The Elbs and Boyland–Sims peroxydisulfate oxidation reactions offer a convenient means of introducing the hydroxy function into phenols and aromatic amines . The oxidation of phenol using peroxydisulfate was first demonstrated by Karl Elbs in 1893 , with E. Boyland later expanding this reaction to include aromatic amines . Concurrently, the successful oxidation of several pyrimidine derivatives was also reported . Since then, the reaction has been extensively researched on various classes of compounds such as phenols, coumarins, pyridines, pyrimidines, quinolines, and others. This has resulted in the production of numerous valuable products. The reaction's appeal lies in its simplicity and the fact that there is no requirement to protect sensitive functional groups, thus making the introduction of hydroxy groups into various compound classes an attractive option. However, both reactions suffer from a significant downside – low yields of target products, rendering them unsuitable for industrial application.

Considering the practical value of the products, as well as the simplicity and convenience of the process, our objective is to enhance the efficiency of the Elbs and Boyland–Sims peroxydisulfate oxidation reactions.

Figure 1: Derivatives of 6-methyluracil and 2-hydroxypyridine demonstrating pharmacological activity: 5-hydroxy-6-methyluracil (a), 5-hydroxy-1,3,6-trimethyluracil (b), milrinone (c), amrinone (d), and pilicide (e).

As described in during preliminary experiments, it was determined that room temperature is inadequate for fully oxidizing substrates. The optimal oxidation temperature for uracils 1 and 4 is between 60–65 °C, whereas for pyridines 7 and 9 it is 45 °C. Heating the reaction mixture at a temperature higher than the optimum level causes the substrates to be overoxidized and leads to destruction of the heterocyclic ring. As a result, the yield of the final products decreases. Furthermore, oxidation is incomplete at temperatures lower than the optimal temperature.

Scheme 1: Peroxydisulfate oxidation of 6-methyluracil and 1,3,6-trimethyluracil. Сonditions: a) (NH4)2S2O8, 24% NaOH, 60 °C, PcM; b) (NH4)2S2O8, 24% NaOH, 60 °C, H2O2; c) H2SO4, 80 °C.

Metal–phthalocyanine complexes (PcM) are recognized as catalysts for gentle, particular oxidation reactions under aerobic and H2O2-based conditions . The catalytic activity of metallophthalocyanines originates from their planar, cyclic structure with a developed π-conjugation system. This makes the fifth and sixth coordination sites of the central metal ion available for coordination with the reactant molecules of the catalytic reaction. Additionally, the π-conjugation system facilitates the redistribution of electron density within the reaction complex, thereby lowering the activation barrier of the reaction . The study employed the following oxidation catalysts for phthalocyanines – PcCo, PcFe(II), PcFe(III), PcMn, PcNi, and PcZn.

The use of catalysts reduced the duration of the oxidation reaction and significantly increased the yield of sulfate derivatives.

In the presence of РсМ, the optimal duration for the oxidation reaction of MU (1) was found to be 4 hours. When the catalyst was not applied, the yield of MU-5-ammonium sulfate 2 was no more than 15%. Subsequently, upon acid hydrolysis of compound 2, HMU (3) was produced. The addition of PcM to the reaction mixture resulted in a significant increase in the yield of compound 2 . The catalysts were added in quantities ranging from 0.00001–0.1 wt %, with the amount of catalyst increasing by a factor of 10 in each successive experiment.

As described in PcFe(II), PcСo, and PcFe(III) exhibited the highest activity in oxidizing reactions of MU (1). Addition of these catalysts in the amount of 0.01–0.05 wt % increased the yield of MU-5-ammonium sulfate 2 to 82–95%. The maximum yield of compound 2, equal to 95%, was obtained when 0.05 wt % PcFe(II) was introduced into the reaction. However, on enhancing the catalyst's quantity to 0.1 wt %, the product yield decreased to 33–45%. Further increase in the quantity of catalyst led to a greater decline in the yield of MU-5-ammonium sulfate, probably due to the destruction of the pyrimidine ring. PcZn turned out to be the least active catalyst, resulting in a yield of MU-5-ammonium sulfate 2 of 72% (0.05 wt %). The catalysts’ activity decreased in the order of PcFe(II) > PcCo > PcFe(III) > PcMn > PcNi > PcZn.

Table 1: Yield dependence of 1,3,6-trimethyluracil-5-ammonium sulfate (5) on the amount and type of catalyst.a

aMole ratio TMU/NaOH/APS 1:4:1.5; 55 °C; 8 h.

In previous studies, various pyridine derivatives such as 2-pyridone, its derivatives, and 4-pyridone , were subjected to the Elbs peroxydisulfate oxidation, resulting in yields of up to 38% for the corresponding 5-hydroxy derivatives (2,5-dihydroxy derivatives). Our study marks the first time pyridine has been involved in the peroxydisulfate oxidation reaction.

Scheme 2: Peroxydisulfate oxidation of pyridine and 2-hydroxypyridine. Сonditions: a) (NH4)2S2O8, 24% NaOH, 45 °C, PcM; b) (NH4)2S2O8, 24% NaOH, 45 °C, H2O2; c) HCl, 85–95 °C.

Table 2: Yield dependence of pyridine-2-ammonium sulfate (8)a and 2,5-dihydroxypyridine (11)b on the amount and type of catalyst.

aMole ratio Py/NaOH/APS 1:4:1.5, 45 °C; 10 h; bmole ratio HPy/NaOH/APS 1:4:2; 45 °C; 8 h.

Scheme 3: Potential mechanism of peroxydisulfate oxidation of 6-methyluracil and 1,3,6-trimethyluracil.

Table 3: Yield dependence of 6-methyluracil-5-ammonium sulfate (2)a and 1,3,6-trimethyluracil-5-ammonium sulfate (5)b on the amount of H2O2.

aMole ratio MU/NaOH/APS 1:4:1.5; 60 °C; 8 h; bmole ratio TMU/NaOH/APS 1:4:1.5; 55 °C; 8 h.

Table 4: Yield dependence of pyridine-2-ammonium sulfate (8) and 2-hydroxypyridine (9) on the amount of H2O2.a

aMole ratio Py/NaOH/APS 1:4:1.5; 45 °С; 10 h.

In conclusion, it is noted that we have identified effective modifications of peroxydisulfate-mediated oxidation reactions that allow us to obtain hydroxylated nitrogen-containing heterocycles in high yields. Our laboratory is currently investigating the application of these modifications to the oxidation of compounds of different classes.

1H and 13C NMR spectra were recorded on a Bruker Avance III 500 MHz spectrometer at 500.13 MHz (1H) and 125.73 MHz (13C) with 5 mm QNP sensors at a constant sample temperature of 298 K. The solvents were DMSO-d6, D2O, CDCl3 and the internal standard was SiMe4. Chemical shifts in the 13C and 1H NMR spectra are given in parts per million (ppm). Elemental analyses were performed on a CHNS Euro-EA 3000 automatic analyzer. Melting points were determined on combinated Boetius tables. IR spectra were obtained on an IR Prestige-21 Shimadzu spectrophotometer in KBr pellets.

Freshly distilled water, 6-methyluracil (99%, Chemical Line LLC, Russia), pyridine (analytically pure grade, Reakhim LLC, Russia), (NH4)2S2O8 (analytically pure grade, Panreac), NaOH (analytically pure grade, Reakhim LLC, Russia), H2SO4 (reagent grade, LLC Sigma Tech, Russia), dimethyl sulfate (99%, Chemical Line LLC, Russia), chloroform (reagent grade, JSC Khimreaktivsnab, Russia) and ethyl alcohol (reagent grade, LLC TD Khimmed, Russia) were used in this work. The phthalocyanine catalysts (Co, FeII, FeIII, Mn, Ni, and Zn phthalocyanines) were synthesized according to the known procedure from phthalonitrile (pure grade, Merck) and crystalline hydrates of the corresponding metal salts: CoCl2·6H2O (pure grade, Reakhim LLC, Russia), Ni(NO3)2·6H2O (analytically pure grade, Reakhim LLC, Russia), Fe(NO3)3·9H2O (pure grade, Reakhim LLC, Russia), FeCl2·4H2O (analytically pure grade, Panreac), MnSO4·5H2O (analytically pure grade, Reakhim LLC, Russia), and ZnSO4·7H2O (analytically pure grade, LLC Reachim, Russia); 1,3,6-trimethyluracil was synthesized according to the method from 6-methyluracil, dimethyl sulfate, and NaOH.

a) Catalysis by РсМ. As described in to a three-necked flask of 100 mL capacity, equipped with a mechanical stirrer, a thermometer, and a reflux condenser, containing 10 mL of distilled water, was added 0.023 mol of the corresponding uracil 1 or 4, followed by the addition of 11 mL of a previously prepared 24% NaOH solution to the obtained suspension. To the obtained thick mass 0.034 mol of (NH4)2S2O8 was added in portions under stirring, after which the calculated amount of the corresponding PcM was added. The reaction mixture was stirred at 60 °C for 4 h (for uracil 4–8 h). After cooling the reaction mixture to room temperature, concentrated H2SO4 was slowly added until pH 6–7 according to litmus paper and left standing for 12 h. The precipitated white crystals were filtered off, washed with water, and dried in air.

6-Methyluracil-5-ammonium sulfate (2). The spectral characteristics are given in .

1,3,6-Trimethyluracil-5-ammonium sulfate (5). The spectral characteristics are given in .

General procedure for the hydrolysis of uracils 2 and 5. As described in in a three-necked flask of 100 mL capacity, equipped with a mechanical stirrer, a reflux condenser, and a dropping funnel, 0.022 mol of compound 2 or 5 was placed, 30 mL of distilled water were added and the mixture heated to 80 °C under constant stirring. Then, 0.022 mol of concentrated H2SO4 was added and the reaction mixture was stirred at the same temperature for 1 h and cooled. The precipitated crystals were filtered off, washed with cold distilled water to pH 6–7 (2 × 5 mL), and recrystallized from ethanol.

5-Hydroxy-6-methyluracil (3). Yield 98%. The spectral characteristics are given in .

5-Hydroxy-1,3,6-trimethyluracil (6). Yield 88%. The spectral characteristics are given in .