Medium-ring Heterocycles Research Articles

Michael Addition Reaction Catalyzed by Imidazolium Chloride to Protect Amino Groups and Construct Medium Ring Heterocycles.

An effective approach for amino protection and construction of a seven-membered ring has been developed. The method uses imidazolium chloride to carry out the Michael addition reaction at low temperatures and perform amino deprotection or construction of a seven-membered ring at high temperatures.

Rapid, quantitative, solvent-free synthesis of medium-ring diaza heterocycles from diketene–acetone adduct and diamines

The synthesis of medium-ring heterocycles remains a challenge largely due to unfavorable energetic factors. We are reporting syntheses of 7–9-member diaza heterocycles that go to completion in 5min, require no solvents, and are quantitative with the only byproducts being acetone and water. The reaction products could be isolated in pure form by simply placing the mixture under vacuum. The reaction sequence possesses many of the hallmarks of a click reaction.

ChemInform Abstract: Synthesis of Phosphorus Containing Medium Ring Heterocycles by Sequential Claisen Rearrangement and Ring Closing Metathesis.

AbstractThe precursors (I), (V), and (VIII) are prepared from the corresponding phenols by Claisen rearrangement.

Synthesis of phosphorus containing medium ring heterocycles by sequential Claisen rearrangement and ring closing metathesis

An efficient method for the synthesis of novel medium ring phosphorus containing heterocycles starting from phenol derivatives by ruthenium catalyzed ring closing metathesis is described. This work deals with a sequential aromatic Claisen-rearrangement, coupling of an allyl/vinyl phosphonate, and ring closing metathesis reaction. All of these reactions were carried out at ambient temperature to afford the medium-sized phosphorus heterocycles in excellent yields.

Amine-directed intramolecular hydroacylation of alkenes and alkynes

Medium-ring heterocycles are prepared via an amine-directed, rhodium(I)-catalyzed intramolecular hydroacylation. The presence of an allyl substituent on the amine accelerates the reaction and increases product yields.

ChemInform Abstract: Synthesis of Novel Isoxazolidines and Medium‐Ring Heterocycles Oxazocines and Oxazonines

Abstractvia intramolecular nitrone cycloaddition

Synthesis of Novel Isoxazolidines and Medium-Ring Heterocycles Oxazocines and Oxazonines

A number of novel oxa-bridged and methylene oxa-bridged bicyclic isoxazolidines have been synthesized using intramolecular nitrone cycloaddition. The reductive cleavage of N-O bonds of the isoxazolidines to provide novel medium-ring heterocycles oxazocines and oxazonines is also described. Keywords: Isoxazolidines, oxazocines, oxazonines, amino alcohols, medium-ring heterocycles, oxa-bridged, methylene, nitrone, cycloaddition, benzoxazocine

Syntheses of 2,3-Dihydro-1,4-Benzodioxins and Bioisosteres as Structural Motifs for Biologically Active Compounds

The 2,3-dihydro-1,4-benzodioxin ring system is present in a large number of structures of therapeutic agents possessing important biological activities. Some of them are antihypertensive agents. Others are involved in nervous breakdown and schizophrenia or represent an attractive therapeutic target for the treatment of glaucoma. The 2,3-dihydro-1,4-benzodioxin core has also been developed for the synthesis of inhibitors of 5-lipoxygenase and accordingly, these 2,3-dihydro-1,4-benzodioxins are useful for the treatment of inflammatory diseases such as asthma and arthritis. The synthesis and reactivity of several bioisosteres of the non-aromatic ring will be discussed. The occurrence of the 2,3-dihydro-1,4-benzodioxin structure in various naturally abundant compounds is also known. The total synthesis of angustureine (a novel 1,2,3,4-tetrahydroquinoline alkaloid with a n-pentyl side chain at position 2) will be presented. The bioisosteric replacement of benzene by pyridine in compounds containing the 2-substituted-2,3-dihydro-1,4-benzodioxin core has yielded derivatives of biological interest in diverse therapeutic areas such as central nervous system and cardiovascular diseases. These promising results have prompted interest in the area of 1,4-dioxino-[2,3-b]pyridine analogues. Several modifications on both the aromatic and the non-aromatic rings will be reviewed, including several transformations of the new heterocycles, such as the Smiles rearrangement. Moreover, the enantiomers of 2- and 3-hydroxymethyl- 2,3-dihydro-1,4-dioxino-[2,3-b]pyridines, important chiral building blocks for the preparation of several biologically active compounds, have been synthesized. We have made an attempt to take into account the largest possible number of original papers, including our research and others. Publications of the last eleven years are included in this review. Keywords: Medium-ring heterocycles, 2,3-dihydro-1,4-benzodioxins, 1,4-dioxino[2,3-b]pyridines, 2,3-dihydro-3-hydroxymethyl-1,4- benzoxazines, 2,3-dihydrospiro-1,4-dioxino[2,3-b]pyridines, Smiles rearrangement, nucleophilic aromatic substitution, novel scaffolds

Study on medium ring heterocycles: synthesis and structure of novel condensed pyrazolo[1,4]diazocinones including single enantiomers

By means of a base-catalysed ring enlargement of triazapentalenoindenes resulting from diasteroselective anhydride-induced ring transformation of chiral aminoalcohol-derived zwitterionic 2,3-dihydroimidazo[2,1- a]phthalazinium-olates, a series of pyrazolo[1,5- d][1,4]diazocin-7(6 H)-ones with central and conformational chirality were obtained in enantiomerically pure form. The possible reasons of the characteristic substrate- and reagent-dependency observed for the diasteroselective ring transformations of the zwitterions were interpreted in terms of the relative energetics of the crucial alternative imidazolinium intermediates disclosed by B3LYP/6-31G(d,p) calculations. The trans-annular opening of three epimeric pairs of triazapentalenoindanones afforded identical pyrazolodiazonine products. This finding suggests that the primarily formed diastereomers, having different asymmetric conformations but the same element of central chirality, undergo ring inversions in one- and two steps, respectively, involved in pathways previously established for the facile racemisation of pyrazolodiazocines with conformational chirality and hydrogen- or methyl-substituent at C1-position. The ring enlargement of triazapentalenoindanones resulted from butyric anhydride-mediated ring transformation of zwitterions with symmetrical substitution pattern afforded highly rigid 1-ethylpyrazolodiazocines in racemic form potentially separable without thermal racemisation. The constitution, conformation and relative configuration of the novel compounds were determined by 1H-, 13C- and 15N-NMR methods including 2D-HSQC, 2D-HMBC and DNOE measurements and the structure of a pyrazolodiazocine was supported by single crystal X-ray diffraction.

Regioselective formation of medium-ring heterocycles of biological relevance by intramolecular cyclization

This brief account describes our progress on the regioselective synthesis of medium-sized heterocycles. Formation of the medium-ring (seven-, eight-, nine-membered) oxa-, aza-, thia, oxa-thia- and aza-thia-heterocycles has been achieved by the intramolecular metal-mediated cyclization (especially Pd-catalyzed), diene and enyne metathesis, thiol-mediated cyclization, iodocyclization and azide-alkyne cycloaddition.

A new and convenient approach to heterotetracyclic benzoxazocines through addition of 1,3-dicarbonyl compounds to quinolinium salts

The synthesis of a series of benzoxazocines has been achieved in good yields by tandem C-alkylation and intramolecular O-alkylation of 1,3-dicarbonyl compounds with quinolinium salts. This is a novel example of the synthesis of eight-membered rings via a tandem process, which provides a method for the synthesis of medium-ring heterocycles.

Amino acid based enantiomerically pure 3-substituted benzofused heterocycles: A new class of antithrombotic agents

A diverse group of novel medium ring heterocycles derived from naturally abundant proteinogenic amino acids were evaluated for their potency towards antithrombotic activity. The more potent benzofused oxazepine and oxazocine scaffolds were diversified by incorporating different amino acids at the position number 3. Further the effect of ring size has also been taken into account and it was observed that the eight-membered oxazocines ane more potent compared to the corresponding oxazepines.

Synthesis, Structure, Reactions, and Photoelectron Spectra of New Mixed Sulfur‐, Selenium‐ or Tellurium and Silicon‐ or Tin‐Containing Heterocycles

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Advances in the Synthesis and Biological Perspectives of Benzannulated Medium Ring Heterocycles

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Advances in the Synthesis and Biological Perspectives of Benzannulated Medium Ring Heterocycles

Benzannulated medium ring heterocycles represent a class of compounds, capable of binding to multiple receptors with high affinity and act as good antagonist. Exploration of these types of compounds in drug discovery is a rapidly emerging area in synthetic chemistry and exploitation of these molecules will help researchers to discover biologically active compounds with a broad range of medicinal values.

Synthesis, Structure, and Chemistry of New, Mixed Group 14 and 16 Heterocycles: Nucleophile-Induced Ring Contraction of Mesocyclic Dications

More than 40 new 4- to 12-membered ring heterocycles containing various combinations of Group 14 and 16 elements Si, Sn, S, Se, and Te have been synthesized and fully characterized. Synthesis of these small-ring as well as medium-ring (mesocyclic) heterocycles from alpha,omega-dihalides is facilitated by the presence of gem-dialkylsilyl and gem-dialkylstannyl groups in the precursors. Conformations of several of the new ring systems in the solid state have been determined by X-ray crystal structure analysis. Oxidation of mixed S(Se, Te)/Si eight-membered ring mesocycles with NOPF6 or Br2 gives dications or a bicyclic dibromide, respectively, which can be characterized by NMR methods. On treatment with nucleophiles, mesocyclic dications, or the corresponding radical cations undergo ring contraction, giving five- or six-membered ring heterocycles. Photolysis of a S/Se four-membered ring heterocycle gives selenoformaldehyde, trapped in 80% yield with 2,3-dimethyl-1,3-butadiene.

Palladium-Mediated Intramolecular Aryl Amination on Furanose Derivatives: An Expedient Approach to the Synthesis of Chiral Benzoxazocine Derivatives and Tricyclic Nucleosides

Pd-catalyzed intramolecular arylamination on sugar derivatives has been accomplished by using bulky biaryl phosphine ligands. An application of this methodology on a variety of D-glucose-derived substrates, 2a-f, led to the synthesis of highly functionalized cis-fused tricyclic oxazocines, 3a-e. The products could subsequently be transformed to the optically active benzoxazocine derivative 4 and tricyclic nucleoside 6. This is the first example of the synthesis of eight-membered rings via intramolecular cycloamination of furanose derivatives, which provides a very useful method for the catalytic synthesis of medium-ring heterocycles.

Palladium- and Copper-Catalyzed Synthesis of Medium- and Large-Sized Ring-Fused Dihydroazaphenanthrenes and 1,4-Benzodiazepine-2,5-diones. Control of Reaction Pathway by Metal-Switching.

For Abstract see ChemInform Abstract in Full Text.

Palladium- and Copper-Catalyzed Synthesis of Medium- and Large-Sized Ring-Fused Dihydroazaphenanthrenes and 1,4-Benzodiazepine-2,5-diones. Control of Reaction Pathway by Metal-Switching

Methods for the synthesis of dihydroazaphenanthrene fused to macrocycles (2) and medium-ring heterocycles (4), as well as 1,4-benzodiazepine-2,5-diones (5), are developed. A distinctly different catalytic property of palladium and copper catalysts was uncovered that leads to the development of a divergent synthesis of two different heterocyclic scaffolds from the same starting materials, simply by metal-switching. Thus, starting from linear amide 3, palladium acetate triggers a domino intramolecular N-arylation/C-H activation/aryl-aryl bond-forming process to provide 4, while copper iodide promotes only the intramolecular N-arylation reaction leading to 5. In combination with the Ugi multicomponent reaction (Ugi-4CR) for the preparation of the linear amides, a two-step synthesis of either the 5,6-dihydro-8H-5,7a-diazacyclohepta[jk]phenanthrene-4,7-dione (4) or 1,4-benzodiazepine-2,5-diones (5), by appropriate choice of metal catalyst, is subsequently developed from very simple starting materials.

Synthesis of medium ring heterocycles using an intramolecular Heck reaction.

Historically, general convergent syntheses of medium ring heterocycles have been difficult to develop. Herein, we describe the synthesis of five classes of heterocycles: dihydrodibenzo[b,f]azepine, -oxocine, and -thiocine and dibenzo[b,f]azepine and -oxepine using a strategy of alkylation followed by highly selective intramolecular Heck arylation reaction. The hetero-tricyclic compounds were available in only two steps starting from commercially available starting materials.