{ "id": "eph43yb62x", "slug": "nozaki-hiyama-kishi-reaction", "title": "Nozaki–Hiyama–Kishi reaction", "updated": "2026-10-25", "topic_path": [ { "id": "physical", "label": "Physical world and mathematics", "api_url": "https://www.edgepedia.org/api/v1/topics/physical" }, { "id": "physical.chemistry", "label": "Chemistry", "api_url": "https://www.edgepedia.org/api/v1/topics/physical.chemistry" }, { "id": "physical.chemistry.methods", "label": "Chemical principles and methods", "api_url": "https://www.edgepedia.org/api/v1/topics/physical.chemistry.methods" }, { "id": "physical.chemistry.methods.chemical-synthesis", "label": "Chemical synthesis", "api_url": "https://www.edgepedia.org/api/v1/topics/physical.chemistry.methods.chemical-synthesis" }, { "id": "physical.chemistry.methods.chemical-synthesis.named-preparative-methods", "label": "Named synthetic methods", "api_url": "https://www.edgepedia.org/api/v1/topics/physical.chemistry.methods.chemical-synthesis.named-preparative-methods" }, { "id": "physical.chemistry.methods.chemical-synthesis.named-preparative-methods.alpha-ho-to-z", "label": "Titles Ho to Z", "api_url": "https://www.edgepedia.org/api/v1/topics/physical.chemistry.methods.chemical-synthesis.named-preparative-methods.alpha-ho-to-z" } ], "geo": [ { "id": "geo.nongeo.t1946.physical.chemistry.methods.chemical-synthesis.named-preparative-methods", "label": "Non-geographic · 1946 to 2000: Named synthetic methods", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1946.physical.chemistry.methods.chemical-synthesis.named-preparative-methods", "path": [ { "id": "geo.nongeo", "label": "Non-geographic", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo" }, { "id": "geo.nongeo.t1946", "label": "Non-geographic · 1946 to 2000", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1946" }, { "id": "geo.nongeo.t1946.physical", "label": "Physical world and mathematics", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1946.physical" }, { "id": "geo.nongeo.t1946.physical.chemistry", "label": "Chemistry", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1946.physical.chemistry" }, { "id": "geo.nongeo.t1946.physical.chemistry.methods", "label": "Chemical principles and methods", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1946.physical.chemistry.methods" }, { "id": "geo.nongeo.t1946.physical.chemistry.methods.chemical-synthesis", "label": "Chemical synthesis", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1946.physical.chemistry.methods.chemical-synthesis" }, { "id": "geo.nongeo.t1946.physical.chemistry.methods.chemical-synthesis.named-preparative-methods", "label": "Named synthetic methods", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1946.physical.chemistry.methods.chemical-synthesis.named-preparative-methods" } ] } ], "excerpt": "The Nozaki–Hiyama–Kishi reaction is a chromium(II)/nickel(II)-mediated coupling of aldehydes or ketones with vinyl or allyl halides forming allylic alcohols, valued for its chemoselectivity, discovered in 1977 and formalized in 1986.", "snippet": "The Nozaki–Hiyama–Kishi reaction is a chromium(II)/nickel(II)-mediated coupling of aldehydes or ketones with vinyl or allyl halides forming allylic alcohols, valued for its chemoselectivity, discovered in 1977 and formalized in 1986.", "node": "physical.chemistry.methods.chemical-synthesis.named-preparative-methods.alpha-ho-to-z", "markdown": "# Nozaki–Hiyama–Kishi reaction\n\nThe Nozaki–Hiyama–Kishi (NHK) reaction is a chromium(II)/nickel(II)-mediated coupling of aldehydes or ketones with vinyl or allyl halides that forms allylic and homoallylic alcohols through a new carbon–carbon bond. It is a Barbier-type (organometallic reagent formed in situ with substrate) process, and it is regarded as one of the most useful and reliable C–C bond-forming reactions in organic synthesis, first discovered in 1977 and formalized in 1986.[1](https://pubs.acs.org/jacsat/article/143/25/9478/576898/Electrochemical-Nozaki-Hiyama-Kishi-Coupling-Scope) Its defining feature is chemoselectivity: the organochromium nucleophile reacts with aldehydes while leaving esters, amides, acetals, nitriles, and even free alcohols untouched.[2](https://www.jstage.jst.go.jp/article/pjab1977/76/8/76_8_123/_pdf)\n\n| Key fact | Detail |\n|---|---|\n| Bond formed | C–C bond between an alkenyl/allyl halide carbon and an aldehyde or ketone carbonyl carbon, giving allylic or homoallylic alcohols[1](https://pubs.acs.org/jacsat/article/143/25/9478/576898/Electrochemical-Nozaki-Hiyama-Kishi-Coupling-Scope) |\n| Reagent system | Stoichiometric CrCl2 with catalytic NiCl2 (0.1–1% w/w) in DMF or DMSO[2](https://www.jstage.jst.go.jp/article/pjab1977/76/8/76_8_123/_pdf) |\n| History | Discovered by Nozaki and Hiyama in 1977; nickel catalysis recognized independently by Kishi and Nozaki; formalized 1986[1](https://pubs.acs.org/jacsat/article/143/25/9478/576898/Electrochemical-Nozaki-Hiyama-Kishi-Coupling-Scope) • [3](https://synarchive.com/named-reactions/nozaki-hiyama-kishi-reaction) |\n| Chemoselectivity | Aldehyde-selective additions in good-to-excellent yields; ketones react in ca. 40% yield[2](https://www.jstage.jst.go.jp/article/pjab1977/76/8/76_8_123/_pdf) |\n| Tolerance | Esters, amides, nitriles, ketones, acetals, ketals, ethers, silyl ethers, alcohols, and olefins survive[4](https://chemistry.illinois.edu/system/files/inline-files/Abstract_Kallemeyn1.pdf) |\n| Landmark application | Kishi's palytoxin synthesis: vinyl organochromium fragment coupling in 80% yield, 1.3:1 dr[4](https://chemistry.illinois.edu/system/files/inline-files/Abstract_Kallemeyn1.pdf) |\n| Recent development | 2024 metallaphotoredox variant eliminates chromium salts and metal reductants entirely[5](https://doi.org/10.1002/anie.202408195) |\n\n## How it works\n\nThe reaction runs on a dual Cr/Ni redox cycle. In the proposed classical cycle, nickel(II) chloride is first reduced to nickel(0) with two equivalents of chromium(II) chloride. The low-valent nickel undergoes oxidative addition into the alkenyl (or allyl) halide bond, and transmetalation (transfer of a metal-bound group between metals) between the resulting alkenyl–nickel species and the chromium(III) salt affords an alkenylchromium reagent. This organochromium nucleophile then adds to the aldehyde to produce the allylic alcohol.[2](https://www.jstage.jst.go.jp/article/pjab1977/76/8/76_8_123/_pdf) Mechanistic work by UV/Vis spectroscopy and spectroelectrochemistry confirmed that low-valent nickel arises from the interaction of the Ni(II) catalyst with CrCl2, though the active species may be a one-electron-reduced nickel species, formally Ni(I), rather than necessarily Ni(0).[6](https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.201003366)\n\nThe organochromium reagent is a mild nucleophile: its low nucleophilicity and weak basicity are what allow aldehyde-selective additions in the presence of ketones, esters, amides, acetals, cyano, and sulfinyl groups, and compatibility has been demonstrated with nitriles, acyls, ketals, ethers, silyl ethers, free alcohols, and olefins.[2](https://www.jstage.jst.go.jp/article/pjab1977/76/8/76_8_123/_pdf) • [4](https://chemistry.illinois.edu/system/files/inline-files/Abstract_Kallemeyn1.pdf) With allylic halides, additions are often stereoconvergent: the allyl organochromium reagent isomerizes through a π-allyl complex followed by bond rotation, so different allylic halide isomers can deliver the same product configuration. γ,γ-Disubstituted allyl halides instead give stereodivergent reactions, because steric hindrance slows the isomerization.[4](https://chemistry.illinois.edu/system/files/inline-files/Abstract_Kallemeyn1.pdf)\n\n## How it is done\n\nThe practical requirements follow from the mechanism. The reaction needs a soluble form of CrCl2; little or no reaction occurs in ether or tetrahydrofuran, so DMF or DMSO is used as solvent. Iodoalkenes are more reactive than bromoalkenes and generally give better yields; alkenyl triflates and mesylates also serve as electrophile partners for the halide component.[2](https://www.jstage.jst.go.jp/article/pjab1977/76/8/76_8_123/_pdf) Normally 0.1–1% w/w of NiCl2 is added to the CrCl2, and the nickel content must be kept low (about 0.01–1% w/w) to avoid formation of dienes by homocoupling of the haloalkenes.[2](https://www.jstage.jst.go.jp/article/pjab1977/76/8/76_8_123/_pdf)\n\nBecause Cr(II) is a weaker reductant than Mg(0) or Sm(II), aldehydes survive the reaction medium, so the reagents can be pre-mixed or combined in a Barbier-type procedure with all components present from the start; the Barbier option is preferred for micro-scale and intramolecular reactions.[2](https://www.jstage.jst.go.jp/article/pjab1977/76/8/76_8_123/_pdf)\n\n## Origin\n\nThe chromium(II) salt solution was prepared by reduction of chromic chloride with lithium aluminum hydride, to which benzaldehyde and allyl chloride were added.[2](https://www.jstage.jst.go.jp/article/pjab1977/76/8/76_8_123/_pdf) Early studies showed strong batch dependence: only certain lots of commercial CrCl2 worked. Trace nickel(II) in the commercial chromium was traced as the cause; doping pure CrCl2 with catalytic NiCl2 gave reproducible Grignard-type additions of haloalkenes to aldehydes.[2](https://www.jstage.jst.go.jp/article/pjab1977/76/8/76_8_123/_pdf) • [4](https://chemistry.illinois.edu/system/files/inline-files/Abstract_Kallemeyn1.pdf) The chromium(II)/nickel(II)-mediated \"Barbier type\" reaction consequently carries all three names.[2](https://www.jstage.jst.go.jp/article/pjab1977/76/8/76_8_123/_pdf) • [7](https://science-of-synthesis.thieme.com/app/text/?id=SD-221-00011) The nickel impurities were essential to the reaction's success.[3](https://synarchive.com/named-reactions/nozaki-hiyama-kishi-reaction) • [1](https://pubs.acs.org/jacsat/article/143/25/9478/576898/Electrochemical-Nozaki-Hiyama-Kishi-Coupling-Scope)\n\n## Variants\n\n**Catalytic chromium.** The standard procedure consumes stoichiometric CrCl2. A method was developed requiring only catalytic amounts of the active Cr(II) species, using 7–15 mol% chromium with manganese(0) as co-reductant to re-reduce Cr(III) to Cr(II) without interfering with the reaction; among metals, a combination of manganese and chlorotrimethylsilane proved suitable, since manganese does not directly reduce organic halides and TMSCl liberates the chromium(III) salt from the product alkoxide.[4](https://chemistry.illinois.edu/system/files/inline-files/Abstract_Kallemeyn1.pdf) • [2](https://www.jstage.jst.go.jp/article/pjab1977/76/8/76_8_123/_pdf) Turnover can also be achieved with zirconocene-derived reagents that remove the alkoxide from the chromium catalyst.[8](https://science-of-synthesis.thieme.com/app/text/?id=SD-202-00237)\n\n**Asymmetric variants.** A chiral bipyridyl alcohol ligand enables catalytic enantioselective NHK allylation of aromatic, α,β-unsaturated, and aliphatic aldehydes and ketones, giving homoallylic alcohols in up to 98% yield and up to 99% ee.[9](https://onlinelibrary.wiley.com/doi/10.1002/adsc.201400945) A later chiral ligand gave catalytic asymmetric allylation and methallylation of aldehydes with 86–96% ee; its Cr–ligand complex was stable enough to be recovered and recycled without loss of enantioselectivity or yield, and the asymmetric methallylation (92% ee) enabled the first total synthesis of FR901512, a cholesterol synthesis inhibitor.[10](https://www.jstage.jst.go.jp/article/tennenyuki/48/0/48_193/_article/-char/en)\n\n**Reductant-free and radical variants (2021–2025).** An electroreductive manifold has rendered the Ni/Cr coupling of vinyl halides with aldehydes more practical, reducing the need for stoichiometric chromium; the 2021 study optimized Ni ligands, Ni and Cr sources, and electrode, electrolyte, and current, using [Cp2ZrCl2](https://www.edgepedia.org/zirconocene-dichloride) (0.5 equiv) to remove the alkoxide from chromium for turnover.[1](https://pubs.acs.org/jacsat/article/143/25/9478/576898/Electrochemical-Nozaki-Hiyama-Kishi-Coupling-Scope) In 2024, Pei Gu and colleagues reported a metallaphotoredox-catalyzed asymmetric NHK reaction in Angewandte Chemie International Edition that eliminates chromium salts and metal reductants entirely, marrying alkenyl (pseudo)halides with aldehydes through a chiral nickel catalyst plus a photocatalyst; in this variant nickel alone performs both oxidative addition and insertion, diverging from the conventional Ni/Cr pathway.[5](https://doi.org/10.1002/anie.202408195) An electrocatalytic asymmetric alkyl-NHK coupling uses Cr electrocatalysis with aliphatic carboxylic acids, as redox-active esters, as alkyl nucleophile synthons.[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC11456316/) A general three-component NHK-type reaction enabled by delayed radical-polar crossover assembles homoallylic alcohols from feedstock chemicals with excellent chemo-, regio-, diastereo-, and enantioselectivities.[12](https://pubs.acs.org/doi/abs/10.1021/jacs.4c14913) In 2025, a dual photoredox/chromium catalytic system coupled thiophenes, butadienes, and aldehydes using catalytic CrCl2 (10 mol%) with a chiral bisoxazoline ligand and a Mes2Acr-tBu2BF4 photocatalyst, tolerating drug- and natural-product-derived aldehydes with high ee.[13](https://www.nature.com/articles/s41467-025-56372-1)\n\n## Applications\n\nThe reaction's tolerance of densely functionalized substrates makes it a workhorse for fragment coupling in complex molecules. In Kishi's palytoxin synthesis, reaction of an aldehyde and a trans-iodoolefin via vinyl organochromium addition gave the trans-allylic benzoate intermediate in 80% yield with a 1.3:1 diastereomeric ratio; Kishi used vinyl chromium additions five times in the synthesis of halichondrin B.[4](https://chemistry.illinois.edu/system/files/inline-files/Abstract_Kallemeyn1.pdf)\n\n**Macrocyclizations** are a particular strength. Intramolecular chromium-mediated coupling of allylic halides and aldehydes gives medium and large rings with high 1,2-anti selectivity, and macrocyclization proceeds with moderate to high stereocontrol owing to the influence of remote asymmetric centers on the transition state.[2](https://www.jstage.jst.go.jp/article/pjab1977/76/8/76_8_123/_pdf) In Danishefsky's total synthesis of eleutherobin, Wittig olefination, radical cyclization, lithiation-induced cyclization, and SmI2 reductive cyclization approaches to the macrocyclic alkene all failed, while the intramolecular NHK reaction gave the desired alcohol in 74% yield and a 15:1 diastereomeric ratio.[4](https://chemistry.illinois.edu/system/files/inline-files/Abstract_Kallemeyn1.pdf)\n\n## Limitations and alternatives\n\nThe principal drawbacks of the conventional reaction are the use of toxic chromium salts in excess, high amounts of metal reductants, and poor enantiocontrol in the unligated reaction.[5](https://doi.org/10.1002/anie.202408195) • [14](https://www.organic-chemistry.org/namedreactions/nozaki-hiyama-coupling.shtm) [Homocoupling](https://www.edgepedia.org/homocoupling) of the haloalkene to dienes is a documented side reaction, controlled by keeping nickel loadings low or adding 4-tert-butylpyridine.[2](https://www.jstage.jst.go.jp/article/pjab1977/76/8/76_8_123/_pdf) • [4](https://chemistry.illinois.edu/system/files/inline-files/Abstract_Kallemeyn1.pdf)\n\nAgainst the nearest alternatives, published comparisons are mostly indirect. Cr(II) is a weaker reductant than Mg(0) or Sm(II), which is precisely why aldehydes survive the NHK medium.[2](https://www.jstage.jst.go.jp/article/pjab1977/76/8/76_8_123/_pdf) The electroreductive, electrocatalytic decarboxylative, metallaphotoredox, and photoredox/Cr variants described above are the current routes to lower chromium consumption and better enantiocontrol.[1](https://pubs.acs.org/jacsat/article/143/25/9478/576898/Electrochemical-Nozaki-Hiyama-Kishi-Coupling-Scope) • [5](https://doi.org/10.1002/anie.202408195) • [11](https://pmc.ncbi.nlm.nih.gov/articles/PMC11456316/) • [13](https://www.nature.com/articles/s41467-025-56372-1)\n\n## References\n\n1. [Electrochemical Nozaki–Hiyama–Kishi Coupling: Scope, Applications, and Mechanism (JACS 2021, 143, 9478)](https://pubs.acs.org/jacsat/article/143/25/9478/576898/Electrochemical-Nozaki-Hiyama-Kishi-Coupling-Scope)\n2. [Nucleophilic addition of organochromium reagents to carbonyl compounds (Proc. Japan Acad., Ser. B)](https://www.jstage.jst.go.jp/article/pjab1977/76/8/76_8_123/_pdf)\n3. [Nozaki–Hiyama–Kishi Reaction (SynArchive)](https://synarchive.com/named-reactions/nozaki-hiyama-kishi-reaction)\n4. [The Nozaki–Hiyama–Kishi Reaction (literature seminar abstract, Kallemeyn, U. Illinois, 2002)](https://chemistry.illinois.edu/system/files/inline-files/Abstract_Kallemeyn1.pdf)\n5. [Pei Gu and colleagues (2024). Chromium‐ and Metal‐Reductant‐Free Asymmetric Nozaki–Hiyama–Kishi (NHK) Reaction Enabled by Metallaphotoredox Catalysis. Angewandte Chemie International Edition.](https://doi.org/10.1002/anie.202408195)\n6. [Cr/Ni-Catalyzed Vinylation of Aldehydes: A Mechanistic Study on the Catalytic Roles of Nickel and Chromium (Chem. Eur. J.)](https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.201003366)\n7. [Science of Synthesis (Thieme), NHK section](https://science-of-synthesis.thieme.com/app/text/?id=SD-221-00011)\n8. [Science of Synthesis: Cr/Ni couplings (reference work)](https://science-of-synthesis.thieme.com/app/text/?id=SD-202-00237)\n9. [A Chiral Bipyridyl Alcohol for Catalytic Enantioselective Nozaki–Hiyama–Kishi Allylation of Aldehydes and Ketones (Adv. Synth. Catal.)](https://onlinelibrary.wiley.com/doi/10.1002/adsc.201400945)\n10. [Development of Catalytic Asymmetric Nozaki-Hiyama Reaction and First Total Synthesis of FR901512](https://www.jstage.jst.go.jp/article/tennenyuki/48/0/48_193/_article/-char/en)\n11. [Electrocatalytic Asymmetric Nozaki–Hiyama–Kishi Decarboxylative Coupling: Scope, Applications, and Mechanism (JACS; open-access copy; publisher DOI 10.1021/jacs.3c13442)](https://pmc.ncbi.nlm.nih.gov/articles/PMC11456316/)\n12. [A General Three-Component Nozaki–Hiyama–Kishi-Type Reaction Enabled by Delayed Radical-Polar Crossover (JACS, 2024/2025)](https://pubs.acs.org/doi/abs/10.1021/jacs.4c14913)\n13. [Photoredox/Cr-catalyzed enantioselective radical-polar crossover transformation via C-H functionalization (Nature Communications, 2025)](https://www.nature.com/articles/s41467-025-56372-1)\n14. [Nozaki-Hiyama-Kishi Coupling (Organic Chemistry Portal)](https://www.organic-chemistry.org/namedreactions/nozaki-hiyama-coupling.shtm)\n\n---\n*Topic: Encyclopedia › Physical world and mathematics › Chemistry › Chemical principles and methods › Chemical synthesis › Named synthetic methods › Titles Ho to Z*\n\n*Initially written Sep 29, 2026 · Edited: Oct 15, 2026; Oct 25, 2026*\n\n*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*\n\nLicense: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license\n", "same_as": [], "url": "https://www.edgepedia.org/nozaki-hiyama-kishi-reaction", "markdown_url": "https://www.edgepedia.org/nozaki-hiyama-kishi-reaction.md", "license": { "name": "Edgepedia Community License 1.0", "url": "https://www.edgepedia.org/edgepedia/license", "summary": "Free with credit, commercial use included. AI training is open to everyone. For other uses, organizations over USD 100M in revenue or 100M monthly users license separately.", "spdx": "LicenseRef-Edgepedia-Community-1.0" }, "credit": "\"Nozaki–Hiyama–Kishi reaction\", Edgepedia (EdgeChat), https://www.edgepedia.org/nozaki-hiyama-kishi-reaction. Edgepedia Community License 1.0.", "credit_md": "\"[Nozaki–Hiyama–Kishi reaction](https://www.edgepedia.org/nozaki-hiyama-kishi-reaction)\", Edgepedia (EdgeChat), [https://www.edgepedia.org/nozaki-hiyama-kishi-reaction](https://www.edgepedia.org/nozaki-hiyama-kishi-reaction). [Edgepedia Community License 1.0](https://www.edgepedia.org/edgepedia/license).", "credit_html": "\"Nozaki–Hiyama–Kishi reaction\", Edgepedia (EdgeChat), https://www.edgepedia.org/nozaki-hiyama-kishi-reaction. Edgepedia Community License 1.0.", "speakable": "The Nozaki–Hiyama–Kishi reaction is a chromium/nickel-mediated coupling of aldehydes or ketones with vinyl or allyl halides forming allylic alcohols, valued for its chemoselectivity, discovered in 1977 and formalized in 1986." }