Ultrasound-promoted rapid and efficient iodination of aromatic and heteroaromatic compounds in the presence of iodine and hydrogen peroxide in water

Article abstract of DOI:10.1080/00397911.2013.879900

A rapid and efficient ultrasound-promoted protocol for iodination of aromatic and heteroaromatic compounds, using molecular iodine in the presence of aqueous hydrogen peroxide in water without any cosolvent, has produced versatile iodinated organic molecules with potential application in organic synthesis and medicine in short reaction times and good to excellent yields. Copyright

Full text of DOI:10.1080/00397911.2013.879900

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Ultrasound-Promoted Rapid and Efficient Iodination
of Aromatic and Heteroaromatic Compounds in the
Presence of Iodine and Hydrogen Peroxide in Water
Irlon M. Ferreira a , Gleison A. Casagrande a , Lucas Pizzuti a & Cristiano Raminelli b
a Universidade Federal da Grande Dourados, Faculdade de Ciências Exatas e Tecnologia,
Rodovia Dourados-Itahum , Dourados , MS , Brazil
b Universidade Federal de São Paulo, Departamento de Ciências Exatas e da Terra ,
Diadema , SP , Brazil
Accepted author version posted online: 16 Apr 2014.Published online: 16 Apr 2014.
To cite this article: Irlon M. Ferreira , Gleison A. Casagrande , Lucas Pizzuti & Cristiano Raminelli (2014): Ultrasound-
Promoted Rapid and Efficient Iodination of Aromatic and Heteroaromatic Compounds in the Presence of Iodine and Hydrogen
Peroxide in Water, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, DOI: 10.1080/00397911.2013.879900
To link to this article: http://dx.doi.org/10.1080/00397911.2013.879900
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ULTRASOUND-PROMOTED RAPID AND EFFICIENT IODINATION OF
AROMATIC AND HETEROAROMATIC COMPOUNDS IN THE PRESENCE
OF IODINE AND HYDROGEN PEROXIDE IN WATER
Irlon M. Ferreira1, Gleison A. Casagrande1, Lucas Pizzuti1,, Cristiano Raminelli2,
1Universidade Federal da Grande Dourados, Faculdade de Ciências Exatas e Tecnologia,
Rodovia Dourados-Itahum, Dourados, MS, Brazil 2Universidade Federal de São Paulo,
Departamento de Ciências Exatas e da Terra, Diadema, SP, Brazil
Address correspondence to Lucas Pizzuti, Universidade Federal da Grande Dourados,
Faculdade de Ciências Exatas e Tecnologia, Rodovia Dourados-Itahum, Km 12,
Dourados, MS 79804-970, Brazil E-mail: lucas.pizzuti@gmail.com Cristiano Raminelli,
Universidade Federal de São Paulo, Departamento de Ciências Exatas e da Terra, Rua
Prof. Artur Riedel, 275, Diadema, SP 09972-270, Brazil.; raminelli@unifesp.br.
Abstract
A rapid and efficient ultrasound-promoted protocol for iodination of aromatic and
heteroaromatic compounds, using molecular iodine in the presence of aqueous hydrogen
peroxide in water without any co-solvent, has produced versatile iodinated organic
molecules with potential application in organic synthesis and medicine in short reaction
times and good to excellent yields.
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KEYWORDS: Iodination reaction; ultrasound; reaction in water; mild reaction
conditions; iodinated organic compounds
INTRODUCTION
Iodinated organic substrates can be considered versatile building blocks in organic
synthesis with application as electrophilic partners in several cross-coupling processes.[1]
In addition, iodinated organic compounds have found use in iodine-lithium1 and iodine-
magnesium[2] exchange reactions. The mentioned transformations can be considered
import tools in the construction of carbon-carbon and carbon-heteroatom bonds,[1–3]
which are employed in total syntheses of complex molecules[4] and in the production of
polymers of importance in materials science.[5] Furthermore, a considerable number of
iodinated organic compounds are biologically active substances[6] or have found
applications in targeted molecular radiotherapy[7] and as contrast media for diagnostic
imaging.[8] Consequently, several approaches for iodofunctionalization of organic
substances have been developed.[9–12] Among them we can mention protocols for
diazotization-iodination[9] and electrophilic iodination using a source of iodine in
combination with an oxidizer[10] as important alternatives.
In general, methods involving iodine or iodide and an oxidizer in aqueous media have
gained particular attention.[10–12] Accordingly, oxidative iodinations of organic
compounds employing molecular iodine and hydrogen peroxide in aqueous media have
emerged as practical protocols.[11] In this context, our research group has recently
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published a communication employing the I2/H2O2 (30%) system in the absence of an
acidic catalyst using water without any co-solvent for the preparation of iodinated
aromatic and heteroaromatic compounds.[12] Although this transformation and many other
oxidative iodofunctionalizations can be considered important methodologies for
introducing an iodine atom into an organic molecule, in most cases, they have the
drawback of being time-consuming processes.[10–12]
In this sense, the use of ultrasound in organic synthesis has proven to be an important
strategy for reducing reaction times and for improving yields.[13] These features of
sonochemistry have been explored in the development of environmentally benign
synthetic methods.[14] There is a wide literature illustrating the mildness and non-
hazardous character of ultrasound and its effectiveness for acceleration of organic
reactions,[15] including our contribution to this area.[16]
To the best of our knowledge there is no method for the iodination of aromatic and
heteroaromatic compounds employing molecular iodine and hydrogen peroxide in water
promoted by ultrasonic irradiation reported in the literature. Having in mind the
requirement for iodinated aromatic and heteroaromatic compounds for synthetic
purposes, along with the virtual applicability of iodinated compounds in medicine, we
focused on development of a methodology which uses molecular iodine as the iodine
source of choice, aqueous hydrogen peroxide as a safe and environmentally accepted
oxidizer and water as a non-flammable and innocuous solvent, employing ultrasonic
irradiation as energy source, in order to produce iodinated aromatic and heteroaromatic
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compounds with potential application in organic synthesis and medicine in high yields
and short reaction times.
RESULTS AND DISCUSSION
Despite the versatility of the protocol previously reported by us for the iodination of
aromatic and heteroaromatic compounds using iodine and hydrogen peroxide in water,[12]
the method published can be considered rather time-consuming. In order to circumvent
such drawback, we decided to apply the ultrasonic irradiation as energy source to reach a
faster methodology for the preparation of iodinated aromatic and heteroaromatic
compounds. As can be seen in Table 1, entry 1, iodinated compound 2a was not obtained
when the reaction of phenol (1a) with 2 equiv of iodine was carried out under ultrasonic
irradiation in the absence of hydrogen peroxide (30%) for 360 min. This experiment was
performed based on evidences involving the production of hydrogen peroxide by water
sonication.[17] When we sonicated phenol (1a) with 2 equiv of iodine and 2 equiv of
hydrogen peroxide for 60 min, 2,4,6-triiodophenol (2a) was obtained in a 43% yield
(Table 1, entry 2). In an attempt to improve the yield, we conducted the same
transformation using 2 equiv of iodine and 4 equiv of hydrogen peroxide (30%). In this
case, the triiodinated phenol 2a was isolated in a satisfactory yield of 74%. When we
allowed substituted phenols 1b-i to react with 1.5 equiv of iodine and 3 equiv of
hydrogen peroxide (30%), the obtained results show that the success of our reaction
depends on the electronic effects promoted by the substituent attached to the aromatic
ring (entries 4-11). The reaction proceeded smoothly for phenols bearing electron
withdrawing substituents such as 4-hydroxyacetophenone (1b) (entry 4), 4-nitrophenol
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(1c) (entry 5) and 4-chlorophenol (1d) (entry 6) providing iodinated phenols in excellent
yields after sonication for 30-60 min. On the other hand, the treatment of 4-
methoxyphenol (1e) with iodine and hydrogen peroxide for 360 min under sonication did
not lead to the formation of the desired product 2e (entry 7). In this reaction the starting
material was completely consumed and a mixture of hydroquinone and unidentified
substances was produced. Besides, the reaction of p-cresol (1f) under sonication for 60
min furnished 2,6-diido-4-methylphenol (2f) in a poor 40% yield (entry 8) along with
unidentified materials. By using 2-bromophenol (1g), which is blocked at the 2-position
with an electron withdrawing substituent, we obtained 2-bromo-4,6-diiodophenol (2g) in
a 96% yield after ultrasonic irradiation for 60 min (entry 9). Accordingly, sonication of
2,6-dichlorophenol (1h) and iodine in the presence of hydrogen peroxide for 45 min,
gave 2,6-dichloro-4-iodophenol (2h) in a 97% yield (entry 10). In the same direction,
allowing 4-hydroxy-3-methoxybenzaldehyde (1i) to react with 1.5 equiv of iodine and 3
equiv of hydrogen peroxide under ultrasonic irradiation for only 30 min, we obtained 4-
hydroxy-3-iodo-5-methoxybenzaldehyde (2i) in a quantitative yield (entry 11). In order
to examine the scope and limitations of our methodology beyond phenol derivatives, we
carried out the reaction of aniline (1j) with 2 equiv of iodine and 4 equiv of hydrogen
peroxide (30%) using water as solvent under ultrasonic irradiation. After 60 min, we
obtained 2,4,6-triiodoaniline (2j) in a 91% yield (entry 12). As can be seen in Table 1,
entry 13, 2-bromo-1,3,5-triiodobenzene (2k) was not obtained even after 360 min of
sonication and the starting material 1k was recovered. This experiment shows that the
success of our reaction depends dramatically on the electronic effects promoted by the
substituent attached to the aromatic ring. When we subjected N-Boc-aniline (1l) to the
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sonication with 2 equiv of iodine and 4 equiv of hydrogen peroxide (30%) in water for 75
min, 4-iodo-N-Boc-aniline (2l) was isolated in a 91% yield (entry 14). This experiment
shows that our reaction is rather sensible to the steric effect exerted by the substituent
bonded to the aromatic ring. In agreement with this finding, when we allowed anisole
(1m) to react with 2 equiv of iodine and 4 equiv of hydrogen peroxide (30%) (entry 15),
we did not observe the formation of ortho-iodinated anisoles. Under the mentioned
conditions, we obtained the monoiodinated anisole 2m in a quantitative yield after
sonication of 90 min. Afterwards, we allowed the reaction of the electron-rich 1,3-
dimethoxybenzene (1n) with 1 equiv of iodine and 2 equiv of hydrogen peroxide (30%)
for 45 min and obtained 1,5-diiodo-2,4-dimethoxybenzene (2n) in a quantitative yield
(entry 16). Ultimately, for producing iodinated heteroaromatic compounds, we carried
out the transformation employing imidazole (1o), 2 equiv of iodine and 4 equiv of
hydrogen peroxide (30%). In this reaction, triiodoimidazole (2o) was produced in an
excellent yield of 95% in only 30 minutes of sonication (entry 17). On the other hand,
when 1-tosylimidazole (1p) was treated with 2 equiv of iodine and 4 equiv of hydrogen
peroxide (30%) in water, 2-iodo-1-tosylimidazole was produced in a 70% yield (2p) after
sonication for 90 min (entry 18). By performing the reaction between thiophene (1q) and
2 equiv of iodine and 4 equiv of hydrogen peroxide (30%) in water under sonication for
75 min, 2,5-diiodothiophene (2q) was produced in an 85% yield (entry 19).
The structures of compounds 2a-q have been assigned on the basis of a variety of
spectroscopic techniques, namely, accordingly to their IR, MS, 1H and 13C NMR spectra.
All substances produced (2a-q) were previously synthesized by other synthetic
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methodologies and provided melting point values and spectral data which are in
agreement with those already published.
CONCLUSIONS
In summary, a rapid and efficient ultrasound-promoted reaction for the preparation of
iodinated aromatic and heteroaromatic compounds has been developed and versatile
organic molecules with potential application in organic synthesis and medicine were
produced in very good yields, under mild and safe reaction conditions, which include
molecular iodine, hydrogen peroxide (30%) and water as solvent.
EXPERIMENTAL
General Methods
Reactions were carried out with a Microtip Probe connected to a Sonics Vibra-cell
Ultrasonic Processor (500 W) operating at 20 KHz (100 W). 1H and 13C NMR spectra
were recorded on a Varian INOVA 300 (300 MHz for 1H and 75 MHz for 13C) and on a
Bruker DRX 500 (500 MHz for 1H and 125 MHz for 13C) spectrometers in CDCl3,
DMSO-d6 or CD3OD solutions using TMS as internal standard. Mass spectra were
produced at 70 eV using a Shimadzu MS-QP5050A mass spectrometer connected to a
Shimadzu GC-17A gas chromatograph or a Varian MS-210 mass spectrometer connected
to a Varian GC-431 gas chromatograph. Infrared spectra were recorded on a Bomem
MB-100 FT-IR spectrometer using KBr pellets in the 4000-400 cm−1 region. Uncorrected
melting point values were recorded on an Instrutherm DF-3600 apparatus.
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General Procedure For Ultrasound-Promoted Iodination Of Aromatic And
Heteroaromatic Compounds
To a suspension of the appropriate aromatic or heteroaromatic compound (1a-q) (2
mmol) and molecular iodine (2-4 mmol) in distilled water (10 mL) was added hydrogen
peroxide 30% (m/v) (4-8 mmol). The mixture was sonicated and the progress of reaction
was monitored by TLC. Afterwards, a saturated sodium thiosulfate aqueous solution (10
mL) was added to the mixture, which was extracted with ethyl acetate (3 × 20 mL). The
organic phase was dried over MgSO4. After filtration, the solvent was evaporated under
reduced pressure. The residue was purified by column chromatography on silica gel using
an appropriate eluent, affording the desired product (2a-q).
Full experimental details and characterization data of products are available in the
Supplementary Content.
Characterization Data For 2,4,6-Triiodophenol (2a) (CAS Number: 609-23-4)
Yield: 0.6980 g (74%); yellowish solid; mp 153-154°C (hexane as eluent) (lit.[18] 152-
153°C); IR (KBr, cm-1): 3439, 3053, 1434, 1369, 1136, 533; 1H NMR 500 MHz (CDCl3,
ppm): 7.93 (s, 2H), 5.77 (s, 1H); 13C NMR 125 MHz (CDCl3, ppm): 153.7, 146.4, 83.3,
83.2; EI-MS (m/z, %): 472 (100.0), 218 (8.3), 127 (7.3).
ACKNOWLEDGMENTS
We gratefully acknowledge the Conselho Nacional de Desenvolvimento Científico e
Tecnológico (CNPq), the Fundação de Amparo à Pesquisa do Estado de São Paulo
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(FAPESP) and the Fundação de Apoio ao Desenvolvimento do Ensino, Ciência e
Tecnologia do Estado de Mato Grosso do Sul (FUNDECT) for financial support.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website. Please
make the words “publisher’s website” a live DOI link.
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Table 1. Synthesis of iodinated aromatic and heteroaromatic compounds (2) by the
reaction of aromatic and heteroaromatic compounds (1) with iodine and hydrogen
peroxide in water under ultrasonic irradiation.a
Entry
1
Aromatic
Iodinated
I2 / H2O2
Time
(min)
Isolated
compound (1)
compound (2)
equivalents
yield (%)
I
OH
I
OH
OH
2 / 0
2 / 2
360
60
60
45
45
45
0
1a
2a
2a
I
I
OH
I
2
3
4
5
6
43
74
97
88
90
1a
I
I
2 / 4
OH
I
OH
1a
2a
I
I
I
O
O
1.5 / 3
1.5 / 3
1.5 / 3
OH
OH
OH
H3C
H3C
2b
1b
I
O N
O2N
OH
2
2c
1c
I
I
Cl
OH
Cl
OH
2d
1d
I
I
I
H3CO
OH
2e
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7
1.5 / 3
1.5 / 3
1.5 / 3
1.5 / 3
1.5 / 3
2 / 4
360
60
0
40
H3CO
OH
1e
I
8
H3C
OH
H3C
OH
OH
1f
2f
I
Br
Br
I
9
OH
OH
60
96
2g
1g
I
Cl
Cl
Cl
10
11
12
13
14
45
97
I
OH
1h
2h
2i
2j
Cl
OCH3
OCH3
OH
O
H
O
30
>99%
91
OH
I
H
1i
I
I
NH2
60
NH2
1j
I
I
I
2 / 4
360
75
0
I
Br
Br
2k
2k
2 / 4
91
NHBoc
1l
2m AOCCHC3 EPTED MANUSCRIPT
I
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15
16
17
18
19
2 / 4
1 / 2
2 / 4
2 / 4
2 / 4
90
45
30
90
75
>99%
>99%
95
OCH3
1m
H3CO
H3CO
I
OCH3
OCH3
2n
1n
I
I
N
N
I
I
I
I
N
H
N
H
2o
1o
N
N
70
N
N
Ts
Ts
2p
1p
85
I
S
S
2q
1q
aReaction conditions: 2 mmol of compound 1, the indicated amount of I2, the indicated
amount of H2O2 (30%) and 10 mL of H2O were maintained under sonication (20 KHz e
100 W) for the period of time presented.
ACCEPTED MANUSCRIPT
15