MRT - Ring Expansion

By: Matthias Junkers, Aldrich ChemFiles 2009, 9.4, 13.

Aldrich ChemFiles 2009, 9.4, 13.

Benefit from MRT & Flow Chemistry: safe & scale-independent handling of diazo reagents.

Potentially hazardous reagents like diazo compounds can be handled safely in microreactors because actual reaction volumes are very small. In a procedure developed at Johnson&Johnson ethyl diazoacetate is used in the presence of BF3•Et2O to expand the six-membered ring of N-Boc-4-piperidone.1 Thorough calorimetric investigations showed that this reaction can only be performed safely at small scales (test runs with 70 mg) in batch reactors. Scale-up to kilogram quantities cannot be recommended due to the risk of overheating and excessive nitrogen formation, leading to dangerous over-pressurization of the reaction vessel. The existing small-scale batch protocol was transferred into a flow process without the need of any further process development achieving a throughput of 91 g per hour at 89% yield.

Inspired by the Johnson&Johnson research this procedure was developed further and is used today by Sigma-Aldrich for the catalog production of N-Boc-hexahydro-1H-azepin-4-one (00833). The microreaction is followed by base induced decarboxylation performed in a conventional batch reactor (Scheme 5).

Scheme 5: Michael addition with subsequent Dieckmann condensation and decarboxylation leads to ring expansion (00833)

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Materials

     

References

  1. Zhang, X.; Stefanick, S.; Villani, F.J. Org. Process Res. Dev. 2004, 8, 455.

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