Synthesis and spectroscopic and structural characterization of three new 2-methyl-4-styrylquinolines formed using Friedländer reactions between (2-aminophenyl)chalcones and acetone

The syntheses and structures are reported for three 4-styrylquinoline derivatives formed by reactions between (2-aminophenyl)chalcones and acetone.


Introduction
The quinoline nucleus constitutes a privileged scaffold because of the wide spectrum of promising biological activity exhibited by its derivatives (Kumar et al., 2009). Among quinoline derivatives, 2-styrylquinolines have been studied extensively, mainly because of their potential as inhibitors of HIV-1 integrase (Leonard & Roy, 2008;Mahajan et al., 2018;Mousnier et al., 2004) and as antimicrobial (Kamal et al., 2015), antifungal (Cieslik et al., 2012) and anticancer agents (Mrozek-Wilczkiewicz et al., 2015. Accordingly, considerable efforts have been made in the development of effective methods for accessing new compounds containing the styrylquinoline scaffold (Musiol, 2020). Unlike 2-styrylquinolines, the 4-styrylquinoline regioisomers have been studied much less, with few published reports related to their synthesis and biological evaluation, which is probably due, at least in part, to a lack of generally applicable methodologies for their synthesis. In general, the published syntheses of 4-styrylquinolines have involved Heck coupling between 4-haloquinolines and different aryl-vinyl compounds (Omar & Hormi, 2009), and Knoevenagel-type condensation reactions between 4-methylquinolines and aromatic aldehydes using expensive and toxic heavy-metal catalysts (Jamal et al., 2016) or microwave irradiation (Lee et al., 2009). The use of palladium catalysts in the cross-coupling reaction between 4-chloroquinolines and alkenyltrifluoroborates under harsh reaction conditions has also been reported (Alacid & Ná jera, 2009). Nonetheless, there still remains a need for alternative approaches for the construction of 4-styrylquinolines starting from readily accessible materials and characterized by high atom efficiency and low cost.
In this context, and as part of an ongoing program exploring the rational use of synthetically available 1-(2-aminophenyl)-3-arylprop-2-en-1-ones (Melé ndez et al., 2020) as appropriate precursors for the synthesis of novel quinoline derivatives, we have recently described a simple and efficient one-pot synthetic approach based on the Friedlä nder reaction to obtain polysubstituted 2-methyl-4-styrylquinolines starting from these simple precursors and different 1,3-dicarbonyl compounds (Melé ndez et al., 2020).

Synthesis and crystallization
For the synthesis of compounds (I)-(III), a mixture of the appropriate 1-(2-aminophenyl)-3-arylprop-2-en-1-ones (A) (Melé ndez et al., 2020; see Scheme 1) (1.0 mmol) and acetone (12.0 mmol) in glacial acetic acid (3 ml) was stirred magnetically and heated at 353 K until the reactions were complete, as judged by the complete consumption of (A) (as monitored by thin-layer chromatography, TLC); the reaction times for completion were 15 h for (I), 19 h for (II) and 14 h for (III). Each reaction mixture was then neutralized with a saturated aqueous sodium carbonate solution and extracted with ethyl acetate (3 Â 50 ml). The combined organic layers were washed with water and dried over anhydrous sodium sulfate, and the solvent was then removed under reduced pressure. In each case, the resulting crude product was purified by flash 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 solid compounds (I)-(III). Crystallization from hexane-ethyl acetate (10:1 v/v) at ambient temperature and in the presence of air gave crystals suitable for single-crystal X-ray diffraction; these were yellow for (I) and (III), and colourless for (II).

Refinement
Crystal data, data collection and refinement details are summarized in Table 1. A small number of bad outlier reflections [636 for (I), 204 and 336 for (II), and 16,0,0 and 339 for (III)] were omitted from the data sets. 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 (alkenic and aromatic) and 0.98 Å (CH 3 ), 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.

Results and discussion
All compounds were fully characterized by standard spectroscopic and analytical methods. In the IR spectra of (I)-(III), the absence of any N-H stretching bands around 3275-3285 cm À1 , which are characteristic in the spectra of (2-aminophenyl)chalcone precurors, was used for monitoring the formation of the quinoline ring. The formation of the 4-styrylquinoline scaffold was confirmed by a detailed analysis of the 1 H, 13 C and 2D NMR spectra, which showed no signals arising from the H atoms of the amino group; neither were there any signals from the carbonyl groups which had been present in the precursor chalcones. Instead, the 13 C spectra of the products contained signals from a new C aryl -H unit (C-3) in the range 117.9-118.5, and two new quaternary aromatic C atoms at 158.7-158.8 (C-2) and 142.2-142.8 (C-4). As in the spectra of the precursor chalcones, the 1 H spectra of products (I)-(III) contained signals from the trans vinylic protons -CH A CH B -, appearing as two doublets (see Section 2.1). Finally, definitive confirmation of the molecular constitutions and the regio-and stereochemistry for compounds (I)-(III) was established by means of single-crystal X-ray diffraction,  These new 2-methylquinoline derivatives (I)-(III) are intended for use as key precursors in the further development of more complex molecules of possible biological value, such as the bis-styrylquinolines (IV) (Scheme 2), (4-styrylquinolin-2-yl)chalcones of the type (V), and the molecular hybrids of types (VI) and (VII), and the work reported here can be regarded as a continuation of an earlier crystallographic study which reported the structures of 2-methyl-4-styrylquinolines having either acetyl or carboethoxy functionalities at position C3 .
The molecules of compounds (I)-(III) exhibit no internal symmetry, as indicated by the key torsion angles (Table 2). They are thus not superimposable upon their mirror images and hence they are all conformationally chiral (Moss, 1996;Flack & Bernardinelli, 1999). The space groups (Table 1) confirm that the crystals of each compound contain equal numbers of the two conformational enantiomers; for each compound, the reference molecule was selected as one having a positive sign for the torsion angle C3-C4-C41-C42 (Table 2). Only in compound (II) is the styryl fragment involved in direction-specific intermolecular interactions, as discussed below, and hence there appears to be no simple interpretation of the conformational differences in compounds (I)-(III), other than to note that the barriers to rotation about the C-C single bonds are generally quite low, typically a few kJ mol À1 (Alkorta & Elguero, 1998).
The supramolecular assembly in compounds (I)-(III) is very simple (Table 3). There is a single hydrogen bond in the structure of (I). In the structure of (II), there is a C-HÁ Á Á(arene) hydrogen bond, but for the intermolecular C-  Table 2 Selected torsion angles ( ) for compounds (I)-(III).

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

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

Figure 1
The molecular structure of compound (I), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level.
HÁ Á ÁN contact, the HÁ Á ÁN distance exceeds the sum, 2.70 Å , of the van der Waals radii for these atoms (Rowland & Taylor, 1996); hence, this is just a normal intermolecular contact with no associated attractive interaction which could be regarded as structurally significant. The C-HÁ Á ÁN contact in compound (III) involves a methyl group (Table 3), where the C-H bonds are of low acidity. More significantly, methyl groups are, in general, likely to be undergoing very fast rotation about the adjacent C-C bond in the solid state (Riddell & Rogerson, 1996, 1997. For methyl groups bonded to planar fragments such as aryl rings, the sixfold barrier to rotation is usually very small, only a few J mol À1 rather than the typical order of magnitude in kJ mol À1 (Naylor & Wilson, 1957;Tannenbaum et al., 1956). Hence, this contact cannot be regarded as struc-turally significant. There arestacking interactions in each structure.
In the structure of (I), inversion-related pairs of molecules are linked by almost linear C-HÁ Á ÁN hydrogen bonds (Table 3) to form centrosymmetric dimers characterized by an R 2 2 (8) motif (Etter, 1990;Etter et al., 1990;Bernstein et al., 1995) (Fig. 4). Dimers of this type are linked into sheets by stacking interactions; the quinoline units of the molecule at (x, y, z), makes dihedral angles of 9.21 (7) with the corresponding rings of the molecules at (x, Ày + 1 2 , z + 1 2 ) and (x, Ày + 1 2 , z À 1 2 ), with ring-centroid separations of 3.7682 (9) Å in each case, with the shortest distance between the centroid of one ring and the plane of the other of 3.5610 (6)   Part of the crystal structure of compound (I), showing the formation of a -stacked sheet of hydrogen-bonded dimers lying parallel to (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.

Figure 5
Part of the crystal structure of compound (II), showing the formation of a -stacked chain of hydrogen-bonded dimers running parallel to [001] 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 3 Parameters (Å , ) for hydrogen bonds and short intermolecular contacts in compounds (I)-(III).

Figure 6
Part of the crystal structure of compound (III), showing the formation of a -stacked chain of hydrogen-bonded dimers running parallel to [010]. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, H atoms not involved in the motif shown have been omitted. operations leads to the formation of a sheet of -stacked dimers lying parallel to (100) (Fig. 4).
In the structure of compound (II), inversion-related pairs of molecules are linked by a C-HÁ Á Á(arene) hydrogen bond to form centrosymmetric dimers (Fig. 5), and these dimers are linked into chains by a singlestacking interaction; the heterocyclic rings in the molecules at (x, y, z) and (Àx + 1, y, Àz + 3 2 ) are strictly parallel, with an interplanar spacing of 3.5058 (6) Å and a ring-centroid separation of 3.6845 (9) Å , corresponding to a ring-centroid offset of 1.1335 (12) Å . By this means, the hydrogen-bonded dimers are linked into a chain running parallel to [001] (Fig. 5).
Although there are no hydrogen bonds in the structure of compound (III), the molecules which are related by translation along the [010] direction are stacked precisely in register with a spacing equal to the unit-cell vector b = 3.8629 (2) Å (Fig. 6). Eight stacks of this kind pass through each unit cell (Fig. 7), but there are no direction-specific interactions between adjacent stacks.
We have previously reported ) the synthesis and structures of a number of 4-styrylquinoline derivatives carrying either acetyl or carboethoxy substituents at position C-3. Of these, three closely related acetyl derivatives were found to be isomorphous, with their molecules linked into simple C(6) chains by a single C-HÁ Á ÁO hydrogen bond. By contrast, the matching set of carboethoxy derivatives all exhibited different crystallization characteristics and different modes of supramolecular assembly, with one forming C(13) chains and the other two forming cyclic centrosymmetric dimers involving C-HÁ Á ÁO hydrogen bonds in one case and C-HÁ Á Á hydrogen bonds in the other. In addition, two other examples carrying acyl substituents have been reported (Melé ndez et al., 2020) on a proof-of-structure basis without detailed structure analysis or description, but subsequent re-examination  found a complex sheet structure in one of them, but no significant intermolecular interactions in the other.
The structures of a number of other styrylquinolines are recorded in the Cambridge Structural Database (CSD; Groom et al., 2016), but it is striking that the majority of these structures are of 2-styrylquinoline derivatives, along with those of a small number of 8-styrylquinolines. This may reflect, at least in part, a lack of efficient, straightforward and versatile routes to other isomeric styrylquinolines. The structure of 2-styrylquinoline itself has been reported three times (Valle et al., 1986;Gulakova et al., 2011;Kuz'mina et al., 2011), as have those of 2-[2-(4-methylphenyl)vinyl]quinoline Kuz'mina et al., 2011;Das et al., 2019) and 2-[2-(3,4methoxyphenyl)vinyl]quinolone Kuz'mina et al., 2011;Sharma et al., 2021). There are two reports on the structure of 2-[2-(3-nitrophenyl)vinyl]quinoline Kuz'mina et al., 2011) and one on the structure of 4-phenyl-2-styrylquinoline (Makela et al., 2021). In all of these 2-styrylquinolines, the molecular skeleton is planar, in marked contrast to the nonplanar conformations of the 4-styrylquinoline derivatives (I)-(III) reported here, and of those reported previously . In both 8-styrylquinoline and 8-[2-(biphenyl-4-yl)vinyl]-2-methylquinoline, the styrylquinoline fragment is planar (Sharma et al., 2015), as found in 2-styrylquinolines but again in marked contrast to 4-styrylquinolines. It is not easy to see why 4-styrylquinolines should adopt nonplanar conformations, while molecules of the 2-styryl and 8-styryl isomers appear consistently to adopt planar forms. 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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq N1 0.35530 (8)  where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max = 0.001 Δρ max = 0.33 e Å −3 Δρ min = −0.26 e Å −3 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.