CN111777536B - Method for preparing asymmetric disulfide - Google Patents

Method for preparing asymmetric disulfide Download PDF

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CN111777536B
CN111777536B CN202010674270.6A CN202010674270A CN111777536B CN 111777536 B CN111777536 B CN 111777536B CN 202010674270 A CN202010674270 A CN 202010674270A CN 111777536 B CN111777536 B CN 111777536B
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reaction
disulfide
phenyl
asymmetric
preparation
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CN111777536A (en
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杨科
宋梦杰
李义
李正义
孙小强
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Changzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/22—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of hydropolysulfides or polysulfides
    • C07C319/24—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of hydropolysulfides or polysulfides by reactions involving the formation of sulfur-to-sulfur bonds

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to the technical field of fine chemical engineering, and discloses a method for preparing asymmetric disulfide. The method comprises the following specific steps: the target product, namely the symmetric disulfide N-phenyl-3- (phenyl disulfanyl) propionamide, can be obtained by taking 3-methylthio-N-phenyl propionamide and diphenyl disulfide as raw materials and N-fluoro-diphenyl sulfonamide as an additive, preferably in an acetonitrile solvent, and heating for reaction. The method is simple and convenient to operate and mild in reaction, 3-methylthio-N-phenylpropionamide and symmetric diphenyl disulfide are used as reaction raw materials, an asymmetric disulfide product is efficiently synthesized in one step, the use of an odorous thiol raw material or a transition metal catalyst is avoided, and the method has potential application value.

Description

Method for preparing asymmetric disulfide
Technical Field
The invention belongs to the field of fine chemical engineering, and relates to a method for preparing asymmetric disulfide N-phenyl-3- (phenyl disulfanyl) propionamide.
Background
Asymmetric disulfide is an important organic compound, the parent skeleton of which is widely existed in various natural products with pharmaceutical activity, and the compound is also an important organic synthesis intermediate. Therefore, how to directly and efficiently synthesize the compounds has attracted great attention from chemists.
At present, two methods are mainly used for synthesizing asymmetric disulfide, the first method uses two different thiols as raw materials to synthesize the asymmetric disulfide through oxidative dehydrogenation, the method has the defects that the smell of the thiols is bad, and the reaction can generate self-coupling to obtain the symmetric disulfide; secondly, a disulfanyl reagent is used to react with a nucleophilic reagent under the action of a transition metal catalyst to obtain a target product, and the reaction has the defects that the metal catalyst is used and the characteristics of environmental protection are not met.
The method uses thioether compounds and symmetrical disulfide compounds as raw materials, uses N-fluoro-diphenyl sulfonamide as an additive to construct target product asymmetric disulfide in one step, has no reported reaction mode, and does not need to use metal catalysts and smelly mercaptan. By using the method, a new asymmetric disulfide N-phenyl-3- (phenyl disulfanyl) propionamide is synthesized.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a high-efficiency and green synthesis method of asymmetric disulfide N-phenyl-3- (phenyl disulfanyl) propionamide.
The invention relates to a method for synthesizing N-phenyl-3- (phenyl disulfanyl) propionamide, which comprises the following steps: sequentially adding 3-methylthio-N-phenyl propionamide, diphenyl disulfide and N-fluoro-diphenyl sulfonamide (NFSI) into a sealed tube containing a reaction solvent, heating and stirring for reaction, and after the reaction is finished, sequentially concentrating a reaction solution and carrying out column chromatography separation to obtain the light yellow solid N-phenyl-3- (phenyl disulfanyl) propionamide.
Further, the reaction solvent of the system of the present invention is acetonitrile, 1, 2-dichloroethane and dichloromethane, preferably acetonitrile.
Further, the concentration of the reaction system in the present invention is 0.05 to 0.2 mol/l, preferably 0.1 mol/l.
Further, in the present invention, 3-methylthio-N-phenylpropionamide, diphenyldisulfide and N-fluorobisbenzenesulfonamide are used in a molar ratio of 1: 1: 1.
further, the reaction temperature in the invention is 60-120 ℃, preferably 80 ℃.
Further, the reaction time in the invention is 8-18 hours, preferably 12 hours.
Compared with the prior art, the invention has the beneficial effects that: 3-methylthio-N-phenylpropionamide and symmetric diphenyl disulfide are used as reaction raw materials, N-fluoro-diphenyl sulfonamide is used as an additive, a brand new asymmetric disulfide product is efficiently synthesized in one step, the method is simple and convenient to operate and mild in reaction, and the use of an odorous and unpleasant thiol raw material or a transition metal catalyst is avoided, so that the method has potential application value.
Detailed Description
The following examples will help illustrate the invention, but do not limit its scope.
Specific example 1: the synthesis method comprises the following steps: acetonitrile (10mL), 3-methylthio-N-phenylpropionamide (1mmol,0.195g), diphenyldisulfide (1mmol,0.218g) and N-fluorobisbenzenesulfonamide (1mmol,0.315g) were added sequentially in a 50mL block, the reaction temperature was controlled at 80 degrees Celsius, and the reaction was stirred vigorously for 12 hours. After the reaction, the reaction solution was concentrated and subjected to column chromatography to obtain N-phenyl-3- (phenyldisulfanyl) propanamide (0.187g, 65%) as a pale yellow solid. The reaction involves the following equation:
Figure BDA0002583494350000021
the nuclear magnetic data and the mass spectrum data of the target product N-phenyl-3- (phenyl disulfanyl) propionamide are as follows:
1H NMR(300MHz,CDCl3)δ7.64–7.02(m,11H),3.06(t,J＝6.8Hz,2H),2.71(t,J＝6.9Hz,2H).
13C NMR(75MHz,CDCl3)δ169.08,137.61,137.16,129.18,129.02,127.88,127.18,124.52,120.07,36.49,34.00.
LCMS(ESI,m/z):290.0[M+H]+.
specific example 2: comparative experiment: acetonitrile (10mL), 3-methylthio-N-phenylpropionamide (1mmol,0.195g) and diphenyl disulfide (1mmol,0.218g) were added sequentially in a 50mL lock tube, the reaction temperature was controlled at 80 ℃ and the reaction was stirred vigorously for 12 hours. After the reaction is finished, reaction liquid is concentrated and separated by column chromatography in sequence, and the target product N-phenyl-3- (phenyl disulfanyl) propionamide cannot be separated. The reaction involves the following equation:
Figure BDA0002583494350000022
specific example 3: comparative experiment: acetonitrile (10mL), 3-methylthio-N-phenylpropionamide (1mmol,0.195g), diphenyldisulfide (1mmol,0.218g), and 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt [ Selectfluor ] (1mmol,0.36g) were added in this order to a 50mL lock tube, the reaction temperature was controlled at 80 degrees Celsius, and the reaction was vigorously stirred for 12 hours. After the reaction is finished, reaction liquid is concentrated and separated by column chromatography in sequence, and the target product N-phenyl-3- (phenyl disulfanyl) propionamide cannot be separated. The reaction involves the following equation:
Figure BDA0002583494350000031
the foregoing describes alternative embodiments of the invention to teach those skilled in the art how to make and reproduce the invention. Some conventional technical aspects have been simplified and omitted for the purpose of teaching the inventive arrangements. Those skilled in the art will appreciate variations from this aspect that fall within the scope of the invention.

Claims (9)

1. A method for preparing asymmetric disulfide is characterized in that: the asymmetric disulfide is N-phenyl-3- (phenyl disulfanyl) propionamide, and the structural formula is as follows:
Figure DEST_PATH_IMAGE002
；
the preparation method of the asymmetric disulfide comprises the following steps:
adding 3-methylthio-N-phenyl propionamide, diphenyl disulfide and N-fluoro-bis-benzene sulfonamide (NFSI) into a reaction solvent in sequence, stirring and reacting under a heating condition, and concentrating and separating column chromatography of a reaction solution in sequence after the reaction is finished to obtain the target product of the asymmetric disulfide N-phenyl-3- (phenyl disulfanyl) propionamide.
2. The process for the preparation of asymmetric disulfides according to claim 1, characterized in that: the molar ratio of the 3-methylthio-N-phenylpropionamide, the diphenyl disulfide and the N-fluoro-bis-benzenesulfonamide is 1: 1: 1.
3. the process for the preparation of asymmetric disulfides according to claim 1, characterized in that: the reaction solvent is acetonitrile, 1, 2-dichloroethane or dichloromethane.
4. The process for the preparation of asymmetric disulfides according to claim 3, characterized in that: the reaction solvent is acetonitrile.
5. The process for the preparation of asymmetric disulfides according to claim 1, characterized in that: the reaction temperature is 60-120 ℃.
6. The process for the preparation of asymmetric disulfides according to claim 5, characterized in that: the reaction temperature was 80 ℃.
7. The process for the preparation of asymmetric disulfides according to claim 1, characterized in that: the concentration of the 3-methylthio-N-phenylpropionamide in the reaction system is 0.05-0.2 mol/L.
8. The process for the preparation of asymmetric disulfides according to claim 7, characterized in that: the concentration of 3-methylthio-N-phenylpropionamide in the reaction system was 0.1 mol/l.
9. The process for the preparation of asymmetric disulfides according to claim 1, characterized in that: the reaction time is 8-18 hours.
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CN113735750B (en) * 2021-10-15 2022-07-22 常州大学 Method for preparing S-substituent-cysteine derivative by NBS (N-bromosuccinimide) at room temperature
CN114853648B (en) * 2022-05-05 2023-03-21 常州大学 Method for preparing asymmetric disulfide by NBS (N-bromosuccinimide) to promote breakage of thioether C-S bond
CN115197179B (en) * 2022-08-04 2023-08-22 常州大学 Method for preparing thioether and disulfide through C-S bond double decomposition reaction without participation of transition metal

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