Proximity-driven metalation has been extensively exploited to achieve reactivity and selectivity in C–H bond activation. Despite the substantial improvement in developing more efficient and practical directing groups, their stoichiometric installation and removal limit efficiency and often applicability as well. Herein, we report the development of an amino acid reagent that reversibly reacts with aldehydes and ketones in situ via imine formation to serve as a transient directing group for activation of inert C–H bonds. Arylation of a wide range of aldehydes and ketones at the β- or γ-positions proceeds in the presence of a Pd catalyst and a catalytic amount of amino acid. The feasibility of achieving enantioselective C–H activation reactions using a chiral amino acid as the transient directing group is also demonstrated.
The development of a Pd(II)-catalyzed enantioselective fluorination of C(sp3)–H bonds would offer a new approach to making chiral organofluorines. However, such a strategy is particularly challenging because of the difficulty in differentiating prochiral C(sp3)–H bonds through Pd(II)-insertion, as well as the sluggish reductive elimination involving Pd–F bonds. Here, we report the development of a Pd(II)-catalyzed enantioselective C(sp3)–H fluorination using a chiral transient directing group strategy. In this work, a bulky, amino amide transient directing group was developed to control the stereochemistry of C–H insertion step and selectively promote C(sp3)–F reductive elimination pathway from Pd(IV)–F intermediate. Stereochemical analysis revealed that while the desired C(sp3)–F formation proceeds via an inner-sphere pathway with retention of configuration, the undesired C(sp3)–O formation occurs through an SN2-type mechanism. The elucidation of the dual mechanism allows us to rationalize the profound ligand effect on controlling reductive elimination selectivity from high-valent Pd species.
Pd-catalyzed C-H functionalizations promoted by transient directing groups remain largely limited to C-H arylation only. Herein, we report a diverse set of ortho-C(sp)-H functionalizations of benzaldehyde substrates using the transient directing group strategy. Without installing any auxiliary directing group, Pd(II)-catalyzed C-H arylation, chlorination, bromination, and Ir(III)-catalyzed amidation, could be achieved on benzaldehyde substrates. The transient directing groups formed in situ via imine linkage can override other coordinating functional groups capable of directing C-H activation or catalyst poisoning, significantly expanding the scope for metal-catalyzed C-H functionalization of benzaldehydes. The utility of this approach is demonstrated through multiple applications, including late-stage diversification of a drug analogue.
We report the development of Pd(II)-catalyzed C(sp3)–H arylation of Weinreb amides. This work demonstrates the first example of using Weinreb amide as a directing group for transition metal-catalyzed C(sp3)–H activation. Both the inductive effect and the potential bidentate coordination mode of the Weinreb amides pose a unique challenge for this reaction development. A pyridinesulfonic acid ligand is designed to accommodate the weak, neutral coordinating property of Weinreb amides via preserving the cationic character of Pd center through zwitterionic assembly of Pd/ligand complexes. DFT studies of the C–H cleavage step indicate that the superior reactivity of 3-pyridinesulfonic acid ligand compared to pyridine, Ac-Gly-OH, and ligandless conditions originates from the stabilization of overall substrate-bound Pd species.
Palladium-catalyzed methylene β-C(sp3)–H arylation of aliphatic ketones using a transient directing group is developed. The use of α-benzyl β-alanine directing group that forms a six-membered chelation with palladium is crucial for promoting the methylene C(sp3)–H bond activation.
Cycloaddition reactions provide an expeditious route to construct ring systems in a highly convergent and stereoselective manner. For a typical cycloaddition reaction to occur, however, the installation of multiple reactive functional groups (π-bonds, leaving group, etc.) are required within the substrates, compromising the overall efficiency or scope of the cycloaddition reaction. Here, we report a palladium-catalyzed [3+2] reaction that utilizes C(sp 3)-H activation to generate the three-carbon unit for formal cycloaddition with maleimides. We implemented a strategy where the initial C(sp 3)-H activation/olefin insertion would trigger a relayed, second remote C(sp 3)-H activation to complete a formal [3+2] cycloaddition. The diastereoselectivity profile of this reaction resembles that of a typical pericyclic cycloaddition reaction in that the relationships between multiple stereocenters are exquisitely controlled in a single reaction. The key to success was the use of weakly coordinating amides as the directing group, as undesired Heck or alkylation pathways were preferred with other types of directing groups. The use of the pyridine-3-sulfonic acid ligands is critical to enable C(sp 3
PdII‐catalyzed C(sp3)−H olefination of weakly coordinating native amides is reported. Three major drawbacks of previous C(sp3)−H olefination protocols, 1) in situ cyclization of products, 2) incompatibility with α‐H‐containing substrates, and 3) installation of exogenous directing groups, are addressed by harnessing the carbonyl coordination ability of amides to direct C(sp3)−H activation. The method enables direct C(sp3)−H functionalization of a wide range of native amide substrates, including secondary, tertiary, and cyclic amides, for the first time. The utility of this process is demonstrated by diverse transformations of the olefination products.
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