Cheap Cu(I)/hexamethylenetetramine (HMTA) catalytic system for C-N coupling reactions

Article abstract of DOI:10.1080/00397911.2010.523857

An efficient C-N coupling reaction of aryl chlorides or bromides with imidazole was successfully performed with cheap and commercially available catalytic system Cu(I)/HMTA. Both aryl bromides and aryl chlorides have been effectively catalyzed by Cu/HMTA, giving products in moderate to good yields. Moreover, aryl halides bearing either electron-withdrawing groups or electron-donating groups could be used in the reaction. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.523857

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Cheap Cu(I)/Hexamethylenetetramine
(HMTA) Catalytic System for C-N Coupling
Reactions
Changsheng Cao a , Zhongbo Lu a , Zhengyuan Cai a , Guangsheng
Pang b & Yanhui Shi a
a College of Chemistry and Chemical Engineering and Key Laboratory
of Biotechnology for Medical Plant, Xuzhou Normal University,
Xuzhou, Jiangsu, China
b State Key Laboratory of Inorganic Synthesis and Preparative
Chemistry, Jilin University, Changchun, Jilin, China
Accepted author version posted online: 18 Jul 2011.Published
online: 14 Sep 2011.
To cite this article: Changsheng Cao , Zhongbo Lu , Zhengyuan Cai , Guangsheng Pang & Yanhui Shi
(2012): Cheap Cu(I)/Hexamethylenetetramine (HMTA) Catalytic System for C-N Coupling Reactions,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 42:2, 279-284
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Synthetic Communications1, 42: 279–284, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.523857
CHEAP Cu(I)/HEXAMETHYLENETETRAMINE (HMTA)
CATALYTIC SYSTEM FOR C-N COUPLING REACTIONS
Changsheng Cao,1 Zhongbo Lu,1 Zhengyuan Cai,1
Guangsheng Pang,2 and Yanhui Shi1
1College of Chemistry and Chemical Engineering and Key Laboratory of
Biotechnology for Medical Plant, Xuzhou Normal University, Xuzhou,
Jiangsu, China
2State Key Laboratory of Inorganic Synthesis and Preparative Chemistry,
Jilin University, Changchun, Jilin, China
GRAPHICAL ABSTRACT
Abstract An efficient C-N coupling reaction of aryl chlorides or bromides with imidazole
was successfully performed with cheap and commercially available catalytic system
Cu(I)/HMTA. Both aryl bromides and aryl chlorides have been effectively catalyzed by
Cu/HMTA, giving products in moderate to good yields. Moreover, aryl halides bearing
either electron-withdrawing groups or electron-donating groups could be used in the
reaction.
Keywords Aryl halides; C-N coupling; imidazole; N-arylimidazole
INTRODUCTION
N-Arylimidazole subunits are found in numerous natural products and in
many biologically active pharmaceuticals.[1–3] Therefore, it is important to develop
a useful method to synthesize these kinds of compounds. In recent years, mild tran-
sition metal-catalyzed cross-coupling of aryl halides with NH-containing hetero-
cycles has been widely developed.[4–6] Despite some limitations of copper catalysts
and the success of palladium-catalyzed reactions, copper-based protocols still attract
great attention because copper is much cheaper, which make them the reactions of
choice in large- and industrial-scale applications. Copper-based catalysts are often
successful where palladium-based procedures have failed.[7] Since the initial report
Received May 1, 2010.
Address correspondence to Yanhui Shi, College of Chemistry and Chemical Engineering and Key
Laboratory of Biotechnology for Medical Plant, Xuzhou Normal University, Xuzhou, Jiangsu, 221116,
China. E-mail: yhshi_2000@126.com
279

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C. CAO ET AL.
Scheme 1. Synthesis of N-arylimidazole compounds.
by Kiyomori et al.[8] various types of ligands and catalytic systems have been
developed.[9–11] However, most of the studies reported employed either iodo- or
bromoarenes as substrates. The coupling of N-H heterocycles with cheaper and less
reactive aryl chloride substrates still remains a challenging problem. In addition,
some of the very efficient nitrogen ligands are rather expensive and may require
multiple steps for their syntheses. Therefore, it is very important to develop a
cost-effective and efficient ligand=catalyst system that facilitates direct C-N cross-
coupling reactions. Herein, we report our studies in using catalytic amounts of
Cu(I) with commercially available and cheap hexamethylenetetramine (HMTA) as
ligand in C-N coupling reactions of aryl halides with imidazole (Scheme 1).
RESULTS AND DISCUSSION
In our search for a cheap and readily available ligand in the C-N coupling, we
started by investigating the C-N coupling reactions of bromobenzene with imidazole
with different cheap available ligands (Table 1, entries 1–3). In Comparison with the
widely used N-donor ligand N,N,N0,N0-tetramethyl-1,2-ethylenediamine (TMEDA),
the HMTA ligand gave a better result under the same conditions. The yield with glu-
cose was good as well, but the purification of the desired product was difficult
because of some by-products due to the messy reaction. To determine the most suit-
able reaction conditions for the N-phenylation of imidazole, the catalytic activities of
Cu(I)=HMTA were examined under different conditions (Table 1, entries 4–11). The
Table 1. Effect of reaction conditions on C-N coupling of imidazole with bromobenzene
Entry
Cat. (5%)
Ligand (5%)
Temp. (ꢀC)
Solvent
Time (h)
GC yield (%)
1
2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
Cu2O
HMTA
TMEDA
Glucose
HMTA
HMTA
HMTA
HMTA
HMTA
HMTA
HMTA
HMTA
130
130
130
110
120
130
140
130
130
130
130
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
Tol.
20
20
20
20
20
20
20
20
20
20
20
95
36
3
80% (messy)
4
62
78
96
96
92
90
95
95
5
6
7
8
9
10
11
DMF
DMF

CHEAP Cu(I)/HMTA FOR C-N COUPLING REACTIONS
281
Table 2. Synthesis of N-arylimidazoles
Entry
1
Aryl halide
Isolated yield (%)
93
2
3
50
72
4
80
5a
76
84
6a
7a
88
8a
60
71
52
96
9a
10a
11
12
95
(Continued )

282
C. CAO ET AL.
Table 2. Continued
Entry
13
Aryl halide
Isolated yield (%)
50
14
15
50
96
aCuI was used instead of CuCl.
results showed that the higher reaction temperature led to better yields (entries 4–7),
and it was found that the copper sources and solvents are not sensitive to the C-N
coupling reaction. Even though the use of dimethyl formamide (DMF) gave the best
results among the solvents that were tested, dimethyl sulfoxide (DMSO) and toluene
are suitable solvents for CuI=HMTA-catalyzed N-arylation of imidazole (entries 9
and 10) as well. Replacing CuI with CuCl or Cu2O did not reduce the catalytic
activity very much (entries 10 and 11). To further expand the reaction scope of this
Cu=HMTA-catalyzed C-N coupling reaction, a wide variety of bromo- or chloro-
benzenes were selected to react with imidazole using 5% CuCl and 5% HMTA with
K2CO3 as base in DMF at 130ꢀC. The results are summarized in Table 2. CuCl was
chosen over CuI because of the relatively low cost of CuCl, and CuCl is rarely
reported in literature as a Cu source in the C-N coupling reaction. However, CuI
has been used in some reactions to obtain better yields (Table 2, entries 5–10). It
is apparent from Table 2 that both aryl bromides and aryl chlorides have been effec-
tively catalyzed by Cu=HMTA, giving products in good yields. Furthermore, the
desired product could be obtained with aryl halides bearing either electron-
withdrawing groups or electron-donating groups. In most cases, the reactions were
completed within 24 h in good yields. It is worth mentioning that steric hindrance
does not play a big role in the reaction (Table 2, entries 3 and 6; entries 11 and 12).
In conclusion, we have developed an efficient and cheap catalyst system for
C-N cross coupling of imidazole with aryl halides using HMTA as ligand, which
is a very cheap and commercially available N-donor compound. The studies indicate
that the Cu(I)=HMTA system has catalyzed N-arylation of imidazole effectively. In
addition, Cu(I)=HMTA can catalyze the coupling reaction with both aryl chlorides
and bromides. In some reactions, CuI can be replaced by low-cost CuCl. The experi-
mental procedure is also very simple and convenient.
EXPERIMENTAL
Melting points were determined on a XT-5B microscopic melting-point spec-
trometer and were uncorrected. 1H NMR spectra were recorded in CDCl3 or

CHEAP Cu(I)/HMTA FOR C-N COUPLING REACTIONS
283
DMSO-d6 with Me4Si as internal standard using a Bruker-400 spectrometer. Elec-
tron impact–mass spectrometry (EI-MS) spectra were obtained with an Agilent
6890A-5973 N gas chromatography–mass spectrometer (GC-MS). The products
were characterized by comparison of their spectroscopic and physical data with
authentic samples synthesized by reported procedures.
General Procedure for the Synthesis of N-Arylimidazole Derivatives
Under an inert atmosphere, a 4-mL reaction vial was charged with K2CO3
(1 mmol), CuI or CuCl (2.5–5% mmol), HMTA (2.5–5% mmol), imidazole
(0.6 mmol), and aryl halide (0.5 mmol). After it was sealed with a cap containing a
polytetrafluoroethylene (PTFE) septum, 1 mL of dry DMF was injected by syringe.
The reaction mixture was heated to 130–140 ꢀC for 20–40 h. The reaction was mon-
itored by GC. After the starting material was completely consumed, the reaction was
stopped and the mixture was cooled to room temperature. The reaction mixture was
passed through a plug of celite and rinsed with 10 mL of ethyl acetate. The filtrate
was washed by 15 mL of H2O. After the organic layer was concentrated, the residue
was purified by column chromatography on silica gel to give the desired product.
Selected Data for Products
1-(4-Methoxyphenyl)-1H-imidazole (3). White solid, mp 64–66 ꢀC;
1H NMR (400 MHz, CDCl3) (d, ppm): 7.77 (s, 1H, NCHN), 7.32–7.18 (m, 4H,
ArH), 7.00 (d, 2H, NCH, J ¼ 8.8 Hz), 3.85 (s, 3H, OCH3); EI-MS: 174.
1
4-Imidazol-1-yl-benzaldehyde (5). White solid, mp 150–152 ꢀC; H NMR
(400 MHz, CDCl3) (d, ppm): 10.01 (s, 1H, CHO), 8.03 (d, 2H, ArH), 8.00 (s, 1H,
NCHN), 7.59 (d, 2H, ArH), 7.40 (s, 1H, NCH), 7.28 (s, 1H, NCH); EI-MS: 172.
1,4-Bis(imidazole-1-yl)-benzene (9). White solid, mp 215–217 ꢀC; 1H NMR
(400 MHz, CDCl3) (d, ppm): 7.89 (s, 2H, 2NCHN), 7.53 (s, 4H, ArH), 7.32 (s, 2H,
NCH), 7.26 (s, 2H, NCH); EI-MS: 210.
1-(4-Nitro-phenyl)-1H-imidazole (12). Orange solid, mp 190–192 ꢀC;
1H NMR (400 MHz, CDCl3) (d, ppm): 8.39 (d, 2H, ArH), 7.98 (s, 1H, NCHN),
7.59 (d, 2H, ArH), 7.38 (s, 1H, NCH), 7.29 (s, 1H, NCH); EI-MS: 189.
1
2-Imidazol-1-yl-benzonitrile (14). White solid, mp 146–148 ꢀC; H NMR
(400 MHz, CDCl3) (d, ppm): 7.79 (s, 1H, NCHN), 7.78–7.39 (m, 4H, ArH), 7.30
(s, 1H, NCH), 7.21 (s, 1H, NCH); EI-MS: 169.
1
2-Imidazol-1-yl-pyrimidine (15). Orange solid, mp 120–122 ꢀC; H NMR
(400 MHz, CDCl3) (d, ppm): 8.70 (d, 2H, 2NCH, J ¼ 4.8 Hz), 8.63 (s, 1H, NCHN),
7.90 (s, 1H, CH), 7.21 (t, 1H, NCH), 7.18 (s, 1H, NCH); EI-MS: 146.
ACKNOWLEDGMENTS
We are grateful to SPF for ROCS, SEM, PAPD; the State Key Laboratory of
Inorganic Synthesis and Preparative Chemistry (2009-06) at Jilin University; the

284
C. CAO ET AL.
Qing Lan Project (08QLT001 and 08QLD006) of the Jiangsu Education Committee;
and the National Science Foundation of China (NSFC) 21071121 for financial sup-
port.
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