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Trifluoroethanol/difluoroethanol reagent as well as preparation method and application thereof

A technology of trifluoroethanol and difluoroethanol, which is applied in the preparation of carbon-based compounds, chemical instruments and methods, and the preparation of hydroxyl compounds, etc., can solve the problems of difficult to control regioselectivity and unstable aldehyde compounds.

Inactive Publication Date: 2021-03-09
WUHAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Commonly used fluoroalkylsilane reagents such as Rupert-Prakash reagent and TMSCF 2 H, etc. are widely used in the synthesis of organic fluorine compounds, but this classic method of activating the C-Si bond with anion to form a carbanion intermediate and nucleophilic addition of an aldehyde compound to obtain the target product still has some shortcomings: 1 ) The regioselectivity in compounds containing multiple aldehyde groups is difficult to control; 2) Many aldehyde compounds, especially alkyl aldehydes, are unstable, and specific aldehydes require multi-step synthesis [a) Y.He, M.-M.Tian, X.-Y.Zhang, X.-S.Fan, Asian J.Org.Chem.2016, 5, 1318; b) W.Ou, G.Zhang, J.Wu, C.Su, ACS Cat.2019, 9, 5178-5183.]

Method used

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  • Trifluoroethanol/difluoroethanol reagent as well as preparation method and application thereof
  • Trifluoroethanol/difluoroethanol reagent as well as preparation method and application thereof
  • Trifluoroethanol/difluoroethanol reagent as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Ethyl 5,5,5-trifluoro-4-hydroxy-2-methylenevalerate, the synthetic route and preparation method are as follows:

[0071]

[0072] Into a dry 10 mL Schlenk tube under a nitrogen atmosphere, add Mn(OAc) 2 4H 2 O (14.7mg, 0.06mmol, 20mol%), 7a (152.4mg, 0.6mmol, 2.0 equiv), DCM (3mL, 0.1 M), 1a (70.2mg, 0.3mmol)) and TBPB (145.7mg, 0.75mmol, 2.5 equivalents), then sealed the tube, heated to 70°C and stirred for 18h, then added TBAF in an ice-water bath at 5°C, stirred for 0.5h, quenched the reaction mixture with water (2mL), and extracted with DCM (3×10mL) , the organic phases were combined and washed with brine, washed with Na 2 SO 4 Dry, hang dry using a rotary evaporator. The crude product was purified by silica gel column chromatography (200×300 mesh), and eluted with PE / EA (20 / 1~10 / 1, v / v) (PE: petroleum ether, EA: ethyl acetate) to obtain 53 mg (product Yield 71%) the target compound as a yellow oil. The product is tested, and the test results are as follows...

Embodiment 2

[0088] 5,5,5-Trifluoro-4-hydroxy-2-methylene-1-phenylpentan-1-one, the synthetic route and preparation method are as follows:

[0089]

[0090] Into a dry 10 mL Schlenk tube under a nitrogen atmosphere, add Mn(OAc) 3 2H 2 O (16.1mg, 0.06mmol, 20mol%), 7b (257.4mg, 0.9mmol, 3.0eq), DCM (3mL, 0.1M), 1a (70.2mg, 0.3mmol)) and TBPB (145.7mg, 0.75mmol, 2.5 equivalents), then seal the sealed tube, heat to 70°C and stir for 14h, after that, in 5°C ice-water bath, add TBAF, stir for 0.5 hour, quench the reaction mixture with water (2mL), and use DCM (3×10mL) extracted, the organic phases were combined and washed with brine, washed with Na 2 SO 4 Drying, using a rotary evaporator to hang dry, the crude product was purified by silica gel column chromatography (200 × 300 mesh), and eluted with PE / EA (20 / 1~10 / 1, v / v) to obtain 53mg (yield 71% ) target compound as a yellow oil. The product is tested, and the test results are as follows:

[0091] R f =0.40 (PE / EA=5 / 1, v / v).

[00...

Embodiment 3

[0098] 1-([[1,1'-biphenyl]-4-yl)-5,5,5-trifluoro-4-hydroxy-2-methylenepentyl-1-one

[0099]

[0100] Into a dry 10 mL Schlenk tube under a nitrogen atmosphere, add Mn(OAc) 3 2H 2 O (16.1 mg, 0.06 mmol, 20 mol%), 7c (326.2 mg, 0.9 mmol, 3.0 equiv), DCM (3 mL, 0.1 M), 1a (70.2 mg, 0.3 mmol)) and TBPB (145.7 mg, 0.75 mmol, 2.5 eq), then seal the sealed tube, heat to 70°C and stir for 14h, after that, add TBAF in 5°C ice-water bath, stir for 0.5h, quench the reaction mixture with water (2mL), and extract with DCM (3×10mL) , the organic phases were combined and washed with brine, washed with Na 2 SO 4 Dry, hang to dry using a rotary evaporator, the crude product is purified by silica gel column chromatography (200×300 mesh), and eluted with PE / EA (20 / 1~10 / 1, v / v) to obtain 74.9 mg (yield 78 %) target compound as a white solid. The product is tested, and the test results are as follows:

[0101] R f =0.50 (PE / EA=5 / 1, v / v), boiling point (mp): 69-71°C.

[0102] NMR spectru...

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Abstract

The invention relates to a trifluoroethanol / difluoroethanol reagent and a preparation method and an application thereof, the chemical structural formula of the trifluoroethanol reagent is shown in thespecification, in the formula, R1, R2 and R3 represent substituent groups on silicon atoms, and R1, R2 and R3 are independently selected from aryl, heteroaryl and alkyl respectively. The trifluoroethylation reagent and the difluoroethylation reagent provided by the invention can be used as synthesis intermediates of a plurality of organic compounds, some of the compounds have pharmaceutical activity, the preparation steps of the compounds are simplified, and the synthesis method is mild in condition and wide in substrate applicability.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and relates to a tri / difluoroalcoholation reagent and its preparation method and application. Background technique [0002] The introduction of fluorine atoms into compounds has become a common strategy in the synthesis of drugs. The introduction of fluorine atoms can improve or change the chemical, physical and biological properties of organic compounds [a) P.Kirsch, Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Wiley- VCH, 2013; b) J.-P.Bégué, D. Bonnet-Delpon, Bioorganic and Medicinal Chemistry Wiley-VCH, Weinheim, 2008; c) C.Ni, M.Hu, J.Hu, Chem.Rev.2015 , 115, 765; d) Liang, T.; Neumann, C.N.; Ritter, T. Angew. Chem., Int. Ed. 2013, 52, 8214; Angew. Chem. 2013, 125, 8372.]. Commonly used fluoroalkylsilane reagents such as Rupert-Prakash reagent and TMSCF 2 H, etc. are widely used in the synthesis of organic fluorine compounds, but this classic method of act...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/08C07D209/34C07C67/343C07C69/732C07J9/00C07C29/34C07C33/48C07J71/00C07C45/68C07C49/835C07C315/04C07C317/22C07C231/12C07C235/28C07D317/54C07J1/00C07C253/30C07C255/56C07D307/46C07C303/28C07C309/65C07C69/76C07C67/31C07C29/147
CPCC07F7/081C07F7/083C07D209/34C07C67/343C07J9/00C07C29/34C07J71/0005C07C45/68C07C315/04C07C231/12C07D317/54C07J1/0011C07C253/30C07D307/46C07C303/28C07C67/31C07C29/147C07C2602/08C07C69/73C07C33/48C07C49/835C07C317/22C07C235/28C07C255/56C07C309/65C07C69/76C07F7/0827C07F7/188C07C29/32C07C317/18C07C69/732C07C33/483C07C69/80C07C45/64C07J71/0031
Inventor 沈晓陈祥龚星星
Owner WUHAN UNIV
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