Reduced 3,4′-bipyrazoles carrying thiophene and thiazole substituents: structures of two intermediates and two products

Reduced 3,4′-bipyrazole-2-carbothioamides are formed in cycloaddition reactions between chalcones and thiosemicarbazide, and these can undergo further cycloaddition reactions to form oxothaazole of thiazole substituents. Structure analysis establishes the regiochemistry of the cycloaddition reactions and shows the very simple patterns of supramolecular assembly in these compounds.


Chemical context
Heterocyclic compounds containing the pyrazole unit have been found to exhibit a wide range of biological activities, including antibacterial and antifungal activity (Rai et al., 2008;Isloor et al., 2009;Vijesh et al., 2013) and analgesic and antiinflammatory activity (Girisha et al., 2010;Isloor et al., 2010;Vijesh et al., 2013). It has also been found that the incorporation of a thiazole or thiazolone substituent often leads to enhanced activity (Sulthana et al., 2015;Havrylyuk et al., 2016), as does the incorporation of a thiophene substituent (Rostom et al., 2009;Bondock et al., 2010). In this connection, a procedure has recently been developed  for the synthesis of reduced 3,4 0 -bipyrazoles incorporating other heterocyclic units such as thiazole, thiazoline and thiophene as integral components. In brief, condensation of a 5-aryloxy-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde with 2-acetylthiophene gives the corresponding chalcone (Shaibah et al., 2020); chalcones of this type can undergo cyclocondensation reactions with semicabazide to provide the intermediate carbothioamides of type (I) (see Scheme). Further condensation of type (I) intermediates with diethyl acetylenedicarboxylate or with 4-bromophenacyl bromide gave the oxothiazolylidene ester (II) or the thiazole (III), respectively (see Scheme). Although the NMR spectra of the intermediates (I) and the products (II) and (III) contained all of the expected signals, it was not possible to establish uniquely from these data the regiochemistry of the cycloaddition reactions leading to their formation, and accordingly we have determined the structures of two representative intermediates (Ia) and (Ib) (Figs. 1 and 2) and of two representative products (II) (Fig. 3) and (III) (Fig. 4).

Structural commentary
Although compounds (Ia), (Ib), (II) and (III) were all crystallized under identical conditions, compound (Ib) crystallized as a hemihydrate, in which the water molecules lies across a twofold rotation axis, while the other three compounds all crystallized in solvent-free form. In each compound, the thiophene substituent is disordered over two sets of atomic sites (Section 6), whose relationship approximately corresponds to a rotation of 180 about the bond C45-C452 (Figs. The structure of the independent components in compound (Ib) showing the atom-labelling scheme and the disorder in the thiophene unit, where the major disorder component is drawn using full lines and the minor disorder component is drawn using broken lines. The water molecule lies across a twofold rotation axis and the displacement ellipsoids are drawn at the 30% probability level.

Figure 1
The molecular structure of compound (Ia) showing the atom-labelling scheme and the disorder in the thiophene unit, where the major disorder component is drawn using full lines and the minor disorder component is drawn using broken lines. Displacement ellipsoids are drawn at the 30% probability level.
atoms of the hydrazine unit in thiosemicarbazide that participate in this reaction step. If the participants had been the two N atoms either side of the thiocarbonyl unit, then the products would have been the regioisomers of type (A), containing a newly formed reduced pyrimidine ring in place of the pyrazole ring actually observed (Fig. 5). Similarly, in the cyclocondensation reactions between the carbothioamides (I) and either diethyl acetylenedicarboxylate or 4-bromophenacyl bromide to form (II) and (III), respectively, alternative regiochemistry is possible in each case, to yield products of types (B) and (C), respectively (Fig. 5). The X-ray analyses reported here have confirmed that the single products formed in each of these cyclocondensation reactions  have structures of types (I)-(III), as opposed to the possible alternative isomers (A)-(C).

Supramolecular features
The supramolecular assembly of compound (Ia) is extremely simple: a single N-HÁ Á ÁN hydrogen bond (Table 1) links molecules that are related by translation into a C(8) (Etter, 1990;Etter et al., 1990;Bernstein et al., 1995) chain running parallel to the [100] direction (Fig. 6), but there are no direction-specific interactions between adjacent chains.
Compound (Ib) is a hemihydrate in which the water component lies across a twofold rotation axis, and the supramolecular aggregation is more complex than that in (Ia). There is an O-HÁ Á ÁN hydrogen bond within the selected asymmetric unit (Table 1)  Possible regioisomers (A)-(C) of compounds (I)-(III), respectively.

Figure 3
The molecular structure of compound (II) showing the atom-labelling scheme and the disorder in the thiophene unit, where the major disorder component is drawn using full lines and the minor disorder component is drawn using broken lines. Displacement ellipsoids are drawn at the 30% probability level.

Figure 4
The molecular structure of compound (III) showing the atom-labelling scheme and the disorder in the thiophene unit, where the major disorder component is drawn using full lines and the minor disorder component is drawn using broken lines. Displacement ellipsoids are drawn at the 30% probability level.
direction, in which the centrosymmetric rings are centred at (0.5, 0.5, 0.5n) where n represents an integer (Fig. 7). Within this chain the water molecules, which act as double donors in O-HÁ Á ÁN hydrogen bonds and double acceptors in N-HÁ Á ÁO hydrogen bonds, are the points of fusion between adjacent rings (Fig. 7). There are three short intermolecular contacts in the structure of compound (II). That involving atom C13 (Table 1) has a very small D-HÁ Á ÁA angle, and so is unlikely to be structurally significant (Wood et al., 2009), while that involving atom C553 applies only to the minor disorder component, and is absent for the majority of the molecules. The only possible significant interaction is thus that involving atom C54, which links inversion-related pairs of molecules to form a cyclic centrosymmetric motif (Fig. 8). There are no significant hydrogen bonds of any type in the structure of compound (III).  Table 1 Hydrogen bonds and short inter-and intramolecular contacts (Å , ). Symmetry codes: (i) 1 + x, y, z; (ii) 1 À x, 1 À y, 1 À z; (iii) x, À1 + y, z; (iv) 2 À x, Ày, 1 À z; (v) À1 + x, y, z.

Figure 6
Part of the crystal structure of compound (Ia) showing the formation of a hydrogen-bonded chain running parallel to the [100] direction. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the H atoms which are bonded to C atoms have been omitted.

Figure 7
Part of the crystal structure of compound (Ib) showing the formation of a hydrogen-bonded chain of spiro-fused rings running parallel to the [001] direction. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the H atoms which are bonded to C atoms have been omitted.

Database survey
Structures have been reported recently for a number of compounds related to those reported here, including precursors and intermediates in the synthetic pathways to compounds (I)-(III). The structures of five examples of 5-aryloxy-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehydes have been reported (Shahani et al., 2011;Vinutha et al., 2014;Glidewell et al., 2019;Kiran Kumar et al., 2019), as have those (Shaibah et al., 2020) of two isostructural chalcones derived from two such carbaldehydes by condensation reactions with 2-acetylthiophene, in each of which the thiophene unit shows the same type of disorder as observed here in compounds (Ia), (Ib), (II) and (III). Structures have also been reported (Cuartas et al., 2017;Kiran Kumar et al., 2019) for several reduced 3,4 0 -bipyrazoles formed by cyclocondensation reactions between chalcones and hydrazine followed by Nacetylation. However, the only structure reported to date of a product in which the 3,4 0 -bipyrazole unit is embedded within a group of other cyclic substituents, as in (I)-(III) is that for the methyl ester analogue of (II) . The original report on this compound provided no crystallographic information other than a molecular structure plot. However, the deposited CIF (CCDC deposition No. 1588961) shows that the reflection data have been subjected to the SQUEEZE procedure (Spek, 2015), although this is not mentioned in the original report. The CIF also shows two sites for the O atom of the aryloxy unit, ca 1.28 Å apart with occupancies of 0.843 (6) and 0.157 (6) and involving some unexpected geometrical features, although all other atoms are reported as being fully ordered. Hence this structure is unlikely to be entirely correct.

Synthesis and crystallization
Samples of compounds (Ia), (Ib), (II) and (III) were prepared using the methods previously reported . Crystals suitable for single-crystal X-ray diffraction were grown by slow evaporation, at ambient temperature and in the presence of air, of solutions in a mixture of ethanol and N,Ndimethylformamide (initial composition 3:1, v/v).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. Several bad outlier reflections were omitted from the refinements. i.e. for (Ia) (4,1,18); for (Ic) (1,1,1), (14,0,0), (15,0,6), (14,1,19), (8,9,7) and (11,3,2); and for (II) (3,10,2) and (0,5,13). All H atoms, apart from those in the minor disorder components, were located in difference maps. The H atoms bonded to C atoms were then treated as riding atoms in geometrically idealized positions with C-H distances of 0.93 Å (alkenyl, aromatic and thienyl), 0.96 Å (CH 3 ), 0.97 Å (CH 2 ) or 0.98 Å (aliphatic C-H), and with U iso (H) = kU eq (C), where k = 1.5 for the methyl groups, which were permitted to rotate but not to tilt, and 1.2 for all other H atoms bonded to C atoms. For the H atoms bonded to N or O atoms, the atomic coordinates were refined with U iso (H) = 1.2U eq (N) or 1.5U eq (O), giving the N-H and O-H distances shown in Table 1. For the minor disorder components, the bonded distances and the 1,3 non-bonded distances were restrained to be the same as the corresponding distances in the major disorder components, subject to s.u. values of 0.01 and 0.02 Å , respectively. In addition, the anisotropic displacement parameters associated with pairs of atomic sites occupying essentially the same regions of physical space were constrained to be equal. Subject to these conditions, the occupancies, in the crystals selected for data collection, of the disordered thienyl units refined to 0.866 (  Part of the crystal structure of compound (II) showing the formation of a cyclic centrosymmetric dimer containing C-HÁ Á Á(arene) hydrogen bonds. For the sake of clarity, the minor disorder components, and the H atoms not involved in the motif shown have been omitted. The atom marked with an asterisk (*) is at the symmetry position (2 À x, Ày, 1 À z).  SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015b); molecular graphics: PLATON (Spek, 2020); software used to prepare material for publication: SHELXL2014 (Sheldrick, 2015b) and PLATON (Spek, 2020).

Refinement
Refinement on F 2 Least-squares matrix: full R[F 2 > 2σ(F 2 )] = 0.056 wR(F 2 ) = 0.112 S = 1.03 4898 reflections 319 parameters 10 restraints Primary atom site location: difference Fourier map Hydrogen site location: mixed H atoms treated by a mixture of independent and constrained refinement

Special details
Experimental. CrysAlis RED, Oxford Diffraction Ltd., 2009 Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Special details
Experimental. CrysAlis RED, Oxford Diffraction Ltd., 2009 Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Special details
Experimental. CrysAlis RED, Oxford Diffraction Ltd., 2009 Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq Occ. (   where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.47 e Å −3 Δρ min = −0.34 e Å −3 Special details Experimental. CrysAlis RED, Oxford Diffraction Ltd., 2009 Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq Occ. (