Microwave-Assisted Copper-Catalyzed Cross-Coupling Reaction of Thiols with Aryl Iodides in Water

Article abstract of DOI:10.1055/s-0034-1379206

Microwave-promoted C-S bond formation from thiols and aryl iodides in the presence of a copper catalyst is reported. A combination of copper(II) oxide and 1,10-phenanthroline catalyzes this reaction. A variety of aryl iodides react smoothly with thiols to provide the corresponding aryl sulfides in good to excellent yields. Notably, the reactions proceed in water with a short reaction time (30 minutes). This system shows broad functional-group tolerance; amino, chloro, bromo, acetyl, and nitro groups are unaffected by the reaction conditions.

Full text of DOI:10.1055/s-0034-1379206

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 181–186
paper
181
Y.-A. Chen et al.
Paper
Synthesis
Microwave-Assisted Copper-Catalyzed Cross-Coupling Reaction
of Thiols with Aryl Iodides in Water
Catalytic Cross-Coupling of Thiols with Aryl Iodides
Yi-An Chen1
Satpal Singh Badsara1
CuO (5.0 mol%)
1,10-phenanthroline
(5.0 mol%)
S
Wan-Ting Tsai
Chin-Fa Lee*
Ar-I
Ar
R
+
HS-R
KOt-Bu, H2O, MW
120 °C, 30 min
64–99%
Department of Chemistry, National Chung Hsing University,
Ar = aryl; R = aryl, alkyl
Taichung, Taiwan 402, R. O. C.
+
8
8
6
4
(2
)
2
8
6
2
5
4
7
cfalee@dragon.nchu.edu.tw
Received: 26.07.2014
Accepted after revision: 01.09.2014
Published online: 15.10.2014
DOI: 10.1055/s-0034-1379206; Art ID: ss-2014-f0467-op
The microwave-assisted technique has gained much at-
tention because of its high efficiency and short reaction
times.16n,17 Although the microwave-assisted copper-cata-
lyzed C–S coupling reaction is known,18 it does have several
limitations in that reaction times of 120–180 minutes are
required and these reactions are performed in organic sol-
vents.18 As part of our ongoing studies on C–S coupling re-
actions,6a,8c,d,10a,d,14,19 we report a microwave-assisted cop-
per-catalyzed C–S bond-formation reaction of aryl iodides
with thiols in water with a short reaction time (30 min-
utes).
Abstract Microwave-promoted C–S bond formation from thiols and
aryl iodides in the presence of a copper catalyst is reported. A combina-
tion of copper(II) oxide and 1,10-phenanthroline catalyzes this reaction.
A variety of aryl iodides react smoothly with thiols to provide the corre-
sponding aryl sulfides in good to excellent yields. Notably, the reactions
proceed in water with a short reaction time (30 minutes). This system
shows broad functional-group tolerance; amino, chloro, bromo, acetyl,
and nitro groups are unaffected by the reaction conditions.
We chose 1-iodo-4-methylbenzene (1a) and benzene-
thiol (2a) as starting materials for determining the optimal
reaction conditions. A 22% yield of sulfide 3a was obtained
when the reaction was performed in water in the presence
of copper(II) oxide with 1,10-phenanthroline (L1; Figure 1)
as a ligand and cesium carbonate as a base at 120 °C in an
oil bath for 24 hours (Table 1, entry 1). To our delight, how-
ever, we obtained a 90% yield of sulfide 3a within 30 min-
utes when microwave heating was applied instead of con-
ventional heating in an oil bath (entry 2). A study of the ef-
fect of various ligands (Figure 1) showed that L1 is among
the best ligands (entries 3–8). We also studied the effect of
various bases (entries 9–14), and we found that potassium
tert-butoxide is superior to other bases, giving a 99% isolat-
ed yield of the product (entry 9). A lower reaction tempera-
ture (entry 15) or a shorter reaction time (entry 16) gave a
reduced yield of the product. A control experiment showed
that only traces of product were detected when the reaction
was carried out in the absence of copper(II) oxide (entry
17). When we used copper(I) oxide or copper(II) acetate as
the catalyst for the coupling reaction in the presence of L1
as the ligand and potassium tert-butoxide as the base, sul-
fide 3a was obtained in 89% and 65% yield, respectively.
Key words microwave heating, copper, cross-coupling, thiols, aryl io-
dides, sulfides
The preparation of aryl sulfides has developed into an
interesting topic for synthetic organic chemists, as these
molecules play important roles in organic synthesis, mate-
rials science, and chemical biology.2–4 Whereas convention-
al methods for preparing aryl sulfides require harsh reac-
tion conditions,5 the transition-metal-catalyzed formation
of C–S bond from thiols and aryl halides proceeds under
mild conditions.6–15 Palladium,7 copper,8 nickel,9 iron,10 in-
dium,11 cobalt,12 gold,13 manganese,14 and silver15 have all
been used as catalysts for this transformation. Remarkably,
copper is the most popular of these metals because of the
low cost of its salts. However, most copper-catalyzed C–S
coupling reactions are performed in organic solvents.8 Envi-
ronmentally friendly catalytic systems in which water is
used as the reaction medium are attractive because water is
safe and abundant.16a–d As a result, water has been used in
many transition-metal-catalyzed cross-coupling reac-
tions16e including C–S bond-forming process.16f–r However,
such reactions have two major limitations. The first is that
long reaction times (24–48 hours)16f–r are required and, sec-
ondly, activated aryl chlorides couple only with aryl thiols:
alkyl thiols cannot be used.16r
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 181–186

182
Y.-A. Chen et al.
Paper
Synthesis
Ph
Ph
reaction. Alkyl thiols 2 (entries 13–21) also reacted
smoothly with aryl iodides 1 to give the corresponding sul-
fides 3 in in good to excellent yields. However, 2-iodopyri-
dine gave only a trace of the corresponding sulfide in its re-
action with 4-methylbenzenethiol (entry 22).
N
N
N
N
N
N
L2
L1
L3
O2N
Table 2 Microwave-Assisted Copper-Catalyzed Coupling Reaction of
Thiols with Iodidesa
PPh3
N
N
N
N
N
N
CuO (5.0 mol%)
L1 (5.0 mol%)
L4
L5
L7
L6
S
HS-R
Ar-I
+
Ar
R
Figure 1 Structures of ligands L1–L7
1
2
KOt-Bu, H2O, MW
3
120 °C, 30 min
Table 1 Optimization of the Reaction Conditionsa
Entry Ar
R
Product
Yieldb (%)
SH
1
3-Tol
2-Tol
4-Tol
Ph
3b
3c
3d
3e
3f
87
93
93
81
91
84
88
96
82
83
97
78
82
83
88
88
72
71
69
65
64
tracec
S
CuO (5.0 mol%)
L (5.0 mol%)
I
2
Ph
+
3
4-ClC6H4
Ph
Me
Me
base, H2O, MW
4
3-MeOC6H4
4-BrC6H4
4-ClC6H4
4-MeOC6H4
4-Tol
2a
1a
Entry Ligand Base
3a
5
Ph
Temp (°C)
Time (min)
Yieldd (%)
6
Ph
3g
3h
3i
1
L1
L1
L2
L3
L4
L5
L6
L7
L1
L1
L1
L1
L1
L1
L1
L1
L1
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
KOt-Bu
KOH
120b
120
120
120
120
120
120
120
120
120
120
120
120
120
110
120
120
720
30
30
30
30
30
30
30
30
30
30
30
30
30
30
10
30
22
90
77
88
14
66
34
22
99
63
57
81
69
78
71
69
trace
7
4-ClC6H4
4-MeOC6H4
Ph
2
8
3
9
3-O2NC6H4
4-Tol
3j
4
10
11
12
13
14
15
16
17
18
19
20
21
22
2-H2NC6H4
Ph
3k
3l
5
4-MeCOC6H4
3-MeCOC6H4
4-MeOC6H4
4-ClC6H4
4-Tol
6
Ph
3m
3n
3o
3p
3q
3r
7
(CH2)11Me
(CH2)11Me
Bn
8
9
10
11
12
13
14
15
16
17c
4-BrC6H4
4-Tol
(CH2)11Me
(CH2)11Me
Bn
NaOt-Bu
K2CO3
Ph
3s
3t
NaOH
Ph
(CH2)11Me
CH2CH(Me)Et
Cy
Et3N
4-Tol
3u
3v
3w
KOt-Bu
KOt-Bu
KOt-Bu
4-Tol
2-pyridyl
4-Tol
a Reaction conditions: 1 (0.6 mmol), 2 (0.5 mmol), CuO (0.025 mmol, 5
mol%), L1 (0.025 mmol, 5 mol%), KOt-Bu (0.75 mmol), H2O (0.5 mL).
b Isolated yield based on thiol.
a Reaction conditions: 1a (0.6 mmol), 2a (0.5 mmol), CuO (0.025 mmol, 5
mol%), ligand (0.025 mmol, 5 mol%), base (0.75 mmol), H2O (0.5 mL).
b The reaction was performed in an oil bath.
c No catalyst was used.
c Detected by GC/MS.
d Isolated yield.
We also carried out similar C–S coupling reactions of
other aryl halides with benzenethiol by using the same cat-
alytic system under similar reaction conditions. However,
neither aryl chlorides nor aryl bromides were suitable sub-
strates for C–S coupling with benzenethiol, as the thiol was
converted into the corresponding disulfide in the reaction
system.
In summary, we have developed an efficient micro-
wave-assisted copper(II) oxide catalyzed cross-coupling re-
action of thiols with aryl iodides in water that gives the cor-
Having identified the optimal conditions, we studied
the scope of this catalytic system with various substrates;
the results are summarized in Table 2.20 Aryl iodides 1 con-
taining electron-donating groups (Table 2, entries 4, 7, and
13) or electron-withdrawing groups (entries 9, 11–12) cou-
pled with aryl thiols 2 to give good yields of the corre-
sponding sulfides 3. Functional groups including chloro
(entries 3, 6, and 7), bromo (entry 5), acetyl (entries 11 and
12), and amino (entry 10) were unaffected by the catalytic
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 181–186

183
Y.-A. Chen et al.
Paper
Synthesis
responding sulfides in good to excellent yields within a
short reaction time. Functional groups such as amino,
chloro, bromo, and acetyl are all tolerated under the condi-
tions employed. Applications of this catalytic system to oth-
er cross-coupling reactions are in progress in our laborato-
ry.
4-Chlorophenyl 4-Tolyl Sulfide (3d)20a
Prepared by following the general procedure from 4-iodotoluene
(131.4 mg, 0.6 mmol) and 4-chlorothiophenol (72.25 mg, 0.5 mmol)
as a colorless oil; yield: 108.8 mg (93%).
1H NMR (400 MHz, CDCl3): δ = 2.34 (s, 3 H), 7.12–7.29 (m, 8 H).
13C NMR (100 MHz, CDCl3): δ = 21.1, 129.1, 130.2, 130.6, 130.7, 132.2,
132.5, 135.9, 138.0.
4-Methoxyphenyl Phenyl Sulfide (3e)20a
All chemicals were purchased from commercial suppliers and were
used without further purification. Flash chromatography was per-
formed on Merck silica gel 60 (230–400 mesh). NMR spectra were re-
corded on a Varian Mercury-400 instrument using CDCl3 as the sol-
vent. Chemical shifts are reported in parts per million (ppm) and ref-
erenced to the residual solvent resonance. Melting points were
determined by using a Büchi 535 apparatus and are uncorrected. The
microwave-heated reactions were carried out on a CEM-Discover SP
instrument (Model No. 908005; Serial No. DU9209).
Prepared by following the general procedure from 4-iodoanisole
(143.3 mg, 0.6 mmol) and thiophenol (0.0525 mL, 0.5 mmol) as a col-
orless oil; yield: 87.8 mg (81%).
1H NMR (400 MHz, CDCl3): δ = 3.80 (s, 3 H), 6.88 (dd, J = 6.4, 2.0 Hz, 2
H), 7.12–7.24 (m, 5 H), 7.41 (dd, J = 6.8, 2.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 55.3, 114.9, 124.2, 125.7, 128.1, 128.9,
135.3, 138.6, 159.8.
4-Bromophenyl Phenyl Sulfide (3f)20a
Aryl Sulfides 3a–v; General Procedure
Prepared by following the general procedure from 1-bromo-4-iodo-
benzene (173.3 mg, 0.6 mmol) and thiophenol (0.0525 mL, 0.5 mmol)
as a colorless oil; yield: 120.6 mg (91%).
1H NMR (400 MHz, CDCl3): δ = 7.15–7.18 (m, 2 H), 7.25–7.41 (m, 7 H).
13C NMR (100 MHz, CDCl3): δ = 120.8, 127.5, 128.3, 131.5, 132.0,
132.2, 134.8, 135.4.
A 4-mL sealable vial equipped with a magnetic stirrer bar was
charged with KOt-Bu (85.7 mg, 0.75 mmol), CuO (1.99 mg, 0.025
mmol), ligand L1 (0.025 mmol), and the appropriate aryl iodide (0.6
mmol) under N2. The vial was sealed with a cap containing a PTFE
septum, and the thiol (0.5 mmol) and H2O (0.5 mL) were added by sy-
ringe. The mixture was heated at 120 °C by microwave irradiation
with stirring for 30 min, then cooled to r.t. and diluted with EtOAc (20
mL). The resulting solution was filtered through a pad of silica gel that
was washed with EtOAc (20 mL). The organic phase was concentrated
to give a crude material that was purified by column chromatography
(silica gel, hexane).
4-Chlorophenyl Phenyl Sulfide (3g)20a
Prepared by following the general procedure from 1-chloro4-iodo-
benzene (144.3 mg, 0.6 mmol) and thiophenol (0.0525 mL, 0.5 mmol)
as a colorless oil; yield: 92.1 mg (84%).
1H NMR (400 MHz, CDCl3): δ = 7.21–7.34 (m, 9 H).
13C NMR (100 MHz, CDCl3): δ = 127.4, 129.23, 129.27, 131.2, 131.9,
Phenyl 4-Tolyl Sulfide (3a)20a
Prepared by following the general procedure from 4-iodotoluene (1a,
131.4 mg, 0.6 mmol) and thiophenol (2a, 0.0525 mL, 0.5 mmol) as a
colorless oil; yield: 99.3 mg (99%).
1H NMR (400 MHz, CDCl3): δ = 2.32 (s, 3 H), 7.11–7.30 (m, 9 H).
132.8, 134.6, 135.0.
4-Chlorophenyl 4-Methoxyphenyl Sulfide (3h)19c
Prepared by following the general procedure from 4-iodoanisole
(143.3 mg, 0.6 mmol) and 4-chlorothiophenol (74.5 mg, 0.5 mmol) as
a colorless oil; yield: 109.9 mg (88%).
13C NMR (100 MHz, CDCl3): δ = 21.1, 126.3, 129.0, 129.7, 130.0, 131.2,
132.2, 137.1, 137.5.
1H NMR (400 MHz, CDCl3): δ = 3.81 (s, 3 H), 6.90 (dd, J = 6.8, 2.4 Hz, 2
H), 7.07 (dd, J = 6.8, 2.0 Hz, 2 H), 7.18 (dd, J = 6.8, 2.4 Hz, 2 H), 7.40 (dd,
J = 6.8, 2.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 55.3, 115.1, 123.6, 129.0, 129.2, 131.5,
135.5, 137.3, 160.0.
Phenyl 3-Tolyl Sulfide (3b)20a
Prepared by following the general procedure from 3-iodotoluene
(0.078 ml, 0.6 mmol) and thiophenol (0.0525 mL, 0.5 mmol) as a col-
orless oil; yield: 87.3 mg (87%).
1H NMR (400 MHz, CDCl3): δ = 2.29 (s, 3 H), 7.03–7.33 (m, 9 H).
13C NMR (100 MHz, CDCl3): δ = 21.2, 126.8, 128.0, 128.3, 129.0, 129.1,
130.7, 131.8, 135.2, 136.0, 139.0.
4-Methoxyphenyl 4-Tolyl Sulfide (3i)14
Prepared by following the general procedure from 4-iodotoluene
(131.4 mg, 0.6 mmol) and 4-methoxythiophenol (0.0633 mL, 0.5
mmol) as a colorless oil; yield: 220.7 mg (96%).
Phenyl 2-Tolyl Sulfide (3c)20a
Prepared by following the general procedure from 2-iodotoluene
(0.078 ml, 0.6 mmol) and thiophenol (0.0525 mL, 0.5 mmol) as a col-
orless oil; yield: 92.9 mg (93%).
1H NMR (400 MHz, CDCl3): δ = 2.37 (s, 3 H), 7.11–7.29 (m, 9 H).
13C NMR (100 MHz, CDCl3): δ = 20.5, 126.3, 126.7, 127.9, 129.1, 129.6,
130.5, 132.9, 133.7, 136.1, 139.9.
1H NMR (400 MHz, CDCl3): δ = 2.26 (s, 3 H), 3.74 (s, 3 H), 6.83 (dd,
J = 6.8, 2.0 Hz, 2 H), 7.03 (d, J = 8.0 Hz, 2 H), 7.11 (d, J = 8.4 Hz, 2 H),
7.34 (dd, J = 6.8, 2.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 20.9, 55.2, 114.7, 125.5, 129.2, 129.7,
134.2, 134.3, 135.9, 159.3.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 181–186

184
Y.-A. Chen et al.
Paper
Synthesis
3-Nitrophenyl Phenyl Sulfide (3j)20c
Benzyl 4-Tolyl Sulfide (3p)20e
Prepared by following the general procedure from 1-iodo-3-nitroben-
zene (150.9 mg, 0.6 mmol) and thiophenol (0.0525 mL, 0.5 mmol) as
a light-yellow liquid; yield: 102.4 mg (82%).
Prepared by following the general procedure from 4-iodotoluene
(131.4 mg, 0.6 mmol) and phenylmethanethiol (0.062 mL, 0.5 mmol)
as a colorless oil; yield: 94.6 mg (88%).
1H NMR (400 MHz, CDCl3): δ = 7.39–7.43 (m, 4 H), 7.46–7.50 (m, 3 H),
1H NMR (400 MHz, CDCl3): δ = 2.20 (s, 3 H), 3.97 (s, 2 H), 6.96 (d, J =
7.98–8.03 (m, 2 H).
8.4 Hz, 2 H), 7.10–7.18 (m, 7 H).
13C NMR (100 MHz, CDCl3): δ = 120.8, 123.0, 128.9, 129.6, 129.8,
13C NMR (100 MHz, CDCl3): δ = 21.0, 39.7, 127.0, 128.4, 128.8, 129.5,
132.0, 133.4, 134.2, 140.5, 148.6.
130.6, 132.4, 136.5, 137.7.
2-(4-Tolylsulfanyl)aniline (3k)20b
1-Bromo-4-(dodecylsulfanyl)benzene (3q)19c
Prepared by following the general procedure from 4-iodotoluene
(131.4 mg, 0.6 mmol) and 2-aminothiophenol (0.0539 mL, 0.5 mmol)
as a light-yellow oil; yield: 89.1 mg (83%).
Prepared by following the general procedure from 1-bromo-4-iodo-
benzene (173.3 mg, 0.6 mmol) and 1-dodecanethiol (0.120 mL, 0.5
mmol) as a colorless oil; yield: 156.4 mg (88%).
1H NMR (400 MHz, CDCl3): δ = 2.26 (s, 3 H), 4.17 (br s, 2 H), 6.70–6.75
(m, 2 H), 6.99–7.04 (m, 4 H), 7.17–7.21 (m, 1 H), 7.43 (dd, J =8.0, 1.6
Hz, 1 H).
1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.25–1.41 (m,
18 H), 1.58–1.64 (m, 2 H), 2.87 (t, J = 7.2 Hz, 2 H), 7.16 (d, J = 8.4 Hz, 2
H), 7.37 (d, J = 8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 20.9, 115.1, 115.3, 118.6, 126.9, 129.7,
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.7, 28.8, 28.9, 29.1, 29.3, 29.5,
130.8, 132.9, 135.4, 137.0, 148.5.
29.5, 29.6, 29.6, 31.9, 33.6, 119.2, 130.2, 131.7, 136.3.
1-[4-(Phenylsulfanyl)phenyl]ethanone (3l)10a
Dodecyl 4-Tolyl Sulfide (3r)14
Prepared by following the general procedure from 1-(4-iodophen-
yl)ethanone (148.0 mg, 0.6 mmol) and thiophenol (0.0525 mL, 0.5
mmol) as a white solid; yield: 111.1 mg (97%); mp 65–66 °C.
Prepared by following the general procedure from 4-iodotoluene
(131.4 mg, 0.6 mmol) and 1-dodecanethiol (0.1225 mL, 0.5 mmol) as
a colorless oil; yield: 104.8 mg (72%).
1H NMR (400 MHz, CDCl3): δ = 2.55 (s, 3 H), 7.21 (dd, J = 6.6, 1.8 Hz, 2
H), 7.39–7.41 (m, 3 H), 7.49–7.51 (m, 2 H), 7.82 (dd, J = 6.8, 2.0 Hz, 2
H).
1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.25–1.30 (m,
16 H), 1.38–1.41 (m, 2 H), 1.57–1.63 (m, 2 H), 2.31 (s, 3 H), 2.86 (t, J =
7.4 Hz, 2 H), 7.08 (d, J = 7.6 Hz, 2 H), 7.24 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 26.5, 127.4, 128.8, 128.9, 129.7, 132.0,
13C NMR (100 MHz, CDCl3): δ = 14.1, 21.0, 22.7, 28.8, 29.2, 29.2, 29.3,
133.9, 134.4, 144.9, 197.1.
29.5, 29.6, 29.6, 29.6, 31.9, 34.3, 129.6, 129.7, 133.1, 135.7.
1-[3-(Phenylsulfanyl)phenyl]ethanone (3m)19e
Benzyl Phenyl Sulfide (3s)10a
Prepared by following the general procedure from 1-(3-iodophen-
yl)ethanone (0.0863 mL, 0.6 mmol) and thiophenol (0.0525 mL, 0.5
mmol) as a yellow oil; yield: 89.0 mg (78%).
Prepared by following the general procedure from iodobenzene
(0.06863 ml, 0.6 mmol) and phenylmethanethiol (0.062 mL, 0.5
mmol) as a colorless oil; yield: 71.3 mg (71%).
1H NMR (400 MHz, CDCl3): δ = 2.54 (s, 3 H), 7.28–7.39 (m, 6 H), 7.43–
1H NMR (400 MHz, CDCl3): δ = 4.09 (s, 2 H), 7.13–7.30 (m, 10 H).
7.46 (m, 1 H), 7.77–7.80 (m, 1 H), 7.89–7.90 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 26.6, 126.5, 127.7, 129.3, 129.4, 129.8,
13C NMR (100 MHz, CDCl3): δ = 38.9, 126.2, 127.1, 128.4, 128.7, 128.8,
129.6, 136.3, 137.3.
131.7, 134.2, 134.5, 137.4, 137.8, 197.4.
Dodecyl Phenyl Sulfide (3t)10a
1-(Dodecylsulfanyl)-4-methoxybenzene (3n)19e
Prepared by following the general procedure from iodobenzene
(0.06863 ml, 0.6 mmol) and 1-dodecanethiol (0.120 mL, 0.5 mmol) as
a colorless oil; yield: 95.7 mg (69%).
1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 7.2 Hz, 3 H), 1.25–1.43 (m,
18 H), 1.60–1.67 (m, 2 H), 2.90 (t, J = 7.2 Hz, 2 H), 7.13–7.16 (m, 1 H),
7.24–7.32 (m, 4 H).
Prepared by following the general procedure from 4-iodoanisole
(143.3 mg, 0.6 mmol) and 1-dodecanethiol (0.1225 mL, 0.5 mmol) as
a colorless solid; yield: 126.4 mg (82%); mp 46–47 °C.
1H NMR (400 MHz, CDCl3): δ = 0.95 (t, J = 7.2 Hz, 3 H), 1.32–1.45 (m,
18 H), 1.61–1.66 (m, 2 H), 2.88 (t, J = 7.4 Hz, 2 H), 3.85 (s, 3 H), 6.88–
6.92 (m, 2 H), 7.38–7.41 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.7, 28.8, 29.1, 29.3, 29.4, 29.5,
29.6, 29.6, 31.9, 33.5, 33.6, 125.5, 128.8, 137.1.
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.7, 28.7, 29.2, 29.3, 29.3, 29.5,
29.6, 29.6, 31.9, 35.8, 55.2, 114.4, 126.9, 132.8, 158.6.
2-Methylbutyl 4-Tolyl Sulfide (3u)19e
1-Chloro-4-(dodecylsulfanyl)benzene (3o)20d
Prepared by following the general procedure from 4-iodotoluene
(131.4 mg, 0.6 mmol) and 2-methylbutane-1-thiol (0.0645 mL, 0.5
mmol) as a colorless oil; yield: 63.0 mg (65%).
1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 7.2 Hz, 3 H), 1.00 (d, J = 6.8
Hz, 3 H), 1.21–1.28 (m, 1 H), 1.49–1.65 (m, 2 H), 2.30 (s, 3 H), 2.70 (dd,
J = 12.4, 7.6 Hz, 1 H), 2.90 (dd, J = 7.6, 12.4 Hz, 1 H), 7.08 (d, J = 8.0 Hz,
2 H), 7.23 (d, J = 8.0 Hz, 2 H).
Prepared by following the general procedure from 1-chloro-4-iodo-
benzene (144.3 mg, 0.6 mmol) and 1-dodecanethiol (0.120 mL, 0.5
mmol) as a colorless oil; yield: 129.0 mg (83%).
1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.25–1.42 (m,
18 H), 1.58–1.65 (m, 2 H), 2.88 (t, J = 7.2 Hz, 2 H), 7.22–7.25 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.7, 28.7, 29.0, 29.1, 29.3, 29.5,
29.6, 29.6, 31.9, 33.8, 128.9, 130.1, 131.5, 135.6.
13C NMR (100 MHz, CDCl3): δ = 11.2, 18.8, 20.9, 28.7, 34.4, 41.4, 129.5,
129.5, 133.6, 135.6.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 181–186

185
Y.-A. Chen et al.
Paper
Synthesis
Cyclohexyl 4-Tolyl Sulfide (3v)19e
(d) Beletskaya, I. P.; Ananikov, V. P. Chem. Rev. 2011, 111, 1596.
(e) Beletskaya, I. P.; Ananikov, V. P. Eur. J. Org. Chem. 2007, 3431.
(f) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003, 42, 5400.
(g) Kondo, T.; Mitsudo, T.-a. Chem. Rev. 2000, 100, 3205.
(h) Procter, D. J. J. Chem. Soc., Perkin Trans. 1 2001, 335.
(7) For selected examples, see: (a) Migita, T.; Shimizu, T.; Asami, Y.;
Shiobara, J.; Kato, Y.; Kosugi, M. Bull. Chem. Soc. Jpn. 1980, 53,
1385. (b) Kosugi, M.; Ogata, T.; Terada, M.; Sano, H.; Migita, T.
Bull. Chem. Soc. Jpn. 1985, 58, 3657. (c) Bryan, C. S.; Braunger, J.
A.; Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 7064. (d) Kuhn,
M.; Falk, F. C.; Paradies, J. Org. Lett. 2011, 13, 4100. (e) Sayah, M.;
Organ, M. G. Chem. Eur. J. 2011, 17, 11719. (f) Qiao, Z.-J.; Liu, H.;
Xiao, X.; Fu, Y.; Wei, J.; Li, Y.-X.; Jiang, X.-F. Org. Lett. 2013, 15,
2594.
Prepared by following the general procedure from 4-iodotoluene
(131.4 mg, 0.6 mmol) and cyclohexanethiol (0.0615 mL, 0.5 mmol) as
a colorless oil; yield: 65.9 mg (64%).
1H NMR (400 MHz, CDCl3): δ = 1.22–1.39 (m, 5 H), 1.58–1.97 (m, 5 H),
2.32 (s, 3 H), 2.99–3.04 (m, 1 H), 7.09 (d, J = 8.4 Hz, 2 H), 7.31 (d, J = 8.4
Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.0, 25.7, 26.0, 33.3, 47.0, 129.4,
131.2, 132.7, 136.8.
Acknowledgment
Financial support from the National Science Council, Taiwan (NSC
101-2113-M-005-008-MY3), the National Chung Hsing University,
and the Center of Nanoscience and Nanotechnology (NCHU) is grate-
fully acknowledged. We also thank Professor Fung-E Hong (NCHU) for
sharing his GC-MS instruments. C.F.L. is a Golden-Jade Fellow of the
Kenda Foundation, Taiwan.
(8) (a) Chen, Y.-J.; Chen, H.-H. Org. Lett. 2006, 8, 5609. (b) Taniguchi,
N. J. Org. Chem. 2007, 72, 1241. (c) Cheng, J.-H.; Yi, C.-L.; Liu, T.-
J.; Lee, C.-F. Chem. Commun. 2012, 48, 8440. (d) Yi, C.-L.; Liu, T.-
J.; Cheng, J.-H.; Lee, C.-F. Eur. J. Org. Chem. 2013, 3910. (e) Bates,
C. G.; Gujadhur, R. K.; Venkataraman, D. Org. Lett. 2002, 4, 2803.
(9) (a) Percec, V.; Bae, J.-Y.; Hill, D. H. J. Org. Chem. 1995, 60, 6895.
(b) Zhang, Y.; Ngeow, K. C.; Ying, J. Y. Org. Lett. 2007, 9, 3495.
(10) (a) Wu, J.-R.; Lin, C.-H.; Lee, C.-F. Chem. Commun. 2009, 4450.
(b) Correa, A.; Carril, M.; Bolm, C. Angew. Chem. Int. Ed. 2008, 47,
2880. (c) Wang, H.-B.; Wang, L.; Shang, J.-S.; Li, X.; Wang, H.-Y.;
Gui, J.; Lei, A.-W. Chem. Commun. 2012, 48, 76. (d) Lin, Y.-Y.;
Wang, Y.-J.; Lin, C.-H.; Chen, J.-H.; Lee, C.-F. J. Org. Chem. 2012,
77, 6100.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379206. Included are 1H and 13C
NMR spectra for compounds 3a–v.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
(11) (a) Reddy, V. P.; Kumar, A. V.; Swapna, K.; Rao, K. R. Org. Lett.
2009, 11, 1697. (b) Reddy, V. P.; Swapna, K.; Kumar, A. V.; Rao, K.
R. J. Org. Chem. 2009, 74, 3189.
References
(12) Wong, Y.-C.; Jayanth, T. T.; Cheng, C.-H. Org. Lett. 2006, 8, 5613.
(13) Morita, N.; Krause, N. Angew. Chem. Int. Ed. 2006, 45, 1897.
(14) Liu, T.-J.; Yi, C.-L.; Chan, C.-C.; Lee, C.-F. Chem. Asian J. 2013, 8,
1029.
(1) These authors contributed equally to this work.
(2) (a) Hutton, J.; Jones, A. D.; Lee, S. A.; Martin, D. M. G.; Meyrick,
B. R.; Patel, I.; Peardon, R. F.; Powell, L. Org. Process Res. Dev.
1997, 1, 61. (b) De Martino, G.; Edler, M. C.; La Regina, G.;
Coluccia, A.; Barbera, M. C.; Barrow, D.; Nicholson, R. I.; Chiosis,
G.; Brancale, A.; Hamel, E.; Artico, M.; Silvestri, R. J. Med. Chem.
2006, 49, 947. (c) Kaldor, S. W.; Kalish, V. J.; Davies, J. F.; Shetty,
B. V.; Fritz, J. E.; Appelt, K.; Burgess, J. A.; Campanale, K. M.;
Chirgadze, N. Y.; Clawson, D. K.; Dressman, B. A.; Hatch, S. D.;
Khalil, D. A.; Kosa, M. B.; Lubbehusen, P. P.; Muesing, M. A.;
Patick, A. K.; Reich, S. H.; Su, K. S.; Tatlock, J. H. J. Med. Chem.
1997, 40, 3979. (d) Liu, G.; Huth, J. R.; Olejniczak, E. T.; Mendoza,
R.; DeVries, P.; Leitza, S.; Reilly, E. B.; Okasinski, G. F.; Fesik, S.
W.; von Geldern, T. W. J. Med. Chem. 2001, 44, 1202.
(3) Brandsma, L.; Arens, J. F. In The Chemistry of the Ether Linkage;
Patai, S., Ed.; Wiley Interscience: London, 1967, Chap. 13, 553.
(4) (a) Dondoni, A. Angew. Chem. Int. Ed. 2008, 47, 8995. (b) Lowe,
A. B. Polym. Chem. 2010, 1, 17. (c) Liu, J.; Yang, J.; Yang, Q.; Wang,
G.; Li, Y. Adv. Funct. Mater. 2005, 15, 1297. (d) Van Bierbeek, A.;
Gingras, M. Tetrahedron Lett. 1998, 39, 6283.
(5) (a) Magens, S.; Plietker, B. Chem. Eur. J. 2011, 17, 8807.
(b) Katritzky, A. R.; Shestopalov, A. A.; Suzuki, K. Synthesis 2004,
1806. (c) Iimura, S.; Manabe, K.; Kobayashi, S. Chem. Commun.
2002, 94. (d) Ahmad, S.; Iqbal, J. Tetrahedron Lett. 1986, 27,
3791. (e) Spessard, G. O.; Chan, W. K.; Masamune, S. Org. Synth.
Coll. Vol. VII; Wiley: London, 1990, 81. (f) Silveira, C. C.; Braga, A.
L.; Larghi, E. L. Organometallics 1999, 18, 5183. (g) Meshram, H.
M.; Reddy, G. S.; Mindu, K. H.; Yadav, J. S. Synlett 1998, 877.
(6) For reviews on transition-metal-catalyzed C–S coupling reac-
tion, see: (a) Lee, C.-F.; Liu, Y.-C.; Badsara, S. S. Chem. Asian J.
2014, 9, 706. (b) Liu, H.; Jiang, X. Chem. Asian J. 2013, 8, 2546.
(c) Eichman, C. C.; Stambuli, J. P. Molecules 2011, 16, 590.
(15) Das, R.; Chakraborty, D. Tetrahedron Lett. 2012, 53, 7023.
(16) (a) Minakata, S.; Komatsu, M. Chem. Rev. 2009, 109, 711.
(b) Blackmond, D. G.; Armstrong, A.; Coombe, V.; Wells, A.
Angew. Chem. Int. Ed. 2007, 46, 3798. (c) Organic Synthesis in
Water; Grieco, P. A., Ed.; Blackie: London, 1998. (d) Mase, N.;
Barbas, C. F. III Org. Biomol. Chem. 2010, 8, 4043. (e) Lipshutz, B.
H.; Ghorai, S. Aldrichimica Acta 2008, 41, 59. (f) Mondal, J.;
Borah, P.; Modak, A.; Zhao, Y.; Bhaumik, A. Org. Process Res. Dev.
2014, 18, 257. (g) Kundu, D.; Chatterjee, T.; Ranu, B. C. Adv.
Synth. Catal. 2013, 355, 2285. (h) Pal, N.; Bhaumik, A. Dalton
Trans. 2012, 41, 9161. (i) Feng, Y.-S.; Qi, H.-X.; Wang, W.-C.;
Liang, Y.-F.; Xu, H.-J. Tetrahedron Lett. 2012, 53, 2914. (j) Ding,
Q.; Liu, X.; Cao, B.; Zong, Z.; Peng, Y. Tetrahedron Lett. 2011, 52,
1964. (k) Hirai, Y.; Uozumi, Y. Chem. Lett. 2011, 40, 934.
(l) Damodara, D.; Arundhathi, R.; Likhar, P. R. Catal. Sci. Technol.
2013, 3, 797. (m) Velmathi, S.; Reena, V.; Pal, R. P.; Vinu, A.
Catal. Lett. 2010, 135, 148. (n) Velmathi, S.; Vijayaraghavan, R.;
Amarendar, C.; Pal, R. P.; Vinu, A. Synlett 2010, 2733. (o) Xu, H.-
J.; Liang, Y.-F.; Zhoua, X.-F.; Feng, Y.-S. Org. Biomol. Chem. 2012,
10, 2562. (p) Rout, L.; Saha, P.; Jammi, S.; Punniyamurthy, T. Eur.
J. Org. Chem. 2008, 640. (q) Xu, H.-J.; Liang, Y.-F.; Cai, Z.-Y.; Qi,
H.-X.; Yang, C.-Y.; Feng, Y.-S. J. Org. Chem. 2011, 76, 2296.
(r) Herrero, M. T.; SanMartin, R.; Domínguez, E. Tetrahedron
2009, 65, 1500.
(17) (a) Appukkuttan, P.; Van der Eycken, E. Eur. J. Org. Chem. 2008,
1133. (b) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.
(c) Lidström, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron
2001, 57, 9225. (d) Larhed, M.; Moberg, C.; Hallberg, A. Acc.
Chem. Res. 2002, 35, 717.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 181–186

186
Y.-A. Chen et al.
Paper
Synthesis
(18) (a) Bagley, M. C.; Dix, M. C.; Fusillo, V. Tetrahedron Lett. 2009, 50,
3661. (b) Tan, C.-M.; Chen, G. S.; Chena, C.-S.; Cherna, J.-W.
J. Chin. Chem. Soc. (Taipei) 2011, 58, 94. (c) Bagley, M. C.; Davis,
T.; Dix, M. C.; Fusillo, V.; Pigeaux, M.; Rokicki, M. J.; Kipling, D.
J. Org. Chem. 2009, 74, 8336. (d) Ranu, B. C.; Saha, A.; Jana, R.
Adv. Synth. Catal. 2007, 349, 2690.
(19) (a) Liu, Y.-C.; Lee, C.-F. Synlett 2013, 24, 2320. (b) Cheng, C.-H.;
Ramesh, C.; Kao, H.-L.; Wang, Y.-J.; Chan, C.-C.; Lee, C.-F. J. Org.
Chem. 2012, 77, 10369. (c) Lai, C.-S.; Kao, H.-L.; Wang, Y.-J.; Lee,
C.-F. Tetrahedron Lett. 2012, 53, 4365. (d) Kao, H.-L.; Lee, C.-F.
Org. Lett. 2011, 13, 5204. (e) Kao, H.-L.; Chen, C.-K.; Wang, Y.-J.;
Lee, C.-F. Eur. J. Org. Chem. 2011, 1776. (f) Chen, C.-K.; Chen, Y.-
W.; Lin, C.-H.; Lin, H.-P.; Lee, C.-F. Chem. Commun. 2010, 46,
282. (g) Liu, Y.-C.; Lee, C.-F. Green Chem. 2014, 16, 357. (h) Yi, C.-
L.; Huang, Y.-T.; Lee, C.-F. Green Chem. 2013, 15, 2476. (i) Zeng,
J.-W.; Liu, Y.-C.; Hsiech, P.-A.; Huang, Y.-T.; Yi, C.-L.; Badsara, S.
S.; Lee, C.-F. Green Chem. 2014, 16, 2644. (j) Huang, Y.-T.; Lu, S.-
Y.; Yi, C.-L.; Lee, C.-F. J. Org. Chem. 2014, 79, 4561. (k) Huang, Y.-
T.; Tsai, W.-T.; Badsara, S. S.; Chan, C.-C.; Lee, C.-F. J. Chin. Chem.
Soc. (Taipei) 2014, 61, 961. (l) Liou, J.-C.; Badsara, S. S.; Huang,
Y.-T.; Lee, C.-F. RSC Adv. 2014, 4, 41237. (m) Badsara, S. S.; Liu,
Y.-C.; Hsieh, P.-A.; Zeng, J.-W.; Lu, S.-Y.; Liu, Y.-W.; Lee, C.-F.
Chem. Commun. 2014, 50, 11374.
(20) (a) Wang, H.; Jiang, L.; Chen, T.; Li, Y. Eur. J. Org. Chem. 2010, 12,
2324. (b) Kun, S.; Yatao, Q.; Yiwu, Y.; Dayong, Z.; Sheng, J. Synlett
2012, 23, 2853. (c) Baig, R. B. N.; Varma, R. S. Green Chem. 2013,
15, 398. (d) Ajiki, K.; Hirano, M.; Tanaka, K. Org. Lett. 2005, 7,
4193. (e) Bastug, G.; Nolan, S. P. J. Org. Chem. 2013, 78, 9303.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 181–186