Polycyclic Heterocycles Research Articles

Asymmetric Synthesis of Polycyclic Heterocyclic Compounds via Friedel-Crafts Reaction/Cyclization Reaction Catalyzed by Nickel Catalyst.

The first highly enantioselective asymmetric Friedel-Crafts reaction/cyclization reaction of 5-aminopyrazoles with 3-alkenyloxindoles to afford polycyclic heterocyclic compounds bearing an all-carbon quaternary stereocenter catalyzed by a complex of NiII with the C2-symmetric bipyridine-N,N'-dioxide ligand L12 has been developed. The relevant products with a wide range of substrates and good functional tolerance were obtained in 89-98% yield with 56-99% ee in the presence of 10 mol % Ni(OTf)2 and 11 mol % L12 in DCM at 25 °C. Moreover, an experiment on scaling up the process along with the transformations of the cycloadducts further emphasized the practical application of the synthesis.

Constructing Nitrogen-Rich Fused [5,6,5]-Tricyclic Frameworks Through Rearrangement: Heat-Resistant Zwitterionic Salt Energetic Materials.

This study synthesized nitrogen-rich [5,6,5] fused compounds through a novel rearrangement reaction. Owing to its unique zwitterionic salt structure, rearrangement product 4-1 exhibits high thermal stability (Td > 250 °C), low sensitivity (IS > 40 J, FS > 360 N), and acceptable detonation velocities and pressures (νD = 8520 m s-1 and P = 32.53 GPa, respectively), which are better than those of TNT and TATB. These indicate the potential of zwitterionic salts as thermally stable energetic materials and provide new synthesis strategies for constructing fused polycyclic heterocycles through rearrangement.

The Chemistry and Biological Effects of Fused 1,2,4-triazolo[4,3-c]pyrimidines and their Isomeric 1,2,4-triazolo[1,5-c]pyrimidines

Concerning polycyclic heterocyclic compounds, fused triazolopyrimidines and their substituted analogs have been studied recently from a chemical and biological point of view. Triazolopyrimidines have eight different positional isomers based on their structural arrangement and nitrogen atom positions. The present review concerns synthesizing 1,2,4- triazolo[4,3-c]pyrimidines and 1,2,4-triazolo[1,5-c]pyrimidines fused with a fivemembered ring containing one heteroatom. The 1,2,4-triazolo[4,3-c]pyrimidines can be prepared by closing the triazole ring on the 4-hydrazinopyrimidine ring, and the 1,2,4- triazolo[1,5-c]pyrimidines can be prepared by closing the triazole ring on the 4- iminopyrimidine-3-amine ring. The transformation of 1,2,4-triazolo[4,3-c]pyrimidine to the more thermodynamically stable isomer triazolo[1,5-c]pyrimidine derivatives via Dimroth rearrangement under different reaction conditions is also discussed. Moreover, the biological activity of both series is presented.

Chemoselective Construction of Polycyclic Heterocycles Containing a [6-6-5] or [7-6-5] Tricyclic Core Skeleton from a 2-Isocyanophenyl Propargylic Ester.

Functionalized isocyanide chemistry represents an important research area in organic synthesis. A structurally unique 2-isocyanophenl propargylic ester has been designed to incorporate the reactivity of isocyanide and propargylic ester. Thus, the reaction of 2-isocyanophenyl propargylic ester and 2-aminoaromatic aldimine facilitates the synthesis of a wide range of polycyclic benzo[b]indolo[3,2-h][1,6]naphthyridine derivatives. Furthermore, reacting with 2-hydroxyaromatic aldimine enables the divergent synthesis of both the aforementioned scaffolds and another structurally distinctive diazabenzo[f]naphtho[2,3,4-ij]azulenes featuring a [7-6-5] core skeleton. Experimental results and DFT calculations suggest that these transformations likely proceed via the in situ generation of a strained cyclopropen-imine species followed by [3+2] cycloaddition. Next, switchable nucleophilic attack/ring-expansion/aromatization and nucleophilic addition/ring-expansion/elimination account for the observed selectivity.

Stereoselective access to furan-fused [5.5.0] bicyclic heterocycles enabled by gold-catalyzed asymmetric [8 + 4] cycloaddition

A gold-catalyzed asymmetric [8 + 4] cycloaddition was developed to afford highly functionalized furan/pyrrole-fused [5.5.0] polycyclic heterocycles with good diastereo- and enantioselectivity.

Electrochemical cascade migratory versus ortho-cyclization of 2-alkynylbenzenesulfonamides.

Efficient control over several possible reaction pathways of free radicals is the chemical basis of their highly selective transformations. Among various competing reaction pathways, sulfonimidyl radicals generated from the electrolysis of 2-alkynylbenzenesulfonamides undergo cascade migratory or ortho-cyclization cyclization selectively. It is found that the incorporation of an extra 2-methyl substituent biases the selective migration of the acyl- over vinyl-linker of the key spirocyclic cation intermediate and thus serves as an enabling handle to achieve the synthetically interesting yet under-investigated cascade migratory cyclization of spirocyclic cations.

A one-pot ultrasound-assisted regio and stereoselective synthesis of indenoquinoxaline engrafted spiropyrrolidines.

A catalyst free ultrasound-assisted regio-/stereoselective modular approach was accomplished for the synthesis of highly constrained indenoquinoxaline engrafted spiro pyrrolidines from easily available substrates. This one-pot strategy utilizes 1,3-dipolar cycloaddition from a four component reaction of ninhydrin, 1,2-phenylenediamine, β-nitrostyrene and benzylamine or amino acids under ultrasound irradiation. The transformation is mild and operationally simple, providing architecturally complex fused spiro polycyclic heterocycles. This synthesis was confined to follow the group-assistant-purification (GAP) chemistry process, which can avoid chromatographic purifications and use of catalysts and allows easy access to a novel class of spiro engrafted polyheterocyclic scaffolds, which may be beneficial in biomedical research/materials science in the near future. This opens an era for the formation of a single exo product, when compared with reported protocols, by merely switching over reaction conditions to US irradiation.

Base-promoted ring-opening/recyclization of naphthoquinones to access benzo[5,6][1,4]thiazino[4,3-b]isoquinoline-7,12-diones at room temperature

A novel and unique nitrogen atom insertion into naphthoquinone rings to construct structurally valuable polycyclic heterocycles at room temperature under transition-metal-free conditions has been described.

Substrate‐ and Catalyst‐Controlled C−H Bond Activation/Annulation for Construction of Pyrido[2,3,4‐de]quinazolinones and Indolo[1,2‐c]quinazolinones

AbstractA substrate and catalyst‐controlled synthetic strategy was employed to construct two distinct types of fused polycyclic heterocycles, namely pyrido[2,3,4‐de]quinazolinones and indolo[1,2‐c]quinazolinones. The most notable advantage of this method is its ability to rapidly generate two different polycyclic scaffolds via a simple C−H activation and subsequent cyclization cascade pathway. Specifically, sulfoxonium ylides played a crucial role in both transformations, serving as a two‐carbon synthon and a one‐carbon synthon, to independently construct the two fused polycyclic scaffolds through [4+2] and [4+1] annulation pathways, respectively.

General Synthesis of N-Alkylindoles from N,N-Dialkylanilines via [4 + 1] Annulative Double C-H Functionalization.

Strategies enabling the construction of indoles and novel polycyclic heterocycles from simple building blocks streamline syntheses in synthetic and medicinal chemistry. Herein, we report a C-H functionalization approach to N-alkylindoles proceeding via a double, site-selective C(sp3)-H/C(sp2)-H [4 + 1] annulation of readily accessed N,N-dialkylanilines. This protocol features a site-selective hydrogen atom transfer by a tuned N-tBu amidyl radical and addition of a sulfonyl diazo coupling partner, which promotes highly site-selective homolytic aromatic substitution of the (hetero)aromatic core. Mild decarboxylation of the annulation product enables the overall introduction of a carbyne equivalent into the N,N-dialkylaniline scaffold. Furthermore, the site-selectivity and mild conditions of the indolization facilitate direct access to N-alkyl indole scaffolds in late-stage functionalization (LSF) settings.

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SELENO(MERCURY)HALOGEN-CONTAINING BENZOTHIAZOLE DERIVATIVES

Derivatives of benzothiazole are sufficiently well researched as substrates for obtaining a number of condensed and hybrid polycyclic heterocycles that exhibit various biological activities, namely, they exhibit anticancer, antimicrobial, antioxidant activity, can be used as antidiabetic agents, analgesics, and inhibitors of viral infections. In this work, the possibility of seleno- and mercury-induced cyclization of 2-cinnamylthiobenzothiazole and the prospect of the usage of seleno- and mercury-containing benzothiazole derivatives as bactericidal and fungicidal agents are investigated. It was established that non-regioselective selenium-induced cyclization of 2-cinnamylbenzothiazole occurs during the reaction of 2-cinnamylthiobenzothiazole with the mixture of selenium dioxide and hydrobromic acid in a chloroform medium; reaction leads to the formation of a mixture of selenium-containing regioisomers of 4-phenyl-3-(tribromo-l4-selanyl)-3,4-dihydro-2H-[1,3]thiazino[2,3-b][1,3]benzothiazolium bromide and 4,4-dibromo-3-[bromo(phenyl)methyl]-3,4-dihydro-2H-4l4-[1,4,3]thiaselenazino[2,3-b][1,3]benzothiazolium bromide. On the other hand, a molecular complex is formed in a ratio of 1:1, when mercuriating of 2-cinnamylthiobenzothiazole with mercury chloride,. Experimentally determined fungicidal properties of seleno-, mercury-, and tellurium-containing derivatives of benzothiazole indicate the prospect of their use as bactericidal and antifungal agents
 Keywords: 2-cinnamylthiobenzothiazole; thiazino[2,3-b][1,3]benzothiazolium, thiaselenazino[2,3-b][1,3]benzothiazolium, molecular complex, fungicidal activity.

Synthesis of Imidazo[1,2-a]pyridine-Fused 1,3-Benzodiazepine Derivatives with Anticancer Activity via a One-Pot Cascade GBB-3CR/Pd(II)-Catalyzed Azide-Isocyanide Coupling/Cyclization Process.

A new one-pot synthesis of imidazo[1,2-a]pyridine-fused 1,3-benzodiazepine derivatives via a sequential GBB-3CR/Pd(II)-catalyzed azide-isocyanide coupling/cyclization process was developed. The Groebke-Blackburn-Bienaymé three-component reactions (GBB-3CR) of 2-aminopyridine, 2-azidobenzaldehydes, and isocyanides in the presence of a catalytic amount of p-toluenesulfonic acid gave azide intermediates without separation. The reaction was followed by using another molecule of isocyanides to produce imidazo[1,2-a]pyridine-fused 1,3-benzodiazepine derivatives in good yields by the Pd(II)-catalyzed azide-isocyanide coupling/cyclization reaction. The synthetic approach produces novel nitrogen-fused polycyclic heterocycles under mild reaction conditions. The preliminary biological evaluation demonstrated that compound 6a inhibited glioma cells efficiently, suggesting potentially broad applications of the approach for synthesis and medicinal chemistry.

Dichotomic Dearomatizations of Benzene vs Pyridine Rings of Sulfonyloxypyridine via (3 + 2) Cycloaddition.

Electron-poor arenesulfonyloxypyridines are selectively dearomatized whether on the pyridine or on the phenyl group through 1,3-dipolar cycloaddition (1,3-DC) involving non-stabilized azomethine ylides (AMY). Electronic effects of substituents on the aromatic rings allow to induce the regioselectivity of the transformation. Novel pyrrolidinic polycyclic heterocycles are thereby produced under mild acidic conditions at room temperature.

A base-mediated dearomatization [2 + 3] annulation of 2-nitrobenzofurans with 4-hydroxycoumarins: A simple and direct synthesis of dihydrofurobenzofuran-coumarins

A simple base-mediated dearomatization [2 + 3] annulation of 2-nitrobenzofurans with 4-hydroxycoumarins has been reported. A series of polycyclic heterocycles bearing dihydrofurobenzofuran and coumarin blocks were synthesized via Michael/nucleophilic substitution cascade reaction in moderate to excellent yields. 2-Nitrobenzothiophene and 4-hydroxyquinolin-2-one are also tolerated in this protocol. The reaction can be carried out on a gram scale. The configuration of product is confirmed by X-ray single crystal structure analysis.

Toward High-Energy and Low-Sensitivity Energetic Materials Based on a Fused [5,5,5,6]-Tetracyclic Backbone.

A route for fused [5,5,5,6]-tetracyclic energetic compounds based on the facile cyclization reaction has been explored. Fused [5,5,5,6]-tetracyclic compound 4 shows a high measured density (1.924 g cm-3), a low sensitivity (IS = 10 J, and FS = 144 N), and an excellent detonation velocity (9241 m s-1), which are much better than those of RDX. The results indicate that compound 4 is a potential candidate as a secondary explosive and provide new insight into the construction of fused polycyclic heterocycles.

Visible light photoredox-catalyzed arylative cyclization to access benzimidazo[2,1-a]isoquinolin-6(5H)-ones.

A photoredox-catalyzed arylative radical cascade involving N-acryloyl-2-arylbenzoimidazoles and diaryliodonium triflates leading to the formation of a broad array of pharmaceutically important arylated-benzimidazo[2,1-a]isoquinolin-6(5H)-ones is described. Importantly, the synthesized benzimidazoisoquinolinones are amenable for further synthetic manipulation and allowed efficient access to benzimidazo-fused polycyclic heterocycles.

Arylformylacetonitriles in Multicomponent Reactions Leading to Heterocycles

AbstractArylformylacetonitriles are versatile and attractive synthons in organic synthesis owing to their high reactivity. Among the numerous transformations involving arylformylacetonitriles, multicomponent reactions (MCRs) offer straightforward and effective routes to assemble the reactants into a wide range of five‐ and six‐membered heterocyclic systems including pyrrole, pyrazole, triazole, furan, pyridine, pyrimidine, and pyran. This review collects the recent advances and applications of arylformylacetonitriles in MCRs for the synthesis of monocyclic or polycyclic heterocycles published in the literature since 2001.

A Diastereoselective Cascade Annulation Approach to Bridged Polycyclic Heterocycles Involving an Unexpected Rearrangement

A diastereoselective cascade annulation between allenoates and in-situ generated isoquinoline N-oxides generating sp3-rich bridged polycyclic heterocycles is disclosed. The reaction proceeds through an unprecedented non-rearomatized rearrangement and allows access to a broad range of bridged heterocycles in 38-93% yields with excellent functional group tolerance and high diastereoselectivity. Density functional theory calculations provided key insights into the possible reaction pathway and the stereoselectivity of this procedure.

Rh(II)-Catalyzed Enynal Cycloisomerization for the Generation of Vinyl Carbene: Divergent Access to Polycyclic Heterocycles

Described herein is an unprecedented example of generating the endocyclic donor–donor vinyl carbene achieved by the dirhodium(II)-catalyzed enynal cycloisomerization. The endocyclic vinyl carbene intermediate could be trapped by a diversity of alkenes, including 1,1-disubstituted alkenes, dienes, and α-methyl styrenes, which could undergo [2 + 1], [4 + 3] cycloaddition and an unexpected formal allylation, respectively, giving spiro and fused polycyclic heterocycles. In these cascade transformations, up to three rings and three stereocenters were constructed in one step with good selectivities. The enantioselective versions were also achieved with up to 84% ee. Mechanistic studies revealed that a concerted intramolecular [2 + 3] cycloaddition was the key step for the generation of vinyl Rh(II) carbene. Detailed studies were conducted to elucidate the intriguing mechanism of the formal allylation.

Inside Cover Picture

The cover picture shows a facile synthetic methodology towards S‐fused multi‐membered polycyclic heterocycles containing five‐membered thiophene, six‐membered thiopyran, and seven‐membered thiepine. A construction strategy for thermally stable thiepine derivatives is thus established. More details are discussed in the article by Zhou et al. on page 13—20.image