Selective hydrogenation reduction method of alpha, beta-unsaturated amide compound

Abstract

The invention discloses a selective hydrogenation reduction method of an alpha, beta-unsaturated amide compound, which comprises the following steps: mixing the alpha, beta-unsaturated amide compound, water, a metal accelerator, a ligand and an organic solvent, carrying out reduction reaction to obtain a reaction solution, and carrying out silica gel column separation and purification on the reaction solution to obtain the alpha, beta-unsaturated amide compound. The method is high in yield, mild in reaction condition, free of pungent smell and environmentally friendly, zinc powder is cheaper and easier to obtain compared with catalysts or accelerators such as molybdenum hexacarbonyl, sodium and ferroferric oxide, water serving as a hydrogen source is easier to obtain compared with hydrogen sources such as phenylsilane and hydrazine, and the reaction condition is simple.

Description

Technical Field

[0001] The invention relates to a selective hydrogenation reduction method for α,β-unsaturated amide compounds, and in particular to a method for reducing the carbon-carbon double bonds of α,β-unsaturated amides using water as a hydrogen source and mediated by zinc powder to generate α,β-saturated amide compounds. Technical Background

[0002] The reduction reaction of carbon-carbon double bonds 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 and practical exploration of reduction systems. Among them, catalytic hydrogenation is a widely studied reduction method, and many methods for reducing α,β-unsaturated amide compounds have been developed so far. For example: Ehud Keinan and Daniel Perez reported a catalytic reduction system using molybdenum hexacarbonyl as a catalyst and phenylsilane as a hydrogen source. This catalytic system can also selectively reduce the carbon-carbon double bonds of α,β-unsaturated amide substances, with a short reaction time and a high yield. However, compared with other cheap metals, molybdenum catalysts are still a relatively expensive metal and are not easy to prepare simply in the laboratory (J.Org.Chem.1987,52,2576-2580). Subsequently, Moon Kim reported a selective carbon-carbon double bond reduction reaction of N,N-dimethylcinnamamide using ferric oxide as a catalyst, hydrazine as a hydrogen source, and ethanol as a solvent. Although the reaction temperature is low and the yield is high, the amount of catalyst and hydrazine used is large, 0.4 and 20 equivalents of amide, respectively, and the toxicity of hydrazine is also high (B. Korean Chem. Soc. 2011, 32 (spc8), 3183-3186.). In addition to the catalytic reduction method, there are also reduction methods involving equivalent metals. For example: In 1993, it was 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 speed is fast and the yield is high, but the corresponding disadvantage is that the preparation process of samarium diiodide is relatively complicated and has high environmental requirements (Chem. Lett. 1993, 1495-1498,). In addition, there are also documents that use equivalent metal sodium (3 equiv) and ethanol (3 equiv) as the reduction system to selectively reduce the carbon-carbon double bond of N, N-dimethylcinnamamide in ether solvent. However, the metal sodium used in this reaction is chemically active, flammable and explosive, and there is a certain degree of danger in the operation (Tetrahedron Lett. 2017, 58, 2757-2760.). Therefore, we have developed a relatively economical and safe reduction method for α, β-unsaturated amide compounds. Summary of the invention

[0003] Combined with the reported technical methods, the present invention 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 object, the technical solution of the present invention is:

[0005] The present invention provides a selective hydrogenation reduction method for an α,β-unsaturated amide compound. The specific method is as follows: in a nitrogen atmosphere, an α,β-unsaturated amide compound as shown in formula (I), water, a metal promoter, a ligand, and an organic solvent are mixed and stirred at 110° C. to 150° C. for 8 to 14 hours for a reduction reaction, and a reaction liquid is obtained after the reaction is completed. The reaction liquid is separated and purified by silica gel column chromatography to obtain an α,β-saturated amide compound as shown in formula (II).

[0006]

[0007] G is

[0008] Wherein, R in formula (I) or formula (II) 1 is selected from benzene or hydrogen atom, R in formula G 2 The catalyst 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-biphenyl-1,10-phenanthroline, bipyridine or 4,4'-dimethyl-2,2'-bipyridine, and the molar ratio of the compound represented by formula (I), water, zinc and the ligand is 1:1~5:3~5:0.1~0.3.

[0009] Furthermore, the organic solvent is tetrahydrofuran, and the volume of the organic solvent is 5 to 10 mL / mmol (preferably 5 mL / mmol) based on the amount of the compound represented by formula (I).

[0010] Furthermore, the molar ratio of the compound represented by formula (I), water, zinc and ligand is 1:5:4:0.2.

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

[0012] Furthermore, the reduction reaction temperature is 150° C. and the reaction time is 12 h.

[0013] Furthermore, the specific operation process of the silica gel column chromatography separation and purification is: concentrating the reaction solution, performing column chromatography, eluting with a mixture of petroleum ether and ethyl acetate as an eluent, collecting the eluate containing the target compound, concentrating, distilling and drying.

[0014] Furthermore, the volume ratio of petroleum ether to ethyl acetate in the mixed liquid of petroleum ether and ethyl acetate is 30 to 50:1.

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

[0016]

[0017] Compared with the prior art, the beneficial effects of the present invention are: higher yield, mild reaction conditions, no irritating odor, environmental protection, compared with catalysts or promoters such as molybdenum hexacarbonyl, sodium, ferrosilicate, etc., zinc powder is cheaper and easier to obtain, compared with hydrogen sources such as phenylsilane and hydrazine, water is easier to obtain as a hydrogen source, and the reaction conditions are relatively simple. DETAILED DESCRIPTION

[0018] Example 1

[0019]

[0020] 2,9-Dimethyl-4,7-biphenyl-1,10-phenanthroline (14.4 mg, 0.04 mmol) was added to a 25 mL Schlenk tube, 1 mL THF was added as solvent, and the reaction was placed in a 150 ° C oil bath and stirred for 12 hours. 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). (Eluent volume ratio: 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 (400MHz, CDCl3) δ8.52–8.50 (d, J=8.0Hz, 1H), 7.59–7.57 (d, J=1.6Hz, 1H), 7.43–7.42 (d, J=4 .0Hz,1H),7.38–7.26(m,8H),6.64–6.63(d,J=4.0Hz,1H),3.26–3.23(m,2H),3.21–3.18(m,2H).

[0022] Example 2

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

[0024] Example 3

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

[0026] Example 4

[0027] The amount of the compound represented by 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, and the yield was 74%.

[0028] Example 5

[0029] The amount of the compound represented by 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, and the yield was 80%.

[0030] Example 6

[0031] No zinc powder was added, and other operations were the same as in Example 1, but 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, and the yield was 70%.

[0034] Example 8

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

[0036] Example 9

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

[0038] Example 10

[0039] Zinc powder was replaced with tin powder, and other operations were the same as in Example 1, but the target compound was not obtained.

[0040] Embodiment 11

[0041] The amount of ligand was changed to (3.6 mg, 0.02 mmol), and the rest of the operation was the same as in Example 1, 37.3 mg, and the yield was 75%.

[0042] Example 12

[0043] The amount of ligand was changed to (21.6 mg, 0.06 mmol), and the remaining operations were the same as in Example 1, 41.8 mg, and the yield was 84%.

[0044] Embodiment 13

[0045] The ligand was replaced with 4,4'-dimethyl-2,2'-bipyridine, and the other operations were the same as in Example 1, 37.3 mg, with a yield of 75%.

[0046] Embodiment 14

[0047] When the compound represented by formula (II) was replaced by ethanol, the target compound was not obtained.

[0048] Embodiment 15

[0049] The reaction time was reduced to 1 h, and other operations were the same as in Example 1, 22.4 mg, with a yield of 45%.

[0050] Example 16

[0051] The solvent was replaced with dimethyltetrahydrofuran, and other operations were the same as in Example 1, 19.9 mg, with a yield of 40%.

[0052] Embodiment 17

[0053] When the volume of the solvent was changed to 2 mL, that is, the volume of the organic solvent was 10 mL / mmol based on the amount of the compound represented by formula (I), the other operations were the same as those in Example 1, 41 mg, and the yield was 82%.

[0054] Embodiment 18

[0055]

[0056] In a tube, 1 mL of THF was added as solvent, and the reaction was placed in a 150°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 of eluent (petroleum ether and ethyl acetate were 250 mL and 5 mL, respectively). (Eluent volume ratio: petroleum ether / ethyl acetate 50:1) The product was obtained as a white solid with a mass of 34 mg and a yield of 85%.

[0057] Characterization data: 1 H NMR (400MHz, CDCl3) δ7.37–7.27(m,7H),6.33–6.32(m,4H),3.18–3.14(m,4H).

[0058] Embodiment 19

[0059]

[0060] Biphenyl-1,10-phenanthroline (14.4 mg, 0.04 mmol) was added to a 25 mL Schlenk tube, 1 mL THF was added as solvent, and the reaction was placed in a 150 ° C oil bath and stirred for 12 hours. 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). (Eluent volume ratio: petroleum ether / ethyl acetate 50:1) The product was obtained as a white solid with a mass of 29 mg and a yield of 85%.

[0061] Characterization data: 1 H NMR (400MHz, CDCl3) δ8.51–8.49(d,J=8.0Hz,1H),7.60–7.58(d,J=8.0Hz,1H),7.50–7.49(d,J=4.0Hz,1H),7.40–7.36(t ,J=8.0Hz,1H),7.32–7.28(m,1H),6.67–6.66(d,J=4.0Hz,1H),3.01–2.96(q,J=1.0Hz,2H),1.40–1.36(t,J=8.0Hz,3H).

[0062] Embodiment 20

[0063]

[0064] 1mmol), 2,9-dimethyl-4,7-biphenyl-1,10-phenanthroline (14.4mg, 0.04mmol) were added to a 25mL Schlenk tube, 1mL THF was added as solvent, and the reaction was placed in a 150℃ oil bath and stirred for 12h. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was purified by column chromatography using about 255mL of eluent (petroleum ether and ethyl acetate were 250mL and 5mL, respectively). (Eluent volume ratio: petroleum ether / ethyl acetate 50:1) The product was obtained as a white solid with a mass of 45mg and a yield of 85%.

[0065] Characterization data: 1 H NMR (400MHz, CDCl3) δ8.24–8.21 (d, J=6.0Hz, 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=2.0Hz,1H),3.19–3.14(m,4H). 13 C NMR (101MHz, CDCl3) δ170.60,162.52,160.13,140.27,135.80,135.67,128.74,128.48,126 .56,124.73,124.70,121.43,121.32,112.05,111.81,108.94,104.25,103.96,37.56,30.39

[0066] Embodiment 21

[0067]

[0068] (14.4 mg, 0.04 mmol) was added to a 25 mL Schlenk tube, 1 mL THF was added as solvent, and the reaction was placed in a 150 ° 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 of eluent (petroleum ether and ethyl acetate were 250 mL and 5 mL, respectively). (Eluent volume ratio: petroleum ether / ethyl acetate 50:1) The product was obtained as a white solid with a mass of 43 mg and a yield of 82%.

[0069] Characterization data: 1 H NMR (400MHz, CDCl3) δ8.49–8.47(d,J=4.0Hz,1H),7.40–7.20(m,8H),3.20–3.18(m,4H),2.28–2.27(d,J=2.0Hz,3H)

Claims

1. A selective hydrogenation reduction method for an α,β-unsaturated amide compound, the specific method being as follows: under a nitrogen atmosphere, an α,β-unsaturated amide compound as shown in formula (I), water, a metal promoter, a ligand, and an organic solvent are mixed and stirred at 110°C to 150°C for 8 to 14 hours for a reduction reaction, and a reaction solution is obtained after the reaction is completed, and the reaction solution is separated and purified by silica gel column chromatography to obtain an α,β-saturated amide compound as shown in formula (II), G is in, In formula (I) or formula (II), R 1 is selected from benzene or hydrogen atom, R in formula G 2 It is selected from CH3 or F, the metal promoter is zinc, the ligand is selected from 2,9-dimethyl-4,7-biphenyl-1,10-phenanthroline, bipyridine or 4,4'-dimethyl-2,2'-bipyridine, and the molar ratio of the compound represented by formula (I), water, zinc and ligand is 1:1~5:3~5:0.1~0.

3.

2. The selective hydrogenation reduction method of an α,β-unsaturated amide compound according to claim 1, characterized in that: The organic solvent is tetrahydrofuran, and the volume of the organic solvent is 5-10 mL / mmol based on the amount of the compound represented by formula (I).

3. The selective hydrogenation reduction method of an α,β-unsaturated amide compound according to claim 1, characterized in that: The molar ratio of the compound represented by formula (I), water, zinc and ligand is 1:5:4:0.

2.

4. The selective hydrogenation reduction method of an α,β-unsaturated amide compound according to claim 1, characterized in that: The ligand is 2,9-dimethyl-4,7-biphenyl-1,10-phenanthroline.

5. The selective hydrogenation reduction method of an α,β-unsaturated amide compound according to claim 1, characterized in that: The reduction reaction temperature is 150° C. and the reaction time is 12 h.

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

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

1.

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

Images