Ethylene glycol, an efficient and recoverable medium for copper-catalyzed N-arylation of diazoles under microwave irradiation

Article abstract of DOI:10.1080/00397911.2015.1135347

Ethylene glycol was used as an efficient and recoverable medium for the reaction of diazoles with aryl iodides and aryl bromides in the presence of CuCl₂ as the catalyst and K₂CO₃ as the base. Consequently, imidazole, benzimidazole, and pyrazole reacted readily under microwave irradiation to give good to excellent yields of their corresponding N-arylated products in relatively short time periods. Apparently, ethylene glycol plays a dual role by activating the catalyst and also providing a homogenous medium for the processes. The reaction medium consisting of the solvent, the base, and the copper salt was recovered and reused successfully in the next several reactions.

Full text of DOI:10.1080/00397911.2015.1135347

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
Ethylene Glycol, an Efficient and Recoverable
Medium for Copper-Catalyzed N-Arylation of
Diazoles Under Microwave Irradiation
Ali Sharifi, Nima Ghonouei & M. Saeed Abaee
To cite this article: Ali Sharifi, Nima Ghonouei & M. Saeed Abaee (2015): Ethylene Glycol,
an Efficient and Recoverable Medium for Copper-Catalyzed N-Arylation of Diazoles Under
Microwave Irradiation, Synthetic Communications, DOI: 10.1080/00397911.2015.1135347
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1135347
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Date: 02 January 2016, At: 22:32

Ethylene Glycol, an Efficient and Recoverable Medium for Copper-Catalyzed N-
Arylation of Diazoles under Microwave Irradiation
Ali Sharifi1, Nima Ghonouei1, M. Saeed Abaee1
1Chemistry and Chemical Engineering Research Center of Iran, Tehran, Iran
Correspondence: A. Sharifi, Chemistry and Chemical Engineering Research Center of
Iran, P.O.Box 14335-186, Tehran, Iran Email: sharifi@ccerci.ac.ir
Supplemental data for this article can be accessed on the publisher’s website.
Abstract
Ethylene glycol was used as an efficient and recoverable medium for the reaction of
diazoles with aryl iodides and aryl bromides in the presence of CuCl2 as the catalyst and
K2CO3 as the base. Consequently, imidazole, benzimidazole, and pyrazole reacted readily
under microwave irradiation to give good to excellent yields of their corresponding N-
arylated products in relatively short time periods. Apparently, ethylene glycol plays a
dual role by activating the catalyst and also providing a homogenous medium for the
processes. The reaction medium consisted of the solvent, the base, and the copper salt
was recovered and reused successfully in next several reactions.
Graphical Abstract:
1

KEYWORDS: N-Arylation, diazole, ethylene glycol, microwave irradiation
INTRODUCTION
N-Arylation of nitrogen atoms of aromatic heterocycles is a common and frequently
practised strategy in synthetic organic chemistry.[1-2] The resulting N-arylated products
have found many applications as biologically[3-4] and medicinally[5-6] active substances. In
this regard, copper-catalyzed reaction of N-heterocycles with aryl halides is one of the
most straight-forward routes to access these compounds. So far, different sets of copper
catalysts, ligands, bases, and solvents have been used to perform N-arylation of
heterocycles.[7-8] Remarkable advances in this area include the use of ligand-free/solvent-
free conditions [9] and aqueous media.[10] Despite these achievements, there is still a
demand to design new protocols involving simpler procedures, greener conditions, and
less expensive reagents and catalysts.
Ethylene glycol (EG) has found many recent uses as a solvent in organic reactions,
because it offers advantages such as low vapor pressure, high chemical and thermal
stability, and low flammability.[11] Its ability for hydrogen bonding enables EG to bind to
substrates and metal ions, and its high polarity makes it a suitable choice as the medium
for microwave (MW)-assisted reactions.[12-14] In addition, since EG can dissolve both
organic and inorganic compounds, it helps provide homogenous conditions for catalytic
processes such as many transition metal-catalyzed reactions.[15-17] EG has also been used
as an auxiliary ligand in copper-catalyzed Ullmann-type[18] arylation of primary or
secondary amines,[19] and in N-arylation of β-amino alcohols.[20] Moreover, EG is used as
2

both the reaction solvent and ligand for copper in the amination of aryl bromides with
ammonia[21] and C–O coupling of aryl bromides with aliphatic diols.[22]
In the framework of our studies to design environmentally benign procedures in the field
of heterocyclic chemistry,[23-25] herein we present the reaction of diazoles with aryl
iodides and aryl bromides in EG medium catalyzed by CuCl2 under MW irradiation.
There are a few examples in the literature for using copper(II) in Ullmann-type reactions
since it is generally believed that Cu(II) is less reactive in these types of reactions. The
difference between Cu(I) and Cu(II) ions in copper-catalyzed cross coupling reactions is
that Cu(I) can directly enter the reaction cycle as the active species, but Cu(II) must first
convert to Cu(I) via the action of a nucleophile in the reaction medium.[26] In the case of
our experiment, we believe that the nucleophilic hydroxyl groups on EG provides the
necessary conditions for the conversion to Cu(I) species in the presence of the base.
Search in the literature shows existence of a single article where the use of EG as the
ligand for Cu(I) catalyzed Ullmann-type reactions in an ionic liquid has been
unsuccessful.[27] We believe that in the present work the use of Cu(II)/EG conditions
combined with MW irradiation has substantially improved the conditions so that the
desired reaction takes place conveniently. The study also shows that there is no need for
the reactions to add extra ligands or solvents, since EG both activates the copper ion and
provides a homogenizing medium for the reaction by dissolving the starting materials as
well as the base and the copper species. In addition, after a simple extraction of the
3

products by ether, the reaction medium could be recovered and reused efficiently in the
next runs.
RESULTS AND DISCUSSION
First, we monitored the effect of different sets of conditions on the model reaction of
imidazole with 4-iodoanisole in EG as shown in Table 1. By using CuCl2 as the copper
source and K2CO3 as the base, the desired N-arylated product was formed in 50% yield
after 24 hours of heating at 130 ºC, while no trace of the O-arylated EG was observed
(entry 1). When the amount of CuCl2 was increased to 10 mol%, a better yield of the
product was obtained (entry 2), but no improvements was observed with further addition
of the catalyst amount (entry 3). Literature survey show precedence for MW irradiation to
improve the scope of the Ullmann-type reactions.[28] When we repeated the reaction
under MW conditions, it took only 30 minutes at 300 W to obtain 95% of the target
product (entry 4). When we used lower ratios of imidazole:4-iodoanisole (entries 5-6) or
took two equivalents of the base, only decreased yields of the isolated product was
obtained (entry 7).
The effect of different Cu(I) and Cu(II) salts was also studied (entries 8-11). As it is
obvious from the results, while all attempted Cu(II) salts gave comparable results, Cu(I)
species were not as efficient and led to lower yields within the same time periods. This
was in agreement with the previous observations by Chae et al in the O-arylation of
EG,[22] where they attributed the enhanced reactivity of the Cu(II) salts to higher
stabilization and solubility of these salts in EG medium. The low yield of the reaction in
4

the absence of EG, or when EG was used in stoichiometric amounts, proved the
determining role of EG in the process (entries 12-13).
Next, we employed the optimized conditions (Table 1, entry 4) to examine the generality
of the procedure. Table 2 summarizes the results for the reactions of imidazole,
benzimidazole, and pyrazole with different aryl halides. Aryl bromides reacted under the
optimized conditions, but their respective reaction times were longer and in some cases
relatively lower yields were obtained (entries 1-2, 13). Aryl halides with p- or m-
substitutions did not interfere with the reaction, but o-substituted derivatives gave only
trace of the expected products. The electronic nature of the substitutions on the aryl
halide also affected the outcome of the reaction. Thus, while electron-donating
substituents such as methyl or methoxy groups were successfully used (entries 2-4, 9-11),
electron deficient counterparts resulted in lower conversions and complex mixtures were
formed.
As it is obvious from Table 2, imidazole reacted more readily with iodobenzene than
benzimidazole and pyrazole did (entries 1, 9, 13). Also, the O-arylation of EG was not
observed in any of the reactions. The generally accepted catalytic cycle for the reaction is
depicted in Figure 1.[29] The first step involves the coordination of the nucleophile to the
copper species in the presence of the base. The observed reactivity order (imidazole >
benzimidazole > pyrrazole >> EG) can be explained by considering both the relative
acidities of the Nu-H bonds (Nu = diazole or EG) and the nucleophilicity of the resulting
anion. Greater N-H acidities would favor easier coordination of the nucleophile to the
5

central Cu ion, and a more nucleophilic anion would favor the reductive elimination step,
and the formation of the product.[30-31] Thus, EG would not bind to copper in the presence
of diazoles because of the lower acidity of the O-H bond compared to those of
heterocyclic N-H bonds.
One of the advantages associated with conducting reactions in EG is that the reaction
medium could be recycled and reused in next experiments. This persuaded us to
investigate the feasibility of recovering and reusing the medium in the model reaction
between imidazole and 4-iodoanisole. Thus, after extracting the product with diethyl
ether, the reaction medium was recovered by removing the volatile portion under reduced
pressure and reused successfully in next several runs without further addition of the base
or the catalyst. Table 3 shows the results for successful recycling of the catalyst.
In summary, we have introduced EG as an efficient medium for the Cu(II)-catalyzed
reactions of aryl iodides and bromides with diazoles under MW irradiation. The catalyst
system is inexpensive and readily available. The selectivity for N-alkylation, short
reaction times, high yields of the products, and the ability to recover the catalyst are
among the advantages of the current method.
EXPERIMENTAL
All reagents and solvents were commercially available and used as received. Progress of
the reactions was monitored by TLC using silica gel coated plates and EtOAc/petroleum
ether mixture (1:1) as the eluent. MW-assisted reactions were carried out in a Milestone
6

Microsynth® instrument. Melting points are uncorrected and are obtained by Buchi
Melting Point 530. 1H NMR (500 MHz) spectra were obtained on a FT-NMR Bruker
Ultra ShieldTM instrument as CDCl3 solutions and the chemical shifts are expressed as δ
units with Me4Si as the internal standard. All products were known and their identity was
confirmed by the comparison of their melting points and their 1H NMR data with those of
authentic compounds available in the literature.
General Procedure For MW-Assisted Cucl2-Catalyzed Preparation Of 1c (Table 2,
Entry 3)
Imidazole (0.13 gr, 2.0 mmol), CuCl2 (0.0134 gr, 0.1 mmol), and K2CO3 (0.41 gr, 3.0
mmol) were added to EG (2.0 mL) and the mixture was stirred thoroughly. Then, 4-
iodoanisole (0.23 gr, 1.0 mmol) was added and the reaction vessel was capped. The
reaction mixture was irradiated at 300 W in the MW instrument for 30 minutes. After
completion of the reaction, water (30.0 mL) was added to the mixture and the organic
portion was extracted with diethyl ether (3 × 10 mL). The combined ethyl acetate layers
were dried over Na2SO4 and evaporated under reduced pressure. The crude product was
purified via a silica gel column using EtOAc/petroleum ether mixtures (1:1) as the eluent
to yield a white solid. 0.22 gr, 95%, m.p: 52-55 °C (found), 57 °C (literature);[32] 1H NMR
(CDCl3, 500 MHz) δ 7.80 (s, 1H); 7.26 (m, 1H); 7.12 (s, 1H); 7.11 (s, 1H); 6.86 (m, 1H);
6.81 (m, 2H); 3.74 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz) δ 159.2, 136.0, 130.8,
130.0, 123.3, 119.0, 115.2, 55.8 ppm.
7

ACKNOWLEDGMENT
The Grant Council at CCERCI is gratefully acknowledged for financial support of this
work.
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10

Table 1. Optimization of the reaction conditions
Entry Imidazole:PhX Catalyst (mol%) Conditions
Time
24 h
24 h
24 h
Yield (%)a
1
2.0:1.0
2.0:1.0
2.0:1.0
2.0:1.0
1.0:1.0
1.0:1.1
2.0:1.0
2.0:1.0
2.0:1.0
2.0:1.0
2.0:1.0
2.0:1.0
2.0:1.0
CuCl2 (5)
120 °C
120 °C
120 °C
50
71
75
2
CuCl2 (10)
CuCl2 (20)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
Cu(OAc)2 (10)
CuBr2 (10)
CuI (10)
3
4
MW, 300W 30 Min 95
MW, 300W 30 Min 70
MW, 300W 30 Min 65
MW, 300Wb 30 Min 60
MW, 300W 30 Min 80
MW, 300W 30 Min 85
MW, 300W 30 Min 50
MW, 300W 30 Min 60
MW, 300Wc 30 Min 5>
MW, 300Wd 30 Min 30
5
6
7
8
9
10
11
12
13
CuCl (10)
CuCl2 (10)
CuCl2 (10)
aIsolated yields;
bTwo equivalents of K2CO3 was used;
cSolvent-free conditions;
dTwo equivalents of EG was used
11

Table 2. Reaction of diazoles with different aryl halides
Entry
X
I
Time (Min) Yield (%)a,b
Product
Ph
30
90
85
N
1
1a
Br 60
N
I
30
82
78
2
1b
N
Br 60
N
OMe
3
4
I
30
95
80
1c
N
N
OMe
1d
Br 30
N
N
12

5
6
Br 90
95
60
1e
N
N
Br 90
1f
N
N
S
7
8
I
I
30
30
90
75
1g
N
N
Ph
N
N
1h
9
I
I
30
30
80
90
1i
N
N
OMe
10
1j
N
N
13

OMe
11
12
Br 30
95
1k
N
N
Ph
I
0.5
86
20
N
1l
Br 1
N
I
1.5
40
20
13
14
1m
N
Br 1.5
N
OMe
I
1.5
38
1n
N
N
aIsolated yields
bReaction conditions: diazole (2.0 mmol), aryl halide (1.0 mmol), CuCl2 (0.1 mmol),
K2CO3 (3.0 mmol), MW irradiation (300 W).
14

Table 3. Successful recycling of the catalyst
Entry Run Yield (%)a
1
2
3
4
1st
2nd 88
95
3rd
4th
80
70
aGC yields
15

Figure 1. The general catalytic cycle
16