Copper(II)-Catalyzed Selective Para Amination of Arylamine with Pyrazole by C?H Functionalization

Article abstract of DOI:10.1002/cctc.201800328

A coordinating activation strategy for selective para amination of arylamine with pyrazole is developed. Various substrates are compatible, giving the corresponding products in moderate to good yields. This strategy provides a practical solution for the efficient synthesis of arylamine-containing pharmacophores from simple starting materials. A single electron transfer mechanism is suggested for this reaction.

Full text of DOI:10.1002/cctc.201800328

Accepted Article
Title: Copper(II)-Catalyzed Selective Para Amination of Arylamine with
Pyrazole via C-H Functionalization
Authors: Jun Xu, Kui Du, Jiabin Shen, Chao Shen, Kejie Chai, and
Pengfei Zhang
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ChemCatChem
10.1002/cctc.201800328
COMMUNICATION
Copper(II)-Catalyzed Selective Para Amination of Arylamine
with Pyrazole via C-H Functionalization
‡
‡
[a]
Jun Xu, Kui Du, Jiabin Shen, Chao Shen, Kejie Chai and Pengfei Zhang*
Abstract: A coordinating activation strategy for selective
para amination of arylamine with pyrazole is developed.
Various substrates are compatible, giving the corresponding
products in moderate to good yields. This strategy provides a
practical solution for the efficient synthesis of arylamine-
containing pharmacophores from simple starting materials. A
single electron transfer mechanism is suggested for this
reaction.
Introduction
Scheme 1 Our strategies for C-H functionalization of arylamine
Nitrogen-containing compounds are highly valuable
skeletons and widely present in ligands, alkaloids,
pharmaceuticals and organic optoelectronic materials.
1
utilization of picolinamide (PA) as directing group. In 2014,
Chen and Carretero demonstrated an efficient approach to
Consequently, it is of great importance to develop general
and efficient methodologies for the construction of C-N bond.
While many classical cross couplings such as
Buchwald−Hartwig, Chan−Lam and Ullmann−Goldberg
aminations have been developed for the C−N bond formation,
the prerequisite utilization of aryl halides led chemists to
consider the direct C-H amination of arenes by transition
selectively install amino motifs onto the ortho position of
4a,b
aniline with alkylamine.
Subsequently, this strategy by Wu
has been employed in peri C-H amination of naphthylamide
5a
too. During the preparation of our manuscript, Wu and co-
workers reported a silver(I)-catalyzed C4-H amination of
5b
1
‑naphthylamine derivatives with azodicarboxylates.
2
However, unstable azodicarboxylates were employed in this
transformation. Furthermore, according to the author's
investigation on reaction mechanism, the substrate was
limited to naphthylamine. Therefore, some important aspects
still need continuous improvement.
metal catalyzed strategy.
As part of nitrogen-containing compounds, arylamines are
2
Recently, our main research interests focus on the C(sp )-
H functionalization facilitated by removable N-containing
4
c,d,6
directing group.
In addition, the development of efficient
approaches for the preparation of functionalized azoles is
very important, since they are significant structural units in
many active compounds. For example, the molecules of
Figure 1 Pharmaceutical molecules contain pyrazole moiety
7
pharmaceutical such as apixaban and crizotinib all have
pyrazole moiety (Figure 1). Herein, we demonstrated a
copper(II)-catalyzed selective para amination of arylamine
with stable pyrazole, which was promoted by the
picolinamide directing group (Scheme 1b).
important structural moieties in organic materials and
pharmaceutical agents. In recent years, the direct C−H
3
functionalization of arylamine by using a bidentate directing
group has received much attention due to the unique
property of bidentate system for selective activation of inert
4
,5
C−H bonds. Among these transformations, considerable
progress has been achieved by some groups for the
construction of C-N bond, who have mainly focused on the
Results and Discussion
We commenced our study by examining the reaction of N-
(naphthalen-1-yl)picolinamide (1a) and pyrazole (2a) in the
[
a]
Dr J. Xu, K. Du, J. Shen, C. Shen, K. Chai and Prof. P. Zhang
College of Material, Chemistry and Chemical Engineering,
Hangzhou Normal University, Hangzhou 310036 (China).
E-mail: chxyzpf@hotmail.com
presence of 15 mol % of CuI, 2.0 equiv of K and 1,2-
2 2 8
S O
dichloroethane (DCE) at 70 °C (Table 1, entry 1). To our
delight, the cross-coupling product at para position of
arylamine was isolated in 33% yield. Encouraged by this
special result, the reaction condition was further screened in
‡
Jun Xu and Kui Du contributed equally.
[]
Supporting information for this article is available on the WWW
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COMMUNICATION
a,b
a,b
Table 1 Optimization of reaction conditions
Table 3 Para amination of aniline
b
Entry
Catalyst
Oxidant
Solvent
Yield [%]
33
1
2
3
4
5
6
7
8
9
CuI
K S
2
K S
2
K S
2
K S
2
K S
2
K S
2
K S
2
O
2 8
O
2 8
O
2 8
O
2 8
O
2 8
O
2 8
O
2 8
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
MeCN
THF
CuBr
2
48
28
25
52
69
0
76
85
Cu(OAc)
CuO
2
Cu(OTf)
2
CuCl
-
2
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
2
2
2
2
2
2
2
2
2
2
2
2
2
(NH
Na
4
)
2
S
2
O
8
2
S
2
O
8
a
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
oxone
PhI(OAc)
TBHP
57
Reaction conditions: 1 (0.2 mmol), 2 (0.8 mmol), CuCl
2
(15 mol %),
o
b
2
trace
trace
trace
0
74
23
40
trace
38
Na
2
S
O
2 8
(0.4 mmol), DCE (2.0 mL), 70 C, 5 h, air. Isolated yields.
2 3
Ag CO
no target product was detected in the absence of metal
catalyst or oxidant (Table 1, entry 7 and 14), these results
demonstrated their importance in this transformation. Further
investigation in solvent and reaction temperature did not
improve the yield (Table 1, entries 15−20).
-
Na
Na
Na
Na
Na
Na
2
S
S
S
S
S
S
2
2
2
2
2
2
O
8
2
2
2
2
2
O
8
O
8
O
8
O
8
O
8
dioxane
DMSO
DCE
DCE
c
19
After obtaining the optimal reaction condition for direct
C−H amination of arylamine, the scope of substrates was
examined, and the results were summarized in Table 2.
Pyrazole derivatives with methyl groups underwent the
amination reaction efficiently, affording corresponding
molecules in good yields (3b, 3d, 3h). In addition, 3-phenyl-
d
20
82
a
Reaction conditions: 1a (0.2 mmol), 2a (0.8 mmol), catalyst (15
mol %), oxidant (0.4 mmol), solvent (2.0 mL), 70 C, 5 h, air. Isolated
o
b
c
o
d
o
yields. Stirred at 50 C. Stirred at 100 C.
order to improve the yield of product 3a. Subsequently, the
investigation of copper catalysts, such as CuBr
CuO, Cu(OTf) as well as CuCl was performed. The yield of
target product 3a was improved to 69% when CuCl was
2 2
, Cu(OAc) ,
1
H-pyrazole also has good reactivity. The corresponding
2
2
product was obtained in 72% yield (3c). Notably, pyrazole
derivatives with functional group such as bromo and iodo
moieties, which could be further functionalized, were
compatible with the optimum conditions (3e, 3f, 3i, 3j).
Meanwhile, the molecular structure of product 3j was proved
by X-ray crystallographic analysis (CCDC NO. 1817979)
2
chosen as a catalyst (Table 1, entried 2-6). Follow-up study
on the screening of oxidants verified that the peroxysulphate
has better promoter action than other oxidants such as
potassium peroxymonosulfate (oxone), iodosobenzene
diacetate (PhI(OAc)
silver carbonate (Ag
isolated yield (85%) of product 3a was obtained by utilizing
2
), tert-butyl hydroperoxide (TBHP) and
(see Supporting Information). Regrettably, pyrazole with
2
CO ) (Table 1, entries 8–13). The best
3
electron-withdrawing group (-NO ) could not be transformed
2
into target product (3g). Besides pyrazole, 1H-benzotriazole,
sodium persulfate (Na
Table 2 Para amination of naphthylamine
2
S
2
O
8
) as oxidant. It is noteworthy that
a,b
which was utilized as corrosion inhibitor of copper and its
8
oxides, was also tolerated and provided the corresponding
product in 55% yield (3k). Furthermore, the substrates
bearing other N-containing bidentate directing groups were
studied, furnishing the corresponding products in moderate
to good yields (3l-o).
In order to expand the scope of application of our catalytic
system, we employed N-phenylpicolinamide as substrates
instead of N-(naphthalen-1-yl)picolinamide. To our delight,
these substrates could also be converted into corresponding
a
2
Reaction conditions: 1 (0.2 mmol), 2 (0.8 mmol), CuCl (15 mol %),
o
b
Na
2
S
O
2 8
(0.4 mmol), DCE (2.0 mL), 70 C, 5 h, air. Isolated yields.
Scheme 2 Gram-scale synthesis and removal of PA group
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yield. However, similar reactions have already been reported
4
a,b
by Chen and Carretero.
Subsequently, substrates 1k and
1
l did not furnish the target products under standard
conditions, which revealed that the N atom of pyridine and
free NH were indispensable in this reaction (Scheme 3b).
Interestingly, the methyl of N-(p-tolyl)picolinamide 1m was
transformed into aldehyde group in 52% yield under the
standard conditions (Scheme 3c). The unexpected product
(
5), however, was not obtained without pyrazole (2a).
Besides, methylbenzene (1n) and N,4-dimethylaniline (1o)
could not be converted into oxidative products either. These
results indicated the importance of pyrazole (2a) and PA
moiety in this C-H oxidation reaction. Further research on the
mechanism of this reaction is still continuing. Next, the
amination reactions were completely suppressed when 2.0
equiv of TEMPO was added. Furthermore, pyrazole radical
generated in situ was captured and the corresponding
adduct 6 was detected by HRMS (Scheme 3d), suggesting
that a radical process might be involved. The lack of kinetic
isotope effect (k≈1.0) between 1f and 1f-D5 indicated that
the C-H cleavage was not involved in the rate determining
9
step (Scheme 3e).
According to the control experimental results and previous
6
,10
works,
we believed that the C-H amination reaction was
controlled by a single electron transfer (SET) mechanism
Scheme 3 Control Experiments
II
(
Scheme 4). Initially, coordination between Cu L
n
and
complex A, which
subsequently underwent a single electron transfer (SET)
II
products in acceptable yields (Table 3, 3p-u).
Subsequently, a gram-scale synthesis of N-(4-(1H-pyrazol-
substrate 1a provided the aryl-Cu L
n
I
1
-yl)naphthalen-1-yl)picolinamide (3a) was performed to
process, supplying the aryl-Cu L
n
complex B. Then, pyrazole
show the synthetic utility of this method, and the product 3a
was obtained in 80% yield (Scheme 2). The PA moiety of
product 3a could be easily removed through hydrolysis,
yielding 4-(1H-pyrazol-1-yl)naphthalen-1-amine (4a) and 2-
picolinic acid (PA) in 91% and 88% yields, respectively.
Control experiments including structure effect of substrates,
radical inhibition as well as kinetic isotope effect were
performed so as to gain more mechanistic insight into this
para amination reaction (Scheme 3). First, we replaced
pyrazole with morpholine to study if the alkylamine was
compatible in this transformation (Scheme 3a). Surprisingly,
the direct C−H amination took place at ortho position instead
of para position, affording corresponding molecule in 78%
radical C, which was generated from pyrazole in the
presence of sodium persulfate (Na
2
S
2
O
8
), attacked aryl-
I
I
Cu L
n
complex B to afford aryl-Cu L
n
complex D. Thereafter,
I
II
aryl-Cu L
n
complex D was transformed into aryl-Cu L
n
complex E in the presence of sodium persulfate (Na
2
S
2
O
8
).
II
After the generation of aryl-Cu L
n
complex F through
deprotonation, aminated product 3a was obtained via a metal
dissociation process.
Conclusions
In summary, we have developed a simple and efficient
method for selective C-H amination on para position of
arylamine via a coordinating activation strategy. This protocol
avoided the utilization of sensitive and expensive reagents.
Various substrates were well tolerated, affording
corresponding products in moderate to good yields. A single
electron transfer (SET) mechanism was proposed after the
confirmation of control experiments. This ideal strategy
provided a powerful tool for the efficient synthesis of
arylamine-containing pharmacophores.
Experimental Section
General Information
All the chemicals were obtained commercially and used without any prior
purification. All products were isolated by short chromatography on a
Scheme 4 Plausible Mechanism
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silica gel (200-300 mesh) column using petroleum ether (60-90°C) and
gradually. The solvent was removed under reduced pressure. The
gathered residue was then purified by silica gel column chromatography
(200–300 mesh silica gel, PE/EA = 5:1).
1
13
ethyl acetate. H and CNMR spectra were recorded on a Bruker
Advance 500 and 600 spectrometers at ambient temperature with CDCl
3
as solvent and tetramethylsilane (TMS) as the internal standard. Melting
points were determined on an X-5 Data microscopic melting point
apparatus. Analytical thin layer chromatography (TLC) was performed on
Merk precoated TLC (silica gel 60 F254) plates. Compounds for HRMS
were analyzed by positive mode electrospray ionization (ESI) using
Agilent 6530 QTOF mass spectrometer.
Acknowledgements
Financial support by the Major Scientific and Technological Innovation
Projects of Hangzhou City (No. 20162011A036) and PCSIRT (IRT 1231).
Keywords: Copper(II)-Catalyzed • Naphthylamine • Aniline •
Pyrazole • C-H Functionalization
General procedure for synthesis of compound 3a-u
A mixture of 1 (0.2 mmol), pyrazole derivatives 2 (0.8 mmol), CuCl
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(95.2 mg, 0.4 mmol) in DCE (2.0 mL) in a 25 mL
o
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(
10 mL). Upon completion of the reaction at 100 C for 12 h, the mixture
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4
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ChemCatChem
10.1002/cctc.201800328
COMMUNICATION
Jun Xu, Kui Du, Jiabin Shen, Chao Shen,
Kejie Chai and Pengfei Zhang*
Page No. – Page No.
Copper(II)-Catalyzed Selective Para
Amination of Arylamine with Pyrazole via C-
H Functionalization
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