CN108821995B - Chiral Schiff base ligand, metal compound, and preparation method and application thereof - Google Patents

Chiral Schiff base ligand, metal compound, and preparation method and application thereof Download PDF

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CN108821995B
CN108821995B CN201810417121.4A CN201810417121A CN108821995B CN 108821995 B CN108821995 B CN 108821995B CN 201810417121 A CN201810417121 A CN 201810417121A CN 108821995 B CN108821995 B CN 108821995B
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汪志勇
桂阳
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University of Science and Technology of China USTC
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Abstract

The invention provides a chiral Schiff base ligand with a structure shown as a formula (1), a chiral metal compound with a structure shown as a formula (2), and a preparation method and application thereof, wherein m is an integer from 1 to 5, n is an integer from 0 to 18, and R is1Is one or more selected from isobutyl, sec-butyl, isopropyl, benzyl and 3-indolyl, R2Is one or more selected from methyl, fluorine, chlorine, nitro and trifluoromethyl, M is one or more selected from metal zinc, copper and scandium, and XIs one or more selected from trifluoromethanesulfonate, bromide ion, acetate, chloride ion and nitrate. Compared with the prior art, the chiral metal compound provided by the invention can catalyze Henry reaction, Michael reaction and Friedel-crafts acylation reaction, especially asymmetric aqueous phase Michael reaction of nitroene and pyrrole, and can realize gram-scale aqueous phase asymmetric reaction, so that a target product with high enantioselectivity and high yield is obtained.

Description

Chiral Schiff base ligand, metal compound, and preparation method and application thereof
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to design and synthesis of a chiral Schiff base ligand, a corresponding metal compound, a preparation method of the metal compound and catalytic application of the metal compound in water-phase asymmetric synthesis.
Background
Asymmetric catalysis and synthesis research are key means and methods for creating chiral substances, are one of the most active fields of chemical research, are closely related to related fields such as chiral medicines, spices, essences, pesticides, food additives and various functional materials which are closely related to human health, and have important theoretical significance and application prospect.
Nitroene compounds can be used as a substrate with bidentate coordination and a chiral metal catalyst to coordinate and synthesize an enantioselective product due to the existence of lone pair electrons on nitroxides, and have attracted extensive attention in recent years.Nitroene is used as a substrate for asymmetric Michael reaction with pyrrole, in 2008, M ü ller group realizes asymmetric Michael reaction of pyrrole and nitroene by using a bimetallic zinc complex as a catalyst, and the reaction is carried out in tetrahydrofuran;[1]in 2013, Wang subject group prepares a novel Schiff base ligand, and pyrrole and nitroene are realized for the first timeAsymmetric Michael addition reaction catalyzed by metallic copper, carried out in organic solvent toluene.[2]In summary, the Michael addition reaction of nitroalkenes and pyrroles is basically carried out in an organic phase, and the asymmetric Michael addition reaction in an aqueous phase is rarely reported.
Similarly, the catalytic system can also be well applied to the Henry reaction of nitromethane and aldehyde and the friedel-crafts acylation reaction of pyrrole and isatin.
Reference to the literature
[1]Trost,B.M.;Müller,C.J.Am.Chem.Soc.2008,130,2438.
[2]Guo F.-F.;Chang,D.-L.;Lai,G.-Y.;Zhu,T.;Xiong,S.-S.;Wang,S.-J.;Wang,Z.-Y.Chem.Eur.J.,2011,1/,11127.
Disclosure of Invention
In view of the above, the present invention aims to provide a novel chiral ligand and a corresponding chiral metal complex synthesized by using the ligand; and a water phase synthesis method for preparing chiral 2- (2-nitro-1-phenylethyl) pyrrole compounds, 2-nitro-1-phenethyl alcohol compounds and 3-hydroxy-3- (2-pyrrolyl) oxoindole compounds by using the chiral metal compound as a catalyst, wherein the chiral metal compound can catalyze water phase Michael reaction, Henry reaction and Friedel-crafts acylation reaction with high enantioselectivity.
Therefore, the invention provides the following technical scheme:
a chiral Schiff base ligand L having the general formula represented by the following formula (1),
Figure BDA0001648082310000021
wherein m is an integer from 1 to 5 and n is an integer having a value from 0 to 18; r1Is one or more selected from isobutyl, sec-butyl, isopropyl, benzyl and 3-indolyl; r2Is one or more selected from methyl, fluorine, chlorine, nitro and trifluoromethyl.
<2> a method of the chiral schiff base ligand L of <1> above, comprising the steps of:
Figure BDA0001648082310000031
reacting amino acid methyl ester A with a protecting group with a Grignard reagent to obtain an amino alcohol compound B:
removing a protecting group from the aminoalcohol compound B to obtain aminoalcohol C; and
the amino alcohol C reacts with the salicylaldehyde compound D to generate the prepared Schiff base ligand L,
wherein m is an integer of 1-5, and n is an integer of 0-18; r1Is selected from one or more of isobutyl, sec-butyl, isopropyl, benzyl and 3-indolyl; r2Is one or more of methyl, fluorine, chlorine, nitro and trifluoromethyl.
<3> A chiral metal complex dissolved in water, which has a general structure represented by the following formula (2) and is generated in situ from a metal ligand L and a metal salt as described in <1> in an aqueous phase,
Figure BDA0001648082310000032
wherein X-Is one or more selected from trifluoromethanesulfonate, bromide ion, acetate, chloride ion and nitrate radical; m is one or more selected from metal zinc, copper and scandium; m is an integer from 1 to 5, n is an integer having a value from 0 to 18; r1Is one or more selected from isobutyl, sec-butyl, isopropyl, benzyl and 3-indolyl; r2Is one or more selected from methyl, fluorine, chlorine, nitro and trifluoromethyl.
The chiral metal complex as set forth in <3>, wherein the molar ratio of the metal salt to the ligand L is (0.5-1): 1.
A method for preparing a chiral metal complex, wherein the method comprises: and (2) carrying out mixed reaction on a metal salt and the ligand L in the formula <1> in a solvent, wherein the molar ratio of the metal salt to the ligand L is (0.5-1): 1, and the metal ion in the metal salt is selected from at least one of copper, zinc and scandium.
<6> the production method according to <5>, wherein the method further comprises adding a surfactant to the reaction mixture, and the molar ratio of the surfactant to the metal salt is (1-10): 1.
<7> use of the chiral metal complex according to the above or the chiral metal complex obtained according to the above preparation method as a catalyst in aqueous phase Michael reaction, Henry reaction and Friedel-crafts acylation reaction.
<8> use of the chiral metal complex according to the above or the chiral metal complex obtained according to the above preparation method as a catalyst in an aqueous phase synthesis process for the preparation of 2- (2-nitro-1-phenylethyl) pyrrole compounds, 2-nitro-1-phenylethanol compounds and 3-hydroxy-3- (2-pyrrolyl) oxoindole compounds.
<9> a process for producing 2- (2-nitro-1-phenylethyl) pyrrole compound, which comprises: mixing the chiral metal compound or the chiral metal compound obtained by the preparation method, a compound shown in a formula (I) and pyrrole or substituted pyrrole in a solvent for reaction to obtain a chiral 2- (2-nitro-1-phenylethyl) pyrrole compound, wherein the molar ratio of the compound shown in the formula (I) to the chiral metal compound is (5-20) to 1,
Figure BDA0001648082310000041
in the formula (I), R is3Selected from phenyl, substituted phenyl, heterocyclyl, cycloalkyl; the substituent in the substituted phenyl is selected from one or more of trifluoromethyl, halogen, C1-C5 alkyl and C1-C5 alkoxy.
<10> a process for producing a 2-nitro-1-phenylethanol compound, wherein the process comprises: mixing the chiral metal compound or the chiral metal compound obtained by the preparation method, a compound shown as a formula (II) and nitromethane in a solvent for reaction to obtain a chiral 2-nitro-1-phenethyl alcohol compound, wherein the molar ratio of the compound shown as the formula (II) to the chiral metal compound is (5-20) to 1,
Figure BDA0001648082310000051
in the formula (II), the R4Selected from phenyl, substituted phenyl, heterocyclyl, cycloalkyl; the substituent in the substituted phenyl is selected from one or more of trifluoromethyl, halogen, C1-C5 alkyl and C1-C5 alkoxy.
<11> a process for producing a 3-hydroxy-3- (2-pyrrolyl) oxoindole compound, which comprises: mixing the chiral metal compound or the chiral metal compound obtained by the preparation method, a compound shown as a formula (III) and pyrrole in a solvent for reaction to obtain a chiral 3-hydroxy-3- (2-pyrrolyl) oxoindole compound, wherein the molar ratio of the compound shown as the formula (III) to the chiral metal compound is (5-20) to 1,
Figure BDA0001648082310000052
in the formula (III), the R5The substituent is selected from one or more of trifluoromethyl, halogen, C1-C5 alkyl and C1-C5 alkoxy.
Compared with the prior art, the chiral metal compound provided by the invention can catalyze Henry reaction, Michael reaction and Friedel-crafts acylation reaction, especially asymmetric aqueous phase Michael reaction of nitroene compounds and pyrrole, and can realize gram-scale aqueous phase asymmetric Michael reaction by taking the chiral metal compound as a catalytic system, so that a target product with high enantioselectivity and high yield is obtained.
Drawings
FIG. 1 shows the target product L obtained in example 11The nuclear magnetic resonance hydrogen spectrum of (a);
FIG. 2 shows the target product L obtained in example 11Nuclear magnetic resonance ofA resonance carbon spectrum;
FIG. 3 shows the target product L obtained in example 22The nuclear magnetic resonance hydrogen spectrum of (a);
FIG. 4 shows the target product L obtained in example 22Nuclear magnetic resonance carbon spectrum of (a);
FIG. 5 is a NMR chart of the objective product (S) -4a obtained in examples 6, 11, 12 and 13;
FIG. 6 is a nuclear magnetic resonance carbon spectrum of the objective product (S) -4a obtained in examples 6, 11, 12 and 13;
FIG. 7 is a NMR hydrogen spectrum of the objective product (S) -4b obtained in example 7;
FIG. 8 is a NMR carbon spectrum of the objective product (S) -4b obtained in example 7;
FIG. 9 is a NMR hydrogen spectrum of the objective product (S) -4c obtained in example 8;
FIG. 10 is a NMR carbon spectrum of the objective product (S) -4c obtained in example 8;
FIG. 11 is a NMR hydrogen spectrum of the objective product (S) -4d obtained in example 9;
FIG. 12 is a NMR carbon spectrum of the objective product (S) -4d obtained in example 9;
FIG. 13 is a NMR chart of the objective product (S) -4e obtained in example 10;
FIG. 14 is a NMR carbon spectrum of the objective product (S) -4e obtained in example 10;
Detailed Description
In a first aspect, the invention provides a chiral schiff base ligand L with a structure shown in formula (1) and a preparation method thereof.
Figure BDA0001648082310000061
In the ligand L of the above formula (1), R1Is one or more selected from isobutyl, sec-butyl, isopropyl, benzyl and 3-indolyl, preferably isobutyl or benzyl, more preferably benzyl; r2 is one or more selected from methyl, fluorine, chlorine, nitro and trifluoromethyl, preferablyIs fluoro, methyl or trifluoromethyl, more preferably trifluoromethyl; m is an integer from 1 to 5, preferably an integer from 1 to 3, more preferably an integer from 1 to 2, most preferably 1; n is an integer from 0 to 18, preferably an integer from 0 to 12, more preferably an integer from 0 to 8, more preferably an integer from 0 to 4, and most preferably 0.
In the present invention, chiral schiff base ligand L having the structure of formula (1) is a novel chiral ligand, which can be derived from amino acids. The amino acid may be at least one selected from the group consisting of leucine, isoleucine, valine, phenylalanine and tryptophan.
Accordingly, the present invention provides a process for the preparation of the chiral schiff base ligand L of the present invention, said process comprising the steps of:
Figure BDA0001648082310000071
reacting amino acid methyl ester A with a protecting group with a Grignard reagent to obtain an amino alcohol compound B with a protecting group;
removing a protecting group from the amino alcohol compound B to obtain amino alcohol C; and
the amino alcohol C reacts with the salicylaldehyde compound D to generate the prepared Schiff base ligand L,
wherein m is an integer of 1-5, and n is an integer of 0-18; r1Is selected from one or more of isobutyl, sec-butyl, isopropyl, benzyl and 3-indolyl; r2 is one or more of methyl, fluoro, chloro, nitro and trifluoromethyl.
Examples of the salicylaldehyde-based compound D that can be preferably used in the present invention include salicylaldehyde having one or more substituents of methyl, fluorine, chlorine, nitro and trifluoromethyl at the 3-position.
In the above-mentioned production method, the amino acid methyl ester A with a protecting group can be obtained via a method for protecting an amino acid carboxyl group which is conventional in the art, and the protecting group shown in the figure is only used (Boc)2One example obtained at O.
An example of the grignard reagent used in the present invention can be obtained by heating a mixture of magnesium strip, iodine, a small amount of 4-bromo-N, N-dimethylphenylethylamine and a solvent such as tetrahydrofuran to reflux to the reaction.
In one embodiment of the present invention, the chiral schiff base ligand derived from the amino acid of the present invention can be prepared by the following method:
Figure BDA0001648082310000081
wherein m is an integer of 1-5, and n is an integer of 0-18; r1Is selected from one or more of isobutyl, sec-butyl, isopropyl, benzyl and 3-indolyl; r2 is one or more of methyl, fluoro, chloro, nitro and trifluoromethyl.
As can be seen from the preparation method of the chiral Schiff base ligand derived from the amino acid shown in the figure, the specific preparation process comprises the following steps: the amino acid is methylated by thionyl chloride in methanol and then (Boc)2O protection to give 2- [ (tert-butoxycarbonyl) amino group]Reacting the-3-amino acid methyl ester A and A with a Grignard reagent to obtain an amino alcohol compound B protected by Boc, removing a protecting group of the compound B under the action of trifluoroacetic acid to obtain an amino alcohol C, and generating the prepared Schiff base ligand L by the amino alcohol C and a salicylaldehyde compound D in methanol.
In a second aspect, the present invention provides a chiral metal complex C of formula (2) dissolved in water, which can be generated in situ in an aqueous phase from a ligand L of the invention and a metal salt.
Figure BDA0001648082310000091
In the above formula (2), X-Is one or more of trifluoromethanesulfonate, bromide ion, acetate, chloride ion and nitrate radical; m is one or more of metal zinc, copper and scandium; m is an integer of 1 to 5, n is an integer of 0 to 18; r1Is one or more selected from isobutyl, sec-butyl, isopropyl, benzyl and 3-indolyl; r2Is selected from methyl, fluorine, chlorine, nitro and triOne or more of fluoromethyl groups.
In a third aspect, the present invention also provides a method for preparing the chiral metal complex of formula (2), which comprises: and (2) mixing and reacting a metal salt and the ligand L of the formula (1) in a solvent to obtain the chiral metal compound.
The solvent suitable for use in the above reaction is selected from one or more of water, toluene, dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran and methyl t-butyl ether.
Preferably, a surfactant selected from one or more of tetra-n-butyl ammonium hexafluorophosphate, tetraethylammonium perchlorate, tetra-n-butyl ammonium bromide, tetraethylammonium iodide, polyvinylpyrrolidone, sodium lauryl sulfate, sodium dodecyl sulfate and sodium hexadecyl benzene sulfonate is further added in the preparation process of the chiral metal complex of the above formula (2); the molar ratio of the surfactant to the metal salt is (1-10) to 1.
The metal salt is not particularly limited as long as it is known to those skilled in the art. The metal salt can be selected from zinc salt, copper salt and scandium salt, wherein the zinc salt can be one or more of zinc chloride, zinc trifluoromethanesulfonate, zinc nitrate and zinc chloride; the copper salt can be one or more of copper trifluoromethanesulfonate, copper bromide, copper acetate, copper chloride and copper nitrate; the scandium salt may be one or more of scandium nitrate, scandium acetate, scandium triflate and scandium chloride. The metal salt in the present invention is preferably a copper salt, more preferably one or more of copper trifluoromethanesulfonate, copper bromide and copper acetate, and most preferably copper bromide.
The molar ratio of the metal salt to the ligand L is (0.5-1.2) to (0.5-1.2), preferably (0.8-1.2) to (0.8-1.2), and more preferably 1: 1. The molar ratio of the copper salt to the ligand L is preferably (0.8-1.2) to (0.8-1.2), and more preferably 1: 1.
In a fourth aspect, the present invention also provides the use of the chiral metal complex of the invention as a catalyst. The chiral metal complexes of the present invention can catalyze all of the Henry reaction, Michael reaction and friedel-crafts acylation reaction, and it can be seen from the following examples that when copper complexes are used as catalysts for these reactions, the enantioselectivity of the products is particularly good. In the Henry reaction, the Michael reaction and the Friedel-crafts acylation reaction, especially the asymmetric aqueous phase Michael reaction of the nitroene compound and the pyrrole, and simultaneously, the chiral copper compound is used as a catalytic system, so that the water phase asymmetric Michael reaction with gram scale can be realized, and the target product with high enantioselectivity and high yield can be obtained.
Therefore, by using the chiral metal complex of the present invention as a catalyst in an aqueous phase reaction, the present invention can also provide a preparation method of a chiral 2- (2-nitro-1-phenylethyl) pyrrole compound, comprising:
the chiral metal compound of the formula (2), the compound shown in the formula (I) and pyrrole or substituted pyrrole are put in a solvent to obtain a chiral 2- (2-nitro-1-phenethyl) pyrrole compound;
Figure BDA0001648082310000101
wherein, R is3Selected from phenyl, substituted phenyl, heterocyclyl, cycloalkyl; the substituent in the substituted phenyl is selected from one or more of trifluoromethyl, halogen, C1-C5 alkyl and C1-C5 alkoxy;
in addition, by using the chiral metal complex of the present invention as a catalyst in an aqueous phase reaction, the present invention may also provide a preparation method of a 2-nitro-1-phenylethanol compound, the preparation method comprising: mixing the chiral metal compound of the formula (2), the compound shown in the formula (II) and nitromethane in a solvent for reaction to obtain the chiral 2-nitro-1-phenethyl alcohol compound.
Figure BDA0001648082310000102
Wherein R4 is selected from phenyl, substituted phenyl, heterocyclyl, cycloalkyl; the substituent in the substituted phenyl is selected from one or more of trifluoromethyl, halogen, C1-C5 alkyl and C1-C5 alkoxy;
in addition, by using the chiral metal complex of the present invention as a catalyst in an aqueous phase reaction, the present invention can also provide a method for preparing a 3-hydroxy-3- (2-pyrrolyl) oxoindole compound, the method comprising: mixing the chiral metal compound of the formula (2), a compound shown in the following formula (III) and pyrrole in a solvent for reaction to obtain the chiral 3-hydroxy-3- (2-pyrrolyl) oxindole compound.
Figure BDA0001648082310000111
In the formula (III), the R5The substituent is selected from one or more of trifluoromethyl, halogen, C1-C5 alkyl and C1-C5 alkoxy.
Preferably, the molar ratio of the compounds shown in the formulas (I), (II) and (III) to the chiral metal compound is (5-20): 1, and the most preferable ratio is 10: 1.
The present invention is not particularly limited in terms of the source of all raw materials, and may be commercially available.
Next, a method for preparing the chiral copper metal complex of the present invention is provided as a specific embodiment of the method for preparing the chiral metal complex of the present invention. Mixing copper salt and ligand L in a solvent for reaction to obtain a chiral copper compound; the solvent is not particularly limited as long as it is well known to those skilled in the art, and in the present invention, one or more of water, toluene, ethyl acetate, methylene chloride, chloroform, 1, 2-dichloroethane, tetrahydrofuran and methyl t-butyl ether are preferable, and water/chloroform (10: 1) is more preferable. The concentration of the copper salt in the reaction system is preferably 0.1-5 mmol/L. In the preparation process, a surfactant is preferably added, and the surfactant is a surfactant well known to those skilled in the art, and is not particularly limited, and in the present invention, one or more of tetra-n-butyl ammonium hexafluorophosphate, tetraethylammonium perchlorate, tetra-n-butyl ammonium bromide, tetraethylammonium iodide, polyvinylpyrrolidone, sodium lauryl sulfate, sodium dodecyl sulfate and sodium hexadecylbenzene sulfonate are preferably used. The mol ratio of the surfactant to the copper salt is preferably (1-10) to 1, more preferably (1-6) to 1, still more preferably (1-4) to 1, still more preferably (1-2) to 1, and most preferably 1: 1; the catalytic efficiency of the chiral copper compound can be improved by adding the surfactant; the mixing temperature is preferably-5 ℃ to 50 ℃, more preferably 10 ℃ to 35 ℃, and most preferably at room temperature; the mixing time is preferably 1-4 h, and more preferably 2-2.5 h.
The invention also provides application of the chiral copper compound as a catalyst for Henry reaction, Michael reaction and Friedel-crafts acylation reaction, and provides a preparation method of 2- (2-nitro-1-phenylethyl) pyrrole compounds, 2-nitro-1-phenylethyl alcohol compounds and 3-hydroxy-3- (2-pyrrolyl) oxindole compounds, which comprises the following steps: reacting the chiral copper compound, the compounds shown in the following formulas (I), (II) and (III) with pyrrole or methane in a solvent to obtain a chiral product;
Figure BDA0001648082310000121
wherein, R is3Selected from phenyl, substituted phenyl, heterocyclic radical and cycloalkyl. The substituent in the substituted phenyl is selected from one or more of trifluoromethyl, halogen, C1-C5 alkyl and C1-C5 alkoxy, preferably one or more of trifluoromethyl, halogen, C1-C3 alkyl and C1-C3 alkoxy, more preferably one or more of trifluoromethyl, halogen, C1-C2 alkyl and C1-C2 alkoxy, and still more preferably one or more of trifluoromethyl, halogen, methyl and methoxy. In the present invention, said R3Most preferred is phenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 2-bromophenyl, 2-chlorophenyl, 1-naphthyl, 2-furyl, 2-thienyl, cyclohexyl or propyl. The R4 is selected from phenyl, substituted phenyl and heterocyclic radical, the substituent in the substituted phenyl is selected from one or more of trifluoromethyl, halogen, alkyl of C1-C5 and alkoxy of C1-C5, preferably trifluoromethyl,One or more of halogen, alkyl of C1-C3 and alkoxy of C1-C3, more preferably one or more of trifluoromethyl, halogen, alkyl of C1-C2 and alkoxy of C1-C2, and still more preferably one or more of trifluoromethyl, halogen, methyl and methoxy; in the present invention, R4 is most preferably phenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-bromophenyl, 1-naphthyl, 2-furyl, 2-thienyl; the R is5One or more selected from trifluoromethyl, halogen, C1-C5 alkyl and C1-C5 alkoxy, preferably one or more selected from trifluoromethyl, halogen, C1-C3 alkyl and C1-C3 alkoxy, more preferably one or more selected from trifluoromethyl, halogen, C1-C2 alkyl and C1-C2 alkoxy, and still more preferably one or more selected from trifluoromethyl, halogen, methyl and methoxy. In the present invention, said R5Most preferred are 7-trifluoromethyl, 7-fluoro, 7-chloro, 7-bromo, 7-methyl, 7-methoxy.
The present invention is not particularly limited in terms of the source of all raw materials, and may be commercially available.
Specifically, a chiral copper complex, compounds shown in the following formulas (I), (II) and (III) and pyrrole or nitromethane are mixed and reacted in a solvent; the molar ratio of the compounds shown in the formulas (I), (II) and (III) to the chiral copper compound is preferably (5-20) to 1, more preferably (8-15) to 1, further preferably (8-12) to 1, and most preferably 10: 1; the solvent is a solvent well known to those skilled in the art, and is not particularly limited, but in the present invention, one or more of water, toluene, ethyl acetate, dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran and methyl t-butyl ether are preferable, and water/chloroform (10: 1) is more preferable; the initial concentration of the compounds shown in the formulas (I), (II) and (III) in the reaction system is preferably 0.1-0.5 mol/L, more preferably 0.1-0.4 mol/L, still more preferably 0.1-0.3 mol/L, and most preferably 0.18 mol/L; the pyrrole or nitromethane is well known to those skilled in the art, and is not particularly limited, and the temperature of the mixing reaction is preferably 0 to 30 ℃, more preferably 0 to 25 ℃, still more preferably 0 to 15 ℃, and most preferably 0 to 10 ℃.
After the preferential separation and purification of the mixed reaction, chiral 2- (2-nitro-1-phenethyl) pyrrole compounds, 2-nitro-1-phenethyl alcohol compounds and 3-hydroxy-3- (2-pyrrolyl) oxindole compounds are obtained; 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: 10-3; 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.
As can be seen from the above description, the present application realizes Lewis acid catalyzed asymmetric aqueous Michael addition reaction of pyrrole paranitroalkenes, Friedel-crafts acylation reaction of pyrrole paraisatin and Henry reaction of nitromethane paraaldehyde. And it was found that catalyzing these reactions with chiral copper complexes can yield highly enantioselective products. The catalyst is easy to prepare, and the method is a method for synthesizing chiral 2- (2-nitro-1-phenethyl) pyrrole compounds, 2-nitro-1-phenethyl alcohol compounds and 3-hydroxy-3- (2-pyrrolyl) oxindole compounds with high enantioselectivity.
To further illustrate the present invention, the following detailed description will be made with reference to specific preparation embodiments of the present invention for the application of a chiral copper complex in the preparation method of chiral 2- (2-nitro-1-phenylethyl) pyrrole compounds, 2-nitro-1-phenylethyl compounds and 3-hydroxy-3- (2-pyrrolyl) oxindole compounds.
1) Preparation of 2- (2-nitro-1-phenylethyl) pyrrole compound
Pyrrole or substituted pyrrole and nitroalkene compounds are respectively added into the metal composite catalyst prepared by the invention, and the mass ratio of the catalyst to the reactant nitroalkene compounds is 1/10; the amount of solvent water/chloroform (10: 1) is preferably such that the initial concentration of the nitroolefin compound as a reactant is 0.18 mol/L. The reaction was carried out at zero degrees Centigrade.
The structural formula of the nitroalkene compound is
Figure BDA0001648082310000141
Wherein R is1Is phenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 2-bromophenyl, 2-chlorophenyl, 1-naphthyl, 2-furyl, 2-thienyl, cyclohexyl or propyl.
The pyrrole or substituted pyrrole (i.e., pyrrole-like structure substrate) includes 4-methyl-3-carboxylic acid ethyl ester pyrrole and the like.
Extracting the reacted solution with ethyl acetate, back-extracting with saturated saline, drying with anhydrous sodium sulfate, spin-drying, passing the residue through silica gel column, and passing through column at volume ratio of 10/1-3/1 with petroleum ether/ethyl acetate system as eluent; the eluent selected in the application is a petroleum ether/ethyl acetate mixed solvent, which is not the requirement of other eluent systems, and the reagent which meets the purpose of elution can be used.
The reaction equation is:
Figure BDA0001648082310000142
the screening process screens copper salt, surfactant, additive and reaction temperature respectively, and the best conditions are as follows: most preferably, the ligand is used as a chiral ligand, copper bromide is used as a copper salt, sodium dodecyl sulfate is used as a surfactant, water is used as a solvent, and the optimal temperature is zero centigrade, so that the yield of 93 percent and the ee value of 91 percent can be obtained.
Figure BDA0001648082310000151
For the substrate, the structure of formula (I) is subjected to substrate extension under the above-described optimal conditions. Any of aromatic, heterocyclic, fused ring, and aliphatic may be used in the reaction system. Considering the electronic effect, the substrate of the para-position different substituents of the benzene ring is firstly detected, and whether the substrate is an electron donating group or an electron withdrawing group, such as trifluoromethyl and methoxy, is found to obtain good results. Then, considering the effect of steric hindrance, the effect of steric hindrance is found to be large, for example, the reaction of the ortho-halogen substituted substrate needs to be heated to 5 ℃ to obtain better yield and selectivity. Likewise, fused ring, heterocyclic, aliphatic substrates are suitable for use in the catalytic system.
2) Preparation of 2-nitro-1-phenethyl alcohol compound
Reacting nitromethane and aldehyde, wherein the mass ratio of the catalyst to the reactant aldehyde is 1/10; the amount of solvent water/chloroform (10: 1) is preferably such that the initial concentration of the reactant isatin-based compound is 0.18 mol/L. The reaction was carried out at zero degrees Centigrade.
The structural formula of the isatin compounds is shown in the specification
Figure BDA0001648082310000152
Wherein R4 is phenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 2-bromophenyl, 2-chlorophenyl, 1-naphthyl, 2-furyl or 2-thienyl.
For the above substrates, the electron effect R is taken into account4Either an electron donating group such as 4-methylphenyl, 4-methoxyphenyl, or an electron withdrawing group such as 4-trifluoromethylphenyl may be suitable for use in the reaction system. In view of steric hindrance, 2-bromophenyl or 2-chlorophenyl may be preferably used. Likewise, fused ring, heterocyclic, aliphatic substrates are suitable for use in the catalytic system.
3) Preparation of 3-hydroxy-3- (2-pyrrolyl) oxindole compounds
Pyrrole reacts with isatin compound, and the mass ratio of the catalyst to the reactant isatin compound is 1/10; the amount of solvent water/chloroform (10: 1) is preferably such that the initial concentration of the reactant isatin-based compound is 0.18 mol/L. The reaction was carried out at zero degrees Centigrade.
The structural formula of the isatin compounds is shown in the specification
Figure BDA0001648082310000161
Wherein R is5Is substituted by 7-trifluoromethyl, 7-fluoro, 7-chloro, 7-bromo, 7-methyl, 7-methoxy, 6-chloro and 5-chloro.
For the above substrates, the electron effect R is taken into account5Either electron donating groups such as 7-methoxy substitution or electron withdrawing groups such as 7-trifluoromethyl substitution may be suitable for use in the reaction system. 6-chloro-substituted substrates may also perform well in view of steric effects. The same halogen substituted substrate on the benzene ring can be well compatible with the system.
Examples
The technical solutions of the present invention will be described more clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The reagents used in the following examples are all commercially available reagents and used as they are.
Example 1
Preparation of chiral schiff base ligand L
The synthetic route is as follows:
Figure BDA0001648082310000162
a round bottom flask was charged with magnesium (0.36g, 15mmol), a small amount of iodine, 4-bromo-N, N-dimethylbenzylamine (0.21g, 1mmol), and tetrahydrofuran (25mL), and the mixture was heated under reflux until the reaction was initiated. Then, a solution of 4-bromo-N, N-dimethylbenzylamine (2.98g, 14mmol) in THF (5mL) was added dropwise over 30 minutes. After the addition was completed, the mixture was refluxed for 2 hours, then cooled to room temperature, and a solution of the compound a (methyl 2- [ (tert-butoxycarbonyl) amino ] -3-phenylpropionate) (1.40g, 5mmol) derived from an amino acid in THF (5mL) was slowly added dropwise over 30min, and the reaction was continued overnight. Quenching with saturated ammonium chloride solution, extracting with ethyl acetate, washing with saturated saline solution, and drying with anhydrous sodium sulfate to obtain crude Boc protected amino alcohol b for direct use in the next step.
The crude product b from the previous step was dissolved in dichloromethane (15mL), trifluoroacetic acid (10mL) was added and stirred at room temperature for 5 h. After the solvent was distilled off under reduced pressure, diluted hydrochloric acid (2M, 5mL) was added, the mixture was washed with ethyl acetate, the aqueous solution was basified with ammonia water, the PH was adjusted to 10, dichloromethane was extracted to obtain an organic phase, which was washed with saturated brine, dried over anhydrous sodium sulfate, and subjected to column chromatography (dichloromethane/methanol/triethylamine 100: 10: 1) after the solvent was distilled off under reduced pressure to obtain an aminoalcohol compound c (1.73g, 83% yield).
Dissolving the compound c (2mmol) in methanol (10mL), adding 2-hydroxy-3-trifluoromethylbenzaldehyde (2mmol), stirring at room temperature for 2h, removing the solvent by distillation under reduced pressure, and performing column chromatography (dichloromethane/methanol ═ 5: 1) to obtain chiral ligand L1(m is 1 and n is 0). The target product L obtained in example 1 was subjected to nuclear magnetic resonance1The nuclear magnetic resonance hydrogen spectrum of the sample was obtained by analysis, as shown in FIG. 1.1H NMR(400MHz,CDCl3):δ 13.91(br,1H),7.64-7.30(m,8H),7.20-7.11(m,5H),7.00-6.94(m,3H),6.80-6.70(m,1H),4.35-4.31(m,1H),3.51-3.22(m,4H),3.10-3.01(m,2H),2.91-2.79(m,1H),2.24(s,6H),2.11(s,6H);
The target product L obtained in example 1 was subjected to nuclear magnetic resonance1The nuclear magnetic resonance carbon spectrum of the sample was obtained by analysis, as shown in FIG. 2.13C NMR(100MHz,CDCl3):δ 165.8,160.0,144.0,142.7,138.7,137.7,137.4,135.1,129.9,129.7,129.3,129.2,128.5,126.5,126.0,125.9,124.9-122.2(q,J=270.0Hz),118.8,118.4-117.5(q,J=30.0Hz),117.3,79.6,78.7,63.9,63.7,45.4,45.2,37.2。
Example 2
Preparation of chiral schiff base ligand L
The synthetic route is as follows:
Figure BDA0001648082310000181
a round bottom flask was charged with magnesium (0.36g, 15mmol), a small amount of iodine, a small amount of 4-bromo-N, N-dimethylphenylethylamine (0.23g, 1mmol), and tetrahydrofuran (25mL), and the mixture was heated under reflux until the reaction was initiated. A solution of 4-bromo-N, N-dimethylphenylethylamine (3.18g, 14mmol) in THF (5mL) was then added dropwise over 30 minutes. After the addition was complete, reflux was continued for 2h, then cooled to room temperature, a solution of methyl ester of the amino acid-derived compound a (2- [ (tert-butoxycarbonyl) amino ] -3-phenylpropionate (1.40g, 5mmol) in THF (5mL) was slowly added dropwise over 30min, the reaction was continued overnight, quenched with saturated ammonium chloride solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate to give a crude product, and column chromatography (dichloromethane/methanol/triethylamine ═ 100: 10: 1) to give the amino alcohol compound b' protected with Boc.
The compound of formula 1 in the previous step was dissolved in dichloromethane (15mL), trifluoroacetic acid (10mL) was added and stirred at room temperature for 5 h. After the solvent was distilled off under reduced pressure, dilute hydrochloric acid (2M, 5mL) was added, washed with ethyl acetate, the aqueous phase solution was made alkaline with ammonia water, the PH was adjusted to 10, dichloromethane was extracted to obtain an organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude aminoalcohol c', which was directly dissolved in the next step.
Dissolving the crude product in the previous step in methanol (10mL), adding 2-hydroxy-3-trifluoromethylbenzaldehyde (2mmol), stirring at room temperature for 2h, distilling under reduced pressure to remove solvent, and performing column chromatography (dichloromethane/methanol ═ 5: 1) to obtain chiral ligand L2(m-2, n-0). The target product L obtained in example 2 was subjected to nuclear magnetic resonance2The nuclear magnetic resonance hydrogen spectrum of the sample was obtained by analysis, as shown in FIG. 3.1HNMR(400MHz,CDCl3)δ 7.48-7.40(m,4H),7.28-7.04(m,9H),4.93(d,J=9.4Hz,1H),4.72-4.60(m,1H),4.13(br,1H),2.90-2.53(m,6H),2.54-2.40(m,4H),2.28(s,6H),2.25(s,6H),1.20(s,9H);
The target product L obtained in example 2 was subjected to nuclear magnetic resonance2The nuclear magnetic resonance carbon spectrum of the sample was obtained by analysis, as shown in FIG. 4.13C NMR(100MHz,CDCl3)δ 155.9,143.7,143.1,139.2,138.7,138.5,129.3,128.7,128.3,128.2,126.1,126.0,125.6,115.7,80.8,79.3,61.4,61.2,46.0,45.4,45.3,36.1,33.7,33.5,28.1。
Example 3
Preparation of chiral copper composite catalyst
Adding CuBr into a 10mL reaction tube2(4.47mg, 0.02mmol), ligand (L) obtained in example 2 above212.35mg, 0.02mmol), sodium dodecylsulfonate (5.45mg, 0.02mmol), solvent water/chloroform (1 mL: 0.1mL) was added, and the mixture was stirred at room temperature for 2 h.
Example 4
Preparation of chiral scandium composite catalyst
Adding CuBr into a 10mL reaction tube2(9.84mg, 0.02mmol), ligand (L) obtained in example 2 above212.35mg, 0.02mmol), sodium dodecylsulfate (5.45mg, 0.02mmol), water/chloroform (1 mL: 0.1mL) as a solvent, and stirred at room temperature for 2 h.
Example 5
Preparation of chiral zinc complex catalyst
Adding CuBr into a 10mL reaction tube2(7.27mg, 0.02mmol), ligand (L) obtained in example 2 above212.35mg, 0.02mmol), sodium dodecylsulfate (5.45mg, 0.02mmol), water/chloroform (1 mL: 0.1mL) as a solvent, and stirred at room temperature for 2 h.
Example 6
Adding CuBr into a 10mL reaction tube2(4.47mg, 0.02mmol), ligand (L) obtained in example 2 above212.35mg, 0.02mmol), sodium dodecylsulfonate (5.45mg, 0.02mmol), water/chloroform solvent (1 mL: 0.1mL), stirred at room temperature for 2h, then cooled at zero degrees Celsius for 30 minutes, β -nitrostyrene (3a) (29.8mg, 0.2mmol) and pyrrole (40.3mg, 0.6mmol) at zero degrees Celsius are added to the reaction tubeThe reaction was stirred. After completion of the reaction (TLC follow-up), extraction with ethyl acetate, back extraction with saturated brine, drying over anhydrous sodium sulfate and spin-drying the resulting residue on a column using petroleum ether/ethyl acetate system as eluent gave the product (S) -4a as a white solid (93% yield, 91% ee).
The target product (S) -4a obtained in example 6 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in FIG. 5.1H NMR(400MHz,CDCl3):δ7.84(br,1H),7.40-7.27(m,3H),7.25-7.20(m,2H),6.68(m,1H),6.16(dd,J=6.0Hz,3.2Hz,1H),6.08(m,1H),4.97(dd,J=12.0Hz,7.2Hz,1H),4.89(t,J=7.5Hz,1H),4.80(dd,J=12.0Hz,7.6Hz,1H)。
The target product (S) -4a obtained in example 6 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum, as shown in FIG. 6.13C NMR(100MHz,CDCl3):δ 138.0,129.2,128.9,128.2,127.9,118.2,108.7,105.8,79.2,42.9。
Example 7
Adding CuBr into a 10mL reaction tube2(4.47mg, 0.02mmol), ligand (L) obtained in example 2 above212.35mg, 0.02mmol), sodium dodecylsulfonate (5.45mg, 0.02mmol), water/chloroform solvent (1 mL: 0.1mL), stirred at room temperature for 2h, then cooled at zero degrees Celsius for 30 minutes, β -nitro-4-chlorostyrene (3b) (36.6mg, 0.2mmol) and pyrrole (40.3mg, 0.6mmol) are added to the reaction tube and the reaction is stirred at zero degrees Celsius after completion of the reaction (TLC follow-up), extracted with ethyl acetate, back extracted with saturated brine, dried over anhydrous sodium sulfate, and the residue obtained by spin-drying is passed through the column using petroleum ether/ethyl acetate system as eluent to give the product (S) -4b as a white solid (95% yield, 94% ee).
The target product (S) -4b obtained in example 7 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in FIG. 7.1H NMR(400MHz,CDCl3):δ 7.86(br,1H),7.34-7.29(m,2H),7.18-7.14(m,2H),6.70(m,1H),6.16(dd,J=6.1Hz,2.8Hz,1H),6.06(s,1H),4.96(dd,J=12.2Hz,7.1Hz,1H),4.86(t,J=7.8Hz,1H),4.77(dd,J=12.2Hz,8.0Hz,1H)。
The target product (S) -4b obtained in example 7 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum, as shown in FIG. 8.13C NMR(100MHz,CDCl3):δ 136.5,134.1,129.4,129.3,128.3,118.5,108.8,106.0,79.0,42.3。
Example 8
Adding CuBr into a 10mL reaction tube2(4.47mg, 0.02mmol), ligand (L) obtained in example 2 above212.35mg, 0.02mmol), sodium dodecylsulfonate (5.45mg, 0.02mmol), water/chloroform solvent (1 mL: 0.1mL), stirred at room temperature for 2h, then cooled at zero degrees Celsius for 30 minutes, β -nitro-4-trifluoromethylstyrene (3c) (43.4mg, 0.2mmol) and pyrrole (40.3mg, 0.6mmol) were added to the reaction tube and stirred at zero degrees Celsius after completion of the reaction (TLC follow-up), extracted with ethyl acetate, back extracted with saturated brine, dried over anhydrous sodium sulfate, and the residue obtained by spin-drying was passed through a column using a petroleum ether/ethyl acetate system as eluent to give the product (S) -4c as a white solid (95% yield, 96% ee).
The target product (S) -4c obtained in example 8 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in FIG. 9.1H NMR(400MHz,CDCl3):δ7.91(br,1H),7.62(d,J=8.1Hz,2H),7.37(d,J=8.1H,2H),6.72(m,1H),6.19(dd,J=6.0Hz,2.9Hz,1H),6.10(m,1H),5.10-4.90(m,2H),4.88-4.80(m,1H)。
The target product (S) -4c obtained in example 8 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum, as shown in FIG. 10.13C NMR(100MHz,CDCl3):δ142.1,130.9-129.9(q,J=32.6Hz),128.4,127.9,126.2,125.2-119.8(q,J=270.6Hz),118.7,108.9,106.3,78.8,42.7。
Example 9
Adding CuBr into a 10mL reaction tube2(4.47mg, 0.02mmol), ligand (L) obtained in example 2 above212.35mg, 0.02mmol), sodium dodecylsulfonate (5.45mg, 0.02mmol), water/chloroform solvent (1 mL: 0.1mL), stirred at room temperature for 2h, then cooled at zero degrees Celsius for 30 minutes, β -nitro-4-methoxystyrene (3d) (35.8mg, 0.2mmol) and pyrrole (40.3mg, 0.6mmol) were added to the reaction tube and stirred at zero degrees Celsius after completion of the reaction (TLC follow-up), extracted with ethyl acetate, back extracted with saturated brine, dried over anhydrous sodium sulfate, and the residue obtained by spin-drying was passed through a column using petroleum ether/ethyl acetate system as eluent to give the product (S) -4d as a white solid (76% yield, 90% ee).
The target product (S) -4d obtained in example 9 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in FIG. 11.1H NMR(400MHz,CDCl3):δ 7.84(br,1H),7.16-7.11(m,2H),6.89-6.83(m,2H),6.68(m,1H),6.15(m,1H),6.06(m,1H),4.95(dd,J=12.0Hz,7.0Hz,1H),4.84(m,1H),4.75(dd,J=12.0Hz,8.1Hz,1H),3.78(s,3H)。
The target product (S) -4d obtained in example 9 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum, as shown in FIG. 12.13C NMR(100MHz,CDCl3):δ 159.3,129.8,129.3,129.1,118.1,114.6,108.6,105.6,79.4,55.3,42.2。
Example 10
Adding CuBr into a 10mL reaction tube2(4.47mg, 0.02mmol), ligand L obtained in example 2 above2(12.35mg, 0.02mmol), sodium dodecylsulfonate (5.45mg, 0.02mmol), water/chloroform solvent (1 mL: 0.1mL), stirred at room temperature for 2h, then cooled at zero degrees Celsius for 30 minutes, β -nitro-2-chlorostyrene nitroene (3e) (36.6mg, 0.2mmol) and pyrrole (40.3mg, 0.6mmol) were added to the reaction tube and the reaction was stirred at zero degrees Celsius after completion (TLC follow-up), extracted with ethyl acetate, back extracted with saturated brine, dried over anhydrous sodium sulfate, and the residue obtained by spin-drying was chromatographed using a petroleum ether/ethyl acetate system as eluent to give the product (S) -4e as a white solid (84% yield, 89% ee).
By usingNuclear magnetic resonance analysis of the target product (S) -4e obtained in example 10 gave a nuclear magnetic resonance hydrogen spectrum, as shown in fig. 13.1H NMR(400MHz,CDCl3):δ 8.01(br,1H),7.45-7.38(m,1H),7.27-7.18(m,2H),7.15-7.09(m,1H),6.70(m,1H),6.18-6.12(m,2H),5.45(m,1H),4.96-4.83(m,2H)。
The target product (S) -4e obtained in example 10 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum, as shown in FIG. 14.13C NMR(100MHz,CDCl3):δ 135.7,133.6,130.2,129.3,129.0,127.9,127.7,118.4,108.7,106.3,77.2,39.3。
Example 11
Adding CuBr into a 10mL reaction tube2(4.47mg, 0.02mmol), ligand (L) obtained in example 1 above111.8mg, 0.02mmol), sodium dodecylsulphonate (5.45mg, 0.02mmol), solvent water/chloroform (1 mL: 0.1mL), stirred at room temperature for 2h and then cooled at zero degrees Celsius for 30min, β -nitrostyrene (3a) (29.8mg, 0.2mmol) and pyrrole (40.3mg, 0.6mmol) are added to the reaction tube and the reaction is stirred at zero degrees Celsius after completion of the reaction (TLC follow-up), extracted with ethyl acetate, back extracted with saturated brine, dried over anhydrous sodium sulphate, and the residue obtained by spin drying is chromatographed using a petroleum ether/ethyl acetate system as eluent to give the product (S) -4a as a white solid (93% yield, 83% ee).
The target product (S) -4a obtained in example 11 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in FIG. 5.1H NMR(400MHz,CDCl3):δ 7.84(br,1H),7.40-7.27(m,3H),7.25-7.20(m,2H),6.68(m,1H),6.16(dd,J=6.0Hz,3.2Hz,1H),6.08(m,1H),4.97(dd,J=12.0Hz,7.2Hz,1H),4.89(t,J=7.5Hz,1H),4.80(dd,J=12.0Hz,7.6Hz,1H)。
The target product (S) -4a obtained in example 11 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum, as shown in FIG. 6.13C NMR(100MHz,CDCl3):δ 138.0,129.2,128.9,128.2,127.9,118.2,108.7,105.8,79.2,42.9。
Example 12
Into a 10mL reaction tube, Sc (OTf)3(9.84mg, 0.02mmol), ligand L obtained in example 2 above2(12.35mg, 0.02mmol), sodium dodecylsulfonate (5.45mg, 0.02mmol), water/chloroform solvent (1 mL: 0.1mL), stirred at room temperature for 2h, then cooled at zero degrees Celsius for 30min, β -nitrostyrene (3a) (29.8mg, 0.2mmol) and pyrrole (40.3mg, 0.6mmol) are added to the reaction tube and the reaction is stirred at zero degrees Celsius after completion of the reaction (TLC follow-up), extracted with ethyl acetate, back extracted with saturated brine, dried over anhydrous sodium sulfate, and the residue obtained by rotary drying is passed through a column using a petroleum ether/ethyl acetate system as eluent to give the product (S) -4a as a white solid (73% yield, 54% ee).
The target product (S) -4a obtained in example 12 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, which is shown in FIG. 5.1H NMR(400MHz,CDCl3):δ 7.84(br,1H),7.40-7.27(m,3H),7.25-7.20(m,2H),6.68(m,1H),6.16(dd,J=6.0Hz,3.2Hz,1H),6.08(m,1H),4.97(dd,J=12.0Hz,7.2Hz,1H),4.89(t,J=7.5Hz,1H),4.80(dd,J=12.0Hz,7.6Hz,1H)。
The target product (S) -4a obtained in example 12 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum, which is shown in FIG. 6.13C NMR(100MHz,CDCl3):δ 138.0,129.2,128.9,128.2,127.9,118.2,108.7,105.8,79.2,42.9。
Example 13
A10 mL reaction tube was charged with Zn (OTf)2(7.27mg, 0.02mmol), ligand L obtained in example 2 above2(12.35mg, 0.02mmol), sodium dodecylsulfonate (5.45mg, 0.02mmol), water/chloroform solvent (1 mL: 0.1mL), stirred at room temperature for 2h, then cooled at zero degrees Celsius for 30 minutes, β -nitrostyrene (3a) (29.8mg, 0.2mmol) and pyrrole (40.3mg, 0.6mmol) are added to the reaction tube and the reaction is stirred at zero degrees Celsius after the reaction is complete (TLC follow-up), extracted with ethyl acetate, back extracted with saturated brineThe residue obtained by drying over anhydrous sodium sulfate was subjected to column chromatography using a petroleum ether/ethyl acetate system as eluent to give the product (S) -4a as a white solid (55% yield, 60% ee).
The target product (S) -4a obtained in example 13 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance hydrogen spectrum, as shown in FIG. 5.1H NMR(400MHz,CDCl3):δ 7.84(br,1H),7.40-7.27(m,3H),7.25-7.20(m,2H),6.68(m,1H),6.16(dd,J=6.0Hz,3.2Hz,1H),6.08(m,1H),4.97(dd,J=12.0Hz,7.2Hz,1H),4.89(t,J=7.5Hz,1H),4.80(dd,J=12.0Hz,7.6Hz,1H)。
The target product (S) -4a obtained in example 13 was analyzed by nuclear magnetic resonance to obtain a nuclear magnetic resonance carbon spectrum, which is shown in FIG. 6.13C NMR(100MHz,CDCl3):δ138.0,129.2,128.9,128.2,127.9,118.2,108.7,105.8,79.2,42.9。

Claims (10)

1. A chiral Schiff base ligand L has a general formula represented by the following formula (1),
Figure FDA0002264138870000011
wherein m is an integer from 1 to 5 and n is an integer having a value from 0 to 18; r1Is one or more selected from isobutyl, sec-butyl, isopropyl, benzyl and 3-indolyl; r2Is one or more selected from methyl, fluorine, chlorine, nitro and trifluoromethyl.
2. A process for the preparation of a chiral schiff base ligand L according to claim 1, comprising the steps of:
Figure FDA0002264138870000012
reacting amino acid methyl ester A with a protecting group with a Grignard reagent to obtain an amino alcohol compound B;
removing a protecting group from the aminoalcohol compound B to obtain aminoalcohol C; and
the amino alcohol C reacts with the salicylaldehyde compound D to generate the prepared Schiff base ligand L,
in the formula, m is an integer of 1 to 5, and n is an integer of 0 to 18; r1Is selected from one or more of isobutyl, sec-butyl, isopropyl, benzyl and 3-indolyl; r2Is one or more of methyl, fluorine, chlorine, nitro and trifluoromethyl.
3. A water-soluble chiral metal complex having a general structure represented by the following formula (2) and generated in situ from the metal ligand L according to claim 1 and a metal salt in an aqueous phase,
Figure FDA0002264138870000021
wherein X-Is one or more selected from trifluoromethanesulfonate, bromide ion, acetate, chloride ion and nitrate radical; m is one or more selected from metal zinc, copper and scandium; m is an integer from 1 to 5, n is an integer having a value from 0 to 18; r1Is one or more selected from isobutyl, sec-butyl, isopropyl, benzyl and 3-indolyl; r2Is one or more selected from methyl, fluorine, chlorine, nitro and trifluoromethyl.
4. The chiral metal complex of claim 3, wherein the molar ratio of the metal salt to the ligand L is (0.5-1): 1.
5. A method of preparing a chiral metal complex, wherein the method comprises: a metal salt and the ligand L in claim 1 are mixed and reacted in a solvent, the molar ratio of the metal salt to the ligand L is (0.5-1): 1, and the metal ion in the metal salt is selected from at least one of copper, zinc and scandium.
6. The preparation method of claim 5, wherein the method further comprises adding a surfactant to the reaction mixture, and the molar ratio of the surfactant to the metal salt is (1-10) to 1.
7. Use of a chiral metal complex according to any one of claims 3 to 4 or obtained according to the preparation process of any one of claims 5 to 6 as a catalyst in an aqueous phase synthesis process for the preparation of 2- (2-nitro-1-phenylethyl) pyrrole-based compounds, 2-nitro-1-phenylethanol-based compounds and 3-hydroxy-3- (2-pyrrolyl) oxindole-based compounds.
8. A method of preparing 2- (2-nitro-1-phenylethyl) pyrroles, comprising: mixing the chiral metal compound of any one of claims 3 to 4 or the chiral metal compound obtained by the preparation method of any one of claims 5 to 6, the compound shown as the formula (I) and pyrrole or substituted pyrrole in a solvent for reaction to obtain a chiral 2- (2-nitro-1-phenylethyl) pyrrole compound, wherein the molar ratio of the compound shown as the formula (I) to the chiral metal compound is (5-20) to 1,
Figure FDA0002264138870000031
in the formula (I), R is3Selected from phenyl, substituted phenyl, heterocyclyl, cycloalkyl; the substituent in the substituted phenyl is selected from one or more of trifluoromethyl, halogen, C1-C5 alkyl and C1-C5 alkoxy.
9. A preparation method of 2-nitro-1-phenethyl alcohol compounds, wherein the method comprises the following steps: mixing the chiral metal compound of any one of claims 3-4 or the chiral metal compound obtained by the preparation method of any one of claims 5-6, a compound shown as a formula (II) and nitromethane in a solvent for reaction to obtain a chiral 2-nitro-1-phenethyl alcohol compound, wherein the molar ratio of the compound shown as the formula (II) to the chiral metal compound is (5-20) to 1,
Figure FDA0002264138870000032
in the formula (II), the R4Selected from phenyl, substituted phenyl, heterocyclyl, cycloalkyl; the substituent in the substituted phenyl is selected from one or more of trifluoromethyl, halogen, C1-C5 alkyl and C1-C5 alkoxy.
10. A preparation method of 3-hydroxy-3- (2-pyrrolyl) oxoindole compounds, wherein the method comprises the following steps: mixing the chiral metal compound of any one of claims 3-4 or the chiral metal compound obtained by the preparation method of any one of claims 5-6, the compound shown as the formula (III) and pyrrole in a solvent for reaction to obtain a chiral 3-hydroxy-3- (2-pyrrolyl) oxindole compound, wherein the molar ratio of the compound shown as the formula (III) to the chiral metal compound is (5-20) to 1,
Figure FDA0002264138870000041
in the formula (III), the R5The substituent is selected from one or more of trifluoromethyl, halogen, C1-C5 alkyl and C1-C5 alkoxy.
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