Method for activating Michael addition reaction by using carbon-hydrogen bonds of heterocyclic carboxylic acid

Abstract

The invention provides a method for activating Michael addition reaction by using a carbon-hydrogen bond of heterocyclic carboxylic acid, and belongs to the technical field of chemical synthesis. The method comprises the following steps: carrying out Michael addition reaction on heterocyclic carboxylic acid and nitroindole under the action of a catalytic system; the catalytic system comprises a catalyst and a cocatalyst, the catalyst is at least one of [Ru (p-cymene) Cl2] 2, RuCl3. 3H2O, RuH2 (CO) (PPh3) 3, RuH2 (PPh3) 3 and Ru3 (CO) 12, and the cocatalyst is at least one of AgSbF6, AgNTf2, Cu (OAc) 2, Zn (OAc) 2, KPF6 and NaPF6. The synthesis method of the aryl heterocyclic derivative is developed and enriched, a valuable new strategy is provided for constructing organic molecules with various structures, and the aryl heterocyclic derivative has important academic value and practical significance.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for activating Michael addition reaction by using carbon-hydrogen bonds of heterocyclic carboxylic acids. Background Art

[0002] Carbon-hydrogen bonds are ubiquitous in organic molecules and have high dissociation energies. How to selectively activate carbon-hydrogen bonds has always been a difficult problem for organic chemists. In recent years, transition metal-catalyzed CH bond activation reactions have gradually become a research hotspot in organic chemistry. This synthetic method has now become an indispensable part of organic chemistry, pharmaceuticals, natural products, and functional molecular material synthesis.

[0003] The CH bond activation reaction also has many advantages that are difficult to compare with other reactions, such as fewer reaction steps, high reaction efficiency, and high regio- and stereo-selectivity. The CH bond activation reaction can activate the CH bonds in adjacent positions by chelating and coordinating the inducing group with the transition metal, and then carry out subsequent reactions to obtain the corresponding target compounds. In recent years, great progress has been made in the application of transition metal catalysts (such as cobalt, palladium, and ruthenium) in CH bond activation, showing advantages such as high reaction selectivity, excellent functional group tolerance, wide substrate universality, and excellent yield.

[0004] Among the many types of transition metal-catalyzed CH bond activation reactions, Michael addition is an important bond-forming strategy that exhibits many advantages. In these transformations, the key step is the in-situ generation of active CMs through CH bond activation, which reduces the number of steps in the synthetic operation and reduces the generation of chemical waste. In addition, in the field of transition metal catalysis, unsaturated compounds to which CH is directly added usually contain synthetic groups or heteroatoms, which can be activated through CH bonds to synthesize more functional synthetic molecules. Therefore, people are paying more and more attention to this research direction.

[0005] In the traditional CH bond functionalization process, the ortho-metalation of the chelating group DG usually acts as a complex with nucleophilic activity, which is added to a substrate to generate an ideal functionalized product ( Figure 1 .a), but this single coordination mode of chelation assistance is very limited in the selection of Michael acceptors, and can only carry out conjugate addition reactions of highly active Michael acceptors, and the product diversity is poor. Although the traditional single coordination mode has been greatly improved in the field of CH bond activation Michael addition reactions ( Figure 1 .b), but for the direct construction of special building blocks, further exploration of new chelation-assisted strategies to achieve efficient CH functionalization is still very necessary. In recent years, people have developed a double coordination chelation-assisted mode, which can enable cyclometallated complexes with better performance and high CH bond activation regioselectivity ( Figure 1 .c).

[0006] Among the many transition metals, divalent ruthenium has very good advantages. Compared with other precious metals such as rhodium and palladium, ruthenium is cheaper and more readily available. In particular, divalent ruthenium catalysts can be easily converted into cyclometalates through CH deprotonation, and the catalysts are relatively stable to oxidants, air and water. In addition, divalent ruthenium is easy to coordinate with the carboxyl group of heterocyclic carboxylic acids in the catalytic Michael addition reaction, which stabilizes the reaction intermediates, lowers the transition state energy, and allows the reaction to proceed in the expected direction. In addition, the uncoordinated carboxylic acid can cause ruthenium to dissociate rapidly, thereby realizing a catalytic cycle and promoting the formation of addition products. Summary of the invention

[0007] The purpose of the present invention is to propose a method for activating the Michael addition reaction using the carbon-hydrogen bond of a heterocyclic carboxylic acid, enrich the synthesis methods of aromatic heterocyclic derivatives, provide a valuable new strategy for constructing organic molecules with diverse structures, and have important academic value and practical significance.

[0008] The technical solution of the present invention is achieved in this way:

[0009] The present invention provides a method for activating Michael addition reaction by using carbon-hydrogen bond of heterocyclic carboxylic acid, wherein heterocyclic carboxylic acid and nitrogen-based indole undergo Michael addition reaction under the action of a catalytic system; the catalytic system comprises a catalyst and a co-catalyst, and the catalyst is [Ru(p-cymene)Cl2]2, RuCl3.3H2O, RuH2(CO)(PPh3)3, RuH2(PPh3)3, Ru3(CO) 12 At least one of the co-catalysts, such as AgSbF6, AgNTf2, Cu(OAc)2, Zn(OAc)2, KPF6, and NaPF6.

[0010] As a further improvement of the present invention, the heterocyclic carboxylic acid is selected from at least one of coumarin-3-carboxylic acid, 1,4-dihydroquinolinone-3-carboxylic acids, and benzopyrone-3-carboxylic acid.

[0011] As a further improvement of the present invention, the nitrogen-based indole is N-(2-pyridyl)indole.

[0012] As a further improvement of the present invention, the heterocyclic carboxylic acid is coumarin-3-carboxylic acid.

[0013] As a further improvement of the present invention, the catalytic system also includes a base, and the base is selected from at least one of K3PO4, Cs2CO3, K2CO3, NaOAc, KOAc, tBuOK, and Et3N.

[0014] As a further improvement of the present invention, the molar ratio of the catalyst to the co-catalyst is 1:3-7.

[0015] As a further improvement of the present invention, the addition amount of the catalytic system is 2-25 mol%.

[0016] As a further improvement of the present invention, the reaction temperature is 110-130° C. and the reaction time is 20-30 h.

[0017] The present invention has the following beneficial effects: by selecting the central metal and optimizing the reaction conditions, the present invention conducts research on the carbon-hydrogen bond activation decarboxylation arylation reaction of heterocyclic carboxylic acid compounds (including coumarin 3-carboxylic acid, 1,4-dihydroquinolinone-3-carboxylic acid, and benzopyrone-3-carboxylic acid) catalyzed by divalent ruthenium, and achieves the synthesis of biologically active and functional aromatic heterocyclic derivatives with high yield and high regioselectivity. The present invention enriches the synthesis methods of aromatic heterocyclic derivatives, provides a valuable new strategy for constructing organic molecules with diverse structures, and has important academic value and practical significance. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative labor.

[0019] Figure 1 It is the basic drawing for the preliminary work;

[0020] Figure 2 It is the hydrogen spectrum of 4-(N-(2-pyridyl)-3-indolyl)benzopyrone compounds;

[0021] Figure 3 It is the carbon spectrum of 4-(N-(2-pyridyl)-3-indolyl)benzopyrone compounds;

[0022] Figure 4 is the hydrogen spectrum of the product obtained in Example 2;

[0023] Figure 5 The carbon spectrum of the product obtained in Example 2;

[0024] Figure 6 is the hydrogen spectrum of the product obtained in Example 3;

[0025] Figure 7 The carbon spectrum of the product obtained in Example 3;

[0026] Figure 8is the hydrogen spectrum of the product obtained in Example 4;

[0027] Fig. 9 This is the carbon spectrum of the product obtained in Example 4. DETAILED DESCRIPTION

[0028] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0029] Example 1

[0030] 1. Synthesis of substituted indoles

[0031] Synthesis route of N-(2-pyridyl)indole:

[0032]

[0033] Indole (50mmol) (R'=H), potassium phosphate (132mmol) and cuprous iodide (5mmol) were added to a 100mL reaction flask, and the argon was replaced repeatedly 5 times. Under the protection of argon, 50mL of toluene was added, and then N,N-dimethylethylenediamine (12mmol) and 2-bromopyridine (60mmol) were added in sequence with a syringe. Finally, the reaction was reacted at 120℃ for 24h. After the reaction was completed, 30mL of saturated brine was added to quench the reaction, and 20mL, 20mL, and 15mL of dichloromethane were used for 3 times, respectively. The organic phases were combined and purified by silica gel column chromatography (PE / EA=50:1) to obtain N-(2-pyridyl)indole.

[0034] Synthesis route of N-(2-pyrimidinyl)indole 5:

[0035]

[0036] Indole (10 mmol) (R'=H) was added to a dry 100 mL three-necked round-bottomed flask, argon was replaced repeatedly 5 times, 25 mL DMF was added under argon, the system was placed in an ice-water bath, sodium hydride (11 mmol) was added in batches and stirred for 30 minutes, and 2-chloropyrimidine (12 mmol) was added. The reaction was placed at 150 ° C for 8 h. After the reaction was completed, 30 mL of ice water was added to quench the reaction, and 20 mL of DCM was used to extract 3 times, the organic phase was combined, and then washed twice with 30 mL of saturated brine, and the product was purified by silica gel column chromatography (PE / EA=10:1).

[0037] 2. Synthesis of substituted coumarin-3-carboxylic acids

[0038] Synthesis route:

[0039]

[0040] Salicylaldehyde (10 mmol) (R'=H), Michaelis acid (30 mmol), and L-glutamic acid (1 mmol) were added to a dry 50 mL round-bottom flask, and 20 mL of ethanol was added, and the reaction system was heated to reflux for 24 h. After the reaction was complete, the system was placed in an environment of -16 ° C for 12 h, filtered, and the solid phase and organic phase were retained. 30 mL of water was added to the organic phase to quench the reaction, extracted with ethyl acetate 3 times, and the organic phases were combined. Purification was performed by silica gel column chromatography (PE / EA=4:1), and the solid phases were combined to obtain substituted coumarin-3-carboxylic acid.

[0041] Synthesis and Characterization of 3-(N-(2-pyridyl)-3-indolyl)benzopyrone Derivatives

[0042] Synthesis route:

[0043]

[0044] Substituted coumarin-3-carboxylic acid (1.2 mmol), zinc acetate (1.0 mmol), [Ru(p-cymene)Cl2]2 (2.5 mol%), and pivalic acid (1.0 mmol) were added to a 25 mL Shrek tube, and the argon was replaced repeatedly for 5 times. Under the protection of argon, 2.0 mL of toluene was added with a syringe to dissolve N-(2-pyridyl)indole (0.4 mmol). Finally, the system was placed in a 120 ° C environment for 24 hours. After the reaction, the insoluble impurities were filtered out with diatomaceous earth and the solvent was concentrated. Purification was performed by silica gel column chromatography (PE / EA=4:1) to obtain 4-(N-(2-pyridyl)-3-indolyl)-2-benzopyrone compounds (R 1 =R 2 =H), white solid, yield 92%, melting point 47.5-48.3°C.

[0045] Hydrogen spectrum Figure 2, 1H NMR (600MHz, CDCl3) δ8.54 (dd, J=4.8, 1.2Hz, 1H), 8.19 (d, J=8.4Hz, 1H), 7.82 (td ,J=8.1,1.8Hz,1H),7.52(d,J=7.9Hz,1H),7.45(d,J=8.2Hz,1H),7.41(s,1H),7.3 6-7.31(m,2H),7.26(s,1H),7.23-7.16(m,4H),7.09(td,J=7.5,1.0Hz,1H),4.71( dd,J=7.9,5.8Hz,1H), 3.30(dd,J=15.9,8.1Hz,1H), 3.15(dd,J=15.8,5.7Hz,1H). Carbon spectrum Figure 3 ,13C NMR(151MHz,DMSO-d6)δ168.4,152.0,151.8,149.2,139.8,135.6,129.1,128.7,128.5,126.5,125.0,1 24.4,124.0,121.7,121.0,120.0,118.7,117.2,114.8,114.3,35.8,31.7.HRMS(ESI)m / z:[M+H]+calcd for C 22 H 16 N2O2 + :341.1290,found:341.1276.

[0046] Example 2

[0047] The difference from Example 1 is that R 1 =F, R 2 =H. The product structure is as follows:

[0048]

[0049] White solid, yield 78%, melting point = 196.2-197.3 ° C. 1H NMR (600MHz, CDCl3) δ 8.53 (d, J = 3.7 Hz, 1H), 8.23 ​​(dd, J = 9.1, 4.5 Hz, 1H), 7.81 (td, J = 8.2, 1.8 Hz, 1H), 7.39-7.32 (m, 3H), 7.17 (ddd, J = 14.4, 8.5, 3.1 Hz, 4H), 7.12-7.05 (m, 2H), 4.66-4.62 (m, 1H), 3.25 (dd, J = 15.8, 7.6 Hz, 1H), 3.14 (dd, J = 15.8, 5.7 Hz, 1H). 13C NMR (151MHz, CDCl3) δ167.7, 159.2, 157.7, 151.6, 148.9, 138.6, 132.4, 128.9 (d, J = 24.4Hz), 128.8 (d, J = 9.2Hz), 12 8.1,125.3,125.0,124.8,120.4,117.3,114.9(d,J=9.0Hz),114.3,112.0,111.9,104.3(d,J=23.8Hz),36.0,32.5.

[0050] Example 3

[0051] The difference from Example 1 is that R 1 =Cl, R 2 =H. The product structure is as follows:

[0052]

[0053] White solid, yield 88%, melting point = 195.8-196.9℃. 1 H NMR (600MHz, CDCl3) δ8.53(dd,J=4.8,1.2Hz,1H),8.18(d,J=8.9Hz,1H),7.82(td,J=8.1,1.9Hz,1H),7.50(d,J=1.9Hz,1H),7.38-7.33(m,3H),7.29(d d,J=8.9,2.0Hz,1H),7.21-7.17(m,3H),7.12(td,J=7.5,0.8Hz,1H),4.65( t, J=6.5Hz, 1H), 3.26 (dd, J=15.8, 7.4Hz, 1H), 3.14 (dd, J=15.8, 5.7Hz, 1H). 13C NMR (151MHz, CDCl3) δ167.6,151.6,151.5,148.7,138.9,134.3,129.3,129.0,128.1,12 7.2,125.2,124.9,124.9,124.1,120.7,118.6,117.6,117.3,114.9,114.6,36.0,32.4.

[0054] Example 4

[0055] The difference from Example 1 is that R 1 =Br, R 2 =H. The product structure is as follows:

[0056]

[0057] White solid, yield 83%, melting point = 198.5-200.3℃.1H NMR (600MHz, CDCl3) δ8.54 (dd, J=4.9, 1.2Hz, 1H), 8.11 (d, J=8.9Hz, 1H), 7.85 (td ,J=8.2,1.9Hz,1H),7.66(d,J=1.8Hz,1H),7.43-7.39(m,2H),7.36-7.33(m,2H), 7.22(dd,J=7.3,5.0Hz,1H),7.20-7.17(m,2H),7.13(td,J=7.5,1.0Hz,1H),4.65 (t,J=6.5Hz,1H),3.26(dd,J=15.8,7.4Hz,1H),3.15(dd,J=15.8,5.7Hz,1H).13C NMR (151MHz, CDCl3) δ167.6,151.7,151.4,148.6,139.0,134.6,130.0,129.0,128.1,12 6.8,125.0,124.9,124.8,121.7,120.7,117.6,117.3,115.2,114.8,114.7,36.1,32.4.

[0058] Example 5-24

[0059] The synthetic route is as follows:

[0060]

[0061]

[0062]

[0063] It can be seen from the above table that the yield is highest when the molar ratio of Zn(OAc)2 and PivOH is 1:1.

[0064] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for activating Michael addition reaction using carbon-hydrogen bonds of heterocyclic carboxylic acids, characterized in that: The heterocyclic carboxylic acid and the nitrogen-based indole undergo Michael addition reaction under the action of a catalytic system; the catalytic system comprises a catalyst and a co-catalyst, and the catalyst is [Ru(p-cymene)Cl2]2, RuCl3.3H2O, RuH2(CO)(PPh3)3, RuH2(PPh3)3, Ru3(CO) 12 At least one of the co-catalysts, such as AgSbF6, AgNTf2, Cu(OAc)2, Zn(OAc)2, KPF6, and NaPF6.

2. The method according to claim 1, characterized in that The heterocyclic carboxylic acid is selected from at least one of coumarin-3-carboxylic acid, 1,4-dihydroquinolinone-3-carboxylic acids, and benzopyrone-3-carboxylic acid.

3. The method according to claim 1, characterized in that The nitrogen-based indole is N-(2-pyridyl)indole.

4. The method according to claim 1, characterized in that: The heterocyclic carboxylic acid is coumarin-3-carboxylic acid.

5. The method according to claim 1, characterized in that: The catalytic system also includes a base, which is selected from at least one of K3PO4, Cs2CO3, K2CO3, NaOAc, KOAc, tBuOK, and Et3N.

6. The method according to claim 1, characterized in that The molar ratio of the catalyst to the co-catalyst is 1:3-7.

7. The method according to claim 1, characterized in that The addition amount of the catalyst system is 2-25 mol%.

8. The method according to claim 1, characterized in that The reaction temperature is 110-130° C. and the reaction time is 20-30 hours.

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