10.1021/jo202358p.s002 Bennett J. Tardiff Bennett J. Tardiff Robert McDonald Robert McDonald Michael J. Ferguson Michael J. Ferguson Mark Stradiotto Mark Stradiotto Rational and Predictable Chemoselective Synthesis of Oligoamines via Buchwald–Hartwig Amination of (Hetero)Aryl Chlorides Employing Mor-DalPhos American Chemical Society 2012 Preferential arylation tri aminophenyl alkylamine position Competition reactions Pd crystallographically catalyst system chemoselective synthesis coordination chemistry studies tetraamine Predictable Chemoselective Synthesis cyclic Buchwald aniline amine moiety reactivity trends acyclic 2012-01-20 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Rational_and_Predictable_Chemoselective_Synthesis_of_Oligoamines_via_Buchwald_Hartwig_Amination_of_Hetero_Aryl_Chlorides_Employing_Mor_DalPhos/2557546 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.