Nanoparticle mediated organic synthesis (NAMO-synthesis): CuI-NP catalyzed ligand free amidation of aryl halides

Article abstract of DOI:10.1039/c4ra06804a

The first CuI-nanoparticle catalyzed ligand free synthesis of N-aryl amides from aryl halides and arylamides/cyclic amides has been developed. This methodology is further extended for the synthesis of nitrogen heterocycles such as benzimidazole, and quinazolinone via intermolecular amidation reaction followed by cyclization. TEM images of the CuI-NP catalyst showed spherical, well-dispersed particles which provide large surface area for reactivity and have good recyclability. This journal is

Full text of DOI:10.1039/c4ra06804a

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Nanoparticle mediated organic synthesis (NAMO-
synthesis): CuI-NP catalyzed ligand free amidation
of aryl halides†‡
Cite this: RSC Adv., 2014, 4, 41631
Received 8th July 2014
Accepted 26th August 2014
*
Atul Kumar and Ajay Kumar Bishnoi
DOI: 10.1039/c4ra06804a
www.rsc.org/advances
The first CuI-nanoparticle catalyzed ligand free synthesis of N-aryl heterogeneous system. Whereas low catalyst loading and
amides from aryl halides and arylamides/cyclic amides has been selectivity as offered by homogeneous system. Beside this
developed. This methodology is further extended for the synthesis of nanoparticles have added advantage of large surface area and
nitrogen heterocycles such as benzimidazole, and quinazolinone via high catalytic activity.7 Almost all the amide arylation reaction
intermolecular amidation reaction followed by cyclization. TEM involves Palladium/ligand based catalytic systems.8 However,
images of the CuI-NP catalyst showed spherical, well-dispersed the replacement of palladium with less expensive copper(I) salt
particles which provide large surface area for reactivity and have good as catalyst would be allowed for economic benets and low
recyclability.
toxicity issues.9 Recently, nano Cu-catalyzed N-arylation of
amines, S-arylation and O-arylation reactions have been repor-
ted.10 To the best of our knowledge, N-aryl amidation have not
Introduction
Transition metal-catalyzed C–N, C–C bond forming processes
are extensively utilized in academia and the pharmaceutical
industry.1 Metal-catalyzed amide arylation reactions of aryl
halides or pseudo halides are an attractive method for synthe-
sizing N-arylamides, which are an important pharmacophore
and present in many clinically approved drugs and natural
products.2–4
In twenty rst century, nanoparticle mediated organic
synthesis has been one of the most progressive research areas.5
Therefore, we wish to introduce here nanoparticle mediated
organic synthesis (NAMO-synthesis), a specic term for the
organic synthesis involving nanoparticles.
The use of nano transition-metal catalysts to perform
organic reaction is becoming increasingly popular.6 Metal
nanoparticles have been enticed the synthetic chemistry due to
the edge over the heterogeneous and homogeneous catalyst.
Metal nano particles offer privilege of heterogeneous and
homogeneous catalyst system. Recyclability and recovery
offered by nanoparticles catalysis keep the main advantage of
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute,
Lucknow, 226031, India. E-mail: dratulsax@gmail.com; Fax: +91-522-26234051;
Tel: +91-522-2612411
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra;
SEM-EDX, TEM images of catalyst. See DOI: 10.1039/c4ra06804a
‡ CDRI communication no: 8779
Fig. 1 Nanoparticle mediated organic synthesis (NAMO-synthesis).
RSC Adv., 2014, 4, 41631–41635 | 41631
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yet been exploited. Thus we developed rst nano Cu catalyzed N- no reaction was observed in the absence of ethylene glycol and
aryl amidation reaction for the synthesis of diverse amides CuI-NP catalyst (Table 1, entries 6,7). Solvent effects were also
(Fig. 1).
screened. Ethylene glycol: 2-propanol was found to be superior
Herein, we report rst nano Cu-catalyzed ligand free N-ary- to the solvents tested (Table 1, entries 7–10). Presumably,
lation of amides using CuI-nanoparticles as the catalyst, ethylene glycol acts as a ligand that is more effective in stabi-
ethylene glycol: 2-propanol (1 : 5) ratio as the solvent under lizing or solubilizing the nano copper complex. Beside these
mild reaction condition. This efficient methodology for aryla- ethylene glycol: 2-propanol system is considered as green
tion of amides have been further utilized for the synthesis of media.12 Among the bases studied, KOH, Na2CO3, KOtBu,
substituted benzimidazoles and quinazolinones, which have a K3PO4, provided lower yields than K2CO3, (Table 1, entries 1–5).
wide range of application in pharmaceutical industry and
material sciences.11
The 1.5 mol% of CuI-nanoparticles showed the best activity
(Table 1, entry 1). We found that 85% yield obtained with 1.5
mol% nanocatalyst, whereas 0.5 mol% nanocatalyst gave 65%
product (Table 1, entry 17).
Result and discussion
The scope of the reaction was explored with a range of
substituted benzamides, cyclic amides and the bromides
showed higher reactivity than the corresponding aryl chloride
(Scheme 1). We were pleased to observe that the aryl bromide
with electron rich, electron-poor, or sterically hindered, all of
them afforded good to excellent yields with nanoparticles of
CuI. We noticed that (1 : 5) ratio of ethylene glycol and
2-propanol as better solvent system for the reaction. Low yields
were obtained when the reaction time, temperature, or amount
of CuI-nanoparticles were reduced. The optimal conditions of
1.5 mol% of CuI-nanoparticles, 1.5 equ. of K2CO3 in ethylene
glycol/2-propanol at 70 ꢀC were used for further investigations.
Aer completion of reaction, the catalyst was recovered from
the reaction mixture by centrifugation and reused for the next
fresh reaction. It is noteworthy that the catalyst could be reused
at least ve times without any signicantly loss of efficiency. We
were pleased to observe that cyclization product aer the
N-arylation of amides were obtained when 2-bromoaniline and
2-bromobenzamide react with benzamides in one pot (Scheme
2 and 3). Next we focused on 2-chloroaniline react with benza-
mides and surprise to obtained the cyclized product, benz-
imidazole only with CuI-nanoparticles in low yields. Therefore,
we suspected that because of large surface area, nanoparticles
have very high catalytic properties as compare to other catalyst.
We commenced our study by investigating the reaction of bro-
mobenzene and benzamide were chosen as the model
substrates to optimize reaction condition, which include the
catalyst, base, and solvent. As shown in Table 1, four copper
catalysts and CuI-nanoparticle were tested at 70 ꢀC temperature
by using 1.5 equ. of K2CO3 as the base in ethylene glycol:
2-propanol (1 : 5) solvent system. The copper(I) salts such as
CuBr, CuCl, Cu2O, and CuI were found to be inferior to CuI-
nanoparticles (Table 1, entries 11–14).
To coincidence, we used ethylene glycol: 2-propanol as the
solvent and we observed that product was obtained without use
of ligand in excellent yield. Control experiments revealed that
Table 1 Optimization of reaction conditions for synthesis of N-aryl
amidesa
Entry
[Cu] (mol%)
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
CuI (np (1.5))
CuI (np (1.5))
CuI (np (1.5))
CuI (np (1.5))
CuI (np (1.5))
—
CuI (np (1.5))
CuI (np (1.5))
CuI (np (1.5))
CuI (np (1.5))
Cu2O
Cu(OAc)2
CuBr
CuCl
CuI (np (3.0))
CuI (np (5.0))
CuI (np (0.5))
CuI (10)
K2CO3
KOtBu
KOH
EG/iPrOH
EG/iPrOH
EG/iPrOH
EG/iPrOH
EG/iPrOH
EG/iPrOH
iPrOH
NMP
DMF
H2O
85
70
72
78
52
—
—
10
—
—
35
30
30
25
84
84
65
50
Na2CO3
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
9
10
11
12
13
14
15
16
17
18
EG/iPrOH
EG/iPrOH
EG/iPrOH
EG/iPrOH
EG/iPrOH
EG/iPrOH
EG/iPrOH
EG/iPrOH
a
Reaction conditions: bromobenzene (1.0 mmol), benzamide (1.5
mmol), CuI-NP (1.5% mole), base (1.5 equ.), EG (ethylene glycol)/
iPrOH (2-propanol) as solvent (10 mL) in 1 : 5 ratio for 5 h at 70 ꢀC.
Isolated yield. np ¼ nanoparticles, DMF ¼ dimethylformamide,
b
NMP ¼ N-methylpyrrolidinone.
Scheme 1 Arylation of simple amides and cyclic amides.
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Scheme 2 One pot synthesis of benzimidazole derivatives.
Fig. 2 (a) SEM images of catalyst before the reaction (b) after the 5th
run (c) TEM images before the reaction (d) after the 5th run, (e) EDX
image of fresh catalyst, and (f) EDX image of catalyst after 5th run.
Scheme 3 One pot synthesis of substituted Quinazolinones.
Table 2 Recyclability of CuI-nanoparticles
It was a heterogeneous process and the catalyst was recy-
clable with slight loss of activity (Table 2). Aer completion of
amidation of bromobenzene, the catalyst was recovered from
the reaction mixture by centrifugation and reused for the fresh
reaction and only a slight decrease in catalytic activity was
observed. The surface property and the composition of the
catalyst were characterized from scanning electron microscope
(SEM), transmission electron microscope (TEM) and energy
dispersive X-ray analysis (EDX). The EDX spectrum (Fig. 2)
further authenticates the presence of Cu in the nanocomposite.
In addition, in the SEM, TEM analysis of CuI-nanoparticles,
interestingly, the shape and size of the nanoparticles remained
unchanged before and aer the reaction.
Catalyst recovery
(%)
Product yield
(%)
Run
1a
2b
3b
4b
5b
95
90
86
82
75
85
84
82
80
75
a
CuI-nanoparticles (1.5 mol%), bromobenzene (1.0 mmol), benzamide
(1.5 mmol) base (1.5 equ.), EG (ethylene glycol)/iPrOH (2-propanol) as
Conclusion
b
solvent (10 mL) in 1 : 5 ratio for 5 h at 70 ꢀC. The recovered catalyst
was used under identical reaction conditions to those for the rst run.
In conclusion, we have demonstrated rst ligand free CuI-
nanoparticle catalyzed N-arylation of amides/cyclic amindes in
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ethylene glycol/2-propanol solvent system under mild condition
in good yields. The methodology is also extended for one pot
synthesis of benzimidazoles and quinazolones in excellent
yields. The catalyst have good recyclability which provides
several advantage, including short reaction time, simple work
up and high yields. The nanoparticle mediated organic
synthesis (NAMO-synthesis) has immense future in application
in the area of medicinal chemistry and material science.
General procedure for the Quinazolinone derivatives in one-
pot
In a typical experiment, a mixture of 2-bromobenzamide (1
mmol), benzamide (1.5 mmol), CuI-NPs (1.5 mol%) and K2CO3
(1.5 equ.) were dissolved in 10 mL of ethylene glycol/2-propanol
(1 : 5) and stirred for the 5 hours at 70 ꢀC temperature. The
reaction was monitored to completion using TLC. At the end of
reaction, the mixture was then cooled to room temperature and
poured into distilled water. The products were extracted using
EtOAc and the organic layer was dried over anhydrous sodium
sulphate (Na2SO4). The solvent was evaporated in vacuo, the
crude products were puried by silica column chromatography
using EtOAc/hexane solvent system.
Experimental section
General procedure for preparation of CuI-nanoparticles
0.464 g (4 mmol) of dimethylglyoxime (dmgH) and 0.400 g (2
mmol) of Cu(OAc)2.H2O were added into 50 mL of absolute
ethanol in sequence, which was stirred at 0 ꢀC for 30 min to get
brown precipitates Cu(dmg) 2. Then the collected precipitates
dispersed in 50 mL of absolute ethanol again, 0.664 g (4 mmol)
KI was added and stirred vigorously for 2 h. Aer that, the
mixture was transferred into 60 mL Teon-lined stainless steel
autoclave. The autoclave was sealed and heated at 180 ꢀC for 6 h,
and then the reactor bomb is allowed to cool to room temper-
ature. Black precipitates were obtained, then centrifugalized
and washed with ethanol and deionized water for three times to
ensure the removal of the impurities. The nal product was
then dried in a vacuum oven at room temperature for 12 h.
Acknowledgements
A.K.B. is thankful to CSIR-SRF New Delhi for nancial support.
The authors also acknowledge analytical facility of CSIR-CDRI
and Dr Rajnish K. Chaturvedi, IITR, for SEM and TEM. Finan-
cial support from CSIR-CDIR network project BSC-0104.
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