CN104710332B - A kind of preparation method of thiazolinyl sulfide - Google Patents

Abstract

The invention discloses a preparation method of alkenyl sulfide: adding disulfide compounds shown in formula II to styrene derivatives shown in formula I, using dimethyl sulfoxide as a reaction solvent, and adding disulfide compounds in iodine Under the action of a simple substance catalyst and a copper catalyst, the reaction is heated under an air atmosphere, and after the reaction is completed, the obtained reaction liquid is post-treated to prepare an alkenyl sulfide represented by formula III. The raw materials used in the method of the invention are low in price, low in cost, high in yield and simple in process.

Description

A kind of preparation method of alkenyl sulfide

technical field

The invention relates to a preparation method of sulfide, in particular to a preparation method of stereoselective trans alkenyl sulfide.

Background technique

Alkenyl sulfides are important synthetic intermediates, widely found in many natural products, and ubiquitous structural units in many biologically active compounds.

The literature Lee, C.-F. (Org. Lett. 2011, 13, 5204) discloses the efficient synthesis of alkenyl sulfides through copper-catalyzed C-S coupling of vinyl halides and mercaptans. The method includes preparation process and purification process.

1. The preparation process is as follows:

With 4-iodomethylene-1-tert-butylcyclohexane as substrate (0.6mmol), add cyclohexyl mercaptan (0.5mmol), Cu ₂ O (0.5mol%), KOH (1mmol), dioxane (0.25 mL) as the solvent, and then reacted at 110°C for 12h to obtain the crude product of trans-[cyclohexyl][(4'-tert-butyl)cyclohexylenemethyl]sulfide.

Second, the purification process is as follows:

The crude product was cooled, vacuum filtered, eluted with ethyl acetate to remove the solid to obtain a crude solution, concentrated, and using petroleum ether as the mobile phase to obtain pure trans-[cyclohexyl][(4'-tert-butyl base) cyclohexylene methyl] sulfide.

The above synthesis method has the advantage of high synthesis efficiency, but this method requires relatively expensive mercaptan or thiophenol; in addition, the substrate vinyl halide selected by this method is relatively expensive, so the cost of using the above synthesis method is relatively high, which is not conducive to industrialization. .

Contents of the invention

Purpose: In order to overcome the deficiencies of the prior art, the present invention provides a method for preparing trans alkenyl sulfides with low cost.

In order to achieve the above object, the technical scheme adopted in the present invention is:

A kind of preparation method of alkenyl sulfide, described method is: add the disulfide compound shown in formula II in the styrene derivative shown in formula I, take dimethyl sulfoxide as reaction solvent, and in Under the action of iodine simple substance catalyst and copper catalyst, heating reaction under air atmosphere, after the reaction finishes, after-treatment of gained reaction liquid makes the alkenyl sulfide shown in formula III;

The chemical reaction formula of the present invention is as follows:

In formula _I or formula III, R is methyl, tert-butyl, fluorine, chlorine or hydrogen;

In formula II or formula III, R ₂ is methyl, fluorine, chlorine or hydrogen.

In formula II, R ₂ on different benzene rings represent the same group.

Preferably R ₁ is hydrogen, 2-methyl, 3-methyl, 4-methyl, 4-chloro or 4-tert-butyl.

Preferably R2 is hydrogen, ₂ -methyl, 3-methyl, 4-methyl, 4-chloro, 2-fluoro or 4-fluoro.

The ratio of the amount of the styrene derivative represented by the formula I to the disulfide compound represented by the formula II is 1:0.5.

The copper catalyst is copper trifluoromethanesulfonate Cu(OTf) ₂ , copper acetate Cu(OAc) ₂ , copper acetylacetonate Cu(acac) ₂ , cuprous iodide CuI, cuprous chloride CuCl or copper oxide CuO, Cu(OTf) ₂ is preferred.

The ratio of the amount of the styrene derivative represented by the formula I to the copper catalyst is 1:0.1-0.3, preferably 1:0.1.

The ratio of the amount of the styrene derivative represented by the formula I to the iodine simple substance catalyst is 1:1-1.5, preferably 1:1.

The reaction temperature of the present invention is generally 120-150° C., preferably 120° C., and the reaction time is generally 5-10 hours, preferably 6 hours.

The volumetric dosage of the dimethyl sulfoxide is generally calculated as the amount of the styrene derivative represented by formula I in the range of 3-10 mL/mmol.

The post-treatment method of the reaction solution is as follows: after the reaction, the reaction solution is filtered, the filtrate is washed with water to remove excess iodine and solvent, the organic phase is combined and then distilled, and the residue obtained is subjected to silica gel column chromatography, the eluent is petroleum ether, and TLC detects The eluate is collected and combined with the eluate containing the product, concentrated by distillation to remove the solvent, and dried in vacuum to obtain the alkenyl sulfide represented by formula III.

The substrate used in the present invention is styrene or its derivatives, disulfide derivatives, and the used copper catalyst Cu(OTf) ₂ , iodine simple substance, etc. are all common products, and the price is lower than that of benzenethiol in the prior art. Or thiophenol and vinyl halide are both cheap, and the preparation method of alkenyl sulfide of the present invention has the advantages of simple process flow, low cost and high yield. In addition, the preparation process of the present invention has less pollution and high atomic economical utilization rate. The synthetic system is cheap.

detailed description

The technical solutions of the present invention will be further described below with specific examples, but the protection scope of the present invention is not limited thereto.

Embodiment one:

Add 52 mg (0.5 mmol) of styrene, 54.5 mg (0.25 mmol) of diphenyl disulfide, 18.1 mg (0.05 mmol) of Cu(OTf) ₂ , and 127 mg (0.5 mmol) of iodine into the reaction test tube, and then add 2 mL DMSO, heated at 120°C for 6 hours, cooled after the reaction, filtered, washed the filtrate with water to remove excess iodine and solvent, combined the organic phase and distilled, the resulting residue was chromatographed on a silica gel column, washed with petroleum ether, detected by TLC, and combined to contain the product The effluent was distilled off by a rotary evaporator to remove the solvent, and dried in vacuo to obtain 78.4 mg of trans-2-phenylthiostyrene as a yellow liquid, with a yield of 74%.

Embodiment two:

Add 59 mg (0.5 mmol) of 2-methylstyrene, 54.5 mg (0.25 mmol) of diphenyl disulfide, 18.1 mg (0.05 mmol) of Cu(OTf) ₂ , and 127 mg (0.5 mmol) of iodine into the reaction test tube , then add 2mL DMSO, heat at 120°C for 6 hours, cool after the reaction, filter, wash the filtrate with water to remove excess iodine and solvent, combine the organic phases and distill, the resulting residue is subjected to silica gel column chromatography, washed with petroleum ether, and detected by TLC , Combine the effluents containing the product, remove the solvent by distillation with a rotary evaporator, and dry in vacuo to obtain 85.8 mg of trans-(2'-methyl)-2-phenylthiostyrene as a yellow liquid, with a yield of 76%. ¹ HNMR (500MHz, CDCl ₃ ) δ7.42-7.40(m, 3H), 7.34-7.31(m, 2H), 7.25-7.23(m, 1H), 7.16-7.14(m, 3H), 6.97(d, J=15.0Hz, 1H), 6.78(d, J=15.0Hz, 1H), 2.33(s, 3H); ¹³ C NMR (125MHz, CDCl ₃ ) δ135.6, 135.5, 135.1, 130.4, 130.0, 129.6, 129.1, 127.6, 126.8, 126.2, 125.4, 124.3, 19.8; LRMS (EI, 70 eV) m/z (%): 226 (M ⁺ , 100), 211 (43), 178 (34).

Embodiment three:

Add 59 mg (0.5 mmol) of 3-methylstyrene, 54.5 mg (0.25 mmol) of diphenyl disulfide, 18.1 mg (0.05 mmol) of Cu(OTf) ₂ , and 127 mg (0.5 mmol) of iodine into the reaction test tube , then add 2mL DMSO, heat at 120°C for 6 hours, cool after the reaction, filter, wash the filtrate with water to remove excess iodine and solvent, combine the organic phases and distill, the resulting residue is subjected to silica gel column chromatography, washed with petroleum ether, and detected by TLC , Combine the effluents containing the product, remove the solvent by distillation with a rotary evaporator, and dry in vacuo to obtain 71.2 mg of trans-(3'-methyl)-2-phenylthiostyrene as a yellow liquid, with a yield of 63%. ¹ HNMR (500MHz, CDCl ₃ ) δ7.42-7.40 (m, 2H), 7.35-7.32 (m, 2H), 7.26-7.24 (m, 2H), 7.20-7.19 (m, 1H), 7.16-7.14 ( m, 2H), 7.06-7.04(M, 1H), 6.86(d, J=15.5Hz, 1H), 6.71(d, J=15.5Hz, 1H), 2.33(s, 3H); ¹³ C NMR (125MHz, CDCl ₃ ) δ138.3, 136.5, 135.4, 132.1, 129.8, 129.1, 128.6, 126.9, 126.7, 123.2, 123.1; LRMS (EI, 70eV) m/z (%): 226 (M ⁺ , 100), 211 ( 30), 178(30).

Embodiment four:

Add 59 mg (0.5 mmol) of 4-methylstyrene, 54.5 mg (0.25 mmol) of diphenyl disulfide, 18.1 mg (0.05 mmol) of Cu(OTf) ₂ , and 127 mg (0.5 mmol) of iodine into the reaction test tube , then add 2mL DMSO, heat at 120°C for 6 hours, cool after the reaction, filter, wash the filtrate with water to remove excess iodine and solvent, combine the organic phases and distill, the resulting residue is subjected to silica gel column chromatography, washed with petroleum ether, and detected by TLC , Combine the effluents containing the product, remove the solvent by distillation with a rotary evaporator, and dry in vacuo to obtain 91.5 mg of trans-(4'-methyl)-2-phenylthiostyrene as a yellow liquid, with a yield of 81%. ¹ HNMR (500MHz, CDCl ₃ ) δ7.40-7.37(m, 2H), 7.33-7.30(m, 2H), 7.24-7.21(m, 3H), 7.12-7.09(m, 2H), 6.81(d, J=15.5Hz, 1H), 6.738(d, J=15.5Hz, 1H), 2.32(s, 3H); ¹³ C NMR (125MHz, CDCl ₃ ) δ137.5, 135.6, 133.8, 132.4, 129.6, 129.4, 129.1, 126.7, 126.0, 121.9, 21.2; LRMS (EI, 70 eV) m/z (%): 226 (M ⁺ , 100), 211 (64), 178 (40).

Embodiment five:

Add 80 mg (0.5 mmol) of 4-tert-butylstyrene, 54.5 mg (0.25 mmol) of diphenyl disulfide, 18.1 mg (0.05 mmol) of Cu(OTf) ₂ , and 127 mg (0.5 mmol) of iodine into the reaction tube Add 2mL DMSO, heat at 120°C for 6 hours, cool after the reaction, filter, wash the filtrate with water to remove excess iodine and solvent, combine the organic phases and distill, the obtained residue is subjected to silica gel column chromatography, petroleum ether rinse, TLC Detect, combine the effluents containing the product, distill off the solvent with a rotary evaporator, and dry in vacuo to obtain 92.4 mg of trans-(4'-tert-butyl)-2-phenylthiostyrene as a yellow liquid with a yield of 69%. ¹ H NMR (500MHz, CDCl ₃ ) δ7.40-7.38(m, 2H), 7.35-7.29(m, 6H), 7.25-7.21(m, 1H), 6.83(d, J=15.5Hz, 1H), 6.75 (d, J=15.5Hz, 1H), 1.31 (s, 9H); ¹³ C NMR (125MHz, CDCl ₃ ) δ150.9, 135.7, 133.8, 132.4, 129.5, 129.1, 126.7, 125.8, 125.6, 122.1, 34.6, 31.2; LRMS (EI, 70eV) m/z (%): 268 (M ⁺ , 80), 253 (100).

Embodiment six:

Add 69.5 mg (0.5 mmol) of 4-chlorostyrene, 54.5 mg (0.25 mmol) of diphenyl disulfide, 18.1 mg (0.05 mmol) of Cu(OTf) ₂ , and 127 mg (0.5 mmol) of iodine into the reaction test tube, Then add 2 mL of DMSO, heat at 120°C for 6 hours, cool after the reaction, filter, wash the filtrate with water to remove excess iodine and solvent, combine the organic phases and distill, and use silica gel column chromatography for the residue, rinse with petroleum ether, and detect by TLC. The effluents containing the product were combined, the solvent was distilled off by a rotary evaporator, and the yellow solid was obtained by vacuum drying, mp 48-49°C, 82.4 mg trans-(2′-chloro)-2-phenylthiostyrene, yield 67%.

Embodiment seven:

52 mg (0.5 mmol) styrene, 61.5 mg (0.25 mmol) 4,4'-dimethyl diphenyl disulfide, 18.1 mg (0.05 mmol) Cu(OTf) ₂ , 127 mg (0.5 mmol) iodine Add 2mL DMSO to the reaction test tube, then add 2mL DMSO, heat at 120°C for 6 hours, cool after the reaction, filter, wash the filtrate with water to remove excess iodine and solvent, combine the organic phases and distill, and use silica gel column chromatography for the residue obtained. Washing, TLC detection, combining the effluents containing the product, distilling off the solvent with a rotary evaporator, and drying in vacuo to obtain 71.2 mg of trans-2-(4'-methyl)-phenylthiostyrene as a yellow liquid with a yield of 63%.

Embodiment eight:

52 mg (0.5 mmol) styrene, 61.5 mg (0.25 mmol) 3,3'-dimethyl diphenyl disulfide, 18.1 mg (0.05 mmol) Cu(OTf) ₂ , 127 mg (0.5 mmol) iodine Add 2mL DMSO to the reaction test tube, then add 2mL DMSO, heat at 120°C for 6 hours, cool after the reaction, filter, wash the filtrate with water to remove excess iodine and solvent, combine the organic phases and distill, and use silica gel column chromatography for the residue obtained. Washing, TLC detection, combining the effluents containing the product, distilling off the solvent with a rotary evaporator, and drying in vacuo to obtain 65.5 mg of trans-2-(3'-methyl)-phenylthiostyrene as a yellow liquid with a yield of 58%.

Embodiment nine:

52 mg (0.5 mmol) styrene, 61.5 mg (0.25 mmol) 2,2'-dimethyl diphenyl disulfide, 18.1 mg (0.05 mmol) Cu(OTf) ₂ , 127 mg (0.5 mmol) iodine Add 2mL DMSO to the reaction test tube, then add 2mL DMSO, heat at 120°C for 6 hours, cool after the reaction, filter, wash the filtrate with water to remove excess iodine and solvent, combine the organic phases and distill, and use silica gel column chromatography for the residue obtained. Washing, TLC detection, combining the effluents containing the product, removing the solvent by distillation with a rotary evaporator, and drying in vacuo to obtain 58.7 mg of trans-2-(2'-methyl)-phenylthiostyrene as a yellow liquid, with a yield of 52%.

Embodiment ten:

Add 52 mg (0.5 mmol) styrene, 63.5 mg (0.25 mmol) 4,4'-difluorodiphenyl disulfide, 18.1 mg (0.05 mmol) Cu(OTf) ₂ , and 127 mg (0.5 mmol) iodine Add 2mL DMSO to the reaction test tube, heat at 120°C for 6 hours, cool down after the reaction, filter, wash the filtrate with water to remove excess iodine and solvent, combine the organic phases and distill, and use silica gel column chromatography to rinse the residue with petroleum ether , TLC detection, combined the effluents containing the product, distilled off the solvent with a rotary evaporator, and dried in vacuo to obtain 70.1 mg of trans-2-(4'-fluoro)-phenylthiostyrene as a yellow liquid, with a yield of 61%.

Embodiment eleven:

Add 52 mg (0.5 mmol) styrene, 63.5 mg (0.25 mmol) 2,2'-difluorodiphenyl disulfide, 18.1 mg (0.05 mmol) Cu(OTf) ₂ , and 127 mg (0.5 mmol) iodine Add 2mL DMSO to the reaction test tube, heat at 120°C for 6 hours, cool down after the reaction, filter, wash the filtrate with water to remove excess iodine and solvent, combine the organic phases and distill, and use silica gel column chromatography to rinse the residue with petroleum ether , TLC detection, combined the effluents containing the product, the solvent was distilled off by a rotary evaporator, and dried in vacuo to obtain 87.4 mg of trans-2-(2'-fluoro)-phenylthiostyrene as a yellow liquid, with a yield of 76%.

Embodiment 12:

Add 52 mg (0.5 mmol) styrene, 71.7 mg (0.25 mmol) 4,4'-dichlorodiphenyl disulfide, 18.1 mg (0.05 mmol) Cu(OTf) ₂ , and 127 mg (0.5 mmol) iodine Add 2mL DMSO to the reaction test tube, heat at 120°C for 6 hours, cool down after the reaction, filter, wash the filtrate with water to remove excess iodine and solvent, combine the organic phases and distill, and use silica gel column chromatography to rinse the residue with petroleum ether , TLC detection, the effluents containing the product were combined, the solvent was distilled off by a rotary evaporator, and dried in vacuo to obtain 86.1 mg of trans-2-(4'-chloro)-phenylthiostyrene as a yellow liquid, with a yield of 70%.

Claims (8)

1. a preparation method of alkenyl sulfide, it is characterized in that described method is: add the disulfide compound shown in formula II in the styrene derivative shown in formula I, take dimethyl sulfoxide as Reaction solvent, and under the effect of iodine simple substance catalyst and copper catalyst, under the effect of air atmosphere heating reaction, after reaction finishes, the alkenyl sulfide shown in formula III is obtained after the reaction liquid aftertreatment; Described copper catalyst is trifluoromethane copper sulfonate; In formula _I or formula III, R is methyl, tert-butyl, fluorine, chlorine or hydrogen; In formula II or formula III, R ₂ is methyl, fluorine, chlorine or hydrogen; In formula II, R ₂ on different benzene rings represent the same group. 2. The method of claim ₁ , wherein said R is hydrogen, 2-methyl, 3-methyl, 4-methyl, 4-chloro or 4-tert-butyl. 3. The method of claim 1, wherein said R ₂ is hydrogen, 2-methyl, 3-methyl, 4-methyl, 4-chloro, 2-fluoro or 4-fluoro. 4. The method according to claim 1, characterized in that the ratio of the amounts of the styrene derivatives represented by the formula I to the disulfide compounds represented by the formula II is 1:0.5. 5. The method according to claim 1, characterized in that the ratio of the amount of the styrene derivative represented by the formula I to the copper catalyst is 1:0.1-0.3. 6. The method according to claim 1, characterized in that the ratio of the amount of the styrene derivative represented by the formula I to the iodine simple substance catalyst is 1:1-1.5. 7. The method according to claim 1, characterized in that the reaction temperature is 120-150° C., and the reaction time is 5-10 h. 8. The method according to claim 1, characterized in that the post-treatment method of the reaction solution is: after the reaction finishes, the reaction solution is filtered, the filtrate is washed with water to remove excess iodine and solvent, and the combined organic phase is distilled, and the residue obtained is obtained by Silica gel column chromatography, the eluent is petroleum ether, the eluent is detected by TLC, the eluent containing the product is collected and combined, the solvent is removed by distillation and concentrated, and the alkenyl sulfide shown in formula III is obtained by vacuum drying.