Methoxy Functionalities Research Articles

Thermolysis and photolysis of two steroidal hydroxamic acid methanesulfonates

Thermolysis or photolysis of N-methanesulfonyloxy-4-aza-5α-cholestan-3-one gave derivatives of 4-azacholestan-3-one, 4-aza-A-nor-B-homocholestan-3-one, 3-aza-A-norcholestane, bis(4-aza-3-oxocholest-5-en-6-yl) methane, and bis(3-aza-A-norcholestan-3-yl) urea. The corresponding 5β-methanesulfonate gave the 5β (coprostane) analogues. Evidence for the mechanism of formation of these products, including a Favorski-like ring contraction and amide oxidation by methanesulfonic acid, is presented. Detailed 1H and 13C assignments are made for many of the products, and ultraviolet absorption for seven steroidal enamides is tabled. Long-range homo- and heteronuclear NMR connectivities were used to confirm the structure of three dimeric compounds and to assign the configuration of the methoxy function of 4-aza-5-methoxy-A-nor-β-homocholestan-3-one to be 5α. Keywords: steroidal enamides, 3-aza-A-norcholestanes, 4-aza-A-nor-B-homocholestanes, aza-Favorskii ring contraction.

Einhorn Reaction for the Synthesis of Aromatic Building Blocks for Macrocyclization.

The present study concerns the synthesis of bis(α-haloacetamidomethyl) and benzyldiamine sythons 1−3 (Scheme 1) through amidomethylation and their application for the preparation of benzoazamacroheterocycles. These synthons are useful as rigid building blocks containing the chromophoric NO_2 group. The methoxy function could be converted to the phenolic OH after ring closure, providing a proton-ionizable group in the macrocyclic cavity. We show three synthetic routes to prepare benzoazamacrocycles using synthons 1−3.

Mycobacteriumbovis BCG genes involved in the biosynthesis of cyclopropyl keto‐ and hydroxy‐mycolic acids

The resurgence of tuberculosis and the emergence of multidrug-resistant mycobacteria necessitate the development of new antituberculosis drugs. The biosynthesis of mycolic acids, essential elements of the mycobacterial envelope, is a good target for chemotherapy. Species of the Mycobacterium tuberculosis complex synthesize oxygenated mycolic acids with keto and methoxy functions. In contrast, the fast-growing Mycobacterium smegmatis synthesizes oxygenated mycolic acids with an epoxy function. We describe the isolation and sequencing of a cluster of four genes from Mycobacterium bovis bacillus Calmette-Guerin (BCG), coding for methyl transferases, and which, when transferred into M. smegmatis, allow the synthesis of ketomycolic acid, in addition to an as yet undescribed mycolic acid, hydroxymycolic acid. These oxygenated mycolic acids, unlike the regular mycolic acids of M. smegmatis, and similar to the mycolic acids of M. bovis, are highly cyclopropanated. Furthermore, there is a perfect match between the structures of the keto- and the hydroxy-mycolic acids. We propose a biosynthetic model in which there is a direct relationship between these two types of mycolic acid.

Facile photolytic demethoxylation of 3-methoxychromones

Photolysis of 3-methoxychromones in methanol furnishes chromones through extrusion of the methoxy function. A conjugate addition of methanol followed by a double methoxy elimination has been proposed to account for the cleavage product.

Synthesis and Characterization of Titanium Complexes Containing Potentially Tridentate Amido‐cyclopentadienyl Ligands

AbstractTwo new titanium complexes of the general type Ti(η5:η1‐C5H4SiMe2NCH2CH2X)Cl2 (X = NMe2 OMe), containing a tridentate ligand, were prepared by reaction of Ti(η5‐C5H4SiMe2Cl)Cl3 with the lithium amide Li(NHCH2CH2X) (X = NMe2, OMe). The 1HNMR chemical shifts for the protons of the ethylene link were found to vary considerably as a function of the temperature, indicating the presence of an equilibrium between the tri‐ and bidentate bonding mode of the ligand. A single‐crystal X‐ray structural analysis of Ti(η5:η1C5H4SiMe2NCH2CH2OMe)Cl2 revealed that the methoxy function is not intramolecularly coordinated in the solid state.

Inhibition of mutagenesis of 2-amino-3-methylimidazo[4,5-ƒ]quinoline (IQ) by coumarins and furanocoumarins, chromanones and furanochromanones

A total of 51 natural and synthetic simple coumarins, furanocoumarins, chromanones, furanochromanones and some structurally related compounds were tested for their antimutagenic potencies with respect to IQ in Salmonella typhimurium TA 98. Antimutagenic potencies were quantified by the inhibitory dose for 50% reduction of mutagenic activity (ID 50) and by the remaining mutagenic activity at the highest dose tested. Antimutagenic activities of the parent compounds were weak (ID 50: 500–750 nmol/plate) but increased in the coumarin series with introduction of hydroxy, methoxy and (or) methyl groups at carbons 4, 5, 6 and 7 (ID 50: 70–400 nmol/plate). However, the antimutagenicity of compounds with hydroxy or methoxy substituents at C-5, C-6 and C-7 all together was low. Moreover, a hydroxy or methoxy function at C-8 greatly reduced antimutagenic potency. This was in part also true for substituents at C-3. Coumarin glycosides and glucuronides of antimutagenic aglycones were, however, inactive. Introduction of a carboxyl function rendered the respective coumarin inactive. Surprisingly, some synthetic coumarins with a bromo or iodo substituent at C-8 or a benzyloxy function at C-5 were found to be very potent antimutagens (ID 50: 9.3–14.5 nmol/plate), whereas analogues possessing a bromo or formyl function at C-5 were less effective (ID 50: 176 and 395 nmol/plate). Furanocoumarins and furanochromanones were very potent antimutagens (ID 50: 5.1–26.5 nmol/plate). In enzyme kinetic experiments with Salmonella the inhibition mechanisms of xanthotoxin and visnagin were concentration dependent, being non-competitive at low concentrations. Reduction of the activity of 7-ethoxy- and 7-methoxyresorufin- O-dealkylases with IC 50 values of 1.2–11.7 μM indicated strong inhibition of cytochrome P-450 1A1 and 1A2 dependent monooxygenases by some of the furanocoumarines and -chromanones. The mutagenic activity of N-hydroxy-IQ in Salmonella, however, was not reduced by any of these compounds. In various experiments designed for modulation of the mutagenic response inhibition of activation of IQ to N-OH-IQ was found to be the only relevant mechanism of antimutagenesis of psoralen, angelicin and khellin.

Uses of hydroxamic acids and of N-alkoxyimidoyl halides in organic synthesis

Although N-hydroxyamides (1) have been known for over a century, the chemistry of 1 is still relatively unexplored. The scope of the present review is a survey of the recent advances of the chemistry of 1 and its derivatives, particularly of new chemical reactions having synthetic utility in organic synthesis developed mainly in our laboratory. The review is divided into two sections. The first section described great utility of divalent positively-charged nitrogen species generated from 1 in synthesis. Electrophilic intramolecular cyclization with an acylnitrenium ion generated from an N-methoxy- or an N-allyloxy-N-chloroamide with anhydrous zinc acetate in nitromethane gave an N-methoxy- or an N-allyloxy nitrogen heterocyclic compound, deprotection of which led to formation of the corresponding N-hydroxy compound. Treatment of an N-hydroxy- or an N-methoxy-N-arylamide and the corresponding lactam with various reagents results in removal of the hydroxy or methoxy function and introduction of nucleophiles at the ortho or para position of the aromatic ring. These methodologies were successfully applied by us for the synthesis of the alkaloid, eupolauramine and for new oxindoles related to the alkaloid, gelsemine, by others. The second section described great utility of N-alkoxyimidoyl halides (2) synthesized from 1. Compounds 2 were readily transformed to other functions such as aldehydes, cyanides, and oximes. This methodology was successfully applied to the synthesis of omega-N-hydroxy-alpha-amino acids in optically pure form which were the key intermediates for the synthesis of hydroxamate-containing siderophores.

Comparison between ‘slow’ and ‘flash’ pyrolysis oils from biomass

This paper presents the results obtained in the characterization of different pyrolysis oils, five oils produced by carbonization and one by flash pyrolysis. Chemical and physical properties such as density, viscosity, elemental composition, char content, water content, solubility and heating value were first determined, then an in-depth chemical characterization was carried out by liquid-liquid fractionation. A diagram indicating the separation procedure, providing four fractions (acids, bases, polars and hydrocarbons), is presented. Polar molecules which were retained in the aqueous layer (‘aqueous’ fraction) are recuperated. Each fraction was subsequently analysed by gas chromatography-mass spectrometry (g.c.-m.s.) and Fourier transform infrared spectroscopy (FT-i.r.). The acidic fraction was the most abundant and contained essentially phenolic structures. However, phenols were differently substituted in the two types of oils: alkyl and methoxy groups in the carbonization oils; methoxy, acidic, aldehydic and ketonic functions in the flash pyrolysis oil. The other fractions present a similar composition for all oils. The basic fraction was always very small; some aromatic N-containing compounds were identified. The ‘polar’ neutral fraction was also small and its characterization was very difficult. The hydrocarbon fraction, especially, was constituted of aromatics and cyclics, and some aliphatics were also identified. The ‘aqueous’ fraction contained mainly carboxylic esters, alcohols and ethers.

Mechanistic studies in strong acids. 15. 4-[(3,4-Dimethoxyphenyl)azo]pyridine: two different pathways in the acid hydrolysis of the two methoxy groups

The kinetics of hydrolysis of the two methoxy functions in the title compound 1 have been determined as a function of sulfuric acid concentration. Basicity constants for azo group protonation have been evaluated for 1 and several other (phenylazo)pyridines. The 4-OMe group in 1 hydrolyzes very readily in aqueous H 2 SO 4 at 25 o C (half-life, seconds to minutes); the 3-OMe group also hydrolyzes, but more slowly (half-life, hours to days). The results extrapolate to a reactivity difference of 7000 in pure water

Pterocarpan phytoalexin biosynthesis in elicitor‐challenged chickpea (Cicer arietinum L.) cell cultures

NADPH:isoflavone oxidoreductase (IFR) is the first soluble enzyme of the pterocarpan-specific part of phytoalexin biosynthesis in chickpea (Cicer arietinum L.). The enzyme was purified to apparent homogeneity by a five-step procedure from chickpea cell cultures treated with yeast extract as elicitor. Analysis by gel filtration and SDS/PAGE showed that the enzyme consists of a single polypeptide with a molecular mass of 36 kDa. Km values for the substrates 2'-hydroxyformononetin, 2'-hydroxypseudobaptigenin and NADPH were 6, 6 and 20 microM, respectively. The IFR showed pronounced specificity for the substitution pattern of isoflavones. We found a 2'-hydroxy group and a 4',5'-methylenedioxy or 4'-methoxy function to be essential for acceptance as substrate. The isoelectric point of the protein was determined as 6.3 by IEF and there is no evidence for the existence of isoenzymes. Partial amino acid sequences of IFR were determined from internal peptides obtained by tryptic digestion of the protein and corresponding oligonucleotides were synthesized. A lambda gt10 cDNA library was constructed using poly(A)-rich RNA isolated from chickpea cell cultures treated with Ascochyta rabiei elicitor. 150 positive clones were obtained by screening 2 x 10(5) clones with an IFR-specific oligonucleotide. The identity of sequenced clones was confirmed by comparison of the deduced amino acid sequence with the internal peptide sequences of purified IFR. The sequence of a 1183-bp clone contained a continuous open reading frame of 954 bases encoding a polypeptide of 318 amino acids with a calculated molecular mass of 35.4 kDa, indicating that a full-length cDNA coding for IFR was isolated.

Synthesis of D3‐sulpiride and its (R) and (S) isomers

AbstractRacemic d3‐sulpiride, (R)‐(+)‐d3‐sulpiride and (S)‐(−)‐d3‐sulpiride (with three deuterium atoms in the methoxy function ortho to the benzamide), as well as (R)‐(+)‐sulpiride and (S)(−)‐sulpiride were synthesized. The structures were characterized by melting points, IR, 1H‐NMR, GC‐MS and polarimetry. The measured [α]D20 was 65° in 5% DMF.

Regioselective introduction of a methoxy group at the benzylic position of isochromane derivatives by cerium(IV) oxidation in methanol.

The oxidation of methoxy-isochromans and -isochromanones with ceric ammonium nitrate in methanol introduced a new methoxy group regioselectively at a benzylic position para to the methoxy function on the aromatic nucleus.

Structure-Activity Studies of Melatonin Analogues in Prepubertal Male Rats

Comparison has been made between the activity of the pineal hormone melatonin, and several analogues and metabolites in inhibiting sexual development in a protein-restricted prepubertal rat model. Eleven melatonin analogues or metabolites were tested with the aim of evaluating the model as a test of the hypothesis that melatonin acts as a prohormone and that the ring schism metabolites (kynurenamines) mediate many of the effects attributable to melatonin. Although the hypothesis could not be confirmed, modification of the melatonin structure by lengthening the acrylamide side chain or by replacing the 5 methoxy function with fluorine resulted in loss of biological potency. Modification of the melatonin structure to block the two known points of metabolism resulted in no significant alteration in biological activity. Thus 6-chloromelatonin (blocking 6-hydroxylation) and 2,3-dihydromelatonin (blocking oxidative cleavage of the C2-C3 bond) and 6-chloro-2,3-dihydromelatonin remained biologically active. The metabolic products of brain indoleamine-2,3-dioxygenase, N-acetyl-N2-formyl-5-methoxy kynurenamine (aFoMK) and N-acetyl-5-methoxy kynurenamine (aMK), paradoxically were also biologically active.

2,4-Diamino-5-benzylpyrimidines as antibacterial agents. 8. The 3,4,5-triethyl isostere of trimethoprim. A study of specificity.

3,4,5-Triethylacetophenone was synthesized in 60% yield by a Friedel-Crafts reaction from 4-ethylacetophenone and converted to 2,4-diamino-5-(3,4,5-triethylbenzyl)pyrimidine (2), a trimethoprim (1) isostere, by standard techniques. This compound is more lipophilic than 1 by three log units (log P, octanol/water). Compound 2 was approximately equipotent with 1 in inhibiting Escherichia coli dihydrofolate reductase (DHFR), 2-fold more potent against P. berghei and N. gonorrhoeae DHFR, and 10 and 25 times better an inhibitor of rat and chicken liver DHFR, respectively. Although the 3,4-dimethoxy analogue 19 was 10-fold less inhibitory to E. coli DHFR than 1, it was 3-4 times more potent on the vertebrate isozymes, whereas the diethyl congener 10 followed 19 in its E. coli DHFR binding but was less active on rat and chicken DHFR. Therefore, a significant portion of the selectivity of 1 for bacterial, as opposed to vertebrate, DHFR, involves the methoxy functions. An analysis of the X-ray data on 1 and 2 complexed with chicken DHFR, coupled with kinetic data, led to the conclusion that the difference in binding energies of the methoxy and ethyl compounds probably involve desolvation factors, as well as direct energies of interaction with protein atoms. Thus, one cannot invoke lipophilicity or shape alone in explaining the relationship in properties of 1 and 2.

Synthesis of D3‐metoclopramide

AbstractMetoclopramide‐d3 with the three deuterium atoms in the methoxy function ortho to the benzamide group was synthesized. A previously published synthesis was followed but was extensively modified in the final steps to increase overall yield. Structure was verified by NMR and GC‐MS.

Energy dependence of the fragmentation of haloanisole molecular ions

Breakdown graphs have been constructed for the isomeric fluoro-, chloro-, and dichloroanisoles from the results of charge exchange experiments. When a halogen atom is ortho or para to the methoxy function, the dominant primary fragmentation reaction involves loss of CH 3 from the molecular ion, while when the halogen atom is meta to the methoxy group, the dominant primary fragmentation reaction involves elimination of formaldehyde from the molecular ion. This differing behaviour arises from a lowering of the critical energy for CH 3 loss by an ortho or para halogen through resonance stabilization of the resulting phenoxy ion. Metastable ion studies show that elimination of formaldehyde occurs by two mechanisms, one involving a four-membered cyclic transition state and one involving a five-membered cyclic transition state. A halogen meta to the methoxy function strongly favours the reaction involving the five-membered cyclic transition state.

Reactions of propargyl alcohols. VII. Lithium aluminium hydride reductions of 1-methoxy-2-phenylpent-3-yn-2-ol, 1-methoxy-3-phenylhex-4-yn-3-ol and 7-methoxy-4-phenylhept-2-yn-4-ol

Lithium aluminium hydride reductions in ether solvents of 1-methoxy-2-phenylpent-3-yn-2-ol (7a), 1-methoxy-3-phenylhex-4-yn-3-ol (7b) and 7-methoxy-4-phenylhept-2-yn-4-ol (7c) are reported. Evidence for methoxy group participation in the reduction process for (7a) and (7b) is presented. Reductions of alkynols (4b), (4c), (7a), (7b) and (7c) with lithium aluminium hydride in benzene are described; alkynol (4a), lacking a methoxy function, failed to react under these reaction conditions.

Selective cleavage of the carbon-sulphur and carbon-oxygen bonds in methoxythioanisoles

Selective cleavage of thioether of ether functions in methoxythioanisoles in hexamethylphosphoramide (HMPA) with sodium gives methoxythiophenols by cleavage of the carbon-sulphur bond. Reactions with sodium isopropanethiolate give instead the thiomethoxyphenols by dealkylation of the methoxy function. When the methoxythioanisoles were treated first with sodium isopropanethiolate and then with sodium complete dealkylation was achieved with formation of mercaptophenols. The present methods have considerable advantages over existing procedures for the synthesis of methoxythiophenols, thiomethoxyphenols and mercaptophenols. The mechanistic implications of the reactions investigated are also discussed.

Crosslinking chemistry and network structure in organic coatings. I. Cure of melamine formaldehyde/acrylic copolymer films

AbstractCrosslinking chemistry and network formation in hydroxy and carboxy functional acrylic copolymer resins cured with representative melamine‐formaldehyde crosslinking agents have been studied by infrared spectroscopy. Network formation in these systems is dominated by two reactions, the condensation of the hydroxy (or carboxy) functionality of the acrylic resin with melamine alkoxy groups to form acrylic‐melamine crosslinks, and the condensation of melamine hydroxy groups to form melamine‐melamine crosslinks. The extents of these reactions have been studied as functions of acrylic resin composition, melamine type and concentration, and cure time and temperature. For melamines with just methoxy functionality, the extent of formation of acrylic‐melamine crosslinks increased steadily with cure temperature. For melamines with substantial hydroxy functionality, the extent of formation of acrylic‐melamine crosslinks increased rapidly then leveled off with increasing cure temperature. The formation of melamine‐melamine crosslinks increased slowly with increasing cure temperature. From these data and a statistical model, effective crosslink densities were calculated. The crosslink densities correlated well with solvent resistance.

Location of double bonds in long chain esters by mass spectroscopy of methoxyhalogeno derivatives prepared from methoxymercuriacetate adducts

AbstractMethyl esters of mono‐, di‐, and triunsaturated long chain fatty acids react quantitatively with mercuric acetate in methanol to produce methoxyacetoxy‐mercuri derivatives. Demercuration of these products with solutions of bromine or iodine in methanol yields methoxybromo or methoxyiodo derivatives readily isolable by thin layer chromatography. Mass spectra of the methoxyhalogeno derivatives of monounsaturated esters are characterized by intense peaks due to loss of halogen and cleavage adjacent to methoxy functions; the latter fragmentation allows the position of the original double bond to be established. The mass spectra of the methoxyhalogeno derivatives of polyunsaturated esters are more complex.