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
acetyloxy
groups are feasible as well. X = Cl usually leads to slow reactions.
The Negishi coupling finds common use in the field of
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.
Negishi and coworkers originally investigated the cross-coupling of
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".
Reaction mechanism
The reaction mechanism is thought to proceed via a standard Pd catalyzed cross-coupling pathway, starting with a Pd(0) species, which is oxidized to Pd(II) in an oxidative addition step involving the organohalide species.[8] This step proceeds with aryl, vinyl, alkynyl, and acyl halides, acetates, or triflates, with substrates following standard oxidative addition relative rates (I>OTf>Br>>Cl).[9]
The actual mechanism of oxidative addition is unresolved, though there are two likely pathways. One pathway is thought to proceed via an
SN2 like mechanism resulting in inverted stereochemistry. The other pathway proceeds via concerted addition
and retains stereochemistry.
Though the additions are cis- the Pd(II) complex rapidly isomerizes to the trans- complex.[10]
Next, the transmetalation step occurs where the organozinc reagent exchanges its organic substituent with the halide in the Pd(II) complex, generating the trans- Pd(II) complex and a zinc halide salt. The organozinc substrate can be aryl, vinyl, allyl, benzyl, homoallyl, or homopropargyl.[8] Transmetalation is usually rate limiting and a complete mechanistic understanding of this step has not yet been reached though several studies have shed light on this process. It was recently determined that alkylzinc species must go on to form a higher-order zincate species prior to transmetalation whereas arylzinc species do not.[11] ZnXR and ZnR2 can both be used as reactive reagents, and Zn is known to prefer four coordinate complexes, which means solvent coordinated Zn complexes, such as ZnXR(solvent)2 cannot be ruled out a priori.[12] Studies indicate competing equilibriums exist between cis- and trans- bis alkyl organopalladium complexes, but that the only productive intermediate is the cis complex.[13][14]
The last step in the catalytic pathway of the Negishi coupling is reductive elimination, which is thought to proceed via a three coordinate transition state, yielding the coupled organic product and regenerating the Pd(0) catalyst. For this step to occur, the aforementioned cis- alkyl organopalladium complex must be formed.[15]
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
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:[16]
Nickel catalyzed systems can operate under different mechanisms depending on the coupling partners. Unlike palladium systems which involve only Pd0 or PdII, nickel catalyzed systems can involve nickel of different oxidation states.[17] Both systems are similar in that they involve similar elementary steps: oxidative addition, transmetalation, and reductive elimination. Both systems also have to address issues of β-hydride elimination and difficult oxidative addition of alkyl electrophiles.[18]
For unactivated alkyl electrophiles, one possible mechanism is a transmetalation first mechanism. In this mechanism, the alkyl zinc species would first transmetalate with the nickel catalyst. Then the nickel would abstract the halide from the alkyl halide resulting in the alkyl radical and oxidation of nickel after addition of the radical.[19]
One important factor when contemplating the mechanism of a nickel catalyzed cross coupling is that reductive elimination is facile from NiIII species, but very difficult from NiII species. Kochi and Morrell provided evidence for this by isolating NiII complex Ni(PEt3)2(Me)(o-tolyl), which did not undergo reductive elimination quickly enough to be involved in this elementary step.[20]
Scope
The Negishi coupling has been applied the following illustrative syntheses: