Pyridazine N-oxides Research Articles

Photoinduced Copper-Catalyzed Cross-Coupling of Acylsilanes with Heteroarenes via Bimetallic Relay.

The transition metal-catalyzed direct coupling reactions involving electron-rich Fischer carbene species are largely underdeveloped and remain a big challenge. Here, a direct coupling reaction of azoles and azine N-oxides is reported with Fischer copper carbene species bearing an α-siloxy group i, which can be in situ generated from acylsilanes catalytically under photoirradiation and redox-neutral conditions. This coupling reaction between electron-rich α-siloxy Fischer Cu-carbene species with hard carbanion nucleophiles may undergo a bimetallic relay process, which is confirmed by the kinetic analysis and in situ NMR analysis. This reaction features mild conditions and remarkable heterocycle compatibility. Notably, this protocol tolerates a series of azole or azine N-oxide derivatives, including benzoxazole, benzothiazole, benzoimidazole, benzoisoxazole, oxazole, oxadiazole, triazolo[4,3-a]pyridine, purine, caffeine, pyridine N-oxide, quinoline N-oxide, pyrazine N-oxide, pyridazine N-oxide, etc. The synthetic value of this approach is demonstrated by the efficient synthesis of a histamine h4 receptor ligand and a marketed drug carbinoxamine.

The photochemical isomerization in pyridazine-N-oxide derivatives

DFT calculations on the photoisomerization reactions of pyridazine N-oxide derivatives are presented. The irradiation of 3,6-diphenylpyridazine N-oxide allowed to obtain the first excited singlet state that underwent to a ring opening reaction induced to the oxygen migration to the adjacent carbon atom, with the formation of a diazo derivative. This intermediate can give a ring closure reaction to give a pyrazole derivative, or, with a higher transition energy, it can lose nitrogen allowing the formation of 2,5-diphenylfuran. The irradiation of 3-phenylpyridazine N-oxide allowed the formation only of 2-phenylfuran. In this case, calculations allowed to explain this behavior. The first excited singlet state gave a photoisomerization reaction with the formation of the corresponding diazo intermediate. This intermediate could not be converted into the corresponding pyrazole derivative because it was converted into a N-formyl pyrazole never reported in literature. The only possible reaction is the loss of nitrogen and the formation of 2-phenylfuran.

In situ fluorescence visualizing of a temperature-dependent photoreaction process of pyridazine N-oxide

The photoreaction processes of pyridazine N-oxide are monitored using photoluminescence spectra in a real-time and in situ manner, and the reaction mechanism is studied by theoretical calculations.

Pyridazine N-Oxides as Photoactivatable Surrogates for Reactive Oxygen Species.

A method for the photoinduced evolution of atomic oxygen from pyridazine N-oxides was developed. This underexplored oxygen allotrope mediates arene C-H oxidation within complex, polyfunctional molecules. A water-soluble pyridazine N-oxide was also developed and shown to promote photoinduced DNA cleavage in aqueous solution. Taken together, these studies highlight the utility of pyridazine N-oxides as photoactivatable O(3P) precursors for applications in organic synthesis and chemical biology.

Detection and Identification of Reaction Intermediates in the Photorearrangement of Pyridazine N-Oxide: Discrepancies between Experiment and Theory.

Photolysis of pyridazine N-oxide (PNO) results in the detection of a complex series of transient phenomena. On the ultrafast (fs) timescale, we could detect the decay of the first singlet excited state of PNO and the formation of a short-lived transient species, which, based on its time-resolved resonance Raman (TR3) spectrum, we assign to oxaziridine 1,2-diaza-7-oxa-bicyclo[4.1.0]hepta-2,4-diene. On a longer (hundreds of ns) timescale, this species rearranges to a ring-opened diazo compound, which we have also detected by time-resolved infrared and TR3 spectroscopy. In addition, we identify 1-oxa-3,4-diazepine as a long-lived species formed in the photochemistry of PNO. This species is formed via its oxirane isomer, which in turn is likely formed directly from the S1 state of PNO via a conical intersection. The barrier determined experimentally for the decay of 1,2-diaza-7-oxa-bicyclo[4.1.0]hepta-2,4-diene (Ea = (7.1 ± 0.5) kcal mol-1) is far larger than any barrier calculated by any method that includes dynamic electron correlation but very close to the barriers calculated at the RHF or CASSCF levels of theory. Many methods (B3LYP, MP2, and MP4) fail to give a minimum structure for 1,2-diaza-7-oxa-bicyclo[4.1.0]hepta-2,4-diene, while M06, M06-2X, MP3, CCSD, or CCSD(T) yield activation energies for its electrocyclic ring opening that are far too small. In addition, we note that several important geometric parameters, both of 1,2-diaza-7-oxa-bicyclo[4.1.0]hepta-2,4-diene and of the transition state of its ring opening reaction, clearly have reached no convergence, even at the fully optimized CCSD(T)/cc-pVTZ level of theory. We therefore suggest that the transient species described in this contribution might be excellent test molecules for further development of highly correlated and density functional theory methods.

Pyridazine N-Oxides as Precursors to 2-Aminofurans: Scope and Limitations in Complexity Building Cascade Reactions.

A method to transform pyridazine N-oxides into 2-aminofurans using a combination of UV light and transition metal catalysis has been developed. These electron-rich species exhibit a surprising range of useful reactivity, including the ability to participate in complexity building cascade processes when reacted with dienophiles. This study also establishes 2-aminofurans as valuable synthons that support modular synthetic entry to the shared heterocyclic core of certain aspidosperma and amaryllidaceae alkaloids.

Synthesis of Nitrogen Heterocycles via Photochemical Ring Opening of Pyridazine N-Oxides.

A photochemical method for the direct synthesis of 1H-pyrazoles from pyridazine N-oxides was developed. This chemistry features a regioselective approach to nonsymmetrically substituted pyridazine N-oxides. Herein, we highlight the first strategic use of photoinduced ring-opening reactions of 1,2-diazine N-oxides for the preparative synthesis of nitrogen heterocycles.

Pyridazine N-Oxides as Precursors of Metallocarbenes: Rhodium-Catalyzed Transannulation with Pyrroles.

Pyridazine N-oxides are used for the first time as precursors of metallocarbenes. These nitrogen-rich heterocycles led to the discovery of a novel acceptor and donor-acceptor enalcarbenoids. The synthetic utility of these metallocarbenes was demonstrated in the rhodium-catalyzed denitrogenative transannulation of pyridazine N-oxides with pyrroles to the valuable alkyl, 7-aryl, and 7-styryl indoles. The transannulation strategy was applied to the synthesis of a potent anticancer agent.

Experimental and theoretical molecular and electronic structures of the N-oxides of pyridazine, pyrimidine and pyrazine

The structures of pyridazine N-oxide, pyrimidine N-oxide and pyrazine N-oxide have been determined by X-ray diffraction for the first time. Comparison with theoretical predictions of the equilibrium structures using the B3LYP method together with a cc-pVTZ basis set, show close agreement with the structural parameters observed, and experimental dipole moments, which suggests that the charge distribution is realistic. An ‘atoms in molecules’ (AIM) analysis of the computed wave-functions shows total electron densities rather different from the classical picture of a dative bond, whereas the same wave-functions subjected to Mulliken analysis show a more conventional view of the electron distribution. This latter procedure allows a bond dipole analysis of the N-oxide charge distribution.

ChemInform Abstract: Reaction of Pyridazine N-Oxides with Pyridynes: Formation of the First Examples of Pyridooxepins.

ChemInform Abstract: Reaction of Pyridazine N-Oxides with Pyridynes: Formation of the First Examples of Pyridooxepins.

ChemInform Abstract: Synthesis and Reactions of Novel Tropono(4,5-b)oxepines.

Reaction of pyridazine N-oxides with 4,5-didehydrotropone resulted in the formation of the novel tropono[4,5-b]oxepines and some chemical properties of the new ring system were examined

Cross-Coupling Reactions of DiazineN-Oxides with Aryl Halides

A reasonably efficient Pd-catalyzed cross-coupling of diazine N-oxides with aryl­halides to afford aryl diazines is reported. In view of the absence of metalated (B, Zn, Mg, Sn) partners, the process may be formally categorized in the C-H-activation group of reactions. The reaction proceeds with pyrazines, pyrimidines, and pyridazine N-oxides to introduce aryl substituents ortho to the N-oxide function. The scope of hetero­cycle substitutent R1 received inadequate attention whereas that of R2, the aryl halides (bromides, iodides, and even chlorides), has been thoroughly investigated in terms of electron-donating and -withdrawing groups. An interesting catalyst inhibitory effect in the coupling reactions of pyrimidine N-oxides was noted but not elucidated.

A New and Convenient Route to Synthesis of Enynones and Dienones from TosMIC.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A New and Convenient Route to Synthesis of Enynones and Dienones from TosMIC

Dilithio- and disodiotosylmethylisocyanides react with pyridine N-oxide and pyridazine N-oxide leading to formation of ring opened unsaturated products which on reaction with aralkyl halides and further hydrolysis result in formation of dienones and enynones respectively.

Nucleophilic Substitution of Hydrogen Atoms in the Pyridazine Series. (Review)

Information has been generalized on the nucleophilic substitution of hydrogen in monocyclic and condensed pyridazines, pyridazine N-oxides, and pyridazinium cations.

Neighboring group effect of pyridazine and pyrazine rings for π-facial selectivity in the reactions of fused isopropylidenenorbornene systems with electrophilic reagents

A series of pyridazine- and pyrazine-fused isopropylidenenorbornenes have been synthesized and the π-facial selectivity of the electrophilic reactions with 4-phenyl-1,2,4-triazole-3,5(4H)-dione (PTAD), m-chloroperbenzoic acid (MCPBA) and N-bromosuccinimide (NBS) has been investigated. The ene reactions with PTAD exhibited exclusive syn selectivity to the heteroaromatic rings except for an isopropylidenenorbornene fused with a pyridazine N-oxide ring. The epoxidations with MCPBA and the ene reactions with NBS afforded mixtures of syn and anti isomers depending on the heteroaromatic rings and substituents. The predominant syn selectivity compared with that of a benzene-fused congener may be attributed to the presence of a strong positive electrostatic potential field over the heteroaromatic ring to stabilize a polar transition state by the electrostatic interaction.

Pyridazine N-oxides. III. Synthesis and "in vitro" antimicrobial properties of N-oxide derivatives based on tricyclic indeno[2,1-c]pyridazine and benzo[f]cinnoline systems.

A number of 9H-indeno[2,1-c]pyridazine N-oxides (3a-c) and benzo[f]cinnoline N-oxides (4,5a-c) have been synthesized and tested for antimicrobial activity. All new products were inactive against Gram negative bacteria and fungi. In contrast, among the compounds synthesized, 3b, 4b and 5b showed a moderate activity against Gram positive Staphylococcus aureus and Staphylococcus epidermidis. Of the present series, the 9-nitro-benzo[f]cinnoline N-oxide 5b possessed the highest activity especially against Trichomonas vaginalis (MIC = 3.9 micrograms/ml).

Neighboring effect by heteroaromatic rings: formation of skeletally rearranged adducts by cycloaddition reaction of norbornadiene-fused pyridazines and pyrazines with 4-phenyl-1,2,4-triazole-3,5(4 H)-dione

Norbornadiene-fused pyridazines and pyrazines reacted with 4-phenyl-1, 2,4-triazole-3,5(4 H)-dione to give skeletally rearranged adducts in moderate yields. A similar reaction with fused pyridazine N-oxides or a fused pyrazine N-oxide resulted in the regioselective formation of the rearranged adduct. The formations of the skeletally rearranged adducts would be ascribed to the intervention of bridged heteroarenium ion intermediates formed by the neighboring group participation of heteroaromatic rings.

Synthesis and Reactions of Novel Tropono[4,5-b]oxepines

Reaction of pyridazine N-oxides with 4,5-didehydrotropone resulted in the formation of the novel tropono[4,5-b]oxepines and some chemical properties of the new ring system were examined

Photochemical oxygenation of phenols by pyrimido[5,4-g]pteridne N-oxide. Comparative studies with pyridazine and isoalloxazine N-oxides

1,3,7,9-Tetrabutylpyrimido[5,4-g]pteridirie-2,4,6,8(1H,3H,7H,9H)-tetraone 5-oxide 1 transfers its N-oxide oxygen to phenols, i.e., phenol 5, p-cresol 6, L-tyrosine methyl ester 7, and p-hydroxyacetanilide (acetaminophen)8, under photochemical conditions to give the corresponding dihydric phenols as major products without any accompanying photochemical intramolecular rearrangements of the N-oxide group taking place. This oxygenation is reasonably explained in terms of a photo-induced single-electron transfer (SET) followed by oxygen-atom transfer (the SET mechanism) which occurs via the initial formation of a charge-transfer complex between compound 1 and the phenols employed. Comparative experiments with 3,10-dibutylisoalloxazine 5-oxide 3 and 3-methylpyridazine 2-oxide 4 well demonstrate the simplicity and the mechanistic characteristics of the photochemistry of compound 1.