Coordination‐Controlled Nickel‐Catalyzed Benzylic Allylation of Unactivated Electron‐Deficient Heterocycles

Abstract

Heterocycles are widespread in pharmaceuticals but methods for their transition metal-catalyzed functionalization remain limited. This report describes a general, mild, and effective nickel-catalyzed benzylic allylation and benzylation of 14 types of heterocyclic aromatic compounds, including pyridines, pyrazines, pyrimidines, pyridazines, triazines, benzimidazoles, oxazoles, thiazoles, as well as 3,3-dimethyl-indoles. The exquisite selectivity for benzylic sites at the 2-position is hypothesized to be controlled by coordination of a heterocyclic nitrogen to Zn(TMP) 2 subverting generally presumed pK a 's of benzylic protons. Furthermore, the broad range of heterocyclic substrates, the diversity of electrophiles, and excellent functional group compatibility suggest its future application to synthesis of complex molecules and library diversification in drug discovery.

Regioselective Benzylic C–H Alumination and Further Functionalization of 2-Alkylpyridines by Yttrium Catalyst

“…By treating an alkylpyridine with a stoichiometric amount of a strong base, such as n BuLi, deprotonation of a benzylic C–H bond can easily occur to afford a benzylic anion, which can participate in nucleophilic substitution/addition to some reactive electrophiles, such as alkyl halides and carbonyl groups . Moreover, by the use of Pd-, Ir-, or Ni-catalysts, such benzylic anions can also react with relatively weak electrophiles, such as aryl halides and allylic esters/carbonates, to afford the corresponding arylated and allylic alkylated products. On the other hand, Lewis acid or Brønsted acid catalyzed benzylic C–H addition reactions have also been extensively studied so far as a complement to the base-promoted reactions.…”