N₂Phos – an easily made, highly effective ligand designed for ppm level Pd-catalyzed Suzuki–Miyaura cross couplings in water

Abstract

A new, biaryl phosphine-containing ligand, N2Phos, forms a 1 : 1 complex with Pd resulting in an active catalyst at the ppm level for Suzuki–Miyaura couplings in water, enabled by an aqueous micellar medium. Notably, aryl chlorides are shown to be amenable substrates.

Water as the reaction medium in organic chemistry: from our worst enemy to our best friend

“…In most cases (except for reactions that readily take place "on water"), the background reaction takes place to varying extents, but rarely with the same levels of conversion and ultimately, yields. Many of the synthetic bene-ts associated with using nanomicelles in water remain to be discovered, as only a few have been disclosed of late, including the "reservoir effect", 59 lipophilic ligand design, 38,120,121 and the "nano-to-nano" effect. 44 Clearly, when water is intimately involved, reactions can be governed by different "rules".…”

Late‐stage Pd‐catalyzed Cyanations of Aryl/Heteroaryl Halides in Aqueous Micellar Media

“…One feature associated with this chemistry in water is the likelihood that the levels of residual palladium [5a–b,9] in each product will be below the imposed FDA limit of 10 mg/dose/day [15] . Using product 20 as a representative example, isolated without special processing, ICP‐MS analysis (Scheme 3a; Figure S2 for other representative compounds) indicated that only 2 ppm Pd was present.…”

“…[1b,4a] Moreover, and invariably, such methodologies take place in waste-generating organic solvents and oftentimes rely on an investment of energy in the form of elevated temperatures over time to achieve reasonable conversions. Thus, in the spirit of creating options for medicinal chemistry and beyond, [5] and with attention to the impact that such chemistry will have on the environment, [6] we now describe a new, indeed unique and reproducible [12] technology. This advancement enables late stage cyanations that addresses all of these major concerns, including its: (1) application to highly functionalized substrates;…”

“…(2) reliance not only on catalysis, but conditions that feature low loadings of Pd; and (3) utilization under very mild conditions in recyclable water (Figure 1a; This work). [5,[8][9] Cyanations were conducted in aqueous micellar media, in which it was determined that nanoreactors composed of inexpensive surfactant Brij-30 (2 wt %) afforded the best results (Table S3). Readily available Zn(CN) 2 (0.55 equiv), and only this source of CN, provided the appropriate amount of cyanide ion.…”

Nickel Nanoparticle Catalyzed Mono‐ and Di‐Reductions of gem‐Dibromocyclopropanes Under Mild, Aqueous Micellar Conditions

“…At andem, 1-pot process involving an initial ppm Pdcatalyzed [26] Suzuki-Miyaura cross-coupling could be performed given the same aqueous micellar conditions characteristic of both reactions (Figure 7). Thus,c yclopropanecontaining biaryl 25 could be accessed via 24 in an overall isolated yield of 86 %.…”