Cycloadditions of Diazoalkenes with P4 and tBuCP: Access to Diazaphospholes.

Diazoalkenes readily react with tert­butylphosphaalkyne (tBuCP) and white phosphorus (P4) to afford novel phosphorus heterocycles, 3H­1,2,4-diazamonophospholes and 1,2,3,4-diazadiphospholes. Both species represent rare examples of neutral heterophospholes. The mechanism of formation and the electronic structures of these formal (3+2) cycloaddition products were analyzed computationally. The new phospholes form structurally diverse coordination compounds with transition metal and main group elements. Given the growing number of stable diazoalkenes, this work offers a straightforward route to neutral aza(di-)phospholes as a new ligand class.

Recent Developments on the Synthesis of Oxygen- and Sulfur-containing Heterocycles and their Derivatives under Visible Light Induced Reactions.

Visible-light-mediated reactions have recently emerged as a powerful strategy for the synthesis of diverse organic molecules under mild reaction conditions. Usually, the reactions are performed at room temperature and thus sensitive functional groups remain unaffected. Thus, this protocol has received intense interest from academia as well as industries. The heterocycles, in general, are of much interest because of their biological activities and application in therapeutics. The Oxygen- and Sulfur-containing heterocyclic compounds have recently attracted attention as these compounds showed promising activities as anti-cancer drugs, antibiotics, antifungal and anti-inflammatory agents among other applications. The synthesis of this class of compounds by efficient and greener routes has become an important target. This review highlights the various procedures for the synthesis of these compounds and their derivatives under visible light-induced reactions. The green aspects and mechanism of each procedure have been discussed.

Photostability of Phenoxazine Derivatives.

Phenoxazine is a commonly used molecular building block, for example in optoelectronic applications and pharmaceuticals. However, it is highly susceptible to rapid photodegradation, especially in halogenated solvents. In the present study, we identify the degradation products in both halogenated and non-halogenated solvents by UV/Vis absorption, NMR spectroscopy and mass spectrometry. We also propose a substitution strategy aimed at effectively suppressing the high photoreactivity. Kinetic studies show that the quantum yield of photodegradation Ï• differs by a factor of more than 1000 between trisubstituted derivatives and N-substituted phenoxazine.

Electrochemical Skeletal Indole Editing via Nitrogen Atom Insertion by Sustainable Oxygen Reduction Reaction.

Skeletal molecular editing gained considerable recent momentum and emerged as a uniquely powerful tool for late-stage diversifications. Thus far, superstoichiometric amounts of costly hypervalent iodine(III) reagents were largely required for skeletal indole editing. In contrast, we herein show that electricity enables sustainable nitrogen atom insertion reactions to give bio-relevant quinazoline scaffolds without stoichiometric chemical redox-waste product. The transition metal-free electro-editing was enabled by the oxygen reduction reaction (ORR) and proved robust on scale, while tolerating a variety of valuable functional groups.

Eco-friendly approaches to 1,3,4-oxadiazole derivatives: A comprehensive review of green synthetic strategies.

This review article offers an environmentally benign synthesis of 1,3,4-oxadiazole derivatives, with a focus on sustainable methodologies that have minimal impact on the environment. These derivatives, known for their diverse applications, have conventionally been associated with synthesis methods that utilize hazardous reagents and produce significant waste, thereby raising environmental concerns. The green synthesis of 1,3,4-oxadiazole derivatives employs renewable substrates, nontoxic catalysts, and mild reaction conditions, aiming to minimize the environmental impact. Innovative techniques such as catalyst-based, catalyst-free, electrochemical synthesis, green-solvent-mediated synthesis, grinding, microwave-mediated synthesis, and photosynthesis are implemented, providing benefits in terms of scalability, cost-effectiveness, and ease of purification. This review emphasizes the significance of sustainable methodologies in the synthesis of 1,3,4-oxadiazole and boots for continued exploration in this research domain.

Recent Progress on Transition Metal Catalyzed Macrocyclizations Based on C-H Bond Activation at Heterocyclic Scaffolds.

Macrocycles are essential in protein-protein interactions and the preferential intake of bioactive scaffolds. Macrocycles are commonly synthesized by late-stage macrolactonizations, macrolactamizations, transition metal-catalyzed ring-closing metathesis, S-S bond-forming reactions, and copper-catalyzed alkyne-azide cycloaddition. Recently, transition metal-catalyzed C-H activation strategies have gained significant interest among chemists to synthesize macrocycles. This article provides a comprehensive overview of the transition metal-catalyzed macrocyclization via C-H bond functionalization of heterocycle-containing peptides, annulations, and heterocycle-ring construction through direct C-H bond functionalization. In the first part, palladium salt catalyzed coupling with indolyl C(sp3)-H and C(sp2)-H bonds for macrocyclization is reported. The second part summarizes rhodium-catalyzed macrocyclizations via site-selective C-H bond functionalization. Earth-abundant, less toxic 3d metal salt Mn-catalyzed cyclizations are reported in the latter part. This summary is expected to spark interest in emerging methods of macrocycle production among organic synthesis and chemical biology practitioners, helping to develop the discipline. We hope that this mini-review will also inspire synthetic chemists to explore new and broadly applicable C-C bond-forming strategies for macrocyclization via intramolecular C-H activation.

N-Benzyl piperidine Fragment in Drug Discovery.

The N-benzyl piperidine (N-BP) structural motif is commonly employed in drug discovery due to its structural flexibility and three-dimensional nature. Medicinal chemists frequently utilize the N-BP motif as a versatile tool to fine-tune both efficacy and physicochemical properties in drug development. It provides crucial cation-π interactions with the target protein and also serves as a platform for optimizing stereochemical aspects of potency and toxicity. This motif is found in numerous approved drugs and clinical/preclinical candidates. This review focuses on the applications of the N-BP motif in drug discovery campaigns, emphasizing its role in imparting medicinally relevant properties. We provide an overview of approved drugs, the clinical and preclinical pipeline, and discuss its utility for specific therapeutic targets and indications, along with potential challenges.

Phosphetene-based polyaromatics: structure-property relationships and chiroptical tuning.

We describe the synthesis of π-extended phosphetene rings (4-member P-rings) flanked with PAH systems of various topologies. These compounds are fully characterized including X-ray diffraction. The impact of both the polyaromatic platform and the P-ring on the structure, and the optical and redox properties are investigated both experimentally and theoretically. Although neither the P centre nor the 4-membered ring significantly takes part in the HOMO or LUMO orbitals, both structural features have an important modulating role in distorting the symmetry of the orbitals, leading to chiroptical properties. The stereogenic P-atom is used as a remote chiral perturbator to induce circularly polarized luminescence of the polyaromatic system. The dissymmetry factor is highly dependent on the polyaromatic topology, as supported by theoretical calculations.

Bioisosteric heterocyclic analogues of natural bioactive flavonoids by scaffold-hopping approaches: State-of-the-art and perspectives in medicinal chemistry.

The flavonoid family is a set of well-known bioactive natural molecules, with a wide range of potential therapeutic applications. Despite the promising results obtained in preliminary in vitro/vivo studies, their pharmacokinetic and pharmacodynamic profiles are severely compromised by chemical instability. To address this issue, the scaffold-hopping approach is a promising strategy for the structural optimization of natural leads to discover more potent analogues. In this scenario, this Perspective provides a critical analysis on how the replacement of the chromon-4-one flavonoid core with other bioisosteric nitrogen/sulphur heterocycles might affect the chemical, pharmaceutical and biological properties of the resulting new chemical entities. The investigated derivatives were classified on the basis of their biological activity and potential therapeutic indications. For each session, the target(s), the specific mechanism of action, if available, and the key pharmacophoric moieties were highlighted, as revealed by X-ray crystal structures and in silico structure-based studies. Biological activity data, in vitro/vivo studies, were examined: a particular focus was given on the improvements observed with the new heterocyclic analogues compared to the natural flavonoids. This overview of the scaffold-hopping advantages in flavonoid compounds is of great interest to the medicinal chemistry community to better exploit the vast potential of these natural molecules and to identify new bioactive molecules.

Domino reactions of chromones with activated carbonyl compounds.

Domino reactions of chromones with activated carbonyl compounds, such as dimethyl acetone-1,3-dicarboxylate and 1,3-diphenylacetone, and with 1,3-bis(silyloxy)-1,3-butadienes, electroneutral equivalents of 1,3-dicarbonyl dianions, allow for a convenient synthesis of a great variety of products. The regioselectivity and course of the reaction depends of the substituent located at carbon C3 of the chromone moiety and also on the type of nucleophile employed.

Bismuth(III) triflate: an economical and environmentally friendly catalyst for the Nazarov reaction.

We describe the use of bismuth(III) triflate as an efficient and environmentally friendly catalyst for the Nazarov reaction of aryl vinyl ketones, leading to the synthesis of 3-aryl-2-ethoxycarbonyl-1-indanones and 3-aryl-1-indanones. By changing the temperature and reaction time, it was possible to modulate the reactivity, allowing the synthesis of two distinct product classes (3-aryl-2-ethoxycarbonyl-1-indanones and 3-aryl-1-indanones) in good to excellent yield. The reaction did not require additives and was insensitive to both air and moisture. Preliminary biological evaluation of some indanones showed a promising profile against some human cancer line cells.

Synthesis and optical properties of bis- and tris-alkynyl-2-trifluoromethylquinolines.

Three bis- or tris-brominated 2-trifluoromethylquinolines have been successfully applied in palladium-catalysed Sonogashira reactions, leading to several examples of alkynylated quinolines in good to excellent yields. Optical properties of selected products have been studied by steady state absorption and fluorescence spectroscopy which give insights of the influence of the substitution pattern and of the type of substituents on the optical properties.

The Catalysts-Based Synthetic Approaches to Quinolines: A Review.

The most common heterocyclic aromatic molecule with potential uses in industry and medicine is quinoline. Its chemical formula is C9H7N, and it has a distinctive double-ring structure with a pyridine moiety fused with a benzene ring. Various synthetic approaches synthesize quinoline derivatives. These approaches include solvent-free synthetic approach, mechanochemistry, ultrasonic, photolytic synthetic approach, and microwave and catalytic synthetic approaches. One of the important synthetic approaches is a catalyst-based synthetic approach in which different catalysts are used such as silver-based catalysts, titanium-based nanoparticle catalysts, new iridium catalysts, barium-based catalysts, iron-based catalysts, gold-based catalysts, nickel-based catalyst, some metal-based photocatalyst, α-amylase biocatalyst, by using multifunctional metal-organic framework-metal nanoparticle tandem catalyst etc. In the present study, we summarized different catalyst-promoted reactions that have been reported for the synthesis of quinoline. Hopefully, the study will be helpful for the researchers.

Unlocking nitrogen compounds' promise against malaria: A comprehensive review.

Plasmodium parasites are the primary cause of malaria, leading to high mortality rates, which require clinical attention. Many of the medications used in the treatment have resulted in resistance over time. Artemisinin combination therapy (ACT) has shown significant results for the treatment. However, mutations in the parasite have resulted in resistance, leading to decreased efficiency of the medications that are currently being used. Therefore, there is a critical need to find novel scaffolds that are safe, effective, and of economic advantage. Literature has reported several potent molecules with diverse scaffolds designed, synthesized, and evaluated against different strains of Plasmodium. With this growing list of compounds, it is essential to collect the data in one place to gain a concise overview of the emerging scaffolds in recent years. For this purpose, nitrogen-containing heterocycles such as ß-carboline, imidazole, quinazoline, quinoline, thiazole, and thiophene have been highly explored due to their wide biological applications. Besides these, another scaffold, benzodiazepine, which is majorly used as a central nervous system depressant, is emerging as an anti-malarial agent. Hence, this review centers on the latest medication advancements designed to combat malaria, emphasizing special attention to 1,4-benzodiazepines as a novel scaffold for antimalarial drug discovery.

Rapid Access to Divergent Fused Polycycles Via One-Pot A3 Coupling and Intramolecular Diels-Alder Reaction.

Divergent nitrogen-containing fused polycyclic ring systems are constructed from simple starting materials via a one-pot aldehyde-alkyne-amine (A3) coupling and intramolecular Diels-Alder reaction. This domino reaction directly furnishes linear 5/5/5 and 5/5/6, or nonlinear 5/5/6/5, polycyclic rings containing an oxa-bridged fused 5/5 bicycle and a 1,6-enyne substructure. One-step derivation of the oxa-bridged 5/5 bicycle leads to a polyfunctionalized 5/5 bicycle with tetrahydrofuran fused back-to-back to pyrroline or a 6/5 bicycle with the hexahydro-1H-isoindole structure, while cycloisomerizing the enyne substructure adds an extra fused 5-membered ring to afford functionalized linear 5/5/5/5 or 5/5/5/5/5 fused ring systems from selected substrates. In addition, the one-pot product can be designed so that the alkyne moiety is hydroalkoxylated to form an additional heterocyle in a linear 5/5/5/6 or nonlinear 5/5/6/5/5 ring system. This diversity-oriented synthetic approach thus allows rapid access to an under-explored structural space for discovery of new biological or non-biological activities or functions.

Anticancer Potential of the S-Heterocyclic Ring Containing Drugs and its Bioactivation to Reactive Metabolites.

Sulfur-containing heterocyclic derivatives have been disclosed for binding with a wide range of cancer-specific protein targets. Various interesting derivatives of sulfur-containing heterocyclics such as benzothiazole, thiazole, thiophene, thiazolidinedione, benzothiophene, and phenothiazine, etc have been shown to inhibit diverse signaling pathways implicated in cancer. Significant progress has also been made in molecular targeted therapy against specific enzymes such as kinase receptors due to potential binding interactions inside the ATP pocket. Sulfur-containing heterocyclic ring metal complexes i. e., benzothiazole, thiazole, thiophene, benzothiophene and phenothiazines are among the most promising active anticancer compounds. However, sulfur heteroaromatic rings, particularly thiophene, are of high structural alert due to their metabolism to reactive metabolites. The mere presence of a structural alert itself does not determine compound toxicity therefore, this review focuses on some specific findings that shed light on factors influencing the toxicity. In the current review, synthetic strategies of introducing the sulfur core ring in the synthesized derivatives are discussed with their structure-activity relationships to enhance our understanding of toxicity mechanisms and develop safer therapeutic options. The sulfur-containing marketed anticancer drugs included in this review direct the synthesis of novel compounds and will help in the development of potent, safer sulfur-based anticancer drugs in near future.

Coinage Metal Complexes of a Sterically Encumbered Anionic Pyridylborate.

Sterically loaded, anionic pyridine has been synthesized and utilized successfully in the stabilization of a isoleptic series of coinage metal complexes. The treatment of [4-(Ph3B)-2,6-Trip2Py]K (Trip=2,4,6-iPr3C6H2) with CuBr(PPh3), AgCl(PPh3) or AuCl(PPh3) (Py=pyridine) afforded the corresponding [4-(Ph3B)-2,6-Trip2Py]M(PPh3) (M=Au, Ag, Cu) complexes, via salt metathesis, as isolable, crystalline solids. Notably, these reactions avoid the facile single electron transfer chemistry reported with the less bulky ligand systems. The X-ray structures revealed that they are two-coordinate metal adducts. The M-N and M-P bond distances are longest in the silver and shortest in the copper adduct among the three group 11 family members. Computational analysis revealed an interesting stability dependence on steric bulk of the anionic pyridine (i. e., pyridyl borate) ligand. A comparison of structures and bonding of [4-(Ph3B)-2,6-Trip2Py]Au(PPh3) to pyridine and m-terphenyl complexes, {[2,6-Trip2Py]Au(PPh3)}[SbF6] and [2,6-Trip2Ph]Au(PPh3) are also provided. The Au(I) isocyanide complex, [4-(Ph3B)-2,6-Trip2Py]Au(CNBut) has been stabilized using the same anionic pyridylborate illustrating that it can support other gold-ligand moieties as well.

Regiodivergent Synthesis of 4- and 5-Sulfenyl Oxazoles from Alkynyl Thioethers.

The regiodivergent synthesis of 4- and 5-sulfenyl oxazoles from 1,4,2-dioxazoles and alkynyl thioethers has been achieved. Gold-catalysed conditions are used to favour the formation of 5-sulfenyl oxazoles via ß-selective attack of the nitrenoid relative to the sulfenyl group. In contrast, 4-sulfenyl oxazoles are formed by α-selective reaction under Brønsted acid conditions from the same substrates. The nature of stabilising gold-sulfur interactions have been investigated by natural bond orbital analysis, showing that the S→Au interactions are significantly stronger in the intermediate that favours the 5-sulfenyl oxazoles. A kinetic survey identifies catalyst inhibition processes. This study into the regiodivergent methods includes the development of telescoped annulation-oxidation protocols for regioselective access to oxazole sulfoxides and sulfones.

Novel Pyrazole-Chalcone Hybrids: Synthesis and Computational Insights Against Breast Cancer.

More women die of breast cancer than of any other malignancy. The resistance and toxicity of traditional hormone therapy created an urgent need for potential molecules for treating breast cancer effectively. Novel biphenyl-substituted pyrazole chalcones linked to a pyrrolidine ring were designed by using a hybridization approach. The hybrids were assessed against MCF-7 and MDA-MB-231 cells by NRU assay. Among them, 8 k, 8 d, 8 m, 8 h, and 8 f showed significantly potent IC50 values: 0.17, 5.48, 8.13, 20.51, and 23.61 µM) respectively, on MCF-7 cells compared to the positive control Raloxifene and Tamoxifen. Furthermore, most active compound 8 k [3-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(2-(2-(pyrrolidin-1-yl)-ethoxy)-phenyl)-chalcone] showed cell death induced through apoptosis, cell cycle arrest at the G2/M phase, and demonstrated decrease of ER-α protein in western blotting study. Docking studies of 8 k and 8 d established adequate interactions with estrogen receptor-α as required for SERM binding. The active hybrids exhibited good pharmacokinetic properties for oral bioavailability and drug-likeness. Whereas, RMSD, RMSF, and Rg values from Molecular dynamics studies stipulated stability of the complex formed between compound 8 k and receptor. All of these findings strongly indicate the antiproliferative potential of pyrazole-chalcone hybrids for the treatment of breast cancer.

Indole as a Versatile Building Block in Cycloaddition Reactions: Synthesis of Diverse Heterocyclic Frameworks.

Indole, a ubiquitous and structurally versatile aromatic compound, has emerged as a key player in the synthesis of diverse heterocyclic frameworks via cycloaddition reactions. These reactions are completely atom-economical and, hence, are considered as green reactions. This review article provides a comprehensive overview of the pivotal role played by indole in the construction of complex and biologically relevant heterocyclic compounds. Here we explore the chemistry of indole-based cycloadditions, highlighting their synthetic utility in accessing a wide array of heterocyclic architectures, including cyclohepta[b]indoles, tetrahydrocarbazoles, tetrahydroindolo[3,2-c]quinoline, and indolines, among others. Additionally, we discuss the mechanistic insights that underpin these transformations, emphasizing the strategic importance of indole as a building block. The content of this article will certainly encourage the readers to explore more work in this area.