A method for simultaneously synthesizing a sulfide compound and a nitrile compound

Abstract

The application provides a method for simultaneously synthesizing thioether compounds and nitrile compounds, and belongs to the technical field of organic synthesis; the thioamide compound, fluoride and acetonitrile are mixed, then a phenylacetylene precursor is added, so that the thioether compound and the nitrile compound are simultaneously synthesized at room temperature; the method is simple and fast, does not need transition metal catalysis, has a wide substrate range, the fluoride source used is cheap and easy to obtain, and does not cause environmental pollution; the method has the advantages of simple process, mild reaction condition, good universality and the like, and the yield of the synthesized thioether compound and nitrile compound is very high, the thioether compound and the nitrile compound can reach 98% at most, and has extremely high industrial popularization value.

Description

A method for simultaneously synthesizing thioether compounds and nitrile compounds Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for simultaneously synthesizing thioether compounds and nitrile compounds. Background Technology

[0002] Organosulfur compounds have been widely used in medicine, biology, agriculture, and optical materials. To date, various preparation methods using different catalysts and promoters have been reported. Currently reported reactions involving organohalides (such as alkenes, aromatics, and heteroaromatic compounds) or organoborides with sulfur sources (thiols, thiophenols, thioamides, potassium xanthate, potassium thiocyanate, elemental sulfur, sodium thiomethoxide, sodium sulfide, carbon disulfide, disulfides, and sulfonyl hydrazides) often employ metal catalysts and heating conditions. However, these methods suffer from poor atom economy and strong odors from the starting materials. Therefore, novel, green, and efficient methods for synthesizing sulfur-containing compounds have always been a hot topic in organic chemistry research.

[0003] Nitriles are naturally found in various bacteria, fungi, plants, and animals, and are widely used as raw materials for the production of various pharmaceuticals, agrochemicals, polymers, and materials. Examples of drugs containing nitrile groups include the antidiabetic drug vildagliptin and the breast cancer treatment drug anastrazole. Furthermore, nitrile functional groups have been used as general intermediates in organic synthesis and can be readily converted into various other important functional groups, namely aldehydes, carboxylic acids, esters, primary amines, imines, oximes, and amides. Various methods for synthesizing nitriles have been developed, including addition reactions involving multiple bonds, oxidation reactions of amines, reduction reactions of nitroalkanes, reactions of alcohols, dehydration or rearrangement reactions of oximes and amylopectins, dehydration of amides, and dehydrogenation sulfidation reactions of thioamides. However, existing methods for synthesizing nitriles often suffer from drawbacks such as very high temperatures, the use of metal catalysts, harsh reaction conditions leading to poor functional group tolerance, the use of stoichiometric reagents, and the generation of metal waste. Therefore, the synthesis of this highly valuable nitrile functional group remains one of the most promising research areas in organic chemistry.

[0004] Both organosulfur ethers and nitriles are widely used organic compounds. Simultaneous synthesis of these compounds could reduce byproducts and improve atom utilization. Furthermore, the significant polarity difference between organosulfur ethers and nitriles makes separation relatively easy and rapid, offering significant industrial potential. However, no literature currently discloses a one-pot method for preparing organosulfur ethers and nitriles using benzylene. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a method for the simultaneous synthesis of thioether compounds and nitrile compounds. This invention involves mixing a thioamide compound, a fluoride, and acetonitrile, and then adding a benzyne precursor to achieve the simultaneous synthesis of thioether compounds and nitrile compounds at room temperature. The method is simple, rapid, requires no transition metal catalysis, has a broad substrate range, uses readily available and inexpensive fluorine sources, and does not cause environmental pollution. The method has advantages such as simple process, mild reaction conditions, and good versatility. Furthermore, the yields of the synthesized thioether compounds and nitrile compounds are very high, reaching up to 98%, making it highly valuable for industrial application.

[0006] To achieve the above-mentioned technical objectives, the present invention employs the following technical means:

[0007] This invention provides a method for simultaneously synthesizing thioether compounds and nitrile compounds, specifically comprising the following steps:

[0008] Thioamide compounds and fluorides are mixed with a solvent under nitrogen protection, and then a benzyne precursor is added dropwise under stirring. After mixing evenly, a mixture is obtained. The mixture is then subjected to nucleophilic protonation desulfurization and dehydrogenation reactions, which simultaneously generate thioether compounds and nitrile compounds.

[0009] Preferably, the thioamide compound comprises:

[0010] Preferably, R in the thioamide compound 2 Including methoxy, 4-phenyl, 3,5-dimethoxy, 3,4,5-trimethoxy, 4-nitro, 3-nitro, 2-nitro, 2,5-chloro, 1-naphthyl, 2-naphthyl, 4-(1H-imidazol-1-yl), 1-methyl-1H-indole, 2-(1H-indole-3-yl), and 1-naphthylethyl.

[0011] Preferably, the benzylene precursor comprises:

[0012] Preferably, R in the benzylene precursor 1 Including hydrogen-based, 4,5-phenyl, 4,5-cyclopentyl, 4,5-dimethoxy, 4,5-dimethyl, 3-methoxy, or 3-fluoro.

[0013] Preferably, the fluoride comprises tetramethylammonium fluoride, and the solvent comprises acetonitrile.

[0014] Preferably, the ratio of the thioamide compound, fluoride and solvent is 0.2 mmol: 0.4 to 0.9 mmol: 2.0 mL.

[0015] Preferably, the stirring speed is 300-450 r / min;

[0016] The benzyne precursor was added at a rate of 2 drops per 100 μL microsyringe. Controlling the dropping rate ensured rapid dispersion of the added raw material in the reaction system, avoiding splashing.

[0017] Preferably, the molar ratio of the thioamide compound to the benzylene precursor is 1:2.0 to 3.0.

[0018] Preferably, the reaction conditions for the nucleophilic protonation desulfurization and dehydrogenation reaction are: 2 hours at room temperature in a closed environment. Compared with the prior art, the beneficial effects of the present invention are:

[0019] This invention involves mixing a thioamide compound, a fluoride, and acetonitrile, adding a benzyne precursor, and synthesizing ethers and nitrile compounds simultaneously in a single step at room temperature. Preferably, the thioamide compound and fluoride are mixed, and then acetonitrile is added to the resulting mixture. Under stirring conditions and at room temperature, the benzyne precursor is added dropwise at a rate of 2 drops / 2 s using a 100 μL microsyringe, and a nucleophilic addition, hydrogen transfer, and desulfurization reaction is carried out under a nitrogen atmosphere. In the nucleophilic addition, hydrogen transfer, and desulfurization reaction described in this invention, the sulfur of the thioamide compound nucleophilically attacks the benzyne to generate an amphoteric intermediate A. A then undergoes proton transfer to generate B. Intermediate B then reacts with one molecule of benzyne to generate C. C then undergoes proton transfer and CS bond breaking to simultaneously generate diphenyl sulfide and benzonitrile.

[0020]

[0021] This invention is the first to propose the simultaneous preparation of thioether and nitrile compounds from benzylene and thioamides, achieving 100% atom utilization and facilitating the separation of the two products due to their significant polarity difference. The provided preparation method is simple and rapid, requires no transition metal catalysis, has a broad substrate range, uses readily available and inexpensive fluorine sources, and utilizes commercially available raw materials, some of which can be easily prepared using amides and Lawson's reagent. It does not cause environmental pollution and boasts advantages such as simple process, mild reaction conditions, high yields (up to 98%) of both thioether and nitrile compounds obtained simultaneously, and good versatility. The described synthesis method has extremely high industrial application value. Detailed Implementation

[0022] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto. The following embodiments are only used to more clearly illustrate the technical solutions of the present invention, and should not be used to limit the scope of protection of the present invention. Experimental methods in the following embodiments that do not specify specific conditions are performed according to conventional methods and conditions in the art, or according to the product instructions. Reagents and raw materials in the following embodiments that do not specify specific components can be prepared by conventional methods or are commercially available.

[0023] The mechanism of the nucleophilic protonation, desulfurization, and dehydrogenation reaction process is as follows:

[0024]

[0025] One of the equations for the nucleophilic addition, hydrogen transfer, and desulfurization reactions is:

[0026]

[0027] After completing the nucleophilic addition, hydrogen transfer, and desulfurization reactions, the present invention preferably removes the solvent from the reaction system under reduced pressure and uses column chromatography to separate the ether and nitrile compounds simultaneously.

[0028] The above mechanism will be explained in detail through the following examples.

[0029] Example 1:

[0030] Accurately weigh 0.2 mmol of p-methoxythiobenzamide and 0.44 mmol of tetramethylammonium fluoride (TMAF) and place them in a 50 mL reaction tube with a polytetrafluoroethylene cap. Vacuum the tube three times and replace the nitrogen gas. Under nitrogen protection, add 2.0 mL of acetonitrile and stir at room temperature for 5 minutes. Then, stir at 450 r / min and add 0.44 mmol of 2-(trimethylsilyl)phenyltrifluoromethanesulfonate, a precursor of benzyne, dropwise. Stir and react at room temperature for 2 hours. After the reaction is complete, remove the solvent under reduced pressure and separate diphenyl sulfide and p-methoxybenzamide.

[0031] The p-methoxybenzonitrile was a white solid with a yield of 23.2 mg, representing a yield of 87%. The prepared p-methoxybenzonitrile was characterized, and its structural formula was determined to be: The characterization results are as follows: 1 HNMR(400MHz,Chloroform-d)δ7.59(d,J=9.0Hz,2H),6.95(d,J=9.0Hz,2H),3.86(s,3H). 13C NMR (100MHz, Chloroform-d) δ162.8,134.0,119.2,114.8,104.0,55.5.

[0032] The above characterization results demonstrate the successful synthesis of p-methoxybenzonitrile.

[0033] The diphenyl sulfide was a colorless liquid with a yield of 23.5 mg, representing a yield of 90%. The prepared diphenyl sulfide was characterized, and its structural formula is as follows: The characterization results are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.36-7.32(m,4H),7.32-7.27(m,4H),7.26-7.21(m,2H). 13 C NMR (100MHz, Chloroform-d) δ135.8,131.0,129.2,127.0,77.3,77.0,76.7.

[0034] The above characterization results indicate that diphenyl sulfide was successfully synthesized.

[0035] In summary, the method described in this embodiment can simultaneously synthesize diphenyl sulfide, a sulfide compound, and p-methoxybenzonitrile, a nitrile compound.

[0036] Example 2:

[0037] Accurately weigh 0.2 mmol of 4-phenylthiobenzamide and 0.44 mmol of TMAF and place them in a 50 mL reaction tube with a polytetrafluoroethylene cap. Vacuum the tube three times and replace the nitrogen gas. Under nitrogen protection, add 2.0 mL of acetonitrile and stir at room temperature for 5 minutes. Then, stir at 450 r / min and add 0.44 mmol of 2-(trimethylsilyl)phenyltrifluoromethanesulfonate, a precursor of benzyne, dropwise. Stir and react at room temperature for 2 hours. After the reaction is complete, remove the solvent under reduced pressure and separate diphenyl sulfide and 4-phenylbenzonitrile.

[0038] The 4-phenylbenzonitrile was a white solid with a yield of 36.2 mg, representing a yield of 95%. The prepared 4-phenylbenzonitrile was characterized, and its structural formula was determined to be: The characterization results are as follows: 1 HNMR(400MHz,Chloroform-d)δ7.70(q,J=8.6Hz,4H),7.59(d,J=7.0Hz,2H),7.48(t,J=7.3Hz,2H),7.45-7.39(m,1H). 13C NMR (100MHz, Chloroform-d) δ145.7,139.2,132.6,129.1,128.7,127.7,127.2,110.9.

[0039] The above characterization results indicate that 4-phenylbenzonitrile was successfully synthesized.

[0040] The characterization of the diphenyl sulfide was consistent with that in Example 1, indicating that the diphenyl sulfide was successfully synthesized.

[0041] In summary, the method described in this embodiment can simultaneously synthesize diphenyl sulfide, a sulfide compound, and 4-phenylbenzonitrile, a nitrile compound.

[0042] Example 3:

[0043] Accurately weigh 0.2 mmol of 3,5-dimethoxybenzoyl thiocyanate and 0.44 mmol of TMAF, and place them in a 50 mL reaction tube with a polytetrafluoroethylene cap. Vacuum the tube three times and replace the nitrogen gas with a vacuum gas. Under nitrogen protection, add 2.0 mL of acetonitrile and stir at room temperature for 5 minutes. Then, stir at 450 r / min and add 0.44 mmol of 2-(trimethylsilyl)phenyltrifluoromethanesulfonate, a precursor of benzyne, dropwise. Stir the reaction at room temperature for 2 hours. After the reaction is completed, remove the solvent under reduced pressure and separate diphenyl sulfide and 3,5-dimethoxybenzonitrile.

[0044] The 3,5-dimethoxybenzonitrile was a white solid with a yield of 31.4 mg, representing a yield of 96%. The prepared 3,5-dimethoxybenzonitrile was characterized, and its structural formula was determined to be: The characterization results are as follows: 1 H NMR (400MHz, Chloroform-d) δ6.76 (d, J = 2.4Hz, 2H), 6.65 (t, J = 4.6Hz, 1H), 3.81 (s, 6H). 13 C NMR (100MHz, Chloroform-d) δ161.0,118.8,113.4,109.9,105.6,55.7.

[0045] The above characterization results demonstrate the successful synthesis of 3,5-dimethoxybenzonitrile.

[0046] The characterization of the diphenyl sulfide was consistent with that in Example 1, indicating that the diphenyl sulfide was successfully synthesized.

[0047] In summary, the method described in this embodiment can simultaneously synthesize diphenyl sulfide, a sulfide compound, and 3,5-dimethoxybenzonitrile, a nitrile compound.

[0048] Example 4:

[0049] Accurately weigh 0.2 mmol of 3,4,5-trimethoxybenzoyl thiocyanate and 0.44 mmol of TMAF, and place them in a 50 mL reaction tube with a polytetrafluoroethylene cap. Vacuum the tube three times and replace the nitrogen gas with a vacuum gas. Under nitrogen protection, add 2.0 mL of acetonitrile and stir at room temperature for 5 minutes. Then, stir at 450 r / min and add 0.44 mmol of 2-(trimethylsilyl)phenyltrifluoromethanesulfonate, a precursor of benzyne, dropwise. Stir the reaction at room temperature for 2 hours. After the reaction is complete, remove the solvent under reduced pressure and separate diphenyl sulfide and 3,4,5-trimethoxybenzonitrile.

[0050] The 3,4,5-trimethoxybenzonitrile was a white solid with a yield of 39.0 mg, representing a yield of 96%. The prepared 3,4,5-trimethoxybenzonitrile was characterized, and its structural formula was determined to be: The characterization results are as follows: 1 H NMR (400MHz, Chloroform-d) δ6.87 (s, 2H), 3.89 (d, J = 8.5Hz, 9H). 13 C NMR (100MHz, Chloroform-d) δ153.6,142.3,119.0,109.5,106.7,61.1,56.4.

[0051] The above characterization results demonstrate the successful synthesis of 3,4,5-trimethoxybenzonitrile.

[0052] The characterization of the diphenyl sulfide was consistent with that in Example 1, indicating that the diphenyl sulfide was successfully synthesized.

[0053] In summary, the method described in this embodiment can simultaneously synthesize diphenyl sulfide, a sulfide compound, and 3,4,5-trimethoxybenzonitrile, a nitrile compound.

[0054] Example 5:

[0055] Accurately weigh 0.2 mmol of 4-nitrothiobenzamide and 0.44 mmol of TMAF and place them in a 50 mL reaction tube with a polytetrafluoroethylene cap. Vacuum the tube three times and replace the nitrogen gas. Under nitrogen protection, add 2.0 mL of acetonitrile and stir at room temperature for 5 minutes. Then, stir at 450 r / min and add 0.44 mmol of 2-(trimethylsilyl)phenyltrifluoromethanesulfonate, a precursor of benzyne, dropwise. Stir and react at room temperature for 2 hours. After the reaction is complete, remove the solvent under reduced pressure and separate diphenyl sulfide and 4-nitrobenzonitrile.

[0056] The 4-nitrobenzene was a white solid with a yield of 26.3 mg, representing a yield of 89%. The prepared 4-nitrobenzene was characterized, and its structural formula was determined to be: The characterization results are as follows: 1 H NMR (400MHz, Chloroform-d) δ8.37 (d, J = 9.0 Hz, 2H), 7.90 (d, J = 9.0 Hz, 2H). 13 C NMR (100MHz, Chloroform-d) δ150.0,133.5,124.3,118.3,116.8.

[0057] The above characterization results indicate that 4-nitrobenzene was successfully synthesized.

[0058] The characterization of the diphenyl sulfide was consistent with that in Example 1, indicating that the diphenyl sulfide was successfully synthesized.

[0059] In summary, the method described in this embodiment can simultaneously synthesize diphenyl sulfide, a sulfide compound, and 4-nitrobenzene, a nitrile compound.

[0060] Example 6:

[0061] Accurately weigh 0.2 mmol of 3-nitrothiobenzamide and 0.44 mmol of TMAF and place them in a 50 mL reaction tube with a polytetrafluoroethylene cap. Vacuum the tube three times and replace the nitrogen gas. Under nitrogen protection, add 2.0 mL of acetonitrile and stir at room temperature for 5 minutes. Then, stir at 450 r / min and add 0.44 mmol of 2-(trimethylsilyl)phenyltrifluoromethanesulfonate, a precursor of benzyne, dropwise. Stir the reaction at room temperature for 2 hours. After the reaction is complete, remove the solvent under reduced pressure and separate diphenyl sulfide and 3-nitrobenzonitrile.

[0062] The 3-nitrobenzene was a yellow solid with a yield of 27.1 mg, representing a yield of 92%. The prepared 3-nitrobenzene was characterized, and its structural formula was determined to be: The characterization results are as follows: 1 H NMR (400MHz, Chloroform-d) δ8.54 (s, 1H), 8.49 (d, J = 8.4Hz, 1H), 8.01 (d, J = 7.8Hz, 1H), 7.75 (t, J = 8.0Hz, 1H). 13 C NMR (100MHz, Chloroform-d) δ148.3,137.6,130.7,127.5,116.5,114.2.

[0063] The above characterization results indicate that 3-nitrobenzene was successfully synthesized.

[0064] The characterization of the diphenyl sulfide was consistent with that in Example 1, indicating that the diphenyl sulfide was successfully synthesized.

[0065] In summary, the method described in this embodiment can simultaneously synthesize diphenyl sulfide, a sulfide compound, and 3-nitrobenzene, a nitrile compound.

[0066] Example 7:

[0067] Accurately weigh 0.2 mmol of 2-nitrothiobenzamide and 0.44 mmol of TMAF and place them in a 50 mL reaction tube with a polytetrafluoroethylene cap. Vacuum the tube three times and replace the nitrogen gas. Under nitrogen protection, add 2.0 mL of acetonitrile and stir at room temperature for 5 minutes. Then, stir at 450 r / min and add 0.44 mmol of 2-(trimethylsilyl)phenyltrifluoromethanesulfonate, a precursor of benzyne, dropwise. Stir and react at room temperature for 2 hours. After the reaction is complete, remove the solvent under reduced pressure and separate diphenyl sulfide and 2-nitrobenzonitrile.

[0068] The 2-nitrobenzene was a yellow solid with a yield of 21.3 mg, representing a yield of 59%. The prepared 2-nitrobenzene was characterized, and its structural formula was determined to be: The characterization results are as follows: 1 H NMR(400MHz,Chloroform-d)δ8.36(s,1H),7.95(s,1H),7.90-7.82(m,2H). 13 C NMR (100MHz, Chloroform-d) δ135.6,134.3,133.7,125.6,114.9,108.1.

[0069] The above characterization results indicate that 2-nitrobenzene was successfully synthesized.

[0070] The characterization of the diphenyl sulfide was consistent with that in Example 1, indicating that the diphenyl sulfide was successfully synthesized.

[0071] In summary, the method described in this embodiment can simultaneously synthesize diphenyl sulfide, a sulfide compound, and 2-nitrobenzene, a nitrile compound.

[0072] Example 8:

[0073] Accurately weigh 0.2 mmol of 2,5-dichlorothiobenzamide and 0.44 mmol of TMAF and place them in a 50 mL reaction tube with a polytetrafluoroethylene cap. Vacuum the tube three times and replace the nitrogen gas with a vacuum gas. Add 2.0 mL of acetonitrile under nitrogen protection and stir at room temperature for 5 minutes. Then, stir at 450 r / min and add 0.44 mmol of 2-(trimethylsilyl)phenyltrifluoromethanesulfonate, a precursor of benzyne, dropwise. Stir and react at room temperature for 2 hours. After the reaction is complete, remove the solvent under reduced pressure and separate diphenyl sulfide and 2,5-dichlorobenzonitrile.

[0074] The 2,5-dichlorobenzonitrile was a white solid with a yield of 24.7 mg, representing a yield of 72%. The prepared 2,5-dichlorobenzonitrile was characterized, and its structural formula was determined to be: The characterization results are as follows: 1 HNMR(400MHz,Chloroform-d)δ7.62(d,J=8.4Hz,1H),7.55(d,J=2.0Hz,1H),7.38(dd,J=8.4,2.0Hz,1H). 13 C NMR (100MHz, Chloroform-d) δ140.1,137.8,134.6,130.3,127.9,115.2,111.9.

[0075] The above characterization results indicate that 2,5-dichlorobenzonitrile was successfully synthesized.

[0076] The characterization of the diphenyl sulfide was consistent with that in Example 1, indicating that the diphenyl sulfide was successfully synthesized.

[0077] In summary, the method described in this embodiment can simultaneously synthesize diphenyl sulfide, a sulfide compound, and 2,5-dichlorobenzonitrile, a nitrile compound.

[0078] Example 9:

[0079] Accurately weigh 0.2 mmol of 1-naphthiobenzamide and 0.44 mmol of TMAF and place them in a 50 mL reaction tube with a polytetrafluoroethylene cap. Vacuum the tube three times and replace the nitrogen gas. Under nitrogen protection, add 2.0 mL of acetonitrile and stir at room temperature for 5 minutes. Then, stir at 450 r / min and add 0.44 mmol of 2-(trimethylsilyl)phenyltrifluoromethanesulfonate, a precursor of benzyne, dropwise. Stir and react at room temperature for 2 hours. After the reaction is complete, remove the solvent under reduced pressure and separate diphenyl sulfide and 1-naphthyl nitrile.

[0080] The 1-naphthonitrile was a yellow liquid with a yield of 28.2 mg, representing a yield of 92%. The prepared 1-naphthonitrile was characterized, and its structural formula was determined to be: The characterization results are as follows: 1 H NMR (400MHz, Chloroform-d) δ8.23(d,J=8.3Hz,1H),8.07(d,J=8.3Hz,1H),7.93-7.88(m,2H),7.71-7.66(m,1H),7.64-7.59(m,1H),7.54-7.49(m,1H). 13 C NMR (100MHz, Chloroform-d) δ133.3,132.9,132.6,132.3,128.6,128.6,127.5,125.1,124.9,117.8,110.2.

[0081] The above characterization results indicate that 1-naphthonitrile was successfully synthesized.

[0082] The characterization of the diphenyl sulfide was consistent with that in Example 1, indicating that the diphenyl sulfide was successfully synthesized.

[0083] In summary, the method described in this embodiment can simultaneously synthesize diphenyl sulfide, a sulfide compound, and 1-naphthonitrile, a nitrile compound.

[0084] Example 10:

[0085] Accurately weigh 0.2 mmol of 2-naphthiobenzamide and 0.44 mmol of LTMAF and place them in a 50 mL reaction tube with a polytetrafluoroethylene cap. Vacuum the tube three times and replace the nitrogen gas. Under nitrogen protection, add 2.0 mL of acetonitrile and stir at room temperature for 5 minutes. Then, stir at 450 r / min and add 0.44 mmol of 2-(trimethylsilyl)phenyltrifluoromethanesulfonate, a benzyne precursor, dropwise. Stir and react at room temperature for 2 hours. After the reaction is complete, remove the solvent under reduced pressure and separate diphenyl sulfide and 2-naphthyl nitrile.

[0086] The 2-naphthonitrile was a white solid with a yield of 27.2 mg, representing a yield of 89%. The prepared 2-naphthonitrile was characterized, and its structural formula was determined to be: The characterization results are as follows: 1 H NMR (400MHz, Chloroform-d) δ8.24 (s, 1H), 7.91 (t, J = 9.0Hz, 3H), 7.67-7.59 (m, 3H). 13 C NMR (100MHz, Chloroform-d) δ134.7,134.2,132.3,129.2,129.0,128.4,128.1,127.7,126.4,119.2,109.4.

[0087] The above characterization results indicate that 2-naphthonitrile was successfully synthesized.

[0088] The characterization of the diphenyl sulfide was consistent with that in Example 1, indicating that the diphenyl sulfide was successfully synthesized.

[0089] In summary, the method described in this embodiment can simultaneously synthesize diphenyl sulfide, a sulfide compound, and 2-naphthonitrile, a nitrile compound.

[0090] Example 11:

[0091] Accurately weigh 0.2 mmol of 4-(1H-imidazol-1-yl)thiobenzamide and 0.44 mmol of TMAF, and place them in a 50 mL reaction tube with a polytetrafluoroethylene cap. Vacuum the tube three times and replace the nitrogen gas with a vacuum gas. Add 2.0 mL of acetonitrile under nitrogen protection and stir at room temperature for 5 minutes. Then, stir at 450 r / min and add 0.44 mmol of 2-(trimethylsilyl)phenyltrifluoromethanesulfonate, a precursor of benzyne, dropwise. Stir the reaction at room temperature for 2 hours. After the reaction is completed, remove the solvent under reduced pressure and separate diphenyl sulfide and 4-(1H-imidazol-1-yl)benzonitrile.

[0092] The 4-(1H-imidazol-1-yl)benzonitrile was a white solid with a yield of 30.0 mg and a yield of 89%. The prepared 4-(1H-imidazol-1-yl)benzonitrile was characterized, and its structural formula was determined as follows: The characterization results are as follows: 1 HNMR(400MHz,Chloroform-d)δ7.95(s,1H),7.81(d,J=8.8Hz,2H),7.54(d,J=8.9Hz,2H),7.35(s,1H),7.27(s,1H). 13 C NMR (100MHz, Chloroform-d) δ140.5,135.3,134.1,131.5,121.4,117.9,117.6,111.0.

[0093] The above characterization results indicate that 4-(1H-imidazol-1-yl)benzonitrile was successfully synthesized.

[0094] The characterization of the diphenyl sulfide was consistent with that in Example 1, indicating that the diphenyl sulfide was successfully synthesized.

[0095] In summary, the method described in this embodiment can simultaneously synthesize diphenyl sulfide, a sulfide compound, and 4-(1H-imidazol-1-yl)benzonitrile, a nitrile compound.

[0096] Example 12:

[0097] Accurately weigh 0.2 mmol of 1-methyl-1H-indole-3-thiobenzamide and 0.44 mmol of TMAF, and place them in a 50 mL reaction tube with a polytetrafluoroethylene cap. Vacuum the tube three times and replace the nitrogen gas with a vacuum gas. Add 2.0 mL of acetonitrile under nitrogen protection and stir at room temperature for 5 minutes. Then, stir at 450 r / min and add 0.44 mmol of 2-(trimethylsilyl)phenyltrifluoromethanesulfonate, a precursor of benzyne, dropwise. Stir and react at room temperature for 2 hours. After the reaction is complete, remove the solvent under reduced pressure and separate diphenyl sulfide and 1-methyl-1H-indole-3-carboxynitrile.

[0098] The 1-methyl-1H-indole-3-carboxynitrile was a brown liquid with a yield of 27.0 mg and a yield of 86%. The prepared 1-methyl-1H-indole-3-carboxynitrile was characterized, and its structural formula was determined as follows: The characterization results are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.75 (d, J = 7.8Hz, 1H), 7.54 (s, 1H), 7.41-7.27 (m, 3H), 3.84 (s, 3H). 13 C NMR (100MHz, Chloroform-d) δ136.0,135.5,127.8,123.9,122.1,119.9,115.9,110.3,85.5,33.6.

[0099] The above characterization results indicate that 1-methyl-1H-indole-3-carboxynitrile was successfully synthesized.

[0100] The characterization of the diphenyl sulfide was consistent with that in Example 1, indicating that the diphenyl sulfide was successfully synthesized.

[0101] In summary, the method described in this embodiment can simultaneously synthesize diphenyl sulfide, a sulfide compound, and 1-methyl-1H-indole-3-carboxynitrile, a nitrile compound.

[0102] Example 13:

[0103] Accurately weigh 0.2 mmol of 2-(1H-indol-3-yl)thiophenylacetamide and 0.44 mmol of TMAF, and place them in a 50 mL reaction tube with a polytetrafluoroethylene cap. Vacuum the tube three times and replace the nitrogen gas with a vacuum gas. Under nitrogen protection, add 2.0 mL of acetonitrile and stir at room temperature for 5 minutes. Then, stir at 450 r / min and add 0.44 mmol of 2-(trimethylsilyl)phenyltrifluoromethanesulfonate, a precursor of benzyne, dropwise. Stir the reaction at room temperature for 2 hours. After the reaction is completed, remove the solvent under reduced pressure and separate diphenyl sulfide and 2-(1H-indol-3-yl)acetonitrile.

[0104] The 2-(1H-indol-3-yl)acetonitrile was a colorless liquid with a yield of 30.0 mg and a yield of 96%. The prepared 2-(1H-indol-3-yl)acetonitrile was characterized, and its structural formula was determined as follows: The characterization results are as follows: 1 H NMR (400MHz, Chloroform-d) δ8.21(s,1H),7.58(d,J=7.9Hz,1H),7.38(d,J=8.2Hz,1H),7.26-7.22(m,1H),7.20-7.16(m,2H),3.82(s,2H). 13 C NMR (100MHz, Chloroform-d) δ136.3,126.0,122.9,122.8,120.3,118.2,118.1,111.5,104.8,14.4.

[0105] The above characterization results indicate that 2-(1H-indol-3-yl)acetonitrile was successfully synthesized.

[0106] The characterization of the diphenyl sulfide was consistent with that in Example 1, indicating that the diphenyl sulfide was successfully synthesized.

[0107] In summary, the method described in this embodiment can simultaneously synthesize diphenyl sulfide, a sulfide compound, and 2-(1H-indol-3-yl)acetonitrile, a nitrile compound.

[0108] Example 14:

[0109] Accurately weigh 0.2 mmol of 1-naphthioacetamide and 0.44 mmol of LTMAF and place them in a 50 mL reaction tube with a polytetrafluoroethylene cap. Vacuum the tube three times and replace the nitrogen gas. Under nitrogen protection, add 2.0 mL of acetonitrile and stir at room temperature for 5 minutes. Then, stir at 450 r / min and add 0.44 mmol of 2-(trimethylsilyl)phenyltrifluoromethanesulfonate, a precursor of benzyne, dropwise. Stir and react at room temperature for 2 hours. After the reaction is complete, remove the solvent under reduced pressure and separate diphenyl sulfide and 1-naphthioacetonitrile.

[0110] The 1-naphthylacetonitrile was a white solid with a yield of 35.3 mg, representing a yield of 98%. The prepared 1-naphthylacetonitrile was characterized, and its structural formula was determined to be: The characterization results are as follows: 1H NMR (400MHz, Chloroform-d) δ7.87 (dd, J=21.4, 8.0Hz, 3H), 7.61-7.52 (m, 3H), 7.45 (t, J=7.5Hz, 1H), 4.09 (s, 2H). 13 C NMR (100MHz, Chloroform-d) δ130.7,129.1,129.0,127.0,126.4,126.3,125.8,125.4,122.4,117.7,21.7.

[0111] The above characterization results indicate that 1-naphthylacetonitrile was successfully synthesized.

[0112] The characterization of the diphenyl sulfide was consistent with that in Example 1, indicating that the diphenyl sulfide was successfully synthesized.

[0113] In summary, the method described in this embodiment can simultaneously synthesize diphenyl sulfide, a sulfide compound, and 1-naphthylacetonitrile, a nitrile compound.

[0114] Example 15:

[0115] Accurately weigh 0.2 mmol of 4-methoxybenzonitrile and 0.44 mmol of TMAF and place them in a 50 mL reaction tube with a polytetrafluoroethylene cap. Vacuum the tube three times and replace the nitrogen gas. Under nitrogen protection, add 2.0 mL of acetonitrile and stir at room temperature for 5 minutes. Then, stir at 450 r / min and add 0.44 mmol of 4,5-dimethyl-2-(trimethylsilyl)phenyltrifluoromethanesulfonate, a precursor of benzyne, dropwise. Stir the reaction at room temperature for 2 hours. After the reaction is complete, remove the solvent under reduced pressure and separate bis(3,4-dimethylphenyl) sulfide and p-methoxybenzonitrile.

[0116] The bis(3,4-dimethylphenyl) sulfide was a white solid with a yield of 47.1 mg, representing a yield of 97%. The prepared bis(3,4-dimethylphenyl) sulfide was characterized, and its structural formula was determined to be: The characterization results are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.11(d,J=7.6Hz,2H),6.97(d,J=7.6Hz,2H),6.88(s,2H),2.33(s,6H),2.22(s,6H). 13 C NMR (100MHz, Chloroform-d) δ137.5,135.5,132.8,132.2,130.3,128.6,19.7,19.4.

[0117] The above characterization results demonstrate the successful synthesis of bis(3,4-dimethylphenyl) sulfide.

[0118] The p-methoxybenzonitrile prepared in this embodiment is as shown in Example 1, which indicates that p-methoxybenzonitrile was successfully synthesized.

[0119] In summary, the method described in this embodiment can simultaneously synthesize diphenyl sulfide, a sulfide compound, and p-methoxybenzonitrile, a nitrile compound.

[0120] Example 16:

[0121] Accurately weigh 0.2 mmol of 4-methoxybenzonitrile and 0.44 mmol of TMAF and place them in a 50 mL reaction tube with a polytetrafluoroethylene cap. Vacuum the tube three times and replace the nitrogen gas. Under nitrogen protection, add 2.0 mL of acetonitrile and stir at room temperature for 5 minutes. Then, stir at 450 r / min and add 0.44 mmol of 4,5-dimethoxy-2-(trimethylsilyl)phenyltrifluoromethanesulfonate as a precursor of benzyne dropwise. Stir the reaction at room temperature for 2 hours. After the reaction is complete, remove the solvent under reduced pressure and separate bis(3,4-dimethoxyphenyl) sulfide and p-methoxybenzonitrile.

[0122] The bis(3,4-dimethoxyphenyl) sulfide was a white solid with a yield of 43.7 mg, representing a yield of 71%. The prepared bis(3,4-dimethoxyphenyl) sulfide was characterized, and its structural formula was determined to be: The characterization results are as follows: 1 H NMR (400MHz, Chloroform-d) δ6.93(d,J=2.4Hz,1H),6.91(d,J=2.0Hz,1H),6.89(d,J=2.0Hz,2H),6.82(s,1H),6.80(s,1H),3.87(s,6H),3.82(s,6H). 13 C NMR (100MHz, Chloroform-d) δ149.3,148.5,127.4,123.9,114.3,111.7,77.0,76.7,56.0,56.0.

[0123] The above characterization results demonstrate the successful synthesis of bis(3,4-dimethoxyphenyl) sulfide.

[0124] The p-methoxybenzonitrile prepared in this embodiment is as shown in Example 1, which indicates that p-methoxybenzonitrile was successfully synthesized.

[0125] In summary, the method described in this embodiment can simultaneously synthesize bis(3,4-dimethoxyphenyl) sulfide and the nitrile compound p-methoxybenzonitrile.

[0126] Example 17:

[0127] Accurately weigh 0.2 mmol of 4-methoxybenzonitrile and 0.44 mmol of TMAF and place them in a 50 mL reaction tube with a polytetrafluoroethylene cap. Vacuum the tube three times and replace the nitrogen gas. Under nitrogen protection, add 2.0 mL of acetonitrile and stir at room temperature for 5 minutes. Then, stir at 450 r / min and add 0.44 mmol of the benzyne precursor 6-(trimethylsilyl)-2,3-dihydro-1H-inden-5-yl trifluoromethanesulfonate dropwise. Stir the reaction at room temperature for 2 hours. After the reaction is complete, remove the solvent under reduced pressure and separate bis(2,3-dihydro-1H-inden-5-yl) sulfide and p-methoxybenzonitrile.

[0128] The bis(2,3-dihydro-1H-inden-5-yl) sulfide was a colorless liquid with a yield of 52.1 mg and a yield of 98%. The prepared bis(2,3-dihydro-1H-inden-5-yl) sulfide was characterized, and its structural formula was as follows: The characterization results are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.21 (s, 2H), 7.13 (s, 4H), 2.86 (q, J = 7.1Hz, 8H), 2.10-2.02 (m, 4H). 13 C NMR (100MHz, Chloroform-d) δ145.4,143.3,133.5,129.1,127.1,124.9,32.7,25.4.

[0129] The above characterization results demonstrate the successful synthesis of bis(2,3-dihydro-1H-inden-5-yl) sulfide.

[0130] The p-methoxybenzonitrile prepared in this embodiment is as shown in Example 1, which indicates that p-methoxybenzonitrile was successfully synthesized.

[0131] In summary, the method described in this embodiment can simultaneously synthesize bis(2,3-dihydro-1H-inden-5-yl) sulfide and the nitrile compound p-methoxybenzonitrile.

[0132] Example 18:

[0133] Accurately weigh 0.2 mmol of 4-methoxybenzonitrile and 0.44 mmol of TMAF and place them in a 50 mL reaction tube with a polytetrafluoroethylene cap. Vacuum the tube three times and replace the nitrogen gas. Under nitrogen protection, add 2.0 mL of acetonitrile and stir at room temperature for 5 minutes. Then, stir at 450 r / min and add 0.44 mmol of 6-(trimethylsilyl)benzo[d][1,3]dioxacyclopenten-5-yl trifluoromethanesulfonate dropwise. Stir the reaction at room temperature for 2 hours. After the reaction is complete, remove the solvent under reduced pressure and separate bis(benzo[d][1,3]dioxacyclopenten-5-yl) sulfide and p-methoxybenzonitrile.

[0134] The bis(benzo[d][1,3]dioxacyclopenten-5-yl) sulfide was a colorless liquid with a yield of 52.1 mg and a yield of 98%. The prepared bis(benzo[d][1,3]dioxacyclopenten-5-yl) sulfide was characterized, and its structural formula was determined to be: The characterization results are as follows: 1 HNMR (400MHz, Chloroform-d) δ6.89(d,J=1.8Hz,1H),6.87(d,J=1.8Hz,1H),6.80(d,J=1.8Hz,2H),6.75(s,1H),6.73(s,1H),5.95(s,4H). 13 C NMR (100MHz, Chloroform-d) δ148.2,147.3,128.7,125.2,111.9,108.8,101.3.

[0135] The characterization results above indicate that bis(benzo[d][1,3]dioxane-5-yl) sulfide was successfully synthesized.

[0136] The p-methoxybenzonitrile prepared in this embodiment is as shown in Example 1, which indicates that p-methoxybenzonitrile was successfully synthesized.

[0137] In summary, the method described in this embodiment can simultaneously synthesize bis(benzo[d][1,3]dioxane-5-yl) sulfide and the nitrile compound p-methoxybenzonitrile.

[0138] Example 19:

[0139] Accurately weigh 0.2 mmol of 4-methoxybenzonitrile and 0.44 mmol of TMAF and place them in a 50 mL reaction tube with a polytetrafluoroethylene cap. Vacuum the tube three times and replace the nitrogen gas. Under nitrogen protection, add 2.0 mL of acetonitrile and stir at room temperature for 5 minutes. Then, stir at 450 r / min and add 0.44 mmol of 3-(trimethylsilyl)naphthyl-2-yltrifluoromethanesulfonate, a precursor of benzyne, dropwise. Stir the reaction at room temperature for 2 hours. After the reaction is complete, remove the solvent under reduced pressure and separate di(naphthyl-2-yl) sulfide and p-methoxybenzonitrile.

[0140] The di(naphthyl-2-yl) sulfide was a white solid with a yield of 37.7 mg, representing a yield of 66%. The prepared di(naphthyl-2-yl) sulfide was characterized, and its structural formula was determined to be: The characterization results are as follows: 1 HNMR (400MHz, Chloroform-d) δ7.87 (d, J = 1.4Hz, 2H), 7.82-7.71 (m, 6H), 7.48-7.41 (m, 6H). 13 C NMR (100MHz, Chloroform-d) δ133.8,133.1,132.3,129.8,128.9,127.7,127.4,126.6,126.2.

[0141] The above characterization results indicate that di(naphthyl-2-yl)thioether was successfully synthesized.

[0142] The p-methoxybenzonitrile prepared in this embodiment is as shown in Example 1, which indicates that p-methoxybenzonitrile was successfully synthesized.

[0143] In summary, the method described in this embodiment can simultaneously synthesize di(naphthyl-2-yl) sulfides and the nitrile compound p-methoxybenzonitrile.

[0144] Example 20:

[0145] Accurately weigh 0.2 mmol of 4-methoxybenzonitrile and 0.44 mmol of TMAF and place them in a 50 mL reaction tube with a polytetrafluoroethylene cap. Vacuum the tube three times and replace the nitrogen gas. Under nitrogen protection, add 2.0 mL of acetonitrile and stir at room temperature for 5 minutes. Then, stir at 450 r / min and add 0.44 mmol of 3-methoxy-2-(trimethylsilyl)phenyltrifluoromethanesulfonate, a precursor of benzyne, dropwise. Stir the reaction at room temperature for 2 hours. After the reaction is complete, remove the solvent under reduced pressure and separate bis(3-methoxyphenyl) sulfide and p-methoxybenzonitrile.

[0146] The bis(3-methoxyphenyl) sulfide was a colorless liquid with a yield of 42.3 mg and a yield of 86%. The prepared bis(3-methoxyphenyl) sulfide was characterized, and its structural formula was determined to be: The characterization results are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.21 (t, J=8.0Hz, 2H), 6.95-6.92 (m, 2H), 6.90-6.88 (m, 2H), 6.78 (ddd, J=8.3, 2.5, 0.8Hz, 2H), 3.75 (s, 6H). 13 CNMR(100MHz,Chloroform-d)δ160.0,136.7,129.9,123.3,116.2,113.0,55.3.

[0147] The above characterization results demonstrate the successful synthesis of bis(3-methoxyphenyl) sulfide.

[0148] The p-methoxybenzonitrile prepared in this embodiment is as shown in Example 1, which indicates that p-methoxybenzonitrile was successfully synthesized.

[0149] In summary, the method described in this embodiment can simultaneously synthesize bis(3-methoxyphenyl) sulfides and the nitrile compound p-methoxybenzonitrile.

[0150] Example 21:

[0151] Accurately weigh 0.2 mmol of 4-methoxybenzonitrile and 0.44 mmol of TMAF and place them in a 50 mL reaction tube with a polytetrafluoroethylene cap. Vacuum the tube three times and replace the nitrogen gas. Under nitrogen protection, add 2.0 mL of acetonitrile and stir at room temperature for 5 minutes. Then, stir at 450 r / min and add 0.44 mmol of 3-fluoro-2-(trimethylsilyl)phenyltrifluoromethanesulfonate, a precursor of benzyne, dropwise. Stir the reaction at room temperature for 2 hours. After the reaction is complete, remove the solvent under reduced pressure and separate bis(3-methoxyphenyl) sulfide and p-methoxybenzonitrile.

[0152] The bis(3-fluorophenyl) sulfide was a colorless liquid with a yield of 26.1 mg, representing a yield of 59%. The prepared bis(3-fluorophenyl) sulfide was characterized, and its structural formula was determined to be: The characterization results are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.32-7.21(m,3H),7.17-7.00(m,03H),7.00-6.89(m,3H). 13C NMR(100MHz,Chloroform-d)δ164.3,164.2,161.8,161.7,138.8,138.7,137.2,137.1,130.6,130.5,1 30.5,126.7,126.7,122.7,122.6,118.0,117.8,114.6,114.5,114.4,114.3,114.1,113.9,77.3,77.0.

[0153] The above characterization results demonstrate the successful synthesis of bis(3-fluorophenyl) sulfide.

[0154] The p-methoxybenzonitrile prepared in this embodiment is as shown in Example 1, which indicates that p-methoxybenzonitrile was successfully synthesized.

[0155] In summary, the method described in this embodiment can simultaneously synthesize bis(3-fluorophenyl) sulfides and the nitrile compound p-methoxybenzonitrile.

[0156] In summary, this invention is the first to propose the simultaneous preparation of thioether compounds and nitrile compounds using benzylene. The provided preparation method is simple and rapid, requires no transition metal catalysis, has a broad substrate range, uses inexpensive and readily available fluorine sources, and does not cause environmental pollution. It has advantages such as simple process, mild reaction conditions, high yield (up to 98%), and good versatility. It has extremely high industrial application value.

[0157] The embodiments described above are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments. Any obvious improvements, substitutions or modifications that can be made by those skilled in the art without departing from the essence of the present invention shall fall within the protection scope of the present invention.

Claims

1. A method for simultaneously synthesizing thioether compounds and nitrile compounds, characterized in that, include: Thioamide compounds and fluorides were mixed with a solvent under nitrogen protection, and then a benzyne precursor was added dropwise under stirring. After thorough mixing, a mixture was obtained. This mixture was then subjected to nucleophilic protonation desulfurization and dehydrogenation reactions, simultaneously generating thioether compounds and nitrile compounds. The thioamide compounds are: R in the thioamide compound 2 Including methoxy, 4-phenyl, 3,5-dimethoxy, 3,4,5-trimethoxy, 4-nitro, 3-nitro, 2-nitro, 2,5-dichloro, 1-naphthyl, 2-naphthyl, 4-(1H-imidazol-1-yl), 1-methyl-1H-indole, 2-(1H-indole-3-yl), 1-naphthylethyl; the benzoyne precursor is: R in the benzylene precursor 1 Including hydrogen, 4,5-dimethoxy, 4,5-dimethyl, 3-methoxy, or 3-fluoro; the structural formula of the thioether compound is: 、 、 or The structural formula of the nitrile compound is: The fluoride is tetramethylammonium fluoride.

2. The method for simultaneously synthesizing thioether compounds and nitrile compounds according to claim 1, characterized in that, The solvent includes acetonitrile.

3. The method for simultaneously synthesizing thioether compounds and nitrile compounds according to claim 1, characterized in that, The ratio of the thioamide compound, fluoride, and solvent used is 0.2 mmol : 0.4 ~ 0.9 mmol : 2.0 mL.

4. The method for simultaneously synthesizing thioether compounds and nitrile compounds according to claim 1, characterized in that, The molar ratio of the thioamide compound to the benzyne precursor is 1:2.0~3.

0.

5. The method for simultaneously synthesizing thioether compounds and nitrile compounds according to claim 1, characterized in that, The reaction conditions for the nucleophilic protonation desulfurization and dehydrogenation reaction are: 2 h at room temperature in a closed environment.

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