The Nozaki-Hiyama-Kishi reaction is a nickel/chromium coupling reaction forming an alcohol from the reaction of an aldehyde with a allyl or vinyl halide.[1] In their original 1977 publication, Tamejiro Hiyama and Hitosi Nozaki [2] reported on a chromium(II) salt solution prepared by reduction of chromic chloride by lithium aluminium hydride to which was added benzaldehyde and allyl chloride:
Compared to Grignard reactions, this reaction is very selective towards aldehydes with large tolerance towards a range of functional groups such as ketones, esters, amides and nitriles. Enals give exclusively 1,2-addition. Solvents of choice are DMF and DMSO, one solvent requirement is solubility of the chromium salts. Nozaki-Hiyama-Kishi reaction is a useful method for preparing medium-size rings.[3]
In 1983 the scope was extended by the same authors to include vinyl halides or triflates and aryl halides [4]. It was observed that the success of the reaction depended on the source of chromium(II) chloride and in 1986 it was found that this is due to nickel impurities [5]. Since then nickel(II) chloride is used as a co-catalyst.
In the same year Yoshito Kishi et al. independently discovered the beneficial effects of nickel in his quest for palytoxin [6]:
Palladium acetate was also found to be an effective cocatalyst.
Nickel is the actual catalyst when small amounts of a nickel salt is added in the reaction. Nickel(II) chloride is first reduced to nickel(0) with 2 equivalents of chromium(II) chloride (as sacrificial catalyst) leaving Chromium(III) chloride. The next step is oxidative addition of nickel into the carbon to halide bond forming an alkenylnickel R-Ni(II)-X intermediate followed by a transmetallation step exchanging NiX with a Cr(III) group to an alkenylchromium R-Cr(III)-X intermediate and regenerating Ni(II). This species reacts with the carbonyl group in a nucleophilic addition.
The amount of nickel used should be low as a direct alkene coupling to a diene is a side reaction.[7]
Related reactions are the Grignard reaction (Magnesium), the Barbier reaction (zinc) and addition reactions involving organolithium reagents.