Ligand-accelerated enantioselective methylene C(sp
            <sup>3</sup>
            )–H bond activation

CONSPECTUS C–H activation and functionalization are on the forefront of modern synthetic chemistry. Imagine if any C–H bond of a molecule could be converted to a C–X bond, where X is target functionality. Collaborations between many experimental and computational groups have led to rapid developments of new C–H functionalization methods. Our groups represent an example of this; we were brought together as part of the NSF-supported Center for Selective C–H Functionalization. Many examples of experimental-computational synergy for selective Pd(II)-catalyzed C–H activation of aryl and alkyl groups are described in this Account. We describe computations by the Houk group made in response to experimental stimuli by the Yu group. The first section discusses the experimental and computational investigations of oxazoline-directed, stereoselective Pd(II)-catalyzed C(sp3)–H bond activation that occurs through the concerted metalation-deprotonation (CMD) pathway involving a monomeric Pd functionality. The second section involves two types of bidentate ligands, mono-N-protected amino acid (MPAA) and acetyl-protected aminoethyl quinoline (APAQ) ligands that facilitate the C–H activation reactions in an internal base mechanism. In the MPAA-assisted remote C–H bond activation, the basic dianionic amidate ligand participates in the deprotonation of a specific C–H bond. This mechanism accounts for the improved reactivity and selectivity in C–H activation reactions with MPAA ligands. The chiral APAQ ligands enable the asymmetric palladium insertion into prochiral C–H bonds on a single methylene carbon center. The origins of the dramatic differences of 5-membered (relatively inactive) and 6-membered chelation (highly active) in the β-methylene C(sp3)–H activation reactions by Pd(II) catalyst were explained with density functional theory (DFT) calculations. This is mainly due to the steric repulsions between the ArF group of substrate and the quinoline group of the ligand. The steric repulsion between the ArF group of substrate and the quinoline group of the acetyl-protected aminomethyl quinoline ligand destabilizes the 5-membered chelate transition structure, increasing the energy of transition state. The third section discusses a mechanism involving a Pd-Ag heterodimeric complex intermediate in the template-directed, Pd(II)-catalyzed meta-functionalization of toluene derivatives and benzoic acid derivatives. The nitrile directing group of the template coordinates with Ag while the Pd is placed adjacent to the meta-C–H bond in the transition state, leading to the observed high meta-selectivity. The dual role of AgOAc as both an oxidant and part of the heteronuclear active species in the mechanism involving PdAg(OAc)3 was determined by DFT calculation. The interaction between the experimental and computational groups, and the interplay that led to these discoveries, are highlighted in this Account.

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“…29 MPAA ligands were ineffective for this transformation. The deprotonated APAQ ligand forms a 6-membered chelate with the Pd(II) center.…”

Section: Palladium-catalyzed C–h Bond Activation With Bidendate LImentioning

confidence: 95%

Experimental–Computational Synergy for Selective Pd(II)-Catalyzed C–H Activation of Aryl and Alkyl Groups

et al. 2017

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“…However, the most straightforward way to synthesize these amino acid derivatives would be to directly employ the N -protected amino acid as the starting material. Inspired by recent developments in ligand-accelerated or ligand-enabled C–H activation reactions545556, we speculated that carboxylate-assisted β-C( sp 3 )-H activation might be achieved by employing a congruous ligand. Thus, we investigated whether synthetically important phenylalanine derivatives14545758596061 could be directly synthesized from phthaloylalanine through arylation of the β-C( sp 3 )–H bond with a carboxyl group as a coordination centre and the assistance of a ligand.…”

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confidence: 99%

Pd-catalysed ligand-enabled carboxylate-directed highly regioselective arylation of aliphatic acids

et al. 2017

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α-amino acids bearing aromatic side chains are important synthetic units in the synthesis of peptides and natural products. Although various β-C-H arylation methodologies for amino acid derivatives involving the assistance of directing groups have been extensively developed, syntheses that directly employ N-protected amino acids as starting materials remain rare. Herein, we report an N-acetylglycine-enabled Pd-catalysed carboxylate-directed β-C(sp3)-H arylation of aliphatic acids. In this way, various non-natural amino acids can be directly prepared from phthaloylalanine in one step in good to excellent yields. Furthermore, a series of aliphatic acids have been shown to be amenable to this transformation, affording β-arylated propionic acid derivatives in moderate to good yields. More importantly, this ligand-enabled direct β-C(sp3)-H arylation could be easily scaled-up to 10 g under reflux conditions, highlighting the potential utility of this synthetic method.

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“…7 Our recent success in ligand-controlled enantioselective methylene arylation further highlights the unique advantage of using monodentate weakly-coordinating directing groups. 8 Recently, the Rao group used a very strong bidentate directing group to achieve the C(sp 3 )–H chlorination and iodination for α-hydrogen containing substrates (Scheme 1, Eq 3). 6f However, β-halogenation of α-halogenated substrates to produce α,β-dihalogenated synthons remain to be demonstrated.…”

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confidence: 99%

Ligand-Enabled Pd(II)-Catalyzed Bromination and Iodination of C(sp³)–H Bonds

et al. 2017

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We herein report the Palladium(II)-catalyzed bromination and iodination of a variety of α-hydrogen-containing carboxylic acid and amino acid derived amides. These reactions are exclusively enabled by quinoline-type ligands. The halogenated products obtained in this reaction are highly versatile and rapidly undergo further diversification. Further, we report the first example of a free carboxylic acid-directed Pd(II)-catalyzed C(sp3)–H bromination, enabled by quinoline ligands.

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Ligand-accelerated enantioselective methylene C(sp ³ )–H bond activation

Cited by 308 publications

References 54 publications

Experimental–Computational Synergy for Selective Pd(II)-Catalyzed C–H Activation of Aryl and Alkyl Groups

Experimental–Computational Synergy for Selective Pd(II)-Catalyzed C–H Activation of Aryl and Alkyl Groups

Pd-catalysed ligand-enabled carboxylate-directed highly regioselective arylation of aliphatic acids

Ligand-Enabled Pd(II)-Catalyzed Bromination and Iodination of C(sp³)–H Bonds

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Ligand-accelerated enantioselective methylene C(sp 3 )–H bond activation

Cited by 308 publications

References 54 publications

Experimental–Computational Synergy for Selective Pd(II)-Catalyzed C–H Activation of Aryl and Alkyl Groups

Experimental–Computational Synergy for Selective Pd(II)-Catalyzed C–H Activation of Aryl and Alkyl Groups

Pd-catalysed ligand-enabled carboxylate-directed highly regioselective arylation of aliphatic acids

Ligand-Enabled Pd(II)-Catalyzed Bromination and Iodination of C(sp3)–H Bonds

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Ligand-accelerated enantioselective methylene C(sp ³ )–H bond activation

Ligand-Enabled Pd(II)-Catalyzed Bromination and Iodination of C(sp³)–H Bonds