CN111662147B - Process for preparing diynes and analogues thereof - Google Patents
Process for preparing diynes and analogues thereof Download PDFInfo
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- CN111662147B CN111662147B CN202010635323.3A CN202010635323A CN111662147B CN 111662147 B CN111662147 B CN 111662147B CN 202010635323 A CN202010635323 A CN 202010635323A CN 111662147 B CN111662147 B CN 111662147B
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Abstract
The invention discloses a method for preparing a plurality of diynes and derivatives thereofA method of producing a biological substance. 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
Technical Field
The invention belongs to the field of catalytic synthesis of fine chemical products, and particularly relates to a method for preparing a diacetylene compound.
Background
Alkynyl groups, one of the most basic reaction units in organic chemistry, can participate in a variety of types of reactions. Alkyne compounds are also widely used in modern organic synthesis, pharmaceutical Chemistry, and materials Chemistry (Diederich.F.; Stang. P.J.; Tykwinski, R.R.Acetylene Chemistry: Chemistry, Biology and Material science, Wiley-VCH, Weinheim.2005).
Compared with single alkyne, diyne can synchronously or stepwise provide 2-4 carbon atoms to participate in the reaction, so that the diyne has more designability and is widely applied to various organic reactions. Wherein two alkynyl groups of the 1, 3-diyne compound are conjugated, which also causes the structure and the electrical property to be different compared with the single alkyne, thereby generating 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 in which both alkynyls participate can be used to construct various classes of organic heterocyclic molecules such as furan, pyrrole, pyrazole, thiophene, silole (Shi, w.; Lei, a-w. tetrahedron letters.2014,55,2763; Kramer, s.; Madsen, j.l.h.; rot lander, m.; Skrydstrup, t.org, lett.2010,12,2758; Wang, l.; Yu x.; Feng x.; Bao, m.j.org. chem.2013,78,1693). The 1, 4-diyne compounds were widely used as building blocks for polyunsaturated fatty acids and their derivatives since 1950 (Durand, s.; Parrain, j.l.; Santelli, m.j.chem.soc., Perkin trans.1,2000,253), and when the three-position carbon atom of 1, 4-diyne is connected with other substituents, can also be used to build structures such as pyrrole, pyridine, furan and furanone (Wang, t.; Shi, s.; Hansmann, m.m.; hasmm, a.s.k.angew.chem., int.ed.2014,53,3715; Xu, y.l.; Teng, q.h.; Ma, x.l.molecules.2017,22,109; Hsu, y.c.; s.a., Li, p.h.; q.h.2012012017, x.l.2017, 22,109; when the three-position carbon atom of 1, 4-diyne is connected with another substituent, and when the aromatic hydrocarbon is obtained by a reaction with an amine. 1,5-, 1, 6-diyne and the like can be used for the construction of carbocyclic and various polycyclic skeletons in addition to heterocyclic skeletons (Wurm, T.; Bucher, J.; Hashimi, A.S.K.Angew.Chem., int.Ed.2017,56,3364; Yoshizaki, S.; Shibata, Y.; Tanaka, K.Angew.Chem., int.Ed.2017,56,3590), and chiral cyclic skeletons can be constructed if the reaction is carried out using a chiral ligand transition metal catalyst, which also becomes an effective means for the synthesis of many natural products and intermediates of pharmaceutical molecules (Kashima, K.; Teraoka, K.; Uekusa, H.; Shibata, Y.; Tanaka K.org.Lett.2016,18,2170).
Due to the diversified application of various diyne compounds in organic synthesis, the synthesis method thereof has been concerned by organic chemists. 1, 3-diynes, in particular asymmetric 1, 3-diynes, are an important class of compounds, and conventional methods include mainly Glaser-Hay coupling and Cadiot-Chodkiewicz coupling (Siemsen, P.; Livingston, R.C.; Diederich, F.Angew.Chem., int.Ed.2000,39,2632; Shi, W.; Luo, Y.; Luo, X.; Chao, L.; Zhang, H.; Wang, J.; Lei, A.J.Am.Chem.Soc.2008,130, 14713). However, the Cu or Ni catalyzed Glaser-Hay coupling reaction usually requires a great excess of alkyne due to the alkyne self-coupling side reaction; the Cadiot-Chodkiewicz coupling reaction needs to pre-functionalize a terminal alkyne into alkynyl bromide to participate in the reaction, and the alkynyl bromide compound is unstable. In recent years there have also been methods to synthesize asymmetric 1, 3-diynes with high efficiency but requiring expensive gold catalysts and additional ligands (Peng, h.; Xi, y.; Shi, x.j.am. chem. soc.2014,136, 13174). There have been some reports on the synthesis of compounds having 1, 4-diyne with heteroatom substituents such as oxygen, nitrogen, etc. in the 3-position (Qiu, y.f.; Yang, f.; Liang, y.m.j.org.chem.2013,78,12018). The synthesis method of 1, 4-diyne which is not substituted at the 3-position or is connected with an alkyl group mostly comes from a route for synthesizing unsaturated fatty acid, and propargyl halide and alkynyl form reagent are adopted to react in the early stage, so that the alkynyl form reagent is required to be prepared in advance, and the requirements on reaction conditions are strict. Various propargyl compounds and alkynylgold were subsequently developedThe reaction of metallates such as lithium alkynyls, aluminum alkynyls, cuprates alkynyls and the like can also be accomplished under copper catalysis, but the atom economy of these reactions remains low (Tedeschi, c.; Saccavini, c.; Chauvin, r.j. organomet. chem.2003,670, 151). In 1992, Jeffery et al reported a process for the preparation of 1, 4-diynes unsubstituted in the 3-position of an alkyl group by coupling a propargyl halide to a terminal alkyne using equivalent amounts of CuI/Na2CO3And is added with [ n-Bu4N][Cl]To increase the yield, thereby avoiding the use of strongly basic alkylmetal reagents for removing alkyne hydrogens, and also greatly increasing the atom economy of the reaction (Jeffery, T.; Gueugnot, S.; Linstrulle, G.tetrahedron Lett.1992,33,5757). However, there have been many improvements to this process and their rapid application to the synthesis of molecules such as unsaturated fatty acids, pheromones, etc., although the use of excessive amounts or even excess metal salts remains a problem; secondly, the method is mainly used for synthesizing alkyl 1, 4-diyne and aryl 1, 4-diyne. Because various methods still have different problems, the development of a more convenient, efficient and green diyne synthesis technology becomes a target for people to explore, and two problems are involved: firstly, how to reduce the use of metal salt to make the metal salt more green, and secondly, how to apply the synthetic method of 1, 4-diyne to aryl to construct 1, 5-diaryl-1, 4-diyne.
Disclosure of Invention
The invention aims to provide a method for preparing diyne and analogues thereof.
The invention provides a method for preparing compounds (namely, diyne and analogues thereof) shown as formulas I, II and III, which comprises the following steps: uniformly mixing propargyl bromide compounds shown in a formula IV, alkyne compounds shown in a formula V, alkali and a catalyst for reaction to obtain compounds shown in a formula I, a formula II or a formula III after the reaction is finished;
preparation of the compound of formula I, the compound of formula VWherein n is 0; r in the formulas IV and V1、R3Independently selected from phenyl, phenyl containing substituent or heterocyclic radical; the substituent is preferably p-methyl, o-methyl, m-methyl or 4-fluoro, and the heterocycle can be thienyl or pyrrolyl in particular; r in the formula IV2Is a hydrogen atom or an alkyl group, which may be in particular a C1-C4 alkyl group, preferably a methyl group.
Preparing the compound shown in the formula II, wherein n is 0; r in the formula IV2Is a hydrogen atom; when R in the formula IV1Is alkyl, R in said formula V3When aryl, 1, 3-diyne with R3To said R1In particular, it may be C1-C6 alkyl, preferably ethyl, R3Preferably phenyl or 4-fluorophenyl; when R in the formula IV1Is aryl, R in said formula V3When it is alkyl or substituted alkyl, 1, 3-diyne with R1To said R1Preferably phenyl or 4-Me phenyl, said R3The alkyl in (A) is C1-C6 alkyl, R3Preferred are phenylmethyl, cyclohexyl or n-propyl.
Preparing the compound shown in the formula III, wherein in the formula V, n is 1,2 or 3; r in the formulas IV and V1、R3Independently selected from phenyl or phenyl containing substituent groups, wherein the substituent groups can be selected from p-methyl, o-methyl, m-methyl or 4-fluorine; the R is1、R3Preferably phenyl; r in the formula IV2Is aryl or alkyl, the aryl can be phenyl, the alkyl can be C1-C4 alkyl, and methyl is preferred.
In the above method, the base may be selected from at least one of: 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 method, the feeding molar amount of the alkyne compound shown in the formula V is 1.2-2 times of that of the propargyl bromide compound shown in the formula IV; when the compound represented by the formula I is prepared, the ratio is preferably 1.2 times or 1.5 times, and when the compounds represented by the formulae II and III are prepared, the ratio is preferably 1.2 times.
In the method, the feeding molar amount of the catalyst is 10-20%, preferably 20% of the propargyl bromide compound shown in the formula IV.
In the above method, the molar amount of the base to be fed is 1.0-1.5 times, preferably 1.0 time, of the propargyl bromide compound represented by the formula IV.
In the above process, the reaction is carried out in a solvent selected from at least one of: 1, 2-dichloroethane, N-dimethylformamide or N, N-dimethylacetamide, preferably N, N-dimethylacetamide.
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 ℃, preferably 40 ℃; the time is 16-20 hours, preferably 16 hours, and the specific reaction time can be detected by thin layer chromatography.
The method further comprises the following steps: after the reaction is finished, the reaction system is subjected to a separation and purification step according to a conventional method. 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 a reaction tube during transfer so as to reduce the transfer loss; 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; the elution is carried out by using a petroleum ether/ethyl acetate mixed solution, the ratio of petroleum ether/ethyl acetate is different according to the polarity of reactants and products, and the volume fraction of ethyl acetate is generally 0-10 percent estimated by a thin layer chromatography result. 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.
For solid products, the purity can be increased by recrystallization, which is generally done: adding a certain amount of dichloromethane into the sample to ensure that the dichloromethane is just completely dissolved, adding a poor solvent n-hexane into the sample, and slowly volatilizing the poor solvent n-hexane to obtain a single crystal of the product.
The method for synthesizing the diyne and the analogues thereof has the following characteristics: (1) the reaction condition is mild, the yield is moderate to excellent, the usage amount of metal salt is greatly reduced, and the method is more green and environment-friendly. (2) The reaction universality is good, 1, 4-diyne or asymmetric 1, 3-diyne can be obtained under the same conditions based on different substrates, and the method can also be used for preparing aryl 1, n-diyne under special substrates.
Drawings
FIG. 1 is the NMR spectrum of the objective product obtained in example 1.
FIG. 2 is the NMR spectrum of the objective product obtained in example 1.
FIG. 3 is the NMR spectrum of the objective product obtained in example 2.
FIG. 4 is the NMR spectrum of the objective product obtained in example 2.
FIG. 5 is the NMR spectrum of the objective product obtained in example 6.
FIG. 6 is the NMR spectrum of the objective product obtained in example 6.
FIG. 7 is the NMR spectrum of the objective product obtained in example 8.
FIG. 8 is the NMR spectrum of the objective product obtained in example 8.
FIG. 9 is the NMR spectrum of the objective product obtained in example 10.
FIG. 10 is the NMR spectrum of the objective product obtained in example 10.
FIG. 11 is a NMR chart of the objective product obtained in example 11.
FIG. 12 is a nuclear magnetic resonance carbon spectrum of the objective product obtained in example 11.
Detailed Description
The present invention is described below with reference to specific embodiments, but the present invention is not limited thereto, and any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the scope of the present invention.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The starting materials used in the following examples, (3-bromo-1-propynyl) benzene and (3-bromo-1-butynyl) benzene were prepared as follows: triphenylphosphine (11mmol) was dissolved in 1, 2-dichloroethane (30mL), followed by dropwise addition of bromine (11mmol) at 0 deg.C, stirring for 30min, and the solution gradually became clear from yellow and suspended. Subsequently, a solution (5mL) of 1, 2-dichloroethane in 3-phenyl-2-propyn-1-ol (10mmol) or 4-phenyl-3-butyn-2-ol (10mmol) was added dropwise to the suspension, the solution gradually becoming clear again as the alcohol was added dropwise, and after the addition, the clear solution was stirred at 0 ℃ for 1 h. Cyclohexane (60mL) was then added, whereupon a white precipitate immediately precipitated, and then stirred at room temperature for a further 30 min. And then filtering the reaction system, washing with cyclohexane, concentrating the filtrate, passing through a column, and washing out the corresponding propargyl bromide with pure petroleum ether, wherein the yield is over 90 percent.
The starting 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, were prepared as follows: a100 mL round-bottomed flask was charged with magneton, CuI (10mg,0.053mmol), and iodobenzene (4-methyliodobenzene, 3-methyliodobenzene, 2-methyliodobenzene, 4-fluoroiodobenzene, 2-iodothiophene) (13.8mmol) in that order, and dried under reduced pressure. Subsequently, anhydrous toluene (14mL), piperidine (3.3mL,33mmol), propargyl alcohol (1.5mL), and palladium dichlorobistriphenylphosphine (17mg,0.024mmol) were added. The reaction was placed under nitrogen and allowed to react at 35 ℃ for 14h, after which the reaction was filtered through celite and spun dry. And then carrying out column chromatography separation on the obtained crude product, wherein the eluent is ethyl acetate: petroleum ether (3:1) to give the corresponding propargyl alcohol [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 ], in a yield of 80 or more.
Triphenylphosphine (11mmol) was dissolved in 1, 2-dichloroethane (30mL), followed by dropwise addition of bromine (11mmol) at 0 deg.C, stirring for 30min, and the solution gradually became clear from yellow and suspended. Subsequently, a solution (5mL) of 1, 2-dichloroethane in which the corresponding propargyl alcohol [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) was dissolved was added dropwise to the suspension, the solution gradually became clear as the dropwise addition of alcohol continued, and after completion of the addition, the clear solution was stirred at 0 ℃ for 1 h. Cyclohexane (60mL) was then added, whereupon a white precipitate immediately precipitated, and then stirred at room temperature for a further 30 min. And then filtering the reaction system, washing with cyclohexane, concentrating the filtrate, passing through a column, and washing out the corresponding propargyl bromide with pure petroleum ether, wherein the yield is over 90 percent.
Example 1 Synthesis of 1, 5-Diphenyl-1, 4-pentadiyne
97.5mg (3-bromo-1-propynyl) benzene (0.5mmol), 76.5mg phenylacetylene (0.75mmol), 14.4mg CuBr (0.1mmol) and 106mg K were weighed out in this order3PO4(0.5mmol) to a 25mL stopcock containing a magnetic stirrer was added 2.5mL of N-dimethylacetamide. The tube was sealed under nitrogen and stirred at 40 ℃ for 16 hours. After the reaction is finished, adding a saturated ammonium chloride solution, extracting for 3 times by ethyl acetate, combining organic phases, drying, concentrating, and then carrying out column separation by using pure petroleum ether as an eluent to obtain 146.9mg of light yellow solid and the separation yield of the target product 1, 5-diphenyl-1, 4-pentadiyne is 68%. FIG. 1 and FIG. 2 show the hydrogen and carbon nuclear magnetic resonance spectra of the product prepared in this example, and it can be seen that the compound has a correct structure.
Example 2 Synthesis of 1, 5-di-p-methylphenyl-1, 4-pentadiyne
104.5mg of 1- (3-bromo-1-propynyl) -4-methylbenzene (0.5mmol), 87mg of p-methylphenylacetylene (0.75mmol) and 14.4mg of C were weighed in this orderuBr(0.1mmol)、106mg K3PO4(0.5mmol) to a 25mL stopcock containing a magnetic stirrer was added 2.5mL of N-dimethylacetamide. The tube was sealed under nitrogen and stirred at 40 ℃ for 16 hours. After the reaction is finished, adding a saturated ammonium chloride solution, extracting for 3 times by ethyl acetate, combining organic phases, drying, concentrating, and then carrying out column separation by using pure petroleum ether as an eluent to obtain 192.7mg of light yellow solid, wherein the separation yield of the target product 1, 5-di-p-methylphenyl-1, 4-pentadiyne is 83%. FIGS. 3 and 4 show the NMR spectrum and the carbon spectrum of the product obtained in this example, and it can be seen that the compound has a correct structure.
Example 3 Synthesis of 1, 5-di-o-methylphenyl-1, 4-pentadiyne
104.5mg of 1- (3-bromo-1-propynyl) -2-methylbenzene (0.5mmol) and 87mg of 2-methylphenylacetylene were weighed in this order
(0.75mmol)、14.4mg CuBr(0.1mmol)、106mg K3PO4(0.5mmol) to a 25mL stopcock containing a magnetic stirrer was added 2.5mL of N-dimethylacetamide. The tube was sealed under nitrogen and stirred at 40 ℃ for 16 hours. After the reaction is finished, adding a saturated ammonium chloride solution, extracting for 3 times by ethyl acetate, combining organic phases, drying, concentrating, and then carrying out column separation by using pure petroleum ether as an eluent to obtain 209.8mg of light yellow oily liquid, wherein the separation yield of the target product 1, 5-di-o-methylphenyl-1, 4-pentadiyne is 89%.
Example 4 Synthesis of 1, 5-di-m-methylphenyl-1, 4-pentadiyne
104.5mg of 1- (3-bromo-1-propynyl) -3-methylbenzene (0.5mmol), 87mg of 3-methylphenylacetylene (0.75mmol), 14.4mg of CuBr (0.1mmol) and 106mg of K were weighed in this order3PO4(0.5mmol) to a 25mL stopcock containing a magnetic stirrer was added 2.5mL of N-dimethylacetamide. The tube was sealed under nitrogen and stirred at 40 ℃ for 16 hours. After the reaction is finished, adding a saturated ammonium chloride solution, extracting for 3 times by ethyl acetate, combining organic phases, drying, concentrating, and then carrying out column separation by using pure petroleum ether as an eluent to obtain 214.7mg of light yellow oily liquid and 93% of the separation yield of the target product 1, 5-di-m-methylphenyl-1, 4-pentadiyne.
Example 5 Synthesis of 1, 5-bis (4-fluoro-phenyl) -1, 4-pentadiyne
106.5mg of 1- (3-bromo-1-propynyl) -4-fluorobenzene (0.5mmol), 90mg of 4-fluorobenzeneacetylene (0.75mmol), 14.4mg of CuBr (0.1mmol) and 106mg of K were weighed in this order3PO4(0.5mmol) to a 25mL stopcock containing a magnetic stirrer was added 2.5mL of N-dimethylacetamide. The tube was sealed under nitrogen and stirred at 40 ℃ for 16 hours. After the reaction is finished, adding a saturated ammonium chloride solution, extracting for 3 times by ethyl acetate, combining organic phases, drying, concentrating, and then carrying out column separation by using pure petroleum ether as an eluent to obtain 168.8mg of white solid and the separation yield of the target product 1, 5-di (4-fluoro-phenyl) -1, 4-pentadiyne is 70%.
Example 6 Synthesis of 3-methyl-1- (3-methylphenyl) -5-phenyl-1, 4-pentadiyne
104.5mg of (3-bromo-1-butynyl) benzene (0.5mmol), 69.6mg of 3-methylphenylacetylene (0.6mmol), 14.4mg of CuBr (0.1mmol) and 106mg of K were weighed in this order3PO4(0.5mmol) to a 25mL stopcock containing a magnetic stirrer was added 2.5mL of N-dimethylacetamide. The tube was sealed under nitrogen and stirred at 40 ℃ for 16 hours. After the reaction is finished, adding a saturated ammonium chloride solution, extracting for 3 times by ethyl acetate, combining organic phases, drying, concentrating, and then carrying out column separation by using pure petroleum ether as an eluent to obtain 222mg of light yellow oily liquid and 91% of the separation yield of the target product 3-methyl-1- (3-methylphenyl) -5-phenyl-1, 4-pentadiyne. FIGS. 5 and 6 show the NMR spectrum and the carbon spectrum of the product obtained in this example, and it can be seen that the compound has a correct structure.
Example 7 Synthesis of 1, 5-bis (2-thiophene) -1, 4-pentadiyne
100.5mg of 2- (3-bromo-1-propynyl) thiophene (0.5mmol), 81.1mg of 2-ethynylthiophene (0.75mmol), 14.4mg of CuBr (0.1mmol) and 106mg of K were weighed in this order3PO4(0.5mmol) to a 25mL stopcock containing a magnetic stirrer was added 2.5mL of N-dimethylacetamide. The tube was sealed under nitrogen and stirred at 40 ℃ for 16 hours. After the reaction is finished, addingSaturated ammonium chloride solution, ethyl acetate extraction 3 times, organic phase combination, drying and concentration, and then using pure petroleum ether as eluent to carry out column separation, thus obtaining 132.4mg of light yellow oily liquid and 58% of separation yield of the target product 1, 5-di (2-thiophene) -1, 4-pentadiyne.
Example 8 Synthesis of 1-phenyl-1, 3-hexadiyne
74mg of 1-bromo-2-pentyne (0.5mmol), 61.2mg of phenylacetylene (0.6mmol), 14.4mg of CuBr (0.1mmol) and 106mg of K were weighed in this order3PO4(0.5mmol) to a 25mL stopcock containing a magnetic stirrer was added 2.5mL of N-dimethylacetamide. The tube was sealed under nitrogen and stirred at 40 ℃ for 16 hours. After the reaction is finished, adding saturated ammonium chloride solution, extracting for 3 times by ethyl acetate, combining organic phases, drying, concentrating, and then carrying out column separation by using petroleum ether/ethyl acetate (100/0-95/5) as an eluent to obtain 139.6mg of colorless oily liquid, wherein the separation yield of the target product 1-phenyl-1, 3-hexadiyne is 82%. FIGS. 7 and 8 show the hydrogen and carbon nuclear magnetic resonance spectra of the product prepared in this example, which shows that the compound has a correct structure.
Example 9 Synthesis of 1- (4-fluorophenyl) -1, 3-hexadiyne
74mg of 1-bromo-2-pentyne (0.5mmol), 72mg of 4-fluoroacetylene (0.6mmol), 14.4mg of CuBr (0.1mmol) and 106mg of K were weighed in this order3PO4(0.5mmol) to a 25mL stopcock containing a magnetic stirrer was added 2.5mL of N-dimethylacetamide. The tube was sealed under nitrogen and stirred at 40 ℃ for 16 hours. After the reaction is finished, adding a saturated ammonium chloride solution, extracting for 3 times by ethyl acetate, combining organic phases, drying, concentrating, and then carrying out column separation by using petroleum ether/ethyl acetate (100/0-95/5) as an eluent to obtain 171.3mg of colorless oily liquid and the separation yield of the target product 1- (4-fluorophenyl) -1, 3-hexadiyne is 92%.
Example 10 Synthesis of 1, 6-Diphenyl-1, 3-hexadiyne
97.5mg (0.5mmol) of (3-bromo-1-propynyl) benzene, 69.6mg of 3-phenyl-1-propynyl (0.6mmol), 14.4mg of CuBr (0.1mmol) and 106mg of K were weighed in this order3PO4(0.5mmol) to a 25mL stopcock containing a magnetic stirrer was added 2.5mL of N-dimethylacetamide. The tube was sealed under nitrogen and stirred at 40 ℃ for 16 hours. After the reaction is finished, adding saturated ammonium chloride solution, extracting for 3 times by ethyl acetate, combining organic phases, drying, concentrating, and then carrying out column separation by using pure petroleum ether as an eluent to obtain 179.4mg of light yellow oily liquid and 78% of the separation yield of the target product 1, 6-diphenyl-1, 3-hexadiyne. FIGS. 9 and 10 show the NMR spectrum and the carbon spectrum of the product obtained in this example, and it can be seen that the compound has a correct structure.
Example 11 Synthesis of 3-methyl-1, 6-diphenyl-1, 5-hexadiyne
104.5mg of (3-bromo-1-butynyl) benzene (0.5mmol), 69.6mg of 3-phenyl-1-propyne (0.6mmol), 14.4mg of CuBr (0.1mmol) and 106mg of K were weighed in this order3PO4(0.5mmol) to a 25mL stopcock containing a magnetic stirrer was added 2.5mL of N-dimethylacetamide. The tube was sealed under nitrogen and stirred at 40 ℃ for 16 hours. After the reaction is finished, adding a saturated ammonium chloride solution, extracting for 3 times by ethyl acetate, combining organic phases, drying, concentrating, and then carrying out column separation by using pure petroleum ether as an eluent to obtain 170.8mg of light yellow oily liquid, wherein the separation yield of the target product 3-methyl-1, 6-diphenyl-1, 5-hexadiyne is 75%. FIGS. 11 and 12 show the NMR spectrum and the carbon spectrum of the product obtained in this example, and it can be seen that the compound has a correct structure.
Example 12 Synthesis of 3-methyl-1, 7-diphenyl-1, 6-heptadiyne
104.5mg of (3-bromo-1-butynyl) benzene (0.5mmol), 78mg of 4-phenyl-1-butyne (0.6mmol), 14.4mg of CuBr (0.1mmol) and 106mg of K were weighed in this order3PO4(0.5mmol) in a solvent containing magnetTo a 25mL stoppered tube of the sexual stirrer was added 2.5mL of N-dimethylacetamide. The tube was sealed under nitrogen and stirred at 40 ℃ for 16 hours. After the reaction is finished, adding a saturated ammonium chloride solution, extracting for 3 times by ethyl acetate, combining organic phases, drying, concentrating, and then carrying out column separation by using pure petroleum ether as an eluent to obtain 175.7mg of light yellow oily liquid, wherein the separation yield of the target product 3-methyl-1, 7-diphenyl-1, 6-heptadiyne is 73%.
Example 13 Synthesis of 1, 5-Diphenyl-1, 4-pentadiyne
97.5mg (3-bromo-1-propynyl) benzene (0.5mmol), 76.5mg phenylacetylene (0.75mmol), 14.4mg CuBr (0.1mmol) and 106mg K were weighed out in this order3PO4(0.5mmol) was placed in a 25mL stopcock containing a magnetic stirrer and 2.5mL N-dimethylacetamide was added. The tube was sealed under nitrogen and stirred at 60 ℃ for 16 hours. After the reaction is finished, adding saturated ammonium chloride solution, extracting for 3 times by ethyl acetate, combining organic phases, drying, concentrating and then carrying out column separation by using pure petroleum ether as an eluant. 77.7mg of a pale yellow solid are obtained, isolated in 54% yield of the desired product 1, 5-diphenyl-1, 4-pentadiyne.
Comparative example 1 Synthesis of 1, 5-Diphenyl-1, 4-pentadiyne
97.5mg (3-bromo-1-propynyl) benzene (0.5mmol), 76.5mg phenylacetylene (0.75mmol), 14.4mg CuBr (0.1mmol) and 106mg K were weighed out in this order3PO4(0.5mmol) to a 25mL stopcock containing a magnetic stirrer was added 2.5mL1, 2-dichloroethane. The tube was sealed under nitrogen and stirred at 100 ℃ for 16 hours. After the reaction is finished, pure petroleum ether is used as an eluent for column separation, and 99mg of light yellow solid is obtained, and the separation yield of the target product 1, 5-diphenyl-1, 4-pentadiyne is 46%.
Comparative example 2 Synthesis of 1, 5-Diphenyl-1, 4-pentadiyne
97.5mg (3-bromo-1-propynyl) benzene (0.5mmol), 76.5mg phenylacetylene (0.75mmol), 14.4mg CuBr (0.1mmol) and 69mg K were weighed in this order2CO3(0.5mmol) to a 25mL stopcock containing a magnetic stirrer was added 2.5mL1, 2-dichloroethane. The tube was sealed under nitrogen and stirred at 100 ℃ for 16 hours. After the reaction is finished, pure petroleum ether is used as eluent for column separation to obtain light yellow solid 73mg, meshThe isolated yield of the title product, 1, 5-diphenyl-1, 4-pentadiyne, was 30%.
Comparative example 3 Synthesis of 1, 5-Diphenyl-1, 4-pentadiyne
97.5mg (3-bromo-1-propynyl) benzene (0.5mmol), 76.5mg phenylacetylene (0.75mmol), 14.4mg CuBr (0.1mmol) and 87mg K were weighed in this order2HPO4(0.5mmol) to a 25mL stopcock containing a magnetic stirrer was added 2.5mL of N-dimethylacetamide. The tube was sealed under nitrogen and stirred at 40 ℃ for 16 hours. After the reaction is finished, adding saturated ammonium chloride solution, extracting for 3 times by ethyl acetate, combining organic phases, drying, concentrating and then carrying out column separation by using pure petroleum ether as an eluant. 103.7mg of a pale yellow solid are obtained, isolated in 48% yield of the desired product 1, 5-diphenyl-1, 4-pentadiyne.
Comparative example 4 Synthesis of 1, 5-Diphenyl-1, 4-pentadiyne
97.5mg (3-bromo-1-propynyl) benzene (0.5mmol), 76.5mg phenylacetylene (0.75mmol), 14.4mg CuBr (0.1mmol) and 106mg K were weighed out in this order3PO4(0.5mmol) to a 25mL stopcock containing a magnetic stirrer was added 2.5mL of N-dimethylacetamide. The tube was sealed under nitrogen and stirred at 60 ℃ for 6 hours. After the reaction is finished, adding saturated ammonium chloride solution, extracting for 3 times by ethyl acetate, combining organic phases, drying, concentrating and then carrying out column separation by using pure petroleum ether as an eluant. 77.7mg of a pale yellow solid are obtained, isolated in 36% yield of the desired product 1, 5-diphenyl-1, 4-pentadiyne.
Claims (9)
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;
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 or pyrrolyl, the alkyl group is C1-C4 alkyl;
in the formula IV, R1、R2Is as defined in formula I; in the formula V, n is 0, R3Is as defined in formula I;
the base is selected from potassium phosphate;
the catalyst is 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% of the compound shown in the formula IV;
the feeding molar dosage of the alkali is 1.0-1.5 times of that of the compound shown in the formula IV;
the reaction is carried out in a solvent selected from the group consisting of n.n-dimethylacetamide;
the reaction is carried out in an inert atmosphere;
in the reaction step, the temperature is 40 ℃; the time is 16-20 hours.
2. 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 C1-C6 alkyl and R3Is phenyl or 4-fluorophenyl;
in the formula IV, R1Is as defined for formula II, R2Is a hydrogen atom;
in the formula V, n is 0, R3Is as defined in formula II;
the base is selected from potassium phosphate;
the catalyst is 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% of the compound shown in the formula IV;
the feeding molar dosage of the alkali is 1.0-1.5 times of that of the compound shown in the formula IV;
the reaction is carried out in a solvent selected from the group consisting of n.n-dimethylacetamide;
the reaction is carried out in an inert atmosphere;
in the reaction step, the temperature is 40-60 ℃; the time is 16-20 hours.
3. The method of claim 2, wherein: the R is1Is ethyl.
4. 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 phenyl or 4-Me phenyl and R3Is a phenylmethyl group;
in the formula IV, R1Is as defined for formula II, R2Is a hydrogen atom;
in the formula V, n is 0, R3Is as defined in formula II;
the base is selected from potassium phosphate;
the catalyst is 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% of the compound shown in the formula IV;
the feeding molar dosage of the alkali is 1.0-1.5 times of that of the compound shown in the formula IV;
the reaction is carried out in a solvent selected from the group consisting of n.n-dimethylacetamide;
the reaction is carried out in an inert atmosphere;
in the reaction step, the temperature is 40 ℃; the time is 16-20 hours.
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 III, R1、R3Are all phenyl, said R2Is C1-C4 alkyl, n is 1 or 2 or 3;
in the formula IV, R1、R2Is as defined in formula III; in the formula V, n and R3Is as defined in formula III;
the base is selected from potassium phosphate;
the catalyst is 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% of the compound shown in the formula IV;
the feeding molar dosage of the alkali is 1.0-1.5 times of that of the compound shown in the formula IV;
the reaction is carried out in a solvent selected from the group consisting of n.n-dimethylacetamide;
the reaction is carried out in an inert atmosphere;
in the reaction step, the temperature is 40 ℃; the time is 16-20 hours.
6. The production method according to any one of claims 1 to 5, characterized in that:
the feeding molar amount of the catalyst is 20% of that of the compound shown in the formula IV;
the feeding molar amount of the alkali is 1.0 time of that of the compound shown in the formula IV.
7. The production method according to any one of claims 1 to 5, characterized in that: 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 of that of the compound shown in the formula IV.
8. The production method according to any one of claims 1 to 5, characterized in that: the inert atmosphere is nitrogen;
in the reaction step, the temperature is 40 ℃; the time period required was 16 hours.
9. The production method according to any one of claims 1 to 5, characterized in that: the method further comprises the following steps: after the reaction is finished, separating and purifying the reaction system; the specific separation method comprises the following steps: 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 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 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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