CN111116676B - N-heterocyclic carbene palladium complex with pterene structure and application thereof - Google Patents

N-heterocyclic carbene palladium complex with pterene structure and application thereof Download PDF

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CN111116676B
CN111116676B CN202010002321.0A CN202010002321A CN111116676B CN 111116676 B CN111116676 B CN 111116676B CN 202010002321 A CN202010002321 A CN 202010002321A CN 111116676 B CN111116676 B CN 111116676B
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黄菊
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Abstract

The invention relates to an N-heterocyclic carbene palladium complex with a pterene structure. The catalyst has a three-dimensional skeleton, can increase steric hindrance, and a carbon-carbon double bond between C11 and C12 of the vinylidene anthracene in the skeleton structure prevents arylamine from overturning around a carbon-nitrogen bond, so that beta-hydrogen elimination and catalyst inactivation are inhibited, the reaction activity of the catalyst is greatly improved, Suzuki-Miyaura coupling reaction between a nitrogen-containing heterocyclic chloride substrate and low-activity nitrogen-containing heterocyclic boric acid is realized, the reaction can be carried out under the mild conditions of air and water, and meanwhile, higher reaction yield is ensured.

Description

N-heterocyclic carbene palladium complex with pterene structure and application thereof
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to an N-heterocyclic carbene-palladium complex with a pterene structure and application thereof.
Background
The construction of aromatic heterocycles by reactions between heterocyclic and heterocyclic building blocks has been an important and challenging component of the C-C, C-N cross-coupling reaction field. The Suzuki-Miyaura coupling reaction can effectively construct a C-C, C-N bond, so that the method is widely applied to the synthesis fields of natural products, agricultural chemicals, pharmaceutical active ingredients, fine chemicals, engineering materials and the like. Over the past decades, transition metal catalyzed Suzuki-Miyaura coupling reactions have been considered the most efficient and reliable method. However, most catalysts used in the reaction are phosphorus-containing ligands, so that these catalysts have serious environmental pollution and the pre-activation cost of the catalysts is high.
The Suzuki-Miyaura coupling reaction of heterocyclic chlorides with heterocyclic boronic acids is of great importance for the pharmaceutical industry for the preparation of biologically active compounds. However, the problem of how to achieve the Suzuki-Miyaura coupling reaction between the ideal heterocyclic chloride and the nitrogen-containing heterocyclic boronic acid has been a challenge to those skilled in the art. In the prior art, a large number of heterocyclic carbene transition metal complexes are developed as catalysts for the cross-coupling reaction of aryl halides for the coupling of heteroaryl halides, in particular for the coupling reaction of five-membered heteroaryl halides and six-membered heteroaryls with heteroatom substituents. Although Suzuki-Miyaura coupling reaction under air conditions between heterocyclic chloride and heterocyclic boronic acid (j.org.chem.2017,82, 10898-.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention discloses an N-heterocyclic carbene palladium complex with a pterene structure. The pterene structure of the complex has a three-dimensional skeleton, so that the steric hindrance is increased, the center of palladium metal is better protected, the thermal stability in the reaction process is greatly improved, and the complex is not easy to oxidize and decompose; the double bond between C11 and C12 in the 9, 10-dihydro-9, 10-ethenylene anthracene skeleton structure can prevent arylamine from turning around carbon-nitrogen bond, the combined action of the above two can inhibit beta-hydrogen elimination and deactivation of catalyst and greatly improve the reaction activity of catalyst, so that when the N-heterocyclic carbene palladium complex with pterene structure is used as catalyst, the Suzuki-Miyaura coupling reaction between heterocyclic chloride and a plurality of nitrogen-containing heterocyclic boric acids with low activity can be realized, and the reaction can be rapidly and efficiently carried out under the conditions of air and water, and simultaneously, higher reaction yield is ensured.
The invention discloses an N-heterocyclic carbene palladium complex with a pterene structure, which is represented by the following structural general formula:
Figure BDA0002353936790000021
wherein,
r is selected from a hydrogen atom, or an alkyl group and an alkoxy group of C1-C22;
r1-r5each independently selected from a hydrogen atom, or an alkyl group and an alkoxy group of C1-C22;
x is selected from hydrogen atom or halogen.
Further, the N-heterocyclic carbene palladium complex with a pterene structure is characterized in that R is selected from a hydrogen atom or an alkyl group and an alkoxy group of C1-C4.
Further, the N-heterocyclic carbene palladium complex with a pterene structure is characterized in that R is selected from a hydrogen atom, a methyl group, an ethyl group, an isopropyl group or an isobutyl group.
Further, the N-heterocyclic carbene palladium complex with a pterene structure is provided, wherein r1-r5Each independently selected from a hydrogen atom, a C1-C4 alkyl group, and an alkoxy group.
Further, the N-heterocyclic carbene palladium complex of the pterene structure is represented by the following structural general formula:
Figure BDA0002353936790000031
further, the N-heterocyclic carbene palladium complex with a pterene structure is selected from the following structures:
Figure BDA0002353936790000032
the invention also aims to provide the application of the N-heterocyclic carbene palladium complex with the pterene structure as a catalyst in Suzuki-Miyaura coupling reaction.
The invention has the following beneficial effects:
the N-heterocyclic carbene palladium complex with the pterene structure is applied to Suzuki-Miyaura coupling reaction as a catalyst, can realize the coupling reaction of heterocyclic chloride and nitrogen-containing heterocyclic boric acid, can be carried out under the mild conditions of air and water, and simultaneously ensures higher reaction yield, thereby greatly improving the industrialization process of the Suzuki-Miyaura coupling reaction and having wide commercialization prospect.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of K1 in example 1.
FIG. 2 is a nuclear magnetic carbon spectrum of K1 in example 1.
FIG. 3 is a nuclear magnetic hydrogen spectrum of K2 in example 2.
FIG. 4 is a nuclear magnetic carbon spectrum of K2 in example 2.
FIG. 5 is a nuclear magnetic hydrogen spectrum of C1 in example 1.
FIG. 6 is a nuclear magnetic carbon spectrum of C1 in example 1.
Fig. 7 is a nuclear magnetic hydrogen spectrum of C2 in example 2.
FIG. 8 is a nuclear magnetic carbon spectrum of C2 in example 2.
FIG. 9 is a nuclear magnetic hydrogen spectrum of C3 in example 3.
FIG. 10 is a nuclear magnetic carbon spectrum of C3 in example 3.
FIG. 11 is a single crystal structural view of C1 in example 1.
Detailed Description
The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Example 1
The chemical synthesis route of the N-heterocyclic carbene palladium complex with the pterene structure is shown as follows.
(1) Synthesis of pterenone compound A
Figure BDA0002353936790000041
Anthracene (1.78g, 10.0mmol) and vinylene carbonate (8.60g, 100.0mmol) were added sequentially to a 100mL thick-walled flask under nitrogen, and the mixture was refluxed at 180 ℃ for 8 hours. After the reaction, the reaction mixture was cooled to room temperature, and methanol was added to the reaction mixture and stirred. After a large amount of solid is separated out from the reaction system, suction filtration is carried out. The solid was washed repeatedly with methanol and dried under vacuum to give white compound a in 82% yield.
(2) Synthesis of pterenediol compound B
Figure BDA0002353936790000051
A250 mL jar was charged with Compound A (2.11g, 8.0mmol), 1, 4-dioxane (90mL) and 4N NaOH solution (5mL) and reacted at 100 ℃ under reflux for 2 h. Cooling to normal temperature, extracting with dichloromethane for 2-3 times, combining organic layers, drying with anhydrous sodium sulfate, spin-drying, and recrystallizing to obtain white compound B with 89% yield.
(3) Synthesis of pterenedione compound C
Figure BDA0002353936790000052
Under the protection of nitrogen, adding dimethyl sulfoxide (1.12mL, 16mmol) and dichloromethane (50mL) into a bottle with a constant pressure dropping funnel, cooling to-70 ℃, dropwise adding trifluoroacetic anhydride (TFAA) (2.03mL, 14.5mmol) through the constant pressure dropping funnel, and continuing stirring for 10 minutes after a system is clarified; then compound B (1.19g, 5mmol) was dissolved in a small amount of a mixture of dichloromethane and dimethyl sulfoxide (DMSO) and slowly added through a constant pressure dropping funnel; after 1.5h, triethylamine (4.63mL, 33mmol) was added dropwise through a constant pressure dropping funnel, stirring was continued for 1.5h, and the temperature was raised to 5 ℃; the reaction solution was poured into 2M hydrochloric acid solution, extracted several times with dichloromethane and water, the organic phase was collected and dried over anhydrous sodium sulfate, filtered, spun dry and recrystallized from (dichloromethane/petroleum ether) to give C as a yellow solid in 85% yield.
(4) Synthesis of pterenediimine Compound L1-L3
Figure BDA0002353936790000061
Wherein,
L1:R1＝R2＝CH(CH3)2,R3＝H；
L2:R1＝R2＝R3＝CH3。
(4a) synthesis of pterenediimine Compound L1
Under the protection of nitrogen, sequentially adding a compound C (0.048g, 2mmol), 2, 6-diisopropylaniline (1.064g, 6mmol), catalytic amount of p-toluenesulfonic acid and toluene into a 100mL bottle, heating, condensing and refluxing for 24h, after the reaction is finished, cooling the reaction liquid to room temperature, performing rotary evaporation to remove the solvent, dissolving the solid with dichloromethane, then recrystallizing with absolute ethanol to separate out yellow crystals, and performing suction filtration to obtain a corresponding diimine product L1 with the yield of 71%.
1H NMR(400MHz,CDCl3)δ7.22(q,J＝5.6Hz,Ar-H,6H),7.18(d,J＝5.0Hz,Ar-H,8H),4.98(s,CH,2H),2.50(dt,J＝13.5,6.8Hz,CH,4H),1.16(d,J＝6.9Hz,CH3，12H),1.03(d,J＝6.8Hz,CH3,12H)。
13C NMR(101MHz,CDCl3)δ158.4,145.5,138.5,136.3,127.3,125.4,124.1,122.8,51.0,28.3,23.3,22.4。
(4b) Synthesis of pterenediimine Compound L2
Under the protection of nitrogen, sequentially adding a compound C (0.048g, 2mmol), 2,4, 6-trimethylaniline (1.064g, 6mmol), catalytic amount of p-toluenesulfonic acid and toluene into a 100mL bottle, heating, condensing and refluxing for 24h, cooling a reaction solution after the reaction is finished, removing the solvent by rotary evaporation, dissolving the solid with dichloromethane, recrystallizing with absolute ethanol, precipitating yellow crystals, and performing suction filtration to obtain the corresponding diimine product L2 with the rate of 79%.
1H NMR(400MHz,CDCl3)δ7.21(s,Ar-H,8H),6.94(s,Ar-H,4H),4.90(s,CH,2H),2.36(s,CH3,6H),1.85(s,CH3,12H)。
13C NMR(101MHz,CDCl3)δ159.8,145.3,138.1,132.5,128.3,127.5,125.4,125.1,51.0,20.8,17.7。
(5) Synthesis of carbene imidazole salt K1-K2
Figure BDA0002353936790000071
Wherein,
K1:R1＝R2＝CH(CH3)2,R3＝H；
K2:R1＝R2＝R3＝CH3。
(5a) synthesis of carbene imidazolium salt K1
Under the protection of nitrogen, the diimine compound (L1) and chloromethyl ethyl ether were added in sequence to a branched bottle, and the reaction was carried out at 100 ℃ for 24 hours. After the reaction, the solution was cooled to room temperature, and anhydrous ether was added to the reaction solution and stirred to produce a large amount of solid. The solid was washed with anhydrous ether several times and filtered to obtain a white powder with a yield of 70%.
1H NMR(400MHz,CDCl3)δ10.45(s,Ar-H,1H),7.61(t,J＝7.8Hz,Ar-H,2H),7.37(d,J＝7.8Hz,Ar-H,4H),7.32(dd,J＝5.3,3.2Hz,Ar-H,4H),7.04(dd,J＝5.4,3.1Hz,Ar-H,4H),5.21(s,CH,2H),2.09(dt,J＝13.6,6.8Hz,CH,4H),1.11(dd,J＝18.3,6.8Hz,CH3,24H)。
13C NMR(101MHz,CDCl3)δ145.2,144.8,143.8,133.8,132.3,127.9,126.2,124.7,124.3,45.8,28.9,24.3,23.2。
(5b) Synthesis of carbene imidazolium salt K2
The synthesis method is similar to K1, and the diimine compound (L2) and chloromethyl ethyl ether are added into a bottle with a branch mouth for reaction for 24 hours, and white powder is obtained after the reaction is finished, and the yield is 72 percent.
1H NMR(400MHz,CDCl3)δ10.35(s,Ar-H,1H),7.35-7.29(m,Ar-H,4H),7.06(s,Ar-H,4H),7.04(dd,J＝5.4,3.1Hz,Ar-H,4H),5.13(s,CH,2H),2.37(s,CH3,6H),1.95(s,CH3,12H)。13C NMR(101MHz,CDCl3)δ144.3,144.2,,141.4,134.6,133.6,130.0,128.8,126.4,124.3,45.9,21.3,17.8。
(6) Synthesis of N-heterocyclic carbene palladium complex with pterene structure
Figure BDA0002353936790000081
Wherein,
C1:R1＝R2＝CH(CH3)2,R3＝H，X＝Cl
C2:R1＝R2＝CH(CH3)2,R3＝H，X＝H
C3:R1＝R2＝R3＝CH3，R3＝H，X＝Cl
(6a) synthesis of N-heterocyclic carbene palladium complex C1 with pterene structure
Under nitrogen protection, carbene imidazole salt (K1) (1mmol), palladium chloride (0.195g, 1.1mmol), potassium carbonate (1.382g, 10mmol) and 3-chloropyridine (10mL) were added in this order to a 25mL vial, and reacted at 80 ℃ for 24 hours. After the reaction, the solution was cooled to room temperature, a small amount of dichloromethane was added, and then the reaction solution was placed on a silica gel column and passed through the column by a flash dry method using dichloromethane. The filtrate was evaporated to give a tan solid. The yellow brown solid is completely dissolved by dichloromethane, and is dripped into a flask containing a large amount of normal hexane under the stirring state to be stirred, and the solid is separated out after a period of time. The normal hexane is repeatedly stirred and washed for a plurality of times, and light yellow solid is obtained by suction filtration, and the yield is 60 percent.
1H NMR(400MHz,CDCl3)δ8.46(d,J＝2.3Hz,Ar-H,1H),8.39(dd,J＝5.6,1.2Hz,Ar-H,1H),7.58(t,J＝7.7Hz,Ar-H,2H),7.49(ddd,J＝8.2,2.2,1.3Hz,Ar-H,1H),7.42(d,J＝7.7Hz,Ar-H,4H),7.22(dd,J＝5.3,3.2Hz,Ar-H,4H),6.99(dd,J＝8.2,5.6Hz,Ar-H,1H),6.93-6.87(m,Ar-H,4H),5.16(s,CH,2H),2.87(dt,J＝13.3,6.6Hz,CH,4H),1.39(d,J＝6.5Hz,CH3,12H),1.02(d,J＝6.8Hz,CH3,12H)。
13C NMR(101MHz,CDCl3)δ150.4,149.4,147.9,146.0,144.8,137.2,132.7,131.7,130.4,124.3,124.3,124.2,47.4,28.3,27.1,23.9。
(6b) Synthesis of N-heterocyclic carbene palladium complex C2 with pterene structure
The synthesis method is the same as C1, carbene imidazole salt K1, palladium chloride, potassium carbonate and pyridine are sequentially added into a bottle with a branch mouth, and the mixture reacts for 24 hours at the temperature of 80 ℃, so that light yellow powder C2 is obtained after post-treatment, and the yield is 65%.
1H NMR(400MHz,CDCl3)δ8.44-8.38(m,Ar-H,2H),7.57(t,J＝7.7Hz,Ar-H,2H),7.48(ddd,J＝7.6,4.6,1.5Hz,Ar-H,1H),7.41(d,J＝7.7Hz,Ar-H,4H),7.21(dt,J＝7.2,3.6Hz,Ar-H,4H),7.03(dd,J＝7.4,6.6Hz,Ar-H,2H),6.93-6.87(m,Ar-H,4H),5.17(d,J＝8.4Hz,CH,2H),2.95-2.82(m,CH2,4H),1.39(d,J＝6.5Hz,CH3,12H),1.01(d,J＝6.8Hz,CH3,12H).
13C NMR(101MHz,CDCl3)δ152.2,151.4,148.0,146.1,144.7,137.2,132.8,130.4,124.9,124.4,124.3,123.9,47.4,28.3,27.1,24.0。
(6c) Synthesis of N-heterocyclic carbene palladium complex C3 with pterene structure
The synthesis method is the same as C1, carbene imidazole salt K2, palladium chloride, potassium carbonate and 3-chloropyridine are sequentially added into a bottle with a branch mouth, the reaction is carried out for 24 hours at the temperature of 80 ℃, and the post-treatment is carried out to obtain faint yellow powder C3, wherein the yield is 70%.
1H NMR(400MHz,CDCl3)δ8.53(d,J＝2.3Hz,Ar-H,1H),8.44(dd,J＝5.6,1.3Hz,Ar-H,1H),7.51(ddd,J＝8.2,2.3,1.3Hz,Ar-H,1H),7.23(dd,J＝5.3,3.2Hz,Ar-H,4H),7.09(s,Ar-H,4H),7.02(dd,J＝8.2,5.6Hz,Ar-H,1H),6.97-6.92(m,Ar-H,4H),4.96(s,CH,2H),2.43(s,CH3,6H),2.13(s,CH3,12H)。
13C NMR(101MHz,CDCl3)δ150.4,149.5,145.9,145.4,144.0,139.3,137.3,136.7,132.8,131.8,129.3,125.3,124.1,123.7,46.8,21.3,19.1。
The nuclear magnetic spectrum of the related intermediate products K1-K2 and the nuclear magnetic spectrum of C1-C3 are shown in figures 1-10.
Example 2 catalysis of Suzuki-Miyaura coupling reaction by N-heterocyclic carbene-Palladium complexes with pterene structures
The experimental procedure for testing the catalytic activity of N-heterocyclic carbene palladium complexes with a pterene structure for Suzuki-Miyaura coupling reactions is as follows:
control experiments were set up with 2-thiopheneboronic acid (1.0mmol), 2-chloropyridine (1.0mmol) as substrate, mixed with sodium carbonate (2mmol) and added to parallel reaction tubes using tetrahydrofuran and water (1:3v/v, 4ml) as solvents, and C1-C3, D1, E1 (0.1 mol% of substrate) as catalysts, respectively. Then reacted at 80 ℃ for 4h in air. After the reaction is finished, adding ethyl acetate and water for extraction for 2-3 times after the parallel reaction tubes are cooled to room temperature. The organic layer was dried over anhydrous sodium sulfate, the remaining reaction solution was rotary evaporated, the product was purified and isolated by thin layer analysis, and the yield was measured by GC.
Wherein the structures of D1 and E1 are shown as the following figures:
Figure BDA0002353936790000101
wherein:
R1＝R2＝CH(CH3)2,R3＝H，X＝Cl
the results of the parallel reaction tube experiments are shown in Table 1.
TABLE 1 yield of each sample from parallel reaction tubes
Catalyst and process for producing the same C1 C2 C3 D1 E1
Yield% 93 89 85 85 67
As can be seen from Table 1, the catalytic effect of C1 is superior to that of several other catalysts when the substituent is isopropyl. The reason for this is that the catalytic performance of the catalyst is closely related to both steric hindrance and electronic effects. Generally, the steric hindrance is too small, a framework structure cannot effectively protect a metal palladium center in the reaction process, the steric hindrance is too large, so that the insertion of a reaction substrate is difficult, and the activity is greatly influenced. The choice of substituents is therefore also of particular importance. FIG. 9 is a single crystal structural view of C1 in example 1.
Example 3
As the reaction activity of the thiopheneboronic acid is higher, the result can not completely reflect the high activity of the pterene skeleton structure catalyst in a comparative experiment, therefore, a series of nitrogen-containing heterocyclic chloride (1.0mmol) and nitrogen-containing heterocyclic boronic acid (1.0mmol) with lower activity are taken as substrates, mixed with sodium carbonate (2mmol), tetrahydrofuran and water (1:3v/v, 4ml) are taken as solvents to be added into a parallel reaction tube, and the N-heterocyclic carbene palladium complex C1-C3 (0.5 mol% of the substrate) disclosed by the invention is taken as a catalyst to be added into the parallel tube. Then reacted at 80 ℃ for 0.5h in air. After the reaction is finished, adding ethyl acetate and water for extraction for 2-3 times after the parallel reaction tubes are cooled to room temperature. Drying the organic layer by anhydrous sodium sulfate, performing rotary evaporation on the residual reaction solution, performing thin-layer analysis, purifying and separating a product, performing nuclear magnetic characterization, determining the structure of the coupling product, and measuring and calculating the yield according to GC.
TABLE 2 yield of Suzuki-Miyaura coupling reactions with different substrates and different catalysts
Figure BDA0002353936790000102
Figure BDA0002353936790000111
Figure BDA0002353936790000121
Figure BDA0002353936790000131
Figure BDA0002353936790000141
From the yield results of the above experiments, it can be seen that the catalyst is an N-heterocyclic carbene palladium complex with a pterene structure C1-C3, which is used as a catalyst for heterocyclic chloride and nitrogen-containing heterocyclic boronic acid with low activity in Suzuki-Miyaura coupling reaction, and the yield thereof is significantly superior to that of the control samples D1 and E1.
Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present invention and do not limit the protection scope of the present invention. It will be understood by those skilled in the art that various deductions and equivalents may be made to the technical solution of the present invention without departing from the spirit and scope of the technical solution of the present invention.

Claims (2)

1. An N-heterocyclic carbene palladium complex with a pterene structure is characterized by having the following structure:
Figure FDA0003608405230000011
2. use of an N-heterocyclic carbene palladium complex with a pterene structure according to claim 1 as a catalyst in Suzuki-Miyaura coupling reactions.
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Easily Prepared Air- and Moisture-Stable Pd–NHC (NHC=N-Heterocyclic Carbene) Complexes: A Reliable, User-Friendly, Highly Active Palladium Precatalyst for the Suzuki–Miyaura Reaction;Christopher J. O"Brien et al.;《Chem. Eur. J.》;20060328;Scheme 1、表2 *
Highly Efficient Bulky α-Diimine Palladium Complexes for Suzuki-Miyaura Cross-Coupling Reaction;Ping Huo et al.;《Chin. J. Chem.》;20170313;363页右栏最后一段，365页右栏最后一段，366页左栏第一段，表2 *

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