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

Abstract

The first cross‐coupling of organozinc nucleophiles with aryl halides was reported in 1977 by Negishi. Unknown to all at the time was the importance of salt additives that were often present as a byproduct from the organozinc preparation. For decades, these salt additives were overlooked until 2006 when it was discovered that two different, yet effective methods for preparing organozinc solutions (i.e. one with salt and one without) provided drastically different results. Since this finding, the exact role of salt additives in cross‐coupling has been debated in the catalysis community. In this Review we highlight all the major discoveries regarding the influence of salt additives on the formation of organozinc reagents and their use in the Negishi reaction. These effects include solubilizing key intermediates, the formation of higher‐order zincates, product inhibition, catalyst protection, and solvent effects.

Enantioselective Total Synthesis of the Marine Macrolides Salarins A and C

“…Lastly, the hindered C15 alcohol was esterified via in situ ketene generation from phosphonocarboxylic acid 26 21 and DIC 22 to give multigram quantities of key phosphonate 11 in 15% yield over 11 steps. Synthesis of the oxazole fragment (Scheme 2) started from methyl acetoacetate (27) via sequential ketoxime formation and hydrogenation to give hydrochloride 28, 23 which was coupled with the known vinyl iodide 29 13,14 to furnish ketoamide 30 in good yield (77%). This later material was then subjected to Wipf's oxazole synthesis, 24 affording multigram quantities of vinyl iodide 31.…”

“…At this point, acrolein (32) was converted into primary iodide 33 via a known procedure. 25 Subsequent insertion of HCl-activated Zn into the primary iodide in the presence of LiCl 26,27 gave organozinc 34 on up to a 10 g scale over both steps. An sp 2 −sp 3 With both key coupling partners prepared, we turned our attention to the preparation of key RCM precursor 10 (Figure 2a) starting with the Still−Gennari 31 olefination of aldehyde 12 with phosphonate 11.…”

“…At this point, acrolein ( 32 ) was converted into primary iodide 33 via a known procedure . Subsequent insertion of HCl-activated Zn into the primary iodide in the presence of LiCl , gave organozinc 34 on up to a 10 g scale over both steps. An sp 2 – sp 3 Negishi coupling between 31 and 34 in the presence of Pd­(OAc) 2 and XPhos proceeded with excellent diastereoselectivity (15:1 Z : E ) and gave multigram quantities of 35 in excellent yield (90%) after removal of the undesired E isomer by chromatography.…”

ppm Pd‐Containing Nanoparticles as Catalysts for Negishi Couplings … in Water

“…Thus, it might rightly be questioned, as unequivocally documented in the 2016 paper by Brown and Bostrom, [6] why Negishi couplings are not used more frequently in organic synthesis. The likely explanation may simply be that they are based on water‐sensitive zinc reagents [7a,b] commonly used in organic solvents and hence, are less “forgiving” in terms of adventitious water present either during their formation and/or their use. Nonetheless, there are now several reports dealing with “on water” reactions of organozinc and even organolithium reagents, including Negishi couplings, that further support the notion that organometallic chemistry of reactive organometallics need not be run under especially dry conditions [7c] .…”

Stereoselective C–O Silylation and Stannylation

“…Organozinc reagents are of great important intermediates which display high reactivity and excelleng chemoselectivity in organic synthesis. [38][39][40][41][42][43][44] Hence, we were attracted to developing the well-activated silyl and stannyl zinc reagents via transmetalation of the corresponding lithium reagents, [45][46] and subsequently devising 3d cobaltcatalyzed cross-couplings [47][48][49][50][51][52][53] with polyfunctionalized alkenyl acetates to build synthetically useful C-Si [54][55][56] and C-Sn [57][58][59][60] bonds via umpolung strategy (Figure 1d). In this work, Me 2 PhSi-ZnOPiv•Li 2 (Cl) (OPiv) and ( n Bu) 3 Sn-ZnCl•LiCl show superior reactivity than the other Si-and Sn-based organometallic reagents.…”