A cheap and efficient method for selective para-iodination of aniline derivatives

Article abstract of DOI:10.1016/j.tetlet.2005.05.117

A new and cheap protocol for controlled iodination in the para-position of various aniline derivatives is presented. It operates under mild conditions by reacting the aniline derivatives with molecular iodine in a mixture of pyridine/dioxane (1/1 vol) at 0°C.

Full text of DOI:10.1016/j.tetlet.2005.05.117

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5421–5423
A cheap and efficient method for selective para-iodination
of aniline derivatives
*
Cyrille Monnereau, Errol Blart and Fabrice Odobel
*
Laboratoire de Synth e` se Organique, UMR CNRS 6513 and FR CNRS 2465, Facult e´ des sciences et techniques de Nantes,
rue de la Houssini e` re—BP 92208, 44322 Nantes Cedex 3, France
2
Received 20 April 2005; revised 20 May 2005; accepted 25 May 2005
Available online 24 June 2005
Abstract—A new and cheap protocol for controlled iodination in the para-position of various aniline derivatives is presented.
It operates under mild conditions by reacting the aniline derivatives with molecular iodine in a mixture of pyridine/dioxane
(
1/1 vol) at 0 °C.
Ó 2005 Elsevier Ltd. All rights reserved.
Iodinated aniline derivatives are useful compounds in
many domains of synthetic organic chemistry. They
are widely used as intermediates for the synthesis of bio-
logically active molecules, including drugs, pesticides
R1
R2
I2
R1
R2
N
I
N
pyridine/ dioxane
0
˚C
1
,2
and fungicides.
Furthermore, the strong electron
Figure 1. General procedure for iodination of aniline derivatives.
donating character of the amino group is currently
exploited for the development of compounds where
charge transfer is required, such as organic dyes or
9
,10
acidic or basic conditions (trifluoroacetic acid,
H SO and KOH). Most of these methods are particu-
3
,4
push–pull electro-optic chromophores for NLO. They
are also employed in a great number of metal-catalysed
cross-coupling reactions since they display a much
higher reactivity than the corresponding brominated or
chlorinated derivatives. In these latter reactions,
electron rich substrates, such as amino derivatives, react
usually sluggishly with the metal catalyst in the initial
oxidative addition step, imposing sometimes the use of
2
4
1
1
larly harsh, costly, environmentally hazardous and
are not compatible with fragile functional groups.
In this letter, we report an exceedingly simple, mild and
efficient procedure for the para-selective iodination of
1
2
aniline derivatives (Fig. 1). In this procedure, besides
the aromatic amine, the only reagent is molecular iodine
dissolved in a mixture of pyridine and dioxane. The
reaction is carried out at low temperature (0 °C), and
offers in most cases, generally within 1 h, a quantitative
conversion of the starting reactant. The results of this
study are summarised in Table 1. The first models we
used were the N-ethyl-N-hydroxyethylaniline and N,N-
dihydroxyethylaniline (Table 1, entries 4 and 5), which
5
the iodo derivatives to achieve good yields.
However, selective iodination of aniline derivatives in
the para-position is quite a complicated task when mild
conditions are required. Amongst the numerous exam-
ples found in the literature, most of them imply the
5
use of activators such as toxic heavy metals (lead, merc-
–8
6
ury and chromium), strong oxidising agents (IO an-
3
3
are highly useful precursors in material sciences. In
ions, silver complexes, H O and NaOCl), or strong
2
2
both cases, the reaction worked with an almost quanti-
tative isolated yield. These two examples demonstrated
that this reaction is totally compatible with the presence
of free hydroxy groups.
Keywords: Aniline iodination; Para-selective; Mild conditions.
*
The reaction conditions were also successfully applied
on alkyl substituted anilines, namely the N,N-dimethyl-
aniline and N,N-dihexylaniline (Table 1, entries 2 and 3).
Corresponding authors. Tel.: +33 251125495; fax: +33 251125402
E.B.), tel.: +33 251125429; fax: +33 251125402 (F.O.); e-mail
addresses: errol.blart@univ-nantes.fr; fabrice.odobel@univ-nantes.fr
(
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.117

5422
C. Monnereau et al. / Tetrahedron Letters 46 (2005) 5421–5423
Table 1. Yield of isolated products following the reaction in Figure 1
Entry
1
Reactant
NH2
Product
Yield (%)
85
I
NH2
N
2
3
N
N
I
I
98
80
N
OH
OH
OH
OH
4
5
96
94
N
N
I
I
N
N
OH
OH
OTIPS
OTIPS
6
7
94
92
N
I
I
N
NH2
NH2
The isolated yield turned out to be lower in the case of
the dihexyl substituted aniline, although an apparently
quantitative conversion of the monomer was observed
by TLC of the raw reaction mixture. This probably re-
sulted from a partial decomposition of the product on
silica gel, which progressively took a light blue color
during the flash column chromatography. The isolated
yield for 4-iodo-N,N-dimethylaniline was slightly higher
than those reported in previous papers (98%) using dif-
In summary the procedure presented in this letter is a
mild and efficient way for controlled iodination in the
para-position of aniline derivatives.
General procedure: the aromatic compound (5 mmol)
was dissolved in dioxane (30 mL) and pyridine
(30 mL) and the solution was cooled to 0 °C. Iodine
(1.90 g, 15 mmol) was added in one portion. The solu-
tion progressively took a dark brown colour. After
1 h, the ice bath was removed and a supplementary por-
tion of iodine (630 mg, 5 mmol) was added if needed.
The solution was further stirred for one hour at room
temperature. A saturated solution of sodium thiosulfate
was then added until the brown colour disappeared. The
mixture was extracted with dichloromethane (200 mL)
and washed with water (200 mL). After evaporation,
the product was filtered through a short plug of silica,
eluted with the appropriate solvent.
1
0
ferent reagents. More interestingly, the same protocol
was applied on the unsubstituted aniline (Table 1, entry
1
be particularly tricky, as one can hardly avoid the for-
). Selective para-iodination of this molecule is known to
7
mation of the ortho-isomer or poly-iodinated material.
Moreover, it generally operates with modest yields. To
our satisfaction, such problems were not encountered
with this protocol and the iodinated product was formed
with a high yield and with an excellent selectivity. The
successful iodination of the O-silyl protected analogue
of the previously used N-ethyl-N-hydroxyethylaniline
(
Table 1, entry 6) evidences the softness of the proce-
Acknowledgment
dure. Such silylated compounds are indeed especially
sensitive to harsh acidic or basic conditions, and we
shall notice that absolutely no deprotection of the prod-
uct was observed consecutively to the reaction. Iodin-
ation of a-aminonaphthalene (Table 1, entry 7) also
operated with a high yield, evidencing the possi-
bility to carry out this reaction with amino naphthyl
derivatives.
This work was supported by the Region des Pays de la
Loire (CPER 18007).
References and notes
1. Merkushev, E. B. Synthesis 1988, 923–937.

C. Monnereau et al. / Tetrahedron Letters 46 (2005) 5421–5423
5423
2
. The Chemistry of Halides, Pseudo-Halides and Azides;
Patai, S., Rappoport, Z., Eds.; John Wiley and Sons:
Chichester, UK, 1995; Suppl. D2.
8. Lambert, C.; Noell, G. J. Chem. Soc., Perkin Trans. 2
2002, 2039–2043.
9. Beshore, D. C.; Dinsmore, C. J. Synth. Commun. 2003, 33,
2423–2427.
10. Adimurthy, S.; Ramachandraiah, G.; Ghosh, P. K.;
Bedekar, A. V. Tetrahedron Lett. 2003, 44, 5099–5101.
11. Smith, M. B.; Guo, L.; Okeyo, S.; Stenzel, J.; Yanella, J.;
LaChapelle, E. Org. Lett. 2002, 4, 2321–2323.
12. This protocol was inspired from a methodology used for
iodination of indolic ring reported by Irie, K.; Hayashi,
H.; Arai, M.; Koshimizu, K. Agric. Biol. Chem. 1986, 50,
2679–2680.
3
. Burland, D. M.; Miller, R. D.; Walsh, C. A. Chem. Rev.
994, 94, 31–75.
1
4
. Le Bouder, T.; Viau, L.; Gu e´ gan, J.-P.; Maury, O.; Le
Bozec, H. Eur. J. Org. Chem. 2002, 3024–3033.
5
6
. Plater, M. J.; Jackson, T. Tetrahedron 2003, 59, 4687–4692.
. Jereb, M.; Zupan, M.; Stavber, S. Chem. Commun. 2004,
2
614–2615.
. Branytska, O. V.; Neumann, R. J. Org. Chem. 2003, 68,
510–9512.
7
9