Tetrahedron Letters 52 (2011) 6554–6559

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Tetrahedron Letters
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Oxidative iodination of carbonyl compounds using ammonium iodide and

oxoneÒ
Marri Mahender Reddy, Macharla Arun Kumar, Peraka Swamy, Nama Narender ⇑
I&PC Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India

a r t i c l e i n f o a b s t r a c t

Article history: A simple, efficient, mild, and regioselective method for oxyiodination of carbonyl compounds has been
Received 29 August 2011 reported by using NH4I as the source of iodine and OxoneÒ as an oxidant. Various carbonyl compounds
Revised 20 September 2011 such as aralkyl ketones, aliphatic ketones (acyclic and cyclic), and b-keto esters proceeded to the respec-
Accepted 22 September 2011
tive a-monoiodinated products in moderate to excellent yields. Unsymmetrical aliphatic ketones reacted
Available online 29 September 2011
smoothly yielding a mixture of 1-iodo and 3-iodo ketones with the predominant formation of 1-
iodoproduct.
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
a-Iodination
Aralkyl ketones
b-Keto esters
Regioselectivity

The chemistry dealing with selective introduction of an iodine O2–H2SO413, NIS–PTSA14, I2–TMOF15, NIS–ionic liquids16, I2–CuO17,
atom into organic molecules has attracted considerable interest I2–urea–H2O218, I2–DME19, HIO4–Al2O320, HTIB–MgI2–MW21,
in the wider scientific community,1 due to the importance of I2–selectfluor™F–TEDA–BF422, and NIS–Lewis acid.23 However,
iodo-substituted organic compounds as valuable synthones or pre- most of these methods have drawbacks, such as use of expensive,
cursors in organic synthesis and in carbon–carbon, carbon–oxygen, hazardous or toxic reagents, tedious work-up procedures, and high
and carbon–nitrogen bond formation.2 Moreover, iodinated com- reaction temperatures for long reaction times. Therefore, the
pounds are widely used in medical diagnostics as contrast agents development of an efficient, environmentally friendly, atom eco-
or radioactively labeled markers.3 a-Iodo ketones are among the nomic (100% with respect to iodine), and selective procedure for
most versatile intermediates in organic synthesis and their high the a-monoiodination of ketones is still desirable. Most methods
reactivity makes them available to react with a large number of for transforming carbonyl compounds to their related a-iodo
nucleophiles to provide a variety of useful compounds.4 Therefore, derivatives rely on the modification of molecular iodine or N-iodo-
a-iodo ketones and their application as reactive intermediates succinimide while the use of other reagents has been less
have attracted considerable attention in various organic transfor- investigated.
mations. a-Iodo ketones are usually prepared indirectly by oxida- OxoneÒ, a potassium triple salt containing potassium peroxy
tive-iodination of olefins5, electrophilic iodination of ketone monosulfate, is an effective oxidant. Due to its stability, water-sol-
derivatives (enol ethers, and acetates)6 or by halogen interchange ubility, ease of transport, nontoxic ‘green’ nature, nonpolluting
of bromo compounds with sodium iodide.7 Due to the difficulties byproducts, and cost-effectiveness, this solid reagent has become
in the synthesis and purification of enol silyl ethers and acetals, di- an increasingly popular reagent for oxidative transformations.24–28
rect conversion of carbonyl compounds into a-iodo compounds In our on-going efforts to achieve environmentally friendlier
has received considerable attention. halogenation procedures, earlier we have reported a method for
Generally, the direct conversion of carbonyl compounds into a- the ring iodination of aromatic compounds using NH4I–OxoneÒ
iodo compounds is commonly achieved using iodine–cerium (IV) system.29 Now, we wish to explore this reagent system for the a-
ammonium nitrate,8 iodine–mercury (II) chloride9, and iodine– iodination of carbonyl compounds. Herewith, we report a milder,
selenium dioxide.10 In recent years a wide variety of methods have efficient, and environmentally benign procedure for the a-iodin-
been developed for the direct a-iodination of carbonyl compounds ation of carbonyl compounds using NH4I and OxoneÒ at room tem-
using different iodonium donating systems, such as, I2-m-iodosyl- perature/reflux temperature without the use of catalyst and as a
benzoic acid11, I2–NaNO2–O2–silica supported H2SO412, KI–NaNO2– possible alternative to overcome the disadvantages described in
the earlier methods (Scheme 1). However, to the best of our knowl-
edge, method for a-iodination of carbonyl compounds using NH4I/
⇑ Corresponding author. Tel.: +91 40 27191703; fax: +91 40 27160387/757.
OxoneÒ system has been unprecedented to date.
E-mail address: [email protected] (N. Narender).

0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.106
 M. M. Reddy et al. / Tetrahedron Letters 52 (2011) 6554–6559 6555

O O We first investigated the effect of different solvents on the

NH4I, Oxone®
R1 iodination of acetophenone using NH4I as iodine source and Ox-
R1
R MeOH, rt / reflux R oneÒ as an oxidant. The best results were obtained when methanol
I was used as a solvent compared to others (DCM, CHCl3, CCl4, EtOH,
R = Alkyl / Aryl
R1 = H / Alkyl / Aryl i-PrOH, t-BuOH, hexane, and THF).
To assess the generality of this method, a variety of ketones
Scheme 1. a-Iodination of ketones. (aralkyl, alkyl, cyclic ketones, and b-keto esters) were investigated

Table 1
Iodination of aralkyl ketones using NH4I and OxoneÒa

Entry Substrate Time (h) Product Yieldb (%)

O O
1 24 c I 86 (4)e
2.3d 92 (6)e

O O
2 48c I 79 (8)e
3d 92 (5)e

O O
46 c I 84 (7)e
3 2.45d 86 (4)e

O O
c I
4 48 81 (9)e
3.3d 92 (5)e

O O
48c I 79 (6)e
5
4d 86 (9)e
Et Et
O O
c
24 52 (26)f
6 2.3d 47 (35)f
OH OH
I
O O
47c I -
7 3.3d 72 (15)g

OH OH
O O
22 c I 71 (6)e (14)h
8
2d 83 (4)e (8)h
MeO MeO
O O
49c I 46
9
8.3d 79 (4)e
Br Br
O O
48c I 81 (2)e
10 8d 93 (4)e

Br Br
O O
48c I 70 (4)e
11
5.3d 86 (4)e
Br Br
O O
48c I 55
12
6.3d 80 (2)e
Cl Cl
(continued on next page)
6556 M. M. Reddy et al. / Tetrahedron Letters 52 (2011) 6554–6559

Table 1 (continued)

Entry Substrate Time (h) Product Yieldb (%)

O O
48c I 68
13 92 (2)e

6d
Cl Cl
O O
48 c I 70 (3)e
14
8d 92 (5)e
F F
O O
48c I 68 (5)e
15 7d 97 (2)e

F F
O O
48c I 74 (4)e
16
4d 92 (5)e
F F
O O
48 c I 52
17
9.3d 92 (3)e
NC NC
O O
48c I 26
18 10d 81

NO2 NO2
O O
48c I 35
19
10d 72
O2N O2N
O O
c
20 48 35
10d 90 (8)e
I
O O
21
Ph 48c
Ph 19
10d 94
OMe
O O
22 Ph 48c Ph -
11d 74
I
O O
I 74 (4)e
23 48c
9d 91 (3)e

O O
84 (2)e
24 48 c I
4d 91 (5)e

O O
80 (4)e
25 11c
I
3.3d 86 (5)e

O 48c O 84 (3)e
2.3d 84 (4)e
I
26
 M. M. Reddy et al. / Tetrahedron Letters 52 (2011) 6554–6559 6557

Table 1 (continued)

Entry Substrate Time (h) Product Yieldb (%)

O O
48c
I 65 (3)e
27 2d 89 (2)e

OMe OMe
O O
22 c I 93 (4)e
28 2d 92 (3)e

O O
OH 3.3c OH 81
29 1d 92
I
O O
a
Reagents conditions: substrate (2 mmol), NH4I (2.2 mmol), OxoneÒ (2.2 mmol), MeOH (10 ml).
b
Products were characterized by 1H NMR, Mass spectra, and quantified by GC.
c
Room temperature.
d
Reflux temperature.
e
a-Methoxy product.
f
1-(2-Hydroxy-5-iodophenyl)ethanone.
g
1-(3-Hydroxy-4-iodophenyl)-2-iodoethanone.
h
2-Iodo-1-(3-iodo-4-methoxyphenyl)ethanone.

for the reaction with NH4I-OxoneÒ reagent system and the results Table 2
are summarized in Tables 1 and 2. All the substrates treated with Iodination of aliphatic ketones and b-keto esters using NH4I and OxoneÒa
1.1 equiv of NH4I and 1.1 equiv of OxoneÒ in methanol at room
Entry Substrate Time Product Yieldb
temperature (or reflux temperature) afforded the corresponding (h) (%)
iodinated compounds in good to excellent yields.30 High yields
O O
were obtained in short reaction time at a reflux temperature.
1 48 I 52
The iodination of a variety of aralkyl ketones proceeded effi-
ciently, to afford the corresponding a-iodo ketones in moderate
to excellent yields (Table 1). The reactivity profile of the substi- O O
I
tuted acetophenones is noteworthy. Acetophenone produced the 2 23 69
corresponding a-iodoproduct in high yields (Table 1, entry 1).
Moderately activating (Table 1, entries 2–5) and deactivating O O
3 11 61 (28)c
(Table 1, entries 9–16) groups present on the aromatic ring of ace- I
tophenone gave moderate to high yields of the corresponding a- O O
4 13 76 (15)c
iodo products, along with small amount of a-methoxy substituted I
product. The position of substitution on the phenyl ring of aceto- O O
5 24 I 55 (17)c
phenone slightly affects the reaction yield (Table 1, entries 9–13).
A moderate yield was obtained when 2-bromo acetophenone
was used (Table 1, entry 9), while high yield of desired product O O O O
was obtained when 3-bromoacetophenone was used (Table 1, en- O 64 (16)d
IO
6 28
try 10). Introduction of highly deactivating groups (NO2, CN) on the
aromatic ring of acetophenone furnished less yields of the desired O O O O
product under the similar reaction conditions (Table 1, entries O
7 2 IO 28 (55)d
17–19).
Highly activating groups (OCH3, OH) present on the aromatic
ring of acetophenone gave very interesting results (Table 1, entries
a
6–8). Aralkyl ketones having an activated aromatic ring possess at Reagents conditions: substrate (2 mmol), NH4I (2.2 mmol), OxoneÒ (2.2 mmol),
MeOH (10 ml), room temperature.
least two reactive sites convenient for electrophilic functionality, b
Products were characterized by 1H NMR, mass spectra, and quantified by GC.
the aromatic ring and the atom alpha to the carbonyl functionality. c
3-Iodo ketones.
A distinct difference of regioselectivity was observed with 2- and 3- d
a-Hydroxy-b-keto esters.
hydroxyacetophenones. In case of 2-hydroxyacetophenone the ring
was regioselectively iodinated and yielded 1-(2-hydroxy-3-iodo-
phenyl)ethanone and 1-(2-hydroxy-5-iodophenyl)ethanone in a-iodinated product in 71% yield, accompanied by a significant
52%, 26%, and 47%, 35% yields, respectively at room temperature amount of respective diiodoproduct (2-iodo-1-(3-iodo-4-methoxy-
and reflux temperature. Whereas 3-hydroxyacetophenone was phenyl)ethanone) (14%yield) and small amount of a-methoxysub-
converted to the respective a-iodinated product and diiodoproduct stituted product. Propiophenone yielded the corresponding a-
(1-(3-hydroxy-4-iodophenyl)-2-iodoethanone) in 72%, 15% yield, iodinated product in moderate yield at room temperature and high
respectively. When 4-methoxyacetophenone subjected to yield at reflux temperature (Table 1, entry 20). Interestingly, 1,2-
iodination under similar conditions provided the corresponding diphenylethanone forms the solvolytic product (1,2-diphenyl-2-
6558 M. M. Reddy et al. / Tetrahedron Letters 52 (2011) 6554–6559

HSO5- + I- HO- I+ + SO42- In conclusion, we have developed an efficient new protocol for
the selective a-monoiodination of the carbonyl compounds using
NH4I and OxoneÒ without metal or mineral acid catalyst. Various
H ketones and b-keto esters can be iodinated by this reagent system
OH +
HO
O under mild conditions affording the corresponding a-iodo prod-
I ucts in moderate to high yields. The present method, which is more
R
HO- I+ R attractive than the existing methods, offers several advantages,
such as commercial availability of the reagents, simple reaction
conditions, no evolution of hydrogen iodide, high yields, economi-
- H2O cal process with easier setup/work-up procedures, and environ-
mentally friendly nature making our method more valuable from
preparative point of view.

O Acknowledgments
O
I
R M.M.R. and M.A.K. acknowledge the financial support from
R
CSIR, India in the form of fellowships. P.S. acknowledges the finan-
Scheme 2. Plausible reaction mechanism. cial support from UGC, India in the form of fellowship.

Supplementary data
methoxyethanone) instead of the expected a-iodinated product
(1,2-diphenyl-2-iodoethanone) in low yield at room temperature Supplementary data associated with this article can be found, in
and excellent yield at reflux temperature (Table 1, entry 21). Fur- the online version, at doi:10.1016/j.tetlet.2011.09.106.
thermore, 1- and 2-acetonaphthones also led to the respective a-
iodinated products in excellent yields (Table 1, entries 23 and 24). References and notes
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 M. M. Reddy et al. / Tetrahedron Letters 52 (2011) 6554–6559 6559

26. Gomzalez-Nunez, M. E.; Mello, R.; Olmos, A.; Asensio, G. J. Org. Chem. 2006, 71, reaction mixture was filtered and the solvent was removed under reduced
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8015–8018. column chromatography using silica gel (230–400 mesh) gave the target
30. General procedure for the iodination of carbonyl compounds: OxoneÒ products. All the products were identified by their 1H NMR, 13C NMR and mass
(2.2 mmol) was slowly added to a well stirred solution of NH4I (2.2 mmol) spectra.
and carbonyl compound (2 mmol) in methanol and the reaction mixture was 31. Kobayashi, K.; Uneda, T.; Kawakita, M.; Morikawa, O.; Konishi, H. Tetrahedron
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