Synthesis and crystal structures of three novel benzimidazole/benzoindolizine hybrids

1 Introduction

The aim of numerous research programs is the discovery of new methods of heterocyclic ring formation because several biological active compounds contain a heterocyclic moiety as a fundamental subunit [1]. Indolizines are aromatic organic compounds containing two condensed rings (5- and 6-membered) and a bridging nitrogen atom. It forms the structural core of a variety of alkaloids such as swainsonine and monomorine, which were prepared for different reasons [2–4]. These molecules have found in various pharmaceutical applications as anti-tuberculosis [5], analgesic [6], antitumor [7], antiviral agents [8, 9] and as histamine H₃ receptor antagonists [10]. Diverse methods for the synthesis of indolizine and benzoindolizine derivatives have been reported in the literature, such as the Tschitschibabin reaction, 1,3-dipolar cycloaddition, and the intramolecular cyclization using acetic anhydride [11]. Among these methods, the 1,3-dipolar cycloaddition of azomethine ylide containing nitrogen in 6-membered ring, such as pyridine, quinoline, and isoquinoline, is one of the most important methods for the construction of the indolizine unit [12–14]. It offers the advantage of removing a few reaction steps to reach the target molecule and a simple workup. Furthermore, this method has recently been reconsidered as a one-pot multicomponent process [15, 16].

In continuation of our research interest on heteroaromatic N-ylides involving multicomponent reactions [17], we report here the synthesis and the crystal structures of three new benzimidazole/benzoindolizine hybrids obtained via 1,3-dipolar cycloaddition of dimethyl acetylenedicarboxylate (DMAD) or dimethyl maleate with 1-(2′-benzimidazolylmethyl)isoquinolinium ylide.

2 Results and discussion

N-((Benzimidazol-2-yl)methyl)-isoquinolinium chloride undergoes a dehydrohalogenation reaction in the presence of triethylamine to give the corresponding isoquinolinium ylide. The reaction of this latter with DMAD gave two types of products that were detected by TLC analysis (Scheme 1). After the usual workup, column chromatography furnished the two products, 1 and 2. The structures of the obtained compounds were established with the help of NMR spectroscopy and single-crystal X-ray diffraction analysis. The pyrrolo[2,1-a]isoquinoline 1 (Fig. 1) results from the oxidative dehydrogenation (aromatization) of the also isolated pyrroline 2, which was initially produced by 1,3-dipolar cycloaddition. The structure of 2 was established by analogy and by spectroscopic comparison with 1. The ¹H NMR spectra of 2 showed characteristic signals at δ = 5.29 (d, J = 13.5 Hz, 1H) and 4.58 ppm (d, J = 13.5 Hz, 1H), assigned to the pyrroline protons. Suitable crystals of compound 2 were obtained by recrystallization from petroleum ether-diethyl ether, and X-ray crystallographic analysis confirmed the trans relative configuration and the stereochemistry (1SR,10bSR) of the two new stereocenters (Fig. 2). Next, we investigated the addition of an activated alkene to the isoquinolium ylide. When isoquinolinium salt was treated with dimethyl maleate using triethylamine as base in chloroform, only the diastereomer 2,3-dihydropyrrolo[2,1-a]isoquinoline-1,2-dicarboxylate 3, with (2SR,3SR) configuration, was obtained in 25 % of yield. The ¹H NMR spectra of 3 showed characteristic signals at δ = 5.85 (d, 1H, J = 4.9 Hz) and 4.35 ppm (d, 1H, J = 4.9 Hz), assigned to the pyrroline protons (Scheme 1). Suitable crystals of compound 3 were obtained by recrystallization from ethyl acetate/hexane. The trans configuration and the stereochemistry (2SR,3SR) of the new stereocenters created in the cycloaddition step were confirmed by X-ray diffraction analysis (Fig. 3).

Scheme 1:

Formation of benzoindolizines derivatives 1-3.

Fig. 1:

Ortep plots of the molecular structure, hydrogen bonding interactions and crystal packing of 1. (a) The molecular structure of 1 showing the atom numbering scheme. Displacement ellipsoids are drawn at 50 % probability level. Molecule B was omitted for clarity. (b) View of weak C–H···O, C–H···N, and N–H···O interactions leading to supramolecular layers along the c axis. (c) Formation of alternating double layers parallel to (010).

Fig. 2:

Ortep plots of the molecular structure, hydrogen bonding interactions and crystal packing of 2. (a) The molecular structure of 2 showing the atom numbering scheme. Displacement ellipsoids are drawn at 50 % probability level. (b) Packing diagram of 2 viewed along the crystallographic a axis showing hydrogen bond as dashed lines (C–H···O, C–H···N, and N–H···O). (c) Part of the crystal structure of the 2 showing the ‘head-to-tail’ arrangement of molecules arranged in columns.

Fig. 3:

Ortep plots of the molecular structure, hydrogen bonding interactions and crystal packing of 3. (a) The molecular structure of 3 showing the atom numbering scheme. Displacement ellipsoids are drawn at 50 % probability level. (b) Interactions of C–H···O, C–H···N, and N–H···O hydrogen bonding, resulting in the formation of an infinite three-dimensional network. (c) A diagram of the layered crystal packing of 3 viewed down the a axis.

The molecular structures of compounds 1, 2, and 3 along with the atomic numbering schemes are shown in Figs. 1, 2, and 3, respectively.

Compound 1, C₂₃H₁₇N₃O₄, crystallizes in the triclinic crystal system (space group P1) (Table 1, Fig. 1a). There are two independent but very similar molecules in the asymmetric unit. The benzo-fused indolizine ring in both molecules is close to planar, with a maximum deviation of 0.136(2) Å (molecule A) and –0.123(2) Å (molecule B). The dihedral angles between the mean planes of the benzo-fused indolizine ring [N(1A)/C(3A)–C(12A)/C(13A)–C(14A)] and the two carbonyl groups [C(14A)–C(15A)/O(4A)/O(3A)] and [C(3A)–C(2A)/O(2A)/O(1A)] are 42.92(7) and 53.75(6)° in molecule A, respectively. In molecule B, the corresponding dihedral angles between [N(1B)/C(3B)–C(12B)/C(13B)–C(14B)] and the two carbonyls groups [C(14B)–C(15B)/O(4B)/O(3B)] and [C(3B)–C(2B)/O(2B)/O(1B)] are 42.51(5)° and 55.41(6)°, respectively. The carbonyl bond lengths C(15A)–O(4A) [1.207(2) Å], C(2A)–O(1A) [1.199(2) Å] (molecule A) and C(15B)–O(4B) [1.214(3) Å], C(2B)–O(1B) (1.203 Å) (molecule B), show a typical double-bond character. The C–N bonds, N(1A)–C(12A) [1.408(2) Å], N(1A)–C(13A) [1.385(3) Å], N(1A)–C(4A) [1.395(2) Å] (molecule A), N(1B)–C(12B) [1.408(3) Å], N(1B)–C(13B) [1.391(2) Å], N(1B)–C(4B) [1.392(3) Å] (molecule B), indicate partial double-bond character (Table 2). In the crystal, both molecules A and B are stabilized by intramolecular C–H···O hydrogen bonding interactions (Fig. 1b, Table 3) and packed with strong intermolecular C–H···N, N–H···O, and C–H···O hydrogen bond interactions for both molecules A and B. The packing of the molecules in the crystal can be described as double layers parallel to the (010) plane along to the b axis (Fig. 1c). The crystal structure is also supported by weak intermolecular Cg···Cg (π-π stacking) interactions between a pyrrole ring and the two aromatic rings of the isoquinoline moiety. Additional C–H···π interactions are observed for both molecules A and B (Table 4).

Compound 2, C₂₃H₁₉N₃O₄, crystallizes in the centrosymmetric space group P2₁/a with Z = 4 (Fig. 2a). The X-ray crystallographic analysis confirmed the trans relative configuration (rel-(1R,10bR)). In the crystal, both enantiomers are present in equal amounts. The benzo-fused dihydroindolizine ring is less planar compared with 1, with a maximum deviation of –0.575(2) Å. The benzimidazole ring is almost planar, compared with compound 1, with a maximum deviation of –0.006(2) Å. The carbonyl group [C(20)/O(1)–O(2)], attached to C(11), forms a dihedral angle of 3.61(11)° with the plane defined by N(1) and C(10)–C(12) atoms, whereas the second carbonyl group [C(22)/O(3)–O(4)], attached to the C10 atom, is rotated by 83.75(20)° out of the same plane. The C(22)=O(3) bond shows a typical double-bond character with bond lengths of 1.205(2) Å, whereas the C(20)=O(1) bond length (1.224(2) Å) is longer than the average bond length (1.200 Å), which is possibly due to the existence of resonance in this part of the pyrroline ring. The C–N bonds N(1)–C(12) [1.384(2) Å] and N(1)–C(1) [1.394(2)] Å indicate partial double-bond character, whereas the bond length N(1)–C(9) [1.481(2) Å] shows single-bond character (Table 2). The methyl hydrogen atoms of carbomethoxy group are in disordered positions. The packing of the molecules in the crystal can be described as an alternating layer parallel to the (–201) plane (Fig. 2c). The crystal structure is stabilized by C–H···π interactions and intermolecular C–H···O hydrogen bonds forming a dimer (Fig. 2b, Table 3). C–H···N, C–H···O, and N–H···O intermolecular interactions bonds also exist. The crystal structure is also stabilized by π-π stacking interactions between phenyl rings of the isoquinoline moiety with a centroid-to-centroid distance of 3.844(1) Å.

Compound 3, C₂₃H₁₉N₃O₄, crystallizes in the monoclinic crystal system (space group P2₁/c) with Z = 4 (Fig. 3a). Owing to the centrosymmetric space group, the crystal contains two enantiomers. The X-ray crystallographic analysis confirmed the trans configuration of the pyrroline unit with (2R,3R) configuration for one enantiomer and (2S,3S) configuration for the other. The benzimidazole ring is almost planar, compared with compounds 1 and 2, with a maximum deviation of –0.011(2) Å. The benzo-fused dihydroindolizine ring is more planar as compared with 2 with maximum deviation of –0.116(2) Å. The dihedral angle between the mean planes of the benzo-fused dihydroindolizine ring [N(1)/C(3)–C(4)/C(14)–C(23)] and benzimidazole group [N(2)/N(3)/C(5)–C(11)] is 78.82°. The carbonyl group [C(13)/O(1)–O(2)], attached to C(14), forms a dihedral angle of 7.86(14)° with the plane of the pyrroline unit defined by N(1), C(4), and C(14)–C(15) atoms, whereas the second carbonyl group [C(2)/O(3)–O(4)] attached to the C3 atom is rotated by 78.93(15)° out of the same plane. The C(2)=O(3) bond show a typical double-bond character with bond lengths of 1.183(2) Å, whereas the C(13)=O(1) bond length, 1.219(2) Å, is longer than the average bond length (1.200 Å), which is possibly due to the existence of resonance in this part of the pyrroline ring. The C–N bonds [N(1)–C(15), 1.385(2) Å, and N(1)–C(23), 1.369(2) Å] indicate a partial double-bond character, whereas the bond length [N(1)–C(4) 1.463(2) Å] shows a single-bond character (Table 2). The large difference between the ³J(H, H) coupling constants for the pyrroline proton signals in compounds 2 [³J(H(9), H(10)) = 13.5 Hz] and 3 [³J(H(3), H(4)) = 4.9 Hz] is justified by the difference in the torsion angles [H(9)–C(9)–C(10)–H(10) = 145.17(1)° in compound 2 and H(3)–C(3)–C(4)–H(4) 110.44(2)° in compound 3]. The packing of the molecules in the crystal can be described as layers in zigzag parallel to the (001) plane along the b axis (Fig. 3c). It is stabilized by the intermolecular C–H···O, C–H···N, and N–H···O hydrogen bonding interactions (Table 3, Fig. 3b). A weak intermolecular Cg···Cg (π-π stacking) interactions between the pyrrole ring and the two aromatic rings of isoquinoline moiety are also present. The carbomethoxy group forms a C–H···π contact to an adjacent imidazole ring, with an H···centroid distance of 2.90 Å (Table 4).

3 Conclusion

The heterocyclic compounds 1–3 were synthesized by the cycloaddition reaction of N-((benzimidazol-2-yl)methyl)-isoquinolinium chloride in the presence of DMAD or dimethyl maleate as dipolarophile. The X-ray crystallographic characterization shows the formation of a 5-membered ring between the pyridine ring and the methylene group. The NMR spectra of compounds 1, 2, and 3 are in full agreement with the crystal structures. X-ray diffraction analysis also revealed that the crystal structures of the three compounds are stabilized by weak C–H···N, C–H···O, and N–H···O hydrogen bond interactions.

4 Experimental section

All chemical reagents and solvents were of analytical grade and were used as received. ¹H NMR and ¹³C NMR spectra were recorded on Varian Mercury 300 spectrometers. 2-((1H-benzo[d]imidazol-2-yl)methyl) isoquinolinium chloride was synthesized following a modified literature procedure [18] starting from isoquinoline.