Cross-coupling of sp3 C-H bonds and alkenes: Catalytic cyclization of alkene-amide substrates

Brenton DeBoef, Columbia University
Stefan J. Pastine, Columbia University
Dalibor Sames, Columbia University


We herein present a new oxidative cyclization of alkene-amide substrates under neutral and catalytic conditions. This overall transformation requires tandem sp3 C-H activation (at the position adjacent to the amide nitrogen) and C-C bond formation. Specifically, pyrrolidine 1 was converted to pyrrolizidinone 3 and indolizidinone 4 in 66% and 17% yield, respectively, in the presence of [Ir(coe)2Cl]2, the carbene ligand IPr (1:1 metal/ligand ratio, 5-10 mol % of Ir), and the hydrogen acceptor (NBE or TBE, 3-10 equiv). The results presented in this study suggest that complex 10 [IPr-Ir(Cl)(substrate)] is the key intermediate in the catalytic cycle. On the mechanistic front, the key advance was the ability to facilitate C-H activation and alkene insertion in tandem, and in preference to β-hydride elimination, in the context of amide substrates. With respect to complex synthesis, catalytic and neutral conditions of this method unlock new exciting opportunities as illustrated by regioselective cyclization of the proline-derived substrate 16. Copyright © 2004 American Chemical Society.