Mechanism of the second sulfenylation of indole

Sulfenylation of indole using a sulfenyl chloride occurs initially at the 3-position of the ring, leading to a 3-indolyl sulfide. When an excess of sulfenyl chloride is used, a second sulfide group is introduced at the 2-position, and an indolyl 2,3-bis-sulfide results. We have demonstrated that this second sulfenylation occurs not by direct introduction of the second sulfide at the 2-position but via initial formation of an indolenium 3,3-bis-sulfide intermediate, followed by migration of one of the sulfide groups to the 2-position. This was achieved by the isolation of two examples of 3H-indole 3,3-bis-sulfides and by subsequent demonstration that they rearrange to the indolyl 2,3-bis-sulfides by treatment with sulfenyl halides.     

Directed oxidative cyclizations to C2- or C4-positions of indole: efficient construction of the bicyclo[4.3.1]decane core of welwitindolinones

Regiocontrolled oxidative cyclizations of 3-substituted indoles are described herein. Specifically, it is shown that the installation of a chloride at C2 alters the inherent propensity for cyclization at the 2-position of indole so as to favor the 4-position, enabling the construction of the unique framework found in most welwitindolinone alkaloids. The chloride functions here as more than a blocking group, as it also provides ready access to the corresponding oxindole.     

Synthesis and spectral properties of polymethine-cyanine dye-nitroxide radical hybrid compounds for use as fluorescence probes to monitor reducing species and radicals

Various hybrid compounds comprised of two types of nitroxide radicals and either a pentamethine (Cy5) or trimethine cyanine (Cy3) were synthesized. The nitroxide radicals were linked either via an ester-bond to one or two N-alkyl carboxyl-terminated groups of Cy5, or via two amido-bonds (aminocarbonyl or carbonylamino group) to the 5-position of the indolenine moieties of Cy5 and Cy3. Changes in fluorescence and ESR intensities of the hybrid compounds were measured before and after addition of Na ascorbate in PBS (pH 7.0) to reduce the radicals. Among the hybrid compounds synthesized, those that linked the nitroxide radicals via an aminocarbonyl residue at the 5-position of the indolenine moieties on Cy5 and Cy3 exhibited a 1.8- and 5.1-fold increase in fluorescence intensity with the reduction of the nitroxide segment by the addition of Na ascorbate, respectively. In contrast, fluorescence intensity was not enhanced in the other hybrid compounds. Thus, the hybrid compounds which exhibited an increase in fluorescent intensity with radical reduction can be used in the quantitative measurement of reducing species such as Fe(2+) and ascorbic acid, and hydroxyl radicals. Because these hybrid compounds have the advantage of fluorescing at longer wavelengths-661 (Cy5) or 568 (Cy3)nm, respectively, they can be used to measure radical-reducing species or radicals either in solution or in vivo.     

Synthetic studies of decursivine derivatives: preparation of key indole alkaloids via α-hydroxyalkylation

2-Hydroxyacetyl indole modified at C-3 position was prepared with an eye to developing a total synthesis of decursivine derivatives (decursivine, serotobenine, moschaminindolol, and flavumindole). The indole was prepared through a sequence of oxalyl chloride introduction at C-3 position of indole and acid chloride reduction with tributyltin hydride. In addition, we report a novel synthesis of fully functionalized Uhle's ketone via ortho-selective α-hydroxyalkylation.     

Synthesis and biological activity of N-(aminoiminomethyl)-1H-indole carboxamide derivatives as Na+/H+ exchanger inhibitors

A series of N-(aminoiminomethyl)-1H-indole carboxamide derivatives were synthesized and their inhibitory potencies against the Na+/H+ exchanger were measured. Variation of the carbonylguanidine group at the 2- to 7-position of the indole ring system showed that a substitution at the 2-position improved the Na+/H+ exchanger inhibitory activity the most in vitro. This led to the synthesis and evaluation of an extensive series of N-(aminoiminomethyl)-1H-indole-2-carboxamide derivatives. Derivatives having an alkyl or substituted alkyl group at the 1-position of the indole ring system showed higher levels of in vitro activities. N-(aminoiminomethyl)- 1-(2-phenylethyl)-1H-indole-2-carboxamide (49) had the strongest activity.     

Metabolic fates of L-tryptophan in Saccharomyces uvarum (Saccharomyces carlsbergensis).

The metabolism of L-tryptophan by Saccharomyces uvarum (carlsbergensis) was investigated by simultaneous measuring of fluxes through kynureninase, through transaminases and into protein using L-[methylene-14C] and L-[side chain-2,3-3H]tryptophan. In yeasts cultivated in synthetic medium (S medium), the flux into protein was predominant, closely followed by the flux leading to 2-3H liberation. The proportion of L-tryptophan metabolized via the latter flux increased over 10-fold (75% of total tryptophan metabolized) as the concentration of L-tryptophan was raised from 5 x 10(-5) to 5 x 10(-4) M. L-Tryptophan metabolized via the kynureninase flux was less than 5% of total tryptophan metabolized. In yeast extract-polypepton-glucose medium (YPG medium), more tryptophan was incorporated into protein than in the S medium. Contribution of the kynureninase flux remained very low. Tryptophan metabolism via each flux changed depending on the growth phase. 2-3H liberation was shown to be primarily due to tryptophol synthesis by high performance liquid chromatography (HPLC) and nuclear magnetic resonance (NMR), indole-3-acetic acid and kynurenic acid also contributing to 2-3H liberation but to a much lesser extent. 2-3H liberation increased dose-dependently at tryptophan concentration higher than 10(-5)M, while the kynureninase flux reached its plateau at 10(-5)M. Formation of tryptophol and indole-3-acetic acid via indole-3-pyruvic acid and indole-3-acetaldehyde with indole aldehyde as a by-product was confirmed using exogenous tryptophan metabolites with indole rings.     

Reactivities of vinyl derivatives of 3-mercaptoindole in reactions with alcohols

The addition of alcohols to 1-vinyl-3-vinylmercapto- and 1-vinyl-3-ethylmercaptoindole was accomplished in the presence of cobalt chloride. It was established that in the case of the divinyl derivative the addition of alcohols takes place only at the vinyl group attached to the nitrogen atom to give 1-(α-alkoxyethyl)-3-vinylmercaptoindoles. The relative reactivities of the vinylmercaptoindoles as a function of the substituent in the 3-position of the indole ring were studied kinetically. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 766–768, June, 1980.     

Enhancing effect of alcoholic solvent on hydrosulfite-hydrogen peroxide chemiluminescence system

In this work, a chemiluminescence (CL) reaction between hydrogen peroxide (H(2)O(2)) and sodium hydrosulfite (NaHSO(3)) was developed. Hydroxyl radical ((?)OH) and sulfite radical ((?)SO(3)(-)) were the main intermediates generated in the NaHSO(3)-H(2)O(2) CL system. Inhibition effects of radical scavengers such as thiourea, chloride ion, nitro blue tetrazolium chloride (NBT), and 5,5-dimethyl-1-pyrroline N-oxide (DMPO) indicated the existence of these two radicals. Singlet oxygen ((1)O(2)) and excited sulfur dioxide (SO(2)*) were emitting species involved in NaHSO(3)-H(2)O(2) CL system. (1)O(2) were confirmed by 1,4-diazobicyclo[2,2,2]octane (DABCO) and sodium azide (NaN(3)), which were specific (1)O(2) scavengers. In addition, electron spin resonance (ESR) spectra clearly show the existence of (1)O(2) and (?)OH. Alcoholic solvent, especially n-butanol, enhanced the ultraweak CL emission more than 40 times. The enhancing effect of alcoholic solvent on NaHSO(3)-H(2)O(2) CL system was ascribed to the formation of solvent cage, which can accelerate the reaction rate and protect the emitting species from quenching by water. The CL emission of the NaHSO(3)-n-butanol-H(2)O(2) system was measured by cutoff filters. The maximum wavelength was located around 490 nm, which belongs to (1)O(2). The wide peak from 400 to 600 nm is the characteristic peak of SO(2)*.     

Regioselective Synthesis of Mixed Indole 2,3-Bis(sulfides). A Study of the Mechanism of the Second Sulfenylation of Indole

Sulfenylation of indole using sulfenyl chlorides leads to the initial formation of a 3-indolyl sulfide, while excess reagent introduces a second sulfide at the 2-position of the ring. The mechanism of this second sulfenylation has not, to date, been rigorously elucidated. The development of the first, regioselective synthesis of mixed indole 2,3-bis(sulfides) has allowed the study of the sulfenylation of 3-indolyl sulfides using a different sulfenyl chloride. Our results afford evidence that the reaction proceeds via an intermediate 3,3-disulfenylated indolenine species, with subsequent migration of one of the sulfide groups to the 2-position.     

Cyclopalladation of the indole ring in palladium(II) complexes of 2N1O-donor ligands and its dependence on the O-donor properties

Synthetic, structural, spectroscopic, and kinetic studies have been carried out on the Pd(II) complexes of new 2N1O-donor ligands containing a pendent indole, 3-(N-2-pyridylmethyl-N-2-hydroxy-5-methoxybenzylamino)ethylindole (HMeO-iepp), 3-(N-2-pyridylmethyl-N-2-hydroxy-5-nitrobenzylamino)ethylindole (HNO2-iepp), and (N-2-pyridylmethyl-3-indolylethylamino)acetic acid (Hiepc) (H denotes a dissociable proton). [Pd(MeO-iepp)Cl] (2), [Pd(NO2-iepp)Cl] (3), and [Pd(iepc)Cl] (4) were prepared and revealed by X-ray analysis to have a pyridine nitrogen, an amine nitrogen, a phenolate or carboxylate oxygen, and a chloride ion in the coordination plane. UV absorption and 1H NMR spectral changes indicated that all the complexes could be converted to the indole-binding complexes where the O donor was replaced by the indole C2 atom by cyclopalladation in DMSO or DMF in the temperature range of 40-60 degrees C. Formation of the indole-binding complex species obeyed the first-order kinetics, from which the activation parameters were estimated. The formation rate was dependent on the properties of the O-donor group, a lower pKa value of its conjugate acid causing faster conversion to the indole-binding species in the order 2 (methoxyphenolate) < 3 (nitrophenolate) < 4 (carboxylate). On the other hand, the ratio of the indole-binding complex to the O-donor complex as a result of the conversion was greater for the complexes with a higher pKa value of the ligand OH group, the order being 2 > 3 > 4.     

Three-coordinate organoboron with a B=N bond: substituent effects, luminescence/electroluminescence and reactions with fluoride

Five new three-coordinate boron compounds with a B=N bond involving an indole or a substituted indole ligand including B(mesityl)2(indolyl), (1), B(mesityl)2(2-Me-indolyl), (2), B(mesityl)2(3-Me-indolyl), (3), B(mesityl)2 (7-Me-indolyl), (4), and B(mesityl)2(3-Ph-indolyl), (5) have been synthesized. The structures of these new compounds were determined by X-ray diffraction analyses. All five compounds are luminescent involving a charge transfer transition between the indolyl pi orbital and the boron p(pi) orbital. The substituent group on the indolyl ring was found to have a subtle impact on the electronic properties of compounds. NMR experiments established that the methyl group at the 7-position of indole is most effective in blocking the rotation of the mesityl group around the B-C bond. The addition of fluoride ions to this group of compounds causes luminescent quenching and an irreversible decomposition of the compounds due to the reaction of the F- adduct with water molecules. The potential use of this group of compounds as blue emitters in electroluminescent (EL) devices was demonstrated by the successful fabrication of a four-layer EL device where 1 was used as the emitter. The EL device displays a blue emission with a maximum luminescence being 1037 cd m(-2) and a maximum current efficiency about 0.7 cd A(-1) at 5 V.     

Biosynthesis of violacein: a genuine intermediate, protoviolaceinic acid, produced by VioABDE, and insight into VioC function

A biosynthetic intermediate of violacein produced by the mixed enzymes of VioABDE was elucidated to be 5-(5-hydroxy-1H-indol-3-yl)-3-(1H-indol-3-yl)-1H-pyrrole-2-carboxylic acid, named protoviolaceinic acid, indicating that VioC, responsible for the final biosynthetic step, works to oxygenate at the 2-position of the right side indole ring, and that the oxygenation reaction to form the central pyrrolidone core proceeds in a non-enzymatic fashion.     

Synthesis of 2-[2H]-2-(1-methylalkyl)succinic acids

We describe a specific procedure for the synthesis of deuterium-labelled 2-(1-methylalkyl)succinate established via alkylation of diethyl malonate,Krapcho decarboxylation reaction with D_2O and hydrolysis reaction.Two novel compounds,2-[~2H]-2-ethylsuccinic acid and 2-[~2H]-2-(1-methylheptyl)succinic acid were prepared via this synthetic route and characterized by mass spectrometry and 'H NMR.The results showed that the 2-(1-methylalkyl)succinic acids were deuterated at the β-position,which is considered as an important reaction centre in the anaerobic degradation of n-alkanes.     

Effect of formic acid addition on water cluster stability and structure

Computational chemistry simulations were performed to determine the effect that the addition of a single formic acid molecule has on the structure and stability of protonated water clusters. Previous experimental studies showed that addition of formic acid to protonated pure water results in higher intensities of large-sized clusters when compared to pure water and methanol-water mixed clusters. For larger, protonated clusters, molecular dynamics simulations were performed on H(+)(H(2)O)(n), H(+)(H(2)O)(n)CH(3)OH, and H(+)(H(2)O)(n)CHOOH clusters, 19-28 molecules in size, using a reactive force field (ReaxFF). Based on these computations, formic acid-water clusters were found to have significantly higher binding energies per molecule. Addition of formic acid to a water cluster was found to alter the structure of the hydrogen-bonding network, creating selective sites within the cluster, enabling the formation of new hydrogen bonds, and increasing both the stability of the cluster and its rate of growth.     

Convenient synthesis of melatonin analogues: 2- and 3-substituted -N-acetylindolylalkylamines

A new method for the synthesis of 2- and 3-substituted indolylalkylamides, derivatives of melatonin, from arylhydrazines and amidoketones by the Fischer reaction was elaborated. The amidoketones can be easily prepared from cyclic imines by reaction with acylpyridinium chloride. This method is a one-step synchronous creation of the selected alkylamide fragment and the indole core. Variation of the arylhydrazines create the desired substituents in the carbocycle of indolylalkylamides and suitable choice of amidoketone can direct the amidoalkyl chain to the 2- or 3-position of the indole.     

Chemiluminescence change of polyphenol dendrimers with different core molecules

Second generation polyphenol dendrimers (PDs) with different core molecules were synthesized, and their chemiluminescence (CL) was measured by reacting the PDs with H2O2 under alkaline conditions. All of the PDs showed a strong CL, more than 120-fold greater than that of gallic acid. Various CL intensities of the PDs were obtained using different core molecules in the PDs. The distance between each dendron in the PD structure is crucial in the PD CL intensity.     

Epoxidation of allyl chloride with H_2O_2 on Ti-ZSM-5 prepared by the isomorphous substitution

The epoxidation of allyl chloride with H2O2 on Ti-ZSM-5 prepared by isomorphous substitution of HZSM-5 with TiCl4 gas was studied. The results show that Ti-ZSM-5 has a high catalytic efficiency for the epoxidation of allyl chloride. The H2O2 utilization reaches 99.50% when the allyl chloride/H2O2 molar ratio is > 1. The effect of solvent species, catalyst concentration, H2O2 and allyl chloride concentration and reaction temperature on the epoxidation was investigated simultaneously. It is found that methanol is the best solvent for the reaction. The reaction rate equation with v = k[Cat. ] [H2O2]1/2-[C3H5Cl] and the apparent activation energy with Ea = 63.462 kJ/mol are obtained according to the kinetics study.     

Peroxomolybdate(VI)-citrate and -malate complex interconversions by pH-dependence. Synthetic, structural and spectroscopic studies

The reaction of potassium molybdate(VI) with biologically relevant ligands, citric and malic acids, in the presence of H2O2 was investigated for the effect of pH variations on the product pattern. That with citric acid led to the formation of the monomeric complex K4[MoO(O2)2(cit)].4H2O (1) in the pH range 7-9, and dimer K5[MoO(O2)(2-)(Hcit)H(Hcit)(O2)2OMo].6H2O (2) (H4cit = citric acid) at pH 3-6 through carboxylate-carboxylic acid hydrogen bonding. The relation with the previously identified K4[MoO3(cit)].2H2O (4) and K4[Mo2O5(Hcit)2].4H2O (5) were shown. These and other intermediates were shown to react in the pH range 3-6 to give a more stable species 2; the reaction sequence was demonstrated either by the protonation from 1 or the deprotonation of [MoO(O2)2(H2cit)](2-) (8). Evidence that 2 exists as a dimer in solution is presented. The reaction with (S)-malic acid afforded Delta-K(2n)[MoO(O2)2((S)-Hmal)]n.nH2O (3) (H3mal = malic acid) that was oxidized further to oxalato molybdate (11) by H2O2. The three complexes 1-3 were characterized by elemental analysis, UV, IR and NMR spectroscopies, in addition to the X-ray structural studies that show citrate and malate being coordinated as bidentate ligands via alpha-alkoxyl and alpha-carboxylate groups. The formation of these complexes is dictated by pH and their thermal stabilities varied with the coordinated hydroxycarboxylate ligands.     

Oligomerization of indole derivatives with incorporation of thiols

Two molecules of indole derivative, e.g. indole-5-carboxylic acid, reacted with one molecule of thiol, e.g. 1,2-ethanedithiol, in the presence of trifluoroacetic acid to yield adducts such as 3-[2-(2-amino-5-carboxyphenyl)-1-(2-mercaptoethylthio)ethyl]-1Hindole-5-carboxylic acid. Parallel formation of dimers, such as 2,3-dihydro-1H,1'H-2,3'-biindole-5,5'-dicarboxylic acid and trimers, such as 3,3'-[2-(2-amino-5-carboxyphenyl) ethane-1,1-diyl]bis(1H-indole-5-carboxylic acid) of the indole derivatives was also observed. Reaction of a mixture of indole and indole-5-carboxylic acid with 2-phenylethanethiol proceeded in a regioselective way, affording 3-[2-(2-aminophenyl)-1-(phenethylthio)ethyl]-1H-indole-5-carboxylic acid. An additional product of this reaction was 3-[2-(2-aminophenyl)-1-(phenethylthio)ethyl]-2,3-dihydro-1H,1'H-2,3'-biindole-5'-carboxylic acid, which upon standing in DMSO-d6 solution gave 3-[2-(2-aminophenyl)-1-(phenethylthio)ethyl]-1H,1'H-2,3'-biindole-5'-carboxylic acid. Structures of all compounds were elucidated by NMR, and a mechanism for their formation was suggested.     

Tautomerization of α,β-and β,γ-unsaturated phosphonium salts resulting from the reaction of triphenylphosphine with β-bromomethacrylic acid. Nucleophilic addition at the γ position of the allyl group in phosphonium salt

Temperature factor was found to be determining in the isomerization of 2-carboxyprop-1-en-1-yl-and 2-carboxyprop-2-en-1-yl(triphenyl)phosphonium bromides. Elevated temperature favors formation of isomer with the double bond in the β,γ position with respect to the phosphonium group. Alkaline hydrolysis at room temperature promotes the reverse isomerization. The isomerization of 2-carboxyprop-1-en-1-yl(triphenyl)phosphonium bromide is hampered by addition of hydrobromic acid, as well as by carrying out its synthesis in the presence of aqueous HBr. Alkaline hydrolysis of 2-carboxyprop-1-enyl(triphenyl)phosphonium bromide and (E)-(2-carboxyvinyl)triphenylphosphonium chloride is accompanied by phenyl group migration to the α-position with formation of 2-methyl-3-(diphenylphosphoryl)-3-phenylpropionic acid and 3-(diphenyl-phosphoryl)-3-phenylpropionic acid, respectively. The possibility for nucleophilic addition at the γ position of the allyl group in 2-carboxyprop-2-enyl(triphenyl)phosphonium bromide was demonstrated using the reaction with triphenylphosphine as an example.