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Trifluoromethylation of trifluoromethyl aryl sulfonium salt to heterocyclic compound under metal trigger

A trifluoromethyl aryl, trifluoromethyl metal technology, applied in the field of trifluoromethylation, can solve the problems of high reaction temperature, strong UV initiation, poor reaction selectivity of trifluoromethylation, etc. Mild conditions and simple operation

Inactive Publication Date: 2011-02-16
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although they can achieve better results for non-heterocyclic systems, it is difficult to achieve trifluoromethylation for heteroatom-containing aromatic rings, especially nitrogen-containing aromatic rings.
Free radical-initiated trifluoromethylation is often rarely used due to its poor reaction selectivity, high reaction temperature or strong UV initiation energy

Method used

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  • Trifluoromethylation of trifluoromethyl aryl sulfonium salt to heterocyclic compound under metal trigger
  • Trifluoromethylation of trifluoromethyl aryl sulfonium salt to heterocyclic compound under metal trigger
  • Trifluoromethylation of trifluoromethyl aryl sulfonium salt to heterocyclic compound under metal trigger

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Experimental program
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Effect test

example 1

[0030] Example 1: preparation of

[0031] In a 2 mL sealed tube, mix 4-iodopyridine (20.5 mg, 0.1 mmol) and [Ph 2 SCF 3 ] + [OTf] -(Trifluoromethyldiphenylsulfonium salt, 81mg, 0.2mmol) was dissolved in DMF (1mL), copper powder (20mg, 0.3mmol) was added, and then sealed and reacted at 60°C for 11h. Yield of fluorine spectrum: 91%.

[0032] 19 F NMR (DMF): δ-65.4 (s, 3F). GC-MS (m / z): 147.0.

example 2

[0033] Example 2: preparation of

[0034] In a 2 mL sealed tube, mix 3-chloro-6-iodopyridazine (24 mg, 0.1 mmol) and [Ph 2 SCF 3 ] + [OTf] - (Trifluoromethyldiphenylsulfonium salt, 81mg, 0.2mmol) was dissolved in DMF (1mL), copper powder (20mg, 0.3mmol) was added, and the tube was locked for 11h at 60°C. Then the heating was stopped, and after the reaction liquid was cooled, it was diluted with diethyl ether (30 mL), and washed three times with water (3×10 mL). The ether layer was separated. Anhydrous Na 2 SO 4 After drying, evaporate to dryness under reduced pressure. The obtained crude product was separated by column chromatography (n-pentane: ether=5:1) to obtain the product (18 mg), yield: 98%.

[0035] 1 H NMR (CDCl 3 ): δ7.81(d, 1H), 7.74(d, 1H). 19 F NMR (CDCl 3 ): δ-66.5(s, 3F).

example 3

[0036] Example 3: preparation of

[0037] In a sealed 2 mL tube, mix 4-iodo-5-methyl-1-phenyl-1H-pyrazole (28.4 mg, 0.1 mmol) and [Ph 2 SCF 3 ] + [OTf] - (Trifluoromethyldiphenylsulfonium salt, 81mg, 0.2mmol) was dissolved in DMF (1mL), copper powder (20mg, 0.3mmol) was added, and the tube was locked for 11h at 60°C. Then the heating was stopped, and after the reaction liquid was cooled, it was diluted with diethyl ether (30 mL), and washed three times with water (3×10 mL). The ether layer was separated. Anhydrous Na 2 SO 4 Dry and evaporate to dryness under reduced pressure. The obtained crude product was separated by column chromatography (petroleum ether: ethyl acetate = 15:1) to obtain the product (21.6 mg), yield: 95%. 1 H NMR (CDCl 3 ): δ7.80(s, 1H), 7.50(m, 3H), 7.43(m, 2H), 2.41(s, 3H). 19 FNMR (CDCl 3 ): δ-56.6(s, 3F). 13 C NMR (CDCl 3 ): δ138.7, 137.7(q, J=2.9Hz), 129.3, 128.8, 125.6, 123.3(q, J=266Hz), 112.3(q, J=37.4Hz), 10.9.

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Abstract

The invention relates to a novel method for trifluoromethylating trifluoromethyl aryl sulfonium salt to a heterocyclic compound. The method comprises the following steps: the trifluoromethyl aryl sulfonium salt is reduced by metal to generate a trifluoromethyl metal compound, and reacts with the heterocyclic compound containing halogen; and a trifluoromethylated heterocyclic product is finally generated. The method is adopted for trifluoromethylating the heterocyclic compound, has simple operation and mild reacting condition, and can obtain a target product with nearly quantitative yield.

Description

technical field [0001] The invention relates to a novel method for trifluoromethylating aromatic heterocyclic compounds by trifluoromethyl aryl sulfonium salts under the trigger of reducing metals. technical background [0002] Aromatic heterocyclic compounds have attracted the attention of medicinal chemists and biochemists because of their strong biological activity. Most of the drugs currently known for clinical use contain heteroatoms. After the trifluoromethyl group is introduced into aromatic heterocyclic compounds, due to the special stability and strong lipophilicity of fluorine atoms, aromatic heterocyclic compounds show stronger biological activity (Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Wiley-VCH, 2004; Chem. Soc. Rev., 2008, 37, 320). Therefore, adopting a simple and effective method to prepare trifluoromethyl-substituted aromatic heterocyclic compounds is conducive to screening more highly active molecules. However, the trifluoro...

Claims

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Application Information

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IPC IPC(8): C07D233/64C07D249/08C07D471/04C07D263/56C07D213/26C07D235/10C07B39/00C07D237/12C07D295/205C07D209/10C07D231/12C07D513/04
Inventor 肖吉昌张成潘
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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