CN111662147A - Process for preparing diynes and analogues thereof - Google Patents

Abstract

The invention discloses a method for preparing various diynes and derivatives thereof. The method uses propargyl bromide compound IV and terminal alkyne compound V as substrates, and reacts in nitrogen-nitrogen dimethylacetamide at 40 ℃ under the condition of monovalent copper as a catalyst and potassium phosphate as alkali in a nitrogen environment to obtain different types of diyne compounds shown in structural formula I, formula II and formula III.

Description

Process for the preparation of diacetylenes and analogs thereof

technical field

The invention belongs to the field of catalytic synthesis of fine chemical products, in particular to a method for preparing diacetylenic compounds.

Background technique

As one of the most basic reaction units in organic chemistry, alkynyl groups can participate in various types of reactions. And alkyne compounds are also widely used in modern organic synthesis, medicinal chemistry, material chemistry and other fields (Diederich.F.; Stang.P.J.; Tykwinski, R.R.Acetylene Chemistry: Chemistry, Biology and Material Science. Wiley-VCH, Weinheim. 2005).

Compared with a single alkyne, diacetylene can provide 2-4 carbon atoms to participate in the reaction simultaneously or in steps, so it has more designability and is widely used in various organic reactions. Among them, 1,3-diyne compounds are conjugated with two alkynyl groups, which also makes its structure and electrical properties different from that of single alkynes, and thus also produces different reactivity. Reactions involving monoalkynyl groups can be used to construct alkynyl-substituted compounds for further modification etc. (Gevorgyan, V.; Takeda, A.; Yamamoto, Y. J. Am. Chem. Soc. 1997, 119, 11313). Reactions involving both alkynyl groups can be used to construct various organic heterocyclic molecules such as furan, pyrrole, pyrazole, thiophene, and silole (Shi, W.; Lei, A-W. Tetrahedron Letters. 2014, 55, 2763; Kramer, S.; Madsen, J.L.H.; Rottlander, M.; Skrydstrup, T. Org, Lett. 2010, 12, 2758; Wang, L.; Yu, X.; Feng, X.; 2013, 78, 1693). 1,4-Diyne compounds have been widely used as building blocks of polyunsaturated fatty acids and their derivatives since 1950 (Durand, S.; Parrain, J.L.; Santelli, M.J.Chem.Soc., Perkin Trans.1, 2000, 253), when the third carbon atom of 1,4-diyne is connected with other substituents, it can also be used to construct structures such as pyrrole, pyridine, furan and furanone (Wang, T.; Shi , S.; Hansmann, M.M.; Hashmi, A.S.K.Angew.Chem., Int.Ed.2014,53,3715; Xu, Y.L.; Teng, Q.H.; Ma, X.L.Molecules.2017,22,109; ;Li,P.H.;Liu,R.S.Chem.Commun.2018,54,2114.), when 1,4-diyne is methylene in three positions, it can react with pyrrole through two hydroarylation reactions under gold catalysis The cycloheptatrienopyrrole skeleton structure was constructed (Hamada, N.; Yoshida, Y.; Oishi, S.; Ohno, H. Org. Lett. 2017, 19, 3875). In addition to the construction of heterocyclic skeletons, 1,5-, 1,6-diynes can also be used in the construction of carbocyclic and various polycyclic skeletons (Wurm, T.; Bucher, J.; Hashmi , A.S.K.Angew.Chem., Int.Ed.2017,56,3364; Yoshizaki, S.; Shibata, Y.; Tanaka, K.Angew.Chem., Int.Ed.2017,56,3590), and if The use of chiral ligands over metal catalysts can also build chiral cyclic skeletons, which have also become an effective means for the synthesis of many natural products and drug molecule intermediates (Kashima, K.; Teraoka, K.; Uekusa, H. .; Shibata, Y.; Tanaka, K. Org. Lett. 2016, 18, 2170).

Due to the diverse applications of various diacetylenic compounds in organic synthesis, their synthetic methods have always attracted the attention of organic chemists. 1,3-Diynes, especially asymmetric 1,3-diynes are one of the important compounds. Traditional methods mainly include Glaser-Hay coupling and Cadiot-Chodkiewicz coupling (Siemsen, P.; Livingston, RC; Diederich). , F.Angew.Chem.,Int.Ed.2000,39,2632; Shi, W.; Luo, Y.; Luo, X.; Chao, L.; Zhang, H.; Wang, J.; Lei, AJ Am. Chem. Soc. 2008, 130, 14713). However, the Glaser-Hay coupling reaction catalyzed by Cu or Ni often requires a large excess of an alkyne due to the occurrence of the alkyne self-coupling side reaction; the Cadiot-Chodkiewicz coupling reaction requires a terminal alkyne to be pre-functionalized into an alkynyl bromide. Involved in the reaction, and alkynyl bromide compounds are not stable. In recent years, there are also some methods to efficiently synthesize asymmetric 1,3-diynes, but they require expensive gold catalysts and additional ligands (Peng, H.; Xi, Y.; Shi, XJAm.Chem.Soc.2014 , 136, 13174). For 1,4-diyne, there have been some reports on the synthesis of compounds with heteroatom substituents such as oxygen and nitrogen at the 3-position (Qiu, YF; Yang, F.; Liang, YMJ Org. Chem. 2013, 78, 12018). For the 1,4-diyne synthesis methods that are unsubstituted at the 3-position or connected with an alkyl group, most of them come from the route of synthesizing unsaturated fatty acids. In the early days, propargyl halides and alkynyl Grignard reagents were often used. reaction, which not only requires the preparation of the alkynyl Grignard reagent in advance, but also requires stricter reaction conditions. Subsequently, the reaction of various propargyl compounds with alkynyl metal compounds such as alkynyl lithium, alkynyl aluminum, alkynyl cuprate, etc. has also been developed. Some reactions can also be completed under the catalysis of copper, but these reactions are atomically economical. Sex remains low (Tedeschi, C.; Saccavini, C.; Chauvin, RJ Organomet. Chem. 2003, 670, 151). In 1992, Jeffery et al. reported a method for the coupling of propargyl halides and terminal alkynes to prepare unsubstituted 1,4-diynes at the 3-position of alkyl groups. This method used an equivalent of CuI/Na ₂ CO ₃ and added [n-Bu ₄ N][Cl] was used to improve the yield, thus avoiding the use of strongly basic alkyl metal reagents to extract the alkyne hydrogen, and the atom economy of the reaction was also greatly improved (Jeffery, T. ; Gueugnot, S.; Linstrumelle, G. Tetrahedron Lett. 1992, 33, 5757). And then there are many improvements to this method and they are quickly applied to the synthesis of unsaturated fatty acids, pheromones and other molecules, but the use of equivalent or even excess metal salts is still a problem; secondly, the above methods are mostly used for alkyl 1,4-diol The synthesis of alkynes and aryl 1,4-diynes still needs to be solved urgently. Since there are still different problems in the above various methods, the development of a more convenient, efficient and green diacetylene synthesis technology has become the goal of people's exploration, which involves two problems: one is how to reduce the use of metal salts to make The second is how to apply the synthetic method of 1,4-diyne to aryl to construct 1,5-diaryl-1,4-diyne.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a method for preparing diynes and their analogs.

The method for preparing compounds represented by formula I, formula II and formula III (that is, diynes and their analogs) provided by the present invention comprises the following steps: combining the propargyl bromide compound represented by formula IV, the compound represented by formula V The alkyne compound, the base and the catalyst are mixed and reacted, and the compound represented by the formula I or the compound represented by the formula II or the compound represented by the formula III is obtained after the reaction;

To prepare the compound represented by the formula I, in the formula V, n=0; in the formula IV and the formula V, R ¹ and R ³ are independently selected from phenyl, substituted phenyl or heterocyclic group; The substituent is preferably p-methyl, o-methyl, m-methyl or 4-fluoro, and the heterocycle can specifically be thienyl or pyrrolyl; R ² in the formula IV is a hydrogen atom or an alkane In particular, the alkyl group may be a C1-C4 alkyl group, preferably a methyl group.

To prepare the compound represented by the formula II, in the formula V, n=0; R ² in the formula IV is a hydrogen atom; when R ¹ in the formula IV is an alkyl group, R ³ in the formula V When it is an aryl group, 1,3-diyne is connected to R ³ , the R ¹ can be C1-C6 alkyl, preferably ethyl, and R ³ is preferably phenyl or 4-fluorophenyl; when R in formula IV ¹ is an aryl group, when R ³ in the formula V is an alkyl group or an alkyl group containing a substituent, 1,3-diyne is connected to R ¹ , and the R ¹ is preferably phenyl or 4-Me phenyl, so The alkyl group in R ³ is a C1-C6 alkyl group, and R ³ is preferably phenylmethyl, cyclohexyl or n-propyl.

To prepare the compound represented by the formula III, in the formula V, n=1 or 2 or 3; in the formula IV and the formula V, R ¹ and R ³ are independently selected from phenyl or substituted phenyl, The substituent can be selected from p-methyl, o-methyl, m-methyl or 4-fluoro; the R ¹ and R ³ are preferably phenyl; R ² in the formula IV is aryl or An alkyl group, the aryl group can be a phenyl group, and the alkyl group can specifically be a C1-C4 alkyl group, preferably a methyl group.

In the above method, the base can be selected from at least one of the following: potassium carbonate, dipotassium hydrogen phosphate and potassium phosphate, preferably potassium phosphate.

In the above method, the catalyst is a monovalent copper catalyst, specifically CuI or CuBr, preferably CuBr.

In the above method, the molar dosage of the alkyne compound shown in the formula V is 1.2-2 times that of the propargyl bromide compound shown in the formula IV; when preparing the compound shown in the formula I, preferably 1.2 times or 1.5 times, preferably 1.2 times when preparing the compounds of formula II and formula III.

In the above method, the molar dosage of the catalyst is 10%-20% of the propargyl bromide compound represented by the formula IV, preferably 20%.

In the above method, the molar dosage of the base is 1.0-1.5 times, preferably 1.0 times, that of the propargyl bromide compound represented by the formula IV.

In the above method, the reaction is carried out in a solvent selected from at least one of the following: 1,2-dichloroethane, N,N-dimethylformamide or N.N-dimethylacetamide, N,N-dimethylacetamide is preferred.

In the above method, the reaction is carried out in an inert atmosphere, such as nitrogen.

In the above method, in the reaction step, the temperature is 40-60°C, preferably 40°C; the time is 16-20 hours, preferably 16 hours, and the specific reaction time can be detected by thin layer chromatography.

The above method also includes: after the completion of the reaction, the reaction system is separated and purified according to a conventional method. The preferred separation method is as follows: transfer the reacted stock solution to a separatory funnel, and add an appropriate amount of ethyl acetate to rinse the reaction tube during transfer to reduce transfer losses; add an appropriate amount of saturated aqueous ammonium chloride solution to the separatory funnel, and use ethyl acetate Ester extraction three times, the organic phases were combined; dried with anhydrous magnesium sulfate, filtered; then the organic phase was concentrated, an appropriate amount of 100-200 mesh silica gel was added, and the column was dry-column; eluted with petroleum ether/ethyl acetate mixed solution, petroleum The ratio of ether/ethyl acetate varies depending on the polarity of the reactants and products, and needs to be estimated by the results of thin layer chromatography. The volume fraction of ethyl acetate is generally 0-10%. The solution containing product I, II or III was collected, concentrated under reduced pressure to remove the solvent, dried in vacuo, weighed and the yield calculated.

For solid products, the purity can be improved by recrystallization. The general method of recrystallization is to add a certain amount of dichloromethane to the sample to make it just completely dissolved, and then add n-hexane, a poor solvent, to slowly volatilize it. , a single crystal of the product can be obtained.

The method for synthesizing diacetylene and its analogs provided by the present invention has the following characteristics: (1) the reaction conditions are mild, the yield is moderate to excellent, the amount of metal salt used is greatly reduced, the method is greener and more environmentally friendly. (2) The reaction has good universality. The same conditions can be used to obtain 1,4-diyne or asymmetric 1,3-diyne based on different substrates. Under special substrates, it can also be used to prepare aryl 1,n - Diynes.

Description of drawings

Fig. 1 is the hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 1.

Fig. 2 is the carbon nuclear magnetic resonance spectrum of the target product obtained in Example 1.

Fig. 3 is the hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 2.

Fig. 4 is the carbon nuclear magnetic resonance spectrum of the target product obtained in Example 2.

FIG. 5 is the hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 6. FIG.

FIG. 6 is the carbon nuclear magnetic resonance spectrum of the target product obtained in Example 6. FIG.

FIG. 7 is the hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 8. FIG.

FIG. 8 is the carbon nuclear magnetic resonance spectrum of the target product obtained in Example 8. FIG.

FIG. 9 is the hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 10. FIG.

Figure 10 is the carbon nuclear magnetic resonance spectrum of the target product obtained in Example 10.

FIG. 11 is the hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 11. FIG.

Figure 12 is the carbon nuclear magnetic resonance spectrum of the target product obtained in Example 11.

Detailed ways

The present invention will be described below through specific embodiments, but the present invention is not limited thereto, and any modifications, equivalent replacements and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention. within.

The experimental methods used in the following examples are conventional methods unless otherwise specified.

The materials, reagents, etc. used in the following examples can be obtained from commercial sources unless otherwise specified.

The raw materials (3-bromo-1-propynyl)benzene and (3-bromo-1-butynyl)benzene used in the following examples can be prepared by the following method: Dissolving triphenylphosphine (11 mmol) In 1,2-dichloroethane (30 mL), bromine (11 mmol) was then added dropwise at 0 °C, stirred for 30 min, and the solution gradually changed from clear yellow to suspension. A solution of 3-phenyl-2-propyn-1-ol (10 mmol) or 4-phenyl-3-butyn-2-ol (10 mmol) in 1,2-dichloroethane (5 mL) was then dissolved It was added dropwise to the suspension, and the solution gradually became clear as the alcohol was added dropwise. After the dropwise addition, the clear solution continued to be stirred at 0 °C for 1 h. Cycloethane (60 mL) was then added, at which point a white precipitate immediately precipitated, and the mixture was stirred at room temperature for another 30 min. Then the reaction system is filtered and washed with cyclohexane, the filtrate is concentrated and then passed through a column, and the corresponding propargyl bromide can be washed out with pure petroleum ether, and the yield is over 90%.

Raw materials used in the following examples 1-(3-bromo-1-propynyl)-4-methylbenzene, 1-(3-bromo-1-propynyl)-3-methylbenzene, 1- (3-Bromo-1-propynyl)-2-methylbenzene, 1-(3-bromo-1-propynyl)-4-fluorobenzene and 2-(3-bromo-1-propynyl) Thiophene can be prepared according to the following method: in a 100mL round-bottomed flask, add magneton, CuI (10mg, 0.053mmol), corresponding iodobenzene (4-methyl iodobenzene, 3-methyl iodobenzene, 2-methyl iodobenzene) iodobenzene, 4-fluoroiodobenzene, 2-iodothiophene) (13.8 mmol), and dried under reduced pressure. Then dry toluene (14 mL), piperidine (3.3 mL, 33 mmol), propargyl alcohol (1.5 mL) and dichloroditriphenylphosphine palladium (17 mg, 0.024 mmol) were added. The reaction was placed under nitrogen protection, and reacted at 35° C. for 14 h, and then the reaction solution was filtered through celite and spin-dried. Then the obtained crude product was separated by column chromatography, and the eluent was ethyl acetate: petroleum ether (3:1) to obtain the corresponding propargyl alcohol [3-(4-methylphenyl)-2-propane] Alkyn-1-ol, 3-(3-methylphenyl)-2-propyn-1-ol, 3-(2-methylphenyl)-2-propyn-1-ol, 3-(4 -Fluorophenyl)-2-propyn-1-ol, 3-(2-thienyl)-2-propyn-1-ol] in a yield of 80 or more.

Triphenylphosphine (11 mmol) was dissolved in 1,2-dichloroethane (30 mL), followed by dropwise addition of bromine (11 mmol) at 0°C, stirring for 30 min, the solution gradually changed from yellow to clear to suspension. The corresponding propargyl alcohols [3-(4-methylphenyl)-2-propyn-1-ol, 3-(3-methylphenyl)-2-propyn-1-ol, , 3-(2-methylphenyl)-2-propyn-1-ol, 3-(4-fluorophenyl)-2-propyn-1-ol, 3-(2-thienyl)-2 -Propyn-1-ol] (10mmol) in 1,2-dichloroethane solution (5mL) was added dropwise to the suspension, the solution gradually became clear as the alcohol was added dropwise, and the dropwise addition was complete. The clear solution was then stirred for 1 h at 0°C. Cycloethane (60 mL) was then added, at which point a white precipitate immediately precipitated, and the mixture was stirred at room temperature for another 30 min. Then the reaction system is filtered and washed with cyclohexane, the filtrate is concentrated and then passed through a column, and the corresponding propargyl bromide can be washed out with pure petroleum ether, and the yield is over 90%.

Example 1. Synthesis of 1,5-diphenyl-1,4-pentadiyne

Weigh 97.5 mg of (3-bromo-1-propynyl)benzene (0.5 mmol), 76.5 mg of phenylacetylene (0.75 mmol), 14.4 mg of CuBr (0.1 mmol), and 106 mg of K ₃ PO ₄ (0.5 mmol) in sequence containing To a 25 mL sealed tube with a magnetic stirrer, 2.5 mL of azathioprine was added. The tube was sealed under nitrogen and stirred at 40°C for 16 hours. After the reaction, saturated ammonium chloride solution was added, extracted with ethyl acetate for 3 times, the organic phases were combined, dried and concentrated, and pure petroleum ether was used as the eluent for column separation to obtain 146.9 mg of pale yellow solid, the target product 1,5-di The isolated yield of phenyl-1,4-pentadiyne was 68%. Fig. 1 and Fig. 2 are the hydrogen nuclear magnetic resonance spectrum and carbon spectrum of the product obtained by the preparation of this example. It can be seen from the figures that the structure of the compound is correct.

Example 2. Synthesis of 1,5-di-p-methylphenyl-1,4-pentadiyne

Weigh in turn 104.5mg 1-(3-bromo-1-propynyl)-4-methylbenzene (0.5mmol), 87mg p-methylphenylacetylene (0.75mmol), 14.4mg CuBr (0.1mmol), 106mg K ₃ PO ₄ (0.5 mmol) was placed in a 25 mL sealed tube with a magnetic stirrer bar, and 2.5 mL of nitrosodimethylacetamide was added. The tube was sealed under nitrogen and stirred at 40°C for 16 hours. After the reaction, saturated ammonium chloride solution was added, extracted with ethyl acetate for 3 times, the organic phases were combined, dried and concentrated, and pure petroleum ether was used as the eluent for column separation to obtain 192.7 mg of pale yellow solid, the target product 1,5-di The isolated yield of p-methylphenyl-1,4-pentadiyne was 83%. Fig. 3 and Fig. 4 are the hydrogen nuclear magnetic resonance spectrum and carbon spectrum of the product prepared in this example, and it can be seen from the figures that the structure of the compound is correct.

Example 3. Synthesis of 1,5-di-o-methylphenyl-1,4-pentadiyne

Weigh 104.5mg of 1-(3-bromo-1-propynyl)-2-methylbenzene (0.5mmol), 87mg of 2-methylphenylacetylene in turn

(0.75 mmol), 14.4 mg CuBr (0.1 mmol), 106 mg K ₃ PO ₄ (0.5 mmol) in a 25 mL sealed tube containing a magnetic stirrer, and 2.5 mL of nitrodimethylacetamide was added. The tube was sealed under nitrogen and stirred at 40°C for 16 hours. After the reaction, saturated ammonium chloride solution was added, extracted with ethyl acetate for 3 times, the organic phases were combined, dried and concentrated, and pure petroleum ether was used as the eluent for column separation to obtain 209.8 mg of pale yellow oily liquid, the target product 1,5- The isolated yield of di-o-methylphenyl-1,4-pentadiyne was 89%.

Example 4. Synthesis of 1,5-dimethylphenyl-1,4-pentadiyne

Weigh 104.5 mg of 1-(3-bromo-1-propynyl)-3-methylbenzene (0.5 mmol), 87 mg of 3-methylphenylacetylene (0.75 mmol), 14.4 mg of CuBr (0.1 mmol), 106 mg of K ₃ PO ₄ (0.5 mmol) was placed in a 25 mL sealed tube containing a magnetic stirrer bar, and 2.5 mL of azathioprine was added. The tube was sealed under nitrogen and stirred at 40°C for 16 hours. After the reaction, saturated ammonium chloride solution was added, extracted with ethyl acetate for 3 times, the organic phases were combined, dried and concentrated, and pure petroleum ether was used as the eluent for column separation to obtain 214.7 mg of pale yellow oily liquid, the target product 1,5- The isolated yield of dimethylphenyl-1,4-pentadiyne was 93%.

Example 5. Synthesis of 1,5-bis(4-fluoro-phenyl)-1,4-pentadiyne

Weigh in turn 106.5mg 1-(3-bromo-1-propynyl)-4-fluorobenzene (0.5mmol), 90mg 4-fluorophenylacetylene (0.75mmol), _14.4mg CuBr (0.1mmol), 106mg K3 PO ₄ (0.5 mmol) was placed in a 25 mL sealed tube containing a magnetic stirrer bar, and 2.5 mL of nitrosodimethylacetamide was added. The tube was sealed under nitrogen and stirred at 40°C for 16 hours. After the reaction, saturated ammonium chloride solution was added, extracted with ethyl acetate 3 times, the organic phases were combined, and after drying and concentration, pure petroleum ether was used as the eluent to carry out column separation to obtain 168.8 mg of white solid, the target product 1,5-bis( 4-Fluoro-phenyl)-1,4-pentadiyne isolated in 70% yield.

Example 6. Synthesis of 3-methyl-1-(3-methylphenyl)-5-phenyl-1,4-pentadiyne

Weigh 104.5 mg (3-bromo-1-butynyl) benzene (0.5 mmol), 69.6 mg 3-methylphenylacetylene (0.6 mmol), 14.4 mg CuBr (0.1 mmol), 106 mg K ₃ PO ₄ (0.5 mmol) in turn. mmol) in a 25 mL sealed tube with a magnetic stir bar, and 2.5 mL of nitrosodimethylacetamide was added. The tube was sealed under nitrogen and stirred at 40°C for 16 hours. After the reaction, saturated ammonium chloride solution was added, extracted with ethyl acetate for 3 times, the organic phases were combined, dried and concentrated, and pure petroleum ether was used as the eluent for column separation to obtain 222 mg of light yellow oily liquid, the target product 3-methyl- The isolated yield of 1-(3-methylphenyl)-5-phenyl-1,4-pentadiyne was 91%. Fig. 5 and Fig. 6 are the hydrogen nuclear magnetic resonance spectrum and carbon spectrum of the product prepared in this example, and it can be seen from the figures that the structure of the compound is correct.

Example 7. Synthesis of 1,5-bis(2-thiophene)-1,4-pentadiyne

Weigh 100.5mg 2-(3-bromo-1-propynyl)thiophene (0.5mmol), 81.1mg 2-ethynylthiophene (0.75mmol), 14.4mg CuBr (0.1mmol), 106mg K ₃ PO ₄ ( 0.5 mmol) in a 25 mL sealed tube containing a magnetic stirrer, and 2.5 mL of nitrosodimethylacetamide was added. The tube was sealed under nitrogen and stirred at 40°C for 16 hours. After the reaction, saturated ammonium chloride solution was added, extracted with ethyl acetate for 3 times, the organic phases were combined, dried and concentrated, and pure petroleum ether was used as the eluent for column separation to obtain 132.4 mg of light yellow oily liquid, the target product 1,5- The isolated yield of bis(2-thiophene)-1,4-pentadiyne was 58%.

Example 8. Synthesis of 1-phenyl-1,3-hexadiyne

Weigh 74 mg of 1-bromo-2-pentyne (0.5 mmol), 61.2 mg of phenylacetylene (0.6 mmol), 14.4 mg of CuBr (0.1 mmol), and 106 mg of K ₃ PO ₄ (0.5 mmol) in 25 mL containing a magnetic stirring bar in turn. In the sealed tube, 2.5 mL of nitrosodimethylacetamide was added. The tube was sealed under nitrogen and stirred at 40°C for 16 hours. After the reaction, saturated ammonium chloride solution was added, extracted with ethyl acetate for 3 times, the organic phases were combined, dried and concentrated, and column separation was carried out with petroleum ether/ethyl acetate (100/0-95/5) as the eluent to obtain no residue. The color oily liquid was 139.6 mg, and the isolated yield of the target product 1-phenyl-1,3-hexadiyne was 82%. Fig. 7 and Fig. 8 are the hydrogen nuclear magnetic resonance spectrum and carbon spectrum of the product prepared in this example, and it can be seen from the figures that the structure of the compound is correct.

Example 9. Synthesis of 1-(4-fluorophenyl)-1,3-hexadiyne

Weigh 74 mg of 1-bromo-2-pentyne (0.5 mmol), 72 mg of 4-fluorophenylacetylene (0.6 mmol), 14.4 mg of CuBr (0.1 mmol), and 106 mg of K ₃ PO ₄ (0.5 mmol) in turn containing a magnetic stirring bar. In a 25 mL sealed tube, 2.5 mL of nitrosodimethylacetamide was added. The tube was sealed under nitrogen and stirred at 40°C for 16 hours. After the reaction, saturated ammonium chloride solution was added, extracted with ethyl acetate for 3 times, the organic phases were combined, dried and concentrated, and column separation was carried out with petroleum ether/ethyl acetate (100/0-95/5) as the eluent to obtain no residue. The color oily liquid was 171.3 mg, and the isolated yield of the target product 1-(4-fluorophenyl)-1,3-hexadiyne was 92%.

Example 10. Synthesis of 1,6-diphenyl-1,3-hexadiyne

Weigh 97.5mg (3-bromo-1-propynyl)benzene (0.5mmol), 69.6mg 3-phenyl-1-propyne (0.6mmol), 14.4mg CuBr (0.1mmol), 106mg K ₃ PO in this order ₄ (0.5 mmol) in a 25 mL sealed tube with a magnetic stirrer, and 2.5 mL of nitrosodimethylacetamide was added. The tube was sealed under nitrogen and stirred at 40°C for 16 hours. After the reaction, saturated ammonium chloride solution was added, extracted three times with ethyl acetate, the organic phases were combined, dried and concentrated, and pure petroleum ether was used as the eluent for column separation to obtain 179.4 mg of pale yellow oily liquid, the target product 1,6- The isolated yield of diphenyl-1,3-hexadiyne was 78%. Figures 9 and 10 are the hydrogen nuclear magnetic resonance spectrum and carbon spectrum of the product prepared in this example. It can be seen from the figures that the structure of the compound is correct.

Example 11. Synthesis of 3-methyl-1,6-diphenyl-1,5-hexadiyne

Weigh 104.5mg (3-bromo-1-butynyl)benzene (0.5mmol), 69.6mg 3-phenyl-1-propyne (0.6mmol), 14.4mg CuBr (0.1mmol), 106mg K ₃ PO in turn ₄ (0.5 mmol) in a 25 mL sealed tube with a magnetic stirrer, and 2.5 mL of nitrosodimethylacetamide was added. The tube was sealed under nitrogen and stirred at 40°C for 16 hours. After the reaction, saturated ammonium chloride solution was added, extracted with ethyl acetate for 3 times, the organic phases were combined, dried and concentrated, and pure petroleum ether was used as the eluent for column separation to obtain 170.8 mg of light yellow oily liquid, the target product 3-methyl The isolated yield of -1,6-diphenyl-1,5-hexadiyne was 75%. Figure 11 and Figure 12 are the hydrogen nuclear magnetic resonance spectrum and carbon spectrum of the product prepared in this example, and it can be seen from the figures that the structure of the compound is correct.

Example 12. Synthesis of 3-methyl-1,7-diphenyl-1,6-heptadiyne

Weigh in turn 104.5mg (3-bromo-1-butynyl)benzene (0.5mmol), 78mg 4-phenyl-1-butyne (0.6mmol), _14.4mg CuBr (0.1mmol), 106mg _K3PO4 (0.5 mmol) in a 25 mL sealed tube containing a magnetic stirrer bar, and 2.5 mL of nitrosodimethylacetamide was added. The tube was sealed under nitrogen and stirred at 40°C for 16 hours. After the reaction, saturated ammonium chloride solution was added, extracted 3 times with ethyl acetate, the organic phases were combined, dried and concentrated, and pure petroleum ether was used as the eluent for column separation to obtain 175.7 mg of pale yellow oily liquid, the target product 3-methyl The isolated yield of -1,7-diphenyl-1,6-heptadiyne was 73%.

Example 13. Synthesis of 1,5-diphenyl-1,4-pentadiyne

Weigh 97.5mg (3-bromo-1-propynyl)benzene (0.5mmol), 76.5mg phenylacetylene (0.75mmol), 14.4mg CuBr (0.1mmol), 106mg K ₃ PO4 (0.5 mmol) in the magnetic 2.5 mL of nitrosodimethylacetamide was added to a 25 mL sealed tube with a stirring bar. The tube was sealed under nitrogen and stirred at 60°C for 16 hours. After the reaction, saturated ammonium chloride solution was added, extracted with ethyl acetate for 3 times, the organic phases were combined, dried and concentrated, and pure petroleum ether was used as the eluent for column separation. 77.7 mg of pale yellow solid was obtained, and the isolated yield of the target product 1,5-diphenyl-1,4-pentadiyne was 54%.

Comparative Example 1. Synthesis of 1,5-diphenyl-1,4-pentadiyne

Weigh 97.5 mg of (3-bromo-1-propynyl)benzene (0.5 mmol), 76.5 mg of phenylacetylene (0.75 mmol), 14.4 mg of CuBr (0.1 mmol), and 106 mg of K ₃ PO ₄ (0.5 mmol) in sequence containing 2.5 mL of 1,2-dichloroethane was added to a 25 mL sealed tube with a magnetic stir bar. The tube was sealed under nitrogen and stirred at 100°C for 16 hours. After the reaction, pure petroleum ether was used as the eluent for column separation to obtain 99 mg of pale yellow solid, and the isolated yield of the target product 1,5-diphenyl-1,4-pentadiyne was 46%.

Comparative Example 2. Synthesis of 1,5-diphenyl-1,4-pentadiyne

Weigh 97.5 mg of (3-bromo-1-propynyl)benzene (0.5 mmol), 76.5 mg of phenylacetylene (0.75 mmol), 14.4 mg of CuBr (0.1 mmol), and 69 mg of K ₂ CO ₃ (0.5 mmol) in sequence containing 2.5 mL of 1,2-dichloroethane was added to a 25 mL sealed tube with a magnetic stir bar. The tube was sealed under nitrogen and stirred at 100°C for 16 hours. After the reaction, pure petroleum ether was used as the eluent for column separation to obtain 73 mg of pale yellow solid, and the isolated yield of the target product 1,5-diphenyl-1,4-pentadiyne was 30%.

Comparative Example 3. Synthesis of 1,5-diphenyl-1,4-pentadiyne

Weigh 97.5 mg of (3-bromo-1-propynyl)benzene (0.5 mmol), 76.5 mg of phenylacetylene (0.75 mmol), 14.4 mg of CuBr (0.1 mmol), and 87 mg of K ₂ HPO ₄ (0.5 mmol) in sequence containing To a 25 mL sealed tube with a magnetic stirrer, 2.5 mL of azathioprine was added. The tube was sealed under nitrogen and stirred at 40°C for 16 hours. After the reaction, saturated ammonium chloride solution was added, extracted with ethyl acetate for 3 times, the organic phases were combined, dried and concentrated, and pure petroleum ether was used as the eluent for column separation. 103.7 mg of a pale yellow solid was obtained, and the isolated yield of the target product 1,5-diphenyl-1,4-pentadiyne was 48%.

Comparative Example 4. Synthesis of 1,5-diphenyl-1,4-pentadiyne

Weigh 97.5 mg of (3-bromo-1-propynyl)benzene (0.5 mmol), 76.5 mg of phenylacetylene (0.75 mmol), 14.4 mg of CuBr (0.1 mmol), and 106 mg of K ₃ PO ₄ (0.5 mmol) in sequence containing To a 25 mL sealed tube with a magnetic stirrer, 2.5 mL of azathioprine was added. The tube was sealed under nitrogen and stirred at 60°C for 6 hours. After the reaction, saturated ammonium chloride solution was added, extracted with ethyl acetate for 3 times, the organic phases were combined, dried and concentrated, and pure petroleum ether was used as the eluent for column separation. 77.7 mg of pale yellow solid was obtained, and the isolated yield of the target product 1,5-diphenyl-1,4-pentadiyne was 36%.

Claims (10)

1. A process for the preparation of a compound of formula I comprising the steps of: uniformly mixing a compound shown as a formula IV, a compound shown as a formula V, alkali and a catalyst for reaction to obtain a compound shown as a formula I after the reaction is finished;

in the formula I, R¹、R³Independently selected from phenyl, substituted phenyl or heterocyclic radical, R²Is a hydrogen atom or an alkyl group;

in the formula IV, R¹、R²Is as defined in formula I; in the formula V, n is 0, R³Is as defined in formula I.

2. The method of claim 1, wherein: the substituent in the substituent-containing phenyl is selected from at least one of the following groups: p-methyl, o-methyl, m-methyl and 4-fluoro, the heterocyclic group is thienyl, pyrrolyl, the alkyl is C1-C4 alkyl, preferably methyl.

3. A method for preparing a compound shown as a formula II comprises the following steps: uniformly mixing a compound shown as a formula IV, a compound shown as a formula V, alkali and a catalyst for reaction to obtain a compound shown as a formula II after the reaction is finished;

in the formula II, R¹Is alkyl and R³Is aryl, or R¹Is aryl and R³Is alkyl or substituted alkyl;

in the formula II, the aryl is connected with 1, 3-diyne;

in the formula IV, R¹Is as defined in formula I, R²Is a hydrogen atom;

in the formula V, n is 0, R³Is as defined in formula I.

4. The production method according to claim 3, characterized in that: in the formula IV, R¹Is alkyl and R in said formula V³Is aryl, 1, 3-diyne or R³To said R¹Is C1-C6 alkyl, preferably ethyl, R³Is phenyl or 4-fluorophenyl;

or, R in the formula IV¹Is aryl and R in said formula V³Is alkyl or substituted alkyl, 1, 3-diyne and R¹To said R¹Is phenyl or 4-Me phenyl, said R³Is phenylmethyl, cyclohexyl or n-propyl.

5. A process for preparing a compound of formula iii, comprising the steps of: uniformly mixing a compound shown as a formula IV, a compound shown as a formula V, alkali and a catalyst for reaction to obtain a compound shown as a formula III after the reaction is finished;

in the formula I, R¹、R³Independently selected from phenyl or substituted phenyl, R²Is aryl or alkyl, n ═ 1 or 2 or 3;

in the formula IV, R¹、R²Is as defined in formula I; in the formula V, n and R³Is as defined in formula I.

6. The method of claim 5, wherein: the R is¹、R³Are all phenyl, said R²Is C1-C4 alkyl, preferably methyl.

7. The production method according to any one of claims 1 to 6, characterized in that: the base is selected from at least one of: potassium carbonate, dipotassium hydrogen phosphate and potassium phosphate, preferably potassium phosphate;

the catalyst is a monovalent copper catalyst, specifically CuI or CuBr, preferably CuBr;

the feeding molar amount of the compound shown in the formula V is 1.2-2 times of that of the compound shown in the formula IV;

the feeding molar amount of the catalyst is 10-20%, preferably 20% of the compound shown in the formula IV;

the molar dosage of the alkali is 1.0-1.5 times, preferably 1.0 time of the compound shown in the formula IV.

8. The method of claim 7, wherein: when the compound shown in the formula I is prepared, the feeding molar amount of the compound shown in the formula V is 1.2-1.5 times of that of the compound shown in the formula IV; when the compounds shown in the formulas II and III are prepared, the feeding molar amount of the compound shown in the formula V is 1.2 times that of the compound shown in the formula IV.

9. The production method according to any one of claims 1 to 8, characterized in that: the reaction is carried out in a solvent selected from at least one of: 1, 2-dichloroethane, N-dimethylformamide and n.n-dimethylacetamide, preferably N, N-dimethylacetamide;

the reaction is carried out in an inert atmosphere, such as nitrogen;

in the reaction step, the temperature is 40-60 ℃, and preferably 40 ℃; the time is 16 to 20 hours, preferably 16 hours.

10. The production method according to any one of claims 1 to 9, characterized in that: the method further comprises the following steps: after the reaction is finished, separating and purifying the reaction system; the preferred separation method is: transferring the stock solution after reaction into a separating funnel, and adding a proper amount of ethyl acetate to wash the reaction tube during transfer; adding a proper amount of saturated ammonium chloride aqueous solution into a separating funnel, extracting for three times by using ethyl acetate, and combining organic phases; drying with anhydrous magnesium sulfate, and filtering; then concentrating the organic phase, adding a proper amount of 100-200-mesh silica gel, and performing dry-process column loading; eluting with petroleum ether/ethyl acetate mixed solution, wherein the volume fraction of ethyl acetate is generally 0-10%; the solution containing the product I, II or III is collected, concentrated under reduced pressure to remove the solvent and dried under vacuum, weighed and the yield calculated.

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