Alkyl Iodides and [11C]CO in Nickel-Mediated Cross-Coupling Reactions: Successful Use of Alkyl Electrophiles containing a β Hydrogen Atom in Metal-Mediated [11C]Carbonylation

Transition metal-mediated cross-coupling reactions of non-activated alkyl electrophiles suffer from competing b-hydride elimination and therefore have limited applications in synthetic organic chemistry. Hereby the first successful use of nickel-mediated carbonylative cross-coupling of non-activated alkyl iodides using [C-11] carbon monoxide is presented. The reaction conditions were optimised for the synthesis of N-(pyridine-2-yl) cyclohexane([C-11] carbonyl)-carboxamide. The nickel(0) complex, Ni(COD) 2, in the presence of bathophenanthroline in the non-polar protic solvent tert-butanol at 100 degrees C offered the highest trapping efficiency (TE) and radiochemical yield (RCY) of 89% and 72%, respectively. The applicability of the method was further explored in the syntheses of five additional ([C-11] carbonyl) amides (6a to 6e in Figure 2) and the TE and RCY in the latter cases were 70-90% and 33-57%, respectively. The presented method has a potential for the development of C-11-labelled PET tracers with a carbonyl group connected to an alkyl chain containing beta hydrogen.