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. 2026 Jul 29;11(31):47113–47121. doi: 10.1021/acsomega.6c07135

Synthesis of Selenylated Dibenzo[b,f]oxepines from an Electrophilic Cyclization Reaction

Liliane S de Farias †, Sabrina B Acosta ‡, Luiz H Dapper †, Bruna R Schneider §, Angelita M Barcellos §, Liane K Soares §, Adriano B de Oliveira ∥, Diego Alves ‡,*, Alex F C Flores †,*, Gabriel P da Costa †,*
PMCID: PMC13470698  PMID: 42598299

Abstract

An efficient FeCl3-mediated intramolecular cyclization of o-alkynyl diaryl ethers with diorganyl diselenides has been developed, providing selenylated dibenzo­[b,f]­oxepines in good to excellent yields under mild conditions. The optimized protocol using 0.6 equiv of diorganyl diselenide and 1 equiv of FeCl3 in DCM at room temperature exhibited a broad substrate scope and high tolerance toward diverse functional groups. This approach occurs by in situ formation of an electrophilic selenium species, which undergoes a 7-endo-dig cyclization to furnish the heterocyclic core. This method provides straightforward access to functionalized dibenzo­[b,f]­oxepines containing selenium, a motif of interest due to its relevance in medicinal chemistry and materials science.

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Introduction

Oxygen heterocycles such as oxepines are valuable scaffolds in synthetic and medicinal chemistry. − Among them, dibenzo­[b,f]­oxepines (DBOs) are particularly attractive − due to their rigid polycyclic architecture and presence in bioactive compounds, including Omigapil (CGP 3466) and fluradoline, as well as natural products with anticancer and anti-inflammatory properties such as Artocarpol A, , Bauhiniastatin 2, and Pacharin (Figure a). − Several strategies have been developed for their construction, − , ranging from classical Friedel–Crafts and xanthene rearrangements to more recent Lewis acid-promoted 7-endo-dig cyclizations of o-phenoxy alkynes, − which offer high efficiency and atom economy (Figure b).

1.

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(a) Dibenzo­[b,f]­oxepines with biological applications. (b) Classical approaches to obtain dibenzo­[b,f]­oxepines. (c) Present work: strategy to obtain the selenylated dibenzo­[b,f]­oxepines 3.

Organoselenium compounds have received remarkable attention due to their high reactivity and broad range of applications in organic synthesis , and medicinal chemistry. − Organoselenium reagents are powerful π-electrophiles broadly used in C–C and C–heteroatom bond formation, especially in oxidative alkyne functionalizations that yield diverse heterocycles. − A wide spectrum of oxidants, including I2, , Selectfluor, , Oxone, , trichloroisocyanuric acid (TCCA), − FeCl3, − CuI, and hypervalent iodine reagents, , enables the formation of highly reactive electrophilic selenium species.

Despite significant progress in DBO synthesis and Se-promoted alkyne cyclizations, selenylated dibenzo­[b,f]­oxepines remain unknown. We now report the first FeCl3-mediated 7-endo-dig electrophilic selenocyclization of o-alkynyl diaryl ethers, providing direct access to Se-functionalized DBOs with a broad scope and high yields (Figure c).

Results and Discussion

We began our studies by focusing on the synthesis of 10-phenyl-11-(phenylselanyl)­dibenzo­[b,f]­oxepine 3a, obtained by reacting 1-phenoxy-2-(phenylethynyl)­benzene 1a with diphenyl diselenide (2a), employing several protocols previously reported in the literature for the generation of electrophilic selenium species (Figure ). The conditions described by Alves et al., in both protocols involving CuI, TCCA, were not efficient in synthesizing the target DBO 3a. Similar results were obtained when potassium persulfate or a mixture of m CPBA and KI was employed as an oxidative system (conditions reported by Zhao et al. and Yan et al.).

2.

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Evaluation of the reported protocol for obtaining selenylated dibenzo­[b,f]­oxepine 3a.

The strategy reported by Braga et al. was also not efficient for obtaining the target seven-membered oxygen heterocycle (3a), where I2/DMSO was used as the catalytic system. The protocol reported by Perin et al. was also evaluated, in which Oxone was used as an oxidant. However, the compound (3a) was not formed when the reaction was performed at room temperature. Conversely, when the temperature was increased to 70 °C, the target DBO 3a was obtained in 50% yield. In this case, some byproducts were also formed. Gratifyingly, the conditions previously reported by Zeni et al. proved to be efficient for this transformation, when the starting materials (1a and 2a) were reacted in the presence of 1 equiv of FeCl3 at room temperature under a nitrogen atmosphere using DCM as the solvent for 1 h. Under these conditions, the target DBO 3a was formed in excellent yield (92%) (Figure ).

With these results in hand, we decided to optimize the FeCl3-mediated 7-endo-dig cyclization reaction of compound 1a with 2a to afford the target DBO (3a). Initially, we evaluated the amount of diphenyl diselenide 2a, increasing its quantity from 0.6 equiv. to 1 equiv.; similar yields of 3a were obtained (92% and 90%, respectively) (Table , entries 1–2). On the other hand, decreasing the amount of 2a to 0.5 equiv. afforded the target DBO (3a) in a slightly lower yield (81%) (Table , entry 3). Based on these observations, 0.6 equiv of 2a was selected as the optimal amount (Table , entry 1).

1. Optimization Conditions for the Synthesis of Selenylated Dibenzo­[b,f]­oxepine 3a .

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entry 2a (equiv) solvent cat. (equiv) yield 3a (%)
1 0.6 DCM FeCl3 (1) 92%
2 1.0 DCM FeCl3 (1) 90%
3 0.5 DCM FeCl3 (1) 81%
4 0.6 DCM FeCl3 (0.5) 43%
5 0.6 DCE FeCl3 (1) 60%
6 0.6 DCM None N.D.
7 0.6 DCM FeCl3 (1) 83
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a

Reactions were carried out with starting material 1a (0.125 mmol) and diphenyl diselenide 2a (as indicated in the table) in solvent (1 mL). TLC followed the reaction progress.

b

The yield of 3a was determined after column chromatography.

c

Reaction performed without a nitrogen atmosphere.

d

Byproducts were formed in the reaction. N.D. not detected.

Subsequently, the influence of FeCl3 on the reaction was evaluated. When 0.5 equiv of FeCl3 was used instead of 1 equiv, the DBO 3a yield decreased significantly (43%) (Table , entry 4), while when the reaction was performed in the absence of FeCl3, the DBO 3a was not detected at all (Table , entry 5). On the basis of several reports using FeCl3 to promote cyclization reactions, some of which employ DCE as the solvent, we decided to replace DCM with DCE; however, the reaction was less efficient compared to that carried out in DCM (Table , entry 6).

The influence of the reaction atmosphere was evaluated. When the reaction was performed under an air atmosphere, compound 3a was obtained in an 83% yield (Table , entry 7). Despite this good result, a small amount of side products was observed, which, due to their similar Rf values, made the purification process difficult. Therefore, we conducted subsequent experiments under a nitrogen atmosphere. It is important to note that no 6-exo-dig or chloroselenation products were obtained in sufficient quantities for complete isolation and characterization during the reaction optimization process.

The optimal conditions were established when compound 1a was reacted with 0.6 equiv of diphenyl diselenide 2a in the presence of 1 equiv of FeCl3, using DCM as the solvent, at room temperature for 1 h under nitrogen (Table , entry 1). With these optimized conditions in hand, we proceeded to evaluate the scope and limitations of the protocol. When the reaction was carried out on a 1 mmol scale to evaluate its scalability and robustness, the desired product 3a was obtained in an isolated yield of 81%, demonstrating that the efficiency of the transformation is well-maintained upon scale-up. This result highlights the practical applicability of the developed protocol under slightly larger scale conditions without a significant loss in yield (Figure ).

3.

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Evaluation of versatility and limitation of scope for the synthesis of substituted selenylated-dibenzo­[b,f]­oxepines.3, reactions were carried out with starting material 1 (0.125 mmol), diorganyl dichacogenide 2 (0.075 mmol, 0.6 equiv) in DCM (1 mL) at room temperature under nitrogen atmosphere for 1 h. N.D.: not detected.

Initially, we began our investigation by examining the influence of substituents attached to the aromatic ring of diaryl diselenides 2, including both electron-donating and electron-withdrawing groups located at the para position of the aromatic ring. The target DBO-selenylated compounds 3b–e were synthesized in yields ranging from moderate to good (67–86%) (Figure ). Similar results were obtained when ortho-methyl- or meta-trifluoromethyl-substituted diselenides were evaluated, affording compounds 3f and 3g in 89 and 77% yield, respectively. Unfortunately, this protocol proved to be restricted when 1,2-bis­(3,5-bis­(trifluoromethyl)­phenyl)­diselenide was used as the starting material; in this case, the target product 3h was not formed. This methodology also proved applicable to dialkyl diselenides, and when dibutyl diselenide was reacted under the standard conditions, the target DBO-selenylated compound 3i was obtained in 53% yield (Figure ).

Subsequently, we focused on evaluating the substituent effects on the o-alkynyl diaryl ether scaffold 1. The phenol-substituted derivatives were examined, and in these cases, the monosubstituted compounds 3j and 3k were synthesized in 90 and 65% yield, respectively. The dihalogen-substituted DBO-selenylated derivative 3l was obtained in good yield (83%), and a similar result was observed for the naphthyl derivative, which afforded the target product 3m in 81% yield. The influence of substituents attached to the alkynyl unit was also evaluated. The presence of a fluorine atom at the para-position of the aromatic ring of 1 led to the target cyclization product 3n in good yield (73%). In contrast, when the 4-OMe-substituted starting material 1 was used, the reaction produced the target product 3o along with side products in an inseparable mixture. Unfortunately, when alkyl substituents such as n-pentyl or −CH2OH were present, the reaction did not proceed (compounds 3p and 3q, Figure ).

Additionally, other diphenyl dichalcogenides were also evaluated, and when diphenyl disulfide was used as the starting material, the target sulfenylated DBO 3r was formed in moderate yield (47%). Conversely, diphenyl ditelluride proved ineffective under the standard conditions, and no traces of the target product 3s were detected. Furthermore, we changed the heteroatom of the starting material from the diaryl ether to the corresponding diaryl sulfide or diaryl selenide. In both cases, the target S- or Se-containing heterocyclic product 3t or 3u was not obtained, and the starting materials were largely recovered unchanged (90–95%) (Figure ).

A series of optimized control experiments provides key evidence to support the mechanistic proposal. When TCCA or Oxone was employed as the external oxidant in EtOH, the product corresponded to selenoethoxylated and chlorinated derivatives being formed, strongly suggesting the formation of a seleniranium ion as a key intermediate under oxidative conditions (Figure ). Consistently, the reaction carried out with PhSeCl 4a predominantly furnished the desired cyclized product 3a, albeit accompanied by side products (Scheme , eq 1). This observation indicates that PhSeCl is a competent selenium electrophile in the transformation but likely not the sole reactive species operating in the catalytic system. −

1. Mechanistic Studies to Synthesize the Selenylated Dibenzo­[b,f]­oxepine 3 .

1

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Additionally, the reaction in the absence of diphenyl diselenide 2a gives the cyclic dibenzo­[b,f]­oxepine, as previously reported. Moreover, no conversion was observed in the absence of FeCl3 (Scheme , eq 2), in agreement with previous studies, − which demonstrated the essential role of FeCl3 in promoting the activation of diorganyl diselenides 2 and enabling the selenocyclization manifold. The reaction carried out in the presence of TEMPO under the optimized conditions afforded the desired product 3a in 80% yield, indicating that a radical pathway is unlikely involved in the transformation (Scheme , eq 3). Altogether, these results support a mechanistic scenario involving (i) FeCl3-mediated oxidation of the diselenide to generate electrophilic selenium species (including, but not limited to, PhSeCl), (ii) formation of a seleniranium intermediate upon addition to the alkyne, and (iii) subsequent intramolecular nucleophilic attack leading to the observed heterocycle. These data also suggest an alternative pathway in which the alkyne is activated directly by an electrophilic iron–selenium species generated in situ.

Based on these mechanistic observations and on well-established precedents reported by Zeni et al., − a plausible dual-pathway mechanism is proposed (Scheme ). Two reaction pathways can be envisioned. The first pathway begins with the formation of the RSeCl species I through the reaction of diorganyl diselenide 2 with FeCl3. Subsequently, I reacts with the alkyne moiety of starting material 1, generating the seleniranium ion II, which is intramolecularly attacked by the aromatic ring, assisted by anchimeric participation of the phenolic oxygen, to afford intermediate III via a 7-endo-dig cyclization. Next, rearomatization of III occurs through the elimination of a hydrogen atom, affording the target selenylated dibenzo­[b,f]­oxepine 3 (pathway A).

2. Proposed Mechanism to Synthesize the Selenylated Dibenzo­[b,f]­oxepine 3 .

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In the second pathway, the selenocyclization leading to the dibenzo­[b,f]­oxepine 3 framework may instead be initiated with activation of the alkyne by an electrophilic iron–selenium complex IV, generated in situ from FeCl3 and the diselenide. The phenolic oxygen stabilizes the developing cationic character and facilitates an intramolecular nucleophilic attack of the aromatic carbon onto the activated alkyne-derived center, triggering ring closure to provide the seven-membered oxepine intermediate III while incorporating the organoselenium moiety into the polycyclic structure. Finally, rearomatization of III furnishes the target product 3 (pathway B, Scheme ). In addition, a third pathway (pathway C) cannot be ruled out. In this scenario, the electrophilic iron–selenium complex IV may serve as a precursor to the seleniranium ion II (pathway C). The resulting species could then participate in the cyclization sequence described in pathway A, suggesting that both mechanistic manifolds may operate simultaneously under the reaction conditions and converge toward the formation of product 3 (Scheme ).

To further demonstrate the synthetic utility of the selenylated dibenzo­[b,f]­oxepine scaffold, compound 3a was selected as a representative substrate for postfunctionalization studies. Initially, the oxidation of the organoselenium moiety was investigated using m-chloroperbenzoic acid ( m CPBA), a well-established oxidant for the selective transformation of selenides into the corresponding oxidized selenium derivatives. Under these conditions, the compound 3a underwent a clean oxidation process, affording product 5 in satisfactory yield (89%) (Scheme , eq 1). This result highlights the potential of the selenium-containing dibenzo­[b,f]­oxepine framework as a versatile synthetic intermediate, enabling further structural diversification through straightforward oxidative transformations. The use of N-bromosuccinimide (NBS) proved effective for this transformation, leading to the formation of product 6 in 81% isolated yield (Scheme , eq 1). These results further highlight the synthetic versatility of the selenium-containing dibenzo­[b,f]­oxepine scaffold. In addition to the oxidation reaction described above, treatment of compound 3a with n BuLi at −78 °C followed by quenching with water as an electrophile led to the formation of product 7 in 73% of conversion, which was detected by GC–MS analysis (Scheme , eq 3). These transformations demonstrate the potential of these organoselenium dibenzo­[b,f]­oxepines as useful synthetic intermediates for further functionalization.

3. Synthetic Utility of the Selenylated Dibenzo­[b,f]­oxepine 3 Scaffold.

3

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To corroborate with the mechanistic study and the spectroscopic analyses of the selenylated dibenzo­[b,f]­oxepine derivatives presented in this work, the molecular structure of 3a was determined using the single-crystal X-ray diffraction technique (SC-XRD). Therefore, clear light orange single crystals suitable for the analysis of the 10-phenyl-11-(phenylselanyl)­dibenzo­[b,f]­oxepine derivative were obtained from a solution in acetone by the slow evaporation of the solvent, at room temperature, within a week. The data collection was performed with a Rigaku XtaLAB Synergy-S diffractometer equipped with a Hypix area detector and a nitrogen-based cryostream open-flow cooler device (Oxford Cryosystems Cryostream 800 PLUS) at 123 K, using monochromatized Cu-Kα radiation (λ = 1.54184 Å). The data collection, cell refinement, data reduction, and absorption correction were performed with the CrisAlisPro software package, ver. 1.171.44.149a. The crystal system and the noncentrosymmetric space group were identified as monoclinic and P1211, which was confirmed by the Flack parameter of 0.070(8). − The crystal structure was solved with SHELXT-2015 , and refined anisotropically using the full-matrix least-squares technique on F 2 for all non-hydrogen atoms with SHELXL-2019/3. , The H atoms were positioned with idealized geometry and refined isotropically using a riding model (HFIX instruction). All hydrogen atoms were attached to sp 2 hybridized carbon atoms, with U iso(H) = 1.2 U eq(C), and the C–H bond lengths were set to 0.9300 Å. The molecular graphic was generated with the DIAMOND software, ver. 3.2e, and the material for publication was prepared with the WinGX, ver. 2023.1, enCIFer, ver. 2026.1.0, and publCIF, ver. 1.9.22_c, software. The database survey was performed with the ConQuest software, ver. 2025.2.0, and the Cambridge Structural Database via WebCSD, ver. 1.9.85. As a result of the SC-XRD analysis, the asymmetric unit of 3a matches the molecular formula, with all atoms being located in general positions (Figure ). The molecule is not planar due to the oxygen atom in the seven-membered ring, with the C1–O1–C26 bond angle of 111.5(2)°, and the observed dihedral angle between the mean planes through the C1/C2/C3/C4/C5/C6 and C21/C22/C23/C24/C25/C26 entities of 60.61(11)°. In addition, due to the free rotation of the peripheral aromatic rings around the internuclear axis of the C7–C8 and Se1–C15 single bonds, the dihedral angle between the C8/C9/C10/C11/C12/C13 and C15/C16/C17/C18/C19/C20 moieties amounts to 58.39(08)°, which contributes to the three-dimensional molecular geometry and the point group of C 1 of this selenylated dibenzo­[b,f]­oxepine derivative. Crystal data, data collection, and structure refinement details for the 3a analysis are summarized in Table .

4.

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Molecular structure of 3a, showing the atom labeling and displacement ellipsoids drawn at the 50% probability level for the non-H atoms.

2. Crystal Data, Data Collection, and Structure Refinement Details for 3a .

chemical formula C26H18OSe
M r 425.36
crystal system monoclinic
space group (IT) 4
space group (H-M) P21 or P1211
space group (hall symbol) P 2yb
temperature (K) 123
a, b, c (Å) 9.0551 (2), 8.6134 (2), 12.9251 (3)
β (°) 105.340 (2)
V (Å3) 972.18 (4)
Z 2
radiation type Cu-Kα
μ (mm–1) 2.71
crystal size (mm) 0.24 × 0.13 × 0.07
diffractometer Rigaku XtaLAB Synergy-S, Dualflex, Hypix area
detector diffractometer
absorption correction Gaussian [using the SCALE3 ABSPACK scaling algorithm embedded within the CrysAlisPro software package ()]
T min, T max 0.495, 1.000
no. of measured, independent, and Observed [I > 2σ(I)] reflections 21,119, 4127, 4077
R int 0.034
(sin θ/λ)max (Å–1) 0.638
R[F 2 > 2σ(F 2)], wR (F 2), S 0.024, 0.062, 1.08
no. of reflections 4127
no. of parameters 253
no. of restraints 1
H atom treatment H atom parameters constrained
Δρmax, Δρmin (e Å–3) 0.22, −0.51
absolute structure flack x determined using 1826 quotients [(I+)–(I−)]/[(I+)+(I−)] ()
absolute structure parameter 0.070 (8)
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To the best of our knowledge and from using database tools such as the ConQuest software, ver. 2025.2.0, (accessed on June 05, 2026) and the Cambridge Structural Database, ver. 1.9.85, (CSD, accessed via WebCSD on June 05, 2026), the crystal structure of 3a is reported in the literature for the first time in this work.

Conclusions

In summary, we have successfully developed an efficient FeCl3-mediated intramolecular cyclization of o-alkynyl diaryl ethers with diorganyl diselenides to afford the corresponding selenylated dibenzo­[b,f]­oxepines in good to excellent yields under mild conditions. The optimized protocol, employing 0.6 equiv of diselenide and 1 equiv of FeCl3 in DCM at room temperature under a nitrogen atmosphere, demonstrated a broad substrate scope and high functional group tolerance. Mechanistic investigations suggest that the transformation proceeds through the in situ generation of an electrophilic selenium species, followed by a 7-endo-dig cyclization pathway leading to the selenylated heterocycle. Despite these promising results, attempts to extend the methodology to diaryl sulfides and selenides did not afford the desired heterocyclic products, indicating a strong influence of the heteroatom on the cyclization outcome. Further studies are currently underway in our laboratory to expand the synthetic applicability of this methodology, including the use of disulfides and ditellurides as chalcogen sources, as well as to gain deeper mechanistic insights into the reaction pathway.

Supplementary Material

ao6c07135_si_001.pdf (4.8MB, pdf)

Acknowledgments

The authors are grateful for the financial support and scholarships from the Brazilian agencies, Conselho Nacional de Desenvolvimento Científico e Tecnológico–CNPq (310635/2022-5 and 405655/2023-1) and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul–FAPERGS (PDJ 23/2551-0001921-3 and PqG – 25/2551-0002917-1). CNPq is also acknowledged for the fellowship for D.A and A.F.C.F. This study was partially financed by the Coordenação de Aperfeiçoamento de Pessoal de Nivel Superior-Brazil (CAPES)–Finance Code 001. The authors would like to thank the Centro Integrado de Análises–CIA-FURG (funded by Finep-CT-INFRA, CAPES–Pró-Equipamentos, and MCTI-CNPq-SisNano2.0) for the analysis performed. The authors also acknowledge Prof. Dr. Javier A. Ellena (São Carlos Institute of Physics, University of São Paulo, 13560-970 São Carlos, SP, Brazil) for the access to the SC-XRD facility (Laboratório Multiusuário de Crystalografia Estrutural). This study was financed, in part, by the São Paulo Research Foundation (FAPESP), Brazil. Process Number #2017/15850-0.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.6c07135.

  • Copy of 1H, 13C­{1H}, and 77Se NMR spectra as well as spectral data of all compounds and the procedures; geometric parameters (Å, °) for 3a from the SC-XRD analysis (PDF)

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

The Article Processing Charge for the publication of this research was funded by the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), Brazil (ROR identifier: 00x0ma614). Conselho Nacional de Desenvolvimento Científico e Tecnológico–CNPq (310635/2022-5 and 405655/2023-1) and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul–FAPERGS (PDJ 23/2551-0001921-3 and PqG – 25/2551-0002917-1).

The authors declare no competing financial interest.

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