4-Styrylquinolines from cyclocondensation reactions between (2-aminophenyl)chalcones and 1,3-diketones: crystal structures and regiochemistry

Structures are reported for two sets of substituted 4-styrylquinolines formed by reactions of (2-aminophenyl)chalcones either with pentane-2,4-dione or, regiospecifically, with ethyl 3-oxobutanoate.


Introduction
Compounds containing 2-styrylquinoline units have attracted interest in recent years because of their potential as anticancer (El-Sayed et al., 2018), anti-HIV (Polanski et al., 2002), antimalarial (Roberts et al., 2017) and antimicrobial (Cieslik et al., 2012) agents, as well as in the treatment of Alzheimer's dementia (Wang et al., 2015). By contrast, analogous compounds containing 4-styryl units have been very much less extensively investigated, probably, at least in part, because of a lack of efficient and versatile methods for their synthesis: such methods have generally been based on coupling reactions requiring the prior synthesis of haloquinolines or (haloalkyl)quinolines, combined with either harsh reaction conditions or the use of expensive heavy-metal catalysts (Omar & Hormi, 2009;Xia et al., 2016). However, a very straightforward synthesis of 4-styrylquinolines has been developed recently (Melé ndez et al., 2020), in which the heterocyclic ring of the quinoline unit is built in situ using a cyclocondensation reaction between a 2 0 -aminochalcone, (A), and a 1,3-dicarbonyl compound (cf. Scheme 1). The chalcone component in this ISSN 2053ISSN -2296 type of cyclization is readily accessible by reaction between 2 0 -aminoacetophenone and an aromatic aldehyde, allowing incorporation of a wide variety of substituents both in the styryl portion and at the 3-position of the quinoline nucleus. We report here the molecular structures and supramolecular assembly of two matched sets, each of three related products: the 3-acetyl derivatives, compounds (I)-(III) (Scheme 1 and Figs. 1-3), where X = Me, were all obtained using pentane-2,4dione as the dicarbonyl component, while the 3-carboethoxy derivatives, compounds (IV)-(VI) , where X = OEt, were all obtained using ethyl 3-oxobutanoate (ethyl acetoacetate). Compounds such as (I)-(III), containing an acetyl group, can act as useful synthetic intermediates, as they can undergo condensation with a further substituted aldehyde to form a chalcone substituent at the 3-position, as exemplified by compound (VIII) (Scheme 2). Such chalcones can themselves then undergo cyclocondensation reactions, for example, with a hydrazine, to form either a pyrazole, under basic conditions (Samshuddin et al., 2014), or a reduced pyrazole ring, under acidic conditions (Jasinski et al., 2010), or with guanidine to form a reduced pyrimidine ring (Nayak et al., 2014), thus giving access to a rich diversity of new 4-styrylquinolin-3-yl heterocycles. In addition to reporting the mol-ecular and supramolecular structures of compounds (I)-(VI), we also briefly consider compounds (VII) and (VIII) (Scheme 2). These have been reported on a simple proof of constitution basis [Cambridge Structural Database (CSD; Groom et al., 2016) refcodes MUMZEC and MUMZIG (Melé ndez et al., 2020)] but without any structure description or discussion; accordingly, we discuss here the supramolecular assembly in these two compounds.

Synthesis and crystallization
Samples of compounds (I)-(VI) were prepared and crystallized following a recently published procedure (Melé ndez et al., 2020).

Refinement
Crystal data, data collection and structure refinement details for compounds (I)-(VI) are summarized in Table 1. Two low-angle reflections which had been attenuated by the beam stop [100 for (I) and 101 for (VI)] were omitted from the data sets before the final refinements; likewise, two bad outlier reflections (639 and 606) were removed from the data set for (IV). All H atoms were located in difference maps and subsequently treated as riding atoms in geometrically idealized positions, with C-H = 0.95 (alkenyl, aromatic and heteroaromatic), 0.98 (CH 3 ) or 0.99 Å (CH 2 ), and with Table 1 Experimental details. Experiments were carried out at 100 K with Mo K radiation using a Bruker D8 Venture diffractometer. Absorption was corrected for by multi-scan methods (SADABS; Bruker, 2016  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 4
The molecular structure of compound (IV), 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.
ethyl 3-oxobutanoate, can, in principle, give two types of product: reaction of the amino group at the acetyl carbonyl group leads to ethyl esters, as exemplified by compounds (IV)-(VI), but reaction of the amino group at the ester carbonyl group would lead to elimination of ethanol with the formation of a 2-quinolone of type (X) (Scheme 2). Again, these reactions appear to lead exclusively to the esters, as exemplified by (IV)-(VI) (Melé ndez et al., 2020), consistent with the greater electrophilicity of a ketonic carbonyl group compared with an ester carbonyl group. On the other hand, 2-aryl-4-quinolones are sometimes formed as by-products arising from an intramolecular cyclization of the chalcone precursor. Compounds (I)-(III), where X = Me and Y = OMe, Br or CF 3 , respectively (Scheme 1 and Figs. 1-3), all crystallize in the space group P2 1 /c with rather similar unit-cell dimensions (Table 1) and very similar molecular conformations (Table 2); each structure can be refined using the coordinates of one of the others as the starting point, provided due alteration is made in the substituent at atom C424 (Figs. 1-3). However, although there are short intermolecular C-HÁ Á ÁO and C-HÁ Á Á(arene) contacts in all three compounds, involving the same sets of atoms (Table 3) The molecular structure of compound (VI), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level.

Figure 7
Part of the crystal structure of compound (I), showing the formation of a chain of rings along [010] built from C-HÁ Á ÁO and C-HÁ Á Á(arene) hydrogen bonds, drawn as dashed lines. For the sake of clarity, H atoms not involved in the motifs shown have been omitted.

Figure 5
The molecular structure of compound (V), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level. Table 2 Selected torsion angles ( ) for compounds (I)-(VIII). (III), the HÁ Á ÁCg distance is quite long and probably of marginal structural significance, whereas it can be regarded as a genuine hydrogen bond in compound (I). On this basis, compounds (I)-(III) can be regarded as isomorphous but not strictly isostructural (Acosta et al., 2009;Blanco et al., 2012). However, in the comparable series of compounds, i.e. (IV)-(VI), where X = OEt, although compounds (IV) and (VI) are both triclinic, in (IV) the inter-axial angles are all less than 90 , but in (VI) they are greater than 90 , so that these two compounds are far from being isomorphous. On the other hand, the third member of this group, compound (V), is monoclinic, so there can be no close similarities within this group. None of the molecules of (I)-(VIII) exhibits any internal symmetry, so that they are all conformationally chiral; in each case, the reference molecule was selected as one having a positive sign for the C3-C4-C41-C42 torsion angle (Table 2), although the space groups confirm that all the compounds have crystallized as conformational racemates.
The supramolecular assembly of compounds (I)-(VI) is determined by C-HÁ Á ÁO and C-HÁ Á Á hydrogen bonds (Table 3). In each of (I)-(III), molecules which are related by translation are linked by a C-HÁ Á ÁO hydrogen bond to form a C(6) (Etter, 1990;Etter et al., 1990;Bernstein et al., 1995) chain running parallel to the [010] direction. In the structure of (I), this is enhanced by a C-HÁ Á Á(arene) hydrogen bond linking molecules related by the 2 1 screw axis along ( 1 2 , y, 1 4 ) to form a chain of rings (Fig. 7). However, in the structures of (II) and (III), the corresponding HÁ Á ÁCg and CÁ Á ÁCg distances are much longer than they are in (I), so that these are possibly better regarded as short adventitious contacts rather than structurally significant hydrogen bonds.

Figure 8
Part of the crystal structure of compound (IV), showing the formation of a C(13) chain running parallel to the [100] direction. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, H atoms bonded to those C atoms which are not involved in the motif shown have been omitted. Atoms marked with an asterisk (*) or a hash (#) are at the symmetry positions (x + 1, y, z) and (x À 1, y, z), respectively.

Figure 9
Part of the crystal structure of compound (V), showing the formation of a centrosymmetric dimer. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, H atoms which are 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). structure also contains a short C-HÁ Á Á(pyridyl) contact, but the long HÁ Á ÁCg distance and the very small C-HÁ Á ÁCg angle indicate that this is probably not structurally significant (Wood et al., 2009). By contrast, in the structure of compound (V), it is the C-HÁ Á ÁO contact which has a very small D-HÁ Á ÁA angle (Table 3), while a C-HÁ Á Á(pyridyl) hydrogen bond links molecules which are related by inversion to form a cyclic centrosymmetric dimer (Fig. 9).
In the structure of compound (VI), there are no C-HÁ Á Á hydrogen bonds or short intermolecular contacts. Instead two C-HÁ Á ÁO hydrogen bonds combine to link inversion-related pairs of molecules into centrosymmetric dimers. The hydrogen bonds involving atoms of type C41 form an R 2 2 (12) ring, while those involving atoms of type C422 generate an R 2 2 (18) ring ( Fig. 10).
We also discuss here the supramolecular assembly of compounds (VII) and (VIII), which, as noted above (x1, Introduction), have been reported on a simple proof of constitution basis, without discussion (Melé ndez et al., 2020). The assembly in (VII) in the space group Pbcn is based upon two C-HÁ Á ÁO hydrogen bonds and one C-HÁ Á Á(arene) hydrogen bond ( Table 3). The two C-HÁ Á ÁO hydrogen bonds link molecules which are related by the a-glide plane at z = 1 4 to form a C(6)C(9)[R 1 2 (7)] chain of rings running parallel to the [100] direction (Fig. 11). In addition, the structure of (VII) contains a C-HÁ Á Á(arene) hydrogen bond which links molecules which are related by the b-glide plane at x = 3 4 to form a chain running parallel to the [010] direction (Fig. 12). The combination of the chain motifs along [100] and [010] generates a complex sheet lying parallel to (001) in the domain 0 < z < 1 2 ; a second sheet of this type, related to the first by inversion, lies in the domain 1 2 < z < 1.0, but there are no direction-specific interactions between adjacent sheets. Even the shortest intermolecular contacts (Table 3) in chalcone (VIII) have HÁ Á ÁA distances which are probably too long for these contacts to be regarded as structurally significant. Part of the crystal structure of compound (VI), showing the formation of a centrosymmetric dimer. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, H atoms which are not involved in the motif shown have been omitted. Atoms marked with an asterisk (*) are at the symmetry position (Àx + 1, Ày + 1, Àz + 1).

Figure 11
Part of the crystal structure of compound (VII), showing the formation of a C(6)C(9)[R 1 2 (7)] chain of rings running parallel to the [100] direction. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, H atoms which are not involved in the motif shown have been omitted.  The structures of several simple 2-styrylquinolines have been published, including those of the unsubstituted 2-styrylquinoline itself (Valle et al., 1986), and of several analogues carrying simple substituents in the phenyl ring (Kuz'mina et al., 2012). In addition, structures have been reported for a number of salts derived from 2-styrylquinolines (Kobkeatthawin et al., , 2009Chantrapromma et al., 2008Chantrapromma et al., , 2014Fun et al., 2013). For all of these compounds, the styryl group was introduced into a preformed quinoline nucleus. 8-Styrylquinoline and its 4-phenylstyryl analogue, whose structures have also been reported (Sharma et al., 2015), were prepared using a rhodiumcatalysed coupling reaction between quinoline N-oxide and the styrene component. Despite the substantial number of structure reports involving 2-styrylquinolines and their derivatives, there are no reports in the CSD of 4-styrylquinolines other than the two examples discussed above, i.e. compounds 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)-4-[2-(4-methoxyphenyl)ethenyl]-2-methylquinoline-3-carboxylate (IV)
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.

sup-19
Acta Cryst. (2020). C76, 883-890 where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max = 0.003 Δρ max = 0.35 e Å −3 Δρ min = −0.42 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.

Ethyl (E)-2-methyl-4-{2-[4-(trifluoromethyl)phenyl]ethenyl}quinoline-3-carboxylate (VI)
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.