1,6-Hydrosulfonylation of p-quinone methides enabled via strain-release-/aromaticity-driven alkyl radical generation and SO₂-capture: synthesis and antiproliferative studies of sulfonylated diarylmethanes

Abstract

The integration of γ-keto sulfones, despite being medicinally relevant building blocks, with the bioactive diarylmethane motif remains elusive. On the other hand, the fixation of SO₂ into organic molecules for accessing value-added products is gaining wide attention in organic synthesis. Herein, we disclose the 1,6-hydrosulfonylation of p-quinone methides via the strain-release driven ring-scission of strained 3°-cyclopropanols in the presence of a SO₂-surrogate like K₂S₂O₅ and a Brønsted acid under visible-light photoredox catalysis to access a library of γ-keto alkylsulfonylated diarylmethanes in moderate to good yields. Also, the 1,6-hydrosulfonylation of p-quinone methides has been developed via aromaticity-driven bond-scission in pro-aromatics like 4-alkyl-1,4-DHPs in the presence of K₂S₂O₅ and a Brønsted acid under visible-light photoredox catalysis to access a library of alkylsulfonylated diarylmethanes. The efficiency of the developed reactions has been established through broad substrate-scope studies, and the mechanistic probing studies have been complemented with DFT calculations to support the proposed mechanisms. In addition, antiproliferative studies revealed oral cancer activity for some of the synthesized sulfonylated diarylmethane derivatives.

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Introduction

The unsymmetrical diarylmethane (DAM) motif is quite ubiquitous in the cyclolignan and secolignan subclasses of lignans,^1,2 among other classes of natural products, as exemplified by podophyllotoxin³ and peperomin H⁴ respectively. Besides, cetirizine⁵ represents a synthetic molecule of pharmaceutical origin (Fig. 1A), underscoring the significance of the DAM motif as a privileged scaffold.⁶ Interestingly, the merger of the DAM motif with sulfones has proven to be quite rewarding in synthetic organic chemistry and from a medicinal chemistry perspective, in terms of reaping better therapeutic potential. The resultant diarylmethyl sulfones (DAMS) have emerged as superior pharmacophoric motifs displaying a wide range of activities in diverse pharmaceutical applications (Fig. 1B).⁷ In this direction, to further amplify the scope of DAMS, we were motivated to integrate the DAM motif with γ-keto sulfones and test the efficacy of the resultant DAMS synthetically and therapeutically. Our motivation was backed by the reputation of γ-keto sulfones as medicinally relevant building blocks by featuring in commercially relevant agrochemicals⁸ and pharmaceuticals.^9,10 Also, the footprint of these fragments in functional materials,^11,12 in addition to their inherent versatility as useful synthetic intermediates,^13–16 made them a lucrative choice. Additionally, to the best of our knowledge, there is no literature precedent for synthesizing γ-keto sulfonylated DAMs, while synthetic routes towards sulfonylated DAMs are documented sporadically.

Fig. 1 Representative examples of (A) DAM-based bioactive compounds; (B) potent compounds containing sulfone-/γ-keto sulfone building blocks; (C) previous work; and (D) present strategy.

Besides transition-metal catalyzed cross-coupling reactions,^17–19 synthetic access to DAMS has been traditionally demonstrated via 2e⁻ retrosynthetic disconnections typically involving the 1,6-conjugate addition of arylsulfinyl anions generated from arylsulfonylhydrazides,^7,20 arylsulfinic acid sodium salts,²¹ or tosylmethyl isocyanide^22,23 onto para-quinone methides (p-QMs). Also, the radical-based p-QM bisfunctionalization strategy²⁴ involving oxidant-assisted generation of aryl sulfonyl radicals from arylsulfonylhydrazides has recently been reported (Fig. 1C). In contrast, there are hardly any visible-light photoredox-catalyzed radical logic-based strategies directed towards accessing DAMS, let alone those involving SO₂-capture. The recent report by Mei et al. for accessing diarylmethyl sulfonamides employing sulfamoyl chloride²⁵ and p-QMs under photoredox catalysis constitutes one such report. In contrast, the one by Wu and coworkers on synthesizing DAMS utilizing alkyltrifluoroborate salts and p-QMs is the sole report involving SO₂-capture via photoredox catalysis.²⁶

SO₂ is one of the serious concerns among other global anthropogenic emissions.²⁷ Due to the enormous SO₂ production every year, the fixation of SO₂ into small molecules has gained a reputation in organic synthesis.^28–30 In particular, accessibility to easy-to-handle organic surrogates like DABCO·(SO₂)₂ or DABSO and rongalite, among a few others, along with bisulfites/metabisulfites of sodium/potassium as inorganic surrogates, has fueled further interest in SO₂-fixation into organic molecules.^31–36 On the other hand, the operational simplicity and easy reaction setup customization, besides mild reaction conditions, have made visible-light photocatalysis the preferred choice in industry and academia for leveraging unique reactivities to develop novel synthetic transformations.^37–43

Indeed, our ongoing interest^44–46 in utilizing anthropogenic gases like SO₂ and its surrogates for value-added chemical synthesis through sustainable means has led us to choreograph the visible-light photoredox catalyzed 1,6-hydrosulfonylation of p-QMs involving SO₂-fixation en route to γ-keto sulfonylated unsymmetrical diarylmethanes for the first time, as well as sulfonylated unsymmetrical diarylmethanes from readily accessible feedstock chemicals (Fig. 1D). In this direction, our working hypothesis was to facilitate the 1,6-hydrosulfonylation of p-QMs with the aid of (a) the γ-keto alkyl sulfonyl radical and (b) the alkyl sulfonyl radical. In turn, access to the γ-keto sulfonyl radical was strategized via strain-release-driven β-keto alkyl radical generation from small-ring carbocycles such as cyclopropanols. Cyclopropanols, by virtue of their innate ring strain,^47–53 under photoredox catalysis, via either an oxidative single electron transfer (SET) process or a hydrogen-atom transfer (HAT) process, were postulated to undergo β-scission and subsequent SO₂-capture to furnish the γ-keto sulfonyl radical for the planned 1,6-bisfunctionalization of p-QMs (Fig. 1D).In contrast, the easy accessibility and favorable redox properties of pro-aromatics like 4-alkyl-1,4-dihydropyridines⁵⁴ (DHPs) motivated us to access the alkyl sulfonyl radical through aromaticity-driven alkyl radical generation from 4-alkyl-1,4-DHPs and ensuing SO₂-capture, for the envisioned bisfunctionalization under photoredox catalysis (Fig. 1D). At the same time, we also anticipated some challenges in the successful realization of each of these hypotheses, such as (i) the radical–radical homo-coupling reaction of the generated diarylmethane radical, (ii) the radical–radical cross-coupling reaction between the generated diarylmethane radical and the β-keto alkyl radical without SO₂-capture, leading to a non-sulfonylated cross-coupled product, and (iii) the undesired radical–radical cross-coupling reaction of the generated species, affording HAT-/other recombination products. Despite these challenges, we succeed in disclosing herein a visible-light photoredox catalyzed bisfunctionalization strategy to access γ-keto sulfonylated/alkyl sulfonylated DAMs via strain-release-driven/aromaticity-driven radical generation and SO₂-fixation. A broad substrate scope has been demonstrated with respect to each of the reactants employed for the two strategies to establish a library of DAMS. Furthermore, an array of useful post-synthetic modifications has been demonstrated utilizing the available functional group handle in the accessed scaffold.

Results and discussion

To test our hypothesis, we commenced our initial investigation employing p-QM 1a and 1-phenylcyclopropanol 2a as the model substrates. An intensive optimization study involving screening different photoredox catalysts (PCs) and light sources, besides testing other variables, including the SO₂ source, oxidant, and solvent, led us to the optimized conditions, as depicted in Fig. 2. Irradiation of an acetonitrile solution of 1a (1 equiv.) and 2a (2 equiv.) with a purple LED (λ_max = 390 nm) in the presence of TFA (1 equiv.), K₂S₂O₅ (1.5 equiv.) and Eosin Y (2 mol%) at room temperature for 1.5 h furnished the desired γ-keto alkylsulfonylated DAM 3aa with an isolated yield of 90% (Fig. 2A, column 1). Encouraged by this outcome, the next step was to investigate the effect of light sources on the reaction. Replacing the purple LED (λ_max = 390 nm) in the reaction with a blue LED (λ_max = 456 nm)/green LED (λ_max = 525 nm) resulted in an inferior yield of the product (Fig. 2A, columns 14 and 15). Although marginal product formation was observed in the individual absence of either light, PC, or acid, no product formation was observed in the combined absence of light, PC, and acid (Fig. 2A, columns 9–12), highlighting their essentiality for the reaction. Additionally, on replacement of Eosin Y with other investigated PC-2 to PC-6, the desired product formation was observed, albeit in lower yields (Fig. 2A, columns 2–6). This indeed proved PC-1 to be an ideal PC compared to the other investigated ones to facilitate strain-release-driven cyclopropanol ring opening. Similarly, replacement of K₂S₂O₅ with other SO₂ surrogates, such as Na₂S₂O₅, NaHSO₃, and DABSO, did not help improve the yield of the desired product 3aa (Fig. 2A, columns 7–9). Lastly, the solvent screening studies revealed DCM/DCE to offer almost the same results, while using other solvents resulted in the diminution of the isolated yield of 3aa [(Fig. 2A, columns 16–19), refer to the SI for further details about optimization studies].

Fig. 2 Reaction optimization. (A) Reaction conditions: 1a (0.12 mmol, 1 equiv.), 2a (0.24 mmol, 2 equiv.), TFA (0.12 mmol, 1 equiv.), K₂S₂O₅ (0.18 mmol, 1.5 equiv.), and Eosin Y (2 mol%) in MeCN (2 mL) irradiated with Kessil purple LED light (390 nm) at rt in a N₂ atmosphere for 1.5 h. (B) Reaction conditions: 1a (0.12 mmol, 1 equiv.), 4a (0.30 mmol, 2.5 equiv.), TFA (0.18 mmol, 1.5 equiv.), K₂S₂O₅ (0.24 mmol, 2 equiv.), K₂S₂O₈ (0.18 mmol, 1.5 equiv.), AgNO₃ (20 mol%), and Eosin Y (5 mol%) in DCE (2 mL) irradiated with Kessil blue LED light (456 nm) at rt in a N₂ atmosphere for 2 h.

Similarly, for the reaction between 1a and 4a, an intensive optimization endeavor involving screening different PCs and light sources and testing other variables led us to the optimized conditions, as depicted in Fig. 2. The optimal efficiency of the photocatalyzed process was found with the blue-LED irradiation (456 nm) of a DCE solution of 1a (1.0 equiv.) and 4a (2.5 equiv.) under an inert atmosphere at room temperature for 2 h in the presence of TFA (1.5 equiv.), K₂S₂O₅ (2 equiv.), K₂S₂O₈ (1.5 equiv.) and AgNO₃ (20 mol%) while employing Eosin Y (5 mol%) as the PC to access 5aa in 75% yield (Fig. 2B, column 1). The complete suppression of the reaction in the absence of light and a profound decrease in reaction efficiency in the absence of PC-1 and acid confirmed the essentiality of both components for the reaction (Fig. 2B, columns 10, 11 and 13). Inferior yields of 5aa were obtained in either of the following cases: when PC-1 was substituted with other investigated catalysts (Fig. 2B, columns 2–6) or when the 456 nm blue-LED was substituted with other light sources (Fig. 2B, columns 14 and 15). Similarly, replacing K₂S₂O₅ with other investigated SO₂-surrogates affected the yield of 5aa to varying extents (Fig. 2B, columns 7–9). Control experiments demonstrated that K₂S₂O₈ and AgNO₃ play a crucial role in synergistically assisting PC-1 in improving the yield of 5aa, as their absence resulted in a substantial decrease in the yield (Fig. 2B, column 12). Solvent screening studies indicated DCE/DCM to be the ideal one among the other investigated solvents for this transformation [(Fig. 2B, columns 16–19), refer to the SI for further details about optimization studies].

With the optimized conditions in hand, the stage was set to demonstrate the robustness of the developed strategies through broad substrate-scope studies to unleash the multiple diversity creation junctures for the accessed DAMS 3 and 5. To begin with, the scope and generality of p-QMs and cyclopropanols for the photoredox-catalyzed reaction were tested first (Scheme 1a). The reaction of p-QM 1b, as well as the analogs 1c–1i bearing either electron-donating (C₄-OH, OAc) or electron-withdrawing (–F, –Cl, –Br, –CN, and –NO₂) substituents at the para-position of the aryl ring in p-QMs, with 2a afforded the desired products 3ba–ia in moderate to good yields (73–86%). Also, the influence of both types of substituents on the ortho- and meta-positions of the aryl ring in p-QM was tested. It must be noted that these substituents were found to have minimal effects on the reactivity, as DAMS 3ja–qa were smoothly accessed and offered the realm of post-synthetic modification. Then, chemoselective 1,6-hydrosulfonylation in p-QM 1r, with an O-allyl arm, was demonstrated smoothly. The analogs with a disubstituted aryl residue in p-QMs were also tested under the optimized conditions to access 3qa–va. Notably, the scope was also extended to include 2-thiophenyl- and 2-pyridyl-tethered p-QMs to access 3wa and 3xa, respectively, in moderate yields. However, attempts to access the DAMS 3ya and 3za from p-QMs tethered with 9-anthracenyl and 4-pyridinyl units were unsuccessful. Lastly, we also extended the scope of the developed conditions to the 1,4-hydrosulfonylation of in situ generated o-QM (1′a) to access 3′aa effortlessly.

Scheme 1 Substrate scope for 1,6/1,4-hydrosulfonylation of QM 1 using 2. ^a 1′ was generated in situ from 2-(hydroxy(phenyl)methyl)phenol; ^b BF₃·OEt₂ was used instead of TFA.

Next, attention was directed toward exploring the scope of various cyclopropanols for hydrosulfonylation of p-QM 1a, and the results are summarized in Scheme 1b. After thoroughly testing 1-phenylcyclopropanol in coupling with diverse p-QMs, the tolerance of other 1-phenylcyclopropanol derivatives bearing electron-donating substituents (–Me, –OMe, and –Ph) as well as electron-withdrawing substituents (–F, –Cl, and –Br) at either the ortho or the para position of the aryl ring was demonstrated by accessing DAMS (3ab–3af) in moderate to good yields (60–81%). Also, cyclopropanols with disubstituted aryl rings were tolerated, as 3ag and 3ah were accessed easily. Furthermore, we could demonstrate the feasibility of the reaction employing diverse alkyl-substituted cyclopropanols. For instance, linear long 1°-alkyl chain substituted, cyclohexyl substituted, and 1-adamantyl substituted cyclopropanols 2i–k were employed to access 3ai–3ak, respectively, in 42–75% yields. Also, cyclopropanols with unsubstituted and substituted benzyl groups showcased good reactivity, as DAMS 3al and 3am were obtained in good yields. Eventually, the efficacy of the developed protocol for pharmaceutically relevant molecules was demonstrated by accessing 3an–3ap in satisfactory yields, through the photoredox catalyzed reaction of 1a with ibuprofen-, naproxen-, and gemfibrozil-derived cyclopropanols while ensuring SO₂ fixation.

After establishing a library of γ-keto sulfonylated DAMs 3 through substrate scope investigation of 1 and 2, the next task of demonstrating hydroalkylsulfonylation employing diverse p-QMs 1 and 4-alkyl-1,4-DHP 4a, as the C-centered radical source, in the presence of SO₂ gas was taken in hand (Scheme 2a). The reaction of p-QM 1b, as well as the analogs 1c–1i bearing either electron-donating (C₄-OH, OAc) or electron-withdrawing (–F, –Cl, –Br, –CN, and –NO₂) substituents at the para-position of the aryl ring in p-QMs, with 4a afforded the desired products 5ba–ia in moderate to good yields (68–77%). Also, p-QMs with aryl rings with ortho- and meta-substituted electron-donating/withdrawing groups were tested, and the corresponding DAMS 5ja–ra were accessed smoothly. Also, the analogs with the disubstituted aryl residue in p-QMs were tested under the optimized conditions to access 5sa-va. Gratifyingly, we could confirm the structure of 5sa (CCDC 2441977) through X-ray crystallographic studies.⁵⁵ Notably, the scope was also extended to include 2-thiophenyl- and 2-pyridyl-tethered p-QMs to access 5wa and 5xa, respectively, in moderate yields. However, attempts to access the DAMS 5ya and 5za from p-QMs tethered with 9-anthracenyl and 4-pyridinyl units were unsuccessful. Lastly, we also extended the scope of the developed conditions to the 1,4-hydrosulfonylation of in situ generated o-QM (1′a) to access 5′aa effortlessly.

Scheme 2 Substrate scope for 1,6/1,4-hydrosulfonylation of QM 1 using 4. ^a 1′ was generated in situ from 2-(hydroxy(phenyl)methyl)phenol; ^b BF₃·OEt₂ was used instead of TFA.

Thereafter, we redirected our focus to exploit a plethora of diversely substituted 4-alkyl-DHPs for reaction with p-QM 1a. As shown in Scheme 2b, C-centered radicals produced from diverse 4-(2°-alkyl)-1,4-DHPs were successfully transferred while fixing SO₂ to afford DAMS in moderate to good yields (5ab–ad). Acyclic and cyclic 2°-alkyl-substituted DHPs with distal functionalities displayed better reactivity under optimized reaction conditions, affording the desired products (5ae–ag). A DHP bearing a tetrahydrofuran ring was also found to be compliant, delivering the corresponding product 5ah in 72% as an inseparable 1 : 1 diastereomeric mixture. Also, we could succeed in accessing 5ai–al while using the 3°-alkyl and homobenzylic groups derived from DHPs 4i–l in SO₂ fixation.

Next, we shifted our attention towards highlighting the scalability and synthetic utility of the accessed DAMS through some useful downstream functional transformations shown in Scheme 3. The photoredox-catalyzed couplings of 1a with 2a and 4a, respectively, at a 3 mmol scale under the established conditions afforded the corresponding DAMS 3aa and 5aa in 74% and 65% yields, respectively. Then, carefully crafted DDQ-mediated oxidation was demonstrated on both 3aa and 5aa to access sulfonylated p-QMs 6 and7, respectively. Also, access to the γ-oxime alkylsulfonylated DAM 8 was demonstrated from 3aa effortlessly. Then, 3aa was utilized to demonstrate the chemoselective reductive deoxygenation of the sulfone to sulfide 9. Esterification of the phenolic-OH in 3ca was demonstrated, besides the desulfonylative oxidation of 3aa/5aa to benzophenone 11. Furthermore, a Ru-catalyzed cross-metathesis reaction was demonstrated on 5ra to access the α,β-unsaturated ester 12. Lastly, we could demonstrate desulfonylative C–N bond formation via benzotriazole addition on 3aa/5aa to access diarylmethane-substituted benzotriazoles 13 and 14, respectively.

Scheme 3 Gram-scale reaction and synthetic transformations on DAMS (3/5).

We next ventured to gain insights into the underlying mechanisms for the reactions involving the coupling of p-QMs (1) with cyclopropanols (2) or 4-alkyl-1,4-DHPs (4), through a series of control experiments and spectroscopic studies shown in Fig. 3, employing 1a and 2a/4a. Firstly, to collect evidence for the radical nature of the reactions, we performed each of the couplings involving 1a and 2a in the presence of different trapping agents highlighted in Fig. 3A. The addition of radical trappers like TEMPO/diphenyl ethylene/BHT to each of the reactions, under the optimal conditions, resulted in either complete suppression or drastic reduction in the yields of the desired products 3aa/5aa (Fig. 3A). Moreover, the TEMPO/diphenyl ethylene/BHT trapped adducts 15–18 (Fig. 3A) could be detected through HRMS (Fig. S1a–d, SI) in the case of the reaction involving 1a and 2a while the adducts 19–21 (Fig. 3A) could be HRMS-traced (Fig. S5a–d, SI) in the case of the reaction involving 1a and 4a. The light on–off experiments (Fig. 3B) conducted for each set of photoredox catalyzed reactions involving 1a and 2a or 4a indicate that the 3aa/5aa formation depends on constant light irradiation under the optimized conditions and rules out the involvement of a radical chain reaction. From the Stern–Volmer quenching studies, in the context of reactions involving 1a and 2a/4a, it was found that there was no significant effect of 2a/4a on the emission profile of the excited PC-1. On the other hand, the incremental addition of 1a was found to exert a significant quenching effect on the emission intensity of PC-1 (Fig. 3C–E), hinting at a SET event between p-QM and excited PC-1.

Fig. 3 (A) Radical inhibition and trapping experiments. (B) Light on–off experiments. (C) Fluorescence quenching spectrum of PC-1′ on incremental addition of 1a (0–25 mM in MeCN; 0–30 mM in DCE). (D) Stern–Volmer quenching plot of PC-1 against varying concentrations of 1a and 2a. (E) Stern–Volmer quenching plot of PC-1 against varying concentrations of 1a and 4a.

Based on the control experiments and detailed mechanistic studies and considering the related literature reports,⁵⁶ the plausible mechanisms underlying the two photoredox-catalyzed reactions developed in the present study are as shown in Scheme 4. First, in the context of the reaction of 1 and 2 involving SO₂-capture, a dual catalytic cycle is proposed. Both the outcome of the fluorescence quenching experiment and the redox potential data of cyclopropanols (E_p = +1.06 − +1.54 V vs. SCE)⁵⁷ and the excited Eosin Y (E_1/2 (EY*/EY⁻) = +0.83 V vs. SCE)⁵⁸ ruled out the thermodynamic feasibility of any electron transfer between them. Therefore, mechanistically, the dual catalytic cycle is postulated to commence with the polarity-matched HAT between excited PC EY* and cyclopropanol 2 to generate the alkoxide I and EY-H. Subsequent strain-release driven ring scission in I produces the β-keto radical II, which on SO₂-capture generates the γ-keto sulfonyl radical III. On the other hand, the other catalytic cycle is postulated to involve the oxidative quenching of excited PC EY* with the proton-coupled p-QM 1 (E_1/2 (EY⁺/EY*) = −1.11 V vs. SCE)⁵⁸ and p-QM (E_red = −0.20 V vs. SCE)^59–62 to generate the diarylmethyl radical IV. Then, the radical–radical cross-coupling between III and IV is presumed to be accountable for the formation of the γ-keto-alkylsulfonylated diarylmethane 3. Lastly, the reverse HAT (RHAT) or reduction of the oxidised PC EY⁺ by EY-H regenerates the photocatalyst EY, thereby closing both the catalytic cycles. Similar to the observation by Wu et al.,⁶³ the enhancement in the HAT-capability of PC EY in the presence of a Brønsted acid, besides facilitating the reductive SET on IV, is proposed to account for the dramatic improvement in the reaction efficiency in the presence of TFA.

Scheme 4 Plausible mechanisms for the synthesis of 3 and 5.

Similarly, the access to 5 through the reaction of 1 and 4via SO₂-capture in the presence of TFA is mechanistically postulated, as shown in Scheme 4B. The photoredox cycle commences with the oxidative quenching of excited PC EY* with the proton-coupled p-QM 1, (E_1/2 (EY⁺/EY*) = −1.11 V vs. SCE)⁵⁸ and p-QM (E_red = −0.20 V vs. SCE)^59–62 to generate the diarylmethyl radical IV and oxidized PC EY⁺. The formation of the other coupling partner is postulated to be derived through pathways a, b, and c, highlighted in Scheme 4B. Through path a, the oxidative SET from the photoexcited 4-alkyl-1,4-DHP ⁶⁴ to the oxidized EY⁺ (E_1/2 (EY⁺/EY) = +0.78 V vs. SCE)⁵⁸ is believed to close the photoredox cycle while facilitating the generation of intermediate V and subsequently the alkyl radical VIvia aromaticity driven C-4 bond scission. Simultaneously, the formation of V and subsequently VI is also postulated through the oxidation of 4-alkyl-1,4-DHP by Ag(I)/Ag(II)-catalysis in the presence of persulfate, as well as directly by persulfate, which constitutes paths b and c, respectively. Subsequent SO₂-capture by the alkyl radical VI gives rise to the alkylsulfonyl radical VII for radical–radical cross-coupling with IV to furnish 5 eventually.

Computational studies

To further strengthen our proposed mechanism, we explored the proposed pathways through density functional theory (DFT) studies at the SMD/PBE0(D3BJ)/def2tzvp//PBE0(D3BJ)/def2svp level of theory. For this, 1b was employed as the model p-QM, while 2a and 4a were used as the model cyclopropanol and 4-alkyl-1,4-DHP partner, respectively. The free energy profile diagram, along with the ChemDraw structures and DFT-optimized geometries of different intermediates and transition states, is depicted in Fig. 4.

Fig. 4 Free energy profiles for the proposed mechanisms (A) and (B) at the SMD/PBE0(D3BJ)/def2tzvp//PBE0(D3BJ)/def2svp level of theory.

For the first reaction comprising a dual catalytic cycle, catalytic cycle-1 involves the reaction of excited PC EY* with protonated p-QM (1b-H⁺) to form IV and EY⁺˙. Here, EY* oxidizes to EY⁺˙, and 1b-H⁺ reduces to IV. The free energy of this reaction is calculated to be −3.3 kcal mol⁻¹, and the C–O bond length changes from 1.316 Å in 1b-H⁺ to 1.355 Å in IV. Catalytic cycle-2 involves 1-phenyl-1-hydroxycyclopropane 2a, which undergoes a HAT reaction with excited PC EY^* to form the alkoxide radical I and [EY-H]˙. The reaction is found to be exergonic with ΔG = −8.1 kcal mol⁻¹ and hence feasible under the reaction conditions. It is important to note that in our recent work⁴⁶ DABCO⁺˙ facilitated the HAT from cyclopropanol, where the reaction was found to be slightly endergonic by ΔG = 4.7 kcal mol⁻¹. Hence, EY* works better as an oxidizing agent than DABCO (1,4-diazabicyclo[2.2.2]octane).

I is an oxygen-centred radical species, and the C–O bond length is found to decrease from 1.390 to 1.280 Å, clearly indicating the development of C–O double bond character. Then, the oxygen-centered radical species I is converted to the carbon-centered radical II through β-scission, via transition state TS1a. At TS1a, the C–O bond length further decreases to 1.249 Å, whereas the breaking C–C bond increases from 1.587 to 1.803 Å, implying a product-like transition state. The activation barrier for this step is −0.5 kcal mol⁻¹, implying the feasibility of the step. The carbon-centered radical II thus formed captures SO₂ to form the γ-keto sulfonyl radical III, and the reaction is spontaneous as ΔG = −13.8 kcal mol⁻¹. Then, radical III couples with IV to form the final product 3ba. This radical coupling is found to be highly exergonic with ΔG = −41.8 kcal mol⁻¹, implying the spontaneity of the process for the synthesis of γ-keto alkylsulfonylated diarylmethanes. Lastly, the spontaneity of the reverse HAT (RHAT) between [EY-H]˙ and EY⁺ or reduction of the oxidised PC EY⁺ by [EY-H]˙ to regenerate the PC EY and thereby close both the catalytic cycles is supported by the free energy change of −36.9 kcal mol⁻¹.

Similarly, in the context of the reaction between 1b and 4a (Fig. 4B), the radical cation V generated through pathways a, b, and c depicted in Scheme 4 facilitates the formation of the isopropyl radical (VI) via the aromaticity-driven C₄-bond scission in V. This step is feasible as ΔG for the process is found to be −0.7 kcal mol⁻¹. Subsequent capture of SO₂ by VI furnishes the sulfur-centered radical VII. The reaction proceeds with the formation of transition state TS1b with an activation barrier of 6.3 kcal mol⁻¹, and the C–S bond length is 1.838 Å. Next, the isopropyl sulfonyl radical VII reacts with the diarylmethyl radical IV (formed similarly to that described vide supra for the first mechanism) to furnish the final product 5ba. The reaction is spontaneous with ΔG = −34.9 kcal mol⁻¹ and favours the synthesis of alkylsulfonylated diarylmethanes.

Biological studies

Taking into account the well-documented therapeutic potential of the DAMS scaffold as well as the γ-ketosulfone motif,^7,9,10 we were motivated to assess the anticancer activity of some selected compounds (entries 1–20, Table 1) against the oral squamous cell carcinomas (OSCC cell lines) H357 and SCC9. The cell viability of these compounds on the OSCC cell lines H357 and SCC9 was determined by MTT assay. All the compounds were screened at 0.5, 2.5, 5, and 10 μM concentrations. Furthermore, we calculated the IC₅₀ (concentration for 50% of the cell death) values of the compounds, which are highlighted in Table 1, from the slope of the cell viability (%) vs. drug concentration (μM) plots in each cell line for each compound. All the tested compounds, except compound 3ao, exhibited greater than 50% reduction in cell viability within 10 μM in both cell lines. Among them, four compounds 3ga, 5ha, 5ia, and 5oa had IC₅₀ ≤ 5 μM in both H357 and SCC9 (entries 1, 15, 16 and 18, Table 1). The plots of cell viability versus concentration for those four compounds are shown in Fig. 5.

Fig. 5 Cell viability versus concentration of compounds.

Table 1 IC₅₀ values of 20 compounds in the H357 and SCC9 cell lines

S. no.	Compounds	IC50 values (in μM)
		H357	SCC9
1	3ga	4.91	4.90
2	3ia	6.25	5.01
3	3na	5.22	5.62
4	3ta	6.54	7.92
5	3ea	5.51	5.24
6	3xa	6.68	5.96
7	3pa	5.33	5.33
8	3oa	6.02	5.61
9	3wa	7.32	5.33
10	3an	8.83	5.19
11	3ao	10.37	5.67
12	3ap	8.27	5.47
13	5fa	7.09	5.87
14	5ga	8.40	8.44
15	5ha	4.74	3.71
16	5ia	5.00	4.37
17	5pa	5.32	5.29
18	5oa	4.02	4.41
19	5xa	8.13	6.96
20	5ta	5.19	5.18

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Conclusions

In conclusion, a visible light photoredox catalyzed 1,6-hydrosulfonylation of p-QMs has been demonstrated for the efficient synthesis of γ-keto alkylsulfonylated and alkylsulfonylated diarylmethanes via the incorporation of sulfur dioxide as a key building block for the sulfonyl functionality. A broad substrate scope, mild reaction conditions, and easily accessible starting materials from feedstock chemicals constitute some of the key highlights of the approach. Some valuable synthetic transformations have been demonstrated on the accessed scaffolds. Control experiments and DFT studies were conducted to gain mechanistic insights. Also, pharmacological investigation of some of the representative compounds from our synthesized library revealed prominent anticancer activity against the tested oral cancer cell lines and provided leads for further investigation.

Author contributions

Conceptualization: T. K. Synthetic studies: D. K. P., T. K. S. and R. K. Computational studies: S. G. P. Manuscript drafting through contribution from all the authors. The final version of the manuscript was approved by all the authors.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the SI. Supplementary information: experimental details, characterization and analytical data. See DOI: https://doi.org/10.1039/d5qo00981b.

CCDC 2441977 contains the supplementary crystallographic data for this paper.⁵⁵

Acknowledgements

T. K. gratefully acknowledges the financial support from the Anusandhan National Research Foundation (ANRF), formerly the Science and Engineering Research Board (SERB), DST, India (CRG/2023/002467). Dr Rupesh Dash from ILS-Bhubaneswar is acknowledged for the bioactivity profiling. D. K. P. thanks the UGC, India, and T. K. S. and R. K. thank the Ministry of Education, India, for the SRFs. All the authors thank their respective institutes for the financial and infrastructural support.

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