Received 31 May 2012
Structures of benzoxazine-fused triazoles as potential diuretic agents
Krishnan Ravikumar,a* Balasubramanian Sridhar,a Jagadeesh Babu Nanubolu,a Venkatasubramanian Hariharakrishnanb and Awadesh Narain Singhb
6,8-Dinitro-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-1-one, C9H5N5O6, (I), a potential diuretic, and its acetylacetone derivative (E)-2-(2-hydroxy-4-oxopent-2-en-3-yl)-6,8-dinitro-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-1-one, C14H11N5O8, (II), both crystallize from methanol but in centrosymmetric and noncentrosymmetric space groups, respectively. To the best of our knowledge, this is the first report of crystal structures of benzoxazine-triazole fused systems. The acetylacetone group in (II) exists as the keto-enol tautomer and is oriented perpendicular to the triazol-3-one ring. Of the two nitro groups present, one is rotated significantly less than the other in both structures. The oxazine ring adopts a screw-boat conformation in (II), whereas it is almost planar in (I). N-HN and N-HO hydrogen bonds form centrosymmetric dimers in (I), while C-HO interactions associate the molecules into helical columns in (II).
Triazole and its derivatives have been attracting interest over the past decade due to their wide range of pharmacological applications (Chen et al., 2000; Duran et al., 2002; Gujjar et al., 2009). Compounds containing triazole have also received considerable attention due to their intriguing physical properties and potential for applications in propellants and explosives (Nimesh & Rajendran, 2010; Katritzky et al., 2006). Furthermore, triazole moieties are attractive connecting units, as they are stable to metabolic degradation and capable of hydrogen bonding (Horne et al., 2004). In recent years, fused triazoles have become increasingly common in pharmaceutical targets and biologically active substances (Lauria et al., 2008).
1,4-Benzoxazines are an important class of molecules and a common heterocyclic scaffold in biologically active and medicinally significant compounds. The therapeutic activities of benzoxazine compounds have been further extended through the development of scaffolds via fusion with different nitrogen heterocycles (e.g. imidazole, triazole, oxazole, pyrimidine etc.). A number of benzoxazines fused with triazoles were synthesized by Shridhar et al. (1984) and evaluated for their diuretic activity. 6,8-Dinitro-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-1-one, (I), was reported to be the most potent of the compounds synthesized, even though it contains none of the usual pharmacophoric features needed for diuretic activity, e.g. a strong acidic group like -COOH, -SO3H or a sulfonamide group, or a strongly basic group such as an amidine group. The present work forms part of a continuing study of the structures of pharmaceutical compounds (Ravikumar & Sridhar, 2009, 2010; Ravikumar et al., 2011) and we report here the crystal structures of (I) and its acetylacetone derivative (E)-2-(2-hydroxy-4-oxopent-2-en-3-yl)-6,8-dinitro-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-1-one, (II).
Compounds (I) and (II) contain heterocyclic ring structures, significant hydrogen-bond acceptor sites and flexible functionalities. Interestingly, both compounds crystallize as solvent-free structures. Compound (I) crystallizes in the centrosymmetric space group P21/n and (II) in the noncentrosymmetric space group Pna21.
The molecular structures of (I) and (II), including the atom-labelling schemes, are shown in Figs. 1 and 2, respectively. The defining feature of the molecular conformations of (I) and (II) is the orientation of the nitro groups. The C7-nitro group is nearly coplanar with the plane of the attached benzene ring [6.8 (1)° in (I) and 3.6 (1)° in (II)], whereas the C1-nitro group is significantly rotated [20.3 (1)° in (I) and 41.5 (1)° in (II)]. This orientational difference may be attributed to repulsion between atom O1 of the C1-nitro group and atom O5 of the neighbouring oxazine ring. It may also be due to the participation of the C1-nitro group only in intermolecular C-HO interactions (Tables 2 and 3). The greater rotation of the C1-nitro group observed in (II) is perhaps due to its interaction with the acetylacetone group.
Computational calculations were performed using the crystallographic structure parameters of (I) and (II) as a starting point. The density functional theory (DFT) method was applied at the B3LYP hybrid exchange correlation function level (Becke, 1993; Lee et al., 1988) using the 6-31G(d,p) basis set (Bauschlicher & Partridge, 1995) as implemented in GAUSSIAN03 (Frisch et al., 2004). The optimized geometry for the C7-nitro group in both structures is coplanar with the plane of the parent benzene ring [-0.53° for (I) and 1.56° for (II)], while for the C1-nitro group it is twisted [31.4° for (I) and 27.8° for (II)] to avoid repulsion between the juxtaposed O atoms, as mentioned above. It can be seen that the computed rotation angles for the nitro groups are slightly different from those observed in the crystal structures, as the calculations were performed on isolated molecules, thus precluding any hydrogen-bonding effects.
Compound (I) contains a strong hydrogen-bond donor (N5-H) and also strong acceptors (N4 and O6) on the triazole ring, which can result in the formation of centrosymmetric motifs such as N-HN dimers (type A; Scheme 2) or amide N-HO dimers (type B). Of the two possible centrosymmetric motifs, type B is stronger than type A because of the higher electronegativity and greater acceptor strength of oxygen over nitrogen (Jeffrey, 1997). Interestingly, the structure of (I) does not contain the stronger type B motif. Instead, it is assembled only by the weaker type A motif (N5-H5NN4).
In order to understand the inherent competition between these two hydrogen-bonded motifs, and thereby to establish their preference of occurrence in similar organic crystal structures, a search of the Cambridge Structural Database (CSD, Version 5.32 with May 2012 updates; Allen, 2002) was undertaken for all molecules containing the 1,2,4-triazol-3-one fragment. The search resulted in 75 hits, of which seven repeated structures were discarded. Of the remaining 68 structures, 25 contain the amide-dimer type B motif, two show the N-HN catemer (type C in Scheme 2), 20 show the amide-catemer motif (type D), one shows the N-HN single-point interaction (type E), two show the N-HO single-point interaction (type F), one is a hetero dimer (type G) and 17 have NH bonded to water, solvent or other strong acceptor groups available in the structure (type H). This trend clearly indicates a preference for motif types B and D. It is surprising to note that none of these 1,2,4-triazol-3-one fragment structures contains the N-HN dimer type A motif, and therefore the very presence of the type A motif in (I) makes the crystal structure interesting. The absence of the type B motif in (I) is likely to arise from the involvement of a carbonyl O atom in the intramolecular C6-H6O6 contact. In (II), all the hydrogen-bonded motifs mentioned above are absent, since the H atom bound to atom N5 is replaced by an acetylacetone group.
In (II), the effect of the acetylacetone substitution is surprisingly seen in the oxazine ring, even though these two groups are a long way apart. It manifests itself in a lengthening of the C3-O5 bond and a narrowing of the bond angles involving atom C3 of the oxazine ring in (II) compared with unsubstituted (I) (Table 1). It could also be surmised that the participation of atom C3 of the oxazine ring in an intermolecular C-HO interaction with atom O8 of the acetylacetone group (Table 3) might have influenced the ring distortion. The conformation of the oxazine ring is nearly planar in (I), whereas it is screw-boat in (II).
There are two tautomeric possibilities for the acetylacetone group in (II), viz. keto-keto or keto-enol, as shown in Scheme 3. The latter tautomeric structure is generally preferred, due to the intramolecular O-HO hydrogen bond which helps to stabilize it (Bertolasi et al., 2008; Caminati & Grabow, 2006). According to Gilli & Gilli (2000), the keto-enol tautomer has a natural tendency to exhibit resonance-assisted hydrogen bonding (Scheme 3), resulting in a strong hydrogen bond between two carbonyl O atoms. In such circumstances, the carbonyl and enol C-O bond lengths are indistinguishable, and the H atom is at the mid-point between the two carbonyl O atoms (Emsley et al., 1988, 1989). This short hydrogen bond in (II) [O8O7 = 2.487 (4) Å] is apparently symmetric, with its H atom located centrally [O8-H8O = 1.23 (10) Å and H8OO7 = 1.34 (9) Å]. The refined isotropic atomic displacement parameter of atom H8O is somewhat larger than normal; its position and atomic displacement parameter were also refined. A contoured Fourier difference map produced by PLATON (Spek, 2009), with the site-occupancy factor of atom H8O set to 0.001, clearly shows that the maximum electron density is at atom H8O, located midway between the two O atoms (Fig. 3). The refined position of the H atom does not necessarily truly represent the majority of the electron-density distribution, and hence an asymmetric nature for this hydrogen bond cannot be precluded. Both carbonyl distances (Table 1) are equivalent and longer than the expected Csp2=O distance of 1.222 Å and shorter than the expected Csp2-OH distance of 1.333 Å in the keto-enol fragment (Allen et al., 1987). Furthermore, the equidistant bonds for C12-C10 [1.400 (4) Å] and C10-C11 [1.399 (5) Å] reflect neither a Csp2-Csp2 (1.455 Å) nor a Csp2=Csp2 bond (1.362 Å) (Allen et al., 1987), but indicate a significant mixed character of both bond types, thus confirming the resonance phenomenon or a partial -electron delocalization in the keto-enol fragment (Bertolasi et al., 1996).
A salient feature of this keto-enol tautomeric form in (II) is its influence on the molecular conformation: it is oriented perpendicular to the triazol-3-one ring [C9-N5-C10-C12 = 99.4 (3)°]. Geometry optimization performed on this molecule using density functional theory (DFT) methods also indicated a twisted conformation, with C9-N5-C10-C12 = 71.6°. An overlay of these two conformations is shown in Fig. 4. Differences in torsion angles between experimentally observed and computationally predicted conformers are normally expected, as the former are affected by the crystal environment. This twisting may be necessary to relieve the van der Waals strain that would be present if the molecule were to exist in a planar conformation (i.e. without twist), since both the methyl groups (C13 and C14) of the acetylacetone and atoms O6 and N4 of the triazol-3-one ring system are prone to maximum repulsion. The energy calculated for the above-mentioned planar conformation is 13.21 kcal mol-1 (1 kcal mol-1 = 4.184 kJ mol-1) higher than that for the twisted conformation.
In the crystal packing of (I), as mentioned above, the molecules form a centrosymmetric dimer connected by intermolecular N5-H5NN4ii hydrogen bonds (Fig. 5) [R22(6) graph-set motif (Etter, 1990; Etter et al., 1990; Bernstein et al., 1995)] [symmetry code: (ii) -x + 1, -y, -z]. Each dimer is further connected to an inversion-related dimer by a quadruple hydrogen-bonding motif via N-HO and a C-HO interactions (Table 2). This quadruple [R44(18)] motif can also be defined in the form of three fused R22(9), R22(12) and R22(9) ring motifs. The alternating arrangement of these motifs facilitates the formation of an infinite tape in the  direction. A C8-H8O1iv interaction connects adjacent tapes in a zigzag fashion [symmetry code: (iv) x + , -y + , z + ].
In the crystal packing of (II), the molecules are essentially associated by C-HO interactions (Table 3) and van der Waals forces. It is interesting to note that the molecules are aligned in helical columns which run in the  direction (Fig. 6) and are interlinked.
Stacking interactions are seen in both structures. In (I), these are between the triazol-3-one and benzene rings [centroid separation = 3.659 (1) Å], whereas in (II) they are between benzene rings [centroid separation = 3.708 (2) Å]. In (I), short intermolecular O6O6 and O6O6i contacts (Table 2) are also observed, which are normal due to the three-centred intra- and intermolecular C6-H6O6 contacts.
In summary, this is the first report to present the crystal structures of benzoxazine-fused triazoles. The crystallographic study shows the formation of the N-HN centrosymmetric dimer motif, rather than the commonly observed N-HO centrosymmetric dimer, between triazol-3-one rings. The resonance-assisted keto-enol tautomer of the acetylacetone group, with enhanced acceptor strength, participates in a C-HO interaction with an oxazine ring. This influences the molecular conformation of the central oxazine ring in the tricyclic fused-ring system. C-HO-driven intermolecular interactions play a significant role in the formation of the supramolecular networks.
| || Figure 1 |
A view of the molecule of (I), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.
| || Figure 2 |
A view of the molecule of (II), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level. The dashed line indicates the intramolecular hydrogen bond.
| || Figure 3 |
A contoured Fourier difference map slice in the plane of the acetylacetone group of (II), with the site occupancy of atom H8O set at 0.001. The refined positions of the atoms are shown by `+' marks. The contour intervals are 0.1 e Å-3.
| || Figure 4 |
A superposition of the molecular conformations of (I) and (II), along with the respective optimized structures, (Io) and (IIo). The overlay was made by making a least-squares fit through the benzene ring of (I). The r.m.s. deviations (Å) with respect to the conformation of (I) (orange in the electronic version of the journal) are: (II) 0.008 (red), (Io) 0.012 (green) and (IIo) 0.011 (cyan).
| || Figure 5 |
A partial packing diagram for (I), viewed along the a axis, showing the formation of R22(6), R22(9) and R44(18) ring motifs. N-HN, N-HO and C-HO interactions are shown as dashed lines. Intermolecular C3-H3BO6iii contacts and H atoms not involved in interactions have been omitted for clarity. Selected atoms of the molecules present in the asymmetric unit are labelled, primarily to provide a key for the coding of the atoms. [Symmetry codes: (i) -x + 2, -y, -z + 1; (ii) -x + 1, -y, -z; (iii) x - 1, y, z; (iv) x + , -y + , z + .]
| || Figure 6 |
A partial packing diagram for (II), viewed along the c axis, showing the formation of helical columns. C-HO interactions are shown as dashed lines. H atoms not involved in interactions have been omitted for clarity. Selected atoms of the molecules present in the asymmetric unit are labelled, primarily to provide a key for the coding of the atoms. [Symmetry codes: (i) -x + 2, -y, z + ; (ii) -x + 2, -y, z - ; (iii) x + , -y + , z.]
The N-bound H atom of (I) and the O-bound H atom of (II) were located in a difference Fourier map and their positions and isotropic displacement parameters were refined. All other H atoms were located in difference density maps, but were positioned geometrically and included as riding atoms, with C-H = 0.93 (aromatic), 0.96 (methyl) or 0.97 Å (methylene) and with Uiso(H) = 1.5Ueq(C) for the methyl groups and 1.2Ueq(C) otherwise. The methyl groups were allowed to rotate but not to tip. In the absence of significant anomalous scatterers, Friedel pairs were merged in (II).
For both compounds, data collection: SMART (Bruker, 2001); cell refinement: SAINT (Bruker, 2001); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: DIAMOND (Brandenburg & Putz, 2005) and Mercury (Macrae et al., 2008); software used to prepare material for publication: SHELXL97.
Supplementary data for this paper are available from the IUCr electronic archives (Reference: CU3013 ). Services for accessing these data are described at the back of the journal.
The authors thank Dr J. S. Yadav, Director, IICT, Hyderabad, for his kind encouragement, and Dr K. Bhanuprakash, I&PC division, IICT, for his support with the computations.
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