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

Additional recommended knowledge

Don't let static charges disrupt your weighing accuracy

How to ensure accurate weighing results every day?

What is the Correct Way to Check Repeatability in Balances?

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