Clean and Efficient Iodination of Thiophene Derivatives

Article abstract of DOI:10.1055/s-0035-1560480

Iodination of thiophene derivatives is realized using a simple, fast, and efficient methodology. Iodination of thiophene and 2- or 3-substituted or 3,4-disubstituted thiophenes with N-iodosuccinimide (NIS) activated with 4-toluenesulfonic acid in ethanol gives pure iodinated products that require no further purification.

Full text of DOI:10.1055/s-0035-1560480

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 3901–3906
paper
3901
J. Grolleau et al.
Paper
Synthesis
Clean and Efficient Iodination of Thiophene Derivatives
Jérémie Grolleau
S
S
PTSA (10 mol%), NIS
EtOH, r.t., 10 min
Pierre Frère
R2
R2
23 examples
up to 99% yield
I
Frédéric Gohier*
R1
R1
University of Angers, MOLTECH-Anjou UMR CNRS 6200,
SCL group, 2 boulevard Lavoisier, 49045 Angers cedex,
France
R1 = H, OMe, Oct, Br, CHO, CH2CN, CH2OH
R2 = H, OMe, Br, CH2CN, CH2OH, SCH2CH2CN, Hex
frederic.gohier@univ-angers.fr
Received: 26.06.2015
Accepted after revision: 26.08.2015
Published online: 11.09.2015
conditions that have been developed for the successfully io-
dination of activated aromatics. However, these routes re-
quire chlorinated solvents, toxic reagents, oxidative condi-
tions, or air/moisture sensitive conditions that cannot be
considered as part of a clean strategy for the iodination of
arenes. More recently, N-iodosaccharin has been designed
as an alternative iodinative reagent with ionic liquids to
promote the clean iodination of electron-enriched, activat-
ed arenes.17 Our interest in the clean and rapid functional-
ization of thiophene has led to the development of a simple
and convenient method for the introduction of iodine using
N-iodosuccinimide in ethanol, a green solvent, with a cata-
lytic amount of 4-toluenesulfonic acid. N-Iodosuccinim-
ide/4-toluenesulfonic acid in various solvents18 has been
previously used for the iodination of thiophene, but these
methods have not been developed and optimized. Our
method has been tested on various substituted thiophenes
and it has been showed to be efficient when the thiophenes
are not completely deactivated.
We first studied the iodination of thiophene (1) with N-
iodosuccinimide using varying additives, solvents, tem-
peratures, and times (Table 1); the parameters that have an
impact on the progress of the reaction are acidic additives
and the solvent. Indeed, without the use of an additive (en-
tries 1 and 2), the reaction takes place very slowly. When 4-
toluenesulfonic acid is added to the mixture, the solution
became darker and after stirring for 10 minutes the N-iodo-
succinimide was consumed completely (entry 3), however a
mixture of monoiodinated thiophene 2 and diiodinated
thiophene 3 is unavoidably obtained. Decreasing the tem-
perature diminished the kinetics of the reaction (entry 4)
and increasing the temperature (entry 5) did not favor
monoiodination. The solvent has a non-negligible impact
on the reaction; water did not solubilize thiophene (1) (en-
try 6), whereas ethanol was an efficient solvent. Other
green solvents, such as ethyl acetate or ethyl lactate (entries
DOI: 10.1055/s-0035-1560480; Art ID: ss-2015-z0402-op
Abstract Iodination of thiophene derivatives is realized using a simple,
fast, and efficient methodology. Iodination of thiophene and 2- or 3-
substituted or 3,4-disubstituted thiophenes with N-iodosuccinimide
(NIS) activated with 4-toluenesulfonic acid in ethanol gives pure iodin-
ated products that require no further purification.
Key words iodination, thiophene, green methodology, regioselectivi-
ty, 4-toluenesulfonic acid, catalysis
Iodinated arenes are valuable intermediates for the pro-
motion of C–C and N–C coupling under mild conditions us-
ing the Suzuki–Miyaura,1 Sonogashira,2 Heck,3 or Buchwald
reaction.4 Such methodology is often used in the field of or-
ganic semiconductors to produce compounds5 dedicated to
organic solar cells and electroluminescent diodes. Re-
searchers have paid increasing attention to the synthesis of
these compounds and particularly syntheses that have re-
duced environmental impact.6 For example, the Suzuki re-
action is preferred to the Stille reaction7 for coupling reac-
tions as it avoids the production of tin residues. Thus, iodin-
ated intermediates are attractive if the introduction of
iodine is clean and efficient. Generally, bromo and chloro
groups are preferred to iodo groups because they are easier
to introduce,8 even though there are numerous methods
available in literature for the iodination of arenes. Oxidative
reagents, such as sodium periodate,9 lead tetraacetate,10
manganese dioxide,11 periodic acid,12 and chromium triox-
ide,13 used together with iodine or potassium iodide are ef-
ficient methods for the synthesis of iodoarenes. An indirect
method using a sequence of deprotonation with butyllithi-
um and anion trapping with iodine has also been devel-
oped.14 N-Iodosuccinimide alone or activated with a Lewis
acid15 and N-chlorosuccinimide/sodium iodide16 are other
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3901–3906

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J. Grolleau et al.
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Synthesis
7 and 8) did not afford good yields. Indeed, activation of N-
iodosuccinimide is more efficient in ethanol than in ethyl
acetate due to the protic properties of ethanol, and N-iodo-
succinimide was not soluble in ethyl lactate hence no reac-
tion took place. Other acidic additives were tested. Acetic
acid (entry 9) was inefficient whereas sulfuric acid (entry
10) afforded a mixture of 2 and 3. Iodination was realized
successfully with a catalytic amount of 4-toluenesulfonic
acid (entry 11) to give predominately 2-iodothiophene (2).
Finally, 2,5-diiodothiophene (3) was obtained pure using 2
equivalents of N-iodosuccinimide (entry 12). This method-
ology was applied to unsymmetrical thiophenes 4, 6, 9, and
12 and the results are gathered in Tables 2–5.
cyano- or ester-substituted thiophenes 4f,g (entries 6 and
7) did not give the products of iodination even at higher
temperatures (100 °C, sealed tube); all attempts to obtain
the iodinated derivatives under microwave irradiation at
100 °C failed. All compounds 5 were obtained in pure form
with only washing of the crude mixture diluted in ethyl ac-
etate with sodium thiosulfate and sodium carbonate solu-
tions required; the products were isolated without column
chromatography.
Table 2 Iodination of 2-Substituted Thiophenes
R
R
S
S
NIS, EtOH, PTSA (10 mol%)
10 min, T °C
I
Table 1 Iodination of Thiophene
4
5
I
S
S
S
time, T °C, additive
I
I
Entry
R
NIS (equiv) Temp (°C)
Product
Yielda (%)
+
NIS (1 equiv), solvent
1
2
3
4
5
6
7
8
OMe
1
25
25
5a
5b
5c
5d
5e
5f
77
98
94
99
94
0
1
2
3
(CH2)7Me
Br
1.1
1.1
1.1
1.1
1.1
1.1
1.1
Entry Additive
(equiv)
Solvent
Temp Time
(°C)
Conversiona
1/2/3
50
CHO
50
1
2
–
EtOH
25
25
25
0
24 h
46:36:17
100:0:0
27:57:16
83:16:0
21:62:17
100:0:0
96:3:0
CH2CN
CO2Et
CN
50
–
EtOH
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
100b
100b
25
3
PTSA (1)
PTSA (1)
PTSA (1)
PTSA (1)
PTSA (1)
PTSA (1)
AcOH (1)
H2SO4 (1)
PTSA (0.1)
PTSA (0.1)
EtOH
5g
5h
0
4
EtOH
CH2OH
98
5
EtOH
50
25
25
25
25
25
25
25
a Isolated yield.
b Experiments carried out in a screw-capped glass tube.
6
H2O
7
EtOAc
EtCOCH(OH)Me
EtOH
We also explored the iodination of the more challenging
3-substituted thiophenes 6 since there are two α-positions
that can be functionalized (Table 3). Thiophenes 6a,d sub-
stituted by strong electron-enriched groups (S and O) in po-
sition 3 cleanly give the products 7a,d of direct monoiodin-
ation in position 2 (entries 1 and 6). Thiophenes 6b,e,f sub-
stituted by poor electron-donating and poor electron-
withdrawing groups, such as hexyl, cyanomethyl, and hy-
droxymethyl, do not afford the products of regiospecific io-
dination (entries 2, 8, and 10) and mixtures of monoiodin-
ated and diiodinated products and starting material were
observed. If monoiodination does not proceed efficiently,
diiodination can be realized using 2.2 equivalents of N-io-
dosuccinimide to give 7b,c,e,f in good yields (entries 3, 5, 9,
and 11).
Iodination of unsymmetrical 3,4-disubstituted thio-
phenes 9a,b (Table 4) takes place cleanly and selectively
(entries 1 and 2). Iodination of 3,4-(ethylenedioxy)thio-
phene (EDOT) 9c with 2.2 equivalents of N-iodosuccinimide
gives diiodo product 11c (entry 4), the use of 1.1 equiva-
lents affords a mixture of starting material and mono- and
diiodinated compounds (entry 3).
8
99:0:0
9
98:0:0
10
11
12b
EtOH
22:62:15
18:64:17
0:0:77c
EtOH
EtOH
a Conversion based on 1H NMR integration of characteristic signals of each
compound.
b NIS (2 equiv).
c Isolated yield.
With these optimized conditions in hand, we decided to
investigate the scope of our iodination reaction either at
room temperature or at 50 °C. Electrophilic aromatic sub-
stitution (SEAr) of 2-substituted thiophenes 4 takes place in
position 5 (Table 2). The reaction of electron-donating
group substituted thiophenes 4a,b took place at room tem-
perature to give 5a,b (entries 1 and 2), whereas some reac-
tions with electron-withdrawing group substituted thio-
phenes required slight heating. Thiophene-2-carbaldehyde
(4d) (entry 4) requires acidic conditions to hydrolyze the
intermediate acetal formed in the course of the reaction at
the end of the reaction; this reaction worked certainly due
to acetal formation. Cyanomethyl-substituted thiophene 4e
(entry 5) requires a reaction temperature of 50 °C, whereas
Other substituted thiophenes have been successfully io-
dinated (Table 5). Iodination of 4-bromo-2-methylthio-
phene (12a) gives 13a in 95% yield (entry 1). Monoiodina-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3901–3906

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J. Grolleau et al.
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Synthesis
Table 3 Iodination of 3-Substituted Thiophenes
Table 5 Iodination of Various Thiophenes
I
S
I
I
S
NIS, EtOH, (10 mol%) PTSA
S
S
S
NIS, EtOH, PTSA (10 mol%)
10 min, T °C
R3
R3
+
I
10 min, T °C
R1
R1
R1
R1
R1
R2
R2
6
7
8
12
Entry R1
13
Yielda (%)
80
R2
R3
NIS
(equiv) (°C)
Temp Product Yielda
(%)
Entry
R
NIS (equiv) Temp (°C) Product
1
2
OMe
1.1
1.1
2.2
1.1
2.2
1.1
2.2
1.1
2.2
1.1
2.2
25
25
50
50
50
25
50c
25
50
25
50c
7a
7b
8b
7c
8c
7d
8d
7e
8e
7f
1
2
Br
H
Me
2.2
1.1
50
25
13a
13b
95
b
(CH2)5Me
(CH2)5Me
Br
–
Hex
3
99
64
61
93
81
S
S
H
H
H
H
95
4
5
Br
OHC
6
S(CH2)2CN
S(CH2)2CN
CH2CN
CH2CN
CH2OH
CH2OH
3
4
1.1
1.1
50
25
13c
13d
79
98
7
b
OCH2CH2O CHO
8
–
a Isolated yield.
9
93
b
10
11
–
8f
99
I
S
S
NIS, EtOH, PTSA (10 mol%)
10 min, 50 °C
a Isolated yield.
b Mixture of compounds obtained and not purified.
c Stirring, 30 min.
S
S
I
14
15 94%
Scheme 1 Diiodination of 2,2′-bithiophene
Table 4 Iodination of 3,4-Disubstituted Thiophene
I
I
S
S
S
NIS, EtOH, PTSA (10 mol%)
The iodinated compounds were obtained in pure form after
10 minutes reaction without using chromatography for
separation. Thiophenes substituted by powerful electron-
withdrawing group do not react, but the reaction proceeds
regioselectively with thiophenes substituted with poor
electron-withdrawing groups and electron-donating
groups. Diiodinated thiophenes are obtained as simply and
as rapidly as monoiodinated thiophenes under the same
conditions using 2.2 equivalents of N-iodosuccinimide.
+
I
R1
R1
R1
10 min, T °C
R2
R2
R2
9
10
11
Entry R1
R2
NIS (equiv) Temp (°C) Product Yielda (%)
1
2
3
4
OMe
CN
Br
1.1
1.1
1.1
2.2
25
25
25
25
10a
10b
10c
11c
94
92
OMe
b
OCH2CH2O
OCH2CH2O
–
87
Characterization of the isolated products was carried out in CDCl3 or
DMSO-d6 at 25 °C. Chemical shifts are reported relative to the solvent
residual value: δ = 7.26 (CDCl3), 2.50 (DMSO-d6) for 1H NMR and
δ = 77.16 (CDCl3), 39.52 (DMSO-d6) for 13C NMR. NMR spectra were
recorded on a 300.1 MHz spectrometer for 1H and 75.7 MHz spec-
trometer for 13C at T = 300 K. Spectra were referenced against the in-
ternal NMR solvent standard. Mass spectra were recorded under EI
mode; the main peaks are described, the peak corresponding to the
molecular mass is expressed as (M+•). Analytical grade solvents were
used.
a Isolated yield.
b Mixture of compounds.
tion takes place regioselectively on 5-hexyl-2,2′-bithio-
phene (12b) and [2,2′-bithiophene]-5-carbaldehyde (12c)
(entries 2 and 3). Iodination of substituted 3,4-(ethylenedi-
oxy)thiophene (EDOT) 12d gave iodinated derivative 13d
almost quantitatively. We also explored iodination of 2,2′-
bithiophene (14); the expected compound 15 was obtained
in good yield using 2.1 equivalents of N-iodosuccinimide
(Scheme 1).
Monoiodothiophenes 2, 5, 7, 10, 13; General Procedure
The thiophene derivative (1 mmol, 1 equiv) was dissolved in EtOH (2
mL) at the temperature indicated in Tables 1–5. Then, NIS (1 or 1.1
equiv, see Tables 1–5) was added followed by PTSA (10% mol). The
mixture was stirred for 10 min, then sat. Na2S2O3 (2 mL) was added.
The mixture was diluted with EtOAc (3 mL). After phase separation,
In conclusion, iodination can be realized on substituted
thiophenes with N-iodosuccinimide and a catalytic amount
of 4-toluenesulfonic acid using ethanol, a green solvent.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3901–3906

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J. Grolleau et al.
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Synthesis
the organic phase was washed with 1 M Na2CO3 solution, dried
(MgSO4), filtered through cotton, and evaporated to give the iodinated
thiophene derivative.
ration, the organic phase was washed with 1 M Na2CO3 solution, dried
(MgSO4), filtered through cotton, and evaporated to give the iodinated
thiophene derivative 5d.
Pale yellow solid; yield: 211 mg (99%); mp 48–50 °C.
Diiodothiophenes 3, 8, 11, 15; General Procedure
IR (KBr): 1680, 1410, 1220, 1032, 961, 791 cm–1
.
The thiophene derivative (100 mg, 1 equiv) was dissolved in EtOH (4
mL) at the temperature indicated in Tables 1–5. Then, NIS (2.2 equiv,
see Tables 1–5) was added followed by PTSA (10% mol). The mixture
was stirred 10 min, then sat. Na2S2O3 (2 mL) was added. The mixture
was diluted with EtOAc (3 mL). After phase separation, the organic
phase was washed with 1 M Na2CO3 solution, dried (MgSO4), filtered
through cotton, and evaporated to give the diiodinated thiophene de-
rivative.
1H NMR (300.1 MHz, CDCl3): δ = 9.77 (s, 1 H, CHO), 7.39 (m, 2 H).
13C NMR (75.7 MHz, CDCl3): δ = 181.2, 149.6, 138.3, 137.2, 88.0.
HRMS (EI): m/z [M]+ calcd for C5H3IOS: 237.8949; found: 237.8945.
2-(5-Iodothiophen-2-yl)acetonitrile (5e)24
Pale yellow oil; yield: 190 mg (94%).
IR (KBr): 2251, 1405, 943, 797, 708 cm–1
.
1H NMR (300.1 MHz, CDCl3): δ = 7.11 (d, J = 3.7 Hz, 1 H), 6.74 (dt,
J = 3.7, 1.0 Hz, 1 H), 3.86 (d, J = 1.0 Hz, 2 H).
13C NMR (75.7 MHz, CDCl3): δ = 137.2, 136.7, 129.0, 116.4, 73.4, 18.6.
HRMS (EI): m/z [M]+ calcd for C6H4NIS: 248.9109; found: 248.9104.
2,5-Diiodothiophene (3)19
Yellow solid; yield: 307 mg (77%); mp 40–42 °C.
IR (KBr): 3076, 1184, 818, 683 cm–1
1H NMR (300.1 MHz, CDCl3): δ = 6.93 (s, 2 H).
.
13C NMR (75.7 MHz, CDCl3): δ = 138.9, 76.4.
HRMS (EI): m/z [M]+ calcd for C4H2I2S: 335.7967; found: 335.7960.
(5-Iodothiophen-2-yl)methanol (5h)25
Pale yellow oil; yield: 206 mg (98%).
IR (KBr): 3500, 1426, 1045, 790 cm–1
1H NMR (300.1 MHz, CDCl3): δ = 7.10 (d, J = 3.6 Hz, 1 H), 6.66 (d,
J = 3.6 Hz, 1 H), 4.76 (s, 2 H), 2.21 (s, 1 H, OH).
13C NMR (75.7 MHz, CDCl3): δ = 150.3, 136.8, 127.1, 73.5, 59.9.
HRMS (EI): m/z [M]+ calcd for C6H5IOS: 239.9106; found: 239.9107.
.
2-Iodo-5-methoxythiophene (5a)20
Pale yellow oil; yield: 162 mg (77%).
IR (KBr): 1667, 1550, 1403, 1151, 631 cm–1
1H NMR (300.1 MHz, CDCl3): δ = 6.90 (d, J = 3.7 Hz, 1 H), 5.92 (d,
J = 3.7 Hz, 1 H), 3.86 (s, 3 H).
.
13C NMR (75.7 MHz, CDCl3): δ = 169.9, 134.5, 105.7, 60.4, 57.4.
HRMS (EI): m/z [M]+ calcd for C5H5IOS: 239.9106; found: 239.9106.
2-Iodo-3-methoxythiophene (7a)26
Colorless oil; yield: 168 mg (80%).
IR (KBr): 1168, 799, 706 cm–1
1H NMR (300.1 MHz, CDCl3): δ = 7.43 (d, J = 6.8 Hz, 1 H), 6.69 (d,
J = 6.8 Hz, 1 H), 3.89 (s, 3 H).
13C NMR (75.7 MHz, CDCl3): δ = 159.8, 130.0, 115.8, 59.2, 53.5.
HRMS (EI): m/z [M]+ calcd for C5H5IOS: 239.9106; found: 239.9105.
.
2-Iodo-5-octylthiophene (5b)21
Colorless oil; yield: 161 mg (98%).
IR (KBr): 2922, 1463, 938, 789 cm–1
1H NMR (300.1 MHz, CDCl3): δ = 7.03 (d, J = 3.6 Hz, 1 H), 6.46 (d,
J = 3.6 Hz, 1 H), 2.79 (t, J = 7.5 Hz, 2 H), 1.60 (m, 2 H), 1.27 (m, 10 H),
0.86 (t, J = 6.5 Hz, 3 H).
13C NMR (75.7 MHz, CDCl3): δ = 152.5, 136.8, 126.1, 69.7, 32.2, 31.9,
30.6, 29.6, 29.5, 29.3, 23.0, 14.5.
HRMS (EI): m/z [M]+ calcd for C12H19IS: 322.0252; found: 322.0241.
.
3-Hexyl-2,5-diiodothiophene (8b)27
Colorless oil; yield: 247 mg (99%).
IR (KBr): 2922, 2853, 1455, 1394, 981, 827 cm–1
.
1H NMR (300.1 MHz, CDCl3): δ = 6.90 (s, 1 H), 2.49 (t, J = 7.9 Hz, 2 H),
1.56 (m, 2 H), 1.33 (m, 6 H), 0.89 (t, J = 6.5 Hz, 3 H).
2-Bromo-5-iodothiophene (5c)22
Colorless oil; yield: 167 mg (94%).
13C NMR (75.7 MHz, CDCl3): δ = 149.6, 137.9, 77.2, 76.0, 32.1, 31.7,
30.0, 28.9, 22.7, 14.3.
IR (KBr): 1684, 1185, 817, 638 cm–1
.
HRMS (EI): m/z [M]+ calcd for C10H14I2S: 419.8906; found: 419.8903.
1H NMR (300.1 MHz, CDCl3): δ = 7.03 (d, J = 3.8 Hz, 1 H), 6.75 (d,
J = 3.8 Hz, 1 H).
13C NMR (75.7 MHz, CDCl3): δ = 137.7, 131.9, 115.3, 72.5.
3-Bromo-2-iodothiophene (7c)28
Colorless oil; yield: 113 mg (64%).
HRMS (EI): m/z [M]+ calcd for C4H2BrIS: 287.8105; found: 287.8098.
IR (KBr): 1488, 1335, 1143, 854, 696 cm–1
.
1H NMR (300.1 MHz, CDCl3): δ = 7.41 (d, 1 H), 6.90 (d, 1 H).
13C NMR (75.7 MHz, CDCl3): δ = 132.3, 130.5, 120.7, 77.0.
HRMS (EI): m/z [M]+ calcd for C4H2BrIS: 287.8105; found: 287.8103.
5-Iodothiophene-2-carbaldehyde (5d)23
Thiophene 4d (1 mmol, 1 equiv) was dissolved in EtOH (2 mL) at
50 °C. Then, NIS (1.1 equiv) was added followed by PTSA (10 mol%).
The mixture was stirred for 10 min, then 1 M HCl solution was added.
After phase separation, sat. Na2S2O3 (2 mL) was added to the organic
phase. The mixture was diluted with EtOAc (3 mL). After phase sepa-
3-Bromo-2,5-diiodothiophene (8c)29
White solid; yield: 255 mg (61%); mp 55–56 °C.
IR (KBr): 1481, 1133, 956, 818 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3901–3906

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Synthesis
1H NMR (300.1 MHz, CDCl3): δ = 7.02 (s, 1 H).
13C NMR (75.7 MHz, CDCl3): δ = 139.1, 121.0, 80.3, 77.4.
HRMS (EI): m/z [M]+ calcd for C4HBrI2S: 413.7072; found: 413.7071.
5,7-Diiodo-2,3-dihydrothieno[3,4-b][1,4]dioxin (11c)30
White solid; yield: 313 mg (87%); mp 181–183 °C.
IR (KBr): 1483, 1358, 1075, 889 cm–1
.
1H NMR (300.1 MHz, DMSO-d6): δ = 4.21 (s, 4 H).
13C NMR (75.6 MHz, DMSO-d6): δ = 143.9, 64.8, 54.1.
HRMS (EI): m/z [M]+ calcd for C6H4I2O2S: 393.8021; found: 393.8021.
3-[(2-Iodothiophen-3-yl)thio]propanenitrile (7d)
Pale yellow oil; yield: 162 mg (93%).
IR (KBr): 2250, 1416, 962, 872, 710 cm–1
.
1H NMR (300.1 MHz, CDCl3): δ = 7.49 (d, J = 4.5 Hz, 1 H), 6.97 (d,
J = 4.5 Hz, 1 H), 3.03 (t, J = 7.3 Hz, 2 H), 2.56 (t, J = 7.3 Hz, 2 H).
13C NMR (75.7 MHz, CDCl3): δ = 135.5, 132.1, 131.2, 117.9, 85.4, 31.4,
3-Bromo-2-iodo-5-methylthiophene (13a)31
Yellow oil; yield: 164 mg (95%).
IR (KBr): 1530, 1168, 959, 818 cm–1
.
18.6.
1H NMR (300.1 MHz, CDCl3): δ = 6.60–6.57 (m, 1 H), 2.45 (d, 3 H).
13C NMR (75.6 MHz, CDCl3): δ = 146.5, 128.5, 119.6, 73.0, 15.8.
HRMS (EI): m/z [M]+ calcd for C5H4BrIS: 301.8262; found: 301.8254.
HRMS (EI): m/z [M]+ calcd for C7H6INS2: 294.8986; found: 294.8983.
3-[(2,5-Diiodothiophen-3-yl)thio]propanenitrile (8d)
Brown powder; yield: 202 mg (81%); mp 92–93 °C.
5-Hexyl-5′-iodo-2,2′-bithiophene (13b)32
IR (KBr): 2245, 1410, 1277, 962, 828 cm–1
.
Yellow oil; yield: 143 mg (95%).
1H NMR (300.1 MHz, CDCl3): δ = 7.11 (s, 1 H), 3.02 (t, J = 7.3 Hz, 2 H),
2.52 (t, J = 7.3 Hz, 2 H).
13C NMR (75.7 MHz, CDCl3): δ = 140.0, 137.5, 117.8, 88.5, 77.8, 31.6,
IR (KBr): 1374, 1128, 1065, 1091 cm–1
.
1H NMR (300.1 MHz, CDCl3): δ = 7.12 (d, J = 3.7 Hz, 1 H), 6.93 (d,
J = 3.6 Hz, 1 H), 6.77 (d, J = 3.7 Hz, 1 H), 6.67 (d, J = 3.6 Hz, 1 H), 2.80 (t,
J = 7.5 Hz, 2 H), 1.70 (m, 2 H), 1.35 (m, 6 H), 0.93 (t, J = 6.8 Hz, 3 H).
13C NMR (75.6 MHz, CDCl3): δ = 146.0, 144.0, 137.6, 133.7, 124.9,
124.4, 123.9, 71.1, 31.7 (2 C), 30.2, 28.9, 22.7.
18.6.
Anal. Calcd for C7H5I2NS2: C, 19.97; H, 1.20; N, 3.33. Found: C, 20.09;
H, 1.10; N, 3.50.
HRMS (EI): m/z [M]+ calcd for C14H17IS2: 375.9816; found: 375.9808.
2-(2,5-Diiodothiophen-3-yl)acetonitrile (8e)
Pale brown powder; yield: 283 mg (93%); mp 63–64 °C.
5′-Iodo-[2,2′-bithiophene]-5-carbaldehyde (13c)33
IR (KBr): 2247, 1399, 966, 813 cm–1
.
White solid; yield 140 mg (79%); mp 179–180 °C.
1H NMR (300.1 MHz, CDCl3): δ = 7.14 (s, 1 H), 3.61 (s, 2 H).
13C NMR (75.7 MHz, CDCl3): δ = 137.4, 136.6, 116.5, 79.7, 77.7, 21.0.
IR (KBr): 1638, 1227, 1050, 786 cm–1
.
1H NMR (300.1 MHz, CDCl3): δ = 9.87 (s, 1 H, CHO), 7.65 (d, J = 3.9 Hz,
1 H), 7.23 (d, J = 3.8 Hz, 1 H), 7.20 (d, J = 3.9 Hz, 1 H), 7.01 (d, J = 3.8
Hz, 1 H).
Anal. Calcd for C6H3I2NS: C, 19.22; H, 0.81; N, 3.74. Found: C, 19.24; H,
0.79; N, 4.01.
13C NMR (75.6 MHz, DMSO-d6): δ = 1834.9, 144.1, 141.5, 140.8, 139.1,
138.4, 128.5, 125.6, 79.2.
2-(2,5-Diiodothiophen-3-yl)methanol (8f)
Brown powder; yield: 266 mg (81%); mp 93–94 °C.
HRMS (EI): m/z [M]+ calcd for C9H5IOS2: 379.8826; found: 319.8823.
IR (KBr): 3187, 1020, 988, 830 cm–1
.
1H NMR (300.1 MHz, CDCl3): δ = 7.13 (s, 1 H), 4.54 (s, 2 H).
13C NMR (75.7 MHz, DMSO-d6): δ = 149.3, 137.9, 79.1, 78.8, 60.0.
HRMS (EI): m/z [M]+ calcd for C5H4I2OS: 365.8072; found: 365.8067.
7-Iodo-2,3-dihydrothieno[3,4-b][1,4]dioxin-5-carbaldehyde
(13d)34
White solid; yield: 170 mg (98%); mp 155–157 °C.
IR (KBr): 1631, 1485, 1434, 1357, 1075, 955 cm–1
.
5-Iodo-4-methoxythiophene-3-carbonitrile (10a)
1H NMR (300.1 MHz, CDCl3): δ = 9.77 (s, 1 H), 4.35 (s, 4 H).
13C NMR (75.6 MHz, CDCl3): δ = 178.8, 147.0, 144.4, 123.4, 65.9, 65.4,
White solid; yield: 191 mg (94%); mp 82–83 °C.
IR (KBr): 3187, 1020, 988, 830 cm–1
.
65.1.
HRMS (EI): m/z [M]+ calcd for C7H5IO3S: 295.9004; found: 295.8995.
1H NMR (300.1 MHz, CDCl3): δ = 7.98 (s, 1 H), 4.02 (s, 3 H).
13C NMR (75.6 MHz, CDCl3): δ = 159.5, 139.5, 112.6, 105.1, 61.9, 61.5.
5,5′-Diiodo-2,2′-bithiophene (15)35
Anal. Calcd for C6H4INOS: C, 27.19; H, 1.52. Found: C, 27.12; H, 1.46.
Pale yellow solid; yield: 237 mg (94%); mp 143–145 °C.
IR (KBr): 1409, 864, 785 cm–1
.
4-Bromo-2-iodo-3-methoxythiophene (10b)
1H NMR (300.1 MHz, CDCl3): δ = 7.14 (d, J = 3.8 Hz, 2 H), 6.78 (d,
J = 3.8 Hz, 2 H).
13C NMR (75.6 MHz, CDCl3): δ = 142.2, 137.8, 125.7, 72.9.
Pale yellow oil; yield: 152 mg (92%).
IR (KBr): 1521, 1334, 990, 732 cm–1
.
1H NMR (300.1 MHz, CDCl3): δ = 7.38 (s, 1 H), 3.88 (s, 3 H).
13C NMR (75.7 MHz, CDCl3): δ = 156.9, 127.3, 105.4, 61.7, 61.6.
HRMS (EI): m/z [M]+ calcd for C5H4BrIOS: 317.8211; found: 317.8207.
HRMS (EI): m/z [M]+ calcd for C8H4I2S2: 417.7844; found: 417.7847.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3901–3906

3906
J. Grolleau et al.
Paper
Synthesis
Acknowledgment
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Rasul, G.; Olah, G. A. J. Am. Chem. Soc. 2004, 126, 15770.
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Heterocycl. Compd. 2012, 48, 1078. (b) Jacobson, K. A.; Shi, D.;
Gallo-Rodriguez, C.; Manning, M. Jr.; Müller, C.; Daly, J. W.;
Neumeyer, J. L.; Kiriasis, L.; Pfleiderer, W. J. Med. Chem. 1993,
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delberg, 2014, 74.
We thank Angers Loire Metropole for the fellowship accorded for the
Ph.D. of C. Moussallem and Region Pays de la Loire for financial sup-
port accorded to the Green-SCO project.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560480.
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Primary Data
Primary data for this article are available online at http://www.thieme-
connect.com/products/ejournals/journal/10.1055/s-00000084 and can
be cited using the following DOI: 10.4125/pd0071th. PmriyDatPmriaryDat104.1
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(22) Notaras, E. G. A.; Lucas, N. T.; Humphrey, M. G.; Willis, A. C.; Rae,
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3901–3906