Radical Deuteration of Alkyl Iodides Catalyzed by Thiol and Mechanistic Studies on Deoxygenation Reactions of Xanthates
Recently, there has been a growing interest in the pharmaceutical industries to incorporate deuterium in drugs candidates to improve their metabolism and pharmacokinetic properties1. A significant number of deuterated drug candidates (heavy drugs) have been synthesized and forwarded to clinical trials, such as Deutetrabenazine (Austedo®, TEVA pharmaceuticals) which is the first deuterated drug on the market. However, preparation of organic compounds selectively labelled with deuterium atom, remains a challenging synthetic problem. Radical deuteration of alkyl halides is one of the most efficient approach to perform this task. It is usually run using organotin deuterides2 but this method has three major drawbacks: organotin deuterides are expensive, toxic3 and led to product contamination.
We report here a method to deuterate alkyl iodides via a radical pathway with deuterated water as source of deuterium atom. Triethylborane is used to initiate and propagate the chain and dodecanethiol is used as a catalyst4. High deuterations and yields are obtained using this method which is compatible with a large range of functional groups.
The development of the deuteration method led us to discoveries that incite us to reinvestigate the mechanism of xanthates deoxygenation described by Wood et al.5 (see below) who used heavy water activated by trialkylboranes as a source of deuterium atom.
[1] Mullard, A. Nat. Rev. Drug Discovery 2016, 15, 219.
[2] Curran, D. P.; Ramamoorthy, P. S. Tetrahedron 1993, 49 (22), 4841–4858.
[3] I. J. Boyer, Toxicology 1989, 55, 253–298.
[4] B. M. Mikhailov; Y. N. Bubnov Zh. Obshch. Khim. 1961, 31, 160-166.
[5] D. A. Spiegel, K. B. Wiberg, L. N. Schacherer, M. R. Medeiros, J. L. Wood, J. Am. Chem. Soc. 2005, 127, 12513–12515.