Oxidation of allylic alcohols to enones, although on paper a simple reaction, usually requires insidiously toxic metals or metalloids such as chromium and selenium or hazardous peroxy- reagents.1 Scale-up of these methods remains particularly challenging. A team from GSK found themselves in precisely this position when developing a synthetic route to a steroid-derived HIV maturation inhibitor (Figure 1).2
In early approaches sodium dichromate oxidation of an olefin intermediate (A) successfully delivered the enone in good yield (83%, NaOAc/Ac2O, toluene/acetic acid, 60°C). Finding methods avoiding the use of chromium reagents was a high priority. t-Butyl hydroperoxide gave the required product in low purity.
Digging back into older literature they found a paper published in 1969 by Thomson describing oxidation of an allylic methylene with N-bromosuccinimide in aqueous calcium carbonate / dioxane under visible light irradiation.3 Repeating these conditions using (A) as substrate gave the enone in low-ish yield (32% after chromatographic isolation). Demonstrating the power of perseverance, the team undertook a detailed process optimisation and understanding experiments. It turned out that light was not required and the reaction worked without requiring base. Yields greater than 90% could be obtained by portionwise addition of NBS to a solution of olefin in aqueous 2-Methyl-THF. The reaction was clean, fast (under 5 min at RT) and robust.
The paper contains experimental details for a 25g reaction in which the product solution was telescoped into the next stage (acetate cleavage) using KOH in methanol. The diol was obtained in 83% yield (Scheme 1).
In the paper they don’t discuss a mechanism. An experiment with inclusion of a radical inhibitor had no influence on the reaction. A fully anaerobic reaction was reported as incomplete however the experimental details describe use of a nitrogen blanket.
This is nice example of a process chemistry team solving a challenging scale-up issue. Hopefully a full paper on this oxidation will forthcoming or others will pick it up and develop the substrate scope.
See you next time.
- Allylic oxidation of olefins to enones, W. Maison et al, Synthesis 2013, 45, 2201-2221.
- Development of an improved route to human immunodeficiency virus maturation inhibitor by chromium-free allylic oxidation and an efficient Henry reaction, J. Strachan et al, Org. Process Res. Dev. 2021, 26, 288-298.
- Direct oxidation of allylic methylene to carbonyl, J. Thomson et al, J. Chem. Soc. D 1969, 20, 1220.