Nozaki-Hiyama-Kishi reaction

What is Nozaki-Hiyama-Kishi reaction?

The Nozaki-Hiyama-Kishi reaction, which involves the coupling of a halide and a carbonyl compound, was first reported in 1977 by Hiyama and Nozak, and then extended by Kishi in 1986. The reaction is also referred to as the Nozaki-Hiyama-Kishi coupling, Nozaki-Hiyama reaction, Hiyama-Nozaki reaction, Kishi-Nozaki reaction, or Nozaki-Hiyama-Kishi Ni(II)/Cr(II) coupling, depending on the context.

An intramolecular version of this reaction to yield a cyclic product is called the Nozaki-Hiyama-Kishi cyclization, while a special version involving an allylic nucleophile is termed the Nozak-Hiyama allylation.

Nozaki-Hiyama-Kishi reaction - general reaction scheme - Nozaki-Hiyama-Kishi coupling - Nozaki-Hiyama reaction -Hiyama-Nozaki reaction - Kishi-Nozaki reaction - Nozaki-Hiyama-Kishi Ni(II)/Cr(II) coupling
Nozaki-Hiyama-Kishi reaction
  • R = alkyl, aryl
  • R’ = alkenyl, allyl, aryl
  • X = halogen, -OTf, sulphonate, phosphate (see list of acronyms)

The Nozaki-Hiyama-Kishi reaction has several desirable features, such as high aldehyde chemoselectivity, mild reaction conditions, and compatibility with a wide range of nucleophiles. These nucleophiles include allyl, propargyl, aryl, and alkenyl halides, alkenyl triflates, allyl sulphonates and phosphates. However, the reaction does have some weaknesses, such as the high toxicity of chromium(II), the need for an excess amount of chromium, and the lack of facial selectivity.

The reaction mechanism involves the nucleophile first reacting with Cr2+ via oxidative insertion, followed by the resulting complex adding to the carbonyl group, and the nickel salt catalyzing the formation of a C-Cr bond. Nozaki-Hiyama-Kishi reaction has been observed to yield different products depending on the nucleophile used, such as (E)-bromofluoroalkene when a bromofluoroalkene is used, or pinacol when an aryl bromide is used with an electron-withdrawing group.

The Nozaki-Hiyama-Kishi reaction can also occur catalytically with only a small amount of Cr2+ present, which is constantly recycled by the nontoxic manganese powder in the presence of trimethylchlorosilane. Other catalytic conditions include the regeneration of Cr2+ by aluminium or via an electrochemical reduction.

Recent developments have enabled the control of enantioselectivity in the presence of some chiral ligands, such as salen, tridentate bis(oxazolinyl)carbazole, and DIANANE (endo,endo-2,5-diaminonorborane).