N-Arylation of Heterocycles Promoted by Cyclen Derivatives

Article abstract of DOI:10.1002/jhet.2188

An efficient copper-catalyzed N-arylation reactions of imidazole, indole, and triazole with aryl or heteroaryl halides using cyclen derivatives as efficient organic base and ligand at moderate temperature have been investigated. The cross-couplings procee

Full text of DOI:10.1002/jhet.2188

Month 2014
N-Arylation of Heterocycles Promoted by Cyclen Derivatives
a
a
a
a
*
Bao-Hua Zhang, Lan-xiang Shi, Si-Jie Liu, and Rui-Xia Guo
College of Chemical Engineering, Shijiazhuang University, Shijiazhuang 050035, China
*
E-mail: kedashilanxiang@126.com
Received November 10, 2013
DOI 10.1002/jhet.2188
Published online in Wiley Online Library (wileyonlinelibrary.com).
An efficient copper-catalyzed N-arylation reactions of imidazole, indole, and triazole with aryl or
heteroaryl halides using cyclen derivatives as efficient organic base and ligand at moderate temperature have
been investigated. The cross-couplings proceed smoothly with good to excellent yields.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
RESULT AND DISCUSSION
Copper-assisted Ullmann-type coupling reactions are
valuable transformations for organic synthesis. Researchers
have extensively applied these reactions in both academic
and industrial settings. However, for a long time, these
reactions had been carried out at high temperature
(normally above 150°C) and many functional groups
could not be tolerated and therefore their usage was
greatly limited. In addition, these reactions often require
the use of stoichiometric amounts of copper reagents,
which, on scale, leads to problems of waste disposal
[1,2]. To overcome these drawbacks, important develop-
ments have been made on modification of the catalytic
system such as improving the solubility of the copper
source via addition of a wide range of ligands. Diamines
[3–5], amino acids [6–8], 1,10-phenanthrolines [9], diols
and triols [10–12], diketones [13], ketone-esters [14],
amino-alcohols [15], diimines [16], imine-amine [17],
diethylsalicylamide [5], etc. were found to be effective
ligands for the copper-catalyzed Ullmann arylation
reaction. In addition, in most reported methods of Ullmann
reactions, inorganic base, which make the transformation
suffer heterogeneous reaction in organic solvents, were
commonly used. Only a few organic bases, such as 1,8-
diazabicyclo[5.4.0]undec-7-ene [18], tetraalkylammonium
salts [19,20], alkoxide [21], and tetraethylenepentamine
[22] have been reported. Therefore, it is necessary to explore
more efficient organic base to simplify the process. Herein,
we reported our preliminary investigations on the use of
cyclen derivatives as base and ligand for the Cu-catalyzed
N-arylation of heterocycles.
Usually, the ligand and base play an important role for a
successful Cu-catalyzed C–N formation reaction. At the
outset of this study, we found that treatment of
iodobenzene (1 equiv) with imidazole (1 equiv), 10 mol%
CuI as catalyst, cyclen (1a, 2 equiv) as a base and ligand
in DMSO at 100°C for 12 h gave the good result, furnish-
ing N-phenylimidazole in 82% yield (entry 1). Encouraged
by this result, different cyclen derivatives (1a–f) were
tested under same conditions. The results are shown in
Table 1.
According to the results in Table 1, it was observed
clearly that the base plays a very important role in the
reaction. We observed that there was no coupling product
when only using CuI. In presence of 1a–f, all reactions were
carried out smoothly and gave the desired N-phenylimidazole
in 51–92% yields. 1f with strong alkaline side chain was
the best, 1b with CO2H group only gave the moderate
yield. Therefore, we could speculate that the main contri-
bution of 1 in this reaction was as base, and followed by
as ligand, which can promote the dissolution of CuI in
DMSO. In addition, the effects of the amount of 1f were
investigated. The 2 equiv 1f was appropriate (entry 7).
The copper source such as CuCl2, CuBr, Cu(OAc)2, and
CuO has been studied in this reaction, all copper sources
can afford satisfactory results, CuI turns out to give the
best result (entries 7, 10–13).
Therefore, the optimal results have been obtained when
imidazole (1.0 equiv) and aryl halide (1.0 equiv) were
allowed to react with 1f (2.0 equiv), CuI (0.1 equiv) in
DMSO 2 mL at 100°C.
Copyright © 2014 HeteroCorporation

B.-H., Zhang, L.-X. Shi, S.-J. Liu, and R.-X. Guo
Vol 000
Table 1
Screening reaction conditions for N-arylation of imidazoles with iodobenzene.a
Entry
1
[Cu]
CuI
Compound 1 (mol%)
Time (h)
12
Yield (%) b
82
2
CuI
12
51
3
4
CuI
CuI
12
12
83
88
5
6
CuI
CuI
12
12
87
92
7
8
9
10
11
12
13
CuI
CuI
CuCl2
CuBr
Cu(OAc)2
CuO
1f (1 mmol)
1f (3 mmol)
1f (2 mmol)
1f (2 mmol)
1f (2 mmol)
1f (2 mmol)
—
12
12
18
16
16
20
12
85
92
85
88
86
75
Trace
CuI
aReaction conditions: iodobenzene (1 mmol), imidazole (1 mmol), [Cu] (0.1 mmol), and 1a–f (2 mmol) in 2 mL in DMSO
at 100°C.
bIsolated yield.
With the optimized conditions in hand, we examined the
scope of the substrates for this catalyst system. As shown in
Table 2, both aryl iodides and bromides gave the coupling
products under the optimized conditions. But the aryl iodides
react more quickly than aryl bromides with the same nucleo-
phile and afford higher yield. The electronic nature of the aryl
halides was also found to have no obvious effect on the
reaction yield (entries 2, 4-7). The obviously reduced yields
of imidazole and 2-iodotoluene, 2-nitroiodobenzene suggest
that the adverse impact of steric hindrance exists in the current
system (entries 3 and 9). The catalyst system developed was
also successfully amenable to the N-arylation of indole and
triazole (entries 16-21).
possible catalytic cycles for our reactions as depicted in
Scheme 1. The chelation of Cu(I) with a cyclen derivative
makes Cu(I) species more reactive toward the oxidative
addition, or/and stabilize the oxidative addition interme-
diates A, thereby promoting the coupling reaction. The
mechanism outlined in Scheme 1 could be used to ex-
plain the phenomena observed, for example, the order I >
Br for ease of halogen displacement from the aromatic
ring. But, more detailed mechanistic studies should be
carried out to clarify these issues.
CONCLUSIONS
On the basis of the oxidative addition/reductive elimi-
nation mechanism [23] and the facts that copper ions can
form chelates with cyclen derivatives, we put forward
We have demonstrated a novel CuI-catalyzed method
for the N-arylation of nitrogen heterocycles with aryl
halides using cyclen derivatives as base and ligand that
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
N-Arylation of Heterocycles Promoted by Cyclen Derivatives
Table 2
CuI-catalyzed N-arylation of imidazole, indole, and triazole with various halides.a
Entry
Nitrogen heterocycle
ArX
Product
Yield (%)b
92
1
2
3
93
82
4
5
6
95
90
84
7
8
9
89
79
72
10
11
89
91
12
13
87
80
14
15
16
82
79
94
(Continues)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

B.-H., Zhang, L.-X. Shi, S.-J. Liu, and R.-X. Guo
Vol 000
Table 2
(Continued)
Entry
Nitrogen heterocycle
ArX
Product
Yield (%)b
17
91
18
86
19
20
93
89
21
85
aOptimized reaction conditions.
bIsolated yields.
Scheme 1
EXPERIMENTAL
proceeded in good to excellent product yields. The present
protocol is applicable to a variety of nitrogen heterocycles
and aryl halides containing electron-donating and electron-
withdrawing properties. A detailed examination of the
scope of the present reaction is currently underway.
The reagents were purchased from Merck, 1H and 13C spectra
were recorded in CDCl3 on a 400 MHz instrument at 400 MHz
(1H) and 100 MHz (13C) with TMS as internal standard; melting
points were recorded on X4 microscope; HRMS were obtained
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
N-Arylation of Heterocycles Promoted by Cyclen Derivatives
on OA-TOF mass spectrometer; Elemental analyses were
performed using C, H, and N elemental analyzer; Flash column
chromatography was performed with 300-mesh and 400-mesh
silica gel.
1-(4-Nitrohenyl)-1H-imidazole (4h).
White solid, mp:201–
1
202°C; H-NMR (400 MHz, CDCl3): δ 8.39 (d, J = 9.0 Hz, 2H),
7.99 (s, 1H), 7.58–7.61 (m, 2H), 7.39 (s, 1H), 7.29 (s, 1H), 6.46
(s, 1H); 13C-NMR (100MHz, CDCl3) δ 146.5, 142.2, 132.0,
126.0, 121.3, 117.9, 105.0; HRMS (M+): Calcd for C9H7N2O2
189.0538, found 189.0538.
General procedure for the synthesis of compounds 4. Aryl or
heteroaryl halides (1 mmol), imodazole, indole or triazole
(1 mmol), [Cu] (0.1 mmol), 1a–f (2 mmol) and 2 mL DMSO
were added to a 10 mL flask, which was subsequently capped
with a rubber balloon. The mixture was stirred in a preheated
oil bath at 100°C for appropriate time. After cooling the
mixtures to the room temperature and partitioned between
water and ethyl acetate, the aqueous layer was extracted
with ethyl acetate. The combined organic layers were
washed with 10% hydrochloric acid and water, dried over
Na2SO4, and concentrated in vacuo. The residuals were
purified by silica-gel column chromatography to afford
corresponding products. The aqueous phase adjusted
pH = 11 with 15% NaOH solution, ethyl acetate extraction,
concentrate, and recycle 1a–f.
1-(2-Nitrohenyl)-1H-imidazole (4i).
White solid, mp:79-
1
80°C; H-NMR (400 MHz, CDCl3): δ 8.01 (d, J = 8.1 Hz, 1H),
7.73–7.77 (m, 1H), 7.61–7.62 (m, 2H), 7.48 (d, J = 7.9 Hz,
1H), 7.22 (s, 1H), 7.08 (s, 1H); 13C-NMR (100 MHz, CDCl3)
δ 140.3, 132.2, 126.7, 125.5, 125.3, 124.6, 123.6, 120.3,
115.3; HRMS (M+): Calcd for C9H7N2O2 189.0538, found
189.0538.
1
1-(Pyridine-3-yl)-1H-imidazole (4j).
Yellow oil; H-NMR
(400 MHz, CDCl3): δ 8.71 (d, 1H), 8.60–8.58 (m, 1H), 7.84 (s,
1H), 7.42–7.39 (m, 1H), 7.42–7.39 (m, 1H), 7.27–7.25 (m, 1H),
7.21 (s, 1H); 13C-NMR (100 MHz, CDCl3) δ 148.7, 142.8,
135.5, 133.8, 131.1, 128.8, 124.2, 118.0; HRMS (M+): Calcd
for C8H7N3 145.0640, found 145.0640.
1-(Phenyl)-1H-imidazole (4a).
Colorless oil; 1H-NMR
(400MHz, CDCl3): δ 7.86 (s, 1H), 7.50–7.21 (m, 7H); 13C-NMR
(100MHz, CDCl3) δ 137.2, 135.5, 130.3, 129.8, 127.4, 121.4,
118.2. Anal. Calcd for C9H8N2: C, 74.98; H, 5.59; N, 19.43.
2-(1H-imidazol-1-yl)-pyrimidine (4k).
White solid,
mp:122–123°C;1H-NMR (400 MHz, CDCl3): δ 8.68–8.67 (d,
2H), 8.60 (s, 1H), 7.87 (t, 1H), 7.19–7.15 (m, 2H); 13C-NMR
(100 MHz, CDCl3) δ 158.7, 154.7, 136.1, 130.6, 118.8, 116.5;
Found: C, 74.96; H, 5.58; N, 19.41.
1-(4-Methylphenyl)-1H-imidazole (4b). White solid, mp:45–46°C;
HRMS (M+): Calcd for C7H6N4 146.0592, found 146.0591.
1
1H-NMR (400 MHz, CDCl3): δ 7.80 (s, 1H), 7.26–7.18 (m, 6H),
2.39 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 137.4, 135.6,
134.9, 130.3, 130.2, 121.3, 118.3, 20.9; Anal. Calcd for
C10H10N2: C, 75.92; H, 6.37; N, 17.71. Found: C, 75.93; H,
1-(Pyridine-2-yl)-1H-imidazole (4l).
Yellow oil; H-NMR
(400 MHz, CDCl3): δ 8.64 (s, 1H), 8.35 (s, 1H), 7.82–7.77 (m,
1H), 7.64–7.63 (t, 1H), 7.36–7.33 (m, 1H), 7.24–7.19 (m, 2H);
13C-NMR (100 MHz, CDCl3) δ 149.1, 138.9, 134.9, 130.5,
121.9, 116.0, 112.2; HRMS (M+): Calcd for C8H7N3 145.0640,
found 145.0641.
6.38; N, 17.71.
1
1-(2-Methylphenyl)-1H-imidazole (4c). White oil; H-NMR
1-(Thien-2-yl)-1H-imidazole (4m).
Yellow oil; 1H-NMR
(400MHz, CDCl3): δ 7.58 (s, 1H), 7.35–7.32 (m, 2H), 7.30–7.27
(m, 1H), 7.22–7.20 (m, 2H), 7.05 (s, 1H), 2.18 (s, 3H); 13C-NMR
(100MHz, CDCl3) δ 137.3, 136.5, 133.7, 131.1, 129.2, 128.6,
126.7, 126.4, 120.3, 17.4; Anal. Calcd for C10H10N2: C, 75.92; H,
(400 MHz, CDCl3): δ 7.81 (s, 1H), 7.43 (dd, 1H), 7.24–7.17 (m,
4H); 13C-NMR (100 MHz, CDCl3) δ 136.2, 135.7, 129.9, 127.1,
121.3, 118.4, 113.1; HRMS (M+): Calcd for C7H6N2S
150.0252, found 150.0251.
6.37; N, 17.71. Found: C, 75.91; H, 6.38; N, 17.71.
1-(4-Methoxyphenyl)-1H-imidazole (4d). Colorless oil; 1H-
1-(4-Methoxyphenyl)-1H-indole (4n). Yellow solid, mp:48–50°C;
1H-NMR (400 MHz, CDCl3): δ 7.69 (d, J = 7.3 Hz, 1H),
7.40–.48 (m, 3H), 7.28 (d, J = 3.0 Hz, 1H), 7.13–7.23 (m,
2H), 7.04 (d, J = 8.7 Hz, 2H), 6.66 (d, J = 3.0 Hz, 1H), 3.86
(s, 3H); 13C-NMR (100 MHz, CDCl3) δ 158.6, 136.7, 133.3,
129.4, 128.8, 126.4, 122.6, 121.5, 120.5, 115.2, 111.8,
103.3, 56.1; HRMS (M+): Calcd for C15H13NO 223.0997,
NMR (400 MHz, CDCl3): δ 7.74 (s, 1H), 7.30–7.27 (m, 2H),
7.19–7.17 (m, 2H), 6.98–6.96 (m, 2H),3.83 (s, 3H); 13C-NMR
(100 MHz, CDCl3) δ 158.8, 135.7, 130.6, 129.9, 123.0, 118.6,
114.8, 55.4; Anal. Calcd for C10H10N2O: C, 68.95; H, 5.79; N,
16.08. Found: C, 68.94; H, 5.78, N, 16.06.
1-(4-Acetamidophenyl)-1H-imidazole (4e).
White solid,
mp:164–166°C; 1H-NMR (400 MHz, CDCl3): δ 10.08 (s, 1H),
8.16 (s, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.66 (s, 1H), 7.55 (d,
J = 9.2 Hz, 2H), 7.08 (s, 1H); 13C-NMR (100 MHz, CDCl3) δ
168.9, 138.8, 135.8, 132.5, 130.2, 121.3, 120.3, 118.3, 24.2;
Anal. Calcd for C11H11N3O: C, 65.66; H, 5.51; N, 20.88.
found 223.0997.
1
1-(4-Chlorophenyl)-1H-indole (4o).
Yellow oil; H-NMR
(400 MHz, CDCl3): δ 7.69 (d, J = 7.1 Hz, 1H), 7.43-7.53 (m,
5H), 7.17–7.30 (m, 3H), 6.69 (d, J = 2.8 Hz, 1H); 13C-NMR
(100 MHz, CDCl3) δ 138.6, 135.9, 132.2, 130.0, 129.5, 127.9,
125.7, 122.8, 121.5, 120.8,111.5, 104.2; HRMS (M+): Calcd for
C14H10ClN 227.0502, found 257.0503.
Found: C, 65.78; H, 5.55; N, 20.68.
1-(4-Fluorophenyl)-1H-imidazole (4f). Colorless oil; 1H-NMR
(400 MHz, CDCl3): δ 7.78 (s, 1H), 7.37–-7.33 (m, 2H),
7.21–7.14 (m, 4H); 13C-NMR (100 MHz, CDCl3) δ 162.8,
160.3, 134.7 (J = 194.4 Hz), 130.3, 123.4 (J = 8.2 Hz),
118.5, 116.6 (J = 22.7 Hz); Anal. Calcd for C9H7FN2: C,
66.66; H, 4.35; F, 11.72; N, 17.27. Found: C, 66.67; H,
4.35, F, 11.71; N, 17.27.
1-(4-Methoxyphenyl)-1H-1,2,4-triazole (4p).
White solid,
mp : 87–88°C; 1H-NMR (400 MHz, CDCl3): δ 8.55 (s, 1H),
8.10 (s, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.9 Hz, 2H),
3.87 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 159.6, 152.7,
141.4, 130.6, 122.0, 115.0; HRMS (M+): Calcd for C9H9N3O
175.0746, found 175.0747.
1-m-Tolyl-1H-1,2,4-triazole (4q).
Colorless oil; 1H-NMR
1-(4-Trifluoromethylphenyl)-1H-imidazole (4g).
White
1
solid, mp:69-70°C; H-NMR (400 MHz, CDCl3): δ 7.93 (s, 1H),
7.76 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.34 (s, 1H),
7.72 (s, 1H); 13C-NMR (100 MHz, CDCl3) δ 139.9, 135.4,
131.1, 129.5 (J = 29.6, 62.5 Hz), 127.2, 123.6 (J = 272.1,
549.0 Hz), 121.2, 117.8; HRMS (M+): Calcd for C10H7F3N2
212.0561, found 212.0560.
(400 MHz, CDCl3): δ 8.52 (s, 1H), 8.07 (s, 1H), 7.48
(s, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H),
7.17 (d, J = 7.5 Hz, 1H), 2.40 (s, 3H); 13C-NMR (100 MHz,
CDCl3) δ 152.7,141.1, 140.2, 137.1, 129.8, 129.2, 120.9,
117.3, 21.6; HRMS (M+): Calcd for C9H9N3 159.0800,
found 159.0797.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

B.-H., Zhang, L.-X. Shi, S.-J. Liu, and R.-X. Guo
Vol 000
[11] Chen, Y.-J.; Chen, H.-H. Org Lett 2006, 8, 5609.
[12] Jiang, D.; Fu, H.; Jiang, Y.; Zhao, Y. J Org Chem 2007, 72,
Acknowledgments. This study was supported by Hebei province
science and technology support project (grant no. 13964002D)
and Shijiazhuang university support project (grant no. XJPT007).
672.
[13] Shafir, A.; Buchwald, S. L. J Am Chem Soc 2006, 128,
8742.
[14] Lv, X.; Bao, W. J Org Chem 2007, 72, 3863.
REFERENCES AND NOTES
[15] Job, G. E.; Buchwald, S. L. Org Lett 2002, 4, 3703.
[16] Altman, R. A.; Buchwald, S. L. Org Lett 2006, 8, 2779.
[17] Zhu, L.; Cheng, L.; Zhang, Y.; Xie, R.; You, J. J Org Chem
[1] Lindley, J. Tetrahedron 1984, 40, 1433.
[2] Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem Rev 2002, 102, 1359.
[3] Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J Am
Chem Soc 2001, 123, 7727.
[4] Klapars, A.; Antilla, J. C.; Buchwald, S. L. J Am Chem Soc
2002, 124, 7421.
[5] Kwong, F. Y.; Buchwald, S. L. Org Lett 2003, 5, 793.
[6] Ma, D.; Cai, Q.; Zhang, H. Org Lett 2003, 5, 2453.
[7] Deng, W.; Wang, Y.-F.; Zou, Y.; Liu, L.; Guo, Q.-X. Tetrahe-
dron Lett 2004, 45, 2311.
2007, 72, 2737.
[18] Huang, H.; Yan, X.-H.; Zhu, W.-L.; Liu, H.; Jiang, H.-L.;
Chen, K.-X. J. Comb Chem 2008, 10, 617–619.
[19] Yang, C.-T.; Fu, Y.; Huang, Y.-B.; Yi, J.; Guo, Q.-X.; Liu, L.
Angew Chem Int Ed 2009, 48, 7398–7401.
[20] Xu, H.-J.; Zheng, F.-Y.; Liang, Y.-F.; Cai, Z.-Y.; Feng, Y.-S.;
Che, D.-Q. Tetrahedron Lett 2010, 51, 669–671.
[21] Xue, F.; Cai, C.-Y.; Sun, H.-M.; Shen, Q.; Rui, J. Tetrahedron
Lett 2008, 49, 4386–4389.
[22] Yang, Q.; Wang, Y.; Yang, L.; Zhang, M. Tetrahedron 2013,
69, 6230–6233.
[23] Cohen, T.; Wood, J.; Dietz, A. G., Jr. Tetrahedron Lett 1974,
15, 3555.
[8] Zhang, H.; Cai, Q.; Ma, D. J Org Chem 2005, 70, 5164.
[9] Han, C.; Shen, R.; Su, S.; Porco, J. A. Org Lett 2003, 5, 133.
[10] Lu, Z.; Twieg, R. J Tetrahedron 2005, 61, 903.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet