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1,4-Benzo[b]dithiine Derivatives Accessed via Ring Expansion of 1,3-Dithioles

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20 August 2026

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21 August 2026

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Abstract
Herein, we disclose an efficient route to the synthesis of brominated 1,4-benzo[b]dithiine derivatives via ring expansion of aromatic 1,3-dithiole promoted by bromine (51% - 94%). The use of a methyl-substituent on aromatic ring lead to formation of an inseparable, equimolar mixture of regioisomers. Additionally, 4-methoxyacetophenone derivative yielded unprecedented dimeric products, which structure was confirmed by single crystal X-ray crystallography. We propose a reaction mechanism, rationalizing the formation of regioisomers originating.
Keywords: 
heterocycles
;  
1
;  
3-dithiole
;  
dithioacetal
;  
4-benzo[b]dithiine
;  
ring expansion
Subject: 
Chemistry and Materials Science  -   Organic Chemistry

1. Introduction

Dithioacetals are a versatile group of organosulfur compounds, typically derived from aldehydes or ketones in presence of thiols. [1] Their most famous application in synthetic methodology is undoubtedly the Corey-Seebach reaction – the umpolung (polarity reversal) of carbonyl group, where they serve as a masked acyl anion equivalent. [2,3,4,5] Nonetheless, their use extends to biological applications [6,7,8,9,10] as well as key intermediates in ring-expansion reactions that enable synthesis of sulfur-heterocycles. [11,12] Among these, 1,4-dithiines constitute an important scaffold, [13] that can serve as antagonists of the human galanin hGAL-1 receptor, [14] or as anthelmintics, [15] while their tetroxide derivatives also show potent biological activity, [16] such as dimethipin, a commercial plant growth regulator. Synthetically, they can be deployed as a masked double bond, allowing for the preservation of the cis configuration of olefins via chemoselective desulfurization reactions. [17] Remarkably, they can serve as allylic alcohol anion equivalents [18] for construction of sugar cores, [19] or alternatively as an allyl cation equivalent to facilitate (3+2) cycloaddition reactions, [20] or as dienophiles in (4+2) cycloadditions [21], similar to their oxidized sulfone forms [22,23,24]. To date, many synthetic pathways to obtain this class of heterocycles have been developed, [25,26] however they primarily focus on 2,3-dihydro-1,4-dithiines. [27,28,29,30,31,32,33,34,35] Their benzene-fused analogues: 1,4-benzo[b]dithiines have not been explored as extensively. Examples of their synthesis include the reaction of 1,8-diketones with Lawesson’s reagent, [36] reactions with in situ generated benzdithiete, [37] transformations from pentathiepins, [38] the aromatization of cyclic ketones, [32] reactions from phenylene tetrasulfide in a presence of molybdenum catalyst, [39] the reaction of ethynylbenziodoxolone with thiols, [40] the Cu-catalyzed diarylthiolation of ynones, [41] and a very recent method by Schneider utilizing 2-iodoaryl alkynyl sulfides. [42] In our effort to expand the chemistry of 1,4-dithiines, we wondered if the ring expansion reaction of dithioacetals derived from aromatic 1,2-dithiols - analogous to the prevalent ethane-1,2-dithiol derived dithioacetals - could serve as a platform to obtain 1,4-benzo[b]dithiines.

2. Results and Discussion

2.1. Chemistry

We have started our investigation from dithioacetalization of aldehydes and acetophenone derivatives with 4-methylbenzene-1,2-dithiol, catalyzed by boron trifluoride etherate. [43,44] A series of dithioles 2 (a-j) were obtained in yields ranging from 79% to 100% (Scheme 1). It should be noted that, for aldehydes (a-b) and acetophenone derivatives (e-j) a new stereogenic center is formed and the resulting dithiole derivatives are obtained as racemic mixtures. Next we have carried out the ring expansion reaction, promoted by bromine – conditions previously described by Caputo et al. [28,45] – for obtaining derivatives of 1,4-dithiines for further broad utilization as intermediates in organic synthesis. We have isolated a series benzo[b][1,4]dithiine derivatives 3 (a-c; and e-i) as an equimolar mixture of regioisomers (2-bromo and 3-bromo). In cases where it was possible, based on 2D-NMR spectra analysis we were able to assign protons and carbon atoms to a respective regioisomer. Alkyl, heterocyclic or aryl groups, including those bearing electron donating or electron withdrawing substituents were well tolerated (51-94%). On the other hand, acetone derivative did not yield expected product, instead we have isolated a dibrominated product 3d (39%), presumably formed by substitution of one of hydrogen atoms of the methyl group by the bromine. Interestingly, the molar ratio of 3d regioisomers is 7:1 (estimated from NMR spectrum), in contrast to the previous results.
Unexpectedly, 4-methoxyacetophenone derivative 2j, upon ring expansion did not yield 3j, but instead two new products: dithiine 4 and dimeric product 5 (Scheme 1). The compounds 4:5 were obtained as a 1:2 molar mixture (per 2j mmol consumed), which we could separate by the means of column chromatography on silica gel. Expectedly 4 is a mixture of regioisomers in a 1:1 ratio. Additionally, we were able to grow a single crystal of compound 5 suitable for X-ray crystallography measurement which unambiguously confirmed its structure (Figure 1).
To gain more insight into the formation of products 4 and 5 we have conducted the ring expansion reaction with altering the amount of bromine (Scheme 2). When one equivalent of bromine was used, we have only obtained product 4 with yield of 65%, and we managed to recover 28% of 2j (estimated from a NMR spectrum). Once we have increased the loading of bromine to 2.2 equivalents, almost all the product 4 (8%), underwent dimerization to 5 in excellent 87% yield. Presumably brominated intermediate product 3j, that we observed in all the other cases studied, is too reactive and undergoes quick dimerization to 5 (for a reaction mechanistic proposal see SM Figure S12).
Chromatographic methods proved futile to separate obtained mixture of regioisomers. Thus we have attempted separation by fractional crystallization using product 3f (see SM for details). We have managed to enrich a single regioisomer of 3f up to 7:1 molar ratio, however we were unable to obtain a pure, single regioisomer. Next, we have attempted derivatization of dithiine 3e and 3g by exhaustive oxidation of sulfide groups to sulfone (Scheme 3). We have obtained 6 with yield 90% (R = Ph) and tetroxide derivative 7 with a yield of 74% (R = 3,4-(MeO)2C6H3-). For the first compound we have successfully grow a single crystal suitable for X-Ray analysis, even more luckily of a single regioisomer 3-bromo-, (Figure 2), while all the crystallization attempts for compound 7 were unsuccessful.

2.2. Mechanistic Considerations

The mechanism of expansion of 1,3-dithiolane/dithiole ring is well established in the literature[11,41]. It is worth noting that 4-methylbenzene-1,2-dithiol leads to formation of racemic dithioacetals from nonsymmetric ketones, as such two possible paths of activating the sulfur can be envisioned for thiolate A (Scheme 4). They diverge into twin intermediate B/B’ and while methyl group increases the electron density at the para position, in principle stabilizing intermediate B’, its effect is too weak to discriminate the other pathway, as such all the compounds (except the acetone derivative) were obtained as an equimolar mixture of regioisomers. Then by intermediates C/C’ and D/D’ a dithiine E and E’ are formed and we have managed to isolate one of such derivatives (4) when 2j was used as a substrate. Otherwise strongly acidic environment and oxidative nature of bromine prompts the formation of bromonium cations F and F’ that are subsequently attacked by bromide, resulting in formation of 3a-3i. We expect that 3j also forms, but under the reaction conditions it quickly dimerizes to 5.
Considering the reaction outliners, starting from the acetone derivative 3d, we presume that the expected monobrominated product is initially formed, but the acidic protons at the methyl group undergo subsequent abstraction by bromide (schematic description provided in SM, Figure S5). We cannot fully explain the predominance of one of the regioisomers (1:7 molar ratio, estimated from 1H-NMR spectrum). Likely the weak inductive effect of the methyl group in the para position of the aromatic fragment causes the divergence.

3. Conclusions

For the first time benzo[b][1,4]dithiine derivatives bearing substituent at the benzene ring were obtained via bromine promoted ring expansion of benzo[b][1,3]dithioles. The products are obtained as an equimolar and inseparable mixture of regioisomers. The use of 4-methoxyacetophenone derivative allowed us to isolate nonbrominated dithiine 4 and its dimer 5, which structure was confirmed by single crystal X-Ray crystallography. Attempts to separate regioisomers were partially successful via crystallization, while for tetroxide derivative 6 we have managed to obtain a crystal structure of a single regioisomer.

4. Experimental

General information on the substrates used (materials), analytical techniques used (methods) and the experimental procedures and characterization data for all obtained compounds are given in SM.
General Procedure for the Synthesis of Dithiine Derivatives,3a-3j
The reactions were performed on a 1-15 mmol scale, in room temperature. To a solution of starting dithioacetal in dry chloroform (10 mL per 1 mmol of substrate), under argon atmosphere, was added dropwise solution of bromine (1.7 equiv) in dry chloroform (5 mL per 1 mmol of bromine) with constant argon flow through reaction flask, to remove released HBr as a byproduct then neutralized. Reaction mixture was stirred for the next 45 min and quenched by addition of water solution of sodium thiosulfate (10%, 50 - 100 mL per 1 mmol of substrate) and solid sodium bicarbonate (5 g per 1 mmol of substrate, in case of no dissolution additional small amount of water was added). Aqueous phase was separated, extracted once with chloroform (same volume as water phase), organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude post reaction mixture. Product was isolated/purified by flash column chromatography (silica gel, eluent: AcOEt:n-hexane) to provide pure product.

Supplementary Materials

The following supporting information can be downloaded at the website of this paper posted on Preprints.org.

Author Contributions

Conceptualization, D.T.L.; methodology, G.G.; investigation, D.T.L. and W.J.D.; writing – original draft preparation, J.B.L. and A.B-B.; writing – review and editing, D.T.L. and W.J.D., J.B.L. and M.M.; formal analysis, M.M.; visualization of mechanism, D.T.L.; supervision, G.G. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the MINISTER of SCIENCE and HIGHER EDUCATION REPUBLIC of POLAND, within the program "Regional Excellence Initiative", grant number RID/SP/0032/2024/01.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

The data supporting this article have been included as part of the Supplementary Materials. CIF files for 5 and 6 have been deposited in CCDC, Nº 2571235 and 2571234, respectively.

Acknowledgments

X-ray diffraction studies were performed at the Laboratory of X-ray Structural Analysis of the Institute of Organic Chemistry of the Polish Academy of Sciences; NMR spectra were recorded in the Laboratory of Spectrometry, Faculty of Chemistry, Rzeszow University of Technology.

Conflicts of Interest

The authors declare no conflicts of interest.

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Scheme 1. Substrate scope of the dithioacetalization reaction followed by a ring expansion reaction leading to benzo[b][1,4]dithiine derivatives.
Scheme 1. Substrate scope of the dithioacetalization reaction followed by a ring expansion reaction leading to benzo[b][1,4]dithiine derivatives.
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Figure 1. Crystal Data of 5. CCDC 2571235 C32H26O2S4, Mr = 570.77, triclinic, P-1 (No. 2), a = 9.6769(11) Å, b = 11.1216(13) Å, c = 14.2025(17) Å, α = 104.035(10)°, β = 93.139(9)°, γ = 101.083(10)°, V = 1447.0(3) Å3, T = 293.15(10) K, Z = 2, Z' = 1, μ(Cu Kα) = 3.232, 4940 reflections measured, 3832 unique (Rint = 0.0182) which were used in all calculations. The final wR2 was 0.2184 (all data) and R1 was 0.0654 (I > 2(I)).
Figure 1. Crystal Data of 5. CCDC 2571235 C32H26O2S4, Mr = 570.77, triclinic, P-1 (No. 2), a = 9.6769(11) Å, b = 11.1216(13) Å, c = 14.2025(17) Å, α = 104.035(10)°, β = 93.139(9)°, γ = 101.083(10)°, V = 1447.0(3) Å3, T = 293.15(10) K, Z = 2, Z' = 1, μ(Cu Kα) = 3.232, 4940 reflections measured, 3832 unique (Rint = 0.0182) which were used in all calculations. The final wR2 was 0.2184 (all data) and R1 was 0.0654 (I > 2(I)).
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Scheme 2. 4-Methoxyacetophenone derivative ring expansion vs dimerization.
Scheme 2. 4-Methoxyacetophenone derivative ring expansion vs dimerization.
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Scheme 3. Exhaustive oxidation of dithiine 3e and 3g to respective tetroxides.
Scheme 3. Exhaustive oxidation of dithiine 3e and 3g to respective tetroxides.
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Figure 2. Crystal Data of 6, CCDC 2571234 C15H11BrO4S2, Mr = 399.27, orthorhombic, Pca21 (No. 29), a = 7.41370(10) Å, b = 12.4876(2) Å, c = 16.3887(2) Å, α = β = γ = 90°, V = 1517.25(4) Å 3, T = 293.15(10) K, Z = 4, Z' = 1, μ(Cu Kα) = 6.409, 14034 reflections measured, 2537 unique (Rint = 0.0320) which were used in all calculations. The final wR2 was 0.0782 (all data) and R1 was 0.0288 (I > 2(I)).
Figure 2. Crystal Data of 6, CCDC 2571234 C15H11BrO4S2, Mr = 399.27, orthorhombic, Pca21 (No. 29), a = 7.41370(10) Å, b = 12.4876(2) Å, c = 16.3887(2) Å, α = β = γ = 90°, V = 1517.25(4) Å 3, T = 293.15(10) K, Z = 4, Z' = 1, μ(Cu Kα) = 6.409, 14034 reflections measured, 2537 unique (Rint = 0.0320) which were used in all calculations. The final wR2 was 0.0782 (all data) and R1 was 0.0288 (I > 2(I)).
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Scheme 4. Mechanistic reaction pathway of a benzo[b][1,3]dithiole derivatives with bromine.
Scheme 4. Mechanistic reaction pathway of a benzo[b][1,3]dithiole derivatives with bromine.
Preprints 229352 sch004
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