Ionic-molecular organocatalysis enabling allylic amination reactions

Highlights•Synthesis of allylamines via ionic-molecular organocatalysis employing phosphines•Control of chemo-, regio-, and stereo-selectivity•Synthesis of pharmaceuticalsSummaryAllylic amines are ubiquitous structural motifs found in drugs, natural products, and medicinally relevant molecules. We report here an "ionic-molecular" organocatalysis as a viable substitute for the metal-dependent allylic amination reactions. Mechanistic highlights supported by 31P nuclear magnetic resonance, high-resolution mass spectrometry, and experimental studies highlight the prior covalent ligation of allylic alcohols via ionic catalysis coupled with nucleophilic phosphine catalysis, yielding allylamines via the SN2′-SN2′ (or SN1-SN2′) pathway. Implementation of this ionic-molecular catalysis in heterocyclic functionalizations (N-allylation) with excellent chemo- (N vs. O), regio- (linear vs. branch), and stereo-selectivity (E vs. Z) and active pharmaceutical ingredient (flunarizine, cinnarizine, and naftifine) synthesis has been successfully demonstrated. The inductively coupled plasma atomic emission spectroscopy analysis of employed catalysts (RuPhos and DPEPhos) and field-emission scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy of representative reactants and solvent (THF) ruled out any traces of transiting metals (Pd, Ni, Fe, Au) commonly employed for the generation of π-allyl metal intermediates, further validating the phenomenon of organocatalysis.Graphical abstract