A direct cross-coupling method of benzylsulfonium salts with thiosulfonate salts

Abstract

The application discloses a direct cross-coupling method of benzyl sulfonium salt and thiosulfonate, and belongs to the technical field of organic compound synthesis. The benzyl sulfonium salt and the thiosulfonate are reacted under the action of a metal in a solvent, and various sulfonium alkane products with moderate to good yield are obtained. The reaction not only uses the benzyl sulfonium salt which is easy to synthesize as a coupling substrate, but also uses the thiosulfonate as a substitute for mercaptan, thereby avoiding the existence of a foul odor and other dangers in the operation process. In addition, the benzyl sulfonium salt can be stored at room temperature, and shows excellent thermodynamic stability. Compared with other electrophilic reagents, the benzyl sulfonium salt is very safe and easy to prepare. The preparation method has the characteristics of mild reaction condition, simple post-treatment, green step, low pollution and high economic benefit.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic compound synthesis, and particularly relates to a direct cross-coupling method of benzyl sulfonium salt and thiosulfonate. BACKGROUND

[0002] Direct coupling between electrophiles without transition metal catalysts has attracted much attention in the synthetic community because most transition metal catalysts and ligands are expensive and environmentally unfriendly. Thiosulfonate is a new type of organic sulfur reagent, which is applied to the synthesis of C-S bond and has been proved to be a multifunctional electrophile. It can be used to construct the corresponding target product by synthesizing C-S bond with substrates containing various directing groups. However, the direct coupling of benzyl sulfonium salt as an electrophile with thiosulfonate has not been developed so far. SUMMARY

[0003] This section is intended to summarize some aspects of the embodiments of the present application and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the abstract and title of the specification of the present application in order to avoid obscuring the purpose of this section, the abstract and the title, and such simplifications or omissions cannot be used to limit the scope of the present application.

[0004] In view of the above and / or problems existing in the prior art, the present application is proposed.

[0005] One of the purposes of the present application is to provide a direct cross-coupling method of benzyl sulfonium salt and thiosulfonate, which has the characteristics of mild reaction conditions, simple post-treatment, green steps, low pollution and high economic benefits.

[0006] To solve the above technical problems, the present application provides the following technical scheme: a direct cross-coupling method of benzyl sulfonium salt and thiosulfonate, the benzyl sulfonium salt shown as formula I and the thiosulfonate shown as formula II are reacted in a solvent under the action of a metal to obtain a compound shown as formula III;

[0007]

[0008] wherein Ar includes one of a phenyl substituent, a 4-methylphenyl substituent, a 2,4,6-trimethylphenyl substituent, a 4-tert-butylphenyl substituent, a 3,4,5-trimethoxyphenyl substituent, a 4-methoxyphenyl substituent, a 1,3-benzodioxolyl substituent, a 4-trifluoromethylphenyl substituent, a 4-trifluoromethoxyphenyl substituent, a 4-carboxymethylphenyl substituent, a 4-cyanophenyl substituent, a 4-fluorophenyl substituent, a 4-phenylphenyl substituent, and a 2-naphthyl substituent.

[0009] R comprises one of a phenyl substituent, a p-methylphenyl substituent, a p-tert-butylphenyl substituent, a p-methoxyphenyl substituent, a p-(trifluoromethyl)phenyl substituent, a 4-fluorophenyl substituent, a 4-chlorophenyl substituent, a 2-pyridyl substituent, a 2-methylfuryl substituent, a benzothiazole substituent, a 2-naphthyl substituent, a benzyl substituent.

[0010] As a preferred embodiment of the direct cross-coupling process of a benzylsulfonium salt with a thiosulfonic acid eye of the present invention, wherein: the benzylsulfonium salt is selected from one of dimethylbenzylsulfonium triflate, dimethyl(4-methylbenzyl)sulfonium triflate, dimethyl(2,4,6-trimethylbenzyl)sulfonium triflate, (4-(tert-butyl)benzyl)dimethylsulfonium triflate, dimethyl(3,4,5-trimethoxybenzyl)sulfonium triflate, dimethyl(4-methoxybenzyl)sulfonium triflate, dimethyl(benzo[d][l,3]dioxol-5-ylmethyl)sulfonium triflate, dimethyl(4-(trifluoromethyl)benzyl)sulfonium triflate, dimethyl(4-(trifluoromethoxy)benzyl)sulfonium triflate, dimethyl(4-(methoxycarbonyl)benzyl)sulfonium triflate, dimethyl(4-(cyano)benzyl)sulfonium triflate, dimethyl(4-(fluorobenzyl)sulfonium triflate, dimethyl([l,l'-biphenyl]-4-ylmethyl)sulfonium triflate, dimethyl(naphthalen-2-ylmethyl)sulfonium triflate.

[0011] As a preferred embodiment of the direct cross-coupling process of a benzylsulfonium salt with a thiosulfonic acid eye of the present invention, wherein: the benzylsulfonium salt is selected from one of dimethylbenzylsulfonium triflate, dimethyl(4-methylbenzyl)sulfonium triflate, dimethyl(2,4,6-trimethylbenzyl)sulfonium triflate, (4-(tert-butyl)benzyl)dimethylsulfonium triflate, dimethyl(3,4,5-trimethoxybenzyl)sulfonium triflate, dimethyl(4-methoxybenzyl)sulfonium triflate, dimethyl(benzo[d][l,3]dioxol-5-ylmethyl)sulfonium triflate, dimethyl(4-(trifluoromethyl)benzyl)sulfonium triflate, dimethyl(4-(trifluoromethoxy)benzyl)sulfonium triflate, dimethyl(4-(methoxycarbonyl)benzyl)sulfonium triflate, dimethyl(4-(cyano)benzyl)sulfonium triflate, dimethyl(4-(fluorobenzyl)sulfonium triflate, dimethyl([l,l'-biphenyl]-4-ylmethyl)sulfonium triflate, dimethyl(naphthalen-2-ylmethyl)sulfonium triflate.

[0012] As a preferred embodiment of the direct cross-coupling process of a benzylsulfonium salt with a thiosulfonic acid eye of the present invention, wherein: the benzylsulfonium salt and the thiosulfonic acid salt are preferably in a molar ratio of 1 :2.

[0013] As a preferred embodiment of the direct cross-coupling process of a benzylsulfonium salt with a thiosulfonic acid eye of the present invention, wherein: the metal is selected from one of manganese, iron, copper, aluminum, bismuth, indium, magnesium, tin, lead, zinc, and the metal is preferably in a molar ratio of 2: 1 with the benzylsulfonium salt.

[0014] As a preferred scheme of the direct cross-coupling method of the benzyl sulfonium salt and the thiosulfonate of the present application, wherein: the solvent is selected from one of tetrahydrofuran, dimethyl sulfoxide, N-methyl pyrrolidone, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, toluene, water, and preferably the solvent is N,N-dimethylformamide.

[0015] As a preferred scheme of the direct cross-coupling method of the benzyl sulfonium salt and the thiosulfonate of the present application, wherein: the reaction temperature is 25-50℃, and preferably the temperature is 50℃.

[0016] As a preferred scheme of the direct cross-coupling method of the benzyl sulfonium salt and the thiosulfonate of the present application, wherein: the reaction time is 6-12h, and preferably the reaction time is 12h.

[0017] In summary, the chemical equation of the optimal reaction condition of the present application is shown as follows:

[0018]

[0019] Compared with the prior art, the present application has the following beneficial effects:

[0020] The present application provides a new method for the direct cross-coupling of benzyl sulfonium salt and thiosulfonate. This reaction not only uses benzyl sulfonium salt, which is easy to synthesize, as the coupling substrate, but also uses thiosulfonate as a substitute for mercaptan compounds, thereby avoiding the presence of malodorous hazards during operation. In addition, benzyl sulfonium salt can be stored at room temperature, showing excellent thermodynamic stability. Compared with other electrophilic reagents, they are also very safe and easy to prepare. The preparation method of the present application has the characteristics of mild reaction conditions, simple post-treatment, green steps, low pollution, and high economic benefits. BRIEF DESCRIPTION OF DRAWINGS

[0021] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings needed in the embodiment description will be briefly introduced as follows. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can also be obtained by those skilled in the art without creative labor. Among them:

[0022] Figure 1 The hydrogen spectrum of the target product benzyl(phenyl)sulfane of the present application embodiment 1;

[0023] Figure 2 The carbon spectrum of the target product benzyl(phenyl)sulfane of the present application embodiment 1.

[0024] Figure 3 The hydrogen spectrum of the target product (4-methylbenzyl)(phenyl)sulfane of the present application embodiment 2;

[0025] Figure 4 Carbon spectrum of the target product (4-methylbenzyl)(phenyl)sulfane of Example 2 of the present application.

[0026] Figure 5 Hydrogen spectrum of the target product benzyl(4-(tert-butyl)phenyl)sulfane of Example 3 of the present application;

[0027] Figure 6 Carbon spectrum for the target product benzyl(4-(tert-butyl)phenyl)sulfane of Example 3 of the invention. DETAILED DESCRIPTION

[0028] In order to make the above objectives, features and advantages of the present application more apparent, specific embodiments of the present application are described in detail below with reference to the description and examples.

[0029] In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present application. However, it will be apparent to one skilled in the art that the present application can be practiced without the specific details and other implementations can be employed. Therefore, the present application is not limited to the details disclosed herein and can be practiced with variations that will be apparent to one skilled in the art. Moreover, well-known structures have not been described in detail in order to avoid obscuring the present application.

[0030] Secondly, the "one embodiment" or "embodiment" referred to herein means that the specific features, structures or characteristics can be included in at least one implementation of the present application. "In one embodiment" appearing in different places in the specification does not mean the same embodiment, nor is it an embodiment that is separate or alternative to other embodiments.

[0031] The raw material benzyl sulfonium salt (Formula I) used in the embodiments of the present application is synthesized with reference to the following literature:

[0032] [1] Wang, W.; Yao, K.; Wu, F. Nickel-Catalyzed Reductive Cross-Coupling of Benzylic Sulfonium Salts with Aryl Iodides. Synlett 2022, 33, 361-366.

[0033] The raw material thiosulfonate salt (Formula II) used in the embodiments of the present application is synthesized with reference to the following literature:

[0034] [2] Moura, I. M. R.; Tranquilino, A.; Sátiro, B. G.; Silva, R. O.; de Oliveira-Silva, D.; Oliveira, R. A.; Menezes, P. H. Unusual Application for Phosphonium Salts and Phosphoranes: Synthesis of Chalcogenides. J. Org. Chem. 2021, 86, 5954-5964.

[0035] Unless otherwise specified, other raw materials used in the examples are commercially available.

[0036] Example 1

[0037] (1) Put the sealed tube equipped with magnetic stirring in the oven to dry for one hour, and then take it out, while hot, and plug in a rubber plug and insert a nitrogen ball;

[0038] (2) After the mixture is cooled to room temperature, add dimethyl benzyl sulfonium triflate (151.2 mg, 0.5 mmol, 1 equiv.), S-phenyl phenylsulfonyl thioate (250.3 mg, 1 mmol, 2 equiv.), and zinc powder (65.4 mg, 1 mmol, 2 equiv.) to the mixture, and then replace the nitrogen in the sealed tube three times. Then add 2 mL of ultra-dry N,N-dimethylformamide to the sealed tube, and stir the mixture at a temperature of 50°C for 12 hours;

[0039] (3) Then quench the reaction using saturated aqueous ammonium chloride solution, and extract with water and ethyl acetate; after washing with saturated aqueous sodium chloride solution and drying with anhydrous sodium sulfate, remove the extract by rotary evaporation, and purify the crude product by silica gel column chromatography, with 200-300 mesh silica gel powder as the stationary phase and petroleum ether as the mobile phase, to obtain 87.4 mg of the target product, which has the following structural formula:

[0040]

[0041] The above target product is characterized, and the results are as shown in Figure 1 and 2 The results are white solid. 1 H NMR (400 MHz, CDCl3): δ 7.39-7.24 (m, 9H), 7.24-7.18 (m, 1H), 4.15 (s, 2H) ppm. 13CNMR (100 MHz, CDC13): δ 137.4, 136.3, 129.8, 128.8 (2C), 128.4, 127.1, 126.3, 39.0 ppm. IR (KBr, neat): v = 1586, 1480, 1437, 1090, 1069, 730, 715, 693 cm -1 HRMS (m / z): calcd for C 13 H 13 S[M+H] + 201.0738, found: 201.0737.

[0042] According to the characterization data, the reaction product prepared is benzyl(phenyl)sulfane; the product yield is calculated to be 87%.

[0043] Example 2

[0044] (1) A sealed tube equipped with a magnetic stirrer is dried in an oven for one hour, and then, while hot, a rubber stopper is inserted and a nitrogen balloon is attached;

[0045] (2) Dimethyl(4-methylbenzyl)sulfonium triflate (158.2 mg, 0.5 mmol, 1 equiv.), S-phenyl phenylsulfonyl thioate (250.3 mg, 1 mmol, 2 equiv.), and zinc powder (65.4 mg, 1 mmol, 2 equiv.) are added to the sealed tube, which is then purged with nitrogen three times. Subsequently, 2 mL of dry N,N-dimethylformamide is added to the sealed tube; the mixture is stirred at a temperature of 80°C for 12 hours;

[0046] (3) The reaction is then quenched using saturated aqueous ammonium chloride solution, and extracted using water and ethyl acetate; the extract is washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then removed by rotary evaporation; the crude product is purified by silica gel column chromatography, with the column chromatography separation conditions being: 200-300 mesh silica gel powder as the stationary phase, and petroleum ether as the mobile phase; finally, 100.9 mg of the target product is obtained, and the chemical structure of the compound is as follows:

[0047]

[0048] The target product is characterized as shown in Figure 3 and 4 , and the result is: white solid; 1H NMR (400 MHz, CDC13): δ 7.37-7.33 (m, 2H), 7.31-7.25 (m, 2H), 7.25-7.18 (m, 3H), 7.13 (d, J = 7.8 Hz, 2H), 4.13 (s, 2H), 2.35 (s, 3H) ppm. 13 C NMR (100 MHz, CDC13): δ 136.7, 136.6, 134.2, 129.4, 129.1, 128.7, 128.6, 126.1, 38.5, 21.1 ppm. IR (KBr, neat): v = 1583, 1511, 1479, 1436, 1089, 822, 738, 691 cm -1 .HRMS (m / z): calcd for C 14 H 15 S [M + H] + 215.0889, found: 215.0884.

[0049] According to the characterization data, the prepared reaction product is (4-methylbenzyl)(phenyl)sulfane; the product yield is calculated to be 94%.

[0050] Example 3

[0051] (1) Put the sealed tube equipped with a magnetic stirrer in the oven to dry for one hour, and then take it out, while hot, plug in the rubber plug and insert a nitrogen ball;

[0052] (2) After the mixture is cooled to room temperature, add benzyl dimethyl sulfonium triflate (151.2 mg, 0.5 mmol, 1 equiv.), S-(4-(tert-butyl)phenyl) phenylsulfide (306.4 mg, 1 mmol, 2 equiv.), and zinc powder (65.4 mg, 1 mmol, 2 equiv.) to the mixture, and then replace the sealed tube with nitrogen three times. Then add 2 mL of super-dry N,N-dimethylformamide to the sealed tube; the mixture is stirred at a temperature of 50°C for 12 hours;

[0053] (3) Then quench the reaction using saturated aqueous ammonium chloride solution, and extract with water and ethyl acetate; after the extract is washed with saturated aqueous sodium chloride solution and dried with anhydrous sodium sulfate, the extract is removed by rotary evaporation, and the crude product is purified by silica gel column chromatography, and the column chromatography separation conditions are: the stationary phase is 200-300 mesh silica gel powder, and the mobile phase is petroleum ether / ethyl acetate 20:1, and finally 107.4 mg of the target product is obtained, and the chemical structural formula of the compound is:

[0054]

[0055] The target product is characterized as follows: Figure 5 and 6The result is shown as follows: colorless oil; 1 H NMR (400 MHz, CDC13): δ 7.38-7.28 (m, 9H), 4.15 (s, 2H), 1.35 (s, 9H) ppm. 13 C NMR (100 MHz, CDC13): δ 149.5, 137.6, 132.8, 129.6, 128.8, 128.4, 127.1, 125.8, 39.2, 34.4, 31.2 ppm. IR (KBr, neat): v = 2962, 1495, 1453, 1362, 1269, 1121, 826, 697 cm -1 HRMS (m / z): calcd for C 17 H 21 S[M+H] + 257.1358, found: 257.1354.

[0056] According to the characterization data, the prepared reaction product is benzyl (4- (tert-butyl) phenyl) sulfane; the product yield is calculated, and the result is 84%.

[0057] Example 4

[0058] Example 4 is basically the same as Example 1, except that the metal in step (2) is different, as shown in Table 1 below:

[0059] Table 1

[0060]

[0061]

[0062] As can be seen from Table 1, no reaction can be carried out without adding metal; under the same reaction conditions, different metals such as manganese, iron, copper, aluminum, bismuth, indium and magnesium can hardly react; while tin, lead and zinc can be successfully synthesized, with zinc being the most optimal, with a yield of 81%.

[0063] Example 5

[0064] Example 5 is basically the same as Example 1, except that the solvent in step (2) is different, as shown in Table 2 below:

[0065] Table 2

[0066] Solvent Yield (%) Tetrahydrofuran 66 Dimethyl sulfoxide 74 N-methylpyrrolidone 61 1,4-dioxane 0 N,N-dimethylformamide 81 N,N-dimethylacetamide 77 Acetonitrile 0 Toluene 0 Water 0

[0067] As can be seen from Table 2, under the same reaction conditions, the reaction is almost impossible to proceed for different solvents such as 1,4-dioxane, acetonitrile, toluene, water; while for tetrahydrofuran, dimethyl sulfoxide, N-methyl pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, they can all be successfully synthesized, and N,N-dimethylformamide is the best with the highest yield of 81%.

[0068] Example 6

[0069] Example 6 is basically the same as Example 1, except that the reaction temperature in step (2) is different, as shown in Table 3 below:

[0070] Table 3

[0071] Temperature Yield (%) 25℃ 41 50℃ 81

[0072] As can be seen from Table 3, under the same reaction conditions, different reaction temperatures such as 25°C and 50°C can all successfully synthesize, and 50°C is the best with the highest yield of 81%.

[0073] Example 7

[0074] Example 7 is basically the same as Example 1, except that the reaction time in step (2) is different, as shown in Table 4 below:

[0075] Table 4

[0076] Reaction time Yield (%) 6h 72 12h 81

[0077] As can be seen from Table 5, under different reaction times such as 6h and 12h, they can all be successfully synthesized, and 12h is the best with the highest yield of 81%.

[0078] Example 8

[0079] Example 8 is basically the same as Example 1, except that in step (2), the benzyl sulfonium salt and the thiosulfonate salt are different, as shown in Table 5 below:

[0080] Table 5

[0081]

[0082]

[0083]

[0084]

[0085] The application provides a transition metal catalyzed direct cross-coupling reaction of benzyl sulfonium salt and thiosulfonate, which uses the benzyl sulfonium salt which is easy to synthesize as a coupling substrate, and uses the thiosulfonate as a substitute of mercaptan, avoids the existence of malodorous and other dangers in the operation process, and the benzyl sulfonium salt can be stored at room temperature, and shows excellent thermodynamic stability, compared with other electrophilic reagents, they are also very safe and easy to prepare.

[0086] It should be noted that the above examples are only used to illustrate the technical solutions of the present application, not to limit it, although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present application, which should be covered in the scope of the claims of the present application.

Claims

1. A process for the direct cross-coupling of benzylsulfonium salts with thiosulfonates, characterized in that: The application relates to a method for preparing a compound of formula III. The benzyl sulfonium salt of formula I and the thiosulfonic acid salt of formula II are reacted in a solvent under the action of a metal to obtain the compound of formula III. (Formula I); (Formula II); (Formula III); Ar is selected from one of a phenyl substituent, a 4-methylphenyl substituent, a 2,4,6-trimethylphenyl substituent, a 4-tert-butylphenyl substituent, a 3,4,5-trimethoxyphenyl substituent, a 4-methoxyphenyl substituent, a 1,3-benzodioxolyl substituent, a 4-trifluoromethylphenyl substituent, a 4-trifluoromethoxyphenyl substituent, a 4-carboxymethylphenyl substituent, a 4-cyanophenyl substituent, a 4-fluorophenyl substituent, a 4-phenylphenyl substituent and a 2-naphthyl substituent; R is selected from one of a phenyl substituent, a p-methylphenyl substituent, a p-tert-butylphenyl substituent, a p-methoxyphenyl substituent, a p-(trifluoromethyl)phenyl substituent, a 4-fluorophenyl substituent, a 4-chlorophenyl substituent, a 2-pyridyl substituent, a 2-methylfuryl substituent, a benzothiazole substituent, a 2-naphthyl substituent and a benzyl substituent; The metal is selected from one of tin, lead and zinc. The solvent is selected from one of tetrahydrofuran, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide and N,N-dimethylacetamide.

2. The direct cross-coupling method of benzylsulfonium salts with thiosulfonate salts according to claim 1, characterized in that: The molar ratio of the benzyl sulfonium salt to the thiosulfonic acid salt is 1:

2.

3. The direct cross-coupling method of benzylsulfonium salts with thiosulfonate salts according to claim 1, characterized in that: The metal is zinc; the molar ratio of the metal to the benzyl sulfonium salt is 2:

1.

4. The direct cross-coupling method of benzylsulfonium salts with thiosulfonate salts according to claim 1, characterized in that: The solvent is N,N-dimethylformamide.

5. The direct cross-coupling method of benzylsulfonium salts with thiosulfonate salts according to any one of claims 1 to 4, characterized in that: The reaction temperature is 25-50 DEG C.

6. The direct cross-coupling method of benzylsulfonium salts with thiosulfonate salts according to any one of claims 1 to 4, characterized in that: The reaction time is 6-12 h.

7. The direct cross-coupling method of benzylsulfonium salts with thiosulfonate salts according to any one of claims 1 to 4, characterized in that: the benzylsulfonium salt is selected from the group consisting of dimethyl benzylsulfonium triflate, dimethyl (4-methylbenzyl)sulfonium triflate, dimethyl (2,4,6-trimethylbenzyl)sulfonium triflate, (4-(tert-butyl)benzyl)dimethylsulfonium triflate, dimethyl (3,4,5-trimethoxybenzyl)sulfonium triflate, dimethyl (4-methoxybenzyl)sulfonium triflate, dimethyl (benzo[ d dimethyl (4-(trifluoromethoxy)benzyl)sulfonium triflate, dimethyl (4-(methoxycarbonyl)benzyl)sulfonium triflate, dimethyl (4-(cyano)benzyl)sulfonium triflate, dimethyl (4-(fluorobenzyl)sulfonium triflate, dimethyl ([1,1 '-biphenyl]-4-ylmethyl)sulfonium triflate, dimethyl (naphthalen-2-ylmethyl)sulfonium triflate.

8. The direct cross-coupling method of benzylsulfonium salts with thiosulfonate salts according to any one of claims 1 to 4, characterized in that: the thiosulfate salt is selected from S - phenyl phenylsulfonylthioate, S - (p-tolyl)phenylsulfonyl sulfate, S - (4-(tert-butyl)phenyl)phenylsulfonyl thioate, S - (4-methoxyphenyl)phenylsulfonyl thioate, S - (4-(trifluoromethyl)phenyl)phenylsulfonyl sulfate, S - (4-fluorophenyl)phenylsulfonyl thioate, S - (4-chlorophenyl)phenylsulfonyl thioate, S - (pyridin-2-yl)phenylsulfonyl thioate, S - (2-methylfuran-3-yl)phenylsulfomethyl sulfate, S - (benzo[ d ]thiazol-2-yl)phenylsulfonyl thioate, S - (naphthalen-2-yl)phenylsulfonyl sulfate, S - benzyl phenylsulfonyl sulfate.

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