monitored by TLC or GC until the raw materials are completely reacted (the reaction time is 12 hours), the reaction liquid after the reaction is completed is filtered by a glass dropper with silica gel, the filter cake is washed by ethyl acetate, the solvent is removed by filtering and concentration under reduced pressure, the residue is separated by column chromatography, and the elution solvent is: ethyl acetate/n-hexane to obtain the target product I-12. (88% yield);1H NMR(400MHz，DMSO-d6)δ：6.94(s，4H)，5.06(s，2H)，4.85(s，2H)，4.45(d， J＝8.0Hz，4H)，2.24(s，6H)，2.14(s，12H)，1.67(s，6H)；13C NMR(100MHz，DMSO-d6)δ：170.4， 139.6，137.8，137.7，135.9，129.9，119.7，75.3，67.8，38.8，20.9，20.0，18.4；HRMS m/z(ESI)calcd for C32H37N2O2([M+H]+)481.2850，found 481.2854.
EXAMPLE 30 Synthesis of Compound I-13
To a Schlenk reaction flask was added 1m (49.8mg, 0.2mmol), Cu (OAc)2(copper acetate, 7.2mg, 0.04mmol), DTBP (di-tert-butyl peroxide, 87.6mg, 0.6mmol) and acetonitrile (1mL) as a solvent, the reaction flask is placed at 70 ℃ and stirred under the condition of air atmosphere for reaction, the reaction progress is monitored by TLC or GC until the raw materials are completely reacted (the reaction time is 12 hours), the reaction liquid after the reaction is completed is filtered by a glass dropper with silica gel, the filter cake is washed by ethyl acetate, the solvent is removed by filtering and concentration under reduced pressure, the residue is separated by column chromatography, and the elution solvent is: ethyl acetate/n-hexane to obtain the target product I-13. (87% yield);1H NMR(400MHz，DMSO-d6)δ：8.01(d，J＝8.4Hz，2H)，7.97(d，J＝8.0Hz，2H)， 7.86(d，J＝6.4Hz，2H)，7.64-7.51(m，6H)，7.41(t，J＝6.0Hz，2H)，4.87(d，J＝2.0Hz，2H)，4.82 (t，J＝6.8Hz，4H)，4.44(d，J＝17.6Hz，2H)，1.63(s，6H)；13C NMR(100MHz，DMSO-d6)δ： 171.6，140.0，138.6，134.6，130.2，129.1，129.0，127.8，127.1，126.2，123.0，118.6，75.5，68.1，39.6， 20.3；HRMS m/z(ESI)calcd for C34H29N2O2([M+H]+)497.2224，found 497.2228.
EXAMPLE 31 Synthesis of Compound I-14
To a Schlenk reaction flask was added 1n (42.6mg, 0.2mmol), Cu (OAc)2(copper acetate, 7.2mg, 0.04mmol), DTBP (di-tert-butyl peroxide, 87.6mg, 0.6mmol) and acetonitrile (1mL) as a solvent, the reaction flask is placed at 70 ℃ and stirred under the condition of air atmosphere for reaction, the reaction progress is monitored by TLC or GC until the raw materials are completely reacted (the reaction time is 12 hours), the reaction liquid after the reaction is completed is filtered by a glass dropper with silica gel, the filter cake is washed by ethyl acetate, the solvent is removed by filtering and concentration under reduced pressure, the residue is separated by column chromatography, and the elution solvent is: ethyl acetate/n-hexane to obtain the target product I-14. (85% yield);1H NMR(400MHz，DMSO-d6)δ：7.37(t，J＝7.6Hz，4H)，7.30(d，J＝6.8Hz，2H)， 7.25(d，J＝7.6Hz，4H)，5.27(s，2H)，5.12(s，2H)，4.62(s，4H)，4.21(s，4H)，1.90(s，6H)；13C NMR (100MHz，DMSO-d6)δ：172.0，140.1，137.1，129.1，128.2，127.9，116.3，75.6，67.7，52.3，39.6， 20.6；HRMS m/z(ESI)calcd for C28H29N2O2([M+H]+)425.2224，found 425.2236.
EXAMPLE 32 Synthesis of Compound I-15
To a Schlenk reaction flask was added 1o (45.4mg, 0.2mmol), Cu (OAc)2(copper acetate, 7.2mg, 0.04mmol), DTBP (di-tert-butyl peroxide, 87.6mg, 0.6mmol) and acetonitrile (1mL) as a solvent, the reaction flask is placed at 70 ℃ and stirred under the condition of air atmosphere for reaction, the reaction progress is monitored by TLC or GC until the raw materials are completely reacted (the reaction time is 12 hours), the reaction liquid after the reaction is completed is filtered by a glass dropper with silica gel, the filter cake is washed by ethyl acetate, the solvent is removed by filtering and concentration under reduced pressure, the residue is separated by column chromatography, and the elution solvent is: ethyl acetate/n-hexane to obtain the target product I-15. (76% yield);1H NMR(400MHz，DMSO-d6)δ：7.29(t，J＝7.6Hz，4H)，7.21(d，J＝6.4Hz，6H)， 5.16(s，2H)，4.85(s，2H)，4.35(s，4H)，3.60(t，J＝6.8Hz，4H)，2.86(t，J＝7.6Hz，4H)，1.67(s， 6H)；13C NMR(100MHz，DMSO-d6)δ：171.6，140.3，138.9，129.2，128.9，126.8，115.7，76.0，67.1， 50.6，46.8，34.5，20.4；HRMS m/z(ESI)calcd for C30H33N2O2([M+H]+)453.2537，found 453.2545.
EXAMPLE 33 Synthesis of Compound I-16
To a Schlenk reaction flask was added 1p (57.4mg, 0.2mmol), Cu (OAc)2(copper acetate, 7.2mg, 0.04mmol), DTBP (di-tert-butyl peroxide, 87.6mg, 0.6mmol) and acetonitrile (1mL) as a solvent, the reaction flask is placed at 70 ℃ and stirred under the condition of air atmosphere for reaction, the reaction progress is monitored by TLC or GC until the raw materials are completely reacted (the reaction time is 12 hours), the reaction liquid after the reaction is completed is filtered by a glass dropper with silica gel, the filter cake is washed by ethyl acetate, the solvent is removed by filtering and concentration under reduced pressure, the residue is separated by column chromatography, and the elution solvent is: ethyl acetate/n-hexane to obtain the target product I-16. (72% yield);1H NMR(400MHz，DMSO-d6)δ：6.84(t，J＝7.6Hz，4H)，6.71(d，J＝7.6Hz，2H)， 5.16(s，2H)，4.85(s，2H)，4.33(s，4H)，3.73(s，6H)，3.70(s，6H)，3.58(t，J＝6.4Hz，4H)，2.78(t，J ＝7.2Hz，4H)，1.68(s，6H)；13C NMR(100MHz，DMSO-d6)δ：171.7，149.2，147.9，140.3，131.4， 121.1，115.7，113.1，112.4，76.0，67.1，56.0，55.9，50.8，46.8，34.1，20.4；HRMS m/z(ESI)calcd for C34H41N2O6([M+H]+)573.2959，found 573.2969.
EXAMPLE 34 Synthesis of Compound I-17
To a Schlenk reaction flask was added 1q (52.6mg, 0.2mmol), Cu (OAc)2(copper acetate, 7.2mg, 0.04mmol), DTBP (di-tert-butyl peroxide, 87.6mg, 0.6mmol) and acetonitrile (1mL) as a solvent, the reaction flask is placed at 70 ℃ and stirred under the condition of air atmosphere for reaction, the reaction progress is monitored by TLC or GC until the raw materials are completely reacted (the reaction time is 12 hours), the reaction liquid after the reaction is completed is filtered by a glass dropper with silica gel, the filter cake is washed by ethyl acetate, the solvent is removed by filtering and concentration under reduced pressure, the residue is separated by column chromatography, and the elution solvent is: ethyl acetate/n-hexane to obtain the target product I-17. (80% yield);1H NMR(400MHz，DMSO-d6)δ：8.00(d，J＝7.6Hz，4H)，7.77(t，J＝7.6Hz，2H)， 7.65(t，J＝7.6Hz，4H)，5.49(s，2H)，5.24(s，2H)，4.79(s，4H)，1.82(s，6H)；13C NMR(100MHz， DMSO-d6)δ：171.3，139.1，138.9，134.9，129.7，128.5，121.0，76.0，67.7，38.4，19.3；HRMS m/z (ESI)calcd for C26H25N2O6S2([M+H]+)525.1149，found 525.1155.
EXAMPLE 35 Synthesis of Compound I-18
To a Schlenk reaction flask was added 1r (55.4mg, 0.2mmol), Cu (OAc)2(copper acetate, 7.2mg, 0.04mmol), DTBP (di-tert-butyl peroxide, 87.6mg, 0.6mmol) and acetonitrile (1mL) as a solvent, the reaction flask is placed at 70 ℃ and stirred under the condition of air atmosphere for reaction, the reaction progress is monitored by TLC or GC until the raw materials are completely reacted (the reaction time is 12 hours), the reaction liquid after the reaction is completed is filtered by a glass dropper with silica gel, the filter cake is washed by ethyl acetate, the solvent is removed by filtering and concentration under reduced pressure, the residue is separated by column chromatography, and the elution solvent is: ethyl acetate/n-hexane to obtain the target product I-18. (82% yield);1H NMR(400MHz，DMSO-d6)δ：7.88(d，J＝8.0Hz，4H)，7.44(d，J＝8.4Hz，4H)， 5.47(s，2H)，5.22(s，2H)，4.77(s，4H)，2.41(s，6H)，1.82(s，6H)；13C NMR(100MHz，DMSO-d6) δ：171.3，145.6，139.2，135.9，130.1，128.6，120.8，76.0，67.7，38.3，21.6，19.4；HRMS m/z(ESI) calcd for C28H29N2O6S2([M+H]+)553.1462，found 553.1468.
example 36 reaction mechanism control test
To the reaction of example 14, TEMPO (2, 2, 6, 6-tetramethylpiperidineoxide) or BHT (2, 6-di-tert-butyl) -4-methylphenol was added as a radical scavenger in 3.2 equivalents, and yields of the target products of the reaction were 88% and 62%, respectively.
It follows that this reaction does not involve a radical process, and that a possible reaction mechanism of the present invention can be deduced as shown by the following formula:
the embodiments described above are only preferred embodiments of the invention and are not exhaustive of the possible implementations of the invention. Any obvious modifications to the above would be obvious to those of ordinary skill in the art, but would not bring the invention so modified beyond the spirit and scope of the present invention.
Claims (4)
1. A preparation method of a 1, 3-diacetylene derivative is characterized by comprising the following steps: adding an alkyl terminal alkyne compound shown in formula 1, a copper catalyst, an oxidant and a solvent into a Schlenk reaction bottle, placing the reaction bottle at a certain temperature under the air atmosphere condition, stirring for reaction, and carrying out aftertreatment after the reaction is completed to obtain a target product 1, 3-diacetylene derivative (I); the reaction formula is shown as follows:
in the compounds represented by formula 1 and formula I, R1Selected from hydrogen, substituted or unsubstituted C6-C8Aryl or substituted or unsubstituted C1-C10An alkyl group; the substituent of the "substitution" is selected from halogen or C1-C6Alkyl groups of (a);
R2represents substituted or unsubstituted C1-C5Alkyl or substituted or unsubstituted C3-C4Acyl, said "substituted" substituent being selected from halogen or C1-C2Alkyl of (2)；
Wherein the copper catalyst is copper acetate Cu (OAc)2The oxidant is di-tert-butyl peroxide (DTBP);
the certain temperature is 70 ℃;
the solvent is acetonitrile.
2. The method of claim 1, wherein the compound of formula 1 is reacted with Cu (OAc)2The molar ratio of (A) to (B) is 1: 0.1-0.3; the molar ratio of the compound of the formula 1 to DTBP is 1: 1-4.
3. The method of claim 2, wherein the compound of formula 1 is reacted with Cu (OAc)2The molar ratio of (A) to (B) is 1: 0.2; the molar ratio of the compound of formula 1 to DTBP was 1: 3.
4. The method of claim 1, wherein the post-processing operation is as follows: filtering the reaction solution by a glass dropper filled with silica gel, washing a filter cake by ethyl acetate, filtering, decompressing and concentrating to remove the solvent, and separating the residue by column chromatography, wherein the elution solvent is: ethyl acetate/n-hexane to obtain the target product 1, 3-diacetylene derivative (I).
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