Introduction

1,3-Oxazine is present in numerous biodynamic heterocycles as the core structure. It provides a focal intermediate for variety of functional group interconversions (Meyers and Smith 1972; Meyers and Malone 1974). 1,3-Oxazine scaffolds exhibit potential biological and pharmacological activities such as anti-tumour (Kuehne and Konopke 1962; Chylinska and Urbanski 1963; Hsu and Lin 1996), antibacterial (Chylinska et al. 1971; Latif et al. 1982), anti-HIV (Pedersen and Pedersen 2000; Cocuzza et al. 2001), analgesic (Kurtz 2005), antihypertensive (Kajino et al. 1991), antithrombotic (Buckman et al. 1998) and antiulcer (Katsura et al. 1991). Moreover, 6-arylbenzoxazines and naphthoxazines possess therapeutic potential for treatment of Parkinson’s disease and as non-steroidal progesterone receptor agonists, respectively (Zhang et al. 2002; Joyce et al. 2003). Some of the biologically active oxazine scaffolds are shown in Fig. 1.

Fig. 1
figure 1

Some biologically active 1, 3-oxazines exhibiting antitumor, anti-Parkinson and non-steroidal progesterone receptor agonists activity

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Multicomponent reaction is an efficient economic methodology which allows multiple bond formation between simple starting materials generating highly complex and diverse substrates in a single step. It results in high atom economy and avoids purification processes for the intermediates (Domling and Ugi 2000; Ruijter et al. 2011). Therefore, this approach is advantageous over conventional linear type synthesis.

Glycerol has promising physical and chemical properties, which allows its use in many organic reactions that employ various homogeneous and heterogeneous chemo- and biocatalysts (Wolfson et al. 2006, 2007, 2009). It has high boiling point, negligible vapour pressure, low toxicity, high polarity, biodegradability and also compatibility with most organic and inorganic compounds. Its manufacture from renewable sources makes it a promising solvent. In addition to this, glycerol also allows isolation of products by simple filtration, extraction and distillation processes. Glycerol has emerged as a green solvent for numerous organic reactions including Pd-catalysed Heck and Suzuki cross-couplings, Cu-catalysed cross-coupling of diaryl diselenides with aryl boronic acids, base- and acid-promoted condensations, catalytic hydrogenation, transfer hydrogenation and asymmetrical reduction (Gu and Jerome 2010; Diaz-Alvarez et al. 2011).

Our group has recently reported the synthesis of novel 3-aryl-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-diones using ionic liquid [Bmim]BF4 as the reaction media (Khanna et al. 2015). However, the use of ionic liquid has several disadvantages such as toxicity because of possible release into the soil or water courses and thus posing a threat to the environment and also high costs make them somewhat impractical for larger industrial applications. Keeping in consideration the need of developing a greener protocol involving environmentally benign, catalyst-free reaction conditions, we investigated the synthesis of 3-aryl-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-diones from 2-hydroxy-1,4-naphthoquinone (1.0 mmol), aromatic amines (1.0 mmol) and formaldehyde (2.0 mmol) with different hydroxylic solvents.

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 νmax cm−1. The 1H NMR and 13C NMR spectra were recorded on Jeol JNM ECX-400P at 400 and 100 MHz, respectively, using trimethylsilane 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.

General procedure for the synthesis of 3-aryl-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-diones (IVa–n) (using IVa as an example)

A mixture of 2-hydroxy-1,4-naphthoquinone (174.1 mg, 1.0 mmol), 4-fluoroaniline (111.12 mg, 1.0 mmol), formalin (60.06 mg, 37 %, w/v, 2.0 mmol) and glycerol (2 mL) was taken in a 50-mL round-bottomed flask. 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 water followed by 2–3 mL of ethanol. The products were characterized by IR, 1H NMR, 13C NMR and mass spectrometry.

Spectral data

3-(4-Fluorophenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (IVa) Khanna et al. (2015)

Yellow solid; m.p. 191–193 °C (Lit. 194–197 °C); IR (νmax cm−1) (KBr): 1676, 1212, 1061; 1H NMR (400 MHz, CDCl3) δ = 8.08–8.02 (m, 2H, ArH), 7.72–7.65 (m, 2H, ArH), 7.09–7.06 (m, 2H, ArH), 6.97–6.92 (m, 2H, ArH), 5.44 (s, 2H, CH2), 4.42 (s, 2H, CH2).

3-(4-Methoxyphenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (IVb) Khanna et al. (2015)

Yellow solid; m.p. 159–161 °C (Lit. 163–164 °C); IR (νmax cm−1) (KBr): 1681, 1214, 1037; 1H NMR (400 MHz, CDCl3) δ = 8.08–8.01 (m, 2H, ArH), 7.69–7.66 (m, 2H, ArH), 7.07 (d, 2H, ArH, J = 9.2 Hz), 6.80 (d, 2H, ArH, J = 8.4 Hz), 5.44 (s, 2H, CH2), 4.40 (s, 2H, CH2), 3.73 (s, 3H, OCH3).

3-(3,5-Dichlorophenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (IVc)

Yellow solid; m.p. 150–152 °C; IR (νmax cm−1) (KBr): 1681, 1214, 1037; 1H NMR (400 MHz, CDCl3) δ = 8.10–8.04 (m, 2H, ArH), 7.74–7.67 (m, 2H, ArH), 6.97–6.95 (m, 3H, ArH), 5.43 (s, 2H, CH2), 4.46 (s, 2H, CH2); 13C NMR (100 MHz, CDCl3) δ = 183.10, 178.67, 155.42, 149.15, 135.82, 134.40, 133.57, 131.43, 130.68, 126.66, 126.56, 126.16, 120.04, 116.63, 79.86, 46.10. HRMS (ESI) m/z calcd. for calcd. for C18H11Cl2NO3: 360.0191, found: 359.0116 [M + H]+.

3-(2-Bromo-4-methylphenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (IVd)

Yellow solid; m.p. 192–194 °C; IR (νmax cm−1) (KBr): 1682, 1218, 1060; 1H NMR (400 MHz, CDCl3) δ = 8.10–8.02 (m, 2H, ArH), 7.71–7.68 (m, 2H, ArH), 7.39 (s, 1H, ArH), 7.20–7.18 (m, 1H, ArH), 6.99–6.97 (m, 1H, ArH), 5.38 (s, 2H, CH2), 4.35 (s, 2H, CH2), 2.44 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ = 183.20, 179.07, 155.26, 144.08, 136.44, 134.26, 133.33, 131.62, 130.74, 129.01, 126.19, 126.07, 122.44, 119.93, 119.22, 83.11, 46.36, 20.36. HRMS (ESI) m/z calcd. for calcd. for C11H7O3: 187.0395, found: 187.0392.

3-(3-Chlorophenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (IVe) Khanna et al. (2015)

Yellow solid; m.p. 173–175 °C (Lit. 173–175 °C); IR (νmax 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).

3-(4-Chlorophenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (IVf) Khanna et al. (2015)

Yellow solid; m.p. 180–182 °C (Lit. 183–184 °C); IR (νmax cm−1) (KBr): 1676, 1212, 1061; 1H NMR (400 MHz, CDCl3) δ = 8.09–8.03 (m, 2H, ArH), 7.73–7.67 (m, 2H, ArH), 7.25–7.22 (m, 2H, ArH), 7.06–7.04 (m, 2H, ArH), 5.47 (s, 2H, CH2), 4.46 (s, 2H, CH2).

3-(4-Bromophenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (IVg) Khanna et al. (2015)

Yellow solid; m.p. 190–192 °C (Lit. 196–198 °C); IR (νmax cm−1) (Film): 1678, 1213, 1058; 1H NMR (400 MHz, CDCl3) δ = 8.09–8.03 (m, 2H, ArH), 7.73–7.67 (m, 2H, ArH), 7.25–7.22 (m, 2H, ArH), 7.06–7.04 (m, 2H, ArH), 5.47 (s, 2H, CH2), 4.46 (s, 2H, CH2).

3-(3-Acetylphenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (IVh) Khanna et al. (2015)

Yellow solid; m.p. 179–181 °C (Lit. 183–184 °C); IR (νmax cm−1) (KBr): 1681, 1206, 1061; 1H NMR (400 MHz, CDCl3) δ = 8.07–8.02 (m, 2H, ArH), 7.70–7.67 (m, 3H, ArH), 7.54–7.52 (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).

3-(4-Iodophenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (IVi)

Yellow solid; m.p. 140–142 °C; IR (νmax cm−1) (KBr): 1682, 1218, 1060; 1H NMR (400 MHz, CDCl3) δ = 8.07–8.02 (m, 2H, ArH), 7.72–7.67 (m, 2H, ArH), 7.54 (d, 2H, ArH, J = 8.4 Hz), 6.88 (d, 1H, ArH, J = 8.4 Hz), 5.45 (s, 2H, CH2), 4.45 (s, 2H, CH2); 13C NMR (100 MHz, CDCl3) δ = 183.20, 178.79, 155.45, 147.15, 138.29, 134.29, 133.43, 131.49, 130.71, 126.57, 126.08, 120.60, 120.08, 85.28, 46.10. HRMS (ESI) m/z calcd. for calcd. for C18H11Cl2NO3: 417.9940, found: 417.9935 [M + H]+.

3-(3-Chloro-4-fluorophenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (IVj) Khanna et al. (2015)

Yellow solid; m.p. 162–164 °C (Lit. 162–164 °C); IR (νmax cm−1) (KBr): 1682, 1216, 1062; 1H NMR (400 MHz, CDCl3) δ = 8.09–8.03 (m, 2H, ArH), 7.73–7.66 (m, 2H, ArH), 7.16–7.14 (m, 1H, ArH), 7.05–6.95 (m, 2H, ArH), 5.42 (s, 2H, CH2), 4.42 (s, 2H, CH2).

3-(4-Chloro-3-nitrophenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (IVk) Khanna et al. (2015)

Yellow solid; m.p. 204–206 °C (Lit. 208–211 °C); IR (νmax cm−1) (Film): 1681, 1212, 1058; 1H NMR (400 MHz, CDCl3) δ = 8.11–8.06 (m, 2H, ArH), 7.76–7.69 (m, 2H, ArH), 7.59 (s, 1H, ArH), 7.45–7.42 (m, 1H, ArH), 7.26–7.25 (m, 1H, ArH), 5.50 (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 (IVl) Khanna et al. (2015)

Yellow solid; m.p. 216–218 °C (Lit. 216–218 °C); IR (νmax 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 (IVm) Khanna et al. (2015)

Yellow solid; m.p. 170–173 °C (Lit. 170–173 °C); IR (νmax cm−1) (Film): 1678, 1212, 1060; 1H NMR (400 MHz, CDCl3) δ = 8.08–8.03 (m, 2H, ArH), 7.72–7.66 (m, 2H, ArH), 7.25 (s, 1H, ArH), 7.14–7.01 (m, 3H, ArH), 5.46 (s, 2H, CH2), 4.47 (s, 2H, CH2).

3-(2-Methylphenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (IVn) Khanna et al. (2015)

Yellow solid; m.p. 160–162 °C (Lit. 160–162 °C); IR (νmax 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).

Results and discussion

We report herein a facile and efficient one-pot synthesis of 3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione derivatives by one-pot three-component condensation of 2-hydroxy-1,4-naphthoquinone, aromatic amines and formaldehyde in glycerol at 50 °C. The optimum reaction conditions were established using 2-hydroxy-1,4-naphthoquinone (I) (1.0 mmol), 4-fluoroaniline (IIa) (1.0 mmol) and formaldehyde (III) (2.0 mmol), as standard components. The model reactions were performed in various hydroxylic solvents such as MeOH, EtOH, water, ethylene glycol, PEG-400, PEG-600 and glycerol under catalyst-free conditions at varying temperatures. Initially, the reaction was attempted in MeOH under reflux which was complete in 10 min and afforded 52 % of the desired 3-(4-fluorophenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione as confirmed by spectral analysis (Table 1, entry 1). The reaction in EtOH under reflux was also complete in 10 min and afforded 54 % of the desired product (Table 1, entry 2). The product formation was also observed when the reaction was carried out in EtOH–water and MeOH–water (1:1, v/v) at reflux, though with inferior yields of 40 and 51 %, respectively (Table 1, entries 3–4). Reaction attempted in ethylene glycol at 60 °C gave the desired naphtho[2,3-e][1,3]oxazine-5,10-dione in higher yield (83 %) (Table 1, entry 5). Reaction in ethylene glycol at higher temperatures (80 and 100 °C) did not have much influence on the reaction yield and time (Table 1, entries 6–7). The above reaction when performed in PEG-400 and PEG-600 resulted in a mixture of products even after 8 h as observed by TLC using ethyl acetate/petroleum ether (30: 70, v/v) as eluent (Table 1, entries 8–9). The same reaction was then attempted using glycerol as the solvent which yielded 91 % of the desired 3-(4-fluorophenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione in just 5 min (Table 1, entry 10).

Table 1 Optimization of reaction conditions for the synthesis of 3-(4-fluorophenyl)-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (IVa)
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Therefore, Table 1 clearly shows that the best optimized reaction condition for the one-pot catalyst-free synthesis of naphtho[2,3-e][1,3]oxazine-5,10-diones was using glycerol as the solvent at 50 °C. To realize the generality of this protocol, a series of naphtho[2,3-e][1,3]oxazine-5,10-dione derivatives were synthesized by one-pot condensation of 2-hydroxy-1,4-naphthoquinone, various aromatic amines and formaldehyde in glycerol at 50 °C. Both electron-withdrawing and electron-releasing aromatic amines were employed under the optimized reaction conditions to yield the desired products in good yields (Fig. 2; Table 2).

Fig. 2
figure 2

One-pot multicomponent synthesis of 3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-diones. Reaction conditions: 2-hydroxy-1,4-naphthoquinone (1.0 mmol), aromatic amines (1.0 mmol) and formaldehyde (2.0 mmol) in glycerol at 50 °C

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Table 2 Synthesis of 3-aryl-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione (IVa–n)
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All our attempts to prepare bis-derivatives from o- and p-phenylene diamines were unsuccessful.

A study regarding the recovery and reuse of glycerol was also performed. The products were separated by simple filtration from the mixture of glycerol and water. The filtrate so obtained was then extracted with ethyl acetate. Ethyl acetate layer was separated and the solvent was removed. The glycerol–water layer was dried at 90 °C under vacuum and then directly reused for reaction. Marginal loss in the yield (90 and 88 %) of IVa was observed in the second and third cycles. However, the yields decreased gradually in fourth and fifth cycle (85 and 82 %).

A probable mechanism involved in the formation of products is outlined in Fig. 3. Initial condensation of formaldehyde and aromatic amine (ArNH2) gives an imine intermediate ‘A’ which further reacts with 2-hydroxy-1,4-naphthoquinone to form ‘B’. Lastly, condensation of ‘B’ with formaldehyde gives ‘C’ with loss of H2O that undergoes cyclization to give the final product IV.

Fig. 3
figure 3

Probable mechanism of the reaction. Glycerol polarizes formaldehyde for attack of aromatic amine leading to imine formation giving A which reacts with 2-hydroxy-1,4-naphthoquinone, and finally, condensation with another mole of formaldehyde gives final product IV with loss of water

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Conclusion

In conclusion, we have developed an eco-friendly catalyst-free methodology for the synthesis of 3-aryl-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-diones from 2-hydroxy-1,4-naphthoquinone, aromatic amines and formaldehyde in glycerol at 50 °C. Inexpensive, environmentally benign reaction media is the advantage of this protocol.