阅读说明：本技术 手性铜复合物及其制备方法和应用 (Chiral copper compound and preparation method and application thereof ) 是由 汪志勇 李金东 于 2019-01-09 设计创作，主要内容包括：本发明提供了一种具有通式(I)结构的手性铜复合物及其制备方法和在手性3-羟基-2-氧代吲哚类化合物合成中的应用,其中,通式(I)中的Ar表示苯基或取代苯基,取代苯基中的取代基团分别为C1～C5的烷基、C1～C5的烷氧基和C1～C5的氟烷基中的一种或多种。该手性铜复合物能高效的催化靛红类化合物的不对称Mukaiyama Aldol反应,能够高对映和非对映选择性得到3-羟基-2-氧代吲哚类化合物,且利用该手性铜复合物将反应放大到克级规模时,产物的立体选择性依然能够得到保持。由该种复合物催化的不对称Mukaiyama Aldol反应对水有很好的耐受性。(The invention provides a chiral copper compound with a structure shown in a general formula (I), a preparation method thereof and application thereof in synthesis of a chiral 3-hydroxy-2-oxoindole compound, wherein Ar in the general formula (I) represents phenyl or substituted phenyl, and substituent groups in the substituted phenyl are respectively one or more of C1-C5 alkyl, C1-C5 alkoxy and C1-C5 fluoroalkyl. The chiral copper compound can efficiently catalyze the asymmetric Mukaiyama Aldol reaction of the isatin compound, can obtain the 3-hydroxy-2-oxoindole compound with high enantioselectivity and diastereoselectivity, and can still maintain the stereoselectivity of the product when the chiral copper compound is used for amplifying the reaction to gram-scale. The asymmetric Mukaiyama Aldol reaction catalyzed by the complex is well-tolerated by water.)

1. A chiral copper complex having a chemical structure represented by the following general formula (I):

wherein, Ar in the general formula (I)₁And Ar₂The substituents in the substituted phenyl group are at least one selected from C1-C5 alkyl, C1-C5 alkoxy and C1-C5 fluoroalkyl.

2. The chiral copper complex according to claim 1, wherein the substituents in the substituted phenyl group represent methyl, methoxy or trifluoromethyl.

3. A method for preparing the chiral copper complex of any one of claims 1-2, the method comprising contacting a divalent copper salt, a chiral ligand L having the structure_AOr L_BThe nitrogen-containing organic base is mixed and reacted in a solvent to prepare the catalyst,

wherein, chiral ligand L_AOr L_BAr in (1)₁And Ar₂The phenyl groups are the same or different and respectively represent phenyl or substituted phenyl, and the substituted groups in the substituted phenyl are respectively one or more selected from C1-C5 alkyl, C1-C5 alkoxy and C1-C5 fluoroalkyl.

4. The process according to claim 3, wherein the divalent copper salt is one or more selected from copper trifluoromethanesulfonate, copper hexafluorotellurate and copper bromide, and the nitrogen-containing organic base is one or more selected from triethylamine, N-ethylmorpholine and triethylenediamine.

5. The method of claim 3, wherein the chiral ligand L_AOr ligand L_BOne or more selected from the following formulae (L1) to (L10):

6. the method of claim 3, wherein the cupric salt, nitrogen-containing organic base and ligand L_AOr ligand L_BThe molar ratio of (1) to (2) is (0.2-2.2) to (0.2-2.2).

7. The method according to claim 3, wherein the solvent is at least one selected from the group consisting of toluene, chloroform, isopropanol and methyl tert-butyl ether.

8. Use of a chiral copper complex according to any one of claims 1-2 or prepared according to the method of any one of claims 3-7 as a catalyst in an asymmetric Mukaiyama Aldol reaction.

9. A method of preparing a chiral 3-hydroxy-2-oxoindole, the method comprising:

mixing at least one of the chiral copper complex of any one of claims 1-2 or the chiral copper complex prepared by the method of any one of claims 3-7 and the compound shown in the following formula (II) with an isatin compound in a solvent for reaction to obtain a chiral 3-hydroxy-2-oxoindole compound,

10. the production method according to claim 9, wherein the method further comprises adding an acidic additive during the reaction, and the acidic additive is selected from at least one of water, hexafluoroisopropanol, and o-fluorophenol.

Technical Field

The invention belongs to the technical field of organic synthesis, and relates to a chiral copper compound, a preparation method thereof and application thereof in synthesis of chiral 3-hydroxy-2-oxoindole compounds.

Background

Aldol (Aldol) reaction is one of the most common methods used by organic chemists to build C-C bonds. The MukaiyamaAldol reaction is the reaction of enolate with carbonyl compounds activated with lewis acids and is considered to be the most successful and most widely used cross aldol condensation reaction.

As carbonyl acceptor, isatin can be easily subjected to asymmetric aldol condensation reaction to obtain optically active 3-hydroxy-2-oxoindole. However, to our knowledge, the catalytic asymmetric Mukaiyama Aldol reaction of isatin has been rarely studied. In 2010, the group a.k.franz reported an enantioselective Mukaiyama Aldol reaction of 5-bromo-N-methylisatorin with an enol silicide catalyzed by a chiral scandium (III) -pyridine bisoxazoline complex to give the desired product in high yield and enantioselectivity (angelw.chem., iht.ed., 2010, 49, 744-747). In addition, in 2012, the week topic group achieved enantioselective aldol condensation of difluoro-substituted enol silicon compounds with isatin catalyzed by bifunctional thiourea catalysts derived from cinchona alkaloids (chem. In 2014, the week topic group further reported the MukaiyamaAldol reaction of enantioselective monofluorinated enolsilyl ethers catalyzed by bifunctional thiourea catalysts with isatin (org. Recently, Alem-n group reported the enantioselective Mukaiyama Aldol reaction of isatin with trimethylsilyl enol silicon compound catalyzed by thiourea bifunctional organic catalysts (chem. Despite the previous work of these breakthroughs, the transition metal-catalyzed asymmetric Mukaiyama Aldol reaction of isatin with enolic silicide still needs intensive research, the applicable range of the substrate needs to be expanded, and the ee value of the corresponding product needs to be further improved.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a chiral copper compound, a preparation method thereof and application of the chiral copper compound as a catalyst in synthesis of a chiral 3-hydroxy-2-oxoindole compound. The chiral copper compound can catalyze and synthesize chiral 3-hydroxy-2-oxoindole compounds with high enantioselectivity.

To this end, the present invention provides the following aspects:

a chiral copper complex having a chemical structure represented by the following general formula (I):

wherein, Ar in the general formula (I)₁And Ar₂May be the same or different and each represents a phenyl group or a substituted phenyl group, and the substituent in the substituted phenyl group is a C1-C5 alkyl group, a C1-C5 alkoxy group or a C1-C5 fluoroalkyl group, preferably a C1-C3 alkyl group, a C1-C3 alkoxy group or a C1-C3 fluoroalkyl group.

The chiral copper complex according to any one of the preceding claims, wherein the substituent in the substituted phenyl group represents a methyl group, a methoxy group or a trifluoromethyl group.

<3>A process for preparing a chiral copper complex of any one of the preceding claims, the process comprising contacting a divalent copper salt, a chiral ligand L having the structure_AOr L_BThe nitrogen-containing organic alkali is mixed and reacted in the solvent to prepare the catalyst,

wherein, the aromatic group Ar involved in the chiral ligand₁And Ar₂The substituted phenyl groups are respectively one or more of C1-C5 alkyl, C1-C5 alkoxy and C1-C5 fluoroalkyl.

The process according to any one of the preceding claims, wherein the divalent copper salt is one or more selected from copper trifluoromethanesulfonate, copper hexafluorotellurate and copper bromide, and the nitrogen-containing organic base is one or more selected from triethylamine, nitroethylmorpholine and triethylenediamine.

<5>The method of any one of the preceding claims, wherein the chiral ligand L_AOr ligand L_BOne or more selected from the following formulae (L1) to (L10):

<6>the method of any one of the preceding claims, wherein the cupric salt, nitrogen-containing organic base and ligand L_AOr ligand L_BThe molar ratio of (0.2-2.2): (0.2-2.2): (0.2-2.2).

The method according to any one of the preceding claims, wherein the solvent is at least one selected from the group consisting of toluene, chloroform, isopropanol and methyl tert-butyl ether.

Use of the chiral copper complex according to any one of <1> -2 > or the chiral copper complex prepared by the method of any one of <3> -7 > as a catalyst in an asymmetric Mukaiyama Aldol reaction.

9. A method of preparing a chiral 3-hydroxy-2-oxoindole, the method comprising:

mixing at least one of the chiral copper compound of any one of the items <1> to <2> or the chiral copper compound prepared by the method of any one of the items <3> to <7>, and the compound shown in the following formula (II) with an isatin compound in a solvent for reaction to obtain a chiral 3-hydroxy-2-oxoindole compound,

the production method according to <9>, wherein the method further comprises adding an acidic additive during the reaction, and the acidic additive is selected from at least one of water, hexafluoroisopropanol, and o-fluorophenol.

The chiral copper compound can efficiently catalyze the asymmetric Mukaiyama Aldol reaction of the isatin compound, can obtain the 3-hydroxy-2-oxoindole compound with high enantioselectivity and diastereoselectivity, and can still maintain the stereoselectivity of the product when the chiral copper compound is used for amplifying the reaction to gram-scale. It is worth mentioning that the asymmetric Mukaiyama Aldol reaction catalyzed by this complex is well tolerated by water.

Drawings

FIG. 1 is a NMR chart of a target product (R, R) -3ab obtained in example 2 of the present invention;

FIG. 2 is a NMR chart of a target product (R, R) -3ab obtained in example 2 of the present invention;

FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of the target product (R, R) -3bb obtained in example 3 of the present invention;

FIG. 4 is a nuclear magnetic resonance carbon spectrum of the target product (R, R) -3bb obtained in example 3 of the present invention;

FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of the target product (R, R) -3cb obtained in example 4 of the present invention;

FIG. 6 is a nuclear magnetic resonance carbon spectrum of the target product (R, R) -3cb obtained in example 4 of the present invention;

FIG. 7 is a NMR chart of (R, R) -3db, which is a target product obtained in example 5 of the present invention;

FIG. 8 is a NMR chart of a target product (R, R) -3db obtained in example 5 of the present invention;

FIG. 9 is a NMR chart of (R, R) -3eb, a target product obtained in example 6 of the present invention;

FIG. 10 is the NMR carbon spectrum of the target product (R, R) -3eb obtained in example 6 of the present invention;

FIG. 11 is a NMR chart of (R, R) -3ad, a target product obtained in example 7 of the present invention;

FIG. 12 is a NMR carbon spectrum of (R, R) -3ad, a target product obtained in example 7 of the present invention;

FIG. 13 is a NMR chart of (S, S) -3mb, a target product obtained in examples 8 to 13 of the present invention;

FIG. 14 is a NMR carbon spectrum of (S, S) -3mb, a target product obtained in examples 8-13 of the present invention;

FIG. 15 is a structural view of an X-ray diffraction single crystal of the objective product (R, R) -3ad obtained in example 7 of the present invention;

fig. 16 is a mass spectrometric detection of chiral copper complexes prepared in example 1.

Detailed Description

In a first aspect of the invention, a chiral copper complex is provided. The chiral copper complex has the structure of formula (I):

wherein Ar of the general formula (I)₁And Ar₂May be the same or different and respectively represent a phenyl group or a substituted phenyl group, and the substituent group in the substituted phenyl group is a C1-C5 alkyl group, a C1-C5 alkoxy group or a C1-C5 fluoroalkyl group, preferably a C1-C3 alkyl group, a C1-C3 alkoxy group or a C1-C3 fluoroalkyl group, more preferably a C1-C2 alkyl group, a C1-C2 alkoxy group and a C1-C2 fluoroalkyl group, still more preferably a methyl group, a methoxy group or a trifluoromethyl group, wherein the fluoroalkyl group represents a monofluoro, polyfluoro or perfluoro substituted alkyl group.

The chiral copper complex of the present invention is an excellent catalyst, which is suitable as a catalyst for aldol reactions. Specifically, the above chiral copper complex of the present invention may be used as a catalyst for Mukaiyama Aldol reaction.

In a second aspect, the present invention provides a process for preparing the above chiral copper complex, which comprises reacting a divalent copper salt (sometimes referred to simply as a copper salt), a nitrogen-containing organic base and a ligand L represented by the following chemical formula_AOr ligand L_BMixing and reacting in a solvent to obtain the chiral copper compound.

Wherein, Ar is_lAnd Ar₂Each independently selected from phenyl or substituted phenyl; the substituent group in the substituted phenyl group is selected from one or more of C1-C5 alkyl, C1-C5 alkoxy and C1-C5 fluoroalkyl, preferably one or more of C1-C3 alkyl, C1-C3 alkoxy and C1-C3 fluoroalkyl, more preferably C1-C2 alkyl, C1-C2 alkoxy and C1-C2 fluoroalkylOne or more, more preferably one or more of methyl, methoxy and trifluoromethyl.

In the present invention, the copper salt is a divalent copper salt well known to those skilled in the art, but from the viewpoint of enhancing the activity of the catalytic center copper atom, one or more of copper trifluoromethanesulfonate, copper bromide and copper hexafluorotellurate are preferably used in the present invention, and copper hexafluorotellurate is more preferably used.

In the present invention, from the viewpoint of enhancing the activity of the catalytic center copper atom, the nitrogen-containing organic base suitably used is one or more of triethylamine, nitrogen ethyl morpholine and triethylene diamine, and nitrogen ethyl morpholine is more preferable.

The cupric salt, nitrogen-containing organic base and ligand L_AOr ligand L_BThe molar ratio of (A) to (B) is (0.2-2.2) to (0.2-2.2), preferably (0.3-2.1) to (0.3-2.1).

In the present invention, the solvent suitable for preparing the chiral copper complex is not particularly limited as long as it is well known to those skilled in the art. However, from the viewpoint of solubility and cost, one or more of toluene, chloroform, isopropanol and methyl t-butyl ether are preferably used in the present invention, and further, isopropanol is preferably used.

In the preparation method of the chiral copper compound, the concentration of the cupric salt in a reaction system is preferably 0.1-5 mmol/L, the temperature of the mixing reaction is preferably-20 ℃, more preferably-20-10 ℃, and the time of the mixing reaction is preferably 1-5 h.

In particular, the ligand L_AOr ligand L_BMost preferably one or more of formulae (L1) to (L10):

the chiral copper compound provided by the invention can be used as a catalyst for Aldol reaction, is particularly suitable for catalyzing Mukaiyama Aldol reaction, is more particularly suitable for asymmetric Mukaiyama Aldol reaction of isatin, can obtain a 3-hydroxy-2-oxoindole compound with high enantioselectivity and diastereoselectivity, and can still maintain the stereoselectivity of a product when the chiral copper compound is used for amplifying the reaction to a gram-scale. It is worth mentioning that the asymmetric Mukaiyama Aldol reaction catalyzed by this complex is well tolerant to water, and when we increase the amount of water added in the reaction up to 300 microliters, the yield, enantioselectivity and diastereoselectivity of the obtained product can be well maintained.

To this end, a third aspect of the present invention provides a process for the preparation of a chiral 3-hydroxy-2-oxoindole compound, the process comprising: in the presence of the chiral copper compound or the chiral copper compound prepared by the method, at least one of the compounds shown in the formula (II) below and an isatin compound are mixed and reacted in a solvent to obtain the chiral 3-hydroxy-2-oxoindole compound.

In the third aspect of the present invention, a copper salt, a nitrogen-containing organic base and a ligand L are provided_AOr ligand L_BAre the same as above, and are not described herein again.

The above formula (II) can also be represented as:

in the third aspect of the present invention, the molar ratio of the compound represented by the formula (II) to the chiral copper complex is (5 to 20) to 1, and more preferably (8 to 15) to 1.

In the invention, the isatin compounds refer to compounds containing substituent groups on benzene rings and nitrogen atoms of isatin. Specific examples thereof include 5-fluoroisatin, 5-chloroisatin, 5-bromoisatin, 5-methylisatorin, 5-methoxyisatin, 6-fluoroisatin, 6-chloroisatin, 6-bromoisatin, 6-methoxyisatin, N-methylisatorin, N-allylisatin, N-phenylisatin and the like.

In the third aspect of the present invention, a chiral copper complex, which may be an unpurified compound, that is, a divalent copper salt, a nitrogen-containing organic base, and a ligand L, a compound represented by formula (II), and isatin are mixed and reacted in a solvent_AOr ligand L_BA reaction product obtained by mixing in a solvent.

Specifically, therefore, the method for preparing the chiral 3-hydroxy-2-oxoindole compound comprises the following steps:

in the first step, cupric salt, nitrogen-containing organic base and ligand L_AOr ligand L_BMixing the mixture in a solvent at a temperature of between 20 ℃ below zero and 10 ℃ to obtain a reaction mixture, wherein the reaction mixture is the chiral copper compound and can be directly used in the next reaction step;

the second step is that: the enol silicide and the isatin compound shown in the formula (2) are respectively added into the reaction mixture obtained in the step.

In the second step, the solvent is a solvent well known to those skilled in the art, and is not particularly limited, and in the present invention, one or more of toluene, chloroform, isopropanol and methyl tert-butyl ether are preferred, and isopropanol is more preferred, the initial concentration of the compound represented by the formula (II) in the reaction system is preferably 0.1 to 0.5 mol/L, and more preferably 0.1 to 0.3 mol/L, and the temperature of the mixing reaction is preferably-20 ℃ to 20 ℃, and more preferably-20 ℃ to 10 ℃.

After the mixing reaction in the second step, the chiral 3-hydroxy-2-oxoindole compound is obtained by separation and purification. The method for separation and purification is a method well known to those skilled in the art, and is not particularly limited, and in the present invention, liquid-liquid separation or solid-liquid separation methods such as column chromatography, liquid chromatography, distillation, recrystallization, and the like are preferred, and column chromatography is more preferred; the eluent of the column chromatography is preferably a mixed solvent of ethyl acetate and petroleum ether; the volume ratio of the ethyl acetate to the petroleum ether is preferably 1: 10-2; in the present invention, it is preferable that the reaction mixture after the mixed reaction is extracted with ethyl acetate, back-extracted with saturated brine, spin-dried, and then subjected to column chromatography.

In addition, the invention unexpectedly discovers that corresponding acidic additives, such as water, hexafluoroisopropanol, o-fluorophenol and the like, can be added in the preparation process of the chiral 3-hydroxy-2-oxoindole compound. Without being bound by any theory, the inventors of the present invention have diligently determined that the addition of these acidic additives (especially water) contributes very well to the increase in the rate and selectivity of the reaction from the viewpoint of optimization.

The chiral divalent copper compound shown in the formula (1) is obtained for the first time, the chiral divalent copper compound is used as a catalyst, the asymmetric Mukaiyama Aldol reaction of an enol silicide similar structure substrate of acetophenone to an isatin compound is realized, and the chiral copper compound catalyst is used for catalyzing the reaction to obtain a product with high enantioselectivity. The chiral divalent copper compound catalyst is easy to prepare, and the method is a method for synthesizing 3-hydroxy-2-oxoindole compounds with different configurations in high enantioselectivity.

The invention has no special limitation on the sources of all raw materials, can be commercially available, and can also be prepared by related methods reported in the literature.

In order to further illustrate the present invention, the following examples are provided to describe more specifically a chiral copper complex and its preparation method, and a preparation method of chiral 3-hydroxy-2-oxoindole compound.

The reagents used in the following examples are all commercially available.