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Synlett 2019; 30(15): 1830-1834
DOI: 10.1055/s-0039-1690163
letter
© Georg Thieme Verlag Stuttgart · New York

Molecular Iodine Catalyzed Hydroxysulfenylation of Alkenes with Disulfides in Aerobic Conditions

Bang-qing Ni∗
School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122, Jiangsu Province, P. R. of China   Email: byron_ni@yeah.net   Email: niutf@jiangnan.edu.cn
,
Yunpeng He
,
Xuejiao Rong
,
Teng-fei Niu  ∗
School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122, Jiangsu Province, P. R. of China   Email: byron_ni@yeah.net   Email: niutf@jiangnan.edu.cn
› Author Affiliations

The authors gratefully acknowledge the National Natural Science Foundation of China (no. 21808085), the China Postdoctoral Science Foundation (2018M630519), and the Natural Science Foundation of Jiangsu Province, China (BK20160164).
Further Information

Publication History

Received: 09 June 2019

Accepted after revision: 31 July 2019

Publication Date:
09 August 2019 (online)

 
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Abstract

An environmentally friendly and efficient strategy has been developed for preparing β-hydroxy sulfides by a molecular-iodine-catalyzed radical reaction. This reaction involves hydroxysulfenylation of alkenes with disulfides in aqueous solution. Air is used as the oxidant without any additives. Control experiments indicated that the oxygen atom of products might come from O2. Both aryl alkenes and aliphatic alkenes were well tolerated in this transformation and afforded the corresponding products in moderate to high yields.


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Key words

hydroxysulfenylation - hydroxy sulfides - iodine catalysis - green chemistry

β-Hydroxy sulfides have found widespread use as convenient intermediates for the construction of biologically active heterocycles,[1] pharmaceuticals,[2] and natural products.[3] Consequently, numerous synthetic methods have been reported for the preparation of these compounds. The classical approaches for accessing these compounds involves the ring opening of epoxides with thiols.[4] Alternatively, the thiol–oxygen co-oxidation reaction of alkenes is another useful method.[5] Despite their great success, these methods involve the use of large excesses of fetid, sensitive, and toxic thiols, possibly hindering their widespread application. Thus, an efficient way for building these useful structures without generating obnoxious odors remains an attractive prospect.

In the past decade, methods for the use of disulfides instead of thiols have been developed for the preparation of β-hydroxy sulfides.[6] Among these, the oxidative sulfidation of alkenes with disulfides has attracted considerable attention. Alkene dihydroxysulfenylation can efficiently introduce a C–O bond and a C–S bond in one step from simple starting materials. For example, Movassagh and Navidi[7] reported a Zn/AlCl3-catalyzed one-pot synthesis of β-hydroxy sulfides from various styrenes and disulfides (Scheme [1a]). Yadav and co-workers[8] disclosed a metal-free radical pathway to afford β-hydroxy sulfides by using Rongalite (HOCH2SO2Na·2H2O) as a promoter under aerobic conditions (Scheme [1b]). Recently, Yan and co-workers[9] reported a HBr/H2O2-mediated sulfidation of styrenes, leading to β-hydroxy sulfides (Scheme [1c]). Although these methods provide efficient routes to β-hydroxy sulfides, most of them have drawbacks, such as the use of toxic catalysts or excessive use of promoters or oxidants. Furthermore, these methods are generally focused exclusively on terminal aryl alkenes, whereas aliphatic alkenes are inert toward these transformations. Therefore, an environmentally friendly and efficient process for preparing such motifs remains highly desirable.

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Scheme 1 Methods for the synthesis of β-hydroxy sulfides

As a classical nonmetallic-element-catalyzed process, molecular-iodine-catalyzed oxidation represents a recent advance in terms of environmental sustainability and cost effectiveness.[10] The Peddinti group[11] recently developed a regioselective synthesis of β-hydroxy sulfides from terminal styrenes and thiophenols by using iodine; however, DMSO was used as the oxidant in this reaction. As an ideal oxidant, molecular oxygen is clean, nontoxic, and environmentally sustainable. In this context, we describe the development of an environmentally friendly and efficient method for an aerobic molecular-iodine-catalyzed hydroxysulfenylation of both aryl and aliphatic alkenes with disulfides to generate β-hydroxy sulfides (Scheme [1d]).

Table 1 Optimization of the Reaction Conditionsa

Entry

Catalyst (mol%)

Oxidant

Temp (°C)

Solvent

Yieldb (%)

1

I2 (20)

air

40

MeCN–H2O

62

2

I2 (20)

O2

40

MeCN–H2O

32

3

I2 (20)

H2O2 c

40

MeCN–H2O

trace

4

I2 (20)

K2S2O8 c

40

MeCN–H2O

trace

5

I2 (20)

air

r.t.

MeCN–H2O

40

6

I2 (20)

air

60

MeCN–H2O

82

7

I2 (20)

air

80

MeCN–H2O

74

8

I2 (20)

air

60

MeOH–H2O

55

9

I2 (20)

air

60

DMSO–H2O

25

10

I2 (20)

air

60

MeCN–H2Od

82

11

I2 (20)

air

60

H2O

trace

12

I2 (30)

air

60

MeOH–H2O

80

13

I2 (10)

air

60

MeOH–H2O

43

a Reaction conditions: 1a (0.5 mmol), 2a (1 mmol), solvent/H2O = 3:1 (2 mL), 2 h.

b Yield of isolated product.

c Two equivalents.

d MeCN/H2O = 1:1.

In our initial study, we chose bis(4-chlorophenyl) disulfide (1a) and styrene (2a) as our model substrates. To our delight, we obtained a 62% yield of the desired product 3a in the presence of I2 in MeCN–H2O (3:1, v/v) at 40 °C under air after two hours (Table [1], entry 1). To obtain an optimum yield, we screened a wide variety of oxidants. O2 gave a low yield of the desired product; instead, more than 50% of diphenyl disulfide was obtained (entry 2). H2O2 and K2S2O8 as oxidants also showed negative effects, giving only trace amounts of the desired product (entries 3 and 4). Consequently, the reaction was carried out on the open air. A study of the reaction temperature showed that 60 °C was the best choice, and the yield of the corresponding product 3a increased to 82% (entry 6). The choice of solvent had a significant impact on the reaction: MeOH–H2O (3:1, v/v) and DMSO–H2O (3:1, v/v) afforded lower yields (entries 8 and 9).When the ratio of MeCN to H2O was 1:1, a similar yield was obtained to that under the model condition (entry 10). However, only trace amount of the desired product was obtained in water (entry 11). Finally, the effect of the amount of the catalyst was also checked. Increasing the amount of I2 to 30 mol% led to a similar yield (entry 12), whereas decreasing the amount of I2 resulted in a significantly lower yield (entry 13). Thus, the optimal experimental conditions were established as follows: disulfide 1 (1 equiv), alkene 2 (2.0 equiv), and I2 (20 mol%) as catalyst in a 1:1 (v/v) mixture of MeCN and H2O (2 mL) under ambient conditions.

With the optimal condition in hand, we examined the scope and generality of the present method.[13] As shown in Scheme [2], diverse aryl alkenes 2 bearing a variety of substituents were employed to react with diaryl disulfides 1 under the optimized reaction conditions to give the corresponding products 3a–k smoothly in moderate to high yields (52–86%). The electronic properties of substituents on the aryl rings of alkene had a slight influence on the reaction, but both electron-donating and electron-withdrawing substituents gave satisfactory results (3g–j). Steric hindrance in the alkene had a significant effect, and aryl alkenes with para-, meta-, or ortho-chloro substituents were successfully converted into the corresponding products 3d–f in yields of 80, 72, and 51%, respectively. Note that, α,α-disubstituted alkenes 2l–n were suitable for this protocol. The α,β-substituted alkenes 2o and 2p also participated in this reaction, but gave only moderate yields, probably due to steric hindrance. Furthermore, aliphatic alkenes such as cyclohexene (2q), 4-methylpent-1-ene (2r), and 4-bromobut-1-ene (2s) also showed good tolerance in this reaction and afforded the corresponding β-hydroxy sulfides 3q–s in moderate yields. In addition, the regioselectivity toward the cyclohexene product 3q was examined; a NOESY NMR showed that the regioisomer of the products is trans, and the relative configuration of 3q is shown in Scheme [2].

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Scheme 2 Substrate scope of the reaction. Reagents and conditions: 1 (0.5 mmol), 2 (1 mmol), I2 (20 mol%), 1:1 MeCN–H2O (2 mL), under open air, 2 h, 60 °C. Isolated yields are reported. NR = no reaction.

The scope of the diaryl disulfide was also investigated. Diaryl disulfides 2t–x with substituents such as fluoro, chloro, methyl, or bromo were suitable for the present reaction conditions, affording the desired products 3t–x in moderate to good yields. The electronic effect of the substituents had a significant influence on the reaction, and bis(4-fluorophenyl) disulfide gave a relatively low yield (52%) of 3w, whereas bis(4-cyanophenyl) disulfide (1y) was inert toward this transformation. Diethyl disulfide (1z) was not suitable for this transformation.

To gain insight into the mechanism, we performed several control experiments. First, a radical trapping experiment was conducted by employing (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), and only an 11% yield of the desired product was obtained (Scheme [3a]), indicating that the reaction might involve a radical pathway. Next, when the reaction carried out without O2, only a trace amount of 3a was obtained (Scheme [3b]), The reaction was completely inhibited when the reaction was carried out in the absence of H2O (Scheme [3c]). Furthermore, when H2O was replaced by H2 18O under the standard conditions, product 3a with no 18O label was detected (Scheme [3d]). These results suggested that the oxygen atom in the product does not originate from H2O, but probably comes from O2.

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Scheme 3 Control experiments

On the basis of these control experiments and previous reports,[8] [9] we propose the plausible mechanism for the present reaction shown in Scheme [4]. Initially, I2 active the disulfide ArSSAr 1 to give the intermediate ArS–I (I).[11] This liberates radical ArS∙ (II) and an iodine free radical.[11] Subsequent addition of II to alkene 2 generates radical III, which reacts with molecular oxygen to give the peroxy radical IV.[5h] Reaction between intermediates III and IV then affords radical V,[12] which reacts with the iodine free radical and abstracts one hydrogen atom from H2O to form the desired product 3 and the catalyst I2.

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Scheme 4 The proposed mechanism

In summary, we have developed an environmentally friendly and effective molecular-iodine-catalyzed reaction for the preparation of β-hydroxy sulfides in aqueous solution.[13] This reaction uses disulfides instead of fetid, sensitive, and toxic thiols. Importantly, air is used as the oxidant without any additive. Furthermore, H2 18O isotope experiment indicated that the oxygen atom of the products comes from O2. Moreover, both terminal aryl alkenes, α,α-substituted aryl alkenes, α,β- substituted aryl alkenes, and aliphatic alkenes are tolerated well in this transformation to give the corresponding products in moderate to high yields, thereby providing a potential route for both academic and industrial applications.


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Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0039-1690163.
  • Supporting Information


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Zoom Image
Scheme 1 Methods for the synthesis of β-hydroxy sulfides
Zoom Image
Scheme 2 Substrate scope of the reaction. Reagents and conditions: 1 (0.5 mmol), 2 (1 mmol), I2 (20 mol%), 1:1 MeCN–H2O (2 mL), under open air, 2 h, 60 °C. Isolated yields are reported. NR = no reaction.
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Scheme 3 Control experiments
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Scheme 4 The proposed mechanism