Seven-membered N-heterocycles Research Articles

Asymmetric Synthesis of Seven-Membered N-Heterocycles and Carbocycles

Asymmetric Synthesis of Seven-Membered N-Heterocycles and Carbocycles

Grubbs-Hoveyda catalysts conjugated to a β-barrel protein: Effect of halide substitution on aqueous olefin metathesis activity

The effect of halide substitution in Grubbs-Hoveyda II catalysts (GHII catalysts) embedded in the engineered β-barrel protein nitrobindin (NB4exp) on metathesis activity in aqueous media was studied. Maleimide tagged dibromido and diiodido derivates of the GHII catalyst were synthesized and covalently conjugated to NB4exp. The biohybrid catalysts were characterized spectroscopically confirming the structural integrity. When the two chloride substituents at ruthenium center were exchanged against bromide and iodide, the diiodo derivative was found to show significantly higher catalytic activity in ring-closing metathesis of α,ω-diolefins, whereas the dibromido derivative was less efficient when compared with the parent dichlorido catalyst. Using the diiodido catalyst, high turnover numbers of up to 75 were observed for ring-closing metathesis (RCM) yielding unsaturated six- and seven-membered N-heterocycles.

Electrochemical oxidative radical cascade cyclization of dienes and diselenides towards the synthesis of seleno-benzazepines.

Selenium-containing compounds are important scaffolds owing to their value in medicinal chemistry, biochemistry and material chemistry. Herein, we report an electrochemical approach to access seleno-benzazepines through an oxidative radical cascade cyclization of dienes with diselenides under metal-free, external oxidant-free and base-free conditions. In a simple undivided cell, various dienes and diselenides were suitable for this transformation, generating the desired products in up to 84% yields. This method provides a green and convenient route for the synthesis of valuable selenium-containing seven-membered N-heterocycles from simple starting materials.

Enantioselective phosphine-catalyzed [6 + 1] annulations of α-allyl allenoates with 1,1-bisnucleophiles.

Organocatalytic annulations between allenes and bisnucleophiles represent one of the most convenient routes to various carbocycles and heterocycles. However, most examples are limited to the formation of five- and six-membered rings, probably owing to relatively easy handling of short-chained biselectrophiles. Here we report long-chained α-allyl allenoate-derived 1,6-biselectrophiles for the first time, enabling a phosphine catalyzed [6 + 1] annulation with readily available 1,1-bisnucleophilic reagents. The reaction proceeds via a tandem γ-umpolung addition and δ'-addition process, smoothly constructing both seven-membered N-heterocycles and carbocycles with a broad scope of substrates, high atom economy and excellent enantioselectivity (up to 99% yield and up to 96% ee). Mechanistic experiments revealed a conversion of the 1,6-dipole into a 1,6-biselectrophilic intermediate through proton abstraction.

Silver-Catalyzed Ring Expansion of Activated N-Heteroarenes via 1,4-Dearomative Addition of Diazomethylphosphonates

AbstractPhosphorus-containing N-heterocycles are important molecular motifs due to their unique structural features and biological activities. In this study, we developed a silver-catalyzed reaction for the construction of phosphorus-containing azepine derivatives via a domino-type dearomatization procedure, followed by ring expansion. In addition, diazomethylphosphonates were employed for the first time as nucleophiles in the 1,4-dearomative addition of activated N-heteroarenes, furnishing cyclopropane-fused piperidine intermediates that were readily restructured into their corresponding azepine derivatives. The reactivities of the diazomethylphosphonates in the developed dearomatization strategy were found to be superior to those of other diazo compounds, thereby resulting in the generation of the desired seven-membered N-heterocycles within a very short reaction time.

Asymmetric hydrogenation of dibenzo-fused azepines with chiral cationic ruthenium diamine catalysts

Highly efficient asymmetric hydrogenation of dibenzo-fused azepines derivatives with chiral cationic Ru diamine catalysts has been developed, giving diverse chiral seven-membered N-heterocycles with excellent results (up to 99% yield and 99% ee).

Iron Catalyzed Dearomatization of Pyridines into Annelated Azepine Derivatives in a One-Step, Three-Component Reaction.

Commercially available Fe(TTP)Cl catalyzes three-component dearomative formal cycloaddition reactions between pyridines, diazo compounds, and coumalates. Diversely substituted annelated seven-membered N-heterocycles could be generated in less than 10 min in one step at room temperature. The reaction is compatible to gram scale. The extension to benzimidazoles in place of pyridines has been successfully demonstrated. The mechanism of this reaction has been carefully examined by computational studies that corroborate the observed regioselectivities.

Mn(III)-Mediated Radical Addition/Cyclization of Isocyanides with Aryl Boronic Acids/Diarylphosphine Oxides: Access to 11-Functionalized Dibenzodiazepines

A Mn(III)-mediated radical addition/cyclization reaction of isocyanides with aryl boronic acids/diarylphosphine oxides has been developed. A series of 11-arylated/-phosphorylated dibenzodiazepines were efficiently constructed in moderate to excellent yields under mild reaction conditions via imidoyl radical process. The present protocol offers novel access to functionalized seven-membered N-heterocycles.

Phosphoric Acid-Catalyzed Enantioselective Synthesis of Axially Chiral Anthrone-based Compounds.

Anthrones and analogues are structural cores shared by diverse pharmacologically active natural and synthetic compounds. The sp2 -rich nature imposes inherent obstruction to introduce stereogenic element onto the tricyclic aromatic backbone. In our pursuit to expand the chemical space of axial chirality, a novel type of axially chiral anthrone-derived skeleton was discovered. This work establishes oxime ether as suitable functionality to furnish axial chirality on symmetric anthrone skeletons through stereoselective condensation of the carbonyl entity with long-range chirality control. The enantioenriched anthrones could be elaborated into dibenzo-fused seven-membered N-heterocycles containing well-defined stereogenic center via Beckmann rearrangement with axial-to-point chirality conversion.

Hypervalent silicate-assisted azidation approach for the substituted azepane motif

An efficient and stereospecific azidation of a cis-disubstituted azepane is described as the first example of hypervalent silicate-assisted nucleophilic azidation on a substituted seven-membered azepane ring. DFT calculations suggest an SN2-like mechanism whereby the azido nucleophile coordinated to the hypervalent silicate presents flexible geometries for the nucleophilic approach. The method provides a viable alternative to the classical Mitsunobu-based approaches in substituted seven-membered N-heterocycles with complex conformational properties.

Regioselective Synthesis of Indole-Fused Seven-Membered N-Heterocycles via Photoredox-Catalyzed Intramolecular Cyclization.

Herein, we describe the construction of indole-fused seven-membered N- and O-heterocycles from indolyl α-diazocarbonyls via photoredox-catalyzed intramolecular cyclization. The photoredox process features operational simplicity, mild conditions, and as low as 0.1 mol % catalyst loading. The tricyclic heterocycles are obtained in yields of 24 to 67% with excellent regioselectivity. The practicality of this protocol is further demonstrated by gram-scale reactions carried out in both batch and continuous flow.

Photoinduced Tandem Cyclization of Alkynes with Phenylsulfinic Acids: Access to Sulfone-Substituted Dioxodibenzothiazepines or Dibenzazepines

AbstractPhotoinduced tandem cyclization of alkynes with phenylsulfinic acids has been accomplished, which gives a mild strategy for the preparation of sulfone-substituted seven-membered N-heterocycles. A variety of scaled-up experiments, further transformations, and mechanistic studies were also operated in the follow-up work.

Synthesis of Azepane Derivatives via Formal 1,3-Migration of Hydroxy and Acyloxy Groups and Selective Annulation.

Formal 1,3-migration of hydroxy and acyloxy groups initiated by α-imino rhodium carbene was achieved, and the following selective annulations of the corresponding zwitterions could efficiently afford azepane derivatives. Benefiting from a time-saving procedure as well as a good functional group tolerance, this unique migration-annulation protocol could provide an efficient tool for synthesizing seven-membered N-heterocycles. The plausible mechanism is discussed.

Photoinduced cascade cyclization of alkynes with NH4SCN: access to SCN-containing dibenzazepines or dioxodibenzothiazepines

Photoinduced tandem cyclization of alkynes with NH4SCN was developed for the synthesis of various SCN-containing seven-membered N-heterocycles.

A Rh(II)- or Ag(I)-Catalyzed Formal C–O Bond Insertion of Cyclic Hemiaminal with Aryl Diazoacetate

AbstractA mild and facile synthetic method via convergent assembly of two reactive intermediates generated in situ has been developed. This method provides an efficient way to construct six- and seven-membered N-heterocycles containing a biaryl linkage. This reaction features a gem-difunctionalization process of diazo compounds with cyclic hemiaminals, delivering α-hydroxyl-β-amino ester derivatives with a tertiary carbon center through a formal C–O bond-insertion transformation.

I2 -Promoted Intramolecular Oxidative Cyclization of Butenyl Anilines: A Facile Route to Benzo[b]azepines.

A metal-free approach for the synthesis of seven-membered N-heterocycles has been developed by the I2 -promoted intramolecular cross-coupling/annulation of butenyl anilines. This cyclization reaction involves C-H activation and C-C bond formation and exhibits good functional group tolerance. A series of benzo[b]azepine derivatives are obtained in moderate to good yields.

Microwave-Assisted N-Allylation/Homoallylation-RCM Approach: Access to Pyrrole-, Pyridine-, or Azepine-Appended (Het)aryl Aminoamides.

A facile and diversity-oriented approach has been developed for the synthesis of pyrrole-, pyridine-, or azepine-appended (het)aryl aminoamides via the N-allylation/homoallylation-ring-closing metathesis (RCM) strategy. Microwave condition was efficiently utilized for N-allylation of (het)aryl aminoamides to synthesize di-, tri-, and tetra-allyl/homoallylated RCM substrates in good yields. All of the RCM substrates were successfully converted to respective pyrroles 6a–h, 13a,b, 15a,b, pyridines 11a–d, 13c, and azepines 7a,b via RCM. All of the five-, six-, and seven-membered N-heterocycles were synthesized in shorter reaction times with excellent yields without isomerization products. A one-pot reaction to synthesize compounds 6a and 6b without isolating corresponding RCM substrates was achieved successfully. The synthetic utility of the compound 6b has been demonstrated by synthesizing biaryl derivatives 17a,b under the microwave Suzuki coupling reaction condition.

Remote Directed Isocyanation of Unactivated C(sp3)-H Bonds: Forging Seven-Membered Cyclic Ureas Enabled by Copper Catalysis.

Reported herein is an unprecedented copper-catalyzed site-selective δ-C(sp3)-H bonds activation of aliphatic sulfonamides for constructing the synthetically useful seven-membered N-heterocycles. A key to success is the use of in-situ-formed amide radicals, to activate the inert C(sp3)-H bond, and inexpensive TMSNCO, as a coupling reagent under mild conditions. To the best of our knowledge, this represents the first use of alkylamine derivatives as a five-membered synthon to prepare a seven-membered N-heterocycles.

Metal-free decarboxylative annulation of N-arylacrylamides with vinyl acids to synthesize benzo[b]azepin-2-ones

An efficient oxidative decarbonylative (3 + 2)/(5 + 2) annulation of N-arylacrylamides with vinyl acids for the synthesis of diverse seven-membered N-heterocycles under metal-free conditions has been developed.

From Wood to Tetrahydro-2-benzazepines in Three Waste-Free Steps: Modular Synthesis of Biologically Active Lignin-Derived Scaffolds.

Inherently complex, lignin-derived aromatic monomers comprising valuable structural moieties present in many pharmaceuticals would serve as ideal substrates for the construction of biologically active molecules. Here, we describe a strategy that incorporates all intrinsic functional groups present in platform chemicals obtained by lignin depolymerization into value-added amines, using sustainable catalytic methods and benign solvents. Our strikingly efficient protocol provides access to libraries of aminoalkyl-phenol derivatives and seven-membered N-heterocycles directly from wood in two, respectively three, waste-free steps. Several molecules in these libraries have shown promising antibacterial or anticancer activities, emphasizing the advantage of this modular synthetic strategy and the potential for drug discovery. The sustainable catalytic pathways presented here can lead to significant benefits for the pharmaceutical industry where reduction of hazardous waste is a prime concern, and the described strategies that lead to high-value products from non-edible biomass waste streams also markedly increase the economic feasibility of lignocellulosic biorefineries.