Copper nitrate-catalyzed α -bromination of aryl ketones with hydrobromic acid

Article abstract of DOI:10.1080/00397911.2015.1121546

An efficient method for α-bromination of aryl ketones, using the combination of molecular oxygen and aqueous hydrobromic acid as a brominating agent in the presence of the copper nitrate, has been developed. This catalytic system, which uses cheap and readily available reactants, shows good atom economy with water as the only by-product.

Full text of DOI:10.1080/00397911.2015.1121546

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Copper nitrate–catalyzed α-bromination of aryl
ketones with hydrobromic acid
Jianqiang Wang, Xiaolei Wang, Zong-Qiang Niu, Jian Wang, Man Zhang & Jing-
Hua Li
To cite this article: Jianqiang Wang, Xiaolei Wang, Zong-Qiang Niu, Jian Wang, Man Zhang &
Jing-Hua Li (2016) Copper nitrate–catalyzed α-bromination of aryl ketones with hydrobromic
acid, Synthetic Communications, 46:2, 165-168, DOI: 10.1080/00397911.2015.1121546
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1121546
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Date: 15 March 2016, At: 07:42

SYNTHETIC COMMUNICATIONS
2016, VOL. 46, NO. 2, 165–168
http://dx.doi.org/10.1080/00397911.2015.1121546
Copper nitrate–catalyzed α-bromination of aryl ketones with
hydrobromic acid
Jianqiang Wang, Xiaolei Wang, Zong-Qiang Niu, Jian Wang, Man Zhang, and Jing-Hua Li
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
ABSTRACT
ARTICLE HISTORY
Received 29 August 2015
An efficient method for α-bromination of aryl ketones, using the
combination of molecular oxygen and aqueous hydrobromic acid as a
brominating agent in the presence of the copper nitrate, has been
developed. This catalytic system, which uses cheap and readily
available reactants, shows good atom economy with water as the only
by-product.
KEYWORDS
Aryl ketones; α-bromination;
catalysis; copper nitrate;
hydrobromic acid
GRAPHICAL ABSTRACT
Introduction
α-Bromination of carbonyl compounds is an important and fundamental reaction in
organic chemistry. α-Bromoketone derivatives are versatile intermediates in the manufac-
ture of pharmaceuticals, agrochemicals, biologically active compounds, and other special
chemicals.[1] Liquid bromine is the most common brominating agent in the synthesis
of α-bromocarbony compounds; however, it has some inherent disadvantages, such as
its highly toxic nature, difficult handling, and low atom efficiency.[2] In past decades,
several safe and user-friendly brominating reagents, such as pyridinium tribromides,[3]
hexamethylenetetramine–bromine complex,[2] dioxane–dibromide,[4] quaternary ammonium
tribromide,[5] and N-bromosuccinimide (NBS),[6] have been developed, yet the preparation
of all these reagents involves liquid bromine as the starting material, so their atom economy
is still poor.
An alternative solution is to use bromide anions as bromine resource during oxidative
bromination. Typically, α-brominations of aryl ketones are carried out with a combination
of bromide anion and a variety of oxidants[7] (such as Oxone and t-BuOOH). All of these
systems require stoichiometric oxidizing agents, which in most cases lead to environmental
problems caused by undesirable by-products. Compared with what was mentioned pre-
viously, hydrogen peroxide–based oxidative bromination is a mild and environmentally
CONTACT Jing-Hua Li
lijh@zjut.edu.cn
College of Pharmaceutical Sciences, Zhejiang University of Technology,
310032, Hangzhou, China.
Supplemental data for this article can be accessed on the publisher’s website.
Color versions of one or more of the figures in this article can be found online at www.tandfonline.com/lsyc.
© 2016 Taylor & Francis

166
J. WANG ET AL.
friendly system, of which the only by-product is water.[8] However, the cost of hydrogen
peroxide is relatively high and its undesirable decomposition cannot be avoided during
the reaction at elevated temperatures.
Molecular oxygen, which is the most abundant and atom-economical oxidant, has been
applied as oxidants in the oxidative brominations of aryl ketones.[9] For example, Zhang
et al. described an efficient aerobic oxidative bromination method for active aromatic com-
pounds and aryl ketones in acetonitrile or ethanol with 20% mol NaNO2 as a catalyst.[10]
We reported an efficient copper nitrate–catalyzed aerobic oxidative bromination of arenes
in water with high conversions and high selectivities.[11] We supposed that this system may
also be expanded to oxidative brominations of carbonyl compounds.
Discussion
Acetophenone was chosen as the test substrate in the light of the method described in our
previous paper.[11] The effect of different solvents (H2O, CH2Cl2, CHCl3, CH3COOH,
CH2ClCH2Cl, CH3CN) on the α-bromination of acetophenone was investigated on an
O2/HBr/Cu(NO3)2 system. The gas chromatography (GC) yields of the reaction in different
solvents were 99% (H2O, isolated yield 91%), 17% (CH2Cl2), 22% (CHCl3), 94%
(CH3COOH), 89% (CH2ClCH2Cl), and 45% (CH3CN), respectively, and among them
H2O shows the best reactivity at 70 °C. A possible reason might be that the bromine formed
in the course of the reaction was extracted by the organic phase (substrate) in which the
bromination occurred more readily. If the organic solvents are used in this reaction, the
bromination will be deactivated due to the dilution of the concentration of bromine and
substrate. The reaction was smoothly carried out for 3.5 h in the presence of 5% mol cata-
lyst to give the target product in 91% isolated yield. Under similar reaction conditions, ali-
phatic ketones were also tested, for example, using acetone as a substrate. We found that
the bromination took place more easily, but the resulting product was a mixture of mono-
bromoacetone and multibromosubstituted acetones, which are hard to separate effectively.
To explore the scope of this oxidative bromination system, a variety of aryl ketones were
examined with Cu(NO3)2 in water, and the corresponding results are listed in Table 1. Aro-
matic compounds were converted into the corresponding brominated compounds in good
to excellent yields at 70 °C except that indanone gave more dibromo- products (entries 1–
4). The bromination tended to take place on the benzene ring and α-position of the sub-
strate, and in those cases electron-rich aromatic compounds were employed. The reaction
would proceed slowly if there were electron-withdrawing groups (EWGs) on the benzene
ring (entries 5–8). It would be harder to take place if the α-position of carbonyl group was
occupied by some groups with steric hindrance (entries 9 and 10). The isolated yields
decreased if there were EWGs in the α-position of aryl ketones, despite the high conversion
of substrates (entries 11 and 12). The compounds with two phenyl rings, such as 1,2-diphe-
nylethanone, were also examined as the substrates (entries 13–18). In these special cases
acetic acid was added to the reaction system as an assistant solvent because the substrates
were not efficiently dispersed in water due to their high melting points.
In summary, we have developed a Cu(NO3)2-catalyzed oxidative α-bromination of aryl
ketones under mild aerobic conditions with HBr as bromine source. This procedure is
advantageous for several reasons: (i) it avoids the use and handling of Br2; (ii) in most cases,
no VOCs (volatile organic compounds) are used as solvents; and (iii) the components in the

SYNTHETIC COMMUNICATIONS
167
Table 1. The Cu(NO3)2-catalyzed oxidative bromination of aromatic compounds with a combination of
HBr and O2.a
Entry
Product
Time [h]
Cu(NO3)2 [mol%]
Isolated yield [%]
1
2
2a R1 ¼ H, R2 ¼ H,R3 ¼ H, R4 ¼ H.
3.5
2
5
5
5
91
93
2b R1 ¼ p-CH3, R2 ¼ H, R3 ¼ H, R4 ¼ H.
2c (o-)R1 R3 ¼ CH2,R2 ¼ H, R4 ¼ H.
3
3
83b
94
4
2d (o-)R1 R3 ¼ CH2CH2, R2 ¼ H, R4 ¼ H.
2e R1 ¼ p-Cl, R2 ¼ H,R3 ¼ H, R4 ¼ H.
2f R1 ¼ o-Cl, R2 ¼ H,R3 ¼ H, R4 ¼ H.
2g R1 ¼ p-F, R2 ¼ H,R3 ¼ H, R4 ¼ H.
2h R1 ¼ p-NO2, R2 ¼ H, R3 ¼ H, R4 ¼ H.
2i R1 ¼ H, R2 ¼ H,R3 ¼ CH3, R4 ¼ H.
2j R1 ¼ H, R2 ¼ H,R3 ¼ CH3, R4 ¼ CH3.
2k R1 ¼ H, R2 ¼ H,R3 ¼ COCH3, R4 ¼ H.
2l R1 ¼ H, R2 ¼ H,R3 ¼ COOEt, R4 ¼ H.
2m R1 ¼ H, R2 ¼ H,R3 ¼ C6H5, R4 ¼ H.
2n R1 ¼ p-F, R2 ¼ H,R3 ¼ C6H5, R4 ¼ H.
2o R1 ¼ p-Cl, R2 ¼ H,R3 ¼ C6H5, R4 ¼ H.
2p R1 ¼ p-CH3, R2 ¼ H, R3 ¼ C6H5, R4 ¼ H.
2q R1 ¼ p-CH3, R2 ¼ H, R3 ¼ p-ClC6H4, R4 ¼ H.
2r R1 ¼ H, R2 ¼ H,R3 ¼ p-ClC6H4, R4 ¼ H.
2
10
5
5
3
89
6
3.5
3.5
6
5
86
7
5
87
8
5
82
9
3
5
92
10
11
12
13d
14d
15d
16d
17d
18d
8
10
5
87
3
84(95)c
81(97)c
90
3
5
4.5
4.5
4.5
4.5
4.5
4.5
5
5
92
5
91
5
87
5
89
5
92
aAerobic oxidative bromination conditions were as follows: entries 1–12, substrates (10 mmol), HBr (12 mmol, 8 mol/L
aqueous solution), Cu(NO3)2 0.5 mmol, O2 balloon (about 0.5–1 L) was used at 70 °C (60 °C for entry 11, 50 °C for entry 12).
bThere is 14% dibromo-product.
cThe number in the parentheses means conversion which is determined by GC.
dSubstrate (10 mmol), HBr (12 mmol, 8 mol/L aqueous solution), Cu(NO3)2 0.5 mmol, acetic acid (12 mL), O2 was pumped into
the reactor at 60 °C.
reaction system, O2(air)–HBr–water, are nontoxic, nonflammable, cheap, and readily avail-
able. Moreover, this aerobic oxidative bromination system exhibits fairly efficient regioselec-
tivity for some aryl ketones. Therefore, this method offers a green system for the organic
solvent-free oxidative bromination of aryl ketones with good atom economy.
Experimental
1H NMR spectra were recorded on a Bruker Avance III 500-MHz spectrometer in CDCl3 using
tetramethylsilane (TMS) as the internal standard and chemical shifts are given in δ relative
to the solvent peak. Thin-layer chromatography (TLC) was performed on silica gel GF 254.
Gas chromatographic (GC) analysis was performed with a Techcomp 7890II instrument fitted
with a SE-54 30 m � 0.32 mm � 0.25 µm capillary column and a FID detector (analytical con-
ditions: oven temperature: 200 °C; injector temperature: 250 °C; detector temperature: 250 °C).
Melting points were determined on a Büchi B-540 melting apparatus and are uncorrected.
Typical procedure for the preparation of α-bromoacetophenone (2a)
The representative example of oxidative bromination is described as follows: A mixture of
1.2 g acetophenone 1a (10 mmol) and 0.121 g Cu(NO3)2•3H2O (0.5 mmol) was stirred and

168
J. WANG ET AL.
an oxygen balloon (about 0.5–1 L) was attached to the reaction system. Then 8 mol/L
aqueous solution of hydrobromic acid (1.5 mL, 12 mmol) was added dropwise to the
mixture. The reaction mixture was then stirred at 70 °C and monitored by TLC or GC.
After the completion of the reaction, the mixture was extracted with CH2Cl2. The organic
extract was first washed with 5% sodium sulfite, saturated sodium bicarbonate solution,
and then water and finally dried over anhydrous magnesium sulfate. The solvent was
removed under vacuum and the residue was purified by column chromatography (silica
gel, petroleum ether/dichloromethane ¼ 3:1) to afford the product, α-bromoacetophenone
1
(2a) in 1.81 g, yield: 91%. Compound 2a: solid, mp: 47–48 °C (lit.[5] 49–50 °C). H NMR
(500 MHz, CDCl3): δ 4.48 (s, 2H), 7.51 (t, J ¼ 7.5 Hz, 2H), 7.63 (t, J ¼ 7.5 Hz, 1H), 8.00
(d, J ¼ 7 Hz, 2H).
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