Yb(OTf)₃-Catalyzed Synthesis of Thiochromeno[2,3-b]chromenes and Their Antiproliferative Study

Abstract

The synthesis of hitherto unreported thiochromeno[2,3-b]chromenes from 4-hydroxy-2H-chromene-2-thiones was investigated with salicylaldehydes and cyclohexane-1,3-diones in the presence of 10 mol% Yb(OTf)₃ in toluene. The three-component reaction proceeds via Knoevenagel condensation between the cyclohexane-1,3-dione and the salicylaldehyde followed by Michael addition with the 4-hydroxy-2H-chromene-2-thione. The products were obtained in good to excellent yields, with retention of the sulfur atom in the heterocycle. This synthetic approach offers a straightforward and reliable method for preparing sulfur-containing heterocycles, potentially expanding the scope of thiochromene chemistry. A molecular docking study was performed on the synthesized derivatives, and two compounds demonstrated a dose-dependent antiproliferative effect and enhanced ROS generation in the MDA-MB-468 triple-negative breast cancer cell line.

4-Hydroxycoumarin is a naturally occurring organic compound and a coumarin derivative, which plays a significant role in biochemistry.[1] [2] [3] [4] [5] Due to its diverse biological activities, there is a continuous interest in developing highly effective synthetic methods for constructing coumarin scaffolds with structural diversity and complexity for medicinal chemistry applications.[6–8] 4-Hydroxydithiocoumarin, a sulfur analogue of 4-hydroxycoumarin, has also been extensively explored for synthesizing various chemical entities, recently reviewed by our group.[9] But, the chemistry of 4-hydroxythiocoumarin remains largely unexplored due to its limited availability. Therefore, our main objective is to study the reactivity patterns of 4-hydroxythiocoumarin and compare them with the reactivity of these two related molecules.

Organosulfur compounds are widely recognized for their diverse synthetic uses and potential pharmaceutical applications.[10] [11] [12] The growing number of approved drugs based on organosulfur compounds has sparked significant interest in incorporating various sulfur functional groups into organic molecules.[13] They are used as nutraceutical agents that can act as direct antioxidants by trapping electrons and also exhibit non-antioxidant effects.[14] These properties include antiplatelet, fibrinolytic, anti-inflammatory, immunomodulatory, and anti-ageing.[15] These attributes make them beneficial in the prevention and treatment of various pathological conditions, such as cardiovascular diseases, cancer, neurodegenerative disorders, and diabetes. Furthermore, sulfur-containing compounds find widespread use in industry, including in the synthesis of polymers and agrochemicals, and in materials science.

Chromenes are a class of compounds that exist in many naturally occurring molecules, such as flavonoids, coumarins, and furanochromenes.[16] [17] [18] Combining chromene with thiochromene can give rise to two intriguing categories of tetracyclic systems: thiochromeno[2,3-b]chromene and thiochromeno[4,3-b]chromene. While the chromeno[2,3-b]chromene core is present in several biologically active natural compounds, thiochromeno[2,3-b]chromene has neither been found in nature nor synthesized to date. We recently reported a similar reaction of 4-hydroxy-2H-chromene-2-thione catalyzed by l-proline that produced chromeno[2,3-b]chromene by eliminating the sulfur from the ring (Scheme [1]).[19a] But, using salicylaldehyde instead of benzaldehyde and changing the catalyst from l-proline to Yb(OTf)₃ produced thiochromeno[2,3-b]chromene with retention of the sulfur atom in the ring system (Scheme [1]).

The present experimental investigation consisted of various 4-hydroxy-2H-chromene-2-thiones 1 synthesized using a previously reported procedure.[19b] After synthesizing the starting materials, we initiated the investigation by taking 4-hydroxy-2H-chromene-2-thione (1a; 35 mg, 0.20 mmol), salicylaldehyde (2a; 25 mg, 0.20 mmol), and dimedone (3a; 28 mg, 0.20 mmol) as the model substrates.

Initially, 4-hydroxy-2H-chromene-2-thione, salicylaldehyde, and dimedone were stirred at room temperature for 12 hours in the presence of 10 mol% Yb(OTf)₃, but no desired product was found (Table [1], entry 1). Then, a similar reaction was performed for 6 hours at 80 °C; surprisingly, a new light yellow compound was isolated in 56% yield (Table [1], entry 2). Initially, from the analysis of ¹H and ¹³C NMR spectra, we thought the compound was similar to the product reported by us previously with the elimination of sulfur from the system. But, the HRMS data suggested the compound­ as being 11-(2-hydroxyphenyl)-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4a) where the sulfur is retained, unlike the previous method. The compound shows signals at δ 9.31 ppm (sharp) for the hydroxyl proton, at δ 1.08 and 1.14 ppm for two methyl groups, and at δ 2.61 and 2.37 ppm for two methylene groups. Furthermore, the benzylic proton shows a chemical shift at δ 5.91 ppm.

After confirming the structure, we focussed on optimizing the reaction conditions to obtain the maximum yield of the product. Thus, the temperature was increased to 100 °C, and the yield of the desired product also increased to 83% (Table [1], entry 3). Upon increasing the temperature to 110 °C, the reaction did not improve (Table [1], entry 4). After changing the amount of catalyst from 10 mol% to 5 and 15 mol%, the optimum catalyst amount was found to be 10 mol% (Table [1], entries 5 and 6). To determine the role of the catalyst, a reaction was carried out at 100 °C in the absence of any catalyst; only a trace amount of product formation was observed (Table [1], entry 7). Other similar catalysts, like Sc(OTf)₃ and Bi(OTf)₃, were also employed, but Yb(OTf)₃ gave the highest yield (Table [1], entries 8 and 9). We also tried l-proline as the catalyst, but no product formation was observed (Table [1], entry 10). Then, the reaction was carried out in different solvent media, such as water and DMF (Table [1], entries 11 and 12). Reaction in water failed, while in DMF, 4a was isolated in 34% yield. Therefore, the optimal reaction conditions are the use of 4-hydroxy-2H-chromene-2-thione, salicylaldehyde, and dimedone in 1:1:1 ratio, with catalysis by Yb(OTf)₃ (10 mol%) in toluene at 100 °C for 6 hours.

Having established the optimal conditions, we studied the effect of substituents on salicylaldehyde. The simple 4-hydroxy-2H-chromene-2-thione (1a), salicylaldehyde (2a), and dimedone (3a) gave the desired product 4a in 83% yield. Salicylaldehydes with electron-withdrawing groups, such as 5-F, 5-Cl, 5-Br, 5-NO₂, 3,5-dichloro, and 3,5-dibromo (4b–4g), underwent smooth reaction without any difficulties with yields ranging from 72% to 91% (Scheme [2]). But, the reaction failed for electron-donating groups, namely, 5-methoxy-, 3-ethoxy- and 4-(dimethylamino)-substituted salicylaldehydes. The cause of reaction failure might be the presence of two strong electron-donating groups present in the salicylaldehyde system. Only 5-methylsalicylaldehyde gave a successful reaction with 67% yield (4h). Reaction with 2-hydroxy-1-naphthaldehyde also failed due to steric hindrance from the two carbonyl groups. The positioning of substituents does not seem to impact the product yields significantly. Strong electron-withdrawing groups like NO₂ on the salicylaldehyde segment gave the product in highest yield. The methodology was equally successful with cyclohexane-1,3-dione giving products 4i and 4j in 59% and 72% yield, respectively. Building upon these promising outcomes, the current methodology was broadened to encompass a range of functionalized 4-hydroxy-2H-chromene-2-thiones reacting with salicylaldehydes and cyclohexane-1,3-diones in toluene, resulting in the formation of the desired products 4k–4ab in moderate to good yields (Scheme [2]). After all the substrates were synthesized, a common trend observed in the results is that electron-withdrawing groups (such as NO₂ or X) on the salicylaldehyde ring enhance the reaction, yielding superior outcomes compared to strong electron-donating groups (such as OMe or NMe₂) due to the different electrophilic properties of the salicylaldehydes. The products were characterized by ¹H, ¹³C, and ¹⁹F NMR spectroscopy and HRMS. Later, we confirmed the structure of the compounds by X-ray crystallography, and it was observed that the sulfur is retained in the ring system. It was also observed from the crystal structure that there is a strong intramolecular hydrogen bond between the 12-carbonyl oxygen and the hydroxyl group of the salicylaldehyde moiety. An ORTEP diagram of compound 4o is shown in Figure S1 (Supporting Information, SI).

In addition, we attempted to extend the protocol with benzaldehyde in lieu of salicylaldehyde, but the results were not that promising as yields were comparatively low and reaction proceeded only in the absence of electron-donating groups. Benzaldehyde with 2-Cl, 3-Cl, 4-Cl, 4-NO₂, and 4-CH₃ substitution resulted in the desired products 5b, 5d–5g in low to moderate yield (Scheme [3]).

A plausible mechanism for the formation of thiochromeno[2,3-b]chromenedione is proposed, as shown in Scheme [4]. Initially, the reaction between salicylaldehyde (2a) and dimedone (3a) generates intermediate A through Knoevenagel condensation. Then, 4-hydroxy-2H-chromene-2-thione (1a) attacks intermediate A through carbon to produce intermediate B. After enolization, it undergoes cyclization by the attack of sulfur to the dimedone moiety, followed by the release of water and the catalyst, leading to the formation of the desired product 4a. Unlike our previous work,[19a] here the system retains the sulfur atom and no H₂S gas was released, which was confirmed by lead acetate test paper. As the lanthanides like ytterbium cation have more affinity towards oxygen, there is preferable attachment with the oxygen of the dimedone moiety rather than the sulfur atom, making the C–O bond weak. This directs the formation of a thiopyran ring rather than the expected pyran ring with the release of H₂S gas.

Predicted Targets of Compound 4a Involved in Cancer Development and Progression

Using the SuperPred platform, a machine learning algorithm was employed to predict potential targets of compound 4a. The algorithm evaluates the structural similarity between the input compound and known bioactive compounds, ranking potential protein targets based on the likelihood of interaction. The highest-ranked predicted targets included DNA-(apurinic or apyrimidinic site) lyase (APEX1), transcription intermediary factor 1-alpha (TRIM24), arachidonate 12-lipoxygenase, endoplasmic reticulum amyloid beta-peptide-binding protein, casein kinase II alpha/beta, cathepsin D (CTSD), dual-specificity protein kinase CLK4 (CLK4), hypoxia-inducible factor 1-alpha (HIF1A), and DNA topoisomerase II alpha (TOP2A). The targets, with probability scores above 90%, are detailed in Table S1 (SI). Many of these proteins are implicated in cancer development and progression, making them relevant for further analysis.

Gene Expression Analysis of Predicted Targets in Breast Cancer

Gene expression analysis using the UALCAN database, based on data from The Cancer Genome Atlas (TCGA), revealed significant expression patterns of the predicted targets in breast invasive carcinoma, including triple-negative breast cancer (TNBC). As shown in Figure [1] and Table S2 (SI), the expression levels of APEX1, TRIM24, HSD17B10, CSNK2A1, CTSD, HIF1A, and TOP2A were found to be consistently overexpressed across all breast cancer cell lines compared to normal tissues. TOP2A exhibited the highest expression fold change, showing a 39.5-fold increase in the basal-like subtype of TNBC compared to normal tissue samples (Table S3, SI). Also, the dysregulated expression of TOP2A has been associated with different types of cancer, and the higher expression is associated with a poor prognosis in highly aggressive types of cancers like TNBC.[20] [21] Given its pronounced overexpression in triple-negative breast cancer, TOP2A was selected as the primary target for subsequent molecular docking studies involving all 28 compounds 4a–4ab.

Binding of Compound 4a and Its Derivatives to TOP2A via Molecular Docking Simulations

Molecular docking simulations were performed using AutoDock Vina to predict the binding poses and affinities of the 28 compounds 4a–4ab with TOP2A (PDB ID 6NOD). The FDA-approved chemotherapeutic drug doxorubicin, a known inhibitor of TOP2A, served as the control and exhibited a binding energy of –10.8 kcal/mol. All 28 test compounds demonstrated favourable binding energies with TOP2A, with compound 4w showing the highest binding energy value. The top four compounds, 4b, 4k, 4w, and 4z, exhibited strong interactions with key amino acid residues of TOP2A, with binding energy values of –10.3, –10.3, –10.4, and –10.1 kcal/mol, and the unmodified compound 4a exhibited a binding energy value of –9.8 kcal/mol. The binding energies and interacting residues for these five compounds, along with doxorubicin, are provided in Table S4 (SI). The binding energy values for the remaining compounds are given in Table S5 (SI). The corresponding 2D interaction profiles are illustrated in Figure S2 (SI). Compounds 4w and 4a have the most favourable binding energies. Furthermore, compounds 4a and 4w have been shown to bind within the same binding pocket as doxorubicin, as illustrated in Figure S3 (SI). Therefore, these compounds were selected for further analysis.

Cell Viability Assay

Following the results of the virtual screening process, compound 4w and its parent compound 4a were chosen for further investigation to assess their effects on MDA-MB-468 and MCF7 breast cancer cell lines. In this study, the MTT assay was utilized to assess the impact of these compounds on cellular viability following a dose-dependent treatment over 48 hours.

Treatment with the parent compound 4a resulted in reduced viability in MDA-MB-468 cells, achieving an IC₅₀ value of approximately 168 μM (Figure [2], A and F). Additionally, compound 4w also significantly decreased cell viability, with a lower IC₅₀ value compared to the parent compound 4a (Figure [2], B and F). In contrast, the IC₅₀ values were much higher in MCF7 cells than in the TNBC cells for both compounds (Figure [2], C, D, and F). Along with this, the IC₅₀ value for doxorubicin was also established (Figure S4, SI). The results indicated a concentration-dependent decrease in cell viability of the MDA-MB-468 TNBC cells. Although the IC₅₀ concentrations for compounds 4a and 4w was higher, their antiproliferative effects in MDA-MB-468 cells were clearly evident. This supports the hypothesis that these compounds may exhibit anticancer properties in aggressive TNBC cells, prompting further investigation into their potential biomedical applications.

Reactive Oxygen Species (ROS) Analysis

Following the study on the antiproliferative activity of the compounds, the generation of reactive oxygen species (ROS) in the MDA-MB-468 cell line was further examined. Elevated intracellular ROS levels can significantly contribute to cellular damage through lipid peroxidation and impaired enzymatic function, ultimately leading to abnormal cell proliferation or death. In this investigation, cells treated with the IC₅₀ concentrations of compounds 4a and 4w for 6 and 24 hours were analyzed for ROS presence in comparison to untreated cells (Figure [2], E). The results indicated that ROS generation increased by 1.3-fold after 6 hours and by 1.5-fold after 24 hours of treatment with the parent compound 4a, relative to untreated cells. Similarly, compound 4w, which exhibited a higher cytotoxic effect on TNBC cells, resulted in a 1.4-fold increase in ROS after 6 hours and a 1.7-fold increase after 24 hours, compared to untreated cells. Both treatment groups, 4a and 4w, showed an increase in green fluorescence, indicating drug-induced ROS generation when compared to untreated cells (Figure [2], E). Notably, ROS levels were higher at the 24-hour mark than at 6 hours for both treatment groups (Figure [3], B and C). Thus, the DCFDA assay results support the findings from the MTT assay, suggesting that the antiproliferative effects observed in TNBC cells could be attributed to ROS-mediated cellular damage.

Live–Dead Cell Imaging

To further correlate the antiproliferative phenomenon and ascertain the anticancer effect of the compounds, live–dead cell imaging of MDA-MB-468 TNBC cells following treatment at IC₅₀ concentrations was investigated. Dual staining of untreated and treated TNBC cells with calcein AM and propidium iodide (PI) was performed for the assay. Live–dead cell imaging of the cells treated with the selected compounds showed an increased presence of PI-stained dead cells in comparison to the untreated condition (Figure [3], A). Among the groups, higher numbers of dead cells were observed on 4w treatment than in 4a treated cells (Figure [3], D). Therefore, the increase in red fluorescence following treatment provided a clear visualization of the anticancer effect of the chosen compound in MDA-MB-468 TNBC cells.

Effect of Compounds 4a and 4w on Cell Cycle Arrest

Afterwards, the effects of compounds 4a and 4w on cell cycle progression were assessed in MDA-MB-468 TNBC cells to analyze the ability of cell proliferation following the treatment. The cell cycle analysis showed that treatment with compound 4w resulted in significant alterations in cell cycle distribution, particularly in the G0/G1 phase which increased from 48.6% to 60.4%, suggesting a marked induction of G0/G1 phase arrest (Figure [4]). This signifies that 4w has a potent effect on inhibiting cell cycle progression in TNBC cells, indicating a higher possibility to target topoisomerase II alpha.[22] [23] In contrast, treatment with compound 4a did not show a significant effect on cell cycle arrest, further highlighting the superior efficacy of its modified derivative, 4w, inducing cell cycle arrest and thus decreasing the cell proliferation ability of the cells.

In conclusion, we successfully synthesized thiochromeno[2,3-b]chromene derivatives through a three-component reaction involving 4-hydroxy-2H-chromene-2-thiones, aryl aldehydes, and cyclohexane-1,3-diones in toluene, catalyzed by ytterbium triflate. The catalyst plays a crucial role in determining the product structure, enabling the retention of the sulfur atom in the framework – distinct from our previous work. Target prediction studies and gene enrichment analysis of the primary compound 4a indicated potential interactions with targets involved in cancer progression. Molecular docking studies were then performed for all compounds, with the parent compound 4a and another with the highest binding affinity (4w) selected for further evaluation. Finally, in vitro assays, including cell viability, ROS generation, and cell cycle analysis, revealed that compounds 4a and 4w demonstrate antiproliferative activity in MDA-MB-468 breast cancer cells. This highlights their promising antiproliferative potential in TNBC cells. Given the limitations and resistance associated with doxorubicin treatment, the development of novel therapeutic molecules with improved efficacy and reduced toxicity is crucial for advancing TNBC treatment. Our findings provide a strong foundation for further optimization and preclinical evaluation of these compounds as potential alternatives in TNBC therapy.

The reagents used in this work were obtained in the highest commercially available purity and utilized without further purification. For synthetic procedures, all reactions were conducted in an open-air environment within predried glassware. Starting materials were prepared following established literature methods.[19b] Crude products were purified via silica gel (60–120 mesh) column chromatography (hexane/EtOAc). Single crystals were obtained by slow evaporation from a 1:1 solution of chloroform and hexane. Melting points were measured using a Büchi B-540 apparatus and are reported without correction. The isolated compounds were characterized using ¹H and ¹³C NMR (Bruker) and high-resolution mass spectrometry (HRMS, Agilent). NMR spectra were recorded in CDCl₃ on either a 400 MHz (for ¹H; 100 MHz for ¹³C), a 500 MHz (for ¹H; 125 MHz for ¹³C), or a 600 MHz (for ¹H; 151 MHz for ¹³C) spectrometer. Chemical shifts were calibrated using residual solvent signals, with CHCl₃ set to 7.26 ppm for ¹H and 77.06 ppm for ¹³C. Chemical shifts are reported in δ units (ppm). The ¹H NMR data includes chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, and combinations thereof), coupling constant(s) (J) in hertz (Hz), and integration. Crystal structure data were collected on a Bruker SMART APEX-II CCD diffractometer, and HRMS was performed using an Agilent mass spectrometer in electrospray ionization–time-of-flight (ESI-TOF) mode.

Synthesis of 4a–4ab (Method A1); General Procedure

4-Hydroxy-2H-chromene-2-thione 1 (0.2 mmol), salicylaldehyde 2 (0.2 mmol), and cyclohexane-1,3-dione 3 (0.2 mmol) were dissolved in toluene (2 mL) in a 10-mL round-bottomed flask. Then, Yb(OTf)₃ (10 mol%) was added to the reaction mixture as a catalyst and the mixture kept in an oil bath at 100 °C under air. The progress of the reaction was monitored periodically by analyzing the reaction mixture using TLC. Upon completion, the mixture was cooled to room temperature. Subsequently, the reaction mixture was concentrated, and the residue was dissolved in DCM (5 mL). The resulting organic phase was washed with brine solution (2 × 5 mL). It was then dried over anhydrous sodium sulfate, and the solvent was evaporated using a rotary evaporator. The crude product obtained was purified by silica gel (60–120 mesh) column chromatography [EtOAc/petroleum ether (PE)].

Synthesis of 5a–5g (Method A2); General Procedure

The same procedure as Method A1 was used, except benzaldehyde 2′ (0.2 mmol) was used in place of salicylaldehyde.

11-(2-Hydroxyphenyl)-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4a)

Following Method A1, compound 4a was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 67 mg (83%); mp 242–244 °C.

¹H NMR (400 MHz, CDCl₃): δ = 9.31 (s, 1 H), 8.17 (dd, J = 7.9, 1.7 Hz, 1 H), 7.66 (ddd, J = 8.7, 7.1, 1.7 Hz, 1 H), 7.43–7.36 (m, 2 H), 7.19 (dd, J = 7.8, 1.7 Hz, 1 H), 7.08 (ddd, J = 8.5, 7.0, 1.5 Hz, 1 H), 6.97 (dd, J = 8.1, 1.4 Hz, 1 H), 6.78–6.71 (m, 1 H), 5.91 (d, J = 1.3 Hz, 1 H), 2.72 (d, J = 16.8 Hz, 1 H), 2.52 (d, J = 17.5 Hz, 1 H), 2.38 (d, J = 4.0 Hz, 2 H), 1.14 (s, 3 H), 1.08 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.7, 175.4, 156.0, 153.8, 146.8, 134.3, 130.0, 129.4, 128.9, 127.5, 126.5, 125.7, 122.8, 120.5, 119.1, 118.4, 117.2, 51.2, 44.0, 34.0, 30.8, 29.2, 26.8.

HRMS (ESI): m/z calcd for C₂₄H₂₀O₄S [M + H⁺]: 405.1156; found: 405.1166.

11-(5-Fluoro-2-hydroxyphenyl)-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4b)

Following Method A1, compound 4b was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 61 mg (72%); mp 248–250 °C.

¹H NMR (500 MHz, CDCl₃): δ = 9.15 (s, 1 H), 8.14 (dd, J = 8.0, 1.7 Hz, 1 H), 7.66 (ddd, J = 8.8, 7.1, 1.8 Hz, 1 H), 7.42–7.35 (m, 2 H), 6.90 (dd, J = 9.0, 5.1 Hz, 1 H), 6.86 (dd, J = 9.6, 3.1 Hz, 1 H), 6.76 (td, J = 8.3, 2.9 Hz, 1 H), 5.85 (s, 1 H), 2.72 (d, J = 17.4 Hz, 1 H), 2.53 (d, J = 17.6 Hz, 1 H), 2.38 (d, J = 8.4 Hz, 2 H), 1.15 (s, 3 H), 1.08 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.7, 175.3, 160.2, 156.0, 149.8, 147.2, 134.4, 129.5, 126.3, 125.8, 122.6, 120.1, 120.0, 117.9, 117.3, 115.5, 115.3, 113.6, 113.4, 51.1, 43.9, 34.0, 31.1, 29.1, 26.7.

¹⁹F NMR (471 MHz, CDCl₃): δ = –123.4.

HRMS (ESI): m/z calcd for C₂₄H₁₉FO₄S [M + H⁺]: 423.1061; found: 423.1065.

11-(5-Chloro-2-hydroxyphenyl)-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4c)

Following Method A1, compound 4c was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 70 mg (80%); mp 226–229 °C.

¹H NMR (500 MHz, CDCl₃): δ = 9.42 (s, 1 H), 8.14 (dd, J = 8.0, 1.7 Hz, 1 H), 7.66 (ddd, J = 8.7, 7.1, 1.7 Hz, 1 H), 7.42–7.35 (m, 2 H), 7.10 (d, J = 2.6 Hz, 1 H), 7.02 (dd, J = 8.6, 2.6 Hz, 1 H), 6.90 (d, J = 8.6 Hz, 1 H), 5.82 (s, 1 H), 2.73 (d, J = 17.4 Hz, 1 H), 2.54 (d, J = 17.4 Hz, 1 H), 2.38 (d, J = 6.5 Hz, 2 H), 1.15 (s, 3 H), 1.09 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.7, 175.4, 156.0, 152.5, 147.4, 134.5, 131.0, 129.4, 128.8, 127.3, 126.3, 125.8, 125.0, 122.5, 120.5, 117.7, 117.3, 51.1, 43.9, 34.0, 31.0, 29.3, 26.6.

HRMS (ESI): m/z calcd for C₂₄H₁₉ClO₄S [M + H⁺]: 439.0766; found: 439.0764.

11-(5-Bromo-2-hydroxyphenyl)-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4d)

Following Method A1, compound 4d was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 81 mg (85%); mp 238–240 °C.

¹H NMR (500 MHz, CDCl₃): δ = 9.44 (s, 1 H), 8.16 (dd, J = 8.0, 1.3 Hz, 1 H), 7.67 (ddd, J = 8.6, 7.0, 1.6 Hz, 1 H), 7.43–7.37 (m, 2 H), 7.24 (d, J = 2.4 Hz, 1 H), 7.16 (dd, J = 8.6, 2.4 Hz, 1 H), 6.85 (d, J = 8.6 Hz, 1 H), 5.83 (s, 1 H), 2.73 (d, J = 17.4 Hz, 1 H), 2.54 (d, J = 17.5 Hz, 1 H), 2.39 (d, J = 3.8 Hz, 2 H), 1.15 (s, 3 H), 1.11 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 191.6, 174.4, 159.4, 155.0, 152.1, 146.3, 133.5, 130.7, 130.5, 129.3, 128.4, 125.4, 124.8, 121.6, 120.0, 116.8, 116.3, 111.2, 50.1, 42.9, 33.0, 30.0, 28.3, 25.5.

HRMS (ESI): m/z calcd for C₂₄H₁₉BrO₄S [M + H⁺]: 483.0261, 485.0240; found: 483.0266, 485.0247.

11-(3,5-Dichloro-2-hydroxyphenyl)-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4e)

Following Method A1, compound 4e was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 74 mg (79%); mp 244–246 °C.

¹H NMR (500 MHz, CDCl₃): δ = 10.00 (s, 1 H), 8.14 (dd, J = 8.4, 1.5 Hz, 1 H), 7.68 (td, J = 7.7, 1.7 Hz, 1 H), 7.42–7.38 (m, 2 H), 7.16 (d, J = 2.5 Hz, 1 H), 7.01 (d, J = 2.5 Hz, 1 H), 5.84 (s, 1 H), 2.74 (d, J = 17.5 Hz, 1 H), 2.54 (d, J = 17.5 Hz, 1 H), 2.39 (d, J = 9.0 Hz, 2 H), 1.15 (s, 3 H), 1.09 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.6, 175.5, 160.7, 156.0, 149.1, 147.7, 134.7, 132.0, 129.1, 129.0, 126.4, 126.0, 126.0, 124.7, 124.6, 122.4, 117.3, 117.3, 51.0, 43.9, 34.0, 31.7, 29.3, 26.6.

HRMS (ESI): m/z calcd for C₂₄H₁₈Cl₂O₄S [M + H⁺]: 473.0376; found: 473.0381.

11-(3,5-Dibromo-2-hydroxyphenyl)-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4f)

Following Method A1, compound 4f was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 91 mg (81%); mp 233–235 °C.

¹H NMR (500 MHz, CDCl₃): δ = 10.15 (s, 1 H), 8.18 (dd, J = 8.0, 1.6 Hz, 1 H), 7.70 (t, J = 7.7 Hz, 1 H), 7.47 (d, J = 2.4 Hz, 1 H), 7.43 (d, J = 8.2 Hz, 2 H), 7.19 (d, J = 2.4 Hz, 1 H), 5.86 (s, 1 H), 2.74 (d, J = 17.5 Hz, 1 H), 2.54 (d, J = 17.6 Hz, 1 H), 2.40 (d, J = 3.7 Hz, 2 H), 1.16 (s, 3 H), 1.11 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.5, 175.6, 160.7, 156.0, 150.6, 147.6, 134.7, 134.6, 132.1, 129.7, 129.2, 126.5, 126.0, 122.4, 117.4, 117.3, 114.3, 111.9, 51.1, 44.0, 34.1, 31.9, 29.4, 26.5.

HRMS (ESI): m/z calcd for C₂₄H₁₈Br₂O₄S [M + H⁺]: 562.9345; found: 562.9347.

11-(2-Hydroxy-5-nitrophenyl)-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4g)

Following Method A1, compound 4g was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 81 mg (91%); mp 259–261 °C.

¹H NMR (400 MHz, CDCl₃): δ = 10.50 (s, 1 H), 8.18 (dd, J = 7.9, 1.6 Hz, 1 H), 8.08 (d, J = 2.4 Hz, 1 H), 7.98 (dd, J = 8.9, 2.8 Hz, 1 H), 7.74–7.68 (m, 1 H), 7.44 (dd, J = 8.4, 2.4 Hz, 2 H), 7.01 (dd, J = 9.0, 1.0 Hz, 1 H), 5.88 (s, 1 H), 2.79 (d, J = 17.6 Hz, 1 H), 2.62 (d, J = 17.6 Hz, 1 H), 2.40 (d, J = 8.1 Hz, 2 H), 1.17 (s, 3 H), 1.10 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.6, 175.8, 160.6, 156.1, 148.5, 141.1, 134.8, 129.4, 129.0, 126.3, 126.1, 125.0, 124.1, 122.3, 119.3, 117.5, 117.2, 51.0, 44.0, 34.1, 31.0, 29.5, 26.4.

HRMS (ESI): m/z calcd for C₂₄H₁₉NO₆S [M + H⁺]: 450.1006; found: 450.1011.

11-(2-Hydroxy-5-methylphenyl)-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4h)

Following Method A1, compound 4h was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 55 mg (67%); mp 242–244 °C.

¹H NMR (500 MHz, CDCl₃): δ = 9.15 (s, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 7.67–7.61 (m, 1 H), 7.41–7.33 (m, 2 H), 6.96 (s, 1 H), 6.87 (s, 2 H), 5.86 (s, 1 H), 2.73 (d, J = 17.3 Hz, 1 H), 2.51 (d, J = 17.4 Hz, 1 H), 2.37 (d, J = 7.2 Hz, 2 H), 2.14 (s, 3 H), 1.15 (s, 3 H), 1.09 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.6, 156.0, 151.3, 146.6, 134.3, 129.9, 129.5, 129.5, 129.2, 127.9, 126.4, 125.6, 122.7, 118.9, 118.4, 117.2, 51.1, 43.9, 34.0, 30.8, 29.4, 26.5, 20.7.

HRMS (ESI): m/z calcd for C₂₅H₂₂O₄S [M + H⁺]: 419.1312; found: 419.1313.

11-(2-Hydroxyphenyl)-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4i)

Following Method A1, compound 4i was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 44 mg (59%); mp 242–244 °C.

¹H NMR (500 MHz, CDCl₃): δ = 9.33 (s, 1 H), 8.16 (d, J = 8.0 Hz, 1 H), 7.65 (t, J = 7.9 Hz, 1 H), 7.39 (dd, J = 8.4, 3.3 Hz, 2 H), 7.16 (d, J = 8.0 Hz, 1 H), 7.08 (d, J = 7.9 Hz, 1 H), 6.97 (d, J = 8.2 Hz, 1 H), 6.74 (t, J = 7.6 Hz, 1 H), 5.94 (s, 1 H), 2.80 (dd, J = 10.1, 4.5 Hz, 2 H), 2.57–2.50 (m, 2 H), 2.15 (dt, J = 10.8, 5.1 Hz, 2 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.8, 175.3, 160.1, 156.0, 153.9, 148.9, 134.2, 131.0, 129.3, 128.9, 127.5, 126.5, 125.7, 122.8, 120.5, 119.0, 118.5, 117.2, 37.7, 30.8, 30.6, 22.2.

HRMS (ESI): m/z calcd for C₂₂H₁₆O₄S [M + H⁺]: 377.0843; found: 377.0842.

11-(2-Hydroxy-5-nitrophenyl)-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4j)

Following Method A1, compound 4j was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 60 mg (72%); mp 197–200 °C.

¹H NMR (500 MHz, CDCl₃): δ = 10.47 (s, 1 H), 8.17 (dd, J = 8.1, 1.9 Hz, 1 H), 8.02 (d, J = 2.5 Hz, 1 H), 7.97 (dd, J = 9.0, 2.6 Hz, 1 H), 7.71 (ddd, J = 8.7, 7.1, 1.9 Hz, 1 H), 7.47–7.40 (m, 2 H), 7.00 (dd, J = 9.0, 1.9 Hz, 1 H), 5.91 (s, 1 H), 2.90–2.80 (m, 2 H), 2.62–2.49 (m, 2 H), 2.20 (ddd, J = 16.2, 11.5, 5.4 Hz, 2 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.9, 175.6, 161.1, 160.6, 156.0, 150.7, 141.2, 134.8, 130.0, 129.4, 126.3, 126.1, 125.0, 124.1, 122.3, 119.1, 117.5, 117.2, 37.6, 30.9, 30.7, 22.1.

HRMS (ESI): m/z calcd for C₂₂H₁₅NO₆S [M + H⁺]: 422.0693; found: 422.0695.

2-Fluoro-11-(2-hydroxyphenyl)-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4k)

Following Method A1, compound 4k was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 68 mg (77%); mp 218–220 °C.

¹H NMR (500 MHz, CDCl₃): δ = 9.13 (s, 1 H), 7.78 (dd, J = 8.0, 3.1 Hz, 1 H), 7.41–7.35 (m, 2 H), 7.18 (dd, J = 7.9, 1.8 Hz, 1 H), 7.07 (td, J = 7.7, 1.8 Hz, 1 H), 6.96 (d, J = 8.2 Hz, 1 H), 6.74 (t, J = 7.5 Hz, 1 H), 5.88 (s, 1 H), 2.72 (d, J = 17.4 Hz, 1 H), 2.51 (d, J = 17.4 Hz, 1 H), 2.37 (d, J = 9.8 Hz, 2 H), 1.14 (s, 3 H), 1.07 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.7, 160.6, 153.7, 152.2, 146.7, 129.8, 129.2, 128.9, 127.5, 122.6, 122.4, 120.5, 119.4, 119.4, 119.1, 117.9, 111.3, 111.1, 51.1, 43.9, 34.0, 30.8, 29.2, 26.7.

¹⁹F NMR (471 MHz, CDCl₃): δ = –113.7.

HRMS (ESI): m/z calcd for C₂₄H₁₉FO₄S [M + Na⁺]: 445.0886; found: 445.0882.

11-(3,5-Dibromo-2-hydroxyphenyl)-2-fluoro-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4l)

Following Method A1, compound 4l was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 83 mg (72%); mp 215–218 °C.

¹H NMR (500 MHz, CDCl₃): δ = 9.91 (s, 1 H), 7.81 (dd, J = 8.0, 2.9 Hz, 1 H), 7.46 (dd, J = 10.7, 3.2 Hz, 2 H), 7.43 (dd, J = 7.3, 2.9 Hz, 1 H), 7.19 (d, J = 2.3 Hz, 1 H), 5.84 (s, 1 H), 2.74 (d, J = 17.5 Hz, 1 H), 2.54 (d, J = 17.5 Hz, 1 H), 2.40 (d, J = 3.4 Hz, 2 H), 1.16 (s, 3 H), 1.10 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.6, 174.8, 161.1, 152.3, 150.5, 147.6, 134.6, 131.9, 129.7, 129.1, 123.7, 123.0, 122.8, 119.6, 119.5, 117.0, 114.4, 112.0, 111.5, 111.3, 51.0, 44.0, 34.1, 31.9, 29.3, 26.5.

HRMS (ESI): m/z calcd for C₂₄H₁₇Br₂FO₄S [M + H⁺]: 580.9251; found: 580.9255.

3-Fluoro-11-(2-hydroxyphenyl)-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4m)

Following Method A1, compound 4m was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 61 mg (69%); mp 201–203 °C.

¹H NMR (500 MHz, CDCl₃): δ = 9.17 (s, 1 H), 8.20 (dd, J = 8.8, 6.2 Hz, 1 H), 7.18 (dd, J = 7.8, 1.6 Hz, 1 H), 7.15–7.08 (m, 3 H), 6.97 (dd, J = 8.2, 1.4 Hz, 1 H), 6.75 (td, J = 7.6, 1.4 Hz, 1 H), 5.89 (s, 1 H), 2.71 (d, J = 17.4 Hz, 1 H), 2.51 (d, J = 17.4 Hz, 1 H), 2.38 (d, J = 5.0 Hz, 2 H), 1.15 (s, 3 H), 1.08 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.7, 174.4, 153.7, 146.6, 135.2, 129.9, 129.2, 129.1, 129.0, 127.4, 120.5, 119.1, 118.5, 108.4, 104.2, 104.0, 100.6, 51.1, 44.0, 34.0, 30.7, 29.2, 26.8.

¹⁹F NMR (471 MHz, CDCl₃): δ = –101.0.

HRMS (ESI): m/z calcd for C₂₄H₁₉FO₄S [M + Na⁺]: 445.0886; found: 445.0877.

2-Chloro-11-(2-hydroxyphenyl)-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4n)

Following Method A1, compound 4n was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 56 mg (64%); mp 231–233 °C.

¹H NMR (500 MHz, CDCl₃): δ = 9.08 (s, 1 H), 8.11 (d, J = 2.6 Hz, 1 H), 7.58 (dd, J = 8.9, 2.7 Hz, 1 H), 7.35 (d, J = 8.9 Hz, 1 H), 7.17 (dd, J = 7.9, 1.7 Hz, 1 H), 7.08 (t, J = 7.6 Hz, 1 H), 6.96 (d, J = 8.0 Hz, 1 H), 6.74 (t, J = 7.5 Hz, 1 H), 5.88 (s, 1 H), 2.72 (d, J = 17.4 Hz, 1 H), 2.51 (d, J = 17.4 Hz, 1 H), 2.37 (d, J = 8.2 Hz, 2 H), 1.14 (s, 3 H), 1.07 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.7, 174.2, 154.3, 153.7, 146.7, 134.4, 131.6, 129.8, 129.2, 129.0, 127.5, 125.7, 123.7, 120.6, 119.1, 119.0, 118.5, 51.1, 43.9, 34.0, 30.8, 29.2, 26.7.

HRMS (ESI): m/z calcd for C₂₄H₁₉ClO₄S [M + H⁺]: 439.0766; found: 439.0769.

2-Chloro-11-(5-chloro-2-hydroxyphenyl)-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4o)

Following Method A1, compound 4o was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 64 mg (68%); mp 246–248 °C.

¹H NMR (500 MHz, CDCl₃): δ = 9.16 (s, 1 H), 8.11 (d, J = 2.6 Hz, 1 H), 7.60 (dd, J = 9.0, 2.6 Hz, 1 H), 7.38 (d, J = 8.9 Hz, 1 H), 7.08 (d, J = 2.6 Hz, 1 H), 7.02 (dd, J = 8.6, 2.6 Hz, 1 H), 6.90 (d, J = 8.7 Hz, 1 H), 5.81 (s, 1 H), 2.72 (d, J = 17.4 Hz, 1 H), 2.54 (d, J = 17.5 Hz, 1 H), 2.39 (d, J = 3.5 Hz, 2 H), 1.15 (s, 3 H), 1.09 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.8, 174.2, 154.3, 152.5, 147.2, 134.6, 131.8, 130.8, 129.4, 128.9, 127.3, 125.7, 125.1, 123.6, 120.6, 119.1, 117.9, 51.1, 43.9, 34.1, 31.0, 29.2, 26.6.

HRMS (ESI): m/z calcd for C₂₄H₁₈Cl₂O₄S [M + H⁺]: 473.0376; found: 473.0379.

11-(5-Bromo-2-hydroxyphenyl)-2-chloro-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4p)

Following Method A1, compound 4p was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 79 mg (76%); mp 205–207 °C.

¹H NMR (500 MHz, CDCl₃): δ = 9.21 (s, 1 H), 8.10 (d, J = 2.6 Hz, 1 H), 7.60 (dd, J = 8.9, 2.5 Hz, 1 H), 7.38 (d, J = 8.9 Hz, 1 H), 7.21 (d, J = 2.4 Hz, 1 H), 7.16 (dd, J = 8.5, 2.5 Hz, 1 H), 6.85 (d, J = 8.5 Hz, 1 H), 5.80 (s, 1 H), 2.73 (d, J = 17.5 Hz, 1 H), 2.54 (d, J = 17.5 Hz, 1 H), 2.39 (d, J = 3.6 Hz, 2 H), 1.15 (s, 3 H), 1.10 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.7, 174.2, 154.3, 153.0, 147.2, 134.6, 131.8, 131.3, 130.2, 129.3, 125.7, 123.5, 121.1, 119.1, 117.9, 112.4, 51.1, 43.9, 34.1, 31.0, 29.3, 26.5.

HRMS (ESI): m/z calcd for C₂₄H₁₈BrClO₄S [M + H⁺]: 516.9871, 518.9850; found: 516.9860, 518.9833.

2-Chloro-11-(3,5-dibromo-2-hydroxyphenyl)-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4q)

Following Method A1, compound 4q was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 95 mg (80%); mp 252–254 °C.

¹H NMR (500 MHz, CDCl₃): δ = 9.85 (s, 1 H), 8.12 (d, J = 2.6 Hz, 1 H), 7.62 (dd, J = 9.0, 2.6 Hz, 1 H), 7.47 (d, J = 2.3 Hz, 1 H), 7.40 (d, J = 8.9 Hz, 1 H), 7.18 (d, J = 2.3 Hz, 1 H), 5.82 (s, 1 H), 2.73 (d, J = 17.5 Hz, 1 H), 2.54 (d, J = 17.4 Hz, 1 H), 2.39 (d, J = 3.7 Hz, 2 H), 1.16 (s, 3 H), 1.09 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.6, 174.3, 161.1, 154.3, 150.4, 147.5, 134.8, 134.7, 132.0, 131.9, 129.7, 129.1, 125.8, 123.4, 119.1, 117.5, 114.4, 112.0, 51.0, 43.9, 34.1, 31.9, 29.3, 26.5.

HRMS (ESI): m/z calcd for C₂₄H₁₇Br₂ClO₄S [M + H⁺]: 596.8956; found: 596.8957.

2-Bromo-11-(2-hydroxyphenyl)-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4r)

Following Method A1, compound 4r was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 74 mg (77%); mp 225–227 °C.

¹H NMR (500 MHz, CDCl₃): δ = 9.07 (s, 1 H), 8.26 (d, J = 2.6 Hz, 1 H), 7.70 (dd, J = 8.9, 2.6 Hz, 1 H), 7.28 (d, J = 8.9 Hz, 1 H), 7.17 (d, J = 7.8 Hz, 1 H), 7.07 (t, J = 7.8 Hz, 1 H), 6.96 (d, J = 8.0 Hz, 1 H), 6.74 (t, J = 7.5 Hz, 1 H), 5.87 (s, 1 H), 2.72 (d, J = 17.4 Hz, 1 H), 2.51 (d, J = 17.5 Hz, 1 H), 2.37 (d, J = 9.0 Hz, 2 H), 1.14 (s, 3 H), 1.07 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.7, 174.0, 154.7, 153.7, 146.6, 137.2, 129.8, 129.2, 129.0, 128.9, 127.4, 124.0, 120.6, 119.2, 119.1, 119.0, 118.6, 51.1, 43.9, 34.0, 30.8, 29.2, 26.7.

HRMS (ESI): m/z calcd for C₂₄H₁₉BrO₄S [M + H⁺]: 483.0261, 485.0240; found: 483.0255, 485.0235.

2-Bromo-11-(5-chloro-2-hydroxyphenyl)-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4s)

Following Method A1, compound 4s was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 85 mg (82%); mp 238–240 °C.

¹H NMR (500 MHz, CDCl₃): δ = 9.17 (s, 1 H), 8.25 (d, J = 2.5 Hz, 1 H), 7.73 (dd, J = 8.9, 2.5 Hz, 1 H), 7.30 (d, J = 8.9 Hz, 1 H), 7.07 (d, J = 2.6 Hz, 1 H), 7.02 (dd, J = 8.6, 2.6 Hz, 1 H), 6.89 (d, J = 8.6 Hz, 1 H), 5.80 (s, 1 H), 2.72 (d, J = 17.4 Hz, 1 H), 2.54 (d, J = 17.4 Hz, 1 H), 2.39 (d, J = 5.1 Hz, 2 H), 1.15 (s, 3 H), 1.09 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.8, 174.0, 160.8, 154.7, 152.4, 147.2, 137.4, 130.8, 129.3, 128.9, 128.9, 127.3, 125.1, 123.8, 120.5, 119.2, 119.2, 118.0, 51.0, 43.9, 34.0, 31.0, 29.2, 26.6.

HRMS (ESI): m/z calcd for C₂₄H₁₈BrClO₄S [M + H⁺]: 518.9850; found: 518.9848.

2-Bromo-11-(2-hydroxy-5-methylphenyl)-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4t)

Following Method A1, compound 4t was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 69 mg (70%); mp 224–226 °C.

¹H NMR (500 MHz, CDCl₃): δ = 8.89 (s, 1 H), 8.28 (d, J = 2.5 Hz, 1 H), 7.72 (dd, J = 8.9, 2.5 Hz, 1 H), 7.30 (d, J = 8.9 Hz, 1 H), 6.94 (d, J = 1.9 Hz, 1 H), 6.87 (d, J = 3.0 Hz, 2 H), 5.84 (s, 1 H), 2.72 (d, J = 17.3 Hz, 1 H), 2.51 (d, J = 17.4 Hz, 1 H), 2.38 (d, J = 4.6 Hz, 2 H), 2.14 (s, 3 H), 1.15 (s, 3 H), 1.08 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.6, 174.1, 154.7, 151.3, 146.4, 137.2, 129.9, 129.7, 129.6, 129.0, 129.0, 127.9, 124.1, 119.2, 119.0, 119.0, 118.7, 51.1, 44.0, 34.1, 30.9, 29.3, 26.5, 20.8.

HRMS (ESI): m/z calcd for C₂₅H₂₁BrO₄S [M + H⁺]: 497.0417, 499.0397; found: 497.0421, 499.0393.

2-Bromo-11-(2-hydroxy-5-nitrophenyl)-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4u)

Following Method A1, compound 4u was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 93 mg (89%); mp 224–226 °C.

¹H NMR (500 MHz, CDCl₃): δ = 10.22 (s, 1 H), 8.29 (d, J = 2.5 Hz, 1 H), 8.06 (d, J = 2.8 Hz, 1 H), 7.98 (dd, J = 8.9, 2.8 Hz, 1 H), 7.78 (dd, J = 9.0, 2.5 Hz, 1 H), 7.35 (d, J = 8.9 Hz, 1 H), 7.01 (d, J = 9.0 Hz, 1 H), 5.85 (s, 1 H), 2.78 (d, J = 17.6 Hz, 1 H), 2.61 (d, J = 17.6 Hz, 1 H), 2.40 (d, J = 10.0 Hz, 2 H), 1.17 (s, 3 H), 1.09 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.7, 174.4, 160.4, 154.8, 148.3, 141.1, 137.7, 129.1, 128.9, 128.9, 125.1, 124.1, 123.6, 119.5, 119.4, 117.4, 51.0, 44.0, 34.1, 31.0, 29.4, 26.4.

HRMS (ESI): m/z calcd for C₂₄H₁₈BrNO₆S [M + H⁺]: 528.0111, 530.0091; found: 528.0114, 530.0095.

11-(2-Hydroxyphenyl)-2,8,8-trimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4v)

Following Method A1, compound 4v was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 60 mg (72%); mp 211–214 °C.

¹H NMR (500 MHz, CDCl₃): δ = 9.37 (s, 1 H), 7.95 (s, 1 H), 7.45 (dd, J = 8.5, 2.1 Hz, 1 H), 7.28 (d, J = 8.5 Hz, 1 H), 7.20–7.15 (m, 1 H), 7.07 (t, J = 7.2 Hz, 1 H), 6.96 (d, J = 8.3 Hz, 1 H), 6.73 (t, J = 7.4 Hz, 1 H), 5.91 (s, 1 H), 2.72 (d, J = 17.3 Hz, 1 H), 2.51 (d, J = 17.5 Hz, 1 H), 2.41 (s, 3 H), 2.37 (d, J = 7.0 Hz, 2 H), 1.14 (s, 3 H), 1.08 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.6, 175.5, 154.4, 153.8, 146.9, 135.8, 135.5, 130.0, 129.5, 128.8, 127.4, 125.7, 122.4, 120.4, 119.1, 118.2, 117.0, 51.2, 44.0, 34.0, 30.8, 29.3, 26.8, 20.9.

HRMS (ESI): m/z calcd for C₂₅H₂₂O₄S [M + H⁺]: 419.1312; found: 419.1315.

11-(5-Fluoro-2-hydroxyphenyl)-2,8,8-trimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4w)

Following Method A1, compound 4w was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 54 mg (59%); mp 194–196 °C.

¹H NMR (500 MHz, CDCl₃): δ = 9.21 (s, 1 H), 7.96 (d, J = 2.3 Hz, 1 H), 7.48 (dd, J = 8.5, 2.3 Hz, 1 H), 7.31 (d, J = 8.6 Hz, 1 H), 6.91 (dd, J = 8.9, 5.1 Hz, 1 H), 6.86 (dd, J = 9.6, 3.1 Hz, 1 H), 6.77 (td, J = 8.4, 3.2 Hz, 1 H), 5.87 (s, 1 H), 2.71 (d, J = 17.4 Hz, 1 H), 2.53 (d, J = 17.4 Hz, 1 H), 2.42 (s, 3 H), 2.39 (d, J = 3.9 Hz, 2 H), 1.15 (s, 3 H), 1.09 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.6, 175.5, 156.1, 154.4, 149.8, 147.2, 136.0, 135.7, 130.7, 129.6, 125.7, 122.3, 120.1, 120.1, 117.8, 117.1, 115.5, 115.3, 113.6, 113.4, 51.1, 44.0, 34.0, 31.2, 29.2, 26.8, 20.9.

HRMS (ESI): m/z calcd for C₂₅H₂₁FO₄S [M + Na⁺]: 459.1042; found: 459.1031.

11-(3,5-Dichloro-2-hydroxyphenyl)-2,8,8-trimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4x)

Following Method A1, compound 4x was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 62 mg (65%); mp 245–247 °C.

¹H NMR (500 MHz, CDCl₃): δ = 10.07 (s, 1 H), 7.94 (d, J = 2.3 Hz, 1 H), 7.49 (dd, J = 8.6, 2.3 Hz, 1 H), 7.31 (d, J = 8.6 Hz, 1 H), 7.16 (d, J = 2.7 Hz, 1 H), 7.00 (d, J = 2.5 Hz, 1 H), 5.85 (s, 1 H), 2.75 (s, 1 H), 2.53 (d, J = 17.1 Hz, 1 H), 2.42 (s, 3 H), 2.39 (d, J = 5.2 Hz, 2 H), 1.15 (s, 3 H), 1.10 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.5, 175.6, 154.4, 149.2, 147.7, 136.2, 135.9, 132.1, 129.2, 129.0, 126.0, 125.7, 124.7, 124.6, 122.1, 117.2, 117.1, 51.1, 43.9, 34.1, 31.7, 29.3, 26.6, 20.9.

HRMS (ESI): m/z calcd for C₂₅H₂₀Cl₂O₄S [M + H⁺]: 487.0533; found: 487.0537.

11-(2-Hydroxy-5-nitrophenyl)-2-methyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4y)

Following Method A1, compound 4y was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 61 mg (71%); mp 219–221 °C.

¹H NMR (500 MHz, CDCl₃): δ = 10.55 (s, 1 H), 8.01 (d, J = 2.8 Hz, 1 H), 7.98–7.93 (m, 2 H), 7.50 (dd, J = 8.6, 2.2 Hz, 1 H), 7.33 (d, J = 8.6 Hz, 1 H), 6.98 (d, J = 8.9 Hz, 1 H), 5.90 (s, 1 H), 2.85 (dt, J = 13.1, 5.0 Hz, 2 H), 2.59–2.50 (m, 2 H), 2.43 (s, 3 H), 2.20 (ddt, J = 16.8, 10.9, 5.2 Hz, 2 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.7, 175.7, 160.9, 160.7, 154.4, 150.6, 141.1, 136.3, 136.0, 130.0, 129.4, 125.6, 124.9, 124.1, 122.0, 119.1, 117.2, 117.0, 37.6, 30.9, 30.7, 22.2, 20.9.

HRMS (ESI): m/z calcd for C₂₃H₁₇NO₆S [M + H⁺]: 436.0850; found: 436.0861.

11-(2-Hydroxyphenyl)-2-methoxy-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4z)

Following Method A1, compound 4z was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 65 mg (75%); mp 243–245 °C.

¹H NMR (500 MHz, CDCl₃): δ = 9.38 (s, 1 H), 7.51 (d, J = 3.2 Hz, 1 H), 7.32 (d, J = 9.2 Hz, 1 H), 7.23 (dd, J = 9.2, 3.1 Hz, 1 H), 7.18 (dd, J = 7.8, 1.6 Hz, 1 H), 7.07 (t, J = 8.0 Hz, 1 H), 6.99–6.94 (m, 1 H), 6.74 (t, J = 7.3 Hz, 1 H), 5.91 (s, 1 H), 3.85 (s, 3 H), 2.72 (d, J = 17.3 Hz, 1 H), 2.51 (d, J = 17.4 Hz, 1 H), 2.37 (d, J = 8.0 Hz, 2 H), 1.14 (s, 3 H), 1.08 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.6, 175.3, 157.2, 153.8, 151.0, 146.9, 130.0, 129.5, 128.8, 127.5, 124.4, 123.3, 120.4, 119.1, 118.6, 117.8, 105.4, 55.9, 51.1, 44.0, 34.0, 30.8, 29.3, 26.8.

HRMS (ESI): m/z calcd for C₂₅H₂₂O₅S [M + H⁺]: 435.1261; found: 435.1258.

11-(5-Fluoro-2-hydroxyphenyl)-2-methoxy-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4aa)

Following Method A1, compound 4aa was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 63 mg (70%); mp 214–216 °C.

¹H NMR (400 MHz, CDCl₃): δ = 9.23 (s, 1 H), 7.50 (d, J = 2.4 Hz, 1 H), 7.33 (dd, J = 9.1, 1.3 Hz, 1 H), 7.26–7.22 (m, 1 H), 6.88 (ddd, J = 20.8, 9.0, 3.6 Hz, 2 H), 6.80–6.73 (m, 1 H), 5.87 (s, 1 H), 3.85 (s, 3 H), 2.72 (d, J = 17.5 Hz, 1 H), 2.52 (d, J = 17.5 Hz, 1 H), 2.39 (d, J = 4.7 Hz, 2 H), 1.15 (s, 3 H), 1.08 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.7, 175.2, 157.3, 149.8, 147.2, 129.6, 124.5, 123.2, 120.1, 120.0, 118.7, 117.3, 115.5, 115.3, 113.6, 113.4, 105.3, 56.0, 51.1, 44.0, 34.0, 31.2, 29.2, 26.8.

HRMS (ESI): m/z calcd for C₂₅H₂₁FO₅S [M + H⁺]: 453.1167; found: 453.1168.

11-(2-Hydroxy-5-methylphenyl)-2-methoxy-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (4ab)

Following Method A1, compound 4ab was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 8:2); yield: 55 mg (61%); mp 222–224 °C.

¹H NMR (500 MHz, CDCl₃): δ = 9.21 (s, 1 H), 7.52 (d, J = 3.1 Hz, 1 H), 7.34 (d, J = 9.1 Hz, 1 H), 7.24 (dd, J = 9.2, 3.0 Hz, 1 H), 6.95 (s, 1 H), 6.87 (s, 2 H), 5.88 (s, 1 H), 3.86 (s, 3 H), 2.72 (d, J = 17.3 Hz, 1 H), 2.51 (d, J = 17.4 Hz, 1 H), 2.37 (d, J = 4.4 Hz, 2 H), 2.14 (s, 3 H), 1.15 (s, 3 H), 1.09 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.6, 175.3, 159.7, 157.2, 151.4, 151.0, 146.7, 130.0, 129.5, 129.5, 129.3, 127.9, 124.4, 123.4, 118.9, 118.6, 117.8, 105.4, 56.0, 51.2, 44.0, 34.0, 30.9, 29.4, 26.5, 20.8.

HRMS (ESI): m/z calcd for C₂₆H₂₄O₅S [M + H⁺]: 449.1418; found: 449.1419.

8,8-Dimethyl-11-phenyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (5a)

Following Method A2, compound 5a was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 9:1); yield: 45 mg (60%); mp 223–225 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.14 (d, J = 8.0 Hz, 1 H), 7.65–7.58 (m, 1 H), 7.52 (d, J = 7.2 Hz, 2 H), 7.41–7.34 (m, 2 H), 7.22 (t, J = 7.4 Hz, 2 H), 7.14 (d, J = 7.3 Hz, 1 H), 5.91 (s, 1 H), 2.67 (d, J = 17.3 Hz, 1 H), 2.44 (d, J = 17.9 Hz, 1 H), 2.35 (d, J = 6.3 Hz, 2 H), 1.12 (s, 3 H), 1.01 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 192.74, 173.63, 158.87, 156.21, 146.25, 142.39, 133.70, 130.33, 128.55, 128.20, 127.19, 126.51, 125.42, 123.84, 118.67, 117.42, 51.59, 44.15, 37.13, 34.13, 29.37, 26.81.

HRMS (ESI): m/z calcd for C₂₄H₂₀O₃S [M + H⁺]: 389.1206; found: 389.1206.

11-(2-Chlorophenyl)-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (5b)

Following Method A2, compound 5b was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 9:1); yield: 44 mg (48%); mp 221–223 °C.

¹H NMR (600 MHz, CDCl₃): δ = 8.09 (d, J = 7.9 Hz, 1 H), 7.74 (d, J = 7.8 Hz, 1 H), 7.60 (t, J = 7.8 Hz, 1 H), 7.37 (d, J = 8.4 Hz, 1 H), 7.32 (t, J = 7.6 Hz, 1 H), 7.29 (d, J = 8.0 Hz, 1 H), 7.15 (t, J = 7.5 Hz, 1 H), 7.07 (t, J = 7.6 Hz, 1 H), 6.05 (s, 1 H), 2.60 (d, J = 17.1 Hz, 1 H), 2.39 (d, J = 17.1 Hz, 1 H), 2.35–2.26 (m, 2 H), 1.11 (s, 3 H), 0.98 (s, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 192.83, 173.66, 159.05, 155.93, 146.25, 139.99, 133.93, 133.69, 132.75, 130.36, 128.54, 128.35, 126.59, 126.48, 125.46, 123.79, 117.37, 117.30, 51.68, 44.06, 37.79, 33.83, 29.14, 26.79.

HRMS (ESI): m/z calcd for C₂₄H₁₉ClO₃S [M + H⁺]: 423.0816; found: 423.0805.

2-Bromo-8,8-dimethyl-11-phenyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (5c)

Following Method A2, compound 5c was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 9:1); yield: 38 mg (40%); mp 192–194 °C.

¹H NMR (600 MHz, CDCl₃): δ = 8.26 (d, J = 2.1 Hz, 1 H), 7.69 (d, J = 8.8 Hz, 1 H), 7.50 (d, J = 7.6 Hz, 2 H), 7.28 (s, 1 H), 7.22 (t, J = 7.6 Hz, 2 H), 7.14 (t, J = 7.3 Hz, 1 H), 5.89 (s, 1 H), 2.67 (d, J = 17.3 Hz, 1 H), 2.44 (d, J = 17.3 Hz, 1 H), 2.39–2.32 (m, 2 H), 1.12 (s, 3 H), 1.01 (s, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 192.67, 172.33, 159.30, 154.94, 146.01, 142.09, 136.63, 130.24, 129.16, 128.61, 128.15, 127.34, 125.13, 119.36, 118.85, 118.80, 51.56, 44.13, 37.15, 34.16, 29.37, 26.83.

HRMS (ESI): m/z calcd for C₂₄H₁₉BrO₃S [M + H⁺]: 467.0311; found: 467.0307.

11-(3-Chlorophenyl)-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (5d)

Following Method A2, compound 5d was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 9:1); yield: 39 mg (44%); mp 212–214 °C.

¹H NMR (600 MHz, CDCl₃): δ = 8.14 (d, J = 8.0 Hz, 1 H), 7.63 (t, J = 7.9 Hz, 1 H), 7.45 (d, J = 4.8 Hz, 2 H), 7.42–7.32 (m, 2 H), 7.19–7.08 (m, 2 H), 5.88 (s, 1 H), 2.67 (d, J = 17.4 Hz, 1 H), 2.46 (d, J = 17.3 Hz, 1 H), 2.41–2.31 (m, 2 H), 1.13 (s, 3 H), 1.01 (s, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 192.67, 173.53, 159.04, 156.23, 146.74, 144.25, 134.24, 133.86, 129.78, 129.21, 128.06, 127.46, 126.83, 126.49, 125.57, 123.73, 118.08, 117.49, 51.53, 44.13, 36.99, 34.16, 29.31, 26.81.

HRMS (ESI): m/z calcd for C₂₄H₁₉ClO₃S [M + H⁺]: 423.0816; found: 423.0813.

8,8-Dimethyl-11-(4-nitrophenyl)-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (5e)

Following Method A2, compound 5e was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 9:1); yield: 48 mg (55%); mp 217–219 °C.

¹H NMR (600 MHz, CDCl₃): δ = 8.12 (d, J = 7.8 Hz, 1 H), 8.09 (d, J = 8.5 Hz, 2 H), 7.70 (d, J = 8.6 Hz, 2 H), 7.65 (t, J = 7.7 Hz, 1 H), 7.41 (d, J = 8.5 Hz, 1 H), 7.38 (t, J = 7.5 Hz, 1 H), 5.96 (s, 1 H), 2.70 (d, J = 17.3 Hz, 1 H), 2.46 (d, J = 17.4 Hz, 1 H), 2.41–2.31 (m, 2 H), 1.14 (s, 3 H), 0.98 (s, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 192.63, 173.48, 159.15, 156.24, 149.68, 147.33, 147.08, 134.10, 129.28, 129.21, 126.43, 125.80, 123.88, 123.58, 117.57, 117.54, 51.45, 44.16, 37.61, 34.16, 29.38, 26.69.

HRMS (ESI): m/z calcd for C₂₄H₁₉NO₅S [M + H⁺]: 434.1057; found: 434.1043.

11-(4-Chlorophenyl)-8,8-dimethyl-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (5f)

Following Method A2, compound 5f was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 9:1); yield: 32 mg (38%); mp 219–221 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.13 (d, J = 7.9 Hz, 1 H), 7.65–7.60 (m, 1 H), 7.46 (d, J = 8.5 Hz, 2 H), 7.39 (d, J = 8.1 Hz, 2 H), 7.18 (d, J = 8.4 Hz, 2 H), 5.85 (s, 1 H), 2.68 (d, J = 13.5 Hz, 1 H), 2.43 (d, J = 17.9 Hz, 1 H), 2.38–2.30 (m, 2 H), 1.12 (s, 3 H), 0.99 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 192.70, 173.55, 158.85, 156.22, 146.42, 140.98, 133.85, 132.93, 130.93, 129.91, 129.65, 128.68, 128.28, 126.47, 125.56, 123.73, 118.30, 117.46, 51.54, 44.12, 36.78, 34.12, 29.39, 26.74.

HRMS (ESI): m/z calcd for C₂₄H₁₉ClO₃S [M + H⁺]: 423.0816; found: 423.0815.

8,8-Dimethyl-11-(p-tolyl)-7,8,9,11-tetrahydro-10H,12H-thiochromeno[2,3-b]chromene-10,12-dione (5g)

Following Method A2, compound 5g was prepared as a yellow solid; purification by chromatography (PE/EtOAc, 9:1); yield: 24 mg (32%); mp 214–216 °C.

¹H NMR (600 MHz, CDCl₃): δ = 8.13 (d, J = 8.0 Hz, 1 H), 7.60 (t, J = 7.8 Hz, 1 H), 7.41 (d, J = 7.9 Hz, 2 H), 7.37 (d, J = 8.6 Hz, 1 H), 7.34 (d, J = 7.0 Hz, 1 H), 7.02 (d, J = 7.9 Hz, 2 H), 5.87 (s, 1 H), 2.66 (d, J = 17.3 Hz, 1 H), 2.44 (d, J = 17.2 Hz, 1 H), 2.39–2.31 (m, 2 H), 2.23 (s, 3 H), 1.12 (s, 3 H), 1.02 (s, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 192.75, 173.63, 158.73, 156.21, 146.03, 139.49, 136.77, 133.64, 130.41, 129.26, 128.08, 126.54, 125.55, 125.36, 123.89, 118.83, 117.39, 109.74, 51.62, 44.15, 36.75, 34.14, 29.36, 26.89, 21.19.

HRMS (ESI): m/z calcd for C₂₅H₂₂O₃S [M + H⁺]: 403.1362; found: 403.1362.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgement

We thank CIF, IIT Guwahati, for their instrumentation facility (HRMS, 600 MHz NMR). We are also grateful to the Department of Chemistry, IIT Guwahati, for the research facility. We also acknowledge the Department of Science and Technology, New Delhi, for providing a single XRD facility to the Department of Chemistry under the FIST programme (Grant No.: SR/FST/CS-II/2017/23C). We are thankful to the editor and referees for their valuable comments and suggestions to improve the manuscript.

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Corresponding Author

Publication History

Received: 13 January 2025

Accepted: 14 May 2025

Accepted Manuscript online:
14 May 2025

Article published online:
12 June 2025

© 2025. Thieme. All rights reserved

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

• References

• 1 Au N, Rettie AE. Drug Metab. Rev. 2008; 40: 355
  Search in Google Scholar
• 2 Jung J.-C, Park O.-S. Molecules 2009; 14: 4790
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• 4 AL-Duhaidahawi D, AL-Zubaidy HF. S, Al-Khafaji K, Al-Amiery A. J. Mol. Struct. 2022; 1247: 131377
  Search in Google Scholar
• 5 Sharma M, Vyas VK, Bhatt S, Ghate MD. Eur. J. Med. Chem. Rep. 2022; 6: 100086
  Search in Google Scholar
• 6 Borah B, Dhar Dwivedi K, Chowhan LR. Asian J. Org. Chem. 2021; 10: 3101
  Search in Google Scholar
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  Search in Google Scholar
• 9 Belal M, Mondal S, Yashmin S, Khan AT. Org. Biomol. Chem. 2022; 20: 715
  Search in Google Scholar
• 10 Ruhee RT, Roberts LA, Ma S, Suzuki K. Front. Nutr. 2020; 7: 64
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• 11 Xu Z, Qiu Z, Liu Q, Huang Y, Li D, Shen X, Fan K, Xi J, Gu Y, Tang Y, Jiang J, Xu J, He J, Gao X, Liu Y, Koo H, Yan X, Gao L. Nat. Commun. 2018; 9: 3713
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• 13 Ahmadi R, Emami S. Eur. J. Med. Chem. 2022; 234: 114255
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