Synthesis of a new polycyclic heterocyclic ring system. Part III. Benzo[b]imidazo[1,5-d][1,4]oxazepine-1,4(2H,5H)-diones

Introduction

Benzodiazepine and benzoxazepine ring systems are common pharmacophores, found in numerous structures with diverse biological activities. Investigations of this class of compounds started 55 years ago, when Sternbach and Reeder published their pioneering work on 1,4-benzodiazepines [1]. The discovery of 1,4-benzodiazepines has been followed by synthesis of a drug for the treatment of anxiety, sleep disorders and epilepsy [1], [2], [3]. Being structurally related to benzodiazepines, benzoxazepine derivatives have gained significant attention among several research groups [4], [5]. A number of compounds with benzoxazepine scaffolds have been described as potent antiviral [6], anticonvulsant [7] and neuroleptic [8] agents. In recent years, several tricyclic pyrrolo-1,5-benzoxazepines (PBOXs) have been studied as promising anticancer candidates due to their ability to induce microtubule depolymerization and apoptosis in numerous cell lines, e.g. human chronic myeloid leukaemia K562, ovarian carcinoma A2780 and neuroblastomas SHSY5Y and SK-N-BE(1) [9], [10], [11], [12]. Compounds PBOX-6 and PBOX-15 (Figure 1) represent the most active PBOX members with low micromolar cytotoxicity [12]. PBOX-6 has shown efficiency in an in vivo mouse mammary carcinoma model, causing the inhibition of tumor growth [13].

Figure 1

Structures of pyrrolo-1,5-benzoxazepines PBOX-6 and PBOX-15.

In continuation of our previous studies on the synthesis of imidazo[5,1-c][1,4]benzothiazines and benzo[b]imidazo[1,5-d][1,5]thiazepines [14], [15], herein we present a method for the preparation of benzo[b]imidazo[1,5-d][1,4]oxazepine-1,4(2H,5H)-diones as new heterocyclic systems. These compounds were inspired by the PBOX compounds and derived by replacing the fused pyrrole ring of the PBOX scaffold with an imidazolone.

Results and discussion

As part of our research on the design and synthesis of novel heterocyclic systems with potential biomedical applications, we developed a convenient five-step approach to tricyclic benzoxazepines containing a fused imidazolone ring. The present method involves the use of benzoxazolones as easily available starting materials that undergo a series of chemical transformations leading to the target molecules.

As depicted in Scheme 1, benzoxazolone derivatives 1–3 were allowed to react with chloroacetone in N,N-dimethylformamide in the presence of potassium carbonate and a catalytic amount of benzyltriethylammonium chloride (TEBA). The milder reaction conditions compared to previously reported methods [16] led to yields of 82%–89%. The resulting 3-(2-oxoalkyl)-benzoxazolones are known to undergo ring transformation to 1-(2-hydroxyphenyl)-3,4-disubstituted-2-imidazolones in the presence of nucleophiles such as primary amines [17], [18]. Therefore, the reaction of compounds 4–6 with methylamine or benzylamine under reflux in n-propanol or 2-methoxyethanol, respectively, led to the formation of imidazolone derivatives 7–12. In the next step, compounds 7–12 were treated with ethyl bromoacetate under basic conditions, yielding esters 13–18 quantitatively. The corresponding carboxylic acids 19–24 were obtained after alkaline hydrolysis of the ester group. Intramolecular acylation of these compounds led to target products 25–30. The intramolecular acylation of 19 was tested under various reaction conditions. No product formation was observed when conducting the reaction in sulfuric acid at room temperature or in a mixture of sulfolane/polyphosphoric acid. The same results were observed at higher temperature (80°C). The use of Eaton’s reagent (P₂O₅-CH₃SO₃H) as a reaction medium at 80°C led to the formation of the desired product at 63% yield after 5 h. The best yield (78%) was achieved in polyphosphoric acid (PPA) at 120°C for 2 h, and these conditions were chosen for the acylation of the series of carboxylic acids 19–24. Due to the powerful catalytic and dehydrating properties of the PPA [19], the reaction proceeds via formation of the mixed anhydride, followed by acylation of the imidazolone fragment at position 5, thus forming the seven-membered oxazepine ring.

Scheme 1

Synthesis of benzo[b]imidazo[1,5-d][1,4]oxazepine-1,4(2H,5H)-diones.

The structure of target tricyclic benzoxazepines with fused imidazolone ring was confirmed by spectroscopic techniques. Two carbonyl bands at 1700 cm⁻¹ and 1650 cm⁻¹ are observed in the IR spectra of compounds 25–30, corresponding to the CO group in the imidazolone ring and the carbonyl group of the oxazepine moiety. In the ¹H NMR spectra of compounds 19–24, the methyl doublet appears at 1.96–2.04 ppm and the corresponding singlet for 25–30 is shifted downfield to 2.44–2.52 ppm. The intramolecular cyclization of 19–24 leading to the formation of a benzoxazepine scaffold is confirmed by the disappearance of the characteristic signal of imidazole-H5 (at 6.45–6.51 ppm in 19–24) in the proton spectra of the final products 25–30. The singlet for the methylene protons of the carboxylic acids is shifted from 4.78–4.81 ppm to 4.58–4.62 ppm in the benzoxazepines. The corresponding ¹³C NMR signals are shifted from 64.8–65.3 ppm to 78.9–79.5 ppm. The carbonyl carbon signals can be seen at 169.4–170.0 ppm in the starting acids and at 188.9–189.6 ppm in the final compounds.

Experimental

Melting points were determined on a Böetius hot-stage microscope and are uncorrected. IR spectra were recorded on a Specord 75 or Thermo Scientific Nicolet iS10 spectrophotometer. ¹H NMR and ¹³C NMR were obtained on Bruker DRX 300, Bruker DRX 400 and Bruker DRX 500 spectrometers. Chemical shifts are reported relative to the solvent peak. Elemental analyses (C, H, N) were carried out on a Vario III microanalyzer. Thin-layer chromatography (TLC) was carried out on silica gel plates (Merck 60 F₂₅₄), using n-heptane/ethyl acetate (7:3 v/v), toluene/chloroform/ethyl acetate (3:1:1 v/v) or chloroform/methanol (9:1 v/v) as eluent. Column chromatography was performed with a Merck 60 silica gel (0.040–0.063 mm, 230–400 mesh).