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](2)/L1; L1 = N-(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, N,N-dialkylhydrazines, and cyclic primary alkylamines > unhindered electron-deficient primary anilines, alpha-branched acyclic primary alkylamines, hindered electron-rich primary anilines >> cyclic and acyclic secondary dialkylamines, secondary alkyl/aryl and diarylamines, alpha,alpha-branched primary alkylamines, and primary amides. The new isomeric ligand N-(4-(di(1-adamantyl)phosphino)phenyOmorpholine (p-Mor-DalPhos, L2) was prepared in 63% yield and was crystallographically characterized; the [Pd(cinnamyl)Cl](2)/L2 catalyst system exhibited divergent reactivity. Application of the reactivity trends established for [Pd(cinnamyl)Cl](2)/L1 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](2)/L1 and 4-chlorotoluene (affording 5a); the alternative regioisomer (5a') was obtained when using [Pd(cinnamyl)Cl](2)/L2. These observations are in keeping with coordination chemistry studies, whereby binding of 2-(4-aminophenypethylamine to the in situ generated [(L1)Pd(p-tolyl)](+) fragment occurred via the primary amine moiety, affording the crystallographically characterized adduct [(L1)Pd(p-tolyl)(NH2CH2CH2(4-C6H4NH2)]+OTf- (7) in 72% yield.