Sulfoxidation of alkenes and alkynes with NFSI as a radical initiator and selective oxidant

Abstract

Sulfoxides are important functional molecules. We develop a short-route (one-pot) synthesis of this class of molecules by reacting thiols with alkenes or alkynes under mild and metal-free conditions. N-Fluorobenzenesulfonimide (NFSI) is used to play dual roles: as a radical initiator for a thiol–ene/–yne reaction to form sulfide adducts, and as efficient oxidant for conversion of the sulfides formed in situ to sulfoxides. Over-oxidation of the sulfoxides to sulfones is avoided in our approach.

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The sulfoxide moiety is a functional group often found in pharmaceuticals and natural products, such as esomeprazole,¹ armodafinil² and alliin.³ Sulfoxides are also used as ligands for metal catalysts with applications in a large set of reactions, including Pummerer⁴ and Mislow–Evans rearrangements.⁵ To date, the synthesis of sulfoxides typically involves oxidation of sulfides using peroxides⁶ and hypervalent iodine reagent⁷ as the oxidants with the assistance of transition metal catalysts.⁸ One challenge of this otherwise widely used two-step protocol lies with over-oxidation of sulfoxides to sulfones.⁶ Here we report a new method that selectively converts alkenes and alkynes to sulfoxides in a one-pot metal-free operation (Fig. 1). N-Fluorobenzenesulfonimide (NFSI), a shelf-stable reagent,⁹ is used as a radical initiator and a selective oxidant. No over-oxidation of sulfoxides to sulfones was observed (Fig. 1).

Fig. 1 Our strategy of NFSI-enabled selective one-pot access to sulfoxides from alkenes/alkynes and thiols.

Notably, Yadav¹⁰ and Lei¹¹ have recently reported reactions of alkenes and thiols under dioxygen to form β-keto sulfoxides and β-oxy sulfoxides. In their reactions, oxidation of the alkene carbon by oxygen occurred concurrently. The NFSI reagent used in our reactions has often been employed as electrophilic fluorinating agent,¹² aminating reagent,¹³ or a combined amino and fluorine source.¹⁴ In radical reactions (SET reactions), it can generate aminyl radical for Cu-catalyzed radical amination of olefins, as reported by Kanai,¹⁵ Zhang¹⁶ and Studer.¹⁷ Zhang and co-workers also developed radical aminofluorination of styrenes using NFSI.¹⁸ In addition, Ritter reported Pd-catalyzed direct radical arene amination with NFSI,¹⁹ and Studer developed radical aminooxygenation of alkenes with NFSI in combination with TEMPONa.²⁰

Our initial design was to combine NFSI and thiol to generate thiyl and aminyl radicals for aminosulfidation of alkenes. We first studied reactions between alkene 1a and thiol 2a with NFSI as a potential radical generator in the presence of K₂CO₃ or K₃PO₄ as the base (Table 1, entry 1). The expected alkene aminosulfidation adduct was not formed. Instead, we found alkene sulfoxidation adduct 3a as the product in 11% yield (entry 1). Additional evaluation of the base effects (Table 1, entries 2–6) indicated that 1,8-diazabicycloundec-7-ene (DBU) performed the best, giving 3a in 72% yield (Table 1, entry 6). Several other solvents studied here did not work as well as toluene (Table 1, entries 7–10). The yield of 3a (based on 1a) could be further improved by increasing the loadings of thiol 2a and NFSI (Table 1, entry 11).

Table 1 Screening of reaction conditions for the reaction of 1a with 2a in the presence of NFSI^a

Entry	Base	Solvent	Yield^b [%]
a Conditions: 1a (0.2 mmol, 1.0 equiv.), 2a (0.24 mmol, 1.2 equiv.), NFSI (130 mol%) and base (50 mol%) in 3.0 mL of solvent at rt for 2–5 h. b Isolated yield based on 1a. c 2a (0.4 mmol, 2.0 equiv.), NFSI (0.36 mmol, 1.8 equiv.).
1	K2CO3 or K3PO4	Toluene	11
2	KOMe	Toluene	23
3	NaOtBu	Toluene	29
4	DIPEA	Toluene	43
5	DABCO	Toluene	66
6	DBU	Toluene	72
7	DBU	THF	52
8	DBU	Dioxane	31
9	DBU	CH3CN	26
10	DBU	EA	48
11	DBU	Toluene	87

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With an acceptable condition (Table 1, entry 11) on hand, we proceeded to explore the scope of the reaction (Table 2). We first examined the reaction between various alkenes and thiol 2a (3a–3p). Styrenes with different substituents or substitution patterns on the phenyl ring worked effectively (3a–3l). Internal alkenes, such as indene (3m), 1,2-dihydronaphthalene (3n), trans-β-methylstyrene (3o) were also effective substrates. Notably, no sulfoxidation products were obtained when aliphatic alkenes were used. Substituents (e.g., CH₃ and Br) could be placed on the phenyl unit of thiol 2a (3q, 3r), while 2-napthyl thiol (3s) was also tolerated.

Table 2 Substrate scope for reactions of alkenes with thiols in the presence of NFSI^a

a Conditions as in Table 1, entry 11; yields (after SiO₂ chromatography purification) were based on olefin 1. b Diastereoselective ratio (d.r.) was determined via¹H NMR analysis of the product mixture.

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We next found that alkynes could be used as substrates (to replace alkenes) under the same condition, affording unsaturated sulfoxides as the products (Table 3). The reactions proceeded smoothly for aryl alkynes with either electron-withdrawing or electron-donating substituents present on the aromatic ring (4a–4e) to afford the desired products (5a–5e) in moderate to excellent yields. Alkyl alkynes (4f, 4i–j) and alkynes bearing an ester (4g) or silyl (4h) moiety were also effective substrates.²¹ The structures of two vinylsulfoxide products (E-5a, E-5d) were unambiguously assigned via X-ray crystallography.

Table 3 Substrate scope for reactions of alkynes with thiols in the presence of NFSI^a

a Alkyne (0.2 mmol), 2a (0.4 mmol), NFSI (0.36 mmol) and DBU (50 mol%), in toluene (3 mL) at rt for 16 h; yields (after SiO₂ chromatography purification) were based on alkyne. b The ratio of E/Z was determined by the weight of isolated E and Z products.

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The proposed reaction pathway is illustrated in Scheme 1. Initially, removal of one electron from thiol 2a by oxidant NFSI^12a,b generates radical cation A that can be subsequently transformed to thiyl radical B after a proton transfer (Scheme 1a). Thereafter, addition of radical B to alkene 1 forms radical intermediate C. A hydrogen atom transfer (HAT) from a molecule of 2a converts C to sulfide D with the regeneration of the thiyl radical intermediate B which returns back into the propagation step (Scheme 1b). Finally, the sulfide D is oxidized to sulfoxide 3 by NFSI. One possible pathway (see ESI† for another possibility) for the oxidation of sulfide D involves nucleophilic addition of the sulfide to the electrophilic fluorine atom of NFSI to afford intermediate E (Scheme 1c). Substitution of the fluorine atom of E by water forms G that then transforms to sulfoxide 3 after a proton transfer process.

Scheme 1 Proposed reaction pathway.

To investigate the reaction mechanism, we performed multiple experiments (Scheme 2). The addition of TEMPO inhibited the formation of 3a (Scheme 2a). In the presence of 150 mol% TEMPO, the formation of sulfoxide product 3a was completely suppressed. The aminooxygenation adduct 6 previously reported by Studer²⁰ was observed in about 5% yield. Adducts 7, 8 and 9 (89% of combined yields based on thiol 2a) were previously reported by Greci and co-workers in a study on the reaction between 2a and TEMPO.²² The use of diphenyl disulfide 7 in place of thiophenol 2a did not lead to desired product 3a (Scheme 2b), suggesting that under the oxidative condition of NSFI the disulphide adduct did not convert to thiol. The oxygen atom in the sulfoxide product came from the trace amount of H₂O present in the solvent, as suggested by an ¹⁸O isotope labelling experiment (Scheme 2c). Additional experiments by adjusting the loadings of NFSI (Scheme 2d) suggest that both the thiol–ene reaction and oxidation reaction are enabled by NFSI. When 30 mol% of NFSI was added, only sulfide adduct 10 was observed. Sulfide 10 could then be transformed under standard conditions to sulfoxide 3a.²³ These experiments (Scheme 2a and b) support the formation of radical intermediate as proposed in Scheme 1a and b. The results (Scheme 2c and d) showed that the formation of sulfide (D, Scheme 1c) and its oxidation occurs in a stepwise process.

Scheme 2 Experiments to probe mechanism.

In summary, we have developed a facile synthesis of sulfoxides from alkenes and alkynes in the presence of NFSI. Sulfoxides are useful structural moieties for construction of natural products and other functional molecules. Our approach provides a metal-free and concise synthesis of this class of molecules. The substrates and reagents used in our approach are either inexpensive or readily available with reasonable cost. NFSI is used as a radical initiator (to initiate the sulfide formation) and a selective oxidant (to transform sulfides to sulfoxides). The oxygen atom in the sulfoxide products was determined to originate from trace water in the reaction mixture, providing a simple way for the incorporation of ¹⁸O isotope to sulfoxide-containing molecules. Further development of related radical reactions, including catalytic versions mediated by carbene organic catalysts, is in progress.

We thank Dr Yongxin Li (NTU) and Dr Rakesh Ganguly for assistance with X-ray structure analysis; We acknowledge financial support by the Singapore National Research Foundation (NRF-NRFI2016-06), the Ministry of Education of Singapore (MOE2013-T2-2-003), Nanyang Technological University (NTU, Singapore), China's Ministry of Education, National Key program for Basic Research (No. 2010CB 126105), Thousand Talent Plan (700059143302), National Natural Science Foundation of China (No. 21132003 and 21472028). Guizhou Province Returned Oversea Student Science and Technology Activity Program, Science and Technology of Guizhou Province, and Guizhou University.

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Footnotes

† Electronic supplementary information (ESI) available: Experimental procedures, mechanistic details, spectroscopic data and copies of ¹H and ¹³C NMR spectra. CCDC 1497084 and 1497085. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6cc08631d

‡ These authors contributed equally to this work.

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