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Updated: Jun 16, 2026

A Microwave-Assisted Direct Heteroarylation of Ketones Using Transition Metal Catalysis
Published on: February 16, 2020
Coordination-Driven Direct C─H Metalation of N-Heterocycles With a Superbasic Co(II) Amide Co(TMP)2
Na Jin1, Manting Mu2, Max García-Melchor2,3,4
1Departement Für Chemie, Biochemie und Pharmazie, Universität Bern, 3012 Bern, Switzerland.
None:
Metalation of N-heterocycles such as pyridines or diazines with conventional alkali metal bases is particularly challenging due to the limited activation of their C─H bonds coupled with the thermal fragility of the resulting organometallic intermediates. Building upon previous work in this area, we demonstrate that the superbasic cobalt(II) amide Co(TMP)2 (TMP = 2,2,6,6-tetramethylpiperidide) enables high-yielding and highly regioselective C─H metalation of a broad range of N-heterocycles via direct, redox-neutral Co(II)-H exchange. This reactivity extends beyond single-site activation, with controlled di-cobaltation of non-activated substrates such as pyrimidine and pyrazine. Via a combination of NMR reaction monitoring, isolation and characterisation of key organometallic intermediates, and density functional theory calculations, we establish that regioselectivity is dictated by coordination effects at positions α to nitrogen, overriding conventional trends based solely on C─H acidity. Exploiting cobalt's redox flexibility, oxidative treatment of the metalated intermediates with iodine enables selective C─N bond formation, giving sterically demanding TMP-substituted heterocycles. Collectively, these findings establish Co(TMP)2 as a mechanistically distinct and versatile reagent for the selective functionalisation of N-heterocycles.
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