CN109590024B - Asymmetric bismuth catalytic system and preparation method and application thereof - Google Patents

Abstract

The invention provides an asymmetric bismuth catalytic system, a preparation method and application thereof, relates to the technical field of asymmetric catalysis, provides the asymmetric bismuth catalytic system, and solves the problem of high substrate specificity of the bismuth catalytic system. The asymmetric bismuth catalytic system consists of a metal active center and a chiral ligand, wherein the metal active center is selected from one or more of bismuth acetate, bismuth hydroxide, bismuth bromide or bismuth iodide, and the chiral ligand is selected from chiral phosphoric acid. The asymmetric bismuth catalytic system is used for catalyzing various types of asymmetric transformation, such as asymmetric allylation of ketone and imine, asymmetric allylation of oxonium ion, asymmetric reaction of imine and phenol substrate, and the like.

Description

Asymmetric bismuth catalytic system, preparation method and application thereof

technical field

The invention relates to the technical field of asymmetric catalysis, in particular to an asymmetric bismuth catalytic system and a preparation method and application thereof.

Background technique

"Chirality" is a term used to express the asymmetry of a compound, which means that the configuration of the compound molecule or some groups in the molecule can be arranged into two forms that are mirror images of each other but cannot overlap.

In asymmetric synthesis, the most effective and most economically valuable is the asymmetric catalytic reaction, which only uses a small amount of chiral catalyst to obtain a large number of new optically active substances, thus becoming a very useful method for synthesizing chiral compounds. An important research topic in the current field of asymmetric synthesis research. With more and more attention paid to the study of asymmetric synthesis reactions, chiral catalysts have become the hot spot and frontier of the whole organic synthesis chemistry, and also represent the development direction of organic synthesis chemistry in the 21st century.

Bismuth is located in the fifth main group of the sixth period in the periodic table, and has special physical and chemical properties. Its compounds have green properties such as low cost, low toxicity, non-carcinogenicity and low radioactivity. Trivalent bismuth compounds have been widely used in organic synthesis as a green Lewis Acid catalyst. However, most of the reactions are achiral, and they are rarely used in the field of asymmetric catalysis. Moreover, because the chiral ligands that can be applied to bismuth catalysis are very limited, usually limited to several ligands as shown below, so that the types of catalytic reactions that can be applied are limited, and there is a very strong specificity for the substrate.

In addition, it has been reported that Bi(OTf) ₃ can form a co-catalytic system with the double cinchona base catalyst (DHQ) ₂ PYR and L-proline. But this co-catalytic system can only catalyze certain types of reactions.

How to develop a new catalytic system to overcome the above limitations of current asymmetric bismuth catalysis is an important research topic in this field.

SUMMARY OF THE INVENTION

The invention provides an asymmetric bismuth catalytic system and a preparation method and application thereof, which overcomes the limitation of the current asymmetric bismuth catalysis, can efficiently realize various types of asymmetric transformations, and solves the substrate limitation of the asymmetric bismuth catalytic system question.

The invention provides an asymmetric bismuth catalytic system, which is composed of a metal active center and a chiral ligand, wherein the metal active center is selected from one or more of bismuth acetate, bismuth hydroxide, bismuth bromide or bismuth iodide species, the chiral ligand is selected from chiral phosphoric acid.

Further, in the catalytic system, the molar ratio of the metal active center to the chiral ligand is 1:1, 1:2, and 1:3.

Further, in the catalytic system, the metal active center is selected from one or more of bismuth acetate and bismuth hydroxide.

Further, the catalytic system can be used to catalyze asymmetric allylation of ketones and imines, asymmetric allylation of oxonium ions, and asymmetric reactions of imines and phenolic substrates.

In another aspect, the present invention provides a method for preparing an asymmetric bismuth catalytic system, which is synthesized in situ by one or more of bismuth acetate, bismuth hydroxide, bismuth bromide or bismuth iodide and chiral phosphoric acid at room temperature.

In another aspect, the present invention provides a kind of application of asymmetric bismuth catalytic system, wherein, one or more of bismuth acetate, bismuth hydroxide, bismuth bromide or bismuth iodide and chiral phosphoric acid are first added into the reaction tube , and then sequentially add the substrate and the reaction solvent, stir at room temperature, and monitor the reaction by thin-layer chromatography; or,

First add one or more of bismuth acetate, bismuth hydroxide, bismuth bromide or bismuth iodide and chiral phosphoric acid into the reaction tube, add the reaction solvent, stir at room temperature for 30min, then add the reaction substrate, and at room temperature While stirring was continued, the reaction was monitored by thin layer chromatography.

Compared with the prior art, the present invention develops an asymmetric diacid catalytic system combining Bi(III) and chiral phosphoric acid, and realizes the chemical selectivity, regioselectivity and diastereoselectivity of the asymmetric catalytic reaction The regulation of , achieves the purpose of activating inert substrates, and can catalyze a series of asymmetric reactions. In addition, bismuth is cheap and easy to obtain, and can exist stably. For the asymmetric bis-acid catalysis strategy, the introduction of green Lewis acid into the asymmetric bis-acid catalysis concept can realize green catalysis.

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

酸性，通过对传统Lewis酸、手性酸结构等因素的改变，能够实现对不对称催化反应的化学选择性、区域选择性和非对映选择性的调控。Asymmetric diacid systems developed by mixing chiral acids and traditional Lewis acids can catalyze a series of asymmetric reactions. Bi-acid catalytic system with multiple acid centers, and enhanced

Acidity, through the modification of traditional Lewis acid, chiral acid structure and other factors, can realize the regulation of chemoselectivity, regioselectivity and diastereoselectivity of asymmetric catalytic reactions.

The Lewis acids of the currently successful asymmetric diacid catalysis strategies are limited to In(III), Sc(III), and _BBr3 . At the same time, due to the "big size" of bismuth and other reasons, it is often limited to Bi(OTf) ₃ , which greatly limits the development of Bi(III) in catalytic reactions.

The inventor of the present invention is not limited to this, provides a broad idea for asymmetric bismuth catalysis, and injects new vitality into double acid catalysis, by selecting bismuth acetate, bismuth hydroxide, bismuth bromide or bismuth iodide One or more of chiral phosphoric acid and chiral phosphoric acid, an asymmetric diacid catalytic system combining Bi(III) and chiral phosphoric acid was developed, realizing chemoselectivity, regioselectivity and non-pairing of asymmetric catalytic reactions. The control of enantioselectivity realizes the activation of inert substrates and can catalyze a series of asymmetric reactions. In addition, bismuth is cheap and easy to obtain and can exist stably. For the asymmetric bis-acid catalysis strategy, the introduction of green Lewis acid into the asymmetric bis-acid catalysis concept can realize green catalysis.

The embodiment of the present invention provides an asymmetric bismuth catalytic system, which is composed of a metal active center and a chiral ligand, wherein the metal active center is selected from one or more of bismuth acetate, bismuth hydroxide, bismuth bromide or bismuth iodide , the chiral ligand is selected from chiral phosphoric acid.

In a further embodiment, the metal active center can be selected from one or more of bismuth acetate and bismuth hydroxide.

In one embodiment, the molar ratio of the metal active center to the chiral ligand may be 1:1, 1:2, 1:3. In other words, the composition of the asymmetric bismuth catalytic system is BiX ₃ (metal active center):CPA (chiral phosphoric acid)=1:1, 1:2, 1:3, wherein X is Ac ^- , OH ^- , Br ^- , or I ^- ; further, X can be Ac ^- , OH ^- .

The asymmetric bismuth catalytic system provided in the embodiment of the present invention solves the problem of the substrate limitation of the current asymmetric bismuth catalytic system, and can efficiently realize various types of asymmetric transformations, for example, it can be used to catalyze the asymmetric transformation of aldehydes, ketones and imines Allylation reaction, asymmetric allylation reaction of oxonium ion, asymmetric reaction of imine and phenolic substrate (such as asymmetric Mannich reaction of imine and phenol) and a series of asymmetric catalysis reaction.

In yet another embodiment, the asymmetric catalytic system can be synthesized in situ by BiX ₃ and CPA at room temperature, wherein BiX ₃ is a metal active center selected from bismuth acetate, bismuth hydroxide, bismuth bromide or bismuth iodide. one or more; CPA is a chiral phosphoric acid.

酸催化剂，但其合成难度大。BiX₃是一类价格低廉、安全低毒的Lewis酸催化剂，但其在不对称催化中具有底物局限性，只能催化专一的反应类型。本发明通过原位混合CPA和BiX₃(X＝Ac^-、OH^-、Br^-、I^-)，实现了不对称铋催化。BiX₃可以与磷酸的膦酰氧形成配位键，不仅增强了磷酸的酸性，同时得到具有多个酸性位点的催化剂，在磷酸催化剂的手性调控下继而实现不对称铋催化，实现了对惰性底物活化的目的，能够催化一系列不对称反应。Chiral phosphoric acid is a class of widely used organic catalysts, but is limited by acidity, which makes it insufficient in activating relatively inert substrates. Existing methods have proposed more acidic

acid catalyst, but its synthesis is difficult. BiX ₃ is a class of inexpensive, safe and low-toxic Lewis acid catalysts, but it has substrate limitations in asymmetric catalysis and can only catalyze specific reaction types. The present invention realizes asymmetric bismuth catalysis by in-situ mixing of CPA and BiX ₃ (X=Ac ^- , OH ^- , Br ^- , I ^- ). BiX ₃ can form a coordinate bond with the phosphonyl oxygen of phosphoric acid, which not only enhances the acidity of phosphoric acid, but also obtains a catalyst with multiple acidic sites. The purpose of inert substrate activation is to catalyze a series of asymmetric reactions.

In yet another embodiment, the present invention provides an application of an asymmetric bismuth catalytic system, wherein one or more of bismuth acetate, bismuth hydroxide, bismuth bromide or bismuth iodide and chiral phosphoric acid are first added to the reaction. tube, then add the substrate and the reaction solvent sequentially, stir at room temperature, and monitor the reaction by thin layer chromatography (TLC); or,

First add one or more of bismuth acetate, bismuth hydroxide, bismuth bromide or bismuth iodide and chiral phosphoric acid into the reaction tube, add the reaction solvent and stir at room temperature for 30min, then add the reaction substrate, at room temperature While stirring was continued, the reaction was monitored by thin layer chromatography.

For the application of metal bismuth Bi in the field of asymmetric bismuth catalysis, the asymmetric bismuth catalyst system provided by the present invention can be used to realize a series of asymmetric catalysis reactions, and can be carried out at normal temperature, and the reaction conditions are mild and easy to use.

For bis-acid catalysis, the present invention breaks the existing limitations and proves that green Bi(III) compounds can be applied to this catalytic concept, which makes bis-acid catalysis no longer limited to In(III), Sc(III) and BBr ₃ , adding a green catalytic wedding dress to bis-acid catalysis.

The asymmetric bismuth catalytic system provided by the present invention and its preparation method and application are further elaborated below with reference to specific examples.

Example 1

Catalysis of asymmetric alkenes with allylboronic acid pinacol ester (1.2 equiv.) and isatin-derived ketimines (1.0 equiv.) as substrates using Bi(OAc) ₃ /CPA catalytic system in ether solution at room temperature Propylation reaction, the reaction equation is as above. Bi(OAc) ₃ and chiral phosphoric acid (S)-A (structure shown in the dotted box on the right above) were added to the reaction tube, and then the substrate and reaction solvent were added in sequence, stirred at room temperature, and monitored by thin-layer chromatography. reaction. The amount of catalyst can be reduced to 1 mol% to obtain 3-allyl-3-aminoindolinone in high yield of 99% and high enantioselectivity (99.5:0.5er (enantiomericratio)) compound, and two drug molecules (+)-AG-041R and (-)-psychotriasine were obtained through multi-step reactions.

Example 2

Bi(OAc) ₃ /CPA catalytic system was used as a catalyst to catalyze the reaction of cyclic N-sulfonyl imide (1.0 equiv.) and allyl boronic acid pinacol ester (1.2 equiv.) as substrates at room temperature. Symmetric allylation reaction, the reaction equation is as above. Bi(OAc) ₃ and chiral phosphoric acid (S)-A were added to the reaction tube, then the substrate and the reaction solvent were added in sequence, stirred at room temperature, and the reaction was monitored by thin layer chromatography. The amount of catalyst can be reduced to 1 mol% to obtain the target product in 91% yield and 94:6 enantioselectivity.

Example 3

Catalysis of N- ₁ -methylenenaphthalene-protected indolequinone (1.0 equiv.) with allylboronic acid pinacol ester (1.2 equiv.) is the asymmetric reaction of the substrate, and the reaction equation is as above. Bi(OAc) ₃ and chiral phosphoric acid (S)-B were added to the reaction tube, and then the substrate and the reaction solvent were added in sequence, stirred at room temperature, and the reaction was monitored by thin layer chromatography. A series of 3-allyl-3-hydroxyindolinone compounds were obtained in up to 99% yield and high enantioselectivity (98:2er).

Example 4

The catalytic system Bi(OH) ₃ /CPA constructed with Bi(OH) ₃ (2 mol%) and (S)-C (2 mol%) was used as a catalyst in 1,4-dioxane catalyzed with N - Asymmetric Mannich reaction of Boc ketimine (1.0 equiv.) and 3,5-dimethoxyphenol (1.2 equiv.) as substrates, the reaction equation is as above. Add Bi(OH) ₃ and chiral phosphoric acid (S)-C into the reaction tube, add the reaction solvent and stir at room temperature for 30 min, then add the reaction substrate, continue stirring at room temperature, and monitor the reaction by thin layer chromatography. The title product was obtained in 90% yield and high enantioselectivity (98:2er).

Example 5

The catalytic system Bi(OAc) ₃ /CPA constructed with Bi(OAc) ₃ (2 mol%) and (S)-A (3 mol%) was used as catalyst in 1,4-dioxane with N - Asymmetric reaction of Boc ketimine (1.0 equiv.) and allylboronic acid pinacol ester (1.2 equiv.) as substrates, the reaction equation is as above. Bi(OAc) ₃ and chiral phosphoric acid (S)-A were added to the reaction tube, then the substrate and the reaction solvent were added in sequence, stirred at room temperature, and the reaction was monitored by thin layer chromatography. The reaction results are shown in Table 1.

Comparative Example 1

Bi(OTf) ₃ (2 mol %) and (S)-A (3 mol %) were used as catalysts in 1,4-dioxane with N-Boc ketimine (1.0 equiv.) and Allylboronic acid pinacol ester (1.2equiv.) was used as the substrate for asymmetric reaction, and the reaction results are shown in Table 1.

Table 1

BiX₃ reaction time/h Yield/% er Example 5 Bi(OAc)₃ 0.5 96 99:1 Comparative Example 1 Bi(OTf)₃ twenty four 30 57:43

It can be seen from the results in Table 1 that the efficiency and enantioselectivity of the Bi(OAc) ₃ /(S)-A catalyst are significantly better than those of the Bi(OTf) ₃ /(S)-A catalyst system. The asymmetric bismuth catalytic system provided in the embodiment of the present invention applies green Bi(III) to the concept of bi-acid catalysis, breaks the limitation of bi-acid catalysis in In(III), Sc(III) and BBr ₃ , and is a bi-acid catalysis system. Added Green Catalytic Wedding Dress. At the same time, it solves the limitation of green Bi(III) in the field of asymmetric catalysis. The asymmetric bismuth catalytic system can efficiently realize various types of asymmetric transformations, such as asymmetric allylation of ketones and imines, Asymmetric allylation of oxonium ions, asymmetric reaction of imines with phenolic substrates, etc.

In the description of this specification, description with reference to the terms "one embodiment," "some embodiments," "example," "specific example," or "some examples", etc., mean specific features described in connection with the embodiment or example , structure, material or feature is included in at least one embodiment or example of the present invention.

In this specification, schematic representations of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

Claims (3)

1. An asymmetric bismuth catalytic system for catalyzing asymmetric allylation of ketones and imines, asymmetric allylation of oxonium ions, or asymmetric mannich reactions of imines and phenolic substrates, consisting of a metal active center and a chiral ligand, wherein the metal active center is selected from bismuth acetate or bismuth hydroxide, and the chiral ligand is selected from chiral phosphoric acid;

the molar ratio of the metal active center to the chiral ligand is 1:1, 1:2, or 1: 3.

2. The method for preparing an asymmetric bismuth catalytic system according to claim 1, wherein the asymmetric bismuth catalytic system is prepared by in situ synthesis of bismuth acetate or bismuth hydroxide and chiral phosphoric acid at room temperature.

3. The application of the asymmetric bismuth catalysis system as claimed in claim 1, wherein the bismuth acetate or bismuth hydroxide and chiral phosphoric acid are added into a reaction tube, then the substrate and the reaction solvent are sequentially added, stirring is carried out at room temperature, and the reaction is monitored by thin layer chromatography; or adding bismuth acetate or bismuth hydroxide and chiral phosphoric acid into a reaction tube, adding a reaction solvent, stirring at room temperature for 30min, adding a reaction substrate, stirring at room temperature, and monitoring the reaction by thin layer chromatography.