Organocatalytic 1,5-trifluoromethylthio-sulfonylation of vinylcyclopropane mediated by visible light in the water phase

Junkai Liu , Hong Yao , Xinnan Li , Hongyu Wu , Aijun Lin , Hequan Yao , Jinyi Xu * and Shengtao Xu *
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P. R. China. E-mail:;

Received 19th March 2020 , Accepted 22nd April 2020

First published on 24th April 2020

1,2-Difunctionalization has developed into a robust tool for the preparation of complex organic molecules, and remote difunctionalization has also aroused widespread interest to achieve pluripotency of difunctionalization. Herein, we report a metal-free organocatalytic system mediated by visible light to realize the remote 1,5-trifluoromethylthio-sulfonylation of vinylcyclopropane with ArSO2SCF3 reagents in the water phase. This reaction exhibits broad functional group compatibility, moderate to good yields, and high regioselectivities and stereoselectivities.


Difunctionalization reactions are efficient and straightforward synthetic methods to introduce diverse functional groups into a molecule in a single step and have attracted extensive attention from synthetic chemists.1 The past decade has witnessed the rapid development of synthetic methods toward difunctionalization of alkenes or alkynes.1 With the extensive study of 1,2-difunctionalization, the development of remote difunctionalization constitutes a prime goal of utmost interest in the difunctionalization field.2 Despite great progress being made in realizing 1,3-3 and 1,4-4 difunctionalization, relatively few methods are available for 1,5-difunctionalization.5 Moreover, those reactions are restricted by the use of transition metals or organic solvents, leading to high cost and/or potential toxicity. Therefore, cheaper and environmentally friendly catalytic systems need to be further developed for 1,5-difunctionalization.

Introducing fluoroalkylthio groups into small molecules has attracted great interest in the academia and the pharmaceutical industry, mainly due to the high lipophilicity of these groups that may dramatically improve the pharmacokinetic properties of drug molecules.6 The sulfone group, another important functional group, can be introduced into drug molecules as bioisosteres of carbonyl, carboxyl, tetrazolium and phosphate groups in order to maintain or improve the biological activity.7 Moreover, sulfones are also useful intermediates, for example, they can be easily converted into alkenes via the Julia olefination.8 These advantages of sulfones and fluoroalkylthio groups have recently aroused considerable interest in developing synthetic methodologies to incorporate sulfonyl and fluoroalkylthio groups together into small molecules.

ArSO2SRf reagents (Rf = CFH2, CF2H, CF3, C2F5 and alkyl), well-developed fluoroalkylthiolating reagents9 and alkylthiolating reagents,10 have been used to introduce sulfonyl and fluoroalkylthio groups together into a small molecule. Most of the research works in this area focused on 1,2-difunctionalization reactions, including ArSO2SCFH2, ArSO2SCF2H, ArSO2SCF3 and ArSO2SC2F5 reagents (Scheme 1a).11 Meanwhile, 1,4-difunctionalization of enynes has also been reported by a radical cascade cyclization (Scheme 1b).12 Despite these significant advances, 1,5-difunctionalization still remains a challenging task mainly due to the difficulty of remote difunctionalization compared with 1,2-difunctionalization.

image file: d0qo00343c-s1.tif
Scheme 1 Fluoroalkylthiolating ArSO2SRf reagent initiated radical difunctionalization reactions.

The visible light photoredox process has recently found many applications in difunctionalization reactions, and it occurs under mild conditions and does not require radical initiators or stoichiometric chemical oxidants or reductants.13 Inspired by the trends in sustainable development, we envisaged that the applications of light and water could offer new vistas in the area and therefore expand the synthetic toolbox for 1,5-difunctionalization. In previous works, we have developed environmentally-friendly reactions in the water phase, which achieved the synthesis of unusual tetracyclic indoles containing a seven-membered ring under microwave irradiation and metal-free C5-selective halogenation of quinoline derivatives.14 Herein, we further developed an environmentally-friendly 1,5-trifluoromethylthio-sulfonylation of vinylcyclopropane catalyzed by eosin Y under visible light in the water phase (Scheme 1c).

Results and discussion

To optimize the reaction conditions, our investigation began with (1-cyclopropylvinyl) benzene (1a) as the model substrate of the addition reaction, S-(trifluoromethyl)-4-chlorobenzenesulfonothioate (2a) as the difunctionalization reagent, eosin Y as the photocatalyst stimulated by visible light, sodium dodecyl sulfate (SDS) as the additive and water as the reaction solvent. The isolated yield of 3aa was 22% when the reaction proceeded at room temperature (Table 1, entry 1). The yield was significantly reduced from 22% to 5% in the absence of SDS (Table 1, entry 2), which indicated the importance of SDS in improving the solubility of organic substrates in the water phase.15 No product was detected without the eosin Y photoredox catalyst or white LED, indicating their necessity for the difunctionalization of α-cyclopropylstyrene (Table 1, entries 3 and 4). After replacing white light with other light, the reaction hardly proceeded, suggesting that white light is the most suitable initiating light (Table 1, entries 5–7). We were pleased to obtain the major isolated product (3aa) in an encouraging 76% yield with 7[thin space (1/6-em)]:[thin space (1/6-em)]1 (Z[thin space (1/6-em)]:[thin space (1/6-em)]E) stereoselectivity by increasing the temperature to 50 °C (Table 1, entry 8), and the crystal structure of 3aa also confirmed the Z configuration. The corresponding E configuration product (E-3aa) was also obtained and confirmed by 1D-NOE as shown in Fig. S2. Moreover, when replacing water with organic solvents, such as dimethyl sulfoxide (DMSO) and dimethyl formamide (DMF), both the yields and stereoselectivities of the Z configuration decreased significantly (Table 1, entries 9 and 10), thus water was the most suitable solvent.
Table 1 The results of various conditions used for the difunctionalization of α-cyclopropylstyrene (1a)a

image file: d0qo00343c-u1.tif

Entry Catalyst Solvent LED Yieldb (%) Z[thin space (1/6-em)]:[thin space (1/6-em)]Ec
a Reaction conditions: 1a (0.1 mmol), 2 (0.15 mmol), eosin Y (0.005 mmol, 5.0 mol%), SDS (0.03 mmol), solvent (1.0 mL), white LED, 5 h, r.t., argon atmosphere. b Isolated yield of the Z configuration. c Determined by LC-MS. d In the absence of SDS. e At 50 °C.
1 Eosin Y H2O White 22
2d Eosin Y H2O White 5
3 None H2O White 0
4 Eosin Y H2O None 0
5 Eosin Y H2O Green Trace
6 Eosin Y H2O Blue Trace
7 Eosin Y H2O Red Trace
8e Eosin Y H2O White 76 7[thin space (1/6-em)]:[thin space (1/6-em)]1
9e Eosin Y DMSO White 35 3[thin space (1/6-em)]:[thin space (1/6-em)]1
10e Eosin Y DMF White 10 1[thin space (1/6-em)]:[thin space (1/6-em)]1

Considering that the configuration was mainly affected by steric hindrance, we further synthesized a total of eight ArSO2SCF3 reagents to fully study the effects of electrical properties and steric hindrance on the stereoselectivity of the reaction (Table 2). Although the unsubstituted (2b), brominated (2c), methyl (2d), trifluoromethyl (2f) and methoxyl (2g)-substituted groups maintained good reactivity, their stereoselectivities were not obviously improved. Fortunately, the stereoselectivity was significantly improved to 13[thin space (1/6-em)]:[thin space (1/6-em)]1 by using S-(trifluoromethyl)-4-(tert-butyl) benzenesulfonothioate (2e) as a difunctionalization reagent. No reaction took place when the ArSO2SCF3 reagent was S-(trifluoromethyl)-2,4,6-triisopropylbenzenesulfonothioate (2h) possibly due to the oversized steric hindrance nearby the reactive site. Finally, we selected 2e as the ArSO2SCF3 reagent of the optimized conditions.

Table 2 The results of various sulfonyl trifluoromethylthio reagents used for the difunctionalization of α-cyclopropylstyrene (1a)a,b
a Reaction conditions: 1a (0.1 mmol), 2 (0.15 mmol), eosin Y (0.005 mmol, 5.0 mol%), SDS (0.03 mmol), solvent (1.0 mL), white LED, 5 h, 50 °C, argon atmosphere. b Isolated yield of the Z configuration and the Z/E ratios were determined by LC-MS.
image file: d0qo00343c-u2.tif

With the optimal conditions in hand, the scope of the organocatalytic and visible light-mediated difunctionalization of vinylcyclopropanes was explored. As summarized in Table 3, a wide range of vinylcyclopropanes were applicable. Moderate to good isolated yields and Z/E ratios of the products were achieved for these para-substituted substrates, such as halogen, alkyl, aryl and methoxyl groups (1a–1h). Substrates bearing one or two substituent groups at different positions of the aromatic ring were all compatible with this reaction (1i, 1j, 1l, 1m). Naphthalene and a series of heteroaromatics, such as furan, thiofuran and pyridine, were all well tolerated under the reaction conditions (1k, 1o, 1p, 1q). In particular, α-cyclopropyl styrene 1n, containing an aldehyde moiety, was also applicable to this reaction, giving the corresponding 1,5-shift difunctionalized product (3ne) in a moderate yield. Considering that aldehyde groups are intolerant in transition metal redox catalyst systems, this is also one of the advantages of visible light mediated organic catalysis systems. Compound 1r with a methyl group in the 2-position of styrene also gave a Z-product in a suitable isolated yield. When replacing the methyl group with an isobutyl group, the reaction could not proceed, possibly due to the large steric effect of the isobutyl group.

Table 3 Substrate scope of difunctionalization of aryl vinylcyclopropanea,b
a Reaction conditions: 1a (0.1 mmol), 2 (0.15 mmol), eosin Y (0.005 mmol, 5.0 mol%), SDS (0.03 mmol), solvent (1.0 mL), white LED, 5 h, 50 °C, argon atmosphere. b Isolated yield of the Z configuration and the Z/E ratios were determined by LC-MS.
image file: d0qo00343c-u3.tif

In addition to the substrates of aryl vinylcyclopropane, alkyl vinylcyclopropane 1s was also applicable (Table 4). Although 3se could be obtained in a moderate yield, the stereoselectivity was poor, presumably because the steric hindrance effect of the benzyl group is not as good as that of the aryl group, resulting in a Z/E ratio of only 2[thin space (1/6-em)]:[thin space (1/6-em)]1.

Table 4 Difunctionalization of alkyl vinylcyclopropanea,b
a Reaction conditions: 1a (0.1 mmol), 2 (0.15 mmol), eosin Y (0.005 mmol, 5.0 mol%), SDS (0.03 mmol), solvent (1.0 mL), white LED, 5 h, 50 °C, argon atmosphere. b The yield of the Z configuration and the Z/E ratio were determined by isolation.
image file: d0qo00343c-u4.tif

Control experiments

The vinylcyclopropane group is known for its reactivity toward α-radicals to give a linear carbon radical, and α-cyclopropylstyrene has been used as a radical clock for several transition-metal catalyzed reactions that proceed via a radical pathway.16 Therefore, some control experiments were conducted as shown in Scheme 2. When TEMPO was added, the reaction was totally inhibited, which indicated its radical nature again (Scheme 2a), and simultaneously the sulfonyl-trifluoromethylthio reagent (2e) rapidly disappeared but vinylcyclopropane remained. In addition, 2e also rapidly disappeared after adding TEMPO under the standard conditions without substrate 1a (Scheme 2b). Such radical clock experiments indicated that the sulfonyl-trifluoromethylthio reagent was initiated first, and single-electron alkene addition enabled carbon-sulfonyl bond formation to provide a key alkyl radical transition terminated with a trifluoromethylthio radical. Furthermore, to investigate whether the reaction is a light-dependent or radical chain reaction, the role of the photocatalyst in this reaction was studied. As shown in Scheme 2c, a control experiment was performed for 0.5 h under the optimal conditions, which resulted in 24% yield. Another control experiment was initially conducted under the optimal conditions for 0.5 h, and then was performed in the dark for 4.5 h (the total reaction time was consistent with the standard reaction time), which produced 27% yield (Scheme 2d). There was no significant difference in yields between these two control experiments. By contrast, a 76% yield was obtained in the standard reaction (Scheme 2e). These results suggested that continuous photocatalysis was indispensable for the effective performance of the reaction.
image file: d0qo00343c-s2.tif
Scheme 2 Control experiments.

Although efforts have been made to explore the mechanism, the detailed mechanism remains unclear. On the basis of these investigations and related reports,16–18 a possible mechanism for the formation of products 3 is presented in Scheme 3. Initially, eosin Y was excited to its excited state (eosin Y)* under visible light irradiation, which is a common pathway mediated by visible light.17 Then substrate 2 was excited to generate free radical I, and the eosin Y/SCF3 complex might be formed. Further reaction of ArSO2 radical I with substrate 1 was followed by a rearrangement of cyclopropane to form intermediate II, which sequentially reacted with the eosin Y/SCF3 complex to generate products 3 and release the eosin Y dye for the next cycle.

image file: d0qo00343c-s3.tif
Scheme 3 Proposed reaction mechanism.


In summary, we have developed an organocatalytic method mediated by visible light in the water phase to achieve trifluoromethylthio-sulfonylation of vinylcyclopropane with 1,5-shift rearrangement. Trifluoromethylthio and sulfonyl were introduced into vinylcyclopropane with moderate to good yields, and excellent regioselectivities and good diastereoselectivities were achieved for the formation of the double bond. The organocatalytic reagent eosin Y is cheaper and more tolerant than transition metal or redox catalyst systems, and the water used as the solvent is also environment-friendly. This protocol provides an efficient, green and metal-free approach for the difunctionalization reaction and demonstrates the feasibility of an organocatalytic system to realize alkene difunctionalization with ArSO2SRf reagents in a single operation.

Conflicts of interest

There are no conflicts to declare.


This study was supported by the National Natural Science Foundation of China (No. 81673306, 81703348, 81874289, and 81903446), the Natural Science Foundation of Jiangsu Province (BK20190564), the China Postdoctoral Science Foundation Grant 2019M652037, and the “Double First-Class” University project CPU2018GY04, CPU2018GY35, China Pharmaceutical University.


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Electronic supplementary information (ESI) available. CCDC 1990849. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d0qo00343c
These authors contributed equally to this work.

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