A Scalable Alternative to Chromium-Mediated Allylic Oxidation

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

Figure 1: GSK HIV maturation inhibitor

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).

Scheme 1: Allylic oxidation and telescoped acetate hydrolysis

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.


  1. Allylic oxidation of olefins to enones, W. Maison et al, Synthesis 2013, 45, 2201-2221.
  2. 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.
  3. Direct oxidation of allylic methylene to carbonyl, J. Thomson et al, J. Chem. Soc. D 1969, 20, 1220.