Practical fluorothiolation and difluorothiolation of alkenes using pyridine-HF and N-thiosuccinimides

Abstract

We have developed highly efficient fluorothiolation and difluorothiolation of alkenes under simple and mild conditions. Our fluorothiolation reagents are the commercially available Olah's reagent (Py-HF) and readily available N-thiosuccinimides. This transition metal-free system offers good chemical yields for a wide range of alkene substrates with excellent regioselectivity and good functional group tolerance.

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Sulfur-containing molecules¹ widely exist in natural products,^2–4 pharmaceuticals^5,6 and agrochemicals.^7–9 Examples include the nonsteroidal anti-inflammatory drug sulindac¹⁰ and the basal cell carcinoma treatment drug vismodegib.¹¹ Therefore, efficient introduction of sulfur atoms into organic molecules has drawn much attention.^12–16 Similarly, the prominent roles of organofluorine compounds in pharmaceuticals, agrochemicals, and materials science^17–21 have encouraged the development of new methods for the generation of C–F bonds.^22–25 Thus, it will be an important topic to incorporate both the fluorine atom and sulfenyl group. Indeed, incorporation of fluorine and sulfur atoms simultaneously into alkenes has been developed by many groups. Saluzzo and coworkers^26,27 reported a direct fluoromethane sulfenylation of alkenes using dimethyl(methylthio)sulfonium fluoroborate (DMTSF) and triethylamine tris-hydrofluoride (Scheme 1a). However, this approach is limited to methane sulfenylation and it is relatively difficult to access DMTSF. Correa and co-workers²⁸ reported that the addition of benzenesulfenyl chloride to alkenes in the presence of silver or mercury fluorides resulted in the formation of β-fluoro phenyl thioethers (Scheme 1b). Although this method is efficient, it still has limitations such as requirements of hazardous sulfenyl chlorides and toxic metal reagents.

Scheme 1 Literature background for fluorothiolation of alkenes.

In 2009, Yoshida and coworkers²⁹ reported an innovative method for fluorothiolation of alkenes using electrochemically generated ArS(ArSSAr)⁺BF₄⁻ (ref. 30) as the fluorothiolated reagent (Scheme 1c). This work reveals that ArS(ArSSAr)⁺BF₄⁻ is firstly generated from electrooxidation of ArSSAr with Bu₄NBF₄ at −78 °C and then added into alkenes. This method avoids using unstable and hazardous reagents. But limitations still exist, such as the requiring low temperature and only being suitable for the introduction of aromatic sulfide (ArS). Therefore, it is highly desirable to develop new strategies for the synthesis of β-fluorinated thioethers which meet the following criteria: (1) avoid the use of expensive, unstable and hazardous reagents and (2) be suitable for a wide range of substrates.

The electrophilic addition of sulfenyl halides to alkenes to yield β-halo thioethers via a bridged episulfonium ion is a well-established reaction.³¹ Inspired by this protocol, we speculate that the direct addition of sulfenyl fluorides to alkenes may also occur. However, sulfenyl fluorides are extremely unstable. Thus, we assume that sulfenyl fluorides could form in situ when using electrophilic SR such as N-thiosuccinimides and hydrogen fluoride. In recent years, our group has developed many transition metal-free halogenations of alkynes and alkenes by using environmentally benign nucleophilic halide reagents enabled by hydrogen bond networks.^25,32–46 Herein, we present widely applicable and highly efficient fluorothiolation and difluorothiolation of alkenes using N-thiosuccinimides and Py-HF under mild conditions with good functional group tolerance (Scheme 1d).

We started the investigation of a fluorothiolation protocol using N-thiosuccinimide 2a and 1-decene 1a as model substrates (Table 1). Firstly, screening of the fluoride source showed that pyridine-HF (Py-HF, 70% HF content) afforded the desired product 3a in 71% yield (Table 1, entry 6). No product was observed using other fluoride sources such as KF, CsF, TBAF, and even Et₃N-HF or DMPU-HF (Table 1, entries 1–5). Further screening of solvents revealed that this transformation could hardly proceed in polar solvents such as DMF, THF, and MeCN (Table 1, entries 9–11). On the other hand, the reaction proceeded well in non-polar solvents (Table 1, entries 6–8). The yield of the desired product 3a could be significantly improved by increasing the reaction temperature to 60 °C (Table 1, entry 12). Finally, for the complete transformation of alkenes into the desired product, five equivalents of Py-HF were needed, and the desired product 3a was obtained in 99% yield (Table 1, entry 14).

Table 1 Optimization of the reaction conditions

Entry^a	[F]	Solvent	Temp. (°C)	Yield^b (%)
a Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), [F] (0.3 mmol), and solvent (1 mL) under air for 12 h at room temperature. b Determined by GC-MS. c 0.5 mmol Py-HF was used.
1	KF	HFIP	rt	0
2	TBAF	DCM	rt	0
3	CsF	DCM	rt	0
4	Et3N-HF	DCM	rt	0
5	DMPU-HF	DCM	rt	0
6	Py-HF	DCM	rt	71
7	Py-HF	DCE	rt	80
8	Py-HF	Tol	rt	60
9	Py-HF	THF	rt	13
10	Py-HF	MeCN	rt	22
11	Py-HF	DMF	rt	0
12	Py-HF	DCE	60	90
13	Py-HF	DCE	80	88
14	Py-HF	DCE	60	99

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With the optimized conditions in hand, we next turned our attention to explore the substrate scope of alkenes (Table 2). Aliphatic terminal alkenes bearing halogen, benzyl, and naphthalene (Table 2, 3b, 3d, and 3e) gave good isolated yields (76%–83%). Internal alkenes such as cyclohexene, cyclooctene, and 4-octylene were also suitable substrates, affording the desired products in good yields from 84% to 90% (Table 2, 3f–3h). According to Yoshida's work²⁹ and the ¹H NMR analysis of products, this transformation proceeded through anti-addition of RS and F to alkenes. As a result, Z-alkenes gave trans-β-fluorinated thioethers, while E-alkenes gave cis-β-fluorinated thioethers.

Table 2 Scope for fluorothiolation of alkenes^a

a Reaction conditions: 1 (0.1 mmol), 2 (0.12 mmol), Py-HF (0.5 mmol), and DCE (1 mL) under air for 12 h at 60 °C. b Isolated yields.

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Then, aliphatic terminal alkenes containing various functional groups were investigated. Aliphatic alkenes bearing esters (OBz) and sulfonyl esters (OTs and OMs) were all well tolerated (Table 2, 3m–3o). Besides, excellent yields could be obtained for aliphatic alkenes bearing heterocyclic moieties such as thiophene, furan, and the derivative of lipoic acid (Table 2, 3i–3k). Also, aliphatic alkenes containing cyano, azide, and amide afforded the corresponding products with moderate to good yields (Table 2, 3p–3r). Notably, ethers sensitive to acids also tolerated these conditions (Table 2, 3s–3v). Similarly, the reaction yields were not affected by functional groups such as nitro, aldehyde, methoxyl, and cyano on substrates. Furthermore, this excellent functional group tolerance enabled potential applications in the synthesis of biologically active natural products, pharmaceuticals, and agrochemicals. For example, this protocol could be successfully applied to the derivatives of adamantanic acid (Table 2, 3w), zaltoprofen (Table 2, 3z), estrone (Table 2, 3x), and glycoside (Table 2, 3y).

After the examination of the alkene scope, we started to explore the scope of N-thiosuccinimides. To our delight, the introduction of electron-donating groups into the aromatic rings of N-arylsulfenylsuccinimides had little influence on this reaction. Also, substitution patterns (ortho, meta, or para) have little effect on the reactivity (Table 2, 3aa–3d and 3af–3ah). However, the presence of electron-withdrawing groups such as the acetyl group led to a significant decrease in the isolated yield (Table 2, 3ae). Besides, this reaction could be extended to N-alkylsulfenylsuccinimides (Table 2, 3ai–3aj), affording the desired products with moderate yields. After exploring the scope of aliphatic alkenes, we started to investigate the scope of aromatic alkenes. Under the optimized conditions, low yields were obtained although the starting materials were completely consumed. This may be due to the fact that aromatic alkenes tend to polymerize under acidic conditions.

The introduction of the difluoromethyl moiety may improve the pharmacokinetic properties of drugs and a large number of difluoromethylated compounds show unique biological activities.^47–49 Compared to the incorporation of the fluorine atom^23,50–58 and trifluoromethyl group,^59–68 difluoromethylations are more challenging.^69–73 Direct^74–80 and indirect^81–86 difluoromethylations are the two main strategies.^87–89 We found that β-bromo-β-fluoroalkyl phenyl thioethers could be obtained after the fluorothiolation of α-bromostyrenes. And a tandem nucleophilic displacement of the bromide leaving group by excess hydrofluoride afforded difluorothiolated products. Along with this line, we explored the difluorothiolation of α-bromostyrenes. Under the optimized conditions, α-bromostyrene was used to examine the scope of N-thiosuccinimides and moderate isolated yields could be obtained (Table 3, 4a–4h). However, no product was observed for the electron-withdrawing group on the phenyl ring of N-arylsulfenylsuccinimide. N-Alkylsulfenylsuccinimides afforded the desired products with a relatively low yield (Table 3, 4i).

Table 3 Difluorothiolation of α-bromostyrenes^a

a Reaction conditions: 1 (0.1 mmol), 2 (0.12 mmol), Py-HF (0.5 mmol), and DCE (1 mL) under air for 12 h at 60 °C. b Isolated yields.

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Encouraged by the success of fluorothiolation of alkenes, we next focused on bromo- and chlorothiolation of alkenes. Instead of pyridine-HF, pyridine-HCl and pyridine-HBr were used as the halogen source. Similarly, good yields (Scheme 2) could also be obtained under the optimized conditions.

Scheme 2 Bromo- and chlorothiolation of alkenes.

Based on the previous studies,^90,91 a plausible reaction pathway for the intermolecular fluorothiolation of alkenes was proposed, as shown in Scheme 3. Firstly, an active intermediate A may be formed when Py-HF and N-thiosuccinimide were mixed under the optimized conditions. Then, sulfonium B may be produced from intermediate A with alkene 1, followed by a nucleophilic attack of the fluorine anion, giving the corresponding fluorothiolated products. When R¹ was bromine, due to the high reactivity of benzyl bromide, difluoromethylated products could be obtained through the nucleophilic displacement of the bromo substituent by excess hydrogen fluoride.

Scheme 3 Plausible mechanism.

Conclusions

In summary, we have developed practical and efficient fluorothiolation and difluorothiolation of alkenes using Py-HF and N-thiosuccinimides under simple and mild conditions. This metal-free system offers good chemical yields and good functional group tolerance.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful to the National Science Foundation of China for financial support (NSFC-21672035).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c9qo01228a

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