TBHP-mediated oxidative cross-coupling of disulfides with ethers through a C(sp3)-H thiolation process

Article abstract of DOI:10.1080/00397911.2014.888081

A new tert-butyl hydroperoxide (TBHP)-mediated oxidative cross-coupling of disulfides with ethers is presented for the synthesis of etherified sulfides. This method is achieved by a C(sp³)-H thiolation strategy under metal-free conditions and provides a simple route to constructing the C-S bonds. Copyright

Full text of DOI:10.1080/00397911.2014.888081

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TBHP-Mediated Oxidative Cross-Coupling
of Disulfides with Ethers through a
C(sp3)-H Thiolation Process
Ya-Ping Hu a & Ri-Yuan Tang b
a Food Science and Technology College , Hunan Agricultural
University , Changsha , China
b College of Chemistry and Materials Engineering , Wenzhou
University , Wenzhou , China
Accepted author version posted online: 03 Apr 2014.Published
online: 09 Jun 2014.
To cite this article: Ya-Ping Hu & Ri-Yuan Tang (2014) TBHP-Mediated Oxidative Cross-Coupling
of Disulfides with Ethers through a C(sp3)-H Thiolation Process, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:14, 2045-2050,
DOI: 10.1080/00397911.2014.888081
To link to this article: http://dx.doi.org/10.1080/00397911.2014.888081
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Synthetic Communications1, 44: 2045–2050, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.888081
TBHP-MEDIATED OXIDATIVE CROSS-COUPLING OF
DISULFIDES WITH ETHERS THROUGH A C(sp3)-H
THIOLATION PROCESS
Ya-Ping Hu1 and Ri-Yuan Tang2
1Food Science and Technology College, Hunan Agricultural University,
Changsha, China
2College of Chemistry and Materials Engineering, Wenzhou University,
Wenzhou, China
GRAPHICAL ABSTRACT
Abstract A new tert-butyl hydroperoxide (TBHP)–mediated oxidative cross-coupling of
disulfides with ethers is presented for the synthesis of etherified sulfides. This method
is achieved by a C(sp3)-H thiolation strategy under metal-free conditions and provides
a simple route to constructing the C-S bonds.
Keywords Cross-coupling reaction; 1,2-disulfides; ethers; oxidation; TBHP
INTRODUCTION
The oxidative cross-coupling reaction comprising a C-H functionalization
process has emerged as one of the most important methodologies for various
chemical bond constructions in organic synthesis; moreover, this reaction remains
an active area of research because it is environmental benign, sustainable, and highly
atom-economical because it avoids the use of halides, pseudohalides, and=or organo-
metallic reagents.[1] Despite impressive progress in the field, examples on the
construction of the C-S bond using the oxidative cross-coupling strategy are quite
rare.[2,3] Recently, the group of Tang et al. established the tert-butyl hydroperoxide
(TBHP)–mediated oxidative thiolation of a sp3 C-H bond adjacent to a nitrogen
Received December 25, 2013.
Address correspondence to Ya-Ping Hu, Food Science and Technology College, Hunan
Agricultural University, Changsha, China. E-mail: huyaping@hunau.net
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
2045

2046
Y.-P. HU AND R.-Y. TANG
Scheme 1. Oxidative cross-coupling with disulfides.
atom to construct the C-S bond without the aid of metals (Scheme 1a).[2a] Herein, we
report that this oxidative cross-coupling strategy could be expanded to a sp3 C-H
bond adjacent to an oxygen atom (ethers).[4] In the presence of TBHP and molecular
sieve, a variety of disulfides reacted with ethers and resulted in the new C-S bond
formation in moderate to good yield (Scheme 1b). Notably, etherified sulfides are
important units found in organic materials, bioactive molecules, and pharmaceuti-
cals and widely serve as valuable intermediates in synthetic chemistry.[5–7]
RESULTS AND DISCUSSION
As shown in Table 1, the reaction between 1,2-diphenyldisulfane (1a) and tetra-
hydrofuran (THF, 2a) was chosen as the model to optimize the reaction conditions.
Disulfide 1a was initially treated with THF 2a and TBHP, and the target product 3aa
was isolated in 21% yield (entry 1). To our delight, the presence of molecular sieve
Table 1. Screening optimal conditionsa
Entry
[O] (equiv)
Additive (mg)
—
T (ꢀC)
Isolated yield (%)
1b
2
TBHP (2)
TBHP (2)
TBHP (4)
TBHP (2)
TBHP (2)
DTBP (2)
DDQ
120
120
120
80
21
91
˚
4 A MS (100)
˚
3
4 A MS (100)
90
35
˚
4
4 A MS (100)
˚
5
4 A MS (100)
130
120
120
120
120
89
78
˚
6
4 A MS (100)
4 A MS (100)
7c
8d
9e
Trace
85
90
˚
˚
TBHP (2)
TBHP (2)
4 A MS (100)
˚
4 A MS (100)
aReaction conditions: 1a (0.3 mmol), 2a (2 mL), [O], and additive for 12 h. TBHP is hydrous (70% in
water solution).
b68% of 1a was recovered.
c>90% of 1a was recovered.
d2a (20 equiv) in nBuOAc (2 mL).
e1a (3 mmol, 0.654 g) for 48 h.

OXIDATIVE CROSS-COUPLING OF DISULFIDES WITH ETHERS
2047
Table 2. Thiolation of disulfides (1) with ethers (2)a
Entry
1
Disulfide 1
Ether 2
Product=isolated yield (%)
2a
R1 ¼ Me (1b)
R1 ¼ Cl (1c)
R1 ¼ Br (1d)
2a
2a
2a
R1 ¼ Me (3ba)=65
R1 ¼ Me (3ca)=87
R1 ¼ Me (3da)=75
2
3
4
2a
5
2a
6
2a
2b
7b
8
9
2b
2c
10
2d
a
˚
Reaction conditions: 1 (0.3 mmol), 2 (2 mL), TBHP (2.0 equiv; 70% in water solution), and 4 A MS
(100) at 120 ꢀC for 12 h.
bFor 48 h.
cThe ratio given in parentheses was determined by 1H NMR analysis.

2048
Y.-P. HU AND R.-Y. TANG
could favor the oxidative cross-coupling reaction.[2a] The yield of product 3aa was
sharply enhanced to 91% when 100 mg molecular sieve was added (entry 2). Identical
results were observed at 4 equiv TBHP and 100 mg molecular sieve (entry 3). Subse-
quently, the effect of the reaction temperatures was examined, and the results
demonstrated that the reaction at 120 ꢀC gave the best yield (entries 2, 4, and 5).
Two other oxidants, di-tert-butyl peroxide (DTBP) and 2,3-dichloro-5,6-dicyano-1,
4-benzoquinone (DDQ), were also tested (entries 6 and 7). Screening revealed that
DTBP was viable to mediate the reaction, albeit reducing the yield (entry 6). How-
ever, DDQ was ineffective for the reaction (entry 7). We were pleased to find that
n
good yield was still achieved when the reaction was carried out in BuOAc (entry
8). It is noteworthy that 3-mmol scale of substrate 1a is successfully performed,
providing the desired product 3aa in 90% yield (entry 9).
With the optimal conditions in hand, we next decided to explore the scope of the
oxidative cross-coupling reaction (Table 2). In the presence of TBHP and molecular
sieve, THF 1a was successfully reacted with various disulfides 1b–1g in moderate to
excellent yields (entries 1–6). Gratifyingly, a number of functional groups, including
Me, Cl, Br, and CO2Me groups, on the aryl ring of disulfides were tolerated well
(entries 1–4). 1,2-Di(p-tolyl)disulfane (1b), for instance, was reacted with THF 2a,
TBHP, and molecular sieve smoothly, providing the target product 3ba in 65% yield
(entry 2). Importantly, halo groups, including Cl and Br groups, were also consistent
with the optimal conditions, thereby facilitating possible additional modifications at
the halogenated positions (entries 2 and 3). It was noted that this oxidative cross-
coupling reaction method could be applied to synthesize new fipronil analog 3fa in
good yields (entry 5).[14] This successful S-S bond cleavage of pyrazole disulfide
followed by the sp3 C-S bond formation would be significant for pesticide and drug
design.[15] To test indoor pesticidal activities, compound 3fa was subsequently dis-
solved in dimethylformamide (DMF), followed by dilution with 0.1% (v=v) tween-80
distilled water. We were happy to find that this solution displayed highly pesticidal
activities (Scheme 2). Notably, aliphatic disulfide, dibenzyldisulfide 1 g, was also
a suitable substrate, furnishing product 3ga in moderate yield after prolonging the
reaction time (entry 6).
To our delight, the optimal conditions were compatible with other ethers, such
as 1,4-dioxane (2b), 1,2-dimethoxyethane (2c), and 2-methoxy-2-methylpropane (2d)
(entries 7–10). The reactions of 1,4-dioxane 2b with diphenyldisulfide (1a) or 1,2-
bis(2-methylfuran-3-yl)disulfane (1h) were efficiently conducted, giving the corre-
sponding products 3ba and 3hb in 63% and 56% yields, respectively (entries 7 and
8). Using 1,2-dimethoxyethane (2c), a mixture of products 3ac and 3ac0 in 50% total
Scheme 2. Indoor pesticidal activity test of product 3ha.

OXIDATIVE CROSS-COUPLING OF DISULFIDES WITH ETHERS
2049
yield with 1:1 ratio (entry 9). Interestingly, bulky 2-methoxy-2-methylpropane (2d)
was also viable for the reaction with THF (1a) and TBHP, leading to the desired
product 3ad isolated in moderate yield (entry 10).
CONCLUSION
In summary, we have illustrated a new oxidative cross-coupling of disulfides
with ethers to form the C(sp3)-S bond through a C(sp3)-H thiolation strategy.
In the presence of TBHP and a molecular sieve, a variety of disulfides, including
aromatic and aliphatic disulfides, were treated with ethers to afford the corresponding
etherified sulfides in moderate to good yields. Notably, this method is simple and
general with a wide range of disulfide compatibility, which provides a new route
to the construction of the C-S bonds.
EXPERIMENTAL
NMR spectroscopy was performed on a Bruker advanced spectrometer
operating at 500 MHz (1H NMR) and 125 MHz (13C NMR). Mass spectrometric
analysis was performed on GC-MS (Shimadzu GCMS-QP2010) and ESI-Q-TOF
(Bruker MicroQTOF-II) instruments.
Typical Experimental Procedure for TBHP-Mediated Oxidative
Cross-Coupling of Disulfides with Ethers
To a Schlenk tube were added disulfide 1 (0.2 mmol), TBHP (2 equiv), 4-A
molecular sieve (100 mg), and ether 2 (2 mL). Then the tube was charged with argon
and stirred at 120 ꢀC (oil bath temperature) for the indicated time until complete
consumption of starting material as monitored by thin-layer chromatography
(TLC) and GC-MS analysis. After the reaction was finished, the reaction mixture
was cooled to room temperature, diluted in ethyl acetate (5 mL), and washed with
brine (3 ꢁ 1 mL). The aqueous phase was extracted with ethyl acetate (3 ꢁ 2 mL).
The combined organic extracts were dried over Na2SO4 and concentrated in
vacuo, and the resulting residue was purified by silica-gel column chromatography
(hexane=ethyl acetate ¼ 20:1) to afford product 3.
2-(Phenylthio)tetrahydrofuran (3aa)[8]
Light yellow oil; 1H NMR (500 MHz, CDCl3) d: 7.43 (d, J¼ 8.0 Hz, 2H),
7.15–7.24 (m, 3H), 5.57 (m, 1H), 3.93–3.98 (m, 1H), 3.87–3.91 (m, 1H), 2.28–2.32
(m, 1H), 1.87–1.97 (m, 2H), 1.79–1.83 (m, 1H); 13C NMR (125 MHz, CDCl3) d:
135.7, 131.1, 128.8, 126.8, 87.1, 67.3, 32.6, 24.8; IR (KBr, cmꢂ1): 2971, 2923, 2869,
1476, 1434, 1040, 1018, 902, 736, 688; LRMS (EI, 70 eV) m=z (%): 180 (Mþ, 5), 71 (100).
FUNDING
We thank the Natural Science Foundation of China (No. 21202121) for
financial support.

2050
Y.-P. HU AND R.-Y. TANG
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
REFERENCES
1. (a) Tobisu, M.; Chatani, N. Angew. Chem. Int. Ed. 2006, 45, 1683; (b) Murahashi, S.-I.;
Zhang, D. Chem. Soc. Rev. 2008, 37, 1490; (c) Li, C.-J. Acc. Chem. Res. 2009, 42, 335;
(d) Mcglacken, G. P.; Bateman, L. M.; Bateman, L. Chem. Soc. Rev. 2009, 38, 2447;
(e) Shabashov, D. Acc. Chem. Res. 2009, 42, 1074; (f) Ashenhurst, J. A. Chem. Soc. Rev.
2010, 39, 540; (g) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40,
5068; (h) Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170; (i) Liu, C.; Zhang, H.; Shi,
W.; Lei, A. Chem. Rev. 2011, 111, 1780; (j) Xie, Y.-X.; Song, R.-J.; Xiang, J.-N.; Li,
J.-H. Chin. J. Org. Chem. 2012, 32, 1555; (k) Yeung, C. S.; Dong, V. M. Chem. Rev.
2011, 111, 1215; (l) Klussmann, M.; Sureshkumar, D. Synthesis 2011, 353.
2. Tang, R.-Y.; Xie, Y.-X.; Xie, Y.-L.; Xiang, J.-N.; Li, J.-H. Chem. Commun. 2011, 47, 12867.
3. For papers on the formation of the C(sp2)-S bonds through the aromatic C-H functionaliza-
tion, see (a) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128,
6790; (b) Inamoto, K.; Arai, Y.; Hiroya, K.; Doi, T. Chem. Commun. 2008, 5529;
(c) Inamoto, K.; Hasegawa, C.; Hiroya, K.; Doi, T. Org. Lett. 2008, 10, 5147; (d) Joyce,
L. L.; Batey, R. A. Org. Lett. 2009, 11, 2792; (e) Zhao, X.; Dimitrijevic, E.; Dong, V. M.
J. Am. Chem. Soc. 2009, 131, 3466; (f) Fukuzawa, S.-I.; Shimizu, E.; Atsuumi, Y.; Haga,
M.; Ogata, K. Tetrahedron Lett. 2009, 50, 2374; (g) Fang, X.-L.; Tang, R.-Y.; Zhong, P.;
Li, J.-H. Synthesis 2009, 4183; (h) Chu, L.; Yue, X.; Qing, F.-L. Org. Lett. 2010, 12,
1644; (i) Zhang, S.-H.; Qian, P.-C.; Zhang, M.-L.; Hu, M.-L.; Cheng, J. J. Org. Chem.
2010, 75, 6732; (j) Sang, P.; Chen, Z.; Zou, J.; Zhang, Y. Green Chem. 2013, 15, 2096.
4. For papers on the oxidative cross coupling with ethers, see (a) Zhang, Y.; Li, C.-J. Angew. Chem.
Int. Ed. 2006, 45, 1949; (b) Pastine, S. J.; McQuaid, K. M.; Sames, D. J. Am. Chem. Soc. 2005,
127, 12180; (c) Zhang, Y.; Li, C.-J. J. Am. Chem. Soc. 2006, 128, 4242; (d) Li, Z.; Yu, R.; Li, H.
Angew. Chem. Int, Ed. 2008, 47, 7497; (e) Cao, K.; Jiang, Y.-J.; Zhang, S.-Y.; Fan, C.-A.;
Tu, Y.-Q.; Pan, Y.-J. Tetrahedron Lett. 2008, 49, 4652; (f) Cheng, K.; Huang, L.-H.; Zhang,
Y.-H. Org. Lett. 2009, 11, 2908; (g) Suematsu, H.; Katsuki, T. J. Am. Chem. Soc. 2009, 131,
14218; (h) Kim, J. Y.; Park, J. C.; Song, H.; Park, K. H. Bull. Korean Chem. Soc. 2010, 31,
3509; (i) Sun, H.; Zhang, Y.; Guo, F.; Zha, Z.; Wang, Z. J. Org. Chem. 2012, 77, 3563; (j) Chen,
L.; Shi, E.; Liu, Z.; Chen, S.; Wei, W.; Li, H.; Xu, K.; Wan, X. Chem. Eur. J. 2011, 17, 4085; (k)
Wei, W.-T.; Zhou, M.-B.; Fan, J.-H.; Liu, Song, W.; R.-J.; Liu, Y.; Hu, M.; Xie, P.; Li, J.-H.
Angew. Chem. Int. Ed. 2013, 52, 3638; (l) Liu, D.; Liu, C.; Li, H.; Lei, A. Angew. Chem. Int,
Ed. 2013, 52, 4453; (m) Guo, S.-L.; Yuan, Y.-Q; Xiang, J.-N. Org. Lett. 2013, 15, 4654.
5. (a) Konaklieva, M. I.; Plotkin, B. J. Recent Pat. Anti-Infect. Drug Discovery 2006, 1, 177;
(b) Legros, J.; Dehli, J. R.; Bolm, C. Adv. Synth. Catal. 2005, 347, 19; (c) Kumagai, H.
Aroma Res. 2004, 5, 312; (d) Mitchell, S. C.; Nickson, R. M.; Waring, R. H. Sulfur Rep.
1993, 13, 279.
6. (a) Sammelson, R. E.; Caboni, P.; Durkin, K. A.; Casida, J. E. Bioorg. Med. Chem. 2004,
12, 3345; (b) Ozoe, Y.; Yagi, K.; Nakamura, M.; Akamatsu, M.; Miyake, T.; Matsumura,
F. Pestic. Biochem. Physiol. 2000, 66, 92.
7. (a) Lange, J. H. M.; vander Neut, M. A. W.; Borst, A. J. M.; Yildirim, M.; van
Stuivenberg, H. H.; van Vliet, B. J.; Kruse, C. G. Bioorg. Med. Chem. Lett. 2010, 20,
2770; (b) Bertenshaw, S. R.; Talley, J. J.; Rogier, D. J.; Graneto, M. J.; Koboldt, C. M.;
Zhang, Y. Bioorg. Med. Chem. Lett. 1996, 6, 2827; (c) Cole, L. M.; Nicholson, R. A.;
Casida, J. E. Pestic. Biochem. Physiol. 1993, 46, 47.
8. Ranu, B. C.; Mandal, T. Tetrahedron Lett. 2006, 47, 6911.