Bidentate, Monoanionic Auxiliary-Directed Functionalization of Carbon–Hydrogen Bonds

Abstract

CONSPECTUS In recent years, carbon–hydrogen bond functionalization has evolved from an organometallic curiosity to mainstream applications in the synthesis of complex natural products and drugs. The use of C–H bonds as a transformable functional group is advantageous because these bonds are the most abundant functionality in organic molecules. One-step conversion of these bonds to the desired functionality shortens synthetic pathways, saving reagents, solvents, and labor. Less chemical waste is generated as well, showing that this chemistry is environmentally beneficial. This Account describes the development and use of bidentate, monoanionic auxiliaries for transition-metal-catalyzed C–H bond functionalization reactions. The chemistry was initially developed to overcome the limitations with palladium-catalyzed C–H bond functionalization assisted by monodentate directing groups. By the use of electron-rich bidentate directing groups, functionalization of unactivated sp3 C–H bonds under palladium catalysis has been developed. Furthermore, a number of abundant base-metal complexes catalyze functionalization of sp2 C–H bonds. At this point, aminoquinoline, picolinic acid, and related compounds are among the most used and versatile directing moieties in C–H bond functionalization chemistry. These groups facilitate catalytic functionalization of sp2 and sp3 C–H bonds by iron, cobalt, nickel, copper, ruthenium, rhodium, and palladium complexes. Exceptionally general reactivity is observed, enabling, among other transformations, direct arylation, alkylation, fluorination, sulfenylation, amination, etherification, carbonylation, and alkenylation of carbon–hydrogen bonds. The versatility of these auxilaries can be attributed to the following factors. First, they are capable of stabilizing high oxidation states of transition metals, thereby facilitating the C–H bond functionalization step. Second, the directing groups can be removed, enabling their use in synthesis and functionalization of natural products and medicinally relevant substances. While the development of these directing groups presents a significant advance, several limitations of this methodology are apparent. The use of expensive second-row transition metal catalysts is still required for efficient sp3 C–H bond functionalization. Furthermore, a disadvantage is the need to install and subsequently remove the relatively expensive directing group.

Site-selective C–H arylation of primary aliphatic amines enabled by a catalytic transient directing group

“…Furthermore, the primary amines with a cyclic alkyl group reacted smoothly in this catalytic system (2j and 2k). Although many successful examples for functionalizing unactivated secondary sp 3 C−H bonds have been reported with the installation of a mono-or bidentate directing group on the substrates [5][6][7][8][9][10][11][12][13][14][15] , direct functionalization of these bonds remains a great challenge with carbonyl compounds using a transient directing group 37 and free aliphatic amines 23,30,31 , presumably due to the inherent steric hindrance. In this catalytic system, substrate 1l with cyclic methylene C−H bonds provided the γ-arylated product 2l in 23% yield, while arylation of noncyclic secondary C−H bonds was not realized.…”

Cobalt-Catalyzed, Aminoquinoline-Directed Functionalization of Phosphinic Amide sp2 C–H Bonds

“…9c This requirement is met in aminoquinoline amides ( 1 ). It is conceivable that the amide functionality in these complexes could be replaced with a phosphinic amide group ( 2 ).…”

Silicon-Tethered Strategies for C–H Functionalization Reactions

“…Recently, Hartwig reported γ -C–H silylation of primary and secondary bonds of alcohols (and ketones via hydrosilylation) employing type-3 tether 23 (Scheme 2) via intramolecular dehydrogenative Si–H/C–H coupling. 41 Other approaches usually rely on the use of strongly coordinating bidentate DGs and/or weakly coordinating groups, introduced by Daugulis 42 and Yu, 43 respectively. The former approach relies on the realization of a N , N -chelation, which was proven efficient for remote TM-catalyzed aliphatic C–H activation reactions.…”