Cesium carbonate-promoted synthesis of aryl methyl sulfides using: S -methylisothiourea sulfate under transition-metal-free conditions

Article abstract of DOI:10.1039/c8ob01758a

In the presence of cesium carbonate, an efficient synthesis of aryl methyl sulfides by the reactions of aryl halides with commercially available S-methylisothiourea sulfate is developed. This odourless and highly crystalline solid can be used as the subst

Full text of DOI:10.1039/c8ob01758a

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: C. Zhang, Y. Zhou,
J. Huang, C. Tu, X. Zhou and G. Yin, Org. Biomol. Chem., 2018, DOI: 10.1039/C8OB01758A.
This is an Accepted Manuscript, which has been through the
Volume 14 Number
1 7 January 2016 Pages 1–372
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
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
author guidelines.
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, outlined
in our author and reviewer resource centre, 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.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 6
View Article Online
DOI: 10.1039/C8OB01758A
Organic & Biomolecular Chemistry
ARTICLE
Cesium carbonate-promoted synthesis of aryl methyl sulfides
using S-methylisothiourea sulfate under transition-metal-free
conditions
Received 00th January 20xx,
Accepted 00th January 20xx
Caiyang Zhang, You Zhou, Jintao Huang, Canhui Tu, Xiaoai Zhou, Guodong Yin*
DOI: 10.1039/x0xx00000x
www.rsc.org/
In the presence of cesium carbonate, an efficient synthesis of aryl methyl sulfides by the reactions of aryl halides with
commercially available S-methylisothiourea sulfate is developed. This odourless and highly crystalline solid can be used as
the surrogate for malodorous methanethiol. The gram-scale reaction also proceeds smoothly without the use of column
chromatography separation. Similarly, 2-(dimethylamino)ethylthio and cyclopropylmethylthio groups can be easily
introduced into the aromatic rings from the corresponding S-[2-(dimethylamino)ethyl]isothiourea dihydrochloride and S-
cyclopropylmethylisothiourea hydrobromide. The possible reaction mechanism is proposed. It is believed that this route to
aryl alkyl sulfides is well competitive in currently known methods due to the wide substrate scope, excellent yields, easy
operation and transition-metal-free conditions.
salts as the substrates by the combination of copper(I) bromide with
zinc(II) trifluoromethanesulfonate.19 Wangelin demonstrated that aryl
Introduction
Aryl methyl sulfide is an ubiquitous structural motif that occurs in a
variety of natural products, such as Roseochelin B,1 Macrophilone
A2 and Collismycin A.3 Thioridazine as an antipsychotic drug also
contains this fragment.4 Meanwhile, methyl sulfides can be
efficiently oxidized to methyl sulfoxides or methyl sulfones with
high selectivity,5 which are usually the key steps for the synthesis of
the nonsteroidal anti-inflammatory drug sulindac6 and pesticide
isoxaflutole.7 Many thiomethyl-containing aromatics are also
attractive candidates for organic semiconductors.8 In addition,
thiomethyl group has been widely used as the leaving group for the
formation of carbon-carbon bond by Liebeskind-Srogl cross-
coupling reaction9 and other transformations.10, 11 Accordingly, the
introduction of thiomethyl group into the aromatic molecules is
particularly significant.12 Generally, the synthesis of aryl methyl
sulfides can be performed through the methylation of malodorous aryl
thiols with methyl iodide13, 14 or dimethylcarbonate catalyzed by ionic
liquids under continuous flow conditions.15 The transition metal-
catalyzed direct C–H methylthiolation of heteroarenes using dimethyl
disulfide or DMSO as the thiomethyl source is one of the feasible
approaches,16 whereas these reactions often afforded the desired aryl
methyl sulfides in moderate yields with the requirement of more than a
stoichiometric amount of metal catalysts.17 Recently, Cai established a
practical palladium-catalyzed decarboxylative methylthiolation of 2-
nitrobenzoic acids by using DMSO as the sulfurizing reagent in the
presence of 2.0 equiv of copper(I) iodine (Scheme 1a).18 Tan found
that this transformation could be achieved using the arenecarboxylate
methyl sulfides can be prepared by the reaction of arene-diazonium salts
with dimethyl disulfide in the presence of organic photoredox catalyst or
base (Scheme 1b).20 Wu and coworkers reported an efficient di-tert-
butyl peroxide (DTBP)-mediated methylthiolation of arylboronic
acids with dimethyl disulfide under metal-free conditions (Scheme
1c).21 Although so many routes have been reported for the
preparation of aryl methyl sulfides, aryl halide is still the most
frequently used starting material due to its easily availability and
diversity. The reaction of aryl halides with a malodorous CH3SNa
solution often gives the thiomethylated products in good yields,22
but the substrates are often limited by the strong base conditions.
Recently, Cheng and coworkers also found a cooper-mediated
methylthiolation of aryl halides with dimethylsulfoxide in the
o
presence of ZnF2 (2.0 equiv) at 150 C (Scheme 1d).23, 24 Apparently,
the development of more green and mild synthetic routes to aryl
methyl sulfides, with improved availability of starting material is still
highly desired.
HO
MeO MeO
HO
MeO
OH
SMe
N
NH
OH
MeS
N
N
N
H2N
MeO
H
OH
O
SMe
COOH
Roseochelin B
Macrophilone A
Me
Collismycin A
O
S
Me
S
O
S O
O
SMe
Sulindac
N
N
N
F
O
F3C
Me
• HCl
Thioridazine
Isoxaflutole
CH2COOH
Fig. 1 Natural products and pharmacological molecules
containing methyl sulfides, methyl sulfoxides and methyl
sulfones.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 6
View Article Online
DOI: 10.1039/C8OB01758A
ARTICLE
Journal Name
Commercially available S-methylisothiourea sulfate (SMT) as electron-donating (OMe) and electron-withdrawing (CN, CF3)
an odourless and highly crystalline solid is easily prepared from groups at the 5-position for 2-bromopyridines also delivered the
cheap thiourea and dimethyl sulfate.25 Although it has been widely target products 3i–k in excellent yields. Notably, the reaction
employed in organic synthesis for the formation of functionalized proceeded smoothly to afford 3l at room temperature. 3-
heterocycles,26 few reports focus on it as the thiomethyl group Bromopyridine, and 4-bromopyridine hydrochloride also gave 3m
source.27 Herein, we report an efficient cesium carbonate-promoted and 3n in good yields. Other mono- and dibromo-substituted
synthesis of aryl methyl sulfides by the reactions of aryl halides with S- heterocyclic substrates, such as thiazole, benzo[d]thiazole,
methylisothiourea sulfate under metal-free conditions, and two pyridazine, pyrimidine, quinolone and isoquinoline were also
representative S-alkylisothiourea salts also deliver the suitable for this transformation, affording the corresponding
corresponding aryl alkyl sulfides with excellent yields (Scheme 1e).
products 3o–w in 88–99% yields.
DMSO, CuI (2 equiv)
PdCl2, PPh3, 160 oC
Table 1 Optimization of reaction conditions for the synthesis of 2-
(methylthio)pyridine (3a)a
Ar
Ar
(a)
(b)
COOH
Ar
Ar
SMe
SMe
MeSSMe
hv or base
+BF4
N2
-
MeSSMe, DTBP
120 oC
(c)
(d)
(e)
Ar
Ar
B(OH)2
X
Ar
Ar
SMe
SMe
Base
(mmol)
K2CO3 (2.0)
Na2CO3 (2.0) DMSO
NaHCO3 (2.0) DMSO
Et3N (2.0)
Temp
(oC)
80
80
80
80
80
80
80
80
80
80
80
60
40
25
100
80
T
3a
Entry
Solvent
DMSO
(h) Yieldb (%)
DMSO, CuI
ZnF2 (2 equiv), 150 oC
1
2
3
4
5
6
7
8
8
8
8
8
8
4
8
8
6
6
6
12
12
24
2
8
4
40
< 5
< 5
0
SMe
H2N
this work
H2SO4
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
NH
2
None
0
Ar
X
Ar
SMe
Cs2CO3 (2.0)
Cs2CO3 (1.5)
Cs2CO3 (1.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
99
94
89
92
85
80
90
75
60
99
95
58
25
0
Cs2CO3, DMSO
Scheme 1 General routes for aryl methyl sulfides.
9c
10d
11e
12
13
14
15
16
17
18
19
Results and discussion
At the start of our study, the reaction of 2-bromopyridine (1a, 0.5
mmol) and S-methylisothiourea sulfate (2a, 0.5 mmol) was carried
out in DMSO at 80 oC in the presence of K2CO3, and the reaction
gave 2-(methylthio)pyridine (3a) in 40% yield (Table 1, entry 1).
Na2CO3, NaHCO3 and Et3N were ineffective for the reactions (Table
1, entries 2–4). No reaction occurred in the absence of the base
(Table 1, entry 5). Satisfyingly, 3a was obtained in nearly
quantitative yield when Cs2CO3 was used (Table 1, entry 6).
Reducing the amount of base or 2a led to a slightly lower yield
(Table 1, entries 7–11). The yield was obviously influenced by the
reaction temperature, and the reaction time can be shortened at
the temperature of 100 oC (Table 1, entries 12–15). This
transformation was also attempted in other different solvents, such
as DMF, EtOH, 1,4-dioxane, H2O and the mixture of DMSO/H2O (v:v,
1:1), and it was found that DMF was also efficient (Table 1, entries
16–20).
EtOH
80
1,4-dioxane 80
4
4
H2O
80
DMSO:H2O
20
Cs2CO3 (2.0)
80
4
0
(1:1)f
a Unless otherwise specified, the reactions were carried out on a 0.5
mmol scale and conducted at 1a/2a = 0.5/0.5 in 3 mL solvent.
b Isolated yield.
c
1a/2a = 0.5/0.4.
d 1a/2a = 0.5/0.3.
e 1a/2a = 0.5/0.25.
f The volume ratio.
With the aforementioned optimized reaction conditions in
hand (Table 1, entry 6), the scope of aryl halides was investigated
(Table 2). The reaction of 2-chloropyridine with 2a also furnished
the desired product 3a in 95% yield. It was found that 3-, 4-, 5- and
6-position methyl substituted 2-bromopyridines were tolerated in
this transformation to deliver the corresponding 3b–e in good
yields. 2-Bromo-5-chloropyridine and 2,5-dibromopyridine gave 2-
(methylthio)pyridine derivatives 3f and 3g in 86% and 84% yields
respectively under the standard reaction conditions, and the 5-
position halogen atom was not replaced by methylthio group due to
its lower reaction activity than 2-position bromo atom. When the
reaction temperature was increased to 110 oC, 2,5-
bis(methylthio)pyridine (3h) was obtained in 80% yield from 2,5-
dibromopyridine. In addition, the substrates bearing strong
Next, it is our desire to effectively obtain the non-heteroaryl
methyl sulfides by using the present strategy. To our delight, it was
found that bromobenzene and iodobenzene could give the
methyl(phenyl)sulfane (4a) in 82% and 85% yields, respectively. The
substrates bearing electron-withdrawing substituents (COOMe,
SO2Me, COMe, NO2, CN, CF3) on phenyl rings also afforded the
expected product 4b–g in excellent results. Nevertheless, a higher
reaction temperature (110 oC) and longer reaction time were
required for electron-donating (Me, OMe) substituted substrates.
Notably, (4-methoxyphenyl)(methyl)sulfane (4i) was only obtained
in 20% yield and 4-(methylthio)phenol (4i’) was isolated as the main
product in 70% yield involving the C-O bond cleavage reaction. We
also found that methyl(naphthalen-1-yl)sulfane (4j) and anthracen-
2 | J. Name., 2013, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 3 of 6
View Article Online
DOI: 10.1039/C8OB01758A
Organic & Biomolecular Chemistry
ARTICLE
Table 2 The scope of (hetero)aryl halidesa,b
SMe
H2N
DMSO, Cs2CO3
80 oC
SMe
Ar
Br +
H2SO4
Ar
NH
2a
2
3, 4
1
Me
N
Me
SMe
Me
Cl
Me
N
SMe
N
SMe
N
3b
SMe
N
SMe
N
SMe
3a
(99%, 4h, X = Br;
95%, 7h, X = Cl)
3e
3f
(90%, 6h) 3c
3d
(90%, 6h)
(86%, 5h)
SMe
(85%, 6h)
(80%, 6h)
3i
3j
3k
3l
MeS
R
R = OMe (92%, 5h)
R = CN (98%, 1h)
R = CF3 (98%, 1h)
Br
SMe
N
SMe
N
SMe
N
SMe
N
N
3m (80%, 9h)
o
R = NO2 (88%, 1h, 25 C)
c
3h (80%, 8h, 110 oC)
3g
3n
(96%, 4h)
(84%, 5h)
N
SMe
SMe
N
N
N
SMe
S
SMe
N
N
MeS
N
SMe
S
N
SMe
MeS
N
3p
3s
3o (97%, 2h)
(95%, 1h)
3q (97%, 3h)
(97%, 3h)
SMe
3t
3r (99%, 1h)
(92%, 6h)
SMe
R
SMe
MeS
SMe
4a
R = H (82%, 8h, X = Br;
85%, 5h, X = I)
R = COOMe (93%, 4h)
R = SO2Me (97%, 2h)
R = COCH3 (96%, 1h)
R = NO2 (96%, 1h)
N
N
N
3u (95%, 6h)
SMe
4b
4c
4d
4e
(95%, 3h, 110 oC)
(80%, 24h)
4j
o
3v
3w
(88%, 3h, 110 C)
SMe
Ph
Ph
Ph
4f R = CN (92%, 2h)
SMe
4g R = CF3 (97%, 1h)
4h R = Me (83%, 16h, 110 oC)
4i R = OMe (20%, 8h, 110 oC)d
SMe
4k (92%, 15h) 4l (95%, 2h, Z/E=1:5)e 4m (95%, 2h)
4n (90%, 6h)
aUnless otherwise specified, all of the reactions were carried out using (hetero)aryl bromides 1
(0.5 mmol), 2a (0.5 mmol) and Cs2CO3 (2.0 mmol) in DMSO (3 mL) at 80 oC.
bIsolated yield.
c4-Bromopyridine hydrochloride was employed as the substrate.
d4-(Methylthio)phenol (4i’) was obtained in 70% yield.
eThe Z/E ratio of starting material (2-bromovinyl)benzene was 1:5.
9-yl(methyl)sulfane (4k) were also obtained in 80% and 92% yields,
respectively. Recently, Su
cross-coupling reaction of alkenyl sulfides by palladium-catalyst sulfides. It is considered that one-pot reaction29 of aryl halides, thiourea
thioetherification of alkenyl halides with thiols.28 Satisfyingly, in the
and alkyl bromides is a more attractive protocol. It has been reported
árez-Pantiga and coworkers reported a
Furthermore, we are expected to prepare the aryl non-methyl
absence of transition metal catalyst, the reaction of mono-, di-, and that the transition-metal catalysis (Cu or Pd) was indispensable for
trisubstituted vinyl bromides with 2a also gave the corresponding this kind of three-component reaction.30,31 In addition, it is hard to
methyl(styryl)sulfane (4l, Z/E = 1:5), (1H-inden-2-yl)(methyl)sulfane avoid the formation of the by-products diaryl disulfides and alkyl
(
4m
)
and methyl(1,2,2-triphenylvinyl)sulfane
(4n
)
in satisfying disulfides.32 recently, Lu reported an efficient synthesis of nitroaryl
thioethers by SNAr reaction in aqueous Triton X-100 using thiourea as the
sulfur source. Nevertheless, the reported substrates are limited to
result.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 6
View Article Online
DOI: 10.1039/C8OB01758A
Organic & Biomolecular Chemistry
ARTICLE
Table 3 The extension of S-alkylisothiourea saltsa,b
SR
H2N
DMSO, Cs2CO3
80 oC
Br
Ar
+
Ar
SR
NH HX
1
2b, c
5
F3C
N
N
S
N
N
N
N
N
S
N
S
S
S
c
c
c
c
5d
(85%, 5h)
5a
5b
5c
(80%, 9h)
(90%, 3h)
(88%, 2h)
N
N
S
N
S
N
S
5e (92%, 2h)c
5g
5f (81%, 9h)
(95%, 0.5h)
aUnless otherwise specified, all of the reactions were carried out using (hetero)aryl bromides
(0.5 mmol), 2b
2c (1.0 mmol) and Cs2CO3 (2.0 mmol) in DMSO (3 mL) at 80 oC.
bIsolated yield.
cS-[2-(dimethylamino)ethyl]isothiourea dihydrochloride (2b) was employed.
1
/
SMe
H2N
Cs2CO3 (60 mmol)
DMSO (25 mL), 80 oC, 3 h
No column
SMe
H2SO4
O2N
O2N
Br +
NH
2a
(3.03 g, 15 mmol) (4.17 g, 15 mmol)
2
4e
(2.30 g, 91%)
1e'
Scheme 2 Gram-scale experiment for the synthesis of 4e
.
particular examples for 2- and 4-nitrobenzene fluorides. No expected
In order to further demonstrate the synthetic utility of this
products were obtained from 3-nitrobenzene fluorides and fluoro- strategy, a representative example for the gram-scale reaction of 1-
substituted heterocycles.33 Therefore, we believe that the use of S- bromo-4-nitrobenzene (1e’) and 2a was explored. It was found that
alkylisothiourea salts as the starting materials is more convenient due the expected yellow solid 4e was expediently isolated in 91% yield
to their easily availability34 and it would avoid the generation of without the use of column chromatography, as shown in Scheme 2.
inseparable by-products.
O
The structural fragment of 2-(dimethylamino)ethylthio
substituted aromatics exists widely in a number of biologically
active molecules and drug candidates. For example, N,N-dimethyl-
2-(3-phenylquinolin-2-yl)sulfanylethanamine is an important 5-HT2
antagonist,35 which is prepared from chlorinated quinoline with the
H2N
NH2
H2N
SMe
NH
2a
Cs2CO3
CH3SH
H2SO4
2
expensive
starting
material
2-(dimethylamino)ethanethiol
2a'
hydrochloride. As shown in Table 3, by using our present method,
available S-[2-(dimethylamino)ethyl]isothiourea dihydrochloride
Cs2SO4 + CO2
(
2b)
+
and several representative products 5a–e were obtained in 80–92%
yields. Similarly, the reactions gave the corresponding 5f and 5g in
excellent yields from S-cyclopropylmethylisothiourea hydrobromide
Cs2CO3
(
2c). Apparently, some functionalized alkylthio groups can be easily
N
SCH3
N
Br
introduced into the aromatic rings compared with the commonly
used methods, especially for the reactions involving the use of not
easily available thiols as the starting materials.
1a
3a
CsBr + CO2 + H2O
Scheme 3 Possible reaction mechanism.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 4
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 5 of 6
View Article Online
DOI: 10.1039/C8OB01758A
Journal Name
ARTICLE
On the basis of these experimental results and previous combined organic layers were dried over anhydrous magnesium
reported work, a possible reaction mechanism was proposed using sulfate and filtered. After removal of the solvent, the residue was
the synthesis of 3a as an example, as shown in Scheme 3. In the drying in vacuum oven to give yellow solid (2.30 g), which was pure
presence of cesium carbonate, S-methylisothiourea sulfate (2a) can enough for structural analysis.
be easily converted into 2a’, simultaneously releasing urea, cesium
sulfate and carbon dioxide. Then, the reaction of 1a with 2a’
furnished the desired product 3a under the basic condition.
Conflicts of interest
There are no conflicts to declare.
Conclusions
In summary, we have developed an efficient method for the
synthesis of aryl methyl sulfides from easily available aryl
halides and with commercially available S-methylisothiourea
sulfate in the presence of cesium carbonate. Cheap, stable and
Acknowledgements
We gratefully acknowledge support from the National Natural
Science Foundation of China (21542009).
odourless crystalline solid S-methylisothiourea sulfate can be
used as the surrogate for malodorous methanethiol. Similarly,
some functionalized alkylthio groups, such as 2-
Notes and references
(dimethylamino)ethylthio and cyclopropylmethylthio group
can be conveniently introduced into the molecules by using
this strategy, while other reported methods usually require
not easily available or non-commercial thiols as the starting
materials. This reaction shows wide substrate scope, excellent
yields, the tolerance of functional groups and easy operation.
The gram-scale reaction also proceeds smoothly and the
product can be easily purified without the use of column
chromatography. Accordingly, it is believed that this route to
aryl alkyl sulfides is well competitive in currently known
methods. The application of S-alkylisothiourea salts in other
organic reactions is underway in our laboratory.
1
R. Wang and M. R. Seyedsayamdost, Org. Lett., 2017, 19,
5138.
2
K. Zlotkowski, W. M. Hewitt, P. Yan, H. R. Bokesch, M. L.
Peach, M. C. Nicklaus, B. R. O’Keefe, J. B. McMahon, K. R.
Gustafson and J. S. Schneekloth Jr, Org. Lett., 2017, 19, 1726.
(a)J. López-Ogalla, G. Saiz and F. E. Palomo, Org. Process Res.
Dev., 2013, 17, 120; (b) S. Gomi, S. Amano, E. Sato, S.
Miyadoh and Y. Kodama, J. Antibiot., 1994, 47, 1385.
X.-Y. Ke, V. W. L. Ng, S.-J. Gao, Y. W. Tong, J. L. Hedrick and
Y.-Y. Yang, Biomaterials, 2014, 35, 1096.
J. Legros, J. R. Dehli and C. Bolm, Adv. Synth. Catal., 2005,
347, 19.
E. Prade, C. Barucker, R. Sarkar, G. Althoff-Ospelt, J. M. L. del
Amo, S. Hossain, Y. Zhong, G. Multhaup and B. Reif,
Biochemistry, 2016, 55, 1839.
3
4
5
6
Experimental
7
8
K. E. Pallett, S. M. Cramp, J. P. Little, P. Veerasekaran, A. J.
Crudace and A. E. Slater, Pest Manag. Sci., 2001, 57, 133.
T. Kimoto, K. Tanaka, M. Kawahata, K. Yamaguchi, S. Otsubo,
Y. Sakai, Y. Ono, A. Ohno and K. Kobayashi, J. Org. Chem.,
2011, 76, 5018.
General Information: All the chemicals were commercially available
and used without further purification. 1H NMR and 13C NMR were
recorded in CDCl3 using Bruker Avance II 300 MHz spectrometer at
300 MHz and 75 MHz, respectively. Chemical shifts are reported
relative to internal standard tetramethylsilane (TMS). Mass spectra
were measured on LCQ Advantage MAX or Solanx70 FT-MS.
Infrared spectra (IR) were obtained as KBr pellet samples using a
Nicolet 5700 FTIR spectrometer. Melting points were determined
using an uncorrected X-4 apparatus. Flash column chromatography
was performed on 200–300 mesh silica gel.
9
(a) H. Prokopcov
,
á and C. O. Kappe, Angew. Chem. Int. Ed.,
2009, 48 2276; (b) L. Betancourt-Mendiola, I. Valois-
Escamilla, T. Arbeloa, J. Bañuelos, I. L. Arbeloa, J. O. Flores-
Rizo, R. Hu, E. Lager, C. F. A. Gómez-Durán, J. L. Belmonte-
Vázquez, M. R. Martínez-González, I. J. Arroyo, C. A. Osorio-
Martínez, E. Alvarado-Martínez, A. Urías-Benavides, B. D.
Gutiérrez-Ramos and B. Z. Tang, E. Peña-Cabrera, J. Org.
Chem., 2015, 80, 5771.
General procedure for aryl alkyl sulfides 3–5
10 (a) S. G. Modha, V. P. Mehta and E. V. Van der Eycken, Chem.
Soc. Rev., 2013, 42, 5042; (b) L. Wang, W. He and Z Yu, Chem.
Soc. Rev., 2013, 42, 599; (c) F. Zhu and Z.-X. Wang, Org. Lett.,
2015, 17, 1601; (d) Z.-J. Quan, Y. Lv, F.-Q. Jing, X.-D. Jia, C. D.
Huo and X. C. Wang, Adv. Synth. Catal., 2014, 356, 325.
A
mixture of (hetero)aryl halides
alkylisothiourea salts (2a, 0.5 mmol; 2b 2c, 1.0 mmol), cesium
carbonate (652 mg, 2.0 mmol) and DMSO (3 mL) was reacted in the
range of room temperature to 110 oC for 0.5
24 h. After
(1, 0.5 mmol), S-
/
–
11 (a) N. Barbero and R. Martin, Org. Lett., 2012, 14, 796; (b) Y.
Uetake, T. Niwa and T. Hosoya, Org. Lett., 2016, 18, 2758. (c)
D. Wang, K. Zhao, C. Xu, H. Miao and Y. Ding, ACS Catal.,
completion of the reaction, the mixture was poured into the water
and extracted with dichloromethane (3×15 mL). The combined
organic layers were dried over anhydrous magnesium sulfate and
filtered. After removal of the solvent, the residue was directly used
for structural analysis or purified by flash column chromatography
on silica gel using petroleum ether or petroleum ether/ethyl
acetate (v:v, 50:1 to 3:1) as the eluent to afford the target products.
2014, 4, 3910. (d) C. Ge, X. Sang, W. Yao, L. Zhang and D.
Wang, Green Chem., 2018, 20, 1805. (e) Z. Xu, X. Yu, X. Sang
and D. Wang, Green Chem., 2018, 20, 2571.
12 (a) X.-F. Wu and K. Natte, Adv. Synth. Catal., 2016, 358, 336;
(b)Q. Gao, X. Wu, Y. Li, S. Liu, X. Meng and A. Wu, Adv. Synth.
Catal., 2014, 356, 2924; (c) E. Jones-Mensah, M. Karki and
J.Magolan, Synthesis, 2016, 48, 1421; (d) S. Liu, H. Xi, J.
Zhang, X. Wu, Q. Gao and A. Wu, Org. Biomol. Chem., 2015,
13, 8807; (e) G. Yin, Z. Wang, A. Chen, M. Gao, A. Wu and Y.
Pan, J. Org. Chem., 2008, 73, 3377.
Gram-scale reaction for the synthesis of 4e
A
mixture of 1-bromo-4-nitrobenzene (3.03 g, 15 mmol), S-
methylisothiourea sulfate (4.17 g, 15 mmol), cesium carbonate
o
(19.55 g, 60 mmol) and DMSO (25 mL) was heated at 80 C for 3 h.
13 (a) Y. Uetake, T. Niwa and T. Hosoya, Org. Lett., 2016, 18,
2758; (b) J. Rong, L. Deng, P. Tan, C. Ni, Y. Gu and J. Hu,
Angew. Chem. Int. Ed., 2016, 55, 2743.
After completion of the reaction, the mixture was poured into the
water and extracted with dichloromethane (3×40 mL). The
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 6 of 6
View Article Online
DOI: 10.1039/C8OB01758A
ARTICLE
14 Y. Jiang, Y. Qin, S. Xie, X. Zhang, J. Dong and D. Ma, Org. Lett., 33 G. Lu and C. Cai, RSC Adv., 2014,
Journal Name
4, 59990.
2009, 11, 5250.
15 T. N. Glasnov, J. D. Holbrey, C. O. Kappe, K. R. Seddon and T.
Yan, Green Chem., 2012, 14, 3071.
16 C. Shen, P. Zhang, Q Sun, S. Bai, T. S. A. Hor and X. Liu, Chem.
Soc. Rev., 2015, 44, 291.
34 A. Jamaleddini and M. R. Mohammadizadeh, Tetrahedron
Lett., 2017, 58, 78.
35 T. P. Blackburn, B. Cox, A. J. Guildford, D. J. L. Count, D. N.
Middlemiss, R. J. Pearce and C. W. Thornber, J. Med. Chem.,
1987, 30, 2252.
17 X. Chen, X.-S. Hao, C. E. Goodhue and J.-Q. Yu, J. Am. Chem.
Soc., 2006, 128, 6790; (b) M. Klečka, R. Pohl, J. Čejka and M.
Hocek, Org. Biomol. Chem., 2013, 11, 5189; (c) C. Dai, Z. Xu,
F. Huang, Z. Yu and Y. F. Gao, J. Org. Chem., 2012, 77, 4414;
(d) L. Chu, X. Yue and F.-L. Qing, Org. Lett., 2010, 12, 1644.
18 (a) Z. Fu, Z. Li, Q. Xiong and H. Cai, Eur. J. Org. Chem., 2014,
2014, 7798; (b) M. Li and J. M. Hoover, Chem. Commun.,
2016, 52, 8733. (c) D. Wang, X. Yu, W. Yao, W. Hu, C. Ge and
X. Shi, Chem. Eur. J., 2016, 22, 5543. (d) Z. Xu, D.-S. Wang, X.
Yu, Y. Yang and D. Wang, Adv. Synth. Catal., 2017, 359, 3332.
(e) R. Huang, Y. Yang, D.-S. Wang, L. Zhang and D. Wang, Org.
Chem. Front., 2018, 5, 203.
19 L. Hu, D. Wang, X. Chen, L. Yu, Y. Yu, Z. Tan and G. Zhu, Org.
Biomol. Chem., 2017, 15, 5674.
20 (a) M. Majek and A. J. von Wangelin, Chem. Commun., 2013,
49, 5507; (b) D. Koziakov, M. Majek and A. J. von Wangelin,
Org. Biomol. Chem., 2016, 14, 11347.
21 X. Wu, J. Lou and G. Yan, Synlett, 2016, 27, 2269.
22 L. Testaferri, M. Tiecco, M. Tingoli, D. Bartoli and A. Massoli,
Tetrahedron, 1985, 41, 1373.
23 F. Luo, C. Pan, L. Li, F. Chen and J. Cheng, Chem. Commun.,
2011, 47, 5304.
24 P. J. A. Joseph, S. Priyadarshini, M. L. Kantam and B.
Sreedhar, Tetrahedron, 2013, 69, 8276.
25 C. A. Barker, S. E. Allison, S. Zlitni, N. D. Nguyen, R. Das, G.
Melacini, A. A. Capretta and E. D. Brown, Bioorg. Med. Chem.
Lett., 2013, 23, 2426.
26 (a) E. da C. Aquino, M. M. Lobo, G. Leonel, M. A. P. Martins,
H. G. Bonacorso and N. Zanatta, Eur. J. Org. Chem., 2017,
2017, 306; (b) Z. Yang, L. Li, J. Zheng, H. Ma, S. Tian, J. Li, H.
Zhang, X. Zhen and X. Zhang, ACS Chem. Neurosci., 2016, 7,
1575; (c) S. Salerno, A. M. Marini, G. Fornaciari, F. Simorini,
C. L. Motta, S. Taliani, S. Sartini, F. D. Settimo, A. N. García-
Argáez, O. Gia, S. Cosconati, E. Novellino, P. D'Ocon, A.
Fioravanti, P. Orlandi, G. Bocci and L. D. Via, Eur. J. Med.
Chem., 2015, 103, 29.
27 (a) P. Fruhmann, T. Weigl-Pollack, H. Mikula, G.
Wiesenberger, G. Adam, E. Varga, F. Berthiller, R. Krska, C.
Hametnera and J. Fröhlich, Org. Biomol. Chem., 2014, 12
5144; (b) D. T. Hurst, J. Heterocycl Chem., 1995, 32, 697. (c)
K. Marciniec, A. Maślankiewicz and M. J. Maślankiewicz, J.
Heterocycl Chem., 2015, 52, 1019.
,
.
.
28 N. Velasco, C. Virumbrales, R. Sanz, S. Suárez-Pantiga, M. A.
and Fernández-Rodríguez, Org. Lett., 2018, 20, 2848.
29 (a) T. Ding, L. Jiang and W. Yi, Org. Lett., 2018, 20, 170; (b) Y.
Li, J. Pu and X. Jiang, Org. Lett., 2014, 16, 2692; (c) B. B. Liu,
X.-Q. Chu, H. Liu, L. Yin, S.-Y. Wang and S.-J. Ji, J. Org. Chem.,
2017, 82, 10174.
30 (a) H. Firouzabadi, N. Iranpoor and M. Gholinejad, Adv.
Synth. Catal., 2010, 352, 119; (b) J. Mondal, A. Modak, A.
Dutta, S. Basu, S. N. Jha, D. Bhattacharyya and A. Bhaumik,
Chem. Commun., 2012, 48, 8000.
31 (a) Z. Qiao, J. Wei and X. Jiang, Org. Lett., 2014, 16, 1212; (b)
J. T. Reeves, K. Camara, Z. S. Han, Y. Xu, H. Lee, C. A. Busacca
and C. H. Senanayake, Org. Lett., 2014, 16, 1196; (c) D. J. C.
Prasad and G. Sekar, Org. Lett., 2011, 13, 1008; (d) K. M.
Wager and M. H. Daniels, Org. Lett., 2011, 13, 4052; (e) V. K.
Akkilagunta and R. R. Kakulapati, J. Org. Chem., 2011, 76
6819.
,
32 (a) X. Ma, L. Yu, C. Su, Y. Yang, H. Li and Q. Xu, Adv. Synth.
Catal., 2017, 359, 1649; (b) J. E. Argüello, L. C. Schmidt and A.
B. Peñéñory, Org. Lett., 2003,
6 | J. Name., 2013, 00, 1-3
5, 4133.
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins