Palladium-catalyzed azlactone anti-isopentenylation method

Abstract

The invention relates to a method for anti-isopentenylation of azlactone regulated and controlled by a palladium catalytic ligand. Specifically, an azlactone compound reacts with isoprene under the action of a zero-valent palladium catalyst and a monophosphine ligand to obtain a trans-isopentenylation product. A series of azlactone anti-isopentenylation derivatives are obtained through simple and safe steps.

Description

Technical Field

[0001] The present invention relates to a palladium-catalyzed method for the transprenylation of azlactones. Background Art

[0002] Modified peptides not only open up a way to study different biological phenomena, but also provide opportunities for the discovery of lead drugs. Because the quaternary carbon center of α-quaternary amino acids can restrict conformational flexibility and improve pharmacokinetic properties, it plays an important role in the synthesis of modified peptides. Therefore, the rapid assembly of quaternary α-alkyl amino acids has become an active research field. Azlactones can be regarded as effective amino acid precursors in organic synthesis. Although great progress has been made in the synthesis of α-quaternary amino acids through the strategy of transition metal-catalyzed allylation of azlactones, there is still little exploration of catalytic transprenylation of azlactones. Considering that the transprenylation group can increase the lipophilicity and binding affinity to biological membranes, it can not only introduce conformational restrictions, but also significantly enhance the biological activity. Therefore, it is very meaningful to introduce this unique group on the α carbon of amino acids. Azlactones can be opened in one step under acidic or alkaline conditions to obtain amino acids or amino acid esters, respectively, and are a good amino acid precursor.

[0003] Based on this, we report a palladium-catalyzed ligand-regulated coupling of azlactones with isoprene. The reaction is mainly catalyzed by metal hydrides. Isoprene can be converted into π-isopentenyl metal species, and then the nucleophilic attack of azlactone can be controlled by catalyst regulation to provide trans-isopentenylated products. This method can be used to construct a series of trans-isopentenylated azlactone compounds. The reaction scheme does not produce equivalent by-products and has excellent regioselectivity, broad functional group tolerance and mild reaction conditions.

[0004] Compared with the traditional azlactone prenylation, the raw materials used in the present invention are cheap and easy to obtain, the conditions are mild and easy to operate, the target product can be obtained in one step, and the product has excellent regional selectivity. The synthesis method of α-transisopentenyl amino acids is enriched, and a new method is provided for the diversity of drug molecules.

[0005] In summary, this paper describes a novel method for the transprenylation of azlactones using simple steps and mild conditions. Summary of the invention

[0006] The object of the present invention is to provide a method for the palladium-catalyzed transprenylation of azlactones.

[0007]

[0008] Reaction Scheme 1: Method for transprenylation of azlactone

[0009] The specific steps are as follows:

[0010] Under the protection of an inert atmosphere, a palladium catalyst, a single ligand, azlactone, isoprene and a solvent are added in sequence, and the reaction is carried out at 40-60° C. for 12-24 hours. After the reaction is completed, a trans-isopentenyl azlactone derivative is separated and obtained.

[0011] The azlactone compound includes one of 2-aryl azlactone to 2-alkyl azlactone; wherein the specific structure of 2-alkyl azlactone is one or more of the following structural formulas:

[0012]

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

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

[0015] The solvent is changed to one or more of toluene, n-hexane, dichloromethane, nitrogen methyl pyrrolidone, tetrahydrofuran, 1,4-dioxane, and ethyl acetate; preferably one or more of toluene and n-hexane. The amount of the solvent is 0.1-1.0 ml per mmol of the azlactone compound, preferably 0.5 ml.

[0016] The ligand is a monophosphine ligand, one or more of the compounds represented by the following structures L1, L2, L3, L4, and L5; preferably L2; the amount of the single ligand is 5-30% molar equivalent (relative to the azlactone compound), preferably 10%-20% molar equivalent;

[0017]

[0018] Azlactone compounds react with isoprene in the presence of a palladium catalyst and a monophosphine ligand to obtain a trans-isoprenylation product.

[0019] The present invention has the following advantages:

[0020] Firstly, the reaction raw materials azlactone and isoprene are simple and easily available. Secondly, the reaction conditions are mild and safe, and the reaction steps are simple and efficient. Finally, the obtained product is a novel trans-isoprenylated azlactone with excellent yield and selectivity. DETAILED DESCRIPTION

[0021] In order to better understand the present invention, the following examples are used for illustration. The reaction 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 azlactone compounds

[0024]

[0025]

[0026]

[0027] It can be seen from the results in Table 1 that different azlactones can be converted into trans-isopentenyl azlactone derivatives with medium to high yields and high regioselectivity with isoprene under the catalysis of palladium.

[0028] Example 1

[0029] The reaction was carried out in a reactor. Palladium catalyst Pd2dba3 (0.005 mmol, tri(dibenzylideneacetone)dipalladium), monophosphine ligand L2 (0.02 mmol), and tert-butanol (0.5 mL) were added in sequence under nitrogen atmosphere, and stirred at room temperature for 20 minutes. Azlactone 1a (0.20 mmol) and isoprene (0.60 mmol) were added to the reaction system, and the reaction time was 24 hours at 40°C. After the reaction, the azlactone trans-isoprenyl derivative 3a was obtained by column chromatography with a yield of 79%. The compound was identified by nuclear magnetic resonance (hydrogen spectrum, carbon spectrum and fluorine spectrum) 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] Embodiment 2:

[0032] The operation process and conditions were the same as those in Example 1, except that the azlactone compound described in Table 1 was different. The yield of product 3b was 78%, and the compound was identified by NMR (hydrogen spectrum and carbon spectrum) 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] Embodiment 3:

[0035] The operation process and conditions were the same as those in Example 1, except that the azlactone compound described in Table 1 was different. The yield of product 3c was 69%, and the structure of the compound was identified by NMR (hydrogen spectrum and carbon spectrum) 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, found 286.1802.

[0037] Embodiment 4:

[0038] The operation process and conditions were the same as those in Example 1, except that the azlactone compound described in Table 1 was different. The yield of product 3d was 83%, and the structure of the compound was identified by NMR (hydrogen spectrum and carbon spectrum) 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] Embodiment 5:

[0042] The operation process and conditions were the same as those in Example 1, except that the azlactone compound described in Table 1 was different. The yield of the product 3e was 77%, and the compound was identified by NMR (hydrogen spectrum, carbon spectrum and fluorine spectrum) 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] Embodiment 6:

[0046] The operation process and conditions were the same as those in Example 1, except that the azlactone compound described in Table 1 was different. The yield of the product 3f was 63%, and the structure of the compound was identified by NMR (hydrogen spectrum and carbon spectrum) 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] Embodiment 7:

[0050] The operation process and conditions were the same as those in Example 1, except that the azlactone compound described in Table 1 was different. The yield of the product 3 g was 63%, and the structure of the compound was identified by NMR (hydrogen spectrum, carbon spectrum and fluorine spectrum) 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] Embodiment 8:

[0054] The operation process and conditions are the same as those in Example 1, except that the azlactone compound described in Table 1 is different from that in Example 1. The yield of the product 3h is 76%, and the structure of the compound is identified by NMR (hydrogen spectrum and carbon spectrum) 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] Embodiment 9:

[0058] The operation process and conditions were the same as those in Example 1, except that the azlactone compound described in Table 1 was different. The yield of product 3i was 80%, and the compound was identified by NMR (hydrogen spectrum and carbon spectrum) 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] Embodiment 10:

[0061] The operation process and conditions were the same as those in Example 1, except that the azlactone compound described in Table 1 was different. The yield of product 3j was 80%, and the structure of the compound was identified by NMR (hydrogen spectrum and carbon spectrum) 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, found 258.1489.

[0063] Embodiment 11:

[0064] The operation process and conditions were the same as those in Example 1, except that the azlactone compound described in Table 1 was different. The yield of the product 3k was 85%, and the structure of the compound was identified by NMR (hydrogen spectrum and carbon spectrum) 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] Embodiment 12:

[0067] The operation process and conditions were the same as those in Example 1, except that the azlactone compound described in Table 1 was different. The yield of product 31 was 73%, and the structure of the compound was identified by NMR (hydrogen spectrum and carbon spectrum) 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] Embodiment 13:

[0071] The operation process and conditions were the same as those in Example 1, except that the azlactone compound described in Table 1 was different. The yield of product 3m was 76%, and the structure of the compound was identified by NMR (hydrogen spectrum, carbon spectrum and fluorine spectrum) 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] Embodiment 14:

[0075] The operation process and conditions were the same as those in Example 1, except that the azlactone compound described in Table 1 was different. The yield of the product 3n was 74%, and the structure of the compound was identified by NMR (hydrogen spectrum and carbon spectrum) 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] Embodiment 15:

[0079] The operation process and conditions were the same as those in Example 1. The difference from Example 1 was that, except for the azlactone compound described in Table 1, the yield of the product 3o was 59%, and the structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) 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] Embodiment 16:

[0083] The operation process and conditions were the same as those in Example 1, except that the azlactone ring compound described in Table 1 was different. The yield of the product 3p was 75%, and the structure of the compound was identified by NMR (hydrogen spectrum and carbon spectrum) 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, operation process and conditions were the same as those in Example 1, except that no palladium catalyst was added and no product 3a was obtained.

[0088] Comparative Example 2:

[0089] The raw materials, operation process and conditions were the same as those in Example 1, except that no ligand L2 was added and no product 3a was obtained.

[0090] Comparative Example 3:

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

[0092] Comparative Example 4:

[0093] The raw materials, operation process and conditions were the same as those 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 those in Example 1, except that the palladium catalyst was replaced with Pd(OAc)2, and the product 3a was not obtained.

Claims

1. A method for the palladium-catalyzed transprenylation of azlactones, characterized in that: Using azlactone 1 and isoprene as raw materials, the anti-isoprenylated azlactone derivative 3 was generated under the action of a monophosphine ligand. The structural formula of the anti-isopentenylated azlactone derivative 3 is as follows: Wherein the substituent R in the azlactone 1 or the trans-isoprenylated azlactone derivative 3 is 1 It is one or more of phenyl, benzyl, biphenyl, 2-methylphenyl, 3-methoxyphenyl, 4-methylphenyl, 3-methylphenyl, 3-tert-butylphenyl, 2-fluorophenyl, 3-chlorophenyl, 4-trifluoromethylphenyl, 3-nitrophenyl, 2-naphthyl, 2-furyl, 2-ester phenyl, and 4-ester phenyl; R 2 It is one or more of methyl, n-butyl, isobutyl, tert-butyl, n-propyl, benzyl, cyclopropyl, ethylmethylthio, methyleneindolyl, hydrogen, phenyl, 2-chlorophenyl, 2-methylphenyl, 3-methoxyphenyl, 2-furyl, and 2-esterphenyl; The monophosphine ligand is one or more of the compounds represented by the following structures L1, L2, L3, L4, and L5; preferably L2; 2. The method according to claim 1, characterized in that: Wherein azlactone 1 includes one or more of the compounds represented by the following structural formula:

3. The method according to claim 1 or 2, characterized in that: Azlactone 1 and isoprene 2 shown in the following formula are used as raw materials to generate trans-isoprenylated azlactone 3 under the action of a palladium catalyst and a monophosphine ligand. The reaction formula is as follows:

4. The method according to claim 1 or 2, characterized in that: The specific steps are as follows: The reaction is carried out in a reactor, and a palladium catalyst, a monophosphine ligand, and a solvent are added in sequence under the protection of an inert atmosphere, and stirred at 20-80° C. (preferably 40-60° C.) for 10-30 minutes (preferably 10-15 minutes); azlactone and isoprene are added to the reaction system, and the reaction is carried out at 40-90° C. (preferably 40-60° C.) for 12-24 hours (preferably 16-20 hours); after the reaction is completed, the azlactone trans-isoprenyl derivative is separated.

5. The method according to claim 3 or 4, characterized in that: The molar ratio of azlactone to isoprene is (1.0:1.0-1.0:6.0), preferably 1.0:3.

0.

6. The method according to claim 3 or 4, characterized in that: The palladium catalyst used is tris(dibenzylideneacetone)dipalladium, and the amount of the palladium catalyst used is 1-5% molar equivalent (relative to the azlactone compound), preferably 1-2.5% molar equivalent.

7. The method according to claim 3 or 4, characterized in that: The solvent is one or more of tert-butyl alcohol, toluene, n-hexane, dichloromethane, nitrogen methyl pyrrolidone, tetrahydrofuran, 1,4-dioxane, and ethyl acetate; preferably one or more of toluene or n-hexane; The amount of the solvent used is 0.1-2.0 ml, preferably 0.5-1.0 ml, per 0.20 mmol of the azlactone compound.

8. The method according to claim 1, 2, 3 or 4, characterized in that: The amount of the single ligand used is 5-30% molar equivalent (relative to the azlactone compound), preferably 10%-20% molar equivalent.

9. The method according to claim 4, characterized in that: The inert gas is one or both of argon and nitrogen.

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