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Trifluoroacetic Acid in 2,2,2-Trifluoroethanol Facilitates S_NAr Reactions of Heterocycles with Arylamines

Lookup NU author(s): Dr Benoit Carbain, Christopher Coxon, Honorine Lebraud, Dr Kris Elliott, Christopher Matheson, Elisa Meschini, Dr Amy Roberts, David Turner, Dr Christopher Wong, Dr Celine CanoORCiD, Professor Roger Griffin, Dr Ian HardcastleORCiD, Emeritus Professor Bernard Golding

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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.

Publication metadata

Author(s): Carbain B, Coxon CR, Lebraud H, Elliott KJ, Matheson CJ, Meschini E, Roberts AR, Turner DM, Wong C, Cano C, Griffin RJ, Hardcastle IR, Golding BT

Publication type: Article

Publication status: Published

Journal: Chemistry: A European Journal

Year: 2014

Volume: 20

Issue: 8

Pages: 2311-2317

Print publication date: 17/02/2014

Online publication date: 23/01/2014

Acceptance date: 05/11/2013

ISSN (print): 0947-6539

ISSN (electronic): 1521-3765

Publisher: Wiley-VCH Verlag GmbH & Co. KGaA

URL: http://dx.doi.org/10.1002/chem.201304336

DOI: 10.1002/chem.201304336

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