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. 2018 Oct 5;8(10):9292-9297.
doi: 10.1021/acscatal.8b03014. Epub 2018 Sep 5.

Ligand-Enabled, Palladium-Catalyzed β-C(sp3)-H Arylation of Weinreb Amides

Hojoon Park  1 , Nikita Chekshin  1 , Peng-Xiang Shen  1 , Jin-Quan Yu  1
Affiliations

Ligand-Enabled, Palladium-Catalyzed β-C(sp3)-H Arylation of Weinreb Amides

Hojoon Park et al. ACS Catal. .

Abstract

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.

Keywords: C(sp3)–H Activation; Ligand Design; Palladium; Pyridinesulfonic Acid; Weinreb Amide.

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Figures

Figure 1.
Figure 1.
Design Principle of Pyridinesulfonic acid Ligand.
Figure 2.
Figure 2.
Computed qh-G (T=343.15 K) Free Energy Profiles for the C(sp3)–H activation step at the M06/SDD, 6–311++G(d,p)(SMD)//ωB97X-D/SDD,6–31+G(d)(SMD) level of theory
Scheme 1.
Scheme 1.
Pd-catalyzed C–H Functionalization Using Neutral, Carbonyl Directing groups
Scheme 2.
Scheme 2.
Gram Scale Reaction / 1 mol% Pd Loading
See this image and copyright information in PMC

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