Copper-mediated stereospecific C-H oxidative sulfenylation of terminal alkenes with disulfides

Article abstract of DOI:10.1039/c5cc06250k

A copper and iodine-mediated C-H oxidative sulfenylation of olefins with diaryl disulfides has been developed for the stereospecific synthesis of vinyl thioether. With the combination of Cu(OTf)₂ and I₂, a variety of terminal alkenes

Full text of DOI:10.1039/c5cc06250k

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: H. Tu, B. Hu, C.
Deng and X. Zhang, Chem. Commun., 2015, DOI: 10.1039/C5CC06250K.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/chemcomm

View Article Online
DOI: 10.1039/C5CC06250K
ChemComm
Page 1 ofC4 hemComm
Dynamic Article Links ►
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
COMMUNICATION
Copper-Mediated Stereospecific C-H Oxidative Sulfenylation of
Terminal Alkenes with Disulfides
Hai-Yong Tu, Bo-Lun Hu, Chen-Liang Deng and Xing-Guo Zhang*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A copper and iodine-mediated C-H oxidative sulfenylation of
olefins with diaryl disulfides has been developed for the
stereospecific synthesis of vinyl thioether. With the
The reaction between styrene 1a and 1,2-diphenyldisulfane 2a
was selected as a model reaction to optimize the reaction
conditions, and the results were summarized in Table 1. We
combination of Cu(OTf)2 and I2, a variety of terminal alkenes 40 initially carried out the reaction of styrene 1a with disulfide 2a
10 underwent the oxidative coupling reaction with various diaryl
disulfides successfully to afford the corresponding E-vinyl
sulfides in moderate to good yields.
and 1 equiv of I2 in DMSO at 120 °C for 6h, the target product 3
was isolated in 12% yields (entry 1). Subsequently, a variety of
copper catalysts were examined with the aim to enhance the
reaction yield. The results disclosed that both copperic and
Vinyl sulfides are essential structural motifs which can be
found in many biologically active molecules and natural
15 products,1 and also are versatile building blocks or intermediates
in organic synthesis,2 such as enol substitutes,3 Michael
acceptors4 and olifen metathesis.5 Consequently, the preparation
of vinyl sulfides has received much attention, and two common
methods are frequently utilized for their synthesis, including
20 transition-metal-catalyzed cross-coupling of vinyl halides with
45 Table 1. Screening conditions a
Entry
1
[I] source
Catalyst
-
Base
Solvent Yield (%)
6
thiol and hydrothiolation of alkynes.7 Traditionally, the vinylic
I2
I2
-
-
-
-
-
-
-
-
-
-
-
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
12
38
61
46
60
64
76
52
11
0
C-H bond sulfenylation could also be realized through
deprotonation by organolithium reagent followed by quenching
with disulfides (eq 1, Scheme 1).8 The tandem
25 addition/elimination reactions of PhSCl with olefins in the
presence of strong base also afford olefinic C-H thiolated
products (eq 2).9 Recently, Deng and co-worker developed a
silver-mediated vinylic C-H bond sulfenylation of enamides with
disulfides.10 However, the utility and applicability of the above
30 reactions was limited by prefunctionalization of starting materials
or/and the harsh reaction conditions. Herein, we report a
convenient and practical method for the stereospecific synthesis
of E-vinyl sulfides by copper-catalyzed, iodine-mediated C-H
bond sulfenylation of terminal olefins with aryl disulfides (eq 3).
2
CuI
I2
3
CuBr
I2
4
CuCl
I2
5
Cu(OAc)2
Cu(TFA)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
I2
6
I2
7
NIS
TBAI
8
9
Cu(OTf)2 PhI(OAc)2
10
11
12
13
14
15
16
17
18b
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
-
0
I2
I2
I2
I2
I2
I2
I2
t-BuOK DMSO
Trace
16
22
27
18
0
35 Scheme 1. Intermolecular vinylic C-H sulfenylation.
K2CO3
DMSO
DMSO
DMF
NEt3
-
-
-
-
DMAc
NMP
DMSO
42
a
Reaction conditions: 1 (0.5 mmol), 2 (0.25 mmol), Cu(OTf)2 (10
mol %), I2 (0.5 mmol) in DMSO (2 mL) under air atmosphere at 120 °C
for 6 h, isolated yield. b At 100 °C .
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

View Article Online
DOI: 10.1039/C5CC06250K
ChemComm
Page 2 of 4
55 Table 2. Copper-Mediated C-H Oxidative Sulfenylation of
copperous salts could promote the oxidative coupling reaction to
provide product in 38-76% yields (entries 2-7). Treatment of
substrate 1a with 2a, elemental iodine and 10 mol % of Cu(OTf)2
in DMSO at 120 °C afforded the desired product 3 in 76% yield
(entry 7). These results prompted us to investigate various iodine
sources, such as NIS, TBAI and PhI(OAc)2. Lower yields were
found for NIS and TBAI, but PhI(OAc)2 was ineffective for this
reaction (entries 8-10). It is noteworthy that reaction did not
proceed completely in the absence of I2 (entry 11), which
Terminal Alkenes with Disulfides a
5
10 suggested that elemental iodine played a key role in the
sulfenylation. Considering that base could facilitate some
elimination reactions, we tested some bases including t-BuOK,
K2CO3 and NEt3. However, all bases disfavoured the
transformation and low yields were obtained (entries 12-14).
15 Some polar solvents were also tested, including DMF, DMAc and
NMP, but all were less effective than DMSO (entries 15-17).
Further investigation revealed that the reaction yield was reduced
sharply to 42% when the reaction was performed at 100 °C (entry
18).
20 Under these optimized conditions, the substrate scopes of
olefins and diaryl disulfides for this vinylic C-H bond
sulfenylation were explored, and the results were shown in Table
2. Firstly, the reaction between styrene 1a and a number of diaryl
disulfides were investigated under the standard conditions. The
25 results disclosed that all ortho-substituted, meta-substituted and
para-substituted disulfide were suitable substrates and afforded
the corresponding products in moderate to good yields. For
example, ortho-tolyl disulfide provided the product 4 in 67%
yield, meta- and para-tolyl disulfides gave the products 5 and 6 in
30 61% and 63% yields, respectively. mono-Fluorinated and
chlorinated diphenyl disulfides afforded the products 7-10 in 61%
- 80% yields. 3.5-Dichlorophenyl disulfide afforded the product
11 in 54% yield. It should be mentioned that electron-deficient 4-
nitrophenyl disulfide provided the product 12 in 67% yield.
35 Subsequently, we investigated the substrate scope of olefins by
a
Reaction conditions: 1 (0.5 mmol), 2 (0.25 mmol), Cu(OTf)2 (10
mol %), I2 (0.5 mmol) in DMSO (2 mL) under air atmosphere at 120 °C
for 6 h, isolated yield. b At 2 mmol sacles. c For 10 h
These results demonstrated that the sulfenylation did not undergo
a coupling reaction of vinyl iodide with disulfide. Subsequently,
we carried out the reaction of 1-octene with disulfide 2a, 10 mol %
examining their reaction with diphenyl disulfide 2a under the 60 Cu(OTf)2, 1 equiv I2 in DMSO. However, the expected vinylic C-
optimal conditions. As expected, ortho-, meta- and para-
substituted styrenes produced vinyl sulfides 13, 14 and 15 in
good yields (76%, 63% and 82%). A 73% yield was obtained for
40 4-tert-butylstyrene. Moderate yields were observed when 2-
H thiolation product could not be obtained, instead, allyl C-H
sulfenylated product 26 was isolated exclusively in 40% yield (eq
2). This finding implied that allyl radical are probably key
intermediate during the sulfenylation of aliphatic olefins.11 Then,
chloro, 3-chloro and 4-chloro styrenes were used as substrates 65 the reaction of styrene 1a with 2a, Cu(OTf)2, I2 in DMSO was
(46%-71%, 17-19). Styrene with an acetamido group was also
transformed to the target product 20 in 79% yield. 2-
Vinylnaphthalene provided the corresponding product 21 in 86%
45 yield. During the investigation of gem-disubstituted ethylenes, a
65% yield was found for ethene-1,1-diyldibenzene, while prop-1-
en-2-ylbenzene gave the product 23 in a 34% yield. Most notably,
a natural product, β-pinene also underwent the C-H sulfenylation
successfully to produce the desired product 24 in 56% yield.
performed under the standard conditions by adding 2.5 equiv of
2,2,6,6-tetramethylpiperidine oxide (TEMPO), a radical
Scheme 2. Control experiments.
50 To probe the mechanism of this C-H oxidative sulfenylation,
some control experiments were conducted as shown in Scheme 2.
Styrene 1a was treated with Cu(OTf)2 and 1 equiv of I2 in DMSO
in the absence of disulfide under the standard conditions, but the
iodized product 25 could not be observed (eq 1, Scheme 2).
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

View Article Online
DOI: 10.1039/C5CC06250K
Page 3 of 4
ChemComm
scavenger (eq 3). As expected, the reaction did not proceed and
In summary,
a
convenient and efficient method for
the product 3 could not be detected. These results indicated that
the C-H oxidative sulfenylation might be involved a free radical
process.
35 stereospecific synthesis of E-vinyl sulfides has been developed by
copper-mediated vinylic C-H oxidative sulfenylation. A variety
of terminal alkenes underwent the oxidative coupling reaction
with various disulfides successfully to afford the corresponding
vinyl sulfides in moderate to good yields. This atom-economic
40 transformation was realized by incorporation of both sulfur atoms
of aryl sulfides onto olefins. The utilization of alkenes without
prefunctionalization and commercially available disulfides as
coupling partners are significant advantages for the usefulness of
this C-H oxidative coupling reaction. The present reaction has
45 broad substrate scope of alkenes and sulfides with excellent
functional group tolerance, which provides a new valuable one-
pot shortcut for stereospecific preparation of vinyl sulfides.
5
Scheme 3. Possible mechanism.
Acknowledgements
50
We thank the National Natural Science Foundation of China (No.
21272177) for financial support.
Notes and references
55
On the basis of the present results and former reported results,12
a plausible mechanism was outlined in Scheme 3. Vinyl iodide
could not be detected in the presence of disulfide and the reaction
College of Chemistry and Materials Engineering, Wenzhou University,
Wenzhou 325035, China. E-mail:zxg@wzu.edu.cn.
Electronic supplementary information (ESI) available: Detailed
synthetic procedures and characterization of new compounds. See DOI:
60 10.1039/c000000x.
†
10 did not proceed in the presence of TEMPO (Scheme 2). These
results suggest that the reaction may proceed through a free
radical pathway. Firstly, aryl disulfide might decompose at high
temperature to form free radical RS·, 13 which reacts with iodine
to produce the RSI and iodine radical (eq 1, Scheme 3).14 The
15 chain propagation of iodine radical with aryl disulfide affords
active RSI and radical RS· (eq 2). The addition of radical RS· to
alkene 1 produces an alkyl radical A. The following oxidation by
I2 and Cu(OTf)2 produces the corresponding carbocation, which
loses a H+ to yield desired product 3-24 (Path 1). Alternatively
20 pathway is also possible (Path 2). The electrophilic addition of
RSI to the double bond of alkene 1 with aid of Cu(OTf)2 affords
unstable three-numbered cyclic sulfonium B, which can be
transformed easily to carbocation C. Finally, the deprotonation of
intermediate C gives the desired product 3-24.
1
(a) J. S. Lazo, K. Nemoto, K. E. Pestell, K. Cooley, E. C. Southwick,
D. A. Mitchell, W. Furey, R. Gussio, D. W. Zaharevitz, B. Joo, P.
Wipf, Mol. Pharmacol., 2002, 61, 720. (b) A. Lavecchia, S.
Cosconati, V. Limongelli, E. Novellino, ChemMedChem, 2006, 1,
540. (c) S. Pasquini, C. Mugnaini, C. Tintori, M. Botta, A. Trejos, R.
K. Arvela, M. Larhed, M. Witvrouw, M. Michiels, F. Christ, Z.
Debyser, F. Corelli, J. Med. Chem., 2008, 51, 5125. (d) H. S. Sader,
D. M. Johnson, R. N. Jones, Antimicrob. Agents Chemother., 2004,
48, 53. (e) P. Johannesson, G. Lindeberg, A. Johanson, G. V.
Nikiforovich, A. Gogoll, B. Synnergren, M. Le Greves, F. Nyberg, A.
Karlen, A. Hallberg, J. Med. Chem., 2002, 45, 1767. (f) M. Ceruti, G.
Balliano, F. Rocco, P. Milla, S. Arpicco, L. Cattel, F. Viola, Lipids,
2001, 36, 629. (g) E. Marcantoni, M. Massaccesi, M. Petrini, G.
Bartoli, M. C. Bellucci, M. Bosco, L. Sambri, J. Org. Chem., 2000,
65, 4553. (h) C. A. Dvorak, W. D. Schmitz, D. J. Poon, D. C. Pryde,
J. P. Lawson, R. A. Amos, A. I. Meyers, Angew. Chem., Int. Ed.,
2000, 39, 1664..
65
70
75
80
85
25 Vinyl sulfone derivatives show a wide range of useful
biological and pharmacological activities.15 To demonstrate the
applicability of this reaction in the synthesis of these types of
molecules, the further transformations of vinyl sulfides was
explored as outlined in Scheme 4. Treatment of product 3 with
30 30 % H2O2 in AcOH at room temperature afforded E-vinyl
sulfone 27 in 72% yield. 16
2
(a) E. Schaumann, Top. Curr. Chem., 2007, 274, 1. (b) A. Sabarre, J.
A. Love, Org. Lett., 2008, 10, 3941. (c) M. Bratz, W. H. Bullock, L.
E. Overman, T. Takemoto, J. Am. Chem. Soc., 1995, 117, 5958. (d)
W. H. Pearson, I. Y. Lee, Y. Mi, P. Stoy, J. Org. Chem., 2004, 69,
9109. (e) T. Mukaiyama, K. Kamio, S. Kobayashi, H. Takei, Bull.
Chem. Soc. Jpn., 1972, 4, 193. (f) R. A. McClelland, Can. J. Chem.,
1977, 55, 548. (g) E. Wenkert, T. W. Ferreira, E. L. Michelotti, J.
Chem. Soc., Chem. Commun., 1979, 637. (h) C. G. Bates, P.
Saejueng, M. Q. Doherty, D. Venkataraman, Org. Lett., 2004, 6,
5005.
Scheme 4. Synthetic applications of 3.
3
B. M. Trost, A. C. Lavoie, J. Am. Chem. Soc., 1983, 105, 5075.
90 4 (a) R. D. Miller, R. Hassig, Tetrahedron Lett., 1985, 26, 2395. (b) H.
Mizuno, K. Domon, K. Masuya, K. Tanino, I. Kuwajima, J. Org.
Chem., 1999, 64, 2648.
5
(a) Z. Liu, J. D. Rainier, Org. Lett., 2005, 7, 131. (b) M. L.
Macnaughtan, J. B. Gary, D. L. Gerlach, M. J. A. Johnson, J. W.
Kampf, Organometallics, 2009, 28, 2880..
95
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

View Article Online
DOI: 10.1039/C5CC06250K
ChemComm
Page 4 of 4
6
For recently selected examples on the cross-coupling reactions of
thiols and aryl/vinyl halides, see: (a) Y.-Y. Lin, Y.-J. Wang, C.-H.
Lin, J.-H. Cheng, C.-F. Lee, J. Org. Chem., 2012, 77, 6100. (b) Q.
Liao, C. Xi, Chin. J. Org. Chem., 2012, 32, 986. (c) H.-L. Kao, C.-F.
Lee, Org. Lett., 2011, 13, 5204. (d) W. You, X. Yan, Q. Liao, C. Xi,
Org. Lett., 2010, 12, 3930. (e) M. S. Kabir, M. Lorenz, M. L. Van
Linn, O. A. Namjoshi, S. Ara, J. M. Cook, J. Org. Chem., 2010, 75,
3626. (f) C.-K. Chen, Y.-W. Chen, C.-H. Lin, H.-P. Lin, C.-F. Lee,
Chem. Commun., 2010, 46, 282. (g) E. Sperotto, G. P. M. van Klink,
J. G. de Vries, G. van Koten, J. Org. Chem., 2008, 73, 5625. (h) A.
Correa, M. Carril, C. Bolm, Angew. Chem., 2008, 120, 2922. Angew.
Chem., Int. Ed., 2008, 47, 2880. (i) Y. Zhang, K. C. Ngeow, J. Y.
Ying, Org. Lett., 2007, 9, 3495. (j) Y. Zheng,; X. Du,; W. Bao,
Tetrahedron Lett., 2006, 47, 1217.
5
10
15 7 For recently selected examples on the hydrothiolation of alkynes, see:
(a) K. Liu, F. Jia, H. Xi, Y. Li, X. Zheng, Q. Guo, B. Shen and Z. Li,
Org. Lett., 2013, 15, 2026. (b) A. D. Giuseppe, R. Castarlenas, J. J.
Pérez-Torrente, M. Crucianelli, V. Polo, R. Sancho, F. J. Lahoz and
L. A. Oro, J. Am. Chem. Soc., 2012, 134, 8171. (c) S. Ranjit, Z.
20
25
30
Duan, P. Zhang and X. Liu, Org. Lett., 2010, 12, 4134. (d) C. J.
Weiss and T. J. Marks, J. Am. Chem. Soc., 2010, 132, 10533. (e) L.
-Torrente, L. A. Oro, ACS Catal., 2013, 3, 2910. (f) S. N.
Riduan, J. Y. Ying, Y. Zhang, Org. Lett., 2012, 14, 1780. (g) Y. Liao,
S. Chen, P. Jiang, H. Qi, G.-J. Deng, Eur. J. Org. Chem., 2013, 6878.
(h) Y. Yang, R. M. Rioux, Chem. Commun., 2011, 47, 6557. (i) R.
Sarma, N. Rajesh, D. Prajapati, Chem. Commun., 2012, 48, 4014. (j)
R. Gerber, C. M. Frech, Chem. Eur. J., 2012, 18, 8901.
(a) M. T. Bresser, P. Knochel, Angew. Chem. Int. Ed., 2011, 50, 1914.
(b) P. J. E. Verdegem, M. C. F. Monnee, J. Lugtenburg, J. Org.
Chem., 2001, 66, 1269. (c) L. Brandsma, H. D. Verkruijsse, C.
Schade, P. von R. Schleyer, J. Chem. Soc. Chem. Commun., 1986,
260. (d) J.-C. Clinet, C. Linstrumelle, Synthesis, 1981, 875.
8
9
Y. Masaki, K. Sakuma, K. Kaji, Chem. Lett., 1979, 1235.
35 10 L. Yang, Q. Wen, F. Xiao, G.-J. Deng, Org. Biomol. Chem., 2014, 12,
9519.
11 (a) X. Wang, Y. Ye, S. Zhang, J. Feng, Y. Xu, Y. Zhang, J. Wang, J.
Am. Chem. Soc., 2011, 133, 16410. (b) A. T. Parsons, S. L.
Buchwald, Angew. Chem., Int. Ed., 2011, 50, 9120.
40 12 (a) Z. Liang, F. Wang, P. Chen, G. Liu, Org. Lett., 2015, 17, 2438.
(b) Z.-J. Yang, B.-L. Hu, C.-L. Deng, X.-G. Zhang, Adv. Synth.
Catal., 2014, 356, 1962.
13 W. C. Danen, D. D. Newkirk, J. Am. Chem. Soc., 1976, 98, 516.
14 K. Goto, G. Yamamoto, B. Tan, R. Okazaki, Tetrahedron Lett., 2001,
45
42, 4875.
15 (a) M. Uttamchandani, K. Liu, R. C. Panicker, S. Q. Yao, Chem.
Commun., 2007, 1518; (b) D. C. Meadows, T. Sanchez, N. Neamati,
T. W. North, J. Gervay-Hague, Bioorg. Med. Chem., 2007, 15, 1127;
(c) R. Ettari, E. Nizi, M. E. D. Francesco, M.-A. Dude, G. Pradel, R.
Vicik, T. Schirmeister, N. Micale, S. Grasso, M. Zappala, J. Med.
Chem., 2008, 51, 988.
50
16 M. V. R. Reddy, M. R. Mallireddigari, V. R. Pallela, P.
Venkatapuram, R. Boominathan, S. C. Bell, E. P. Reddy, Bioorg.
Med. Chem., 2005, 13, 1715.
4
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]