Heteroatom-Promoted Polyhexagonal Saddle-Shaped Molecular Structures and their Supramolecular Coassembly with C60.

Molecules with curved architecture can exhibit unique optoelectronic properties due to the concave-convex π-surface. However, synthesizing negatively curved saddle-shaped aromatic systems has been challenging due to the internal structural strain. Herein, we report the facile synthesis of two polyhexagonal molecular systems, 1 and 2, with saddle shape geometry by judiciously varying the aromatic moiety, avoiding the harsh synthetic methods as that of heptagonal aromatic saddle systems. The unique geometry preferences of B, N, and S furnish suitable curvature to the molecules, featuring saddle shape. The saddle geometry also enables them to interact with fullerene C60 , and the supramolecular interactions of fullerene C60 with 1 and 2 modify their optoelectronic properties. Crystal structure analysis reveals that 1, with a small π-surface, forms a double columnar array of fullerenes in the solid state. In contrast, 2 with a large π-surface produces a supramolecular capsule entrapping two discrete fullerenes. The intermolecular interactions between B, N, S, and the aryl-π surface of the host and C60 guest are the stabilizing factors for creating these supramolecular structures. Comprehensive computational, optical, and Raman spectroscopic studies establish the charge transfer interactions between B-N doped heterocycle host and fullerene C60 guest.

Urea Ligand-Promoted Chainwalking Heteroannulation for the Synthesis of 6- and 7-membered Azaheterocycles.

Typical approaches to heterocycle construction require significant changes in synthetic strategy even for a change as minor as increasing the ring size. The ability to access multiple heterocyclic scaffolds through a common synthetic approach, simply through trivial modification of one reaction component, would enable facile access to diverse libraries of structural analogues of core scaffolds. Here, we show that urea-derived ligands effectively promote Pd-mediated chainwalking processes to enable remote heteroannulation for the rapid construction of six- and seven-membered azaheterocycles under essentially identical reaction conditions. This method demonstrates good functional group tolerance and effectively engages sterically hindered substrates. In addition, this reaction is applicable to target-oriented synthesis, demonstrated through the formal synthesis of antimalarial alkaloid galipinine.

Boron-Nitrogen-Containing Benzene Valence Isomers.

Benzene is one of the most ubiquitous structural motifs in chemistry. The valence isomers of benzene have also attracted synthetic chemists' attention due to their unique structures, bonding, and reactivity. We have been investigating boron-nitrogen-containing benzene valence isomers via photoisomerization of 1,2-azaborines. In this contribution, we summarize recent developments of these highly strained BN-heterocyclic compounds including their synthesis, characterization, proposed mechanism of formation, and their potential applications.

Regioselective Partial Hydrogenation and Deuteration of Tetracyclic (Hetero)aromatic Systems Using a Simple Heterogeneous Catalyst.

The introduction of added '3-dimensionality' through late-stage functionalisation of extended (hetero)aromatic systems is a powerful synthetic approach. The abundance of starting materials and cross-coupling methodologies to access the precursors allows for highly diverse products. Subsequent selective partial reduction can alter the core structure in a manner of interest to medicinal chemists. Herein, we describe the precise, partial reduction of multicyclic heteroaromatic systems using a simple heterogeneous catalyst. The approach can be extended to introduce deuterium (again at late-stage). Excellent yields can be obtained using simple reaction conditions.

Leveraging Pyrazolium Ylide Reactivity to Access Indolizine and 1,2-Dihydropyrimidine Derivatives.

N-Heterocyclic ylides are important synthetic precursors to rapidly build molecular complexity. Pyrazolium ylides have largely been unexplored, and we demonstrate their diverse utility in this report. We show that these readily accessible building blocks can be used to construct different heterocyclic skeletons by varying the coupling partner. Indolizines can be formed via an N-deletion type mechanism when reacting pyrazolium salts with electron deficient alkynes. 1,2-Dihydropyrimidines can be formed via a rearrangement mechanism when reacting pyrazolium ylides with isocyanates. These reactions enable access to valuable heteroarenes without the need for transition metal catalysis, high temperatures, or strong bases.

Synthesis of Bench-stable Polycyclic Organophosphorus Heterocycles via Staudinger-type Annulations of ortho-Azidophenols.

The formation of a five- or six-membered ring is known to stabilize unstable molecular structures such as hemiacetals. This idea can also be extended to stabilize other high-coordinated p-block element species. Herein, we synthesized two novel polycyclic organophosphorus heterocycles via Staudinger-type annulations. Reactions of either ortho-phosphinoarenesulfonyl fluorides 1 or ortho-phosphinobenzoic acid methyl esters 4 with ortho-azidophenols 2 gave rise to penta-coordinated P(V) heterocycles, benzo-benzo-1,2,3-thiazaphospholo-1,3,2-oxazaphosphole (B-B-TAP-OAP) 3 and benzo-benzo-1,2-azaphospholo-1,3,2-oxazaphosphol-12-one (B-B-AP-OAP) 5 in satisfactory yields. It is remarkable that heterocycles 3 and 5 are both bench-stable and exhibit considerable stability in a 10 % aqueous tetrahydrofuran solution. Preliminary computational studies disclosed that the formation of nitrogen gas is the key driving force for the annulations. In addition, the formation of a strong Si-F bond is another contributor to the annulation of 1 and 2.

Structure and Photophysics of N-Tolanyl-phenochalcogenazines and their Radical Cations.

The study focuses on the structural and photophysical characteristics of neutral and oxidized forms of N-tolanyl-phenochalcogenazines PZX-tolan with X=O, S, Se, and Te. X-ray crystal structure analyses show a pseudo-equatorial (pe) structure of the tolan substituent in the O, S, and Se dyads, while the Te dyad possesses a pseudo-axial (pa) structure. DFT calculations suggest the pe structure for O and S, and the pa structure for Se and Te as stable forms. Steady-state and femtosecond-time resolved optical spectroscopy in toluene solution indicate that the O and S dyads emit from a CT state, whereas the Se and Te dyads emit from a tolan-localized state. The T1 state is tolan-localized in all cases, showing phosphorescence at 77 K. The heavy atom effect of chalcogens induces intersystem crossing from S1 to Tx, resulting in a decreasing S1 lifetime from 2.1 ns to 0.42 ps. The T1 states possess potential for singlet oxygen sensitization with a high quantum yield (ca. 40 %) for the O, S, and Se dyads. Radical cations exhibit spin density primarily localized at the heterocycle. EPR measurements and quasirelativistic DFT calculations reveal a very strong g-tensor anisotropy, supporting the pe structure for the S and Se derivatives.

Skeletal Editing of Isatins for Heterocycle Molecular Diversity.

Isatins have been widely used in the preparation of a variety of heterocyclic compounds, where the skeletal editing of isatins has shown significant advantages for the construction of diverse heterocycles. This review highlights the progress made in the last decade (2013-2023) in the skeletal editing of the isatin scaffold. A series of ring expansion reactions for the construction of quinoline skeleton, quinolone skeleton, polycyclic quinazoline skeleton, medium-sized ring skeleton, as well as a series of ring opening reactions for the generation of 2-(azoly)aniline skeleton by the cleavage of C-C bond and C-N bond are highlighted. It is hoped that this review will provide some understanding of the chemical transformations of isatins and contribute to the further realization of its molecular diversity.

Novel orexin receptor agonists based on arene- or pyridine-fused 1,3-dihydro-2H-imidazole-2-imines.

A structurally novel class of benzo- or pyrido-fused 1,3-dihydro-2H-imidazole-2-imines was designed and evaluated in an inositol phosphate accumulation assay for Gq signaling to measure agonistic activation of the orexin receptor type 2 (OX2R). These compounds were synthesized in 4-9 steps overall from readily available starting materials. Analogs that contain a stereogenic methyl or cyclopropyl substituent at the benzylic center, and a correctly configured alkyl ether, alkoxyalkyl ether, cyanoalkyl ether, or α-hydroxyacetamido substituted homobenzylic sidechain were identified as the most potent activators of OX2R coupled Gq signaling. Our results also indicate that agonistic activity was stereospecific at both the benzylic and homobenzylic stereogenic centra. We identified methoxyethoxy-substituted pyrido-fused dihydroimidazolimine analog 63c containing a stereogenic benzylic methyl group was the most potent agonist, registering a respectable EC50 of 339 nM and a maximal response (Emax) of 96 % in this assay. In vivo pharmacokinetic analysis indicated good brain exposure for several analogs. Our combined results provide important information towards a structurally novel class of orexin receptor agonists distinct from current chemotypes.

Synthesis and antibacterial activities of heterocyclic ring-fused 20(S)-protopanaxadiol derivatives.

Multidrug-resistant (MDR) bacterial infections are becoming a life-threatening issue in public health; therefore, it is urgent to develop novel antibacterial agents for treating infections caused by MDR bacteria. The 20(S)-protopanaxadiol (PPD) derivative 9 was identified as a novel antibacterial hit compound in screening of our small synthetic natural product-like (NPL) library. A series of novel PPD derivatives with heterocyclic rings fused at the C-2 and C-3 positions of the A-ring were synthesized and their antibacterial activities against Staphylococcus aureus (S. aureus) Newman strain and MDR S. aureus strains (USA300, NRS-1, NRS-70, NRS-100, NRS-108, NRS-271, XJ017, and XJ036) were evaluated. Among these compounds, quinoxaline derivative 56 (SH617) exhibited the highest activity with MICs of 0.5-4 µg/mL against the S. aureus Newman strain and the eight MDR S. aureus strains. Its antibacterial activity was comparable to that of the positive control, vancomycin. In the zebrafish, 56 revealed no obvious toxicity even at a high administered dose. In vivo, following a lethal infection induced by USA300 strains in zebrafish, 56 exhibited significantly increased survival rates in a dose-dependent manner.

Multicomponent synthesis of 3-(1H-indol-3-yl)-2-phenyl-1H-benzo[f]indole-4,9-dione derivatives.

Herein, we report a one-pot greener methodology for the synthesis of 3-(1H-indol-3-yl)-2-phenyl-1H-benzo[f]indole-4,9-dione derivatives by the multicomponent reaction of arylglyoxal monohydrate, 2-amino-1,4-naphthoquinone, and indole in acetonitrile medium under reflux conditions in the presence of 10 mol% sulfamic acid as a catalyst in 20-30 min of reaction time. Three new bonds have formed (2 C-C, 1 C-N) in this methodology. Bioactive moieties such as indole, pyrrole and naphthoquinone are present in our product. This methodology is also applicable in gram-scale synthesis. A wide variety of substrates were tested to find the generality of the methodology and good yield of the products were obtained in a very short reaction time. Along with the operational simplicity of the methodology, purification process of the products is easier by simple recrystallization process. All the synthesized products were characterized by spectroscopic techniques such as FTIR, 1H NMR, 13C NMR, and HRMS.

Oxidative Coupling of Hydroquinone Derivatives with Olefins to Dihydrobenzofurans.

Dihydrobenzofuran is an important skeleton for bioactive compounds and natural products. Hydroquinones can be easily modified into substituted hydroquinones, which effectively undergo oxidation to produce the corresponding benzoquinone derivatives. Benzoquinones are reactive electrophiles that are frequently utilized in coupling with olefins to dihydrobenzofurans. Herein, we report the one-pot oxidative coupling of hydroquinones bearing an electron-withdrawing group at the C2 position with olefins to dihydrobenzofurans in the presence of the Lewis acidic FeCl3 and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) oxidant. Furthermore, this method was applied to the oxidative coupling of N-electron-withdrawing group-substituted 4-aminophenol.

Annulated Heterocyclic[g]Coumarin Composites: Synthetic Approaches and Bioactive Profiling.

Coumarins, widely abundant natural heterocyclic compounds, are extensively employed in creating various biologically and pharmacologically potent substances. The hybridization of heterocycles presents a key opportunity to craft innovative multicyclic compounds with enhanced biological activity. Fusing different heterocyclic rings with the coumarin structure presents an intriguing method for crafting fresh hybrid compounds possessing remarkable biological effects. In the pursuit of creating heterocyclic-fused coumarins, a wide range of annulated heterocyclic[g]coumarin composites has been introduced, displaying impressive biological potency. The influence of the linear attachment of heterocyclic rings to the coumarin structure on the biological performance of the resulting compounds has been investigated. This review centers on the synthetic methodologies, structural activity relationship investigation, and biological potentials of annulated heterocyclic[g]coumarin composites. We conducted searches across several databases, including Web of Science, Google Scholar, PubMed, and Scopus. After sieving, we ultimately identified and included 71 pertinent studies published between 2000 and the middle of 2023. This will provide valuable perspectives for medicinal chemists in the prospective design and synthesis of lead compounds with significant therapeutic effects, centered around heterocycle-fused coumarin frameworks.

A Comprehensive Examination of Heterocyclic Scaffold Chemistry for Antitubercular Activity.

Tuberculosis is a communicable disease which affects humans particularly the lungs and is transmitted mainly through air. Despite two decades of intensive research aimed at understanding and combating tuberculosis, persistent biological uncertainties continue to hinder progress. Nowadays, heterocyclic compounds have proven themselves in effective treatment of tuberculosis because of their wide range of biological and pharmacological activities. Antituberculosis or antimycobacterial agents encompass a broad array of compounds utilized singly or in conjunction to combat Mycobacterium infections, spanning from tuberculosis to leprosy. Here, we summarize the synthesis of various heterocyclic compounds which includes the greener synthetic route as well as use of nano compounds as catalyst along with their anti TB activities.

Synthesis and evaluation of larvicidal efficacy against C. pipiens of some new heterocyclic compounds emanated from 2-cyano-N'-(2-(2,4-dichlorophenoxy)acetyl)acetohydrazide.

Several infectious diseases are transmitted and spread by mosquitoes, and millions of people die annually from them. The mosquito, Culex pipiens is a responsible for the emergence of various Virus in Egypt. So, we devote our work to evaluate the larvicidal efficacy against C. pipiens of some new heterocyclic compounds containing chlorine motifs. The implementation was emanated from using 2-cyano-N'-(2-(2,4-dichlorophenoxy)acetyl)acetohydrazide (3) as scaffold to synthesize some new heterocyclic compounds. The structures of the synthesized compounds were interpreted scrupulously by spectroscopic and elemental analyses. Thereafter, the larvicidal activity against C. pipiens of thirteen synthesized compounds was estimated. Noteworthy, cyanoacetohydrazide derivative 3 and 3-iminobenzochromene derivative 12 showed a fabulous potent efficacy with LC50 equal to 3.2 and 3.5 ppm against C. pipiens, respectively, and are worth being further evaluated in the field of pest control.

Recent Advances in the Synthesis of Rosettacin.

Camptothecin and its analogues show important antitumor activity and have been used in clinical studies. However, hydrolysis of lactone in the E ring seriously attenuates the antitumor activity. To change this situation, aromathecin alkaloids are investigated in order to replace camptothecins. Potential antitumor activity has obtained more and more attention from organic and pharmaceutical chemists. As a member of the aromathecin alkaloids, rosettacin has been synthesized via different methods. This review summarizes recent advances in the synthesis of rosettacin.

Coordinative Compounds Based on Unsaturated Carboxylate with Versatile Biological Applications.

This review presents an overview of the biological applications of coordinative compounds based on unsaturated carboxylates accompanied by other ligands, usually N-based heterocyclic species. The interest in these compounds arises from the valuable antimicrobial and antitumor activities evidenced by some species, as well as from their ability to generate metal-containing polymers suitable for various medical purposes. Therefore, we describe the recently discovered aspects related to the synthesis, structure, and biological activity of a wide range of unsaturated carboxylate-containing species and metal ions, originating mostly from 3d series. The unsaturated carboxylates encountered in coordinative compounds are acrylate, methacrylate, fumarate, maleate, cinnamate, ferulate, coumarate, and itaconate. Regarding the properties of the investigated compounds, it is worth mentioning the good ability of some to inhibit the development of resistant strains or microbial biofilms on inert surfaces or, even more, exert antitumor activity against resistant cells. The ability of some species to intercalate into DNA strands as well as to scavenge ROS species is also addressed.

Iodine-Catalyzed Cascade Annulation of 4-Hydroxycoumarins with Aurones: Access to Spirocyclic Benzofuran-Furocoumarins.

An attractive approach for the preparation of spirocyclic benzofuran-furocoumarins has been developed through iodine-catalyzed cascade annulation of 4-hydroxycoumarins with aurones. The reaction involves Michael addition, iodination, and intramolecular nucleophilic substitution in a one-step process, and offers an efficient method for easy access to a series of valuable spirocyclic benzofuran-furocoumarins in good yields (up to 99%) with excellent stereoselectivity. Moreover, this unprecedented protocol provides several advantages, including readily available materials, an environmentally benign catalyst, a broad substrate scope, and a simple procedure.

Room Temperature Diels-Alder Reactions of 4-Vinylimidazoles.

In the course of studying Diels-Alder reactions of 4-vinylimidazoles with N-phenylmaleimide, it was discovered that they engage in cycloaddition at room temperature to give high yields of the initial cycloadduct as a single stereoisomer. In certain cases, the product precipitated out of the reaction mixture and could be isolated by simple filtration, thereby avoiding issues with aromatization observed during chromatographic purification. Given these results, intramolecular variants using doubly activated dienophiles were also investigated at room temperature. Amides underwent cycloaddition at room temperature in modest yields, but the initial adducts were not isolable with Nimid-benzyl-protected systems. Attempts to extend these results to the corresponding esters and hydroxamate were less successful with these substrates only undergoing cycloaddition at elevated temperatures in lower yields. Density functional theory calculations were performed to evaluate the putative transition states for both the inter- and intramolecular variants to rationalize experimental observations.

Reaction of Pyrrolobenzothiazines with Schiff Bases and Carbodiimides: Approach to Angular 6/5/5/5-Tetracyclic Spiroheterocycles.

1H-Pyrrole-2,3-diones, fused at [e]-side with a heterocycle, are suitable platforms for the synthesis of various angular polycyclic alkaloid-like spiroheterocycles. Recently discovered sulfur-containing [e]-fused 1H-pyrrole-2,3-diones (aroylpyrrolobenzothiazinetriones) tend to exhibit unusual reactivity. Based on these peculiar representatives of [e]-fused 1H-pyrrole-2,3-diones, we have developed an approach to an unprecedented 6/5/5/5-tetracyclic alkaloid-like spiroheterocyclic system of benzo[d]pyrrolo[3',4':2,3]pyrrolo[2,1-b]thiazole via their reaction with Schiff bases and carbodiimides. The experimental results have been supplemented with DFT computational studies. The synthesized alkaloid-like 6/5/5/5-tetracyclic compounds have been tested for their biotechnological potential as growth stimulants in the green algae Chlorella vulgaris.