The face selectivity of 1,3-dipolar cycloaddition reactions of 4-butyloxycarbonyl-3,4,5,6-tetrahydropyridine 1-oxide

A study of the stereo- and face selectivity of the cycloaddition reactions of a series of mono- and disubstituted alkenes with 4-butyloxycarbonyl-3,4,5,6-tetrahydropyridine 1-oxide has been carried out. Rate constants for the cycloaddition of the nitrone to methyl acrylate, styrene, and methyl methacrylate have been determined at various temperatures by ¹H NMR spectroscopy. The activation parameters indicate the concerted nature of the reaction. The 4-substituted nitrone is found to be more reactive than its unsubstituted counterpart 3,4,5,6-tetrahydropyridine 1-oxide. The addition reactions have displayed a very high degree of face selectivity (9:1), and those reactions in micellar media are found to be very efficient. Conformational analysis and peracid-induced ring opening of a cycloadduct has been carried out to give second-generation cyclic nitrones.     

Transition metal ion complexes of thiosemicarbazones derived from 2-acetylpyridineN-oxide. I. The 4-methyl derivative

Summary TheN-methyl-2-[1-(2-pyridinyl-1-oxide)ethylidene]hydrazinecarbothioamide, HLO4M, has been used to prepare a series of Co^III, Ni^II and Cu^II complexes. Species with two deprotonated LO4M ligands, one LO4M and one HLO4M ligand, two HLO4M ligands and one HLO4M ligand with two small anionic ligands have been isolated. The deprotonated LO4M bonds as a tridentate ligandvia theN-oxide oxygen, the imine nitrogen (N¹ and the sulphur while the HLO4M ligand coordinates primarily as a bidentate ligandvia only the first two atoms listed above. I.r., electronic, mass and e.s.r. spectra have been used to determine the nature of these complexes. One of the more striking differences between these compounds and those prepared with other thiosemicarbazones of 2-acetylpyridine and 2-acetylpyridineN-oxide is that tetrahedral yellow [Ni(HL)X₂] rather than planar brown [NiLX] (X=Cl or Br) solids have been isolated with this ligand. Other differences in the nature of the coordination spheres of the various metal ions occur with this particular ligand when compared to previously studied thiosemicarbazone complexes.NATO Fellow, on leave from Medical Faculty, Istanbul University.     

The Reaction of N-Oxide with Ethyl Bromoacetate

The reaction of 4-methoxypyridine 1-oxide with ethyl bromoacetate was found to produce a high yield of ethyl glyoxylate, trimethylamine N-oxide and pyridine 1-oxide also afforded the glyoxylate but in lower yield in the reaction, and 4-nitropyridine 1-oxide was found to be inactive with bromoacetate. Pyridine 1-oxide and trimethylamine N-oxide exhibit the same stoichiometry, while 4-methoxypyridine 1-oxide follows a different course.     

Lithiation-methylation of thiasilinane 1-oxides

Lithiation-methylation of 3,3-dimethyl-1λ⁴,3-thiasilinane 1-oxide and 4,4-dimethyl-1λ⁴,4-thiasilinane 1-oxide under the action of butyllithium or lithium diisopropylamide and methyl iodide was studied. In both cases, monomethylation proceeds selectively α to the sulfoxide group to form 2,3,3-trimethyl-1λ⁴,3-thiasilinane 1-oxide and 2,4,4-trimethyl-1λ⁴,4-thiasilinane 1-oxide, respectively. Subsequently, 2,3,3-trimethyl-1λ⁴,3-thiasilinane 1-oxide undergoes monomethylation into the same α position to give 2,2,3,3-tetramethyl-1λ⁴,3-thiasilinane 1-oxide, while 4,4-dimethyl-1λ⁴,4-thiasilinane 1-oxide is dimethylated into the neighboring α’ position to form two stereoisomers of 2,4,4,6-tetramethyl-1λ⁴,4-thiasilinane 1-oxide with axial-equatorial or equatorial-equatorial methyl groups in the 2 and 6 positions.     

Differentiation of Constitutional Isomer of 2,2a,3,4-Tetrahydro- 4-methyl-2a-phenyl-2-(thiophen-2-yl)-1H-azeto[2,1-d][1,5] benzothiazepin-1-one-5-oxide and Fragmentations of 2,3-Dihydro- 2,4-diphenyl-1,5-benzothiazepine-1-oxide/-1,1-dioxide

Introduction Mostimportantantibioticspossessarepresen- tativestructureofaβ-lactamfusedfive-orsix- memberedheterocyclicringcontainingnitrogenand sulfuratoms.Forinstance,theeffectiveantibi- otics,penicillin,penamandpenem,havefusedthi- azolidine-β-lactam,andtheeffectiveantibiotics, cephalosporinandcephem,arefuseddihydroth- iazine-β-lactams[1].Recently,someβ-lactam derivativeshavealsobeenrecognizedasthein- hibitorsofhumanleukocytaseelastase[2]andserine protease[3].Thesynthesisofbicyclicβ-lact…     

Differentiation of Constitutional Isomer of 2,2a,3,4-Tetrahydro- 4-methyl-2a-phenyl-2- （thiophen-2-yl）- 1H-azeto [-2,1-d] [- 1,51benzothiazepin-1-one-5-oxide and Fragmentations of 2,3-Dihydro-2,4-diphenyl-1,5-benzothiazepine-l-oxide／- 1,1-d

Mass spectrometric behaviour of 2,2a, 3,4-tetrahydro-4-methyl-2a-phenyl-2- (thiophen-2-yl)- 1H-azeto [-2,1-d-J1-1,5-]benzothiazepin-l-one-5-oxide and 2,3-dihydro-2,4-diphenyl-1,5-benzothiazepine-l-oxide/-1,1-dioxide have been studied with the aid of mass-analyzed ion kinetic energy spectrometry and accurate mass measurements under electron impact ionization. The monooxide derivatives showed a tendency to eliminate an alkene or an oxygen atom. 1H-Azeto[-2,1-d][1,5]benzothiazepin-1-one-5-oxide could also eliminate the thiophen- 2-ylketene molecule via a reverse [-2 q- 2 ~ cycloaddition. 2,3-Dihydro-2,4-diphenyl- 1,5-benzothiazepine-1-oxide/-1, 1-dioxide could eliminate SO2 or SO, respectively. The structure of 2,2a, 3, 4-tetrahydro-4-methyl-2a-phenyl-2- (thiophen-2-yl)-1H-azeto 1-2,1-d-] [1,5 -] benzothiazepin-1-one-5-oxide was identified on the basis of its fragmentation. The identification was supported by the fragmentations of model compound, 2,3-dihydro-2,4-diphenyl-1,5-benzothiazepine-1-oxide/-1,1-dioxide.     

Reactions of 4-Nitroquinoline 1-Oxide with Aluminum Chloride

4-Nitroquinoline 1-oxide reacts with aluminum chloride to give 4-chloroquinoline 1-oxide. Aluminum chloride with 4-nitroquinoline 1-oxide forms a molecular complex in which it acts as electron acceptor and effective nucleophilic reagent (a source of chloride ions).     

Studies in ring-opening polymerization. III. 5-methyl-5-propyl and 5-methyl-5-isopropyl-1,3,2-dioxathiolan-4-one 2-oxide

5-Methyl-5-propyl-1,3,2-dioxathiolan-4-one 2-oxide (MPAS) and 5-methyl-5-isopropyl-1,3,2-dioxathiolan-4-one 2-oxide (MiPAS), which are isomers of the previously studied 5,5-diethyl-1,3,2-dioxathiolan-4-one 2-oxide (DEAS), have been synthesized and their polymerizability compared with that of the last compound. The two unsymmetrically substituted monomers polymerize by a mechanism which is substantially identical to that of their symmetrically substituted counterpart. In dry nonhydroxylic solvents the rate-determining process is the primary scission of the ring, which takes place with elimination of sulfur dioxide and concurrent ring contraction to form an α-lactone intermediate. In this reaction, the parent acid, produced by reaction of the monomer with adventitious traces of moisture, acts as the initiating species. The resultant polymers are all hydroxyl/carboxyl-terminated, but, whereas those derived from the two unsymmetrically substituted monomers are amorphous and readily soluble in a variety of organic solvents, those derived from the diethyl-substituted ring have been shown to be highly crystalline materials which dissolve in very few solvents. The relative polymerization rates are illustrated by the first-order rate constants for decomposition in nitrobenzene at 90°C: DEAS, 20.1 × 10^?5 sec^?1; MiPAS, 11.0 × 10^?5 sec^?1; MPAS, 9.7 × 10^?5 sec^?1. The role of the substituents in determining the magnitude of these constants is discussed in terms of both the Thorpe-Ingold effect and electron donation at C-5.     

Reaction of 6-chloro-2-[1-methyl-2-(N-methylthiocarbamoyl)]-hydrazinoquinoxaline 4-oxide with dimethyl acetylenedicarboxylate

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 4a with methyl or phenyl isothiocyanate gave 6-chloro-2-[1-methyl-2-(N-methylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 7a or 6-chloro-2-[1-methyl-2-(N-phenylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 7b , respectively, whose reaction with dimethyl acetylenedicarboxylate afforded 6-chloro-2-[N-methyl-N-(5-methoxycarbonylmethylene-3-methyl-4-oxo-2-thioxoimidazolidin-1-yl)]aminoquinoxaline 4-oxide 8a or 6-chloro-2-[N-methyl-N-(5-methoxycarbonylmethylene-4-oxo-3-phenyl-2-thioxoimidazolidin-1-yl)]aminoquinoxaline 4-oxide 8b , respectively.     

铂和铜电极上4-硝基吡啶-1-氧化物还原过程研究

4-氨基吡啶是一种重要的精细化工产品, 为探讨其电化学合成过程的反应机理, 采用循环伏安法、库仑电解等方法对强酸性条件下4-硝基吡啶-1-氧化物的电化学行为进行了研究. 结果表明: 4-硝基吡啶-1-氧化物在铂电极上主要经历电化学-化学-电化学(ECE)还原历程, 并生成4-羟胺吡啶-1-氧化物; 对铜电极而言, 当电位高于－0.65 V时主要经历ECE还原历程, 并生成4-羟胺吡啶-1-氧化物; 当电位低于－0.85 V时经历ECE还原历程生成的4-羟胺吡啶-1-氧化物, 可发生进一步4e^－还原, 并生成4-氨基吡啶.     

The synthesis and reactions of certain pyridazine 1-oxides

Nucleophilic displacement reactions under acidic and basic conditions have been studied with 4,6-dinitro-3-methoxypyridazine 1-oxide ( 1 ) and with 6-chloro-3-methoxy-4-nitropyridazine 1-oxide ( 2 ). Depending on the nature of the nucleophilic reagent and the conditions of the reaction we have found that the chloro group, the nitro group, as well as the methoxy group of 1 and 2 may be displaced by the nucleophile. This type of compound possesses significant in vitro antifungal activity.     

Reactions of substituted pyridines and their N-oxides with ethanolic sodium hydroxide and various alkoxides

2-Benzoylpyridine 1-oxide with ethanoiic sodium hydroxide yielded acyl nucleophilic displacement products and a redox product, 2-(α-hydroxybenzyl)pyridine. 3-Benzoylpyridine 1-oxide under the same conditions yielded only a reduction product, 3-(α-hydroxybenzyl)-pyridine 1-oxide, whereas 4-benzoylpyridine 1-oxide yielded only a redox product, 4-(α-hydroxy-benzyl)pyridine. The redox reaction which is promoted by base occurs with an α-hydroxybenzylpyridine 1-oxide which results from a carbonyl reduction of the starting material. The benzoyl-pyridine 1-oxides reacted qualitatively the same with sodium ethoxide or isopropoxide as they did with ethanoiic sodium hydroxide, but they reacted differently with potassium t-butoxide or aluminum isopropoxide. The cyano- and benzenesulfonyl-pyridine 1-oxides reacted with ethanolic sodium hydroxide to yield pyridinecarboxylic acids and 1-hydroxypyridones, respectively.     

3-amino-1,2,4-benzotriazine 4-oxide: characterization of a new metabolite arising from bioreductive processing of the antitumor agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine).

Tirapazamine (1) is a promising antitumor agent that selectively causes DNA damage in hypoxic tumor cells, following one-electron bioreductive activation. Surprisingly, after more than 10 years of study, the products arising from bioreductive metabolism of tirapazamine have not been completely characterized. The two previously characterized metabolites are 3-amino-1,2,4-benzotriazine 1-oxide (3) and 3-amino-1,2,4-benzotriazine (5). In this work, 3-amino-1,2,4-benzotriazine 4-oxide (4) is identified for the first time as a product resulting from one-electron activation of the antitumor agent tirapazamine by the enzymes xanthine/xanthine oxidase and NADPH:cytochrome P450 oxidoreductase. As part of this work, the novel N-oxide (4) was unambiguously synthesized and characterized using NMR spectroscopy, UV-vis spectroscopy, LC/MS, and X-ray crystallography. Under conditions where the parent drug tirapazamine is enzymatically activated, the metabolite 4 is produced but readily undergoes further reduction to the benzotriazine (5). Thus, under circumstances where extensive reductive metabolism occurs, the yield of the 4-oxide (4) decreases. In contrast, the isomeric two-electron reduction product 3-amino-1,2,4-benzotriazine 1-oxide (3) does not readily undergo enzymatic reduction and, therefore, is found as a major bioreductive metabolite under all conditions. Finally, the ability of the 4-oxide metabolite (4) to participate in tirapazamine-mediated DNA damage is considered.     

Lanthanide perchlorate complexes of 4-cyano pyridine-N-oxide, 4-chloro 2-picoline-N-oxide and 4-dimethyl amino-2-picoline-N-oxide

Complexes of lanthanide perchlorates with 4-cyano pyridine-1-oxide, 4-chloro 2-picoline-1-oxide and 4-dimethyl-amino 2-picoline-1-oxide have been isolated for the first time and characterized by analysis, conductance, infrared, NMR and electronic spectra. The complexes of 4-cyano pyridine-1-oxides have the composition Ln(CyPO)₆(ClO₄)₃. 2H₂O (Ln=La, Sm, Dy and Ho); Ln(CyPO)₇ (ClO₄)₃. 2H₂O (Ln=Pr, Nd, Er and Yb); and Ln(CyPO)₅ (ClO₄)₃. 2H₂O (Ln=Gd and Tb). The complexes of 4-chloro 2-picoline-1-oxide analyse for the formulae Ln(CpicO)₆ (ClO₄)₃ (Ln=La, Pr, Nd and Ho); and Ln (CpicO)₅ (ClO₄)₃ (Ln=Er and Yb), and those of 4-dimethylamino 2-picoline-1-oxide for Ln(DMPicO)₆ (ClO₄)₃ (Ln=La and Nd); Ln(DMPicO)₇ (ClO₄)₃ (Ln=Gd, Er and Yb); and Ln(DMPicO)₈ (ClO₄)₃ (Ln=Dy and Ho).     

Studies on pyrazines. 19 . A novel formation of alkenynylpyrazines in palladium-catalyzed reaction of 2-chloropyrazine and its N-oxide with acetylenes

Reaction of 3-chloropyrazine 1 -oxide ( 1 ) with 1-hexyne ( 2a ) in the presence of tetrakis(triphenylphosphine)-palladium(O) and potassium acetate in DMF afforded 3-(1-hexynyl)pyrazine 1 -oxide ( 3a ) and 3-(2-butyl-1-octen-3-ynyl)pyrazine 1-oxide ( 4a ). The novel formation of 4a was elucidated to result from codimerization of 3a with 2a . The details of reaction are discussed on the basis of findings in palladium(O)-catalyzed reaction of other chloroheterocycles.     

Synthesis of 1,2-diazepino[3,4-b]quinoxalines and pyrido[3′,4′:9,8][1,5,6]oxadiazonino[3,4-b]quinoxalines via a 1,3-dipolar cycloaddition reaction

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 8 with furfural, 3-methyl-2-thiophene-carbaldehyde, 2-pyrrolecarbaldehyde, 4-pyridinecarbaldehyde and pyridoxal hydrochloride gave 6-chloro-2-[2-(2-furylmethylene)-1-methylhydrazino]quinoxaline 4-oxide 5a , 6-chloro-2-[1-methyl-2-(3-methyl-2-thienyl-methylene)hydrazino]quinoxaline 4-oxide 5b , 6-chloro-2-[1-methyl-2-(2-pyrrolylmethylene)hydrazino]quinoxa-line 4-oxide 5c , 6-chloro-2-[1-methyl-2-(4-pyridylmethylene)hydrazino]quinoxaline 4-oxide 5d and 6-chloro-2-[2-(3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridylmethylene)-1-methylhydrazino]quinoxalme 4-oxide 5e , respectively. The reaction of compound 5a or 5b with 2-chloroacrylonitrile afforded 8-chloro-3-(2-furyl)-4-hydroxy-1-methyl-2,3-dihydro-1H-1,2-diazepino[3,4-b]quinoxaline-5-carbonitrile 6a or 8-chloro-4-hydroxy-1-methyl-3-(3-methyl-2-thienyl)-2,3-dihydro-1H-1,2-diazepino[3,4-b]quinoxaline-5-carbonitrile 6b , respectively, while the reaction of compound 5e with 2-chloroacrylonitrile furnished 11-chloro-7,13-dihydro-4-hydroxy-methyl-5,14-methano-1,7-dimethyl-16-oxopyrido[3′,4′:9,8][1,5,6]oxadiazonino[3,4-b]quinoxaline 7.     

Reaction of 2-(5-aminopyrazol-1-yl)quinoxaline 4-oxides with dimethyl acetylenedicarboxylate

The reaction of 6-chloro-2-hydrazinoquinoxaline 4-oxide 6 with ethyl 2-(ethoxymethylene)-2-cyanoacetate or (1-ethoxyethylidene)malononitrile gave 2-(5-amino-4-ethoxycarbonylpyrazol-1-yl)-6-chloroquinoxaline 4-oxide 7a or 2-(5-amino-4-cyano-3-methylpyrazol-1-yl)-6-chloroquinoxaline 4-oxide 7b , respectively. The reaction of compound 7a or 7b with dimethyl acetylenedicarboxylate resulted in the 1,3-dipolar cycloaddition reaction and then ring transformation to afford 4-(5-amino-4-ethoxycarbonylpyrazol-1-yl)-8-chloro-1,2,3-trismethoxycarbonylpyrrolo[1,2-α]quinoxaline 8a or 4-(5-amino-4-cyano-3-methylpyrazol-1-yl)-8-chloro-1,2,3-trismethoxycarbonylpyrrolo[1,2-α]quinoxaline 8b , respectively.     

Pyridazines. IV. The synthesis and some reactions of acetylpyridazines

Two 3-acetylpyridazines have been prepared. N-Oxidation of 3-acetylpyridazine ( 6 ) gave only 3-acetylpyridazine 1-oxide ( 7 ). During the N-oxidation of 3-acetyl-6-methoxypyridazine ( 10 ), three primary products, namely, 3-acetyl-6-methoxypyridazine 1-oxide ( 12 ), 3-acetyl-6-methoxy-pyridazine 2-oxide ( 13 ), 3-acetylpyridazin-6-one ( 14 ) and an artifact, 3-methoxypyridazine 1-oxide ( 15 ) were obtained. Furthermore, it has been shown that 3-methoxypyridazine 1-oxide ( 15 ) can be obtained in quantitative yield by treatment of 3-acetyl-6-methoxypyridazine 2-oxide ( 13 ) with dilute sodium hydroxide solution at room temperature. This represents a novel deacylation reaction. Nitration of 3-acetylpyridazine 1-oxide, ( 7 ) gave 3,4-bis(3′-pyridazinoyl)furoxan 1′,1′-dioxide ( 19 ) rather than a simple nitration product. 3-Acetyl-pyridazine ( 6 ) and 3-acetyl-6-methoxypyridazine ( 10 ) also gave furoxans ( 22 and 23 ) upon nitration.     

Facile Synthesis of Novel Pentofuranose Analogs of Phospha Sugar Derivatives

Novel pentofuranose analogs of phospha sugar derivatives were synthesized starting from 1-phenyl-2-phospholene 1-oxide ( 1 ). First, the allylic oxidation of 1-phenyl-2-phospholene 1-oxide ( 1 ) with CrO 3 in Ac 2 O-AcOH or 3-hydroxy-1-phenyl-2-phospholene ( 2 ) with MnO 2 afforded 1-phenyl-4-oxo-2-phospholene 1-oxide ( 3 ). The C-5 alkylation of 3 in the presence of NaH by using benzyl bromide or methyl iodide as electrophiles afforded the target title compounds.     

Preparation and covalent hydration of 4H-imidazole derivatives

2,4,4-Trimethyl-5-phenyl-4H-imidazole, 4H-imidazole 3-oxide, and 4H-imidazole 1,3-dioxide were synthesized from 1-hydroxy-2,5,5-trimethyl-4-phenyl-3-imidazoline and 3-imidazoline 3-oxide, The action of hydrogen chloride on these compounds and on 2,4,4-trimethyl-5-phenyl-4H-imidazole 1-oxide gives products of the addition of water or alcohol — derivatives of 4-hydroxy-2-imidazolinium chlorides.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1246–1251, September, 1972.