Synthesis of 3-iodothiophenes via iodocyclization of (Z)-thiobutenynes

Article abstract of DOI:10.1016/j.tetlet.2013.10.118

A simple synthesis of 3-iodothiophenes was demonstrated using a wide range of (Z)-thioenynes. The key step in the iodocyclofunctionalization was the selective reduction of the triple bond in (Z)-thioenynes by the addition of iodine as an electrophilic age

Full text of DOI:10.1016/j.tetlet.2013.10.118

Tetrahedron Letters 55 (2014) 52–55
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 3-iodothiophenes via iodocyclization
of (Z)-thiobutenynes
Amanda S. Santana a, Diego B. Carvalho a, Nadla S. Cassemiro a, Luiz H. Viana a, Gabriela R. Hurtado a,
Marcos S. Amaral a, Najla M. Kassab a, Palimécio G. Guerrero Jr. b, Sandro L. Barbosa c, Miguel J. Dabdoub d,
Adriano C. M. Baroni a,
⇑
a LASQUIM—Laboratório de Síntese e Química Medicinal, Centro de Ciências Biológicas e da Saúde e Instituto de Química, Universidade Federal do Mato Grosso do Sul, UFMS,
Campo Grande, MS 79070-900, Brazil
b Departamento de Química e Biologia, DAQBi, Universidade Tecnológica Federal do Paraná, UTFPR, Curitiba, PR 80230-901, Brazil
c Departamento de Farmácia-Bioquímica, Universidade Federal do Vale do Jequitinhonha e Mucuri, Diamantina, MG 39100-000, Brazil
d Departamento de Química, Universidade de São Paulo, Av. Bandeirantes, 3900, Ribeirão Preto, SP 14040-901, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple synthesis of 3-iodothiophenes was demonstrated using a wide range of (Z)-thioenynes. The key
step in the iodocyclofunctionalization was the selective reduction of the triple bond in (Z)-thioenynes by
the addition of iodine as an electrophilic agent. The 3-iodothiophenes were obtained in good to excellent
yields of 61–92%. The 3-iodothiophenes were used as substrates in Sonogashira cross-coupling reactions
to obtain thiophene acetylenes.
Received 26 September 2013
Revised 17 October 2013
Accepted 20 October 2013
Available online 31 October 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
(Z)-Thiobutenynes
Iodocyclization
3-Iodothiophenes
Sonogashira cross coupling
Organochalcogen compounds have been investigated in recent
decades because of their many applications in synthetic organic
chemistry,1 preparation of new materials2 and medicinal
chemistry.3
through the electrophilic cyclization reactions11 of (Z)-thiobuteny-
nes 2a–k.
The (Z)-thiobutenynes 2a–k were synthesized by the addition
of organothiolate anions to diacetylenes 1a–k using C4H9SSC4H9/
NaBH4 or C4H9SH/bases as a reducing system (Scheme 1).12,13
Synthesizing the (Z)-thiobutenynes 2 with C4H9SH/TBAOH as a
reducing system resulted in improved efficiency compared with
C4H9SH/NaOH because TBAOH provided a phase-transfer catalyst
that increased the solubility and reactivity of the butylthiolate an-
ion (Scheme 1).13
The studies involving the electrophilic cyclization reactions
were focused on optimizing the reaction conditions to prepare 3-
iodothiophenes 3 in high yields.
Initially, we tested the cyclization reaction using (Z)-thi-
obutenyne 2a as the starting material in several solvents, such as
CH2Cl2,13 THF, MeCN, and EtOH, followed by the addition of I2
(1.1 equiv) or ICl (1.1 equiv) as electrophilic agents.
Chalcogen atoms such as S, Se and Te can be easily introduced
into organic molecules via nucleophilic and electrophilic addition
reactions.1 These organochalcogens have been widely used in the
formation of new carbon–carbon bonds in palladium-catalyzed Su-
zuki-,4 Negishi-,5 and Sonogashira-type6 cross-coupling reactions.
The most studied organochalcogen species are organosulfur
compounds.1d,7 For example, the thiophene moiety is found in var-
ious chemical compounds, with a broad range of applications in
the electronics industry to produce electroluminescent diodes
(OLED), organic field effect transistors (OFET), photovoltaic cells,
sensors, semiconductors, liquid crystals and displays.2,8 Organosul-
fur compounds also play an important role in medicinal chemistry3
because of their lower toxicity compared to organoselenium and
organotellurium reagents.1c,3d,9,10
Because of the great interest in developing new and effective
drugs containing thiophene groups, the aim of this systematic
study was the preparation of 3-iodothiophenes 3 (Scheme 2)
R1
NaOH or TBAOH
R1
R2
C4H9SH/ EtOH/ reflux
C4H9S
1a-k
2a-k
R2
⇑
Corresponding author. Tel.: +55 67 3345 7365.
E-mail address: adriano.baroni@ufms.br (A.C.M. Baroni).
Scheme 1.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.118

A. S. Santana et al. / Tetrahedron Letters 55 (2014) 52–55
53
I
However, the synthesis of disubstituted 3-iodothiophene 3i
failed under identical reaction conditions of iodocyclization in
Scheme 2 (Table 1, entry 1). This led us to study other reaction con-
ditions to prepare 3-iodothiophenes 3i–k (Table 1).
Ph
E+
C4H9S
CH2Cl2
r.t.
Ph
Ph
S
3a
2a
Ph
The reaction of (Z)-thiobutenynes 2i–k with I2, using dichloro-
methane as the solvent, gave exclusively diiodobutadienes 4i, j in
low yields (Table 1, entries 1–3). By using (Z)-thiobutenyne 2k, a
mixture containing a 1:1 ratio of 3-iodothiophene 3k and diiodo-
butadiene 4k was obtained (Table 1, entry 4).
E+= I2, ICl
I2= 82%
ICl= 20%
Scheme 2.
The reaction of (Z)-thiobutenyne 2k and I2/CH2Cl2 at room tem-
perature (48 h) and under reflux at 40 °C (72 h) gave 3-iodothio-
phene 3k exclusively in 45% and 60% yields, respectively
(Table 1, entries 5 and 6). No improvement in synthesizing 3-iodo-
thiophene 3k was observed when CHCl3 was used as the solvent
(Table 1, entries 7 and 8).
Table 1
Optimization of reaction conditions for 3i–k synthesisa
I
C4H9S
I2
I
C4H9S
+
solvent
R
2i-k
S
I
R
R
4i-k
3i-k
However, when using 1,2-dichloroethane as the solvent at
70 °C, a high yield of 80% for 3-iodothiophene 3k was obtained in
1 h (Table 1, entry 9) and a yield of 68% was obtained for 3-iodo-
thiophene 3i after 2 h (Table 1, entry 10).
Given these excellent results, we synthesized a wide range of 3-
iodothiophenes to further investigate the scope and limitations of
the iodocyclization reactions, as shown in Table 2.
The iodocyclization of 2a–c containing phenyl and aromatic
activating p-OMe groups occurred in 5 min, leading to 3-iodothi-
ophenes 3a–c in yields ranging from 82% to 92% (Table 2, entries
1–3). Compounds 3d–h were obtained in 15–30 min, in yields
ranging from 61% to 84% (Table 2, entries 4–8).
Entry
R
T (°C)
Solvent
Time (h)
Yieldb (%)
3
4
1
2
3
4
5
6
7
8
9
C6H13
C6H13
C4H9
Ph
Ph
Ph
Ph
Ph
Ph
C6H13
rt
rt
rt
rt
rt
40
rt
60
70d
70d
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CHCl3
1,2-(CH2Cl)2
1,2-(CH2Cl)2
6
0
0
0
25
45
60
25
45
80
68
35
30
35
25
0c
48
24
0.5
48
72
48
48
1
0c
0c
0c
0c
10
2
0c
a
The disubstituted 3-iodothiophenes 3i–k (Table 2, entries 9–11)
were obtained in 1–2 h and in good yields (65–80%), using 1,2-
dichloroethane as the solvent.
The proposed mechanism presented here for the formation of 3-
iodothiophenes 3a–k (Fig. 1) is similar to the mechanism proposed
by Dabdoub et al. for the formation of 3-iodotellurophenes.14
First, (Z)-thiobutenynes 2a–k undergo an electrophilic addition
of iodine at their corresponding triple bonds to give the intermedi-
ates 5. Pathway a shows the attack of the electron pair of a sulfur
Reaction conditions: compound 2i-k (1.0 mmol), I2 (1.1 mmol), appropriate
solvent (14 ml).
b
c
Ratio detected by 1H NMR (300 MHz) of the crude products.
Yields of isolated products.
d
Addition of electrophile at 70 °C.
The best result was achieved when compound 2a (1.0 mmol) in
CH2Cl2 reacted for 5 min with I2 (1.1 equiv) at room temperature,
producing 2,5-diphenyl-3-iodo-thiophene 3a in 82% yield
(Scheme 2). Using ICl instead of I2 as the electrophile, the cycliza-
tion gave an unsatisfactory yield of 20% for thiophene 3a.
on the
a-carbon of the R2 groups, leading to the formation of
intermediates 6 and the subsequent elimination of iodobutane,
Table 2
Scope of iodocyclization of (Z)-thiobutenynesa
I
R1
I2
C4H9S
R1
R2
CH2Cl2 or
1,2-dichloroethane
S
3a-k
2a-k
R2
Entry
1
(Z)-Thiobutenyne
Solvent
CH2Cl2
Time (h/min)
5
T (°C)
Product
Yield (%)
82
Ph
I
C4H9S
rt
rt
rt
rt
Ph
S
Ph
2a
3a
Ph
p-MeOPh
I
C4H9S
2b
2
3
4
CH2Cl2
CH2Cl2
CH2Cl2
5
5
92
90
77
p-MeOPh
PhOMe-p
S
3b
PhOMe-p
m,p-MeOPh
I
C4H9S
m,p-MeOPh
p-ClPh
PhOMe-p,m
S
3c
2c
PhOMe-p,m
p-ClPh
I
C4H9S
2d
15
PhCl-p
S
3d
PhCl-p
(continued on next page)

54
A. S. Santana et al. / Tetrahedron Letters 55 (2014) 52–55
Table 2 (continued)
Entry
(Z)-Thiobutenyne
Solvent
CH2Cl2
Time (h/min)
20
T (°C)
Product
Yield (%)
65
C4H9
I
C4H9S
5
rt
C4H9
C4H9
S
3e
2e
C4H9
C6H13
C4H9S
I
6
7
CH2Cl2
CH2Cl2
20
30
rt
rt
61
78
C6H13
C6H13
S
3f
2f
C6H13
HO
I
PhCl-
Ph
p
HO
S
3g
C4H9S
2g
PhCl-p
HO
I
8
CH2Cl2
30
rt
84
HO
S
3h
C4H9S
2h
2i
Ph
H
I
9
10
11
1,2-Dichloroethane
1,2-Dichloroethane
1,2-Dichloroethane
2
2
1
70b
70b
70b
68
65
80
C4H9S
C4H9
S
S
S
3i
I
C6H13
C4H9
Ph
H
C4H9S
C6H13
2j
3j
I
H
C4H9S
Ph
2k
3k
a
Reaction conditions: compound 2a-k (2.0 mmol), dropwise addition of I2 (2.2 mmol) in appropriate solvent (28 ml).
Dropwise addition of I2 at 70 °C.
b
generating the 3-iodothiophenes 3a–k. Iodobutane was detected
as a byproduct in all of the reactions listed in Table 2. On the other
hand, diiodobutadienes 4i–k (Fig. 1) are formed by the attack of the
bonded to R2 groups are longer in 2i–k than those of the sulfur
and carbon in trisubstituted (Z)-thiobutenynes 2a–h, thus favoring
pathway b. Because of the steric hindrance effects between alkyl or
aryl groups and C4H9S- group bonded in the same sp2 carbon, this
proximity in 2a–h favors the attack of sulfur on the carbon con-
taining the iodonium ion in intermediates 5, leading to pathway
a (Fig. 1) and the formation of aromatic trisubstituted 3-iodothi-
ophenes 3a–h.
iodide anion (pathway b) on the a
-carbon of the R2 groups in 5.14 In
this case, iodobutane was not detected as a byproduct when
(Z)-thiobutenynes 2i, j were used as starting materials in CH2Cl2.
We observed the formation of 3k, diiodobutadiene 4k, and a
smaller proportion of iodobutane in the iodocyclization of (Z)-thi-
obutenyne 2k in CH2Cl2 (Table 1, entry 4). Increases in reaction
times and temperature (Table 1, entries 5–8) favored the formation
of 3-iodothiophene 3k.
Structure calculations for compounds 2a, 2k and intermediates
5a, 5k were performed using a computer modeling program.15 The
minimized structures showed that the distances between the sul-
A possible explanation for the formation of diiodobutadienes
fur atom and the a-sp carbon of the Ph group in (Z)-thiobutenynes
4i–k is that the distances between the sulfur and
a
-sp carbon
2a and 2k are 1.976 Å and 3.726 Å, respectively. The distances be-
tween the sulfur atom and the sp2 carbon of iodonium intermedi-
ates 5a and 5k are 1.241 Å and 3.072 Å, respectively (Fig. 2).
The larger distances between the sulfur and sp carbon present
in (Z)-thiobutenynes 2i–k and their intermediates such as 5
C4H9S
R1
R1
C4H9S
I
pathway b
I2
I
a
R1
R2
I
4
CH2Cl2
S
I
R2
2
H
b
C4H9
Ph
R2
R1 = H
R2 = C6H13 (4i), C4H9 (4j), Ph (4k)
5
C4H9S
C4H9S
pathway a
Ph
Ph
Ph
º
º
3.726 A
2k
1.976 A
2a
I
I
I
C4H9I
I
H
Ph
Ph
R1
R2
S
S
C4H9
S
C4H9
R1
R2
S
º
º
C4H9
1.241 A
3.072 A
3
5a
5k
I
6
Figure 2. Calculation of distances between the sulfur and carbon atoms.
Figure 1. Proposed reaction mechanism.

A. S. Santana et al. / Tetrahedron Letters 55 (2014) 52–55
55
R
References and notes
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H
R
, 24h, reflux
S
I
7a - R = C5H11; 81%
7b - R = Ph; 78%
S
3a
1. BuLi (1,2 equiv), THF, 0 ºC, 2h
2. H2O
S
8
75%
Scheme 3. Reactions of (Z)-thiobutenyne 3a.
required changes in the reaction conditions, such as solvent ex-
change (1,2-dichloroethane) and increasing the temperature to
70 °C, to obtain good yields of the more thermodynamically stable
3-iodothiophenes 3i–k (Table 2, entries 9–11).
Considering the possibility of new applications in organic syn-
thesis, we investigated the cross-coupling reactions of 3-iodothio-
phene 3a with terminal acetylenes in Sonogashira cross-coupling
type reactions16 and the removal of iodine by the reaction of com-
pound 3a with n-BuLi (Scheme 3).17
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Software 1999).
The formation of thiophene acetylenes 7a, b occurred in 24 h in
yields of 81% and 78%, respectively. The attack of the BuLi on the
iodine atom gave thiophene 8 in 75% yield (Scheme 3).
We developed an efficient methodology for the synthesis of
3-iodothiophenes in good to excellent yields. We are currently
studying the synthesis of other compounds via cross-coupling
Sonogashira reactions18 to increase the number of samples
synthesized. Reactions with BuLi will be performed, and the
lithium intermediate will be captured with other electrophiles
(ketones or aldehydes) for the synthesis of new alcohol derivatives
with potential activity against neglected diseases.
Acknowledgments
This study was supported by Grants from FUNDECT-MS, PROPP-
UFMS, CNPq and CAPES. We thank Dr. Janet W. Reid (JWR Associ-
ates) for assistance with English corrections. Special thanks go to
Dr. Norberto P. Lopes and José C. Tomas (Faculty of Pharmaceutical
Sciences of Ribeirão Preto—USP—Brazil) for providing the facilities
for the High Mass Resolution analysis.
16. Vuligonda, V.; Thacher, S. M.; Chandraratna, R. A. S. J. Med. Chem. 2001, 44,
2298.
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Ferreira, A. G. Synth. Commun. 2008, 38, 4379.
Supplementary data
18. Nazario, C. E. D.; Santana, A. S.; Kawasoko, C. Y.; Carollo, C. A.; Hurtado, G. R.;
Viana, L. H.; Barbosa, S. L.; Guerrero, P. G.; Marques, F. A.; Dabdoub, V. B.;
Dabdoub, M. J.; Baroni, A. C. M. Tetrahedron Lett. 2011, 54, 4177.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.10.118.