General

Column chromatography was carried out on 0.04- 0.063 mm (Merck) silica gel, thin layer chromatography was carried out on aluminum backed silica plates by Merck and plates were revealed using a UV 254 light. Infrared (KBr, cm⁻¹) spectroscopy was calculated on a Pye-Unicam SP3-100 instrument. ¹H NMR spectra were detected at King Abdel-Aziz University using a Varian (400 MHz) EM 390 USA instrument. The peaks of the spectroscopy were recorded as Single (s), Double (d), Triple (t) and Quartet (q). ¹³C-NMR spectra were recorded at King Abdel- Aziz University, Saudi Arabia, on a JNM – LA spectrometer (100 MHz). Chloroform was used for both ¹H and ¹³C-NMR using TMS. Mass spectra were recorded at the National Research Centre, Cairo , Egypt on a JEOL -JMS-AX 500. On an analyzer (Elementar Vario EL 1150ºC) the elemental analysis was reported.

Compounds 4, 5, 6a-d, 7a-d, 8a-d 9a-d and 10a-d, -(((R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-tri-

methyltridecyl)chroman-6-yloxy) = (α-tocopheryl) Synthesis of 1-((R)-2,5,7,8-tetramethyl-2-((4R,8R)- 4,8,12-trimethyltridecyl) chroman-6-yloxy)propan-2- one (2).

A mixture of compound 1 (α-tocopherol) (2.15 g, 0.005 mol), chloroacetone (0.41 mL, 0.005 mol) and NaOH (0.20 g, 0.005 mol) in dimethylformamide (20 mL) were stirred for 24 h at room temperature, ethylacetate (25 mL) and brine (10 mL) were added, the aqueous was extracted with ethylacetate (10 mL × 2), the combined ethylacetate was washed with brine (10 mL × 2) and water (10 mL x 1), dried over MgSO₄. Then, the solvent was removed, to obtain derivative 2 as colorless oil, 1.57 g, yield, 65%. IR (KBr) ν_max 1700 (C=O) cm^–1. ¹H NMR (Chloroform) δ, ppm: 5.20 (2H, s, OCH₂), 2.35 (3H, s, CH₃, O=C-CH₃), 2.20 (3H, s, CH₃), 2.10 (3H, s, CH₃), 1.92 (3H, m, 3CH), 1.65 (6H, m, 2CH₃), 1.45 (22H, m, 11CH₂), 0.97 (12H, m, 4CH₃). ¹³CNMR δ, ppm: 11.6, 12.5, 15.7, 19.5, 20.4, 21.5, 22.5, 22.7, 23.9, 24.5, 24.6, 24.8, 25.9, 27.9, 31.3, 31.5, 32.2, 36.3, 37.5, 38.6, 39.4, 40.1, 70.2, 74.7, 117.5, 123.1, 125.5, 128.3, 129.1, 147.9, 148.1, 206.0 (C, CO). MS m/z (%): 486 [M⁺-1, 60], Anal. Calcd. for C₃₂H₅₄O₃: C, 78.96; H, 11.18. Found C, 78.77; H, 11.00. 2-(1-((R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12- trimethyltridecyl)chroman-6-yloxy) propan-2- ylidene)hydrazinecarboxamide (3).

In ethanol (50 mL) semicarbazide hydrochloride (1.12 g, 0.01 mmol), mixed with sodium acetate (1.23 g, 0.015 mol) was refluxed for 30 min. The precipitated sodium chloride was filtered from the hot solution and derivative (2) (4.86 g, 0.01 mol) was added to the hot solution. The reaction mixture was heated at reflux for a further 2hrs., then diluted with ethylacetate (50 mL) and brine (30 mL), the aqueous was extracted with ethylacetate (15 mL × 2), the combined ethylacetate was washed with brine (20 mL × 2), water (20 mL × 1), dried over MgSO₄. After removal of the solvent, the residue was purified by Colum chromatography (hexane/ ethylacetate V/V 10:1) to give pale yellow oil, 3.26 g, yield 60%. IR (KBr) ν_max 3400, 3350, 3149 (NH, NH₂); 1655 (C=O-amide) cm^–1. ¹H NMR (Chloroform) δ, ppm: 8.95 (1H, s, NH); 6.01 (2H, s, NH₂); 4.20 (2H, s, OCH₂), 1.91 (3H, s, CH₃), 2.20 (3H, s, CH₃), 2.10 (3H, s, CH₃), 1.92 (3H, m, 3CH), 1.65 (6H, m, 2CH₃), 1.46 (22H, m, 11CH₂), 0.95 (12H, m, 4CH₃). ¹³CNMR δ, ppm: 11.9, 12.5, 15.7, 19.4, 20.4, 21.3, 22.7, 22.8, 23.7, 24.4, 24.5, 24.6, 25.9, 27.9, 31.3, 31.5, 32.3, 36.3, 37.5, 38.5, 39.4, 40.2, 70.1, 74.5, 117.7, 123.1, 125.5, 128.4, 129.2, 147.7, 148.2, 155.5, 157.0 (C, CO). MS m/z (%): 544 [M⁺, 20], Anal. Calcd. for C₃₃H₅₇N₃O₃: C, 72.88; H, 10.56; N,7.73. Found C, 72.65; H, 10.38; N,7.55 . 4-(α-tocopheryl) methyl)-1,2,3-thiadiazole (4).

Thionyl chloride (5 mL) was stirred at 0ºC and the semicarbazone 3 (5.44 g, 0.01 mol) was added in small portion. The mixture was stirred at room temperature overnight until no more hydrogen chloride was produced. The remaining thionyl chloride was evaporated under vacuum. Methylene chloride (15 mL) was added and the resulting mixture was decomposed with saturated sodium carbonate. The organic layer was washed with water and dried on anhydrous sodium sulfate. The product 4 was purified by column chromatography (hexane/ethylacetate V/V 10:1) to give colorless oil, 2.90 g, yield 60%. IR (KBr) ν_max 3073, 2920, 2850, 1463 cm^–1. ¹H NMR (Chloroform) δ, ppm: 8.15 (1H, s, CH-Thiadiazole), 4.23 (2H, s, OCH₂), 2.22 (3H, s, CH₃), 2.11 (3H, s, CH₃), 1.90 (3H, m, 3CH), 1.65 (6H, m, 2CH₃), 1.45 (22H, m, 11CH₂), 0.96 (12H, m, 4CH₃). ¹³CNMR δ, ppm: 11.8, 12.6, 15.7, 19.5, 20.5, 21.3, 22.8, 22.9, 23.7, 24.5, 24.6, 24.8, 25.9, 27.9 , 31.3, 31.5, 32.2, 36.3, 37.3, 38.5, 39.1, 40.3, 70.2 , 74.7, 117.5, 123.2, 125.5, 128.1, 132.1, 147.6, 148.1, 155.6. MS m/z (%): 529 [M⁺-1, 15], Anal. Calcd. for C₃₂H₅₂N₂O₂S: C, 72.68; H, 9.91; N, 5.30. Found C, 72.61; H, 9.88; N, 5.00. 4-(α-tocopheryl ) methyl)-1,2,3-selenadiazole (5).

Semicarbazone 3 (5.44 g, 0.01mol) was dissolved in glacial acetic acid with vigorous stirring and gentle heating to 70ºC. The solution was treated with selenium dioxide powder (1.66 g, 0.015 mmol, and the mixture was kept under vigorous stirring. After ca. 2 min the color of the mixture becomes red. The reaction was complete in 24 hrs. The mixture was filtered to remove unreacted selenium and the filtrates poured into ice water and extracted with Chloroform (3 × 50 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate solution. dried over magnesium sulphate and the solvent was removed under vacuum to afford the crude compound 5, which was further purified by column chromatography (hexane/ ethylacetate V/V 10:1) to give pale yellow oil compound 5, 2.87 g, yield 50%. IR (KBr) ν_max 3073, 2920, 2850, 1463 cm^–1. ¹H NMR (Chloroform) δ, ppm: 8.50 (1H, s, CH-Selenadiazole), 4.25 (2H, s, OCH₂), 2.10 (3H, s, CH₃), 1.95 (3H, s, CH₃), 1.92 (3H, m, 3CH), 1.65 (6H, m, 2CH₃), 1.45 (22H, m, 11CH₂), 0.96 (12H, m, 4CH₃). ¹³CNMR δ, ppm: 11.9, 12.6, 15.7, 19.5, 20.5, 21.3, 22.8, 22.9, 23.7, 24.5, 24.8, 24.9, 25.9, 27.9 , 31.3, 31.5, 32.2, 36.3, 37.3, 38.5, 39.1, 40.3, 70.2 , 74.7, 117.5, 123.2, 125.5, 128.1, 132.1, 147.6, 148.1, 155.3. MS m/z (%): 602 [M⁺ + Na⁺, isotope Se-patern,10], Anal. Calcd. for C₃₂H₅₂N₂O₂Se: C, 66.76; H, 9.10; N,4.87. Found C, 66.61; H, 9.88; N, 4.67. 4-(α-tocopheryl) methyl)-1,2,3-telluradiazole (6).

Similarly, TeO₂ was used in the prior technique to synthesis 1,2,3-selenadiazole, but the end product was not obtained 6. Synthesis of 1-(4-substitutedphenyl)-2-( α-tocopheryl) ethanone (7a-d).

General Procedure

In dimethylformamide (20 mL), 4-substituted phenacy bromide (4-methoxy;4-nitro-4-fluoro and 4-cyano) (0.005 mol) and NaOH (0.20 g, 0.005 mol) were added to the derivative 1 (2.15 g, 0.005 mol). Mixed compounds were stirred for 24 hrs, at room temperature, then added ethylacetate (30 mL) and brine (20 mL). The aqueous was extracted with ethylacetate (15 mL × 2), the combined ethylacetate was washed with brine (15 mL × 2), water (15 mL × 1), and dried over MgSO₄. After that, the solvent was removed and the products obtained without purification as pale yellow oil compounds 7a-d;

7a; 1.73 g, yield, 60 %. IR (KBr) ν_max 1685 (C=O) cm^–1. ¹H NMR (Chloroform) δ, ppm: 7.50, 8.00 (4H, m, Ph-ring) , 4.92 (2H, s, OCH₂), 3.95 (3H, s, Ph-OCH₃), 2.20 (3H, s, CH₃), 2.20 (3H, s, CH₃), 1.90 (3H, m, 3CH), 1.65 (6H, m, 2CH₃), 1.45 (22H, m, 11CH₂ ), 0.97 (12H, m, 4CH₃). ¹³CNMR δ, ppm: 11.8, 12.8, 15.9, 19.7, 20.5, 21.3, 22.6, 22.7, 23.7, 24.5, 24.8, 24.9, 25.9, 27.9, 31.3, 31.5, 32.2, 36.5, 37.5, 38.3, 39.2, 40.2, 55.3, 70.1, 74.9, 113.6, 114.4, 117.7, 123.1, 124.8, 126.4, 128.3, 129.1, 130.6, 147.8, 148.2, 163.9, 193.0 (C, CO). MS m/z (%): 579 [M⁺, 30], Anal. Calcd. for C₃₈H₅₈O₄: C, 78.85; H, 10.10. Found C, 78.80; H, 10.00.

7b; 4.16 g, yield, 70 %. IR (KBr) ν_max 1695 (C=O) cm^–1. ¹H NMR (Chloroform) δ, ppm: 7.25, 8.50 (4H, m, Ph-ring) , 4.95 (2H, s, OCH₂), 2.22 (3H, s, CH₃), 2.20 (3H, s, CH₃), 1.92 (3H, m, 3CH), 1.66 (6H, m, 2CH₃), 1.45 (22H, m, 11CH₂), 0.96 (12H, m, 4CH₃).¹³CNMR δ, ppm: 11.9, 12.8, 15.9, 19.5, 20.4, 21.3, 22.7, 22.8, 23.7, 24.2, 24.3, 24.7, 25.9, 27.9, 31.3, 31.5, 32.4, 36.6, 37.5, 38.3, 39.2, 40.1, 70.2, 74.9, 113.6, 114.3, 117.6, 123.0, 124.7, 126.3, 128.2, 129.0, 130.7, 147.8, 148.3, 162.4, 171.0 (C, CO).

MS m/z (%): 593 [M⁺, 20], Anal. Calcd. for C₃₇H₅₅NO₅: C, 74.83; H, 9.34; N, 2.36. Found C, 74.82; H, 9.30; N, 2.11.

7c; 3.68 g, yield, 65 %. IR (KBr) ν_max 1690 (C=O) cm^–1. ¹H NMR (Chloroform) δ, ppm: 7.15, 8.20 (4H, m, Ph-ring), 4.75 (2H, s, OCH₂), 2.20 (3H, s, CH₃), 2.19 (3H, s, CH₃), 1.86 (3H, m, 3CH), 1.68 (6H, m, 2CH₃), 1.45 (22H, m, 11CH₂), 0.95 (12H, m, 4CH₃). ¹³CNMR δ, ppm: 11.8, 12.8, 15.9, 19.5, 20.4, 21.3, 22.7, 22.8, 23.7, 24.2, 24.3, 24.7, 25.9, 27.9, 31.3, 31.5, 32.4, 36.6, 37.5, 38.3, 39.2, 40.1, 70.2, 74.9, 113.6, 114.3, 117.6, 123.0, 124.7, 126.3, 128.2, 129.0, 130.7, 147.8, 148.3, 162.4, 170.0 (C, CO).

MS m/z (%): 567 [M⁺, 25], Anal. Calcd. for C₃₇H₅₅FO₃: C, 78.40; H, 9.78. Found C, 78.22; H, 9.55.

7d; 3.44 g, yield, 60 %. IR (KBr) ν_max 2217 (CN); 1690 (C=O) cm^–1. ¹H NMR (Chloroform) δ, ppm: 7.12, 8.50 (4H, m, Ph-ring), 4.55 (2H, s, OCH₂), 2.15 (3H, s, CH₃), 2.19 (3H, s, CH₃), 1.82 (3H, m, 3CH), 1.65 (6H, m, 2CH₃), 1.45 (22H, m, 11CH₂), 0.99 (12H, m, 4CH₃). ¹³CNMR δ, ppm: 11.9, 12.8, 15.9, 19.5, 20.4, 21.3, 22.7, 22.8, 23.7, 24.2, 24.3, 24.7, 25.9, 27.9, 31.3, 31.5, 32.4, 36.6, 37.5, 38.3, 39.2, 40.1, 70.2, 74.9, 113.5, 114.3, 116.8, 118.3, 123.0, 124.7, 126.3, 128.2, 129.0, 130.7, 147.8, 148.2, 162.8, 174.0 (C, CO).

MS m/z (%): 573 [M⁺-1, 30], Anal. Calcd. for C₃₈H₅₅NO₃: C, 79.53; H, 9.66; N, 2.44. Found C, 79.52; H, 9.45; N, 2.33. 2-(1-(4-substitutedphenyl)-2-(α-tocopheryl) ethylidene)hydrazinecarboxamide (8a-d)

In ethanol (50 mL) semicarbazide hydrochloride (0.01 mmol), mixed with sodium acetate (0.015 mol) was heated under reflux for 30 min. The precipitated sodium chloride was filtered from the hot solution and derivatives (7a-d) (0.01 mol) were added to the hot solution. The reaction mixture was heated for a further 2hrs., then diluted with ethylacetate (50 mL) and brine (30 mL), the aqueous was extracted with ethyl acetate (15 mL × 2), the combined ethylacetate was washed with brine (20 mL × 2), water (20 mL x 1), dried over MgSO₄. After removal of the solvent, the residue was purified by Colum chromatography (hexane/ethylacetate V/V 10:1) to give pale yellow oil compounds (8a-d),

8a; 3.50 g, yield 55 %. IR (KBr) ν_max 3400,3350,3149 (NH, NH₂); 1665 (C=O-amide) cm^–1. ¹H NMR (Chloroform) δ, ppm: 9.59 (1H, s, NH); 7.50, 8.00 (4H, m, Phenyl-ring); 6.95 (2H, s, NH₂); 3.98 (3H, s, OCH₃); 4.20 (2H, s, OCH₂), 2.15 (3H, s, CH₃), 2.19 (3H, s, CH₃), 1.86 (3H, m, 3CH), 1.65 (6H, m, 2CH₃), 1.45 (22H, m, 11CH₂), 0.97 (12H, m, 4CH₃). ¹³CNMR δ, ppm: 11.9, 12.8, 15.9, 19.5, 20.8, 21.5, 22.7, 22.8, 23.8, 24.4, 24.7, 24.9, 25.9, 27.9, 31.3, 31.5, 32.3, 36.5, 37.6, 38.7, 39.8, 40.2, 55.8, 74.8, 114.5, 114.8, 115.2, 116.3, 117.6, 123.1, 125.8, 128.4, 128.8, 129.0, 147.5, 148.4, 162.5, 155.5, 157.0 (C, CO). MS m/z (%): 635 [M⁺ -1, 40]. Anal. Calcd. for C₃₉H₆₁N₃O₄: C, 73.66; H, 9.67.

8b; 3.90 g, yield 60 %. IR (KBr) ν_max 3420,3350,3149 (NH, NH₂); 1665 (C=O-amide) cm^–1. ¹H NMR (Chloroform) δ, ppm: 9.59 (1H, s, NH); 7.20, 8.50 (4H, m, Phenyl-ring); 6.95 (2H, s, NH₂); 4.50 (2H, s, OCH₂), 2.20 (3H, s, CH₃), 2.19 (3H, s, CH₃), 1.85 (3H, m, 3CH), 1.68 (6H, m, 2CH₃), 1.46 (22H, m, 11CH₂), 0.97 (12H, m, 4CH₃). ¹³CNMR δ, ppm: 11.8, 12.8, 15.9, 19.4, 20.7, 21.5, 22.6, 22.8, 23.6, 24.4, 24.7, 24.9, 25.9, 27.9, 31.4, 31.5, 32.2, 36.5, 37.5, 38.7, 39.7, 40.1, 74.8, 114.5, 114.8, 115.2, 116.3, 117.6, 123.1, 125.7, 128.5, 128.8, 129.0, 147.5, 148.4, 162.5, 155.5, 158.0 (C, CO). MS m/z (%): 650 [M⁺ -1, 50], Anal. Calcd. for C₃₈H₅₈N₄O₅: C, 70.12; H, 8.98; N, 8.61. Found C, 70.00; H, 8.75; N, 8.35.

8c; 3.90 g, yield 60 %. IR (KBr) ν_max 3400, 3350, 3149 (NH, NH₂); 1655 (C=O-amide) cm^–1. ¹H NMR (Chloroform) δ, ppm: 9.50 (1H, s, NH); 7.25, 8.00 (4H, m, Phenyl-ring); 6.90 (2H, s, NH₂); 4.50 (2H, s, OCH₂), 2.19 (3H, s, CH₃), 2.07 (3H, s, CH₃), 1.86 (3H, m, 3CH), 1.67 (6H, m, 2CH₃), 1.46 (22H, m, 11CH₂), 0.95 (12H, m, 4CH₃). ¹³CNMR δ, ppm: 11.9 12.8, 15.9, 19.4, 20.7, 21.5, 22.6, 22.8, 23.6, 24.4, 24.7, 24.8, 25.9, 27.9, 31.4, 31.5, 32.2, 36.5, 37.5, 38.7, 39.7, 40.1, 74.8, 114.5, 114.8, 115.2, 116.3, 117.6, 123.1, 125.7, 128.5, 128.8, 129.0, 147.5, 148.4, 162.5, 155.5, 159.0 (C, CO). MS m/z (%): 623 [M⁺ -1, 10], Anal. Calcd. for C₃₈H₅₈ FN₃O₃: C, 73.16; H, 9.37; N, 6.74. Found C, 73.10; H, 9.15; N, 6.55.

8d; 3.79 g, yield 60%. IR (KBr) ν_max 3400, 3350, 3149 (NH, NH₂); 1655 (C=O-amide); 2217 (CN) cm^–1. ¹H NMR (Chloroform) δ, ppm: 9.59 (1H, s, NH); 7.25, 8.00 (4H, m, Phenyl-ring); 6.95 (2H, s, NH₂); 4.50 (2H, s, OCH₂), 2.18 (3H, s, CH₃), 2.19 (3H, s, CH₃), 1.87 (3H, m, 3CH), 1.67 (6H, m, 2CH₃), 1.46 (22H, m, 11CH₂), 0.95 (12H, m, 4CH₃).1³CNMR δ, ppm: 11.8, 12.8, 15.9, 19.4, 20.7, 21.5, 22.6, 22.8, 23.7, 24.4, 24.7, 24.8, 25.9, 27.9, 31.4, 31.5, 32.2, 36.5, 37.5, 38.7, 39.7, 40.1, 74.8, 114.5, 114.8, 115.2, 116.3, 117.6, 118.5, 123.1, 125.7, 128.5, 128.8, 129.0, 147.5, 148.4, 162.5, 155.5, 157.8 (C, CO). MS m/z (%): 630 [M⁺ +1, 20], Anal. Calcd. for C₃₉H₅₈ N₄O₃: C, 74.25; H, 9.27; N, 8.88. Found C, 74.15; H, 9.10; N, 8.65. 5-(4-substitutedphenyl)-4-(α-tocopheryl) methyl)- 1,2,3-thiadiazole (9a-c).

Thionyl chloride (5 mL) was stirred at 0ºC and the semicarbazone derivatives 8a-d (0.01 mol) was added in small portion. After that the mixture was stirred at room temperature overnight until no more HCl gas was produced. The remaining thionyl chloride was evaporated under vacuum. CH₂Cl₂ (15 mL) was added and the resulting mixture was decomposed with saturated sodium carbonate. The organic layer was washed with water and dried on anhydrous sodium sulfate. The products 9a-d were purified by column chromatography (hexane/ ethylacetate V/V 10:1) to give pale yellow oil compounds 9a-d;

9a; 2.54 g, yield 40%. IR (KBr) ν_max 3073, 2920, 2850, 1463 cm^–1. ¹H NMR (Chloroform) δ, ppm: 7.00- 8.20 (4H, m, Ph-ring), 4.20 (2H, s, OCH₂), 3.95 (3H, s, OCH₃), 2.19 (3H, s, CH₃), 2.19 (3H, s, CH₃), 1.85 (3H, m, 3CH), 1.69 (6H, m, 2CH₃), 1.45 (22H, m, 11CH₂), 0.90 (12H, m, 4CH₃). ¹³CNMR δ, ppm: 11.9, 12.5, 15.6, 19.5, 20.5, 21.6, 22.7, 22.8, 23.5, 24.5, 24.6, 24.8, 25.9, 27.9, 31.4, 31.6, 32.4, 36.6, 37.7, 38.3, 39.5, 40.1, 55.6, 70.1, 74.3, 114.5, 115.7, 117.6, 123.2, 125.3, 128.4, 128.5, 129.4, 130.8, 132.3, 132.0, 147.5, 148.4, 155.5. MS m/z (%): 634 [M⁺-1, 25], Anal. Calcd. for C₃₉H₅₈N₂O₃S: C, 73.77; H, 9.21; N, 4.41. Found C, 73.65; H, 9.00; N, 4.20.

9b; 2.93 g, yield 45 %. IR (KBr) ν_max 3073, 2920, 2850, 1463 cm^–1. ¹H NMR (Chloroform) δ, ppm: 7.00-8.30 (4H, m, Ph-ring), 4.20 (2H, s, OCH₂), 2.20 (3H, s, CH₃), 2.16 (3H, s, CH₃), 1.85 (3H, m, 3CH), 1.65 (6H, m, 2CH₃), 1.46 (22H, m, 11CH₂), 0.95 (12H, m, 4CH₃). ¹³CNMR δ, ppm: 11.9, 12.5, 15.9, 19.5, 20.5, 21.5, 22.8, 22.9, 23.5, 24.3, 24.6, 24.8, 25.9, 27.9, 31.4, 31.5, 32.2, 36.6, 37.6, 38.3, 39.5, 40.2, 70.1, 74.2, 114.5, 115.7, 117.6, 123.2, 125.5, 128.4, 128.5, 129.4, 130.8, 132.3, 132.0, 147.8, 148.2, 156.5. MS m/z (%): 649 [M⁺-1, 15], Anal. Calcd. for C₃₈H₅₅N₃O₄S: C, 70.22; H, 8.53; N, 6.47. Found C, 70.15; H, 8.40; N, 6.27.

9c; 2.49 g, yield 40 %. IR (KBr) ν_max 3073, 2920, 2850, 1463 cm^–1. ¹H NMR (Chloroform) δ, ppm: 7.00-8.50 (4H, m, Ph-ring), 4.50 (2H, s, OCH₂), 2.20 (3H, s, CH₃), 2.15 (3H, s, CH₃), 1.85 (3H, m, 3CH), 1.65(6H, m, 2CH₃), 1.44 (22H, m, 11CH₂), 0.95 (12H, m, 4CH₃). ¹³CNMR δ, ppm: 11.6, 12.5, 15.9, 19.5, 20.5, 21.5, 22.8, 22.9, 23.5, 24.3, 24.6, 24.8, 25.9, 27.9, 31.4, 31.5, 32.2, 36.6, 37.6, 38.3, 39.5, 40.2, 70.1, 74.2, 114.5, 115.7, 117.6, 123.2, 125.5, 128.4, 128.5, 129.4, 130.8, 132.3, 132.0, 147.8, 148.2, 154.5. MS m/z (%): 622 [M⁺-1, 10], Anal. Calcd. for C₃₈H₅₅FN₂O₂S: C, 73.27; H, 8.90; N, 4.50 Found C, 73.05; H, 8.70; N, 4.35.

9d; 2.52 g, yield 40 %. IR (KBr) ν_max 3073, 2920, 2850, 1463; 2217 (CN) cm^–1. ¹H NMR (Chloroform) δ, ppm: 7.00-8.30 (4H, m, Ph-ring), 4.20 (2H, s, OCH₂), 2.21 (3H, s, CH₃), 2.19 (3H, s, CH₃), 1.85 (3H, m, 3CH), 1.65 (6H, m, 2CH₃), 1.46 (22H, m, 11CH₂), 0.95 (12H, m, 4CH₃). ¹³CNMR δ, ppm: 11.8, 12.5, 15.9, 19.5, 20.5, 21.5, 22.8, 22.9, 23.5, 24.3, 24.6, 24.8, 25.9, 27.9, 31.4, 31.5, 32.2, 36.6, 37.6, 38.3, 39.5, 40.2, 70.1, 74.2, 114.5, 115.7, 117.6, 118,3, 123.2, 125.5, 128.4, 128.5, 129.4, 130.8, 132.3, 132.0, 147.8, 148.2, 155.5. MS m/z (%): 629 [M⁺-1, 20], Anal. Calcd. for C₃₉H₅₅N₃O₂S: C, 74.36; H, 8.80; N, 6.67. Found C, 74.15; H, 8.60; N, 6.45. 5-(4-substitutedphenyl)-4-(α-tocopheryl) methyl)- 1,2,3-selenadiazole (10a-c).

Semicarbazone 8a-d (0.01 mol) was dissolved in gl. CH₃COOH and gentle heating to 70ºC. Selenium dioxide powder (0.015 mmol) was added and the mixture was kept under vigorous stirring. After 2 min. the color of the mixture becomes red. The reaction was complete in 24 hrs., unreacted selenium was removed and the filtrates poured into ice water and extracted with Chloroform (3×50 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate solution. dried over magnesium sulphate and the solvent was removed under vacuum to afford the crude compound 5, which was further purified by column chromatography (hexane/ethylacetate V/V 10:1) to give pale yellow oil compounds 10a-d.

10a; 2.38 g, yield 35 %. IR (KBr) ν_max 3073, 2920, 2850, 1463 cm^–1. ¹H NMR (Chloroform) δ, ppm: 7.00-7.99 (4H, m, Ph-ring), 4.95 (2H, s, OCH₂), 3.95 (3H, s, OCH₃), 2.21 (3H, s, CH₃), 2.19 (3H, s, CH₃), 1.85 (3H, m, 3CH), 1.65 (6H, m, 2CH₃), 1.45 (22H, m, 11CH₂), 0.95 (12H, m, 4CH₃). ¹³CNMR δ, ppm: 11.9, 12.5, 15.6, 19.5, 20.5, 21.6, 22.7, 22.8, 23.5, 24.5, 24.6, 24.8, 25.9, 27.9, 31.4, 31.6, 32.4, 36.6, 37.7, 38.3, 39.5, 40.1, 55.6, 70.1, 74.3, 114.5, 115.7, 117.6, 123.2, 125.3, 128.4, 128.5, 129.4, 130.8, 132.3, 132.0, 147.5, 148.4, 152.5. MS m/z (%): 682 [M⁺, 40], Anal. Calcd. for C₃₉H₅₈N₂O₃Se: C, 68.70; H, 8.57; N, 4.11. Found C, 68.55; H, 8.51; N, 4.10.

10b; 2.79 g, yield 40 %. IR (KBr) ν_max 3073, 2920, 2850, 1463 cm^–1. ¹H NMR (Chloroform) δ, ppm: 7.15-8.50 (4H, m, Ph-ring), 4.99 (2H, s, OCH₂), 2.20 (3H, s, CH₃), 2.18 (3H, s, CH₃), 1.86 (3H, m, 3CH), 1.64 (6H, m, 2CH₃), 1.45 (22H, m, 11CH₂), 0.96 (12H, m, 4CH₃). ¹³CNMR δ, ppm: 11.9, 12.5, 15.9, 19.5, 20.5, 21.5, 22.8, 22.9, 23.5, 24.3, 24.6, 24.8, 25.9, 27.9, 31.4, 31.5, 32.2, 36.6, 37.6, 38.3, 39.5, 40.2, 70.1, 74.2, 114.5, 115.7, 117.6, 123.2, 125.5, 128.4, 128.5, 129.4, 130.8, 132.3, 132.0, 147.8, 148.2, 156.5. MS m/z (%): 697 [M⁺, 25], Anal. Calcd. for C₃₈H₅₅N₃O₄Se: C, 65.50; H, 7.96; N, 6.03. Found C, 65.35; H, 7.90; N, 6.00.

10c; 2.01 g, yield 30 %. IR (KBr) ν_max 3073, 2920, 2850, 1463 cm^–1. ¹H NMR (Chloroform) δ, ppm: 7.10-8.20 (4H, m, Ph-ring), 4.90 (2H, s, OCH₂), 2.20 (3H, s, CH₃), 2.07 (3H, s, CH₃), 1.86 (3H, m, 3CH), 1.65 (6H, m, 2CH₃), 1.45 (22H, m, 11CH₂), 0.95 (12H, m, 4CH₃). ¹³CNMR δ, ppm: 11.6, 12.5, 15.9, 19.5, 20.5, 21.5, 22.8, 22.9, 23.5, 24.3, 24.6, 24.8, 25.9, 27.9, 31.4, 31.5, 32.2, 36.6, 37.6, 38.3, 39.5, 40.2, 70.1, 74.2, 114.5, 115.7, 117.6, 123.2, 125.5, 128.4, 128.5, 129.4, 130.8, 132.3, 132.0, 147.8, 148.2, 152.5. MS m/z (%): 670 [M⁺, 10], Anal. Calcd. for C₃₈H₅₅FN₂O₂Se: C, 68.14; H, 8.28; N, 4.18 Found C, 68.00; H, 8.15; N, 4.15.

10d; 2.37 g, yield 35 %. IR (KBr) ν_max 3073, 2920, 2850, 1463; 2221 (CN) cm^–1. ¹H NMR (Chloroform) δ, ppm: 7.00-8.00 (4H, m, Ph-ring), 4.20 (2H, s, OCH₂), 2.21 (3H, s, CH₃), 2.19 (3H, s, CH₃), 1.85 (3H, m, 3CH), 1.65 (6H, m, 2CH₃), 1.46 (22H, m, 11CH₂), 0.96 (12H, m, 4CH₃). ¹³CNMR δ, ppm: 11.8, 12.5, 15.9, 19.5, 20.5, 21.5, 22.8, 22.9, 23.5, 24.3, 24.6, 24.8, 25.9, 27.9, 31.4, 31.5, 32.2, 36.6, 37.6, 38.3, 39.5, 40.2, 70.1, 74.2, 114.5, 115.7, 117.6, 118,3, 123.2, 125.5, 128.4, 128.5, 129.4, 130.8, 132.3, 132.0, 147.8, 148.2, 154.5. MS m/z (%): 676 [M⁺-1, 10], Anal. Calcd. for C₃₉H₅₅N₃O₂Se: C, 69.21; H, 8.19; N, 6.21. Found C, 69.15; H, 8.12; N, 6.15.

Assay for Biological Activity

Chemistry

Our target compounds (4, 9a-d) and (5, 10a-d) respectively, two pathways were followed; The first way, started from α-Tocopherol with chloroacetone in the presence of dimethylformamide/NaOH to give derivative (2) followed by the reaction with semicarbazide hydrochloride forming derivative (3) namely, vitamin e/ hydrazine- carboxamide. IR spectroscopy analysis of compounds (3) appeared characteristic bands for semicarbazone derivative at 3400, 3350, 3149 (NH, NH₂); 1655 (ketone-amide) cm^–1. Also, ¹H and ¹³C NMR spectroscopy supported the synthesized novel compound 3. ¹H-NMR (Chloroform) δ = 8.95 (1H, s, NH); 6.00 (2H, s, NH₂); 4.20 (2H, s, OCH₂), 1.91 (3H, s, CH₃) 2.17 (3H, s, CH₃, 2-CH₃), 2.09 (3H, s, CH₃, 5-CH₃) in addition data confirmed the peaks for the number of hydrogen in vitamin e. For ¹³C-NMR data agreement with the number of carbon atoms. Reactions of compound 3 with thionyl chloride and selenium dioxide with ring closure gave our targeted compounds 4 and 5 respectively. While reaction of 3 with tellurium oxide in acetic acid as a solvent to give 1,2,3-telluradiazole derivative (6) was failed (Scheme 1). All spectroscopic data with agreement with our targeted compounds 4 and 5. For example, IR data showed disappearance of (NH, NH₂) and (C=O) groups as a results of ring closure for both two products 4 and 5. The second way, started from α-Tocopherol with 4-substituted phenacybromide (4-methoxy;4-nitro-4-fluoro and 4-cyano) in the presence of dimethylformamide/NaOH to form derivatives (7a-d) followed by the reaction with NH₂CONHNH₂.HCl in the presence of sodium acetate forming derivatives (8a-d). Reaction of derivatives 8a-d with thionyl chloride and selenium dioxide yielding new products (9a-d) and (10a-d) respectively. The results of the spectroscopic examination agreed with the newly synthesized compounds 9a-d and 10a-d. The end product (11a-d) (Scheme 1) was not produced using the same method to synthesize 1,2,3-thia/selenadiazole derivatives. TeO₂ was used in replacement of SOCl₂/ SeO₂. Whereas a similar reaction with tellurium dioxide was not successful in the formation of 1,2,3-telluradiazole, the reaction may pass through polymeric or telluroxodiazole intermediates, causing tellurium loss and formation of an active free radical.

Scheme 1:

Synthesis of vitamin e containing thiadiazole and selenadiazole derivatives by the reaction of Vitamin E with chloro acetone and/ or acetophenone derivatives

Antimicrobial Activity

Compounds (4, 5, 9a-d, and 10a-d) were studied and tested for antibacterial activity against Gram-positive (Bacillus cereus (B. cereus) and Gram-negative (Pseudomonas aeruginosa (P. aeruginosa) and Salmonella typhimurium (S. typhimurium) bacteria. The data in the findings are displayed (see Table 1). Data showed that α-tocopherol as a parent compound has no antibacterial activity against the tested organisms. Both Gram-positive and Gram-negative bacteria were inhibited by the activated synthesized compounds 4 and 9a-d. Compound 4 exhibited inhibition zones at (14) and (13) mm against Gram-negative bacteria (P. aeruginosa) and (S. typhimurium), respectively, while 9d (4-CN-substituted/1,2,3-thiadiazole/-tocopherol) showed excellent activity against Gram-positive bacteria S. aureus (19 mm) and P. Subtilis (18 mm). Furthermore, compound 9d inhibited Gram-negative bacteria (P. aeruginosa) and (S. typhimurium) in zones 15 and 16 mm. This indicates that the newly activated compound 9d, in addition to compounds 4, 9a, 9b, and 9c, have antibacterial activity and broad spectrum for both Gram (negative and positive) bacteria. From the data listed in (Table 1) the order of reactivity against bacteria as follows: 9d>9a>9c>9b>4. However, derivatives (1,2,3-selenadiazole/ α-tocopherol) (5 and 10a-d) exhibit moderate antibacterial effect against only Gram-positive bacteria, Bacillus cereus (B. cereus) & Staphylococus aureus (S. aureus). On the other hand, Gram-negative bacteria, demonstrated resistance to all compounds (5 and 10a-d). As a result, connecting vitamin e to the 1,2,3-thiadiazole ring activated the parent molecule (1) vitamin e (α-tocopherol), yielding a novel biological class of compounds 9d, 9a, 9c, and 9b in addition compound 4.