Catalysts for the Amination of Heteroaryl and Aryl Halides
A R T I C L E S
the primary amines; (2) heteroaryl halides,11,12,15,17,19,24–32 which
are important for medicinal chemistry applications, but have
reacted more slowly with narrower scope and with higher
catalyst loadings than aryl halides; and (3) aryl iodides, which
react more slowly and provide lower yields than aryl bromides
in couplings with amine nucleophiles,15,17,33–45 despite the higher
reactivity of aryl iodides in most other palladium-catalyzed
cross-coupling processes.46–49
Replacement of phosphine ligands in the catalyst by primary
amine nucleophiles or by heteroaryl substrates through a basic
heterocyclic nitrogen is one possible side reaction that limits
the lifetime of the catalyst. Ammonia,50 pyridine,50 and ben-
zylamine51 have been shown to displace the phosphine from
the arylpalladium(II) halide complex {Pd[P(o-tolyl)3](Ar)(Br)}2
(Ar ) p-tol, p-tBuC6H4).50 More recently, benzylamine and
pyridine have been shown to displace the phosphine from
Pd[P(tBu)3](Ar)(Br) (Ar ) o-tol, Ph) to form [Pd(pyridine)2(o-
tol)Br] and [Pd(PhCH2NH2)2(Ph)Br] and free ligand.52 Appar-
ently the high basicity of the alkylphosphine does not sufficiently
stabilize the Pd(II)-P bond toward the less hindered nitrogen
donors. These amine and pyridine complexes do not catalyze
the reactions of amines with aryl chlorides. Therefore, a more
reactive catalyst for the coupling of primary amines or heteroaryl
halides might contain a bisphosphine ligand that (1) binds the
metal strongly enough to prevent the ligand replacement and
(2) has the properties to promote oxidative addition and
reductive elimination.
The Josiphos ligand with one di-tert-butylphosphino and one
dicyclohexylphosphino group (CyPF-tBu)53 is now commer-
cially available, and the ligand is stable to air and moisture (vide
infra). The conformation of the backbone of this ligand is more
rigid than that of many other bisphosphines because the
orientation of the methyl group and the ferrocenyl group directs
the phosphorus electron pairs toward the metal center. Thus,
we considered that the combination of the severe steric
hindrance, conformational preferences of the backbone and
strong electron donation of this Josiphos ligand could create a
catalyst for the amination of heteroaryl halides that would be
reactive, but also long-lived.36,54
In a preliminary communication,52 we showed that the
complex generated from this ligand coupled primary nitrogen
nucleophiles with heteroaryl and aryl chlorides with catalyst
loadings of only 10-100 ppm. Here, we report a broad range
of studies of C-N couplings catalyzed by a combination of
Pd(OAc)2 and CyPF-tBu. We show that the coupling occurs in
high yield and with high turnover numbers with alkylamines
and some arylamines. Comparisons of the activity of this catalyst
to that of catalysts containing monophosphines and carbenes
show the value of the Pd(OAc)2 and CyPF-tBu system for the
reactions of primary amines, and studies of derivatives of this
ligand illustrate the importance of the conformational rigidity
to obtain high activity.
2. Results and Discussion
2.1. Identification of Conditions for Coupling of Chloropyri-
dines with ppm-Levels of Palladium. To begin to assess the
activity of catalysts generated from a palladium precursor and
hindered Josiphos ligands, we focused on the challenging
reaction of the unactivated heteroaryl chloride 3-chloropyridine
with an unhindered primary amine. This reaction was studied
in the presence of catalysts containing equimolar amounts of
the Josphos ligand CyPF-tBu and a palladium precursor in a
variety of solvents, with different bases at various temperatures.
The yields of the desired N-octyl-3-aminopyridine were evalu-
ated after 10 h by GC analysis.
Reactions catalyzed by the complex generated from Pd(OAc)2
were much faster than those generated from Pd(dba)2 or
PdCl2(PhCN)2. The reaction catalyzed by the combination of
Pd(OAc)2 and CyPF-tBu was even complete after 1 h with only
0.05 mol % catalyst. We attribute this difference in reactivity
to the slow dissociation of dba from complexes of the type
(chelate)Pd(dba).55 Reactions in the presence of NaO-tBu
occurred in high yield, while reactions of this heteroaryl chloride
with weaker bases, such as Cs2CO3, K2CO3, and K3PO4, led to
no products or low conversions. (For reactions of more activated
aryl halides with the weaker bases see section 2.9.2.) Reactions
conducted with NaO-tBu as base in DME (dimethoxyethane)
were faster than those in toluene, THF, and 1,4-dioxane, but
the coupling reaction did occur in these relatively nonpolar,
aprotic solvents, and useful procedures for coupling reactions
in toluene were developed (vide infra). Reactions in other more
polar solvents, such as DMF and DMSO, formed only trace
amounts of the desired products.
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