Carbon-sulfur bond formation from 2-halochalcogenophenes via copper catalyzed thiol cross-coupling

Article abstract of DOI:10.1016/j.tetlet.2005.02.102

We present herein our results of the thiol coupling reaction of 2-halochalcogenophenes with Cu(I) and establish the first route to prepare (2-sulfides)-chalcogenophenes in good yields. The reaction performed with both electron donating and electron withdrawing substituents on thiol in the absence of any supplementary additives. In addition, the reaction proceeded cleanly under mild reaction conditions and was sensitive to nature of catalyst, base, and solvent.

Full text of DOI:10.1016/j.tetlet.2005.02.102

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2647–2651
Carbon–sulfur bond formation from 2-halochalcogenophenes
via copper catalyzed thiol cross-coupling
Gilson Zeni*
´ ´ ´
Laboratorio de Sıntese, Reatividade, Avaliac¸a˜o Farmacologica e Toxicidade de Organocalcogenios, CCNE,
UFSM, Santa Maria, Rio Grande do Sul, CEP 97105-900, Brazil
ˆ
Received 19 January 2005; revised 11 February 2005; accepted 14 February 2005
Abstract—We present herein our results of the thiol coupling reaction of 2-halochalcogenophenes with Cu(I) and establish the first
route to prepare (2-sulfides)-chalcogenophenes in good yields. The reaction performed with both electron donating and electron
withdrawing substituents on thiol in the absence of any supplementary additives. In addition, the reaction proceeded cleanly under
mild reaction conditions and was sensitive to nature of catalyst, base, and solvent.
Ó 2005 Elsevier Ltd. All rights reserved.
Chalcogenide compounds have found such wide utility
because their effects on an extraordinary number of very
different reactions, including many carbon–carbon bond
formations,1 under relatively mild reaction conditions.
In addition, they have become attractive synthetic tar-
gets because of their chemo-, regio-, and stereoselective
reactions,2 use in a wide variety of functional groups,
thus avoiding protection group chemistry and useful
biological activities.3 Among chalcogenides, the chalco-
genophenes (telurophene and selenophene) derivatives
play an important role in organic synthesis because of
their excellent electrical properties, processibility, and
environmental stability. But studies of their chemistry
are hampered by poor availability of material.
or co-catalyst. In this way, we present our first results of
a copper catalyzed coupling reaction between 2-halo-
chalcogenophenes 1 and thiols (Scheme 1).
The starting 2-iodochalcogenophene was readily avail-
able by using the metalation of chalcogenophene7 3 with
n-butyllithium to give 2-(lithium)chalcogenophene
derivatives. The treatment of 2-(lithium)chalcogenoph-
ene with iodine leads to the formation of the 2-iodochal-
cogenophene, isolated in 55–85% yield after purification
(Scheme 2).8 Conversely, the 2-bromochalcogenophene
was prepared via bromination of chalcogenophene 3
with NBS in a mixture of CH2Cl2 and AcOH in 50–
62% yield (Scheme 2).9
The palladium catalyzed carbon–carbon bond forma-
tion, a key stage in the synthesis of many currently inter-
esting heterocycle-incorporated compounds,4 has
proved to proceed generally and effectively. By contrast,
there are no reports on the use of halogenated selenoph-
enes or tellurophenes as electrophilic substrate for the
carbon–sulfur bond formation using palladium or cop-
per cross-coupling reactions.5 Considering the advant-
ages of using copper catalysts, less expensive and toxic
than palladium salts, we investigated a new methodol-
ogy to build a carbon–sulfur bond,6 without any ligand
R1SH, CuI, KOH
R
R
SR1
X
Y
2
dioxane, reflux
Y
1
1
Y= Se, Te; X = I, Br; R = H, C4H9, C6H5; R = alkyl, aryl, benzyl
Scheme 1.
1) n-BuLi/THF
NBS
2) I2
R
Br
R
I
Y
R
Y
Y
CHCl2, AcOH
3
1a - Y = Te; R = Ph - 72 %
1b - Y = Te; R = C4H9 - 85 %
1c - Y = Se; R = H - 55 %
1d - Y = Te; R = Ph - 50 %
1e - Y = Se; R = H - 55 %
Keywords: Tellurides; Selenides; Sulfides; Copper cross-coupling;
Selenophene; Tellurophene.
*
Tel.: +55 55 220 8140; fax: +55 55 220 8978; e-mail: gzeni@
quimica.ufsm.br
Scheme 2.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.102

2648
G. Zeni / Tetrahedron Letters 46 (2005) 2647–2651
Since our initial studies have focused on the develop-
ment of an optimum set of reaction conditions, the cou-
pling reaction of 2-halochalcogenophenes with thiols
was examined in order to optimize the reaction condi-
tions. In this way, 2-iodo-5-phenyltellurophene 1a
(0.5 mmol), 4-methoxybenzenethiol (0.5 mmol), and
KOH (1 mmol) as base, in dioxane were treated, at
room temperature, with different copper catalysts and
after 15 min at this temperature, the mixture was
refluxed for different reaction times (Scheme 3).
or morpholine (1 mmol) and no reaction was observed.
By using K3PO4, NaOH, K2CO3, Cs2CO3, Na2CO3,
and EtONa (1 mmol), moderate yields were obtained
(15–28%). However, by using KOH, the sulfide was
formed in 85% isolated yield. We also investigated the
influence of the solvent in the coupling reaction. THF,
dichloromethane, toluene, and benzene did not give
the expected sulfides. In acetonitrile and N,N-dimethyl-
formamide only a small amount of coupling product
was formed, while the use of dioxane afforded sulfides
in higher yields.
As shown in Table 1, Cu(II) catalysts such as Cu(acac)2,
Cu(CH3CO2)2, CuCl2, CuBr2, and Cu(CF3SO3)2 did not
exhibit catalytic activity in this reaction and only the
staring materials were recovered, even so long reaction
time was used (entries 1–5). The Cu(I) catalysts such
as CuCN, CuBr, and CuCl gave unsatisfactory yields
of the desired enynes (entries 6–8). The optimal catalyst
was CuI and the reaction was greatly enhanced by using
CuI from 1% to 5 % (entries 10–12). Furthermore, we
observed that the addition of CuI (10 mol %) promoted
a conversion of 88% (entry 9) instead 85% of the CuI
(5 mol %) (entry 10) without any acceleration of the
reaction. In addition, no coupling reactions were ob-
served when the reaction was carried out in the absence
of CuI (entry 13).
We found that the use of CuI (5 mol %), dioxane
(5 mL), 1a (0.5 mmol), the appropriate thiol (0.7 mol),
and KOH (1 mmol) at reflux was optimal, and these
conditions were subsequently applied to all other sub-
strates in this study.10 The results are summarized in
Table 2.
Inspections of Table 2 show that the reaction worked
well for a variety of iodides. It should be pointed out
that functional groups such as methoxy, chloro, alkyl,
and benzyl were unaffected. It is noteworthy that the
reaction is not sensitive to the electronic nature of
functional groups present in the thiols. In addition, no
significant influence of the substituents at 5-position in
the 2-iodotellurophene was observed (Table 2, entries
8–20).
The nature of the base was critical for the success of the
coupling. The reaction of 2-iodo-5-phenyltellurophene
1a (0.5 mmol) with 4-methoxybenzenethiol (0.7 mmol)
and CuI (5 mol %) in dioxane were refluxed with differ-
ent bases such as triethylamine, pyrrolidine, piperidine
Further, we observed that coupling of bromide 1d–e
with thiols, using our standard catalytic system for the
coupling reaction described in Table 2, gave lower yields
than that of corresponding iodides 1a–c (Table 3). How-
ever, when the catalytic system was changed to CuI
(10 mol %) and the base was changed to K3PO4, the
yields were greatly improved (Table 3). To investigate
the scope of the reaction, the 2-bromochalcogenophene
1d–e (0.5 mmol)were reacted with thiols (0.7 mmol) in
presence of CuI (10 mol %), dioxane (5 mL), and
K3PO4 (1 mmol) at reflux. The reactions of 2-bromosel-
enophenes with thiols bearing a neutral, electron-rich
and electron-poor group gave the desired product in
good yields (Table 3, entries 1–3). At last, the use of
more functionalized 2-bromotellurophenes afforded simi-
lar isolated yields with a higher reaction time (Table 3,
entries 4–6).
SH
[Cu], base
+
solvent, reflux
Ph
S
OCH3
Te
Ph
I
Te
1a
2k
OCH3
Scheme 3.
Table 1. Reaction conditions optimization
SH
[Cu], base
+
solvent, reflux
Ph
S
OCH3
Te
Ph
I
Te
In summary, we have explored the thiol coupling reac-
tion of 2-halochalcogenophenes with Cu(I) and estab-
lished the first route to (2-sulfides)-chalcogenophenes
in good yields. The reaction performed with both elec-
tron donating and electron withdrawing substituents
on thiol in the absence of any supplementary additives.
The advantages of the Cu(I) in a ligand-free system in-
clude its lower cost and it is important when considering
the scale-up of a reaction. In addition, the reaction pro-
ceeded cleanly under mild reaction conditions and was
sensitive to nature of catalyst, base and solvent. The
pharmacological activities of these compounds are
1a
2k
OCH3
Entry
Copper catalyst (mol %)
Time (h)
Yield, 2k (%)
1
Cu(acac)2 (10)
Cu(CH3CO2)2 (10)
CuBr2 (10)
CuCl2 (10)
Cu(CF3SO3)2 (10)
CuCN (10)
CuBr (10)
36
36
36
36
36
20
20
20
8
NR
NR
NR
NR
NR
12
2
3
4
5
6
7
8
22
8
CuCl (10)
CuI (10)
9
88
85
1
10
11
12
13
CuI (5)
CuI (3)
CuI (1)
8
under study in our laboratory. Analysis of the H and
13C NMR spectra showed that all the obtained products
presented data in full agreement with their assigned
structures.
20
20
36
63
50
NR

G. Zeni / Tetrahedron Letters 46 (2005) 2647–2651
Table 2. Sulfides prepared from 2-iodochalcogenophene 1a–c and thiols
2649
R1SH (0.7 mmol), CuI (5 mol %)
KOH (1 mmol), dioxane (5 mL), reflux
R
SR1
Y
2a-t
R
I
Y
1a-c
Entry
1
Chalcogenophene
Thiol
Product
Time (h)
8
Yield (%)
n-C12H25SH
82
80
80
S(n-C12H25
)
I
Se
2a
Se
1c
2
3
1c
n-C3H7SH
8
8
S(n-C3H7)
Se
2b
SH
1c
S
Se
2c
SH
4
5
6
1c
1c
1c
8
10
9
85
79
77
S
OCH3
Se
2d
H3CO
SH
Cl
S
Se
2e
Cl
SH
Cl
S
S
Se
Cl
2f
SH
Se
7
1c
10
88
Cl
Cl
2g
8
n-C12H25SH
12
12
12
8
85
80
82
90
77
80
Ph
I
S(n-C12H25)
Ph
Te
Te
1a
2h
9
1a
1a
1a
1a
1a
n-C3H7SH
S(n-C3H7)
Ph
Te
Te
2i
SH
10
11
12
13
S
Ph
2j
SH
S
OCH3
Ph
Te
Te
H3CO
SH
2k
Cl
S
8
Ph
Cl
2l
SH
Cl
8
S
S
Ph
Te
Te
Cl
2m
SH
Ph
14
15
1a
9
89
85
Cl
Cl
2n
n-C12H25SH
12
n-Bu
S(n-C12H25
)
I
n-C4H9
Te
Te
1b
2o
(continued on next page)

2650
G. Zeni / Tetrahedron Letters 46 (2005) 2647–2651
Table 2 (continued)
Entry
Chalcogenophene
Thiol
Product
Time (h)
12
Yield (%)
78
16
17
18
1b
n-C3H7SH
S(n-C3H7)
n-C4H9
Te
Te
2p
SH
1b
1b
8
8
91
82
S
OCH3
n-C4H9
H3CO
SH
2q
Cl
S
n-C4H9
Te
Cl
2r
SH
Cl
19
20
1b
1b
10
10
80
88
n-C4H9
S
S
Te
Te
Cl
Cl
2s
SH
n-C4H9
Cl
2t
Table 3. Coupling products obtained using 2-bromochalcogenophene 1d-e and thiols
R1SH (0.7 mmol), CuI (10 mol %)
K3PO4 (1 mmol), dioxane (5 mL), reflux
R
Br
R
SR1
Y
Y
2u-z
1d-e
Entry
1
Bromine
Thiol
Product
Time (h)
8
Yielda,b (%)
75(12)
n-C12H25SH
S(n-C12H25
)
Br
Se
1e
Se
2u
SH
2
3
1e
1e
8
70(15)
65(18)
S
S
OCH3
Se
2v
H3CO
Cl
SH
Cl
12
Se
2w
4
5
6
n-C12H25SH
18
15
18
73(15)
78(35)
68(21)
S(n-C12H25
)
Ph
Ph
Br
Te
Te
Te
1d
2x
SH
1d
1d
S
OCH3
Ph
H3CO
SH
2y
Cl
S
Ph
2z
Te
Cl
a The reactions were carried out using CuI (10 mol %) and K3PO4 as base.
b Yield in parentheses correspond to reactions performed in CuI (10 mol %) and using KOH as base.
Acknowledgements
References and notes
We are grateful to FAPERGS, CAPES, and CNPq for
the financial support.
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and 1.7 Hz), 7.29–7.11 (m, 2 H), 2.83 (t, 2 H, J = 7.2 Hz),
1.62 (sex, 2 H, J = 7.2 Hz), 1.48–1.16 (m, 18 H), 0.88, (t, 3
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