Methylthio Substituents Research Articles

Altering the Acidity and Solution Properties of Bilirubin. Methoxy and Methylthio Substituents

Substitution of electron-withdrawing groups at the alpha-position of an aliphatic carboxylic acid can be expected to increase the acidity of the acid. Methoxy and methylthio groups are especially effective; they increase the acidity of acetic acid by approximately 1.1 pK(a) units. Bilirubin, the water-insoluble pigment of jaundice, has two propionic acids, and an alpha-methoxy or alpha-methylthio substituent in each propionic acid can be expected to lower the pK(a) similarly and thus alter its solubility properties. (A previously synthesized analogue, alpha,alpha'-difluororubin (4), is soluble in water.) Two new analogues of bilirubin, alpha,alpha'-dimethoxyrubin (1) and alpha,alpha'-bis(methylthio)rubin (2), have been synthesized, separated into diastereomers, and analyzed. The isomers are shown by NMR to adopt intramolecularly hydrogen-bonded ridge-tile-shaped conformations. Like bilirubin, both 1 and 2 are insoluble in water. Unlike bilirubin, 1 is soluble in dilute aqueous bicarbonate, but 2 is insoluble, which would not be predicted from the expectation that 1 and 2 have the same pK(a). The data hint at a much larger steric size of SCH(3) relative to OCH(3).

β,β-Disubstituted oligothiophenes, a new oligomeric approach towards the synthesis of conducting polymers

Abstract The electropolymerization of methylthio-substituted oligothiophenes 2 – 4 has been studied. Theoretical and experimental results reveal that only 4,4′-disubstituted derivatives yield polymeric films. The reason for this is that electron-donating methylthio (=methylsulphonyl) substituents in the ‘outer’ β -positions of the starting compounds 2 – 4 , which cause high spin densities at the corresponding α -C atoms, favour fast coupling steps between the reacting oligomers during all stages of the electropolymerization. All data clearly indicate that the electropolymerization of donor-substituted thiophenes is not a chain propagation process but a series of successive ‘dimerization’ steps. The resulting polymers have been characterized by voltammetric measurements, in situ conductivity experiments and spectroelectrochemistry.

Dimethyl ether chemical ionization mass spectrometry of alpha-amino acids.

Dimethyl ether (DME) is a useful reagent gas for the characterization of a variety of diverse biologically important or environmentally significant classes of compounds. In this work the gas-phase ion-molecule reactions of DME with 23 alpha-amino acids were investigated and the collision-induced dissociation (CID) fragmentations of the protonated molecules and their most prominent adduct ions were studied. The identities and relative abundances of the adduct ions varied widely and, not unexpectedly, were dependent on the nature of the R substituent in H2NCH(R)CO2H. With a few exceptions, notably serine and threonine, protonated molecules and [M + 13]+ adduct ions were highly abundant, and in most cases methoxymethylene cations [M + 45]+ were also prominent. The solvated methoxymethylene cation [M + 91]+ was seen in very modest abundance or not at all, except for serine and threonine, when it was the most abundant. CID fragmentations of the protonated molecules generated in the DME plasma showed similar characteristics to those generated by fast atom bombardment in that sequential elimination of H2O and CO to the iminium ion was the predominant process in the majority of cases, and was also accompanied by the loss of NH3 in the cases of cysteine, glutamine, ornithine and lysine. Loss of NH3 alone was the predominant process for tryptophan, and for arginine and methionine the fragmentations were dominated by the guanidino and methylthio substituents, respectively.

Synthesis of isobatzelline B

6,7-Dimethoxy-4-methylquinoline has been converted in nine steps into the sulfur-containing pyrrolo[4,3,2- de]quinoline marine alkaloid isobatzelline B. This constitutes the first total synthesis of an alkaloid of the group which contains a methylthio substituent.

Active Site Models for Galactose Oxidase. Electronic Effect of the Thioether Group in the Novel Organic Cofactor.

The electronic effect of the thioether linkage between Tyr 272 and Cys 228 (the novel organic cofactor) of galactose oxidase has been examined by using model compounds, 2-(methylthio)-p-cresol (1H), 2-(methylthio)-4,6-dimethylphenol (2H), and 2-(methylthio)-4-methyl-6-[[bis[2-(2-pyridyl)ethyl]amino]methyl]phenol (3H), the physicochemical properties of which are compared to those of 2-[[bis[2-(2-pyridyl)ethyl]amino]methyl]-4-methylphenol (4H) and p-cresol (5H). (1)H NMR and electrochemical studies indicate that the methylthio group has essentially an electron-donating nature. On the other hand, the lower pK(a) values of 1H and 2H as compared to that of 5H suggest that the methylthio group also has a 2ppi-3dpi electron conjugative effect, stabilizing the negative charge on the phenolate oxygen. Furthermore, the electron-sharing conjugative effect of the substituent in the radical state has been clearly demonstrated by ESR studies and semiempirical molecular orbital calculations. Dimer copper(II) complexes [Cu(II)(2)(3(-)())(2)](PF(6))(2) (7) and [Cu(II)(2)(4(-)())(2)](PF(6))(2) (8) were prepared, and the crystal structures were determined by the X-ray diffraction method. Electrochemical analyses of the monomeric species [Cu(II)(3(-)())(py)](PF(6)) (9) and [Cu(II)(4(-)())(py)](PF(6)) (10) generated in situ by adding an external ligand such as pyridine (py) reveal that the methylthio substituent in the copper complex shows electronic effects similar to those of the free ligand stabilizing the phenoxyl radical state of the cofactor moiety in the Cu(II) complex.

Synthesis and structure-activity relationship of pyrazolo[3,4-d]pyrimidines: potent and selective adenosine A1 receptor antagonists.

A series of 12 substituted 1-phenylpyrazolo[3,4-d]pyrimidines were synthesized and evaluated for rat brain adenosine A1 and A2a receptor binding affinity. Substituents at C-4 and C-6 were varied in order to define these regions in terms of molecular recognition by the receptor subtypes. At C-4, the effects of a mercapto, methylthio, and amino substituent were evaluated, while at C-6, amides with varying alkyl groups extending from the alpha-carbon were examined. This study identified both potent and selective adenosine A1 receptor antagonists. The most potent of the 12 compounds was alpha-[(4-amino-1-phenylpyrazolo[3,4-d]pyrimidin-6-yl)thio]hexanamide (14); with an A1 Ki of 0.939 nM and an A2a Ki of 88.3 nM, this compound is 94-fold A1 selective. The most selective of the 12 compounds was alpha-[[4-(methylthio)-1-phenylpyrazolo[3,4-d]pyrimidin-6-yl]thio]hex anamide (10); with an A1 Ki of 6.81 nM and an A2a Ki > 40 000 nM, this compound is > 5900-fold A1 selective. The structure-activity relationships for the complete series has identified discrete structural differences between the A1 and A2a receptors with respect to the binding of pyrazolo[3,4-d]pyrimidines. This study resulted in prediction that increased A1 affinity could be achieved by incorporation of NH-alkyl substituents at C-4. This was confirmed by synthesis of alpha-[[4-(methylamino)-1-phenylpyrazolo[3,4-d]pyrimidin-6-yl]thiol] hexanamide (15) which was found to have an A1 Ki of 0.745 nM.

1-Acetyl-5-benzyl-2-methylthio-5H-imidazol-4-one

Atoms of the imidazolone ring in the title compound, C 13 H 14 N 2 O 2 S, are approximately coplanar. The N(1) acetyl group lies close to the plane while the C(2) methylthio substituent is twisted by about 7 o from it. The imidazolone and phenyl rings face each other, the dihedral angle between their perpendiculars being 53.4 (3) o

Comparison of bipolaron-like charge state generation in the oxidative doping of α,ω-dithienyl and α,ω-diphenyl polyenes stabilized by methoxy and methylthio substituents

Several α,ω-dithienyl and diphenyl polyenes substituted with mesomerically interactive methylthio substituents have been synthesized by Wittig condensation. These polyenes can be oxidatively doped with SbCl5 in solution to yield stable bipolaron-like charge states. The methylthio-substituted bipolaron spectra are considerably more red-shifted in the diphenyl polyene series than the methoxy-substituted counterparts, or the methylthiothienyl series. The potential of these states for enhanced non-linear optical response is presented.

Quinazoline antifolates inhibiting thymidylate synthase: 4-thio-substituted analogs

We report the synthesis of four new 4-thio-5,8-dideazafolic acid analogues and a 4-(methylthio) analogue structurally related to the thymidylate synthase (TS) inhibitor N10-propargyl-5,8-dideazafolic acid. Three N10-propargyl-4-thio-5,8-dideazafolic acid analogues had C2 amino, hydrogen, and methyl substituents. A 4-thio and a 4-(methylthio) compound each with hydrogen at C2 and ethyl at N10 were also synthesized. In general, the synthetic route involved thionation of the appropriate 4-oxoquinazoline; the sulfur thus introduced was then protected by methylation. Further protection with a pivaloyl group was required for the quinazoline bearing a 2-amino substituent. The protected quinazolines were treated with N-bromosuccinimide and the resulting 6-(bromomethyl) compounds were then coupled to the appropriate N-monoalkylated diethyl N-(4-aminobenzoyl)-L-glutamate in N,N-dimethylacetamide with calcium carbonate as base. The 4-thio-5,8-dideazafolic acids were obtained by removal of the methylthio group with sodium hydrosulfide, followed by deprotection of the carboxyl groups with cold dilute alkali. For the compound containing a pivaloyl protecting group, hot dilute alkali was used. To obtain the 5,8-dideazafolic acid containing a 4-(methylthio) substituent, the corresponding diester was treated with lithium hydroxide which selectively deprotected the carboxyl groups. The five compounds were tested as inhibitors of L1210 TS. It was found that replacement of the 4-oxygen of the quinazoline moiety by sulfur did not alter the TS inhibition. However, the introduction of a methylthio substituent at position 4 severely impaired TS inhibition. All 4-thio compounds were less cytotoxic to L1210 cells in culture than their 4-oxo counterparts.

Orally active aldose reductase inhibitors derived from bioisosteric substitutions on tolrestat

A series of aldose reductase inhibitors was prepared in which structural modifications were made to three positions of the potent, orally active inhibitor tolrestat (1), namely, the 6-methoxy substituent, thioamide sulfur, and the N-methyl moiety. These compounds were evaluated in two in vitro systems: an isolated enzyme preparation from bovine lens to assess their intrinsic inhibitory activity and an isolated rat sciatic nerve assay to determine their ability to penetrate membranes of nerve tissue. These compounds were also evaluated in vivo as inhibitors of galactitol accumulation in the lens, sciatic nerve, and diaphragm of galactose-fed rats. Bioisosteric replacement of the 6-methoxy group of 1 with a methylthio substituent gave 5, and replacement of the thioamide substituent of 1 with a cyanoamidine gave 7. Both 5 and 7 retained high in vitro potency but were less potent in vivo than 1. Replacement of the tolrestat N-methyl group by a carbomethoxy moiety gave 10 and led to a substantial reduction in activity in each of the three assays employed. However, this same structural modification on oxo-tolrestat (2) led to 11 and resulted in an enhancement of the intrinsic activity and a comparable in vivo potency. The isolated nerve data suggest that some compounds in these series do not readily penetrate into peripheral nerves, and this presumably is a factor in their lack of oral activity.

The directing ability of the methylthio substituent in lithiation reactions of thiophenes

The directing ability of the methylthio substituent in lithiation reactions of thiophenes

Synthesis of aryl methylthio ethers employing α-oxoketene dithioacetals

Abstract Reaction of α-oxoketene dithioacetals with methallyl magnesium chloride followed by acid treatment affords simple and annulated aryl methylthio ethers. The methylthio substituent can be easily removed with Raney Ni, undergo a Ni catalyzed substitution reaction with Grignard reagents, or serve as a directing and protecting group in Friedel-Crafts acylation reactions.

Synthetic approaches to haplophytine. 2. Synthesis of 4-methylamino-1-(2-furanyl)-2-phenyl-2-(2-pivaloylamidophenyl)butan-1-one

Approaches to the synthesis of compounds related to the 7-aryl-7-[3-(1-hydroxy-2-aminophenyl)]-9-methylamino-5,6-dioxononanoic acid moiety (3) of the alkaloid haplophytine and its dihydrobromide are described. Treatment of the dianion of phenyl (o-pivaloylamidophenyl)methane with 2-furancarboxaldehyde followed by oxidation of the resulting alcohol gives 1-(2-furanyl)-2-phenyl-2-(2-pivaloylamidophenyl)ethanone (14). This on allylation gives 1-allyloxy-1-(2-furanyl)-2-phenyl-2-(2-pivaloylamidophenyl)ethene (20), which on being heated at 80–95 °C undergoes an intramolecular Diels–Alder reaction. Heating the resulting product or 20 at 165 °C converts them to the C-allylation product of 14, 1-(2-furanyl)-2-phenyl-2-(2-pivaloylamidophenyl)pent-4-en-1-one (22). Oxidation of 22 gives 4-(2-furoyl)-1,2,3,4-tetrahydro-4-phenyl-1-pivaloyl-2-quinolinol, which on Borch reduction gives 4-methylamino-1-(2-furanyl)-2-phenyl-2-(2-pivaloylamidophenyl)butan-1-one (24) and 2-(2-furanyl)-1-methyl-3-phenyl-3-(2-pivaloylamidophenyl)pyrrolidine. Compound 24 is a potential advanced intermediate for the synthesis of compounds related to 3. Experiments directed to the incorporation of a methoxyl or methylthio substituent at the C-5 position of the furan ring of 24 are also described.

2‐Methylthio‐7‐desazainosin und sein α‐Anomer — Debenzylierung von Thionucleosiden mit Bortrichlorid

2‐Methylthio‐7‐deazainosine and its α‐Anomer — Debenzylation of Thionucleosides with Boron TrichlorideDebenzylation of the sugar moiety of pyrrolo[2,3‐d]pyrimidine nucleosides without affecting methoxy or methylthio substituents of the chromophore has been accomplished by the action of boron trichloride/dichloromethane at — 78°C. Applying this method to the protected derivatives 1b or 2b the methylthio nucleosides 3 and 4 were obtained in high yields.

ChemInform Abstract: ANTIMALARIALS. 9. METHYLTHIO‐ AND METHYLSULFONYL‐SUBSTITUTED 9‐PHENANTHRENEMETHANOLS

AbstractPhenylessigsäuren (I) und 2‐Nitro‐benzaldehyde (II) werden zu Stilbenen (III) kondensiert, die dann nach Pschorr zu den Phenanthrenen (IV) cyclisiert werden.

Synthesis and pharmacological properties of 4-piperazino-5-methylthiopyrimidines. Selection of new antiemetic agents.

We have synthetized a series of 22 new 4-piperazinopyrimidines bearing a methylthio substituent in the 5 position of the pyrimidine ring. These compounds have been obtained by separation of the isomers formed during nucleophilic attack of the corresponding 2,4,6-trichloropyrimidine by amines. Pharmacological screening has shown that this chemical series displays a very interesting profile, which includes antiemetic, tranquilizing, analgesic, antiserotonin, and musculotropic-spasmolytic properties. We have particularly selected for clinical investigations two compounds with powerful antiemetic activity: 2-methylamino-4-(N-methylpiperazino)-5-methylthio-6-chloropyrimidine and 2-isopropylamino-4-(H-methylpiperazino)-5-methylthio-6-chloropyrimidine.

Axial Preference of Methylthio Substituent in Dioxaphosphorinanyl Ring System

The spatial disposition of a 2-methylthio group in the 4-methyl-1,3,2-dioxaphosphorinanyl ring system was studied by stereochemical correlation, 1H, 13C and 81P NM-R. It has been established that a CH3S-group prefers an axial orientation much more strongly than does a methoxy group.

Photoelectron spectra and molecular properties V: The perturbation of the benzene π system by methylthio substituents

Photoelectron spectra and molecular properties V: The perturbation of the benzene π system by methylthio substituents

The relative abilities of methoxy and methylthio substituents to stabilize double bonds

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTThe relative abilities of methoxy and methylthio substituents to stabilize double bondsJack Hine, Louis G. Mahone, and Charles L. LiottaCite this: J. Org. Chem. 1967, 32, 8, 2600–2609Publication Date (Print):August 1, 1967Publication History Published online1 May 2002Published inissue 1 August 1967https://doi.org/10.1021/jo01283a053RIGHTS & PERMISSIONSArticle Views252Altmetric-Citations16LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (1 MB) Get e-Alerts Get e-Alerts

ORTHO PARTICIPATION IN THE CONVERSION OF syn-BENZALDOXIME ESTERS TO NITRILES

Substituted syn-benzaldoxime esters are transformed, in an alcoholic solution, to the corresponding nitriles according to first-order kinetics. All ortho substituents were observed to accelerate the rate of nitrile formation relative to the corresponding para derivative. While the ko/kp ratios for the bromo, chloro, fluoro, methoxy, and methyl substituents fall within the range of 2 to 9, the iodo and methylthio substituents are 119 and 11 000 respectively. Isotopic replacement of the aldoximino hydrogen by deuterium gives rise to a kinetic isotope effect, kH/kD being 5.21 for syn-o-chlorobenzaldoxime p-toluenesulfonate, 1.22 for syn-o-iodobenzaldoxime p-toluenesulfonate, and 1.23 for syn-o-methylthiobenzaldoxime o-iodobenzoate. The marked enhancement of rate and the absence of an appreciable isotope effect are considered to be associated with sulfur and iodine participation in the rate-determining step. A mechanism which is capable of explaining the results observed is suggested.