untitled European Journal of Chemistry 2 (1) (2011) 51‐57 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2011 EURJCHEM DOI:10.5155/eurjchem.2.1.51‐57.249 European Journal of Chemistry Journal homepage: www.eurjchem.com Studies with aza‐heterocyclic N‐oxides: Synthesis of some new aromatic N‐oxide derivatives Ahmed Ali Faddaa, Fathy Mohamed Abdelrazekb,* and Ahmed Mahmoud Foudaa aChemistry Department, Faculty of Science, Mansoura University, Mansoura, EG‐35516, Egypt bChemistry Department, Faculty of Science, Cairo University, Giza, EG‐12613, Egypt *Corresponding author at: Chemistry Department, Faculty of Science, Cairo University, Giza, EG‐12613, Egypt. Tel.: +202.35676601; fax: +202.35727556. E‐mail address: prof.fmrazek@gmail.com (F.M. Abdelrazek). ARTICLE INFORMATION ABSTRACT Received: 16 August 2010 Received in revised form: 04 October 2010 Accepted: 28 October 2010 Online: 31 March 2011 KEYWORDS Benzofuroxan derivative (1a) reacts with the cyanoacetanilides (2a‐d) to give the benzimidazole derivatives (3a‐d). Benzofuroxan (1b) reacts with rhodanine derivatives (4a,b) in presence of sodium ethoxide to give the arylaminobenzoimidazole derivatives (6a,b); while the last reaction afforded the thiazolidinone derivatives (8a,b) and the o‐ benzoquinone dioxime derivatives (9a,b) when it was repeated in the presence of sodium acetate. Moreover, a series of quinoxalinyl 1,4‐di‐N‐oxide derivatives were prepared starting from quinoxalin‐1,4‐di‐N‐oxide derivatives (10a‐c). Plausible mechanisms to account for the formation of the products are discussed. Heterocyclic N‐oxides Benzofuroxan Rhodanine o‐Quinone dioximes Thiocarbohydrazide Curtius rearrangement 1. Introduction Over the last three decades we have been involved in a program aiming to develop new simple procedures or novel precursors for the synthesis of heterocyclic compounds of biological interest from cheap laboratory available starting materials to be evaluated as biodegradable agrochemicals [1‐ 8]. Benzofuroxans display several biochemical and pharmacological properties and specific studies were devoted to these aspects [9‐11]. Several authors have reported about the biological importance of quinoxaline 1,4‐dioxides (QdNO's) since 1940's. Classical and more recent methods of the synthesis of the quinoxaline 1,4‐dioxides and some of their most important reactions were also reported [12,13]. Furthermore quinoxaline 1,4‐di‐N‐oxide derivatives were reported to exhibit hypoxia‐selective cytotoxins and anticancer activities [14,15] as well as mycobacterium tuberculostatic activities [16,17]. In view of these facts and in continuation of our earlier interest [18‐20], we report here the results of our investigations on benzofuroxans 1‐oxide (1a‐b) and quinoxaline 1,4‐di‐N‐oxide (10a‐c) derivatives (Scheme 1). N O N O N O N O R R 1a-c 1a, R= 5-CH3 1b, R= H 1c, R= 6-CH3 10a, R= H, R'= COCH3 10b, R= CH3, R'= COCH3 10c, R= CH3, R'= COOC2H5 N N R' CH3 O O R Scheme 1 2. Experimental All melting points are recorded on Gallenkamp electric melting point apparatus and are uncorrected. The IR spectra (υ, cm‐1; KBr) were recorded on Perkin Elmer Infrared Spectrophotometer Model 157, Grating. The 1H NMR spectra were run on Varian Spectrometer at 200 MHz using TMS as an internal reference and DMSO‐d6 as solvent and chemical shifts are expressed in δ (ppm). The mass spectra (EI) were run at 70 eV with Kratos MS equipment and/or a Varian MAT 311 A Spectrometer. Elemental analyses were carried out at the micro analytical center of Cairo University, Giza, Egypt. Benzofuroxans (1a,b) were prepared according to a procedure reported previously [21]. 2.1. Synthesis of 2‐(arylcarbamoyl)‐1‐hydroxy‐5‐methyl‐1H‐ benzo[d]imidazole‐3‐oxide (3a‐d) A mixture of benzofuroxan (1a) (0.45 g, 3 mmol) and cyanoacetanilide derivatives (2a) (0.523 g, 3 mmol), (2b) (0.523 g, 3 mmol), (2c) (0.571 g, 3 mmol) or (2d) (0.571 g, 3 mmol) was stirred in ethanol (30 mL) with piperidine (3 mL) overnight. The obtained precipitates were filtered off, dried and recrystallized from ethanol to afford the benzimidazole derivatives (3a‐d). 3a, Dirty yellow solid, M.p.: 217 oC. Yield: 70%. IR (KBr, max, cm‐1): 3430 (OH), 3250 (NH), 1660 (C=O), 1620 (C=N), 1236, 1317 (N→O). 1H NMR (DMSO, δ ppm): 2.0 (s, 1H, OH), 2.12 (s, 3H, CH3), 2.34 (s, 3H, CH3), 7.06‐7.50 (m, 7H, Ar‐H), 9.15 (s, 1H, NH). MS (m/z, %): 296 (M+‐1, 26). Anal. Calcd. for C16H15N3O3 (297.31): C, 64.64; H, 5.09. Found: C 64.56; H, 5.12. 3b, Dirty yellow solid, M.p.: 206 oC. Yield: 75%. IR (KBr, max, cm‐1): 3452 (OH), 3226 (NH), 1691 (C=O), 1618 (C=N), 52 Fadda et al. / European Journal of Chemistry 2 (1) (2011) 51‐57 1231, 1323 (N→O). 1H NMR (DMSO, δ ppm): 2.0 (s, 1H, OH), 2.34 (s, 6H, 2CH3), 7.06‐7.56 (m, 7H, Ar‐H), 9.15 (s, 1H, NH). MS (m/z, %): 297 (M+, 60). Anal. Calcd. for C16H15N3O3 (297.31): C, 64.64; H, 5.09; N, 14.13. Found: C 64.41; H, 4.97; N, 14.37. 3c, Yellowish red solid, M.p.: 196 oC. Yield: 60%. IR (KBr, max, cm‐1): 3448 (OH), 3248 (NH), 1680 (C=O), 1632 (C=N), 1236, 1335 (N→O). 1H NMR (DMSO, δ ppm): 2.0 (s, 1H, OH), 2.34 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 6.73‐7.50 (m, 7H, Ar‐H), 9.15 (s, 1H, NH). MS (m/z, %): 313 (M+, 33). Anal. Calcd. for C16H15N3O4 (313.31): C, 61.34; H, 4.83; N, 13.41. Found: C 61.19; H, 4.86; N, 13.56. 3d, Reddish yellow solid, M.p.: 300 oC. Yield: 77%. IR (KBr, max, cm‐1): 3437 (OH), 3236 (NH), 1687 (C=O), 1627 (C=N), 1234, 1314 (N→O). 1H NMR (DMSO, δ ppm): 2.34 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 7.07‐7.50 (m, 7H, Ar‐H), 9.15 (br., s, 1H, NH). MS (m/z, %): 314 (M++1, 43). Anal. Calcd. for C16H15N3O4 (313.31): C, 61.34; H, 4.83. Found: C 61.37; H, 4.88. 2.2. Synthesis of 1‐hydroxy‐1H‐benzo[d]imidazole‐3‐oxides (6a, b) A mixture of benzofuroxan (1b) (0.45 g, 3 mmol) and rhodanine derivatives (4a) (0.67 g, 3 mmol) or (4b) (0.718 g, 3 mmol) was heated under reflux for 6 hours in ethanol (30 mL) in the presence of sodium ethoxide (0.069 g, 3 mmol). The reaction mixture was left to stand at room temperature for 3 hours, then poured into crushed ice and acidified with dilute HCl, effervescence with evolution of CO2 was observed. The formed precipitate was filtered, dried and crystallized from ethanol to give benzimidazole derivatives (6a,b). 6a, Reddish brown crystals, M.p.: 254 oC. Yield: 70%. IR (KBr, max, cm‐1): 3250 (NH), 1248, 1343 (N→O). 1H NMR (DMSO, δ ppm): 2.0 (s, 1H, OH), 2.2 (s, 3H, CH3), 4.10 (s, 1H, NH), 6.85‐8.56 (m, 8H, Ar‐H). MS (m/z, %): 239 (M+‐16, 15). Anal. Calcd. for C14H13N3O2 (255.27): C, 65.87; H, 5.13. Found: C, 65.53; H, 5.32. 6b, Reddish brown crystals, M.p.: 160 oC. Yield: 60%. IR (KBr, max, cm‐1): 3250 (NH), 1248, 1343 (N→O). 1H NMR (DMSO, δ ppm): 2.0 (s, 1H, OH), 2.34 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 4.10 (s, 1H, NH), 6.18‐7.50 (m, 8H, Ar‐H). MS (m/z, %): 272 (M++1, 16). Anal. Calcd. for C14H13N3O3 (271.27): C, 61.99; H, 4.83; N, 15.49. Found: C, 61.74; H, 5.11; N, 15.56. 2.3. Synthesis of 2,2'‐dithiano‐Δ5,5'‐bi‐4‐thiazolidinones (8a,b) A mixture of benzofuroxan (1b) (0.45 g, 3 mmol), rhodanine derivatives (4a) (0.67 g, 3 mmol) or (4b) (0.718 g, 3 mmol), and catalytic amount of anhydrous sodium acetate (0.5 g, 6 mmol) in acetic acid (20 mL) was heated on water bath at 90 oC for 2‐3 hours. The reaction mixture was then filtered, dried then heated with hot ethanol filtered while hot to give 4‐ thiazolidinone dimers (8a,b). 8a, Dark yellow solid, M.p.: > 300 oC. Yield: 82%. IR (KBr, max, cm‐1): 3232 (NH), 1248, 1343 (N→O). 1H NMR (DMSO, δ ppm): 2.42 (s, 6H, 2CH3), 6.89‐7.59 (m, 8H, Ar‐H). MS (m/z, %): 442 (M+, 75). Anal. Calcd. for C20H14N2O2S4 (442.60): C, 54.27; H, 3.19; N, 6.33; S, 28.98. Found: C, 54.40; H, 3.26; N, 6.25; S, 29.08. 8b, Reddish brown solid, M.p.: >300 oC. Yield: 90%. IR (KBr, max, cm‐1): 3250 (NH), 1236, 1335 (N→O). 1H NMR (DMSO, δ ppm): 3.80 (s, 6H, 2OCH3), 6.91‐7.50 (m, 8H, Ar‐H). MS (m/z, %): 474 (M+, 12). Anal. Calcd. for C20H14N2O4S4 (474.60): C, 50.61; H, 2.97. Found: C, 50.58; H, 2.93. 2.4. Synthesis of 3‐methyl‐E‐2‐(1‐(2‐(hydrazinecarbono thioyl)‐hydrazono)‐ethyl)‐ quinoxalin‐1,4‐dioxide (12) To a boiling solution of 10a (0.655 g, 3 mmol) in methanol (15 mL) containing 2 drops of conc. HCl, was added a methanolic solution of thiocarbohydrazide (11) (0.318 g, 3 mmol in 10 mL methanol) with stirring. The reaction mixture was refluxed for 5 hours and then allowed to stand at room temperature overnight. The separated product was filtered off and recrystallized from methanol to give 12. Yellow crystals, M.p.: 237 oC. Yield: 72%. IR (KBr, max, cm‐1): 1250 (C=S), 1320 (N→O), 1620 (C=N), 3220 (NH), 3410 (NH2). 1H NMR (DMSO, δ ppm): 1.81 (s, 3H, CH3), 2.01 (s, 2H, NH2), 2.9 (s, 3H, CH3), 8.2‐ 8.6 (m, 4H, Ar‐H), 8.68 (br. s., 2H, 2NH). MS (m/z, %): 308 (M++2, 43). Anal. Calcd. for C12H14N6O2S (306.34): C, 47.05; H, 4.61; N, 27.43; S, 10.47. Found: C, 46.91; H, 4.64; N, 27.50; S 10.55. 2.5. Reaction of 12 with formic acid: Formation of 3‐methyl‐ E‐2‐(1‐(2‐(1,3,4‐thiadiazol‐2‐yl)‐hydrazono)‐ethyl)‐ quinoxaline 1,4‐dioxide (15) A mixture of 12 (1 g, 3 mmol) and formic acid (15 mL) was heated under reflux for 4 hours. The reaction mixture was then allowed to stand overnight at room temperature. The excess formic acid was evaporated under vacuo and the residue was crystallized from ethanol to give 15. Dark yellow crystals, M.p.: 80 oC. Yield: 60%. IR (KBr, max, cm‐1): 3315 (NH), 1610 (C=N), 1330 (N→O). 1H NMR (DMSO, δ ppm): 2.91 (s, 3H, CH3), 2.95 (s, 3H, CH3), 7.0 (s, 1H, NH), 7.5 (s, 1H, CH), 8.1‐8.6 (m, 4H, Ar‐H). MS (m/z, %): 316 (M+, 71). Anal. Calcd. for C13H12N6O2S (316.34): C, 49.36; H, 3.82. Found: C, 49.39; H, 3.87. 2.6. Synthesis of 2,6‐dimethyl‐3‐(2‐hydroxy‐2‐oxoindolin‐3‐ yl)acetyl)‐ quinoxaline‐1,4‐dioxide (16) To a mixture of isatin (0.397 g, 2.7 mmol) and 2,6‐dimethyl‐ 3‐acetylquinoxaline‐1,4‐dioxide (10b) (0.627 g, 2.7 mmol) in absolute ethanol (15 mL), 5 drops of piperidine were added and the reaction mixture was allowed to stand overnight at room temperature. The separated crystals was filtered off and crystallized from ethanol to give 16. Dark yellow powder, M.p.: >300 oC. Yield: 90%. IR (KBr, max, cm‐1): 1335 (N→O), 1700 (cyclic imide), 3447 (OH). 1H NMR (DMSO, δ ppm): 2.33 (s, 3H, CH3), 2.91 (s, 3H, CH3), 3.65 (s, 1H, OH), 4.13 (s, 2H, CH2), 6.85‐ 7.72 (m, 7H, Ar‐H), 8.2 (s, 1H, NH). MS (m/z, %): 379 (M+, 14). Anal. Calcd. for C20H17N3O5 (379.37): C, 63.32; H, 4.52; N, 11.08. Found: C, 63.25; H, 4.47; N, 11.00. 2.7. Synthesis of (E)‐2,6‐dimethyl‐3‐(2‐oxoindolin‐3‐ ylidene)acetyl)‐quinoxalin‐1,4‐dioxide (17) A mixture containing 16 (1.897 g, 5 mmol), (0.5 mL) conc. HCl, and glacial acetic acid (20 mL) was refluxed for 2 hours and then left to stand at room temperature overnight, fine needles were formed. The formed precipitate was filtered off and recrystallized from acetic acid to give 17. Brownish yellow powder, M.p.: 265 oC. Yield: 65%. IR (KBr, max, cm‐1): 1725 (α,β‐unsaturated ketone), 1330 (N→O). 1H NMR (DMSO, δ ppm): 2.34 (s, 3H, CH3), 2.91 (s, 3H, CH3), 6.97‐8.74 (m, 7H, Ar‐ H), 7.32 (s, 1H, CH), 8.2 (s, 1H, NH). MS (m/z, %): 362 (M++1, 35). Anal. Calcd. for C20H15N3O4 (361.35): C, 66.48; H, 4.18; N, 11.63. Found: C, 66.40; H, 4.13; N, 11.70. 2.8. Synthesis of 3‐cinnamoyl‐2,6‐dimethyl‐quinoxalin‐1,4‐ dioxides (18) A mixture of 2‐methyl‐3‐acetyl‐quinoxalin‐1,4‐dioxide (10a) (0.655 g, 3 mmol) and benzaldehyde (0.318 g, 3 mmol) in methanolic sodium hydroxide (10 mL, 5%) was stirred for 5‐10 minutes at room temperature. The formed yellow to orange precipitate was filtered off, washed with water and crystallized from the appropriate solvent (acetic acid) to give the cinnamoyl derivative 18. Yellow crystals, M.p.: 197 oC. Yield: 80%. IR (KBr, max, cm‐1): 1725 (C=O), 1590 (C=C), 1242, 1325 (N→O). 1H NMR (DMSO, δ ppm): 2.31 (s, 3H, CH3), 2.9 (s, 3H, CH3), 6.7 (d, Fadda et al. / European Journal of Chemistry 2 (1) (2011) 51‐57 53 1H, CH), 7.7 (d, 1H, CH), 7.2‐7.8 (m, 8H, Ar‐H). MS (m/z, %): 321 (M++1, 23). Anal. Calcd. for C19H16N2O3 (320.34): C, 71.24; H, 5.03. Found: C, 71.19; H, 5.00. 2.9. Synthesis of 2,6‐dimethyl‐3‐(5‐phenyl‐4,5‐dihydro‐1H‐ pyrazole‐3‐yl)quinoxalin‐1,4‐dioxide (19) To a solution of 18 (0.961 g, 3 mmol) in ethanol (15 mL), hydrazine hydrate (98%, 0.0751 g, 1.5 mmol) was added. The reaction mixture was refluxed for 3 hours and left to cool. The crystalline precipitate was filtered off, dried and crystallized from ethanol to give 19. Yellowish crystals, M.p.: 184 oC. Yield: 70%. IR (KBr, max, cm‐1): 3250 (NH), 1620 (C=N), 1320 (N→O). 1H NMR (DMSO, δ ppm): 2.3 (s, 3H, CH3), 2.9 (s, 3H, CH3), 3.9 (dd, J=1.90 Hz, 1H, CH), [3.19 (dd, J=1.85 Hz, 1H), 3.44 (dd, J=1.85 Hz, 1H) CH2], 7.06‐7.72 (m, 8H, Ar‐H), 8.3 (s, 1H, NH). MS (m/z, %): 333 (M+‐1, 63). Anal. Calcd. for C19H18N4O2 (334.37): C, 68.25; H, 5.43. Found: C, 68.00; H, 5.20. 2.10. The reaction of 18 with phenyl hydrazine: Synthesis of 2,6‐dimethyl‐3‐(1,5‐diphenyl‐4,5‐dihydro‐1H‐pyrazol‐3‐yl)‐ quinoxaline‐1,4‐dioxide (20) Compound 18 (0.961 g, 3 mmol) was boiled with phenyl hydrazine (0.162 g, 1.5 mmol) in acetic acid (10 mL) for 3 hours. The reaction mixture was left to cool and poured into crushed ice. The formed precipitate was filtered, dried and crystallized from ethanol to give 20. Lemon yellow crystals, M.p.: 105 oC. Yield: 67%. IR (KBr, max, cm‐1): 1620 (C=N), 1320 (N→O). 1H NMR (DMSO, δ ppm): 2.34 (s, 3H, CH3), 2.91 (s, 3H, CH3), 3.90 (dd, J=1.95 Hz, 1H, CH), 3.20 (dd, J=1.88 Hz, 1H), 3.40 (dd, J=1.88 Hz, 1H) CH2, 7.2‐7.5 (m, 13H, Ar‐H). MS (m/z, %): 410 (M+, 62). Anal. Calcd. for C25H22N4O2 (410.47): C, 73.15; H, 5.40; N, 13.65. Found: C, 73.00; H, 5.11; N, 13.58. 2.11. The reaction of 18 with hydroxylamine hydrochloride: Synthesis of 2,6‐dimethyl‐3‐(5‐phenyl‐4,5‐dihydroisoxazol‐3‐ yl)‐quinoxaline‐1,4‐dioxide (21) A mixture of 18 (0.961 g, 3 mmol), hydroxylamine hydrochloride (0.104 g, 1.5 mmol), sodium hydroxide (0.1 g, 2.5 mmol) and ethanol (15 mL) was refluxed for 4 hours. After cooling, the separated material was filtered off and crystallized from ethanol to give 21. Light yellow crystals, M.p.: 102 oC. Yield: 72%. IR (KBr, max, cm‐1): 1626 (C=N), 1340 (N→O). 1H NMR (DMSO, δ ppm): 2.34 (s, 3H, CH3), 2.91 (s, 3H, CH3), [3.13 (dd, J=2.03 Hz, 1H), 3.39 (dd, J=2.03 Hz, 1H) CH2], 5.96 (dd, J=2.09 Hz, 1H, CH), 7.06‐7.70 (m, 8H, Ar‐H). MS (m/z, %): 335 (M+, 18). Anal. Calcd. for C19H17N3O3 (335.36): C, 68.05; H, 5.11; N, 12.53. Found: C, 68.30; H, 5.36; N, 12.65. 2.12. Synthesis of 2,6‐dimethyl‐3‐(2‐pyridinyl‐4,6‐ diphenyl)quinoxalin‐1,4‐dioxide (24) To a solution of phenacyl pyridinium bromide (22) (0.834 g, 3 mmol) and ammonium acetate (2 g) in glacial acetic acid (10 mL) a solution of 18 (0.961 g, 3 mmol) in glacial acetic acid (10 mL) was added gradually with continuous stirring. The reaction mixture was refluxed for 2 h and then left to cool and poured into crushed ice. The formed precipitate was filtered off, dried and crystallized from methanol to afford 24. Yellowish brown crystals, M.p.: 186 oC. Yield: 80%. IR (KBr, max, cm‐1): 3000‐3077 (CH streching), 1620 (C=N), 1330 (N→O). 1H NMR (DMSO, δ ppm): 2.35 (s, 3H, CH3), 2.93 (s, 3H, CH3), 8.11 and 8.56 (2s, 2H, Py H`s), 7.06‐8.30 (m, 13H, Ar‐H). MS (m/z, %): 419 (M+, 30). Anal. Calcd. for C27H21N3O2 (419.47): C, 77.31; H, 5.05. Found: C, 77.09; H, 4.89. 2.13. Synthesis of 3‐(6‐amino‐5‐cyano‐4‐phenylpyridine‐2‐ yl)‐2,6‐dimethyl‐quinoxalin‐1,4‐dioxide (25) A mixture of 18 (0.961 g, 3 mmol), malononitrile (0.198 g, 3 mmol) and ammonium acetate (0.164 g, 2 mmol) was heated at 150 oC for 4 hours. The solid material was washed with water and recrystallized from benzene to give 25. Coffee Brown crystals, M.p.: 100 oC. Yield: 70%. IR (KBr, max, cm‐1): 3470 (NH2), 2220 (CN), 1640 (C=N), 1320 (N→O). 1H NMR (DMSO, δ ppm): 2.30 (s, 3H, CH3), 2.90 (s, 3H, CH3), 7.05‐7.70 (m, 8H, Ar‐ H), 7.60 (s, 2H, NH2), 8.2 (s, 1H, py‐H). MS (m/z, %): 383 (M+, 90). Anal. Calcd. for C22H17N5O2 (383.40): C, 68.92; H, 4.47; N, 18.27. Found: C, 69.03; H, 4.53; N, 18.45. 2.14. Synthesis of 2,6‐dimethyl‐3‐(hydrazinecarbonyl)‐ quinoxalin‐1,4‐dioxide (26) A mixture of 2,6‐dimethyl‐3‐carboethoxyquinoxalin‐1,4‐ dioxide (10c) (0.787 g, 3 mmol) and hydrazine hydrate (80%, 3 mL) in absolute ethanol (20 mL) was refluxed for 6 hours and left to stand overnight at room temperature. The separated crystals were filtered off, dried and crystallized from ethanol to give 26. Yellow crystals, M.p.: 218 oC. Yield: 70%. IR (KBr, max, cm‐1): 3380 (NH2), 3350 (NH), 1650 (C=O), 1330 (N→O). 1H NMR (DMSO, δ ppm): 2.00 (s, 2H, NH2), 2.30 (s, 3H, CH3), 2.91 (s, 3H, CH3), 7.06 (s, 1H, Ar‐H), 7.23 (d, 1H, Ar‐H), 7.70 (d, 1H, Ar‐H), 8.00 (s, 1H, NH). Anal. Calcd. for C11H12N4O3 (248.24): C, 53.22; H, 4.87; N, 22.57. Found: C, 53.07; H, 4.91; N, 22.64. 2.15. Synthesis of 2,6‐dimethyl‐3‐(5‐thioxo‐1',3',4'‐ oxadiazolo‐2'‐yl)‐quinoxalin‐1,4‐dioxide (27) A mixture of 26 (1.201 g, 5 mmol) in ethanol (10 mL), potassium hydroxide (0.281 g, 5 mmol) in water (3 mL) and carbon disulfide (0.381 g, 5 mmol) was heated under reflux for 7 hours or until the evolution of H2S ceased. The reaction mixture was left to cool, poured into crushed ice and acidified with conc. HCl. The precipitate was filtered off, washed with water, dried and crystallized from ethanol to give 27. Brownish crystals, M.p.: 210 oC. Yield: 85%. IR (KBr, max, cm‐1): 1595 (C=N), 1330 (N→O), 1300‐1100 (C=S), 2600‐2620 (SH). 1H NMR (DMSO, δ ppm): 2.34 (s, 3H, CH3), 2.90 (s, 3H, CH3), 7.00 (s, 1H, NH), 7.06 (s, 1H, Ar‐H), 7.23 (d, 1H, Ar‐H), 7.70 (d, 1H, Ar‐H). MS (m/z, %): 290 (M+, 33). Anal. Calcd. for C12H10N4O3S (290.30): C, 49.65; H, 3.47. Found: C, 49.77; H, 3.54. 2.16. Synthesis of 3,7‐dimethyl‐1,4‐dioxyquinoxaline‐2‐ carboxylic acid N`‐(3,7‐dimethyl‐1,4‐dioxyquinoaline‐2‐ carbonyl)hydrazide derivative (29) A mixture of 26 (0.721 g, 3 mmol), acetoacetanilide (0.532 g, 3 mmol) in glacial acetic acid (15 mL) was refluxed for 3 h. After cooling, the precipitate was filtered off, dried and recrystallized from acetic acid to give 29. Dark yellow powder, M.p.: >300 oC. Yield: 60%. IR (KBr, max, cm‐1): 3250, 3280 (NH/NH), 1700 (two C=O), 1327 (N→O). 1H NMR (DMSO, δ ppm): 2.55 (s, 6H, 2CH3), 2.91 (s, 6H, 2CH3), 6.80‐7.60 (m, 6H, Ar‐H), 9.50 (br. s., 2H, NH/NH). MS (m/z, %): 432 (M+‐32, 20). Anal. Calcd. for C22H20N6O6 (464.43): C, 56.89; H, 4.34; N, 18.10. Found: C, 56.97; H, 4.42; N, 18.36. 2.17. Synthesis of 3‐(3‐carboxamido‐2,6‐dimethyl‐1‐ phenylquinoxalin‐1,4‐dioxide)thiourea (30) Phenylisothiocyanate (0.406 g, 3 mmol) was added to a solution of 26 (0.721 g, 3 mmol) in ethanol (20 mL) and the reaction mixture was heated for 4 hours on water bath then left to cool. The precipitated solid product was filtered off and 54 Fadda et al. / European Journal of Chemistry 2 (1) (2011) 51‐57 crystallized from ethanol to give 30. Orange crystals, M.p.: 192 oC. Yield: 88%. IR (KBr, max, cm‐1): 3250, 3300, 3350 (NH/NH), 1220 (C=S), 1350 (N→O). 1H NMR (DMSO, δ ppm): 2.00 (s, 1H, NH), 2.34 (s, 3H, CH3), 2.90 (s, 3H, CH3), 4.20 (s, 1H, NH), 6.80‐ 7.70 (m, 8H, Ar‐H), 9.35 (s, 1H, NH), 9.55 (s, 2H, NH/NH). MS (m/z, %): 383 (M+, 80). Anal. Calcd. for C18H17N5O3S (383.42): C, 56.38; H, 4.47; N, 18.27. Found: C, 56.32; H, 4.41; N, 18.38. 2.18. Synthesis of 3‐(2,6‐dimethylquinoxalin‐1,4‐dioxide)‐5‐ mercapto‐4‐phenyl‐4H‐1,2,4‐triazole (31) A solution of 30 (1.15 g, 3 mmol) in potassium hydroxide (10%, 20 mL) was refluxed for 8 hours. The reaction mixture was kept to stand overnight at room temperature, then poured into crushed ice and acidified with dilute acetic acid. The solid product was filtered off, washed with water, dried and crystallized from ethanol to give 31. Orange powder, M.p.: 248 oC. Yield: 70%. IR (KBr, max, cm‐1): 2600‐2550 (SH), 1600 (C=N), 1337 (N→O), 1300‐1100 (C=S). 1H NMR (DMSO, δ ppm): 2.35 (s, 3H, CH3), 2.91 (s, 3H, CH3), 3.42 (s, 1H, SH), 7.05‐7.55 (m, 8H, Ar‐H). MS (m/z, %): 365 (M+, 5), 366 (M++1, 10). Anal. Calcd. for C18H15N5O2S (365.41): C, 59.16; H, 4.14; N, 19.17; S, 8.78. Found: C, 59.32; H, 4.27; N, 19.10; S, 8.85. 2.19. Synthesis of 3‐(2,6‐dimethylquinoxalin‐1,4‐dioxide)‐2‐ phenylimino‐4‐thiazolidinone (32) To a solution of 30 (1.15 g, 3 mmol) in glacial acetic acid (20 mL) was added monochloroacetic acid (0.284 g, 3 mmol) and anhydrous sodium acetate (0.3 g). The reaction mixture was refluxed for 8 hours, then left to cool at room temperature and then poured into crushed ice. The separated solid was filtered off, washed thoroughly with water, dried and crystallized from ethanol to give 32. Light yellow crystals, M.p.: 86 oC. Yield: 60%. IR (KBr, max, cm‐1): 3250 (NH), 1680, 1600 (C=O), 1535 (C=N), 1335 (N→O). 1H NMR (DMSO, δ ppm): 2.34 (s, 3H, CH3), 2.90 (s, 3H, CH3), 4.10 (s, 2H, CH2), 7.06‐7.70 (m, 8H, Ar‐H). MS (m/z, %): 423 (M+, 20). Anal. Calcd. for C20H17N5O4S (423.45): C, 56.73; H, 4.05; N, 16.54; S, 7.57. Found: C, 56.68; H, 4.08; N, 16.45; S, 7.60. 2.20. Synthesis of 3‐carbazido‐2,6‐dimethylquinoxalin‐1,4‐ dioxide (33) To a suspension of 26 (0.721 g, 3 mmol) in dioxane (10 mL) and acetic acid (10 mL), sodium nitrite (0.5 g) in water (1.3 mL) was added with stirring at 0‐2 oC. Stirring was continued for further 30 minutes after complete addition of sodium nitrite solution. The separated material was filtered off, washed with water and crystallized from acetic acid to give 33. Yellow crystals, M.p.: 78 oC. Yield: 55%. IR (KBr, max, cm‐1): 2157 (strong N3), 1691 (CO), 1341 (N→O). 1H NMR (DMSO, δ ppm): 2.35 (s, 3H, CH3), 2.93 (s, 3H, CH3), 7.08 (s, 1H, Ar‐H), 7.21 (d, J=7.5 Hz, 1H, Ar‐H), 7.65 (d, J=7.5 Hz, 1H, Ar‐H). MS (m/z, %): 259 (M+, 35). Anal. Calcd. for C11H9N5O3 (259.22): C, 50.97; H, 3.50; N, 27.02. Found: C, 51.02; H, 3.56; N, 27.17. 2.21. Synthesis of 2,6‐dimethyl‐3‐ethoxycarbonylamino quinoxalin‐1,4‐dioxide (34) The azide 33 (0.778 g, 3 mmol) in absolute ethanol (30 mL) was refluxed for 5 hours and the reaction mixture was filtered while hot to remove any insoluble material. The filtrate was evaporated and the residue crystallized from ethanol to give 34. Yellow crystals, M.p.: 200 oC. Yield: 72%. IR (KBr, max, cm‐1): 3382 (NH), 1723 (CO, ester), 1339 (N→O). 1H NMR (DMSO, δ ppm): 1.80 (t, J=13.7 Hz, 3H, CH3), 2.30 (s, 3H, CH3), 2.90 (s, 3H, CH3), 3.50 (q, J=13.7 Hz, 2H, CH2), 6.70‐7.30 (m, 3H, Ar‐H), 8.00 (s, 1H, NH). MS (m/z, %): 277 (M+, 13). Anal. Calcd. for C13H15N3O4 (277.28): C, 56.31; H, 5.45; N, 15.15. Found: C, 56.43; H, 5.57; N, 15.27. 2.22. Synthesis of 2,6‐dimethyl‐3‐isocyanatoquinoxalin‐1,4‐ dioxide (35) The azide 33 (0.778 g, 3 mmol) in dry toluene (20 mL) was refluxed for 3 hours. After cooling, the separated material was filtered off, dried and crystallized from benzene to give 35. Reddish crystals, M.p.: 244 oC. Yield: 66%. IR (KBr, max, cm‐1): 1700 (C=O), 1330 (N→O). 1H NMR (DMSO, δ ppm): 2.38 (s, 3H, CH3), 2.91 (s, 3H, CH3), 7.30 (d, J=8.30 Hz, 1H, H7), 7.70 (d, J=8.30 Hz, 1H, H8), 7.06 (s, 1H, H5). MS (m/z, %): 230 (M+‐1, 70). Anal. Calcd. for C11H9N3O3 (231.21): C, 57.14; H, 3.92. Found: C, 57.01; H, 3.80. 2.23. Synthesis of 3‐amino‐2,6‐dimethylquinoxalin‐1,4‐ dioxide (36) The carbazide 33 (0.778 g, 3 mmol) in acetic acid (5 mL) and dioxane (5 mL) was heated for 30 minutes and then left to cool. The reaction mixture was poured into water (30 mL) and then extracted with ether (three times), dried over anhydrous magnesium sulfate; the solvent was evaporated under vacuo to afford 36. Greyish crystals, M.p.: 202 oC. Yield: 70%. IR (KBr, max, cm‐1): 3480‐3440 (NH2), 1350 (N→O). 1H NMR (DMSO, δ ppm): 2.34 (s, 3H, CH3), 2.90 (s, 3H, CH3), 6.90 (s, 2H, NH2), 6.06‐7.70 (m, 3H, Ar‐H). MS (m/z, %): 189 (M+‐16, 50), 173 (100). Anal. Calcd. for C10H11N3O2 (205.21): C, 58.53; H, 5.40. Found: C, 58.62; H, 5.52. 2.24. Diazotization and coupling of 40 with β–naphthol: Synthesis of 2,6‐dimethyl‐E‐3((2‐hydroxynaphthalen‐1‐ yl)diazenyl)‐quinoxalin‐1,4‐dioxide (37) 2,6‐Dimethyl‐3‐aminoquinoxalin‐1,4‐dioxide (36) (0.616 g, 3 mmol) was dissolved in conc. hydrochloric acid (6 mL) and cooled to 0 oC in ice bath. Cold aqueous solution of sodium nitrite (0.3 g in 5 mL water) was added in small portions to the above amine hydrochloride solution. To the resulting sodium salt solution was added a cold solution of β–naphthol (0.433 g, 3 mmol) in sodium hydroxide (10%, 10 mL), the precipitated solid material was filtered off, washed with water and crystallized from ethanol to give 37. Orange powder, M.p.: 238 oC. Yield: 80%. IR (KBr, max, cm‐1): 3500 (OH), 1618 (C=N), 1495 (N=N), 1345 (N→O). 1H NMR (DMSO, δ ppm): 2.30 (s, 3H, CH3), 2.96 (s, 3H, CH3), 5.40 (s, 1H, OH), 7.06‐8.07 (m, 9H, Ar‐ H). MS (m/z, %): 360 (M+, 27). Anal. Calcd. for C20H16N4O3 (360.37): C, 66.66; H, 4.48; N, 15.55. Found: C, 66.57; H, 4.53; N, 15.68. 3. Results and discussion It is well established that Benzofuroxan derivatives exist at room temperature as a mixture of tautomers. The substituents in the benzene ring could occupy the 5‐ or 6‐position and the proportion of both tautomers in the equilibrium depends on the electronic characteristics of the substituents [22]. The reaction of benzofuroxan (BFO) 1a with the cyano‐ acetanilides 2a‐d in the presence of piperidine as catalyst at room temperature afforded the 2‐(arylcarbamoyl)‐1‐hydroxy‐ 5‐methyl‐1H‐benzo[d]imidazol‐3‐oxide derivatives 3a‐d, respectively; (Scheme 2). Scheme 2 Fadda et al. / European Journal of Chemistry 2 (1) (2011) 51‐57 55 A probable mechanism, in line with other carbanion reactions of BFO's is outlined in (Scheme 3). N O N O H3C 1a CNCHCONHAr N O NH3C H C O NC CONHAr H3C N O N O CN H CONHAr N NH3C O O H CONHArN NH3C O OH CONHAr 3a-d Scheme 3 The structures of 3a‐d were elucidated from their spectral and elemental analysis. Thus, the IR spectra of 3a‐d reveal the presence of OH and NH groups (3430 and 3250 cm‐1), respectively, amide carbonyl (1660 cm‐1), C=N (1620 cm‐1) and (N→O) functions (1236, 1317 cm‐1). The 1H NMR spectrum of 3d shows two singlets each integrated for 3H at δ 2.34 and 3.83 attributable to methyl and methoxy protons, respectively, and the aromatic protons appears at δ 7.07‐7.50 (m, 7H, Ar‐H), while the NH proton appears as a broad singlet at δ 9.15 ppm. Moreover, rhodanines are important anticonvulsant [16], anti‐inflammatory [17], antitubercular [18], and antibacterial agents [19]. So, compounds having a combination of benzofuroxan with rhodanine moieties are expected to posses marked biological properties. Unexpectedly when 1b was reacted with rhodanines 4a,b as active methylene compounds, in the presence of sodium ethoxide, 1‐hydroxy‐2‐(arylamino)‐ 1H‐benzo[d]imidazole‐3‐oxide 6 was obtained instead of the thioxospirobenzoimidazole‐thiazolidine‐1,3‐dioxide 5 (Scheme 4). Scheme 4 The IR, 1H NMR and mass spectra of 6a,b are in agreement with their proposed structures (Scheme 5). If the above reaction afforded compound 5, so, it would not have shown bands in both the IR and 1H NMR spectrum for NH group. On the other hand, we report here the reaction of BFO's with rhodanine in the presence of a weaker base, such as freshly fused sodium acetate and drops of acetic acid. This versatile synthesis has afforded novel compounds hitherto inaccessible by classical synthetic methods. Thus, surprisingly, the reaction of rhodanines 4a,b with benzofuroxan 1a,b and catalytic amount of freshly fused sodium acetate does not give the expected spiro benzimidazolyl‐4‐thiazolidinone 5, but resulted in the formation of 2,2'‐dithiano‐Δ5,5'‐bi‐4‐thiazo lidinones 7a,b which are auto‐oxidized to 2,2'‐dithiano‐Δ5,5'‐bi‐ 4‐thiazolidinones 8a,b, in which the benzofuroxan acts as oxidizing agent and in the same time it was reduced to o‐quinone dioxime 9. The oxidizing capacity [21] of benzofuroxan and its ability to oxidize rhodanine to the dimer derivatives 8a,b via the formation of 7 based on initial one or two electron oxidation and the subsequent formation of o‐ quinone dioximes 9a,b as side products are illustrated in (Scheme 6). The structures were assigned to the bi‐ thiazolidinones class on the basis of the chemical shift of the methyl groups and aromatic rings in the 1H NMR spectra. Scheme 5 Scheme 6 In addition, thiocarbohydrazide has been reported to show tubercular activities [30], in vitro and high insecticidal activity towards the house‐fly in comparison with DDT [31]. Thus, the quinoxaline N‐dioxide 10a reacts with the thiocarbohydrazide 11 to afford the condensation product 12 which reacts with excess formic acid to give 3‐methyl‐E‐2‐(1‐(2‐(1,3,4‐thiadiazol‐ 2‐yl)hydrazono)ethyl)‐quinoxaline‐1,4‐dioxide 15 presumably via the intermediates 13 and 14. Here, formic acid was expected to reduce the C=N to the corresponding secondary amine, however, formylation of NH2 group took place and the intermediate 14 was formed, which then loses a water molecule to give 15. All attempts to isolate the intermediate 14 failed (Scheme 7). Structures 12 and 15 were established on the basis of analytical and spectral data (see experimental part). On the other hand, it has been found that the reaction of isatin with quinoxaline derivatives 10b [29], in the presence of piperidine, afforded 3‐(2‐hydroxy‐2‐oxoindolin‐3‐yl)acetyl)‐ 2,6‐dimethyl‐quinoxalin‐1,4‐dioxide 16, in quantitative yield (Scheme 8). The structure of 16 was established from micro analytical data as well as the IR spectrum which showed well defined bands in the region 3447 cm‐1 (OH) and 1700 cm‐1 (cyclic imide). Dehydration of 16 by dilute alcoholic hydro‐ chloric acid or by hydrochloric acid in the presence of acetic acid gave (E)‐2,6‐dimethyl‐3‐(2‐oxoindolin‐3‐ylidene)acetyl) quinoxaline‐1,4‐dioxide 17 in good yield. IR spectrum of 17 56 Fadda et al. / European Journal of Chemistry 2 (1) (2011) 51‐57 showed a characteristic band at 1725‐1703 cm‐1 (α,β‐ unsaturated ketone). 10a 12 14 15 HCOOH H2NNHCSNHNH2+ N N CH3 O O CH3 N H N H N S NH2 N N CH3 O O CH3 N H N H N S N H O H N N CH3 O O CH3 N N HN S NH OH -H2O N N CH3 O O CH3 N N HN S N N N CH3 O O CH3 N H N N S N 10a, R= H, R'= COCH3; b, R= CH3, R'= COCH3; c, R= CH3, R'= COOC2H5 N N R' CH3 O O R N N CH3 O O O CH3 11 13 Scheme 7 Scheme 8 α,β‐Unsaturated ketones provide a valuable intermediate for building up various heterocycles. Thus, condensation of hydrazine hydrate or phenyl hydrazine with 3‐cinnamoyl‐2,6‐ dimethylquinoxaline‐1,4‐dioxide 18 in boiling ethanol yielded the yellow pyrazoline derivative, 2,6‐dimethyl‐3‐(5‐phenyl‐4,5‐ dihydro‐1H‐pyrazol‐3‐yl)quinoxaline‐1,4‐dioxide 19 and its N‐ phenyl isomer 20, respectively. The formation of an isoxazoline ring could be effected by the reaction of 18 with hydroxylamine. Thus, when 18 was boiled with hydroxylamine hydrochloride in alcoholic sodium hydroxide solution, the corresponding isoxazoline; 3‐(3‐ quinoxaliolyl‐2,6‐dimethyl‐1,4‐dioxide)‐5‐phenyl‐4,5‐dihydro‐ 1H‐isoxazoline 21 was obtained (Scheme 9). Scheme 9 Krohnke [30] and Madhar [31] studied the reactivity of pyridinium ylides; however their synthetic applications remained unexplored. With a view to explore the synthetic potentiality of this reaction we report here the synthesis of 3‐ pyridyl‐2,6‐dimethylquinoxaline‐1,4‐dioxide 24 via the cyclization reaction of the α,β–unsaturated ketone 18 with N‐ phenacyl pyridinium bromide 22 in acetic acid in the presence of ammonium acetate as the cyclization agent. The reaction presumably proceeds via the intermediary of ylide carbanion which is generated from pyridinium salt (Scheme 10). This undergoes Michael type addition to α,β– unsaturated carbonyl systems to yield 1,5‐dicarbonyl pyridinium derivative 23 as intermediate which on reaction with ammonium acetate gave 24. Ph O Ar 18 + N CH2COPh Br- AcOH N Ph O H Ph ArO Br- NHBr- NH4OAc 2322 N Ph ArPh 24 Ar= N N O O CH3 H3C N N CH3 O O H3C 25 N Ph NH2 CN CH2(CN)2 Scheme 10 The condensation of 18 with malononitrile in the presence of ammonium acetate gave 3‐(6‐amino‐5‐cyano‐4‐phenyl pyridine‐2‐yl)‐2,6‐dimethylquinoxaline‐1,4‐dioxide 25. Struc‐ tures 24 and 25 were supported by 1H NMR and IR spectral data (see experimental part). When 2,6‐dimethyl‐3‐carbethoxyquinoxalin‐1,4‐dioxide 10c was allowed to react with hydrazine hydrate (80%), 2,6‐ dimethyl‐3‐(hydrazinecarbonyl)‐quinoxalin‐1,4‐dioxide 26 was obtained. Treatment of 26 with potassium hydroxide and carbon disulphide gave 2,6‐dimethyl‐3‐(5‐thioxo‐4,5‐dihydro‐ 1',3',4'‐oxadiazol‐2'‐yl)quinoxalin‐1,4‐dioxide 27. Unexpectedly, when the hydrazide 26 was heated with acetoacetanilide in the presence of acetic acid, the product was not the expected 3‐pyrazole‐1‐carbonylquinoxaline derivative 28 but the 3,7‐dimethyl‐1,4‐dioxyquinoxaline‐2‐carboxylic acid N`‐(3,7‐dimethyl‐1,4‐dioxyquinoaline‐2‐carbonyl)hydrazide derivative 29 was obtained (Scheme 11). On refluxing the hydrazide 26 in dry ethanol with phenylisothiocyanate, the 1‐phenyl‐3‐(2,6‐dimethyl‐3‐carbox amido‐quinoxalin‐1,4‐dioxide)thiourea 30 was separated out. Heating the thiourea derivative 30 under reflux with chloroacetic acid and sodium acetate in acetic acid produced 3‐ (2,6‐dimethylquinoxalin‐1,4‐dioxide)‐2‐phenylimino‐4‐thia‐ zolidinone 32 in good yield (Scheme 12). Scheme 11 Scheme 12 Fadda et al. / European Journal of Chemistry 2 (1) (2011) 51‐57 57 The IR, 1H NMR and mass spectra of 26‐32 are in agreement with the proposed structures as shown in the experimental part. 2,6‐Dimethyl‐3‐carbohydrazidoquinoxalin‐1,4‐dioxide 26 on treatment with HNO2 gave 2,6‐dimethyl‐3‐carbazidoquin oxalin‐1,4‐dioxide 33 which on refluxing with ethanol for 5 h produced 2,6‐dimethyl‐3‐ethoxycarbonylamino quinoxalin‐1,4‐ dioxide 34 in good yield. The IR spectra of compounds 33 and 34 were in agreement with assigned structures. The decomposition of azides to isocyanate and nitrogen is known as the Curtius rearrangement. The reaction is a preparative method for isocyanate and compounds derivable from isocyanates, such as urethans, ureas, amides, and amines. When coupled with a hydrolytic step, the Curtius rearrangement becomes a particular procedure for replacing the azide group by an amino group. Thus azides undergo rearrangement in inert solvents like benzene, toluene and chloroform, forming isocyanates. In the presence of polar solvents like alcohol or water, the resulting isocyanate will react with these solvents to form urethans or ureas. Amines or their salts are obtained by hydrolysis of the isocyanate, urethans or ureas. However, heating of the carbazide 33 in toluene for 3 hours gives the isocyanate derivative 35. On the other hand, hydrolysis of the carbazide 33 yielded the corresponding 3‐amino‐2,6‐dimethylquinoxalin‐1,4‐dioxide derivative 36, which is diazotized and coupled with β–naphthol in alkaline medium to afford the corresponding azo‐β‐naphthol derivative 37 (Scheme 13). Scheme 13 4. Conclusion We could prepare some novel benzimidazole and thiazolidinone derivatives from Benzofuroxan. Moreover, a series of quinoxalinyl 1,4‐di‐N‐oxide derivatives could be derived from quinoxalin‐1,4‐di‐N‐oxides. Plausible mechanisms to account for the formation of the products are suggested. All the reactions are eco‐friendly, no heavy metals or hazardous solvents (mostly ethanol and acetic acid) are involved. Acknowledgement F. M. Abdelrazek thanks the Alexander von Humboldt Foundation (Germany) for granting short research fellowships and Prof. Dr. Peter Metz, Institute of Organic Chemistry, TU‐ Dresden, for his kind hospitalities. This work was also supported in part by the Research fund of the Faculty of Science, Cairo University. References [1]. Fadda, A. A.; Abdelrazek, F. M.; El‐Habbal, M. M. Indian J. Chem. 1986, 25B, 194‐196. [2]. Abdelrazek, F. M.; Fadda, A. A. Z. Naturforsch., 1986, 41B, 499‐501. [3]. Abdelrazek, F. M.; Salah, A. M. Bull. Chem. Soc. Jpn., 1993, 66(6), 1722‐ 1726. [4]. Fadda, A. A.; Refaat, H. M.; Biehl, E. Heterocycles 1996, 43(1), 23‐32. [5]. Abdelrazek, F. M.; Salah El‐Din, A. M.; Mekky, A. E. Tetrahedron; 2001, 57, 6787‐6791. [6]. Abdelrazek, F. M.; Metz, P.; Metwally, N. H.; El‐Mahrouky, S. F. Arch. Pharm. Chem. Life Sci. (Weinheim); 2006, 339(8), 456‐460. [7]. Abdelrazek, F. M.; Fadda, A. A.; Mohamed, K. S.; Ghieth, H. M. M; Etman, H. A. Eur. J. Chem. 2010, 1(2), 90‐95. [8]. Abdelrazek, F. M.; Fadda, A. A.; Elsayed, A. N.; Synth. Commun. 2011, 41, 1119‐1126. [9]. Dahbi, S; Methnani, E; Bisseret, P. Tetrahedron Lett. 2010, 51, 5516‐ 5520. [10]. Cerecetto, H.; Porcal, W. “Pharmacological Properties of Furoxans and Benzofuroxans: Recent Developments”. Mini reviews in Med. Chem. 2005, 5 (1), 57‐71. [11]. Medana, C.; Visentin, S.; Grosa, G.; Fruttero, R.; Gasco, A. Farmaco 2001, 56(10), 799‐802. [12]. Carta, A.; Corona, P.; Loriga, M. Curr. Med Chem. 2005, 12(19), 2259‐ 2272. [13]. Aguirre, G; Boiani, L; Boiani, M; Cerecetto, H; Maio, R. D; Gonza´lez, M; Porcal, W; Denicola, A; Piro, O. E.; Castellano, E.E; Sant`Anna C. M. R; Barreiro, E. J. Bioorg. Med. Chem. 2005, 13, 6336‐6346. [14]. Amin, K. M.; Ismail, M. M. F.; Noaman, E.; Soliman, D. H.; Ammar, Y. A. Bioorg. Med. Chem. 2006, 14, 6917‐6923. [15]. Ismail, M. M. F.; Amin, K. M.; Noaman, E.; Soliman, D. H.; Ammar, Y. A. Eur. J. Med. Chem. 2010, 45, 2733‐2738. [16]. Jaso, A.; Zarranz, B.; Aldana, I.; Monge, A. Eur. J. Med. Chem. 2003, 38, 791‐800. [17]. Ancizu, S.; Moreno, E.; Solano, B.; Villar, R.; Burguete, A.; Torres, E.; Pérez‐S, S.; Aldana, I.; Monge, A. Bioorg. Med. Chem. 2010, 18, 2713‐ 2719. [18]. Fadda, A. A.; Abdel‐Halim, M. S.; Etman, H. A.; Fouda, A. Monatsh. Chem. 1995, 126, 1217‐1223. [19]. Fadda, A. A.; Bondock, S.; Khalifa, W. Eur. J. Med. Chem. 2007, 42, 948‐ 954. [20]. Fadda, A. A.; Abd El‐Latif, E.; Bondock, S. B.; Samir, A. Synth. Commun. 2008, 38, 4352‐4368. [21]. Paetzold, F.; Zauner, F.; Heyer, T. Synth. Commun. 1992, 22(2), 281‐ 288. [22]. Carta, A.; Corona, P.; Loriga, M. Curr. Med. Chem. 2005, 12, 2259‐2272. [23]. Carta, A.; Piras, S.; Loriga, M. Mini‐Rev. Med. Chem. 2006, 6, 1179‐ 1200. [24]. Li, X.; Yang, K. H.; Li, W. L. Drugs Future 2006, 31, 979‐989. [25]. Lima, L. M.; Barreiro, E. J. Curr. Med. Chem. 2005, 12, 23‐49. [26]. Inbaraj, J. J.; Motten, A. G. Chem. Res. Toxicol. 2003, 16, 164‐170. [27]. Jaso, A.; Zarranz, B. Eur. J. Med. Chem. 2003, 38, 791‐800. [28]. Jaso, A.; Zarranz, B. Bioorg. Med. Chem. 2004, 12, 3711‐3721. [29]. Fadda, A. A.; Abdel‐Halim, M. S.; Etman, H. A.; Fouda, A. Monatsh. Chem. 1995, 126, 1217‐1223. [30]. Khan, B. R.; Huda, Q. M. N. M.; Islam, R. Bangladesh J. Pathology 1988, 3, 1‐4. [31]. Cline, R. E.; Pearce, G. W. J. Insect. Physiol. 1966, 12, 135‐139.