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. 2015 Apr 21;48(4):1053-64.
doi: 10.1021/ar5004626. Epub 2015 Mar 10.

Bidentate, monoanionic auxiliary-directed functionalization of carbon-hydrogen bonds

Olafs Daugulis  1 , James Roane  1 , Ly Dieu Tran  1
Affiliations

Bidentate, monoanionic auxiliary-directed functionalization of carbon-hydrogen bonds

Olafs Daugulis et al. Acc Chem Res. .

Abstract

In recent years, carbon-hydrogen bond functionalization has evolved from an organometallic curiosity to a tool used in 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 sp(3) C-H bonds under palladium catalysis has been developed. Furthermore, a number of abundant base-metal complexes catalyze functionalization of sp(2) 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 sp(2) and sp(3) 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 sp(3) C-H bond functionalization. Furthermore, the need to install and subsequently remove the relatively expensive directing group is a disadvantage.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1
Auxiliary Design
Scheme 2
Scheme 2
Auxiliaries for sp3 C–H Bond Arylation
Scheme 3
Scheme 3
Arylation of sp3 C–H Bonds in Carboxamides
Scheme 4
Scheme 4
Picolinamide-Directed Arylation of C–H bonds
Scheme 5
Scheme 5
Alkylation of C–H Bonds
Scheme 6
Scheme 6
Amino Acid Functionalization
Scheme 7
Scheme 7
Mechanistic Considerations
Scheme 8
Scheme 8
Possible Reaction Mechanism
Scheme 9
Scheme 9
Sulfenylation of sp2 C–H Bonds
Scheme 10
Scheme 10
Amination of sp2 C–H Bonds
Scheme 11
Scheme 11
Etherification of sp2 C–H Bonds
Scheme 12
Scheme 12
Fluorination of C–H Bonds
Scheme 13
Scheme 13
Coupling with Alkynes
Scheme 14
Scheme 14
Coupling with Alkenes
Scheme 15
Scheme 15
Carbonylation of sp2 C–H Bonds
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