Enantioselective Intramolecular α-Arylation of Benzylamine Derivatives: Synthesis of a Precursor to Levocetirizine

Rakesh K. Saunthwal*, Maria Schwarz, Rajendra K. Mallick, William Terry-Wright, Jonathan Clayden*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

7 Citations (Scopus)
35 Downloads (Pure)

Abstract

A practical, transition metal-free method allows the enantioselective synthesis of α,α-diarylmethylamines by asymmetric α-arylation of benzylamines. Enantioselective lithiation of N′-aryl-N-benzyl-N-isopropyl ureas using a chiral lithium amide base generates a benzyllithium that undergoes an unactivated stereospecific intramolecular nucleophilic aromatic substitution to generate an α,α-diarylmethylamine in the form of its urea derivative, in up to >99 % ee. Treatment with acid induces an “azatropic shift” with retention of configuration, the product of which may be hydrolysed to the target amine.

Original languageEnglish
Article numbere202216758
JournalAngewandte Chemie - International Edition
Volume62
Issue number14
Early online date25 Jan 2023
DOIs
Publication statusPublished - 27 Mar 2023

Bibliographical note

Funding Information:
Financial support was provided by the EU through Marie Sklodowska Curie fellowships 839739 (COOPCAT) and 101023251 (PHOTOLITH), the ERC through Advanced Grant 883786 (DOGMATRON), and the Royal Society of Chemistry for an Undergraduate Research Bursary (to WTW).

Publisher Copyright:
© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.

Keywords

  • Arylation
  • Benzylamine
  • Chiral Lithium Amide
  • Enantioselective
  • Levocetirizine

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