Practical and Scalable Kinetic Resolution of BINOLs Mediated by a Chiral Counterion

Abstract BINOLs are valuable and widely used building blocks, chiral ligands, and catalysts that are effective across a remarkable range of different chemical transformations. Here we demonstrate that an ammonium salt catalyzed kinetic resolution of racemic BINOLs with benzyl tosylate proceeds with s up to 46. This is a scalable and practical process that can be applied across >30 different C 2‐ and non‐C 2‐symmetric BINOLs. Implementation of this method enables the enantioselective synthesis of a wide range of BINOL derivatives with over 99:1 e.r.


General Information
Reactions requiring moisture-sensitive reagents were carried out in flame-dried glassware, under an atmosphere of argon (balloon pressure). Dichloromethane, tetrahydrofuran and toluene were purified by filtration through activated alumina columns employing the method of Grubbs et al. 1 Water was purified by an Elix® UV-10 system. Reagents were used directly as supplied by major chemical suppliers, or following purification procedures described by Perrin and Armarego. 2 Petrol 40-60 refers to the fraction of petroleum ether which boils in the range 40-60°C. Brine refers to a saturated aqueous solution of sodium chloride.
Infrared spectra were prepared as a neat film and were recorded using a Bruker Tensor 27 FTIR spectrometer using an ATR module.

1-Bromo-6-methoxynaphthalene (57)
Br OMe Following a modified literature procedure. 6 Triphenylphosphite (28.9 mL, 34.1 g, 110 mmol, 1.1 equiv.) was dissolved in CH 2 Cl 2 (300 mL) and the resulting solution was cooled to -78°C. Bromine (6.15 mL, 20.3 g, 120 mmol, 1.20 equiv.) was added followed by dropwise addition of Et 3 N (18.1 mL, 13.2 g, 130 mmol, 1.30 equiv.) over 30 minutes. 6-Methoxy-3,4dihydronaphthalen-1(2H)-one (17.6 g, 100 mmol, 1.00 equiv.) was added and the reaction was warmed to room temperature and stirred for 16 hours after which time the reaction was heated at 45°C for 2 hours. Upon cooling to room temperature saturated Na 2 SO 3 solution was added and the resulting solution was extracted three times with CH 2 Cl 2 . The combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. Purification via flash column chromatography (39:1 petroleum ether 40-60 -CH 2 Cl 2 to 19:1 petroleum ether 40-60 -CH 2 Cl 2 ) afforded the vinyl bromide which was found to be unstable and was therefore used immediately in the next reaction.
The product of the previous step (18.5 g, crude) was dissolved in benzene (155 mL) and DDQ (19.3 g, 85.1 mmol) was added and the reaction was stirred at room temperature for 2 hours after which time saturated Na 2 SO 3 solution was added and the resulting suspension was extracted 3 times with EtOAc. The combined organic layers were washed 3 times with saturated NaHCO 3 solution, brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. Purification via flash column chromatography (39:1 petroleum ether 40-60 -CH 2 Cl 2 to 19:1 petroleum ether 40-60 -CH 2 Cl 2 ) afforded 1-bromo-6-methoxynaphthalene (57) (6.93 g, 29% over 2 steps) as a light-yellow oil.
The crude oxime ether was dissolved in acetic acid (568 mL). Pd(OAc) 2 (1.59 g, 7.01 mmol, 5 mol% equiv.) and N-bromosuccinimide (30.3 g, 170 mmol, 1.20 equiv.) were added and the reaction was heated at 80°C for 1 hour. On cooling to room temperature, the reaction mixture was filtered through celite and concentrated. The residue was dissolved in Et 2 O and the resulting solution was washed with water, washed three times with NaOH solution (1 M), washed with brine and concentrated to give the crude product which was used without further purification.
The crude brominated oxime ether was dissolved in 2:3 dioxane-6M HCl (710 mL) and the solution was heated under reflux for 1 hour. On cooling to room temperature, the solution was extracted three times with Et 2 O and the combined organic layers were washed with NaOH solution (1 M), brine and concentrated to give the crude product. Recrystallization from hexane-EtOAc afforded 8-bromo-6-methoxy-3,4-dihydronaphthalen-1(2H)-one (58) (21.0 g, 58%) as an off-white solid.
The crude alcohol was dissolved in PhMe (411 mL ) was added and the reaction was heated at 40°C for 2 hours and cooled to room temperature. The solvent was removed in vacuo and the residue was suspended in 1:4 CH 2 Cl 2 -petroleum ether 40-60 and filtered through a short silica plug eluting with the same solvent mixture. The solvent was removed in vacuo to give the crude product which was used without further purification.
The crude alkene was dissolved in CH 2 Cl 2 (411 mL) and cooled to 0°C. BBr 3 (9.50 mL, 24.7 g, 99.0 mmol, 1.20 equiv.) was added dropwise over 5 minutes and the reaction was allowed to warm to room temperature and stirred for 16 hours. The reaction was cooled to 0°C and quenched by dropwise addition of water. The resulting biphasic solution was extracted three times with CH 2 Cl 2 and the combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was recrystallised from hexane-EtOAc to give give 1-bromo-3-methoxynaphthalene (56) (12.9 g, 70%) as a yellow solid.
Reaction setup for general procedure A.
*Benzyl tosylate was prepared following a literature procedure 12 and stored at −20 °C in the dark.
**The reaction time was varied between different substrates to achieve the desired conversion. Typical reaction times were between 24 and 48 hours. ***Piperidine was added to consume excess benzyl tosylate. This is done to stop the reaction at the desired conversion and to prevent side product formation during purification.

Kinetic resolution equations 15
Consider a reaction in which enantiomers R and S of the starting material react to give enantiomers R' and S' of the product, respectively.
After a certain period of time, assuming, without loss of generality that enantiomer S reacts faster than enantiomer R, we have the enantiomeric excess of the starting material given by Considering also that the conversion c is given by the formula
Assuming that each enantiomer reacts according to first order kinetics and that there is no background reaction and no other side-reactions, the ratio between the reaction rate of enantiomer S (k s ) and that of enantiomer R (k R ) is called the S-factor (s). From these assumptions an equation can be derived for s as a function of c and ee: ( 2) S63

Determination of Absolute Stereochemistry
The absolute stereochemistry of MeBINOL (1) and MeBnBINOL (Bn-1) were determined by chiral HPLC comparison with authentic samples prepared from commercially available (R)-BINOL and (S)-BINOL respectively. The optical rotation of MeBINOL (1) is consistent with the value reported in the literature. 17 17, 12067. S104

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