Solvent-Free and Liquid-Phase Iodination of Thiophene Derivatives with Potassium Dichloroiodate Monohydrate

Article abstract of DOI:10.1055/s-0039-1690795

Iodination of a series of benzene and thiophene derivatives by potassium dichloroiodate monohydrate was studied with and without a solvent. The liquid substrates tend to be more reactive in water while the solid substrates afford better yields in dichloromethane or under the solvent-free conditions. The 2-substituted thiophenes show good to excellent yields whereas the yield for 3-substituted and 3,4- or 2,4-disubstituted thiophenes and benzene derivatives are significantly lower. The mechanochemical reaction of 5-carbaldehyde-2,2′-bithiophene shows excellent yields, while 2,2′-bithiophene gives practical yields only in dichloromethane. In the case of thiophene and N -acetyl- p -toluidine, electrophilic iodination is accompanied by a small extent of chlorination.

Full text of DOI:10.1055/s-0039-1690795

SYNTHESIS
0
0
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9
-
7
8
8
1
1
4
3
7
-
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1
0
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©
Georg Thieme Verlag Stuttgart · New York
2020, 52, 1140–1146
paper
1140
en
Synthesis
G. Sereda et al.
Paper
Solvent-Free and Liquid-Phase Iodination of Thiophene Derivatives
with Potassium Dichloroiodate Monohydrate
Grigoriy Sereda*a
Akash Mamon Sarkar*a
Anwar Hussaina
0
0
0
0-0
0
0
2-1
1
2
1-8
2
1
1
R
R
solvent
R
2 2
+ KICl ·H O
0
0
0
0-0
0
0
2-
0
2
7
7-6
9
1
6
+
H
H
I
H
S
S
I
I
S
Nikolai Zefirov † b
a
Department of Chemistry, University of South Dakota, Vermillion,
SD 57069, USA
O
akash.mamon@gmail.com
grigoriy.sereda@usd.edu
S
H
S
H
solid state
H
S
b
†
Department of Chemistry, Moscow State University, Moscow
O
S
I
KICl2·H2O
119899, Russian Federation
quant.
Deceased
Received: 13.10.2019
Accepted after revision: 29.12.2019
Published online: 23.01.2020
convenient pathway for the selective iodination of organic
compounds. By the inspiration from nature, enzymatic for-
mation of C–I bond, hydrogen peroxide or molecular oxy-
gen co-catalyzed with vanadium, iron or flavin are used for
the oxidative conversion of less active iodide to an active io-
donium species.14 The well-established iodonium ion syn-
DOI: 10.1055/s-0039-1690795; Art ID: ss-2019-m0580-op
Abstract Iodination of a series of benzene and thiophene derivatives
by potassium dichloroiodate monohydrate was studied with and with-
out a solvent. The liquid substrates tend to be more reactive in water
while the solid substrates afford better yields in dichloromethane or un-
der the solvent-free conditions. The 2-substituted thiophenes show
good to excellent yields whereas the yield for 3-substituted and 3,4- or
12c
thons for the iodination are N-iodosuccinimide, N-iodo-
saccharin,15 iodine monochloride, and bis(pyridinium)io-
16
17
donium tetrafluoroborate (IPy BF ). Iodination of aromatic
2
4
2,4-disubstituted thiophenes and benzene derivatives are significantly
compounds with molecular iodine is inconvenient and usu-
ally augmented by oxidative reagents. All of the reagents
are excellent iodinating agents but, each of those has its
own disadvantages. Either these protocols are often high
chemical and/or energy consuming, requiring long reaction
lower. The mechanochemical reaction of 5-carbaldehyde-2,2′-bithio-
phene shows excellent yields, while 2,2′-bithiophene gives practical
yields only in dichloromethane. In the case of thiophene and N-acetyl-p-
toluidine, electrophilic iodination is accompanied by a small extent of
chlorination.
18
time or producing a substantial amount of wastes. High
water and air sensitivity and (or) toxicity restrict the use of
organometallic compounds as precursors for aryl iodides.
From the viewpoint of green chemistry, researchers fa-
Keywords iodination, thiophene derivatives, mechanochemical reac-
tion, benzene derivatives, inverse-gated NMR
Iodinated derivatives of arenes are widely used as versa-
vor the molecular iodine (I ) as an iodinating reagent. There
2
tile intermediates in medicinal chemistry, as X-ray contrast
are two disadvantages, however. First, the low reactivity of I2
due to low electrophilicity towards the majority of organic
compounds and second, the generation of HI as by-product,
1
agents, radioactively labeled markers in radioimmunoassays,
2
3
reagents in biochemistry, agrochemicals, reagents in com-
4
18
binatorial techniques, synthetic organic chemistry, materi-
als chemistry, and polymer chemistry. The relatively weak
which can reduce the C–I bonds in the product. Still, sev-
5
eral practical protocols are available where the generated
HI may be mitigated with alkali or pyridine or scavenged by
various oxidants.19
carbon–iodine bond is very reactive due to the size of the
iodine atom, particularly, in iodine–lithium and iodine–
magnesium exchange reactions. Thus, iodinated derivatives
of arenes are valuable precursors for the cross-coupling of
carbon–carbon and carbon–heteroatom bonds using
Potassium tetrachloroiodate(III) is a good iodinating re-
agent for olefins and it is easy to prepare and store in large
amounts.20 However, the yields of iodochlorination of ole-
fins with potassium tetrachloroiodate are lowered by the
mismatch of the Cl:I molar ratio: required for iodochlorina-
tion with elimination of chloride ion is 2:1; potassium di-
chloroiodate has 2:1, potassium tetrachloroiodate has 4:1.
Disproportionation of the I(III) in water leads to the accu-
6
7
8
9
10
Suzuki–Mayaura, Negishi, Stille, Sonogashira, Heck, or
11
Buchwald, reactions. The application of iodothiophene
derivatives have been well established in the field of con-
ductive polymers, organic solar cells, and electrolumines-
12
cent diodes.
20
Unlike chlorination and bromination reagents, iodina-
tion reagents are less reactive towards most of the aromatic
rings, which calls for more reactive synthetic equivalents of
mulation of I(V) oxidizers. Specifically, the oxidized iodine
–
exists in the form of IO , which oxidizes olefins in an acidic
3
medium. Its I(I) counterpart, potassium dichloroiodate (KICl2)
is also used as an electrophilic iodinating agent in both
+
13
the iodonium (I ) ion. Electrophilic iodination is the most
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, 1140–1146
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

1
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Synthesis
G. Sereda et al.
Paper
addition and substitution reaction.21 For iodochlorination of
olefins, it gives better yields compared to potassium tetra-
Elimination of HI from the products of addition along
with the products of possible electrophilic iodination may
be the source of chlorinated products on the reaction mix-
ture. We were able to detect traces of chlorinated counter-
20
chloroiodate(III). In addition, KICl2 and its tetraalkyl-
ammonium counterparts are capable for solvent-free iodina-
20,22
13
tion.
Potassium dichloroiodate has been used for the iodina-
parts (2S) in the iodinated products by C NMR spectrosco-
py. The iodinated and chlorinated thiophenes are very hard
23
24
21b
1
tion of urea, arenes, and heterocyclic compounds.
to distinguish by H NMR, but the heavy atom effect makes
13
Here we report on potassium dichloroiodate as a new re-
agent for the electrophilic iodination of thiophene deriva-
tives. This reagent, which is less toxic than ICl, is easy to
prepare and convenient to store. For the first time, we used
solid KICl ·H O for the solvent-free mechanoactivated io-
C NMR an appropriate method for accomplishing this. We
integrated the NMR signals of 13C connected to Cl and I un-
der the acquisition conditions eliminating the NOE effect
(inverse-gated broad band decoupling) and the complete
nuclear relaxation (the relative integral values become con-
sistent at the time of delay exceeding 10 s for iodochloro-
thiophene and 7 s for 2-chloro-N-acetyl-p-toluidine).
Solvents exert substantial influence on the course of a
reaction based on their polarity, solvation ability, hydrogen
bond formation, and dissolving power.27 To observe the sol-
vent effect on iodination with KICl ·H O, we explored
2
2
dination of thiophene and benzene derivatives.
Iodination of thiophene (1) produced a mixture of its
monoiodinated and diiodinated derivatives (Scheme 1) in
an approximate ratio of 2:3, which is calculated by GC-MS
peak integration. The volatile 2-iodothiophene (2) (bp 73
°
2
C) was detected in the reaction mixture by GC-MS, and
,5-diiodothiophene (3) was isolated in 30% yield.
2
2
CH Cl , MeOH, MeCN, and H O. While increasing the reac-
2
2
2
tion temperature in CH Cl from 25 °C to 50 °C increases the
2
2
yields of both iodination products at the good selectivity for
-bromo-2-iodothiophene (5) (Table 1, entries 2, 3), the
+
KICl2
+
I
I
I
S
S
S
4
1
2
3
best reaction outcome was achieved in an aqueous solution
at 50 °C (entry 4). Garden and co-workers also observed ex-
cellent efficiency of iodination with aqueous solution of
KICl2.2 The solubility of the substrate in water was low, so
the reaction proceeded under heterogeneous conditions,
and the product mixture is also insoluble in water. Interest-
ingly, iodination was much more efficient in a water sus-
pension (both the starting material and the products have
poor solubility in water) than in other polar solvents
[MeOH ( = 1.7) and MeCN ( = 3.92), Table 1, entries 5,6],
which points at a possible accelerating effect of the liquid-
solid interface on the reaction pathway. Water is not always
the best medium for iodination though. Thus, Grolleau and
co-workers did not observe any iodinated products of thio-
phene with N-iodosuccinimide in water.1 Interestingly,
despite the general trend of polar solvents to favor iodina-
tion, we observed much higher yield in less polar methanol
(35%) than in more polar acetonitrile (6%). This is indicative
of the involvement of H-bonding in the stabilization of the
transition state and is consistent with the best yield in wa-
ter even under the heterogeneous conditions.
Scheme 1 Iodination of thiophene with KICl ·H O
2
2
1b
In order to optimize the iodination conditions (Table 1),
we selected 3-bromothiophene, whose iodination products
are less volatile, and their mixture was easier to isolate and
analyze.
Table 1 Iodination of 3-Bromothiophene with KICl ·H O
2
2
Br
Br
Br
+
KICl2
+
I
I
I
S
S
S
4
5
6
2c
Entry
Solvent Time Temp Product Yield Unreacted start-
(
h)
(°C)
(%)
ing materials (%)a
1b
(
312c
CH
CH
CH
2
2
2
Cl
Cl
Cl
2
2
2
6.0
25
30
–
Thiophene)
212c
625
526
20c
1
2
3
4
1.0
1.0
1.0
25
50
50
48
10
11
11
15
46
9
Interestingly, both mono- and di-iodination of thio-
phene-3-carbaldehyde (7) proceeded both in water and in
alcohols despite the strong electron-withdrawing effect of
the CHO group (Table 2). Again, the aqueous environment
was most efficient allowing uncommon iodination even to
the carbon adjacent to the carbon bearing the aldehyde
group (Table 2, entry 1). The structures of both products of
iodination have been confirmed by single crystal X-ray dif-
fractometry.
625
526
H
2
O
625
526
526
526
65
35
6
5
6
MeOH
1.0
1.0
50
50
47
53
MeCN
a
1
Calculated by H NMR integration.
b
According to 13C NMR, iodination was accompanied by 2% of chlorination
1
The molar ratios of the products were determined by H
(
structure 2S in SI).
The yield was determined by GC-MS.
c
NMR integration of signals at  = 9.56 (s, 1 H), 7.49 (s, 1 H)
for 2,5-diiodothiophene-3-carbaldehyde (9) and at  = 9.76
©
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Synthesis
G. Sereda et al.
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Table 2 Iodination of Thiophene-3-carbaldehyde with KICl ·H O
2
2
CHO
+
CHO
CHO
I
KICl2
+
I
I
S
S
S
7
8
9
Entry
1
Sub:KICl
2
Time (h)
13.0
Temp (°C)
25
Solvent
Product
Yield (%)
Unreacted starting materials (%)a
8
1:2
H
2
O
9
8
9
8
8
38
10
17
15
5
2
1:2
1:2
13.0
13.0
25
25
EtOH
17
64
3
MeOH
a
1
Estimated by H NMR integration.
(
d, 1 H), 7.52 (dd, 1 H), 7.35 (d, 1 H) for 2-iodothiophene-4-
thiophene (EDOT) in the same solvent resulted in a black
solid product not soluble in a range of solvents. This may be
due to oxidative polymerization of EDOT by KICl ·H O. The
carbaldehyde (8). In all reaction runs, diiodination domi-
nates over monoiodination.
2
2
The iodination conditions optimized for 2-substituted
thiophenes were found to be much more efficient than for
their 3-substituted counterparts (Table 3).
FTIR spectrum of the unidentified product of polymeriza-
tion has an adsorption band at around 1067 cm– (Figure
1
28
1S, SI), which is the characteristic for the thiophene ring.
The iodination by KICl ·H O proceeded smoothly for
Contrary to the polymerization in dichloromethane, the re-
action of EDOT with KICl ·H O in water gave the monoio-
dinated product in 63% yield (entry 3).
2
2
disubstituted thiophenes as well (Table 4). While iodination
of 4-bromo-2-methylthiophene in dichloromethane pro-
duced 3-bromo-2-iodo-5-methylthiophene (Table 4, entry
2
2
We found that iodination of thiophenes with KICl ·H O
2
2
1
) in very good yield (76%), iodination of 3,4-ethylenedioxy-
can be substantially improved by mechanoactivation with
grinding under the solvent-free condition, affording in
some instances excellent yields. The solid-state iodination
of 2,2′-bithiophene-5-carbaldehyde (14) quantitatively pro-
duces 5′-iodo-2,2′-bithiophene-5-carbaldehyde (15) in
quantitative yield (Table 5, entry 1). Hajipour and co-work-
ers also observed quantitative yield for the iodination of
anisole in solvent-free medium with tetramethylammoni-
um dichloroiodate.30 The obtained product is pure by H
NMR analysis without chromatography and recrystalliza-
tion. When dichloromethane is used as a solvent, the
Table 3 Iodination of 2-Substituted Thiophenes with KICl ·H O
2
2
+
KICl2
R
R
I
S
S
10
11
Entry
R
Sub:KICl
2
Time (h) Temp (°C) Product
Yield (%)
1
1
2
3
CHO
1:2
1:2
1:2
13.0
1.0
25
50
50
11a12c
11b12c
11c12c
70
82
90
Br
n-C
8
H
17
1.0
Table 4 Iodination of Disubstituted Thiophenes with KICl ·H O
2
2
R2
R3
R2
R3
+
KICl2
R1
R1
I
S
S
12
13
1
2
3
Entry
1
R , R , R
Sub:KICl
2
Time (h)
1.0
Temp (°C)
Solvent
Product
Yield (%)
76a
Unreacted starting
materials (%)
a
1
13a12c
R = Me
R = H
R = Br
1:2
50
CH
CH
2
Cl
2
2
5
2
3
1
2
R = H
R –R = OCH
1:2
1:2
1.0
1.0
50
25
2
Cl
un-identified
–
0
2
3
2
CH
CH
2
O
O
1
13b29
3
R = H
R –R = OCH
H
2
O
63
22
2
3
2
2
a
1
Yields calculated by H NMR integration of the reaction mixture.
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Synthesis
G. Sereda et al.
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Table 5 Mechanoactivated Iodination of Thiophene Derivatives with KICl ·H O
2
2
S
S
+
KICl2
I
S
O
S
O
15
14
quant.
Entry
1
Substrate
Sub:KICl
1:2
2
Time (min)
15
Solvent
Product
Yield (%)
quant.b
Unreacted starting
materials (%)a
S
S
S
grinding, no solvent
–
O
O
O
S
O
O
O
I
S
S
S
S
S
1
512c
512c
512c
2
3
1:2
1:2
15
15
CH
2
Cl
2
89b
30
–
S
S
I
1
H
2
O
51
I
S
S
1
4
5
1:2
1:2
60
60
grinding, no solvent
unidentified
–
–
–
S
CH
2
Cl
2
I
80b
S
S
S
S
I
1
612c
a
1
Identified by H NMR integration of characteristic signals.
b
13
According to C NMR analysis, iodination was not accompanied by any chlorination.
reaction proceeds in 89% yield (Table 5, entry 2) and in wa-
ter the yield was only 30% with a significant amount of un-
reacted starting material (entry 3).
er crystals of this amide compared with more brittle crys-
tals of the parent amine. Monoiodination of p-hydroxy-
benzaldehyde by KICl ·H O was efficient both in
2
2
In contrast, KICl ·H O oxidizes 2,2′-bithiophene under
the solid-state conditions into a polymer (Table 5, entry 4)
and iodinates it in dichloromethane as a solvent (80%, entry
dichloromethane (43% of the monoiodo derivative, entry 5),
and especially in water (65% yield of the diiodo derivative in
10 min, entry 6).
2
2
5
). The excessive reactivity of the brittle crystals (entry 4)
In conclusion, potassium dichloroiodate monohydrate is
an efficient reagent for the iodination of thiophenes. The
reaction is sensitive to the conditions and often provides
very good yields and selectivity of monoiodination, espe-
cially in water and for 2-substituted thiophenes. It is sensi-
tive to the conditions but is not substantially affected by the
nature of the substituent in the thiophene ring. The solid-
state solvent-free technique of mechanoactivation signifi-
cantly affects iodination by potassium dichloroiodate
monohydrate, often rendering the reaction quantitative.
The more brittle crystals of the organic substrate tend to be
more reactive than soft crystals under the mechanoactivat-
ed conditions.
leads to the high extent of polymerization, which was not
observed for the soft crystals (entry 1). This is consistent
with the higher reactivity of the brittle crystals in the
mechanoactivated iodochlorination reported by Sereda and
co-workers.
We have further explored the potential of KICl ·H O for
31
2
2
the iodination of benzene derivatives (Table 6).
The iodination of p-toluidine at the ortho-position to
the amino group gives mono- and diiodinated products in
13% and 40% yield, respectively (Table 6, entry 1) in di-
chloromethane at room temperature. Another group ob-
served similar yields of diiodoaniline in aqueous HCl with
KICl2.
24b
Conducting this reaction under the solvent-free
conditions slightly decreased the yields (entry 2). Acetyla-
tion of the amino group of p-toluidine expectedly decreases
reactivity towards iodination in dichloromethane (entry 3),
and almost completely suppresses it under the solid-state
grinding conditions (entry 4). The low reactivity of N-ace-
tyl-p-toluidine upon grinding can be partly due to the soft-
All reagents were purchased from Sigma-Aldrich and Alfa Aesar
chemicals and used without further purification. Characterization of
products was performed by NMR in CDCl3 or DMSO-d , GS-MS, and
6
single crystal X-ray crystallography. Chemical shifts are recorded on
TM
1
Bruker, Ascend 400 MHz spectrometer for H NMR relative to the
solvent residual value:  = 7.28 (CDCl ) and 2.50 (DMSO-d ) and for
3
6
©
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Synthesis
G. Sereda et al.
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Table 6 Iodination of Benzene Derivatives with KICl ·H O
2
2
I
R1
R1
I
R1
I
+
KICl2
+
R2
R2
R2
17
18
19
Entry
1
R1, R2
Sub:KICl
1:1
2
Time (h)
1.0
Temp (°C)
25
Solvent
Product
Yield (%)
Unreacted starting
materials (%)a
1
19a32
R = NH
2
2
CH
2
Cl
2
40
13
36
9
32
2
R = Me
1
8a33
19a32
8a33
2a
3
R = NH
1
1:1
1.0
25
grinding, no solvent
29
2
R = Me
1
1
18b34
18b34
18c35
19b35
31b
R = NHCOMe
1:2
1:2
1:1
1:2
1.0
1.0
25
25
50
50
CH
grinding, no solvent
CH Cl
2
Cl
2
44
75
3
2
R = Me
1
4
5
6
a
R = NHCOMe
5
2
R = Me
1
43c
65
R = OH
2.0
2
2
2
R = CHO
1
R = OH
10 min
H
2
O
7
2
R = CHO
a
b
c
1
Calculated by H NMR integration.
According to 13C NMR analysis, iodination was accompanied by 6% of chlorination (structure 3S in SI).
Purified by recrystallization from EtOH.
13
C NMR  = 77.03 (CDCl ) and 39.98 (DMSO-d ) at 298 K. GC-MS
Iodination of Thiophenes and Benzene Derivatives with KICl ·H O;
2 2
3
6
spectra were recorded on Shimadzu, GCMS-QP2010, Japan. The ana-
lytical grade solvents were used for all analysis.
General Procedure
The conditions for the iodination of thiophene derivatives were opti-
mized by repeating the reaction for different times, substrates and re-
agent ratios, and temperatures (Table 1). The progress of the reaction
was monitored by TLC. The substrate (1 mmol) was dissolved or sus-
X-ray quality crystals were grown from CH Cl [2-iodo-4-thiophene-
2
2
carboxyaldehyde, 5-iodo-2,2′-bithiophene-5-carbaldehyde, 4-hy-
droxy-3,5-diiodobenzaldehyde, and 5′-iodo-[2,2′-bithiophene]-5-car-
boxyaldehyde] and from 5% (v/v) EtOH in CH Cl [5-iodothiophene-2-
pended in the solvent (5 mL). Next, KICl ·H O (510 mg, 2 mmol) was
2
2
2 2
carboxyaldehyde, 2,5-diiodothiophene-3-carboxyaldehyde and N-(2-
iodo-4-methylphenyl)acetamide]. Single crystals were mounted on a
glass fiber. The X-ray crystallographic data were collected on Bruker
CCD APEXII diffractometer at 100 K using MoK radiation. The cell
constants were determined after integration from approximately
added to the mixture. The mixture was stirred for the time and at the
temperature specified in Tables 1–5. The r.t. reactions were carried
out in a glass vial, and the elevated temperature reactions were car-
ried out in a pressure tube sealed with a screw cap, in an oil bath. The
progress of the reaction was monitored by TLC. An aliquot of aq
8
000 reflections. The structures were solved by SIR92 and refines
Na
was then washed with H
action mixtures carried out in H
5 mL) and then washed with H O (3 × 5 mL). The combined organic
2
S
2
O
3
(5 mL, 5% v/v) was added to quench the reaction. The mixture
O (3 × 5 mL) in a separatory funnel. The re-
O first were extracted with CH Cl (3
were done on SHELXL-97 using direct method. The WinGX crystallo-
graphic software was used for data reduction and refinement.
2
2
2
2
×
2
layers were dried (MgSO ) and filtered through Whatman filter paper
Potassium Dichloroiodate Monohydrate (KICl ·H O)
4
2
2
(diameter 9 cm, pore size 11 m). The iodinated product was ob-
21a
KICl ·H O was synthesized by modification of a known procedure.
2
2
tained by evaporation of the filtrate. The purified product was ob-
tained by column chromatography or recrystallization. For p-hy-
KI (20 g) was dissolved in an aliquot of H O (20 mL). Subsequently, a
2
constant flow of Cl gas was passed through the stirred solution of KI.
2
droxybenzaldehyde, 0.5 mmol of the substrate was dissolved in H O
2
The precipitated black I had started to dissolve again by making the
2
(
5 mL), and then KICl ·H O (510 mg, 2 mmol) was added to the mix-
2 2
solution brown. The Cl gas was continuously passed and at a certain
2
ture. Next, the mixture was allowed to stir for 10 min at 50 °C. The
precipitate was filtered through Whatman filter paper (diameter 9
cm, pore size 11 m) and purified by recrystallization from CH Cl .
point few particles being undissolved, the Cl2 gas flow was stopped,
and the solution was stirred for 10 min. If all the precipitate had dis-
solved, then a few KI crystals were added, and the mixture was stirred
for 10 more min. The process was repeated if necessary. Finally, a sta-
ble solution with few crystals of I2 was obtained. The reaction flask
was then closed with a stopper and kept overnight in a refrigerator.
The needle shaped orange crystals were collected by filtration.
2
2
The solid-state reactions were performed by mixing of the substrate
and reagent in a mortar and grinding with a pestle for the time speci-
fied in Tables 5 and 6, to obtain a homogeneous mixture. The aqueous
solution of Na S O (5 mL, 5% v/v) was used to quench the reaction.
2
2
3
The product was collected by filtration through Whatman filter paper
diameter 9 cm, pore size 11 m).
(
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, 1140–1146

1
145
Synthesis
G. Sereda et al.
Paper
,5-Diiodothiophene (3)12c (Table 1, entry 1)
For X-ray analysis, single crystal was grown from CH Cl .
2 2
36
2
1
Yield: 100 mg (30%); yellow oil.
H NMR (CDCl ):  = 9.89 (s, 1 H), 7.68 (d, J = 4.4 Hz, 1 H), 7.25 (d, J =
3
1
4.4 Hz, 1 H), 7.22 (d, J = 4.4 Hz, 1 H), 7.04 (d, J = 4.4 Hz, 1 H).
H NMR (CDCl ):  = 6.96 (s, 1 H).
3
13
13
C NMR (DMSO-d ):  = 184.5, 144.6, 142.0, 141.2, 139.6, 138.9,
C NMR (CDCl ):  = 138.8, 76.1.
6
3
129.1, 126.1, 79.7.
4
-Bromo-2-iodothiophene (5)26 (Table 1, entry 4)
5
,5′-Diiodo-2,2′-bithiophene (16)12c (Table 5, entry 5)
Yield: 188 mg (65%); yellow oil.
Yield: 334 mg (80%); yellow solid; mp 165–168 °C (Lit.12c mp 165 °C).
1
H NMR (CDCl ):  = 7.44 (d, J = 5.4 Hz, 1 H), 6.92 (d, J = 5.4 Hz, 1 H).
3
1
H NMR (CDCl ):  = 7.17 (d, J = 3.3 Hz, 1 H), 6.81 (d, J = 3.3 Hz, 1 H).
3
-Bromo-2,5-diiodothiophene (6)25 (Table 1, entry 4)
13C NMR (CDCl
):  = 142.1, 137.7, 125.6, 72.6.
3
3
Yield: 37 mg (9%); yellow oil.
2-Iodo-4-methylaniline (18a)33 (Table 6, entry 1)
Yield: 30 mg (13%); reddish brown solid; mp 38–41 °C (Lit.33 mp 39–
1
H NMR (CDCl ):  = 6.78 (s, 1 H).
3
4
1
0 °C).
2-Iodothiophene-4-carbaldehyde (8) (Table 2, entry 1)
H NMR (CDCl ):  = 7.49 (s, 1 H), 6.97 (d, J = 9.0 Hz, 1 H), 6.68 (d, J =
Yield: 23 mg (10%); colorless solid; mp >260 °C.
3
9.0 Hz, 1 H), 2.23 (s, 3 H).
36
For X-ray analysis, single crystal was grown from CH Cl .
2
2
1
H NMR (CDCl ):  = 9.76 (s, 1 H), 7.52 (d, J = 5.3 Hz, 1 H), 7.35 (d, J =
.3 Hz, 1 H).
N-(2-Iodo-4-methylphenyl)acetamide (18b)34 (Table 6, entry 3)
3
5
37
Yield: 85 mg (31%); colorless solid; mp 132–135 °C (CH Cl ) (Lit. mp
2
2
133 °C).
2,5-Diiodothiophene-3-carbaldehyde (9) (Table 2, entry 1)
For X-ray analysis, single crystal was grown from 5% (v/v) EtOH in
Yield: 138 mg (38%); colorless solid; mp 99–100 °C.
36
CH Cl .
2
2
For X-ray analysis, single crystal was grown from 5% (v/v) EtOH in
1
H NMR (CDCl ):  = 8.03 (d, J = 5.6 Hz, 1 H), 7.62 (s, 1 H), 7.35 (s, 1 H),
.16 (d, J = 5.6 Hz, 1 H), 2.29 (s, 3 H), 2.24 (s, 3 H).
3
36
CH Cl .
2
2
7
1
H NMR (CDCl ):  = 9.56 (s, 1 H), 7.49 (s, 1 H).
3
1
3
4-Hydroxy-3-iodobenzaldehyde (18c)35 (Table 6, entry 5)
Yield: 106 mg (43%); white solid; mp 105–109 °C (CH Cl ) (Lit. mp
C NMR (CDCl ):  = 185.2, 143,6, 136.6, 91.3, 79.1.
3
35
2
2
5
-Iodothiophene-2-carbaldehyde (11a)12c (Table 3, entry 1)
109–114 °C).
Yield: 166 mg (70%); yellow solid; mp 47–50 °C (Lit.12c mp 48–50 °C).
1
H NMR (CDCl ):  = 9.83 (s, 1 H), 8.24 (d, J = 1.8 Hz, 1 H), 7.82 (dd, J =
3
1
13
0.5 Hz, 1.8 Hz, 1 H), 7.14 (d, J = 10.5 Hz, 1 H), 5.94 (s, 1 H).
For X-ray analysis, single crystal was grown from 5% (v/v) EtOH in
36
CH Cl .
C NMR (CDCl ):  = 189.7, 160.3, 140.9, 132.3, 131.4, 115.5, 86.0.
2
2
3
1
H NMR (CDCl ):  = 9.8 (s, 1 H), 7.42 (s, 2 H).
3
2,6-Diiodo-4-methylaniline (19a)32 (Table 6, entry 1)
Yield: 143 mg (40%); reddish brown solid; mp 112–114 °C (Lit.32 mp
13
C NMR (CDCl ):  = 181.2, 149.6, 138.3, 137.1, 87.9.
3
118 °C).
2
-Bromo-5-iodothiophene (11b)12c (Table 3, entry 2)
Yield: 237 mg (82%); reddish brown oil.
36
For X-ray analysis, single crystal was grown from CH Cl .
2
2
1
1
H NMR (CDCl ):  = 7.48 (s, 1 H), 2.19 (s, 3 H).
H NMR (CDCl ):  = 6.78 (d, J = 4.0 Hz, 1 H), 7.06 (d, J = 4.0 Hz, 1 H).
3
3
13
13
C NMR (CDCl ):  = 143.8, 139.8, 131.0, 81.5, 19.3.
3
C NMR (CDCl ):  = 137.5, 131.7, 115.3, 72.4.
3
4-Hydroxy-3,5-diiodobenzaldehyde (19b)35
(Table 6, entry 6)
-Iodo-5-octylthiophene (11c)12c (Table 3, entry 4)
2
35
Yield: 243 mg (65%); white solid; mp 203–206 °C (CH Cl ) (Lit. mp
Yield: 290 mg (90%); brown oil.
2
2
197 °C).
1
H NMR (CDCl ):  = 7.06 (d, J = 4.7 Hz, 1 H), 6.49 (d, J = 4.7 Hz, 1 H),
3
36
For X-ray analysis, single crystal was grown from CH Cl .
2
1
.80 (t, J = 7.3 Hz, 2 H), 1.65 (m, 2 H), 1.32 (m, 10 H), 0.91 (t, 3 H).
2
2
1
3
H NMR (CDCl ):  = 9.77 (s, 1 H), 8.23 (s, 2 H), 6.29 (s, 1 H).
3
C NMR (CDCl ):  = 152.2, 136.6, 125.8, 69.3, 31.9, 31.5, 30.2, 29.3,
3
29.2, 29.0, 22.7, 14.1.
-Iodo-3,4-ethylenedioxythiophene (13b)29 (Table 4, entry 3)
Funding Information
2
Yield: 168 mg (63%); yellow solid; mp >260 °C.
Funding from the University of South Dakota Department of Chemis-
1
H NMR (DMSO-d ):  = 6.85 (s, 1 H), 4.24 (s, 4 H).
try is appreciated.
U
n
i
v
ersity of
S
o
uth
D
a
k
ota ()
6
13
C NMR (DMSO-d ):  = 144.4, 141.5, 105.4, 65.4, 64.8, 54.6.
6
Acknowledgment
5
′-Iodo-[2,2′-bithiophene]-5-carbaldehyde (15)12c (Table 5, entry 1)
Yield: 319 mg (quant.); yellow solid; mp 179–181 °C (Lit.12c mp 179–
Authors are grateful to Dr. Sykes for helping to collect the single crys-
tal X-ray data and for solving the structures in some instances.
180 °C).
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, 1140–1146

1
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Synthesis
G. Sereda et al.
Paper
Supporting Information
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S
u
p
p
orit
n
g Inform ati
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u
p
p
orti
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©
2020. Thieme. All rights reserved. Synthesis 2020, 52, 1140–1146