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Method for synthesizing optically active trifluoromethyl compound by asymmetric conjugate addition reaction of organic boronic acid and alpha, beta-unsaturated ketone

An organic boronic acid, conjugated addition technology, applied in the preparation of organic compounds, organic chemical methods, organic addition and other directions, can solve the problem that trifluoromethyl compounds are not reported, and achieve product yield and enantioselectivity Good properties, simple post-treatment and mild reaction conditions

Active Publication Date: 2019-08-02
HENAN NORMAL UNIV
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AI Technical Summary

Problems solved by technology

[0004] So far, organoboronic acids and β-CF without the participation of transition metals 3 The synthesis of optically active trifluoromethyl compounds by asymmetric conjugate addition of -α,β-unsaturated ketones has not been reported

Method used

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  • Method for synthesizing optically active trifluoromethyl compound by asymmetric conjugate addition reaction of organic boronic acid and alpha, beta-unsaturated ketone
  • Method for synthesizing optically active trifluoromethyl compound by asymmetric conjugate addition reaction of organic boronic acid and alpha, beta-unsaturated ketone
  • Method for synthesizing optically active trifluoromethyl compound by asymmetric conjugate addition reaction of organic boronic acid and alpha, beta-unsaturated ketone

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022]

[0023]

[0024]

[0025] [a] Reaction condition: β-CF 3 -α,β-unsaturated ketone 1a (0.1mmol), trans-2-phenylvinylboronic acid 2a (0.12mmol), (S)-2,15-Br 2 -DHTP(0.01mmol),Mg(O t Bu) 2 (0.01mmol), Molecular sieves (50 mg), and 1.0 mL of anhydrous solvent in N 2 Stirring under atmosphere. [b] Isolated yield. [c] ee value obtained by HPLC chiral analysis. [d] 0.5mL DCE.

[0026] In the screening process of reaction conditions, the influence of different solvents on the reaction was first investigated (entries 1-6), and finally 1,2-dichloroethane (DCE) was selected as the solvent. When the reaction concentration increased, the product yield Both efficiency and enantioselectivity were improved (entry 7). Subsequently, the influence of different chiral catalysts on the reaction was investigated (entries 8-14), and Cat 1 was finally determined to be the best catalyst. At the same time, the effects of temperature and catalyst dosage on the reaction were invest...

Embodiment 2

[0031]

[0032] Under nitrogen protection, add 50mg Molecular sieves, chiral catalyst Cat1 (4.9mg, 0.01mmol, 10mol%), magnesium tert-butoxide (1.7mg, 0.01mmol, 10mol%), β-CF 3 -α,β-unsaturated ketone 1b (20.0mg, 0.1mmol) and organoboronic acid 2a (17.7mg, 0.12mmol, 1.2equiv), pumped and exchanged gas 3 times, then added dry 1,2-dichloroethane ( 0.5mL), stirred at 25°C for 48h. TLC spot plate tracking until the disappearance of raw material 1b, add 0.1mL water to quench the reaction, remove the solvent under reduced pressure and then directly separate and purify by fast silica gel column chromatography (the eluent is dichloromethane / petroleum ether volume ratio 1 / 5) to obtain the target product 3ba, 93% yield, 94% ee.

[0033] 3ba white solid (28.4mg, yield 93%); mp 41-43°C; HPLC (Daicel Chiralcel OD-H, n-hexane / isopropanol=90:10, flow rate 0.8mL / min, λ=254nm)t R (minor) = 6.68min,t R (major)=8.09min, ee=94%; [α] D 17 =-20.0(c1.0,CH 2 Cl 2 ); 1 H NMR (400MHz, CDCl ...

Embodiment 3

[0035]

[0036] Under nitrogen protection, add 50mg Molecular sieves, chiral catalyst Cat1 (4.9mg, 0.01mmol, 10mol%), magnesium tert-butoxide (1.7mg, 0.01mmol, 10mol%), β-CF 3 -α,β-unsaturated ketone 1c (23.0mg, 0.1mmol) and organoboronic acid 2a (17.7mg, 0.12mmol, 1.2equiv), pumped and exchanged gas 3 times, then added dry 1,2-dichloroethane ( 0.5mL), stirred at 25°C for 48h. Tracked by TLC until the raw material 1c disappeared, the reaction was quenched by adding 0.1mL of water, and the solvent was removed under reduced pressure, followed by rapid silica gel column chromatography (eluent: dichloromethane / petroleum ether volume ratio 1 / 5) to separate and purify to obtain the target product 3ca, 98% yield, 94% ee.

[0037] 3ca white solid (33.0mg, yield 98%); mp 82-84°C; HPLC (Daicel Chiralcel OD-H, n-hexane / isopropanol=90:10, flow rate 0.8mL / min, λ=254nm)t R (minor)=9.61min,t R (major)=21.21min, ee=94%; [α] D 17 =-3.1(c2.0, CH 2 Cl 2 ); 1 H NMR (400MHz, CDCl 3 )...

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Abstract

The invention discloses a method for synthesizing an optically active trifluoromethyl compound by asymmetric conjugate addition reaction of an organic boronic acid and alpha, beta-unsaturated ketone,and belongs to the technical field of asymmetric synthesis in the organic chemistry. A reaction equation is as shown in the specification. The method comprises the following specific steps: taking beta-CF3-alpha, beta-unsaturated ketone 1 and organic boric acid 2 as raw materials, and carrying out the asymmetric conjugate addition reaction to obtain the trifluoromethyl compound in the presence ofchiral tetrabenzocyclooctatetraenic or chiral binaphthol catalysts, as well as molecular sieves and magnesium tert-butoxide additives, wherein R<1> is selected from phenyl, substituted phenyl, 2-naphthyl, 1-naphthyl, 2-thienyl, 3-thienyl and cyclohexyl, and R<2> is selected from styryl, 2-furanyl and 2-benzofuranyl. The method has the advantages that reaction raw materials are easy to obtain, reaction conditions are mild, post-treatment is simple, the catalyst can be recycled and reused, the product yield and the enantioselectivity are good to excellent, and the product contains a trifluoromethyl chiral center.

Description

technical field [0001] The invention belongs to the field of asymmetric synthesis in organic chemistry, in particular to a method for synthesizing an optically active trifluoromethyl compound through the asymmetric conjugate addition reaction of organic boric acid and α, β-unsaturated ketone. Background technique [0002] Chiral compounds containing trifluoromethyl groups widely exist in biologically active molecules and drug molecules. Unfortunately, natural trifluoromethyl compounds are very rare in nature. Therefore, the development of universal and efficient synthesis of trifluoromethyl compounds, especially those containing trifluoromethyl Compounds with fluoromethyl chiral centers are crucial in organic synthesis (Chem. Rev. 2011, 111, 455.). Using an asymmetric catalytic method to convert latent chiral trifluoromethyl-containing substrates into chiral trifluoromethyl-containing products is one of the main methods for obtaining such compounds (Chin, J.Org.Chem.2019, 39...

Claims

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Application Information

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IPC IPC(8): C07C45/69C07C201/12C07D333/22C07D307/46C07C49/813C07C49/84C07C205/45C07C49/567C07B37/02
CPCC07B37/02C07B2200/07C07C45/69C07C201/12C07D307/46C07D333/22C07C2601/14C07C49/813C07C49/84C07C205/45C07C49/567Y02P20/584
Inventor 柴国利汪娟郭蓉
Owner HENAN NORMAL UNIV
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