The application and synthesis of 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl

2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl is a kind of large sterically hindered phosphine ligand, which can be used for the palladium catalyzed cross coupling reaction of aminoethyl trifluoroborate and electron-deficient aryl bromide. Its appearance is as follows:

Figure 1 Appearance of 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl 

Chemical synthesis

2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl  can be synthesized by single step according to previous work [1]. An oven-dried 100 mL round-bottomed flask equipped with a magnetic stirbar and a reflux condenser was capped with a rubber septum, fitted with an argon inlet adapter, and then evacuated and backfilled with argon (this sequence was repeated three times). The reaction vessel was charged with 1,3-diisopropoxybenzene (1.5 g, 7.7 mmol, 1.1 equiv.), dry hexane (16 mL) and n-butyllithium (3.2 mL, 2.5 M solution in hexanes, 8.0 mmol, 1.2 equiv.). The reaction mixture was heated to reflux for 2.5 h (bath temperature of 80 °C). Maintaining the reaction mixture at reflux, 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 an additional 1 h. At this point the reaction mixture was cooled to room temperature.

Analysis (GC) of a reaction aliquot (quenched by addition to ethanol) indicated that complete consumption of the 2-bromochlorobenzene and clean conversion to 2-bromo-2',6'-diisopropoxybiphenyl had occurred. Dry THF (16 mL) was added via syringe through the septum and the resulting reaction mixture was cooled to -78 °C. n-Butyllithium (3.1 mL, 2.5 M solution in hexanes, 7.7 mmol, 1.1 equiv.) was added dropwise via syringe over 15 min. The resulting mixture was stirred at -78 °C for 1 h. Neat chlorodicyclohexylphosphine (1.5 mL, 6.8 mmol, 1.0 equiv) was then added via syringe. The reaction mixture was stirred at -78 °C for 1 h and then allowed to slowly warm to room temperature. The mixture was filtered through a pad of flash silica gel topped with a layer of celite, eluting with ethyl acetate (400 mL). The filtrate was concentrated under reduced pressure to provide a yellow solid. Recrystallization from ethanol provided (2.24 g, 71%) of 2 as a white solid, 2-(2',6'-Diisopropoxyphenyl)phenyldicyclohexylphosphine (2), yield (2.24 g, 71%) mp 123-124 °C.

The spectroscopic data is as follows: ¹H NMR (400 MHz, C6D6) δ: 7.53 (d, J = 7.6 Hz, 1H), 7.30-7.14 (m, 4H), 6.49 (d, J = 8.3 Hz, 2H), 4.22 (sept, J = 6.0 Hz, 2H), 1.93-1.62 (m, 12H), 1.41-1.14 (m, 10H), 1.12 (d, J = 6.0 Hz, 6H), 0.96 (d, J = 6.0 Hz, 6H). ¹³C NMR (100 MHz, C6D6) δ: 157.0, 144.7, 144.4, 137.8, 137.6, 132.4, 132.3, 131.9, 131.9, 126.4, 123.9, 123.9, 106.6, 70.3, 35.2, 35.0, 30.9, 30.8, 30.7, 30.6, 28.0, 28.0, 27.9, 27.3, 22.6, 22.3 (observed complexity due to P-C splitting; definitive assignments have not been made) 31P NMR (121 MHz, C6D6) δ: -8.84. IR (neat, cm-1): 2919, 2848, 1594, 1461, 1447, 1380, 1246, 1135, 1113, 1061. Anal. Calcd for C30H43O2P: C, 77.22; H, 9.29. Found: C, 77.22; H, 9.41.

The optimal catalyst/ligand loadings were found to be 2 mol % of Pd(OAc)₂ and 4 mol % of ligand. The use of 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl  as ligand provided the highest product ratios.

[2]Zarzuelo et al. 2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl. e-EROS Encyclopedia of Reagents for Organic Synthesis, 2010, 1-6.

[3]Milne et al. An extremely active catalyst for the Negishi cross-coupling reaction. J. Am. Chem. Soc. 2004, 126, 13028.

[4]Dreher et al. Suzuki-Miyaura Cross-Coupling Reactions of Primary Alkyltrifluoroborates with Aryl Chlorides. J. Org. Chem. 2009, 74, 3626.