Chiral beta-diester selenoethers and Michael addition preparation method thereof
阅读说明：本技术 手性β-二酯硒醚类化合物及其Michael加成的制备方法 (Chiral beta-diester selenoethers and Michael addition preparation method thereof ) 是由 黄湧 陈杰安 李恩 于 2021-08-20 设计创作，主要内容包括：本申请涉及有机化合物合成技术领域,具体提供了一种手性β-二酯硒醚类化合物及其Michael加成的制备方法。该手性β-二酯硒醚类化合物的分子结构通式如说明书式I所示：该手性β-二酯硒醚类化合物具有高官能团性和结构多样性,因此,可以为手性β-二酯硒醚类化合物在药物中间体合成和功能材料的应用中提供多样化选择,特别是应用于丙二酸酯的产物的合成和功能材料的制备。(The application relates to the technical field of organic compound synthesis, and particularly provides a chiral beta-diester selenide compound and a Michael addition preparation method thereof. The molecular structural general formula of the chiral beta-diester selenide compound is shown as an instruction formula I: the chiral beta-diester selenide compound has high functional group and structural diversity, so that the compound can provide diversified selections for the chiral beta-diester selenide compound in the synthesis of drug intermediates and the application of functional materials, and is particularly applied to the synthesis of malonate products and the preparation of functional materials.)
1. A chiral beta-diester selenide compound is characterized in that the molecular structural general formula of the chiral beta-diester selenide compound is shown as formula I:
wherein R is1、R2And R3Are identical or different C1-C20Alkyl radical, C1-C20Heteroalkyl group, C3-C20Cycloalkyl radical, C3-C20Heterocycloalkyl radical, C2-C20Alkenyl radical, C2-C20Heteroalkenyl, C3-C20Cycloalkenyl radical, C3-C20Heterocycloalkenyl, C2-C20Alkynyl, C2-C20Heteroalkynyl, C3-C20Cycloalkynyl group, C3-C20Heterocycloalkynyl, C1-C20Alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, heteroaryloxy, aryl (C)1-C20) Alkyl, heteroaryl (C)1-C20) Alkyl radical, C2-C20Alkenyl (C)1-C20) Alkyl radical, C2-C20Alkynyl (C)1-C20) Alkyl, cyano (C)1-C20) Alkyl and C1-C20Alkyloxycarbonyl (C)1-C20) Any one of alkyl groups.
2. The chiral β -diester selenoethers as claimed in claim 1 wherein R is1、R2And R3Are identical or different C1-C10Alkyl radical, C1-C10Heteroalkyl group, C3-C10Cycloalkyl radical, C3-C10Heterocycloalkyl radical, C2-C10Alkenyl radical, C2-C10Heteroalkenyl, C3-C10Cycloalkenyl radical, C3-C10Heterocycloalkenyl, C2-C10Alkynyl, C2-C10Heteroalkynyl, C3-C10Cycloalkynyl group, C3-C10Heterocycloalkynyl, C1-C10Alkoxy radical, C1-C10Alkyloxycarbonyl (C)1-C10) Alkyl radical, C3-C8Aryl radical (C)1-C10) Alkyl radical, C2-C10Alkenyl (C)1-C10) Alkyl radical, C2-C10Alkynyl (C)1-C10) Alkyl, cyano (C)1-C10) Alkyl, substituted (C)3-C8) Aryl group, (C)3-C8) Heteroaryl, substituted (C)3-C8) Any one of heteroaryl groups.
3. The chiral β -diester selenoethers as claimed in claim 2 wherein R is1、R2And R3Is C1-C5Alkyl radical, C1-C5Alkyloxycarbonyl (C)1-C5) Alkyl, phenyl (C)1-C3) Alkyl radical, C2-C5Alkenyl (C)1-C3) Alkyl radical, C2-C5Alkynyl (C)1-C3) Alkyl, cyano (C)1-C3) Alkyl, halogen-substituted phenyl, alkoxy-substituted furan, alkoxy-substituted pyridine, C3-C8Heteroaryl-substituted phenyl, C3-C8Heteroaryl substituted furans and C3-C8Any one of heteroaryl substituted pyridines.
4. The chiral β -diester selenoethers according to any one of claims 1 to 3, wherein the chiral β -diester selenoethers comprise at least one of the following structural formulae I1 to I3:
5. a method for the preparation of a Michael addition of chiral β -diester selenoethers as claimed in any one of claims 1 to 4, comprising the steps of:
providing a selenol compound A and an alkene diester compound B shown in the following structural general formulas:
A：R1-SeH B：
adding the selenol compound A and the alkene diester compound B into a reaction system containing a nitrogen heterocyclic carbene catalyst, an alkali reagent and a water absorption additive, and reacting at the temperature of-100-25 ℃ to obtain the chiral beta-diester selenide compound.
6. The method for preparing the chiral β -diselenide compound by Michael addition according to claim 5, wherein the molar ratio of the N-heterocyclic carbene catalyst to the base reagent is (0.1-20) to (0.1-20).
7. The method for preparing the chiral β -diester selenoethers according to claim 6 by Michael addition, wherein the molar ratio of the N-heterocyclic carbene catalyst, the base reagent and the selenol compound A is (0.1-20): (1-100).
8. The method for preparing the Michael addition of the chiral β -diester selenoethers according to claim 5, wherein the azacyclo-carbene catalyst is selected from nitrogen-containing heterocyclic compounds represented by the following structural formula C and/or structural formula D:
C：D：
wherein X is identical or different boron tetrafluoride anions or chloride ions, and Y is an oxygen atom or a sulfur atom; r4、R5And R6Are identical or different aryl radicals (C)1-C20) Alkyl, heteroaryl (C)1-C20) Any of alkyl, aryl, and substituted aryl.
9. The method of claim 5, wherein the base reagent is at least one selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1,5, 7-triazabicyclo (4.4.0) dec-5-ene, triethylamine, diisopropylethylamine, bistrimethylaminolithium, bistrimethylaminosodium, bistrimethylaminopotassium, diisopropylaminolithium, n-butyllithium, t-butyllithium, methyllithium, sodium methoxide, sodium ethoxide, and sodium ethylmercaptide.
10. The method of claim 5, wherein the water-absorbing additive is selected from the group consisting of anhydrous sodium sulfate, anhydrous magnesium sulfate, pre-activated 13x molecular sieve, and a mixture thereof,Molecular sieve,Molecular sieves andat least one of molecular sieves.
Technical Field
The application belongs to the technical field of organic compound synthesis, and particularly relates to a chiral beta-diester selenide compound and a Michael addition preparation method thereof.
Background
Selenium is a trace element, and chemists have increasingly paid attention to organic selenium compounds and have significant influence on the fields of medicinal chemistry, material chemistry, chemical biology, biochemistry and the like. While chiral organoselenium compounds are synthesized mainly from chiral substrates or controlled by chiral catalysts, methods controlled by chiral substrates have been significantly developed, but the strategy of asymmetric catalytic synthesis is less concerned.
Currently, asymmetric selenium Michael additions mainly utilize electrophiles or nucleophiles of selenium. The reported selenium Michael reaction is the Michael addition of arylselenols to ketenes using chiral cinchona-based catalysts, but the ee value is only 43% at the maximum. These methods have a number of disadvantages, for example: 1) the asymmetric reaction of aryl selenium is designed only, and the asymmetric catalytic reaction of alkyl selenium is not realized; 2) asymmetric Michael addition has not yet achieved synthesis with high stereoselectivity; 3) the alkenyl ester compound has not been reported to be asymmetric selenium Michael. Therefore, there is a need for a novel synthesis method that overcomes the drawbacks of the prior art, particularly those described above.
Disclosure of Invention
The application aims to provide chiral beta-diester selenoethers and a preparation method of Michael addition thereof, and aims to solve the problems of limited substrate and low enantioselectivity in the existing asymmetric selenium Michael addition.
In order to achieve the purpose of the application, the technical scheme adopted by the application is as follows:
in a first aspect, the application provides a chiral beta-diester selenide compound, wherein the molecular structural general formula of the chiral beta-diester selenide compound is shown as formula I:
wherein R is1、R2And R3Are identical or different C1-C20Alkyl radical, C1-C20Heteroalkyl group, C3-C20Cycloalkyl radical, C3-C20Heterocycloalkyl radical, C2-C20Alkenyl radical, C2-C20Heteroalkenyl, C3-C20Cycloalkenyl radical, C3-C20Heterocycloalkenyl, C2-C20Alkynyl, C2-C20Heteroalkynyl, C3-C20Cycloalkynyl group, C3-C20Heterocycloalkynyl, C1-C20Alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, heteroaryloxy, aryl (C)1-C20) Alkyl, heteroaryl (C)1-C20) Alkyl radical, C2-C20Alkenyl (C)1-C20) Alkyl radical, C2-C20Alkynyl (C)1-C20) Alkyl, cyano (C)1-C20) Alkyl and C1-C20Alkyloxycarbonyl (C)1-C20) Any one of alkyl groups.
In a second aspect, the present application provides a method for preparing the above chiral β -diester selenoethers by Michael addition, comprising the following steps:
providing a selenol compound A and an alkene diester compound B shown in the following structural general formulas:
A：R1-SeH B：
adding the selenol compound A and the alkene diester compound B into a reaction system containing a nitrogen heterocyclic carbene catalyst, an alkali reagent and a water absorption additive, and reacting at the temperature of-100-25 ℃ to obtain the chiral beta-diester selenide compound.
The chiral beta-diester selenide compound provided by the application can provide raw materials or reaction intermediates for synthesis of drug intermediates and preparation of functional materials; and the chiral beta-diester selenide compounds have high functional group, so that diversified choices can be provided for the beta-diester selenide compounds in the synthesis of drug intermediates and the application of functional materials.
The Michael addition method of the chiral beta-diester selenide compounds provided by the application is a novel asymmetric C-Se bond construction method, and has the following advantages:
firstly, the application adopts an organic micromolecule asymmetric catalytic system to realize Michael addition of the chiral beta-diester selenide compounds.
Secondly, according to the Michael addition method, on one hand, a simple selenol compound reagent is used as a nucleophilic reagent to attack an alkene diester compound, so that a target product precursor with high enantioselectivity and a wide range is efficiently and greenly prepared, and a chiral beta-diester selenide compound with potential application is obtained; on the other hand, the reactant selects simple and easily available selenol and commercial diester alkene as the reactant, the raw material is very easy to obtain, and the reactant can be directly used for preparation production without additional modification protection before reaction, so that the operation steps are simplified, the reaction route is shortened, in addition, the forward reaction rate is high, and the production efficiency is obviously improved.
Thirdly, in the Michael addition process of the application, the Michael addition process of the chiral beta-diester selenide compounds is a conjugate addition reaction, so that the atom utilization rate and the reaction efficiency of reactants are high, the generation yield of reaction products is favorably improved, in addition, the selenol compound A and the alkene diester compound B are prepared by one-step reaction in a reaction system containing a nitrogen heterocyclic carbene catalyst, an alkali reagent and a water absorption additive, the preparation method has simple process and low requirement on reaction conditions, the reaction process is safe and controllable, and the operation in the preparation production process is simplified.
Fourthly, the method provided by the application obviously reduces the production cost of preparing the beta-diester selenide compounds, and also greatly expands the designability and application prospect of the compounds. The addition product obtained by the method has high functional group, so that the addition product is more diversified in the synthesis of a drug intermediate and the application of a functional material, can be widely used for the synthesis of the drug intermediate and the preparation of the functional material, can effectively reduce the economic cost for the preparation of the drug intermediate and the functional material, and provides the environmental friendliness.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present application more clearly apparent, the present application is further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the present application and are not intended to limit the present application.
The compounds and derivatives thereof referred to in the examples of the present invention are named according to the IUPAC (International Union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, Ohio) naming system. Accordingly, the groups of compounds specifically referred to in the examples of the present invention are illustrated and described as follows:
with respect to "hydrocarbon group", the minimum and maximum values of the carbon atom content in a hydrocarbon group are indicated by a prefix, e.g., the prefix (C)a-Cb) Alkyl represents any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, (C)1-C6) Alkyl refers to alkyl groups containing one to six carbon atoms.
"alkoxy" refers to a straight or branched, monovalent, saturated aliphatic chain bonded to an oxygen atom and includes, but is not limited to, groups such as methoxy, ethoxy, propoxy, butoxy, isobutoxy, t-butoxy, and the like. (C)a-Cb) Alkoxy means any straight or branched, monovalent, saturated aliphatic chain in which an alkyl group containing "a" to "b" carbon atoms is bonded to an oxygen atom.
"alkyl" refers to a straight or branched, monovalent, saturated aliphatic chain including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, and the like.
"heteroalkyl" means a straight or branched, monovalent, saturated aliphatic chain attached to at least one heteroatom, such as, but not limited to, methylaminoethyl or other similar groups.
"alkenyl" refers to straight or branched chain hydrocarbons having one or more double bonds, including but not limited to, groups such as ethenyl, propenyl, and the like.
"Heteroalkenyl" means a straight or branched chain hydrocarbon with one or more double bonds attached to at least one heteroatom, including but not limited to, for example, vinylaminoethyl or other similar groups.
"alkynyl" refers to a straight or branched chain hydrocarbon with one or more triple bonds, including but not limited to, for example, ethynyl, propynyl, and the like.
"Heteroalkynyl" means a straight or branched chain hydrocarbon with one or more triple bonds attached to at least one heteroatom, including but not limited to, groups such as ethynyl, propynyl, and the like.
"aryl" refers to a cyclic aromatic hydrocarbon including, but not limited to, phenyl, naphthyl, anthryl, phenanthryl, and the like.
"heteroaryl" refers to a monocyclic or polycyclic or fused ring aromatic hydrocarbon in which one or more carbon atoms have been replaced with a heteroatom such as nitrogen, oxygen, or sulfur. If the heteroaryl group contains more than one heteroatom, these heteroatoms may be the same or different. Heteroaryl groups include, but are not limited to, groups such as benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyranyl, furanyl, imidazolyl, indazolyl, indolizinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazinyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridine [3,4-b ] indolyl, pyridyl, pyrimidinyl, pyrrolyl, quinolizinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiatriazolyl, thiazolyl, thienyl, triazinyl, triazolyl, xanthenyl, and the like.
"cycloalkyl" refers to a saturated monocyclic or polycyclic alkyl group, possibly fused to an aromatic hydrocarbon group. Cycloalkyl groups include, but are not limited to, groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indanyl, tetrahydronaphthyl, and the like.
"Heterocycloalkyl" means a saturated monocyclic or polycyclic alkyl group, possibly fused to an aromatic hydrocarbon group, in which at least one carbon atom has been replaced by a heteroatom such as nitrogen, oxygen or sulfur. If the heterocycloalkyl group contains more than one heteroatom, these heteroatoms may be the same or different. Heterocycloalkyl groups include, but are not limited to, groups such as azepanyl, azetidinyl, indolinyl, morpholinyl, pyrazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuryl, tetrahydroquinolinyl, tetrahydroindazolyl, tetrahydroindolyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinoxalinyl, tetrahydrothiopyranyl, thiazolidinyl, thiomorpholinyl, thioxanthyl, and the like.
"cycloalkenyl" refers to an unsaturated, monocyclic or polycyclic alkenyl group with one or more double bonds, possibly fused to an aromatic hydrocarbon group, including, but not limited to, cyclic ethenyl, cyclopropenyl, or other similar groups.
"Heterocycloalkenyl" means an unsaturated, monocyclic or polycyclic alkenyl radical having one or more double bonds, possibly condensed with an aromatic hydrocarbon radical, in which at least one carbon atom is replaced by a heteroatom such as nitrogen, oxygen or sulfur. If the heterocycloalkyl group contains more than one heteroatom, these heteroatoms may be the same or different.
"cycloalkynyl" refers to an unsaturated, monocyclic or polycyclic alkynyl group having one or more triple bonds, possibly fused to an aromatic hydrocarbon group, including, but not limited to, cycloalkynyl, cyclopropynyl, or the like.
"Heterocycloalkynyl" means an unsaturated, monocyclic or polycyclic alkynyl radical having one or more triple bonds, possibly condensed with an aromatic hydrocarbon radical, in which at least one carbon atom has been replaced by a heteroatom such as nitrogen, oxygen or sulfur. If the heterocycloalkyl group contains more than one heteroatom, these heteroatoms may be the same or different.
The first aspect of the embodiments of the present application provides a chiral β -diester selenide compound, where the molecular structural general formula of the chiral β -diester selenide compound is shown in formula I:
in the general formula I, R1、R2And R3Are identical or different C1-C20Alkyl radical, C1-C20Heteroalkyl group, C3-C20Cycloalkyl radical, C3-C20Heterocycloalkyl radical, C2-C20Alkenyl radical, C2-C20Heteroalkenyl, C3-C20Cycloalkenyl group、C3-C20Heterocycloalkenyl, C2-C20Alkynyl, C2-C20Heteroalkynyl, C3-C20Cycloalkynyl group, C3-C20Heterocycloalkynyl, C1-C20Alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, heteroaryloxy, aryl (C)1-C20) Alkyl, heteroaryl (C)1-C20) Alkyl radical, C2-C20Alkenyl (C)1-C20) Alkyl radical, C2-C20Alkynyl (C)1-C20) Alkyl, cyano (C)1-C20) Alkyl and C1-C20Alkyloxycarbonyl (C)1-C20) Any one of alkyl groups;
when R is1、R2And R3Are identical or different C1-C20Alkyl, in some embodiments, C1-C20The alkyl group may be (C)1-C10) Alkyl, (C)1-C5) Alkyl, (C)1-C4) Alkyl, (C)1-C3) Alkyl, (C)1-C2) Alkyl groups, and the like. In some embodiments, (C)1-C20) The alkyl group may be specifically a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a pentyl group, an isopentyl group, etc.
When R is1、R2And R3Are identical or different (C)1-C20) When it is heteroalkyl, in one embodiment, (C)1-C20) The heteroalkyl group may be (C)1-C10) Heteroalkyl group, (C)1-C5) Heteroalkyl group, (C)1-C4) Heteroalkyl group, (C)1-C3) Heteroalkyl group, (C)1-C2) Heteroalkyl groups and the like. In some embodiments, the heteroatom may be a halogen, nitrogen atom, sulfur atom, or the like.
When R is1、R2And R3Are identical or different (C)3-C20) Cycloalkyl, in one embodiment, (C)3-C20) The cycloalkyl group may be (C)3-C10) Cycloalkyl radicals、(C3-C5) Cycloalkyl group, (C)3-C4) Cycloalkyl groups, and the like. In one embodiment, (C)3-C20) Cycloalkyl groups may be cyclopropyl, cyclobutyl, cyclopentyl, and the like.
When R is1、R2And R3Are identical or different (C)3-C20) When it is a heterocycloalkyl group, in one embodiment, (C)3-C20) The heterocycloalkyl group may be (C)3-C10) Heterocycloalkyl group, (C)3-C10) Heterocycloalkyl group, (C)3-C5) Heterocycloalkyl group, (C)3-C4) Heterocycloalkyl, and the like. In one embodiment, the heteroatom may be a halogen, nitrogen atom, sulfur atom, or the like.
When R is1、R2And R3Are identical or different (C)2-C20) Alkenyl, in one embodiment, (C)2-C20) The alkenyl group may be (C)3-C10) Alkenyl, (C)3-C5) Alkenyl, (C)3-C4) Alkenyl, (C)2-C3) Alkenyl groups, and the like. In some embodiments, (C)2-C20) The alkenyl group may be ethenyl, propenyl, butenyl, pentenyl, etc.
When R is1、R2And R3Are identical or different (C)2-C20) (iii) heteroalkenyl, in one embodiment, (C)2-C20) The heteroalkenyl group can be (C)2-C10) Heteroalkenyl, (C)3-C10) Heteroalkenyl, (C)3-C5) Heteroalkenyl, (C)3-C4) Heteroalkenyl, (C)2-C3) Heteroalkenyl and the like. In some embodiments, the heteroatom may be a halogen, nitrogen atom, sulfur atom, or the like.
When R is1、R2And R3Are identical or different (C)3-C20) Cycloalkenyl in one embodiment, (C)3-C20) Cycloalkenyl can be (C)3-C10) Cycloalkenyl group, (C)3-C5) Cycloalkenyl group, (C)3-C4) Cycloalkenyl groups, and the like. In some casesIn the examples, (C)3-C20) Cycloalkenyl can be cyclopropenyl, cyclobutenyl, cyclopentenyl and the like.
When R is1、R2And R3Are identical or different (C)3-C20) When heterocycloalkenyl, in one embodiment, (C)3-C20) The heterocycloalkenyl group may be (C)3-C10) Heterocycloalkenyl, (C)3-C5) Heterocycloalkenyl, (C)3-C4) Heterocycloalkenyl, and the like. In some embodiments, the heteroatom may be a halogen, nitrogen atom, sulfur atom, or the like.
When R is1、R3And R3Are identical or different (C)2-C20) Alkynyl, in one embodiment, (C)2-C20) Alkynyl may be (C)2-C10) Alkynyl, (C)3-C10) Alkynyl, (C)3-C5) Alkynyl, (C)3-C4) Alkynyl, (C)2-C3) Alkynyl and the like. In some embodiments, (C)2-C20) The alkynyl group may be an ethynyl group, propynyl group, butynyl group, pentynyl group or the like.
When R is1、R2And R3Are identical or different (C)2-C20) When heteroalkynyl is present, (C) is, in one embodiment2-C20) The heteroalkynyl can be (C)2-C10) Heteroalkynyl, (C)3-C10) Heteroalkynyl, (C)3-C5) Heteroalkynyl, (C)3-C4) Heteroalkynyl, (C)2-C3) Heteroalkynyl, and the like. In some embodiments, the heteroatom may be a halogen, nitrogen atom, sulfur atom, or the like.
When R is1、R2And R3Are identical or different (C)3-C20) Cycloalkynyl, in one embodiment, (C)3-C20) The cycloalkynyl group can be (C)3-C10) Cycloalkynyl, (C)3-C5) Cycloalkynyl, (C)3-C4) Cycloalkynyl, and the like. In some embodiments, (C)2-C20) The cycloalkynyl group can be cyclopropynyl, cyclobutynyl,Cyclopentynyl, and the like.
When R is1、R2And R3Are identical or different (C)3-C20) When heterocycloalkynyl, in one embodiment, (C)3-C20) The heterocycloalkynyl can be (C)3-C10) Heterocycloalkynyl, (C)3-C5) Heterocycloalkynyl, (C)3-C4) Heterocycloalkynyl, and the like. In some embodiments, the heteroatom may be a halogen, nitrogen atom, sulfur atom, or the like.
When R is1、R2And R3Are identical or different (C)1-C20) In the case of alkoxy, in one embodiment, (C)1-C20) The alkoxy group may be (C)1-C10) Alkoxy group, (C)1-C8) Alkoxy group, (C)1-C6) Alkoxy group, (C)1-C4) Alkoxy group, (C)1-C3) Alkoxy group, (C)1-C2) An alkoxy group. In some embodiments, (C)1-C20) Alkoxy groups may be, but are not limited to, methyloxy, ethyloxy, propyloxy, and the like.
When R is1、R2And R3When the aryl groups are the same or different, the aryl groups may be, but are not limited to, monocyclic aryl groups, polycyclic aryl groups, and fused ring aryl groups. In one embodiment, the aryl group is a monocyclic aryl group. In some embodiments, aryl is phenyl.
When R is1、R2And R3When the same or different substituted aryl groups are present, the substituted aryl groups may be, but are not limited to, phenyl groups substituted singly or multiply in the ortho, meta, or para positions. Substituents include, but are not limited to, alkyl, substituted alkyl, halogen, alkoxyamino, nitro, -NR7R8、-NR7-CO-NR8、-OCONR7、-PR7R8、-SOR7、-SO2-R7、-SiR7R8R9、-BR7R8Wherein R is7、R8、R9Which may be the same or different is as R above1、R3The groups shown. Wherein is substitutedWhen the radical is alkyl, alkyl such as, but not limited to, methyl, ethyl, propyl, butyl, isobutyl; when the substituent is a substituted alkyl group, the water absorbing additive is a substituted alkyl group such as, but not limited to, trifluoromethyl, trichloromethyl, trifluoroethyl, trichloroethyl; when the substituent is halogen, halogen such as, but not limited to, fluorine, chlorine, bromine, iodine; when the substituent is an alkoxy group, the water absorbing additive alkoxy group is, for example, but not limited to, a methyloxy group, an ethyloxy group, a propyloxy group. In one embodiment, the substituted aryl group may also be cyano (C)1-C10) Alkyl radical (C)3-C8) Aryl, substituted (C)3-C8) And (4) an aryl group.
When R is1、R2And R3When the same or different heteroaryl groups are present, in one embodiment, the heteroaryl group can be (C)3-C8) Heteroaryl, furan, thiophene.
When R is1、R2And R3In the case of identical or different substituted heteroaryl groups, in one embodiment the substituted heteroaryl groups may be substituted (C)3-C8) Heteroaryl, alkoxy substituted furan, (C)3-C8) Heteroaryl substituted furans, aliphatic chain substituted thiophenes.
When R is1、R2And R3When the same or different aryloxy groups are present, in one embodiment, the aryloxy group can be phenoxy, naphthoxy, anthracenoxy, phenanthroxy.
When R is1、R2And R3Are identical or different aryl radicals (C)1-C20) When it is an alkyl group, in one embodiment, the aryl group (C)1-C20) The alkyl group may be aryl (C)1-C10) Alkyl, phenyl (C)1-C10) Alkyl, phenyl (C)1-C5) Alkyl, phenyl (C)1-C4) Alkyl, phenyl (C)1-C3) Alkyl, phenyl (C)1-C2) Alkyl groups, and the like. In some embodiments, aryl (C)1-C20) The alkyl group can be phenylmethyl, phenylethyl, phenylpropyl, phenylbutyl, phenylisobutyl, phenylpentyl, phenylIsoamyl and phenyl neopentyl.
When R is1、R2And R3Are identical or different heteroaryl (C)1-C20) When alkyl, in one embodiment, the heteroaryl (C)1-C20) The alkyl group may be heteroaryl (C)1-C10) Alkyl, heteroaryl (C)1-C10) Alkyl, heteroaryl (C)1-C5) Alkyl, heteroaryl (C)1-C4) Alkyl, heteroaryl (C)1-C3) Alkyl, heteroaryl (C)1-C2) Alkyl groups, and the like. Wherein the heteroaryl group may be (C)3-C8) Heteroaryl, furan, pyridine, and the like.
When R is1、R2And R3Are identical or different (C)2-C20) Alkenyl (C)1-C20) When it is an alkyl group, in one embodiment, the group (C)2-C20) Alkenyl (C)1-C20) The alkyl group may be (C)2-C10) Alkenyl (C)1-C10)、(C2-C5) Alkenyl (C)1-C3). In certain embodiments, the (C)2-C20) Alkenyl (C)1-C20) The alkyl group may be 2-butenyl, 2-pentenyl, 3-hexenyl, 3-heptenyl, etc.
When R is1、R2And R3Are identical or different (C)2-C20) Alkynyl (C)1-C20) When it is an alkyl group, in one embodiment, the group (C)2-C20) Alkynyl (C)1-C20) The alkyl group may be (C)2-C10) Alkynyl (C)1-C10) Alkyl, (C)2-C5) Alkynyl (C)1-C3) An alkyl group. In certain embodiments, the (C)2-C20) Alkynyl (C)1-C20) The alkyl group may be 2-butynyl, 2-pentynyl, 3-hexynyl, 3-heptynyl, etc.
When R is1、R2And R3Are identical or different cyano groups (C)1-C20) Alkyl, in one embodiment, the cyano (C)1-C20) The alkyl group may be cyano (C)1-C10) Alkyl, cyano (C)1-C5) Alkyl, cyano (C)1-C4) Alkyl, cyano (C)1-C3) Alkyl, cyano (C)1-C2) Alkyl groups, and the like. In certain embodiments, cyano (C)1-C20) The alkyl group may be cyanomethyl, cyanoethyl, cyanopropyl, cyanobutyl, cyanopentyl, or the like.
When R is1、R2And R3Are identical or different C1-C20Alkyloxycarbonyl (C)1-C20) When it is alkyl, in one embodiment, the C1-C20Alkyloxycarbonyl (C)1-C20) The alkyl group may be (C)1-C10) Alkyloxycarbonyl (C)1-C10) Alkyl, (C)1-C5) Alkyloxycarbonyl (C)1-C5) Alkyl, (C)1-C4) Alkyloxycarbonyl (C)1-C4) Alkyl, (C)1-C3) Alkyloxycarbonyl (C)1-C3) Alkyl, (C)1-C2) Alkyloxycarbonyl (C)1-C2) Alkyl groups, and the like. In some embodiments, the alkyloxycarbonylalkyl group can be an ethoxycarbonylethyl group, ethoxycarbonylmethyl group, methoxycarbonylethyl group, methoxycarbonylmethyl group, propoxycarbonylpropyl group, propoxycarbonylethyl group, propoxycarbonylmethyl group, and the like.
In some embodiments, R1、R2And R3Are identical or different C1-C10Alkyl radical, C1-C10Heteroalkyl group, C3-C10Cycloalkyl radical, C3-C10Heterocycloalkyl radical, C2-C10Alkenyl radical, C2-C10Heteroalkenyl, C3-C10Cycloalkenyl radical, C3-C10Heterocycloalkenyl, C2-C10Alkynyl, C2-C10Heteroalkynyl, C3-C10Cycloalkynyl group, C3-C10Heterocycloalkynyl, C1-C10Alkoxy radical, C1-C10Alkyloxycarbonyl (C)1-C10) Alkyl radical, C3-C8Aryl radical (C)1-C10) Alkyl radical, C2-C10Alkenyl (C)1-C10) Alkyl radical, C2-C10Alkynyl (C)1-C10) Alkyl, cyano (C)1-C10) Alkyl, substituted (C)3-C8) Aryl group, (C)3-C8) Heteroaryl, substituted (C)3-C8) Any one of heteroaryl groups.
In some embodiments, R1、R2And R3Is C1-C5Alkyl radical, C1-C5Alkyloxycarbonyl (C)1-C5) Alkyl, phenyl (C)1-C3) Alkyl radical, C2-C5Alkenyl (C)1-C3) Alkyl radical, C2-C5Alkynyl (C)1-C3) Alkyl, cyano (C)1-C3) Alkyl, halogen-substituted phenyl, alkoxy-substituted furan, alkoxy-substituted pyridine, C3-C8Heteroaryl-substituted phenyl, C3-C8Heteroaryl substituted furans and C3-C8Any one of heteroaryl substituted pyridines.
Further, the chiral beta-diester selenoethers comprise at least one of the following structural formulas I1-I3:
the chiral beta-diester selenide compounds provided by the embodiment of the application have structural diversity and can be widely applied to synthesis of drug intermediates, particularly malonate products and preparation of functional materials. The chiral beta-diester selenide compound has high functional group, so that diversified choices can be provided for the application of the chiral selenide in the synthesis of drug intermediates and functional materials.
The chiral beta-diester selenide compounds provided by the embodiment of the application can be prepared by the following method.
The second aspect of the embodiments of the present application provides a method for preparing a chiral β -diester selenide compound by Michael addition, which includes the following steps:
s01, providing a selenol compound A and an alkene diester compound B shown in the following structural general formulas:
A：R1-SeH B：
s02, adding the selenol compound A and the alkene diester compound B into a reaction system containing a nitrogen heterocyclic carbene catalyst, an alkali reagent and a water absorption additive, and reacting at the temperature of-100-25 ℃ to obtain the chiral beta-diester selenide compound shown in the formula I.
Specifically, in step S01, R in the molecular structural formula of selenol compound a is1The group represented by the formula and the R in the molecular structure general formula I of the chiral beta-diester selenide compound1The groups represented are the same. R in the molecular structural formula of diester compound B2、R3The group represented by the formula and R in the structural general formula I of the chiral beta-carbon-based selenide compound2、R3The groups represented are the same. For economy of disclosure, further description is omitted here.
The selenol compound a and the alkene diester compound B in step S01 may be prepared by themselves in accordance with a conventional preparation method, or may be directly obtained commercially.
The reactant raw materials provided by the embodiment of the application are very easy to obtain, and the reactant before reaction does not need to be additionally modified and can be directly used for preparation production, so that the operation steps are simplified, and the reaction route is shortened; the production cost is obviously reduced.
In step S02, it is known from the structural formula of the reactant alkene diester compound B that the reactant selenol compound a acts as a nucleophile and attacks the alkene diester substrate, so that the two reactants undergo a conjugate addition reaction. Therefore, the atom utilization rate of reactants is effectively improved, the limitation of a substrate can be widened, and the target product precursor with high enantioselectivity and extremely wide range is efficiently and greenly prepared, so that the chiral beta-diester selenide compound with potential application value is obtained through simple reduction reaction.
The conjugate addition reaction formula of the selenol compound a and the alkene diester compound B in the step S02 in the reaction environment and system in the step S02 is as follows:
in the chemical reaction formula, the nitrogen heterocyclic carbene catalyst, the alkali reagent and the water absorption additive act synergistically, so that the catalytic system is low in toxicity, the atom utilization rate and the reaction efficiency are improved, and byproducts are few; meanwhile, the reaction process is safe and controllable, and the operation in the preparation production process is simplified. The N-heterocyclic carbene catalyst can provide better non-covalent bond interaction, so that the enantiomeric excess (ee) value of a product is improved in the catalytic reaction process; the base reagent is used to react with the azacyclocarbene catalyst to deprotonate the azacyclocarbene reagent to form an activated protic base catalyst. The contents of the three components are in a certain range under a certain proportion condition, so that the reaction has high catalytic efficiency, and a target product with nearly single absolute configuration is obtained.
In order to make the synergistic catalytic system exert more effective catalytic action, in one embodiment, the molar ratio of the N-heterocyclic carbene catalyst to the alkali reagent is (0.1-20): (0.1-20). Under the condition, under the synergistic action of the N-heterocyclic carbene catalyst and the alkali reagent, the reaction has high catalytic efficiency, and the ee value of a reaction product is favorably improved. Preferably, the molar ratio of the N-heterocyclic carbene catalyst to the alkali reagent is (0.2-20):2 (1-10), and in this case, the target product with nearly single absolute configuration is favorably obtained. In another embodiment, the molar ratio of the azacyclocarbene catalyst to the alkali reagent is 1 (1-9). In another embodiment, the molar ratio of the N-heterocyclic carbene catalyst to the alkali reagent is 1 (1-8). In another embodiment, the molar ratio of the N-heterocyclic carbene catalyst to the alkali reagent is 1 (1-7). In another embodiment, the molar ratio of the N-heterocyclic carbene catalyst to the alkali reagent is 1 (1-6). In another embodiment, the molar ratio of the N-heterocyclic carbene catalyst to the alkali reagent is 1 (1-5). In another embodiment, the molar ratio of the N-heterocyclic carbene catalyst to the alkali reagent is 1 (1-4). In another embodiment, the molar ratio of the N-heterocyclic carbene catalyst to the alkali reagent is 1 (1-3). In another embodiment, the molar ratio of the N-heterocyclic carbene catalyst to the alkali reagent is 1 (1-2). In one embodiment, the molar ratio of azacyclocarbene catalyst to base reagent is 1: 1.
In one embodiment, the mole ratio of the N-heterocyclic carbene catalyst, the alkali reagent and the selenol compound A is (0.1-20): (0.2-40). In this case, the reaction has high catalytic efficiency, which is beneficial to improving the ee value of the reaction product. In some embodiments, the addition amount of the N-heterocyclic carbene catalyst and the alkali reagent in the reaction system is controlled to be the molar ratio of the N-heterocyclic carbene catalyst to the selenol compound A (0.2-20) to 2 (1-10).
In some embodiments, the azacyclo-carbene catalyst is at least one of a triazole azacyclo-carbene or a bifunctional azacyclo-carbene catalyst. In specific experiments, the bifunctional N-heterocyclic carbene catalyst can catalyze the reaction to be carried out more efficiently, but different carbene catalysts can cause products to have different enantioselectivities. In one embodiment, the azacyclo-carbene catalyst is selected from nitrogen-containing heterocyclic compounds represented by the following structural formula C and/or structural formula D:
C：D：
in the structural general formulas C and D, X is identical or different boron tetrafluoride anions or chloride ions, and Y in the structural general formula D is an oxygen atom or a sulfur atom; r4、R5And R6Are identical or different aryl radicals (C)1-C20) Alkyl, heteroaryl (C)1-C20) Any of alkyl, aryl, and substituted aryl.
Further, the alkali agent is at least one selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1,5, 7-triazabicyclo (4.4.0) dec-5-ene, triethylamine, diisopropylethylamine, bistrimethylsilyl lithium, bistrimethylsilyl sodium, bistrimethylsilyl potassium, diisopropylamino lithium, n-butyllithium, t-butyllithium, methyllithium, sodium methoxide, sodium ethoxide and sodium ethylmercaptide.
In the reaction process of step S02 in the embodiment of the present application, the presence of water molecules easily disturbs the highly ordered transition state intermediate through hydrogen bond interaction, so that the embodiment of the present application introduces a water absorption additive into the reaction system to remove water in the reaction system, thereby effectively improving the enantioselectivity of the target product; meanwhile, the water absorption additive can ensure that the reaction system is in an anhydrous state, and under the condition, the alkali reagent cannot be quenched during reaction. In one embodiment, the water absorbing additive is selected from at least one of the following: anhydrous sodium sulfate, anhydrous magnesium sulfate, preactivated 13X molecular sieve,Molecular sieve,Molecular sieves andand (3) a molecular sieve. Wherein, the preactivated 13 × molecular sieve is the molecular sieve obtained by heating and dehydrating the 13 × molecular sieve. The water absorbing additive is mainly used for controlling the anhydrous requirement of the reaction system, so the water absorbing additive can be used according to the reaction time and the solvent of the specific reaction systemProperties, etc., such as sufficient addition to achieve hydration free reaction system. In one embodiment, the ratio of the water absorbing additive enumerated above to the solvent for the reactant is controlled to 100 mg/mL.
In conclusion, in the preparation process of the chiral beta-diester selenide compound, the nitrogen heterocyclic carbene, the alkali reagent and the water absorbing reagent have synergistic effect, so that the catalytic system has low toxicity, high atom utilization rate and production efficiency, safe and controllable reaction process, and simplified operation in the preparation production process. Meanwhile, in a reaction system containing the N-heterocyclic carbene, the alkali reagent and the water absorbing reagent, the toxicity of the reaction residues is reduced to the minimum, the pollution to the environment in the production process is reduced, and the steps and the operation for removing the residues after the reaction are simplified. In addition, the proportion and the addition amount of the azacarbene catalyst, the alkali reagent and the reactant are flexibly adjusted, so that the high atom utilization rate and the production efficiency are further improved, and the production of byproducts is reduced.
The reaction temperature range applicable to the reaction system in the embodiment of the application is-100 ℃ to 25 ℃. In order to further improve the reaction efficiency and the enantioselectivity of the reaction product, in one embodiment, the reaction temperature of the reaction system is-100 ℃ to-40 ℃. In another embodiment, the reaction temperature of the reaction system is from-40 ℃ to-20 ℃. In another embodiment, the reaction temperature of the reaction system is-20 ℃ to 0 ℃. In another embodiment, the reaction temperature of the reaction system is 0 ℃ to 10 ℃. In another embodiment, the reaction temperature of the reaction system is 10 ℃ to 25 ℃. The reaction time in the environment of the temperature of each preferred reaction should be such that the above reactants are sufficiently reacted, for example, the reaction time may be 6 to 48 hours, or longer.
In the above reaction system, a certain amount of solvent is optionally added. Such solvents include, but are not limited to, diethyl ether, tetrahydrofuran, dichloromethane, toluene. In one embodiment, the solvent is added in a molar ratio of solvent to catalyst such that (1000- > 1000000): 1.
the chiral beta-diester selenide compounds provided by the embodiment of the application or the chiral beta-diester selenide compounds prepared by the Michael addition method have high functional group property, and can be widely applied to the research fields of organic synthetic chemistry, biochemistry, asymmetric catalysis, pesticides and medicines.
The following description will be given with reference to specific examples.
Example 1
This example provides (R) -2- (2- (hexylseleno) -2- (4-methoxyphenyl) ethyl) malonic acid diethyl ester and a preparation method thereof. The structural formula of the ((R) -2- (2- (hexylseleno) -2- (4-methoxyphenyl) ethyl) diethyl malonate is shown as the following molecular structural formula I1:
the preparation method comprises the following steps:
triazole carbene-thiourea bifunctional catalyst (0.01mmol, 0.1 equivalent (equiv.)), 13X molecular sieve (100mg) and n-hexylselenol nucleophile (0.2mmol, 2.0 equiv.)) were dissolved in 1.2mL of the mixed solvent of the pretreated diethyl ether, sealed with a rubber stopper, and then gas was replaced under argon atmosphere (3 times), bis (trimethylsilyl) aminolithium (LiHMDS) (1mol/L, tetrahydrofuran/ethylbenzene solution, 10 μ L, 0.10 equiv.)) was slowly added, and gas was replaced again under argon atmosphere (3 times). The tube was sealed with a sealing film and then stirred at-90 ℃ for 1 hour. Diethyl (E) -2- (4-methoxystyryl) malonate (0.10mmol, 1.0equiv.) was prepared as a solution of diethyl ether (0.6mL), and slowly injected using an injection pump (3 hours injection time), after which the mixture was reacted at-90 ℃ for 24 hours. After complete consumption of chalcone, the mixture was directly purified by column chromatography on silica gel (ethyl acetate and n-hexane as eluent) to give the desired product, and the enantioselectivity of the product was determined by chiral HPLC to give the desired product I1 in 95% yield and 90% ee.
The result of the correlation characterization analysis is as follows:1H NMR(400MHz,CD2Cl2)δ7.23(d,J＝8.7Hz,2H),6.83(d,J＝8.7Hz,2H),4.53(d,J＝11.7Hz,1H),4.25(qd,J＝7.1,3.5Hz,2H),4.04-3.87(m,3H),3.79(s,3H),2.58-2.26(m,2H),1.57-1.44(m,2H),1.32(t,J＝7.1Hz,3H),1.30-1.17(m,6H),1.02(t,J＝7.1Hz,3H),0.87(t,J＝7.0Hz,3H).13C NMR(101MHz,CD2Cl2)δ167.43,166.85,158.85,132.64,129.22,113.70,61.94,61.58,59.13,55.30,40.15,31.37,30.20,29.66,25.12,22.61,13.99,13.90,13.70.HRMS(ESI-TOF)[M+Na]calculated for[C21H32O5SeNa]+467.1307,observed 467.1308.Specific Rotation[α]D 25＝-70.6(c＝1.0in CH2Cl2) HPLC (Chiralpak-AD-H column, ethanol/hexane ═ 2.5/97.5,1.0mL/min): t (minor) 18.088min, t (major) 12.825min.
Example 2
This example provides (R) -2- (2- (4-methoxyphenyl) -2- (neopentyl seleno) ethyl) malonic acid diethyl ester and a preparation method thereof. The structural formula of the (R) -2- (2- (4-methoxyphenyl) -2- (neopentyl seleno) ethyl) diethyl malonate is shown as the following molecular structural formula I2:
the preparation method refers to the preparation method of (R) -2- (2- (hexylseleno) -2- (4-methoxyphenyl) ethyl) diethyl malonate in example 1, and is different from the preparation method of (R) -2- (2- (hexylseleno) -2- (4-methoxyphenyl) ethyl) diethyl malonate by adopting neopentyl selenol (0.2mmol) instead of n-hexylselenol. The reaction solution is directly separated and purified by silica gel column chromatography (ethyl acetate and normal hexane are used as eluent) to obtain the target product, colorless liquid, the yield is 96 percent, and the ee value is 95 percent.
The product I2 prepared was subjected to characterization data analysis, the result of which was1H NMR(400MHz,CD2Cl2)δ7.23(d,J＝8.6Hz,2H),6.83(d,J＝8.6Hz,2H),4.45(d,J＝11.7Hz,1H),4.30-4.17(m,2H),4.03-3.87(m,3H),3.79(s,3H),2.43(s,2H),1.33(t,J＝7.1Hz,3H),1.01(t,J＝7.1Hz,3H),0.90(s,9H).13C NMR(101MHz,CD2Cl2)δ167.40,166.81,158.84,132.66,129.40,113.64,61.94,61.57,59.37,55.30,41.16,41.05,31.94,29.18,14.00,13.69..HRMS(ESI-TOF)[M+Na]calculated for[C20H30O5SeNa]+453.1151,observed 453.1152.Specific Rotation[α]D 25＝-81.3(c＝1.0in CH2Cl2) HPLC (Chiralpak-IC-H column, ethanol/hexane ═ 1/99,1.0mL/min): t (minor) -10.685 min, t (major) -8.931 min.
Example 3
This example provides diethyl 2- ((R) -2- (4-methoxyphenyl) -2- (((S) -2-methylbutyl) seleno) ethyl) malonate and a method for preparing the same. The structural formula of diethyl 2- ((R) -2- (4-methoxyphenyl) -2- (((S) -2-methylbutyl) seleno) ethyl) malonate is shown as the following molecular structural formula I3:
the preparation method is as follows (R) -2- (2- (hexylseleno) -2- (4-methoxyphenyl) ethyl) diethyl malonate preparation method in example 1, except that (S) -2-methylbutane-1-selenol (0.2mmol) is adopted to replace cyclopentylselenol. The reaction solution is directly separated and purified by silica gel column chromatography (ethyl acetate and normal hexane are used as eluent) to obtain a target product, namely a colorless liquid, the yield is 96 percent, and the de value is 90 percent.
The product I3 prepared was subjected to characterization data analysis, which resulted in:1H NMR(400MHz,CD2Cl2)δ7.23(d,J＝8.7Hz,2H),6.83(d,J＝8.7Hz,2H),4.50(d,J＝11.7Hz,1H),4.25(qd,J＝7.1,4.0Hz,2H),4.04-3.88(m,3H),3.79(s,3H),2.46(dd,J＝11.8,6.0Hz,1H),2.33(dd,J＝11.8,7.2Hz,1H),1.50-1.43(m,1H),1.35-1.28(m,4H),1.18-1.10(m,1H),1.02(t,J＝7.1Hz,3H),0.89-0.78(m,6H).13C NMR(101MHz,CD2Cl2)δ167.43,166.84,158.85,132.67,129.28,113.69,61.93,61.57,59.22,55.30,40.55,35.42,32.97,29.40,19.46,13.99,13.69,11.19.HRMS(ESI-TOF)[M+Na]calculated for[C20H30O5SeNa]+453.1151,observed 451.1149.Specific Rotation[α]D 25＝-69.0(c＝1.0in CH2Cl2) HPLC (Chiralpak-IC-H column, ethanol/hexane ═ 2.5/97.5,1.0mL/min): t (minor) 21.237min, t (major) 13.610min.
The above description is only exemplary of the present application and should not be taken as limiting the present application, as any modification, equivalent replacement, or improvement made within the spirit and principle of the present application should be included in the protection scope of the present application.
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