The Role of LiBr and ZnBr₂ on the Cross‐Coupling of Aryl Bromides with Bu₂Zn or BuZnBr

Abstract

The impact of LiBr and ZnBr2 salts on the Negishi coupling of alkylZnBr and dialkylzinc nucleophiles with both electron‐rich and ‐poor aryl electrophiles has been examined. Focusing only on the more difficult coupling of deactivated (electron‐rich) oxidative addition partners, LiBr promotes coupling with BuZnBr, but does not have such an effect with Bu2Zn. The presence of exogenous ZnBr2 shuts down the coupling of both BuZnBr and Bu2Zn, which has been shown before with alkyl electrophiles. Strikingly, the addition of LiBr to Bu2Zn reactions containing exogenous ZnBr2 now fully restores coupling to levels seen without any salt present. This suggests that there is a very important interaction between LiBr and ZnBr2. It is proposed that Lewis acid adducts are forming between ZnBr2 and the electron‐rich Pd0 centre and the bromide from LiBr forms inorganic zincates that prevent the catalyst from binding to ZnBr2. This idea has been supported by catalyst design as chlorinating the backbone of the NHC ring of Pd‐PEPPSI‐IPent to produce Pd‐PEPPSI‐IPentCl catalyst now gives quantitative conversion, up from a ceiling of only 50 % with the former catalyst.

Salt to Taste: The Critical Roles Played by Inorganic Salts in Organozinc Formation and in the Negishi Reaction

“…While zinc salts certainly sequester free halides that can at times be crucial for coupling, recent studies have provided insights into some other harmful effects zinc salts have on Negishi coupling. In 2019 Organ published an investigation on an aryl−alkyl coupling that showed no dependence on LiBr [43] . The coupling of 50 a with salt‐free n ‐Bu 2 Zn ( 1 ) was studied as a model reaction for a challenging coupling due to the electron rich electrophile and the Lewis basic amine that can coordinate readily to palladium.…”

Experimental study of the [ZnCl2(THF)2] catalyzed cis/trans-isomerization of [Pd(C6Cl2F3)Me(PPh3)2] and of the transmetalation of trans-[PdCl(C6Cl2F3)(PPh3)2] with [ZnMeCl(THF)2]

“…[7,8,9] The coordination of anions to the organozinc species leads to anionic species "zincates", whose exact composition is not always easily established, and whose reactivity differs substantially from neutral organozinc reagents. [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] Finally, the halogen coordinated to the zinc in haloorganozinc reagents, (whose halogen may proceed from any of the reagents used in its synthesis), also plays a relevant role. A. Lei et al carried out mechanistic studies using in situ IR and X-Ray…”

“…The isomerization catalyzed by poor nucleophiles, such as [ZnCl2(solv)2] remains unproven until now, although the role of zinc halides in other steps of the Negishi reaction has been reported. [25] In this work we study the effect of the ligand in solution on the transmetalation between trans-…”

A Path to More Sustainable Catalysis: The Critical Role of LiBr in Avoiding Catalyst Death and its Impact on Cross‐Coupling

“…[8] Initially,i tw as viewed that their presence was not problematic-ironically,t heir presence is essential for any coupling to take place at all. [9] We, [9,10] and others, [6,11] have proposed the interplay between LiBr with the alkylzinc reagent to form zincates that, through heightened nucleophilicity,h elp drive the TM step of the cross-coupling catalytic cycle. We have found that arylzinch a-lides also require LiBr to couple.…”

“…We, and others, have proposed the interplay between LiBr with the alkylzinc reagent to form zincates that, through heightened nucleophilicity, help drive the TM step of the cross‐coupling catalytic cycle. We have found that arylzinc halides also require LiBr to couple .…”