Aryl methyl sulfides via SNAr using DMSO as the source of the thiomethyl moiety

Article abstract of DOI:10.1016/j.tetlet.2014.07.058

A unique synthesis of aryl methyl sulfides is reported proceeding via reduction of dimethylsulfoxide to dimethylsulfide at elevated temperature in the presence of Hunig's base followed by nucleophilic aromatic substitution and demethylation. Activated aryl fluorides, chlorides, and nitrobenzenes are suitable substrates with 13 examples provided. Dimethylsulfoxide serves as a simple and inexpensive formal source of the thiomethyl moiety.

Full text of DOI:10.1016/j.tetlet.2014.07.058

Tetrahedron Letters 55 (2014) 5323–5326
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Aryl methyl sulfides via SNAr using DMSO as the source
of the thiomethyl moiety
⇑
Ebenezer Jones-Mensah, Jakob Magolan
Department of Chemistry, University of Idaho, Moscow, ID 83844, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A unique synthesis of aryl methyl sulfides is reported proceeding via reduction of dimethylsulfoxide to
dimethylsulfide at elevated temperature in the presence of Hunig’s base followed by nucleophilic aro-
matic substitution and demethylation. Activated aryl fluorides, chlorides, and nitrobenzenes are suitable
substrates with 13 examples provided. Dimethylsulfoxide serves as a simple and inexpensive formal
source of the thiomethyl moiety.
Received 22 May 2014
Revised 15 July 2014
Accepted 16 July 2014
Available online 22 July 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Dimethylsulfoxide
Nucleophilic aromatic substitution
Methyl sulfides
Thiomethyl
Hunig’s base
OH
Aryl methyl sulfide, sulfoxide, and sulfone functionalities are
commonplace in pharmaceutical and agrochemical discovery pro-
grams.1 Examples include the FDA approved antipsychotic (1),2
anti-inflammatory (2),3 and antibiotic (3)4 drugs and the pesticide
(4)5 illustrated in Figure 1.
O
S
O
N
N
SMe
Me
Me
F
In general, the aryl C–S bond can be accessed via reaction of aryl
lithiums with alkyldisulfides or elemental sulfur,6 transition metal
catalyzed cross-coupling with sulfides or sulfinic acid salts,7 or
nucleophilic aromatic substitution (SNAr) reaction between
activated aryl halides and thiolate anions.8 Thiols have also been
used directly as SNAr substrates in the presence of cesium
carbonate.9 Access to aryl methyl sulfides via SNAr requires non-
volatile derivatives of toxic and malodorous methanethiol gas:
sodium methylthiolate (NaSMe),10 or (methylthio)trimethylsilane
(TMSSMe).11 Herein we report an alternative, and relatively inex-
pensive, route to aryl methyl sulfides by means of an atypical SN-
Ar-type reaction characterized by the unprecedented role of
dimethylsulfoxide (DMSO) as a formal source of the thiomethyl
moiety.
Sulindac
Me
Thioridazine
(2)
(1)
O
O S O O
Me
F
S
O
O
N
O
Cl
N
H
F
3C
OH
Cl
Florfenicol
Isoxaflutole
(4)
(3)
Figure 1. Aryl methyl sulfides, sulfoxides, and sulfones of pharmaceutical and
agrochemical relevance.
NH2
This work was initiated by the serendipitous observation
illustrated in Scheme 1. As part of our synthetic methodology
development in the area of polycyclic aromatic scaffolds, we
attempted to prepare biarylamine 7 via SNAr reaction between
1-fluoro-2-nitrobenzene (5) and 1-naphthalenamine (6). This reac-
tion was previously accomplished by McComas et al. by treatment
NO2
NO2
NO2
6
SMe
F
DIPEA
DMSO
189°C,
NH
+
8
7
24 h
5
not
observed
major
product
⇑
Corresponding author. Tel.: +1 208 885 4023; fax: +1 208 885 6173.
E-mail address: jmagolan@uidaho.edu (J. Magolan).
Scheme 1. Unanticipated formation of sulfide 8.
http://dx.doi.org/10.1016/j.tetlet.2014.07.058
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

5324
E. Jones-Mensah, J. Magolan / Tetrahedron Letters 55 (2014) 5323–5326
sulfide 8 was a result of redox chemistry between DMSO and
O2
initiation
Hunig’s base to produce dimethyl sulfide which then served as
the nucleophilic partner in a nucleophilic aromatic substitution
reaction.
NR3
NR2
A potential mechanism is illustrated in Scheme 2.
NR2
10
10
At elevated temperature, activation of DMSO (9) by reaction
with an electrophilic iminium (10), some of which may be formed
via air oxidation, can result in intermediate 11 which may undergo
intramolecular proton transfer (via 6-membered transition state)
as shown to liberate an aldehyde, an amine, and zwitterionic spe-
cies 12. A subsequent fragmentation with intramolecular proton
transfer as illustrated would yield an iminium species (10) and
dimethylsulfide (DMS, 13). At this point, SNAr reaction between
DMS and aryl fluoride 6 can yield 15 via the Meisenheimer inter-
mediate 14. Nucleophilic demethylation of 15 leads to the
observed aryl methyl sulfide product 8.
Some support for our proposed mechanism was obtained when
this reaction was performed in deuterated DMSO and monitored
by 1H NMR. In addition to the formation of the trideuteromethyl
sulfide 16 as expected, we observed amines 17 and 18 which are
indicators of oxidation of Hunig’s base as predicted by our mecha-
nistic hypothesis (Scheme 3).
H
H
Me
2C
R2N
O
S Me
NR3
11
O
S
S
NR2
-RCHO
-R2NH
SMe2
Me
Me
H
13
9
NR3
12
F
NO2
Me
6
Me
NR3
S Me
F
S
SMe
Me
NO2
NO2
NO2
8
15
14
Scheme 2. Proposed mechanism.
Dimethylsulfoxide, in the presence of various activating addi-
tives, is a common terminal oxidant for the oxidation of alcohols13
and various other substrates.14 To our knowledge the dimethylsul-
fide byproduct that results from all DMSO-based oxidations has not
yet been made useful as a substrate in a subsequent transformation.
We sought to optimize the observed transformation into a suit-
able synthetic tool as summarized in Table 1. In the absence of
DIPEA no reaction is observed (entry 1). Furthermore, when the
temperature is decreased to 100 °C or 150 °C no reaction takes
place with only starting materials recovered (entries 2 and 3). With
2.0 equiv of DIPEA in refluxing DMSO, conversions of 26, 47, and
100 percent are observed at 12, 16, and 22 h, respectively. With
diisopropylamine (DIPA) as additive (entry 7) we observe some
formation of the diisopropylaniline resulting from nucleophilic
substitution of DIPA (compound C, R = iPr). Similarly, reaction with
piperidine yields exclusively the N-substitution product (entry 8,
compound C, NR2 = piperidine). Triethylamine is also a suitable
additive (entry 9). The reaction also proceeds to complete
NO2
NO2 CD3
S
F
DIPEA
+
HN
+
H2N
DMSO-d6
189 °C
6
16
17
observed by 1H NMR
18
Scheme 3. Result of reaction in deuterated DMSO.
with diisopropylethylamine (DIPEA) in refluxing dimethylformam-
ide (DMF).12 Our brief optimization included a trial reaction in
dimethylsulfoxide which, surprisingly, failed to yield 7 but rather
resulted in substantial recovery of 2-(methylthio)nitrobenzene
(8) in addition to unreacted 1-naphthalenamine (6).
The only potential source of the sulfur atom incorporated in sul-
fide 8 was the solvent. We thus hypothesized that the formation of
Table 1
Reaction optimization
NO2
NO2
NO2
NR2
SMe
+
F
additive
DMSO
19
8
5
Entry
Additive (equiv)
Temp (°C)
Time (h)
Conversion (%)a
Ratio (8:19)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
None
189
100
150
189
189
189
189
189
189
189
189
189
189
189
24
22
22
12
16
22
22
22
22
22
22
22
72
12
0
0
0
26
47
100
100
100
100
100
95
20
100
100
n/a
n/a
n/a
1:0
1:0
1:0
1:0.3
0:1
1:0
1:0
1:0
1:0
1:0
1:0b
DIPEA (2.0)
DIPEA (2.0)
DIPEA (2.0)
DIPEA (2.0)
DIPEA (2.0)
DIPA (2.0)
piperidine
Et3N (2.0)
DIPEA (1.0)
DIPEA (0.5)
DIPEA (0.1)
DIPEA (0.4)
DIPEA (1.0) + H2O (1.0)
a
Determined by NMR.
Isolated yield of compound 8 was 80%.
b

E. Jones-Mensah, J. Magolan / Tetrahedron Letters 55 (2014) 5323–5326
5325
conversion in 22 h when the amount of DIPEA is reduced to
N
O2
NO2
Br
1.0 equiv (entry 11) and to 95% conversion in 22 hours with just
0.5 equiv. When the amount of amine is reduced to 0.1 equiv con-
version falls to 20% (entry 12). Given that for each mole of tertiary
amine, 3 moles of DMSO can potentially be reduced to DMS, we
assume that a minimum of 0.33 equiv of DIPEA is required for com-
plete substrate consumption. Indeed, complete conversion is
observed with 0.4 equiv of DIPEA after prolonged reaction time
(3 days). Finally, addition of 1.0 equiv of water along with 1.0 equiv
of the DIPEA increases the rate of reaction relative to base alone
with complete conversion in just 12 h and a yield of 80% after
workup and chromatography (entry 14). The specific role of water
in this process remains unclear. Addition of greater volumes of
water does not further improve the reaction rate.
N
24
F
N
O2
22
23
Figure 2. Substrates found to be unsuitable for this chemistry.
To explore the substrate scope of this transformation, we
applied our preferred reaction conditions (DIPEA 1.0 equiv; water
1.0 equiv; refluxing DMSO) to a series of substrates as shown in
Table 2. Reaction of 4-fluoronitrobenzene (20b) results in
4-(methylthio)nitrobenzene (21b) in 81% yield after 12 h reaction
time (entry 2). As expected, the p-chloro derivative (20c) is less
reactive yielding only 49% of the same sulfide product (21b) after
a prolonged 3-day reaction (entry 3). We were pleased to find that
p-dinitrobenzene (20d) is also readily converted to 21b with com-
plete consumption of starting material after just 6 h and 80% iso-
lated yield (entry 4). Aryl cyanides 20e–20g are also suitable
substrates however isolated yields are lower than with their anal-
ogous nitrobenzenes. 4-(methylthio)benzonitrile (21c) is prepared
from the corresponding aryl fluoride (20e) and chloride (20f)
substrates in 66% and 21% yields, respectively (entries 5 and 6).
In addition, reaction of 2-fluorobenzonitrile (20g) results in
2-(methylthio)benzonitrile (21d) in 62% yield (entry 7). Two
fluorobenzaldehyde substrates (20h and 20i) are suitable precur-
sors for the corresponding 4- and 2-(methylthio)benzaldehydes
(21e and 21f) in 60% and 64% yields, respectively (entries 8 and 9).
We found that 2-(methylthio)benzaldehyde (21f) can also be
readily obtained from 2-nitrobenzaldehyde (20j) in 56% isolated
yield with complete substrate consumption observed after 15 h
(entry 9). Finally, 2,6-difluorobenzonitrile (20k) and 2,6-dichloro-
benzonitrile (20l) both react to give the mono-substitution prod-
ucts 21g and 21h in 63% and 52% yields, respectively (entries 11
and 12).
Three substrates found unsuitable for this transformation are
illustrated in Figure 2. Two traditionally poor SNAr substrates,
4-bromonitrobenzene (22) and m-dinitrobenzene (23), failed to
yield methylthio ethers using our procedure. We observed mainly
unreacted starting material with some decomposition after pro-
longed reaction times. Regrettably, 2-fluoropyridine (24) is also
an unsuitable substrate with only apparent decomposition evident
under these reaction conditions.
In summary, we disclose an unusual transformation that yields
aryl methyl sulfides from activated fluoro-, chloro, and nitrobenz-
enes via an unprecedented nucleophilic aromatic substitution pro-
cess that relies on the in situ reduction of DMSO to DMS at elevated
temperature in the presence of a tertiary amine. As a formal source
of the thiomethyl moiety, DMSO is preferable in terms of cost effi-
ciency to NaSMe or TMSSMe. We hope that our convenient alterna-
tive to these traditional nucleophiles may find use in medicinal
chemistry efforts. We presently continue to explore methodologies
based on in situ reduction of sulfoxides to sulfides further syn-
thetic applications forthcoming.
Table 2
Reaction scope
e u v
DIPEA 1
i
q
(
)
e
M
S
X
e u v
H2
1
i
q
)
O
(
R
R
re ux
fl
DM
SO
20
21
Entry Substrate
Product
Time (h) Yielda (%)
N
O2
N
O2
e
M
21
F
S
1
2
12
12
80
81
a
20
a
F
C
N
e
21b
M
S
20b
N
O2
O2
O2
N
O2
l
c
20
3
4
5
6
21b
21b
72
6
49
80
66
21
N
N
O2
20d
F
e
M
S
e
20
c
24
24
21
N
N
C
N
C
l
C
20f
21c
C
C
N
N
C
e
M
S
F
7
8
24
48
62
60
20
21d
g
F
e
21
M
S
e
20h
O
O
O
O
e
M
21f
F
S
9
24
15
64
56
20i
O
N
O2
10
21f
Acknowledgment
20
j
N
N
C
C
This work was supported by the University of Idaho. We thank
Dr. Alex Blumenfeld for assistance with NMR analysis.
e
21
F
F
F
M
S
11
12
18
24
63
52
20k
g
N
N
C
C
Supplementary data
e
M
S
21h
l
l
l
C
C
C
20l
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.07.
058.
a
Isolated yields (single run).

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2181; (c) Itoh, T.; Mase, T. Org. Lett. 2004, 6, 4587–4590; (d) Zheng, N.;
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