Rational and Predictable Chemoselective Synthesis of Oligoamines via Buchwald–Hartwig Amination of (Hetero)Aryl Chlorides Employing Mor-DalPhos

We report a diverse demonstration of synthetically useful chemoselectivity in the synthesis of di-, tri-, and tetraamines (62 examples) by use of Buchwald–Hartwig amination employing a single catalyst system ([Pd­(cinnamyl)­Cl]<sub>2</sub>/<b>L1</b>; <b>L1</b> = <i>N</i>-(2-(di­(1-adamantyl)­phosphino)­phenyl)­morpholine, Mor-DalPhos). Competition reactions established the following relative preference of this catalyst system for amine coupling partners: linear primary alkylamines and imines > unhindered electron-rich primary anilines, primary hydrazones, <i>N</i>,<i>N</i>-dialkylhydrazines, and cyclic primary alkylamines > unhindered electron-deficient primary anilines, α-branched acyclic primary alkylamines, hindered electron-rich primary anilines ≫ cyclic and acyclic secondary dialkylamines, secondary alkyl/aryl and diarylamines, α,α-branched primary alkylamines, and primary amides. The new isomeric ligand <i>N</i>-(4-(di­(1-adamantyl)­phosphino)­phenyl)­morpholine (<i>p</i>-Mor-DalPhos, <b>L2</b>) was prepared in 63% yield and was crystallographically characterized; the [Pd­(cinnamyl)­Cl]<sub>2</sub>/<b>L2</b> catalyst system exhibited divergent reactivity. Application of the reactivity trends established for [Pd­(cinnamyl)­Cl]<sub>2</sub>/<b>L1</b> toward the chemoselective synthesis of di-, tri-, and tetraamines was achieved. Preferential arylation was observed at the primary alkylamine position within 2-(4-aminophenyl)­ethylamine with [Pd­(cinnamyl)­Cl]<sub>2</sub>/<b>L1</b> and 4-chlorotoluene (affording <b>5a</b>); the alternative regioisomer (<b>5a′</b>) was obtained when using [Pd­(cinnamyl)­Cl]<sub>2</sub>/<b>L2</b>. These observations are in keeping with coordination chemistry studies, whereby binding of 2-(4-aminophenyl)­ethylamine to the in situ generated [(<b>L1</b>)­Pd­(<i>p</i>-tolyl)]<sup>+</sup> fragment occurred via the primary amine moiety, affording the crystallographically characterized adduct [(<b>L1</b>)­Pd­(<i>p</i>-tolyl)­(<i>N</i>H<sub>2</sub>CH<sub>2</sub>CH<sub>2</sub>(4-C<sub>6</sub>H<sub>4</sub>NH<sub>2</sub>)]<sup>+</sup>OTf<sup>–</sup> (<b>7</b>) in 72% yield.