Divergent reactivities of o-haloanilides with CuO nanoparticles in water: A green synthesis of benzoxazoles and o-hydroxyanilides

Article abstract of DOI:10.1039/c3ra46820h

In the present study, three divergent reaction paths emerged when o-haloanilides were subjected to CuO nanoparticles in water. o-Halo (I, Br) phenylbenzamides in the presence of CuO nanoparticles and Cs₂CO ₃ in water at 100 °C provided o-hydroxyphenyl benzamides as the major product. However, a complete change in selectivity was observed in the presence of an organic base/ligand (TMEDA), giving 2-arylbenzoxazole as the exclusive product. The above selectivities were not clearly distinct when the corresponding alkylamides were treated either in the presence or absence of the ligand. A number of o-halophenyl alkylamides provided either exclusively o-dehalogenated products or a mixture of o-dehalogenated and o-hydroxylated products, but none gave 2-alkylbenzoxazoles. In addition to the above selectivities, the use of an environmentally friendly solvent (water) and base, and the recyclability of the catalyst make this procedure a benign alternative to the existing methods for the synthesis of these molecules, viz. o-hydroxybenzamides and o-arylbenzoxazoles.

Full text of DOI:10.1039/c3ra46820h

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Divergent reactivities of o-haloanilides with CuO
nanoparticles in water: a green synthesis of
benzoxazoles and o-hydroxyanilides†
Cite this: RSC Adv., 2014, 4, 10770
*
Nilufa Khatun, Srimanta Guin, Saroj Kumar Rout and Bhisma K. Patel
In the present study, three divergent reaction paths emerged when o-haloanilides were subjected to CuO
nanoparticles in water. o-Halo (I, Br) phenylbenzamides in the presence of CuO nanoparticles and Cs2CO3
in water at 100 ꢀC provided o-hydroxyphenyl benzamides as the major product. However, a complete
change in selectivity was observed in the presence of an organic base/ligand (TMEDA), giving 2-
arylbenzoxazole as the exclusive product. The above selectivities were not clearly distinct when the
corresponding alkylamides were treated either in the presence or absence of the ligand. A number of o-
halophenyl alkylamides provided either exclusively o-dehalogenated products or a mixture of o-
dehalogenated and o-hydroxylated products, but none gave 2-alkylbenzoxazoles. In addition to the
above selectivities, the use of an environmentally friendly solvent (water) and base, and the recyclability
of the catalyst make this procedure a benign alternative to the existing methods for the synthesis of
these molecules, viz. o-hydroxybenzamides and o-arylbenzoxazoles.
Received 19th November 2013
Accepted 16th December 2013
DOI: 10.1039/c3ra46820h
www.rsc.org/advances
process) comes into play, which is highly advantageous from a
green chemistry perspective. In homogeneous catalysis, even
Introduction
though the metal catalysts used are in catalytic amounts relative
to the starting materials, they are usually non-recoverable at the
end, which is undesirable from an industrial point of view. The
use of nano-crystalline metal oxides as catalysts circumvents
these recoverability problems to an extent, as they usually
remain insoluble in reaction media and can then be easily
ltered out to be reused. In addition, these nanomaterials, in
particular copper salts, bearing high surface area and reactive
morphologies, are known to catalyse a variety of cross-coupling
reactions for the construction of C–N, C–O and C–S bonds via
dehalogenative paths.4,6a The inert C–F and C–Cl bonds are
oen overlooked for dehalogenative heteroarylation, however if
they could be made to react using an active copper oxide nano-
catalyst, a larger substrate scope could be achieved. It is worth
mentioning that in most cases the copper oxide nanoparticles
work under ligand-free conditions to provide the desired results.
However, in some cases an orthogonal selectivity has been ach-
ieved using salts of copper with the assistance of ligands.5
On the whole, a greener synthesis could be accomplished if a
CuO nanoparticle catalysed process could be carried out in an
aqueous medium. This procedure has the additional advan-
tages of high efficiency, simplied work-up and isolation
procedures, and catalyst recyclability. The above catalyst (CuO
nanoparticles) and solvent (water) combination has recently
been explored for the synthesis of 2-amino benzothiazoles via
C–S bond formation in ortho-halo substituted unsymmetrical
thioureas.6a Accordingly, it was envisaged that a similar strategy
involving an intramolecular C–O bond formation could be
In recent times, concerns about environmental sustainability
have emerged as a priority issue amongst the scientic
community. These ever mounting concerns have thrown chal-
lenges to researchers for the design and development of more
sustainable protocols, which in turn have pushed greener
syntheses to the fore. As per the guidelines for a greener
synthesis, the use of environmentally non-compatible organic
solvents should be avoided, to do away with detrimental effects
such as toxicity, hazards, pollution and waste treatment.
Subsequently, much effort is made to nd sustainable reaction
media. Notably, using water as a solvent offers a number of
benets to address these problems. Water is cheap, readily
available, non-toxic and non-ammable, properties which are
desirable from the environmental and economic perspectives of
synthetic processes. Other advantages over conventional
organic solvents include improved reactivities and selectivities
of certain substrates in aqueous media. In order to explore these
advantages, the number of water mediated reaction protocols
has increased.1–3 However, a reaction conducted in aqueous
media is not necessarily green if the waste generated by the use
of stoichiometric quantities of reagents is taken into account.
This is where the use of catalytic quantities of reagents (catalytic
Department of Chemistry, Indian Institute of Technology Guwahati, 781 039, Assam,
India. E-mail: patel@iitg.ernet.in; Fax: +91-3612690762
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra.
CCDC 919285 and 919286. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c3ra46820h
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implemented with ortho-halo substituted anilides for the transformation. Organic bases such as DABCO and Et3N (Table
synthesis of yet another class of biologically important scaf- 1, entries 6 and 7) were also found to be completely ineffective.
folds, viz. 2-substituted benzoxazoles.
An increase in the catalyst loading to 5 mol% and the use of the
base Cs2CO3 (2 equiv.) provided a superior yield of 72% within 2
h (Table 1, entry 8). Finally, this was chosen as the optimised
procedure for the o-hydroxylation of anilides (1a0) from o-
Results and discussion
To pursue the above objective, o-iodoacetanilide (1a) was iodoacetanilide (1a).
selected as a model substrate for our investigation. Taking cues
With the above optimised conditions in hand, substrate 2a
from our recent work,6a when substrꢀate 1a was treated with 2 was chosen for the next study, which gave an inseparable
equiv. K2CO3 in water (5 mL) at 100 C, no product formation mixture of the o-dehalogenated product (2a00) and o-hydroxyl-
was observed even aer 24 h, as the starting material remained ated product (2a0) in a ratio of 1 : 2 (63%). Similarly, substrate 3a
unreacted. The use of Cs2CO3 (2 equiv.) in lieu of K2CO3 also yielded an inseparable mixture of the o-hydroxylated product
failed to provide any of the desired products. A base mediated (3a0) and 3a00 in a ratio of 1 : 1 (51%) under the optimised
metal-free intramolecular C–S bond formation was recently conditions. No trace of hydroxylated product was observed
achieved by our group6a for thioamidic substrates possessing when substrate 4a was subjected to these reaction conditions.
ortho iodo and bromo substituents, but for substrates with ortho Only the o-dehalogenated product (4a00) was isolated, along with
chloro and uoro substituents, the use of a metal catalyst (CuO recovery of the starting material. Such a copper-catalysed o-
nanoparticles) was essential.6a As the base mediated C–O bond dehalogenation reaction was recently reported in the liter-
formation failed, we sought to use a metal catalyst which might ature.5f Interestingly, when N-(2-iodophenyl)benzamide (5a),
facilitate the reaction. o-Iodoacetanilide (1a) was treated with where a phenyl moiety instead of a methyl group is attached to
CuO nanoparticles (2.5 mol%) in the presence of Cs2CO3 (2 the carbonyl group of an amide, was treated under these reac-
equiv.) in an aqueous medium at 100 ꢀC. Interestingly, total tion conditions, the reaction proceeded smoothly, giving the o-
consumption of the starting material was observed, associated hydroxylated product (5a0) in 65% isolated yield aer 4 h. The
with the formation of two new products with lower Rf values structure of the product (5a0) was conrmed by X-ray crystallo-
than the starting substrate. Surprisingly, the major product graphic analysis, as shown in Fig. 1. When N-(2-iodophenyl)-
obtained was found to be o-hydroxyacetanilide (1a0), obtained in 4-chlorobenzamide (6a) was treated under the optimised
59% isolated yield, rather than the expected 2-substituted conditions, formation of the benzoxazole (6aa) (12%) was
benzoxazole (1aa), while the minor product was found to be o- observed along with formation of the hydroxylated product (6a0)
hydroxyaniline, which probably formed via the hydrolysis of o- (58%). The formation of benzoxazole 6aa occurs via an intra-
hydroxyacetanilide (1a0). To the best of our knowledge, no such molecular dehalogenative C–O bond formation starting from 6a,
report on the copper-catalysed synthesis of o-hydroxyanilide the strategy that we envisaged at the beginning. An identical
from o-haloanilide is known in the literature. There is only a result was observed when substrate 7a was treated under the
single report, in which o-hydroxybenzamides were prepared via optimised conditions, which again gave a mixture of the o-
a ligand assisted copper-catalysed (CuI) hydroxylation of o-hal- hydroxybenzamide (7a0) and benzoxazole (7aa). When the o-iodo
obenzamides in neat water.7 This methodology seems to have group was replaced with an o-bromo group, as in the case of
two disadvantages, rstly the use of an expensive ligand, and substrate 1b, the major product formed (57%) was again the o-
secondly the fact that the metal catalyst was not recovered. In hydroxylated acetanilide (1a0), but the reaction took a slightly
the present case, when 1a was treated with CuI (5 mol%) in the longer time (5 h) compared to the corresponding o-iodo substrate
presence of Cs2CO3 (2 equiv.) under ligand-free conditions, only (1a), as shown in Table 2. For an aromatic amide, when the o-iodo
41% yield of 1a0 was obtained aer 28 h. Replacing CuI with substituent was replaced with an o-bromo substituent, as in the
copper oxide nanoparticles was expected to provide an case of N-(2-bromophenyl)benzamide (5b) under the present
improvement over the present methodology in terms of catalyst optimised conditions, the yield of benzoxazole (5aa) increased to
recovery, short reaction time and high yield. Thus, continuing 22%, though the hydroxylated product was still found to be the
with the optimisation, a set of reactions were carried out in major product (5a0) (53%). Unfortunately, o-chloroacetanilide (1c)
order to obtain the best possible yield. A careful time dependent failed to react under the present optimised conditions, and the
study showed that the major product, o-hydroxyacetanilide starting material was completely recovered.
(1a0), slowly hydrolyses to the corresponding o-hydroxyaniline. A
The hydroxylation reaction seems to be assisted by the
further requirement was to improve the percentage yield of the directing group, where the (–NHCOR/Ar) moiety serves as the
hydroxylated product by reducing the hydrolysis of o-hydrox- directing group/ligand. As shown in Table 2, substrates 6a, 7a
yacetanilide (1a0). To achieve this, a comparatively mild base and 5b gave mixtures of the o-hydroxylated and benzoxazole
such as K2CO3 was used instead of Cs2CO3, but the yield of 1a0 products, thus the hydroxylation might proceed via the deha-
decreased to 53% (Table 1, entry 4) and the reaction took a logenative hydroxylation (C–O bond formation) of the o-halo
longer time (7 h). It seems that the rate of hydrolysis of o- groups or via a benzoxazole intermediate (6aa, 7aa and 5aa,
hydroxyacetanilide (1a0) to its corresponding o-hydroxyaniline is respectively), which may open up to form the o-hydroxylated
faster than the hydroxylation of o-iodoacetanilide (1a) under the product by nucleophilic attack of water in the presence of base
present reaction conditions. Another mild inorganic base, at 100 ꢀC. To rule out the latter possibility, when the preformed
Na2CO3 (Table 1, entry 5) was found to be ineffective for this benzoxazole (5aa) was treated under the present reaction
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Table 1 Optimisation of the reaction conditions for the formation of the ortho-hydroxylation producta
Entry
Catalyst (mol%)
Base (equiv.)
Temp. (ꢀC)
Time (h)
Yield of 1a0b (%)
1.
2.
3.
4.
5.
6.
7.
8.
Nil
Nil
K2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
K2CO3 (2)
Na2CO3 (2)
DABCO (2)
Et3N (2)
100
100
100
100
100
100
100
100
24
24
4
—
—
59
53
—
—
—
72
CuO (2.5)
CuO (2.5)
CuO (2.5)
CuO (2.5)
CuO (2.5)
CuO (5)
7
24
24
24
2
Cs2CO3 (2)
a
b
Reactions were monitored by TLC. Isolated yield.
natural products and medicinally signicant compounds.8 The
classical methods employed for the synthesis of the benzox-
azole framework originate from o-aminophenols, but they are
oen limited by unavailability of suitably substituted starting
materials. Sometimes, the requirement of harsh reaction
conditions, such as use of strong acids, elevated temperatures
and toxic solvents, makes them unsuitable from a green
chemistry perspective.9 Recently, the use of cross-coupling
reactions4a,10 and C–H activation of bisaryl oxime ethers11a hel-
ped to overcome some of the drawbacks. A metal-free approach
Fig. 1 ORTEP view of N-(2-hydroxyphenyl)benzamide (5a0).
conditions, no o-hydroxylated product (5a0) was observed. To to the synthesis of benzoxazoles with K2CO3 in DMSO at 140 ꢀC
conrm the involvement of the directing group (–NHCOR/Ar), using o-bromo and o-iodo substrates was recently reported.11b
when simple o-iodoaniline was treated, no hydroxylated
Though these reactions are high yielding, the use of water as
product was obtained; these experiments conrmed the active a solvent in organic synthesis is always welcome from an envi-
role of the anilide/benzamide group in this hydroxylation ronmental point of view. In order to suppress the competitive
process. Based on these observations, a plausible mechanism for hydroxylation in the above cases and to form exclusively ben-
the formation of o-hydroxylated anilides from the corresponding zoxazole, further optimisation was carried out using relatively
o-haloanilides is proposed in Scheme 1. In the presence of strong inert N-(2-bromophenyl)benzamide (5b) as a model substrate,
base and at high temperature, water molecules are dissociated and the results are summarised in Table 3. The use of inorganic
into hydroxide ions. The interactions between the morphologi- bases such as Cs2CO3 and K2CO3 was excluded, as they gave
cally active CuO nanoparticles and anilide may lead to the mixtures of hydroxylated and benzoxazole products, as shown
formation of a Cu-cluster (A), which on oxidative addition to the in Table 1 (entries 3 and 4) and Table 3 (entry 2). We then
C–X (X ¼ Br, I) bond may give intermediate B (Scheme 1). The in switched to organic bases like Et3N, diazabicyclooctadiene
situ generated hydroxide ion then coordinates to the interme- (DABCO), N,N0-dimethylethylenediamine (DMEDA), N,N,N0,N0-
diate complex (B), leading to the formation of another interme- tetramethylethylenediamine (TMEDA), etc., and the results are
diate complex (C). Complex C then undergoes an intermolecular summarised below (Table 3). Use of Et3N (2 equiv.) was
hydroxylation via the reductive elimination of CuO nanoparticles, completely unsatisfactory for giving benzoxazole, but DABCO (2
which continues the catalytic cycle.4a,e,6a Complex B may undergo equiv.) showed some improvement, giving 40% yield of ben-
dehalogenation, as shown in Scheme 1.5f
zoxazole (5aa) aer 24 h, along with unreacted substrate 5b.
Substrates 6a, 7a and 5b gave o-hydroxylated products, along Interestingly, using different 1,2-diamines resulted in a clear
with traces of benzoxazole, as shown in Table 2. If the hydrox- improvement in the yield of the benzoxazole product, as shown
ylation (intermolecular C–O bond formation) path could be in Table 3. Use of the DMEDA (2 equiv.)/CuO system gave 72%
suppressed and intramolecular C–O bond formation could be yield of 5aa, while use of the TMEDA (2 equiv.)/CuO system
facilitated by suitably altering the reaction parameters, improved the yield up to 80%, as shown in Table 3 (entries 5 and
the synthesis of important heterocyclic skeletons, viz. benzox- 6). Remarkably, when the TMEDA loading was increased to 3.5
azoles, could be accomplished. Benzoxazoles are important equiv. from 2 equiv., a further improvement in the yield (90%)
heterocycles which are found in a number of biologically active was observed within a shorter reaction time of 5 h. The presence
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Table 2 CuO nano-catalysed syntheses of o-hydroxyanilides from o-haloanilides via intermolecular hydroxylationsa
Substrate
Productb
Time (h)
2
Yieldc (%)
72
2
7
63
51
3
4
73
65
15
10
5
1a0
57
22
1a0
12
00
a
b
Reactions were monitored by TLC. Conrmed by IR and 1H and 13C NMR. c Isolated yield.
of a phase transfer catalyst such as tetrabutylammonium water (5 mL) at a temperature of 100 ꢀC were chosen as the
bromide (TBAB, 20 mol%) helped overcome the solubility optimised conditions for the synthesis of benzoxazoles from o-
problem, and the yield improved up to 93%. It is imperative to halobenzanilides.
mention here that the use of TMEDA completely suppresses the
With the new optimised reaction conditions in hand, the
formation of the hydroxylated product. Thus, catalyst (nano scope of this transformation was then extended further toward
CuO, 5 mol%), TMEDA (3.5 equiv.) and TBAB (20 mol%) in the synthesis of various benzoxazole derivatives. As shown in
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Table 4 CuO nano-catalysed syntheses of 2-aryl benzoxazoles from
2-bromo benzanilidesa
Substrate
Productb
Time (h) Yieldc (%)
4
2
93
75
1.5
3
56
Scheme 1 Plausible mechanism for the CuO nano-catalysed inter-
molecular hydroxylation and dehalogenation reactions.
64
95
78
81
89
95
84
Table 3 Optimisation table for benzoxazole formationa
2
14
Catalyst
Entry (mol%)
Base (equiv.)
Time (h) (5a0)b (%) (5aa)b (%)
2
2
1
5
1.
2.
3.
4.
5.
6.
7.
8.
Nil
Cs2CO3 (2)
Cs2CO3 (2)
Et3N (2)
DABCO (2)
DMEDA (2)
TMEDA (2)
TMEDA (3.5)
TMEDA (3.5)c
24
22
24
24
15
10
5
0
53
0
0
0
0
0
0
0
22
0
40
72
80
90
93
CuO (5)
CuO (5)
CuO (5)
CuO (5)
CuO (5)
CuO (5)
CuO (5)
4
a
b
c
Reactions were monitored by TLC. Isolated yield. 20 mol% TBAB
was used.
Table 4, this method could be applied to a broad range of
substrates. The proposed methodology worked well for a wide
variety of substrates containing various substituents on either
of the aryl moieties of the anilides. First, benzanilides derived
from o-bromoaniline and various aromatic acid chlorides were
subjected to these optimised reaction conditions. Substrates
6b–12b underwent intramolecular C–O bond formation
smoothly to provide good to excellent yields of the corre-
sponding benzoxazoles (6aa–12aa), as shown in Table 4. Aryl
moieties of benzanilide possessing electron donating substitu-
ents such as p-OMe (7b), p-Et (8b), p-Me (9b) and p-SMe (10b),
and electron withdrawing substituents such as p-Cl (6b), p-CF3
(11b) and p-F(12b) reacted efficiently, giving good yields of the
respective benzoxazoles. The effects of substituents on the o-
bromo aniline moiety of benzanilides were also examined. The
presence of moderately activating substituents such as –Me
(13b–17b) and activating –OMe (18b–22b) resulted in prompt
6
1
90
64
12
1
86
85
86
7
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Table 4 (Contd.)
Substrate
Productb
Time (h) Yieldc (%)
Fig. 2 ORTEP view of benzoxazole product 24aa.
1
4
80
94
71
73
86
48
54
72
scope of this methodology, and o-chlorobenzanilides were
chosen. Chloro and uoro substrates are generally overlooked
due to their inertness toward cross-coupling reactions. For Cu/
Pd-catalysed intramolecular dehalogenative C–X (X ¼ O, N and
S) bond formation using o-halo ureas, guanidines and thio-
ureas, the order of reactivity is I > Br > Cl.12 Various o-chlor-
oanilides (5c, 6c and 7c) reacted well under these CuO
nanoparticle-catalysed conditions to give the respective ben-
zoxazoles 5aa, 6aa and 7aa in good to moderate yields, as
shown in Table 5, though the reactions took longer times. This
slow reaction rate is perhaps due to the high bond energy of C–
Cl bonds compared to C–Br bonds. The electronic effects of
the substituents present on the o-chloroanilines of the o-
chlorobenzanilides were further examined. It seems that the
presence of electron withdrawing substituents on the o-
chloroaniline moiety of benzanilide (8c, 9c, 10c, 11c and 12c)
retards the reaction, giving lower yields of the corresponding
products (26aa, 29aa, 27aa, 30aa and 31aa), as shown in
Table 5. Unfortunately, when N-(o-iodophenyl)alkylamides,
such as 1a, 2a and 4a, were treated under the present
conditions, the reactions failed to yield intramolecularly
cyclised 2-alkyl benzoxazoles, as shown in Scheme 2. Substrate
1a gave an inseparable mixture (57%) of the 2-hydroxylated
(1a0) and o-dehalogenated (1a00) products in an equimolar
ratio. Similarly, substrates 2a and 4a, when treated under
the present conditions, gave neither the expected benzox-
azoles nor the o-hydroxylated products; the isolated products
were found to be the o-dehalogenated products, 2a00 and 4a00
respectively.
11
10
13
25
18
11
32
50
Reactions were monitored by TLC. b Conrmed by IR and 1H and 13
C
a
NMR. c Isolated yield.
Intramolecular C–S bond formation using o-uoro
benzoxazole formation to afford products 13aa–17aa and 18aa– substituted unsymmetrical thioureas and CuO nanoparticles
22aa respectively in good to excellent yields within shorter was found to be quite effective.6a But the above optimised
reaction times. Substrates 23b and 24b, possessing both conditions were found to be quite ineffective when o-uo-
moderately activating –Me and weakly deactivating –Br robenzanilide (5d) was chosen as the substrate, giving only 20%
substituents on the aromatic amines, also underwent intra- yield of the product (5aa) aer 2 days. This is in contrast to our
molecular C–O bond formation, yielding the corresponding recent reports6a,c, where C–S bond formation is much more
benzoxazoles 23aa and 24aa respectively in high yields. The facile than C–O bond formation in intramolecular dehaloge-
structure of product 24aa was further conrmed by X-ray crys- native cyclisation reactions. A plausible mechanism for the
tallographic analysis, as shown in Fig. 2. On the other hand, formation of benzoxazoles is outlined in Scheme 3. First, highly
benzanilides possessing electron withdrawing substituents, active CuO nanoparticles coordinate to o-halobenzanilides to
such as p-COCH3 (25b), p-Cl (26b), p-Br (27b) and p-CF3 (28b) on form complex A, which may then undergo oxidative addition at
the aromatic amine moiety, took longer times and yielded the the C–X bond of the o-halobenzanilide substrate, resulting in
corresponding benzoxazoles 25aa, 26aa, 27aa and 28aa respec- the formation of complex B. Deprotonation of the resulting
tively in modest yields, as shown in Table 4.
complex B with TMEDA base generates intermediate complex
Aer successfully synthesising benzoxazoles from various o- C0. Ultimately, a reductive elimination provides the benzoxazole
bromobenzanilides, we then sought to increase the substrate derivatives, with concomitant release of CuO nanoparticles.4a,e,6a
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Table 5 CuO nano-catalysed syntheses of o-arylbenzoxazoles from
o-chloro and o-fluorobenzanilidesa
Substrate
Productb
Time (h) Yieldc (%)
24
28
64
71
Scheme 3 Plausible mechanism for benzoxazole formation.
23
49
40
39
52
47
47
52
47
51
50
54
The 1,2-diamine (TMEDA) may play a double role of ligand13
and base. The cleavage of the C–X bond, i.e. the oxidative
addition step, is probably the rate determining step, as the
halide reactivity follows the order of Br > Cl > F.
The efficiency of the recovered catalyst was assessed through
a series of reactions where N-(2-bromophenyl)benzamide (5b)
was used as the starting material. In the rst cycle, 99.2%
conversion (by GC) was observed aer 4 h under the optimised
conditions. The product was then extracted with ethyl acetate,
and the aqueous layer containing the suspended CuO nano-
catalyst was then subjected to the next run. In the second run,
98.7% conversion was observed aer 6 h, while in the third
round the yield dropped to 93.5% aer 7.5 h. In the fourth and
h rounds of catalyst recycling, the yields obtained were 90.4%
and 89.4% respectively, aer time lapses of 9 h and 11 h
respectively. To maintain the basicity of the medium, in each
run 2.5 additional equiv. of TMEDA was added to the reaction
mixture. Without the addition of extra TMEDA, the reactions
became sluggish, and lower conversion was observed. Aer the
third and h cycles, the morphology of the water-dispersed
CuO nanoparticles was determined by TEM and powder XRD
(Fig. 3 and 4). The aqueous layer containing the dispersed
catalyst was centrifuged, washed with water, dried and then
taken for further characterisation. A comparative study of the
TEM and powder XRD of the fresh catalyst and the recovered
catalyst aer the third and h cycles suggests that the cata-
lyst agglomerates during the recycling process, thereby
reducing its efficiency in each run. This is quite signicant
aer the third cycle; the catalyst starts degrading and a slight
50
20
Reactions were monitored by TLC. b Conrmed by IR and 1H and 13
C
a
NMR. c Isolated yield.
Fig. 3 TEM images of CuO nanoparticles: (a) fresh, (b) after third cycle,
(c) after fifth cycle.
Scheme 2 Products obtained from N-(o-iodophenyl)alkylamides.
10776 | RSC Adv., 2014, 4, 10770–10778
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(B) General procedure for the synthesis of 2-
phenylbenzoxazole (5aa) from N-(2-bromophenyl)benzamide
(5b) using copper oxide nano-catalyst
To a suspension of N-(2-bromophenyl)benzamide (5b) (1 mmol)
in water (5 mL) was added CuO nanoparticles (5 mol%), TMEDA
(3.5 equiv.) and tetrabutylammonium bromide (TBAB, 20 mol
%), and the reaction mixture was heated to 100 ꢀC. The progress
of the reaction was monitored by TLC. Aer 4 h, total conversion
was observed as indicated by TLC, and the reaction mixture was
cooled down to room temperature and extracted with ethyl
acetate (3 ꢁ 10 mL). The combined organic layer was then dried
over anhydrous Na2SO4, and the ethyl acetate was removed
under reduced pressure. The crude product was then puried
by silica gel column chromatography eluting with 1 : 19 petro-
leum ether–EtOAc to give the pure product (5aa) in 93% yield
(181 mg).
Fig. 4 Powder X-ray diffraction patterns of CuO nanoparticles: (a)
fresh, (b) after third cycle, (c) after fifth cycle.
Acknowledgements
phase change was observed, however the main structure
remains intact.
BKP acknowledges the support of this research by the Depart-
ment of Science and Technology (DST) (SR/S1/OC-79/2009), New
Delhi, and the Council of Scientic and Industrial Research
(CSIR) (02(0096)/12/EMR-II). NK, SG and SKR thank CSIR for
fellowships. Thanks are due to the Central Instruments Facility
(CIF) IIT Guwahati for the NMR spectra and DST-FIST for the
XRD facilities.
Conclusion
In conclusion, three distinct reaction paths have been
observed when o-haloanilides are treated with CuO nano-
particles in water at 100 ꢀC. From this study, it has clearly
emerged that o-halo (I, Br) phenylbenzamides furnishe o-
hydroxyphenylbenzamides as the major products, along with
traces of 2-arylbenzoxazoles when treated with CuO nano-
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