Single point activation of pyridines enables reductive hydroxymethylation |
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Authors: | Bruno Marinic Hamish B Hepburn Alexandru Grozavu Mark Dow Timothy J Donohoe |
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Institution: | Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA UK.; AstraZeneca, Silk Road, Macclesfield SK10 2NA UK |
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Abstract: | The single point activation of pyridines, using an electron-deficient benzyl group, facilitates the ruthenium-catalysed dearomative functionalisation of a range of electronically diverse pyridine derivatives. This transformation delivers hydroxymethylated piperidines in good yields, allowing rapid access to medicinally relevant small heterocycles. A noteworthy feature of this work is that paraformaldehyde acts as both a hydride donor and an electrophile in the reaction, enabling the use of cheap and readily available feedstock chemicals. Removal of the activating group can be achieved readily, furnishing the free NH compound in only 2 steps. The synthetic utility of the method was illustrated with a synthesis of (±)-Paroxetine.Pyridines can be activated at a single point with a new benzyl group, followed by dearomative functionalisation at C3 using formaldehyde. |
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