# Synthesis and Preliminary Screening of the Biological Activity of Sulindac Sulfoximine Derivatives
## 3 Results and Discussion  
### Synthesis of Sulindac Derivatives  
Sulindac methyl ester **1a** was prepared by reacting sulindac **2a** with methanol in BF\({}_{3}\)CH\({}_{3}\)OH for 4h at 50 \({}^{\circ}\)C and subsequently purifying by chromatography. Sulindac methyl ester sulfoximine **1b** was synthesized by applying a literature protocol [18,19] (Scheme 1). Sulindac methyl ester **1a** was reacted with (diacetoxyiodo)benzene [Ph(IACO)\({}_{2}\)] and ammonium carbamate [NH\({}_{2}\)COONH\({}_{4}\)] in MeOH for 30 min and later purified by chromatography (Scheme 1). An attempt to obtain sulindac sulfoximine **2b** directly from sulindac **2a**, by using the NH transfer shown in the previous Scheme, gave low yields and separation issues. On the other hand, we synthesized **2b** by the hydrolysis of sulindac methyl ester sulfoximine **1b** (Scheme 2). **Methyl (Z)-2-(5-fluoro-2-methyl-1-(4-(methylsulfonylbenzylidene)-1H-inden-3-yl) acetate (1a). ** Compound 1a was synthesized according to the literature [20] by adding 300 mg (0.84 mmol) of sulindac **2a** and 1.29 mL (1.68 mmol) of BF\({}_{3}\)CH\({}_{3}\)OH to a 50 mL flask in 8 mL of methanol. The mixture is reacted for 4 h at 50 \({}^{\circ}\)C. After this time, the solvent is evaporated under vacuum. The crude mixture is purified by silica gel column chromatography using diethyl ether as eluent, to yield a yellow solid product (295 mg, 95% yield). **1H-NMR (CDCl\({}_{3}\), 500 MHz) \(\delta\) 7.74-7.69 (m, 2H), 7.68-7.63 (m, 2H), 7.15 (broad s, 1H), 7.14 (dd, \(J\) = 8.4, \(J\) = 5.2 Hz, 1H), 6.87 (dd, \(J\) = 9.0, \(J\) = 2.4 Hz, 1H), 6.56 (ddd, \(J\) = 9.0, \(J\) = 8.4, \(J\) = 2.4 Hz, 1H), 3.71 (s, 3H), 3.57 (s, 2H), 2.81 (s, 3H), 2.20 (s, 3H). **\({}^{13}\)**C-NMR** (CDCl\({}_{3}\), 125 MHz) \(\delta\) 170.7, 163.3 (d, \(J\) = 246.2 Hz), 146.7 (d, \(J\) = 7.9 Hz), 145.5, 141.7, 139.7, 138.2, 131.7 (d, \(J\) = 2.7 Hz), 130.2, 129.5 (d, \(J\) = 2.7 Hz), 128.2, 123.8, 123.6 (d, \(J\) = 6.6 Hz), 110.8 (d, \(J\) = 22.4 Hz), 106,1 (d, \(J\) = 24.2 Hz), 52.2, 43.9, 31.6, 10.5. **Methyl-(Z)-2-(5-fluoro-2-methyl-1-(4-(methylsulfonylbenzylidene)-1H-inden-3-yl)acetate (1b). ** Compound **1b** was synthesized by adding 370 mg (1 mmol) of sulindac methyl ester **1a**, 970 mg (3 mmol) of (diacetoxiodo)benzene and 310 mg (4 mmol) of ammonium carbamate to a 50 mL flask in 5 mL of methanol. The mixture was reacted for 30 min at room temperature. After this time, the solvent was evaporated under vacuum. The crude mixture was purified by silica gel column chromatography using \(n\)-hexane/acetone 1:1 as eluent, to yield a yellow oil product (320 mg, 82 % yield). HRMS(ESI-TOF), \(m/z\): calculated for [C\({}_{21}\)H\({}_{20}\)FNO\({}_{3}\)S + Na]\({}^{+}\) 408.1046, found [M + Na]\({}^{+}\) 408.1047. \({}^{1}\)**H-NMR** (CDCl\({}_{3}\), 500 MHz) \(\delta\) 8.04-8.01 (m, 2H), 7.68-7.63 (m, 2H), 7.12-7.06 (m, 2H), 6.83 (dd, \(J\) = 8.8, \(J\) = 2.2 Hz, 1H), 6.52 (td, \(J\) = 8.9, \(J\) = 2.3 Hz, 1H), 3.67 (s, 3H), 3.58 (broad s, 1H) 3.53 (s, 2H), 3.24 (s, 3H), 2.16 (m, 3H). \({}^{13}\)**C-NMR** (CDCl\({}_{3}\), 125 MHz) \(\delta\) 170.6, 163.4 (d, \(J\) = 247 Hz), 146.8 (d, \(J\) = 8.8 Hz), 142.2 (d, \(J\) = 2.5 Hz), 141.3, 138.1, 133.1, 132.2 (d, \(J\) = 2.3 Hz), 130.2, 128.0, 127.3, 123.6 (d, \(J\) = 9.0 Hz), 110.8 (d, \(J\) = 22.7 Hz), 106,2 (d, \(J\) = 24.0 Hz), 52.2, 45.8, 31.5, 10.5. **(Z)-2-(5-fluoro-2-methyl-1-(4-(methylsulfonylbenzylidene)-1H-inden-3-yl)acetic acid (2b). ** Sulindac methyl ester sulfoximine (0.1 g, 0.26 mmol) 1b was added to an aqueous solution 1 M of sodium hydroxide (0.5 mmol) and 5 mL of ethanol. The mixture was stirred for 30 min at room temperature. After this time, the ethanol was evaporated. The crude mixture was treated with a saturated ammonium chloride solution and extracted three times with ethyl acetate. The combined organic layers were dried with anhydrous Na\({}_{2}\)SO\({}_{4}\) and concentrated under vacuum.