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A straightforward method for the synthesis of spaced, phenyl-linked bis(thiohydantoin) derivatives and (thio)hydantoins spiro-fused to pyrroline ring has been developed. All the synthetic strategies here presented rely on initial aza-Michael addition followed by acylation/regioselective ring-closure step involving DD, primary amine and iso(thio)cyanate in a 3-CR providing 1,3,5-trisubstituted (thio)hydantoins. The choice of opportune acyclic reagents in the sequential 3-CR followed by 1,4-nucleophilic addition/intramolecular ring closing and 1,3-dipolar cycloaddition permits a number of C–N and C–C formation that realizes different kind of linkage between several pharmacophores.

1,2-Diaza-1,3-dienes (DDs) undergo, under neutral conditions, N-nucleophilic attack from a 4-ethoxycarbonylisoxazol-5-one derivative. The first aza-Michael addition is followed by an intramolecular second, affording a fused heterobicyclic system that, upon ring opening and decarboxylation processes, gives rise to novel substituted imidazoles with an acetate functionality in the 2-position. On the contrary, under the same reaction conditions, 3-phenylisoxazol-5-one provides a double Michael addition at two units of DD involving first the C-4 and then the N-2 of the heterocycle. The resulting diadduct spontaneously undergoes ring-opening/ring-closing process that concludes with a ring enlargement of the heterocycle providing the 1,3-oxazin-6-one derivative.

Unknown spiro-cyclopropanated 1-aminopyrrol-2-ones are regioselectively prepared in high yields by Bi(OTf)3-catalyzed one-pot ‘Mukaiyama–Michael addition/cyclization/ring-contraction’ reactions of 1,2-bis(trimethylsilyloxy)cyclobutene with 1,2-diaza-1,3-butadienes at room temperature.

The synthesis of substituted 2,3-dihydro-1,4-thiazines, fused cycloalkyl-1,4-thiazines, 1,4-benzothiazines and fused cycloalkyl-1,4-benzothiazines by 1,4-addition of 1,2-aminothiols to 1,2-diaza-1,3-dienes bearing carboxylate, carboxamide, or phosphorylated groups and subsequent internal heterocyclization is described. The reaction of carboxylated 1,2-diaza-1,3-butadienes with 2-(butylamino)ethanethiol affords 1,4-thiazinan-3-ones. The solid-phase reaction of polymer-bound 1,2-diaza-1,3-butadienes with 1,2-aminothiols produces 2,3-dihydro-1,4-thiazines and 1,4-benzothiazines.

New 1-cycloalkenyl-1-diazenes have been obtained in good yields from cyclic β-ketoesters and hydrazine derivatives. They furnished new cycloalkyl[d][1,3]thiazolines with thioamides or new spirocycloalkyl-thiazolinones with thioureas. Moreover they gave, with imidazolidine-2-thione and tetrahydropyrimidine-2-thione, new and interesting spiro[cycloalkyl-1,2′-imidazo[2,1-b][1,3]thiazole] or spiro[cycloalkyl-1,2′-[1,3]thiazolo[3,2-a]pyrimidine] derivatives, respectively. Cycloalkyl[d][1,3]thiazolines were useful for the further preparation of unknown thia-triaza-tricyclo derivatives. Novel hexahydro-1,3-benzothiazoles have been achieved by reaction of N,N′-dialkylthioureas on N-1-phenyl-2-(1-cyclohexenyl)-1-diazene-1-carboxyamide. The acidic hydrolysis of spirocycloalkyl-thiazolinones produced 2-imino-5-(ω-carboxyalkyl)-4-thiazolidinones.

The solid-phase synthesis of 4-triphenylphosphoranylidene-4,5-dihydropyrazol-5-ones, 4-aminocarbonyl-pyrroles, 4-methoxy-1 H -pyrazol-5(2 H )-ones and 2-thiazolin-4-ones using polymer-bound 1,2-diaza-1,3-butadienes is reported.

1,2-Diaza-1,3-butadienes react with N,N′-diarylthioureas to give 2-(arylimino)-2,3-dihydrothiazole derivatives, whereas with N,N′-dialkylthioureas to afford 5,5-disubstituted 3-alkyl-2-(alkylimino)-thiazolidin-4-one derivatives. Under basic conditions, these last products surprisingly give rise to 2-thioxo-1,3,7-triazaspiro[4.4]non-8-en-4-one and 5-oxo-4-(4-substituted 5-oxo-2-thioxoimidazolidin-4-yl)-2,5-dihydro-1H-pyrazole derivatives. In acidic medium, 5,5-disubstituted 3-alkyl-2-(alkylimino)-thiazolidin-4-ones are converted into 2-(alkylimino)-1-thia-3,7-diazaspiro[4.4]non-8-en-4-ones. X-Ray crystal structures of two products were determined.

In the presence of sodium methoxide in catalytic amount, conjugated azoalkenes smoothly add at room temperature (phenylsulphonyl)acetamide, methyl (phenylsulphonyl)acetate, methyl (phenylsulphinyl)acetate, (arylsulphonyl)acetonitriles, bis(phenylsulphonyl)methane, and (arylsulphonyl)nitromethane to yield the corresponding α-functionalized hydrazone derivatives by 1,4-addition. In some cases these hydrazones were isolated, while in others their formation is accompanied by olefination products. Under the same reaction conditions and/or in methanol by means of gentle heating, several of these adducts give rise to the related α,β-olefinated hydrazone derivatives as pure isomeric forms or as EE EZ mixtures by loss of the nitro, sulphonyl or sulphinyl group. It is noteworthy that for β-cyano-β-arylsulphonyl adducts it was mainly detected the elimination of the arylsulphonyl group affording β-cyano-α,β-olefinated hydrazones, while for analogous β-nitro-β-arylsulphonyl adducts it was principally observed the loss of the nitro moiety producing β-arylsulphonyl-α,β-olefinated hydrazones.

1-Substituted 4-alkoxy-, 4-alkylthio-, and 4-aryloxy-1H-pyrazol-5(2H)-ones have been prepared by the reaction of conjugated azoalkenes with alcohols, thiols, and phenols. In some cases the intermediate hydrazones were isolated, while in others the products were obtained in one step. 1-Unsubstituted 4-alkoxy-, 4-alkylthio-, and 4-aryloxy-1H-pyrazol-5(2H)-ones were produced by methanolysis of the corresponding 1-substituted derivatives under reflux. Some of these compounds were studied by molecular mechanics calculations, as well as deuterium induced shifts (DIS) on 13C chemical shifts, and tentative conclusion was drawn about their tautomerism and conformations. X-Ray crystal structure determinations of 1-(aminocarbonyl)-3-methyl-4-methoxy-1H-pyrazol-5(2H)-one 4e and 3-methyl-4-methoxy-1H-pyrazol-5(2H)-one 5a demonstrated that both molecules exist in the crystal exclusively in the HN-CO tautomeric form. Some previously reported structural assignments in some pyrazolones and hydroxypyrazoles were corrected.

The title compounds were obtained by reaction of conjugated azoalkenes with activated methinic derivatives bearing a propargylic residue. 1-Ureido-3-propargyl-2,3-dihydropyrrol-2-ols gave in the presence of Cu(I) catalyst the 2,5-dimethyl-3-ethoxycarbonyl-4-(2-oxopropyl)-1-(N′-phenylureido)-pyrrole, while in the presence of Pd(0) or Au3+ the 3,6-dimethyl-5-ethoxycarbonyl-4-propargyl-1,4-dihydropyridazine was obtained by ring opening and ring expansion reaction. The propargylic side chain of 1-ureido-3-propargylpyrroles and 1-ureido-3-propargyl-3-phosphono-1H-pyrrol-2(3H)-ones was functionalised by means of palladium and/or copper catalysed coupling reactions with aryl or vinyl triflates and halides.

Thiocarboxylic acids smoothly attack conjugated azoalkenes at room temperature to give hydrazone 1,4-adducts that exhibit tautomerism with the corresponding enamino forms. These adducts when treated with sodium hydride in tetrahydrofuran at room temperature lead to 1-alkoxycarbonyl- or 1-aminocarbonyl-3-methyl-4-acylthio-1 H -pyrazol-5( 2H )-ones. The same adducts in chloroform with trifluoroacetic acid under reflux produce 1-alkoxycarbonyl- or 1-aminocarbonyl-3-methyl-4-acylthio- 5-alkoxypyrazoles. In acidic media with aqueous tetrahydrofuran the 1,4-adducts undergo hydrolysis affording 2-acylthio-3-oxobutanoate derivatives that exhibit enol-keto tautomerism. The 1-alkoxycarbonyl- and 1-aminocarbonyl-3-methyl-4-acylthio-1 H -pyrazol- 5(2 H )-one derivatives in methanol under reflux undergo solvolysis to give, after a few minutes, simple 3-methyl-4-acylthio- 1 H -pyrazol-5(2 H )-ones and, after a few' hours, 4,4′-dithiobis(3-methyl-1 H -pyrazol-5(2 H )-ones), while 1-alkoxycarbonyl- and 1-aminocarbonyl-3-methyl-4-acylthio-5-alkoxypyrazole derivatives are resistant to the same reaction conditions even over several days. X-Ray diffraction studies of some 1-alkoxycarbonyl-and 1-aminocarbonyl-3-methyl-4-acylthio- 1 H -pyrazol-5(2 H )-ones have been performed in order to determine the structure of the pyrazole ring in all such compounds, as well as the conformational situation in the solid slate of the substituents on N-1. These investigations confirm the reconsideration of the structure assignments frequently recurring in the literature for some 5- and 3- hydroxypyrazoles.

Unknown 2-hydroxy-3-nitro-2,3-dihydro-1-aminopyrrole derivatives were directly obtained by easy reaction of conjugated azoalkenes with 2-nitro-1,3-indanedione. The treatment of the same reagents with benzoylnitromethane or β-nitroesters gave α,β-olefinated-γ-carbonyl- or α,β-olefinated-γ-alkoxycarbonylhydrazone derivatives, respectively. New asymmetric α-azinohydrazones were isolated from the reaction of the above-mentioned materials with some β-nitroketone tosylhydrazones.

The simple, mild and selective conversion in good yields of 2-chlorohydrazone into 2-oxohydrazone derivatives is reported. The reaction easily occurs via 2-azidohydrazone intermediates and represents a convenient procedure for the useful transformation of the methylene into carbonyl group.

The simple and direct synthesis in good yields of substituted pyrazoles and 4-triphenylphosphoranylidene-4,5-dihydropyrazol-5-ones is reported. These products have been prepared by heterocyclization under different reaction conditions of some 1,5-zwitterionic species obtained from the 1,4-conjugate addition of triphenylphosphine to the azo-ene system of conjugated azoalkenes.

New 1-amino-4-triphenylphosphoranylidene-5-oxo-2-pyrrolines or α,β-unsaturated hydrazones have been obtained in good yield under different reaction conditions by Wittig-type reaction of some conjugated azoalkenes with carboalkoxymethylene triphenylphosphorane. The isolation and characterization of 1,4-adduct intermediate showed that the reaction mechanism implicates only 1,6-zwitterionic intermediate without cycloadduct production, as usually suggested for the Wittig reaction. The crystal structure of one of 1-amino-4-tripheny1phosphorany1ide-ne-5-oxo-pyrrolines obtained has been elucidated by X-ray diffraction study, showing the resonance between the neutral and 1,4-dipolar form.

The reactions of conjugated aroylazoalkenes with β-diketones and β-ketoesters in the presence and in the absence of copper(II) chloride as catalyst have been studied. In the first case, 1-aminopyrrole derivatives have been obtained, while in the second case the formation of 2-hydroxy-4-pyrrolines as stable intermediates has been frequently detected. The observations on the conditions of the formation of either or both products, as well as the proof of the easy conversion of 2-hydroxy-4-pyrrolines into pyrrole derivatives elucidate the much debated behaviour of these reactions.

Aliphatic tosylhydrazides upon treatment with diborane followed by alkaline hydrolysis yield aliphatic hydrocarbons. Aromatic hydrocarbons are produced when aromatic tosylhydrazides undergo heating in presence of diborane and are subsequently oxidated by KIO4. A discussion on the structures of intermediate products is reported.

The rates of base-catalyzed hydrogen-deuterium exchange at C-2 in some 5-substituted benzothiazoles and in thiazolo[4,5- c ]pyridine were studied. Transmission through the thiazole ring of the effects of substituents in the benzothiazoles and of the polar effects of the aza group in the thiazolopyridine, was assessed from these data.