Amination of aryl chlorides in water catalyzed by cyclopalladated ferrocenylimine complexes with commercially available monophosphinobiaryl ligands

Article abstract of DOI:10.1016/j.tetlet.2006.12.130

The easily accessible, air- and moisture-stable cyclopalladated ferrocenylimine complex 3 was found to be a highly active one-component precatalyst for the amination of aryl chlorides in water in the presence of inexpensive KOH and t-BuOH as a base and an additive, respectively.

Full text of DOI:10.1016/j.tetlet.2006.12.130

Tetrahedron Letters 48 (2007) 1619–1623
Amination of aryl chlorides in water catalyzed by cyclopalladated
ferrocenylimine complexes with commercially available
monophosphinobiaryl ligands
Chen Xu, Jun-Fang Gong and Yang-Jie Wu*
*
Department of Chemistry, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Key Laboratory of Applied
Chemistry of Henan Universities, Zhengzhou University, Zhengzhou 450052, PR China
Received 1 November 2006; revised 21 December 2006; accepted 22 December 2006
Available online 4 January 2007
Abstract—The easily accessible, air- and moisture-stable cyclopalladated ferrocenylimine complex 3 was found to be a highly active
one-component precatalyst for the amination of aryl chlorides in water in the presence of inexpensive KOH and t-BuOH as a base
and an additive, respectively.
Ó 2007 Elsevier Ltd. All rights reserved.
The palladium-catalyzed coupling of amines with aryl
halides or sulfonates, commonly dubbed Buchwald–
Hartwig amination, has evolved into a versatile and effi-
cient synthetic transformation for the preparation of
sors) except for those one-component precatalysts such
as palladacycles. From an economic and practical point
of view, a process featuring an efficient and easy-to-han-
dle catalytic system in combination with an inexpensive
solvent and base would be highly desirable. Water has
clear advantages as a solvent in organic synthesis
1
aromatic amines. A number of Pd complexes derived
from bulky and electron-rich alkylphosphine ligands
are reported to be effective catalysts for the coupling
of notoriously unreactive but relatively cheap aryl chlo-
rides with amines. Some of the notable examples include
9
because it is cheap, readily available and nontoxic. To
our knowledge, only one account has been reported con-
cerning the aminations of limited substrates in water in
1
b,2
2c
the Buchwald’s monophosphinobiaryl ligand family,
Hartwig’s ferrocenylalkylphosphines,
the presence of an inexpensive KOH base. There have
1
c,3
Beller’s di-1-
been, however, several reports which demonstrated that
the addition of water did not impede the amination or
adamantyl(n-butyl)phosphine and pyrrole-, indole- or
4
10
imidazole-based alkylmonophosphines as well as sev-
could even be beneficial.
5
eral lately developed alkylphosphines. In addition,
other strategies such as using bicyclic triaminophos-
We have found cyclopalladated ferrocenylimine–tri-
cyclohexylphosphine complexes are very efficient for
the Suzuki reaction of aryl chlorides with phenylboronic
6
phines, sterically hindered N-heterocyclic carbenes
7
(
NHCs) as ligands, and palladacycles as the precata-
8
11
lysts, also provide efficient catalytic systems for this
transformation.
acid. These precatalysts combine the stability imparted
by a palladacycle framework with the high activity com-
monly associated with alkylphosphine ligands. Follow-
ing this work, we prepared two new cyclopalladated
ferrocenylimine complexes 2 and 3 from the reaction
of cyclopalladated ferrocenylimine dimer 1 with com-
mercially available 2-(dicyclohexylphosphanyl)biphenyl
The Buchwald–Hartwig aminations with the above-
mentioned catalytic systems were usually run in an
organic solvent in the presence of strong bases such as
t-BuONa or t-BuOK and an excess of ligand was
required (commonly 2-fold with respect to Pd precur-
0
(DCPB) or 2-dicyclohexylphosphanyl-2 -(N,N-dimethyl-
amino)biphenyl (DCPAB) (Scheme 1).
Keywords: Amination; Aryl chloride; Water; Cyclopalladated ferrocen-
ylimine complex; Monophosphinobiaryl ligand.
The two complexes are air- and moisture-stable both in
the solid state and in solution. Despite the fact that com-
plex 2 could, in principle, exist in both cis and trans
*
Corresponding authors. Tel.: +86 371 67763207; fax: +86 371 67766667
J.-F.G.); e-mail addresses: gongjf@zzu.edu.cn; wyj@zzu.edu.cn
(
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.130

1620
C. Xu et al. / Tetrahedron Letters 48 (2007) 1619–1623
N
N
L
PCy2
PCy2
Fe
Pd Cl
Fe
Pd
CH Cl , r.t.
Me2N
2
2
Cl
2
L
1
2
3
: L = DCPB
: L = DCPAB
DCPB
DCPAB
Scheme 1.
mation of a single isomer. While complex 3 showed two
peaks at d 65.7 and 64.7 ppm, suggesting the formation
1
1
of isomers in solution. The single-crystal X-ray analy-
sis confirms that complexes 2 and 3 are trans complexes
in the solid state and the molecular structure of complex
3
is shown in Figure 1.
We first chose the coupling of chlorobenzene with p-
toluidine as the model reaction to evaluate the effective-
ness of the new palladacycles in the amination of aryl
chlorides in water and to optimize the reaction condi-
1
2
tions (Table 1). It was disappointing to find at the
beginning that the isolated yield of the coupled product
was only 31% with 1 mol % of 3 in the presence of
3
equiv of KOH (entry 1). However, when the strong
organic base t-BuOK was used, the yield increased
dramatically to 98% (entry 2). Since t-BuOK would
hydrolyze to give t-BuOH and KOH in water, 4 equiv
of t-BuOH was added with KOH as the base in the fol-
lowing experiments. As expected, chlorobenzene could
be coupled very efficiently with p-toluidine giving 4-
methyldiphenylamine in a 98% yield (entry 3). On the
basis of this finding, we also examined the effect of some
other alcohols such as EtOH, n-BuOH, i-PrOH and
cyclohexanol. However, all the four alcohols proved to
be ineffective (yields in 28%, 42%, 35% and 33%, respec-
tively; data not shown). Testing different bases (e.g.,
Figure 1. Molecular structure of complex 3. Hydrogen atoms are
omitted for clarity, thermal ellipsoids at 30% probability. Selected
˚
bond lengths (A) and angles (°): Pd(1)–C(6) 2.010(8), Pd(1)–N(1)
2.149(7), Pd(1)–P(1) 2.271(2), Pd(1)–Cl(1) 2.404(2) and C(6)–Pd(1)–
N(1) 79.6(3), C(6)–Pd(1)–P(1) 90.6(3), P(1)–Pd(1)–Cl(1) 92.79(8),
N(1)–Pd(1)–Cl(1) 92.1(2).
forms corresponding to the relative disposition of the
coordinate P-ligand to the imino nitrogen, the only sig-
NaOH, K
CO , Na CO , K PO ) in the presence of t-
2
3 2 3 3 4
3
1
nal at d 59.5 ppm in P NMR spectra suggested the for-
BuOH revealed that KOH was the most effective base
Table 1. Optimization of reaction conditions for the coupling of chlorobenzene with p-toluidine
Pd Cat., Water
Cl + H2N
CH3
HN
CH3
Base
a
Entry
Catalyst (mol %)
Base
Yield (%)
b
1
3 (1)
3 (1)
3 (1)
3 (1)
3 (1)
3 (1)
3 (1)
2 (1)
1 (1)
KOH
t-BuOK
KOH
31
98
98
63
20
44
22
44
0
b
2
3
4
5
6
7
8
9
NaOH
K
3
PO
4
Na
2
CO
3
2 3
K CO
KOH
KOH
KOH
KOH
KOH
KOH
KOH
10
11
12
13
14
1/PCy
1/DCPAB (0.5/2)
PdCl /DCPAB (1/2)
Pd(OAc)
Pd (dba)
3
(0.5/2)
0
68
24
59
50
2
2
/DCPAB (1/2)
2
3
/DCPAB (0.5/2)
Conditions: PhCl/p-toluidine/base/t-BuOH = 1:1.2:3:4 (molar ratio), H
2
O, reaction temperature 95 °C, 24 h.
a
Isolated yield.
b
t-BuOH was not added.

C. Xu et al. / Tetrahedron Letters 48 (2007) 1619–1623
1621
(
entries 4–7). The second effective base was NaOH,
coupling of aryl chlorides11 (entries 9–10). A significant
increase in activity was observed with 1/DCPAB system
(68%, entry 11) and it was more active than the com-
monly used Pd(0) or Pd(II) precursors (Pd (dba) or
which is also a hydroxide base and gave a moderate
yield (63%, entry 4).
2
3
Then the activities of several related catalytic systems in
the same model reaction were investigated. Among
them, complex 3 was found to be the most active one-
component precatalyst. The similar complex 2 without
a N,N-dimethylamino group in comparison with com-
plex 3 generated the coupled product only in a 44% yield
under the same conditions (Table 1, entry 8). The
dimeric complex 1 and 1/PCy3 system were inactive
PdCl2 and Pd(OAc) ) in combination with DCPAB
(entries 12–14).
2
With the optimized reaction conditions (complex 3 as
precatalyst, KOH, t-BuOH, water) in hand, the coupling
reactions between chlorobenzene and a variety of
amines were carried out to explore the scope of this
system (Table 2). The desired coupled products were
obtained in excellent yields (90–96%) with 1 mol % of
although PCy was an excellent ligand for the Suzuki
3
Table 2. Arylation of various amines with chlorobenzene catalyzed by 3
Pd Cat., Water
2
Cl + H N R
NHR
KOH, t-BuOH
a
Entry
1
Amine
Catalyst (mol %)
1
Product
Yield (%)
92
NH2
NH
H C
3
H C
3
2
1
96
NH2
NH
CH3
NH2
CH
3
3
4
1
1
NH
90
93
H C
3
H3C
NH2
HN
H CO
H CO
3
3
5
6
7
1
1
1
88
90
72
NH2
NH
EtO
NH2
EtO
NH
OCH3
NH2
OCH
NH
CH3
3
CH3
8
9
NH2
CH3
2
1
NH
CH3
66
81
CH3
N
H CHN
3
1
1
1
1
1
0
1
2
3
4
PhCH
2
NH
2
2
0.5
1
PhCH NH
72
96
51
67
73
2
PhCH
2
NH
PhCH NH
2
C
4
H
9
NH
2
1
C H NH
4 9
NH
1
NH
N
2
HN
O
1
O
Conditions: PhCl/amine/KOH/t-BuOH = 1:1.2:3:4 (molar ratio), H
Isolated yield.
2
O, reaction temperature 95 °C, 24 h.
a

1622
C. Xu et al. / Tetrahedron Letters 48 (2007) 1619–1623
complex 3 in the case of electron-neutral primary aryl-
tions (Table 3). Similar to the results of varying amine
part, good to excellent yields (87–97%) were obtained
with 1 mol % of the catalyst in the reactions between
p-toluidine and the electron-neutral aryl chlorides
including o-chlorotoluene (entries 1–3). Even the elec-
tron-rich 4-chloroanisole could afford the desired prod-
uct in an excellent yield (94%, entry 4). Also similarly, an
obvious decrease in yields was observed in the case of
2-chloroanisole and very sterically hindered 2-chloro-m-
xylene (entries 5–6). For electron-deficient aryl chlorides
such as 3-chloronitrobenzene and 4-chloroacetophe-
none, the coupling proceeded very efficiently with a cat-
alyst loading as low as 0.5 mol % and 73% yield could
still be obtained with 0.2 mol % of the catalyst (entries
7–10). Since the coupling of arylamines containing
amines even including the one with an o-CH group
3
(
entries 1–4). For electron-rich primary arylamines with
an alkoxy group in the meta or para-position, the yields
decreased slightly but still were very high (88% and 90%,
entries 5–6). A further decrease in the yield was observed
when the alkoxy group was located in the ortho-position
(
72%, entry 7). The very sterically hindered 2,6-dimethyl-
aniline could provide the corresponding arylamine in a
6% yield with 2 mol % of catalyst (entry 8). A second-
6
ary arylamine gave a good yield (81%, entry 9). Com-
pared with the results of arylamines, the present
catalytic system was found to be less effective for the
coupling of aliphatic primary or secondary amines with
the exception that benzylamine afforded an excellent
yield (entries 10–14). Finally, it needed to be pointed
out that the coupling of arylamines containing –NO2,
–NO or –CO– group were found to be unsuccessful
2
in the previous study, the efficient coupling of aryl
–
OH or –CO– group with chlorobenzene was
chlorides containing –NO or –CO– group provided a
2
unsuccessful.
valuable complement for the preparation of the
corresponding arylamines. Finally, the coupling of a
heteroaryl chloride (3-chloropyridine) with p-toluidine
gave the desired product in a 78% yield (entry 11).
The scope of the amination was further investigated by
varying the aryl chlorides under the optimized condi-
Table 3. Amination of various aryl chlorides with p-toluidine catalyzed by 3
Pd Cat., Water
ArCl + H2N
CH
3
Ar HN
CH3
KOH, t-BuOH
a
Entry
1
Aryl halide
H C
Catalyst (mol %)
1
Product
H3C
Yield (%)
97
3
Cl
NH
CH3
CH3
Cl
CH
3
2
3
1
1
87
NH
CH
3
Cl
NH
CH3
97
4
5
H CO
Cl
1
1
H CO
3
NH
CH
3
94
81
3
OCH3
Cl
OCH3
NH
CH3
CH3
CH3
NH
6
7
Cl
2
CH3
61
98
CH3
CH3
O
O
0.5
H CC
Cl
H3CC
NH
NH
CH3
3
O
O
8
9
0.1
0.1
39
52
H CC
Cl
H CC
CH3
3
3
O N
O N
2
2
Cl
NH
CH3
O N
O N
2
2
1
1
0
1
0.2
1
73
78
Cl
NH
CH3
Cl
NH
CH3
N
N
Conditions: aryl chloride/p-toluidine/KOH/t-BuOH = 1:1.2:3:4 (molar ratio), H
Isolated yield.
2
O, reaction temperature 95 °C, 24 h.
a

C. Xu et al. / Tetrahedron Letters 48 (2007) 1619–1623
1623
In conclusion, we have demonstrated that easily accessi-
ble, air- and moisture-stable cyclopalladated ferrocenyl-
imine complex 3 is an effective precatalyst for the
coupling of a variety of electronically and structurally
diverse aryl chlorides with various amines in water.
The advantages of the present process include an easy-
to-handle one-component precatalyst, the use of water
as a solvent as well as inexpensive KOH and t-BuOH
as a base and an additive, respectively.
Chem. Eur. J. 2004, 10, 2983; (b) Harkal, S.; Rataboul, F.;
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Org. Chem. 2006, 71, 3928; (b) Xie, X.; Zhang, T.; Zhang,
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6. Urgaonkar, S.; Verkade, J. G. J. Org. Chem. 2004, 69,
135, and references cited therein.
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Acknowledgements
1
P. J. Org. Chem. 2001, 66, 7729; (c) Marion, N.; Navarro,
O.; Mei, J.; Stevens, E. D.; Scott, N. M.; Nolan, S. P. J.
Am. Chem. Soc. 2006, 128, 4101, and references cited
therein.
We thank the National Natural Science Foundation
of China (20472074) and the Innovation Fund for
Outstanding Scholar of Henan Province (0621001100)
for the financial support of this work. We are grateful
to Mr. Jeffrey Misiaszek and Dr. Yusheng Wu for the
valuable discussion on this Letter.
8. For palladacyclic precatalysts in amination of aryl chlo-
rides see: (a) Schnyder, A.; Indolese, A. F.; Studer, M. H.;
Blaser, U. Angew. Chem., Int. Ed. 2002, 41, 3668; (b)
Viciu, M. S.; Kelly, R. A., III; Stevens, E. D.; Naud, F.;
Studer, M.; Nolan, S. P. Org. Lett. 2003, 5, 1479; (c)
Bedford, R. B.; Cazin, C.; Coles, S. J.; Gelbrich, T. P.;
Horton, N.; Hursthouse, M. B.; Light, M. E. Organomet-
allics 2003, 22, 987; (d) Bedford, R. B.; Blake, M. E. Adv.
Synth. Catal. 2003, 345, 1107; (e) Zim, D.; Buchwald, S. L.
Org. Lett. 2003, 5, 2413.
. (a) Grieco, P. A. Organic Synthesis in Water; Blackie
Academic & Professional: New York, 1998; (b) Li, C. J.;
Chan, T. H. Organic Reaction in Aqueous Media; Wiley &
Sons: New York, 1998.
0. (a) Kuwano, R.; Utsunomiya, M.; Hartwig, J. F. J. Org.
Chem. 2002, 67, 6479; (b) Yin, J.; Zhao, M. M.; Huffman,
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Supplementary data
Electronic supplementary data: general experimental
procedure for the synthesis of complexes 2 and 3, their
characterization data including crystal structure data,
crystal structure of 2 including selected bond lengths
and angles. Supplementary data associated with this
article can be found, in the online version, at
doi:10.1016/j.tetlet.2006.12.130.
9
1
References and notes
1
. For reviews see: (a) Schlummer, B.; Scholz, U. Adv. Synth.
Catal. 2004, 346, 1599, and references cited therein; (b)
Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U.
Adv. Synth. Catal. 2006, 348, 23; (c) Hartwig, J. F. Synlett
1
1
1. (a) Gong, J. F.; Liu, G. Y.; Du, C. X.; Zhu, Y.; Wu, Y. J.
J. Organomet. Chem. 2005, 690, 3963; (b) Xu, C.; Gong, J.
F.; Yue, S. F.; Zhu, Y.; Wu, Y. J. Dalton Trans. 2006,
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730.
2
006, 9, 1283.
. (a) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed.
999, 38, 2413; (b) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.;
2. General amination procedure: In a Schlenk tube, a
solution of prescribed amount of catalyst, aryl chloride
2
1
(
0.5 mmol), amine (0.6 mmol), base (1.5 mmol) and tert-
Yin, J.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1158; (c)
Huang, X. H.; Anderson, K. W.; Zim, D.; Jiang, L.;
Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
butanol (0.192 mL, 2 mmol) in water (3.0 mL) was evac-
uated and charged with nitrogen. The operation was
repeated three times. Then the reaction mixture was
heated at 95 °C (reaction temperature) for 24 h. After
cooling, the reaction mixture was extracted three times
with dichloromethane. The combined organic layers were
6
653.
3
. (a) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F.
J. Org. Chem. 2002, 67, 5553; (b) Shen, Q.; Shekhar, S.;
Stambuli, J. P.; Hartwig, J. F. Angew. Chem., Int. Ed.
4
washed with water, dried (MgSO ) and evaporated to
2
005, 44, 1371.
dryness. The products were isolated by flash chromato-
4
. (a) Rataboul, F.; Zapf, A.; Jackstell, R.; Harkal, S.;
Riermeier, T.; Monsees, A.; Dingerdissen, U.; Beller, M.
1
graphy on silica gel, and analyzed by H NMR.