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- Title
Skeletal metalation of lactams through a carbonyl-to-nickel-exchange logic.
- Authors
Zhong, Hongyu; Egger, Dominic T.; Gasser, Valentina C. M.; Finkelstein, Patrick; Keim, Loris; Seidel, Merlin Z.; Trapp, Nils; Morandi, Bill
- Abstract
Classical metalation reactions such as the metal-halogen exchange have had a transformative impact on organic synthesis owing to their broad applicability in building carbon-carbon bonds from carbon-halogen bonds. Extending the metal-halogen exchange logic to a metal-carbon exchange would enable the direct modification of carbon frameworks with new implications in retrosynthetic analysis. However, such a transformation requires the selective cleavage of highly inert chemical bonds and formation of stable intermediates amenable to further synthetic elaborations, hence its development has remained considerably challenging. Here we introduce a skeletal metalation strategy that allows lactams, a prevalent motif in bioactive molecules, to be readily converted into well-defined, synthetically useful organonickel reagents. The reaction features a selective activation of unstrained amide C–N bonds mediated by an easily prepared Ni(0) reagent, followed by CO deinsertion and dissociation under mild room temperature conditions in a formal carbonyl-to-nickel-exchange process. The underlying principles of this unique reactivity are rationalized by organometallic and computational studies. The skeletal metalation is further applied to a direct CO excision reaction and a carbon isotope exchange reaction of lactams, underscoring the broad potential of metal-carbon exchange logic in organic synthesis. Classical metalation reactions in organic synthesis typically involve metal-halogen exchange. Here, the authors introduce a metal-carbon exchange strategy that enables the skeletal editing of biologically relevant lactams by a Ni(0) compound.
- Subjects
ISOTOPE exchange reactions; METALATION; EXCHANGE reactions; LACTAMS; ORGANIC synthesis; LOGIC design
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-40979-3