Copper-catalyzed Ullmann coupling under ligand- and additive-free conditions. Part 2: S-Arylation of thiols with aryl iodides

Article abstract of DOI:10.1016/j.tetlet.2008.01.060

S-Arylation of a wide variety of substituted aryl and aliphatic thiols with aryl halides catalyzed by copper iodide under mild ligand- and additive-free conditions (ⁿBu₄NBr, PhMe, NaOH, reflux, 22 h) is accomplished in good to excellent product yields (up to 96%).

Full text of DOI:10.1016/j.tetlet.2008.01.060

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Tetrahedron Letters 49 (2008) 2023–2025
Copper-catalyzed Ullmann coupling under ligand- and additive-free
conditions. Part 2: S-Arylation of thiols with aryl iodides
Pongchart Buranaprasertsuk a,b, Joyce Wei Wei Chang a, Warinthorn Chavasiri b,
Philip Wai Hong Chan a,*
a Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
b Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
Received 26 October 2007; revised 25 December 2007; accepted 10 January 2008
Available online 15 January 2008
Abstract
S-Arylation of a wide variety of substituted aryl and aliphatic thiols with aryl halides catalyzed by copper iodide under mild ligand-
and additive-free conditions (nBu4NBr, PhMe, NaOH, reflux, 22 h) is accomplished in good to excellent product yields (up to 96%).
Ó 2008 Elsevier Ltd. All rights reserved.
In the preceding Letter,1 we described an efficient
copper iodide-catalyzed process for the O-arylation of
phenols and alcohols with equimolar amounts of aryl
halides under mild ligand- and additive-free conditions.
In an extension of this work, we wondered if a similar cat-
alytic system could be developed for S-arylations. Indeed,
we were keen to explore whether such an approach could
provide a convenient route to aryl sulfides, a class of com-
pounds commonly used in organic synthesis as building
blocks and a prevalent structural unit found in many
natural products and compounds of biological and materi-
als importance.2,3 Recently, a number of groups have been
reported that the copper-catalyzed Ullmann S-arylation of
thiols in the presence of a ligand or additive could over-
come some of the problems traditionally associated with
this reaction, which include high temperatures (typically
above 140 °C), prolonged reaction times, the need for
polar solvents such as HMPA, stoichiometric amounts
of the metal catalyst, and low yields.3–11 Despite these
advances, examples of analogous reactions that do not
require a ligand or additive in tandem with aryl halides
as starting materials have remained sparse, which would
be desirable from an economical perspective. Herein, we
report the copper iodide-catalyzed S-arylation of a wide
variety of thiols with equimolar amounts of aryl iodides
in yields of up to 96% under ligand- and additive-free con-
ditions (Scheme 1). It is noteworthy to highlight that in all
instances, the present procedure was found to proceed in
R1
R2
CuI (10 mol %)
R1
S
R2
+
SH
I
nBu4NBr, NaOH
PhMe, reflux, 22 h
1
2
3
R1, R2 = H, alkyl, aryl, halide
Scheme 1.
*
Corresponding author. Tel.: +65 6316 8760; fax: +65 6791 1961.
E-mail address: waihong@ntu.edu.sg (P. W. H. Chan).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.060

2024
P. Buranaprasertsuk et al. / Tetrahedron Letters 49 (2008) 2023–2025
Table 1
Table 1 (continued)
CuI-catalyzed S-arylation of aryl thiols 1a–e with aryl iodides 2a–ia
Entry
Substrates Product
Yieldb (%)
Me
R
Me
20
21
22
23
1e + 2b
1e + 2e
1e + 2f
1e + 2g
3q, R = Cl
3r, R = NO2
3s, R = Me
96
81
95
R
SH
SH
SH
Me
Me
1e
3t, R = OMe 81
S
1a, R = Me
1d
1b, R = OMe
1c, R = Cl
Me
Me
I
I
R
I
Me
Me
24
1e + 2h
3u
96
2a, R = H
2e, R = NO2
2h
2i
S
2b, R = Cl 2f, R = Me
2c, R = Br 2g, R= OMe
2d, R = F
Me
Yieldb (%)
a
All reactions were performed for 22 h with CuI: nBu4NBr:1:2:NaOH,
Entry
Substrates
Product
molar ratio = 1:1:10:10:20 in PhMe at reflux.
Me
b
Isolated yield.
1
2
3
4
5
6
1a + 2a
1a + 2b
1a + 2c
1a + 2d
1a + 2e
1a + 2f
3a, R = H
3b, R = Cl
3c, R = Br
3d, R = F
3e, R = NO2
3f, R = Me
95
96
96
96
80
94
good to excellent yields being comparable to those
obtained for the analogous ligand or additive promoted
reactions.7b,11b,12
S
R
Initially, we found that the conditions reported previ-
ously for the N-arylation of nitrogen heterocycles with aryl
iodides also worked well for the coupling of a variety of
substituted aryl thiols and aryl iodides (Table 1).13 In the
presence of 10 mol % of CuI as a catalyst, 10 mol % of
nBu4NBr as a phase transfer catalyst, and NaOH (2 equiv)
in toluene at reflux for 22 h, S-arylation of 4-methylbenze-
nethiol 1a (1 equiv) with a variety of aryl iodides bearing
either electron-withdrawing or electron-donating substitu-
ents (1 equiv) was shown to give the corresponding prod-
ucts in excellent yields of 80–96% (entries 1–6).14
Notably, this included the ability to exploit the difference
in reactivity of aryl halides (I ꢀ Br > Cl > F) by coupling
1a and the aryl iodide selectively in the presence of sub-
strates containing aryl bromides, chlorides and fluorides.
Similarly, the coupling of aryl thiols and aryl iodides con-
taining various electron-withdrawing and electron-donat-
ing substrate combinations was found to proceed in good
to excellent yields (entries 7–13). The present procedure
was also shown to work well for the S-arylation of aryl
thiols and aryl iodides in which either or both the starting
materials contained sterically demanding ortho-substitu-
ents such as a methyl group or a fused benzene ring. In
all the instances, the present procedure was found to pro-
ceed in good to excellent yields (entries 14–24).
OMe
7
8
9
1b + 2b
1b + 2e
1b + 2g
3g, R = Cl
3h, R = NO2
3i, R = OMe
90
78
78
S
R
Cl
S
10
11
12
13
1c + 2b
1c + 2e
1c + 2f
1c + 2g
3j, R = Cl
80
80
81
62
3k, R = NO2
3b, R = Me
3g, R = OMe
R
Cl
S
14
1c + 2i
3l
80
15
16
17
18
1a + 2h
1d + 2f
1d + 2b
1d + 2e
3m, R = Me
96
94
95
90
Me
S
S
To define the scope of the present reaction, the S-aryl-
ation of a representative aliphatic thiol, ethanethiol 1f, with
a variety of aryl iodides was also examined (Scheme 2).
Analogous to our findings for the Cu-catalyzed O-arylation
of alcohols, we found the reactivity of 1f to be solvent and
base dependent. When 1f was treated with either 1 equiv of
3n, R = Cl
3o, R = NO2
R
Me
n
19
1d + 2h
3p
95
2b or 2f in the presence of CuI (10 mol %) and Bu4NBr
(10 mol %) in toluene at reflux for 22 h, the corresponding
Me
ethyl(aryl)sulfane adducts 4a and 4b were obtained in only

P. Buranaprasertsuk et al. / Tetrahedron Letters 49 (2008) 2023–2025
2025
R1
R1
CuI (10 mol %)
I
EtS
+
EtSH
nBu4NBr, K3PO4
DMF, reflux, 22 h
R2
R2
2b, R1 = H, R2 = Cl
2f, R1 = H, R2 = Me
2j, R1 = R2 = Me
1f
4a, 86% yield
4b, 82% yield
4c, 86% yield
Scheme 2.
hedron Lett. 1986, 27, 6129–6132; (f) Nagai, Y.; Irie, A.; Nakamura,
H.; Hino, K.; Uno, H.; Nishimura, H. J. Med. Chem. 1982, 25, 1065–
1070.
50% yield in both the cases. In contrast, repetition of these
reactions but with DMF as a solvent and K3PO4 as a base
was found to give 4a and 4b in yields of 86% and 82%,
respectively. Under similar conditions, S-arylation of 1f
with 2j was found to give 4c in 86% yield.
In summary, we have developed a practical copper-cat-
alyzed procedure for the S-arylation of thiols with aryl
iodides that proceeded in good to excellent yields. The
present protocol is applicable to a variety of thiols and aryl
iodides containing electron-withdrawing, electron-donat-
ing and sterically demanding substrate combinations under
mild conditions. Further investigation of the scope and
applications of this reaction is currently underway and will
be reported in due course.
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This work was supported by a College of Science Start-
Up Grant from Nanyang Technological University.
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14. Typical experimental procedure: To a round bottom flask containing
thiol 1 (2 mmol), aryl iodide 2 (2 mmol), CuI (0.2 mmol), nBu4NBr
(0.2 mmol) and NaOH (4 mmol) under a N2 atmosphere was added
toluene (1.3 mL). The reaction mixture was vigorously refluxed for
22 h. On cooling to room temperature, saturated NH4Cl (20 mL) was
added and the organic layer was extracted with Et2OAc (3 Â 20 mL).
The combined organic layers were washed with brine (20 mL), dried
over MgSO4, filtered and concentrated under reduced pressure. The
residue was purified by silica gel flash column chromatography to
afford the title compound.