Iodination of activated arenes using silfen: An improved protocol

Article abstract of DOI:10.1016/S0040-4039(02)02262-1

A simple and direct method for the iodination of activated arenes, using molecular iodine and silfen (silica supported ferric nitrate nonahydrate) as an oxidant, is presented. The reactions are performed at 20°C in dichloromethane. The method provides an easy access to the corresponding iodinated products in good yields. The observed orientation effects are in agreement with those based on general aromatic electrophilic substitution theory.

Full text of DOI:10.1016/S0040-4039(02)02262-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9457–9459
Iodination of activated arenes using silfen: an improved protocol
†
Rutuja D. Tilve,* Varughese M. Alexander and Bhushan M. Khadilkar
Applied Chemistry Division, Institute of Chemical Technology, University of Mumbai, Matunga, Mumbai-400 019, India
Received 18 July 2002; revised 27 September 2002; accepted 4 October 2002
Abstract—A simple and direct method for the iodination of activated arenes, using molecular iodine and silfen (silica supported
ferric nitrate nonahydrate) as an oxidant, is presented. The reactions are performed at 20°C in dichloromethane. The method
provides an easy access to the corresponding iodinated products in good yields. The observed orientation effects are in agreement
with those based on general aromatic electrophilic substitution theory. © 2002 Elsevier Science Ltd. All rights reserved.
Iodoarenes are valuable and versatile synthetic interme-
diates with wide applications in medicine and biochem-
istry. Recent progress in organotransition metal
been demonstrated that attempts to carry out the same
reactions in solvents, without a support, either fre-
quently fail or result in the formation of mixtures of
products.
1
chemistry has renewed the importance of these iodoare-
nes. The transformations of iodine in iodoarenes, to
diverse functional groups, by transition metal catalysts2,
has been a popular and fruitful area of investigation.
Despite the importance of iodoarenes and the long
history of aromatic electrophilic halogenation, the lack
of reactivity of molecular iodine has hindered extensive
progress towards their efficient synthesis.
Over the last few years, we have been actively involved
in utilising surface-mediated reactions and have found
them useful in carrying out various synthetic organic
12
transformations.
We have already published our
results on oxidation of alcohols and aromatisation of
,4-dihydropyridines using silfen (silica supported ferric
1
13
nitrate nonahydrate) as a mild oxidant. Silfen is pre-
pared under solvent-free conditions and possesses no
handling and storage problems. In continuation of
Synthetic methods involving a source of positive iodine
+
i.e. I as the reactive species, seem to be the most
14
convenient procedure for the direct iodination of are-
our progressive investigation into the applications of
this mild oxidant, we herein wish to report a mild,
efficient and regioselective monoiodination of activated
3
nes. A wide array of reagents and methods involving
4
5
molecular iodine, in combination with oleum, CrO
3,
6
7
8
9
F , Pb (OAc) , Hg salts, nitrogen dioxide and
CF SO Ag have been documented. However, most of
15
2
4
arenes, using molecular iodine and silfen. This com-
1
0
3
3
munication deals with the scope and limitations of this
newly developed iodination method (Scheme 1).
these methods require large volumes of mineral acids,
high reaction temperatures, the use of expensive/non-
ecofriendly/sensitive metallic reagents and the genera-
tion of large amounts of toxic waste. Hence, a
convenient method involving mild reaction conditions
is highly desirable.
To gain some preliminary information on this syntheti-
cally useful reaction, control experiments were per-
formed. For all these studies, an activated arene i.e.
anisole was the substrate of choice. We studied the
influence of different factors on the reaction kinetics.
Thus, solvent and the amount of oxidant were varied.
During the past decade, the technique of surface-medi-
ated reactions has gained much interest and popularity.
In comparison to their homogeneous counterparts, the
advantages of these reactions include mild conditions
1
1
enhanced selectivity and increased yields. It has also
*
Corresponding author. Tel.: 91-22-4145616; e-mail: rutujatilve@
yahoo.co.in
†
This work is dedicated to our research guide, the late Dr. B. M.
Khadilkar.
Scheme 1. Iodination of activated arenes using molecular
iodine and silfen as an oxidant.
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02262-1

9
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R. D. Til6e et al. / Tetrahedron Letters 43 (2002) 9457–9459
Table 1. Effect of solvent on the reaction time at 20°C, using silfen (5 mmol content of Fe(NO ) ·9H O)
3
3
2
Solvent
CH CN
CH Cl
PhMe
6
Et O
THF
12
3
2
2
2
Reaction time (h)
4.5
3.5
10
Our observations revealed that, amongst the various
solvents used, dichloromethane was the most effective,
giving a short reaction time and clean product. Basic
solvents such as diethyl ether and tetrahydrofuran were
found to be detrimental to this reaction, most probably
due to complexation to the oxidant. The results are
compiled in Table 1.
20% of the nitrated product was obtained. When the
molar ratio was 1.0:0.55:0.50 respectively, 95% of p-
iodoanisole was obtained exclusively (entry 2). How-
ever, after further decreasing the Fe(NO ) ·9H O
3
3
2
content, it was observed that on isolation, only 80% of
the iodinated product was obtained after 3.5 h (entry
3). Hence, all further reactions were performed with the
most effective molar ratio, i.e. 1.0:0.55:0.50, respec-
tively. To our surprise, in a blank reaction performed
without supporting the Fe(NO ) ·9H O on silica gel,
However, when the same reaction was performed at
reflux temperature, along with the formation of the
major p-iodoanisole, a considerable amount of nitra-
tion product was obtained. This prompted us to carry
out all further investigations at 20°C, as it was found to
favour the iodination reaction. (Conversions monitored
3
3
2
anisole was found to remain unconsumed even after 7
h. On isolation, only 50% of p-iodoanisole was
obtained. Thus, the role of silica gel as an inexpensive
support is justified.
1
6
by GC).
With a better understanding of the reaction variables, a
series of arenes were subjected to iodination in the
presence of molecular iodine and silfen. Electronically
rich arenes were iodinated smoothly, while benzene and
electron-deficient arenes such as chlorobenzene and
bromobenzene were recovered unchanged even after 48
h. The results are compiled in Table 3.
In an attempt to optimise the reaction conditions, we
examined the effect of the oxidant loading on the silica
gel. For this purpose, the molar ratios of ferric nitrate
nonahydrate on silica gel were varied. The results are
compiled in Table 2.
15
During the course of our studies, we found that when
anisole, iodine and ferric nitrate supported on silica gel
were taken (entry 1) along with 80% of p-iodoanisole,
The products obtained, after the reaction, resulted from
the regioselective iodination of the aromatic ring. The
Table 2. Effect of variation of the oxidant loading on the silica gel (4 g); reaction performed at 20°C in dichloromethane for
.5 h
3
Entry
Molar ratios (anisole:iodine:Fe(NO ) ·9H O)
Yielda (%)
3
3
2
Iodination
Nitration
1
2
3
1.0:0.55:1.0
1.0:0.55:0.50
1.0:0.55:0.25
80
95
80
20
–
–
a
Isolated yields.
Table 3. Iodination of activated arenes using molecular iodine and silfen as an oxidant
Entry
Substrate
Time (h)
Product
Yielda (%)
1
2
3
4
5
6
7
8
9
Methoxybenzene
Ethoxybenzene
3.5
4
2.5
2.5
6
6
28
2
14
2
24
48
48
48
1-Iodo-4-methoxybenzene
1-Iodo-4-ethoxybenzene
4-Iodo-1-methoxy-2-methylbenzene
2-Iodo-1-methoxy-4-methylbenzene
2-Chloro-4-iodo-1-methoxybenzene
1-Iodo-2-methoxynaphthalene
4,4%-Diiododiphenyl ether
2-Iodothiophene
2-Iodo-1,4-dimethoxybenzene
2-Iodo-1,3,5-trimethylbenzene
2-Iodo-1,4-dimethylbenzene
–
95
90
84
80
84
85
80
47
84
92
60
–
1-Methoxy-2-methylbenzene
1-Methoxy-4-methylbenzene
2-Chloro-1-methoxybenzene
2-Methoxynaphthalene
Diphenyl ether
Thiophene
1,4-Dimethoxybenzene
1,3,5-Trimethylbenzene
1,4-Dimethylbenzene
Benzene
Chlorobenzene
Bromobenzene
10
11
12
13
14
–
–
–
–
a
Isolated yields.

R. D. Til6e et al. / Tetrahedron Letters 43 (2002) 9457–9459
9459
regioselectivity observed may be explained from the
result that iodination occurs at a more electron rich and
less sterically hindered position. This character is
strongly reflected in the iodination of anisole, phene-
tole, 2-methylanisole and 2-chloroanisole (entries 1, 2, 3
and 5), where the iodination occurred at the p-position
to the alkoxy group. As anticipated, o-iodination
occurred only when the p-position was occupied (entry
5. Lulinski, P.; Skulski, L. Bull. Chem. Soc. Jpn. 1997, 70,
1665.
6. Chambers, R. D.; Skinner, C. J.; Atherton, M. J.; Moil-
let, J. S. J. Chem. Soc., Perkin Trans. 1 1996, 1659.
7. Krassowska-Swiebocka, B.; Lulinski, P.; Skulski, L. Syn-
thesis 1995, 926.
8. Bachki, A.; Foublelo, F.; Yus, M. Tetrahedron 1994, 50,
5139.
9. Noda, Y.; Kashima, M. Tetrahedron Lett. 1997, 35, 6225.
10. Kobayashi, Y.; Kumadaki, I.; Yoshida, T. J. Chem Res.
(S) 1977, 215.
11. (a) Clark, J. H. Catalysis of Organic reactions by Sup-
ported Inorganic reagents; VCH: New York, 1994; (b)
Clark, J. H.; Macquarrie, D. J.; Kybett, A. P. Supported
Reagents: Preparation, Analysis and Applications; VCH:
New York, 1992; (c) Clark, J. H.; Price, P. M.; Macquar-
rie, D. J. J. Chem. Soc., Dalton Trans. 2000, 101.
12. (a) Khadilkar, B. M.; Borkar, S. D. Tetrahedron Lett.
1997, 38, 1641; (b) Khadilkar, B. M.; Borkar, S. D. J.
Chem. Technol. Biotechnol. 1998, 71, 209; (c) Khadilkar,
B. M.; Bendale, P. M. Tetrahedron Lett. 1998, 39, 5867;
(d) Khadilkar, B. M.; Madyar, V. R. Synth. Commum.
2002, 32, 1732; (e) Khadilkar, B. M.; Upadhyaya, D. J.
Synth. Commum. 2002, 32, 1867.
4
). Regioselective diiodination of diphenyl ether, a
binuclear arene (entry 7) has been achieved by con-
trolling the stoichiometry. Also, a-iodination of an
activated heterocycle, thiophene (entry 8) was obtained.
Monoiodothiophene serves as a useful intermediate in
the synthesis of conjugated materials, self-assembled
monolayers and as bioactive reagents in antitumour
1
7
therapy.
Attempts to gain an insight into the mechanistic details
of this reaction have not yet been achieved. Pre-
+
sumably, the electrophile I is generated in situ by the
reaction of molecular I and silfen. The spent material
2
obtained after iodination, is found to be effective in
Friedel–Crafts alkylation, another industrially impor-
1
8
tant reaction.
13. Khadilkar, B. M.; Borkar, S. D. Synth. Commum. 1998,
In conclusion, we have established silfen as an econom-
ical, efficient, ecofriendly oxidant for regioselective
monoiodination. The ease of this present protocol is
expected to make this methodology useful in the field of
synthetic organic chemistry. To enhance the synthetic
utility of this method, its applications to other hetero-
cycles are being pursued.
28, 207.
14. For the present studies, silfen was prepared as follows:
Fe(NO ·9H O (2 g, 5 mmol) was cogrinded with silica
gel (4 g, SRL 230–400 mesh, BET surface 385.6 m g ,
)
3
3
2
2
−1
3
−1
pore volume 0.65 cm g ) in an agate mortar. A pale
yellow free flowing mixture was obtained, which was used
without any further activation.
1
5. Silfen was prepared as cited in Ref. 14. In a representa-
tive procedure, to 10 mmol of substrate and 5.5 mmol of
iodine in 15 ml dichloromethane, silfen (5 mmol content
of Fe(NO ) ·9H O) was added. The reaction was then
Acknowledgements
3
3
2
stirred for the specified time, at 20°C. On completion
monitored by TLC and GC) the reaction mixture was
(
We gratefully acknowledge BRNS (99/37/39/BRNS/
filtered and the organic solution successively washed with
aqueous sodium thiosulphate solution. The combined
organic extracts were dried using anhydrous sodium sul-
phate and evaporated under reduced pressure. The
residue thus obtained was purified by column chromatog-
raphy (silica gel) to furnish the pure iodo products. The
products are characterised by their physical constants,
IR, NMR and GC–MS.
1
749) for financial assistance and the G. D. Gokhale
Trust for awarding a fellowship to one of the authors.
We thank Prof. S. D. Samant and Prof. V. R. Kanetkar
from MUICT for their valuable suggestions with this
manuscript.
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of 10°C min . The column used was SE-30 (length 2
metres).
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