Contra-thermodynamic Hydrogen Atom Abstraction in the Selective C-H Functionalization of Trialkylamine N-CH3Groups.
We report a simple one-pot protocol that affords functionalization of N-CH3groups in N-methyl-N,N-dialkylamines with high selectivity over N-CH2R or N-CHR2groups. 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-CH3groups. The intermediates that result react in situ with organometallic nucleophiles in a single pot, affording novel and highly selective homologation of N-CH3groups. 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.
WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde , 295 Cathedral Street, Glasgow G1 1XL, United Kingdom.|GlaxoSmithKline Medicines Research Centre , Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom.
Joshua P
JP
Barham
GlaxoSmithKline Medicines Research Centre , Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom.
Matthew P
MP
John
WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde , 295 Cathedral Street, Glasgow G1 1XL, United Kingdom.
John A
JA
Murphy