Novel azaenamines incorporating a tetrahydrothiophene moiety were prepared. Michael addition of an azaenamine with a,bunsaturated nitriles took place to give [1]benzothieno[3¢,2¢:5,6]pyrimido[1,2-b]pyridazine (thia-triaza-benzo[a]fluorene) derivatives. The condensation with malononitrile resulted in the formation of a [1]benzothieno[3¢,2¢:5,6]pyrimido[1,2-b]pyridazine-4-carbonitrile. The azaenamine also reacted with aldehydes and piperidine to give Mannich products.Compounds containing the tetrahydrobenzothiophene (THBT) moiety are selective HCV polymerase inhibitors, 1 selective versus human DNA polymerase and calf thymus. 1 These compounds also have diverse pharmacological activities including antibacterial, 2 immunodulatory, 3 anti-inflammatory, 4 antidiabetic, antiplatelet activating factor, 5 and antiviral activity. 6,7 In continuation of our interest in azaenamine chemistry, [8][9][10][11][12] we report here a new synthesis of azaenamines containing the 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate and -carboxamide moieties. Also we report the chemical reactivity of the synthesized azaenamines. Thus, it has been found that coupling acetoacetic acid with the 3-(ethoxycarbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-diazonium chloride (3a) and the 3-carboxamide 3b afforded the corresponding pyruvaldehyde-1-arylhydrazones 5a and 5b in 73% and 68% yields, respectively. Although, the appearance of NH at very low field implies the presence of an azaenamine in the syn-form 6, in related work we obtained an X-ray crystal structure for an azaenamine analogue that indicated that it exists in the antiform 5. 10 The low field hydrazone NH at d = 12 is not, thus, due to deshielding by hydrogen bonding as we believed, but most likely results from the delocalization of the nitrogen lone pair [cf. Scheme 1 structure 5(II)]. It is clear that azaenamines can be seen as bidentate ligands since they have two nucleophilic and two electrophilic centers. Due to an interest in developing syntheses for biologically interesting fused pyridazines 8,12,13 herein, we report an efficient route for the Michael addition reaction of azaenamines 5 to a,b-unsaturated nitriles. As stated above, the CH group of the azaenamine is quite nucleophilic as a result of the hydrazone lone pair delocalization. Thus, in a preliminary study, we found that reacting compound 5a with ethyl 2-cyano-3-phenylacrylate (7a) afforded a product for which several isomeric structures seemed possible. Structures involving addition on the acyl methyl group was readily ruled out on the basis of the 1 H NMR spectrum, which revealed a methyl signal at d = 2.36. Acyclic structures were also excluded based on 1 H NMR spectra analysis, which showed in addition to the methyl signal, a singlet signal at d = 5.09 for H4 of the pyridazine and a broad signal at d = 11.19 for the NH group. The resulting product was assigned the tetracyclic structure 10 based on mass spectroscopy and NMR analysis, which revealed the absence of an OEt group on the thiophene ring. IR and 13 C NMR...

The 2-picolinium N-ylide 4, generated in situ from the N-acylmethyl-2-picolinium bromide 3, underwent cycloaddition to N-phenylmaleimide or carbon disulfide to give the corresponding cycloadducts 6 and 8, respectively similar reactions of compound 3 with some electron-deficient alkenes in the presence of MnO2 yielded the products 11 and 12. In addition, reaction of 4 with arylidene cyanothioacetamide and malononitrile derivatives afforded the thiophene and aniline derivatives 15 and 17, respectively. Heating of picolinium bromide 3 with triethylamine in benzene furnished 2-(2-thienyl)indolizine (18). The structures of the isolated products were confirmed by elemental analysis as well as by 1H- and 13C-NMR, IR, and MS data. Both the stereochemistry and the regioselectivity of the studied reactions are discussed. The biological activity of the newly synthesized compounds was examined and showed promising results.

This study aimed for the synthesis of new heterocyclic compounds incorporating sulfamoyl moiety suitable for use as antimicrobial agents via a versatile, readily accessible N-[4-(aminosulfonyl)phenyl]-2-cyanoacetamide (3). The 2-pyridone derivatives were obtained via reaction of cyanoacetamide with acetylacetone or arylidenes malononitrile. Cycloaddition reaction of cyanoacetamide with salicyaldehyde furnished chromene derivatives. Diazotization of 3 with the desired diazonium chloride gave the hydrazone derivatives 13a–e. Also, the reactivity of the hydrazone towards hydrazine hydrate to give Pyrazole derivatives was studied. In addition, treatment of 3 with elemental sulfur and phenyl isothiocyanate or malononitrile furnished thiazole and thiophene derivatives respectively. Reaction of 3 with phenyl isothiocyanate and KOH in DMF afforded the intermediate salt 17 which reacted in situ with 3-(2-bromoacetyl)-2H-chromen-2-one and methyl iodide afforded the thiazole and ketene N,S-acetal derivatives respectively. Finally, reaction of 3 with carbon disulfide and 1,3-dibromopropane afforded the N-[4-(aminosulfonyl) phenyl]-2-cyano-2-(1,3-dithian-2-ylidene)acetamide product 22. All newly synthesized compounds were elucidated by considering the data of both elemental and spectral analysis. The compounds were evaluated for both their in vitro antibacterial and antifungal activities and showed promising results.

A series of new 8-arylhydrazono-2-(benzylsulfanyl)-7H-purin-6-ones 6 were synthesized, their electronic absorption spectra in different organic solvents of varying polarities were investigated and their acid dissociation constants in both the ground and excited states were determined spectrophotometrically. The tautomeric structures of such products were elucidated by spectral analyses and correlation of their acid dissociation constants with the Hammett equation. The results indicated that the studied compounds 6 exist predominantly in the hydrazone tautomeric form 6A in both the ground and excited states.

The three-component Biginelli-like cyclocondensation reaction of enamines 1, urea, and aldehydes in dioxane/acetic acid efficiently afforded the corresponding 6-unsubstituted 3,4-dihydropyrimidin-2(1H)-ones 2 in good yields (Scheme 1, Table). The corresponding reaction of azaenamine (¼ hydrazone) 7 with benzaldehyde and urea afforded 6-acetyl-1,2,4-triazin-3(2H)-ones in good yields (Scheme 3).