key: cord-0061414-jigotdtb
authors: Ivanov, Sergey M.; Koltun, Denis S.
title: Synthesis and crystal structures of 7,8-bromo (dibromo)-3-tert-butylpyrazolo[5,1-c][1,2,4]triazines
date: 2021-03-29
journal: Struct Chem
DOI: 10.1007/s11224-021-01768-0
sha: 34b913a1386249cfa39d9e3f9a30600cf4f58d45
doc_id: 61414
cord_uid: jigotdtb

Single crystal structures in a series of 7-bromo-, 8-bromo-, and 7,8-dibromo-3-tert-butylpyrazolo[5,1-c][1,2,4]triazin-4(1H)-ones have been investigated by X-ray diffraction. Novel 7-bromo- and 7,8-dibromo-3-tert-butylpyrazolo[5,1-c][1,2,4]triazines were synthesized by reduction of triazine carbonyl with dehydrative aromatization in acidic media, and their XRD structural features were compared with that of the 4-oxo analogs. The lengths and bond angles and the packing of molecules in crystals have been considered. Non-valence interactions for some of the studied compounds were observed. Correlations between the presence of bromine atoms at different positions and structural features are determined. [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11224-021-01768-0.

The qualitative and quantitative structural aspects of heterocyclic compounds are of interest in terms of their utility for the certain mechanistic and synthetic studies [1] [2] [3] , as well as for various biological applications [4] [5] [6] . It is known that most of the six-membered saturated heterocycles prefer the chair conformations [7, 8] , while the aromatics are nearly planar. The significant deviations can often be the result of combination of steric and electronic factors [9] .

Fused triazines exhibit diverse conformational behavior depending on the nature of an annulated ring [10, 11] . Azolo [1, 2, 4] triazines [12] constitute an important class of such compounds which have found broad use a s e f f e c t i v e a n t i v i r a l a g e n t s , e . g . , 1 , 2 , 4triazolo [5,1-с] [1, 2, 4] triazine (triazavirin) [13] and pyrrolo [2,1-f] [1, 2, 4] triazine (remdesivir) [14, 15] . Nevertheless, the structural features of such systems are still relatively poorly studied. In continuation of our studies on the chemical and structural properties of functionalized pyrazolo [5,1-c] [1, 2, 4] triazines [16] [17] [18] [19] [20] [21] , in the present work, we discuss the single crystal structures in a series of brominated 4-oxo-and novel 4unsubstituted-3-tert-butylpyrazolo [5,1-c] [1, 2, 4] triazines, including bond lengths and angles, non-valence interactions, and packing modes.

Melting points were determined on a STUART Melting point SMP30 apparatus. IR spectra were recorded in KBr pellets using Agilent Cary 660 FTIR infrared spectrophotometer. NMR spectra were recorded on Bruker AM-300 or AV-600 spectrometers operating at working frequencies of 300 ( 1 H), 75 or 151 MHz ( 13 C). Chemical shifts were related to that of the CHCl 3 ( 1 H), or CDCl 3 ( 13 C). High resolution mass spectra were recorded on a Bruker MicroTOF II instrument in positive ion mode (capillary voltage 4500 V) using electrospray ionization (ESI) and methanol or acetonitrile as a solvent. Elemental analysis was performed on a PerkinElmer Series II 2400 Elemental Analyzer. All reagents were obtained from commercial sources and used without additional purification. Starting compounds 1a,b, 2a-d, and 3a were synthesized as described in literature (Scheme 1) [17] [18] [19] [20] .

General procedure for the synthesis of compounds 3b and 3c (Scheme 2)

Compound 1b (1.23 g, 4.90 mmol) was dissolved in a mixture of DMF (10 ml), NEt 3 (1 ml, 7.17 mmol), and Boc 2 O (1.1 g, 5.04 mmol). To the resulting solution, NaN 3 (10 mg, 1.53 × 10 -4 mol) was added, and the reaction mixture was heated at 60°C for 15 min with stirring. Then, it was cooled and added to 100 ml of water. The formed precipitate was filtered, washed with H 2 O (3 × 50 ml) and heptane (2 × 15 ml), dried in air, and suspended in a mixture of TMSBr (4 ml, 30.31 mmol) and MeCN (10 ml). To this suspension, t-BuONO (5 ml, 42.04 mmol) was added dropwise over 20 min and with vigorous stirring. After the addition was complete, the black reaction mixture was further stirred for 1 h at 50°C. After cooling to r.t., MeOH (15 ml) and NaBH 4 (1 g, 26.43 mmol) were simultaneously added in small portions with stirring over 30 min. After the addition was complete, the mixture was further stirred at 50°C for 30 min. Then, it was cooled to 0°C , conc. HCl/H 2 O solution (15 ml) was added slowly, and the red reaction mixture was stirred for 2 h at r.t. Next, H 2 O (100 ml), Na 2 HPO 4 ·2H 2 O (20 g, 112.37 mmol), EtOAc (30 ml), and heptane (50 ml) were added in one portion, and the biphasic mixture was stirred vigorously for 20 min at r.t. The organic phase was separated, dried with crystalline K 2 CO 3 and anhydrous MgSO 4 , and filtered. The solvents were removed in vacuo, and the residue was purified by two-fold flash column chromatography (eluted with EtOAc:heptane = 1:100 -3:200) to give compounds 3b and 3c. For X-ray single crystal studies, all compounds were recrystallized by slow solvent evaporation at r.t. from nearly saturated solutions in ethyl acetate/dimethylsulfoxide mixture (10:1 v/v). Crystallization of 2d from the same solvent mixture provided a mixture of two polymorph modifications: 2d•DMSO (major component, colorless blocks on a flask's bottom, over 95%) and non-solvated 2d (minor, colorless blocks on flask's walls). X-ray data collection and refinement X-ray diffraction data were collected at 100 K on a Bruker Quest D8 diffractometer equipped with a Photon-III area-detector (graphite monochromator, shutterless φand ω-scan technique), using Mo K α -radiation (0.71073 Å). The intensity data were integrated by the SAINT program [22] and corrected for absorption and decay using SADABS [23] . The structure was solved by direct methods using SHELXT [24] and refined on F 2 using SHELXL-2018 [25] .

For 2a,b,d, 2d•DMSO, and 3a: all non-hydrogen atoms were refined with individual anisotropic displacement parameters. The locations of atom H1 in 2a,b,d, 2d•DMSO, and all hydrogen atoms in 3a were found from the electron density-difference map; they were refined with individual isotropic displacement parameters. All other hydrogen atoms were placed in ideal calculated positions and refined as riding atoms with relative isotropic displacement parameters. The molecule of non-solvated 2d is disordered over 2 positions with the ratio of 0.9613(6):0.0387 (6) .

For 2c and 3b,c: all non-hydrogen atoms were refined with anisotropic displacement parameters. Positions of atoms H1A and H1B in 2c were found from the electron density-difference map and were restrained at the distance of 0.84(3) Å from N1A/ N1B, correspondingly. All other hydrogen atoms in 2c and 3b,c were placed in ideal calculated positions and refined as riding atoms with relative isotropic displacement parameters. A rotating group model was applied for methyl groups in 2c. The studied crystal of 2c was refined as a 2-component twin with the domain ratios of 0.407(2):0.593(2) and the twin law of (1.00 0.55 0.98, 0.00 -1.00 0.00, 0.01 0.00 −1.00) (the second major domain is rotated from the first one by 179.9°about reciprocal axis 1 0 0).

The SHELXTL program suite [22] was used for molecular graphics. Displacement ellipsoids are set to the 50% probability level on all figures below. See Electronic Supplementary Material (ESM) for more details on X-ray data collection and refinement.

Crystal data, data collection, and structure refinement details for 2a-d and 3a-c are summarized in Tables 1 and 2. Bond distances and angles, as well as additional ORTEP drawings, are presented in ESM for this paper. The structures have been deposited at the Cambridge Crystallographic Data Center with the reference CCDC numbers 2065233-2065240; they also contain the supplementary crystallographic data. These data can be obtained free of charge from the CCDC via http://www.ccdc.cam.ac.uk/data_request/cif.

The starting compounds 1a,b were prepared by cyclocondensation of 4-amino-6-tert-butyl-3-methylsulfanyl-1,2,4-triazin-5-one with cyanoacetic acid derivatives in pyridine (Scheme 1) [18] . Hydrolysis of the pyrazole ester moiety in 1a and diazotization using tert-butyl nitrite gave 7-unsubstituted acid, which is converted to compound 2a by halodecarboxylation [17] . Alternatively, treatment of 1a,b with trimethylsilylbromide/t-BuONO followed by bromination or selective reduction of the CO 2 Et group with diborane led to compounds 2b or 2d, respectively [18, 19] . Compound 2c [18] was prepared by a selective C(8)-site Li/Br exchange in 2b using n-butyl lithium at low temperature, and further protonation.

Aromatic triazine 3a was synthesized from 2d by reduction/ oxidative nitration sequence [19] . In order to further investigate the structural effects of bromine substitution on the aromatic pyrazolo[5,1-c][1,2,4]triazine system, we set the task of switching the oxygen atom to hydrogen at the C4 position and comparing the structure of the obtained compounds. Novel 4unsubstituted pyrazolotriazines 3b,c were prepared by decarboxylative N(1)-acylation of the carboxylic acid 1b with with further dehydrative aromatization of hydroxytriazine 5 in acidic media gave a mixture of compounds 3b and 3c in 57% overall yield. Formation of compound 3c can be explained in terms of electrophilic heteroaromatic ipso-substitution [26] of Br + by H + . Crystals were successfully grown for all the isolated compounds and X-ray diffraction analyses were carried out.

Molecular structure description Series of 7-or 8-monobromo compounds 2a,c and 3a,c are crystallized from ethyl acetate/dimethylsulfoxide (10:1) mixture in the monoclinic (the P2 1 /c space group for 2a and P2 1 /n for 3c), triclinic (the P1 space group for 2c), and orthorhombic (Pnma for 3a) crystal systems without inclusion of solvent molecules into the crystal lattice. Compound 2d was simultaneously crystalized from ethyl acetate/DMSO (10:1) mixture at r.t. in two forms: as single crystals of non-solvated 7-bromo-3-tert-butyl-8-methylpyrazolo [5,1-c] [1, 2, 4] triazin-4(1H)one 2d in the orthorhombic crystal system (the Pbca space group), and as a 1:1 solvate with dimethylsulfoxide 2d· DMSO in the triclinic crystal system (the P1 space group). 7,8-Dibromo pyrazolotriazines 2b and 3b were also crystallized from EtOAc/DMSO (10:1) mixture in the orthorhombic (Pbca) and monoclinic groups (P2 1 /n) respectively. All studied crystal structures (Figs. 1, 2, and 3 ) exhibit similar geometries; yet, some subtle differences will be mentioned. Results of X-ray diffraction studies for compounds 2a-d and 3a-c are presented in Tables 3, 4 , 5, and 6.

A slight increase in the C7-Br bond length compared to C8-Br for compounds 2c (1.854 (5) Å) and 2a (1.8658 (13) Å), respectively, is observed, which demonstrated the different πelectron density distribution in the conjugated system. The other bond distances are similar in both molecules. We were able to successfully switch the oxygen atom in 4-oxo derivative 2c to hydrogen and structurally characterize novel 7-bromo-3-tertbutylpyrazolo [5,1-c] [1, 2, 4] triazine 3c as well. The latter compound was investigated by X-ray diffraction method, and it was found that, for 3c, the N1-N2, C3-C4, and N5-N6 bond lengths are shorter than the corresponding bonds in compounds 2a,c (Table 3) , which indicate substantial increase in triazine ring conjugation for 3c compared to 2a and 2c. The Br atom in aromatic derivative 3c deviates more from the plane than in compounds 2a, c (~4°for 3c and~2°for 2a,c) , which can be explained by non-valence interactions, e.g., Br···N2 = 3.35 Å, H4···N1 = 2.35 Å ( Table 6 ). The C-C bond lengths within the It is worth noting that the crystallization of 2d carried out under the same conditions gave two types of crystals-nonsolvated and with inclusion of DMSO molecules into the crystal lattice. Both compounds have a similar structure, but the bromine atom in non-solvated 2d deviates more from the pyrazole plane (~2°for 2d and <1°for 2d·DMSO), which can be explained by the large contribution of non-valent intermolecular interactions. The added methyl group at the C8 position and switching the oxygen atom to hydrogen at the C4 site was expected to change the molecular geometry-the Br-C7-C8-C9 torsion angle for 3a is 180.000(1)°compared to 3c (175.93(8)°). It is interesting to note that this angle remains practically unchanged for 4-oxopyrazolotriazines 2d (178.20(14)°) and 2c (178.2(4)°). Other torsion angles in compound 3a were approximately equal to 180°, which indicated a more pronounced aromatic character. The distances C8-C14 and C7-Br are similar for all compounds and vary from 1.489(3) Å to 1.4953(11) Å and from 1.8629(19) Å to 1.8670(8) Å, respectively.

Finally, the crystal structures of 7,8-dibromo-4oxopyrazolo [5,1-c] [1, 2, 4] triazine 2b and its 4-unsubstituted analog 3b were investigated. Both compounds readily produced single crystals and their structures were determined by X-ray diffraction. The C7-Br and C8-Br bond lengths in 7,8dibromopyrazolo [5,1-c] [1, 2, 4] triazines 2b and 3b have similar values which vary from 1.851(7) Å (C7-Br for 3b) to 1.8576(16) Å (C8-Br for 2b). The two bromine atoms in 2b deviate from the plane by~2°, while the corresponding atoms in 3b are held practically coplanar towards the whole bicyclic s y s t e m . S i m i l a r l y , t h e C 1 0 ( M e 3 ) moiety in 4oxopyrazolotriazine 2b is located outside of the triazine ring (with a deviation of about 4°), while the corresponding atom in 4-unsubstituted analog 3b is located practically within the plane (N1-N2-C3-C10 = 179.9(6)°). The N1-N2, C3-C4, and N5-C4 bond lengths are significantly shorter in 3b when compared to 2b, which proved the presence of a conjugated aromatic system in 3b.

The molecules form infinite 1D chains via hydrogen bonding along the c (2a) or b (2b, 2c, 2d, 2d·DMSO, 3c) axes: atom H1 interacts with both N6 and O1 atoms of a neighboring molecule (Figs. 1, 2, and 3) . The experimental N1-H1 bond distances in all the studied compounds vary from 0.81(3) Å to 0.95Å (Table 6 ). It should be mentioned that these interactions are somewhat different among the studied crystals. Thus, the shortest donor···acceptor (D···A) distance and the largest D-H···A angle correspond to the bond N1-H1···O1 in 2d· DMSO, while the longest H-bond among the series was observed for compound 3c. On the contrary, C8-Me and C8-Br substituted analogs 3a,b do not tend to form any significant Hbonds. All the 4-oxo derivatives except for 2a ( Fig. 1 ) exhibit two types of hydrogen bonds between N1H and N6 or O1 atoms. It is worth noting that both hydrogen bonds are nearly equal in 2b and 2d (Figs. 2 and 3 and Table 6 ).

C8-Br in compound 2a is coordinated with N5 and N2 atoms of the nearby molecules at nearly identical distances of 3.35-3.38Å. Similarly, C7-Br in compounds 2b,d is coordinated with N2 (N2···Br = 3.41-3.42Å). However, bromine in a crystal lattice of analogous compound 2c with a vacant C8 position is surrounded by t-Bu groups and did not form any significant halogen bonds [27] , apparently due to the competing H-bonding.

Molecules of compound 3c exhibited short contacts (N2··· Br = 3.347(1)Å) which resemble that for 2b and 2d. An addition of C8-Me substituent to the aromatic pyrazolotriazine 3c led to considerable changes in the intermolecular interactions. Thus, every second molecule of 3a provided the bromine to form a pronounced halogen bond with the nearby azoheterocycle (N6···Br = 3.014Å, Fig. 2 ). In compound 3b, Symmetry codes: (i) x, −y+3/2, z+1/2; (ii) −x+3/2, y−1/2, z; (iii) −x+3/2, y+1/2, z; (iv) x−1, y, z C8-Br and N6 atoms also form halogen bonds with the distance of 3.254(7) Å (Fig. 3 ).

To summarize, a total of eight isomeric pyrazole ring brominated 3-tert-butylpyrazolo[5,1-c] [1, 2, 4] triazines have been for the first time investigated by X-ray single crystal diffraction analyses. Novel 7-bromo-and 7,8-dibromo-3-tert-butylpyrazolo[5,1c] [1, 2, 4] triazines were synthesized by reduction of triazine carbonyl with dehydrative aromatization in acidic media, and their XRD structural features were compared with that of the 4-oxo analogs. The experimental results revealed a marked increase in the aromatic character on switching oxygen atom in C4 position to hydrogen, which is indicated by the shortening of the heterocyclic bond lengths and smoothing of the torsion angles. Nonvalence interactions and different packing modes depending upon the position of the bromine atoms were also considered.

The online version contains supplementary material available at https://doi.org/10.1007/s11224-021-01768-0.

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