Skeletal metalation of lactams through a carbonyl-to-nickel-exchange logic
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Date
2023
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Journal Article
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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.
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14 (1)
Pages / Article No.
5273
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Nature
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09634 - Morandi, Bill / Morandi, Bill
02024 - Small Molecule Crystallography Center
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184658 - Catalytic synthesis of unprotected amines and heterocycles (SNF)
757608 - Shuttle Catalysis for Reversible Molecular Construction (EC)
757608 - Shuttle Catalysis for Reversible Molecular Construction (EC)