Highly reactive, general and long-lived catalysts for palladium-catalyzed amination of heteroaryl and aryl chlorides, bromides, and iodides: Scope and structure-activity relationships

Article abstract of DOI:10.1021/ja077074w

We describe a systematic study of the scope and relationship between ligand structure and activity for a highly efficient and selective class of catalysts containing sterically hindered chelating alkylphosphines for the amination of heteroaryl and aryl chlorides, bromides, and iodides. In the presence of this catalyst, aryl and heteroaryl chlorides, bromides, and iodides react with many primary amines in high yields with part-per-million quantities of palladium precursor and ligand. Many reactions of primary amines with both heteroaryl and aryl chlorides, bromides, and iodides occur to completion with 0.0005-0.05 mol % catalyst. A comparison of the reactivity of this catalyst for the coupling of primary amines at these loadings is made with catalysts generated from hindered monophosphines and carbenes, and these data illustrate the benefits of chelation. Studies on structural variants of the most active catalyst indicate that a rigid backbone in the bidentate structure, strong electron donation, and severe hindrance all contribute to its high reactivity. Thus, these complexes constitute a fourth-generation catalyst for the amination of aryl halides, whose activity complements catalysts based on monophosphines and carbenes.

Full text of DOI:10.1021/ja077074w

Published on Web 04/30/2008
Highly Reactive, General and Long-Lived Catalysts for
Palladium-Catalyzed Amination of Heteroaryl and Aryl
Chlorides, Bromides, and Iodides: Scope and
Structure–Activity Relationships
Qilong Shen, Tokutaro Ogata, and John F. Hartwig*
Department of Chemistry, Yale UniVersity, P.O. Box 208107, New HaVen,
Connecticut 06520-8107, and Department of Chemistry, UniVersity of Illinois, 600 South
Mathews AVenue, Urbana, Illinois 61801
Received September 12, 2007; E-mail: jhartwig@uiuc.edu
Abstract: We describe a systematic study of the scope and relationship between ligand structure and
activity for a highly efficient and selective class of catalysts containing sterically hindered chelating
alkylphosphines for the amination of heteroaryl and aryl chlorides, bromides, and iodides. In the presence
of this catalyst, aryl and heteroaryl chlorides, bromides, and iodides react with many primary amines in
high yields with part-per-million quantities of palladium precursor and ligand. Many reactions of primary
amines with both heteroaryl and aryl chlorides, bromides, and iodides occur to completion with 0.0005–0.05
mol % catalyst. A comparison of the reactivity of this catalyst for the coupling of primary amines at these
loadings is made with catalysts generated from hindered monophosphines and carbenes, and these data
illustrate the benefits of chelation. Studies on structural variants of the most active catalyst indicate that a
rigid backbone in the bidentate structure, strong electron donation, and severe hindrance all contribute to
its high reactivity. Thus, these complexes constitute a fourth-generation catalyst for the amination of aryl
halides, whose activity complements catalysts based on monophosphines and carbenes.
1. Introduction
The palladium-catalyzed cross-coupling of amines with aryl
halides has become a principal method for the formation of C-N
bonds at aromatic systems (eq 1).1–5 In the past 10 years,
extensive efforts from different groups have led to the discovery
of a variety of catalysts that are capable of coupling a wide
scope of amines with aryl halides under mild reaction conditions.
However, previously reported catalyst loadings for this trans-
formation were often higher than are needed to make the large-
scale synthesis of pharmaceutical intermediates or other bulk
fine chemicals (>0.1 mol %) economical and to make the
removal of palladium from the final product simple to conduct.
These factors have limited the use of the coupling of amines to
produce less expensive intermediates and commodity building
blocks.6,7
Three general classes of reagents react slowly and require
high loading of catalyst, even with most of the most recently
developed systems:8 (1) primary alkylamines,9–23 which form
substantial amounts of product from diarylation in the absence
of an ortho substituent on the haloarene reagent or an excess of
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9
6586 J. AM. CHEM. SOC. 2008, 130, 6586–6596
10.1021/ja077074w CCC: $40.75
2008 American Chemical Society

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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Studies to determine the efficiency of the catalyst showed
that the reactions of 3-chloropyridine with octylamine in DME
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A R T I C L E S
Shen et al.
Table 1. Coupling of Heteroaryl Halides with Primary Alkylamines Catalyzed by Pd(OAc)2 and CyPF-tBu (1:1)a
entry
Ar
X
R
cat. (%)
conditions
yield (%)b
1
2
3
4
5
6
7
8
2-Py
Cl
Br
I
Cl
Br
Cl
Br
I
Cl
Cl
Cl
Cl
Br
Cl
Br
Br
I
octyl
octyl
octyl
Bn
0.001
0.0005
0.005
0.001
0.0005
0.01
0.005
0.05
0.05
0.005
0.005
0.005
0.005
0.01
0.005
0.005
0.05
0.01
0.05
1.0
0.05
0.01
0.005
0.05
1.0
0.005
0.05
100 °C, 48 h
110 °C, 12 h
110 °C, 12 h
100 °C, 10 h
110 °C, 12 h
70 °C, 12 h
60 °C, 12 h
110 °C, 12 h
100 °C, 24 h
90 °C, 24 h
90 °C, 24 h
100 °C, 24 h
100 °C, 36 h
100 °C, 24 h
100 °C, 48 h
100 °C, 48 h
100 °C, 12 h
100 °C, 48 h
100 °C, 12 h
70 °C, 16 h
100 °C, 24 h
90 °C, 24 h
100 °C, 36 h
100 °C, 48 h
70 °C, 10 h
100 °C, 16 h
100 °C, 36 h
100 °C, 48 h
100 °C, 48 h
90 °C, 15 h
100 °C, 36 h
86
84
96
85
83
98
96
98
99
96
93
99
99
95
99
93
96
79
78
67
91
83
93
80
75
82
83
80
60
91
93
Bn
cyclohexyl
cyclohexyl
sBu
9d
10
11
12c
13
14
15
16
17
18
19
20
21d
22
23
24
25
26
27
28e
29
30
31
1- methylbenzylf
octyl
3-Me-2-Py
3-Py
octyl
octyl
octyl
Bn
Bn
sBu
iBu
Cl
I
cyclohexyl
cyclohexyl
tBu
Cl
Cl
Cl
Br
I
Cl
Cl
I
Br
Cl
Cl
Br
1- methylbenzylg
octyl
4-Py
octyl
octyl
PhC(O)-
octyl
octyl
cyclohexyl
cyclohexyl
octyl
2-pyrazinyl
1,3-pyrimidyl-5-
3-quinolinyl
1-iso-quinolinyl
4-iso-quinolinyl
1.0
0.01
0.005
0.005
octyl
a Reactions conducted with a 1:1 ratio of metal to ligand, 1 mmol aryl halide, 1.2 equiv amine, and 1.4 equiv NaO-tBu in 1 mL DME. b Isolated
yield. c Reaction performed without using a drybox. d from phenethylamine that is stated to be 99% ee. e Using K3PO4 as the base. f 96% ee. g 95% ee.
occurred to completion after 24 h at 90 °C in 93% isolated yield
with only 50 ppm of catalyst. These data correspond to a
turnover number of 18,600. Reactions conducted with 10 ppm
of Pd(OAc)2 and ligand occurred to partial (65%) conversion
at 100 °C after 48 h. Reactions in toluene were slower but did
occur to completion after 24 h at 90 °C with 0.05 mol % of
catalyst and to 80% conversion with only 0.01 mol % catalyst.
It was important to mix the catalyst components before they
contacted the reagents or base. Although an effect of premixing
the catalyst has been noted previously,56 it is particularly
important in the current work because the concentrations of
catalyst and ligand are so low. At such low concentrations, the
rate of complexation of the ligand to palladium is expected to
be slow. Without pre-forming the complex, Pd(OAc)2 would
be expected to decompose in the presence of amine and base
to form palladium black. Thus, the reactions were conducted
by first mixing 1.0 M solutions of Pd(OAc)2 and CyPF-tBu
without any added reagents or base. This solution was then
diluted, and a portion of the solution was added to the haloarene
and base in DME prior to addition of amine.
2.2. Scope of the Amination of Heteroaryl and Aryl Chlo-
rides, Bromides, and Iodides with Primary Alkylamines. Reac-
tions of heteroaryl chlorides, bromides, and iodides with primary
alkylamines are summarized in Table 1. The reaction conditions
optimized for the amination of aryl chlorides were also effective
for the amination of aryl bromides and iodides. Generally, the
rates for amination of heteroaryl bromides were slightly faster
than those for amination of heteroaryl chlorides, and equal or
slightly lower loadings of catalyst could be used. In contrast,
the rates for amination of heteroaryl iodides were slower than
those for amination of heteroaryl bromides and more catalyst
was needed, but reactions of aryl iodides occurred with much
greater efficiency than with previous catalysts33,36,38,41 and with
sufficient scope and efficiency to create a useful process.
Pyridyl chlorides, bromides, and iodides bearing the halogen
in the 2, 3, or 4-position underwent reaction with a variety of
primary alkylamines in high yield with loadings of catalyst
between 5 and 500 ppm (Table 1, entries 1–19, 21–24, and
26–31). For example, the reaction of octylamine with 2-bro-
mopyridine occurred with only 5 ppm of the catalyst at 60 °C
for 48 h to afford 98% of the product (Table 1, entry 2). These
results correspond to a turnover number of 196,000, which is
the highest turnover number observed for any palladium-
catalyzed amination of an aryl halide. The average turnover
frequency is roughly 4000/h. The analogous process with
chloride and iodide leaving groups occurred in high yield (entries
1 and 3). Other comparative data in this table consistently show
that the yield and turnover numbers are as high or higher for
reactions of aryl bromides as for aryl chlorides, and that high
yields are obtained for reactions of aryl iodides with only 5–10
times more catalyst. Not only reactions of pyridyl halides, but
reactions of quinolinyl, isoquinolinyl and pyrazyl chlorides,
bromides, and iodides occurred in high yield with catalyst
loadings (Table 1, entries 26–27 and 29–31) that are nearly 2
(56) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1144.
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Catalysts for the Amination of Heteroaryl and Aryl Halides
A R T I C L E S
to 3 orders of magnitude lower than those reported for the
reaction of pyridyl halides with any primary amine.12 As one
comparison, the coupling of benzylamine with 2-chloropyridine
occurred in 85% yield with only 10 ppm of the catalyst,
corresponding to a turnover number of 85,000 (Table 1, entry
4), whereas the same reaction conducted with 2-(di-tert-
butylphosphino)biphenyl occurred with 196 turnovers.12
conducted at temperatures closer to 150 °C.62 Nucleophilic
substitution of 3-choropyridines are often 104-105 slower than
those of 2- and 4-chloropyridines,63–65 and we obtained less
than 10% product from the uncatalyzed reaction of 3-chloro-
pyridine with octylamine in DME and less than 20% from the
uncatalyzed reaction in DMSO after 24 h at 110 °C.
2.3. Comparison to the Amination of Heteroaryl Chlo-
rides Catalyzed by Complexes of CyPF-tBu to Reactions Cata-
lyzed by Complexes of Xphos And SIPr. Palladium catalysts
based on dialkylphosphinobiaryl ligands developed by Buchwald
and co-workers are highly active for the coupling of amines
with aryl halides.12,13,32 Recently, this group compared the two
catalyst systems for the reaction of hexylamine with 4-chlo-
rophenol,32 in part, to assess the importance of chelation on
the amination of heteroaryl systems. This reaction conducted
with the catalyst based on Xphos occurred with faster rates and
in higher yield than the one we reported using CyPF-tBu as
ligand. However, this example required the highest catalyst
loading of any of the reactions we published using CyPF-tBu,
and this work made no comparisons of catalyst lifetimes.
Our interest in the use of sterically hindered chelating ligands
for the C-N coupling has focused on identifying catalysts that
are reactive, but also long-lived.52 To address this issue more
specifically, we have now compared the yields and turnover
numbers for reactions of primary amines with 3-chloropyridine
using low loadings of several different catalysts. We previously
emphasized that palladium catalysts generated from N-hetero-
cyclic carbene ligands form N,N-dialkylaminopyridines from
secondary amines and halopyridines with high turnover num-
bers.11 Thus, we also tested reactions of primary amines with
3-chloropyridine using the allylpalladium halide adduct of this
ligand (NHC)Pd(R-allyl)Cl, which Nolan recently reported to
be an efficient catalyst for some combinations of aryl halides
and amines.31,66
The steric hindrance of the catalyst did not prohibit reactions
of more sterically hindered primary amines. tert-Butylamine
reacted in good yield with 3-chloropyridine (Table 1, entry 20),
although 1.0 mol % of palladium was needed. The reactions of
less hindered R-branched primary amines, such as cyclohexyl-
amine and sec-butylamine, occurred in high yield with only
0.005–0.05 mol % palladium (Table 1, entries 6–9, 16, 18–19,
21, and 29). This loading is more than an order of magnitude
lower than that of previous reactions of R-branched primary
amines with the corresponding haloarenes.
Enantiomerically enriched amines containing stereogenic
centers R to the nitrogen have been shown to undergo race-
mization in competition with cross-coupling when Pd(0) and
monodendate ligands, such as P(o-tolyl)3 or PPh3, were used
as the catalyst.57,58 This racemization is proposed to result from
reversible ꢀ-hydrogen elimination, which should occur more
readily from complexes containing monophosphine ligands than
from those containing bisphosphine ligands.59,60 Consistent with
this hypothesis, the coupling of 2- or 3-chloropyridine with
enantioenriched (99% ee) R-phenethylamine gave the heteroaryl-
amine products in high yield with >95% ee in the presence of
only 0.05 mol % of the catalyst (Table 1, entries 9 and 21).
In addition to the remarkable reactivity and stability of this
catalyst, it is highly chemoselective for monoarylation of
primary amines. Although noted above Table 1, it is important
to emphasize that no diarylation products were observed in any
case by GC/MS.
Table 2 provides a comparison of the activity and
selectivity of catalysts containing CyPF-tBu 1, the most
recently developed biaryl phosphine Xphos 2, and the catalyst
containing the SIPr carbene 3 for the reaction of 3-chloro-
pyridine with ocylamine. The data in this table correspond
to reactions under the reported optimal conditions for each
of the catalyst systems.12,66 Reaction of 3-chloropyridine with
1.2 equiv of octylamine in the presence of 0.005 mol % of
Pd(OAc)2/CyPF-tBu afforded a 92% yield of the N-octyl
aminopyridine with no side product from diarylation that
Finally, this coupling is not particularly sensitive to oxygen.
CyPF-tBu is air stable, both as a solid and in solution. Samples
left in air as solids or as solutions in toluene or DME for at
least 24 h were unchanged, as determined by 1H NMR and 31
P
NMR spectroscopy. Thus, reactions conducted with Pd(OAc)2
and CyPF-tBu can be assembled easily outside of a drybox.
Identical catalytic activity was observed for reactions performed
in a dry box or under inert atmosphere using common Schlenk
techniques. For example, the reaction of 3-chloropyridine with
octylamine assembled inside a drybox with 0.005 mol % of the
catalyst occurred in 95% yield, and the same reaction conducted
outside of a drybox using Schlenk techniques occurred in 99%
yield.
1
could be detected by GC/MS or H NMR spectroscopy. In
contrast, the reaction conducted with an order of magnitude
more catalyst from Xphos 2 (0.05 mol %) led to less than 40%
conversion. This reaction with 100–200 times more catalyst
(0.1–0.5 mol %) occurred to full conversion, but the selectivity
for monoarylation vs diarylation was only 2.4:1–2.6:1. Consis-
tent with the published work,12 reactions in DME were much
Considering that these heteroaryl systems are electron-poor,
the coupling reactions might occur, at least in part, by
uncatalyzed processes. Thus, reactions with and without catalyst
were conducted in parallel.61 Only reactions of quinolines and
isoquinolines generated any measurable quantity of products.
Conversions were below 40%, even at 100 °C for 48 h, in these
cases. Reactions of 2- and 4-chloropyridines occur more readily
in polar solvents or under high pressure, but are typically
(61) Control experiments without catalyst were conducted under reaction
conditions that were identical to those conducted with catalyst. A 10
µL aliquot was withdrawn from the reaction vial and analyzed for
conversion by GC.
(62) Giam, C. S. In Pyridine and Its DeriVatiVes; Abramovitch, R. A., Ed.;
John Wiley & Sons: New York, 1974; Vol. 3, pp 41.
(63) Hashimoto, S.; Otani, S.; Okamoto, T.; Matsumoto, K. Heterocycles
1988, 27, 319.
(57) Wagaw, S.; Rennels, R. A.; Buchwald, S. L. J. Am. Chem. Soc. 1997,
119, 8451.
(64) Miller, J., Ed. Aromatic Nucleophilic Substitution; Elsevier: Amster-
dam, 1968; Vol. 8.
(58) Catellani, M.; Catucci, C.; Celentano, G.; Ferraccioli, R. Synlett 2001,
6, 803.
(65) Vinter-Pasquier, K.; Jamart-Gregoire, B.; Caubere, P. Heterocycles
1997, 45, 2113.
(59) Hartwig, J. F.; Richards, S.; Baranano, D.; Paul, F. J. Am. Chem. Soc.
1996, 118, 3626.
(66) Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.; Nolan,
S. P. J. Am. Chem. Soc. 2006, 128, 4101.
(60) Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 7010.
9
J. AM. CHEM. SOC. VOL. 130, NO. 20, 2008 6589

A R T I C L E S
Shen et al.
Table 2. Comparison of the Activity of CyPF-tBu, Xphos, and SIPr for the Reactions of a Heteroaryl Chloride with a Primary Alkylaminea
entry
catalyst
loading
solvent
T [°C]b
t [h]
conversionc (%)
A/B
1
2
3
4
5
6
7
8
Pd(OAc)2/1
Pd(OAc)2/2
Pd(OAc)2/2
Pd(OAc)2/2
Pd(dba)2/2
Pd(OAc)2/2
Pd(OAc)2/2
Pd(dba)2/2
3
0.005
0.05
0.1
0.1
0.1
0.5
0.5
0.5
DME
90
90
90
90
90
90
90
90
24
24
24
24
24
12
24
12
24
48
12
100(92)
40
85(80)
14
47
88(81)
74
83
<10
58
100:0
5.4:1
2.4:1
-
4.8/1
2.6:1
4.1:1
3.0/1
-
toluene
toluene
DME
toluene
toluene
DME
toluene
DME
DME
9
10
11
0.005
0.05
0.5
110
110
110
3
3
>25:1
7.6:1
DME
100(71)
a The experiments were conducted with a 1:1 ratio of Pd/CyFP-tBu or 1:2 ratio of Pd/Xphos, 1 mmol 3-chloropyridine and 1.2 equiv of 1-octylamine,
and 1.4 equiv base in 1.0 mL of solvent. b Bath temperature. c Determined by 1H NMR analysis of the crude product. Isolated yields are indicated in
parentheses.
Table 3. Coupling of Aryl Halides with Primary Alkylamines
Catalyzed by Pd(OAc)2 and CyPF-tBu (1:1)a
slower than those in toluene. Reactions conducted with Pd-
(dba)2, instead of Pd(OAc)2, occurred with similar selectivity
(3.0:1–4.8:1).
Likewise, reactions of 3-chloropyridine with 1.2 equiv of
octylamine in the presence of 0.005 mol % (NHC)Pd(R-allyl)Cl
(3) occurred to less than 50% conversion. The same reaction in
the presence of a higher loading of (NHC)Pd(R-allyl)Cl occurred
to full conversion, but with moderate selectivity (7.6:1) for
formation of monoarylation vs diarylation products. The pub-
lished reactions were conducted with KO-tBu as base; in our
hands, these reactions were faster when conducted with NaO-
tBu as base, and the data from these faster reactions are reported
in Table 2.
These results demonstrate that catalysts generated from CyPF-
tBu ligand 1 are particularly effective for the coupling of
heteroaryl chlorides with primary alkylamines. In combination
with the previous data comparing different catalysts for the
reaction of 4-chlorophenol,32 our data also illustrate that different
catalysts possess different beneficial properties, and the optimal
catalyst often depends on the synthetic context.
2.4. Scope of the Amination of Aryl Chlorides, Bromides,
and Iodides with Primary Alkylamines. Reactions of aryl chlo-
rides, bromides, and iodides with primary alkylamines occurred
in high yield without changing the reaction conditions from that
of entry 11 in Table 1. The reactions of a series of aryl halides
with several primary alkylamines in the presence of NaOtBu
base and the catalyst generated from Pd(OAc)2 and CyPF-tBu
1 are summarized in Table 3. In general, high yields of coupled
products were formed from the amination of electron-deficient
and electron-neutral aryl halides when using only 10–500 ppm
of catalyst. Higher catalyst loadings (0.1–1.0 mol %) were
required to obtain high yields of products from the amination
of electron-rich aryl halides, but these reactions also occurred
in high yields.
entry
R1
X
R
cat. (%)
conditions
yield (%b
1
2
3
4
5
6
7
8
H
Cl cyclohexyl 0.05
Br cyclohexyl 0.01
Cl Bn
Br Bn
Cl octyl
Br octyl
100 °C, 36 h
100 °C, 24 h
99
96
99
97
98
99
96
94
83
90
75
81
87
82
92
67
99
92
98
99
99
94
97
95
97
98
97
0.005 100 °C, 48 h
0.001 100 °C, 36 h
0.01
0.005 100 °C, 36 h
0.05
2-Me
100 °C, 48 h
I
octyl
100 °C, 8 h
100 °C, 24 h
100 °C, 48 h
100 °C, 24 h
100 °C, 18 h
100 °C, 36 h
100 °C, 24 h
100 °C, 24 h
100 °C, 48 h
100 °C, 36 h
80 °C, 24 h
80 °C, 48 h
80 °C, 48 h
2-MeO
4-Me
Br cyclohexyl 0.05
9
Cl iBu
0.1
10c
11
12d
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Br iBu
0.05
0.05
0.02
0.05
0.5
0.1
1.0
0.005
I
I
iBu
iBu
Br sBu
I
sBu
Cl octyl
octyl
Cl iBu
4-MeO
4-cyano
3-MeO
I
Br cyclohexyl 0.005
Cl Bn 0.005
Bn
Br cyclohexyl 0.01
I
0.005 100 °C, 48 h
100 °C, 36 h
100 °C, 18 h
100 °C, 8 h
100 °C, 48 h
100 °C, 36 h
100 °C, 48 h
100 °C, 24 h
I
I
cyclohexyl 0.05
octyl
naphathyl
2-iPr
2,6-Di-Me Cl octyl
Br octyl
0.05
0.05
0.1
0.05
0.5
Br iBu
Br sBu
a Reactions conducted with a 1:1 ratio of metal to ligand 1 mmol
ArX (X ) Cl, Br, I), 1.2 equiv amine and 1.4 equiv NaO-tBu in 1 mL
DME. b Isolated yields. c 3.0 equiv of octylamine used. d Reaction with
5.5 g of 4-iodotoluene (25.0 mmol).
to completion in 97% and 99% isolated yield with only 10 and
50 ppm of catalyst (Table 3, entries 4 and 3), corresponding to
turnover numbers of 97,000 and 19,800. Reactions of several
other haloarenes occurred in similarly high yield with a similar
Reactions of linear primary amines were fast and occurred
in high yield with 0.005–0.1 mol % catalyst (Table 3, entries
3–7, 9–12, 19–20, and 23–24). For example, reaction of
benzylamine with bromobenzene and chlorobenzene occurred
9
6590 J. AM. CHEM. SOC. VOL. 130, NO. 20, 2008

Catalysts for the Amination of Heteroaryl and Aryl Halides
A R T I C L E S
Scheme 1. Comparison of the Reactivity of Aryl Chlorides vs Aryl
Bromides and Aryl Bromides vs Aryl Iodides in the Presence of
Pd(OAc)2 and CyPF-tBu (1:1)a
amount of catalyst. The maximum turnover numbers for the
reactions of primary alkylamines with aryl chlorides exceeded
those achieved previously for reactions of this type by nearly 2
orders of magnitude.12 They also exceeded the maximum
turnover numbers for the reactions of primary alkyl amines with
aryl bromides by nearly an order of magnitude.56
High yields were also obtained for reactions of aryl iodides
with linear primary amines in the presence of just 5–10 times
more catalyst than needed for reactions of aryl bromides and
chlorides. For instance, the reaction of octylamine with 2-bro-
motoluene and 2-iodotoluene occurred to completion with 0.005
mol % and 0.05 mol % of catalyst and formed the coupled
product in 99% and 96% yield, respectively (Table 3, entries 6
and 7). Reactions of several other iodoarenes occurred in
similarly high yield with similar amounts of catalyst. These
reactions exceeded the maximum turnover numbers for the
reactions of primary alkyl amines with aryl iodides by more
than an order of magnitude.35
Hindered, ortho-substituted aryl halides also reacted with
primary alkylamines with low catalyst loadings (Table 3, entries
5–8, and 24). For example, the reaction of 1-bromo-2-iso-
propylbenzene with iso-butylamine formed the coupled product
in 95% yield in DME after 48 h at 100 °C in the presence of
0.05 mol % catalyst, and the reaction of 2,6-disubstituted aryl
bromides and chlorides occurred with octylamine with only
0.05–0.1 mol % catalyst. However, reactions of 2,6-disubstituted
aryl bromides with R-branched primary alkylamines required a
higher 0.5 mol % catalyst (Table 3, entry 27) to occur in high
yield. The most hindered bromoarenes occurred with lower
loadings in the presence of catalysts generated from monodentate
ligands. Nolan reported that the reaction of benzylamine with
2,6-dimethyl-1-bromobenzene at 80 °C using just 0.001 mol %
of a carbene-ligated allyl-Pd complex occurred to form 88%
yield of coupled product.66 Reactions of less hindered bro-
moarenes and of aliphatic amines with palladium-carbene ctalysts
are either unreported66 or require loadings near 1 mol %.16
Reactions of R-branched primary amines were somewhat
slower and required more catalyst than those of linear primary
amines, but the required loadings remained lower than those
used previously. For example, the reaction of cyclohexylamine
with chlorobenzene occurred in high yield with 0.05 mol %
palladium (TON ) 1980) (Table 3, entry 2), and this loading
of catalyst is more than an order of magnitude lower than that
of previously reported reactions of R-branched primary amines
with chloroarenes.12 Reactions of the acyclic, R-branched sec-
butylamine occurred in high yield with 0.01–1.0 mol % of the
catalyst.
Like the coupling of primary amines with heteroaryl halides,
the coupling of primary amines with electron-poor or neutral
aryl halides occurred without the formation of diarylamines in
amounts detectable by GC/MS. Products from diarylation were
observed by GC/MS only for the reaction of octylamine with
chloroanisole and iodoanisole.12 However, the diarylation side-
product was reduced to 5% if an excess of octylamine (3.0
equiv) was used.
To develop a better understanding of the reactivity of the
aryl chlorides, bromides, and iodides, several competition ex-
periments were conducted that would reveal the origin of the
differences in relative rates. In the first experiment, equimolar
amounts of 4-bromotoluene and 4-chlorotoluene were allowed
to react with 1.0 equiv of octylamine in the presence of 0.01
mol % of the catalyst. As shown in Scheme 1, more than 95%
conversion of the bromide was observed after 10 h at 110 °C,
a
a Reagents and conditions: Isolated yield. i. 0.01 mol % Pd(OAc)2,
0.01 mol % CyPF-tBu, 1.4 equiv. NaO-tBu, DME, 100 °C, 10 h; ii. 0.005
mol % Pd(OAc)2, 0.005 mol % CyPF-tBu, 1.4 equiv. NaO-tBu, DME,
100 °C, 20 h; iii. 0.05 mol % Pd(OAc)2, 0.05 mol % CyPF-tBu, 1.4 equiv.
NaO-tBu, DME, 100 °C, 20 h; 0.5 mol % Pd(OAc)2, 0.5 mol % CyPF-tBu,
1.4 equiv NaO-tBu, DME, 100 °C, 20 h.
while less than 5% conversion of the chloride occurred. In a
separate experiment, the reaction of 1-bromo-4-chlorobenzene
with octylamine at 110 °C for 24 h occurred to full conversion
to afford N-octyl-4-chloroaniline in 95% yield. No N-octyl-4-
bromoaniline was detected by GC/MS. Thus, the catalyst
generated from Pd(OAc)2 and CyPF-tBu is highly reactive
toward chloroarenes, but it maintains the conventional high
selectivity for reaction of a bromoarene over a chloroarene.
Similar experiments showed that the aryl iodide functionality
was more reactive than the aryl bromide. Although this greater
reactivity of an iodoarene is typically observed for palladium-
catalyzed cross-coupling, the greater reactivity of aryl bromides
than aryl iodides toward primary amines in separate vessels with
the current catalyst made it unclear whether this order of
reactivity would be observed when the two halides were present
in the same system. Competition studies reveal an inhibitory
effect of the iodide.
In one experiment, equimolar amounts of 4-iodotoluene and
4-bromotoluene were allowed to react with 1.0 equiv of
octylamine in the presence of 0.05 mol % of the catalyst.
Although bromotoluene alone reacted to full conversion with
octylamine in much less than 20 h in the presence of 0.05%
catalyst, little bromotoluene reacted in the system containing
iodotoluene. As shown in Scheme 1, 66% conversion of the
iodide was observed after 20 h at 100 °C, while less than 6%
conversion of the bromide was observed. Likewise, the reaction
of 1-bromo-4-iodobenzene with octylamine at 110 °C for 20 h
with the same amount of catalyst occurred to 57% conversion
after 20 h at 100 °C, and N-octyl-4-bromoaniline was the
exclusive product. Thus, the catalyst was fully selective for
reactions of aryl iodides over aryl bromides, but the presence
of the aryl iodide inhibits the reaction of the aryl bromide.
9
J. AM. CHEM. SOC. VOL. 130, NO. 20, 2008 6591

A R T I C L E S
Shen et al.
Table 4. Comparison of the Activity of CyPF-tBu, Xphos, and SiPr for the Reactions of 4-Chlorotoluene with a Primary Alkylaminea
entry
catalyst
loading
solvent
T [°C]b
t [h]
conversion (%)c
A:B
1
2
3
4
5
6
7
8
9
Pd(OAc)2/1
Pd(OAc)2/2
Pd(dba)2/2
Pd(OAc)2/2
Pd(OAc)2/2
Pd(dba)2/2
3
0.01
0.05
0.1
0.1
0.5
DME
100
100
100
100
100
100
110
110
110
48
48
48
48
12
12
48
48
12
100(95)
13
25
100:0
18:1
10:1
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
16
39:1
96(91)
100(93)
40
76
100
2.7:1
2.3:1
>50:1
15.3:1
4.3:1
0.5
0.005
0.05
0.5
3
3
a The experiments were conducted with a 1:1 ratio of Pd/CyFP-tBu or 1:2 ratio of Pd/Xphos, 1 mmol of 4-chlorotoluene and 1.2 equiv 1-octylamine,
and 1.4 equiv base in 1.0 mL solvent. b Bath temperature. c Determined by 1H NMR analysis of the crude product. Isolated yields are indicated in
parentheses.
Table 5. Coupling of Heteroaryl and Aryl Halides with Primary
mol %) occurred to full conversion, but formed only a 2.7:1
ratio of monoarylation to diarylation product. Reactions
Amines Catalyzed by Pd(OAc)2 and CyPF-tBu (1:1) in Toluenea
conducted with this ligand and Pd(dba)2 instead of Pd(OAc)2
as palladium precursor occurred with similar selectivity (2.3:
1). Reactions of 4-chlorotoluene with 1.2 equiv of octylamine
in the presence of 0.005 mol % (NHC)Pd(R-allyl)Cl 3
occurred to less than 50% conversion. The same reaction in
the presence of a 0.5 mol % of (NHC)Pd(R-allyl)Cl occurred
to full conversion, but formed a 4.3:1 ratio of products from
monoarylation and diarylation.
entry
Ar
X
R-tBu
cat. (%)
yield (%)b
1
2
3
4
5
6
7
8
9
10
2-Py
3-Py
3-Py
Ph
4-Tol
2-Py
3-Py
Ph
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
I
octyl
octyl
4-tolylamino
octyl
0.01
0.05
0.1
0.05
0.02
0.01
0.01
0.005
0.2
98
98
66
99
99
92
99
99
99
93
iBu
2.6. Catalytic Amination of Heteroaryl and Aryl Chl-
orides, Bromides, and Iodides with Primary Amines in To-
luene. In some settings, toluene would be preferred over DME
as solvent. The reactions of a series of heteroaryl and aryl halides
with several primary amines in toluene in the presence of
Pd(OAc)2 and CyPF-tBu are summarized in Table 5. These
reactions occurred in similarly high yields as the reactions in
DME. These reactions were somewhat slower than those in
DME, and the yields in Table 5 were obtained with 2–10 times
more catalyst than those in DME. Nevertheless, these loadings
are 1–2 orders of magnitude lower than those reported for the
corresponding reaction of an aryl halide with any primary
amine.12,56 Although speculative at this stage, we have consid-
ered that the ability of DME to ligate an alkali metal might
make the alkoxide base stronger and increase the rate of
formation of the amido intermediate. Alternatively, the proper-
ties of the solvent and base could affect the relative concentration
of active and dormant complexes in the system.
2.7. Scope of the Amination of Heteroaryl and Aryl Cho-
rides, Bromides, and Iodides with Primary Arylamines. The
reactions of primary arylamines with aryl halides are simpler
to catalyze than those of primary alkylamines because ꢀ-hy-
drogen elimination does not compete with reductive elimination,
and many palladium complexes catalyze the couplings of aryl
halides with arylamines. However, catalyst loadings are often
quite high, and diarylation of the aniline can be a competing
process. To address issues of catalyst lifetime and selectivity,
we have studied the reactions of heteroaryl and aryl chlorides,
octyl
Bn
Bn
3-Py
2-Tol
iBu
I
cyclohexyl
0.05
a Reactions conducted with a 1:1 ratio of metal to ligand, 1 mmol
ArX (X ) Cl, Br, I), 1.2 equiv amine and 1.4 equiv NaO-tBu in 1 mL
toluene. b Isolated yield.
Although further data are needed to reveal the origin of this
inhibitory effect, we presume that the alkali metal iodide
product, not the iodoarene itself, retards the rate of the reaction.
Consistent with this hypothesis, the addition of NaI to the
reaction of bromotoluene in DME retarded the reaction.
2.5. Comparison to the Amination of Aryl Halides Catalyzed
by Complexes of CyPF-tBu to Reactions Catalyzed by Com-
plexes of Xphos And SIPr. A comparison of the reactivity of
catalysts generated from CyPF-tBu, Xphos, and SIPr for the
coupling of octylamine with a prototypical chlorarene is
provided in Table 4. These studies again showed the
unusually long lifetimes and high monoarylation selectivity
of the Pd-CyPF-tBu system. Reactions of 4-chlorotoluene
with 1.2 equiv of octylamine in the presence of 0.01 mol %
of Pd(OAc)2/CyPF-tBu afforded 95% yields of the N-
octyltoluidine without detectable amounts of side products
from diarylation. In contrast, the same reaction conducted
with 0.01 mol % of the catalyst generated from Xphos ligand
2 occurred to less than 25% conversion. This reaction
conducted with higher loadings of Pd(OAc)2 and Xphos (0.5
9
6592 J. AM. CHEM. SOC. VOL. 130, NO. 20, 2008

Catalysts for the Amination of Heteroaryl and Aryl Halides
A R T I C L E S
Table 6. Coupling of Heteroaryl and Aryl Halides with Primary Arylamines Catalyzed by Pd(OAc)2 and CyPF-tBu (1:1)a
entry
Ar
X
Ar′
cat. (%)
conditions
yieldb
1
2
3
4
5
6
7
8
2-Py
3-Py
Cl
Br
Cl
Cl
Cl
Cl
Br
I
Br
Br
Br
Br
Cl
Br
Br
Br
Cl
Br
Cl
Br
Br
I
4-Tol
4-Tol
1-naphthyl
4-Tol
2-anisyl
2-Py
4-anisyl
4-anisyl
2-pyrimidyl
2-prazinyl
4-Tol
4-Tol
4-Tol
4-Tol
2-Py
2-benzothiazolyl
4-anisyl
4-anisyl
4-anisyl
4-anisyl
4-Tol
0.1
100 °C, 24 h
60 °C, 48 h
86
95
98
93
99
97
80
97
96
92
52
84
99
95
81
62
99
97
99
94
96
99
89
89
0.05
0.05
0.05
0.05
0.5
0.05
0.05
1.0
1.0
1.0
0.05
0.05
0.005
1.0
100 °C, 24 h
100 °C, 24 h
100 °C, 24 h
100 °C, 24 h
100 °C, 48 h
100 °C, 24 h
110 °C, 20 h
110 °C, 20 h
100 °C, 48 h
100 °C, 38 h
100 °C, 24 h
110 °C, 20 h
100 °C, 30 h
100 °C, 36 h
100 °C, 24 h
100 °C, 48 h
100 °C, 24 h
100 °C, 48 h
100 °C, 48 h
100 °C, 24 h
100 °C, 48 h
100 °C, 48 h
9
10
11c
12
13
14
15
16
17
18
19
20
21
22
23
24
1,3-pyrimidyl-5-4-iso-quinolinyl
4-iso-quinolinyl
Ph
1.0
4-Tol
0.05
0.05
0.05
0.05
0.05
0.05
0.5
3-anisyl
2-Tol
4-Tol
4-Tol
4-Tol
2,5-dimephenyl
2-cyclohexylphenyl
Br
Br
0.05
a Reactions conducted with a 1:1 ratio of metal to ligand, 1 mmol ArX (X ) Cl, Br, I), 1.2 equiv amine, and 1.4 equiv NaO-tBu in 1 mL DME.
b Isolated yield. c Using K3PO4 as the base.
Table 7. Coupling of Aryl Chlorides and Bromides with Secondary
bromides, and iodides with primary aromatic amines catalyzed
by the combination of Pd(OAc)2 and CyPF-tBu.
Amines Catalyzed by Pd(OAc)2 and CyPF-tBu (1:1)a
The scope of the reactions of primary aromatic amines with
heteroaryl and aryl halides are summarized in Table 6. Although
these reactions were slower than the reactions of primary
alkylamines, high yields of reactions of heteroaryl and aryl
halides with electron-rich primary aryl amines were obtained
using only 0.005–0.1 mol % catalyst (Table 6, entries 1–5, 7–8,
11–13, 17–22, and 24). These catalyst loadings are 1 or 2 orders
of magnitude lower than those of prior catalyst systems for
reactions of aryl chlorides or bromides with unhindered primary
aryl amines.12 Nolan reported one example of the extremely
hindered 2,6-di-iso-propylaniline with the hindered chloroarene
2,6-dimethyl-1-chlorobenzene in the presence of 0.01 mol %
of catalyst to give 93% isolated yield.66
Reactions of electron-deficient primary heteroaryl amines also
occurred in the presence of the combination of Pd(OAc)2 and
CyPF-tBu, but were slower and required higher catalyst loadings
than the reactions of electron-rich primary arylamines (Table
6, entries 6, 9–10, and 15–16).26 Nevertheless, 2-aminopyridine,
2-aminopyrimidine, and 2-aminobenzothiazole (Table 6, entries
6, 9, 10, 15, and 16) coupled with chlorobenzene and or
bromobenzene to afford the desired products in 62–97% yields
in the presence of 0.5–1.0 mol % catalyst.
entry
Ar
amine
cat. (%)
conditions
yield (%)b
1
2
3
4
5
6
7
8
9
2-Py
3-Py
4-Py
N-methyl-aniline 1.0
morpholine
di-4-anisidine
70 °C, 3 h
90 °C, 12 h
70 °C, 12 h
70 °C, 10 h
57
69
50
84
56
69
86
86
82
1.0
1.0
1.0
1-isoquinolinyl N-Me-aniline
Ph
N-Me-aniline
dibutylamine
diphenylamine
morpholine
0.05 100 °C, 48 h
0.5
0.5
0.1
100 °C, 24 h
100 °C, 20 h
100 °C, 48 h
4-Tol
3-anisyl
morpholine
0.05 100 °C, 48 h
a Reactions were conducted with a 1:1 ratio of metal to ligand, 1
mmol ArX (X ) Cl, Br), 1.2 equiv amine, and 1.4 equiv NaO-tBu in 1
mL DME. b Isolated yield.
and acyclic amines occurred in moderate to good yields in the
presence of 1.0 mol % of the catalyst. For example, the
amination of 3-chloropyridine with morpholine in DME gave
the coupled product in 69% yield. Reactions of aryl bromides
with secondary amines occurred in higher yield than reactions
of aryl chlorides. For instance, morpholine reacted with 4-bro-
motoluene and 3-bromoanisole in the presence of 0.1 and 0.05
mol % catalyst to give the desired products in 86% and 82%
yield, respectively (Table 7, entries 8 and 9). The acyclic
secondary amines dibutylamine and diphenylamine required 0.5
mol % catalyst to form the coupled product in acceptable yield
(Table 7, entries 6 and 7). We presume that the slower rate of
reactions of acyclic secondary amines results from slower
formation of the amido complex from the more hindered
secondary amines.
2.8. Catalytic Amination of Heteroaryl and Aryl Chlorides
and Bromides with Secondary Amines. The combination of
Pd(OAc)2 and the Josiphos ligand CyPF-tBu is highly selective
for monoarylation of primary amines. Thus, the reactions of
secondary amines are likely to be slower. Consistent with this
logic, only a limited number of substrate combinations reacted
in high yield at low catalyst loading. These data are summarized
in Table 7.
Reactions of aryl chlorides with secondary amines were slow,
and substantial amounts of hydrodehalogenation product were
observed. However, reactions of heteroaryl chlorides with cyclic
Thus, coupling of secondary amines is currently best con-
ducted with third-generation catalysts containing sterically bulky,
9
J. AM. CHEM. SOC. VOL. 130, NO. 20, 2008 6593

A R T I C L E S
Shen et al.
electron-rich, monodentate alkylphosphines or carbenes.11,31,66,67
Yet, if one wished to use a single catalyst for coupling of
primary amines and secondary amines, the catalyst containing
the Josiphos ligand would be competent for coupling of many
examples of both classes of amines.
Table 8. Coupling of Functionalized Heteroaryl Chlorides with
Primary Amines Catalyzed by Pd(OAc)2 and CyPF-tBu (1:1)a
2.9. Scope of the Amination of Functionalized Heteroaryl
and Aryl Chlorides, Bromides, and Iodides with Primary Alkyl-
amines.
2.9.1. Catalytic Amination of Functionalized Heteroaryl
Chlorides with Primary Alkylamines. Despite advances in the
scope of palladium-catalyzed amination reactions, reactions of
amines with functionalized heteroaryl chlorides remains
challenging.32,68–71 The strong NaO-tBu base, more than the
palladium catalyst, limits the tolerance of the process to ancillary
functionality. Several approaches have been followed to address
functional group compatability.72–75 By one approach, reactions
between secondary amines and chloroarenes containing protic
functionality have been shown to occur when using lithium
bis(trimethylsilyl)amide (LiN(SiMe3)2) as base.74,75
Here we show that the combination of CyPF-tBu as ligand
and LiN(SiMe3)2 as base leads to the coupling of a variety of
primary amines with heteroaryl chlorides containing protic
functionality. These reactions required higher catalyst loadings
(0.5 mol %) than reactions of chloroarenes lacking protic
functionality, but they occurred in good to excellent yields.
Reactions of these substrates conducted with the weaker bases
K3PO4 or Cs2CO3, instead of LiN(SiMe3)2, occurred to low
conversion, and reactions conducted with NaO-tBu gave only
trace amounts of the desired coupled product.
The results in Table 8 summarize the scope of the couplings
of heteroaryl chlorides containing protic functionality. Each
reaction occurred to full conversion and formed the coupled
product in high yield with little side product. In some cases,
the isolated yields were lower than those for reactions of less
functionalized products because of the loss of some of these
highly polar products during purification by column chroma-
tography. For example, the reactions of N-(5-chloro-2-pyridi-
nyl)acetamide with octylamine and sec-butyl amine in the
presence of 0.5 mol % of palladium and ligand afforded 65%
and 96% isolated yields of the desired products, respectively.
Likewise, heteroaryl chlorides containing functional groups, such
as a free alcohol and phenol, reacted in acceptable isolated yields
with 0.5 mol % catalyst.
a Reactions conducted with a 1:1 ratio of metal to ligand 1 mmol
ArCl, 1.2 equiv amine and 1.4 equiv LiN(SiMe3)2 in 1 mL DME.
b Isolated yields.
reacted in high yields with only 0.05–0.5 mol % catalyst loading.
Reactions of aryl chlorides containing an enolizable ketone also
gave the desired products in good yield in the presence of
LiN(SiMe3)2, while reactions of the corresponding aryl bromide
and iodide gave more complicated mixtures, even when 2.0 mol
% of the catalyst was used. These reactions were better
conducted with K3PO4 as base (vide infra). The reaction of 4′-
chloro-acetophenone with primary amines occurred in higher
yield under somewhat more dilute conditions. The side product
formation from R-arylation was minimized, although not fully
eliminated, when the concentration of the reaction solution was
decreased from 1 to 0.2 M (Table 9, entry 7).
As mentioned earlier in this paper, reactions catalyzed by
complexes of the hindered Josiphos ligand conducted with weak
bases13,14,56,76,77 occur more slowly than reactions catalyzed by
complexes of monodentate ligands conducted with weak bases.
Nevertheless, reactions of haloarenes containing electron-
withdrawing groups, such as enolizable keto, carboalkoxy, or
nitro groups, occurred fast enough to give the coupled product
in high yield when K3PO4 was used as base. Reactions of aryl
chlorides, bromides, and iodides bearing an enolizable keto
group in the para position or a carbomethoxy group in the meta
or para position occurred to completion and gave good to
excellent yields of the coupled product (Table 9, entries 8, 10,
and 25–28). Reactions of purely aliphatic amines with the
chloroarene that contained a carboalkoxy group ortho to the
chloride were slower. However, acceptable yields were obtained
for the reaction of methyl-2-chlorobenzoate with benzylamine
using 2.0 mol % catalyst at 110 °C (Table 9, entry 29).
Previous reactions of primary alkylamines with aryl chlorides,
bromides, and iodides possessing potentially reactive functional
2.9.2. Catalytic Amination of Functionalized Aryl Chlorides,
Bromides, and Iodides with Primary Alkylamines. The reactions
of primary amines with haloarenes containing the same types
of functional groups occurred in high yield in the presence of
LiN(SiMe3)2 as base (Table 9). Aryl chlorides, bromides, and
iodides containing functional groups, such as a free alcohol,
phenol, carboxylic acid, primary amide, or secondary amide
(67) Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998, 39,
617.
(68) Scott, J. P. Synlett 2006, 2083.
(69) Queiroz, M.-J. R. P.; Begouin, A.; Ferreira, I. C. F. R.; Kirsch, G.;
Calhelha, R. C.; Barbosa, S.; Estevinho, L. M. Eur. J. Org. Chem.
2004, 3679.
(70) Luker, T. J.; Beaton, H. G.; Whiting, M.; Mete, A.; Cheshire, D. R.
Tetrahedron Lett. 2000, 41, 7731.
(71) Castellote, I.; Vaquero, J. J.; Alvarez-builla, J. Tetrahedron Lett. 2004,
45, 769.
(72) Wolfe, J. P.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6359.
(73) Lee, D.-Y.; Hartwig, J. F. Org. Lett. 2005, 7, 1169.
(74) Harris, M. C.; Huang, X.; Buchwald, S. L. Org. Lett. 2002, 4, 2885.
(75) Urgaonkar, S.; Verkade, J. G. AdV. Synth. Cat. 2004, 346, 611.
(76) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 9722.
(77) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.;
Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575.
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6594 J. AM. CHEM. SOC. VOL. 130, NO. 20, 2008

Catalysts for the Amination of Heteroaryl and Aryl Halides
A R T I C L E S
Table 10. Comparison of the Activity of Josiphos CyPF-tBu
Analogs for the Coupling of Heteroaryl Chloride with Primary
Alkylamine
Table 9. Coupling of Functionalized Aryl Halides with Primary
Amines Catalyzed by Pd(OAc)2 and CyPF-tBu (1:1).a
entry
-FG
X
R
cat. (%)
conditions
yield (%)b
entry
ligand
loading
temp. (°C)
time (h)
yield (%)
1
2
3
4
-4-CO2H
Cl octyl
Br octyl
Br sBu
0.05 100 °C, 20 h
0.05 100 °C, 20 h
0.05 100 °C, 20 h
0.05 100 °C, 48 h
0.5 100 °C, 20 h
0.05 100 °C, 20 h
81
72
92
78
67
85
91
74
61
78
87
82
98
67
74
72
47
83
89
84
85
81
70
72
94
77
91
97
82
79
1
2
3
4
5
6
7
8
CyPF-tBu 1
0.005
1.0
0.005
0.005
1.0
90
90
90
90
90
90
90
90
100
90
90
90
90
90
90
90
24
24
24
24
24
24
24
24
48
24
24
24
24
24
24
24
93
67
<5
<5
46
48
62
50
16
PPF-tBu 4
MePF-tBu 5
I
sBu
EtPF-tBu 6
5
-4-C(O)NH2
-4-C(O)CH3
Cl iBu
6
Br iBu
CyPF-Cy 7
7c
8d
9
Cl octyl
Cl octyl
Cl octyl
0.5
0.5
70 °C, 20 h
110 °C, 24 h
CyPF-Ph 8
1.0
tBuPF-Cy 9
0.005
0.005
0.001
0.005
0.005
0.005
0.005
0.005
0.005
0.005
10
11
11
12
13
14
15
16
17
0.05 100 °C, 16 h
10d
11c
12d
I
octyl
1.0
110 °C, 24 h
70 °C, 20 h
9
10
11
12
13
14
15
16
93
Cl cyclohexyl 0.5
Br cyclohexyl 1.0
<5
<5
<5
<5
<5
<5
110 °C, 24 h
0.05 100 °C, 20 h
13 -4-NHC(O)CH3 Br octyl
14 octyl
15 -3-NHC(O)CH3 Cl cyclohexyl 0.05 100 °C, 24 h
I
0.5
110 °C, 20 h
16 -4-CH2OH
17
Br iBu
iBu
0.05 100 °C, 48 h
0.05 100 °C, 20 h
I
18 -4-CH(OH)CH3 Cl sBu
19 -4-CH2CH2OH Cl octyl
0.5
0.5
0.5
0.5
100 °C, 18 h
100 °C, 20 h
100 °C, 20 h
100 °C, 20 h
100 °C, 36 h
100 °C, 20 h
100 °C, 18 h
110 °C, 24 h
110 °C, 48 h
110 °C, 24 h
110 °C, 24 h
110 °C, 24 h
110 °C, 24 h
20 -3-OH
21
22
Cl Bn
Br Bn
Br cyclohexyl 0.5
I cyclohexyl 1.0
23
24 -4-OH
25d -4-CO2Me
26d -4-CO2Et
27d -3-CO2Me
28d
Cl octyl
2.0
1.0
2.0
1.0
1.0
2.0
1.0
Cl iBu
I
sBu
Cl iBu
Br iBu
Cl Bn
29d -2-CO2Me
30d -4-NO2
I
octyl
a Reactions conducted with a 1:1 ratio of metal to ligand, 1.0 mmol
ArX (X ) Cl, Br, I), 1.2 equiv amine, and 2.4 equiv LiN(SiMe3)2 in 1
mL DME. b Isolated yields. c Reactions run at 0.2 M. d Using K3PO4 as
the base.
groups were limited to those of electron-poor aryl chlorides and
bromides containing an ester or nitro functionality.13,76 No
examples of reactions of primary alkylamines with chloro-,
bromo-, or iodo-arenes containing the other functional groups
of Table 9 have been published previously using catalysts other
than that containing the Josiphos CyPF-tBu ligand.
2.10. Comparison of the Reactivity of Catalysts Generated
from Analogs of CyPF-tBu. To identify the structural elements
of CyPF-tBu that give rise to high activity and stability, we
evaluated the catalytic activity of complexes containing several
analogs of this ligand. These analogs (Table 10) include
derivatives of CyPF-tBu that lack the methyl group of the
backbone or bear a more bulky iso-propyl group, contain less
hindered alkyl groups on the phosphorus, are partially oxidized,
or have the positions of the two phosphino groups interchanged.
In addition, we prepared ligands that contain backbones
mimicking the structures of the ferrocenyl bisphosphines.
To determine whether the true catalyst in this system contains
both phosphino groups bound to palladium, ligand 13, in which
one phosphino group has been oxidized, and ligand 14, in which
one phosphino group was replaced by an oxazoline, were
studied. The reactivity of catalysts generated from these ligands
for the coupling of 3-chloropyridine with octylamine were
compared to that of catalysts generated from CyPF-tBu. The
reaction conducted with CyPF-tBu occurred in 93% isolated
yield after 24 h at 90 °C in the presence of 0.005 mol % of
Pd(OAc)2/CyPF-tBu. In contrast, this reaction conducted with
13 or 14 as ligand formed only small amounts of the coupled
product under similar reaction conditions. This experiment
suggests that palladium complexes of the bis(phosphine) ligand
are the catalytically active species in the reaction and that both
of the phosphino groups in CyPF-tBu are important for the high
catalytic activity in the amination process.
Ligands 5–7 containing less hindered alkylphosphino groups
formed much less active catalysts than did CyPF-tBu. The
catalysts generated from these ligands formed the coupled
product in <5% to 48% yields (Table 10, entries 3–5). The
catalysts generated from ligands 4 or 8 containing diphe-
nylphosphino groups were more active than those containing
dimethylphosphino or diethylphosphino groups, but formed the
coupled product in only 67 and 48% yields, even with 1.0 mol
% loading (Table 10, entries 2 and 6). Moreover, ligand 9, in
which the two phosphino groups of the most reactive ligand 1
were transposed, led to a less active catalyst (Table 10, entry
8). We do not have a firm explanation for the lower reactivity
of transposed ligand 9 vs ligand 1.
Ligand 10 lacking the backbone methyl group formed a
catalyst that coupled 3-chloropyridine with octylamine. How-
ever, the reaction of these substrates in the presence of the
catalyst containing ligand 10 occurred at least 5 times slower
9
J. AM. CHEM. SOC. VOL. 130, NO. 20, 2008 6595

A R T I C L E S
Shen et al.
than the reaction catalyzed by the complex containing CyPF-
tBu (Table 10, entry 8). The catalyst generated from ligand 11
containing a slightly larger propyl group reacted with rates and
lifetimes (Table 10, entries 9–10) that are similar to those for
reactions conducted with catalysts generated from ligand 1.
Even ligands 15–16 containing backbones related to the 1,2-
disubstituted ferrocenyl group generated much less reactive
catalysts at 0.005 mol % loadings. Ligand 15 should generate
a complex with a slightly smaller bite angle than that generated
from ligand 1. However, the backbone would be expected to
be substantially less rigid without the combination of the anti
arrangement of the ferrocenyl unit and backbone methyl group
in the coordinated ligand. The bite angle in the complex
generated from ligand 16 would also be slightly smaller than
that generated from PPF-tBu because the complex of 16 would
contain a six-membered ring fused to the chelate ring. The
backbone of this ligand could be more rigid than that in 15
because of the relative stereochemistry of the chromium
carbonyl unit and the backbone methyl group. However, the
carbonyl groups bound to chromium can suffer nucleophilic
attack by the combination of amine and base, and this attack
could open a pathway to catalyst decomposition.
The complex of ligand 17 containing a Xanthane backbone
in place of the ferrocenyl-1-ethyl group would contain a
slightly larger bite angle than that of CyPF-tBu, and the utility
of 4,6-diphenylphosphino-10,10-dimethylxantane (Xantphos)
as ligand for cross-coupling has been attributed to its large
bite angle. However, the reaction of 3-chloropyridine with
octylamine catalyzed by Pd(OAc)2 and 17 occurred in much
lower conversion than it did when catalyzed by Pd(OAc)2
and CyPF-tBu.
From these results, we conclude that the following structural
features that are specific to CyPF-tBu lead to the high efficiency
of the Pd-CyPF-tBu catalyst: (1) a rigid backbone resulting from
the relative stereochemistry of the backbone methyl group and
ferrocenyl unit, which causes the ligand to bind tightly to
palladium and prevents the displacement of the ligand from
Pd(II) by primary amines and basic heterocycles; (2) strong
electron donation of the two alkylphosphino groups, which
promotes the oxidative addition of less reactive haloarenes; (3)
steric bulk of the phosphino groups, which discourages diary-
lation of the primary amine substrates, facilitates dissociation
of ligand from (chelate)2Pd(0) to form the reactive inter-
mediate (chelate)Pd(0), and makes reductive elimination from
the arylpalladium amido complexes fast; and (4) stability of
the ferrocene unit and hindered backbone methine hydrogen to
the reagents in the system.
3. Conclusions
In summary, we have shown that palladium complexes
generated from the Josiphos ligand CyPF-tBu are general, highly
efficient catalysts for the coupling of heteroaryl and aryl
chlorides and bromides with primary nitrogen nucleophiles.
Reactions catalyzed by the complexes generated in situ from
Pd(OAc)2 and ligand 1 occur with turnover numbers that are
typically 1 or 2 orders of magnitude higher than those of related
couplings by previous catalysts. The process exhibits a broad
scope and a high tolerance for functional groups, including
cyano, keto, free carboxylate, amido, carboalkoxy, aromatic,
and aliphatic hydroxyl and amino groups.
The efficiency of palladium catalysts containing this ligand
for the amination process is believed to result from an unusual
combination of (1) a rigid backbone which causes the ligand to
bind to palladium tightly enough to prevent displacement by
primary amines and basic heterocycles; (2) strong electron
donation, which promotes the oxidative addition of less reactive
haloarenes; and (3) steric bulk that disfavors diarylation,
facilitates the generation of the (chelate)Pd(0) intermediate, and
promotes reductive elimination from the arylpalladium amido
complexes.
The strengths of the catalyst reported here complement those
of previously reported catalysts that contain hindered mono-
dentate ligands. The catalyst in the current work is less reactive
toward secondary amines than primary amines, while the
catalysts for aminations of chloroarenes reported previously are
less reactive toward primary amines than secondary amines.
In future work, we will define more precisely the mechanism
of the coupling process with this catalyst and will follow these
design principles with the goal of developing readily accessible
ligands for the reactions of secondary amines and nitrogen
heterocycles with low loading of catalyst.
Acknowledgment. We thank the NIH (GM-55382) for sup-
port of this work, Johnson-Matthey for PdCl2, and Solvias for the
Josiphos ligands.
Supporting Information Available: All experimental proce-
dures and spectroscopic data of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JA077074W
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6596 J. AM. CHEM. SOC. VOL. 130, NO. 20, 2008