Diethyl 3-(4-Bromobenzoyl)-7-(4-pyridyl)indolizine-1,2-dicarboxylate

Abstract

The title compound, C₂₆H₂₁BrN₂O₅ (Compound 4), was obtained via our previously described procedure with modifications, i.e., via a facile one-pot three component reaction starting from commercially available materials. Compound 4 was crystallized from nitromethane. It crystalized in a triclinic crystal system, in the P-$\overline{1}$ space group. The crystal structure of 4 is described herein. Hirsfeld surface analysis, generated by the Crystal Explorer 21 software, was used to visualize the intermolecular close contacts in the title compound. The electrostatic, dispersion, and total energies in the crystal structure were calculated using the same program.

1. Introduction

Pyrrolo [1,2-a]pyridine, commonly known as indolizine, is a N-bridgehead fused ring system resulting from the fusion of pyridine with pyrrole. The numbering of the atoms from the indolizine scaffold is presented in Figure 1.

Indolizine derivatives exhibit significant biological and optical properties and, as a consequence, have been the subject of various reviews [1,2,3,4,5,6]. Notably, hydrogenated indolizine derivatives are naturally occurring compounds with remarkable biological activities [7,8,9]. There are two main strategies for the synthesis of indolizines: syntheses starting from substituted pyrroles, and synthetic methods starting from pyridine and its derivatives [1,2,3,4,5,6,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26]. Notably, 1,3-dipolar cycloaddition reactions between pyridinium N-ylides and acetylenic or olefins are among the most efficient synthetic procedures for the synthesis of indolizine and azaindolizine derivatives [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27]. Herein, we report the synthesis—by one-pot three-component reaction—and crystal structure of diethyl 3-(4-bromobenzoyl)-7-(4-pyridyl)indolizine-1,2-dicarboxylate (Compound 4).

2. Results and Discussion

2.1. Structural Commentary

Compound 4 was previously obtained by us in two steps, starting from commercially available materials [25]. In the present work, the synthesis of the same compound was achieved by a novel procedure comprising a one-step three-component reaction (Scheme 1). The synthesis was performed by heating in 1,2-epoxybutane under reflux of the reagents 4,4′-bipyridyl (Compound 1), 2,4′-dibromoacetophenone (Compound 2), and diethyl acetylenedicarboxylate (Compound 3) (Scheme 1). The purity of the crude compound was confirmed by NMR spectroscopy (Figures S1 and S2).

Crystals of 4 that were suitable for single-crystal X-ray structural analysis were obtained by crystallization from a nitromethane solution. Compound 4 crystallizes in the triclinic P-1 space group with one molecule in the asymmetric unit. The molecular structure of 4 is shown in Figure 2. To compare the structure of 4 with those of other similarly substituted indolizine derivatives, we conducted a survey of the Cambridge Structural Database [28]. Our search yielded crystal structures of 13 indolizine derivatives with carbomethoxy or carboethoxy groups in positions 1 and 2 and a benzoyl group, substituted or unsubstituted, in position 3 [29]. In these derivatives, the C1=O1 group of the benzoyl substituent is always oriented towards C20-H20, forming a short intramolecular H20···O1 contact of ca. 2.30 Å. The benzoyl group is slightly rotated around the bond to the indolizine system, with the absolute value of the N1-C8-C1-O1 torsion angle in the range of 5.5–24.6° if the 5 position of the indolizine is left unsubstituted. In 4, the short H20···O1 contact was 2.34 Å and the N1-C8-C1-O1 torsion angle was 21.5 (4)°. The carboalkoxy group in position 1 of the indolizine system was also slightly twisted with respect to the plane of aromatic heterocycle and adopted two alternative arrangements, with the carbonyl or alkoxy group being oriented towards C12-H12. In both cases, short contacts were formed, i.e., H12···O4 or H12···O5 (2.33–2.55 Å), and in the analyzed crystal structures, the population of these two alternative orientations was almost the same. In the crystal structure of 4, the carboethoxy group in position 1 had its carbonyl group oriented towards H12 with a H12···O4 distance of 2.48 Å. This group was almost coplanar, with an indolizine aromatic system with a torsion angle C11-C10-C22-O4 of −5.1 (5)°. In turn, the carboalkoxy group in position 2, due to steric overcrowding, had to be strongly twisted with respect to the aromatic ring. The absolute value of the C8-C9-C21-O2 torsion angle was close to 70 or 110°, depending on the orientation of the carboalkoxy group. In 4, the value of this torsion angle was −71.1 (4)°. The nearly perpendicular orientation of the two carboethoxy substituents led to a short intramolecular contact between C21 and O5 or O4, with the mean value of 2.76 Å when the C8-C9-C21-O2 torsion angle was about 70° and 2.92 Å when this torsion angle was about 110°. In 4, the intramolecular contact C21···O5 was 2.786 Å. The pyridine substituent in position 7 of the indolizine system was only slightly twisted, forming a dihedral angle of 7.5 (3)° with the fused-ring system.

The crystal packing of 4 was found to be mostly driven by π···π stacking interactions between inversion center related molecules which organized themselves into infinite stacks aligned parallel to the a axis. These interactions occurred between the indolizine aromatic systems (interplanar distance 3.487 Å) and the indolizine system and the pyridine substituent (centroid-to-centroid distance 3.621 Å). These stacks were additionally stabilized by C-H···N interactions (H···N2ⁱ = 2.464 (3) Å, C7···N2ⁱ = 3.393(4) Å, C7-H-N2ⁱ = 177°, symmetry code (i): 2 − x, − y, 1 − z). There were two contacts between molecules in the adjacent stacks that were shorter than the sum of the van der Waals radii, i.e., C16-H16···O1ⁱ interactions (H···Oⁱ = 2.565 (2), C···Oⁱ = 3.489 (4) Å, C-H···Oⁱ = 172°, symmetry code (i): 1 + x, 2 + y, −z) and C24-H24A···Br1ⁱ interactions (H···Brⁱ = 2.947 (5) Å, C···Brⁱ = 3.804 (4) Å, C-H···Brⁱ = 149°, symmetry code (i): 1 − x, 2 − y, −z).

The crystal packing of the molecules was driven by several hydrogen bonds. A supramolecular dimer between two neighboring molecules formed through N···H-C bonds, where the nitrogen atom belongs to the pyridine moiety and the hydrogen atom comes from the bromobenzene moiety (Figure 3). Bromine was also involved in hydrogen bonds with a neighboring methyl group, Br···H-C = 2.947 (5) (Br···C = 3.804 (4) Å), Br-H-C = 149.2°, creating another supramolecular dimer. Also, the carbonyl unit linking the phenyl unit with indolizine was involved in a short contact with the pyridine neighboring unit. Additionally, π-π interactions were formed between pyridine and indolizine rings (Figure 3). A list of bond distances for 4 is presented in Table S1.

A search in the Cambridge Crystallographic Database (CSD) showed only two structures with a 7-pyridylindolizine framework with refcodes QATJAX [26] and TOMDUW [27], respectively. The similarities arose from the same hydrogen bonds they established on the one hand while, on the other hand, it was observed that the bulk of the substituent on the indolizine unit was correlated with the torsion angle between the pyridine and indolizine moieties and with the absence or presence of the π-π interactions. The representative lengths and angles are comparatively represented in

Table 1. Selection of short contacts present in the crystal structures of 4, TOMDUW, and QATJAX.

Compound	4	TOMDUW	QATJAX
(Py)N···H-C (Å)	2.464 (3)	2.734 (3)	2.737 (2)
(Py)N-H-C (°)	177.3 (3)	146.5 (2)	172.9 (2)
C-H···O(carbonyl) (Å)	2.796 (2)	2.706 (2)	2.741 (2)
C-H-O(carbonyl) (°)	171.6 (2)	144.9 (2)	145.2 (2)
π-π interactions—centroid-centroid (Å)	3.86	3.78	-
Py-indolizine torsion angle (°)	8.4 (4)	0.6 (4)	22.7 (3)
Reference	This work	[26]	[27]

where TOMDUW = ethyl 3-cyano-7-(pyridyl)indolizine-1-carboxylate; QATJAX = (1-benzoyl-2-phenyl-7-(pyridin-4-yl)indolizin-3-yl)(4-methoxyphenyl)methanone; Py = pyridine.

.

2.2. Hirshfeld Surface Analysis

Hirshfeld surface analysis is a very useful tool used for the visualization of intermolecular contacts that are shorter than the sum of van der Waals radii. In the present work, Hirshfeld surface (HS) and energy frameworks were performed using Crystal Explorer 21 [30]. The two-dimensional fingerprints plots derived from the HS analysis (Figure 4) supported the role of various intermolecular forces, such as N···H, O···H and Br···H interactions, in terms of contributing to the molecular stability and organization within the crystal.

Figure 5 depicts the HS plotted over d_norm and the shape index for 4. HS analysis is commonly used to highlight intermolecular close contacts, represented as red spots [31], while the shape index serves as a valuable tool for enhancing the complementarity between two molecules [24]. In the HS analysis, six red spots corresponded to intermolecular interactions N···H, O···H, and Br···H and their reciprocal interactions are enhanced in Figure 5a,b. As was previously mentioned, the similarities between 4 and the two structures with a 7-pyridylindolizine frameworks from literature with refcodes QATJAX [26] and TOMDUW [27] are due to the same hydrogen bonds they established (Figure S3). The shape index visualization in Figure 5c clearly indicates the presence of π-π interactions, as shown by the red triangles. For enhanced visibility, these red triangles are encircled with black circles in Figure 5d.

The energy frameworks generated at the HF/3-21 level for a cluster within a radius of 3.8 Å indicated that the primary contribution came from π-π stacking interactions (Figure S4).

3. Materials and Methods

X-Ray Crystallography

Single-crystal X-ray diffraction data were collected by a XtaLAB Synergy, Dualflex, and a HyPix diffractometer using Mo Kα radiation. The unit cell determination and data integration were carried out using the CrysAlisPro package from Oxford Diffraction [32]. Multi-scan correction for absorption was applied. The structure was solved with the SHELXT program using the intrinsic phasing method and refined by the full-matrix least-squares method on F² with SHELXL [33,34]. Olex2 was used as an interface to the SHELX programs [35]. An anisotropic model was used for the refinement of non-hydrogen atoms. Hydrogen atoms were added in idealized positions and refined using a riding model. Selected crystallographic data and structure refinement details are provided in Table S2 and the corresponding CIF files. The supplementary crystallographic data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; (Tel: (+44) 1223 336 408; Fax: (+44) 1223-336-033; or deposit@ccdc.cam.ac.uk; http://www.ccdc.cam.ac.uk).

4. Experimental

Synthesis of diethyl 3-(4-bromobenzoyl)-7-(4-pyridyl)indolizine-1,2-dicarboxylate (Compound 4): 4,4′-Bipyridyl (Compound 1) (3 mmol), 2,4′-dibromoacetophenone (Compound 2) (3 mmol), and diethyl acetylenedicarboxylate (Compound 3) (3.5 mmol) were stirred under reflux in 20 mL 1,2-epoxybutane for 10 hrs. The 1,2-epoxybutane was removed in vacuum and the residue was triturated with ethanol before the precipitate was filtered. The resulting Compound 4 was purified by crystallization from nitromethane solution, yielding yellow crystals. Yield: 61%.

5. Conclusions

The crystal structure of diethyl 3-(4-bromobenzoyl)-7-(4-pyridyl)indolizine-1,2-dicarboxylate has been described. The compound was synthesized using an efficient, one-pot synthesis using commercially available materials.