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. 2017 Dec 1;8(12):8198-8203.
doi: 10.1039/c7sc03876c. Epub 2017 Oct 9.

The α-tertiary amine motif drives remarkable selectivity for Pd-catalyzed carbonylation of β-methylene C-H bonds

Kirsten F Hogg  1 , Aaron Trowbridge  1 , Andrea Alvarez-Pérez  1 , Matthew J Gaunt  1
Affiliations

The α-tertiary amine motif drives remarkable selectivity for Pd-catalyzed carbonylation of β-methylene C-H bonds

Kirsten F Hogg et al. Chem Sci. .

Abstract

The selective C-H carbonylation of methylene bonds in the presence of traditionally more reactive methyl C-H and C(sp2)-H bonds in α-tertiary amines is reported. The exceptional selectivity is driven by the bulky α-tertiary amine motif, which we hypothesise orientates the activating C-H bond proximal to Pd in order to avoid an unfavourable steric clash with a second α-tertiary amine on the Pd centre, promoting preferential cyclopalladation at the methylene position. The reaction tolerates a range of structurally interesting and synthetically versatile functional groups, delivering the corresponding β-lactam products in good to excellent yields.

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Figures

Scheme 1
Scheme 1. Overview of C–H carbonylation of aliphatic amines.
Scheme 2
Scheme 2. Pharmaceuticals and alkaloids containing the ATA motif.
Scheme 3
Scheme 3. Mechanistic hypothesis for C–H activation of ATAs.
Scheme 4
Scheme 4. Selectivity of ATA methylene C–H carbonylation.
Scheme 5
Scheme 5. N-Benzyl ATA substrate scope for selective methylene C–H carbonylation. aRatio of β-lactam 2 to γ-benzolactam 3.
Scheme 6
Scheme 6. Transformation of β-lactam products.
See this image and copyright information in PMC

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