Formation of 1-(thiazol-2-yl)-4,5-dihydropyrazoles from simple precursors: synthesis, spectroscopic characterization and the structures of an intermediate and two products

(E)-1-(4-Methoxyphenyl)-3-[4-(prop-2-ynyloxy)phenyl]prop-2-en-1-one undergoes a cyclocondensation reaction with thiosemicarbazide to form the corresponding 4,5-dihydropyrazole-1-arbothioamide, which in turn undergoes further cycloaddition with phenacyl bromides to form 4,5-dihydro-1-(thiazol-2-yl)pyrazoles. The molecules adopt an overall T-shape structure. Different combinations of hydrogen bonds link the molecules into ribbons or sheets.

Accordingly, we have sought to combine pyrazole and thiazole pharmacophores in a single molecular skeleton and synthesized triaryl-substituted (thiazol-2-yl)pyrazole compounds (C3,C5-aryl substitutions on the pyrazole ring and C4-aryl substitution on the thiazole ring). We report here the synthesis of 1-(thiazolol-2-yl)-4,5-dihydropyrazoles from simple precursors. The reaction sequence is summarized in Fig. 1: a base-catalysed condensation reaction between 4-methoxybenzaldehyde (A) and a substituted acetophenone (B) yields the chalcone intermediate (I) (Shaibah et al., 2020). Compound (I) undergoes a cyclocondensation reaction with a thiosemicarbazide to provide thioamide intermediate (C), which in turn undergoes a further cyclocondensation reaction with a phenacyl bromide to give the thiazolyl-dihydropyrazoles (II) and (III) .
The proposed synthetic route, as also applied to synthesize many of the aforementioned related compounds, was selected because in some cases, we have introduced mesoionic moieties like sydnone as a part of the triaryl. These sydnones are somewhat sensitive towards vigorous reaction conditions. Under the present conditions selected, the products are stable and the reactions gave reasonably good yields. The chosen synthetic routes of the reported compounds in this study are straightforward with limited steps and readily accessible, cheap starting materials, and yields are reasonably high (Nayak et al., 2013;Bansal et al., 2020). The biological activities of few of the related triaryl-substituted (thiazol-2yl)pyrazole compounds have been reported in the literature, such as Salian et al. (2017) have demonstrated radical scavenging capacity owing to the destabilization of the radical formed during oxidation. In the present study, compounds (I)-(III) and the intermediate (C) have been characterized spectroscopically. Chalcone intermediate (I) (Fig. 2) and the di- The molecular structure of compound (I) showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.

Figure 1
The reaction sequence leading to the formation of compounds (I)-(III). hydro(thiazolyl)pyrrazole products (II) and (III) (Figs. 3 and 4) have also been characterized, and their structures will be described here.

Structural commentary
For the thiazolylpyrazole products (II) and (III), and for the intermediates (I) and (C) (Fig. 1), the 1 H NMR spectra contained all of the expected signals (Section 5). In particular, the spectra of each of (I), (II) and (III) contained signals from an ABX spin system arising from the H atoms bonded to atoms C4 and C5 (Figs. 2 and 3), consistent with the formation of a new 4,5-dihydropyrazole ring.
In the structure of the chalcone intermediate (I) (Fig. 2), the two aryl rings are both twisted away from the plane of the central spacer unit, atoms C11, C1, O1, C2, C3, C31 [maximum planar deviation of 0.033 (2) Å for C3 atom]. The dihedral angles between this spacer unit and the rings (C11-C16) and (C31-C36) are 21.48 (7) and 8.98 (7) , respectively, while the dihedral angle between the (C11-C16) ring and the prop-2ynyloxy unit (O14, C17, C18, C19) is 73.48 (13) . The molecule of (I) exhibits no internal symmetry and so is conformationally chiral, but the centrosymmetric space group confirms that equal numbers of the two conformational enantiomers are present.
Compounds (II) and (III), differing only in the presence or absence of a methyl group at the arylthiazolyl substituent, and are isomorphous and isostructural ( Fig. 1 and Table 2). In the molecules of (II) and (III), there is a stereogenic centre at atom C5 and, for each, the reference molecule was selected as one having the R-configuration at atom C5. However, the space group confirms that both compounds have crystallized as racemic mixtures: this is as expected, as the synthesis of (II) and (III) involves no reagents that could plausibly induce enantioselectivity. In each of these compounds, the dihydropyrazole ring is effectively planar (Alex & Kumar, 2014). The maximum deviations from the mean planes through the ring atoms are 0.44 (3) Å for atom C4 in (II) and only 0.012 (2) Å for atom C3 in (III). The dihydro-pyrazole ring has been found to be effectively planar among triaryl-substituted (thiazol-2yl)pyrazole compounds available in the literature (see Chemical context and Database survey for references).
In each of (I)-(III), the methoxy C atom is coplanar with the adjacent aryl ring [the maximum deviation of atom C37 in (I) and C57 in (II) and (III) from the respective planes are 0.003 (2), 0.529 (5) and 0.405 (7) Å , respectively).
Associated with this coplanarity, the values of the two exocyclic C-C-O angles, at atom C34 in (I) and at atom C54 in each of (II) and (III), differ by ca 10 , as typically found in planar alkoxyarenes (Seip & Seip, 1973;Ferguson et al., 1996;Kiran Kumar, Yathirajan, Foro et al., 2019;Kiran Kumar et al., 2020). Overall, both the molecules (II) and (III) adopt a T-shaped structure with the pyrazole C5-substituent anisyl units forming the blade. The remaining part of molecule, the thiazolyl-pyrazole ring and its substituents form a more or less planar structure, which constitutes the stock of the T-shape. The angle between the plane of the anisyl unit and the remaining part of molecule is 71.8 (1) and 75.3 (1) in (II) and (III), respectively. Both molecules adopt a more or less similar conformation and a superimposed image of (II) and (III) is shown in Fig. 5.

Supramolecular features
The supramolecular assembly of the chalcone (I) depends upon two hydrogen-bond-like interactions, one each of the  The molecular structure of compound (II) showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.

Figure 4
The molecular structure of compound (III) showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.

Figure 6
Part of the crystal structure of compound (I) showing the formation of a hydrogen-bonded ribbon of centrosymmetric rings running parallel to the [010] direction. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the H atoms bonded to the C atoms which are not involved in the motifs shown have been omitted.
sheet of this type, related to the first by the action of the glide planes lies in the domain 0.5 < y < 1.0, but there are no direction-specific interactions between adjacent sheets. With the exception of this, there are no significant differences in the packing of (II) and (III). In (III), a C5-H5Á Á Á(alkyne) interaction, also referred as a T-shaped C-HÁ Á Á interaction (McAdam et al., 2012) is observed, with the shortest H5Á Á ÁC38 i [symmetry code: (i) À 1 2 + x, 1 2 À y, 1 2 + z] distance being 2.74 Å and a C5-H5Á Á ÁC38 angle of 159 . In (II), two such short contacts of the C-HÁ Á Á(alkyne) type are observed, with H4AÁ Á ÁC39 i and H5Á Á ÁC38 i distances of 2.80 and 2.81 Å , respectively, which are only 0.10 and 0.09 Å shorter than the sum of of corresponding van der Waals radii.

Database survey
We briefly compare the structures reported here with those of some related compounds. A search for triaryl-substituted (thiazol-2-yl)pyrazoles in the Cambridge Structural Database (Version 2021.1; Groom et al., 2016) yielded nine structures that have C3,C5-aryl substitutions in the pyrazole ring and C4aryl substitution in the thiazole ring, CSD entries: BAKLOQ, DADQEH, DADQIL, IDOMOF, JUNRAN, MEWQUC, WIGQIO, WOCFEC and PUVVAG (for references, see Chemical context). BAKLOQ, and PUVVAG have fused thiazol and phenyl rings. All these structures are characterized by a T-shaped structure with pyrazole C5-aryl substituents forming its blade and the remaining part of the molecule, the thiazol-2-yl-pyrazole ring and its substituents, forming a more or less planar structure, which constitutes the stock of the Tshape. Classical hydrogen bonding is not observed in any of these compounds. The dihydropyrazole rings are effectively planar in all these compounds.
Finally, we note that the Cambridge Structural Database (Groom et al., 2016) records 55 chalcone structures, which were determined as part of the long-time collaboration between the Yathirajan group and the late Professor Jerry P. Jasinski.

Special details
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
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.