An efficient green synthesis of 5H-spiro[benzo[4,5]imidazo[1,2-c]quinazoline-6,3′-indolin]-2′-ones catalyzed by iodine in ionic liquids

Introduction

Pantoprazole [1] and mizolastine [2] are benzimidazole derivatives for the treatment of peptic ulcer disease (Figure 1). They are also effective proton-pump inhibitors. Gefitinib [3] and erlotinib [4] are quinazoline drugs used in the treatment of lung and breast cancers, respectively.

Figure 1

Drugs bearing benzimidazole or quinazoline moieties.

To the best of our knowledge, little effort has been devoted to the synthesis of benzimidazoquinazolines in the past few years [5], [6], [7], [8]. The main approach to the construction of such compounds is the condensation of 2-(1H-benzo[d]imidazol-2-yl)aniline with different carbonyl compounds, such as aldehydes, ketones and isatins [9], [10], [11], [12], [13]. The reaction with isatin [12], [13] provides a benzimidazoquinazoline which is part of a spirocyclic indole system. In our recent study, benzene-1,2-diamine was allowed to react with 2-nitrobenzaldehyde in EtOH, and the mixture was then treated with hydrazine hydrate in the presence of Fe(C) to give 2-(1H-benzo[d]imidazol-2-yl)aniline (1). In this paper, we describe an efficient synthesis of 5H-spiro[benzo[4, 5]imidazo[1,2-c]quinazoline-6,3′-indolin]-2′-ones 3a–l by the reaction of 1 and isatins 2 in the presence of iodine (a Lewis acid catalyst) in ionic liquid 1-butyl-3-methylimidazolium bromide ([BMIm]Br). This is a continuation of our research devoted to the development of new methods for the preparation of heterocyclic compounds catalyzed by iodine in ionic liquids [14], [15], [16].

Results and discussion

In the synthesis of 3a, it was found that the use of [BMIm]Br gave the best result (78%) for the reaction conducted at 50°C in the presence of 1 mol% iodine. Other ionic liquids, including 1-propyl-3-methylimidazolium bromide ([PMIm]Br), 1-ethyl-3-methylimidazolium bromide ([EMIm]Br), [BMIm]BF₄, [PMIm]BF₄ and [EMIm]BF₄, all afforded 3a in slightly lower yields. In the screening of the catalyst amount, the use of 5 mol% iodine increased the yield to 86%, but larger amounts of iodine did not improve the yield. An increase in the reaction temperature to 80°C resulted in an increase of the yield to 89%. Subsequently, compounds 3b–l (Scheme 1) were obtained in high yields of 86–91% by the reaction of substituted isatins including 4-Cl, 5-Me, 6-Br, 7-F and 4,6-dichloro derivatives under similar reaction conditions.

For the structure confirmation, a single crystal of 3i was obtained from a mixture of DMF, EtOH and water and used for X-ray diffraction analysis [17]. There are two molecules of 3i, two molecules of DMF and a molecule of EtOH in a cell unit. To observe the structure of 3i clearly, only a single molecule of 3i is shown in Figure 2, while other molecules including the solvents have been deleted for clarity.

Figure 2

The crystal molecular structure of 3i.

The X-ray diffraction analysis indicates that the pyrimidine moiety adopts a half-chair conformation. The atoms N2, C7, C8, C13 and N3 are coplanar, while the atom of C14 deviates from the defined plane by 0.399(2) Å. Other moieties including benzimidazole, benzene (C8~C13) and indole are all flat structures, and the mean deviations are 0.018(2), 0.009(2) and 0.018(2) Å, respectively. The pyrimidine ring is approximately parallel to the benzimidazole and benzene (C8~C13) rings, forming the dihedral angles of 6.3(1)° and 0.1(1)°, respectively. The pyrimidine is largely perpendicular to the indole ring, forming a dihedral angle of 88.3(1)°.

Scheme 1

Iodine-catalyzed synthesis of 3 in ionic liquid.

Conclusion

Iodine is an efficient catalyst for the synthesis of spiro[benzo[4,5]imidazo[1,2-c]quinazoline-6,3′-indolin]-2′-one derivatives in an ionic liquid. Comparing other methods, the developed procedure has the advantages of high yields and mild conditions and is environmentally benign.

Experimental

Melting points were determined in open capillaries and are uncorrected. IR spectra were recorded on a Tensor 27 spectrometer in KBr pellets. ¹H NMR spectra were obtained at 400 MHz in a solution in DMSO-d₆ with Me₄Si as an internal standard using a Bruker-400 spectrometer. HR-MS analyses were carried out using a Bruker-micro-TOF-Q-MS analyzer.