A simple and efficient 2N2O-Cu(II) complex as a catalyst for N-arylation of imidazoles in water

Article abstract of DOI:10.1002/aoc.3317

Four inexpensive and air- and moisture-stable 2N2O-Cu complexes were synthesized, one of which proved to exhibit good catalytic activity for the N-arylation of imidazoles in water. A variety of aryl iodides and aryl bromides underwent coupling with imidazoles promoted by the catalytic system with moderate to excellent yields.

Full text of DOI:10.1002/aoc.3317

Full Paper
Received: 4 January 2015
Revised: 19 February 2015
Accepted: 8 March 2015
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/aoc.3317
A simple and efficient 2N2O–Cu(II) complex as a
catalyst for N-arylation of imidazoles in water
Yashuai Liu, Ningning Gu, Ping Liu*, Jianwei Xie, Bin Dai and Yan Liu
Four inexpensive and air- and moisture-stable 2N2O–Cu complexes were synthesized, one of which proved to exhibit good cata-
lytic activity for the N-arylation of imidazoles in water. A variety of aryl iodides and aryl bromides underwent coupling with imid-
azoles promoted by the catalytic system with moderate to excellent yields. Copyright © 2015 John Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
Keywords: N-arylation; copper-catalyzed; N,O ligand; imidazoles; water
internal standard and CDCl3 as solvent. EI mass spectra were mea-
sured with an LC/Q-TOF MS (Micromass, UK). All reagents were of
Introduction
The synthesis of N-arylimidazole derivatives is of significant impor-
tance because their structural motifs are a common occurrence in
numerous drugs, natural products and energetic materials.[1] In
the last decade, Cu-catalyzed C–N coupling reaction has proven
suitable for the direct N-arylations of imidazole derivatives. To this
end, significant efforts have been devoted to the development of
transition metal-catalyzed C–N coupling reactions.[2–4] Several clas-
ses of monodentate, bidentate and polydentate chelators have
thereby been developed to increase the reaction rates and lower
substantially the reaction temperature.[5–18] However, it is worth
noting that these protocols are generally operated using volatile or-
ganic solvents with transition metal ions. From the standpoint of
green chemistry, the development of environmentally benign reac-
tion media, such as water that is nontoxic, cheap and readily avail-
able, in place of organic solvents would be desirable.[19,20] Hence, as
part of our endeavors towards the development of environmentally
friendly protocols, efforts were directed towards performing
C–X (X = C, N) reactions using water as the sole reaction medium.
Schiff base ligands are recognized as some of the most efficient
auxiliaries, and many Schiff base metal complexes are used as ex-
cellent catalysts in various organic transformations.[21] Based on
our previous research,[22] herein we report a soluble 2N2O–Cu com-
plex (1) as catalyst for the N-arylation of imidazoles in water. This
catalytic system has several advantages: (1) 2N2O–Cu(II) complex
is easy to synthesize; (2) use of water as a green solvent that is used
in place of organic solvents, and the N-arylation reactions can be
performed without an inert gas atmosphere and with low catalyst
loading; and (3) the work-up procedure is simple with excellent
yields and broad substrate range.
analytical grade quality and commercially obtained.
Synthesis of Complexes 1–4
A solution of 2 mmol of substituted amine and 2 mmol of sodium 3-
formyl-4-hydroxybenzenesulfonate in 10 ml of 50% ethanol was
stirred at 60 °C for 5 h. Then 1 mmol of Cu(OAc)2ꢀH2O in 10 ml of
50% ethanol was added to that solution, and the mixture was
stirred at 60 °C for 2 h. After cooling to room temperature, the reac-
tion solution was diluted with 50ml of acetone and filtered. The
solid product was collected and dried under vacuum to afford the
desired complexes 1–4.
Complex 1. Yield 75%. Anal. Calcd for C26H18CuN2Na2O8S2 (%): C,
47.31; H, 2.75; N, 4.24; S, 9.72. Found (%): C, 46.57; H, 2.77; N, 4.20; S,
9.69. MS (negative), m/z: [(M ꢁ Na)]+ calculated, 659.0; found, 659.6.
IR (KBr, cmꢁ1): 3441 (OH), 1612 (C¼N), 1184 (SO3Na).
Complex 2. Yield 70%. Anal. Calcd for C28H22CuN2Na2O8S2 (%): C,
48.87; H, 3.22; N, 4.07; S, 9.32. Found (%): C, 48.43; H, 3.28; N, 3.98; S,
9.27. MS (negative), m/z: [(M ꢁ Na)]+, calculated, 664.0; found, 664.2.
IR (KBr, cmꢁ1): 3433 (OH), 1628 (C¼N), 1169 (SO3Na).
Complex 3. Yield 72%. Anal. Calcd for C28H22CuN2Na2O10S2 (%):
C, 46.70; H, 3.08; N, 3.89; S, 8.91. Found (%): C, 46.80; H, 2.54; N,
3.84; S, 8.79. MS (negative), m/z: [(M ꢁ Na)]+, calculated, 690.6;
found, 690.2. IR (KBr, cmꢁ1): 3448 (OH), 1616 (C¼N), 1184 (SO3Na).
Complex 4. Yield 75%. Anal. Calcd for C26H14Cl4CuN2Na2O8S2 (%):
C, 39.14; H, 1.77; N, 3.51; S, 8.04. Found (%): C, 39.05; H, 1.81; N, 3.45;
S, 8.01. MS (negative), m/z: [(M ꢁ Na)]+, calculated: 771.8; found,
772.2. IR (KBr, cmꢁ1): 3430 (OH), 1608 (C¼N), 1184 (SO3Na).
Experimental
*
Correspondence to: Ping Liu, School of Chemistry and Chemical Engineering/Key
Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan,
Shihezi University, Shihezi 832003, China. E-mail: liuping1979112@aliyun.com
Materials and Instrumentation
All reactions were carried out in air under magnetic stirring condi-
tions unless otherwise noted. 1H NMR spectral data were recorded
with a Bruker DPX-400 spectrometer using tetramethylsilane as
School of Chemistry and Chemical Engineering/Key Laboratory for Green
Processing of Chemical Engineering of Xinjiang Bingtuan, Shihezi University,
Shihezi 832003, China
Appl. Organometal. Chem. (2015)
Copyright © 2015 John Wiley & Sons, Ltd.

Y. Liu et al.
Table 1. Optimization of reaction conditionsa
General Procedure for N-Arylation of Imidazoles and
Derivatives
To a 5 ml sealed tube was added complex 1 (0.05 mmol), aryl iodide
or bromide (0.5mmol), imidazole or 1H-benzo[d]imidazole
(0.75 mmol), NaOH (1mmol) and water (1ml). The mixture was
stirred at 100 °C for 12 h. After cooling to room temperature, the
mixture was quenched with 10 ml of water and extracted with
EtOAc (3× 20 ml). The combined EtOAc extracts were dried with
anhydrous Na2SO4, filtered and the solvent was removed under re-
duced pressure. The residue was purified using flash column chro-
matography on silica gel with PE–EtOAc (from 2:1 to pure EtOAc) as
the eluent to afford the desired products. All N-arylimidazoles re-
ported herein are known products and were characterized using
melting point, 1H NMR spectroscopy and GC-MS, the results of
which were compared with previously reported literature.
Entry
Catalyst
Base
Additive
Yield (%)b
1
—
CuI
NaOH (4 equiv.)
NaOH (4 equiv.)
NaOH (4 equiv.)
NaOH (4 equiv.)
NaOH (4 equiv.)
NaOH (4 equiv.)
NaOH (4 equiv.)
NaOH (4 equiv.)
NaOH (2 equiv.)
NaOH (2 equiv.)
NaOH (2 equiv.)
KOH (2 equiv.)
Na2CO3 (2 equiv.)
NEt3 (2 equiv.)
TBAB/10%
TBAB/10%
TBAB/10%
TBAB/10%
TBAB/10%
TBAB/10%
TBAB/10%
SDBS/10%
TBAB/10%
TBAB/10%
TBAB/5%
0
Trace
Trace
95
2
3
Cu(OAc)2
1/10%
2/10%
3/10%
4/10%
1/10%
1/10%
1/5%
4
5
Trace
95
6
7
Trace
Trace
95
8
9
10
11
12
13
14
15
76
Results and Discussion
1/2%
15
1/10%
1/10%
1/10%
1/10%
TBAB/10%
TBAB/10%
TBAB/10%
TBAB/10%
57
Complexes 1–4 could be conveniently synthesized by condensa-
tion of the corresponding amines with 5-sulfonatosalicylaldehydes
and a sequential addition of copper acetate with good yields (Fig. 1).
To evaluate the catalytic efficiency of complexes 1–4, the C–N cou-
pling of 4-iodotoluene with 1H-imidazole was chosen as a model
reaction with complexes 1–4 (10 mol%) in the presence of NaOH
(4 equiv.) and tetrabutylammonium bromide (TBAB; 10mol%) at
100 °C for 20 h in water. No desired product is observed in the ab-
sence of catalyst (Table 1, entries 1–3). Gratifyingly, complexes 1
and 3 exhibit high catalytic activity for this coupling reaction
(Table 1, entries 4 and 6), which both give the desired product in
95% yields, but complexes 2 and 4 show low catalytic activity
(Table 1, entries 5 and 7). The results show that the electronic ef-
fects and steric hindrance of the ligands have an obvious relation
with the catalytic activity, and the electron-rich aryl-substituted N,
O bidentate ligands can effectively promote the oxidative addition
and reductive elimination of the central copper probably due to the
increasing electron density and steric hindrance.
Trace
Trace
Trace
Cs2CO3 (2 equiv.)
aReaction conditions: 4-iodotoluene (0.5 mmol), 1H-imidazole (1.0 mmol),
complexes 1–4 (5–10 mol%), base (1–2 mmol), TBAB (5–10 mol%),
H2O (1 ml), 100 °C, 20 h.
bIsolated yields.
Table 2. N-arylation of imidazoles catalyzed by complex 1a
Subsequently, we selected complex 1 as catalyst to further inves-
tigate the effects of the other conditions on this reaction. Sodium
dodecyl-benzenesulfonate (SDBS) as phase-transfer catalyst fails
to show better performance than TBAB (Table 1, entry 8). Decreasing
the dosage of NaOH to 2 equiv. still leads to the corresponding
product in 95% yield (Table 1, entry 9). Among other bases
examined, only KOH is effective for the catalysis, affording 57%
yield of the desired product (Table 1, entries 12–15). Furthermore,
the dosages of complex 1 and TBAB are also key parameters in
the reaction. The results show that decreasing the loading of complex
1 or TBAB reduces the yield of the desired product (Table 1, entry
10). When the dosage of complex 1 is 2%, the yield is the lowest
(Table 1, entry 11). Thus, complex 1 (10 mol%), NaOH (2 equiv.)
and TBAB (10 mol%) in water at 100 °C are defined as the optimized
reaction conditions for additional study.
Entry
R, X
Het-NH
Product
Yield (%)b
1
H, I (5b)
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6b
6b
6b
6b
7b
7c
7d
7e
7f
99
94
29
59
86
70
92
40
42
85
32
68
77
61
46
2
4-OEt, I (5c)
2-Me, I (5d)
4-COMe, I (5e)
4-NO2, I (5f)
4-Ph, I (5 g)
4-Cl, I (5 h)
4-CH3, Br (5i)
4-NO2, Br (5j)
2-Bromopyridine (5 k)
2-Bromothiophene (5 l)
4-Me, I (5a)
5b
3
4
5
6
7 g
7 h
7a
7f
7
8
9
10
11
12
13
14
15
7i
7j
7 k
7 l
5f
7 m
7n
5 g
aReaction conditions: aryl halide (0.5 mmol), 1H-imidazole (1.0 mmol),
complex 1 (10 mol%), NaOH (1.0 mmol), TBAB (10 mol%), H2O (1 ml),
100 °C, 20 h.
bIsolated yields.
Figure 1. Structures of complexes 1–4.
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Cu-catalyzed N-arylation of imidazole in water
[5] a) R. Gujadhur, D. Venkataraman, T. J. Kintigh, Tetrahedron Lett. 2001,
42, 4791–4793; b) R. K. Gujadhur, C. G. Bates, D. Venkataraman, Org.
Lett. 2001, 3, 4315–4317.
The scope of substrates was then investigated using the optimal
reaction conditions (Table 2). We first studied the N-arylation of 1H-
imidazole with various aryl iodides. In general, most aryl iodides
react with imidazole smoothly to give the desired products with
moderate to excellent yields, such as iodobenzene, 1-ethoxy-4-
iodobenzene, 1-iodo-4-nitrobenzene, 1-chloro-4-iodobenzene
and 4-iodo-1,1′-biphenyl leading to the N-arylated products with
70–99% yields (Table 2, entries 1, 2, 5–7). When 1-(4-iodophenyl)
ethanone is used as the coupling partner, the yield drops to 59%
(Table 2, entry 4). Also we can see that sterically demanding ortho
substituents such as 1-iodo-2-methylbenzene hamper the N-
arylation reaction (Table 2, entry 3). Although aryl bromides, such
as 1-bromo-4-methylbenzene and 1-bromo-4-nitrobenzene, are
less reactive than aryl iodides, 40 and 42% yields are still obtained,
respectively (Table 2, entries 8 and 9). Interestingly, heteroaryl bro-
mides are also coupled with imidazole to afford the desired product
with 85 and 32% yields, respectively (Table 2, entries 10 and 11). To
our delight, aryl iodides react with 1H-benzo[d]imidazole and the
corresponding products with moderate to good yields are achieved
under the optimized reaction conditions. For example,
iodobenzene, 1-iodo-4-methylbenzene and 1-iodo-4-nitrobenzene
afford the corresponding products with 61–77% yields (Table 2,
entries 12–14). When 4-iodo-1,1′-biphenyl as substrate reacts with
1H-benzo[d]imidazole, the arylated product with 46% yield is
obtained (Table 2, entry 15).
[6] M. Yang, F. Liu, J. Org. Chem. 2007, 72, 8969–8971.
[7] a) A. Kiyomori, J.-F. Marcoux, S. L. Buchwald, Tetrahedron Lett. 1999, 40,
2657–2660; b) L. Liu, M. Frohn, N. Xi, C. Dominguez, R. Hungate,
P. J. Reider, J. Org. Chem. 2005, 70, 10135–10138; c) A. A. Kelkar,
N. M. Patil, R. V. Chaudhari, Tetrahedron Lett. 2002, 43, 7143–7146; d)
Y.-H. Liu, C. Chen, L.-M. Yang, Tetrahedron Lett. 2006, 47, 9275–9278.
[8] a) J. C. Antilla, A. Klapars, S. L. Buchwald, J. Am. Chem. Soc. 2002, 124,
11684–11688; b) A. Klapars, X. Huang, S. L. Buchwald, J. Am. Chem.
Soc. 2002, 124, 7421–7428; c) B. Mallesham, B. M. Rajesh, P. R. Reddy,
D. Srinivas, S. Trehan, Org. Lett. 2003, 5, 963–965; d) P.-S. Wang,
C.-K. Liang, M.-K. Leung, Tetrahedron 2005, 61, 2931–2939; e)
E. Alcalde, I. Dinares, S. Rodriguez, C. Garcia de Miguel, Eur. J. Org.
Chem. 2005, 1637–1643; f) P. E. Maligres, S. W. Krska, P. G. Dormer,
J. Org. Chem. 2012, 77, 7646–7651.
[9] F. Y. Kwong, A. Klapars, Org. Lett. 2002, 4, 581–584.
[10] Y.-J. Chen, H.-H. Chen, Org. Lett. 2006, 8, 5609–5612.
[11] D. Jiang, H. Fu, Y. Jiang, Y. Zhao, J. Org. Chem. 2007, 72, 672–674.
[12] F. Y. Kwong, S. L. Buchwald, Org. Lett. 2003, 5, 793–796.
[13] a) A. Shafir, S. L. Buchwald, J. Am. Chem. Soc. 2006, 128, 8742–8743; b)
Z. Xi, F. Liu, Y. Zhou, W. Chen, Tetrahedron 2008, 64, 4254–4259; c)
X. H. Zhu, L. Su, L. Y. Huang, G. Chen, J. L. Wang, H. C. Song,
Y. Q. Wan, Eur. J. Org. Chem. 2009, 635–642.
[14] X. Lv, W. Bao, J. Org. Chem. 2007, 72, 3863–3867.
[15] a) H.-J. Cristau, P. P. Cellier, J.-F. Spindler, M. Taillefer, Chem. Eur. J. 2004,
10, 5607–5622; b) Z. Q. Wu, Z. Q. Jiang, D. Wu, H. F. Xiang, X. G. Zhou,
Eur. J. Org. Chem. 2010, 1854–1857; c) Z. Q. Wu, L. Zhou, Z. Q. Jiang,
D. Wu, Z. K. Li, X. G. Zhou, Eur. J. Org. Chem. 2010, 4971–4975; d)
Y. Wang, Z. Wu, L. X. Wang, Z. K. Li, X. G. Zhou, Chem. Eur. J. 2009, 15,
8971–8974.
[16] a) D. Ma, Q. Cai, H. Zhang, Org. Lett. 2003, 5, 2453–2455; b) D. Ma, Q. Cai,
Synlett 2004, 128–130; c) Q. Cai, W. Zhu, H. Zhang, Y. Zhang, D. Ma,
Synthesis 2005, 496–499; d) H. Zhang, Q. Cai, D. Ma, J. Org. Chem.
2005, 70, 5164–5173; e) X. Lv, Z. Wang, W. Bao, Tetrahedron 2006, 62,
4756–4761.
[17] a) Z. Lu, R. J. Twieg, S. D. Huang, Tetrahedron Lett. 2003, 44, 6289–6292;
b) Z. Lu, R. Twieg, Tetrahedron Lett. 2005, 46, 2997–3001.
[18] H. Rao, H. Fu, Y. Jiang, Y. Zhao, J. Org. Chem. 2005, 70, 8107–8109.
[19] M. Carril, R. SanMartin, E. Domínguez, Chem. Soc. Rev. 2008, 37,
639–647.
[20] For some selected examples, see a) L. Liang, Z. K. Li, X. Zhou, Org. Lett.,
2009, 11, 3294–3297; b) Y. Wang, Z. Wu, L. Wang, Z. Li, X. Zhou, Chem.
Eur. J. 2009, 15, 8971–8974; c) J. Xie, X. Zhu, M. Huang, F. Meng,
W. Chen, Y. Wan, Eur. J. Org., Chem. 2010, 17, 3219–3223; d) X. Li,
D. Yang, Y. Jiang, H. Fu, Green Chem. 2010, 12, 1097–1106; e) Y. Li,
X. Zhu, F. Meng, Y. Wan, Tetrahedron 2011, 67, 5450–5454; f)
K. G. Thakur, D. Ganapathy, G. Sekar, Chem. Commun. 2011, 47,
5076–5078; g) D. Wang, F. Zhang, D. Kuang, J. Yu, J. Li, Green Chem.
2012, 14, 1268–1271; h) Q. Yang, Y. Wang, D. Lin, M. Zhang,
Tetrahedron Lett. 2013, 54, 1994–1997; i) B. Yang, L. Liao, Y. Zeng,
X. Zhu, Y. Wan, Catal. Commun. 2014, 45, 100–103.
Conclusions
We have developed a novel and general catalytic method for
N-arylation of 1H-imidazoles promoted by complex 1 in water.
The system is efficient for the coupling of imidazoles with ArX
(X= I, Br) to give products in moderate to excellent yields. The easy
availability of the catalyst, mild reaction conditions, experimental
simplicity and broad substrate scope are the features of the
catalytic method presented in this paper.
Acknowledgments
We gratefully acknowledge financial support of this work by the Na-
tional Natural Science Foundation of China (nos. 21103114 and
21463022), and Shihezi University Training Programme for Distin-
guished Youth Scholars (no. 2014ZRKXJQ05).
[21] a) S. Matsunaga, M. Shibasaki, Chem. Commun. 2014, 50, 1044–1057; b)
S. Matsunaga, M. Shibasaki, Synthesis 2013, 45, 421–437; c) M. Nath,
P. K. Saini, Dalton Trans. 2011, 40, 7077–7121.
[22] a) F.-T. Wu, P. Liu, X.-W. Ma, J.-W. Xie, B. Dai, Chin. J. Chem. 2013, 24,
893–896; b) Y.-L. Jiao, N. N. Yan, J.-W. Xie, X.-W. Ma, P. Liu, B. Dai, Chin.
J. Chem. 2013, 31, 267–270; c) Y. Liu, Q. Zhang, X.-W. Ma, P. Liu,
J.-W. Xie, B. Dai, Z.-Y. Liu, Int. J. Org. Chem. 2013, 3, 185–189; d) Y. Liu,
W. Liu, Q. Zhang, P. Liu, J.-W. Xie, B. Dai, J. Chem. Res. 2013, 37, 636–637.
References
[1] N. R. Candeias, L. C. Branco, P. M. Gois, C. A. M. Afonso, A. F. Trindade,
Chem. Rev. 2009, 109, 2703–2802.
[2] J. F. Hartwig in Modern Amination Methods (Ed.: A. Ricci), Wiley-VCH,
Weinheim, 2000, pp. 195–262.
[3] a) J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc. 1997, 119, 6054–6058; b)
C. Desmarets, R. Schneider, Y. Fort, J. Org. Chem. 2002, 67, 3029–3036;
c) S. Tasler, B. H. Lipshutz, J. Org. Chem. 2003, 68, 1190–1199.
[4] a) F. Monnier, M. Taillefer, Angew. Chem. Int. Ed. 2009, 48,
6954–6971; b) M. G. Boswell, F. G. Yeung, C. Wolf, Synlett
2012, 23, 1240–1244; c) Y.-C. Teo, F.-F. Yong, G. S. Lim,
Tetrahedron Lett. 2011, 52, 7171–7174.
Supporting Information
Additional supporting information may be found in the online ver-
sion of this article at the publisher’s web-site.
Appl. Organometal. Chem. (2015)
Copyright © 2015 John Wiley & Sons, Ltd.
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