A method for synthesizing phenanthridinone compounds by palladium catalysis

Abstract

The invention discloses a method for synthesizing phenanthridinone compounds by palladium catalysis, the method is in an organic solvent system, using 2 bromobenzamide compounds and o-bromobenzoic acid as raw materials, using metal palladium salt as catalyst, adding alkali and ligand stirring reaction, after reacting completely under the conditions of 100~120 DEG C, phenanthridinone compounds are obtained after reaction solution post-processing. The present invention selects o-halobenzoic acid as raw material, using metal palladium salt as catalyst, constructs optimal reaction system, Pd catalyzes 2 bromobenzamides and o-bromobenzoic acid by palladium association benzene intermolecular [4+2] cyclization reaction, provides a kind of modular method of phenanthridinone skeleton conveniently. The method is prepared using one-pot method, and raw materials are easy to obtain, and reaction conditions are mild, and system is green and environmentally friendly, and product is easily separated and purified, and highly purified phenanthridinone compounds can be obtained efficiently and in high yield.

Description

Technical Field

[0001] The present invention relates to the technical field of fine chemical organic synthesis, and in particular to a method for synthesizing phenanthridinone compounds catalyzed by palladium. Background Art

[0002] Phenanthridinone is an important class of nitrogen-containing heterocyclic compounds and is a key core unit of many natural products and bioactive molecules, such as hepatitis C therapeutic agents and trypsin inhibitors with anti-tumor activity.

[103] PJ34 PARP inhibitors can affect the way cancer cells replicate, exhibiting promising anti-cancer activity and are used to treat related diseases. They are also found in many natural products, such as Phenaglydon, Crinasiadine, and Trisphaeridine (structural formula below), all of which are based on the phenanthridinone skeleton.

[0003]

[0004] In recent years, many methods have been developed to synthesize phenanthridinone derivatives, among which benzamide is one of the preferred starting materials for scientists because it has the same fragment as phenanthridin-6(5H)one.

[0005] In 2007, Furuta et al. developed a palladium-mediated domino reaction to facilitate the synthesis of phenanthridinone derivatives. Two amide molecules undergo aryl-aryl coupling and deamidation to form a C-N bond. The versatility of this reaction and its applicability to a wide range of substrates make it useful for the development of bioactive derivatives.

[0006]

[0007] In 2011, Li's group achieved the synthesis of biologically important phenanthridinone by reacting N-methoxybenzamide with iodobenzene, firstly through an Ullmann coupling reaction of the C-N bond under palladium catalysis, and then through an oxidative coupling dehydrogenation reaction. Through a one-pot method to construct CC and C-N bonds, it involved four bond breaking and two bond formation.

[0008]

[0009] In 2012, Cheng's group replaced iodobenzene with phenylboronic acid and reported that the rhodium-catalyzed efficient double C-H bond activation and cyclization of N-methoxybenzamide with arylboronic acid provided a direct and general method for the phenanthridinone structure, forming highly regioselective C-C and C-N bonds under mild conditions, providing a wide range of substituted phenanthridinones.

[0010]

[0011] In 2012, Larock's group reported the palladium-catalyzed reaction of o-halogenated benzamides with a benzyne precursor (o-trimethylsilylphenyl trifluoromethanesulfonate) to generate N-substituted phenanthridinones in good yields. This method provides this important heterocyclic system in a single step under relatively mild reaction conditions by simultaneously forming both CC and CN bonds and allowing the presence of a variety of functional groups.

[0012]

[0013] In 2018, the Hoover group developed a nickel-catalyzed oxidative decarboxylative cyclization of simple benzamides and (hetero)aromatic carboxylates. This reaction provides access to a large number of phenanthridinones and their heterocyclic analogs, highlighting the practicality and versatility of oxidative decarboxylative coupling strategies for C-C bond formation.

[0014]

[0015] Although methods for synthesizing phenanthridinones from benzylene have been reported, their substrates are relatively limited, so it is particularly important to develop a method with wider substrate applicability. Summary of the Invention

[0016] The present invention aims to provide a method for the palladium-catalyzed synthesis of phenanthridinone compounds. The method is prepared by a one-pot process, is simple to operate, has readily available reaction raw materials, mild reaction conditions, a green and environmentally friendly reaction system, and the product is easy to separate and purify, and can produce high-purity phenanthridinone compounds with high efficiency and high yield. In addition, the method is suitable for synthesizing various highly functionalized phenanthridinone compounds, and a natural product is synthesized by refluxing the phenanthridinone product in trifluoromethanesulfonic acid in one step, providing a more convenient and easier-to-operate method for the synthesis of natural products, further enriching the application prospects of the method in the preparation of natural products.

[0017] To achieve the above object, the present invention adopts the following technical solutions:

[0018] The present invention provides a method for synthesizing a phenanthridinone compound using palladium catalysis. The method comprises adding a 2-bromobenzamide compound represented by formula (1) and an o-bromobenzoic acid represented by formula (2) as reaction raw materials into an organic solvent, stirring and reacting the mixture at 100 to 120° C. under the catalysis of a metal palladium salt and in the presence of a base and a ligand. After the reaction is complete, the reaction liquid is treated to obtain a phenanthridinone compound represented by formula (3).

[0019] The structural formula of the 2-bromobenzamide compound shown in formula (1) is

[0020] The structural formula of o-bromobenzoic acid shown in formula (2) is

[0021] The structural formula of the phenanthridinone compound shown in formula (3) is

[0022] Wherein, R1 and R2 are both selected from hydrogen, alkyl, alkoxy, heteroaryl or halogen;

[0023] The organic solvent is one of N,N-dimethylformamide, toluene, 1,2-dichloroethane, 1,4-dioxane, acetonitrile, chloroform, and dimethyl sulfoxide;

[0024] The metal palladium salt is one of palladium acetate, palladium dichloride, and tetrakistriphenylphosphine palladium;

[0025] The ligand is one of triphenylphosphine, o-phenanthroline, and L-proline;

[0026] The base is one of cesium carbonate, sodium carbonate and potassium carbonate;

[0027] The molar ratio between the 2-bromobenzamide compound represented by formula (1) and the o-bromobenzoic acid represented by formula (2) is 1:(1.5-2).

[0028] Preferably, the reaction temperature is 110-120° C., and the molar ratio between the 2-bromobenzamide compound represented by formula (1) and the o-bromobenzoic acid represented by formula (2) is 1:1.5.

[0029] Preferably, the solvent is N,N-dimethylformamide, and the amount of the organic solvent used is 4 mL / mmol based on the amount of the 2-bromobenzamide compound represented by formula (1).

[0030] Preferably, the metal palladium salt is palladium acetate.

[0031] Preferably, the amount of the metal palladium salt is 10 mol% of the 2-bromobenzamide compound represented by formula (1).

[0032] Preferably, the ligand is triphenylphosphine, and the amount of the ligand used is 20 mol% of the 2-bromobenzamide compound represented by formula (1).

[0033] Preferably, the amount of the base used is 100 mol% of the 2-bromobenzamide compound represented by formula (1).

[0034] Preferably, the reaction is followed by TLC detection until the reaction is complete, and the developing solvent used for TLC tracking reaction is a petroleum ether / ethyl acetate mixture with a volume ratio of 15:1.

[0035] Preferably, the method for treating the reaction liquid is as follows: after the reaction is completed, the reaction liquid is poured into water, extracted with ethyl acetate, and then the organic phase is backwashed with water, dried over anhydrous calcium chloride, distilled under reduced pressure, and then separated by silica gel column chromatography, and the obtained eluate is distilled under reduced pressure and dried to obtain the phenanthridinone compound shown in formula (3).

[0036] Preferably, the eluent of the silica gel column chromatography is a petroleum ether / ethyl acetate mixture with a volume ratio of 30:1.

[0037] The reaction principle of the present invention is as follows: the present invention uses o-halobenzoic acid as raw material and metal palladium salt as catalyst to construct an optimal reaction system. Pd catalyzes the intermolecular [4+2] cyclization reaction of 2-bromobenzamide and o-bromobenzoic acid through palladium-associated benzene, providing a convenient modular method for the phenanthridinone skeleton. The reaction mechanism of palladium catalysis is shown in the attached figure. Figure 1 As shown, o-bromobenzoic acid reacts with palladium to form a palladium intermediate, which removes bromine and carbon dioxide under alkaline conditions to form a benzyne intermediate. 2-bromobenzamide palladium reacts with 2-bromobenzamide to form a palladium intermediate, which attacks benzyne to generate C(sp 2 )-N bond coupling, followed by debromination and reductive elimination to give the final product.

[0038] Compared with the prior art, the present invention has the following advantages:

[0039] (1) The o-halogenated benzoic acid used in the present invention is a widely used and easily available structural unit in organic synthesis, and is widely used to construct heterocyclic or fused ring skeletons;

[0040] (2) The present invention adopts a one-pot preparation method, which is simple to operate, the reaction raw materials are readily available, the reaction conditions are mild, the reaction system is green and environmentally friendly, and the reaction products are easy to separate and purify, and high-purity phenanthridinone compounds can be prepared efficiently and in high yield;

[0041] (3) The present invention is suitable for synthesizing various highly functionalized phenanthridinone compounds and is suitable for large-scale industrial production. In addition, the natural product is synthesized in one step by refluxing the phenanthridinone product in trifluoromethanesulfonic acid, which provides a more convenient and easier-to-operate method for the synthesis of natural products, further enriching the application prospects of this method in the preparation of natural products. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 A reaction mechanism diagram of the palladium-catalyzed synthesis of phenanthridinone compounds provided by the present invention;

[0043] Figure 2 For Example 1 phenanthridinone 3a 1 H-NMR nuclear magnetic resonance spectrum;

[0044] Figure 3 For Example 1 phenanthridinone 3a13 C-NMR nuclear magnetic resonance spectrum;

[0045] Figure 4 For Example 2 phenanthridinone 3b 1 H-NMR nuclear magnetic resonance spectrum;

[0046] Figure 5 For Example 2 phenanthridinone 3b 13 C-NMR nuclear magnetic resonance spectrum;

[0047] Figure 6 For Example 3 phenanthridinone 3c 1 H-NMR nuclear magnetic resonance spectrum;

[0048] Figure 7 For Example 3 phenanthridinone 3c 13 C-NMR nuclear magnetic resonance spectrum;

[0049] Figure 8 For Example 4 phenanthridinone 3d 1 H-NMR nuclear magnetic resonance spectrum;

[0050] Figure 9 For Example 4 phenanthridinone 3d 13 C-NMR nuclear magnetic resonance spectrum;

[0051] Figure 10 For Example 5 phenanthridinone 3e 1 H-NMR nuclear magnetic resonance spectrum;

[0052] Figure 11 For Example 5 phenanthridinone 3e 13 C-NMR nuclear magnetic resonance spectrum.

[0053] Figure 12 For Example 6 phenanthridinone 3f 1 H-NMR nuclear magnetic resonance spectrum;

[0054] Figure 13 For Example 6 phenanthridinone 3f 13 C-NMR nuclear magnetic resonance spectrum.

[0055] Figure 14 For example 7 natural product 4 1 H-NMR nuclear magnetic resonance spectrum;

[0056] Figure 15 For example 7 natural product 4 13 C-NMR nuclear magnetic resonance spectrum;

[0057] Figure 1In the figure, 1 and 2 represent reaction raw materials 1 and 2, respectively; 3 represents the reaction product; and I, II, III, V, and VI represent reaction intermediates, respectively. DETAILED DESCRIPTION

[0058] The present invention is further described in detail below with reference to the embodiments.

[0059] Example 1

[0060] Exploration of factors affecting the experiment

[0061]

[0062] In order to study the influence of various factors on the reaction yield, the present invention changes the reaction temperature, catalyst, ligand and base for the same reaction substrate, and obtains the yield under different reaction conditions as shown in Table 1 below:

[0063] Table 1 Palladium-catalyzed synthesis of phenanthridinone compounds

[0064]

[0065] From the data in Table 1, it can be concluded that the optimal reaction conditions are: palladium acetate as the metal palladium salt, triphenylphosphine as the ligand, cesium carbonate as the base, DMF as the solvent, and 120°C as the reaction temperature.

[0066] Example 2 Preparation of phenanthridinone derivative 3a

[0067]

[0068] 2-Bromobenzamide 1a (0.214 g, 1.0 mmol), o-bromobenzoic acid 2a (0.301 g, 1.5 mmol), triphenylphosphine (0.053 g, 20% mmol), cesium carbonate (0.326 g, 1.0 mmol) and palladium acetate (0.022 g, 10% mmol) were added to a 25 mL Shrek bottle equipped with a magnetic stirrer. N,N-dimethylformamide (4 mL) was added and stirred until uniform. The mixture was then placed in an oil bath at 120°C and stirred continuously. TLC (developing solvent: V 石油醚 :V 乙酸乙酯 =15:1) detection substrate disappearance, the reaction is completed. The reaction solution was poured into water (30mL), extracted with ethyl acetate (3×10mL), the organic phases were combined, and then backwashed with water (3×10mL). After drying with anhydrous calcium chloride, filtering, and vacuum distillation, a viscous solid was obtained. Finally, silica gel column chromatography (eluent: V 石油醚 :V 乙酸乙酯 =30:1) to obtain a white solid, which was confirmed to be a phenanthridine derivative 3a by NMR and MS, with a yield of 71%.

[0069] Spectral analysis data 3a:

[0070] White solid; 1 H NMR (CDCl3, 400MHz):δ H 8.55(d,J=8.0Hz,1H),8.32–8.25(m,2H),7.76(t,J=7.6Hz,1H),7.61–7.53(m,2H),7.42(d,J=8.4Hz,1H),7.33(t,J=7.6Hz,1H),3.82(s,3H)( Figure 2 );

[0071] 13 C NMR(CDCl3,101MHz):161.7,138.0,133.5,132.4,129.6,128.9,127.9,125.6,123.2,122.5,121.6,119.3,115.0,30.0( Figure 3 ).

[0072] Example 3

[0073] 1a in Example 2 was replaced by 1b, and other conditions were the same as in Example 2. The yield was 67%.

[0074]

[0075] Spectral analysis data 3b:

[0076] White solid; 1 H NMR (CDCl3, 400MHz):δ H 8.62(d,J=7.6Hz,1H),8.39–8.34(m,2H),7.82(t,J=8.0Hz,1H),7.67–7.60(m,2H),7.5 1(d,J=8.4Hz,1H),7.38(t,J=8.0Hz,1H),4.54(q,J=6.8Hz,2H),1.48(t,J=7.2Hz,3H)( Figure 4 );

[0077] 13 C NMR (CDCl3, 101MHz):δ C 161.1,136.9,133.5,132.3,129.5,128.7,127.9,125.6,123.5,122.2,121.5,119.5,114.9,37.7,12.7( Figure 5 ).

[0078] Example 4

[0079] 1c was used to replace 1a in Example 2. Other conditions were the same as those in Example 2. The yield was 73%.

[0080]

[0081] Spectral analysis data 3c:

[0082] White solid; 1 H NMR (CDCl3, 400MHz):δ H 8.56(d,J=8.0Hz,1H),8.29(t,J=9.2Hz,2H),7.76(t,J=7.2Hz,1H),7.61–7.52(m,2H),7.41(d,J= 8.4Hz,1H),7.31(t,J=7.6Hz,1H),4.36(t,J=7.6Hz,1H),1.90–1.80(m,2H),1.09(t,J=7.2Hz,3H)( Figure 6 );

[0083] 13 C NMR(CDCl3,101MHz):161.4,137.1,133.6,132.4,129.5,128.8,127.9,125.5,123.4,122.2,121.5,119.5,115.1,44.2,20.7,11.4( Figure 7 ).

[0084] Example 5

[0085] 1d was used to replace 1a in Example 2. Other conditions were the same as those in Example 2. The yield was 69%.

[0086]

[0087] Spectral analysis data 3d:

[0088] White solid; 1 H NMR (CDCl3, 400MHz):δ H 8.55(d,J=8.0Hz,1H),8.28(t,J=8.8Hz,2H),7.75(t,J=8.0Hz,1H),7.60–7.52(m,2H),7.41(d,J=8.4Hz,1H ),7.31(t,J=7.6Hz,1H),4.40(t,J=7.6Hz,1H),1.83–1.76(m,2H),1.58–1.49(m,2H),1.02(t,J=7.6Hz,3H)( Figure 8 );

[0089] 13 C NMR (CDCl3, 101MHz):δ C 161.3,137.1,133.5,132.3,129.5,128.8,127.9,125.5,123.4,122.2,121.5,119.5,115.1,42.5,29.5,20.4,13.9( Figure 9 ).

[0090] Example 6

[0091] 1e was used to replace 1a in Example 2. Other conditions were the same as those in Example 2. The yield was 68%.

[0092]

[0093] Spectral analysis data 3e:

[0094] White solid; 1 H NMR (CDCl3, 400MHz):δ H 8.63(d,J=8.0Hz,1H),8.30(t,J=7.6Hz,2H),7.80(t,J=7.6Hz,1H),7.62(t,J=7.6Hz,1H),7.40(t,J=8.0Hz,1H),7.32–7.21(m,7H),5.67(s,2H)( Figure 10 );

[0095] 13 C NMR (CDCl3, 101MHz):δ C 161.9,137.3,136.6,133.8,132.7,129.5,129.2,128.8,128.0,127.2,126.5,125.4,123.3,122.6,121.7,119.5,116.0,46.5( Figure 11 ).

[0096] Example 7

[0097] 1f was used to replace 1e in Example 6, and other conditions were the same as those in Example 2. The yield was 64%.

[0098]

[0099] Spectral analysis data 3f:

[0100] White solid; 1 H NMR (CDCl3, 400MHz):δ H8.43(s,1H),8.26(d,J=8.0Hz,1H),8.20(d,J=8.4Hz,1H),7.62(d,J=8.4 Hz,1H),7.39–7.35(m,1H),7.31–7.21(m,7H),5.67(s,2H),2.55(s,3H)( Figure 12 );

[0101] 13 C NMR (CDCl3, 101MHz):δ C 162.0,138.2,137.0,136.6,134.0,131.4,129.0,128.9,128.8,127.1,126.5,125.2,123.0,122.5,121.7,119.7,116.0,46.4,21.4( Figure 13 ).

[0102] Example 8 Preparation of natural product Phenaglydon (4)

[0103]

[0104] 5-Benzyl-8-methylphenan-6(5H)-one (50 mg) prepared in Example 7 was added to a Shrek bottle (25 mL), trifluoromethanesulfonic acid (2.0 mL) was added, and the mixture was heated to reflux temperature with stirring and monitored by TLC until the reaction of the raw material was complete (about 10 h). The mixture was neutralized to neutrality with 10% sodium hydroxide solution and extracted with ethyl acetate (20.0 mL × 2). The organic layer was dried and the organic layer was rotary evaporated to recover ethyl acetate; the residue was separated by column chromatography (the volume ratio between ethyl acetate and petroleum ether was 1:20) to obtain a white solid.

[0105] Spectral analysis data 4:

[0106] White solid; 1 H NMR (CDCl3, 400MHz):δ H 10.67(s,1H),8.39(s,1H),8.21(d,J=8.4Hz,2H),7.63(d,J=8.4Hz,1H),7.4 8(t,J=7.6Hz,1H),7.37(d,J=7.6Hz,1H),7.30(t,J=7.6Hz,1H),2.56(s,3H)( Figure 14 );

[0107] 13 C NMR (CDCl3, 101MHz):δ C162.7,138.1,135.5,134.2,132.3,129.0,128.1,125.5,122.9,122.7,122.0,118.8,116.4,21.4( Figure 15 ).

[0108] This example successfully conducted a derivatization experiment to synthesize the natural product Phenaglydon, further enriching the application prospects of the present invention in the preparation of natural products.

Claims

1. A method for synthesizing phenanthridinone compounds by palladium catalysis, characterized in that: The 2-bromobenzamide compound represented by formula (1) and o-bromobenzoic acid are added to an organic solvent as reaction raw materials, and stirred to react at 100-120°C under the catalysis of a metal palladium salt and in the presence of a base and a ligand. After the reaction is complete, the reaction liquid is treated to obtain a phenanthridinone compound represented by formula (3); The structural formula of the 2-bromobenzamide compound represented by formula (1) is ; The structural formula of the phenanthridinone compound shown in formula (3) is ; wherein R1 is selected from hydrogen; R2 is selected from one of Me, Et, Pr, Bu, and Bn; The organic solvent is N , N - one of dimethylformamide, toluene, 1,2-dichloroethane, 1,4-dioxane, acetonitrile, chloroform, and dimethyl sulfoxide; The metal palladium salt is one of palladium acetate and palladium dichloride; The ligand is triphenylphosphine; The base is one of cesium carbonate, sodium carbonate and potassium carbonate; The molar ratio between the 2-bromobenzamide compound represented by the formula (1) and o-bromobenzoic acid is 1:(1.5-2).

2. The method for synthesizing phenanthridinone compounds by palladium catalysis according to claim 1, wherein The reaction temperature is 110-120° C., and the molar ratio of the 2-bromobenzamide compound represented by formula (1) to o-bromobenzoic acid is 1:1.

5.

3. The method for synthesizing phenanthridinone compounds by palladium catalysis according to claim 1, wherein: The organic solvent is N , N -dimethylformamide, the ratio of the amount of the organic solvent to the amount of the 2-bromobenzamide compound represented by formula (1) is 4 mL:1 mmol.

4. The method for synthesizing phenanthridinone compounds by palladium catalysis according to claim 1, wherein: The metal palladium salt is palladium acetate.

5. The method for synthesizing phenanthridinone compounds by palladium catalysis according to claim 1, wherein: The amount of the metal palladium salt used is 10 mol% of the 2-bromobenzamide compound represented by formula (1).

6. The method for synthesizing phenanthridinone compounds by palladium catalysis according to claim 1, wherein: The amount of the ligand used is 20 mol% of the 2-bromobenzamide compound represented by formula (1).

7. The method for synthesizing phenanthridinone compounds by palladium catalysis according to claim 1, wherein: The amount of the base used is 100 mol% of the 2-bromobenzamide compound represented by formula (1).

8. The method for synthesizing phenanthridinone compounds by palladium catalysis according to claim 1, wherein: The reaction was followed by TLC detection until completion. The developing solvent used for TLC tracking was a mixture of petroleum ether and ethyl acetate with a volume ratio of 15:

1.

9. The method for synthesizing phenanthridinone compounds by palladium catalysis according to claim 1, wherein: The method for treating the reaction liquid is as follows: after the reaction is completed, the reaction liquid is poured into water, extracted with ethyl acetate, and then the organic phase is backwashed with water, dried over anhydrous calcium chloride, distilled under reduced pressure, and then separated by silica gel column chromatography, and the obtained eluate is distilled under reduced pressure and dried to obtain the phenanthridinone compound shown in formula (3).

10. The method for synthesizing phenanthridinone compounds by palladium catalysis according to claim 9, characterized in that: The eluent of the silica gel column chromatography is a petroleum ether / ethyl acetate mixture with a volume ratio of 30:1.

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