Contra-thermodynamic hydrogen atom abstraction in the selective C−H functionalization of trialkylamine N‑CH3 groups

Joshua P. Barham, Matthew P. John, John A. Murphy

Research output: Contribution to journalArticle

33 Citations (Scopus)
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Abstract

We report a simple one-pot protocol that affords functionalization of N-CH3 groups in N-methyl-N,N-dialkylamines with high selectivity over N-CH2R or N-CHR2 groups. The radical cation DABCO+•, prepared in situ by oxidation of DABCO with a triarylaminium salt, effects highly selective and contra-thermodynamic C−H abstraction from N-CH3 groups. The intermediates that result react in situ with organometallic nucleophiles in a single pot, affording novel and highly selective homologation of N-CH3 groups. Chemoselectivity, scalability, and recyclability of reagents are demonstrated, and a mechanistic proposal is corroborated by computational and experimental results. The utility of the transformation is demonstrated in the late-stage site-selective functionalization of natural products and pharmaceuticals, allowing rapid derivatization for investigation of structure−activity relationships.
Original languageEnglish
Pages (from-to)15482−15487
Number of pages6
JournalJournal of the American Chemical Society
Volume138
Issue number47
Early online date18 Nov 2016
DOIs
Publication statusPublished - 30 Nov 2016

Keywords

  • hydrogen aton abstraction
  • medicinal chemistry
  • opioid chemistry

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