Nitration and nitrosation of 2, 6-dialkylphenols

Summary The nitration and nitrosation of various 2,6-dialkylphenols have been carried out with the production of 4-nitro- and 4-nitroso-2,6-dialkylphenols.     

Unexpected and expeditious entry into trifluoromethyl aziridines from substituted beta-dicarbonyl compounds

[Reaction: see text]. One-pot aziridinations were obtained starting from substituted 2,2,2-trifluoroethyl beta-dicarbonyl compounds with nosyloxycarbamates in the presence of an excess of CaO as base. The unexpected ring closure reaction takes place at room temperature, leading to the N-protected alpha-trifluoromethyl aziridines with good yields. The reaction pathway seems to be influenced by the choice of the base.     

Domino Wittig Diels-Alder reaction: an expeditious entry into the AB ring system of furanosesquiterpenes

A domino Wittig Diels-Alder reaction has been employed in delineating a short and flexible synthetic stratagem for ready access to the AB ring system and the tricyclic framework of furanosesquiterpenes, such as the bioactive natural products, furodysin and furodysinin.     

New insights into the acid-promoted reaction of caffeic acid and its esters with nitrite: decarboxylation drives chain nitrosation pathways toward novel oxime derivatives and oxidation/fragmentation products thereof

In 0.05 M acetate buffer, pH 4, containing 1% methanol, caffeic acid (1a) (2 x 10(-3) M) reacted smoothly with nitrite (NO(2)(-)) (4 x 10(-3) M) to afford as main products the novel 2-hydroxy- and 2-methoxyaldoximes 7a,b, the 2-oxoaldoxime 9a, 3,4-dihydroxybenzoic acid, 3,4-dihydroxybenzaldehyde, and the known furoxan 3c and benzoxazinone 4b in smaller amounts. At lower 1a concentration (e.g., 1 x 10(-4) M), 7a was the main product, whereas with 0.1 M 1a and 0.5 M NO(2)(-) 3c and 9a were prevailing. At pH 2, 7a was still the most abundant product, together with 3,4-dihydroxybenzaldehyde and some 9a, whereas at pH 1 9a and 3,4-dihydroxybenzaldehyde were formed in higher yields. No evidence for ring nitration products, including the previously reported 4,5-dihydroxy-2-nitrobenzaldehyde, was obtained. At 2 x 10(-3) M concentration and at pH 4, caffeic acid methyl ester (1b) reacted with NO(2)(-) chiefly via ring nitration and/or dimerization to give 5a, the novel nitrated neolignan derivative 10, and the parent 6. Chlorogenic acid (1c) afforded only the ring nitrated derivative 5b. A unifying mechanism for the reaction of 1a and its esters with NO(2)(-) is proposed involving reversible formation of nitroso intermediates via chain nitrosation at the 2-position of the (E)-3-(3,4-dihydroxyphenyl)propenoic system. In the case of 1a, decarboxylation would drive the nitroso intermediates toward the formation of oximes 7a,b and 3c, reflecting nucleophilic addition of water, methanol, and NO(2)(-), and their oxidation or breakdown products, viz. 9a, 3,4-dihydroxybenzaldehyde, 3,4-dihydroxybenzoic acid, and the benzoxazinone 4b. In the case of esters 1b,c, to which decarboxylation is precluded, ring nitration or dimerization become the favored routes, triggered by preliminary oxidation at the catechol moiety.     

Diisobutylaluminium-promoted regioselective de-O-methylation of cyclodextrins: an expeditious entry to selectively modified cyclodextrins

Substituted cyclodextrins carrying methyl groups on the primary rim undergo highly regioselective de-O-methylation in the presence of benzyl groups, using diisobutylaluminium. This gave access to AD or AB di-6-O-demethylated derivatives, which were fully characterised by NMR, MS and chemical degradation using the hex-5-enose method. Direct functionalisation of these derivatives, for example by glycosylation, makes this method an attractive procedure for the preparation of modified cyclodextrins.     

Palladium-catalyzed arylation of ketone enolates: an expeditious entry to tamoxifen-related 1,2,2-triarylethanones

[reaction: see text]. After a rigorous study on the effect of several catalytic systems, a simple, high yielding procedure for the preparation of 1,2,2-triarylethanones, skeletal analogues of tamoxifen, is presented. Apart from the economic and environmental advantages involved, this palladium-catalyzed arylation of deoxybenzoin enolates features a lack of ortho-arylation side reactions. In addition, an alternative approach from acetophenones to the target triarylethanone system is also announced.     

Vitamin E chemistry. Nitration of non-alpha-tocopherols: products and mechanistic considerations

In contrast to the alpha-form permethylated at the aromatic ring, non-alpha-tocopherols possess free aromatic ring positions which enable them to act as potent scavengers of electrophiles in vivo and in vitro. In preparation of enzymatic studies involving peroxynitrite and other nitrating systems, the behavior of non-alpha-tocopherols under nitration conditions was studied. The nitration products of beta-, gamma-, and delta-tocopherol were identified, comprehensively analytically characterized, and their structure was supported by X-ray crystal structure analysis on truncated model compounds. Even under more drastic nitration conditions, no erosion of the stereochemistry at 2-C occurred. The nitrosation of gamma-tocopherol and delta-tocopherol was re-examined, showing the slow oxidation of the initial nitroso products to the corresponding nitro derivatives by air to be superimposed by a fast equilibrium with the tautomeric ortho-quinone monoxime, which only in the case of gamma-tocopherol released hydroxyl amine at elevated temperatures to afford the stable ortho-quinone. Mononitration of delta-tocopherol selectively proceeded at position 5. This selectivity can be explained by the theory of strain-induced bond localization (SIBL) to the quinoid nitration intermediates. Bisnitration was only insignificantly disfavored by the first nitro group, so that under normal nitration conditions offering an excess of nitrating species only the bisnitration product was found.     

Copper-catalyzed Perkin-acyl-Mannich reaction of acetic anhydride with pyridine: expeditious entry to unconventional piperidines

A regioselective introduction of a methoxycarbonyl methyl group at the C(2) position of unsubstituted pyridine has been accomplished with catalytic amounts of copper(II) triflate in mild reaction conditions. The N-acetyl-1,2-dihydropyridyl acetic acid methyl ester obtained is a valuable building block for the synthesis of new polyfunctionalized piperidine derivatives bearing unconventional substitution patterns.     

The cysteine radical cation: structures and fragmentation pathways

A theoretical study on the structures, relative energies, isomerization reactions and fragmentation pathways of the cysteine radical cation, [NH(2)CH(CH(2)SH)COOH].+, is reported. Hybrid density functional theory (B3LYP) has been used in conjunction with the 6-311++G(d,p) basis set. The isomer at the global minimum, Captodative-1, has the structure NH(2)C.(CH(2)SH)C(OH)(2)+; the stability of this ion is attributed to the captodative effect in which the NH(2) functions as a powerful pi-electron donor and C(OH)(2)+ as a powerful pi-electron acceptor. Ion Distonic-S-1, H(3)N(+)CH(CH(2)S.)COOH, in which the radical is formally situated on the S atom, is higher in enthalpy (DeltaH degrees (0)) than Captodative-1 by 6.1 kcal mol(-1), but is lower in enthalpy than another isomer Distonic-C-1, H(3)N(+)C.(CH(2)SH)COOH, by 8.2 kcal mol(-1). Isomerization of the canonical radical cation of cysteine, [H(2)NCH(CH(2)SH)COOH].+, (Canonical-1), to Captodative-1 has an enthalpy of activation of 25.8 kcal mol(-1), while the barrier against isomerization of Canonical-1 to Distonic-S-1 is only 9.6 kcal mol(-1). Two additional transient tautomers, one with the radical located at C(alpha) and the charge on SH(2), and the other a carboxy radical with the charge on NH(3), are reported. Plausible fragmentation pathways (losses of small molecules, CO(2), CH(2)S, H(2)S and NH(3), and neutral radicals COOH. , HSCH(2). and NH(2).) from Canonical-1 are examined.     

Ugi/Aldol sequence: expeditious entry to several families of densely substituted nitrogen heterocycles

Complexity from simplicity: Nitrogen-containing heterocycles have been assembled by means of unprecedented domino processes designed to take advantage of diversity assembly using strategically decorated Ugi products. The aldol reaction is the second common denominator which enables sequences of up to five steps in one pot, thus producing unique molecular architectures in rapid fashion.     

Interaction of anthralin with cysteine: a new entry into the chemistry of biologically active anthrones.

Evidence is reported that under physiological conditions anthralin (I), an antipsoriatic drug , reacts with cysteine to give an ether-insoluble adduct which was formulated as 1,8-dihydroxy-10-(2-amino-2-carboxyethylthio)-9-anthrone (III) by model studies and unambiguous synthesis.     

Metathesis reaction of formaldehyde acetals: an easy entry into the dynamic covalent chemistry of cyclophane formation

The acid-catalyzed transacetalation of formaldehyde acetals (formal metathesis) is a suitable reaction for the generation of well-behaved Dynamic Libraries of cyclophane formals. The composition of the equilibrated mixtures solely depends on concentration, and is totally independent of whether the feedstock is any of the pure cyclic oligomers, or a mixture of oligomers/polymers. Effective Molarities related to the formation of the lower cyclic oligomers were directly measured as their equilibrium molar concentrations above the critical monomer concentration. The finding that silver cation acts as a selective binder toward the cyclic dimer C2, coupled with the "proof reading and editing" capability of our quickly equilibrating system, translated into significant amplifications of C2 when the equilibrated mixtures were exposed to the action of the silver template. These results highlight the potential of Dynamic Combinatorial Chemistry as a powerful tool for the preparation in synthetically useful amounts of an otherwise elusive macrocyclic compound. The possibility of using a mixture of high molecular weight byproducts as feedstock adds considerably to the practical value of the procedure.     

The remarkable chemistry of trannulenes: green fluorinated fullerenes with unconventional aromaticity

We report the first reaction of trannulenes involving their thermal isomerization to a new class of compounds termed "triumphenes". The thermodynamically controlled conversion of trannulenes into triumphenes is accompanied by an unprecedented migration of three organic addends from one hemisphere of the fullerene cage to another. The reaction products, bearing aliphatic substituents, might find applications in materials science as strong electron acceptors due to the presence of fifteen electron-withdrawing fluorine atoms in their molecular framework. It was revealed that the isomerization of trannulenes can be affected by the presence of unsaturated compounds in the reaction mixture. Heating of trannulenes C(60)F(15)R(3) with C(60), C(70), anthracene, or pentacene at reflux in 1,2-dichlorobenzene yields fluorinated derivatives C(60)F(14)R(2)A, which possess a fused cyclic addend A. The products of this reaction have "triumphene-type" addition patterns and seem to be formed through an unprecedented sequence of elimination, addition, and isomerization steps. The molecular structure of a representative triumphene was proven unambiguously by X-ray single-crystal diffraction analysis and by NMR spectroscopy. The reactions revealed here open up numerous opportunities for chemical derivatization of fluorinated fullerenes. This method promises to provide a new path towards valuable photoactive materials and a new generation of fullerene-based compounds that are suitable for biomedical applications.     

The fragmentation pathways of protonated glycine: A computational study

Numerous studies have demonstrated that protonated aliphatic amino acids, [H2NCHRCO2H + H]+, fragment in the gas phase to form iminium ions, H2N=CHR+. Unfortunately none of these studies have probed the structure of the neutral(s) lost as well as the mechanism of fragmentation. Three main mechanisms have been previously proposed: (1) loss of the combined elements of H2O and CO; (2) loss of dihydroxycarbene (HO)2C: and (3) loss of formic acid, HC(=O)OH. Herein, ab initio and density functional theory calculations have been used to calculate the key reactants, transition states, and products of these and several other competing reaction channels in the fragmentation of protonated glycine. The loss of the combined elements of H2O and CO is thermodynamically and kinetically favored over the alternative formic acid or (HO)2C fragmentation processes.     

Spirocyclic diaminocarbenes: synthesis, coordination chemistry, and investigation of their dimerization behavior

Nonaromatic, "saturated", spirocyclic N-heterocyclic diaminocarbenes 11 can be obtained from spirocyclic imidazolidin-2-thiones 10 by reductive desulfurization with potassium. The unsymmetrically N,N'-substituted spirocyclic imidazolidin-2-thiones were obtained by reaction of ketimines 9 with lithium N-butyl-N-lithiomethyldithiocarbamate (6). 13C NMR spectroscopy revealed that the unsymmetrically N,N'-substituted spirocyclic imidazolidin-2-ylidene 11 a undergoes a slow, acid-catalyzed dimerization to give the enetetramine 11 a=11 a, which exists in two isomeric forms (syn and anti). This reaction is reversible under special circumstances. Carbenes of type 11 react with [W(CO)6] to yield air-stable carbene complexes of type [W11(CO)5] (14). The molecular structures of two derivatives 14 a and 14 b were established by X-ray crystallography and show clear distortion of the five-membered N-heterocyclic ring, caused by the spirocyclic molecular structure of the carbene ligands of type 11.     

Extraribosomal cyclic tetradepsipeptides beauverolides: profiling and modeling the fragmentation pathways

Profiling of cyclic tetradepsipeptides beauverolides was tested as a chemotaxonomic tool for fungal strain identification/discrimination. Two new tetradepsipeptides, beauverolides Q and R, were characterized by tandem mass spectrometry. Specific elimination of 113 atomic mass units from both protonated and sodiated molecules of beauverolides is ubiquitous for all 12 most dominant congeners evaluated in this profiling study. Reconstruction of the total ion chromatogram, according to this neutral fragment release, was used for data filtering and selectivity enhancement. Selective ring opening and fragment ion formation of beauverolide I are discussed in detail utilizing high-level theoretical modeling of the fragmentation pathways.     

Oxidative dimerization of aromatic amines using tBuOI: entry to unsymmetric aromatic azo compounds

It's all the hype: An oxidative dimerization reaction of aromatic amines utilizing tert-butyl hypoiodite (tBuOI) under mild reaction conditions leads to aromatic azo compounds. The method allows access to unsymmetric aromatic azo compounds, which are difficult to prepare by conventional synthetic methods, in a selective manner.     

Proton mobility and main fragmentation pathways of protonated lysylglycine

Theoretical model calculations were performed to validate the 'mobile proton' model for protonated lysylglycine (KG). Detailed scans carried out at various quantum chemical levels of the potential energy surface (PES) of protonated KG resulted in a large number of minima belonging to various protonation sites and conformers. Transition structures corresponding to proton transfer reactions between different protonation sites were determined, to obtain some energetic and structural insight into the atomic details of these processes. The rate coefficients of the proton transfer reactions between the isomers were calculated using the Rice-Ramsperger-Kassel-Marcus (RRKM) method in order to obtain a quantitative measure of the time-scale of these processes. Our results clearly indicate that the added proton is less mobile for protonated KG than for peptides lacking a basic amino acid residue. However, the energy needed to reach the energetically less favorable but-from the point of view of backbone fragmentation-critical amide nitrogen protonation sites is available in tandem mass spectrometers operated under low-energy collision conditions. Using the results of our scan of the PES of protonated KG, the dissociation pathways corresponding to the main fragmentation channels for protonated KG were also determined. Such pathways include loss of ammonia and formation of a protonated alpha-amino-epsilon-caprolactam. The results of our theoretical modeling, which revealed all the atomic details of these processes, are in agreement with the available experimental results.