Metal-free catalytic synthesis of diaryl thioethers under mild conditions

Article abstract of DOI:10.1039/c6nj00322b

A novel method to synthesize diaryl thioethers from aryl halides and carbon disulfide catalyzed by the 1,8-diazabicyclo[5,4,0]undec-7-enium acetate [DBUH][OAc] ionic liquid (IL) under solvent-free conditions has been developed. This metal-free catalytic system displayed high efficiency for coupling aryl halides with CS₂ to deliver thioethers. Compared to the conventional methods, no metal catalyst was needed, instead of which the DBU-based ILs played the catalyst and solvent roles simultaneously. Some reactions were carried out under mild conditions (55 °C, 0.5 h), giving moderate to high yields. Moreover, compared with the rare reports, the reaction of the aryl chlorides and fluorides with CS₂ could smoothly react in this catalytic system. The products were easily separated from the ILs which could be reused at least three times. The present method provides an efficient and environment-friendly catalytic approach to synthesize diaryl thioethers.

Full text of DOI:10.1039/c6nj00322b

View Article Online
View Journal
NJC
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: X. Cao, P. Zhang
and H. Zheng, New J. Chem., 2016, DOI: 10.1039/C6NJ00322B.
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/njc

Page 1 of 10
New Journal of Chemistry
View Article Online
DOI: 10.1039/C6NJ00322B
Metal-Free Catalytic Synthesis of Diaryl Thioethers under Mild
Conditions
XianꢀTing Cao, PengꢀFei Zhang, and Hui Zheng*
College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University,
Hangzhou 310016, China.
Abstract: A novel method to synthesize diaryl thioethers from aryl halides and
carbon disulfide catalyzed by 1, 8ꢀdiazabicyclo [5, 4, 0] undecꢀ7ꢀenium acetate
[DBUH][OAc] ionic liquid (IL) under solventꢀfree conditions has been developed.
This metalꢀfree catalytic system displayed high efficiency for coupling aryl halides by
CS2 to deliver thioethers. Compared to the conventional methods, no any metal
catalyst was needed, instead of which the DBUꢀbased ILs played the catalyst and
solvent roles simultaneously. Some reactions were carried out at mild conditions
(55 °C, 0.5 h), giving moderate to high yields. Moreover, compared with the rare
reports, the reaction of the aryl chlorides and fluorides with CS2 could smoothly react
in this catalytic system. The products were easily separated from the ILs which could
be reused at least three times. The present method provides an efficient and
environmentꢀfriendly catalytic approach to synthesize diaryl thioethers.
Introduction
Sulfurꢀcontaining functional groups are very important motifs, particularly, diaryl
thioethers and their derivatives are common structural features in pharmacologically
active compounds and in material sciences.1 Therefore, the carbonꢀsulfur (CꢀS) bond
forming methodology is of strategic importance in synthetic chemistry, which has
received much attention. Traditional methods for CꢀS bond formation often require
harsh reaction conditions, such as the use of toxic and high boiling polar solvents
quinoline, HMPA, or N,Nꢀdimethylacetamide and at elevated temperatures as high as
200 °C.2 In order to overcome these shortcomings, transitionꢀmetalꢀcatalyzed
coupling systems were developed. A variety of metals, such as Pd,3 Co,4 In,5 Cu,6 Fe,7
8
and Ni
were applied in the synthesis of diaryl thioethers. However, these
metalꢀcatalyzed reactions require, odorous, expensive, and less available arenethiols,
which are prone to undergo oxidative homocoupling to produce disulfides as
byproducts. Alternative sulfur sources have been developed based on aryl halides or
pseudo halides, yielding thiourea,9 thiolates,10 thioacetamide,11 potassium ethyl
xanthogenate,12 thiocyanate,13 metal sulfides,14 and carbon disulfide.15 These
approaches, however demand higher temperature, excess amount of reagents (>1.0
equiv) and long reaction time(>10 h) with the involvement of metal catalysis,
protection of N2 and usage of organic solvents. Following the guidance of green
chemistry, designing an environmentꢀfriendly way to synthesize diaryl thioethers is
considered of high practical value, particularly for the pharmaceutical companies who

New Journal of Chemistry
Page 2 of 10
View Article Online
DOI: 10.1039/C6NJ00322B
herald for environmental awareness to reduce or even to avoid metal residues. Hence,
the metalꢀfree catalytic systems for preparing diary thioethers are highly in demand.
Initially, we focus on the green synthetic method to capture CO2 and CS2, and convert
it into valuable chemicals via DBUꢀbased reversible ionic liquid. We found it is
effective to fix CX2 (O, S) in DBUꢀbased IL to construct CꢀC and CꢀS bond. 16 To
screen the catalytic effect of this type IL, we synthesized different ILs, such as
[DBUH][OAc], [DBUH][Cl], [DBUH][HSO4], [DBUH][PhCOO] and [DBUH]
[EtCOO] etc. While other ILs are solid except [DBUH][OAc] at room temperature.
Herein, we report a simple, metalꢀfree green method for the synthesis of the diaryl
thioethers based on the novel recyclable catalytic systems via reaction of CS2 and aryl
halides by employing ionic liquid [DBUH][OAc] as catalyst and solvent at the same
time, and it is a part of our continuous effort toward C−S bond formation using CS2.16
Result and discussion
The influence of the amount of CS2 on the reaction was initially investigated. When
0.25 equiv of CS2 (relative to 1ꢀiodoꢀ4ꢀnitrobenzene 1) was introduced to the model
reaction at the presence of [DBUH][OAc], 2 was obtained in 76% yield (Table 1,
entry 1). The best yield (91%, Table 1, entry 2) was obtained when 0.5 equiv of CS2
was used. Both conditions yielded nonꢀobservable compound 3. However, when the
amount of CS2 was increased to 1.0, 2.0 and 3.0 equiv, the ratio of disulfide products 3
was gradually increasing (Table 1, entries 3, 4 and 5). It might be caused that excess
CS2 reacted with reactant 1, forming 4ꢀnitrobenzenethiol which can produce
byꢀproduct 3 by coupling reaction. The results showed that 0.5 equiv of CS2 was the
optimal condition to synthesize diaryl thioethers.
Table 1. The influence of the amount of CS2 on the reaction.a
Entry
Equiv of CS2
Yield of 2 (%)b
Yield of 3 (%)b
1
2
3
4
5
0.25
0.5
1.0
2.0
3.0
76
91
48
44
33
0
0
36
40
45
a
b
Reaction conditions: 1ꢀiodoꢀ4ꢀnitrobenzene (1 mmol), [DBUH][OAc] (5 mmol) at 55 °C.
Isolated yield.
Generally, the organic solvents are necessary in this type reaction of synthesizing
diaryl thioethers.2ꢀ8 However, some high boiling point organic solvents are hardly

Page 3 of 10
New Journal of Chemistry
View Article Online
DOI: 10.1039/C6NJ00322B
removed during the postꢀtreatment if they are employed in reaction, which will
pollute the products. Especially for the medicine industry, the residual solvents in
pharmaceuticals are strictly limited. Development of a solventꢀfree green method
would minimize the residual solvent problems. In our study, the influence of different
solvents and solventꢀfree on the reaction were investigated. The nonꢀpolar solvents
acetonitrile, toluene and ethyl acetate were used in this system and good yields were
obtained (Table 2, entry 2ꢀ4). However, the polar solvents (alcohols, acetic acid and
water) tended to give yields between low to trace amount, presumably due to the low
solubility of the substrate in polar solvents. Surprisingly, the solventꢀfree condition
yielded the best yield of 91% in our reaction (Table 2, entry 1). We speculated that
[DBUH][OAc] played both solvent and catalytic roles at the same time and formed a
highly efficient catalytic system for this coupling reaction. For this model, we
screened the temperature ranging from room temperature to 100℃. It was found that
the best temperature was 55℃, and the reaction cannot go through completely at
lower temperature and has byꢀproduct at higher temperature, so we selected 55℃ as
the optimum temperature.
Table 2. The reaction of 1ꢀiodoꢀ4ꢀnitrobenzene and CS2 in different solvents with [DBUH][OAc].a
Entry
Solvent
Yield b (％)
1
2
3
4
5
6
7
8
Solventꢀfree
CH3CN
91
72
PhCH3
71
CH3COOCH2CH3
CH3CH2OH
CH3OH
71
59
23
CH3COOH
H2O
Trace
Trace
a Reaction conditions: 1ꢀiodoꢀ4ꢀnitrobenzene (1 mmol), CS2 (0.5 mmol), [DBUH][OAc] (5 mmol),
solvent (5 mmol) at 55 °C. b Isolated yield.
In order to expand the scope of this catalytic system, various aryl halides were then
examined. The common samples of different aryl iodides and bromides were tested
firstly (Table 3). The experimental results disclosed that the substrates bearing
electronꢀwithdrawing groups have higher reactivity, which reacted smoothly to render
the corresponding symmetric diaryl thioethers in moderate to high yileds (60ꢀ91%).
The nitro group on the substrates are especially favorable for increasing the reactivity,
the reaction of which could be carried out in mild conditions (55 °C, 0.5 h) (Table 3,

New Journal of Chemistry
Page 4 of 10
View Article Online
DOI: 10.1039/C6NJ00322B
entries 1, 2, and 6). The coupling of heteroaryl bromides with CS2 also performed
well (Table 3, entries 10 and 11). Nonetheless, the substrates without substituent
group or with the electronꢀdonating groups gave relatively low yields (Table 3, entries
8 and 9).
Significantly, the catalyst [DBUH][OAc] used in this reaction was found to remain
catalytic ability after being three times. Yet the product yields only decline slightly
(reducing from 91% in the first run to 81% in the third run). This result indicated that
this catalytic system was recyclable for catalyzing the coupling reaction of CS2 with
aryl halides.
Table 3. Synthesis of various diaryl thioethers from aryl iodides and bromides.a
Entry
1
Substrate
Product
Temp (°C) Time (h) Yield (%)b
55
0.5
91, 87c, 81d
(X = I)
X = I, Br
87 (X = Br)
2
3
4
55
95
95
0.5
5.5
5.5
88 (X = I)
87 (X = Br)
X = I, Br
78 (X = I)
72 (X = Br)
X = I, Br,
68 (X = I)
65 (X = Br)
X = I, Br
5
6
120
55
5.5
1.5
68 (X = I)
60 (X = Br)
X = I, Br
81

Page 5 of 10
New Journal of Chemistry
View Article Online
DOI: 10.1039/C6NJ00322B
7
95
5.5
73
S
O
O
CH3
H3C
I
8
9
145
145
5.5
5.5
35
30
10
11
12
100
100
120
5.5
5.5
5.5
80
70
72 (X = I)
65 (X = Br)
X = I, Br
a Reaction conditions: aryl halides (1 mmol), CS2 (0.5 mmol), [DBUH][OAc] (5 mmol); b Isolated
yield, c Yield of the product (runs: 2), d Yield of the product (runs: 3).
In the crossꢀcoupling reactions, aryl chlorides and fluorides, particularly the latter, are
often much less reactive than the corresponding iodides and bromides.17 In order to
demonstrate the generality of substrates and further expand the application of this
catalytic system, we employed aryl chlorides and fluorides as the substrates (Table 4).
It was fortunately found that both aryl chlorides and fluorides could also react well
with CS2 in this catalytic system to furnish diaryl thioethers in considerably high
yields. Some substrates could even react and achieve good yields at as low
temperature as 55 °C (Table 4, entries 1 and 2). Our catalytic system do not need
special metal catalysts and higher temperature as the previous literatures illustrated
for the coupling reaction of aryl chlorides and fluorides.18
Table 4. Synthesis of various diaryl thioethers from aryl chlorides and fluorides.a
Entry
1
Substrate
Product
Temp(°C)
55 (X =Cl)
60 (X = F)
Time(h) Yield (%)b
0.5
85 (X = Cl)
92 (X = F)

New Journal of Chemistry
Page 6 of 10
View Article Online
DOI: 10.1039/C6NJ00322B
X = Cl, F
X = Cl, F
X = Cl, F
2
3
4
55
1.0
5.5
5.5
82 (X = Cl)
80 (X = F)
95 (X =Cl)
100 (X =F)
60 (X = Cl)
65 (X = F)
95
55 (X = Cl)
50 (X = F)
X = Cl, F
5
6
120
120
5.5
5.5
40
70 (X = Cl)
62 (X = F)
X = Cl, F
a Reaction conditions: aryl halides (1 mmol), CS2 (0.5 mmol), [DBUH][OAc] (5 mmol), b Isolated
yield.
A plausible pathway was outlined in Scheme 1. The ILs [DBUH][OAc] 6 reacted with
CS2 to give intermediate 7 and 8, which was reported by literature,15 and then the
nucleophilic substitution reaction occurred between the substrates and 8 to yield
intermediate 9 which was detected by GC/MS (Fig. 1). The key intermediate 10, was
formed by the reaction of [DBUH][OAc] and 9, which then reacted with aryl halides
via nucleophilic substitution, resulted the product 5 and another ILs [DBUH][X] (X=
I, Br, Cl, F). Acetic acid reacted with [DBUH][X] and yielded 6, becoming a
recyclable catalytic system.

Page 7 of 10
New Journal of Chemistry
View Article Online
DOI: 10.1039/C6NJ00322B
Scheme 1. The possible reaction pathway
Figure 1. The GC/MS data of the intermediate 9.
Conclusion
In summary, we have developed an efficient [DBUH][OAc]ꢀpromoted coupling
reaction of different aryl halides with CS2 as an inexpensive, conveniently available
and easyꢀtoꢀhandle sulfide surrogate under solventꢀfree conditions. The generated
products were easily separated from the ILs which could be reclaimed at least three
times. The CꢀS bond formation is readily accomplished to afford symmetrical
thioethers in moderate to high yields under mild conditions. The operational
simplicity and environmental friendliness of this method highlights its potential
application in organic synthesis and pharmaceutical industry.
Experimental
General procedure for preparation of ionic liquid [DBUH][OAc]: To a 150 mL
threeꢀnecked flask was added 20 mmol of DBU. Acetic acid (20 mmol) was then
added slowly dropwise in ice bath. After dropwise addition, the ice bath was removed
and the reaction mixture was stirred at room temperature for 24 h. The oil residue was

New Journal of Chemistry
Page 8 of 10
View Article Online
DOI: 10.1039/C6NJ00322B
dried in vacuo at 60℃ for 24 h to afford [DBU][OAc] as a light yellow, viscous
liquid. The characteristic data is accord with the literature.19
The general procedure of preparing all products is similar. Taking the model reaction
as an example (Table 3, entry 1): 1ꢀIodoꢀ4ꢀnitrobenzene (1 mmol) and [DBUH][OAc]
(5 mmol) were added into a 10 mL bottle. The reactor was placed in a heating
apparatus at 55 °C. After 0.5 h, the residue was suspended in Et2O, and the mixture
was purified by column chromatography. An example was presented in supporting
materials.
Acknowledgements
We are grateful to the Program for Changjiang Scholars and Innovative Research
Team in Chinese University (IRT 1231) and Zhejiang Provincial Natural Science
Foundation of China (LZ16B020002) for providing financial support.
References
1 (a) S. Pasquini, C. Mugnaini, C. Tintori, M. Botta, A. Trejos, R. K. Arvela, M. Larhed, M. Witvrouw, M.
Michiels, F. Christ, Z. Debyser and F. Corelli, J. Med. Chem. 2008, 51, 5125ꢀ5129; (b) B. Stump, C. Eberle, M.
Kaiser, R. Brun, R. L. KrauthꢀSiegel and F. Diederich, Org Biomol Chem. 2008, 6, 3935ꢀ3947; (c) A. Gangjee, Y.
B. Zeng, T. Talreja, J. J. McGuire, R. L. Kisliuk and S. F. Queener, J. Med. Chem. 2007, 50, 3046ꢀ3053; (d) G. De
Martino, M. C. Edler, G. La Regina, A. Coluccia, M. C. Barbera, D. Barrow, R. I. Nicholson, G. Chiosis, A.
Brancale, E. Hamel and M. Artico, R. Silvestri, J. Med. Chem. 2006, 49, 947ꢀ954.
2 (a) J. R. Campbell, J. Org. Chem. 1964, 29, 1830ꢀ1833; (b) A. V. Bierbeek and M. Gingras, Tetrahedron Lett.
1998, 39, 6283ꢀ6286; (c) J. Lindley, Tetrahedron 1984, 40, 1433ꢀ1456; (d) T. Yamamoto and Y. Sekine, Can. J.
Chem. 1984, 62, 1544ꢀ1547; (e) R. J. S. Hickman, B. J. Christie, R. W. Guy and T. White, Aust. J. Chem. 1985, 38,
899ꢀ904; (f) J..Ham, I. Yang and H. Kang, J. Org. Chem. 2004, 69, 3236ꢀ3239.
3 (a) T. Itoh and T. Mase, Org. Lett. 2004, 6, 4587ꢀ4590; (b) M. Murata and S. L. Buchwald, Tetrahedron 2004,
60, 7397ꢀ7403; (c) M. A. FernandezꢀRodroeguez, Q. Shen and J. F. Hartwig, Chem.-Eur. J. 2006, 12, 7782ꢀ7796;
(d) M. A. FernandezꢀRodroeguez, Q. Shen and J. F. Hartwig, J. Am. Chem. Soc. 2006, 128, 2180ꢀ2181.
4
(
a) Y.ꢀC. Wong, T. T. Jayanth and C.ꢀH. Cheng, Org. Lett. 2006, 8, 5613ꢀ5616; (b) M.ꢀT. Lan, W.ꢀY. Wu, S.ꢀH.
Huang, K.ꢀL. Luo and F.ꢀY Tsai, RSC Adv. 2011, 1, 1751ꢀ1755.
a) V. P. Reddy, A. V. Kumar, K. Swapna and K. R. Rao, Org. Lett. 2009, 11, 1697ꢀ1700; (b) V. P. Reddy, K.
5
(
Swapna, A. V. Kumar and K. R. Rao, J. Org. Chem. 2009, 74, 3189ꢀ3191.
6 (a) S.ꢀL. Zhang and H.ꢀJ Fan, Organometallics 2013, 32, 4944ꢀ4951; (b) A. Kamal, V. Srinivasulu, N. S. R. C.
Murty, N. Shankaraiah, N. Nagesh, T. S. Reddy and A. V. S. Rao, Adv. Synth. Catal. 2013, 355, 2297ꢀ2307; (c) L.
Rout, T. K. Sen and T. Punniyamurthy, Angew. Chem. Int. Ed. 2007, 46, 5583ꢀ5586; (d) S. Bhadra, B. Sreedhar
and B. C. Ranu, Adv. Synth. Catal. 2009, 351, 2369ꢀ2378; (e) M. S. Kabir, M. Lorenz, M. L. Van Linn, O. A.
Namjoshi, S. Ara and J. M. Cook, J. Org. Chem. 2010, 75, 3626ꢀ3643; (f) Y.ꢀB. Huang, C.ꢀT. Yang, J. Yi, X.ꢀJ.
Deng, Y. Fu and L. Liu, J. Org. Chem. 2011, 76, 800ꢀ810; (g) C. GonzalezꢀArellano, R. Luque and D. J.
Macquarrie, Chem. Commun. 2009, 1410ꢀ1412; (h) C. K. Chen, Y. W. Chen, C. H. Lin, H. P. Lin and C. F. Lee,
Chem. Commun. 2010, 46, 282ꢀ284.
7 (a) S. L. Buchwald and C. Bolm, Angew. Chem. Int. Ed. 2009, 48, 5586ꢀ5587; (b) J. R. Wu, C. H. Lin and C. F.
Lee, Chem. Commun. 2009, 4450ꢀ4452; (c) A. Correa, M. Carril and C. Bolm, Angew. Chem., Int. Ed. 2008, 47,

Page 9 of 10
New Journal of Chemistry
View Article Online
DOI: 10.1039/C6NJ00322B
2880ꢀ2883; (d) W.ꢀY. Wu, J.ꢀC. Wang, F.ꢀY. Tsai, Green Chem. 2009, 11, 326ꢀ329.
8 (a) X. –B. Xu, J. Liu, J. J. Zhang; Y.ꢀW. Wang and Peng, Y. Org.Lett. 2013, 15, 550ꢀ553; (b) Y. Zhang, K. N.
Ngeow and J. Y. Ying, Org. Lett. 2007, 9, 3495ꢀ3498; c) J. Zhang, C. M. Medley, J. A. Krause and H. Guan,
Organometallics 2010, 29, 6393ꢀ6401; (d) S. Jammi, P. Barua, L. Rout, P. Saha and T. Punniyamurthy,
Tetrahedron Lett. 2008, 49, 1484ꢀ1487.
9 (a) M. Kuhn, F. C. Falk and J. Paradies, Org. Lett. 2011, 13, 4100ꢀ4103; (b) H. Firouzabadi, N. Iranpoor and M.
Gholinejad, Adv. Synth. Catal. 2010, 352, 119ꢀ124.
10 N. Park, K. Park, M. Jang and S. Lee, J. Org. Chem. 2011, 76, 4371ꢀ4378.
11 C. Tao, A. Lv, N. Zhao, S. Yang, X. Liu, J. Zhou, W. Liu and J. Zhao, Synlett 2011, 134ꢀ138.
12 D. J. C. Prasad and G. Sekar, Org. Lett. 2011, 13, 1008ꢀ1011.
13 (a) F. Ke, Y. Qu, Z. Jiang, Z. Li, D. Wu and X. Zhou, Org. Lett. 2011, 13, 454ꢀ457; (b) M. Cai, R. Xiao, T.
Yan and H. Zhao, J. Organomet. Chem. 2014, 749, 55ꢀ60.
14 Y. Li, C. Nie, H. Wang, X. Li, F. Verpoort and C. Duan, Eur. J. Org. Chem. 2011, 7331ꢀ7338.
15 P. Zhao, H. Yin, H. Gao and C. Xi, J. Org. Chem. 2013, 78, 5001ꢀ5006.
16 H. Zheng, X. Cao, K. Du, J. Xu and P. Zhang, Green Chem., 2014, 16, 3142ꢀ3148.
17 (a) M. Arisawa, T. Suzuki, T. Ishikawa and M Yamaguchi,. J. Am.Chem. Soc. 2008, 130, 12214ꢀ12215; (b) M.
Arisawa, T. Ichikawa and M. Yamaguchi, Org. Lett. 2012, 14, 5318ꢀ5321.
18 (a) C. Uyeda, Y. Tan, G. C. Fu and J. C. Peters, J. Am. Chem. Soc. 2013, 135, 9548ꢀ9552; (b) N. Singh, R.
Singh, D. S. Raghuvanshi and K. N. Singh, Org. Lett. 2013, 15, 5874ꢀ5877.
19 A. Ying, L. Liu, G. Wu, G. Chen, X. Chen and W. Ye, Tetrahedron Lett. 2009, 50, 1653–1657.

New Journal of Chemistry
Page 10 of 10
View Article Online
DOI: 10.1039/C6NJ00322B
The green method of preparing diaryl thioethers by employing [DBUH][OAc] as the
role of catalyst and solvent simultaneously