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Method for synthesizing 4,6-substituted 3,4- dihydro-pyran-2-ketone derivative

A derivative and dihydro technology, applied in organic compound/hydride/coordination complex catalysts, chemical instruments and methods, chemical/physical processes, etc., can solve problems such as harsh reaction conditions, difficult operation, and difficult control. Achieve mild reaction conditions, easy operation and good yield

Inactive Publication Date: 2009-07-15
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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Problems solved by technology

[0003] At present, there are not many reports on the efficient synthesis of 4,6-substituted 3,-4-dihydro-pyran-2-one derivatives in the literature, although in recent years people have developed some synthetic pyran-2-one derivatives under mild conditions. The ketone method, but the 5-position of the product generally requires the presence of an electron-withdrawing group, and for the 4,6-position substituted 3,-4-dihydro-pyran-2-one derivatives without substituents at the 5-position There are not many syntheses, and most of them are obtained by condensation of corresponding acids or esters under strong acidic conditions or high temperature conditions. The reaction conditions are relatively harsh, difficult to control, and difficult to operate.

Method used

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  • Method for synthesizing 4,6-substituted 3,4- dihydro-pyran-2-ketone derivative
  • Method for synthesizing 4,6-substituted 3,4- dihydro-pyran-2-ketone derivative
  • Method for synthesizing 4,6-substituted 3,4- dihydro-pyran-2-ketone derivative

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1: Preparation of thiazole nitrogen heterocyclic carbene precursor salt

[0027] Under the protection of argon at room temperature, in a dry reaction tube, dissolve 4,5-dimethylthiazole or 4-methyl-5-hydroxyethylthiazole (1.0mmol) in 10mL of dry acetonitrile. Under certain conditions, (1.0 mmol) benzyl bromide or benzyl chloride was slowly added dropwise to the system, and refluxed for 3 hours. After the reaction was completed, it was naturally cooled to room temperature, and under rapid stirring, 30 mL of ethyl acetate was slowly added dropwise to the system, and a large amount of white solids precipitated out of the system, which was then left to stand. After filtration, a white solid was obtained, which was the precursor salt of thiazole carbenes.

[0028] C1: bromide (3-benzyl-4,5-dimethylthiazole)

[0029] 3-Benzyl-4,5-dimethylthiazolium bromide

[0030]

[0031] Solid, 91% yield. 'H NMR (300MHZ, DMSO) 6 more or less 7.492-7.324 (m, 5H), 5.809 (s,...

Embodiment 2

[0061] Embodiment 2: optimization of catalyst and reaction conditions

[0062] Table 1. Screening of nitrogen heterocyclic carbene catalysts a

[0063]

[0064]

[0065] a 1 Condition: 7a (0.2mmol), 20mol% catalyst., and 30mol% 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), tetrahydrofuran (THF) (1.0mL), 40 ℃. b use 1 H NMR determination. c Yield (Isolated yield).

[0066] Table2. Screening of reaction conditions α

[0067]

[0068]

[0069]

[0070] α Reaction conditions: 7a (0.2 mmol), x mol% 5, and y mol% 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in solvent (1.0 mL).

[0071] b Isolated yields. Wherein, DCM is dichloromethane, toluene is toluene, EtOAc is ethyl acetate, DMSO is dimethyl sulfoxide, and dioxane is dioxane.

Embodiment 3

[0072] Example 3: Synthesis of 3,4-dihydropyran-2-ones

[0073]

[0074] Under the protection of argon at room temperature, in a dry reaction tube, 2-acyl-1-formylcyclopropane 7 (1.0 mmol), thiazolium salt 5 (0.05 mmol), DBU (45 μL), Molecular sieves (100 mg), dissolved in 5 mL of dry 1,4-dioxane, stirred at 65 ° C, after the reaction was completed, naturally cooled to room temperature, filtered with diatomaceous earth, washed with dichloromethane, evaporated to dryness, column Chromatography (diethyl ether / petroleum ether=1 / 4-1 / 8) yielded compound 8.

[0075] P1: 4,6-diphenyl-3,4-dihydropyran-2-one

[0076] 4,6-diphenyl-3,4-dihydropyran-2-one

[0077]

[0078] Colorless oily liquid, 92% yield. 1 H NMR (CDCl 3 , 300MHz) δ 2.80 (dd, 1H, J 1 =8.7Hz,J 2 =15.9Hz), 3.04(dd,1H,J 1 =6.6Hz,J 2 =15.9Hz), 3.98(m, 1H), 5.97(d, 1H, J=3.9Hz), 7.26-7.44(m, 8H), 7.66-7.69(m, 2H); 13 C NMR (75MHz, CDCl 3 ): δ 36.9, 37.2, 104.2, 124.6, 127.0, 127.5, 128.5, 129.1, 129.2, 132.1,...

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Abstract

The invention provides a method for effectively synthesizing a 4,6-substituted 3,-4-dihydro-pyran-2one derivative by efficiently synthesizing aldehyde-substituted cyclopropane compound with N-heterocyclic carbene as a catalyst. Compared with the existing method, the method has the advantages of wide suitable substrate range, convenient catalyst acquisition, mild reaction condition, simple operation, and high reaction efficiency. The method is performed without any metallic salt compounds, which is good for drug production and treatment.

Description

technical field [0001] The invention relates to a method for synthesizing 4,6-substituted 3,-4-dihydro-pyran-2-one derivatives through ring expansion of aldehyde group-substituted cyclopropane compounds. The method is to catalyze the ring expansion reaction of cyclopropane compounds substituted by aldehyde group by the nitrogen heterocyclic carbene generated on-site by the action of the precursor salt of nitrogen heterocyclic carbene and alkali, and efficiently synthesize the aldehyde group to replace 4, and the 6-position to replace 3,- 4-Dihydro-pyran-2-one derivatives. Background technique [0002] In recent years, organic small molecule catalysis has attracted widespread attention from academia and industry all over the world due to its advantages of easy synthesis, convenient structure modification, and no heavy metal residue [(a) Seayad, J.; List, B.Org .Biomol.Chem.2005,3,719-724.(b) Dalko, P.I.; Moisan, L.Angew.Chem.Int.Ed.2004,43,5138-5175.], wherein by nitrogen he...

Claims

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Application Information

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IPC IPC(8): C07D309/32B01J31/02
Inventor 游书力李公强赵卓安
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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