Nickel-catalyzed N-arylation of amines with arylboronic acids under open air

Article abstract of DOI:10.1016/j.tetlet.2019.04.004

In this study, a well-defined, novel NHC-Ni complex was developed and used to catalyze the N-arylation of alkyl- and arylamines with arylboronic acids in a rare version of Chan-Lam coupling. Although the same coupling using copper catalysts has been widely studied, the nickel-catalyzed version is rare and normally requires 10–20 mol% catalyst loading. This novel NHC-Ni complex in combination with 4,4′-dimethyl-2,2′-bipyridine, however, proved to be an effective catalyst that lowered the required catalyst loading to only 2.0 mol%.

Full text of DOI:10.1016/j.tetlet.2019.04.004

Tetrahedron Letters xxx (xxxx) xxx
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Tetrahedron Letters
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Nickel-catalyzed N-arylation of amines with arylboronic acids under
open air
⇑
⇑
Shin Ando , Yurina Hirota, Hirofumi Matsunaga, Tadao Ishizuka
Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi Chuo-ku, Kumamoto 862-0973, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
In this study, a well-defined, novel NHC-Ni complex was developed and used to catalyze the N-arylation
of alkyl- and arylamines with arylboronic acids in a rare version of Chan-Lam coupling. Although the
same coupling using copper catalysts has been widely studied, the nickel-catalyzed version is rare and
normally requires 10–20 mol% catalyst loading. This novel NHC-Ni complex in combination with 4,40-
dimethyl-2,20-bipyridine, however, proved to be an effective catalyst that lowered the required catalyst
loading to only 2.0 mol%.
Received 5 March 2019
Revised 1 April 2019
Accepted 2 April 2019
Available online xxxx
Keywords:
NHC
Ó 2019 Elsevier Ltd. All rights reserved.
Nickel catalyst
Chan-Lam
CAN coupling
Introduction
catalyst, but fewer investigations have used Ni catalysts compared
with those using Cu catalysis [9]. In particular, Ni-catalyzed ver-
N-Alkyl and N-aryl aniline derivatives are highly important
chemicals in pharmaceutical, agrochemical, and materials sciences.
The classic copper-mediated arylation of amines with arylhalides is
known as the Ullmann-Goldberg coupling, which is normally uti-
lized for the preparation of these chemicals [1]. The development
of palladium-catalyzed coupling between arylhalides and amines
is recognized as Buchwald-Hartwig coupling [2], which has
resulted in reports of numerous transitional-metal catalyzed cou-
plings to form CAN bonds [3]. Currently, Pd, Ni, and Cu are com-
monly used as catalysts for Buchwald-Hartwig coupling (Fig. 1)
[4]. As an alternative, Chan-Lam coupling between amines and
arylboronic acids under aerobic conditions has been effective in
the presence of copper [5]. Compatibility with a wide range of
functional groups and the unique chemoselectivity of Chan-Lam
coupling has attracted a number of chemists and resulted in
expanded applications to form CAC, CAS, CAO, and CAX (X = Cl,
Br, and I) bonds [6]. The original conditions reported in 1998 used
excess stoichiometric amounts of copper [5a,b]; therefore,
reactions using catalytic amounts of copper have been
extensively studied [7]. For example, Schaper and co-workers
recently found that copper(II) pyridyliminoarylsulfonate com-
plexes can catalyze N-arylations with a loading of 2.5 mol% [8].
For the same transformation, nickel has also proven to be a useful
sions require high catalyst loading, and the development of a novel
catalytic system would be an important development towards
addressing this problem. Herein, we report an effective NHC-nickel
catalyzed arylation of amines via Chan-Lam coupling. In this study,
we found that 2.0 mol% of a novel NHC-Ni complex C1 and 4,40-
dimethyl-2,20-bipyridine (dmbpy) co-ligands effectively catalyzes
this reaction. To the best of our knowledge, this is the first example
of an NHC-Ni complex catalyzed Chan-Lam coupling reaction.
Over the past decade, NHC-Ni complexes have shown unique
reactivities in the coupling of amides [10] and the coupling and
reduction of aryl ethers [11]. NHC-supported Ni catalysts are gen-
erally prepared in situ using air-sensitive Ni(COD)2 as a nickel
source and are used directly without further purification [12].
Well-defined classes of NHC-Ni precatalysts have been developed,
but these are not as frequently mentioned as their d10 counterpart
palladium catalysts. In this highly sought-after area, [(NHC)NiCpCl]
half-sandwich complexes are good examples that can be accessed
via simple heating of the NHC precursors in the presence of nicke-
locene [13]. This family is applied to catalytic reactions such as
Suzuki-Miyaura coupling [14], Buchwald-Hartwig amination [15],
and Kumada-Tamao-coupling [16] via activation by organometallic
reagents, alkoxide, or arylboronic acids. Our group recently devel-
oped original NHCs equipped with a bicyclic architecture on the
non-carbenic carbons, which we referred to as DHASI, and one of
these DHASI ligands was successfully applied to Ni half-sandwich
complexes. The developed [Ni(DHASIiPr)CpCl] complex showed
high activity and a wide scope of substrates during Suzuki-Miyaura
⇑
Corresponding authors.
E-mail addresses: ando@gpo.kumamoto-u.ac.jp (S. Ando), tstone@gpo.kumamo-
to-u.ac.jp (T. Ishizuka).
https://doi.org/10.1016/j.tetlet.2019.04.004
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: S. Ando, Y. Hirota, H. Matsunaga et al., Nickel-catalyzed N-arylation of amines with arylboronic acids under open air, Tetrahedron
Letters, https://doi.org/10.1016/j.tetlet.2019.04.004

2
S. Ando et al. / Tetrahedron Letters xxx (xxxx) xxx
Table 1
Optimization of the reaction conditions of Ni-catalyzed arylation of amines.
Entry
X
Y
Co-Ligand
Yield 3a (%)
1
2
3
4
2
2
2
2
2
2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
none
L1
L2
L3
L4
L2
L2
L2
L1
L2
L3
L2
L2
L2
L2
6
32
37
36
30
2
5
6b
7c
44
0
8c,d
9c,e
10c,e
11c,e
12c,e,f
13c,e,g
14c,e,h
15c,e,i
Fig. 1. N-arylations of amines through representative coupling reactions and an
overview of this study.
43
60
56
27
32
6
coupling [17]. During the investigation, we found that [Ni(DHA-
SIiPr)CpCl] catalyzed the homo-coupling of phenylboronic acids
under air, where the TON (turn-over number) was more than
100. Motivated by this promising catalytic activity, we envisioned
a DHASI-supported Ni half-sandwich complex that could be useful
as an effective precatalyst in a Ni-catalyzed Chan-Lam coupling.
0
a
The yield was calculated using 1H NMR with 2-acetonaphthalene as an internal
standard.
b
Under an Ar atmosphere.
The reaction was performed for 8 h.
Complex C2 was used instead of C1.
A mixture of toluene/DMF (19/1) was used as a solvent.
The reaction was performed at 90 °C.
Complex C3 was used instead of C1.
c
d
e
f
Results and discussion
We began our study by fine-tuning the reaction conditions with
[Ni(DHASICy)CpCl] complex C1, which was newly synthesized for
this work (see Table 1, and the ESI for a full list of the conditions
tested). In the reports of previous work, DBU [9a,b,d] and 1,1,3,3-
tetramethylguanidine [9c] worked better than inorganic bases; in
contrast, K2CO3 and K3PO4 were the only bases that worked for
the coupling of morpholine and phenylboronic acid with our
NHC-Ni complex C1 (see also Table S1). Boroxine and other
boronate derivatives did not suit the coupling using NHC-Ni
catalysis (Table S8). The use of co-ligands significantly improved
the conversion, and dmbpy L2 proved to be the best among all
the co-ligands tested (Entries 1–5, and Table S3). The use of an
excess amount of phenylboronic acid was preferable to an excess
amount of amine partners (Entry 3 vs. 7), and an additional
aprotic polar co-solvent (see also Table S6), especially DMF,
helped to afford the product in a better yield (Entries 9–11). The
reaction at a higher temperature resulted in a decreased yield
(Entry 12). The use of [Ni(DHASIiPr)CpCl] C2 [17], which is a robust
precatalyst for Suzuki-Miyaura coupling, was fruitless (Entry 8),
and the Ni half-sandwich complex C3 supported by SIPr [15a],
which is one of the most widely used NHCs, was inferior to C1
g
h
i
NiCl2ꢀ6H2O was used instead of complex C1.
The reaction was performed without the addition of a Ni source.
(Entry 13). Nickel(II) chloride hexahydrate also provided the
coupled product, albeit with lower activity than that of NHC-Ni
complexes (Entry 14). Obviously, aerobic conditions and a Ni
catalyst are crucial elements for this transformation (Entries 6
and 15). We chose the conditions shown in entry 10 as optimal
for the nickel-catalyzed arylation of amines.
With the optimal reaction conditions in hand, we tested the sub-
strate scope for the N-phenylation of amines using [Ni(DHASICy)
CpCl] C1 and dmbpy (Figs. 2 and 3). Aliphatic amines coupled with
phenylbononic acid in a moderate to good yield, with the noted
exception of piperidine (3a–3e). It should be noted that benzy-
lamine and its coupled product 3e was not oxidized during the cou-
pling. Acetamide and tert-butylcarbamate were also amenable to
this coupling and resulted in a moderate yield, while the more
acidic cyclic carbamate and p-toluenesulfonamide gave signifi-
cantly lower yields (3h–3i). On average, the coupling using aniline
Please cite this article as: S. Ando, Y. Hirota, H. Matsunaga et al., Nickel-catalyzed N-arylation of amines with arylboronic acids under open air, Tetrahedron
Letters, https://doi.org/10.1016/j.tetlet.2019.04.004

S. Ando et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Fig. 2. Substrate scope for the N-phenylation of aliphatic-, aromatic-, and heteroaromatic-amines.
Fig. 3. Substrate scope for arylation using a variety of arylboronic acids.
derivatives was more effective than when using aliphatic amines,
and electron-rich and electron-deficient anilines were coupled with
phenylboronic acid to give good yields (3j–3p). On the other hand,
sterically hindered substrates were somewhat problematic, and
their use resulted in moderate to poor yields (3q–3t). The N-aryla-
tion of indole did not effectively proceed (3w, see Fig. S3 for a list of
incompatible substrates), but 4-amino- and 2-amino-pyridines
reacted smoothly to give the arylated products (3u and 3v).
We subsequently tested the effect of arylboronic acids on this
coupling reaction (Fig. 3). Although the o-substituted arylboronic
acids were influenced by steric repulsion (4a–4c), p-substituted
arylboronic acids were amenable to this coupling (4d–4h).
was conducted under the optimal conditions, and the coupled pro-
duct was obtained in a 53% yield which retained an optical purity
of >98%ee. The racemization of 1-phenylethylamine is known to be
catalyzed by some metals including Ni nanoparticles [18], but this
was not the case for this reaction.
Finally, we checked whether the racemization of an amine at a
benzylic position would occur using (S)-1-phenylethylamine (>98%
ee) as a substrate (Eq. (1)). The coupling with phenylboronic acid
Please cite this article as: S. Ando, Y. Hirota, H. Matsunaga et al., Nickel-catalyzed N-arylation of amines with arylboronic acids under open air, Tetrahedron
Letters, https://doi.org/10.1016/j.tetlet.2019.04.004

4
S. Ando et al. / Tetrahedron Letters xxx (xxxx) xxx
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Please cite this article as: S. Ando, Y. Hirota, H. Matsunaga et al., Nickel-catalyzed N-arylation of amines with arylboronic acids under open air, Tetrahedron
Letters, https://doi.org/10.1016/j.tetlet.2019.04.004