CN114773247A - Method for synthesizing asymmetric selenium sulfide by cross coupling of diselenide and sulfoxide - Google Patents

Abstract

The invention discloses a method for synthesizing asymmetric selenium sulfide by cross-coupling of diselenide and sulfoxide. The method adopts the cross-coupling reaction of diselenide compound and sulfoxide compound under simple synthesis conditions. , a series of different asymmetric selenium sulfides were prepared. The strategy is characterized by no metal involvement, simple conditions, wide substrate range, good functional group tolerance, and high yield, providing an efficient and green route for the preparation of asymmetric selenosulfides in a highly concise manner.

Description

A kind of method for cross-coupling of diselenide and sulfoxide to synthesize asymmetric selenosulfide

technical field

The application belongs to the technical field of organic synthesis, and in particular relates to a method for synthesizing asymmetric selenosulfide by cross-coupling of diselenide and sulfoxide.

Background technique

Although chemists have made significant progress in synthesizing asymmetric disulfides in recent decades, their analogs, selenosulfides, have remained largely unexplored. Selenocysteine (Sec) is a protein amino acid and many selenoproteins are oxidoreductases. Selenocysteine and cysteine (Cys) share many similar properties with only minor differences in electronegativity, ionic radius, and available oxidation states. However, it is worth noting that the pKa of the selenol group in Sec (~5.3) is much lower than that of the thiol in Cys (~8.3), and the redox potential of Sec is lower than that of Cys (-381vs-180mV). These facts suggest that Sec is largely deprotonated at physiological pH and is very sensitive to redox regulation.

Although this has not been verified, it is theoretically reasonable to speculate that Sec can easily react with some reactive sulfur species to form selenium sulfide (RSeSH), similar to the formation of RSSH. Many other questions about RSeSH remain unanswered, such as what are their intracellular targets and to what extent these responses affect signaling. Addressing these issues requires a better understanding of RSeSH chemistry. The invention utilizes the cross-coupling of diselenide and sulfoxide to generate asymmetric selenium sulfide, and constructs a selenium sulfide synthesis method with simple conditions, good yield and wide substrate range.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a method for synthesizing asymmetric selenium sulfides, which can prepare a series of different asymmetric selenium sulfides under simple synthesis conditions through the cross-coupling reaction of diselenide compounds and sulfoxide compounds. Selenium sulfide. The strategy is characterized by no metal involvement, simple conditions, wide substrate range, good functional group tolerance, and high yield, providing an efficient and green route for the preparation of asymmetric selenosulfides in a highly concise manner.

According to a method for synthesizing asymmetric selenosulfide by cross-coupling of diselenide and sulfoxide provided by the invention, the method comprises the following steps:

The diselenide compound shown in formula 1, the sulfoxide compound shown in formula 2, (NH ₄ ) ₂ S ₂ O ₈ and alkali are sequentially added to the reactor, and the reaction is heated and stirred. The asymmetric selenium sulfide shown in formula 3; the reaction formula is as follows:

In the above reaction formula, R ₁ and R ₂ are independently selected from substituted or unsubstituted C _6-20 aryl, and substituted or unsubstituted C ₂ -C ₂₀ heteroaryl.

R ₃ , R ₄ are independently of each other selected from substituted or unsubstituted C _1-20 alkyl, substituted or unsubstituted C _3-20 cycloalkyl, substituted or unsubstituted C _6-20 aryl, substituted or unsubstituted C 6-20 aryl Substituted C _2-20 heteroaryl.

Wherein, the alkali is selected from any one or a mixture of potassium phosphate, potassium tert-butoxide, potassium hydroxide, sodium methoxide and sodium hydroxide. Preferably, the base is selected from potassium tert-butoxide.

In any part of the present invention, the C _6-20 aryl group is preferably a C _6-14 aryl group, and typical aryl groups include phenyl, naphthyl, anthracenyl, phenanthryl, pyrenyl, indenyl, fluorene Base et al.

The C ₂ -C ₂₀ heteroaryl group is preferably a C ₂ -C ₁₂ heteroaryl group, and typical heteroaryl groups include pyridyl, thienyl, furyl, carbazolyl, pyrimidinyl, pyrazinyl, pyridazine base, indolyl, benzoindolyl, benzofuranyl, benzothienyl, triazolyl, quinolinyl, pteridyl and the like.

The C _1-20 alkyl group is preferably a C _1-12 alkyl group, more preferably a C _1-6 alkyl group. Typical alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like.

The C _3-20 cycloalkyl group is preferably a C _3-8 cycloalkyl group. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

In any part of the present invention, the substituents in the substituted or unsubstituted are selected from halogen (fluorine, chlorine, bromine, or iodine), C _1-6 alkyl, C _1-6 alkoxy, C _{1 -6} alkylthio, -CN, -NO ₂ , C _1-6 alkyl acyl, C _1-6 haloalkyl, C _6-12 and the like. Specifically, the substituents in the substituted or unsubstituted are selected from, for example, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, methoxy, ethoxy, tert-butoxy, methylthio, ethylthio, -CN, -NO ₂ , acetyl, trifluoromethyl , phenyl, naphthyl, etc.

Preferably, in the above reaction formula, R ₁ and R ₂ are independently selected from substituted or unsubstituted phenyl groups; R ₃ and R ₄ are independently selected from substituted or unsubstituted C _1-6 alkyl groups, wherein the Substituents in said substituted or unsubstituted have as previously defined herein.

Further preferably, in the above reaction formula, R ₁ , R ₂ are independently selected from phenyl, methyl, ethyl, n-propyl, tert-butyl, fluorine, chlorine, bromine, iodine, methoxy, ethyl One or more substituted phenyl groups of oxy, tert-butoxy, methylthio, -CN, _-NO2 , acetyl, trifluoromethyl or phenyl. R ₃ , R ₄ are independently of each other selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl .

Most preferably, R ₁ , R ₂ are simultaneously selected from phenyl, o-chlorophenyl, p-chlorophenyl, m-chlorophenyl, p-methylphenyl, m-methylphenyl, o-methylphenyl, 2- Naphthyl, 1-naphthyl, p-trifluoromethylphenyl, m-trifluoromethylphenyl, o-trifluoromethylphenyl; R ₃ , R ₄ are simultaneously selected from methyl, ethyl or n-propyl.

According to the aforementioned method of the present invention, wherein, the molar ratio of the diselenide compound represented by formula 1, (NH ₄ ) ₂ S ₂ O ₈ and alkali is 1:1～10:1～10, preferably 1:1: 2 to 5:3 to 6, most preferably 1:3:4.

According to the aforementioned method of the present invention, the method is in the presence of an organic solvent or does not use an organic solvent, and the organic solvent is selected from any one of benzene, toluene, xylene, chlorobenzene, carbon tetrachloride, DMF, etc. or several mixed solvents. Preferably, the method of the present invention does not use an organic solvent. In this case, the amount of the sulfoxide compound shown in formula 2 may not be particularly limited, and the amount added is sufficient to make the material evenly dispersed and facilitate stirring. For example, when DMSO is used as the reaction raw material, it simultaneously serves as the reaction solvent.

According to the aforementioned method of the present invention, the reaction temperature of the heating and stirring reaction is 100-160°C, preferably 130-150°C, and most preferably 150°C; the reaction time is 8-24 hours, preferably 10-20 hours, and the most It is preferably 12 hours. The method can be carried out in an inert atmosphere, an oxygen atmosphere or an air atmosphere, preferably in an inert atmosphere. The inert atmosphere is a nitrogen atmosphere or an argon atmosphere, preferably a nitrogen atmosphere.

According to the aforementioned method of the present invention, the post-processing operation is as follows: after the reaction is completed, the reaction mixture is quenched by adding water, extracted with ethyl acetate, the organic phases are combined, dried and concentrated, and the residue is separated by silica gel column chromatography to obtain Asymmetric selenium sulfide of formula 3.

The method of the present invention has the following beneficial effects:

The present invention reports for the first time that a series of different asymmetric selenium sulfides can be prepared under simple synthesis conditions through the cross-coupling reaction of diselenide compounds and sulfoxide compounds. The strategy is characterized by no metal involvement, simple conditions, wide substrate range, good functional group tolerance, and high yield, providing an efficient and green route for the preparation of asymmetric selenosulfides in a highly concise manner.

Description of drawings

Figure 1. The hydrogen NMR spectrum of compound 3a.

Figure 2 C NMR spectrum of compound 3a.

Figure 3 shows the hydrogen NMR spectrum of compound 3b.

Fig. 4 C NMR spectrum of compound 3b.

Figure 5. The hydrogen NMR spectrum of compound 3c.

Figure 6 C NMR spectrum of compound 3c.

Figure 7. The hydrogen NMR spectrum of compound 3d.

Fig. 8 C NMR spectrum of compound 3d.

Figure 9. The hydrogen NMR spectrum of compound 3e.

Figure 10 C NMR spectrum of compound 3e.

Detailed ways

The present invention will be further described in detail below in conjunction with specific embodiments. In the following, unless otherwise specified, the methods used are conventional methods in the art, and the reagents/raw materials used can be purchased through conventional commercial channels without further purification, and/or prepared by known synthetic routes get.

Embodiment 1-13 Reaction condition optimization test

Using diphenyl diselenide and dimethyl sulfoxide shown in formula 1 as template substrates, the influence of different reaction conditions on the yield of the target product was explored, and representative examples 1 to 13 were selected. The results are shown in Table 1. The reaction formula is as follows:

Table 1:

Reaction conditions: a: diselenide (0.2 mmol), additive (1.0 mmol), base (0.6 mmol), DMSO (2.0 mL), 140° C., nitrogen, 12 h, the yield was separated by column chromatography. b: Air atmosphere. c: Oxygen atmosphere. d: base (0.8 mmol). e: additive (0.6 mmol). f: additive (0.6 mmol), base (0.8 mmol).

After a lot of experimental exploration and research, the inventors found that using (NH ₄ ) ₂ S ₂ O ₈ as an additive and K ₃ PO ₄ as a base, reacting in DMSO at 140° C. for 24 hours can produce the desired product with a yield of 47%. The desired asymmetric selenium sulfide (Example 1). After screening the additives, we found that using ( _{NH4 ) 2S2O8} was the optimal additive and the optimal equivalent weight was ₃ (Example 12). After screening for bases, we found that t-BuOK had a better boosting effect (Example 4) and found it to be the best at 4 equivalents (Example 10). When the reaction was carried out at 150°C, the yield improved (Example 12) and the time could be shortened to 12 hours (Example 13). Finally, we took (NH ₄ ) ₂ S ₂ O ₈ (3 equiv), t-BuOK (4 equiv), 12 hours, 150° C., nitrogen atmosphere as optimal conditions (Example 13).

Taking Example 13 as an example, the reaction typical test operation of the present invention is as follows:

A 20 mL pressure tube equipped with a stirring magnet was charged with diphenyl diselenide (0.2 mmol), (NH ₄ ) ₂ S ₂ O ₈ (3.0 equiv), t-BuOK (4.0 equiv) dimethyl sulfoxide (2mL). The reaction mixture was stirred at 150°C for 12 hours under nitrogen protection. After the reaction, 10 mL of water was added to the reaction mixture, extracted with ethyl acetate (3×10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was then purified by silica gel flash chromatography to obtain the desired product of formula 3a (29 mg, 72%). Yellow oily liquid; ¹ H NMR (500MHz, CDCl ₃ ) δ 7.65-7.58(m, 2H), 7.31(m, 2H), 7.26(m, 1H), 2.61(s, 3H); ¹³ C NMR(125MHz) , CDCl ₃ ) δ 131.7, 130.2, 129.2, 127.5, 22.3.

On the basis of optimizing the reaction conditions (Example 13), the inventors further expanded the substrate scope of diselenide and found that the inductive effect of the substituent has a certain influence. When the substituent is an electron withdrawing group such as halogen, trifluoro When the methyl group is used, the yield of the corresponding product is generally higher, and when the substituent is an electron donating group, the yield of the corresponding product is relatively low. Among them, the target product yield of 57% can also be obtained by using dinaphthyl diselenide. The result is as follows:

Product structure characterization:

Compound 3b: yellow oily liquid (41 mg, 86%); ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.84-7.82 (m, 1H), 7.34-7.29 (m, 2H), 7.21-7.18 (m 1H), 2.60(s, 3H); ¹³ C NMR (125MHz, CDCl ₃ ) 132.8, 131.1, 129.5, 128.1, 127.8, 127.6, 22.0. HRMS(ESI): calculated for C ₇ H ₇ ClSSeH[M+H] ⁺ 238.9195, found 238.9199.

Compound 3c: yellow oily liquid (29 mg, 66%); ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.52 (d, J=8.0 Hz, 2H), 7.13 (d, J=7.9 Hz, 2H), 2.59 ( s, 3H), 2.34 (s, 3H); ¹³ C NMR (125MHz, CDCl ₃ ) δ 137.8, 131.1, 130.0, 128.2, 22.3, 21.1. HRMS(ESI): calculated for C ₈ H ₁₀ SSeH[M+H] ^+218.9741 , found 218.9738.

Compound 3d: yellow solid (29 mg, 57%).; Mp 52.5-54.6; ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.28 (d, J=8.3 Hz, 1H), 8.05 (dd, J ₁ =7.1 Hz, J ₂ =1.3 Hz, 1H), 7.89-7.82 (m, 2H), 7.62-7.52 (m, 2H), 7.48-7.43 (m, 1H), 2.62 (s, 3H); ¹³ C NMR (125 MHz) , CDCl ₃ )δ134.2,130.5,130.1,129.0,128.7,126.7,126.3,125.8,22.1.HRMS(ESI):calculated for C ₁₁ H ₁₁ SSeH[M+H] ⁺ 254.9741,found 254.9735.

Compound 3e: yellow oily liquid (46 mg, 85%); ¹ H NMR (500 MHz, CDCl ₃ ), δ 7.73 (d, J=8.1 Hz, 2H), 7.57 (d, J=8.1 Hz, 2H), 2.63 (s, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 136.7, 129.0, 126.1, 126.0, 125.9 (q, J=12.5 Hz), 125.9, 22.3; ¹⁹ F NMR (470 MHz, CDCl ₃ ) δ-62.5 ( s, 3F); HRMS(ESI): calculated for C ₈ H ₇ F ₃ SSeH[M+H] ⁺ 272.9459, found 272.9455.

The above-mentioned embodiments are only preferred embodiments of the present invention, rather than an exhaustive list of feasible implementations of the present invention. For those skilled in the art, without departing from the principle and spirit of the present invention, any obvious changes made to it should be considered to be included in the protection scope of the claims of the present invention.

Claims (10)

1. A method for synthesizing asymmetric selenium sulfide by cross coupling diselenide and sulfoxide is characterized by comprising the following steps:

diselenide compounds represented by formula 1, sulfoxide compounds represented by formula 2, (NH) are sequentially added into a reactor₄)₂S₂O₈And alkali, heating and stirring for reaction, and performing post-treatment after the reaction to obtain the asymmetric selenium sulfide shown in the formula 3; the reaction formula is as follows:

in the above reaction formula, R₁,R₂Independently of one another, are selected from substituted or unsubstituted C_6-20Aryl, substituted or unsubstituted C₂-C₂₀A heteroaryl group;

R₃,R₄independently of one another, from substituted or unsubstituted C_1-20Alkyl, substituted or unsubstituted C_3-20Cycloalkyl, substituted or unsubstituted C_6-20Aryl, substituted or unsubstituted C_2-20A heteroaryl group;

wherein the alkali is selected from one or a mixture of more of potassium phosphate, potassium tert-butoxide, potassium hydroxide, sodium methoxide and sodium hydroxide.

2. The method of claim 1, wherein R is₁,R₂Independently of one another, from substituted or unsubstituted phenyl; r is₃,R₄Independent of each otherIs selected from substituted or unsubstituted C_1-6An alkyl group, wherein the substituents in the substituted or unsubstituted alkyl group have the meanings as defined in claim 1.

3. The method of claim 2, wherein R is₁,R₂Independently of one another, from phenyl, by methyl, ethyl, n-propyl, tert-butyl, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, tert-butoxy, methylthio, -CN, -NO₂Phenyl substituted with one or more of acetyl, trifluoromethyl or phenyl. R is₃,R₄Independently of one another, from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl.

4. The method of claim 3, wherein R is₁,R₂And is selected from phenyl, o-chlorophenyl, p-chlorophenyl, m-chlorophenyl, p-methylphenyl, m-methylphenyl, o-methylphenyl, 2-naphthyl, 1-naphthyl, p-trifluoromethylphenyl, m-trifluoromethylphenyl, o-trifluoromethylphenyl; r₃,R₄And is selected from methyl, ethyl or n-propyl.

5. The process according to any one of claims 1 to 4, wherein the base is selected from potassium tert-butoxide.

6. The method according to any one of claims 1 to 4, wherein the diselenide compound represented by formula 1, (NH)₄)₂S₂O₈The feeding molar ratio of the alkali to the alkali is 1: 1-10, preferably 1: 2-5: 3-6, and most preferably 1:3: 4.

7. The method according to any one of claims 1 to 4, wherein no organic solvent is used.

8. The method according to any one of claims 1 to 4, wherein the reaction temperature of the heating and stirring reaction is 100 to 160 ℃, preferably 130 to 150 ℃, and most preferably 150 ℃; the reaction time is 8 to 24 hours, preferably 10 to 20 hours, and most preferably 12 hours.

9. The process according to any one of claims 1 to 4, wherein the process is carried out in an inert atmosphere, an oxygen atmosphere or an air atmosphere, preferably in an inert atmosphere; the inert atmosphere is a nitrogen atmosphere or an argon atmosphere, and preferably a nitrogen atmosphere.

10. The method according to any one of claims 1 to 4, characterized in that the post-processing operation is as follows: after the reaction is finished, adding water into the reaction mixture for quenching, extracting by ethyl acetate, combining organic phases, drying and concentrating, and separating the residue by silica gel column chromatography to obtain the asymmetric selenium sulfide shown in the formula 3.

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