Allyl sulfone compound and preparation method and application thereof
阅读说明：本技术 一种烯丙基砜类化合物及其制备方法与应用 (Allyl sulfone compound and preparation method and application thereof ) 是由 解沛忠 孙作恋 罗德平 于 2019-10-16 设计创作，主要内容包括：本发明公开了一种烯丙基砜类化合物及其制备方法与应用。本发明通过在惰性气体氛围下,将烯丙醇、亚磺酸、四(三苯基膦)钯、双(三氟甲基磺酰基)酰亚胺钙依次加入到反应溶剂中,30℃条件下搅拌反应12～48h；其中,所述烯丙醇、亚磺酸、四(三苯基膦)钯、双(三氟甲基磺酰基)酰亚胺钙的当量比为1：(1.5～2)：(1％～3％)：(5％～10％)；将反应液中的反应溶剂除去后再进行纯化,得到烯丙基砜类化合物。本发明制备方法经济性高、适用的底物范围广泛；并且,所得烯丙基砜类化合物有潜在的药物活性和生物活性,是在生物和药物活性分子中广泛存在的重要骨架。(The invention discloses an allyl sulfone compound and a preparation method and application thereof. Sequentially adding allyl alcohol, sulfinic acid, palladium tetrakis (triphenylphosphine) and calcium bis (trifluoromethylsulfonyl) imide into a reaction solvent in an inert gas atmosphere, and stirring and reacting for 12-48 h at the temperature of 30 ℃; wherein the equivalent ratio of allyl alcohol, sulfinic acid, tetrakis (triphenylphosphine) palladium and calcium bis (trifluoromethylsulfonyl) imide is 1: (1.5-2): (1-3%): (5-10%); and removing the reaction solvent in the reaction liquid, and then purifying to obtain the allyl sulfone compound. The preparation method has high economy and wide applicable substrate range; in addition, the obtained allyl sulfone compound has potential pharmaceutical activity and biological activity and is an important skeleton widely existing in biological and pharmaceutical active molecules.)
1. An allyl sulfone compound, which is characterized in that the chemical structural formula of the compound is shown as the following formula (I):
in the above formula (I), R1Is aryl or alkyl; r2～R5Any of hydrogen radicals, aryl radicals and alkyl radicals.
2. A process for the preparation of the allylic sulfone compound of claim 1, comprising the steps of:
(1) sequentially adding allyl alcohol, sulfinic acid, tetrakis (triphenylphosphine) palladium and calcium bis (trifluoromethylsulfonyl) imide into a reaction solvent in an inert gas atmosphere, and stirring and reacting for 12-48 h at the temperature of 30 ℃; wherein the equivalent ratio of allyl alcohol, sulfinic acid, tetrakis (triphenylphosphine) palladium and calcium bis (trifluoromethylsulfonyl) imide is 1: (1.5-2): (1-3%): (5-10%);
(2) and removing the reaction solvent in the reaction liquid, and then purifying to obtain the allyl sulfone compound.
3. The method for preparing an allylsulfone compound according to claim 2, wherein in the step (1), the inert gas is argon;
the allyl alcohol comprises primary cinnamyl alcohol allyl alcohol, secondary allyl alcohol and tertiary allyl alcohol;
the sulfinic acid is any one of phenyl sulfinic acid, 3-methyl phenyl sulfinic acid, methyl sulfinic acid, cyclohexane sulfinic acid, camphor sulfinic acid and benzyl sulfinic acid;
the reaction solvent is any one of 1, 2-dichloroethane, tetrahydrofuran and N, N-dimethylacetamide.
4. The method for producing an allylsulfone compound according to claim 3, wherein the allyl alcohol is any one of cinnamyl alcohol, p-methylcinnamyl alcohol, p-fluorocinnamyl alcohol, trans-2-octen-1-ol, 1-phenylpropan-2-en-1-ol, 2-methyl-1-phenyl-2-propen-1-ol, and 2-phenylbut-3-en-2-ol.
5. The method for preparing an allylsulfone compound according to claim 4, wherein the allyl alcohol is 1-phenylprop-2-en-1-ol.
6. The method for preparing the allyl sulfone compound as claimed in claim 5, wherein the method for synthesizing the 1-phenylprop-2-en-1-ol comprises the following steps:
A. adding benzaldehyde into a tetrahydrofuran solvent at room temperature to obtain a solution 1; adding a vinyl Grignard reagent into the solution 1 at 0 ℃, and stirring for 2 hours to obtain a reaction mixture; wherein the ratio of the quantities of the benzaldehyde, the vinyl Grignard reagent and the tetrahydrofuran solvent is 10 mmol: (15-20) mmol: (10-20) mL;
B. the reaction mixture was quenched by addition to saturated ammonium chloride, extracted 3 times with ethyl acetate, the organic phases combined, dried over anhydrous magnesium sulfate, the solvent removed with a rotary evaporator, and the residue purified by column silica gel chromatography with petroleum ether and ethyl acetate to give 1-phenylprop-2-en-1-ol as a pale yellow liquid.
7. The method for preparing an allylsulfone compound according to claim 3, wherein the sulfinic acid is a sulfinic acid such as phenylsulfinic acid;
the reaction solvent is N, N-dimethylacetamide.
8. The method for preparing an allylsulfone compound of claim 7, wherein the method for synthesizing the phenylsulfinic acid comprises the following steps:
A. dissolving sodium benzene sulfinate in water, adding tert-butyl methyl ether, slowly adding hydrochloric acid with the mass fraction of 36-38% within 2 minutes, and stirring the mixture for 10 minutes; wherein the ratio of the quantities of the sodium benzene sulfinate, the hydrochloric acid, the water and the tert-butyl methyl ether is 17.5 mmol: (1-2) mL: (10-15) mL: (5-10) mL;
B. the mixture was transferred to a separatory funnel, the aqueous layer was removed, the organic layer was concentrated on a rotary evaporator until the solvent disappeared, and the obtained white solid was dried in vacuo to give benzenesulfinic acid.
9. The method for preparing an allylsulfone compound according to claim 2, wherein in the step (2), the reaction solvent is removed by extraction with EA and vacuum rotary evaporation; the purification adopts thin layer chromatography, and the developing agent system is petroleum ether/ethyl acetate.
10. Use of the allylic sulfone of claim 1 as a scaffold for biologically and pharmaceutically active molecules.
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and particularly relates to an allyl sulfone compound and a preparation method and application thereof.
Background
Sulfones play an important role in organic synthesis and are also widely found in many biologically active natural products and in some well-established drugs (e.g., eletriptan ([2H ] -SB-3CT) for the treatment of migraine, MMP-9 inhibitors for the treatment of prostate cancer).
Furthermore, the widespread distribution of the allylsulfone backbone in biologically and pharmaceutically active molecules (e.g. anticancer agents, cysteine protease inhibitors, antibacterial agents, herbicides) has also attracted considerable attention. Therefore, the development of synthetic methods for allyl sulfone has attracted considerable attention in the synthetic community. Existing synthetic methods include the use of transition metal catalyzed (oxidation) -cross-coupling reactions and hydrosulfiding by the use of highly reactive allylic substrates and sulfinyl nucleophiles. However, from an environmental and economic point of view, it is very attractive to develop an energy-saving and efficient green synthesis method using nontoxic, inexpensive, readily available and relatively harmless raw materials, and particularly to a method using allyl alcohol as a raw material and water as a byproduct.
Disclosure of Invention
The invention aims to provide an allyl sulfone compound.
The invention further aims to provide a preparation method of the allyl sulfone compound.
The invention further aims to provide application of the allyl sulfone compound.
The invention is realized by the following steps that the chemical structural formula of the compound is shown as the following formula (I):
in the above formula (I), R1Is aryl or alkyl; r2～R5Any of hydrogen radicals, aryl radicals and alkyl radicals.
The invention further discloses a preparation method of the allyl sulfone compound, which comprises the following steps:
(1) sequentially adding allyl alcohol, sulfinic acid, tetrakis (triphenylphosphine) palladium and calcium bis (trifluoromethylsulfonyl) imide into a reaction solvent in an inert gas atmosphere, and stirring and reacting for 12-48 h at the temperature of 30 ℃; wherein the equivalent ratio of allyl alcohol, sulfinic acid, tetrakis (triphenylphosphine) palladium and calcium bis (trifluoromethylsulfonyl) imide is 1: (1.5-2): (1-3%): (5-10%);
(2) and removing the reaction solvent in the reaction liquid, and then purifying to obtain the allyl sulfone compound.
Preferably, in step (1), the inert gas is argon;
the allyl alcohol comprises primary cinnamyl alcohol allyl alcohol, secondary allyl alcohol and tertiary allyl alcohol;
the sulfinic acid is any one of phenyl sulfinic acid, 3-methyl phenyl sulfinic acid, methyl sulfinic acid, cyclohexane sulfinic acid, camphor sulfinic acid and benzyl sulfinic acid;
the reaction solvent is any one of 1, 2-dichloroethane, tetrahydrofuran and N, N-dimethylacetamide.
Preferably, the allyl alcohol is any one of cinnamyl alcohol, p-methyl cinnamyl alcohol, p-fluoro cinnamyl alcohol, trans-2-octen-1-ol, 1-phenylprop-2-en-1-ol, 2-methyl-1-phenyl-2-propen-1-ol and 2-phenylbut-3-en-2-ol.
Preferably, the allyl alcohol is 1-phenylprop-2-en-1-ol.
Preferably, the synthesis method of the 1-phenylprop-2-en-1-ol comprises the following steps:
A. adding benzaldehyde into a tetrahydrofuran solvent at room temperature to obtain a solution 1; adding a vinyl Grignard reagent into the solution 1 at 0 ℃, and stirring for 2 hours to obtain a reaction mixture; wherein the ratio of the quantities of the benzaldehyde, the vinyl Grignard reagent and the tetrahydrofuran solvent is 10 mmol: (15-20) mmol: (10-20) mL;
B. the reaction mixture was quenched by addition to saturated ammonium chloride, extracted 3 times with ethyl acetate, the organic phases combined, dried over anhydrous magnesium sulfate, the solvent removed with a rotary evaporator, and the residue purified by column silica gel chromatography with petroleum ether and ethyl acetate (PE/EA ═ 50:1 to 10:1) to give 1-phenylpropan-2-en-1-ol as a pale yellow liquid.
Preferably, the sulfinic acid is phenyl sulfinic acid; the reaction solvent is N, N-dimethylacetamide.
Preferably, the method for synthesizing the phenylsulfinic acid comprises the following steps:
A. dissolving sodium benzene sulfinate in water, adding tert-butyl methyl ether, slowly adding hydrochloric acid with the mass fraction of 36-38% within 2 minutes, and stirring the mixture for 10 minutes; wherein the ratio of the quantities of the sodium benzene sulfinate, the hydrochloric acid, the water and the tert-butyl methyl ether is 17.5 mmol: (1-2) mL: (10-15) mL: (5-10) mL;
B. the mixture was transferred to a separatory funnel, the aqueous layer was removed, the organic layer was concentrated on a rotary evaporator until the solvent disappeared, and the obtained white solid was dried in vacuo to give benzenesulfinic acid.
Preferably, in step (2), the reaction solvent is removed by extraction with EA (50mL x 3 times) followed by vacuum rotary evaporation; the purification adopts a thin layer chromatography method, namely, a system mixture is uniformly coated on a silica gel plate, the silica gel plate is dried by a blower, the silica gel plate is placed in a spreading cylinder containing a developing agent PE/EA (2: 1-3: 1), when a solvent reaches the front edge of the solvent, silica gel powder at the position of a product is scraped off under the detection of an ultraviolet lamp, EA (60mL for 3 times) is washed off in a sand core funnel instrument to obtain the product, and the developing agent system is petroleum ether/ethyl acetate (PE/EA: 2: 1-3: 1).
The invention further discloses application of the allyl sulfone compound in serving as a skeleton of bioactive molecules and pharmaceutical active molecules.
The invention discloses a preparation method and application of an allyl sulfone compound. The allyl alcohol raw material, sulfinic acid, tetrakis (triphenylphosphine) palladium and calcium bis (trifluoromethylsulfonyl) imide are sequentially added into a reaction solvent, stirred under the condition of argon and 30 ℃ for catalytic reaction, and the obtained reaction liquid is purified after the reaction solvent is removed to obtain the allyl sulfone compound. The synthesis method has high economy and wide applicable substrate range, and the obtained allyl sulfone compound has potential pharmaceutical activity and biological activity and is an important skeleton widely existing in biological and pharmaceutical active molecules.
Compared with the defects and shortcomings of the prior art, the invention has the following beneficial effects:
(1) part of the raw materials used by the method is low-cost commercial cinnamyl alcohol raw materials, and the obtained by-product is only water, so that the method is high in atom economy, green and environment-friendly;
(2) the method of the invention needs not very harsh conditions, the substrate has wide application range, for example, allyl alcohol can be various substituted phenyl, heterocycle and alkyl;
(3) the process of the invention is applicable to different types of allyl alcohol;
(4) the allyl sulfone compound has wide application prospect in biologically and pharmaceutically active molecules (such as anticancer agents, cysteine protease inhibitors, antibacterial agents and herbicides).
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of (cinnamoylsulfonyl) benzene;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of (cinnamoylsulfonyl) benzene.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.