1-(2′-Benzimidazolylmethyl)-pyridinium ylide in the one-pot synthesis of indolizine and benzimidazo[1,2-a]pyridine derivatives

1 Introduction

N-Phenacylpyridinium salts have found applications as reagents in the organic synthesis of diverse classes of substances [1–3]. Their heteroanalogues, with a heterocyclic ring such as pyridine or pyrazine instead of a phenacyl group, have been used successfully to extend the classical synthesis of indolizine derivatives [4, 5]. The use of these salts offers the advantage of removing a few reaction steps to reach the target molecule and a simple workup. Furthermore, it has recently been reconsidered as a one-pot multicomponent process [6, 7].

Previously, we have reported that bicyclic mesoionic thiazolo[3,2-a]imidazole derivatives can be formed by a reaction involving carbon disulfide and imidazolium N-ylide generated in situ from N-phenacyl-2-bromoimidazolium salts, in the presence of Et₃N [8].

In continuation of our research interest in heteroaromatic N-ylides involving multicomponent reactions, we report here our results concerning the reactivity of (2′-benzimidazolylmethyl)pyridinium ylide towards both dimethyl maleate and some alkynes as dipolarophiles. Pyridone and indolizine derivatives containing a benzimidazole unit were achieved as a result of these reactions.

2 Results and discussion

In a preliminary exploratory study, a mixture of 1-[(1H-benzo[d]imidazol-2-yl)methyl] pyridinium chloride 1 (Scheme 1), which was prepared from the reaction of pyridine with 2-(chloromethyl)-1H-benzo[d]imidazole as described previously [9–11], and dimethyl acetylenedicarboxylate (DMAD) was stirred at ambient temperature using chloroform as solvent and in the presence of triethylamine for 24 h (Scheme 2).

Scheme 1:

Preparation of 1-[(1H-benzo[d]imidazol-2-yl)methyl] pyridinium chloride 1.

Scheme 2:

Formation of indolizines derivatives 2a-d.

After general workup, the obtained compound was fully characterized by ¹H, ¹³C NMR, and mass spectra. The formation of indolizine 2a was further confirmed by crystal structure determination (Fig. 1). Compound 2a comes from the dehydrogenation of the initially formed cycloadduct in air. The intermediates, dihydroindolizines and tetrahydroindolizine, were not stable enough to be isolated.

Fig. 1:

Oak ridge thermal ellipsoid plots (ORTEP) of the molecular structures of 1, 2a, 2b, 2c, 2d in the crystal and atom numbering scheme adopted (displacement ellipsoids at the 50 % probability level; H atoms with arbitrary radii; blue: nitrogen, red: oxygen, yellow: chloride).

This result clearly showed that, due to the electron withdrawing ability of the pyridinium moiety, the methylene is acidic, and a 1,3-dipolar cycloaddition of the in situ generated ylide with DMAD took place. The favorable effect of the benzimidazole substituent on the intermediate carbanion stability was confirmed by comparison with a phenyl substituent. The presence of the benzimidazole group is essential, since no adducts were reported in the literature using N-benzylpyridinium chloride.

To further extend the utility of this reaction, the reactivity of other activated dipolarophiles was explored using the same procedure. Four functionalized indolizines were successfully prepared in 30–45 % yields, and their structures were confirmed by X-ray crystallography and NMR spectroscopy (Scheme 2, Fig. 1, Tables 1 and 2).

It should be mentioned that the cyclization reactions of 1 proceed to yield 2c and 2d instead of the others possible regioisomers. The position of the ester group at the indolizine unit in compounds 2c and 2d was confirmed by the structure determinations in the solid state by X-ray diffraction (Fig. 1). It could be noted that the formation of an indolizine was not observed when pyridinium N-ylide was stirred with other alkynes, such as phenylacetylene, propyne, pentyne, or hexyne.

In the following, the crystal and molecular structure of 2a shall be described in more detail (Tables 3–5). Information on the other solid-state structures may be taken from the deposited crystallographic CIF files (see below). Compound 2a crystallizes in the monoclinic crystal system (space group P2₁/a with Z = 4). The indolizine ring is close to planarity with a maximum deviation of 0.023(1) Å at atom C(3). The benzimidazole ring is almost planar, with a maximum deviation of 0.031(1) Å at C(19) and forms a dihedral angle with the indolizine ring of 29.88(2)°. The carbonyl group (C(7)/O(3)–O(4)), attached to C(6), forms a dihedral angle of 25.83(7)° with the plane defined by the atoms N(1), C(5)–C(6), C(11)–C(12), while the second carbonyl group (C(10)/O(1)–O(2)) attached to the C(11) atom is rotated by 47.94(5)° out of the same plane. Bond lengths and angles are in the expected range [12, 13]. The C–N bonds (N(1)–C(1) 1.382(1), N(1)–C(5) 1.393(1), N(1)–C(12) 1.392(1) Å) in compound 2a indicate partial double bond character (Table 3, Fig. 2). The packing of the molecule 2a in the crystal can be described as alternating layers parallel to the (301̅) plane. It is stabilized by N–H⋯O hydrogen bonding interactions (Table 4, Fig. 2). The carbomethoxy methyl group forms a C–H⋯π contact to both imidazole and benzene rings of an adjacent benzimidazole unit. In addition, the interaction C(18)–H(18)⋯π with an approximately 3.513(1) Å distance has also been observed (Table 5). The packing is consolidated by slipped π–π stacking with a centroid-to-centroid distance of 3.593(1) between pyrrole and pyridine rings of indolizine with symmetry operation ½ + x, ½ – y, z.

Fig. 2:

View of the crystal structure of 2a in a projection along [010] showing the formation of layers parallel to the (301̅) plane of 2a. Hydrogen bonds are shown as red dashed lines (N–H⋯O) connecting these layers.

Next, we tried the utility of pyridinium N-ylide for the construction of other heterocyclic moieties. We decided to test this 1,3-dipolar addition reaction in the presence of an alkene as dipolarophile. In this regard, N-pyridinium salt 1 was treated with dimethyl maleate in the presence of triethylamine as base using chloroform as solvent (Scheme 3).

Scheme 3:

Formation of 1-oxo-benzimidazo[1,2-a]pyridine-3-carboxylate.

Surprisingly, and in contrast to the foregoing reaction results, when the pyridinium N-ylide was treated with dimethyl maleate, a polycyclic product 3 was generated in about 25 % of yield. Compound 3 was the main product which could be easily isolated and identified. The structure of 3 was unambiguously confirmed by a crystal structure determination (Fig. 3, Table 2).

Fig. 3:

ORTEP plot of the molecular structure of 3 in the crystal and atom numbering scheme adopted (displacement ellipsoids at the 50 % probability level; H atoms with arbitrary radii).

Although the exact mechanism of this reaction is not very clear, a plausible reaction course of pyridinium ylide with dimethyl maleate is proposed in Scheme 4. The 1-(1-(1H-benzo [d]imidazol-2-yl)-4-methoxy-2-(methoxycarbonyl)-4-oxobutyl)pyridinium chloride A was formed by a Michael addition reaction of pyridinium ylide to the dimethyl maleate. This intermediate undergoes an elimination reaction to generate the dimethyl 2-((1H-benzo[d]imidazol-2-yl)methylene)succinate B. This latter could be deprotonated by Et₃N giving, via a six-membered ring N-cyclization process, the corresponding 1-oxo-benzimidazo[1,2-a]pyridine derivative 3.

Scheme 4:

Proposed mechanism for the formation of 3.

3 Conclusion

In conclusion, the 1,3-dipolar cycloaddition reactions of 1-(2′-benzimidazolylmethyl)pyridinium ylide with various electron-deficient alkynes and an alkene as dipolarophiles were investigated. Thus, the corresponding substituted indolizine derivatives were obtained in the presence of activated alkynes. Unexpectedly, the reaction of pyridinium N-ylide with dimethyl maleate gave an unexpected methyl 1-oxo-benzimidazo[1,2-a]pyridine-3-carboxylate. Further investigations of these reactions using others reagents were carried out in our laboratory.

4 Experimental section

Melting points were determined on an Electrothermal Digital Melting Point Apparatus (IA9200, Electrothermal, Stone, Staffordshire, UK) and are uncorrected. ¹H NMR and ¹³C NMR spectra were recorded on a BRUKER 250 DXP (Bruker Instruments, Germany) and VARIAN Mercury 300 spectrometers (Varian Medical Systems, Palo Alto, CA, USA). Chemical shifts (δ values) are expressed in ppm. High-resolution mass spectra were recorded on an LC-MS instrument (Agilent 1200 LC-Agilent 6500 Accurate Mass) and were carried out at the Instituto de Química Orgánica General (Spanish National Research Council, CSIC, Madrid, Spain). Thin layer chromatography (TLC) was carried out on precoated Merck silica gel aluminum sheets 60 F₂₅₄.