Biaryl compounds are extremely important structural motifs in natural products, biologically active components and pharmaceuticals. Selective synthesis of biaryls by distinguishing the subtle reactivity difference of distal arene C−H bonds are significantly challenging. Herein, we describe para‐selective C−H arylation, which is acheived by a unique combination of a meta‐directing group and norbornene as a transient mediator. Upon direct meta‐C−H palladation, one‐bond relay palladation occurs in presence of norbornene and subsequently para‐C−H arylation is achieved for sulfonates, phosphonates and phenols bearing 2,6‐disubstitution patterns. The protocol is amenable to electron‐deficient aryl iodides. Multisubstituted arenes and phenols are obtained by postsynthetic modification of the products. The protocol allows the synthesis of hexa‐substituted benzene by sequential selective distal C−H functionalization.

Directed C À Hfunctionalization has been realized as ac omplimentary technique to achieve borylation at ad istal position of aliphatic amines.H ere,w ed emonstrated the oxidative borylation at the distal d-position of aliphatic amines using various borylating agents,apalladium catalyst, and ar ightly tuned ligand in the presence of ac heap oxidant. Moreover,a no rganopalladium d-C(sp 3 )-H-activated intermediate has been isolated and crystallographically characterized to get mechanistic insight.Scheme 1. d-Borylation of aliphatic amines.

Biaryl compounds are extremely important structural motifs in natural products, biologically active components and pharmaceuticals. Selective synthesis of biaryls by distinguishing the subtle reactivity difference of distal arene C−H bonds are significantly challenging. Herein, we describe para‐selective C−H arylation, which is acheived by a unique combination of a meta‐directing group and norbornene as a transient mediator. Upon direct meta‐C−H palladation, one‐bond relay palladation occurs in presence of norbornene and subsequently para‐C−H arylation is achieved for sulfonates, phosphonates and phenols bearing 2,6‐disubstitution patterns. The protocol is amenable to electron‐deficient aryl iodides. Multisubstituted arenes and phenols are obtained by postsynthetic modification of the products. The protocol allows the synthesis of hexa‐substituted benzene by sequential selective distal C−H functionalization.

Transition metal catalysis plays a pivotal role in transforming unreactive C–H bonds. However, regioselective activation of distal aliphatic C–H bonds poses a tremendous challenge, particularly in the absence of directing templates. Activation of a methylene C–H bond in the presence of methyl C–H is underexplored. Here we show activation of a methylene C–H bond in the presence of methyl C–H bonds to form unsaturated bicyclic lactones. The protocol allows the reversal of the general selectivity in aliphatic C–H bond activation. Computational studies suggest that reversible C–H activation is followed by β-hydride elimination to generate the Pd-coordinated cycloalkene that undergoes stereoselective C–O cyclization, and subsequent β-hydride elimination to provide bicyclic unsaturated lactones. The broad generality of this reaction has been highlighted via dehydrogenative lactonization of mid to macro ring containing acids along with the C–H olefination reaction with olefin and allyl alcohol. The method substantially simplifies the synthesis of important bicyclic lactones that are important features of natural products as well as pharmacoactive molecules.

Selective transformation of unactivated CH bonds is one of the notable advances in synthetic chemistry in last 20 years to streamline the synthesis of complex organic molecules. Transition metal catalysis has become a powerful tool to convert unreactive aliphatic CH bonds into an array of useful functionalities.1-3 Nonetheless, selective transformation of distal aliphatic CH bonds still presents a significant challenge, more so in absence of an exogenous directing group.4-5 In this context, aliphatic acids have been identified as the choice of substrates that could be functionalized without utilizing any extra directing group. However, the weak coordination of carboxylate group has been shown to activate mostly the methyl group at  or  position, limiting the scope and applicability of aliphatic acids.6-8 Herein, we have developed a ligand enabled palladium catalyzed protocol that activates the challenging methylene CH bond of aliphatic acids in presence of methyl CH bonds to form bicyclic lactones in an intramolecular manner (mid to large size). The reported protocol allows the reversal of the general selectivity in aliphatic CH bond activation. Computational mechanistic studies suggest that the CH activation in the cycloalkane ring of the starting material is followed by -hydride elimination to give Pd-coordinated cycloalkene, C-O cyclization, and another -hydride elimination to provide bicyclic unsaturated lactones. The scope of this previously unfamiliar reaction mode has been highlighted via dehydrogenative lactonization of mid to macro ring containing acids along with CH olefination reaction with olefin and allyl alcohol. Furthermore, synthesis of a variety of complex molecules via formal synthesis of natural products underscore the generality and significance of this reaction and suggestive of a new mode of CH activation reactions in aliphatic acids that could simplify the synthesis of bicyclic lactones, that are important features of numerous natural products as well as pharmacoactive molecules.