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

An air-stable, robust, and well-defined copper(II)-7-azaindole-N-oxide-based catalyst [Cu2II(7-AINO)4] (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 N-, S-, and O-nucleophiles, including azoles, aminoazoles, (hetero)arylthiols, and phenols. Notably, they also exhibit substantial compatibility with a wide range of functional groups. Furthermore, the catalyst demonstrates significant selectivity for -NH sites of aminoazoles and -SH sites of aminothiophenols over -NH2 sites in both cases, enhancing its versatility. Exploiting the catalyst's chemo- and regioselective properties, we have successfully demonstrated the applicability of our methodology in synthesizing various drug molecules. Specifically, Epirizole analogue, Nilotinib, and Vortioxetine were successfully synthesized using our protocol.

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. Pyrazolopyridines are a group of privileged heterocyclic cores in kinase drug discovery, which are present in several inhibitors that have been developed against various cancers. Notably, selpercatinib, glumetinib, camonsertib and olverembatinib have either received approval or are in late-phase clinical studies. This review presents the success stories employing pyrazolopyridine scaffolds as hinge-binding cores to address various challenges in kinase-targeted drug discovery research.

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. The designed N-alkynylated 7-azaindoles were further subjected to Cu-/Ir-catalyzed alkyne-azide cycloaddition (CuAAC/IrAAC) or "click" reaction for the rapid synthesis of 1,4-/1,5 disubstituted 1,2,3-triazole decorated 7-azaindoles. A mechanistic study based on density functional theory (DFT) calculations and ultraviolet-visible (UV) spectroscopic studies revealed that the CuI and DMAP combination formed a [CuII(DMAP)2I2] species, which acts as an active catalyst. The DFT method was used to assess the energetic viability of an organometallic in the C-N bond formation pathway originating from the [CuII(DMAP)2I2] complex. We expect that the newly designed Cu/DMAP/alkyne system will offer valuable insights into the field of Cu-catalyzed transformations.

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 in or ex situ 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. However, the one-pot chloroform-based carbonylation reaction requires strong basic conditions for hydrolysis of chloroform that may affect functional group tolerability of substrates and scale-up reactions. These limitations can be overcome by a two-chamber reactor (COware) that can be utilized for ex situ CO generation through hydrolysis of chloroform in one chamber and facilitating safe carbonylation reactions in another chamber under mild conditions. The versatility of this "Chloroform-COware" technique is explored through palladium-catalyzed aminocarbonylation of medicinally relevant heterocyclic cores, viz., isoquinoline and quinoline.