of catalyst (entries 1 and 11). In all cases with this substrate
combination, yields exceeded 95%. Reactions to form
sterically hindered diarylamines also occurred in short
reaction times at room temperature. 2-Chlorotoluene reacted
with 2,6-dimethylaniline (entry 9) in only 4 h at room
temperature with 1 mol % of catalyst. It should be noted,
however, that sterically hindered secondary amines, such as
diphenylamine and dicyclohexylamine (not shown), did not
provide coupling products, even at higher catalyst loadings
(2 mol %) and higher temperatures (70 °C).
Scheme 1. Proposed Catalytic Cycle for Amination Reaction
Reactions of acyclic secondary amines and less hindered
anilines occurred at room temperature using 2 mol % of
catalyst with rates that were comparable to those with tert-
butylphosphine ligands. Dibutylamine and N-methylaniline
reacted with 4- and 2-chlorotoluene, respectively (entries 2
and 8), to form the coupled product in 86-97% yield, and
aniline reacted with 4-chlorotoluene in 82% yield (entry 4).
N-Methylaniline reacted with the activated aryl chloride,
4-chlorobenzonitrile, in only 3 h with 1 mol % of catalyst
(entry 10).
This catalyst system was less effective for reactions of
primary alkylamines with aryl chlorides than others reported
previously (entry 3).8,16 Reaction rates were slower, and
substantial amounts of hydrodehalogenation product were
observed. Even aryl chlorides with ortho substituents reacted
poorly, resulting in low conversion of the coupled product.
For this class of amine, Nolan’s unsaturated imidazolium
ligand and hindered phosphine ligands appear to be more
favorable, although not ideal.
temperatures are roughly 80 °C lower than those for reactions
involving sterically hindered monophosphines as ligands.8b
Thus, it appears that the strong binding of the carbene ligands
to the metal center27 prevents competitive inhibition by the
pyridine substrates. Benzophenone imine, which might also
compete with a monodentate ligand for coordination to
palladium, also reacted to give good yields of coupled
product; at 55 °C complete conversion occurred after 18 h
using 2 mol % of catalyst. This reaction is also milder than
those involving sterically hindered monophosphines.8b
Although drybox procedures were used for the substrates
examined in Table 1, a drybox is not required to successfully
perform these reactions. In one set of experiments all of the
solid components (1 mol % of Pd(dba)2, 1 mol % of 1, and
2.0 equiv of NaO-t-Bu) were weighed in air. In these
experiments an additional half equivalent of alkoxide was
used in case quenching of the base occurred due to
adventitious moisture. The reaction flask was then evacuated
and placed under an atmosphere of N2. Aryl chloride, reagent
grade DME (Aldrich), and amine were then added without
degassing from bottles stored in air. Under these conditions,
the coupling of morpholine with 4-chlorotoluene gave a 95%
isolated yield, which was indistinguishable from that ob-
served when drybox procedures were used.
Arylpiperazines are an important class of medicinal
compound and have been prepared using the palladium-
catalyzed amination reaction with primarily aryl bromides
and iodides as coupling partners.4,23 One reaction of an aryl
chloride was reported by Koie et al. using P(t-Bu)3/Pd(dba)2
as catalyst resulting in an 88% conversion by GC analysis.4
Using the carbene system, 4-chlorotoluene coupled with
piperazine to form the N-aryl product in moderate yield (entry
6); higher temperatures than those used for dialkyl monoam-
ines were necessary.
Coupling of bromopyridines using aryl bisphosphines has
been reported,24 and the reaction of bromopyridines using
tert-butyl monophosphines has been accomplished.4 How-
ever, when monophosphines are used, the reaction of pyridine
substrates is typically slower than reactions using simple
aromatic substrates.8b The pyridine substrate may compete
with the phosphine for coordination to palladium,25,26 thereby
inhibiting the coupling reactions. Thus, the activity of the
palladium/carbene catalyst for reactions of chloropyridines
is remarkable (entries 12 and 13). Morpholine reacted with
2-chloropyridine in only 3 h at room temperature with 1 mol
% of catalyst. Reaction with the less electron deficient
3-chloropyridine also occurred at room temperature, this time
after 20 h when using 2 mol % of catalyst. These reaction
The fast reaction rates for this catalyst system led us to
determine the activity at higher temperatures with a lower
catalyst loading. When using 0.02 mol % of catalyst and
0.08 mol % of 1, reactions of morpholine with chlorotoluene
occurred in essentially quantitative yields after 7 h at 100
°C. This reaction provides 5000 turnovers. At this catalyst
loading, the catalyst cost is roughly one tenth the cost of the
other reaction components, even with these structurally
simple reagents. In fact, the alkoxide is the most expensive
reaction component when this catalyst loading is used. The
value of a system that would display higher turnover numbers
for this class of amination reaction is limited, unless it
provides similar activity with a less costly base.
(23) Zhao, S.; Miller, A. K.; Berger, J.; Flippin, L. A. Tetrahedron Lett.
1996, 37, 4463.
(24) Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1996, 61, 7240
(25) Paul, F.; Patt, J.; Hartwig, J. F. Organometallics 1995, 14, 3030.
(26) Widenhoefer, R. A.; Zhong, H. A.; Buchwald, S. L. Organometallics
1996, 15, 2745.
(27) Huang, J. K.; Schanz, H. J.; Stevens, E. D.; Nolan, S. P.
Organometallics 1999, 18, 2370.
Org. Lett., Vol. 2, No. 10, 2000
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