Highly Versatile β‑C(sp³)–H Iodination of Ketones Using a Practical Auxiliary

The first example of palladium­(II)-catalyzed β-C­(sp³)–H iodination of a wide range of ketones using a commercially available aminooxyacetic acid auxiliary has been achieved. This L, X-type directing group overcomes the limitations of the transient directing group approach for C­(sp³)–H functionalization of ketones. Practical advantages of this method include simple installation of the auxiliary without chromatography, exceptional tolerance of α-functional groups, as well as alkenes and alkynes, and rapid access to diverse sterically hindered quaternary centers

Ligand-Promoted Alkylation of C(sp³)–H and C(sp²)–H Bonds

9-Methylacridine was identified as a generally effective ligand to promote a Pd­(II)-catalyzed C­(sp³)–H and C­(sp²)–H alkylation of simple amides with various alkyl iodides. This alkylation reaction was applied to the preparation of unnatural amino acids and geometrically controlled tri- and tetrasubstituted acrylic acids

Ligand-Enabled <i>Meta</i>-C–H Alkylation and Arylation Using a Modified Norbornene

2-Carbomethoxynorbornene is identified as a more effective transient mediator to promote a Pd­(II)-catalyzed <i>meta</i>-C­(sp²)–H alkylation of amides with various alkyl iodides as well as arylation with previously incompatible aryl iodides. The use of a tailor-made quinoline ligand is also crucial for this reaction to proceed

Synthesis of Fluorenone Derivatives through Pd-Catalyzed Dehydrogenative Cyclization

Palladium-catalyzed dual C–H functionalization of benzophenones to form fluorenones by oxidative dehydrogenative cyclization is reported. This method provides a concise and effective route toward the synthesis of fluorenone derivatives, which shows outstanding functional group compatibility

An Epoxide-Mediated Deprotection Method for Acidic Amide Auxiliary

A practical method for the removal of a versatile acidic amide auxiliary has been developed. Facile alcoholysis of the amide in the presence of KOAc is enabled by an epoxide, which mechanistically resembles the removal of the Myers’ auxiliary. The protocol has been applied to the removal of a variety of amide substrates and their C–H functionalization products with high efficiency and low cost, representing a step forward toward the development of a versatile directing group for C–H activation

Ligand-Enabled γ‑C(sp³)–H Activation of Ketones

We report the first example of Pd­(II)-catalyzed γ-C­(sp³)–H activation of ketones directed by a practical 2,2-dimethyl aminooxyacetic acid auxiliary. 2-Pyridone ligands are identified to enable C­(sp³)–H activation for the first time. A rare six-membered palladacycle intermediate is isolated and characterized to elucidate the reaction mechanism. Both (hetero)­arylation and vinylation of γ-C­(sp³)–H bonds are demonstrated. Sequential β- and γ-C­(sp³)–H (hetero)­arylation of muscone showcases the utility of this method for late-stage diversification. A convenient Mn­(II)-catalyzed auxiliary removal is also developed to further underscore the practicality of this transformation

Ligand-Enabled γ‑C(sp³)–H Activation of Ketones

We report the first example of Pd­(II)-catalyzed γ-C­(sp³)–H activation of ketones directed by a practical 2,2-dimethyl aminooxyacetic acid auxiliary. 2-Pyridone ligands are identified to enable C­(sp³)–H activation for the first time. A rare six-membered palladacycle intermediate is isolated and characterized to elucidate the reaction mechanism. Both (hetero)­arylation and vinylation of γ-C­(sp³)–H bonds are demonstrated. Sequential β- and γ-C­(sp³)–H (hetero)­arylation of muscone showcases the utility of this method for late-stage diversification. A convenient Mn­(II)-catalyzed auxiliary removal is also developed to further underscore the practicality of this transformation

Palladium(II)-Catalyzed Enantioselective C(sp³)–H Activation Using a Chiral Hydroxamic Acid Ligand

An enantioselective method for Pd­(II)-catalyzed cross-coupling of methylene β-C­(sp³)–H bonds in cyclobutanecarboxylic acid derivatives with arylboron reagents is described. High yields and enantioselectivities were achieved through the development of chiral mono-<i>N</i>-protected α-amino-<i>O</i>-methylhydroxamic acid (MPAHA) ligands, which form a chiral complex with the Pd­(II) center. This reaction provides an alternative approach to the enantioselective synthesis of cyclobutanecarboxylates containing α-chiral quaternary stereocenters. This new class of chiral catalysts also show promises for enantioselective β-C­(sp³)–H activation of acyclic amides

Ligand-Enabled Stereoselective β‑C(sp³)–H Fluorination: Synthesis of Unnatural Enantiopure <i>anti</i>-β-Fluoro-α-amino Acids

A quinoline-based ligand was shown to promote palladium-catalyzed β-C­(sp³)–H fluorination for the first time. A range of unnatural enantiopure fluorinated α-amino acids were obtained through sequential β-C­(sp³)–H arylation and subsequent stereoselective fluorination from readily available l-alanine

Versatile Alkylation of (Hetero)Aryl Iodides with Ketones via β‑C(sp³)–H Activation

We report Pd­(II)-catalyzed β-C­(sp³)–H (hetero)­aryl­ation of a variety of ketones using a commercially available 2,2-dimethyl amino­oxy­acetic acid auxiliary. Facile installation and removal of the auxiliary as well as its superior scope for both ketones and (hetero)­aryl iodides overcome the significant limitations of the previously reported β-C­(sp³)–H arylation of ketones. The ready availability of ketones renders this reaction a broadly useful method for alkyl–(hetero)­aryl coupling involving both primary and secondary alkyls