阅读说明：本技术 一种轴手性联芳基化合物及手性芴醇化合物的制备方法 (Preparation method of axial chiral biaryl compound and chiral fluorenol compound ) 是由 周强辉 刘泽水 于 2020-06-30 设计创作，主要内容包括：本发明公开了一种轴手性联芳基化合物及手性芴醇化合物的制备方法。该制备方法以芳基碘化物、芳基溴化物和烯烃为起始原料,在钯催化剂、膦配体、手性降冰片烯衍生物以及碱的作用下,在50℃到150℃下于有机溶剂中搅拌反应,即可得到联芳基轴手性化合物及手性芴醇化合物。该方法所用的原料廉价易得,反应条件温和,底物普适性好,产率高,制备过程简单。所制备的联芳基轴手性化合物可应用于新型手性配体及手性催化剂的合成。(The invention discloses a preparation method of an axial chiral biaryl compound and a chiral fluorenol compound. The preparation method comprises the steps of taking aryl iodide, aryl bromide and olefin as initial raw materials, and stirring and reacting in an organic solvent at 50-150 ℃ under the action of a palladium catalyst, a phosphine ligand, a chiral norbornene derivative and alkali to obtain a biaryl axial chiral compound and a chiral fluorenol compound. The method has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, good substrate universality, high yield and simple preparation process. The prepared biaryl axial chiral compound can be applied to synthesis of novel chiral ligands and chiral catalysts.)

1. A preparation method of an axial chiral biaryl compound is characterized by comprising the following steps:

under the protection of argon, taking aryl iodide A, aryl bromide B and a termination reagent C as initial raw materials, stirring and reacting in an organic solvent G under the action of a palladium catalyst D, a chiral norbornene derivative E and an alkali F until the reaction is finished, filtering, concentrating and purifying by column chromatography to obtain the axial chiral biaryl compound shown as the formula I,

the reaction formula is as follows:

wherein:

R¹-R⁵selected from hydrogen, aryl, heterocyclic aryl, alkyl, ester group, aldehyde group, carboxyl, hydroxyl, silicon group, amino, cyano, nitro, amido, sulfonyl, alkoxy, alkenyl, alkynyl or halogen;

m represents R⁴M is more than or equal to 0 and less than or equal to 3; when m is more than or equal to 2, the two groups can be the same or different;

n represents R⁵N is more than or equal to 0 and less than or equal to 3; when n is more than or equal to 2, the two groups can be the same or different;

t represents a terminating agent, including alkene, alkyne, boric acid, borate, cyanide and alcohol;

Ar¹and Ar²Are aromatic hydrocarbons and heterocyclic aromatic hydrocarbons.

2. A preparation method of a chiral fluorenol compound is characterized by comprising the following steps:

under the protection of argon, taking aryl iodide A and aryl bromide B as initial raw materials, stirring and reacting in an organic solvent G under the action of a palladium catalyst D, a ligand H, a chiral norbornene derivative E and an alkali F until the reaction is finished, filtering, concentrating and purifying by column chromatography to obtain a chiral fluorenol compound shown as a formula II;

the reaction formula is as follows:

wherein:

R¹-R⁵is one or more of aryl, heterocyclic aryl, alkyl, ester group, aldehyde group, carboxyl, hydroxyl, silicon base, amino, cyano, nitro, amido, sulfonyl, alkoxy, alkenyl, alkynyl and halogen;

m represents R⁴M is more than or equal to 0 and less than or equal to 3, and when m is more than or equal to 2, the two groups can be the same or different;

n represents R⁵N is more than or equal to 0 and less than or equal to 3, and when n is more than or equal to 2, the two groups can be the same or different;

Ar¹and Ar²Are aromatic hydrocarbons and heterocyclic aromatic hydrocarbons.

3. The method for producing an axial chiral biaryl compound according to claim 1, wherein: the terminating agent C is selected from alkenes, alkynes, aryl boric acids or boric acid esters, alkyl boric acids or boric acid esters, cyanides, nitriles and ketones.

4. The method for preparing axial chiral biaryl compound and chiral fluorenol compound according to claim 1 or 2, wherein the palladium catalyst D is selected from Pd (PPh)₃)₄、Pd(dba)₂、Pd₂(dba)₃、Pd(OAc)₂、Pd(PhCN)₂Cl₂、Pd(MeCN)₂Cl₂、PdCl₂、PdI₂、[Pd(allyl)Cl]₂Any one or more of them.

5. The method for preparing an axial chiral biaryl compound and a chiral fluorenol compound according to claim 1 or 2, wherein the chiral norbornene derivative E has a structural formula:

wherein:

i)R⁶is a substituent on the left five-membered ring, p represents the number of the substituent, and p is more than or equal to 0 and less than or equal to 8; r⁷Is a substituent on a double bond, q represents the number of the substituent, and q is more than or equal to 0 and less than or equal to 2;

ii)R⁶，R⁷any one or more of aryl, heterocyclic aryl, alkyl, ester group, aldehyde group, carboxyl, hydroxyl, silicon base, amino, cyano, nitro, amido, sulfonyl, alkoxy, alkenyl, alkynyl or halogen;

iii) when the number of the substituents on the left five-membered ring is 2 or more, the substituents may be the same or different; when the number of the substituent groups on the double bond is 2, the substituent groups can be the same or different;

iv)R⁶and R⁷The substituents may be the same or different.

6. The method for preparing axial chiral biaryl compounds and chiral fluorenol compounds as claimed in claim 1 or 2, wherein the base F is selected from any one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, cesium acetate, tripotassium phosphate, potassium formate, sodium hydroxide and sodium tert-butoxide.

7. The method for preparing axial chiral biaryl compound and chiral fluorenol compound according to claim 1 or 2, wherein the solvent G is selected from methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dimethyl ethylene glycol ether, methyl tert-butyl ether, 1, 4-dioxahexane, 1, 3-dioxahexane, dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, C_4-12Saturated alkane of (C)_3-12Fluoro or chloro alkane, benzene, toluene, xylene, trimethylbenzene, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamideAcetone, N-methylpyrrolidone, acetonitrile, C_3-12Any one or more of the saturated alkyl nitriles of (1).

8. The method for producing an axial chiral biaryl compound according to claim 1, wherein: the phosphine ligand H is selected from triarylphosphines, trialkylphosphines, dicyclohexyl (2',4',6 '-triisopropyl- [1,1' -diphenyl ] -2-yl) phosphine, dicyclohexyl (2',4',6 '-triisopropyl-3, 6-dimethoxy- [1,1' -diphenyl ] -2-yl) phosphine, dicyclohexyl (2',6' -dimethoxy- [1,1 '-diphenyl ] -2-yl) phosphine, 2' - (dicyclohexylphosphino) -N, N-dimethyl- [1,1 '-diphenyl ] -2-amine, dicyclohexyl (2',6 '-diisopropoxy- [1,1' -diphenyl ] -2-yl) phosphine, bis (tert-butyl) phosphine, Any one or more of tri (2-furyl) phosphine, (3S,5S,7S) -adamantan-1-yl ((1R,5S) -adamantan-2-yl) (butyl) phosphine.

9. An axial chiral biaryl compound characterized by: prepared by the method of claim 1.

10. A chiral fluorenol compound, characterized in that: prepared by the process of claim 2.

Technical Field

The invention relates to a preparation method of an axial chiral biaryl compound and a chiral fluorenol compound, belonging to the field of organic synthesis.

Background

The axial chiral biaryl backbone is a very important class of structural units widely found in natural products, pharmaceutical molecules and chiral materials with biological activity ([1] q.li, l.green, n.venkataraman, i.shiyanovskaya, a.khan, a.urbas, j.w.doane, j.am.chem.soc.2007,129, 12908; [2] j.e.smyth, n.m.butler, p.a.keller, nat.prod.rep.2015,32,1562; [3] j.clayden, w.j.moran, p.j.edwards, s.r.lantte, angelw.chem.int.ed.2009, 48,6398). In addition, chiral ligands and catalysts having an axial chiral biaryl group as a skeleton have an important role in asymmetric catalytic reactions ([1] R.Noyori, H.Takaya, Acc.chem.Res.1990,23,345; [2] Y.Chen, S.Yekta, A.K.Yudin, chem.Rev.2003,103, 3155; [3] D.Parmar, E.Sugiono, S.Raja, M.Rueping, chem.Rev.2014,114, 9047). Given the importance of such structural backbones, chemists have developed a number of synthetic methods, including: (1) asymmetric cross-coupling or oxidative self-coupling of aryl-aryl groups ([1] t.hayashi, k.hayashizaki, t.kiyoi, y.ito, j.am.chem.soc.1988,110, 8153; [2] r.giri, b. -f.shi, k.m.engle, n.maugel, j. -q.yu, chem.soc.rev.2009,38,3242); (2) (dynamic) kinetic resolution and desymmetrization of biaryls ([1] J. L. Gustafson, D.Lim, S.J.Miller, Science 2010,328,1251; [2] G.Ma, M.P.Sibi, chem.Eur.J.2015, 21, 11644); (3) one aromatic ring in the asymmetric building biaryl (a. link, c.sparr, chem.soc.rev.2018,47,3804); (4) a shift in central handedness to axial chirality (a. link, c.sparr, chem.soc.rev.2018,47,3804); (5) asymmetric ring opening reaction of a strained diaryl cyclic compound (K.ZHao, L.Duan, S.Xu, J.Jiang, Y.Fu, Z.Gu, Chem 2018,4,599) and the like. However, most of these methods require the prior synthesis of a substrate having a specific functional group or require a relatively complicated catalyst, which greatly limits the range of applications of these methods. Therefore, it is very important to develop a new method for synthesizing the compound with high efficiency and simplicity. The method takes easily obtained aryl iodide, aryl bromide and olefin as initial raw materials, and the axial chiral biaryl compound can be obtained by stirring and reacting the raw materials in an organic solvent at 50-150 ℃ under the action of a palladium catalyst, a phosphine ligand, a chiral norbornene derivative and alkali. The method has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, good substrate universality, high yield and simple preparation process. The prepared biaryl axial chiral compound can be applied to synthesis of novel chiral ligands and chiral catalysts.

Disclosure of Invention

In order to solve the defects in the prior art, the invention provides an axial chiral biaryl compound and a preparation method of a chiral fluorenol compound. The method has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, good substrate universality, high yield and simple preparation process. The two compounds have the same intermediate, namely an axial chiral palladium intermediate, can form an axial chiral biaryl compound under the condition of adding a termination reagent, and can generate intramolecular termination reaction when the substrate has a carbonyl structure without adding the termination reagent, so that the chiral fluorenol compound is formed.

The technical scheme provided by the invention is as follows:

one of the purposes of the invention is to provide a preparation method of an axial chiral biaryl compound, which comprises the following steps:

under the protection of argon, taking aryl iodide A, aryl bromide B and a termination reagent C as initial raw materials, stirring and reacting in an organic solvent G under the action of a palladium catalyst D, a chiral norbornene derivative E and an alkali F until the reaction is finished, filtering, concentrating and purifying by column chromatography to obtain the axial chiral biaryl compound shown as the formula I.

The reaction formula is as follows:

wherein:

R¹-R⁵selected from aryl, heterocyclic aryl, alkyl, ester group, aldehyde group, carboxyl, hydroxyl,Silicon, amino, cyano, nitro, amido, sulfonyl, alkoxy, alkenyl, alkynyl or halogen;

m represents R⁴M is more than or equal to 0 and less than or equal to 3; when m is more than or equal to 2, the two groups can be the same or different;

n represents R⁵N is more than or equal to 0 and less than or equal to 3; when n is more than or equal to 2, the two groups can be the same or different;

t represents a terminating agent, including alkene, alkyne, boric acid, borate, cyanide and alcohol;

Ar¹and Ar²Are aromatic hydrocarbons and heterocyclic aromatic hydrocarbons.

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

under the protection of argon, taking aryl iodide A and aryl bromide B as initial raw materials, stirring and reacting in an organic solvent G under the action of a palladium catalyst D, a ligand H, a chiral norbornene derivative E and an alkali F until the reaction is finished, filtering, concentrating and purifying by column chromatography to obtain a chiral fluorenol compound shown as a formula II;

the reaction formula is as follows:

wherein:

R¹-R⁵is one or more of aryl, heterocyclic aryl, alkyl, ester group, aldehyde group, carboxyl, hydroxyl, silicon base, amino, cyano, nitro, amido, sulfonyl, alkoxy, alkenyl, alkynyl and halogen;

m represents R⁴M is more than or equal to 0 and less than or equal to 3; when m is more than or equal to 2, the two groups can be the same or different;

n represents R⁵N is more than or equal to 0 and less than or equal to 3; when n is more than or equal to 2, the two groups can be the same or different;

Ar¹and Ar²Are aromatic hydrocarbons and heterocyclic aromatic hydrocarbons.

Further, in the preparation method of the axial chiral biaryl compound, the termination reagent C is selected from alkene, alkyne, aryl boric acid or boric acid ester, alkyl boric acid or boric acid ester, cyanide, nitrile compound and ketone compound.

Further, in the preparation method of the axial chiral biaryl compound or the chiral fluorenol compound, the palladium catalyst D is selected from Pd (PPh)₃)₄、Pd(dba)₂、Pd₂(dba)₃、Pd(OAc)₂、Pd(PhCN)₂Cl₂、Pd(MeCN)₂Cl₂、PdCl₂、PdI₂、[Pd(allyl)Cl]₂Any one or more of them. Preferably Pd (OAc)₂。

Further, in the preparation method of the axial chiral biaryl compound or the chiral fluorenol compound, the structural formula of the chiral norbornene derivative E is as follows:

wherein:

i)R⁶is a substituent on the left five-membered ring, p represents the number of the substituent, and p is more than or equal to 0 and less than or equal to 8; r⁷Is a substituent on a double bond, q represents the number of the substituent, and q is more than or equal to 0 and less than or equal to 2;

ii)R⁶，R⁷any one or more of aryl, heterocyclic aryl, alkyl, ester group, aldehyde group, carboxyl, hydroxyl, silicon base, amino, cyano, nitro, amido, sulfonyl, alkoxy, alkenyl, alkynyl or halogen;

iii) when the number of the substituents on the left five-membered ring is 2 or more, the substituents may be the same or different; when the number of the substituent groups on the double bond is 2, the substituent groups can be the same or different;

iv)R⁶and R⁷The substituents may be the same or different.

Further, in the preparation method of the axial chiral biaryl compound or the chiral fluorenol compound, the base F is selected from any one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, cesium acetate, tripotassium phosphate, potassium formate, sodium hydroxide and sodium tert-butoxide. Potassium carbonate is preferred.

Further, in the preparation method of the axial chiral biaryl compound or the chiral fluorenol compound, the solvent G is selected from methanol, ethanol, isopropanol, tert-butyl alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dimethyl ethylene glycol ether, methyl tert-butyl ether, 1, 4-dioxane, 1, 3-dioxane, dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, C_4-12Saturated alkane of (C)_3-12Fluoro or chloro alkane, benzene, toluene, xylene, trimethylbenzene, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, acetone, N-methylpyrrolidone, acetonitrile, C_3-12Any one or more of the saturated alkyl nitriles of (1). Acetonitrile is preferred.

Further, in the method for preparing the axial chiral biaryl compound, the phosphine ligand H is selected from triarylphosphine, trialkylphosphine, dicyclohexyl (2',4',6' -triisopropyl- [1,1' -diphenyl ] -2-yl) phosphine, dicyclohexyl (2',4',6' -triisopropyl-3, 6-dimethoxy- [1,1' -diphenyl ] -2-yl) phosphine, dicyclohexyl (2',6' -dimethoxy- [1,1' -diphenyl ] -2-yl) phosphine, 2' - (dicyclohexylphosphino) -N, N-dimethyl- [1,1' -diphenyl ] -2-amine, dicyclohexyl (2',6' -diisopropyloxy- [1,1' -diphenyl ] -2-yl) phosphine, tris (2-furyl) phosphine, any one or more of (3S,5S,7S) -adamantan-1-yl ((1R,5S) -adamantan-2-yl) (butyl) phosphine. Tris (2-furyl) phosphine is preferred.

The invention also aims to provide an axial chiral biaryl compound prepared by the method.

The fourth object of the present invention is to provide a chiral fluorenol compound prepared by the above method.

In the preparation method of the axial chiral biaryl compound or the chiral fluorenol compound, the reaction time is 1-48 hours, and the reaction temperature is 50-130 ℃. The heating process can adopt oil bath (such as silicone oil, paraffin oil, etc.) or other heating methods.

The invention preferably carries out post-treatment, including suction filtration, concentration and purification, on the reaction product after the reaction is finished. The suction filtration process can be carried out using a sand core funnel under reduced pressure. The concentration process can adopt a method of reduced pressure distillation and the like, for example, reduced pressure concentration by a rotary evaporator. The purification method can adopt column chromatography separation and purification.

The method can efficiently prepare the axial chiral biaryl compound and the chiral fluorenol compound, and has the following beneficial effects:

1. the main raw materials related by the invention are aryl iodide, aryl bromide and olefin, and the raw materials can be commercialized reagents, do not need special treatment, and have low price and various varieties;

2. the method has very good enantioselectivity, and the ee value of the obtained product is as high as 99%.

3. The catalyst used in the reaction related to the method is a cheap metal palladium salt, and is an important supplement compared with other catalysts or complexes and the like;

4. the catalytic amount of norbornene derivative used in the reaction related to the method of the present invention is greatly reduced compared with the amount of norbornene used in the previous reaction;

5. the reaction related to the method has good tolerance and universality to functional groups, and the substituent can be alkyl, alkoxy, cyano, ester group, nitro, halogen atoms (F, Cl, Br) and the like.

6. The method can prepare a large amount of (gram-grade) axial chiral biaryl compounds and chiral fluorenol compounds, and lays a good foundation for industrial production.

Detailed Description

The present invention is further illustrated by the following examples, it being noted that the invention is not limited to the examples described below.