Oxidative cyclization of aldehyde thiosemicarbazones induced by potassium ferricyanide and by tris(p-bromophenyl)amino hexachloroantimoniate. A joint experimental and computational study

Abstract

The oxidative ring closure reaction of some aryl-substituted thiosemicarbazones induced by "bona fide" one-electron abstracting agents was investigated, by means of both experimental and computational techniques. The corresponding 1,2,4-triazole derivatives were the only cyclization products observed. The occurrence of two slightly different mechanistic pathways for the reaction is discussed. Keywords:Oxidative cyclization, thiosemicarbazones, 1,2,4-triazoles IntroductionThe cyclization of suitable open-chain organic molecules is a classical and very popular approach to the synthesis of heterocyclic derivatives, owing to both the large variety of heterocycles accessible through this way, and the large variety of conditions under which the reaction can be performed.1,2 Noticeably, when more than one product can be obtained at the same time in a particular reaction, good to excellent selectivities can often be achieved (and sometimes reverted) by means of a suitable choice of the cyclizing agent and conditions. [2][3][4][5] Frequently, such cyclization reactions are induced by acidic media or electrophilic reagents. In the latter case, this might involve de facto a formal oxidation of the organic substrate, as an implicit consequence of the process (the cyclo-etherification or lactonization of unsaturated alcohols and acids induced by halogens or sulfinyl and selanyl halides provides a typical case). 3,[5][6][7][8][9][10][11][12][13] In other occasions, the cyclization mechanism involves a plain oxidation stepelectron abstraction or dehydrogenation -prior to the actual ring closure step. Examples of these reactions have been recently reviewed. Aldehyde semicarbazones and thiosemicarbazones 1 are typical substrates which may undergo ring closure processes induced by an oxidizing agent, to afford the corresponding 1,2,4-triazole 2 and 1,3,4-oxa-or -thiadiazole 3 derivatives (Scheme 1). There is now enough evidence that the reaction may follow very different courses, depending on the substrate structure (in particular on the alkyl or aryl substituent groups placed on its main molecular framework) and on the oxidizing agent used. In particular, we have been interested in the oxidation of aryl-substituted thiosemicarbazones induced by high-valent (Fe) metal salts. [19][20][21][22][23] Despite the apparent similarity of these reagents, surprisingly we observed that very different results -both in terms of reaction regiochemistry and yields, and in terms of reaction kinetics -can be achieved by the use of different salts, depending on the hardness/softness of the metal cation (or, more properly, of the solvated metal-counteranion complex), as well as on its intrinsic oxidizing strength. On the grounds of a careful analysis of all available data, we proposed 2a,22,23 (Scheme 2) that the formation of the 1,2,4-triazole ring could be induced by an attack of the oxidizing agent on the tail thioamide-like moiety of the molecule, followed by a single electron transfer (s.e.t.) step and then by a rate-limiting ring clo...

Synthesis and mass spectrometry of some arylidene-hydrazinyl-thiazolines and their 2-arylidene-N-(3-chlorophenyl)hydrazinecarbothioamide precursors

“…Thioacetazone is one of the oldest and cheapest antibiotics used as a second line drug for tuberculosis treatment [7]. Aldehyde thiosemicarbazones are also appropriate substrates for the preparation of five or six membered heterocyclic rings that contain two heteroatoms such on treating them with oxidizing or other cyclizing agents [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. In this context, nitrogen and sulfur-containing 4-thiazolines (2,3-dihydrothiazoles) and their derivatives are considered as important classes of heterocyclic compounds due to their frequent appearance in natural products and medicinal drugs [23][24][25].…”

Synthesis and Structural Assessment of Methyl 2-(4-Phenyl-5-(Pyridin-2-yl)-4H-1,2,4-Triazol-3-yl)Thioacetate (phpy2NS) and Its Complex with HgCl2

“…Reactions may follow different routes depending on the open chain substrate (thiosemicarbazone) structure as well as the nature of the cyclizing agent. Metal cations represent an interesting class of oxidizing agents [2]. The oxidative cyclization of thiosemicarbazones is influenced by the hardness/softness of the metal cation as well as by its oxidizing strength, and can lead to the formation of 1,2,4-triazoline-5-thione, its tautomeric form 1,2,4-triazole-5-thiol, 1,3,4-thiadiazole-2amine, or 1,3,4-thiadiazoline-2-imine derivatives.…”