A Safe and Scaleable Amine to Nitrone Oxidation

Redesigning a reaction to avoid thermally unstable intermediates leads to a simpler process.  Nitrone (2) was required as an intermediate in the synthesis of (3), a potential anxiolytic, anti-depressant and a potential agent to overrule the addictive properties of drugs of abuse.  The nitrone was prepared by oxidation of amine (1) initially using the Davis reagent (4).  Thermal hazard assessments showed that the Davis reagent decomposes exothermically after 9 min at 75oC and after 1.5 hr at 60oC, so alternative methodology was needed.  A catalytic version was developed whereby the amine (1) and 5 mol % of sulphonylimine (5) were treated with m-chloroperbenzoic acid.  This protocol had the added advantage of minimising the amount of sulphonylimine waste generated at the end of the reaction.  Subsequently it was found that the Davis reagent was not needed at all, as the reaction could be carried out by adding mCPBA directly to amine (1) in dichloromethane.  Furthermore, after a simple aqueous work-up the dichloromethane solution of nitrone (2) could be used directly in the next stage of the synthesis without the need to isolate (2), which itself was thermally unstable.  This work was presented by Fred Stappers, Janssen Pharmaceutica, at Scientific Update’s Oxidation and Reduction Conference held in London on October 28th and 29th, 2002 and has subsequently been published in Organic Process Research and Development (2002, 6(6), 911-914).