untitled European Journal of Chemistry 5 (2) (2014) 267‐271 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2014 Eurjchem Publishing ‐ Printed in the USA http://dx.doi.org/10.5155/eurjchem.5.2.267‐271.913 European Journal of Chemistry Journal homepage: www.eurjchem.com Synthesis and characterization of novel heterocycles based on tetrazine and hydrazonoyl halides Abdelwahed Rashad Sayed a,b,*, Shar Saad Al‐Shihry a and Mohsen Abdel‐Motaal Gomaa a,c a Department of Chemistry, Faculty of Science, King Faisal University, Hofuf, 31982, Saudi Arabia b Department of Chemistry, Faculty of Science, University of Beni Suef, Beni Suef, 62511, Egypt c Department of Chemistry, Faculty of Science, University of Minia, Minia, 61519, Egypt *Corresponding author at: Department of Chemistry, Faculty of Science, King Faisal University, Hofuf, 31982, Saudi Arabia. Tel.: +966.3.561009338. Fax: +966.3.5886437. E‐mail address: arsayed@kfu.edu.sa (A.R. Sayed). ARTICLE INFORMATION ABSTRACT DOI: 10.5155/eurjchem.5.2.267‐271.913 Received: 01 September 2013 Received in revised form: 12 October 2013 Accepted: 12 October 2013 Online: 30 June 2014 KEYWORDS The present work describes the preparation and characterization of new pyridazine, thiohydrazonate, bis‐pyrazole, bis‐triazole and polypyrazoles based on tetrazine and hydrazonoyl halides. The structures of the newly synthesized were elucidated on the basis of their spectral data FT‐IR, NMR, Mass and elemental analysis. Triazole Pyrazole Tetrazine Bismalimide Thiohydrazonate Hydrazonoyl halides 1. Introduction 1,2,4,5‐Tetrazine is a strongly colored (red) molecule which is planar [1]. S‐Tetrazines have been studied for several decades because their spectroscopic and photo dissociation properties lend themselves to modeling. Tetrazines are highly reactive for aromatic compounds, forming cycloaddition compounds. 1,2,4,5‐Tetrazines with a large variety of substi‐ tuents in the 3‐ and 6‐positions of the heterocyclic are easily accessible, and due to their potential role in inverse‐type Diels‐ Alder reactions, members of this heterocyclic class have found widespread use in many fields of organic chemistry [2]. The pyridazine nucleus is of considerable interest because of its synthetic applications [3‐5], and important pharmacological activities [6,7], most of them related to the cardiovascular system [8,9]. The interest in the chemistry of hydrazonoyl halides is a consequence of the fact that they undergo a wide variety of reactions which provide routes to many of heterocyclic compounds [10‐13]. The 1,3‐dipolar cycloaddition, also known as the Huisgen cycloaddition [14], is a classic reaction in organic chemistry consisting of the reaction of a dipolarophile with a 1,3‐dipolar compound that allows the production of various five membered heterocycles. Most of dipolarophiles are alkenes, alkynes and molecules possessing related heteroatom functional groups. A survey of literature revealed that pyrazoles belong among the most representative five‐ membered heterocyclic systems [15]. We report herein a convenient and efficient synthesis of new heterocycles based on tetrazine and hydrazonoyl halides. 2. Experimental 2.1. Instrumentation and chemicals All the chemicals were purchased from Aldrich and Fluka, and used without further purification. Melting points were measured on an electrothermal Gallenkamp melting point apparatus and are uncorrected. The 1H and 13C NMR spectra were recorded in DMSO‐d6 with tetramethylsilane (TMS) as an internal standard using 300 MHz Varian Gemini spectrometer. The IR spectra were measured on a Fourier Transform and Pye Unicam Infrared spectrophotometers using potassium bromide wafer. Mass spectra were recorded on a GC/MS‐QP 1000 EX spectrometer at an ionizing potential of 70 eV. Elemental microanalyses were carried out at the Microanalytical Center of Cairo University, Giza, Egypt. 268 Sayed et al. / European Journal of Chemistry 5 (2) (2014) 267‐271 Scheme 1 The identification of compounds from different experi‐ ments were secured by mixed melting point’s and super imposable IR spectra. The starting reagents 1 [16], 12 [17], 15 [18], 16 [19], 20 [20], 21 [21], and 25 [22] were prepared as previously described. 2.2. Synthesis 2.2.1. Synthesis of 4,4'‐((5R,8S)‐5,6,7,8‐tetrahydro‐5,8‐ methanophthalazine‐1,4‐diyl)diphenol (3) and 4,4'‐ (pyridazine‐3,6‐diyl)diphenol (6) To a dry 100 mL round‐bottom flask were charged 3,6‐bis‐ phenolyl‐1,2,4,5‐tetrazine (1) (2.66 g, 10 mmol) and bicycle [2.2.1]hept‐2‐ene (2) or bicyclo[2.2.1]hept‐2,5‐diene (4) (10 mmol) in DMF at room temperature. The solution were stirred, the progress of reaction was monitored by disappear of red color and TLC, when the reactions were stopped and DMF was removed. The final separation of the products dried and recrystallized from DMF‐MeOH (5:15, v:v) to give the final products (Scheme 1). 4,4'‐((5R,8S)‐5,6,7,8‐Tetrahydro‐5,8‐methanophthalazine‐ 1,4‐diyl)diphenol (3): Color: Pale Yellow. Yield: 92%. M.p.: ˃ 350 oC. FT‐IR (KBr, ν, cm‐1): 3219 (OH) (br, phenol), 1612 (C=N) (pyridazine), 1601 (C=C) (unsaturated). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.42‐1.83 (q, 4H, CH2), 2.21 (d, 2H, CH2), 3.68 (p, 2H, CH), 7.12 (d, 4H, J = 9 Hz, Ar‐H), 7.71 (d, 4H, J = 9 Hz, Ar‐ H), 10.53 (s, 2H, OH). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 24.4, 43.3, 50.1, 116.2, 122.1, 131.4, 152.1, 152.2, 160.9. MS (EI, m/z (%)): 330 (M+, 79). Anal. calcd. for C21H18N2O2: C, 76.34; H, 5.49; N, 8.48. Found: C, 76.29; H, 5.50; N, 8.46 %. 4,4'‐(Pyridazine‐3,6‐diyl)diphenol (6): Color: Green. Yield: 96%. M.p.: ˃ 300 oC. FT‐IR (KBr, ν, cm‐1): 3138 (OH) (br, phenol), 1608 (C=N) (pyridazine), 1593 (C=C) (unsaturated). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 6.68 (d, 4H, J = 9 Hz, Ar‐ H), 7.95‐8.18 (m, 6H, Ar‐H), 10.02 (s, 2H, OH). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 116.1, 124.0, 126.3, 128.4, 156.3, 159.9. MS (EI, m/z (%)): 264 (M+, 61). Anal. calcd. for C16H12N2O2: C, 72.72; H, 4.58; N, 10.60. Found: C, 72.69; H, 4.62; N, 10.58 %. 2.2.2. Synthesis of (1,2,4,5‐tetrazine‐3,6‐diyl)bis(4,1‐ phenylene) diacetate (9) In 50 mL of acetic anhydradide 8 (20.4 g, 0.2 mol), 3,6‐bis‐ phenolyl‐1,2,4,5‐tetrazine (2.66 g, 0.01 mol) 1 is refluxed for 5 h at 140 oC. The mixture was cooled; the solid filtered and washed will with methanol, recrystallized from DMF to give final product 9 (Scheme 1). (1,2,4,5‐Tetrazine‐3,6‐diyl)bis(4,1‐phenylene) diacetate (9): Color: Violet. Yield: 94%. M.p.: ˃ 300 oC. FT‐IR (KBr, ν, cm‐1): 1752 (C=O) (ester), 1598 (C=C) (unsaturated), 1368 (CH3). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 2.31 (s, 6H, CH3), 7.01‐8.39 (m, 8H, Ar‐H). MS (EI, m/z (%)): 350 (M+, 89). Anal. calcd. for C18H14N4O4 : C, 61.71; H, 4.03; N, 15.99; Found: C, 61.69; H, 3.98; N, 15.92 %. 2.2.3. Synthesis of (1,2,4,5‐tetrazine‐3,6‐diyl)bis(4,1‐ phenylene) bis(phenylcarbamate) (11) A mixture of 3,6‐bis‐phenolyl‐1,2,4,5‐tetrazine (2.66 g, 0.01 mol) 1 and phenylisocyanate (2.38 g, 0.02 mol) 10 in 100 mL of dry DMF. The flask was then submerged into a 50 °C oil bath and magnetic stirring and the reaction was held at 50 °C for approximately 24 h when the reaction was stopped and the DMF was removed by rotary evaporation. The resulting precipitate was recrystallized from DMF‐EtOH (5:15, v:v) to give final product 11. 13C NMR spectra for 11 could not be recorded. This was due to the poor solubility of the isolated products in the NMR solvents trialled (Scheme 1). (1,2,4,5‐Tetrazine‐3,6‐diyl)bis(4,1‐phenylene)bis(phenyl carbamate) (11): Color: Purple. Yield: 92%. M.p.: ˃ 300 oC. FT‐ IR (KBr, ν, cm‐1): 3110 (NH) (carbamate), 1715 (C=O) (carba‐ mate), 1595 (C=C) (unsaturated), 1164 (C‐O) (carbamate). Sayed et al. / European Journal of Chemistry 5 (2) (2014) 267‐271 269 N N Br H N SH N N S H N 12 13 14 - HBr Scheme 2 N Cl H N ArH3C O H N H N S NH2N C Ph N S H N ArH3C O H N N NH2NPh H EtOH Ar: 4-CH3C6H4 15 16 17 H Scheme 3 Scheme 4 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 6.41‐8.40 (m, 18H, Ar‐H), 10.41 (s, 2H, NH). MS (EI, m/z (%)): 504 (M+, 62). Anal. calcd. for C28H20N6O4 : C, 66.66; H, 4.00; N, 16.66. Found: C, 66.41; H, 3.98; N, 16.71 %. 2.2.4. Synthesis of (Z)‐Phenyl N'‐phenylpyridine‐2‐carbo hydrazonothioate (14) A mixture of 1‐{bromo(pyridine‐2‐yl)methylene}‐2‐ phenylhydrazine (2.75 g, 10 mmol) 12 and the appropriate of thiophenol (1.10 g, 10 mmol) 11 in pyridine or EtONa (20 mL) was stirred at room temperature for 15 h. The reaction mixture was then poured onto ice‐cold hydrochloric acid with stirring. The solid that precipitated was collected. The resulting solids filtered, washed with water and recrystallized from MeOH (Scheme 2). (Z)‐Phenyl N'‐phenylpyridine‐2‐carbohydrazonothioate (14): Color: Yellow brown. Yield: 62%. M.p.: 75 oC. FT‐IR (KBr, ν, cm‐ 1): 3189 (NH), 1618 (C=N). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 7.16‐8.08 (m, 14H, Ar‐H, pyrdinyl), 10.48 (s, 1H, NH). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 112.9, 116.6, 122.1, 124.3, 127.76, 128.45, 129.9, 132.1, 136.9, 133.7, 143.8, 149.5, 151.1, 154.5. MS (EI, m/z (%)): 305 (M+, 60). Anal. calcd. for C18H15N3S: C, 70.79; H, 4.95; N, 13.76. Found: C, 70.63; H, 4.94; N, 13.81%. 2.2.5. Synthesis of (1Z,2E)‐2‐benzylidenehydrazinecarbo hydrazonic (Z)‐2‐oxo‐N'‐(p‐tolyl)propanehydrazonic thioanhydride (17) 1‐(2‐p‐Tolylhydrazono)‐1‐chloropropan‐2‐one (0.21 g, 10 mmol) 15 and phenylmethylene carbonothioic dihydrazide 16 in ethanol (40 mL) was refluxed for 30 minutes. The reaction mixture was cooled and solid formed was collected and recrystallized from DMF‐EtOH (5:15, v:v) (Scheme 3). (1Z,2E)‐2‐benzylidenehydrazinecarbohydrazonic (Z)‐2‐oxo‐ N'‐(p‐tolyl)propanehydrazonic thioanhydride (17): Color: Yellow. Yield: 95%. M.p.: 215 oC. FT‐IR (KBr, ν, cm‐1): 3098 (=NH), 1595 (C=N), 1316 (CH3). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 2.20 (s, 3H, CH3), 2.39 (s, 3H, CH3), 5.85 (s, 2H, NH2), 7.08‐7.81 (m, 10H, Ar‐H and =CH), 10.06 (s, 1H, NH), 10.67 (s, 1H, NH). MS (EI, m/z (%)): 368 (M+, 11). Anal. calcd. for C18H20N6OS: C, 58.68; H, 5.47; N, 22.81. Found: C, 58.61; H, 5.42; N, 22.79 %. 2.2.6. Synthesis of 1,5‐diphenyl‐3,7‐di(pyridin‐2‐yl)pyrazolo [3,4‐f]indazole‐4,8(1H,5H)‐dione (19) To an oven‐dried round bottom flask was added 1,4‐ quinone (0.54 g, 5 mmol) 14 and 1‐{bromo(pyridine‐2‐ yl)methylene}‐2‐phenylhydrazine (2.75 g, 10 mmol) 12 and 20 mL dry chloroform and 4 mL DMF in the presence of excess triethylamine (1.52 g, 15 mmol). The round bottom flask was attached to a reflux condenser. The reaction mixture solution was heated to reflux for 12 h. The cold reaction mixture was then poured onto ice‐cold hydrochloric acid with stirring. The solid that precipitated was collected, washed with water to give final product 19, and dried to open air. The structure was elucidated on the basis of spectral data. Deep green solid recrystallized from MeOH (Scheme 4). 1,5‐diphenyl‐3,7‐di(pyridin‐2‐yl)pyrazolo[3,4‐f]indazole‐ 4,8(1H,5H)‐dione (19): Color: Deep green. Yield: 85%. M.p.: 205 oC. FT‐IR (KBr, ν, cm‐1): 3101 (Ar‐H), 1650 (C=O), 1604 (C=N), 1550 (pyridiny), 1488 (C=C), 1157 (N‐N). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 6.89‐8.74 (m, 18H, Ar‐H and pyrdinyl). MS (EI, m/z (%)): 494 (M+, 28). Anal. calcd. for C30H18N6O2: C, 72.87; H, 3.67; N, 16.99. Found: C, 72.93; H, 3.59; N, 16.84%. 270 Sayed et al. / European Journal of Chemistry 5 (2) (2014) 267‐271 Scheme 5 2.2.7. Synthesis of 3,3'‐(3,3'‐(1,4‐phenylene)bis(1,4‐diphenyl‐ 1H‐1,2,4‐triazole‐3(4H)‐yl‐5(4H)‐ylidene))bis(pentane‐2,4‐ dione) (23) To a mixture ketene N,S‐acetal (2.49 g, 10 mmol) 21 and bis‐hydrazonoyl dichlorides (1.92 g, 5 mmol) 20 in ethanol (30 mL) and DMF (10 mL) was added triethylamine (5 mmol) and the mixture was refluxed till methanethiol ceased to evolve 4‐6 h. The precipitate that was formed was filtered off and crystallized from DMF:EtOH mixture (5:15, v:v) to give 3,3’‐ bis(1,2,4‐triazole) derivative 23 (Scheme 5). 3,3'‐(3,3'‐(1,4‐Phenylene)bis(1,4‐diphenyl‐1H‐1,2,4‐triazole‐ 3(4H)‐yl‐5(4H)‐ylidene))bis(pentane‐2,4‐dione) (23): Color: Brown. Yield: 40%. M.p.: 200 oC. FT‐IR (KBr, ν, cm‐1): 1715 (C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 2.06 (s, 12H, 4CH3), 6.82‐8.11 (m, 24H, ArH). MS (EI, m/z (%)): 712 (M+, 56). Anal. calcd. for C44H36N6O4: C, 74.14; H, 5.09; N, 11.79. Found: C, 74.11; H, 5.14; N, 11.83 %. 2.2.8. Reaction of 1‐((3aR,7aS)‐1‐phenyl‐3a,4,5,6,7,7a‐ hexahydro‐1H‐4,7‐methanoindazol‐3‐yl)‐4‐((3aS,4S,7R, 7aR)‐1‐phenyl‐3a,4,5,6,7,7a‐hexahydro‐1H‐4,7‐ methanoindazol‐3‐yl)benzene (24) A mixture of 4‐[N,N’‐diphenyl(bis‐hydrazonoyl dichlorides)]benzene (1.92 g, 5 mmol) 20 and bicycle [2.2.1]hept‐2‐ene ( 0.94 g, 10 mmol) 2 in DMF (20 mL) was boiled under reflux for 5 h. The cold reaction mixture was then poured onto ice‐cold hydrochloric acid with stirring. The solid that precipitated was collected. The resulting solids filtered, washed with water and recrystallized from EtOH (Scheme 45). 1‐((3aR,7aS)‐1‐phenyl‐3a,4,5,6,7,7a‐hexahydro‐1H‐4,7‐ methanoindazol‐3‐yl)‐4‐((3aS,4S,7R,7aR)‐1‐phenyl‐3a,4,5,6,7,7a‐ hexahydro‐1H‐4,7‐methanoindazol‐3‐yl)benzene (24): Color: Green yellow. Yield: 71%. M.p.: 320 oC. FT‐IR (KBr, ν, cm‐1): 1620 (C=N). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.48 (q, 8H, CH2), 2.23 (d, 4H, CH2), 3.04 (p, 2H, CH), 3.38 (s, 2H, CH), 4.22 (s, 2H, CH), 5.34 (s, 2H, CH), 6.65‐8.19 (m, 14H, ArH). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 24.1, 27.6, 32.9, 54.1, 68.2, 113.1, 119.7, 121.2, 122.1, 126.3, 130.2, 144.1, 149.2. MS (EI, m/z (%)): 498 (M+, 16). Anal. calcd. for C34H34N4: C, 81.89; H, 6.87; N, 11.24. Found: C, 81.83; H, 6.90; N, 11.27 %. 2.2.9. Synthesis of polypyrazole based on bismalimide (27) A suspension of bis‐hydrazonoyl dichlorides (1.53 g, 5 mmol) 25 and bis‐maleimide (1.92 g, (5 mmol) 26 in 20 mL of DMF was heated at 105‐110 °C until a slightly yellow solution was formed. The obtained solution was flashed with N2 during 40 min, cooled to 75 °C, and stirred for 43 h. Cooling to the ambient temperature interrupted the reaction, and the solution was dropped into 100 mL of water. The obtained polymer adduct 27 was filtered off, and after reprecipitation from DMF into ethanol, the polymer was dried in a vacuum at ambient temperature (Scheme 6). Bis‐Malimide (27): Color: Yellow brown. Yield: 65%. FT‐IR (KBr, ν, cm‐1): 1705 (C=O), 1555 (C=C). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 3.95 (s, 2H, CH2), 4.24 (d, 1H, CH), 5.19 (s, 1H, CH), 6.14‐7.79 (m, 13H, Ar‐H). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 41.9, 44.1, 53.8, 114.4, 116.1, 121.3, 126.9, 127.7, 129.8, 131.9, 133.6, 135.1, 137.2, 140.9, 142.3, 142.9, 169.9, 170.1. 3. Results and discussion Electron‐deficient heterocyclic tetrazine have proven to be useful reagents that often participate in well‐defined inverse electron demand Diels‐Alder reactions with electron‐rich dienophiles, providing rapid access to a range of highly substituted heterocyclic systems [23]. We have extended these principles to prepare new pyridiazines by reacting of 3,6‐bis‐ phenolyl‐1,2,4,5‐tetrazine 1 with bicycle[2.2.1]hept‐2‐ene 2 or bicycle[2.2.1]hept‐2,5‐diene 4 in DMF at room temperature. We use symmetric alkene to help us to give one isolated product. Sayed et al. / European Journal of Chemistry 5 (2) (2014) 267‐271 271 Scheme 6 The progress of reaction was monitored by disappearance of red color of tetrazine and TLC to give one compound that appeared to be pyridazine as supported by 13C NMR spectroscopy which showed pyridazine in oxidized. Treatment of 3,6‐bis‐phenolyl‐1,2,4,5‐tetrazine 1 with acetic anhydride 8 under heating to give 3,6‐bis‐phenylacetate‐1,2,4,5‐tetrazine 9 in good yield. Also, reaction of 3,6‐bisphenolyl‐1,2,4,5‐tetrazine 1 with phenyl isocyanate 10 to give 3,6‐bis‐(phenyl phenylcarbamate)‐1,2,4,5‐tetrazine 11 as shown in Scheme 1. Structures of 3, 6, 9 and 11 were confirmed by elemental analysis and spectra data. Previously reported arylhydrazonates had great attention and were prepared by reaction of phenols with hydrazonoyl [24]. Thiohydrazonate prepared by treating hydrazonoyl halides 12 or 15 with thiophenol 13 or phenylmethylene carbonothioic dihydrazide 16 to give the final product 14, 17 as shown in Scheme 2 and 3. It is well known that 1,3‐dipolar cycloaddtion reactions with 1,4‐quinones provide a convenient one step synthesis of condensed heterocyclic quinones [25]. Nitrilimine 18 generated in situ, by the action of triethylamine on the corresponding hydrazonoyl halides 12, was allowed to react with 1,4‐quinone 14 via cycloaddation to afford the final product 19 as shown in Scheme 4. The chemical shifts of pyrazoline protons are analogue to those observed for some closely related pyrazoline derivatives [26] should be appear at 4.64‐4.70 ppm but when examined auto oxidation happened. The required 2‐cyano‐3‐methylthio‐3‐phenylaminoacrylo nitrile 21 was prepared by the reaction of malononitrile with phenyl isothiocyanate in DMF in the presence of potassium hydroxide and the resulting thiolate was methylated with methyl iodide to give 2‐cyano‐3‐methylthio‐3‐phenylamino acrylonitrile 21 [21]. Recently, the synthesis of bis‐triazoles [27] from reactions of hydrazonoyl halides with ketene‐N,S‐ acetal was reported. These principles were extended to the reaction of bis‐hydrazonoyl dichlorides 20 with two mole equivalents of 21 in refluxing DMF:EtOH (5:15, v:v) in the presence of triethylamine proceeded smoothly to give a product that was identified as 3,3’‐bis‐(1,2,4‐triazole) derivative 23. Treatment of bis‐hydrazonoyl dichlorides 20 with bicycle [2.2.1]hept‐2‐ene 2 in DMF/TEA under heating to give final product 24 in good yield. The structures of the products 23 and 24 were elucidated on the basis of its microanalysis and spectra data as shown in Scheme 5 (see Experimental). The synthetic utility of nitrilimine cycloaddition reactions in the most cases deals with construction of low molecular weight five‐membered heterocyclic ring systems [21]. The presented paper deals with the synthesis and investigations of new polymers which were prepared via 1,3‐dipolar polycycloaddition of bis‐hydrazonoyl dichlorides 26 and bis‐ maleimide 27, two maleic protons (H1 and H2) can be assigned as multiplet at 4.24 and 5.19 ppm. The 13C NMR spectrum showed sharp peaks for the pyrazolidine function at 77.3 and two signals for maelic carbone 74.5 and 42.8 ppm. The molecular weight of the polymer could not be recorded. This was due to poor solubility of isolated product in THF. Thermal properties of polymer was investigated by DSC measurements (TG) for polymer was found at 71 °C and (Tm) was found at 260 oC. 4. Conclusion In summary, the synthesis of novel tetrazine, pyridazines, thiohydrazonate, bis‐pyrazole, bis‐triazole and polypyrazoline‐ bismaleimide derivatives based on tetrazine and hydrazonoyl halides are reported. Acknowledgements The financial support of this work (Project no: 130178) by the Deanship of Scientific Research, King Faisal University is appreciated. References [1]. Boulton, J. A.; McKillop, A. In Comprehensive Heterocyclic Chemistry, Pergamon, New York, 1984. [2]. Sauer, J. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. Pergamon Press Oxford, 1996, pp. 901. [3]. Pal, M.; Batchu, V. R.; Khanna, S.; Yeleswarapu K. R. Tetrahedron 2002, 58, 9933‐9940. [4]. Tisler, M.; Stanovnik, B. In Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic: San Diego, 1990, pp. 1. [5]. Coates, W. J.; McKillop, A. Synthesis 1993, 3, 334‐342. [6]. Heinisch, G.; Kopelent, H. In Progress in Medicinal Chemistry, Ellis, G. P., West, G. B., Eds., Elsevier: Amsterdam, 1992, 29, pp. 141‐183. [7]. Ungureanu, M.; Mangalagiu, I.; Grosu, G.; Petrovanu, M. Ann. Pharm. Fr. 1997, 55(2), 69‐72. [8]. Pita, B.; Sotelo, E.; Saurez, M.; Ravina, E.; Ochoa E.; Verdecia, Y.; Novoa, H.; Blaton, N.; de Ranter, C. Peeters O. M., Tetrahedron 2000, 56, 2473‐ 2479. [9]. Campos, M.; Estevez, I.; Ravina, E.; Orallo, F. Gen. Pharmacol. 1998, 30, 201‐207. [10]. Sayed, A. R. Tetrahedron 2012, 68(13), 2784‐2789. [11]. Sayed, A. R.; Wiggins, J. S. J. Appl. Poly. Sci. 2011, 120(2), 623‐630. [12]. Sayed, A. R. Tetrahedron Lett. 2010, 51, 4490‐4493. [13]. Sayed, A. R.; Wiggins, J. S. Polymer 2008, 49(9), 2253‐2259. [14]. Huisgen, R. Angew. Chem. Int. Ed. Engl. 1963, 10, 565‐598. [15]. Varvounis, G.; Fiamegos, Y.; Pilidis, G. Adv. Heterocycl. Chem. 2001, 80, 75‐165. [16]. Jaroslaw, S. Syn. Comm. 2000, 30(6), 1083‐1094. [17]. Sayed, A. R.; Youssef, M. M. Eur. J. Med. Chem. in review, 2014. [18]. Eweiss, N. F.; Osman, A. J. Heterocycl. Chem. 1980, 17, 1713‐1717. [19]. Badawy, M. A.; Abdelhady, S. A.; Ibrahim, Y. A. Liebigs Ann. Chem. 1990, 4, 393‐395. [20]. Sayed, A. R. Tetrahedron 2013, 69, 5293‐5298. [21]. Finnerty, J.; Mitschke, U.; Wentrup, C. J. Org. Chem. 2002, 67, 1084‐ 1092. [22]. Shawali, A. S.; Farag, A. F.; Albar, H. A.; Dawood, K. M. Tetrahedron 1993, 49, 2761‐2766. [23]. Boger, D. L.; Weinreb, S. M. Hetero Diels‐Alder Methodology in Organic Synthesis; Academic Press: San Diego, CA, 1987. [24]. Shawali, A. S.; Hassaneen, H. M. Tetrahedron 1972, 28, 5903‐5909. [25]. Argyropoulos, N. G.; Mentzafos, D.; Terzis, A. J. Heterocylic Chem. 1990, 27, 1983‐1988. [26]. Argyropoulos, N. G.; Coutouli‐Argyrop, E. P. Iakobidis Chim. Chron. New Ser. 1964, 13, 161‐165. [27]. Shawali, A. S.; Sayed, A. R.; Zayed, M. M. J. Sulfur Chem. 2011, 32(4), 311‐314.