Skeletal metalation of lactams through a carbonyl-to-nickel-exchange logic

Hongyu Zhong, Dominic T. Egger, Valentina C. M. Gasser, Patrick Finkelstein, Loris Keim, Merlin Z. Seidel, Nils Trapp and Bill Morandi ()
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Hongyu Zhong: ETH Zürich
Dominic T. Egger: ETH Zürich
Valentina C. M. Gasser: ETH Zürich
Patrick Finkelstein: ETH Zürich
Loris Keim: ETH Zürich
Merlin Z. Seidel: ETH Zürich
Nils Trapp: ETH Zürich
Bill Morandi: ETH Zürich

Nature Communications, 2023, vol. 14, issue 1, 1-9

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40979-3

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