Access to lincomycin N-oxide isomers controlled by reaction conditions

Oxidation of lincomycin with H₂O₂ in alkaline media leads to N-oxides, besides the conversion of thiomethyl group into sulfoxides and sulfones. NH₄OH favors formation of the S-isomer; both R- and S-isomers of the N-oxide are formed in the presence of NaOH. Addition of acetonitrile markedly accelerates the reaction.     

Synthesis and reactions of 3-halomethyl-substituted oxazine N-oxides

A series of 3-halomethyl-5,6-dihydro-1,2-oxazine N-oxides (halogen = Cl, Br, I) is prepared from 4-phenyl-3,6,6-trimethyl-5,6-dihydro-4H-oxazine N-oxide by means of a silylation/halogenation sequence. The obtained halogenated N-oxides undergo reactions typical of cyclic six-membered nitronates including 1,3-dipolar cycloaddition, addition of nucleophiles, and substitution of the halogen by C-, S-, and N-nucleophiles.     

A novel reagent combination for the oxidation of highly electron deficient pyridines to N-oxides: trifluoromethanesulfonic anhydride/sodium percarbonate

A novel reagent combination, Tf₂O/Na₂CO₃·1.5H₂O₂, has been developed for the oxidation of highly electron deficient pyridines to their corresponding N-oxides. The N-oxidation reaction, utilizing the in situ generated peracid, proceeds under mild conditions that allow for a number of functional groups and substitution patterns on the pyridine ring.     

2<Emphasis Type="Italic">H</Emphasis>-Benzimidazole <Emphasis Type="Italic">N</Emphasis>-oxides: synthesis,chemical properties,and biological activity

The review presents and summarizes comprehensive data starting from 2006 on the synthesis of mono- and di-N-oxides of 2H-benzimidazoles and their chemical properties. Especial attention was paid to the chemical transformations of 2H-benzimidazole 1,3-dioxides upon heating to give 3H-2,1,4-benzoxadiazine 4-oxides and 2H-benzimidazole mono-N-oxides. The biological activity of compounds was covered.     

A novel method for the reduction of sulfoxides and pyridine N-oxides with the system silane/MoO2Cl2

A novel method for the reduction of sulfoxides and pyridine N-oxides using a silane and a catalytic amount of MoO₂Cl₂ in excellent yields and with a wide functional group tolerance is reported. A green protocol for this reaction was developed in water with the air-stable catalytic system PMHS/MoO₂Cl₂(H₂O)₂.     

Sulfonium ylides derived from 2-hydroxy-benzoquinones: crystal and molecular structure and their one-step conversion into Mannich bases by amine N-oxides

Reaction of 2-hydroxy-para-benzoquinones with DMSO/Ac₂O produced dimethylsulfonium ylides, of which crystal structures as well as solid and liquid state NMR spectra were recorded. The ylides react with tertiary methylamine N-oxides in a one-pot, multi-step process to 3-methylamino-substituted benzoquinones. The mechanism starts with a deoxygenative deprotonation of the amine N-oxides, followed by a formal electrophilic displacement of DMSO by the resulting carbonium-iminium ion.     

Straightforward synthesis of enantiopure 2-aminomethyl and 2-hydroxymethyl pyrrolidines with complete stereocontrol

A practical synthesis of 2-aminomethyl- and 2-hydroxymethyl-3,4-dihydroxypyrrolidines via stereocontrolled addition of TMSCN and LiCH₂OMOM to chiral 3,4 dihydro-2H-pyrroline N-oxides is reported.     

Direct arylation of azine N-oxides with aryl triflates

Palladium catalyzed direct arylation of azine N-oxides using aryl triflates to afford the corresponding 2-aryl azine N-oxides is described. The reaction is carried out with a range of both N-oxides and aryl triflates. The arylation can be carried out in sequence to yield differentially diarylated products. The regioselectivity and scope of 3-substituted azine N-oxides are investigated. The method is applied to the synthesis of a compound that exhibits antimalarial and antimicrobial activities.     

Reactions of 1,1,1-trihalo-3-nitrobut-2-enes with enamines derived from cycloalkanones. Rearrangement of trifluoromethylated 1,2-oxazine N-oxide into 1-pyrroline N-oxides and stereochemistry of the products

1,2-Oxazine N-oxides derived from (E)-1,1,1-trifluoro-3-nitrobut-2-ene and cyclohexanone enamines underwent spontaneous rearrangement with ring contraction to give 1-pyrroline N-oxides. Reactions of (E)-1,1,1-trifluoro(trichloro)-3-nitrobut-2-enes with N-cyclopent-enylmorpholine resulted in a series of novel CX₃-containing nitroalkyl enamines and g-nitro ketones; the stereochemistry of the synthesized compounds were studied by NMR spectroscopy and X-ray diffraction.     

Transferring oxygen isotopes to 1,2,4-benzotriazine 1-oxides forming the corresponding 1,4-dioxides by using the HOF·CH3CN complex

Heterocyclic benzotriazine N-oxides are an interesting class of experimental anticancer and antibacterial agents. Analogs with ¹⁸O incorporated into the N-oxide group may offer useful mechanistic tools. We describe the use of H₂¹⁸OF·CH₃CN in a fast, readily executed and high-yielding preparation of 1,2,4-benzotriazine 1,4-dioxides containing an ¹⁸O-label at the 4-oxide position.     

Chiral pyridine N-oxides derived from monoterpenes as organocatalysts for stereoselective reactions with allyltrichlorosilane and tetrachlorosilane

The synthesis of enantiomerically pure C₂-symmetric dipyridylmethane ligands and related N,N′-dioxides is reported. A procedure for the synthesis of a few new enantiomerically pure C₂-symmetric pyridine N-oxides and the preparation of four pyridine N-oxides with oxygen and nitrogen atoms as further coordinating elements in the heterocycle framework is described. All compounds were prepared from naturally occurring monoterpenes. These new compounds were assessed as organocatalysts in two different reactions, namely the allylation of aldehydes with allyltrichlorosilane that afforded homoallylic alcohols in good yields and up to 85% ee and the stilbene oxide opening by the addition of tetrachlorosilane that gave chlorohydrin in quantitative yield and up to 70% ee.     

A fast route for the synthesis of tetrazolyl oximes by a novel multicomponent reaction between Z-chlorooximes,isocyanides and trimethylsilyl azide

A library of twenty variously decorated 1,5-disubstituted-(1H-tetrazol-5-yl)methanone oximes was prepared in one single synthetic step exploiting the combination of (Z)-chlorooximes, isocyanides and trimethylsilyl azide. The formal [3+1] cycloaddition between isocyanides and nitrile N-oxides with respect to the [3+1] cycloaddition between isocyanides and azides prevails, while the direct attack of azide onto nitrile N-oxides remains competitive. Finally, an intramolecular cyclization of a (1H-tetrazol-5-yl)methanone oxime to a benzoisoxazole tetrazole is reported for the first time.     

Investigation of Symphytum cordatum alkaloids by liquid-liquid partitioning, thin-layer chromatography and liquid chromatography-ion-trap mass spectrometry

From the alkalised crude extract of Symphytum cordatum (L.) W.K. roots, pyrrolizidine alkaloids (PAs) were extracted as free tertiary bases and polar N-oxides in a merely one-step liquid-liquid partitioning (LLP) in separation funnel and subsequently pre-fractionated by preparative multiple-development (MD) thin-layer chromatography (TLC) on silica gel plates. In this way three alkaloid fractions of different polarities and retention on silica gel plates were obtained as: the most polar N-oxides of the highest retention, the tertiary bases of medium retention, and diesterified N-oxides of the lowest retention. The former fraction was reduced into free bases by sodium hydrosulfite and purified by LLP on Extrelut-NT3 cartridge. It was further analysed together with the two other fractions by high-performance liquid chromatography (HPLC)-ion-trap mass spectrometry with atmospheric pressure chemical ionization (APCI) interface on XTerra C₁₈ column using a gradient elution. Based on MSⁿ spectra, 18 various alkaloids have been tentatively determined for the first time in this plant as the following types of structure: echimidine-N-oxide (three diasteroisomers), 7-sarracinyl-9-viridiflorylretronecine (two diasteroisomers), echimidine (two diasteroisomers), lycopsamine (two diasteroisomers), dihydroechinatine-N-oxide, dihydroheliospathuline-N-oxide, lycopsamine-N-oxide (three diasteroisomers), 7-acetyllycopsamine-N-oxide, symphytine-N-oxide (two diasteroisomers) and 2″,3″-epoxyechiumine-N-oxide.     

A general method for the deoxygenation of aromatic N-oxides using RuCl3·xH2O

An efficient, simple and selective method for the deoxygenation of aromatic N-oxides, such as N-arylnitrones, azoxybenzenes, N-heteroarene N-oxides using ruthenium(III) chloride to afford deoxygenated products in excellent yields, is described.     

Probing the metal complexing ability of bis-quinolizidine N-oxides: Synthesis, spectroscopy and crystal structures

New ZnX₂ (X = Cl, Br) complexes with sparteine N1-oxide, sparteine epi-N16-oxide, lupanine (2-oxosparteine) N-oxide and α-isosparteine N-oxide were obtained and characterized by spectroscopic and crystallographic methods. Complexation with N1-oxides involves inversion of the configuration at the N16 atom of sparteine, converting its C ring from a boat into a chair form, whereas the structure of sparteine epi-N16-oxide, typified by the trans boat/chair C/D quinolizidine moiety, remains unchanged upon complexation. Coordination of zinc salts in the above compounds is realized solely through the oxygen atom of the N-O group and is accompanied by protonation of the “not-N-oxide” nitrogen atom. At variance lupanine N-oxide forms bis-monodentate complexes with ZnX₂ utilizing both the N-oxide and the lactam carbonyl oxygen atoms to bridge the neighboring ZnX₂ units, while reaction of α-isosparteine N-oxide with ZnX₂ leads to formation of complex salts of the general formula [H(−)α-Sp(N-oxide)][(ZnX₃)(H₂O)].     

Photocatalytic deoxygenation of N–O bonds with rhenium complexes: from the reduction of nitrous oxide to pyridine N-oxides

The accumulation of nitrogen oxides in the environment calls for new pathways to interconvert the various oxidation states of nitrogen, and especially their reduction. However, the large spectrum of reduction potentials covered by nitrogen oxides makes it difficult to find general systems capable of efficiently reducing various N-oxides. Here, photocatalysis unlocks high energy species able both to circumvent the inherent low reactivity of the greenhouse gas and oxidant N₂O (E⁰(N₂O/N₂) = +1.77 V vs. SHE), and to reduce pyridine N-oxides (E_1/2(pyridine N-oxide/pyridine) = −1.04 V vs. SHE). The rhenium complex [Re(4,4′-tBu-bpy)(CO)₃Cl] proved to be efficient in performing both reactions under ambient conditions, enabling the deoxygenation of N₂O as well as synthetically relevant and functionalized pyridine N-oxides.

A rhenium-based photocatalyst enables the deoxygenation of several compounds containing N–O bonds, such as N₂O and pyridine N-oxides.     

Selective synthesis of 2-substituted pyridine N-oxides via directed ortho-metallation using Grignard reagents

Addition of i-PrMgCl to pyridine N-oxides in THF at −78 °C generates selectively an ortho-metallated species, which can be trapped with various electrophiles to generate 2-substituted pyridine N-oxides. Furthermore, by applying a double metal-catalyzed cross-coupling, direct arylation of the pyridine N-oxides is achieved.     

Synthesis of 5-alkyl-5-aryl-1-pyrroline N-oxides from 1-aryl-substituted nitroalkanes and acrolein via Michael addition and nitro reductive cyclization

A general method for accessing 5-alkyl-5-aryl-1-pyrroline N-oxides (AAPOs) has been established using readily available aryl bromides, nitroalkanes, and acrolein as the starting materials. The palladium-catalyzed arylation of nitroalkanes gave the 1-aryl-substituted nitroalkanes, which underwent the Et₃N-catalyzed Michael addition with acrolein at room temperature to afford the 4-aryl-4-nitroaldehydes. The latter were then subjected to the nitro reductive cyclization using Zn–HOAc in EtOH at 0 °C followed by warming the reaction mixture to room temperature for 24 h, furnishing the 5-alkyl-5-aryl-1-pyrroline N-oxides in good overall yields. Selected examples of 1,3-dipolar cycloaddition of the cyclic nitrones with methyl methacrylate were also described.     

Synthesis of 1,2,3,4-tetrazine 1,3-dioxides annulated with 1,2,3-triazoles and 1,2,3-triazole 1-oxides

1,2,3,4-Tetrazine 1,3-dioxides annulated with 1,2,3-triazoles and 1,2,3-triazole 1-oxides have been synthesized by the reaction of 4-amino-5-(tert-butyl-NNO-azoxy)-2-R-2H-1,2,3-triazoles (R=Me, i-Pr, t-Bu) and their 1-oxides (R=H, Me, Et, i-Pr) with the HNO₃/H₂SO₄/Ac₂O system. Their thermal stability, spectroscopic, and X-ray properties have been studied.     

The crystal and molecular structure of N2H5[M(N2H3COO)3]·H2O (M∈{Co, Zn}) isomorphic compounds—an X-ray crystallographic, vibrational spectroscopic and quantum-chemical study

A systematic study of N₂H₅[M(N₂H₃COO)₃]·H₂O (M∈{Co, Zn}) type of compounds, which are typical model systems for transition metal complexes with α-amino acids (the latter are not obtainable in crystalline form), was carried out. The crystal structures of these compounds were solved by X-ray crystallographic methods. FTIR spectra at room and low temperature (∼100 K) as well as Raman spectra at room temperature were recorded, and analyzed in details. Also, the geometries of the Zn(N₂H₃COO)₃⁻ and N₂H₅⁺ species were fully optimized at ab initio HF and B3LYP/6-31+G(d,p) level of theory, and subsequent vibrational analyses were performed on the basis of which several important reassignments of the IR and Raman bands were proposed. In order to study the binding energetics and the ligand-cation charge-transfer interactions within the Zn(N₂H₃COO)₃⁻ complex, NBO analysis was carried out, employing the second-order perturbation theory analysis of the Fock matrix (i.e., its Kohn-Sham analog) within the NBO basis.