Mechanistic Study of SmI₂‐Mediated Reformatsky Reaction for Macrolactam Formation Using a Cyclopropyl Group as a Probe

Abstract

A mechanistic study using a cyclopropylmethyl radical clock as a probe to investigate the formation of a macrolactam ring via an SmI2‐mediated intramolecular Reformatsky reaction is experimentally explored. The results of our study indicate that the key SmIII‐enolate intermediate is formed by cleavage of a C−Br bond in an anion‐mediated β‐elimination, and then eventually undergoes an intramolecular aldol condensation to form the macrolactam ring.

Mechanism of SmI2 Reduction of 5-Bromo-6-oxo-6-phenylhexyl Methanesulfonate Studied by Spin Trapping with 2-Methyl-2-nitrosopropane

“…EPR analysis of the resulting trapped species support a mechanism in which direct reduction of the carbon–bromine bond results in an α-centered radical rather than a ketyl radical intermediate. While a recent study has shown some experimental support for the presence of ketyl radical intermediates in similar reductions, the substrates for that study contained electronically dissimilar α-bromoamides . Further support that SmI 2 reduction of α-bromoketones proceeds through an α-centered radical was established through spin-trapping studies using deuterium-labeled and differentially substituted substrates.…”

“…While a recent study has shown some experimental support for the presence of ketyl radical intermediates in similar reductions, the substrates for that study contained electronically dissimilar α-bromoamides. 20 Further support that SmI 2 reduction of α-bromoketones proceeds through an α-centered radical was established through spin-trapping studies using deuterium-labeled and differentially substituted substrates. These studies should facilitate further development of novel carbon−carbon bond forming reactions through the generation of samarium enolates.…”