CN111825580B

CN111825580B - Method for synthesizing aromatic hydrocarbon trifluoromethylthio compound

Info

Publication number: CN111825580B
Application number: CN201910308386.5A
Authority: CN
Inventors: 刘杰; 亚斯; 易文斌
Original assignee: Nanjing University of Science and Technology
Current assignee: Nanjing University of Science and Technology
Priority date: 2019-04-17
Filing date: 2019-04-17
Publication date: 2022-02-18
Anticipated expiration: 2039-04-17
Also published as: CN111825580A

Abstract

The invention discloses a method for synthesizing an arene trifluoromethylthio compound. The method comprises the following steps: reacting sodium trifluoromethanesulfonate with diphenyl phosphorus chloride at room temperature under the protection of argon, adding aniline compound and tert-butyl nitrite in sequence after reacting for a period of time, and adding CuSO₄And acetonitrile is used as a solvent as a catalyst, the reaction is fully carried out at 70 +/-5 ℃, the reaction is cooled to room temperature after the reaction is finished, the extraction and the reduced pressure distillation are carried out, and the reaction mixture is separated and purified by column chromatography to obtain the aromatic hydrocarbon trifluoromethylthio compound. The method has the advantages of simple and safe process operation, high reaction conversion rate, economical and practical raw materials, less three wastes and no need of treating additional organic solvents.

Description

Method for synthesizing aromatic hydrocarbon trifluoromethylthio compound

Technical Field

The invention relates to the field of organic synthesis, in particular to a method for synthesizing an aromatic ring trifluoromethylthio compound.

Technical Field

The compound containing trifluoromethylthio group has been widely applied in the fields of medicine, pesticide, material and the like. For example, the anticoccidial veterinary drugs Toltrazuril, the insecticide Vaniliprole and the stimulant Tiflorex, etc. all contain trifluoromethylthio groups. Reacting trifluoromethylthio (SCF)₃) The incorporation of groups into aromatic molecules is of interest to the pharmaceutical and agrochemical industries where the high lipophilicity and high electron withdrawing ability of the group are of great importance. Current industrial processes for the formation of trifluoromethyl aryl sulfides typically involve multiple staged processes requiring harsh conditions, limited nature by other substituents on the ring, and detrimental to the environment. There is therefore a great need for a simple, straightforward process for forming these compounds. Several methods for preparing trifluoromethyl aryl sulfides have been reported, but these methods are based on preformed thioaryl units (such as ArSCl and ArSCN) and require an excess of expensive reagents, direct trisThe fluoromethylation reaction requires relatively complicated conditions. Stable and easily available CF₃SO₂Na (Langlois reagent) has been the in situ generation of CF in recent years using reducing and catalytic conditions₃An electrophilic trifluoromethylthio reagent for S.

Document 1(T.Billard, S.Large, B.R.Langlois, Preparation of Trifluoromethyl Sulfides or Selenides from Trifluoromethyl Sulfides or Selenides [ J.Billard, S.Lange, B.R.Langlois]Tetrahedron lett, 1997,38, 65-68). A method of using CF based on pre-formed Ar-SCN is reported₃SiMe₃And TBAF, a method for effecting trifluoromethylthio modification on an aromatic ring. In addition, the reaction is also extended to the trifluromethyl selenization reaction, with most product yields ranging from 30% to 80%.

Document 2(D.J.Adams, A.Goddard, J.H.Clark, D.J.Macquarry, trifluoromethyl thiomethylation: a simple, affinity route to trifluoromethyl aryl sulfides [ J.J.]Chem. Commun.,2000, 987-988) discloses the preliminary preparation of a diazonium phenyl tetrafluoroborate (Ar-N)₂ ⁺BF₄ ^-) Using a metal trifluoromethylthio reagent (CuSCF)₃) Realizes the modification of the aromatic ring through trifluoromethylthio. Most of the product yields were between 60% and 95%.

Document 3(K.Jouvin, C.Matheis, L.J.Goosen, Synthesis of Aryl Tri-and Difluoromethyl Thioethers via C. phi. HThiocyanation/fluorination Cascade [ J ], chem.Eur.J.2015,21, 14324-14327) developed a one-pot, two-step C-H thiocyanide/Fluoroalkylation process with electron-rich aromatics as substrate, with an inexpensive thiocyanate source and TMSCF3 to achieve trifluoromethylation of aromatics in a majority of product yields of 60% to 90%.

However, the above three methods have some disadvantages as follows:

(1) certain fluorine-containing agents present serious environmental concerns, are expensive, and present safety concerns;

(2) the starting materials need to be prepared in advance, the process is complicated, and the synthesis means does not meet the expected simple and efficient synthesis.

(3) The method has a limited range of substrates, focuses on electron-rich aromatics, and limits the applicability of the method.

Disclosure of Invention

The invention aims to provide a method for synthesizing aromatic hydrocarbon trifluoromethylthio compound with low toxicity, low cost, simple process and wide applicability.

The technical scheme for realizing the invention is as follows: a process for synthesizing an aromatic trifluoromethylthio compound comprising the steps of:

reacting sodium trifluoromethanesulfonate (A) with diphenyl phosphorus chloride (B) at room temperature under the protection of argon, adding aniline compound (C) and tert-butyl nitrite (D) in sequence after reacting for a period of time, and adding CuSO₄(E) And acetonitrile is used as a solvent as a catalyst, the reaction is fully carried out at 70 +/-5 ℃, the reaction is cooled to room temperature after the reaction is finished, the extraction and the reduced pressure distillation are carried out, and the reaction mixture is separated and purified by column chromatography to obtain the aromatic hydrocarbon trifluoromethylthio compound (F).

In the formula (C) or the formula (F), R is any one of 4-phenyl, 4-cyclohexyl and 4-cyano.

Preferably, the molar ratio of the sodium trifluoromethanesulfonate (A), the diphenyl phosphorus chloride (B), the aniline compound (C) and the tert-butyl nitrite (D) is 1: 1: 1:1.5.

Preferably, the CuSO₄In an amount of the aniline compound (C)20mol％。

Preferably, the reaction is carried out at room temperature for 30min or more.

Preferably, the reaction is carried out at 70. + -. 5 ℃ for 12 hours or more.

Compared with the prior art, the invention has the following remarkable advantages:

(1) avoids using dangerous substrates and low-toxicity reagents, has less three wastes and is environment-friendly.

(2) The preparation of the initial raw materials is not needed, and the cost is reduced.

(3) The used substrate has wide range.

(4) The reaction steps are simple, the conversion rate is high, the conditions required by the reaction are easy to achieve, and the product obtained by separation and purification is high in purity.

Drawings

FIG. 1 is a scheme of 4-phenyl-1-trifluoromethylsulfanyl benzene¹H NMR chart.

FIG. 2 is a scheme showing 4-phenyl-1-trifluoromethylsulfanyl benzene¹⁹F NMR chart.

FIG. 3 is a scheme showing 4-cyclohexyl-1-trifluoromethylsulfanyl benzene¹H NMR chart.

FIG. 4 is a schematic representation of 4-cyclohexyl-1-trifluoromethylsulfanyl benzene¹⁹F NMR chart.

FIG. 5 is a schematic representation of 4-cyano-1-trifluoromethylsulfanyl benzene¹H NMR chart.

FIG. 6 is a drawing showing the preparation of 4-cyano-1-trifluoromethylsulfanyl benzene¹⁹F NMR chart.

Detailed Description

For a better understanding of the present invention, the technical solutions of the present invention are specifically described below by way of specific examples and accompanying drawings.

The synthetic route of the invention is as follows:

example 1

In N₂Adding diphenyl phosphorus chloride (2.20g, 10mmol) and sodium trifluoromethanesulfonate (1.56g,10mmol) under protection, adding 20mL of CeCN, stirring at room temperature for 30min under sealed condition, and adding N₂Protection of4-phenylaniline (1.69g, 10mmol), tert-butyl nitrite (1.54g, 15mmol) and anhydrous CuSO were added successively₄(0.32g, 2mmol), heating to 70 ℃ under sealed conditions, stirring at constant temperature for 12h, fully reacting, cooling to room temperature, extracting the reaction solution with a mixture of dichloromethane and water for 3 times, separating to obtain an organic layer, drying with anhydrous sodium sulfate, and distilling under reduced pressure to remove the solvent. The crude product was isolated via column chromatography (eluent ethyl acetate and petroleum ether) to give the 4-phenyl-1-trifluoromethylsulfanylbenzene product in 58% yield.

Process for preparing 4-phenyl-1-trifluoromethylsulfanyl benzene¹The H NMR is shown in figure 1, 4-phenyl-1-trifluoromethylsulfanyl benzene¹⁹F NMR is shown in FIG. 2.

¹H NMR(500MHz,CDCl₃)δ7.71(d,J＝8.2Hz,2H),7.62(d,J＝8.3Hz,2H),7.58(d,J＝7.8Hz,2H),7.46(t,J＝7.6Hz,2H),7.39(t,J＝7.3Hz,1H).

¹⁹F NMR(470MHz,CDCl₃)δ-42.08(s).。

Example 2

In N₂Adding diphenyl phosphorus chloride (2.20g, 10mmol) and sodium trifluoromethanesulfonate (1.56g,10mmol) under protection, adding 20mL of CeCN, stirring at room temperature for 30min under sealed condition, and adding N₂4-Cyclohexylaniline (1.69g, 10mmol), tert-butyl nitrite (1.54g, 15mmol) and anhydrous CuSO were added in this order under protection₄(0.32g, 2mmol), heating to 70 ℃ under sealed conditions, stirring at constant temperature for 12h, fully reacting, cooling to room temperature, extracting the reaction solution with a mixture of dichloromethane and water for 3 times, separating to obtain an organic layer, drying with anhydrous sodium sulfate, and distilling under reduced pressure to remove the solvent. The crude product was isolated via column chromatography (eluent ethyl acetate and petroleum ether) to give the 4-cyclohexyl-1-trifluoromethylsulfanylbenzene product in 65% yield.

Process for preparing 4-cyclohexyl-1-trifluoromethylsulfanyl benzene¹H NMR is shown in FIG. 3, 4-cyclohexyl-1-trifluoromethylsulfanyl benzene¹⁹F NMR is shown in FIG. 4.

¹H NMR(500MHz,CDCl₃)δ7.57(d,J＝8.0Hz,2H),7.26(d,J＝8.0Hz,2H),2.54(s,1H),1.88(d,J＝8.9Hz,4H),1.41(t,J＝10.6Hz,4H),1.27(s,2H).

¹⁹F NMR(470MHz,CDCl₃)δ-42.40(s).。

Example 3

In N₂Adding diphenyl phosphorus chloride (2.20g, 10mmol) and sodium trifluoromethanesulfonate (1.56g,10mmol) under protection, adding 20mL of CeCN, stirring at room temperature for 30min under sealed condition, and adding N₂Under protection, 4-cyanoaniline (1.69g, 10mmol), tert-butyl nitrite (1.54g, 15mmol) and anhydrous CuSO were added in sequence₄(0.32g, 2mmol), heating to 70 ℃ under sealed conditions, stirring at constant temperature for 12h, fully reacting, cooling to room temperature, extracting the reaction solution with a mixture of dichloromethane and water for 3 times, separating to obtain an organic layer, drying with anhydrous sodium sulfate, and distilling under reduced pressure to remove the solvent. The crude product was isolated via column chromatography (eluent ethyl acetate and petroleum ether) to give the 4-cyano-1-trifluoromethylsulfanyl benzene product in 55% yield.

Process for preparing 4-cyano-1-trifluoromethylthio group¹H NMR is shown in FIG. 5, for 4-cyano-1-trifluoromethylthio¹⁹F NMR is shown in FIG. 6.

¹H NMR(500MHz,CDCl₃)δ7.77(d,J＝8.2Hz,2H),7.72(d,J＝8.1Hz,2H).

¹⁹F NMR(470MHz,CDCl₃)δ-40.82(s).。

The above embodiments do not limit the present invention in any way, and all technical solutions obtained by means of equivalent substitution or equivalent transformation fall within the protection scope of the present invention.

Claims

1. A method for synthesizing an aromatic hydrocarbon trifluoromethylthio compound, which is characterized by comprising the following steps:

reacting sodium trifluoromethanesulfonate A with diphenyl phosphorus chloride B at room temperature under the protection of argon, sequentially adding aniline compound C and tert-butyl nitrite D after reacting for a period of time, and simultaneously adding CuSO₄E is used as a catalyst, acetonitrile is used as a solvent, the reaction is fully carried out at the temperature of 70 +/-5 ℃, the reaction is cooled to room temperature after the reaction is finished, the extraction and the reduced pressure distillation are carried out, and the reaction mixture is separated and purified by column chromatography to obtain the aromatic hydrocarbon trifluoromethylthio groupCompound F

，

In the formulas C and F, R is any one of 4-phenyl, 4-cyclohexyl and 4-cyano.

2. The process of claim 1, wherein the molar ratio of sodium trifluoromethylsulfinate, diphenylphosphorus chloride, aniline compound and tert-butyl nitrite is 1: 1: 1:1.5.

3. The method of claim 1, wherein the CuSO is₄The amount of (B) is 20mol% based on the aniline compound.

4. The method of claim 1, wherein the reaction is carried out at room temperature for 30min or more.

5. The method of claim 1, wherein the reaction is carried out at 70 ± 5 ℃ for a sufficient time of 12 hours or more.