Aerobic oxidative α-iodination of carbonyl compounds using molecular iodine activated by a nitrate-based catalytic system

Article abstract of DOI:10.1016/j.tetlet.2014.08.055

The novel reaction system comprising air/NH₄NO_3(cat.)/I₂/H₂SO_4(cat.)is introduced as a simple, safe, cheap, efficient, and regioselective mediator for direct aerobic oxidative α-iodination of aryl, heteroaryl, alkyl, and cycloalkyl methyl ketones. The reaction system enabled the moderate to quantitative regioselective iodination of a large range of different methyl ketone derivatives including those bearing oxidizable heteroatom (S, N) substituents. Several activated aromatic compounds were also efficiently and selectively iodinated. The practical applicability of the presented reaction system was shown on 20 mmol scale under ambient pressure and 100% conversion of substrate was achieved.

Full text of DOI:10.1016/j.tetlet.2014.08.055

Tetrahedron Letters 55 (2014) 5643–5647
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Tetrahedron Letters
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Aerobic oxidative
a-iodination of carbonyl compounds using
molecular iodine activated by a nitrate-based catalytic system
Rok Prebil a, Stojan Stavber a,b,
⇑
a
ˇ
Laboratory for Organic and Bioorganic Chemistry at ‘Jozef Stefan’ Institute, Jamova 39, 1000 Ljubljana, Slovenia
b Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, Jamova 39, 1000 Ljubljana, Slovenia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 June 2014
Revised 17 July 2014
Accepted 13 August 2014
Available online 19 August 2014
The novel reaction system comprising air/NH4NO3(cat.)/I2/H2SO4(cat.) is introduced as a simple, safe, cheap,
efficient, and regioselective mediator for direct aerobic oxidative
a-iodination of aryl, heteroaryl, alkyl,
and cycloalkyl methyl ketones. The reaction system enabled the moderate to quantitative regioselective
iodination of a large range of different methyl ketone derivatives including those bearing oxidizable
heteroatom (S, N) substituents. Several activated aromatic compounds were also efficiently and
selectively iodinated. The practical applicability of the presented reaction system was shown on 20 mmol
scale under ambient pressure and 100% conversion of substrate was achieved.
Keywords:
Air
Ammonium nitrate
Nitrogen oxides
Iodination
Ó 2014 Elsevier Ltd. All rights reserved.
Aryl methyl ketones
Iodo-substituted organic compounds, particularly
a
-iodo
of alternative strategies. For the a-iodination of methyl ketone
methyl ketones and iodoaromatics, are among the most versatile
intermediates and valuable synthons or precursors for car-
bonAcarbon, carbonAnitrogen, or carbonAoxygen bond formation
in combinatorial synthesis.1 Due to their useful properties, iodin-
ated organic compounds have found widespread use in medicine,
particularly in medical diagnostics as contrast agents or radioac-
tively labeled markers, pharmacology, agricultural chemistry, and
biochemistry.2 Moreover iodomethyl ketones are usually prepared
indirectly by oxidative iodination of olefins,3 electrophilic iodin-
ation of ketone derivatives (enol ethers and acetates),4 or by halo-
gen interchange of bromo compounds with sodium iodide.5
Because of the difficulties in the synthesis and purification of enol
derivatives, iodonium donating systems, such as NIS-PTSA,10 I2-
DME,11 HIO4-Al2O3,12 I2-F-TEDA-BF4,13 NIS-Lewis acid14 have been
employed. These latter methods are useful for the introduction of
iodine into organic compounds, however, because of the high chem-
ical- and energy-consuming protocols for the production of the
reagents, these are low atom economy processes producing large
excesses of waste, representing just some of the limitations for their
use on industrial scale.
On the other hand, it is well known that in nature electrophilic
halogenations mainly occur by enzymatically supported oxidative
halogenation processes, in conjunction with vanadium, iron, or fla-
vin co-catalysis, using hydrogen peroxide (H2O2) or molecular oxy-
gen (O2) as natural oxidants for the transformation of inactive
iodide into the active iodonium species necessary for car-
bonAiodine bond formation.15
In spite of some well-known drawbacks of hydrogen peroxide
and its variants, such as high cost and its undesirable decomposi-
tion into H2O and ½O2 during reactions influenced by higher tem-
peratures and/or impurities and traces of metallic catalysts, which
are often used to activate it, OxoneÒ16 and urea–H2O217 have been
successfully employed for aerobic oxidative iodination of organic
compounds. On the other hand, molecular oxygen, as the most
abundant oxidant, providing high atom economy for transforma-
tions of organic compounds is still an attractive and challenging
research subject from the viewpoint of green approaches to
organic synthesis and for industrial use. Transformations of organic
silyl ethers and acetals, one-step
a-iodination would be the most
preferred choice and has lately received much attention.
The standard sources, molecular iodine (I2) and the iodide anion
(IÀ), have often been used for the preparation of iodinated organic
compounds, but since I2 is often poorly reactive and the iodide anion
is a weak nucleophile, electrophilic iodination has long been recog-
nized as the most convenient approach for selective iodination.6
Generally, the direct conversion of methyl ketone derivatives into
a
-iodo compounds is usually achieved using I2-Ce(NO3)4,7
I2-HgCl2,8 and I2-SeO2,9 while in the last few years substantial
efforts have been directed toward the invention and development
⇑
Corresponding author. Tel.: +386 1 477 36 60; fax: +386 1 477 38 22.
E-mail address: stojan.stavber@ijs.si (S. Stavber).
http://dx.doi.org/10.1016/j.tetlet.2014.08.055
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

5644
R. Prebil, S. Stavber / Tetrahedron Letters 55 (2014) 5643–5647
Table 1
compounds using molecular oxygen usually need transition metal
catalysis to promote the reaction rate and selectivity to partial oxi-
dation products. For this purpose, organometallic complexes
[(NH4)2Ce(NO3)6,18 H5PV2Mo10O4019, and Bi(NO3)Á5H2O-BiCl320] or
nanoparticles21 are often used, while nitrites [NaNO2,22 NO2
gas23], nitrates [Mg(NO3)2,24 NH4NO325] or nitric acid (HNO3)26 as
transition metal-free catalysts for aerobic transformations of
organic compounds have recently been used. Nitrogen oxides
(NO/NO2), as highly oxidative species, also play an important role
as reactive compounds which are useful in several chemical27
and biological applications.28 Over the last two decades, many arti-
cles have reported efficient and selective iodinations of organic
compounds under aerobic oxidative conditions exploiting the
NO/NO2 oxidative catalytic redox cycle in combination with molec-
ular oxygen as the oxidant. For this purpose nitrites (NaNO2) in
combination with acids, as a good source of nitrogen oxides,29
were mainly used, while nitrate-based reaction systems were
researched less extensively, mostly for iodination of aromatic com-
pounds.30 To the best of our knowledge, no data are available on
Effect of temperature and amounts of added catalysts on the efficiency of the air/
NH4NO3(cat.)/I2/H2SO4(cat.) reaction system for the
a
-iodination of 1-(4-methoxy-
phenyl)ethanone (1b)a,b
O
CH3
O
CH2I
air, NH4NO3(cat.), I2, H2SO4(cat.)
MeCN, 24 h
H3CO
H3CO
1b
2b
.
Entry
NH4NO3 (mol %)
H2SO4 (mol %)
Temp (°C)
Conversionb (%)
1
2
3
4
5
6
20
20
20
20
10
20
10
20
10
20
5
20
20
40
40
60
60
45
65
67
88
92
95
10
a
Reaction conditions: 1-(4-methoxyphenyl)ethanone (1b) (1 mmol), NH4NO3
(10–20 mol %), I2 (50 mol %), H2SO4 (10–20 mol %), MeCN (2 mL), balloon filled with
1 L of air, 60 °C, 24 h.
b
Conversions of 1b into 2b were determined from the 1H NMR spectra of the
crude reaction mixtures.
the direct aerobic
a-iodination of aryl and alkyl methyl ketones
using molecular iodine activated by a full metal-free nitrate-based
reaction system.
(2 mL) was studied and 60 °C was found to be the best choice
(entry 6). Next, varying the amount of added catalyst NH4NO3 and
acid H2SO4 in MeCN (2 mL) at different temperatures was studied
(entries 2, 4, and 5), and after analysis of the 1H NMR spectra of
the crude reaction mixture, the optimal conditions were found
(Table 1, entries 5 and 6).
Control experiments highlighting the essential role of each
member of the described reaction system, that is, aerial oxygen,
NH4NO3 as the catalyst, and H2SO4 as the activator were per-
formed. All the control experiments gave negative results under
argon or under air. In the absence of any of the components of
the reaction system, 1-(4-methoxyphenyl)ethanone (1b) was not
In the context of our projects focusing on aerobic oxidative halo-
genation under environmentally friendly conditions,29 we now
report the discovery and development of a novel full metal-free
nitrate-based reaction system for the efficient and chemoselective
aerobic oxidative iodination of methyl ketone derivatives, alpha to
the carbonyl group and aromatic compounds, in high yields, using
ammonium nitrate (NH4NO3) as a cheap and readily accessible
source of nitrogen oxides (NO/NO2) under acidic conditions.
In our recently published paper we reported an efficient and
regioselective reaction system consisting of air/NH4NO3(cat.)
/
I
2(cat.)/HCl for the a-chlorination of aryl and alkyl methyl ketones
under aerobic oxidative conditions.31 The use of a catalytic amount
of molecular iodine enabled moderate to quantitative and regiose-
converted into
a-iodo derivative (2b). These data are summarized
in SI (Table S3).
lective
a
-chlorination, while using 50 mol % of I2 and HCl as the
Encouraged by these preliminary results, we applied the air/
NH4NO3(cat.)/I2/H2SO4(cat.) reaction system under the optimized
conditions for the a-iodination of a series of aryl and alkyl methyl
ketones. As can be seen from Table 2, a variety of aryl, heteroaryl,
and alkyl methyl ketones could be efficiently and selectively con-
catalyst, 2-iodo-1-(4-methoxyphenyl)ethanone 2b as the main
and 2-chloro-1-(4-methoxyphenyl)ethanone as the side product
were formed. Because of the increasing worldwide demand for
such iodomethyl ketone derivatives, synthesized in direct one-step
reactions under environmentally friendly conditions, optimization
of the air/NH4NO3(cat.)/I2/H+ reaction system for aerobic oxidative
iodination of methyl ketones has been undertaken.
Optimization studies were executed on a model compound,
1-(4-methoxyphenyl)ethanone (1b). The best acid to support the
process quantitatively was found to be H2SO4 (aqueous 96%
solution) [see Table S1 in Supporting information (SI)]. Hence the
air/NH4NO3(cat.)/I2/H2SO4(cat.) reaction system was studied further.
The use of organic solvents in chemical processes is one of the
most conflicting issues from the green chemistry point of view.32
Solvent losses are a major contributor to high E (environmental)
factors. In order to establish an environmentally friendly reaction
process, different solvents were tested. Unfortunately low to
moderate conversions were achieved for aerobic oxidative
iodination in cyclopentyl methyl ether, 2-methyltetrahydrofuran,
a mixture of MeCN and H2O, (4:1) and pure H2O. The highest
conversion was achieved, in the environmentally acceptable,
MeCN (see Table S2 in SI).
verted into their corresponding
a-iodo derivatives in high yields
in 1–25 h.33 In general, we found that electron-withdrawing and
electron-donating substituents on the phenyl ring supported the
transformation of substrates 1a–e into their iodomethyl deriva-
tives 2a–e efficiently and regioselectively (alpha to carbonyl posi-
tion). On the other hand, in the case of strongly activated aromatic
rings 1f and 1g, substituted with two or three methoxy substitu-
ents, regioselective iodination of only the aromatic ring occurred,
producing mono iodinated aromatic derivatives 2f and 2g. Next,
the efficiency and selectivity of the present reaction system was
examined on two additional aromatic methyl ketones, 1-(naphtha-
len-2-yl)ethanone (1h) and 1-(9H-fluoren-2-yl)ethanone (1i). After
1H NMR spectral analysis of the crude reaction mixtures, we found
that only a-iodination had occured, producing 2-iodo-1-(naphtha-
len-2-yl)ethanone (2h) and 1-(9H-fluoren-2-yl)-2-iodoethanone
(2i). 3,4-Dihydronaphthalen-1(2H)-one 1j was also iodinated alpha
to the carbonyl group in good yield.
The presence of functional groups bearing oxidizable or acid-sen-
sitive heteroatoms such as sulfur or nitrogen in the target molecules
could represent additional reaction centers for side reactions. As can
be seen from Table 2, we examined the efficiency and selectivity of
the air/NH4NO3(cat.)/I2/H2SO4(cat.) reaction system for heteroaryl
methyl ketones in order to make the methodology more general.
1-(Thien-2-yl)ethanone (1k) was efficiently and selectively
converted into the corresponding iodomethyl ketone derivative
2k. Nitrogen-containing 1-(1H-pyrrol-2-yl)ethanone (1l) and 1-(1-
We also wanted to optimize the reaction system
(air/NH4NO3(cat.)/I2/H2SO4(cat.)
quantitative conversion of the model compound into the desired
-iodinated product in MeCN. Different parameters such as the
) further in order to achieve
a
reaction temperature and amount of added catalyst were investi-
gated (Table 1). Firstly, the efficiency of the reaction system at
different reaction temperatures (20, 40, and 60 °C) using NH4NO3
(20 mol %) and H2SO4 (10 mol %) (aqueous 96% solution) in solvent

R. Prebil, S. Stavber / Tetrahedron Letters 55 (2014) 5643–5647
5645
Table 2
different alkyl and cycloalkyl methyl ketones. We found that for
successful transformation of the starting substrate into the desired
product, slightly higher amounts of the catalyst (NH4NO3) and acid
(H2SO4) were needed in order to obtain high yields. Firstly, nonan-
5-one (1p) and nonan-2-one (1r) were tested. Iodination of 1p
occurred efficiently and regioselectively alpha to the carbonyl
group, while in the case of 1r, a mixture of 3-iodononan-2-one
(2r-1) and 1-iodononan-2-one (2r-2) was isolated in the ratio
1.6:1. The regioselectivity of the reaction system was further
studied on 4-methylpentan-2-one (1s) and again a mixture of
two products was obtained, 1-iodo-4-methylpentan-2-one (2s-1)
and 3-iodo-4-methylpentan-2-one (2s-2) in a 3:1 ratio. Also,
1-acetyladamantane (1t), a common structural type in pharmaceu-
Aerobic oxidative a-iodination of aryl, heteroaryl, and alkyl methyl ketones using the
air/NH4NO3(cat.)/I2/H2SO4(cat.) reaction systema,b,c,d
O
R1
1a-u
air, NH4NO3(cat.), I2, H2SO4(cat.)
MeCN, 60 °C
O
R1 CH2I
CH3
2a-u
O
O
O
CH2I
CH2I
CH2I
H3CO
F
2a, (24 h, 75%, 67%) 2b, (24 h, 96%, 85%) 2c, (23 h, 94%, 87%)
O
O
O
CH3
OCH3
CH2I
I
CH2I
HO
tical compounds, was efficiently and selectively
to 75% yield. As a representative of cycloalkyl methyl ketones,
4-tert-butylcyclohexanone was successfully converted into
a-iodinated in up
O2N
H3CO
OCH3
2d, (24 h, 93%, 85%) 2e, (25 h, 72%, 67%) 2f, (6 h, 100%, 85%)
a
O
CH3
OCH3
mixture of trans-2-iodo-4-tert-butylcyclohexanone (2u-1) and
cis-2-iodo-4-tert-butylcyclohexanone (2u-2) in a 1.4:1 ratio.
After selective ring iodination of polysubstituted aryl methyl
ketones 2f and 2g (see Table 2) using air/NH4NO3(cat.)/I2/H2SO4(cat.)
in acetonitrile, we extended the range of tested poly alkyl and alk-
oxy group substituted aromatics 3a–c. As is evident from the
results collected in Table 3, quantitative conversions were
achieved for all the tested substrates. In the case of anisole (3a),
iodination occurred selectively only at the para position and 1-
iodo-4-methoxybenzene (4a) was isolated in up to 95% yield.
1-Iodo-2,4-dimethoxybenzene (4b), and 2-iodo-1,3,5-trimethyl-
benzene (4c) were also obtained in good yields.
O
O
H3CO
I
CH2I
CH2I
OCH3
2g, (1.5 h, 100%, 92%) 2h, (25 h, 100%, 90%) 2i, (20 h, 78%, 55%)
H
O
O
O
N
I
S
CH3
CH2I
I
2j, (18 h, 83%, 74%) 2k, (18 h, 75%, 68%) 2l, (1 h, 100%, 98%)
CH3
N
O
O
O
O
O
O
CH2I
CH2I
CH3
We additionally checked the practical applicability of our new
procedure for large scale use.35 Thus we treated 3 g (20 mmol) of
1-(4-methoxyphenyl)ethanone (1b) in MeCN (50 mL) with NH4-
NO3 (20 mol %, 320 mg), I2 (50 mol %, 2.54 g) and H2SO4 (aqueous
O
I
2m, (1 h, 100%, 98%) 2n, (23h, 97%, 82%) 2o, (23 h, 67%, 58%)
O
O
O
+
96% solution, 10 mol %, 222.7 lL) in a 100 mL glass reactor
CH2I
2r-1
I
I
2r-2
equipped with a glass condenser open to the air at 60 °C. After
25 h, the reaction was complete; a white solid was filtered off
and identified as ammonium sulfate. The solvent was distilled off
under reduced pressure, and the crude reaction mixture was
extracted with ethyl acetate (3 Â 10 mL) and analyzed by 1H
NMR spectroscopy. Spectroscopic data of the crude reaction mix-
ture showed 100% iodination of the starting substrate alpha to
the carbonyl group, and 2-iodo-1-(4-methoxyphenyl)ethanone
(2b) was isolated without the need for further purification.
Oxidative iodination29b–d and bromination22e of organic
compounds catalyzed with nitrogen oxides (NO/NO2) using air as
2p, (7h, 94%, 58%)
2r-1 and 2r-2, (7 h, 91%, 88% of a mixture
in the 1.6:1 ratio)
O
CH2I
O
O
+
CH3
2s-2
CH2I
I
2s-1
2s-1 and 2s-2, (3 h, 100%, 80% of a mixture 2t, (7 h, 93%, 75%)
in the 3:1 ratio)
O
O
+
I
I
-Bu
-Bu
t
t
2u-1
2u-2
2u-1and 2u-2, (4 h, 100%, 85% of a mixture
in the 1.4:1 ratio)
a
Reaction conditions: substrate (1 mmol), NH4NO3 (10–25 mol %), I2 (50 mol %),
H2SO4 (5–12.5 mol %), MeCN (2 mL), balloon filled with 1 L of air, 60 °C, 1–25 h;
Table 3
exact reaction conditions for each product are given in SI.
Aerobic oxidative iodination of activated aromatic compounds using air/NH4NO3(cat.)
/
b
Conversions were determined from the 1H NMR spectra of the crude reaction
I2/H2SO4(cat.) in MeCNa,b,c,d
mixtures.
c
Yields were determined from the 1H NMR spectra after purification of the crude
I
reaction mixtures by column or preparative chromatography.
air, NH4NO3(cat.), I2, H2SO4(cat.)
d
Values in brackets: (reaction time, conversion, yield).
R
R
MeCN, 60 °C
3a-c
4a-c
methyl-1H-pyrrol-2-yl)ethanone (1m) underwent 100%
regioselective iodination of the aromatic ring at position 4, thus pro-
ducing 1-(4-iodo-1H-pyrrol-2-yl)ethanone (2l) and 1-(4-iodo-1-
methyl-1H-pyrrol-2-yl)ethanone (2m) in yields of 98%. The oxy-
gen-containing heterocyclic methyl ketone derivative 1-(2,3-dihy-
drobenzo[b] [1,4]dioxin-6-yl)ethanone (1n) was efficiently
converted into the corresponding iodomethyl derivative 2n.
Acetyl-substituted coumarins often possess bioactivity of pharma-
ceutical interest,34 and we thus chose 3-acetyl-2H-chromen-2-one
(1o) as a substrate, which underwent selective conversion into 3-
(2-iodoacetyl)-2H-chromen-2-one 2o in moderate yield.
CH3
OCH3
OCH3
I
I
I
H3C
CH3
OCH3
4a, (2 h, 100%, 95%) 4b, (20 min, 100%, 96%) 4c, (10min, 100%, 98%)
a
Reaction conditions: substrate (1 mmol), NH4NO3 (20 mol %), I2 (50 mol %),
H2SO4 (aqueous 96% solution, 10 mol %), balloon filled with 1 L of air, 60 °C, 10–
120 min; exact reaction conditions for each product are given in SI.
Conversions were determined from the 1H NMR spectra of the crude reaction
b
mixtures.
Yields were determined from the 1H NMR spectra after purification of the crude
c
reaction mixtures by column or preparative chromatography.
The reactivity, efficiency, and regioselectivity of the air/NH4
NO3(cat.)/I2/H2SO4(cat.) reaction system was further examined, using
d
Values in brackets: (reaction time, conversion, yield).

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NH4NO3 + H2SO4
4HNO3
HNO3 + (NH4)2SO4 (1)
4NO2 + 2H2O + O2
(2)
Air
H2O
1/2 I2
(O2)
I2
A
HI
S-H
S-I
NO
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.
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to NO when it completes the oxidation of iodide, while the oxida-
tion of NO to NO2 is a process accomplished with the aerial oxygen.
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In conclusion, we have developed
NH4NO3(cat.)/I2/H2SO4(cat.) reaction system for the efficient and
selective -iodination of aryl, heteroaryl, alkyl, and cycloalkyl
a four-component air/
a
methyl ketones, while in the case of strongly activated aryl methyl
ketones, regioselective iodination on the aromatic ring was
observed. In addition, efficient and selective iodination of activated
aromatic compounds was achieved and will be elaborated in more
detail along with an increased variety of substrates. It was shown
that each member of the reaction system had an essential role.
The use of NH4NO3 as a simple, inexpensive, and metal-free
catalyst is possible in open-air instead of higher-pressure
oxygen-conditions (autoclave or balloon technique). The generation
of minimum amounts of waste and the possibility of process
scale-up, including recovery of some possible hazardous solvents
and the reactants, make the methodology useful and interesting
from both environmental and economic points of view.
27. Wertz, S.; Studer, A. Green Chem. 2013, 15, 3116.
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Biological Applications, Wiley-VCH: Weinheim, 2005.
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Iskra, J.; Stavber, S.; Zupan, M. Tetrahedron Lett. 2008, 49, 893; (c) Stavber, G.;
Iskra, J.; Zupan, M.; Stavber, S. Green Chem. 2009, 11, 1262; (d) Stavber, G.;
Iskra, J.; Zupan, M.; Stavber, S. Adv. Synth. Catal. 2008, 350, 2921.
30. (a) Filimonov, V. D.; Kulmanakova, Y. Y.; Yusubov, M. S.; Perederina, I. A.; Chi, K.
W.; Poleshchuk, O. K. Russ. J. Org. Chem. 2004, 40, 917; (b) Dorfman, Y. A.;
Aleshkova, M. M. Russ. J. Org. Chem. 1997, 33, 1585; (c) Yusubov, M. S.;
Perederina, I. A.; Filimonov, V. D.; Jin, H. W.; Chi, K. W. Russ. J. Org. Chem. 1999,
35, 1191; (d) Radner, F. Acta Chem. Scand. 1989, 43, 902; (e) Radner, F. J. Org.
Chem. 1988, 53, 3548.
Acknowledgments
31. Prebil, R.; Stavber, S. Adv. Synth. Catal. 2014, 356, 1266.
32. Sheldon, R. A. Chem. Soc. Rev. 2012, 41, 1437.
We are grateful to the staff of the National NMR Centre at the
National Institute of Chemistry, Ljubljana, Slovenia. The authors
are also grateful to the Slovenian Research Agency (contracts:
Programme ARRS P1-0134 and Young Researchers Fellowship
ARRS1000-08-310039), and CIPKeBiB [European Regional
Development Fund (OP 13.1.1.02.0005)].
33. General procedure for the aerobic oxidative iodination of methyl ketones and
aromatic compounds: A 10 mL glass flask equipped with a magnetic stir bar was
charged with a methyl ketone (1 mmol) and dissolved in MeCN (2 mL). To the
thermostated solution NH4NO3 (10–25 mol %), I2 (50 mol %) and H2SO4
(aqueous 96% solution, 10–20 mol %) were added and the flask was further
equipped with a balloon filled with air (1 L) and magnetically stirred at 60 °C.
The consumption of starting material was monitored by TLC. After completion
of the reaction, the mixture was cooled to room temperature, diluted with
EtOAc (10 mL), and insoluble material identified as ammonium sulfate was
filtered off. The filtrate neutralized with NaHCO3 (aqueous 10% solution, 2 mL)
and Na2S2O3 (aqueous 10% solution, 2 mL) and phase was separated. The water
phase was washed with EtOAc additionally two times (2 Â 5 mL). The combined
organic phase was dried over anhydrous Na2SO4 and the solvent distilled under
reduced pressure. The crude product obtained was analyzed by 1H NMR. Finally
the crude product was purified using column chromatography (SiO2, n-hexane/
CH2Cl2 elution) and preparative thin layer chromatography to afford pure
material, which was compared to authentic samples. Detailed data, concerning
catalyst loading, reaction times, yields of pure products and their spectroscopic
and other identification data are given in SI in the chapter Characterization data
of isolated final products. Characterization, for example, 1-(9H-fluoren-2-yl)-2-
iodoethanone (2i): 1-(9H-Fluoren-2-yl)ethanone (1 mmol, 208.3 mg), NH4NO3
(0.15 mmol, 12 mg), I2 (0.50 mmol, 126.7 mg), H2SO4 (aqueous 96% solution,
Supplementary data
Supplementary data (full experimental details and characteriza-
tion data for all products can be found in the supplementary data)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.08.055.
References and notes
1. (a) Erian, A. W.; Sherif, S. M.; Gaber, H. M. The Chemistry of
a-Haloketones,
a
-Haloaldehydes and -Haloimines; John Wiley and Sons: Chichester, 1988;
a
(b) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002,
102, 1359; (c) Diederich, F.; Stang, P. J. Metal-Catalysed Cross-Coupling Reactions;
0.10 mmol, 5.56 lL), 2 mL MeCN, balloon filled with 1 L of air, 60 °C, 20 h were

R. Prebil, S. Stavber / Tetrahedron Letters 55 (2014) 5643–5647
35. Scale-up procedure for the aerobic oxidative
5647
used; crystallization from acetone; yield: 187.2 mg (55%) yellow solid, mp 163–
164 °C. 1H NMR (303 MHz, CDCl3+two drops of DMSO, 25 °C, TMS): d (ppm) 3.92 (s,
2H), 4.41 (s, 2H), 7.32–7.44 (m, 2H), 7.54–7.59 (m, 1H), 7.77–7.84 (m, 2H), 7.96–8.02
(m, 1H), 8.13 (s, 1H); 13C NMR (76.2 MHz, CDCl3+two drops of DMSO, 25 °C): d
(ppm) 2.3, 36.6, 119.6, 120.7, 125.0, 125.3, 126.9, 128.1, 128.1, 131.5, 139.9, 143.2,
144.3, 146.8, 192.4; MS (ESI): m/z 335 ((M+H)+, 100%); HR-MS (ESI): m/z = 334.9925,
calcd for C15H12IO: 334.9933; Anal. calcd for C15H11IO: C, 53.92; H, 3.32; found: C,
54.39; H, 3.05. 3-(2-Iodoacetyl)-2H-chromen-2-one (2o): 3-Acetyl-2H-chromen-2-
one (1 mmol, 188.2 mg), NH4NO3 (0.20 mmol, 16 mg), I2 (0.50 mmol, 126.7 mg),
a
-iodination of 1-(4-
methoxyphenyl)ethanone: A 100 mL glass reactor equipped with a magnetic
stir bar was charged with 1-(4-methoxyphenyl)ethanone (20 mmol, 3 g) and
dissolved in MeCN (50 mL). To a thermostated solution (thermostated for
30 min at 60 °C), NH4NO3 (10–25 mol %), I2 (50 mol %) and H2SO4 (aqueous 96%
solution, 10–20 mol %) were added in 2 min intervals and the reactor equipped
with
a condenser open to the air. The mixture was magnetically stirred
(500 rpm) at 60 °C for 25 h. The consumption of starting material was
monitored by TLC. After completion of the reaction, the mixture was cooled
to room temperature and insoluble material identified as ammonium sulfate
was filtered off and washed with fresh MeCN. After evaporation of the filtrate,
the mixture was dissolved in fresh EtOAc, quantitatively transferred into a
separation funnel and the organic phase neutralized with NaHCO3 (aqueous
10% solution, 5 mL), Na2S2O3 (aqueous 10% solution, 5 mL) and the solvent
distilled under reduced pressure. The water phase was washed with EtOAc
additionally two times (2 Â 10 mL). The combined organic phase was dried
over anhydrous Na2SO4 and the solvent distilled under reduced pressure. The
crude product obtained was analyzed by 1H NMR.
H2SO4 (aqueous 96% solution, 0.1 mmol, 5.56 lL), 2 mL MeCN, balloon filled with 1 L
of air, 60 °C, 23 h were used; column chromatography (SiO2, CH2Cl2); yield:
182.2 mg (58%), yellow solid; mp 135–138 °C. 1H NMR (303.0 MHz, CDCl3, 25 °C,
TMS): d (ppm) 4.68 (s, 2H), 7.34–7.46 (m, 2H), 7.64–7.76 (m, 2H), 8.66 (s, 1H); 13
C
NMR (76.2 MHz, CDCl3, 25 °C): d (ppm) 6.8, 116.7, 118.1, 121.4, 125.1, 130.2, 134.9,
149.5, 155.3, 158.6, 190.1; MS (ESI): m/z 314.9 ((M+H)+, 100%); HR-MS (ESI): m/
z = 314.9523, calcd for C11H8IO3: 314.9518.
34. Mohamed, H. M.; Abd El-Wahab, A. H. F.; El-Agrody, A. M.; Bedair, A. H.; Eid, F.
A.; Khafagy, M. M.; Abd-El-Rehem, K. A. Beilstein J. Org. Chem. 2011, 7, 1688.