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.

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 + OHZnX (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]

The 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

References