CN112409408A - Chiral phosphorus sulfur compound and Michael addition method thereof - Google Patents

Chiral phosphorus sulfur compound and Michael addition method thereof Download PDF

Info

Publication number
CN112409408A
CN112409408A CN202011294694.6A CN202011294694A CN112409408A CN 112409408 A CN112409408 A CN 112409408A CN 202011294694 A CN202011294694 A CN 202011294694A CN 112409408 A CN112409408 A CN 112409408A
Authority
CN
China
Prior art keywords
radical
alkyl
group
heteroaryl
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202011294694.6A
Other languages
Chinese (zh)
Inventor
黄湧
陈杰安
李恩
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Bay Laboratory Pingshan Biomedical R & D And Transformation Center
Original Assignee
Shenzhen Bay Laboratory Pingshan Biomedical R & D And Transformation Center
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenzhen Bay Laboratory Pingshan Biomedical R & D And Transformation Center filed Critical Shenzhen Bay Laboratory Pingshan Biomedical R & D And Transformation Center
Priority to CN202011294694.6A priority Critical patent/CN112409408A/en
Publication of CN112409408A publication Critical patent/CN112409408A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
    • C07F9/5333—Arylalkane phosphine oxides or thioxides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
    • C07F9/5325—Aromatic phosphine oxides or thioxides (P-C aromatic linkage)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/59—Hydrogenated pyridine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
    • C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)

Abstract

The application relates to the technical field of organic compound synthesis, and provides a chiral phosphorus-sulfur compound and a Michael addition method thereof. The Michael addition method of the chiral phosphorus-sulfur compound comprises the following steps: respectively providing a phosphorus-sulfur compound A and a nitroolefin compound B shown in the following structures: a:
Figure DDA0002784881730000011
B：
Figure DDA0002784881730000012
adding the phosphorus-sulfur compound A and the nitroolefin compound B into a catalyst containing nitrogen heterocyclic carbene, a proton additive, an alkali reagent and a getterIn the reaction system of the water additive, the chiral beta-nitro-phosphorus-sulfur compound shown in the following structural general formula (I) is obtained by reacting at the temperature of-80 ℃ to 25 ℃,

Description

Chiral phosphorus sulfur compound and Michael addition method thereof
Technical Field
The application belongs to the technical field of organic compound synthesis, and particularly relates to a chiral phosphorus-sulfur compound and a Michael addition method thereof.
Background
The organic phosphorus compound is a very useful functional compound and has wide application prospect in the fields of organic synthetic chemistry, biochemistry, asymmetric catalysis, pesticides and medicine research. With the rapid development of asymmetric synthesis technology, the organophosphate compounds with chiral centers attract considerable attention of chemists due to the potential biological activity thereof, and the enantioselective synthesis thereof also achieves remarkable results.
The chiral phosphate compound can be used as a synthetic intermediate to participate in asymmetric organic catalytic conversion, or can be used as a ligand to participate in metal-catalyzed asymmetric reaction. The asymmetric catalytic reaction of the phosphorus-containing nucleophilic reagent added to various electrophilic reagents provides a direct and convenient way for synthesizing the chiral phosphorus-containing compounds. The asymmetric phosphorus Michael reaction (Michael reaction) is one of the most efficient means for synthesizing this class of compounds from the point of view of methodology and atom economy, and this type of phosphorus Michael reaction has been attracting much attention from chemists.
At present, the catalysts adopted by the existing asymmetric phosphorus Michael addition comprise quinoline, thiourea and guanidine, and a method for preparing an asymmetric phosphorus-containing compound by directly selecting a chiral substrate is also available. However, these methods have a number of disadvantages, such as: 1) asymmetric addition of heteroatom-containing nucleophiles to beta, beta-disubstituted nitroolefins has not been achieved; 2) nucleophiles are limited to phosphate or phosphorus oxygen compounds; 3) the activation mode is single; 4) high yields and high enantioselectivities of the product cannot be achieved simultaneously. Therefore, there is a need for a new synthesis method that overcomes the drawbacks of the prior art, particularly those described above.
Disclosure of Invention
The application aims to provide a chiral phosphorus-sulfur compound and a Michael addition method thereof, and aims to solve the problems that in the existing asymmetric phosphorus Michael addition, the reaction based on a beta, beta-disubstituted Michael acceptor is limited, the type of a phosphorus-sulfur compound as a nucleophilic reagent is limited, and the activation mode is single.
In order to achieve the purpose of the application, the technical scheme adopted by the application is as follows:
in a first aspect, the present application provides a chiral phosphorus-sulfur compound, a water absorption additive, and a chiral phosphorus-sulfur compound represented by the following structural formula (i):
Figure BDA0002784881720000011
in the formula, 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 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) Any one of an alkyl group and an alkyloxycarbonylalkyl group;
R4is hydrogen atom, cyano, C1-C20Ester group, C1-C20Heteroalkyl group, C1-C20Perfluoroalkyl radical, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Heteroalkenyl, C2-C10Alkynyl, C2-C10Heteroalkynyl, C3-C8Aryl radical (C)1-C10) Alkyl radical, C2-C10Alkenyl (C)1-C10) Alkyl radical, C2-C10Alkynyl (C)1-C10) Any of alkyl groups.
In some embodiments, the water absorbing additive 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 radical (C)3-C8) Aryl, substituted (C)3-C8) Aryl group, (C)3-C8) Heteroaryl, substituted (C)3-C8) Any of heteroaryl groups.
In some embodiments, the water absorbing additive R4Is a hydrogen atom, C1-C5Perfluoroalkyl radical, C1-C5Ester group, C1-C10Any one of heteroalkyl groups.
In some embodiments, the water absorbing additive 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, alkoxySubstituted phenyl, alkoxy substituted furan, alkoxy substituted pyridine, C3-C8Heteroaryl-substituted phenyl, C3-C8Heteroaryl substituted furans, C3-C8Any of heteroaryl substituted pyridines; and/or
Water-absorbing additive R4Is hydrogen atom, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, heptafluoroisopropyl, C1-C10Alkoxyalkyl group, (C)1-C10) Alkyloxycarbonyl (C)1-C10) Any of alkyl groups.
The chiral beta-nitro phosphorus sulfur compound shown in the structural general formula (I) of the water absorption additive comprises one of the following structural formulas I1-I21:
Figure BDA0002784881720000021
Figure BDA0002784881720000031
Figure BDA0002784881720000041
in a second aspect, the present application provides a Michael addition method of a chiral phosphine sulfide compound, comprising the steps of:
respectively providing a phosphorus-sulfur compound A and a nitroolefin compound B shown in the following structures:
A：
Figure BDA0002784881720000042
B：
Figure BDA0002784881720000043
adding a water-absorbing additive phosphorus sulfur compound A and a water-absorbing additive nitroolefin compound B into a reaction system containing a nitrogen heterocyclic carbene catalyst, a proton additive, an alkali reagent and a water-absorbing additive, and reacting at the temperature of-80-25 ℃ to obtain a chiral beta-nitro phosphorus sulfur compound shown in the following structural general formula (I),
Figure BDA0002784881720000044
wherein, in the phosphorus-sulfur compound A of the water absorption additive and the chiral beta-nitro phosphorus-sulfur compound of the water absorption additive, R1、R2Are 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) Any one of an alkyl group and an alkyloxycarbonylalkyl group;
in the water-absorbing additive nitroolefin compound B and the water-absorbing additive chiral beta-nitrophosphite sulfur compound R3Is a reaction with R1、R2Identical 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) Any one of an alkyl group and an alkyloxycarbonylalkyl group; r4Is hydrogen atom, cyano, C1-C20Perfluoroalkyl radical, C1-C20Ester group, C1-C20Heteroalkyl group, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Heteroalkenyl, C2-C10Alkynyl, C2-C10Heteroalkynyl, C3-C8Aryl radical (C)1-C10) Alkyl radical, C2-C10Alkenyl (C)1-C10) Alkyl radical, C2-C10Alkynyl (C)1-C10) Any of alkyl groups.
In some embodiments, the water absorbing additive 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 radical (C)3-C8) Aryl, substituted (C)3-C8) Aryl group, (C)3-C8) Heteroaryl, substituted (C)3-C8) Any of heteroaryl groups.
In some embodiments, the water absorbing additive R4Is a hydrogen atom, C1-C5Perfluoroalkyl radical, C1-C5Ester group, C1-C10Any one of heteroalkyl groups.
In some embodiments, the water absorbing additive 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, C3-C8Any one of heteroaryl substituted pyridines.
In some embodiments, the water absorbing additive R4Is hydrogen atom, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, heptafluoroisopropyl, C1-C10Alkoxyalkyl group, (C)1-C10) Alkyloxycarbonyl (C)1-C10) Any of alkyl groups.
In some embodiments, the water absorbing additive azacyclo-carbene catalyst, the water absorbing additive base reagent, and the water absorbing additive protic additive are present in a molar ratio of (0.1-20): (0.2-40).
In some embodiments, the water absorbing additive azacyclo-carbene catalyst, the water absorbing additive alkaline agent, the water absorbing additive protic additive, and the water absorbing additive compound a are present in a molar ratio of (0.1-20): (0.2-40): (1-100).
In some embodiments, the water absorbing additive azacyclo-carbene catalyst is selected from nitrogen-containing heterocyclic compounds represented by the following structural formula C and/or structural formula D:
C：
Figure BDA0002784881720000051
D：
Figure BDA0002784881720000052
wherein X in the structural general formula C of the water absorption additive is carbon atom or oxygen atom, and n is 0 or 1;
in the general structural formulas C and D, Z is identical or different boron tetrafluoride anion or chloride ion, R5Is 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, (C)2-C20) Alkenyl (C)1-C20) Alkyl, (C)2-C20) Alkynyl (C)1-C20) Alkyl, cyano (C)1-C20) Any of alkyl groups; r6And R7Are identical or different C1-C20Alkyl radical, C1-C20Heteroalkyl, aryl (C)1-C20) Alkyl, heteroaryl (C)1-C20) Any of alkyl, aryl, and substituted aryl.
In some embodiments, the water-absorbing additive base agent is at least one of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, 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, diisopropyllithium, n-butyllithium, t-butyllithium, methyllithium, sodium methoxide, sodium ethoxide, sodium ethylmercaptide.
In some embodiments, the water absorbing additive is at least one of the compounds represented by the following structures:
Figure BDA0002784881720000061
in some embodiments, the water absorbing additive is anhydrous sodium sulfate, anhydrous magnesium sulfate, a pre-activated 13 × molecular sieve, a zeolite,
Figure BDA0002784881720000062
molecular sieve,
Figure BDA0002784881720000063
Molecular sieves and
Figure BDA0002784881720000064
at least one of molecular sieves.
In a third aspect, the present application provides the use of the chiral phosphorothioic compound or the chiral phosphorothioic compound prepared by the Michael addition method in the synthesis of pharmaceutical intermediates, the preparation of functional materials, metal ligands and metal complexes.
The chiral phosphorus-sulfur compound provided by the application can provide raw materials or reaction intermediates for synthesis of drug intermediates and preparation of functional materials, metal ligands and metal complexes; and because the water absorption additive chiral phosphorus sulfur compound has high functional group, the method can provide diversified choices for the chiral phosphorus sulfur compound in the synthesis of drug intermediates, the application of functional materials, metal ligands and metal compounds.
The Michael addition method of the chiral phosphorus-sulfur compound provided by the application provides a novel construction method of an asymmetric C-P bond, and the method has the following advantages:
firstly, the application adopts an organic micromolecular asymmetric catalytic system to realize Michael addition of the chiral phosphorus-sulfur compound.
Secondly, according to the Michael addition method, on one hand, a simple phosphorus-sulfur compound reagent is used as a nucleophilic reagent to attack a common nitroolefin substrate (beta position can be disubstituted or monosubstituted), so that a target product precursor with high enantioselectivity and an extremely wide range is efficiently and greenly prepared, and a beta-nitrophosulfur compound with potential application is obtained; on the other hand, the reactants adopt simple and easily obtained phosphorus-sulfur compounds and commercialized nitroolefins as the reactants, the raw materials are very easy to obtain, and the reactants 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 phosphorus-sulfur compound is a conjugate addition reaction, so that the atom utilization rate and the reaction efficiency of reactants are high, the generation yield of a reaction product is favorably improved, in addition, the phosphorus-sulfur compound A and the nitroolefin compound B are prepared by one-step reaction in a reaction system containing a nitrogen heterocyclic carbene catalyst, a proton additive, 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-nitro-phosphorus-sulfur compound, and also greatly expands the designability and application prospect of the compound. 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, the application of a functional material, a metal ligand and a metal compound, can be widely used for the synthesis of the drug intermediate and the preparation of a chiral ligand and 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.
The chiral phosphorus-sulfur compound or the chiral phosphorus-sulfur compound prepared by the Michael addition method has high functional group property, and can be widely applied to the fields of organic synthetic chemistry, biochemistry, asymmetric catalysis, pesticides and medicine research, such as the fields of synthesis of pharmaceutical intermediates, particularly compounds containing the quaternary carbon center structure, and preparation of functional materials.
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.
In a first aspect, the embodiments of the present application provide a chiral phosphorus-sulfur compound, which is a water absorption additive, and is represented by the following structural formula (i):
Figure BDA0002784881720000091
in the general structural 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 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) Any one of an alkyl group and an alkyloxycarbonylalkyl group.
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 methyl, ethyl, propyl, butyl, iso-butylButyl, pentyl, isopentyl, and the like.
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 group, (C)3-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 embodiments, (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、R2And 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, in one instanceIn the examples, (C)2-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 may be cyclopropynyl, cyclobutynyl, cyclopentynyl, or 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 water-absorbing additive aryl group may be, but is not limited to, a monocyclic aryl group, a polycyclic aryl groupAryl, fused ring aryl. In one embodiment, the aryl group is a monocyclic aryl group. In some embodiments, aryl is phenyl.
When R is1、R2And R3When the aryl groups are the same or different, the aryl groups substituted by the water-absorbing additive 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, -NR5R6、-NR5-CO-NR6、-OCONR5、-PR5R6、-SOR5、-SO2-R5、-SiR5R6R7、-BR5R6Wherein R is5、R6、R7Which may be the same or different is as R above1、R2The groups shown. Wherein, when the substituent is alkyl, the water absorbing additive is 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, the water absorbing additive halogen is, for example, 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 may be phenylmethyl, phenylethyl, phenylpropyl, phenylbutyl, phenylisobutyl, phenylpentyl, phenylisopentyl, phenylneopentyl.
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 beIs 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 R3When the alkyl groups are the same or different alkyl oxycarbonylalkyl groups, in one embodiment, the alkyl oxycarbonylalkyl groups 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 ethoxycarbonylethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, methoxycarbonyl-ethylAlkylcarbonylmethyl, propoxycarbonylpropyl, propoxycarbonylethyl, propoxycarbonylmethyl and the like.
In some embodiments, the water absorbing additive 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 radical (C)3-C8) Aryl, substituted (C)3-C8) Aryl group, (C)3-C8) Heteroaryl, substituted (C)3-C8) Any of heteroaryl groups.
In some embodiments, the water absorbing additive 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, C3-C8Any one of heteroaryl substituted pyridines.
In the general structural formula (I), R4Is hydrogen atom, cyano, C1-C20Ester group, C1-C20Heteroalkyl group, C1-C20Perfluoroalkyl radical, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Heteroalkenyl, C2-C10Alkynyl, C2-C10Heteroalkynyl, C3-C8Aryl radical (C)1-C10) Alkyl radical, C2-C10Alkenyl (C)1-C10) Alkyl radical, C2-C10Alkynyl (C)1-C10) Any of alkyl groups. The general formula (I) in this case is easy to construct quaternary carbon center, and has good reactivity when used for synthesis of drug intermediates, preparation of functional materials, metal ligands and metal complexes.
When R is4Is C1-C20When there is perfluoroalkyl group, C1-C20The perfluoroalkyl group may be trifluoromethyl, pentafluoroethyl, heptafluoropropyl, heptafluoroisopropyl, etc. Under the condition, the structural general formula (I) contains fluoroalkyl, so that the composite has better biocompatibility and higher medicinal value, and can be used for synthesizing a medicinal intermediate.
When R is4Is C1-C20In the case of an ester group, C1-C20The ester group can be methyl ester, ethyl ester, propyl ester, isopropyl ester, n-butyl ester, etc.
When R is4Is C1-C20When it is heteroalkyl, C1-C20The heteroalkyl group may be C1-C10Alkoxyalkyl group, (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 water absorbing additive R4Is a hydrogen atom, C1-C5Perfluoroalkyl radical, C1-C5Ester group, C1-C10Any one of heteroalkyl groups.
Water-absorbing additive R4Is hydrogen atom, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, heptafluoroisopropyl, C1-C10Alkoxyalkyl group, (C)1-C10) Alkyloxycarbonyl (C)1-C10) Any of alkyl groups.
The chiral beta-nitro phosphorus sulfur compound provided by the embodiment of the application has structural diversity, and can be widely applied to the synthesis of pharmaceutical intermediates, particularly heterocyclic compounds and the preparation of functional materials.
In some embodiments, the chiral β -nitrophosphite sulfur compound of the general structural formula (I) of the water absorbing additive comprises one of the following structural formulas I1 to I21:
Figure BDA0002784881720000121
Figure BDA0002784881720000131
the chiral phosphorus-sulfur compound provided by the embodiment of the application can provide raw materials or reaction intermediates for synthesis of drug intermediates and preparation of functional materials, metal ligands and metal compounds; and because the water absorption additive chiral phosphorus sulfur compound has high functional group, the method can provide diversified choices for the chiral phosphorus sulfur compound in the synthesis of drug intermediates, the application of functional materials, metal ligands and metal compounds.
The chiral phosphorus-sulfur compound provided by the embodiment of the application can be prepared by the following method.
In a second aspect, the present application provides a Michael addition method for chiral phosphine-sulfur compounds, comprising the following steps:
s01, respectively providing a phosphorus-sulfur compound A and a nitroolefin compound B shown in the following structures:
A：
Figure BDA0002784881720000141
B：
Figure BDA0002784881720000142
s02, adding a water absorption additive phosphorus sulfur compound A and a water absorption additive nitroolefin compound B into a reaction system containing an N-heterocyclic carbene catalyst, a proton additive, an alkali reagent and a water absorption additive, and reacting at a temperature of-80-25 ℃ to obtain a chiral beta-nitro phosphorus sulfur compound shown in the following structural general formula (I),
Figure BDA0002784881720000143
wherein, in the phosphorus-sulfur compound A of the water absorption additive and the chiral beta-nitro phosphorus-sulfur compound of the water absorption additive, R1、R2Are 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) Any one of an alkyl group and an alkyloxycarbonylalkyl group;
in the water-absorbing additive nitroolefin compound B and the water-absorbing additive chiral beta-nitrophosphite sulfur compound R3Is a reaction with R1、R2Identical 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) Any one of an alkyl group and an alkyloxycarbonylalkyl group; r4Is hydrogen atom, cyano, C1-C20Perfluoroalkyl radical, C1-C20Ester group, C1-C20Heteroalkyl group, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Heteroalkenyl, C2-C10Alkynyl, C2-C10Heteroalkynyl, C3-C8Aryl radical (C)1-C10) Alkyl radical, C2-C10Alkenyl (C)1-C10) Alkyl radical, C2-C10Alkynyl (C)1-C10) Any of alkyl groups.
Specifically, in step S01, R in the molecular structural formula of the phosphorus-sulfur compound A1、R2The group is represented by the formula R1 and R in the molecular structure general formula (I) of the chiral 1, 2-diamine compound in the embodiment of the invention2The groups represented are the same. R in the molecular structural formula of nitroolefin compound B3、R4Group represented byR in the structural general formula (I) of the chiral beta-nitrophosphite sulfur compound3、R4The groups represented are the same. For economy of disclosure, further description is omitted here.
The phosphorus-sulfur compound a and the nitroolefin compound B in step S01 may be prepared by themselves in accordance with an existing preparation method, or may be directly obtained commercially.
In some embodiments, R in the phosphorus sulfur compound A and the nitroolefin compound B1、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 radical (C)3-C8) Aryl, substituted (C)3-C8) Aryl group, (C)3-C8) Heteroaryl, substituted (C)3-C8) Any of heteroaryl groups. In the chiral beta-nitro-phosphorus-sulfur compound obtained correspondingly, 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 radical (C)3-C8) Aryl, substituted (C)3-C8) Aryl group, (C)3-C8) Heteroaryl, substituted (C)3-C8) One of the heteroaryl groups.
In some embodiments, R in the phosphorus sulfur compound A and the nitroolefin compound B1、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, C3-C8Any one of heteroaryl substituted pyridines. In the chiral beta-nitro-phosphorus-sulfur compound obtained correspondingly, 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, C3-C8One of heteroaryl substituted pyridines.
In some embodiments, R in the nitroolefin compound B4Is a hydrogen atom, C1-C5Perfluoroalkyl radical, C1-C5Ester group, C1-C10Any one of heteroalkyl groups. In the chiral beta-nitro-phosphorus-sulfur compound obtained correspondingly, R4Is a hydrogen atom, C1-C5Perfluoroalkyl radical, C1-C5Ester group, C1-C10One of the heteroalkyl groups.
In some embodiments, R in the nitroolefin compound B4Is hydrogen atom, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, heptafluoroisopropyl, C1-C10Alkoxyalkyl group, (C)1-C10) Alkyloxycarbonyl (C)1-C10) Any of alkyl groups. In the chiral beta-nitro-phosphorus-sulfur compound obtained correspondingly, R4Is hydrogen atom, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, heptafluoroisopropyl, C1-C10Alkoxyalkyl group, (C)1-C10) Alkyloxycarbonyl (C)1-C10) One of the alkyl groups.
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 can be seen from the structural formula of the reactant nitroolefin compound B that the reactant phosphorous-sulfur compound a acts as a nucleophile and can attack the nitroolefin 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-nitrophosulfur compound with potential application value is obtained through simple reduction reaction.
The reaction formula of the phosphorus-sulfur compound a and the nitroolefin compound B in step S02 in the reaction environment and system in step S02 is as follows:
Figure BDA0002784881720000151
in the chemical reaction formula, the nitrogen heterocyclic carbene catalyst, the proton additive, 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 alkali reagent is used for reacting with the N-heterocyclic carbene catalyst to deprotonate the N-heterocyclic carbene reagent to form an activated proton alkali catalyst; the proton additive is used as a protonic acid catalyst, can coexist with an alkali reagent and a nitrogen heterocyclic carbene catalyst within a certain pKa value range to form protonic acid, and synergistically promotes the catalytic cycle of the reaction, so that the transition state arrangement of the reaction is more ordered. 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 mole ratio of the N-heterocyclic carbene catalyst, the alkali reagent and the proton additive is (0.1-20): (0.1-20): (0.2-40). Under the condition, the reaction has high catalytic efficiency under the synergistic action of the N-heterocyclic carbene catalyst, the proton additive and the alkali reagent, 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 to the proton additive is (0.2-20):2 (1-10), and in this case, the target product with nearly single absolute configuration can be obtained. In another embodiment, the molar ratio of the azacyclocarbene catalyst to the alkali reagent to the proton additive is 1:2 (1-9). In another embodiment, the molar ratio of the N-heterocyclic carbene catalyst, the alkali reagent and the proton additive is 1:2 (1-8). In another embodiment, the mole ratio of the N-heterocyclic carbene catalyst, the alkali reagent and the proton additive is 12 (1-7). In another embodiment, the molar ratio of the N-heterocyclic carbene catalyst, the alkali reagent and the proton additive is 1:2 (1-6). In another embodiment, the molar ratio of the N-heterocyclic carbene catalyst, the alkali reagent and the proton additive is 1:2 (1-5). In another embodiment, the molar ratio of the N-heterocyclic carbene catalyst, the alkali reagent and the proton additive is 1:2 (1-4). In another embodiment, the molar ratio of the N-heterocyclic carbene catalyst, the alkali reagent and the proton additive is 1:2 (1-3). In another embodiment, the molar ratio of the N-heterocyclic carbene catalyst, the alkali reagent and the proton additive is 1:2 (1-2). In a specific embodiment, the molar ratio of the azacyclocarbene catalyst, the base reagent and the proton additive is 1:2: 1.
In one embodiment, the mole ratio of the water absorption additive N-heterocyclic carbene catalyst, the water absorption additive alkali reagent, the water absorption additive proton additive and the water absorption additive compound A is (0.1-20): 0.2-40): 1-100. 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, the alkali reagent and the proton additive in the reaction system is controlled to be (0.2-20):2, (1-10): 1-100) in the molar ratio with the compound A.
In some embodiments, the azacyclo-carbene catalyst is at least one of imidazole azacyclo-carbene, thiazole azacyclo-carbene and triazole azacyclo-carbene. In specific experiments, imidazole azacyclo-carbene, thiazole azacyclo-carbene and triazole azacyclo-carbene can catalyze the reaction more efficiently, but different carbene catalysts can cause products to have different enantioselectivities. In one embodiment, the water absorbing additive N-heterocyclic carbene catalyst is selected from nitrogen-containing heterocyclic compounds shown in the following structural formula C and/or structural formula D:
C：
Figure BDA0002784881720000161
D：
Figure BDA0002784881720000162
wherein X in the structural general formula C of the water absorption additive is carbon atom or oxygen atom, and n is 0 or 1;
in the general structural formulas C and D, Z is identical or different boron tetrafluoride anion or chloride ion, R5Is 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, (C)2-C20) Alkenyl (C)1-C20) Alkyl, (C)2-C20) Alkynyl (C)1-C20) Alkyl, cyano (C)1-C20) Any of alkyl groups; r6And R7Are identical or different C1-C20Alkyl radical, C1-C20Heteroalkyl, aryl (C)1-C20) Alkyl, heteroaryl (C)1-C20) Any of alkyl, aryl, and substituted aryl.
In one embodiment, the protic additive is selected from at least one of the following compounds.
Figure BDA0002784881720000181
The proton additive can efficiently promote protonation of an initial addition product (a negative ion addition product formed in situ after the Michael addition of the aliphatic chain amine compound A to the nitroolefin compound B), inhibit the progress of a retro-Michael reaction and further realize a reaction with high enantioselectivity.
In one embodiment, the base reagent may be selected from at least one of the following compounds: 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, potassium dihydrogen phosphate, DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene), TBD (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 some embodiments, the base reagent is selected from organic base reagents comprising at least one of DBU, TBD, triethylamine and diisopropylethylamine, so that the obtained reaction system can avoid the use of a metal catalyst, strictly realize no metallization of the whole reaction system, reduce the environmental pollution pressure and obtain a target product with higher medical application value.
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,
Figure BDA0002784881720000191
Molecular sieve,
Figure BDA0002784881720000192
Molecular sieves and
Figure BDA0002784881720000193
and (3) a molecular sieve. Wherein, the preactivated 13 × molecular sieve is the molecular sieve obtained by heating and dehydrating the 13 × molecular sieve. Since the water absorbing additive is mainly used for controlling the anhydrous requirement of the reaction system, the water absorbing additive can be added according to the reaction time, the solvent characteristic and the like of the specific reaction system, such as sufficient addition, so as to realize the anhydrous state of the reaction system. In one embodiment, the ratio of the water absorbing additive to the solvent of the water absorbing additive reactant enumerated above is controlled to be 100 mg/mL.
In conclusion, in the process of preparing the chiral phosphorus-sulfur compound, the nitrogen heterocyclic carbene, the alkali reagent, the proton additive and the water removal reagent have the 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, the proton additive and the water removal reagent, the toxicity of 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, the proton additive 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.
In the embodiment of the application, under the synergistic effect of the N-heterocyclic carbene and the proton additive, namely the protonic acid dual-catalytic system, the reaction system can be smoothly carried out even at a lower temperature, and the applicable reaction temperature range is-80 ℃ 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-80 ℃ 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. In one embodiment, the solvent is added in a molar ratio of solvent to catalyst such that (1000- > 1000000): 1.
the Michael addition method of the chiral phosphorus-sulfur compound provided by the embodiment of the application provides a novel asymmetric C-P bond construction method, and the method has the following advantages:
first, the embodiment of the application adopts an organic small molecule asymmetric catalytic system, so that Michael addition of a chiral phosphorus-sulfur compound is realized, and a proper alkali reagent is selected to avoid the use of a metal catalyst, so that the whole reaction system is strictly free from metallization, and the environmental pollution pressure is reduced.
Secondly, in the Michael addition method of the embodiment of the present application, on one hand, a simple phosphorothioic compound reagent is used as a nucleophile to attack a common nitroolefin substrate (the β position may be disubstituted or monosubstituted), so that a target product precursor with high enantioselectivity and an extremely wide range is efficiently and greenly prepared, and a β -nitrophosphorothioic compound with potential application is obtained; on the other hand, the reactants adopt simple and easily obtained phosphorus-sulfur compounds and commercialized nitroolefins as the reactants, the raw materials are very easy to obtain, and the reactants 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 embodiment of the application, the Michael addition process of the chiral phosphorus-sulfur compound is a conjugate addition reaction, so that the atom utilization rate and the reaction efficiency of reactants are high, and the generation yield of a reaction product is favorably improved.
Fourthly, the method provided by the embodiment of the application obviously reduces the production cost of the beta-nitro-phosphorus-sulfur compound, and also greatly expands the designability and application prospect of the compound. 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, the application of a functional material, a metal ligand and a metal compound, can be widely used for the synthesis of the drug intermediate and the preparation of a chiral ligand and 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.
In a third aspect, embodiments of the present application provide applications of the chiral phosphine-sulfur compound or the chiral phosphine-sulfur compound prepared by the Michael addition method in synthesis of pharmaceutical intermediates, preparation of functional materials, metal ligands and metal complexes.
In the embodiment of the application, the drug intermediate refers to an intermediate compound used in the process of synthesizing the drug; the functional material may be a luminescent material, a bio-application material, a mechanical material, etc., without being limited thereto; the metal ligand refers to a complex formed by ligand and metal atom or ion through coordination bond, namely a metal complex; the metal complex refers to a complex formed by coordination and complexation of a metal ligand and a metal.
The chiral phosphorus-sulfur compound provided by the embodiment of the application or the chiral phosphorus-sulfur compound prepared by the Michael addition method has high functional group property, can be widely applied to the fields of organic synthetic chemistry, biochemistry, asymmetric catalysis, pesticides and medicine research, such as the fields of synthesis of medicine intermediates, particularly compounds containing a quaternary carbon center structure and preparation of functional materials, can effectively reduce the economic cost for preparing the medicine intermediates, the functional materials, metal ligands and metal compounds, and provides the environmental friendliness of the chiral phosphorus-sulfur compound.
The following description will be given with reference to specific examples.
Example 1
This example provides a (S) -diphenyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorothioic compound and a method for preparing the same. The structural formula of the (S) -diphenyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorus sulfur compound is shown as the following molecular structural formula I1:
Figure BDA0002784881720000201
the preparation method comprises the following steps:
in a 10mL tube, a mesitylene-substituted indanol-derived triazole carbene catalyst (0.01mmol, 0.1 equivalent (equiv.)) and a phosphorus-sulfur nucleophile (0.1mmol, 1.0equiv.), binaphthol (R-BINOL, 0.02mmol, 0.2equiv.) were dissolved in 1.6mL of a mixed solvent of pretreated ethylbenzene and cyclohexane in a ratio of 9:1, sealed with a rubber stopper, followed by gas replacement (3 times) under an argon atmosphere, bis (trimethylsilyl) aminolithium (LiHMDS) (1mol/L, tetrahydrofuran/ethylbenzene solution, 8 μ L, 0.08equiv.), and gas replacement (3 times) again under an argon atmosphere. The tube was sealed with a sealing film and then stirred at-40 ℃ for 1 hour. A solution (0.6mL) of ethylbenzene and cyclohexane (9: 1 in volume ratio) was prepared from a nitroalkene compound (0.12mmol, 1.2equiv.), and the mixture was reacted at-40 ℃ for 24 hours after the injection was completed by slowly injecting the solution (1 hour injection time) using a sample injection pump. After complete consumption of the phosphorus sulfur compound, the mixture was directly purified by separation on silica gel column chromatography (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,CDCl3)δ8.09–8.01(m,2H),7.67(ddd,J＝12.9,8.5,1.3Hz,2H),7.61–7.56(m,1H),7.49(ddd,J＝9.0,6.9,3.7Hz,2H),7.42(td,J＝7.4,1.9Hz,1H),7.34(d,J＝7.9Hz,2H),7.31–7.25(m,3H),7.20(t,J＝7.7Hz,2H),5.87(ddq,J＝13.4,6.7,1.9Hz,1H),5.31(dd,J＝13.9,4.5Hz,1H).13C NMR(101MHz,CDCl3)δ134.02(d,J＝10.1Hz),133.83(d,J＝9.9Hz),132.79(d,J＝3.0Hz),132.37(d,J＝4.0Hz),129.21(d,J＝3.0Hz),129.03(d,J＝3.0Hz),128.44(d,J＝13.1Hz),128.19(d,J＝74.7Hz),127.97(d,J＝10.1Hz),127.89,126.91(d,J＝13.1Hz),125.62(q,J＝286.8Hz),76.59(d,J＝11.2Hz),61.90(q,J＝25.3Hz),29.72.31P NMR(162MHz,CDCl3)δ57.57.HRMS(ESI-TOF)[M+H]calculated for[C21H18F3NO2PS]+436.0748,observed 436.0742.HPLC(Chiralpak-AD-H column,98.5:1.5hexane/ethanol,flow rate:1.0mL/min):tmajor＝10.258min；tminor9.094 min. This result further confirmed the molecular structure of the product as described above for molecular structure I1.
Example 2
This example provides a (S) -di-p-tolyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorothioic compound and a method for preparing the same. The structural formula of the (S) -di-p-tolyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorus sulfur compound is shown as the following molecular structural formula I2:
Figure BDA0002784881720000211
the preparation process was carried out in accordance with the preparation process of (S) -diphenyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorothioic compound of example 1, except that p-methyldiphenylphosphorothioic compound (0.1mmol) was used in place of the diphenylphosphorothioic compound. The reaction solution was directly separated and purified by silica gel column chromatography (ethyl acetate and n-hexane as eluent) to obtain the target product as a white solid with a yield of 94% and an ee value of 95%.
The product I2 prepared was subjected to characterization data analysis, the result of which was1H NMR(400MHz,CDCl3)δ7.91(dd,J＝12.9,8.1Hz,2H),7.53–7.46(m,2H),7.34–7.26(m,5H),7.22(dd,J＝8.6,7.0Hz,2H),7.07(dd,J＝8.3,3.5Hz,2H),5.81(ddt,J＝12.5,6.5,2.0Hz,1H),5.29(dd,J＝14.0,4.6Hz,1H),2.41(s,3H),2.32(s,3H).13C NMR(101MHz,CDCl3)δ143.60(d,J＝3.1Hz),143.15(d,J＝3.0Hz),134.17(d,J＝10.1Hz),133.81(d,J＝10.1Hz),129.23(d,J＝4.0Hz),129.13,129.09(d,J＝2.0Hz),128.69(d,J＝13.1Hz),127.95(d,J＝5.1Hz),127.78(d,J＝3.0Hz),125.68(q,J＝286.8Hz),124.62(d,J＝77.8Hz),123.98(d,J＝86.9Hz),76.38(d,J＝10.1Hz),62.01(q,J＝31.3Hz),29.72,21.44(d,J＝10.1Hz).31P NMR(162MHz,CDCl3)δ56.66.HRMS(ESI-TOF)[M+Na]calculated for[C23H21F3NNaO2PS]+486.0880,observed 486.0877.HPLC(Chiralpak-AD-H column,98.5:1.5hexane/ethanol,flow rate:1.0mL/min):tmajor＝18.865min；tminorThis result further confirmed the molecular structure of the product as described above for molecular structure I2.
Example 3
This example provides an (S) -di-p-tolyl (1,1, 1-trifluoro-2- (4-methoxyphenyl) -3-nitropropane-2-yl) phosphorothioic compound and a method for preparing the same. The structural formula of the (S) -di-p-tolyl (1,1, 1-trifluoro-2- (4-methoxyphenyl) -3-nitropropane-2-yl) phosphorothioic compound is shown as the following molecular structural formula I3:
Figure BDA0002784881720000221
the preparation was carried out in accordance with the preparation of (S) -diphenyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorothioic compound in example 1, except that p-methyldiphenylphosphorothioic compound (0.1mmol) was used in place of diphenylphosphorothioic compound and (E) -1-methoxy-4- (3,3, 3-trifluoro-1-nitroprop-1-en-2-yl) benzene was used in place of (E) - (3,3, 3-trifluoro-1-nitroprop-1-en-2-yl) benzene (0.12 mmol). 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 which is a white solid with the yield of 98 percent and the ee value of 93 percent.
The product I3 prepared was subjected to characterization data analysis, which resulted in:1H NMR(400MHz,CDCl3))δ7.92(dd,J＝12.8,8.1Hz,2H),7.55–7.47(m,2H),7.29(dd,J＝8.3,3.4Hz,2H),7.24–7.19(m,2H),7.09(dd,J＝8.2,3.5Hz,2H),6.79–6.72(m,2H),5.77–5.68(m,1H),5.26(dd,J＝13.9,4.6Hz,1H),3.79(s,3H),2.41(s,3H),2.33(s,3H).13CNMR(101MHz,CDCl3)δ160.09(d,J＝3.0Hz),143.54(d,J＝3.0Hz),143.14(d,J＝3.0Hz),134.25(d,J＝10.0Hz),133.82(d,J＝10.1Hz),130.78(d,J＝15.2Hz),129.13(d,J＝13.1Hz),128.73(d,J＝13.1Hz),125.74(d,J＝286.8.0Hz),124.44(d,J＝76.8Hz),124.30(d,J＝86.8Hz),119.33(d,J＝5.1Hz),113.14(d,J＝2.0Hz),76.25(d,J＝12.1Hz),61.67(q,J＝25.3Hz),61.17,55.33,21.45(d,J＝9.1Hz).31P NMR(162MHz,CDCl3)δ55.87.HRMS(ESI-TOF)[M+Na]calculated for[C24H23F3NNaO3PS]+516.0986,observed 516.0981.HPLC(Chiralpak-AD-H column,95:5hexane/ethanol,flow rate:1.0mL/min):tmajor＝23.810min；tminorthis result further confirmed the molecular structure of the product as described above for molecular structure I3.
Example 4
This example provides an (S) -di-p-tolyl (1,1, 1-trifluoro-3-nitro-2- (thiophen-3-yl) propan-2-yl) phosphorothioic compound and a method for preparing the same. A (S) -di-p-tolyl (1,1, 1-trifluoro-3-nitro-2- (thiophen-3-yl) propan-2-yl) phosphorothioic compound has the following molecular formula I4:
Figure BDA0002784881720000231
the preparation was carried out according to the preparation of (S) -diphenyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorothioic compound in example 1, except that p-methyldiphenylphosphorothioic compound (0.1mmol) was used instead of diphenylphosphorothioic compound and (Z) -2- (3,3, 3-trifluoro-1-nitroprop-1-en-2-yl) thiophene instead of (E) - (3,3, 3-trifluoro-1-nitroprop-1-en-2-yl) benzene (0.12 mmol). 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, white solid, yield 90 percent and ee value 94 percent.
The product I4 prepared was subjected to characterization data analysis, which resulted in:1H NMR(400MHz,CDCl3)δ7.91(dd,J＝13.0,8.1Hz,2H),7.65–7.57(m,2H),7.33–7.25(m,3H),7.14–7.06(m,3H),6.88(dd,J＝5.1,3.8Hz,1H),5.67(ddd,J＝13.1,6.5,1.6Hz,1H),5.28(dd,J＝13.1,4.9Hz,1H),2.41(s,3H),2.33(s,3H).13C NMR(101MHz,CDCl3)δ143.71(d,J＝3.0Hz),143.17(d,J＝3.0Hz),133.95(d,J＝11.1Hz),133.55(d,J＝10.1Hz),130.10(d,J＝15.1Hz),129.23(d,J＝13.1Hz),128.82(d,J＝14.1Hz),127.24(d,J＝4.0Hz),126.25(d,J＝2.0Hz),125.06(d,J＝286.8Hz),124.86(d,J＝77.8Hz),124.02(d,J＝87.9Hz),78.47(d,J＝11.1Hz),60.52(q,J＝26.3Hz),29.72,21.52(d,J＝1.0Hz),21.42(d,J＝3.0Hz).31P NMR(162MHz,CDCl3)δ58.35.HRMS(ESI-TOF)[M+Na]calculated for[C21H19F3NNaO2PS2]+492.0445,observed 492.0441.HPLC(Chiralpak-AD-H column,97.5:2.5hexane/ethanol,flow rate:1.0mL/min):tmajor＝25.084min；tminorthis result further confirmed the molecular structure of the product as described above for molecular structure I4.
Example 5
This example provides an (S) -di-p-tolyl (1,1, 1-trifluoro-3-nitro-2- (4-nitrophenyl) propan-2-yl) phosphorothioic compound and a method for preparing the same. The structural formula of the (S) -di-p-tolyl (1,1, 1-trifluoro-3-nitro-2- (4-nitrophenyl) propan-2-yl) phosphorothioic compound is shown as the following molecular structural formula I5:
Figure BDA0002784881720000232
the preparation is as described in example 1 for S) -diphenyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorothioic compound, except that p-methyldiphenylphosphorothioic compound (0.1mmol) is used instead of diphenylphosphorothioic compound and (E) -1-nitro-4- (3,3, 3-trifluoro-1-nitroprop-1-en-2-yl) benzene is used instead of (E) - (3,3, 3-trifluoro-1-nitroprop-1-en-2-yl) benzene (0.12 mmol). 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 which is a white solid with the yield of 99 percent and the ee value of 90 percent.
The product I5 prepared was subjected to characterization data analysis, which resulted in:1H NMR(400MHz,CDCl3)δ7.96(dd,J＝13.0,8.1Hz,2H),7.56–7.48(m,2H),7.29(ddd,J＝17.5,8.5,2.8Hz,4H),7.22–7.17(m,2H),7.10(dd,J＝8.2,3.5Hz,2H),5.88–5.79(m,1H),5.18(dd,J＝14.0,4.4Hz,1H),2.42(s,3H),2.34(s,3H).13C NMR(101MHz,CDCl3)δ143.87(d,J＝3.0Hz),143.45(d,J＝3.0Hz),135.41(d,J＝4.0Hz),134.10(d,J＝10.1Hz),133.77(d,J＝10.1Hz),130.57(d,J＝2.0Hz),129.33(d,J＝13.1Hz),128.83(d,J＝13.1Hz),127.89(d,J＝3.0Hz),126.53(d,J＝4.0Hz),125.59(q,J＝287.9Hz),124.21(d,J＝77.8Hz),123.66(d,J＝87.9Hz),76.33(d,J＝11.1Hz),61.70(q,J＝25.3Hz),29.84,21.47(d,J＝11.1Hz).31PNMR(162MHz,CDCl3)δ57.26.HRMS(ESI-TOF)[M+Na]calculated for[C23H20F3N2NaO4PS]+531.0731,observed 531.0726.HPLC(Chiralpak-AD-Hcolumn,97.5:2.5hexane/ethanol,flow rate:1.0mL/min):tmajor＝17.134min；tminorthis result further confirmed the molecular structure of the product as described above for molecular structure I5.
Example 6
This example provides an (S) -di-p-tolyl (1,1, 1-trifluoro-2- (3-fluorophenyl) -3-nitropropane-2-yl) phosphonium sulfide compound and a method for preparing the same. The structural formula of the (S) -di-p-tolyl (1,1, 1-trifluoro-2- (3-fluorophenyl) -3-nitropropane-2-yl) phosphorus sulfur compound is shown as the following molecular structural formula I6:
Figure BDA0002784881720000241
the preparation was carried out in accordance with the preparation of (S) -diphenyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorothioic compound in example 1, except that p-methyldiphenylphosphorothioic compound (0.1mmol) was used in place of diphenylphosphorothioic compound and (E) -1-fluoro-3- (3,3, 3-trifluoro-1-nitroprop-1-en-2-yl) benzene was used in place of (E) - (3,3, 3-trifluoro-1-nitroprop-1-en-2-yl) benzene (0.12 mmol). The reaction solution was directly separated and purified by silica gel column chromatography (ethyl acetate and n-hexane as eluent) to obtain the target product as a white solid with a yield of 88% and an ee value of 92%.
The product I6 prepared was subjected to characterization data analysis, which resulted in:1H NMR(400MHz,CDCl3))δ7.94(dd,J＝13.0,8.1Hz,2H),7.60–7.52(m,2H),7.31(dd,J＝8.3,3.4Hz,2H),7.21–7.16(m,2H),7.10(dd,J＝8.2,3.6Hz,2H),7.07–6.96(m,2H),5.85(ddd,J＝14.0,6.6,1.9Hz,1H),5.22(dd,J＝14.0,4.4Hz,1H),2.42(s,3H),2.32(s,3H).13C NMR(101MHz,CDCl3)δ163.04(d,J＝3.0Hz),160.60(d,J＝3.0Hz),143.65(d,J＝43.4Hz),133.97(d,J＝11.1Hz),130.51(d,J＝12.1Hz),129.31(d,J＝13.1Hz),129.16(d,J＝3.0Hz),128.78(d,J＝14.1Hz),125.50(d,J＝286.8.0Hz),124.59(d,J＝78.8Hz),124.77,123.84(d,J＝86.9Hz),116.69(d,J＝25.3Hz),115.95(d,J＝17.2Hz),76.67(d,J＝14.1Hz),61.48(q,J＝29.3Hz),29.72,21.51(d,J＝2.0Hz),21.38(d,J＝2.0Hz).31P NMR(162MHz,CDCl3)δ57.98.HRMS(ESI-TOF)[M+Na]calculated for[C23H20F4NNaO2PS]+504.0786,observed504.0779.HPLC(Chiralpak-AD-H column,97.5:2.5hexane/ethanol,flow rate:1.0mL/min):tmajor＝15.292min；tminorthis result further confirmed the molecular structure of the product as described above for molecular structure I6.
Example 7
This example provides (S) - (2- (3-bromophenyl) -1,1, 1-trifluoro-3-nitropropan-2-yl) di-p-tolyl phosphorothioic compound and its preparation method. The structural formula of the (S) - (2- (3-bromophenyl) -1,1, 1-trifluoro-3-nitropropan-2-yl) di-p-tolyl phosphorus sulfide compound is shown as the following molecular structural formula I7:
Figure BDA0002784881720000251
the preparation was carried out according to the preparation of (S) -diphenyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorothioic compound in example 1, except that p-methyldiphenylphosphorothioic compound (0.1mmol) was used instead of diphenylphosphorothioic compound and (E) -1-bromo-3- (3,3, 3-trifluoro-1-nitroprop-1-en-2-yl) benzene was used instead of (E) - (3,3, 3-trifluoro-1-nitroprop-1-en-2-yl) benzene (0.12 mmol). 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 which is a white solid with the yield of 98 percent and the ee value of 90 percent.
The product I7 prepared was subjected to characterization data analysis, which resulted in:1H NMR(400MHz,CDCl3)δ7.94(dd,J＝13.0,8.1Hz,2H),7.57–7.49(m,2H),7.42(dq,J＝8.0,1.7Hz,1H),7.32(dt,J＝8.3,4.6Hz,3H),7.28–7.25(m,1H),7.16–7.09(m,3H),5.81(ddt,J＝12.1,6.5,2.0Hz,1H),5.23(dd,J＝14.2,4.5Hz,1H),2.42(s,3H),2.35(s,3H).13C NMR(101MHz,CDCl3)δ143.90(d,J＝3.0Hz),143.59(d,J＝3.0Hz),134.01(d,J＝11.1Hz),133.75(d,J＝10.0Hz),132.20(d,J＝2.0Hz),132.00(d,J＝3.0Hz),130.26(d,J＝5.1Hz),129.35(d,J＝13.1Hz),129.06(d,J＝3.0Hz),128.84(d,J＝13.1Hz),125.46(d,J＝286.8Hz),124.29(d,J＝78.8Hz),123.25(d,J＝87.9Hz),121.81(d,J＝4.0Hz),76.16(d,J＝11.1Hz),61.76(q,J＝29.3Hz),29.72,21.52(d,J＝1.0Hz),21.42(d,J＝1.0Hz).31P NMR(162MHz,CDCl3)δ57.69.HRMS(ESI-TOF)[M+Na]calculated for[C23H20BrF3NNaO2PS]+563.9986,observed 563.9980.HPLC(Chiralpak-IF-H column,98:2hexane/ethanol,flow rate:1.0mL/min):tmajor＝5.091min；tminorthis result further confirmed the molecular structure of the product as described above for molecular structure I7.
Example 8
This example provides a (R) - (2-nitro-1-phenylethyl) di-p-tolyl phosphorus sulfide compound and a preparation method thereof. The structural formula of the (R) - (2-nitro-1-phenylethyl) di-p-tolyl phosphorus-sulfur compound is shown as the following molecular structural formula I8:
Figure BDA0002784881720000252
the preparation was carried out in accordance with the preparation of (S) -diphenyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorothioic compound in example 1, except that p-methyldiphenylphosphorothioic compound (0.1mmol) was used in place of diphenylphosphorothioic compound and (E) - (2-nitrovinyl) benzene was used in place of (E) - (3,3, 3-trifluoro-1-nitroprop-1-en-2-yl) benzene (0.12 mmol). The reaction solution was directly separated and purified by silica gel column chromatography (ethyl acetate and n-hexane as eluent) to obtain the target product as a white solid with a yield of 95% and an ee value of 90%.
The product I8 prepared was subjected to characterization data analysis, which resulted in:1H NMR(400MHz,CDCl3)δ8.10–7.98(m,2H),7.39(dd,J＝8.2,2.9Hz,2H),7.36–7.25(m,4H),7.22–7.12(m,3H),7.02(dd,J＝8.2,3.0Hz,2H),5.16(ddd,J＝13.6,11.9,4.4Hz,1H),4.79–4.60(m,2H),2.44(s,3H),2.26(s,3H).13C NMR(101MHz,CDCl3)δ143.20(d,J＝3.0Hz),142.36(d,J＝3.0Hz),131.82(d,J＝10.0Hz),131.59(d,J＝10.0Hz),131.25(d,J＝5.1Hz),129.99(d,J＝12.1Hz),129.53(d,J＝5.1Hz),128.92(d,J＝13.1Hz),128.43(d,J＝3.0Hz),128.30(d,J＝2.0Hz),127.16,126.18(d,J＝25.3Hz),76.31(d,J＝10.0Hz),46.09,45.60,21.48(d,J＝14.1Hz).31P NMR(162MHz,CDCl3)δ45.51.HRMS(ESI-TOF)[M+Na]calculatedfor[C22H22NO2NaPS]+418.1007,observed 418.1002.HPLC(Chiralpak-AD-Hcolumn,97.5:2.5hexane/ethanol,flow rate:1.0mL/min):tmajor＝7.782min；tminorthis result further confirmed the molecular structure of the product as described above for molecular structure I8.
Example 9
This example provides a (R) - (2-nitro-1- (2- (trifluoromethyl) phenyl) ethyl) di-p-tolyl phosphorothioic compound and a method for preparing the same. The structural formula of the (R) - (2-nitro-1- (2- (trifluoromethyl) phenyl) ethyl) di-p-tolyl phosphorus sulfur compound is shown as the following molecular structural formula I9:
Figure BDA0002784881720000261
the preparation was carried out according to the preparation of (S) -diphenyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorothioic compound in example 1, except that p-methyldiphenylphosphorothioic compound (0.1mmol) was used instead of diphenylphosphorothioic compound and (E) -1- (2-nitrovinyl) -2- (trifluoromethyl) benzene was used instead of (E) - (3,3, 3-trifluoro-1-nitroprop-1-en-2-yl) benzene (0.12 mmol). The reaction solution was directly separated and purified by silica gel column chromatography (ethyl acetate and n-hexane as eluent) to obtain the desired product as a white solid with a yield of 74% and an ee value of 88%.
The product I9 prepared was subjected to characterization data analysis, which resulted in:1H NMR(400MHz,CDCl3)δ8.21–8.09(m,2H),8.06(dt,J＝7.8,1.7Hz,1H),7.46(dd,J＝8.0,2.7Hz,2H),7.40–7.29(m,2H),7.21–7.05(m,3H),6.94(dd,J＝8.0,3.1Hz,2H),5.56(td,J＝11.7,3.4Hz,1H),5.15(ddd,J＝14.0,11.4,4.9Hz,1H),4.59(ddd,J＝14.0,6.5,3.5Hz,1H),2.48(s,3H),2.25(s,3H).13C NMR(101MHz,CDCl3),142.54(d,J＝3.0Hz),133.03(d,J＝2.1Hz),132.11(dd,J＝52.4,10.4Hz),131.57,130.21(d,J＝12.3Hz),130.01(d,J＝2.8Hz),129.39(d,J＝4.0Hz),128.75(d,J＝13.2Hz),127.76(d,J＝2.6Hz),127.22(d,J＝14.7Hz),127.08,126.12(d,J＝61.0Hz),125.02,76.50,43.57,43.08,29.46,21.65(d,J＝17.5Hz).31P NMR(162MHz,CDCl3)δ46.73.HRMS(ESI-TOF)[M+H]calculated for[C23H22NO2F3PS]+464.1055,observed 464.1059.HPLC(Chiralpak-AD-H column,80:20hexane/ethanol,flow rate:1.0mL/min):tmajor＝10.746min；tminorthis result further confirmed the molecular structure of the product as described above for molecular structure I9.
Example 10
This example provides a (R) - (2-nitro-1- (3- (trifluoromethyl) phenyl) ethyl) di-p-tolyl phosphorothioic compound and a method for preparing the same. The structural formula of the (R) - (2-nitro-1- (3- (trifluoromethyl) phenyl) ethyl) di-p-tolyl phosphorus-sulfur compound is shown as the following molecular structural formula:
Figure BDA0002784881720000271
the preparation was carried out according to the preparation of (S) -diphenyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorothioic compound in example 1, except that p-methyldiphenylphosphorothioic compound (0.1mmol) was used instead of diphenylphosphorothioic compound and (E) -1- (2-nitrovinyl) -3- (trifluoromethyl) benzene was used instead of (E) - (3,3, 3-trifluoro-1-nitroprop-1-en-2-yl) benzene (0.12 mmol). 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, namely a white solid, the yield is 90 percent, and the ee value is 84 percent.
The product I10 prepared was subjected to characterization data analysis, which resulted in:1H NMR(400MHz,CDCl3)δ8.05(dd,J＝12.2,8.1Hz,2H),7.64(d,J＝7.7Hz,1H),7.50–7.39(m,3H),7.36(t,J＝7.8Hz,1H),7.32–7.23(m,2H),7.16(s,1H),7.03(dd,J＝8.1,2.8Hz,2H),5.19(ddd,J＝14.1,11.5,4.3Hz,1H),4.84–4.60(m,2H),2.45(s,3H),2.27(s,3H).13C NMR(101MHz,CDCl3)δ143.66(d,J＝3.0Hz),143.07(d,J＝3.1Hz),132.41(d,J＝4.8Hz),132.02,131.92(d,J＝9.9Hz),131.45(d,J＝10.5Hz),130.27(d,J＝12.4Hz),129.18(d,J＝13.1Hz),128.84(d,J＝2.5Hz),127.07(d,J＝4.3Hz),126.45(d,J＝42.7Hz),125.62(d,J＝37.3Hz),125.23(d,J＝3.4Hz),123.74(d,J＝272.5Hz),75.67(d,J＝9.7Hz),62.05,46.15,45.66,21.53(d,J＝25.8Hz).31P NMR(162MHz,CDCl3)δ45.95.HRMS(ESI-TOF)[M+H]calculated for[C23H22NO2F3PS]+464.1055,observed 464.1057.HPLC(Chiralpak-AD-H column,97.5:2.5hexane/ethanol,flow rate:1.0mL/min):tmajor＝13.538min；tminorthis result further confirmed the molecular structure of the product as described above for molecular structure I10.
Example 11
This example provides a (R) - (1- (3-chloro-4-fluorophenyl) -2-nitroethyl) -di-p-tolyl phosphorothioic compound and a preparation method thereof. The structural formula of the (R) - (1- (3-chloro-4-fluorophenyl) -2-nitroethyl) di-p-tolyl phosphorus sulfide compound is shown as the following molecular structural formula I11:
Figure BDA0002784881720000281
the preparation was carried out according to the preparation of (S) -diphenyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorothioic compound in example 1, except that p-methyldiphenylphosphorothioic compound (0.1mmol) was used instead of diphenylphosphorothioic compound and (E) -2-chloro-1-nitro-4- (2-nitrovinyl) benzene was used instead of (E) - (3,3, 3-trifluoro-1-nitroprop-1-en-2-yl) benzene (0.12 mmol). The reaction solution was directly separated and purified by silica gel column chromatography (ethyl acetate and n-hexane as eluent) to obtain the desired product as a white solid with a yield of 81% and an ee value of 84%.
The product I11 prepared was subjected to characterization data analysis, which resulted in:1H NMR(400MHz,CDCl3)δ8.02(dd,J＝12.2,8.1Hz,2H),7.46–7.31(m,4H),7.25(dd,J＝6.4,2.4Hz,1H),7.21(ddd,J＝8.5,4.4,2.1Hz,1H),7.09(dd,J＝8.0,2.8Hz,2H),6.96(d,J＝8.6Hz,1H),5.07(d,J＝1.8Hz,1H),4.73–4.57(m,2H),2.44(s,3H),2.30(s,3H).13CNMR(101MHz,CDCl3)δ158.20(d,J＝253.9Hz),143.32(dd,J＝62.2,3.0Hz),131.87,131.82,131.77,131.55(d,J＝10.5Hz),130.26(d,J＝12.4Hz),129.28(d,J＝13.1Hz),129.10(d,J＝7.4Hz),128.57,126.58(d,J＝35.0Hz),125.76(d,J＝29.6Hz),121.05(d,J＝20.7Hz),116.51(d,J＝23.5Hz),76.08(d,J＝10.2Hz),45.14,44.65,21.59(d,J＝14.2Hz).31P NMR(162MHz,CDCl3)δ45.45.HRMS(ESI-TOF)[M+Na]calculated for[C22H20NO2FNaPSCl]+470.0517,observed470.0521.HPLC(Chiralpak-AD-H column,97.5:2.5hexane/ethanol,flow rate:1.0mL/min):tmajor＝17.140min；tminorthis result further confirmed the molecular structure of the product as described above for molecular structure I11.
Example 12
This example provides a (R) - (1- (2-bromofluorophenyl) -2-nitroethyl) di-p-tolyl phosphorothioic compound and a preparation method thereof. The structural formula of the (R) - (1- (2-bromophenyl) -2-nitroethyl) di-p-tolyl phosphorus sulfide compound is shown as the following molecular structural formula I12:
Figure BDA0002784881720000282
the preparation was carried out in accordance with the preparation of (S) -diphenyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorothioic compound in example 1, except that p-methyldiphenylphosphorothioic compound (0.1mmol) was used in place of diphenylphosphorothioic compound and (E) -1-bromo-2- (2-nitrovinyl) benzene was used in place of (E) - (3,3, 3-trifluoro-1-nitroprop-1-en-2-yl) benzene (0.12 mmol). The reaction solution was directly separated and purified by silica gel column chromatography (ethyl acetate and n-hexane as eluent) to obtain the target product as a white solid with a yield of 79% and an ee value of 83%.
The product I12 prepared was subjected to characterization data analysis, which resulted in:1H NMR(400MHz,CDCl3)δ8.21–8.09(m,2H),8.06(dt,J＝7.8,1.7Hz,1H),7.46(dd,J＝8.0,2.7Hz,2H),7.40–7.29(m,2H),7.21–7.05(m,3H),6.94(dd,J＝8.0,3.1Hz,2H),5.56(td,J＝11.7,3.4Hz,1H),5.15(ddd,J＝14.0,11.4,4.9Hz,1H),4.59(ddd,J＝14.0,6.5,3.5Hz,1H),2.48(s,3H),2.25(s,3H).13C NMR(101MHz,CDCl3)δ143.84(d,J＝2.9Hz),142.49(d,J＝3.1Hz),132.55(d,J＝9.9Hz),132.03,131.72(d,J＝10.6Hz),131.06,130.23(d,J＝12.5Hz),129.71(d,J＝4.1Hz),128.76,128.63,127.73,126.78,125.06,124.26,77.37,41.27,40.79,21.60(d,J＝27.1Hz).31P NMR(162MHz,CDCl3)δ48.19.HRMS(ESI-TOF)[M+Na]calculated for[C22H21NO2NaPSBr]+496.0106,observed 496.0105.HPLC(Chiralpak-AD-Hcolumn,80:20hexane/ethanol,flow rate:1.0mL/min):tmajor＝7.611min；tminorthis result further confirmed the molecular structure of the product as described above for molecular structure I12.
Example 13
This example provides a (R) - (2-nitro-1- (thien-3-yl) ethyl) di-p-tolyl phosphorothioic compound and a method for preparing the same. The structural formula of the (R) - (2-nitro-1- (thiophene-3-yl) ethyl) di-p-tolyl phosphorus sulfur compound is shown as the following molecular structural formula I13:
Figure BDA0002784881720000291
the preparation was carried out according to the preparation of (S) -diphenyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorothioic compound in example 1, except that p-methyldiphenylphosphorothioic compound (0.1mmol) was used instead of diphenylphosphorothioic compound and (E) -3- (2-nitrovinyl) thiophene instead of (E) - (3,3, 3-trifluoro-1-nitroprop-1-en-2-yl) benzene (0.12 mmol). The reaction solution was directly separated and purified by silica gel column chromatography (ethyl acetate and n-hexane as eluent) to obtain the target product as a white solid with a yield of 89% and an ee value of 86%.
The product I13 prepared was subjected to characterization data analysis, which resulted in:1H NMR(400MHz,CDCl3)δ7.99(dd,J＝12.2,8.1Hz,2H),7.47(dd,J＝12.9,8.1Hz,2H),7.37(dd,J＝8.0,2.5Hz,2H),7.20–7.06(m,3H),7.02(t,J＝2.7Hz,1H),6.83(dd,J＝4.8,3.8Hz,1H),5.12–4.95(m,2H),4.73–4.62(m,1H),2.43(s,3H),2.30(s,3H).13C NMR(101MHz,CDCl3)δ143.42(d,J＝2.9Hz),142.75(d,J＝3.1Hz),132.89,131.86(d,J＝9.9Hz),131.67(d,J＝10.4Hz),130.14(d,J＝12.3Hz),129.23(d,J＝13.1Hz),128.55(d,J＝6.4Hz),126.96,126.77(d,J＝2.6Hz),126.44(d,J＝3.1Hz),126.07,77.61,42.64,42.12,21.63(d,J＝7.6Hz).31P NMR(162MHz,CDCl3)δ45.18.HRMS(ESI-TOF)[M+Na]calculated for[C20H20NNaO2PS2]+424.0565,observed 424.0568.HPLC(Chiralpak-AD-H column,80:20hexane/ethanol,flowrate:1.0mL/min):tmajor＝10.260min；tminorthis result further confirmed the molecular structure of the product as described above for molecular structure I13.
Example 14
This example provides a (R) - (1-nitro-4-phenylbutan-2-yl) di-p-tolyl phosphorothioic compound and a method for preparing the same. The structural formula of the (R) - (1-nitro-4-phenylbutan-2-yl) di-p-tolyl phosphorus-sulfur compound is shown as the following molecular structural formula I14:
Figure BDA0002784881720000301
the preparation was carried out in accordance with the preparation of (S) -diphenyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorothioic compound in example 1, except that p-methyldiphenylphosphorothioic compound (0.1mmol) was used in place of diphenylphosphorothioic compound and (E) - (4-nitrobut-3-en-1-yl) benzene was used in place of (E) - (3,3, 3-trifluoro-1-nitroprop-1-en-2-yl) benzene (0.12 mmol). The reaction solution was directly separated and purified by silica gel column chromatography (ethyl acetate and n-hexane as eluent) to obtain the target product as a white solid with a yield of 93% and an ee value of 90%.
The product I14 prepared was subjected to characterization data analysis, which resulted in:1H NMR(400MHz,CDCl3)δ8.21–8.09(m,2H),8.06(dt,J＝7.8,1.7Hz,1H),7.46(dd,J＝8.0,2.7Hz,2H),7.40–7.29(m,2H),7.21–7.05(m,3H),6.94(dd,J＝8.0,3.1Hz,2H),5.56(td,J＝11.7,3.4Hz,1H),5.15(ddd,J＝14.0,11.4,4.9Hz,1H),4.59(ddd,J＝14.0,6.5,3.5Hz,1H),2.48(s,3H),2.25(s,3H).13C NMR(101MHz,CDCl3)δ143.00(d,J＝2.9Hz),142.79(d,J＝2.9Hz),140.26,131.47(d,J＝6.4Hz),131.37(d,J＝6.1Hz),129.92(d,J＝12.4Hz),129.73(d,J＝12.7Hz),128.67,128.63,127.49(d,J＝28.5Hz),126.83,126.48,76.19(d,J＝7.3Hz),36.86,36.31,33.40(d,J＝9.8Hz),30.29,21.61.31P NMR(162MHz,CDCl3)δ47.44.HRMS(ESI-TOF)[M+Na]calculated for[C24H26NO2NaPS]+446.1314,observed 446.1314.HPLC(Chiralpak-AD-H column,80:20hexane/ethanol,flow rate:1.0mL/min):tmajor＝7.234min；tminorthis result further confirmed the molecular structure of the product as described above for molecular structure I14.
Example 15
This example provides a (R) - (1-nitrononyl-2-yl) di-p-tolyl phosphorothioated compound and a method for preparing the same. The structural formula of the (R) - (1-nitrononyl-2-yl) di-p-tolyl phosphorus-sulfur compound is shown as the following molecular structural formula I15:
Figure BDA0002784881720000302
the preparation was carried out in accordance with the preparation of (S) -diphenyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorothioic compound in example 1, except that p-methyldiphenylphosphorothioic compound (0.1mmol) was used in place of diphenylphosphorothioic compound and (E) -1-nitronon-1-ene was used in place of (E) - (3,3, 3-trifluoro-1-nitroprop-1-en-2-yl) benzene (0.12 mmol). The reaction solution was directly separated and purified by silica gel column chromatography (ethyl acetate and n-hexane as eluent) to give the desired product as a colorless oil in 93% yield and 91% ee.
The product I15 prepared was subjected to characterization data analysis, which resulted in: h NMR (400MHz, CDCl)3)δ7.85(ddd,J＝25.9,12.5,8.1Hz,4H),7.40–7.21(m,4H),4.61–4.40(m,2H),3.61(dt,J＝11.4,5.8Hz,1H),2.36(t,J＝4.5Hz,6H),1.72–1.61(m,2H),1.24(s,2H),1.19(dd,J＝14.1,7.0Hz,2H),1.09(m,6H),0.82(t,J＝7.2Hz,3H).13CNMR(101MHz,CDCl3)δ142.94(d,J＝2.9Hz),142.74(d,J＝2.9Hz),131.47(d,J＝4.6Hz),131.36(d,J＝4.2Hz),129.92(d,J＝12.3Hz),129.67(d,J＝12.7Hz),127.72(d,J＝7.1Hz),126.91(d,J＝9.2Hz),76.27(d,J＝7.5Hz),37.75,37.20,31.67,29.40,28.85,28.34,27.37(d,J＝9.9Hz),22.67,21.58,14.16.31P NMR(162MHz,CDCl3)δ47.45.HRMS(ESI-TOF)[M+Na]calculated for[C23H32NO2NaPS]+440.1784,observed 440.1784.HPLC(Chiralpak-AD-H column,97.5:2.5hexane/ethanol,flow rate:1.0mL/min):tmajor＝10.104min；tminorThis result further confirmed the molecular structure of the product as described above for molecular structure I15.
Example 16
This example provides a (R) - (1-cyclohexyl-2-nitroethyl) di-p-tolyl phosphorus sulfide compound and a method for preparing the same. The structural formula of the (R) - (1-cyclohexyl-2-nitroethyl) di-p-tolyl phosphorus-sulfur compound is shown as the following molecular structural formula I16:
Figure BDA0002784881720000311
the preparation was carried out in accordance with the preparation of (S) -diphenyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorothioic compound in example 1, except that p-methyldiphenylphosphorothioic compound (0.1mmol) was used in place of diphenylphosphorothioic compound and (E) - (2-nitrovinyl) cyclohexane was used in place of (E) - (3,3, 3-trifluoro-1-nitroprop-1-en-2-yl) benzene (0.12 mmol). The reaction solution was directly separated and purified by silica gel column chromatography (ethyl acetate and n-hexane as eluent) to obtain the target product as a white solid with a yield of 94% and an ee value of 93%.
The product I16 prepared was subjected to characterization data analysis, which resulted in:1H NMR(400MHz,CDCl3)δ7.86(ddd,J＝17.0,12.5,8.1Hz,4H),7.27(dd,J＝9.9,4.1Hz,4H),4.74(ddd,J＝14.5,9.0,5.5Hz,1H),4.52–4.35(m,1H),3.62(ddd,J＝13.1,6.4,2.7Hz,1H),2.38(s,3H),2.36(s,3H),2.19(d,J＝6.3Hz,1H),1.88–1.65(m,2H),1.55(d,J＝15.6Hz,2H),1.46(d,J＝11.9Hz,1H),1.24(s,1H),1.11–0.98(m,4H).13C NMR(101MHz,CDCl3)δ142.75(d,J＝2.9Hz),142.63(d,J＝3.1Hz),131.40(d,J＝3.3Hz),131.29(d,J＝2.9Hz),129.85(d,J＝12.2Hz),129.68(d,J＝12.7Hz),128.31(d,J＝20.5Hz),127.50(d,J＝23.4Hz),73.09(d,J＝8.3Hz),41.91(d,J＝53.7Hz),37.70,34.06(d,J＝10.1Hz),29.17,27.00,26.11(d,J＝41.3Hz),21.58(d,J＝6.5Hz).31P NMR(162MHz,CDCl3)δ46.73.HRMS(ESI-TOF)[M+Na]calculated for[C12H14NaO2S]+424.1471,observed 424.1469.HPLC(Chiralpak-AD-H column,80:20hexane/ethanol,flow rate:1.0mL/min):tmajor＝7.174min；tminorthis result further confirmed the molecular structure of the product as described above for molecular structure I16.
Example 17
This example provides a tert-butyl (R) -4- (2- (di-p-tolylthiophosphoryl) -3-nitropropyl) piperidine-1-carboxylate compound and a method for preparing the same. The structural formula of the (R) -4- (2- (di-p-tolylthiophosphoryl) -3-nitropropyl) piperidine-1-carboxylic acid tert-butyl ester compound is shown as the following molecular structural formula I17:
Figure BDA0002784881720000321
the preparation was carried out in accordance with the preparation of (S) -diphenyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorothioic compound in example 1, except that p-methyldiphenylphosphorothioic compound (0.1mmol) was used in place of diphenylphosphorothioic compound and tert-butyl (E) -4- (2-nitrovinyl) piperidine-1-carboxylate was used in place of (E) - (3,3, 3-trifluoro-1-nitroprop-1-en-2-yl) benzene (0.12 mmol). The reaction solution was directly separated and purified by silica gel column chromatography (ethyl acetate and n-hexane as eluent) to obtain the target product as a white solid with a yield of 96% and an ee value of 93%.
The product I17 prepared was subjected to characterization data analysis, which resulted in:1H NMR(400MHz,CDCl3)δ7.96–7.85(m,2H),7.85–7.75(m,2H),7.40–7.10(m,4H),4.60–4.35(m,2H),3.95(s,1H),3.80–3.65(m,1H),2.55–2.40(d,J＝12.0Hz,2H),2.37(s,3H),2.36(s,3H),1.70–1.45(m,4H),1.39(s,9H),1.23(s,2H),1.01(s,1H),0.97–0.88(m,1H),0.82–0.70(m,1H).13C NMR(101MHz,CDCl3)δ175.07,154.77,143.12(d,J＝2.9Hz),143.01(d,J＝3.0Hz),131.41(d,J＝10.0Hz),129.98(d,J＝12.3Hz),129.75(d,J＝12.7Hz),127.40,126.60,79.50,76.59(d,J＝7.2Hz),35.29,34.55(d,J＝55.0Hz),33.63(d,J＝9.7Hz),32.63,31.47,29.81,28.54,21.59.31P NMR(162MHz,CDCl3)δ47.98.HRMS(ESI-TOF)[M+Na]calculated for[C27H37N2O4NaPS]+539.2104,observed 539.2103.HPLC(Chiralpak-OD-H column,97:3hexane/ethanol,flow rate:1.0mL/min):tmajor＝9.074min；tminorthis result further confirmed the molecular structure of the product as described above for molecular structure I17.
Example 18
This example provides a (R) - (6- (methylthio) -1-nitrohex-2-yl) di-p-methylphosphite sulfide compound and a method for preparing the same. The structural formula of the R) - (6- (methylthio) -1-nitrohex-2-yl) di-p-methylphosphite compound is shown as the following molecular structural formula I18:
Figure BDA0002784881720000322
the preparation was carried out according to the preparation of (S) -diphenyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorothioic compound in example 1, except that p-methyldiphenylphosphorothioic compound (0.1mmol) was used instead of diphenylphosphorothioic compound and (E) -methyl (6-nitrohex-5-enyl) thioether was used instead of (E) - (3,3, 3-trifluoro-1-nitroprop-1-en-2-yl) benzene (0.12 mmol). 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, white solid, yield is 85 percent, and ee value is 90 percent.
The product I18 prepared was subjected to characterization data analysis, which resulted in:1H NMR(400MHz,CDCl3)δ7.84(ddd,J＝23.5,12.5,8.1Hz,4H),7.27(t,J＝8.7Hz,4H),4.68–4.31(m,2H),3.73–3.47(m,1H),2.37(s,2H),2.37(s,3H),2.28(t,J＝7.1Hz,2H),1.99(s,3H),1.77–1.62(m,2H),1.40(dt,J＝15.2,7.2Hz,3H),1.30–1.11(m,2H).13C NMR(101MHz,CDCl3)δ143.03(d,J＝3.0Hz),142.86(d,J＝2.8Hz),131.45(d,J＝3.7Hz),131.35(d,J＝3.3Hz),129.95(d,J＝12.4Hz),129.75(d,J＝12.7Hz),127.57,126.75,76.19(d,J＝7.4Hz),37.70,37.15,33.69,28.93,27.96,26.48(d,J＝9.8Hz),21.59,15.59.HRMS(ESI-TOF)[M+H]calculated for[C21H29NO2PS2]+422.1372,observed 444.1175.HPLC(Chiralpak-IC-H column,98:2hexane/ethanol,flow rate:1.0mL/min):tmajor＝13.996min；tminorthis result further confirmed the molecular structure of the product as described above for molecular structure I18.
Example 19
This example provides a (R) - (4- (5-methylfuran-2-yl) -1-nitrobutane-2-yl) di-p-tolyl phosphorothioic compound and a method for preparing the same. The structural formula of the R) - (4- (5-methylfuran-2-yl) -1-nitrobutane-2-yl) di-p-tolyl phosphorus-sulfur compound is shown as the following molecular structural formula I19:
Figure BDA0002784881720000331
the preparation was carried out in accordance with the preparation of (S) -diphenyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorothioic compound in example 1, except that p-methyldiphenylphosphorothioic compound (0.1mmol) was used in place of diphenylphosphorothioic compound and (E) -2-methyl-5- (4-nitrobut-3-en-1-yl) furan was used in place of (E) - (3,3, 3-trifluoro-1-nitroprop-1-en-2-yl) benzene (0.12 mmol). 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, white solid, yield 90% and ee value 90%.
The product I19 prepared was subjected to characterization data analysis, which resulted in:1H NMR(400MHz,CDCl3)δ7.82(dd,J＝12.4,8.2Hz,2H),7.72(dd,J＝12.8,8.2Hz,2H),7.33–7.19(m,4H),5.93–5.70(m,2H),4.60–4.43(m,2H),3.67(ddd,J＝15.6,7.9,4.0Hz,1H),2.53(dt,J＝14.0,6.8Hz,1H),2.42(t,J＝7.7Hz,1H),2.37(s,3H),2.36(s,3H),2.20(s,3H),2.12–1.94(m,2H).13C NMR(101MHz,CDCl3)δ151.62,151.03,142.98(d,J＝2.9Hz),142.75(d,J＝3.0Hz),131.46(d,J＝3.1Hz),131.35(d,J＝2.9Hz),129.89(d,J＝12.4Hz),129.70(d,J＝12.7Hz),127.51(d,J＝26.7Hz),126.70(d,J＝28.7Hz),107.13,106.08,76.03(d,J＝7.1Hz),36.27(d,J＝55.4Hz),27.24,25.72,25.61,21.60,13.64.31P NMR(162MHz,CDCl3)δ47.63.HRMS(ESI-TOF)[M+Na]calculated for[C23H26NO3NaPS]+450.1263,observed450.1265.HPLC(Chiralpak-IC-H column,98:2hexane/ethanol,flow rate:1.0mL/min):tmajor＝10.699min；tminorthis result further confirmed the molecular structure of the product as described above for molecular structure I19.
Example 20
This example provides a (R) - (1-nitro-4- (thien-2-yl) but-2-yl) di-p-tolyl phosphorothioic compound and a method for preparing the same. The structural formula of the (R) - (1-nitro-4- (thiophene-2-yl) butyl-2-yl) di-p-tolyl phosphorus sulfur compound is shown as the following molecular structural formula I20:
Figure BDA0002784881720000341
the preparation was carried out according to the preparation of (S) -diphenyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorothioic compound in example 1, except that p-methyldiphenylphosphorothioic compound (0.1mmol) was used instead of diphenylphosphorothioic compound and (E) -2- (4-nitrobut-3-en-1-yl) thiophene instead of (E) - (3,3, 3-trifluoro-1-nitroprop-1-en-2-yl) benzene (0.12 mmol). The reaction solution was directly separated and purified by silica gel column chromatography (ethyl acetate and n-hexane as eluent) to obtain the target product as a white solid with a yield of 95% and an ee value of 93%.
The product I20 prepared was subjected to characterization data analysis, which resulted in:1H NMR(400MHz,CDCl3)δ7.83(dd,J＝12.4,8.2Hz,2H),7.71(dd,J＝12.8,8.1Hz,2H),7.26(ddd,J＝10.9,7.7,2.6Hz,4H),7.11(dd,J＝5.1,1.1Hz,1H),6.89(dd,J＝5.1,3.4Hz,1H),6.69–6.60(m,1H),4.61–4.46(m,2H),3.69(ddd,J＝12.1,8.7,3.6Hz,1H),2.89–2.76(m,1H),2.62(dd,J＝15.4,7.7Hz,1H),2.37(d,J＝2.3Hz,6H),2.11–1.99(m,2H).13C NMR(101MHz,CDCl3)δ143.07(d,J＝2.9Hz),142.87(d,J＝2.9Hz),142.68,131.47(d,J＝4.5Hz),131.37(d,J＝4.2Hz),129.95(d,J＝12.4Hz),129.78(d,J＝12.7Hz),127.34(d,J＝23.9Hz),127.05,126.53(d,J＝25.5Hz),125.29,123.88,76.12(d,J＝7.3Hz),36.43(d,J＝55.2Hz),30.63,29.84,27.43(d,J＝10.1Hz),21.62.31P NMR(162MHz,CDCl3)δ47.40.HRMS(ESI-TOF)[M+H]calculated for[C22H25NO2PS2]+430.1059,observed 430.1060.HPLC(Chiralpak-IC-H column,98:2hexane/ethanol,flow rate:1.0mL/min):tmajor＝9.162min；tminorthis result further confirmed the molecular structure of the product as described above for molecular structure I20.
Example 21
The embodiment provides an (S) -di-p-tolyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorus oxide oxygen compound and a preparation method thereof, wherein the compound is used as a chiral phosphorus oxygen ligand and applied to the field of metal ligands. The structural formula of the (S) -di-p-tolyl (1,1, 1-trifluoro-3-nitro-2-phenylprop-2-yl) phosphorus oxide oxygen compound is shown as the following molecular structural formula I21:
Figure BDA0002784881720000351
the preparation method comprises the following steps:
compound I2(0.1mmol) was dissolved in 1.0mL of pretreated dichloromethane at 10, and the oxidant m-chloroperoxybenzoic acid (0.2mmol) was added at room temperature and stirred at room temperature overnight. The reaction was then quenched with aqueous potassium hydroxide (10 wt%, 10mL), the aqueous phase was extracted twice with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate for 1 hour and filtered, and the organic phase was concentrated and directly purified by silica gel column chromatography (ethyl acetate and n-hexane as eluent) to give I21 as a white solid with 98% yield and 94% ee.
The product I21 prepared was subjected to characterization data analysis, which resulted in:1H NMR(400MHz,CDCl3)δ7.75(dd,J＝11.2,8.0Hz,2H),7.37–7.24(m,9H),7.05(dd,J＝8.2,3.5Hz,2H),5.77–5.68(m,1H),5.21(dd,J＝14.1,3.8Hz,1H),2.40(s,3H),2.29(s,3H).13CNMR(101MHz,CDCl3)δ143.96(d,J＝3.0Hz),143.42(d,J＝3.0Hz),132.91(d,J＝10.0Hz),132.49(d,J＝9.1Hz),129.43(d,J＝12.1Hz),128.81(d,J＝13.1Hz),128.20(d,J＝2.0Hz),127.96(d,J＝5.1Hz),125.46(q,J＝285.8Hz),124.76(d,J＝97.9Hz),124.52(d,J＝108.1Hz),99.99,74.50(d,J＝7.1Hz),60.85(q,J＝22.2Hz),29.71,21.64(d,J＝1.0Hz),21.52(d,J＝1.0Hz).31P NMR(162MHz,CDCl3)δ30.86.HRMS(ESI-TOF)[M+H]calculated for[C23H22F3NO3P]+448.1289,observed 448.1285.HPLC(Chiralpak-IC-H column,80:20hexane/ethanol,flow rate:1.0mL/min):tmajor＝10.443min；tminorthis result further confirmed the molecular structure of the product as described above for molecular structure I21.
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.

Claims (10)

1. A Michael addition method of a chiral phosphorus-sulfur compound is characterized by comprising the following steps:
respectively providing a phosphorus-sulfur compound A and a nitroolefin compound B shown in the following structures:
A：
Figure FDA0002784881710000011
B：
Figure FDA0002784881710000012
adding the phosphorus-sulfur compound A and the nitroolefin compound B into a reaction system containing an N-heterocyclic carbene catalyst, a proton additive, an alkali reagent and a water absorption additive, and reacting at the temperature of-80-25 ℃ to obtain a chiral beta-nitro phosphorus-sulfur compound shown in the following structural general formula (I),
Figure FDA0002784881710000013
wherein in the phosphorus-sulfur compound A and the chiral beta-nitro phosphorus-sulfur compound, R1、R2Are 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, alkaneAny of an oxycarbonylalkyl group;
in the nitroolefin compound B and the chiral beta-nitrophosphite sulfur compound, R3Is a reaction with R1、R2Identical 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) Any one of an alkyl group and an alkyloxycarbonylalkyl group; r4Is hydrogen atom, cyano, C1-C20Perfluoroalkyl radical, C1-C20Ester group, C1-C20Heteroalkyl group, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Heteroalkenyl, C2-C10Alkynyl, C2-C10Heteroalkynyl, C3-C8Aryl radical (C)1-C10) Alkyl radical, C2-C10Alkenyl (C)1-C10) Alkyl radical, C2-C10Alkynyl (C)1-C10) Any of alkyl groups.
2. The Michael addition process for a chiral phospha-sulfur compound as claimed in claim 1, wherein said 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 radical (C)3-C8) Aryl, substituted (C)3-C8) Aryl group, (C)3-C8) Heteroaryl, substituted (C)3-C8) Any one of heteroaryl; and/or
The R is4Is a hydrogen atom, C1-C5Perfluoroalkyl radical, C1-C5Ester group, C1-C10Any one of heteroalkyl groups.
3. The Michael addition process for a chiral phospha-sulfur compound as claimed in claim 1, wherein said 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, C3-C8Heteroaryl substituted pyridinesAny one of (a); and/or
The R is4Is hydrogen atom, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, heptafluoroisopropyl, C1-C10Alkoxyalkyl group, (C)1-C10) Alkyloxycarbonyl (C)1-C10) Any of alkyl groups.
4. A Michael addition process of a chiral phosphorus sulfur compound as claimed in any one of claims 1 to 3, wherein the molar ratio of said azacyclo-carbene catalyst, said basic reagent and said protic additive is (0.1-20): (0.2-40); and/or
The molar ratio of the N-heterocyclic carbene catalyst, the alkali reagent, the proton additive and the compound A is (0.1-20): (0.2-40): (1-100).
5. A Michael addition process of a chiral phosphorus sulfur compound according to any one of claims 1 to 3, wherein the azacyclo-carbene catalyst is selected from nitrogen containing heterocyclic compounds represented by the following general structural formula C and/or general structural formula D:
C：
Figure FDA0002784881710000031
D：
Figure FDA0002784881710000032
wherein X in the structural general formula C is a carbon atom or an oxygen atom, and n is 0 or 1;
in the general structural formulas C and D, Z is identical or different boron tetrafluoride anion or chloride ion, R5Is 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, (C)2-C20) Alkenyl (C)1-C20) Alkyl, (C)2-C20) Alkynyl (C)1-C20) Alkyl, cyano (C)1-C20) Any of alkyl groups; r6And R7Are identical or different C1-C20Alkyl radical, C1-C20Heteroalkyl, aryl (C)1-C20) Alkyl, heteroaryl (C)1-C20) Any of alkyl, aryl, substituted aryl; and/or
The alkali reagent is at least one 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, bistrimethylsilyl amino lithium, bistrimethylsilyl sodium, bistrimethylsilyl potassium, diisopropylamino lithium, n-butyl lithium, tert-butyl lithium, methyllithium, sodium methoxide, sodium ethoxide and sodium ethylmercaptide; and/or
The proton additive is at least one of the compounds shown in the following structure:
Figure FDA0002784881710000041
Figure FDA0002784881710000042
and/or
The water absorption additive is anhydrous sodium sulfate, anhydrous magnesium sulfate, preactivated 13 multiplied by molecular sieve,
Figure FDA0002784881710000043
Molecular sieve,
Figure FDA0002784881710000051
Molecular sieves and
Figure FDA0002784881710000052
at least one of molecular sieves.
6. A chiral phosphorus-sulfur compound is characterized in that the chiral phosphorus-sulfur compound is shown as the following structural general formula (I):
Figure FDA0002784881710000053
in the formula, 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 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) Any one of an alkyl group and an alkyloxycarbonylalkyl group;
R4is hydrogen atom, cyano, C1-C20Ester group, C1-C20Heteroalkyl group, C1-C20Perfluoroalkyl radical, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Heteroalkenyl, C2-C10Alkynyl, C2-C10Heteroalkynyl, C3-C8Aryl radical (C)1-C10) Alkyl radical, C2-C10Alkenyl (C)1-C10) Alkyl radical, C2-C10Alkynyl (C)1-C10) Any of alkyl groups.
7. The chiral phosphorus sulfur compound of claim 6, 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 radical (C)3-C8) Aryl, substituted (C)3-C8) Aryl group, (C)3-C8) Heteroaryl, substituted (C)3-C8) Any one of heteroaryl; and/or
The R is4Is a hydrogen atom, C1-C5Perfluoroalkyl radical, C1-C5Ester group, C1-C10Any one of heteroalkyl groups.
8. The chiral phosphorus sulfur compound of claim 7, 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, C3-C8Any of heteroaryl substituted pyridines; and/or
The R is4Is hydrogen atom, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, heptafluoroisopropyl, C1-C10Alkoxyalkyl group, (C)1-C10) Alkyloxycarbonyl (C)1-C10) Any of alkyl groups.
9. The chiral phosphorus-sulfur compound of any one of claims 6 to 8, wherein the chiral β -nitrophosphosulfur compound of formula (I) comprises one of the following structures I1 to I21:
Figure FDA0002784881710000061
Figure FDA0002784881710000071
10. use of a chiral phosphorothioate compound as defined in any one of claims 7 to 9 or a chiral phosphorothioate compound produced by the Michael addition process as defined in any one of claims 1 to 6 in the synthesis of pharmaceutical intermediates, functional materials, metal ligands and the preparation of metal complexes.
CN202011294694.6A 2020-11-18 2020-11-18 Chiral phosphorus sulfur compound and Michael addition method thereof Pending CN112409408A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202011294694.6A CN112409408A (en) 2020-11-18 2020-11-18 Chiral phosphorus sulfur compound and Michael addition method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202011294694.6A CN112409408A (en) 2020-11-18 2020-11-18 Chiral phosphorus sulfur compound and Michael addition method thereof

Publications (1)

Publication Number Publication Date
CN112409408A true CN112409408A (en) 2021-02-26

Family

ID=74774438

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202011294694.6A Pending CN112409408A (en) 2020-11-18 2020-11-18 Chiral phosphorus sulfur compound and Michael addition method thereof

Country Status (1)

Country Link
CN (1) CN112409408A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113680385A (en) * 2021-08-23 2021-11-23 深圳湾实验室坪山生物医药研发转化中心 N-heterocyclic carbene-thiourea double-functional group catalyst and preparation method and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009263233A (en) * 2008-04-21 2009-11-12 Tokyo Univ Of Science Method for producing asymmetrically catalyzed michael reaction product, and method for producing pharmaceutical compound
CN105367427A (en) * 2015-11-04 2016-03-02 北京大学深圳研究生院 Chiral 1,2-diamine compound and preparation method and application thereof
CN107146910A (en) * 2016-03-01 2017-09-08 微宏动力系统（湖州）有限公司 Additive for lithium secondary cell electrolyte and preparation method thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009263233A (en) * 2008-04-21 2009-11-12 Tokyo Univ Of Science Method for producing asymmetrically catalyzed michael reaction product, and method for producing pharmaceutical compound
CN105367427A (en) * 2015-11-04 2016-03-02 北京大学深圳研究生院 Chiral 1,2-diamine compound and preparation method and application thereof
CN107146910A (en) * 2016-03-01 2017-09-08 微宏动力系统（湖州）有限公司 Additive for lithium secondary cell electrolyte and preparation method thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PUDOVIK A. N. ET AL.: "Addition of partial esters of phosphorus acids to nitroisoamylene and ethyl vinyl sulfone" *
STN REGISTRY: "RN172508-13-3等" *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113680385A (en) * 2021-08-23 2021-11-23 深圳湾实验室坪山生物医药研发转化中心 N-heterocyclic carbene-thiourea double-functional group catalyst and preparation method and application thereof
CN113680385B (en) * 2021-08-23 2023-05-23 深圳湾实验室坪山生物医药研发转化中心 N-heterocyclic carbene-thiourea bifunctional group catalyst and preparation method and application thereof

Similar Documents

Publication Publication Date Title
CN104892547B (en) A kind of method that catalysis of carbonyl is combined to alpha-keto amide compound
WO2010036921A2 (en) Slow release of organoboronic acids in cross-coupling reactions
CN104592236A (en) Method for synthesis of chiral heterocyclic nucleoside analogue by asymmetric [3+2] cycloaddition
CN112409408A (en) Chiral phosphorus sulfur compound and Michael addition method thereof
CN113620762A (en) Ketene compound and preparation method and application thereof
WO2011103435A2 (en) Methods for forming protected organoboronic acids
CN105367427A (en) Chiral 1,2-diamine compound and preparation method and application thereof
Wang et al. Enantio-and regioselective [2+ 2+ 2] cycloaddition of BN-diynes for construction of CB axial chirality
CN111925356B (en) Synthesis method and application of chiral quinoline-imidazoline ligand
CN112321544B (en) Chiral quaternary carbon cyanide and preparation method thereof
CN111793017B (en) Preparation method of lactam compound
CN109942617B (en) Alpha-tetra-substituted chiral alkynone compound and preparation method and application thereof
CN113620851A (en) Chiral beta-diester selenoethers and Michael addition preparation method thereof
CN110590690B (en) Sp catalyzed by copper 2 Alkenyl reaction method for hybridized carbon-hydrogen bond
CN113860983A (en) Chiral beta-carbon-based selenide compound and preparation method and application thereof
CN112457219A (en) Beta-carbonyl chiral amino compound and preparation method thereof
CN113713858B (en) Alpha alkylation reaction catalyst of nitrile and preparation method thereof
CN112479948A (en) Beta-sulfuryl chiral amino compound and preparation method thereof
CN111499542A (en) Preparation method of cycloenone compound containing α -cyano substituted quaternary carbon center
CN110683928A (en) Preparation method of alpha-chiral carbonyl heterocyclic compound
CN113387837B (en) Photo-oxidation-reduction catalysis method
CN117050017A (en) Axis chiral alkenyl-sulfur ylide compound and preparation method thereof
CN117050050A (en) Alkynyl-sulfur ylide compound and preparation method thereof
CN112430249A (en) Metal complex and preparation method thereof
CN106366032B (en) Application of the chiral organic base in water phase and an oil phase system chirality sulfur-bearing benzazolyl compounds

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination