Efficient, three-component synthesis of 1-aryl-2, 3-dihydro-3-phenyl-1H-naphth[1,2-e][1,3] oxazines derivatives, using LaCl^sub 3^/ClCH^sub 2^COOH as an environmentally benign and green catalytic system

Abstract

1-aryl-2,3-dihydro-3-phenyl-1H-naphth[1,2-e][1,3] oxazines are synthesized in good to excellent yields in the presence of LaCl^sub 3^/ClCH^sub 2^COOH as an inexpensive and environmentally benign catalytic system under solvent-free conditions.

Headnote

KEYWORDS

Naphth[1,2-e][1,3] oxazines;

Heterocycle;

2-naphthol;

Aromatic aidehydes;

Green catalyst;

Lanthanum chloride.

Abstract. 1-aryl-2,3-dihydro-3-phenyl-1H-naphth[1,2-e][1,3] oxazines are synthesized in good to excellent yields in the presence of LaCl^sub 3^/ClCH^sub 2^COOH as an inexpensive and environmentally benign catalytic system under solvent-free conditions.

© 2014 Sharif University of Technology. All rights reserved.

1. Introduction

The N,O-containing heterocycles have received significant attention due to their biochemical activities [1,2]. Additionally, naphthoxazines and their derivatives possess important biological properties, including analgesic, anti-convulsant, anti-tubercular, anti-bacterial and anti-cancer [3-6], and have attracted far more interest due to their therapeutic potential for the treatment of Parkinson's disease [7,8]. The tautomeric character of 1,3-O,N-heterocycles offers a great number of synthetic possibilities [9-11]. Because of the importance of naphthoxazines, the synthesis of new derivatives of these compounds is an important and useful task in organic chemistry.

Multi-Component Reactions (MCRs) are powerful and useful synthetic tools to produce complex organic molecules due to the formation of carboncarbon and carbon-heteroatom bonds in a one-pot process [12-14]. Therefore, the design of novel MCRs has attracted great attention from research groups working in medicinal chemistry and drug discovery.

However, the reported methods for the synthesis of 1,3-diaryl-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazines involve the condensation reaction of 2-naphthol and various substituted aryl and hetero aryl aldehydes in the presence of dry methanolic ammonia, via known two-step reactions [15-17]. In this paper, we report an environmentally benign, solvent-free approach for the synthesis of new naphthoxazine derivatives via multi-component reactions in the presence of LaCl3/ClCH2COOH (Scheme 1).

2. Experimental

2.1. Materials and methods

Chemicals were either prepared in our laboratory or purchased from Merck or Fluka chemical companies, and were used without any further purification. All reactions were monitored by TLC, and petroleum-ether EtOAc, 3:1. Melting points were determined with a hot-plate microscope apparatus. IR spectra were recorded in KBr, using a BRUKER FT-IR spectrophotometer. 1H and 13C NMR spectra were recorded on a Bruker 400-MHz spectrometer using CDCl3 and TMS as the solvent and internal standard, respectively.

2.1.1. Synthesis of phenylmethanimine

A round-bottomed flask (100 ml) was charged with a 6.6 M ammonia solution in methanol (23 ml) and then benzaldehyde (1 g, 9.4 mmol) was added dropwise over time increments of 5 minutes at ambient temperature. After the addition was complete, the reaction mixture was leftstirring for 24 h at 20C. The precipitate formed was filtered and washed with hexane and, finally, dried at room temperature to give phenylmethanimine as white powder, 95% yield [18].

2.2. General procedure for the preparation of 1-aryl-2,3-dihydro-3-phenyl-1H-naphth[1,2-e][1,3] oxazine using LaCl3/ClCH2COOH catalytic system

Typically, a mixture of 2-naphthol (0.144 g, 1 mmol), phenylmethanimine (0.116 g, 1.1 mmol), benzaldehyde (1 mmol), lanthanum (III) chloride (0.04 g, 0.16 mmol) and chloroacetic acid (0.189 g, 2.0 mmol) was heated at 125°C under stirring for the required amount of time. The progress of the reaction was checked periodically using TLC and, after completion of the reaction, the mixture was diluted with CHCl3/CH3OH (3:1). The solvent was evaporated and the crude product was recrystallized from EtOH to afford the final product. Other substituted aromatic aldehydes also reacted well under the same conditions, giving the corresponding product with excellent yields (Table 1). All the products obtained were characterized by spectroscopic methods such as IR, 1H NMR and 13C NMR, and have been identified by comparison of the spectral data and melting point with those obtained in authentic samples.

Note: In all IR spectra of products, the OH bond disappeared and sharp signals of NH bond at about 3400 cm-1 were emerged.

The spectral data for some selected compounds are presented as follows:

2.2.1. Spectra data of 2,3-dihydro-1,3-diphenyl-1H-naphth[1,2-e][1,3] oxazine (3a)

Yield 94%; yellow solid, m.p. 143-145C. IR (KBr) v (cm-1): 3426(NH), 3057, 1594, 1244. 1H NMR (CDCl3, 400 MHz,): δ (ppm): 6.44 (s, 1H, CH), 6.53 (brd, 1H, NH), 6.79 (s, 1H, CH), 7.03(d, 2H, J =8 Hz, arom), 7.15 (d, 1H, J = 7 Hz, arom), 7.16 (d, 3H, J = 8 Hz, arom) 7.36-750 (m, 4H, arom), 7.50-7.72 (m, 3H, arom), 7.76-7.941 (m, 3H, arom); 13C NMR (CDCl3, 100 MHz): δ (ppm): 37.16 (Nph-CHAr-NH), 87.40 (O-CHAr-NH), 117.36, 118.03, 119.31, 122.71, 122.99, 123.44, 124.26, 125.47, 126.40, 126.54, 126.81, 128.27, 128.45, 128.49, 128.81, 129.02, 129.35, 130.56, 131.08, 131.48, 134.84. 143.39.

2.2.2. Spectra data of 4-(2, 3-dihydro-3-phenyl-1Hnaphth[1, 2-e][1,3]oxazin-1-yl) phenol (3c)

Yield 94%; violet solid, m.p. 158-160°C. IR (KBr) v (cm-1): 3471(NH), 3163, 3064 (OH), 1514, 1249 cm-1. 1H NMR (CDCl3, 400 MHz): δ (ppm): 6.47 (s, 1H, CH), 6.53 (brd, 1H, NH), 6.72 (s, 1H, CH), 7.03-7.50 (m, 7H, arom), 7.50-7.70 (m, 3H, arom), 7.84 (d, 5H, J = 7:5 Hz, arom), 8.43(s, 1H, OH). 13 C NMR (CDCl3, 100 MHz): δ (ppm): 38.04 (Nph-CHAr-NH), 87.06 (O-CHAr-NH), 117.04, 117.34, 118.03, 119.39, 122.70, 124.25, 126.39, 126.80, 128.27, 128.49, 128.81, 129.05, 129.37, 130.63, 131.07, 131.46, 141.63, 142.07, 142.42.

2.2.3. Spectra data of 1-(2-chlorophenyl)2,3-dihydro-3-phenyl-1H-naphth [1,2-e][1,3]oxazine (3g)

Yield 97%; white powder, m.p. 135-137°C. IR (KBr) v (cm-1): 3354(NH), 3057, 1895, 1594, 1240 cm-1; 1H NMR (CDCl3, 400 MHz): δ (ppm): 6.46 (s, 1H, CH), 6.52 (brd,1H, NH), 6.64 (s, 1H, CH), 7.03 (t, 1H, J = 8:5 Hz, arom), 7.17-7.32 (m, 4H, arom), 7.42-7.51 (m, 3H, arom), 7.54 (d, 1H, J = 9 Hz, arom), 7.67 (t, 3H, J = 8 Hz, arom), 7.8-7.98 (m, 3H, arom). 13C NMR (CDCl3, 100 MHz): δ (ppm): 37.66 (Nph-CHAr-NH), 89.49 (O-CHAr-NH), 117.36, 118.04, 119.31, 122.51, 123.44, 124.26, 125.44, 126,40, 126.54, 128.27, 128.45, 128.49, 128.58, 128.66, 128.81, 128.87, 129.02, 129.35, 130.56, 131.48, 134.88, 144.34.

2.2.4. Spectra data of 1-(2,4-dichlorophenyl)-2,3-dihydro-3-phenyl-1H-naphth[1,2-e][1,3]oxazine (3h)

Yield 98%; white powder, m.p. 148-150°C. IR (KBr) v (cm-1): 3409 (NH), 2957, 1236, 803 cm-1. 1H NMR (CDCl3, 400 MHz) δ (ppm): 6.51(s, 1H, CH), 6.79(s, 1H, NH), 6.92 (s, 1H, CH), 7.02 (t, 1H, J = 8 Hz, arom), 7.15 (t, 2H, J = 7:5 Hz, arom), 7.35-7.71 (m, 9H, arom), 7.86 (m, 2H, arom). 13C NMR (CDCl3, 100 MHz): δ (ppm): 38.04 (Nph-CHAr-NH), 86.37 (O-CHAr-NH), 117.48, 118.11, 122.69, 123.15, 123.24, 124.58, 126.38, 126.79, 127.07, 127.97, 128.26, 128.47, 128.85, 129.15, 130.17, 130.61, 130.93, 131.05, 131.60, 132.71, 148.73, 148.93.

2.2.5. Spectra data of 1-(3-nitrophenyl)2,3-dihydro-3-phenyl-1H-naphth [1,2-e][1,3]oxazine (3i)

Yield 95%; yellow powder, m.p. 176-178°C. IR (KBr) v (cm-1): 3492(NH), 3234, 3063, 1247 cm-1; 1H NMR (CDCl3, 400 MHz): δ (ppm): 6.53 (s, 1H, CH), 6.90 (brd, 1H, NH), 7.02(s, 1H, CH), 7.14(d, 2H, J = 8 Hz, arom), 7.21 (m, 2H, arom), 7.42 (m, 3H, arom), 7.51 (d, 2H, J = 8:5 Hz, arom), 7.53-7.73 (m, 3H, arom), 7.81 (m, 2H, arom), 7.87 (t, 1H, J = 9 Hz, arom). 13C NMR (CDCl3, 100 MHz): δ (ppm): 37.82 (Nph-CHAr-NH), 87.82 (O-CHAr-NH), 118.45, 122.86, 122.99, 123.12, 124.67, 124.81, 127.22, 127.36, 128.68, 128.90, 129.07, 129.22, 129.28, 129.35, 129.42, 129.44, 129.53, 129.93, 131.50, 149.18.

3. Results and discussion

To optimize and find the best conditions, the reaction of 2-naphthol (1 mmol), benzaldehyde (1 mmol) and phenylmethanimine (1.1 mmol), in the presence of LaCl3 (0.16 mmol) was performed in different solvents, and the results are summarized in Table 2 (entries 1-5). High yield and short reaction time were obtained when the reaction was carried out in the presence of chloroacetic acid.

In another study, the condensation of 2-naphthol, 4-hydroxybenzaldehyde and phenylmethanimine was examined in the presence of different quantities of LaCl3 at 125°C temperature (Figure 1). As Figure 1 indicates, reasonable results were obtained when the reaction was performed using 0.04 g of lanthanum chloride. No improvement in the reaction results was observed by increasing the amount of catalyst.

To optimize the temperature in the mentioned reaction, we have carried out a model study with benzaldehyde and 2-naphthol and phenylmethanimine using LaCl3/ClCH2COOH at various temperatures under solvent-free conditions (Table 3). Table 3 clearly demonstrates that 125C is an effective temperature in terms of reaction time and yields.

After optimizing the conditions, the generality of this method was examined by the reaction of 2-naphthol with different kinds of aromatic aldehydes (2a-2j) and phenylmethanimine, using LaCl3/ClCH2COOH as a catalyst under solvent-free conditions.

The proposed mechanism for synthesis of 1-aryl-2,3-dihydro-3-phenyl-1H-naphthol[ 1,2-e][1,3] oxazines has been shown in Scheme 2.

4. Conclusion

In summary, we have developed a practical method for preparation of new naphth[1,2-e][1,3]oxazines derivatives in the presence of LaCl3/ClCH2COOH, as an efficient, inexpensive, readily available and environmentally benign catalytic system. This green methodology has the advantages of mild reaction conditions, short reaction times, good yields, easily accessible starting materials, and easy purification of products, which makes it a useful and reliable method for the synthesis of the described compounds. In addition, it is consistent with a green chemistry approach, since no organic solvent is needed.

Acknowledgment

We gratefully acknowledge the funding support received for this project from the Research Council of Shahid Bahonar University of Kerman.

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