Negishi coupling

The Negishi coupling is a cross coupling reaction in organic chemistry involving an organozinc compound, an organic halide and a nickel or palladium catalyst creating a new carbon-carbon covalent bond:^[1][2]

• The halide X can be chloride, bromine or iodine but also a triflate or acetyloxy group with as 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 or alkyl.
• The metal M in the catalyst is nickel or palladium
• The ligand L in the catalyst can be triphenylphosphine, dppe, BINAP or chiraphos

Palladium catalysts in general have higher chemical yields and higher functional group tolerance.

The reaction is named after Ei-ichi Negishi who received the 2010 Nobel Prize in Chemistry for the discovery and development of this reaction.

Reaction mechanism

The active catalyst in this reaction is zerovalent (M⁰) and the reaction in general proceeds through an oxidative addition step of the organic halide followed by transmetalation with the zinc compound and then reductive elimination:

Both organozinc halides and diorganozinc compounds can be used as starting materials. In one model system it was found that in the transmetalation step the former give the cis-adduct R-Pd-R' resulting in fast reductive elimination to product while the latter gives the trans-adduct which has to go through a slow trans-cis isomerization first.^[3]

A common side reaction is homocoupling. In one Negishi model system the formation of homocoupling was found to be the result of a second transmetalation reaction between the diarylmetal intermediate and arylmetal halide ^[4]:

Ar–Pd–Ar' + Ar'–Zn–X → Ar'–Pd–Ar' + Ar–Zn–X

Ar'–Pd–Ar' → Ar'–Ar' + Pd(0) (homocoupling)

Ar–Zn–X + H₂O → Ar–H + HO–Zn–X (reaction accompanied by dehalogenation)

Scope

The Negishi coupling has been applied in the synthesis of a 2,2'-bipyridine from 2-bromopyridine with tetrakis(triphenylphosphine)palladium(0),^[5] the synthesis of a biphenyl from o-tolylzinc chloride and o-iodotoluene and tetrakis(triphenylphosphine)palladium(0),^[6] the synthesis of 5,7-hexadecadiene from 1-decyne and (Z)-1-hexenyl iodide.^[7]

Structure of hexaferrocenylbenzene, C₆[(η⁵-C₅H₄)Fe(η⁵-C₅H₅)]₆

Negishi coupling has been applied in the synthesis of hexaferrocenylbenzene:^[8]

with hexaiodidobenzene, diferrocenylzinc and tris(dibenzylideneacetone)dipalladium(0) in tetrahydrofuran. The yield is only 4% signifying substantial crowding around the aryl core.

In a novel modification palladium is first oxidized by the haloketone 2-chloro-2-phenylacetophenone 1 and the resulting palladium OPdCl complex then accepts both the organozinc compound 2 and the organotin compound 3 in a double transmetalation:^[9]

External links

• The Negishi coupling at www.organic-chemistry.org: Link
• Negishi coupling - synthetic protocols from organic-reaction.com

References

1. ^ Anthony O. King, Nobuhisa Okukado and Ei-ichi Negishi (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. 
2. ^ Strategic Applications of Named Reactions in Organic Synthesis Laszlo Kurti, Barbara Czako Academic Press (March 4, 2005) ISBN 0-12-429785-4
3. ^ Juan A. Casares, Pablo Espinet, Beatriz Fuentes, and Gorka Salas (2007). "Insights into the Mechanism of the Negishi Reaction: ZnRX versus ZnR2 Reagents". J. Amer. Chem. Soc. 129 (12): 3508. doi:10.1021/ja070235b. PMID 17328551. 
4. ^ Revealing a Second Transmetalation Step in the Negishi Coupling and Its Competition with Reductive Elimination: Improvement in the Interpretation of the Mechanism of Biaryl Syntheses Qiang Liu, Yu Lan, Jing Liu, Gang Li, Yun-Dong Wu and Aiwen Lei J. Am. Chem. Soc., Article ASAP doi:10.1021/ja903277d
5. ^ Adam P. Smith, Scott A. Savage, J. Christopher Love, and Cassandra L. Fraser (2004), "Synthesis of 4-, 5-, and 6-methyl-2,2'-bipyridine by a Negishi cross-coupling strategy: 5-methyl-2,2'-bipyridine", Org. Synth., http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=v78p0051 ; Coll. Vol. 10: 517 
6. ^ Ei-ichi Negishi, Tamotsu Takahashi, and Anthony O. King (1993), "Synthesis of biaryls via palladium-catalyzed cross-coupling: 2-methyl-4'-nitrobiphenyl", Org. Synth., http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv8p0430 ; Coll. Vol. 8: 430 
7. ^ Ei-ichi Negishi, Tamotsu Takahashi, and Shigeru Baba (1993), "Palladium-catalyzed synthesis of conjugated dienes", Org. Synth., http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv8p0295 ; Coll. Vol. 8: 295 
8. ^ Yong Yu, Andrew D. Bond, Philip W. Leonard, Ulrich J. Lorenz, Tatiana V. Timofeeva, K. Peter C. Vollhardt, Glenn D. Whitener and Andrey A. Yakovenko (2006). "Hexaferrocenylbenzene". Chem. Commun. (24): 2572–2574. doi:10.1039/b604844g. PMID 16779481. 
9. ^ Yingsheng Zhao, Haibo Wang, Xiaohui Hou, Yanhe Hu, Aiwen Lei, Heng Zhang, and Lizheng Zhu (2006). "Oxidative Cross-Coupling through Double Transmetallation: Surprisingly High Selectivity for Palladium-Catalyzed Cross-Coupling of Alkylzinc and Alkynylstannanes". J. Amer. Chem. Soc. 128 (47): 15048. doi:10.1021/ja0647351. PMID 17117830.