The chemical diversification of small molecules through carbon-hydrogen (C–H) bond activation is an effective strategy to access new chemical space with unparalleled economical benefits by reducing time and costs of chemical synthesis. Despite the obvious advantages of C–H activation and established methods, this approach remains underutilized for radiolabeling small molecule drugs. In this contribution, a new method to gain access to a variety of organic small molecule drugs through C–H radioiodination with the use catalytic amounts of air-stable copper(II) sources under ambient conditions has been identified. Initially, to identify the appropriate catalyst system, we tested a series of metal salts as Lewis acids in the absence of oxidants to catalyze the radioiodination of anisole using iodine-125 sodium iodide in acetonitrile. We envisioned a gentle route for C–H activation that would be amenable to late-stage functionalization of organic small molecule drugs, and therefore found it critical to omit the use of harsh oxidizing agents or high temperatures. With Cu(II) sources, we were able to radiolabel anisole at the para position with radiochemical conversion greater than 90%. Next, we evaluated a set of (hetero)arenes that are chemical fragments of known small molecule drugs by performing radioiodination with iodine-125 sodium iodide. We identified various (hetero)arenes as suitable substrates for radioiodination, most notably pyrrolo-pyridines, pyrido-indoles, azaindoles, and activated benzenes. We then performed the radioiodination of small molecule drugs under identical conditions; GSK923295, AZD9496, mivebresib, GSK2879552, sotorasib, tozasertib, KU-55933, and venetoclax. Radiochemical conversions of all small molecule drugs ranged from 70-90%, with the exception of sotorasib, which gave a lower yield of 40% and a mixture of ortho- para- substituents on the phenol moiety. In summary, we identified a new method for C–H radioiodination of small molecule drugs under mild conditions that enables access to new radiopharmaceuticals.

C–H radioiodination of small molecule drugs

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.