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A Nickel(II)‐Mediated Thiocarbonylation Strategy for Carbon Isotope Labeling of Aliphatic Carboxamides
Author(s) -
Pedersen Simon S.,
Donslund Aske S.,
Mikkelsen Jesper H.,
Bakholm Oskar S.,
Papp Florian,
Jensen Kim B.,
Gustafsson Magnus B. F.,
Skrydstrup Troels
Publication year - 2021
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202005261
Subject(s) - chemistry , isotopic labeling , thioester , sulfide , carbon monoxide , nickel sulfide , reductive elimination , acylation , combinatorial chemistry , alkyl , isotope , organic chemistry , catalysis , enzyme , physics , quantum mechanics
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.