阅读说明：本技术 一种手性配体及其在催化制备光学活性二级醇中的应用 (Chiral ligand and application thereof in catalytic preparation of optically active secondary alcohol ) 是由 赵蓓 余齐顺 陆澄容 于 2020-07-31 设计创作，主要内容包括：本发明公开了一种手性配体及其在催化制备光学活性二级醇中的应用,本发明设计合成了一类新的手性配体,配体的结构式为：<Image he="355" wi="539" file="DDA0002612788790000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,R<Sup>1</Sup>、R<Sup>2</Sup>独立选自氢、C1-C4烷基、CF<Sub>3</Sub>或甲氧基,R<Sup>3</Sup>选自C1-C4烷基,可用于简单酮的不对称硼氢化反应。本发明利用三价稀土金属硅胺化合物和手性配体原位催化,其催化剂的用量为反应物酮的10mol％,产物收率可达95％,产物的ee值可达到63％。较少的催化剂用量也有利于稀土资源高效利用和节能环保,利于产物的提纯。本发明反应条件温和,无需添加剂,能高效催化酮的不对称硼氢化。(The invention discloses a chiral ligand and application thereof in preparing optically active secondary alcohol by catalysis, wherein the invention designs and synthesizes a new chiral ligand, and the structural formula of the ligand is as follows: wherein R is 1 、R 2 Independently selected from hydrogen, C1-C4 alkyl, CF 3 Or methoxy, R 3 Selected from C1-C4 alkyl groups, can be used for asymmetric hydroboration reaction of simple ketone. The invention utilizes the combination of trivalent rare earth metal and silicon amineThe product and chiral ligand are catalyzed in situ, the dosage of the catalyst is 10 mol% of the reactant ketone, the product yield can reach 95%, and the ee value of the product can reach 63%. The small amount of the catalyst is also beneficial to the efficient utilization of rare earth resources, energy conservation and environmental protection, and is beneficial to the purification of products. The method has mild reaction conditions, does not need additives, and can efficiently catalyze the asymmetric hydroboration of the ketone.)

1. A chiral ligand, wherein the ligand has the formula:

wherein R is¹、R²Independently selected from hydrogen, C1-C4 alkyl, CF₃Or a methoxy group; r³Selected from C1-C4 alkyl.

2. A process for the preparation of a chiral ligand according to claim 1, comprising the steps of:

adding (1R,2R) -N- (p-methyl benzenesulfonyl) -1, 2-diphenyl ethylene diamine into an anhydrous ether solvent, adding triethylamine as an acid-binding agent, dropwise adding benzoyl chloride shown in the formula (4) into an ice water bath, slowly heating to 20-30 ℃ after dropwise adding, and stirring for reacting for 3-5 hours to obtain the chiral ligand;

wherein R is¹、R²Independently selected from hydrogen, C1-C4 alkyl, CF₃Or a methoxy group.

3. Use of a chiral ligand according to claim 1 in the catalytic preparation of an optically active secondary alcohol.

4. The use according to claim 3, characterized in that it comprises the following steps:

under the conditions of no water, no oxygen and protective atmosphere, ketone shown in the formula (1) and pinacol borane (HBPin) are subjected to reaction in an organic solvent at-30 ℃ to 30 ℃ under the in-situ catalysis of the chiral ligand and a trivalent rare earth metal silamine compound, and after the reaction is completed, the optically active secondary alcohol shown in the formula (2) is obtained by quenching, wherein the reaction route is as follows:

wherein R is alkyl;

the trivalent rare earth metal silicon amine compound is as follows: RE [ N (SiMe)₃)₂]₃；

RE is La element, Nd element, Eu element, Sm element, Yb element or Y element.

5. The use according to claim 4, wherein the molar ratio of the ketone, the pinacolborane, the trivalent rare earth metal silamine compound and the chiral ligand is 10:20:1: 1-2.

6. Use according to claim 4, wherein the reaction time is 8-24 h.

7. The use according to claim 4, wherein the organic solvent is one or more of tetrahydrofuran, 1, 4-dioxane, dimethyl ether, dichloromethane, tetrahydrofuran and 1, 4-dioxane.

8. Use according to claim 4, wherein the protective atmosphere is argon or nitrogen.

9. The use according to claim 4, wherein the reaction is quenched with silica gel after the reaction is complete.

10. The use of claim 4, further comprising the step of purifying the product by column chromatography after the reaction is completed.

Technical Field

The invention relates to a chiral ligand and application thereof in preparing optically active secondary alcohol by catalysis, belonging to the technical field of catalysts.

Background

The optically active secondary alcohol is an extremely important active biomolecule precursor and widely exists in molecular fragments of various natural products and artificially synthesized medicines; as an intermediate in organic synthesis, optically active secondary alcohols are important chiral source reagents. Asymmetric hydroboration reduction of ketones is the most direct and most convenient way to obtain optically active secondary alcohols.

At present, reports about the preparation of optically active secondary alcohols by asymmetric hydroboration reaction catalyzed by metal complexes:

(1) in 2015, the terrestrially developed group reported the first asymmetric hydroboration reaction catalyzed by a metallic Co complex involving pinacolborane. The reaction uses a metal Co complex with stable pyridine oxazoline ligand as a catalyst, aryl ketone as a raw material and pinacol borane as a reducing agent, has good adaptability to a substrate, can realize more than 90 percent of conversion rate of most substrates within 2 hours at room temperature, and has the highest ee value of 99 percent (see Guo, J.; Chen, J.H.; Lu, Z.Chem.Commun.2015,51, 5725) for example).

(2) In 2017, a Gade project group reports that the manganese chelate complex is used for catalyzing asymmetric hydroboration reaction of pinacol borane high-efficiency simple ketone, and the yield can reach 99% within 2h of 2.5 mol% of catalyst consumption. The reaction is suggested to be catalytic in nature by metal hydrides (see: Vasilenko, v.; blisus, c.k.; Wadepohl, h.; Gade, l.h. angelw.chem.int.ed.2017, 56,8393.).

(3) In 2018, Zhao Bei topic group prepared various aryloxy functionalized chiral ligands with diphenyl prolinol as basic skeleton, and synthesized corresponding rare earth metal complexes. Asymmetric hydroboration of both aromatic and α, β -unsaturated ketones has good results when pinacolborane is used as the reducing agent (see: Song, p.; Lu, c.r.; Fei, z.h.; Zhao, b.; Yao, y.m.j. org. chem.2018,83,6093.).

(4)2019, Magnus topic group utilized (R) - (+) -BINOL ligand and MgBu₂The asymmetric hydroboration reaction of the pinacol borane high-efficiency ketone is catalyzed in situ, the yield can reach 99 percent within 3 hours at the temperature of minus 40 ℃, and the ee value can reach 98 percent.In previous reports, it was generally believed that asymmetric hydroboration of ketones is essentially catalytic for metal hydrides, but this article suggested different reaction mechanisms by spectral characterization and DFT calculations (see: Alban, F.; Marc, M.; Bholanath, M.; Luigi, C.; Magnus, R.Angew.Chem., int.Ed.2019,58,17567.).

(5) In 2020, Magnus subjects utilized (R) - (+) -BINOL ligand and AlMe₃Asymmetric hydroboration of in situ catalyzed heterocyclic ketones with very good yields and ee values for most substrates within 2h using only 1 mol% of catalyst (see: Yury, l.; iulia, p.; bholaath, m.; Miguel, D, V, g.; Luigi, c.; Magnus, r.j.am.chem.soc.2019,141, 19415.).

In summary, there are only a few reports on metal-catalyzed asymmetric hydroboration reactions. Therefore, the method has important research value for realizing the asymmetric hydroboration reaction of simple ketone by selecting a proper metal reagent and assisting a proper chiral ligand.

Disclosure of Invention

In order to solve the technical problems, the invention provides a series of novel chiral ligands for preparing the optically active secondary alcohol, and the chiral ligands have the advantages of easily modified structure, small using amount of catalysts, mild reaction conditions, simple and convenient separation and purification, and can synthesize the optically active secondary alcohol with high yield and high selectivity.

A first object of the present invention is to provide a chiral ligand, which has the structural formula:

wherein R is¹、R²Independently selected from hydrogen, C1-C4 alkyl, CF₃Or a methoxy group; r³Selected from C1-C4 alkyl.

In the present invention, chiral ligand H is abbreviated₂LⁿWherein n is an integer of 1 to 5, specifically:

when R is¹Is 4-tert-butyl, R²Is hydrogen, R³Is methyl, the chiral ligand is named H₂L¹；

When R is¹Is 4-trifluoromethyl, R²Is hydrogen, R³Is methyl, the chiral ligand is named H₂L²；

When R is¹、R²Is 2, 6-dimethyl, R³Is methyl, the chiral ligand is named H₂L³；

When R is¹、R²Is 2,4, 6-trimethyl, R³Is methyl, the chiral ligand is named H₂L⁴；

When R is¹、R²Is 2,4, 6-trimethoxy, R³Is methyl, the chiral ligand is named H₂L⁵。

The second purpose of the invention is to provide a preparation method of the chiral ligand, which comprises the following steps:

adding (1R,2R) -N- (p-methyl benzenesulfonyl) -1, 2-diphenyl ethylene diamine into an anhydrous ether solvent, adding triethylamine as an acid-binding agent, dropwise adding benzoyl chloride shown in the formula (4) into an ice water bath, slowly heating to 20-30 ℃ after dropwise adding, and stirring for reacting for 3-5 hours to obtain the chiral ligand;

wherein R is¹、R²Independently selected from hydrogen, C1-C4 alkyl, CF₃Or a methoxy group.

The third purpose of the invention is to provide the application of the chiral ligand in the catalytic preparation of the optically active secondary alcohol.

Further, the application comprises the following steps:

under the conditions of no water, no oxygen and protective atmosphere, ketone shown in the formula (1) and pinacol borane (HBPin) are subjected to reaction in an organic solvent at-30 ℃ to 30 ℃ under the in-situ catalysis of the chiral ligand and a trivalent rare earth metal silamine compound, and after the reaction is completed, the optically active secondary alcohol shown in the formula (2) is obtained by quenching, wherein the reaction route is as follows:

wherein R is alkyl;

the trivalent rare earth metal silicon amine compound is as follows: RE [ N (SiMe)₃)₂]₃；

RE is La element, Nd element, Eu element, Sm element, Yb element or Y element.

Preferably, the most enantioselective reaction temperature is-10 ℃.

Further, the molar ratio of the ketone, the pinacol borane, the trivalent rare earth metal silamine compound and the chiral ligand is 10:20:1: 1-2. Preferably, the most enantioselective molar ratio is 10:20:1: 1.

Further, the reaction time is 8-24 h. Preferably, 12h is selected as reaction time.

Further, the organic solvent is one or a mixture of tetrahydrofuran, 1, 4-dioxane, dimethyl ether, dichloromethane, tetrahydrofuran and 1, 4-dioxane. Preferably, the enantioselectivity is best when a mixed solution of 1mL tetrahydrofuran and 1mL 1, 4-dioxane is used as the solvent.

Further, the protective atmosphere is argon or nitrogen.

Further, silica gel (SiO) is used after the reaction is finished₂) The reaction was quenched.

Further, the method also comprises a step of purifying the product by adopting column chromatography after the reaction is finished.

The invention has the beneficial effects that:

1. the invention designs and synthesizes a new chiral ligand which can be used for asymmetric hydroboration reaction of simple ketone.

2. The invention utilizes trivalent rare earth metal silicon amine compound and ligand for in-situ catalysis, the dosage of the catalyst is 10 mol% of reactant ketone, the product yield can reach 95%, and the ee value of the product can reach 63%. The small amount of the catalyst is also beneficial to the efficient utilization of rare earth resources, energy conservation and environmental protection, and is beneficial to the purification of products.

3. The method has mild reaction conditions, does not need additives, and can efficiently catalyze the asymmetric hydroboration of the ketone.

Detailed Description

The present invention is further described below in conjunction with specific examples to enable those skilled in the art to better understand the present invention and to practice it, but the examples are not intended to limit the present invention.