An efficient copper-catalyzed cross-coupling reaction of thiols with aryl iodides

Article abstract of DOI:10.1002/ejoc.201001667

Commercially available Cu₂O powder is a very reactive catalyst for the coupling of thiols to aryl iodides. A variety of functional groups including esters, unprotected amines, alcohols, and heterocycles tolerate the reaction conditions. Moreover, di-ortho-substituted aryl iodides with sterically demanding substrates were also coupled to give the desired aryl thioethers in good to excellent yields. Copyright

Full text of DOI:10.1002/ejoc.201001667

FULL PAPER
DOI: 10.1002/ejoc.201001667
An Efficient Copper-Catalyzed Cross-Coupling Reaction of Thiols with Aryl
Iodides
Hsin-Lun Kao,[a] Chin-Keng Chen,[a] Yu-Jen Wang,[a] and Chin-Fa Lee*[a]
Keywords: Copper / Cross-coupling / Sulfur / Thioethers / Homogeneous catalysis
Commercially available Cu2O powder is a very reactive cata-
lyst for the coupling of thiols to aryl iodides. A variety of func-
tional groups including esters, unprotected amines, alcohols,
and heterocycles tolerate the reaction conditions. Moreover,
di-ortho-substituted aryl iodides with sterically demanding
substrates were also coupled to give the desired aryl thio-
ethers in good to excellent yields.
reactions under ligand-free conditions;[17] however, there
are some difficulties in this system: (1) CuO nanoparticles
are expensive; (2) low yields were generally obtained when
electron-rich aryl iodides were employed, and (3) highly po-
lar solvents (DMSO) were required. More recently, In2O3
nanoparticles were reported to show similar catalytic ac-
tivity, but they possess similar limitations at a higher
cost.[18]
Thus, it is desirable to develop a general method that is
capable of overcoming the aforementioned synthetic limita-
tions and cost. Herein, we report that commercially avail-
able Cu2O powder is a very reactive (0.5 mol-%) catalyst in
combination with KOH or KOEt as the base for the cou-
pling reaction of thiols with aryl iodides in the absence of
an added ligand.
Introduction
Transition-metal-catalyzed cross-coupling reactions of
aryl halides with heteroatom nucleophiles are powerful
methods for constructing carbon–heteroatom bonds.[1–4]
While having access to aryl thioethers is important in the
preparation of pharmaceutically and biologically relevant
compounds, several challenges still remain.[5,6] As a result
of the strong binding affinity of thiols for transition metals,
the metal catalysts are often poisoned, leading to decreased
activity.[7] Despite this unfavorable route, Migita reported
the first palladium-catalyzed coupling reaction of thiols
with aryl halides in 1980,[8] and more recent studies have
revealed that the efficiency of the C–S coupling reaction can
be improved through the combination of palladium with
appropriate ligands.[9] Besides palladium, transition metals
such as nickel,[10] iron,[11] indium,[12] cobalt,[13] and cop-
per[14] have also been reported. These protocols rely on the
presence of ancillary ligands, and recently, a metal-cata-
lyzed coupling reaction under ligand-free conditions has
gained considerable attention.[15–18] van Koten et al. re-
ported the copper-catalyzed coupling reaction of aryl
iodides in amide solvent[17,19] without a ligand.[16a] There
are some limitations with van Koten’s system. First, the
thiols used were limited to aryl thiols; only one alkyl thiol
was coupled with iodobenzene in moderate yield. Second,
sterically bulky aryl iodides were not involved.
Results and Discussion
Initially, we screened 4-iodotoluene and 1-dodecanethiol
as model substrates to determine optimal reaction con-
ditions. The results are summarized in Table 1. KO-
tBu[9c,9d,10b,11a,14h,14k] and NaOtBu,[8a,9c–9e,11a,11b,14d,14i–14k]
are commonly used as bases for C–S coupling reactions;
however, when the reaction was carried out with KOtBu
in DMSO, a low yield of 3a was obtained along with its
regioisomer 4a (Table 1, Entry 1; 3a/4a = 92:8). Compound
4a is the product of a benzyne intermediate, and similar
reactivity has been observed in the copper-catalyzed aryl-
ation of arenes.[20] Although amide solvents have been
shown to be effective in C–S coupling reactions, a low yield
of 3a (Table 1, Entry 2; 3a/4a = 79:21) was observed when
the reaction was performed in DMF. To our delight, good
yields were obtained when reactions were carried out in
DME (Table 1, Entry 3) and dioxane (Table 1, Entry 4;
86% isolated yield), and the formation of 4a was totally
suppressed under these conditions. To exclude the possibil-
ity of metal contaminants,[14i] the reaction was performed
A variety of nanosurfaced materials have recently been
considered as new catalysts for organic synthesis owing to
their high surface area and high reactivity.[15] Commercially
available CuO nanoparticles (surface area: 29 cm2/g) were
demonstrated to be active catalysts for C–S bond-forming
[a] Department of Chemistry, National Chung Hsing University,
Taichung, Taiwan 402, ROC, Taiwan
Fax: +886-4-2286-2547
E-mail: cfalee@dragon.nchu.edu.tw
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001667.
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Efficient Cu-Catalyzed Cross-Coupling Reaction of Thiols with Aryl Iodides
by using highly pure Cu2O (Ͼ99.99%, Aldrich) as a metal and 3o in excellent yields. Functional groups including un-
source. Importantly, a comparable isolated yield (86%) protected amines (Table 2, Entries 11, 12, and 19), alcohols
rules out any trace metal impurity catalyzing the reaction (Table 2, Entry 20), halides (Table 2, Entries 21, 24), esters
(Table 1, Entry 5). Weaker bases such as KOEt, KOMe, (Table 2, Entry 22), enolizable ketones (Table 2, Entries 23
[9b,14b]
KOH,[12] NaOH, K3PO4, and K2CO3
were examined and 24), and heterocycle-containing moieties (Table 2, En-
(Table 1, Entries 6–14), and the results revealed that KOEt, tries 9, 10, 17, and 18) were all tolerated by the reaction
KOMe, and KOH were more effective than KOtBu, giving conditions employed. Moreover, sterically demanding di-
the product in excellent yields (Table 1, Entries 6, 7, and ortho-substituted aryl iodides also underwent the cross-cou-
8, respectively). The study of various copper salts (Table 1, pling reaction to give the desired products (Table 2, En-
Entries 15–17) demonstrated that Cu2O is the most effective tries 6–8, 15, and 16) in good to excellent yields. We also
copper source. The mixture of 3a/4a (74:26 ratio) was ob- examined the coupling reactions of some alkyl thiols with
tained in a low combined yield when the reaction was car- aryl iodides under van Koten’s conditions[16a] (Table 2, En-
ried out without a catalyst (Table 1, Entry 18). No desired tries 1–4; results shown in parentheses), and the products
coupling product was detected when 4-iodotoluene was re- were obtained in very low yields. These results suggested
placed by bromobenzene or chlorobenzene under the same that the combination of Cu2O/KOH in dioxane is a general
conditions.
and efficient system for the copper-catalyzed coupling reac-
tion of aryl iodides with thiols under ligand-free conditions.
Table 1. Optimization of Cu2O-catalyzed coupling reaction of 4-
iodotoluene with 1-dodecanethiol.[a]
Conclusions
We have reported that commercially available Cu2O pow-
der can be applied as a very reactive catalyst for the cou-
pling reaction of thiols with aryl iodides under ligand-free
conditions. There are many advantages to our system:
(1) Cu2O powder is cheap; (2) catalyst loading is as low as
0.5 mol-%, resulting in good to excellent yields and selectiv-
ity;[14j] (3) functional groups such as esters, unprotected
amines, alcohols, and heterocycles are all tolerated; (4) steri-
cally demanding substrates were also shown to be good
coupling partners. Understanding the mechanism of this
catalytic system is currently underway in our laboratory.
Entry
[Cu]
Base
Solvent
Yield
[%][b]
Ratio
(3a/4a)[c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
CuI
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOEt
DMSO
DMF
DME
26
66
84
92:8
79:21
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
98 (86)
99 (86)[d]
100 (91)
100 (99)
100 (99)
KOMe
KOH
Experimental Section
NaOtBu
NaOH
K3PO4
K2CO3
Na2CO3
Et3N
KOtBu
KOtBu
KOtBu
KOtBu
13
72
53
53
26
2
82
90
85
7
General Information: All chemicals were purchased from commer-
cial suppliers and were used without further purification. Toluene
was dried with sodium; dioxane, DME, DMSO, and DMF were
dried with CaH2 and stored in the presence of activated molecular
sieves. All reactions were carried out under an inert atmosphere.
Flash chromatography was performed on Merck silica gel 60 (230–
400 mesh).
CuCl
CuO
–
Analysis: NMR spectra were recorded with a Varian Unity Inova-
600 or a Varian Mercury-400 instrument by using CDCl3 as the
solvent. Chemical shifts are reported in parts per million (ppm)
and referenced to the residual solvent resonance. Standard abbrevi-
ations indicating multiplicity were used as follows: s = singlet, d =
doublet, t = triplet, dd = doublet of doublets, q = quartet, m =
multiplet, br. = broad. Melting points were determined by using a
Büchi 535 apparatus. GC–MS analyses were performed with an HP
5890 GC equipped with an HP 5972 MS. High-resolution mass
spectra were carried out with a Jeol JMS-HX 110 spectrometer by
the services at the National Chung Hsing University.
74:26
[a] Reaction conditions unless otherwise stated: Cu2O (97%,
0.005 mmol, 0.5 mol-%); for CuI, CuCl, and CuO (0.01 mmol,
1.0 mol-%), 4-iodotoluene (1.5 mmol), 1-dodecanethiol (1.0 mmol),
base (2.0 mmol), in solvent (0.5 mL). [b] GC yield using tridecane
as the internal standard. [c] The ratio was determined by 1H NMR
spectroscopy and GC–MS techniques. [d] Cu2O (Ͼ99.99%) was
used. Values in parentheses refer to isolated yields.
As illustrated in Table 2, a number of thiols and aryl
iodides were also investigated as coupling partners. Aryl
iodides possessing electron-donating or electron-withdrawing
groups were successfully coupled to alkyl (Table 2, En-
tries 1–12) and aryl thiols (Table 2, Entries 13–24) to afford
the products in good to excellent yields. 4-Iodoanisole was
General Procedure for the Cu2O-Catalyzed Coupling Reaction of 4-
Iodotoluene with 1-Dodecanethiol (Table 1): A 4-mL sealable tube
equipped with
a magnetic stir bar was charged with base
(2.0 mmol), Cu2O (0.7 mg, 0.005 mmol), and 4-iodotoluene
(327 mg, 1.5 mmol) in a dry box under a nitrogen atmosphere. The
readily coupled with thiols to give products 3d, 3e, 3f, 3n, vial was then sealed with a cap containing a PTFE septum and
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H.-L. Kao, C.-K. Chen, Y.-J. Wang, C.-F. Lee
FULL PAPER
Table 2. Cu2O-catalyzed coupling reaction of aryl iodides with thiols.[a]
[a] Reaction conditions unless otherwise stated: Cu2O (0.005 mmol, 0.5 mol-%), aryl iodide (1.2 mmol), thiol (1.0 mmol), KOH
(2.0 mmol), in dioxane (0.5 mL), 6 h. [b] 24 h. [c] CuI (0.025 mmol, 2.5 mol-%), aryl iodide (1.0 mmol), thiol (1.3 mmol), K3PO4
(1.1 mmol), in NMP (0.19 mL), 100 °C, 16 h; see ref.[16a] for details. [d] Aryl iodide (1.0 mmol), thiol (1.1 mmol). [e] 12 h. [f] 9 h. [g] KOEt
as base. [h] DME as solvent.
removed from the dry box. Under a nitrogen atmosphere, solvent
(0.5 mL) and 1-dodecanethiol (0.24 mL, 1.0 mmol) were added by
syringe, and the reaction vessel was heated at 110 °C in an oil bath.
After stirring at this temperature for 6 h, the heterogeneous mixture
was cooled to room temperature and diluted with ethyl acetate
(20 mL). The resulting solution was directly filtered through a pad
of Celite then washed with ethyl acetate (20 mL) and concentrated
to give the crude material, which was then purified by column
chromatography (SiO2, hexane and CH2Cl2 or EtOAc) to yield 3a.
Dodecyl p-Tolyl Sulfide (3a): Following the above general procedure
and using KOH (112.0 mg, 2.0 mmol), 1-dodecanethiol (0.24 mL,
1.0 mmol), 4-iodotoluene (327.0 mg, 1.5 mmol). Purification (SiO2,
hexane) provided 3a (Table 1, Entry 8)[21] as a colorless oil (288 mg,
1
99% yield). H NMR (400 MHz, CDCl3): δ = 0.86 (t, J = 6.8 Hz,
3 H), 1.23–1.63 (m, 20 H), 2.30 (s, 3 H), 2.85 (t, J = 7.2 Hz, 2 H),
7.07 (d, J = 8.4 Hz, 2 H), 7.22 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 14.1, 21.0, 22.7, 28.8, 29.16, 29.24, 29.3,
29.5, 29.57, 29.63, 31.9, 34.4, 129.6, 129.8, 133.2, 135.8 ppm.
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Efficient Cu-Catalyzed Cross-Coupling Reaction of Thiols with Aryl Iodides
General Procedure for the Cu2O-Catalyzed Coupling Reaction of orless oil (Table 2, Entry 5).[14a] 1H NMR (400 MHz, CDCl3): δ =
Aryl Iodides with Thiols (Table 2): A 4-mL sealable tube equipped
with a magnetic stir bar was charged with KOH (112.0 mg,
1.21–1.93 (m, 10 H), 2.88–2.91 (m, 1 H), 3.76 (s, 3 H), 6.82 (d, J
= 9.6 Hz, 2 H), 7.37 (d, J = 9.6 Hz, 2 H) ppm. 13C NMR
2.0 mmol) or KOEt (168.0 mg, 2.0 mmol), Cu2O (0.7 mg, (100 MHz, CDCl3): δ = 25.6, 25.9, 33.2, 47.7, 55.1, 114.1, 124.8,
0.005 mmol), and aryl iodide (1.2 mmol) in a dry box under a nitro-
gen atmosphere. The vial was then sealed with a cap containing a
PTFE septum and removed from the dry box. Under a nitrogen
atmosphere, dioxane or DME (0.5 mL) and 1-dodecanethiol
(0.24 mL, 1.0 mmol) were added by syringe, and the reaction vessel
was heated at 110 °C in an oil bath. After stirring at this tempera-
ture for 6–24 h, the heterogeneous mixture was cooled to room
temperature and diluted with ethyl acetate (20 mL). The resulting
solution was directly filtered through a pad of Celite and then
washed with ethyl acetate (20 mL) and concentrated to give the
crude material, which was then purified by column chromatog-
raphy (SiO2, hexane and CH2Cl2 or EtOAc) to give 3.
135.4, 159.1 ppm.
Cyclohexyl(mesityl)sulfane (3g): Following the general procedure
and using KOH (112.0 mg, 2.0 mmol), cyclohexanethiol (0.123 mL,
1.0 mmol),
and
2-iodo-1,3,5-trimethylbenzene
(295.0 mg,
1.2 mmol). Purification (SiO2, hexane) provided 3g (194 mg, 83%
yield) as a colorless oil (Table 2, Entry 6). 1H NMR (400 MHz,
CDCl3): δ = 1.20–1.85 (m, 10 H), 2.24 (s, 3 H), 2.49 (s, 6 H), 2.74–
2.80 (m, 1 H), 6.90 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 20.9, 22.2, 25.8, 26.2, 33.6, 47.3, 128.7, 129.6, 137.6, 143.1 ppm.
HRMS (EI): calcd. for C15H22S 234.1442; found 234.1441.
(2-Ethyl-6-methylphenyl)(2-methylbutyl)sulfane (3h): Following the
general procedure and using KOH (112.0 mg, 2.0 mmol), 2-meth-
ylbutane-1-thiol (0.125 mL, 1.0 mmol), and 1-ethyl-2-iodo-3-meth-
ylbenzene (295.0 mg, 1.2 mmol). Purification (SiO2, hexane) pro-
vided 3h (200 mg, 90% yield) as a colorless oil (Table 2, Entry 7).
1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 7.2 Hz, 3 H), 1.02
(d, J = 8.8 Hz, 3 H), 1.20–1.27 (m, 4 H), 1.49–1.61 (m, 2 H), 2.50
(dd, J = 8.4, 14.0 Hz, 1 H), 2.59 (s, 3 H), 2.64 (dd, J = 8.4, 14.0 Hz,
1 H), 2.95–3.01 (m, 2 H), 7.08–7.16 (m, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 11.3, 16.1, 19.0, 22.0, 28.2, 28.8, 35.3, 43.5,
126.4, 128.0, 128.1, 134.1, 143.0, 148.7 ppm. HRMS (EI): calcd.
for C14H22S 222.1442; found 222.1435.
(2-Methylbutyl)(p-tolyl)sulfane (3b): Following the general pro-
cedure and using KOH (112.0 mg, 2.0 mmol), 2-methylbutane-1-
thiol (0.125 mL, 1.0 mmol), and 4-iodotoluene (262.0 mg,
1.2 mmol). Purification (SiO2, hexane) provided 3b (174 mg, 90%
yield) as a colorless oil (Table 2, Entry 1). 1H NMR (400 MHz,
CDCl3): δ = 0.88 (t, J = 4.8 Hz, 3 H), 1.00 (d, J = 6.8 Hz, 3 H),
1.19–1.27 (m, 1 H), 1.47–1.64 (m, 2 H), 2.29 (s, 3 H), 2.70 (dd, J
= 7.2, 12.4 Hz, 1 H), 2.89 (dd, J = 7.2, 12.4 Hz, 1 H), 7.06 (d, J =
6.4 Hz, 2 H), 7.23 (d, J = 6.4 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 11.2, 18.8, 20.9, 28.7, 34.4, 41.4, 129.5, 129.6, 133.6,
135.5 ppm. HRMS (EI): calcd. for C12H18S 194.1129; found
194.1131.
Cyclohexyl(2-ethyl-6-methylphenyl)sulfane (3i): Following the gene-
ral procedure and using KOH (112.0 mg, 2.0 mmol), cyclohex-
anethiol (0.123 mL, 1.0 mmol), and 1-ethyl-2-iodo-3-methylbenz-
ene (295.0 mg, 1.2 mmol). Purification (SiO2, hexane) provided 3i
Cyclohexyl(p-tolyl)sulfane (3c): Following the general procedure
and using KOH (112.0 mg, 2.0 mmol), cyclohexanethiol (0.125 mL,
1.0 mmol), and 4-iodotoluene (262.0 mg, 1.2 mmol). Purification
(SiO2, hexane) provided 3c (177 mg, 86% yield) as a colorless oil
(Table 2, Entry 2).[9c] 1H NMR (400 MHz, CDCl3): δ = 1.18–2.01
(m, 10 H), 2.31 (s, 3 H), 2.98–3.04 (m, 1 H), 7.09 (d, J = 9.2 Hz, 2
H), 7.31 (d, J = 9.2 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 21.0, 25.7, 26.0, 33.3, 47.0, 129.5, 131.1, 132.7, 136.8 ppm.
1
(216 mg, 92% yield) as a colorless oil (Table 2, Entry 8). H NMR
(400 MHz, CDCl3): δ = 1.19–1.85 (m, 13 H), 2.55 (s, 3 H), 2.75–
2.83 (m, 1 H), 2.97 (m, 2 H), 7.13 (m, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 15.9, 22.4, 25.8, 26.2, 28.2, 33.6, 47.9,
126.3, 127.9, 128.1, 132.4, 143.5, 149.3 ppm. HRMS (EI): calcd.
for C15H22S 234.1442; found 234.1446.
Dodecyl(4-methoxyphenyl)sulfane (3d): Following the general pro-
cedure and using KOH (112.0 mg, 2.0 mmol), 1-dodecanethiol
(0.24 mL, 1.0 mmol), and 4-iodoanisole (281.0 mg, 1.2 mmol). Pu-
rification (SiO2, hexane) provided 3d (270 mg, 86% yield) as a col-
orless solid (Table 2, Entry 3).[22] M.p. 44–45 °C (ref.[22] 44–45 °C)
1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.25–
1.40 (m, 18 H), 1.57 (m, 2 H), 2.81 (t, J = 7.6 Hz, 2 H), 3.80 (s, 3
H), 6.84 (d, J = 8.4 Hz, 2 H), 7.34 (d, J = 8.4 Hz, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 14.0, 22.6, 28.6, 29.1, 29.3, 29.46,
29.53, 29.58, 29.6, 31.9, 35.7, 55.1, 114.4, 127.0, 132.8, 158.6 ppm.
3-(Cyclohexylthio)pyridine (3j): Following the general procedure
and using KOH (112.0 mg, 2.0 mmol), cyclohexanethiol (0.123 mL,
1.0 mmol), and 3-iodopyridine (245.0 mg, 1.2 mmol). Purification
(SiO2; hexane/EtOAc, 6:1) provided 3j (148 mg, 77% yield) as a
1
colorless oil (Table 2, Entry 9). H NMR (400 MHz, CDCl3): δ =
1.23–2.05 (m, 10 H), 3.08–3.13 (m, 1 H), 7.21–7.26 (m, 1 H), 7.70–
7.73 (m, 1 H), 8.46–8.48 (m, 1 H), 8.64 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 25.3, 25.6, 32.9, 46.4, 123.2, 131.9, 139.2,
147.3, 152.2 ppm. HRMS (EI): calcd. for C11H15NS 193.0925;
found 193.0920.
4(4-Methoxyphenyl)(2-methylbutyl)sulfane (3e): Following the gene-
ral procedure and using KOH (112.0 mg, 2.0 mmol), 2-methylbut-
ane-1-thiol (0.125 mL, 1.0 mmol), and 4-iodoanisole (281.0 mg,
1.2 mmol). Purification (SiO2, hexane) provided 3e (178 mg, 85%
yield) as a colorless oil (Table 2 Entry 4). 1H NMR (400 MHz,
CDCl3): δ = 0.86 (t, J = 5.2 Hz, 3 H), 0.98 (d, J = 6.8 Hz, 3 H),
1.19–1.26 (m, 1 H), 1.47–1.60 (m, 2 H), 2.65 (dd, J = 7.6, 12.4 Hz,
1 H), 2.84 (dd, J = 7.6, 12.4 Hz, 1 H), 3.76 (s, 3 H), 6.82 (d, J =
5.2 Hz, 2 H), 7.32 (d, J = 5.2 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 11.1, 18.6, 28.5, 34.3, 42.8, 55.0, 114.3, 127.4, 132.4,
158.4 ppm. HRMS (EI): calcd. for C12H18OS 210.1078; found
210.1072.
3-(2-Methylbutylthio)pyridine (3k): Following the general procedure
and using KOH (112.0 mg, 2.0 mmol), 2-methylbutane-1-thiol
(0.125 mL, 1.0 mmol), and 3-iodopyridine (245.0 mg, 1.2 mmol).
Purification (SiO2; hexane/EtOAc, 6:1) provided 3k (140 mg, 77%
yield) as a colorless oil (Table 2, Entry 10). 1H NMR (400 MHz,
CDCl3): δ = 0.88 (t, J = 5.2 Hz, 3 H), 1.00 (d, J = 7.6 Hz, 3 H),
1.26–1.30 (m, 1 H), 1.49–1.6 (m, 2 H), 2.74 (dd, J = 6.4, 13.6 Hz,
1 H), 2.91 (dd, J = 6.4, 13.6 Hz, 1 H), 7.15–7.20 (m, 1 H), 7.58–
7.63 (m, 1 H), 8.37–8.39 (m, 1 H), 8.55 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 11.0, 18.5, 28.4, 34.2, 40.5, 123.2, 134.4,
136.2, 146.4, 149.5 ppm. HRMS (EI): calcd. for C10H15NS
181.0920; found 181.0928.
Cyclohexyl(4-methoxyphenyl)sulfane (3f): Following the general
procedure and using KOH (112.0 mg, 2.0 mmol), cyclohexanethiol
(0.123 mL, 1.0 mmol), and 4-iodoanisole (281.0 mg, 1.2 mmol). Pu-
rification (SiO2, hexane) provided 3f (218 mg, 98% yield) as a col-
2-(Cyclohexylthio)aniline (3l): Following the general procedure and
using KOH (112.0 mg, 2.0 mmol), cyclohexanethiol (0.135 mL,
1.1 mmol), and 2-iodoaniline (219.0 mg, 1.0 mmol). Purification
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H.-L. Kao, C.-K. Chen, Y.-J. Wang, C.-F. Lee
FULL PAPER
(SiO2; hexane/EtOAc, 20:1) provided 3l (193 mg, 93% yield) as a
green oil (Table 2, Entry 11). 1H NMR (400 MHz, CDCl3): δ =
1.19–2.02 (m, 10 H), 2.88–2.98 (m, 1 H), 4.41 (s, 2 H), 6.66–6.78
(m, 2 H), 7.10–7.18 (m, 1 H), 7.36–7.42 (m, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 26.0, 26.4, 33.9, 47.2, 115.1, 117.2, 118.5,
130.1, 137.6, 149.2 ppm. HRMS (EI): calcd. for C12H17NS
207.1082; found 207.1089.
H), 7.22–7.30 (m, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
33.6, 123.8, 126.3, 127.7, 129.1, 129.8, 134.7, 137.6 ppm.
3-Pyridyl Phenyl Sulfide (3s): Following the general procedure and
using KOH (112.0 mg, 2.0 mmol), thiophenol (0.10 mL, 1.0 mmol),
and 3-iodopyridine (246.0 mg, 1.2 mmol). Purification (SiO2; hex-
ane/EtOAc, 9:1) provided 3s (165 mg, 88% yield) as a yellow oil
(Table 2, Entry 18).[23] 1H NMR (400 MHz, CDCl3): δ = 7.11–7.14
(m, 1 H), 7.15–7.33 (m, 5 H), 7.51–7.54 (m, 1 H), 8.38–8.41 (m, 1
H), 8.52 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 123.7,
127.6, 129.2, 131.5, 133.4, 133.7, 137.6, 147.7, 150.8 ppm.
2-(2-Methylbutylthio)aniline (3m): Following the general procedure
and using KOH (112.0 mg, 2.0 mmol), 2-methylbutane-1-thiol
(0.137 mL, 1.1 mmol), and 2-iodoaniline (219.0 mg, 1.0 mmol). Pu-
rification (SiO2; hexane/EtOAc, 20:1) provided 3m (177 mg, 91%
yield) as a brown oil (Table 2, Entry 12). 1H NMR (400 MHz,
CDCl3): δ = 0.84 (t, J = 8.8 Hz, 3 H), 0.98 (d, J = 9.2 Hz, 3 H),
1.17–1.24 (m, 1 H), 1.46–1.57 (m, 2 H), 2.57 (dd, J = 7.2, 12.4 Hz,
1 H), 2.74 (dd, J = 7.2, 12.4 Hz, 1 H), 4.31 (s, 2 H), 6.64–6.88
(m, 2 H), 7.04–7.09 (m, 1 H), 7.34–7.36 (m, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 11.1, 18.6, 28.4, 34.6, 41.9, 114.7, 118.4,
118.8, 129.1, 135.1, 147.7 ppm. HRMS (EI): calcd. for C11H17NS
195.1082; found 195.1074.
2-Phenylsulfanylaniline (3t): Following the general procedure and
using KOH (112.0 mg, 2.0 mmol), thiophenol (0.10 mL, 1.0 mmol),
and 2-iodoaniline (263.0 mg, 1.2 mmol). Purification (SiO2; hex-
ane/EtOAc, 9:1) provided 3t (176 mg, 88% yield) as a yellow oil
(Table 2, Entry 19).[24] 1H NMR (400 MHz, CDCl3): δ = 4.28 (br.
s, 2 H), 6.74–6.80 (m, 2 H), 7.07–7.13 (m, 3 H), 7.20–7.25 (m, 3
H), 7.45–7.47 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
114.2, 115.3, 118.7, 125.3, 126.4, 128.9, 131.1, 136.8, 137.4,
148.8 ppm.
4-Methoxyphenyl Phenyl Sulfide (3n): Following the general pro-
cedure and using KOH (112.0 mg, 2.0 mmol), thiophenol (0.10 mL,
1.0 mmol), and 4-iodoanisole (281.0 mg, 1.2 mmol). Purification
(SiO2; hexane/EtOAc, 10:1) provided 3n (184 mg, 86% yield) as a
colorless oil (Table 2, Entry 13).[9c] 1H NMR (400 MHz, CDCl3): δ
= 3.83 (s, 3 H), 6.89 (d, J = 8.8 Hz, 2 H), 7.09–7.26 (m, 5 H), 7.41
(d, J = 8.8 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 55.3,
114.9, 124.3, 125.7, 128.2, 128.9, 135.3, 138.6, 159.8 ppm.
[2-(Phenylthio)phenyl]methanol (3u): Following the general pro-
cedure and using KOH (112.0 mg, 2.0 mmol), thiophenol (0.10 mL,
1.0 mmol), and 2-iodobenzyl alcohol (281.0 mg, 1.2 mmol). Purifi-
cation (SiO2; hexane/EtOAc, 9:1) provided 3u (155 mg, 72% yield)
as a colorless oil (Table 2, Entry 20).[13] 1H NMR (400 MHz,
CDCl3): δ = 2.69 (br. s, 1 H), 4.71 (s, 2 H), 7.13–7.23 (m, 6 H),
7.26–7.33 (m, 2 H), 7.45 (d, J = 7.2 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 63.1, 126.4, 128.20, 128.23, 128.3, 129.1,
129.3, 132.1, 133.7, 135.9, 142.2 ppm.
4-Methylphenyl 4-Methoxyphenyl Sulfide (3o): Following the gene-
ral procedure and using KOH (112.0 mg, 2.0 mmol), 4-methoxy-
thiophenol (0.125 mL, 1.00 mmol), and 4-iodoanisole (281.0 mg,
1.2 mmol). Purification (SiO2, hexane) provided 3o (189 mg, 77%
yield) as a white solid (Table 2, Entry 14).[9c] 1H NMR (400 MHz,
CDCl3): δ = 3.78 (s, 6 H), 6.83 (d, J = 8.8 Hz, 4 H), 7.27 (d, J =
8.8 Hz, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 55.3, 114.7,
127.4, 132.7, 158.9 ppm.
4-Bromophenyl 4-Methoxyphenyl Sulfide (3v): Following the general
procedure and using KOH (112.0 mg, 2.0 mmol), 4-methoxy-
thiophenol (0.125 mL, 1.0 mmol), and 1-bromo-4-iodobenzene
(338.0 mg, 1.2 mmol). Purification (SiO2; hexane/EtOAc, 9:1) pro-
vided 3v (218 mg, 74% yield) as a yellow oil (Table 2, Entry 21).[21]
1H NMR (400 MHz, CDCl3): δ = 3.81 (s, 3 H), 6.90 (d, J = 8.4 Hz,
2 H), 7.07 (d, J = 8.4 Hz, 2 H), 7.18 (d, J = 8.8 Hz, 2 H), 7.40 (d,
J = 8.8 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 55.3,
115.1, 123.7, 128.9, 129.2, 131.5, 135.4, 137.3, 160.0 ppm.
Mesityl Phenyl Sulfide (3p): Following the general procedure and
using KOH (112.0 mg, 2.0 mmol), thiophenol (0.10 mL, 1.0 mmol),
and 2-iodo-1,3,5-trimethylbenzene (295.0 mg, 1.2 mmol). Purifica-
tion (SiO2, hexane) provided 3p (195 mg, 86% yield) as a colorless
oil (Table 2, Entry 15).[13] 1H NMR (400 MHz, CDCl3): δ = 2.32
(s, 3 H), 2.38 (s, 6 H), 6.90–6.92 (m, 2 H), 7.01 (s, 2 H), 7.02–7.07
(m, 1 H), 7.15–7.19 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 21.1, 21.6, 124.4, 125.4, 126.9, 128.8, 129.3, 138.3, 139.1,
143.6 ppm.
Ethyl 4-Phenylsulfanylbenzoate (3w): Following the general pro-
cedure and using KOEt (168.0 mg, 2.0 mmol), thiophenol
(0.10 mL, 1.0 mmol), and ethyl-4-iodobenzoate (0.2 mL,
1.2 mmol). Purification (SiO2; hexane/EtOAc, 9:1) provided 3w
(144 mg, 56% yield) as a colorless oil (Table 2, Entry 22).[13] 1H
NMR (400 MHz, CDCl3): δ = 1.35 (t, J = 7.2 Hz, 3 H), 4.33 (q, J
= 7.2 Hz, 2 H), 7.19 (d, J = 8.8 Hz, 2 H), 7.34–7.39 (m, 3 H), 7.44–
7.48 (m, 2 H), 7.88 (d, J = 8.8 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 14.2, 60.8, 127.6, 127.8, 128.4, 129.5, 130.0, 132.5,
133.5, 144.0, 166.1 ppm.
2-Ethyl-6-methylphenyl Phenyl Sulfide (3q): Following the general
procedure and using KOH (112.0 mg, 2.0 mmol), thiophenol
(0.10 mL, 1.0 mmol), 2-ethyl-6-methyliodobenzene (295.0 mg,
1.2 mmol). Purification (SiO2, hexane) provided 3q (227 mg, 99%
yield)as a colorless oil (Table 2, Entry 16). 1H NMR (400 MHz,
CDCl3): δ = 1.17 (t, J = 7.6 Hz, 3 H), 2.39 (s, 3 H), 2.86 (q, J =
7.6 Hz, 2 H), 6.90–6.92 (m, 2 H), 7.03–7.07 (m, 1 H), 7.15–7.21 (m,
4 H), 7.25–7.30 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
15.8, 21.8, 28.4, 124.5, 125.5, 127.0, 128.5, 128.8, 129.5, 129.7,
138.6, 144.0, 149.7 ppm. HRMS (EI): calcd. for C15H16S 228.0973;
found 228.0979.
1-[3-(Phenylthio)phenyl]ethanone (3x): Following the general pro-
cedure and using KOH (112.0 mg, 2.0 mmol), thiophenol (0.10 mL,
1.0 mmol), 3Ј-iodoacetophenone (0.17 mL, 1.2 mmol), and DME
(0.5 mL). Purification (SiO2; hexane/EtOAc, 9:1) provided 3x
(130 mg, 57% yield) as a yellow oil (Table 2, Entry 23).[14k] 1H
NMR (400 MHz, CDCl3): δ = 2.52 (s, 3 H), 7.26–7.37 (m, 6 H),
7.41–7.44 (m, 1 H), 7.75–7.77 (m, 1 H), 7.76–7.77 (m, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 26.3, 126.3, 127.4, 129.1, 129.2,
129.6, 131.5, 134.2, 134.3, 137.3, 137.6, 197.0 ppm.
2-(Phenylsulfanyl)-N-methylimidazole (3r): Following the general
procedure and using KOH (112.0 mg, 2.0 mmol), 2-mercapto-1-
methylimidazole (114.0 mg, 1.0 mmol), and iodobenzene (0.13 mL,
1.2 mmol). Purification (SiO2; hexane/EtOAc, 2:1) provided 3r
(161 mg, 85% yield) as a yellow oil (Table 2, Entry 17).[11b] 1H
NMR (400 MHz, CDCl3): δ = 3.68 (s, 3 H), 7.11 (d, J = 1.2 Hz, 1
1-[3-(4-Chlorophenylthio)phenyl]ethanone (3y): Following the gene-
ral procedure and using KOH (112.0 mg, 2.0 mmol), 4-chloro-
thiophenol (173.0 mg, 1.0 mmol), 3Ј-iodoacetophenone (0.17 mL,
1.2 mmol), and DME (0.5 mL). Purification (SiO2; hexane/EtOAc,
9:1) provided 3y (133 mg, 51% yield) as a yellow oil (Table 2, En-
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1776–1781

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try 24). H NMR (400 MHz, CDCl3): δ = 2.56 (s, 3 H), 7.26–7.37
(m, 4 H), 7.39–7.41 (m, 1 H), 7.45–7.47 (m, 1 H), 7.81 (dt, J = 7.6,
1.6 Hz, 1 H), 7.90 (t, J = 1.6 Hz, 1 H) ppm. 13C NMR (100 MHz,
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134.8, 136.8, 138.0, 197.2 ppm. HRMS (EI) calcd. for C14H11OSCl
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Financial support by the National Science Council, Taiwan
(NSC99-2113-M-005–004-MY2) and the National Chung Hsing
University are gratefully acknowledged. We thank Prof. Fung-E
Hong for generously sharing his GC–MS instruments.
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Received: December 13, 2010
Published Online: February 10, 2011
Eur. J. Org. Chem. 2011, 1776–1781
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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