An efficient catalytic protocol for the three-component assembly of benzyl bromides, carbon monoxide, and alkyl zinc reagents to give benzyl alkyl ketones is described, and represents the first nickel-catalyzed carbonylative coupling of two sp -carbon fragments. The method, which relies on the application of nickel complexed with an NN -type pincer ligand and a controlled release of CO gas from a solid precursor, works well with a range of benzylic bromides. Mechanistic studies suggest the intermediacy of carbon-centered radicals.

An extensive range of functionalized aliphatic ketones with good functional‐group tolerance has been prepared by a NiI‐promoted coupling of either primary or secondary alkyl iodides with NN2 pincer NiII‐acyl complexes. The latter were easily accessed from the corresponding NiII‐alkyl complexes with stoichiometric CO. This Ni‐mediated carbonylative coupling is adaptable to late‐stage carbon isotope labeling, as illustrated by the preparation of isotopically labelled pharmaceuticals. Preliminary investigations suggest the intermediacy of carbon‐centered radicals.

The development of a nickel-mediated aminocarbonylation utilizing NN -pincer Ni-complexes, alkylzinc reagents, stoichiometric carbon monoxide and amines is described for the first time, which can be adapted to late-stage carbon-isotope labeling. This work expands the scope of the highly established palladium-promoted version of the reaction, by allowing carbon-sp fragments to take part in the three-component reaction. Finally, the results obtained show a remarkable effect of the pincer ligand for the reductive elimination step with the amine, which is followed by C NMR spectroscopy studies.

Access to b-Ketonitrilest hrough Nickel-Catalyzed Carbonylative Couplingo fa-Bromonitrilesw ith AlkylzincR eagents Aske S. Donslund, KarolineT .N eumann, NicklasP .C orneliussen,E bbe K. Grove, Domenique Herbstritt,K im Daasbjerg, and Troels Skrydstrup* [a] Scheme1.Establishedm ethods for the synthesiso fb-ketonitriles by:a)acylation of metalated nitriles,b )palladium-catalyzed carbonylative cross couplings, and c) nickel-catalyzed carbonylativecross coupling.[a] A.

As eries of pharmaceutically relevant small molecules and biopharmaceuticals bearing aliphatic carboxamides have been successfully labeled with carbon-13. Key to the successo ft his novel carbon isotopel abeling 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.E ither the use of 13 C-SilaCOgen or 13 C-COgen allows for the stoichiometric additiono fi sotopically labeled carbon monoxide. Subsequento ne-pot acylation of as eries of structurally diverse amines provides the desired 13 C-la-beled carboxamides in good yields. Asingle electron transfer pathway is proposedb etween the Ni II -acyl complexes and the disulfide providing ar eactive Ni III -acyl sulfide intermediate, which rapidly undergoes reductivee limination to the desired thioester.B yf urthero ptimization of the reactionp arameters, reaction times down to only 11 min were identified, opening up the possibility of exploring this chemistry for carbon-11i sotope labeling. Finally,t his isotope labeling strategyc ould be adapted to the synthesis of 13 C-labeled liraglutide and insulind egludec, representing two antidiabetic drugs.