A Robust Nickel Catalyst for Cyanomethylation of Aldehydes: Activation of Acetonitrile under Base-Free Conditions

摘要

Nucleophilic addition of α-cyano carbanions to carbonyl substrates is a synthetically important process as it provides easy access to a large variety of pharmaceutically important compounds through the resultant β-hydroxy nitriles. This method is straightforward and avoids the use of highly toxic cyanide salts (for the ring-opening of epoxides), but is often limited to activated nitriles (e.g., α-arylnitriles, pK_a values of ca. 22 in DMSO) with increased acidity of the α-CH protons. Utilization of unactivated simple alkylnitriles, such as acetonitrile (pK_u-=31.3 in DMSO), is challenging as it generally requires a strong base to generate the desired carbanions. The employed reaction conditions are incompatible with base-sensitive substrates, and in some cases, lead to the loss of the hydroxy group by dehydration. For cyanomethylation of carbonyl substrates in particular, efforts have been made to circumvent the deprotonation of acetonitrile by catalytically activating Me,SiCH2CN using a base, fluoride, or N-heterocyclic carbene (NHC).