Tris(4-bromophenyl)aminium
Hexachloroantimonate-Mediated
Intermolecular C(sp2)–C(sp3) Free Radical
Coupling of Vindoline with β‑Ketoesters and Related Compounds
posted on 2021-12-29, 01:13authored byJiajun Zhang, Srinivas R. Paladugu, Rachel M. Gillard, Anindya Sarkar, Dale L. Boger
A powerful
tris(4-bromophenyl)aminium hexachloroantimonate
(BAHA) mediated regioselective intermolecular coupling reaction of
vindoline with a wide range of substrates that include β-ketoesters,
β-diketones, β-ketoaldehydes, β-ketonitriles, β-ketolactones,
β-ketolactams, β-cyanoesters, and malononitriles is detailed.
The BAHA-promoted intermolecular sp3/sp2 coupling,
representing a special class of selective C–H functionalization
reactions with direct carbon–carbon bond formation, proceeds
with generation of a quaternary center bound to the aryl C15 center
of vindoline capable of accommodating of the vinblastine C16′
methyl ester and functionalized for subsequent divergent heterocycle
introduction. A comprehensive examination of the reaction scope, optimization
of subtle reaction parameters, and key insights into the reaction
mechanism are described. Contrary to what might be prevailing expectations,
studies suggest the plausible mechanism entails initial single-electron
oxidation of the substrate enolate, not vindoline, and subsequent
regiospecific addition of the resulting electrophilic radical to vindoline.
As such and beyond the new arylation reaction with vindoline, the
studies define a host of new, previously unrecognized, applications
of BAHA and related triarylaminium radical cations that arises from
their ability to generate stabilized electrophilic radicals from β-ketoesters
and related substrates under nonreducing and metal-free conditions.
Those exemplified herein include mediating stabilized enolate free
radical arylation, dimerization, allylation, alkene addition, and
α-oxidation reactions.