A three-step pathway from (2-aminophenyl)chalcones to novel styrylquinoline–chalcone hybrids: synthesis and spectroscopic and structural characterization of three examples

Three new styrylquinoline–chalcone hybrids are been syntheized using a three-step reaction sequence. In two of them, a combination of hydrogen bonds and π–π stacking interactions generates three-dimensional assemblies, but in the third, only a single weak π–π stacking interaction is present, linking the molecules into chains.

Their syntheses have presented a challenge because of the need for harsh reaction conditions and/or expensive catalysts normally required to couple the styryl fragment to the quinoline nucleus (Alacid & Ná jera, 2009;Chaudhari et al., 2013;Dabiri et al., 2008;Jamal et al., 2016), although some alternative and versatile methodologies have been also described to overcome such obstacles (Satish et al., 2019;Melé ndez et al., 2020).

Synthesis and crystallization
Compounds (IIa) and (IIc) were prepared using the procedure recently described by Vera et al. (2022) for the synthesis of compound (IIb).
For the synthesis of compounds (III), a suspension of the appropriate 2-methyl-4-styrylquinoline (II) (1.0 mmol) and selenium dioxide (2.0 mmol) in 1,4-dioxane (5 ml) was stirred and heated at 373 K for the appropriate time. After the complete consumption of (II) [as monitored by thin-layer chromatography (TLC)], dichloromethane (15 ml) was added and the residual solid was removed by filtration. 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 mixtures as eluent (compositions ranged from 7:1 to 2:1 v/v) to give the required formyl intermediates (IIIa)-(IIIc) as solid compounds.
For the synthesis of compounds (IV), a mixture of the appropriate 2-formyl intermediate (III) (1.0 mmol), 1-acetonaphthone (1.0 mmol) and potassium hydroxide (1.1 mmol) in ethanol (3 ml) was stirred at 298 K for the appropriate time. After complete consumption of (III) (monitored by TLC), the resulting precipitate was collected by filtration, washed with water (15 ml) and ethanol (10 ml), and then recrystallized from chloroform-ethanol to afford the target molecular hybrids (IV).
Compound ( Full details of the spectroscopic characterization are included in the supporting information.

Refinement
Crystal data, data collection and refinement details for compounds (IVa)-(IVc) are summarized in Table 1. Two bad outlier reflections (124 and 3,6,12) were omitted from the data set for compound (IVb). All H atoms were located in difference maps and then treated as riding atoms in geometrically idealized positions, with C-H distances of 0.95 Å and U iso (H) = 1.2U eq (C).

Results and discussion
We have recently reported (Vera et al., 2022) a high-yield synthesis of the 2-methyl-4-styrylquinoline (IIb) using the Friedlä nder cyclocondensation between the chalcone (Ib) (see Scheme 1) and acetone, along with its spectroscopic and crystallographic characterization. Using the same methodology, we have now prepared the corresponding styrylquinolines (IIa) and (IIc) in yields of 86 and 73%, respectively. All of the precursors (IIa)-(IIc) underwent selective oxidation with selenium dioxide to give the corresponding 2-formyl intermediates (IIIa)-(IIIc) with yields in the range 89-96% (see Section 2.1). Finally, Claisen-Schmidt condensation in the intermediates (III) with 1-acetonaphthone (1-acetylnaphthalene) gave the target hybrid products (IV) with yields in the range 81-95%. Compounds (IIa), (IIc), (IIIa)-(IIIc) and (IVa)-(IVc) were all fully characterized by FT-IR and 1 H/ 13 C NMR spectroscopy, and by high-resolution mass spectrometry (HRMS); full details of the spectroscopic characterization are provided in the supporting information.
The main spectroscopic features for the precursors (IIa) and (IIc) matched perfectly those of previously reported analogues (Vera et al., 2022). The IR spectra of the formyl intermediates (III) showed the characteristic absorption band for the C O group at 1699-1708 cm À 1 , and their 1 H and 13 C NMR spectra contained the corresponding signals for the formyl group in the ranges � 10. 24-10.25 and 194.1-194.2, respectively. The presence of stretching vibration bands in the range 1727-1731 cm À 1 , attributed to a conjugated carbonyl group, are the salient features in the IR spectra of compounds The molecular structure of compound (IVb), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level.

Figure 1
The molecular structure of compound (IVa), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level.
(IVa)-(IVc). The formation of molecular hybrids (IV) was established by disappearance of the formyl signals from both the 1 H and 13 C NMR spectra, and by the appearance of signals from the newly formed 3-arylpropen-1-one fragment. As far as the Claisen-Schmidt condensation is concerned, it proceeded in a highly stereoselective manner, giving exclusively the E-stereoisomers, as indicated by the 1 H NMR spectra. The trans configuration of the arylpropen-1-one fragment was deduced on the basis of the coupling constant values ( 3 J HA,HB = 15.9 Hz) between H A and H B (�,�-enonic H atoms), whose signals in the 1 H NMR spectra appear at � 7.91-7.93 and 7.78-7.79, respectively.
We also report here the molecular and supramolecular structures of the hybrid products (IVa)-(IVc) which fully confirm the molecular structures deduced from the spectroscopic data, in particular, the E-configuration of both the styryl and the chalcone moieties ( Figs. 1-3). This synthetic pathway (see Scheme 1) is extremely versatile, in that it permits the introduction of substituents in both rings of the quinoline portion (cf. Rodríguez et al., 2020), as well as in the styryl component (Vera et al., 2022), while the Claisen-Schmidt reaction step introduces a very wide range of synthetic options. In addition, the presence of the chalcone unit in the compounds of type (IV) provides scope for an extensive variety of further synthetic elaborations utilizing this fragment (Powers et al., 1998;Mohamed & Abuo-Rahma, 2020).

Figure 3
The molecular structure of compound (IVc), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level.
contrast, the crystals of (IVc) are monoclinic. None of the molecules in the products (IV) exhibits any internal symmetry, so that they are all conformationally chiral (Moss, 1996;Flack & Bernardinelli, 1999); the centrosymmetric space groups (Table 1) confirm that equal numbers of the two conformational enantiomers are present in each case. For each of (IVa)-(IVc), the reference molecule was selected as one having a positive sign for the torsion angle C3-C4-C41-C42 (Table 2). Overall the molecular conformations of (IVa) and (IVb) are quite similar, but that for (IVc) shows a marked difference in the orientation of the acyl fragment relative to the rest of the molecule, corresponding to a rotation of ca 180 � around the C22-C23 bond (Table 2 and Figs. 1-3). The supramolecular assembly in compound (IVa) is threedimensional and it dependes upon a combination of C-H� � �O and C-H� � �N hydrogen bonds (Table 3), and two different �-� stacking interactions. The formation of the three-dimensional framework structure is readily analysed in terms of three one-dimensional substructures (Ferguson et al., 1998a,b;Gregson et al., 2000), which, in the interests of clarity and simplicity, are illustrated separately. Inversion-related pairs of molecules are linked by almost linear C-H� � �O hydrogen bonds to form cyclic centrosymmetric dimers containing an R 2 2 (8) (Etter, 1990;Etter et al., 1990;Bernstein et al., 1995) ring, and this dimeric unit can be regarded as the basic building block in the overall structure.   Table 3 Hydrogen bonds and short intermolecular contacts (Å , � ) for compounds (IVa)-(IVc).

Figure 4
Part of the crystal structure of compound (IVa), showing the formation of a ribbon of alternating R 2 2 (8) and R 2 2 (20) rings running parallel to [101]. 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 (IVa), showing the linking of the R 2 2 (8) dimers by a �-stacking interaction between pyridine rings, so forming a chain along [100]. 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 linking of these dimeric units by C-H� � �N hydrogen bonds gives rise to a ribbon running parallel to the [101] direction ( Fig. 4), in which R 2 2 (8) rings centred at (n, 1 2 , 1 2 À n) alternate with R 2 2 (20) rings centred at ( 1 2 + n, 1 2 , À n), where n represents an integer in each case. The pyridine rings of the molecules at (x, y, z) and (À x + 1, À y + 1, À z + 1) are strictly parallel with an interplanar spacing of 3.2877 (5) Å and a ringcentroid separation of 3.5372 (7) Å , corresponding to a ringcentroid offset of 1.305 (2) Å . This interaction links the R 2 2 (8) dimers to generate a second chain, this time running parallel to the [100] direction (Fig. 5). In the final substructure, the carbocyclic ring of the quinoline unit at (x, y, z) and the styryl ring at (À x + 1, À y + 2, À z + 1) make an interplanar angle of only 6.37 (7) � ; the ring-centroid separation is 3.7818 (9) Å and the shortest perpendicular distance between the centroid of one ring and the plane of the other is 3.4535 (6) Å , corresponding to a ring-centroid offset of 1.541 (2)  The supramolecular assembly in compound (IVb) is also three-dimensional, built from a combination of C-H� � �O and C-H� � �� hydrogen bonds, and two �-� stacking interactions; the short intermolecular C-H� � �N contact in (IVb) ( Table 3) is probably not structurally significant, as the H� � �N distance is only a little less than the sum, 2.70 Å , of the van der Waals radii (Rowland & Taylor, 1996). As in (IVa), the formation of the three-dimensional structure in (IVb) can be analysed in terms of three one-dimensional substructures, based on the linking of the R 2 2 (8) dimers formed by the C-H� � �O hydrogen bonds (Table 3). The linking of the R 2 2 (8) dimers by the C-H� � �� hydrogen bonds gives rise to a chain of rings running parallel to the [011] direction ( Fig. 7) in which the R 2 2 (8) rings are centred at (0, 1 2 + n, 1 2 + n), and they alternate with the rings formed by C-H� � �� hydrogen bonds which are centred at (0, n, n), where n represents an integer in each case.
The two substructures formed by the �-� stacking interactions are entirely analogous to those formed in (IVa), such that they need no separate illustration. The pyridine rings at (x, y, z) and (À x + 1, À y + 1, À z + 1) in (IVb) have a ringcentroid offset of 1.319 (2) Å , and the carbocyclic ring of the quinoline unit at (x, y, z) and the styryl ring at (À x + 1, À y, À z + 1), which make an interplanar angle of only 2.38 (7) � , have a centroid offset of ca 1.576 (4)  The direction-specific intermolecular interactions in the structure of (IVc) are all weak. There are C-H� � �N contacts between inversion-related pairs of molecules (Table 3); although these are almost linear, the H� � �N and C� � �N distances are long for hydrogen bonds and, indeed, checkCIF (Spek, 2020; https://checkcif.iucr.org/) raises a mild alert on these grounds. These contacts are perhaps best regarded as research papers 6 of 9 Vera et al. � Three novel styrylquinoline-chalcone hybrids Acta Cryst. (2023). C79

Figure 6
Part of the crystal structure of compound (IVa), showing the linking of the R 2 2 (8) dimers by a �-stacking interaction between carbocyclic rings, so forming a chain along [110]. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, H atoms not involved in the motif shown have been omitted. being close to the margin of structural significance, but they serve to link the molecules into cyclic centrosymmetric R 2 2 (8) dimers (Fig. 8). On the other hand, the short intermolecular C-H� � �O contact (Table 3) has a very small D-H� � �A angle, such that the associated interaction is probably negligible (Wood et al., 2009). In addition, molecules of (IVc) which are related by translation along [100] are stacked in register and for the ring containing atom C231 (Fig. 3), the interplanar spacing is 3.5843 (6) Å , associated with a ring-centroid separation of 3.9184 (9) Å and a ring-centroid offset of 1.584 (2)   Part of the crystal structure of compound (IVc), showing the formation of a �-stacked chain along [100]. For the sake of clarity, H atoms have all been omitted.

Figure 10
Projections along [010] of the cyclic dimers in (a) compound (IVa) and (b) compound (IVb). Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, H atoms not involved in the motifs shown have been omitted. The atoms marked with an asterisk (*) are at the symmetry position (À x, À y + 1, À z + 1). Note the different locations of the origin and the different orientations of the axes. adjacent molecules, forming a chain running parallel to the [100] direction ( Fig. 9), leading overall to a stack of weakly hydrogen-bonded dimers.
It is interesting to note the structural contrasts between compounds (IVa) and (IVb) on the one hand, and compound (IVc) on the other, in terms of their space groups (Table 1), their molecular conformations (Table 2 and Figs. 1-3), the range of direction-specific intermolecular interactions and their modes of supramolecular assembly, as discussed above. All these points are associated with a change in the identity and location of a single monoatomic substituent in the styryl unit, but it is not easy to determine whether any one of these factors could be regarded as a possible cause of the effects observed in any, or all, of the others. Although the two triclinic compounds (IVa) and (IVb) have different inter-axial angles (Table 1) and different modes of supramolecular assembly, in both, the assembly is based on a cyclic centrosymmetric R 2 2 (8) dimer built from C-H� � �O hydrogen bonds (Table 3). It is thus striking that projections of the dimers in (IVa) and (IVb), viewed along [010], are extremely similar (Fig. 10), despite the different locations of the origin and the different orientations of the axes.
We have recently reported (Vera et al., 2022) the structures of a number of 2-methyl-4-styrylquinolines of type (II) (see Scheme 1; all prepared using Friedlä nder cyclocondensation reactions, as here). In each of (E)-4-(4-fluorostyryl)-2methylquinoline and (E)-2-methyl-4-[4-(trifluoromethyl)styryl]quinoline, the molecules are linked into cyclic centrosymmetric dimers by hydrogen bonds, of the C-H� � �N and C-H� � �� types, respectively, and these dimers are further linked by �-� stacking interactions to form sheets in the fluoro compound and chains in the trifluoromethyl analogue. By contrast, there are no significant intermolecular interactions in the structure of (E)-4-(2,6-dichlorostyryl)-2-methylquinoline. All of these type (II) compounds have molecular skeletons in which the styryl and quinoline units are non-coplanar, as reported here for compounds (IVa)-(IVc). This appears to be the case for all of the 4-styrylquinolines which have been structurally characterized so far, in contrast to the 2-and 8-styrylquinolines, where the two ring systems appear always to be effectively coplanar (Vera et al., 2022;Ardila et al., 2022).

Summary
We have developed a highly versatile and efficient three-step synthesis of a novel class of styrylquinoline-chalcone hybrids based on only very simple and readily available starting materials, such as simple aldehydes and ketones, and we have characterized by spectroscopic means (IR, 1 H/ 13 C NMR and HRMS) three products and all of the intermediates on the pathways leading to them, and we have determined the molecular and supramolecular structures of the three products. 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).