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Synthesis method of phenylpropionic acid compound

A technology of phenylpropionic acid and synthesis method, which is applied in the field of activating amide compound carbonyl β-position sp3C-H bond to synthesize phenylpropionic acid compound, and achieves the effects of good tolerance, mild reaction conditions, and easy introduction and removal.

Active Publication Date: 2015-05-06
ZHENGZHOU UNIV
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

In recent years, there have been reports in the literature on the synthesis of benzene derivatives through direct functionalization of C-H bonds ( Angew. Chem. Int. Ed. 2007, 46 , 3135 –3138.; J. Am. Chem. Soc. 2005, 127 , 5936-5945.), but most of them are concentrated in the more lively sp 2 C-H bond, due to the higher bond energy of saturated C-H bond, so sp 3 The direct arylation reaction of C-H bond is rarely reported ( Acc. Chem. Res. 2003, 36 , 234-245; J. Am. Chem. Soc. 2010, 132 , 3965–3972), which makes the scope of application of the reaction very limited

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  • Synthesis method of phenylpropionic acid compound

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Embodiment 1

[0022] The preparation method of the phenylpropionic acid of the present embodiment is as follows:

[0023] (1) Preparation of 2-propionamidopyridine-1-oxide

[0024] Under the protection of inert gas, weigh propionic acid (6 mmol), 2-aminopyridine nitrogen oxide (660 mg, 6 mmol), DMAP (73.3 mg, 0.6 mmol) into a 100 mL three-necked flask, add 30 mL of water dichloromethane. 30 mL of anhydrous dichloromethane solution containing EDCI (1.14 g, 7.2 mmol) was added dropwise in an ice-water bath. After the dropwise addition was completed, the ice-water bath was removed, and the mixture was stirred at room temperature for 8 hours. After the reaction was completed, add 50 mL of anhydrous dichloromethane to the reaction liquid for dilution, and then use 15 mL (3×5 mL) of 1mol / L dilute hydrochloric acid solution and 15 mL (3×5 mL) of saturated sodium bicarbonate solution respectively , 35 mL (3×10 mL) of saturated brine, combined the organic phases, and dried over anhydrous sodium s...

Embodiment 2

[0033] The preparation method of the 2-methyl-3-phenylpropionic acid of the present embodiment is as follows:

[0034] (1) Preparation of 2-(2-methyl-3-benzylpropionamido)pyridine-1-oxide

[0035] According to the method described in step (2) of Example 1, the difference is that the substrate and reagent used are: 2-(2-methylpropionamido)pyridine-1-oxide (0.2 mmol, 36 mg), PhI ( 1.2 mmol, 135 μL), Pd(OAc) 2 (10 mol%, 4.5 mg), K 2 HPO 4 ·3H 2 O (0.5 mmol, 115mg), DMSO 1 mL in air at 120 o The reaction was carried out at C for 26 hours to obtain 21.7 mg of 2-(2-methyl-3-benzylpropionamido)pyridine-1-oxide, with a yield of 42%;

[0036] Melting point 86-88 o c. 1 H NMR (400 MHz, CDCl 3 ) δ 10.01 (s, N H , 1H), 8.45 (dd, J = 8.5, 1.7 Hz, 1H, Ar- H ), 8.21 (dd, J = 6.5, 1 Hz, 1H, Ar- H ), 7.33 (t, J = 1.24 Hz, 1H, Ar- H ), 7.30-7.18 (m, 5H, Ph- H ), 6.98-6.94 (m, 1H, Ar- H ), 3.14 (q, J = 7.0 Hz, 1H, CH 3 (CH 2 )C H ), 2.89-2.82 (m,1H, CH 3 (CH H )CH),...

Embodiment 3

[0040] The preparation method of the 2,2-dimethyl-3-phenylpropionic acid of the present embodiment is as follows:

[0041] (1) Preparation of 2-(2,2-dimethyl-3-benzylpropionamido)pyridine-1-oxide

[0042] According to the method described in step (2) of Example 1, the difference is that the substrate and reagent used are: 2-(2,2-dimethylpropionamido)pyridine-1-oxide (0.2 mmol, 38.8 mg) , PhI (1.2 mmol, 135 μL), Pd(OAc) 2 (10 mol%, 4.5 mg), K 2 HPO 4 ·3H 2 O (0.5 mmol, 115mg), DMSO 1 mL in air at 120 o The reaction was carried out at C for 26 hours to obtain 23.4 mg of 2-(2,2-dimethyl-3-benzylpropionamido)pyridine-1-oxide, with a yield of 43%;

[0043] 1 H NMR (400 MHz, CDCl 3 ) δ 10.35 (s, N H , 1H), 8.49 (d, J = 6.8 Hz, 1H, Ar- H ), 8.22 (d, J = 6.5 Hz, 1H, Ar- H ), 7.34 (t, J = 8.0 Hz, 1H, Ar- H ), 7.25-7.19 (m, 3H, Ph- H ), 7.13 (d, J = 6.7 Hz, 2H, Ph- H ), 6.99-6.95 (t, J = 7.3 Hz, 1H, Ar- H ), 2.97 (s, 2H, C H 2 C(CH 3 ) 2 ), 1.35 (s,6H, C...

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Abstract

The invention discloses a method for directly achieving direct arylation reaction of benzene and carbonyl beta-bite sp3C-H bonds employing palladium acetate as a catalyst under the action of bidentate guide base, so as to synthesize a phenylpropionic acid compound. The method comprises the following steps: sequentially adding a 2-propionamido-pyridine-1-oxide, palladium acetate, gibbsite dipotassium phosphate, an aryl iodide compound and dimethylsulfoxide to a shrek tube in an air atmosphere, and reacting for 20-30 hours; after the reaction is ended, cooling to a room temperature, extracting, drying, concentrating and carrying out chromatographic separation to obtain an arylated product; dissolving the obtained arylated product into an ethanol solution of NaOH and reacting for 20-30 hours; and after reaction is ended, neutralizing, extracting, drying, concentrating and carrying out column chromatography to obtain the phenylpropionic acid compound. The method is mild in reaction condition, and good in functional group tolerance; an external additive is not needed; and the carbonyl beta-bite sp3C-H bonds in the 2-propionyl aminopyridine-1-oxide can be directly arylated.

Description

technical field [0001] The invention relates to an activated amide compound carbonyl β-position sp 3 C-H bond to synthesize the method of phenylpropionic acid compounds. This method uses aliphatic carboxylic acid as the starting material to introduce N , O - The bidentate directing group, under the catalysis of palladium acetate, the arylation reaction of the carbonyl β position is realized with high selectivity, and finally the directing group is removed to obtain phenylpropionic acid compounds. Background technique [0002] Phenylpropionic acid and its derivatives are ubiquitous in the pharmaceutical, pesticide and petrochemical industries, and the carboxyl group in phenylpropionic acid itself is an active group that can be used as an intermediate to react with other compounds, thereby synthesizing many materials used in fuels and liquid crystals. , medicine and other important compounds. For example, the acidic substance synthesized with phenylpropionic acid as the pa...

Claims

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Application Information

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IPC IPC(8): C07C57/30C07C57/38C07C57/58C07C51/06
CPCC07C51/06C07C2601/02C07D213/89C07C57/30C07C61/39C07C57/58
Inventor 牛俊龙杨新燕郝新奇张林宝赵雪梅任保增宋毛平
Owner ZHENGZHOU UNIV