Nanodomain cubic copper (I) oxide as reusable catalyst for the synthesis of amides by amidation of aryl halides with isocyanides

Article abstract of DOI:10.1016/j.tetlet.2014.12.060

An environmentally benign chemical process for the C-C coupling of aryl halides with isocyanides in aqueous medium has been developed using cubic copper (I) oxide nanoparticles as reusable catalyst. The use of nano-catalyst eliminates the use of any stabi

Full text of DOI:10.1016/j.tetlet.2014.12.060

Tetrahedron Letters 56 (2015) 623–626
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Nanodomain cubic copper (I) oxide as reusable catalyst for the
synthesis of amides by amidation of aryl halides with isocyanides
Swarbhanu Sarkar a, , , Rammyani Pal a, , Manas Roy b, , Nivedita Chatterjee a, , Sabyasachi Sarkar c,
⇑
Asish Kumar Sen a,
⇑
a Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Kolkata 700 032, India
b Department of Chemistry, Lovely Professional University, Phagwara, Punjab 144411, India
c Department of Chemistry, Indian Institute of Engineering Science and Technology, Shibpur, Howrah 711103, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An environmentally benign chemical process for the C–C coupling of aryl halides with isocyanides in
aqueous medium has been developed using cubic copper (I) oxide nanoparticles as reusable catalyst.
The use of nano-catalyst eliminates the use of any stabilizing ligands or additives as well as the use of
organic solvents. The catalyst exhibited comparable efficiency up to three recycles and was found to
be very effective for the synthesis of varied amides leading to biologically significant scaffold.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 20 October 2014
Revised 8 December 2014
Accepted 10 December 2014
Available online 16 December 2014
Keywords:
Copper (I) oxide nanoparticle
Reusable catalyst
Amidation
Aryl halides
Isocyanide
In the last few decades, there has been an increasing demand
for the development of environmentally friendly chemical pro-
cesses leading to the synthesis of a variety of organic compounds
in the laboratory which may be expanded in industrial scale.
Chemical transformations involving metal-mediated coupling
reactions in aqueous medium have attracted attentions of many
researchers.1 Although, the inadequate solubility of many organic
molecules in water prevents the wide applicability of aqueous
medium in organic reactions, the introduction of sonication had
provided a plausible way out to this limitation. Ultrasonic tech-
niques disperse insoluble molecules with uniform shapes and
geometry and thus often influence reaction mechanism consider-
ably resulting in a significant change in reaction rate and yield
compared to conventional procedures.2,3 Therefore, the use of
ultrasonication may be an easy alternative for executing organic
transformations in aqueous solvent leading to ‘Green reaction’.
Palladium-catalysed carbonylation of aromatic halides with
various nucleophiles is an effective way for the synthesis of esters,
amides, and many heterocyclic compounds having amide or ester
linkages.4 Homogeneous palladium catalyst provides high reaction
rate and high yield of the products in the presence or absence of
the ligands, such as phosphines, carbenes, amines or dibenzylide-
neacetones (dba). However, homogeneous palladium catalyst can-
not be reused which is a major drawback. This problem may be
avoided by employing heterogeneous Pd-catalysis.5 The use of
solid support such as activated charcoal or various oxides like sil-
ica, alumina, ZrO2 or TiO2, or even the use of Pd-nanoparticles is
a promising option.6–8 Pd-catalyst supported on silica, alumina,
etc. sometimes requires drastic reaction conditions, whereas, with
Pd-nanoparticles the same reaction can be executed under moder-
ate reaction condition (due to large surface area of the nanoparti-
cles the catalytic activity is increased). However, the reaction still
requires costly Pd-salts, toxic carbon monoxide environment (5–
60 bar pressure) and elevated reaction temperature with stoichi-
ometric amount of base to regenerate the catalyst.9 Such drawback
limits the wide scope of these types of coupling reaction. Thus,
direct amidation of aryl halides under mild reaction conditions
without using hazardous chemicals still remains as a challenge to
organic chemists.
Introduction of isocyanides may offer a suitable alternative for
the synthesis of amides.10 It is reported that the amides have been
synthesized via Pd-catalysed C–C coupling reactions of aryl halides
with isocyanides11 which simplified the metal-mediated synthesis
without the involvement of carbon monoxide. These prompted us
to develop a green protocol by which amides can be synthesized
from corresponding aryl halides and isocyanides using a recyclable
and cheap catalyst in water under mild reaction conditions.
⇑
Corresponding authors. Tel.: +91 33 24995806; fax: +91 33 24735197.
E-mail addresses: swarbhanu_2005@yahoo.co.in (S. Sarkar), aksen@iicb.res.in
(A.K. Sen).
Contributed equally to the work.
http://dx.doi.org/10.1016/j.tetlet.2014.12.060
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

624
S. Sarkar et al. / Tetrahedron Letters 56 (2015) 623–626
Table 1
O
Effect of different Cu(I) compounds and bases for the synthesis of amide (3a) in
aqueous medium
X
R2
Cu2O nanoparticle
Water, Base
N
H
R1
R2-NC
R1
Entrya
Catalyst
Base
Yieldb (%)
2
1
3
1
2
3
4
5
CuI
CuI
CuI
CuCl
[(IPr)2Cu]PF6
Cu2O
Cu2O
K2CO3
Cs2CO3
KOH
Cs2CO3
Cs2CO3
Cs2CO3
DBU
0
0
0
0
0
0
0
X = Br, I
Scheme 1. Nanodomain copper (I) oxide mediated amidation of iodobenzene with
isocyanides.
6
7
8
9
10
11
12
Nano-Cu2O
Nano-Cu2O
Nano-Cu2O
Nano-Cu2O
Nano-Cu2O
Cs2CO3
DBU
50
53
55
62
82c
Utilization of copper (I) complexes/salts may be a suitable
alternative towards this endeavour, but, it often requires anaerobic
condition or the use of stabilizing ligands or extended reaction
time.12 This leads to a decrease in the efficiency of the catalyst
for reuse. It has been established that nanodomain copper (I) oxide
shows substantial enhancement in reactivity, stability in aqueous
medium, environmental compatibility and large surface/volume
ratio which make it more promising in chemical transformations13
compared to bulk copper (I) oxide. So, the application of cuprous
oxide nanoparticles is an attractive strategy to execute organic
reaction under green condition.14 Numerous methods have been
reported in the literature for the synthesis of copper (I) oxide in
the nanodomain with varied morphologies viz. cubes,15 spheres,16
wires,17 polyhedral18 and hollow-structures.19 However, the appli-
cation of these nanoparticles in organic synthesis is not well docu-
mented.20 Our present study reveals direct aminocarbonylation of
aryl halides with isocyanides using recyclable cubic nano-copper
(I) oxide resulting in benzamides via C–C cross-coupling reaction
(Scheme 1).
iPr2EtN
Lutidine
Lutidine
a
Reactions were performed using iodobenzene 1a (10 mmol), phenyl isocyanide
2a (10 mmol), catalyst (10 mol %), base (10 mmol), in water (1 mL) under sonication
(80 °C) for 1 h under aerobic condition.
b
Recovered yield; some losses during purification were inevitable in certain
cases.
c
Base (50 mmol).
XRD plot with 2h values at 29.42°, 36.38°, 42.31°, 61.43°, 73.66°
and 77.47° were ascribed as the crystal plane of 110, 111, 200,
220, 311 and 222, respectively (d-spacing value, crystallite size
and other data in Supplementary information). The scanning elec-
tron microscopy (SEM) (Fig. 1b) and transmission electron micros-
copy (TEM) images (Fig. 1c) confirmed the regular cubic shape of
the Cu2O particles with an average edge length of 180 20 nm.
These nano-copper (I) oxides were used in the current study. Fur-
thermore, the oxidation state of the nanoparticles was confirmed
by FT-IR analysis (Fig. S2, SI). The appearance of a strong peak at
around 627 cmÀ1 indicates Cu(I)–O starching frequency and the
absence of any peak around 512 cmÀ1 clearly indicates the absence
of even trace amount of Cu(II)–O as contaminant in the synthe-
sized nanoparticles.22
Cubic cuprous oxide nanoparticles used in the strategy were
synthesized under completely non-hazardous reaction condition
by reduction of cupric chloride dihydrate in water using fructose
as reducing as well as capping agent at 60 °C. Figure 1 illustrates
the formation of uniform nanodomain cuprous oxide nanoparti-
cles. The powder XRD pattern (Fig. 1a) indicates the typical reflec-
tion patterns of cuprite (JCPDS No. 77-0199).21 The peaks in the
Figure 1. (a) Powder XRD patterns; (b) SEM and (c) TEM image of cuprous oxide nanoparticles before reaction; (d) TEM image of cuprous oxide nanoparticles after three time
use.

S. Sarkar et al. / Tetrahedron Letters 56 (2015) 623–626
625
Table 2
Reactions of isocyanides (1a–c) with aryl halides (2a–f) leading to amides (3a–j) in aqueous medium
Entrya
Aryl halide
Isocyanide
Product
Yieldb (%)
I
O
CN
Y
N
H
Y
Z
Z
1
2
3
4
5
1a
1a
1a
1a
2a: Y = H, Z = H
3a: Y = Z = H
82
83
84
87
88
2b: Y = CH3, Z = H
2c: Y = OCH3, Z = H
2d: Y = F, Z = H
3b: Y = CH3, Z = H
3c: Y = OCH3, Z = H
3d: Y = F, Z = H
1a
2e: Y = CH3, Z = NO2
3e: Y = CH3, Z = NO2
COPh
COPh
O
I
N
H
Y
Z
6
7
8
9
1b
1b
1b
1b
Br
2b
2c
2d
2e
3f: Y = CH3, Z = H
3g: Y = OCH3, Z = H
3h: Y = F, Z = H
82
84
84
80
3i: Y = CH3, Z = NO2
10
2a
3a
74
1c
NC
COPh
O
N
H
11
1b
85
2f
3j
a
Reactions were performed using aryl halides 1a–c (10 mmol), isocyanides 2a–f (10 mmol), Cu2O nanomaterial (10 mol %), lutidine (50 mmol), in water (1 mL) under
sonication (80 °C) for 1 h under aerobic condition.
b
Recovered yield; some losses during filtration were inevitable in certain cases.
In an initial attempt iodobenzene (1a) and phenyl isocyanide
(2a) were used as model compounds for the optimization of the
reaction condition (Table 1). The use of commercially available
copper (I) salts as catalyst in the presence of organic or inorganic
bases under sonication did not produce any product even after pro-
longed heating (5 h) at elevated temperature (90 °C). We used
Cs2CO3, K2CO3 as well as KOH to study the effect of inorganic salts
and alkali (Table 1, entries 1–3) but without success. Similar obser-
vation was made with other bulk copper (I) salts (Table 1). The rel-
evance of using cuprous oxide nanoparticles was investigated next.
It was found that under similar conditions and in the presence of
cuprous oxide nanoparticles the reaction proceeded well with con-
siderable yield. The effect of different bases was also explored sub-
sequently (Table 1). Lutidine was found to give maximum yield
when employed in 5.0 mol equiv (Table 1, entries 11 and 12). We
also performed the reaction under stirring with a magnetic stirrer
using nano-catalyst and lutidine. But, the yield was low (ꢀ50%).
This clearly indicates that sonication is essential for smooth pro-
gress of the reaction and for higher yield. It dispersed all reactants
and insoluble nano-catalyst allowing them to come in close prox-
imity for better interaction between the catalyst and the reactants.
With the optimized reaction conditions, the scope and generality
of the approach were investigated using aryl or aliphatic isocyanides
and aryl halides (Table 2). Irrespective of the nature of aliphatic or
aromatic isocyanides used, amides were generated in good to excel-
lent yield. Under similar reaction conditions corresponding bromide
1c (Table 2, entry 10) was also found to be equally efficient. All reac-
tions yielded amides as the major product and the structures of all
new products were confirmed by NMR and HRMS analysis.
the morphology of the catalyst remained unchanged even after
three uses. The TEM image of the recovered nanoparticles after
three recycles is shown in Figure 1d. However, the catalyst exhib-
ited a marginal loss in activity when used for the fourth time and
might be due to the surface passivation under the reaction condi-
tions used. The XRD data showed that the d-values of the nano-cat-
alyst remain unchanged after 3 recycles.
A plausible mechanism for the formation of amides via copper
(I) mediated amidation of halides with isocyanides is depicted in
Scheme 2. It is expected that oxidative addition of Ar-X to Cu(I)
species gives intermediate (I). The intermediate (I) undergoes
Table 3
Reusability of cuprous oxide nanoparticles for the synthesis of amides (3a)a
Reusability of the nano-catalyst
% Yield of final product
1st
82
2nd
79
3rd
77
4th
63
a
Yield of the recovered pure product 3a; some losses during isolation are inev-
itable in certain cases.
R
N
R-N
Cu(I)
Ar-X
III
Ar-Cu-X
C
III
XCu
Ar
Base
H2O
I
II
R
R
H
N
N
N
Ar
R
III
The reusability of the nanoparticles towards the synthesis of
amide (3a) was also investigated and the results are abridged in
Table 3. After each reaction, the nano-catalyst was separated by
centrifugation and washed with EtOH–H2O before reuse. The cata-
lyst was recovered in nearly 95% yield in all cases. It was found that
HOCu
Ar
HO
Ar
O
Cu(I)
III
IV
Scheme 2. Plausible mechanism for the formation of amide via Cu(I) mediated
amidation of halides with isocyanides.

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The authors express their gratitude to the Director, IICB for lab-
oratory facilities, the Council of Scientific and Industrial Research
(CSIR), New Delhi, India, for providing fellowships to S.S., R.P. and
N.C. The DERB, DST, New Delhi is thanked for providing a Raja
Ramanna Fellowship to S.S. at IIEST, Shibpur. We are also thankful
to Dr. T. Sarkar and Mr. K. Sarkar for recording NMR and ESI-MS.
Supplementary data
21. Park, J. C.; Kim, J.; Kwon, H.; Song, H. Adv. Mater. 2009, 21, 803.
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Satyanarayana, N. Mater. Res. Bull. 2007, 42, 1619.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.12.
060.
23. General reaction procedure for the synthesis of benzamides (3a–g): In an open
round-bottomed flask, aryl halides 1a–c (10 mmol), isocyanides 2a–f
(10 mmol), Cu2O nanomaterial (10 mol %), lutidine (50 mmol), and water
(1 mL) was added and the mixture was sonicated (80 °C) for 1 h under aerobic
condition when TLC indicated formation of a new product. The mixture was
extracted with ethyl acetate (25 mL Â 3), and washed thoroughly with water.
Column chromatography produced pure product. The nanoparticles were
washed with ethanol–water twice for reuse.
References and notes
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24. Representative physical data of the synthesized compounds (3g): 1H NMR (CDCl3,
300 MHz): d = 3.73 (3H, s), 6.72 (2H, d, J = 9 Hz), 7.22–7.39 (m, 7H), 7.44 (1H, t,
J = 8.5 Hz), 7.52 (2H, t, J = 7.2 Hz), 7.70 (1H, d, J = 7.2 Hz); 13C NMR (DMSO-d6,
75 MHz): d = 55.15, 92.07, 113.62, 122.92, 122.99, 126.07, 127.82, 127.92,
128.34, 128.90, 129.40, 130.04, 133.09, 140.00, 149.59, 157.36, 166.36 ppm;
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