2,6-Bis(2-methylhydrazine-1-carbonyl)pyridine 1-oxide as an Efficient Ligand for Copper-Catalyzed C–N Coupling Reaction in Water

Article abstract of DOI:10.1007/s10562-018-2321-8

Abstract: Cu₂O/2,6-bis(2-methylhydrazine-1-carbonyl)pyridine 1-oxide was found to be an efficiently catalytic system for the N-arylation of imidazole, indole, benzimidazole, pyrrole, benzylamine and ethanolamine with aryl iodides and bromides by using NaOH as base in the presence of 20?mol% (n-Bu)₄NBr, and water as solvent at 130?°C in 24?h, and giving the N-arylated products in moderate to excellent yields.

Full text of DOI:10.1007/s10562-018-2321-8

Catalysis Letters
https://doi.org/10.1007/s10562-018-2321-8
2,6-Bis(2-methylhydrazine-1-carbonyl)pyridine 1-oxide as an Efficient
Ligand for Copper-Catalyzed C–N Coupling Reaction in Water
Xiaochuang Wang1 · Fei Meng2 · Jie Zhang1 · Jianwei Xie1 · Bin Dai1
Received: 30 November 2017 / Accepted: 28 January 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
Cu2O/2,6-bis(2-methylhydrazine-1-carbonyl)pyridine 1-oxide was found to be an efficiently catalytic system for the N-aryla-
tion of imidazole, indole, benzimidazole, pyrrole, benzylamine and ethanolamine with aryl iodides and bromides by using
NaOH as base in the presence of 20 mol% (n-Bu)4NBr, and water as solvent at 130 °C in 24 h, and giving the N-arylated
products in moderate to excellent yields.
Graphical Abstract
Cu2O, L1
Ar-NR1R2
NHR1R2
H
H
Ar-X
N
N
NaOH, TBAB
H2O, 130 oC, 24 h
N
N
O
L1
N
27 examples
25-95 % yield
H
H
X = I, Br
O
O
NHR1R2: imidazoles, indole, pyrrole, benzylamine, ethanolamine
Keywords Ligand · C–N coupling · Aryl halides · Copper catalyst · Water
1 Introduction
extended reaction time and narrow functional-group tol-
erance, limited its applications. Over the past decade, sig-
nificant improvements have been achieved to improve its
efficiency and selectivity by using various ligands, such as
1,2-diamines, amino acid, diols, imines, ß-diketones and
others [3–7]. While significant progress has been made in
the transformation described above, it is still highly desirable
to develop an easily accessible, economical and environmen-
tally friendly solution for this type of reactions.
The works of copper-catalyzed formation of C–N bond have
made great progress after the pioneering works of Ullmann
and Goldberg and have become one of the most powerful
integrated strategies for building nitrogen-containing inter-
mediates, which exist in natural products, pharmaceuti-
cals and pesticides [1, 2]. However, several drawbacks of
Ullmann-type coupling reactions, including stoichiometric
amounts of copper reagents, high reaction temperature,
In spite of advances of organic transformations using
organic solvents, its drawbacks can’t be ignored, including
healthy problems, violating the principle of environmental
friendliness. In terms of the requirements of green chem-
istry, various environmentally benign reaction media have
been used as substitutes such as water, supercritical fluids
and ionic liquids [8]. Obviously, water is the most attractive
one because of its inimitable characters of nontoxic, cheap,
and readily available [9, 10]. Therefore, during recent years,
water has been successfully employed as a highly desira-
ble solvents for organic transformations [10–14], of which
copper-based amination of aryl halides in aqueous media
or even in pure water has also been established [8, 15–24].
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s10562-018-2321-8) contains
supplementary material, which is available to authorized users.
* Jianwei Xie
cesxjw@foxmail.com
1
School of Chemistry and Chemical Engineering/Key
Laboratory for Green Processing of Chemical Engineering
of Xinjiang Bingtuan, Shihezi University, Shihezi 832003,
China
2
Guangdong Bioengineering Institute, Guangdong Academy
of Science, Guangzhou 510316, China
Vol.:(0123456789)
1 3

X. Wang et al.
Previously, we have designed and synthesized a novel
series of 2-(hydrazinecarbonyl)pyridine N-oxides [25, 26]
and its structural analogues [27] as ligands for copper-
catalyzed N-arylation of nitrogen nucleophiles in water
(Scheme 1). The results indicated that the N-oxide/anionic
phenolate and acylhydrazine moieties of the ligands were
the active sites, which might coordinate with the copper ion
as the catalytic center in these catalytic systems. However,
because of the relatively narrow substrate scopes of these
examples mentioned above, we therefore set out to look for
an improved catalyst system for this transformation. Herein,
we optimized and designed 2,6-bis(2-methylhydrazine-
1-carbonyl)pyridine 1-oxides as the ligands for C–N cou-
pling reaction in water.
that copper catalyst of the reaction mixture was essential
(entry 9). The following screening of various bases, includ-
ing NaOH, KOH, K2CO3, K3PO4 and Cs2CO3, indicated that
NaOH to be the best one in 75% yield (entries 5 and 10–13).
Furthermore, temperatures lower than 120 °C resulted in
inferior product yield while dramatically increased the yield
when temperatures higher than 130 °C and prolong the reac-
tion time to 24 h (entries 14–16). Decreasing the loading
of ligand resulted in lower yields (entry 17). In summary,
the optimal conditions for the N-arylation process in water
consist of the combination of Cu2O (10 mol%), NaOH (2
equiv.), L1 (20 mol%), TBAB (20 mol%) at 130 °C for 24 h
without the protection of inert gas.
In order to explore the scope of the application of the
catalytic system, a variety of functionalized aryl iodides and
bromides were aminated with nitrogen nucleophiles in water
under the optimized reaction conditions, and the results were
demonstrated in Tables 2 and 3. As shown in Table 2, to
our delight, most of the nitrogen-containing heterocycle and
amines with aryl iodides reacted well to afford the corre-
sponding products in moderate to excellent yields (38–95%).
Electron-donating groups seemed to be more beneficial than
electron-withdrawing groups for these catalytic system. No
obvious electronic effects were observed for para- and meta-
substituted aryl iodides, however, steric hindrance of ortho-
substituents resulted in a lower reactivity and afforded lower
yield (entry 4). The amination of heteroaryl iodides, includ-
ing dibenzothiophene (entry 10) and quinoline (entries 11,
14 and 17), proved to be successful. Notably, the coupling
of aryl iodides with other N-containing nucleophiles, such
as indole, benzimidazole, pyrrole, and benzylamine, did
2 Results and Discussion
To evaluate the catalytic efficiency of the catalyst, imidazole
and iodobenzene were chosen as model substrates for the
coupling reaction in water. The standardized protocol was
carried out by using imidazole (1.5 equiv.), iodobenzene (1
equiv.), base (2 equiv.), Cu source (10 mol%), and ligand
(20 mol%) in water at 120 °C for 12 h. The results are shown
in Table 1.
Between the two ligands used, L1 exhibited much higher
catalytic ability than L0 (entries 1 and 2). As the better
ligand was determined, we next examined copper sources,
and CuCl, Cu2O, CuO combined with L1 afforded the
N-arylated product in good yields of 70, 75, and 73% respec-
tively (entries 4, 5, and 7). Control experiment certificated
Scheme 1 Previous works and
Cu powder, L
this work
H
Ar-X
Ar-N-Het
N
Het-NH
KOH, TBAB
H2O, 120 °C, 12 h
Het-NH: imidazoles, pyrrole
N
O
N
H
X = I, Br
Ref. 25
O
L
CuO, L
H
N
Ar-X
X = I
Ar-N-Het
Ar-NR1R2
Het-NH
NaOH, TBAB
H2O, 120 °C, 12 h
Het-NH: imidazoles, indole
N
O
NHn-C12H25
O
L
Ref. 26
O
CuSO4, L
H
N
Ar-X
NHR1R2
NaOH, TBAB
N
H
OH
X = I, Br
Ref. 27
H2O, 120 °C, 24 h
NHR1R2: imidazoles, pyrazole, indole, aniline
benzylamine
L
Cu2O, L
Ar-NR1R2
NHR1R2
Ar-X
NaOH, TBAB
H2O, 130 oC, 24 h
H
H
N
N
X = I, Br
N
H
N
O
L
N
H
NHR1R2: imidazoles, indole, pyrrole, benzylamine,
ethanolamine
O
O
This work
1 3

2,6-Bis(2-methylhydrazine-1-carbonyl)pyridine 1-oxide as an Efficient Ligand for…
Table 1 Screening reaction conditions for N-arylation of imidazole with iodobenzene
H
H
N
N
N
N
[Cu], L
RHN
N
O
NHR
N
I
N
O
O
Base, TBAB
H2O, 120 oC, 12 h
H
L0: R = H
L1: R = CH3
Entry
[Cu]
Ligand
Base
Yield (%)a
1
2
3
4
5
6
7
8
Cu
Cu
CuI
CuCl
Cu2O
Cu(OAc)2
CuO
L0
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
KOH
K2CO3
K3PO4
Cs2CO3
NaOH
NaOH
NaOH
NaOH
40
56
61
70
75
64
73
68
trace
67
25
40
10
72
81
95
78
CuSO4
–
9
10
11
12
13
14b
15c
16c,d
17c,d,e
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Reaction conditions iodobenzene (0.5 mmol), imidazole (0.75 mmol), [Cu] (10 mol %), L (20 mol %), TBAB (20 mol %), base (1 mmol), H2O
(1 mL), 120 °C, 12 h
aIsolated yield
bReaction temperature: 100 °C
cReaction temperature: 130 °C
dReaction time: 24 h
e0 mol % of L1
occur smoothly (entries 12–18). Interestingly, the reaction
was highly chemoselective; for example, reaction of etha-
nolamine only gave the N-arylated product under present
conditions (entry 19). As a result of lower activity of aryl
bromides than that of iodides, the coupling reaction of aryl
bromides provided slightly lower yields (Table 3, entries
1–5), and fortunately, heteroaryl bromides also coupled with
imidazole to give the corresponding products in moderate
yields (Table 3, entries 6–8).
electron-donating ability of the ligand could make this com-
plex very 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 nitrogenous
heterocycle to form III. Reductive elimination of III led to
the coupling products and regenerated the catalytic species I.
3 Conclusions
A large scale synthesis was performed by taking 5 mmol
of iodobenzene and 7.5 mmol of imidazole in 10 mL of
H2O at 130 °C for 24 h, and the reaction proceeded with-
out any difficulty to obtain N-aryl product 3a in 89% yield
(Scheme 2).
In summary, this effort has led to the identification of
2,6-bis(2-methylhydrazine-1-carbonyl)pyridine 1-oxide as
an ideal ligand for promoting copper-catalyzed Ullmann-
type coupling reactions of aryl halides with nitrogen nucleo-
philes in water. The protocol demonstrated broad substrate
scopes with good isolated yields. Further studies of this
A proposed mechanism for the present coupling reaction
is shown in Scheme 3. In the presence of NaOH, Cu2O might
react with L1 to afford Cu(I) complex I, in which the strong
1 3

X. Wang et al.
Table 2 Cu-catalyzed N-arylation of nitrogen nucleophiles with aryl iodides using 2,6-bis(2-methylhydrazine-1-carbonyl)pyridine 1-oxide as
ligand in water
H
H
Cu2O, L1
NHR1R2
N
N
Ar-I
Ar-NR1R2
N
N
N
NaOH, TBAB
H2O, 130 oC, 24 h
H
H
1
2
3
O
O
L1
O
Entry
1
Ar-X
Product
Yield (%)a
95
I
N
N
3a
I
N
N
2
3
92
87
3b
3c
O
O
O
O
I
N
N
I
N
N
4
48
3d
O
O
I
N
N
5
6
7
90
71
60
3e
3f
EtO
EtO
I
N
N
I
I
N
N
3g
Ph
Ph
N
N
8
89
77
40
3h
3i
Cl
O
Cl
O
I
N
N
9
I
N
N
10b
3j
S
S
1 3

2,6-Bis(2-methylhydrazine-1-carbonyl)pyridine 1-oxide as an Efficient Ligand for…
Table 2 (continued)
Entry
11
Ar-X
Product
Yield (%)a
I
N
N
95
3k
3l
N
N
I
I
N
N
12
60
38
70
60
67
N
13
3m
3n
3o
3p
I
N
14
N
N
I
H
15c
16c
N
I
I
H
N
O
N
O
H
N
17c
80
3q
N
I
H
N
18c
19c
50
61
3r
3s
Cl
Cl
H
N
I
OH
Reaction conditions ArI (0.5 mmol), R1R2NH (0.75 mmol), Cu2O (0.05 mmol), L1 (20 mol %), TBAB (20 mol %), NaOH (1 mmol), H2O
(1 mL), 130 °C, 24 h
aIsolated yield
bReaction time: 36 h
cNHR1R2 (1.5 mmol)
1 3

X. Wang et al.
Table 3 Cu-catalyzed
N-arylation of imidazole with
aryl bromides using 2,6-bis(2-
methylhydrazine-1-carbonyl)
pyridine 1-oxide as ligand in
water
Entry
1
Ar–Br
Product
Yield (%)a
Br
N
N
50
3b
O
O
Br
N
N
2
25
3f
Br
N
O
O
N
O
O
3
48
3t
Br
N
N
4
67
3i
O
O
Br
Br
N
N
5
6
53
67
3h
Cl
S
Cl
S
N
N
3u
Br
Br
N
N
N
7
8
71
28
3v
N
N
3w
N
S
S
Reaction conditions ArI (0.5 mmol), Het-NH (0.75 mmol), Cu2O (0.05 mmol), L1 (20 mol %), TBAB
(20 mol %), NaOH (1 mmol), H2O (1 mL), 130 °C, 24 h
aIsolated yield
1 3

2,6-Bis(2-methylhydrazine-1-carbonyl)pyridine 1-oxide as an Efficient Ligand for…
Scheme 2 Large-scale reaction
N
Cu2O, L1
of N-arylation of imidazole with
N
N
iodobenzene in water
I
N
NaOH, TBAB
H2O, 130 oC, 24 h
H
5 mmol
7.5 mmol
3a, 89%, 0.64g
3.1.2 General Procedure for the Synthesis of 3a–3w
NaOH
O
O
L1
Ar-NR1R2
Cu2O
N
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), L1 (0.1 mmol) and water (1 mL). The
mixture was stirred at 130 °C for 24 h. The reaction mixture
was extracted with ethyl acetate (3×10 mL), washed with
water and brine, dried over anhydrous Na2SO4, and concen-
trated 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.
NH
NH
O
N
H
N
Cu
Ar-X
I
Oxidative
addition
Reductive
elimination
O
O
N
NH
N
O
N
NH
N
O
O
O
NH
NH
N
Ar
II
X
NR1R2
H
N
Ar
III
Acknowledgements We gratefully acknowledge the Natural Science
H
Foundation of China (21606153) for the financial support.
NHR1R2 + NaOH
NaX + H2O
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