Green Synthesis of Aryl Naphthoxazine-2-thiones Using NiFe2O4@SiO2 n Pr@GA Under Ultrasound Irradiation

In multi-component reactions (MCRs) more than two components of raw materials are reacted and transformed into products. Among the advantages of MCRs are convenience and low cost, owing to the need for less energy and labor compared to multi-step reactions. Oxazines have antibacterial, antifungal, anti-inflammatory, antitumor antirheumatic, anticonvulsant and anticancer properties. Given their biological activities and the possibility of structural isomerism, a number of different approaches have been taken to the preparation of these important heterocycles, often relying on the use of particular catalysts or reaction techniques. In spite of the merits of previous research efforts, there remains a need for simple green methods for the efficient preparation of naphtho[1,2-e]oxazine-3-thiones. In continuation of our exploration of green methods in synthetic organic chemistry, we now report on the synthesis of aryl naphthoxazine-2-thiones, formed under ultrasound irradiation using MCRs among aldehydes, a-naphthol or b-naphthol, and thiourea at room temperature in the presence of glucosamine-functionalized silica-coated Fe3O4 nanoparticles (NiFe2O4@SiO2 Pr@GA) (Figure 1, Scheme 1). The preparation and complete characterization of the catalyst are described in the Experimental section and Supplementary Materials. In order to optimize the reaction conditions, our experiments included an examination of solvents, temperatures, the presence or absence of ultrasound irradiation and the nature and quantity of the catalyst (Tables 1-4), using as a model the MCR among 4-chlorobenzaldehyde 1a (1mmol), thiourea 2 (1mmol), and b-naphthol 3a (1mmol) to produce 1(4-chlorophenyl)-3H-naphtho[1,2-e][1,3]oxazine-3-thione 4a. The following observations sum up our findings. In the absence of catalyst or ultrasound (Table 1, Entry 1), the yield was only 50%, even after 48 hours of reaction at room temperature in water. The addition of ultrasound or catalyst individually led to big increases in the yield and shorter reaction times (Table 1, Entries 8 and 11), but the highest yield and shortest reaction time was obtained when both ultrasound and the catalyst were used (Table 1, Entry 12).

In multi-component reactions (MCRs) more than two components of raw materials are reacted and transformed into products. Among the advantages of MCRs are convenience and low cost, owing to the need for less energy and labor compared to multi-step reactions. 1 Oxazines have antibacterial, antifungal, anti-inflammatory, antitumor antirheumatic, anticonvulsant and anticancer properties. [2][3][4] Given their biological activities and the possibility of structural isomerism, 5 a number of different approaches have been taken to the preparation of these important heterocycles, [6][7][8][9][10][11] often relying on the use of particular catalysts 12,13 or reaction techniques. 14 In spite of the merits of previous research efforts, there remains a need for simple green methods for the efficient preparation of naphtho [1,2-e]oxazine-3-thiones. In continuation of our exploration of green methods in synthetic organic chemistry, [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] we now report on the synthesis of aryl naphthoxazine-2-thiones, formed under ultrasound irradiation using MCRs among aldehydes, a-naphthol or b-naphthol, and thiourea at room temperature in the presence of glucosamine-functionalized silica-coated Fe 3 O 4 nanoparticles (NiFe 2 O 4 @SiO 2 n Pr@GA) ( Figure 1, Scheme 1). The preparation and complete characterization of the catalyst are described in the Experimental section and Supplementary Materials. In order to optimize the reaction conditions, our experiments included an examination of solvents, temperatures, the presence or absence of ultrasound irradiation and the nature and quantity of the catalyst (Tables 1-4), using as a model the MCR among 4-chlorobenzaldehyde 1a (1 mmol), thiourea 2 (1 mmol), and b-naphthol 3a (1 mmol) to produce 1-(4-chlorophenyl)-3H-naphtho[1,2-e] [1,3]oxazine-3-thione 4a. The following observations sum up our findings. In the absence of catalyst or ultrasound ( Table 1, Entry 1), the yield was only 50%, even after 48 hours of reaction at room temperature in water. The addition of ultrasound or catalyst individually led to big increases in the yield and shorter reaction times ( Table 1, Entries 8 and 11), but the highest yield and shortest reaction time was obtained when both ultrasound and the catalyst were used (Table 1, Entry 12).
Six common solvents were studied for the process ( Table 2). It was found that H 2 O was best in terms of over-all yield and short reaction time. Water clearly has the advantage of being the greenest choice among these solvents.
The preparation of 4a was carried out at 0, 25, 40 and 60 C (Table 3), and the results showed that the optimum temperature for this reaction was 25 C.
Finally, the synthesis of model product 4a with different amounts of NiFe 2 O 4 @SiO 2 n Pr@GA at room temperature was investigated (Table 4), and it was found that using 0.1 g of the desired catalyst per mmol of aldehyde gave the best results.
To examine the scope of the procedure, a number of different aldehydes, thiourea and a-naphthol or b-naphthol were reacted under the optimal conditions, and the results are summarized in Table 5. Yields were uniformly excellent (range 90-97%) and there did not appear to be any strong dependence of yields on the nature of substituents. Interestingly, one factor distinguishes the present findings from previous studies on the preparation of aryl naphthoxazine-2-thione compounds; 24 in the past, this MCR is reported as leading to aryl 2,5-dihydronaphtho [1,3]oxazine-2-thiones. Under our conditions, however, dehydrogenation generally occurred, and title aryl naphthoxazine-2- thiones were produced, with the exception of 4f. We surmise that, in most cases, the dehydrogenation leads to the aromatization of the heterocyclic ring and, as a result, to the greater stability of the product formed. The short reaction times observed are attributable to the combined benefits of the catalyst and acoustic cavitation. [25][26][27] The recylcability and reusability of the catalyst were studied in the model preparation of 4a. At the end of the reaction, the magnetically-separated catalyst was washed and dried at 80 C (see Experimental section). The catalyst was used again for subsequent experiments under the same reaction conditions. As shown in Table 6, yields decreased only slightly after reusing the catalyst six times.     In conclusion, we have investigated NiFe 2 O 4 @SiO 2 n Pr@GA as a new, effective and reusable catalyst for the preparation of aryl naphthoxazine-2-thiones in water at room temperature under ultrasound. The procedure is characterized by high yields, good product purity and the avoidance of organic solvents. In general, the title products formed represent the combination of MCR and subsequent dehydrogenation, making this preparation distinct from previous ones.

Experimental section
For the ultrasound reactions, Astra 3D apparatus was used (9.5 dm3, 45 kHz frequency, input power with heating, 305W, number of transducers, 2) from TECNO-GAZ was used. Chemicals were purchased from Merck and Fluka and used as received. Melting points were measured on an Electro-thermal 9100 apparatus and are uncorrected. 1 H NMR spectra were obtained on a Bruker DRX 500 Avance spectrometer in CDCl 3 as solvent and with TMS as internal standard. FT-IR spectra were recorded on a Shimadzu FT-IR-8400S spectrometer. Elemental analyses were recorded on a Carlo-Erba EA1110CNNO-S analyzer. FE-SEM was done on a FESEM FEI Quanta 400 FEG instrument. VSM measurements were obtained on a SQUID-VSM instrument. XRD data were achieved using an Xpert X-ray powder diffraction instrument. Mass analysis was performed on an ELAN DRC-2 analyzer.

Synthesis of NiFe 2 O 4 and NiFe 2 O 4 @SiO 2 n PropylCl magnetic nanoparticles
The NiFe 2 O 4 and NiFe 2 O 4 @SiO 2 n PropylCl magnetic nanoparticles (MNPs) were prepared as previously noted. [28][29]   Synthesis of NiFe 2 O 4 @SiO 2 n Propyl@GA nanoparticles under ultrasound irradiation A mixture of NiFe 2 O 4 @SiO 2 n PropylCl MNPs (0.5 g), glucosamine (0.5 g) and distilled water (15 mL) was placed in a Pyrex glass open vessel and irradiated in a water bath under silent conditions by ultrasound (45 kHz) at room temperature for 30 min. Then, triethylamine (5 mL) was added and irradiated at room temperature for 10 min. Then ethanol was added (30 mL) and the catalyst product was separated by filtration. The catalyst was warmed in an oven at 50 C for 24 h. The structure of the nanocatalyst obtained was confirmed by FT-IR, EDX, XRD, VSM, TEM and SEM spectroscopy, which are available in the Supplementary Material in the online version or from the corresponding author upon request.
General procedure for the preparation of aryl naphthoxazine-2-thiones (4a-l) A mixture of the appropriate aldehyde (1 mmol), a-naphthol or b-naphthol (1 mmol), thiourea (1 mmol) and 0.1 g NiFe 2 O 4 @SiO 2 n Pr@GA was irradiated at room temperature for the required reaction time according to thin layer chromatography (TLC; silica gel 60 F 254 , ethyl acetate: n-hexane (1: 2)). After completion of the reaction, the resulting mixture was dissolved in hot ethanol (20 mL). The catalyst was separated by a 1.4 Tesla external magnet and washed with hot distilled water (5 mL) and ethanol (5 mL) two times, then dried as noted above for re-use. The resulting aryl naphthoxazine-2-thione was isolated and purified using recrystallization with hot ethanol (5 mL) two times. All of the compounds of this study were known materials and were identified by comparing the appropriate physical and spectroscopic data with those previously reported. 28