CN110668943A - A simple synthesis method of palladium metal-catalyzed polysubstituted aryl ketone compounds - Google Patents

Abstract

The invention specifically designs a simple method for synthesizing a polysubstituted aryl ketone compound under the catalysis of palladium metal, belonging to the technical field of organic compound process application. As is well known, aryl ketone structures are widely existed in molecular structures of many clinical drugs, and the introduction of the aryl ketone structures into small molecules is one of important strategies for modifying the molecular structures of the drugs. The structure of the aryl ketone is relatively stable, and the introduction of the aryl ketone structure can improve the metabolic stability of the medicament by blocking metabolic sites, prolong the action time of the medicament and improve the bioavailability of the medicament.

Description

A simple synthesis method of palladium metal-catalyzed polysubstituted aryl ketone compounds

technical field

A simple method for synthesizing polysubstituted aryl ketone compounds catalyzed by palladium metal belongs to the technical field of organic compound technology application.

Background technique

The synthetic methods of aryl ketone compounds have been reported. For example, in the commonly used Friedel-Crafts acylation reaction, the hydrogen atom on the aromatic ring is replaced by an acyl group under the action of Lewis acid of aromatic hydrocarbon, and finally an aromatic ketone is formed. However, the raw material for Friedel-Crafts acylation requires that the aromatic ring has electron-donating groups, such as methyl, methoxy, etc.; the aromatic ring substituted with electron-withdrawing groups increases the difficulty of the reaction. In general, this method has a narrow substrate range and harsh reaction conditions. Aromatic ketones are widely found in pharmaceuticals, agricultural chemicals and polymers, and are often used as dyes, photosensitizers, and have extremely high application value. In addition, carbonyl compounds can be converted into compounds containing benzyl functional groups through a series of reactions, and the next chemical reaction can be carried out. Aryl ketone compounds are a class of important biologically active molecules. Aryl ketone compounds can improve the metabolic stability of biomolecules. They are important drug molecules and intermediates in the synthesis of natural products, and have very high application value and research significance. As shown in the figure below, the free phenol OXi8008 is a strong inhibitor of tubulin assembly, which can further synthesize anti-cancer drugs. The novel backbone of the novel polymer Rubialatins B can alter the biological activity of the molecule, as shown (Figure 1).

SUMMARY OF THE INVENTION

The invention overcomes the defects of the prior art, and proposes for the first time that an active ester generated by dicyclohexylcarbodiimide (DCC) and an aryl carboxylic acid is used as the electrophilic reagent for the Catellani reaction to react with the aryl iodide, which is simple and efficient. A series of polysubstituted aryl ketones were synthesized.

As shown in the figure (Fig. 2), the present invention uses aryl iodide, aryl carboxylic acid and ketene compound as starting materials, and under the action of metal palladium catalyst, reacts in a reaction solvent to synthesize aryl ketone compound.

where Ar is an aryl group.

In the present invention, the dosage ratio of the starting materials 1, 2 and 3 is 1:4:1.5.

In the present invention, the catalyst is allyl palladium chloride dimer or palladium acetate.

Preferably, the catalyst is allyl palladium chloride dimer.

In the present invention, the ligand is trifuryl phosphine.

In the present invention, the base is Cs ₂ CO ₃ .

In the present invention, the additive is DCC.

The solvent described in the present invention is toluene. The amount of solvent described therein is 2 ml.

In the present invention, the reaction temperature is 90 ^℃ .

In the present invention, the reaction time is 10 hours.

Specifically, the synthesis method of the present invention is to add reactant 2 (0.2 mmol), catalyst (5 mol%), ligand (10 mol%), alkali (0.6 mmol) to a 25ml Schlenk reaction tube, and change nitrogen three times by vacuuming , and then reactant 1, reactant 3, additive DCC, norbornene and solvent toluene were added, and the reaction was carried out at 90 ^° C for 10 hours. The progress of the reaction was monitored by TLC. After the reaction is completed, silica gel is directly added, spin-dried through column chromatography, and pure target product 4 is obtained by separation.

The advantages of the synthetic product of the present invention include: the raw materials used in the synthetic method of the present invention are cheap and easy to obtain, the properties are very stable, and no special method is required for preservation. The catalysts and ligands used in the present invention are also commonly used commercial reagents, are very stable, have the characteristics of low cost, high yield, simple process and less pollution.

In the present invention, the synthetic method of aryl ketone compounds is a very potential method for modifying biologically active molecules, and the innovatively designed reaction route of the present invention provides a widely applicable synthetic method for modifying such compounds.

In the present invention, for the first time, a novel electrophilic reagent is used in the Catellani reaction. Electrophiles are active ester intermediates formed by DCC and aryl carboxylic acids.

In the present invention, aryl iodide and carboxylic acid are used as reaction substrates, and the aryl ketone compound is obtained by the reaction. The reaction operation is simple, the reaction conditions are mild, the yield is high, and the large-scale production is scaled up.

Description of drawings

Figure 1 shows drugs and bioactive molecules containing aryl ketone structures.

Figure 2 is the general reaction formula of the synthesis method.

Figure 3 is a reaction diagram using allylpalladium(II) chloride dimer as a catalyst.

Figure 4 is a reaction diagram using palladium acetate as a catalyst.

Figure 5 is a reaction diagram of 2-iodoisopropylbenzene with benzoic acid and butyl acrylate.

Fig. 6 is the reaction diagram of 1-iodonaphthalene with benzoic acid and butyl acrylate.

Figure 7 is a reaction diagram of 2-iodotoluene with p-toluic acid and butyl acrylate.

Figure 8 is a reaction diagram of 2-iodotoluene with p-chlorobenzoic acid and butyl acrylate.

Fig. 9 is a reaction diagram of 2-iodotoluene with m-acetylbenzoic acid and butyl acrylate.

Figure 10 is a reaction diagram of 2-iodotoluene with benzoic acid and 1-penten-3-one.

Figure 11 is a reaction diagram of 2-iodotoluene with benzoic acid and ethyl acrylate.

Detailed ways

The present invention will be further described in detail with reference to the following specific examples, and the protection content of the present invention is not limited to the following examples. Variations and advantages that can occur to those skilled in the art without departing from the spirit and scope of the inventive concept are included in the present invention, and the appended claims are the scope of protection. The process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are all common knowledge and common knowledge in the field, and the present invention has no special limited contents. The data given in the following examples include specific operating and reaction conditions and products. The product structure was identified by nuclear magnetic resonance ( ¹ H NMR, ¹⁹ F NMR, ¹³ C NMR) and HRMS.

Example 1, (E)-butyl 3-(2-benzoyl-6-methylphenyl)acrylate (Figure 3).

To a 25ml Schlenk reaction tube, add reactant 2a (0.8 mmol), catalyst [PdCl(C ₃ H ₅ )] ₂ (2.5 mol%), ligand TFP (10 mol%), base Cs ₂ CO ₃ (0.6 mmol) , the vacuum was replaced with nitrogen three times, and then the reactant 1a (0.2 mmol, 1.0 equiv.), the reactant 3a (1.5 mmol), the additive DCC (0.9 mmol), the norbornene (0.5 mmol) and the solvent toluene (2 mL) was added, and the reaction was allowed to react at 90 ^° C for 10 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, silica gel was directly added, and the mixture was spin-dried and passed through column chromatography to obtain the pure target product 4a (53.5 mg, 83%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.30-7.69 (m, 3H), 7.54 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 7.34 (t, J = 7.2 Hz, 2H), 7.27 (d, J = 6.8 Hz, 1H), 5.88 (d, J = 16 Hz, 1H), 4.06 (t, J = 6.4 Hz, 2H), 2.42 (s, 3H), 1.61-1.53 (m, 2H), 1.37-1.27 (m, 2H), 0.91 (t, J = 7.6Hz, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ): δ 198.4, 165.9, 141.6,139.5, 137.5, 137.5, 133.2, 133.2, 132.1, 129.8, 128.4, 128.3, 126.4, 125.0, 64.3, 30.5, 20.5, 19.0, 13.7.HRMS(ESI) calcd forC ₂₁ H ₂₂ O. ₃ Na [M ⁺ Na] found 345.1465.

Example 2, (E)-butyl 3-(2-benzoyl-6-methylphenyl)acrylate (Figure 4).

Into a 25ml Schlenk reaction tube, add reactant 2a (0.8 mmol), catalyst Pd(OAc) ₂ (5 mol%), ligand TFP (10 mol%), base Cs ₂ CO ₃ (0.6 mmol), change nitrogen by vacuum Three times, reactant 1a (0.2 mmol, 1.0 equiv.), reactant 3a (0.3 mmol), additive DCC (0.9 mmol), norbornene (0.5 mmol) and solvent toluene (2 mL) were added, and the reaction was carried out at 90 ^°C . The reaction was carried out at C for 10 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, silica gel was directly added, and the mixture was spin-dried and passed through column chromatography to obtain the pure target product 4a (50.2 mg, 78%). The analysis data is the same as that of Example 1.

Example 3, (E)-butyl 3-(2-benzoyl-6-isopropylphenyl)acrylate (Figure 5).

To a 25ml Schlenk reaction tube, add reactant 2a (0.8 mmol), catalyst [PdCl(C ₃ H ₅ )] ₂ (2.5 mol%), ligand TFP (10 mol%), base Cs ₂ CO ₃ (0.6 mmol) , the vacuum was changed to nitrogen three times, and then the reactant 1b (0.2 mmol, 1.0 equiv.), the reactant 3a (0.3 mmol), the additive DCC (0.9 mmol), the norbornene (0.5 mmol) and the solvent toluene (2 mL) was added, and the reaction was allowed to react at 90 ^° C for 10 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, silica gel was directly added, and the mixture was spin-dried and passed through column chromatography to obtain pure target product 4b (63%). ¹ H NMR (400 MHz, CDCl ₃ ): δ7.740 (d, J = 16 Hz, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.34 (q, J = 6.8 Hz, 3H), 7.20 (d, J = 7.6 Hz, 1H), 5.75 (d, J = 16.4 Hz, 1H), 3.98 (t , J = 6.8 Hz, 2H), 3.15-3.08 (m, 1H), 1.53-1.46 (m, 2H), 1.29-1.17 (m, 9H), 0.84 (t, J = 7.2 Hz, 3H). ¹³ C NMR (100 MHz, CDCL ₃ ): Δ 198.5, 165.7, 147.8, 142.1, 139.5, 137.7, 133.1, 132.4, 129.7,128.5, 128.4, 126.2, 125.5, 64.3, 29.8, 23.5, 19.0, 13.7. HRMS(ESI) calcd for C ₂₃ H ₂₆ O ₃ Na [M+Na] ⁺ 373.1780, found 373.1773.

Example 4, (E)-butyl 3-(2-benzoylnaphthalen-1-yl)acrylate (Figure 6).

To a 25ml Schlenk reaction tube, add reactant 2a (0.8 mmol), catalyst [PdCl(C ₃ H ₅ )] ₂ (2.5 mol%), ligand TFP (10 mol%), base Cs ₂ CO ₃ (0.6 mmol) , the vacuum was changed to nitrogen three times, and then the reactant 1c (0.2 mmol, 1.0 equiv.), the reactant 3a (0.3 mmol), the additive DCC (0.9 mmol), the norbornene (0.5 mmol) and the solvent toluene (2 mL) was added, and the reaction was allowed to react at 90 ^° C for 10 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, silica gel was directly added, and the mixture was spin-dried and passed through column chromatography to obtain the pure target product 4c (49.1 mg, 69%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.15-8.10 (m, 2H), 7.94 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 7.6 Hz, 2H), 7.62 (q, J = 3.2 Hz, 2H), 7.57-7.52 (m, 2H), 7.41 (t, J = 7.6 Hz, 2H), 6.09 (d, J = 16.4 Hz, 1H), 4.11 (t, J = 6.4 Hz, 2H) ), 1.64-1.57 (m, 2H), 1.39-1.30 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ): δ 198.4,165.4,140.9, 137.6, 136.6, 133.9, 133.3, 132.0 131.0, 129.8, 129.0, 128.6,128.5, 127.5, 126.8, 125.3, 125.0, 30.6, 19.1, 13.7.HRMS (ESI) CALCD FORC ₂₄ H ₂₂ O ₃ Na [ M+Na] ⁺ 381.1467, found 381.1465.

Example 5, (E)-butyl 3-(2-methyl-6-(4-methylbenzoyl)phenyl)acrylate (Figure 7).

To a 25ml Schlenk reaction tube, add reaction 2b (0.8 mmol), catalyst [PdCl(C ₃ H ₅ )] ₂ (2.5 mol%), ligand TFP (10 mol %), base Cs ₂ CO ₃ (0.6 mmol), Evacuate and change nitrogen three times, and then add reactant 1a (0.2 mmol, 1.0 equiv.), reactant 3a (0.3 mmol), additive DCC (0.9 mmol), norbornene (0.5 mmol) and solvent toluene (2 mL) , the reaction was carried out at 90 ^o C for 10 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, silica gel was directly added, spin-dried and passed through column chromatography to obtain the pure target product 4d (46.5 mg, 72%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.71 (d, J = 16 Hz, 1H ), 7.61 (d, J = 8 Hz, 2H), 7.35-7.30 (m, 2H), 7.24 (d, J = 6.8 Hz, 1H), 7.20 (d, J = 8Hz, 2H), 5.89 (d, J = 16 Hz, 1H), 4.06 (t, J = 6.4 Hz, 2H), 2.40 (d, J = 7.2 Hz , 6H), 1.60-1.53 (m, 2H), 1.37-1.27 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ): δ198.0, 166.0 , 144.1, 141.6, 139.9, 137.5, 134.9, 133.0, _131.9 , 130.0, 129.2, 128.2, 126.2, 124.9, 64.3, 30.5, 21.7, 20.5, 19.0, _{13.7 Hd4calc} OC +Na] ⁺ 359.1623, found 359.1622.

Example 6, (E)-butyl 3-(2-(4-chlorobenzoyl)-6-methylphenyl)acrylate (Figure 8).

To a 25ml Schlenk reaction tube, add reaction 2c (0.8 mmol), catalyst [PdCl(C ₃ H ₅ )] ₂ (2.5 mol%), ligand TFP (10 mol %), base Cs ₂ CO ₃ (0.6 mmol), Evacuate and change nitrogen three times, and then add reactant 1a (0.2 mmol, 1.0 equiv.), reactant 3a (0.3 mmol), additive DCC (0.9 mmol), norbornene (0.5 mmol) and solvent toluene (2 mL) , the reaction was carried out at 90 ^o C for 10 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, silica gel was directly added, and the mixture was spin-dried and passed through column chromatography to obtain the pure target product 4e (47.6 mg, 65%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.74-7.68 (m, 3H), 7.33-7.29 (m, 2H), 7.22 (dd, J ₁ = 8.0 Hz, J ₂ =2Hz, 2H), 6.87 ( d, J = 8.8 Hz, 2H), 5.90 (d, J = 16 Hz, 1H), 4.06 (t, J = 6.4Hz, 2H), 3.85 (s, 3H), 2.41 (s, 3H), 1.61- 1.54 (m, 2H), 1.36-1.27 (m, 2H), 0.90 (t, J = 7.6 Hz, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ): δ 197.0, 166.1, 163.7, 141.5, 140.0, 137.5, 132.8, 132.3, 131.8, 130.3, 128.3, 126.0, 124.8, 113.7, 64.3, 55.5, 30.6, 20.5, 19.1, 13.7. HRMS(ESI) calcd forC ₂₁ H ₂₁ ClO ₃ Na [M ⁺ Na] found 379.1076.

Example 7, (E)-butyl 3-(2-(3-acetylbenzoyl)-6-methylphenyl)acrylate (Figure 9).

To a 25ml Schlenk reaction tube, add reaction 2d (0.2 mmol), catalyst [PdCl(C ₃ H ₅ )] ₂ (2.5 mol%), ligand TFP (10 mol%), base Cs ₂ CO ₃ (0.6 mmol), Evacuate and change nitrogen three times, and then add reactant 1a (0.2 mmol, 1.0 equiv.), reactant 3a (0.3 mmol), additive DCC (0.9 mmol), norbornene (0.5 mmol) and solvent toluene (2 mL) , the reaction was carried out at 90 ^o C for 10 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, silica gel was directly added, spin-dried and passed through column chromatography to obtain the pure target product 4f (57 mg, 82%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.30 (s, 1H), 8.14 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 8 Hz, 1H), 7.71 (d, J = 16 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.41-7.35 (m, 2H), 7.29-7.27 (m, 1H), 5.86 (d, J = 16.4 Hz, 1H), 4.06 (t , J = 6.4 Hz, 2H), 2.62 (s, 3H), 2.43(s, 3H), 1.60-1.53 (m, 2H), 1.36-1.26 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ): δ 197.5, 197.1, 165.8, 141.6, 138.9, 138.0, 137.8, 137.3, 134.1, 133.4, 132.7, 132.5, 129.3, 128.9, 14.5, 128 , 30.5, 26.7, 20.4, 19.1, 13.7. HRMS(ESI) calcd for C ₂₃ H ₂₄ O ₄ Na [M+Na] ⁺ 387.1573, found387.1576.

Example 8, (E)-1-(2-benzoyl-6-isopropylphenyl)pent-1-en-3-one (Figure 10).

To a 25ml Schlenk reaction tube, add reaction 2a (0.8 mmol), catalyst [PdCl(C ₃ H ₅ )] ₂ (2.5 mol%), ligand TFP (10 mol%), base Cs ₂ CO ₃ (0.6 mmol), Evacuate and change nitrogen three times, and then add reactant 1a (0.2 mmol, 1.0 equiv.), reactant 3b (0.3 mmol), additive DCC (0.9 mmol), norbornene (0.5 mmol) and solvent toluene (2 mL) , the reaction was carried out at 90 ^o C for 10 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, silica gel was directly added, spin-dried and passed through column chromatography, and 4g (61.2 mg, 95%) of pure target product was isolated and obtained. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.71 (d, J = 7.6 Hz, 2H), 7.60 (d, J = 16.4 Hz, 1H), 7.54 (t, J =7.2 Hz, 1H), 7.41 ( t, J = 7.6 Hz, 2H), 7.38-7.33 (m, 2H), 7.28 (dd, J ₁ = 6.8Hz, J ₂ = 2, 1H), 6.15 (d, J = 16.4 Hz, 1H), 2.45 -2.39 (m, 5H), 0.98 (t, J =7.2 Hz, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ): δ 200.0, 198.4, 139.4, 139.2, 137.6, 137.5, 133.5, 133.3, 132.5, 132.2, 129.7, 128.5, 128.3, 126.5, 34.0, 20.4, 7.9. HRMS(ESI) calcd for C ₁₉ H ₁₈ O ₂ Na [M+Na] ⁺ 301.1205, found 301.1217.

Example 9, (E)-ethyl 3-(2-benzoyl-6-methylphenyl)acrylate (Figure 11).

To a 25ml Schlenk reaction tube, add reactant 2a (0.8 mmol), catalyst [PdCl(C ₃ H ₅ )] ₂ (2.5 mol%), ligand TFP (10 mol%), base Cs ₂ CO ₃ (0.6 mmol) , the vacuum was changed to nitrogen three times, and then the reactant 1a (0.2 mmol, 1.0 equiv.), the reactant 3c (0.3 mmol), the additive DCC (0.9 mmol), the norbornene (0.5 mmol) and the solvent toluene (2 mL) was added, and the reaction was allowed to react at 90 ^° C for 10 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, silica gel was directly added, and the mixture was spin-dried and passed through column chromatography to obtain the pure target product for 4 h (54.7 mg, 93%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.73 (t, J = 8 Hz, 3H), 7.55 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.37- 7.31 (m, 2H), 7.26 (d, J = 6 Hz, 1H), 5.88 (d, J = 16 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 2.42 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H). ¹³ C NMR (100MHz, CDCl ₃ ): δ 198.3, 165.8, 141.7, 139.5, 137.5, 137.5, 133.3, 133.2, 132.2, 129.8, 128.4, 125.2, 12 , 60.4, 20.5, 14.1. HRMS(ESI) calcdforC ₁₉ H ₁₈ O ₃ Na [M+Na] ⁺ 317.1154, found 317.1160.

Claims (9)

1. a synthetic method of a palladium metal-catalyzed polysubstituted aryl ketone compound, is characterized in that, with aryl iodide, benzoic acid, DCC and butyl acrylate as raw material, under the effect of palladium catalyst, through multi-step series connection The reaction is reacted in the reaction solvent to obtain the acylation product of the aryl iodide, and the reaction equation is shown in the following formula:

where Ar is an aryl group. 2. the synthetic method of the polysubstituted aryl ketone compound catalyzed by palladium metal as claimed in claim 1, is characterized in that, described catalyzer is allyl palladium (II) chloride dimer or palladium acetate. 3 . The method for synthesizing a palladium metal-catalyzed polysubstituted aryl ketone compound according to claim 1 , wherein the ligand is tris(2-furyl) phosphine hydrogen. 4 . 4 . The method for synthesizing a palladium metal-catalyzed polysubstituted aryl ketone compound according to claim 1 , wherein the base is Cs ₂ CO ₃ . 5 . 5. the synthetic method of the palladium metal-catalyzed polysubstituted aryl ketone compound as claimed in claim 1, is characterized in that, described additive is DCC. 6. The synthetic method of the palladium metal-catalyzed polysubstituted aryl ketone compound as claimed in claim 1, wherein the solvent is toluene. 7. The amount of solvent described therein is 2 ml. 8. the synthetic method of the palladium metal-catalyzed polysubstituted aryl ketone compound as claimed in claim 1, is characterized in that, described reaction temperature is 90 ^℃ . 9. the synthetic method of the polysubstituted aryl ketone compound catalyzed by palladium metal as claimed in claim 1, is characterized in that, described reaction time is 10 hours.

Images