Highly efficient and clean method for direct α-iodination of aromatic ketones

Article abstract of DOI:10.1055/s-2007-983880

Under neutral reaction conditions, aromatic ketones were transformed into the corresponding α-iodo ketones in high yields by the combination of copper(II) oxide and iodine. The reaction mechanism showed that copper(II) oxide played multiple roles through random self-sorting. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983880

PAPER
3113
Highly Efficient and Clean Method for Direct a-Iodination of Aromatic
Ketones
D
a
irec
t
a-
Iodination
u
of Aromatic
o
Ketones dong Yin,a Meng Gao,a Nengfang She,a Shengli Hu,a Anxin Wu,*a Yuanjiang Pan*b
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, Central China Normal University,
Wuhan 430079, P. R. of China
E-mail: chwuax@mail.ccnu.edu.cn
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
E-mail: panyuanjiang@zju.edu.cn
b
Received 13 June 2007; revised 17 July 2007
study, p-methoxyacetophenone (1a) was chosen as a mod-
el substrate to find the optimal conditions (Table 1). Since
Stavber and co-workers reported that the solvent played
an important role in the direct iodination of alkyl aryl ke-
tones, and that even the regiochemistry of the iodination
process could be regulated merely by the solvent,12d we
first investigated the effect of different solvents, as well as
the reaction temperature, on the conversion of p-methoxy-
acetophenone (1a) into the corresponding a-iodo ketone
1b (Table 1).
Abstract: Under neutral reaction conditions, aromatic ketones
were transformed into the corresponding a-iodo ketones in high
yields by the combination of copper(II) oxide and iodine. The reac-
tion mechanism showed that copper(II) oxide played multiple roles
through random self-sorting.
Key words: aromatic ketones, iodine, a-iodo ketones, multifunc-
tional reagent, self-sorting
a-Iodo ketones are among the most versatile intermedi-
ates in organic synthesis and their high reactivity makes
them available to react with a large number of nucleo-
philes to provide a variety of useful compounds.1 In addi-
tion, many iodoorganic compounds are biologically active
molecules, often used in medicine as drugs or diagnostic
aids, such as radioactively labeled markers or contrasting
agents, and therefore their related chemistry has attracted
broad interest.2 a-Iodo ketones are usually prepared from
olefins,3 ketones derivatives4 (enol silyl ethers and ace-
tates), or by halogen interchange of bromo compounds
with sodium iodide.5 Due to the difficulties in the synthe-
sis and purification of enol silyl ethers and acetates, a
number of methods for direct a-iodination of ketones with
different iodonium-donating systems have been reported
more recently. Examples are KI/KIO3/H2SO4,6 NaI/H2O2/
H2SO4,7 I2/HgCl2,8 I2/AgNO3,9 I2/Cu(OAc)2/AcOH10 (the
method was limited to aliphatic ketones and enol silyl
ether), I2/CAN,11 I2/N–F reagent,12 SeO2/I2/AcOH,13 and
other systems.14–18 However, most of these systems have
drawbacks, such as cumbersome workup procedures,
acidic reaction conditions (formation of the acid in situ),
the use of expensive, complicated, or sensitive regents,
and the generation of hazardous waste. Therefore, the de-
velopment of an efficient, economic and environmentally
friendly method is still desirable.
As shown by the data collected in Table 1, methanol was
found to be a suitable solvent for performing the conver-
sion (Table 1, entries 2 and 3), and this transformation
was also attempted in other solvents such as ethanol,
dichloromethane, tetrahydrofuran, acetonitrile, and
Ar
O
Ar
O
CuO, I2
MeOH
R
R
I
Scheme 1 Access to a-iodo ketones from the reaction of aromatic
ketones with iodine and copper(II) oxide in methanol
Table 1 Effect of Solvent and Temperature on the Iodination of
p-Methoxyacetophenonea
O
O
I
CuO, I2
MeO
MeO
1a
1b
Entry
Solvent
MeOH
MeOH
MeOH
EtOH
Temp (°C) Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
20
40
65
78
40
65
81
80
15
10
1
0
94
99
91
0
Herein we report an efficient method, based on our recent
work,19 for the synthesis of a-iodo ketones by reaction of
the corresponding aromatic ketones with copper(II) oxide
and iodine in methanol (Scheme 1). To the best of our
knowledge, this is a previously unreported method for
direct a-iodination of aromatic ketones. For the present
2
CH2Cl2
THF
8
8
0
MeCN
benzene
8
0
8
0
SYNTHESIS 2007, No. 20, pp 3113–3116
x
x.
x
x
.
2
0
0
7
Advanced online publication: 11.09.2007
DOI: 10.1055/s-2007-983880; Art ID: F09407SS
© Georg Thieme Verlag Stuttgart · New York
a Reagents and conditions: CuO (>98% powder, 1 equiv), I2 (1 equiv).
b Isolated yield.

3114
G. Yin et al.
PAPER
benzene. When ethanol was used as the solvent, 1b was into the corresponding a-iodo ketones 2b–18b were
also obtained, in 91% yield (Table 1, entry 4). However, examined (Table 2). Acetophenone and its derivatives
it was interesting to find that in the aprotic solvents no re- bearing electron-donating groups on the phenyl rings
actions occurred after eight hours (Table 1, entries 5–8).20 were readily transformed into the corresponding 1-aryl-
At room temperature (20 °C) in methanol, no reaction was substituted 2-iodoethanones in near-quantitative yields
observed either (Table 1, entry 1). If the reaction temper- (Table 2, entries 1–5). Even substrates 6a and 7a contain-
ature was elevated to 40 °C or 65 °C, the conversion ing a sensitive functional group (hydroxy) formed a-iodo
proceeded smoothly, although a longer reaction time was ketones 6b and 7b in 91% and 84% yield, respectively
required in the former case (Table 1, entries 2 and 3). (Table 2, entries 6 and 7). Substrates bearing electron-
Under optimized conditions, treatment of p-methoxy- withdrawing groups on the phenyl rings (8a–10a) gave
acetophenone (1a) with 1.0 molar equivalent iodine and slightly lower yields, and needed longer reaction times
1.0 molar equivalent finely powdered copper(II) oxide (Table 2, entries 8–10).
in methanol at reflux for one hour afforded the corre-
sponding a-monoiodo ketone 1b in 99% yield (Table 1,
entry 3).
a-Iodo ketone 11b, containing the strongly electron-with-
drawing nitro group on the phenyl ring, was obtained in
53% yield along with the dimethyl ketal product 11c in
To assess the generality of the method and to evaluate the 40% yield (Table 2, entry 11). Much to our satisfaction,
electronic influence of the aromatic ring substituents, the naphthyl and hetaryl methyl ketones also led to the corre-
transformations of various other aromatic ketones 2a–18a sponding products in excellent yields (Table 2, entries
12–16). The non-methyl ketone indan-1-one (17a) also
Table 2 Preparation of a-Iodo Ketones ArCOCH(R)I 1b–18b by
Reaction of Ketones ArCOCH2R with Copper(II) Oxide and Iodine in
yield (Table 2, entry 17). However, the expected a-iodo
Refluxing MeOH
gave the expected product 17b, which was isolated in 85%
ketone product 2-iodo-1,2-diphenylethanone (18b) of 1,2-
Product Time Yielda
diphenylethanone (18a) was easily converted into the sol-
volytic product 2-methoxy-1,2-diphenylethanone (18c)
(Table 2, entry 18). It was a pity to find that when
cyclohexanone was used as the substrate, the dimethyl
ketal 2-iodo-1,1-dimethoxycyclohexane was the major
product.4a,11a,21
Entry Ar
R
(h)
(%)
1
2
PMP
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
1b
2b
1
99
Ph
1
96
3
Tol
3b
1
95
A possible reaction mechanism is shown in Scheme 2.
Copper(II) oxide plays multiple roles in this reaction.
First, it acts as the oxidizing agent or catalyst to convert
molecular iodine into the reacting iodonium ion (I+) spe-
cies, analogous to the function of other copper salts re-
ported by Dalla Cort.4b In addition, copper(II) oxide could
act as a weak base to neutralize hydrogen iodide, and re-
oxidize iodide ion (I–) into molecular iodine (I2), which
forms together with insoluble copper(I) oxide and water.
4
4-EtOC6H4
1,3-benzodioxol-5-yl
4-HOC6H4
3-HOC6H4
4-PhC6H4
4-ClC6H4
4-BrC6H4
4-O2NC6H4
1-Naph
4b
1
87
5
5b
1
98 (7512c
91
)
6
6b
2
7
7b
2
84
8
8b
3
83
9
9b
5
83
10
11
12
13
14
15
16
10b
11b
12b
13b
14b
15b
16b
6
87
H
I
53b
92
OH
+
12
3
O
I
δ+ δ−
I
I
2-Naph
3
93
CuO
6-methoxy-2-naphthyl
2-furyl
2
98
– HI
1
93
I2 + CuI + H2O
2-thienyl
O
1
91
O
O
I
85 (69,13
17c
17b
18b
1
4
5515b
)
I
Scheme 2 A possible reaction mechanism
18
Ph
Ph
18d
a Isolated yield.
Support for this mechanism may be provided by the fol-
lowing experiments and phenomena: (a) That treatment of
1a with iodine in refluxing methanol without copper(II)
oxide did not afford the corresponding iodo ketone dem-
b The dimethyl ketal product 4-O2NC6H4C(OMe)2CH2I (11c) was
isolated in 40% yield.
c The drawn compound represents the product ArCOCH(R)I.
d The major product was PhCOCH(OMe)Ph (18c, 80%).
Synthesis 2007, No. 20, 3113–3116 © Thieme Stuttgart · New York

PAPER
Direct a-Iodination of Aromatic Ketones
3115
RCOCH3 + 1/2 CuO + 3/4 I2
ucts, and inexpensive reagents should make it a valuable
alternative to the existing methods.
RCOCH2I + 1/2 CuI + 1/2 H2O
Equation 1
Finely powdered CuO was purchased from commercial sources
(>98%). 1H and 13C NMR spectra were recorded on a Varian Mer-
cury 400 spectrometer operating at 400 and 100 MHz, respectively.
Chemical shifts are reported in ppm relative to the internal standard
of TMS. IR spectra of samples as KBr pellets were recorded on a
PE-983 spectrophotometer. MS was carried out on a Finnigan Trace
MS spectrometer or by the ESI method on a Quattro LCZ spectrom-
eter (Waters-Micromass, Manchester, UK) with a nanospray inlet.
Column chromatography was performed on silica gel (200–300
mesh).
Direct a-Iodination of Aromatic Ketones; General Procedure
Finely powdered CuO (0.40 g, 5.0 mmol) and I2 (1.27 g, 5.0 mmol)
were added to a well-stirred soln of the ketone (5.0 mmol) in anhyd
MeOH (20 mL). The mixture was stirred for 5 min and then re-
fluxed. After disappearance of the reactant (1–12 h, monitored by
TLC), the mixture was filtered and the solvent was removed under
reduced pressure. The residue was poured into 10% Na2S2O3 soln
(50 mL), the mixture was extracted with EtOAc (3 × 30 mL), and
the organic layer was dried (Na2SO4). Removal of the solvent and
purification of the residue by column chromatography or recrystal-
lization (cyclohexane) gave the target products.
Figure 1 1H NMR spectroscopic monitoring (400 MHz, CDCl3,
298 K) of the reaction of 1a with iodine in the presence of copper(II)
oxide. Reagents and conditions: (a) 1a, CDCl3; in all following cases:
1a (1 equiv), CuO (1 equiv), CDCl3, and (b) I2 (0.40 equiv), 59%; (c)
I2 (0.60 equiv), 79%; (d) I2 (0.75 equiv), 95%; (e) I2 (0.80 equiv),
>99%.
1-(4-Ethoxyphenyl)-2-iodoethanone (4b)
IR (KBr): 3298, 2980, 2935, 1657, 1600, 1422, 1259, 1177, 1097,
1035 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.46 (t, J = 7.2 Hz, 3 H), 4.12 (q,
J = 7.2 Hz, 2 H), 4.32 (s, 2 H, CH2I), 6.94 (d, J = 8.8 Hz, 2 H), 7.98
(d, J = 8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 1.7, 14.4, 63.7, 114.3, 126.0,
131.4, 163.4, 191.6.
onstrates the catalytic role of copper(II) oxide. (b) The
formation of insoluble copper(I) oxide was observed. (c)
To further confirm the reoxidation of iodide ion to molec-
ular iodine, we investigated the effect of the molar ratio of
iodine/substrate (1a) on the yield. In theory, if iodide ion
is reoxidized to molecular iodine, the reaction would be
completed when the amount of iodine equals 0.75 equiv-
alents of substrate (Equation 1). The yield was evaluated
by 1H NMR spectroscopy of the reaction mixture after 16
hours. It was found that when the amount of iodine was
less than 0.75 equivalents, reactant was left behind
(Figure 1, runs b and c). Product 1b was obtained in 95%
yield when the amount of iodine equaled 0.75 molar
equivalent of substrate (Figure 1, run d). When the
amount of iodine was continuously increased to 0.80
equivalents, 1b was obtained in near-quantitative yield
(>99%) (Figure 1, run e). This implies that iodide ion was
reoxidized to iodine during the reaction process, as other-
wise the amount of iodine would not be less than 1.00 mo-
lar equivalent of substrate.
ESI-MS: m/z (%) = 312.7 (100) [M + Na+].
1-(3-Hydroxyphenyl)-2-iodoethanone (7b)
IR (KBr): 3387, 1662, 1595, 1448, 1292, 1204 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.36 (s, 2 H), 5.85 (s, 1 H), 7.11–
7.13 (m, 1 H), 7.34–7.39 (m, 1 H), 7.52–7.56 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 1.8, 115.5, 121.5, 121.7, 130.1,
134.6, 156.4, 194.1.
MS (EI, 70 eV): m/z (%) = 262 (69), 127 (38), 121 (100), 107 (72).
1-Biphenyl-4-yl-2-iodoethanone (8b)15a
IR (KBr): 3430, 1679, 1599, 1174, 986, 760 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.39 (s, 2 H), 7.40–7.50 (m, 3 H),
7.62–7.72 (m, 4 H), 8.07 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 1.7, 127.2, 127.4, 128.4, 128.9,
129.6, 132.0, 139.5, 146.4, 192.3.
In conclusion, an efficient method for the direct synthesis
of a-iodo ketones by the combination of copper(II) oxide
and iodine was described. The reaction mechanism shows
copper(II) oxide acting as a multifunctional reagent by
random self-sorting. One part of copper(II) oxide serves
as a catalyst, and another part of copper(II) oxide can
serve as a base to consume the additional product hydro-
gen iodide in situ and to regenerate iodine. The advan-
tages of the present method in terms of high yields, short
reaction times, mild reaction conditions, neutral reaction
medium, ease of manipulation, formation of cleaner prod-
MS (EI, 70 eV): m/z (%) = 322 (90), 196 (23), 181 (93), 151 (100).
1-(2-Iodo-1,1-dimethoxyethyl)-4-nitrobenzene (11c)
IR (KBr): 2941, 1530, 1350, 1281, 1111, 1064, 1045 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.24 (s, 6 H), 3.49 (s, 2 H), 7.69
(d, J = 8.8 Hz, 2 H), 8.24 (d, J = 8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 9.6, 49.8, 100.5, 123.1, 128.5,
146.2, 147.8.
MS (EI, 70 eV): m/z (%) = 306, (8) [M – OCH3], 195 (100), 150
(74).
2-Iodo-1-(6-methoxy-2-naphthyl)ethanone (14b)
IR (KBr): 3433, 1676, 1619, 1479, 1387, 1270, 1140 cm–1.
Synthesis 2007, No. 20, 3113–3116 © Thieme Stuttgart · New York

3116
G. Yin et al.
PAPER
1H NMR (400 MHz, CDCl3): d = 3.96 (s, 3 H), 4.46 (s, 2 H), 7.16–
7.23 (m, 2 H), 7.79 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 1 H),
8.00 (dd, J = 8.4, 1.6 Hz, 1 H), 8.45 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 1.9, 55.4, 105.7, 119.9, 125.0,
127.3, 127.6, 128.7, 130.7, 131.2, 137.5, 160.0, 192.4.
(11) The method was limited to aliphatic ketones: (a) Horiuchi,
C. A.; Kiji, S. Bull. Chem. Soc. Jpn. 1997, 70, 421.
(b) Horiuchi, C. A.; Kiji, S. Chem. Lett. 1988, 31.
(12) (a) Pavlinac, J.; Stavber, S.; Zupan, M. Synthesis 2006,
2603. (b) Pavlinac, J.; Stavber, S.; Zupan, M. J. Org. Chem.
2006, 71, 1027. (c) Jereb, M.; Stavber, S.; Zupan, M.
Synthesis 2003, 853. (d) Stavber, S.; Jereb, M.; Zupan, M.
Chem. Commun. 2002, 488.
MS (EI, 70 eV): m/z (%) = 326 (100), 253 (8), 199 (15), 185 (94),
171 (67), 127 (39).
(13) Bekaert, A.; Barberan, O.; Gervais, M.; Brion, J. D.
Tetrahedron Lett. 2000, 41, 2903.
(14) Whang, J. P.; Yang, S. G.; Kim, Y. H. Chem. Commun.
1997, 1355.
(15) (a) Rao, M. L. N.; Jadhav, D. N. Tetrahedron Lett. 2006, 47,
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Alami, M.; Brion, J.-D. Synthesis 2006, 1537. (c) Lee, J. C.;
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Acknowledgment
This work was supported by the Central China Normal University,
the National Natural Science Foundation of China (grant nos.
20472022 and 20672042), and the Scientific Research Foundation
for the Returned Overseas Chinese Scholars, State Education Min-
istry (no. [2005]383). We also thank Zhejiang University for perfor-
ming the structural analysis.
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Synthesis 2007, No. 20, 3113–3116 © Thieme Stuttgart · New York