Halogenation of aromatic methyl ketones using oxone and sodium halide

Article abstract of DOI:10.1081/SCC-100107011

Aromatic methyl ketones undergo α-halogenation on treatment with sodium halide in the presence of oxone in aqueous methanol. However, electron-rich hetero aromatic methyl ketones afford ring bromination products preferentially.

Full text of DOI:10.1081/SCC-100107011

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HALOGENATION OF AROMATIC METHYL KETONES
USING OXONE® AND SODIUM HALIDE
Eun-Hoo Kim a , Bon-Suk Koo a , Choong-Eui Song b & Kee-Jung Lee c
a Department of Industrial Chemistry, Hanyang University, Seoul, 133-791, Korea
b Korea Institute of Science and Technology, Seoul, 136-791, Korea
c Department of Industrial Chemistry, Hanyang University, Seoul, 133-791, Korea
Published online: 16 Aug 2006.
To cite this article: Eun-Hoo Kim , Bon-Suk Koo , Choong-Eui Song & Kee-Jung Lee (2001) HALOGENATION OF AROMATIC
METHYL KETONES USING OXONE® AND SODIUM HALIDE, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:23, 3627-3632, DOI: 10.1081/SCC-100107011
To link to this article: http://dx.doi.org/10.1081/SCC-100107011
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SYNTHETIC COMMUNICATIONS, 31(23), 3627–3632 (2001)
HALOGENATION OF AROMATIC
METHYL KETONES USING OXONEÕ
AND SODIUM HALIDE
Eun-Hoo Kim,1 Bon-Suk Koo,1
Choong-Eui Song,2 and Kee-Jung Lee1,
*
1Department of Industrial Chemistry,
Hanyang University, Seoul 133-791, Korea
2Korea Institute of Science and Technology,
Seoul 136-791, Korea
ABSTRACT
Aromatic methyl ketones undergo a-halogenation on treat-
ment with sodium halide in the presence of oxoneÕ in aqueous
methanol. However, electron-rich hetero aromatic methyl
ketones afford ring bromination products preferentially.
a-Halo ketones have a wide range of application in organic synthesis
and are generally prepared by direct side chain halogenation of the
corresponding ketones.1 For example, phenacyl bromide is a protecting
group for acids and phenols in peptide syntheses2 and 2-chloroacetylpyr-
roles are useful intermediates in the synthesis of medicinally useful
*Corresponding author.
3627
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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3628
KIM ET AL.
compounds3 and as building blocks in the preparation of naturally occur-
ring porphyrins.4
Potassium hydrogen persulfate (KHSO5), which is commercially avail-
able as oxoneÕ, can be used for the oxidation of alkenes,5 arenes,6 amines,7
imines,8 sulfides,9 selenides,10 a-amino acids,11 acetals,12 and the carbonyl
regeneration from thioacetals,13 oximes14 and nitroalkanes.15 Recent reports
have dealt with the use of oxoneÕ and aqueous sodium halides as a
convenient halogenating reagent to achieve oxidation of a,b-enones,16
bromination of pyrimidines,17 and halogenation of toluene.5
We decide to test oxoneÕ and sodium halides on a variety of aromatic
methyl ketones in aqueous methanol. Our results are complied in table, and
yields are reported after isolation.
A mixture of acetophenone (0.96 mL, 8 mmol), sodium bromide (4.2 g,
40 mmol), and oxoneÕ (9.8 g, 16 mmol) in 30 mL of aqueous methanol (1 : 1
by volume) at reflux afforded 71% yield of 2-bromoacetophenone 1 (entry 1).
Under the same conditions using sodium chloride gave 2-chloroacetophe-
none 2a (19%) and 2,2-dichloroacetophenone 2b (28%) (entry 2). Similarly,
2-bromopropiophenone 3 was obtained in modest yield (entry 3).
We next turned our attention to a-halogenation of heteroaromatic
methyl ketones. Under the conditions of 2-acetylthiophene, sodium
bromide, and oxoneÕ (2 : 2.5 : 1) at r.t., ring bromination product, 2-acetyl-
5-bromothiophene 4 (60%) was the only product (entry 4). However, adding
more sodium bromide and oxoneÕ (1 : 2.5 : 1) at reflux, 5-bromo-2-bromo-
acetylthiophene 5a (42%) and 2-bromoacetyl-4,5-dibromothiophene 5b
(7%) were produced (entry 5).
In the case of electron-rich 2-acetylpyrrole, 2-acetyl-5-bromopyrrole 6
(81%) was the only product (entry 6), but 2-acetyl-3,4,5-tribromopyrrole 7a
(85%) and 2-bromoacetyl-3,4,5-tribromopyrrole 7b (1%) were produ-
ced rapidly within 0.1 h using excess NaBr and oxoneÕ at r.t. (entry 7).
Analogous bromination of 2-acetyl-1-methylpyrrole afforded 2-acetyl-5-
bromo-1-methylpyrrole 8 in 56% yield (entry 8), and even if using excess
NaBr and oxoneÕ only ring bromination products, 8 (30%) and 2-acetyl-
4,5-dibromo-1-methylpyrrole 9 (60%) were obtained (entry 9).

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AROMATIC METHYL KETONES
3629
In summary, we have shown that a convenient, easy handed a-halo-
genation of aromatic methyl ketones can be performed using in situ genera-
tion of halogens from oxoneÕ/NaX. However, this procedure was not
reliable in the case of electron-rich heterocyclic systems due to preferential
nuclear halogenation. The structure of the compounds were fully assigned
on the basis of analytical and spectroscopic data.
EXPERIMENTAL
Melting points were determined in open capillaries with an
Electrothermal melting point apparatus and are uncorrected. Progress of
reactions were followed by TLC using silica gel with fluorescent indicator
1
coated on aluminium sheets. H NMR spectra were recorded at 300 MHz
in CDCl3 using TMS as an internal standard. Elemental analyses were
performed using a Carlo Erba EA 1180 element analyzer.
General Procedure for the Halogenation
of Aromatic Methyl Ketones (1–9)
To a stirred solution of ketone (8 mmol) in aqueous methanol (30 mL,
1 : 1 by volume) was added sodium halide (10 or 20 or 40 mmol) and oxoneÕ
(4 or 8 or 16 mmol). Reactions were continuously monitored by thin-layer
chromatography and stirred at reflux temperature (or r.t.) for the time
indicated in Table. After cooling the reaction mixture was quenched with
aqueous sodium thiosulfate, and extracted with dichloromethane
(3 Â 50 mL). The combined organic layers were washed with water, dried
over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was
chromatographed on a silica gel column and eluted with hexane-EtOAc
10 : 1 to give the products (Table).
The spectral and analytical data of products are as follows:
1: mp 49ꢀ (Lit.18 49–51ꢀ). 1H NMR d 4.45 (s, 2H), 7.36–7.59
(m, 3H), 7.87–8.05 (m, 2H).
2a: mp 53–54ꢀ (Lit.19 53–54ꢀ). H NMR d 4.73 (s, 2H), 7.47–7.65
1
(m, 3H), 7.94–7.97 (m, 2H).
2b: oil (Lit.20 bp 132–134ꢀ/13 Torr). 1H NMR d 6.69 (s, 1H),
7.50–7.69 (m, 3H), 8.06–8.11 (m, 2H).
3: oil (Lit.21 bp 64–66ꢀ/1 Torr). 1H NMR d 1.85 (d, J ¼ 6.5 Hz, 3H),
5.28 (q, J ¼ 6.5 Hz, 1H), 7.39–7.55 (m, 3H), 7.97–8.00 (m, 2H).

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KIM ET AL.
Table. Halogenation of Aromatic Methyl Ketones Using OxoneÕ and Sodium
Halidesa
aA 1 : 1 MeOH/H2O ratio is used. b Yields are based on isolated products purified by
column chromatography. c The ratio of substrate : NaX : Oxone is 1 : 5 : 2. d The ratio
of substrate : NaBr : Oxone is 1 : 1.25 : 0.5. e The ratio of substrate : NaBr : Oxone is
f
1 : 2.5 : 1. Room temperature.

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AROMATIC METHYL KETONES
3631
4: mp 91–92ꢀ (Lit.22 92.5–93.5ꢀ). 1H NMR d 2.51 (s, 3H), 7.10
(d, J ¼ 3.9 Hz, 1H), 7.43 (d, J ¼ 3.9 Hz, 1H).
5a: mp 90–91ꢀ (Lit.23 91ꢀ). 1H NMR
d 4.33 (s, 2H), 7.19
(d, J ¼ 4.1 Hz, 1H), 7.60 (d, J ¼ 4.1 Hz, 1H).
5b: mp 61–63ꢀ. 1H NMR d 4.31 (s, 2H), 7.64 (s, 1H). IR (KBr) cmꢁ1
:
1666, 1503, 1382, 1196, 947, 842, 652, 586. Anal. Calcd for
C6H3Br3OS: C, 19.86; H, 0.83; S, 8.84. Found: C, 19.71; H,
0.75; S, 8.61.
6: mp 104–105ꢀ. H NMR d 2.42 (s, 3H), 6.90 (d, J ¼ 1.4 Hz, 1H),
1
7.04 (d, J ¼ 1.4 Hz, 1H), 9.99 (brs, 1H). IR (KBr) cmꢁ1: 3262,
1646, 1541, 1390, 1130, 943, 823, 749, 609, 532. Anal. Calcd for
C6H6BrNO: C, 38.33; H, 3.22; N, 7.45. Found: C, 38.19; H 3.09;
N 7.18.
7a: mp 155–156ꢀ. H NMR d 2.63 (s, 3H), 10.08 (s, 1H). IR (KBr)
1
cmꢁ1: 3215, 1635, 1511, 1429, 1386, 1017, 947, 714, 598. Anal.
Calcd for C6H4Br3NO: C, 20.84; H, 1.17; N, 4.05. Found: C,
20.59; H, 1.35; N, 3.81.
7b: mp 110–112ꢀ. H NMR d 3.87 (s, 2H), 9.39 (s, 1H). IR (KBr)
1
cmꢁ1: 3297, 1654, 1584, 1425, 1378, 1266, 1021, 974, 757, 547.
Anal. Calcd for C6H3Br4NO: C, 16.97; H, 0.71; N, 3.30. Found:
C, 16.62; H, 0.60; N, 3.01.
8: oil. 1H NMR d 2.41 (s, 3H), 3.95 (s, 3H), 6.23 (d, J ¼ 4.3 Hz, 1H),
6.94 (d, J ¼ 4.3 Hz, 1H). IR (neat) cmꢁ1: 1650, 1522, 1464, 1390,
1328, 1234, 1192, 1110, 1060, 943, 916, 812. Anal. Calcd for
C7H8BrNO: C, 41.61; H, 3.99; N, 6.93. Found: C, 41.45; H,
3.70; N, 6.61.
9: mp 54–55ꢀ. 1H NMR d 2.41 (s, 3H), 3.99 (s, 3H), 7.01 (s, 1H). IR
(KBr) cmꢁ1: 1712, 1588, 1429, 1386, 1266, 1157, 994, 815, 722.
Anal. Calcd for C7H7Br2NO: C, 29.93; H, 2.51; N, 4.99. Found:
C, 29.74; H, 2.20; N, 4.72.
ACKNOWLEDGMENTS
This work was supported by Hanyang University, Korea, made in the
program year of 1999.
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Received in the UKOctober 30, 2000

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