Optimization and Scale-Up of a Suzuki−Miyaura Coupling Reaction: Development of an Efficient Palladium Removal Technique

Abstract

A ligand-solvent-base screen was performed on a Suzuki-Miyaura coupling reaction, and the screening data, followed by a set of focused experiments, helped to optimize reaction conditions. Further work was carried out that centered on reducing the level of residual palladium in the isolated product. Treatment of the reaction mixture with toluene and 20% aqueous NaHSO 3 at elevated temperature lowered the palladium content from ∼8000 ppm to 100 ppm or less. The Suzuki-Miyaura coupling and palladium removal process were demonstrated on 20-L scale, are highly efficient and cost-effective, and require short cycle times.

ChemInform Abstract: Practical Aspects of Carbon—Carbon Cross‐Coupling Reactions Using Heteroarenes

“…181 Extraction with 20% NaHSO 3 at 60°C during 1 h has been shown to be capable of bringing down the palladium concentration from 8000 ppm to 36 ppm from a Suzuki product where Pd(OAc) 2 /dppf was used as the catalyst. 182 Especially for this review, it is interesting to note that basic heterocyclic Suzuki products have been freed from palladium by simple extraction of an acidic solution with organic solvents, most likely the method of choice from the cost point of view. This led to reduction of the Pd level from 8000 to <50 ppm.…”

Metal catalyst-free amination of meso-bromoporphyrins: an entry to supramolecular porphyrinoid frameworks

“…1 H NMR (300 MHz, CDCl 3 ; d, ppm): 9.72 (H-meso, 1H,s),2H,d,3 J¼4.5 Hz),2H,d,3 J¼4.5 Hz), 2H,d,3 J¼4.8 Hz),2H,d,3 J¼4.8 Hz),4H,d,4 J¼1.8 Hz),2H,t,4 J¼1.8 Hz),2H,d,3 J¼8.6 Hz), 2H,d,3 …”

“…5-(2-Aminoethylamino)-10,20-bis (3,5-di-tertbutylphenyl)porphyrin (1f) Following the general procedure with tetrahydrofuran, after 24 h of reflux, chromatography (dichloromethane/methanol 10:1, R f ¼0.32) and recrystallization from diethyl ether, porphyrin 1f was obtained as a dark purple powder (38 mg, 78% yield). 1 H NMR (200 MHz, CDCl 3 ; d, ppm): 9.65 (H-meso,1H, s), 2H,d,3 J¼4.7 Hz),2H,d,3 J¼4.7 Hz), 8.84 (H-b, 2H, d, 3 J¼4.7 Hz), 8.71 (H-b, 2H, d, 3 3.2.7. 5-(2-Hydroxyethylamino)-10,20-bis (3,5-di-tertbutylphenyl)porphyrin (1g) Following the general procedure with tetrahydrofuran, after 24 h of reflux and chromatography (dichloromethane/methanol 100:2.5, R f ¼0.23), the porphyrin 1g was obtained as a dark purple oil (15 mg, 30% yield).…”

“…Following the general procedure with tetrahydrofuran, after 20 h of reflux and chromatography (dichloromethane/hexane 7:3, R f ¼0.10), the porphyrin 2a was obtained as a dark green solid (25 mg, 52% yield). 1 H NMR (200 MHz, CDCl 3 ; d, ppm): 9.61 1H,s),2H,d,3 J¼4.8 Hz),2H,d,3 -10,20-diphenylporphyrin (2b) Following the general solvent-free procedure, after 2 h of reflux, chromatography (dichloromethane, R f ¼0.15) and recrystallization, porphyrin 2b was obtained as a dark purple powder (25 mg, 50% yield). 1 H NMR (200 MHz,CDCl 3 ;d,1H,s),2H,d,3 J¼4.6 Hz),2H,d,3 J¼4.6 Hz),2H,d,3 J¼4.6 Hz), 2H,d,3 J¼4.6 Hz),4H,m) Following the general solvent-free procedure, after 1.5 h of reflux, chromatography (dichloromethane/hexane 8:2, R f ¼0.14) and recrystallization, porphyrin 2c was obtained as a dark purple powder (21 mg, 40% yield).…”

“…1,2 However for pharmaceutical applications, where amine functionalities abound, even at low catalyst loadings, a complete removal of the transition (or noble) metal catalysts still remains a challenge and drastically augments the costs, if large scale chromatographic separations have to be performed. Very recently, scavenging of palladium to 100 ppm was demonstrated by means of a simple sodium bisulfite wash at 60 C, 3 however other functionalities in the final coupled molecules must resist this reductive treatment. Porphyrins can be easily reduced to chlorins or even bacteriochlorins under these conditions.…”