An iron-catalyzed C–S bond-forming reaction of carboxylic acids and hydrocarbons via photo-induced ligand to metal charge transfer

Abstract

Sulfur-containing compounds are commonly present in both natural and synthetic bioactive molecules. The ability to construct C–S bonds using inexpensive and easily accessible raw materials under mild conditions is an area of significant interest in organic synthesis. In this study, we introduce a novel photo-induced iron-catalyzed strategy that facilitates the transformation of alkyl and heteroaryl carboxylic acids into their respective thioether products. Furthermore, our method also enables the site-selective synthesis of thioethers and sulfoxides from unreactive hydrocarbons under a reaction atmosphere of N₂ or air. This procedure is operationally simple and readily scalable and provides access to high-value sulfur-containing compounds from simple raw materials in one step.

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Introduction

C–S bond-forming reactions are significant transformations in chemistry¹ since sulfur-containing compounds are prevalent in nature, particularly in biologically active molecules and drug candidates.² Meanwhile, the transformations of C–S bond formation have garnered considerable attention in various other research fields, including organic synthesis,³ materials chemistry,⁴ and agriculture.⁵ Recent advancements in transition-metal-catalysis⁶ and electrochemical oxidative cross-coupling⁷ have facilitated efficient C–S bond formation. Notably, low-cost light energy has become an attractive option in organic synthesis due to its sustainability, efficiency, and eco-friendliness amidst the increasing concern regarding energy consumption and sustainability.⁸ Extensive research and applications of photogenerated carbon and heteroatom radicals have led to the effective construction of valuable molecular frameworks.⁹ Consequently, the construction of C–S bonds via photocatalytic processes holds great promise.

Carboxylic acids are abundant, structurally diverse, and versatile synthetic sources that are widely used in organic synthesis.¹⁰ In the past few years, visible light-mediated decarboxylative functionalization reactions have made tremendous progress,¹¹ particularly through a photo-induced ligand-to-metal charge transfer (LMCT) strategy that employs Earth-abundant transition metals such as copper and iron salts for bond homolysis processes to achieve decarboxylation.¹² It should be noted that performing direct decarboxylation of aromatic carboxylic acids under mild conditions is considered a significant challenge as the process is a thousand times slower than that of alkyl carboxylic acids.¹³ It has been recently demonstrated that the photo-induced LMCT process can be utilized to facilitate the decarboxylation of aryl carboxylic acids. Ritter and co-workers have described the decarboxylative fluorination,^12c hydroxylation,^12d and sulfoximination^12e of aryl carboxylic acids under violet light using a stoichiometric copper catalyst. MacMillan and co-workers have reported copper-catalyzed decarboxylative borylation and halogenation via an ultraviolet (UV)-induced LMCT strategy.^12f,h

Building on previous seminal work¹⁴ and our recent effort on C–S bond construction (Scheme 1a),¹⁵ we hypothesized that the Fe-LMCT strategy could be used to achieve the decarboxylative thiolation reaction for both aliphatic and aromatic carboxylic acids. Additionally, we anticipated that the reaction atmosphere can serve as a distinguishing factor for the chemoselectivity, selectively achieving thiolation and sulfinylation (Scheme 1b). In our proposed strategy, thiosulfonate (PhSO₂-SR) as a key reaction precursor can be readily synthesized via a one-step process, allowing for the sequential production of various high value-added thioethers (under a N₂ atmosphere) and sulfoxides (under an air atmosphere) through the attack of alkyl radicals generated by the respective photo-induced Fe-LMCT processes of carboxylic acids or hydrocarbons. As part of our ongoing interest in developing novel photochemical transformations,¹⁶ we herein report an iron LMCT catalytic strategy that allows for the decarboxylative thiolation reaction of alkyl and (hetero)aryl carboxylic acids, as well as C(sp³)–H thiolation and sulfinylation of unreactive hydrocarbons. In contrast to our previously developed protocol of C–H thiolation and sulfinylation that utilized sodium sulfinate as the coupling counterpart and identified water as a key determinant of chemoselectivity,¹⁵ this work reveals that the reaction atmosphere (under N₂ or air) results in the formation of two different types of products, thioether and sulfoxide. Furthermore, the photo-induced iron-catalyzed C(sp³)–H sulfonyl fluorination reaction has also been established.

Scheme 1 C–S bond-forming reaction via the photo-induced LMCT strategy.

Results and discussion

To evaluate the synthetic potential of the above-mentioned design for the decarboxylative C–S bond forming reaction, we began our investigation by employing 3,3-dimethylbutyric acid (1), S-phenyl benzenethiosulfonate (2), Cs₂CO₃ (50 mol%) and Fe(NO₃)₃·9H₂O (10 mol%) under 390 nm light irradiation and under a N₂ atmosphere in CH₃CN. As expected, the photochemical reaction delivered the desired decarboxylative thiolation product 3 in 54% yield (Table 1, entry 1). Afterwards, our focus turned toward the investigation of the effect of various bases on the reaction. Among the bases that were screened, including Na₂CO₃, NaHCO₃, NaOH, and K₂CO₃, it was found that K₂CO₃ was the most effective base, resulting in a yield of 91% of product 3 (entries 2–5). In the interim, we also investigated the amount of base, and our findings demonstrated that 50 mol% K₂CO₃ concentration offered the optimal result (entries 6 and 7). Attempts to replace Fe(NO₃)₃·9H₂O with Fe(acac)₃ resulted in a slight decrease in the yield (entry 8), while the use of Fe(OTf)₃ and Fe₂(SO₄)₃ led to a substantial loss of the reaction efficiency (entries 9 and 10). Furthermore, switching to other solvents, such as toluene, THF and DCE, did not result in any improvement compared to CH₃CN (entries 11–13). Finally, control experiments revealed that both the iron catalyst and light irradiation were critical for this transformation (entries 14 and 15).

Table 1 Optimization studies^a

Entry	Fe cat. (10 mol%)	Base	Solvent	3 (%)
a Reaction conditions: 1 (0.40 mmol, 2.0 equiv.), 2 (0.20 mmol, 1.0 equiv.), iron catalyst (10 mol%), base (50 mol%) in CH3CN (2 mL, 0.1 M), 35 °C, 390 nm LEDs, N2 atmosphere, 6 h. b Yields are of isolated products after chromatographic purification. c 10 mol% K2CO3. d 1.0 equiv. of K2CO3. e The reaction was performed in the dark. N.D. = Not detected.
1	Fe(NO3)3·9H2O	Cs2CO3	CH3CN	54
2	Fe(NO3)3·9H2O	Na2CO3	CH3CN	89
3	Fe(NO3)3·9H2O	NaHCO3	CH3CN	41
4	Fe(NO3)3·9H2O	NaOH	CH3CN	78
5	Fe(NO 3 ) 3 ·9H 2 O	K 2 CO 3	CH 3 CN	91
6^c	Fe(NO3)3·9H2O	K2CO3	CH3CN	80
7^d	Fe(NO3)3·9H2O	K2CO3	CH3CN	72
8	Fe(acac)3	K2CO3	CH3CN	85
9	Fe(OTf)3	K2CO3	CH3CN	25
10	Fe2(SO4)3	K2CO3	CH3CN	34
11	Fe(NO3)3·9H2O	K2CO3	Toluene	86
12	Fe(NO3)3·9H2O	K2CO3	THF	40
13	Fe(NO3)3·9H2O	K2CO3	DCE	33
14	—	K2CO3	CH3CN	N.D.
15^e	Fe(NO3)3·9H2O	K2CO3	CH3CN	N.D.

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With the optimized reaction conditions in hand, we proceeded to investigate the substrate diversity of this decarboxylative thiolation reaction. A broad range of functionalized carboxylic acids, including primary, secondary, and tertiary alkyl carboxylic acids, heteroaromatic carboxylic acids, carboxyl-containing drug molecules and natural products, can be readily converted into the corresponding thioether products with high efficiency. As shown in Scheme 2, we initially conducted the exploration of the substrate scope using primary alkyl carboxylic acids and thiosulfonates as reaction partners. Thiosulfonates bearing different substituents on the aromatics, including both electron-donating and electron-withdrawing functional groups, could be all employed as viable substrates to undergo the desired decarboxylative thiolation (3–10). Substrates bearing a heterocycle also worked well (8). A series of primary alkyl carboxylic acids containing ketone (15), alkene (16), alkyne (17), and amide moieties (18 and 19) were screened, and they were all found to be efficiently transformed into the corresponding thiolated products in moderate to high yields. Moreover, benzylic carboxylic acids (12 and 13) were found to be suitable under the standard conditions. With regard to secondary alkyl carboxylic acids, cyclic substrates with different ring sizes (4–6 membered rings) were all converted into the corresponding products in 32–77% yields (21 and 24–28). Secondary carboxylic acids bearing acyclic hydrocarbons also worked well (20, 22 and23). Furthermore, it was found that the reaction was well tolerated by tertiary carboxylic acids, resulting in the formation of the corresponding products in yields that were deemed acceptable (29–32). After making slight adjustments to the reaction conditions and conducting an extensive screening of aromatic carboxylic acid substrates (Tables S2 and S4, see the ESI for details†), we made a significant advancement in our research by expanding the substrate scope to heteroaromatic carboxylic acids. Our synthetic protocol demonstrated high efficiency in converting a wide range of substituted picolinic and quinaldic acids into the corresponding diaryl thioethers (33–48). The chemoselectivity profile of our method was nicely illustrated by the fact that arenes bearing fluoride (34, 35, and 45), chloride (36 and 43), bromide (36 and 44), ester (37), trifluoromethyl (38), and methoxy (41 and 42) moieties could be well accommodated under the standard conditions. Notably, thiosulfonates bearing naphthyl and furanyl groups were tolerated, as shown by the formation of products 46 and 47 in 52% and 58% yields, respectively.

Scheme 2 Substrate scope of decarboxylative thiolation and sulfinylation. Reaction conditions: carboxylic acid (0.40 mmol, 2.0 equiv.), thiosulfonate (0.2 mmol, 1.0 equiv.), Fe(NO₃)₃·9H₂O (0.02 mmol, 10 mol%), K₂CO₃ (0.10 mmol, 50 mol%) in CH₃CN (2 mL, 0.1 M), 35 °C, 390 nm LEDs, N₂ atmosphere, 5 h. Yields are of isolated products after chromatographic purification. ^aFeBr₃ (0.02 mmol, 10 mol%), tetrabutylammonium bromide (0.08 mmol, 40 mol%), K₂CO₃ (0.10 mmol, 50 mol%) in CH₃CN (2 mL, 0.1 M), 35 °C, 390 nm LEDs, N₂ atmosphere, reaction time: 8 h. ^bCarboxylic acid (0.20 mmol, 1.0 equiv.). ^cThe reaction was performed under an air atmosphere, 12 h. ^dGram-scale reaction: 1.04 g of quinoline-2-carboxylic acid was subjected to the gram scale reaction.

Inspired by our previous work on photo-induced C(sp³)–H thiolation and sulfinylation using sodium sulfinate as the coupling counterpart,¹⁵ we wondered whether an air atmosphere could serve as an efficient oxygen source to oxidize the generated thioethers to sulfoxides, thereby providing a novel synthetic route for decarboxylative sulfinylation.^14b,17 Regrettably, the decarboxylative sulfinylation reaction of alkyl carboxylic acids failed, probably because the generated alkyl radical species through decarboxylation are highly susceptible to oxidative degradation by atmospheric oxygen.^12i,18 However, when we investigated the reaction of heteroaromatic carboxylic acids as potential alternatives, we were fortunately able to detect the formation of the corresponding sulfoxide products despite their relatively low yields (49–53).

To further substantiate the practicality and suitability of this decarboxylative thiolation reaction, we undertook a comprehensive investigation into the feasibility of late-stage modifications for an array of complex carboxylic acid precursors, given the abundance of carboxylic acids in natural products and pharmaceutical compounds. Notably, we successfully converted diverse drug active molecules, natural products and amino acid derivatives, including sulbactam (54), Z-GLU-OME (55), chlorambucil (56), oxaprozin (57), (−)-menthol (58), ribosic acid (59), N-Cbz-D-alanine (60), and gemfibrozil (61), into their respective thiolated products upon decarboxylation. Encouragingly, these transformations were smoothly achieved with reasonable yields, ranging from 39% to 63%, which would offer enormous opportunities for late-stage modification of biologically active molecules and drug candidates.

C(sp³)–H functionalization reactions of hydrocarbons have recently emerged as a vibrant research field in organic synthesis.¹⁹ Selective functionalization of unreactive C(sp³)–H bonds to produce high value-added chemicals is not only highly rewarding in organic chemistry but also yet to be fully explored. We recently disclosed photo-induced iron-catalyzed C(sp³)–H thiolation and sulfinylation reactions, both employing sodium sulfinate as the coupling counterpart. Interestingly, despite the similar conditions of these two reactions, the key factor that caused the difference in the resulting products was the amount of water. We wondered whether there would be other factors that also affect the chemoselectivity. Our study was initiated by employing cyclohexane and S-phenyl benzenethiosulfonate (2) as model substrates. The optimal conditions were obtained to furnish the C(sp³)–H thiolation product 62 in 91% yield under a N₂ atmosphere after a comprehensive optimization of the reaction conditions by screening the iron catalyst, additive, solvent, and light source,²⁰ whereas C(sp³)–H sulfinylation was successfully achieved under an air atmosphere. The method demonstrated a wide range of substrate applicability for C(sp³)–H thiolation, allowing for the efficient synthesis of aryl sulfides from inert alkanes. Various functionalized thiosulfonates and alkanes were successfully converted into the corresponding thioether products 62–84 (Scheme 3). As regards substitutions on the aromatic ring, ortho-, meta-, and para-substituted S-aryl benzenethiosulfonates containing functional groups such as halogen (63–65), trifluoromethyl (66), alkyl (67, 68, and 71) and methoxy moieties (69 and 70) were all tolerated. The reaction with naphthalene, thiophene, and benzo[d]thiazole-substituted thiosulfonates also proceeded smoothly to give the products in reasonable yields (72–74). Cycloalkanes bearing different ring sizes (7-, 8-, and 12-membered rings) could achieve the desired C(sp³)–H thiolation in acceptable yields (75–77). It is noteworthy that adamantane reacts with thiosulfonate in an unconventionally regioselective manner.²¹ Furthermore, C(sp³)–H thiolation took place exclusively at the β-carbon atoms of 3-pentanone, resulting in the desired product in 34% yield (81). Direct C–H thiolation can also be applied to ethers and amides (82 and 83). Due to the low bond dissociation energy (BDE) of the neighboring C–H bonds of oxygen and nitrogen,²² the C(sp³)–H thiolation reaction tended to occur predominantly at their α-positions. The C–H thiolation of the aldehyde substrate gave 84 in 45% yield with complete site-selectivity for the C(acyl)–H bond. A large-scale experiment of cyclohexane and S-phenyl benzenethiosulfonate on a 10 mmol scale was performed in order to evaluate the practical uses of this photochemical process, albeit its yields being slightly lower than those obtained in small-scale experiments.

Scheme 3 Substrate scope of C(sp³)–H thiolation and sulfinylation. Reaction conditions: alkane substrate (2.0 mmol, 10.0 equiv.), thiosulfonate (0.2 mmol, 1.0 equiv.), FeCl₃ (0.02 mmol, 10 mol%), LiCl (0.02 mmol, 10 mol%) in CH₃CN (2 mL, 0.1 M), 35 °C, 390 nm LEDs, N₂ atmosphere, 5 h. Yields are of isolated products after chromatographic purification. ^aGram-scale reaction: cyclohexane (50.0 mmol, 5.0 equiv.), thiosulfonate (10.0 mmol, 1.0 equiv.), FeCl₃ (0.5 mmol, 5 mol%), LiCl (0.5 mmol, 5 mol%) in CH₃CN (50 mL, 0.2 M), 35 °C, 390 nm LEDs, N₂ atmosphere, 24 h. ^bRegioselectivity (r.r.) was determined by crude ¹H NMR analysis. ^cReaction time: 8 h.

Inspired by our previous work,¹⁵ we wondered whether air could serve as an oxygen source to oxidize the generated thioethers to sulfoxides, thereby providing a photochemical protocol for C(sp³)–H sulfinylation. To confirm our hypothesis, the reaction of cyclohexane and S-phenyl benzenethiosulfonate (2) took place under an atmosphere of air. Surprisingly, we obtained 88% yield of the corresponding sulfoxide product 85, without the detection of the thioether product. As shown in Scheme 3, thiosulfonates bearing electron-donating groups or electron-withdrawing groups on the aromatics were well tolerated (85–95), which is similar to the C(sp³)–H thiolation described above. para-Fluoro, methoxy, methyl, tert-butyl, and trifluoromethyl, meta-bromo and ortho-chloro substituted thiosulfonates were all suitable for this sulfenylation (86–92). Satisfactorily, this method worked well to install condensed and heterocyclic moieties onto unreactive C(sp³)–H bonds (94 and 95). The yields were maintained in an acceptable range when cycloalkanes with different ring sizes were used for C–H sulfinylation (96–99). In addition, 2,3-dimethylbutane also participated in the reaction with a moderate yield (100, 37%) and excellent regioselectivity (α : β > 20 : 1).

Having established the synthetic protocols for C(sp³)–H thiolation and sulfinylation, we next sought to investigate the C(sp³)–H sulfonylation reaction of simple hydrocarbons. Sulfonyl fluorides have found significant use as reactive probes in chemical biology and molecular pharmacology.²³ Herein, we achieved photo-induced C(sp³)–H sulfonyl fluorination by utilizing the 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) as the SO₂ source and N-fluorobenzenesulfonimide (NFSI) as the oxidant and fluorinating agent. At present, it was found that cycloalkanes can be successfully applied to the photochemical process, delivering the desired alkyl sulfonyl fluorides 101–103 in moderate yields (Scheme 4).

Scheme 4 Substrate scope of C(sp³)–H sulfonyl fluorination. Reaction conditions: alkane substrate (2.0 mmol, 10.0 equiv.), DABSO (0.2 mmol, 1.0 equiv.), NFSI (0.4 mmol, 2.0 equiv.), FeCl₃ (0.02 mmol, 10 mol%), in CH₃CN (2 mL, 0.1 M), 390 nm LEDs, N₂ atmosphere, 12 h. Yields are of isolated products after chromatographic purification.

In order to gain a better understanding of the mechanism behind the visible-light-induced iron-catalyzed decarboxylation reaction, we conducted a radical-clock experiment of 2-cyclopropylacetic acid (104) with S-phenyl benzenethiosulfonate (2). As anticipated, we were able to detect the ternary ring-opening product 105 (Scheme 5a), which indicated that the reaction may proceed via a radical process. To investigate the product distribution under an air atmosphere, we carried out the decarboxylative reaction under air. Surprisingly, the desired thioether and sulfoxide products were not generated, which is unlike that observed in the C–H thiolation and sulfinylation processes. Instead, the formation of aldehydes 106 and 110via decarboxylative oxidation was observed (Scheme 5b).¹²ⁱ This experimental phenomenon further clarified why aliphatic sulfoxides cannot be prepared using a decarboxylative approach by controlling the reaction atmosphere. To further demonstrate the advantages of the iron species as an efficient photosensitizer, we compared the reaction yields using four different types of commonly utilized photocatalysts²⁴ under the standard conditions. However, the reaction did not proceed to a significant extent with any of these photocatalysts, underscoring the unique and exceptional catalytic performance of iron in driving this reaction (Scheme 5c).

Scheme 5 Mechanistic studies.

In addition, we carried out several mechanistic studies of C(sp³)–H thiolation and sulfinylation of hydrocarbons. The kinetic isotope effect (KIE) experiment was firstly carried out to probe the rate-determining step. Under the standard conditions of C–H thiolation for 2 h, the reaction furnished a mixture of thioether 62 and isotopically labeled 62-d₁₁ in 70% overall yield, in which the ratio of 62 and 62-d₁₁ was 1.0. The same k_H/k_D value was obtained when performing the KIE experiments of C(sp³)–H sulfinylation. These KIE values revealed that hydrogen/deuterium atom abstraction is not a rate-determining step (Scheme 5e). A series of control experiments were subsequently conducted. The C–H thiolation reaction did not proceed when ferrous chloride (FeCl₂) was used in place of ferric chloride (FeCl₃), while the reaction provided the desired product 62 in 65% yield in the presence of NFSI as the oxidant (Scheme 5f). To further verify the hydrogen atom abstraction (HAT) species in the reaction process, we used iron nitrate to conduct the reaction. As expected, the reaction could not proceed at all. However, when LiCl as the chlorine source was added into the system, the ferric salts including Fe(OTf)₃, Fe(acac)₃, and Fe(NO₃)₃·9H₂O could all efficiently promote the reaction to work well. The above results suggested that the coordination of high valent iron species with chloride is the key to generating free chlorine radicals, which would undergo the following HAT process (Scheme 5g).

Combining the above experimental results and literature survey,^12,14d,15 a plausible pathway for the photo-induced iron-catalyzed decarboxylative thiolation reaction was proposed, as shown in Scheme 5d. The carboxylic acid substrate (1) is deprotonated with the action of a base and readily forms a carboxylate-iron(III) intermediate (B), which undergoes a photo-induced ligand-to-metal charge-transfer (LMCT) process to afford the iron(II) complex as well as an aroyloxy radical species (C). Rapid decarboxylation of radical C occurs to release a key alkyl radical intermediate (D), which attacks the thiosulfonate (2) to form a thioether product (3) while generating a sulfonyl radical species (E). The sulfonyl radical is capable of converting iron(II) into iron(III) and completing the iron catalytic cycle.

Furthermore, a detailed description of the plausible pathway for iron-catalyzed C(sp³)–H thiolation and sulfoxidation was proposed, which is outlined in Scheme 5h.¹⁵ The process begins with an iron(III) complex (A′). Under 390 nm light irradiation, the iron complex (A′) generates its excited state (B′), which can easily form a reduced iron(II) species (C′) while releasing a highly active chloride radical via a LMCT event. The hydrogen-atom-transfer (HAT) process between the chlorine radical and the alkane substrate produces an alkyl radical intermediate (D′), which is subsequently trapped by the thiosulfonate (2) to provide the desired C(sp³)–H thiolated product (62) while generating a sulfonyl radical species (E′) that could further oxidize the iron(II) species (C′). Under an air atmosphere, the formed thioether product (62) was further oxidized to a sulfoxide (85).^14d

Conclusions

In summary, we have developed an efficient approach to construct diverse C–S bonds through a photo-induced iron-catalyzed LMCT strategy that effectively converts carboxylic acids and unreactive hydrocarbons. By modulating the reaction atmosphere, we have demonstrated the ability to control the chemoselective production of both thioethers and sulfoxides. More importantly, our strategy exhibits remarkable versatility and broad applicability in the field of decarboxylative thiolation, especially for the functionalization of (hetero)aromatic carboxylic acids, which has not been reported by other methods. In addition, this methodology can be employed for the late-stage modification of complex molecules, which adds significant value to its practical utility. Further development of new photochemical reactions is underway in our laboratory.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful for the financial support from the National Natural Science Foundation of China (No. 22101066), the Science and Technology Plan of Shenzhen (No. JCYJ20210324133001004, JCYJ20220531095016036, and GXWD20220817131550002), the Natural Science Foundation of Guangdong (No. 2022A1515010863), and the Guangdong Basic and Applied Basic Research Foundation (No. 2021A1515220069). W. X. is grateful for the Talent Recruitment Project of Guangdong (No. 2019QN01L753). The project was also supported by the Fundamental Research Funds for the Central Universities (Grant No. HIT.OCEF.2022039), State Key Laboratory of Urban Water Resource and Environment (Harbin Institute of Technology) (No. 2022TS23), and the Open Research Fund of the School of Chemistry and Chemical Engineering, Henan Normal University.

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Footnotes

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3qo01081c

‡ These authors contributed equally to this work.

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