Aerobic oxidative iodination of organic molecules activated by sodium nitrite

Article abstract of DOI:10.1016/j.tetlet.2007.11.167

Aerobic oxidative iodination activated by sodium nitrite occurs effectively and selectively with 100% iodine atom economy with air as the oxidant. Silica-supported sulfuric acid was used for the activation of the catalyst and iodination. Thus, I₂/NaNO₂/air/silica-supported H₂SO₄ in acetonitrile iodinated aromatics, ketones and aldehydes effectively at ambient temperature.

Full text of DOI:10.1016/j.tetlet.2007.11.167

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 893–895
Aerobic oxidative iodination of organic molecules
activated by sodium nitrite
a,
a
a,b
*
Jernej Iskra , Stojan Stavber , Marko Zupan
a Laboratory of Organic and Bioorganic Chemistry, Department of Physical and Organic Chemistry, ‘Jozˇef Stefan’ Institute, Jamova 39,
1000 Ljubljana, Slovenia
b Faculty of Chemistry and Chemical Technology, University of Ljubljana, Asˇkercˇeva 5, 1000 Ljubljana, Slovenia
Received 25 July 2007; revised 19 November 2007; accepted 27 November 2007
Available online 4 December 2007
Abstract
Aerobic oxidative iodination activated by sodium nitrite occurs effectively and selectively with 100% iodine atom economy with air as
the oxidant. Silica-supported sulfuric acid was used for the activation of the catalyst and iodination. Thus, I2/NaNO2/air/silica-sup-
ported H2SO4 in acetonitrile iodinated aromatics, ketones and aldehydes effectively at ambient temperature.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Iodination; Halogenation; Haloperoxidation; Hydrogen peroxide; Green chemistry; Aerobic halogenation; Organo-halogen compounds
Iodinated organic molecules are important compounds
in synthetic chemistry, and are used widely in the pharma-
ceutical and chemical industries creating high demand for
efficient and economical methods for their production.1
Due to the negative impacts that chemicals can have on
the environment, for example, chlorinated hydrocarbons
and VOCs, scientists are trying to adapt existing chemical
processes into more environmentally benign methods.2 In
the field of halogenation, this necessity reflects the revival
of the oxidative halogenation reaction first reported in
1924 by Leulier and Speyer.3 This is because of the atom
economy of the halogen atoms during oxidative halogena-
tion, which is 100% due to the regeneration of the residual
halogenide ion by oxidation into a reactive molecular hal-
ogen. The most environmentally benign oxidants are
hydrogen peroxide and oxygen.4 While H2O2 is often used
in oxidative halogenations,5 especially in metal-catalyzed
examples,6 oxygen is seldom used and only arenes were
iodinated in an oxygen atmosphere by metal-catalyzed
iodination with polyoxometalate and bismuth salts as cata-
lysts or lower nitrogen oxide species in AcOH/CF3COOH/
Ac2O.7 Recently, Liang and Hu’s group reported the tran-
sition-metal free aerobic oxidation of alcohols and oxida-
tive bromination of arenes and aryl ketones with
NaNO2/HBr/TEMPO under an oxygen atmosphere.8 It
might be possible to use NaNO2 for iodination reactions,
however, HI is unstable and I2 is the preferred iodinating
reagent, while air would be a safer alternative to hazardous
oxygen gas. The presence of acid, however, is obligatory
because it converts NaNO2 into nitrogen oxides, which
are the true catalysts in the oxidation reactions. The acid
is also an excellent activator of iodine for the iodination
of less reactive substrates.
As part of our continued interest in developing ‘greener’
methods for halogenation, we studied the air/I2/NaNO2/
acid system for the aerobic oxidative iodination of organic
molecules. First, we performed the iodination of anisole 1
(as a model substrate) using an air/I2/NaNO2 system in
the presence of 0.1 M equiv of H2SO4 and obtained 4-iodo-
anisole 2, quantitatively (Scheme 1). We also found that a
Lewis acid (ethereal solution of BF3) was an effective acti-
vator of the aerobic NaNO2-catalyzed iodination. Also,
because less reactive substrates require a higher amount
of acid, we investigated solid acids that have the potential
to be recycled. Using strongly acidic ion-exchange resins
*
Corresponding author. Tel.: +386 1 477 3631; fax: +386 1 477 3822.
E-mail address: jernej.iskra@ijs.si (J. Iskra).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.167

894
J. Iskra et al. / Tetrahedron Letters 49 (2008) 893–895
Table 1
OMe
OMe
Aerobic iodination of arenes with iodine activated by NaNO2 and silica-
supported acid
0.5 equiv. I2 / NaNO2 (5%) / acid
CH3CN, 22 °C, 12 h
Substrate
Acid
(mmol)
Time
(h)
Product
Yielda
(%)
1
I
MeO
I
OMe
MeO
OMe
2
0.05
1b
98
85
87
H2SO4 (0.1 equiv.):
BF3.OEt2 (0.2 equiv.):
100%
94%
3
4
Dowex (0.5 equiv.):
50% H2SO4/SiO2 (0.1 equiv.):
76%
100% (96%)
tBu
OH
t
Bu
OH
0.25
0.25
12
20
6
Scheme 1.
5
I
I
(sulfonated polystyrene/DVB matrix, Dowex 50W) the
reaction of 1 took place with only 76% conversion with
0.5 equiv of acid. Next, 50% sulfuric acid supported on sil-
ica was prepared and used as reported in the literature.9
Iodination of 1 was effective with silica-supported acid
(0.1 M equiv) and 2 was formed selectively and quantita-
tively. Different solvents (EtOAc, tert-butylmethyl ether,
water and EtOH) were also tested; however, acetonitrile
was by far the best.
OH
OH
7
8
I
NHAc
NHAc
1
1
24
24
97
95
9
10
t
Bu
Me
t
Bu
Me
Further, we investigated the effect of silica-supported
acid on the aerobic NaNO2-catalyzed oxyiodination
(Fig. 1). Although a blank experiment without the presence
of acid yielded only trace amounts of 4-iodoanisole, con-
version, gradually increased as the quantity of acid was
increased reaching a maximum at 7.5 mol % of sulfuric
acid in the reaction mixture.
11
12
I
I
0.25
5
94
14
Reaction conditions: 1 mmol of substrate, 127 mg I2 (0.5 mmol), 2 mg
13
a
NaNO2 (0.03 mmol), 50% H2SO4/SiO2 (3.62 mmol H2SO4/g), 2 mL
MeCN.
Finally, we investigated the aerobic iodination of vari-
ous aromatic and carbonyl compounds using the air/I2/
NaNO2/acid system (Table 1). In a typical preparative
experiment we dissolved 1 mmol of anisole 1 in 2 mL of
acetonitrile, added 0.5 mmol of I2, 0.03 mmol of NaNO2
and 21 mg of silica-supported 50% H2SO4 (0.075 mmol of
H2SO4, 3.62 mmol H2SO4/g), covered the flask with a bal-
loon filled with air and stirred the contents at 22 °C for 6 h.
At the end of the reaction, the mixture was diluted with
hexane–EtOAc (9:1) and the solid acid filtered off. The
organic phase was firstly discoloured by adding a few drops
of 37% NaHSO3, neutralized by the addition of NaHCO3,
dried over Na2SO4 and the inorganic salts filtered off. After
the removal of the solvents we obtained pure 4-iodoanisole
2 as determined by NMR spectroscopy, while further puri-
fication on a short silica column gave 2 in 96% yield
b
0 °C.
(Scheme 1). Various aromatic derivatives were selectively
iodinated including p-tert-butylphenol 5, which usually
gives a mixture of mono- and diiodo products, while the
reactivity of the system was manipulated by varying the
amount of acid. The method was also applicable for
the iodination of ketones. Various ketones (dialkyl 15, aryl-
alkyl 17, b-ketoester 19 and cyclic ketone 21) were iodin-
ated by tuning the reactivity by adjusting the amount of
acid; no formation of diiodo products was observed
(Scheme 2). Aldehydes 23 and 25 were also iodinated using
this method, albeit a-iodo aldehydes 24 and 26 are less
stable and begin to decompose during isolation.
Importantly, the aerobic iodination procedure produced
no organic waste and as the iodination of anisole 1
required only 10 mol % of H2SO4 for quantitative iodin-
ation, we performed an experiment on a 1 g scale (1/0.5
equiv. I2/0.03 equiv NaNO2/0.1 equiv H2SO4conc./MeCN,
0.5 M). After stirring for 3 h at 22 °C, the reaction mixture
was poured over crushed ice and the resulting white precip-
itate filtered off. From this we obtained a 93% yield of pure
4-iodoanisole.
100
80
60
40
20
0
0
0.025 0.05 0.075 0.1 0.125
molar equivalents of H2SO4/SiO2
In conclusion, NaNO2-activated aerobic oxidative
iodination presents a rare system, where air is used as the
oxidant for the regeneration of I2 from eluted HI and thus
Fig. 1. The effect of silica-supported H2SO4 on the conversion of anisole 1
(0.5 equiv I2/air/0.03% NaNO2, MeCN (0.5 M), 3 h, 22 °C).

J. Iskra et al. / Tetrahedron Letters 49 (2008) 893–895
895
of Slovenia. The authors are grateful to the staff of the
National NMR Centre at the National Institute of Chem-
istry in Ljubljana and the staff of the Mass Spectroscopy
Centre at the JSI.
0.5 equiv. I2
O
O
I
air / 0.03 equiv. NaNO2
R2
R1
R1
R2
H2SO4-SiO2, CH3CN, 22 °C
HA(mol%)
15: R1=Bu, R2=Pr,
17: R1=Ph, R2=H,
19: R1=Ph, R2=COOEt,
21: 1-tetralone,
0.50,
0.25, 12 h: 18 (91%)
0.05, 2 h: 20 (94%)
0.10, 12 h: 22 (91%)
2 h: 16 (85%)
References and notes
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0.5 equiv. I2
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CHO
I
CHO
R
0.25 H2SO4-SiO2
CH3CN, 22 °C, 5 h
R
23 25
,
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R=Pr: 26 (81%)
Scheme 2.
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enables 100% iodine atom economy (Scheme 3). Acidic
conditions are a requisite for both NaNO2-catalysis and
iodination reactions where the amount of acid employed
is used to tune the reactivity of the system. The method
offers an effective system for metal-free iodination of aro-
matics, ketones and aldehydes. Furthermore, there is no
organic waste from the reaction and the isolation proce-
dure is straightforward requiring only the separation of
the organic product from the inorganic salts.
Acknowledgements
This research has been supported by the Ministry of
Higher Education, Science and Technology of the Republic
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