A highly efficient precatalyst for amination of aryl chlorides: Synthesis, structure and application of a robust acenaphthoimidazolylidene palladium complex

Article abstract of DOI:10.1039/c1cc15503b

A robust palladium NHC complex was synthesized and exhibits exceptional activity and selectivity as a precatalyst in the amination of aryl chlorides and tolerates a wide range of substrates at low catalyst loadings.

Full text of DOI:10.1039/c1cc15503b

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COMMUNICATION
A highly efficient precatalyst for amination of aryl chlorides: synthesis,
structure and application of a robust acenaphthoimidazolylidene
palladium complexw
Tao Tu,* Weiwei Fang and Jian Jiang
Received 6th September 2011, Accepted 10th October 2011
DOI: 10.1039/c1cc15503b
A robust palladium NHC complex was synthesized and exhibits
exceptional activity and selectivity as a precatalyst in the
amination of aryl chlorides and tolerates a wide range of
substrates at low catalyst loadings.
Due to various potential applications of aryl amines in chemistry,
materials science and industries,1 it is a very active and intriguing
research field to develop an efficient practical protocol to synthesize
them. In comparison with other traditional methodologies,2
Fig. 1 Pyridine-stabilized palladium NHC complexes.
the palladium catalyzed amination of aryl halides represents a
potential applications in catalysis and soft matter aspects.9,10
powerful tool for its high level of selectivity, mild reaction
conditions and excellent tolerance to functional groups.3 In
And we found that the less intensively studied ylidenes derived
from benzimidazolium or other p-extended arylimidazolium
salts behave differently. As stronger s-donors and weaker
p-acceptors they increase the electron density of the metal
center improving the catalytic activity.10,11 Following this
concept, we now report the synthesis of a robust palladium
NHC complex 2 and explore its catalytic potential towards
amination at low catalyst loadings.
terms of cost, robustness and availability, aryl chlorides
represent highly desirable electrophiles as alternatives for aryl
bromides, iodides and triflates,4 although their reactivity is
relatively low. Therefore, the amination of chloroarenes is still
considered as a challenge, especially, at a low catalyst loading.
Until now, a variety of bulky tertiary phosphines were
designed and synthesized for this purpose, and some of them
like Buchwald’s biaryl phosphines revealed high activity in the
amination.5 In contrast to air sensitive phosphines, N-heterocyclic
carbenes (NHCs) represent environmentally friendly robust
ligands and have exhibited much promise in palladium catalyzed
amination.6,7 Recently, Organ and coworkers reported pyridine
stabilized NHC palladium complexes 1 (Fig. 1), which demon-
strated high activity towards amination,6 in some cases, the
precatalysts even tolerated sterically encumbered substrates.
However, their application as a practical protocol is still
hampered by the facts that (1) a high catalyst loading (usually
2–10 mol%) is required to achieve a satisfied conversion, (2)
the arylation of weak nucleophilic anilines and heterocyclic
substrates still represents a challenging task, and (3) a mild
catalytic system that tolerates secondary amines and primary
amines at the same time is still unknown.8
Palladium complex 2 was readily accessible in a good yield
from the corresponding acenaphthoimidazolium salt by heating
with PdCl2 and K2CO3 in neat 3-chloropyridine. Yellow needle-
shaped crystals were obtained by slow diffusion of petroleum
ether into a dichloromethane solution of complex 2, which were
suitable for single crystal diffraction analysis. The molecular
structure of complex 2 is depicted in Fig. 1. As anticipated the
space around the Pd center is quite congested in contrast to its
imidazol-2-ylidene analogues. The two phenyl rings are almost
perpendicular to the plane of the acenaphtho-ring; the distance of
Pd–C is 1.960(6) A, which is shorter than that in 112 due to the
stronger s-donor property of the acenaphtho-ring.
Initially, various reaction conditions were investigated in the
amination of chlorobenzene with morpholine (Table 1). In the
presence of DME, t-BuOK and complex 2, the yield of
product 3 was merely unchanged when the catalyst loading
was reduced from 1 mol% to 0.5 mol%, even when the
temperature was lowered from 80 1C to 25 1C (94–96%, entries
1–4, Table 1). Upon further decrease of the catalyst loading to
0.05 mol% after 24 hours at 80 1C, a 73% yield was still
obtained (entry 5, Table 1). By extending the reaction time to
48 hours or slightly increasing the catalyst loading to 0.075 mol%,
83% and 91% yields of 3 were observed, respectively (entries 6
and 7, Table 1). Other inorganic and organic bases such as
Recently, we have developed a series of pyridine-bridged
pincer NHC metal complexes and have demonstrated their
Department of Chemistry, Fudan University, 220 Handan Road,
200433, Shanghai, China. E-mail: taotu@fudan.edu.cn;
Fax: +86 21-65102412
w Electronic supplementary information (ESI) available: Synthesis of
complex 2 and other experimental details. CCDC 847153. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c1cc15503b
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12358 Chem. Commun., 2011, 47, 12358–12360
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Table 1 Condition screening and optimizationa
heterocyclic and bulky chloroarenes all afforded excellent
yields (6–9, 95–98%) indicating an inconspicuous stereo-electronic
effect. If the catalyst loading increased to 0.5 mol%, sterically
more demanding substrates, such as 9-chloroanthracene and
2-chloro-1,3-dimethylbenzene, were also successfully coupled
to provide 10 and 11 in 78% and 93% yields, respectively. The
weaker base Cs2CO3 promoted reactions when arenes with a
specific electronic nature, such as 4-chloronitro-benzene and
2-chloropyrazine, were applied (6c and 8, >99% and 95%)
with 0.5 mol% of complex 2. In addition, under the same
conditions 7 could be prepared on a 16 gram (100 mmol) scale in
a quantitative yield which demonstrates the protocol scalability.
Encouraged by the aforementioned results, a number of
cyclic amines and anilines were also tested. The coupling of
N-methylpiperazine with chlorobenzene and 2-chloropyridine
provided up to quantitative yields (12a and 12b, >99% and
93%, respectively). At 0.5 mol% catalyst loading, N-phenyl-
piperazine was smoothly coupled with 2-chloropyridine to
produce 12c in a 93% yield. The ring size of cyclic amines
exhibited an unnoticeable effect; pyrrolidine, piperidine and
azepane resulted in similar yields (97–98%, 13a–c). When
N-methylanilines were involved, the electronic properties of
the substituents in the phenyl ring hardly influenced the
results, affording the products 14a–c in 93–96% yields. The
protocol was further extended to diarylation of piperazine in a
90% yield of 15 under the standard conditions indicating the
powerful applicability of complex 2.
Entry
2 (mol%)
Solvent
Temp./1C
Yieldb (%)
1
2
3
4
5
6
7
8
1
0.5
0.5
0.5
0.05
0.05
0.075
0.075
0.075
0.075
0.075
/
DME
DME
DME
DME
DME
DME
DME
Toluene
THF
80
80
50
25
80
80
80
80
80
80
50
80
96
96
95
94
73
83c
91
93
92
98
30
29d
9
10
11
12
Dioxane
Dioxane
Dioxane
a
b
2 mmol scale for 24 h. Isolated yield. After 48 h. After 72 h.
c
d
Cs2CO3, Et3N and DBU afforded unsatisfactory results
(o58%, see ESIw), which confirmed that the choice of base
is critical.6,13 Dioxane resulted in a better yield than toluene
and THF, (98% vs. 92 and 93% entries 8–10, Table 1). Upon
further decreasing the temperature to 50 1C, a yield compar-
able to that in the blank test was observed (30 and 29%,
entries 11 and 12, Table 1).
With a defined catalytic system, the scope of reactions with
various amines was then explored. As shown in Table 2, the
protocol well tolerates diverse electronic and steric substituents
on both sides of the reacting partners, as well as heterocyclic
substrates. The relative position of substituents in the arenes
hardly affected the efficiency of the coupling process; almost
identical results were observed with o-, m-, p-chlorotoluene
(4a–c, 97–98%). The protocol was further extended to other
electron-rich substrates; for instance, p-chloroanisole afforded
an 89% yield of 5a. Almost a quantitative yield of 5b was
achieved when p-piperidylchlorobenzene was tested with a
0.5 mol% catalyst loading. To our delight, electron-deficient,
Primary amines were regarded as rather poor partners in the
previously reported Pd–NHC and most Pd–phosphine cataly-
tic systems. Therefore, various primary amines were also
involved to evaluate the catalytic activity of precatalyst 2
(Table 3). To our delight, only monoamination product 16
was obtained (77% yield) in the presence of 0.075 mol%
catalyst, which could be further enhanced to 95% by increas-
ing the catalyst loading to 0.5 mol%. The amination of
sterically encumbered substrates constitutes a challenging
task, especially for primary amines. Therefore, 2,6-dimethyl-
chlorobenzene was selected in the further investigation. Under
optimal conditions, the amination by aniline proceeded very
Table 2 Amination of chloroarenes with secondary aminesa
Table 3 Amination of chloroarenes with primary aminesa
a
b
2 mmol scale for 24 h. Isolated yield. With 0.5 mol% 2. Cs2CO3
c
d
a
b
2 mmol scale with 0.5 mol% 2. Isolated yield. With 0.075 mol% 2.
c
e
with 0.5 mol% 2. 100 mmol scale with 0.5 mol% 2.
c
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well to afford 17 in a 97% yield. Similar results (88–96%) were
also observed with products 18–24, which further demon-
strated that electronic and steric properties of the substituents
in the arylamines are fully compatible. Electron-donating
groups facilitate the amination and are slightly more efficient
than electron-deficient groups (91–92% vs. 88% for 19a and
20 vs. 19b). To our surprise, more hindered substrates, such as
2,4,6-trimethylaniline and 2,6-diisopropyl-aniline, even resulted
in better yields (95% and 96% for 22 and 23 respectively) than
naphthylamine (89%, 24). Aliphatic primary amines were also
tolerated, again, the bulky amine resulted in a higher yield
(97% vs. 91%, 26 vs. 25). When a chiral amine was applied, a
94% yield was obtained for the product 27 without influencing
the configuration of the chiral center.
Beside various secondary amines, a wide range of primary
amines were coupled successfully with aryl chlorides in a
monoarylation manner at low catalyst loadings demonstrating
exceptional reactivity, selectivity and stability of the molecular
catalyst derived from complex 2. The protocol represents a
general, practical and scalable approach to access various
structurally intriguing and functionalized arylamines.
Financial support from the National Natural Science Foun-
dation of China (No. 20902001), the Shanghai Municipal and
Technology Commission (2010MCIMKF04 and Qimingxing
Program No. 10A1400500) and the Shanghai Leading Academic
Discipline Project (B108) is gratefully acknowledged.
Notes and references
In order to clarify the possibility of Pd nanoparticles acting
as catalytic species in the amination, catalyst poisoning experi-
ments were involved (see ESIw). At first, a set of mercury tests14
were performed under standard conditions. With 0.075 mol%
precatalyst 2, one drop of Hg was added to the reaction
mixture after 0, 0.5, 1, 3, 6 and 12 hours resulting in 50%,
91%, 91%, 90%, 94%, and 98% yields for product 3, which
suggested that the reaction may follow the NHC–Pd(0) molecular
catalytic route. Secondly, an excess of poly(4-vinylpyridine)
(PVPy) was also included in the catalyst poisoning experi-
ments.14 A 97% isolated yield of 3 confirmed that the mole-
cular catalyst derived from complex 2 played the real role in
the reaction, which may arise from the strong s-donating
property of acenaphthoimidazol-ylidene which stabilized the
Pd–C bond and avoided the formation of Pd nanoparticles.
To further extend the potential application of our protocol
in the pharmaceutical targets, the syntheses of key intermediates
for the antibiotic drug Linezolid and non-steroidal anti-
inflammatory drug Mefenamic acid were performed. The
coupling between o-chloro-fluorobenzene and morpholine
proceeded well with 1 mol% complex 2 and afforded product
28 in 72% (Scheme 1a), which was readily further converted
into Linezolid according to the reported procedure.15a In the
literature, compound 29 was prepared from Mefenamic acid in
four steps under harsh reaction conditions.15b However, with
0.5 mol% complex 2, the amination of 2-chlorobenzonitrile
with 2,3-dimethylaniline resulted in 80% isolated yield of 29
(Scheme 1b), which can be scaled up to 20 mmol. By hydration
of 29, Mefenamic acid was obtained in 95% yield.
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Scheme 1 Synthesis of intermediates of (a) Linezolid and (b) Mefenamic
acid.
c
12360 Chem. Commun., 2011, 47, 12358–12360
This journal is The Royal Society of Chemistry 2011