Utility of E-1-(4-Acetamidobenzoyl)-2-Oxirane Carboxylic Acid in Synthesis Some Fused Heterocycles and Spiro Compounds

The present work deals with the reaction of 4-(4-Acetyl amino phenyl-4-oxobut-2-enoic acid (1) with hydrogen peroxide afforded oxirane derivative 2.The latter compound was treated with 2-amino-5-aryl-1,3,4-thiadiazole to yield imidazolo[2,1-b]thiadiazole derivatives 4.The new heterocyclic compounds 4 are used as a key starting materials to synthesize some hetrocycles include pyrrolo-thiadiazolo imidazole , pyridazinone and spiro derivatives .The behavior of the pyridazinone compounds towards different electrophilic and nucleophilic reagents were investigated. The structure of the newly synthesized compounds were elucidated by elemental analysis and spectroscopic data.


Introduction
(E)-4-aryl-4-oxo-2-butenoic acids have been shown that the substitution pattern on the aroyl moiety influences the antiproliferative activity [1]and they have activated double bond,Half-wave reduction potentials (E1/2) [2] display good correlations with Hammett sigma value, attempts to obtain good correlations using frontier orbitals of the molecules.Also,they have emerged the most promising drug candidates [3] which are selective for integrase S-1360 [4] and class of Human immunodeficiency virus type1(HIV-1) integrase inhibitors [5] .Spiroindoline [6]and imidazoline [7] derivatives can be evaluated for their binding affinities and antagonistic activities at neuropeptide Y Y5 receptor and good brain penetration. Also, spironolactone is as effective as thiazides in treating mild hypertension without inducing hypokalemia or increased secretion of aldosterone [8,9] and eplerenone ,a specific aldosterone antagonist approved by the food and drug administration ,appears to have a much lower affinity for androgen and progesterone receptors , reduced incidence of sexual disturbances [10] and useful agent in treatment of hepertension and congestive heart failure , treatment of diabetics complication and aldose reductase inhibitors [13]. The most notably ketoconazole [11,12] which have been successful as antifungal agents and when spiroimidazolderivatives [14] was combined with an tibacterial agent (vancomycin, ciprofloxacin) that observed antagonistic activity results from the competitive binding of the medicine molecules into fungi cells receptors.
3-phenylamino-(substituted phenyl)isoxazolines [15]were evaluated for their in vitro antifungal activity and on the proliferative response of human mononuclear peripheral blood cells to phytohemagglutinin A (PHA) [16].Recently,it reported [17] the synthesized new class of oxadiazoles by cyclization of the terminal carboxylic group of 3-aroyl propionic acids into oxadiazole nucleus that an objective of developing better anti-inflammatory and analgesic agents. Also, pyridazin-2-ylmethyl-2-substituted 1,3,4-oxadiazol e [18] screened for antibacterial, antifungal and antitubercular activity. The effects of 1,3,4 thiadiazole derivatives on the central nervous system (CNS) of mice were studied [19].Imidazolooxazole derivatives [20] via treatment of imidazolederivatives with oxirane have been tested for antimycobacterial activity .
The α -substituted hydrazone intermediates 5 undergo to internal ring closure via[3+2] instead of[4+2] cyclization process to generate pyrrole derivatives 7 rather than 4,5-dihydropyridazines 8 [27,28]. The ring closure is promoted in the intermediates 5 by the presence of an acidic hydrogen originally placed in position 4 of the azo-ene system , and promote the thermo chemically allowed[4+2] cyclization to afford the competitive product 9 . Formation of the pyridazinone 9 is due to stability of the bond length and binding energy [29]  Similarity , the compounds 4 were allowed to react with hydroxyl amine in the presence of pyridine afford pyrrole derivatives 11 and spiro isomers 12 (scheme 4). Unsymmetrical hydrazine derivatives also can be affected on regio selectivity in which electronic and steric factors play an important rule .This can be affected on the reaction path that depends on stability of intermediate and the product. Thus, when the compounds 4 were allowed to react with phenyl hydrazine afforded the pyridazinone derivatives 13 and pyrrole derivatives 14. The latter compounds have low yield due to the steric phenyl group is outweigh intramolecular hydrogen bond and becomes a driving force to regioselective isomer 13. Also , the compounds 4 have been reacted with carbon electrophiles ,when 4 were allowed to react with acetic anhydride, they afforded furo[2,3-d] thiadiazolo[3,2-a]imidazole derivatives 15 scheme 4.
The present work is succeeded to synthesis of a series of some important heterocycles and spiro compounds from 4-acetamido phenyl-4-oxo-2-butenoic acid and for the first time,synthesis of pyridazinone derivatives bearing 4-heteryl moiety inside to aromatic substituents in the position 6 that enhances the biological profile many fold than their parent nuclei.

Experimental
All melting points are uncorrected.and were determined on a stuart electric melting point apparatus.Elemental analyses were carried out at the Microanalytical Center, National Research Center, Cairo, Egypt. By Elementar Viro El Microanalysis IR spectra (KBr) were recorded on infrared spectrometer FT-IR 400D using OMNIC program and are reported frequency of absorption in terms of cm-1 and H-NMR spectra recorded on a Bruker spectrophotometer at 400 MHz using TMS as internal standard and withresidual signals of the deuterated solvent δ = 7.26 ppm for CDCl3 and δ 2.51 ppm for DMSO-d6. C-NMR spectra were recorded on the same spectrometer at 100 MHz and referenced to solvent signals δ = 77 ppm for CDCl3 and δ 39.50 ppm for DMSO-d6.DEPT 135 NMR spectroscopy were used where appropriate to aid the assignment of signals in the H and C-NMR spectra. The mass spectra were recorded on Shimadzu GCMS-QP-1000 EX mass spectrometer at 70 e.v using the electron ionization technique. Homogeneity of all compounds synthesized was checked by TLC. General Procedure of starting Material in literature [21].

Compounds 7,9,10
A mixture of 4(0.01 mol) and hydrazine hydrate (0.01mol) in ethanol (50 mL) and was heated under reflux for 5h. The reaction mixture was allowed to cool and the product was filtered, dried, and were recrystallized from suitable solvent, using the column chromatograph is necessary to separate the compounds 7 and 10.

Compounds of 11and 12
A mixture of 4(0.01 mol) and hydroxyl amine hydrochloride (1.03 g ;0.015mol) in boiling pyridine (50 mL )and was heated under reflux for 6h. The reaction mixture was allowed to cool, pour into ice/HCl and the product was filtered, dried , and were recrystallized from toluene afford 11 and ethanol afford 12