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Refiguring The Equation For [2+2+1] Cycloadditions

In situ generation of carbon monoxide provides flexibility in preparing γ-lactams and bicyclic γ-lactams

by Stephen K. Ritter
November 17, 2014 | A version of this story appeared in Volume 92, Issue 46

Chemists in Japan have developed a versatile variation on the Pauson-Khand reaction—a type of [2+2+1] cycloaddition—leading to the synthesis of new γ-lactams (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja509171a). These five-membered cyclic amides are useful intermediates for synthesizing bioactive molecules for drug discovery as well as for ring-opening polymerizations. In a normal Pauson-Khand reaction, an alkyne and an alkene are coupled via carbon monoxide to form a cyclopentenone. By using an imine in place of the alkene, the end product is a γ-lactam. Sensuke Ogoshi and colleagues at Osaka University have found that a nickel(0) phosphine catalyst works best to mediate γ-lactam synthesis. But formation of the key cyclic nickel intermediate is hampered by formation of catalytically unreactive nickel carbonyl complexes when using CO gas. They reasoned that using phenyl formate in solution as a surrogate for CO could produce CO in situ, which controls CO concentration to prevent nickel carbonyl formation and further enables renewal of the catalytic cycle (shown). The researchers also discovered that using norbornene instead of an alkyne leads to bicyclic γ-lactams.


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