Solid-phase organic synthesis of α-iodo ketones using recyclable resin-bound selenium bromide

Article abstract of DOI:10.3184/174751912X13280376652307

A novel facile method for the traceless solid-phase synthesis of α-iodo ketones using a recyclable resin-bound selenium bromide reagent is reported. Various ketones and α-dicarbonyl compounds can be converted to the corresponding α-iodo-substituted compou

Full text of DOI:10.3184/174751912X13280376652307

100 RESEARCH PAPER
FEBRUARY, 100–102
JOURNAL OF CHEMICAL RESEARCH 2012
Solid-phase organic synthesis of a-iodo ketones using recyclable
resin-bound selenium bromide
Xue-Chun Mao, Xiao-Ling Liu*, Qiang Deng and Shou-Ri Sheng
College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, 330022, P. R. China
A novel facile method for the traceless solid-phase synthesis of α-iodo ketones using a recyclable resin-bound
selenium bromide reagent is reported. Various ketones and β-dicarbonyl compounds can be converted to the corre-
sponding α-iodo-substituted compounds in excellent yields and purities with simple workup procedure and mild
conditions.
Keywords: α-iodo ketone, solid-phase synthesis, resin-bound selenium bromide
α-Iodo ketones are important building blocks in organic syn-
thesis and their high reactivity makes them available to react
with a large number of nucleophiles to provide a variety of
useful compounds.1 Moreover, some α-iodo ketones possess
biological activity and their properties have attracted con-
siderable attention in the medicinal field.2 Generally, α-iodo
method for traceless cleavage of a selenium resin,21 and under
further optimised conditions, the target compound 1-phenyl-2-
iodoethanone (3a) was obtained in 98% yield and with excel-
lent purity (98%) by treatment of 3a with CH3I–NaI in DMF
at 75 °C overnight. To assess the generality of the method and
to evaluate the electronic influence of the aromatic ring sub-
stituents, the transformations of various other ketones (1b–e)
into the corresponding α-iodo ketones (3b–e) were further
explored (Table 1). As seen from Table 1, propiophenone (1b)
and acetophenone derivatives (1c–e) bearing electron-donating
or electron-withdrawing groups on the phenyl ring were all
readily transformed into the corresponding 1-arylsubstituted
2-iodoethanones (3b–e) in excellent yields, which suggests
that any change in an electronic factor of the phenyl ring has
little effect on the reaction outcome (entries 3–5). On the other
hand, cyclic ketones, likewise underwent smooth α-iodination.
For example, cyclohexanone (entry 6), and cyclopentanone
(entry 7) all gave the corresponding α-iodo products in 92%
(3f) and 93% (3g) yields with good purities (>95%), respectively.
Furthermore, examination of 1,3-diketones (1h–i) showed
them also to give the corresponding α-iodoketones with good
purities but in slightly lower yields (entries 8 and 9). However,
in the case of unsymmetrical aliphatic ketones, for example,
2-butanone, two regioisomers of 1-iodo-2-butanone and 3-iodo-
2-butanone (55:45 by 1H NMR) as a mixture were obtained in
74% yield.
It should be noted that, after completing the cleavage reac-
tion of the selenium resin, the recovered methyl selenide resin
(4) is easily converted to selenium bromide resin, which can be
reused for further production of α-iodo ketones. For example,
after the third regeneration and use, the purity of 1-phenyl-2-
iodoethanone (3a) (entry 1) remained almost the same as when
the first prepared selenium bromide resin was used but with a
slight decrease in yield.
In summary, we have developed a new and efficient protocol
for the traceless solid-phase synthesis of α-iodo ketones
with excellent yields and easy workup procedure employing a
selenium-based traceless linker strategy. Moreover, the poly-
meric selenium bromide reagent can be regenerated and reused
as an environmentally friendly benign reagent.
4
ketones are prepared from olefins,3 ketone derivatives (enol
silyl ethers and acetates), or by halogen interchange of bromo
compounds with sodium iodide.5 Alternatively, the iodonium-
donating systems such as KI/KIO3/H2SO46 and NaI/H2O2/
H2SO47 were used for α-iodination of ketones. Additionally,
molecular iodide8 or with oxidising agents such as I2/HgCl2,9
I2/SeO2/AcOH,10 I2/N–F reagent,11 I2/oxone,12 I2/CuO,13 I2/
MnO2,14 I2/O2/NaNO215 and I2/m-iodobenzoic acid16 were used
to access these compounds. Ionic liquids,17 microwave irradia-
tion18 and hypervalent iodine reagents19 have also been utilised
for similar transformations. Alhough several reported methods
provide good yields, many of these approaches suffer from
limitations such as cumbersome workup procedures, acidic
reaction conditions (formation of the acid in situ), the use
of expensive, or inconvenient and environmentally harmful
reagents, and the generation of hazardous waste. Therefore,
the development of an efficient, economic and environmen-
tally friendly method is still desirable. Recently, the polymeric
selenium reagents20 have been now developed for solid-phase
organic synthesis (SPOS) with a combined advantage of
decreased volatility and simplification of the product work-up.
As part of an ongoing research programme focused on the use
of resin-bound selenium reagents in SPOS,21 we report here
the simple preparation of α-iodo ketones based on resin-bound
selenium bromide. To our knowledge, this is a previously unre-
ported method for the α-iodination of ketones. The method is
illustrated using acetophenone in the Scheme 1.
In our initial experiments, acetophenone (1a) was selected
as a representative case to investigate this method. As shown in
Scheme 1, treatment of a THF-swollen suspension of cross-
linked (1%) polystyrene-bound selenium bromide20 with the
lithium enolate of 1a for a short time (30min) afforded a pale
yellow resin-bound 1-phenyl-2-selenoethanone (2a) in near-
quantitative yield, monitored by FT-IR showing a strong car-
bonyl absorption at 1712 cm–1. Then, following the published
Scheme 1
* Correspondent. E-mail: liuxiaoling@jxnu.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2012 101
Table 1 The yields and purities of α-iodo ketones (3a–i)
were prepared using standard literature procedures. THF was distilled
from sodium-benzophenone immediately prior to use.
Entry
Ketone (1)
Product (3)
Yield/%a Purity/%b
Preparation of α-iodo ketones 3a–i; general procedure
98
98
To a stirring solution of LDA (1.40 mmol) in THF (5 mL) under nitrogen
at –78 °C was added dropwise a solution of the carbonyl compound
(1) (1.40 mmol) in THF (5 mL) over 5 min. After stirring for an addi-
tional 10 min, polystyrene-supported selenium bromide (1.0 g) was
added rapidly. The mixture was warmed to room temperature over
a 15 min period and stirred for 15 min. After being acidified with
glacial acetic acid, the α-seleno ketone resin (2) was collected by
filtration and washed successively with H2O, THF and CH2Cl2 (2 ×
10 mL of each). Then NaI (1.0 g) and CH3I (1.0 mL) under nitrogen
was added to a suspension of the swollen resin 2 in anhydrous DMF
(10 mL). The mixture was stirred at 75 °C overnight and then cooled
to room temperature. The mixture was filtered and the residual resin
4 was washed with CH2Cl2 (10 × 3 mL). The filtrate was washed suc-
cessively with saturated NaHCO3 (30 mL), saturated Na2S2O3 (30 mL)
and H2O (10 ×3 mL), dried over anhydrous MgSO4 and concentrated
to afford crude products 3a–i with 94–98% purity determined by
HPLC, which were further purified by passing the crude product
through a silica gel chromatographic column (hexane–EtOAc, 10:1)
to afford the pure products for their structure analyses if necessary.
97c
95d
94e
97c
96d
96e
1
1a
1b
3a
3b
2
3
97
97
96
98
1c
1d
1e
3c
3d
3e
4
5
6
96
94
92
97
95
96
All of the products were satisfactorily characterised by 1H NMR, 13
C
NMR and IR, and are identified with the previously reported data in
the literature.
1-Phenyl-2-iodoethanone (3a): Colourless oil (lit.12 oil); 1H NMR:
δ = 7.98 (d, J = 7.2 Hz, 2H), 7.58 (t, J = 7.6 Hz, 1H), 7.48 (t, J =
7.2 Hz, 2H), 4.36 (s, 2H); 13C NMR: δ = 191.0, 137.6, 135.8, 133.8,
130.4, 33.5; IR (film): ν = 1697 cm–1.
1-Phenyl-2-iodopropanone (3b): Colourless oil (lit.7 oil); 1H NMR:
δ = 8.97–8.95 (m, 2H), 7.58–7.54 (m, 3H), 4.40–4.37 (m, 1H), 1.90
(d, J = 7.6 Hz, 3H); 13C NMR: δ = 191.2, 137.5, 135.8, 133.3, 130.1,
31.3, 18.6; IR (film): ν = 1702 cm–1.
1-(4-Methylphenyl)-2-iodoethanone (3c): Colourless oil (lit.7 oil);
1H NMR: δ = 7.90 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 4.33
(s, 2H), 2.44 (s, 3H); 13C NMR: δ = 191.5, 140.7, 129.6, 127.2, 124.4,
63.0, 21.5; IR (film): ν = 1695 cm–1.
1f
3f
7
8
93
90
96
94
1-(4-Methoxyphenyl)-2-iodoethanone (3d): White solid, m.p. 60–
61 °C (lit.15 m.p. 58–59.5 °C); 1H NMR: δ = 7.95 (d, J = 8.8 Hz, 2H),
6.96 (d, J = 8.8 Hz, 2H), 4.32 (s, 2H), 3.85 (s, 3H); 13C NMR: δ =
191.6, 163.5, 131.3, 126.0, 114.5, 63.7, 55.2; IR (KBr): ν = 1667 cm–1.
1-(4-Bromophenyl)-2-iodoethanone (3e): Colourless oil (lit.7 oil);
1H NMR: δ = 8.12 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 4.37
(s, 2H); 13C NMR: δ = 192.1, 138.2, 134.5, 132.6, 128.2, 33.8; IR
(film): ν = 1680 cm–1.
1g
3g
1h
3h
2-Iodocyclohexanone (3f): Colourless oil (lit.3 oil); 1H NMR:
δ = 4.22 (t, J = 6.4 Hz, 1H), 2.37 (t, J = 6.4 Hz, 2H), 1.70–1.64 (m,
2H), 1.61–1.55 (m, 2H), 1.45–1.40 (m, 2H); 13C NMR: δ = 198.2,
42.3, 32.1, 29.4, 26.5, 25.1; IR (film): ν = 1710 cm–1.
9
85
95
1
2-Iodocyclopentanone (3g): Colourless oil (lit.12 oil); H NMR:
1i
3i
δ = 4.10 (t, J = 6.0 Hz, 1H), 2.45 (t, J = 6.0 Hz, 2H), 1.78–1.66 (m,
2H), 1.52–1.48 (m, 2H); 13C NMR: δ = 201.6, 41.5, 31.8, 26.0, 16.5;
IR (film): ν = 1718 cm–1.
a Isolated yields based on polymer-supported selenium bromide
(1.20 mmol Br/g).
b Determined by HPLC of the crude cleavage product.
c With the first regenerated selenium bromide resin.
d With the second regenerated selenium bromide resin.
e With the third regenerated selenium bromide resin.
2-Iodo-1,3-diphenylpropane-1,3-dione (3h): White solid, m.p.
105–106°C (lit.12 m.p. 104 °C); 1H NMR: δ = 8.05 (d, 4H, J = 8.0 Hz),
7.58 (t, J = 7.2 Hz, 2H), 7.46 (t, J = 8.0 Hz, 4H), 6.95 (s, 1H); 13C
NMR: δ = 190.2, 134.2, 133.3, 129.5, 129.2, 34.1; IR (KBr): ν = 1695,
1665 cm–1.
1
3-Iodopentane-2,4-dione (3i): Colourless oil (lit.12 oil); H NMR:
δ = 5.02 (s, 1H), 2.50 (s, 6H); 13C NMR: δ = 203.2, 199.5, 33.8, 27.2,
23.5; IR (film): ν = 3433, 1733 cm–1.
Experimental
Melting points were uncorrected. 1H NMR (400 MHz) and 13C NMR
(100 MHz) spectra were recorded on a Bruker Avance (400 MHz)
spectrometer, using CDCl3 as the solvent and TMS as internal reference.
FTIR spectra were taken on a Perkin-Elmer SP One FT-IR spectro-
photometer. HPLC analysis was carried out on Agilent 1100 automated
system having a PDA detector (λmax = 254 nm) using a gradient run
of 0–100% MeCN in H2O (1 mL min−1) on a RP-18e column (150 ×
4.6 mm). Polystyrene (H 1000, 100–200 mesh, cross-linked with 1%
divinylbenzene) for preparation of selenium bromide resin (elemental
analysis Br, 1.20 mmol g−1)20 was purchased from Nankai University,
the other starting materials were purchased from commercial sources
and used without further purification; some of the starting materials
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (No. 21062007), NSF
of Jiangxi Province (No. 2009GZH0016) and the Research
Program of Jiangxi Province Department of Education (No.
GJJ10385, GJJ11380).
Received 31 December 2011; accepted 16 January 2012
Paper 1100983 doi: 10.3184/174751912X13280376652307
Published online: 23 February 2012

102 JOURNAL OF CHEMICAL RESEARCH 2012
13 G.D. Yin, M. Gao, N.F. She, S.L. Hu, A.X. Wu and Y.J. Pan, Synthesis,
References
2007, 3113.
1
2
3
4
5
6
A.W. Erian, S.M. Sherif and H.M. Gaber, Molecules, 2003, 8, 793.
R.H. Seevers and R.E. Counsell, Chem. Rev., 1982, 82, 575.
G. Cardillo and M. Shimisu, J. Org. Chem., 1977, 42, 4268.
G.M. Rubottom and R.C. Mott, J. Org. Chem., 1979, 44, 1731.
Y.D. Vankar and G. Kumaravel, Tetrahedron Lett., 1984, 25, 233.
T. Okamoto, T. Kakinami, T. Nishimura, I. Hermawan and S. Kajigaeshi,
Bull. Chem. Soc. Jpn.,1992, 65, 1731.
14 G. Le Bras, O. Provot, A. Bekaert, J.-F. Peyrat, M. Alami and J.-D. Brion,
Synthesis, 2006, 1537.
15 G. Stavber, J. Iskra, M. Zupan and S. Stavber, Green. Chem., 2009, 11,
1262.
16 M.S. Yusubov, R.Y. Yusubova, T.V. Funk, K.-W. Chi, A. Kirschning and
V.V. Zhdankin, Synthesis, 2010, 3681.
17 H.M. Meshram, P.N. Reddy, P. Vishnu, K. Sadashiv and J.S. Yadav,
Tetrahedron Lett., 2006, 47, 991.
18 J.C. Lee, J.Y. Park, S.Y. Yoon, Y.H. Bae and S.J. Lee, Tetrahedron Lett.,
2004, 45, 191.
19 J.N. Moorthy, K. Senapati and N. Singhal, Tetrahedron Lett., 2009, 50,
2493.
7
J. Barluenga, M. Marco-Arias, F. González-Bobes, A. Ballesteros and
J.M. González, Chem. Commun., 2004, 2616.
8
9
M.L.N. Rao and D.N. Jadhav, Tetrahedron Lett., 2006, 47, 6883.
J. Barluenga, J.M. Martinez-Gallo, C. Najera and M. Yus, Synthesis, 1986,
678.
10 A. Bekaert, O. Barberan, M. Gervais and J.-D. Brion, Tetrahedron Lett.,
2000, 41, 2903.
20 K.C. Nicolaou, J. Pastor, S. Barluenga and N. Winssinger, Chem. Commun.,
1998, 1947.
11 S. Stavber, M. Jereb and M. Zupan, Chem. Commun., 2002, 488.
12 P. Goswami, S. Ali, Md. M. Khan and A.T. Khan, Arkivoc, 2007, 82.
21 S.R. Sheng, Q. Xin, X.L. Liu, W.K. Sun, R. Guo and X. Huang, Synthesis,
2006, 2293.

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