Highly reactive, general, and long-lived catalysts for coupling heteroaryl and aryl chlorides with primary nitrogen nucleophiles

Article abstract of DOI:10.1002/anie.200462629

Resisting pathways for decomposition followed by palladium complexes of monodentate ligands is one characteristic of the highly reactive but long-lived catalyst generated from the Josiphos ligand L and palladium. It catalyzes under mild conditions the coupling of primary amines with chloropyridines and chloroarenes in high yield with low catalyst loadings (see scheme).

Full text of DOI:10.1002/anie.200462629

Angewandte
Chemie
Arene–Amine Coupling
Highly Reactive, General, and Long-Lived
Catalysts for Coupling Heteroaryl and Aryl
Chlorides with Primary Nitrogen Nucleophiles**
Qilong Shen, Shashank Shekhar, James P. Stambuli, and
John F. Hartwig*
During the past decade, the palladium-catalyzed amination of
ꢀ
aryl halides has become a principal method to form the C N
bonds of aromatic amines.[1–4] Although current catalysts are
capable of coupling a wide range of amines with aryl halides,
reactions with these catalysts have several limitations: the
catalysts have short lifetimes in the reactions of primary
amines with chloroarenes, even when conducted with the
most recently developed, highly active catalysts containing
basic, hindered alkylmonophosphines;[5–15] the reactions of
primary alkyl amines with heteroaryl chloride reagents, which
are important for the synthesis of biologically active mole-
cules, have limited scope and require large amounts of
catalyst;[7,8,11,13,15–20] and the reactions of primary alkyl amines
with chloroarenes that possess common protic functional
groups have not been described.
We now report on catalysts that can overcome these
limitations. Our approach, which is based upon the selection
of ligands that combine steric hindrance, strong electron
donation, and tight chelation, leads to a catalyst that
simultaneously possesses long lifetimes and displays high
activity for reactions of primary nitrogen nucleophiles with
chloropyridines. Many of the reactions occur with part-per-
million quantities of catalyst and with turnover numbers that
exceed those of previous catalysts by two or more orders of
magnitude.
To identify the factors that would improve catalyst
lifetime over that of current catalysts, we studied the reactions
of primary amines and pyridine with aryl palladium(ii) halide
complexes and bisphosphine palladium(0) complexes bearing
a basic, hindered alkyl monophosphine.[21–23] Addition of
benzylamine or pyridine (py) to the palladium(0) complex
[Pd(PtBu3)2] led to no reaction [Eq. (1)]. However, addition
of benzylamine or pyridine to the aryl palladium(ii) halide
complex [Pd(PtBu3)(Ar)(Br)] (Ar= o-Tol, Ph) displaced the
tBu3PꢀPdꢀPtBu3 þ py ! no reaction
ð1Þ
[*] Q. Shen, S. Shekhar, Dr. J. P. Stambuli, Prof. Dr. J. F. Hartwig
Department of Chemistry
Yale University
P.O. Box 208107, New Haven, CT 06520-8107 (USA)
Fax: (+1)203-432-6144
E-mail: john.hartwig@yale.edu
[**] We thank the National Institutes of Health (GM-55382) for support
of this work, Johnson-Matthey for a gift of PdCl2, Solvias for a gift of
the Josiphos ligands, and Boehringer Ingelheim for unrestricted
support. We thank Leslie Bienen for assistance in manuscript
preparation.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2005, 44, 1371 –1375
DOI: 10.1002/anie.200462629
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1371

Communications
phosphine
to
form
the
free
ligand
[Pd(py)2(o-Tol)Br]
and
complexes do not catalyze the amination of aryl chlorides.
To prevent displacement of the phosphine ligand, while
maintaining the steric and electronic properties of the
hindered alkyl monophosphines, we evaluated complexes
containing hindered alkyl bisphosphines as catalysts for the
coupling of primary amines with heteroaryl and aryl chlorides.
A series of possible structures of palladium(0) complexes of
chelating phosphines are summarized in Figure 1. The
unsaturated (chelate)Pd0 fragment adds aryl halides[26] and
[Pd(PhCH2NH2)2(Ph)Br][24]
or
[Eq. (2)].[25] Although displacement of hindered aromatic
phosphines occurs from aryl palladium(ii) complexes,[24,25] the
greater basicity of alkyl phosphines should make complexes
of these ligands more stable toward displacement by amines
and pyridines. Apparently, the higher basicity does not
increase the strength of the bond between palladium(ii) and
a hindered alkyl phosphine enough to prevent displacement
by the less hindered nitrogen donors. Displacement of the
ligand from palladium accounts for the slow reactions of
primary amines and pyridines because amine and pyridine
Figure 1. Potential structures of Pd0 complexes with bisphosphine
ligands and the Josiphos ligand L employed in this study. Cy=cyclo-
hexyl.
Table 1: Coupling of heteroaryl chlorides with primary amines catalyzed by Pd(OAc)2 and L.[a]
Entry
Product
Cat.
[mol%]
Cond.
Yield
[%][b]
Entry
Product
Cat.
[mol%]
Cond.
Yield
[%][b]
258C,
5 h
908C,
12 h
1
2
3
1.0
99
86
89
15
16
17
1.0
1.0
1.0
85
85
99
1008C,
48 h
708C,
16 h
0.001
0.005
708C,
16 h
708C,
16 h
708C,
12 h
708C,
8 h
4
0.01
98
18
1.0
93
708C,
16 h
908C,
24 h
5
6
7
1.0
1.0
1.0
73
92
99
19
20
21
0.01
1.0
83
99
75
708C,
16 h
708C,
10 h
708C,
16 h
708C,
24 h
1.0
708C,
18 h
908C,
48 h
8
1.0
99
96
93
22
23
24
0.005
0.01
94
60
89
908C,
30 h
1008C,
48 h
9
0.005
0.005
708C,
24 h
1008C,
48 h
10
0.001
1008C,
24 h
908C,
15 h
11
12
13
14
0.01
0.01
0.01
1.0
95
90
79
67
25
26
27
0.005
0.005
0.05
91
82
91
1008C,
48 h
1008C,
16 h
1008C,
48 h
1008C,
24 h
708C,
16 h
[a] Reactions conducted with a 1:1 ratio of metal to ligand, 1 mmol ArCl, 1.2 equiv amine, and 1.4 equiv NaOtBu in 1 mL 1,2-dimethoxyethane (DME).
[b] Yield after isolation. [c] From (1-phenylethyl)amine that is stated to be 99% ee.
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Chemie
must be readily generated for high reactivity. Many bisphos-
phines form (chelate)2Pd complexes that slowly dissociate
their ligands. Because this dissociation precedes oxidative
addition, these complexes tend to add aryl halides slowly.[27]
Others, such as 1,1’-ferrocenylphosphines, are flexible enough
to adopt conformations that link two metals, or possess k1
coordination modes.[28] Ligands that adopt k1 coordination
modes will be more easily displaced by amines and pyridines
than those that adopt chelating structures. Thus, we selected
hindered alkyl bisphosphines with rigid backbones to disfavor
formation of stable (chelate)2Pd0 complexes containing two
bidentate ligands, to disfavor formation of complexes with k1
structures, and to favor generation of the (chelate)Pd0 frag-
ment.[29]
The Josiphos ligand with one di-tert-butylphosphanyl and
one dicyclohexylphosphanyl group shown in Figure 1[30] is
now commercially available, but has rarely been used
successfully in catalytic chemistry. It is air-stable, both as a
solid and in solution for at least 24 h, as determined by
1H NMR and 31P NMR spectroscopy. The combination of the
severe steric hindrance, conformational preferences of the
backbone, and recent success in generating catalysts for the
coupling of aryl tosylates[31,32] led us to study complexes of this
ligand as catalysts for the amination of
104 to 105 slower than that of 2- and 4-chloropyridines.[34]
Besides the generality of the reaction, the turnover
numbers are remarkable. High yields were observed for
reactions between pyridyl chlorides and unhindered primary
amines with loadings of metal salt and ligand between 10 and
50 ppm (Table 1, entries 2, 3, 9, 10, 22, 24–26). Some previous
reactions of chloropyridines with low loadings of palladium
were conducted with high loadings of ligand.[15] This is
misleading because the ligand is typically more expensive
than the metal.
Hindered primary amines, such as tert-butylamine, as well
as benzophenone hydrazone and benzophenone imine, also
reacted in high yields with chloropyridines (Table 1, entries 5–
7, 14, 16, 17, 20). These reactions required more catalyst,
although the loading remained at or below 1 mol%. The more
hindered 2-chloro-3-methylpyridine also reacted with octyl-
amine in high yield (Table 1, entry 9). Even benzamide
reacted with 2- and 4-chloropyridine with this catalyst
(entries 8, 21). No coupling of amides with a pyridyl chloride
has previously been reported with any catalyst. No products
from coupling of primary nitrogen nucleophiles with hetero-
aryl chlorides to form di-heteroaryl amines were observed in
any case by GC/MS.
heteroaryl and aryl chlorides.
Table 2: Coupling of aryl chlorides with primary amines catalyzed by Pd(OAc)2 and L.[a]
Reactions of heteroaryl chlorides
with primary nitrogen nucleophiles cat-
alyzed by a combination of this Josiphos
ligand and Pd(OAc)2 are summarized in
Table 1. Catalysts generated from
Pd(OAc)2 were more reactive than
those generated from [Pd(dba)2]. Pyr-
idyl chlorides bearing the halogen in the
2-, 3-, or 4-position underwent reaction
with a variety of primary amines and
related nucleophiles in high yield at
room temperature or with mild heating.
In contrast, similar reactions in the
presence of catalysts with hindered
monodentate or aromatic bisphosphine
ligands were conducted with high cata-
lyst loadings or at high temperatures.
Not only reactions of pyridyl chlorides,
but reactions of quinolinyl, isoquino-
linyl, and pyrazyl chlorides, occurred
Entry Product
Cat.
[mol%]
Cond.
Yield Entry Product
[%][b]
Cat.
[mol%]
Cond.
Yield
[%][b]
908C,
48 h
1008C,
48 h
1008C,
48 h
808C,
20–24 h
1
2
3
0.005
0.01
0.05
94
98
93
13
14
15
0.005
0.005
0.1
99
98
90
1008C,
48 h
1008C,
48 h
1008C,
1008C,
48 h
4
5
0.1
0.1
92
97
16
17
0.05
0.01
99
87
48 h[c]
1008C,
36 h
808C,
20–24 h
1008C,
48 h
1008C,
48 h
6
0.05
0.05
1.0
92
83
94
99
99
18
19
20
21
22
23
0.1
1.0
1.0
1.0
1.0
1.0
82
61
77
86
87
82
1008C,
48 h
808C,
20–24 h
7
under
mild
conditions
(Table 1,
1008C,
18–24 h
808C,
20–24 h
entries 22–26).
8
Reactions without catalyst were con-
ducted in parallel with the catalyzed
ones. Only reactions of quinolines and
isoquinolines generated any measurable
quantity of products, and conversions
were below 40% in these cases. Reac-
tions of 2- and 4-chloropyridines occur
more readily in polar solvents or under
high pressure but are typically con-
ducted at temperatures closer to
1508C.[33] Nucleophilic substitution of
3-chloropyridines is often by a factor of
808C,
20–24 h
808C,
20–24 h
9
0.005
0.05
1008C,
48 h
1008C,
18–24 h
10
1008C,
36 h
808C,
20–24 h
11
12
0.5
99
68
1008C,
18–24 h
0.01
[a] Reactions conducted with a 1:1 ratio of metal to ligand, 1 mmol ArCl, 1.2 equiv amine, and 1.4 equiv
NaOtBu in 1 mL DME. [b] Yield after isolation. [c] 3.0 equiv of octylamine used.
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The turnover numbers of 86000, 18600, and 8300 for the
groups.[37–41] Our results (Table 3) show that catalysts con-
taining the hindered Josiphos ligand extend the scope of the
reactions of functionalized substrates to include the coupling
of primary amines with chloroarenes bearing protic function-
ality. This catalyst system is less reactive with weak bases than
reactions of 2-, 3- and 4-chloropyridine with octylamine are an
order of magnitude higher than those for reactions of any
amine with the corresponding bromopyridine[29,35] and about
two orders of magnitude higher than those for reactions of
any amine with the chloropyri-
dine,[7,8] and the value of 86000 is
Table 3: Coupling of functionalized aryl chlorides with primary amines catalyzed by Pd(OAc)2 and L.[a]
nearly three orders of magnitude
greater than those reported for the
reaction of a pyridyl chloride with
any primary amine.[8] To achieve
such high turnover numbers with
equal amounts of ligand and palla-
dium, we mixed the dilute solutions
of Pd(OAc)2 and ligand before
adding the amine or heterocyclic
substrate. Presumably the combi-
nation of amine and base leads to
the reduction of palladium(ii) to
palladium(0).
These high activities in reac-
tions of chloropyridines led us to
perform reactions of chloroarenes
using the same catalyst. Results
(displayed in Table 2) show simi-
larly high yields with low catalyst
loadings. Reaction of octylamine
with chlorobenzene occurred to
completion in 48 h and formed
the coupled product in 94% yield
at 908C, with only 50 ppm of cata-
lyst (entry 1). This yield under
these conditions corresponds to a
turnover number of 18800. This
value exceeds the maximum turn-
over numbers achieved previously
for the reaction of an aryl chloride
with any amine by nearly an order
of magnitude and the maximum
Entry Product
Cat.
[mol%]
Cond.
Yield Entry Product
[%][b]
Cat.
[mol%]
Cond.
Yield
[%][b]
1008C,
18 h
1008C,
20 h
1
2
3
4
0.5
0.5
0.5
0.5
90
70
83
87
10
11
12
13
0.5
0.5
0.5
0.5
84
87
92
69
1008C,
20 h
708C,
20 h
1008C,
18 h
708C,
20 h
1008C,
20 h
708C,
20 h
1008C,
20 h
1008C,
20 h
5
0.5
86
14
0.5
67
1008C,
18 h
1008C,
20 h
6
7
2.0
2.0
72
66
15
16
0.05
0.05
81
85
1008C,
20 h
1008C,
24 h
1008C,
18 h
1008C,
24 h
8
9
0.5
0.5
85
67
17
18
0.05
0.05
74
99
1008C,
20 h
1008C,
20 h
[a] Reactions conducted with a 1:1 ratio of metal to ligand, 1.0 mmol ArCl, 1.2 equiv amine, and
2.4 equiv LHMDS in 1 mL DME. [b] Yield after isolation.
turnover numbers for the reaction of a primary alkyl amine by
nearly two orders of magnitude. Reactions of several other
combinations of primary amines and chloroarenes (entries 9,
13, 14) occurred in similarly high yields with the same amount
of catalyst. The reactions of a-branched primary amines, for
example, the reaction of cyclohexylamine with chloroben-
zene, required more catalyst, but occurred in high yield with
only 0.05 mol% palladium (TON = 1980, Table 2, entry 10).
This loading of catalyst is more than an order of magnitude
lower than that of previous reactions of a-branched primary
amines with chloroarenes.[8] In addition, reactions of sec-
butylamine occurred in high yield with 0.01–1 mol% catalyst
(entries 16–18). Reactions of benzophenone hydrazone and
benzophenone imine occurred in high yield with 1.0 mol%
catalyst (entries 19–23). Catalyst loadings have not yet been
optimized with these reagents. Products from diarylation
were observed by GC/MS only for the reaction of octylamine
with 4-chloroanisole.[36]
those generated from monodentate ligands.[9,10,21,38,42] How-
ever, complexes of this Josiphos ligand catalyze reactions of
primary amines with chloroarenes possessing a free alcohol,
phenol, carboxylic acid, amide, or enolizable ketone func-
tionality in high yields with LHMDS (= LiN(SiMe3)2) as
base.[40,41] Reactions of primary alkyl amines with aryl
chlorides possessing related functional groups were previ-
ously limited to electron-poor aryl chlorides containing an
ester functionality.[9,42] No examples of reactions of primary
amines with chloroarenes containing the functional groups of
the substrates collected in Table 3 have been published
previously.
Thus far, no single combination of metal and ligand
generates the most reactive catalyst for coupling of all types of
amines and aryl halides. The strengths of the catalyst reported
here complement those of previously reported catalysts that
contain hindered monodentate ligands. The former is less, the
latter more reactive toward secondary than toward primary
amines. The high reactivity of catalysts containing the
hindered bis(dialkyl) phosphanyl Josiphos ligand L results
One benefit of the palladium-catalyzed route to N-aryl
amines is the high tolerance of the reaction for functional
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Experimental Section
Representative procedures: Procedure without a glovebox (Table 1,
entry 2):
A stock solution (100 mL) containing Pd(OAc)2 (1 ꢀ
10ꢀ3 mmol) and CyPF(tBu) (1 ꢀ 10ꢀ3 mmol) was added to a 4-mL
vial containing 2-chloropyridine (0.114 g, 1.00 mmol) and NaOtBu
(0.135 g, 1.40 mmol) in 1.0 mL of DME. Octylamine (0.155 g,
1.20 mmol) was then added by syringe. The vial was sealed with a
cap containing a PTFE septum, and the reaction mixture was stirred
at 1008C until the 2-chloropyridine was consumed, as determined by
gas chromatography. The reaction solution was adsorbed directly
onto silica gel, and the product was isolated by eluting with hexane/
ethyl acetate (85:15) to give 3-(N-octylamino)pyridine as a yellow
solid (178.1 mg, 86% yield).
[19] B. U. W. Maes, K. T. J. Loones, G. L. F. Lemiere, R. A. Dom-
misse, Synlett 2003, 1822.
[20] G. Burton, P. Cao, G. Li, R. Rivero, Org. Lett. 2003, 5, 4373.
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Procedure with a glovebox (Table 1, entry 1): An oven-dried
resealable Schlenk flask capped with a rubber septum was evacuated
and backfilled with N2. To the flask was added NaOtBu (0.135 g,
1.40 mmol) and a stirring bar. The flask was evacuated and backfilled
with N2 three times. To the flask was then added 3-chloropyridine
(0.114 g, 1.00 mmol, 95.0 mL), DME (1.0 mL), a stock solution
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[25] F. Paul, J. Patt, J. F. Hartwig, Organometallics 1995, 14, 3030.
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[29] Some early reactions of pyridyl bromides with amines were
reported with more flexible and aromatic bisphosphines, but the
scope and activity of these catalytic reactions were limited,
particularly with primary amines and chloropyridines: S. Wagaw,
S. L. Buchwald, J. Org. Chem. 1996, 61, 7240.
(5.0 mL) containing Pd(OAc)2 (5.0 ꢀ 10ꢀ5 mmol) and
L (5.0 ꢀ
10ꢀ5 mmol), and octylamine (0.155 g, 1.20 mmol). The rubber
septum was wrapped with vinyl electrical tape to prevent leaking.
The resulting mixture was stirred for 48 h at 1008C until the 3-
chloropyridine was consumed, as determined by gas chromatography.
The reaction solution was adsorbed directly onto silica gel, and the
product was isolated by eluting with hexane/ethyl acetate (85:15) to
give 204.3 mg (99%) of 3-(N-octylamino)pyridine as a yellow solid.
Received: November 16, 2004
Published online: January 21, 2005
[30] (R)-(ꢀ)-Di-tert-butyl-{1-[(S)-2-(dicyclohexylphosphanyl)ferro-
cenyl]ethyl}phosphine [158923-11-6], Strem catalog number 26-
0975.
[31] For early success with less hindered and less electron-donating
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[34] S. Hashimoto, S. Otani, T. Okamoto, K. Matsumoto, Hetero-
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[35] M. Nishiyama, T. Yamamoto, Y. Koie, Tetrahedron Lett. 1998, 39,
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[36] With 3 equiv of amine, no diarylation product was observed
(Table 2, entry 4).
[37] J. P. Wolfe, S. L. Buchwald, Tetrahedron Lett. 1997, 38, 6359.
[38] J. P. Wolfe, S. L. Buchwald, J. Org. Chem. 2000, 65, 1144.
[39] S. Lee, M. Jorgensen, J. F. Hartwig, Org. Lett. 2001, 3, 2729.
[40] For the use of this base to improve functional-group tolerance
with other catalysts, see: M. C. Harris, X. Huang, S. L. Buchwald,
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[41] S. Urgaonkar, J. G. Verkade, Adv. Synth. Catal. 2004, 346, 611.
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Keywords: amination · heterocycles · homogenenous catalysis ·
P ligands · palladium
.
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