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
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.
Topics & Concepts
Enantioselective synthesisBenzylamineChemistryIntramolecular forceLithium amideIsopropylAmideStereospecificityNucleophilic substitutionStereochemistryCombinatorial chemistryMedicinal chemistryOrganic chemistryCatalysisCoordination Chemistry and OrganometallicsAsymmetric Synthesis and CatalysisCatalytic C–H Functionalization Methods