A method of palladium catalyzed azlactone trans-prenylation

Abstract

The present application relates to a kind of palladium catalytic ligand regulated azlactone retroisoprenylation method. Specifically, azlactone compound and isoprene react under the action of zero-valent palladium catalyst and monophosphine ligand, and retroisoprenylation product is obtained. A series of azlactone retroisoprenylation derivatives are obtained by simple and safe steps in the present application.

Description

Technical Field

[0001] This invention relates to a palladium-catalyzed method for the de-isopentylation of acrylonitrile. Background Technology

[0002] Modified peptides not only open a pathway for studying various biological phenomena but also provide opportunities for lead drug discovery. The quaternary carbon center of α-quaternary amino acids plays a crucial role in the synthesis of modified peptides because it can restrict conformational flexibility and improve drug pharmacokinetic properties. Therefore, the rapid assembly of quaternary α-alkyl amino acids has become an active research area. Acetyl lactones can be considered effective amino acid precursors in organic synthesis. While significant progress has been made in the synthesis of α-quaternary amino acids via the allylation strategy of transition metal-catalyzed acrylolides, exploration of the catalytic anti-isopentenylation of acrylolides is still limited. Considering that the anti-isopentenyl group can increase lipophilicity and binding affinity to biological membranes, it can not only introduce conformational restriction but also significantly enhance biological activity. Therefore, introducing this unique group onto the α-carbon of amino acids is highly significant. Acetyl lactones can be ring-opened in either acidic or basic conditions to yield amino acids or amino acid esters in a single step, making them excellent amino acid precursors.

[0003] Based on this, we report a palladium-catalyzed ligand-regulated coupling of acrylonitrile with isoprene. This reaction is primarily catalyzed by a metal hydride, converting isoprene into a π-isopentenyl metal species. Subsequently, the nucleophilic attack of the acrylonitrile can be controlled by the catalyst to provide the anti-isopentenylated product. This method can be used to construct a series of anti-isopentenylated acrylonitrile compounds. The reaction scheme produces no stoichiometric byproducts and exhibits excellent regioselectivity, broad functional group tolerance, and mild reaction conditions.

[0004] Compared to traditional isopentenylation of acrylonitrile, the raw materials used in this invention are inexpensive and readily available, the conditions are mild and easy to operate, and the target product can be obtained in one step with excellent regioselectivity. This enriches the synthetic methods for α-trans-isopentenyl amino acids and provides a new approach for the diversification of drug molecules.

[0005] In summary, this paper describes a simple and mild method for the de-isopentenylation of acrylonitrile. Summary of the Invention

[0006] The purpose of this invention is to provide a palladium-catalyzed method for the de-isopentylation of acrylonitrile.

[0007]

[0008] Reaction Equation 1: Method for the de-isopentenylation of acrylonitrile

[0009] The specific steps are as follows:

[0010] Under an inert atmosphere, palladium catalyst, monoligand, acrylonitrile, isoprene, and solvent were added sequentially, and the reaction was carried out at 40-60°C for 12-24 hours. After the reaction was completed, the trans-isoprenyl acrylonitrile derivative was isolated.

[0011] The acrylonitrile compounds include one of 2-aryl acrylonitrile to 2-alkyl acrylonitrile; wherein the 2-alkyl acrylonitrile has a specific structure of one or more of the following structural formulas:

[0012]

[0013] The preferred molar ratio of acrylonitrile to isoprene is 1.0:3.0.

[0014] The palladium catalyst used is tris(dibenzylideneacetone)dipalladium, and the amount of palladium catalyst used is 1-5% molar equivalent (relative to the acrylonitrile compound), preferably 1-2.5% molar equivalent.

[0015] The solvent may be changed to one or more of toluene, n-hexane, dichloromethane, N-methylpyrrolidone, tetrahydrofuran, 1,4-dioxane, and ethyl acetate; preferably one or more of toluene and n-hexane, and the amount of solvent used is 0.1-1.0 mL per millimole of acrylonitrile compound, preferably 0.5 mL.

[0016] The ligand is a monophosphine ligand, one or more of the compounds shown in the structures L1, L2, L3, L4, and L5 below; preferably L2; the amount of the monoligand is 5-30% molar equivalent (relative to the acrylonitrile compound), preferably 10%-20% molar equivalent;

[0017]

[0018] Acetyl lactones react with isoprene in the presence of palladium catalyst and monophosphine ligand to yield anti-isoprenylated products.

[0019] The present invention has the following advantages:

[0020] First, the reactants, acrylonitrile and isoprene, are both simple and readily available. Second, the reaction conditions are mild and safe, and the reaction steps are concise and efficient. Finally, the obtained product is a novel type of anti-isoprenylated acrylonitrile with excellent yield and selectivity. Detailed Implementation

[0021] To better understand the present invention, the following examples are provided for illustration. The reaction raw materials and results of Examples 1-16 are shown in Table 1. Among them, 3a is a known product.

[0022]

[0023] Table 1. Reaction results of different acrylonitrile compounds

[0024]

[0025]

[0026]

[0027] As can be seen from the results in Table 1, different acrylonitriles can be converted into trans-isoprenyl acrylonitrile derivatives with medium to high yields and high regioselectivity under palladium catalysis.

[0028] Example 1

[0029] The reaction was carried out in a reactor under a nitrogen atmosphere by sequentially adding palladium catalyst Pd2dba3 (0.005 mmol, tris(dibenzylacetone)dipalladium), monophosphine ligand L2 (0.02 mmol), and tert-butanol (0.5 mL), and stirring at room temperature for 20 minutes. Then, acrylonitrile 1a (0.20 mmol) and isoprene (0.60 mmol) were added to the reaction system, and the reaction was carried out at 40 °C for 24 hours. After the reaction was completed, column chromatography was used to separate the acrylonitrile trans-isoprenylated derivative 3a in 79% yield. The structure of the compound was identified by NMR (1H, 1C, and fluorine spectra) and high-resolution mass spectrometry.

[0030] 7.45(m,2H),6.06(dd,J=17.7,10.5Hz,1H),5.16–5.10(m,2H),1.45(s,3H),1.20(s,3H),1.17(s,3H). 13 HRMS calculated for C 15 H 18 NO2[M+H] + 244.1332, found 244.1336.

[0031] Example 2:

[0032] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the acrylonitrile compounds described in Table 1 were different. The yield of product 3b was 78%. The structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0033] (m,1H),7.51–7.46(m,2H),6.07(dd,J=17.3,11.0Hz,1H),5.14–5.10(m,2H),1.92–1.88(m, 2H),1.19(s,3H),1.17(s,3H),1.16–1.11(m,1H),1.04–0.95(m,1H),0.87(t,J=7.3Hz,3H). 13 HRMS calculated for C 17 H 22 NO2[M+H] + 272.1645, found 272.1644.

[0034] Example 3:

[0035] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the acrylonitrile compounds described in Table 1 were different. The 3C yield of the product was 69%. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0036] (m,1H),7.53–7.45(m,2H),6.06(dd,J=17.3,11.0Hz,1H),5.15–5.07(m,2H),1.96(dd,J=13.9,5.5Hz,1H),1.81( dd,J=13.9,7.1Hz,1H),1.50–1.38(m,1H),1.17(s,3H),1.13(s,3H),0.86(d,J=6.7Hz,3H),0.79(d,J=6.6Hz,3H). 13 HRMS calculated for C 18 H 24 NO2[M+H] + 286.1802, found286.1802.

[0037] Example 4:

[0038] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the acrylonitrile compounds described in Table 1 were different. The 3-day yield of the product was 83%. The structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0039]

[0040] (m,1H),7.41–7.34(m,2H),7.11–7.02(m,5H),6.22(dd,J=17.8,10.6Hz,1H),5.23–5.16(m,2H),3.20(s,2H),1.29(s,3H),1.26(s,3H). 13 C NMR(100MHz,Chloroform-d)δ178.8,159.6,142.6,134.9,132.4,130.5,128.7,128.1,127.8,127.0,126.0,114.7,79.7,43.2,38.8,22.2,22.0.HRMS calculated for C 21 H 22 NO2[M+H] + 320.1645, found 320.1645.

[0041] Example 5:

[0042] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the acrylonitrile compounds described in Table 1 were different. The yield of product 3e was 77%. The structure of the compound was identified by NMR (H1N, C1N and fluorine spectra) and high-resolution mass spectrometry.

[0043]

[0044] 7.55(m,1H),7.52–7.47(m,2H),6.06(dd,J=17.2,11.0Hz,1H),5.16–5.10(m,2H),2.37–2 .30(m,1H),2.27–2.22(m,2H),2.22–2.14(m,1H),2.03(s,3H),1.19(s,3H),1.16(s,3H). 13 HRMS calculated for C 17 H22 NO2S[M+H] + 304.1366, found 304.1366.

[0045] Example 6:

[0046] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the acrylonitrile compounds described in Table 1 were different. The yield of product 3f was 63%. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0047]

[0048] NMR(400MHz,Chloroform-d)δ8.04–7.98(m,2H),7.61–7.54(m,1H),7.52–7.45(m,2H),5.93(dd,J=17.5,10.7 Hz,1H),5.13(dd,J=17.4,1.0Hz,1H),5.11(dd,J=10.7,0.9Hz,1H),4.16(s,1H),1.295(s,3H),1.291(s,3H). 13 HRMScalculated for C 14 H 16 NO2[M+H] + 230.1176, found 230.1175.

[0049] Example 7:

[0050] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the acrylonitrile compounds described in Table 1 were different. The yield of the product was 63% (3g). The structure of the compound was identified by NMR (H1N, C1N, and fluorine spectra) and high-resolution mass spectrometry.

[0051]

[0052] 7.05–6.99(m,2H),6.87(d,J=2.4Hz,1H),6.28(dd,J=17.8,10.5Hz,1H),5.25–5.18(m,2H),3.46–3.31(m,2H),1.32(s,3H),1.31(s,3H). 13C NMR(100MHz,Chloroform-d)δ179.5,159.7,142.8,135.7,132.2,128.5,127.92,127.87,1 26.0,123.7,121.8,119.8,119.4,114.5,110.8,109.2,80.4,43.0,28.4,22.3,22.2.HRMS calculated for C 23 H 23 N₂O₂[M+H] + 359.1754, found 359.1755.

[0053] Example 8:

[0054] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the acrylonitrile compound described in Table 1 was different. The product yield was 76% after 3 hours. The structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0055]

[0056] 8.0Hz,1H),7.11(dd,J=8.3,2.5Hz,1H),6.06(dd,J=17.8,10.5Hz,1H),5.17–5.09(m,2H),3.87(s,3H),1.45(s,3H),1.20(s,3H),1.17(s,3H). 13 HRMS calculated for C 16 H 20 NO3[M+H] + 274.1438, found 274.1440.

[0057] Example 9:

[0058] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the acrylonitrile compounds described in Table 1 were different. The yield of product 3i was 80%. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0059] 3i7.31–7.26(m,2H),6.06(dd,J=17.8,10.5Hz,1H),5.15–5.09(m,2H),2.42(s,3H),1.44(s,3H),1.19(s,3H),1.16(s,3H). 13 HRMS calculated for C 16 H 20 NO2[M+H]+258.1489,found 258.1487.

[0060] Example 10:

[0061] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the acrylonitrile compounds described in Table 1 were different. The yield of product 3j was 80%. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0062] –5.09(m,2H),2.42(s,3H),1.45(s,3H),1.20(s,3H),1.17(s,3H). 13 HRMS calculated for C 16 H 20 NO2[M+H] + 258.1489, found258.1489.

[0063] Example 11:

[0064] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the acrylonitrile compounds described in Table 1 were different. The yield of product 3k was 85%. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0065] 2H),3.96(s,3H),1.47(s,3H),1.20(s,3H),1.18(s,3H). 13HRMS calculated for C 17 H 20 NO4[M+H] + 302.1387, found 302.1384.

[0066] Example 12:

[0067] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the acrylonitrile compounds described in Table 1 were different. The yield of product 31 was 73%. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0068]

[0069] 5.11(m,2H),1.47(s,3H),1.21(s,3H),1.19(s,3H). 13 C NMR(100MHz,Chloroform-d)δ179.7,161.4(d,J=260.4Hz),156.7(d,J=5.3Hz),142.1,134.2(d,J=8.7Hz), 130.7, 124.4 (d, J = 3.9Hz), 117.2 (d, J = 21.1Hz), 114.9, 114.7 (d, J = 10.1Hz), 74.1, 42.8, 21.7, 21.6, 19.7. 19 F NMR(375MHz,Chloroform-d)δ-108.7.HRMS calculated for C 15 H 17 FNO2[M+H] + 262.1238, found 262.1239.

[0070] Example 13:

[0071] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the acrylonitrile compounds described in Table 1 were different. The product 3m yield was 76%. The structure of the compound was identified by NMR (H1N, C1N and fluorine spectra) and high-resolution mass spectrometry.

[0072]

[0073] 1H),7.55–7.52(m,1H),7.43(t,J=7.9Hz,1H),6.03(dd,J=17.2,11.1Hz,1H),5.16–5.11(m,2H),1.45(s,3H),1.20(s,3H),1.17(s,3H). 13 HRMS calculated for C 15 H 17 ClNO2[M+H] + 278.0942, found 278.0943.

[0074] Example 14:

[0075] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the acrylonitrile compounds described in Table 1 were different. The yield of product 3n was 74%. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0076]

[0077] 6.02(dd,J=17.8,10.5Hz,1H),5.18–5.10(m,2H),1.47(s,3H),1.21(s,3H),1.18(s,3H). 13 C NMR(100MHz,Chloroform-d)δ179.5,158.7,142.0,134.3(q,J=32.8Hz),134.1,129.5, 128.4, 125.9 (q, J = 3.8Hz), 123.7 (q, J = 272.6Hz), 115.0, 74.7, 42.9, 21.7, 21.6, 19.7. 19 F NMR(375MHz,Chloroform-d)δ-63.2.HRMS calculated for C 16 H 17 F3NO2[M+H] + 321.1206, found 312.1209.

[0078] Example 15:

[0079] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that, except for the different acrylonitrile compounds described in Table 1, the yield of product 3O was 59%. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0080]

[0081] 7.70–7.62(m,1H),7.60–7.50(m,2H),6.15(dd,J=17.4,10.9Hz,1H),5.22–5.14(m,2H),1.54(s,3H),1.28(s,3H),1.26(s,3H). 13 C NMR(100MHz,Chloroform-d)δ179.8,159.5,142.4,134.0,133.5,131.0,130.2,12 8.9,128.3,126.6,126.2,124.8,121.9,114.8,75.0,42.9,21.9,21.8,20.0.HRMS calculated for C 19 H 20 NO2[M+H] + 294.1489, found 294.1491.

[0082] Example 16:

[0083] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the acrylonitrile ring compounds described in Table 1 were different. The 3p yield of the product was 75%. The structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0084]

[0085] (dd,J=17.9,10.4Hz,1H),5.17–5.10(m,2H),1.46(s,3H),1.20(s,3H),1.18(s,3H). 13 CNMR(100MHz,Chloroform-d)δ178.9,152.0,146.8,142.0,141.0,116.9,114.9,112.1,73.8,42.8,21.64,21.63,19.9.HRMS calculated for C 13 H 16 NO3[M+H] + 234.1125, found 234.1127.

[0086] Comparative Example 1:

[0087] The raw materials, operating procedures and conditions were the same as in Example 1, except that no palladium catalyst was added and product 3a was not obtained.

[0088] Comparative Example 2:

[0089] The raw materials, operating procedures and conditions were the same as in Example 1, except that ligand L2 was not added and product 3a was not obtained.

[0090] Comparative Example 3:

[0091] The raw materials, operating procedures and conditions were the same as in Example 1, except that the ligand was replaced with tribenzylphosphine, and product 3a was obtained in a yield of 45%.

[0092] Comparative Example 4:

[0093] The raw materials, operating procedures and conditions were the same as in Example 1, except that the ligand was replaced with dppe (1,2-bis(diphenylphosphine)ethane), and product 3a was obtained in a yield of 4%.

[0094] Comparative Example 5:

[0095] The raw materials, operating procedures and conditions were the same as in Example 1, except that the palladium catalyst was replaced with Pd(OAc)2, and product 3a was not obtained.

Claims

1. A palladium-catalyzed method for the de-isopentenylation of acrylonitrile, characterized in that: Using acrylonitrile 1 and isoprene as raw materials, a reverse isoprene-modified acrylonitrile derivative 3 was generated in a solvent under the action of palladium catalyst and monophosphine ligand; The reaction formula is as follows: ； Acetyl lactone 1: ； The structural formula of the anti-isoprenylated acrylonitrile derivative 3 is as follows: The substituent R in acrylonitrile 1 or trans-isoprenylated acrylonitrile derivative 3 1 It is one of phenyl, benzyl, biphenyl, 2-methylphenyl, 3-methoxyphenyl, 4-methylphenyl, 3-methylphenyl, 3-tert-butylphenyl, 2-fluorophenyl, 3-chlorophenyl, 4-trifluoromethylphenyl, 3-nitrophenyl, 1-naphthyl, 2-furanyl, 2-esterylphenyl, and 4-esterylphenyl; R 2 It is one of methyl, n-butyl, isobutyl, tert-butyl, n-propyl, benzyl, cyclopropyl, ethyl methylthio, methylene indolyl, hydrogen, phenyl, 2-chlorophenyl, 2-methylphenyl, 3-methoxyphenyl, 2-furanyl, and 2-esterylphenyl; The monophosphine ligand is L2 as described below; ; The palladium catalyst used was tris(dibenzylacetone)dipalladium.

2. The method according to claim 1, characterized in that: Acetyl lactone 1 includes compounds with the following structural formulas: 。 3. The method according to claim 1, characterized in that: The specific steps are as follows: The reaction was carried out in a reactor under an inert atmosphere by sequentially adding palladium catalyst, monophosphine ligand, and solvent, and stirring at 20-80 °C for 10-30 minutes. Then, acrylonitrile and isoprene were added to the reaction system, and the reaction was carried out at 40-90 °C for 12-24 hours. After the reaction was completed, the acrylonitrile anti-isoprenylated derivative was isolated.

4. The method according to claim 3, characterized in that: The molar ratio of acrylonitrile to isoprene is 1.0:1.0-1.0:6.

0.

5. The method according to claim 3, characterized in that: The amount of palladium catalyst relative to the acrylonitrile compound is 1-5% molar equivalent.

6. The method according to claim 3, characterized in that: The solvent is one or more of the following: tert-butanol, toluene, n-hexane, dichloromethane, N-methylpyrrolidone, tetrahydrofuran, 1,4-dioxane, and ethyl acetate; The amount of solvent used is 0.1-2.0 mL per 0.20 mmol acrylonitrile compound.

7. The method according to claim 1, 2, or 3, characterized in that: The amount of monophosphine ligand relative to the acrylonitrile compound is 5-30% molar equivalent.

8. The method according to claim 3, characterized in that: The inert atmosphere is either argon or nitrogen.

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