Palladium-catalyzed aryl cyanations with [14C]KCN: Synthesis of14C-labelled fadrozole, a potent aromatase inhibitor

Abstract

The potent aromatase inhibitor [14C]Fadrozole (1), was prepared in a single radiosynthetic step via a palladium(0)-catalyzed cyanation of the imidazole-containing aryl iodide 2b with [14C]KCN. Attempted preparation of 2b by metal-halogen interchange of the corresponding aryl bromide 2a with tert-butyl lithium followed by quenching with iodine afforded only the imidazole iodide 5 via disproportionation of the intermediate anion. The desired precursor was finally synthesized through a three-step sequence beginning with the alkylation of known imidazole derivative 8 with 4-iodobenzylbromide. This alkylation product was treated with thionyl chloride to convert a side chain hydroxyl to its corresponding primary chloride 10. Cyclization of chloride 10 using LDA/TMEDA gave the desired aryl iodide 2b. While initial attempts at the palladium(0)-catalyzed cyanation of 2b with unlabelled KCN in THF at reflux gave modest yields of Fadrozole, the reaction with [14C]KCN afforded only trace amounts of [14C]Fadrozole. By including Copper(I) iodide as a co-catalyst and using deoxygenated THF, the palladium(0)-catalyzed cyanation of 2b gave [14C]Fadrozole in 39% radiochemical yield with >99% radiochemical purity. Copyright © 2000 John Wiley & Sons, Ltd.