Arylthianthrenium Salts Enabled Palladium-Catalyzed Regioselective Arylation: Access to Value-Added 7-Azaindoles.

A step-economic and efficient palladium-catalyzed protocol for regioselective C-2 arylation of 7-azaindoles with arylthianthrenium salts has been developed under base- and ligand-free conditions. The reaction proceeds smoothly with broad substrate scope, requires low catalyst loading, exhibits excellent functional group tolerance, and provides C-2 arylated products in moderate to excellent yields. Moreover, given the ready availability of arylthianthrenium salts from simple arenes, this strategy offers a valuable platform for the late-stage functionalization of structurally complex and bioactive molecules.

(Methyl)thianthrenium Salt Enabled Monoselective -Methylation and -(-Methyl) Labeling: Late-Stage Functionalization of Arylamides.

Herein, we report a practical and efficient approach for the monoselective -methylation of arylamide substrates using (methyl)thianthrenium triflate as an effective methylating agent. This strategy enables late-stage selective -monomethylation of structurally complex bioactive molecules with excellent efficiency and selectivity. Notably, the protocol facilitates monoselective -(-methyl) incorporation, providing access to isotopically labeled compounds of pharmaceutical interest for drug discovery and development.

CuF-Catalyzed Chan-Lam Reaction of Saccharin: Solvent-Controlled Chemodivergent Synthesis of -Arylsaccharin and Methyl 2-(-Arylsulfamoyl)benzoates.

A solvent-controlled CuF-catalyzed Chan-Lam coupling of saccharin with arylboronic acids is reported, enabling the chemodivergent synthesis of -arylsaccharin derivatives in dichloroethane and methyl 2-(-arylsulfamoyl)benzoates in MeOH. A saccharin-DMAP zwitterion complex was isolated, which provided crucial mechanistic insights for the product distribution. This chemodivergent synthesis transformed saccharin into versatile synthons for the synthesis of a tianeptine analogue and an endothelin antagonist analogue, highlighting its pharmaceutical relevance.

HFIP-Promoted Regioselective Hydrofunctionalization of Enamides and -Vinyl Azoles.

An efficient and regioselective method for the intermolecular hydrofunctionalization of enamides and -vinyl azoles has been developed, enabling the formation of diverse C-S, C-O, C-N, and C-C bonds. This transition-metal-free, additive-free, and Brønsted acid-free protocol employs hexafluoroisopropanol (HFIP) as the sole reagent, which plays a dual role: formation of iminium carbocation intermediate and facilitating nucleophile generation through its hydrogen-bonding network. The reaction demonstrates exceptional substrate versatility, accommodating thiophenols, alcohols, heterocyclic amines, as well as -free indoles, pyrroles, and carbazoles as nucleophiles, proceeding via a Markovnikov-selective hydrofunctionalization pathway.

CuF/DTBP-Catalyzed Chan-Lam Coupling of Oxazolidinones with Arylboronic Acid Pinacol Ester: Scope and Application.

A new combination of CuF/DTBP-catalyzed -arylation of oxazolidinones, amides, amines, and azoles has been explored with arylboronic acid pinacol esters (arylBpin). This methodology has also been applied to the synthesis of oxazolidinone-based marketed drugs, including Rivaroxaban, Linezolid, Sutezolid, and Toloxatone. Mechanistic investigations using various spectroscopic techniques and DFT studies revealed the role of DTBP/MeOH in the catalytic process.

Combined Arthroscopic Anterior Cruciate Ligament Reconstruction and Distal Femoral Osteotomy in a Patient of Bilateral Genu Valgum - A Rare Case Report.

Introduction: Anterior cruciate ligament (ACL) injury sometimes is associated with genu valgum. Valgus malalignment poses concerns due to its potential to increase strain on the ACL, thereby elevating the risk of osteoarthritis in the lateral compartment of the knee. However, lacune still exists regarding the concomitant reconstruction of ACL and distal femoral osteotomy in ACL-deficit knee with genu valgum.

Ex Situ Generation of D for Reductive Deuteration: Scope and Application to Late-Stage Functionalization.

An efficient deuteration method through the ex situ generation of D for the reductive deuteration of biologically significant α-substituted acrylic acids and enamide derivatives is reported. This method was successfully applied to the synthesis of deuterated analogs of marketed NSAIDs such as ibuprofen, flurbiprofen, and naproxen. Additionally, it facilitates late-stage deuteration of enamides and -vinylated drugs.

Iodine-Catalyzed Regioselective C-3 Chalcogenation of 7-Azaindoles: Access to Benzothiophene-Fused 7-Azaindole Analogs.

An iodine-catalyzed method has been reported for efficient regioselective C-3 sulfenylation, selenylation, thiocyanation, and selenocyanation of -free 7-azaindoles using thiophenols, diselenides, potassium thiocyanates, and selenocyanates, respectively. This approach showcases high efficiency and remarkable versatility, facilitating the synthesis of diverse chalcogenated 7-azaindoles. Additionally, the sulfenylated derivatives have been further diversified to generate a new array of benzothiophene-fused 7-azaindole cores of pharmaceutical interest.

Exploiting Chloroform-COware Chemistry for Pd-Catalyzed Carbonylation of Naturally Occurring and Medicinally Relevant Phenols.

In this study, a ligand-free palladium-catalyzed carbonylation of phenols is conducted under ambient conditions, utilizing the "Chloroform-COware" chemistry. The developed methodology enables the conversion of diverse medicinally relevant phenols, encompassing both natural and synthetic derivatives, into their respective aryl ester counterparts. This transformation is achieved through the reaction with a broad spectrum of aryl and heteroaryl iodides.

Pyrazolopyridine-based kinase inhibitors for anti-cancer targeted therapy.

The need for effective cancer treatments continues to be a challenge for the biomedical research community. In this case, the advent of targeted therapy has significantly improved therapeutic outcomes. Drug discovery and development efforts targeting kinases have resulted in the approval of several small-molecule anti-cancer drugs based on ATP-mimicking heterocyclic cores.

Ullmann-Type -, -, and -Arylation Using a Well-Defined 7-Azaindole--oxide (7-AINO)-Based Copper(II) Catalyst: Scope and Application to Drug Synthesis.

An air-stable, robust, and well-defined copper(II)-7-azaindole--oxide-based catalyst [Cu(7-AINO)] (abbreviated as Cu(II)-7-AINO) has been demonstrated as an efficient catalyst for various Ullmann-type coupling reactions. This easily prepared and cost-effective catalyst facilitates the arylation and heteroarylation of diverse -, -, and -nucleophiles, including azoles, aminoazoles, (hetero)arylthiols, and phenols. Notably, they also exhibit substantial compatibility with a wide range of functional groups.

CuI/DMAP-Catalyzed Oxidative Alkynylation of 7-Azaindoles: Synthetic Scope and Mechanistic Studies.

An efficient and practical method for the N-alkynylation of 7-azaindoles has been established by using CuI/DMAP catalytic system at room temperature and in open air. This simple protocol has been successfully employed in the synthesis of a wide range of N-alkynylated 7-azaindoles with good yields. Also, this approach is well-suited for large-scale N-alkynylation reactions.

Two-Chamber-Enabled Hydrogenation Reactions Using Al-HO/NaOH: Access to Pharmaceuticals.

In this study, an efficient method for hydrogenation reactions has been reported in a short reaction time using a two-chamber reactor. This process involves the ex situ generation of H gas using aluminum-water in the presence of NaOH. This technique was applied to reduce various functional groups, including carbonyl, nitro, alkene, alkyne, and azide.

Carbonylative Transformations Using a DMAP-Based Pd-Catalyst through Ex Situ CO Generation.

A phosphine-free, efficient protocol for aminocarbonylation and carbonylative Suzuki-Miyaura coupling has been developed using a novel palladium complex, [Pd(DMAP)(OAc)]. The complex was successfully synthesized using a stoichiometric reaction between Pd(OAc) and DMAP in acetone at room temperature and characterized using single-crystal X-ray analysis. Only 5 mol % catalyst loading was sufficient for effective carbonylative transformations.

CuF/MeOH-Catalyzed N-Selective Chan-Lam Coupling of Hydantoins: Method and Mechanistic Insight.

An efficient and practical N-arylation of hydantoins with substituted aryl/heteroaryl boronic acids has been established, assisted by CuF/MeOH under the base and ligand-free conditions at room temperature and open air. The protocol is general, and various N-arylated hydantoins have been prepared in excellent yields with exclusive regioselectivity. The CuF/MeOH combination was explored further to furnish selective N-arylation of 5-fluorouracil nucleosides.

Synthesis of C3,C6-Diaryl 7-Azaindoles via One-Pot Suzuki-Miyaura Cross-Coupling Reaction and Evaluation of Their HIV-1 Integrase Inhibitory Activity.

There is a continuing demand of new inhibitors of HIV-1 Integrase (HIV-1 IN) due to mutations of HIV-1. This study aims to develop the synthesis of 3,6-diaryl 7-azaindoles and introspect the role of aryl groups on the strand transfer (ST) inhibition of HIV-1 IN. An efficient and chemo-selective one-pot method is established for the synthesis of the unexplored diverse C3 → C6 diaryl 7-azaindoles starting from 6-chloro-3-iodo--protected 7-azaindoles.

CuF/DMAP-Catalyzed N-Vinylation: Scope and Mechanistic Study.

CuF/DMAP has been established as an excellent catalytic system for vinylsilane-promoted N-vinylation of amides and azoles at room temperature without an external fluoride source. A mechanism has been proposed on the basis of the isolation of reactive intermediate [Cu(DMAP)Cl], fluoride ion-assisted transmetalation, and ultraviolet-visible spectroscopic studies. The catalytic efficiency of the synthesized and structurally characterized [Cu(DMAP)Cl] complex has been demonstrated.

Exploiting Coordination Behavior of 7-Azaindole for Mechanistic Investigation of Chan-Lam Coupling and Application to 7-Azaindole Based Pharmacophores.

Multiple spectroscopic techniques, along with single-crystal X-ray analysis, have been used to reveal the detailed structural and electronic information on reaction intermediates of a new copper(II)-DBU catalytic system for the N-arylation of 7-Azaindole. The reaction mixture of Chan-Lam cross-coupling yields two dimeric copper(II)-7-azaindole complexes, including one attached with DBU, prior to adding arylboronic acid and are confirmed structurally and spectroscopically. A suitable mechanism has been proposed using the dimeric copper(II) complex as a catalyst for the coupling reactions.

Palladium-Catalyzed Aminocarbonylation of Isoquinolines Utilizing Chloroform-COware Chemistry.

The carbonyl group forms an integral part of several drug molecules and materials; hence, synthesis of carbonylated compounds remains an intriguing area of research for synthetic and medicinal chemists. Handling toxic CO gas has several limitations; thus, using safe and effective techniques for or generation of carbon monoxide from nontoxic and cheap precursors is highly desirable. Among several precursors that have been explored for the generation of CO gas, chloroform can prove to be a promising CO surrogate due to its cost-effectiveness and ready availability.

Development of Azaindole-Based Frameworks as Potential Antiviral Agents and Their Future Perspectives.

The azaindole (AI) framework continues to play a significant role in the design of new antiviral agents. Modulating the position and isosteric replacement of the nitrogen atom of AI analogs notably influences the intrinsic physicochemical properties of lead compounds. The intra- and intermolecular interactions of AI derivatives with host receptors or viral proteins can also be fine tuned by carefully placing the nitrogen atom in the heterocyclic core.

Short Synthesis of Molnupiravir (EIDD-2801) a Thionated Uridine Intermediate.

Molnupiravir (MK-4482, EIDD-2801) is an experimental drug that has been demonstrated to be effective for the treatment of COVID-19 in human clinical trials. Herein, we report a concise synthesis of the drug a novel thionated derivative that relies on one-pot methodologies, thus decreasing the number of purification steps required. This route provides the drug in an overall 62% yield and >99% purity and uses cheap and readily available bulk chemicals, thereby providing an affordable synthesis of the drug for cheaper and wider global accessibility.

C-H activation reactions of nitroarenes: current status and outlook.

Ring substitution reactions of nitroarenes remain an under-developed area of organic synthesis, confined to the narrow domains of SAr and SArH reactions. While searching for alternative methodologies, we took stock of the C-H activation reactions of nitroarenes which unearthed a variety of examples of nitro directed regioselective C-H functionalization reactions such as -arylation, -benzylation/alkylation, and -allylation, oxidative Heck and C-H arylation reactions on (hetero)aromatic rings. A collective account of these reactions is presented in this review to showcase the existing landscape of C-H activation reactions of nitroarenes, to create interest in this field for further development and propagate this strategy as a superior alternative for ring substitution reactions of nitroarenes.

Recent developments in selective -arylation of azoles.

Transition-metal based carbon-heteroatom (C-X) bond formation has attracted the attention of synthetic chemists over the past few years because the resultant aryl/heteroaryl motifs are important substructures in many natural products, pharmaceuticals, etc. Several efficient protocols such as Buchwald-Hartwig amination, Ullmann coupling, Chan-Lam coupling and metal-free approaches have proved beneficial in C-X bond formation. Selective arylation of one hetero-centre over other centres without protection/deprotection thus allowing minimum synthetic manipulation has been achieved for several substrates using these protocols.

Recent Advances in Functionalization of Pyrroles and their Translational Potential.

Among the known aromatic nitrogen heterocycles, pyrrole represents a privileged aromatic heterocycle ranging its occurrence in the key component of "pigments of life" to biologically active natural products to active pharmaceuticals. Pyrrole being an electron-rich heteroaromatic compound, its predominant functionalization is legendary to aromatic electrophilic substitution reactions. Although a few excellent reviews on the functionalization of pyrroles including the reports by Baltazzi in 1963, Casiraghi and Rassu in 1995, and Banwell in 2006 are available, they are fragmentary and over fifteen years old, and do not cover the modern aspects of catalysis.