N-Arylation of azaheterocycles with aryl and heteroaryl halides catalyzed by iminodiacetic acid resin-chelated copper complex

Article abstract of DOI:10.1016/j.cclet.2009.08.012

Iminodiacetic acid resin-chelated copper(II) complex is effective in cross-coupling reactions between azaheterocycles and aryl or heteroaryl halides, providing N-arylated products in good to excellent yields. The copper catalyst is air stable and can be readily recovered and reused with minimal loss of activity for three runs.

Full text of DOI:10.1016/j.cclet.2009.08.012

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 51–54
www.elsevier.com/locate/cclet
N-Arylation of azaheterocycles with aryl and heteroaryl halides
catalyzed by iminodiacetic acid resin-chelated copper complex
*
Xiang Mei Wu , Yan Wang
College of Chemistry and Life Science, Lishui University, Zhejiang 323000, China
Received 18 May 2009
Abstract
Iminodiacetic acid resin-chelated copper(II) complex is effective in cross-coupling reactions between azaheterocycles and aryl
or heteroaryl halides, providing N-arylated products in good to excellent yields. The copper catalyst is air stable and can be readily
recovered and reused with minimal loss of activity for three runs.
# 2009 Xiang Mei Wu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: N-Arylation; Copper; Azaheterocycle; Iminodiacetic acid resin
Of the methods used for the preparation of N-arylheterocycles, the classic Ullmann-type arylation is the most
important, but it is often limited by the harsh reaction conditions and the requirement of stochiometric or greater amounts
of copper reagents [1]. The large use of N-arylheterocycles as intermediates in organic synthesis and their importance as
structural motifs in a great number of compounds in pharmaceutical and biologicalareas have prompted the development
of alternative methods for the formation of aryl–nitrogen bonds [2]. Amongst them, organometal reagents [3] instead of
aryl halides as the coupling substrates or employing palladium complexes as the catalyst [4] are manifested due to mild
reaction conditions. However, the former normally needs an additional step to convert aryl halides into the corresponding
organometal reagents andthelater requires relativelyexpensive andair-sensitive catalysts. Recently, Buchwald, Taillefer
and others have discovered and developed thatN-arylation of azaheterocycles with aryl halides could be conducted under
comparatively mild conditions by using an in situ generated catalyst from a copper source and nitrogen and/or oxygen
based ligands such as 1,10-phenanthroline [5], diamines [6], salicylamides [7], amino acids [8] and 8-hydroxyquinoline
[9]etc., which has led to a resurgence ofinterestinUllmann-typecouplingreactionsdueto the economicattractiveness of
copper. So far, to our knowledge, although iminodiacetic acid loaded onto the shell-layer of poly(methylacrylic acid) has
been used as a ligand for palladium in Heck and Suzuki reaction successfully [10], there has been no report on the use of
iminodiacetic acid resin (abbreviate as IDAAR), a commercial and inexpensive polymeric material, which contains a
functional group of [N(CH2COOH)2] and can coordinate directly with metal ions using the nitrogen and oxygen atom
[11], as a ligand in Cu-catalyzed aromatic substitution chemistry. Therefore, we report here the N-arylation of
azaheterocycles with aryl and heteroaryl halides using copper-complexed iminodiacetic acid resin, designated IDAAR-
Cu(II), as catalyst and NaOH as base (Scheme 1).
* Corresponding author.
E-mail address: ls.wxm7162@yahoo.com.cn (X.M. Wu).
1001-8417/$ – see front matter # 2009 Xiang Mei Wu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2009.08.012

52
X.M. Wu, Y. Wang / Chinese Chemical Letters 21 (2010) 51–54
Scheme 1.
IDAAR-Cu(II) can be easily prepared from CuSO4Á5H2O and iminodiacetic acid resin in aqueous solution and is
stable in air [11]. Copper content in the catalyst was determined by AAS to be 10 wt.% of Cu.
Initially, the coupling reaction of imidazole with iodobenzene was chosen as model reaction to optimize the
reaction conditions. In the presence of 10 mol.% of Cu (molar ratio to iodobenzene) and 2 equiv of NaOH in DMF at
120 8C in a nitrogen atmosphere, to our delight, the reaction afforded the desired cross-coupling product in 65% yield
(Table 1, entry 1). Encouraged by this result, we examined the effect of different solvents on the coupling reaction.
DMSO was clearly the best choice, acetonitrile and CH3OH provided slightly lower yields, while less polar solvents
like toluene delivered little desired coupling product (entries 2–5). Of the bases tested, the organic amine bases such as
Bu3N and Et3N were ineffective (entries 6 and 7). Moderate yields were afforded by using K2CO3, Cs2CO3 and
K3PO4Á3H2O (entries 8–10). Both KOH and NaOH were effective bases and the latter was chosen for the study of the
reactions described below since it is much cheaper. Moreover, we have observed that the recovered catalyst by simple
filtration decreased only slightly in its second and third use under the same reaction conditions (entry 2). As a control
experiment, CuSO4Á5H2O (10 mol.%) was employed as catalyst for the above reaction and a lower yield was found in
comparison with that obtained with IDAAR-Cu(II) (entry 12).
The scope of the reaction was studied with various aryl halides, as summarized in Table 2. Both the electron-rich
and electron-deficient aryl iodides, as well as electron-deficient aryl bromide with imidazole delivered the
corresponding products in high yields (Table 2, entries 1–5). For electron-neutral aryl bromide, moderate yield of the
desired product was obtained (entry 6). Especially, heteroaromatic bromides such as 2-bromopyridine, 2-
bromothiophene and 2-ethyl-5-bromothiophene also proved to be a highly efficient coupling partner and good results
were obtained (entries 7–9). Unfortunately, this catalytic system is ineffective for chlorobenzene unless it was
activated by electron-withdrawing substituent like a nitro group (entry 10). With respect to the nucleophilic reagent, a
variety of other azaheterocycles, such as benzimidazole, pyrazole and indole were successfully coupled with
iodobenzene to give the corresponding N-arylated products in good yields (entries 11–14). This reaction seemed
Table 1
N-arylation of iodobenzene with imidazole in different conditionsa.
Entry
Solvent
Base
Time/h
Yield (%)b
1
2
DMF
NaOH
NaOH
NaOH
NaOH
NaOH
Et3N
24
24
24
24
24
36
36
24
24
24
24
24
65
95,92c,90d
DMSO
Acetonitrile
Toluene
CH3OH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
3
70
<5
60
4
5
6
<5
<5
50
7
Bu3N
8
K2CO3
Cs2CO3
K3PO4Á3H2O
KOH
9
52
10
11
12e
75
96
NaOH
80
a
Reaction conditions: 1.0 mmol iodobenzene; 1.4 mmol imidazole; 0.1 mmol IDAAR-Cu(II); 2.0 mmol base; solvent 1.0 mL; 120 8C.
Isolated yield.
b
c
d
e
The second run.
The third run.
0.1 mmol CuSO4Á5H2O as catalyst.

X.M. Wu, Y. Wang / Chinese Chemical Letters 21 (2010) 51–54
53
Table 2
N-arylation of azaheterocycles with aryl and heteroaryl halidesa.
Entry
1
Substrates
Product
Yield (%)b
95
2
3
4
5
6
7
as 1
as 1
as 1
as 1
as 1
as 1
92
93
96
88
80
83
8
9
as 1
as 1
72
65
10
11
as 1
35
98
12
13
75
65
70
14
a
Reaction conditions: 1.0 mmol aryl or heteroaryl halide; 1.4 mmol azaheterocycles; 2.0 mmol NaOH; 1.0 mL DMSO; 0.1 mmol IDAAR-Cu(II);
120 8C.
b
Isolated yield.

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X.M. Wu, Y. Wang / Chinese Chemical Letters 21 (2010) 51–54
sensitive to the steric hindrance on the nucleophilic reagent. Indeed, the yields were relatively lower when
benzimidazole and 2-methylimidzaole were employed as nucleophilic reagents.
In summary, the iminodiacetic acid resin-chelated copper complex provided satisfactory yields in the N-arylation of
azaheterocycles with aryl and heteroaryl halides. Further study of the scope of the application of IDAAR-Cu(II) is in
progress in our laboratory.
1. Experimental
Melting points were obtained of a XT4A melting point apparatus and were uncorrected. 1H NMR and 13C NMR
spectra were recorded at 300 MHz and 75 MHz with Bruker Avance 300 spectrometer using CDCl3 as solvent and
tetramethylsilane as internal standard. GC analyses were conducted using a Trace GC/Thermo Finnigan equipped with
an SE-54 capillary column (25 m) and an FID detector. Elemental analysis was performed on a Thermo Finnigan Flash
EA microanalyzer.
General procedure: Aryl or heteroaryl halide (1 mmol), azaheterocycles (1.4 mmol), NaOH (2.0 mmol), DMSO
(1.0 mL) and IDAAR-Cu(II) (0.10 mmol Cu) were taken in a 25 mL two-neck flask. The mixture was heated at 120 8C
in a nitrogen atmosphere for required time by magnetic stirring. After cooling to room temperature, the product was
diluted with H2O, extracted with EtOAc, washed with H2O and brine, dried over MgSO4, filtered, and evaporated, and
purified by chromatography on silica gel to obtain the desired products. The purity of the isolated product was
determined by GC analysis.
Selected data: 1-Phenyl-1H-imidazole. Viscous oil. 1H NMR (CDCl3): d 7.15 (s, 1H), 7.22 (s, 1H), 7.28–7.32 (m,
3H), 7.39–7.43 (m, 2H), 7.79 (s, 1H). 13C NMR (75 MHz): d 118.2, 121.4, 127.4, 129.8, 130.3, 135.5, 137.3. 1-(5-
Ethylthiophen-2-yl)-1H-imidazole. Viscous oil. 1H NMR (CDCl3): d 1.30 (t, 3H, J = 7.5 Hz), 2.76–2.83 (m, 2H), 6.62
(d, 1H, J = 3.6 Hz), 6.76 (d, 1H, J = 3.6 Hz), 7.12 (s, 2H), 7.69 (s, 1H). 13C NMR (75 MHz): d 15.7, 23.6, 118.9, 120.3,
122.1, 129.9, 135.9, 137.1, 144.3. Anal. Calcd. for C9H10N2S: C, 60.64; H, 5.65; N, 15.72. Found: C, 60.70; H, 5.78; N
15.68.
Acknowledgment
This work was supported by the Natural Science Foundation of Zhejiang Province (No. Y407240).
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