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

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

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].

Scope

The Negishi coupling has been applied in the synthesis of a 2,2'-bipyridine from 2-bromopyridine with Tetrakis(triphenylphosphine)palladium(0) ^[4], the synthesis of a biphenyl from o-tolylzinc chloride and o-iodotoluene and Tetrakis(triphenylphosphine)palladium(0) ^[5], the synthesis of 5,7-Hexadecadiene from 1-decyne and (Z)-1-hexenyl iodide ^[6]

The Negishi coupling has been applied in the synthesis of hexaferrocenylbenzene ^[7]:

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 ^[8]:

References

1. ^ 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 Anthony O. King, Nobuhisa Okukado and Ei-ichi Negishi Journal of the Chemical Society, Chemical Communications, 1977, 683 - 684 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. ^ Insights into the Mechanism of the Negishi Reaction: ZnRX versus ZnR2 Reagents Juan A. Casares, Pablo Espinet, Beatriz Fuentes, and Gorka Salas J. Am. Chem. Soc.; 2007; 129(12) pp 3508 - 3509; (Communication) doi:10.1021/ja070235b
4. ^ Adam P. Smith, Scott A. Savage, J. Christopher Love, and Cassandra L. Fraser Organic Syntheses, Coll. Vol. 10, p.517 (2004); Vol. 78, p.51 (2002) Article
5. ^ Ei-Ichi Negishi, Tamotsu Takahashi, and Anthony O. K Organic Syntheses, Coll. Vol. 8, p.430 (1993); Vol. 66, p.67 (1988) Article
6. ^ Ei-Ichi Negishi, Tamotsu Takahashi, and Shigeru Baba Organic Syntheses, Coll. Vol. 8, p.295 (1993); Vol. 66, p.60 (1988) Article.
7. ^ Hexaferrocenylbenzene 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 Chemical Communications, 2006, 2572 - 2574 doi:10.1039/b604844g
8. ^ Oxidative Cross-Coupling through Double Transmetallation: Surprisingly High Selectivity for Palladium-Catalyzed Cross-Coupling of Alkylzinc and Alkynylstannanes Yingsheng Zhao, Haibo Wang, Xiaohui Hou, Yanhe Hu, Aiwen Lei, Heng Zhang, and Lizheng Zhu J. Am. Chem. Soc.; 2006; 128(47) pp 15048 - 15049; (Communication) doi:10.1021/ja0647351