Transition Metal Catalyzed Free‐Amine (−NH₂) Directed C−H Bond Activation and Functionalization for Biaryl Frameworks

Abstract

Transition-metal-catalyzed direct transformation of inert CÀ H bond has revolutionized the arsenal of main-stream organic synthesis, providing a new upfront to forge structurally enriched and biologically relevant scaffolds in a step-and atom-economical way. Past decades have accounted for the major developments in this realm, proclaiming excellent site-selectivity by exploiting a variety of coordinating directing groups (DGs). Consideration of versatile, abundant, sp 3 -hybridized free-amine (À NH 2 ) functionality for the same purpose has always been a formidable task owing to its innate reactivity. In recent years, free-amine functionality has emerged as a potent DG for a wide range of CÀ C and C-heteroatom bonds formations and annulation cascades. In this review article, we have discussed the advancements of free-amine directed CÀ H activation/functionalization reactions towards biaryl frameworks made within a decade (2012 to 2021).

Cobalt(III)-Catalyzed Free-Amine-Directed Site-Selective Allylation in 2-Aminobiaryls with Vinyl Cyclopropanes

“…In this context, the utilization of common organic functionalities, such as carboxylic acids, amides, ketones, esters, etc., as directing groups (DGs) is advantageous. − However, unlike the aforementioned functional groups, the potential of the native amine (−NH 2 ) functionality to act as a directing group has not been realized fully (Scheme a), despite the ubiquitous distribution of amine or its derivatives in biorelevant molecules . The dormant progress in this area of research can be attributed to the native reactivity of the free amine functionality such as coordination with a metal catalyst leading to its deactivation, substrate oxidation, although to a lesser extent for aromatic amines, under the reaction conditions, and innate nucleophilic reactivity en route to undesired side reactions (Scheme a) . Thus, exploration of sustainable free-amine-directed C–H activation reactions is highly desirable.…”

Regioselective ortho C–H insertion of N-nitrosoanilines with naphthoquinone carbenes

“…2 The direct C–H arylation of aromatic amines provides an expedient access to biarylamines. 3 However, electrophilic arylation of aromatic amines poses challenges due to the competitive reactivity with the electron-rich amino group. Recently, a strategy involving the transient conversion of aromatic amines to N -nitrosoanilines has emerged, facilitating the electrophilic C–H functionalization of these substrates.…”

Divergent construction of 3-(indol-2-yl)succinimide/maleimide and fused benzodiazepine skeletons from 2-(1H-indol-1-yl)anilines and maleimides

“…4 Meanwhile, the use of free amino groups as DGs for inert C–H bond functionalization has aroused intensive interest as the omnipresence of amino groups in pharmaceuticals and drug candidates makes this strategy particularly powerful for late-stage functionalization of such bioactive molecules. 5 Moreover, after the initial C–H bond functionalization, the free amino group's strong nucleophilicity often triggers intramolecular condensation reactions to afford more sophisticated molecular scaffolds. In this regard, Sun et al have developed a synthesis of 1,2-fused-indole diazepines via Pd-catalyzed [5 + 2] annulation of o -indoloanilines with alkynes or diazo compounds by using the free amino group as a traceless DG (Scheme 1a and b).…”