HIO4/Al2O3 as a new system for iodination of activated aromatics and 1,3-dicarbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2006.03.102

The use of a periodic acid/alumina system for the iodination of activated aromatics and 1,3-dicarbonyl compounds is described.

Full text of DOI:10.1016/j.tetlet.2006.03.102

Tetrahedron Letters 47 (2006) 3525–3528
HIO4/Al2O3 as a new system for iodination of activated
aromatics and 1,3-dicarbonyl compounds
Mohammad A. Khalilzadeh,a,* Abolfazl Hosseini,a Mojtaba Shokrollahzadeh,b
Mohammad R. Halvagar,c Daryoush Ahmadi,b Farajollah Mohannazadehb and
Mahmoud Tajbakhsha,*
aDepartment of Chemistry, Islamic Azad University, Qaemshahr, Iran
bDepartment of Chemistry, Mazandaran University, Babolsar 47416-1467, Iran
cChemistry and Chemical Engineering Research Center of Iran, Iran
Received 8 February 2006; revised 3 March 2006; accepted 15 March 2006
Available online 5 April 2006
Abstract—The use of a periodic acid/alumina system for the iodination of activated aromatics and 1,3-dicarbonyl compounds is
described.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Iodobenzene derivatives are valuable intermediates in
organic synthesis, medicine, and biochemistry.1 They
are widely used in synthesis to form carbon–carbon
and carbon–heteroatom bonds in transition metal cata-
lyzed processes such as the Heck, Still, Suzuki, and
Ullmann-type coupling reactions.2–4
iodination of activated aromatics and 1,3-dicarbonyl
compounds involving periodic acid adsorbed on alu-
mina (HIO4/Al2O3). Periodic acid has been widely used
in organic synthesis,9 however, it can be unreactive and
this disadvantage can be overcome by absorption of the
reagent onto alumina. Such a supported reagent is more
reactive and has the advantage of being easy to remove
from the organic product by filtration. Other advantages
of HIO4/Al2O3 in comparison to other reagents are mild
reaction conditions, enhanced selectivity, and increased
yields.10
Due to the poor electrophilic strength of iodine, direct
iodination of aromatic rings with iodine is difficult and
requires the presence of an activating agent in order to
produce a strongly electrophilic I+ species. In recent
years, direct iodination methods have been developed
using iodonium-donating reagents. However, most of
these methods require toxic reagents, harsh conditions,
the use of expensive, complicated or sensitive reagents,
and the generation of hazardous waste.5
The use of periodic acid as an iodinating agent was first
reported by Japanese investigators who used it in the
presence of iodine for iodination of activated aromatic
compounds.11
On the other hand, 1,3-dicarbonyl compounds are
versatile intermediates in organic chemistry.6 Most
methods to transform 1,3-dicarbonyl compounds to
their related a-iodo-derivatives rely on modification of
N-iodosuccinimide7 whilst the use of other reagents have
been less investigated.8 Therefore, we report a milder,
efficient, and environmentally benign procedure for the
We have found that periodic acid can be readily decom-
posed on alumina in aqueous media to produce iodine,
as a change of color was evident. This evidence
prompted us to investigate HIO4/Al2O3 for the direct
iodination of aromatic compounds. As a model we stud-
ied the iodination of mesitylene in different solvents
(Table 1).
Our observation revealed that, amongst the various sol-
vents, 1,4-dioxane was the most effective, giving a short
reaction time, and high yield. To our surprise, in a blank
reaction performed without supporting the HIO4 on
Keywords: Iodination; Periodic acid; Solid phase; 1,3-Dicarbonyl
compounds; Alumina; Activated aromatic compounds.
*
Corresponding authors. Tel.: +98 11252 34338; fax: +98 11252
42002; e-mail: tajbaksh@umz.ac.ir
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.102

3526
M. A. Khalilzadeh et al. / Tetrahedron Letters 47 (2006) 3525–3528
Table 1. Effect of solvent on the reaction yield at reflux using HIO4/Al2O3 in the introduction of mesytilene
Solventa
H2O/CHCl3
H2O/CH3CN
H2O/acetoneb
H2O/CH2Cl2
H2O/1,4-dioxane
Time (h)
Yield (%)
4
55
5
30
3
40
4
50
1.5
80
a HIO4 is decomposed in aqueous media and an organic solvent is used to dissolve organic compounds. Typically, we dissolved 2.5 g of periodic acid
in a minimum amount of water (2 ml) and then added 5 g of alumina and 10 ml of organic solvent.12
b Iodoacetone was detected.
alumina, mesitylene was found to remain unconsumed
even after 5 h. Thus the role played by the alumina is
justified.
depicted in Table 2, these compounds were recovered
unreacted even after 10 h (entries 7 and 18).
We have also employed our reagent system for the
iodination of compounds containing an acidic hydro-
gen. Fatiadi reported the iodination of 1,3-dicarbonyl
compounds with periodic acid in AcOH,8 however,
our reagent system showed a greater yield for the diio-
dination. It was found that b-dicarbonyl compounds 1,
which are unsubstituted at the a-position undergo diio-
dination to afford high yields of 2 upon treatment with
HIO4/Al2O3 (Table 3). We were not able to achieve
mono-iodination, only diiodinated products were ob-
tained. As expected, exposure of a-mono-substituted
compounds 3 to HIO4/Al2O3 under the same reaction
conditions afforded mono-iodinated products 4. Table
3 shows some representative examples of this transfor-
mation. b-Dicarbonyl compounds were iodinated in
good to excellent yields using the HIO4/Al2O3 system
in dioxane (Table 3, entries 1–5). Ethyl cyanoacetate
showed good reactivity and was iodinated in high yield
(entry 6). To extend our investigation, we employed
our system for the iodination of less active carbonyl
compounds. Treatment of acetophenone and 2-nitro-
propane with HIO4/Al2O3 afforded iodinated product
in high yields (entries 8 and 9). 1,1-Dimethoxyethane
was also iodinated in high yield (Table 3, entry 7).
Surprisingly, high selectivity was obtained with aceto-
phenone compared with acetone, which produced a
mixture of mono and diiodo products.
With a better understanding of the reaction variables, a
series of arenes were subjected to iodination with periodic
acid on alumina in dioxane. In all the reactions, we
observed regioselective iodination occurring at the more
active and less sterically hindered position (Table 2).
This system was very mild and mono-iodination was
observed in all cases. Alkyl benzenes were the most
active substrates in the iodination by HIO4/Al2O3.
Surprisingly, methoxy and hydroxy benzene derivatives,
despite their marked activity in electrophilic reactions,
gave lower yields. Although, iodination of aniline,
N,N-dialkylanilines, and phenol led to decomposition
of these substrates, it was thought that perhaps com-
plexation of the oxygen and nitrogen atoms with the
oxidant was responsible for inhibiting the iodination
process.
However, when the reaction of phenol and anilines (en-
tries 8, 16, and 17) were performed at reflux, trace
amounts of iodinated products along with unidentified
by-products, which did not contain iodine and other
oxidized products were obtained.9 This problem could
be overcome using phenols possessing two substituents
in the ortho positions. We have extended our reaction
to a series of unactivated aromatic compounds as
Table 2. Iodination of activated arenes using HIO4/Al2O3
Entry
Substrate
Product
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
1,3,5-Trimethylbenzene
1,2-Dimethylbenzene
1,3-Dimethylbenzene
1,4-Dimethylbenzene
Methoxybenzene
Benzylphenylether
Diphenylether
Phenol
2,6-Dimethylphenol
2,6-Di-tert-butylphenol
2,3-Dimethylphenol
3-Methoxyphenol
3,5-Dimethoxyphenol
2,3-Dimethoxyphenol
4-Hydroxybenzaldehyde
N,N-Dimethylaniline
N,N-Diethylaniline
Chlorobenzene
2-Iodo-1,3,5-trimethylbenzene
1,2-Dimethyl-4-iodobenzene
1,3-Dimethyl-4-iodobenzene
1,4-Dimethyl-2-iodobenzene
1-Iodo-4-methoxybenzene
4-Iodo-benzylphenylether
No reaction
1.5
2.5
2
2.5
2.5
5
12
—
3
90
79
81
80
70
40
—
—
75
78
70
72
80
75
—
—
—
—
Decomposed
2,6-Dimethyl-4-iodophenol
2,6-Di-tert-butyl-4-iodophenol
2,3-Dimethyl-4-iodophenol
4-Iodo-3-methoxyphenol
3,5-Dimethoxy-4-iodophenol
2,3-Dimethoxy-4-iodophenol
No reaction
Decomposed
Decomposed
No reaction
3
8
4.5
3.5
3.5
12
—
—
12
a Yields refer to isolated products.

M. A. Khalilzadeh et al. / Tetrahedron Letters 47 (2006) 3525–3528
Table 3. Iodination of various carbonyl compounds and alkenes with HIO4/Al2O3
3527
Entry
Carbonyl compound
Iodinated product
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
CH3COCH2CO2Et
CH3COCH2COCH3
CH2(COOEt)2
CHPh(COOEt)2
PhCOCH2COPh
NCCH2CO2Et
CHCH3(OEt)2
CHNO2(CH3)2
PhCOCH3
CH3COCI2CO2Et
CH3COCI2COCH3
CI2(COOEt)2
CIPh(COOEt)2
PhCOCI2COPh
NCCI2CO2Et
CICH3(OEt)2
CINO2(CH3)2
PhCOCH2I
1.5
1
2.5
1.5
2
2
1.5
2
93
95
80
90
90
80
87
75
2
1
3
92
10
11
Stilbeneb
Benzyl phenyl ketone
2-Iodophenyl ethanol
Acetophenone
90c
50c,d
Styrene
<10
92
12
Styrenee
Acetophenone
2
a Isolated and unoptimized yields.
b Reaction conducted at room temperature.
c Reaction yield based on GC analysis.
d 2-Iodophenylethanol was characterized by comparison with an authentic sample prepared either by reduction of a-iodoacetophenone or according
to the literature procedure.13
e Reaction conducted at reflux.
In conclusion, we have developed a simple method using
commercially available reagents for the direct iodination
of activated aromatics and dicarbonyl compounds under
mild conditions.
O
I
O
I
O
O
O
HIO4 / Al2O3
X
X
Y
Y
X
X
Y
Y
1
2
4
Typical procedure: Periodic acid (2.5 g) was dissolved in
water (2.5 ml) and added to a mixture of alumina (5 g)
and dioxane (10 ml) and stirred for 2 h at reflux or at
room temperature (a brown color was observed). Then,
the arene or b-dicarbonyl compound (5 mmol) was dis-
solved in dioxane (3 ml) and added to the above mix-
ture. After the appropriate time (reaction was
monitored by TLC and GC) the reaction mixture was
filtered and the resulting filtrate extracted with diethyl
ether. The ether layer was successively washed with
aqueous sodium bisulfite (5%) and water (2 · 15 ml)
and dried over anhydrous Na2SO4. After filtration and
evaporation of the solvent, the crude product was crys-
tallized or subjected to column chromatography. The
products were characterized from their physical con-
stants and NMR, IR, and GC–MS spectra.
O
R
O
I
O
HIO4 / Al2O3
R
3
Attempts to iodinate stilbene using HIO4/Al2O3 led to
formation of the oxidized product, benzyl phenyl ketone
in excellent yield. Similarly, styrene underwent oxidation
at reflux and gave not only acetophenone in 92% yield
but also gave a mixture of acetophenone and 2-iodophen-
yl ethanol at room temperature (Table 3, entries 11 and
12).
In order to probe selectivity issues with regard to this
chemistry, pentan-2,4-dione 5 and phenyl acetylene 6
were exposed to HIO4/Al2O3 under standard conditions,
leading to the chemoselective diiodination product 7 as
the major product accompanied by phenyl iodoethyne
8 in very low yield.
Acknowledgement
Financial support of this work from the Research Coun-
cil of Mazandaran and Azad University is gratefully
acknowledged.
O
O
References and notes
HIO4/Al2O3
+
PhC CH
H3C
CH3
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Ph
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8%
8
70%
7

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