Nicholas reaction

What is Nicholas reaction?

The Nicholas reaction, named after its discoverer Nicholas et al. in 1971, involves a nucleophilic substitution on a propargylic alcohol, ether, or ester by a carbon or heteroatom nucleophile. Nicholas reaction requires the generation of a carbocation by a strong Lewis acid, which is stabilized by the formation of a hexacarbonyldicobalt alkyne complex. Finally, the alkyne moiety is liberated by oxidation with cerium ammonium nitrate (CAN) or N-methylmorpholine N-oxide.

Nicholas reaction - general reaction scheme - Nicholas propargylic substitution
Nicholas reaction
  • R1, R3 = H, alkyl, aryl
  • R2 = H, alkyl, acyl, Tf
  • Nu = Carbon or heteroatom nucleophile (see list of acronyms)

Nicholas reaction is also known as the Nicholas cyclization or Nicholas propargylic substitution. The propargylic cation can be generated from a propargylic alcohol, ether, or ester using a strong Lewis acid such as BF3·OEt2, TiCl4, or GeCl4. However, some milder Lewis acids such as MgBr2, LiCl, LiBr, and ZnBr2 are not strong enough for this reaction. The montmorillonite K-10 is found to be an effective promoter for this reaction.

The nucleophile can be either a carbon-nucleophile, such as an enolate, arene, or heterocycle, or a heteroatom-nucleophile, such as an alcohol, epoxide, or carboxylic acid. However, the cobalt-mediated cyclization is reversible, and an equilibrium exists at the propargylic center through a fluxional cationic intermediate. Therefore, the original stereochemistry of the substrate is usually lost upon treatment by a Lewis acid.

It is worth noting that the use of an Evans’s oxazoline enolate in coupling with a propargylic cation to generate high stereoselectivity is specifically referred to as the Nicholas-Schreiber reaction.

References

Nicholas, K. M., and Pettit, R. (1971). An alkyne protecting group. Tetrahedron Letters, 12(37), 3475-3478. https://doi.org/10.1016/S0040-4039(01)97209-0

Shares