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. 2026 Sep 3;31(17):3094. doi: 10.3390/molecules31173094

Design, Synthesis and Anticancer Evaluation of Novel SO2F-Containing Medicinally Privileged Structures via Ketone-Directed C–H Functionalization

Seungwan Kim 1,†, Lingayya Rajaka 1,2,†, Saegun Kim 3,†, In Jae Bang 2, Hyun Woo Lee 1, Minseo Choi 4, Jihyo Lee 1, Myunghwa Jung 1, Hyosik Woo 1, Sangil Han 5, Ki Yong Lee 1,6, Hyun Jin Kim 4,7,*, Ha Ryong Kim 1,6,*, Sang Hoon Han 1,*
Editors: Luciana Machado Ramos, Aleksandar Pashev
PMCID: PMC13567039  PMID: 42738753

Abstract

The weakly coordinating ketone group-directed C–H functionalizations of chromones, flavones, 1,4-naphthoquinones, (thio)xanthones, and acridones with ethenesulfonyl fluoride under rhodium(III) or ruthenium(II) catalysis are described. These protocols efficiently provide a range of chromone-based scaffolds and xanthone analogues bearing an SO2F group with excellent site-selectivity and functional group compatibility. The practicality of this approach was demonstrated by simple SuFEx conjugations with representative biologically relevant molecules, DNA conjugation, and Michael addition with a secondary amine. All the synthesized derivatives were initially screened for their in vitro cytotoxic activity against human lung adenocarcinoma A549 cells. In particular, compound 5aa with a xanthone scaffold was found to be highly cytotoxic.

Keywords: ketone-directed C–H functionalization, chromone derivatives, xanthone derivatives, ethenesulfonyl fluoride, cytotoxic activity

1. Introduction

Natural product-inspired scaffolds such as chromones, flavones, xanthones, thioxanthones, acridones, and 1,4-naphthoquinones constitute an important class of privileged structures that are widely distributed in natural products, pharmaceuticals, and biologically active small molecules [1,2,3,4,5]. These scaffolds exhibit diverse biological activities, including anticancer, antibacterial, antiviral, antioxidant, and anti-inflammatory effects (Figure 1) [1,2,3,4,5,6,7,8,9,10,11]. Consequently, considerable efforts have been devoted to the synthesis of structurally diversified analogues for structure-activity relationship (SAR) studies and the discovery of new therapeutic agents [12,13]. Despite their biological significance, efficient methods for the direct diversification of these medicinally relevant heterocyclic frameworks remain highly desirable.

Figure 1.

Figure 1

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Representative and biologically relevant chromones, flavones, xanthones, thioxanthones, acridones, and 1,4-naphthoquinones.

Transition-metal-catalyzed C–H functionalization has emerged as one of the most powerful and atom-economical strategies for the direct modification of complex molecules [14]. In particular, Rh(III)- and Ru(II)-catalyzed ketone-directed C–H activation has enabled the site-selective functionalization of chromones, flavones, xanthones, quinones, and related heterocyclic scaffolds, providing rapid access to structurally diverse analogues without requiring prefunctionalized substrates [15,16,17,18]. Numerous transformations, such as alkylation, amidation, and amination, have been successfully developed over the past decade [19]. Nevertheless, these methods have primarily focused on structural diversification, while comparatively little attention has been paid to the installation of synthetically versatile functional groups that enable further downstream derivatization.

Among recently developed coupling partners, ethenesulfonyl fluoride (ESF) has emerged as a particularly attractive bifunctional synthetic building block [20]. In addition to serving as an electron-deficient alkene for transition-metal-catalyzed C–C bond formation, ESF introduces a sulfonyl fluoride (SO2F) functionality that remains intact throughout the coupling process [21,22]. The retained SO2F group serves as a versatile handle for Sulfur(VI) Fluoride Exchange (SuFEx) chemistry, a highly efficient click reaction that has attracted increasing attention in synthetic chemistry, medicinal chemistry, and chemical biology [23,24]. Owing to its unique combination of chemical stability and controllable reactivity, the sulfonyl fluoride functionality enables rapid and selective post-synthetic diversification with a variety of biologically relevant nucleophiles [25]. Consequently, incorporation of an SO2F handle into biologically privileged scaffolds provides a unique opportunity to combine molecular diversification with subsequent functionalization through SuFEx chemistry. This modular derivatization substantially expands the synthetic utility of the resulting molecules and offers opportunities for future bioconjugation applications, including peptide conjugation, protein modification, and the development of antibody-drug conjugates (ADCs) [26]. Despite these attractive features, the integration of ESF-mediated C–H functionalization with medicinally important heterocyclic scaffolds remains largely unexplored [27].

Herein, we report Rh(III)- or Ru(II)- catalyzed ketone-directed C–H olefination of chromones, flavones, (thio)xanthone derivatives, 1,4-naphthoquinones, and acridones using ethenesulfonyl fluoride as a bifunctional coupling partner. This protocol provides efficient access to diverse alkenyl sulfonyl fluoride derivatives with good functional-group compatibility. Notably, the sulfonyl fluoride functionality is retained throughout the transformation, enabling efficient post-synthetic diversification through SuFEx conjugation with a representative amino acid derivative and analgesic acetaminophen. Furthermore, all synthetic compounds have been screened for cytotoxic activity against human lung adenocarcinoma A549 cells. Moreover, compounds selected from the initial activity screening were further tested against various cancer cell lines, such as human breast adenocarcinoma cells (MCF-7), human liver carcinoma cells (HepG2), and human ovarian carcinoma cells (SKOV3). Taken together, the observed cytotoxic activity and conjugation capability highlight the potential utility of these compounds as versatile platforms for future bioconjugation and targeted therapeutic applications.

2. Results and Discussion

To identify the optimal reaction conditions, the coupling reaction of 4H-chromen-4-one (1a) with ethenesulfonyl fluoride (2a) was selected as a model transformation (Table 1). A broad range of reaction conditions was examined, and representative results from these studies are summarized in Table 1. We initially employed PivOH as the additive under conditions adapted from a previously reported Rh(III)-catalyzed C–H functionalization protocol [15]. Under these conditions, the reaction of 1a with 2a in the presence of [RhCp*Cl2]2 and AgSbF6 afforded the desired product 3a in 17% yield (Table 1, entry 1). A similar result was obtained with AcOH, providing 3a in 21% yield (Table 1, entry 2). Subsequent screening of additives identified AgOAc as the most effective additive (Table 1, entries 3–9). Interestingly, replacement of the Rh(III) catalyst with [Ru(p-cymene)Cl2]2 in the presence of Cu(OAc)2 afforded 3a in 83% yield, indicating that the transformation could also be efficiently promoted by a Ru(II) catalyst (Table 1, entry 10). Further optimization of the Ru(II)-catalyzed conditions (Table 1, entries 11 and 12) revealed that the combination of [Ru(p-cymene)Cl2]2 (2.5 mol%), AgSbF6 (10 mol%), and Cu(OAc)2 (50 mol%) in DCE at 90 °C for 12 h under air afforded 3a in 91% yield. Meanwhile, the reaction temperature was investigated for the Rh(III)-catalyzed system, and lowering the temperature from 120 to 60 °C did not diminish the reaction efficiency, affording 3a in 98% yield (Table 1, entry 13). In contrast, only a trace amount of product was detected at room temperature (Table 1, entry 14). Finally, reducing the loading of AgOAc from 200 to 150 mol% maintained the excellent reaction efficiency, affording 3a in 98% yield, whereas a further reduction to 100 mol% led to a decreased yield of 82% (Table 1, entries 15 and 16). Thus, the conditions shown in entry 15 were selected as the optimized Rh(III)-catalyzed conditions. Control experiments confirmed that both the Rh(III) catalyst and AgSbF6 were essential, as no reaction occurred in the absence of either component (Table 1, entries 17 and 18).

Table 1.

Selected optimization of reaction conditions a.

graphic file with name molecules-31-03094-i001.jpg
Entry Additive (mol%) Temp. Yield (%) b
1 PivOH (200) 120 °C 17
2 AcOH (200) 120 °C 21
3 Ag2O (200) 120 °C 40
4 AgTFA (200) 120 °C 30
5 NaOAc (200) 120 °C 9
6 AgOAc (200) 120 °C 89
7 Ag2CO3 (200) 120 °C 84
8 CuOAc (200) 120 °C 79
9 Cu(OAc)2 (200) 120 °C 80
10 c Cu(OAc)2 (200) 120 °C 83
11 c Cu(OAc)2 (200) 90 °C 88
12 c Cu(OAc)2 (50) 90 °C 91
13 AgOAc (200) 60 °C 98
14 AgOAc (200) R.T. trace
15 AgOAc (150) 60 °C 98
16 AgOAc (100) 60 °C 82
17 d AgOAc (150) 60 °C N.R.
18 e AgOAc (150) 60 °C N.R.
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a Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol, 1.2 equiv), [RhCp*Cl2]2 (2.5 mol%), additive (quantity noted), DCE (1 mL) under air at noted temperature for 12 h in pressure tubes. b Yield by flash column chromatography. c [Ru(p-cymene)Cl2]2 (2.5 mol%) was used as a catalyst. d The reaction was carried out in the absence of catalyst. e The reaction was carried out in the absence of AgSbF6.

With the optimized reaction conditions in hand, the substrate scope of chromone-based scaffolds with ethenesulfonyl fluoride (ESF) was investigated, as summarized in Figure 2. Both electron-donating and electron-withdrawing substituents at the C6-position of the chromone ring were generally well tolerated, providing the desired products 3b–3e in good to excellent yields (75–95%). Among the disubstituted chromones, 3-bromo-6-chlorochromone 1f remained reactive, although the corresponding product 3f was obtained in a diminished yield (40%). In contrast, 6-chloro-7-methylchromone 1g afforded 3g in 87% yield. Notably, however, the aldehyde-substituted substrate 1h failed to undergo the transformation under the optimized reaction conditions. This lack of reactivity may be attributed to bidentate coordination of the aldehyde and ketone carbonyl groups to the metal center, potentially interfering with the catalytic cycle. Furthermore, substitution at the C2-position was also compatible with the present catalytic system. C2-substituted chromones bearing an electron-donating methyl group or an electron-withdrawing ester group afforded the corresponding products 3i and 3j in 93% and 75% yields, respectively. Encouraged by these results, the substrate scope was further extended to 2-aryl-substituted chromones, commonly known as flavones. Flavone derivatives were also suitable substrates, delivering the desired products 3k–3o in consistently high yields (77–91%), thereby demonstrating the broad applicability of the protocol to structurally diverse chromone-based scaffolds.

Figure 2.

Figure 2

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Scope of Chromone-based scaffolds with Ethenesulfonyl Fluoride a. a Reaction conditions: 1a–1o (0.2 mmol), 2a (0.24 mmol, 1.2 equiv), [RhCp*Cl2]2 (2.5 mol %), AgSbF6 (10 mol %), AgOAc (150 mol %), DCE (1 mL) under air at 60 °C for 12 h in pressure tubes. b Yield by flash column chromatography.

Next, we extended the substrate scope to xanthone analogues under the optimized Ru(II)-catalyzed conditions using ethenesulfonyl fluoride (ESF), as summarized in Figure 3. Xanthone (4a) underwent smooth olefination to afford the corresponding mono-olefinated product 5a in 50% yield together with the bis-olefinated product 5aa in 19% yield. In contrast, thioxanthone (4b) exhibited lower reactivity, affording the corresponding mono- and bis-olefinated products 5b and 5ba in 39% and 6% yields, respectively. Attempts to improve the formation of the bis-olefinated products by increasing the loading of ESF (10 equiv. for 4a and 6 equiv. for 4b) were unsuccessful, resulting in diminished overall reactivity. Chloro-substituted thioxanthone 4c afforded a separable mixture of regioisomeric mono-olefinated products 5c and 5c’ in 39% and 15% yields, respectively, while only a trace amount of the corresponding bis-olefinated product 5ca was detected. Interestingly, the trifluoromethyl-substituted thioxanthone 4d proved to be a suitable substrate, delivering 5d in 60% yield, which was further improved to 80% by increasing the amount of ESF. Moreover, N-methylacridone (4e) was also compatible with the present catalytic system, albeit giving 5e in a modest yield (10%), which was slightly improved to 23% by increasing the amount of ESF to 10 equivalents. Finally, the substrate scope was further expanded to 1,4-naphthoquinone derivatives. 1,4-Naphthoquinone (4f) and 2-methyl-1,4-naphthoquinone (4g) afforded the corresponding mono-olefinated products 5f and 5g in 36% and 53% yields, respectively, together with minor amounts of the bis-olefinated products 5fa and 5ga. In addition, 2-methoxy-1,4-naphthoquinone (4h) smoothly underwent the transformation to furnish 5h in 72% yield, which was further improved to 96% by increasing the amount of ESF.

Figure 3.

Figure 3

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Scope of xanthone analogues with Ethenesulfonyl Fluoride a. a Reaction conditions: 4a–4h (0.2 mmol), 2a (0.6 mmol, 3 equiv), [Ru(p-cymene)Cl2]2 (2.5 mol %), AgSbF6 (10 mol %), Cu(OAc)2 (50 mol %) DCE (1 mL) under air at 90 °C for 12 h in pressure tubes. b Yield by flash column chromatography. c 2a (1.2 mmol, 6 equiv) was used. d 2a (2 mmol, 10 equiv) was used.

To gain mechanistic insight, the deuterium-labeling experiments were carried out using AcOD under the conditions shown in Scheme 1. In the absence of ESF, treatment of 1a with AcOD resulted in 49% deuterium incorporation at the C5-position of the recovered chromone. When the reaction was performed in the presence of ESF, deuterium incorporation at the C5-position of the recovered starting material (14% D) was again observed, whereas no detectable deuterium incorporation was found in the olefinated product 3a. These results suggest that the initial C–H activation step might be reversible. The absence of deuterium incorporation in the olefinated product is also consistent with the proposed catalytic pathway involving β-hydride elimination, as suggested by previous studies [27,28,29].

Scheme 1.

Scheme 1

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Deuterium-labeling experiment.

To further highlight the robustness and practicality of the developed protocol, the reaction was successfully performed on a gram scale under the optimized reaction conditions (Scheme 2), affording 3a in 91% yield (1.16 g).

Scheme 2.

Scheme 2

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Scale-up experiment.

To further demonstrate the synthetic utility of the vinyl sulfonyl fluoride products, representative downstream transformations were investigated (Scheme 3). Initially, intermolecular SuFEx reactions of 3a with the protected amino acid derivative of tyrosine and commercially available drug acetaminophen proceeded smoothly to afford the corresponding sulfonate derivatives 6a and 6b in 72% and 95% yields, respectively. Surprisingly, treatment of 3a with morpholine did not undergo SuFEx substitution but instead furnished the corresponding Michael addition product 6c in 77% yield, while retaining the sulfonyl fluoride functionality for further SuFEx derivatization. Finally, to explore the potential utility of these compounds as bioconjugation handles, preliminary DNA conjugation experiments were carried out using an amino-modified DNA headpiece (NH2-AOP-headpiece) under aqueous conditions (DMSO/D.I. water = 1:1, v/v) in the presence of DBU. To our delight, successful formation of the desired DNA-conjugated product 6d was confirmed by UPLC-HRMS analysis, demonstrating the compatibility of the sulfonyl fluoride scaffold with DNA under the reaction conditions employed.

Scheme 3.

Scheme 3

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Synthetic Applications of the SuFEx-Active Product.

All the synthesized SO2F-containing chromones, xanthones, naphthoquinones, and acridones were initially screened for cytotoxic activity against human lung adenocarcinoma A549 cells, and the results are summarized in Table 2. The A549 cancer cells were exposed for 24 h to increasing concentrations of all compounds, and cell viability was determined using the WST-8 assay. In particular, compounds 3a, 3b, 3c, 3d, 3m, and 5aa exhibited EC50 values below 15 μM and were selected for further evaluation. Thus, those compounds were further tested against various cancer cell lines, such as human breast adenocarcinoma cells (MCF-7), human liver carcinoma cells (HepG2), and human ovarian carcinoma cells (SKOV3), as shown in Table 3. Compound 3c displayed cytotoxicity in A549 and HepG2 cells, with EC50 values of 9.13 ± 0.36 and 7.26 ± 0.44 μM, respectively. In addition, compound 3d also exhibited cytotoxic activity, with EC50 values of 11.79 ± 0.52, 11.55 ± 0.16, 7.0 ± 1.0, and 14.28 ± 0.39 μM in A549, MCF-7, HepG2, and SKOV3 cells, respectively. Notably, compound 5aa showed the overall most favorable EC50 values among the six selected compounds across the additionally tested cell lines. These results reveal that SO2F-containing chromone and xanthone derivatives might have potential as anti-cancer agents.

Table 2.

Cytotoxicity of synthetic compounds against human A549 cancer cell lines a.

Compound EC50 (μM) Compound EC50 (μM) Compound EC50 (μM)
3a 12.03 ± 0.99 3k 48.4 ± 2.7 5c >50
3b 11.93 ± 0.69 3l 16.5 ± 1.1 5c’ >50
3c 9.13 ± 0.36 3m 13.56 ± 0.56 5d 21.84 ± 0.18
3d 11.79 ± 0.52 3n >50 5e 48.6 ± 1.3
3e 22.7 ± 1.5 3o >50 5f 27.36 ± 0.47
3f 49.74 ± 0.78 5a 25.04 ± 0.07 5fa >50
3g 15.98 ± 0.24 5aa 10.44 ± 0.40 5g >50
3i 17.4 ± 1.1 5b >50 5ga >50
3j 48.3 ± 4.6 5ba >50 5h 19.48 ± 0.26
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a EC50 values are presented as the mean ± SD from three independent experiments. EC50 was defined as the concentration of a compound required to reduce cell viability to 50% of the vehicle-control value.

Table 3.

Cytotoxicity of selected compounds against various human cancer cell lines a.

Compound A549
(EC50, μM)		 MCF-7
(EC50, μM)		 SKOV3
(EC50, μM)		 HepG2
(EC50, μM)
3a 12.03 ± 0.99 14.86 ± 0.92 24.02 ± 0.92 13.04 ± 0.68
3b 11.93 ± 0.69 24.1 ± 1.9 29.6 ± 1.1 27.14 ± 0.90
3c 9.13 ± 0.36 15.54 ± 0.45 20.5 ± 1.7 7.26 ± 0.44
3d 11.79 ± 0.52 11.55 ± 0.16 14.28 ± 0.39 7.0 ± 1.0
3m 13.56 ± 0.56 12.53 ± 0.91 29.6 ± 2.6 26.35 ± 0.64
5aa 10.44 ± 0.40 14.08 ± 0.33 6.0 ± 1.1 3.73 ± 0.28
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a EC50 values are presented as the mean ± SD from three independent experiments. EC50 was defined as the concentration of a compound required to reduce cell viability to 50% of the vehicle-control value.

3. Materials and Methods

3.1. General Information and Methods

All the experiments were carried out in a well-ventilated fume hood under ambient reaction conditions. Commercially available reagents were used without additional purification, unless otherwise stated. Ethenesulfonyl fluoride (2a) was purchased from TCI (Tokyo, Japan). Chromone, flavone, xanthone, thioxanthone, napthoquinone, and acridone were purchased from TCI. Sealed tubes (13 × 100 mm) were purchased from Fisher Scientific (Waltham, MA, USA), dried in an oven overnight, and cooled at room temperature before use. Thin-layer chromatography was carried out using plates coated with Kieselgel 60 F254 (Merck, Darmstadt, Germany). Nuclear magnetic resonance spectra (1H, 13C and 19F NMR) were recorded on a JEOL 400 (Akishima, Japan), Bruker 400 and 600 MHz NMR instrument (Billerica, MA, USA) in CDCl3 solution, and chemical shifts are reported as parts per million (ppm). Resonance patterns are reported with the notations s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (broad). Coupling constants (J) are reported in hertz (Hz). IR spectra were recorded on a JASCO FT/IR4600 spectrophotometer (Hachioji, Japan) and are reported as cm−1. High-resolution mass spectra (HRMS) were recorded on a JEOL JMS-700 spectrometer (Akishima, Japan).

3.2. Experimental Procedures

3.2.1. Typical Procedure for the Synthesis of SO2F-Containing Chromone-Based Scaffolds

To an oven-dried sealed tube charged with 4H-chromen-4-one (1a) (29.2 mg, 0.2 mmol, 100 mol %), [RhCp*Cl2]2 (3.1 mg, 0.005 mmol, 2.5 mol %), AgSbF6 (6.8 mg, 0.02 mmol, 10 mol %), AgOAc (50.0 mg, 0.3 mmol, 150 mol %), 1,2-dichloroethane (1 mL), was added ethenesulfonyl fluoride (2a) (26.4 mg, 0.24 mmol, 120 mol %). The reaction mixture was stirred for 12 h at 60 °C. After completion of the reaction, the reaction mass was cooled to room temperature. The crude reaction mass was purified by flash column chromatography (n-hexanes/EtOAc = 2:1) to afford 3a (50.0 mg) in 98% yield.

3.2.2. Typical Procedure for the Synthesis of SO2F-Containing Xanthone Analogues

To an oven-dried sealed tube charged with 9H-xanthen-9-one (4a) (39.2 mg, 0.2 mmol, 100 mol %), [Ru(p-cymene)Cl2]2 (3.1 mg, 0.005 mmol, 2.5 mol %), AgSbF6 (6.8 mg, 0.02 mmol, 10 mol %), Cu(OAc)2 (18.2 mg, 0.1 mmol, 50 mol %), 1,2-dichloroethane (1 mL), was added ethenesulfonyl fluoride (2a) (66.1 mg, 0.6 mmol, 300 mol %). The reaction mixture was stirred for 12 h at 90 °C. After completion of the reaction, the reaction mass was cooled to room temperature. The crude reaction mass was purified by flash column chromatography (n-hexanes/EtOAc = 5:1) to afford 5a (30.5 mg) in 50% yield.

3.2.3. Deuterium-Labeling Experiments

To an oven-dried sealed tube charged with 4H-chromen-4-one (1a) (29.2 mg, 0.2 mmol, 100 mol %), [RhCp*Cl2]2 (3.1 mg, 0.005 mmol, 2.5 mol %), AgSbF6 (6.8 mg, 0.02 mmol, 10 mol %), AgOAc (33.4 mg, 0.2 mmol, 100 mol %), 1,2-dichloroethane (1 mL), was added AcOD (24.4 mg, 0.4 mmol, 200 mol %). The reaction mixture was stirred for 12 h at 60 °C. After completion of the reaction, the reaction mass was cooled down to room temperature. The crude reaction mass was purified by flash column chromatography (n-hexanes/EtOAc = 2:1) to afford deuterio-1a (28.9 mg) in 98% yield. In case of the presence of ethenesulfonyl fluoride (2a) (66.1 mg, 0.6 mmol, 300 mol %). The reaction mixture was stirred for 0.5 h at 60 °C. After completion of the reaction, the reaction mass was cooled down to room temperature. The crude reaction mass was purified by flash column chromatography (n-hexanes/EtOAc = 2:1) to afford 3a (15.3 mg) in 30% yield and deuterio-1a (20.0 mg) in 68% yield.

3.2.4. Scale-Up Experiment

To an oven-dried sealed tube charged with 4H-chromen-4-one (1a) (730.7 mg, 5.0 mmol, 100 mol %), [RhCp*Cl2]2 (77.2 mg, 0.125 mmol, 2.5 mol %), AgSbF6 (171.8 mg, 0.5 mmol, 10 mol %), AgOAc (1251.8 mg, 7.5 mmol, 150 mol %), 1,2-dichloroethane (10.0 mL), was added ethenesulfonyl fluoride (2a) (660.6 mg, 6.0 mmol, 120 mol %). The reaction mixture was stirred for 12 h at 60 °C. After completion of the reaction, the reaction mass was cooled to room temperature. The crude reaction mass was purified by flash column chromatography (n-hexanes/EtOAc = 2:1) to afford 3a (1.16 g) in 91% yield.

3.2.5. Experimental Procedure for 6a

To an oven-dried sealed tube was added (E)-2-(4-oxo-4H-chromen-5-yl)ethene-1-sulfonyl fluoride (3a) (25.4 mg, 0.1 mmol, 100 mol %), protected tyrosine (44.3 mg, 0.15 mmol, 150 mol %), and Cs2CO3 (65.1 mg, 0.2 mmol, 200 mol %), and acetonitrile (1 mL). The reaction mixture was stirred for 2 h at 25 °C. After completion of the reaction as indicated by TLC analysis, the crude reaction mass was purified by flash column chromatography (n-hexanes/EtOAc = 1:1) to afford 6a (38.2 mg) in 72% yield.

3.2.6. Experimental Procedure for 6b

(E)-2-(4-Oxo-4H-chromen-5-yl)ethene-1-sulfonyl fluoride (3a) (25.4 mg, 0.1 mmol, 100 mol %), acetaminophen (22.6 mg, 0.15 mmol, 150 mol %), and Cs2CO3 (65.1 mg, 0.2 mmol, 200 mol %), acetonitrile (1 mL) were added to an oven-dried sealed tube. The reaction mixture was stirred for 2 h at 25 °C. After completion of the reaction as indicated by TLC analysis, the crude reaction mass was purified by flash column chromatography (n-hexanes/EtOAc = 1:4) to afford 6b (36.7 mg) in 95% yield.

3.2.7. Experimental Procedure for 6c

To an oven-dried sealed tube charged with (E)-2-(4-oxo-4H-chromen-5-yl)ethene-1-sulfonyl fluoride (3a) (25.4 mg, 0.1 mmol, 100 mol %), morpholine (13.0 mg, 0.15 mmol, 150 mol %), acetonitrile (1 mL). The reaction mixture was allowed to stir for 2 h at 25 °C. After completion of the reaction as indicated by TLC analysis, the crude reaction mass was purified by flash column chromatography (n-hexanes/EtOAc = 1:1) to afford 6c (26.3 mg) in 77% yield.

3.2.8. Experimental Procedure for DNA SuFEx Conjugation

A solution of DNA-NH2 (20 nmol, 4 mM in deionized water, 5 μL) was added to an EP tube (Eppendorf Tube®, Eppendorf, Hamburg, Germany) containing water (45 μL). Then a solution of 3a (0.2 M in CH3CN, 25 μL, 250 eq) and a solution of DBU (0.1 M in CH3CN, 25 μL, 125 eq) were added. The reaction tube was mixed by vortex at 70 °C. After 12 h, 10% by volume of 5 M NaCl solution was added, followed by cold ethanol (2.5 times by volume, ethanol stored at −20 °C). The reaction tube was allowed to stand for 10 min at −80 °C, then centrifuged at 15,000 RPM for 30 min. After discarding the supernatant, the precipitate was freeze-dried and analyzed with UPLC to check the desired DNA-conjugated product 6d.

3.2.9. Cell Lines and Culture Conditions

Human lung adenocarcinoma A549 cells, human hepatocellular carcinoma HepG2 cells, human breast adenocarcinoma MCF-7 cells, and human ovarian adenocarcinoma SK-OV-3 cells were obtained from the Korean Cell Line Bank (Seoul, Republic of Korea). A549 cells were maintained in RPMI 1640 medium supplemented with 25 mM HEPES and NaHCO3, HepG2 cells were maintained in minimum essential medium (MEM), and MCF-7 and SK-OV-3 cells were maintained in Dulbecco’s modified Eagle’s medium (DMEM). All culture media were supplemented with 10% fetal bovine serum and 1% penicillin–streptomycin. All cells were maintained at 37 °C in a humidified atmosphere containing 5% CO2.

3.2.10. Cancer Cell Viability Assay (WST-8 Assay)

Cells were seeded in 96-well plates (SPL Life Sciences, Pocheon, Republic of Korea) at a density of 1.0 × 104 cells/well in 100 μL of culture medium and incubated for 24 h. The culture medium was then removed, and the cells were exposed for 24 h to nine concentrations of each compound prepared by 2-fold serial dilution, with a maximum concentration of 50 μM. The corresponding concentration of DMSO was used for the vehicle-control group. Following compound exposure, the treatment medium was removed, and 100 μL of fresh culture medium containing 10 μL of Quanti-MAX WST-8 Cell Viability Assay Kit reagent (#QM5000, Biomax, Guri, Republic of Korea) and 90 μL of culture medium was added to each well. The cells were incubated at 37 °C for 1 h in a 5% CO2 incubator. Absorbance was measured at 440 nm with a reference wavelength of 690 nm using an Epoch microplate spectrophotometer (BioTek, Winooski, VT, USA). The WST-8 assay was performed in three independent experiments, and cell viability was calculated relative to the vehicle-control group in each experiment. EC50 values were calculated separately for each experiment by four-parameter logistic sigmoidal regression using SigmaPlot 12.0 and are presented as the mean ± standard deviation (SD). The EC50 was defined as the compound concentration required to reduce cell viability by 50%.

3.3. Characterization Data for All Synthesized Products

(E)-2-(4-Oxo-4H-chromen-5-yl)ethene-1-sulfonyl fluoride (3a) [22]: 50.0 mg (98%); Pale yellow solid; m.p. 146–148 °C; 1H NMR (600 MHz, CDCl3) δ 9.20 (d, J = 15.2 Hz, 1H), 7.85 (d, J = 5.8 Hz, 1H), 7.73–7.71 (m, 1H), 7.62 (dd, J = 8.5, 1.2 Hz, 1H), 7.44 (d, J = 7.5 Hz, 1H), 6.69 (dd, J = 15.4, 2.2 Hz, 1H), 6.36 (d, J = 5.9 Hz, 1H) ppm; 13C NMR (150 MHz, CDCl3) δ 178.25, 157.54, 154.86, 149.50 (d, J = 3.3 Hz), 133.52, 133.18, 125.41, 122.65, 121.96, 120.84 (d, J = 28.0 Hz), 114.35 ppm; 19F NMR (376 MHz, CDCl3) δ 61.68 ppm; FT-IR (CHCl3, film) υ 3075, 1643, 1614, 1472, 1391, 1345, 1226, 1186, 1107, 981, 868, 831, 747 cm−1; HRMS (FAB+) calcd for C11H8FO4S [M+H]+ 255.0122, found 255.0123.

(E)-2-(6-Methyl-4-oxo-4H-chromen-5-yl)ethene-1-sulfonyl fluoride (3b): 40.3 mg (75%); White solid; m.p. 174–176 °C; 1H NMR (600 MHz, CDCl3) δ 8.62 (d, J = 15.8 Hz, 1H), 7.82 (d, J = 5.9 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 6.38 (dd, J = 15.8, 2.3 Hz, 1H), 6.32 (d, J = 5.9 Hz, 1H), 2.44 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 178.02, 155.70, 154.81, 150.35 (d, J = 3.3 Hz), 136.46, 133.11, 131.21, 123.09, 121.89 (d, J = 26.9 Hz), 119.79, 113.94, 20.21 ppm; FT-IR (CHCl3, film) υ 3072, 2923, 1644, 1396, 1342, 1228, 1188, 895, 828 cm−1; HRMS (FAB+) calcd for C12H10FO4S [M+H]+ 269.0278 found 269.0280.

(E)-2-(6-Fluoro-4-oxo-4H-chromen-5-yl)ethene-1-sulfonyl fluoride (3c): 51.8 mg (95%); White solid; m.p. 166–168 °C; 1H NMR (600 MHz, CDCl3) δ 9.06 (d, J = 15.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 (dd, J = 9.3, 4.3 Hz, 1H), 7.53 (t, J = 9.5 Hz, 1H), 6.97 (dd, J = 16.0, 1.0 Hz, 1H), 6.35 (d, J = 5.9 Hz, 1H) ppm; 13C NMR (150 MHz, CDCl3) δ 178.10 (d, J = 3.3 Hz), 157.64 (d, J = 255.3 Hz), 154.81, 153.95, 140.83 (d, J = 3.3 Hz), 124.78 (dd, J = 28.0, 14.3 Hz), 123.45 (d, J = 9.3 Hz), 123.18 (d, J = 2.7 Hz), 122.45 (d, J = 27.4 Hz), 118.34 (d, J = 13.2 Hz), 114.04 ppm; FT-IR (CHCl3, film) υ 3086, 1637, 1461, 1402, 1360, 1294, 1189, 918, 839 cm−1; HRMS (FAB+) calcd for C11H7F2O4S [M+H]+ 273.0028, found 273.0031.

(E)-2-(6-Chloro-4-oxo-4H-chromen-5-yl)ethene-1-sulfonyl fluoride (3d): 53.7 mg (93%); White solid; m.p. 173–175 °C; 1H NMR (600 MHz, CDCl3) δ 8.46 (d, J = 15.8 Hz, 1H), 7.85 (d, J = 6.0 Hz, 1H), 7.77 (d, J = 8.9 Hz, 1H), 7.53 (d, J = 9.1 Hz, 1H), 6.68 (dd, J = 15.7, 2.2 Hz, 1H), 6.35 (d, J = 5.9 Hz, 1H) ppm; 13C NMR (150 MHz, CDCl3) δ 176.98, 155.79, 155.01, 146.14 (d, J = 3.3 Hz), 135.34, 130.42, 129.98, 124.28 (d, J = 7.7 Hz), 124.12, 121.57, 114.16 ppm; FT-IR (CHCl3, film) υ 3073, 2920, 2850, 1640, 1619, 1581, 1447, 1402, 1338, 1282, 1228, 1191, 994, 876, 802, 754 cm−1; HRMS (FAB+) calcd for C11H7ClFO4S [M+H]+ 288.9732, found 288.9735.

(E)-2-(6-Bromo-4-oxo-4H-chromen-5-yl)ethene-1-sulfonyl fluoride (3e): 53.4 mg (80%); White solid; m.p. 163–165 °C; 1H NMR (600 MHz, CDCl3) δ 8.39 (dd, J = 15.8, 6.0 Hz, 1H), 7.95 (d, J = 9.1 Hz, 1H), 7.85 (dd, J = 6.0, 2.5 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 6.60 (dt, J = 15.8, 2.5 Hz, 1H), 6.36 (dd, J = 6.0, 3.7 Hz, 1H) ppm; 13C NMR (150 MHz, CDCl3) δ 176.69, 156.26, 155.03, 148.32 (d, J = 3.3 Hz), 138.31, 132.63, 124.62, 124.05 (d, J = 27.5 Hz), 121.60, 119.27, 114.11 ppm; FT-IR (CHCl3, film) υ 3069, 3033, 2921, 2850, 1639, 1617, 1578, 1445, 1400, 1338, 1200, 991, 950, 871, 803, 744, 703 cm−1; HRMS (FAB+) calcd for C11H7BrFO4S [M+H]+ 332.9227, found 332.9230.

(E)-2-(3-Bromo-6-chloro-4-oxo-4H-chromen-5-yl)ethene-1-sulfonyl fluoride (3f): 29.5 mg (40%); White solid; m.p. 224–226 °C; 1H NMR (600 MHz, CDCl3) δ 8.43 (d, J = 15.8 Hz, 1H), 8.24 (s, 1H), 7.82 (d, J = 8.9 Hz, 1H), 7.56 (d, J = 9.1 Hz, 1H), 6.70 (dd, J = 15.7, 2.2 Hz, 1H) ppm; 13C NMR (150 MHz, CDCl3) δ 171.90, 155.44, 153.61, 145.44 (d, J = 3.3 Hz), 135.86, 130.80 (d, J = 4.4 Hz), 125.06, 124.88, 122.32, 121.45, 111.78 ppm; FT-IR (CHCl3, film) υ 3073, 2920, 2850, 1640, 1619, 1447, 1402, 1338, 1282, 1228, 1191, 1110, 994, 943, 876, 802, 754, 707 cm−1; HRMS (FAB+) calcd for C11H6BrClFO4S [M+H]+ 366.8837, found 368.8995.

(E)-2-(6-Chloro-7-methyl-4-oxo-4H-chromen-5-yl)ethene-1-sulfonyl fluoride (3g): 52.8 mg (87%); White solid; m.p. 161–163 °C; 1H NMR (600 MHz, CDCl3) δ 8.45 (d, J = 15.8 Hz, 1H), 7.80 (d, J = 5.9 Hz, 1H), 7.46 (s, 1H), 6.62 (dd, J = 15.7, 2.2 Hz, 1H), 6.31 (dd, J = 6.0, 2.1 Hz, 1H), 2.56 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 176.84, 155.26, 154.77, 146.96 (d, J = 3.3 Hz), 144.22, 130.63 (d, J = 4.4 Hz), 124.17, 123.99, 122.29, 121.68, 114.00, 21.94 ppm; FT-IR (CHCl3, film) υ 3062, 2921, 1747, 1649, 1595, 1456, 1444, 1396, 1348, 1283, 1221, 1187, 1052, 944, 876, 818, 762, 699 cm−1; HRMS (FAB+) calcd for C12H9ClFO4S [M+H]+ 302.9889, found 302.9893.

(E)-2-(2-Methyl-4-oxo-4H-chromen-5-yl)ethene-1-sulfonyl fluoride (3i): 49.9 mg (93%); White solid; m.p. 144–146 °C; 1H NMR (600 MHz, CDCl3) δ 9.24 (d, J = 15.4 Hz, 1H), 7.69–7.66 (m, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 7.4 Hz, 1H), 6.68 (dd, J = 15.4, 2.2 Hz, 1H), 6.17–6.16 (m, 1H), 2.39 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 178.81, 165.91, 157.48, 149.65 (d, J = 3.3 Hz), 133.15, 132.91, 125.04, 121.63, 121.38, 120.53 (d, J = 28.0 Hz), 111.93, 20.35 ppm; FT-IR (CHCl3, film) υ 3070, 2924, 2852, 1646, 1617, 1587, 1567, 1475, 1438, 1400, 1368, 1188, 1117, 1029, 958, 865, 840, 793, 752 cm−1; HRMS (FAB+) calcd for C12H10FO4S [M+H]+ 269.0278, found 269.0282.

Methyl (E)-5-(2-(fluorosulfonyl)vinyl)-4-oxo-4H-chromene-2-carboxylate (3j): 46.9 mg (75%); White solid; m.p. 183–185 °C; 1H NMR (600 MHz, CDCl3) δ 9.14 (d, J = 15.4 Hz, 1H), 7.80–7.76 (m, 2H), 7.49 (d, J = 5.7 Hz, 1H), 7.10 (s, 1H), 6.72 (dd, J = 15.4, 2.2 Hz, 1H), 4.03 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 179.05, 160.62, 157.02, 151.59, 148.72 (d, J = 3.3 Hz), 134.47, 133.10, 125.99, 122.41, 122.13, 121.52 (d, J = 28.6 Hz), 116.05, 53.84 ppm; FT-IR (CHCl3, film) υ 3083, 2956, 2922, 2853, 1746, 1644, 1587, 1471, 1396, 1307, 1263, 1171, 1102, 969, 920, 888, 797, 747 cm−1; HRMS (FAB+) calcd for C13H10FO6S [M+H]+ 313.0177, found 313.0181.

(E)-2-(4-Oxo-2-phenyl-4H-benzo[h]chromen-5-yl)ethene-1-sulfonyl fluoride (3k): 69.3 mg (91%); Pale yellow solid; m.p. 255–257 °C; 1H NMR (600 MHz, CDCl3) δ 9.36 (d, J = 15.2 Hz, 1H), 8.67–8.65 (m, 1H), 8.05–8.03 (m, 2H), 8.02–7.99 (m, 1H), 7.86 (s, 1H), 7.85–7.81 (m, 2H), 7.63–7.61 (m, 3H), 6.96 (s, 1H), 6.80 (dd, J = 15.3, 2.2 Hz, 1H) ppm; 13C NMR (150 MHz, CDCl3) δ 178.88, 162.43, 150.41, 134.58, 132.11, 131.41, 130.65, 129.50, 129.20, 128.96, 128.69, 126.47, 126.45, 125.98, 125.59, 122.93, 119.63, 119.45, 118.15, 109.98 ppm; FT-IR (CHCl3, film) υ 3074, 2914, 2845, 1637, 1618, 1452, 1399, 1364, 1186, 1105, 954, 867, 772, 749 cm−1; HRMS (FAB+) calcd for C21H14FO4S [M+H]+ 381.0591, found 381.0593.

(E)-2-(4-Oxo-2-phenyl-4H-chromen-5-yl)ethene-1-sulfonyl fluoride (3l): 58.2 mg (88%); White solid; m.p. 213–215 °C; 1H NMR (600 MHz, CDCl3) δ 9.30 (d, J = 15.4 Hz, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 3.2 Hz, 2H), 7.59–7.53 (m, 3H), 7.46 (dd, J = 5.5, 3.0 Hz, 1H), 6.82 (s, 1H), 6.72 (d, J = 15.4 Hz, 1H) ppm; 13C NMR (150 MHz, CDCl3) δ 179.02, 163.06, 157.28, 149.46 (d, J = 2.7 Hz), 133.44, 133.05, 132.19, 131.06, 129.32, 126.47, 125.28, 121.82 (d, J = 6.6 Hz), 120.90, 120.71, 108.78 ppm; FT-IR (CHCl3, film) υ 3076, 3004, 2921, 2851, 1626, 1591, 1567, 1476, 1404, 1377, 1194, 1119, 961, 902, 866, 853, 747 cm−1; HRMS (FAB+) calcd for C17H12FO4S [M+H]+ 331.0435, found 331.0443.

(E)-2-(7-Methoxy-4-oxo-2-phenyl-4H-chromen-5-yl)ethene-1-sulfonyl fluoride (3m): 63.5 mg (88%); White solid; m.p. 213–216 °C; 1H NMR (400 MHz, CDCl3) δ 9.25 (d, J = 15.4 Hz, 1H), 7.89 (dd, J = 8.1, 1.7 Hz, 2H), 7.58–7.50 (m, 3H), 7.10 (d, J = 2.4 Hz, 1H), 6.98 (dd, J = 2.5, 0.8 Hz, 1H), 6.72 (s, 1H), 6.68 (dd, J = 15.5, 2.2 Hz, 1H), 3.97 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 178.43, 163.14, 162.58, 159.10, 149.41 (d, J = 2.9 Hz), 134.30, 131.97, 131.16, 129.27, 126.32, 120.88 (d, J = 27.8 Hz), 115.72, 114.64, 108.58, 103.40, 56.33 ppm; FT-IR (CHCl3, film) υ 3072, 1637, 1593, 1398, 1353, 1220, 1187, 1160, 1106, 959, 837, 774 cm−1; HRMS (FAB+) calcd for C18H14FO5S [M+H]+ 361.0540, found 361.0546.

(E)-2-(3-Methoxy-4-oxo-2-phenyl-4H-chromen-5-yl)ethene-1-sulfonyl fluoride (3n): 62.0 mg (86%); White solid; m.p. 213–215 °C; 1H NMR (600 MHz, CDCl3) δ 9.32 (d, J = 15.4 Hz, 1H), 8.13–8.10 (m, 2H), 7.74–7.69 (m, 2H), 7.55–7.53 (m, 3H), 7.45 (dd, J = 6.8, 2.3 Hz, 1H), 6.74 (dd, J = 15.4, 2.2 Hz, 1H), 3.90 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 175.91, 156.26, 155.28, 149.43 (d, J = 3.3 Hz), 142.41, 133.26, 133.13, 131.30, 130.35, 128.86, 128.61, 124.88, 121.90, 121.81, 120.84 (d, J = 28.0 Hz), 60.37 ppm; FT-IR (CHCl3, film) υ 3081, 3060, 2953, 2921, 2852, 1736, 1630, 1612, 1591, 1446, 1402, 1379, 1232, 1187, 1080, 929, 863 cm−1; HRMS (FAB+) calcd for C18H14FO5S [M+H]+ 361.0540, found 361.0542.

(E)-2-(6-Methoxy-4-oxo-2-phenyl-4H-chromen-5-yl)ethene-1-sulfonyl fluoride (3o): 55.5 mg (77%); White solid; m.p. 250–252 °C; 1H NMR (600 MHz, CDCl3) δ 9.51 (d, J = 15.7 Hz, 1H), 7.91 (d, J = 7.2 Hz, 2H), 7.72 (d, J = 9.2 Hz, 1H), 7.57–7.52 (m, 3H), 7.42 (d, J = 9.4 Hz, 1H), 7.30 (d, J = 15.8 Hz, 1H), 6.79 (s, 1H), 4.03 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 179.58, 162.28, 156.42, 151.82, 142.52, 132.01, 131.15, 129.28, 126.39, 123.56 (d, J = 26.4 Hz), 122.78, 122.53, 118.11, 117.63, 108.67, 56.79 ppm; FT-IR (CHCl3, film) υ 3098, 3055, 2921, 2852, 1632, 1570, 1468, 1451, 1386, 1370, 1290, 1202, 1183, 1135, 1059, 997, 912, 872 cm−1; HRMS (FAB+) calcd for C18H14FO5S [M+H]+ 361.0540, found 361.0542.

(E)-2-(9-Oxo-9H-xanthen-1-yl)ethene-1-sulfonyl fluoride (5a): 30.5 mg (50%); White solid; m.p. 205–207 °C; 1H NMR (600 MHz, CDCl3) δ 9.25 (d, J = 15.3 Hz, 1H), 8.31 (dd, J = 7.9, 1.7 Hz, 1H), 7.77 (t, J = 8.1 Hz, 2H), 7.67 (dd, J = 8.5, 1.3 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.44–7.39 (m, 2H), 6.73 (dd, J = 15.4, 2.3 Hz, 1H) ppm; 13C NMR (150 MHz, CDCl3) δ 177.92, 157.19, 155.54, 150.12 (d, J = 3.3 Hz), 135.56, 134.45, 134.00, 126.96, 124.76, 124.29, 122.33, 121.79, 120.76 (d, J = 28.0 Hz), 119.60, 117.88 ppm; FT-IR (CHCl3, film) υ 3078, 2920, 1644, 1614, 1585, 1565, 1468, 1394, 1352, 1236, 1210, 1186, 1143, 869, 855, 787, 742 cm−1; HRMS (FAB+) calcd for C15H10FO4S [M+H]+ 305.0278, found 305.0281.

(1E,1′E)-2,2′-(9-Oxo-9H-xanthene-1,8-diyl)bis(ethene-1-sulfonyl fluoride) (5aa): 15.7 mg (19%); White solid; m.p. 265–267 °C; 1H NMR (600 MHz, CDCl3) δ 9.09 (d, J = 15.3 Hz, 2H), 7.82–7.79 (m, 2H), 7.68 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 7.5 Hz, 2H), 6.73 (dd, J = 15.4, 2.2 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 178.49, 156.48, 149.46, 135.00, 134.25, 125.14, 121.65, 121.44, 120.09 ppm; FT-IR (CHCl3, film) υ 3075, 2922, 2850, 1637, 1614, 1584, 1562, 1474, 1397, 1356, 1211, 1186, 1155, 1003, 956, 917, 863, 793, 758 cm−1; HRMS (FAB+) calcd for C17H11F2O6S2 [M+H]+ 412.9960, found 412.9967.

(E)-2-(9-Oxo-9H-thioxanthen-1-yl)ethene-1-sulfonyl fluoride (5b): 25.0 mg (39%); Orange solid; m.p. 165–167 °C; 1H NMR (600 MHz, CDCl3) δ 8.88 (d, J = 15.2 Hz, 1H), 8.55 (dd, J = 8.1, 1.6 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.68–7.65 (m, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.54–7.51 (m, 1H), 7.40 (d, J = 7.4 Hz, 1H), 6.59 (dd, J = 15.3, 2.3 Hz, 1H) ppm; 13C NMR (150 MHz, CDCl3) δ 181.06, 152.82 (d, J = 2.8 Hz), 139.64, 136.74, 136.20, 132.94, 131.91, 130.13, 130.05, 129.12, 127.75, 127.63, 127.09, 125.73, 118.53 (d, J = 27.5 Hz) ppm; FT-IR (CHCl3, film) υ 3076, 3058, 2955, 2919, 2851, 1686, 1623, 1445, 1393, 1317, 1214, 1193, 1159, 1079, 954, 937, 858, 752 cm−1; HRMS (FAB−) calcd for C15H9FO3S2 [M]+ 319.9977, found 319.9980.

(1E,1′E)-2,2′-(9-Oxo-9H-thioxanthene-1,8-diyl)bis(ethene-1-sulfonyl fluoride) (5ba): 5.2 mg (6%); Orange solid; m.p. 184–186 °C; 1H NMR (600 MHz, CDCl3) δ 8.72 (d, J = 14.8 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.70 (t, J = 7.6 Hz, 2H), 7.46 (d, J = 7.2 Hz, 2H), 6.63 (dd, J = 15.2, 2.1 Hz, 2H) ppm; 13C NMR (150 MHz, CDCl3) δ 182.26, 151.29 (d, J = 3.3 Hz), 138.44, 136.53, 132.46, 128.67, 128.64, 128.15, 119.78 (d, J = 28.0 Hz) ppm; FT-IR (CHCl3, film) υ 3070, 2954, 2920, 2851, 1695, 1609, 1574, 1448, 1397, 1189, 961, 861, 776 cm−1; HRMS (FAB+) calcd for C17H11F2O5S3 [M+H]+ 428.9731, found 428.9736.

(E)-2-(7-Chloro-9-oxo-9H-thioxanthen-1-yl)ethene-1-sulfonyl fluoride (5c): 27.7 mg (39%); Pale yellow solid; m.p. 197–200 °C; 1H NMR (600 MHz, CDCl3) δ 8.86 (d, J = 15.2 Hz, 1H), 8.55 (d, J = 2.3 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.70–7.67 (m, 1H), 7.63 (dd, J = 8.6, 2.4 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 7.3 Hz, 1H), 6.60 (dd, J = 15.2, 2.3 Hz, 1H) ppm; 13C NMR (150 MHz, CDCl3) δ 180.07, 148.84 (d, J = 3.3 Hz), 137.86, 135.94, 134.19, 133.63, 133.56, 133.16, 131.61, 130.39, 129.75, 128.69, 127.31, 125.76, 121.43 (d, J = 27.5 Hz) ppm; FT-IR (CHCl3, film) υ 3076, 2957, 2920, 2851, 1714, 1619, 1578, 1446, 1396, 1315, 1274, 1189, 1096, 950, 860, 760 cm−1; HRMS (FAB+) calcd for C15H9ClFO3S2 [M+H]+ 354.9660, found 354.9661.

(E)-2-(2-Chloro-9-oxo-9H-thioxanthen-1-yl)ethene-1-sulfonyl fluoride (5c’): 10.7 mg (15%); Pale yellow solid; m.p. 161–163 °C; 1H NMR (600 MHz, CDCl3) δ 8.53 (dd, J = 8.1, 1.7 Hz, 1H), 8.43 (d, J = 15.7 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.68–7.65 (m, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.53–7.51 (m, 1H), 6.50 (dd, J = 15.7, 2.3 Hz, 1H) ppm; 13C NMR (150 MHz, CDCl3) δ 180.05, 152.42 (d, J = 3.3 Hz), 139.35, 136.93, 134.40, 133.58, 133.29, 132.26, 131.08, 129.72, 129.17, 127.90, 127.28, 127.22, 118.99 (d, J = 27.5 Hz) ppm; FT-IR (CHCl3, film) υ 2953, 2920, 2852, 1708, 1629, 1590, 1460, 1376, 1235, 1164, 1081, 816, 754 cm−1; HRMS (FAB+) calcd for C15H9ClFO3S2 [M+H]+ 354.9660, found 354.9669.

(E)-2-(9-Oxo-7-(trifluoromethyl)-9H-thioxanthen-1-yl)ethene-1-sulfonyl fluoride (5d): 46.7 mg (60%); Red solid; m.p. 159–161 °C; 1H NMR (600 MHz, CDCl3) δ 8.86 (d, J = 17.9 Hz, 1H), 7.86 (dd, J = 8.4, 2.1 Hz, 1H), 7.76 (dd, J = 8.2, 1.5 Hz, 1H), 7.73–7.71 (m, 3H), 7.46 (dt, J = 7.2, 1.2 Hz, 1H), 6.62 (dd, J = 15.2, 2.3 Hz, 1H) ppm; 13C NMR (150 MHz, CDCl3) δ 180.09, 151.98 (d, J = 3.3 Hz), 139.90, 138.83, 136.84, 132.48, 132.16, 129.86, 129.28, 129.06, 128.74 (q, J = 3.3 Hz), 128.14, 127.47 (q, J = 4.4 Hz), 127.24, 126.57, 119.19 (d, J = 27.5 Hz) ppm; FT-IR (CHCl3, film) υ 3084, 2919, 1729, 1706, 1672, 1612, 1526, 1494, 1458, 1422, 1348, 1232, 1189, 916, 790, 744 cm−1; HRMS (FAB+) calcd for C16H9F4O3S2 [M+H]+ 388.9924, found 388.9924.

(E)-2-(10-Methyl-9-oxo-9,10-dihydroacridin-1-yl)ethene-1-sulfonyl fluoride (5e): 6.4 mg (10%); Yellow solid; m.p. 240–242 °C; 1H NMR (600 MHz, CDCl3) δ 9.20 (d, J = 15.3 Hz, 1H), 8.51 (dd, J = 8.0, 1.7 Hz, 1H), 7.79–7.74 (m, 2H), 7.70 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.36–7.33 (m, 1H), 7.22 (d, J = 7.0 Hz, 1H), 6.60 (dd, J = 15.3, 2.2 Hz, 1H), 3.95 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 178.83, 153.14 (d, J = 3.0 Hz), 143.82, 142.31, 135.22, 134.48, 133.29, 127.97, 123.50, 122.33, 122.10, 120.36, 118.45 (d, J = 26.9 Hz), 118.13, 114.99, 34.70 ppm; FT-IR (CHCl3, film) υ 3079, 2955, 2919, 2851, 1737, 1595, 1497, 1462, 1396, 1373, 1278, 1188, 1171, 1071, 868, 781, 747 cm−1; HRMS (FAB+) calcd for C16H13FNO3S [M+H]+ 318.0595, found 318.0600.

(E)-2-(5,8-Dioxo-5,8-dihydronaphthalen-1-yl)ethene-1-sulfonyl fluoride (5f): 19.2 mg (36%); Brown solid; m.p. 192–194 °C; 1H NMR (600 MHz, CDCl3) δ 8.81 (d, J = 15.4 Hz, 1H), 8.30 (dd, J = 7.7, 1.4 Hz, 1H), 7.86 (t, J = 7.7 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.05–7.01 (m, 2H), 6.74 (dd, J = 15.4, 2.3 Hz, 1H) ppm; 13C NMR (150 MHz, CDCl3) δ 185.97, 149.02, 139.69, 137.93, 134.24, 134.10, 133.38, 129.91, 122.36, 122.17 ppm; FT-IR (CHCl3, film) υ 3071, 2952, 2917, 2849, 1708, 1654, 1608, 1398, 1328, 1293, 1215, 1185, 1086, 1037, 962, 860, 762 cm−1; HRMS (FAB−) calcd for C12H7FO4S [M]+ 266.0049, found 266.0042.

(1E,1′E)-2,2′-(5,8-Dioxo-5,8-dihydronaphthalene-1,4-diyl)bis(ethene-1-sulfonyl fluoride) (5fa): 8.3 mg (11%); Brown solid; m.p. 178–180 °C; 1H NMR (600 MHz, CDCl3) δ 8.69 (d, J = 15.4 Hz, 2H), 7.81 (s, 2H), 7.07 (s, 2H), 6.75 (dd, J = 15.4, 2.2 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 185.17, 148.33, 138.73, 136.15, 134.33, 131.18, 122.98 (d, J = 29.2 Hz) ppm; FT-IR (CHCl3, film) υ 3073, 2954, 2920, 2851, 1713, 1661, 1614, 1461, 1390, 1329, 1278, 1219, 1186, 1094, 952, 856, 840, 769, 744 cm−1; HRMS (FAB−) calcd for C14H8F2O6S2 [M]+ 373.9730, found 373.9729.

(E)-2-(6-Methyl-5,8-dioxo-5,8-dihydronaphthalen-1-yl)ethene-1-sulfonyl fluoride (5g) [27]: 29.8 mg (53%); Brown solid; m.p. 193–195 °C; 1H NMR (600 MHz, CDCl3) δ 8.84 (d, J = 15.2 Hz, 1H), 8.31 (dd, J = 7.8, 1.5 Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 6.87 (q, J = 1.6 Hz, 1H), 6.73 (dd, J = 15.4, 2.3 Hz, 1H), 2.22 (d, J = 1.6 Hz, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 185.85, 184.73, 149.23 (d, J = 2.7 Hz), 147.73, 136.67, 135.09, 133.86, 133.78, 133.66, 132.89, 130.05, 121.93 (d, J = 28.0 Hz), 16.31 ppm; FT-IR (CHCl3, film) υ 3073, 2916, 2848, 1651, 1617, 1402, 1321, 1279, 1219, 1193, 1115, 995, 864, 756 cm−1; HRMS (FAB+) calcd for C13H10FO4S [M+H]+ 281.0278, found 281.0280.

(1E,1′E)-2,2′-(6-Methyl-5,8-dioxo-5,8-dihydronaphthalene-1,4-diyl)bis(ethene-1-sulfonyl fluoride) (5ga) [27]: 16.4 mg (21%); Brown solid; m.p. 169–170 °C; 1H NMR (600 MHz, CDCl3) δ 8.72 (d, J = 14.5 Hz, 1H), 8.67 (d, J = 15.2 Hz, 1H), 7.79–7.76 (m, 2H), 6.93 (q, J = 1.6 Hz, 1H), 6.74 (dd, J = 2.4, 1.3 Hz, 1H), 6.72 (dd, J = 2.3, 1.3 Hz, 1H), 2.23 (d, J = 1.5 Hz, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 185.89, 185.01, 148.90 (d, J = 3.3 Hz), 148.67, 148.56 (d, J = 3.3 Hz), 136.15, 135.82, 134.07 (d, J = 4.4 Hz), 131.56, 131.42, 122.68, 122.51 (d, J = 8.8 Hz), 122.35, 16.54 ppm; FT-IR (CHCl3, film) υ 3073, 2954, 2920, 2851, 1713, 1654, 1613, 1462, 1400, 1321, 1219, 1186, 1145, 1022, 958, 863, 842, 773, 749 cm−1; HRMS (FAB−) calcd for C15H10F2O6S2 [M]+ 387.9887, found 387.9889.

(E)-2-(6-Methoxy-5,8-dioxo-5,8-dihydronaphthalen-1-yl)ethene-1-sulfonyl fluoride (5h): 42.7 mg (72%); Brown solid; m.p. 221–223 °C; 1H NMR (600 MHz, CDCl3) δ 8.86 (d, J = 15.5 Hz, 1H), 8.34 (dd, J = 7.8, 1.5 Hz, 1H), 7.80 (t, J = 7.7 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 6.70 (dd, J = 15.4, 2.2 Hz, 1H), 6.20 (s, 1H), 3.93 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 185.68, 179.39, 159.90, 149.61 (d, J = 3.3 Hz), 134.59, 133.55, 133.08, 132.53, 130.08, 129.77, 121.70 (d, J = 28.0 Hz), 111.03, 56.80 ppm; FT-IR (CHCl3, film) υ 3079, 3056, 2952, 2921, 2852, 1730, 1684, 1643, 1614, 1459, 1402, 1374, 1327, 1240, 1191, 1120, 1063, 965, 863, 812, 754 cm−1; HRMS (FAB+) calcd for C13H10FO5S [M+H]+ 297.0227, found 297.0229.

Methyl (S,E)-2-((tert-butoxycarbonyl)amino)-3-(4-(((2-(4-oxo-4H-chromen-5-yl)vinyl)sulfonyl)oxy)phenyl)propanoate (6a): 38.2 mg (72%); White solid; m.p. 83–84 °C; 1H NMR (600 MHz, CDCl3) δ 8.81 (d, J = 15.4 Hz, 1H), 7.82 (d, J = 5.8 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.37 (d, J = 7.5 Hz, 1H), 7.27 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 6.65 (d, J = 15.4 Hz, 1H), 6.35 (d, J = 6.0 Hz, 1H), 5.28 (d, J = 8.3 Hz, 1H), 4.57 (q, J = 6.7, 6.1 Hz, 1H), 3.68 (s, 3H), 3.09 (qd, J = 13.1, 5.1 Hz, 2H) 1.39 (s, 9H) ppm; 13C NMR (150 MHz, CDCl3) δ 178.12, 172.13, 157.45, 155.23, 154.57, 148.76, 147.16, 135.34, 134.01, 133.37, 130.79, 125.32, 123.50, 122.53, 122.40, 121.17, 114.20, 80.02, 54.38, 52.33, 37.67, 28.36 ppm; FT-IR (CHCl3, film) υ 3351, 3074, 2974, 2952, 2923, 2852, 1734, 1704, 1643, 1592, 1503, 1474, 1363, 1347, 1283, 1233, 1198, 1143, 1113, 1017, 981, 869, 835, 788, 704 cm−1; HRMS (FAB+) calcd for C26H28NO9S [M+H]+ 530.1479, found 530.1486. [α]D [20] 41.5 (c 1.0, MeOH).

4-Acetamidophenyl (E)-2-(4-oxo-4H-chromen-5-yl)ethene-1-sulfonate (6b): 36.7 mg (95%); White solid; m.p. 208–209 °C; 1H NMR (600 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.79 (d, J = 15.4 Hz, 1H), 8.28 (d, J = 6.0 Hz, 1H), 7.86–7.83 (m, 1H), 7.77 (dd, J = 11.6, 8.0 Hz, 2H), 7.62 (d, J = 8.9 Hz, 2H), 7.49 (d, J = 15.4 Hz, 1H), 7.30 (d, J = 9.1 Hz, 2H), 6.35 (d, J = 5.9 Hz, 1H), 2.02 (s, 3H) ppm; 13C NMR (150 MHz, DMSO-d6) δ 178.00, 168.42, 156.97, 156.22, 145.30, 144.17, 138.33, 133.78, 132.48, 125.76, 124.08, 122.78, 121.59, 121.54, 119.98, 113.54, 23.94 ppm; FT-IR (CHCl3, film) υ 3303, 3276, 3199, 3139, 3080, 1674, 1636, 1608, 1540, 1504, 1473, 1402, 1365, 1351, 1309, 1262, 1230, 1199, 1165, 1150, 1121, 1036, 1008, 980, 953, 869, 849, 792, 746, 708 cm−1; HRMS (FAB+) calcd for C19H16NO6S [M+H]+ 386.0693, found 386.0692.

2-Morpholino-2-(4-oxo-4H-chromen-5-yl)ethane-1-sulfonyl fluoride (6c): 26.3 mg (77%); Orange sticky oil; 1H NMR (600 MHz, CDCl3) δ 7.79 (d, J = 5.9 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 6.30 (d, J = 5.9 Hz, 1H), 4.12 (dd, J = 14.8, 7.0 Hz, 1H), 3.92 (ddd, J = 14.8, 6.5, 2.9 Hz, 2H), 3.67 (t, J = 4.7 Hz, 4H), 2.59–2.56 (m, 2H), 2.53–2.49 (m, 2H) ppm; 13C NMR (150 MHz, CDCl3) δ 179.64, 158.26, 153.93, 137.28, 132.68, 125.44, 123.04, 119.39, 114.63, 67.15, 56.63, 53.39 (d, J = 12.6 Hz), 50.04 ppm; FT-IR (CHCl3, film) υ 3072, 2954, 2922, 2852, 1681, 1644, 1590, 1556, 1463, 1393, 1347, 1285, 1228, 1186, 1154, 1105, 1067, 1033, 981, 869, 832, 792, 761, 696, 673 cm−1; HRMS (EI+) calcd for C15H16FNO5S [M]+ 341.0733, found 341.0730.

4. Conclusions

In conclusion, we described the rhodium(III)/ruthenium(II)-catalyzed C–H olefination reactions of chromones, flavones, (thio)xanthone derivatives, 1,4-naphthoquinones, and acridones with ethenesulfonyl fluoride to afford medicinally important SO2F-containing compounds. These methodologies have demonstrated good substrate compatibility and functional group tolerance. In addition, the synthetic utility of the protocol was demonstrated through gram-scale synthesis and diverse SuFEx transformations with various nucleophiles. Notably, successful DNA conjugation highlights the potential of these SO2F-containing scaffolds for DNA-encoded library (DEL) chemistry. Furthermore, all synthesized compounds were evaluated for cytotoxic activity against human lung adenocarcinoma A549 cell lines. Six compounds exhibiting EC50 values below 15 μM were further evaluated against human breast adenocarcinoma MCF-7, human liver carcinoma HepG2, and human ovarian carcinoma SKOV3 cells. Among the selected compounds, compound 5aa, showing a high cytotoxic effect, was further screened against other cancer cell lines and was found to exhibit cytotoxic effect. These preliminary cytotoxicity results suggest that synthesized compounds, especially compounds such as compound 5aa, warrant further biological investigation.

Acknowledgments

The authors gratefully acknowledge the financial support.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules31173094/s1.

molecules-31-03094-s001.zip (4MB, zip)

Author Contributions

S.K. (Seungwan Kim): Validation, Formal analysis, Investigation, Data curation. L.R.: Investigation, Data curation, Writing—review & editing. S.K. (Saegun Kim): Conceptualization, Methodology, Funding acquisition. I.J.B.: Investigation, Data curation, Resources. H.W.L.: Formal analysis, Investigation. M.C.: Formal analysis, Investigation. J.L.: Validation, Investigation. M.J.: Validation, Investigation. H.W.: Validation, Investigation. S.H.: Conceptualization, Methodology. K.Y.L.: Conceptualization, Resources. H.J.K.: Conceptualization, Resources, Writing—review & editing, Supervision, Funding acquisition. H.R.K.: Conceptualization, Resources, Writing—review & editing, Supervision, Funding acquisition. S.H.H.: Conceptualization, Methodology, Resources, Writing—original draft, Writing—review & editing, Visualization, Supervision, Project administration, Funding acquisition. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The original contributions presented in this study are included in the Article and Supplementary Materials. Supplementary Materials are available for 1H and 13C NMR copies of all products and DNA conjugation data.

Conflicts of Interest

The authors declare no conflicts of interest.

Funding Statement

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2025-00557885, RS-2025-25399773, and RS-2023-00235550). This work was supported by the Global TIPS R&D Program of the Korea Technology and Information Promotion Agency for SMEs (TIPA), funded by the Ministry of SMEs and Startups (MSS) (RS-2026-25613028). In addition, this work was supported by Korea Environment Industry & Technology Institute (KEITI) through the Technology Development Project for Safety Management of Household Chemical Products Program, funded by the Korea Ministry of Environment (MOE) (project number: 202300230430).

Footnotes

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

molecules-31-03094-s001.zip (4MB, zip)

Data Availability Statement

The original contributions presented in this study are included in the Article and Supplementary Materials. Supplementary Materials are available for 1H and 13C NMR copies of all products and DNA conjugation data.

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