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.

Abstract

Structures are reported for two matched sets of substituted 4-styryl­quino­lines which were prepared by the formation of the heterocyclic ring in cyclo­condensation reactions between 1-(2-amino­phen­yl)-3-aryl­prop-2-en-1-ones with 1,3-dicarbonyl com­pounds. (E)-3-Acetyl-4-[2-(4-meth­oxy­phen­yl)ethen­yl]-2-methyl­quino­line, C₂₁H₁₉NO₂, (I), (E)-3-acetyl-4-[2-(4-bromo­phen­yl)ethen­yl]-2-methyl­quino­line, C₂₀H₁₆BrNO, (II), and (E)-3-acetyl-2-methyl-4-{2-[4-(tri­fluoro­meth­yl)phen­yl]ethen­yl}quino­line, C₂₁H₁₆F₃NO, (III), are isomorphous and in each structure the mol­ecules are linked by a single C—H⋯O hydrogen bond to form C(6) chains. In (I), but not in (II) or (III), this is augmented by a C—H⋯π(arene) hydrogen bond to form a chain of rings; hence, (I)–(III) are not strictly isostructural. By contrast with (I)–(III), no two of ethyl (E)-4-[2-(4-meth­oxy­phen­yl)ethen­yl]-2-methyl­quino­line-3-carboxyl­ate, C₂₂H₂₁NO₃, (IV), ethyl (E)-4-[2-(4-bromo­phen­yl)ethen­yl]-2-methyl­quino­line-3-carboxyl­ate, C₂₁H₁₈BrNO₂, (V), and ethyl (E)-2-methyl-4-{2-[4-(tri­fluoro­meth­yl)phen­yl]ethen­yl}quino­line-3-carboxyl­ate, C₂₂H₁₈F₃NO₂, (VI), are isomorphous. The mol­ecules of (IV) are linked by a single C—H⋯O hydrogen bond to form C(13) chains, but cyclic centrosymmetric dimers are formed in both (V) and (VI). The dimer in (V) contains a C—H⋯π(pyrid­yl) hydrogen bond, while that in (VI) contains two independent C—H⋯O hydrogen bonds. Comparisons are made with some related structures, and both the regiochemistry and the mechanism of the heterocyclic ring formation are discussed.

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 (Meléndez et al., 2020 ▸), in which the heterocyclic ring of the quino­line unit is built in situ using a cyclo­condensation reaction between a 2′-amino­chalcone, (A), and a 1,3-dicarbonyl com­pound (cf. Scheme 1). The chalcone com­ponent in this type of cyclization is readily accessible by reaction between 2′-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-2,4-dione as the dicarbonyl com­ponent, while the 3-carboeth­oxy derivatives, com­pounds (IV)–(VI) (Figs. 4 ▸–6 ▸ ▸), 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 mol­ecular 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 (Meléndez et al., 2020 ▸)] but without any structure description or discussion; accordingly, we discuss here the supra­molecular assembly in these two com­pounds.

Figure 1.

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

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 4.

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

Figure 5.

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

Figure 6.

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

Experimental  

Synthesis and crystallization  

Samples of com­pounds (I)–(VI) were prepared and crystallized following a recently published procedure (Meléndez 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 01 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 (CH₃) or 0.99 Å (CH₂), 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 com­pounds (VII) and (VIII), the published structures (Meléndez et al., 2020 ▸) were inverted and the atom labelling adjusted slightly in order to bring them into full conformity with com­pounds (I)–(VI) (cf. Tables 2 ▸ and 3 ▸); the modified versions of the CIFs for (VII) and (VIII) are provided in the supporting information. Examination of the structure for (VIII) using PLATON (Spek, 2020 ▸) showed that the unit cell contains two voids, each of volume 60 ų and centred at (0, , 0) and (, 0, ), but further examination using SQUEEZE (Spek, 2015 ▸) showed that these voids contained negligible electron density.

Table 1. Experimental details.

Experiments were carried out at 100 K with Mo Kα radiation using a Bruker D8 Venture diffractometer. Absorption was corrected for by multi-scan methods (SADABS; Bruker, 2016 ▸). H-atom parameters were constrained.

	(I)	(II)	(III)
Crystal data
Chemical formula	C21H19NO2	C20H16BrNO	C21H16F3NO
M r	317.37	366.24	355.35
Crystal system, space group	Monoclinic, P21/c	Monoclinic, P21/c	Monoclinic, P21/c
a, b, c (Å)	8.2595 (4), 6.4279 (3), 31.9064 (14)	8.0849 (3), 6.6692 (2), 31.1063 (10)	8.0822 (4), 6.6567 (4), 32.1024 (17)
α, β, γ (°)	90, 93.674 (2), 90	90, 95.005 (1), 90	90, 90.576 (2), 90
V (Å3)	1690.47 (14)	1670.85 (10)	1727.05 (16)
Z	4	4	4
μ (mm−1)	0.08	2.46	0.11
Crystal size (mm)	0.23 × 0.16 × 0.09	0.17 × 0.11 × 0.04	0.20 × 0.08 × 0.06
Data collection
T min, T max	0.947, 0.993	0.810, 0.906	0.942, 0.994
No. of measured, independent and observed [I > 2σ(I)] reflections	39800, 4197, 3528	38342, 3839, 3434	19648, 3959, 3363
R int	0.051	0.034	0.032
(sin θ/λ)max (Å−1)	0.668	0.650	0.650
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S	0.040, 0.111, 1.06	0.030, 0.073, 1.03	0.041, 0.101, 1.04
No. of reflections	4197	3839	3959
No. of parameters	220	210	237
Δρmax, Δρmin (e Å−3)	0.33, −0.23	0.56, −0.76	0.28, −0.23

	(IV)	(V)	(VI)
Crystal data
Chemical formula	C22H21NO3	C21H18BrNO2	C22H18F3NO2
M r	347.40	396.26	385.37
Crystal system, space group	Triclinic, P	Monoclinic, P21/n	Triclinic, P
a, b, c (Å)	9.5301 (8), 10.3513 (8), 10.3621 (8)	9.5709 (6), 10.6119 (7), 18.2074 (10)	8.7465 (10), 9.9436 (11), 11.1116 (11)
α, β, γ (°)	65.374 (3), 86.583 (3), 76.376 (3)	90, 90.939 (2), 90	105.446 (4), 99.763 (4), 97.204 (4)
V (Å3)	902.23 (13)	1849.0 (2)	903.08 (17)
Z	2	4	2
μ (mm−1)	0.09	2.24	0.11
Crystal size (mm)	0.30 × 0.12 × 0.05	0.25 × 0.18 × 0.15	0.27 × 0.20 × 0.18
Data collection
T min, T max	0.954, 0.996	0.595, 0.715	0.954, 0.980
No. of measured, independent and observed [I > 2σ(I)] reflections	44489, 4158, 3440	54534, 4588, 4098	59876, 4491, 3692
R int	0.053	0.041	0.042
(sin θ/λ)max (Å−1)	0.650	0.667	0.667
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S	0.052, 0.128, 1.07	0.022, 0.056, 1.02	0.044, 0.120, 1.05
No. of reflections	4158	4588	4491
No. of parameters	238	228	255
Δρmax, Δρmin (e Å−3)	0.36, −0.21	0.35, −0.42	0.43, −0.43

Computer programs: APEX3 (Bruker, 2018 ▸), SAINT (Bruker, 2017 ▸), SHELXT2014 (Sheldrick, 2015a ▸), SHELXL2014 (Sheldrick, 2015b ▸) and PLATON (Spek, 2020 ▸).

Table 2. Selected torsion angles (°) for com­pounds (I)–(VIII).

Compound	C3—C4—C41—C42	C41—C42—C421—C422	C2—C3—C31—O31	C2—C3—C31—O32
(I)	46.40 (16)	13.78 (18)	66.18 (15)
(II)	46.8 (3)	14.8 (3)	68.2 (2)
(III)	49.0 (2)	13.0 (2)	69.52 (18)
(IV)	48.8 (2)	1.2 (3)	73.7 (2)	−104.85 (17)
(V)	51.4 (2)	10.6 (2)	−102.56 (17)	75.88 (15)
(VI)	34.8 (2)	−17.7 (2)	−99.75 (16)	76.46 (15)
(VII)	51.0 (5)	2.0 (5)	71.5 (4)
(VIII)	54.17 (19)	−4.0 (2)	−97.59 (15)

Table 3. Hydrogen bonds and short intra­molecular contacts (Å, °) for com­pounds (I)–(VIII).

Cg1, Cg3, Cg4 and Cg5 represent the centroids of the N1/C2–C4/C4A/C8A, C421–C426, C311–C316 [present in (VII) only] and C331–C336 [present in (VIII) only] rings, respectively; ring 2 com­prises atoms C4A/C5–C8/C8A.

	D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
(I)	C41—H41⋯O31i	0.95	2.41	3.2527 (15)	148
	C426—H426⋯Cg3ii	0.95	2.77	3.5252 (13)	138
(II)	C41—H41⋯O31i	0.95	2.37	3.283 (2)	161
	C426—H426⋯Cg3ii	0.95	2.91	3.7071 (19)	142
(III)	C41—H41⋯O31i	0.95	2.42	3.3290 (17)	161
	C426—H426⋯Cg3ii	0.95	3.00	3.7621 (15)	138
(IV)	C32—H32B⋯O424iii	0.99	2.57	3.406 (2)	142
	C423—H423⋯Cg1iv	0.95	2.91	3.4894 (19)	120
(V)	C423—H423⋯O31v	0.95	2.59	3.2197 (17)	124
	C426—H426⋯Cg1iv	0.95	2.74	3.5961 (16)	151
(VI)	C41—H41⋯O31iv	0.95	2.54	3.4922 (18)	178
	C422—H422⋯O31iv	0.95	2.56	3.3924 (19)	146
(VII)	C41—H41⋯O31vi	0.95	2.37	3.300 (5)	167
	C422—H422⋯O31vi	0.95	2.57	3.506 (4)	169
	C426—H426⋯Cg4vii	0.95	2.67	3.549 (4)	155
(VIII)	C334—H334⋯O31viii	0.95	2.61	3.542 (2)	168
	C7—H7⋯Cg5ix	0.95	2.93	3.6437 (16)	133
	C422—H422⋯Cg1x	0.95	2.93	3.6300 (17)	132

Symmetry codes: (i) x, y + 1, z; (ii) −x + 1, y − , −z + ; (iii) x + 1, y, z; (iv) −x + 1, −y + 1, −z + 1; (v) −x + , y + , −z + ; (vi) x − , y, −z + ; (vii) −x + , y − , z; (viii) x − 1, y, z; (ix) x + , −y + , z − ; (x) x + , −y + , z + .

Results and discussion  

In reactions between a chalcone of type (A) (Scheme 1) and a symmetrical 1,3-diketone, such as pentane-2,4-dione, only a single product is possible, namely, the 3-acetyl-2-methyl­quino­line derivative, as exemplified by com­pounds (I)–(III). However, a com­parable reaction involving an unsymmetrical diketone, such as 1-phenyl­butane-1,3-dione can give two regioisomers, such as (VII), if the amino group reacts at the acetyl carbonyl group, or the alternative (IX) if the reaction occurs at the benzoyl carbonyl group. In general, reactions with this ketone lead exclusively to the 3-benzoyl-2-methyl isomers, as exemplified by (VII), rather than to the 3-acetyl-2-phenyl alternative exemplified by (IX) (Meléndez et al., 2020 ▸), which is consistent with the greater reactivity in the nucleophilic addition reaction of acetyl groups com­pared with benzoyl groups (Bürgi et al., 1974 ▸; Katritzsky et al., 1995 ▸; Meléndez et al., 2020 ▸). Similarly, the reaction of a chalcone of type (A) with an unsymmetrical diketo com­pound, such as 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) (Meléndez 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 CF₃, respectively (Scheme 1 and Figs. 1 ▸–3 ▸ ▸), all crystallize in the space group P2₁/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—H⋯O and C—H⋯π(arene) contacts in all three com­pounds, involving the same sets of atoms (Table 3 ▸), in each of com­pounds (II) and (III), the H⋯Cg 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—H⋯O and C—H⋯π hydrogen bonds (Table 3 ▸). In each of (I)–(III), mol­ecules which are related by translation are linked by a C—H⋯O 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—H⋯π(arene) hydrogen bond linking mol­ecules related by the 2₁ screw axis along (, y, ) to form a chain of rings (Fig. 7 ▸). However, in the structures of (II) and (III), the corresponding H⋯Cg and C⋯Cg 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 7.

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

A single C—H⋯O hydrogen bond links the mol­ecules of com­pound (IV) which are related by translation into a C(13) chain running parallel to the [100] direction (Fig. 8 ▸). This structure also contains a short C—H⋯π(pyrid­yl) contact, but the long H⋯Cg distance and the very small C—H⋯Cg 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—H⋯O contact which has a very small D—H⋯A angle (Table 3 ▸), while a C—H⋯π(pyrid­yl) hydrogen bond links mol­ecules which are related by inversion to form a cyclic centrosymmetric dimer (Fig. 9 ▸).

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 − 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 (−x + 1, −y + 1, −z + 1).

In the structure of com­pound (VI), there are no C—H⋯π hydrogen bonds or short inter­molecular contacts. Instead two C—H⋯O hydrogen bonds combine to link inversion-related pairs of mol­ecules into centrosymmetric dimers. The hydrogen bonds involving atoms of type C41 form an (12) ring, while those involving atoms of type C422 generate an (18) ring (Fig. 10 ▸).

Figure 10.

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 (−x + 1, −y + 1, −z + 1).

We also discuss here the supra­molecular assembly of com­pounds (VII) and (VIII), which, as noted above (§1, Introduction), have been reported on a simple proof of constitution basis, without discussion (Meléndez et al., 2020 ▸). The assembly in (VII) in the space group Pbcn is based upon two C—H⋯O hydrogen bonds and one C—H⋯π(arene) hydrogen bond (Table 3 ▸). The two C—H⋯O hydrogen bonds link mol­ecules which are related by the a-glide plane at z = to form a C(6)C(9)[(7)] chain of rings running parallel to the [100] direction (Fig. 11 ▸). In addition, the structure of (VII) contains a C—H⋯π(arene) hydrogen bond which links mol­ecules which are related by the b-glide plane at x = 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 < ; a second sheet of this type, related to the first by inversion, lies in the domain < z < 1.0, but there are no direction-specific inter­actions between adjacent sheets. Even the shortest inter­molecular contacts (Table 3 ▸) in chalcone (VIII) have H⋯A distances which are probably too long for these contacts to be regarded as structurally significant.

Figure 11.

Part of the crystal structure of com­pound (VII), showing the formation of a C(6)C(9)[(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.

Figure 12.

Part of the crystal structure of com­pound (VII), showing the formation of a chain built from C—H⋯π(arene) hydrogen bonds, drawn as dashed lines, running parallel to the [010] direction. 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., 2008 ▸, 2009 ▸; Chantrapromma et al., 2008 ▸, 2014 ▸; Fun 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 rhodium-catalysed 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 (VII) and (VIII) (CSD refcodes MUMZEC and MUMZIG, respectively; Meléndez et al., 2020 ▸).

Supplementary Material

CCDC references: 2021528, 2021527, 2021526, 2021525, 2021524, 2021523

Funding Statement

This work was funded by Vicerrectoría de Investigación y Extensión de la Universidad Industrial de Santander grant 2497.