PhIO promoted synthesis of nitrile imines and nitrile oxides within a micellar core in aqueous media: a regiocontrolled approach to synthesizing densely functionalized pyrazole and isoxazoline derivatives

Abstract

A highly efficient and general protocol has been developed for the facile synthesis of highly diversified 1,3,5-trisubstituted pyrazoles and 3,5-disubstituted 2-isoxazolines through one-pot tandem intermolecular, as well as intramolecular, dipolar [3 + 2] cycloaddition reactions. Chemoselective oxidation of aldohydrazone to nitrile imine and aldoximes to nitrile oxides by iodosobenzene in neutral aqueous media was performed. The scope of the reactions in regiocontrolled dipolar cycloaddition with olefins in the presence of PhIO toward highly substituted pyrazole and isoxazoline derivatives has been demonstrated. SDS converted the initially floating reaction mass and the organo-oxidant PhIO into a homogeneous mixture, which on stirring became a turbid emulsion. The micellar arrangement was confirmed by dynamic light scattering and optical microscopy. The new, green and metal free synthetic method enabled the execution of regiocontrolled tandem cycloaddition oxidation sequences leading to a library of pyrazole and isoxazoline derivatives.

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Introduction

Among various popular synthetic strategies in organic chemistry, undoubtedly, the versatility of cycloaddition reactions has been exploited successfully in the targeted synthesis of pyrazoles, through dipolar [3 + 2] cycloaddition between a CN₂ (nitrile imine) and a C₂ (olefin) moiety; and likewise a 1,3-dipolar cycloaddition of nitrile oxides to C–C unsaturated bonds has been well recognized for the synthesis of isoxazolines. The introduction of new oxidants and new dipolarophiles have led to notable advances in the 1,3-dipolar cycloaddition.¹ To the best of our knowledge, only a few references exist concerning the synthesis of pyrazoles and isoxasolines via 1,3-dipolar cycloaddition. However, each method has its own scope, efficiency and limitations. Some of them suffer from certain drawbacks such as the use of hazardous organic solvents,² air-sensitive costly metal catalysts,³ the use of stoichiometric and even excess amounts of strong acids⁴ and lower yields⁵ of the desired products. The major limitation in the case of isoxazoline synthesis is the propensity of nitrile oxides to undergo rapid dimerization to furoxan N-oxide.⁶ However, this problem can be circumvented by generating the nitrile oxide species in situ in the presence of a multifold excess of the olefinic trap.

Iodosylarenes and their derivatives are generally strong oxidizing agents, and have found broad applications in organic synthesis as reagents for oxygenation and oxidative functionalization of organic substrates.⁷ The surging interest in iodine compounds, combined with their benign environmental character and commercial availability, encouraged our group to investigate a polyvalent iodine compound PhIO for use in the aforesaid dipolar cycloaddition reactions. The nitrile imine cycloaddition reactions are generally performed with unstable chloro- and bromoaldohydrazone precursors at higher temperatures in the presence of a base.⁸ In this paper, we wish to disclose the excellent oxidizing properties of iodosobenzene, as it has transformed aldohydrazone to nitrile imine and aldoximes to corresponding nitrile oxides in aqueous media at room temperature.

The temptation to exploit the virtues of eco-friendly reaction protocols was compelling, which led us to apply aqueous media for the cycloaddition reaction. The use of water reduces the use of harmful organic solvents and it is regarded as an important research topic in green chemistry.⁹ In addition, water has unique physical and chemical properties, and by utilizing these it would be possible to tune the reactivity or selectivity, which cannot be attained with organic solvents.¹⁰ However, organic reactions in water are often limited in scope due to the poor solubility of the organic compounds. This problem may be overcome by using surfactants to form colloidal dispersions with the organic compounds in water.

Herein, we report the application of PhIO in the presence of sodium dodecyl sulfate as the active surfactant for the intermolecular, as well as intramolecular, [3 + 2]-cycloadditions of 1,3-dipoles to dipolarophiles, leading to the formation of 1,3,5-trisubstituted pyrazoles in an aqueous environment for the first time. Furthermore, this optimized protocol was also extended to the synthesis of a set of 3,5-disubstituted 2-isoxazolines.

Results and discussion

In Scheme 1, we have depicted the basic features of our strategy directed toward the synthesis of 1,3,5-trisubstituted pyrazoles within the context of a research program devoted to the design and synthesis of novel heterocyclic systems,¹¹using unconventional solvent based multicomponent reactions.

Scheme 1 Synthesis of functionalized pyrazoles.

At the outset of this work, we examined the one-pot tandem cycloaddition reaction with 3-nitrobenzaldehyde (1), phenyl hydrazine (2) and methyl acrylate (3) as the model substrates (Scheme 1), in the presence of a wide spectrum of commercially available oxidants like CAN, CeCl₃, chloramine-T, PhI(OAc)₂, PhIO and metal Lewis acid catalysts in ethanol, at room temperature.

The initial investigation into the generation of the nitrile imine dipolar complex (I, Scheme 1) focused on the application of oxidants (Table 1, entries 1–5) and metal Lewis acid catalysts (Table 1, entries 6 and 7) to the one-pot tandem cycloaddition reaction with 3-nitrobenzaldehyde (1), phenyl hydrazine (2) and methyl acrylate (3) in ethanol medium. However, it was in vain. Gratifyingly, attempts with the organic oxidant iodosobenzene (PhIO) generated the dipolar complex (I, Scheme 1), and the expected pyrazole derivative was obtained. Ethanol was taken as the primary choice of the solvent as in this solvent all the reactants remained as a homogeneous mixture. One important facet of green chemistry is the eradication of solvents in chemical processes or the replacement of hazardous solvents with relatively benign solvents. Development of environmentally benign and economical syntheses is an area of research that is being vigorously pursued, by avoiding the use of harmful organic solvents. Hence, we have tried to synthesize the heterocyclic scaffold in aqueous media, applying a suitable surfactant/PhIO combination to enhance the rate of the reaction.

Table 1 Evaluation of the optimum reaction conditions for pyrazole formation^a

Entry	Additives	Reaction conditions	Time (h)	Yield^b (%)
a Reaction conditions: 3-nitrobenzaldehyde (1 mmol), phenyl hydrazine (1 mmol), methyl acrylate (1 mmol), 5 ml solvent, rt.b Isolated yields of pure products.
1	CAN, 1.0 equiv.	EtOH	24	0
2	CeCl3, 1.0 equiv.	EtOH	24	0
3	Oxone, 1.0 equiv.	EtOH	24	0
4	Chloramine-T, 1.0 equiv.	EtOH	24	0
5	PhI(OAc)2, 1.0 equiv.	EtOH	24	0
6	Ni(OAc)2	EtOH	24	0
7	Cu(OTf)2, (10 mol %)	EtOH	24	0
8	PhIO, 1.0 equiv.	EtOH	8	28
9	PhIO, 1.0 equiv.	H2O	8	36
10	PhIO, 1.0 equiv.	Triton X-100 (10 mol%), H2O	7	41
11	PhIO, 1.0 equiv.	CTAB (10 mol%), H2O	7.5	43
12	PhIO, 1.5 equiv.	SDS (10 mol%), H2O	5	60
13	PhIO, 2.0 equiv.	SDS (10 mol%), H2O	5	89
14	PhIO, 2.5 equiv.	SDS (10 mol%), H2O	5	89

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We have studied the influence of three commercially available surfactants, CTAB (cationic), SDS (anionic), and Triton X-100 (neutral), in search of suitable conditions in which to synthesize the heterocyclic scaffold in aqueous media. PhIO/SDS combinations outperformed all other oxidants and metal Lewis acid catalysts, in order to deliver the targeted scaffold at room temperature. It is pertinent to mention that the addition of surfactants converted the initially floating reaction mass into a homogeneous mixture, which on stirring became a turbid emulsion. The formation of a micellar system by using SDS enhanced the solubility and thereby the reactivity of PhIO. This observation implies that there was formation of micelles or colloidal aggregates. The average sizes of the colloidal particles formed from SDS and the reaction mixture in water were measured by dynamic light scattering (DLS), and the shape of the colloidal aggregates was nearly spherical with around 200 nm in diameter (Fig. 1b). Formation of emulsion droplets in the present reaction system was also confirmed by optical microscopy (Fig. 1a).

Fig. 1 (a) Optical microscopic image showing micellar aggregates in the reaction media and (b) DLS study of the reaction media showing the formation of aggregates.

To find the optimized amount of PhIO, the reaction was carried out by varying the amount of PhIO on the model reaction (Table 1). The conversion of pyrazole derivative increased linearly up to 2.0 equivalent of PhIO and became almost steady when the amount was further increased beyond this. Therefore 2.0 equivalents PhIO is sufficient to promote the reaction, leading to the expected heterocycles in excellent yields.

Having identified these optimal conditions, we set out to explore the scope for this new reaction, and the results are summarized in Table 2. All reactions were performed under the developed reaction conditions without individual optimization. At the R₁ position, various electron-donating and electron-withdrawing groups on the aryl ring were compatible with the reaction conditions. Aliphatic and acid/base-sensitive heterocycles such as 2-thienyl and 2-furyl groups were also compatible with the mild [3 + 2] cycloaddition–oxidation reaction conditions (products 4e–g, 4n). Moreover, the one-pot tandem cycloaddition reaction was well established with a set of activated, as well as unactivated, dipolarophiles and excellent yields of the desired products.

Table 2 Substrate scope for pyrazole synthesis^a

a Reaction conditions: aldehyde (1 mmol), phenyl hydrazine (1 mmol), olefin (1 mmol), PhIO (2.0 mmol), SDS (10 mol%), 5 ml H2O, at room temperature for stipulated time.
4a, 85%, 6.5 h	4b, 88%, 6 h	4c, 91%, 5 h	4d, 89%, 5 h
4e, 87%, 5 h	4f, 86%, 5 h	4g, 91%, 4.5 h	4h, 92%, 8 h
4i, 81%, 8.5 h	4j, 86%, 8 h	4k, 87%, 8 h	4l, 85%, 6 h
4m, 81%, 7 h	4n, 84%, 6.5 h	4o, 83%, 8.5 h

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Under the optimized reaction conditions, we also explored the synthesis of pyrazole derivatives, installing nitroolefin as the dipolarophile. This pyrazole formation reaction was quite general with respect to hydrazine and aldehydes with a variety of substituents, and the yields ranged from moderate to good. At the R₁ position, both alkyl and aryl groups were well tolerated, providing multifunctionalized pyrazole derivatives (Table 3).

Table 3 Pyrazole synthesis^a from nitroolefin

a Reaction conditions: aldehyde (1 mmol), phenyl hydrazine (1 mmol), β-nitrostyrene (1 mmol), 3 (1 mmol), PhIO (2.0 mmol), SDS (10 mol%), 5 ml H2O, at room temperature for stipulated time.
5a, 94%, 7 h	5b, 81%, 7 h	5c, 82%, 6.5 h	5d, 82%, 8 h

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We have extended this green approach to the synthesis of various 3,5-disubstituted 2-isoxazolines (Table 4). Aryl, heteroaryl or alkyl groups at the R₁ position afforded corresponding isoxazolines in excellent yields. In terms of R₁ substituents, the meta-, and para-substituted aryl groups, and the electron-rich and electron-deficient aryl groups were also highly compatible, while the various activated, as well as unactivated, dipolarophiles easily provided good to excellent yields of the corresponding isoxazolines.

Table 4 Substrate scope for isoxazoline synthesis^a

a Reaction conditions: aldehyde (1 mmol), hydroxy amine hydrochloride (1 mmol), sodium acetate (1 mmol), olefin (1 mmol), PhIO (1.0 mmol), SDS (10 mol%), 5 ml H2O, at room temperature for stipulated time.
6a, 92%, 2.5 h	6b, 89%, 2.5 h	6c, 84%, 3 h	6d, 85%,3.5 h
6e, 90%, 3 h	6f, 90%, 3 h	6g, 91%, 2.5 h	6h, 92%, 2.5 h
6i, 81%, 3 h

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Finally, the intramolecular cycloaddition oxidation reactions were also successful under the particular experimental conditions and afforded the corresponding biologically active chroman fused pyrazole, dihydro-isoxazole and an isoxazole derivative in excellent yields (Scheme 2).

Scheme 2 Intramolecular cycloaddition oxidation reactions.

In all cases, the progress of the reaction was monitored by TLC. The structures of the desired products were characterized by ¹H and ¹³C NMR, IR and HRMS spectral data. The X-ray crystal structures (see ESI†) of 1,3,5-trisubstituted pyrazole (Fig. 2a) and 3,5-disubstituted 2-isoxazoline (Fig. 2b) further confirmed the product identities.

Fig. 2 (a) ORTEP diagram of the single-crystal X-ray structure of 4-(4-fluoro-phenyl)-3-isopropyl-1-phenyl-1H-pyrazole (5a).† (b) ORTEP diagram of the single-crystal X-ray structure of 3-(4-bromo-phenyl)-5-phenyl-4,5-dihydro-isoxazole (6f).†

The reaction driving force in micelles may be related to the hydrophobic force, which compressed the reactants together in a highly compact arrangement of complexes within a restricted, hydrophobic domain. In light of the above results, a revised mechanism of pyrazole and isoxazoline formation may be proposed, as outlined in Schemes 3, 4 and 5. Thus, the most likely pathway for the cycloaddition is proposed to be as follows: Initially the reaction passed through a simple condensation reaction between the aldehyde and nitrogen nucleophile to produce the corresponding aldohydrazone (Scheme 3, I) and aldoxime (Scheme 5, I) compounds. Then, in the case of pyrazole formation (Scheme 3), the N-benzylidene-N′-phenyl-hydrazine (I) was oxidized by an equivalent of PhIO, to generate the corresponding nitrile imine dipolar species (III) with the concomitant loss of PhI and a water molecule. Nitrile imine dipolar species followed the unidirectional formal [3 + 2]-cycloaddition pathways with the olefinic substrate, to afford the five-member heterocycles (IV). Next, the cycloaddition product (Scheme 3, IV) was smoothly oxidised by another equivalent of PhIO giving an aromatic pyrazole nucleus (Scheme 3, P).

Scheme 3 Plausible reaction pathway for pyrazole synthesis.

Scheme 4 Plausible reaction pathway for pyrazole synthesis from nitroolefins.

Scheme 5 Plausible reaction pathway for isoxazoline synthesis.

During the reaction of hydrazone with nitroolefin, the nucleophilic attack of hydrazone to nitroolefin afforded a Michael addition product V, which did not cyclize to a pyrazolidine intermediate IV under the reaction conditions. PhIO has shown excellent activity in promoting the reaction to the desired track, by oxidizing the hydrazone to the corresponding nitrile imine dipolar species¹² which cannot undergo Michael addition reaction. Then a concerted cycloaddition reaction takes place to give a 4-nitropyrazolidine intermediate IV. The key intermediate IV then undergoes a slow oxidation by PhIO, to furnish the pyrazole product (P) by the elimination of HNO₂.

During the formation of isoxazolines, PhIO oxidized aldoximes to nitrile oxides via the transition state II (Scheme 5), which then participated in a cycloaddition to an unsaturated bond, giving the desired product. In case of isoxazoline derivatives, a further aromatization step was not achieved even after increasing the amount of PhIO. Hence, one equivalent of PhIO was sufficient to promote the dipolar cycloaddition reaction.

The reaction of N-monosubstituted hydrazones and oximes with various 1,3-dipolar species showed excellent regioselectivity under the developed reaction conditions. No side products, such as cycloaddition products X, Y or the Michael addition product V (Fig. 3), were isolated during the course of the reaction. Hence the reaction was completely regiocontrolled, and this feature made the PhIO mediated cycloaddition reaction a high yielding synthetic protocol for obtaining the desired pyrazole and isoxazoline derivatives.

Fig. 3 Regioisomers of a pyrzole, an isoxazoline and a Michael addition product.

Conclusion

In summary, an efficient and very practical PhIO promoted tandem [3 + 2] dipolar cycloaddition reaction to pyrazole and isoxazoline derivatives has been established, by performing the reaction as a one-pot operation in water. This reaction can be carried out under mild conditions, which gave rapid access to a variety of heterocyclic molecules. A wide range of alkenes, bearing not only aryl groups but also alkyl groups, effectively participated in the reactions. Also, a number of functionalities, such as fluoro, bromo, nitro and methoxy, are tolerated under the developed reaction conditions. The operational simplicity, mild reaction conditions, excellent yield of the desired product, and minimal environmental impact are notable features of this procedure. Hence, it is a useful addition to the existing methods.

Experimental section

General procedure for the synthesis of pyrazoles

A mixture of an aldehyde (1 mmol), phenyl hydrazine (1 mmol) and olefin derivatives (1 mmol) was added to a well stirred solution of SDS (10 mol %) in 5 ml H₂O at room temperature. Then PhIO (2.0 mmol) was added portion-wise to the resulting mixture, carefully maintaining the temperature at 0 °C. When the addition was complete, the reaction was allowed to attain room temperature and stirring was continued for the required period of time (monitored by TLC). After completion of the reaction, the mixture was extracted with ethyl acetate (3 × 10 ml). Removal of ethyl acetate under reduced pressure and purification of the crude product by column chromatography (silica gel 100–200 mesh) provided pure products. All compounds were well characterized by ¹H, ¹³C NMR, FT-IR and HRMS analysis.

3-(3-Nitro-phenyl)-1-phenyl-1H-pyrazole-4-carboxylic acid methyl ester (4d). Yield: 89%, (0.287 g); M.p. 120–121 °C; characteristics: yellow crystalline solid.

¹H NMR (300 MHz, CDCl₃): δ 8.62 (s, 1H), 8.15–8.05 (m, 2H), 7.78 (d, 1H, J = 8.4 Hz), 7.55–7.41 (m, 4H), 7.33 (s, 1H), 7.24 (t, 1H, J = 8 Hz), 3.76 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 164.1, 149.2, 142.8, 139.1, 135.1, 131.1, 129.8, 129.5, 128.6, 128.2, 126.1, 123.7, 123.1, 120.7, 113.5, 109.7, 52.3; HRMS (ESI-TOF) m/z: [M + H]⁺ calculated for C₁₇H₁₄N₃O₄: 324.0984, found: 324.0980; IR (KBr) cm⁻¹: 1089.7, 1248.8, 1347.1, 1525.1, 1601.8, 1736.9, 2955.3, 3285.9; anal. calcd for C₁₇H₁₃N₃O₄: C: 63.16; H: 4.05; N: 13.00%, found: C: 63.11; H: 4.01; N: 13.01%.

1-(4-Nitro-phenyl)-3-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester (4h). Yield: 92%, (0.310 g); M.p. 115–116 °C; characteristics: yellow crystalline solid.

¹H NMR (300 MHz, CDCl₃): δ 8.28 (d, 2H, J = 8.7 Hz), 7.80 (d, 2H, J = 8.7 Hz), 7.66 (d, 2H, J = 8.7 Hz), 7.40–7.29 (m, 4H), 4.26 (q, 2H, J = 7.1), 1.27 (t, 3H, J = 7.2); ¹³C NMR (75 MHz, CDCl₃): δ 158.9, 152.8, 147.2, 145.0, 134.9, 131.5, 128.9, 126.5, 125.9, 124.0, 123.9, 111.0, 67.7, 14.1; HRMS (ESI-TOF) m/z: [M + H]⁺ calculated for C₁₈H₁₆N₃O₄: 338.1141, found: 338.1140; IR (KBr) cm⁻¹: 1110, 1241.7, 1306.8, 1526.4, 1597.9, 1721.7, 2937.8, 3132.8; anal. calcd for C₁₈H₁₅N₃O₄: C: 64.09; H: 4.48; N: 12.46%, found: C: 64.09; H: 4.46; N: 12.42%.

4-(4-Fluoro-phenyl)-3-isopropyl-1-phenyl-1H-pyrazole (5a). Yield: 94%, (0.263 g); M.p. 80–81 °C; characteristics: yellow crystalline solid.

¹H NMR (300 MHz, CDCl₃): δ 7.76 (s, 1H), 7.62 (d, 2H, J = 7.8 Hz), 7.40–7.14 (m, 5H), 7.06–6.97 (m, 2H), 3.13 (m, 1H), 1.25 (d, 6H, J = 6.9 Hz); ¹³C NMR (75 MHz, CDCl₃): δ 157.2, 140.2, 137.5, 130.1, 129.9, 129.4, 127.5, 126.5, 126.1, 125.4, 121.6, 118.8, 115.6, 115.3, 114.9, 26.5, 22.6; HRMS (ESI-TOF) m/z: [M + H]⁺ calculated for C₁₈H₁₈FN₂: 281.1454, found: 281.1450; IR (KBr) cm⁻¹: 1174.8, 1241.2, 1504.3, 1575.5, 1608.9, 2850.8; anal. calcd for C₁₈H₁₇FN_2: C: 77.12; H: 6.11; N: 9.99%, found: C: 77.10; H: 6.10; N: 9.98%.

2-Phenyl-2,4-dihydro-chromeno[4,3-c]pyrazole (7a). Yield: 91%, (0.226 g); M.p. 79–80 °C (Lit: 81–82 °C); characteristics: yellow crystalline solid.

¹H NMR (300 MHz, CDCl₃): δ 7.80 (dd, 1H, J = 7.5 Hz, 1.8 Hz), 7.65–7.60 (m, 2H), 7.41–7.34 (m, 3H), 7.24–7.12 (m, 1H), 6.98–6.87 (m, 3H), 5.27 (s, 2H); ¹³C NMR (75 MHz, CDCl₃): δ 156.4, 154.1, 135.8, 133.1, 130.0, 129.6, 129.1, 126.3, 122.7, 122.3, 122.1, 122.1, 119.2, 117.4, 63.3; HRMS (ESI-TOF) m/z: [M + H]⁺ calculated for C₁₆H₁₃N₂O: 249.1028, found: 249.1025; IR (KBr) cm⁻¹: 1089.6, 1229.8, 1471.3, 1502.8, 1599.3, 1689.9, 2800.3; anal. calcd for C₁₆H₁₂N₂O: C: 77.40; H: 4.87; N: 11.28%, found: C: 77.45; H: 4.84; N: 11.25%.

General procedure for the synthesis of isoxazolines

The reaction was performed via the same method for pyrazoles. A mixture of an aldehyde (1 mmol), hydroxyl amine hydrochloride (1 mmol), sodium acetate (1 mmol), and olefin derivatives (1 mmol) was added to a well stirred solution of SDS (10 mol %) in 5 ml H₂O at room temperature. Then PhIO (1.5 mmol) was added portion-wise to the resulting mixture, carefully maintaining the temperature at 0 °C. When the addition was complete the reaction was allowed to attain room temperature, and stirring was continued for the required period of time (monitored by TLC). After completion of the reaction, the mixture was extracted with ethyl acetate (3 × 10 ml). Removal of ethyl acetate under reduced pressure and purification of the crude product by column chromatography (silica gel 100–200 mesh, ethyl acetate–hexane as eluent) provided pure products. All compounds were well characterized by ¹H, ¹³C NMR, FT-IR and HRMS analysis.

3-(3-Nitro-phenyl)-4,5-dihydro-isoxazole-5-carboxylic acid ethyl ester (6b). Yield: 89%, (0.235 g); M.p. 66–67 °C (Lit: 65–67 °C); characteristics: white crystalline solid.

¹H NMR (300 MHz, CDCl₃): δ 8.30 (s, 1H), 8.17 (d, 1H, J = 8.4 Hz), 7.98 (d, 1H J = 7.8 Hz), 7.56–7.51 (m, 1H), 5.22 (dd, 1H, J = 10.2, 7.8 Hz), 4.20 (q, 2H, J = 7.1 Hz), 3.70–3.63 (m, 2H), 1.25 (t, 3H, J = 7.2 Hz); ¹³C NMR (75 MHz, CDCl₃): δ 169.8, 154.6, 148.3, 132.4, 130.1, 129.8, 124.9, 121.9, 78.8, 62.4, 38.4, 14.1; HRMS (ESI-TOF) m/z: [M + H]⁺ calculated for C₁₂H₁₃N₂O₅: 265.0824, found: 265.0820; IR (KBr) cm⁻¹: 1145.7, 1210.9, 1463.7,1548.1, 1720.6, 2863.3, 2933.4, 3012.3, 3548.5; anal. calcd for C₁₂H₁₃N₂O₅: C: 54.55; H: 4.58; N: 10.60%, found: C: 54.54; H: 4.56; N: 10.62%.

3,5-Diphenyl-4,5-dihydro-isoxazole (6e). Yield: 90%, (0.200 g); M.p. 70–72 °C (Lit: 75–76 °C); characteristics: yellow crystalline solid.

¹H NMR (300 MHz, CDCl₃): δ 7.65–7.51 (m, 2H), 7.31–7.21 (m, 8H), 5.61 (dd, 1H, J = 10.2, 8.1 Hz), 3.65 (dd, 1H, J = 16.6,10.8 Hz), 3.21 (dd, 1H, J = 16.8, 8.4 Hz); ¹³C NMR (75 MHz, CDCl₃): δ 156.0, 140.8, 137.4, 130.2, 129.1, 129.0, 128.1, 128.0, 126.1, 125.9, 82.5, 43.1; HRMS (ESI-TOF) m/z: [M + H]⁺ calculated for C₁₅H₁₄NO: 224.1075, found: 224.1072; IR (KBr) cm⁻¹: 1059.3, 1212.7, 1453.0, 1599.6, 2830, 3030.2, 3532.2; anal. calcd for C₁₅H₁₃NO: C: 80.69; H: 5.87; N: 6.27%, found: C: 80.66; H: 5.89; N: 6.29%.

3a,4-Dihydro-3H-chromeno[4,3-c]isoxazole (7b). Yield: 92%, (0.161 g); M.p. 60–62 °C (Lit: 62–64 °C); characteristics: white crystalline solid.

¹H NMR (300 MHz, CDCl₃): δ 7.68 (d, 1H, J = 7.5 Hz), 7.26–7.18 (m, 1H), 6.92–6.83 (m, 2H), 4.60–4.53 (m, 2H), 4.01–3.94 (m, 1H), 3.89–3.75 (m, 2H); ¹³C NMR (75 MHz, CDCl₃): δ 155.6, 152.8, 132.5, 125.6, 121.8, 117.4, 113.0, 70.6, 69.2, 45.9; HRMS (ESI-TOF) m/z: [M + H]⁺ calculated for C₁₀H₁₀NO₂: 176.0712, found: 176.0710; IR (KBr) cm⁻¹: 1026.3, 1209.2, 1410.4, 1560.3, 1710.1, 2896.3, 3010.5, 3566.9; anal. calcd for C₁₀H₉NO₂: C: 68.56; H: 5.18; N: 8.00%, found: C: 68.58; H: 5.16; N: 8.01%.

4H-Chromeno[4,3-c]isoxazole (7c). Yield: 90%, (0.155 g); M.p. 42–43 °C (Lit: 42 °C); characteristics: white crystalline solid.

1H NMR (300 MHz, CDCl₃): δ 8.24 (s, 1H), 7.91 (dd, 1H, J = 7.6, 1.5 Hz), 7.42–7.36 (m, 1H), 7.16–7.04 (m, 2H), 5.27 (s, 2H); 13C NMR (75 MHz, CDCl₃): δ 154.8, 153.6, 150.6, 132.1, 124.5, 122.4, 117.9, 113.9, 111.1, 61.3; HRMS (ESI-TOF) m/z: [M + H]⁺ calculated for C₁₀H₈NO₂: 174.0555, found: 174.0553; IR (KBr) cm⁻¹: 1045.6, 1211.8,1496.8, 1501.1, 1705.1, 2988.9, 3112.5, 3496.9; anal. calcd for C₁₀H₇NO₂: C: 69.36; H: 4.07; N: 8.09%, found: C: 69.38; H: 4.09; N: 8.07%.

Acknowledgements

We acknowledge the financial support from the University of Calcutta. G. P. thanks CSIR, New Delhi, India, for her Senior Research Fellowship (Grant no. 09/028(0792)/2010 EMR-I). S. P. and P. P. G. thank U. G. C., New Delhi, India for the grant of their Senior Research Fellowships. Crystallography was performed at the DST-FIST, India-funded Single Crystal Diffractometer Facility at the Department of Chemistry, University of Calcutta. We are thankful to Professor Laksmi N. Hazra of the Applied Photonics Department of C. U. for providing an optical microscope. We are also thankful to Dr Dilip K. Maiti, Department of Chemistry, C. U. for providing a ‘Dynamic Light Scattering’ facility.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 941068 (5a) and 945312 (6f). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ra46129g

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