Method for preparing fluoromethyl thioester compounds from aromatic olefins in one step

Abstract

The present invention discloses a one-step method for preparing fluoromethyl thioester compounds from aromatic olefins. Under heating conditions, the aromatic olefin compounds are used as starting materials, fluoromethyl thiobenzenesulfonate is used as a fluoromethylthiolation reagent, and an oxidant, a catalyst, and an organic solvent are added for reaction to obtain the fluoromethyl thioester compounds. The method of the present invention uses inexpensive and readily available aromatic olefin compounds as starting materials, fluoromethyl thiobenzenesulfonate is used as a fluoromethylthiolation reagent that is stable at room temperature, a mild peroxide compound as an oxidant, a copper salt as a catalyst, and acetonitrile as a solvent. The corresponding fluoromethyl thioester compounds are obtained by heating the reaction in air for a certain period of time. This synthetic method features mild conditions, simple operation, environmental friendliness, a wide range of substrate applicability, and good functional group tolerance. Most importantly, it represents the first development of a new pathway for the direct synthesis of fluoromethyl thioesters from aromatic olefins.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and relates to a method for preparing fluoromethyl thioester compounds in one step by using aromatic olefins as raw materials. Background Art

[0002] In drug design, monofluoromethylthio (-SCFH2), difluoromethylthio (-SCF2H) and trifluoromethylthio (-SCF3) can not only serve as electronic isosteres to replace lipophilic groups such as amides, alcohols, thiols and hydroxamic acids, but also act as hydrogen bond donors to improve binding selectivity and regulate the biological activity of lead compounds. Due to their special properties, they have attracted widespread attention in recent years. Introducing fluorine atoms or fluorine-containing groups into molecules has also become a common means of designing new lead compounds.

[0003] In the past five years, chemists have made great progress in the synthesis of monofluoro, difluoro and trifluoromethyl thioesters. Methods for preparing one or more of the monofluoro, difluoro and trifluoromethyl thioesters from acyl chlorides, acids and aldehydes have been reported.

[0004] Olefins are a class of products produced in coal chemical, petrochemical, or bioresource conversion. They are abundant, inexpensive, and structurally diverse, making them important raw materials for the preparation of more complex organic compounds in both academia and industry. Currently, no methods for synthesizing mono-, di-, and trifluoromethyl thioesters from olefins have been reported. Therefore, the development of a method for synthesizing fluoromethyl thioesters from olefins is urgently needed. Summary of the Invention

[0005] The present invention aims to provide a method for preparing fluoromethyl thioester compounds from aromatic olefins in one step, and aims to provide a general method for synthesizing monofluoro, difluoro and trifluoromethyl thioester series compounds from olefins in one step with simple operation, mild conditions, wide substrate adaptability and good functional group tolerance.

[0006] The technical solution adopted by the present invention is a method for preparing fluoromethyl thioester compounds from aromatic olefins in one step. Under heating conditions, the aromatic olefin compounds are used as starting materials, fluoromethyl thiobenzenesulfonate is used as a fluoromethylthiolation reagent, an oxidant, a catalyst and an organic solvent are added to react, and the fluoromethyl thioester compounds are obtained.

[0007] The present invention is also characterized in that:

[0008] The specific preparation steps of fluoromethyl thioester compounds are as follows:

[0009] Step 1: Add aromatic olefin compound 1, fluoromethyl benzenesulfonate 2, oxidant A, oxidant B, and catalyst to a flask. Then, add a solvent to the flask under an air atmosphere, heat and continuously stir to react. During the reaction, monitor the reaction by thin layer chromatography until the starting material no longer decreases, then stop the reaction to obtain the reactant. The reaction formula is as follows:

[0010]

[0011] In formula (1), R 1 is selected from phenyl, monosubstituted phenyl, polysubstituted phenyl, 2-naphthyl; the substituent of monosubstituted phenyl is C1-C4 alkyl, acetoxy, fluorine, chlorine, bromine, iodine, ester group, cyano group, trifluoromethyl, methoxy group, R f Selected from CH2F, CF2H, CF3;

[0012] Step 2: Remove the solvent from the reactant by rotary evaporation under reduced pressure to obtain a reaction residue, which is then purified by a rapid silica gel column to obtain the corresponding fluoromethyl thioester compound 3.

[0013] Oxidant A is a 70% aqueous solution of tert-butyl hydroperoxide, and oxidant B is K2S2O8.

[0014] The catalyst is a divalent copper salt CuSO4, Cu(NO3)2 or a trivalent iron salt FeCl3, Fe2(OTf)3;

[0015] The catalyst is preferably Cu(NO3)2 or CuSO4.

[0016] The organic solvent is acetonitrile or 1,2-dichloroethane;

[0017] The organic solvent is preferably acetonitrile.

[0018] The molar ratio of benzenesulfonic acid fluoromethyl thioester 2 to aromatic olefin compound 1 is 1:1-2, preferably 1:1.5-1.7.

[0019] The molar ratio of benzenesulfonic acid fluoromethyl thioester 2 to the catalyst is 1:0.05-0.2, preferably 1:0.08-0.12.

[0020] The molar ratio of benzenesulfonic acid fluoromethyl thioester 2, oxidant A and oxidant B is 1:1-4:1-4.

[0021] The heating temperature is 65 to 100°C, preferably 82°C.

[0022] The reaction residue was purified by column chromatography.

[0023] The present invention can obtain a higher yield when 70% tert-butyl hydroperoxide aqueous solution (TBHP) and K2S2O8 are used as oxidants. Other oxidants such as H2O2, DTHP, Na2S2O8, and (NH4)2S2O8 have very low yields or even no reaction in the method of the present invention.

[0024] The beneficial effects of the present invention are as follows: compared with the method for preparing fluoromethyl thioester compounds in the prior art, the present invention has the following advantages: 1) the starting raw materials, aromatic olefin compounds, catalyst copper salts or iron salts, and peroxide compound oxidants used are all cheap and readily available reagents; 2) the three fluoromethyl thioesters of benzenesulfonate used are stable at room temperature, non-volatile, and easy to prepare; 3) the reaction atmosphere of the present invention is air, and no argon or oxygen atmosphere is required, which is easy to implement and saves costs; 4) the method of the present invention has mild conditions, simple operation, and is environmentally friendly as a whole; 4) most importantly, the present invention develops a new route for synthesizing fluoromethyl thioesters from aromatic olefins, which is a general route for synthesizing the three fluoromethyl thioester compounds and has good tolerance to common functional groups, especially halogens (F, Cl, Br, I), because they are commonly used connection sites in many coupling reactions, and the structure of the product obtained by the method of the present invention can be conveniently further modified. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is the compound 3aa prepared in Example 1 of the present invention 1 H NMR spectrum;

[0026] Figure 2 is the compound 3aa prepared in Example 1 of the present invention 13 C NMR spectrum;

[0027] Figure 3 is the compound 3aa prepared in Example 1 of the present invention 19 F NMR spectrum;

[0028] Figure 4 is the compound 3ba prepared in Example 2 of the present invention 13 C NMR spectrum;

[0029] Figure 5 is the compound 3ca prepared in Example 3 of the present invention 13 C NMR spectrum;

[0030] Figure 6 is the compound 3da prepared in Example 4 of the present invention 13 C NMR spectrum;

[0031] Figure 7 is the compound 3ea prepared in Example 5 of the present invention 13 C NMR spectrum;

[0032] Figure 8 is the compound 3fa prepared in Example 6 of the present invention 13 C NMR spectrum;

[0033] Figure 9 is the compound 3ga prepared in Example 7 of the present invention 13 C NMR spectrum;

[0034] Figure 10 is the compound 3ha prepared in Example 8 of the present invention 13 C NMR spectrum;

[0035] Figure 11 is the compound 3ia prepared in Example 9 of the present invention 13 C NMR spectrum;

[0036] Figure 12 is the compound 3ja prepared in Example 10 of the present invention 13 C NMR spectrum;

[0037] Figure 13 is the compound 3ka prepared in Example 11 of the present invention 13 C NMR spectrum;

[0038] Figure 14 is the compound 31a prepared in Example 12 of the present invention 13 C NMR spectrum;

[0039] Figure 15 is the compound 3mb prepared in Example 13 of the present invention 13 C NMR spectrum;

[0040] Figure 16 is the compound 3nc prepared in Example 14 of the present invention 13 C NMR spectrum;

[0041] Figure 17 is the compound 3ob prepared in Example 15 of the present invention 13 C NMR spectrum;

[0042] Figure 18 is the compound 3pc prepared in Example 16 of the present invention 13 C NMR spectrum;

[0043] Figure 19 is the compound 3qb prepared in Example 17 of the present invention 13 C NMR spectrum. DETAILED DESCRIPTION

[0044] The present invention will be described in detail below with reference to the accompanying drawings and specific embodiments.

[0045] The synthesis method of the present invention comprises the following steps: adding a benzene aromatic olefin compound 1, a benzenesulfonic acid fluoromethyl thioester 2, and the required oxidant A, oxidant B, catalyst, and solvent into a single-necked flask; stirring the mixture at 65-100° C. to react (the reaction time is determined by different substrates); monitoring the reaction by thin-layer chromatography until the starting material no longer decreases, stopping the reaction, and removing the solvent by rotary evaporation under reduced pressure. The residue is then purified by rapid silica gel column chromatography to obtain the corresponding fluoromethyl thioester compound 3.

[0046] The preparation method of the present invention is specifically described below by way of examples:

[0047] Example 1

[0048] Procedure: A 5 mL single-necked flask was charged with 0.25 mmol of m-methylstyrene 1a and 0.15 mmol of difluoromethylbenzenesulfonate 2a. 0.0075 mmol of Cu(NO₃)₂, 0.45 mmol of K₂S₂O₃, and 0.45 mmol of TBHP were then added and sealed with a rubber stopper. CH₃CN (0.3 mL) was then added via syringe and the reaction was continued at 82°C. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified on a flash silica gel column to afford the corresponding difluoromethylthioester compound 3aa in 65% yield.

[0049]

[0050] The above product difluoromethyl thioester compound 3aa 1 H NMR spectrum Figure 1 As shown, 13 C NMR images Figure 2 As shown, 19 FNMR images Figure 3 As shown, from Figure 1 、 Figure 2 and Figure 3 The following data can be obtained:

[0051] S-(difluoromethyl)-3-methylbenzothioate(3aa).Colourless oil(19.7mg,65%).Eluant:ethyl acetate / petroleum ether(1:100,R f =0.30). 1H NMR (400MHz, CDCl3) δ7.69 (dd, J = 4.5, 2.3Hz, 2H), 7.49 (t, J = 55.2Hz, 1H), 7.46 (d, J = 7.6Hz, 1H), 7.38 (d, J = 7.9Hz, 1H), 2.43 (s, 3H) ppm; 19 F NMR (376MHz, CDCl3) δ-99.51 (d, J = 55.6Hz, 2F) ppm; 13 C NMR (101MHz, CDCl3) δ 187.5, 139.3, 135.7, 129.1, 128.2, 125.0, 120.8 (t, J = 272.7Hz), 21.4ppm.

[0052] Example 2

[0053] Procedure: A 5 mL single-necked flask was charged with 0.25 mmol of p-ethylstyrene 1b and 0.15 mmol of difluoromethylbenzenesulfonate 2a. 0.015 mmol of Cu(NO₃)₂, 0.45 mmol of K₂S₂O₃, and 0.45 mmol of TBHP were then added and sealed with a rubber stopper. CH₃CN (0.3 mL) was then added via syringe and the reaction was continued at 82°C. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified on a flash silica gel column to afford the corresponding difluoromethylthioester compound 3ba in a 72% yield.

[0054]

[0055] The above product difluoromethyl thioester compound 3ba 13 C NMR images Figure 4 As shown, from Figure 4 The following data can be obtained:

[0056] S-(difluoromethyl)-4-ethylbenzothioate(3ba).Colourless oil(23.3mg,72%).Eluant:ethyl acetate / petroleum ether(1:100,R f =0.30). 1 H NMR (400MHz, CDCl3) δ7.86–7.79(m,2H),7.49(t,J=55.3Hz,1H),7.32(d,J=8.4Hz,2H),2.73(q,J=7.6Hz,2H),1.27(t,J=7.6Hz,3H)ppm; 19F NMR (376MHz, CDCl3) δ-99.46 (d, J = 55.6Hz, 2F) ppm; 13 C NMR (100MHz, CDCl3) δ 186.8 (t, J = 3.2Hz), 152.2, 133.3 (t, J = 2.6Hz), 128.6, 127.9, 120.7 (t, J = 269.9Hz), 29.1, 15.1ppm.

[0057] Example 3

[0058] Procedure: A 5 mL single-necked flask was charged with 0.25 mmol of o-methylstyrene 1c and 0.15 mmol of difluoromethylbenzenesulfonate 2a. 0.03 mmol of Cu(NO)₃, 0.45 mmol of K₂S₂O₃, and 0.45 mmol of TBHP were then added and sealed with a rubber stopper. CH₃CN (0.3 mL) was then added via syringe and the reaction was allowed to proceed at 82°C. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified on a flash silica gel column to afford the corresponding difluoromethylthioester compound 3ca in 75% yield.

[0059]

[0060] The above product difluoromethyl thioester compound 3ca 13 C NMR images Figure 5 As shown, from Figure 5 The following data can be obtained:

[0061] S-(difluoromethyl)-2-methylbenzothioate(3ca).Colourless oil(22.7mg,75%).Eluant:ethyl acetate / petroleum ether(1:100,R f =0.30). 1 H NMR (400MHz, CDCl3) δ7.76(dd,J=7.8,1.4Hz,1H),7.48(td,J=7.5,1.4Hz,1H),7.43(t,J=55.2Hz,1H)),7.35–7.28(m,2H),2.53(s,3H)ppm; 19 F NMR (376MHz, CDCl3) δ-100.12 (d, J = 55.4Hz, 2F) ppm; 13C NMR (101MHz, CDCl3) δ 188.8, 138.5, 135.4, 133.4, 132.3, 129.1, 126.4, 120.9 (t, J = 269.8Hz), 21.1ppm.

[0062] Example 4

[0063] Procedure: A 5 mL single-necked flask was charged with 0.25 mmol of p-tert-butylstyrene 1d and 0.15 mmol of difluoromethylbenzenesulfonate 2a. 0.03 mmol of CuSO₄, 0.45 mmol of K₂S₂O₄, and 0.45 mmol of TBHP were then added and sealed with a rubber stopper. CH₃CN (0.3 mL) was then added via syringe and allowed to react at 82°C. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified on a flash silica gel column to afford the corresponding difluoromethylthioester compound 3da in a 60% yield.

[0064]

[0065] The above product difluoromethyl thioester compound 3da 13 C NMR images Figure 6 As shown, from Figure 6 The following data can be obtained:

[0066] S-(difluoromethyl)-4-(tert-butyl)benzothioate(3da).White solid(21.9mg,66%).Mp:53–55℃.Eluant:ethyl acetate / petroleum ether(1:100,R f =0.30). 1 H NMR (400MHz, CDCl3) δ7.86–7.81(m,2H),7.54–7.49(m,2H),7.49(t,J=55.2Hz,1H),1.35(s,9H)ppm; 19 F NMR (376MHz, CDCl3) δ-99.51 (d, J = 56.7Hz, 2F) ppm; 13 C NMR (101MHz, CDCl3) δ 186.9, 159.1, 133.1 (t, J = 2.6Hz), 127.7, 126.2, 120.8 (t, J = 269.8Hz), 35.5, 31.1ppm.

[0067] Example 5

[0068] Procedure: A 5 mL single-necked flask was charged with 0.25 mmol of p-fluorostyrene 1e and 0.15 mmol of difluoromethylbenzenesulfonate 2a. 0.012 mmol of FeCl₃, 0.45 mmol of K₂S₂O₃, and 0.45 mmol of TBHP were then added and sealed with a rubber stopper. CH₃CN (0.3 mL) was then added via syringe and allowed to react at 82°C. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified on a flash silica gel column to afford the corresponding difluoromethylthioester compound 3ea in a 44% yield.

[0069]

[0070] The above product difluoromethyl thioester compound 3ea 13 C NMR images Figure 7 As shown, from Figure 7 The following data can be obtained:

[0071] S-(difluoromethyl)-4-fluorobenzothioate(3ea).Colourless oil(13.6mg,44%).Eluant:ethyl acetate / petroleum ether(1:100,R f =0.30). 1 H NMR (400MHz, CDCl3) δ7.96–7.90(m,2H),7.48(t,J=55.2Hz,1H),7.22–7.16(m,2H)ppm; 19 F NMR (376MHz, CDCl3) δ-99.25 (d, J=55.3Hz, 2F), -102.59 (s, 1F)ppm; 13 C NMR (101MHz, CDCl3) δ 185.9, 166.8 (d, J = 257.8Hz), 132.0 (d, J = 2.9Hz), 130.5 (d, J = 9.7Hz), 120.6 (t, J = 270.7Hz), 116.5 (d, J = 22.4Hz) ppm.

[0072] Example 6

[0073] Procedure: A 5 mL single-necked flask was charged with 0.25 mmol of p-chlorostyrene 1f and 0.15 mmol of difluoromethylbenzenesulfonate 2a. 0.012 mmol of Fe(OTf), 0.45 mmol of KSO, and 0.45 mmol of TBHP were then added and sealed with a rubber stopper. CHCN (0.3 mL) was then added via syringe and allowed to react at 82°C. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified on a flash silica gel column to afford the corresponding difluoromethylthioester 3fa in 48% yield.

[0074]

[0075] The above product difluoromethyl thioester compound 3fa 13 C NMR images Figure 8 As shown, from Figure 8 The following data can be obtained:

[0076] S-(difluoromethyl)-4-chlorobenzothioate(3fa).White solid 15.9mg,48%).Mp:31–32℃.Eluant:ethyl acetate / petroleum ether(1:100,R f =0.30). 1 H NMR (400MHz, CDCl3) δ7.85–7.82(m,2H),7.52–7.46(m,2H),7.48(t,J=55.2Hz,1H)ppm; 19 F NMR (376MHz, CDCl3) δ-99.26 (d, J = 55.1Hz, 2F) ppm; 13 C NMR (101MHz, CDCl3) δ 186.3, 141.6, 134.0 (t, J = 2.6Hz), 129.6, 129.0, 120.5 (t, J = 270.9Hz) ppm.

[0077] Example 7

[0078] Procedure: 1 g of m-bromostyrene (0.25 mmol) and 0.15 mmol of difluoromethylbenzenesulfonate 2a were added to a 5 mL single-necked flask. 0.018 mmol of CuSO₄, 0.45 mmol of K₂S₂O₄, and 0.45 mmol of TBHP were then added, and the flask was sealed with a rubber stopper. 1,2-Dichloroethane (0.3 mL) was then added to the flask via syringe and allowed to react at 82°C. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified on a flash silica gel column to afford the corresponding difluoromethylthioester compound 3ga in 62% yield.

[0079]

[0080] The above product difluoromethyl thioester compound 3ga 13 C NMR images Figure 9 As shown, from Figure 9 The following data can be obtained:

[0081] S-(difluoromethyl)-3-bromobenzothioate(3ga).Colourless oil(24.7mg,62%).Eluant:ethyl acetate / petroleum ether(1:100,R f =0.30). 1 H NMR (400MHz, CDCl3) δ8.05–8.01(m,1H),7.84–7.76(m,2H),7.48(t,J=55.2Hz,1H),7.41–7.37(m,1H)ppm; 19 F NMR (376MHz, CDCl3) δ-99.94 (d, J = 55.6Hz, 2F) ppm; 13 C NMR (101MHz, CDCl3) δ186.3,137.8,137.3,130.7,130.6,126.3,123.5,120.4(t,J= 272.7Hz)ppm.IR:2926,2854,2360,2341,1687,1197,1078,936,941,785,711,688cm -1 .

[0082] Example 8

[0083] Procedure: A 5 mL single-necked flask was charged with 0.25 mmol of p-iodostyrene 1h and 0.15 mmol of difluoromethylbenzenesulfonate 2a. 0.015 mmol of Cu(NO3)2, 0.45 mmol of K2S2O8, and 0.45 mmol of TBHP were then added and sealed with a rubber stopper. CH3CN (0.3 mL) was then added via syringe and allowed to react at 65°C. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified on a flash silica gel column to afford the corresponding difluoromethylthioester 3ha in 54% yield.

[0084]

[0085] The above product difluoromethyl thioester compound 3ha 13 C NMR images Figure 10As shown, from Figure 10 The following data can be obtained:

[0086] S-(difluoromethyl)-4-iodobenzothioate(3ha).White solid(25.4mg,54%).Mp:59–60℃.Eluant:ethyl acetate / petroleum ether(1:100,R f =0.30). 1 H NMR (400MHz, CDCl3) δ7.90–7.85(m,2H),7.61–7.57(m,2H),7.48(t,J=55.1Hz,1H)ppm; 19 F NMR (376MHz, CDCl3) δ-99.27 (d, J = 55.1Hz, 2F) ppm; 13 C NMR (101MHz, CDCl3) δ 186.9, 138.5, 135.0 (t, J = 2.5Hz), 128.8, 120.4 (t, J = 271.0Hz), 103.2ppm.

[0087] Example 9

[0088] Procedure: A 5 mL single-necked flask was charged with 0.25 mmol of p-acetoxystyrene 1i and 0.15 mmol of difluoromethylbenzenesulfonate 2a. 0.015 mmol of Cu(NO)₃, 0.45 mmol of K₂S₂O₃, and 0.45 mmol of TBHP were then added and sealed with a rubber stopper. CH₃CN (0.3 mL) was then added via syringe and the reaction was allowed to proceed at 100°C. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified on a flash silica gel column to afford the corresponding difluoromethylthioester compound 3ia in 70% yield.

[0089]

[0090] The above product difluoromethyl thioester compound 3ia 13 C NMR images Figure 11 As shown, from Figure 11 The following data can be obtained:

[0091] 4-(((difluoromethyl)thio)carbonyl)phenyl acetate(3ia).Colourless oil(25.8mg,70%).Eluant:ethyl acetate / petroleum ether(1:50,R f=0.30). 1 H NMR (400MHz, CDCl3) δ7.96 (d, J = 8.8Hz, 1H), 7.51 (t, J = 55.2Hz, 1H), 7.28 (d, J = 8.7Hz, 2H), 2.36 (s, 3H) ppm; 19 F NMR (376MHz, CDCl3) δ-99.36 (d, J = 55.1Hz, 2F) ppm; 13 C NMR (101MHz, CDCl3) δ186.2,168.7,155.7,133.1,129.4,122.5,120.6(d,J=270.6Hz ),21.3ppm.IR:2920,2849,2360,1762,1680,1598,1189,1162,1076,900,786,686cm -1 .HRMS(ESI)forC 10 H8F2O3SNa(M+Na + ):Calcd:269.0053,Found:269.0054.

[0092] Example 10

[0093] Procedure: A 5 mL single-necked flask was charged with 0.15 mmol of methyl p-vinylbenzoate 1j and 0.15 mmol of difluoromethylbenzenesulfonate 2a. 0.015 mmol of Cu(NO₃)₂, 0.45 mmol of K₂S₂O₃, and 0.45 mmol of TBHP were then added and sealed with a rubber stopper. CH₃CN (0.3 mL) was then added via syringe and reacted at 82°C. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified on a flash silica gel column to afford the corresponding difluoromethylthioester compound 3ja in a 46% yield.

[0094]

[0095] The above product difluoromethyl thioester compound 3ja 13 C NMR images Figure 12 As shown, from Figure 12 The following data can be obtained:

[0096] 4-(((difluoromethyl)thio)carbonyl)phenyl acetate(3ja).White solid(15.5mg,46%).Mp:42–43℃.Eluant:ethyl acetate / petroleum ether(1:80,R f =0.30).1 H NMR (400MHz, CDCl3) δ8.22–8.12(m,2H),8.00–7.91(m,2H),7.50(t,J=55.1Hz,1H),3.96(s,3H)ppm; 19 F NMR (376MHz, CDCl3) δ-99.40 (d, J = 55.3Hz, 2F) ppm; 13 C NMR (101MHz, CDCl3) δ 187.0, 165.9, 138.8 (t, J = 2.6Hz), 135.6, 130.5, 127.7, 120.4 (t, J = 271.3Hz), 52.8ppm.

[0097] Example 11

[0098] Procedure: A 5 mL single-necked flask was charged with 0.030 mmol of p-cyanostyrene 1k and 0.15 mmol of difluoromethylbenzenesulfonate 2a. 0.015 mmol of Cu(NO₃)₂, 0.60 mmol of K₂S₂O₃, and 0.60 mmol of TBHP were then added and sealed with a rubber stopper. CH₃CN (0.3 mL) was then added via syringe and the reaction was allowed to proceed at 82°C. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified on a flash silica gel column to afford the corresponding difluoromethylthioester 3ka in 37% yield.

[0099]

[0100] The above product difluoromethyl thioester compound 3ka 13 C NMR images Figure 13 As shown, from Figure 13 The following data can be obtained:

[0101] S-(difluoromethyl)-4-cyanobenzothioate(3ka).White solid(11.8mg,37%).Mp:70–71℃.Eluant:ethyl acetate / petroleum ether(1:20,R f =0.30). 1 HNMR (400MHz, CDCl3) δ8.03–7.96(m,2H),7.84–7.80(m,2H),7.49(t,J=54.9Hz,1H)ppm; 19 F NMR (376MHz, CDCl3) δ-99.17 (d, J = 55.1Hz, 2F) ppm; 13C NMR (101MHz, CDCl3) δ 186.5, 138.6 (t, J = 2.5Hz), 133.0, 128.1, 120.1 (t, J = 273.7Hz), 118.2, 117.5ppm.

[0102] Example 12

[0103] Procedure: A 5 mL single-necked flask was charged with 0.25 mmol of p-trifluoromethylstyrene 1l and 0.15 mmol of difluoromethylbenzenesulfonate 2a. 0.015 mmol of Cu(NO3)2, 0.15 mmol of K2S2O8, and 0.15 mmol of TBHP were then added and sealed with a rubber stopper. CH3CN (0.3 mL) was then added via syringe and the reaction was allowed to proceed at 82°C. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified on a flash silica gel column to afford the corresponding difluoromethylthioester compound 3la in a 40% yield.

[0104]

[0105] The above product difluoromethyl thioester compound 31a 13 C NMR images Figure 14 As shown, from Figure 14 The following data can be obtained:

[0106] S-(difluoromethyl)-4-(trifluoromethyl)benzothioate(3la).White solid(15.4mg,40%).Mp:44–45℃.Eluant:ethyl acetate / petroleum ether(1:40,R f =0.70). 1 H NMR (400MHz, CDCl3) δ8.01 (d, J = 8.2Hz, 2H), 7.78 (d, J = 8.2Hz, 2H), 7.50 (t, J = 55.0Hz, 1H) ppm; 19 F NMR (376MHz, CDCl3) δ-63.02 (s), -99.25 (d, J = 55.1Hz) ppm; 13 C NMR (101MHz, CDCl3) δ 186.8, 138.4 (t, J = 2.6Hz), 136.1 (q, J = 32.9Hz), 128.1, 126.3 (q, J = 3.7Hz). 123.4 (q, J = 273.1Hz), 120.3 (q, J = 271.6Hz) ppm.

[0107] Example 13

[0108] Procedure: A 5 mL single-necked flask was charged with 0.25 mmol of p-styrene 1m and 0.15 mmol of benzenesulfonic acid monofluoromethyl thioester 2b. 0.015 mmol of CuSO4, 0.15 mmol of K2S2O8, and 0.45 mmol of TBHP were then added and the flask was sealed with a rubber stopper. Then, CH3CN (0.3 mL) was added via syringe and reacted at 82°C. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified on a flash silica gel column to yield the corresponding difluoromethyl thioester compound 3mb in a 63% yield.

[0109]

[0110] The above product difluoromethyl thioester compound 3mb 13 C NMR images Figure 15 As shown, from Figure 15 The following data can be obtained:

[0111] S-(fluoromethyl)-benzothioate(3mb).Colourless oil(16.1mg,63%).Eluant:ethyl acetate / petroleum ether(1:500,R f =0.30). 1 H NMR (400MHz, CDCl3) δ7.98 (d, J = 7.6Hz, 2H), 7.63 (t, J = 7.4Hz, 1H), 7.49 (t, J = 7.6Hz, 2H), 6.06 (s, 1H), 5.94 (s, 1H) ppm; 19 F NMR (376MHz, CDCl3) δ-191.56 (t, J = 50.6Hz) ppm; 13 C NMR (101MHz, CDCl3) δ188.1, 136.0, 134.4, 129.0, 127.9, 80.8 (d, J = 215.5Hz) ppm.

[0112] Example 14

[0113] Procedure: A 5 mL single-necked flask was charged with 0.25 mmol of 2,4-dimethylstyrene 1n and 0.15 mmol of benzenesulfonic acid trifluoromethyl thioester 2c. 0.015 mmol of Cu(NO3)2, 0.30 mmol of K2S2O8, and 0.45 mmol of TBHP were then added and sealed with a rubber stopper. CH3CN (0.3 mL) was then added via syringe and allowed to react at 82°C. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified on a flash silica gel column to afford the corresponding difluoromethyl thioester compound 3nc in a 68% yield.

[0114]

[0115] The above product difluoromethyl thioester compound 3nc 13 C NMR images Figure 16 As shown, from Figure 16 The following data can be obtained:

[0116] S-(trifluoromethyl)2,4-dimethylbenzothioate(3nc).Colourless oil(23.9mg,72%).Eluant:ethyl acetate / petroleum ether(1:120,R f =0.30). 1 H NMR (400MHz, CDCl3δ7.62(d,J=7.9Hz,1H),7.11(d,J=9.0Hz,2H),2.51(s,3H),2.38(s,3H)ppm; 19 F NMR(376MHz,CH2Cl2)δ-40.24ppm; 13 C NMR (101MHz, CDCl3) δ182.9, 152.7, 132.94 (d, J = 2.9Hz), 128.8, 128.3 (q, J = 311.1Hz), 1 28.0,29.2,15.1ppm.IR:2983,2849,2360,2340,1723,1611,1148,1099,943,838,631cm -1 .HRMS(ESI)for C 10 H9F3OSNa(M+Na + ):Calcd:257.0218,Found:257.0217.

[0117] Example 15

[0118] Procedure: A 5 mL single-necked flask was charged with 0.25 mmol of 3,4-cycloethylstyrene 1o and 0.15 mmol of benzenesulfonic acid monofluoromethyl thioester 2b. 0.015 mmol of FeCl3, 0.45 mmol of K2S2O8, and 0.15 mmol of TBHP were then added and the flask was sealed with a rubber stopper. 1,2-Dichloroethane (0.3 mL) was then added to the flask via syringe and allowed to react at 82°C. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified on a flash silica gel column to afford the corresponding difluoromethyl thioester compound 3ob in a 53% yield.

[0119]

[0120] The above product difluoromethyl thioester compound 3ob 13 C NMR images Figure 17 As shown, from Figure 17 The following data can be obtained:

[0121] S-(fluoromethyl)bicyclo[4.2.0]octa-1(6),2,4-triene-3-carbothioate(3ob).Colourless oil(15.6mg,53%).Eluant:ethyl acetate / petroleum ether(1:500,R f =0.30). 1 H NMR (400MHz, CDCl3) δ7.91(dd,J=7.7,1.5Hz,1H),7.69(t,J=1.3Hz,1H),7.19(dd,J=7.7,0.9Hz,1H),6.08(s,1H),5.95(s,1H),3.26(s,4H)ppm; 19 F NMR (376MHz, CDCl3) δ-192.23. (t, J = 49.9Hz) ppm; 13 C NMR (101MHz, CDCl3) δ188.3,153.7,146.5,135.0,127.4,123.0,122.0,80.9(d,J= 214.5Hz),30.2,29.5ppm.IR:2927,2851,2360,2340,1716,1275,1260,764,750cm -1 .HRMS(ESI)for C 10 H9FOSNa(M+Na + ):Calcd:219.0250,Found:219.0248.

[0122] Example 16

[0123] Procedure: A 5 mL single-necked flask was charged with 0.25 mmol of 2-vinylnaphthalene 1p and 0.15 mmol of benzenesulfonic acid trifluoromethyl thioester 2c. 0.015 mmol of CuSO4, 0.45 mmol of K2S2O8, and 0.30 mmol of TBHP were then added and sealed with a rubber stopper. CH3CN (0.3 mL) was then added via syringe and allowed to react at 82°C. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified on a flash silica gel column to yield the corresponding difluoromethyl thioester compound 3pc in a 56% yield.

[0124]

[0125] The above product difluoromethyl thioester compound 3pc 13 C NMR images Figure 18 As shown, from Figure 18 The following data can be obtained:

[0126] S-(trifluoromethyl)naphthalene 2-carbothioate(3pc).Yellow solid(20.7mg,56%).Mp:47–49℃.Eluant:ethyl acetate / petroleum ether(1:100,R f =0.30). 1 H NMR (400MHz, CDCl3) δ8.39 (d, J=1.9Hz, 1H), 8.04–7.81 (m, 4H), 7.64 (dddd, J=24.3, 8.1, 6.9, 1.4Hz, 2H) ppm; 19 F NMR(376MHz,CH2Cl2)δ-40.36ppm; 13 C NMR (101MHz, CDCl3) δ183.2, 136.4, 132.4 (t, J = 2.8Hz), 132.3, 129.9, 129.7, 129.6, 129.3, 128.2 (q, J = 310.1Hz), 128.0, 127.6, 122.6ppm.

[0127] Example 17

[0128] Procedure: A 5 mL single-necked flask was charged with 0.25 mmol of p-methoxystyrene (1q) and 0.15 mmol of benzenesulfonic acid monofluoromethyl thioester (2b). 0.012 mmol of Cu(NO3)2, 0.45 mmol of K2S2O8, and 0.60 mmol of TBHP were then added and sealed with a rubber stopper. CH3CN (0.3 mL) was then added via syringe and allowed to react at 82°C. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified on a flash silica gel column to afford the corresponding monofluoromethyl thioester compound 3qb in a 42% yield.

[0129]

[0130] The above product monofluoromethyl thioester compound 3qb 13 C NMR images Figure 19 As shown, from Figure 19 The following data can be obtained:

[0131] S-(fluoromethyl)-4-methoxybenzothioate(3qb).White solid(12.6mg,42%).Mp:56–57℃.Eluant:ethyl acetate / petroleum ether(1:30,R f =0.30). 1 H NMR (400MHz, CDCl3) δ7.97 (d, J = 8.9 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 6.05 (s, 1H), 5.93 (s, 1H), 3.88 (s, 3H) ppm; 19 F NMR (376MHz, CDCl3) δ-191.69 (t, J = 50.7Hz) ppm; 13 C NMR (101MHz, CDCl3) δ186.4, 164.6, 130.3, 128.9, 114.2, 80.9 (d, J = 214.8Hz), 55.7ppm.

[0132] Example 18

[0133] Procedure: A 5 mL single-necked flask was charged with 0.225 mmol of p-methoxystyrene (1q) and 0.15 mmol of benzenesulfonic acid monofluoromethyl thioester (2b). 0.012 mmol of Cu(NO3)2, 0.60 mmol of K2S2O8, and 0.60 mmol of TBHP were then added and the flask was sealed with a rubber stopper. CH3CN (0.3 mL) was then added via syringe and reacted at 62°C. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified on a flash silica gel column to afford the corresponding monofluoromethyl thioester compound 3qb in a 31% yield.

[0134]

[0135] Example 19

[0136] Procedure: A 5 mL single-necked flask was charged with 0.255 mmol of p-methoxystyrene (1q) and 0.15 mmol of benzenesulfonic acid monofluoromethyl thioester (2b). 0.012 mmol of Cu(NO3)2, 0.60 mmol of K2S2O8, and 0.60 mmol of TBHP were then added and the flask was sealed with a rubber stopper. CH3CN (0.3 mL) was then added via syringe and allowed to react at 62°C. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified on a flash silica gel column to afford the corresponding monofluoromethyl thioester compound 3qb in a 30% yield.

[0137]

[0138] Example 20

[0139] Procedure: A 5 mL single-necked flask was charged with 0.255 mmol of p-methoxystyrene (1q) and 0.15 mmol of benzenesulfonic acid monofluoromethyl thioester (2b). 0.012 mmol of Cu(NO3)2, 0.60 mmol of K2S2O8, and 0.60 mmol of TBHP were then added and the flask was sealed with a rubber stopper. CH3CN (0.3 mL) was then added via syringe and allowed to react at 100°C. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified on a flash silica gel column to afford the corresponding monofluoromethyl thioester compound 3qb in a 28% yield.

[0140]

[0141] The present invention uses aromatic olefin compounds as starting materials, copper salts or iron salts as catalysts, and peroxide compounds as oxidants, all of which are inexpensive and readily available reagents. The three fluoromethyl benzenesulfonate esters used are stable at room temperature, non-volatile, and easy to prepare. The present invention as a whole has mild conditions, simple operation, and is environmentally friendly. Most importantly, the present invention develops a new pathway for synthesizing fluoromethyl thioesters from aromatic olefins. The pathway is a universal pathway for synthesizing the three fluoromethyl thioester compounds and has good tolerance to common functional groups, especially halogens (F, Cl, Br, I), as these are commonly used connection sites in many coupling reactions, facilitating further modification of the structure of the product obtained by the method of the present invention.

Claims

1. A method for preparing fluoromethyl thioester compounds from aromatic olefins in one step, characterized in that: The specific preparation steps are as follows: Step 1: Add aromatic olefin compound 1, fluoromethyl benzenesulfonate 2, oxidant A, oxidant B, and catalyst to a flask. Then, add a solvent to the flask under an air atmosphere, heat and continuously stir to react. During the reaction, monitor the reaction by thin layer chromatography until the starting material no longer decreases, then stop the reaction to obtain the reactant. The reaction formula is as follows: In formula (1), R 1 is selected from phenyl, monosubstituted phenyl, 2-naphthyl; the substituent of monosubstituted phenyl is C1-C4 alkyl, acetoxy, fluorine, chlorine, bromine, iodine, cyano, trifluoromethyl, methoxy, R f Selected from CH2F, CF2H, CF3; Step 2: removing the solvent from the reactant by rotary evaporation under reduced pressure to obtain a reaction residue, and purifying the reaction residue by rapid silica gel column to obtain the corresponding fluoromethyl thioester compound 3; The oxidant A is a 70% aqueous solution of tert-butyl hydroperoxide, the oxidant B is K2S2O8; the catalyst is CuSO4, Cu(NO3)2 or FeCl3; and the solvent is acetonitrile or 1,2-dichloroethane.

2. The method for preparing fluoromethyl thioester compounds from aromatic olefins in one step according to claim 1, characterized in that: The molar ratio of the benzenesulfonic acid fluoromethyl thioester 2 to the aromatic olefin compound 1 is 1:1-2.

3. The method for preparing fluoromethyl thioester compounds from aromatic olefins in one step according to claim 2, characterized in that: The molar ratio of the benzenesulfonic acid fluoromethyl thioester 2 to the aromatic olefin compound 1 is 1:1.5-1.

7.

4. The method for preparing fluoromethyl thioester compounds from aromatic olefins in one step according to claim 3, characterized in that: The molar ratio of the fluoromethyl benzenesulfonate 2 to the catalyst is 1:0.05-0.2, the molar ratio of the fluoromethyl benzenesulfonate 2, the oxidant A, and the oxidant B is 1:1-4:1-4, and the heating temperature is 65-100°C.

5. The method for preparing fluoromethyl thioester compounds from aromatic olefins in one step according to claim 4, characterized in that: The catalyst is Cu(NO3)2 or CuSO4, and the molar ratio of benzenesulfonic acid fluoromethyl thioester 2 to the catalyst is 1:0.08-0.

12.

6. The method for preparing fluoromethyl thioester compounds from aromatic olefins in one step according to claim 5, characterized in that: The heating temperature is 82°C.

7. The method for preparing fluoromethyl thioester compounds from aromatic olefins in one step according to claim 6, characterized in that: The solvent is acetonitrile.

8. The method for preparing fluoromethyl thioester compounds from aromatic olefins in one step according to claim 1, characterized in that: The reaction residue was purified by column chromatography.

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