Preparation method of 2-dicyclohexylphosphon-2′,6′-diisopropoxy-1,1′-biphenyl_Industrial additives

Background and overview^[1]

2-Dicyclohexylphosphon-2′,6′-diisopropoxy-1,1′-biphenyl is a phosphine ligand. Transition metal-catalyzed cross-coupling is an effective tool for building C-C, C-N and C-O bonds in organic synthesis. There has been an ongoing focus on developing the most effective ligands to improve catalyst performance. Ligands play an important role in stabilizing and activating the central metal atom and fine-tuning the conversion selectivity. Currently, phosphine ligands remain the most important ligand class for cross-coupling.

Preparation^[1]

Step 1, preparation of 1,3-diisopropoxybenzene

In an oven-dried 500 mL round-bottom flask equipped with a magnetic stir bar and reflux condenser, add resorcinol (11.0 g, 100 mmol, 1 equivalent) and K₂CO₃ (55.2 g, mmol, 4 equiv), install an argon inlet fitting on the rubber septum, then evacuate it and refill it with argon (repeat this process 3 times). 2-Bromopropane (49.2 g, 37.7 mL, mmol, 4 equiv) and N,N-dimethylformamide (200 mL) were added and the reaction mixture was heated at 70 °C for 24 h. The reaction mixture was then cooled to room temperature, water (1 L) and diethyl ether (200 mL) were added, and the layers were separated. Extract the aqueous phase with diethyl ether (2 × 200 mL). The combined organic extracts were dried (Mg2SO4) and concentrated under reduced pressure. The crude product was purified by passing the poloxamer 188 through a short silica gel chromatography column, eluting with hexane/EtOAc (9:1) until the yellow band reached the bottom of the column. The combined fractions were evaporated to give 1,3-diisopropoxybenzene (18.5 g, 95%) as a colorless oil.

Step 2, preparation of 2-dicyclohexylphosphon-2′,6′-diisopropoxy-1,1′-biphenyl industrial additive

Cover an oven-dried 100 mL round-bottom flask equipped with a magnetic stir bar and reflux condenser with a rubber septum and fitted with an argon inlet fitting, then evacuate and backfill with argon (repeat this process 3 Second-rate). To the reaction vessel, add 1,3-diisopropoxybenzene (1.5 g, 7.7 mmol, 1.1 equiv), anhydrous hexane (16 mL), and n-butyllithium (3.2 mL, 2.5 M solution in hexane , 8.0 mmol, 1.2 equivalent). The reaction mixture was heated to reflux for 2.5 hours (bath temperature 80°C). The reaction mixture was kept at reflux and neat 2-bromochlorobenzene (0.8 mL, 6.8 mmol, 1.0 equiv) was added dropwise via syringe over 50 min with vigorous stirring. The resulting suspension was stirred at 80°C for a further 1 hour. At this point, the reaction mixture was cooled to room temperature. Analysis (GC) of reaction aliquots (quenched by the addition of ethanol) showed that complete consumption of 2-bromochlorobenzene and complete conversion to 2-bromo-2′,6′-diisopropoxybiphenyl had occur. Anhydrous THF (16 mL) was added via syringe through the septum and the resulting reaction mixture was cooled to -78 °C. Add n-butyllithium (3.1 mL, 2.5 M solution in hexanes, 7.7 mmol, 1.1 equiv) dropwise via syringe over 15 minutes. The resulting mixture was stirred at -78°C for 1 h. Then pure chlorodicyclohexylphosphine (1.5 mL, 6.8 mmol, 1.0 equiv) was added via syringe. The reaction mixture was stirred at -78°C for 1 h and then allowed to warm slowly to room temperature. The mixture was filtered through a flash pad of silica gel covered with a layer of diatomaceous earth and eluted with ethyl acetate (mL). The filtrate was concentrated under reduced pressure to obtain a yellow solid. Recrystallization from ethanol gave 2-dicyclohexylphosphon-2′,6′-diisopropoxy-1,1′-biphenyl (2.24 g, 71%) as a white solid.