CN115677674A - Preparation method of heterocyclic compound containing indolone and 3-acyl benzofuran or indole structure - Google Patents
Preparation method of heterocyclic compound containing indolone and 3-acyl benzofuran or indole structure Download PDFInfo
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Abstract
The invention discloses a preparation method of a heterocyclic compound containing indolone and 3-acyl benzofuran or indole structure, which comprises the following steps: reacting palladium acetate, bis-diphenylphosphinopropane, TFBen, triethylene diamine, iodoarene compounds and o-hydroxy/o-aminophenylalkyne compounds at 100 ℃ for 24 hours, and after the reaction is completed, carrying out post-treatment to obtain the heterocyclic compound containing the indolone and the 3-acyl benzofuran or indole structure. The reaction raw materials are cheap and easy to obtain, the substrate applicability is good, the reaction raw materials can be compatible with various functional groups, TFBen is used as a carbonyl source, and the operation is simple. Meanwhile, the method can form a plurality of chemical bonds including three C-C bonds and one C-O/C-N bond through one-step reaction, and provides a new method for synthesizing the carbonyl-containing diheterocyclic compound.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a heterocyclic compound containing indolone and 3-acylbenzofuran or indole structures.
Background
Heterocyclic compounds with structural diversity and complexity have important implications for drug discovery, biological research and exploration, and molecules with different heterocyclic backbones may have more biological or pharmaceutical properties. Therefore, the synthesis of heterocyclic compounds with diverse structural features has attracted increasing interest in pharmaceutical chemistry (angelw. Chem. Int. Ed.2019,58, 15016). Indolones are a special class of heterocyclic backbones, often found in a variety of biologically active compounds. Such as semaxanib, highly potent and selective VEGFR (flk-1/kdr) inhibitors with potential anti-tumor activity; horsfiline, a sindol alkaloid isolated from bacillus hollisae, is commonly used as a herbal medicine. Indolones also play an important role in organic synthesis as key intermediates. In addition, 3-acylbenzofuran and 3-acylindole have various biological activities as important heterocyclic compounds, and their synthesis methods have been continuously explored due to their excellent pharmaceutical efficacy. Amiodarone, which has high-efficiency and broad-spectrum antiarrhythmic effect clinically. Pravadoline, which shows significant analgesic activity in humans. Therefore, it is of great research interest to explore new and efficient synthetic methods for the rapid construction of different polyheterocyclic molecules, particularly those containing indolone and 3-acylbenzofuran or indole structures.
In recent years, palladium-catalyzed Heck cascades have attracted considerable attention from organic chemists as an important reaction for the synthesis of complex compounds (acc. Such reactions are carried out by intramolecular palladium-on-carbon of the olefin, and the resulting palladium alkyl species can be further converted in a variety of ways. Where insertion of CO into an alkyl palladium species can yield a variety of cyclic carbonyl-containing compounds (j.am. Chem. Soc.2016,138, 10838). More recently, palladium-catalyzed heck cyclization of alkyne-containing nucleophiles has provided a strategy for synthesizing bis-heterocyclic products. However, palladium-catalyzed carbonylation cyclization of alkyne-containing nucleophiles has never been reported. Thus, we have developed a palladium-catalyzed cascade of palladium-on-carbon/carbonylation cyclization reactions to construct heterocyclic compounds containing indolone and 3-acylbenzofuran or indole structures. The method allows the synthesis of bis-heterocyclic molecules with indolone and 3-acylbenzofuran or indole molecules in a simple one-step conversion. Furthermore, in this reaction, TFBen is used as a convenient and efficient carbonyl source.
Disclosure of Invention
The invention provides a preparation method of a heterocyclic compound containing indolone and 3-acyl benzofuran or indole structure, which has the advantages of simple reaction steps, cheap and easily-obtained raw materials, good substrate applicability and compatibility with various functional groups. The method is characterized in that a plurality of chemical bonds including three C-C bonds and one C-O/C-N bond can be formed through one-step reaction, and a new method is provided for synthesizing the carbonyl-containing bis-heterocyclic compound.
A preparation method of heterocyclic compounds containing indolone and 3-acyl benzofuran or indole structures comprises the following steps: reacting a palladium catalyst, bis-diphenylphosphinopropane, TFBen (CAS: 1957190-76-9), triethylene diamine, iodoaromatic compounds and o-hydroxy/o-aminophenylacetylene compounds at 90-110 ℃ for 20-28 hours, and after the reaction is completed, carrying out post-treatment to obtain the heterocyclic compounds containing indolone and 3-acyl benzofuran or indole structures;
the structure of the aryl iodide compound is shown as the formula (II):
the structure of the o-hydroxyl/o-aminophenylalkyne compound is shown as the formula (III):
the structure of the heterocyclic compound containing the indolone and the 3-acyl benzofuran or indole structure is shown as the formula (I):
in formulae (I) to (III), R 1 Is H, C 1 ～C 5 Alkyl radical, C 1 ～C 5 Alkoxy, trifluoromethyl, phenyl, benzyl, thiophene or halogen;
R 2 is C 1 ～C 5 Alkyl or phenyl;
R 3 is C 1 ～C 5 Alkyl or phenyl;
R 4 is H, C 1 ～C 5 Alkyl radical, C 1 ～C 5 Alkoxy, trifluoromethyl, halogen;
R 5 is thienyl, substituted or unsubstituted phenyl, and the substituent on the phenyl is C 1 ～C 5 Alkyl radical, C 1 ～C 5 An alkoxy group.
The molar ratio of the palladium catalyst to the bis (diphenylphosphinopropane) to the triethylene diamine is 0.02;
R 1 ～R 5 the substitution positions of (a) are para and meta.
The reaction formula is as follows:
in the present invention, the optional post-processing procedure includes: filtering, mixing the sample with silica gel, and finally purifying by column chromatography to obtain the corresponding heterocyclic compound containing the indolone and the 3-acyl benzofuran or indole structure, wherein the column chromatography purification is a technical means commonly used in the field.
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. At this time, the iodoaromatic hydrocarbon compound is easily available, and the reaction yield is high.
Preferably, R 4 Is H, methyl, trifluoromethyl, thiophene or Cl; r 5 Is thienyl, substituted or unsubstituted phenyl, and the substituent on the phenyl is methyl or methoxy. In this case, the o-hydroxy/o-aminophenylacetylene compounds are readily available and the reaction yields are high.
The iodo-aromatic compound and the o-hydroxy/o-aminophenylalkyne compound for preparing the heterocyclic compound containing the indolone and the 3-acyl benzofuran or indole structure are cheap and widely exist in the natural world, and preferably, the iodo-aromatic compound comprises the following components in percentage by mol: o-hydroxy/o-aminophenylacetylene compounds: the palladium catalyst = 1.2 to 1.5; as a further preference, the aromatic iodo compound: o-hydroxy/o-aminophenylacetylene compounds: palladium catalyst = 1.5.
Preferably, the reaction time is 24 hours, and if the reaction time is too long, the reaction cost increases, and conversely, it is difficult to ensure the completion of the reaction.
Preferably, the reaction is carried out in 1, 4-dioxane, the amount of 1, 4-dioxane is sufficient to dissolve the starting material well, and the amount of 1, 4-dioxane used is about 1 to 2mL for 0.2mmol of iodoaromatic compound.
Preferably, the palladium catalyst is palladium acetate, which is relatively inexpensive among a large number of palladium catalysts, and the reaction efficiency is high when palladium acetate is used as the catalyst.
Preferably, the heterocyclic compound containing indolone and 3-acyl benzofuran or indole structure is one of compounds shown in formula (I-1) to formula (I-5):
the compounds represented by the formulae (I-1) to (I-5) are unknown compounds.
In the preparation method, the palladium acetate, the bis-diphenylphosphinopropane and the triethylene diamine are generally commercially available products and can be conveniently obtained from the market.
Compared with the prior art, the invention has the beneficial effects that: the O-hydroxyl or O-aminophenylacetylene compound is used as a sulfur source, the preparation method is simple, the operation is easy, the post-treatment is simple and convenient, the reaction starting raw materials are cheap and easy to obtain, the tolerance range of the substrate functional group is wide, the reaction efficiency is high, and a plurality of chemical bonds including three C-C bonds and one C-O/C-N bond can be formed through one-step reaction. Can synthesize various heterocyclic compounds containing indolone and 3-acyl benzofuran or indole structures according to actual needs, and has strong practicability.
Detailed Description
The invention is further described with reference to specific examples.
Examples 1 to 15
Adding palladium acetate, bis (diphenylphosphinopropane), TFBen, triethylene diamine, iodoarene compounds (II) and o-hydroxy/o-aminophenylacetylene compounds (III) into a 15mL sealed tube according to the raw material ratio in Table 1, then adding 1, 4-dioxane (2 mL), mixing and stirring uniformly, reacting according to the reaction conditions in Table 2, filtering after the reaction is finished, stirring a sample with silica gel, and purifying by column chromatography to obtain corresponding heterocyclic compounds (I) containing indolone and 3-acylbenzofuran or indole structures, wherein the reaction process is shown as the following formula:
TABLE 1 raw material addition amounts of examples 1 to 15
TABLE 2
In tables 1 and 2, T is the reaction temperature, T is the reaction time, me is methyl, CF 3 Is trifluoromethyl, ph isPhenyl, OMe methoxy and thiophenyl thienyl.
Structure confirmation data of the compounds prepared in examples 1 to 5:
nuclear magnetic resonance of heterocyclic Compound (I-1) containing indolone and 3-acylbenzofuran Or indole Structure obtained in example 1 (I-1) 1 H NMR and 13 c NMR) the data were:
1 H NMR(400MHz,CDCl 3 )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＝7.8 Hz,1H),3.40(d,J＝16.9Hz,1H),3.32(d,J＝16.9Hz,1H),3.22(s,3H), 1.27(s,3H).
13 C NMR(101MHz,CDCl 3 )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.
nuclear magnetic resonance of heterocyclic compound (I-2) containing indolone and 3-acylbenzofuran or indole structure prepared in example 2 (I-2) 1 H NMR and 13 c NMR) the data detected were:
1 H NMR(400MHz,CDCl 3 )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).
13 C NMR(101MHz,CDCl 3 )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.
nuclear magnetic resonance of heterocyclic Compound (I-3) containing indolone and 3-acylbenzofuran Or indole Structure obtained in example 3 (I-3) 1 H NMR and 13 c NMR) the data were:
1 H NMR(400MHz,CDCl 3 )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).
13 C NMR(101MHz,CDCl 3 )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.
nuclear magnetic resonance of heterocyclic compound (I-4) containing indolone and 3-acylbenzofuran or indole structure prepared in example 4 (I-4) 1 H NMR and 13 c NMR) the data detected were:
1 H NMR(400MHz,CDCl 3 )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).
13 C NMR(101MHz,CDCl 3 )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.
made of fruitNuclear magnetic resonance of heterocyclic compound (I-5) containing indolone and 3-acylbenzofuran or indole structure prepared in example 5 ( 1 H NMR and 13 c NMR) the data detected were:
1 H NMR(400MHz,CDCl 3 )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).
13 C NMR(101MHz,CDCl 3 )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 (9)
1. a preparation method of a heterocyclic compound containing indolone and 3-acyl benzofuran or indole structure is characterized by comprising the following steps: reacting a palladium catalyst, a ligand, a benzyne-1, 3, 5-trimethyl triformate (TFBen), alkali, an iodoaromatic compound and an o-hydroxy or o-aminophenylacetylene compound at 90-110 ℃ for 20-28 hours, and after the reaction is completed, carrying out post-treatment to obtain the heterocyclic compound containing the indolone and the 3-acyl benzofuran or indole structure;
the structure of the iodo-aromatic compound is shown as the formula (II):
the structure of the o-hydroxyl or o-aminophenylalkyne compound is shown as the formula (III):
the structure of the heterocyclic compound containing the indolone and the 3-acyl benzofuran or indole structure is shown as the formula (I):
in the formulae (I) to (III), R 1 Is H, C 1 ～C 5 Alkyl radical, C 1 ～C 5 Alkoxy, trifluoromethyl, phenyl, benzyl, thiophene or halogen;
R 2 is C 1 ～C 5 Alkyl or phenyl;
R 3 is C 1 ～C 5 Alkyl or phenyl;
R 4 is H, C 1 ～C 5 Alkyl radical, C 1 ～C 5 Alkoxy, trifluoromethyl, halogen;
R 5 is thienyl, substituted or unsubstituted phenyl, and the substituent on the phenyl is C 1 ～C 5 Alkyl radical, C 1 ～C 5 An alkoxy group.
2. The method of claim 1, wherein R is selected from the group consisting of 1 Is H, methyl, trifluoromethyl, phenyl or benzyl;
R 2 is methyl, n-butyl or phenyl;
R 3 is methyl, n-butyl or phenyl.
3. The method for preparing heterocyclic compound containing indolone and 3-acyl benzofuran or indole structure as claimed in claim 1, wherein R is 4 Is H, methyl, trifluoromethyl, thiophene or Cl;
R 5 is thienyl, substituted orUnsubstituted phenyl, the substituents on said phenyl being methyl or methoxy.
4. The method for preparing heterocyclic compounds containing indolone and 3-acylbenzofuran or indole structure according to claim 1, wherein the iodo-aromatic compound is represented by the following formula (I): o-hydroxy or o-aminophenylacetylene compounds: TFBen: palladium catalyst: ligand: the alkali = 1.2 to 1.5.
5. The method for preparing heterocyclic compounds containing indolone and 3-acyl benzofuran or indole structure as claimed in claim 1, wherein the reaction uses 1, 4-dioxane as solvent.
6. The method for preparing heterocyclic compounds containing indolone and 3-acyl benzofuran or indole structures as claimed in claim 1, wherein the palladium catalyst is palladium acetate.
7. The method for preparing heterocyclic compound containing indolone and 3-acyl benzofuran or indole structure as claimed in claim 1, wherein said ligand is bis diphenylphosphinopropane.
8. The method for preparing heterocyclic compound containing indolone and 3-acyl benzofuran or indole structure as claimed in claim 1, wherein said base is triethylenediamine.
9. The method for preparing the heterocyclic compound containing the indolone and the 3-acylbenzofuran or indole structure according to claim 1, wherein the heterocyclic compound containing the indolone and the 3-acylbenzofuran or indole structure is one of compounds represented by formula (I-1) to formula (I-5):
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