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

Abstract

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.

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Introduction

In recent times, concerns about environmental sustainability have emerged as a priority issue amongst the scientific community. These ever mounting concerns have thrown challenges 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 find sustainable reaction media. Notably, using water as a solvent offers a number of benefits to address these problems. Water is cheap, readily available, non-toxic and non-flammable, 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 process) comes into play, which is highly advantageous from a green chemistry perspective. In homogeneous catalysis, even 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 filtered 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 often 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 achieved 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 advantages of high efficiency, simplified 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 implemented with ortho-halo substituted anilides for the synthesis of yet another class of biologically important scaffolds, viz. 2-substituted benzoxazoles.

Results and discussion

To pursue the above objective, o-iodoacetanilide (1a) was selected as a model substrate for our investigation. Taking cues from our recent work,^6a when substrate 1a was treated with 2 equiv. K₂CO₃ in water (5 mL) at 100 °C, no product formation was observed even after 24 h, as the starting material remained unreacted. The use of Cs₂CO₃ (2 equiv.) in lieu of K₂CO₃ also failed to provide any of the desired products. A base mediated metal-free intramolecular C–S bond formation was recently achieved by our group^6a for thioamidic substrates possessing ortho iodo and bromo substituents, but for substrates with ortho chloro and fluoro substituents, the use of a metal catalyst (CuO nanoparticles) was essential.^6a As the base mediated C–O bond formation failed, we sought to use a metal catalyst which might facilitate the reaction. o-Iodoacetanilide (1a) was treated with CuO nanoparticles (2.5 mol%) in the presence of Cs₂CO₃ (2 equiv.) in an aqueous medium at 100 °C. Interestingly, total consumption of the starting material was observed, associated with the formation of two new products with lower R_f values than the starting substrate. Surprisingly, the major product obtained was found to be o-hydroxyacetanilide (1a′), obtained in 59% isolated yield, rather than the expected 2-substituted benzoxazole (1aa), while the minor product was found to be o-hydroxyaniline, which probably formed via the hydrolysis of o-hydroxyacetanilide (1a′). To the best of our knowledge, no such report on the copper-catalysed synthesis of o-hydroxyanilide from o-haloanilide is known in the literature. There is only a single report, in which o-hydroxybenzamides were prepared via a ligand assisted copper-catalysed (CuI) hydroxylation of o-halobenzamides in neat water.⁷ This methodology seems to have two disadvantages, firstly the use of an expensive ligand, and secondly the fact that the metal catalyst was not recovered. In the present case, when 1a was treated with CuI (5 mol%) in the presence of Cs₂CO₃ (2 equiv.) under ligand-free conditions, only 41% yield of 1a′ was obtained after 28 h. Replacing CuI with copper oxide nanoparticles was expected to provide an improvement over the present methodology in terms of catalyst recovery, short reaction time and high yield. Thus, continuing with the optimisation, a set of reactions were carried out in order to obtain the best possible yield. A careful time dependent study showed that the major product, o-hydroxyacetanilide (1a′), slowly hydrolyses to the corresponding o-hydroxyaniline. A further requirement was to improve the percentage yield of the hydroxylated product by reducing the hydrolysis of o-hydroxyacetanilide (1a′). To achieve this, a comparatively mild base such as K₂CO₃ was used instead of Cs₂CO₃, but the yield of 1a′ decreased to 53% (Table 1, entry 4) and the reaction took a longer time (7 h). It seems that the rate of hydrolysis of o-hydroxyacetanilide (1a′) to its corresponding o-hydroxyaniline is faster than the hydroxylation of o-iodoacetanilide (1a) under the present reaction conditions. Another mild inorganic base, Na₂CO₃ (Table 1, entry 5) was found to be ineffective for this transformation. Organic bases such as DABCO and Et₃N (Table 1, entries 6 and 7) were also found to be completely ineffective. 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 (1a′) from o-iodoacetanilide (1a).

Table 1 Optimisation of the reaction conditions for the formation of the ortho-hydroxylation product^a

Entry	Catalyst (mol%)	Base (equiv.)	Temp. (°C)	Time (h)	Yield of 1a′^b (%)
a Reactions were monitored by TLC.b Isolated yield.
1.	Nil	K2CO3 (2)	100	24	—
2.	Nil	Cs2CO3 (2)	100	24	—
3.	CuO (2.5)	Cs2CO3 (2)	100	4	59
4.	CuO (2.5)	K2CO3 (2)	100	7	53
5.	CuO (2.5)	Na2CO3 (2)	100	24	—
6.	CuO (2.5)	DABCO (2)	100	24	—
7.	CuO (2.5)	Et3N (2)	100	24	—
8.	CuO (5)	Cs2CO3 (2)	100	2	72

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With the above optimised conditions in hand, substrate 2a was chosen for the next study, which gave an inseparable mixture of the o-dehalogenated product (2a′′) and o-hydroxylated product (2a′) in a ratio of 1 : 2 (63%). Similarly, substrate 3a yielded an inseparable mixture of the o-hydroxylated product (3a′) and 3a′′ in a ratio of 1 : 1 (51%) under the optimised conditions. No trace of hydroxylated product was observed when substrate 4a was subjected to these reaction conditions. Only the o-dehalogenated product (4a′′) was isolated, along with recovery of the starting material. Such a copper-catalysed o-dehalogenation reaction was recently reported in the literature.^5f Interestingly, when N-(2-iodophenyl)benzamide (5a), where a phenyl moiety instead of a methyl group is attached to the carbonyl group of an amide, was treated under these reaction conditions, the reaction proceeded smoothly, giving the o-hydroxylated product (5a′) in 65% isolated yield after 4 h. The structure of the product (5a′) was confirmed by X-ray crystallographic analysis, as shown in Fig. 1. When N-(2-iodophenyl)-4-chlorobenzamide (6a) was treated under the optimised conditions, formation of the benzoxazole (6aa) (12%) was observed along with formation of the hydroxylated product (6a′) (58%). The formation of benzoxazole 6aa occurs via an intramolecular dehalogenative C–O bond formation starting from 6a, the strategy that we envisaged at the beginning. An identical result was observed when substrate 7a was treated under the optimised conditions, which again gave a mixture of the o-hydroxybenzamide (7a′) and benzoxazole (7aa). When the o-iodo group was replaced with an o-bromo group, as in the case of substrate 1b, the major product formed (57%) was again the o-hydroxylated acetanilide (1a′), but the reaction took a slightly longer time (5 h) compared to the corresponding o-iodo substrate (1a), as shown in Table 2. For an aromatic amide, when the o-iodo substituent was replaced with an o-bromo substituent, as in the case of N-(2-bromophenyl)benzamide (5b) under the present optimised conditions, the yield of benzoxazole (5aa) increased to 22%, though the hydroxylated product was still found to be the major product (5a′) (53%). Unfortunately, o-chloroacetanilide (1c) failed to react under the present optimised conditions, and the starting material was completely recovered.

Fig. 1 ORTEP view of N-(2-hydroxyphenyl)benzamide (5a′).

Table 2 CuO nano-catalysed syntheses of o-hydroxyanilides from o-haloanilides via intermolecular hydroxylations^a

Substrate	Product^b	Time (h)	Yield^c (%)
a Reactions were monitored by TLC.b Confirmed by IR and ^1H and ^13C NMR.c Isolated yield.
		2	72
		2	63
		7	51
		3	73
		4	65
		15
		10
	1a′	5	57
		22
	1a′	12	00

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The hydroxylation reaction seems to be assisted by the directing group, where the (–NHCOR/Ar) moiety serves as the directing group/ligand. As shown in Table 2, substrates 6a, 7a and 5b gave mixtures of the o-hydroxylated and benzoxazole products, thus the hydroxylation might proceed via the dehalogenative hydroxylation (C–O bond formation) of the o-halo groups or via a benzoxazole intermediate (6aa, 7aa and 5aa, respectively), which may open up to form the o-hydroxylated product by nucleophilic attack of water in the presence of base at 100 °C. To rule out the latter possibility, when the preformed benzoxazole (5aa) was treated under the present reaction conditions, no o-hydroxylated product (5a′) was observed. To confirm the involvement of the directing group (–NHCOR/Ar), when simple o-iodoaniline was treated, no hydroxylated product was obtained; these experiments confirmed the active role of the anilide/benzamide group in this hydroxylation process. Based on these observations, a plausible mechanism for the formation of o-hydroxylated anilides from the corresponding o-haloanilides is proposed in Scheme 1. In the presence of strong base and at high temperature, water molecules are dissociated into hydroxide ions. The interactions between the morphologically active CuO nanoparticles and anilide may lead to the formation of a Cu-cluster (A), which on oxidative addition to the C–X (X = Br, I) bond may give intermediate B (Scheme 1). The in situ generated hydroxide ion then coordinates to the intermediate complex (B), leading to the formation of another intermediate complex (C). Complex C then undergoes an intermolecular hydroxylation via the reductive elimination of CuO nanoparticles, which continues the catalytic cycle.^4a,e,6a Complex B may undergo dehalogenation, as shown in Scheme 1.^5f

Scheme 1 Plausible mechanism for the CuO nano-catalysed intermolecular hydroxylation and dehalogenation reactions.

Substrates 6a, 7a and 5b gave o-hydroxylated products, along with traces of benzoxazole, as shown in Table 2. If the hydroxylation (intermolecular C–O bond formation) path could be suppressed and intramolecular C–O bond formation could be facilitated by suitably altering the reaction parameters, the synthesis of important heterocyclic skeletons, viz. benzoxazoles, could be accomplished. Benzoxazoles are important heterocycles which are found in a number of biologically active natural products and medicinally significant compounds.⁸ The classical methods employed for the synthesis of the benzoxazole framework originate from o-aminophenols, but they are often 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 reactions^4a,10 and C–H activation of bisaryl oxime ethers^11a helped to overcome some of the drawbacks. A metal-free approach to the synthesis of benzoxazoles with K₂CO₃ in DMSO at 140 °C using o-bromo and o-iodo substrates was recently reported.^11b

Though these reactions are high yielding, the use of water as a solvent in organic synthesis is always welcome from an environmental point of view. In order to suppress the competitive hydroxylation in the above cases and to form exclusively benzoxazole, further optimisation was carried out using relatively inert N-(2-bromophenyl)benzamide (5b) as a model substrate, and the results are summarised in Table 3. The use of inorganic bases such as Cs₂CO₃ and K₂CO₃ was excluded, as they gave mixtures of hydroxylated and benzoxazole products, as shown in Table 1 (entries 3 and 4) and Table 3 (entry 2). We then switched to organic bases like Et₃N, diazabicyclooctadiene (DABCO), N,N′-dimethylethylenediamine (DMEDA), N,N,N′,N′-tetramethylethylenediamine (TMEDA), etc., and the results are summarised below (Table 3). Use of Et₃N (2 equiv.) was completely unsatisfactory for giving benzoxazole, but DABCO (2 equiv.) showed some improvement, giving 40% yield of benzoxazole (5aa) after 24 h, along with unreacted substrate 5b. Interestingly, using different 1,2-diamines resulted in a clear improvement in the yield of the benzoxazole product, as shown in Table 3. Use of the DMEDA (2 equiv.)/CuO system gave 72% yield of 5aa, while use of the TMEDA (2 equiv.)/CuO system improved the yield up to 80%, as shown in Table 3 (entries 5 and 6). Remarkably, when the TMEDA loading was increased to 3.5 equiv. from 2 equiv., a further improvement in the yield (90%) was observed within a shorter reaction time of 5 h. The presence of a phase transfer catalyst such as tetrabutylammonium bromide (TBAB, 20 mol%) helped overcome the solubility problem, and the yield improved up to 93%. It is imperative to mention here that the use of TMEDA completely suppresses the formation of the hydroxylated product. Thus, catalyst (nano CuO, 5 mol%), TMEDA (3.5 equiv.) and TBAB (20 mol%) in water (5 mL) at a temperature of 100 °C were chosen as the optimised conditions for the synthesis of benzoxazoles from o-halobenzanilides.

Table 3 Optimisation table for benzoxazole formation^a

Entry	Catalyst (mol%)	Base (equiv.)	Time (h)	(5a′)^b (%)	(5aa)^b (%)
a Reactions were monitored by TLC.b Isolated yield.c 20 mol% TBAB was used.
1.	Nil	Cs2CO3 (2)	24	0	0
2.	CuO (5)	Cs2CO3 (2)	22	53	22
3.	CuO (5)	Et3N (2)	24	0	0
4.	CuO (5)	DABCO (2)	24	0	40
5.	CuO (5)	DMEDA (2)	15	0	72
6.	CuO (5)	TMEDA (2)	10	0	80
7.	CuO (5)	TMEDA (3.5)	5	0	90
8.	CuO (5)	TMEDA (3.5)^c	4	0	93

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With the new optimised reaction conditions in hand, the scope of this transformation was then extended further toward the synthesis of various benzoxazole derivatives. As shown in 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 corresponding benzoxazoles (6aa–12aa), as shown in Table 4. Aryl moieties of benzanilide possessing electron donating substituents 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 benzoxazole formation to afford products 13aa–17aa and 18aa–22aa respectively in good to excellent yields within shorter reaction times. Substrates 23b and 24b, possessing both moderately activating –Me and weakly deactivating –Br substituents on the aromatic amines, also underwent intramolecular C–O bond formation, yielding the corresponding benzoxazoles 23aa and 24aa respectively in high yields. The structure of product 24aa was further confirmed by X-ray crystallographic analysis, as shown in Fig. 2. On the other hand, benzanilides possessing electron withdrawing substituents, such as p-COCH₃ (25b), p-Cl (26b), p-Br (27b) and p-CF₃ (28b) on the aromatic amine moiety, took longer times and yielded the corresponding benzoxazoles 25aa, 26aa, 27aa and 28aa respectively in modest yields, as shown in Table 4.

Table 4 CuO nano-catalysed syntheses of 2-aryl benzoxazoles from 2-bromo benzanilides^a

Substrate	Product^b	Time (h)	Yield^c (%)
a Reactions were monitored by TLC.b Confirmed by IR and ^1H and ^13C NMR.c Isolated yield.
		4	93
		2	75
		1.5	56
		3	64
		2	95
		14	78
		2	81
		2	89
		1	95
		5	84
		6	90
		1	64
		12	86
		1	85
		7	86
		1	80
		4	94
		11	71
		10	73
		13	86
		25	48
		18	54
		11	72
		32	50

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Fig. 2 ORTEP view of benzoxazole product 24aa.

After successfully synthesising benzoxazoles from various o-bromobenzanilides, we then sought to increase the substrate scope of this methodology, and o-chlorobenzanilides were chosen. Chloro and fluoro substrates are generally overlooked due to their inertness toward cross-coupling reactions. For Cu/Pd-catalysed intramolecular dehalogenative C–X (X = O, N and S) bond formation using o-halo ureas, guanidines and thioureas, the order of reactivity is I > Br > Cl.¹² Various o-chloroanilides (5c, 6c and 7c) reacted well under these CuO nanoparticle-catalysed conditions to give the respective benzoxazoles 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 (1a′) and o-dehalogenated (1a′′) products in an equimolar ratio. Similarly, substrates 2a and 4a, when treated under the present conditions, gave neither the expected benzoxazoles nor the o-hydroxylated products; the isolated products were found to be the o-dehalogenated products, 2a′′ and 4a′′ respectively.

Table 5 CuO nano-catalysed syntheses of o-arylbenzoxazoles from o-chloro and o-fluorobenzanilides^a

Substrate	Product^b	Time (h)	Yield^c (%)
a Reactions were monitored by TLC.b Confirmed by IR and ^1H and ^13C NMR.c Isolated yield.
		24	64
		28	71
		23	47
		49	52
		40	47
		39	51
		52	50
		47	54
		50	20

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Scheme 2 Products obtained from N-(o-iodophenyl)alkylamides.

Intramolecular C–S bond formation using o-fluoro substituted unsymmetrical thioureas and CuO nanoparticles was found to be quite effective.^6a But the above optimised conditions were found to be quite ineffective when o-fluorobenzanilide (5d) was chosen as the substrate, giving only 20% yield of the product (5aa) after 2 days. This is in contrast to our recent reports^6a,c, where C–S bond formation is much more facile than C–O bond formation in intramolecular dehalogenative cyclisation reactions. A plausible mechanism for the formation of benzoxazoles is outlined in Scheme 3. First, highly active CuO nanoparticles coordinate to o-halobenzanilides to form complex A, which may then undergo oxidative addition at the C–X bond of the o-halobenzanilide substrate, resulting in the formation of complex B. Deprotonation of the resulting complex B with TMEDA base generates intermediate complex C′. Ultimately, a reductive elimination provides the benzoxazole derivatives, with concomitant release of CuO nanoparticles.^4a,e,6a 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.

Scheme 3 Plausible mechanism for benzoxazole formation.

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 first cycle, 99.2% conversion (by GC) was observed after 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 after 6 h, while in the third round the yield dropped to 93.5% after 7.5 h. In the fourth and fifth rounds of catalyst recycling, the yields obtained were 90.4% and 89.4% respectively, after 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. After the third and fifth 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 after the third and fifth cycles suggests that the catalyst agglomerates during the recycling process, thereby reducing its efficiency in each run. This is quite significant after the third cycle; the catalyst starts degrading and a slight phase change was observed, however the main structure remains intact.

Fig. 3 TEM images of CuO nanoparticles: (a) fresh, (b) after third cycle, (c) after fifth cycle.

Fig. 4 Powder X-ray diffraction patterns of CuO nanoparticles: (a) fresh, (b) after third cycle, (c) after fifth cycle.

Conclusion

In conclusion, three distinct reaction paths have been observed when o-haloanilides are treated with CuO nanoparticles 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 nanoparticles in water at 100 °C in the presence of Cs₂CO₃ and in the absence of ligand. Interestingly, the presence of the ligand/base TMEDA changes the selectivity, giving exclusively 2-arylbenzoxazole. However, from the present study no clear preference in reactivity was observed when o-halophenylalkylamides were treated in the presence or absence of ligand. The use of an environmentally friendly solvent (water), base and a recyclable catalyst make this procedure a benign alternative to the existing methods for the syntheses of two interesting classes of molecules, viz. o-hydroxybenzamides and 2-arylbenzoxazoles.

(A) General procedure for the synthesis of N-(2-hydroxyphenyl)acetamide (1a′) from N-(2-iodophenyl)acetamide (1a) using copper oxide nano-catalyst

To a suspension of N-(2-iodophenyl)acetamide (1a) (1 mmol) in water (5 mL) was added CuO nanoparticles (5 mol%) and Cs₂CO₃ (2.0 mmol), and the reaction mixture was heated to 100 °C. After completion of the reaction (2 h) as determined by TLC, the crude reaction mixture was cooled to room temperature and extracted with ethyl acetate (3 × 10 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was then purified over a column of silica gel using petroleum ether–EtOAc (3 : 2) as eluent to give the pure product (1a′) in 72% yield (108 mg).

(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. After 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 purified by silica gel column chromatography eluting with 1 : 19 petroleum ether–EtOAc to give the pure product (5aa) in 93% yield (181 mg).

Acknowledgements

BKP acknowledges the support of this research by the Department of Science and Technology (DST) (SR/S1/OC-79/2009), New Delhi, and the Council of Scientific 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.

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Footnote

† 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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