A method for synthesizing 4-alkylpyridine compounds by continuous light flow

Abstract

The present invention discloses a method for the photocontinuous flow synthesis of 4-alkylpyridine compounds. This method involves dissolving a maleic acid pyridinium ester compound and a redox-active ester compound represented by Formula II, then introducing the dissolved compounds into a photocontinuous flow microreactor. Under the photocontinuous flow conditions, a highly regioselective free radical addition reaction is achieved between the molecules, yielding a series of 4-alkylpyridine compounds. This method requires no external photocatalyst, utilizes readily available raw materials, operates under mild reaction conditions, and exhibits a rapid reaction rate without significant amplification effects. This method provides a novel approach for the gram-scale synthesis of 4-alkylpyridine compounds.

Description

Technical Field

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

[0002] Pyridine is a heterocyclic aromatic compound, and the introduction of its derivative skeleton into a molecule can significantly improve 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 currently reported methods for synthesizing 4-alkylpyridine compounds: the first method is a Minisci-type decarboxylation alkylation reaction using maleic acid pyridinium ester as 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 is for the alkane substrate that activation site is more, and regioselectivity is poor, and it is easy to obtain the product (Chem.Sci.2022,13,12527-12532.) of multiple alkylation. The third method is the radical addition reaction of photocatalytic maleic acid pyridinium ester and redox active ester, and the method uses noble metal iridium photocatalyst, and reaction cost is high, and it is difficult to industrial application (Org.Biomol.Chem.2022,20,1969-1973). Therefore, develop a kind of raw material simple and easy to get, reaction condition is mild, high regioselectivity, economical environmental protection and be easy to industrial application, the method for efficiently synthesizing 4- alkylpyridine compounds is of great significance. Summary of the Invention

[0003] The present invention aims to provide a novel method for synthesizing 4-alkylpyridine compounds by photocontinuous flow from maleic acid pyridinium ester compounds and redox-active ester compounds. The method avoids the use of precious metal photocatalysts, does not require an external photosensitizer, has simple and readily available raw materials, mild reaction conditions, high regioselectivity, can be subjected to photocontinuous flow amplification production, and simultaneously has the concept of being green, economical, and environmentally friendly.

[0004] The present invention provides a method for synthesizing 4-alkylpyridine compounds by photocontinuous flow, comprising: dissolving a maleic acid pyridinium ester compound represented by Formula I and a redox-active ester compound represented by Formula II in an organic solvent under inert gas protection; inputting the resulting mixed solution into a photocontinuous flow microreactor via 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 to obtain 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 the continuous flow microreactor; the residence time in the continuous flow microreactor is 0.5 to 10.0 minutes; and separating and purifying the output product of the continuous flow microreactor to obtain a 4-alkylpyridine compound represented by 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, R 2 It represents any one of tert-butyl, cyclohexyl, 1-adamantyl, tetrahydropyranyl, N-Boc cyclopentyl, 3-methylesterbicyclo[1.1.1]pentanyl, Boc-DL-prolinyl, ethylcyclopentanyl, 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 high regioselectivity and precise regulation, and has a wide substrate range; and the use of light continuous flow technology increases the synthesis rate of 4-alkylpyridine compounds without an 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 with reference to the embodiments, but the protection scope of the present invention is not limited to these embodiments.

[0017] Example 1

[0018] Under an argon atmosphere, the maleic acid pyridinium ester (3.0 mmol) represented by formula I-1 and the tert-butyl active ester (4.5 mmol) represented by formula II-1 were dissolved in N,N-dimethylacetamide (10.0 mL), and the resulting 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, and 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 its 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 was replaced by an equal molar amount of the cyclohexyl active ester represented by formula II-2. The other steps were the same as in Example 1 to obtain a yellow oily liquid product with the structural formula shown in IV-2. The yield was 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 was replaced by an equimolar amount of 1-adamantyl active ester represented by formula II-3. The other steps were the same as in Example 1 to obtain a yellow solid product having the structural formula shown in IV-3 in a yield of 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. This data is 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 was replaced by an equimolar amount of tetrahydropyranyl active ester represented by formula II-4. The other steps were the same as in Example 1 to obtain a yellow liquid product having the structural formula shown in IV-4 in a yield of 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. This data is 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 was replaced with an equimolar amount of Boc-DL-proline active ester represented by formula II-5. The other steps were the same as in Example 1 to obtain a yellow solid product having the structural formula shown in IV-5 in a yield of 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. This data is consistent with the known literature report (Org. Biomol. Chem. 2022, 20, 1969-1973).

[0037] Example 6

[0038] In this example, the tert-butyl active ester in Example 1 was replaced with an equimolar amount of BCP ester active ester represented by formula II-6. The other steps were the same as in Example 1 to obtain a light yellow solid product with the structural formula shown in IV-6. The yield was 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. This data is 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 was replaced by an equimolar amount of ethylcyclopentane active ester represented by formula II-6. The other steps were the same as in Example 1 to obtain a yellow solid product with the structural formula shown in IV-7. The yield was 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. This data is consistent with known literature reports (J. Am. Chem. Soc. 2021, 143, 11927-11933).

[0045] Example 8

[0046] In this example, the pyridinium maleate in Example 2 was replaced with an equal molar amount of 3-phenylpyridinium maleate shown in Ⅰ-2. The other steps were the same as in Example 2 to obtain a colorless liquid product with the structural formula shown in IV-8. The yield was 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. This data is consistent with the known literature report (Org. Biomol. Chem. 2022, 20, 1969-1973).

[0049] Example 9

[0050] In this example, 3-methoxy pyridinium maleate shown in I-3 was used in place of the pyridinium maleate in Example 2. The other steps were the same as in Example 2 to obtain a yellow liquid product with the structural formula shown in IV-9. The yield was 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 the 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 the other raw materials were increased in proportion. The other steps were the same as in Example 1 to obtain 4.1 g of a light yellow oily liquid product with a yield of 67%.

[0055] Example 11

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

Claims

1. A method for synthesizing pyridine compounds by photocontinuous flow, characterized in that: Under inert gas protection, a maleic acid pyridinium ester compound represented by formula I and a redox-active ester compound represented by formula II are dissolved in an organic solvent, the resulting mixed solution is pumped into a photocontinuous flow microreactor and irradiated with light, and the residence time of the mixed solution in the photocontinuous 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 then input into the 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 pyridine compound represented by formula IV; the reaction equation is shown below: 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 pyrrolidinyl, 3-methylcarboxylate bicyclo[1.1.1]pentanyl, ethylcyclopentanyl, 4,4-difluorocyclohexyl, benzyl, cycloheptyl, 1-methylcyclohexyl, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, and 3,3-difluorocyclopropyl.

2. The method for photocontinuous flow synthesis of pyridine 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 pyridine 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 pyridine 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 pyridine compounds according to claim 1, wherein: The wavelength of the light source used for the illumination is between 365 nm and 610 nm.

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

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