Free-radical hydroxymethylation of ketimines generated in situ: a one-pot multicomponent synthesis of β,β-disubstituted-β-aminoalcohols

We report how an acidic TiCl4-Zn/t-BuOOH system is able to promote the one-pot multicomponent synthesis of β,β-disubstituted-β-aminoalcohols via nucleophilic addition of a hydroxymethyl radical to activated ketimines generated in situ in methanol solvent. While ketimines are generally recognized as less reactive and less stable when compared with aldimines, Ti(IV) plays a key role in facilitating their formation and in enhancing their electrophilic character. As a consequence, the reaction occurs at room temperature and under non-anhydrous conditions in just 1 h, without requiring either the preformation of the ketimine or protection of the amino group. The scope of the reaction is widely explored and a possible mechanism is discussed.