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Preparation method of chiral tetra-substituted allenic acid compound based on palladium catalysis system
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A technology catalyzed by allenoic acid and palladium, which is applied in the preparation of hydroxyl compounds, organic compounds, and carbon monoxide reaction to prepare carboxylic acids, etc. It can solve the problems of poor functional group tolerance, low atom economy, narrow substrate range, etc., and achieve an improvement Reaction yield, accelerated target conversion, effect of inhibited coordination
Pending Publication Date: 2022-08-02
FUDAN UNIV
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The above method has the disadvantages of low reaction yield, narrow substrate range, poor functional group tolerance, and low atom economy.
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[0088] Add [Pd(π-allyl)Cl] to a dry Schlenk reaction tube 2 (0.0015 g, 0.004 mmol), chiral bisphosphine ligand (S)-L4d (0.0148 g, 0.012 mmol), (S)-CPA-1 (0.0039 g, 0.005 mmol). After the reaction tube was plugged with a rubber stopper, the vacuum pump was connected, and the argon was replaced three times under an argonatmosphere. 0.8 mL), bromobenzene (211 μL, d=1.49 g / mL, 0.3144 g, 2 mmol), water (72 μL, d=1.0 g / mL, 0.072 g, 4 mmol). After the argon gas was turned off, the reaction tube was placed in a liquid nitrogen bath to freeze for 3 minutes, a carbon monoxideballoon (about 1 liter) was inserted, and the carbon monoxide was replaced three times under a carbon monoxideatmosphere, and then the liquid nitrogen bath was removed. After the reaction system returned to room temperature and melted into a liquid , the r...
Embodiment 2
[0090]
[0091] The operation is the same as in Example 1. [Pd(π-allyl)Cl] 2(0.0037g, 0.01mmol), chiral bisphosphine ligand (S)-L4d (0.0366g, 0.03mmol), (S)-CPA-1 (0.0601g, 0.075mmol), (±)-1b (0.1104g) , 0.5mmol), bromobenzene (527μL, d=1.49g / mL, 0.7860g, 5mmol), water (180μL, d=1.0g / mL, 0.18g, 10mmol), toluene (2mL), at 50°C, The reaction was carried out for 12 hours. Flash column chromatography (eluent: petroleumether (60~90℃) / ethyl acetate=20 / 1, then 10 / 1) to obtain chiral allenoic acid product (S)-2b (0.0841g, 68%) : oil; 88%ee (HPLC conditions: AS-H column, hexane / i PrOH=98 / 2,1.0mL / min,λ=214nm,t R (major)=9.5min,t R (minor)=13.0min); 1 H NMR (400MHz, CDCl 3 ): δ=7.33(td, J 1 =7.8Hz,J 2 =1.7Hz,1H,Ar-H),7.27-7.21(m,1H,Ar-H),7.12(td,J 1 =7.5Hz,J 2 =1.1Hz,1H,Ar-H),7.07-7.00(m,1H,Ar-H),2.36-2.24(m,2H,CH 2 ),2.24-2.13(m,3H,CH 3 ),1.53-1.41(m,2H,CH 2 ),1.39-1.27(m,2H,CH 2 ),0.89(t,J=7.2Hz,2H,CH 2 ); 13 C NMR (100MHz, CDCl 3 ): δ=212.9(d, J=1.6Hz), 173....
Embodiment 3
[0093]
[0094] The operation is the same as in Example 1. [Pd(π-allyl)Cl] 2 (0.0037g, 0.01mmol), chiral bisphosphine ligand (S)-L4d (0.0367g, 0.03mmol), (S)-CPA-1 (0.0402g, 0.05mmol), (±)-1c (0.1104g) , 0.5mmol), bromobenzene (527μL, d=1.49g / mL, 0.7860g, 5mmol), water (180μL, d=1.0g / mL, 0.18g, 10mmol), toluene (2mL), at 50°C, The reaction was carried out for 12 hours. Flash column chromatography (eluent: petroleumether (60~90℃) / ethyl acetate=20 / 1, then 10 / 1) to obtain chiral allenoic acid product (S)-2c (0.0847g, 68%) : white solid; 91%ee (HPLC conditions: AS-H column, hexane / i PrOH=98 / 2,1.0mL / min,λ=214nm,t R (major)=8.0min,t R (minor)=11.8min); Melting point: 104.1-105.2°C (petroleumether / DCM); 1 H NMR (400MHz, CDCl 3 ):δ=7.34-7.23(m,1H,Ar-H),7.16(d,J=8.0Hz,1H,Ar-H),7.07(dt,J 1 =10.4Hz,J 2 =2.0Hz,1H,Ar-H),6.94(td,J 1 =7.9Hz,J 2 =2.3Hz,1H,Ar-H),2.33(t,J=7.4Hz,2H,CH 2 ),2.17(s,3H,CH 3 ),1.51-1.41(m,2H,CH 2 ),1.41-1.30(m,2H,CH 2 ),0.88(t,J=7.4Hz,2H,CH ...
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Abstract
The invention discloses a preparation method of a chiral tetra-substituted allenic acid compound based on a palladiumcatalysissystem, which comprises the following steps: reacting tertiarypropargylalcohol with carbon monoxide and water in an organic solvent under the action of a palladium catalyst, a chiral diphosphine ligand, organic phosphoric acid and an organic additive to obtain the chiral tetra-substituted allenic acid compound. The high-optical-activity allenic acid compound with axial chirality is directly constructed in one step, and the theoretical yield can reach 100%. The method has the advantages of simple operation, easily available raw materials and reagents, mild reaction conditions, wide substrate universality, good functional group compatibility, high enantioselectivity (77-96% ee) in the reaction, and good compatibility with a substrate containing a complex natural product or a drug molecular skeleton in the reaction. The high-optical-activity allenic acid compound obtained by the invention can be used as an important intermediate for constructing compounds such as a gamma-butyrolactone compound containing a tetra-substituted chiral quaternary carbon center, tetra-substituted allenol, tetra-substituted allenal, tetra-substituted allenone, tetra-substituted allenamide and the like.
Description
technical field [0001] The invention belongs to the technical field of chemical synthesis, in particular to a method for directly synthesizing tetra-substituted allenoic compounds with high optical activity. Background technique [0002] Chiral allenes are widely found in natural products, drug molecules and materials science, and are a very important class of compounds (Ref: (a) Hoffmann- A.; Krause, N. Angew. Chem., Int. Ed. 2004, 43, 1196. (b) Rivera-Fuentes, P.; Diederich, F. Angew. Chem., Int. Ed. 2012, 51, 2818 .).) The axial chirality accumulated carbon-carbon double bonds in this class of compounds can be efficiently converted into central chiral compounds through one or more steps, which has important application value in synthetic chemistry. Therefore, how to efficiently construct highly optically active compounds Chiral allenes are of great interest to synthetic chemists. How to construct tetra-substituted chiral quaternary carbon centers has been extensively ...
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