I₂/Aqueous TBHP-Catalyzed Coupling of Amides with Methylarenes/Aldehydes/Alcohols: Metal-Free Synthesis of Imides

We present a metal-free method for the synthesis of imides by the direct coupling of NH-amides with methylarenes under iodine/aqueous TBHP conditions. The optimized conditions worked very well with benzaldehydes and benzyl alcohol and furnished the corresponding imides in good to excellent yields. A series of control and radical scavenger experiments were also performed, which suggested the involvement of radical pathways. The labeling experiment in the presence of ¹⁸O-labeled H₂O suggested water as a source of oxygen in the imides

Metal-Free Approach for the Synthesis of <i>N</i>‑Aryl Sulfoximines via Aryne Intermediate

A metal-free and operationally simple <i>N</i>-arylation of <i>NH</i>-sulfoximines with aryne precursors is reported. Transition metal-free reaction conditions and shorter reaction times are the highlights of the present method. The mild optimized condition was also found to be suitable with enantiopure substrates

Metal-free Cross-Dehydrogenative Coupling of <i>HN</i>-azoles with α‑C(sp³)‑H Amides via C–H Activation and Its Mechanistic and Application Studies

A metal-free one step coupling reaction between various <i>N</i>-azole rings and diverse α-C­(sp³)-H containing amides has been developed under oxidative reaction conditions. Commercially available tetrabutyl ammonium iodide (TBAI) in the presence of terbutylhydroperoxide (TBHP), under neat reaction condition, efficiently catalyzed the coupling. Various azole types, such as 1<i>H</i>-benzotriazoles, 1<i>H</i>-1,2,3-triazoles, 1<i>H</i>-1,2,4-triazoles, 1<i>H</i>-tetrazoles, 1<i>H</i>-pyrazoles, and 1<i>H</i>-benzimidazoles, and α-C­(sp³)-H containing amides, such as <i>N</i>,<i>N</i>-dimethylacetamide, <i>N</i>,<i>N</i>-dimethylbenzamide, <i>N</i>-methylacetamide, <i>N</i>,<i>N</i>-diethylacetamide, <i>N</i>-methylpyrrolidine, and pyrrolidine-2-one, were successfully employed for the coupling. A series of designed and controlled experiments were also performed in order to study the involvement of the different intermediates. Based on the evidence, a plausible mechanism is also proposed. These novel, simple, rapid, attractive, and straightforward transformations open the way of the construction of novel highly functionalized <i>N</i>-azoles via direct covalent N–H bond transformations onto N–C bonds. This approach allows to the synthesis of complex molecules requiring number of steps using classical synthetic ways. In addition, the range of α-C­(sp³)-H containing amide substrates is virtually unlimited highlighting the potential value of this simple system for the construction of complex heterocyclic molecules, such as fused azoles derivatives

Metal-free Cross-Dehydrogenative Coupling of <i>HN</i>-azoles with α‑C(sp³)‑H Amides via C–H Activation and Its Mechanistic and Application Studies

A metal-free one step coupling reaction between various <i>N</i>-azole rings and diverse α-C­(sp³)-H containing amides has been developed under oxidative reaction conditions. Commercially available tetrabutyl ammonium iodide (TBAI) in the presence of terbutylhydroperoxide (TBHP), under neat reaction condition, efficiently catalyzed the coupling. Various azole types, such as 1<i>H</i>-benzotriazoles, 1<i>H</i>-1,2,3-triazoles, 1<i>H</i>-1,2,4-triazoles, 1<i>H</i>-tetrazoles, 1<i>H</i>-pyrazoles, and 1<i>H</i>-benzimidazoles, and α-C­(sp³)-H containing amides, such as <i>N</i>,<i>N</i>-dimethylacetamide, <i>N</i>,<i>N</i>-dimethylbenzamide, <i>N</i>-methylacetamide, <i>N</i>,<i>N</i>-diethylacetamide, <i>N</i>-methylpyrrolidine, and pyrrolidine-2-one, were successfully employed for the coupling. A series of designed and controlled experiments were also performed in order to study the involvement of the different intermediates. Based on the evidence, a plausible mechanism is also proposed. These novel, simple, rapid, attractive, and straightforward transformations open the way of the construction of novel highly functionalized <i>N</i>-azoles via direct covalent N–H bond transformations onto N–C bonds. This approach allows to the synthesis of complex molecules requiring number of steps using classical synthetic ways. In addition, the range of α-C­(sp³)-H containing amide substrates is virtually unlimited highlighting the potential value of this simple system for the construction of complex heterocyclic molecules, such as fused azoles derivatives

Metal-free Cross-Dehydrogenative Coupling of <i>HN</i>-azoles with α‑C(sp³)‑H Amides via C–H Activation and Its Mechanistic and Application Studies

A metal-free one step coupling reaction between various <i>N</i>-azole rings and diverse α-C­(sp³)-H containing amides has been developed under oxidative reaction conditions. Commercially available tetrabutyl ammonium iodide (TBAI) in the presence of terbutylhydroperoxide (TBHP), under neat reaction condition, efficiently catalyzed the coupling. Various azole types, such as 1<i>H</i>-benzotriazoles, 1<i>H</i>-1,2,3-triazoles, 1<i>H</i>-1,2,4-triazoles, 1<i>H</i>-tetrazoles, 1<i>H</i>-pyrazoles, and 1<i>H</i>-benzimidazoles, and α-C­(sp³)-H containing amides, such as <i>N</i>,<i>N</i>-dimethylacetamide, <i>N</i>,<i>N</i>-dimethylbenzamide, <i>N</i>-methylacetamide, <i>N</i>,<i>N</i>-diethylacetamide, <i>N</i>-methylpyrrolidine, and pyrrolidine-2-one, were successfully employed for the coupling. A series of designed and controlled experiments were also performed in order to study the involvement of the different intermediates. Based on the evidence, a plausible mechanism is also proposed. These novel, simple, rapid, attractive, and straightforward transformations open the way of the construction of novel highly functionalized <i>N</i>-azoles via direct covalent N–H bond transformations onto N–C bonds. This approach allows to the synthesis of complex molecules requiring number of steps using classical synthetic ways. In addition, the range of α-C­(sp³)-H containing amide substrates is virtually unlimited highlighting the potential value of this simple system for the construction of complex heterocyclic molecules, such as fused azoles derivatives

Cross-Dehydrogenative Coupling of Azoles with α‑C(sp³)–H of Ethers and Thioethers under Metal-Free Conditions: Functionalization of H–N Azoles via C–H Activation

A metal-free cross-dehydrogenative coupling method for the synthesis of <i>N</i>-substituted azoles has been developed. The TBAI/TBHP system catalyzed the coupling of azoles with ethers and thioethers via α-C­(sp³)–H activation. Under the optimized conditions, a diverse range of un/substituted azoles such as 1<i>H</i>-benzimidazole, 9<i>H</i>-purine, 1<i>H</i>-benzotriazole, 1<i>H</i>-1,2,3-triazole, 1<i>H</i>-1,2,4-triazole, and 1<i>H</i>-pyrazole were successfully employed for coupling with various ethers and thioethers such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, diethyl ether, tetrahydrothiophene, and 1,3-dithiolane

Cross-Dehydrogenative Coupling of Azoles with α‑C(sp³)–H of Ethers and Thioethers under Metal-Free Conditions: Functionalization of H–N Azoles via C–H Activation

A metal-free cross-dehydrogenative coupling method for the synthesis of <i>N</i>-substituted azoles has been developed. The TBAI/TBHP system catalyzed the coupling of azoles with ethers and thioethers via α-C­(sp³)–H activation. Under the optimized conditions, a diverse range of un/substituted azoles such as 1<i>H</i>-benzimidazole, 9<i>H</i>-purine, 1<i>H</i>-benzotriazole, 1<i>H</i>-1,2,3-triazole, 1<i>H</i>-1,2,4-triazole, and 1<i>H</i>-pyrazole were successfully employed for coupling with various ethers and thioethers such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane, diethyl ether, tetrahydrothiophene, and 1,3-dithiolane

Design of Novel 3‑Pyrimidinylazaindole CDK2/9 Inhibitors with Potent In Vitro and In Vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model

In the present study, a novel series of 3-pyrimidinylazaindoles were designed and synthesized using a bioinformatics strategy as cyclin-dependent kinases CDK2 and CDK9 inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription. The present approach gives new dimensions to the existing SAR and opens a new opportunity for the lead optimizations from comparatively inexpensive starting materials. The study led to the identification of the alternative lead candidate <b>4ab</b> with a nanomolar potency against CDK2 and CDK9 and potent antiproliferative activities against a panel of tested tumor cell lines along with a better safety ratio of ∼33 in comparison to reported leads. In addition, the identified lead <b>4ab</b> demonstrated a good solubility and an acceptable in vivo PK profile. The identified lead <b>4ab</b> showed an in vivo efficacy in mouse triple-negative breast cancer (TNBC) syngeneic models with a TGI (tumor growth inhibition) of 90% without any mortality growth inhibition in comparison to reported leads