Synthesis and structure of 6-amino-5-nitro-2-propargylsulfanyl-4(3H)-pyrimidinone

Pyrimidine derivatives are known to be biologically active, with antiviral [1, 2], antitumor [3–5], antimycotic [6–8], HIV-1 [9–11] and anti-COVID-19 [12] activities.

Nitrosobenzenes can be oxidized to nitro compounds by oxidizing agents such as permanganate, chromate, hexacyanoferrate, Caro's acid [13], nitric acid, nitrogen dioxide and nitrogen monoxide [14], hypochlorite and hydrogen peroxide in alkaline medium [15], and in a mixture of hydrogen peroxide with nitric acid in glacial acetic acid as a solvent [16]. Nitrosobenzene can be oxidised by peroxocarboxylic acids. Thus, peroxotrifluoroacetic acid reacts in a solution of methylene chloride when boiling with nitrosobenzene to form nitrobenzene [17]. 5-Nitrosopyrimidine is oxidized to 5-nitropyrimidine by hydrogen peroxide using trifluoroacetic acid as a solvent [18].

In the present paper, we continue the discussion of substituted nitrosobenzene oxidation reactions on the example of 6-amino-5-nitroso-2-propargylsulfanyl-4( 3H )-pyrimidinone interaction with tert butyl hydroperoxide.

Experimental

The starting 6-amino-5-nitroso-2-propargylsulfanyl-4( 3H )-pyrimidinone was previously obtained by 6-amino-2-propargylsulfanyl-4( 3H )-pyrimidinone nitrosation according to the known procedure [19].

Synthesis of 6-amino-5-nitro-2-propargylsulfanyl-4( 3H )-pyrimidinone (1).

6-Amino-5-nitroso-2-propargylsulfanyl-4( 3H )-pyrimidinone (0.04 g, 0.19 mmol) was dissolved in 10 ml of dimethylformamide, then 70 % aqueous solution of tert -butyl hydroperoxide (0.017 g,

0.19 mmol) was added. The mixture was kept for 24 h at 20 °C. After the solvent evaporation, the oily dark green product was recrystallized from benzene. As a result, 0.023 g (40 %) of beige crystals of 1 with MP > 300 °C, with decomposition, was obtained.

IR spectrum, ν, сm^–1: 3290 (NH 2 ), 2923, 2855 (S–H), 1684 (C=O), 1653, 1595 (NO 2 ), 1517, 1507, 1419, 1457, 1448, 1437, 1395, 1388, 1363, 1283, 1247, 1223, 1180, 1122, 1066, 1015, 976, 804, 486, 444, 419.

• ¹H NMR (500 MHz, DMSO- d 6 ) δ 10.89 (s, 1H, NH), 7.77 (s, 2H, NH 2 ), 3.87 (s, 2H, SCH 2 ), 3.12 (s, 1H, С≡CH).

Found, %: С 40.10, Н 4.25. For C 20 H 26 N 10 O 8 S 2 calculated, %: С 40.13, Н 4.38.

IR spectrum of compound 1 was recorded on a Shimadzu IRAffinity-1S FTIR-spectrometer; sample was prepared by pelletting with KBr (absorption region 4000–400 cm^–1).

• ¹H NMR spectrum was recorded on a Bruker DRX-500 spectrometer (500 MHz) in DMSO, the internal standard was TMS.

X-ray diffraction analysis of crystalline substance 1 was performed on a Bruker D8 QUEST automatic four-circle diffractometer (Mo K α -emission, λ 0.71073 Å, graphite monochromator).

Data collection and editing, unit-cell parameters refinement, and correction for absorption were carried out in SMART and SAINT-Plus software [20]. All calculations aimed at solving and refining the structure of compound 1 were performed in SHELXL/PC [21] and OLEX2 software [22]. Structure 1 was determined by direct methods and refined with the least squares method in the anisotropic approximation for non-hydrogen atoms.

Crystal Data for C 20 H 26 N 10 O 8 S 2 ( M 598.63 g/mol): triclinic, space group Pī, a 7.267(7) Å, b 12.857(12) Å, c 15.417(15) Å, α 85.89(7)°, β 88.33(4)°, γ 75.16(4)°, V 1389(2) ų, Z 2, μ Mo 0.254 mm^–1, D calc 1.432 g/cm³, 31188 reflections measured, 5646 unique reflections ( R int 0.0410), the number of refinement variables 386, GOOF 1.029 , R factors for F ² > 2 σ ( F ²): R 1 0.0364, wR 2 0.0894, R factors for all reflections R 1 0.0553, wR 2 0.0991.

The full tables of atomic coordinates, bond lengths, and bond angles were deposited with the Cambridge Crystallographic Data Centre (CCDC 2050940 for compound 1; ; .

Results and Discussion

In the present work, the synthesis of 6-amino-5-nitro-2-propargylsulfanyl-4( 3H )-pyrimidinone has been carried out by the reaction of 6-amino-5-nitroso-2-propargylsulfanyl-4( 3H )-pyrimidinone with tert butyl hydroperoxide at room temperature at an equimolar ratio of reactants:

t -BuOOH

O2N

H2N

+ t -BuOH

Compound 1 is a crystalline substance, soluble in aromatic hydrocarbons, resistant to moisture and air oxygen.

Structure 1 has been determined by X-ray diffraction analysis and confirmed by IR and NMR ¹H spectroscopy. Suitable for X-ray diffraction analysis crystals were obtained after recrystallization of the reaction product from benzene.

In the IR spectrum of compound 1 , there are absorption bands at 3290 cm^–1 (NH 2 , st ), 2855 cm^–1 (S–CH 2 , st ), 1684 cm^–1 (C=O, st ) [23]. The broad absorption band of the N=O group with a maximum at 1559 cm^–1, characteristic for the starting compound [19], is absent in 1 . Instead, there is an intensive band at 1595 cm^–1 due to NO 2 -group stretching vibrations [23].

The ¹H NMR spectrum of 1 contains singlets of the SCH 2 protons at 3.87 ppm and С≡CH at 3.12 ppm. Downfield, there are signals of NH 2 group protons at 7.77 ppm. In an even farther downfield region, there is a singlet of pyrimidine ring NH protons at 10.89 ppm.

According to X-ray diffraction data, in crystal 1 there are two types of crystallographically independent molecules a and b , the geometric parameters of which are equal within the error limits, therefore, in the following, we discuss the structural data of molecule 1 a . The substance crystallizes in the form of a solvate with dimethylformamide (Fig. 1).

Fig. 1. Structure 1 ( a and b ) showing thermal ellipsoids at 30% probability. Hydrogen atoms have been omitted for clarity. Selected bond lengths (Å) and angles (°): C(5)–N(1) 1.317(2), C(6)–N(2) 1.452(2), C(3)–S(1) 1.748(2), C(3)–N(4) 1.352(2), C(3)–N(3) 1.303(3), N(2)–O(1) 1.223(2), N(2)–O(2) 1.209(2); S(1)C(3)N(3) 120.4(1), C(3)N(3)C(8) 117.7(1), O(1)N(2)O(2) 122.3(2), C(2)S(1)C(3) 100.3(1)

The compound has a struc ture simila r to the struc tur e of 2 -amino-5-nitropyrimidine and 6-methylamino-4-methylthio-5-nitro-2- p he n y lp y r i mi dine [24, 25]. The nitro- and thio- group planes are coplanar with the pla ne of the he te r oc y c lic f r a gm e nt. T he le n gths of the e xocy c lic C –NO 2 and C–NH 2 bonds are 1.452(2) and 1. 317( 2) Å, whic h is usu a l f or c o mpounds of the se c la ss e s. T he C Ar –S distance is 1.748(2) Å.

T he s tr u c tu r al or g a niza t ion of molecules in a crystal is due to hydrogen bonds O· · · H ( 1. 91 ( 2) – 2 . 70( 1 ) Å) ( Fig . 2) a n d int e rmolecular interactions between nitrogen and oxy g e n a toms N· · · O (2.767(3)– 2. 984(3) Å) ( Fig . 3) . T h e dis ta nce s betwe e n nitr og e n a nd oxygen atoms are slightly less than t he sum of Va n d e r W a als r adi i of N a nd O a toms (3. 15 Å) [26]. There are also face-to-face stacking i nt e r ac t ions, th e di stanc es b e twe e n c e n tr o ids of a r oma ti c r i ng s a r e 4. 13 –4.46 Å.

Fig. 2. Hydrogen bonds O···H in 1. Selected bond lengths (Å): 1.91(2), 1.97(2), 2.55(2), 2.59(3), 2.60(2), 2.66(2), 2.70(1)

Fig. 3. The intermolecular interactions in 1. Selected bond lengths (Å): N···O (2.767(3), 2,788(3), 2.924(3), 2.984(3))

Conclusion

The oxidation reaction of 6-amino-5-nitroso-2-propargylsulfanyl-4( 3H )-pyrimidinone with tert butyl hydroperoxide at equimolar ratio in dimethylformamide leads to formation of 6-amino-5-nitro-2-propargylsulfanyl-4( 3H )-pyrimidinone, the structural organization of which is due to hydrogen bonds and other short contacts as well as stacking interactions.

Acknowledgments

We are grateful to V.V. Sharutin for the X-ray diffraction analysis.