Iodination Method Eases Route To Radiolabeled Drugs

Iodine atoms are among the periodic table’s premier placeholders. Chemists can use them to reserve a spot on an aromatic ring prior to cobbling together new carbon-carbon bonds. Or they can swap them for tritium to make radiolabeled compounds. The challenge is incorporating iodine into molecules safely and selectively, which typically requires difficult-to-use reagents. Now, Jin-Quan Yu’s lab at Scripps Research Institute California has teamed with chemists at pharmaceutical firm Bristol-Myers Squibb to develop a palladium-catalyzed reaction that uses molecular iodine (I₂) to transform C–H bonds into C–I bonds (J. Am. Chem. Soc. 2013, DOI: 10.1021/ja4055492). “Iodine is a dream reagent,” Yu says. “It’s cheap, stable, and safe.” Iodine normally lacks the oxidizing power to promote C–H functionalization, and if the reaction does proceed, PdI₂ tends to crystallize out of solution, killing reactivity. Yu’s team overcame those problems by employing an electron-withdrawing amide auxiliary group to facilitate C–H activation and added cesium acetate to convert PdI₂ to a reactive species. The new method readily adds iodine to heterocycles prevalent in drug molecules, such as pyridines. Yu’s team is patenting the chemistry, and BMS is using the method to incorporate tritium as a radiotracer in studies of drug metabolism in animals. Scripps also has an agreement with Sigma-Aldrich to commercialize the iodinated building blocks (see page 8).