A method for preparing a heterocyclic compound containing indole ketone and 3-acylbenzofuran or indole structure

Abstract

The invention discloses a method for preparing a heterocyclic compound containing indolone and 3-acylbenzofuran or indole structure, comprising the following steps: reacting palladium acetate, bis(diphenylphosphine) propane, TFBen, triethylenediamine, iodoaromatic compounds and o-hydroxyl / o-aminobenzyne compounds at 100°C for 24 hours, and after the reaction is complete, post-processing to obtain the heterocyclic compound containing indolone and 3-acylbenzofuran or indole structure. The reaction raw materials are cheap and easy to obtain, the substrate has good applicability and can be compatible with a variety of functional groups, TFBen is used as a carbonyl source, and the operation is simple. At the same time, the method can form multiple chemical bonds, including three C-C bonds and one C-O / C-N bond, through a one-step reaction, and provides a new method for the synthesis of carbonyl-containing bicyclic heterocyclic compounds.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for preparing a heterocyclic compound containing indole ketone and 3-acylbenzofuran or indole structure. Background Art

[0002] Heterocyclic compounds with structural diversity and complexity have an important impact on drug discovery, biological research and exploration, and molecules with different heterocyclic skeletons may have more biological or pharmaceutical properties. Therefore, the synthesis of heterocyclic compounds with diverse structural characteristics has attracted more and more interest in medicinal chemistry (Angew. Chem. Int. Ed. 2019, 58, 15016). Indolone is a special class of heterocyclic skeletons that often appear in a variety of biologically active compounds. For example, semaxanib, a highly efficient and selective VEGFR (flk-1 / kdr) inhibitor with potential antitumor activity; Horsfiline, a sindol alkaloid isolated from Horsfiline, is commonly used as a herbal medicine. As a key intermediate, indolone also plays an important role in organic synthesis. In addition, 3-acylbenzofuran and 3-acylindole, as important heterocyclic compounds, have multiple biological activities. Due to their excellent drug efficacy, people have been continuously exploring their synthesis methods. Amiodarone, clinically exhibits efficient and broad-spectrum antiarrhythmic effects. Pravadoline, which shows significant analgesic activity in humans. Therefore, it is of great research significance to explore new and effective synthetic methods to rapidly construct different polyheterocyclic molecules, especially those containing indolone and 3-acylbenzofuran or indole structures.

[0003] In recent years, palladium-catalyzed Heck cascade reactions have attracted widespread attention from organic chemists as an important reaction for synthesizing complex compounds (Acc.Chem.Res.2020,53,1605). Such reactions are carried out by intramolecular carbon palladiumization of olefins, and the resulting alkyl palladium species can be further transformed through a variety of pathways. Among them, the insertion of CO into alkyl palladium species can obtain a variety of ring-containing carbonyl compounds (J.Am.Chem.Soc.2016,138,10838). Recently, palladium-catalyzed heck cyclization of alkyne-containing nucleophiles provides a strategy for synthesizing diheterocyclic products. However, palladium-catalyzed carbonylation cyclization of alkyne-containing nucleophiles has never been reported. Therefore, we developed a palladium-catalyzed cascade carbon palladium / carbonylation cyclization reaction to construct heterocyclic compounds containing indolone and 3-acylbenzofuran or indole structures. This method allows the synthesis of diheterocyclic molecules with indolone and 3-acylbenzofuran or indole molecules in a simple one-step transformation. Moreover, TFBen was used as a convenient and efficient carbonyl source in this reaction. Summary of the invention

[0004] The present invention provides a method for preparing a heterocyclic compound containing an indole ketone and a 3-acylbenzofuran or indole structure, wherein the reaction steps are simple, the raw materials are cheap and readily available, the substrate has good applicability and is compatible with a variety of functional groups. The method is characterized in that multiple chemical bonds, including three CC bonds and one CO / CN bond, can be formed through a one-step reaction, thereby providing a new method for synthesizing bicyclic heterocyclic compounds containing carbonyl groups.

[0005] A method for preparing a heterocyclic compound containing an indolone and a 3-acylbenzofuran or indole structure, comprising the following steps: reacting a palladium catalyst, bis(diphenylphosphine) propane, TFBen (CAS: 1957190-76-9), triethylenediamine, an iodoaromatic compound and an o-hydroxyl / o-aminobenzylene compound at 90-110° C. for 20-28 hours, and after the reaction is complete, post-treating to obtain the heterocyclic compound containing an indolone and a 3-acylbenzofuran or indole structure;

[0006] The structure of the iodinated aromatic compound is shown in formula (II):

[0007]

[0008] The structure of the o-hydroxyl / o-aminobenzylene compound is shown in formula (III):

[0009]

[0010] The structure of the heterocyclic compound containing indole ketone and 3-acylbenzofuran or indole structure is shown in formula (I):

[0011]

[0012] In formulas (I) to (III), R 1 is H, C1-C5 alkyl, C1-C5 alkoxy, trifluoromethyl, phenyl, benzyl, thiophene or halogen;

[0013] R 2 is C1-C5 alkyl or phenyl;

[0014] R 3 is C1-C5 alkyl or phenyl;

[0015] R 4 is H, C1-C5 alkyl, C1-C5 alkoxy, trifluoromethyl, halogen;

[0016] R 5 It is a thienyl group, a substituted or unsubstituted phenyl group, and the substituent on the phenyl group is a C1-C5 alkyl group or a C1-C5 alkoxy group.

[0017] The molar ratio of the palladium catalyst, bis(diphenylphosphine)propane and triethylenediamine is 0.02:0.02:2.5;

[0018] R 1 ~R 5 The substitution positions are para and meta.

[0019] The reaction formula is as follows:

[0020]

[0021] In the present invention, the optional post-treatment process includes: filtration, silica gel mixing, and finally column chromatography purification to obtain the corresponding heterocyclic compound containing indolone and 3-acylbenzofuran or indole structure. Column chromatography purification is a commonly used technical means in the field.

[0022] Preferably, R 1 is H, methyl, trifluoromethyl, phenyl or benzyl, R 2 is methyl, n-butyl or phenyl; R 3 is methyl, n-butyl or phenyl. In this case, the iodinated aromatic compounds are easy to obtain and the reaction yield is high.

[0023] Preferably, R 4 is H, methyl, trifluoromethyl, thiophene or Cl; R 5is a thienyl group, a substituted or unsubstituted phenyl group, and the substituent on the phenyl group is a methyl group or a methoxy group. In this case, the o-hydroxyl / o-aminobenzylene compound is easy to obtain, and the reaction yield is high.

[0024] The iodinated aromatic compounds and o-hydroxyl / o-aminobenzylene compounds used to prepare heterocyclic compounds containing indolone and 3-acylbenzofuran or indole structures are relatively cheap and widely exist in nature. Preferably, on a molar basis, the iodinated aromatic compounds: o-hydroxyl / o-aminobenzylene compounds: palladium catalyst = 1:1.2-1.5:0.05-0.1; and further preferably, on a molar basis, the iodinated aromatic compounds: o-hydroxyl / o-aminobenzylene compounds: palladium catalyst = 1:1.5:0.1.

[0025] Preferably, the reaction time is 24 hours. Too long a reaction time will increase the reaction cost, and conversely it will be difficult to ensure the completeness of the reaction.

[0026] Preferably, the reaction is carried out in 1,4-dioxane, and the amount of 1,4-dioxane used is sufficient to dissolve the raw materials well. The amount of 1,4-dioxane used for 0.2 mmol of iodinated aromatic compound is about 1-2 mL.

[0027] Preferably, the palladium catalyst is palladium acetate. Among many palladium catalysts, palladium acetate is relatively cheap, and the reaction efficiency is higher when palladium acetate is used as a catalyst.

[0028] As a further preference, the heterocyclic compound containing indole ketone and 3-acylbenzofuran or indole structure is one of the compounds represented by formula (I-1) to formula (I-5):

[0029]

[0030]

[0031] The compounds represented by formula (I-1) to (I-5) are unknown compounds.

[0032] In the above preparation method, the palladium acetate, bis(diphenylphosphine)propane and triethylenediamine are generally commercially available products and can be easily obtained from the market.

[0033] Compared with the prior art, the beneficial effects of the present invention are as follows: using o-hydroxyl or o-aminobenzylene compounds as sulfur sources, the preparation method is simple, easy to operate, simple post-treatment, cheap and readily available starting materials for the reaction, a wide tolerance range for substrate functional groups, high reaction efficiency, and the formation of multiple chemical bonds, including three CC bonds and one CO / CN bond, through a one-step reaction. A variety of heterocyclic compounds containing indolone and 3-acylbenzofuran or indole structures can be synthesized according to actual needs, and the practicability is relatively strong. DETAILED DESCRIPTION

[0034] The present invention is further described below in conjunction with specific embodiments.

[0035] Examples 1 to 15

[0036] According to the raw material ratio in Table 1, palladium acetate, diphenylphosphine propane, TFBen, triethylenediamine, iodinated aromatic compound (II) and o-hydroxy / o-aminobenzyne compound (III) were added to a 15 mL sealed tube, and then 1,4-dioxane (2 mL) was added, mixed and stirred evenly, and reacted according to the reaction conditions in Table 2. After the reaction was completed, the mixture was filtered, mixed with silica gel, and purified by column chromatography to obtain the corresponding heterocyclic compound (I) containing indolone and 3-acylbenzofuran or indole structure. The reaction process is shown in the following formula:

[0037]

[0038] Table 1 Amount of raw materials added in Examples 1 to 15

[0039]

[0040] Table 2

[0041]

[0042]

[0043] In Table 1 and Table 2, T is the reaction temperature, t is the reaction time, Me is a methyl group, CF3 is a trifluoromethyl group, Ph is a phenyl group, OMe is a methoxy group, and thiopheyl is a thiophenyl group.

[0044] The structural confirmation data of the compounds prepared in Examples 1 to 5 are as follows:

[0045] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0046]

[0047] 1 H NMR (400MHz, CDCl3) δ7.73(d,J=7.7Hz,1H),7.58–7.56(m,2H), 7.50–7.44(m,4H),7.31–7.27(m,1H),7.25(d,J=7.1Hz,1H),7.21(d,J= 7.5Hz,1H),7.04(d,J=7.1Hz,1H),6.94(t,J=7.5Hz,1H),6.82(d,J=7.8Hz,1H),3.40(d,J=16.9Hz,1H),3.32(d,J=16.9Hz,1H),3.22(s,3H), 1.27(s,3H).

[0048] 13 C NMR (101MHz, CDCl3) δ194.6,180.2,158.9,153.7,143.8,133.2, 130.4,129.8,129.2,128.6,127.8,126.5,125.3,123.9,122.0,121.9,121.9, 117.7,111.0,108.1,49.7,45.7,26.4,24.4.

[0049] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0050]

[0051] 1 H NMR (400MHz, CDCl3) δ8.56(s,1H),7.81(d,J=7.7Hz,1H),7.60–7.58(m,2H),7.49–7.44(m,4H),7.31(t,J=7.3Hz,1H),7.25(t,J=7.4Hz, 1H),7.13(t,J=7.6Hz,1H),7.02(d,J=7.3Hz,1H),6.92–6.88(m,2H), 3.44(d,J=17.2Hz,1H),3.38(d,J=17.2Hz,1H),1.32(s,3H).

[0052] 13C NMR (101MHz, CDCl3) δ194.5,182.4,159.3,153.8,140.9,133.8, 130.5,129.9,129.3,128.7,127.8,126.5,125.4,124.1,122.1,122.0,122.0, 117.7,111.1,110.0,49.6,46.1,24.7.

[0053] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0054]

[0055] 1 H NMR (400MHz, CDCl3) δ7.98(d,J=2.7Hz,1H),7.80–7.78(m,1H), 7.48(d,J=8.4Hz,1H),7.40(d,J=5.0Hz,1H),7.35–7.30(m,3H),7.22(t, J=7.7Hz,1H),7.09(d,J=7.3Hz,1H),6.92(t,J=7.5Hz,1H),6.85(d,J=7.8Hz,1H),3.62(d,J=16.9Hz,1H),3.56(d,J=16.9Hz,1H),3.28(s,3H), 1.41(s,3H).

[0056] 13 C NMR (101MHz, CDCl3) δ193.9,180.3,154.6,153.2,143.8,133.4, 130.3,128.4,127.8,127.5,126.2,125.6,125.2,124.0,122.1,121.9,121.5, 116.8,111.2,108.1,50.2,45.8,26.4,24.6.

[0057] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0058]

[0059] 1H NMR (400MHz, CDCl3) δ8.16 (d, J=8.6Hz, 1H), 7.61 (t, J=6.9Hz, 1H), 7.54–7.48 (m, 3H), 7.30–7.29 (m, 4H), 7.18 (t, J=7.4Hz, 2H), 7.08 (d, J=7.8Hz,2H),6.88(t,J=7.4Hz,1H),6.81–6.76(m,2H),3.20(s,3H), 2.66(d,J=17.5Hz,1H),2.53(d,J=17.4Hz,1H),2.36(s,3H),2.32(s,3H), 0.99(s,3H).

[0060] 13 C NMR (101MHz, CDCl3) δ195.1,180.2,145.2,143.7,142.8,135.4, 134.5,134.3,133.3,131.7,130.7,130.0,129.5,127.8,127.54,127.45,127.1, 126.8,122.4,121.8,121.7,121.6,114.5,107.9,49.3,45.2,26.3,24.5,21.5, 21.2.

[0061] The NMR ( 1 H NMR and 13 C NMR) detection data are:

[0062]

[0063] 1 H NMR (400MHz, CDCl3) δ8.42(d,J=8.9Hz,1H),8.09(s,1H),7.66–7.59(m,2H),7.53(s,2H),7.31–7.26(m,4H),7.17(t,J=7.7Hz,1H),7.12 (d,J=8.2Hz,2H),6.86(t,J=7.5Hz,1H),6.80(d,J=7.8Hz,1H),6.77(d,J=7.3Hz,1H),3.20(s,3H),2.65(d,J=17.2Hz,1H),2.49(d,J=17.2Hz, 1H),2.35(s,3H),0.99(s,3H).

[0064] 13C NMR(101MHz,CDCl3)δ194.4,180.0,145.9,144.4,143.6,137.5, 135.1,133.0,131.8,131.5,130.5,129.9,129.7,128.0,127.8,126.929(q,J= 32.3Hz),126.928,124.3(q,J=272.2Hz),122.4(q,J=3.3Hz),122.0,121.8, 121.5,119.9(q,J=4.0Hz),115.1,108.1,49.2,45.3,26.3,24.4,21.6。

Claims

1. A method for preparing a heterocyclic compound containing indole ketone and 3-acylbenzofuran or indole structure, characterized in that: The method comprises the following steps: reacting a palladium catalyst, a ligand, benzene-1,3,5-triyl tricarboxylate, a base, an iodinated aromatic compound and an o-hydroxyl or o-aminobenzyne compound at 90 to 110° C. for 20 to 28 hours, and after the reaction is complete, post-treating to obtain the heterocyclic compound containing indolone and 3-acylbenzofuran or indole structure; The structure of the iodinated aromatic compound is shown in formula (II): The structure of the o-hydroxyl or o-aminobenzylene compound is shown in formula (III): The structure of the heterocyclic compound containing indole ketone and 3-acylbenzofuran or indole structure is shown in formula (I): In formulas (I) to (III), R 1 is H, C1-C5 alkyl, C1-C5 alkoxy, trifluoromethyl, phenyl, benzyl, thiophene or halogen; R 2 is C1-C5 alkyl or phenyl; R 3 is C1-C5 alkyl or phenyl; R 4 is H, C1-C5 alkyl, C1-C5 alkoxy, trifluoromethyl, halogen; R 5 is a thienyl group, a substituted or unsubstituted phenyl group, and the substituent on the phenyl group is a C1-C5 alkyl group or a C1-C5 alkoxy group; The reaction used 1,4-dioxane as solvent; The palladium catalyst is palladium acetate; The ligand is bis(diphenylphosphino)propane; The base is triethylenediamine.

2. The method for preparing a heterocyclic compound containing indole ketone and 3-acylbenzofuran or indole structure according to claim 1, characterized in that: R 1 is H, methyl, trifluoromethyl, phenyl or benzyl; R 2 is methyl, n-butyl or phenyl; R 3 It is methyl, n-butyl or phenyl.

3. The method for preparing a heterocyclic compound containing indole ketone and 3-acylbenzofuran or indole structure according to claim 1, characterized in that: R 4 is H, methyl, trifluoromethyl or Cl; R 5 is a thienyl group, a substituted or unsubstituted phenyl group, and the substituent on the phenyl group is a methyl group or a methoxy group.

4. The method for preparing a heterocyclic compound containing indole ketone and 3-acylbenzofuran or indole structure according to claim 1, characterized in that: In terms of molar amount, iodinated aromatic compound: o-hydroxy or o-aminobenzyne compound: benzene-1,3,5-triyl tricarboxylate: palladium catalyst: ligand: base = 1: 1.2-1.5: 7-8: 0.05-0.1: 0.05-0.1: 2-2.

5.

5. The method for preparing a heterocyclic compound containing indole ketone and 3-acylbenzofuran or indole structure according to claim 1, characterized in that: The heterocyclic compound containing indole ketone and 3-acylbenzofuran or indole structure is one of the compounds shown in the following formula:

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