| Negishi coupling | |
|---|---|
| Named after | Ei-ichi Negishi |
| Reaction type | Coupling reaction |
| Identifiers | |
| Organic Chemistry Portal | negishi-coupling |
| RSC ontology ID | RXNO:0000088 |
The Negishi coupling is a widely employed transition metal catalyzed cross-coupling reaction. The reaction couples organic halides or triflates with organozinc compounds, forming carbon-carbon bonds (C-C) in the process. A palladium (0) species is generally utilized as the catalyst, though nickel is sometimes used.[1][2] A variety of nickel catalysts in either Ni0 or NiII oxidation state can be employed in Negishi cross couplings such as Ni(PPh3)4, Ni(acac)2, Ni(COD)2 etc.[3][4][5]
- The leaving group X is usually chloride, bromide, or iodide, but triflate and acetyloxy groups are feasible as well. X = Cl usually leads to slow reactions.
- The organic residue R = alkenyl, aryl, allyl, alkynyl or propargyl.
- The halide X' in the organozinc compound can be chloride, bromine or iodine and the organic residue R' is alkenyl, aryl, allyl, alkyl, benzyl, homoallyl, and homopropargyl.
- The metal M in the catalyst is nickel or palladium
- The ligand L in the catalyst can be triphenylphosphine, dppe, BINAP, chiraphos or XPhos.
Palladium catalysts in general have higher chemical yields and higher functional group tolerance.
The Negishi coupling finds common use in the field of total synthesis as a method for selectively forming C-C bonds between complex synthetic intermediates. The reaction allows for the coupling of sp3, sp2, and sp carbon atoms, (see orbital hybridization) which make it somewhat unusual among the palladium-catalyzed coupling reactions. Organozincs are moisture and air sensitive, so the Negishi coupling must be performed in an oxygen and water free environment, a fact that has hindered its use relative to other cross-coupling reactions that require less robust conditions (i.e. Suzuki reaction). However, organozincs are more reactive than both organostannanes and organoborates which correlates to faster reaction times.
The reaction is named after Ei-ichi Negishi who was a co-recipient of the 2010 Nobel Prize in Chemistry for the discovery and development of this reaction.
Negishi and coworkers originally investigated the cross-coupling of organoaluminum reagents in 1976 initially employing Ni and Pd as the transition metal catalysts, but noted that Ni resulted in the decay of stereospecifity whereas Pd did not.[6] Transitioning from organoaluminum species to organozinc compounds Negishi and coworkers reported the use of Pd complexes in organozinc coupling reactions and carried out methods studies, eventually developing the reaction conditions into those commonly utilized today.[7] Alongside Richard F. Heck and Akira Suzuki, El-ichi Negishi was a co-recipient of the Nobel Prize in Chemistry in 2010, for his work on "palladium-catalyzed cross couplings in organic synthesis".
- ^ King AO, Okukado N, Negishi Ei (1977). "Highly general stereo-, regio-, and chemo-selective synthesis of terminal and internal conjugated enynes by the Pd-catalysed reaction of alkynylzinc reagents with alkenyl halides". Journal of the Chemical Society, Chemical Communications (19): 683. doi:10.1039/C39770000683.
- ^ Kürti L, Czakó B (2007). Strategic applications of named reactions in organic synthesis : background and detailed mechanisms ; 250 named reactions. Amsterdam: Elsevier Academic Press. ISBN 978-0-12-429785-2.
- ^ Zhou, Jianrong (Steve); Fu, Gregory C. (December 2003). "Cross-Couplings of Unactivated Secondary Alkyl Halides: Room-Temperature Nickel-Catalyzed Negishi Reactions of Alkyl Bromides and Iodides". Journal of the American Chemical Society. 125 (48): 14726–14727. doi:10.1021/ja0389366. ISSN 0002-7863. PMID 14640646.
- ^ Negishi, Eiichi; King, Anthony O.; Okukado, Nobuhisa (1977-05-01). "Selective carbon-carbon bond formation via transition metal catalysis. 3. A highly selective synthesis of unsymmetrical biaryls and diarylmethanes by the nickel- or palladium-catalyzed reaction of aryl- and benzylzinc derivatives with aryl halides". The Journal of Organic Chemistry. 42 (10): 1821–1823. doi:10.1021/jo00430a041. ISSN 0022-3263.
- ^ Gavryushin, Andrei; Kofink, Christiane; Manolikakes, Georg; Knochel, Paul (2005-10-01). "Efficient Cross-Coupling of Functionalized Arylzinc Halides Catalyzed by a Nickel Chloride−Diethyl Phosphite System". Organic Letters. 7 (22): 4871–4874. doi:10.1021/ol051615+. ISSN 1523-7060. PMID 16235910.
- ^ Baba S, Negishi E (1976). "A novel stereospecific alkenyl-alkenyl cross-coupling by a palladium- or nickel-catalyzed reaction of alkenylalanes with alkenyl halides". Journal of the American Chemical Society. 98 (21): 6729–6731. doi:10.1021/ja00437a067.
- ^ Negishi E, King AO, Okukado N (1977). "Selective carbon-carbon bond formation via transition metal catalysis. 3. A highly selective synthesis of unsymmetrical biaryls and diarylmethanes by the nickel- or palladium-catalyzed reaction of aryl- and benzylzinc derivatives with aryl halides". The Journal of Organic Chemistry. 42 (10): 1821–1823. doi:10.1021/jo00430a041.