Conversion of 2-methyl-4-styrylquinolines into 2,4-distyrylquinolines: synthesis, and spectroscopic and structural characterization of five examples

Five new 4-(arylvinyl)-2-styrylquinolines have been synthesized using indium chloride-catalyzed condensation reactions between their 4-(arylvinyl)-2-methyl- analogues and either mono- or diketones. The supramolecular arrangements range from isolated molecules via hydrogen-bonded dimers and sheets to three-dimensional framework structures.

The work reported here can be regarded as a continuation of an earlier crystallographic study which reported the structures of 4-styrylquinolines having different substituents at the C2 and C3 positions Vera et al., 2022;Ardila et al., 2022).

Synthesis and crystallization
For the synthesis of compounds (IIa)-(IIe), a mixture of the appropriate 2-methyl-4-styrylquinoline, (I) (see Scheme 1), prepared as described previously (Melé ndez et al., 2020;Vera et al., 2022) (1.0 mmol), the appropriate aromatic aldehyde (4.0 mmol) and indium trichloride (10 mmol%) in dry toluene (1.2 ml) was stirred magnetically and heated at 393 K until the reactions were complete, shown by the complete consumption of (I), as monitored by thin-layer chromatography (TLC). The reaction times for completion were 18 h for (IIa), 16 h for (IIb), 17 h for (IIc) and 21 h for both (IId) and (IIe). Each reaction mixture was then allowed to cool to ambient temperature, washed with chloroform and the resulting suspension was removed by filtration before the filtrate was concentrated under reduced pressure. In each case, the resulting crude product was purified by silica-gel column chromato-graphy using heptane-ethyl acetate mixtures as eluent (compositions ranged from 10:1 to 2:1 v/v) to give the required solid products (IIa)-(IIe). Crystallization from ethyl acetateheptane, at ambient temperature and in the presence of air, gave crystals suitable for single-crystal X-ray diffraction.
In the NMR data listed below, unprimed ring atoms form part of the quinoline units; ring atoms carrying a single prime form part of the styryl units attached at position C2 of the quinoline system; ring atoms carrying double primes form part of the styryl units attached at position C4 for compounds (IIa) and (IIb), or part of the benzoyl units attached at position C3 for compounds (IIc)-(IIe); and ring atoms carrying triple primes form part of the styryl units attached at position C4 for compounds (IIc)-(IIe

Refinement
Crystal data, data collection and refinement details for compounds (IIa)-(IIe) are summarized in Table 1. For compound (IId), the reflection 100, which had been attenuated by the beam stop, was removed from the data set. In addition, a small number of bad outlier reflections [104 for (IIa) and 141, 231, 241, 033 and 303 for (IIc)] were also removed. Compound (IIc) was handled as a nonmerohedral twin, with twin matrix (À 0.053, 0.000, 0.947/0.000, À 1.000, 0.000/1.053, 0.000, 0.053) and with refined twin fractions of 0.865 (2) and 0.135 (2). In compound (IIe), the thienyl unit was disordered over two sets of atomic sites having unequal occupancies. For the minor-disorder component, the bonded distances and the 1,3 nonbonded distances were restrained to be the same as the corresponding distances in the majordisorder component, subject to s.u. values of 0.01 and 0.02 Å ,

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respectively. In addition, the anisotropic displacement parameters for pairs of partial-occupancy atoms occupying essentially the same physical space were constrained to be identical. All H atoms, apart from those in the minor-disorder component of compound (IIe), were located in difference maps and then treated as riding atoms in geometrically idealized positions, with C-H = 0.95 Å and U iso (H) = 1.2U eq (C); the H atoms in the minor-disorder component of compound (IIe) were included in the refinement in exactly the same manner. Subject to these conditions, the refined occupancy values for the disorder components of (IIe) were 0.926 (3) and 0.074 (3). In the final difference map, the largest maximum of 1.65 e Å À 3 was 0.86 Å from atom Br24, while the largest minimum of À 1.18 e Å À 3 was 0.66 Å from Br24. While these features might indicate some further minor disorder, the anisotropic displacement parameters provided no support for this possibility, which was therefore not pursued further.
The formation of the second styryl fragment in products (IIa)-(IIe) was established by the disappearance from both the 1 H and 13 C NMR spectra of the signals from the methyl group at position C2, and their replacement by new sets of signals corresponding to the newly-introduced C and H atoms; thus, eight new C atoms in each case and seven new H atoms in (IIa), five in (IIb) and six in each of (IIc)-(IIe). In each case, the Knoevenagel-type condensation proceeded in a highly stereoselective manner giving exclusively the E stereoisomers, as indicated by the 1 H NMR spectra. The E configuration of the newly-formed styryl fragment was deduced on the basis of the coupling constant values ( 3 J HA 0 ,HB 0 ca 16.0 Hz) between HA 0 and HB 0 . The constitutions of compounds (IIa)-(IIe), which were deduced from the spectroscopic data, were then fully confirmed by the results of single-crystal X-ray diffraction, which additionally provided information on the molecular conformations and the intermolecular interactions in the solid state.
The versatility of this synthetic route to 2,4-distyrylquinolines and their analogues is underpinned by the possibility of incorporating a wide variety of substituents into the initial chalcone precursor, into the ketone employed in the annulation step and into the aldehyde used in the final condensation step.
In compound (IIe), the thiophene unit is disordered over two sets of atomic sites having occupancies of 0.926 (3) and 0.074 (3), such that the two disorder forms are related by a rotation of approximately 180 � around the exocyclic C-C bond; the dihedral angle between the mean planes of the two disorder components is only 4(2) � .

Figure 1
The molecular structure of compound (IIa), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level.
The molecules of compounds (IIa)-(IIe) exhibit no internal symmetry and hence these compounds are all conformationally chiral (Moss, 1996;Flack & Bernardinelli, 1999), but the centrosymmetric space groups (Table 1) confirm that equal numbers of the two conformational enantiomers are present in each of (IIa)-(IIe).
For the 3-benzoyl products (IIc)-(IIe), the reference molecules are all such that the torsion angle C2-C3-C31-C311 has a positive sign (Table 2), while the value of the torsion angle C3-C4-C41-C42 in (IIc) is markedly different from those in the other four compound reported here (Table 2 and Figs. 1-5). In each of (IIa)-(IIe), the 2-styryl unit is close to being coplanar with the quinoline unit, while the 4-substituent is twisted well out of the plane of the quinoline unit. These observations thus complement the general pattern in styrylquinolines that we have noted previously (Vera et al., 2022;Ardila et al., 2022). Amongst the styrylquinolines whose structures are recorded in the Cambridge Structural Database The molecular structure of compound (IIb), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level.

Figure 3
The molecular structure of compound (IIc), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level.

Figure 4
The molecular structure of compound (IId), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level. The molecular structure of compound (IIe), showing the conformational disorder and the atom-labelling scheme. The major-disorder component is drawn with full lines and the minor-disorder component is drawn using broken lines. Displacement ellipsoids are drawn at the 50% probability level.

Figure 6
Part of the crystal structure of compound (IIb), showing the formation of a C(8) chain parallel to [010], built from C-H� � �N hydrogen bonds, which are drawn as dashed lines. For the sake of clarity, H atoms which are not involved in the motif shown have been omitted.

Figure 7
Part of the crystal structure of compound (IIb), showing the formation of a chain parallel to [001], built from C-H� � ��(arene) hydrogen bonds, which are drawn as dashed lines. For the sake of clarity, H atoms which are not involved in the motif shown have been omitted.

Figure 8
Part of the crystal structure of compound (IIb), showing the formation of a centrosymmetric dimer built from C-H� � ��(arene) hydrogen bonds, which are drawn as dashed lines. For the sake of clarity, H atoms which are not involved in the motif shown have been omitted.
out of the plane of the quinoline unit by a rotation about the exocyclic bond corresponding to C4-C41 in the numbering system used here. Despite this, there are some unexpected differences in the molecular orientations of the two arylvinyl units (Figs. 1-5 and Table 2). Thus, the orientation of the 2-styryl substituent in (IIb) differs from that in each of (IIa) and (IIc)-(IIe) by a rotation about the C2-C21 bond of approximately 180 � . In addition, the orientation of the 4-stryl unit in (IIc) differs markedly from that in each of the other examples, but the torsion angle C3-C4-C41-C42 shows quite a wide range of variation (Table 2). These differences in conformation cannot reasonably be explained in terms of the patterns of hydrogen bonding discussed below (cf. Table 3).
The patterns of supramolecular assembly in compounds (IIa)-(IIe) show some wide variations. Despite the large numbers of aromatic rings and C-H bonds in the molecules of (IIa), the crystal structure contains no significant directionspecific intermolecular interactions of any sort. By contrast, in the dichloro analogue (IIb), a combination of one C-H� � �N hydrogen bond and two independent C-H� � ��(arene) hydrogen bonds (Table 3) links the molecules into a threedimensional framework structure, whose formation is readily analysed in terms of three simple substructures (Ferguson et al., 1998a,b;Gregson et al., 2000). The C-H� � �N hydrogen bonds link molecules of (IIb) which are related by the 2 1 screw axis along ( 1 4 , y, 3 4 ) to form a C(8) (Etter, 1990;Etter et al., 1990;Bernstein et al., 1995) chain running parallel to the [010] direction ( Fig. 6). In the second substructure, the C-H� � � �(arene) hydrogen bond having atom C6 as the donor links molecules which are related by the c-glide plane at y = 1 to form a chain running parallel to the [001] direction (Fig. 7). Part of the crystal structure of compound (IIc), showing the formation of a chain of rings running parallel to the [101] direction and built from two independent C-H� � ��(arene) hydrogen bonds, which are drawn as dashed lines. For the sake of clarity, H atoms which are not involved in the motif shown have been omitted.

Figure 10
Part of the crystal structure of compound (IId), showing the formation of a cyclic R 2 2 (20) dimer built from C-H� � �O hydrogen bonds, which are drawn as dashed lines. For the sake of clarity, H atoms which are not involved in the motif shown have been omitted.

Figure 11
Part of the crystal structure of compound (IIe), showing the formation of a sheet lying parallel to {100} and built from a combination of C-H� � �O and C-H� � ��(arene) hydrogen bonds, which are drawn as dashed lines. For the sake of clarity, the minor-disorder component and H atoms which are not involved in the motif shown have been omitted.
The combination of the chains along [010] and [001] generates a sheet lying parallel to (100) in the domain 0 < x < 1 2 . A second sheet, related to the first by inversion, lies in the domain 1 2 < x < 1.0, and adjacent sheets are linked by the third substructure which takes the form of a cyclic centrosymmetric dimer built from C-H� � ��(arene) hydrogen bonds having atom C422 as the donor (Fig. 8).
The short intermolecular C-H� � �O contact in compound (IIc) has a very small C-H� � �O angle (Table 3), and so cannot be regarded as structurally significant (Wood et al., 2009). However, the co-operative action of two C-H� � ��(arene) hydrogen bonds links molecules which are related by the n-glide plane at y = 1 4 into a chain of rings running parallel to the [101] direction (Fig. 9). The structure also contains a third C-H� � ��(arene) contact, involving atom C5, but here the H� � �A distance is quite long; if this were regarded as structurally significant, its action would be to link the chains of rings into a sheet parallel to (101).
A single C-H� � �O hydrogen bond links inversion-related molecules of compound (IId) into a cyclic centrosymmetric R 2 2 (20) dimer (Fig. 10), but there are no direction-specific interactions between adjacent dimers.
In the crystal structure of compound (IIe), the C-H� � �O contact involving atom C8 is not structurally significant (Wood et al., 2009), but the combination of the C-H� � �O hydrogen bond involving atom C425 with the two C-H� � ��(arene) hydrogen bonds links the molecules into a complex sheet lying parallel to (100) in the domain 1 4 < x < 3 4 (Fig. 11). A second sheet, related to the first by the action of the 2 1 screw axes, lies in the domain 3 4 < x < 1.35, but there are no direction-specific interactions between adjacent sheets.
It is of interest briefly to compare the supramolecular assembly in compounds (IIa)-(IIe) reported here with those of some simpler 2-methyl-4-styrylquinoline analogues. Crystal structures have been reported (Vera et al., 2022) for compounds (IIIa)-(IIIc) (see Scheme 2), which have no substituent at position C3 of the quinoline unit, and are thus related to compounds (IIa) and (IIb) reported here. In the crystal structure of (IIIa), the molecules are linked into sheets by a combination of C-H� � �N hydrogen bonds and �-� stacking interactions, while a similar combination of interactions links the molecules of (IIIb) into chains of rings. There are no hydrogen bonds in the structure of (IIIc), but a �-� stacking interaction links the molecules into stacks.
Compounds of the type (IV) (see Scheme 2), carrying a 3-acetyl substituent, are thus analogous to compounds (IIc)-(IIe). Compounds (IVa)-(IVc) are isomorphous ; in each, the molecules are linked into chains by a C-H� � �O hydrogen bond, but only in (IVa) is this augmented by a C-H� � �� hydrogen bonds to form a chain of rings. Thus, although (IVa)-(IVc) are isomorphous, they are not strictly isostructural.

Summary
We have developed an efficient and highly versatile route to 2,4-distyrylquinolines and to their 2-arylvinyl analogues, using only simple and readily accessible building blocks such as simple aldehydes and ketone. We have characterized by spectroscopic means (IR, 1 H and 13 C NMR spectroscopy, and HRMS) five representative examples and we have determined their molecular and crystal structures, which fully confirm the molecular constitutions deduced from the spectroscopic data, as well as providing further information on their molecular conformations in the solid state, and on their supramolecular assemblies. 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).

2,4-Bis[(E)-2-phenylethenyl]quinoline (IIa)
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.

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.