阅读说明：本技术 一种手性δ-硝基烯酮类化合物及其不对称合成方法与应用 (Chiral delta-nitroketene compound and asymmetric synthesis method and application thereof ) 是由 夏爱宝 封凯祥 许丹倩 于 2019-09-04 设计创作，主要内容包括：本发明公开了一种手性δ-硝基烯酮类化合物及其不对称合成方法与应用,解决了远端手性难以控制的问题,并且在保留不饱和化学键的基础上,实现选择性不对称加成。本发明所述的手性δ-硝基烯酮类化合物具有手性是一类很重要的手性前体化合物,而且硝基可以转化成胺基,可广泛用于手性胺类化合物的合成中,具有广泛的应用空间；本发明的合成方法,操作简单,反应条件温和,显现出良好的反应特性,反应收率高、选择性好。(The invention discloses a chiral delta-nitroketene compound, an asymmetric synthesis method and application thereof, solves the problem that far-end chirality is difficult to control, and realizes selective asymmetric addition on the basis of keeping unsaturated chemical bonds. The chiral delta-nitroketene compound has chirality, is an important chiral precursor compound, can convert nitryl into amido, can be widely used for synthesizing chiral amine compounds, and has wide application space; the synthesis method disclosed by the invention is simple to operate, mild in reaction conditions, high in reaction yield and good in selectivity, and good in reaction characteristics.)

1. a chiral delta-nitroalkenone compound of formula (i):

in the formula (i), R₁、R₂Each independently is H, C1-C20 alkyl, C1-C20 alkenyl, C1-C20 alkynyl, methoxy, phenyl substituted by fluorine atom, phenyl substituted by chlorine atom, phenyl substituted by bromine atom, heterocyclic group, alkyl with halogen atom, and ester group with C1-C20.

2. The chiral delta-nitroalkenones of claim 1, wherein R is₁Selected from one of the following: H. C1-C20 alkyl group, cyano-substituted methyl group, 2,2, 2-trifluoroethyl group, methoxy group, phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, furyl group, thienyl group, 1-naphthyl group, 2-naphthyl group, benzyl group, 2-fluorobenzyl group, 3-fluorobenzyl group, 4-fluorobenzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 4-chlorobenzyl group, 2-bromobenzyl group, 3-bromobenzyl group, 2-trifluoroethyl group, methoxy group, phenyl group, 2-fluorophenyl group, 3-chlorophenyl group, 4, 4-bromobenzyl, benzyloxy, fluoroA substituted phenyl group, a chlorine atom substituted phenyl group, a bromine atom substituted phenyl group, a fluorine atom substituted methyl group, a chlorine atom substituted methyl group, a bromine atom substituted methyl group, a methyl formate group, a methyl acetate group, a methyl propionate group, a methyl butyrate group, an ethyl formate group, an ethyl acetate group, an ethyl propionate group, an ethyl butyrate group, a vinyl group, an ethynyl group, an allyl group, a propargyl group; r₂Selected from one of the following: H. C1-C20 alkyl group, cyano-substituted methyl group, 2,2, 2-trifluoroethyl group, methoxy group, phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, furyl group, thienyl group, 1-naphthyl group, 2-naphthyl group, benzyl group, 2-fluorobenzyl group, 3-fluorobenzyl group, 4-fluorobenzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 4-chlorobenzyl group, 2-bromobenzyl group, 3-bromobenzyl group, 2-trifluoroethyl group, methoxy group, phenyl group, 2-fluorophenyl group, 3-chlorophenyl group, 4, 4-bromobenzyl, benzyloxy, phenyl substituted by fluorine atom, phenyl substituted by chlorine atom, phenyl substituted by bromine atom, methyl substituted by fluorine atom, methyl substituted by chlorine atom, methyl substituted by bromine atom, methyl formate, methyl acetate, methyl propionate, methyl butyrate, ethyl formate, ethyl acetate, ethyl propionate, ethyl butyrate, vinyl, ethynyl, allyl and propargyl.

3. The chiral δ -nitroenones according to claim 1, characterized in that the chiral δ -nitroenones of formula (i) are one of the following:

4. an asymmetric synthesis method of the chiral delta-nitroketene compound as claimed in claim 1, characterized in that the synthesis method comprises the following steps: mixing a chiral primary amine catalyst, a cocatalyst and an organic solvent A, adding a dienone compound shown in formula (ii) and a benzyl nitrobenzene compound shown in formula (iii) under the stirring condition, reacting for 12-36 h at-20-40 ℃, and after the reaction is finished, carrying out post-treatment on reaction liquid to obtain a compound shown in formula (i);

in the formulae (i), (ii) and (iii), R₁、R₂Each independently is H, C1-C20 alkyl, C1-C20 alkenyl, C1-C20 alkynyl, methoxy, fluorine atom phenyl substituent, chlorine atom phenyl substituent, bromine atom phenyl substituent, heterocyclic substituent, halogen atom alkyl, and C1-C20 ester group.

5. The method of claim 4, wherein the chiral primary amine catalyst is selected from one of the compounds of formulae (iv) to (x):

6. the method of claim 4, wherein the cocatalyst is one of: HCl, HBr, H₂SO₄、HBF₄、HPF₆、CH₃COOH、CF₃COOH、CF₃SO₃H. Benzoic acid, o-fluorobenzoic acid, m-fluorobenzoic acid, p-fluorobenzoic acid, phenylacetic acid, p-methylbenzoic acid, o-nitrobenzoic acid, m-nitrobenzoic acid, p-nitrobenzoic acid, o-trifluoromethylbenzoic acid, m-trifluoromethylbenzoic acid, p-trifluoromethylbenzoic acid, benzenesulfonic acid, p-methylbenzenesulfonic acid, p-dodecylbenzenesulfonic acid, alpha-naphthalenesulfonic acid, beta-naphthalenesulfonic acid, alpha-naphthylacetic acid, oleic acid, stearic acid, n-dodecylsulfonic acid, methacrylic acid, preferably the acid is benzoic acid.

7. The method of claim 4, wherein the organic solvent A is one of the following: dichloromethane, chloroform, diethyl ether, isopropyl ether, tetrahydrofuran, 1, 4-dioxane, ethyl acetate, toluene, xylene, trifluorotoluene, thionyl chloride, N-dimethylformamide, acetonitrile, methanol, ethanol, isopropanol; the volume usage amount of the organic solvent A is 2.5-10 mL/mmol based on the amount of the dienone compound (ii).

8. The method according to claim 4, wherein the molar ratio of the dienone compound (ii) to the benzylnitrobenzene compound (iii) is 1:1 to 6; the molar ratio of the dienone compound (ii) to the chiral primary amine catalyst is 1: 0.15-0.25; the molar ratio of the dienone compound (ii) to the cocatalyst is 1: 0.15-0.25.

9. The method according to claim 4, wherein the post-treatment method of the reaction solution comprises: after the reaction is finished, extracting the reaction liquid by using dichloromethane, distilling the extract liquid to remove the solvent, performing column chromatography separation on the obtained concentrate by using 200-300-mesh silica gel, performing TLC (thin layer chromatography) detection by using an eluent which is a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1:4 and a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1:4 as a developing agent to obtain an eluent containing the target compound, and performing vacuum rotary evaporation to dry the eluent to obtain the compound shown in the formula (i).

10. Use of a chiral δ -nitroalkenone compound of claim 1 in the preparation of a precursor of a chiral compound.

(I) technical field

The invention relates to a chiral delta-nitroketene compound and an asymmetric synthesis method and application thereof.

(II) background of the invention

Asymmetric catalytic synthesis is the most effective method for realizing asymmetric value-added and obtaining optically active substances by chemical means, wherein organic small molecule catalysis realizes efficient asymmetric catalytic synthesis of chiral substances by simulating enzyme catalysis, overcomes the defect of high specificity of enzyme catalysis with wider universality, solves the problem of toxic residue caused by application of a metal catalyst in catalytic reaction from the source, and has the advantages of low price, mild reaction conditions, easy preparation, easy recycling and the like, so that organic functional small molecule catalysis gradually becomes a research hotspot of organic synthesis reaction and asymmetric catalytic reaction.

In recent decades, the research on small molecule catalysis, particularly primary amine catalysis, has rapidly progressed in the field of organic synthesis. In the past decades, primary amine catalysis has made great success in chiral asymmetric tandem reactions, and in particular, in the aspect of catalyzing carbonyl compounds, unmodified carbonyl compounds can be directly activated in situ, and original carbonyl structures of the carbonyl compounds are retained, so that the atom economic benefit is greatly improved, the requirements of green chemistry are met, and the method has a wide development space. On the asymmetric catalysis of carbonyl compounds with a plurality of unsaturated bonds, the reasons that the nucleophilic sites are more, the selectivity is poor, the far-end reaction sites are not easy to activate, and the stereoselectivity is difficult to control are always a big difficulty in organic synthesis. The delta-site asymmetric functionalization of the polyunsaturated carbonyl compound not only can provide a brand-new method for modern organic synthesis, but also provides good methods for some important pharmaceutical active fragments, and is very important.

Therefore, the invention adopts chiral primary amine catalyst, carries out asymmetric 1, 6-addition reaction by the activation of vinylogous imine ions under mild conditions, explores a simple route for synthesizing chiral delta-nitroketene compounds, and has the following reaction formula.

Disclosure of the invention

The invention aims to provide a chiral delta-nitroketene compound, an asymmetric synthesis method and application thereof, solves the problem that far-end chirality is difficult to control, and realizes selective asymmetric addition on the basis of keeping unsaturated chemical bonds.

In order to achieve the purpose, the invention adopts the following technical scheme:

the invention provides a chiral delta-nitroketene compound shown in a formula (i):

in the formula (i), R₁、R₂Each independently is H, C1-C20 alkyl, C1-C20 alkenyl, C1-C20 alkynyl, methoxy, phenyl substituted by fluorine atom, phenyl substituted by chlorine atom, phenyl substituted by bromine atom, heterocyclic group, alkyl with halogen atom, and ester group with C1-C20.

Further, R₁Selected from one of the following: H. C1-C20 alkyl group, cyano-substituted methyl group, 2,2, 2-trifluoroethyl group, methoxy group, phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, furyl group, thienyl group, 1-naphthyl group, 2-naphthyl group, benzyl group, 2-fluorobenzyl group, 3-fluorobenzyl group, 4-fluorobenzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 4-chlorobenzyl group, 2-bromobenzyl group, 3-bromobenzyl group, 2-trifluoroethyl group, methoxy group, phenyl group, 2-fluorophenyl group, 3-chlorophenyl group, 4, 4-bromobenzyl, benzyloxy, phenyl substituted by fluorine atom, phenyl substituted by chlorine atom, phenyl substituted by bromine atom, methyl substituted by fluorine atom, methyl substituted by chlorine atom, methyl substituted by bromine atom, methyl formate, methyl acetate, methyl propionate, methyl butyrate, ethyl formate, ethyl acetate, ethyl propionate, ethyl butyrate, vinyl, ethynyl, allyl and propargyl. More preferably, R1 is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, furyl, thienyl, 1-naphthyl, 2-naphthyl, benzyloxy, a fluorine atom substituent, a chlorine atom substituent, a bromine atom substituent, a fluorine atom substituted methyl, a chlorine atom substituted methyl, a bromine atom substituted methyl, a methyl formate group, a methyl acetate group, a methyl propionate group, a methyl butyrate group, an ethyl formate group, an ethyl acetate group, an ethyl propionate group, an ethyl butyrate group, a vinyl group, an ethynyl group, an allyl group, and a propargyl group.

Further, R₂Selected from one of the following: H. C1-C20 alkyl group, cyano-substituted methyl group, 2,2, 2-trifluoroethyl group, methoxy group, phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, furyl group, thienyl group, 1-naphthyl group, 2-naphthyl group, benzyl group, 2-fluorobenzyl group, 3-fluorobenzyl group, 4-fluorobenzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 4-chlorobenzyl group, 2-bromobenzyl group, 3-bromobenzyl group, 2-trifluoroethyl group, methoxy group, phenyl group, 2-fluorophenyl group, 3-chlorophenyl group, 4, 4-bromobenzyl, benzyloxy, phenyl substituted by fluorine atom, phenyl substituted by chlorine atom, phenyl substituted by bromine atom, methyl substituted by fluorine atom, methyl substituted by chlorine atom, methyl substituted by bromine atom, methyl formate, methyl acetate, methyl propionate, methyl butyrate, ethyl formate, ethyl acetate, ethyl propionate, ethyl butyrate, vinyl, ethynyl, allyl and propargyl. More preferably, R2 is a hydrogen, methyl, methoxy or chlorine atom substituent.

Further, the chiral δ -nitroalkenone compound represented by the formula (i) is preferably one of the following:

the invention also provides an asymmetric synthesis method of the chiral delta-nitroketene compound shown in the formula (i), which comprises the following steps:

mixing a chiral primary amine catalyst, a cocatalyst and an organic solvent A, adding a dienone compound shown in formula (ii) and a benzyl nitrobenzene compound shown in formula (iii) under the stirring condition, reacting for 12-36 h at-20-40 ℃, and after the reaction is finished, carrying out post-treatment on reaction liquid to obtain a compound shown in formula (i);

in the formulae (i), (ii) and (iii), R₁、R₂Each independently is H, C1-C20 alkyl, C1-C20 alkenyl, C1-C20 alkynyl, methoxy, fluorine atom phenyl substituent, chlorine atom phenyl substituent, bromine atom phenyl substituent, heterocyclic substituent, halogen atom alkyl, and C1-C20 ester group.

R in the formulae (i) and (ii)₁Selected from one of the following: H. C1-C20 alkyl group, cyano-substituted methyl group, 2,2, 2-trifluoroethyl group, methoxy group, phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, furyl group, thienyl group, 1-naphthyl group, 2-naphthyl group, benzyl group, 2-fluorobenzyl group, 3-fluorobenzyl group, 4-fluorobenzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 4-chlorobenzyl group, 2-bromobenzyl group, 3-bromobenzyl group, 2-trifluoroethyl group, methoxy group, phenyl group, 2-fluorophenyl group, 3-chlorophenyl group, 4, 4-bromobenzyl, benzyloxy, phenyl substituted by fluorine atom, phenyl substituted by chlorine atom, phenyl substituted by bromine atom, methyl substituted by fluorine atom, methyl substituted by chlorine atom, methyl substituted by bromine atom, methyl formate, methyl acetate, methyl propionate, methyl butyrate, ethyl formate, ethyl acetate, ethyl propionate, ethyl butyrate, vinyl, ethynyl, allyl and propargyl.

R in the formulae (i) and (iii)₂Selected from one of the following: H. C1-C20 alkyl, cyano-substituted methyl, 2,2, 2-trifluoroethyl, methoxy, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, furyl, thienyl, 1-naphthyl, 2-naphthyl,Benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, benzyloxy, phenyl substituted with a fluorine atom, phenyl substituted with a chlorine atom, phenyl substituted with a bromine atom, methyl substituted with a fluorine atom, methyl substituted with a chlorine atom, methyl substituted with a bromine atom, methyl formate, methyl acetate, methyl propionate, methyl butyrate, ethyl formate, ethyl acetate, ethyl propionate, ethyl butyrate, vinyl, ethynyl, allyl, propargyl.

In the step of the synthesis method of the present invention, the chiral primary amine catalyst may be selected from one of the compounds represented by formulas (iv) to (x), preferably a compound represented by formula (iv):

in the step of the synthesis method of the invention, the cocatalyst can be one of the following: HCl, HBr, H₂SO₄、HBF₄、HPF₆、CH₃COOH、CF₃COOH、CF₃SO₃H. Benzoic acid, o-fluorobenzoic acid, m-fluorobenzoic acid, p-fluorobenzoic acid, phenylacetic acid, p-methylbenzoic acid, o-nitrobenzoic acid, m-nitrobenzoic acid, p-nitrobenzoic acid, o-trifluoromethylbenzoic acid, m-trifluoromethylbenzoic acid, p-trifluoromethylbenzoic acid, benzenesulfonic acid, p-methylbenzenesulfonic acid, p-dodecylbenzenesulfonic acid, alpha-naphthalenesulfonic acid, beta-naphthalenesulfonic acid, alpha-naphthylacetic acid, oleic acid, stearic acid, n-dodecylsulfonic acid, methacrylic acid, preferably the acid is benzoic acid.

In the steps of the synthesis method of the invention, the organic solvent A can be one of the following: dichloromethane, chloroform, diethyl ether, isopropyl ether, tetrahydrofuran, 1, 4-dioxane, ethyl acetate, toluene, xylene, trifluorotoluene, thionyl chloride, N-dimethylformamide, acetonitrile, methanol, ethanol, isopropanol, preferably toluene; the volume usage amount of the organic solvent A is 2.5-10 mL/mmol, preferably 5mL/mmol, based on the amount of the dienone compound (ii).

In the steps of the synthesis method, the molar ratio of the dienone compound (ii) to the benzyl nitrobenzene compound (iii) is 1: 1-6, preferably 1: 3.

In the steps of the synthetic method, the molar ratio of the dienone compound (ii) to the chiral primary amine catalyst is 1: 0.15-0.25, preferably 1: 0.2;

in the step of the synthesis method, the molar ratio of the dienone compound (ii) to the cocatalyst is 1: 0.15-0.25, preferably 1: 0.2.

In the steps of the synthetic method, the reaction temperature is preferably 25 ℃, and the reaction time is 24 hours.

In the steps of the synthetic method, the post-treatment of the reaction solution can adopt the following method: after the reaction is finished, extracting the reaction liquid with dichloromethane, distilling the extract to remove the solvent, performing column chromatography separation on the obtained concentrate with 200-300-mesh silica gel, wherein an eluent is a mixed solution of ethyl acetate and petroleum ether with a volume ratio of 1:4, detecting a target compound by TLC (a developing solvent is a mixed solution of ethyl acetate and petroleum ether with a volume ratio of 1: 4) spot plate, collecting the target compound by using a test tube to obtain an eluent containing the target compound, and performing vacuum rotary evaporation to dry the eluent to obtain the compound shown in the formula (i).

The asymmetric synthesis method of the chiral delta-nitroketene compound is specifically recommended to be carried out according to the following steps:

mixing a chiral primary amine catalyst (iv), benzoic acid and toluene, adding a dienone compound shown in formula (ii) and a benzyl nitrobenzene compound shown in formula (iii) under the stirring condition, reacting for 24 hours at 25 ℃, after the reaction is finished, extracting a reaction solution by using dichloromethane, distilling an extract to remove a solvent, performing column chromatography separation on the obtained concentrate by using 200-300-mesh silica gel, collecting an eluent containing a target compound, concentrating and drying to obtain a compound shown in formula (i), wherein the eluent is a mixed solution of ethyl acetate and petroleum ether with a volume ratio of 1: 4; the volume usage amount of the toluene is 5mL/mmol based on the amount of the substance of the dienone compound (ii); the molar ratio of the dienone compound (ii) to the benzyl nitrobenzene compound (iii) is 1: 3; the molar ratio of the dienone compound (ii) to the chiral primary amine catalyst (iv) is 1: 0.2; the molar ratio of the dienone compound (ii) to the benzoic acid is 1: 0.2.

The chiral delta-nitroketene compound prepared by the invention has an extendable and modified structure such as ketene and nitro, and the invention also provides an application of the chiral delta-nitroketene compound in preparing a chiral compound precursor, for example, a chiral diphenylethylenediamine compound can be obtained by reduction and nitroamination and aromatization reaction of cyclohexenone, and a chiral pyrrolidine compound with biological activity (J.Org.chem.2010,75, 1402-1409) can be generated by reduction and further a michael reaction of nitro. Therefore, the nitroketene compound can be developed to obtain the corresponding amine chiral compound through the conversion of the nitro group, and can be utilized in the asymmetric catalytic reaction.

The chiral delta-nitroketene compound is an important synthetic intermediate, and compared with the prior art, the chiral delta-nitroketene compound has the advantages that:

(1) the chiral delta-nitroketene compound has chirality, is an important chiral precursor compound, can convert nitryl into amido, can be widely used for synthesizing chiral amine compounds, and has wide application space;

(2) the synthesis method disclosed by the invention is simple to operate, mild in reaction conditions, high in reaction yield and good in selectivity, and good in reaction characteristics.

(IV) detailed description of the preferred embodiments

The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto.