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, 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 N-(4-(di­(1-adamantyl)­phosphino)­phenyl)­morpholine (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-aminophenyl)­ethylamine 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.