A Nickel(II)-Mediated Thiocarbonylation Strategy for Carbon Isotope Labeling of Aliphatic Carboxamides

A series of pharmaceutically relevant small molecules and biopharmaceuticals bearing aliphatic carboxamides have been successfully labeled with carbon-13. Key to the success of this novel carbon isotope labeling technique is the observation that ¹³ C-labeled Ni^II -acyl complexes, formed from a ¹³ CO insertion step with Ni^II -alkyl intermediates, rapidly react in less than one minute with 2,2'-dipyridyl disulfide to quantitatively form the corresponding 2-pyridyl thioesters. Either the use of ¹³ C-SilaCOgen or ¹³ C-COgen allows for the stoichiometric addition of isotopically labeled carbon monoxide. Subsequent one-pot acylation of a series of structurally diverse amines provides the desired ¹³ C-labeled carboxamides in good yields. A single electron transfer pathway is proposed between the Ni^II -acyl complexes and the disulfide providing a reactive Ni^III -acyl sulfide intermediate, which rapidly undergoes reductive elimination to the desired thioester. By further optimization of the reaction parameters, reaction times down to only 11 min were identified, opening up the possibility of exploring this chemistry for carbon-11 isotope labeling. Finally, this isotope labeling strategy could be adapted to the synthesis of ¹³ C-labeled liraglutide and insulin degludec, representing two antidiabetic drugs.