Sulfonic Acid Functionalized Nano-γ-Al2O3: A New, Efficient, and Reusable Catalyst for Synthesis of 3-Substituted-2H-1,4-Benzothiazines

A simple and efficient synthetic protocol has been developed for the synthesis of 3-substituted-2H-1,4-benzothiazines by using a novel sulfonic acid functionalized nano-γ-Al2O3 catalyst, devoid of corrosive acidic, and basic reagents. The developed method has the advantages of good to excellent yields, short reaction times, operational simplicity, and a recyclable catalyst. The catalyst can be prepared by a simple procedure from inexpensive and readily available nano-γ-Al2O3 and has been shown to be recoverable and reusable up to six cycles without any loss of activity.

There are several methods available for the preparation of 1,4-benzothiazine derivatives including the ring expansion of benzothiazoles or benzothiazolines [15,16], basic mediated reactions of o-aminothiophenols withbromoacetophenones [17], HCl-catalyzed reactions of onitrobenzenesulfenyl chlorides with ketones [18], treatment of aminothioalkenols with p-TsOH or H 3 PO 4 [19], reaction of bis(o-aminophenyl)-disulfide with ketones [20], the condensation of o-aminothiophenols and 2-bromo-1-arylethanones using KHSO 4 [21], and simultaneous reduction of nitro group and S-S bond in nitrodisulfides induced by low-valent titanium reagent [22]. Despite the importance of these reported protocols many suffer from drawbacks such as the use of expensive reagents, harsh reaction conditions, prolonged reaction times, cumbersome product isolation procedures, low yields more stoichiometric amount of catalyst. Hence, to explore a mild, efficient, and environmentally benign recyclable synthetic protocol for the 1,4-benzothiazine derivatives is highly desirable.
In recent times, the development of environmentally benign, green, and easily recyclable catalyst for the production of fine chemicals has been an area of growing interest. In this context, solid acid catalysts play prominent role in organic synthesis under heterogeneous reaction conditions. Various solid acid catalysts like zeolite [23], heteropoly Scheme 2: Synthesis of 3-substituted-2H-1,4-benzothiazines using sulfonic acid functionalized nano--Al 2 O 3 .
As a part of our endeavors towards the development of efficient and environmentally benign synthetic methodologies using economic and eco-friendly heterogeneous catalysts [27,29], we have investigated the synthesis of 3-substituted-2H-1,4-benzothiazines from o-aminothiophenols andbromoketones in the presence of a novel sulfonic acid functionalized nano--Al 2 O 3 catalyst in EtOH at reflux temperature (Scheme 1).

Results and Discussion
Sulfonic acid functionalized nano--Al 2 O 3 was easily prepared by the reaction of nano--Al 2 O 3 with 1,3-propanesultone (Scheme 2), and it was characterized by FT-IR, Xray powder diffraction (XRD), thermogravimetric analysis (TGA), and transmission electron microscopy (TEM). The amount of sulfonic acid loaded on the surface of nano--Al 2 O 3 is determined by TG analysis and confirmed by ionexchange pH analysis. To achieve suitable conditions for the synthesis of 3substituted-2H-1,4-benzothiazines, we tested the reaction of o-aminothiophenol 1 with 2-bromo-1-phenyl-ethanone 2 as a simple model system in EtOH at reflux temperature using various catalysts ( Table 1). As could be seen in Table 1, the best result was obtained with 50 mg/mmol of sulfonic acid functionalized nano--Al 2 O 3 as the catalyst in EtOH at reflux temperature (entry 3). Using less catalyst resulted in lower yields, whereas higher amounts of catalyst did not affect reaction times and yields. When this reaction was carried out without sulfonic acid functionalized nano--Al 2 O 3 or nano--Al 2 O 3, the yield of the expected product was low. In the presence of p-TsOH, sulfamic acid, or silica sulfuric acid, the product was obtained in moderate yield.  To find the optimal solvent for this reaction, the model reaction was carried out at reflux temperature using EtOH, H 2 O, CH 2 Cl 2 , THF, and CH 3 CN as solvents. It is shown in Table 2 that the reaction using EtOH (96%) or CH 3 CN (97%) 4 The Scientific World Journal as the solvents gave the corresponding product 3-phenyl-2H-1,4-benzothiazine in high yields ( Table 2, entries 8 and 2). From the economic and environmental point of view, EtOH was chosen as the reaction medium for all further reactions. Furthermore, the relation between the yields of the model reaction and temperature was also studied. We carried out the reaction at temperatures ranging from 25 ∘ C to reflux temperature using EtOH as the reaction medium ( Table 2, entries 5-8), finding that the yields of desired product 3phenyl-2H-1,4-benzothiazine were improved as the temperature was increased. Therefore, the best reaction conditions were obtained in EtOH under refluxed temperature. In order to demonstrate the versatility of the sulfonic acid functionalized nano--Al 2 O 3 promoted synthesis of 3-substituted-2H-1,4-benzothiazines, a series ofbromoketones were treated with various o-aminothiophenols ( Table 3). The reactions proceeded in EtOH at reflux temperature within a short time to afford the products. The reaction of o-aminothiophenol with various -bromoketones resulted in high yields of 3-substituted-2H-1,4-benzothiazines. The structures of the products were established from their spectral properties (IR, 1 H NMR, and elemental analysis) and also by comparison with the available literature data.
To demonstrate the recyclability of the catalyst, after each cycle the reaction mixture was allowed to cool and the catalyst was recovered by simple filtration, washed with EtOH, and dried in an oven at 100 ∘ C for 30 min prior to use. The catalyst was reused for the same reaction without further activation. The reaction proceeded smoothly even after six cycles, without any extension of reaction time or marked loss in yield ( Figure 5).
The formation of product may be explained by the reaction of -bromoketone 2 with sulfonic acid functionalized nano--Al 2 O 3 which forms an oxonium ion. Later it reacts with o-aminothiophenol and subsequent cyclization result in expected product (Scheme 3).

Conclusion
In conclusion, we have developed a novel and reusable sulfonic acid functionalized nano--Al 2 O 3 catalyst for an

Materials and
Instrumentation. -Alumina powder with particle size at about 20 nm was purchased from Aladdin (Shanghai, China) and was used without further purification. Other reagents and starting materials were purchased from commercial resources and were used as received. All products were characterized by comparison of their spectral and The Scientific World Journal physical data with those previously reported. Progress of the reactions was monitored by TLC.
XRD patterns were recorded using a Cu K radiation source on a D8 Advance Bruker powder diffractometer. TEM studies were performed using a JEM 2100 transmission electron microscope on an accelerating voltage of 150 kV. TGA curves are recorded using a DT-40 thermoanalyzer. IR spectra were determined on FTS-40 infrared spectrometer. 1 H NMR spectra were determined on Bruker AV-400 spectrometer at room temperature using tetramethylsilane (TMS) as an internal standard (CDCl 3 solution); coupling constants (J) were measured in Hz. Elemental analysis was performed by a Vario-III elemental analyzer. Melting points were determined on an XT-4 binocular microscope and were uncorrected.

Synthesis of Sulfonic Acid Functionalized Nano--Al
Nano--Al 2 O 3 (6 g) was suspended in 600 mL of 0.1 M toluene solution of 1,3-propanesultone and the colloidal solution was refluxed for 48 h. The sulfonated nano--Al 2 O 3 was isolated and purified by repeated washing and centrifugation. It was characterized by FT-IR, XRD, TGA, SEM, and TEM. The amount of sulfonic acid loaded on the surface of nano--Al 2 O 3 was determined by TG analysis and confirmed by ionexchange pH analysis.

Ion-Exchange pH Analysis.
To an aqueous solution of NaCl (1 M, 25 mL) with a primary pH 5.93, the catalyst (500 mg) was added and the resulting mixture was stirred for 2 h after which the pH of solution decreased to 1.81. This is equal to a loading of 0.78 mmol SO 3 H⋅g −1 .

General Procedure for the Synthesis of 3-Substituted-2H-1,4-Benzothiazines.
To a suspension of a -bromoketones (1 mmol) and sulfonic acid functionalized nano--Al 2 O 3 (50 mg) in EtOH (10 mL), o-aminothiophenol (1 mmol) was added slowly and the mixture was stirred at reflux temperature. The reaction was monitored by TLC. After completion, the reaction mixture was filtered. The catalyst was washed with EtOH, dried, and reused for a consecutive run under the same reaction conditions. Evaporation of the solvent followed by recrystallization from EtOAc gave the desired product in good to high yields.