Cu2O/Cs2CO3/DMF: An efficient catalytic system for N-arylation of imidazole with aryl halides under ligand-free conditions

Article abstract of DOI:10.1080/00397911.2017.1353633

A ligand-free Cu-catalyzed protocol for the Ullmann-type N-arylation of N-containing heterocycles with aryl or heteroaryl iodides and bromides has been established. A broad range of functional groups is well tolerated on both of the cross-coupling partners, producing the desired products in good to excellent yields.

Full text of DOI:10.1080/00397911.2017.1353633

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Cu O/Cs CO /DMF: An efficient catalytic system for
2
2
3
N-arylation of imidazole with aryl halides under
ligand-free conditions
Xiaochuang Wang, Meiji Wang & Jianwei Xie
To cite this article: Xiaochuang Wang, Meiji Wang & Jianwei Xie (2017): Cu O/Cs CO /DMF: An
2
2
3
efficient catalytic system for N-arylation of imidazole with aryl halides under ligand-free conditions,
Synthetic Communications, DOI: 10.1080/00397911.2017.1353633
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1353633
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Date: 02 August 2017, At: 06:58

Cu O/Cs CO /DMF: An efficient catalytic system for
2
2
3
N-arylation of imidazole with aryl halides under ligand-free
conditions
Xiaochuang Wang
School of Chemistry and Chemical Engineering/Key Laboratory for Green Processing of
Chemical Engineering of Xinjiang Bingtuan, Shihezi University, Shihezi, Xinjiang, China
Meiji Wang
School of Chemistry and Chemical Engineering/Key Laboratory for Green Processing of
Chemical Engineering of Xinjiang Bingtuan, Shihezi University, Shihezi, Xinjiang, China
Jianwei Xie
School of Chemistry and Chemical Engineering/Key Laboratory for Green Processing of
Chemical Engineering of Xinjiang Bingtuan, Shihezi University, Shihezi, Xinjiang, China
Address correspondence to Jianwei Xie. Tele.: +86-993-2057213. Fax: +86-993-2057270.
E-mail: cesxjw@foxmail.com
ABSTRACT
1

A ligand-free Cu-catalyzed protocol for the Ullmann-type N-arylation of N-containing
heterocycles with aryl or heteroaryl iodides and bromides has been established. A broad range of
functional groups are well tolerated on both of the cross-coupling partners, producing the desired
products in good to excellent yields.
KEYWORDS: aryl halides, C-N coupling, CU
2
O/CS
2
CO /DMF, heterocycles, ligand-free
3
Introduction
N-Heterocycles are important building blocks of numerous natural products, materials
and biologically active molecules,[1] and they are often found in drug exploitation because
N-hetercocycles moieties exhibit improved pharmaceutical activities and physicochemical
properties, both of which are important for efficiency and bioavailability of a drug.[2]
Traditionally, the preparation of these moieties always rely on classical Ullmann cross-coupling
reaction.[3] However, the drawbacks, such as high reaction temperatures, stoichiometric amounts
of copper salts and limited substrate scopes, are existent, and neither of them was energy saving
nor ecologically friendly. To overcome these disadvantages, a great deal of endeavor on
modification of these transformations has been made over the past several years by using
different kinds of practical mono- and bidentate ligands.[4] Despite these successes, the
development of an efficient and simple copper-based ligand-free catalytic system for
Ullmann-type C-N coupling reactions would represent a major advance. Recently, several
heterogeneous C-N cross-coupling reactions catalyzed by copper species were reported with the
2

advantages of simplified isolation of the products and easy recovery and recyclability of the
catalysts under ligand-free conditions, such as supported copper or copper nanoparticles (e. g.,
CELL-Cu(0),[5] Cu
Cu@Cu
NPs-RGO,[10]
montmorillonite,[13] CuO NPs/SiO
nanoparticles (e. g., CuO NPs,[17] electrospun CuO NPs,[18] and CuCr
copper salts (e. g., CuCl,[20] CuI,[21] Cu O[22] and Cu powder[23]). As part of our studies on
copper-catalyzed N-arylations of nucleophiles,[24] in this paper, we report herein
Cu O/Cs CO /DMF as an efficient catalytic system for direct N-arylation of imidazole with aryl
iodides and bromides under ligand-free conditions. Notably, there were two related articles
should be illustrated which used Cu O as catalyst for C-N coupling reactions. One is that Bolm
et al.[22a] reported Cu
O-catalyzed N-arylation of sulfoximines and nitrogen-containing
O coated Cu NPs,[6] Cu or Cu /4 Å, RGO/Cu NPs,[8] Cu NPs/Zeolite,[9]
Cu O/nano-CuFe CuO
,[11] NPs/MWCNT,[12] Cu+
,[14] Fe O,[15] and Cu NTs[16]), copper
@TiO /Cu O/TiO
NPs,[19]) or simple
0
2+
[7]
2
2
O
2
2
O
4
-
2
3
O
4
2
2
2
2
O
2 4
2
2
2
3
2
2
heterocycles (mainly are pyrrole, triazole, indole and benzimidazole), with aryl iodides and
bromides, and there was no example of imidazole. The other is that Xu et al.[22b] developed a
Cu
2
O/KOH/DMSO system for N-arylation of imidazoles under N
2
atmosphere for 24 hours.
O/Cs CO /DMF catalytic
Compared to the reported system mentioned above, the present Cu
2
2
3
system exhibited higher efficiency with excellent yields, relatively milder conditions and broader
functional group tolerance.
Results and Discussion
3

To investigate the optimum reaction conditions, in our initial experiment, we chose
-iodotoluene and imidazole as the model substrates to optimize copper sources, bases, reaction
4
temperature and time, and the results are shown in Table 1. Among the copper sources
investigated, preliminary results showed that most of Cu(0), Cu(I) and Cu(II) salts were more or
less equally active, and Cu
out in the absence of copper salts, and afforded the desired product in 25% yield (entry 9). Of all
the tested bases, including K PO , Cs CO , KOH and K CO , indicated Cs CO was the best one
2
O was the most effective (entries 1–8). Blank experiment was carried
3
4
2
3
2
3
2
3
in an excellent yield of 99% (entries 10–13). DMF and DMSO were found to be the solvents in
choice, while 1,4-dioxane and 1,2-dichloroethane (DCE) were much less effective (entries 11
and 14–16). Inferior product yields were observed for the reaction with lowering the reaction
temperature to 100 °C (18% yield, entry 17), decreasing the amounts of copper reagent to 5%
(
88% yield, entry 18), or shortening the reaction time to 8 h (89% yield, entry 19). Therefore, we
can draw a conclusion that the optimal conditions for this cross-coupling reaction consist of the
combination of halide (1 equiv), N-containing heterocycles (1.5 equiv.), Cu O (10 mol%) and
Cs CO (2 equiv) at 120°C for 12 h without protection from air or moisture.
2
2
3
With this optimized procedure in hand, we subsequently explored the scope of the
reaction and screened a wide range of aryl iodides and bromides and N-containing heterocycles.
The results were listed in Table 2. The effect of several aryl iodides used in the reaction was
firstly investigated by using imidazole as a substrate (entries 1–14). In general, most of aryl
4

iodides worked well to afford the corresponding products in good to excellent yields under the
standard conditions. Ortho-substituted substrates did not hamper the reaction and an 80% of
yield was obtained (entry 6). Chloro, fluoro, keto, cyano, nitro and naphthalene groups were all
tolerated on the aryl iodide component. The heterocycles, such as benzimidazole (entry 15),
indole (entry 16) and pyrrole (entry 17) were found to be effective nucleophiles for the coupling
reactions in 63%, 73% and 91% yield, respectively. We were pleased to find that the C-N
coupling reaction also proceeded smoothly for aryl bromide, whether they were electron-rich,
electron-neutral or electron-poor, gave the desired product in in 66–94% yields (entries 18–25)
only by prolonging the reaction time to 24 h (entry 18, 20, 21 and 25) or increasing the
temperature to 130°C (entry 19) or for some examples. Moreover, it is notable that the effect of
the strong electron-withdrawing is beneficial for these transformations (entries 22–24). Reactions
of 2-bromopyridine and 2-bromothiophene provided the corresponding heteroaryl imidazole in
9
4% and 68% yields, respectively (entries 24 and 25). By contrast, the reaction of chlorobenzene
did not occur under the same condition (entry 26).
Conclusions
In conclusion, we have developed an operationally simple method for Cu O-catalyzed
2
C-N cross-coupling reaction under ligand-free conditions without the protection of an inert gas.
A variety of phenyl or heteroaryl iodides and bromides with excellent functional compatibility
were coupled with nitrogen nuclephiles, including imidazole, benzimidazole, indole and pyrrole
5

affording good to excellent isolated yields. The ligand-free conditions, experimental simplicity
and broad substrate scope are the features of the method presented in the current paper.
Experimental
Materials and methods
Unless otherwise stated, all reagents were purchased from commercial suppliers 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 Merck silica gel GF254 plates and visualized by exposure to UV light (254 nm).
1
All N-arylated products are characterized by H NMR and GC-MS, which were compared with
1
the previously reported data. H NMR spectra was recorded at room temperature on a Bruker
Avance III HD 400 instrument at 400 MHz. Mass spectra were recorded on GC-MS (Agilent
7
890A/5975C) instrument under EI model. HRMS were measured on Thermo Scientific LTQ
Orbitrap XL ESI-Technique.
General procedure for the synthesis of N-arylated products 3a-3t
A 10 mL vial was charged with aryl halide (0.5 mmol), Cs
2
CO
3
(1 mmol), Cu O (0.05
2
mmol), N-containing heterocycles (0.75 mmol), DMF (1 mL) and a magnetic stir bar. The
mixture was stirred at 120 ℃ (130 ℃ for entry 19). The reaction mixture was held at this
temperature for 12 hours (24 h for entry 18, 20, 21 and 25). After allowing the mixture to cool to
6

room temperature, the reaction mixture was extracted with ethyl acetate (3×10 mL), dried over
anhydrous Na SO , and concentrated in vacuo. The residue was purified by silica gel
chromatography (ethyl acetate/petroleum ether as the eluent) to provide the target products
a-3t.
2
4
3
Supporting information
1
Full experimental section, analytical data for compounds 3a-3t, and the copies of H and
13C NMR spectra can be found via the “Supplementary Content” section of this article’s
webpage.
Acknowledgments
We thank the Natural Science Foundation of China (NSFC, no. 21606153) and the
Ministry of Education Innovation Team (no. IRT15R46) for the financial support for this work.
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Table 1. Screening reaction conditions for copper-catalyzed N-arylation of imidazole with
4
-iodotoluenea
b
Entry
[Cu]
CuI
Base
Solvent
DMF
Yield (%)
1
2
3
4
5
6
7
8
9
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
55
52
57
69
63
54
31
46
25
70
99
88
50
98
48
CuBr
CuCl
DMF
DMF
Cu
2
O
DMF
Cu
Cu(OAc)
CuO
DMF
2
DMF
DMF
CuSO
4
DMF
-
DMF
1
1
1
1
1
1
0
1
2
3
4
5
Cu
Cu
Cu
Cu
Cu
Cu
2
2
2
2
2
2
O
K
3
PO
CO
KOH
CO
4
DMF
O
O
O
O
O
Cs
2
3
DMF
DMF
K
2
3
DMF
Cs
Cs
2
CO
3
3
DMSO
1,4-Dioxane
2
CO
1
0

1
1
1
1
6
7
8
9
Cu
Cu
Cu
Cu
2
2
2
2
O
O
O
O
Cs
Cs
Cs
Cs
2
2
2
2
CO
CO
CO
CO
3
3
3
3
DCE
DMF
DMF
DMF
trace
18c
88d
89e
a
Reaction conditions: 4-iodotoluene (0.5 mmol), imidazole (0.75 mmol), [Cu] (10 mol %), base (1 mmol), solvent (1 mL), 120
o
b
c
o
d
e
2
C,12 h; Isolated yield; Reaction temperature: 100 C; Reaction time: 8 h; 5 mol % of Cu O.
1
1

Table 2. Scope of the optimized Cu
O-catalyzed N-arylationa
2
Entry
1
ArX
Het-NH
Product
Yield (%)b
99
3a
3b
3c
3d
2
3
4
92
84
63
5
6
7
8
9
3e
3f
71
80
83
96
86
77
3g
3h
3i
1
0
3j
1
2

1
1
3k
78
1
1
1
2
3
4
3l
3m
3n
95
95
96
1
1
1
1
1
2
2
2
5
6
7
8
9
0
1
2
3o
3p
3q
3a
3b
3r
3h
3l
63
73
91
66c
60d
89c
73c
74
1
3

2
2
3
4
3m
3s
84
94
2
2
5
6
3t
68c
3g
trace
a
c
b
Reaction conditions: ArX (0.5 mmol), Het-NH (0.75 mmol), Cu
Reaction time: 24 h; d Reaction temperature: 130 C.
2 2 3
O (0.05 mmol), Cs CO (1 mmol), DMF (1 mL); Isolated yield;
o
1
4