New Short Strategy for the Synthesis of the Dibenz[b,f]oxepin Scaffold

In this report a short and efficient synthesis of the dibenz[b,f]oxepin framework through intramolecular SNAr and McMurry reactions is described. The diaryl ethers required for the McMurry reaction have been obtained in good yields under microwave-assisted conditions of the reaction of salicylaldehydes with fluorobenzaldehydes without catalysts. Application of an intramolecular McMurry reaction to the synthesized diarylethers using TiCl4/Zn in THF gave the target dibenzo[b,f]oxepin system in 53%–55% yields.


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which exhibits significant growth inhibition activity against several human cancer lines [9]. From the same plant, Kittakoop et al. have described bauhinoxepin J, which shows potent antimycobacterial and antimalarial activities, as well as tumor growth inhibitory activity, against KB cells [10]. Bulbophylol B is another interesting example isolated from Bulbophyllum kwangtungense Schlecht (fam. Orchidaceae), which displays significant cytotoxicity against human epithelial carcinoma (HeLa) and human erythromyeloblastoid leukemia (K562) cell lines [11].

bauhinoxepin A bauhiniastatin 1 bauhinoxepin J bulbophylol
Synthetic approaches to natural dibenzo[b,f]oxepins have been directed mainly to the preparation of dihydro derivatives. For example, the total synthesis of bauhinoxepin J using an intramolecular persulfate-mediated radical addition to a quinone was described by Krauss and Kim [12]. Furthermore, Katoh et al. [13] have also recently described their synthesis using the reaction of an aryllithium derivative with a phenylacetaldehyde and subsequent internal nucleophilic addition/elimination sequences as key steps. Yao et al. have described the synthesis of bulbophylol employing Wittig, selective reduction and intramolecular Ullmann reactions as key steps (18% overall yield over 12 steps) [14]. It is noteworthy that the synthesis of bauhinoxepin A and bauhiniastatin 1 are not reported, probably because the described routes to dibenzo[b,f]oxepins are multi-step procedures or require the preparation of complex starting materials [15]. Some interesting approaches have been described recently, but they are limited to the synthesis of dibenz[b,f]oxepincarboxylic acid derivatives [16,17]. In connection with our interest on the synthesis of bioactive heterocyclic quinones [18,19], herein we describe a convenient procedure for the preparation of the dibenzo[b,f]oxepin scaffold.
Retrosynthetic analysis of the tricyclic system I led us to consider two strategies (Scheme 1). Approach A, is via an intramolecular Ullmann, or nucleophilic aromatic substitution (S N Ar) reaction [20]. Path B, was envisaged through an intramolecular McMurry reaction, which has been used successfully in the synthesis of natural products [21], but there are no precedents for the preparation of dibenzo[b,f]oxepins using it, except for sulfur and selenium analogues [22].

Results and Discussion
First, we focused our research on the synthesis of a Z-stilbene. To achieve our objective, we planned to apply the Wittig reaction that gives high Z selectivity when both the ylide and benzaldehyde incorporate ortho-halo and ortho-alkoxy substituents [23,24]. Thus, Wittig reaction of o-bromobenzyltriphenylphosphonium salt 1 [23] with 2-formylphenyl-4-methylbenzene sulfonate (2) in the presence of potassium t-butoxide gave stilbene 3 (87%) as a single isomer. Attempts to obtain dibenzo[b,f]oxepin 5a directly from compound 3, by applying an intramolecular palladium-catalyzed biaryl ether formation using Pd(OAc) 2 and tri(o-tolyl)phosphine as described by Harayama et al. for an aza-analog [25] were unsuccessful. Cleavage of the p-toluenesulfonate group under standard basic conditions (KOH/EtOH-H 2 O) gave phenol 4 which was directly converted to dibenzo[b,f]oxepin 5a (72%) by treatment with cesium carbonate in DMSO at 180 °C under microwave irradiation (Scheme 2). Scheme 2. Synthesis of dibenzoxepin 5a by intramolecular S N Ar reaction. Considering the low synthetic efficiency of the Wittig process, we focused our attention on the intramolecular McMurry reaction. Therefore, we concentrated our attention on the preparation of suitable diaryl ether precursors. The synthesis of o-phenoxybenzaldehydes by Ullmann or S N Ar nucleophilic aromatic substitution reactions of salicylaldehydes with aryl halides normally requires harsh conditions, long reaction times and often gives low yields [26][27][28]. Considering the successful application of microwave irradiation to improve the nucleophilic S N Ar reaction of activated aryl halides with phenols [29], we decided to use this methodology to obtain diaryl ethers 8. Therefore, preliminary experiments were carried out in order to determine the optimal conditions for the synthesis of 8a using highly polar solvents such as DMSO or DMA and K 2 CO 3 or Cs 2 CO 3 as bases [20]. The reaction of 1.2 equivalents of 2-hydroxybenzaldehyde (6a) with 1.0 equivalent of 2-fluoro-benzaldehyde (7a) and K 2 CO 3 (2 equiv.) in DMSO using microwave irradiation over a wide temperature range was examined. The best result was obtained when the reaction was carried out at 120 °C (Table 1, entry 3) with a 73% yield of dialdehyde 8a and at higher temperatures a progressive degradation of compound 8a was observed. Similar results were obtained using DMA and Cs 2 CO 3 as solvent and base, respectively (Table 1, entry 14). Using the optimized conditions, 2-fluoro-6-(2formylphenoxy)-benzaldehyde (8b) and 2-(2-formylphenoxy)-6-methoxybenzaldehyde (8c) were obtained in 80% and 82% yield. Finally, the treatment of dialdehyde 8a with TiCl 4 (3.0 equiv.) and Zn (6.0 equiv.) in THF at reflux for 2.5 h gave compound 5a in 55% yield through an intramolecular McMurry coupling reaction. Similarly, dialdehydes 8b and 8c underwent intramolecular McMurry coupling to give dibenzoxepins 5b and 5c (53%-55%) (Scheme 3). The mechanism of the McMurry reaction is still under debate, but new evidences suggest participation of a metallopinacol intermediate formed by dimerization of ketyl radicals [30][31][32][33]. A possible mechanism for our route is shown in Scheme 4. [Ti]

General Procedure for the McMurry Reaction
To a stirred suspension of zinc powder (98.1 mg, 3.0 mmol) in anhydrous THF (40 mL) cooled to −5 °C under an argon atmosphere, TiCl 4 (284.5 mg, 1.5 mmol) was slowly added via syringe keeping the temperature under 0 °C. The reaction mixture was allowed to warm to room temperature and then heated at reflux for 2.5 h. The reaction was quenched with saturated NH 4 Cl solution and extracted with CH 2 Cl 2 (3 × 20 mL). The combined organic layers were dried (MgSO 4 ) and concentrated. The crude material was purified by flash chromatography (hexanes) to give the desired product.

Conclusions
In conclusion, we have developed a short synthesis of dibenzo[b,f]oxepin derivatives using S N Ar and intramolecular McMurry reactions. An efficient process to obtain diarylethers through S N Ar reaction of salicylaldehydes with fluorobenzaldehydes using microwave irradiation is described. McMurry reaction of diarylethers using TiCl 4 and Zn in THF afforded the target tricyclic system in reasonable yields (53%-55%). Further work on the synthesis of natural and pharmacologically active dibenzo[b,f]oxepins are under way.