Recyclable nanoparticulate copper mediated synthesis of naphthoxazinones in PEG-400: A green approach

Article abstract of DOI:10.1016/j.tetlet.2011.07.016

An efficient methodology employing copper nanoparticles for the preparation of 2-naphthol condensed 1,3-oxazinone derivatives employing one-pot condensation reaction in the presence of K₂CO₃ and copper nanoparticles in PEG-400 is des

Full text of DOI:10.1016/j.tetlet.2011.07.016

Tetrahedron Letters 52 (2011) 4835–4839
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Recyclable nanoparticulate copper mediated synthesis of naphthoxazinones
in PEG-400: a green approach
Ajeet Kumar a, Amit Saxena a, Manika Dewan a, Arnab De b, Subho Mozumdar a,
⇑
a Department of Chemistry, University of Delhi, Delhi 110 007, India
b Department of Microbiology and Immunology, Columbia University Medical Centre, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient methodology employing copper nanoparticles for the preparation of 2-naphthol condensed
1,3-oxazinone derivatives employing one-pot condensation reaction in the presence of K2CO3 and copper
nanoparticles in PEG-400 is described which offers several advantages, viz. high yields, clean reaction,
short reaction times, recyclability of the catalyst and simple workup procedure. PEG-400 was found to
be the best solvent out of a range of solvents examined for this scheme. Moreover, PEG could stabilize
the nanoparticles from oxidation and thus could increase the catalyst efficiency by escalating the TON
(Turn over Number) and TOF (Turn over Frequency) of the catalyst, making the protocol greener, eco-
friendly and environmentally benign.
Received 16 May 2011
Revised 3 July 2011
Accepted 5 July 2011
Available online 14 July 2011
Keywords:
Copper nanoparticles
Oxazinone
Condensation reaction
Nanocatalysis
Ó 2011 Elsevier Ltd. All rights reserved.
Polyethyleneglycol
Aromatic condensed oxazinone derivatives have received con-
siderable attention due to the attractive pharmacological proper-
ties associated with their heterocyclic scaffold.1 Since many of
these heterocyclic systems exhibit biological activities such as
anti-inflammatory, antiulcer, antipyretic, antihypertensive and
antifungal, these derivatives have become an integral part of phar-
macologically important heterocyclic compounds.2–6 Some of them
also act as 5-HT ligands,7 DP receptor antagonists,8 integrin antag-
onists,9 platelet fibrinogen receptor antagonists,10 calmodulin
antagonists,11 inhibitors of the transforming growth factor b
(TGF-b) signaling pathway,12 soybean lipoxygenase,13 Janus kinase
(JAK) and other protein kinases.14 Moreover, benzo[1,4]oxazin-3-
one analogs act as effective potassium channel openers, immuno-
modulating reagents, etc.15,16 This class of heterocyclic compounds
has also been used as precursors in the synthesis of phosphinic li-
gands for asymmetric catalysis.17 Therefore, aromatic condensed
oxazinone derivatives scaffold can be viewed as a ‘privileged struc-
ture’ among pharmaceutical compounds.18,19 Inspite of their high
potential, there are only few reports which describe the synthesis
of naphthalene-condensed oxazinone derivatives.20–23 In general,
all these methods require elevated temperature non recyclable cat-
alyst except those reported by Chaskar et al.20 Besides, a multi-step
and cumbersome reaction involving the use of harsh conditions is
required for the synthesis of starting materials such as amino
alkylnaphthol. Therefore, development of simple, robust and safer
methodologies for the synthesis of naphthoxazinone derivatives is
of prime interest for obtaining these products under conditions
tolerated by sensitive functional groups from both synthetic and
environmental points of view. The role of copper nanoparticles in
coupling chemistry has been well documented.24–27 The process
described here is chemo-selective and offers the rapid facile con-
densation of b-naphthol, aldehydes and urea to form oxazinone
derivatives with high yields using monodispersed and easily recy-
clable copper nanoparticles. This process is cost effective and eco-
friendly as it is a one-pot synthesis with easy workup and does not
require special conditions such as elevated temperature and harsh
reagents, etc. Moreover, in typical cases where metal salts and
other complexes are used as catalysts, an excessive amount of cat-
alysts (usually in grams) is required which at the end of the reac-
tion cycle gets eliminated as a ‘waste product’ producing the
effluent which is often toxic and hazardous. However, the process
developed by us requires lesser quantity of catalyst for carrying out
the catalytic reaction (usually in microgram) thus decreasing the
amount of effluent to considerable level. Moreover, copper nano-
particles have been used for various applications including antimi-
crobial activity and no evidence of toxicity has been reported for
low dosages.28,29 Therefore, we can claim that our approach is
greener, eco-friendly and environmentally benign. Further, poly
(ethylene glycol) (PEG) is also a biologically acceptable polymer
used widely in pharmaceutical and biomedical applications as
tools for diagnostics and has not been used widely as a solvent
medium but has been used as a support for various organic
transformations.30–33 The low toxicity of copper nanoparticles
⇑
Corresponding author. Tel.: +91 9810728438.
E-mail address: subhoscom@yahoo.co.in (S. Mozumdar).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.016

4836
A. Kumar et al. / Tetrahedron Letters 52 (2011) 4835–4839
and ability of PEG to stabilize the copper nanoparticles encouraged
us to couple them together to evaluate their utility in the synthesis
of 2-naphthol condensed 1,3-oxazinone derivatives. In this com-
munication, we wish to draw attention toward an efficient and
environmentally benign protocol for the formation of naphthalene
condensed oxazinone derivatives. During the preliminary trials, it
was found that a mixture of b-naphthol (2 mmol), benzaldehyde
(2 mmol), urea (3 mmol) and K2CO3 (0.3 mmol) in the presence
of a catalytic amount of copper nanoparticles (0.001 g) in PEG-400
(3 ml) at room temperature for 45 min under air atmosphere
Table 1
Synthesis of b-naphthalene condensed oxazinone derivatives
Entry
Aldehyde
CHO
Products
Time (min)/yield (%)
45/93
M.P/B.P (°C)
H
N
O
1
217
188
2
2
O
CHO
H3CO
H
N
O
H3CO
2
3
60/90
60/82
O
CHO
OCH3
OCH3
OCH3
H
N
O
215
215
2
2
OCH3
O
CHO
OCH3
HO
O2N
F
HO
H
N
O
4
60/82
OCH3
O
CHO
H
N
O
O2N
5
6
7
8
60/81
60/74
60/89
60/93
207
202
205
218
2
2
2
2
O
CHO
H
N
O
F
O
CHO
CHO
CHO
Cl
H
N
O
Cl
O
O
Br
H
N
O
Br
HO
H
N
O
HO
O
9
60/82
60/81
182
307
2
2
O
O
CHO
H
N
O
10
O
Reaction conditions: b-naphthol (2 mmol), aldehyde (2 mmol) and urea (3 mmol) and K2CO3 (0.3 mmol), copper nanoparticles (15 nm; 0.001 g) PEG-400 (3 ml) at room
temperature under air atmosphere. Isolated pure crystallized product.

A. Kumar et al. / Tetrahedron Letters 52 (2011) 4835–4839
4837
CHO
O
OH
Cu- nanoparticles
O
+
NH2
H2N
+
K2CO3, PEG-400, air
N
H
O
Scheme 1.
Table 2
and the reactants could be recovered as sticky mixture (Scheme 2).
An unexpected reaction took place in case of reaction with N-
methyl urea. As depicted from the proposed mechanism this
reaction should have taken place but we were not able to recover
the product in significant yield. Moreover, with N-N0-dimethyl
urea, no product could be obtained and all the starting materials
could be recovered (Scheme 3).
This may be due to the presence of substituted amino group
which could limit the formation of acylimine intermediate and
thus inhibit the reaction to proceed. In addition, replacement of
Optimization of different catalysts
Entry
1
Catalyst
Yield (%)/time (hr)
PTSA in DMSO
PTSA in PEG-400
58/12
63/4
30/6
45/3
65/4
73/1
2
3
4
5
Ni-nanoparticles in ethanol
Ni-nanoparticles in PEG-400
Copper-nanoparticles in ethanol
Copper-nanoparticles in PEG-400
PEG-400
No reaction
Intermediate formation
96/1
PEG-400 + K2CO3
Copper-nanoparticles in PEG-400 + K2CO3
b-naphthol with
a-naphthol prevented the reaction to proceed.
Moreover, no products were obtained by using naphthalene-2-
afforded 1,2-dihydro-1-phenylnaphtho[1,2-e][1,3]oxazine-3-one
(Table 1, entry 1) in 93% yield (Scheme 1).34
thiol instead of b-naphthol (Scheme 4).
In order to elucidate the role of copper nanoparticles, a con-
trolled reaction was also carried out using aldehydes and b-naph-
thol, urea and K2CO3 (0.3 mmol) in PEG-400 (3 ml) without using
copper nanoparticles.
Various metal nanoparticles in different solvents were used for
the synthesis of the naphthalene-condensed oxazinone derivatives
by reacting b-naphthol, benzaldehyde and urea. Their catalytic effi-
ciencies were evaluated (Table 2) and it was observed that the
highest yield was achieved when copper nanoparticles and K2CO3
with PEG-400 were used (Table 2, entry 5). To investigate the ver-
satility of the methodology, a number of aldehydes with b-naph-
thol bearing various functionalities were reacted in the presence
of urea, K2CO3 and catalytic amount of copper nanoparticles
(0.001 g) in PEG-400. The products obtained are tabulated in Table
1 and the proposed reaction mechanism that accounts for the
novel multicomponent reaction is shown in Figure 1. It may be
proposed that similar to several classical multi-component con-
densations, the initial event in this reaction is the condensation
of aldehyde and urea to give reactive acylimine intermediate. Sub-
sequently, the resulting acylimine intermediate undergoes a cycli-
zation with b-naphthol affording the corresponding products and
ammonia. No naphthoxazinones products were obtained when
urea was replaced with thiourea even after 24 h of vigorous stirring
The reaction did not proceed even after 48 h and the starting
materials could be recovered as such. Although the same reaction
did proceed when copper nanoparticles were used alone in the ab-
sence of PEG-400, but the yield depreciated by 30% and it took
more than 4 h for the reaction to move toward completion.
It is postulated that electronic factors can play a significant role
in this copper nanoparticles mediated condensation reaction in
PEG-400 as a recyclable reaction media. Various new innovations
were observed during the developmental steps of the protocol.
Among them the fashion in which the reactants were added to
the reaction mixture was the most important factor. The sequence
of addition of reactant played a dramatic role and influenced the
course of product formation. In other words, products obtained
were defined by the sequential addition of the reactant which if
not followed led to the formation of entirely new products. Further
investigations are being carried out to understand the scope of
Figure 1. Proposed mechanism for the synthesis of b-naphthalene condensed oxazinone derivatives.

4838
A. Kumar et al. / Tetrahedron Letters 52 (2011) 4835–4839
CHO
S
OH
Cu- nanoparticles
+
+
NHMe
H2N
No Reaction
K2CO3, PEG-400, air
Scheme 2.
CHO
CHO
H
O
O
H
N
N
O
OH
OH
O
Cu- nanoparticles
+
+
NHMe
NHMe
H2N
O
+
+
NHMe
NH2Me
K2CO3, PEG-400, air
+
+
Side product
Low yield (30%)
Cu- nanoparticles
K2CO3, PEG-400, air
Scheme 3.
MeHN
No reaction
CHO
OH
O
Cu- nanoparticles
+
NH2
NH2
No Reaction
H2N
H2N
+
K2CO3, PEG-400, air
CHO
O
Cu- nanoparticles
SH
+
+
No Reaction
K2CO3, PEG-400, air
Scheme 4.
these new findings. The reaction when carried out by adding the
aldehyde and urea followed by b-naphthol gave the desired naph-
thalene condensed oxazinone products in quantitative yield.
Various solvents were used in order to estimate the scope and lim-
itations of the reaction and the results obtained have been tabu-
lated in Figure 2. Table 1, entry 1 was selected and the reaction
outlined above was carried out in the chosen solvents. In DMSO
and acetonitrile the reaction was observed to be very slow,
whereas, in ethanol the reaction went smoothly and gave good
yield but after completion of the reaction, the copper-nanoparticles
got oxidized and could not be recovered.
However, the nanoparticles were found to be stable and reaction
went to 81% completion in ethylene glycol but as ethylene glycol,
is not safe to handle, it was not considered further. Clearly, PEG-
400 stood out as the solvent of choice, with its fast conversion,
quantitative yield in lesser time, green, non-toxic and potentiality
for providing stability to the catalyst, that is, copper-nanoparticles
and ability to serve as an efficient recyclable medium.
In order to explore the recyclability of the catalyst, the copper
nanoparticles in PEG-400 were used as catalyst for the same reac-
tion repeatedly and the change in their catalytic activity was stud-
ied. The relation between the number of cycles of the reaction and
the catalytic activity in terms of yield of the products is presented
in the Figure 3. It was found that copper nanoparticles and PEG
could be reused for five cycles with negligible loss of their activity.
In THF no products could be recovered even after 24 h of vigor-
ous stirring and the reactants were recovered as sticky precipitates.
Figure 2. Optimization of the solvent media for the synthesis of naphthalene
condensed 1-phenyl-1,2-dihydro-naphtho[1,2-e][1,3]oxazin-3-one in various sol-
vents. Reaction conditions: b-naphthol (2 mmol), benzaldehyde (2 mmol) and urea
(3 mmol) and K2CO3 (0.3 mmol), copper nanoparticles (15 nm; 0.001 g) solvent
(3 ml) at room temperature for 1 h under air atmosphere. Isolated pure crystallized
product.
Figure 3. Recyclability of catalyst for the synthesis of naphthalene condensed 1-
phenyl-1,2-dihydro-naphtho[1,2-e][1,3]oxazin-3-one. Reaction conditions: b-naph-
thol (2 mmol), benzaldehyde (2 mmol) and urea (3 mmol) and K2CO3 (0.3 mmol),
copper nanoparticles (15 nm; 0.001 g) PEG-400 (3 ml) at room temperature for 1 h
under air atmosphere. Isolated pure crystallized product.

A. Kumar et al. / Tetrahedron Letters 52 (2011) 4835–4839
14. Bethiel, R.S.; Ludeboer, M. U.S. Patent Appl. US 2004097504 A1, 2004.
4839
It has already been reported earlier that with the increasing
number of reaction cycles, the catalytic activity of the copper nano-
particles decreases.24 This might be due to the slow oxidation of
the copper nanoparticles in different organic media. It can there-
fore be said that PEG not only acts as a green and environmentally
benign reaction media but also provides stability to the nanoparti-
cles from being oxidized. Nanoparticles could be recovered by sep-
arating them from the reaction mixture by mild centrifugation.
In conclusion, it can be said that a simple, eco-friendly, green
and efficient procedure for the synthesis of naphthalene condensed
oxazinone derivatives from diverse carbonyl compounds (alde-
hydes) with urea is reported for the first time by our research
group using inexpensive, easily recyclable, monodispersed copper
nanoparticles as catalysts in biocompatible, economical and reus-
able, PEG-400. The method is very efficient and avoids the use of
expensive reagents, high temperatures and leads to improved
product yields. To the best our knowledge, this is the first report
on copper nanoparticles catalyzed synthesis of naphthaoxazinone
derivatives in reusable PEG-400 and this new procedure opens
an important chapter in the efficient recyclability of copper nano-
particles as an important catalyst. The ambient conditions, high
reaction rates, excellent product yields and easy work-up proce-
dures at room temperature not only makes this methodology an
alternative platform to the conventional acid/base catalyzed
thermal process but also brings it under the umbrella of environ-
mentally greener and safer synthetic procedures. Additional appli-
cations of this technique are currently under investigation.
15. Caliendo, G.; Perissutti, E.; Santagada, V.; Ferdinando, F.; Severino, B.;
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34. Typical procedure for the copper nanoparticles catalyzed 1,3-oxazin-3-ones
derivatives.
To a mixture of benzaldehyde (2 mmol), urea (3 mmol) and K2CO3 (0.3 mmol)
in PEG-400 (3 mL) copper-nanoparticles (15 nm; 0.001 g) were added, finely
mixed together and allowed to stir for 5 min at room temperature and then b-
naphthol (2 mmol) was added. The resulting reaction mixture was stirred at
room temperature for a specified period (Table 1). The progress of the reaction
was monitored by thin layer chromatography (TLC). After the completion of
the reaction, as indicated by TLC the reaction mixture was centrifuged
(5000 rpm, 7 min) to pellet out the copper nanoparticles. The particles were
then washed with absolute PEG to remove all the organic impurities. These
particles were reused for evaluating the performance in the next reaction. The
organic PEG layer containing reaction mixture was extracted with dry diethyl
ether as PEG is insoluble in ether. The ethereal layer was decanted, dried,
concentrated under reduced pressure and then the product so obtained was
recrystallized from hexane-EtOAc (3:1) to afford the pure product in >90%
yields (Table 1). The recovered PEG and copper nanoparticles were reused for
consecutive runs to evaluate the scope of recyclability of the reaction.
Structural assignments of the products are based on their 1H NMR, 13C NMR,
FT-IR and Mass analysis. The analysis of complete spectral and compositional
data revealed the formation of Naphthaoxazinone products with excellent
purity.
Acknowledgments
S.M. and A.K. acknowledge the financial support from the
Department of Science & Technology (DST) and Council of Scien-
tific Industrial Research (CSIR), Government of India, respectively.
Supplementary data
Supplementary data (procedural details of synthesis of copper
nanoparticles and its characterization data) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.07.016.
Characterization data of some important Compounds:
References and notes
1-Phenyl-1,2-dihydro-naphtho[1,2-e][1,3]oxazin-3-one (Table 1 entry;1)
White Powder, MP = 217–219 °C; IR (KBr)
m .
max: 3293, 1730, 1519 cmꢀ1 1H
1. Waxman, L.; Darke, P. L. Antiviral Chem. Chemother. 2000, 11, 1.
2. Kalluraya, B.; Sreenivasa, S. Farmaco 1998, 53, 399.
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Reider, P. J.; Labelle, M.; Gauthier, J. Y.; Xiang, Y. B.; Zamboni, R. J. J. Org. Chem.
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Falgueyret, J. P.; Friesen, R. W.; Girrard, M.; Girard, Y.; Guay, J.; Tagari, P.;
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Tominc, M.; Addicks, E.; Giannis, A.; Stegnar, M.; Dolenc, M. S. Eur. J. Med. Chem.
2005, 125.
NMR (300 MHz, DMSO-d6): d = 6.19 (d, J = 2.1 Hz, 1H, CH), 7.24–8.00 (m, 11H,
Ar–H), 8.83 (br s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): d = 54.20, 114.50,
117.32, 123.57, 125.54, 127.42, 127.81, 128.47,129.08, 129.32, 129.41, 130.68,
130.86, 143.34, 147.85, 149.77, Mass (M++H) = 275.041.
1-(4-Fluro-Phenyl)-1,2-dihydro-naphtho[1,2-e][1,3]oxazin-3-one (Table
1
entry; 6)
Light Brown, MP = 202–204 °C; IR (KBr) m .
max: 3233, 3149, 1731 cmꢀ1 1H NMR
(300 MHz, DMSO-d6): d = 6.22 (s, 1H, CH), 7.33–8.03 (m, 10H, Ar–H), 8.92(s,
1H, NH); 13C NMR (75 MHz, DMSO-d6): d = 53.47, 114.06, 117.31, 123.50,
125.62, 127.91, 128.06, 129.17, 129.29, 129.37, 129.41, 130.89, 133.05, 142.24,
147.90, 149.62; Mass (M++H) = 294.087.
1-(4-Chloro-Phenyl)-1,2-dihydro-naphtho[1,2-e][1,3]oxazin-3-one (Table 1
entry; 7)
White Powder, MP = 205–207 °C; IR (KBr)
m .
max: 3223, 3144, 1732 cmꢀ1 1H
NMR (300 MHz, DMSO-d6): d = 6.24 (s, 1H, CH), 7.31–8.01 (m, 10H, Ar–H), 8.91
(s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): d = 53.46, 114.05, 117.31, 123.50,
125.62, 127.92, 128.06, 129.13, 129.21, 129.37, 129.42, 130.89, 133.06, 142.25,
147.90, 149.64; Mass (M++H) = 311.057.
1-(4-Bromo-Phenyl)-1,2-dihydro-naphtho[1,2-e][1,3]oxazin-3-one (Table 1
entry; 8)
11. Kajino, N.; Shibouta, Y.; Nishikawa, K.; Meguro, K. Chem. Pharm. Bull. 1991, 11,
2896.
12. Gellibert, F. J.; Payne, A. Int. Patent Appl. WO 2003097639 A1, 2003.
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Nadrah, K.; Tominc, M.; Addicks, E.; Giannis, A.; Stegnar, M.; Dolenc, M. S. J.
Heterocycl. Chem. 2004, 4, 605.
Off White Powder, MP = 218–219 °C; IR (KBr) m .
max: 3223, 3144, 1732 cmꢀ1 1H
NMR (300 MHz, DMSO-d6): d = 6.21(s, 1H, CH), 7.31–8.01 (m, 10H, Ar–H), 8.94
(s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): d = 53.44, 113.01, 117.29,122.51,
125.67, 127.91, 128.06, 129.13, 129.20, 129.35, 129.41, 130.89, 133.06, 142.23,
147.91, 149.64; Mass (M++H)=355.055.