Synthesis, and spectroscopic and structural characterization of three new styrylquinoline–benzimidazole hybrids

Three new 4-styrylquinoline–benzimidazole hybrids have been synthesized in a two-step reaction sequence. The styrylquinoline fragments are all nonplanar and the molecules are linked into two- or three-dimensional arrays by N—H⋯O and C—H⋯π hydrogen bonds.

The benzimidazole nucleus also constitutes a privileged scaffold which has been extensively studied as a potential building block for the development of biologically active molecules with diverse applications as therapeutic agents, including anticancer agents (e.g. dovitinib and selumetinib) (Herná ndez-Romero et al., 2021), anthelmintics (e.g. albendazole, mebendazole and thabendazole) (Salahuddin et al., 2017) or antacids and anti-ulcer agents (e.g. omeprazole, lansoprazole and pantoprazole) (Gurvinder et al., 2013).

Synthesis and crystallization
The 4-styrylquinoline precursors of type (I) (see Scheme 1) were prepared using a previously reported method (Melé ndez et al., 2020;Rodríguez et al., 2020). In the NMR data listed below, for compounds (III), unprimed ring atoms form part of the quinoline unit, ring atoms carrying a single prime form part of the benzimidazole unit and ring atoms carrying a double prime form part of the styryl unit (see Figs. 1 and 2).
For the synthesis of the formyl intermediates of type (II), a suspension of the appropriate 4-styrylquinoline-3-carboxylate (I) (Melé ndez et al., 2020; see Scheme 1) (1.0 mmol) and selenium dioxide (2.0 mmol) in 1,4-dioxane (5 ml) was stirred and heated at 373 K for the time required to complete the reaction. After the complete consumption of (I) [as monitored by thin-layer chromatography (TLC)], dichloromethane (15 ml) was added and the resulting suspension was filtered. The solvent was removed under reduced pressure and the resulting crude products were purified by flash column chromatography on silica gel using hexane-ethyl acetate (10:1 v/v) as eluent to give the required formyl intermediates (IIa)-(IIc) as solid compounds.

Figure 2
The molecular structure of compound (IIIb), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level.

Figure 1
The molecular structure of compound (IIIa), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level. 1707 (C O formyl/ester ), 1628 (C N), 1560 (C C vinyl ), 1513 (C C arom ), 1463 (C C arom ), 987 ( C-H trans  For the synthesis of the benzimidazole products of type (III), a suspension of the appropriate formyl derivatives (II) (1.0 mmol), o-phenylenediamine (1.0 mmol) and ceric ammonium nitrate (CAN) (10 mol%) in methanol (2 ml) was magnetically stirred at ambient temperature for the time required to complete the reaction. After the complete consumption of (II) (as monitored by TLC), methanol was removed under reduced pressure and the crude products were purified by flash column chromatography on silica gel using hexane-ethyl acetate (8:1 v/v) as eluent to yield the target hybrid products (IIIa)-(IIIc), which were then recrystallized from hexane-ethyl acetate (7:1 v/v), at ambient temperature and in the presence of air, to give yellow crystals suitable for single-crystal X-ray diffraction.

Refinement
Crystal data, data collection and refinement details for compounds (IIIa)-(IIIc) are summarized in Table 1. For each of these compounds, one bad outlier reflection, i.e. 396 for (IIIa), 303 for (IIIb) and 105 for (IIIc), was omitted from the data set. All H atoms were located in difference maps. H atoms bonded to C atoms were then treated as riding atoms in geometrically idealized positions, with C-H distances of 0.95 (alkenic and aromatic), 0.98 (CH 3 ) or 0.99 Å (CH 2 ) 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. For the H atoms bonded to N atoms, the atomic coordinates were refined with U iso (H) = 1.2U eq (N), giving the N-H distances shown in Table 3.
For compound (IIIa), the final difference map contained one fairly large maximum, 0.61 e Å À3 , at 0.5175, 0.8375, 0.7907. An attempt to treat this as the O atom of a partialoccupancy water molecule gave a refined occupancy of 0.057 (3), but the angles subtended at this site by every pair of potential donors and/or acceptors which were within plausible hydrogen-bonding range were all less than 60 , some of them barely half the idealized tetrahedral value. Accordingly, this possibility was discounted.
For compound (IIIc), the crystals were consistently of poor quality; this compound crystallizes in the space group P2 1 /n with Z 0 = 3 and, for the best crystal examined, the R int value was 0.176. In molecule 1 of (IIIc), containing atom N11, the ester group is disordered over two sets of atomic sites having unequal occupancy. For the minor disorder component, the bonded distances and the [1,3] nonbonded distances were restrained to have the same values as the corresponding distances in the major component, subject to s.u. values of 0.01 and 0.02 Å , respectively. In addition, the anisotropic displacement parameters for pairs of partial-occupancy atoms within essentially the same physical space were constrained to be equal. Conventional refinement then converged only to R 1 = 0.132 and wR 2 = 0.391, and examination of the structure of (IIIc) at this point using PLATON (Spek, 2020) confirmed that no additional crystallographic symmetry was present and that twinning was also absent. However, PLATON showed that the structure formed by the molecules of (IIIc) enclosed two voids, centred at (0,0,0) and ( 1 2 , 1 2 , 1 2 ) and each of volume ca 314 Å 3 , and that corresponding voids in unit cells related by translation along [010] are connected, thus forming continuous channels along (0, y, 0) and ( 1 2 , y, 1 2 ). Further examination of this structure using the SQUEEZE procedure (Spek, 2015) indicated that each void contained around 55 electrons not hitherto accounted for, equivalent to just over one molecule of hexane per void. The largest peaks in the difference map for (IIIc) lie within the channels, in the form of a zigzag chain, but no convincing solvent model could be developed from these peaks. It seems possible that the channels contain partialoccupancy disordered and possibly mobile hexane molecules. Accordingly, the reflection data were subjected to the SQUEEZE procedure (Spek, 2015), and the resultant modified reflection file was used for the refinement reported here; the final refined values of the site-occupancy factors for the disordered ester group were 0.765 (7) and 0.235 (7).
Compounds (IIa)-(IIc) and (IIIa)-(IIIc) were all fully characterized using IR, 1 H and 13 C NMR spectroscopy, and high-resolution mass spectrometry (see Section 2.1). The formation of the required benzimidazole-quinoline molecular hybrid products (IIIa)-(IIIc) was confirmed by the disappearance of the formyl signals from both the 1 H and 13 C NMR spectra, and their replacement by new sets of signals corresponding to the five H atoms and seven C atoms of the newly formed benzimidazole ring, and by the appearance of new signals in the IR spectra corresponding to the N-H unit of the newly-formed benzimidazole ring.
The precursors of type (I) were prepared (Melé ndez et al., 2020; Rodríguez et al., 2020) using a two-step reaction sequence starting from 2-aminoacetophenone, a substituted benzaldehyde and a 1,3-dicarbonyl compound. With such simple starting materials, a wide range of substituted derivatives is readily available, opening the way to the formation of a rich and diverse library of substituted styrylquinoline-benzimidazole products and their analogues.
The constitutions of compounds (IIIa)-(IIIc), which were deduced from the spectroscopic data, were fully confirmed by the results of single-crystal X-ray diffraction (Figs. 1-3), which additionally provided information on the molecular conformations and the intermolecular interactions in the solid state. Compound (IIIc) crystallizes with Z 0 = 3, but a search for possible additional crystallographic symmetry revealed none; it will be convenient to refer to the molecules of (IIIc) containing atoms N11, N21 and N31 (Fig. 3) as molecules 1-3, respectively.
In all the molecules of (IIIa)-(IIIc), the benzimidazole fragments have the N-H unit directed away from the ester group, so precluding the possibility intramolecular N-HÁ Á ÁO Part of the crystal structure of compound (IIIa), showing the formation of a C(7) chain built from N-HÁ Á ÁO hydrogen bonds and running parallel to the [001] direction. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, H atoms not involved in the motif shown have been omitted.

Figure 5
Part of the crystal structure of compound (IIIa), showing the formation of a chain built from C-HÁ Á Á hydrogen bonds and running parallel to the [010] direction. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, H atoms not involved in the motif shown have been omitted. Table 2 Selected torsion and dihedral angles ( ) for compounds (IIIa)-(IIIc).
The term dihedral here refers to the dihedral angle between the pyridine and the imidazole rings. In order to specify an asymmetric unit in which the three independent molecules of (IIIc) were linked by hydrogen bonds, it was necessary to select molecule 2 (x = 2) to be the conformational enantiomer opposite from those selected for molecules 1 and 3 (x = 1 and 3) (see text). For ease of comparison, the values of the torsion angles cited for x = 2 refer to the inverted molecule at (Àx, Ày, Àz) so that the values refer to corresponding conformational enantiomers for all three molecules, with positive values for the torsion angles Cx3-Cx4-Cx41-Cx41.

Compounds (IIIa) and (IIIb)
À168.5 (4) 155.1 (4) 171.9 (4) Dihedral 12.4 (3) 32.26 (11) 23.24 (18) hydrogen bonding; the pyridine and imidazole rings are not coplanar, as shown by the dihedral angles between their planes (Table 2). In one of the molecules of (IIIc), the ester group is disordered over two sets of atomic sites, having occupancies 0.765 (7) and 0.235 (7)  titanium complexes in which the quinolone N atom and one of the imidazole N atoms are both coordinated to Ti, forming a five-membered ring, and hence the conformations of the organic ligands in these compounds are not usefully comparable with those in metal-free systems. The orientations of the ester groups relative to the pyridine ring may be a consequence of the N-HÁ Á ÁO hydrogen bond (see below), as in every molecule in (IIIa)-(IIIc), the carbonyl O atom acts as an acceptor in such an interaction. While compounds (IIIa) and (IIIb) crystallize in the solvent-free form, compound (IIIc) contains disordered solvent within continuous channels; hence, it is to be expected that the supramolecular assembly for (IIIc) will differ from those of (IIIa) and (IIIb), as the Z 0 value immediately indicates.
For compound (IIIa), the supramolecular assembly is based upon three hydrogen bonds, one of the N-HÁ Á ÁO type and two of the C-HÁ Á Á type (Table 2), and the combination of these three interactions links the molecules of (IIIa) into a three-dimensional framework structure. However, the formation of the framework is readily analysed in terms of three simple substructures (Ferguson et al., 1998a,b;Gregson et al., 2000), each involving just one type of hydrogen bond.
In the first substructure, molecules of (IIIa) which are related by the c-glide plane at y = 3 4 are linked by N-HÁ Á ÁO to form a C(7) (Etter, 1990;Etter et al., 1990;Bernstein et al., 1995) chain running parallel to the [001] direction (Fig. 4). A second substructure involves the C-HÁ Á Á hydrogen bond having atom C422 as the donor (Table 2); this interaction links molecules of (IIIa) which are related by the 2 1 screw axis along Part of the crystal structure of compound (IIIa), showing the formation of a cyclic centrosymmetric motif built from C-HÁ Á Á hydrogen bonds and linking adjacent (100) sheets. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, H atoms not involved in the motif shown have been omitted. The atom marked with an asterisk (*) is at the symmetry position (Àx + 1, Ày + 1, Àz + 1). Table 3 Hydrogen bonds (Å , ) for compounds (IIIa)-(IIIc).

Figure 7
Part of the crystal structure of compound (IIIb), showing the formation of a C (7)  (1, y, 3 4 ) to form a chain running parallel to the [010] direction (Fig. 5). The combination of the chains along [010] and [001] gives rise to a sheet lying parallel to (100). Adjacent sheets are then linked by the third substructure, which is built from C-HÁ Á Á hydrogen bonds having atom C426 as the donor, which links inversion-related molecules from adjacent sheets (Fig. 6), so completing the three-dimensional assembly.
An N-HÁ Á ÁO hydrogen bond is also present in the structure of compound (IIIb) ( Table 3), and this links molecules which are related by the 2 1 screw axis along ( 1 4 , y, 3 4 ) to form a C(7) chain running parallel to the [010] direction (Fig. 7). The C-HÁ Á Á hydrogen bond (Table 3) links inversion-related molecules in adjacent chains into a cyclic centrosymmetric motif (Fig. 8), which links the [010] chains into a sheet lying parallel to (101). There are no direction-specific interactions between adjacent sheets in (IIIb); the only other short intermolecular contact in the structure involves a C-H bond in a methyl group, which is almost certainly undergoing rapid rotation about the adjacent C-C bond (Riddell & Rogerson, 1996, 1997. The hydrogen-bonded supramolecular assembly in compound (IIIc), where Z 0 = 3, is also two-dimensional and can readily be analysed in terms of two simple substructures. In the first of these, the three independent N-HÁ Á ÁO hydrogen bonds of compound (IIIc) are linked by two N-HÁ Á ÁO hydrogen bonds (Table 3) to form a linear three-molecule aggregate, and aggregates of this type which are related by translation are linked by a third N-HÁ Á ÁO hydrogen bond to form a C 3 3 (21) chain running parallel to the [100] direction (Fig. 9). The formation of this chain is thus analogous to those formed in compounds (IIIa) and (IIIb) (Figs. 4 and 7), but it is interesting to note that the components of the chains formed   Part of the crystal structure of compound (IIIb), showing the formation of a cyclic centrosymmetric motif built from C-HÁ Á Á hydrogen bonds and linking adjacent [010] chains. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, H atoms not involved in the motif shown have been omitted. The atom marked with an asterisk (*) is at the symmetry position (Àx + 1, Ày + 1, Àz + 1).

Figure 9
Part of the crystal structure of compound (IIIc), showing the formation of a C 3 by N-HÁ Á ÁO hydrogen bonds are related by a c-glide plane in (IIIa), by a 2 1 screw axis in (IIIb) and by translation in (IIIc).
The second substructure in (IIIc) is built from two C-HÁ Á Á hydrogen bonds in which molecule 3 acts as a twofold donor and molecule 2 acts as a twofold acceptor. These two interactions generate a chain running parallel to the [010] direction (Fig. 10). The combination of the chains running parallel to [100] and [010] generates a sheet lying parallel to (001) and occupying the domain 1 2 < z < 1.0; a second sheet, related to the first by inversion, occupies the domain 0 < z < 1 2 , but there are no direction-specific interactions between adjacent sheets.
In summary, therefore, we have developed an efficient and versatile synthetic route to novel hybrid (E)-2-(1H-benzo-[d]imidazol-2-yl)-4-styrylquinolines from very simple starting materials; we have fully characterized by spectroscopic means (IR, 1 H and 13 C NMR spectroscopy, and HR-MS) three representative examples, together with one intermediate on the pathway to each product, and we have determined the molecular and supramolecular structures of the three products thus formed. Spek, A. L. (2020). Acta Cryst. E76, 1-11. Vera, D. R., Mantilla, J. P., Palma, A., Cobo, J. & Glidewell, C. (2022) For all structures, data collection: APEX3 (Bruker, 2018); cell refinement: SAINT (Bruker, 2017); data reduction: SAINT (Bruker, 2017); program(s) used to solve structure: SHELXT2014 (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).  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.

Ethyl (E)-2-(1H-benzo[d]imidazol-2-yl)-4-(4-methylstyryl)quinoline-3-carboxylate (IIIc)
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. (