Crystal structures of three 6-aryl-2-(4-chlorobenzyl)-5-[(1H-indol-3-yl)methyl]imidazo[2,1-b][1,3,4]thiadiazoles

In the crystals of three new 6-aryl-2-(4-chlorobenzyl)-5-[(1H-indol-3-yl)methyl]imidazo[2,1-b][1,3,4]thiadiazoles (where aryl is phenyl, 4-fluorophenyl or 4-bromophenyl), the molecules are linked by a combination of N—H⋯N and C—H⋯π interactions to form chains when the 6-aryl substituent is phenyl or 4-fluorophenyl and a three-dimensional framework when the 6-aryl group is 4-bromophenyl.

. Each type of molecule forms a C(8) chain motif built from N-HÁ Á ÁN hydrogen bonds, which for the fully ordered molecule is reinforced by C-HÁ Á Á interactions. In compound (II), the chlorobenzyl unit is again disordered, with occupancies 0.822 (6) and 0.178 (6), and the molecules form C(8) chains similar to those in (I), reinforced by C-HÁ Á Á interactions involving only the major disorder component. The chlorobenzyl unit in compound (III) is also disordered with occupancies of 0.839 (5) and 0.161 (5). The molecules are linked by a combination of one N-HÁ Á ÁN hydrogen bond and four C-HÁ Á Á interactions, forming a three-dimensional framework.

Chemical context
Imidazo[2,1-b][1,3,4]thiadiazole is a versatile nucleus for the elaboration of novel heterocyclic compounds as it can readily be substituted at any position of 2, 5 or 6 . A wide range of such derivatives have been evaluated for their biological activities, which encompass anti-cancer, anticonvulsant, anti-fungal, anti-inflammatory and anti-microbial activity, as well as analgesic and anaesthetic properties (Bhongade et al., 2016). The recently reported indolinone derivative, 6-(4-bromophenyl)-2-(4-chlorobenzyl)-5-[(1H-indolin-2-one-3-yl)methylidene]imidazo[2,1-b][1,3,4]thiadiazole (disarib), has been shown to act as a powerful inhibitor of the anti-apoptotic protein BCL2, and to cause significant tumour regression without any significant side effects Vartak et al., 2016). With these observations in mind, we have synthesized analogues of disarib, replacing the indolinone substituent with an indolylmethyl unit, while at the same time varying the substituent in the 6-aryl ring, and here we report the preparation, and the molecular and supramolecular structures of the title three compounds (I)-(III) as shown in Figs. 1-3.

Structural commentary
Although compounds (I) and (II) crystallize in the same space group (P2 1 /c) with Z 0 = 2 and 1, respectively, compound (III) crystallizes in the non-centrosymmetric space group (P2 1 2 1 2 1 ). Despite the close similarity in the chemical constitution of compounds (I)-(III), no two of these compounds are isomorphous. None of the molecules exhibits any internal symmetry, so that all of them are conformationally chiral. The centrosymmetric space group for the compounds (I) and (II) show that these have crystallized as conformational racemates. On the other hand, all of the molecules in the crystal of compound (III) in the Sohncke space group have the same conformation; there is no reason to suppose that the crystallization of (III) has involved conformational resolution so that this compound has probably crystallized as a conformational conglomerate (Bernal et al., 1996). In this conformational enantiomer, the torsion angle of C5-C6-C61-C62 is À41.3 (6) , and the reference molecules in (I) and (II) have the same negative sign for this torsion angle (Table 1).

Figure 1
The structures of the two independent molecules of compound (I), showing the atom-labelling scheme and the disorder in one of the molecules. Displacement ellipsoids are drawn at the 30% probability level, and in the disordered fragment, the major disorder component is drawn using full lines and the minor disorder component is drawn using broken lines.

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

Figure 2
The molecular structure of compound (II), showing the atom-labelling scheme and the disorder. Displacement ellipsoids are drawn at the 30% probability level, and in the disordered fragment, the major disorder component is drawn using full lines and the minor disorder component is drawn using broken lines.
The orientation of the chlorobenzyl unit relative to that of the central imidazo[2,1-b][1,3,4]thiadiazole ring system differs quite significantly between compounds (I) and (II) on the one hand and with that in compound (III) on the other, as indicated by the torsion angles Sx1-Cx2-Cx27-Cx21/Cx31 (Table 1). This may be associated with the observation that this unit in (I) and (II) acts as a hydrogen-bond donor but not as an acceptor, while in (III) as an acceptor but not a donor (Table 2). Similarly, the orientation of the indolemethylene group relative to the imidazo[2,1-b][1,3,4]thiadiazole unit shows considerable differences between compounds (I) and (II) on the one hand and compound (III) on the other, as shown by the torsion angles Nx4-Cx5-Cx51-Cx53 and Cx5-Cx51-Cx53-Cx52 (Table 1), although the indole unit acts as both a donor and an acceptor of hydrogen bonds in all three compounds (Table 2). A small change in a single monoatomic substituent thus effects significant changes in both the crystallization characteristics and the molecular conformations in compounds (I)-(III).

Supramolecular features
In the crystal of compound (I), the molecules of type 1, which are related by a 2 1 screw axis, are linked by N-HÁ Á ÁN hydrogen bonds, forming a C(8) chain motif running along [010] (Fig. 4). Similarly, the type 2 molecules, which are related by another 2 1 screw axis, form a second C(8) chain along [010]. These chains differ in that the second chain is reinforced by two C-HÁ Á Á interactions, whereas in the first chain, only the minor disorder component takes part in such an interaction; in the major disorder component, the shortest intermolecular 20 Part of the crystal structure of compound (I), showing two C(8) chains running along the [010] direction, one built from N-HÁ Á ÁN hydrogen bonds and the other from N-HÁ Á ÁN and C-HÁ Á Á interactions shown as dashed lines. For the sake of clarity, the minor disorder component and the H atoms not involved in the interactions have been omitted. Table 1 Selected torsion angles ( ) for compounds (I)-(III).
The supramolecular structure of compound (III) contains an N-HÁ Á ÁN hydrogen bond, as in (I) and (II), along with four C-HÁ Á Á interactions, which have rather long HÁ Á ÁCg distances ( Table 2). The N-HÁ Á ÁN hydrogen bond links molecules, which are related by translation, to form a C(8) chain along [010] (Fig. 6). Two C-HÁ Á Á interactions, involving atoms C51 and C62 (Table 2), cooperatively link molecules, which are related by a 2 1 screw axis along the x axis, to form a chain along the [100] direction (Fig. 7). Finally, two C-HÁ Á Á interactions involving atoms C65 and C62 form similar contacts to the aryl rings of both disorder components, generating a chain of molecules related by a 2 1 screw axis running along [001] (Fig. 8)

Figure 9
The reaction sequence used for the synthesis of compounds (I)-(III). means of successive condensation with a substituted phenacyl bromide to form the 2,5-disubstituted imidazo[2,1-b][1,3,4]thiadiazoles, (B), followed by Vilsmeier-Haack formylation to give the corresponding 5-carbaldehydes, (C), and finally reductive condensation with indole in the presence of triethylsilane and trifluoroacetic acid (Appleton et al., 1993) to form the products (I)-(III). We have also prepared the 4-chlorophenyl analogue (X = Cl), but unfortunately no crystals of this compound have yet been obtained, only a viscous gum.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. In each compound, the chlorobenzyl unit was disordered over two sets of atomic sites having unequal occupancies. In each case, the bond lengths and the 1,3-distances in the minor disorder component were restrained to be the same as the equivalent distances in the major disorder component, subject to s.u. values of 0.01 and 0.02 Å , respectively, and the anisotropic displacement parameters for pairs of partial-occupancy atoms occupying essentially the same physical space were constrained to be equal. In addition, it was found necessary to constrain the minor component of the disordered chlorobenzyl group in (II) to be planar. Apart from those in the minor disorder components, all H atoms 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 0.93 Å (aromatic and heteroaromatic) or 0.97 Å (CH 2 ), and with U iso (H) = 1.2U eq (C). For the H atoms bonded to N atoms, the atomic coordinates were refined with U iso (H) = 1.2U eq (N), giving refined N-H distances of 0.83 (3)-0.99 (5)     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.

2-(4-Chlorobenzyl)-6-(4-fluorophenyl)-5-[(1H-indol-3-yl)methyl]imidazo[2,1-b][1,3,4]thiadiazole (II)
Crystal data 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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq Occ. (<1) S1 0.29020 (4) 0.26704 (6)    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.