Prototropic Rearrangement Research Articles

Reductive elimination of alkoxy group in anthraquinone derivatives

Anthraquinone derivatives are constantly in a focus of synthetic chemists due to a diversity of valuable biological, photochemical and redox properties. However, quinone core limits applicability of chemical transformations making a search for new methods of modification of anthraquinones highly demanded. A convenient approach of regioselective reductive α-alkoxy group cleavage of anthraquinone derivatives was developed and evaluated. Most effectively transformation goes via a zinc reduction of quinone moiety and prototropic rearrangement in acidic media followed by the alkoxy group elimination. Strong donors in β-position of anthraquinone core are crucial for transformation and provide the elimination exclusively from α-position. The method simplifies an access to some bioactive 1,3-substituted anthraquinones and was applied for synthesis of natural products, e.g., rubiadin 1-methyl ether, anthragallol 1,2-dimethyl ether, and damnacanthol.

Base-mediated reactions of diethyl malonates derivatives with perfluorinated olefins: Novel synthetic routes to multifunctional ionomer precursors

A novel synthetic method for the preparation of per- and polyfluorinated unsaturated 2-substituted malonates is presented involving the deprotonation of the starting diethyl malonate by a strong base, followed by in situ addition of the C-nucleophile to the terminal double bond of the perfluorinated olefin. Subsequent elimination of the corresponding leaving groups and restoring of the double bond leads to the target bifunctional perfluorinated olefins. In the case of unsubstituted diethyl malonate, the elimination is accompanied by a prototropic rearrangement with a double bond migration and the addition of a second equivalent of the C-nucleophile forming the tetrafunctional internal olefins. The reaction conditions, factors affecting the reactivity and regioselectivity of the process, the choice of reagent as well as the course of competitive reactions are also discussed.

A one-pot assembly of Δ2-isoxazolines from ketones, aryl acetylenes and hydroxylamine: Revisiting the mechanism in terms of quantum chemistry

A mechanism of the sequential reaction of ketones with arylacetylenes and hydroxylamine in the presence of KOBut/DMSO followed by the treatment of the reaction mixture with H2O and KOH yielding Δ2-isoxazolines is investigated using a DFT approach by the example of the assembly of (4R,5S)-5-benzyl-4-ethyl-3-methyl-4,5-dihydroisoxazole from pentan-2-one, phenylacetylene and NH2OH·HCl. Activation energies were estimated for successive stages of nucleophilic addition of a ketone carbanion to a triple bond (vinylation), addition of hydroxylamine to a carbonyl group and subsequent dehydration of the carbinolamine formed (oximation), base-assisted E/Z-isomerization of the oxime group, probable prototropic rearrangement of the β,γ-unsaturated oxime to the α,β-unsaturated structure and) intramolecular nucleophilic attachment to a double bond of α,β- or β,γ-unsaturated oxime with the formation of a five-membered heterocycle. It was shown that it is not the α,β-unsaturated oxime that participates in the ring closure, as previously assumed, but the β,γ-unsaturated form.

Quantum Chemical Study of Mechanisms of Organic Reactions: VII. Reaction of Ethane-1,2-dithiol with 1,3-Dichloropropene in the System Hydrazine Hydrate–KOH

A mechanism has been proposed for the reaction of 1,3-dichloropropene with ethane-1,2-dithiol in the system hydrazine hydrate–potassium hydroxide on the basis of DFT quantum chemical calculations [B3LYP/6-311++G(d,p)]. The proposed mechanism involves several consecutive steps, in particular nucleophilic substitution of chlorine at the sp3-hybridized carbon atom by sulfur, prototropic allylic rearrangement of the monosubstitution product with double bond migration toward the sulfur atom, dithiolane ring closure via nucleophilic attack of the second thiolate group on the carbon atom in the γ-position with respect to the second chlorine atom, and prototropic allylic rearrangement of 2-vinyl-1,3-dithiolane to more stable 2-ethylidene-1,3-dithiolane.

Biomimetic Oxidative Deamination Catalysis via ortho-Naphthoquinone-Catalyzed Aerobic Oxidation Strategy

An ortho-naphthoquinone-catalyzed oxidative deamination reaction has been developed where the molecular oxygen and water serve as the sole oxidant and nucleophile. The current aerobic deamination reaction proceeds via the ketimine formation between ortho-naphthoquinones and amines followed by the prototropic rearrangement and hydrolysis by water, representing a biomimetic oxidative deamination of amine species in the human body by the liver and kidneys. The compatibility of ortho-naphthoquinone organocatalysts with molecular oxygen and water opens up a new biomimetic catalyst system that can function as versatile deaminases for a variety of amine-containing molecules such as amino acids and DNA nuclear bases.

Organocatalytic Intramolecular [4+2] Cycloaddition between In Situ Generated Vinylidene ortho‐Quinone Methides and Benzofurans

AbstractDescribed herein is the enantioselective construction of oxygen‐containing [5‐6‐5] tricyclic heterocycles by an organocatalyzed asymmetric [4+2] cycloaddition of vinylidene ortho‐quinone methides and benzofurans. According to this methodology, a series of oxygen‐containing [5‐6‐5] tricyclic heterocycles with various functional groups were synthesized in excellent enantio‐ and diastereoselectivities (>99 % ee, >20:1 d.r.). Furthermore, the deuterium‐labeling experiments and high‐resolution mass spectroscopy demonstrated that a vinylidene ortho‐quinone methide intermediate was involved and possibly resulted from a prototropic rearrangement of 2‐ethynylphenol. Remarkably, a catalyst loading as low as 0.1 mol %, and a gram‐scale synthesis were achieved for this transformation.

Organocatalytic Intramolecular [4+2] Cycloaddition between In Situ Generated Vinylidene ortho-Quinone Methides and Benzofurans.

Described herein is the enantioselective construction of oxygen-containing [5-6-5] tricyclic heterocycles by an organocatalyzed asymmetric [4+2] cycloaddition of vinylidene ortho-quinone methides and benzofurans. According to this methodology, a series of oxygen-containing [5-6-5] tricyclic heterocycles with various functional groups were synthesized in excellent enantio- and diastereoselectivities (>99 % ee, >20:1 d.r.). Furthermore, the deuterium-labeling experiments and high-resolution mass spectroscopy demonstrated that a vinylidene ortho-quinone methide intermediate was involved and possibly resulted from a prototropic rearrangement of 2-ethynylphenol. Remarkably, a catalyst loading as low as 0.1 mol %, and a gram-scale synthesis were achieved for this transformation.

Biotransformation of Dimethenamid-P by the basidiomycete Irpex consors

Twenty-nine basidiomycetes were screened in surface and liquid cultures for their capability to biotransform the chloroacetamide herbicide Dimethenamid-P (DMTA-P). The basidiomycete Irpex consors converted 70% of the herbicide (0.5 g L−1 DMTA-P) in liquid cultures within 6 days, applying a minimal medium under non-ligninolytic conditions. Nine transformation products of DMTA-P were identified by liquid chromatography–mass spectrometry analysis of the culture supernatants. The four main metabolites were isolated and subjected to GC-MS analysis and NMR spectroscopy. The analyses revealed that the thiophene ring was oxidized at three different positions. Metabolite M1 was identified as the S-oxide, which was isolable and relatively stable at room temperature. In metabolite M2, one methyl substituent of the thiophene ring was hydroxylated. The two metabolites M3A and M3B were diastereomers, but fully separated by HPLC. Here, oxidation of the aromatic CH carbon resulted in prototropic rearrangement to an αβ-unsaturated thiolactone. None of the three major metabolites of DMTA-P has been described before.

New insights in oxybutynin chemical stability: Identification in transdermal patches of a new impurity arising from oxybutynin N-oxide rearrangement

Oxybutynin hydrochloride (Oxy), the first choice drug used for the management of urinary incontinence, is available in different types of formulations. However, due to its better lipophylicity and permeability, Oxyfree base was used in the new topical formulations such as transdermal patch and gel. The presence of an unprecedented impurity (Oxy-EK) in transdermal patches led to reinvestigate the chemical stability of Oxyfree base in oxidative conditions assigning, to Oxy-EK, the structure of (3E)-4-(N,N-diethylamino)-2-oxo-3-buten-1-yl 1-cyclohexyl-1-phenylglycolate. Oxy-EK arises from the prototropic rearrangement of oxybutynin N-oxides leading to the formation of an enamino ketone function which shows a long-wavelength UV-absorption. The total synthesis of Oxy-EK was performed, allowing to propose it as the indicator of stability for oxidative degradation of Oxy free base in transdermal formulations. The presence in the structure of Oxy-EK of an α,β-unsaturated carbonyl function, a potential Michael acceptor, suggested the need of evaluating its possible mutagenic power. Accordingly, the Ames test was performed: at nontoxic concentrations, Oxy-EK did not increase the number of revertant colonies in all strains tested both in the absence and presence of the exogenous metabolic activator S9.

Dihydrogen catalysis of the reversible formation and cleavage of C-H and N-H bonds of aminopyridinate ligands bound to (η(5) -C5 Me5 )Ir(III.).

This study focuses on a series of cationic complexes of iridium that contain aminopyridinate (Ap) ligands bound to an (η(5) -C5 Me5 )Ir(III) fragment. The new complexes have the chemical composition [Ir(Ap)(η(5) -C5 Me5 )](+) , exist in the form of two isomers (1(+) and 2(+) ) and were isolated as salts of the BArF (-) anion (BArF =B[3,5-(CF3 )2 C6 H3 ]4 ). Four Ap ligands that differ in the nature of their bulky aryl substituents at the amido nitrogen atom and pyridinic ring were employed. In the presence of H2 , the electrophilicity of the Ir(III) centre of these complexes allows for a reversible prototropic rearrangement that changes the nature and coordination mode of the aminopyridinate ligand between the well-known κ(2) -N,N'-bidentate binding in 1(+) and the unprecedented κ-N,η(3) -pseudo-allyl-coordination mode in isomers 2(+) through activation of a benzylic C-H bond and formal proton transfer to the amido nitrogen atom. Experimental and computational studies evidence that the overall rearrangement, which entails reversible formation and cleavage of H-H, C-H and N-H bonds, is catalysed by dihydrogen under homogeneous conditions.

A practical route to substituted 7-aminoindoles from pyrrole-3-carboxaldehydes.

Among privileged structures, indoles occupy a central place in medicinal chemistry and alkaloid research. Here we report a flexible and efficient conversion of pyrrole-3-carboxaldehydes to substituted 7-amino-5-cyanoindoles. Phosphine addition to fumaronitrile proceeds with prototropic rearrangement of the initially formed zwitterion to the thermodynamically favored phosphonium ylide, which is poised for in situ Wittig olefination. The predominantly E-alkene product positions the allylic nitrile for facile intramolecular Hoeben–Hoesch reaction in the presence of BF3·OEt2. Syntheses of 2,5- and 3,5-disubstituted 7-aminoindoles are illustrated. Additionally, dianion alkylation of the allylic nitrile is demonstrated to furnish, after cyclization, 5,6-disubstituted 7-aminoindoles to further exemplify this scalable and high-yielding method.

ChemInform Abstract: Base‐Catalyzed Schmittel Cycloisomerization of o‐Phenylenediyne‐Linked Bis(arenol)s to Indeno[1,2‐c]chromenes.

AbstractThe present cycloisomerization of (I) to (II) proceeds under transition metal‐free basic conditions involving a domino sequence of the prototropic rearrangement into a putative vinylidene o‐quinone methide intermediate and subsequent formal inverse‐electron‐demand hetero Diels—Alder cycloaddition.

Base-catalyzed Schmittel cycloisomerization of o-phenylenediyne-linked bis(arenol)s to indeno[1,2-c]chromenes

We describe the transition metal-free base-catalyzed Schmittel cycloisomerization reactions of o-phenylene-linked bis(arenol)s to indeno[1,2-c]chromene derivatives through prototropic rearrangement (tautomerization) to a putative vinylidene o-quinone methide intermediate with an enyne-allene system followed by a formal inverse-electron-demand hetero Diels–Alder cycloaddition. The preliminary results on catalytic asymmetric cycloisomerization with chiral bases are also disclosed.

ChemInform Abstract: A One‐Pot Approach to Δ2‐Isoxazolines from Ketones and Arylacetylenes.

AbstractThe process involves at least five separate mechanistic steps: addition of ketones to arylacetylenes, oximation of the resulted β,γ‐unsaturated ketones, E→Z isomerization of the oximes (for oximes of alkyl‐ and cycloalkyl ketones), prototropic rearrangement of oximes of β,γ‐unsaturated ketones to oximes of α,β‐unsaturated ketones, and their final cyclization.

Intramolecular Hydroamination Reactions Catalyzed by Neutral and Cationic Group IV Pyridylamido Complexes

AbstractZrIV and HfIV benzyl (neutral or cationic) and amido catalysts stabilized by pyridylamido ligands are found to be good candidates for the intramolecular hydroamination/cyclization of primary and secondary aminoalkenes. In particular, cationic monobenzyl derivatives have shown remarkable catalytic activity for the production of five and six‐membered N‐containing heterocycles from secondary amino alkenes. In addition, ZrIV and HfIV amido derivatives that are produced by a temperature‐controlled prototropic rearrangement have provided evidence of the central role played by the metal coordination sphere in promoting such catalytic transformations efficiently.

Prototropic isomerization of dihydropyridazinecarboxylic and dihydropyridazinedicarboxylic acid esters

3,5-Disubstituted 1,4-dihydropyridazine-4-carboxylic and 4,6-disubstituted 2,5-dihydropyridazine-3,5-dicarboxylic acid esters undergo isomerization into 2,5-dihydropyridazine-4-carboxylate and 1,4-dihydropyridazine-3,5-dicarboxylate derivatives, respectively, by the action of a catalytic amount of a mineral acid or strong base at 20°C. The transformation may be regarded as prototropic rearrangement, and it includes two consecutive 1,2-hydride shifts. The direction of the isomerization is determined by higher thermodynamic stability of the isomer containing a β-aminoacrylate fragment.

Different Rearrangement Behaviour of the Cation or Anion Derived from the Diels–Alder Adduct of 9‐Ferrocenylanthracene and 1,4‐Benzoquinone: Ring‐Opening or Paddlewheel Formation

Prototropic rearrangement of the Diels-Alder adduct (3a) of 9-ferrocenylanthracene and 1,4-benzoquinone potentially furnishes 9-ferrocenyl-1,4-dihydroxytriptycene (3b) incorporating a C(2v) symmetrical paddlewheel moiety. However, reaction of 3a with HBF(4) unexpectedly yields instead 9-ferrocenyl-10-(2,5-dihydroxyphenyl)anthracene (4) via cleavage of the C9-C12 bond to generate initially a ferrocenyl-stabilized cation. Treatment of 3a with sodium hydride and iodomethane yields 1,4-dimethoxy-9-ferrocenyltriptycene (3c) in high yield but, surprisingly, also leads to fission of the C9-C12 bond resulting, after methylation, in the formation of 9-hydroxy-9-ferrocenyl-10-(2-hydroxy-5-methoxyphenyl)dihydroanthracene (12), which readily dehydrates on silica to form 9-ferrocenyl-10-(2-hydroxy-5-methoxyphenyl)anthracene (8). The X-ray crystal structures of 3a, 3c and 4 are reported.

Reaksi Penataan Ulang Sigmatropik Hidrogen [1,3] Secara Termal Dan Reaksi Penataan Ulang Prototropik [1,3] Yang Dikatalisis Oleh Katalis Transfer Fase (PTC) , [18]-Crown Ether-6: Semi-Sintesis Vanili Dari Eugenol

Semi-synthesis of vanillin from eugenol can be divided into two step reactions namely, isomerization of eugenol into isoeugenol, and cleavage oxidation of isomerization product into expected reaction product (vanillin). In this work isomerization of eugenol or eugenyl acetate into isoeugenol or isoeugenyl acetate has been done via the following reactions: (1) Sigmatropic hydrogen (1,3) thermalic rearrangement reaction: direct heating of eugenol or eugenyl acetate at 220oC for 8 hours can produce 52.2% of isoeugenol or 65.7% of isoeugenyl acetate (both chemical yields are measured by means nmr-spectrometer), where products are viscose yellow-brownish liquid as mixture of unseparated starting material and isomerization product. (2) Prototropic (1,3) rearrangement catalyzed by phase transfer catalyst (PTC): (18)-crown ether-6 at room temperature can be afforded 71.4% of isoeugenol as light yellow liquid (mixture of unseparated starting material and isomerization product). Without any separation of mixture between isomerization product and starting material followed by subsequent cleavage oxidation using KMnO4 as oxidator in neutral condition catalyzed by phase transfer catalyst: (18)- crown ether-6 at room temperature for 3 hours can be yielded 16.5-22.9% of vanillin (from the starting material; eugenol or eugenyl acetate). The spectroscopical data of synthetical vanillin is not rather different with the spectroscopical data of authentical natural vanillin. Keywords: Eugenol, isoeugenol, vanillin, sigmatropic, prototropic

A primary hydrogen–deuterium isotope effect observed at the single-molecule level

The covalent chemistry of reactants tethered within a single protein pore can be monitored by observing the time-dependence of ionic current flow through the pore, which responds to bond making and breaking in individual reactant molecules. Here we use this 'nanoreactor' approach to examine the reaction of a quinone with a thiol to form a substituted hydroquinone by reductive 1,4-Michael addition. Remarkably, a primary hydrogen-deuterium isotope effect is readily detected at the single-molecule level during prototropic rearrangement of an initial adduct. The observation of individual reaction intermediates allows the measurement of an isotope effect whether or not the step involved is rate limiting, which would not be the case in an ensemble measurement.

Investigation of novel and reinvestigation of known cyclopentadienylphosphanes: News on [1,5] sigmatropic rearrangements

Ph 2P(C 5HMe 4) ( 1) was found to undergo a prototropic rearrangement contrary to previous reports. The first detailed investigation of a cyclopentadienylphosphane to undergo such a reaction is presented. One of the two tautomers of 1 which were observed represents the kinetic product, the other one is the thermodynamic product. The two isomers exhibit pronounced differences with respect to their chemical reactivity. Thermodynamic and kinetic data of the isomerisation process were determined. A novel, electron rich cyclopentadienylphosphane, the phosphorus diamide (Me 2N) 2P(C 5HMe 4) ( 2), was synthesised and was also found to undergo a prototropic rearrangement. The characteristics of the isomerisation process are fully consistent with the findings on 1. The molecular structure of the kinetic product of 2 was established by means of single crystal X-ray diffraction analysis. Me 2P(C 5H 4 tBu) ( 3) is presented as another novel cyclopentadienylphosphane. The mixture of isomers of 3 in thermodynamic equilibrium was investigated in detail with respect to the molecular structures of the tautomers. The results of this study suggested a reinvestigation of the parent compound Ph 2P(C 5H 4 tBu) ( 4) and findings differing from an earlier report in some details are presented.