BippyPhos: A Single Ligand With Unprecedented Scope in the Buchwald- Hartwig Amination of (Hetero)aryl Chlorides

Reaction Scheme


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, ?-branched acyclic primary alkylamines, hindered electron-rich primary anilines > cyclic and acyclic secondary dialkylamines, secondary alkyl/aryl and diarylamines, ?,?-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.



In an inert atmosphere glovebox, [Pd(cinnamyl)Cl]2 (1 mol % Pd, from a toluene stock solution) and Mor-DalPhos (L1, 2 mol %) were combined, along with sufficient toluene so as to create a 0.5 M solution of the aryl chloride in the final reaction solution. This mixture was added to a vial containing a stir bar and NaOtBu (67 mg, 0.70 mmol). The vial was sealed with a cap containing a PTFE septum and removed from the glovebox. 3-Chloroaniline (53 uL, 0.50 mmol) and (3,5-dimethylphenyl)amine (69 uL, 0.55 mmol) were added via microlitre syringe. The reaction was heated at 110 �C for 16 h (unoptimized) and the consumption of the aryl chloride was confirmed by use of GC methods. The reaction mixture was then cooled, opened to air, filtered through a layer of neutral alumina and the alumina was then washed with dichloromethane (15 mL). Following removal of solvent from the combined eluent, the crude product was purified via column chromatography on silica (4:1 hex/ EtOAc), affording N-(3,5-dimethylphenyl)benzene-1,3-diamine (4a) as a brown oil in 60% isolated yield (64 mg, 0.30 mmol).



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