Method for preparing alkylamide

Abstract

The invention relates to a method for preparing alkylamide. Specifically, under the catalytic condition of copper, alkyl olefin and hydroxylamine derivatives are used for preparing alkyl amide by a one-pot method in the atmosphere of carbon monoxide. Starting from simple and easily available raw materials and a cheap catalyst, a series of alkylamides with different functionalities are obtained through carbonylation reaction.

Description

Technical Field

[0001] The invention relates to a method for synthesizing alkyl amide. Background Art

[0002] Amide compounds are commonly found in fine chemicals, natural products, bioactive molecules and polymers. Amides are widely present in our daily lives, especially as important core structures of bioactive compounds and drug molecules. Traditional methods for synthesizing such compounds require the use of stoichiometric coupling reagents or precious metal palladium and rhodium catalysts, and undergo multi-step reactions. However, there are few reports on the one-step synthesis of amide compounds by a multi-component one-pot reaction using a cheap metal-catalyzed carbonylation method.

[0003] Here, we developed a copper-catalyzed one-step method for the synthesis of alkyl amides from the hydroamidation of alkyl olefins. Using readily available alkyl olefins as reaction substrates and carbon monoxide as the carbonyl source, we were able to convert these raw materials into a range of amides with different substituents in high yields and high selectivity under mild conditions.

[0004] In summary, this paper describes a cheap, efficient, and highly regioselective method for the preparation of amide compounds. Summary of the invention

[0005] The present invention is directed to a process for the preparation of alkylamides.

[0006]

[0007] Bz is benzoyl;

[0008] The specific operation steps are as follows (reaction equation 1):

[0009] The reaction is carried out in a high-pressure reactor. The catalyst, ligand, silane, base, alkyl olefin 1, and hydroxylamine derivative 2 are weighed, and the reaction is placed in a carbon monoxide gas atmosphere. The reaction is carried out at an ambient temperature of 40-70° C. (preferably 50-60° C.) for 12-20 hours (preferably 16 hours). After the reaction is completed, amide 4 is separated.

[0010] The amount ratio of alkyl olefin 1 is 0.1-2.5 mmol, preferably 0.3 mmol.

[0011] The amount ratio of hydroxylamine derivative 2 is 0.1-3.0 mmol, preferably 0.2 mmol.

[0012] The catalyst is copper acetate (Cu(OAc)2), cuprous iodide (CuI), cuprous bromide (CuBr), copper bromide (CuBr2), preferably copper acetate (Cu(OAc)2);

[0013] The ligand is one or more of (R)-(-)-5,5'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphine]-4,4'-di-1,3-benzodioxolane, 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (XantPhos), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP), 1,3-bis(diphenylphosphino)propane (dppp), and tricyclohexylphosphine, preferably (R)-(-)-5,5'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphine]-4,4'-di-1,3-benzodioxolane, and the amount of the ligand is 5-50 mol%, preferably 5-10 mol% of the amount of the hydroxylamine derivative 2;

[0014] The gas pressure of carbon monoxide is 5-60 atmospheres, preferably 5-20 atmospheres.

[0015] The base is one or more of cesium fluoride, potassium carbonate, potassium phosphate, sodium carbonate and cesium carbonate, preferably cesium fluoride. The amount of the base is 120 mol%-600 mol%, preferably 200 mol%-400 mol%, based on 2 mol of the hydroxylamine derivative.

[0016] The silane is one or more of dimethylphenylsilane, triethylsilane, diphenylsilane, polymethylhydrogensiloxane, diethoxymethylsilane, and phenylsilane, preferably polymethylhydrogensiloxane, and the amount used is 100mol%-800mol%, preferably 200mol%-400mol%, based on 2 moles of the hydroxylamine derivative.

[0017] The solvent is one or more of dimethylformamide, tetrahydrofuran, trifluorotoluene, dimethyl sulfoxide, 1,4-dioxane, and 1,2-dichloroethane, preferably 1,2-dichloroethane, and the amount used is 1.0 mL.

[0018] The invention starts from simple and readily available raw materials and cheap catalysts, and obtains a series of alkyl amides with different functional groups through carbonylation reaction.

[0019] The present invention has the following advantages:

[0020] Cheap and commercially available alkyl olefins and hydroxylamine derivatives are selected as starting materials, and bulk gas carbon monoxide is used as the carbonyl source. These raw materials are converted into alkyl amide 4 in high yield under the catalysis of cheap metal copper catalyst. The reaction is direct and efficient, with the characteristics of reaction step economy, high regioselectivity, and good compatibility of functional groups in the reaction system. DETAILED DESCRIPTION

[0021] In order to better understand the present invention, the following examples are provided for illustration. The reaction materials and results of Examples 1-10 are shown in Table 1.

[0022]

[0023]

[0024]

[0025]

[0026] Example 1

[0027] The reaction was carried out in a reactor. First, 0.01 mmol of anhydrous copper acetate (5 mol% of the amount of hydroxylamine derivative 2) was added as a catalyst, 0.012 mmol of phosphine ligand (R)-(-)-5,5′-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphine]-4,4′-di-1,3-benzodioxolane (6 mol% of the amount of hydroxylamine derivative 2), cesium fluoride (300 mol% of the amount of hydroxylamine derivative 2a), alkyl olefin 1a (0.3 mmol), hydroxylamine derivative 2a (0.2 mmol), polymethylhydrogensiloxane (0.6 mmol) and solvent 1,2-dichloroethane (1.0 mL) (the total charge amount in the reactor was 18% of the volume of the reactor), and then carbon monoxide gas was added and discharged into the reactor three times, and then 10 bar of carbon monoxide gas was added. The reaction was carried out at 60° C. for 16 hours. After the reaction was completed, compound 4a was separated by column chromatography with a yield of 77%. The structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0028] The test data are as follows:

[0029] 4a: 1 H NMR (400MHz, CDCl3) δ7.26 (dd, J=9.8, 5.1Hz, 2H), 7.21-7.12 (m, 3H), 4.61-4.51 (m, 1H), 3.76 (d, J=13.4Hz, 1H), 2.94 (td, J=13.2, 2.4Hz, 1H), 2. 64 (t, J=6.9Hz, 2H), 2.51 (td, J=12.9, 2.4Hz, 1H), 2.33 (t, J=7.0Hz, 2H) , 1.73-1.53 ​​(m, 7H), 1.05 (dt, J=16.9, 5.5Hz, 2H), 0.93 (d, J=6.4Hz, 3H).

[0030] 13 C NMR (101MHz, CDCl3) δ171.3, 142.3, 128.4, 128.3, 125.7, 46.0, 42.0, 35.8, 34.7, 33.8, 33.4, 31.3, 31.1, 25.1, 21.7.

[0031] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 17 H 26 NO 260.2009; Found: 260.2006.

[0032] Embodiment 2:

[0033] The operation process and conditions were the same as those in Example 1, except that the yield of raw material 1, 4b in Table 1 was 69%, and the structure of the compound was identified by NMR (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0034] 4b: 1 H NMR (400MHz, CDCl3) δ4.67-4.44 (m, 1H), 3.80 (d, J=13.6Hz, 1H), 2.97 (td, J=13.1, 2.5Hz, 1H), 2.51 (td, J=12.8, 2.4Hz, 1H), 2.4 2-2.21 (m, 2H), 1.76-1.51 (m, 5H), 1.31 (dd, J=7.3, 3.7Hz, 4H), 1.15-1.02 (m, 2H), 0.93 (d, J=6.5Hz, 3H), 0.89 (t, J=6.9Hz, 3H).

[0035] 13 C NMR (101MHz, CDCl3) δ171.6, 46.0, 42.0, 34.8, 33.9, 33.5, 31.7, 31.2, 25.2, 22.5, 21.7, 14.0.

[0036] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 12 H 24 NO 198.1852; Found: 198.1851.

[0037] Embodiment 3:

[0038] The operation process and conditions were the same as those in Example 1, except that the yield of raw material 1, 4c in Table 1 was 63%, and the structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0039] 4c: 1H NMR (400MHz, CDCl3) δ4.55 (d, J=13.3Hz, 1H), 3.79 (d, J=13.5Hz, 1H), 2.94 (ddd, J=21.1, 15.6, 5.1Hz, 2H), 2.73 (t, J =4.5Hz, 1H), 2.60-2.42 (m, 2H), 2.32 (t, J = 7.6Hz, 2H), 1.82-1.40 (m, 9H), 1.19-0.99 (m, 2H), 0.93 (d, J = 6.4Hz, 3H).

[0040] 13 C NMR (101MHz, CDCl3) δ171.1, 52.2, 47.1, 46.0, 42.0, 34.7, 33.8, 33.2, 32.3, 31.1, 25.9, 25.2, 21.7.

[0041] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 13 H 24 NO 226.1802; Found: 226.1794.

[0042] Embodiment 4:

[0043] The operation process and conditions were the same as those in Example 1, except that the yield of raw material 1, 4d in Table 1 was 70%, and the structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0044] 4d: 1 H NMR (400MHz, CDCl3) δ4.65-4.50 (m, 1H), 3.79 (d, J=13.6Hz, 1H), 2.96 (td, J=13.1, 2.5Hz, 1H), 2.50 (td, J=12. 8, 2.3Hz, 1H), 2.39-2.23(m, 2H), 1.76-1.58(m, 8H), 1.53-1.44(m, 2H), 1.30-1.01(m, 6H), 0.97-0.81(m, 5H).

[0045] 13 C NMR (101MHz, CDCl3) δ171.9, 46.0, 42.0, 37.6, 34.8, 33.8, 33.2, 33.0, 31.1, 31.1, 26.6, 26.3, 21.7.

[0046] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C15 H 28 NO 238.2165; Found: 238.2159.

[0047] Embodiment 5:

[0048] The operation process and conditions were the same as those in Example 1, except that the yield of raw material 2, 4e in Table 1 was 78%, and the structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0049] 4e: 1 H NMR (400MHz, CDCl3) δ7.25 (d, J=7.1Hz, 2H), 7.17 (d, J=7.6Hz, 3H), 3.58-3.48 (m, 2H), 3.41-3.25 ( m, 2H), 2.64 (t, J=6.9Hz, 2H), 2.38-2.25 (m, 2H), 1.72-1.57 (m, 6H), 1.51 (dd, J=10.8, 5.6Hz, 4H).

[0050] 13 C NMR (101MHz, CDCl3) δ171.2, 142.3, 128.4, 128.3, 125.7, 46.7, 42.6, 35.8, 33.3, 31.3, 26.6, 25.6, 25.1, 24.6.

[0051] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 16 H 24 NO 246.1852; Found: 246.1860.

[0052] Embodiment 6:

[0053] The operation process and conditions were the same as those in Example 1, except that the yield of the raw material 2, 4f in Table 1 was 67%, and the structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0054] 4f: 1 H NMR (400MHz, CDCl3) δ7.27 (dd, J=9.2, 5.6Hz, 2H), 7.23-7.11 (m, 3H), 3.63 (dd, J=10.7, 4. 6Hz, 6H), 3.52-3.33 (m, 2H), 2.65 (t, J=6.8Hz, 2H), 2.41-2.24 (m, 2H), 1.72-1.61 (m, 4H).

[0055] 13C NMR (101MHz, CDCl3) δ171.6, 142.2, 128.4, 128.3, 125.8, 67.0, 66.7, 46.0, 41.9, 35.7, 33.0, 31.1, 24.8.

[0056] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 15 H 22 NO2248.1645; Found: 248.1648.

[0057] Embodiment 7:

[0058] The operation process and conditions are the same as those of Example 1, except that the yield of 4 g of raw material 2 in Table 1 is 70%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0059] 4g: 1 H NMR (400MHz, CDCl3) δ7.31-7.23 (m, 2H), 7.22-7.14 (m, 3H), 4.76 (d, J=7.5Hz, 1H), 4.04 (s, 1H), 2.63 (dd, J=15.3, 8.8Hz, 2H), 2.51-2.18 (m, 2H), 1.93-1.08 (m, 17H).

[0060] 13 C NMR (101MHz, CDCl3) δ172.1, 142.5, 128.4, 128.3, 125.7, 35.9, 33.4, 31.4, 25.3, 13.9.

[0061] HRMS (ESI-TOF) m / z: [M+K] + Calcd for C 18 H 27 NOK 312.1724; Found: 312.1723.

[0062] Embodiment 8:

[0063] The operation process and conditions are the same as those in Example 1, except that the raw materials 1 and 2 in Table 1 have a 4h yield of 62%, and the compounds are identified by NMR (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0064] 4h: 1H NMR (400MHz, CDCl3) δ8.07 (d, J=8.3Hz, 1H), 7.93-7.80 (m, 1H), 7.72 (d, J=8.1Hz, 1H), 7.55-7.43(m, 2H), 7.41-7.36(m, 1H), 7.31(d, J=6.8Hz, 1H), 5.25(d, J=6.7H z, 1H), 3.87-3.70 (m, 1H), 3.17-3.04 (m, 2H), 2.21 (t, J=7.3Hz, 2H), 2.15-2.03 (m , 2H), 1.99-1.85(m, 2H), 1.75-1.57(m, 3H), 1.46-1.29(m, 2H), 1.18-1.06(m, 2H).

[0065] 13 C NMR (101MHz, CDCl3) δ171.6, 137.8, 133.9, 131.9, 128.8, 126.8, 126.2, 125.9, 125.5, 125.5, 123.9, 48.1, 36.4, 33.3, 32.4, 26.6, 25.6, 24.9.

[0066] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 20 H 25 NO 296.2009; Found: 296.2007.

[0067] Embodiment 9:

[0068] The operation process and conditions were the same as those in Example 1, except that the yield of raw material 1, 4i in Table 1 was 54%, and the structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0069] 4i: 1 H NMR (400MHz, CDCl3) δ4.58 (d, J=13.3Hz, 1H), 3.84 (d, J=13.4Hz, 1H), 3.02-2.90 (m, 1H), 2.58-2.43 (m, 2H), 1.95 (q, J=11.1Hz, 4H), 1.70-1.45 (m, 16H), 1.17-1.01 (m, 2H), 0.94 (d, J=6.4Hz, 3H), 0.83 (d, J=6.8Hz, 3H).

[0070] 13C NMR (101MHz, CDCl3) δ172.1, 46.2, 46.2, 42.2, 42.1, 40.4, 39.9, 39.3, 37.3, 34.9, 34.8, 34.4, 34.2, 33.9, 33.8, 31.1, 28.7, 21.8, 13.3, 13.1.

[0071] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 20 H 34 NO 304.2635; Found: 304.2639.

[0072] Embodiment 10:

[0073] The operation process and conditions were the same as those in Example 1, except that the yield of raw materials 1, 4j in Table 1 was 63%, and the structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0074] 4j: 1 H NMR (400MHz, CDCl3, mixture of rotamers) δ7.54-7.43(m, 2H), 7.37-7.03(m, 8H), 4.68-4.25(m, 2H), 2.85(d, J=50.4Hz, 3H), 2.47-2.28(m, 1H), 2.24-2.01 (m, 1H), 1.55 (ddd, J=10.9, 7.3, 3.6Hz, 1H), 1.01 (dd, J=16.5, 7.3Hz, 3H), 0.39-0.18 (m, 6H).

[0075] 13 C NMR (101MHz, CDCl3, mixture of rotarners) δ173.4, 173.1, 137.7, 137.6, 136.9, 1334.0, 133.9, 129.1, 129.0, 128.9, 128.6, 128.1, 127.8 , 127.8, 127.5, 127.3, 126.4, 53.4, 50.9, 35.4, 35.2, 34.8, 34.2, 16.2, 15.3, 14.7, 13.9, -4.7, -5.3, -5.4.

[0076] HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 20 H 27 NOSiNa 348.1754; Found: 348.1755.

[0077] Embodiment 11:

[0078] The operation process and conditions are the same as those in Example 1, except that the raw material 1 and raw material 2 in Table 1 have a 4k yield of 72%, and the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0079] Product application examples:

[0080] Product 4k It has been shown to have important biological activities.

[0081] 1. DAINIHON JOCHUGIKU CO., LTD.-JP2018 / 48084, 2018, A.

[0082] 2.Science, 2020, 369, 970-974.

[0083] 3. Angew.Chem.Int.Ed., 2013, 52, 2231-2234.

[0084] 4.Chem.Sci., 2016, 7, 969-975.

[0085] Comparative Example 1

[0086] The reaction process and conditions are the same as those of Example 1 except that when the carbon monoxide gas pressure is changed to 3 bar (gauge pressure), the yield of the product of Example 1 is 31%;

[0087] Comparative Example 2

[0088] The reaction process and conditions are the same as those in Example 1 except that when the carbon monoxide gas pressure is 65 bar (gauge pressure), the yield of the product in Example 1 is 12%.

[0089] Comparative Example 3

[0090] The reaction process and conditions are the same as those of Example 1 except that when the reaction temperature is changed to 30° C., the yield of the product of Example 1 is 15%;

[0091] Comparative Example 4

[0092] The reaction process and conditions are the same as those in Example 1 except that when the reaction temperature is 80° C., the yield of the product in Example 1 is 30%.

[0093] Comparative Example 5

[0094] The reaction process and conditions are the same as those in Example 1 except that when the reaction time is changed to 5 hours, the yield of the product in Example 1 is 48%; (short reaction time means incomplete reaction)

[0095] Comparative Example 6

[0096] The reaction process and conditions are the same as those in Example 1 except that when the reaction time is 40 hours, the yield of the product in Example 1 is 76%.

[0097] Comparative Example 7

[0098] The reaction process and conditions are the same as those in Example 1 except that when the copper catalyst is replaced by copper oxide, the yield of the product in Example 1 is 6%.

[0099] Comparative Example 8

[0100] The reaction process and conditions are the same as those in Example 1 except that when cesium fluoride is replaced by lithium tert-butoxide, the yield of the product in Example 1 is 5%.

[0101] Example 9

[0102] The reaction process and conditions are the same as those of Example 1, except that when the polymethylhydrogensiloxane is replaced by triethoxysilane, the yield of the product of Example 1 is 5%.

[0103] Example 10

[0104] The reaction process and conditions are the same as those of Example 1, except that when 1,2-dichloroethane is replaced by ethyl acetate, the yield of the product of Example 1 is 13%.

Claims

1. A method for preparing an alkylamide, characterized in that: The reaction formula for generating different substituted alkyl amides 4 using alkyl olefins 1, hydroxylamine derivatives 2, and carbon monoxide 3 as raw materials is as follows: R' is one to five of C1-C20 alkyl, cyclohexyl, 2-adamantyl, dimethylphenylsilyl, 1-naphthylethyl, oxirane, monochloro C1-C20 alkyl (e.g. monochlorohexyl), phenylbenzyl, and phenylbutyl, preferably 1 to 3; R is a C1-C20 alkyl group or hydrogen, preferably including hydrogen and / or methyl; Formula 2 is a hydroxylamine derivative, wherein R 1 , R 2 are each independently one to five of benzyl, cyclohexyl, hydrogen, phenyl, tert-butyl, and ethyl, or R 1 , R 2 and the N connected to them together form the piperidinyl or a piperidinyl group having a substituent, or The substituents on the piperidinyl group are C1-C10 alkyl groups, preferably one to four of methyl, ethyl, propyl and butyl groups.

2. The method for preparing an alkylamide according to claim 1, characterized in that: The specific steps are as follows: The reaction is carried out in a high-pressure reactor. The copper catalyst, ligand, base, alkyl olefin 1, hydroxylamine derivative 2, silane and solvent are weighed into the high-pressure reactor. The atmosphere in the reactor is placed in a carbon monoxide 3 gas atmosphere. The reaction is carried out at an ambient temperature of 40-70° C. (preferably 50-60° C.) for 12-20 hours (preferably 16-18 hours). After the reaction is completed, amide 4 is separated.

3. The method according to claim 2, characterized in that: The copper catalyst is copper acetate (Cu(OAc)2), cuprous iodide (CuI), cuprous bromide (CuBr), copper bromide (CuBr2), preferably copper acetate, and the amount of the catalyst used is 1-20 mol%, preferably 5-10 mol% of the amount of the hydroxylamine derivative 2.

4. The method according to claim 2, characterized in that: Ligand It is one or more of (R)-(-)-5,5'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphine]-4,4'-di-1,3-benzodioxolane (R-DTBM-Segphos), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthene (XantPhos), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP), 1,3-bis(diphenylphosphino)propane (dppp), and tricyclohexylphosphine, preferably (R)-(-)-5,5'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphine]-4,4'-di-1,3-benzodioxolane, and the amount of the ligand used is 5-50 mol%, preferably 5-10 mol% of the amount of the hydroxylamine derivative 2.

5. The method according to claim 2, characterized in that: The base is one or more of cesium fluoride, potassium carbonate, potassium phosphate, sodium carbonate and cesium carbonate, preferably cesium fluoride. The amount of the base is 120mol%-600mol%, preferably 200mol%-400mol% based on 2 moles of the hydroxylamine derivative.

6. The method according to claim 2, characterized in that: The gas pressure of carbon monoxide is 5 to 60 atmospheres, preferably 5 to 20 atmospheres.

7. The method according to claim 2, characterized in that: The silane is one or more of dimethylphenylsilane, triethylsilane, diphenylsilane, polymethylhydrogensiloxane, diethoxymethylsilane, and phenylsilane, preferably polymethylhydrogensiloxane, and the amount used is 100mol%-800mol%, preferably 200mol%-400mol%, based on 2 moles of the hydroxylamine derivative.

8. The method according to claim 2, characterized in that: The solvent is one or more of dimethylformamide, tetrahydrofuran, trifluorotoluene, dimethyl sulfoxide, 1,4-dioxane, and 1,2-dichloroethane, preferably 1,2-dichloroethane. The amount of the solvent used per 0.2 mmol of the hydroxylamine derivative 2 is 0.5-5 mL, preferably 1-2 mL.

9. The method according to claim 2, characterized in that: The amount of the alkyl olefin 1 is 100 mol% to 500 mol%, preferably 120 mol% to 200 mol%, of the amount of the hydroxylamine derivative 2.

10. The method according to claim 2, characterized in that: The total loading amount of the copper catalyst, the ligand, the base, the alkyl olefin 1, the hydroxylamine derivative 2, the silane and the solvent in the reaction kettle is 70% or less of the volume of the reaction kettle.

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