A Simple and Versatile Amide Directing Group for C−H Functionalizations

Abstract

Achieving selective C–H activation at a single and strategic site in the presence of multiple C–H bonds can provide a powerful and generally useful retrosynthetic disconnection. In this context, the directing group serves as a compass to guide the transition metal to C–H bonds using distance and geometry as powerful recognition parameters to distinguish between proximal and distal C–H bonds. However, the installation and removal of directing groups is a practical drawback. To improve the utility of this approach, one can seek solutions in three directions. First, simplifying the directing group; Second, use of common functional groups or protecting groups as directing groups; Third, attaching the directing group to substrates via a transient covalent bond to render directing groups catalytic. This review describes the rational development of an extremely simple and yet broadly applicable directing group for Pd(II), Rh(III) and Ru(II) catalysts, namely, the N-methoxy amide (CONHOMe). Through collective efforts in the community, a wide range of C–H activation transformations using this type of simple directing groups has been developed.

Formation of α-chiral centers by asymmetric β-C(sp 3 )–H arylation, alkenylation, and alkynylation

“…However, the analogous amide substrate prepared by condensing the N -Phth-protected-2-aminoisobutyric acid with 2,3,5,6-tetrafluoro-4-(trifluoromethyl)aniline is not reactive under these conditions, presumably due to the steric bulkiness of this substrate which may prevent coordination. To reduce the steric hindrance of the substrate, we prepared the N -methoxy amide 3 of N -phthaloyl-protected 2-amino-isobutyric acid (32, 33; Fig. 2C).…”

Palladium(0)-Catalyzed Benzylic C(<i>sp</i>³)–H Functionalization for the Concise Synthesis of Heterocycles and Its Applications

“…These results indicate that the presence of CO was important to the success of this reaction, and that its inclusion was compatible with the addition of PivOH. Based on these results, we screened a variety of different reaction temperatures, ligands, and additives against this reaction (Table 1, entries [5][6][7][8][9][10][11][12][13][14]. The optimum temperature for this reaction was determined 120°C, although the reaction also proceeded at 100°C, albeit in a lower yield (Table 1, entries 5 and 6).…”

“…[9][10][11][12][13][14][15][16][17][18][19][20] Under Pd catalysis, there are two main approaches for activating unreactive C(sp 2 )-H and C(sp 3 )-H bonds, including: i) an intramolecular approach; and ii) a directing group approach. A variety of different directing groups and reaction conditions involving Pd catalysts have been developed for extending the substrate scope of C-H functionalization reactions.…”

Synthesis of Isoquinolinones via Regioselective Palladium-Catalyzed C–H Activation/Annulation

“…The coordination of the metal center to the heteroatom-containing functional group-such as benzamides [33][34][35][36], aryl imines [37], and anilides [38][39][40]-directs and facilitates selective cleavage of Csp 2 -H bond to form the metallacycle. Migratory insertion of an alkene or alkyne forms the advanced intermediates, which undergo the subsequent reductive elimination to afford the heterocyclic product.…”