Modular synthesis of benzothiophene-fused pentalenes reveals substituent-dependent antiaromaticity

Abstract

Antiaromatic π-electron systems provide unique electronic features arising from the cyclic conjugation of 4n π-electrons, yet synthetic access to strongly antiaromatic heteroarene-fused scaffolds remains limited. Here we report a general synthetic route to benzothiophene-fused pentalenes via the first thiophene analogue of Brand's bicyclo[3.3.0]octadiene-2,6-dione intermediate. The pre-installation of the bicyclic five-membered-ring core at an early stage of synthesis enables efficient annulation of benzothiophene moieties and late-stage diversification at the 1,4-positions through the 1,2-addition of organometallic nucleophiles, followed by optimized dehydration. This strategy affords a series of benzothiophene-fused pentalenes bearing diverse aryl, heteroaryl, and alkynyl substituents in practical yields, with isolation by simple filtration. The benzothiophene-fused pentalenes thus obtained exhibit strong antiaromatic character that correlates with electronic effects, consistent with the topological charge stabilization rule. This work establishes a versatile platform for probing substituent-dependent antiaromaticity and for designing functional materials based on strongly antiaromatic π-systems.

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Introduction

Antiaromatic π-electron systems exhibit distinct electronic properties such as narrow HOMO–LUMO gaps,¹ amphoteric redox behavior,² and low-lying triplet excited states,^3,4 making them attractive frameworks for optoelectronic materials.⁵ Among these, pentalene (1), a bicyclic conjugated hydrocarbon with two fused five-membered rings, is a prototypical antiaromatic framework (Fig. 1a, top).⁶ Owing to its planarity and minimal bond-angle strain among 4n π-electron hydrocarbons, pentalene and its derivatives have been considered promising building blocks for functional materials.⁷ To exploit the characteristic properties of pentalene derived from its antiaromatic character, a variety of annulated derivatives have been developed.^8–33 Dibenzo[a,e]pentalene (2) and its derivatives have been most extensively investigated due to their high stability,^8–23 although the strong aromatic character of benzene rings diminishes the antiaromatic character of the pentalene cores (Fig. 1a, bottom left). In contrast, the annulation with weakly aromatic heteroarenes such as thiophene preserves the antiaromatic character of pentalene,^24,25 giving rise to dithieno[a,e]pentalene (3),^{11a,12b,25,26} benzothiophene-fused (4), and its π-expanded analogues^22e as thermally stable compounds (Fig. 1a, bottom right). These heteroarene-fused pentalenes offer an attractive platform for optoelectronic materials, yet their synthesis remains challenging due to the lack of general and efficient synthetic methods.

Fig. 1 (a) Effect of fused aromatic rings on the antiaromaticity of pentalene 1. (b) Previous synthetic methodologies of dibenzo[a,e]pentalenes 2. (c) Synthetic strategy in the present study.

Previous synthetic routes for dibenzo[a,e]pentalenes were mostly based on intra- or intermolecular cyclization of phenylacetylenes (Fig. 1b).^9–18 However, analogous reactions with thiophene-based substrates have generally failed or afforded poor yields (Fig. 1b).^25,31 We hypothesized that these difficulties stem primarily from increased ring strain and higher reactivity of strongly antiaromatic dithieno[a,e]pentalene under the reaction conditions. Indeed, our recent studies indicated that benzothiophene-fused pentalenes can strongly coordinate to Ni(0),³⁴ inhibiting the desired reaction.

To overcome these limitations, we revisited the classical strategy, which constructs the pentalene framework from a benzannulated bicyclo[3.3.0]octadiene-2,6-dione precursor (5, Fig. 1b). This method, originally reported by Brand in 1912,⁸ and recently refined by Esser and co-workers,^20,21 enables transition metal-free formation of the dibenzo[a,e]pentalene framework. We herein report the development of a new synthetic route of benzothiophene-fused pentalenes 4 via the corresponding benzothiophene-fused bicyclo[3.3.0]octadiene-2,6-dione intermediate (6) derived from bicyclo[3.3.0]octane-2,6-dione 7 (Fig. 1c). This approach allows late-stage introduction of diverse substituents to the 1,4-positions of the pentalene core, affording a new family of stable yet strongly antiaromatic compounds. The resulting compounds provide a versatile platform for elucidating the substituent effects on antiaromaticity and the corresponding physical properties.

Results and discussion

In Esser's improved synthesis of dibenzo[a,e]pentalene derivatives based on Brand's approach, the key intermediate, a benzannulated bicyclo[3.3.0]octadiene-2,6-dione 5, was prepared in only three steps via dimerization of ethyl phenylacetate followed by hydrolysis and intramolecular cyclization (Fig. 2a, top).^20a,22h However, our attempts to apply these conditions to ethyl thienylacetate failed, yielding a complex mixture rather than the desired dimer (Fig. 2a, bottom), indicating the need for an alternative synthetic strategy to access thiophene-fused analogues.

Fig. 2 (a) A previous synthetic method of benzannulated bicyclo[3.3.0]octadiene-2,6-dione 5 (top) and the result of our preliminary investigation using ethyl thienylacetate (bottom). (b) The synthetic strategy of benzothiophene-fused bicyclo[3.3.0]octadiene-2,6-dione 6 in this work.

We therefore focused on the synthesis of benzothiophene-fused pentalene 4 through a new benzothiophene analogue of Brand's intermediate (6; Fig. 2b). Bicyclo[3.3.0]octane-2,6-dione (7) was chosen as the key starting material, as it embeds the fused five-membered-ring motif of the pentalene core from the outset.³⁵ Introducing the principal source of ring strain at an early stage of synthesis avoids the strain accumulation that hampers conventional approaches in which the pentalene core is constructed only at the end. The benzothiophene rings were to be constructed laterally around this scaffold to furnish the hexacyclic compound 8, followed by benzylic oxidation to the desired diketone 6.

Following this strategy, a benzothiophene analogue of Brand's intermediate, 6, could be successfully synthesized as shown in Scheme 1. The Ti-mediated nucleophilic addition of 2-bromobenzothiol to 7 and subsequent dehydration³⁶ afforded the alkenyl sulfide 9 in 37% yield. A Pd-catalyzed intramolecular cyclization efficiently produced the benzothiophene-fused bicyclo[3.3.0]octadiene 8 in 85% yield.‡ Regioselective benzylic oxidation of 8 proved challenging, yet PhI(OAc)₂/TBAI³⁷ enabled regioselective conversion to the acetoxylated intermediate 10, which upon hydrolysis gave the desired diol 11 in 59% overall yield for two steps. Finally, PCC oxidation of 11 gave the desired diketone 6 in 73% yield. This compound represents the first thiophene-annulated analogue of Brand's intermediate and a versatile precursor to pentalene frameworks.

Scheme 1 Synthesis of a key intermediate 6.

We next examined the construction of benzothiophene-fused pentalenes from 6. The 1,2-addition of Grignard reagents to 6 proceeded smoothly in the presence of CeCl₃ under conditions essentially the same as those reported for the synthesis of dibenzo[a,e]pentalene derivatives.^20a However, subsequent dehydration gave a different outcome, indicating that modification of the reaction conditions was required (Scheme 2). Specifically, for the preparation of benzothiophene-fused pentalene 4a bearing 3,5-bis(trifluoromethyl)phenyl groups as a model compound, the corresponding Grignard reagent was subjected to the reaction with 6 in the presence of CeCl₃ to afford the bis(benzyl alcohol) 12a in 79% yield (Scheme 2). In contrast, the following dehydration using the catalytic amount of TsOH·H₂O produced the desired pentalene 4a in only 17% yield, with a ring-opened compound 13a as the major product in 45% yield (entry 1 in Table 1).§ A similar ring-opening reaction has been reported in the synthesis of a highly strained cyclophane-type dibenzo[a,e]pentalene.^21a In line with this observation, the low yield of 4a accompanied by the ring opening suggests that thiophene fusion introduces additional strain. Increasing the amount of TsOH·H₂O reversed the product ratio (entries 2 and 3), and 3.0 equivalents afforded the desired pentalene 4a in 74% yield (entry 3).

Scheme 2 Transformation of a key intermediate 6 to aryl-substituted diol 12a.

Table 1 Effect of the equivalents of TsOH for the dehydration of 12a

Entry	x	Yield^a
		4a	13a
a Isolated yield.
1	0.1	17%	45%
2	2.0	65%	21%
3	3.0	74%	23%

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With the optimized conditions, diverse benzothiophene-fused pentalenes 4 were synthesized from the common intermediate 6 by 1,2-addition of the corresponding Grignard reagents or organolithium reagents in the presence of CeCl₃ (Fig. 3). The scope includes derivatives bearing electron-withdrawing 3,5-(CF₃)₂C₆H₃ (4a), relatively neutral (Ph, 4b), and electron-donating (4-MeOC₆H₄, 4c) aryl groups, as well as heteroaryl (2-thienyl, 4d), and triisopropylsilyl (TIPS)ethynyl groups (4e). Notably, the final dehydration step induced precipitation of desired products 4, enabling facile isolation by simple filtration without chromatography. This route thus provides practical access to structurally diverse benzothiophene-fused pentalenes.

Fig. 3 Synthesis of benzothiophene-fused pentalenes 4a–e bearing various substituents at 1,4-positions. (a) Synthetic conditions. (b) Molecular structures of 4a–e and the isolated yields for Steps 1 and 2. TIPS = triisopropylsilyl. (c) X-ray crystal structure of 4e (thermal ellipsoids drawn at 50% probability; black: carbon, orange: sulfur, yellow: silicon). Hydrogen atoms and the minor disordered components are omitted for clarity. Selected bond lengths: C1*–C2 = 1.490(2) Å, C2–C3 = 1.382(2) Å, C3–C4 = 1.452(2) Å, C4–C1 = 1.375(2) Å.

Single-crystal X-ray diffraction of 4e unambiguously confirmed the formation of benzothiophene-fused pentalenes (Fig. 3c and S1–S2). The crystal structure of 4b has been reported previously.³⁴ Both 4b and 4e featured a highly planar benzothiophene-fused pentalene core, forming slipped π–π stacking arrangements along the molecular long axis (Fig. S2). The peripheral C–C bonds of the pentalene cores displayed pronounced bond-length alternation, consistent with strong antiaromatic character. The C–C bonds fused to the thiophene rings were relatively short, indicating double-bond character.

The UV/vis/NIR absorption spectra of 4a–e exhibited weak, broad first absorption bands at around 600–1100 nm, typical of cyclic 4n π-electron systems, along with a more intense second band around 500 nm (Fig. 4a). Compared with dibenzo[a,e]pentalene (2, R = SiMe₃, λ_max = 503 nm)²⁵ and dithieno[a,e]pentalene (3, R = SiMe₃, λ_max = 639 nm),²⁵ the first absorption bands of 4a–e (λ_max at around 800 nm) were markedly red-shifted, reflecting enhanced antiaromatic character of the pentalene core and π-expansion. Cyclic voltammetry showed reversible oxidation and reduction waves (Fig. 4b), confirming their amphoteric redox behavior.

Fig. 4 Photophysical and electrochemical properties of benzothiophene-fused pentalenes 4a–e. (a) UV/Vis/NIR electronic absorption spectra of 4a (purple), 4b (blue), 4c (green), 4d (red), and 4e (beige) in THF. In the inset spectra, minor discontinuities around 700 nm (marked with ×) arise from the grating changeover of the spectrophotometer, and the increased noise near 900 nm (marked with *) is due to the detector sensitivity around the PMT–InGaAs switching wavelength (∼830 nm). (b) Cyclic voltammograms of 4a–e in THF and CH₂Cl₂ (0.5 mM) for reductive and oxidative regions, respectively; scan rate: 50 mV s⁻¹, supporting electrolyte: [n-Bu₄N][PF₆] (0.1 M). All potentials referenced vs. Fc/Fc⁺. The plus (+) signs indicate the half-wave potentials (E_1/2) of the reversible redox waves in the cyclic voltammograms.

The redox potentials reflected the electronic nature of the substituents: the most electron-withdrawing 4a exhibited E_1/2,ox = +0.48 V and E_1/2,red = −0.97 V (vs. Fc/Fc⁺), whereas the electron-donating 4c showed the half-wave potentials E_1/2,ox = +0.16 V and E_1/2,red = −1.36 V (vs. Fc/Fc⁺), respectively. These results demonstrate that the electronic properties of benzothiophene-fused pentalene can be finely tuned by varying the substituents. The HOMO–LUMO gaps estimated from redox onsets (1.17–1.37 eV, Table S2) were significantly smaller than those of 2 (2.48 eV)²⁵ and 3 (1.87 eV),²⁵ consistent with the enhanced antiaromatic character and efficient π-conjugation.

To quantify the degree of antiaromatic character, the paratropicity strength, a magnetic descriptor of antiaromaticity, was estimated by computing the NICS(1.7)_zz values³⁸ for 4a–d and 4e′ at the M06-2X/6-31++G(2d,p)//M06-2X/6-31++G(d) level of theory (Fig. 5a).¶ All compounds exhibited large positive values in the range from +19.2 ppm to +24.4 ppm, confirming pronounced antiaromaticity relative to dibenzo[a,e]pentalene 2 (R = Ph, +3.8 ppm). The anisotropy of the induced current density (ACID) plot³⁹ for 4a calculated at the same level of theory clearly indicated that a paramagnetic ring current exists along the 8-membered-ring periphery of the pentalene moiety (Fig. 5b). Notably, the trend in NICS(1.7)_zz values, 4c (+19.2 ppm) < 4d (+19.8 ppm) < 4b (+20.3 ppm) < 4a (+23.6 ppm) < 4e′ (+24.4 ppm), intuitively correlates with the electron-withdrawing strength of the substituents. This result is consistent with recent observations in alkylthio-substituted dibenzo[a,e]pentalene and its sulfone analogue,^20e and underscores the importance of the electronic effects of substituents in modulating antiaromaticity.

Fig. 5 Substituent-dependent antiaromatic character of benzothiophene-fused pentalenes 4a–e. A model compound 4e′, in which the TIPS groups were replaced with TMS groups, was used instead of 4e to reduce computational costs. (a) NICS 2D plots at 1.7 Å of the z axis and NICS(1.7)_zz values of 4a–d and 4e′. (b) ACID plot of 4a (isosurface value = 0.03). NICS and ACID calculations were conducted at the M06-2X/6-31++G(2d,p) and M06-2X/6-31G(d), respectively, using the optimized geometries at the M06-2X/6-31++G(d) level of theory. The xy planes were set on the mean planes defined by the benzothiophene-fused pentalene frameworks. The magnetic field in the ACID calculations was chosen to be parallel to the z axis, which is oriented in a perpendicular direction to the paper plane and pointing towards the reader. Only the π-electron contribution was used. (c) Schematic representations based on the topological charge stabilization rule. For 4f, NBO 2p_z occupancies at each carbon atom are shown. The numbers with relatively high and low 2p_z occupancies are shown in red and blue, respectively.

To rationalize these substituent effects, we applied the topological charge stabilization rule, originally proposed by Gimarc⁴⁰ and recently utilized by Wu et al., to understand the positional effects of heteroatom doping on the paratropicity of indacene-based PAHs.⁴¹ According to this rule, the 1,4-carbons of pristine pentalene possess partial positive character (δ⁺); thus, electron-donating substituents stabilize the system, while electron-withdrawing groups destabilize it (Fig. 5c). Consequently, the former are expected to weaken, and the latter to enhance, the antiaromatic character. This interpretation is consistent with the observed trend in NICS values and provides an intuitive explanation for the substituent-dependent modulation of the antiaromatic character of pentalene. These results demonstrate that the electronic effects of both the fused ring system and the substituents cooperatively determine the degree of antiaromatic character of the pentalene moiety. In particular, the introduction of strongly electron-withdrawing groups effectively enhances the antiaromatic character of the pentalene core.

Conclusions

In conclusion, we developed a versatile and general synthetic route to benzothiophene-fused pentalenes through a thiophene analogue of Brand's bicyclo[3.3.0]octadiene-2,6-dione intermediate. Pre-installation of the bicyclic five-membered-ring framework enabled efficient annulation of benzothiophene units and late-stage diversification at the 1,4-positions, overcoming the limitations of conventional approaches to hereroarene-fused pentalenes. The resulting compounds constitute a new family of stable yet strongly antiaromatic compounds, whose electronic and magnetic properties can be finely tuned by substituents. These findings provide a robust platform for understanding substituent effects on antiaromaticity and offer design principles for future functional materials based on antiaromatic π-systems.

This work was supported by JST CREST Grant Number JPMJCR23O2 (for A.F.), and JSPS KAKENHI Grant Numbers JP20H05864, JP21H01916, and JP24H00458 (for A.F.), and JP24KJ1436 (for R.I.). The authors thank the iCeMS Analysis Center for providing access to the NMR spectrometer. The synchrotron single-crystal X-ray diffraction measurements were performed at the BL02B1 beamline of SPring-8 with the approval of the Japan Synchrotron Radiation Research Institute (JASRI; project no. 2024A1699).

Author contributions

R. I.: investigation, methodology, formal analysis, data curation, funding acquisition, visualization, writing – original draft. K. Y.: conceptualization, supervision, writing – review & editing. A. F.: conceptualization, data curation, formal analysis, funding acquisition, project administration, supervision, visualization, writing – review & editing.

Conflicts of interest

There are no conflicts to declare.

Data availability

Data supporting this article are included in the supplementary information (SI). Supplementary information is available. See DOI: https://doi.org/10.1039/d5sc09325b.

CCDC 2504966 (4e) contains the supplementary crystallographic data for this paper.⁴²

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Footnotes

† Present address: Department of Applied Chemistry, Graduate School of Engineering, The University of Osaka, Suita, Osaka 565-0871, Japan.

‡ The yield of this intramolecular cyclization reaction was found to be sensitive to the type of ligand and base used in the reaction. The effect of the ligand and base is shown in Table S1.

§ The proposed reaction mechanism for this ring-opening reaction is shown in Scheme S1.

¶ X-ray crystal data were available only for compounds 4b and 4e. Geometry optimizations were therefore performed for 4a–d and 4e′, and the optimized structures were used for further analyses. To reduce computational costs, a model compound 4e′, in which the TIPS groups were replaced with TMS groups, was used instead of 4e. Several density functionals were tested using 4e′ as a model system, given that NICS values are sensitive to even subtle differences in bond-length distributions, as noted in ref. 43. As a result, the M06-2X density functional gave the best agreement with the experimental C–C bond lengths of the pentalene core determined by X-ray crystallographic analysis. See the SI for details.

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