INTRODUCTION

Qualitative and quantitative structural characteristics of heterocyclic compounds are significant in studying reaction mechanisms as well as in the synthesis of novel biologically active materials [1-4]. It is well known that the majority of saturated six-membered heterocycles adopt the chair conformation whereas the structure of aromatic derivatives is almost planar [5-9]. Deviations from the planarity may arise due to a set of various steric and electronic factors [10].

Conformational features of polycyclic triazines largely depend on the nature of the annelated cycle. Azolo[1,2,4]triazines [11] is an important class of biologically active compounds applied as effective antiviral drugs, such as triazavirin (1,2,4-triazolo[5,1-с][1,2,4]triazine) and remdesivir(pyrrolo[2,1-f][1,2,4]triazine) [12, 13]. Nonetheless, the structural features of hydrogenated azolotriazines still remain poorly studied. We have previously considered the chemical properties and structures of several aromatic and partially saturated azolo[1,2,4]triazines [14-18]. In this work, for the first time we investigated the structures of a series of 3-tert-butyl-3,4-dihydropyrazolo[5,1-с][1,2,4]triazine-3,4-diyl dicarboxylates by single crystal X-ray diffraction (XRD) and discussed their bond lengths and bond angles together with molecular packings in the crystals.

EXPERIMENTAL

Materials and methods. The melting point was determined on a STUART Melting point SMP30 apparatus. IR spectra were recorded on an Agilent Cary 660 FTIR spectrometer with KBr as a thin layer or pellets. NMR spectra were obtained on Bruker AM-300 or Bruker AV-600 spectrometers with working frequencies of 300 MHz (1H), 75 MHz, or 125 MHz (13C). CHCl3 (1H) and CDCl3 (13C) were used as the internal standards. High resolution spectra were measured on a Bruker MicroTOF II instrument with electronic sputtering ionization. The measurements were performed on positive ions (capillary voltage 4500 V); solvents were methanol or acetonitrile. The elemental analysis was performed on a PerkinElmer Series II 2400 Elemental Analyzer. Merck 60 (200 µm) silica gel was used for chromatography. Initial compounds 1 and 2a were prepared by the procedure described previously [19].

Single crystal XRD. For the study the crystals of compounds 3a,b and 4a were grown by slow evaporation of the solvent from their saturated solutions in EtOAc at room temperature.

Reflections were collected on a Quest D8 Bruker single crystal diffractometer (Photon-III detector, graphite monochromator, λ(MoKα) = 0.71073 Å) at 100 K. Reflection intensity data were obtained using the SAINT program [20] and crystal absorption correction was applied semi-empirically based on equivalent reflections using SADABS/TWINABS [20, 21]. The structures were solved by direct methods using SHELXS [22] and refined by the least squares technique in the anisotropic (isotropic for hydrogen atoms) full-matrix approximation on F2 using the SHELXL-2018 program [23]. Positions of all ordered hydrogen atoms in 3a,b and 4a are found from the electron density difference map. For molecular graphics we employed the SHELXTL program [20].

A crystal of compound 3a is a two-component twin with a domain ratio of 0.533(2):0.467(2) and the [–1 0 0, 0 –1 0, 0.191 0 –1] twinning law. The rotating group model was applied for methyl groups. Since the crystal of compound 3b completely decomposed at 100 K (the temperature was lowered by 60 K/h), it was coated with epoxy resin. The reflections of 3b were recorded at 300 K and 200 K (the temperature was lowered by 120 K/h). The crystal also slowly decomposed at 200 K, which caused an increase in Rint and R1 values (for independent reflections). At 300 K the С16, С17, and O4 atoms are disordered over two positions with a ratio of 0.742(6):0.258(6). At 200 K the disordering of only O4 atom was modeled (0.891(6):0.109(6)) because the amount of residual electron density is insufficient to model well the disordering of C16, C17 atoms and hydrogen atoms at C17.

Crystallographic data for 3a,b and 4a structures have been deposited with the Cambridge Crystallography Data Center. Deposition numbers and the most important characteristics are listed in Table 1.

General synthesis procedure for compounds 3a and 3b. One portion of compound 2a (0.5 g, 2.6 mmol) was added to a mixture of EtOAc (5.0 mL), benzoic acid (3.0 g, 24.57 mmol, for 3a) or acetic acid (5 g, 83.3 mmol, for 3b), and NBS (10.0 g, 56.19 mmol). The mixture was refluxed at 60 °C (3a) or 30-35 °C (3b) for 5 h. After cooling to room temperature, EtOAc (50.0 mL) and heptane (10.0 mL) were added. The mixture obtained was added with a portion of a mixture of K2CO3 (10.0 g, 72.36 mmol) and \(\text{N}(n\text{-Bu})_{4}^{+}\text{Br}^{-}\) (10 mg, 3.1·10–5 mmol) in water (100.0 mL), and the heterogeneous mixture obtained was vigorously stirred for 1 h at room temperature. The organic phase was separated, washed with water (3×100 mL), dried with crystalline K2CO3 and anhydrous MgSO4, and filtered off. After the evaporation of solvents the precipitate was purified chromatographically (eluent EtOAc:heptane = 1:50-1:30), and 0.81 g of compound 3a (72%) or 0.75 g of 3b (94%) were obtained.

(±)(3S,4S)-7-Bromo-3-tert-butyl-8-methyl-3,4-dihydropyrazolo[5,1-c][1,2,4]triazine-3,4-diyl dibenzoate (4a). To a mixture of compound 1 (3.0 g, 10.74 mmol) with TMSBr (3.0 mL, 22.73 mmol) in acetonitrile (20.0 mL) t-BuONO (6.0 mL, 50.44 mmol) was added dropwise with stirring for 20 min. The reaction mixture was heated to 80 °C for 1 h; the reaction course was controlled by thin layer chromatography (TLC). After the evaporation of solvents the precipitate was dissolved in Et2O (20.0 mL), BF3·Et2O (10.0 mL, 81.03 mmol) was added, and cooled to 0 °C in an ice bath. After cooling, small portions of LiBH4 (1.5 g, 68.87 mmol) were added to the reaction mixture during 2 h. The mixture obtained was left overnight at room temperature (the formation of compound 2b was controlled by TLC). Then water cooled to 0 °C was added dropwise (100.0 mL) and EtOAc (20.0 mL), and the mixture was stirred for 30 min. To the heterogeneous mixture obtained KOH (10.0 g, 178.24 mmol) and \(\text{N}(n\text{-Bu})_{4}^{+}\text{Br}^{-}\) (0.5 g, 1.55 mmol) were added and heated with stirring to 70-80 °C for 1 h. After cooling, it was extracted with CHCl3/EtOAc (2:1, 4 × 50 mL). The combined organic phase was dried with anhydrous MgSO4, filtered off, and the filtrate was evaporated in a vacuum. To the precipitate obtained EtOAc (5.0 mL), benzoic acid (3.0 g, 24.57 mmol), and NBS (12.0 g, 67.42 mmol) were added. The mixture was refluxed at 100 °C for 5 h. After cooling to room temperature, EtOAc (50.0 mL), heptane (10.0 mL), water (100.0 mL), K2CO3 (10.0 g, 72.36 mmol), \(\text{N}(n\text{-Bu})_{4}^{+}\text{Br}^{-}\) (10 mg, 3.1·10–5 mmol) were successively ordered. The heterogeneous mixture obtained was vigorously stirred for 1 h at room temperature. The organic phase was separated, washed with water (3×100 mL), dried with anhydrous K2CO3 and MgSO4, filtered off, and the filtrate was evaporated in a vacuum. The precipitate was purified by double flash-chromatography (eluent EtOAc:heptane = 1:50-1:30), and 3.57 g of compound 4a (65%) were obtained: yellow crystals, m.p. 186-187 °C. 1H NMR spectrum (CDCl3, δ, ppm, J, Hz): 8.08 (d, 4H, 4 o-CH Ph, 3J = 7.7), 7.88 (s, 1H, C4H), 7.50-7.63 (m, 6Н, 2 p- and 4 m-CH Ph), 2.44 (s, 3H, C8CH3), 1.35 (s, 9H, C(CH3)3). 13C NMR spectrum (CDCl3, δ, ppm): 164.80, 164.31 (2 COPh), 141.42 (C3), 134.24, 133.90 (2 p-CH Ph), 132.22 (C7Br), 130.54, 130.13, 129.39, 128.84 (2 m- and 2 o-CH Ph), 128.72, 128.33 (2 ipso-C Ph), 120.38 (C8a), 97.51 (C8), 77.59 (C4H), 41.57 (C(CH3)3), 26.30 (C(CH3)3), 8.27 (C8CH3). IR, cm–1: 3013, 2994, 2978, 2940 (CH), 1752, 1717 (2 CO), 1600, 1583, 1565, 1481, 1493, 1434, 1451, 1399, 1350, 1369, 1316, 1264, 1240, 1180, 1194, 1133, 1065, 1085, 1055, 1025, 997, 938, 875, 843, 800, 705, 686, 668, 638, 611. Found [M]+ 511.0964. Calculated [M]+ for C24H23BrN4O4 511.0975. Found (%): C 56.32, H 4.55, N 10.98. Calculated for C24H23BrN4O4 (%): C 56.37, H 4.53, N 10.96.

Table 1 Crystallographic Data and Single Crystal XRD Details
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7,8-Dibromo-3-tert-butyl-3,4-dihydropyrazolo[5,1-c][1,2,4]triazine-3,4-diyl dibenzoate (4b). One portion of compound 2d (1 g, 3 mmol) was added to a mixture of benzoic acid (3.0 g, 24.57 mmol) and NBS (5.0 g, 28.09 mmol) in EtOAc (10 mL). The solution obtained was heated to 100 °C for 2 h. After cooling to room temperature the precipitate was dissolved in a mixture of EtOAc (30 mL) and heptane (10 mL). To the organic phase a mixture of K2CO3 (10 g, 72.36 mmol) and \(\text{N}(n\text{-Bu})_{4}^{+}\text{Br}^{-}\) (10 mg, 3.1·10–5 mmol) in water (100 mL) was added and stirred for 1 h. The organic phase was separated, washed with water (3×100 mL), dried with anhydrous MgSO4, filtered off, and the filtrate was evaporated in a vacuum. The precipitate was purified chromatographically (eluent EtOAc:heptane = 1:50-1:40) and 1.14 g (66%) of compound 4b were obtained: yellow viscous fluid, m.p. < 0 °C. 1H NMR spectrum (CDCl3, δ, ppm, J, Hz): 8.11-8.07 (m., 4H, 4 o-CH Ph), 7.91 (s, 1H, C4H), 7.51-7.66 (m, 6Н, 2 p- and 4 m-CH Ph), 1.35 (s, 9H, С(CH3)3). 13C NMR spectrum (CDCl3, δ, ppm): 164.88, 164.20 (2COPh), 141.13 (C3), 134.45, 134.09 (2 p-CH Ph), 132.33 (C7Br), 130.56, 130.16, 128.92, 128.79 (2 m- and 2 o-CH Ph), 129.08, 127.98 (2 ipso-C Ph), 101.96, 98.04 (C8a, C8), 77.36 (C4H), 41.75 (C(CH3)3), 26.21 (C(CH3)3). IR, cm–1: 3063, 3014, 2994, 2978, 2941 (CH), 1758, 1716, 1691 (2 CO), 1675, 1652, 1642, 1623, 1599, 1583, 1560, 1546, 1521, 1494, 1480, 1448, 1400, 1366, 1348, 1316, 1294, 1257, 1269, 1238, 1174, 1126, 1083, 1066, 1052, 1023, 996, 938, 870, 888, 845, 799, 707, 685, 644, 619, 565, 544, 464. Found [M]+ 574.9915. Calculated [M]+ for C23H20Br2N4O4 574.9924. Found (%): C 47.87, H 3.48, N 9.75. Calculated for C23H20Br2N4O4 (%): C 47.94, H 3.50, N 9.72.

RESULTS AND DISCUSSION

3-tert-Butyl-3,4-dihydropyrazolo[5,1-с][1,2,4]triazine-3,4-diyl dicarboxylates 3a,b were previously synthesized [24] by the interaction of aromatic 3-tert-butyl-pyrazolo[5,1-с][1,2,4]triazines with N-bromosuccinimide in the presence of respective carboxylic acids. We found that 3-tert-butyl-8-methyl-1,4-dihydropyrazolo[5,1-c][1,2,4]triazine 2а is readily brominated in the presence of acetic or benzoic acids. Thus, prolonged heating of cyclic hydrazone 2a with NBS in the BzOH/EtOAc mixture or in an excess of glacial AcOH results in good yields of dicarboxylates 3a and 3b respectively (Scheme 1).

Scheme 1
scheme 1

Preparation of dicarboxylates 3a and 3b, and compound 4a. Reagents and conditions: NBS, PhCO2H, EtOAc, 100 °C, 5 h (1); NBS, AcOH, 30-35 °C (2); NBS, PhCO2H/EtOAc, 60 °C, 5 h (3).

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The XRD results for compounds 3a and 3b are summarized in Table 1. The triazine ring of the 3а heterocycle adopts the twist-conformation with the equatorial arrangement of the tert-butyl group as a conformational anchor and axial carboxylate moieties fixed in the trans-configuration. The molecular packing in the 3a crystal represents 1D extended chains along the c axis (Fig. 1). The crystal of compound 3b decomposed on cooling to 100 K. The crystal coated with epoxy resin also slowly decomposed at 200 K, which caused an appreciable increase in Rint and R1 values (based on independent reflections) at this temperature. We have experimentally observed a 26.3 Å3 decrease in the unit cell volume on cooling from 300 K to 200 K (3.2%), which can be explained by a decrease in the thermal motion of the O4–C16–C17 fragment: the distance between disordered O4A and O4B shortened from 0.99(1) Å to 0.93(3) Å (Fig. 2). The most significant structural change is an increase in the acetate torsion angle at the С4 position (by 5.6° for С16А–О3–С4–Н4 and by 22.3° for С16B–О3–С4–Н4). At different temperatures changes in the crystal structure of 3b were also revealed in the structure of the triazine ring: N1–N2–C3–O1, N1–N2–C3–C10, and N1–N2–C3–C4 torsion angles decrease by approximately 2° (Fig. 2, Table 2).

We managed to covert readily available compound 1 into dibenzoate 4a without isolating intermediate products. The synthesis involves diazotization of the C7 position, reduction of the ring and the side chain under the influence of BH3/BF3 [15, 19], and in situ oxidation of intermediate 2b with a NBS/BzOH mixture (Scheme 1). Target compound 4a was obtained in a good yield.

The single crystal XRD results for compound 4a are summarized in Table 1. In the 4a molecule, the aromatic pyrazole ring and substituents are located in one plane with a deviation of 1-3° (Table 2), while the triazine ring is in the twist-conformation. Unlike analogue 3а, not containing a bromine atom, in 3b and 4a, the tert-butyl group takes the position close to axial, with the equatorial carboxylate groups being in the trans-configuration (Fig. 3). The molecular packing in the 4a crystal is shown in Fig. 4. Compound 4a forms intermolecular halogen bonds [25] between Br and O2 atoms of the neighboring molecules with a length of 3.086(1) Å, the С7–Br–O2 angle being 161.12(6)°.

Fig. 1
figure 1

Molecular structure of compound 3а and its packing in the crystal. Hydrogen atoms of Me and Ph groups are omitted.

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Fig. 2
figure 2

Molecular structure of compound 3b at 200 K (a) and 300 K (b). Hydrogen atoms are omitted.

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Table 2 Torsion Angles in Compounds 3a,b and 4a, deg
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Fig. 3
figure 3

Molecular structure of compound 4a. Hydrogen atoms of alkyl and phenyl groups are omitted.

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The removal of the bromine atom from the С7 position of compound 4а led to an insignificant (0.01-0.02 Å) decrease in С8–С11, С7–С8, and N5–N6 bond lengths and C9–C8–C11 and N6–C7–C8 bond angles (1-2°). It is worth noting that on passing from phenyl groups in compound 3а to methyl ones in 3b, a decrease in C3–O1 and С4–O3 bond lengths from 1.459(6) Å and 1.435(2) Å to 1.435(2) Å and 1.422(2) Å, respectively, is observed (Table 3). On the contrary, due to a change in the volume of the substituent, a weakening of С3–С10 and N5–N6 bonds is observed: by 0.03 Å and 0.01 Å respectively. In diacetate 3b, the N2–C3–O1 and O1–C3–C(t-Bu) bond angles decreased by 5-6° in comparison with similar ones in dibenzoate 3a. In turn, the N1–N2–C3–O1 and N2–C3–C4–O3 torsion angles increased by ~6° and ~10° respectively, which may be explained by some relaxation of steric hindrance in the 3b molecule.

Due to pronounced structural features of carboxylate 4a brominated at the С7 position, it was interesting to investigate by single crystal XRD the structure of similar compound 4b containing bromine atoms at С7 and С8 positions. Previously undescribed compound 4b was isolated in treating aromatic 7,8-dibromopyrazolotriazine 5 [26] with N-bromosuccinimide in the presence of benzoic acid (Scheme 2).

Scheme 2
scheme 2

Preparation of compound 4b. Reagents and conditions: NBS, PhCO2H/EtOAc, 100 °C, 2 h.

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The IR spectrum of dibenzoate 4b contains intense characteristic bands at 1758 cm–1 and 1716 cm–1, which we assigned to stretching vibrations of two carbonyl groups. In the 1H NMR spectrum, we observed signals of С4–Н hydrogen atoms at 7.91 ppm (C4H) and also two phenyl groups at 7.51-8.11 ppm. The 13C NMR spectrum (experiment - test for bound protons, APT) and the high-resolution mass spectrum corresponded to the expected ones. Product 4b was isolated as a viscous fluid which we failed to crystallize under diverse experimental conditions.

Fig. 4
figure 4

Molecular packing of compound 4a in the crystal.

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Table 3 Selected Bond Lengths in Compounds 3a,b and 4a (Å)
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CONCLUSIONS

The structures of 7-R1-8-methyl-3-tert-butyl-3,4-dihydropyrazolo[5,1-с][1,2,4]triazine-3,4-diyl diacetate (R1 = H) and dibenzoates (R1 = H, Br) are studied by single crystal XRD for the first time. The observed conformations of the triazine ring largely depended on the nature of substituents in the heterocyclic core, which may be explained by the combined action of spatial effects and intermolecular non-valent interactions. The trans-arrangement of carboxylate moieties was confirmed in all compounds studied. A decrease in the unit cell volume of the diacetate crystal on cooling from 300 K to 200 K is experimentally found. Bond lengths and bond angles as well as the molecular packing in the crystals are considered.

ACKNOWLEDGMENTS

The single crystal XRD analysis was performed in the Department of Structural studies of the Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, Moscow.