Solvent Effects on the Selectivity of Palladium‐Catalyzed Suzuki‐Miyaura Couplings

Abstract

The use of polar solvents MeCN or dimethylformamide (DMF) was previously shown to induce a selectivity switch in the Pd/P t Bu 3 -catalyzed Suzuki-Miyaura coupling of chloroaryl triflates. This phenomenon was attributed to the ability of polar solvents to stabilize anionic transition states for oxidative addition. However, we demonstrate that selectivity in this reaction does not trend with solvent dielectic constant. Unlike MeCN and DMF, water, alcohols, and several polar aprotic solvents such as MeNO 2 , acetone, and propylene carbonate provide the same selectivity as nonpolar solvents. These results indicate that the role of solvent on the selectivity of Suzuki-Miyaura couplings may be more complex than previously envisioned. Furthermore, this observation has the potential for synthetic value as it greatly broadens the scope of solvents that can be used for chloride-selective cross coupling of chloroaryl triflates.

Chemodivergence between Electrophiles in Cross‐Coupling Reactions

“… Nonpolar and many polar non‐coordinating solvents promote Suzuki coupling at chloride with Pd/P t Bu 3 , while only polar coordinating solvents favor reaction at triflate [26] …”

“…The hypothesis that polar solvents promote oxidative addition at anionic bisligated palladium is consistentw ith the experimentally observed difference between the Suzuki vs. Stille coupling in DMF.H owever,N eufeldt and co-workersr ecently reportedt he puzzlingo bservation that selectivity in the Pd/ P t Bu 3 -catalyzed Suzukic ouplingo f2 does not necessarily trend with solventp olarity (Scheme 7). [26] Some very polar solvents such as acetone, propylene carbonate, water,a nd alcohols provide the same chloride selectivity as nonpolar solvents like THF and toluene. In fact, DMF,M eCN, and af ew other solvents (NMP,D MSO, PhCN) that promote reaction at triflate are apparent outliers.…”

“…In this system, Scheme7.Nonpolar and manyp olar non-coordinating solvents promote Suzuki coupling at chloride with Pd/P t Bu 3 ,w hile only polar coordinating solvents favor reaction at triflate. [26] Scheme8.NHC ligand-controlled chemodivergent Suzuki coupling of chlor < oaryltriflates. [27] Scheme9.Ni-and Pd-catalyzed cross-Ullmanncoupling that exploits these metals'c omplementary chemoselectivities.…”

Competent synthesis of biaryl analogs via asymmetric Suzuki–Miyaura cross-coupling for the development of anti-inflammatory and analgesic agents

“…Palladium catalysts have several disadvantages including their high cost and the potential for fatal contamination of pharmaceutical products. As a result, many researchers have looked into palladium composites that can be easily separated at ultra-low catalyst loadings [ 18 ], wherein solvents like acetone, toluene, THF, acetonitrile, and DMF, which are slightly more expensive, deadly, and difficult to recycle, are the most often employed solvents for these coupling processes [ 19 ]. Suzuki–Miyaura reactions in water are a hot topic of research, although most substrates and catalysts are insoluble in water [ 20 – 22 ].…”

Scope and limitation of propylene carbonate as a sustainable solvent in the Suzuki–Miyaura reaction

“…They highlighted the similar selectivity of the solvents and the synthetic value of it. 21 PC was used with no loss of enantioselectivity in an iridium-and rhodiumphosphite/oxazoline catalytic system catalysed asymmetric hydrogenation of functionalized cyclic b-enamines, 22 and in cathodic reduction of aryl halides, considered for its high dielectric permittivity. 23 PC was used in an aminophosphine palladium pincer-catalyzed carbonylative Sonogashira reaction with 10 À4 mol%, while the Suzuki-Miyaura cross-coupling reaction was carried out at 10 À6 mol%.…”