Regioselective synthesis of 2,3,4- or 2,3,5-trisubstituted pyrroles via [3,3] or [1,3] rearrangements of O-vinyl oximes

The regioselective synthesis of 2,3,4- or 2,3,5-trisubstituted pyrroles has been achieved via [3,3] and [1,3] sigmatropic rearrangements of O-vinyl oximes, respectively. Iridium-catalyzed isomerization of easily prepared O-allyl oximes enables rapid access to O-vinyl oximes. The regioselectivity of pyrrole formation can be controlled by either the identity of the α-substituent or through the addition of an amine base. When enolization is favored, a [3,3] rearrangement followed by a Paal-Knorr cyclization provides a 2,3,4-trisubstituted pyrrole; when enolization is disfavored, a [1,3] rearrangement occurs prior to enolization to produce a 2,3,5-trisubstituted pyrrole after cyclization. Optimization and scope of the O-allyl oxime isomerization and subsequent pyrrole formation are discussed and mechanistic pathways are proposed. Conditions are provided for selecting either the [3,3] rearrangement or the [1,3] rearrangement product with β-ester O-allyl oxime substrates.     

Synthesis of aza-heterocycles from oximes by amino-Heck reaction

Oxidative addition of oximes to palladium(0) complexes generates alkylideneaminopalladium(II) species, which are utilized as key intermediates for carbon-nitrogen bond formation. Various aza-heterocycles, such as pyrrole, pyridine, isoquinoline, spiroimine, and azaazulene, can be synthesized from O-pentafluorobenzoyloximes having an olefinic moiety via an intramolecular Heck-type reaction (amino-Heck reaction) by treatment with a catalytic amount of a Pd(0) complex.     

Microwave-assisted syntheses of N-heterocycles using alkenone-, alkynone- and aryl-carbonyl O-phenyl oximes: formal synthesis of neocryptolepine

This research aimed to provide a new and "clean" synthetic method that would enable both known and novel N-heterocycles to be prepared efficiently. O-Phenyl oximes were found to be excellent precursors for iminyl radicals with a variety of acceptor side chains. Dihyropyrroles were made in good yields from O-phenyl oximes containing pent-4-ene acceptors. The analogous process with a hex-5-enyl acceptor did not yield a dihydropyridine, probably because the 6-exo-trig ring closure of the iminyl radical was too slow to compete with H-atom abstraction. The iminyl radical from a precursor with a pent-4-yne type side chain underwent ring closure followed by rearrangement to afford a pyrrole derivative. Suitably substituted iminyl radicals ring closed readily onto aromatic acceptors, thus enabling several polycyclic systems to be accessed. Quinolines were made from 3-phenylpropanones via their O-phenyl oximes. Syntheses of phenanthridines starting from 2-formylbiphenyls were particularly efficient, and this approach enabled the natural product trisphaeridine to be made. Starting from 2-phenylnicotinaldehyde derivatives, ring closures of the derived iminyl radicals onto the phenyl rings yielded benzo[h][1,6]naphthyridines. Similarly, ring closure onto a phenyl ring from a benzothiophene-based iminyl yielded a benzo[b]thieno[2,3-c]quinoline. By way of contrast, iminyl radical ring closure onto pyridine rings was not observed. However, iminyl radicals did cyclize onto indoles, enabling indolopyridines to be prepared. The latter route was exploited in a short formal synthesis of neocryptolepine starting from 2-((1H-indol-3-yl)methyl)cyclohexanone.     

Porphyrins with exocyclic rings. Part 21: Influence of pyrrolic and carbocyclic ring alkyl substituents on the synthesis of porphyrins bearing six-membered exocyclic rings

A series of 5-substituted 4,5,6,7-tetrahydroindoles were prepared by reacting 4-substituted cyclohexanones with phenylhydrazones derived from esters of acetoacetic acid under Knorr-type reaction conditions. Related 6,6-dimethyltetrahydroindoles were also prepared by reacting dimedone with oximes by the Knorr pyrrole syntheses, followed by selective reduction of the remaining ketone moiety with diborane. The substituted tetrahydroindoles were regioselectively oxidized with lead tetraacetate to give the related 7-acetoxy derivatives, and these reacted with 5-unsubstituted pyrrole esters to give pyrrolyltetrahydroindoles. In one case, a bromo substituent was used to protect the β-position of the pyrrole reactant. Cleavage of the benzyl ester protective groups with hydrogen over Pd/C, which also removes the bromo-protective group, gave four dipyrrole carboxylic acids. These were condensed with a dipyrrylmethane dialdehyde using the MacDonald ‘2+2’ condensation to give substituted porphyrins with six-membered exocyclic rings. These structures are useful for comparison to porphyrin samples found in organic-rich sediments such as oil shales and petroleum. The presence of methyl substituents on the six-membered ring for the tetrahydroindole precursors slightly decreases the yields for porphyrin synthesis, and this effect is enhanced when the system becomes more sterically crowded due to the presence of an ethyl group of the adjacent pyrrole ring. 5-Alkyl substituted tetrahydroindoles were also converted to tetrapropanoporphyrins via a cyclotetramerization procedure. The alkyl substituents again decreased the yields, although 5-alkyl substituents were found to have a far less deleterious effect than 6-alkyl groups. In addition to providing samples to help assign the vibrational spectra of geoporphyrin samples, these results demonstrate that highly substituted porphyrin systems can be prepared from tetrahydroindole derivatives.     

Indole and Isatin Oximes: Synthesis, Reactions, and Biological Activity. (Review)

Data on methods for the production of isatin and indole aldoximes, ketoximes, and amidoximes and their reactions are reviewed. Individual syntheses of new heterocycles from indole and isatin oximes are discussed. The principal results from investigation of the biological activity of derivatives of the oximes are also presented.     

Pyrroles from ketoximes and acetylene.

2-Aryl- and 1-viny1-2-pyrroles were synthesized by condensation of p-substituted acetophenone oximes with acetylene under pressure in superalkaline media (KOH/DMSO). The initially formed nitrogen-unsubstituted pyrroles can be vinylated in the presence of acetylene. Lithium hydroxide, which is completely inactive in the vinylation step, was found to be a selective catalyst for the construction of a pyrrole ring from oximes of aliphatic aromatic ketones. In the case of aliphatic and cycloaliphatic ketoximes (for example, cyclohexanone oxime) LiOH has virtually no catalytic effect on the reaction. The yields of 1-viny1-2-ary1-pyrroles depend substantially on the substituent in the phenyl ring. The structures of the synthesized compounds were confirmed by the IR, PMR, UV, and ¹³C NMR spectra.See [1] for communication II.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 489–491, April, 1978.     

Pyridine Oximes: Synthesis, Reactions, and Biological Activity. (Review)

Data on methods for the production of pyridine aldoximes, ketoximes, amidoximes, and their derivatives and their reactions are reviewed. The synthesis of new heterocycles from pyridine oximes is discussed separately. The principal results of research into the biological activity of the oximes are presented.     

Furan and Thiophene Oximes: Synthesis, Reactions, and Biological Activity. (Review)

Data on methods for the production of furan and thiophene aldoximes, ketoximes, and amidoximes and their reactions are reviewed. The synthesis of new heterocycles from furan and thiophene oximes and the biological activity of derivatives of the oximes are discussed individually.     

Quinoline Oximes: Synthesis,Reactions, and Biological Activity. (Review)

Data on the production and the reactions of quinoline aldoximes and ketoximes and their derivatives are reviewed. The synthesis of new heterocycles based on quinoline oximes is examined separately. The main results from investigation of the biological activity of quinoline oximes are presented.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 163–190, February, 2005.     

Electroreduction of aromatic oximes: diprotonation, adsorption, imine formation, and substituent effects

Aromatic oximes are reduced in aqueous solution in a four-electron process. The reducible species in the pH range 5-8 is a diprotonated form of the oxime. This species is generated in the course of electrolysis in the vicinity of the electrode surface from the adsorbed neutral form of the oxime. The reduction is initiated by a cleavage of the N-O bond. The diprotonation facilitates the reduction process by the preformation of OH2+ as a good leaving group and by a positive charge on the azomethine nitrogen. Diprotonation has been proven based on shapes of i = f(pH) plots, by observed shifts of half-wave potentials with pH and by comparison with the reduction of nitrones. Some observed deviations from theoretical i = f(pH) plots were attributed to the role of adsorption on the rate of protonation. Adsorption is also responsible for dips on some of the i-E curves. Adsorption plays a role at concentrations as low as 1 x 10(-5) M, when the electrode surface is still not fully covered. This indicates that catalyzed protonation occurs on islets of adsorbed materials. At pH 2-5 the studied oximes in the vicinity of the electrode are predominately present in a protonated form, which is less strongly adsorbed. In this pH range the protonation takes place in a homogeneous reaction layer of the electrode. It yields a monoprotonated form, which is reduced. The separation of two two-electron waves observed for some oximes in acidic media serves as an experimental proof of the formation of imines as reduction intermediates. This separation is caused by the differences in pKa values of protonated forms of oximes and imines. The effects of substituents in the para position on the benzene ring are characterized by correlation with the Hammett substituent constant sigmax. This has been proven at pH 1.5 for substituted benzaldehyde oximes and at pH 5.0 for substituted acetophenone oximes.     

Studies in pyran,its analogs,and related compounds

The lithium aluminum hydride reduction of the ethers and tosylates of chroman-4-one oxime and related compounds has been studied. It has been found that the ethers of the oximes, like the oximes, do not undergo a normal, but rather an anomalous, reduction. The tosylates of the oximes exhibit a higher tendency to undergo anomalous reduction than the corresponding oximes. During the synthesis of the ethers of the oximes it was established that the use of dimethylformamide as the medium for alkylation of the oxime salts helps to suppress the side reaction forming nitrones.For part XXXVII, see [23].     

Synthesis of acenaphtho[1,2-x]heterocycles and spiro[acenaphthylene 1-isoxazoles]

Methyl (Z)-(1,2-dihydro-2-oxo-1-acenaphthylenylidene)acetate 1 gives with hydroxylamine the oximes 2 and the pyrrole derivative 4 , whereas with hydrazines affords the pyridazinones 5 and 6 . A pyridazine derivative 8 is also isolated from the reaction of (1,2-dihydro-2-oxo-1-acenaphthylenylidene)acetone 7 with hydrazine hydrate. Reaction between the spiro-derivative 9 and hydroxylamine hydrochloride gives oxime 10 , whereas Wittig olefination of 9 with ylide 11 yields compound 12 which by reaction with 2,4,6-trimethylbenzonitrile oxide ( 13 ) affords the dispiro-derivatives 14 . Finally from the reaction of acenaphthylene-1,2-quinone ( 17 ) with the bisylide 16 the acenaphtho[1,2-c]thiophene ( 18 ) is formed.     

Oximes of five-membered heterocyclic compounds with three and four heteroatoms 2. Synthesis of derivatives,reactions, and biological activity (Review)

Data on the reactions of triazole, tetrazole, dioxazole, oxadiazole, and thiadiazole aldoximes, ketoximes, and amidoximes, their synthesis, and the reactions of their derivatives are reviewed. The synthesis of new heterocycles based on the oximes of five-membered heterocyclic compounds with three and four heteroatoms is examined separately. The principal results from investigation of the biological activity of ethers of these oximes are also presented. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 963–990, July, 2008.     

Photochemical radical cyclization of γ,δ-unsaturated ketone oximes to 3,4-dihydro-2H-pyrroles

3,4-Dihydro-2H-pyrroles are synthesized from γ, δ-unsaturated oximes by photochemical radical cyclization with 1,5-dimethoxynaphthalene (DMN) as the sensitizer. The cyclization of alkyl ketone O-acetyloximes proceeds via photosensitized electron transfer in the presence of acetic acid, while conjugated oximes of aryl and α,β-unsaturated ketones are cyclized via energy transfer.     

Pyrroles from ketoximes and acetylene. 19. Regioselectivity of the reaction of alkyl benzyl ketoximes with acetylene

Alkyl benzyl ketoximes react with acetylene at 60–150 °C in MOH-dimethyl sulfoxide (M = Li, K) primarily by means of the methylene group of the benzyl grouping, which is primarily anti-oriented with respect to the hydroxy group, to give 2-alkyl-3-phenylpyrroles in greater than 70% yields. The specific participation of the antimethylene group in the construction of a pyrrole ring constitutes evidence against mechanisms that include a [3,3]-sigmatropic shift in O-vinyl oximes. It follows from the results obtained that the reaction proceeds through an anti-dianion of the benzyl type stabilized by conjugation with the aromatic ring.See [1] for communication 18.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 193–198, February, 1982.     

取代查耳酮肟电化学氧化机理的研究

研究了７种取代查耳酮肟的电化学行为。用氢氧化钠底液热解石墨工作电极，取代查耳酮肟的电极过程为１ｅ氧化不可逆吸附电极过程。它们的氧化电位随取代基吸电子能力的增强而增高，并与它们相应的Ｈａｍｍｅｔｔ常数呈线性关系。取代查耳酮肟的电化学氧化机理为先失去一个电子生成ｉｍｉｎｏｘｙ自由基，然后由基对分子内烯键进行环化加成，脱氢后形成３，５－二聚代异恶唑。用控电位电解和紫外吸收光谱检测了部份电化学氧化产物，证     

Simultaneous determination of pirprofen and its metabolite, the pyrrole derivative, in plasma by high-performance liquid chromatography

A method for the simultaneous determination of pirprofen and its metabolite, the pyrrole derivative, in human plasma is described. The two compounds and the butyric acid analogue of the pyrrole derivative used as internal standard are extracted from plasma with chloroform, then back-extracted into an alkaline buffer. After addition of acid, the aqueous phase is assayed by high-performance liquid chromatography using a fixed-wavelength ultraviolet detector at 254 nm. The limit of quantitation is 0.1 micrograms/ml (0.396 mumol/l for pirprofen and 0.400 mumol/l for the pyrrole derivative).     

Theoretical study of anion binding to calix[4]pyrrole: the effects of solvent,fluorine substitution,cosolute, and water traces

The binding of different anions to calix[4]pyrrole has been studied by means of molecular dynamics coupled to thermodynamic integration calculations. The effect of different apolar solvents, octafluoro substitution, and the change in binding free energy derived from the presence of cosolute and water traces (the hydrated salt used to introduce the anion in the solution) were examined. Calculations allow us to rationalize the differential binding of ions to calix[4]pyrrole and octafluorocalix[4]pyrrole as well as to predict the behavior in new solvents for which experimental data are not available yet. It is found that both calix[4]pyrrole and octafluorocalix[4]pyrrole have a dramatic preference for F- in the gas phase and pure aprotic solvents, but the situation can change dramatically in protic solvents or in the presence of the hydrated cation which is used as cosolute of the anion. Overall, our results provide interesting clues for a better understanding of the process detected experimentally as "binding".     

Tetrathiafulvalene-calix[4]pyrroles: synthesis, anion binding, and electrochemical properties

The syntheses of monotetrathiafulvalene-calix[4]pyrrole 5 and bistetrathiafulvalene-calix[4]pyrrole 6, prepared from the acid-catalyzed condensation of monopyrrolo[3,4-d]tetrathiafulvalene (MPTTF, 7) with acetone in the presence of tripyrrane 8 and dipyrromethane 9, respectively, are described. Compound 5 and the previously reported tetrathiafulvalene-calix[4]pyrrole 4 both adopt a 1,3-alternative conformation in the solid state, as determined from X-ray crystallographic analysis. The anion binding properties of the tetrathiafulvalene-calix[4]pyrroles 5 and 6, as well as those of the parent meso-octamethylcalix[4]pyrrole (1), were investigated in acetone using (1)H NMR spectroscopic and isothermal titration calorimetry (ITC) techniques and, within the error limits of the methods, were generally found to give concordant results. On the basis of the results of the ITC studies carried out in 1,2-dichloroethane, increasing the number of tetrathiafulvalene units annulated to the calix[4]pyrrole system serves to enhance the anion binding affinities substantially but at the price of lowered selectivity. Cyclic voltammetry (CV) studies, carried out in 1,2-dichloroethane, provided evidence of an anion-dependent electrochemical response with Cl(-) and Br(-) ions. This response was particularly dramatic in the case of the monotetrathiafulvalene-calix[4]pyrrole 5, with a DeltaE(max) of -145 mV being seen after the addition of approximately 1 equiv of Cl(-) ion.     

取代苯甲醛肟和取代苯乙酮肟电化学氧化机理的研究

研究了１０种取代苯甲醛肟和５种取代苯乙酮肟的电化学氧化机理。这二类肟的氧化电位随取代基吸电子能力的增大而增高，并与它们相应的Ｈａｍｍｅｔｔ常数有线性关系。它们在电化学氧化过程中均有ｉｍｉｎｏｘｙ自由基生成，但最后产物各不相同。用控制电位电解和紫外吸收光谱检法验证了部分电化学氧化产物。因此，电化学氧化法可作为由肟类产生ｉｍｉｎｏｘｙ自由基的一种方法。