Thianthrenium-Enabled Sulfonylation via Electron Donor-Acceptor Complex Photoactivation

SUMMARY

Sulfone-containing compounds are prevalent building blocks in pharmaceuticals and other biomolecules, and they serve as key intermediates in the synthesis of complex scaffolds. During the past decade, several methods have been developed to access sulfones. These strategies, however, require the use of strong reaction conditions, limiting their substrate scope. Recently, visible light-mediated transformations have emerged as novel platforms to access unprecedented structural motifs. This report demonstrates a thianthrenium-enabled sulfonylation via intra-complex charge transfer to generate transient aryl- and persistent sulfonyl radicals that undergo selective coupling to generate alkyl- and (hetero)aryl sulfones under ambient conditions. Importantly, this strategy allows retention of halide handles, presenting a complementary approach to transition metal-mediated photoredox couplings. Furthermore, this sulfonylation allows high functional group tolerance and is amenable to late-stage functionalization of complex biomolecules. Mechanistic investigations support the intermediacy of electron donor-acceptor (EDA) complexes.

Graphical Abstract

An operationally simple sulfonylation of activated arenes was achieved to render privileged sulfone structures. This is enabled by a photoinduced electron donor-acceptor (EDA) complex strategy, using thianthrenium tetrafluoroborates and sodium sulfinates, under mild conditions. This strategy allows the late-stage sulfonylation of relevant bioactive molecules, such as gemfibrozil and fenofibrate, as well as the retention of halogen handles.

The bigger picture

Given their importance in medicinal chemistry, agrochemicals, and materials science, numerous methods have been developed for the synthesis of sulfones. Traditional strategies require the use of harsh reaction conditions or employ expensive catalysts. Recently, electron donor-acceptor (EDA) complex photoactivation has been enlisted as a powerful strategy in organic synthesis because it avoids the use of exogenous photosensitizers and allows the rapid assembly of diverse structural motifs under ambient conditions. This report describes a thianthrenium-enabled sulfonylation via intra-complex charge transfer to generate transient aryl- and persistent sulfonyl radicals that undergo selective coupling. This strategy is amenable to late-stage functionalization and enables the retention of halide handles that can be harnessed for further derivatization.

INTRODUCTION

The sulfone skeleton is among the most important sulfur-containing organic motifs, with applications in materials science, agrochemicals, and pharmaceuticals.^1–8 Because of its unique biological and chemical activities, it is frequently found embedded within the structures of valuable building blocks used in the synthesis of medicinally relevant scaffolds,^9–13 including the antibiotic dapsone used to treat cutaneous infections, the rice herbicide cafenstrole, the lipid-lowering agent neosartoryone A,¹⁴ and the antiemetic and antipsychotic agent amisulpride used in the treatment of postoperative nausea and vomiting.

Given the importance of sulfonyl moieties, several research strategies have been developed to install these scaffolds.^15–17 Classical routes to access sulfone-containing compounds proceed via direct oxidation of sulfides. These methods, however, require harsh reaction conditions and suffer from poor chemoselectivities or incomplete oxidation, affording the corresponding sulfoxide. In addition, these strategies are not environmentally friendly because they employ stoichiometric quantities of toxic and/or strong oxidants (e.g., peroxy acids or periodate reagents).^18–23 In this context, several photoredox transformations have emerged to address these limitations and serve as alternative approaches to generate sulfones under mild conditions.^15,24 Some of these reactions are based on photoinduced sulfur dioxide insertion using DABSO {1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct} or metabisulfite salts (Na₂S₂O₅ or K₂S₂O₅), which require the use of exogeneous photocatalysts.^25–27 Other routes to construct (hetero)aryl sulfones^28–29 proceed through photoredox/nickel dual catalysis using aryl halides and sulfinate salts under base-free, room temperature conditions (Scheme 1.2 A). These methods, however, are not compatible with C_sp³-SO₂Na sulfinates. More recently, a visible-light-mediated, copper-catalyzed sulfonylation of aryl halides with sulfinates was disclosed, transpiring via in situ formation of a photoexcitable Cu(I) species.³⁰

Scheme 1.

Importance of sulfone-containing compounds and recent photoredox approaches to access this motif.

Electron donor-acceptor (EDA) complex photoactivation has emerged as a complementary platform to generate carbon- and heteroatom-based radicals under very mild conditions, because of its ability to use visible light to activate colorless substances in the absence of exogenous photocatalysts. This synthetic approach relies on the association of an electron-donor compound D and an electron-acceptor molecule A to generate a new molecular aggregate in the ground state that can be activated by visible-light to yield a radical ion pair. Subsequently, this intermediate can undergo an irreversible homolytic fragmentation event to form high-energy radical species that can engage in various transformations, such as radical-radical coupling [forming product (P) in Scheme 1.2 B].³¹ Although photochemical sulfonylation reactions have been reported (Scheme 1.2 B), these transformations typically proceed via UV light irradiation³² or by the use of Hantzsch ester (HE) as a terminal photoreductant.³³ In general, these methods undergo C–X bond activation, precluding the possibility to carry a halide handle through the process for further derivatization. Other EDA-mediated strategies, catalyzed by cetrimonium bromide (CTAB), are limited to the synthesis of β-iodo-substituted sulfone derivatives.³⁴

In recent years, sulfonium salts have been used as versatile reagents for C–H activation through C–S bond cleavage to construct new C–C bonds.³⁵ In particular, the thianthrenation of arenes is a highly selective aromatic C–H activation process that proceeds without the incorporation of directing groups.³⁶ The formation of thianthrenium salts 1 typically allows high functional group tolerance under mild conditions and can be performed in late-stage functionalization. Precedented reports from the Ritter group describe the synthesis and applications of thianthrenium salts 1 in several cross-couplings (e.g., etherification, Miniscitype reactions, the synthesis of sulfonamides, and tritium labelling).^37–40 Additionally, Ritter and coworkers demonstrated that thianthrenium salts serve as suitable aryl radical precursors in amination,⁴¹ trifluoromethylation⁴² and fluorination reactions⁴³ via copper metallaphotoredox catalysis.

Given the inherent advantages of EDA complex photoactivation, our group has recently applied this strategy to the preparation of trifluoromethylthiolated organic building blocks from the association of 1,4-dihydropyridines with N-(trifluoromethylthio)phthalimide,⁴⁴ as well as in a Giese-type addition on solid-phase.⁴⁵ Further studies demonstrated the merger of charge-transfer complexes and nickel-catalyzed cross-couplings for C(sp³)–C(sp²) bond formation with diverse (hetero)aryl halides^46–47 using alkyl redox-active esters (RAE) as electron-acceptors and commercially available HE as an organic photoreductant. Inspired by these advances, we envisioned a sulfonylation reaction through EDA complex photoactivation, using functionalized thianthrenium salts 1 as electron-deficient acceptors and sodium sulfinates 2 as electron-rich donors under visible light irradiation (Scheme 1.3). This proposed transformation would enable the formation of a C(sp²)-SO₂ bond via indirect CH activation from C-S bond cleavage of 1, as an operationally simple approach to sulfones. To the best of our knowledge, thianthrenium salts 1 have not been previously activated through EDA complexes, and we herein demonstrate that these salts 1 serve as suitable electron acceptors through this paradigm.

RESULTS AND DISCUSSION

The feasibility of the envisioned sulfonylation reaction was investigated using sulfonium salt 1a and sodium benzenesulfinate (2a) as model substrates (Table 1). Several bases were screened as additives (entries 1–7), showing that the best result was obtained with cesium carbonate (Cs₂CO₃). Other carbonated bases, as well as potassium phosphate tribasic, displayed comparable results. However, the use of sodium- or ammonium acetate led to diminished formation of sulfone 3a in comparison to reactions conducted with no base (entry 1). Increasing the amount of 2a and the loading of Cs₂CO₃ resulted in improved product formation (entries 8–10), with the optimal conditions utilizing 3 equiv of sodium sulfinate 2a and 2 equiv of Cs₂CO₃ (entry 10). To test role of Cs₂CO₃, the experiment was carried out in the presence of CsF (entry 11). In the event, the reaction was successful in forming sulfone 3a, although to a lesser extent than when using Cs₂CO₃. Also, the mixture of Cs₂CO₃ and 1a under 390 nm light (see Table S7 in supplemental information) left 1a practically unreacted, with some formation of biphenyl. Therefore, it is likely that a counterion exchange between the sodium ion of the sulfinate and cesium ion occurs, which gives rise to a more efficient interaction between the electron-acceptor 1a and the electron-donor 2a. DMSO serves as the best solvent for this transformation, providing the best solubility for all the components of the reaction. The supplemental information shows a detailed solvent screen as well as further optimization of the reaction concentration. Next, we explored the feasibility of this transformation using different light sources. Although blue light is a good option to obtain the desired product, the conversion is slightly lower than when using purple light (entries 10 vs 12), because unreacted 1a was detected by LCMS under blue light conditions. The use of green light is not beneficial for this transformation, as 1a is unreactive under these conditions. The formation of sulfone 3a was not detected in the absence of light (entry 14), validating the photochemical nature of this transformation.

Table 1.

Optimization of the reaction conditions

Entry	Additive	Equiv of Additive	3a/IS GC yield (%)a
1	none	none	23
2	CS2CO3	1	43
3	K2CO3	1	39
4	Na2CO3	1	37
5	K3PO4	1	30
6	NaOAc	1	18
7	NH4OAc	1	19
8b	Cs2CO3	1	52
9b	Cs2CO3	2	69
10b,c	Cs2CO3	2	87 (78d)
11b,c	CsF	2	63
12b,c,e	Cs2CO3	2	72
13b,c,f	Cs2CO3	2	Traces
14b,c, g	Cs2CO3	2	no reaction

Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), base, dry and degassed DMSO (0.2 M) at room temperature under purple Kessil^® (390 nm) irradiation for 16 h.

^aCalculated against 1,3,5-trimethoxybenzene as internal standard (IS).

^b3 equiv of 2a.

^cSolvent 0.13 M for 1a.

^dIsolated yield at 0.5 mmol scale.

^eBlue Kessil^® (456 nm).

^fGreen Kessil^® (525 nm).

^gNo light.

With suitable conditions in hand, the scope of this sulfonylation was investigated (Scheme 2). Different aryl thianthrenium salts 1 and sodium sulfinates 2 were successfully subjected to this EDA-mediated photoinduced strategy. The evaluation of various sodium (hetero)aryl sulfinates 2 revealed that this reaction tolerates the unsubstituted phenyl ring (3a) and a wide range of electron-withdrawing (3b-f, 3ad) and electron-donating groups (3g-j, 3z). It is noteworthy that sulfone 3c serves as a suitable intermediate in the total synthesis of dapsone, demonstrating the utility of this EDA process in pharmaceutical applications. Medicinally relevant heterocyclic sulfinate scaffolds were amenable electron donors, affording the corresponding quinolinyl- (3l), pyridinyl- (3m), imidazolyl- (3n), and thienyl (3aa) sulfone derivatives in moderate yields. Additionally, dansyl sulfinate derivative 2m afforded the corresponding sulfone 3k in 46% yield. This sulfonylation method was further extended to alkyl sulfinates, generating the desired cyclopropylsulfone 3o, cyclohexylsulfone 3r, and methylsulfones 3p-q. Such substrates were unsuccessful radical precursors in photoredox/nickel dual catalysis.

Scheme 2. Scope of the sulfonylation reaction.

Reaction conditions: Thianthrenium salt (1, 0.5 mmol, 1.0 equiv), sodium sulfinate (2, 1.5 mmol, 3.0 equiv), Cs₂CO₃ (1.0 mmol, 2 equiv) in DMSO (3.75 mL, 0.13 M) under purple light irradiation (Kessil lamp, λ_max = 390 nm). Yields correspond to isolated products after chromatographic purification.^a3 mmol scale reaction. See the supplemental information for further details.

Next, several thianthrenium salts 1 were investigated, showing that this reaction tolerates different functional groups, including ethers (3s, 3x, 3y-ab, 3ad, 3aj-ak), aldehydes (3s), esters (3t, 3ab, 3ae, 3ag-ak), amides (3u, 3ac), and halides (3y-aa, 3ag, 3ah, 3aj). Notably, ether thianthrenium salt 1d reacted with complete retention of the bromide handle to afford sulfones 3y-aa, serving as a complementary approach to photoredox/nickel cross-coupling catalysis^28–29 and other EDA complex sulfonylation conditions^32–33 that proceed through C–X bond activation. Additionally, sulfone 3y was successfully synthesized on gram scale to validate the synthetic utility of this sulfonylation. Although in some cases arene was formed as a result of hydrogen atom transfer to the aryl radial generated, this was only a minor byproduct observed. Electron-rich and electron-poor heterocycles also served as suitable (hetero)aryl radical sources, affording the desired thienylsulfone 3w and pyridylsulfone 3x in high yields. The thianthrenated precursors of 3w and 3x (1r and 1s) are colored, thus the UV-Vis comparison of these substrates with 1a was considered. Indeed, the difference in terms of absorption is remarkable (see supplemental information Figure S7). In these two specific cases, and the under the standard reaction conditions, a parallel mechanism based on C-S bond cleavage of the thianthrenium salt for the generation of the heteroaryl radical and the thianthrenium cation radical may be operating.

To demonstrate the applicability of this sulfonylation reaction in late-stage functionalization, several functionalized biomolecules and pharmaceuticals were subjected to the reaction conditions, generating the corresponding sulfones from lipid-lowering agents gemfibrozil (3ae) and fenofibrate (3ag), antifungal bifonazole (3af), as well as anti-inflammatory compounds including flurbiprofen (3p, 3ah), salicin (3ai), and indomethacin (3aj-ak). Partial deprotection of the indole moiety present in indomethacin thianthrenium salt 1m was observed, leading to the isolation of sulfones 3aj and 3ak.

In an attempt to elucidate the mechanism of this sulfonylation reaction, ultraviolet/visible (UV/Vis) and radical trapping studies were performed (Figure 1). To probe the formation of an intermediate EDA complex, the UV/Vis absorption spectra of each individual reaction component as well as the reaction mixture were measured in DMSO (Figure 1A). Sodium benzenesulfinate (2a, black line) displays an absorption band in the near ultraviolet range, and biphenyl-thianthrenium tetrafluoroborate salt 1a (red line) shows a small absorption band in the visible light region, while a mixture of the two (1a + 2a, blue line) exhibits a bathochromic shift and stronger brown color, derived from the formation of a new molecular aggregate in the ground state. Interestingly, the addition of Cs₂CO₃ to the mixture (pink line) results in an improvement in the bathochromic shift, with a visible light absorption band tailing to the 425–600 nm region (see the supplemental information). Radical trapping experiments using TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxyl radical) and 1,1-diphenylethene, performed under the reaction conditions, support the formation of the corresponding radicals from sodium sulfinate 2 and thianthrenium tetrafluoroborate salt 1 (Figure 1B). The addition of TEMPO led to diminished formation of sulfone 3a with a 19% isolated yield alongside the corresponding TEMPO adduct 4, as confirmed via ¹H NMR and HRMS analysis. Moreover, compounds 5 and 6 were identified by HRMS analysis when this sulfonylation reaction was performed in the presence of 1,1-diphenylethene and the yield of 3a dramatically decreased. The addition of the biphenyl radical, stemming from 1a, to 1,1-diphenylethene led to substrate 6, while compound 5 stems from the generation of a sulfonyl radical from 2a followed by extrusion of sulfur dioxide. Additional mechanistic studies revealed that 1a does not suffer photolysis upon irradiation at 390 nm in DMSO, and only traces of biphenyl were detected (see supplemental information).

Figure 1.

UV/vis studies, radical trapping experiments and proposed mechanism. A) UV/vis absorption spectra measured in DMSO (1a 0.13 M, 2a 0.39 M, Cs₂CO₃ 0.26 M) and visual appearance of individual reaction components and their corresponding mixtures. B) Strategies for the detection of radical intermediates. C) Proposed mechanism for the construction of sulfones by EDA complex photoactivation from thianthrenium salts and sodium sulfinates

^a Calculated against 1,3,5-trimethoxybenzene as internal standard (IS).^bIsolated yield.

Based on this mechanistic insight, a plausible mechanism for this sulfonylation is proposed in Figure 1C. The association of the electron-rich sulfinate anion 2’ and the electron-deficient thianthrenium salt 1’ generates a molecular aggregate in the ground state. Excitation at 390 nm leads to the formation of an electron donor-acceptor (EDA) complex followed by an intra-complex single-electron transfer (SET) event from 2’ to 1’, generating the radical anion B and persistent sulfonyl radical C. The irreversible fragmentation of B produces thianthrene as the leaving group and the corresponding transient aryl radical D. Species C and D engage in selective radical-radical coupling to furnish the desired sulfone 3. Notably, the generated thianthrene serves as a precursor for the synthesis of thianthrenium salt 1, thereby allowing recycling of this reagent in an overall atom-economical transformation.

In summary, this thianthrenium-enabled sulfonylation via electron-donor/electron-acceptor complex photoactivation enables facile construction of C(sp²)- and C(sp³)-SO₂ bonds via C-H activation. This transformation tolerates a wide palette of functional groups, including halide and nitro handles, as well as highly functionalized bioactive molecules, such as salicin or indomethacin. Mechanistic investigations support a scenario in which this sulfonylation reaction proceeds via the intermediacy of a charge transfer complex that undergoes photoexcitation under visible-light irradiation to generate a transient aryl radical and a persistent sulfonyl radical, which undergo selective coupling. This report serves as a general blueprint for the activation of thianthrenium salts in the absence of exogenous metal complexes or photocatalysts.

EXPERIMENTAL PROCEDURES

Resource availability

Lead contact

Further information and requests for resources should be directed to and will be fulfilled by the lead contact, Gary A. Molander (gmolandr@sas.upenn.edu).

Materials availability

This study did not involve the design of unique reagents or catalysts for chemical synthesis.

Data and code availability

There is no dataset or code associated with this publication. All relevant procedures and experimental data are provided in the supplemental information.

General procedure for the sulfonylation of thianthrenium salts via EDA complex photoactivation

To an 8 mL vial equipped with a magnetic stir bar and a rubber septum was added Cs₂CO₃ (2 equiv), thianthrenium salt (1a-s, 1.0 equiv, 0.50 mmol), and sodium sulfinate salt (2a-t, 3.0 equiv, 1.50 mmol). The vial was evacuated three times via an inlet needle, then purged with argon. The vial was then charged with dry, degassed DMSO (0.13 M, 3.8 mL) via syringe. The reaction mixture was irradiated for 16 h with a Kessil PR160-purple LED lamp (30 W High Luminous DEX 2100 LED, λ_max = 390 nm) as described in the “Workflow” section (see supplemental information). The temperature of the reaction was maintained at approximately room temperature via a fan. Upon completion, the reaction mixture was poured into a separatory funnel and extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layers were washed with brine, dried (Na₂SO₄), and the volatiles were removed under reduced pressure. The crude mixture was subjected to automated flash column chromatography for purification.

HIGHLIGHTS.

Efficient formation of C(sp²)–SO₂ bonds via visible-light-mediated EDA complex strategy Simultaneous generation of a transient aryl- and persistent sulfonyl radicals Late-stage sulfonylation of highly functionalized bioactive compounds or pharmaceuticals Atom economy: Thianthrene leaving group reused to construct new thianthrenium salts