NBS-driven sulfonylation of phenols with sodium sulfinates via oxidative O–S cross coupling

Abstract

NBS-driven oxidative O–S cross coupling reaction for sulfonylation of phenols and alcohols with sodium sulfinates is presented. This operationally simple and environmentally benign strategy proceeds under mild conditions and exhibits excellent functional group compatibility. Moreover, the utility and potential synthetic value of this methodology were well demonstrated through the modification of bioactive molecules.

Under benign conditions, NBS-driven oxidative O–S cross coupling reaction for sulfonylation of phenols and alcohols with sodium sulfinates is presented.

Introduction

One of the central objectives of modern synthetic chemistry is the construction of various bonds by new and versatile methods. Over the last few decades, the cross-coupling reaction has emerged as one of the most powerful, reliable, and convenient ways to form C–C (carbon–carbon) and C–X (carbon–heteroatom) bonds in molecular synthesis as well as in the discovery, exploitation, and industrialization of novel drugs, agricultural chemicals, and functional materials. These reactions are fundamentally based on the bond formation of nucleophiles and electrophiles.¹ Driven by the need for green and sustainable chemistry, synthetic chemists have pursued more efficient, facile and user-friendly oxidative cross-coupling reactions to accomplish atom-economical and step-economical transformations.² Such reactions have enabled access to highly significant functional molecules that are inaccessible through other approaches. Among myriad oxidative cross-coupling reactions, oxidative S–O coupling reactions still remain scarce, but hold great, largely unexploited potential owing to easy over-oxidation, fragmentation and poisoning metal catalyst of sulfur.^3,4

Sulfonate esters are important organosulfur compounds widely found in pharmaceuticals, agrochemicals, and functional materials.⁵ Conventional sulfonylation strategies, in addition to preactivated sulfonyl reagents (e.g., sulfonyl chlorides, sulfonic anhydrides), often necessitate strong oxidants or harsh reaction conditions, and suffer from cumbersome procedures, environmental concerns, and poor compatibility with acid-sensitive functional groups.⁶ For example, Meshram et al. reported the sulfonylation of alcohols and phenols with sulfonyl chlorides for the synthesis of sulfonate esters (Scheme 1a).^6b Khodaei developed a sulfonylation reaction between phenols and thiols in the presence of hydrogen peroxide and phosphorus oxychloride (Scheme 1b).⁷ More recently, sulfonylation of phenols and sodium sulfinates involved radical mechanism pathway has been demonstrated via iodine-mediated oxidation and electrochemistry, respectively (Scheme 1c).⁸ Notably, these two approaches exhibit limited efficiency toward highly sterically hindered alcohols and phenols. Moreover, sulfonylation using sodium sulfinates containing a nitro group remains unexplored.

Scheme 1. Methods for the synthesis of sulfonate esters via oxidative cross-coupling strategy.

Based on our research interests in oxidative cross-coupling reactions,⁹ herein we established a practical, facile, and efficient N-bromosuccinimide (NBS)-driven oxidative O–S cross-coupling strategy for the sulfonylation of phenols with sodium sulfinates via an ionic pathway (Scheme 1d). Notably, this transformation tolerates sodium sulfinate with nitryl group and sterically demanding substrate, including hindered phenols, alcohols and bulky sodium sulfinates.

Results and discussion

4-Phenylphenol (1a) and sodium p-tolylsulfinate (2a) were selected as the model substrate and sulfonyl source, respectively to establish the model reaction (Table 1). Fortunately, the target sulfonate ester 3aa was smoothly obtained in 97% isolated yield when the reaction conducted by using NBS as benign oxidant, NaOH as the base, THF/H₂O (9/1) as the co-solvent system, at room temperature for 12 h in air (Table 1, entry 1). Control experiments demonstrated that NBS, and an ethereal solvent, THF, played essential roles in this transformation (Table 1, entries 2−5). The reaction also worked well in 1,4-dioxane/H₂O (Table 1, entry 6) but sluggishly in MeCN/H₂O, MeOH/H₂O and DMF/H₂O (Table 1, entries 7−9). Subsequently, various organic and inorganic bases were screened, replacement of NaOH with DBU drastically diminished the yield of 3aa to 41%. In contrast, KOH and Na₂CO₃ proved more effective, furnishing 3aa in 95% and 69% yields, respectively, albeit still lower than that obtained with NaOH. Reducing the NaOH loading to 0.3 equivalents resulted in a significant decrease in the yield of 3aa (Table 1, entries 10–13). Furthermore, the influence of different oxidants and NBS loading were also investigated. When NIS and NCS were used as the oxidant, the desired sulfonate ester 3aa was obtained in lower yield compared to that of NBS, which might be attributed to the favorable reactivity of the in situ generated sulfonyl bromide intermediate: the S–Br bond is sufficiently electrophilic for coupling yet stable enough to avoid decomposition, unlike the less reactive S–Cl (from NCS) or the overly labile S–I (from NIS). Reducing the NBS loading to 1.4–1.8 equivalents proved detrimental to the reaction efficiency, with isolated yields dropping to 32% to 91% (Table 1, entries 14–18). It's worth noting that this reaction proceeded without interference from electrophilic side reactions on the aromatic ring,¹⁰ exhibiting excellent chemoselectivity.

Table 1. Optimization of the reaction conditions^a.

Entry	Change from standard conditions	Yieldb (%)
1	None	97
2	Without H2O	65
3	Without THF	Trace
4	Without NaOH	48
5	Without NBS	n.d.
6	1,4-Dioxane instead of THF	83
7	MeCN instead of THF	42
8	MeOH instead of THF	Trace
9	DMF instead of THF	Trace
10	KOH instead of NaOH	95
11	Na2CO3 instead of NaOH	69
12	DBU instead of NaOH	41
13	NaOH (0.3 equiv.)	89
14	NIS instead of NBS	50
15	NCS instead of NBS	55
16	NBS (1.8 equiv.)	91
17	NBS (1.6 equiv.)	70
18	NBS (1.4 equiv.)	32

^aReaction conditions: 1a (0.50 mmol), 2a (1.00 mmol), NBS (2.0 equiv.), NaOH (0.5 equiv.), THF/H₂O (9/1) (3 mL), 12 h; n.d. = not detected.

^bThe yield of 3aa is isolated yield.

To demonstrate the generality of the oxidative O–S cross coupling reaction, the substrate scope was evaluated. The scope of phenols was first investigated under the standard conditions with sodium p-tolylsulfinate (Scheme 2). Phenols with diverse substituents on the aromatic ring (phenyl, hydrogen, methoxy, methyl, amide, ester, fluoro, chloro, bromo, iodo, nitryl, cyano, and trifluoromethyl groups) reacted with 2a to afford the corresponding sulfonate esters 3aa–3pa in excellent yields. Both electron-donating and electron-withdrawing phenols were compatible, suggesting that this reaction might not be sensitive to the electronic effect. Methyl group at the different positions of the aromatic ring of phenols were well tolerated, smoothly furnishing the corresponding products in good yields (3da, 3ea, and 3fa). Additionally, dimethyl substituted phenol proved to be good substrates, affording 3ga in 58% yield. Moreover, aliphatic alcohols also performed well, delivering 3qa and 3ra in improved yields relative to previous reports.^8b Given that sulfonate esters are common units in bioactive molecules, we further applied this protocol to natural phenols. Carvacrol, thymol, eugenol, anuvex, and raspberry ketone all worked well with sodium p-toluenesulfinate 2a to provide the corresponding sulfonate esters (3sa–3wa) in moderate to excellent yields. Notably, this protocol exhibited excellent tolerance toward sterically hindered substrates, as both phenols and alcohols bearing bulky substituents furnished the desired products in good yields (3fa, 3ra, 3sa, 3ta, 3ua, and 3va).

Scheme 2. Scope of phenols. Reaction conditions: 1 (0.50 mmol), 2a (1.00 mmol), NBS (2.0 equiv.), NaOH (0.5 equiv), THF/H₂O (9/1) (3 mL), 12 h. ^aThe result is presented by ref. 8b.

Next, the scope of sodium sulfinates was examined (Scheme 3). Both electron-deficient and electron-rich arene sulfinates served as competent coupling partners, giving the corresponding products (3ab–3aj) in moderate to excellent yields. The successful formation of 3ai demonstrated that this protocol tolerates sterically hindered sulfinates. Unexpectedly, sodium 4-nitrobenzenesulfinate, bearing a strongly electron-withdrawing nitro group, proceeded well under the standard conditions and afforded 3aj in moderate yield. Heteroaryl and fused-ring sodium sulfinates could be readily converted to the corresponding products (3ak–3am) in moderate to good yields. In addition, this protocol proved applicable to aliphatic sulfinates, as exemplified by the successful conversion of sodium cyclohexanesulfinate to 3an in moderate yield.

Scheme 3. Scope of phenols. Reaction conditions: 1a (0.50 mmol), 2 (1.00 mmol), NBS (2.0 equiv.), NaOH (0.5 equiv.), THF/H₂O (9/1) (3 mL), 12 h. ^aRef. 8 is not compatible with sodium 4-nitrobenzenesulfinate.

To gain an in-depth understanding of the underlying oxidative O–S cross-coupling mechanism, several mechanistic experiments were conducted. The addition of TEMPO (2.0 equiv.) did not inhibit the oxidative coupling reaction of 1a and 2a, and the target product was obtained in a comparable yield (Scheme 4a), thus excluding a radical pathway. Treatment of sodium p-tolylsulfinate 2a with NBS afforded 4-methyl-benzenesulfonyl bromide 4a (4-MePhSO₂Br) in 48% yield (Scheme 4b), which probably acts as a pivotal intermediate in this transformation. The direct conversion of 1a and isolated 4a to 3aa under NaOH-mediated conditions provided compelling evidence for the intermediacy of sulfonyl bromide 4a (Scheme 4c). Taken together, these findings suggest that this reaction proceeds via an ionic pathway. Based on these results, the pathway shown in Scheme 5 is proposed: deprotonation of the phenol gives intermediate A. Meanwhile, sodium sulfinite reacts with NBS to generate sulfonyl bromide 4. Subsequent nucleophilic substitution between A and 4 accesses the desired products 3.

Scheme 4. Mechanistic experiments.

Scheme 5. Proposed mechanistic pathway.

Conclusions

In summary, a practical and efficient NBS-driven oxidative O–S cross-coupling protocol for sulfonylation of phenols and alcohols has been developed under mild conditions. This reaction is charactered by broad substrate scope, high functional group tolerance, and operational simplicity. The successful application to bioactive molecules highlights the practical utility of this method. This work complements and extends prior reports on both the mechanism and substrate scope of sulfonylation. Further investigations into efficient and sustainable oxidation-induced transformations are currently underway in our group.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included in the electronic supplementary information (SI). Supplementary information: general information, synthetic procedure, and the NMR spectrum of the final product. See DOI: https://doi.org/10.1039/d6ra04347j.