An efficient and confluent approach for the synthesis of novel 3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione derivatives by a three component reaction in ionic liquid

Abstract

A catalyst free multicomponent reaction (MCR) capable of affording a wide range of novel 3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione derivatives via one pot three component condensation of 2-hydroxy-1,4-naphthoquinone, aromatic amine and formaldehyde in ionic liquid [bmim]BF₄ is reported. Mild reaction conditions, high yields, short reaction time, and easy separation are some of the salient features of the present protocol.

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1. Introduction

Quinone scaffolds are common in nature and are reported to play important physiological roles in animals and plants.¹ Also 1,4-naphthoquinone is a raw material for various pharmaceutical and agrochemical industries. Its derivatives exhibit biological responses such as antiallergic,² antithrombotic,³ antiviral⁴ apoptosis,⁵ lipoxygenase inhibitors,^6,7 anti-ringworm⁸ and also human DNA topoisomerase I and II inhibitors.⁹ The two carbonyl groups present in 1,4-naphthoquinone behave as crucial chromophore that accounts for its bioactivities owing to their ability to accept electrons.¹⁰ It has been reported that incorporation of nitrogen into naphthoquinone derivatives results in increased anticancer,¹¹ molluscicidal¹² and antibacterial activities.¹³ 1,3-Oxazine heterocycles also exhibit biological activities such as analgesic, anticonvulsant, antitubercular, antibacterial, anticancer¹⁴ and also high activity against a variety of HIV-1 mutant strain.¹⁵ Moreover, 6-arylbenzoxazines have been reported as potent non-steroidal progesterone receptor agonists.¹⁶

Multicomponent reactions (MCRs) constitute powerful and efficient synthetic tool in organic, combinatorial and medicinal chemistry¹⁷ due to minimized waste generation, avoidance of intermediate isolation and purification steps. Mannich reaction is a useful carbon–carbon bond formation reaction in organic synthesis. Reported Mannich reactions involve condensation of enolizable ketones with formaldehyde and amines, though there are also few examples of Mannich reaction involving phenols and naphthols.¹⁸ In continuation of our studies on the synthesis of novel heterocycles using environmentally benign methodologies,¹⁹ we attempted synthesis of novel 3-aryl-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-diones using Mannich reaction in ionic liquid.

2. Results and discussion

This is the first report on the synthesis of highly functionalized 3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione derivatives via one pot three component condensation of 2-hydroxy-1,4-naphthoquinone, aromatic amines and formaldehyde in ionic liquid [bmim]BF₄ at 50 °C. The optimization for the reaction was evolved after attempting model reactions of 2-hydroxy-1,4-naphthoquinone (1.0 mmol), 4-methoxyaniline (1.0 mmol) and formaldehyde (2.0 mmol) in different solvents without any catalyst and also under neat conditions (Scheme 1). The reaction was first attempted using water as the solvent at 50 °C. The reaction was incomplete even after 5 h, though, a new product was formed. The new product was separated and identified as desired 3-(4-methoxyphenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (2a) in 44% yield (Table 1, entry 1). The reaction was then attempted under neat condition. The reaction was incomplete after 5 h, yielding 41% of the desired product after separation (Table 1, entry 2). The same reaction carried out using PEG-400 as the solvent at 50 °C resulted in a mixture of products (Table 1, entry 3) while the reaction performed in ionic liquid [bmim]Br at 50 °C was found to be complete in 15 min as monitored by TLC (eluent: ethyl acetate-petroleum ether, 30 : 70, v/v). After workup, the desired product 2a was obtained in 70% yield (Table 1, entry 4). Replacement of the ionic liquid [bmim]Br by [bmim]Cl as the reaction media did not have any significant effect on the yield (Table 1, entry 5) while reaction in ionic liquid [bmim]BF₄ yielded 87% of the product 2a (Table 1, entry 6). Reaction attempted in ionic liquid [bmim]BF₄ at higher temperature didn't show any significant difference in time and yield of the reaction (Table 1, entry 7). The reactions attempted using DCM and toluene as solvents, led to inferior yields of the desired product (Table 1, entries 8 and 9).

Scheme 1

Table 1 Optimization of reaction conditions for the synthesis of 3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione derivatives^a

Entry	Solvent	Temp.	Time	Yield (%)
a Reaction conditions: 2-hydroxy-1,4-naphthoquinone (1.0 mmol), 4-methoxyaniline (1.0 mmol) and formaldehyde (2.0 mmol) and solvent.b Incomplete reaction.c Mixture of products.
1	H2O	50 °C	5 h	44^b
2	—	50 °C	5 h	41^b
3	PEG-400	50 °C	1 h	—^c
4	[bmim]Br	50 °C	15 min	70
5	[bmim]Cl	50 °C	15 min	73
6	[bmim]BF4	50 °C	15 min	87
7	[bmim]BF4	80 °C	15 min	89
8	DCM	Reflux	30 min	64
9	Toluene	50 °C	35 min	58

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Therefore, a catalyst free reaction of 2-hydroxy-1,4-naphthoquinone (1.0 mmol), 4-methoxyaniline (1.0 mmol) and formaldehyde (2.0 mmol) in [bmim]BF₄ (2 mL) at 50 °C was considered to be the optimum condition for the synthesis of naphtho[2,3-e][1,3]oxazine-5,10-diones. Subsequently, reactions of a variety of aromatic amines were attempted with 2-hydroxy-1,4-naphthoquinone and formaldehyde under optimized conditions. All the reactions proceeded smoothly and were found to be complete in 15–25 min giving the corresponding novel naphtho[2,3-e][1,3]oxazine-5,10-dione derivatives in high yields (Scheme 2). The results have been summarized in Table 2.

Scheme 2

Table 2 Synthesis of 3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione derivatives^a

Entry	Compounds	R	Time (min)	Yield (%)
a Reaction conditions: 2-hydroxy-1,4-naphthoquinone (1.0 mmol), amine (1.0 mmol) and formaldehyde (2.0 mmol) and [bmim]BF4 (2 mL).
1	2a	4-OMe	15	89
2	2b	4-Cl	15	88
3	2c	2-Me	20	87
4	2d	4-Me	15	90
5	2e	4-Br	15	88
6	2f	4-F	15	85
7	2g	4-F, 3-Cl	20	90
8	2h	4-(COCH3)	15	91
9	2i	3-Cl	20	90
10	2j	4-Cl, 3-(NO2)	20	88
11	2k	4-(NO2)	20	89
12	2l	3-Br	15	90
13	2m	3,4-(Cl)2	20	89
14	2n	2-Cl	15	91
15	2o	3-(NO2)	15	90

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The structures of all the novel compounds were identified by IR, NMR (¹H, ¹³C) and mass spectral analysis. IR spectra of the compound 2a showed peaks at 1681 cm⁻¹ (carbonyl stretch), 1214 (symmetric C–O stretch) and 1037 cm⁻¹ (symmetric C–O stretch). The four methylene protons appeared as two singlets for two protons each at δ 4.40 (Ar–CH₂–N–) and 5.44 (–O–CH₂–N–). The eight aromatic protons appeared in the range of δ 8.07–6.79. The two methylene carbons in the ¹³C NMR appeared at δ 46.67 and 82.44. The methyl carbon of OMe group appeared at δ 55.51. The carbonyl carbons appeared at δ 179.00. The 12 aromatic carbons and two olefinic carbons appeared in the range of δ 114.60–155.56. The position of peaks for methyl, methylene, methine and quaternary carbons were assigned by DEPT spectra of compound 2a. The ESI-HRMS of 2a did not show molecular ion peak but showed two prominent peaks due to fragmentation. The molecular ion peak was not observed even at low energy (∼60 ev). One peak at m/z = 136.0755 corresponding to C₆H₄(OMe)N=CH₂ (Schiff base) and the second peak at m/z = 187.0392 corresponding to C₁₁H₆O₃, the fragment left after loss of Schiff base fragment from the molecular ion were observed. Both the peaks were observed as [M + H]⁺ of that fragment. The oxazines have been reported to undergo dissociation to give fragment ions.²⁰ The possible fragmentation pattern is shown in Scheme 3.

Scheme 3 Possible fragmentation pattern observed in 2a.

In addition, the structure of the synthesized novel 3-(4-fluorophenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (2f) has been confirmed by the single crystal X-ray diffraction analysis (Fig. 1). A single crystal of 2f suitable for X-ray diffraction was obtained by vapour diffusion of hexane into chloroform solution of compound at room temperature.

Fig. 1 X-ray crystal structure of 2f.†

The crystal data including the structure refinement are shown in Table 3. The crystal packing shows 2 molecules in a unit cell (Fig. 2a). The crystal structure shows that nitrogen atom deviates from the plane of oxazine ring containing rest of the atoms by an angle of 81.23°. The X-ray analysis of compound 2f revealed two types of interactions namely, C–H⋯O and C–H⋯π (Fig. 2b). Intramolecular C–H⋯O interactions were observed between carbonyl oxygens of naphthoquinone ring and hydrogen of oxazine ring/hydrogen of naphthoquinone ring with distance of 2.5 Å, which stabilizes the molecule in a lattice. Intermolecular hydrogen bonding interactions were also observed between carbonyl oxygens of naphthoquinone ring and hydrogen of amine ring with a distance of 2.7 Å. Besides hydrogen bonding interactions, both intra and inter C–H⋯π interactions are also observed in the crystal lattice with a distance of 3.6 and 4.8 Å respectively (Table 4).

Table 3 Crystal data and structure refinement data for the title compound

Formula	C18H12FNO3
Formula weight (g)	309.29
Temperature	293(2) K
Wavelength	0.71073 Å
Crystal system, space group	Triclinic, P1̄
Unit cell dimensions	a = 7.6164(5) Å alpha = 92.548(8) deg
	b = 8.1700 (8) Å beta = 103.893(8) deg
	c = 12.1539 (12) Å gamma = 108.383(8) deg
Volume	690.75(12) Å^3
Z, calculated density	2, 1.487 g cm^−3
Absorption coefficient	0.111 mm^−1
F(000)	320
Crystal size	0.04 × 0.02 × 0.01 mm
Theta range for data collection	3.86 to 28.37 deg
Limiting indices	−9 ≤ h ≤ 9, −9 ≤ k ≤ 9, −14 ≤ l ≤ 14
Reflections collected/unique	9651/2420 [R(int) = 0.0163]
Completeness to theta = 25.00	99.9%
Absorption correction	Semi-empirical from equivalents
Max. and min. transmission	1.00000 and 0.89765
Refinement method	Full-matrix least-squares on F^2
Data/restraints/parameters	2420/0/209
Goodness-of-fit on F^2	1.020
Final R indices [I > 2sigma(I)]	R1 = 0.0531, wR2 = 0.1461
R indices (all data)	R1 = 0.0613, wR2 = 0.1405
Largest diff. peak and hole	0.4100 and −0.3100 e A^−3

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Fig. 2 (a) View of crystal packing of 2f shown along b axis; (b) C–H⋯O and C–H⋯π interactions in the crystal packing of 2f.

Table 4 Intramolecular and intermolecular hydrogen bonding geometries of the 2f^a

D-H⋯A	D-H (Å)	H⋯A (Å)	D⋯A (Å)	D-H⋯A (Å)
a D, donor; A, acceptor. Symmetry codes: (i) 1 − x, −y, 1 − z; (ii) 1 − x, 1 − y, 2 − z.
C2–H2⋯O1^i	0.930(3)	2.545(2)	2.821(3)	97.5(2)
C5–H5⋯O2^ii	0.930(3)	2.558(2)	2.834(3)	97.5(2)
C11–H11⋯O1	0.970(2)	2.554(2)	2.779(3)	80.6(1)
C15–H15⋯O1	0.930(2)	2.694(2)	3.346(3)	132.5(2)

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A probable mechanism involved in the formation of products is outlined in Scheme 4. Firstly, condensation of formaldehyde and amine (ArNH₂) gives imine intermediate ‘A’ which reacts with 2-hydroxy-1,4-naphthoquinone to form ‘B’. The condensation of ‘B’ with formaldehyde gives ‘C’ with loss of H₂O which undergoes cyclization to give the final product 2.

Scheme 4 Probable mechanistic pathway for the synthesis of 3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione derivatives (2).

Finally, the recovery and reuse of the ionic liquid [bmim]BF₄ was examined. The products were separated by simple filtration from the mixture of ionic liquid and water. The filtrate so obtained was then extracted with ether. Ether was removed by distillation and the ionic liquid was dried at 90 °C under vacuum. Reaction was then attempted in recovered ionic liquid. Marginal loss in the yield (83% and 80%) of 2a was observed in the second and third cycles. However, the yields decreased gradually in fourth and fifth cycles (77% and 74%) as depicted in Fig. 3.

Fig. 3 Reusability of ionic liquid [bmim]BF₄.

3. Experimental

All the chemicals were commercial and purchased from Sigma-Aldrich or Merck and used as received. Thin layer chromatography (GF254) was used to monitor reaction progress. Melting points were measured on Buchi M-560 melting point apparatus and are uncorrected. IR (KBr) spectra were recorded on a Perkin-Elmer FTIR spectrophotometer and the values are expressed as ν_max cm⁻¹. The ¹H NMR and ¹³C NMR spectra were recorded on Jeol JNM ECX-400P at 400 and 100 MHz respectively, using TMS as internal standard. The chemical shift values are recorded on δ scale and the coupling constants (J) are in Hz. Mass spectral data were recorded on Agilent 6520 QT of (ESI-HRMS) mass spectrometer.

3.1. Data collection and refinement

The intensity data for compound 2f was collected on an Oxford Xcalibur CCD diffractometer equipped with graphite monochromatic MoK_α radiation (λ 0.71073 Å) at 293(2) K. A multiscan absorption correction was applied. The structure was solved by direct methods and refined by full-matrix least squares refinement techniques on F² using SHELXL-97.²¹ The coordinates of non-hydrogen atoms were refined anisotropically using SHELXL-97. The positions of hydrogen atoms were obtained from difference Fourier maps and were included in the final cycles of refinement. All calculations were done using the Wingx software package.²²†

3.2. General procedure for the synthesis of 3-aryl-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-diones (2a–o)

A mixture of 2-hydroxy-1,4-naphthoquinone (1.0 mmol), aromatic amine (1.0 mmol), formalin (37%, w/v, 2.0 mmol) and [bmim]BF (2 mL) was placed in a 50 mL round-bottomed flask and the contents were stirred magnetically in an oil-bath maintained at 50 °C for appropriate time as indicated in Table 2. The progress of the reaction was monitored by TLC using ethyl acetate : petroleum ether (30 : 70, v/v) as eluent. After completion of the reaction, the reaction mixture was allowed to cool at room temperature and diluted with water (5 mL). The solid separated was collected by filtration at pump and washed with 2–3 mL ethanol. The products were further purified by recrystallization from chloroform. The products were characterized by IR, ¹H NMR, ¹³C NMR, ¹⁹F NMR, mass spectra and an X-ray crystallographic study. ¹³C NMR data of 2j, 2k and 2o could not be recorded due to their low solubility. ESI-HRMS analysis of the compounds did not show the molecular ion peak, instead showed fragmentation. The molecular ion peak was not observed even at low energy (∼60 ev).

3.3. Spectral data

3-(4-Methoxyphenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (2a). Yellow solid; m.p. 163–164 °C; IR (ν_max cm⁻¹) (KBr): 1681, 1214, 1037; ¹H NMR (400 MHz, CDCl₃) δ = 8.07–8.01 (m, 2H, ArH), 7.71–7.66 (m, 2H, ArH), 7.06 (d, 2H, ArH, J = 9.32 Hz), 6.79 (d, 2H, ArH, J = 8.56 Hz), 5.44 (s, 2H, CH₂), 4.40 (s, 2H, CH₂), 3.72 (s, 3H, OCH₃); ¹³C NMR (100 MHz, CDCl₃) δ = 179.00 (Cq), 155.56 (Cq), 141.22 (Cq), 134.20 (+, CH), 133.28 (+, CH), 131.60 (Cq), 130.76 (Cq), 126.50 (+, CH), 126.01 (+, CH), 120.77 (+, CH), 120.08 (Cq), 114.60 (+, CH), 82.44 (−, CH₂), 55.51 (+, CH₃), 46.67 (−, CH₂). HRMS (ESI) m/z calcd for C₈H₁₀NO: 136.0762, found: 136.0755; calcd for C₁₁H₇O₃: 187.0395, found: 187.0392.

3-(4-Chlorophenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (2b). Yellow solid; m.p. 183–184 °C; IR (ν_max cm⁻¹) (KBr): 1682, 1218, 1060; ¹H NMR (400 MHz, CDCl₃) δ = 8.09–8.03 (m, 2H, ArH), 7.73–7.66 (m, 2H, ArH), 7.25–7.21 (m, 2H, ArH), 7.06–7.03 (m, 2H, ArH), 5.47 (s, 2H, CH₂), 4.46 (s, 2H, CH₂); ¹³C NMR (100 MHz, CDCl₃) δ = 183.21, 178.81, 155.52, 146.05, 134.28, 133.43, 131.51, 130.72, 129.41, 127.76, 126.56, 126.07, 120.03, 119.97, 81.07, 46.28.

3-(2-Methylphenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (2c). Yellow solid; m.p. 160–162 °C; IR (ν_max cm⁻¹) (KBr): 1680, 1222, 1066; ¹H NMR (400 MHz, CDCl₃) δ = 8.11–8.01 (m, 2H, ArH), 7.71–7.65 (m, 2H, ArH), 7.22–7.17 (m, 2H, ArH), 7.09–7.01 (m, 2H, ArH), 5.37 (s, 2H, CH₂), 4.24 (s, 2H, CH₂), 2.37 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ = 183.35, 179.18, 155.54, 147.36, 134.20, 133.27, 132.29, 131.67, 131.38, 130.80, 126.86, 126.51, 126.07, 125.03, 121.04, 119.83, 83.36, 45.99, 18.33.

3-(4-Methylphenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (2d). Yellow solid; m.p. 165–166 °C; IR (ν_max cm⁻¹) (KBr): 1678, 1208, 1060; ¹H NMR (400 MHz, CDCl₃) δ = 8.07–8.01 (m, 2H, ArH), 7.71–7.65 (m, 2H, ArH), 7.08–7.01 (m, 4H, ArH), 5.47 (s, 2H, CH₂), 4.45 (s, 2H, CH₂), 2.24 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ = 178.98, 155.65, 145.07, 134.19, 133.28, 132.29, 131.58, 130.76, 129.96, 126.49, 126.00, 120.20, 118.84, 81.70, 46.31, 20.53. HRMS (ESI) m/z calcd for C₈H₁₀N: 120.0813, found: 120.0805, calcd for C₁₁H₇O₃: 187.0395, found: 187.0390.

3-(4-Bromophenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (2e). Yellow solid; m.p. 196–198 °C; IR (ν_max cm⁻¹) (Film): 1678, 1213, 1058; ¹H NMR (400 MHz, CDCl₃) δ = 8.08–8.02 (m, 2H, ArH), 7.72–7.65 (m, 2H, ArH), 7.36 (d, 2H, ArH, J = 8.56 Hz), 6.98 (d, 2H, ArH, J = 8.56 Hz), 5.45 (s, 2H, CH₂), 4.45 (s, 2H, CH₂); ¹³C NMR (100 MHz, CDCl₃) δ = 183.20, 178.79, 155.51, 146.52, 134.29, 133.42, 132.35, 131.50, 130.72, 126.57, 126.07, 120.31, 120.04, 115.18, 80.91, 46.21. HRMS (ESI) m/z calcd for C₇H₇BrN: 183.9762, found: 183.9760; calcd for C₁₁H₇O₃: 187.0395, found: 187.0401.

3-(4-Fluorophenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (2f). Yellow solid; m.p. 194–197 °C; IR (ν_max cm⁻¹) (KBr): 1676, 1212, 1061; ¹H NMR (400 MHz, CDCl₃) δ = 8.09–8.03 (m, 2H, ArH), 7.72–7.66 (m, 2H, ArH), 7.10–7.07 (m, 2H, ArH), 6.98–6.93 (m, 2H, ArH), 5.45 (s, 2H, CH₂), 4.43 (s, 2H, CH₂); ¹³C NMR (100 MHz, CDCl₃) δ = 183.27, 178.89, 158.65 (d, ¹J_C–F = 241.22 Hz), 155.56, 143.86 (d, ⁴J_C–F = 1.91 Hz), 134.26, 133.38, 131.55, 130.75, 126.55, 126.06, 120.69 (d, ³J_C–F = 7.63 Hz), 119.95, 116.03 (d, ²J_C–F = 21.93 Hz), 81.89, 46.61; ¹⁹F NMR (376 MHz, CDCl₃) δ = −120.35 (s, 1F, ArF). HRMS (ESI) m/z calcd for C₇H₇FN: 124.0563, found: 124.0560, calcd for C₁₁H₇O₃: 187.0395, found: 187.0390.

3-(3-Chloro-4-fluorophenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (2g). Yellow solid; m.p. 162–164 °C; IR (ν_max cm⁻¹) (KBr): 1682, 1216, 1062; ¹H NMR (400 MHz, CDCl₃) δ = 8.09–8.02 (m, 2H, ArH), 7.73–7.66 (m, 2H, ArH), 7.16–7.14 (m, 1H, ArH), 7.05–7.03 (m, 1H, ArH), 6.99–6.94 (m, 1H, ArH), 5.42 (s, 2H, CH₂), 4.42 (s, 2H, CH₂); ¹³C NMR (100 MHz, CDCl₃) δ = 183.20, 178.75, 155.47, 154.03 (d, ¹J_C–F = 243.14 Hz), 144.44 (d, ⁴J_C–F = 2.86 Hz), 134.34, 133.50, 131.51, 130.74, 126.63, 126.12, 121.07, 119.87, 118.60 (d, ³J_C–F = 6.67 Hz), 117.07 (d, ²J_C–F = 21.93 Hz), 81.20, 46.61.

3-(4-Acetylphenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (2h). Yellow solid; m.p. 183–184 °C; IR (ν_max cm⁻¹) (KBr): 1681, 1206, 1061; ¹H NMR (400 MHz, CDCl₃) δ = 8.08–8.03 (m, 2H, ArH), 7.72–7.66 (m, 3H, ArH), 7.54–7.53 (m, 1H, ArH), 7.38–7.29 (m, 2H, ArH), 5.52 (s, 2H, CH₂), 4.52 (s, 2H, CH₂), 2.56 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ = 197.68, 183.17, 178.78, 155.64, 147.76, 138.40, 134.28, 133.43, 131.53, 130.74, 126.57, 126.10, 122.58, 120.16, 117.86, 117.80, 80.76, 46.01, 26.77.

3-(3-Chlorophenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (2i). Yellow solid; m.p. 173–175 °C; IR (ν_max cm⁻¹) (KBr): 1678, 1209, 1052; ¹H NMR (400 MHz, CDCl₃) δ = 8.12–8.05 (m, 2H, ArH), 7.74–7.68 (m, 2H, ArH), 7.22–7.18 (m, 1H, ArH), 7.12–7.11 (m, 1H, ArH), 7.02–6.95 (m, 2H, ArH), 5.49 (s, 2H, CH₂), 4.49 (s, 2H, CH₂); ¹³C NMR (100 MHz, CDCl₃) δ = 183.19, 178.79, 155.54, 148.58, 135.19, 134.29, 133.44, 131.50, 130.72, 130.45, 126.58, 126.09, 122.55, 120.13, 118.61, 116.49, 80.58, 46.09. HRMS (ESI) m/z calcd for C₇H₇ClN: 140.0267, 140.0269, calcd for C₁₁H₇O₃: 187.0395, found: 187.0406.

3-(4-Chloro-3-nitrophenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (2j). Yellow solid; m.p. 208–211 °C; IR (ν_max cm⁻¹) (Film): 1681, 1212, 1058; ¹H NMR (400 MHz, CDCl₃) δ = 8.11–8.05 (m, 2H, ArH), 7.74–7.69 (m, 3H, ArH), 7.59–7.58 (m, 1H, ArH), 7.44 (d, 1H, J = 9.16 Hz, ArH), 5.49 (s, 2H, CH₂), 4.52 (s, 2H, CH₂).

3-(4-Nitrophenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (2k). Yellow solid; m.p. 216–218 °C; IR (ν_max cm⁻¹) (film): 1679, 1213, 1060; ¹H NMR (400 MHz, CDCl₃) δ = 8.19–8.16 (m, 2H, ArH), 8.10–8.05 (m, 2H, ArH), 7.75–7.68 (m, 2H, ArH), 7.14–7.12 (m, 2H, ArH), 5.54 (s, 2H, CH₂), 4.59 (s, 2H, CH₂).

3-(3-Bromophenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (2l). Yellow solid; m.p. 170–173 °C; IR (ν_max cm⁻¹) (Film): 1678, 1212, 1060; ¹H NMR (400 MHz, CDCl₃) δ = 8.09–8.03 (m, 2H, ArH), 7.72–7.66 (m, 2H, ArH), 7.26 (brs, 1H, ArH), 7.14–7.08 (m, 2H, ArH), 7.04–7.02 (m, 1H, ArH), 5.46 (s, 2H, CH₂), 4.47 (s, 2H, CH₂); ¹³C NMR (100 MHz, CDCl₃) δ = 183.20, 178.80, 148.73, 134.30, 133.45, 131.51, 130.72, 126.59, 126.10, 125.48, 123.26, 121.48, 120.14, 116.95, 80.52, 46.13.

3-(3,4-Dichlorophenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (2m). Yellow solid; m.p. 196–198 °C; IR (ν_max cm⁻¹) (Film): 1677, 1214, 1057; ¹H NMR (400 MHz, CDCl₃) δ = 8.09–8.03 (m, 2H, ArH), 7.73–7.66 (m, 2H, ArH), 7.30 (d, 1H, J = 9.16 Hz, ArH), 7.20–7.19 (m, 1H, ArH), 6.96–6.93 (m, 1H, ArH), 5.44 (s, 2H, CH₂), 4.45 (s, 2H, CH₂); ¹³C NMR (100 MHz, CDCl₃) δ = 178.70, 146.92, 134.38, 133.54, 130.94, 129.74, 126.64, 126.14, 125.84, 120.23, 119.98, 117.91, 80.41, 46.25.

3-(2-Chlorophenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (2n). Yellow solid; m.p. 212–215 °C; IR (ν_max cm⁻¹) (KBr): 1684, 1262, 1044; ¹H NMR (400 MHz, CDCl₃) δ = 8.11–8.03 (m, 2H, ArH), 7.72–7.66 (m, 2H, ArH), 7.38 (d, 1H, J = 6.88 Hz, ArH), 7.30 (d, 1H, J = 8.36 Hz, ArH), 7.15–7.13 (m, 1H, ArH), 7.06–7.02 (m, 1H, ArH), 5.43 (s, 2H, CH₂), 4.40 (s, 2H, CH₂); ¹³C NMR (100 MHz, CDCl₃) δ = 183.21, 179.02, 155.24, 145.23, 134.28, 133.37, 131.63, 130.81, 130.77, 128.76, 127.79, 126.53, 126.10, 125.77, 122.20, 119.96, 82.62, 46.00.

3-(3-Nitrophenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (2o). Yellow solid; m.p. 224–226 °C; IR (ν_max cm⁻¹) (film): 1677, 1212, 1058; ¹H NMR (400 MHz, CDCl₃) δ = 8.09–8.04 (m, 2H, ArH), 7.94 (s, 1H, ArH), 7.81 (d, 1H, J = 6.84 Hz, ArH), 7.72–7.69 (m, 2H, ArH), 7.45–7.41 (m, 2H, ArH), 5.53 (s, 2H, CH₂), 4.55 (s, 2H, CH₂). HRMS (ESI) m/z calcd for C₇H₇ClN: 151.0508, found: 151.0522, calcd for C₁₁H₇O₃: 187.0395, found: 187.0390.

4. Conclusion

In conclusion, we have developed an efficient, clean, and confluent approach for the synthesis of novel 3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione derivatives via reaction of 2-hydroxy-1,4-naphthoquinone, 4-fluoroaniline, and formaldehyde in [bmim]BF₄ at 50 °C. The protocol is environmentally benign, has a high atom-economy and offers recyclability of the reaction media i.e. [bmim]BF₄. The 3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione derivatives synthesized are of great interest for their potential biological activity.

Acknowledgements

G.K. and K.A. thank the Council of Scientific and Industrial Research, New Delhi, India for the grant of junior research fellowship and senior research fellowship, respectively.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1049284. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra06169e

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