Trifluoroacetic acid in 2,2,2-trifluoroethanol facilitates SNAr reactions of heterocycles with arylamines

Benoit Carbain, Christopher R. Coxon, Honorine Lebraud, Kristopher J. Elliott, Christopher J. Matheson, Elisa Meschini, Amy R. Roberts, David M. Turner, Christopher Wong, Céline Cano, Roger J. Griffin, Ian R. Hardcastle, Bernard T. Golding

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

Small-molecule drug discovery requires reliable synthetic methods for attaching amino compounds to heterocyclic scaffolds. Trifluoroacetic acid-2,2,2-trifluoroethanol (TFA-TFE) is as an effective combination for achieving SNAr reactions between anilines and heterocycles (e.g., purines and pyrimidines) substituted with a leaving group (fluoro-, chloro-, bromo- or alkylsulfonyl). This method provides a variety of compounds containing a "kinase-privileged fragment" associated with potent inhibition of kinases. TFE is an advantageous solvent because of its low nucleophilicity, ease of removal and ability to solubilise polar substrates. Furthermore, TFE may assist the breakdown of the Meisenheimer-Jackson intermediate by solvating the leaving group. TFA is a necessary and effective acidic catalyst, which activates the heterocycle by N-protonation without deactivating the aniline by conversion into an anilinium species. The TFA-TFE methodology is compatible with a variety of functional groups and complements organometallic alternatives, which are often disadvantageous because of the expense of reagents, the frequent need to explore diverse sets of reaction conditions, and problems with product purification. In contrast, product isolation from TFA-TFE reactions is straightforward: evaporation of the reaction mixture, basification and chromatography affords analytically pure material. A total of 45 examples are described with seven discrete heterocyclic scaffolds and 2-, 3- and 4-substituted anilines giving product yields that are normally in the range 50-90 %. Reactions can be performed with either conventional heating or microwave irradiation, with the latter often giving improved yields.

Original languageEnglish
Pages (from-to)2311-2317
Number of pages7
JournalChemistry - A European Journal
Volume20
Issue number8
DOIs
Publication statusPublished - 17 Feb 2014

Keywords

  • catalysis
  • heterocyclic drugs
  • synthetic methods
  • trifluoroethanol

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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