Intramolecular Arylation Reaction Research Articles

Comprehensive Review on the Synthesis of [1,2,3]Triazolo[1,5-a]Quinolines.

This report outlines the evolution and recent progress about the different protocols to synthesize the N-heterocycles fused hybrids, specifically [1,2,3]triazolo[1,5-a]quinoline. This review encompasses a broad range of approaches, describing several reactions for obtaining this since, such as dehydrogenative cyclization, oxidative N-N coupling, Dieckmann condensation, intramolecular Heck, (3+2)-cycloaddition, Ullman-type coupling and direct intramolecular arylation reactions. We divided this review in three section based in the starting materials to synthesize the target [1,2,3]triazolo[1,5-a]quinolines. Starting materials containing quinoline or triazole units previously formed, as well as starting materials which both quinoline and triazole units are formed in situ. Different methods of obtaining are described, such as metal-free or catalyzed conditions, azide-free, using conventional heating or alternative energy sources, such as electrochemical and photochemical methods. Mechanistic insights underlying the reported reactions were also described in this comprehensive review.

Regioselective Synthesis of the Tetrahydrocarbazole Core of Akuammiline Alkaloids via Palladium-Catalyzed Intramolecular Arylation Reaction.

Tetrahydrocarbazole is the central core for several biologically active alkaloids, and regioselective synthesis of this core is a challenging task. Herein, we report an efficient strategy for the synthesis of this core involving palladium-catalyzed intramolecular arylation reaction with excellent regioselectivity (>99%) starting from N-phenyl-bromoalkene without having any relocation of double bonds via competitive palladium-catalyzed isomerization reaction. Broad functional group tolerance and exclusive regioselectivity have been observed for meta-substituted halide substrates. Furthermore, this reaction can be scalable on the gram scale.

Design and synthesis of 1,2-dihydroquinoline/chromene fused sugar triazole frameworks by copper-catalyzed one-pot click and intramolecular arylation reactions.

Expedient copper-catalyzed one-pot click and intramolecular arylation reactions have been developed for the synthesis of 1,2-dihydroquinoline/chromene-fused triazoles with varying sugar functionalities. It has been observed that the additive TMEDA greatly facilitates this copper-catalyzed cyclization. This reaction involves two mechanistically distinct reactions i.e. an atom-economical click reaction and a direct arylation of a sugar triazole. This method provides rapid and simple access to fused sugar triazoles in moderate to good yields. All the key products were characterized using 1H and 13C NMR and HRMS data.

Novel oxoisochromene synthesisviachemoselective O–H insertion of 1,3-dicarbonyl compounds and subsequent Pd-catalyzed intramolecular arylation reaction

Chemoselective O–H insertion of 1,3-diketones under transition metal-free conditions gives rise to vinyl ethers; Subsequent Pd-catalyzed intramolecularO-arylation of vinyl ethers leads to novel oxoisochromenes.

Discovery of tricyclic HIV-1 integrase-LEDGF/p75 allosteric inhibitors by intramolecular direct arylation reaction

We have been conducting exploratory research to develop human immunodeficiency virus type-1 (HIV-1) integrase-LEDGF/p75 allosteric inhibitors (INLAIs). Here, we report on a newly designed compound with a tricyclic scaffold that shows promise as an inhibitor. Various scaffolds were synthesized by intramolecular direct arylation reaction to fix the position of a lipophilic side chain required for antiviral activity. Among these, the compound having an N-mesyl dihydrophenanthridine ring showed the best antiviral activity. Compound 42i, prepared by side chain optimization of the C-4 and C-6 positions, exhibited high antiviral activity against wild-type (WT) and the T174I mutant (EC50 (WT) = 4.6 nM, EC50 (T174I) = 83 nM) with a good PK profile. Based on co-crystal structural analysis of compound 42i and WT HIV-1 IN CCD, we discuss the interaction important for high antiviral activity.

SYNTHESIS, REACTIVITY AND BIOLOGICAL PROPERTIES OF AMINOPYRAZOLES

In this research a new polyheterocyclic compounds endowed with various biological activities using different aminopyrazoles as starting reagents were sinthesized. We have developed a bibliographic study bearing the interest, the different methods of the synthesis and reactivity of aminopyrazoles. We have used the aminocyanopyrazoles in the preparation of new aromatic heterocycles by carrying out cyclization reactions of the two extracyclic functions amine and nitrile. Some of the obtained compound have shown interesting biological activities and fluorescence properties. We then dealt with the C-4 arylation reactions by activation of the palladium-catalyzed C-H bond of 5-aminopyrazole carrying the cyclopropyl group in the C3 position. This study is then extended to amination reactions. Finally, the synthesis of polyheterocyclic compounds involving intramolecular arylation and amination reactions is reported.

Bowl‐Shaped Pentagon‐ and Heptagon‐Embedded Nanographene Containing a Central Pyrrolo[3,2‐b]pyrrole Core

AbstractA bowl‐shaped nitrogen‐doped nanographene composed of a pyrrolo[3,2‐b]pyrrole core substituted with six arene rings circularly bonded with one another has been prepared via a concise synthetic strategy encompassing the multicomponent tetraarylpyrrolopyrrole (TAPP) synthesis, the Scholl reaction, and intramolecular direct arylation. This synthesis represents the first case of programmed sequential intramolecular direct arylation reactions utilizing the different reactivity of C–Br and C–Cl bonds. The target compound contains two central pentagons confined between two adjacent heptagons—the inverse Stone–Thrower–Wales topology. The presence of both five‐ and seven‐membered rings in the final structure is responsible for interesting properties such as a perpendicularly aligned dipole moment, absorption and fluorescence in the orange‐red region, weak emission originating from the charge‐transfer character of a low‐energy absorption band, and a high lying HOMO. In the solid state slipped convex‐to‐convex π–π stacking dominates.

Bowl-Shaped Pentagon- and Heptagon-Embedded Nanographene Containing a Central Pyrrolo[3,2-b]pyrrole Core.

A bowl-shaped nitrogen-doped nanographene composed of a pyrrolo[3,2-b]pyrrole core substituted with six arene rings circularly bonded with one another has been prepared via a concise synthetic strategy encompassing the multicomponent tetraarylpyrrolopyrrole (TAPP) synthesis, the Scholl reaction, and intramolecular direct arylation. This synthesis represents the first case of programmed sequential intramolecular direct arylation reactions utilizing the different reactivity of C-Br and C-Cl bonds. The target compound contains two central pentagons confined between two adjacent heptagons-the inverse Stone-Thrower-Wales topology. The presence of both five- and seven-membered rings in the final structure is responsible for interesting properties such as a perpendicularly aligned dipole moment, absorption and fluorescence in the orange-red region, weak emission originating from the charge-transfer character of a low-energy absorption band, and a high lying HOMO. In the solid state slipped convex-to-convex π-π stacking dominates.

Recent Advances in Asymmetric Functionalization of Olefins Induced by Chiral Hypervalent Iodine Reagents

The functionalization of olefins induced by chiral hypervalent iodine reagents is a basic method for obtaining enantiomerically enriched chiral molecules and biologically active natural products. It is one of the new and promising fields in asymmetric synthesis. Throughout the past 20 years development in this area, on the one hand, stereoselective functionalizations of alkenes such as disulfonyloxylation, diacetoxylation, dihalogenation, diamination, hydroxylation-sulfonyloxylation and halogenation-alkylation and carbonylation have been successfully achieved with chiral hypervalent iodine reagents through intermolecular reactions, in which various functionalized products were enantioselectively obtained. On the other hand, many of hetero-cyclic compounds such as γ-butyrolactones, chromans, isochromans, oxazolidinones, piperidines, pyrrolidines and aziridines can be synthesized by intramolecular oxidative lactonization, etherification, amidation, arylation and other reactions, in which hypervalent iodine reagents can provide efficient methods for the synthesis of chiral heterocyclic compounds. In addition, various functionalization reactions of olefins mediated by chiral hypervalent iodine reagents can afford target compounds with excellent yield and enantioselectivity. Thus, this methodology has also been used in the total synthesis of natural products. The functionalization of olefins induced by chiral hypervalent iodine reagents and their applications in the total synthesis of natural products are reviewed.

Highly selective Diels-Alder and Heck arylation reactions in a divergent synthesis of isoindolo- and pyrrolo-fused polycyclic indoles from 2-formylpyrrole.

A highly regio-, chemo- and stereoselective divergent synthesis of isoindolo- and pyrrolo-fused polycyclic indoles is herein described, starting from 2-formylpyrrole and employing Diels–Alder and Heck arylation reactions. 3-(N-Benzyl-2-pyrrolyl)acrylates and 4-(pyrrol-2-yl)butenones underwent a highly endo-Diels–Alder cycloaddition with maleimides to furnish octahydropyrrolo[3,4-e]indoles, which served as precursors in the regioselective synthesis of aza-polycyclic skeletons via an intramolecular Heck arylation reaction. Through the latter reaction, the 3-(N-benzyl-2-pyrrolyl)acrylates give rise to 3-(pyrrolo[2,1-a]isoindol-3-yl)acrylates. A further oxidative aromatization of the polycyclic intermediates provides the corresponding polycyclic pyrrolo-isoindoles and isoindolo-pyrrolo-indoles. A theoretical study on the stereoselective Diels–Alder reactions, carried out by calculating the endo/exo transition states, revealed the assistance of non-covalent interactions in governing the endo stereocontrol.

Synthetic Approach to Readily Accessible Benzofuran-Fused Borondipyrromethenes as Red-Emitting Laser Dyes.

We took advantage of the chemoselective meso-functionalization of 2,3,5,6-tetrabromo-8-methylthioBODIPY 6 to prepare a series of 2,3,5,6-tetrabromo-8-arylBODIPY derivatives suitable for SNAr substitution reactions with phenols exclusively at positions 3 and 5. Pd(0)-catalyzed intramolecular arylation reaction ensued on the remaining brominated positions 2 and 6 to give a new family of benzofuran-fused BODIPY dyes. This method utilizes readily available starting materials and allows for the preparation of the title compounds with excellent functional group tolerance. Moreover, it was demonstrated that the methodology described herein is amenable for the incorporation of biomolecules. The photophysical and lasing properties of the benzofuran-fused BODIPY dyes were thoroughly analyzed with the aid of electrochemical measurements and quantum mechanical simulations. These dyes show bright and intriguing emission (both fluorescence and laser) toward the red edge of the visible spectrum with remarkable tolerance under strong and continuous irradiation.

Synthesis of Benzopyran-Fused Flavone Derivatives via Microwave-Assisted Intramolecular C–H Activation

A microwave-assisted intramolecular direct arylation method for the synthesis of benzopyran-fused flavone derivatives containing natural flavone backbones is described. Different polyalkoxy flavones were synthesized and functionalized with 2-bromobenzyl bromide. The resulting compounds were subjected to palladium-catalyzed intramolecular direct arylation reactions supported by microwave irradiation to produce fused tetracyclic flavones. In the case of the 7-substituted chrysin derivative, the regioselectivity of the coupling was also examined.

Sequential Copper‐Catalyzed Sonogashira Coupling, Hydroamination and Palladium‐Catalyzed Intramolecular Direct Arylation: Synthesis of Azepino‐Fused Isoindolinones

A sequential copper‐catalyzed Sonogashira coupling followed by an intramolecular hydroamination and palladium‐catalyzed intramolecular direct arylation reaction was developed to provide a convenient and modular approach for the synthesis of useful azepino‐fused isoindolinones. Nineteen azepino‐fused isoindolinones were prepared in moderate to high (22–90 %) yields. The developed protocol tolerated various functional groups and involved the formation of one carbon–nitrogen and two carbon–carbon bonds in a one‐pot fashion. The palladium‐catalyzed intramolecular direct arylation step involved formation of an unusual eight‐membered palladacycle.

Catalytic Synthesis of Chiral Phosphole Oxides via Desymmetric C–H Arylation of o-Bromoaryl Phosphine Oxides

A palladium-catalyzed intramolecular direct arylation reaction of o-bromoaryl phosphine oxides was developed to afford a variety of P-stereogenic phosphole oxides in good yields. The enantioselectivities were closely associated with the specific structures of substrates, which ranged from 4–94%. As a result of ready availability of starting materials and simple operation to improve the enantioselectivities of the products with low ee values, the method provides a simple and straightforward procedure for the synthesis of P-stereogenic phosphole oxides.

Synthesis of Tricyclic Isoxazoles via Sequential [3+2] Dipolar Cycloaddition­ and Palladium-Catalyzed Intramolecular Arylation Reactions

An efficient synthetic route to tricyclic isoxazoles via sequential copper-catalyzed 1,3-dipolar cycloaddition and palladium-catalyzed intramolecular arylation of isoxazoles is described. Based on these reactions, a convenient one-pot synthesis of the tricyclic isoxazoles from terminal alkyne and hydroximoyl chlorides by using a cascade process was also developed.

Conjugated Thiophene-Fused Isatin Dyes through Intramolecular Direct Arylation.

We report on the design, synthesis, and properties of innovative, planar, π-conjugated compounds in which a thiophene ring is fused with the skeleton of the naturally occurring dye isatin. The synthesis is achieved in high yields making use of an intramolecular direct arylation reaction as the key step, making the overall process potentially scalable. The synthetic sequence has been demonstrated also for an isatin bearing fluorine substituents on the aromatic ring. NMR and X-ray studies demonstrate the crosstalk occurring between the fused, coplanar, and conjugated moieties, making these novel dyes with a donor-acceptor character. Cyclic voltammetry and UV-vis studies confirm very interesting HOMO-LUMO levels and energy gaps for the new compounds.

Impregnated palladium on magnetite as catalyst for direct arylation of heterocycles

Palladium impregnated on magnetite is an efficient, cheap and easy to prepare catalyst for the direct arylation of heterocycles. Good yields are afforded under relatively mild conditions and a broad substrate scope is evident. The catalyst is regioselective in many cases, affording arylated products, at the C2- or C3-position (depending of the heterocycle used). The methodology can be extended to prepare chromenes through an intramolecular direct arylation reaction. Some evidence is provided for two catalyst deactivation pathways, which prevents efficient recycling.

Substituted azafluorenones: access from dihalogeno diaryl ketones by palladium-catalyzed auto-tandem processes and evaluation of their antibacterial, antifungal, antimalarial and antiproliferative activities

Substituted azafluorenones were synthesized from dihalogeno diaryl ketones under palladium catalysis by combining, in auto-tandem processes, Suzuki coupling and intramolecular arylation reactions. Different dihalogenated diaryl ketones, prepared by sequential deprotocupration-aroylation, were identified as suitable substrates to this purpose. Conditions were identified to allow successful syntheses of several 6-/7-arylated 4-azafluorenones, 1-substituted 4-azafluorenones, 2-phenyl-3-azafluorenone, and 4-phenyl-3-azafluorenone from 3-(bromobenzoyl)-2-chloropyridines, 3-benzoyl-4-bromo-2-chloropyridines, 4-benzoyl-2,5-dichloropyridine, and 4-benzoyl-2,3-dichloropyridine, respectively. Some of the synthesized compounds exhibit interesting biological properties.

Lithium Choreography Determines Contrasting Stereochemical Outcomes of Aryl Migrations in Benzylic Carbamates, Ureas and Thiocarbamates

AbstractThe intramolecular arylation reactions of lithiated derivatives of ureas, carbamates and thiocarbamates generally proceed stereospecifically, but the reaction is stereochemically retentive with ureas and thiocarbamates, whereas it is stereochemically invertive with carbamates. Using DFT calculations, we have studied the mechanism of the intramolecular attack of a thiocarbamate‐stabilised carbanion on an N‐aryl substituent and compared the details of the calculated reaction pathway with the corresponding reactions of carbamate‐ and urea‐stabilised carbanions. The different stereochemical outcomes observed in the rearrangements of carbamates and thiocarbamates arise from the sulfur–carbon interaction in the thiocarbamate, which enhances the stabilisation of the anion. As a result, the solvated lithium cation takes different pathways across the potential energy surfaces that lead to stereochemically divergent outcomes. Additionally, we investigated the importance of the intramolecular nature of the aryl migration and compared the pathway for aryl migration within a urea with that of a hypothetical, experimentally unfeasible, intermolecular reaction. The results throw light on the reason why aryl migrations are successful even with much more electron‐rich rings than would be tolerated in a typical intermolecular nucleophilic aromatic substitution.

ChemInform Abstract: Intramolecular Direct Arylation and Heck Reactions in the Formation of Medium‐Sized Rings: Selective Synthesis of Fused Indolizine, Pyrroloazepine and Pyrroloazocine Systems.

ChemInform Abstract: Intramolecular Direct Arylation and Heck Reactions in the Formation of Medium‐Sized Rings: Selective Synthesis of Fused Indolizine, Pyrroloazepine and Pyrroloazocine Systems.