Micelle Enhanced Auto-Oxidative Hydroxysulfenylation of Alkenes

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Micelle enhanced auto-oxidative hydroxysulfenylation of alkenes Beichen Zhang, Tongtong Liu, Yueying Bian, Tao Lu, and Jie Feng ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.7b04213 • Publication Date (Web): 09 Dec 2017 Downloaded from http://pubs.acs.org on December 13, 2017

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Micelle enhanced auto-oxidative hydroxysulfenylation of alkenes Beichen Zhang†, Tongtong Liu†, Yueying Bian†, Tao Lu*† and Jie Feng*† †State Key Laboratory of Natural Medicines, Department of Organic Chemistry, China Pharmaceutical University, No. 24 Tongjiaxiang Road, Nanjing, 210009, P.R. China. E-mail: 1020162519@ cpu.edu.com ABSTRACT: The organic solvent free auto-oxidative radical hydroxysulfenylation of olefins in micellar system was presented which enables the simultaneous C-O and C-S couplings to be performed in a green and sustainable manner, using oxygen as the only oxidant. Particularly noteworthy is the finding that micelle attributed to enhance both selectivity and reactivity for the C-S coupling. Meanwhile, radical mechanism was figured out, distinguished from traditional nucleophilic addition mechanism in water-like system.

Within this process, thiyl radical was initiated directly by environmentally benign and sustainable O2. Subsequent reversible addition of the thiyl radical to olefin could lead to hydroperoxy sulfides in presence of O2 (Scheme 2). This key intermediate, as of its high reactivity, can easily undergo transformations to sulfoxides, sulfides, hemithioacetals, etc. resulting 28 in low reaction selectivity.

Key words: radical, olefin difunctionalization, oxygen, C-S coupling, Brij L4, recyclable

INTRODCUTION Difunctionalization of olefins has received continuous interests as it provides a synthetic useful route to introduce vicinal 1-7 substituents. Among them, hydroxysulfenylation of olefins is one of the most versatile and convenient pathways toward simultaneous C-O and C-S bond formation affordding β8-10 hydroxysulfides in one pot. β-hydroxysulfides is a class of important building blocks and 11-12 intermediates for functionalized molecules, pharmaceuti13 14 cals, and natural products . Earlier olefin hydroxysulfenylation methods mainly include free radical process (typically 15 thiol-oxygen co-oxidation (TOCO) method ) and nonradical 16-18 process . TOCO methods usually require transition metal or peroxides to initiated mercapto radical. While in nonradical process, the thiol attacks the alkenes in an anti-Markonikov 19 manner. For example, Rao reported the nonradical hydroxy20 sulfenylation in β-cyclodextrin/H2O system and Kamal presented an ionic liquid mediated β-hydroxysulfides preparation method with [bmim][BF4]/H2O (Scheme 1).

Scheme 2. Mechanism insight for “auto-oxidation” hydroxysulfenylation process Solvent effects may have the vital impact on the selectivity for auto-oxidation hydroxysulfenylation. As reported, Lei’s 29 group fulfilled the selective synthesis of β-oxysulfoxides and β-hydroxysulfides in DMSO and DCE respectively; Tang’s 30 group described the auto oxidative hydroxysulfenylation reaction for both electron-deficient and electron-rich alkenes 31 in MeCN/DCE system. Zhou’s group achieved air oxidative radical hydroxysulfurization in DMF with catalytic amount of tert-butyl hydroperoxide. Screened out all the literatures, however, the known protocols concerns more about organic system but rare involved to green solvent, i.e. water. The environmental issues caused by the usage water-miscible reaction media (DMF, DMSO, CH3CN etc.) restrict their otherwise convenient and widely applications in C-S formation. Meanwhile, PPh3 workup is needed to reduce the formed hydroperoxyl sulfides in these organic solvent systems, leading to bench workup problems and produce extra wastes, which doesn’t 32 meet the green chemistry principle . 33-36

Scheme 1. Methods for olefin hydroxysulfenylation Although olefins hydroxysulfenylation strategies have been well-suited, they have recent again revived chemist’ interests 21-27 owing to development of “radical auto-oxidation” process .

On the other hand, the unique properties of water system arouse our interests in its behaviors for the desired C-S radical protocol. Actually, the thiol-Micheal addition to form 1Habstract product in water is a well-known reaction in textbook. The above-mentioned water-like systems such as the βCD/H2O, [bmim][BF4]/H2O although could afford β19,20 hydroxysulfides, but all ruled out the radical possibility . In

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this regard, the challenges of radical hydroxysulfenylation in water system lie not only yield β-hydroxysulfides, but also to overcome potential competitive radical and non-radical byreactions. Surfactant contains amphiphiles that, in water, could spontaneously self-aggregate to form nanomicelles that could serve unique interface effect and stabilized react atmosphere, that lead to excellent selectivities for many valued types of reac34, 35 tions. which may also provide a solution for this protocol. Thus, in continuation of our interests in oxidative coupling 37, 38 and micelles catalysis , we wish to present here a green and convenient auto-oxidative radical hydroxysulfenylation protocol in surfactant/H2O system. RESULTS AND DISCUSSION At the start of our work, the reaction of thiophenol 1a with styrene 2a in aqueous micelle was used as a model reaction (Table 1). The direct comparison reaction with equimolar substrates in pure water only yield 1H-abstract hydrothiolation product, while the yield could boosted to 28% after the addition of 2 wt % Brij L4 (Table 1, entry 2). Table 1 Optimization for olefin hydroxysulfenylation

Entry

1a/

Surfactant/Solvent

2a

Con c.

a

Yield (%) 3a

b

1:1

H2O

0.5M

Tra ce

91

c

1:1

2 wt % Brij L4/H2O

0.2M

28

52

c

3

2:1

2 wt % Brij L4/H2O

0.2M

56

30

4

2:1

2 wt%Brij L23/H2O

0.2M

55

7

5

2:1

0.2M

35

20

2

6

2:1

2 wt% C20/H2O

Brij

2 wt% O20/H2O

Brij

considering both yield and cost (SI, Table S2). Ionic surfactant system was not suitable for the comprising coupling. And it was revealed that both surfactant and substrates concentration were closely related to the yield (Table 1, entry 10-12). Satisfactory yield could be achieved with substrates concentration increase to maximum 0.2M. If substrates/surfactant ratio was too high, it would lead to a significant decrease of yield, giving more thioether product 4a (SI, Table S3). Further screening focused on the stoichiometric source of Oxygen (SI, Table S4). Adding of peroxide didn’t lead to any promotion to the yield, but speed up the consumption of thiophenol to form disulfide. Anaerobic conditions didn’t give any desired product (Table 1, entry 13). In reverse, there is a great increase of yield under oxygen atmosphere which decreases the production of byproduct 4a (Table 1, entry 11). Reaction temperature was also tested (SI, Table S5), minor difference o was shown when temperature varies from 20-45 C. More byproduct could be seen when the reaction was warmed to more o than 60 C, probably due to the poor stability of 3a. Following optimization, several substrates were treated with the developed micelle system to assess the generality and scope of this technology (Scheme 3). Thiophenols with various substituents such as 4-chloro, 3-methyl, 4-methyl, di-methyl, and 4-bromo (3j-3m, 3o) showed good tolerance based on isolated yields of the desired β-hydroxysulfides derivatives. Comparatively, electron-deficient thiophenol yield the product in less yields. For example, 4-fluoro-thiophenol reacted with ethene-1,1-diyldibenzene in the yield of 54% (3n), while 4-CF3 thiophenol failed to couple with styrene (SI-6,3t).

4a

c

1

OH

71

Cl

Cl

80

3

3d, RT, 4 h, 73%

8

2:1

2wt% Tergitol®/H2O

0.2M

78

4

S

0.2M

Tra ce

70

2 wt % Brij L4/H2O

0.3M

57

33

11

2:1

2 wt % Brij L4/H2O

0.2M

80

5

12

2:1

2 wt % Brij L4/H2O

0.1M

77

Tra ce

2 wt % Brij L4/H2O

O

0.2M

0

84

Experienced by our previous work, the presence of a surfactant may be crucial for the observed reactivity. Screening of surfactants using different surfactants identified Brij L4 (2 wt %) as the preferred amphiphile in water (Table 1, entry 3-9)

3f, RT, 4 h, 80%

3e, RT, 4 h, 82%

OH

OH

S

3g, RT, 6 h, 26%c

O

Cl

Cl

O 3i, .RT, 4 h, 5%(80% d)

3h, RT, 6 h, 57%

OH

OH

OH

S

S

S

3j, RT, 4 h, 65%

OH

OH S

S

S

Br

F

3m,RT, 4 h, 82%

3l, RT, 4 h, 83%

3k, RT, 4 h, 73%

OH

a

reaction conditions: 4-chlorothiophenol (0.25 mmol), ethene-1,1-diyldibenzene (0.125 or 0.25 mmol), O2 balloon, RT, 4 b c h; GC-MS yield with naphthalene as internal standard; und der air; under argon.

S N

S

Cl

2:1

2:1

Cl

OH

10

d

OH O

0.2M

13

OH S

2 wt% TPGS-750M/H2O

2 wt % SDS/H2O

3c, RT, 4 h, 59%

3b, RT, 4 h, 65%

S

2:1

2:1

Cl

Cl 3a, RT, 4 h, 76%

5

S

S

OH

0.2M

OH

OH

S

7

9

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3n, RT, 4 h, 64%

3o, RT, 4 h,70%

Scheme3. Substrates scope of hydroxysulfenylation in mia celle. Reaction conditions: 4-chlorothiophenol (0.25 mmol), b ethene-1,1-diyldibenzene (0.125 mmol), RT, 4 h, isolated yield； c d GC-Ms yield, the yield of 1H-abstract product.

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The coupling is also amenable to neutral and electrondonating group substituted styrenes (3c-3e), while styrene with electron-withdrawing substitutes is prior to thiol-Micheal addition instead of the radical coupling (3i). Interestingly, styrene connected with a hydrophilic group(3f) could yield the product in 80%, 15% more than that of styrene.Besides styrene, α,α-substituted olefin(3l-3o) and α,β-substituted olefin (3g, 3h) were also suited for the optimized conditions, but only giving moderate yield, probably due to the steric hindrance . Another feature unique to this water-based protocol is the opportunity to recycle the aqueous medium. Once the coupling is complete, in-flask extraction with minimum amounts of a single organic solvent (e.g., EtOAc) allows for isolation of the desired product, while the reaction medium remains. Repetition of the process affords similar results, tested for two additional cycles (Scheme 4). Thus, E-factor was calculated to be 15.6 without consideration of aqueous wastes. Reccling experiment OH Ph Ph

S

Run

1

Yield 76

Cl

3 77

kg waste

=

E-Factor

2 79

kg product value

based on

Another important consideration, equimolar experiment has also been investigated (Scheme 5). The fact that olefin and thiol are taken in equimolar ratio, the yields should be no more than 50%, as thiol acts as the reducing agent in the radical mechanism. The yield in our case is around 50%. Interest1 ingly, H NMR tracking revealed that partial surfactant Brij L4 was oxidized to give alkyl alcohol. Regularly, the nucleophile attack is difficult to disrupt C-O bond, but radical may. Actually, peroxide (TBHP) together with thiophenol react with Brij L4 in our later experiment could also get alky alcohol (SI, Scheme S6). Thus, adequate evidence has proven that this coupling undergoes a radical pathway, different from other “net” water systems. Evidence has also begun to occur suggesting that the micelle system may be in play, seemingly providing the react interface and atmosphere. The fact that oxygen amount dissolved in micelle is far more than that in water, almost even level in hexane (Figure 1) which may accelerate the auto-oxidation of thiophenol. And the distribution of olefins and thiophenols within micelles may vary as of their molecular polarity which avoids premature homo-coupling of radicals. Moreover, hydroxysulfenylation product formed may release from the micelle interface and inhibit self-redox, to some extent, which may account for the excellent selectivity.

15.6 35.0

total organic solvent aqueous waste included

Scheme4. Recycling experiment and E-Factor calculation. Insofar as gaining insight regarding the mechanism involved, detailed literature studies on oxygen-mediated hydroxysulfenylation have led to the conclusion that thiyl radicals are 29 initiated with oxygen. Under micelle conditions, the radical initiation was prohibited in the presence of TEMPO or BHT (Scheme 5). On the contrast, adding of photocatalyst and LED irritation could improve the formation speed of radical process (SI, Table S7). The usage of dithioether to replace thiophenol gives no product (Scheme 5). Likely, the triumph to use thioether also yields no product. Ph

a)

radical capture

4-ClPhSH + 1a

2a

OH Ph Ph

S

Ph O2, 2 wt% Brij L4/H 2O

Figure 1. DO experiment At last, a gram scale synthesis was taken using 3,5dimethylthiophenol and ethene-1,1-diyldibenzene in the yield of 67%, which offers a potential sustainable production method for both laboratory synthesis and industrial applications (Scheme 6).

3a

Cl

"radical capture"

Yield of 3a 0%

TEMPO BHT

+

Trace

2 wt.Brij L4/H 2O, O2 balloon

HO

S

20 oC, 4 h

SH

Cl Ph b)

Ir(ppy 3)Cl3, O2

S

4-ClPhSH + Ph Blue LEDs, 60 min 2a

1a

OH Ph + Ph 3a

Cl

Ph S

Ph

Cl

3a 0%

Ph

d) Cl

S + SH

O2

Ph

OH Ph Ph

S

2 wt % Brij L4/H 2 O

Cl

1a e)

2 wt % Brij L4/H 2 O

2a

Cl

Cl 3a 0%

SH +

O2

Ph Ph

Cl 1a (1 equiv)

S

2 wt % Brij L4/H 2 O

2a (1 equiv)

Cl

OH Ph Ph

3a, 52%

3p

Scheme 6. Large scale synthesis

75% (compared to 1a) OH Ph S Ph

O2

+

S

S

Cl

26%

c) Cl

0.79g 67%

S

CONCLUSION In summary, a robust micelle enhanced radical hydroxysulfenylation coupling is reported. The reaction has considerable generality, proceeds in moderate-to-excellent yields, and with high chemoselectivity. Preliminary mechanistic studies indicate the potential radical pathways and highlight micelle’s privilege. Moreover, the procedure is especially attractive from the environmental and sustainable perspective, as evidenced by both relative low E Factors, the opportunities for recycling of the entire aqueous reaction medium and large scale production potentiality.

Supporting Information

Scheme 5. control experiments.

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All experimental procedures, characterization, and NMR spectra were included. Supporting information is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] *E-mail: [email protected] Notes The authors declare no competing financial interests. ACKNOWLEDGMENT We warmly thank National Natural Science Foundation of China (21702232) for financial support of this work. REFERENCES (1) Egami, H.; Sodeoka, M. Trifluoromethylation of Alkenes with Concomitant Introduction of Additional Functional Groups. Angew. Chem., Int. Ed. 2014, 53(32), 8294-8308, DOI 10.1002/anie.201309260. (2) Chemler, S. R.; Bovino, M. T. Catalytic Aminohalogenation of Alkenes and Alkynes. ACS Catal. 2013, 3(6), 1076-1091, DOI 10.1021/cs400138b. (3) Muñiz, K.; Martínez, C. Development of Intramolecular Vicinal Diamination of Alkenes: From Palladium to Bromine Catalysis. J. Org. Chem. 2013, 78(6), 2168-2174, DOI 10.1021/jo302472w. (4) Huang, S.-X.; Ding, K.-L. Asymmetric Bromoamination of Chalcones with a Privileged N,N'-Dioxide/Scandium(III) Catalyst. Angew. Chem., Int. Ed. 2011, 50(34), 7734-7736, DOI 10.1002/anie.201101076. (5) Bataille, C.J. R.; Donohoe, T. J. Osmium-Free Direct synDihydroxylation of Alkenes. Chem. Soc. Rev. 2011, 40(1), 114-128, DOI 10.1039/B923880H. (6) Wang, F.; Yu, S.; Li, X. Transition metal-catalysed couplings between arenes and strained or reactive rings: combination of C-H activation and ring scission. Chem. Soc. Rev. 2016, 45(23), 6462-6477, DOI 10.1039/C6CS00371K. (7) Fang, G.; Bi, X. Silver-catalysed reactions of alkynes: recent advances. Chem. Soc. Rev., 2015, 44(22), 8124-8173, DOI 10.1039/ C5CS00027K. (8) Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Thiyl Radicals in Organic Synthesis. Chem. Rev. 2014, 114(5), 2587-2693, DOI 10.1021/cr400441m. (9) Yin, C.; Huo, F.; Zhang, J.; Martinez-Manez, R.;Yang, Y.; Lv, H.; Li, S. Thiol-addition reactions and their applications in thiol recognition. Chem. Soc. Rev. 2013, 42(14), 6032-6059, DOI 10.1039/C3CS60055F. (10) Xi, H.; Deng, B.; Zong, Z.; Lu, S.; Li, Z. Hydroxysulfenylation of Electron-Deficient Alkenes through an Aerobic Copper Catalysis. Org. Lett., 2015, 17 (5), 1180-1183, DOI 10.1021/acs.orglett.5b00112. (11) Mitsudome, T.; Takahashi, Y.; Mizugaki, T.; Jitsukawa, K.; Kaneda, K. Hydrogenation of Sulfoxides to Sulfides under Mild Conditions Using Ruthenium Nanoparticle Catalysts. Angew. Chem. Int. Ed., 2014, 53(32), 8348-8351, DOI 10.1002/anie.201403425. (12) Sahu, D.; Dey, S.; Pathak, T.; Ganguly, B. Regioselectivity of Vinyl Sulfone Based 1,3-Dipolar Cycloaddition Reactions with Sugar Azides by Computational and Experimental Studies. Org. Lett., 2014, 16(8), 2100-2103, DOI 10.1021/ol500461s. (13) Luly, J. R.; Yi, N.; Soderquist, J.; Stein, H.; Cohen, J.; Perun, T. J.; Plattner, J. J. New Inhibtors of Human Renin That Contain Novel LeuVal Replacements. J. Med. Chem. 1987, 30(9), 1609-1616, DOI 10.1021/jm00392a015. (14) Corey, E. J.; Clark, D. A.; Goto, G.; Marfat, A.; Mioskowski, C.; Samuelsson, B.; Hammarstrom, S. Stereospecific Total Synthesis of a "Slow Reacting Substance" of Anaphylaxis, Leukotriene C-1. J. Am. Chem. Soc. 1980, 102, 1436-1439, DOI 10.1021/ja00524a045. (15) Kharasch, M. S.; Nudenberg, W.; Mantell, G. J. Reactions of Atoms and Free Radicals in Solution. J. Org. Chem. 1951, 16, 524-527, DOI 10.1021/jo01144a005.

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Micelle interface enables the auto-oxidative radical hydroxysulfenylation of olefins: high atom-economy, facile, selective and recyclable.

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