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Article

Metal-Free C(sp3)–S Bond Cleavage of Thioethers to Selectively Access Aryl Aldehydes and Dithioacetals

by
Dan Yuan
,
Yong Huang
,
Long Tang
* and
Ke Yang
*
Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, School of Petrochemical Engineering, Changzhou University, Changzhou 213164, China
*
Authors to whom correspondence should be addressed.
Chemistry 2025, 7(3), 89; https://doi.org/10.3390/chemistry7030089
Submission received: 30 April 2025 / Revised: 24 May 2025 / Accepted: 27 May 2025 / Published: 29 May 2025
(This article belongs to the Special Issue Organic Chalcogen Chemistry: Recent Advances)
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Abstract

:
Metal-free C(sp3)–S bond cleavage of thioethers was achieved using NCS as a critical additive. A wide range of arylmethyl thioethers were successfully transformed into aryl aldehydes with satisfactory yields in chloroform. Meanwhile, employing fluorobenzene as the solvent enables the selective formation of dithioacetals from arylmethyl thioethers, achieving moderate to good yields. Notably, dithioacetals were first prepared through a metal-free C(sp3)–S bond cleavage and subsequent thioacetalization process. Furthermore, these simple and efficient approaches also provide complementary strategies for accessing important aryl aldehydes and dithioacetals.

1. Introduction

Thioethers, as important sulfur-containing compounds, serve as crucial precursors in organic synthesis [1,2,3,4,5,6]. Their diverse transformations have recently garnered significant attention across various fields, including biological, pharmaceutical, and materials chemistry [7,8,9,10,11]. Thioethers exhibit substantial potential for selective C–S bond cleavage, enabling the construction of various organic compounds [12,13,14,15,16,17,18,19,20,21,22,23,24]. Previous research in this area has mainly focused on the insertion of different transition metals into C–S bonds, thereby achieving selective cleavage of these bonds [12,13,14,15,16,17]. However, investigations into metal-free approaches for cleaving C(sp3)–S bonds have been relatively scarce [18,19,20,21,22,23,24]. Consequently, the development of novel metal-free strategies for C(sp3)–S bond cleavage is highly desirable [25].
Aldehydes and dithioacetals represent a significant class of chemical products and organic synthesis intermediates, with broad applications in pharmaceuticals, food additives, and polymer materials [26,27,28,29,30,31]. Although substantial efforts have been made in constructing these compounds [32,33,34], only one report describes the C(sp3)–S bond cleavage of thioethers for the synthesis of aryl aldehydes using benzoyl chloride and dimethyl sulfoxide (Figure 1a) [35]. In addition, the Bakuzis group also reported the synthesis of alkyl aldehydes from thioethers via a cascade reaction involving chlorination and hydrolysis, utilizing NCS (N-chlorosuccinimide) and Cu(II) reagents (Figure 1b) [36]. Very recently, our group reported an NBS-mediated C(sp3)–S bond cleavage of thioethers to access alkyl bromides [37]. In our continuous efforts in sulfur chemistry [38,39,40], we herein report an NCS-mediated C(sp3)–S bond cleavage of thioethers to selectively access aryl aldehydes and dithioacetals. Furthermore, this is the first example of preparing dithioacetals from thioethers through a cascade C(sp3)–S bond cleavage and thioacetalization process (Figure 1c). Notably, this NCS-mediated process exhibits a significant degree of substrate dependence. Specifically, the use of α-thioamides with NCS results in the formation of α-thio-β-chloroacrylamides [41,42].

2. Results and Discussion

Our investigation commenced with the reaction of benzyl methyl sulfide (1a) with NCS (1.5 eq.) in CHCl3 at room temperature, and the desired benzaldehyde (2a) was isolated in an 80% yield within 3.0 h (Scheme 1). Notably, the oxygen in benzaldehyde originates from the water in the solvent. Next, a systematic evaluation of various solvents, including DCM, DCE, MeCN, 1,4-dioxane, DMSO, DMF, MeOH and PhMe, demonstrated that none provided superior results compared to CHCl3 (Table 1, entries 1–8). The use of DMSO or MeOH resulted in only trace amounts of product formation, as substrate 1a remained largely unreacted in these solvents. Subsequently, the replacement of NCS with other electrophilic halogenation reagents, such as DCDMH, NCP, NBS, NIS, Selectfluor, and NFSI, failed to yield any observable improvements (Table 1, entries 9–14). It should be noted that the use of NIS or Selectfluor failed to provide the desired product 2a, as these reagents are incapable of activating substrate 1a. Subsequent examination revealed that altering the amount of NCS, either by increasing or decreasing it, did not enhance the yield of 2a (Table 1, entries 15–16). Finally, in the absence of NCS, no desired product 2a was detected (Table 1, entry 17).
With the optimized reaction conditions in hand, the substrate scope of arylmethyl thioethers was investigated (Scheme 2 and Figure S1). Firstly, biphenyl-containing substrate provided the desired product 2b in 85% yield. Furthermore, a variety of benzyl methylthioethers with electron-donating (Me and t-Bu) and electron-withdrawing (F, Cl, Br, I and NO2) groups at the para-, meta-, or ortho-positions on the phenyl ring were well-tolerated in this reaction and provided the desired products 2c–j in good yields. Notably, these functional groups could be easily converted into other important moieties, further highlighting the synthetic applicability and versatility of this approach. In addition, the use of naphthalenyl substrates also afforded the desired products 2k and 2l in good yields. Separately, various substituents including Et, i-Pr, Bn and Ph on the sulfur atom were also tested, providing the desired products in moderate to good yields.
Additionally, the scope of alkyl methylthioethers (Figure S2) was further investigated, as illustrated in Scheme 3. A variety of alkyl methylthioethers 3a–e, incorporating amide, carboxyl, ester, carbonyl, and n-butyl groups, were tested in this reaction. Unfortunately, these thioether substrates failed to yield the desired products 4a–e because they lacked β-aryl groups. In this reaction, the presence of a β-aryl group is crucial for the formation of the thionium intermediate. Consequently, this functional group transformation is restricted to arylmethyl thioethers.
Interestingly, the reaction of phenyl benzylthioether (1p) with NCS (1.5 eq.) in toluene at room temperature for 12 h afforded (phenylmethylene)bis(phenylsulfane) (5a, 9%), benzaldehyde (2a, 24%), 1,2-diphenyldisulfane (6, 7%) and S-phenyl benzothioate (7, 48%) (Scheme 4). Based on these results, we propose that dithioacetal 5a is formed through the thioacetalization reaction between benzaldehyde (2a) and in situ-generated phenylthiol. 1,2-Diphenyldisulfane (6) is produced from the oxidation of phenylthiol. Additionally, the oxidation of the methylene group on phenyl benzylthioether (1p) can also yield S-phenyl benzothioate (7). It should be noted this method achieved a maximum yield of 50% for dithioacetal products.
To enhance the yield of dithioacetal 5a, the reaction conditions were investigated. The initial solvent screening revealed that fluorobenzene was the optimal solvent (Table 2, entries 1–7). Specifically, only aromatic solvents enabled the formation of product 5a and S-phenyl benzothioate. Notably, the use of fluorobenzene resulted in a higher yield compared to toluene, which can be attributed to its stronger polarity that more effectively stabilizes the cationic intermediates during the reaction process. In addition, the use of CHCl3 with NCS (1.5 eq.) could efficiently facilitate the formation of 1,2-diphenyldisulfane. To our delight, the yield of 5a increased to 34% when 1.0 equivalent of NCS was used (Table 2, entry 8). However, the formation of S-phenyl benzothioate did not occur when using NCS (1.0 eq.), as the amount of NCS was insufficient to achieve this process. When NCS (2.0 eq.) was used, only a trace amount of 5a was observed (Table 2, entry 9). This is likely attributed to the fact that this reaction selectively provided S-phenyl benzothioate. Finally, the use of other electrophilic halogenation reagents, such as NBS, NIS, Selectfluor, NFSI, DCDMH, and NCP, either failed to generate product 5a or resulted in significantly reduced yields of 5a (Table 2, entries 10–15). The use of NBS, NIS, Selectfluor, or NFSI failed to isolate the desired products, as these reagents are unable to activate substrate 1p in fluorobenzene. It is worth noting that DCDMH (1.0 eq.) selectively afforded S-phenyl benzothioate in a moderate yield, which may be attributed to its unique chemical structure and reactivity.
With the optimal conditions for preparing dithioacetals obtained, the substrate scope of arylmethyl thioethers was investigated (Scheme 5 and Figure S1). As expected, the introduction of various electron-donating (Me) and electron-withdrawing (Cl and Br) groups on the benzyl skeletons afforded the desired products 5b–e in moderate yields. However, the use of 4-methoxybenzyl(phenyl)sulfane failed to produce the corresponding product 5f. Furthermore, both benzyl ethylthioether and benzyl methylthioether served as suitable substrates, affording the desired products 5g and 5h in 29% and 31% yields, respectively. Additionally, substituents such as ethyl and chlorine on the phenyl skeletons also yielded the desired products 5i–j in moderate yields, whereas substrates containing MeO groups still did not work. It is worth noting that the substrates containing MeO groups on the phenyl rings underwent decomposition in our reactions.
To demonstrate the synthetic practicability of our methods, two Gram-scale reactions were carried out for the synthesis of benzaldehyde (2a) and (phenylmethylene)bis(phenylsulfane) (5a). By adjusting the amount of reaction solvent used, both products 2a and 5a were isolated in 75% and 31% yields, respectively (Scheme 6).
To better understand this reaction, two control experiments were conducted in Scheme 7. First, the reaction of thioether 1p with NCS (1.5 eq.) in chloroform at room temperature for 3 h yielded product 2a (57%), 1,2-diphenyldisulfane (30%), and recovered 1p (25%) (Scheme 7a). Second, the reaction of thioether 1p with NCS (1.0 eq.) in fluorobenzene at room temperature for 12 h provided product 5a (34%), product 2a (42%), 1,2-diphenyldisulfane (5%) and recovered 1p (10%) (Scheme 7b). These results suggest that in situ-generated phenylthiol may be oxidized to diphenyl disulfide by NCS or air. Additionally, in the solvent of fluorobenzene, a condensation reaction between phenylthiol and 2a could yield product 5a by using 1.0 equivalent of NCS.
Based on previous work and control experiments, a proposed mechanism is provided in Scheme 8 [37,38,39,40,41,42,43,44,45]. Initially, benzyl phenylthioether (1p) reacts with NCS to form cationic intermediate A and succinimide anion B. Subsequently, succinimide anion B deprotonates intermediate A to generate the thionium intermediate C and succinimide. Next, a nucleophilic attack by water on thionium intermediate C yields hemithioacetal D along with the release of HCl. In the presence of HCl and H2O, hemithioacetal D undergoes hydrolysis to produce the desired product 2a and PhSH. In addition, dithioacetal product 5a can be formed from either D or 2a through a condensation reaction with the in situ generated PhSH. Notably, the in situ generated PhSH can also be oxidized into PhSSPh by NCS or air.

3. Materials and Methods

3.1. General Information

All the solvents and commercially available reagents were purchased and used directly. Thin layer chromatography (TLC) was performed on EMD precoated plates (silica gel 60 F254, Art 5715, Yantai Jiangyou Silica gel Development Co., Ltd., Yantai, China) and visualized by fluorescence quenching under UV light. Column chromatography was performed on EMD Silica Gel 60 (200–300 Mesh, Shanghai Titan Technology Co., Ltd., Shanghai, China) using a forced flow of 0.5–1.0 bar. The 1H and 13C NMR spectra were obtained on Bruker AVANCE III–300 and 400 spectrometers (Bruker Corporation, Billerica, MA, USA). 1H NMR data were reported as chemical shift (δ ppm), multiplicity, coupling constant (Hz), and integration. 13C NMR data were reported in terms of chemical shift (δ ppm), multiplicity, and coupling constant (Hz). GC-MS analysis was obtained using Shimadzu GCMS-QP2010Plus with electron ionization (EI) (Shimadzu Co., Ltd., Tokyo, Japan).
Arylmethyl thioethers (1) and alkyl methylthioethers (4) were purchased from Energy-chemical (Shanghai, China), BLDpharm (Shanghai, China), Chemieliva (Chongqing, China), Atomax Chemicals (Shenzhen, China), HE Chemical (Changzhou, China), Adamas-beta® (Shanghai, China), TCI (Shanghai, China), J&K@ (Shanghai, China), or Sigma-Aldrich (Shanghai, China).

3.2. Optimization of the Reaction Conditions for Benzaldehyde 2a

A 25 mL round-bottom flask was charged with benzyl methyl thioether (1a, 55.2 mg, 0.4 mmol), undried solvent (4.0 mL, with natural humidity) and electrophilic halogenation reagents (0.4–0.8 mmol). The reaction was then stirred vigorously at room temperature (25 °C) for 3 h. After the reaction was finished, the mixture was concentrated in vacuo, the residue was purified by flash chromatography on silica gel using petroleum ether/dichloromethane as the eluent to yield the product 2a.

3.3. Synthetic Procedures for the Synthesis of Products 2

A 25 mL round-bottom flask was charged with arylmethyl thioethers (1, 0.4 mmol), undried CHCl3 (4.0 mL, with natural humidity) and NCS (80.1 mg, 0.6 mmol). The reaction was then stirred vigorously at room temperature (25 °C) for 3 h. After the reaction was finished, the mixture was concentrated in vacuo, the residue was purified by flash chromatography on silica gel using petroleum ether/dichloromethane as the eluent to yield the products 2.
Benzaldehyde (2a). Colorless oil, 34.0 mg, 80% (known compound [46]). 1H NMR (300 MHz, CDCl3) δ 10.03 (s, 1H), 7.91–7.87 (m, 2H), 7.67–7.61 (m, 1H), 7.56–7.51 (m, 2H).13C NMR (75 MHz, CDCl3) δ 192.44, 136.41, 134.49, 129.77, 129.02.
[1,1′-Biphenyl]-4-carboxaldehyde (2b). White solid, 62.0 mg, 85% (known compound [47]). 1H NMR (300 MHz, CDCl3) δ 9.99 (s, 1H), 7.91–7.87 (m, 2H), 7.71–7.68 (m, 2H), 7.59–7.55 (m, 2H), 7.45–7.32 (m, 3H).13C NMR (75 MHz, CDCl3) δ 191.98, 147.22, 139.74, 135.22, 130.31, 129.05, 128.51, 127.71, 127.40.
4-Methylbenzaldehyde (2c). Colorless oil, 40.0 mg, 83% (known compound [48]). 1H NMR (300 MHz, CDCl3) δ 9.96 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 7.8 Hz, 2H), 2.44 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 192.08, 145.60, 134.20, 129.89, 129.74, 21.88.
4-(Tert-butyl)benzaldehyde (2d). Yellow oil, 54.5 mg, 84% (known compound [49]). 1H NMR (300 MHz, CDCl3) δ 9.98 (s, 1H), 7.82 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 1.36 (s, 9H).13C NMR (75 MHz, CDCl3) δ 192.12, 158.48, 134.08, 129.73, 126.01, 35.37, 31.08.
4-Fluorobenzaldehyde (2e). Colorless oil, 38.7 mg, 78% (known compound [50]). 1H NMR (300 MHz, CDCl3) δ 9.97 (s, 1H), 7.95–7.89 (m, 2H), 7.25–7.19 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 190.55, 166.55 (d, J = 256.7 Hz), 132.98 (d, J = 2.7 Hz), 132.26 (d, J = 9.7 Hz), 116.38 (d, J = 22.2 Hz).
4-Chlorobenzaldehyde (2f). White solid, 46.0 mg, 82% (known compound [51]). 1H NMR (300 MHz, CDCl3) δ 9.99 (s, 1H), 7.83 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 190.91, 140.98, 134.72, 130.93, 129.48.
4-Bromobenzaldehyde (2g). White solid, 54.7 mg, 74% (known compound [51]). 1H NMR (300 MHz, CDCl3) δ 9.98 (s, 1H), 7.77–7.74 (m, 2H), 7.71–7.68 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 191.10, 135.08, 132.47, 131.00, 129.81.
4-Nitrobenzaldehyde (2h). White solid, 40.5 mg, 67% (known compound [52]). 1H NMR (300 MHz, CDCl3) δ 10.10 (s, 1H), 8.33 (d, J = 8.7 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 190.34, 151.14, 140.06, 130.51, 124.33.
3-Chlorobenzaldehyde (2i). Colorless oil, 44.5 mg, 79% (known compound [52]). 1H NMR (300 MHz, CDCl3) δ 9.98 (s, 1H), 7.86 (t, J = 1.6 Hz, 1H), 7.79–7.76 (m, 1H), 7.63–7.59 (m, 1H), 7.49 (t, J = 7.8 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 190.88, 137.82, 135.48, 134.42, 130.40, 129.33, 127.99.
2-Iodobenzaldehyde (2j). White solid, 75.2 mg, 81% (known compound [53]). 1H NMR (300 MHz, CDCl3) δ 10.08 (s, 1H), 7.98–7.95 (m, 1H), 7.91–7.87 (m, 1H), 7.50–7.44 (m, 1H), 7.32–7.27 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 195.79, 140.67, 135.50, 135.14, 130.28, 128.75, 100.73.
1-Naphthalenecarboxaldehyde (2k). White solid, 53.7 mg, 86% (known compound [54]). 1H NMR (300 MHz, CDCl3) δ 10.40 (s, 1H), 9.25 (d, J = 8.5 Hz, 1H), 8.10 (dd, J = 8.2, 1.4 Hz, 1H), 8.01–7.98 (m, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.74–7.56 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 193.72, 136.83, 135.45, 133.86, 131.54, 130.67, 129.22, 128.61, 127.11, 125.01.
2-Naphthalenecarboxaldehyde (2l). White solid, 50.0 mg, 80% (known compound [55]). 1H NMR (300 MHz, CDCl3) δ 10.17 (s, 1H), 8.35 (s, 1H), 8.03–7.90 (m, 4H), 7.68–7.57 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 192.32, 136.47, 134.62, 134.12, 132.66, 129.56, 129.15, 129.13, 128.11, 127.12, 122.78.

3.4. Synthetic Procedures for the Synthesis of Products 4

A 25 mL round-bottom flask was charged with alkyl methylthioethers (3, 0.4 mmol), NCS (80.1 mg, 0.6 mmol) and undried CHCl3 (4.0 mL, with natural humidity). The reaction was then stirred vigorously at room temperature for 3 h. After the reaction was finished, the mixture was detected by TLC and GC-MS.

3.5. Optimization of the Reaction Conditions for (Phenylmethylene)bis(phenylsulfane) (5a)

A 25 mL round-bottom flask was charged with phenyl benzylthioether (1p, 80.1 mg, 0.4 mmol), electrophilic halogenation reagents (0.4–0.8 mmol) and undried solvent (4.0 mL, with natural humidity). The reaction was then stirred vigorously at room temperature (25 °C) for 12 h. After the reaction was finished, the mixture was concentrated in vacuo, the residue was purified by flash chromatography on silica gel using petroleum ether/ethyl acetate as the eluent to yield products 5a, 2a, 6 or 7.

3.6. Synthetic Procedures for the Synthesis of Products 5

A 25 mL round-bottom flask was charged with arylmethyl thioether (1, 0.4 mmol), NCS (53.4 mg, 0.4 mmol) and undried fluorobenzene (4.0 mL, with natural humidity). The reaction was then stirred vigorously at room temperature for 12 h. After the reaction was finished, the mixture was concentrated in vacuo, the residue was purified by flash chromatography on silica gel using petroleum ether/ethyl acetate as the eluent to yield the products 5.
(Phenylmethylene)bis(phenylsulfane) (5a). White solid, 42.0 mg, 34% (known compound [56]). 1H NMR (300 MHz, CDCl3) δ 7.37–7.31 (m, 6H), 7.29–7.20 (m, 9H), 5.42 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 139.67, 134.55, 132.55, 128.86, 128.50, 128.07, 127.90, 127.82, 60.45.
1-[Bis(phenylthio)methyl]-4-methylbenzene (5b). White solid, 41.8 mg, 32% (known compound [57]). 1H NMR (300 MHz, CDCl3) δ 7.29–7.23 (m, 4H), 7.20–7.13 (m, 8H), 6.99 (d, J = 8.1 Hz, 2H), 5.34 (s, 1H), 2.23 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 137.86, 136.69, 134.84, 132.34, 129.21, 128.83, 127.76, 127.67, 60.19, 21.20.
1-[Bis(phenylthio)methyl]-4-chlorobenzene (5c). White solid, 37.6 mg, 27% (known compound [58]). 1H NMR (300 MHz, CDCl3) δ 7.28–7.24 (m, 4H), 7.21–7.13 (m, 10H), 5.30 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 138.30, 134.04, 133.70, 132.78, 129.25, 128.94, 128.61, 128.07, 59.78.
1-[Bis(phenylthio)methyl]-4-bromobenzene (5d). White solid, 46.3 mg, 30% (known compound [57]). 1H NMR (300 MHz, CDCl3) δ 7.40–7.29 (m, 6H), 7.27–7.21 (m, 8H), 5.36 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 138.82, 134.00, 132.77, 131.56, 129.55, 128.95, 128.08, 121.86, 59.83.
1-[Bis(phenylthio)methyl]-3-chlorobenzene (5e). Colorless oil, 39.0 mg, 29% (known compound [58]). 1H NMR (300 MHz, CDCl3) δ 7.29–7.24 (m, 5H), 7.21–7.17 (m, 6H), 7.14–7.07 (m, 3H), 5.28 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 141.73, 134.26, 133.92, 132.85, 129.66, 128.96, 128.18, 128.15, 128.06, 126.06, 59.96.
(Phenylmethylene)bis(ethylsulfane) (5g). Colorless oil, 24.5 mg, 29% (known compound [59]). 1H NMR (300 MHz, CDCl3) δ 7.46–7.43 (m, 2H), 7.36–7.25 (m, 3H), 4.92 (s, 1H), 2.64–2.49 (m, 4H), 1.22 (t, J = 7.4 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 140.52, 128.53, 127.80, 127.71, 52.47, 26.25, 14.30.
(Phenylmethylene)bis(methylsulfane) (5h). Colorless oil, 23.0 mg, 31% (known compound [60]). 1H NMR (300 MHz, CDCl3) δ 7.43–7.40 (m, 2H), 7.36–7.24 (m, 3H), 4.78 (s, 1H), 2.10 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 139.69, 128.54, 127.88, 127.63, 56.50, 15.00.
(Phenylmethylene)bis(p-tolylsulfane) (5i). White solid, 29.0 mg, 22% (known compound [61]). 1H NMR (300 MHz, CDCl3) δ 7.27–7.14 (m, 9H), 6.97 (d, J = 8.0 Hz, 4H), 5.24 (s, 1H), 2.23 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 139.99, 138.03, 133.15, 130.85, 129.58, 128.37, 127.90, 61.30, 21.19.
(Phenylmethylene)bis((4-chlorophenyl)sulfane) (5j). White solid, 49.0 mg, 33% (known compound [57]). 1H NMR (300 MHz, CDCl3) δ 7.25–7.11 (m, 13H), 5.26 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 139.03, 134.46, 134.33, 132.64, 129.18, 128.74, 128.48, 127.96, 60.95.

3.7. Synthetic Procedures for the Synthesis of (Phenylmethylene)bis(phenylsulfane) (5a), Benzaldehyde (2a), 1,2-Diphenyldisulfane (6) and S-Phenyl Benzothioate (7)

A 25 mL round-bottom flask was charged with phenyl benzylthioether (1p, 80.1 mg, 0.4 mmol), NCS (80.1 mg, 0.6 mmol) and undried toluene (4.0 mL, with natural humidity). The reaction was then stirred vigorously at room temperature (25 °C) for 12 h. After the reaction was finished, the mixture was concentrated in vacuo, the residue was purified by flash chromatography on silica gel using petroleum ether/ethyl acetate as the eluent to yield 5a (11.0 mg, 9%), 2a (10.0 mg g, 24%), 6 (6.1 mg, 7%) and 7 (41.0 mg, 48%).
1,2-Diphenyldisulfane (6). White solid, 6.1 mg, 7% (known compound [62]). 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 7.7 Hz, 4H), 7.31 (t, J = 7.6 Hz, 4H), 7.23 (t, J = 7.3 Hz, 2H). MS (EI, m/z): calcd for C12H10S2 [M]+, 218.02; found, 218.00.
S-Phenyl benzothioate (7). White solid, 41.0 mg, 48% (known compound [63]). 1H NMR (300 MHz, CDCl3) δ 8.06–8.03 (m, 2H), 7.65–7.59 (m, 1H), 7.57–7.45 (m, 7H). 13C NMR (75 MHz, CDCl3) δ 190.16, 136.69, 135.13, 133.68, 129.55, 129.28, 128.79, 127.52, 127.40.

3.8. Synthetic Procedures for Gram-Scale Reactions

A 50 mL round-bottom flask was charged with benzyl methyl thioether (1a, 1.1 g, 8 mmol), undried CHCl3 (20.0 mL, with natural humidity) and NCS (1.60 g, 12 mmol). The reaction was then stirred vigorously at room temperature (25 °C) for 3 h. After the reaction was finished, the mixture was concentrated in vacuo, the residue was purified by flash chromatography on silica gel using petroleum ether/dichloromethane as the eluent to yield the product 2a (0.637 g, 75%).
A 50 mL round-bottom flask was charged with phenyl benzylthioether (1p, 1.0 g, 5 mmol), undried fluorobenzene (20.0 mL, with natural humidity) and NCS (0.668 g, 5 mmol). The reaction was then stirred vigorously at room temperature (25 °C) for 12 h. After the reaction was finished, the mixture was concentrated in vacuo, the residue was purified by flash chromatography on silica gel using petroleum ether/ethyl acetate as the eluent to yield the product 5a (0.470 g, 31%).

3.9. Control Experiments

A 25 mL round-bottom flask was charged with phenyl benzylthioether (1p, 80.1 mg, 0.4 mmol), NCS (80.1 mg, 0.6 mmol) and undried CHCl3 (4.0 mL, with natural humidity). The reaction was then stirred vigorously at room temperature (25 °C) for 3 h. After the reaction was finished, the mixture was concentrated in vacuo, the residue was purified by flash chromatography on silica gel using petroleum ether/dichloromethane as the eluent to yield 2a (24.2 mg g, 57%), 6 (26.1 mg, 30%) and 1p (20. 0 mg, 25%).
A 25 mL round-bottom flask was charged with phenyl benzylthioether (1p, 80.1 mg, 0.4 mmol), NCS (53.4 mg, 0.4 mmol) and undried fluorobenzene (4.0 mL, with natural humidity). The reaction was then stirred vigorously at room temperature (25 °C) for 3 h. After the reaction was finished, the mixture was concentrated in vacuo, the residue was purified by flash chromatography on silica gel using petroleum ether/ethyl acetate as the eluent to yield the 5a (42.0 mg, 34%), 2a (17.8 mg g, 42%), 6 (4.5 mg, 5%) and 1p (8.0 mg, 10%).

4. Conclusions

In summary, we developed a metal-free and NCS-mediated C(sp3)–S bond cleavage of thioethers to selectively prepare aryl aldehydes and dithioacetals. The reaction of arylmethyl thioethers with 1.5 equivalent of NCS in chloroform solvent yielded a variety of aryl aldehydes in good yields. Moreover, dithioacetals could be obtained from arylmethyl thioethers using 1.0 equivalent of NCS and fluorobenzene as solvent. These simple methods not only exhibited excellent functional group compatibility but also demonstrated high synthetic practicability. Additionally, these metal-free strategies represent important complementary approaches for accessing aryl aldehydes and dithioacetals in organic chemistry.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/chemistry7030089/s1, Figure S1: arylmethyl thioethers; Figure S2: alkyl methylthioethers; Figures S3–S47: 1H, and 13C NMR Spectra.

Author Contributions

Synthesis and characterization, D.Y. and Y.H.; data curation, D.Y. and Y.H.; writing—original draft preparation, L.T. and K.Y.; writing—review and editing, L.T. and K.Y.; funding acquisition, D.Y., L.T. and K.Y. All authors have read and agreed to the published version of the manuscript.

Funding

K.Y. and L.T. are grateful for financial support from the Changzhou University. D.Y. is grateful for financial support from Postgraduate Research and Practice Innovation Program of Jiangsu Province (SJCX25_1651).

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Acknowledgments

We acknowledge the analytical testing support from Analysis and Testing Center, NERC Biomass of Changzhou University.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
NCSN-Chlorosuccinimide
NCPN-Chlorophthalimide
DCDMH1,3-Dichloro-5,5-dimethylhydantoin
NBSN-Bromosuccinimide
NISN-Iodosuccinimide
Selectfluor1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)
NFSIN-Fluorobenzenesulfonamide
DCMDichloromethane
DCE1,2-Dichloroethane
DMSODimethyl sulfoxide
DMFN,N-Dimethylformamide

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Chemistry 07 00089 g001
Figure 1. The synthesis of aldehydes and their derivatives through C(sp3)–S bond cleavage of thioethers.
Figure 1. The synthesis of aldehydes and their derivatives through C(sp3)–S bond cleavage of thioethers.
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Scheme 1. NCS-mediated C(sp3)–S bond cleavage of benzyl methyl sulfide to access benzaldehyde.
Scheme 1. NCS-mediated C(sp3)–S bond cleavage of benzyl methyl sulfide to access benzaldehyde.
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Chemistry 07 00089 sch002
Scheme 2. Scope of arylmethyl thioethers for aryl aldehydes. Reaction conditions: 1 (0.4 mmol), NCS (0.6 mmol), CHCl3 (4.0 mL), room temperature (25 °C), 3 h. Isolated yields.
Scheme 2. Scope of arylmethyl thioethers for aryl aldehydes. Reaction conditions: 1 (0.4 mmol), NCS (0.6 mmol), CHCl3 (4.0 mL), room temperature (25 °C), 3 h. Isolated yields.
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Chemistry 07 00089 sch003
Scheme 3. Scope of alkyl methylthioethers. Reaction conditions: 3 (0.4 mmol), NCS (0.6 mmol), CHCl3 (4.0 mL), room temperature (25 °C), 3 h. Isolated yields.
Scheme 3. Scope of alkyl methylthioethers. Reaction conditions: 3 (0.4 mmol), NCS (0.6 mmol), CHCl3 (4.0 mL), room temperature (25 °C), 3 h. Isolated yields.
Chemistry 07 00089 sch003
Chemistry 07 00089 sch004
Scheme 4. NCS-mediated C(sp3)–S bond cleavage of benzyl phenyl sulfide to access (phenylmethylene)bis(phenylsulfane), benzaldehyde, 1,2-diphenyldisulfane and S-phenyl benzothioate.
Scheme 4. NCS-mediated C(sp3)–S bond cleavage of benzyl phenyl sulfide to access (phenylmethylene)bis(phenylsulfane), benzaldehyde, 1,2-diphenyldisulfane and S-phenyl benzothioate.
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Chemistry 07 00089 sch005
Scheme 5. Scope of arylmethyl thioethers for dithioacetals. Reaction conditions: 1 (0.4 mmol), NCS (0.4 mmol), fluorobenzene (4.0 mL), room temperature (25 °C), 12 h. Isolated yields.
Scheme 5. Scope of arylmethyl thioethers for dithioacetals. Reaction conditions: 1 (0.4 mmol), NCS (0.4 mmol), fluorobenzene (4.0 mL), room temperature (25 °C), 12 h. Isolated yields.
Chemistry 07 00089 sch005
Chemistry 07 00089 sch006
Scheme 6. Gram-scale synthesis of benzaldehyde (2a) and (phenylmethylene)bis(phenylsulfane) (5a).
Scheme 6. Gram-scale synthesis of benzaldehyde (2a) and (phenylmethylene)bis(phenylsulfane) (5a).
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Chemistry 07 00089 sch007
Scheme 7. Control experiments. (a) The reaction of thioether 1p with NCS (1.5 eq.) in chloroform; (b) the reaction of thioether 1p with NCS (1.0 eq.) in fluorobenzene.
Scheme 7. Control experiments. (a) The reaction of thioether 1p with NCS (1.5 eq.) in chloroform; (b) the reaction of thioether 1p with NCS (1.0 eq.) in fluorobenzene.
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Chemistry 07 00089 sch008
Scheme 8. Proposed mechanism.
Scheme 8. Proposed mechanism.
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Table 1. Optimization of reaction conditions for benzaldehyde (2a) a.
Table 1. Optimization of reaction conditions for benzaldehyde (2a) a.
EntryElectrophilic Halogenation Reagents (eq.)Solvent (mL)Yield (2a, %)
1NCS (1.5)DCM61
2NCS (1.5)DCE54
3NCS (1.5)MeCN56
4NCS (1.5)1,4-Dioxane62
5NCS (1.5)DMSOtrace
6NCS (1.5)DMF65
7NCS (1.5)MeOHtrace
8NCS (1.5)PhMe52
9DCDMH (1.5)CHCl338
10NCP (1.5)CHCl375
11NBS (1.5)CHCl370
12NIS (1.5)CHCl3trace
13Selectfluor (1.5)CHCl3trace
14NFSI (1.5)CHCl344
15NCS (1.0)CHCl351
16NCS (2.0)CHCl373
17-CHCl30
a Reaction conditions: 1a (0.4 mmol), electrophilic halogenation reagents (0.4–0.8 mmol), solvent (4.0 mL), room temperature (25 °C), 3 h. Isolated yields.
Table 2. Optimization of reaction conditions for (phenylmethylene)bis(phenylsulfane) (5a) a.
Table 2. Optimization of reaction conditions for (phenylmethylene)bis(phenylsulfane) (5a) a.
EntryElectrophilic Halogenation Reagents (eq.)Solvent (mL)Yield (5a, %)Yield (2a, %)Yield (6, %)Yield (7, %)
1NCS (1.5)PhF1321740
2NCS (1.5)PhCF36221047
3NCS (1.5)MeCN043250
4NCS (1.5)DCE050280
5NCS (1.5)CHCl3071380
6NCS (1.5)THF0tracetrace0
7NCS (1.5)MeOH0tracetrace0
8NCS (1.0)PhF344250
9NCS (2.0)PhFtracetracetrace73
10NBS (1.0)PhF0tracetrace0
11NIS (1.0)PhF0tracetrace0
12Selectfluor (1.0)PhF0tracetrace0
13NFSI (1.0)PhF0tracetrace0
14DCDMH (1.0)PhF0tracetrace45%
15NCP (1.0)PhF1230100
a Reaction conditions: 1p (0.4 mmol), electrophilic halogenation reagents (0.4–0.8 mmol), solvent (4.0 mL), room temperature (25 °C), 12 h. Isolated yields.
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Yuan, D.; Huang, Y.; Tang, L.; Yang, K. Metal-Free C(sp3)–S Bond Cleavage of Thioethers to Selectively Access Aryl Aldehydes and Dithioacetals. Chemistry 2025, 7, 89. https://doi.org/10.3390/chemistry7030089

AMA Style

Yuan D, Huang Y, Tang L, Yang K. Metal-Free C(sp3)–S Bond Cleavage of Thioethers to Selectively Access Aryl Aldehydes and Dithioacetals. Chemistry. 2025; 7(3):89. https://doi.org/10.3390/chemistry7030089

Chicago/Turabian Style

Yuan, Dan, Yong Huang, Long Tang, and Ke Yang. 2025. "Metal-Free C(sp3)–S Bond Cleavage of Thioethers to Selectively Access Aryl Aldehydes and Dithioacetals" Chemistry 7, no. 3: 89. https://doi.org/10.3390/chemistry7030089

APA Style

Yuan, D., Huang, Y., Tang, L., & Yang, K. (2025). Metal-Free C(sp3)–S Bond Cleavage of Thioethers to Selectively Access Aryl Aldehydes and Dithioacetals. Chemistry, 7(3), 89. https://doi.org/10.3390/chemistry7030089

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