Weinreb Amides as Directing Groups for Transition Metal-Catalyzed C-H Functionalizations

Abstract

Weinreb amides are a privileged, multi-functional group with well-established utility in classical synthesis. Recently, several studies have demonstrated the use of Weinreb amides as interesting substrates in transition metal-catalyzed C-H functionalization reactions. Herein, we review this part of the literature, including the metal catalysts, transformations explored so far and specific insights from mechanistic studies.

Keywords: C-H functionalization; amides; catalysis; directing groups; transition metals.

Figure 1

The ‘textbook’ application of Weinreb amides: generation of mono-addition products resulting from nucleophilic attack on their carbonyl groups.

Figure 2

A generic representation of a Weinreb amide-directed catalytic C-H functionalization (TM = transition metal).

Scheme 1

Ru(II)-catalyzed C-H oxidation of arenes directed by a Weinreb amide group. (a) Representative scope of the reaction with respect to arene substituents; (b) Reduction of the Weinreb amide to reveal aldehyde functionality.

Scheme 2

Ru(II)-catalyzed oxidative C-H ortho-alkenylation of Weinreb amides; selected products and proposed mechanism.

Scheme 3

Ru-catalyzed C-H olefination using directed by cyclic Weinreb amides without N-O bond cleavage. Putative intermediates 9a–c are suggested to arise from the insertion of Ru into the substrate N-O bond.

Scheme 4

An initial example of the Weinreb amide-directed Co(III)-catalyzed ortho-C-H allylation.

Scheme 5

Selected examples of C-H transformations enabled by a Co(III)-catalyzed system.

Figure 3

A mechanism proposed by Yoshino and Matsunaga for the Co(III)-catalyzed C-H allylation of Weinreb amides.

Scheme 6

Pd-catalyzed C-H arylation of (a) aryl and (b) benzyl amides. Yields in parentheses refer to the amount of di-arylated products detected.

Figure 4

Mechanism proposed by Wang and co-workers for the C-H ortho-arylation of Weinreb amides proceeding via Pd(IV) intermediates.

Scheme 7

Bhanage’s C-H arylation using aniline as the electrophile source.

Scheme 8

Yu and co-workers’ protocol for the oxidative ortho C-H acetoxylation of benzylic Weinreb amides. Yields in parentheses refer to the amount of di-olefinated products detected.

Scheme 9

Yu and co-workers’ protocol for the oxidative ortho C-H acetoxylation of benzylic Weinreb amides. Yields in parentheses refer to the amount of di-acetoxylated products detected.

Scheme 10

Kapur and co-workers’ reaction for the ortho C-H halogenation of aromatic Weinreb amides.

Figure 5

An adapted version of the mechanism proposed by Kapur and co-workers for the Pd-catalyzed ortho C-H halogenation of aromatic Weinreb amides. X = Cl⁻, Br⁻ or I⁻.

Scheme 11

Selected scope from Yu and co-workers’ Pd-catalyzed C(sp³)-H arylation protocol enabled by Weinreb amide directing groups.

Scheme 12

A Rh(III)-catalyzed, Weinreb amide-directed alkene hydroarylation.

Scheme 13

Selected examples from Wang and co-workers’ oxidative Rh-catalyzed C-H alkenylation directed by Weinreb amides. ^a [Cp*RhCl₂]₂ (2.5 mol%) and AgSbF₆ (10 mol%) loadings were used. ^b A reaction temperature of 130 °C was used.

Figure 6

An adapted version of the mechanism proposed by Wang and co-workers for the oxidative C-H alkenylation of aromatic Weinreb amides catalyzed by Rh(III).

Scheme 14

Rh-catalyzed olefination of aromatic Weinreb amides enabled by Ru photocatalysis.

Figure 7

Mechanism proposed by Rueping and co-workers for the oxidative C-H olefination of aromatic Weinreb amides catalyzed by Rh(III) in the presence of a Ru photocatalyst.

Scheme 15

Ir-catalyzed ortho-C-H borylation of an arene using the Weinreb amide as a directing group.

Scheme 16

Ir-catalyzed enantioselective C-H hydroarylation of an olefin, directed by a Weinreb amide.

Scheme 17

Ir-catalyzed C-H iodination of Weinreb amides developed by the Martín-Matute group. ^a Ratio of isomers is indicated in parenthesis; the major isomer is shown.