WO2017215110A1 - 一种非对称硫醚的合成方法 - Google Patents

一种非对称硫醚的合成方法 Download PDF

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WO2017215110A1
WO2017215110A1 PCT/CN2016/095469 CN2016095469W WO2017215110A1 WO 2017215110 A1 WO2017215110 A1 WO 2017215110A1 CN 2016095469 W CN2016095469 W CN 2016095469W WO 2017215110 A1 WO2017215110 A1 WO 2017215110A1
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substituted
phenyl
group
naphthyl
mmol
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French (fr)
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纪顺俊
褚雪强
徐小平
曹文斌
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Suzhou University
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Suzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
    • C07C321/12—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to acyclic carbon atoms
    • C07C321/18—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to acyclic carbon atoms of an acyclic unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B45/00—Formation or introduction of functional groups containing sulfur
    • C07B45/06—Formation or introduction of functional groups containing sulfur of mercapto or sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/26—Separation; Purification; Stabilisation; Use of additives
    • C07C319/28—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
    • C07C321/12—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
    • C07C321/12—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to acyclic carbon atoms
    • C07C321/20—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/18—Radicals substituted by singly bound hetero atoms other than halogen by sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/10—Dibenzothiopyrans; Hydrogenated dibenzothiopyrans
    • C07D335/12—Thioxanthenes
    • 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
    • C07F11/00—Compounds containing elements of Groups 6 or 16 of the Periodic Table
    • C07F11/005—Compounds containing elements of Groups 6 or 16 of the Periodic Table compounds without a metal-carbon linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2527/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
    • C07C2527/06—Halogens; Compounds thereof
    • C07C2527/08—Halides
    • C07C2527/12—Fluorides

Definitions

  • the invention belongs to the field of organic chemistry, and in particular relates to a method for synthesizing asymmetric thioether.
  • Asymmetric thioethers are an important class of sulfur-containing compounds. Their skeletons are not only widely found in natural products, pharmaceutically active molecules, but also as advanced materials and metal ligands, or as important organic synthesis intermediates.
  • Asymmetric thioether compounds are widely used in biomedical applications, such as:
  • Methionine is one of the essential amino acids that make up the human body. It is involved in protein synthesis. Because it cannot be produced in the body itself, it must be obtained from the outside. The lack of methionine will cause the protein synthesis in the body to be blocked and cause damage to the body. . At present, methionine is synthesized by a coupling reaction of a halide with a thiol and its related derivatives under transition metal catalysis.
  • Cilastatin is a thienamycin antibiotic with a carbapenem ring, and a commercially available antibacterial drug obtained by semi-synthesis of thienamycin is isolated from a streptomycin S. cattleya culture solution. For sepsis caused by sensitive bacteria, infective endocarditis, osteomyelitis, arthritis, skin and soft tissue infections. At present, Cilastatin is generally prepared by direct addition of an unsaturated compound to a thiol or a derivative thereof under transition metal or metal-free conditions.
  • Cinanserin can be used to treat mental illnesses.
  • cinnacilin is prepared by the addition of a thiol or a derivative thereof to an alkyne under the action of a transition metal catalyst.
  • an object of the present invention is to provide a method for synthesizing an asymmetric thioether, which provides a mild reaction environment and environmental friendliness.
  • the invention provides a method for synthesizing asymmetric thioether, comprising the following steps:
  • R 1 is selected from phenyl, substituted phenyl, naphthyl, substituted naphthyl, thienyl or substituted thienyl
  • R 2 is selected from hydrogen, phenyl, substituted phenyl, naphthyl, substituted naphthyl, thienyl or Substituting a thienyl group; or R 1 , R 2 forming an anthracene ring or a thioxanthene ring with the C to which it is attached;
  • R 3 is selected from hydrogen or an alkyl group
  • R 4 is selected from the group consisting of hydrogen, phenyl, substituted phenyl, naphthyl, substituted naphthyl, thienyl or substituted thienyl, R 5 is selected from hydrogen; or R 4 , R 5 forms an anthracene or thiox with the C to which it is attached ring;
  • R 6 is selected from an alkyl group or a substituted alkyl group
  • X is selected from Cl, Br or I
  • the oxysulfide salt includes sodium thiosulfate and/or sodium sulfite.
  • R 1 is selected from the group consisting of phenyl, C1-C5 alkyl-substituted phenyl, C1-C5 alkoxy-substituted phenyl, halogen-substituted phenyl, naphthyl, C1-C5 alkyl-substituted naphthyl, a C1-C5 alkoxy-substituted naphthyl group, a halogen-substituted naphthyl group, a thienyl group, a C1-C5 alkyl-substituted thienyl group, a C1-C5 alkoxy-substituted thienyl group or a halogen-substituted thienyl group;
  • R 2 is selected from the group consisting of hydrogen, phenyl, C1-C5 alkyl-substituted phenyl, C1-C5 alkoxy-substituted phenyl, halogen-substituted phenyl, naphthyl, C1-C5 alkyl-substituted naphthyl, C1 a C5 alkoxy-substituted naphthyl group, a halogen-substituted naphthyl group, a thienyl group, a C1-C5 alkyl-substituted thienyl group, a C1-C5 alkoxy-substituted thienyl group or a halogen-substituted thienyl group;
  • R 3 is selected from the group consisting of hydrogen and C1-C5 alkyl
  • R 4 is selected from the group consisting of hydrogen, phenyl, C1-C5 alkyl-substituted phenyl, halogen-substituted phenyl, naphthyl, C1-C5 alkyl-substituted naphthyl, halogen-substituted naphthyl, thienyl, C1-C5 An alkyl-substituted thienyl group or a halogen-substituted thienyl group;
  • the R 6 is selected from the group consisting of a C1-C30 alkyl group, a cyano-substituted C1-C20 alkyl group, a benzyl group, a C1-C5 alkyl-substituted benzyl group, a halogen-substituted benzyl group, a fluorenyl group, and a formula ( Any of the structural substituents of a-1) to (a-9):
  • m 1 , m 2 , m 3 , n, q, p 1 , p 2 , r 1 , r 2 and e are independently selected from integers of 0 to 5. .
  • the structural compound of the formula (I) is specifically 1,1-diphenylprop-2-en-1-ol, 1,1-bis(4-fluorophenyl)prop-2-enyl- 1-alcohol, 1,1-bis(4-chlorophenyl)prop-2-en-1-ol, 1,1-bis(4-bromophenyl)prop-2-en-1-ol, 1,1-bis(4-methylphenyl)prop-2-en-1-ol, 1,1-bis(4-methoxyphenyl)prop-2-en-1-ol, 1 -Phenyl-1-p-methylphenyl-2-en-1-ol, 1-(3,4-dimethylphenyl)-1-phenylprop-2-en-1-ol, 1 -Phenyl-1-p-bromophenylpropan-2-en-1-ol, 1-phenyl-1-ofluorophenylprop-2-en-1-ol, 1-(naphthalen-2-yl
  • the structural compound of the formula (II) is specifically p-cyanobenzyl chloride, m-cyanobenzyl chloride, p-trifluoromethylbenzyl chloride, o-bromobenzyl chloride, p-methylbenzyl bromide, 9-bromofluorene, ( 4-(Chloromethyl)phenyl)(1H-indol-1-yl)methanone, ((3aR,5S,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydroxy- 3aH-bis[1,3]dioxo[4,5-b:4',5'-d]pyran-5-yl)methyl 4-(chloromethyl)phenyl ester, chloroacetonitrile, 1- Ethyl bromoacetate, 2-bromo-N,N-diethylpropionamide, bromopropyne, (3-chloropropyl-1-yn
  • the molar ratio of the structural compound of the formula (I), the structural compound of the formula (II) and the oxysulfide salt is 1: (1.5 to 3): (2 to 4).
  • the temperature of the reaction is from 20 to 90 °C.
  • the reaction time is from 3 to 8 hours.
  • step a) after the reaction of the structural compound of the formula (I), the structural compound of the formula (II) and the oxysulfide salt, the extraction, drying and column chromatography are sequentially carried out to obtain an asymmetric sulfur having the structure of the formula (III). ether.
  • the solvent is water.
  • the present invention provides a method of synthesizing an asymmetric thioether as compared with the prior art.
  • the method provided by the present invention comprises the following step a), under the catalytic condition of tetrabutylammonium halide, the structural compound of the formula (I), the structural compound of the formula (II) and the oxysulfide are reacted in a solvent to obtain the formula (III).
  • R 1 is selected from phenyl, substituted phenyl, naphthyl, substituted naphthyl, thienyl or substituted thienyl
  • R 2 is selected from hydrogen, phenyl, substituted phenyl, naphthyl, substituted naphthyl, thienyl or Substituted thienyl; or R 1 , R 2 forms an anthracene or thioxan ring with the C to which it is attached
  • R 3 is selected from hydrogen or alkyl
  • R 4 is selected from hydrogen, phenyl, substituted phenyl, naphthyl, substituted naphthalene a thiophene group or a substituted thienyl group
  • R 5 is selected from hydrogen
  • R 4 , R 5 forms an anthracene ring or a thioxanthene ring with the C to which it is attached
  • R 6 is selected from an alkyl
  • the method provided by the invention adopts a one-pot method to prepare an asymmetric thioether by using a substituted aryl allyl alcohol compound, a substituted alkyl halide and a sulfoxide as a reaction raw material, and a tetrabutylammonium halide as a catalyst.
  • the method has the advantages of low cost and easy availability, simple and mild catalytic conditions, no need for transition metal participation, and high yield.
  • the reaction is carried out in an aqueous phase in accordance with green chemical requirements.
  • the experimental results show that a series of asymmetric thioethers with potential biological and pharmacological activities can be synthesized by the method provided by the invention, and the product yield is up to 91%.
  • the invention provides a method for synthesizing asymmetric thioether, comprising the following steps:
  • R 1 is selected from phenyl, substituted phenyl, naphthyl, substituted naphthyl, thienyl or substituted thienyl
  • R 2 is selected from hydrogen, phenyl, substituted phenyl, naphthyl, substituted naphthyl, thienyl or Substituting a thienyl group; or R 1 , R 2 forming an anthracene ring or a thioxanthene ring with the C to which it is attached;
  • R 3 is selected from hydrogen or an alkyl group
  • R 4 is selected from the group consisting of hydrogen, phenyl, substituted phenyl, naphthyl, substituted naphthyl, thienyl or substituted thienyl, R 5 is selected from hydrogen; or R 4 , R 5 forms an anthracene or thiox with the C to which it is attached ring;
  • R 6 is selected from an alkyl group or a substituted alkyl group
  • X is selected from Cl, Br or I
  • the oxysulfide salt includes sodium thiosulfate and/or sodium sulfite.
  • the structural compound of the formula (I), the structural compound of the formula (II) and the oxysulfide are reacted in a solvent under the catalytic conditions of tetrabutylammonium halide.
  • the structure of the structural compound of the formula (I) is as follows:
  • R 1 is selected from phenyl, substituted phenyl, naphthyl, substituted naphthyl, thienyl or substituted thienyl, preferably phenyl, C1-C5 alkyl substituted phenyl, C1-C5 alkane Oxy-substituted phenyl, halogen-substituted phenyl, naphthyl, C1-C5 alkyl-substituted naphthyl, C1-C5 alkoxy-substituted naphthyl, halogen-substituted naphthyl, thienyl, C1-C5 alkane a substituted thiophenyl group, a C1-C5 alkoxy-substituted thienyl group or a halogen-substituted thienyl group, more preferably from phenyl, fluorophenyl, chlorophen
  • R 3 is selected from hydrogen or an alkyl group, preferably from hydrogen, a C1-C5 alkyl group, more preferably from hydrogen, methyl or ethyl.
  • R 4 is selected from hydrogen, phenyl, substituted phenyl, naphthyl, substituted naphthyl, thienyl or substituted thienyl, preferably phenyl substituted by hydrogen, phenyl, C1-C5 alkyl, Halogen-substituted phenyl, naphthyl, C1-C5 alkyl-substituted naphthyl, halogen-substituted naphthyl, thienyl, C1-C5 alkyl-substituted thienyl or halogen-substituted thienyl, more preferably hydrogen, benzene Base, fluorophenyl, chlorophenyl, bromophenyl, naphthyl or thienyl, most preferably selected from hydrogen, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl or na
  • the structural compound of the formula (I) is specifically 1,1-diphenylprop-2-en-1-ol (1), 1,1-bis(4-fluoro Phenyl)prop-2-en-1-ol (2), 1,1-bis(4-chlorophenyl)prop-2-en-1-ol (3), 1,1-double (4 -Bromophenyl)prop-2-en-1-ol (4), 1,1-bis(4-methylphenyl)prop-2-en-1-ol (5), 1,1- Bis(4-methoxyphenyl)prop-2-en-1-ol (6), 1-phenyl-1-p-methylphenyl-2-en-1-ol (7), 1- (3,4-Dimethylphenyl)-1-phenylprop-2-en-1-ol (8), 1-phenyl-1-p-bromophenylpropan-2-en-1-ol (9), 1-phenyl-1-ofluorophenylprop-2-en-1-ol
  • R 1 may be selected from hydrogen, fluorine, chlorine, bromine, methyl, methoxy or dimethyl
  • R 2 may be selected from hydrogen and fluorine.
  • R 1 may be selected from hydrogen, fluorine, chlorine or bromine
  • R 2 may be Selected from hydrogen, fluorine, chlorine or bromine.
  • R 6 is selected from an alkyl group or a substituted alkyl group, preferably a C1-C30 alkyl group, a cyano-substituted C1-C20 alkyl group, a benzyl group, a C1-C5 alkyl-substituted benzyl group, or a halogen substituent.
  • m 1 , m 2 , m 3 , n, q, p 1 , p 2 , r 1 , r 2 and e are independently selected from integers of 0 to 5. .
  • the structural compound of the formula (II) is specifically p-cyanobenzyl chloride (23), m-cyanobenzyl chloride (24), p-trifluoromethylbenzyl chloride (25), ortho Bromobenzyl chloride (26), p-methylbenzyl bromide (27), 9-bromoindole (28), (4-(chloromethyl)phenyl)(1H-indol-1-yl)methanone (29) ,((3aR,5S,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydroxy-3aH-bis[1,3]dioxo[4,5-b:4',5 '-d]pyran-5-yl)methyl 4-(chloromethyl)phenyl ester (30), chloroacetonitrile (31), ethyl 1-bromoacetate (32), 2-bromo-N , N-diethylpro
  • R may be selected from cyano, trifluoromethyl, bromo or methyl, and X may be selected from chlorine or bromine.
  • the oxysulfide salt comprises sodium thiosulfate and/or sodium sulfite, preferably sodium thiosulfate; the solvent is preferably water.
  • the molar ratio of the structural compound of the formula (I), the structural compound of the formula (II) and the oxysulfide salt is preferably 1: (1.5 to 3): (2 to 4), more preferably 1: (1.5 to 2): 2 to 2.4), most preferably 1:2:2.4.
  • the molar ratio of the tetrabutylammonium halide to the structural compound of the formula (I) is preferably (0.01 to 1):1. It is more preferably (0.1 to 0.5): 1, and most preferably 0.2:1.
  • the ratio of the solvent to the structural compound of the formula (I) is preferably (0.1 to 10) mL: (0.1 to 0.5) mmol, more preferably (0.5 to 2) mL: (0.1 to 0.5) mmol, most preferably 1 mL: 0.3 mmol.
  • the reaction in the process of reacting the structural compound of the formula (I), the structural compound of the formula (II) and the oxysulfide salt in a solvent, the reaction is preferably carried out under a closed condition; the temperature of the reaction is preferably 20 °. 90 ° C, more preferably 25 to 80 ° C, most preferably 70 to 80 ° C, most preferably 80 ° C; the reaction time is preferably 3 to 8 h, more preferably 5 to 6 h. After completion of the reaction, a reaction liquid was obtained, which was subjected to extraction, drying and column chromatography in that order.
  • the extracting agent is preferably ethyl acetate; the desiccant used for drying is preferably anhydrous sodium sulfate; the stationary phase used in the column chromatography is preferably 300-400 mesh silica gel; the mobile phase used in the column chromatography Preferred are ethyl acetate and petroleum ether.
  • the method provided by the invention adopts a one-pot method to prepare an asymmetric thioether by using a substituted aryl allyl alcohol compound, a substituted alkyl halide and a sulphur oxygen salt as a reaction raw material and a tetrabutylammonium halide as a catalyst.
  • the method has the advantages of low cost and easy availability, simple and mild catalytic conditions, no need for transition metal participation, and high yield.
  • the reaction is carried out in an aqueous phase in accordance with green chemical requirements.
  • the experimental results show that a series of asymmetric thioethers with potential biological and pharmacological activities can be synthesized by the method provided by the invention, and the product yield is up to 91%.
  • the obtained reaction product was pure 4-((3,3-diarylallylthio)methyl)benzonitrile (purity >95%); the product yield was calculated, and the result was calculated. It is 76%.
  • the obtained reaction product is pure 4-((3,3-bis(4-fluorophenyl)allylthio)methyl)benzonitrile (purity >95%); The rate was calculated and the result was 82%.
  • the obtained reaction product is pure 4-((3,3-bis(4-chlorophenyl)allylthio)methyl)benzonitrile (purity >95%); The rate is calculated and the result is 80%.
  • the obtained reaction product is pure 4-((3,3-bis(4-bromophenyl)allylthio)methyl)benzonitrile (purity >95%); The rate was calculated and the result was 71%.
  • the obtained reaction product was pure 4-((3,3-p-tolylallylthio)methyl)benzonitrile (purity >95%); the product yield was calculated, and the result was calculated. It is 76%.
  • the obtained reaction product was pure 4-((3,3-p-methoxyphenylallylthio)methyl)benzonitrile (purity >95%); Calculated, the result is 60%.
  • the obtained reaction product was pure 4-((3-phenyl-3-p-tolylthio)methyl)benzonitrile (purity >95%); the yield of the product was calculated, and the result was calculated. It is 67%.
  • reaction product was pure 4-((3-(3,4-dimethylphenyl)-3-phenylallylthio)methyl)benzonitrile (purity >95). %); Calculated for product yield, the result was 79%.
  • the obtained reaction product is pure 4-((3-phenyl-3-p-bromophenylthio)methyl)benzonitrile (purity >95%); the product yield is calculated, The result was 67%.
  • reaction solution is successively dried through ethyl acetate, anhydrous sodium sulfate and column chromatography (column chromatography separation conditions:
  • the stationary phase is 300-400 mesh silica gel
  • the mobile phase is ethyl acetate (A) and petroleum ether (B)
  • the mobile phase change procedure (A:B) is 1:20 ⁇ 1:6), and 0.0669 g of reaction product is obtained. .
  • the obtained reaction product is pure 4-((3-phenyl-3-o-fluorophenylthio)methyl)benzonitrile (purity >95%); the product yield is calculated, The result was 62%.
  • the obtained reaction product is pure 4-((3-(naphthalen-2-yl)-3-phenylallylthio)methyl)benzonitrile (purity >95%);
  • the product yield was calculated and found to be 76%.
  • the obtained reaction product is pure 4-((2-methyl-3,3-diphenylallylthio)methyl)benzonitrile (purity >95%); The rate was calculated and the result was 74%.
  • the obtained reaction product is pure 4-((2-(9H- ⁇ -9-yl))ethylthio)methyl)benzonitrile (purity >95%); Calculated, the result is 58%.
  • the obtained reaction product is pure 4-((2-(9H-thioxan-9-yl))ethylthio)methyl)benzonitrile (purity >95%); The rate was calculated and the result was 62%.
  • the obtained reaction product was a pure product of 4-(cinnamoylthiomethyl)benzonitrile (purity >95%); the product yield was calculated to be 23%.
  • the obtained reaction product was pure (E)-4-((1,3-diphenylallylthio)methyl)benzonitrile (purity >95%); The calculation was performed and the result was 74%.
  • the obtained reaction product was pure (E)-4-((1,3-bis(4-fluorophenyl)allylthio)methyl)benzonitrile (purity >95%) Calculate the product yield and the result is 91%.
  • the obtained reaction product was pure (E)-4-((1,3-bis(4-chlorophenyl)allypropylthio)methyl)benzonitrile (purity >95%)
  • the product yield was calculated and found to be 72%.
  • the obtained reaction product was pure (E)-4-((1,3-bis(4-bromophenyl)allypropylthio)methyl)benzonitrile (purity >95%)
  • the product yield was calculated and found to be 83%.
  • the obtained reaction product was pure (E)-4-((1,3-bis(naphthalen-2-yl)allylthio)methyl)benzonitrile (purity >95%)
  • the product yield was calculated and found to be 43%.
  • the obtained reaction product was pure (E)-4-((1,3-bis(thiophen-2-yl)allylthio)methyl)benzonitrile (purity >95%)
  • the product yield was calculated and the result was 60%.
  • reaction product was pure (E)-4-((2-methyl-1,3-bisphenylallylthio)methyl)benzonitrile (purity >95%)
  • product yield was calculated and found to be 74%.
  • the obtained reaction product was pure (E)-3-((1,3-diphenylallylthio)methyl)benzonitrile (purity >95%); The calculation was performed and the result was 66%.
  • the obtained reaction product is pure (E)-(1,3-diphenylallyl)(4-(trifluoromethyl)benzyl) sulfide (purity >95%);
  • the product yield was calculated and found to be 67%.
  • the obtained reaction product was pure (E)-(2-bromobenzyl)(1,3-diphenylallyl) sulfide (purity >95%); Calculated, the result was 73%.
  • the obtained reaction product is pure (E)-(4-methylbenzyl)(1,3-diphenylallyl) sulfide (purity >95%); The calculation was performed and the result was 86%.
  • the obtained reaction product is pure (E)-(1,3-diphenylallyl)(9H-fluoren-9-yl) sulfide (purity >95%); The rate was calculated and the result was 72%.
  • reaction product was pure (E)-1-(4-((1,3-diphenylallypropylthio)methyl)phenyl)-1H-indole (purity) >95%); Calculated for product yield, the result was 42%.
  • the obtained reaction product was ((3aR, 5S, 5aS, 8aS, 8bR)-2,2,7,7-tetramethyltetrahydroxy-3aH-bis[1,3]dioxo [ 4,5-b: 4',5'-d]pyran-5-yl)methyl 4-((E)-1,3-diphenylallylthio)methyl)phenyl ester Product (purity >95%); calculated for product yield, the result was 68%.
  • the obtained reaction product was pure (E)-2-(1,3-diphenylallylthio)acetonitrile (purity >95%); the product yield was calculated and the result was 89%.
  • the obtained reaction product was pure (ethyl acetate) (purity >95%) of ethyl (E)-4-(1,3-diphenylallylthio)-3-oxobutanoate;
  • the product yield was calculated and the result was 85%.
  • the obtained reaction product was pure (E)-2-(1,3-diphenylallylthio)-N,N-diethylpropionamide (purity >95%).
  • the product yield was calculated and the result was 65%.
  • the obtained reaction product is a pure product of (E)-(1,3-diphenylallyl)(prop-2-ynyl) sulfide (purity >95%); The rate is calculated and the result is 90%.
  • the obtained reaction product is a pure product of (E)-(1,3-diphenylallyl)(phenylprop-2-ynyl) sulfide (purity >95%); The yield was calculated and found to be 66%.
  • reaction solution was successively dried over ethyl acetate, anhydrous sodium sulfate and column chromatography (column separation Conditions:
  • the stationary phase is 300-400 mesh silica gel
  • the mobile phase is ethyl acetate (A) and petroleum ether (B)
  • the mobile phase change procedure (A:B) is 1:20 ⁇ 1:6), which gives 0.0642 g. reaction product.
  • reaction product was pure (E)-4-((E)-1,3-diphenylallylthio)but-2-enoic acid ethyl ester (purity >95). %); Calculated for product yield, the result was 63%.
  • the obtained reaction product is ((E)-3,7-dimethyloctyl-2,6-dienyl)((E)-1,3-diphenylallyl)sulfide Pure product of ether (purity >95%); calculated for product yield, the result was 74%.
  • the obtained reaction product was pure (E)-tert-butyl (1,3-diphenylallyl) sulfide (purity >95%); the product yield was calculated, and the result was calculated. It is 72%.
  • the obtained reaction product is a pure product of (E)-nonylalkyl (1,3-diphenylallyl) sulfide (purity >95%); the product yield is calculated, and the result is calculated. It is 79%.
  • the obtained reaction product is a pure product of (E)-4-(1,3-diphenylallylthio)butyronitrile (purity >95%); the product yield is calculated, The result was 71%.
  • the obtained reaction product was a pure product of (E)-4-(1,3-diphenylallylthio)butyric acid ethyl ester (purity >95%); Calculated, the result was 83%.

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Abstract

提供一种非对称硫醚的合成方法。该方法包括以下步骤 a)、在四丁基卤化铵催化条件下，式(I)结构化合物、式(II)结构化合物和硫氧盐在溶剂中进行反应，得到具有式(III)结构的非对称硫醚；其中，R 1选自苯基、取代苯基、萘基、取代萘基、噻吩基或取代噻吩基，R 2选自氢、苯基、取代苯基、萘基、取代萘基、噻吩基或取代噻吩基；或 R 1、R 2与其所连接的C形成芴环或噻吨环；R 3选自氢或烷基；R 4选自氢、苯基、取代苯基、萘基、取代萘基、噻吩基或取代噻吩基，R 5选自氢；或 R 4、R 5与其所连接的 C 形成芴环或噻吨环；R 6选自烷基或取代烷基；X选自 Cl、Br或 I。

Description

一种非对称硫醚的合成方法
本申请要求于2016年06月15日提交中国专利局、申请号为201610423506.2、发明名称为“一种非对称硫醚的合成方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于有机化学领域，尤其涉及一种非对称硫醚的合成方法。
背景技术
非对称硫醚是一类重要的含硫化合物，其骨架不仅广泛存在于天然产物、药物活性分子中，也可以作为先进材料和金属配体，还是重要的有机合成中间体。
非对称硫醚化合物在生物医药方面应用的及其广泛，例如：
甲硫氨酸(Methionine)是构成人体的必需氨基酸之一，参与蛋白质合成，因其不能在体内自身生成，所以必须由外部获得，缺乏甲硫氨酸就会导致体内蛋白质合成受阻，造成机体损害。目前甲硫氨酸多采用在过渡金属催化下卤化物与硫醇及其相关衍生物的偶联反应合成。
Cilastatin为具有碳青霉烯环的硫霉素类抗生素，由链霉素S.cattleya培养液中分离出硫霉素经半合成制取的市售抗菌药。用于敏感菌引起的败血症、感染性心内膜炎、骨髓炎、关节炎、皮肤和软组织感染等。目前Cilastatin多采用在过渡金属或无金属条件下硫醇或其衍生物对不饱和化合物的直接加成制得。
辛那舍林(Cinanserin)可用于治疗精神类疾病。目前辛那舍林多采用硫醇或其衍生物在过渡金属催化剂作用下对炔烃的加成制得。
可见，目前合成非对称硫醚的方法在反应过程中不可避免的使用到剧毒、恶臭、敏感易变质的硫醇类化合物，此外需要昂贵的金属催化剂和苛刻的反应条件(无水、无氧等)，这些缺点都严重的制约着该方法的实际运用。因此，非对称硫醚类化合物的新型合成方法的开发一直是有机化学及药物化学的热点研究领域。
发明内容
有鉴于此，本发明的目的在于提供一种非对称硫醚的合成方法，本发明提供的方法反应条件温和，环境友好。
本发明提供了一种非对称硫醚的合成方法，包括以下步骤：
a)、在四丁基卤化铵催化条件下，式(I)结构化合物、式(II)结构化合物和硫氧盐在溶剂中进行反应，得到具有式(III)结构的非对称硫醚；
Figure PCTCN2016095469-appb-000001
其中，R1选自苯基、取代苯基、萘基、取代萘基、噻吩基或取代噻吩基，R2选自氢、苯基、取代苯基、萘基、取代萘基、噻吩基或取代噻吩基；或R1、R2与其所连接的C形成芴环或噻吨环；
R3选自氢或烷基；
R4选自氢、苯基、取代苯基、萘基、取代萘基、噻吩基或取代噻吩基，R5选自氢；或R4、R5与其所连接的C形成芴环或噻吨环；
R6选自烷基或取代烷基；
X选自Cl、Br或I；
所述硫氧盐包括硫代硫酸钠和/或亚硫酸钠。
优选的，R1选自苯基、C1～C5烷基取代的苯基、C1～C5烷氧基取代的苯基、卤素取代的苯基、萘基、C1～C5烷基取代的萘基、C1～C5烷氧基取代的萘基、卤素取代的萘基、噻吩基、C1～C5烷基取代的噻吩基、C1～C5烷氧基取代的噻吩基或卤素取代的噻吩基；
R2选自氢、苯基、C1～C5烷基取代的苯基、C1～C5烷氧基取代的苯基、卤素取代的苯基、萘基、C1～C5烷基取代的萘基、C1～C5烷氧基取代的萘基、卤素取代的萘基、噻吩基、C1～C5烷基取代的噻吩基、C1～C5烷氧基取代的噻吩基或卤素取代的噻吩基；
R3选自氢、C1～C5烷基；
R4选自氢、苯基、C1～C5烷基取代的苯基、卤素取代的苯基、萘基、C1～C5烷基取代的萘基、卤素取代的萘基、噻吩基、C1～C5烷基取代的噻吩基或卤素取代的噻吩基；
优选的，所述R6选自C1～C30烷基、氰基取代的C1～C20烷基、苄基、C1～C5烷基取代的苄基、卤素取代的苄基、芴基和具有式(a-1)～式(a-9)结构取代基中的任一种：
Figure PCTCN2016095469-appb-000002
Figure PCTCN2016095469-appb-000003
式(a-3)～式(a-9)中，m1、m2、m3、n、q、p1、p2、r1、r2和e独立地选自0～5的整数。
优选的，所述式(I)结构化合物具体为1,1-二苯基丙-2-烯基-1-醇、1,1-双(4-氟苯基)丙-2-烯基-1-醇、1,1-双(4-氯苯基)丙-2-烯基-1-醇、1,1-双(4-溴苯基)丙-2-烯基-1-醇、1,1-双(4-甲基苯基)丙-2-烯基-1-醇、1,1-双(4-甲氧基苯基)丙-2-烯基-1-醇、1-苯基-1-对甲基苯基-2-烯-1-醇、1-(3,4-二甲基苯基)-1-苯基丙-2-烯基-1-醇、1-苯基-1-对溴苯丙-2-烯基-1-醇、1-苯基-1-邻氟苯基丙-2-烯基-1-醇、1-(萘-2-基)-1-苯基丙-2-烯基-1-醇、2-甲基-1,1-二苯基丙-2-烯基-1-醇、9-烯基-9H-芴基-9-醇、9-烯基-9H-噻吨基-9-醇、1-苯基丙-2-烯基-1-醇、(E)-1,3-二苯基丙-2-烯基-1-醇、(E)-1,3-双(4-氟苯基)丙-2-烯基-1-醇、(E)-1,3-双(4-氯苯基)丙-2-烯基-1-醇、(E)-1,3-双(4-溴苯基)丙-2-烯基-1-醇、(E)-1,3-双(萘-2-基)丙-2-烯基-1-醇、(E)-1,3-双(噻吩-2-基)丙-2-烯基-1-醇或(E)-2-甲基-1,3-二苯基丙-2-烯基-1-醇。
优选的，所述式(II)结构化合物具体为对氰基苄氯、间氰基苄氯、对三氟甲基苄氯、邻溴苄氯、对甲基苄溴、9-溴芴、(4-(氯甲基)苯基)(1H-吲哚-1-基)甲酮、((3aR,5S,5aS,8aS,8bR)-2,2,7,7-四甲基四羟基-3aH-双[1,3]二氧代[4,5-b:4',5'-d]吡喃-5-基)甲基4-(氯甲基)苯酯、氯乙腈、1-溴代乙酰乙酸乙酯、2-溴代-N,N-二乙基丙酰胺、溴丙炔、(3-氯丙基-1-炔基)苯、4-溴巴豆酸乙酯、香叶基溴、碘代碘丁烷、碘代正癸烷、4-氯丁腈或4-溴丁 酸乙酯。
优选的，所述式(I)结构化合物、式(II)结构化合物和硫氧盐的摩尔比为1:(1.5～3):(2～4)。
优选的，所述反应的温度为20～90℃。
优选的，所述反应的时间为3～8h。
优选的，步骤a)中，式(I)结构化合物、式(II)结构化合物和硫氧盐反应结束后，依次进行萃取、干燥和柱层析，得到具有式(III)结构的非对称硫醚。
优选的，所述溶剂为水。
与现有技术相比，本发明提供了一种非对称硫醚的合成方法。本发明提供的方法包括以下步骤a)、在四丁基卤化铵催化条件下，式(I)结构化合物、式(II)结构化合物和硫氧盐在溶剂中进行反应，得到具有式(III)结构的非对称硫醚；
Figure PCTCN2016095469-appb-000004
Figure PCTCN2016095469-appb-000005
其中，R1选自苯基、取代苯基、萘基、取代萘基、噻吩基或取代噻吩基，R2选自氢、苯基、取代苯基、萘基、取代萘基、噻吩基或取代噻吩基；或R1、R2与其所连接的C形成芴环或噻吨环；R3选自氢或烷基；R4选自氢、苯基、取代苯基、萘基、取代萘基、噻吩基或取代噻吩基，R5选自氢；或R4、R5与其所连接的C形成芴环或噻吨环；R6选自烷基或取代烷基；X选自Cl、Br或I；所述硫氧盐包括硫代硫酸钠和/或亚硫酸钠。本发明提供的方法以取代芳基烯丙醇类化合物、取代烷基卤化物和硫氧盐作为反应原料，以四丁基卤化铵作为催化剂，采用一锅法制备得 到非对称硫醚。该方法原料廉价易得，催化条件简单、温和，无需过渡金属参与，产率较高。此外，在本发明的优选实现方式中，反应在水相中进行，符合绿色化学要求。实验结果表明，采用本发明提供的方法能够合成一系列有潜在生物和药理活性的非对称硫醚，产品产率最高大于91％。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
本发明提供了一种非对称硫醚的合成方法，包括以下步骤：
a)、在四丁基卤化铵催化条件下，式(I)结构化合物、式(II)结构化合物和硫氧盐在溶剂中进行反应，得到具有式(III)结构的非对称硫醚；
Figure PCTCN2016095469-appb-000006
其中，R1选自苯基、取代苯基、萘基、取代萘基、噻吩基或取代噻吩基，R2选自氢、苯基、取代苯基、萘基、取代萘基、噻吩基或取代噻吩基；或R1、R2与其所连接的C形成芴环或噻吨环；
R3选自氢或烷基；
R4选自氢、苯基、取代苯基、萘基、取代萘基、噻吩基或取代噻吩基，R5选自氢；或R4、R5与其所连接的C形成芴环或噻吨环；
R6选自烷基或取代烷基；
X选自Cl、Br或I；
所述硫氧盐包括硫代硫酸钠和/或亚硫酸钠。
在本发明提供的合成方法中，式(I)结构化合物、式(II)结构化合物和硫氧盐在四丁基卤化铵催化条件下在溶剂中进行反应。其中，所述式(I)结构化合物的结构如下：
Figure PCTCN2016095469-appb-000007
式(I)中，R1选自苯基、取代苯基、萘基、取代萘基、噻吩基或取代噻吩基，优选自苯基、C1～C5烷基取代的苯基、C1～C5烷氧基取代的苯基、卤素取代的苯基、萘基、C1～C5烷基取代的萘基、C1～C5烷氧基取代的萘基、卤素取代的萘基、噻吩基、C1～C5烷基取代的噻吩基、C1～C5烷氧基取代的噻吩基或卤素取代的噻吩基，更优选自苯基、氟苯基、氯苯基、溴苯基、甲基苯基、二甲基苯基、甲氧基苯基、萘基或噻吩基，最优选自苯基、4-氟苯基、邻氟苯基、4-氯苯基、4-溴苯基、对溴苯基、4-甲基苯基、对甲基苯基、3,4-二甲基苯基、4-甲氧基苯基、萘-2-基或噻吩-2-基；R2选自氢、苯基、取代苯基、萘基、取代萘基、噻吩基或取代噻吩基，优选自氢、苯基、C1～C5烷基取代的苯基、C1～C5烷氧基取代的苯基、卤素取代的苯基、萘基、C1～C5烷基取代的萘基、C1～C5烷氧基取代的萘基、卤素取代的萘基、噻吩基、C1～C5烷基取代的噻吩基、C1～C5烷氧基取代的噻吩基或卤素取代的噻吩基，更优选自氢、苯基、氟苯基、氯苯基、溴苯基、甲基苯基、二甲基苯基、甲氧基苯基、萘基或噻吩基， 最优选自氢、苯基、4-氟苯基、邻氟苯基、4-氯苯基、4-溴苯基、对溴苯基、4-甲基苯基、对甲基苯基、3,4-二甲基苯基、4-甲氧基苯基、萘-2-基或噻吩-2-基；或R1、R2与其所连接的C形成芴环或噻吨环。
式(I)中，R3选自氢或烷基，优选自氢、C1～C5烷基，更优选自氢、甲基或乙基。
式(I)中，R4选自氢、苯基、取代苯基、萘基、取代萘基、噻吩基或取代噻吩基，优选自氢、苯基、C1～C5烷基取代的苯基、卤素取代的苯基、萘基、C1～C5烷基取代的萘基、卤素取代的萘基、噻吩基、C1～C5烷基取代的噻吩基或卤素取代的噻吩基，更优选自氢、苯基、氟苯基、氯苯基、溴苯基、萘基或噻吩基，最优选自氢、苯基、4-氟苯基、4-氯苯基、4-溴苯基或萘-2-基、噻吩-2-基；R5选自氢；或R4、R5与其所连接的C形成芴环或噻吨环；
在本发明提供的一个实施例中，所述式(I)结构化合物具体为1,1-二苯基丙-2-烯基-1-醇(1)、1,1-双(4-氟苯基)丙-2-烯基-1-醇(2)、1,1-双(4-氯苯基)丙-2-烯基-1-醇(3)、1,1-双(4-溴苯基)丙-2-烯基-1-醇(4)、1,1-双(4-甲基苯基)丙-2-烯基-1-醇(5)、1,1-双(4-甲氧基苯基)丙-2-烯基-1-醇(6)、1-苯基-1-对甲基苯基-2-烯-1-醇(7)、1-(3,4-二甲基苯基)-1-苯基丙-2-烯基-1-醇(8)、1-苯基-1-对溴苯丙-2-烯基-1-醇(9)、1-苯基-1-邻氟苯基丙-2-烯基-1-醇(10)、1-(萘-2-基)-1-苯基丙-2-烯基-1-醇(11)、2-甲基-1,1-二苯基丙-2-烯基-1-醇(12)、9-烯基-9H-芴基-9-醇(13)、9-烯基-9H-噻吨基-9-醇(14)、1-苯基丙-2-烯基-1-醇(15)、(E)-1,3-二苯基丙-2-烯基-1-醇(16)、(E)-1,3-双(4-氟苯基)丙-2-烯基-1-醇(17)、(E)-1,3-双(4-氯苯基)丙-2-烯基-1-醇(18)、 (E)-1,3-双(4-溴苯基)丙-2-烯基-1-醇(19)、(E)-1,3-双(萘-2-基)丙-2-烯基-1-醇(20)、(E)-1,3-双(噻吩-2-基)丙-2-烯基-1-醇(21)或(E)-2-甲基-1,3-二苯基丙-2-烯基-1-醇(22)。在本发明中，具有式(1)～(22)结构的式(I)结构化合物的具体结构如下：
Figure PCTCN2016095469-appb-000008
式(1)～式(10)中，对应相应编号化合物的命名，R1可选自氢、氟、氯、溴、甲基、甲氧基或二甲基，R2可选自氢、氟、氯、溴、甲基、甲氧基或二甲基；式(16)～式(19)中，对应相应编号化合物的命名，R1可选自氢、氟、氯或溴，R2可选自氢、氟、氯或溴。
在本发明中，所述式(II)结构化合物的结构如下：
Figure PCTCN2016095469-appb-000009
式(II)中，R6选自烷基或取代烷基，优选自C1～C30烷基、氰基取代的C1～C20烷基、苄基、C1～C5烷基取代的苄基、卤素取代的苄基、芴基和具有式(a-1)～式(a-9)结构取代基中的任一种：
Figure PCTCN2016095469-appb-000010
式(a-3)～式(a-9)中，m1、m2、m3、n、q、p1、p2、r1、r2和e独立地选自0～5的整数。
在本发明提供的一个实施例中，所述式(II)结构化合物具体为对氰基苄氯(23)、间氰基苄氯(24)、对三氟甲基苄氯(25)、邻溴苄氯(26)、对甲基苄溴(27)、9-溴芴(28)、(4-(氯甲基)苯基)(1H-吲哚-1-基)甲酮(29)、((3aR,5S,5aS,8aS,8bR)-2,2,7,7-四甲基四羟基-3aH-双[1,3]二氧代[4,5-b:4',5'-d]吡喃-5-基)甲基4-(氯甲基)苯酯(30)、氯乙腈(31)、1-溴代乙酰乙酸乙酯(32)、2-溴代-N,N-二乙基丙酰胺(33)、溴丙炔(34)、(3-氯丙基-1-炔基)苯(35)、4-溴巴豆酸乙酯(36)、香叶基溴(37)、碘代碘丁烷(38)、碘代正癸烷(39)、4-氯丁腈(40)或4-溴丁酸乙酯(41)。在本发明中，具有式(23)～(41)结构的式(II)结构化合物的具体结构如下：
Figure PCTCN2016095469-appb-000011
式(23)～式(27)中，对应相应编号化合物的命名，R可选自氰基、三氟甲基、溴或甲基，X可选自氯或溴。
在本发明中，所述硫氧盐包括硫代硫酸钠和/或亚硫酸钠，优选为硫代硫酸钠；所述溶剂优选为水。所述式(I)结构化合物、式(II)结构化合物和硫氧盐的摩尔比优选为1:(1.5～3):(2～4)，更优选为1:(1.5～2):(2～2.4)，最优选为1:2:2.4。所述四丁基卤化铵与式(I)结构化合物的摩尔比优选为(0.01～1)：1。更优选为(0.1～0.5)：1，最优选为0.2：1。所述溶剂与式(I)结构化合物的的用量比优选为(0.1～10)mL：(0.1～0.5)mmol，更优选为(0.5～2)mL：(0.1～0.5)mmol，最优选为1mL：0.3mmol。
在本发明中，式(I)结构化合物、式(II)结构化合物和硫氧盐在溶剂中进行反应的过程中，所述反应优选在密闭条件下进行；所述反应的温度优选为20～90℃，更优选为25～80℃，最优选为70～80℃，最最优选为80℃；所述反应的时间优选为3～8h，更优选为5～6h。反应结束后，得到反应液，所述反应液依次进行萃取、干燥和柱层析。其中，所述萃取使用 的萃取剂优选为乙酸乙酯；所述干燥使用的干燥剂优选为无水硫酸钠；所述柱层析使用的固定相优选为300～400目硅胶粉；所述柱层析使用的流动相优选为乙酸乙酯和石油醚。柱层析处理结束后，得到具有式(III)结构的非对称硫醚：
Figure PCTCN2016095469-appb-000012
式(III)中，R1～R6的选择范围与式(I)和式(II)中保持一致，在此不再赘述。
本发明提供的方法以取代芳基烯丙醇类化合物、取代烷基卤化物和硫氧盐作为反应原料，以四丁基卤化铵作为催化剂，采用一锅法制备得到非对称硫醚。该方法原料廉价易得，催化条件简单、温和，无需过渡金属参与，产率较高。此外，在本发明的优选实现方式中，反应在水相中进行，符合绿色化学要求。实验结果表明，采用本发明提供的方法能够合成一系列有潜在生物和药理活性的非对称硫醚，，产品产率最高大于91％。
为更清楚起见，下面通过以下实施例进行详细说明。
实施例1
4-((3,3-二芳基烯丙基硫代)甲基)苯腈的合成
称取0.3mmol 1,1-二苯基丙-2-烯基-1-醇(0.0631克)，0.6mmol对氰基苄氯(0.0910克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱 层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0778克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.49–7.42(m,2H),7.38–7.33(m,3H),7.29–7.25(m,3H),7.22–7.18(m,2H),7.18–7.13(m,4H),6.08(t,J＝7.8Hz,1H),3.63(s,2H),3.18(d,J＝7.8Hz,2H)ppm；
根据表征数据可知，制得的反应产物为4-((3,3-二芳基烯丙基硫代)甲基)苯腈纯品(纯度＞95％)；对产品产率进行计算，结果为76％。
实施例2
4-((3,3-双(4-氟苯基)烯丙基硫代)甲基)苯腈的合成
称取0.3mmol 1,1-双(4-氟苯基)丙-2-烯基-1-醇(0.0739克)，0.6mmol对氰基苄氯(0.0910克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0932克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.51(d,J＝8.3Hz,2H),7.24(d,J＝8.2Hz,2H),7.16–7.09(m,4H),7.09–7.03(m,2H),7.00–6.94(m,2H),6.01(t,J ＝7.8Hz,1H),3.65(s,2H),3.14(d,J＝7.9Hz,2H)ppm；
根据表征数据可知，制得的反应产物为4-((3,3-双(4-氟苯基)烯丙基硫代)甲基)苯腈纯品(纯度＞95％)；对产品产率进行计算，结果为82％。
实施例3
4-((3,3-双(4-氯苯基)烯丙基硫代)甲基)苯腈的合成
称取0.3mmol 1,1-双(4-氯苯基)丙-2-烯基-1-醇(0.0837克)，0.6mmol对氰基苄氯(0.0910克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0865克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.56–7.52(m,2H),7.38–7.35(m,2H),7.29–7.24(m,4H),7.13–7.08(m,4H),6.08(t,J＝7.9Hz,1H),3.66(s,2H),3.16(d,J＝7.9Hz,2H)ppm；
根据表征数据可知，制得的反应产物为4-((3,3-双(4-氯苯基)烯丙基硫代)甲基)苯腈纯品(纯度＞95％)；对产品产率进行计算，结果为80％。
实施例4
4-((3,3-双(4-溴苯基)烯丙基硫代)甲基)苯腈的合成
称取0.3mmol 1,1-双(4-溴苯基)丙-2-烯基-1-醇(0.1104克)，0.6mmol对氰基苄氯(0.0910克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.1361克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.54–7.47(m,4H),7.42–7.38(m,2H),7.21(d,J＝8.3Hz,2H),7.05–6.99(m,4H),6.07(t,J＝7.9Hz,1H),3.64(s,2H),3.12(d,J＝7.9Hz,2H)ppm；
根据表征数据可知，制得的反应产物为4-((3,3-双(4-溴苯基)烯丙基硫代)甲基)苯腈纯品(纯度＞95％)；对产品产率进行计算，结果为71％。
实施例5
4-((3,3-对甲苯基烯丙基硫代)甲基)苯腈的合成
称取0.3mmol 1,1-双(4-甲基苯基)丙-2-烯基-1-醇(0.0715克)，0.6mmol对氰基苄氯(0.0910克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时； 反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0898克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.45(d,J＝8.3Hz,2H),7.16(dd,J＝7.8,5.7Hz,4H),7.09(s,4H),7.03(d,J＝8.0Hz,2H),6.00(t,J＝7.8Hz,1H),3.62(s,2H),3.18(d,J＝7.8Hz,2H),2.41(s,3H),2.33(s,3H)ppm；
根据表征数据可知，制得的反应产物为4-((3,3-对甲苯基烯丙基硫代)甲基)苯腈纯品(纯度＞95％)；对产品产率进行计算，结果为76％。
实施例6
4-((3,3-对甲氧基苯基烯丙基硫代)甲基)苯腈的合成
称取0.3mmol 1,1-双(4-甲氧基苯基)丙-2-烯基-1-醇(0.0811克)，0.6mmol对氰基苄氯(0.0910克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0970克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.50–7.44(m,2H),7.19(d,J＝8.3Hz, 2H),7.16–7.12(m,2H),7.09–7.04(m,2H),6.90–6.85(m,2H),6.83–6.79(m,2H),5.93(t,J＝7.8Hz,1H),3.85(s,3H),3.80(s,3H),3.63(s,2H),3.18(d,J＝7.8Hz,2H)ppm；
根据表征数据可知，制得的反应产物为4-((3,3-对甲氧基苯基烯丙基硫代)甲基)苯腈纯品(纯度＞95％)；对产品产率进行计算，结果为60％。
实施例7
4-((3-苯基-3-对甲苯基硫代)甲基)苯腈的合成
称取0.3mmol 1-苯基-1-对甲基苯基-2-烯-1-醇(0.0673克)，0.6mmol对氰基苄氯(0.0910克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0745克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.45(d,J＝8.1Hz,2H),7.34(dd,J＝4.1,2.4Hz,1H),7.27(d,J＝7.2Hz,1H),7.22–7.19(m,1H),7.18–7.13(m,3.0Hz,4H),7.09(s,2H),7.03(d,J＝8.0Hz,1H),6.09–6.00(m,1H),3.62(d,J＝2.1Hz,2H),3.18(dd,J＝9.1,7.9Hz,2H),2.41(s,1.5H),2.33(s,1.5H) ppm；
根据表征数据可知，制得的反应产物为4-((3-苯基-3-对甲苯基硫代)甲基)苯腈纯品(纯度＞95％)；对产品产率进行计算，结果为67％。
实施例8
4-((3-(3,4-二甲基苯基)-3-苯基烯丙基硫代)甲基)苯腈的合成
称取0.3mmol 1-(3,4-二甲基苯基)-1-苯基丙-2-烯基-1-醇(0.0715克)，0.6mmol对氰基苄氯(0.0910克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0886克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.47–7.42(m,2H),7.36–7.32(m,1.8H),7.28–7.26(m,1.2H),7.24–7.20(m,1H),7.18–7.09(m,3.2H),7.04(d,J＝7.8Hz,0.7H),6.98(s,0.5H),6.93–6.86(m,1.5H),6.02(t,J＝7.8Hz,1H),3.62(d,J＝3.3Hz,2H),3.18(dd,J＝12.1,7.8Hz,2H),2.31(s,1.5H),2.24(d,J＝4.3Hz,3H),2.22(s,1.5H)ppm；
根据表征数据可知，制得的反应产物为4-((3-(3,4-二甲基苯基)-3-苯基烯丙基硫代)甲基)苯腈纯品(纯度＞95％)；对产品产率进行计算，结果为79％。
实施例9
4-((3-苯基-3-对溴苯基硫代)甲基)苯腈的合成
称取0.3mmol 1-苯基-1-对溴苯基-2-烯-1-醇(0.0868克)，0.6mmol对氰基苄氯(0.0910克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0840克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.53–7.44(m,3H),7.41–7.35(m,3H),7.29–7.26(m,1H),7.22(d,J＝8.3Hz,1H),7.18–7.11(m,3H),7.08–7.01(m,2H),6.11–6.03(m,1H),3.63(d,J＝10.7Hz,2H),3.15(dd,J＝7.9,3.6Hz,2H)ppm；
根据表征数据可知，制得的反应产物为4-((3-苯基-3-对溴苯基硫代)甲基)苯腈纯品(纯度＞95％)；对产品产率进行计算，结果为67％。
实施例10
4-((3-苯基-3-邻氟苯基硫代)甲基)苯腈的合成
称取0.3mmol 1-苯基-1-对溴苯基-2-烯-1-醇(0.0685克)，0.6mmol对氰基苄氯(0.0910克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反 应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0669克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.48(d,J＝8.2Hz,1H),7.42(d,J＝8.2Hz,1H),7.38–7.26(m,4H),7.23(d,J＝5.0Hz,1H),7.21–7.17(m,1H),7.16–7.11(m,3H),7.10–7.01(m,2H),6.22(t,J＝7.7Hz,0.45H),6.02(t,J＝7.6Hz,0.55H),3.65(s,2H),3.24(d,J＝7.7Hz,1.1H),3.10(d,J＝7.7Hz,0.9H)ppm；
根据表征数据可知，制得的反应产物为4-((3-苯基-3-邻氟苯基硫代)甲基)苯腈纯品(纯度＞95％)；对产品产率进行计算，结果为62％。
实施例11
4-((3-(萘-2-基)-3-苯基烯丙基硫代)甲基)苯腈合成
称取0.3mmol 1-(萘-2-基)-1-苯基丙-2-烯基-1-醇(0.0781克)，0.6mmol对氰基苄氯(0.0910克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得 到0.0678克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.93–7.79(m,3H),7.69(d,J＝8.5Hz,0.5H),7.50–7.40(m,3.5H),7.40–7.33(m,2.5H),7.32–7.24(m,4.5H),7.13(d,J＝8.3Hz,1.2H),6.99(d,J＝8.3Hz,0.8H),6.42(t,J＝7.7Hz,0.45H),5.96(t,J＝7.8Hz,0.55H),3.71(s,1.1H),3.59–3.48(m,0.9H),3.40(d,J＝7.8Hz,1.1H),2.94(d,J＝7.7Hz,0.9H)ppm；
根据表征数据可知，制得的反应产物为4-((3-(萘-2-基)-3-苯基烯丙基硫代)甲基)苯腈纯品(纯度＞95％)；对产品产率进行计算，结果为76％。
实施例12
4-((2-甲基-3,3-二苯基烯丙基硫代)甲基)苯腈的合成
称取0.3mmol 2-甲基-1,1-二苯基丙-2-烯基-1-醇(0.0673克)，0.6mmol对氰基苄氯(0.0910克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0806克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.49–7.44(m,2H),7.30–7.22(m,6H), 7.16(d,J＝8.3Hz,2H),7.13–7.09(m,3H),7.08(s,1H),3.60(s,2H),3.24(s,2H),1.89(s,3H)ppm；
根据表征数据可知，制得的反应产物为4-((2-甲基-3,3-二苯基烯丙基硫代)甲基)苯腈纯品(纯度＞95％)；对产品产率进行计算，结果为74％。
实施例13
4-((2-(9H-芴-9-基亚)乙基硫代)甲基)苯腈的合成
称取0.3mmol 9-烯基-9H-芴基-9-醇(0.0625克)，0.6mmol对氰基苄氯(0.0910克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0593克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.73(d,J＝7.5Hz,1H),7.69(d,J＝7.5Hz,1H),7.60(d,J＝7.5Hz,1H),7.51(d,J＝7.7Hz,1H),7.45(d,J＝8.2Hz,2H),7.40–7.34(m,2H),7.32–7.27(m,3H),7.22–7.16(m,1H),6.61(t,J＝8.2Hz,1H),3.81(d,J＝8.2Hz,2H),3.75(s,2H)ppm；
根据表征数据可知，制得的反应产物为4-((2-(9H-芴-9-基亚)乙基硫代)甲基)苯腈纯品(纯度＞95％)；对产品产率进行计算，结果为 58％。
实施例14
4-((2-(9H-噻吨-9-基亚)乙基硫代)甲基)苯腈的合成
称取0.3mmol 9-烯基-9H-噻吨基-9-醇(0.0721克)，0.6mmol对氰基苄氯(0.0910克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0867克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.52–7.45(m,2H),7.44–7.40(m,1H),7.35–7.26(m,5H),7.26–7.23(m,1H),7.20–7.14(m,1H),7.04(d,J＝8.3Hz,2H),5.88(t,J＝7.7Hz,1H),3.53(s,2H),3.35(d,J＝7.7Hz,2H)ppm；
根据表征数据可知，制得的反应产物为4-((2-(9H-噻吨-9-基亚)乙基硫代)甲基)苯腈纯品(纯度＞95％)；对产品产率进行计算，结果为62％。
实施例15
4-(肉桂基硫代甲基)苯腈的合成
称取0.3mmol 1-苯基丙-2-烯基-1-醇(0.0403克)，0.6mmol对氰基苄氯(0.0910克)，0.72mmol硫代硫酸钠(0.1138克)， 0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0867克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.60(d,J＝8.3Hz,2H),7.43(d,J＝8.3Hz,2H),7.36–7.29(m,4H),7.28–7.25(m,1H),6.36(d,J＝15.7Hz,1H),6.18–6.09(m,1H),3.72(s,2H),3.21(dd,J＝7.3,0.9Hz,2H)ppm；
根据表征数据可知，制得的反应产物为4-(肉桂基硫代甲基)苯腈纯品(纯度＞95％)；对产品产率进行计算，结果为23％。
实施例16
(E)-4-((1,3-二苯基烯丙基硫代)甲基)苯腈的合成
称取0.3mmol(E)-1,3-二苯基丙-2-烯基-1-醇(0.0631克)，0.6mmol对氰基苄氯(0.0910克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0848克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.60–7.54(m,2H),7.39(s,1H),7.37–7.30(m,8H),7.29–7.27(m,1H),7.27–7.21(m,2H),6.43–6.32(m,2H),4.44(d,J＝7.7Hz,1H),3.75–3.60(m,2H)ppm；
根据表征数据可知，制得的反应产物为(E)-4-((1,3-二苯基烯丙基硫代)甲基)苯腈纯品(纯度＞95％)；对产品产率进行计算，结果为74％。
实施例17
(E)-4-((1,3-双(4-氟苯基)烯丙基硫代)甲基)苯腈的合成
称取0.3mmol(E)-1,3-双(4-氟苯基)丙-2-烯基-1-醇(0.0739克)，0.6mmol对氰基苄氯(0.0910克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0993克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.60(d,J＝8.3Hz,2H),7.38(d,J＝8.2Hz,2H),7.35–7.29(m,4H),7.07–6.97(m,4H),6.35(d,J＝15.7Hz,1H),6.26–6.19(m,1H),4.41(d,J＝8.4Hz,1H),3.74–3.61(m,2H)ppm；
根据表征数据可知，制得的反应产物为(E)-4-((1,3-双(4-氟苯基)烯丙基硫代)甲基)苯腈纯品(纯度＞95％)；对产品产率进行计算，结果为 91％。
实施例18
(E)-4-((1,3-双(4-氯苯基)烯丙基硫代)甲基)苯腈的合成
称取0.3mmol(E)-1,3-双(4-氯苯基)丙-2-烯基-1-醇(0.0837克)，0.6mmol对氰基苄氯(0.0910克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0887克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.60(d,J＝8.2Hz,2H),7.37(d,J＝8.2Hz,2H),7.34–7.25(m,8H),6.41–6.21(m,2H),4.39(d,J＝7.9Hz,1H),3.75–3.59(m,2H)ppm；
根据表征数据可知，制得的反应产物为(E)-4-((1,3-双(4-氯苯基)烯丙基硫代)甲基)苯腈纯品(纯度＞95％)；对产品产率进行计算，结果为72％。
实施例19
(E)-4-((1,3-双(4-溴苯基)烯丙基硫代)甲基)苯腈的合成
称取0.3mmol(E)-1,3-双(4-溴苯基)丙-2-烯基-1-醇(0.1104克)，0.6mmol对氰基苄氯(0.0910克)，0.72mmol硫代硫酸钠(0.1138 克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.1242克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.62–7.58(m,2H),7.48–7.42(m,4H),7.37(d,J＝8.3Hz,2H),7.24–7.18(m,4H),6.35–6.25(m,2H),4.37(d,J＝7.0Hz,1H),3.73–3.60(m,2H)ppm；
根据表征数据可知，制得的反应产物为(E)-4-((1,3-双(4-溴苯基)烯丙基硫代)甲基)苯腈纯品(纯度＞95％)；对产品产率进行计算，结果为83％。
实施例20
(E)-4-((1,3-双(萘-2-基)烯丙基硫代)甲基)苯腈的合成
称取0.3mmol(E)-1,3-双(萘-2-基)丙-2-烯基-1-醇(0.0931克)，0.6mmol对氰基苄氯(0.0910克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得 到0.0566克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.89–7.76(m,8H),7.70(s,1H),7.60–7.54(m,4H),7.51–7.42(m,5H),7.39(d,J＝8.2Hz,2H),6.67–6.54(m,2H),4.68(d,J＝7.3Hz,1H),3.79–3.63(m,2H)ppm；
根据表征数据可知，制得的反应产物为(E)-4-((1,3-双(萘-2-基)烯丙基硫代)甲基)苯腈纯品(纯度＞95％)；对产品产率进行计算，结果为43％。
实施例21
(E)-4-((1,3-双(噻吩-2-基)烯丙基硫代)甲基)苯腈的合成
称取0.3mmol(E)-1,3-双(噻吩-2-基)丙-2-烯基-1-醇(0.0667克)，0.6mmol对氰基苄氯(0.0910克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0674克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.60(d,J＝8.3Hz,2H),7.42(d,J＝8.2Hz,2H),7.27(d,J＝1.3Hz,1H),7.19(dd,J＝4.6,1.4Hz,1H),7.01–6.94(m,4H),6.56(d,J＝15.5Hz,1H),6.14(dd,J＝15.5,8.6Hz,1H),4.67(d,J＝ 8.6Hz,1H),3.82–3.70(m,2H)ppm；
根据表征数据可知，制得的反应产物为(E)-4-((1,3-双(噻吩-2-基)烯丙基硫代)甲基)苯腈纯品(纯度＞95％)；对产品产率进行计算，结果为60％。
实施例22
(E)-4-((2-甲基-1,3-双苯基烯丙基硫代)甲基)苯腈的合成
称取0.3mmol(E)-2-甲基-1,3-二苯基丙-2-烯基-1-醇(0.0673克)，0.6mmol对氰基苄氯(0.0910克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0793克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.59(d,J＝8.2Hz,2H),7.40(d,J＝8.2Hz,2H),7.38–7.30(m,8H),7.27–7.21(m,3H),6.58(s,1H),4.43(s,1H),3.75–3.63(m,2H),1.82(d,J＝1.1Hz,3H)ppm；
根据表征数据可知，制得的反应产物为(E)-4-((2-甲基-1,3-双苯基烯丙基硫代)甲基)苯腈纯品(纯度＞95％)；对产品产率进行计算，结果为74％。
实施例23
(E)-3-((1,3-二苯基烯丙基硫代)甲基)苯腈的合成
称取0.3mmol(E)-1,3-二苯基丙-2-烯基-1-醇(0.0631克)，0.6mmol间氰基苄氯(0.0910克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0677克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.57–7.50(m,3H),7.42–7.38(m,2H),7.36–7.31(m,6H),7.30–7.21(m,3H),6.46–6.33(m,2H),4.45(d,J＝7.7Hz,1H),3.73–3.58(m,2H)ppm；
根据表征数据可知，制得的反应产物为(E)-3-((1,3-二苯基烯丙基硫代)甲基)苯腈纯品(纯度＞95％)；对产品产率进行计算，结果为66％。
实施例24
(E)-(1,3-二苯基烯丙基)(4-(三氟甲基)苄基)硫醚的合成
称取0.3mmol(E)-1,3-二苯基丙-2-烯基-1-醇(0.0631克)，0.6mmol对三氟甲基苄氯(0.1167克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析 分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0773克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.63(d,J＝8.0Hz,2H),7.48(d,J＝8.0Hz,2H),7.46–7.38(m,7H),7.37–7.29(m,3H),6.53–6.39(m,2H),4.52(d,J＝7.6Hz,1H),3.84–3.70(m,2H).ppm；
根据表征数据可知，制得的反应产物为(E)-(1,3-二苯基烯丙基)(4-(三氟甲基)苄基)硫醚纯品(纯度＞95％)；对产品产率进行计算，结果为67％。
实施例25
(E)-(2-溴苄基)(1,3-二苯基烯丙基)硫醚的合成
称取0.3mmol(E)-1,3-二苯基丙-2-烯基-1-醇(0.0631克)，0.6mmol邻溴苄氯(0.1233克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0868克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝δ7.54(dd,J＝8.0,1.3Hz,1H), 7.44–7.40(m,2H),7.40–7.35(m,3H),7.35–7.27(m,5H),7.27–7.25(m,1H),7.24–7.20(m,1H),7.13–7.06(m,1H),6.53–6.35(m,2H),4.59(d,J＝8.3Hz,1H),3.87–3.73(m,2H)ppm；
根据表征数据可知，制得的反应产物为(E)-(2-溴苄基)(1,3-二苯基烯丙基)硫醚纯品(纯度＞95％)；对产品产率进行计算，结果为73％。
实施例26
(E)-(4-甲基苄基)(1,3-二苯基烯丙基)硫醚的合成
称取0.3mmol(E)-1,3-二苯基丙-2-烯基-1-醇(0.0631克)，0.6mmol对甲基苄溴(0.1110克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0852克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.41–7.35(m,4H),7.35–7.25(m,5H),7.24–7.17(m,3H),7.12(d,J＝7.6Hz,2H),6.48–6.34(m,2H),4.45(d,J＝6.8Hz,1H),3.70–3.57(m,2H),2.34(s,3H)ppm；
根据表征数据可知，制得的反应产物为(E)-(4-甲基苄基)(1,3-二苯基烯丙基)硫醚纯品(纯度＞95％)；对产品产率进行计算，结果为86％。
实施例27
(E)-(1,3-二苯基烯丙基)(9H-芴-9-基)硫醚的合成
称取0.3mmol(E)-1,3-二苯基丙-2-烯基-1-醇(0.0631克)，0.6mmol 9-溴芴(0.1471克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0854克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.72–7.69(m,1H),7.62–7.57(m,2H),7.51(d,J＝7.3Hz,1H),7.38–7.33(m,1H),7.31(d,J＝1.9Hz,1H),7.30–7.25(m,5H),7.23–7.19(m,1H),6.94–6.90(m,2H),6.88–6.83(m,2H),6.00–5.92(m,1H),5.62(d,J＝15.6Hz,1H),4.93(s,1H),4.17–4.10(m,1H)ppm；
根据表征数据可知，制得的反应产物为(E)-(1,3-二苯基烯丙基)(9H-芴-9-基)硫醚纯品(纯度＞95％)；对产品产率进行计算，结果为72％。
实施例28
(E)-1-(4-((1,3-二苯基烯丙基硫代)甲基)苯基)-1H-吲哚的合成
称取0.3mmol(E)-1,3-二苯基丙-2-烯基-1-醇(0.0631克)， 0.6mmol(4-(氯甲基)苯基)(1H-吲哚-1-基)甲酮(0.1618克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0574克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝8.40(d,J＝8.2Hz,1H),7.74–7.67(m,2H),7.63–7.58(m,1H),7.46(d,J＝8.0Hz,2H),7.42–7.35(m,6H),7.34–7.26(m,6H),7.26(d,J＝1.5Hz,1H),6.62(d,J＝3.8Hz,1H),6.52–6.34(m,2H),4.51(d,J＝7.7Hz,1H),3.82–3.68(m,2H)ppm；
根据表征数据可知，制得的反应产物为(E)-1-(4-((1,3-二苯基烯丙基硫代)甲基)苯基)-1H-吲哚纯品(纯度＞95％)；对产品产率进行计算，结果为42％。
实施例29
((3aR,5S,5aS,8aS,8bR)-2,2,7,7-四甲基四羟基-3aH-双[1,3]二氧代[4,5-b:4',5'-d]吡喃-5-基)甲基4-(((E)-1,3-二苯基烯丙基硫代)甲基)苯酯的合成
称取0.3mmol(E)-1,3-二苯基丙-2-烯基-1-醇(0.0631克)，0.6mmol((3aR,5S,5aS,8aS,8bR)-2,2,7,7-四甲基四羟基-3aH-双[1,3]二氧代[4,5-b:4',5'-d]吡喃-5-基)甲基4-(氯甲基)苯酯(0.2477克)，0.72mmol硫 代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.1227克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝8.00(d,J＝8.2Hz,2H),7.37(d,J＝7.9Hz,6H),7.34–7.30(m,3H),7.30–7.21(m,3H),6.39(d,J＝7.3Hz,2H),5.58(d,J＝5.0Hz,1H),4.66(dd,J＝7.9,2.6Hz,1H),4.54(dd,J＝11.5,4.9Hz,1H),4.44(dd,J＝11.1,7.3Hz,2H),4.38–4.32(m,2H),4.22–4.17(m,1H),3.77–3.61(m,2H),1.53(s,3H),1.49(s,3H),1.36(s,3H),1.34(s,3H)ppm；
根据表征数据可知，制得的反应产物为((3aR,5S,5aS,8aS,8bR)-2,2,7,7-四甲基四羟基-3aH-双[1,3]二氧代[4,5-b:4',5'-d]吡喃-5-基)甲基4-(((E)-1,3-二苯基烯丙基硫代)甲基)苯酯纯品(纯度＞95％)；对产品产率进行计算，结果为68％。
实施例30
(E)-2-(1,3-二苯基烯丙基硫代)乙腈的合成
称取0.3mmol(E)-1,3-二苯基丙-2-烯基-1-醇(0.0631克)，0.6mmol氯乙腈(0.0453克)，0.72mmol硫代硫酸钠(0.1138克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结 束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.1130克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.54–7.49(m,2H),7.49–7.43(m,2H),7.36–7.30(m,2H),7.29–7.24(m,2H),6.58(d,J＝15.6Hz,1H),6.31(dd,J＝15.6,9.0Hz,1H),4.83(d,J＝8.9Hz,1H),3.31–3.06(m,2H)ppm；
根据表征数据可知，制得的反应产物为(E)-2-(1,3-二苯基烯丙基硫代)乙腈纯品(纯度＞95％)；对产品产率进行计算，结果为89％。
实施例31
(E)-4-(1,3-二苯基烯丙基硫代)-3-氧代丁酸乙酯的合成
称取0.3mmol(E)-1,3-二苯基丙-2-烯基-1-醇(0.0631克)，0.6mmol 1-溴代乙酰乙酸乙酯(0.0453克)，0.72mmol硫代硫酸钠(0.0988克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0901克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.43–7.38(m,4H),7.37–7.28(m,5H), 7.25–7.21(m,1H),6.56(d,J＝15.7Hz,1H),6.34(dd,J＝15.7,9.0Hz,1H),4.59(d,J＝9.1Hz,1H),4.21–4.14(m,2H),3.61(s,2H),3.44–3.27(m,2H),1.26(t,J＝7.2Hz,3H)ppm；
根据表征数据可知，制得的反应产物为(E)-4-(1,3-二苯基烯丙基硫代)-3-氧代丁酸乙酯的纯品(纯度＞95％)；对产品产率进行计算，结果为85％。
实施例32
(E)-2-(1,3-二苯基烯丙基硫代)-N,N-二乙基丙酰胺的合成
称取0.3mmol(E)-1,3-二苯基丙-2-烯基-1-醇(0.0631克)，0.6mmol 2-溴代-N,N-二乙基丙酰胺(0.1249克)，0.72mmol硫代硫酸钠(0.0988克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0692克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.46–7.40(m,2H),7.40–7.32(m,4H),7.32–7.26(m,3H),7.25–7.19(m,1H),6.57–6.48(m,1H),6.47–6.38(m,1H),4.71(d,J＝8.4Hz,1H),3.62–3.55(m,1H),3.48–3.37(m,2H),3.35–3.29(m,1H),3.27–3.13(m,2H),3.10–2.94(m,1H),1.57–1.47(m,3H),1.11–1.04(m,3H),1.00–0.91(m,3H)ppm；
根据表征数据可知，制得的反应产物为(E)-2-(1,3-二苯基烯丙基硫代)-N,N-二乙基丙酰胺的纯品(纯度＞95％)；对产品产率进行计算，结果为65％。
实施例33
(E)-(1,3-二苯基烯丙基)(丙-2-炔基)硫醚的合成
称取0.3mmol(E)-1,3-二苯基丙-2-烯基-1-醇(0.0631克)，0.6mmol溴丙炔(0.0714克)，0.72mmol硫代硫酸钠(0.0988克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0714克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.48–7.43(m,2H),7.41–7.35(m,3H),7.34–7.25(m,5H),6.59(d,J＝15.6Hz,1H),6.39(dd,J＝15.6,8.9Hz,1H),4.87(d,J＝8.9Hz,1H),3.24(dd,J＝16.9,2.6Hz,1H),3.09(dd,J＝16.9,2.6Hz,1H),2.30(t,J＝2.6Hz,1H)ppm；
根据表征数据可知，制得的反应产物为(E)-(1,3-二苯基烯丙基)(丙-2-炔基)硫醚的纯品(纯度＞95％)；对产品产率进行计算，结果为90％。
实施例34
(E)-(1,3-二苯基烯丙基)(苯丙-2-炔基)硫醚的合成
称取0.3mmol(E)-1,3-二苯基丙-2-烯基-1-醇(0.0631克)，0.6mmol 1-苯基-3-氯-1-丙炔(0.0904克)，0.72mmol硫代硫酸钠(0.0988克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0669克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.50–7.44(m,4H),7.42–7.37(m,3H),7.37–7.35(m,1H),7.35–7.27(m,6H),7.25–7.21(m,1H),6.61(d,J＝15.7Hz,1H),6.48–6.39(m,1H),4.93(d,J＝8.8Hz,1H),3.48(d,J＝16.8Hz,1H),3.34(d,J＝16.8Hz,1H)ppm；
根据表征数据可知，制得的反应产物为(E)-(1,3-二苯基烯丙基)(苯丙-2-炔基)硫醚的纯品(纯度＞95％)；对产品产率进行计算，结果为66％。
实施例35
(E)-4-((E)-1,3-二苯基烯丙基硫代)丁-2-烯酸乙酯的合成
称取0.3mmol(E)-1,3-二苯基丙-2-烯基-1-醇(0.0631克)，0.6mmol 4-溴巴豆酸乙酯(0.1158克)，0.72mmol硫代硫酸钠(0.0988克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL 的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0642克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.43–7.39(m,3H),7.39–7.32(m,4H),7.31–7.27(m,2H),7.25–7.21(m,1H),6.96–6.89(m,1H),6.48(d,J＝15.7Hz,1H),6.36(dd,J＝15.7,8.6Hz,1H),5.88–5.81(m,1H),4.57(d,J＝8.6Hz,1H),4.24–4.17(m,2H),3.29–3.21(m,1H),3.17–3.09(m,1H),1.30(t,J＝7.1Hz,3H)ppm；
根据表征数据可知，制得的反应产物为(E)-4-((E)-1,3-二苯基烯丙基硫代)丁-2-烯酸乙酯的纯品(纯度＞95％)；对产品产率进行计算，结果为63％。
实施例36
((E)-3,7-二甲基辛-2,6-二烯基)((E)-1,3-二苯基烯丙基)硫醚的合成
称取0.3mmol(E)-1,3-二苯基丙-2-烯基-1-醇(0.0631克)，0.6mmol香叶基溴(0.1303克)，0.72mmol硫代硫酸钠(0.0988克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析 分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0801克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.43–7.40(m,2H),7.39–7.36(m,2H),7.35–7.26(m,5H),7.24–7.20(m,1H),6.50–6.36(m,2H),5.31–5.24(m,1H),5.14–5.07(m,1H),4.60(d,J＝7.5Hz,1H),3.20–3.12(m,1H),3.11–3.03(m,1H),2.12–2.00(m,4H),1.69(s,3H),1.62(s,3H),1.57(s,3H)ppm；
根据表征数据可知，制得的反应产物为((E)-3,7-二甲基辛-2,6-二烯基)((E)-1,3-二苯基烯丙基)硫醚的纯品(纯度＞95％)；对产品产率进行计算，结果为74％。
实施例37
(E)-叔丁基(1,3-二苯基烯丙基)硫醚的合成
称取0.3mmol(E)-1,3-二苯基丙-2-烯基-1-醇(0.0631克)，0.6mmol正丁烷(0.1104克)，0.72mmol硫代硫酸钠(0.0988克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0611克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.44–7.37(m,4H),7.36–7.25(m,5H),7.24–7.20(m,1H),6.49(d,J＝15.7Hz,1H),6.44–6.34(m,1H),4.59(d,J＝8.4Hz,1H),2.54–2.42(m,2H),1.61–1.54(m,2H),1.43–1.33(m,2H),0.88(t,J＝7.3Hz,3H)ppm；
根据表征数据可知，制得的反应产物为(E)-叔丁基(1,3-二苯基烯丙基)硫醚的纯品(纯度＞95％)；对产品产率进行计算，结果为72％。
实施例38
(E)-癸烷基(1,3-二苯基烯丙基)硫醚的合成
称取0.3mmol(E)-1,3-二苯基丙-2-烯基-1-醇(0.0631克)，0.6mmol正癸烷(0.1609克)，0.72mmol硫代硫酸钠(0.0988克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0869克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.44–7.37(m,4H),7.36–7.29(m,4H),7.29–7.26(m,1H),7.24–7.21(m,1H),6.49(d,J＝15.7Hz,1H),6.43–6.35(m,1H),4.59(d,J＝8.4Hz,1H),2.54–2.39(m,2H),1.63–1.51(m,3H),1.37–1.24(m,13H),0.88(t,J＝6.8Hz,3H)ppm；
根据表征数据可知，制得的反应产物为(E)-癸烷基(1,3-二苯基烯丙基)硫醚的纯品(纯度＞95％)；对产品产率进行计算，结果为79％。
实施例39
(E)-4-(1,3-二苯基烯丙基硫代)丁腈的合成
称取0.3mmol(E)-1,3-二苯基丙-2-烯基-1-醇(0.0631克)，0.6mmol 4-氯丁腈(0.0621克)，0.72mmol硫代硫酸钠(0.0988克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0621克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.42–7.37(m,4H),7.35–7.26(m,5H),7.25–7.22(m,1H),6.52(d,J＝15.6Hz,1H),6.42–6.34(m,1H),4.60(d,J＝8.7Hz,1H),2.68–2.53(m,2H),2.49–2.42(m,2H),1.95–1.86(m,2H)ppm；
根据表征数据可知，制得的反应产物为(E)-4-(1,3-二苯基烯丙基硫代)丁腈的纯品(纯度＞95％)；对产品产率进行计算，结果为71％。
实施例40
(E)-4-(1,3-二苯基烯丙基硫代)丁酸乙酯的合成
称取0.3mmol(E)-1,3-二苯基丙-2-烯基-1-醇(0.0631克)，0.6mmol 4-溴丁酸乙酯(0.1170克)，0.72mmol硫代硫酸钠(0.0988克)，0.06mmol四丁基碘化铵(0.0222克)，于20mL的试管反应管中，加1mL水作溶剂，封口密闭，80℃下搅拌反应5小时；反应结束后，反应液依次经过乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:20→1:6)，得到0.0844克反应产物。
对上述反应产物进行表征，结果为：
1H NMR(400MHz,CDCl3):δ＝7.44–7.39(m,3H),7.38–7.35(m,2H),7.34–7.30(m,3H),7.29–7.26(m,1H),7.24–7.21(m,1H),6.50(d,J＝15.6Hz,1H),6.42–6.34(m,1H),4.60(d,J＝8.7Hz,1H),4.13–4.06(m,2H),2.60–2.45(m,2H),2.44–2.37(m,2H),1.99–1.85(m,2H),1.22(t,J＝7.2Hz,3H)ppm；
根据表征数据可知，制得的反应产物为(E)-4-(1,3-二苯基烯丙基硫代)丁酸乙酯的纯品(纯度＞95％)；对产品产率进行计算，结果为83％。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。对所公开的实施例的上述说明，使本领域专技术人员能够实现或使用本发明，对这些实施例的多种修改对本领域专业技术人员来说将是显而易见的。本文中所定义的一般原理可以在不脱离本发明的精 神或范围的情况下，在其它实施例中实现。因此，本发明将不会被限制于本文所示的这些实施例，而是要符合与本文所公开的原理和新颖性特点相一致的最宽的范围。

Claims (10)

  1. 一种非对称硫醚的合成方法，包括以下步骤：
    a)、在四丁基卤化铵催化条件下，式(I)结构化合物、式(II)结构化合物和硫氧盐在溶剂中进行反应，得到具有式(III)结构的非对称硫醚；
    Figure PCTCN2016095469-appb-100001
    其中，R1选自苯基、取代苯基、萘基、取代萘基、噻吩基或取代噻吩基，R2选自氢、苯基、取代苯基、萘基、取代萘基、噻吩基或取代噻吩基；或R1、R2与其所连接的C形成芴环或噻吨环；
    R3选自氢或烷基；
    R4选自氢、苯基、取代苯基、萘基、取代萘基、噻吩基或取代噻吩基，R5选自氢；或R4、R5与其所连接的C形成芴环或噻吨环；
    R6选自烷基或取代烷基；
    X选自Cl、Br或I；
    所述硫氧盐包括硫代硫酸钠和/或亚硫酸钠。
  2. 根据权利要求1所述的合成方法，其特征在于，R1选自苯基、C1～C5烷基取代的苯基、C1～C5烷氧基取代的苯基、卤素取代的苯基、萘基、C1～C5烷基取代的萘基、C1～C5烷氧基取代的萘基、卤素取代的萘基、噻吩基、C1～C5烷基取代的噻吩基、C1～C5烷氧基取代的噻吩基或卤素取代的噻吩基；
    R2选自氢、苯基、C1～C5烷基取代的苯基、C1～C5烷氧基取代的苯基、卤素取代的苯基、萘基、C1～C5烷基取代的萘基、C1～C5烷氧基取代的萘基、卤素取代的萘基、噻吩基、C1～C5烷基取代的噻吩基、C1～C5 烷氧基取代的噻吩基或卤素取代的噻吩基；
    R3选自氢、C1～C5烷基；
    R4选自氢、苯基、C1～C5烷基取代的苯基、卤素取代的苯基、萘基、C1～C5烷基取代的萘基、卤素取代的萘基、噻吩基、C1～C5烷基取代的噻吩基或卤素取代的噻吩基。
  3. 根据权利要求1所述的合成方法，其特征在于，所述R6选自C1～C30烷基、氰基取代的C1～C20烷基、苄基、C1～C5烷基取代的苄基、卤素取代的苄基、芴基和具有式(a-1)～式(a-9)结构取代基中的任一种：
    Figure PCTCN2016095469-appb-100002
    式(a-3)～式(a-9)中，m1、m2、m3、n、q、p1、p2、r1、r2和e独立地选自0～5的整数。
  4. 根据权利要求1所述的合成方法，其特征在于，所述式(I)结构化合物具体为1,1-二苯基丙-2-烯基-1-醇、1,1-双(4-氟苯基)丙-2-烯基-1-醇、1,1-双(4-氯苯基)丙-2-烯基-1-醇、1,1-双(4-溴苯基)丙-2-烯基-1-醇、1,1-双(4-甲基苯基)丙-2-烯基-1-醇、1,1-双(4-甲氧基苯基)丙-2-烯基-1-醇、1-苯基-1-对甲基苯基-2-烯-1-醇、1-(3,4-二甲基苯基)-1-苯基丙-2-烯基-1-醇、 1-苯基-1-对溴苯丙-2-烯基-1-醇、1-苯基-1-邻氟苯基丙-2-烯基-1-醇、1-(萘-2-基)-1-苯基丙-2-烯基-1-醇、2-甲基-1,1-二苯基丙-2-烯基-1-醇、9-烯基-9H-芴基-9-醇、9-烯基-9H-噻吨基-9-醇、1-苯基丙-2-烯基-1-醇、(E)-1,3-二苯基丙-2-烯基-1-醇、(E)-1,3-双(4-氟苯基)丙-2-烯基-1-醇、(E)-1,3-双(4-氯苯基)丙-2-烯基-1-醇、(E)-1,3-双(4-溴苯基)丙-2-烯基-1-醇、(E)-1,3-双(萘-2-基)丙-2-烯基-1-醇、(E)-1,3-双(噻吩-2-基)丙-2-烯基-1-醇或(E)-2-甲基-1,3-二苯基丙-2-烯基-1-醇。
  5. 根据权利要求1所述的合成方法，其特征在于，所述式(II)结构化合物具体为对氰基苄氯、间氰基苄氯、对三氟甲基苄氯、邻溴苄氯、对甲基苄溴、9-溴芴、(4-(氯甲基)苯基)(1H-吲哚-1-基)甲酮、((3aR,5S,5aS,8aS,8bR)-2,2,7,7-四甲基四羟基-3aH-双[1,3]二氧代[4,5-b:4',5'-d]吡喃-5-基)甲基4-(氯甲基)苯酯、氯乙腈、1-溴代乙酰乙酸乙酯、2-溴代-N,N-二乙基丙酰胺、溴丙炔、(3-氯丙基-1-炔基)苯、4-溴巴豆酸乙酯、香叶基溴、碘代碘丁烷、碘代正癸烷、4-氯丁腈或4-溴丁酸乙酯。
  6. 根据权利要求1所述的合成方法，其特征在于，所述式(I)结构化合物、式(II)结构化合物和硫氧盐的摩尔比为1:(1.5～3):(2～4)。
  7. 根据权利要求1所述的合成方法，其特征在于，所述反应的温度为20～90℃。
  8. 根据权利要求7所述的合成方法，其特征在于，所述反应的时间为3～8h。
  9. 根据权利要求1所述的合成方法，其特征在于，步骤a)中，式(I)结构化合物、式(II)结构化合物和硫氧盐反应结束后，依次进行萃取、干燥和柱层析，得到具有式(III)结构的非对称硫醚。
  10. 根据权利要求1～9任一项所述的合成方法，其特征在于，所述溶剂为水。
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