The Nozaki–Hiyama–Kishi (NHK) reaction refers to the coupling reaction of allylic halides, alkenyl halides, or alkenyl triflates with aldehydes in the presence of nickel/chromium catalysts.

In 1977, Tamejiro Hiyama and Hitoshi Nozaki discovered this reaction. They reported a chromium(II) salt solution prepared by reducing chromium chloride with lithium aluminum hydride, into which benzaldehyde and allyl chloride were added. In 1983, they expanded the scope to include vinyl halides or triflates and aryl halides. In 1986, during the total synthesis of Polytoxin, Yoshito Kishi discovered the role of nickel chloride in this reaction. The presence of nickel significantly broadened the substrate scope.

• Reagents: Nickel catalyst, chromium catalyst, solvent

• Reactants: Aldehyde, allylic halides, alkenyl halides, or alkenyl triflates

• Products: Homoallylic alcohols (or enol derivatives)

• Reaction Type: Coupling reaction

Experimental Tips:

• Palladium acetate can also act as an effective catalyst for this reaction;

• Chromium salts are toxic—proper safety precautions must be taken during handling;

• Alkenes are prone to direct coupling to form dienes, so the amount of nickel should be kept low;

• The reaction typically proceeds at room temperature under mild, neutral conditions with excellent functional group tolerance.

Reaction Mechanism

Nozaki–Hiyama–Kishi Reaction Mechanism

Original Literature:

• Yoshitaka Okude, Shigeo Hirano, Tamejiro Hiyama, and Hitosi Nozaki. J. Am. Chem. Soc., 1977, 99(9), 3179–3181.

• Kazuhiko Takai, Keizo Kimura, Tooru Kuroda, Tamejiro Hiyama, and Hitosi Nozaki. Tetrahedron Letters, 1983, 24(47), 5281–5284.

• K. Takai, M. Tagashira, T. Kuroda, K. Oshima, K. Utimoto, H. Nozaki. J. Am. Chem. Soc., 1986, 108(19), 6048–6050.

Notable References:

• Nozaki–Hiyama–Kishi Reactions Catalytic in Chromium, J. Am. Chem. Soc., 1996, 118(49), 12349–12357.

• A Highly Enantioselective Catalyst for the Asymmetric Nozaki–Hiyama–Kishi Reaction of Allylic and Vinylic Halides, Angew. Chem., 2003, 42(9), 1032–1035.

• Role of the Nozaki–Hiyama–Takai–Kishi Reaction in the Synthesis of Natural Products, Chem. Rev., 2017, 117(12), 8420–8446.