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A rapid, practical and scalable method for the reductant and tansition‐metal‐free synthesis of a variety of novel 2,4‐disubstituted tetrahydropyridines and tetrahydroquinolines is disclosed. The method is based upon dearomative functionalization of pyridines or quinolines to generate amino nitrile intermediates as masked iminium ions, which then react rapidly with various Grignard reagents in complete stereocontrol. [ABSTRACT FROM AUTHOR]

This study reports the invention of di‐ or trifunctionalization of readily available pyridines (including all the pyridine substrates utilized in this paper, such as 3‐cyanopyridine and 3‐chloropyridine) through dearomative functionalization‐oxidative rearomatization under transition‐metal‐ and reductant‐free conditions. Although a two‐step operation is required, the crude product of the first step could be used in the next step directly. Typically, 3‐π‐EWG pyridines undergo difunctionalization, whereas 3‐σ‐EWG pyridines participate in trifunctionalization, affording multisubstituted piperidines. Computational studies provide detailed insights for their distinct reactivity in the title reaction. [ABSTRACT FROM AUTHOR]

While remarkable progress has recently been made for the direct C−H‐functionalization of azines, its application is still limited by a lack of accessible functional groups (primarily carbon‐based) and poor regioselectivity. In contrast, C2‐functionalized pyridines and quinolines can be easily synthesized by treating readily available N‐oxides with various reagents under appropriate activation conditions. This review seeks to comprehensively document the available synthetic methods for introducing functional groups at the C2 position of pyridines and quinolines. In this work, we highlight recent developments in the C2‐functionalization of pyridine and quinoline N‐oxides and address both the mechanisms and regioselectivity of the reactions. We also describe the pathways and reactive species involved in these processes and highlight a number of medically relevant nitrogen heteroaromatics. [ABSTRACT FROM AUTHOR]

A series of tetrasubstituted 7-azabenzofurans displays remarkable pan-genotype inhibition of HCV NS5B polymerase. One of them has been identified as a potential clinical candidate. Completely different from the original synthesis of a common and key intermediate for this class of compounds, two novel and improved synthetic approaches are developed. Almost every step of the synthesis has been optimized, including several important but not fully explored transformations, such as radical bromination with methyl pyridine and cyanide substitution with TMSCN. The 7-azabenzofuran core is prepared by an acylation-heterocyclization reaction, using acyl chloride as both the reactant and the activation reagent for the N -oxide substrate. Compared with the BMS synthesis, the overall yield has been tripled, and those harmful or cost-effective synthetic steps have been reduced. Furthermore, a transition-metal-free synthetic method for the construction of 3-cyano substituted 7-azabenzofurans is presented. Image 1 • Two practical synthetic approaches to a common and key intermediate for BMT-052. • 7 steps, total yield: 51%; average yield: 91% per step. • Harmful or cost-effective synthetic steps have been reduced. [ABSTRACT FROM AUTHOR]