A method for selective hydrogenation reduction of alpha, beta-unsaturated amide compounds

Abstract

The application discloses a selective hydrogenation reduction method of an alpha, beta-unsaturated amide compound. After mixing the alpha, beta-unsaturated amide compound, water, a metal promoter, a ligand and an organic solvent, a reduction reaction is carried out, and a reaction liquid is obtained after the reaction is completed. The alpha, beta-saturated amide compound is obtained by separating and purifying the reaction liquid through a silica gel column. The application has high yield, mild reaction condition, no irritating odor and is environment-friendly. Compared with a hexacarbonylmolybdenum, sodium, ferroferric oxide and other catalysts or promoters, the zinc powder is more inexpensive and easy to obtain. Compared with a phenylsilane and hydrazine and other hydrogen sources, the water as the hydrogen source is more easy to obtain, and the reaction condition is relatively simple.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for selective hydrogenation reduction of α,β-unsaturated amide compounds, in particular to a method for reduction of carbon-carbon double bond of α,β-unsaturated amide by zinc powder mediated water as hydrogen source to generate α,β-saturated amide compounds. TECHNICAL BACKGROUND

[0002] Reduction of carbon-carbon double bond of α,β-unsaturated amide compounds has important applications in the field of organic synthesis. For many years, chemists have been committed to the establishment of reduction system and practical exploration. Among them, catalytic hydrogenation is a widely studied reduction method, and so far a variety of methods for reducing α,β-unsaturated amide compounds have been developed. For example: Ehud Keinan and Daniel Perez reported a catalytic reduction system using molybdenum hexacarbonyl as catalyst and phenylsilane as hydrogen source. This catalytic system can also selectively reduce the carbon-carbon double bond of α,β-unsaturated amide compounds, with shorter reaction time and higher yield. However, compared with other inexpensive metals, molybdenum catalyst is still a relatively expensive metal and is not easy to be prepared simply in the laboratory ( J. Org. Chem. 1987, 52 , 2576-2580). Subsequently, Moon Kim reported a selective reduction of carbon-carbon double bond of N,N-dimethyl cinnamamide using ferric oxide as catalyst, hydrazine as hydrogen source and ethanol as solvent. Although the reaction temperature is lower and the yield is higher, the amount of catalyst and hydrazine is large, which is 0.4 and 20 equivalents of amide respectively, and the toxicity of hydrazine is also large ( B. Korean Chem. Soc. 2011, 32 (spc8) , 3183-3186.). In addition to the catalytic reduction method, there are also equivalent metal involved reduction methods reported. For example: in 1993, there are documents reported that the combination of samarium diiodide (4 equiv) and water (1 mL) can selectively reduce the carbon-carbon double bond of cinnamamide (0.5 mmol, 1 equiv). The reaction is fast and the yield is high, but the corresponding disadvantage is that the preparation process of samarium diiodide is complex and has high environmental requirements ( Chem. Lett. 1993, 1495-1498,). In addition, there are documents that use equivalent sodium metal (3 equiv) and ethanol (3 equiv) as reduction system to selectively reduce the carbon-carbon double bond of N,N-dimethyl cinnamamide in diethyl ether solvent. However, the selected sodium metal is chemically active, flammable and explosive, and there is a certain risk in operation ( Tetrahedron Lett. 2017, 58, 2757-2760.). Therefore, we developed a relatively economical and safe method for the reduction of α,β-unsaturated amide compounds. SUMMARY

[0003] In combination with the reported technical method, the present application reduces α,β-unsaturated amide compounds by using cheap zinc powder to generate α,β-saturated amide compounds, thereby providing a new method for synthesizing α,β-saturated amide compounds.

[0004] To achieve the above-mentioned purpose, the technical scheme of the present application is as follows:

[0005] The present application provides a selective hydrogenation reduction method for α,β-unsaturated amide compounds, and the specific method is as follows: under a nitrogen atmosphere, α,β-unsaturated amide compounds, water, metal promoters, ligands, and organic solvents shown in formula (I) are mixed and stirred at 110 ℃ ~ 150 ℃ for 8 ~ 14 h to carry out a reduction reaction, and after the reaction is completed, a reaction liquid is obtained, and the reaction liquid is separated and purified by a silica gel column to obtain α,β-saturated amide compounds shown in formula (II),

[0006]

[0007] G is or

[0008] In formula (I) or formula (II), R 1 is selected from benzene or a hydrogen atom, R 2 in formula G is selected from CH3 or F, the metal promoter is zinc (which can be zinc powder), the ligand is selected from 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline, bipyridine, or 4,4'-dimethyl-2,2'-bipyridine, and the mass ratio of the compound shown in formula (I), water, zinc, and the ligand is 1:1~5:3~5:0.1~0.3.

[0009] Further, the organic solvent is tetrahydrofuran, and the volume of the organic solvent is 5 ~ 10 mL / mmol (preferably 5 mL / mmol) based on the mass of the compound shown in formula (I).

[0010] Further, the mass ratio of the compound shown in formula (I), water, zinc, and the ligand is 1:5:4:0.2.

[0011] Further, the ligand is 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline.

[0012] Further, the reduction reaction temperature is 150 ℃, and the reaction time is 12 h.

[0013] Further, the specific operation process of the silica gel column chromatography separation and purification is as follows: the reaction solution is concentrated, column chromatography is carried out, a mixture of petroleum ether and ethyl acetate is used as an eluent to elute, the eluent containing the target compound is collected, concentrated and distilled, and dried.

[0014] Further, the volume ratio of petroleum ether to ethyl acetate in the mixture of petroleum ether and ethyl acetate is 30-50:1.

[0015] Further, the α, β-unsaturated amide compound is one of the following:

[0016] .

[0017] Compared with the prior art, the present application has the advantages of high yield, mild reaction conditions, no irritating odor, environmental protection, and the like. DETAILED DESCRIPTION

[0018] Example 1

[0019]

[0020] (E)-1-(1H-indol-1-yl)-3-phenylprop-2-en-1-one (49.8 mg, 0.2 mmol), zinc powder (52 mg, 0.8 mmol), water (18 mg, 1 mmol), 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline (14.4 mg, 0.04 mmol) were added into a 25 mL Schlenk tube under nitrogen atmosphere, 1 mL THF was added as a solvent, and the reaction was stirred in a 150 o C oil bath for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was purified by column chromatography using about 255 mL of eluent (petroleum ether and ethyl acetate were 250 mL and 5 mL, respectively). (The volume ratio of the eluent was petroleum ether / ethyl acetate 50:1). The product was obtained as a white solid, with a mass of 42 mg and a yield of 84%.

[0021] Characterization data: 1 H NMR (400 MHz, CDCl3) δ 8.52 – 8.50 (d, J = 8.0 Hz,1H),7.59 – 7.57 (d, J = 1.6Hz,1H),7.43 – 7.42 (d, J= 4.0 Hz, 1H), 7.38 – 7.26 (m, 8H), 6.64 – 6.63 (d, J = 4.0 Hz, 1H), 3.26 – 3.23 (m, 2H), 3.21 – 3.18 (m, 2H).

[0022] Example 2

[0023] The temperature was reduced to 130 °C and the other operations were the same as in Example 1, 39.8 mg, yield 80%.

[0024] Example 3

[0025] The temperature was reduced to 110 °C and the other operations were the same as in Example 1, 37.3 mg, yield 75%.

[0026] Example 4

[0027] The amount of compound as shown in formula (II) was changed to (3.6 mg, 0.2 mmol), and the other operations were the same as in Example 1, 36.8 mg, yield 74%.

[0028] Example 5

[0029] The amount of compound as shown in formula (II) was changed to (10.8 mg, 0.6 mmol), and the other operations were the same as in Example 1, 39.8 mg, yield 80%.

[0030] Example 6

[0031] Without adding zinc powder, the other operations were the same as in Example 1, and the target compound was not obtained.

[0032] Example 7

[0033] The amount of zinc powder was changed to (26 mg, 0.4 mmol), and the other operations were the same as in Example 1, 34.8 mg, yield 70%.

[0034] Example 8

[0035] The zinc powder was replaced with zinc bromide, and the other operations were the same as in Example 1, and the target compound was not obtained.

[0036] Example 9

[0037] The zinc powder was replaced with magnesium powder, and the other operations were the same as in Example 1, and the target compound was not obtained.

[0038] Example 10

[0039] Replace zinc powder with tin powder, and other operations are the same as example 1. The target compound is not obtained.

[0040] Example 11

[0041] Replace the amount of ligand with (3.6 mg, 0.02 mmol), and other operations are the same as example 1. 37.3 mg, yield 75%.

[0042] Example 12

[0043] Replace the amount of ligand with (21.6 mg, 0.06 mmol), and other operations are the same as example 1. 41.8 mg, yield 84%.

[0044] Example 13

[0045] Replace the ligand with 4,4'-dimethyl-2,2'-bipyridine, and other operations are the same as example 1. 37.3 mg, yield 75%.

[0046] Example 14

[0047] Replace the compound as shown in formula (II) with ethanol. The target compound is not obtained.

[0048] Example 15

[0049] Reduce the reaction time to 1 h, and other operations are the same as example 1. 22.4 mg, yield 45%.

[0050] Example 16

[0051] Replace the solvent with dimethyltetrahydrofuran, and other operations are the same as example 1. 19.9 mg, yield 40%.

[0052] Example 17

[0053] Change the volume of the solvent to 2 mL, that is, when the volume of the organic solvent is 10 mL / mmol based on the amount of substance of the compound as shown in formula (I), other operations are the same as example 1. 41 mg, yield 82%.

[0054] Example 18

[0055] (E)-3-phenyl-1-(1H-pyrrol-1-yl)prop-2-en-1-one (39.8 mg, 0.2 mmol), zinc powder (52 mg, 0.8 mmol), water (18 mg, 1 mmol), 2,9-dimethyl-4,7-diphenyl-1,10- phenanthroline (14.4 mg, 0.04 mmol) were added into a 25 mL Schlenk tube under nitrogen atmosphere, 1 mL THF was added as solvent, the reaction was stirred in a 150 o C oil bath for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was purified by column chromatography using about 255 mL eluent (petroleum ether and ethyl acetate were 250 mL, 5 mL) to obtain the product. (eluent volume ratio: petroleum ether / ethyl acetate 50:1) The product was obtained as a white solid with a mass of 34 mg, a yield of 85%.

[0056] Characterization data: 1 H NMR (400 MHz, CDCl3) δ 7.37 – 7.27 (m, 7H), 6.33 – 6.32(m, 4H), 3.18 – 3.14 (m, 4H).

[0057] Example 19

[0058] (E)-3-phenyl-1-(1H-pyrrol-1-yl)prop-2-en-1-one (34.6 mg, 0.2 mmol), zinc powder (52 mg, 0.8 mmol), water (18 mg, 1 mmol), 2,9-dimethyl-4,7-diphenyl-1,10- phenanthroline (14.4 mg, 0.04 mmol) were added into a 25 mL Schlenk tube under nitrogen atmosphere, 1 mL THF was added as solvent, the reaction was stirred in a 150 o C oil bath for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was purified by column chromatography using about 255 mL eluent (petroleum ether and ethyl acetate were 250 mL, 5 mL) to obtain the product. (eluent volume ratio: petroleum ether / ethyl acetate 50:1) The product was obtained as a white solid with a mass of 34 mg, a yield of 85%.

[0059] Characterization data: 1 H NMR (400 MHz, CDCl3) δ 8.51 – 8.49 (d, J = 8.0 Hz, 1H),7.60 – 7.58 (d, J= 8.0 Hz, 1H), 7.50 – 7.49 (d, J = 4.0 Hz, 1H), 7.40 – 7.36(t, J = 8.0 Hz, 1H), 7.32 – 7.28 (m,1H), 6.67 – 6.66 (d, J = 4.0 Hz, 1H),3.01 – 2.96 (q, J = 1.0 Hz, 2H), 1.40 – 1.36 (t, J = 8.0 Hz, 3H).

[0060] Example 20

[0061]

[0062] (E)-1-(6-fluoro-1H-indol-1-yl)-3-phenylprop-2-en-1-one (53.4 mg, 0.2 mmol), zinc powder (52 mg, 0.8 mmol), water (18 mg, 1 mmol), 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline (14.4 mg, 0.04 mmol) were added into a 25 mL Schlenk tube under nitrogen atmosphere, 1 mL THF was added as solvent, the reaction was placed in a 150 o C oil bath and stirred for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was purified by column chromatography using about 255 mL eluent (petroleum ether and ethyl acetate were 250 mL, 5 mL, respectively). (eluent volume ratio: petroleum ether / ethyl acetate 50:1) to obtain the product as a white solid, with a mass of 45 mg, a yield of 85%.

[0063] Characterization data: 1 H NMR (400 MHz, CDCl3) δ 8.24 – 8.21 (d, J = 6.0 Hz, 1H),7.46 – 7.43 (m, 1H), 7.36 – 7.23 (m, 6H), 7.04 – 6.99 (m,1H), 6.57 – 6.56 (d, J = 2.0 Hz, 1H), 3.19 – 3.14 (m, 4H). 13C NMR (101 MHz, CDC13) δ 170.60, 162.52, 160.13, 140.27, 135.80, 135.67, 128.74, 128.48, 126.56, 124.73, 124.70, 121.43, 121.32, 112.05, 111.81, 108.94, 104.25, 103.96, 37.56, 30.39

[0064] Example 21

[0065]

[0066] (E)-1-(3-methyl-1H-indol-1-yl)-3-phenylprop-2-en-1-one (52.6 mg, 0.2 mmol), zinc powder (52 mg, 0.8 mmol), water (18 mg, 1 mmol), 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline (14.4 mg, 0.04 mmol) were added into a 25 mL Schlenk tube under nitrogen atmosphere, 1 mL THF was added as solvent, the reaction was stirred in 150 o C oil bath for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was purified by column chromatography using about 255 mL eluent (petroleum ether and ethyl acetate were 250 mL, 5 mL, respectively). (eluent volume ratio: petroleum ether / ethyl acetate 50:1) to obtain the product as a white solid, with a mass of 43 mg, a yield of 82%.

[0067] Characterization data: 1 H NMR (400 MHz, CDC13) δ 8.49 - 8.47 (d, J = 4.0 Hz, 1H), 7.40 - 7.20 (m, 8H), 3.20 - 3.18 (m, 4H), 2.28 - 2.27 (d, J = 2.0 Hz, 3H).

Claims

1. A method for selectively hydrogenating and reducing an α, β-unsaturated amide compound, specifically as follows: under a nitrogen atmosphere, mixing an α, β-unsaturated amide compound as shown in formula (I), water, a metal promoter, a ligand, and an organic solvent, and stirring at 110 ℃ to 150 ℃ for 8 to 14 hours to perform a reduction reaction, obtaining a reaction liquid after the reaction is completed, and separating and purifying the reaction liquid through a silica gel column to obtain an α, β-saturated amide compound as shown in formula (II), G is or wherein R in formula (I) or formula (II) 1 R in formula G is selected from benzene or a hydrogen atom 2 R in formula (I) is selected from CH3 or F, the metal promoter is zinc, the ligand is selected from 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline, bipyridine or 4,4'-dimethyl-2,2'-bipyridine, the mass ratio of the compound shown in formula (I), water, zinc and the ligand is 1:1~5:3~5:0.1~0.

3.

2. The selective hydrogenation reduction method for α,β-unsaturated amide compounds as described in claim 1, characterized in that, The organic solvent is tetrahydrofuran, and the volume of the organic solvent is 5 to 10 mL per mmol of the amount of substance of the compound shown in formula (I).

3. The selective hydrogenation reduction method for α,β-unsaturated amide compounds as described in claim 1, characterized in that, The ratio of the amount of substance of the compound shown in formula (I), water, zinc, and the ligand is 1:5:4:0.

2.

4. The selective hydrogenation reduction method for α,β-unsaturated amide compounds as described in claim 1, characterized in that, The ligand is 2, 9-dimethyl-4, 7-diphenyl-1, 10-phenanthroline.

5. The selective hydrogenation reduction method for α,β-unsaturated amide compounds as described in claim 1, characterized in that, The reduction reaction temperature is 150 ℃, and the reaction time is 12 hours.

6. The selective hydrogenation reduction method for α,β-unsaturated amide compounds as described in claim 1, characterized in that, The specific operation process of the silica gel column chromatography separation and purification is as follows: concentrating the reaction liquid, performing column chromatography, using a mixture of petroleum ether and ethyl acetate as an eluent to elute, collecting the eluent containing the target compound, and concentrating, distilling, and drying.

7. The selective hydrogenation reduction method for α,β-unsaturated amide compounds as described in claim 6, characterized in that, The volume ratio of petroleum ether to ethyl acetate in the mixture of petroleum ether and ethyl acetate is 30 to 50:

1.

8. The selective hydrogenation reduction method for α,β-unsaturated amide compounds as described in claim 1, characterized in that, The α, β-unsaturated amide compound is one of the following: 。

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