Synthetic method of visible light promoted pyrimidine compound

Abstract

The invention relates to the technical field of organic synthetic chemistry, in particular to a visible light promoted pyrimidine compound synthesis method. Amino ketene and amidine salt are used as raw materials, DBU is used as alkali, stirring reaction is carried out under visible light, and the pyrimidine compound is obtained. The method is simple and convenient to operate, does not need transition metal and photocatalyst, and has the advantages of greenness and environmental protection. Besides, the synthesis method is mild in reaction condition, simple and convenient to operate and free of water-free and oxygen-free operation, opens up a new path for synthesis of pyrimidine compounds, and has wide application prospects and important research value.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthetic chemistry, and in particular to a method for synthesizing a pyrimidine compound promoted by visible light. Background Art

[0002] As an important class of nitrogen heterocyclic compounds, pyrimidine compounds have attracted great attention due to their unique structural characteristics and wide range of biological activities. This type of compound has a high degree of structural diversity and can be functionalized through a variety of synthetic pathways, thus giving it a wide range of applications in the fields of medicine, materials and pesticides. For example, pyrimidine derivatives have shown excellent antibacterial, anticancer and antiviral activities in drug development, providing an important chemical skeleton for the design of new drugs. At the same time, pyrimidine compounds have also been used to develop functional materials with optical properties, especially in optoelectronic devices. They show great potential. Therefore, the synthesis research of pyrimidine compounds has received extensive attention (Eur. J. Org. Chem., 2017, 2856-2865).

[0003] Although the reported synthetic methods provide various methods for the synthesis of pyrimidine compounds, there are still some limitations. For example, some methods require the use of expensive and difficult-to-recycle metal catalysts, and have poor applicability to certain substrates; although microwave-assisted technology is highly efficient, it has high equipment requirements and is not suitable for large-scale synthesis. Therefore, the synthesis of pyrimidine compounds still needs to be further optimized to develop a new reaction system with simple operation, wide substrate applicability, mild reaction conditions, and green environmental protection to meet the needs of fields such as medicinal chemistry and materials science.

[0004] In recent years, visible light-induced chemical reactions have gradually become an important synthetic strategy due to their green and efficient characteristics. Through the generation of active intermediates under mild conditions, efficient construction of various chemical bonds can be achieved. Amino enone compounds are a class of compounds with simple structures and easy to obtain, with unique reactivity, and are widely used in organic synthesis. However, literature research shows that there is no report on the method of efficiently constructing heterocyclic compounds using amino enone compounds and formamidine hydrochloride as raw materials under visible light irradiation. Here, the present application makes full use of the green and sustainable advantages of photocatalytic reactions, combines DBU as a base, and develops a visible light-induced reaction system to achieve efficient synthesis of nitrogen heterocyclic pyrimidine compounds. Summary of the invention

[0005] The object of the present invention is to provide a method for synthesizing a pyrimidine compound promoted by visible light to solve the problems raised in the above background technology.

[0006] To achieve the above object, the present invention provides the following technical solution: a method for synthesizing a pyrimidine compound promoted by visible light, comprising the following steps:

[0007] In an organic solvent, an amino enone compound having a structure as shown in formula (I) and an amidine salt having a structure as shown in formula (II) are used as reaction raw materials, and a reaction is carried out in the presence of a base in an open air at room temperature under visible light irradiation. After the reaction is completed, the reaction solution is decompressed to remove the solvent to obtain a crude product, and the crude product is purified by column chromatography to obtain a pyrimidine compound having a structure as shown in formula (III). The reaction equation is shown below:

[0008]

[0009] Wherein, the compound of formula (I) is an amino enone compound, R 1 is naphthyl, furanyl, thienyl, pyridyl, benzofuranyl, phenyl, or phenyl substituted with a substituent, wherein the substituent is halogen, alkyl, alkylnitro, or alkoxy; the compound of formula (II) is an amidine salt; R 2 is 3-6 carbon ring alkyl, naphthyl, furyl, phenyl, phenyl with one substituent, wherein the substituent is halogen, alkyl, alkyl nitrogen, alkoxy;

[0010] Preferably, the molar ratio of the amino enone compound of the structure represented by formula (I) to the amidine salt of the structure represented by formula (II) is 1:2 to 2:1, preferably 1:1, and the DBU is 1 to 3 equivalents, preferably 3 equivalents.

[0011] Preferably, the base is any one of potassium phosphate, potassium carbonate, potassium tert-butoxide, triethylamine, pyridine and DBU, preferably DBU.

[0012] Preferably, the organic solvent is any one of acetonitrile, methanol, ethanol, nitromethane, dichloroethane, toluene, chlorobenzene and xylene, preferably methanol.

[0013] Preferably, the irradiation light source for the reaction is any one of sunlight, fluorescent lamp, tungsten lamp and LED lamp, preferably LED lamp.

[0014] Preferably, the reaction time is 20h-30h.

[0015] Preferably, after the reaction is completed, the reaction solution is concentrated under reduced pressure, and the concentrate is separated by column chromatography, using a mixed solution of petroleum ether and ethyl acetate as an eluent, wherein the volume ratio of petroleum ether:ethyl acetate is (50-1):1, and the eluate is collected, and the solvent is evaporated to obtain a pyrimidine compound with a structure shown in formula (III).

[0016] Compared with the prior art, the present invention has the following beneficial effects:

[0017] (1) The present invention does not require expensive transition metal catalysts and photocatalysts, and has low cost; it uses visible light as an energy source, which meets the requirements of green chemistry.

[0018] (2) The present invention can be carried out under air and room temperature conditions, the reaction conditions are mild, the operation is simple, and it has high practicality.

[0019] (3) The functional groups of the present invention have good compatibility and provide a new method for synthesizing various substituted pyrimidine compounds. DETAILED DESCRIPTION

[0020] 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.

[0021] The present invention provides the following technical solution: a method for synthesizing a pyrimidine compound promoted by visible light, comprising the following steps:

[0022] In an organic solvent, an amino enone compound having a structure as shown in formula (I) and an amidine salt having a structure as shown in formula (II) are used as reaction raw materials, and a reaction is carried out in the presence of a base in an open air at room temperature under visible light irradiation. After the reaction is completed, the reaction solution is decompressed to remove the solvent to obtain a crude product, and the crude product is purified by column chromatography to obtain a pyrimidine compound having a structure as shown in formula (III). The reaction equation is shown below:

[0023]

[0024] Wherein, the compound of formula (I) is an amino enone compound, R 1 is naphthyl, furanyl, thienyl, pyridyl, benzofuranyl, phenyl, or phenyl substituted with a substituent, wherein the substituent is halogen, alkyl, alkylnitro, or alkoxy; the compound of formula (II) is an amidine salt; R 2 It is a 3-6 carbon ring alkyl group, naphthyl, furyl, phenyl, or a phenyl group having a substituent, wherein the substituent is a halogen, an alkyl group, an alkyl nitrogen group, or an alkoxy group.

[0025] The irradiation light source of the reaction is an LED lamp; the base is DBU; and the organic solvent is methanol.

[0026] Example 1

[0027] The reaction equation is shown below:

[0028]

[0029] Into a 20 ml test tube equipped with a magnetic stirrer, 3-(dimethylamino)-1-phenyl-2-propene-1-one (0.5 mmol), benzamidine hydrochloride (0.5 mmol), DBU (1.5 mmol), and MeOH (2 ml) were added. After the addition was completed, a fluorescent lamp was placed 2 cm away from the test tube. The reaction was allowed to proceed at room temperature for 20 hours under open conditions. After the reaction was completed, the organic phase was subjected to a rotary evaporator to remove the solvent, and the residue was purified by a silica gel column (silica gel specification was 200 mesh to 300 mesh, and the eluent was petroleum ether / ethyl acetate = 40 / 1) to obtain 96 mg of the target compound with a yield of 83%.

[0030] The NMR spectrum data of the obtained product are: 1 H NMR (400MHz, CDCl3): δ8.73 (d, J = 5.3Hz, 1H), 8.51–8.48 (m, 2H), 8.15–8.11 (m, 2H), 7.50–7.41 (m, 7H). 13 C NMR (100MHz, CDCl3): δ164.6,163.9,157.9,137.9,137.0,131.0,130.78,129.0,127.3,114.6.

[0031] Example 2

[0032]

[0033] Into a 20 ml test tube equipped with a magnetic stirrer, 3-(dimethylamino)-1-(4-fluorophenyl)-2-propene-1-one (0.5 mmol), benzamidine hydrochloride (0.5 mmol), DBU (1.5 mmol), and MeOH (2 ml) were added. After the addition was completed, a fluorescent lamp was placed 2 cm away from the test tube. The reaction was allowed to proceed at room temperature for 20 hours under open conditions. After the reaction was completed, the organic phase was subjected to a rotary evaporator to remove the solvent, and the residue was purified by a silica gel column (silica gel specification was 200 mesh to 300 mesh, and the eluent was petroleum ether / ethyl acetate = 10 / 1) to obtain 100 mg of the target compound with a yield of 80%.

[0034] The NMR spectrum data of the obtained product are: 1 H NMR (400MHz, CDCl3): δ8.64 (d, J = 5.3Hz, 1H), 8.48–8.40 (m, 2H), 8.11–8.01 (m, 2H), 7.46–7.31 (m, 3H), 7.09–7.02 (m, 2H). 13C NMR (100MHz, CDCl3): δ164.6,162.7,157.9,137.8,130.9,129.3,129.2,128.6,128.3,115.9,114.1. 19 FNMR (376MHz,CDCl3):δ-109.39.

[0035] Example 3

[0036]

[0037] Into a 20 ml test tube equipped with a magnetic stirrer, 3-(dimethylamino)-1-(4-bromophenyl)-2-propene-1-one (0.5 mmol), benzamidine hydrochloride (0.5 mmol), DBU (1.5 mmol), and MeOH (2 ml) were added. After the addition was completed, a fluorescent lamp was placed 2 cm away from the test tube. The reaction was allowed to proceed at room temperature for 20 hours under open conditions. After the reaction was completed, the organic phase was subjected to a rotary evaporator to remove the solvent, and the residue was purified by a silica gel column (silica gel specification was 200 mesh to 300 mesh, and the eluent was petroleum ether / ethyl acetate = 20 / 1) to obtain 120 mg of the target compound with a yield of 77%.

[0038] The NMR spectrum data of the obtained product are: 1 H NMR (400MHz, CDCl3): δ8.69(d,J=5.2Hz,1H),8.45(dd,J=6.8,3.0Hz,2H),7.98–7.92(m,2H),7.52(d,J=8.4Hz,2H),7.45–7.36(m,4H). 13 CNMR (100MHz, CDCl3): δ164.7,162.7,158.1,137.7,135.8,132.2,130.9,128.7,128.6,128.3,125.7,114.2.

[0039] Example 4

[0040]

[0041] Into a 20 ml test tube equipped with a magnetic stirrer, 3-(dimethylamino)-1-(4-trifluoromethylphenyl)-2-propene-1-one (0.5 mol), benzamidine hydrochloride (0.5 mmol), DBU (1.5 mmol), and MeOH (2 ml) were added. After the addition was completed, a fluorescent lamp was placed 2 cm away from the test tube. The reaction was allowed to proceed at room temperature for 20 hours under open conditions. After the reaction was completed, the organic phase was subjected to a rotary evaporator to remove the solvent, and the residue was purified by a silica gel column (silica gel specification was 200 mesh to 300 mesh, and the eluent was petroleum ether / ethyl acetate = 10 / 1) to obtain 113 mg of the target compound with a yield of 75%.

[0042] The NMR spectrum data of the obtained product are: 1 H NMR (400MHz, CDCl3): δ8.68 (d, J = 5.2 Hz, 1H), 8.44 ( dd, J = 6.7, 3.0 Hz, 2H), 8.13 ( d, J = 8.1 Hz, 2H), 7.62 ( d, J = 8.1 Hz, 2H), 7.39 ( p, J = 3.2 Hz, 4H). 13 C NMR (100MHz, CDCl3): δ164.8,162.3,158.3,140.3,137.5,132.4,131.0,128.7,128.4,127.5,125.9,125.8,114.8. 19 F NMR (376 MHz, CDCl3): δ-62.72.

[0043] Example 5

[0044]

[0045] Into a 20 ml test tube equipped with a magnetic stirrer, 3-(dimethylamino)-1-(naphthalene-2-yl)-2-propene-1-one (0.5 mmol), benzamidine hydrochloride (0.5 mmol), DBU (1.5 mmol), and MeOH (2 ml) were added. After the addition was completed, a fluorescent lamp was placed 2 cm away from the test tube. The reaction was allowed to proceed at room temperature for 20 hours under open conditions. After the reaction was completed, the organic phase was passed through a rotary evaporator to remove the solvent. The residue was purified by a silica gel column (silica gel specification was 200-300 mesh, and the eluent was petroleum ether / ethyl acetate = 20 / 1) to obtain 114 mg of the target compound with a yield of 81%.

[0046] The NMR spectrum data of the obtained product are: 1H NMR (400MHz, CDCl3): δ8.66(d,J=5.3Hz,1H),8.51(dd,J=7.6,1.9Hz,3H),8.14(dd,J =8.6,1.8Hz,1H),7.81(dd,J=12.2,7.7Hz,2H),7.76–7.69(m,1H),7.50–7.34(m,6H). 13 C NMR (100MHz, CDCl3): δ164.6,163.7,157.9,138.0,134.7,134.2,133.3,130.8,128.7,127.8,127.5,126.7,124.1,114.7. .

[0047] Example 6

[0048]

[0049] Into a 20 ml test tube equipped with a magnetic stirrer, 3-(dimethylamino)-1-(benzofuran-2-yl)-2-propene-1-one (0.5 mmol), benzamidine hydrochloride (0.5 mmol), DBU (1.5 mmol), and MeOH (2 ml) were added. After the addition was completed, a fluorescent lamp was placed 2 cm away from the test tube. The reaction was allowed to proceed at room temperature for 20 hours under open conditions. After the reaction was completed, the organic phase was subjected to a rotary evaporator to remove the solvent, and the residue was purified using a silica gel column (silica gel specification was 200 mesh to 300 mesh, and the eluent was petroleum ether / ethyl acetate = 25 / 1) to obtain 98 mg of the target compound with a yield of 72%.

[0050] The NMR spectrum data of the obtained product are: 1 H NMR (400MHz, CDCl3): δ8.68(dd,J=5.1,1.1Hz,1H),8.45–8.42(m,2H),7.62(d,J=1.1Hz,1H),7.54( dd,J=7.9,1.3Hz,1H),7.47–7.37(m,5H),7.25(ddd,J=8.4,7.2,1.3Hz,1H),7.14(t,J=7.5Hz,1H). 13 C NMR (100MHz, CDCl3): δ164.6,158.2,155.8,153.5,137.5,130.9,128.6,128.4,126.4,123.6,122.3,113.5,111.8,108.3.

[0051] Example 7

[0052]

[0053] Into a 20 ml test tube equipped with a magnetic stirrer, 3-(dimethylamino)-1-phenyl-2-propene-1-one (0.5 mmol), 4-methylbenzamidine hydrochloride (0.5 mmol), DBU (1.5 mmol), and MeOH (2 ml) were added. After the addition was completed, a fluorescent lamp was placed 2 cm away from the test tube. The reaction was allowed to proceed at room temperature for 20 hours under open conditions. After the reaction was completed, the organic phase was passed through a rotary evaporator to remove the solvent. The residue was purified by a silica gel column (silica gel specification was 200 mesh to 300 mesh, and the eluent was petroleum ether / ethyl acetate = 30 / 1) to obtain 95 mg of the target compound with a yield of 77%.

[0054] The NMR spectrum data of the obtained product are: 1 H NMR (400MHz, CDCl3): δ8.71(d,J=5.2Hz,1H),8.41–8.37(m,2H),8.15–8.10(m,2H),7.47–7.41(m,4H),7.23(d,J=8.0Hz,2H),2.35(s,3H). 13 CNMR (100MHz, CDCl3): δ164.7,163.8,157.8141.0,137.1,130.9,129.4,129.0,128.3,127.2,114.3,21.6.

[0055] Example 8

[0056]

[0057] Into a 20 ml test tube equipped with a magnetic stirrer, 3-(dimethylamino)-1-phenyl-2-propene-1-one (0.5 mmol), 4-fluorobenzamidine hydrochloride (0.5 mmol), DBU (1.5 mmol), and MeOH (2 ml) were added. After the addition was completed, a fluorescent lamp was placed 2 cm away from the test tube. The reaction was allowed to proceed at room temperature for 20 hours under open conditions. After the reaction was completed, the organic phase was subjected to a rotary evaporator to remove the solvent, and the residue was purified by a silica gel column (silica gel specification was 200 mesh to 300 mesh, and the eluent was petroleum ether / ethyl acetate = 30 / 1) to obtain 99 mg of the target compound with a yield of 79%.

[0058] The NMR spectrum data of the obtained product are: 1 H NMR (400MHz, CDCl3): δ8.73(d,J=5.3Hz,1H),8.55–8.48(m,2H),8.16–8.10(m,2H),7.53–7.42(m,4H),7.11(t,J=8.7Hz,2H). 13C NMR (100MHz, CDCl3): δ166.0,163.9,157.9,136.9,134.1,131.1,130.4,129.0,127.2,115.4,114.5.

[0059] Example 9

[0060]

[0061] Into a 20 ml test tube equipped with a magnetic stirrer, 3-(dimethylamino)-1-phenyl-2-propene-1-one (0.5 mmol), 4-chlorobenzamidine hydrochloride (0.5 mmol), DBU (1.5 mmol), and MeOH (2 ml) were added. After the addition was completed, a fluorescent lamp was placed 2 cm away from the test tube. The reaction was allowed to proceed at room temperature for 20 hours under open conditions. After the reaction was completed, the organic phase was passed through a rotary evaporator to remove the solvent. The residue was purified by a silica gel column (silica gel specification was 200-300 mesh, and the eluent was petroleum ether / ethyl acetate = 30 / 1) to obtain 108 mg of the target compound with a yield of 81%.

[0062] The NMR spectrum data of the obtained product are: 1 H NMR (400MHz, CDCl3): δ8.74(d,J=5.3Hz,1H),8.45(d,J=8.3Hz,2H),8.17–8.09(m,2H),7.55–7.38(m,6H). 13 C NMR (100MHz, CDCl3): δ164.0,163.7,157.9,136.9,136.8,136.4,131.1,129.7,129.0,128.8,127.2,114.7.

[0063] Example 10

[0064]

[0065] Into a 20 ml test tube equipped with a magnetic stirrer, 3-(dimethylamino)-1-phenyl-2-propene-1-one (0.5 mmol), cyclopropylcarboximidamide hydrochloride (0.5 mmol), DBU (1.5 mmol), and MeOH (2 ml) were added. After the addition was completed, a fluorescent lamp was placed 2 cm away from the test tube. The reaction was allowed to proceed at room temperature for 20 hours under open conditions. After the reaction was completed, the organic phase was subjected to a rotary evaporator to remove the solvent, and the residue was purified by a silica gel column (silica gel specification was 200 mesh to 300 mesh, and the eluent was petroleum ether / ethyl acetate = 30 / 1) to obtain 67 mg of the target compound with a yield of 68%.

[0066] The NMR spectrum data of the obtained product are: 1H NMR (400MHz, CDCl3): δ8.51(d,J=5.3Hz,1H),8.04–7.94(m,2H),7.46–7.33(m,4H),2 .24(tt,J=8.4,4.0Hz,1H),1.15(dt,J=6.8,3.2Hz,2H),1.02(dt,J=8.3,3.3Hz,2H). 13 C NMR (100MHz, CDCl3): δ172.2,163.5,157.3,137.0,130.8,128.9,127.1,113.5,18.4,10.8.

[0067] In summary, the present invention provides a method for synthesizing a pyrimidine compound promoted by visible light, wherein DBU is used as a base, and an amino ketone compound and an amidine salt undergo an intermolecular addition reaction under visible light irradiation to obtain a pyrimidine compound. The present invention uses visible light as an energy source, has mild reaction conditions and environmental protection characteristics; does not need to exclude air and moisture, has a simple operation process, and has a wide range of functional group compatibility, showing broad application potential.

[0068] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing a pyrimidine compound promoted by visible light, characterized in that: The following steps are involved: In an organic solvent, an amino enone compound having a structure as shown in formula (I) and an amidine salt having a structure as shown in formula (II) are used as reaction raw materials, and a reaction is carried out in the presence of a base in an open air at room temperature under visible light irradiation. After the reaction is completed, the reaction solution is decompressed to remove the solvent to obtain a crude product, and the crude product is purified by column chromatography to obtain a pyrimidine compound having a structure as shown in formula (III). The reaction equation is shown below: Wherein, the compound of formula (I) is an amino enone compound, R 1 is naphthyl, furanyl, thienyl, pyridyl, benzofuranyl, phenyl, or phenyl substituted with a substituent, wherein the substituent is halogen, alkyl, alkylnitro, or alkoxy; the compound of formula (II) is an amidine salt; R 2 is 3-6 carbon ring alkyl, naphthyl, furyl, phenyl, phenyl with one substituent, wherein the substituent is halogen, alkyl, alkyl nitrogen, alkoxy; The irradiation light source of the reaction is an LED lamp; the base is DBU; and the organic solvent is methanol.

2. The method for synthesizing a pyrimidine compound promoted by visible light according to claim 1, characterized in that: The molar ratio of the amino enone compound of the structure represented by formula (I) to the amidine salt of the structure represented by formula (II) is 1:1, and the added amount of DBU is 3 equivalents.

3. The method for synthesizing a pyrimidine compound promoted by visible light according to claim 1, characterized in that: The reaction time is 20h.

4. The method for synthesizing a pyrimidine compound promoted by visible light according to claim 1, characterized in that: After the reaction is completed, the reaction solution is concentrated under reduced pressure, and the concentrate is separated by column chromatography, using a mixed solution of petroleum ether and ethyl acetate as an eluent, wherein the volume ratio of petroleum ether:ethyl acetate is (1-50):1, and the eluate is collected and the solvent is evaporated to obtain the pyrimidine compound represented by formula (III).

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