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

A new biaryl phosphine-containing ligand from an active palladium catalyst for ppm level Suzuki–Miyaura couplings, enabled by an aqueous micellar reaction medium. A wide array of functionalized substrates including aryl/heteroaryl bromides are amenable, as are, notably, chlorides. The catalytic system is both general and highly effective at low palladium loadings (1000–2500 ppm or 0.10–0.25 mol%). Density functional theory calculations suggest that greater steric congestion in N2Phos induces increased steric crowding around the Pd center, helping to destabilize the 2 : 1 ligand–Pd(0) complex more for N2Phos than for EvanPhos (and less bulky ligands), and thereby favoring formation of the 1 : 1 ligand–Pdo complex that is more reactive in oxidative addition to aryl chlorides.


General Information
Unless otherwise specified, all of the reactions were run under and inert atmosphere of argon.
Silica gel TLC plates (UV 254 indicator, thickness 200 mm standard grade, glass backed and 230-400 mesh from Merck) or Aluminum Oxide 60 F254 polyester basked plates (Sigma-Aldrich, 0.2 mm thick) were used. The developed TLC plate was analyzed by a UV lamp (254 nm). The plates were further analyzed with the use of an aqueous potassium permanganate stain or butanolic vanillin and developed with a heat gun. All commercially available reagents were used without further purification. A 2 wt % TPGS-750-M/H2O solution was prepared by dissolving TPGS-750-M in degassed HPLC grade water.
TPGS-750-M was made as described previously 1 and is also commercially available. Tetrahydrofuran (THF) and toluene were all taken from an Innovative Technologies Solvent Purification System (SOS) and used immediately. N,N-Dimethylformamide (DMF) and dimethylsulfoxide (DMSO) were stored over activated 4Å molecular sieves and were purchased from Fisher Scientific. K3PO4 tribasic was purchased from Sigma-Aldrich and used without further purification. The source of Pd(OAc)2 was either Spectrum Chemicals or Johnson Matthey. Reagents were purchased from Sigma-Aldrich, Combi-Blocks, Alfa Aesar, or Acros Organics. n-Butyllithium was purchased from Sigma-Aldrich and was titrated with diphenylacetic acid prior to use. Flash chromatography was performed using Silicycle Silicaflash® P60 unbonded grade silica. 1 H and 13 C NMR were recorded at 25 o C on either a Varian Unity Inova 500 MHz or a Varian Unity Inova 600 MHz spectrometers in CDCl3 with residual CHCl3 ( 1 H = 7.26 ppm, 13 C = 77.16 ppm) as the internal standard. Chemical shifts are reported in parts per million (ppm). The data presented will be reported as follows; chemical shift, multiplicity (s = singlet, bs = broad singlet, d = doublet, dd = doublet of doublet, t = triplet, q = quartet, quin = quintet, m = multiplet), coupling constant (if applicable) and integration. HRMS data were recorded on a Waters Micromass LCT TOF ES+ Premier mass spectrometer using ESI ionization. In solution. To an oven dried 3-neck round bottom flask equipped with a stir bar under argon were added 2,7-dibromonaphthalene (1 equiv), potassium t-butoxide (3 equiv), and Pd-PEPPSI-iPent (0.02 equiv). The reaction flask was evacuated and backfilled three times with argon. The flask was sealed with a rubber septum after which N,N-dibenzylamine (2.05 equiv) was added via syringe followed by anhydrous toluene (0.5 M). The reaction flask was sealed with a rubber septum and a water jacketed condenser was attached. The reaction was set to stir at 80 o C for 16 h. Upon completion, the reaction was cooled to rt. The solvent was removed under reduced pressure. The crude reaction mixture was added to a beaker and distilled H2O was added. The suspension was set to stir for 30 min. The beakers' contents were then vacuum filtered, and the filtered material was allowed to dry. The dried mixture was transferred to a flask and sonicated with several portions of hexanes. The material was vacuum filtered and washed with hexanes and allowed to dry. The product (86% yield) was obtained as a white solid and used without any further purification. Using Mechanochemistry. The amination was run in a 30 mL stainless steel Form Tech Scientific grinding jar (https://www.FormTechScientific.com). To the jar was added 1.72 g (6.00 mmol, 1 equiv) of 2,7-dibromonaphthalene, 2.02 g (18.0 mmol, 3 equiv) potassium t-butoxide, and 95.0 mg (0.120 mmol, 0.02 equiv) Pd-PEPPSI-IPent, and a 1/2" stainless steel ball. The jar was closed, leaving a slight gap where the two halves join together. The middle of the jar was wrapped with Parafilm and flushed with argon for several min. After this, 2.48 mL (12.3 mmol, 2.05 equiv) N,N-dibenzylamine was added by syringe through the Parafilm. The Parafilm was removed and the jar was fully sealed. The reaction vessel was placed in a modified SPEX 8000M Mixer/mill and run for 10 h at 40 °C. Afterwards, the dry, yellow-orange reaction mixture was scraped out of the vial onto a watch glass using a metal spatula.

Synthesis and Analytical Data for N2Phos
The dry reaction mixture was finely divided up using the metal spatula. This was then added to a beaker and suspended with stirring in distilled H2O for 30 min to remove salt. The beaker's contents were then vacuum filtered and allowed to dry. The dried mixture was transferred to a recovery flask. This was sonicated in several portions of hexanes and transferred to a Buchner funnel, washed a final time with hexanes, and allowed to dry. The product (2.806 g, 90% yield) was obtained as a white solid.  brine (4x the volume of organic solvent) to remove DMF. The resulting organic mixture was dried with anhydrous Na2SO4 and reduced under pressure. The compound was used without further purification.
Aryl bromide (1 equiv), base (2 equiv), aryl boronic acid (1.5 equiv) and Pd(dppf)Cl2 (2 mol %) were charged into a 3-neck round bottom flask under a continuous flow of argon. Upon addition of solids the flask was evacuated and then refilled with argon 3 times. Degassed toluene and water were then added to the reaction vessel in a 10:1 ratio of toluene to water. A reflux condenser was attached and the reaction was set to stir for 16 h at 80 o C. Upon completion, the reaction was diluted with EtOAc and the organic mixture was washed with water, and then brine. The resulting organic layer was dried over anhydrous Na2SO4 and the solvent was reduced under vacuum. The resulting crude mixture was

Recycle Study
The initial reaction was set up according to the general procedure. After 4 h, the reaction media was extracted three times with MTBE and the combined organic layers were dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude reaction mixture was purified via flash chromatography.
Recycling of the surfactant solution involved first sparging the reaction vial with argon followed by addition of aryl bromide (0.5 mmol), aryl boronic acid (0.625 mmol), the base (0.5 mmol) and fresh catalyst solution (0.1 mL). The reaction vial was then flushed with argon, capped, and sealed with Teflon tape. R separated and the organic layer was dried over anhydrous Na2SO4. The mixture was concentrated under vacuum and the crude mixture was purified via flash chromatography.