阅读说明：本技术 一种1,1-二卤代-1-丁烯-3-炔类化合物的合成方法 (Synthesis method of 1, 1-dihalogen-1-butene-3-alkyne compound ) 是由 刘运奎 鲍汉扬 郑立孟 于 2019-08-27 设计创作，主要内容包括：本发明公开了一种1,1-二卤代-1-丁烯-3-炔类化合物的合成方法,其特征在于：所述的方法按如下步骤进行：将金催化剂、钠盐NaBARF加入Schlenk管中,抽真空换保护气体三次,将式I所示的炔卤化合物溶解于有机溶剂中,在保护气体存在下,加入到上述反应管中,在25-50℃下搅拌反应0.5-3h,反应结束后得到反应液经后处理得到式II所示的1,1-二卤代-1-丁烯-3-炔类化合物；所述金催化剂、钠盐与式I所示的炔卤化合物的物质的量之比为0.02-0.1:0.1:1。本发明所述的方法可以合成现存的方法难以制备的偕二卤烯烃类化合物,反应的选择性高；催化剂用量少,毒性较低；反应条件较温和,节约能源消耗；产率高,底物普适性强,操作简便等优点。(The invention discloses a synthesis method of a 1, 1-dihalogen-1-butene-3-alkyne compound, which is characterized by comprising the following steps: the method comprises the following steps: adding a gold catalyst and sodium salt NaBARF into a Schlenk tube, vacuumizing for three times to change protective gas, dissolving an alkyne halide compound shown as a formula I into an organic solvent, adding the alkyne halide compound into the reaction tube in the presence of the protective gas, stirring for reacting for 0.5-3h at 25-50 ℃, and after the reaction is finished, obtaining a reaction liquid, and carrying out aftertreatment to obtain a 1, 1-dihalogen-1-butene-3-alkyne compound shown as a formula II; the mass ratio of the gold catalyst, the sodium salt and the alkyne halide compound shown in the formula I is 0.02-0.1:0.1: 1. The method can synthesize the gem-dihaloalkene compounds which are difficult to prepare by the existing method, and has high reaction selectivity; the catalyst has less dosage and lower toxicity; the reaction condition is mild, and the energy consumption is saved; high yield, strong substrate universality, simple and convenient operation and the like.)

1. a method for synthesizing 1, 1-dihalogen-1-butene-3-alkyne compounds is characterized by comprising the following steps: the method comprises the following steps:

adding a gold catalyst and sodium salt NaBARF into a Schlenk tube, vacuumizing for three times to change protective gas, dissolving an alkyne halide compound shown as a formula I into an organic solvent, adding the alkyne halide compound into the reaction tube in the presence of the protective gas, stirring for reacting for 0.5-3h at 25-50 ℃, and after the reaction is finished, obtaining a reaction liquid, and carrying out aftertreatment to obtain a 1, 1-dihalogen-1-butene-3-alkyne compound shown as a formula II; the mass ratio of the gold catalyst, the sodium salt and the alkyne halide compound shown in the formula I is 0.02-0.1:0.1: 1;

formula I or formula II:

R₁is one of Me, H, propyl, OMe, pentoxy, tert-butyl, Cl and Br.

X is Cl, Br or I.

2. The method of claim 1, wherein: the gold catalyst is one of the following structures:

3. the method of claim 1, wherein: the gold catalyst is

4. The method of claim 1, wherein: the organic solvent is one of dichloromethane, 1, 2-dichloroethane, 1, 4-dioxane, toluene, ethyl acetate, dimethyl sulfoxide, tetrahydrofuran and N, N-dimethylformamide.

5. The method of claim 1, wherein: the organic solvent is dichloromethane.

6. The method of claim 1, wherein: the total amount of the organic solvent added is 10mL/mmol based on the amount of the substance of the alkyne halide represented by the formula I.

7. The method of claim 1, wherein: the reaction temperature is 25 ℃, and the reaction time is 1.5 h.

8. The method of claim 1, wherein: the mass ratio of the gold catalyst, the sodium salt and the alkyne halide compound shown in the formula I is 0.05:0.1: 1.

9. The method of claim 1, wherein: the post-treatment method of the reaction solution comprises the following steps: after the reaction is finished, extracting the obtained reaction liquid by using dichloromethane, combining organic layers, adding 100-200-mesh column chromatography silica gel, decompressing and distilling to remove the solvent, carrying out silica gel column chromatography separation on the obtained crude product, eluting by using petroleum ether as an eluent, tracking the elution process by TLC, collecting eluent containing a target product, combining the eluent and distilling to remove the solvent to obtain the 1, 1-dihalogen-1-butene-3-alkyne compound shown in the formula II.

(I) technical field

The invention relates to a synthetic method of an organic compound, in particular to a synthetic method of a 1, 1-dihalogen-1-butene-3-alkyne compound.

(II) background of the invention

The geminal dihalo-olefin compound is a common organic synthesis intermediate, is widely applied to coupling reaction catalyzed by transition metal, and can effectively construct C-C bond, C-N bond, C-O bond and the like. Compared with monosubstituted olefins, the geminal dihalogenated olefin compound can be designed as a substrate of organic tandem reaction to synthesize various heterocyclic frameworks with high biological activity, for example, 2- (2 ', 2' -dibromo) vinyl-N-methylsulfonylaniline and diphenyl diselenide (sulfur) ether are used as raw materials in the Wang Lei of Suzhou university in 2012, and a series of 2-bromo-3-phenylselenium (sulfur) indole and derivatives thereof are synthesized through a tandem cyclization strategy. In addition, the Wangli subject group also takes 2- (2 ', 2' -dibromo) vinyl benzene (sulfur) phenol and phenyl trimethoxy silane as raw materials, so that elimination-intramolecular addition-Hiyama coupling is completed in a reaction system in a relay manner, and a series of 2-phenyl benzofuran (thiophene) and derivatives thereof are synthesized.

Currently, gem-dihalo-olefinic compounds are mainly synthesized by Witting reactions, such as in-situ formation of ylide (Ph) from carbon tetrabromide and triphenylphosphine₃P＝CBr₂) Further reacting with aldehyde or ketone to obtain the geminal dibromo olefin. Although this method has the advantages of cheap and easily available raw materials and simple operation, the process requires excessive triphenylphosphine, the atom economy is low, the carbon tetrabromide used also has toxicity, and it is difficult to apply the method to some ketone compounds with large steric hindrance, and it is also difficult to synthesize some gem-dihaloolefin compounds substituted by special functional groups.

In view of the existing background, the development of a synthetic route with simple and easily-obtained raw materials, simple operation, high selectivity and mild reaction for synthesizing the 1, 1-dihalogen-1-butene-3-alkyne compound has important academic value and wide application prospect.

Disclosure of the invention

In view of the deficiencies of the prior art, the present invention is directed to a process for the preparation of 1, 1-dihalo-1-butene-3-acetylenic compounds.

A method for synthesizing 1, 1-dihalogen-1-butene-3-alkyne compounds specifically comprises the following steps:

adding a gold catalyst and sodium salt NaBARF into a Schlenk tube, vacuumizing and changing protective gas for three times, dissolving an alkyne halide compound shown in a formula I into an organic solvent, adding the alkyne halide compound into the reaction tube in the presence of the protective gas, stirring and reacting for 0.5-3h (preferably 1.5h) at 25-50 ℃ (preferably 25 ℃), and carrying out aftertreatment on reaction liquid after the reaction is finished to obtain a 1, 1-dihalogen-1-butene-3-alkyne compound shown in a formula II; the mass ratio of the gold catalyst, the sodium salt and the alkyne halide compound shown in the formula I is 0.02-0.1:0.1:1 (preferably 0.05:0.1: 1);

formula I or formula II:

R₁is one of Me, H, propyl, OMe, pentoxy, tert-butyl, Cl and Br.

X is Cl, Br or I.

Further, the gold catalyst is one of the following structures:

still further, the gold catalyst is preferably

The sodium salt NaBARF has the structure as follows:

further, the organic solvent is one of dichloromethane, 1, 2-dichloroethane, 1, 4-dioxane, toluene, ethyl acetate, dimethyl sulfoxide, tetrahydrofuran and N, N-dimethylformamide.

Still further, the organic solvent of the present invention is preferably dichloromethane.

Further, the total amount of the organic solvent added in the present invention is 10mL/mmol based on the amount of the alkyne halide represented by formula I.

Further, the post-treatment method of the reaction solution comprises the following steps: after the reaction is finished, extracting the obtained reaction liquid by using dichloromethane, combining organic layers, adding 100-200-mesh column chromatography silica gel, decompressing and distilling to remove the solvent, carrying out silica gel column chromatography separation on the obtained crude product, eluting by using petroleum ether as an eluent, tracking the elution process by TLC, collecting eluent containing a target product, combining the eluent and distilling to remove the solvent to obtain the 1, 1-dihalogen-1-butene-3-alkyne compound shown in the formula II.

The starting alkyne halides used in the present invention can be prepared by the person skilled in the art on their own according to the methods disclosed in the literature.

Compared with the prior art, the invention has the beneficial effects that:

the method can synthesize the gem-dihaloalkene compounds which are difficult to prepare by the existing method, and has high reaction selectivity; the catalyst has less dosage and lower toxicity; the reaction condition is mild, and the energy consumption is saved; high yield, strong substrate universality, simple and convenient operation and the like.

(IV) detailed description of the preferred embodiment

The invention will be further illustrated by the following examples, without limiting the scope of the invention:

the general method for synthesizing the halogenated phenylacetylene compound comprises the following steps:

taking the synthesis of (chloroethynyl) benzene as an example:

a solution of phenylacetylene (0.51g,5mmol) in anhydrous tetrahydrofuran (10mL) was added to a nitrogen blanketed 50 mL round bottom flask. After the reaction system was cooled to-78 ℃, N-butyllithium (2.5M N-hexane solution, 2.40mL,6.0mmol) was slowly added dropwise, and the resulting mixed reaction solution was stirred at-78 ℃ for 30min, and then NCS (N-chlorosuccinimide) (7.34g,6.60mmol) was added in one portion under nitrogen protection. The reaction was warmed to room temperature and stirred for an additional 12 h. Quenching the reaction by using saturated ammonium chloride after the reaction is finished, extracting by using ether, taking an organic phase, drying by spinning, carrying out column chromatography separation and elution by using petroleum ether as an eluent, collecting eluent containing a target product, and removing the solvent to obtain (chloroethynyl) benzene with the yield of 81%.