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Stereoselective palladium-catalyzed C(sp3)–H mono-arylation of piperidines and tetrahydropyrans with a C(4) directing group

  • Piticari, A-S
  • Antermite, D
  • Higham, J
  • Moore, H
  • Webster, M
  • Bull, J
Publication Date
Feb 28, 2022
Spiral - Imperial College Digital Repository
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A selective Pd-catalyzed C(3)–H cis-functionalization of piperidine and tetrahydropyran carboxylic acids is achieved using a C(4) aminoquinoline amide auxiliary. High mono- and cis-selectivity is attained by using mesityl carboxylic acid as an additive. Conditions are developed with significantly lower reaction temperatures (≤50 °C) than other reported heterocycle C(sp3)–H functionalization reactions, which is facilitated by a DoE optimization. A one-pot C–H functionalization-epimerization procedure provides the trans-3,4-disubstituted isomers directly. Divergent aminoquinoline removal is accomplished with the installation of carboxylic acid, alcohol, amide and nitrile functional groups. Overall fragment compounds suitable for screening are generated in 3-4 steps from readily-available heterocyclic carboxylic acids.

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