Cs2CO3-promoted carbon–sulfur bond construction via cross dehydrogenative coupling of thiophenols with acetonitrile

Article abstract of DOI:10.1016/j.tetlet.2017.08.067

A novel protocol for the construction of carbon–sulfur bonds has been achieved via halogen-free Cs₂CO₃-promoted cross dehydrogenative coupling (CDC) of thiophenols with acetonitrile. This transformation provides a straightforward route to the synthesis of sulfenylated acetonitriles in up to 80% yield.

Full text of DOI:10.1016/j.tetlet.2017.08.067

Accepted Manuscript
Cs2CO3-promoted carbon−sulfur bond construction via cross dehydrogenative
coupling of thiophenols with acetonitrile
Qian Chen, Yulin Huang, Xiaofeng Wang, Chunxiao Wen, Xinxing Yan, Jiekun
Zeng
PII:
S0040-4039(17)31090-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.08.067
TETL 49257
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 July 2017
24 August 2017
28 August 2017
Please cite this article as: Chen, Q., Huang, Y., Wang, X., Wen, C., Yan, X., Zeng, J., Cs2CO3-promoted carbon
−sulfur bond construction via cross dehydrogenative coupling of thiophenols with acetonitrile, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.08.067
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Qian Chen, Yulin Huang, Xiaofeng Wang, Chunxiao Wen, Xinxing Yan, Jiekun Zeng

1
Tetrahedron Letters
journal homepage: www.els evier.com
−sulfur bond construction
Cs2CO3-promoted carbon
coupling of thiophenols with acetonitrile
via cross dehydrogenative
Qian Chena,b,∗, Yulin Huanga, Xiaofeng Wanga, Chunxiao Wena, Xinxing Yana, Jiekun Zenga
a School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou 510006, China
b Key Laboratory of Functional Molecular Engineering of Guangdong Province, South China University of Technology, Guangzhou 510640, China
ARTICLE INFO
ABSTRACT
Article history:
Received
A novel protocol for the construction of carbon−sulfur bonds has been achieved via halogen-free
Cs2CO3-promoted cross dehydrogenative coupling (CDC) of thiophenols with acetonitrile. This
transformation provides a straightforward route to the synthesis of sulfenylated acetonitriles in
up to 80% yield.
Received in revised form
Accepted
Available online
© 2017 Published by Elsevier Ltd.
Keywords:
Thiophenols
Sulfenylation
−sulfur bond
Carbon
Cross dehydrogenative coupling
Thioethers have attracted considerable attention in organic
synthesis due to their significant biological activity1,2 and their
participation in the synthesis of heterocycles,3 β-keto sulfones,4
α,β-unsaturated carbonyl compounds,5 and others.6 In particular,
arylthioacetonitriles act as a key intermediate in the synthesis of
urea transporters,7 which are potential targets for development of
drugs with a novel diuretic mechanism. These examples highlight
the importance of sulfides bearing an electron-withdrawing group
in organic synthesis. Therefore, this kind of sulfides is highly
desirable, and a variety of useful synthetic methods have been
well documented. Traditionally, α-sulfenylated carbonyl
compounds or arylthioacetonitriles have been synthesized by
nucleophilic substitution of halides with thiols8 or disulfides9
(Figure 1a). The alternative synthetic methods mainly employ the
reactions of carbonyl compounds with thiol sources such as
sulphenyl halides, disulfides, sulfonothioates, sulfenamides, and
N-(phenylthio)succinimide (Figure 1b).10 However, toxic
transition metals or strong alkaline conditions were often used in
these reactions, thus making these transformations not
environmentally friendly. Moreover, the pre-functionalized
starting materials are high-cost and/or moisture-sensitive. Thus,
the development of a convenient and efficient protocol for the
construction of carbon−sulfur bonds is still desirable.
bonds.12 The oxidative CDC has also been applied to α-
sulfenylation of carbonyl compounds (Figure 1c), while these
coupling protocols mainly relies on the use of halogenated
reagents and/or strong oxidants.13 Most recently, Song and Jiao
reported a Cs2CO3-catalyzed aerobic oxidative CDC reaction of
thiols with phosphonates.14 The possible mechanism showed that
disulfides are reaction intermediates generated via the oxidative
coupling of thiols in the presence of Cs2CO3 and O2. We then
envisioned that α-sulfenylation of acetonitrile, which paid less
attention, might be realized through the CDC reaction of thiols
with acetonitrile using O2 as the oxidant under weak alkaline
conditions. Herein, we report a halogen-free Cs2CO3-promoted
carbon−sulfur bond construction via the CDC reaction of
thiophenols with acetonitrile (Figure 1d).
The cross dehydrogenative coupling (CDC) reactions are
powerful methods in organic synthesis that can avoid the use of
pre-functionalized substrates.11 Recently, the CDC reactions
involving thiols have attracted much attention because this
strategy represents more straightforward, efficient, and atom
Figure 1. Synthesis of sulfides bearing an electron-withdrawing group.
−sulfu −heteroatom
r and sulfur
e—co—nom—ic to construct carbon
∗ Corresponding author. Tel.: +86-20-3932-2231; fax: +86-20-3932-2235; E-mail address: qianchen@gdut.edu.cn (Q. Chen).

2
Tetrahedron
Table 2
In comparison with previous carbon−sulfur bond forming
Scope of thiophenolsa,b
reactions under strong alkaline conditions,15 we first carried out a
reaction of diphenyl disulfide 1a (0.2 mmol) as a reaction
intermediate in the CDC reaction14 with acetonitrile (1 mL) in the
o
presence of Cs2CO3 (1 equiv) at 80 or 100 C, while only trace
amounts of the desired 2-(phenylthio)acetonitrile 2a were
detected (Table 1, entries 1 and 2). When the reaction was carried
out at 120 °C, the yield of 2a was significantly increased (38%,
entry 3). We then turned to screen other weak inorganic bases.
The use of K2CO3 or CsOAc failed to give the desired product
(entries 4 and 5), and the use of K3PO4 afforded 2a in a low yield
of only 17% (entry 6). When the reaction was carried out at 140
oC in the presence of Cs2CO3, the product yield increased to 46%
(entry 7). The increase of Cs2CO3 amount reduced the yield
(entries 8 and 9), while the decrease of Cs2CO3 amount (0.5
equiv) improved the yield (55%, entry 10). The use of 2 mL of
acetonitrile gave 2a in 64% yield (entry 11). However, more
acetonitrile (3 mL) did not improve the yield of 2a (entry 12).
We then employed thiophenol 1b as the thiol source instead of
disulfides. Thus, the corresponding disulfide was generated via
the oxidative coupling of thiols in the presence of Cs2CO3 and air
at room temperature.14 The desired product 2b was obtained in
o
67% yield when the reaction temperature was then set at 140 C
(entry 13). It is noteworthy that disulfenylated products were
observed in trace amounts or not detected for all the optimization
of reaction conditions.
a
Reaction conditions: 1 (0.4 mmol) and Cs2CO3 (0.1 mmol) in CH3CN (2
o
mL) stirring at room temperature under air for 3 h, and then stirring at 140 C
Table 1
Optimization of reaction conditionsa,b
in a sealed tube for 15 h.
b Isolated yield based on 1.
c Reaction conditions see Table 1, entry 11.
To investigate the scope of the α-sulfenylation protocol, we
applied the optimized reaction conditions to a variety of
thiophenols 1 and the results are illustrated in Table 2. Electron-
rich thiophenols bearing different groups such as alkyl groups,
OMe, and NH2 at para, ortho or meta or at both positions of
aromatic rings were all well tolerated for the CDC reaction to
smoothly give the corresponding arylthioacetonitriles 2b–g, 2i–l,
2n, and 2o in 41–80% isolated yields, and disulfenylated
acetonitriles 3 were observed in only trace amounts. It is
noteworthy that thiophenols bearing an OH group failed to afford
the desired 2h and 2m probably due to the acidity of phenols. For
the reaction of electron-deficient thiophenols, the yields of
disulfenylated acetonitriles 3 significantly increased. This could
be because the electron-withdrawing groups enhance the acidity
of methylene compounds 2, and the subsequent sulfenylation of 2
affords 3. Thus, thiophenols bearing a meta halogen atom
afforded 2p–r and 3p–r in moderate yields. Thiophenols bearing
a halogen atom at ortho or para position gave monosulfenylated
products 2s–v in 27–62% yields, while disulfenylated products
3s–v were obtained in poor yields. When thiophenol bearing two
chlorine atoms was employed, the disulfenylated product 3w was
isolated as major product. It is noteworthy that the reaction of
sterically hindered naphthalene-2-thiol successfully afforded
monosulfenylated product 2x in 59% yield. However, the
reaction of heteroaromatic thiols such as pyridine-4-thiol,
thiophene-2-thiol and 2-methylfuran-3-thiol with acetonitrile
failed to give the desired products. In addition, the CDC of
aliphatic thiols with acetonitrile was also attempted.
Unfortunately, benzylthiol and cyclohexylthiol failed to give the
coupling products.
Thiol
source
Yield of
2 (%)
Entry
1
Base (equiv)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
K2CO3 (1.0)
CsOAc (1.0)
K3PO4 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (2.0)
Cs2CO3 (1.5)
CH3CN
1 mL
1 mL
1 mL
1 mL
1 mL
1 mL
1 mL
1 mL
1 mL
T (oC)
80
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
<5
8
2
100
120
120
120
120
140
140
140
140
140
140
140
3
38
0
4
5
0
6
17
46
40
38
55
64
62
67
7
8
9
10
11
12
Cs2CO3 (0.50) 1 mL
Cs2CO3 (0.50) 2 mL
Cs2CO3 (0.50) 3 mL
Cs2CO3 (0.25) 2 mL
13c
a
Reaction conditions: 1a (0.2 mmol) and base in CH3CN stirring in a
sealed tube for 15 h.
b
1
Yield based on 1 was determined by H NMR analysis of crude products
Having succeeded in α-sulfenylation of acetonitrile, we were
encouraged to explore α-sulfenylation of other polar aprotic
solvents under same conditions. To our delight, when the
reaction of 1b with acetone was carried out, the desired
using an internal standard.
c Reaction conditions: 1b (0.4 mmol) and Cs2CO3 (0.1 mmol) in CH3CN (2
o
mL) stirring at room temperature under air for 3 h, and then stirring at 140 C
in a sealed tube for 15 h.

3
sulfenylated acetone 2y was isolated in high yield (93%, scheme
1a). However, sulfenylation of ethyl acetate failed due to the
insolubility of Cs2CO3 in EtOAc (scheme 1b). Moreover, α-
sulfenylation of nitromethane gave the desired 2z in poor yield
(Scheme 1c).
Supplementary data (these data include experimental details,
1
analytical data, H and 13C NMR spectra of compounds 2 and 3)
associated with this article can be found, in the online version, at
http://...
References and notes
1.
(a) Trost, B. M. Chem. Rev. 1978, 78, 363−382; (b) Lee, C.-F.; Liu, Y.-
C.; Badsara, S. S. Chem. Asian J. 2014, 9, 706−722; (c) Chauhan, P.;
Mahajan, S.; Enders, D. Chem. Rev. 2014, 114, 8807−8864.
2.
For selected examples, see: (a) Gendron, F.-P.; Halbfinger, E.; Fischer,
B.; Duval, M.; D’Orléans-Juste, P.; Beaudoin, A. R. J. Med. Chem.
2000, 43, 2239−2247; (b) Regina, G. L.; Coluccia, A.; Brancale, A.;
Piscitelli, F.; Gatti, V.; Maga, G.; Samuele, A.; Pannecouque, C.; Schols,
D.; Balzarini, J.; Novellino, E.; Silvestri, R. J. Med. Chem. 2011, 54,
1587−1598; (c) Regina, G. L.; Bai, R.; Rensen, W.; Coluccia, A.;
Piscitelli, F.; Gatti, V.; Bolognesi, A.; Lavecchia, A.; Granata, I.; Porta,
A.; Maresca, B.; Soriani, A.; Iannitto, M. L.; Mariani, M.; Santoni, A.;
Brancale, A.; Ferlini, C.; Dondio, G.; Varasi, M.; Mercurio, C.; Hamel,
E.; Lavia, P.; Novellino, E.; Silvestri, R. J. Med. Chem. 2011, 54,
8394−8406; (d) Klečka, M.; Pohl, R.; Čejka, J.; Hocek, M. Org. Biomol.
Chem. 2013, 11, 5189−5193; (e) Yonova, I. M.; Osborne, C. A.;
Morrissette, N. S.; Jarvo, E. R. J. Org. Chem. 2014, 79, 1947−1953.
(a) Sasaki, T.; Hayakawa, K.; Ban, H. Tetrahedron 1982, 38, 85−91; (b)
Kukolja, S.; Draheim, S. E.; Pfeil, J. L.; Cooper, R. D. G.; Grvaves, B.
J.; Holmes, R. E.; Neel, D. A.; Huffman, G. W.; Webber, J. A.; Kinnick,
M. D.; Vasileff, R. T.; Foster, B. J. J. Med. Chem. 1985, 28, 1886−1896;
(c) Matthews, J. M.; Qin, N.; Colburn, R. W.; Dax, S. L.; Hawkins, M.;
McNally, J. J.; Reany, L.; Youngman, M. A.; Baker, J.; Hutchinson, T.;
Liu, Y.; Lubin, M. L.; Neeper, M.; Brandt, M. R.; Stone, D. J.; Flores, C.
M. Bioorg. Med. Chem. Lett. 2012, 22, 2922−2926.
Scheme 1. α-Sulfenylation of other polar aprotic solvents.
According to the experimental results and previous
literatures,14,15 a plausible mechanism for α-sulfenylation of
acetonitrile is outlined in Scheme 2. First, thiyl radical is
generated from the autoxidation of thiol 1 in the presence of
Cs2CO3 and dioxygen, and thiyl radical undergoes homocoupling
to produce disulfide 4.14 Acetonitrile then reacts with Cs2CO3 at
high temperature to form intermediate 5. Finally, the nucleophilic
attack of 5 on 4 affords α-sulfenylated acetonitrile 2. In addition,
a second sulfide group is introduced at the α-position of 2 to form
disulfenylated acetonitrile 3.
3.
4.
(a) Loghmani-Khouzani, H.; Hajiheidari, D. J. Fluorine Chem. 2010,
131, 561−569; (b) Chang, M.-Y.; Cheng, Y.-C.; Lu, Y.-J. Org. Lett.
2014, 16, 6252−6255; (c) Saraiva, M. T.; Costa, G. P.; Seus, N.;
Schumacher, R. F.; Perin, G.; Paixᾶo, M. W.; Luque, R.; Alves, D. Org.
Lett. 2015, 17, 6206−6209.
5.
6.
(a) Hok, S.; Schore, N. E. J. Org. Chem. 2006, 71, 1736−1738; (b)
Kumar, A.; Sharma, S.; Tripathi, V. D.; Srivastava, S. Tetrahedron
2010, 66, 9445−9449.
(a) Trost, B. M.; Salzmann, T. N.; Hiroi, K. J. Am. Chem. Soc. 1976, 98,
4887−4902; (b) Orena, M.; Porzi, G.; Sandri, S. Tetrahedron Lett. 1992,
33, 3797−3800; (c) Enders, D.; Piva, O.; Burkamp, F. Tetrahedron 1996,
52, 2893−2908; (d) Rigby, J. H.; Laxmisha, M. S.; Hudson, A. R.; Heap,
C. H.; Heeg, M. J. J. Org. Chem. 2004, 69, 6751−6760; (e) Guney, T.;
Kraus, G. A. Org. Lett. 2013, 15, 613−615.
7.
8.
Anderson, M. O.; Zhang, J.; Liu, Y.; Yao, C.; Phuan, P.-W.; Verkman,
A. S. J. Med. Chem. 2012, 55, 5942−5950.
(a) Romero-Ortega, M.; Fuentes, A.; González, C.; Morales, D.; Cruz, R.
Synthesis 1999, 225−227; (b) Ranu, B. C.; Jana, R. Adv. Synth. Catal.
2005, 347, 1811−1818; (c) Rashid, M. A.; Reinke, H.; Langer, P.
Tetrahedron Lett. 2007, 48, 2321−2323; (d) Rashid, M. A.; Rasool, N.;
Adeel, M.; Reinke, H.; Fischer, C.; Langer, P. Tetrahedron 2008, 64,
3782−3793; (e) Shibatomi, K.; Narayama, A.; Soga, Y.; Muto, T.;
Iwasa, S. Org. Lett. 2011, 13, 2944−2947; (f) Mancini, A.; Chelini, A.;
Di Capua, A.; Castelli, L.; Brogi, S.; Paolino, M.; Giuliani, G.; Cappelli,
A.; Frosini, M.; Ricci, L.; Leonelli, E.; Giorgi, G.; Giordani, A.;
Magistretti, J.; Anzini, M. Eur. J. Med. Chem. 2017, 126, 614−630.
(a) Huang, X.; Zheng, W.-X. Synth. Commun. 1999, 29, 1297−1301; (b)
Ranu, B. C.; Mandal, T. J. Org. Chem. 2004, 69, 5793−5795; (c) Peppe,
C.; Borges de Castro, L. Can. J. Chem. 2009, 87, 678−683.
Scheme 2. Proposed mechanism.
In summary, we have developed
a protocol for the
construction of carbon−sulfur bonds via Cs2CO3-promoted cross
dehydrogenative coupling (CDC) of thiophenols with acetonitrile,
which provides a facile methodology for the synthesis of
sulfenylated acetonitriles. We envision that the reaction mode
outlined here will have potential applications in organic synthesis.
9.
−sulfu
r and
are ongoing and will be reported in due
Further investigations on the construction of carbon
−heteroatom bonds
course.
sulfur
10. For recent examples, see: (a) Yadav, V. K.; Babu, K. G.; Parvez, M. J.
Org. Chem. 2004, 69, 3866−3874; (b) Wang, W.; Li, H.; Wang, J.; Liao,
L. Tetrahedron Lett. 2004, 45, 8229−8231; (c) Deng, K.; Chalker, J.;
Yang, A.; Cohen, T. Org. Lett. 2005, 7, 3637−3640; (d) Jereb, M.;
Togni, A. Org. Lett. 2005, 7, 4041−4043; (e) Jereb, M.; Togni, A. Chem.
Eur. J. 2007, 13, 9384−9392; (f) Anbou, H.; Umeda, R.; Nishiyama, Y.
Bull. Chem. Soc. Jpn. 2011, 84, 1248−1250; (g) Arisawa, M.; Nihei, Y.;
Yamaguchi, M. Tetrahedron Lett. 2012, 53, 5729−5732; (h) Zou, L.-H.;
Priebbenow, D. L.; Wang, L.; Mottweiler, J.; Bolm, C. Adv. Synth.
Catal. 2013, 355, 2558−2563; (i) Rahaman, R.; Devi, N.; Barman, P.
Tetrahedron Lett. 2015, 56, 4224−4227; (j) Liu, Y.-W.; Badsara, S. S.;
Liu, Y.-C.; Lee, C.-F. RSC Adv. 2015, 5, 44299−44305; (k) Devi, N.;
Rahaman, R.; Sarma, K.; Barman, P. Eur. J. Org. Chem. 2016, 384−388.
11. For recent reviews, see: (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335−344;
(b) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215−1292; (c)
Acknowledgments
This work was supported by the Science and Technology
Planning Project of Guangdong Province (2015A020211026 and
2017A010103044), 100 Young Talents Programme of
Guangdong University of Technology (220413506), and the
Open Fund of the Key Laboratory of Functional Molecular
Engineering of Guangdong Province (2016kf07, South China
University of Technology).
Supplementary data

4
Tetrahedron
Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111,
1780−1824; (d) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41,
3464−3484; (e) Girard, S. A.; Knauber, T.; Li, C.-J. Angew. Chem., Int.
Ed. 2014, 53, 74−100; Angew. Chem. 2014, 126, 76−103.
12. For recent examples, see: (a) Huang, Z.; Zhang, D.; Qi, X.; Yan, Z.;
Wang, M.; Yan, H.; Lei, A. Org. Lett. 2016, 18, 2351−2354; (b) Zhu, Y.;
Chen, T.; Li, S.; Shimada, S.; Han, L.-B. J. Am. Chem. Soc. 2016, 138,
5825−5828; (c) Sun, J.-G.; Yang, H.; Li, P.; Zhang, B. Org. Lett. 2016,
18, 5114−5117; (d) Wang, P.; Tang, S.; Huang, P.; Lei, A. Angew.
Chem., Int. Ed. 2017, 56, 3009−3013.
13. (a) Tan, J.; Liang, F.; Wang, Y.; Cheng, X.; Liu, Q.; Yuan, H. Org. Lett.
2008, 10, 2485−2488; (b) Yadav, J. S.; Reddy, B. V. S.; Jain, R.;
Baishya, G. Tetrahedron Lett. 2008, 49, 3015−3018; (c) Cao, H.; Yuan,
J.; Liu, C.; Hu, X.; Lei, A. RSC Adv. 2015, 5, 41493−41496; (d) Varun,
B. V.; Gadde, K.; Prabhu, K. R. Org. Lett. 2015, 17, 2944−2947; (e)
Varun, B. V.; Gadde, K.; Prabhu, K. R. Org. Biomol. Chem. 2016, 14,
7665−7670; (f) Siddaraju, Y.; Prabhu, K. R. Org. Lett. 2016, 18,
6090−6093.
14. Song, S.; Zhang, Y.; Yeerlan, A.; Zhu, B.; Liu, J.; Jiao, N. Angew.
Chem., Int. Ed. 2017, 56, 2487−2491.
15. (a) Zhang, X.; Zhou, X.; Xiao, H.; Li, X. RSC Adv. 2013, 3,
22280−22284; (b) Liu, Y.; Zhang, Y.; Hu, C.; Wan, J.-P.; Wen, C. RSC
Adv. 2014, 4, 35528−35530; (c) Liu, X.; Cui, H.; Yang, D.; Dai, S.;
Zhang, T.; Sun, J.; Wei, W.; Wang, H. RSC Adv. 2016, 6, 51830−51833.
Highlights
1. The cross dehydrogenative coupling reaction of
thiophenols with acetonitrile has been achieved.
2. The reactions afford sulfenylated acetonitriles
in the presence of Cs2CO3 and air.
3. The protocol is halogen-, metal-, and strong
oxidant-free.