Method for synthesizing 4-alkyl pyridine compound through continuous light flow

Abstract

The invention discloses a method for synthesizing a 4-alkyl pyridine compound through continuous light flow, which comprises the following steps: dissolving a pyridine ester maleate compound and a redox active ester compound as shown in a formula II, inputting into a continuous light flow microreactor, and realizing intermolecular high-regioselectivity free radical addition reaction under the condition of continuous light flow to obtain the 4-alkyl pyridine compound. A series of 4-alkyl pyridine compounds are obtained. According to the method, no additional photocatalyst is needed, raw materials are simple and easy to obtain, reaction conditions are mild, the reaction rate is high, no obvious amplification effect exists, and a novel method is provided for gram-scale synthesis of the 4-alkyl pyridine compound.

Description

Technical Field

[0001] The invention belongs to the technical field of photocontinuous flow chemistry, and in particular relates to a method for synthesizing 4-alkylpyridine compounds from redox-active ester compounds and maleic acid pyridine ester compounds through photocontinuous flow. Background Art

[0002] Pyridine is a heterocyclic aromatic compound, and the introduction of its derivative skeleton into the molecule can significantly improve the biological activity. 4-Alkylpyridine is an important organic synthesis intermediate, widely used in the synthesis of medicines, pesticides, spices and fine chemical products (Drug Des. Devel. Ther. 2021, 15, 4289-4338.). Therefore, the highly selective synthesis of 4-alkylpyridine compounds has important research significance. There are three methods for the synthesis of 4-alkylpyridine compounds reported so far: the first method is a Minisci-type decarboxylation alkylation reaction using maleic acid pyridine ester as a raw material. This method uses a reactant amount of persulfate to catalyze carboxylic acid to generate alkyl radicals, which can easily lead to excessive oxidation of alkyl radicals. At the same time, excessive use of persulfate can cause environmental pollution (J. Am. Chem. Soc. 2021, 143, 11927-11933.). The second method is the reaction of light continuous flow alkane and maleic acid pyridinium ester, and the method has poor regioselectivity for alkane substrates with more activation sites, and it is easy to obtain a variety of alkylated products (Chem.Sci.2022,13,12527-12532.). The third method is the free radical addition reaction of photocatalytic maleic acid pyridinium ester and redox active ester, and the method uses a noble metal iridium photocatalyst, and the reaction cost is high, and it is difficult to industrial application (Org.Biomol.Chem.2022,20,1969-1973). Therefore, it is a kind of raw material that is easy to obtain, mild reaction conditions, high regioselectivity, economic and environmental protection and easy to industrial application, and the method for efficiently synthesizing 4-alkylpyridine compounds is of great significance. Summary of the invention

[0003] The purpose of the present invention is to provide a new method for synthesizing 4-alkylpyridine compounds by photocontinuous flow from maleic acid pyridine ester compounds and redox-active ester compounds. The method avoids the use of precious metal photocatalysts, does not require external photosensitizers, has simple and readily available raw materials, mild reaction conditions, high regional selectivity, can be used for photocontinuous flow amplification production, and has the concept of green economy and environmental protection.

[0004] The method for synthesizing 4-alkylpyridine compounds by photocontinuous flow provided by the present invention comprises: dissolving a maleic acid pyridine ester compound shown in formula I and a redox-active ester compound shown in formula II in an organic solvent under the protection of an inert gas, inputting the obtained mixed solution into a photocontinuous flow microreactor through a pump and irradiating the mixed solution with light, controlling the residence time of the mixed solution in the photocontinuous flow microreactor to be 8 to 20 minutes, and obtaining an intermediate III; mixing the output intermediate III with 1,8-diazobisspiro[5.4.0]undec-7-ene (DBU) dissolved in an organic solvent and inputting the mixed solution into a continuous flow microreactor, and the residence time in the continuous flow microreactor is 0.5 to 10.0 minutes; separating and purifying the output product of the continuous flow microreactor, and obtaining a 4-alkylpyridine compound shown in formula IV; the reaction equation is as follows:

[0005]

[0006] Where R 1 represents any one of H, C1-C4 alkyl, C1-C4 alkoxy, halogen, phenyl, C1-C4 alkyl-substituted phenyl, C1-C4 alkoxy-substituted phenyl, and halogenated phenyl, and R 2 It represents any one of tert-butyl, cyclohexyl, 1-adamantyl, tetrahydropyranyl, N-Boc cyclopentyl, 3-methylesterbicyclo[1.1.1]pentyl, Boc-DL-prolinyl, ethylcyclopentyl, 4,4-difluorocyclohexyl, benzyl, cycloheptyl, 1-methylcyclohexyl, cyclopropyl, 1-methylcyclopropyl, cyclobutyl and 3,3-difluorocyclopropyl.

[0007] In the above synthesis method, the molar ratio of the maleic acid pyridinium ester compound to the redox-active ester compound is preferably 1:1 to 1.5.

[0008] In the above synthesis method, it is further preferred that the concentration of the maleic acid pyridinium ester compound in the mixed solution is 0.1 to 0.8 mol / L.

[0009] In the above synthesis method, the organic solvent is preferably any one of N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, acetonitrile, methanol, ethanol, ethyl acetate, dichloromethane and dimethyl sulfoxide.

[0010] In the above synthesis method, it is preferred that the wavelength of the light source used for the illumination is between 365 and 610 nm.

[0011] In the above synthesis method, the amount of the 1,8-diazobispiro[5.4.0]undec-7-ene is preferably 2.0 to 3.0 times the molar amount of the maleic acid pyridinium ester compound.

[0012] In the above synthesis method, the reaction temperature in the photocontinuous flow microreactor is preferably 25-50°C.

[0013] In the above synthesis method, the reaction temperature in the continuous flow microreactor is preferably 20-30°C.

[0014] The beneficial effects of the present invention are as follows:

[0015] The present invention combines the advantages of continuous flow technology and photocatalysis, realizes the synthesis of 4-alkylpyridine compounds without the addition of external photosensitizers, can achieve precise regulation of high regional selectivity, and has a wide substrate range; and the use of light continuous flow technology increases the synthesis rate of 4-alkylpyridine compounds, has no amplification effect, and can achieve the synthesis of 4-alkylpyridine compounds on a scale of more than gram level. DETAILED DESCRIPTION

[0016] The present invention is further described in detail below in conjunction with the embodiments, but the protection scope of the present invention is not limited to these embodiments.

[0017] Example 1

[0018] Under argon atmosphere, maleic acid pyridinium ester (3.0 mmol) shown in formula I-1 and tert-butyl active ester (4.5 mmol) shown in formula II-1 were dissolved in N, N-dimethylacetamide (10.0 mL), and the obtained mixed solution was input into Corning light continuous flow microreactor A through a pump, irradiated with a light source with a wavelength of 385 nm, and the temperature of Corning light continuous flow microreactor A was set to 35°C. The residence time of the mixed solution in Corning light continuous flow microreactor A was controlled to be 10 minutes to obtain intermediate III-1; the output intermediate III and DBU (9.0 mmol) dissolved in N, N-dimethylacetamide (10.0 mL) were respectively introduced from both ends of the T-interface and mixed and then input into continuous flow microreactor B, and stayed in continuous flow microreactor B for 1 minute. The reactants were extracted with ethyl acetate, the concentrated organic phase was collected, and separated by column chromatography to obtain a light yellow oily liquid product with a structural formula as shown in formula IV-1, and the yield was 68%.

[0019]

[0020] The NMR spectrum data of the obtained product are: 1 H NMR (400MHz, CDCl3) δ8.51 (d, J = 5.2Hz, 2H), 7.28 (d, J = 6.4Hz, 2H), 1.31 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 156.0, 149.7, 120.8, 34.7, 30.6. This data is consistent with known literature reports (J. Am. Chem. Soc. 2021, 143, 11927-11933).

[0021] Example 2

[0022] In this example, the tert-butyl active ester in Example 1 is replaced by an equimolar amount of the cyclohexyl active ester shown in formula II-2, and the other steps are the same as in Example 1 to obtain a yellow oily liquid product with the structural formula shown in IV-2, and the yield is 72%.

[0023]

[0024] The NMR spectrum data of the obtained product are: 1 H NMR (400MHz, CDCl3) δ8.58–8.38(m,2H),7.11(d,J=5.3Hz,2H),2.48(d,J=3.0Hz,1H),1.85 (d,J=3.5Hz,4H),1.79–1.71(m,1H),1.46–1.31(m,4H),1.26(ddt,J=9.4,6.5,3.0Hz,1H); 13 C NMR (100 MHz, CDCl3) δ 156.6, 149.7, 122.4, 43.8, 33.5, 26.5, 25.9. This data is consistent with known literature reports (J. Am. Chem. Soc. 2021, 143, 11927-11933).

[0025] Example 3

[0026] In this example, the tert-butyl active ester in Example 1 is replaced by an equimolar 1-adamantyl active ester of formula II-3, and the other steps are the same as in Example 1 to obtain a yellow solid product with the structural formula shown in IV-3, and the yield is 67%.

[0027]

[0028] The NMR spectrum data of the obtained product are: 1 H NMR (400MHz, CDCl3) δ8.52(d,J=6.0Hz,2H),7.27(dd,J=4.8,1.6Hz,2H),2.12(s,3H),1.90(s,6H),1.83–1.74(m,6H); 13 C NMR (100 MHz, CDCl3) δ 160.0, 149.8, 120.5, 42.5, 36.7, 36.4, 28.8. The data are consistent with known literature reports (J. Am. Chem. Soc. 2021, 143, 11927-11933).

[0029] Example 4

[0030] In this example, the tert-butyl active ester in Example 1 is replaced by an equimolar amount of tetrahydropyranyl active ester shown in formula II-4, and the other steps are the same as in Example 1 to obtain a yellow liquid product with the structural formula shown in IV-4, and the yield is 42%.

[0031]

[0032] The NMR spectrum data of the obtained product are: 1 H NMR(400MHz, CDCl3)δ8.56(d,J=6.1Hz,2H),7.19(d,J=6.1Hz,2H),4.15–4.08(m, 2H),3.62–3.51(m,2H),2.80(dt,J=10.8,5.2Hz,1H),1.81(dt,J=6.0,3.7Hz,4H); 13 C NMR (100 MHz, CDCl3) δ 154.9, 149.6, 122.3, 68.0, 40.9, 32.9. The data are consistent with known literature reports (J. Am. Chem. Soc. 2021, 143, 11927-11933).

[0033] Example 5

[0034] In this example, the tert-butyl active ester in Example 1 is replaced by an equimolar amount of Boc-DL-proline active ester shown in formula II-5, and the other steps are the same as in Example 1 to obtain a yellow solid product with the structural formula shown in IV-5, and the yield is 52%.

[0035]

[0036] The NMR spectrum data of the obtained product are: 1 H NMR (400MHz, CDCl3) δ8.53(d,J=5.4Hz,2H),7.11(d,J=5.0Hz,2H),4.73(dd,J=8.6,4.7Hz, 1H),3.62(d,J=6.9Hz,2H),2.43–2.27(m,1H),1.94–1.73(m,3H),1.46(s,3H),1.20(s,6H); 13 C NMR (100 MHz, CDCl3) δ 154.2, 149.6, 120.8, 79.8, 60.5, 59.9, 47.3, 47.1, 35.5, 34.3, 28.4, 28.1, 23.6, 23.2. The data are consistent with the known literature reports (Org. Biomol. Chem. 2022, 20, 1969-1973).

[0037] Example 6

[0038] In this example, the tert-butyl active ester in Example 1 is replaced by an equimolar BCP ester active ester of formula II-6, and the other steps are the same as in Example 1 to obtain a light yellow solid product with the structural formula shown in IV-6, and the yield is 36%.

[0039]

[0040] The NMR spectrum data of the obtained product are: 1 H NMR (400MHz, CDCl3) δ8.54(d,J=4.9Hz,2H),7.13(d,J=4.2Hz,2H),3.71(s,3H),2.35(s,6H); 13 C NMR (100 MHz, CDCl3) δ 170.2, 149.5, 148.6, 121.6, 53.3, 51.9, 40.9, 37.4. The data are consistent with known literature reports (J. Am. Chem. Soc. 2021, 143, 11927-11933).

[0041] Example 7

[0042] In this example, the tert-butyl active ester in Example 1 is replaced by an equimolar amount of ethylcyclopentane active ester shown in formula II-6, and the other steps are the same as in Example 1 to obtain a yellow solid product with the structural formula shown in IV-7, and the yield is 53%.

[0043]

[0044] The NMR spectrum data of the obtained product are: 1 H NMR (400MHz, CDCl3) δ8.51–8.42(m,2H),7.15–7.03(m,2H),2.67–2.52(m,2H) ,1.84–1.72(m,3H),1.67–1.58(m,4H),1.55–1.48(m,2H),1.18–1.06(m,2H); 13 C NMR (100 MHz, CDCl3) δ 152.1, 149.7, 124.0, 39.7, 37.0, 34.6, 32.7, 25.3. The data are consistent with known literature reports (J. Am. Chem. Soc. 2021, 143, 11927-11933).

[0045] Example 8

[0046] In this example, 3-phenylmaleic acid pyridinyl ester shown in Ⅰ-2 is used in equal moles to replace the maleic acid pyridinyl ester in Example 2, and the other steps are the same as Example 2 to obtain a colorless liquid product with the structural formula shown in IV-8, and the yield is 62%.

[0047]

[0048] The NMR spectrum data of the obtained product are: 1 H NMR(400MHz, CDCl3)δ8.52(d,J=5.3Hz,1H),8.41(s,1H),7.49–7.37(m,3H),7.33–7.22(m, 3H),2.68(tt,J=12.0,3.1Hz,1H),1.86–1.61(m,5H),1.53–1.33(m,2H),1.36–1.05(m,3H); 13 C NMR (100 MHz, CDCl3) δ 154.4, 150.3, 148.6, 137.9, 137.2, 129.5, 128.4, 127.6, 121.4, 39.7, 33.8, 26.4, 26.0. The data are consistent with the known literature reports (Org. Biomol. Chem. 2022, 20, 1969-1973).

[0049] Example 9

[0050] In this example, 3-methoxymaleic acid pyridinyl ester shown in Ⅰ-3 is used to replace the maleic acid pyridinyl ester in Example 2 with an equal molar amount, and the other steps are the same as Example 2 to obtain a yellow liquid product with the structural formula shown in IV-9, and the yield is 66%.

[0051]

[0052] The NMR spectrum data of the obtained product are: 1 H NMR (400MHz, CDCl3) δ8.21 (s, 1H), 8.19 (d, J = 5.0Hz, 1H), 7.11 (d, J = 4.9Hz, 1H), 3.91(s,3H),2.93(tt,J=11.6,3.2Hz,1H),1.91–1.63(m,5H),1.52–1.15(m,5H); 13 C NMR (100 MHz, CDCl3) δ 153.6, 145.4, 142.9, 132.7, 121.6, 56.2, 36.6, 32.4, 26.8, 26.3; the data are consistent with known literature reports (Org. Biomol. Chem. 2022, 20, 1969-1973.).

[0053] Example 10

[0054] In Example 1, the amount of maleic acid pyridinium ester represented by Formula Ⅰ-1 was increased to 45 mmol, and other raw materials were increased in proportion. The other steps were the same as in Example 1, and 4.1 g of light yellow oily liquid product was obtained with a yield of 67%.

[0055] Embodiment 11

[0056] In Example 3, the amount of maleic acid pyridinium ester represented by Formula I-3 was increased to 55 mmol, and other raw materials were increased in proportion. The other steps were the same as in Example 3, and 7.3 g of yellow solid product was obtained with a yield of 63%.

Claims

1. A method for synthesizing 4-alkylpyridine compounds by photocontinuous flow, characterized in that: Under the protection of inert gas, the maleic acid pyridine ester compound represented by formula I and the redox active ester compound represented by formula II are dissolved in an organic solvent, the obtained mixed solution is input into a light continuous flow microreactor through a pump and illuminated, and the residence time of the mixed solution in the light continuous flow microreactor is controlled to be 10 to 30 minutes to obtain an intermediate III; the output intermediate III and 1,8-diazobisspiro[5.4.0]undec-7-ene dissolved in an organic solvent are mixed and input into a continuous flow microreactor, and the residence time in the continuous flow microreactor is 0.5 to 5 minutes; the output product of the continuous flow microreactor is separated and purified to obtain a 4-alkylpyridine compound represented by formula IV; the reaction equation is as follows: Where R 1 represents any one of H, C1-C4 alkyl, C1-C4 alkoxy, halogen, phenyl, C1-C4 alkyl-substituted phenyl, C1-C4 alkoxy-substituted phenyl, and halogenated phenyl, and R 2 It represents any one of tert-butyl, cyclohexyl, 1-adamantyl, tetrahydropyranyl, N-Boc cyclopentyl, 3-methylesterbicyclo[1.1.1]pentyl, Boc-DL-prolinyl, ethylcyclopentyl, 4,4-difluorocyclohexyl, benzyl, cycloheptyl, 1-methylcyclohexyl, cyclopropyl, 1-methylcyclopropyl, cyclobutyl and 3,3-difluorocyclopropyl.

2. The method for photocontinuous flow synthesis of 4-alkylpyridine compounds according to claim 1, characterized in that: The molar ratio of the maleic acid pyridinium ester compound to the redox active ester compound is 1:1 to 1.

5.

3. The method for photocontinuous flow synthesis of 4-alkylpyridine compounds according to claim 1 or 2, characterized in that: The concentration of the maleic acid pyridinium ester compound in the mixed solution is 0.1-0.8 mol / L.

4. The method for photocontinuous flow synthesis of 4-alkylpyridine compounds according to claim 1, characterized in that: The organic solvent is any one of N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, acetonitrile, methanol, ethanol, ethyl acetate, dichloromethane and dimethyl sulfoxide.

5. The method for photocontinuous flow synthesis of 4-alkylpyridine compounds according to claim 1, characterized in that: The wavelength of the light source used for the illumination is between 365 and 610 nm.

6. The method for photocontinuous flow synthesis of 4-alkylpyridine compounds according to claim 1, characterized in that: The amount of the 1,8-diazobispiro[5.4.0]undec-7-ene used is 2.0 to 3.0 times the molar amount of the maleic acid pyridinium ester compound.

7. The method for photocontinuous flow synthesis of 4-alkylpyridine compounds according to claim 1, characterized in that: The reaction temperature in the optical continuous flow microreactor is 25-50°C.

8. The method for photocontinuous flow synthesis of 4-alkylpyridine compounds according to claim 1, characterized in that: The reaction temperature in the continuous flow microreactor is 20-30°C.

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