Contra-thermodynamic Hydrogen Atom Abstraction in the Selective C–H Functionalization of Trialkylamine N‑CH3 Groups

• Published in: Journal of the American Chemical Society 2016-11, Vol.138 (47), p.15482-15487
• Main Authors: Barham, Joshua P, John, Matthew P, Murphy, John A
• Format: Article
• Language: English
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.6b09690

We report a simple one-pot protocol that affords functionalization of N-CH 3 groups in N-methyl-N,N-dialkylamines with high selectivity over N-CH 2R 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-CH 3 groups. The intermediates that result react in situ with organometallic nucleophiles in a single pot, affording novel and highly selective homologation of N-CH 3 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.