Room-temperature nickel-catalyzed amination of heteroaryl/aryl chlorides with Ni(II)-(σ-Aryl) complex as precatalyst

Article abstract of DOI:10.1016/j.jorganchem.2011.03.038

The room-temperature cross-coupling of heteroaryl and aryl chlorides with secondary cyclic amines can be effected using Ni(II)-(σ-aryl) complex as pre-catalyst. Some useful aromatic and heteroaromatic amine derivatives were readily synthesized in moderate to good yields in the presence of the Ni(II)-(σ-aryl) complex/NHC/KO^tBu/toluene system.

Full text of DOI:10.1016/j.jorganchem.2011.03.038

Journal of Organometallic Chemistry 696 (2011) 2482e2484
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Journal of Organometallic Chemistry
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Communication
Room-temperature nickel-catalyzed amination of heteroaryl/aryl chlorides with
Ni(II)e( -Aryl) complex as precatalyst
s
,
,
Xin-Heng Fan a b, Gang Li a, Lian-Ming Yang a
*
a Beijing National Laboratory for Molecular Sciences (BNLMS), Laboratory of New Materials, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
b Graduate School of Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The room-temperature cross-coupling of heteroaryl and aryl chlorides with secondary cyclic amines can
Received 28 February 2011
Received in revised form
30 March 2011
be effected using Ni(II)-(s-aryl) complex as pre-catalyst. Some useful aromatic and heteroaromatic amine
derivatives were readily synthesized in moderate to good yields in the presence of the Ni(II)-(
s-aryl)
complex/NHC/KOtBu/toluene system.
Accepted 31 March 2011
Ó 2011 Elsevier B.V. All rights reserved.
Keywords:
Amination
(Hetero)aryl chloride
Cross-coupling
Nickel
Room-temperature reaction
1. Introduction
couplings of aryl and heteroaryl chlorides with various nitrogen-
containing substrates. Lipshutz extended this methodology by
using a heterogeneous Ni(0)-on-charcoal catalyst [11]. In view of
the facts that air-sensitive Ni(0) sources are difficult to handle and
the pre-treatment of Ni(II) precursors with strong reducing
reagents such as n-BuLi, Grignard reagents or NaH could decrease
compatibility of the reactions with functional groups, Knochel
utilized polymethylhydrosiloxane (PMHS) as a mild and effective
reductant in the Ni(II) precatalyst with excellent results [12].
Our group explored a more facile protocol for aromatic CeN
bond-forming reactions by employing stable arylnickel(II) halides
complexes as catalyst precursors, where the Ni(II) precursor, in
conjunction of NHC ligands, could be ‘self-activated’ to the Ni(0)
species without the need of additional reducing agents [13,14].
Very recently, Nicasio revealed the first room-temperature nickel-
catalyzed amination of (hetero)aryl chloride utilizing a preformed
organonickel(II) complex, [(NHC)Ni(allyl)Cl], as easily-activated
precatalyst [15].
From a synthetic point of view, room-temperature transformations
represent a highly desirable process. However, room-temperature
nickel-catalyzed aminations have been extremely rare, and the
diverse protocols for this goal remain to urgently be needed. Based on
our previous studies [13,14] and inspired by Nicasio’s work [15], we
were interested in exploring the possibility of room-temperature
nickel-catalyzed aromatic aminations by utilizing a special class of
Ni(II) complexes, trans-haloarylbis(triphenylphosphine)nickel(II), as
(Hetero)aryl amines constitute an important class of building
blocks extensively used in the synthesis of pharmaceuticals,
agrochemicals and chemical materials, etc [1]. Therefore, the
development of efficient and practical methods for the formation of
aromatic CeN bonds (the BuchwaldeHartwig reaction) is of
particular interest to synthetic chemists. In catalytic amination
reactions, palladium-based systems certainly represent the most
widely used class of catalysts that allow (hetero)aryl halides/
pseudohalides to be effectively aminated under mild reaction
conditions [2,3]. On the other hand, the choice of nickel complexes
as alternatives has been attracting considerable interest due to
their low cost and potential high reactivity towards easily-available
but relatively inert substrates (e.g., aryl chlorides and sulfonates)
without the use of specially tailored ligands.
Buchwald in 1997 first reported the nickel-catalyzed amination
of aryl chlorides in the presence of Ni(0)/DPPF or 1,10-phenan-
throline [4]. Bolm provided the example for the amination of aryl
tosylates with sulfoximines by employing BINAP as ligand for
Ni(0) [5]. Fort developed the Ni(II)eNaHebipyridine [6e9] and
Ni(II)eNaHeNHC [10] systems as efficient catalysts for the
* Corresponding author. Tel.: þ86 10 62565609; fax: þ86 10 6255 9373.
E-mail address: yanglm@iccas.ac.cn (L.-M. Yang).
0022-328X/$ e see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2011.03.038

X.-H. Fan et al. / Journal of Organometallic Chemistry 696 (2011) 2482e2484
2483
Table 2
catalyst precursors, which have successfully been applied in some
catalytic CeN [13,14,18] and CeC [16,17] coupling reactions. The
Ni(II)e( -aryl) complexes are easily prepared from cheap starting
materials and insensitive to air and moisture, making them highly
preferred catalyst precursors [19]. Herein, we wish to disclose our
preliminary findings concerning nickel-catalyzed aminations of aryl
and heteroaryl halides at room temperature.
a
Room-Temperature Ni(II)-Catalyzed Amination of Aryl/Heteroaryl chloride.
s
R
NH
R'
R
N Ar
R'
C-1/IPrHCl
KOtBu, toluene
Cl Ar
Entry
1
Amine
CleAr
Product
Yieldb(%)
99
Cl
N
O
2. Results and discussion
HN
A catalytic room-temperature amination of chlorobenzene with
morpholine was performed to screen the optimal reaction condi-
tions (Table 1). In an initial trial, we found that a combination of
Ni(PPh3)2(1-naphthyl)Cl (C-1), IPr,HCl and NaOtBu, which was
effective for the same reaction under the heating conditions [13],
did not cause any conversion to occur (Table 1, entry 1), but the
desired product can be obtained in almost quantitative yield if
NaOtBu is replaced with KOtBu (entry 2). The reason is likely that
the basicity of NaOtBu is weak so that it is unable to free an effective
IPr ligand from its hydrochloric salt precursor IPr,HCl. This was
further confirmed when IPr,HCl was not added to the reaction
2
3
92
98
HN
HN
N
O
Cl
Cl
N
O
4
5
90
N
O
Cl
HN
HN
O
O
Cl
N
O
70c
Ph
Ph
6
7
82d
88
O
N
N
O
Cl
Cl
HN
HN
N
Cl
system (entry 3). The use of another Ni(II)e(s-aryl) complex,
N
N
O
O
Ni(PPh3)2(1-naphthyl)Br (C-2), offered an excellent outcome
similar to C-1 did (entry 4), but commonly used Ni(II) sources such
as Ni(acac)2 and Ni(PPh3)2Cl2 were ineffective for this reaction
(entries 5 and 6), indicating that the catalytically active Ni(0)
species was not produced from these Ni(II) precursors under these
mild conditions. It was found that a 1:0.5e2 molar ratio of C-1 to
IPr,HCl seemed to be a suitable range for giving excellent results
(entries 2, 7 and 8 vs. entry 9). Among other ligands used,
PCy3,HBF4 (entry 10), PPh3 (entry 11) and 2,20-bipyridine (entry 12)
Cl
N
8
9
98
80
HN
HN
N
O
N
N
N
N
Cl
O
N
N
10
11
12
Cl
N
O
99
90
50
HN
HN
HN
S
S
N
Cl
N
O
N
O
N
Cl
Table 1
13
14
69
63
HN
HN
Screening of conditions for Ni(II)-catalyzed amination of chlorobenzene. a
N
N
N
Cl
N
O
N
O
Ni(II)/Ligand
Cl
N
N
O
HN
O
Cl
Base, Solvent
Cl
N
15
16
72
80
HN
N
N
N
O
Entry [Ni(II)] b (mol%) Ligand (mol%)
Base
NaOtBu toluene
Solvent (5 mL) Yieldc (%)
Cl
HN
N
N
1
2
3
C-1 (5)
C-1 (5)
C-1 (5)
IPr,HCl d (5)
IPr,HCl (5)
none
0
99
0
97
0
n-Bu
N
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
THF
17
N
70
HN
HN
S
n-Bu
4
5
C-2 (5)
Ni(acac)2 (5)
IPr,HCl (5)
IPr,HCl (5)
N
Cl
18
19
N
79
HN
N
O
6
Ni(PPh3)2Cl2 (5) IPr,HCl (5)
0
52e
7
8
9
C-1 (5)
C-1 (5)
C-1 (5)
C-1 (5)
C-1 (5)
C-1 (5)
C-1 (5)
C-1 (5)
C-1 (5)
C-1 (5)
C-1 (3)
IPr,HCl (10)
IPr,HCl (2.5)
IPr,HCl (1.25)
99
99
50
0
0
0
60
27
22
23
95
80
44
HN
NH
Cl
N
N
n-Bu
n-Bu
n-Bu
n-Bu
20
21
N
trace
trace
23
PCy3,HBF4 (10) KOtBu
HN
Cl
Cl
10
11
12
13
14
15
16
17
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
H
N
PPh3 (10)
Bipy e (5)
NH2
DPPF f (5)
Phena g (5)
IPr,HCl (5)
IPr,HCl (5)
IPr,HCl (6)
IPr,HCl (3)
IPr,HCl (1.5)
22
n-C12H25NH2
N
Cl
11
toluene
a
Reaction conditions: the chloride (1 mmol), amine (3 mmol), C-1(0.05 mmol),
IPr,HCl (0.05 mmol), KOtBu (4 mmol), toluene(5 mL), room temperature (ca. 23 ꢀC), 24 h.
a
Reaction conditions: chlorobenzene (1.0 mmol), morpholine (3.0 mmol), base
(4.0 mmol), toluene (5 mL), room temperature (ca. 23 ꢀC), 24 h.
b
Isolated yield.
b
C-1: Ni(PPh3)2(1-naphthyl)Cl; C-2: Ni(PPh3)2(1-naphthyl)Br.
Isolated yield.
c
C-1 (0.15 mmol), IPr,HCl (0.15 mmol).
c
d
Morpholine (6 mmol), C-1 (0.10 mmol), IPr,HCl (0.10 mmol), KOtBu (8 mmol),
d
IPr,HCl: 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride.
toluene (10 mL).
e
Bipy: 2,20-bipyridine.
e
Chlorobenzene (3 mmol), piperazine (1 mmol), C-1(0.10 mmol), IPr,HCl
f
DPPF: 1,10-bis(diphenylphosphino)ferrocene.
(0.10 mmol).
g
Phena: 1,10-phenanthroline.

2484
X.-H. Fan et al. / Journal of Organometallic Chemistry 696 (2011) 2482e2484
did not promote the reaction at all, and DPPF (entry 13) and 1,10-
phenanthroline (entry 14) worked poorly. Apparently, toluene was
the solvent of choice and far superior to ethereal solvents like
dioxane (entry15) and THF (entry 16). In attempts to reduce the
catalyst loadings, we found that although it was feasible for the
reaction to use only 3 mmol% the Ni(II) complex associated with
2 equiv IPr,HCl, a reduced ratio of ligands would substantially
affect the yields (entry 17). Thus, our standard reaction conditions
were finally selected according to entry 2 of Table 1.
followa catalytic cycle of the Ni(0)eNi(II) shuttle involving sequential
oxidative addition, transmetalation, and reductive elimination. The
rate-determining step of the amination reaction is unclear at present.
With the help of base, 1,3-bis(2,6-diisopropylphenyl)imidazolium
chloride frees HCl and offers 1,3-bis(2,6-diisopropylphenyl)imidazol-
2-ylidene, a strongly
s-donating N-heterocyclic carbene, as ligand
which can effectively stabilize the Ni(0) species. Interestingly, mor-
pholine displayed the best reactivity among all the secondary amines
used, but the reason cannot be explained clearly at present and
further work will be needed.
Next, a wide range of (hetero)aryl chlorides and some cyclic
secondary amines were examined under the optimized reaction
conditions. As shown in Table 2, morpholine were N-arylated with
both electron-neutral (entries 1 and 2) and -rich (entries 3 and 4)
chloroarenes in excellent yields; in the case of the substrate bearing
ketone group (entry 5), good yield was achieved when the catalyst
loadings were increased; and p-dichlorobenzene can be doubly
aminated in a higher yield (entry 6). Particularly, heteroaryl chlo-
rides seem to be a class of eletrophilic substrates very suitable for
the coupling reaction. 2-Chloropyridine (entry 7), 3-chloropyridine
(entry 8), 2-chloroquinoline (entry 9), 2-chlorobenzothiazole (entry
10) and 2-chlorobenzoxazole (entry 11) were well coupled with
morpholine, giving high yields of 80e99%. For two other amines
piperidine and pyrrolidine, they did not react very well with aryl
chlorides. For example, the reaction of piperidine and chloroben-
zene afforded only a medium yield of 50% (entry 12), and that of
pyrrolidine almost gave no product (trace amounts of the desired
product, unlisted in Table 2). Generally, heteroaryl chlorides could
react with piperidine (entries 13 and 14) or pyrrolidine (entries
15e18) with good yields. Double arylation of piperazine could
proceed with an acceptable yield of 52% (entry 19). In addition, some
other kinds of amines were also tested in this study. Acyclic
secondaryamine gave onlya trace amount of the product (entry 20);
almost no reaction took place for aniline as well (entry 21). Inter-
estingly, for primary amine (e.g.,1-dodecanamine), both mono- and
di-coupled products were produced with lower yields (entry 22),
and upon increasing the molar amount of 2-chloroquinoline to
3-fold that of the amine, 45% yield of the di-coupled product could
be achieved, with the mono-coupled product being a yield of only 7%.
As shown in Fig. 1, the catalytically active species might be the
Ni(0) species that could be formed in-situ from the reaction of
3. Conclusions
In summary, we have disclosed a simple, efficient protocol for
the room-temperature aromatic CeN cross-coupling reaction
utilizing the Ni(II)e(s
-aryl) complex/NHC/KOtBu system, and some
arylamine and particularly heteroaryl amine derivatives can be
readily synthesized under very mild conditions. Further study to
expand the scope of both substrates is ongoing in our laboratory.
4. Experimental section
General procedure for the room-temperature amination of (hetero)
aryl halides catalyzed by the Ni(II)e(s
-aryl) complex/NHC/KOtBu. An
oven-dried 25-mL three-necked flask was charged with KOtBu
(4 mmol), Ni(PPh3)2(1-naphthyl)Cl (C-1) (0.05 mmol) and IPr,HCl
(0.05 mmol). Then the aryl or heteroaryl halide (1 mmol) if solid
and amine if solid (3 mmol) were added. The flask was evacuated
and backfilled with nitrogen, with the operation being repeated
twice. The halide and amine if liquid, dried toluene (5 ml) were
added via syringe at this time. The reaction mixture was stirred at
room temperature for 24 h, and filtered through a silica-gel pad
that was washed with ethyl acetate. The combined organic phases
were evaporated under reduced pressure and the residue purified
by silica-gel column chromatography to give the desired product.
Acknowledgments
Ni(II)e(
s-aryl) complex with the amine (i.e., by transmetalation of
the nucleophilic reactant and subsequent reductive elimination prior
to the normal reaction). We presumed that the mechanism might
The authors thank National Natural Science Foundation of China
(Project No. 20872142) for financial support of this work.
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LmNi(II)
LmNi(II)
NRR'
Cl
KCl + tBuOH
HNRR' + KOtBu
Fig. 1. A possible mechanistic pathway for the amination reaction.