a Reaction conditions: 4a (0.2 mmol), [Ni] (2.0 mol%), L (2.4 mol%), [H] source (1.2 equiv.), base (1.5 equiv.), solvent (2.0 mL), -25 oC, 0.8 - 4.0 h. b Isolated yield.c Determined by HPLC with chiral column. Et2O: ethyl ether, DCM: dichloromethane, EA: ethyl acetate, i PrOH: isopropanol, CB: catecholborane, DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene, DIPEA:N ,N -diisopropylethylamine.
With the optimum conditions in hand, the substrate scope of this methodology was examined. Firstly, the aryl ring in α,β-unsaturated ketones with different functional groups including ortho -,meta - and para -substitutions could be reacted well to afford the target products in high yields and excellent enantiomeric excesses (5a-5l ). The ortho -substituents were methyl (5b : 99% yield, 99% ee), methoxyl (5c : 96% yield, 99% ee) and cyano (5d : 99% yield, 96% ee). Themeta -substituents were methyl (5e : 99% yield, 98% ee) and halogen (5f , 5g , 5h : 91-99% yield, 97-98% ee). The para -substituents were methyl (5i : 97% yield, 97% ee), halogen (5j : 96% yield, 98% ee and5k : 99% yield, 98% ee) and phenyl (5l : 99% yield, 98% ee). When the naphthyl was employed as substituent group, excellent yield and enantiomeric excess (5m : 99% yield, 98% ee) were observed. Secondly, α’-substituents, such as ethyl (5n : 99% yield, 98% ee) and n -propyl (5o : 99% yield, 94% ee), were also suitable for this reductive reaction in high yields and enantiomeric excesses under the standard conditions. But when α’-substituent was changed to isopropyl (5p ), the enantiomeric excess decreased to moderate 65% ee.
Moreover, the heteroaromatic substrate, like furan, could also work smoothly to deliver the desired product in excellent enantiomeric excess (5q : 76% yield, 94% ee). β,β-Disubstituted enones (4r and 4s ) were successfully participated to afford the reductive products (5r : 88% yield, 74% ee and5s : 85% yield, 58% ee), respectively. Subsequently, we attempted to use the (E )-2-benzylidenecyclohexanone (4t ) as the substrate to explore the substrate scope. Unfortunately, the enantiomeric excess was unsatisfied (5t : 93% yield, 26% ee). In addition, chalcone substrate (4u ) underwent 1,2-reduction to afford the chiral alcohol in moderate yield and enantiomeric excess after a series of ligands screening (5u : 76% yield, 68% ee,L9 ), and a small amount of sideproduct of 1,4-reduction (24% yield) was also observed. For the substrate 5v with strong electron-withdrawing trifluoromethyl group, 91% yield and moderate 74% of enantiomeric excess were obtained. Finally, the substrates with α’-substituent such as methoxycarbonyl group and benzyl were investigated, and the results were also unsatisfactory.
Scheme 3 Substrate scope for α,β-unsaturated ketones
Scheme 4 Scale-up experiment
To demonstrate the practicality of this methodology, the asymmetic reduction at the 6.84 mmol scale of 4a was proceeded under the standard conditions, and the reductive product 5a was isolated in 99% yield and 96% ee without loss of activity. Notably, the chiral ligand PYMCOX (R p)-L2 could be recovered with 97% isolated yield by flash silica gel column chromatography. These results showed the potential application of [2.2]paracyclophane-derived oxazole-pyrimidine ligands.
Conclusions
In conclusion, we have successfully designed and synthesized a series of [2,2]paracyclophane-derived oxazole-pyrimidine ligands from the chiral [2,2]paracyclophane-derived aminophenol, and successfully applied them in nickel-catalyzed asymmetric 1,2-reduction of α,β-unsaturated ketones, affording the chiral allylic alcohols with up to 99% yield and 99% ee. Meanwhile, the chiral ligand could be conveniently recovered at gram-scale with high yield through flash column chromatography. Highlights of this work involve a series of easily accessible chiral ligands, inhibition of asymmetric 1,4-reduction, wide substrate scope and mild reaction condition. Further efforts to expand other fertile metal-catalyzed asymmetric reactions are currently under investigation in our laboratories.
Experimental
Procedures for synthesis of chiral PYMCOX ligands(Rp)-L1-10
Method A : typical procedure for synthesis of PYMCOX (Rp)-L1: A stirred solution of sodium (18.4 mg, 0.8 mmol) in methanol (16.0 mL) was cooled to 0 oC. After sodium was fully consumed, 2-cyanopyrimidines 2 (8.0 mmol) were added. The resulting mixture was warmed to room temperature and stirred for 24 hours. Then, the chiral [2.2]paracyclophane-derived aminophenol (R p)-L1 (1.920 g, 8.0 mmol) was added. The mixture was stirred at 50 oC for 24 hours. Then, the volatiles were evaporated under the reduced pressure. The crude residue was dissolved in dichloromethane, and water (10 mL) was added. The aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure. The crude residue was purified by flash column chromatography on silica gel using hexanes/ethyl acetate as eluent (20/1 - 5/1) to give the desirable chiral PYMCOX ligand (R p)-L1 1.460 g with 56% yield.
The same method was used for the synthesis of (R p)-L2 -9 . These chiral PYMCOX ligands are solid, and could be further purified by recrystallization with acetone and hexanes.
Method B: the synthesis of PYMCOX (Rp)-L10: The 4-trifluoromethyl-pyrimidine-2-carbonitrile (0.350 g, 2.0 mmol) was dissolved in a solution of hydrogen chloride in water (6 M, 10 mL) and heated at reflux temperature overnight. The reaction mixture was cooled to room temperature, and concentrated under the reduced pressure. Toluene (10 mL) was then added and the mixture was concentrated under the reduced pressure. This process was repeated with 1,4-dioxane and ethyl ether. Then the solids were filtered off. The filtrate was concentrated under the reduced pressure to afford 0.410 g of 4-trifluoromethyl-pyridine-2-carboxylic acid as white solid, which was directly used in the next step without the further purification.
The chiral aminophenol (R p)-1 (0.240 g, 1.0 mmol) and 4-trifluoromethyl-pyridine-2-carboxylic acid (0.288 g, 1.5 mmol) were dissolved in dichloromethane (5.0 mL). Then, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 0.383 g, 2.0 mmol) and 1-hydroxybenzotriazole (HOBt, 0.304 g, 2.0 mmol) were added at 0 oC under nitrogen gas. The mixture was stirred at room temperature for 18 hours. Water (10 mL) was added to quench the reaction. The aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure to give amide intermediate.
A solution of the above amide intermediate (0.487 g, 1.0 mmol) andp -toluenesulfonic acid monohydrate (0.285 g, 1.5 mmol) inp -xylene (10 mL) was stirred at 120 oC (oil bath temperature) for 24 h. After cooled to room temperature, saturated sodium carbonate solution (10 mL) was added. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure. The crude residue was purified by flash column chromatography on silica gel using hexanes/dichloromethane/ethyl acetate (15/1/1) as eluent to give the chiral PYMCOX ligand (R p)-L10 .
General procedure fornickel-catalyzed 1,2-reduction of α,β-unsaturated ketones: In a nitrogen-filled glovebox, Ni(COD)2 (2.2 mg, 0.008 mmol, 2.0 mol%), (R p)-2-(4-methylpyrimidin-2-yl)[2.2] paracyclophano[4,5-d ]oxazole (PYMCOX L2 ) (3.3 mg, 0.0096 mmol, 2.4 mol%), and 1,4-diazobicyclo[2.2.2]octane (DABCO, 67.8 mg, 0.6 mmol) were added to a 10 mL Schlenk tube, equipped with a magnetic stirring bar. Then, toluene (1.6 mL) was added and the mixture was stirred for 10 min before addition of pinacolborane (HBpin) (70 μL, 0.48 mmol). The reaction tube was sealed with a Teflon screw cap, removed from glovebox and stirred for 10 min in a cooling bath at -25oC before the α,β-unsaturated ketones 4 (0.4 mmol in 0.4 mL toluene) solution was added by syringe. Then the reaction mixture was stirred at this temperature for 1-8 h. A saturated solution of ammonium fluoride in methanol (1.0 mL) was added, and the mixture was removed from the cooling bath, then stirred at room temperature for 30 min and followed by addition of water (2.0 mL) and ethyl acetate (3.0 mL). The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure. The residue was purified by chromatography on silica gel using hexanes/ethyl acetate as eluent (20/1 - 5/1) to afford the desirable chiral product allylic alcohols 5 .
The enantiomeric excesses were determined by HPLC analysis using the chiral column. The racemates could be prepared by the Luche or sodium borohydride reduction at 0 oC.
Supporting Information
The supporting information for this article is available on the WWW under https://doi.org/10.1002/cjoc.2023xxxxx.
Acknowledgement
Financial support from National Natural Science Foundation of China (22171260) and K. C. Wong Education Foundation of CAS (GJTD-2020-08) is acknowledged.
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