Glycerol ingrained copper: An efficient recyclable catalyst for the N-arylation of amines with aryl halides

Article abstract of DOI:10.1016/j.tetlet.2013.03.062

A copper-catalyzed coupling reaction of aryl halides with various aromatic and cyclic amines by using glycerol as a green recyclable solvent has been developed efficiently. The glycerol embedded copper catalyst could readily be separated from the reaction mixture and reused for several runs without any loss in catalytic efficiency.

Full text of DOI:10.1016/j.tetlet.2013.03.062

Tetrahedron Letters 54 (2013) 2740–2743
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Glycerol ingrained copper: an efficient recyclable catalyst for the N-arylation
of amines with aryl halides
⇑
Praveen K. Khatri, Suman L. Jain
Chemical Sciences Division, CSIR-Indian Institute of Petroleum, Mohkampur, Dehradun 248005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A copper-catalyzed coupling reaction of aryl halides with various aromatic and cyclic amines by using
glycerol as a green recyclable solvent has been developed efficiently. The glycerol embedded copper cat-
alyst could readily be separated from the reaction mixture and reused for several runs without any loss in
catalytic efficiency.
Received 30 January 2013
Revised 15 March 2013
Accepted 17 March 2013
Available online 22 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Glycerol
Copper
Coupling
C–N bond formation
Aryl halide
In recent years, development of recyclable catalytic system
using green solvents obtained from renewable resources has at-
tracted much interest.1 With the increase in biodiesel production
world-wide, the amount of glycerol, a by-product of biodiesel pro-
duction is inevitably increasing. The recent studies have estab-
lished that glycerol owing to its desirable physicochemical
properties such as high polarity, low toxicity and flammability,
high boiling point and ability to dissolve both organic and inor-
ganic compounds can be considered as a green solvent for various
organic transformations.2–9 N-Arylation of amines is an important
reaction because arylamines are ubiquitous in the tremendous
important fields such as pharmaceuticals, agrochemicals, pig-
ments, and electronic materials.10–14 The classical Ullmann reac-
tion has been known for N-arylation in the presence of copper at
higher temperature.15 However, the utility of classical Ullmann
coupling is mainly limited by its harsh reaction conditions, such
as high temperatures (ca. 200 °C), the stoichiometric use of copper
compounds, and poor substrate scope.16 Subsequently, various re-
ports have appeared for N-arylation of amines using copper ligand
or/and copper salts as catalysts.17,18 Very recently, ligand-free N-
arylation of amines by using CuI salts has appeared, which seems
to be a promising approach for the synthesis of N-arylamines.19
However, in most of the cases reported methods require toxic
and volatile higher boiling solvents like (DMF, DMSO) to perform
the reaction.20 Taking into account the impact of chemical pro-
cesses on the environment, the search for innovative concepts for
the substitution of volatile organic solvents has become a subject
of intensive research in recent decades. Recently, more environ-
mentally friendly and recyclable solvents such as low molecular-
mass PEG and ionic liquids were evaluated as reaction media in
cross coupling reactions.19b,21 These solvents allow easy separation
of products as well as catalyst recycling. However, high prices and
lack of data about the toxicity and bio-compatibility for ionic liq-
uids are still debatable. In continuation of our on-going research
on the development of enviro-economic synthetic methodolo-
gies,22 herein we report an efficient methodology for the N-aryla-
tion of various amines including aromatic and cyclic amines by
using glycerol as green solvent and copper acetylacetonate as cat-
alyst (Scheme 1). In the present work copper embedded glycerol
could efficiently be reused for several runs.
For initial studies we have chosen N-arylation of aniline with
iodobenzene as the model reaction. The results of these optimiza-
tion experiments are summarized in Table 1. At first, we studied
the effect of catalyst concentration on the reaction by changing
the amount of the copper acetylacetonate catalyst from 1 to
5 mol % as shown in Table 1 (entries 1–3). The N-arylation of iodo-
benzene (1.0 mmol) and aniline (1.5 mmol) with Cu(acac)2
Cu(acac)2
H
Y
X
+
R
NH2
Y
N R
Glycerol, KOH
100 C, 15 h
°
R=aryl, cyclic
X=I, Br; Y=Cl, OCH3, CH3
⇑
Corresponding author.
E-mail address: suman@iip.res.in (S.L. Jain).
Scheme 1. Copper-catalyzed N-arylation of amines.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.062

P. K. Khatri, S. L. Jain / Tetrahedron Letters 54 (2013) 2740–2743
2741
Table 1
(1 mol %) in glycerol (5.0 mL) in the presence of KOH (2 mmol) at
80 °C, afforded biphenylamine in 58% isolated yield in 12 h (Table 1,
entry 1). However, by increasing the reaction time from 12 to 15 h
and temperature to 100 °C, the product yield was found to be in-
creased (Table 1, entry 1). Furthermore, by increasing the catalyst
concentration from 1 to 2 mol %, the reaction was found to be in-
creased and was completed in 15 h (Table 1, entry 2). Further, with
the increase in catalyst concentration to 5 mol %, no marginal effect
on the reaction rate was observed (Table 1, entry 3). Thus, based on
these findings, it was concluded that the best results were obtained
when the reaction temperature of the system was kept at 100 °C
and reaction time was 15 h. Further, it was also observed via
NMR, TLC, and column chromatography that no side products, such
as Ar–Ar coupling products, were formed during the reaction. The
presence of base was found to be vital and in its absence no reac-
tion could take place under otherwise similar reaction conditions
(Table 1, entry 4). Similarly, the reaction was found to be slow in
the presence of KOH without adding copper catalyst under similar
reaction conditions (Table 1, entry 5). Changing the base from KOH
to K2CO3 and KOtBu showed only a marginal change in product
yield (Table 1, entries 6 and 7). Furthermore we studied the
Screening reaction conditions for N-arylation of aniline with iodobenzenea
Entry
Catalyst (mol %)
Temp (°C)
Time (h)
Base
Convb (%)
1
2
3
4
5
6
7
8
Cu(acac)2(1)
Cu(acac)2(2)
Cu(acac)2(5)
Cu(acac)2(1)
–
Cu(acac)2(1)
Cu(acac)2(1)
Cu(OAc)2(1)
CuCl2(1)
80100100
100
100
100
100
100
100
100
100
121515
15
12
15
15
15
15
15
15
KOH
KOH
KOH
––
KOH
K2CO3
KOtBu
KOH
KOH
KOH
KOH
KOH
6090c95d
100
96
––
30
94
97
85
82
9
10
11
12
CuI(1)
Cu(acac)2(1)
Cu(acac)2(1)
100
100
100
15
15
15
87
60e
42f
a
b
c
Reaction conditions: aniline (1.5 mmol), iodobenzene (1.0 mmol).
Conversion determined by GC–MS.
The reaction was carried out at 80 °C for 12 h and then increased the temper-
ature to 100 °C for additional 3 h.
d
Reaction was performed at 100 °C for 15 h.
Reaction was performed in DMSO.
Reaction was performed in DMF solvent in place of glycerol.
e
f
Table 2
Copper in glycerol-catalyzed N-arylation of aminesa
Entry
Aryl halide
Amine
Product
Yieldb (%)
92
I
NH2
NH2
1
N
H
I
I
2
3
98
85
97
70
84
80
98
92
96
95
94
N
H
NH2
N
H
Cl
I
I
NH2
NH2
Cl
4
N
H
Cl
Cl
5
N
H
H3CO
H3CO
Cl
I
I
NH2
NH2
H3CO
H3CO
Cl
6
N
H
7
N
H
I
NH2
NH2
NH2
8
N
H
H3CO
H3C
H3C
H3C
I
H3CO
H3C
H3C
H3C
9
N
H
I
I
10
11
N
H
NH2
N
H
I
NH2
NH2
12
13
N
H
Br
N
H
82
80
Br
I
NH2
N
H
14
15
NH
N
85
(continued on next page)

2742
P. K. Khatri, S. L. Jain / Tetrahedron Letters 54 (2013) 2740–2743
Table 2 (continued)
Entry
Aryl halide
Amine
NH
NH
Product
Yieldb (%)
H3C
I
16
88
87
H3C
N
17
I
N
a
Reaction conditions: aryl halide (1 mmol), amine (1.5 mmol), KOH (2 mmol), Cu(acac)2 (2 mol %), glycerol (5 ml).
Isolated yields.
b
coupling of iodobenzene with aniline by using different copper
Studies toward the mechanism insight and the role of glycerol in
this reaction are under progress.
salts such as CuI, CuCl2, and Cu(OAc)2. Among various copper salts,
copper acetylacetonate was found to be promising for this trans-
formation. The results of these experiments are shown in Table 1
(entries 8–10). We also performed the reaction of aniline with
iodobenzene in solvents such as DMF and DMSO under otherwise
identical experimental conditions. The reaction was found to be
slow and gave low yield of N-arylated product as shown in Table 1,
entries 11 and 12. Thus, based on these results, the optimum reac-
tion conditions for this transformation were found to be as follows:
catalyst (2 mol %) in the presence of KOH at 100 °C and reaction
time 15 h. Next, we generalized the reaction by selecting a variety
of amines including aromatic, aliphatic, and cyclic under the de-
scribed experimental conditions. The results are summarized in
Table 2. Different primary amines including aromatic, and cyclic
were coupled successfully and afforded excellent yield of the mono
N-arylated product (Table 2, entries 1–14). Experiments on substi-
tuted aryl halides were carried out with OMe-, Cl, and Me-contain-
ing substrates. In all cases, the reaction progressed efficiently with
>85% conversion of the substrates. The presence of Cl-substituent
did not affect the reaction and corresponding 4-chloro substituted
diphenylamine was obtained in 97% yield from the reaction of ani-
line and 4-chloro iodobenzene (Table 2, entry 4). In the present
method, we could successfully use 1-bromobenzene in place of
iodobenzene for the C–N coupling reaction with amines as shown
in Table 2 (entries 13 and 14). Similarly, good to high yields were
obtained for the cyclic secondary amines (Table 2, entries 15–
17). In all cases, the reaction was found to be selective for mono
N-arylation and afforded corresponding mono N-arylated products
without any evidence for the formation of any by-product.
At the end of the reaction, the product was isolated by extrac-
tion with diethyl ether and the remaining glycerol layer containing
copper catalyst was reused as such for the subsequent experi-
ments. The recovered glycerol containing copper catalyst was suc-
cessfully reused for six runs without any loss of catalytic activity.
The results of recyclability are presented in Table 3. These results
confirm that the catalytic system presented herein satisfies the
conditions for heterogeneous catalysts of ease of separation, recy-
clability and consistent catalytic activity. The developed method
shows an efficient recycling of the catalyst by using a sustainable
solvent and provided higher product yields under comparatively
mild reaction conditions.
In summary, we have developed an efficient and recyclable cat-
alytic system by employing glycerol as a sustainable solvent for the
N-arylation of various amines with aryl halides in excellent yields.
Both the copper acetylacetonate and KOH base are soluble in
glycerol; therefore after isolating the product by extraction with
diethyl ether, catalyst and base embedded in glycerol can be suc-
cessfully reused as such for several runs. The use of glycerol not
only makes the product recovery easier but also provides a unique
approach for the recycling of the catalyst and base. Furthermore,
glycerol is greener and safer than DMF and DMSO, which makes
the developed method more environmentally friendly.
References and notes
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Table 3
Results of recycling experimentsa
Run
1
2
3
4
5
6
Conv.b
94
94
92
92
90
90
a
Conditions: iodobenzene (1 mmol), aniline (1.5 mmol), KOH (2 mmol),
Cu(acac)2 (2 mol %), glycerol (5 ml) at 100 °C.
b
Conversion was determined by GC–MS.

P. K. Khatri, S. L. Jain / Tetrahedron Letters 54 (2013) 2740–2743
2743
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amine (1.5 mmol), Cu(acac)2 (2 mol %), and KOH (2 mmol). The resulting
mixture was heated at 100 °C for 15 h under N2 atmosphere. After completion,
the reaction mixture was cooled to room temperature and was extracted with
diethylether to isolate the reaction products. The combined organic layers
were washed twice with brine solution (10 ml Â2) and dried over anhydrous
sodium sulfate followed by the evaporation of solvent under reduced pressure
to yield the crude product. The remaining glycerol layer containing copper
catalyst was reused for recycling experiments. The crude product was purified
by column chromatography over silica gel using ethyl acetate and hexane (2:8)
as eluents; conversion and selectivity of the product was determined by GC–
MS results.
24. Gadd, K. F. Educ. Chem. 1981, 18, 176.
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23. General procedure for the synthesis of secondary amines: To a 25 ml round
bottomed flask containing glycerol (5 ml) were added aryl halide (1 mmol),