CN110437114B - Method for synthesizing asymmetric cyanoalkyl disulfide - Google Patents

Method for synthesizing asymmetric cyanoalkyl disulfide Download PDF

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CN110437114B
CN110437114B CN201910723485.XA CN201910723485A CN110437114B CN 110437114 B CN110437114 B CN 110437114B CN 201910723485 A CN201910723485 A CN 201910723485A CN 110437114 B CN110437114 B CN 110437114B
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CN110437114A (en
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王红梅
卢晓刚
符飞燕
高润利
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Institute Of Chemical Defense Chinese Academy Of Military Sciences
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/22—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of hydropolysulfides or polysulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Abstract

The invention relates to a method for synthesizing asymmetric cyano alkyl disulfide, which takes thiourea and alkyl Bunte salt as a sulfur source, alkyl halide as a raw material, sodium dodecyl benzene sulfonate as an auxiliary reagent and sodium carbonate as alkali to react in water to obtain the asymmetric cyano alkyl disulfide compound. The method avoids using mercaptan with pungent smell as a sulfur source, achieves the aim of environmental protection, and is simple in reaction operation, mild in reaction condition and suitable for large-scale production.

Description

Method for synthesizing asymmetric cyanoalkyl disulfide
Technical Field
The invention relates to a method for synthesizing asymmetric cyano alkyl disulfide.
Background
Sulfur chemistry has gained considerable attention over the past several decades. The sulfur-containing compounds are widely applied to various fields of pharmacy, agriculture, chemistry and the like. Furthermore, organosulfur compounds have a significant impact in the field of materials, for example, sulfur atoms have a strong force on the physical and electronic surfaces of some materials. Natural products, particularly marine natural products, have sulfur-containing compounds present therein. The metabolites of marine organisms have great scientific research value, and effective medicinal molecules can be screened out through the research on the metabolites. For example, a class of natural product thiodiketopyrazine complexes (ETP) with unique structures show superior activity against poliovirus. Therefore, the method for constructing the asymmetric disulfide bond has great reference value for synthesizing sulfur compounds with biological activity.
At present, the synthesis methods of the symmetric disulfide are many, but the methods are not suitable for the synthesis of the asymmetric disulfide. Asymmetric disulfides can be prepared in general in three ways: (1) two different thiols with oxidizing agents, e.g. I2、H2O2DDQ, DMSO, DEAD and the like are subjected to coupling reaction to obtain the product; (2) thiols or thiol derivatives with sulfinyl derivatives or other compounds having a readily leaving group by SN2, reacting to obtain; for example, the reaction of 5, 5-dimethyl-2-thio-1, 3, 2-dioxin-2-disulfonyl derivatives studied by Wit et al with the corresponding thiols gives dialkyl disulfides, diaryl disulfides, aryl-alkyl disulfides and also asymmetric L-cysteineAnd L-cystine disulfide, the yield is generally high. Hunter et al, using benzotriazole as the leaving group, synthesized asymmetric disulfides in a one-pot procedure with desirable results. 1-chlorobenzotriazole was used as an oxidizing agent in experiments, which is economical and environmentally friendly, and which is capable of efficiently converting a thiol into the corresponding N-sulfinyl derivative, which is then reacted with another thiol to give an asymmetric disulfide. (3) Different thioethers are obtained by the exchange reaction under the catalysis of transition metal.
However, these methods still have some drawbacks and deficiencies:
(1) reagents of high toxicity, e.g. Br, involved in the reaction2，SOCl2，S2Cl2And SO2Cl2Or some harsh PH conditions.
(2) Most of the reactions use mercaptan as a sulfur source, and the mercaptan is an environmentally-unfriendly reagent with large pungent smell, can cause certain potential toxicity to human bodies, and is not easy to produce on a large scale.
(3) Organic solvents have a certain toxicity, are expensive and cause certain pollution to the environment.
Thiourea and sodium thiosulfate are basic chemical raw materials, are low in price and easy to obtain, and are ideal mercaptan replacement reagents. Recently, Firouzabadi et al studied the reaction of thiourea to synthesize symmetric disulfide, but the reaction of asymmetric disulfide was not further explored. The problem group of Jiangxue has also carried out corresponding research on asymmetric aryl alkyl disulfide, and sodium thiosulfate is used as a sulfur source to obtain a target product by an oxidation-reduction method, but the method is only suitable for synthesis of aryl sulfide, and dioxane is used as a solvent, so that the solvent has certain toxicity. Although there are many methods for synthesizing thioethers, it is essential to develop a more efficient and environmentally friendly method for constructing C-S.
Disclosure of Invention
In order to solve the defects, the invention adopts thiourea and alkyl Bunte salt as a sulfur source, alkyl halide as a raw material and water as a reaction solvent, and explores an efficient and green method for synthesizing asymmetric cyanoalkyl disulfide.
The method for synthesizing the asymmetric cyano alkyl disulfide has the following reaction formula:
Figure GSB0000190381910000021
wherein: x is I or Br; r1Is 3-cyanopropyl or 5-cyanopentyl; r2Is n-hexyl, n-heptyl, isopentyl, n-butyl, n-pentyl, isobutyl, cyclohexyl or cyclopentyl;
the method for synthesizing the asymmetric cyanoalkyl disulfide comprises the following steps:
sequentially adding alkyl Bunte salt, thiourea, sodium carbonate, Sodium Dodecyl Benzene Sulfonate (SDBS), halogenated alkane and water into a reaction bottle for reaction, wherein the molar ratio of the alkyl Bunte salt, the thiourea, the sodium carbonate, the sodium dodecyl benzene sulfonate and the halogenated alkane is 1-1.25: 1.2-1.5: 0.032-0.375: 1; then heating and reacting at 50-100 ℃ under the protection of nitrogen, wherein the heating time is 3-7 hours; after the solution is cooled to room temperature, adding 5mL of water, extracting the obtained mixture with ethyl acetate for 3 times and 15 mL/time, combining organic phases, drying with 2-5 g of anhydrous magnesium sulfate, filtering with filter paper, and concentrating under vacuum pressure of 80-100 mmHg at 40-50 ℃ to obtain a crude product; purifying the obtained crude product by 200-300-mesh silica gel column chromatography, and using 200-500 mL petroleum ether/ethyl acetate with the mass ratio of 20: 1 as eluent to obtain the asymmetric cyanoalkyl disulfide.
The invention has the beneficial effects that:
(1) in the process of synthesizing the asymmetric cyanoalkyl disulfide, the sulfurization reagents are alkyl Bunte salt and thiourea, the price is low, the sulfuration reagents are easy to obtain, the use of mercaptan with potential toxicity and pungent smell is avoided, and the method is suitable for large-scale industrial production;
(2) strong acid or strong alkali conditions are not needed in the reaction, an additional reducing agent or an oxidizing agent is not needed, transition metal catalysis is not needed, the method is economical and practical, and the reaction conditions are relatively mild;
(3) the solvent system based on water is selected, so that the use of organic solvents which have high toxicity and high price and cause certain pollution to the environment is avoided, the method is environment-friendly, accords with the green chemical concept, and is simple in aftertreatment and simple and convenient in experimental operation.
Drawings
FIG. 14 preparation of (hexyldithio) butyronitrile1H NMR、13C NMR chart
In the figure: a is 4- (hexyldithiol) butanenitrile1H NMR(300MHz，CD3OD) diagram, b is 4- (hexyldithio) butyronitrile13C NMR(75MHz，CD3OD) map;
ordinate is peak intensity in ppm on the ordinate; the abscissa is the chemical shift in ppm.
FIG. 24 preparation of- (heptyldithio) butanenitrile1H NMR、13C NMR chart
In the figure: a is 4- (heptyldithio) butanenitrile1H NMR chart, b is 4- (heptyldithio) butyronitrile13C NMR chart;
ordinate is peak intensity in ppm on the ordinate; the abscissa is the chemical shift in ppm.
FIG. 34 preparation of (isopentyldithio) butanenitrile1H NMR、13C NMR chart
In the figure: a is 4- (isopentyldithio) butanenitrile1H NMR chart, b for 4- (isopentyldithio) butanenitrile13C NMR chart;
ordinate is peak intensity in ppm on the ordinate; the abscissa is the chemical shift in ppm.
FIG. 44 preparation of (butyldithio) butyronitrile1H NMR、13C NMR chart
In the figure: a is 4- (butyldithio) butyronitrile1H NMR chart, b is 4- (butyldithio) butyronitrile13C NMR chart.
Ordinate is peak intensity in ppm on the ordinate; the abscissa is the chemical shift in ppm.
FIG. 54 preparation of (pentyldithio) butyronitrile1H NMR、13C NMR chart
In the figure: a is 4- (pentyldi)Thio) butyronitrile1HNMR picture-b is 4- (pentyldithio) butyronitrile13A CNMR map.
Ordinate is peak intensity in ppm on the ordinate; the abscissa is the chemical shift in ppm.
FIG. 64 preparation of (isobutyldithio) butanenitrile1H NMR、13C NMR chart
In the figure: a is 4- (isobutyldithio) butanenitrile1H NMR chart, b for 4- (isobutyldithio) butanenitrile13C NMR chart.
Ordinate is peak intensity in ppm on the ordinate; the abscissa is the chemical shift in ppm.
FIG. 74 preparation of- (sec-butyldithio) butyronitrile1H NMR、13C NMR chart
In the figure: a is 4- (sec-butyldithio) butyronitrile1H NMR chart, b for 4- (sec-butyldithio) butyronitrile13C NMR chart;
ordinate is peak intensity in ppm on the ordinate; the abscissa is the chemical shift in ppm.
FIG. 84 of (cyclohexyldithio) butyronitrile1H NMR、13C NMR chart
In the figure: a is 4- (cyclohexyldithio) butanenitrile1H NMR chart, b for 4- (cyclohexyldithio) butanenitrile13C NMR chart;
ordinate is peak intensity in ppm on the ordinate; the abscissa is the chemical shift in ppm.
FIG. 94 of cyclopentyldithio) butanenitrile1H NMR、13C NMR chart
In the figure: a is 4- (cyclopentyldithio) butanenitrile1H NMR chart, b for 4- (cyclopentyldithio) butanenitrile13C NMR chart;
ordinate is peak intensity in ppm on the ordinate; the abscissa is the chemical shift in ppm.
FIG. 106 preparation of (isopentyldithio) hexanenitrile1H NMR、13C NMR chart
In the figure: process for preparation of 6- (isopentyldithio) hexanenitrile1An H NMR chart of the sample solution,process for preparation of 6- (isopentyldithio) hexanenitrile13C NMR chart;
ordinate is peak intensity in ppm on the ordinate; the abscissa is the chemical shift in ppm.
FIG. 116 preparation of (pentyldithio) hexanenitrile1H NMR、13C NMR chart
In the figure: a is 6- (pentyldithio) hexanenitrile1H NMR chart, b is 6- (pentyldithio) hexanenitrile13C NMR chart;
ordinate is peak intensity in ppm on the ordinate; the abscissa is the chemical shift in ppm.
FIG. 126 preparation of (hexyldithio) hexanenitrile1H NMR、13C NMR chart
In the figure: a is 6- (hexyldithio) hexanenitrile1H NMR chart, b is 6- (hexyldisulfide) hexanenitrile13C NMR chart;
ordinate is peak intensity in ppm on the ordinate; the abscissa is the chemical shift in ppm.
Detailed Description
Example 1
Preparation of 4- (hexyldithio) butyronitrile
Figure GSB0000190381910000041
In a 10mL reaction flask containing magnetons, 3-cyanopropyl sodium thiosulfate (203mg, 1mmol, 1.25equiv.), thiourea (73mg, 0.96mmol, 1.20equiv.), sodium carbonate (102mg, 0.96mmol, 1.20equiv.), sodium dodecylbenzenesulfonate (34.8mg, 0.1mmol, 0.125equiv.), 1-bromohexane (132mg, 0.8mmol, 1equiv.) and water (1mL) were added in this order, and the mixture was reacted at 80 ℃ under nitrogen for 7 hours with stirring. The reaction was cooled to room temperature, 5mL of water were added, the mixture was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, dried over anhydrous magnesium sulfate 4g, filtered through filter paper, the solvent was removed under reduced vacuum (vacuum 95mmHg, heating temperature 48 ℃) and column chromatography gave 4- (hexyldithio) butyronitrile (eluent polarity: petroleum ether/ethyl acetate 20: 1). Yield: 83 percent;1H NMR(300MHz，CD3OD)2.75(t，J＝7.1Hz，2H)，2.68(t，J＝7.4Hz，2H)，2.55(t，J＝7.2Hz，2H)，2.07-1.95(m，2H)，1.72-1.60(m，2H)，1.44-1.24(m，6H)，0.92-0.84(m，3H).13C NMR(75MHz，CD3OD)120.8，39.8，37.7，32.9，30.5，29.5，26.2，23.9，16.3，14.7..
example 2
Preparation of 4- (hexyldithio) butyronitrile
Figure GSB0000190381910000042
In a 10mL reaction flask containing magnetons, 3-cyanopropyl sodium thiosulfate (203mg, 1mmol, 1.25equiv.), thiourea (73mg, 0.96mmol, 1.20equiv.), sodium carbonate (102mg, 0.96mmol, 1.20equiv.), sodium dodecylbenzenesulfonate (34.8mg, 0.1mmol, 0.125equiv.), 1-iodohexane (169mg, 0.8mmol, 1equiv.) and water (1mL) were added in this order, and the reaction was stirred at 80 ℃ for 7 hours under nitrogen protection. The reaction was cooled to room temperature, 5mL of water were added, the mixture was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, dried over anhydrous magnesium sulfate 4g, filtered through filter paper, the solvent was removed under reduced vacuum (vacuum 95mmHg, heating temperature 48 ℃) and column chromatography gave 4- (hexyldithio) butyronitrile (eluent polarity: petroleum ether/ethyl acetate 20: 1). Yield: 89 percent;1H NMR、13the C NMR analysis data were identical to those of example 1.
Example 3
Preparation of 4- (heptyldithio) butanenitrile
Figure GSB0000190381910000051
In a 10mL reaction flask equipped with magnetons, 3-cyanopropyl sodium thiosulfate (203mg, 1mmol, 1.25equiv.), thiourea (73mg, 0.96mmol, 1.20equiv.), sodium carbonate (102mg, 0.96mmol, 1.20equiv.), sodium dodecylbenzenesulfonate (34.8mg, 0.1mmol, 0.125equiv.), 1-bromoheptane (142mg, 0.8mmol, 1equiv.) and water (1mL) were sequentially added) And stirring the mixture for 7 hours at the temperature of 80 ℃ under the protection of nitrogen. The reaction was cooled to room temperature, 5mL of water were added, the mixture was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, dried over anhydrous magnesium sulfate 4g, filtered through filter paper, the solvent was removed under reduced vacuum (vacuum 95mmHg, heating temperature 48 ℃) and the column was separated by column chromatography to give 4- (heptyldithio) butyronitrile (eluent polarity: petroleum ether/ethyl acetate 20: 1). Yield: 76%;1H NMR(300MHz，CD3OD)2.76(t，J＝7.0Hz，2H)，2.69(t，J＝7.3Hz，2H)，2.55(t，J＝7.1Hz，2H)，2.07-1.95(m，2H)，1.73-1.59(m，2H)，1.44-1.22(m，8H)，0.94-0.83(m，3H).13C NMR(75MHz，CD3OD)120.5，39.5，37.4，32.9，30.2，30.0，29.5，25.9，23.7，16.1，14.4.
example 4
Preparation of 4- (isopentyldithio) butyronitrile
Figure GSB0000190381910000052
In a 10mL reaction flask containing magnetons, 3-cyanopropyl sodium thiosulfate (203mg, 1mmol, 1.25equiv.), thiourea (73mg, 0.96mmol, 1.20equiv.), sodium carbonate (102mg, 0.96mmol, 1.20equiv.), sodium dodecylbenzenesulfonate (34.8mg, 0.1mmol, 0.125equiv.), 1-bromo-3-methylbutane (120mg, 0.8mmol, 1equiv.) and water (1mL) were added in this order, and the mixture was reacted at 80 ℃ under nitrogen for 7 hours. The reaction was cooled to room temperature, 5mL of water was added, the mixture was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, dried over 4g of anhydrous magnesium sulfate, filtered through filter paper, the solvent was removed under reduced pressure (vacuum 95mmHg, heating temperature 48 ℃ C.), and column chromatography was carried out to give 4- (isopentyldithio) butyronitrile (eluent polarity: petroleum ether/ethyl acetate 20: 1). Yield: 87 percent;1H NMR(300MHz，CDCl3)2.77(t，J＝6.9Hz，2H)，2.69(t，J＝7.8Hz，2H)，2.51(t，J＝7.3Hz，2H)，2.13-2.02(m，2H)，1.72-1.62(m，1H)，1.55(q，J＝7.3Hz，2H)，0.91(d，J＝6.1Hz，6H).13C NMR(75MHz，CDCl3)118.6，37.9，36.6，36.1，26.9，24.2，22.0，15.4.
example 5
Preparation of 4- (butyldithio) butyronitrile
Figure GSB0000190381910000061
In a 10mL reaction flask containing magnetons, 3-cyanopropyl sodium thiosulfate (203mg, 1mmol, 1.25equiv.), thiourea (73mg, 0.96mmol, 1.20equiv.), sodium carbonate (102mg, 0.96mmol, 1.20equiv.), sodium dodecylbenzenesulfonate (34.8mg, 0.1mmol, 0.125equiv.), 1-bromobutane (108mg, 0.8mmol, 1equiv.) and water (1mL) were added in this order, and the reaction was stirred at 80 ℃ for 7 hours under nitrogen protection. The reaction was cooled to room temperature, 5mL of water were added, the mixture was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, dried over 4g of anhydrous magnesium sulfate, filtered through filter paper, the solvent was removed under reduced pressure (vacuum 95mmHg, heating temperature 48 ℃) and column chromatography gave 4- (butyldithio) butyronitrile (eluent polarity: petroleum ether/ethyl acetate 20: 1). Yield: 75 percent;1H NMR(300MHz，CDCl3)2.76(t，J＝5.9Hz，2H)，2.51(t，J＝7.0Hz，2H)，2.13-2.02(m，2H)，1.76-1.65(m，1H)，1.58-1.47(m，1H)，1.34-1.23(m，4H)，0.98(t，J＝7.4Hz，3H).13C NMR(75MHz，CDCl3)119.2，48.1，37.3，29.0，24.7，20.3，15.9，11.7.
example 6
Preparation of 4- (pentyldithio) butanenitrile
Figure GSB0000190381910000062
In a 10mL reaction flask containing magnetons, 3-cyanopropyl sodium thiosulfate (203mg, 1mmol, 1.25equiv.), thiourea (73mg, 0.96mmol, 1.20equiv.), sodium carbonate (102mg, 0.96mmol, 1.20equiv.), sodium dodecylbenzenesulfonate (34.8mg, 0.1mmol, 0.125equiv.), 1-bromopentane (120mg, 0.8mmol, 1equiv.) and water (1mL) were added in this order, and the mixture was reacted at 80 ℃ under nitrogen for 7 hours. Cooling the reactionAfter cooling to room temperature, 5mL of water are added, the mixture is extracted with ethyl acetate (15 mL. times.3), the organic phases are combined, dried over 4g of anhydrous magnesium sulfate, filtered through a filter paper, the solvent is removed under reduced vacuum (vacuum 95mmHg, heating temperature 48 ℃) and the 4- (pentyldithio) butyronitrile is obtained after column chromatography (eluent polarity: petroleum ether/ethyl acetate 20: 1). Yield: 73 percent;1H NMR(300MHz，CDCl3)2.77(t，J＝6.8Hz，2H)，2.68(t，J＝7.4Hz，2H)，2.51(t，J＝7.0Hz，2H)，2.14-2.02(m，2H)，1.73-1.58(m，2H)，1.42-1.28(m，4H)，0.94-0.86(m，3H).13C NMR(75MHz，CDCl3)119.2，39.0，36.7，30.8，29.0，24.7，22.4，15.9，14.1.
example 7
Preparation of 4- (isobutyldithio) butyronitrile
Figure GSB0000190381910000071
In a 10mL reaction flask containing magnetons, 3-cyanopropyl sodium thiosulfate (203mg, 1mmol, 1.25equiv.), thiourea (73mg, 0.96mmol, 1.20equiv.), sodium carbonate (102mg, 0.96mmol, 1.20equiv.), sodium dodecylbenzenesulfonate (34.8mg, 0.1mmol, 0.125equiv.), 1-bromo-2-methylpropane (120mg, 0.8mmol, 1equiv.) and water (1mL) were added in this order, and the mixture was reacted at 80 ℃ under nitrogen for 7 hours. The reaction was cooled to room temperature, 5mL of water was added, the mixture was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, dried over anhydrous magnesium sulfate (4 g), filtered through filter paper, the solvent was removed under reduced vacuum (vacuum 95mmHg, heating temperature 48 ℃) and column chromatography gave 4- (isobutyldithio) butyronitrile (eluent polarity: petroleum ether/ethyl acetate 20: 1). Yield: 11 percent;1H NMR(300MHz，CDCl3)2.77(t，J＝6.5Hz，2H)，2.60(d，J＝5.9Hz，2H)，2.52(t，J＝6.8Hz，2H)，2.14-2.03(m，2H)，1.99-1.87(m，1H)，1.00(d，J＝6.1Hz，6H).13C NMR(75MHz，CDCl3)119.2，48.6，36.4，28.4，24.7，21.9，15.9.
example 8
Preparation of 4- (sec-butyldithio) butyronitrile
Figure GSB0000190381910000072
In a 10mL reaction flask containing magnetons, 3-cyanopropyl sodium thiosulfate (203mg, 1mmol, 1.25equiv.), thiourea (73mg, 0.96mmol, 1.20equiv.), sodium carbonate (102mg, 0.96mmol, 1.20equiv.), sodium dodecylbenzenesulfonate (34.8mg, 0.1mmol, 0.125equiv.), 2-bromobutane (108mg, 0.8mmol, 1equiv.) and water (1mL) were added in this order, and the reaction was stirred at 80 ℃ for 7 hours under nitrogen protection. The reaction was cooled to room temperature, 5mL of water were added, the mixture was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, dried over 4g of anhydrous magnesium sulfate, filtered through filter paper, the solvent was removed under reduced vacuum (vacuum 95mmHg, heating temperature 48 ℃) and column chromatography gave 4- (sec-butyldithio) butyronitrile (eluent polarity: petroleum ether/ethyl acetate 20: 1). Yield: 20 percent;1H NMR(300MHz，CDCl3)2.81-2.70(m，3H)，2.51(t，J＝7.1Hz，2H)，2.14-2.01(m，2H)，1.77-1.65(m，1H)，1.61-1.47(m，1H)，1.31(d，J＝6.7Hz，3H)，0.98(t，J＝8.3Hz，3H).13C NMR(75MHz，CDCl3)119.2，48.1，37.3，29.0，24.7，20.3，15.9，11.7.
example 9
Preparation of 4- (cyclohexyl-dithio) -butanenitrile
Figure GSB0000190381910000073
In a 10mL reaction flask containing magnetons, 3-cyanopropyl sodium thiosulfate (203mg, 1mmol, 1.25equiv.), thiourea (73mg, 0.96mmol, 1.20equiv.), sodium carbonate (102mg, 0.96mmol, 1.20equiv.), sodium dodecylbenzenesulfonate (34.8mg, 0.1mmol, 0.125equiv.), bromocyclohexane (130mg, 0.8mmol, 1equiv.) and water (1mL) were added in this order, and the mixture was reacted at 80 ℃ under nitrogen for 7 hours. The reaction was cooled to room temperature, 5mL of water was added, the mixture was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, and 4g of anhydrous magnesium sulfate was driedDrying, filtering with filter paper, removing solvent under reduced pressure (vacuum degree of 95mmHg, heating temperature of 48 deg.C), and separating by column chromatography to obtain 4- (cyclohexyl-dithio) -butyronitrile (eluent polarity: petroleum ether/ethyl acetate 20: 1). Yield: 12 percent;1H NMR(300MHz，CDCl3)2.76(t，J＝6.9Hz，2H)，2.51(t，J＝6.9Hz，2H)，2.13-1.97(m，3H)，1.84-1.57(m，4H)，1.45-1.22(m，5H)，0.96(t，J＝7.2Hz，1H).13C NMR(75MHz，CDCl3)119.2，49.6，37.6，33.0，26.2，25.7，24.7，15.9.
example 10
Preparation of 4- (cyclopentyldithio) butanenitrile
Figure GSB0000190381910000081
In a 10mL reaction flask equipped with magnetons, 3-cyanopropyl sodium thiosulfate (203mg, 1mmol, 1.25equiv.), thiourea (73mg, 0.96mmol, 1.20equiv.), sodium carbonate (102mg, 0.96mmol, 1.20equiv.), sodium dodecylbenzenesulfonate (34.8mg, 0.1mmol, 0.125equiv.), bromocyclopentane (130mg, 0.8mmol, 1equiv.) and water (1mL) were added in this order, and the mixture was reacted at 80 ℃ under nitrogen for 7 hours. The reaction was cooled to room temperature, 5mL of water were added, the mixture was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, dried over anhydrous magnesium sulfate 4g, filtered through filter paper, the solvent was removed under reduced vacuum (vacuum 95mmHg, heating temperature 48 ℃) and column chromatography gave 4- (cyclopentyldithio) butyronitrile (eluent polarity: petroleum ether/ethyl acetate 20: 1). Yield: 41 percent;1H NMR(300MHz，CDCl3)3.32-3.22(m，1H)，2.79(t，J＝6.9Hz，2H)，2.51(t，J＝7.1Hz，2H)，2.14-2.03(m，2H)，2.03-1.90(m，2H)，1.79-1.53(m，6H).13C NMR(75MHz，CDCl3)119.2，50.2，36.9，33.2，24.8，15.9.
example 11
Preparation of 6- (isopentyldithio) hexanenitrile
Figure GSB0000190381910000082
In a 10mL reaction flask containing magnetons, sodium 5-cyanopentylthiosulfate (231mg, 1mmol, 1.25equiv.), thiourea (73mg, 0.96mmol, 1.20equiv.), sodium carbonate (102mg, 0.96mmol, 1.20equiv.), sodium dodecylbenzenesulfonate (34.8mg, 0.1mmol, 0.125equiv.), 1-bromo-3-methylbutane (118mg, 0.8mmol, 1equiv.) and water were added in this order, and the mixture was reacted at 80 ℃ under nitrogen for 7 hours. The reaction was cooled to room temperature, 5mL of water was added, the mixture was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, dried over 4g of anhydrous magnesium sulfate, filtered through filter paper, the solvent was removed under reduced pressure (vacuum 95mmHg, heating temperature 48 ℃) and 6- (isopentyldithio) hexanenitrile was obtained after column chromatography (eluent polarity: petroleum ether/ethyl acetate 20: 1). Yield: 92 percent;1H NMR(300MHz，CDCl3)2.73-2.63(m，4H)，2.36(t，J＝7.1Hz，2H)，1.79-1.63(m，5H)，1.61-1.49(m，4H)，0.90(d，J＝6.6Hz，6H).13C NMR(75MHz，CDCl3)119.3，38.0，38.0，36.9，36.8，28.0，27.2，26.9，26.9，24.8，24.7，22.0，16.8.
example 12
Preparation of 6- (pentyldithio) hexanenitrile
Figure GSB0000190381910000091
In a 10mL reaction flask containing magnetons, 5-cyanopentyl sodium thiosulfate (231mg, 1mmol, 1.25equiv.), thiourea (73mg, 0.96mmol, 1.20equiv.), sodium carbonate (102mg, 0.96mmol, 1.20equiv.), sodium dodecylbenzenesulfonate (34.8mg, 0.1mmol, 0.125equiv.), 1-bromopentane (120mg, 0.8mmol, 1equiv.) and water (1mL) were added in this order, and the reaction was stirred at 80 ℃ for 7 hours under nitrogen protection. The reaction was cooled to room temperature, 5mL of water was added, the mixture was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, dried over 4g of anhydrous magnesium sulfate, filtered through filter paper, the solvent was removed under reduced pressure (vacuum 95mmHg, heating temperature 48 ℃ C.), and column chromatography gave 6- (pentyldithio) hexanenitrile (eluent polarity: petroleum) which was purified by column chromatographyEther/ethyl acetate 20: 1). Yield: 90 percent;1H NMR(300MHz，CDCl3)2.67(t，J＝7.4Hz，4H)，2.36(t，J＝7.1Hz，2H)，1.80-1.62(m，6H)，1.61-1.50(m，2H)，1.41-1.24(m，4H)，0.94-0.84(m，3H).13C NMR(75MHz，CDCl3)119.7，39.3，39.2，38.4，38.4，30.8，29.0，28.4，27.6，25.2，25.2，22.4，17.2，14.1.
example 13
Preparation of 6- (hexyldithio) hexanenitrile
Figure GSB0000190381910000092
In a 10mL reaction flask containing magnetons, sodium 5-cyanopentylthiosulfate (231mg, 1mmol, 1.25equiv.), thiourea (73mg, 0.96mmol, 1.20equiv.), sodium carbonate (102mg, 0.96mmol, 1.20equiv.), sodium dodecylbenzenesulfonate (34.8mg, 0.1mmol, 0.125equiv.), 1-bromohexane (132mg, 0.8mmol, 1equiv.) and water (1mL) were added in this order, and the reaction was stirred at 100 ℃ for 7 hours under nitrogen protection. The reaction was cooled to room temperature, 5mL of water were added, the mixture was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, dried over 4g of anhydrous magnesium sulfate, filtered through filter paper, the solvent was removed under reduced pressure (vacuum 95mmHg, heating temperature 48 ℃) and 6- (hexyldithio) hexanenitrile was obtained after column chromatography (eluent polarity: petroleum ether/ethyl acetate 20: 1). Yield: 55 percent;1H NMR(300MHz，CDCl3)2.67(t，J＝7.4Hz，4H)，2.36(t，J＝7.1Hz，2H)，1.78-1.63(m，6H)，1.61-1.52(m，2H)，1.44-1.23(m，6H)，0.92-0.84(m，3H).13C NMR(75MHz，CDCl3)119.7，39.3，39.2，38.4，38.4，31.5，29.3，28.4，28.3，27.6，25.2，25.2，22.7，17.2，14.2.
example 14
Preparation of 4- (hexyldithio) butyronitrile
Figure GSB0000190381910000101
In a 10mL reaction flask containing magnetons, 3-cyanopropyl sodium thiosulfate (203mg, 1mmol, 1.25equiv.), thiourea (73mg, 0.96mmol, 1.20equiv.), sodium carbonate (102mg, 0.96mmol, 1.20equiv.), sodium dodecylbenzenesulfonate (34.8mg, 0.1mmol, 0.125equiv.), 1-bromohexane (132mg, 0.8mmol, 1equiv.) and water (1mL) were added in this order, and the reaction was stirred at 80 ℃ for 3 hours under nitrogen protection. The reaction was cooled to room temperature, 5mL of water were added, the mixture was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, dried over anhydrous magnesium sulfate 4g, filtered through filter paper, the solvent was removed under reduced vacuum (vacuum 95mmHg, heating temperature 48 ℃) and column chromatography gave 4- (hexyldithio) butyronitrile (eluent polarity: petroleum ether/ethyl acetate 20: 1). Yield: 73 percent;1H NMR、13the C NMR analysis data were identical to those of example 1.
Example 15
Preparation of 4- (hexyldithio) butyronitrile
Figure GSB0000190381910000102
In a 10mL reaction flask containing magnetons, 3-cyanopropyl sodium thiosulfate (203mg, 1mmol, 1.25equiv.), thiourea (73mg, 0.96mmol, 1.20equiv.), sodium carbonate (102mg, 0.96mmol, 1.20equiv.), sodium dodecylbenzenesulfonate (34.8mg, 0.1mmol, 0.125equiv.), 1-bromohexane (132mg, 0.8mmol, 1equiv.) and water (1mL) were added in this order, and the mixture was reacted at 50 ℃ under nitrogen for 7 hours. The reaction was cooled to room temperature, 5mL of water were added, the mixture was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, dried over anhydrous magnesium sulfate 4g, filtered through filter paper, the solvent was removed under reduced vacuum (vacuum 95mmHg, heating temperature 48 ℃) and column chromatography gave 4- (hexyldithio) butyronitrile (eluent polarity: petroleum ether/ethyl acetate 20: 1). Yield: 64 percent;1H NMR、13the C NMR analysis data were identical to those of example 1.
Example 16
Preparation of 4- (hexyldithio) butyronitrile
Figure GSB0000190381910000103
In a 10mL reaction flask containing magnetons, 3-cyanopropyl sodium thiosulfate (203mg, 1mmol, 1.25equiv.), thiourea (73mg, 0.96mmol, 1.50equiv.), sodium carbonate (102mg, 0.96mmol, 1.20equiv.), sodium dodecylbenzenesulfonate (34.8mg, 0.1mmol, 0.125equiv.), 1-bromohexane (132mg, 0.8mmol, 1equiv.) and water (1mL) were added in this order, and the reaction was stirred at 80 ℃ for 7 hours under nitrogen protection. The reaction was cooled to room temperature, 5mL of water were added, the mixture was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, dried over anhydrous magnesium sulfate 4g, filtered through filter paper, the solvent was removed under reduced vacuum (vacuum 95mmHg, heating temperature 48 ℃) and column chromatography gave 4- (hexyldithio) butyronitrile (eluent polarity: petroleum ether/ethyl acetate 20: 1). Yield: 70 percent;1H NMR、13the C NMR analysis data were identical to those of example 1.
Example 17
Preparation of 4- (hexyldithio) butyronitrile
Figure GSB0000190381910000111
In a 10mL reaction flask containing magnetons, 3-cyanopropyl sodium thiosulfate (203mg, 1mmol, 1.25equiv.), thiourea (73mg, 0.96mmol, 1.20equiv.), sodium carbonate (102mg, 0.96mmol, 1.50equiv.), sodium dodecylbenzenesulfonate (34.8mg, 0.1mmol, 0.125equiv.), 1-bromohexane (132mg, 0.8mmol, 1equiv.) and water (1mL) were added in this order, and the reaction was stirred at 80 ℃ for 7 hours under nitrogen protection. The reaction was cooled to room temperature, 5mL of water were added, the mixture was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, dried over anhydrous magnesium sulfate 4g, filtered through filter paper, the solvent was removed under reduced vacuum (vacuum 95mmHg, heating temperature 48 ℃) and column chromatography gave 4- (hexyldithio) butyronitrile (eluent polarity: petroleum ether/ethyl acetate 20: 1). Yield: 78 percent;1H NMR、13the C NMR analysis data were identical to those of example 1.
Example 18
Preparation of 4- (hexyldithio) butyronitrile
Figure GSB0000190381910000112
In a 10mL reaction flask containing magnetons, 3-cyanopropyl sodium thiosulfate (203mg, 1mmol, 1.25equiv.), thiourea (73mg, 0.96mmol, 1.20equiv.), sodium carbonate (102mg, 0.96mmol, 1.20equiv.), sodium dodecylbenzenesulfonate (34.8mg, 0.1mmol, 0.375equiv.), 1-bromohexane (132mg, 0.8mmol, 1equiv.) and water (1mL) were added in this order, and the mixture was reacted at 80 ℃ under nitrogen for 7 hours with stirring. The reaction was cooled to room temperature, 5mL of water were added, the mixture was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, dried over anhydrous magnesium sulfate 4g, filtered through filter paper, the solvent was removed under reduced vacuum (vacuum 95mmHg, heating temperature 48 ℃) and column chromatography gave 4- (hexyldithio) butyronitrile (eluent polarity: petroleum ether/ethyl acetate 20: 1). Yield: 72 percent;1H NMR、13the C NMR analysis data were identical to those of example 1.
Example 19
Preparation of 4- (hexyldithio) butyronitrile
Figure GSB0000190381910000121
In a 10mL reaction flask containing magnetons, 3-cyanopropyl sodium thiosulfate (162mg, 0.8mmol, 1equiv.), thiourea (73mg, 0.96mmol, 1.20equiv.), sodium carbonate (102mg, 0.96mmol, 1.20equiv.), sodium dodecylbenzenesulfonate (34.8mg, 0.1mmol, 0.125equiv.), 1-bromohexane (132mg, 0.8mmol, 1equiv.) and water (1mL) were added in this order, and the mixture was reacted at 80 ℃ under nitrogen for 7 hours with stirring. The reaction was cooled to room temperature, 5mL of water were added, the mixture was extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, dried over anhydrous magnesium sulfate 4g, filtered through filter paper, the solvent was removed under reduced vacuum (vacuum 95mmHg, heating temperature 48 ℃) and column chromatography gave 4- (hexyldithio) butyronitrile (eluent polarity: petroleum ether/ethyl acetate 20: 1). Yield of：35％；1H NMR、13The C NMR analysis data were identical to those of example 1.
Example 20
Preparation of 4- (hexyldithio) butyronitrile
Figure GSB0000190381910000122
In a 10mL reaction flask containing magnetons, 3-cyanopropyl sodium thiosulfate (162mg, 0.8mmol, 1equiv.), thiourea (73mg, 0.96mmol, 1.20equiv.), sodium carbonate (102mg, 0.96mmol, 1.20equiv.), sodium dodecylbenzenesulfonate (34.8mg, 0.1mmol, 0.032equiv.), 1-bromohexane (132mg, 0.8mmol, 1equiv.) and water (1mL) were added in this order, and the mixture was reacted at 80 ℃ under nitrogen for 7 hours with stirring. The reaction is cooled to room temperature, 5mL of water is added, the mixture is extracted with ethyl acetate (15 mL. times.3), the organic phases are combined, dried over anhydrous magnesium sulfate (2-5 g), filtered through filter paper, the solvent is removed under vacuum reduced pressure (vacuum degree 95mmHg, heating temperature 48 ℃), and the 4- (hexyldithio) butyronitrile is obtained after column chromatography separation (eluent polarity: petroleum ether/ethyl acetate 20: 1). Yield: 80 percent;1H NMR、13the C NMR analysis data were identical to those of example 1.
TABLE 1 novel asymmetric cyanoalkyl disulfide compounds of the invention
Figure GSB0000190381910000123
Figure GSB0000190381910000131

Claims (1)

1. A method for synthesizing asymmetric cyanoalkyl disulfide is characterized in that the reaction formula for synthesizing the asymmetric cyanoalkyl disulfide is as follows:
Figure FSB0000190381900000011
wherein: x is I or Br; r1Is 3-cyanopropyl or 5-cyanopentyl; r2Is n-hexyl, n-heptyl, isopentyl, n-butyl, n-pentyl, isobutyl, cyclohexyl or cyclopentyl;
the method for synthesizing the asymmetric cyano alkyl disulfide comprises the following steps:
sequentially adding alkyl Bunte salt, thiourea, sodium carbonate, Sodium Dodecyl Benzene Sulfonate (SDBS), halogenated alkane and water into a reaction bottle for reaction, wherein the molar ratio of the alkyl Bunte salt, the thiourea, the sodium carbonate, the sodium dodecyl benzene sulfonate and the halogenated alkane is 1-1.25: 1.2-1.5: 0.032-0.375: 1; then heating and reacting at 50-100 ℃ under the protection of nitrogen, wherein the heating time is 3-7 hours; after the solution is cooled to room temperature, adding 5mL of water, extracting the obtained mixture with ethyl acetate for 3 times and 15 mL/time, combining organic phases, drying with 2-5 g of anhydrous magnesium sulfate, filtering with filter paper, and concentrating under vacuum pressure of 80-100 mmHg at 40-50 ℃ to obtain a crude product; purifying the obtained crude product by 200-300-mesh silica gel column chromatography, and using 200-500 mL petroleum ether/ethyl acetate with the mass ratio of 20: 1 as eluent to obtain the asymmetric cyanoalkyl disulfide.
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