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

Murphy, John and Barham, Joshua and John, Matthew (2016) Contra-thermodynamic hydrogen atom abstraction in the selective C−H functionalization of trialkylamine N‑CH3 groups. Journal of the American Chemical Society, 138 (47). 15482−15487. ISSN 0002-7863

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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.