Research Article

A general catalytic β-C–H carbonylation of aliphatic amines to β-lactams

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Science  18 Nov 2016:
Vol. 354, Issue 6314, pp. 851-857
DOI: 10.1126/science.aaf9621

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CO takes the lead to make β-lactam rings

Strained β-lactam rings are a key feature of penicillin and some other drugs. Willcox et al. designed a versatile route to these four-membered ring motifs through the palladiumcatalyzed coupling of carbon monoxide with secondary amines. The bulky carboxylate ligand appears to facilitate preliminary CO incorporation into a Pd anhydride, which is then attacked by the amine to set up ring closure via C–H activation. This approach broadens the substrate scope compared with a previous scheme in which C–H activation preceded CO insertion.

Science, this issue p. 851

Abstract

Methods for the synthesis and functionalization of amines are intrinsically important to a variety of chemical applications. We present a general carbon-hydrogen bond activation process that combines readily available aliphatic amines and the feedstock gas carbon monoxide to form synthetically versatile value-added amide products. The operationally straightforward palladium-catalyzed process exploits a distinct reaction pathway, wherein a sterically hindered carboxylate ligand orchestrates an amine attack on a palladium anhydride to transform aliphatic amines into β-lactams. The reaction is successful with a wide range of secondary amines and can be used as a late-stage functionalization tactic to deliver advanced, highly functionalized amine products of utility for pharmaceutical research and other areas.

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