Negishi Cross-Coupling of Substrates Bearing Relatively Acidic Protons

organozinc reagents - cross-coupling - aryl halides

Significance

Alkyl- or arylzinc halides are believed to be incompatible with the presence of acidic protons like free OH or NH₂ groups. However, in many cases the rate of their protonation allows performing the Negishi cross-coupling even in the presence of such acidic groups. The organozinc compounds are readily available directly from the corresponding halides. This method allows a simple one-pot reaction leading to a new C-C bond formation.

Comment

The rate of the protonation of organo-zinc species decreases in the row aryl > alkyl > benzyl. Benzylzinc is quenched by aniline at 25 ˚C only within several hours. In most of the reactions, Pd(OAc)₂/S-Phos catalytic system was used. However, cheaper Ni(II)/Ph₃P is almost equally useful, at least for the coupling of aryl- and benzylic zinc halides. Slow addition of the zinc reagent with a syringe pump is always advantageous in this ­reaction.