Cu2O/1-(2-methylhydrazine-1-carbonyl)-isoquinoline 2-oxide catalyzed C-N cross-coupling reaction in aqueous media

Article abstract of DOI:10.1016/j.tet.2019.05.067

An experimentally simple, efficient, and inexpensive catalyst system was developed for the N-arylation of imidazole, indole, pyrrole, alkyl alcohol amines, and alkyl amines with aryl iodides and bromides. The reaction proceeds in water-ethanol media at 120 °C for 12 h with Cu₂O as the catalyst, 1-(2-methylhydrazine-1-carbonyl)-isoquinoline 2-oxide (L2) as the ligand, NaOH as the base to generate a wide range of N-arylated products in moderate to excellent yields. Aqueous medium, ease of operation, and broad substrate scope give the process a benign environmental profile.

Full text of DOI:10.1016/j.tet.2019.05.067

Accepted Manuscript
Cu O/1-(2-methylhydrazine-1-carbonyl)-isoquinoline 2-oxide catalyzed C-N cross-
2
coupling reaction in aqueous media
Jian-Wei Xie, Zhen-Bin Yao, Xiao-Chuang Wang, Jie Zhang
PII:
S0040-4020(19)30629-5
https://doi.org/10.1016/j.tet.2019.05.067
TET 30388
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 March 2019
Revised Date: 26 May 2019
Accepted Date: 31 May 2019
Please cite this article as: Xie J-W, Yao Z-B, Wang X-C, Zhang J, Cu O/1-(2-methylhydrazine-1-
2
carbonyl)-isoquinoline 2-oxide catalyzed C-N cross-coupling reaction in aqueous media, Tetrahedron
(2019), doi: https://doi.org/10.1016/j.tet.2019.05.067.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Cu2O/1-(2-methylhydrazine-1-carbonyl)-
isoquinoline 2-oxide catalyzed C-N cross-
coupling reaction in aqueous media
Leave this area blank for abstract info.
Jian-Wei Xiea,*, Zhen-Bin Yaob, Xiao-Chuang Wangb, Jie Zhangb
aCollege of Chemistry and Bioengineering, Hunan University of Science and Engineering, Yangzitang Road,
Yongzhou 425100, China
bSchool of Chemistry and Chemical Engineering/Key Laboratory for Green Processing of Chemical
Engineering of Xinjiang Bingtuan, Shihezi University, Shihezi 832003, China

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Cu2O/1-(2-methylhydrazine-1-carbonyl)-isoquinoline 2-oxide catalyzed C-N cross-
coupling reaction in aqueous media
Jian-Wei Xie a, , Zhen-Bin Yaob, Xiao-Chuang Wangb and Jie Zhangb
a College of Chemistry and Bioengineering, Hunan University of Science and Engineering, Yangzitang Road, Yongzhou 425100, China
b School of Chemistry and Chemical Engineering/Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, Shihezi University,
Shihezi 832003, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An experimentally simple, efficient, and inexpensive catalyst system was developed for the N-
arylation of imidazole, indole, pyrrole, alkyl alcohol amines, and alkyl amines with aryl iodides
and bromides. The reaction proceeds in water-ethanol media at 120 oC for 12 h with Cu2O as the
catalyst, 1-(2-methylhydrazine-1-carbonyl)-isoquinoline 2-oxide (L2) as the ligand, NaOH as
the base to generate a wide range of N-arylated products in moderate to excellent yields.
Aqueous medium, ease of operation, and broad substrate scope give the process a benign
environmental profile.
Available online
Keywords:
1-(2-Methylhydrazine-1-carbonyl)-isoquinoline 2-
oxide
2009 Elsevier Ltd. All rights reserved
.
Copper
C-N coupling
Aqueous media
———
Corresponding author. Tel.: +86-746-638-1164; e-mail: cesxjw@foxmail.com

2
Tetrahedron
ACCEPTED MANUSCRIPT
1. Introduction
in H2O (1 mL) at 120 °C for 12 h. When we used 1-(2-substituted
hydrazine-1-carbonyl)-isoquinoline 2-oxide L1 and L2 as
ligands, L2 exhibited higher catalytic ability than L1 (Entries 1
and 2). Meanwhile, there are no product detected, when 1-(2-
substituted hydrazine-1-carbonyl)-quinoline 2-oxide L3 and L4
were used as the ligands. As the best ligand was determined, we
next examined copper sources. Preliminary results showed that
most of Cu(I) and Cu(II) salts were more or less equally active
(Entries 5-10). In particular, Cu2O combined with L2 provided
the best catalytic effect (Entry 7). Control experiment indicated
that only trace product was formed in the absence of any Cu
source (Entry 11). Among various bases examined, including
NaOH, KOH, K2CO3, K3PO4 and Cs2CO3, NaOH was the most
superior in 62% yield (Entries 7 and 12-15). Various surfactants
were also tested, such as SDS, PEG-400 and PEG-1000, but none
of them showed a higher performance than TBAB (Entries 17–
19). It is notable that using mixed EtOH and water (1:1) as the
reaction media is favorable for the reaction (Entries 20-25). In
summarize, the highest yield of 1-(4-chlorophenyl)-1H-imidazole
(3f) was obtained when the reaction between 1 equiv. of 4-
bromochlorobenzene and 1.5 equiv. of imidazole was performed
with 10 mol% Cu2O, 20 mol% L2, 20 mol% TBAB, and 2 equiv.
of NaOH in 1 mL EtOH/H2O (1/1, v/v) at 120 oC for 12h without
protection from air or moisture.
Transition metal catalyzed carbon-nitrogen cross-coupling
reactions play an very important role in the preparation of N-aryl
amine moieties, which is often found in biological active
compounds, pesticides, pharmaceutical and material sciences.1
Among them, copper/ligand-catalyzed Ullmann-type reaction is
one of the most useful protocols for these transformation due to
its economic attractiveness, low toxicity, and air and moisture
stability.2 In general, the catalytic centre in the catalytic system is
the copper complex, which is formed from copper species and
additive mono- or bidentate ligand. And the efficiency,
generality, and chemoselectivity of the catalytic system are
depended on the nature of ligands.3 Therefore, development of
novel Cu ligands and optimization of catalytic conditions are
important topics for Cu-catalyzed C-N coupling reaction study.
To date, many efficient N,O-, N,N-, or O,O-bidentate ligands
have been developed to promote the amination of aryl halides
that made the conditions of Ullmann-type C-N coupling reaction
mild.4 However, most of these processes are carried out
commonly in organic solvents like DMF, DMSO, NMP and so
on, which do not meet the requirements of green chemistry
strategy.
On the other hand, pyridine N-oxides and hydrazides moieties
have long been recognized as attractive ligands for coordination
to various metal ions, and application them as the ligand for
copper-based C-N cross-coupling reaction have also been
reported. For example, Zhou et al. established the first 1,2-bis(2-
pyridyl)-ethane-N,N-dioxides-assisted copper-catalyzed method
for N-arylation of imidazoles with aryl halides in water, and the
high catalytic efficiency may be attribute to the coordination
ability and superior solubility of the ligand.5 Thereafter, 2-
carboxylic acid-quinoline-N-oxide,6 8-hydroxyquinolin-N-oxide,7
pyrrolidine N,N-dioxides8, and N-(1-oxy-2-picolyl)oxalamic
acids,9 were found to be effective ligands for Cu-catalyzed
Ullmann-type C-N coupling in water or in organic solvents. Wan
group reported several copper-catalyzed N-arylation protocols
using different types of hydrazides as the ligands.10 In 2011,
acylhydrazine- and acylhydrazone-type ligands-assisted CuI-
catalyzed C-N cross-coupling reactions of aryl bromides with N-
heterocycles approach was reported.11 Recently, we developed a
series of hydrazinecarbonyl pyridine N-oxides, which was
composed of hydrazides and pyridine N-oxides moieties, as the
novel ligand for the copper-based N-arylation reaction in water.12
As mentioned above, the activity and stability of the
copper/ligand catalytic system can be modified and tuned by
varying the steric and electronic properties of the structure of
ligands. Therefore, as an extension we herein report an efficient
amination of aryl iodides and bromides method by using Cu2O/1-
(2-methylhydrazine-1-carbonyl)isoquinoline 2-oxide as the
catalytic system in H2O/EtOH media (Fig. 1).
With the optimized reaction conditions in hand, we initiated
our investigation into the scope of the Cu2O/L2-catalyzed
amination of several aryl halides and the results are summarized
in Table 2. As expected, a variety of N-containing nucleophiles
such as imidazoles, pyrroles, indoles, alcoholamine and aliphatic
amine were applied with various of (hetero)aryl iodides or
bromides to give the corresponding products in moderate to
excellent isolated yields under the optimized conditions. Most of
aryl iodides bearing with electron-rich, electron-neutral or
electron-poor substituents reacted with imidazole afforded the
coupling products in 59-96% yield (Entries 1-8). Other
heterocycles, such as indole and pyrrole were found to be
effective nucleophiles for the coupling reactions in 42 and 93%
yield, respectively (Entries 9 and 10). Notably, the coupling
reactions of 4-iodoanisole with aliphatic amines were also
successful with favorable yields under the optimized conditions
(Entries 11-14). Importantly, the catalytic system exhibited
excellent chemo-selectivity in the presence of multiple
potentially reactive groups. For example, reaction with aliphatic
aminoalcohols only gave the N-arylated products, which could be
used in the synthesis of complex active molecules. And we can
find that the coupling of aminoalcohols with fewer methylene
groups (n = 2 and 3) give higher yields (Entries 15-19). However,
in the case of 4-aminophenol, there was only 18% yield obtained
(Entry 20). Compared with aryl iodides, aryl bromides reacted
with nucleophiles more slowly and afford lower yields (Entries
21-25). In addition, it is remarkable that aryl heterocycle halides
such as 4-bromopyridine can couple with imidazole in higher
yields in this catalytic system (Entry 26). Unfortunately, it is
regretful that
Table 1. Screening reaction conditions for copper-catalyzed
N-arylation of imidazole with 4-bromochlorobenzenea.
Fig. 1 Ligand structures in our previous works and the present work.
2. Results and Discussion
First, we selected the challenging coupling of 4-
bromochlorobenzene with imidazole as model substrates to
optimize the conditions. As shown in Table 1, we initially
screened ligands with 10 mol % Cu powder as a catalyst, 2 equiv.
of NaOH as a base, 10 mol % TBAB as a phase transfer catalyst

3
Yieldb
(%)
Table 2. Cu O/L2 catalysed N-arylation of imidazole with
ACCEPTED MANUSCRIPT
2
Entry
[Cu]
L
PTC
Base
Solvent
aryl halides in watera.
1
Cu
L1 TBAB
L2 TBAB
L3 TBAB
L4 TBAB
L2 TBAB
L2 TBAB
L2 TBAB
L2 TBAB
L2 TBAB
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
KOH
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
17
L2
Cu2O,
NHR1R2
(hetero)Ar-X
(hetero)Ar-NR1R2
2
Cu
41
NaOH, TBAB
1
2
3
X = I, Br
EtOH/H2O (1/1, v/v)
3
Cu
trace
trace
43
o
120 C, 12 h
4
Cu
5
CuI
Yield[b]
(%)
6
CuBr
Cu2O
CuSO4
CuO
38
Entry
1
(hetero)Ar-X
Product
7
62
8
35
3a
96
9
34
10
11
12
13
14
15
16
17
18
19
20
21
Cu(OAc)2 L2 TBAB
40
-
L2 TBAB
L2 TBAB
L2 TBAB
L2 TBAB
L2 TBAB
L2 TBAB
L2 SDS
trace
60
2
3
4
3b
3c
3d
88
78
92
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
K2CO3
K3PO4
10
28
Cs2CO3 H2O
9
NaOH
NaOH
NaOH
H2O
34c,d
trace
trace
10
MeO
I
H2O
L2 PEG400
H2O
L2 PEG2000 NaOH
H2O
L2
L2
-
-
NaOH
NaOH
EtOH
t-BuOH
30c
5
6
7
8
9
3e
3f
68
95
59
74
42
56
EtOH/H2O
(1/1)
22
23
24
Cu2O
Cu2O
Cu2O
Cu2O
L2 TBAB
L2 TBAB
L2 TBAB
L2 TBAB
NaOH
NaOH
NaOH
NaOH
70
64
64
65
t-BuOH
/H2O (1/1)
t-BuOH
/H2O (1/2)
3g
3h
3i
t-BuOH
/H2O (2/1)
25
a
Reaction conditions: 4-bromochlorobenzene (0.5 mmol),
imidazole (0.75 mmol), [Cu] (10 mol %), TBAB (20 mol %), L
(20 mol %), base (1 mmol), solvent (1 mL, v/v), 120 °C , 12 h; b
Isolated yield; c Temperature: 100 °C; d Reaction time: 24 h.
Scheme 1. Large-scale reaction of N-arylation of imidazole
with 4-methoxyiodobenzene.
the amination of aryl chlorides did not occur under this condition.
10
11
12
13
3j
93c
60c
40c
31c
In addition, a large scale synthesis was carried out under the
standard conditions. Using 4-methoxyiodobenzene (5 mmol) and
imidazole (7.5 mmol), the reaction proceeded without any
difficulty to obtain the corresponding coupling product 3a in 84%
yield (Scheme 1).
3k
3l
To investigate the practical application of Cu2O/L2 catalytic
system, we set out to highlight the utility of our methodology by
applying it to the concise synthesis of pyrrolo[1,2-a]quinoxaline,
a drug-like active molecule. As shown in Scheme 2, pyrrole-2-
carboxaldehyde (0.5 mmol) and 2-iodoaniline (0.75 mmol) were
used as substrates under the optimized reaction conditions to
afford the desired cross-coupled product in 61% yield.
3m

4
Tetrahedron
ACCEPTED MANUSCRIPT
Based on the previously literature reports,13,14 a possible
mechanism for the Cu2O/L2-catalyzed Ullmann-type C-N
coupling reaction under the present conditions is shown in
Scheme 3. We proposed that Cu2O might react with L2 to afford
a seven-member reactive species I in the presence of NaOH, in
which the electron-donating ability of the ligand could make this
complex active toward the oxidative addition with an aryl halide.
The oxidation addition of I with aryl halides provided Cu(III)
complex II, which might interacts with nucleophiles to form III,
followed by reductive elimination to provide the desired product
and regenerate active Cu(I) species I.
14
3n
51c
15
16
3o
3p
88c
93c
17
18
3q
3r
81c
50c
19
20
21
3s
3t
3f
44c
18c
70
Scheme 3. Proposed mechanism.
3. Conclusion
In summary, an efficient, simple operation, eco-friendly
methodology for the C-N cross-coupling reaction is presented,
featuring that 1-(2-methylhydrazine-1-carbonyl)isoquinoline 2-
oxide as an ideal ligand for promoting Cu2O-catalyzed Ullmann-
type coupling reactions of aryl halides with several N-containing
nucleophiles in aqueous media. Most of aryl bromides and
iodides provided the target N-arylated products in satisfactory
yields without the protection of an inert atmosphere. Mildness,
low-cost, experimental simplicity, and ability to use aqueous
media are the advantages of the method that make it particularly
well suited for applications.
Br
22
23
24
3e
3u
3a
48
58
57
Ac
4. Experimental
4.1. General
All reagents were purchased from Adamas-beta and used
without further purification. Column chromatography was
performed with silica gel (200-300 mesh) purchased from
Qingdao Haiyang Chemical Co. Ltd. Thin-layer chromatography
was carried out with silica gel 60 F254 glass plates and
25
26
3v
66
89
1
visualized by exposure to UV light (254 nm). H NMR spectra
3w
and 13C NMR spectra were recorded at room temperature on a
Bruker Avance III HD 400 instrument at 400 MHz and 100 MHz,
respectively. Mass spectra were recorded on GC-MS (Agilent
7890A/5975C) instrument under EI model. Electrospray
ionization high-resolution mass spectra (ESI-HRMS) were
recorded on a Thermo Scientific LTQ Orbitrap XL high-
resolution mass spectrometer. Fourier transform infrared spectra
(FT-IR) was measured between 500 and 4000 cm-1 using Thermo
Nicolet Avatar 360.
aReaction conditions: (hetero)ArX (0.5 mmol), R1R2NH (0.75
mmol), Cu2O (0.05 mmol), L2 (20 mol %), TBAB (20 mol %),
NaOH (1 mmol), EtOH/H2O = 1/1 (v/v) (1 mL), 120 °C, 12 h;
bIsolated yield; cNHR1R2: 1.5 mmol.
4.2. General procedure for the synthesis of 3a-3w and 6
Scheme 2. Cu2O/L2-catalyzed concise synthesis of
pyrrolo[1,2-a]quinoxaline.
A 25 mL Schlenk tube was charged with Cu2O (0.05 mmol),
ArX (0.5 mmol), NHR1R2 (0.75 mmol), NaOH (1 mmol), TBAB
(0.1 mmol), L2 (0.1 mmol) and H2O/EtOH (1 mL, 1/1, v/v). The
mixture was stirred at 120 °C for 12 h. The reaction mixture was

5
extracted with ethyl acetate (3×10 mL), washed with water and
Supplementary Material
ACCEPTED MANUSCRIPT
brine, dried over anhydrous Na2SO4, and concentrated in vacuo.
The residue was purified by flash column chromatograph on
silica gel (ethyl acetate/petroleum ether as the eluent) to provide
the target products 3a-3w and 6.
Supplementary data (ligand synthesis procedure, H and 13C
NMR data plus their copies) associated with this article can be
found in the online version.
1
Acknowledgments
We gratefully acknowledge the Natural Science Foundation of
China (21606153 and 21868032) and the construct program of
applied characteristic discipline in Hunan University of Science
and Engineering for the financial support.
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