A method for the iron-mediated hydroalkylation of azauracils under photo-irradiation conditions

Abstract

The present application relates to the field of organic synthesis methodology, in particular to a kind of iron-mediated preparation method of hydrogenation alkylation of azauracil under light condition.The method first applies ligand-metal charge transfer (LMCT) mechanism to the hydrogenation alkylation reaction of uracil, uses cheap and easily available abundance metal iron as catalyst, uses alkane as alkylation raw material without pre-functionalization, reaction condition is mild, functional group tolerance is good, product yield can reach 75%~94%, suitable for late modification of drug molecules and bioactive molecules.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis methodology, specifically to a method for preparing azauracil by hydrogenation under iron-mediated light irradiation. Background Technology

[0002] Nitrogen-containing heterocycles are core groups in many natural and synthetic compounds, widely found in pharmaceutical and functional material systems. Uracil, as an important class of nitrogen-containing aromatic heterocyclic compounds, has attracted widespread attention due to its significant biological activities across multiple pharmacological dimensions. Studies have shown that several important bioactive molecules and clinical drugs contain uracil structures, such as diclazuril, c-Met kinase inhibitors, 5-HT1A receptor modulators, and 6-azauridine (an antiviral agent). Given the wide range of applications and significant value of uracil, effective structural modification is crucial for expanding its application scope and enhancing its drug activity. Modifying uracil with alkenes can improve its drug activity, making it possible for this product to be used in the pharmaceutical field.

[0003] Utilizing aliphatic CH bonds as potential nucleophiles is one of the most attractive reactions for molecular construction in synthetic chemistry, given their prevalence in organic molecules. However, the high bond dissociation energy of sp bonds (BDE ≥ 100 kcal / mol) limits their application. Photoreduction-mediated hydrogen activation transfer (LMCT) strategies via noble metal complexes (iridium and rhodium) have been established as an effective means for efficiently activating CH bonds. Recently, photoinduced LMCT has revealed a unique mechanistic picture for inexpensive 3d metal complexes (such as nickel, copper, or iron) and shows broad application potential in the functionalization of aliphatic CH bonds.

[0004] The ligand-to-metal charge transfer (LMCT) mechanism exhibits unique advantages in organic synthesis. Compared to traditional photoreductive oxidation catalysis, the LMCT mechanism achieves electron transfer from the ligand to the metal center by exciting the complex formed between the ligand and metal ions under light irradiation, thereby initiating the breaking of chemical bonds or the activation of functional groups in the ligand. This method features mild reaction conditions, good tolerance to functional groups, and the absence of external photosensitizers. Currently, the LMCT mechanism has been successfully applied to various reactions, such as CH bond activation and decarboxylation functionalization. However, its application in the CH bond functionalization of azauracil has not yet been reported. Summary of the Invention

[0005] This invention provides a method for the preparation of azauracil by hydrogenation alkylation under iron-mediated light irradiation. The method uses common alkanes and uracil as starting materials, adds ferric chloride and sodium chloride, and uses acetonitrile as a solvent. The reaction is carried out under light irradiation at room temperature. This invention successfully achieves the efficient synthesis of hydrogenated alkylated uracil derivatives. This strategy cleverly utilizes the ligand-metal charge transfer reaction mechanism, employs abundant metallic iron as a catalyst, and uses inexpensive sodium chloride as an additive to effectively achieve a high-efficiency reaction. The reaction can be successfully completed at room temperature, exhibiting excellent functional group tolerance.

[0006] The objective of this invention is achieved through the following technical solution: A method for preparing azauracil by hydrogenation under iron-mediated light irradiation includes the following steps: Under nitrogen atmosphere, alkanes, uracil derivatives, catalysts, additives, and solvents were added to a reaction tube in proportion. The mixture was stirred under light at room temperature, and the reaction was monitored by TCL. After the reaction was completed, the mixture was extracted with ethyl acetate and water. The combined organic phases were then distilled under reduced pressure and separated by column chromatography to obtain the pure product. .

[0007] In the formula, substituent R1 is one of hydrogen, benzyl, naphthalenebenzyl, alkyl, alkenyl, or ester-substituted alkyl; R2 is one of benzyl, naphthalenebenzyl, alkyl, alkenyl, ester-substituted, or phenyl-substituted alkyl; and substituent R3 is a cycloalkane, wherein the cycloalkane is one of cyclohexane, adamantane, or tetrahydrofuran.

[0008] Furthermore, the catalyst is one of ferric chloride and ferric chloride, preferably ferric chloride.

[0009] Furthermore, the solvent is one of ethanol, acetonitrile, and dichloromethane, preferably acetonitrile.

[0010] Furthermore, the additive is one of sodium chloride and lithium chloride, preferably sodium chloride.

[0011] Furthermore, the illumination conditions are provided by using a light source with a wavelength of 365 nm, 390 nm or 420 nm, with 390 nm being the preferred wavelength.

[0012] Furthermore, the ratio of the uracil derivative to the alkane is 1:(1~5), preferably 1:3.

[0013] Furthermore, the feed ratio of the uracil derivative to the catalyst is 1:(0~0.2), preferably 1:0.1.

[0014] Furthermore, the ratio of the uracil derivative to the additive is 1:(0~0.3), preferably 1:0.1.

[0015] Furthermore, the reaction time for this synthesis method is 12-24 h, preferably 12 h.

[0016] Furthermore, the target product, the alkylated azauracil derivative, was purified by column chromatography using a mixed solvent system of petroleum ether and ethyl acetate, with a volume ratio of petroleum ether to ethyl acetate of 15:1.

[0017] The mechanism of this invention is as follows: under light irradiation, the iron catalyst additive forms chlorine radicals, which abstract hydrogen from alkanes to form alkyl radicals, which then react with the positive ion of azauracil to generate the target product.

[0018] Compared with the prior art, the present invention has the following advantages: (1) This invention realizes the hydrogenation-alkylation reaction of alkanes and uracil, and constructs a series of hydrogenated alkylated uracil derivatives. The reaction uses ferric chloride, an inexpensive and readily available abundance metal, as a catalyst and sodium chloride, a green and economical additive, and can be carried out at room temperature with good functional group tolerance.

[0019] (2) The present invention uses alkanes as alkyl raw materials and does not require prefunctionalization.

[0020] (3) Ligand-metal charge transfer was applied for the first time to the hydrogenation and alkylation of uracil. Attached Figure Description

[0021] Figure 1 This is the proton NMR spectrum of the target product obtained in Example 1; Figure 2 This is the carbon spectrum of the target product obtained in Example 1; Figure 3 This is the proton spectrum of the target product obtained in Example 2; Figure 4 This is the carbon spectrum of the target product obtained in Example 2; Figure 5 This is the proton spectrum of the target product obtained in Example 3; Figure 6 This is the carbon spectrum of the target product obtained in Example 3; Figure 7 This is the proton NMR spectrum of the target product obtained in Example 4; Figure 8 This is the carbon spectrum of the target product obtained in Example 4. Detailed Implementation

[0022] The present invention will be further described below through specific embodiments, but the scope of protection and implementation of the present invention are not limited thereto.

[0023]

[0024] Example 1 In a reaction tube with a stir bar, weighed 2,4-dibenzyl-1,2,4-triazine-3,5(2H,4H)-dione (0.2 mmol), cyclohexane (0.6 mmol), ferric chloride (0.02 mmol), sodium chloride (0.02 mmol), and acetonitrile (2 mL) were added sequentially. The tube was placed under a 390 nm lamp and stirred at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, the mixture was extracted with ethyl acetate and saturated brine. The combined organic phases were subjected to vacuum distillation, followed by column chromatography to obtain the final product (R)-2,4-dibenzyl-6-cyclohexyl-1,2,4-triazine-3,5-dione, with a yield of 92%.

[0025] The proton and carbon spectra of the obtained target product are as follows: Figure 1 and Figure 2 As shown, the structural characterization data is as follows: 1 H NMR (600 MHz, Chloroform- d ) d 7.33–7.29 (m, 2H), 7.28–7.19 (m,7H), 7.18–7.15 (m, 1H), 4.91 (d, J = 14.1 Hz, 1H), 4.85 (d, J = 14.1 Hz, 1H), 4.67 (d, J = 14.3 Hz, 1H), 4.45 (d, J = 14.3 Hz, 1H), 4.09 (d, J = 6.3 Hz,1H), 3.13–3.00 (m, 1H), 1.67–1.58 (m, 2H), 1.58–1.49 (m, 3H), 1.36 (d, J =11.6 Hz, 1H), 1.12–0.89 (m, 4H), 0.82–0.74 (m, 1H). 13 C NMR (101 MHz, CDCl3) d170.0, 153.0, 137.5, 136.3, 128.9, 128.6, 128.6, 128.4, 127.9, 127.4, 63.6,53.2, 43.5, 36.0, 29.5, 29.1, 26.9, 25.8, 25.8. HRMS(ESI) m / z calcd forC 23 H 27 N3NaO2 (M+Na) + : 400.1995, found 400.1994.

[0026] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0027] Example 2 In a reaction tube with a stir bar, weighed 2,4-bis(4-methylbenzyl)-1,2,4-triazin-3,5(2H,4H)-dione (0.2 mmol), cyclohexane (0.6 mmol), ferric chloride (0.02 mmol), sodium chloride (0.02 mmol), and acetonitrile (2 mL) were added sequentially. The tube was placed under a 390 nm lamp and stirred at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, the mixture was extracted with ethyl acetate and saturated brine. The combined organic phases were subjected to vacuum distillation, followed by column chromatography to obtain the final product (R)-6-cyclohexyl-2,4-bis(4-methylbenzyl)-1,2,4-triazinone-3,5-dione, with a yield of 90%.

[0028] The proton and carbon spectra of the obtained target product are as follows: Figure 3 and Figure 4 As shown, the structural characterization data is as follows: 1 H NMR (400 MHz, Chloroform- d ) d 7.29 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.15–7.07 (m, 4H), 4.95 (d, J = 14.0 Hz, 1H), 4.87 (d, J =14.0 Hz, 1H), 4.70 (d, J = 14.2 Hz, 1H), 4.48 (d, J= 14.2 Hz, 1H), 4.13 (s,1H), 3.12 (d, J = 7.6 Hz, 1H), 2.33 (s, 3H), 2.31 (s, 3H), 1.74–1.67 (m, 2H), 1.67–1.54 (m, 3H), 1.45 (d, J = 10.0 Hz, 1H), 1.23–0.96 (m, 4H), 0.90–0.79 (m, 1H). 13 C NMR (101 MHz, CDCl3) d 170.1, 152.9, 137.6, 137.0, 134.6, 133.3,129.2, 129.03, 128.89, 128.67, 63.6, 52.9, 43.2, 36.0, 29.5, 29.1, 26.0,25.7, 25.7, 21.1. HRMS(ESI) m / z calcd for C 25 H 32 N3O2 + (M+H) + : 406.2489, found406.2488.

[0029] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0030] Example 3 In a reaction tube with a stir bar, weighed 2,4-bis(4-chlorobenzyl)-1,2,4-triazin-3,5(2H,4H)-dione (0.2 mmol), cyclohexane (0.6 mmol), ferric chloride (0.02 mmol), sodium chloride (0.02 mmol), and acetonitrile (2 mL) were added sequentially. The tube was placed under a 390 nm lamp and stirred at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, the mixture was extracted with ethyl acetate and saturated brine. The combined organic phases were subjected to vacuum distillation, followed by column chromatography to obtain the final product (R)-6-cyclohexyl-2,4-bis(4-chlorobenzyl)-1,2,4-triazinone-3,5-dione, with a yield of 94%.

[0031] The structural characterization data of the obtained target product are shown below: 1 H NMR (400 MHz, Chloroform- d ) d7.36–7.31 (m, 2H), 7.31–7.27 (m,5H), 7.27–7.24 (m, 1H), 4.92 (d, J = 14.1 Hz, 1H), 4.86 (d, J = 14.1 Hz, 1H), 4.68 (d, J = 14.3 Hz, 1H), 4.51 (d, J = 14.3 Hz, 1H), 4.17 (d, J = 6.5 Hz, 1H), 3.15 (t, J = 7.0 Hz, 1H), 1.73–1.59 (m, 5H), 1.42 (d, J = 9.6 Hz, 1H), 1.22–0.97 (m, 4H), 0.91–0.80 (m, 1H). 13 C NMR (101 MHz, CDCl3) d 169.9, 152.9,135.9, 134.7, 133.9, 133.3, 130.4, 130.3, 128.8, 128.5, 63.6, 52.6, 43.0,36.1, 29.5, 29.1, 25.9, 25.8, 25.7. HRMS(ESI) m / z calcd for C 23 H 25 Cl2N3NaO2 (M+Na) + : 468.1216. found 468.1219.

[0032] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0033] Example 4 In a reaction tube with a stir bar, weighed 2,4-bis(4-cyanobenzyl)-1,2,4-triazin-3,5(2H,4H)-dione (0.2 mmol), cyclohexane (0.6 mmol), ferric chloride (0.02 mmol), sodium chloride (0.02 mmol), and acetonitrile (2 mL) were added sequentially. The tube was placed under a 390 nm lamp and stirred at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, the mixture was extracted with ethyl acetate and saturated brine. The combined organic phases were subjected to vacuum distillation, followed by column chromatography to obtain the final product (R)-6-cyclohexyl-2,4-bis(4-cyanobenzyl)-1,2,4-triazinone-3,5-dione, with a yield of 93%.

[0034] The structural characterization data of the obtained target product are shown below: 1 H NMR (400 MHz, Chloroform- d ) d 7.63 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.4 Hz, 4H), 5.01 (d, J = 14.4 Hz, 1H), 4.95 (d, J = 14.4 Hz, 1H), 4.77 (d, J = 14.6 Hz, 1H), 4.63 (d, J = 14.6 Hz, 1H), 4.42(d, J = 6.7 Hz, 1H), 3.22 (t, J = 6.9 Hz, 1H), 1.76–1.59 (m, 5H), 1.43 (d, J = 10.4 Hz, 1H), 1.27–0.96 (m, 4H), 0.95–0.82 (m, 1H). 13 C NMR (101 MHz, CDCl3) d 169.8, 152.9, 142.5, 141.5, 132.4, 132.2, 129.6, 129.3, 118.6, 118.4,111.8, 111.2, 63.5, 53.0, 43.4, 36.1, 29.5, 29.0, 25.8, 25.8, 25.7. HRMS(ESI) m / z calcd for C 25 H 26 N5O2 (M+H) + : 428.2081 found 428.2084.

[0035] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0036] Example 5 In a reaction tube with a stir bar, weighed 2,4-bis(naphthylbenzyl)-1,2,4-triazin-3,5(2H,4H)-dione (0.2 mmol), cyclohexane (0.6 mmol), ferric chloride (0.02 mmol), sodium chloride (0.02 mmol), and acetonitrile (2 mL) were added sequentially. The tube was placed under a 390 nm lamp and stirred at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, the mixture was extracted with ethyl acetate and saturated brine. The combined organic phases were subjected to vacuum distillation, followed by column chromatography to obtain the final product (R)-6-cyclohexyl-2,4-bis(naphthylbenzyl)-1,2,4-triazinone-3,5-dione, with a yield of 90%.

[0037] The structural characterization data of the obtained target product are shown below: 1 H NMR (400 MHz, Chloroform- d ) d 7.85 (s, 1H), 7.83–7.72 (m, 7H), 7.56–7.52 (m, 1H), 7.49–7.42 (m, 5H), 5.17 (d, J = 14.1 Hz, 1H), 5.11 (d, J =14.1 Hz, 1H), 4.92 (d, J = 14.3 Hz, 1H), 4.68 (d, J = 14.3 Hz, 1H), 4.17 (d, J = 4.7 Hz, 1H), 3.20–3.10 (m, 1H), 1.74–1.61 (m, 3H), 1.57–1.42 (m, 3H), 1.22–0.97 (m, 3H), 0.9–0.77 (m, 2H). 13 C NMR (101 MHz, CDCl3) d170.1, 153.1,135.0, 133.7, 133.2, 133.2, 132.9, 132.7, 128.5, 128.2, 127.9, 127.9, 127.8,127.6, 127.6, 126.7, 126.6, 126.2, 126.1, 126.0, 125.8, 63.7, 53.4, 43.7,36.0, 29.5, 29.2, 25.9, 25.8, 25.6. HRMS(ESI) m / z calcd for C 31 H 31 N3NaO2 (M+Na) + : 500.2309, found 500.2308.

[0038] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0039] Example 6 In a reaction tube with a stir bar, weighed 2,4-dipropyl-1,2,4-triazine-3,5(2H,4H)-dione (0.2 mmol), cyclohexane (0.6 mmol), ferric chloride (0.02 mmol), sodium chloride (0.02 mmol), and acetonitrile (2 mL) were added sequentially. The tube was placed under a 390 nm lamp and stirred at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, the mixture was extracted with ethyl acetate and saturated brine. The combined organic phases were subjected to vacuum distillation, followed by column chromatography to obtain the final product (R)-6-cyclohexyl-2,4-dipropyl-1,2,4-triazine-3,5-dione, with a yield of 85%.

[0040] The structural characterization data of the obtained target product are shown below: 1 H NMR (400 MHz, Chloroform- d ) d 4.18 (s, 1H), 3.78–3.58 (m, 3H), 3.35–3.26 (m, 1H), 3.22 (d, J = 7.0 Hz, 1H), 1.93 (d, J = 12.2 Hz, 1H), 1.88–1.72 (m, 3H), 1.72–1.52 (m, 6H), 1.37–1.13 (m, 4H), 1.06–0.96 (m, 1H), 0.92(q,J = 7.5 Hz, 6H). 13 C NMR (101 MHz, CDCl3) d 170.5, 153.1, 63.7, 51.1,42.0, 36.2, 29.7, 29.1, 26.1, 26.0, 25.9, 21.7, 20.5, 11.2. HRMS(ESI) m / z calcd for C 15 H 27 N3NaO2 (M+Na) + : 304.1995, found 304.1994.

[0041] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0042] Example 7 In a reaction tube with a stir bar, weighed 2,4-diallyl-1,2,4-triazine-3,5(2H,4H)-dione (0.2 mmol), cyclohexane (0.6 mmol), ferric chloride (0.02 mmol), sodium chloride (0.02 mmol), and acetonitrile (2 mL) were added sequentially. The tube was placed under a 390 nm lamp and stirred at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, the mixture was extracted with ethyl acetate and saturated brine. The combined organic phases were subjected to vacuum distillation, followed by column chromatography to obtain the final product ((R)-6-cyclohexyl-2,4-diallyl-1,2,4-triazine-3,5-dione), with a yield of 87%.

[0043] The structural characterization data of the obtained target product are shown below: 1 H NMR (400 MHz, Chloroform- d ) d 5.93–5.77 (m, 2H), 5.30–5.14 (m,4H), 4.42–4.29 (m, 3H), 4.22 (dd, J = 14.9, 6.1 Hz, 1H), 4.00 (dd, J = 14.9, 6.5 Hz, 1H), 3.25 (d, J = 7.1 Hz, 1H), 1.95 (d, J = 12.7 Hz, 1H), 1.85–1.72(m, 3H), 1.68 (d,J = 9.8 Hz, 1H), 1.58 (d, J = 10.5 Hz, 1H), 1.31–1.14 (m,4H), 1.06–0.95 (m, 1H). 13 C NMR (101 MHz, CDCl3) d 170.1, 152.6, 132.6, 131.9,118.8, 117.4, 63.7, 52.3, 42.4, 36.1, 29.5, 29.2, 26.0, 25.9, 25.8. HRMS(ESI) m / z calcd for C 15 H 24 N3O2 (M+H) + : 278.1863, found 278.1861.

[0044] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0045] Example 8 In a reaction tube with a stir bar, weighed di-tert-butyl-2,2'-(3,5-dioxo-1,2,4-triazine-2,4(3H,5H)-diyl)diacetate (0.2 mmol), cyclohexane (0.6 mmol), ferric chloride (0.02 mmol), sodium chloride (0.02 mmol), and acetonitrile (2 mL) were added sequentially. The mixture was placed under a 390 nm lamp and stirred at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, the mixture was extracted with ethyl acetate and saturated brine. The combined organic phases were subjected to vacuum distillation, followed by column chromatography to obtain the final product, di-tert-butyl-2,2'-(6-cyclohexyl-3,5-dioxo-1,2,4-triazine-2,4-diyl)(R)-diacetate, with a yield of 90%.

[0046] The structural characterization data of the obtained target product are shown below: 1 H NMR (400 MHz, Chloroform- d ) d 4.80 (d, J = 7.5 Hz, 1H), 4.46–4.29(m, 3H), 3.99 (d, J = 17.4 Hz, 1H), 3.42 (t, J= 7.2 Hz, 1H), 2.06–1.96 (m,1H), 1.86 (d, J = 12.5 Hz, 1H), 1.80–1.62 (m, 4H), 1.48 (s, 9H), 1.46 (s, 9H), 1.34–1.16 (m, 4H), 1.08–0.96 (m, 1H). 13 C NMR (101 MHz, CDCl3) d 170.5,168.0, 167.0, 153.7, 82.6, 82.0, 63.6, 51.7, 42.1, 36.3, 29.7, 28.7, 28.0,28.0, 26.1, 25.9. HRMS(ESI) m / z calcd for C 21 H 35 N3NaO6 (M+Na) + : 448.2418, found448.2420.

[0047] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0048] Example 9 In a reaction tube with a stir bar, weighed 2-benzyl-4-(4-(tert-butyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (0.2 mmol), cyclohexane (0.6 mmol), ferric chloride (0.02 mmol), sodium chloride (0.02 mmol), and acetonitrile (2 mL) were added sequentially. The tube was placed under a 390 nm lamp and stirred at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, the tube was extracted with ethyl acetate and saturated brine. The combined organic phases were subjected to vacuum distillation, followed by column chromatography to obtain the final product (R)-2-benzyl-4-(4-(tert-butyl)phenyl)-6-cyclohexyl-1,2,4-triazine-3,5-dione, with a yield of 90%.

[0049] The structural characterization data of the obtained target product are shown below: 1 H NMR (600 MHz, Chloroform- d ) d 7.39 (d, J = 7.3 Hz, 2H), 7.35 (d, J= 8.3 Hz, 2H), 7.31–7.27 (m, 4H), 7.26–7.23 (m, 1H), 4.98 (d, J = 14.1 Hz, 1H), 4.93 (d, J = 14.1 Hz, 1H), 4.67 (d, J = 14.2 Hz, 1H), 4.55 (d, J = 14.2Hz, 1H), 4.18 (s, 1H), 3.17–3.11 (m, 1H), 1.74–1.65 (m, 2H), 1.63–1.56 (m,3H), 1.45–1.40 (m, 1H), 1.30 (s, 9H), 1.20–1.04 (m, 3H), 1.01–0.94 (m, 1H), 0.88–0.80 (m, 1H). 13 C NMR (151 MHz, CDCl3) d 170.1, 152.9, 150.8, 137.6,133.3, 128.7, 128.7, 128.4, 127.4, 125.5, 63.7, 52.84, 43.5, 36.1, 34.5,31.3, 29.5, 29.3, 26.0, 25.9, 25.8. HRMS(ESI) m / z calcd for C 27 H 35 N3NaO2 (M+Na) + : 456.2621, found 456.2618.

[0050] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0051] Example 10 In a reaction tube with a stir bar, weighed 4-methyl-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione (0.2 mmol), cyclohexane (0.6 mmol), ferric chloride (0.02 mmol), sodium chloride (0.02 mmol), and acetonitrile (2 mL) were added sequentially. The tube was placed under a 390 nm lamp and stirred at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, the mixture was extracted with ethyl acetate and saturated brine. The combined organic phases were subjected to vacuum distillation, followed by column chromatography to obtain the final product 6-cyclohexyl-4-methyl-2-phenyl-1,2,4-triazine-3,5-dione, with a yield of 92%.

[0052] The structural characterization data of the obtained target product are shown below: 1 H NMR (400 MHz, Chloroform- d ) d 7.47–7.36 (m, 3H), 7.15 (dd, J =7.5, 1.8 Hz, 2H), 4.57 (d, J = 5.3 Hz, 1H), 3.41–3.35 (m, 1H), 3.20 (s, 3H), 2.02 (dd, J = 13.3, 3.4 Hz, 1H), 1.95–1.85 (m, 1H), 1.84–1.76 (m, 2H), 1.71(d, J = 10.5 Hz, 2H), 1.37–1.21 (m, 4H), 1.14–1.03 (m, 1H). 13 C NMR (101 MHz, CDCl3) d 170.7, 153.0, 134.8, 129.1, 128.6, 128.4, 64.0, 37.5, 36.6, 29.7, 29.4, 26.1, 25.9.

[0053] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0054] Example 11 In a reaction tube with a stir bar, weighed 2-(4-chlorophenyl)-2-(2,6-dichloro-4-(4-methyl-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetonitrile (0.2 mmol), cyclohexane (0.6 mmol), ferric chloride (0.02 mmol), sodium chloride (0.02 mmol), and acetonitrile (2 mL) were added sequentially. The tube was placed under a 390 nm lamp and stirred at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, the mixture was extracted with ethyl acetate and saturated brine. The combined organic phases were subjected to vacuum distillation, followed by column chromatography to obtain the final product 2-(4-chlorophenyl)-2-(2,6-dichloro-4-(6-cyclohexyl-4-methyl-3,5-dioxo-1,2,4-triazin-2-yl)phenyl)acetonitrile, with a yield of 93%.

[0055] The structural characterization data of the obtained target product are shown below: 1 H NMR (400 MHz, Chloroform- d ) d 7.88 (s, 2H), 7.28 – 7.23 (m, 2H), 7.21 (d, J = 2.5 Hz, 2H), 6.05 (s, 1H), 4.52 (d, J = 8.3 Hz, 1H), 3.44-3.38(m, 1H), 3.16 (s, 3H), 1.95 – 1.87 (m, 1H), 1.75 – 1.65 (m, 3H), 1.62 (d, J =11.3 Hz, 2H), 1.40 – 1.29 (m, 1H), 1.25 – 1.01 (m, 4H). 13 C NMR (101 MHz, CDCl3) d 170.5, 151.8, 143.1, 135.6, 134.1, 131.3, 129.0, 128.2, 126.2, 120.4, 116.6, 64.0, 36.9, 36.8, 29.9, 28.7, 27.6, 25.9, 25.9.

[0056] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0057] Example 12 In a reaction tube with a stir bar, weighed 2-(4-(tert-butyl)benzyl)-1,2,4-triazine-3,5-dione (0.2 mmol), cyclohexane (0.6 mmol), ferric chloride (0.02 mmol), sodium chloride (0.02 mmol), and acetonitrile (2 mL) were added sequentially. The tube was placed under a 390 nm lamp and stirred at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, the mixture was extracted with ethyl acetate and saturated brine. The combined organic phases were subjected to vacuum distillation, followed by column chromatography to obtain the final product R)-2-(4-(tert-butyl)benzyl)-6-cyclohexyl-1,2,4-triazine-3,5-dione, with a yield of 75%.

[0058] The structural characterization data of the obtained target product are shown below: 1 H NMR (600 MHz, Chloroform- d ) d 7.31 (s, 4H), 6.94 (s, 1H), 4.90 (d, J = 4.2 Hz, 2H), 4.13 (s, 1H), 3.22 (d, J = 6.7 Hz, 1H), 1.91–1.83 (m, 2H), 1.77–1.69 (m, 2H), 1.66 (d, J = 11.7 Hz, 1H), 1.56–1.51 (m, 1H), 1.29 (s,9H), 1.24–1.14 (m, 4H), 1.04–0.95 (m, 1H). 13 C NMR (151 MHz, CDCl3) d 170.2,154.3, 150.4, 134.2, 128.4, 125.3, 63.4, 42.6, 36.1, 34.5, 31.3, 29.7, 29.0,26.1, 25.9. HRMS(ESI) m / z calcd for C 20 H 29 N3NaO2 (M+Na) + : 366.2152, found366.2153.

[0059] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0060] Example 13 In a reaction tube with a stir bar, weighed 2,4-dibenzylazuraidine (0.2 mmol), adamantane (0.6 mmol), ferric chloride (0.02 mmol), sodium chloride (0.02 mmol), and acetonitrile (2 mL) were added sequentially. The tube was placed under a 390 nm lamp and stirred at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, the mixture was extracted with ethyl acetate and saturated brine. The combined organic phases were subjected to vacuum distillation, followed by column chromatography to obtain the final product (6R)-6-(adamantane-1-yl)-2,4-dibenzyl-1,2,4-triazine-3,5-dione, with a yield of 80%.

[0061] The structural characterization data of the obtained target product are shown below: 1 H NMR (400 MHz, Chloroform- d ) d 7.38 (d, J = 7.1 Hz, 2H), 7.35–7.28(m, 7H), 7.27–7.24 (m, 1H), 5.00 (d, J = 14.1 Hz, 1H), 4.94 (d, J = 14.1 Hz, 1H), 4.81 (d, J = 14.3 Hz, 1H), 4.46 (d, J = 14.3 Hz, 1H), 4.27 (s, 1H), 3.78(d, J = 11.3 Hz, 1H), 1.98–1.90 (m, 2H), 1.85–1.67 (m, 8H), 1.63–1.47 (m,4H), 1.36 (d, J = 12.0 Hz, 1H). 13 C NMR (101 MHz, CDCl3) d 170.1, 153.0,137.6, 136.3, 128. 9, 128.6, 128.5, 128.4, 127.9, 127.4, 58.8, 53.5, 43.5,41.4, 38.6, 38.3, 37.9, 31.8, 31.4, 28.9, 27.6, 27.5, 27.5. HRMS(ESI) m / z calcd for C 27 H 31 N3NaO2 (M+Na) +: 452.2308, found 452.2307.

[0062] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0063] Example 14 In a reaction tube with a stir bar, weighed 2,4-dibenzyl-1,2,4-triazine-3,5(2H,4H)-dione (0.2 mmol), tetrahydrofuran (0.6 mmol), ferric chloride (0.02 mmol), sodium chloride (0.02 mmol), and acetonitrile (2 mL) were added sequentially. The tube was placed under a 390 nm lamp and stirred at room temperature for 12 hours. The reaction was monitored by TCL. After the reaction was completed, the mixture was extracted with ethyl acetate and saturated brine. The combined organic phases were subjected to vacuum distillation, followed by column chromatography to obtain the final product 2,4-diphenyl-6-(tetrahydrofuran-2-yl)-1,2,4-triazine-3,5-dione, with a yield of 85%.

[0064] The structural characterization data of the obtained target product are shown below: 1 H NMR (400 MHz, Chloroform- d ) d 7.45–7.38 (m, 3H), 7.37–7.19 (m,13H), 5.06–4.89 (m, 3H), 4.78 (d, J = 10.4 Hz, 1H), 4.74 (d, J = 10.3 Hz,1H), 4.57 (s, 1H), 4.52 (d, J = 9.3 Hz, 2H), 4.44 (d, J = 6.0 Hz, 1H), 4.38(d, J = 11.9 Hz, 1H), 3.70–3.72 (m, 1H), 3.72–3.63 (m, 2H), 3.50–3.45 (m,1H), 3.36 (d, J = 10.6 Hz, 1H), 2.04–1.83 (m, 5H), 1.83–1.67 (m, 1H). 13 C NMR (101 MHz, CDCl3) d169.8, 169.1, 153.2, 137.4, 137.2, 136.5, 136.4, 128.8,128.7, 128.7, 128.6, 128.5, 128.5, 128.3, 128.3, 127. 8, 127.3, 78.6, 75.2,69.1, 61.2, 61.0, 53.5, 53.1, 43.8, 29.1, 27.5, 26.1, 25.0. HRMS(ESI) m / z calcd for C 21 H 24 N3O3 (M+H) + : 366.1812 found 366.1820.

[0065] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0066] Example 15 The difference between Example 15 and Example 1 is that the catalyst used is ferric chloride, while the other conditions are exactly the same.

[0067] Examples 15 and 1 investigated the effect of the catalyst on the yield. The results are shown in Table 1. When ferric chloride was used, the Fe(III) complex absorbed a photon, which excited an electron to jump from the ligand to the Fe(III) center, directly inducing homolytic cleavage of the Fe(III)–ligand bond to generate a reduced Fe(II) and a highly active ligand radical. However, ferric chloride was more difficult to initiate the reduction process, so the yield was lower.

[0068] Table 1. Effect of different catalysts on yield

[0069] Example 16

[0070] The difference between Example 16 and Example 1 is that the additive used is lithium chloride, while the other conditions are exactly the same.

[0071] Example 16 and Example 1 investigated the effect of additives on yield. The results are shown in Table 2. Different cations have different effects. Sodium has a lower ionization energy and stronger metallicity. The yield difference between the two is not significant. Sodium chloride was chosen because it is a common table salt, more abundant in resources, and inexpensive.

[0072] Table 2. Effect of different additives on yield

[0073] Example 17

[0074] The difference between Example 17 and Example 1 is that the solvent used is ethanol, while the other conditions are exactly the same.

[0075] Example 18

[0076] The difference between Example 18 and Example 1 is that the solvent used is dichloromethane, while the other conditions are exactly the same.

[0077] Examples 17, 18, and 1 investigated the effect of solvent on yield, and the results are shown in Table 3. Acetonitrile can form a stable complex with the reducing agent of ferric chloride, resulting in a high yield. Ethanol may partially quench the generated chlorine radicals, and dichloromethane cannot coordinate with the reducing agent of ferric chloride, resulting in a low yield.

[0078] Table 3. Effect of different solvents on yield

[0079] Example 19

[0080] The difference between Example 19 and Example 1 is that the light source is 365 nm, while the other conditions are exactly the same.

[0081] Example 20

[0082] The difference between Example 20 and Example 1 is that the light source is 420 nm, while the other conditions are exactly the same.

[0083] Examples 19, 20 and 1 investigated the effect of light source on yield. The results are shown in Table 4. The energy of light affects the yield. Too strong light energy may damage the system, while too weak light energy is insufficient to stimulate the reaction.

[0084] Table 4. Effect of light source on yield

[0085] Example 21

[0086] The difference between Example 21 and Example 1 is that 2,4-dibenzylazuracil (0.2 mmol) and cyclohexane (1 mmol) were used, while the other conditions were exactly the same.

[0087] Example 22

[0088] The difference between Example 22 and Example 1 is that 2,4-dibenzylazuracil (0.2 mmol) and cyclohexane (0.2 mmol) were used, while the other conditions were exactly the same.

[0089] Examples 21, 22, and 1 investigated the effect of feedstock addition on yield. When the ratio of 2,4-dibenzylazuracil to cyclohexane was 1:1, the yield was not high, and there was excess 2,4-dibenzylazuracil. In order to convert it to the target product as completely as possible, the equivalent of cyclohexane was increased. When the ratio of 2,4-dibenzylazuracil to cyclohexane was 1:5, the yield was not much different from that when the ratio was 1:3. Based on economic cost considerations, it was not necessary to increase the equivalent by too much.

[0090] Table 5. Effect of Feed Ratio on Yield

[0091] Example 23

[0092] The difference between Example 23 and Example 1 is that no catalyst is added, but all other conditions are exactly the same.

[0093] Example 24

[0094] The difference between Example 24 and Example 1 is that the catalyst addition amount is 0.04 mmol, while the other conditions are exactly the same.

[0095] Examples 23, 24 and 1 investigated the effect of catalyst addition on yield. The results are shown in Table 6. The reaction was very poor without catalyst, indicating that catalyst is necessary. The effect of 0.04 mmol catalyst and 0.02 mmol catalyst is not significantly different, so there is no need to add too much.

[0096] Table 6. Effect of catalyst dosage on yield

[0097] Example 25

[0098] The difference between Example 25 and Example 1 is that no additives are added, but all other conditions are exactly the same.

[0099] Example 26

[0100] The difference between Example 26 and Example 1 is that the amount of additive added is 0.06 mmol, while the other conditions are exactly the same.

[0101] Examples 25, 26, and 1 investigated the effect of catalyst addition on yield, and the results are shown in Table 7. The reaction could proceed without additives, but the effect was not good. Adding additives significantly improved the yield, but excessive additives did not significantly improve the yield. Therefore, Example 1 was selected.

[0102] Table 7. Effect of additive dosage on yield

[0103] Example 27

[0104] The difference between Example 27 and Example 1 is that the reaction time is 48 hours, while the other conditions are exactly the same.

[0105] Examples 27 and 1 investigated the effect of reaction time on yield. The results are shown in Table 8. The yield did not change significantly after increasing the reaction time. Based on the principle of saving time, Example 1 was selected.

[0106] Table 8. Effect of reaction time on yield

Claims

1. A method for preparing azauracil by hydrogenation under iron-mediated light irradiation, characterized in that: The following steps are included: Under nitrogen atmosphere, alkanes, uracil derivatives, catalysts, additives, and solvents were added to a reaction tube in proportion. The mixture was stirred under light at room temperature, and the reaction was monitored by TCL. After the reaction was completed, the mixture was extracted with ethyl acetate and water. The combined organic phases were then distilled under reduced pressure and separated by column chromatography to obtain the pure product. ； In the formula, substituent R1 is one of hydrogen, benzyl, naphthalenebenzyl, alkyl, alkenyl, or ester-substituted alkyl; R2 is one of benzyl, naphthalenebenzyl, alkyl, alkenyl, ester-substituted, or phenyl-substituted alkyl; and substituent R3 is a cycloalkane, wherein the cycloalkane is one of cyclohexane, adamantane, or tetrahydrofuran.

2. The method for preparing azauracil by hydrogenation under iron-mediated light irradiation according to claim 1, characterized in that: The catalyst is either ferric chloride or ferric chloride.

3. The method for preparing azauracil by hydrogenation under iron-mediated light irradiation according to claim 1, characterized in that: The solvent is one of ethanol, acetonitrile, and dichloromethane.

4. The method for preparing azauracil by hydrogenation under iron-mediated light irradiation according to claim 1, characterized in that: The additive is one of sodium chloride and lithium chloride.

5. The method for preparing azauracil by hydrogenation under iron-mediated light irradiation according to claim 1, characterized in that: The illumination conditions are provided by using a light source with a wavelength of 365 nm, 390 nm, or 420 nm.

6. The method for preparing azauracil by hydrogenation under iron-mediated light irradiation according to claim 1, characterized in that: The ratio of the uracil derivative to the alkane is 1:(1~5).

7. The method for preparing azauracil by hydrogenation under iron-mediated light irradiation according to claim 1, characterized in that: The feed ratio of the uracil derivative to the catalyst is 1:(0~0.2).

8. The method for preparing azauracil by hydrogenation under iron-mediated light irradiation according to claim 1, characterized in that: The ratio of the uracil derivative to the additive is 1:(0~0.3).

9. The method for preparing azauracil by hydrogenation under iron-mediated light irradiation according to claim 1, characterized in that: The reaction time for this synthesis method is 12-24 hours.

10. The method for preparing azauracil by hydrogenation under iron-mediated light irradiation according to claim 1, characterized in that: The eluent for column chromatography separation is a mixed solvent system of petroleum ether and ethyl acetate, with a volume ratio of petroleum ether to ethyl acetate of 15:1.

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