Alkyl trifluoromethyl sulfide compounds and methods for their synthesis
By using a three-component reaction catalyzed by an inexpensive organic photocatalyst, the regioselectivity problem in the synthesis of alkyl trifluoromethyl sulfide compounds has been solved, achieving the efficient and environmentally friendly synthesis of alkyl trifluoromethyl sulfide compounds with broad application potential.
Patent Information
- Application Number
- CN202510106987.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-23
- Publication Date
- 2026-02-17
- Estimated Expiration
- 2045-01-23
AI Technical Summary
Existing technologies struggle to synthesize alkyl trifluoromethylthio compounds efficiently and mildly, especially due to the challenges of regioselective trifluoromethylthiolation of alkyl groups with multiple C-H bonds, and the use of precious metal photosensitizers or poor atom economy in traditional methods.
Inexpensive organic photocatalysts such as 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile, 2,4,5-tris(9-carbazolyl)-6-(N-methylaniline)isophthalonitrile or eosin were used as catalysts. The reaction was carried out under nitrogen protection with blue light irradiation, and a three-component reaction was carried out with an unactivated olefin, a trifluoromethyl sulfide source and a free radical hydrogen source. The reaction was then post-treated to obtain an alkyl trifluoromethyl sulfide compound.
The synthesis of alkyl trifluoromethyl sulfide compounds with high regioselectivity has been achieved, avoiding the use of precious metals. It is characterized by simple operation, environmental friendliness and high efficiency. The products can be further oxidized to trifluoromethyl alkyl sulfone or trifluoromethyl alkyl sulfonyl imide.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the fields of medicine, organic chemical industry and fine chemical industry, and in particular to an alkyl trifluoromethyl sulfide compound and a synthesis method thereof. BACKGROUND
[0002] Trifluoromethylthio group (SCF3) has a high lipophilicity constant (Hansch constant SCF3: 1.44). When it is introduced into the skeleton of a drug molecule, it can greatly improve the ability of the drug molecule to penetrate the cell membrane, and can also enhance the absorption and utilization of the active ingredients of the drug by the organism. In addition, trifluoromethylthio group has strong electron-withdrawing ability (Hammett constant SCF3: σ p = 0.50, σ m = 0.40). Its presence can change the electron cloud density and polarity of the molecular skeleton, thereby improving the pharmacokinetic effect (Xu, X.-H.; Matsuzaki, K.; Shibata, N. Chem. Rev. 2015, 115, 731-764.).
[0003] However, there is currently no efficient and mild method for synthesizing drug molecules containing alkyl trifluoromethylthio groups. Traditional methods mainly use halogen-fluorine exchange or trifluoromethylation of mercaptans. Recently, visible light-promoted redox reactions can be used to directly trifluoromethylthioize C-H bonds to synthesize various alkyl trifluoromethyl sulfide compounds (Mukherjee, S.; Maji, B.; Tlahuext-AcaA.; Glorius, F. J. Am. Chem. Soc. 2016, 138, 50, 16200-16203; Xu, W.; Ma, J.; Yuan, X.-A.; Dai, J.; Xie J.; Zhu, C. Angew. Chem. Int. Ed. 2018, 57, 10357-10361; Zhang, H.; Wang, Q.; Wang, Y.; Yuan, Z.; Gao, F.; Britto, R. Asian J. Org. Chem. 2021, 10, 2570.). Although these synthesis strategies have made great progress, it is still difficult to control the regioselective trifluoromethylthioization of alkyl groups due to the multiple carbon-hydrogen bonds in the alkyl group. In the existing reports, organic workers use alkyl carboxylic acids, alkyl dihydropyridines, etc. as alkyl radical sources to synthesize alkyl trifluoromethyl sulfide compounds (Candish, L.; Pitzer, L.; A.; Glorius, F. Chem. Eur. J. 2016, 22, 4753-4756; Lipp, A.; Badir, S. O.; Gutierrez, O. Molander, G. A. Adv. Synth. Catal. 2021, 363, 3507-3520). However, some of these strategies use expensive iridium complexes as photosensitizers, which is not in line with the concept of green chemistry synthesis. Some reactions have poor atom economy and low atom utilization. SUMMARY
[0004] The purpose of the present application is to provide a green and simple method for synthesizing alkyl trifluoromethyl sulfide. Nitrogen is used as an inert atmosphere, and inorganic base, organic photocatalyst, non-activated olefin (compound 1), trifluoromethylthio source (compound 2) and free radical hydrogen source (compound 3) are added to the reaction solvent. Blue light is used for irradiation, and under the catalysis of the organic photocatalyst, the non-activated olefin, the trifluoromethylthio source and the free radical hydrogen source undergo a three-component reaction, and then after treatment, different substituted alkyl trifluoromethyl sulfide compounds are obtained.
[0005] The method of the present application uses inexpensive carbazolyl molecules or organic dye molecules as organic photosensitive catalysts, and has the advantages of mild reaction conditions, less environmental pollution, simple operation and good functional group tolerance.
[0006] The specific process of the reaction is as follows:
[0007]
[0008] wherein R is and the para-substituent R' of the aromatic ring is methyl, ethyl, isopropyl, methoxy, bromine, chlorine, and R can also be R 1 can be cyclohexyl, 4-methylphenyl, methyl acetate.
[0009] The above reaction conditions are as follows: under the protection of nitrogen, at room temperature, the synthesis is carried out by KESSILE blue light (45W) irradiation for 18 hours.
[0010] The reaction solvent is N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or acetonitrile (MeCN).
[0011] The free radical hydrogen source is R 1 -SH, R 1 can be cyclohexyl, 4-methylphenyl, methyl acetate;
[0012] The trifluoromethylthio source is N-trifluoromethylthio saccharin or N-trifluoromethylthio phthalimide.
[0013] The inorganic base is: dipotassium hydrogen phosphate (K2HPO4), potassium dihydrogen phosphate (KH2PO4), disodium hydrogen phosphate (Na2HPO4), sodium dihydrogen phosphate (NaH2PO4).
[0014] The photocatalyst used is: 2,4,5,6-tetrakis (9-carbazolyl) -m-benzene dicarbonitrile (4CzIPN), 2,4,5-tris (9-carbazolyl) -6- (N-methyl aniline) m-benzene dicarbonitrile (3CzMPAIPN), eosin Y (Y Eosin Y), and the amount of organic photocatalyst is 2 mmol% of the number of moles of non-activated olefin.
[0015] The molar ratio of non-activated olefin, trifluoromethylthio source and free radical hydrogen source is 1:2:1.
[0016] The general structure of the obtained alkyl trifluoromethyl sulfide compound is: The R group can be And the para-substituted group R' of the aromatic ring is methyl, ethyl, isopropyl, methoxy, bromine, chlorine, and the R group can be
[0017] The three-component reaction post-processing of the present application uses a sodium hypochlorite solution with a content of 7.5%, which removes the unreacted mercaptan; then only simple thin layer chromatography is needed for separation and purification, with petroleum ether: ethyl acetate = 70:1-50:1 as the developing agent, the product is separated by thin layer chromatography, and the solvent is removed by vacuum concentration to obtain pure alkyl trifluoromethyl sulfide compound.
[0018] Beneficial effects:
[0019] The present application avoids the use of noble metal photosensitive catalyst, uses inexpensive 4CzIPN, 3CzMPAIPN, eosin Y as photocatalyst, and the catalyst is simple to prepare and has high catalytic efficiency; uses non-activated olefin which is widely available in the industry as a substrate, and under mild photo-oxidation and reduction conditions, it can realize the high regioselectivity of the anti-Markovnikov hydrogen trifluoromethylthio reaction of non-activated olefin. In addition, the obtained alkyl trifluoromethyl sulfide compound can be further oxidized to obtain trifluoromethyl alkyl sulfone or trifluoromethyl alkyl sulfoximine, which can be used as an important synthetic intermediate. DETAILED DESCRIPTION
[0020] The reaction raw material N-trifluoromethylthioglycine or N-trifluoromethylthiophthalimide of the present application is synthesized according to the literature (Xu, C.; Ma, B.; Shen, Q. Angew. Chem. Int. Ed. 2014, 53, 9316-9320; Xing, S.; Zhu, Y.-Y.; Liu, W.; et al. Org. Lett. 2022, 24, 3378-3383.); another raw material olefin is a commercial product or obtained by condensation of the corresponding carboxylic acid with an alkenyl alcohol; the free radical hydrogen source is a commercial product, including cyclohexyl mercaptan, p-methyl thiophenol, 2-mercapto methyl acetate; the photocatalyst 4CzIPN is synthesized according to the literature (Huang, H.; Yu, C.; Zhang, Y. et al. J. Am. Chem. Soc. 2017, 139, 9799-9802); the reaction solvent is a commercial product.
[0021] The present application will be described in detail below with examples, and each reaction is shown in the following formula:
[0022]
[0023] Example 1
[0024] p-methyl benzoic acid-3-butenyl ester (1a, 0.1 mmol), N-trifluoromethylthioglycine (2a, 0.2 mmol), cyclohexyl mercaptan (3a, 0.1 mmol), NaH2PO4(0.1 mmol), MeCN (1 mL), 4CzIPN (2 mmol%) were added to a Schlenk reaction tube, and gas replacement was carried out to make the reaction under nitrogen protection. The reaction tube was placed under the condition of blue light irradiation, and the reaction time was 18 h at room temperature. After the reaction was completed, 2 mL of acetonitrile was added, and then 0.5 mL of 7.5% sodium hypochlorite solution was added, and stirred at room temperature for 30 minutes. Then separate the liquid, collect the organic phase, and then concentrate under reduced pressure to obtain the crude product, and then separate by thin layer chromatography to obtain the target product 4a, with a yield of 90%. 1 H NMR (400 MHz, CDCl3) δ 8.02-7.87 (m, 2H), 7.30-7.24 (m, 2H), 4.39-4.31 (m, 2H), 2.99 (t, J = 6.8 Hz, 2H), 2.44 (s, 3H), 1.97-1.87 (m, 4H).
[0025] Example 2
[0026] p-Tolylbut-3-enyl carbonate (1a, 0.1 mmol), N-trifluoromethylthioglycine (2a, 0.2 mmol), cyclohexylthiol (3a, 0.1 mmol), NaH2PO4(0.1 mmol), MeCN (1 mL), 3CzMPAIPN (2 mmol%) were added to a Schlenk tube, which was subjected to a gas exchange so that the reaction was carried out under nitrogen protection. The reaction tube was placed under blue light irradiation, at room temperature, for a reaction time of 18 h. After the reaction was completed, 2 mL of acetonitrile were added, followed by 0.5 mL of a 7.5% sodium hypochlorite solution, which was stirred at room temperature for 30 minutes. Then the phases were separated and the organic phase was collected, which was then concentrated under reduced pressure to obtain the crude product, which was separated by thin layer chromatography to obtain the target product 4a with a yield of 53%.
[0027] Example 3
[0028] p-Tolylbut-3-enyl carbonate (1a, 0.1 mmol), N-trifluoromethylthioglycine (2a, 0.2 mmol), cyclohexylthiol (3a, 0.1 mmol), NaH2PO4(0.1 mmol), MeCN (1 mL), Eosin Y (2 mmol%) were added to a Schlenk tube, which was subjected to a gas exchange so that the reaction was carried out under nitrogen protection. The reaction tube was placed under blue light irradiation, at room temperature, for a reaction time of 18 h. After the reaction was completed, 2 mL of acetonitrile were added, followed by 0.5 mL of a 7.5% sodium hypochlorite solution, which was stirred at room temperature for 30 minutes. Then the phases were separated and the organic phase was collected, which was then concentrated under reduced pressure to obtain the crude product, which was separated by thin layer chromatography to obtain the target product 4a with a yield of 17%.
[0029] Example 4
[0030] p-Tolylbut-3-enyl carbonate (1a, 0.1 mmol), N-trifluoromethylthiophthalimide (2b, 0.2 mmol), cyclohexylthiol (3a, 0.1 mmol), KH2PO4(0.1 mmol), MeCN (1 mL), 4CzIPN (2 mmol%) were added to a Schlenk tube, which was subjected to a gas exchange so that the reaction was carried out under nitrogen protection. The reaction tube was placed under blue light irradiation, at room temperature, for a reaction time of 18 h. After the reaction was completed, 2 mL of acetonitrile were added, followed by 0.5 mL of a 7.5% sodium hypochlorite solution, which was stirred at room temperature for 30 minutes. Then the phases were separated and the organic phase was collected, which was then concentrated under reduced pressure to obtain the crude product, which was separated by thin layer chromatography to obtain the target product 4a with a yield of 71%.
[0031] Example 5
[0032] p-Toluic acid-3-butenyl ester (1a, 0.1 mmol), N-trifluoromethylthio saccharin (2a, 0.2 mmol), cyclohexyl mercaptan (3a, 0.1 mmol), NaH2PO4(0.1 mmol), DMF (1 mL), 4CzIPN (2 mmol%) were added into a Schlenk tube, which was purged with argon to ensure the reaction under nitrogen atmosphere. The reaction tube was placed under blue light irradiation, and the reaction time was 18 h at room temperature. After the reaction was completed, 2 mL of acetonitrile was added, followed by 0.5 mL of 7.5% sodium hypochlorite solution, and stirred at room temperature for 30 min. Then the liquid was separated, and the organic phase was collected, and then concentrated under reduced pressure to obtain the crude product, which was separated by thin layer chromatography to obtain the target product 4a with a yield of 28%.
[0033] Example 6
[0034] p-Toluic acid-3-butenyl ester (1a, 0.1 mmol), N-trifluoromethylthio saccharin (2a, 0.2 mmol), cyclohexyl mercaptan (3a, 0.1 mmol), NaH2PO4(0.1 mmol), DMSO (1 mL), 4CzIPN (2 mmol%) were added into a Schlenk tube, which was purged with argon to ensure the reaction under nitrogen atmosphere. The reaction tube was placed under blue light irradiation, and the reaction time was 18 h at room temperature. After the reaction was completed, 2 mL of acetonitrile was added, followed by 0.5 mL of 7.5% sodium hypochlorite solution, and stirred at room temperature for 30 min. Then the liquid was separated, and the organic phase was collected, and then concentrated under reduced pressure to obtain the crude product, which was separated by thin layer chromatography to obtain the target product 4a with a yield of 33%.
[0035] Example 7
[0036] p-Toluic acid-3-butenyl ester (1a, 0.1 mmol), N-trifluoromethylthio saccharin (2a, 0.2 mmol), p-tolyl mercaptan (3b, 0.1 mmol), NaH2PO4(0.1 mmol), MeCN (1 mL), 4CzIPN (2 mmol%) were added into a Schlenk tube, which was purged with argon to ensure the reaction under nitrogen atmosphere. The reaction tube was placed under blue light irradiation, and the reaction time was 18 h at room temperature. After the reaction was completed, 2 mL of acetonitrile was added, followed by 0.5 mL of 7.5% sodium hypochlorite solution, and stirred at room temperature for 30 min. Then the liquid was separated, and the organic phase was collected, and then concentrated under reduced pressure to obtain the crude product, which was separated by thin layer chromatography to obtain the target product 4a with a yield of 7%.
[0037] Example 8
[0038] p-Toluic acid-3-butenyl ester (1a, 0.1 mmol), N-trifluoromethylthioglycine (2a, 0.2 mmol), 2-mercaptoacetic acid methyl ester (3c, 0.1 mmol), NaH2PO4(0.1 mmol), MeCN (1 mL), 4CzIPN (2 mmol%) were added to a Schlenk reaction tube, which was subjected to a gas exchange so that the reaction was carried out under nitrogen protection. The reaction tube was placed under blue light irradiation, and the reaction time was 18 h at room temperature. After the reaction was completed, 2 mL of acetonitrile was added, and then 0.5 mL of 7.5% sodium hypochlorite solution was added, and stirred at room temperature for 30 min. Then the liquid was separated, and the organic phase was collected, and then concentrated under reduced pressure to obtain the crude product, and then separated by thin layer chromatography to obtain the target product 4a, with a yield of 18%.
[0039] Example 9
[0040] p-Toluic acid-3-butenyl ester (1a, 0.1 mmol), N-trifluoromethylthioglycine (2a, 0.2 mmol), 2-mercaptoacetic acid methyl ester (3c, 0.1 mmol), NaH2PO4(0.1 mmol), MeCN (1 mL), 4CzIPN (2 mmol%) were added to a Schlenk reaction tube, which was subjected to a gas exchange so that the reaction was carried out under nitrogen protection. The reaction tube was placed under blue light irradiation, and the reaction time was 18 h at room temperature. After the reaction was completed, 2 mL of acetonitrile was added, and then 0.5 mL of 7.5% sodium hypochlorite solution was added, and stirred at room temperature for 30 min. Then the liquid was separated, and the organic phase was collected, and then concentrated under reduced pressure to obtain the crude product, and then separated by thin layer chromatography to obtain the target product 4a, with a yield of 18%.
[0041] Example 10
[0042] p-Toluic acid-3-butenyl ester (1a, 0.1 mmol), N-trifluoromethylthioglycine (2a, 0.2 mmol), 2-mercaptoacetic acid methyl ester (3c, 0.1 mmol), NaH2PO4(0.1 mmol), MeCN (1 mL), 4CzIPN (2 mmol%) were added to a Schlenk reaction tube, which was subjected to a gas exchange so that the reaction was carried out under nitrogen protection. The reaction tube was placed under blue light irradiation, and the reaction time was 18 h at room temperature. After the reaction was completed, 2 mL of acetonitrile was added, and then 0.5 mL of 7.5% sodium hypochlorite solution was added, and stirred at room temperature for 30 min. Then the liquid was separated, and the organic phase was collected, and then concentrated under reduced pressure to obtain the crude product, and then separated by thin layer chromatography to obtain the target product 4a, with a yield of 18%.
[0043] Example 11
[0044] p-Toluic acid-3-butenyl ester (1a, 0.1 mmol), N-trifluoromethylthioglycine (2a, 0.2 mmol), cyclohexylthiol (3a, 0.1 mmol), KH2PO4(0.1 mmol), MeCN (1 mL), 4CzIPN (2 mmol%) were added into a Schlenk tube, which was subjected to gas exchange so that the reaction was carried out under nitrogen protection. The reaction tube was placed under blue light irradiation, and the reaction time was 18 h at room temperature. After the reaction was completed, 2 mL of acetonitrile was added, and then 0.5 mL of 7.5% sodium hypochlorite solution was added, and stirred at room temperature for 30 min. Then the organic phase was collected, and then concentrated under reduced pressure to obtain the crude product, and then separated by thin layer chromatography to obtain the target product 4a with a yield of 79%.
[0045] Example 12
[0046] p-Toluic acid-3-butenyl ester (1a, 0.1 mmol), N-trifluoromethylthioglycine (2a, 0.2 mmol), cyclohexylthiol (3a, 0.1 mmol), KH2PO4(0.1 mmol), MeCN (1 mL), 4CzIPN (2 mmol%) were added into a Schlenk tube, which was subjected to gas exchange so that the reaction was carried out under nitrogen protection. The reaction tube was placed under blue light irradiation, and the reaction time was 18 h at room temperature. After the reaction was completed, 2 mL of acetonitrile was added, and then 0.5 mL of 7.5% sodium hypochlorite solution was added, and stirred at room temperature for 30 min. Then the organic phase was collected, and then concentrated under reduced pressure to obtain the crude product, and then separated by thin layer chromatography to obtain the target product 4a with a yield of 79%. 1 H NMR (400 MHz, CDC13) δ 7.95 (d, J = 8.2 Hz, 2H), 7.29-7.26 (m, 2H), 4.41-4.31 (m, 2H), 2.96 (t, J = 6.7 Hz, 2H), 2.71 (q, J = 7.6 Hz, 2H), 1.94-1.85 (m, 4H), 1.26 (t, J = 7.6 Hz, 3H).
[0047] Example 13
[0048] p-Isopropylbenzoic acid-3-butenyl ester (1c, 0.1 mmol), N-trifluoromethylthio saccharin (2a, 0.2 mmol), cyclohexylthiol (3a, 0.1 mmol), NaH2PO4(0.1 mmol), MeCN (1 mL), 4CzIPN (2 mmol%) were added into a Schlenk tube, which was subjected to gas replacement so that the reaction was carried out under the protection of nitrogen. The reaction tube was placed under the condition of blue light irradiation, and the reaction time was 18 h at room temperature. After the reaction was completed, 2 mL of acetonitrile was added, and then 0.5 mL of 7.5% sodium hypochlorite solution was added, which was stirred at room temperature for 30 min. Then the liquid was separated, and the organic phase was collected, which was concentrated under reduced pressure to obtain the crude product, and then the target product 4c was obtained by thin layer chromatography separation with a yield of 76%. 1 H NMR (400 MHz, CDCl3) δ 8.00-7.92 (m, 2H), 7.34-7.28 (m, 2H), 4.37-4.32 (m, 2H), 3.02-2.92 (m, 3H), 1.92-1.83 (m, 4H), 1.27 (d, J = 6.9 Hz, 6H).
[0049] Example 14
[0050] p-Isopropylbenzoic acid-3-butenyl ester (1c, 0.1 mmol), N-trifluoromethylthio saccharin (2a, 0.2 mmol), cyclohexylthiol (3a, 0.1 mmol), NaH2PO4(0.1 mmol), MeCN (1 mL), 4CzIPN (2 mmol%) were added into a Schlenk tube, which was subjected to gas replacement so that the reaction was carried out under the protection of nitrogen. The reaction tube was placed under the condition of blue light irradiation, and the reaction time was 18 h at room temperature. After the reaction was completed, 2 mL of acetonitrile was added, and then 0.5 mL of 7.5% sodium hypochlorite solution was added, which was stirred at room temperature for 30 min. Then the liquid was separated, and the organic phase was collected, which was concentrated under reduced pressure to obtain the crude product, and then the target product 4c was obtained by thin layer chromatography separation with a yield of 76%. 1 H NMR (400 MHz, CDCl3) δ 8.03-7.96 (m, 2H), 6.95-6.89 (m, 2H), 4.36-4.27 (m, 2H), 3.86 (s, 3H), 2.96 (t, J = 6.6 Hz, 2H), 1.94-1.82 (m, 4H).
[0051] Example 15
[0052] p-Bromobenzoic acid-3-butenyl ester (1e, 0.1 mmol), N-trifluoromethylthio saccharin (2a, 0.2 mmol), cyclohexylthiol (3a, 0.1 mmol), NaH2PO4(0.1 mmol), MeCN (1 mL), 4CzIPN (2 mmol%) were added into a Schlenk tube, which was subjected to gas exchange so that the reaction was carried out under the protection of nitrogen. The reaction tube was placed under the condition of blue light irradiation, and the reaction time was 18 h at room temperature. After the reaction was completed, 2 mL of acetonitrile was added, and then 0.5 mL of 7.5% sodium hypochlorite solution was added, which was stirred at room temperature for 30 min. Then the organic phase was collected, and then concentrated under reduced pressure to obtain the crude product, which was separated by thin layer chromatography to obtain the target product 4e with a yield of 75%. 1 H NMR (400 MHz, CDCl3) δ 7.95-7.86 (m, 2H), 7.62-7.55 (m, 2H), 4.35 (t, J = 5.9 Hz, 2H), 2.96 (t, J = 6.7 Hz, 2H), 1.92-1.86 (m, 4H).
[0053] Example 16
[0054] p-Chlorobenzoic acid-3-butenyl ester (1f, 0.1 mmol), N-trifluoromethylthio saccharin (2a, 0.2 mmol), cyclohexylthiol (3a, 0.1 mmol), NaH2PO4(0.1 mmol), MeCN (1 mL), 4CzIPN (2 mmol%) were added into a Schlenk tube, which was subjected to gas exchange so that the reaction was carried out under the protection of nitrogen. The reaction tube was placed under the condition of blue light irradiation, and the reaction time was 18 h at room temperature. After the reaction was completed, 2 mL of acetonitrile was added, and then 0.5 mL of 7.5% sodium hypochlorite solution was added, which was stirred at room temperature for 30 min. Then the organic phase was collected, and then concentrated under reduced pressure to obtain the crude product, which was separated by thin layer chromatography to obtain the target product 4f with a yield of 78%. 1 H NMR (400 MHz, CDCl3) δ 8.07-7.90 (m, 2H), 7.50-7.37 (m, 2H), 4.35 (t, J = 6.0 Hz, 2H), 2.96 (t, J = 6.7 Hz, 2H), 1.99-1.82 (m, 4H).
[0055] Example 17
[0056] 1-naphthoic acid-3-butenyl ester (1 g, 0.1 mmol), N-trifluoromethylthioglycamate (2a, 0.2 mmol), cyclohexyl mercaptan (3a, 0.1 mmol), NaH2PO4(0.1 mmol), MeCN (1 mL), 4CzIPN (2 mmol%) were added into a Schlenk tube, which was purged with argon to ensure the reaction under nitrogen atmosphere. The reaction tube was placed under blue light irradiation, and the reaction time was 18 h at room temperature. After the reaction was completed, 2 mL of acetonitrile was added, and then 0.5 mL of 7.5% sodium hypochlorite solution was added, and stirred at room temperature for 30 min. Then the liquid was separated, and the organic phase was collected, and then concentrated under reduced pressure to obtain the crude product, which was separated by thin layer chromatography to obtain the target product 4g, with a yield of 76%. 1 H NMR (400 MHz, CDC13) δ 8.90 (d, J = 8.7 Hz, 1H), 8.20-8.15 (m, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 7.4 Hz, 1H), 7.65-7.59 (m, 1H), 7.57-7.48 (m, 2H), 4.44 (t, J = 5.9 Hz, 2H), 2.98 (t, J = 6.8 Hz, 2H), 2.02-1.85 (m, 4H).
[0057] Example 18
[0058] 2-(alkenylbutoxy)naphthalene (1h, 0.1 mmol), N-trifluoromethylthioglycamate (2a, 0.2 mmol), cyclohexyl mercaptan (3a, 0.1 mmol), NaH2PO4(0.1 mmol), MeCN (1 mL), 4CzIPN (2 mmol%) were added into a Schlenk tube, which was purged with argon to ensure the reaction under nitrogen atmosphere. The reaction tube was placed under blue light irradiation, and the reaction time was 18 h at room temperature. After the reaction was completed, 2 mL of acetonitrile was added, and then 0.5 mL of 7.5% sodium hypochlorite solution was added, and stirred at room temperature for 30 min. Then the liquid was separated, and the organic phase was collected, and then concentrated under reduced pressure to obtain the crude product, which was separated by thin layer chromatography to obtain the target product 4h, with a yield of 67%. 1 H NMR (400 MHz, CDC13) δ 8.22 (d, J = 8.6 Hz, 1H), 7.86-7.71 (m, 3H), 7.57 (t, J = 7.7 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.38-7.26 (m, 1H), 4.26-4.16 (m, 2H), 3.09-3.00 (m, 2H), 2.06-1.98 (m, 4H).
[0059] Example 19
[0060] N-(3-butenyl)benzamide (1j, 0.1 mmol), N-trifluoromethylthioglycamate (2a, 0.2 mmol), cyclohexanethiol (3a, 0.1 mmol), NaH2PO4(0.1 mmol), MeCN (1 mL), 4CzIPN (2 mmol%) were added into a Schlenk tube, which was purged with argon to ensure the reaction under nitrogen atmosphere. The reaction tube was placed under blue light irradiation, and the reaction time was 18 h at room temperature. After the reaction was completed, 2 mL of acetonitrile was added, and then 0.5 mL of 7.5% sodium hypochlorite solution was added, and stirred at room temperature for 30 min. Then the liquid was separated, and the organic phase was collected, and then concentrated under reduced pressure to obtain the crude product, which was separated by thin layer chromatography to obtain the target product 4j with a yield of 90%. 1 H NMR (400 MHz, CDC13) δ 8.12-8.10 (m, 2H), 7.51 (t, J = 7.7 Hz, 1H), 7.49-7.32 (m, 3H), 7.31-7.21 (m, 2H), 4.44 (t, J = 6.7 Hz, 2H), 2.85 (t, J = 6.9 Hz, 2H), 2.36-2.23 (m, 2H), 1.33-1.23 (m, 2H).
[0061] Example 20
[0062] N-(3-butenyl)benzamide (1j, 0.1 mmol), N-trifluoromethylthioglycamate (2a, 0.2 mmol), cyclohexanethiol (3a, 0.1 mmol), NaH2PO4(0.1 mmol), MeCN (1 mL), 4CzIPN (2 mmol%) were added into a Schlenk tube, which was purged with argon to ensure the reaction under nitrogen atmosphere. The reaction tube was placed under blue light irradiation, and the reaction time was 18 h at room temperature. After the reaction was completed, 2 mL of acetonitrile was added, and then 0.5 mL of 7.5% sodium hypochlorite solution was added, and stirred at room temperature for 30 min. Then the liquid was separated, and the organic phase was collected, and then concentrated under reduced pressure to obtain the crude product, which was separated by thin layer chromatography to obtain the target product 4j with a yield of 90%. 1 H NMR (400 MHz, CDC13) δ 8.12-8.10 (m, 2H), 7.51 (t, J = 7.7 Hz, 1H), 7.49-7.32 (m, 3H), 7.31-7.21 (m, 2H), 4.44 (t, J = 6.7 Hz, 2H), 2.85 (t, J = 6.9 Hz, 2H), 2.36-2.23 (m, 2H), 1.33-1.23 (m, 2H).
[0063] Example 21
[0064] Example 1 5-(but-3-en-1 -ylthio)-1 -methyl-1 H-tetrazole (1k, 0.1 mmol), N- trifluoromethylthio saccharin (2a, 0.2 mmol), cyclohexanethiol (3a, 0.1 mmol), NaH2PO4(0.1 mmol), MeCN (1 mL), 4CzIPN (2 mmol%) were added into a Schlenk tube, which was subjected to a gas exchange so that the reaction was carried out under nitrogen protection. The reaction tube was placed under blue light irradiation, and the reaction time was 18 h at room temperature. After the reaction was completed, 2 mL of acetonitrile was added, followed by 0.5 mL of 7.5% sodium hypochlorite solution, and stirred at room temperature for 30 min. Then the liquid was separated, and the organic phase was collected, and then concentrated under reduced pressure to obtain the crude product, which was separated by thin layer chromatography to obtain the target product 4k with a yield of 49%. 1 H NMR (400 MHz, CDC13) δ 3.91 (s, 3H), 3.36 (t, J = 7.1 Hz, 2H), 2.92 (t, J = 7.1 Hz, 2H), 2.00 - 1.91 (m, 2H), 1.90 - 1.82 (m, 2H).
[0065] Example 22
[0066] 5-(but-3-en-1 -ylthio)-1 -methyl-1 H-tetrazole (1k, 0.1 mmol), N- trifluoromethylthio saccharin (2a, 0.2 mmol), cyclohexanethiol (3a, 0.1 mmol), NaH2PO4(0.1 mmol), MeCN (1 mL), 4CzIPN (2 mmol%) were added into a Schlenk tube, which was subjected to a gas exchange so that the reaction was carried out under nitrogen protection. The reaction tube was placed under blue light irradiation, and the reaction time was 18 h at room temperature. After the reaction was completed, 2 mL of acetonitrile was added, followed by 0.5 mL of 7.5% sodium hypochlorite solution, and stirred at room temperature for 30 min. Then the liquid was separated, and the organic phase was collected, and then concentrated under reduced pressure to obtain the crude product, which was separated by thin layer chromatography to obtain the target product 4k with a yield of 49%. 1 H NMR (400 MHz, CDC13) δ 3.91 (s, 3H), 3.36 (t, J = 7.1 Hz, 2H), 2.92 (t, J = 7.1 Hz, 2H), 2.00 - 1.91 (m, 2H), 1.90 - 1.82 (m, 2H).
[0067] Example 23
[0068] Into a Schlenk tube was placed 4-methylbenzoic acid (4-(trifluoromethylthio)) butyl ester (4a, 0.1 mmol), m-chloroperbenzoic acid (0.5 mmol), DCM (1 mL). The reaction was carried out at room temperature for 1 h. After the reaction was completed, 2 mL of 20% aqueous sodium thiosulfate solution was added, stirred at room temperature for 0.5 h, then extracted with DCM, separated, and the organic phase was collected, then concentrated under reduced pressure to obtain the crude product, which was separated by thin layer chromatography to obtain the target product trifluoromethyl alkyl sulfone 5 with a yield of 82%. 1 H NMR (400 MHz, CDC13) δ 7.91 (d, J = 7.9 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H), 4.37 (t, J = 6.0 Hz, 2H), 3.33 (t, J = 7.8 Hz, 2H), 2.41 (s, 3H), 2.17-2.09 (m, 2H), 2.03-1.95 (m, 2H).
[0069] Example 24
[0070] Into a Schlenk tube was placed 4-methylbenzoic acid (4-(trifluoromethylthio)) butyl ester (4a, 0.1 mmol), ammonium carbamate (0.2 mmol), iodo phenyl diacetic acid (0.3 mmol), trifluoroethanol (1 mL). The reaction was carried out at room temperature for 6 h. After the reaction was completed, the obtained crude product was dissolved in a mixed solvent of 6 M hydrochloric acid and acetonitrile, and stirred at room temperature for 12 h. After the reaction was completed, saturated sodium bicarbonate solution was added to neutral, then extracted with DCM, separated, and the organic phase was collected, then concentrated under reduced pressure to obtain the crude product, which was separated by thin layer chromatography to obtain the target product trifluoromethyl alkyl sulfonamide 6 with a yield of 77%. 1 H NMR (400 MHz, CDC13) δ 7.48-7.44 (m, 3H), 7.30 (s, 1H), 7.30-7.28 (m, 2H), 7.27-7.23 (m, 2H), 7.19 (dd, J = 7.6, 1.9 Hz, 2H), 5.98 (s, 1H), 4.57 (s, 2H), 2.19 (s, 3H).
Claims
1. A method for synthesizing an alkyl trifluoromethyl sulfide compound, characterized by, The synthesis method steps are as follows: (1) under the protection of nitrogen, an inorganic base, an organic photocatalyst, a non-activated olefin, a trifluoromethylthio source and a free radical hydrogen source are added into a reaction solvent; (2) under the catalysis of the organic photocatalyst, the non-activated olefin, the trifluoromethylthio source and the free radical hydrogen source are subjected to a three-component reaction by adopting blue light irradiation, and then aftertreatment is performed to obtain an alkyl trifluoromethyl sulfide compound with different substitutions; The organic photocatalyst is 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile 4CzIPN, 2,4,5-tris(9-carbazolyl)-6-(N-methylanilino) isophthalonitrile 3CzMPAIPN or eosin Y Eosin Y. The non-activated alkenes have the structural formula ; The source of trifluoromethylthio group is: N - trifluoromethylthiosaccharin or N - trifluoromethylthiophthalimide; The structural formula of the free radical hydrogen source is: ; wherein R1 is cyclohexyl, 4-methylphenyl, methyl acetate group; The alkyl trifluoromethyl sulfide compound has a structural formula of: ; wherein R is , and the para substituent R' of the aromatic ring is methyl, ethyl, isopropyl, methoxy, bromo, chloro, or R is , , , , or .
2. The method for synthesizing the alkyl trifluoromethyl sulfide compound as described in claim 1, characterized in that, The reaction solvent is: N,N dimethylformamide, dimethylsulfoxide, acetonitrile.
3. The method for synthesizing the alkyl trifluoromethyl sulfide compound as described in claim 1, characterized in that, The inorganic base is dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate NaH2PO4, and the amount of the inorganic base is 1 equivalent.
4. The method for synthesizing the alkyl trifluoromethyl sulfide compound as described in claim 1, characterized in that, The amount of the organic photocatalyst is 2 mol% of the number of moles of the non-activated olefin.
5. The method for synthesizing the alkyl trifluoromethyl sulfide compound as described in claim 1, characterized in that, The molar ratio of the non-activated olefin, the trifluoromethylthio source and the free radical hydrogen source is 1:2:
1.
6. The method for synthesizing the alkyl trifluoromethyl sulfide compound according to claim 1, characterized in that, The three-component reaction conditions are as follows: the synthesis is performed at room temperature for 18 hours; and after the three-component reaction, a 7.5% sodium hypochlorite solution is used for aftertreatment to remove the unreacted mercaptan.