Recent advances in the synthesis and functionalization of 1,2,5-oxadiazole 2-oxides

Among the variety of nitrogen heterocycles, the furoxan (1,2,5-oxadiazole 2-oxide) scaffold has attracted considerable attention owing to its ability to release NO under physiological conditions. Therefore, significant efforts of organic chemists have been directed toward the construction of new drug candidates containing the NO-donor furoxan subunit connected to a known pharmaceutical or a potential pharmacophore by CC/CN bonds or through an appropriate linker. This digest summarizes the recent information concerning both new synthetic approaches for the furoxan ring construction and various methods for the functionalized furoxan synthesis with particular focus on the last three years. Methods for the furoxan ring formation including cyclodimerization of nitrile oxides, nitrosation of unsaturated compounds, and acylation of dinitromethane sodium salt are reviewed. The functionalization of furoxan ring is represented by nucleophilic substitution of nitro and arylsulfonyl groups as well as by different condensations of cyano-, carbonyl- and carboxyfuroxan derivatives. Synthesis of hybrid structures combining NO-donor furoxan ring and some pharmacophoric moiety is also considered.     

[1,2,5]Oxadiazolo[3,4-d]pyridazine 1,5,6-trioxides: efficient synthesis via the reaction of 3,4-bis(hydroxyimino)methyl)-1,2,5-oxadiazole 2-oxides with a mixture of concentrated nitric and trifluoroacetic acids and structural characterization

An efficient synthesis of [1,2,5]oxadiazolo[3,4-d]pyridazine 1,5,6-trioxides (1) from 3,4-bis(hydroxyimino)methyl)-1,2,5-oxadiazole 2-oxides using a mixture of concentrated nitric and trifluoroacetic acids has been developed. The scope of the unconventional reaction was established. The 4,7-dinitro[1,2,5]oxadiazolo[3,4-d]pyridazine 1,5,6-trioxide 1f represents a new high energy compound, unfortunately with low thermal stability. The parent [1,2,5]oxadiazolo[3,4-d]pyridazine 1,5,6-trioxide 1c was studied by single-crystal X-ray diffraction analysis which revealed a planar molecule with an unusually long intracyclic NN bond of 1.668(5)?Å and unexpected exo-cyclic bond angles at the nitroxyl nitrogen atoms. In the crystal, the molecules of 1c are bound to each other by strong π-π stacking and CH?O hydrogen bonding interactions into a three-dimensional framework that results in a high crystal density of 1.833?gcm^?3.     

Reduction of 3,4-bis(4-amino-1,2,5-oxadiazol-3-yl)-1,2,5-oxadiazole 2-oxide

Russian Journal of Organic Chemistry -     

Reaction of Aliphatic Diazo Compounds with Dinitrogen Trioxide. A Facile route to 3,4-Disubstituted 1,2,5-Oxadiazole-2-oxides(Furoxans)

As part of our continuing studies¹of the chemistry of diazo compounds, we have investigated the reaction of α-diazosulfones, α-diazoketones and ethyl diazoacetate with dinitrogen trioxide. When a solution of the diazo compound is allowed to react at 0–5° with excess n₂O₃ ² in CH₂Cl₂, and almost instantaneous evolution of a gas (presumably nitrogen) is observed. Work-up afforded 3,4–disubstituted furoxans (I–VII, see Table) in good Yields.     

Sulfur nitride in organic chemistry. 6. Preparation of 3,4-disubstituted 1,2,5-thiadiazoles by the reaction of sulfur nitride with acetylenes

The reaction of sulfur nitride (1) with acetylenes (2a-m) was carried out in refluxing toluene to give 1,2,5-thiadiazoles (3a-m) as a major product.     

Reaction of 3,6-disubstituted 4-nitropyridazine 1-oxides with methanolic ammonia and liquid ammonia

Reaction of 3-chloro-6-methyW-nitropyridazine 1-oxide ( 5 ) with methanolic ammonia at 0° led to a replacement of the chlorine atom by a methoxy group as well as by an amino group. Reaction of the 3-methoxy-6-methyl-4-nitropyridazine 1-oxide ( 6 ) with the same reagent led to amino-demethoxylation; this replacement reaction was very slow. Attempts to perform these reactions with liquid ammonia failed. Pmr spectroscopy of solutions of compound 6 in methanolic ammonia revealed that no σ-adduct was present. However in liquid ammonia a 1:1 σ-adduct at C-5 i.e. 12b was formed. 3,6-Dimethoxy-4-nitropyridazine 1-oxide (7) gave with methanolic ammonia an amino-demethoxylation at C-6. No σ-adduct could be detected by pmr spectroscopy. However, in liquid ammonia convincing pmr data were obtained showing the presence of a 1:1 σ-adduct at C-5.     

Reaction of 1,2,5-thiadiazolo[3,4-d]pyrimidine-5,7-dione 2-oxide with water

The products of the reaction of 1,2,5-thiadiazolo[3,4-d]pyrimidine-5,7-dione 2-oxide with water, viz. 1,2,5-thiadiazolo[3,4-d]pyrimidine-5,7-dione 2-oxide dihydrate and 6-amino2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-sulfamic acid, were isolated and characterized by X-ray diffraction.Translated from Zhurnal Obshchei Khimii, Vol. 74, No. 10, 2004, pp. 1728–1732.Original Russian Text Copyright © 2004 by Yavolovskii, Ganin, Fonar, Simonov, Chumakov, Bochelli.This revised version was published online in April 2005 with a corrected cover date.     

Synthesis and properties of vinyl ethers of 3,4-di(hydroxymethyl)-1,2,5-oxadiazole

The direct vinylation of 3,4-di(hydroxymethyl)-1,2,5-oxadiazole by acetylene was accomplished for the first time; its mono- and divinyl ethers were synthesized in the presence of cadmium acetate. The physicochemical and spectral properties and conformational structure of the synthesized compounds were studied. It was shown that the s-trans-trans-conformation is the most profitable for the divinyl ether of 3,4-di(hydroxymethyl)-1,2,5-oxadiazole.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1044–1047, August, 1984.     

Substituent and solvent effects on the beta-heterolysis reaction of beta-hydroxy arylethyl radicals

Time-resolved conversion of a series of beta-hydroxy arylethyl radicals with electron-donating and -withdrawing aromatic substituents to their corresponding styrene radical cation via heterolytic loss of the beta-hydroxy leaving group was examined with nanosecond laser flash photolysis. In all cases, the reaction was catalyzed by added perchloric acid. Radicals 2a-d reacted via a pre-equilibrium protonation mechanism in acidic 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), and measuring rate constants for radical cation formation as a function of acid content allowed for the determination of absolute rate constants ranging from 3.6 x 10(6) to 3.8 x 10(7) s(-1) for the loss of water from the protonated beta-hydroxy arylethyl radicals 2a-d, as well as the acidity constants, pKa approximately 1.5 (in HFIP), for the protonated radicals. The 4-methoxy-substituted beta-hydroxy arylethyl radical 2e reacted by rate determining protonation in HFIP with a second-order rate constant of k(H+) = 7.8 x 10(8) M(-1) s(-1). However, in acetonitrile, 2,2,2-trifluoroethanol, and mixtures of these two solvents, 2e reacted by pre-equilibrium protonation, allowing for solvent effects on the rate constant for loss of water from the protonated radical 2e to be determined. With use of these data, substituent electronic effects on the kinetics of the beta-heterolysis reaction are discussed. Differences in the effect of solvent on the rate constant for loss of water from the protonated beta-hydroxy arylethyl radicals and other beta-substituted arylethyl radicals are also discussed.     

Substituent and solvent effects on the rate of the reaction of 2-methyl-4-phenyl-thiazole ethiodide with substituted benzaldehydes

Condensation of 2-methyl-4-phenyl-thiazole ethiodide (1) with aromatic aldehydes in presence of piperidine as base catalyst has been studied kinetically at different temperatures. The rate in presence of low concentration of piperidine (<0.5M) is found to be represented by the third order equationv=k [1] [aldehyde] [piperidine]. On the other hand the rate in presence of 1.013M piperidine is represented by the second-order equation:v=k [1] [aldehyde]. It is concluded from the kinetic results that the dehydration step of the intermediate aldol compound is the rate determining step of the reaction. The dependence of the mechanism of the reaction and the thermodynamic parameters of activation on the molecular structure of the various aromatic aldehydes used is discussed. In various organic solvents, the rate of the reaction increases as the dielectric constant of the medium is increased. The energy of activation and the thermodynamic parameters of activation were calculated and discussed in terms of solvent properties.

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Substituenten- und Lösungsmittel-Effekte auf die Geschwindigkeit der Reaktion zwischen 2-Methyl-4-phenylthiazol-ethiodid und substituierten Benzaldehyden

Zusammenfassung Die Kinetik dieser Kondensation wurde bei verschiedenen Piperidinkonzentrationen (basischer Katalysator), unter Variation der Temperatur und in Abhängigkeit von der Polarität des Lösungsmittels für verschiedene substituierte Benzaldehyde untersucht. Bei niedriger Piperidinkonzentration gehorcht die Reaktion einer Gleichung dritter Ordnung:v=k [Thiazo] [Ald.] [Pip.]; bei großer Konzentration (1.013M) gilt eine Gleichung zweiter Ordnung:v=k [Thizol] [Ald.]. Es wird ein Mechanismus vorgeschlagen, wobei der geschwindigkeitsbestimmende Schritt die Dehydratisierung des intermediär gebildeten Aldols ist. Aktivierungsenergien und andere thermodynamische Parameter wurden bestimmt und im Hinblick auf die Lösungsmittelpolarität diskutiert.

     

Studies on the preparation of 3,4-disubstituted 2-methoxypyridines

The synthesis of 2-methoxy-4-methylpyridine-3-carbonitrile (3) and its conversion, by way of alkylation of the C(4) methyl group, into the pyrodyl acetic acid ester 6 is described.     

1,2,5-Thiadiazole 2-oxides: selective synthesis,structural characterization,and electrochemical properties

A new general procedure for the selective synthesis of 1,2,5-thiadiazole 2-oxides (including fused derivatives) 8a,b,c,g,h from the reaction of vic-glyoximes with S₂Cl₂ and pyridine in acetonitrile was elaborated together with general procedure for the synthesis of 1,2,5-thiadiazoles 7a–i, 10, 12, and 14 from the same starting materials and reagents. Molecular structures of 3,4-dimethyl-1,2,5-thiadiazole 2-oxide 8a and [1,2,5]thiadiazolo[3,4-b]quinoxaline 10 were confirmed by single-crystal X-ray diffraction. Electrochemical properties of 1,2,5-thiadiazole 2-oxides 8 were studied by cyclic voltammetry and different behavior was observed for monocyclic and benzo-fused derivatives. With compounds 8g and 17, previously unknown deoxygenation of 2,1,3-benzothiadiazole 1-oxides was discovered by electrochemical reduction, and resulted 2,1,3-benzothiadiazoles 7g and 19 were detected in the forms of their radical anions by EPR spectroscopy combined with DFT calculations.     

Novel reactions of 6,7-dimethoxy-3,4-dihydroisoquinoline and 3,4-dihydro-β-carboline with dipolarophiles

New reactions of 6,7-dimethoxy-3,4-dihydroisoquinoline and 3,4-dihydro-β-carboline with various electron-deficient olefins are described. ‘One-pot’ generation and cycloaddition of the 1,3- and 1,4-dipoles formed from these heterocycles with a range of alkene dipolarophiles affords cycloadducts in good yields with high regio- and stereoselectivity.     

Polarography of some 2,1,3-benzothiadiazoles,benzofurazans, 2,1,3-benzoselenadiazoles,and 3,4-disubstituted and fused 1,2,5-thiadiazoles

The redox behavior has been determined in acetonitrile solutions at a mercury and platinum electrode for 2,1,3-benzo(group VI)diazoles, and 3,4-disubstituted and fused 1,2,5-thiadiazoles. The derivatives studied contained alkyl, phenyl, bromo, chloro, cyano, nitro, methylsulfonyl, and trifluoromethylsulfonyl groups. All ring systems and their derivatives are reversibly reduced initially in a one-electron step, to their respective radical anion, but the nitro and bromo derivatives are reduced preferentially at the substituent group. The potential at which the production of the radical anion occurred became more anodic as the electron withdrawing ability of the substituent and the number of substituents increased.     

Substituent effect on the reaction mechanism of proton transfer in formamide

MP2 and B3LYP methods at 6‐311++G** basis set have been used to explore proton transfer in keto‐enol forms of formamide and to investigate the effect of substituent, i.e., H, F, Cl, OH, SH, and NH₂ on their transition states. Additionally, the vibrational frequencies of aforementioned compounds are calculated at the same levels of theory. It is proposed that the barrier heights values in kJ/mol for F, Cl, OH, and SH substituents are significantly greater than that of the bare tautomerization reaction, implying the importance of the substituents effect on the intramolecular proton transfer. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2012