Synthesis of phenacyl bromides via K2S2O 8-mediated tandem hydroxybromination and oxidation of styrenes in water

Article abstract of DOI:10.1039/c3gc40515j

Non-transition metal-catalyzed synthesis of phenacyl bromides was achieved through K₂S₂O₈-mediated tandem hydroxybromination and oxidation of styrenes. The advantages of this reaction are its excellent functional group compatibility, mild reaction conditions (60 °C) and use of pure water as reaction medium. Based upon experimental observations, a plausible reaction mechanism is proposed.

Full text of DOI:10.1039/c3gc40515j

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Synthesis of phenacyl bromides via K2S2O8-mediated
tandem hydroxybromination and oxidation of styrenes
in water†
Cite this: DOI: 10.1039/c3gc40515j
Qing Jiang,a Wenbing Shenga,b and Cancheng Guo*a
Received 18th March 2013,
Accepted 8th May 2013
Non-transition metal-catalyzed synthesis of phenacyl bromides was achieved through K2S2O8-mediated
tandem hydroxybromination and oxidation of styrenes. The advantages of this reaction are its excellent
functional group compatibility, mild reaction conditions (60 °C) and use of pure water as reaction
medium. Based upon experimental observations, a plausible reaction mechanism is proposed.
DOI: 10.1039/c3gc40515j
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employ hazardous or low atom-efficient brominating reagents
and/or require the use of environmentally undesirable organic
Introduction
Phenacyl bromides are important molecules because they are solvents and/or sometimes even transition metals. Therefore,
widely used as precursors of various pharmaceutically impor- the development of new, mild and environmentally friendly
tant heteroaromatics such as imidazoles, selenazoles, and oxa- approaches for the direct synthesis of phenacyl bromides
zoles.1 Traditionally, phenacyl bromides were mainly obtained from styrenes still remains a highly desirable goal in organic
from acetophenones with liquid bromine in the presence of synthesis.
protic and Lewis acids.2 Although bromine is hazardous with
Recently, from economical and environmental points of
associated risks in handling and transport, it is still being view, the use of water as a solvent has attracted much interest
used by industry as well as academia due to its low cost, easy because of its innate advantages, such as low cost, ready avail-
availability, and the lack of a better alternative. Alternatively, ability, non-toxicity, and inflammability.10 Use of water will
a few procedures for a-bromination of acetophenones avoid- reduce the use of harmful organic solvents and is regarded as
ing liquid bromine involve N-bromosuccinimide (NBS) and an important subject in green chemistry. In addition, water
4,4-dibromo-2,6-di-tert-butyl-cyclohexa-2,5-dienone.3 However, has unique physical and chemical properties, which allow us
these brominating reagents have some limitations including to realize reactivities that cannot be attained in organic sol-
their low atom efficiency and use of molecular bromine for vents. Despite the advantages that water possesses, the syn-
their preparation. In general, direct conversion of styrenes to thesis of phenacyl bromides from styrenes by using pure water
phenacyl bromides is synthetically more advantageous than as the reaction medium without the addition of any organic
that involving acetophenones since they are less expensive and co-solvents is scarce.4 Herein, we report that phenacyl bro-
readily available. In fact, examples for the conversion of sty- mides can be efficiently synthesized via K2S2O8-mediated
renes to phenacyl bromides are much less abundant and more tandem hydroxybromination and oxidation of styrenes using
limited; phenacyl bromides have been synthesized by the reac- KBr as a bromine source in the presence of water.
tion of styrenes with HBr–H2O2 in water,4 HBr in ethyl acetate
under visible-light irradiation,5 NBS–IBX in DMSO,6 NaBr–
NaBrO3–98% sulfuric acid in 1,4-dioxane,7 HBr–H2O2–
Results and discussion
NH4VO3–KBr in H2O–CHCl3,8 and sodium bromite in acetic
acid.9 Nevertheless, there still remains much room for
Inspired by recent reports that K2S2O8 can be used to mediate
oxidative transformations,11 and the fact that the hydroxybro-
improvement of the method, because the reactions usually
mination of styrenes is well documented in the literature,12 we
envision that a tandem hydroxybromination and oxidation of
styrenes can occur in the presence of K2S2O8. To test our
hypothesis, the K2S2O8-mediated reaction of styrene 1a with
KBr as a bromine source was selected as a benchmark reac-
tion. As shown in Table 1, the use of H2O as a solvent at 60 °C
yielded the desired phenacyl bromide 2a in 84% yield (Table 1,
aCollege of Chemistry and Chemical Engineering, Hunan University,
Changsha 410082, P. R. China. E-mail: ccguo@hnu.edu.cn
bHunan University of Chinese Medicine, Changsha 410082, P. R. China
†Electronic supplementary information (ESI) available: characterization data
and Copies of 1H and 13C NMR spectra for the products. See DOI:
10.1039/c3gc40515j
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Table 1 Optimization of the reaction conditionsa
Table 2 Synthesis of phenacyl bromides from styrenes in the presence of
a
K2S2O8
Oxidant
(equiv.)
Bromine source
(equiv.)
Yieldb
(%)
Entry
Solvent
Entry Substrate
1
Product
Yieldb (%)
76
1
2
3
4
5
6
7
8
K2S2O8 (2.5)
None
KBr (2.0)
KBr (2.0)
KBr (2.0)
KBr (2.0)
KBr (2.0)
KBr (2.0)
KBr (2.0)
KBr (2.0)
KBr (2.0)
NaBr (2.0)
NH4Br (2.0)
KBr (2.0)
KBr (2.0)
KBr (2.0)
H2O
H2O
84
0
<5
<5
<5
0
K2S2O8 (2.5)
K2S2O8 (2.5)
K2S2O8 (2.5)
K2S2O8 (2.5)
K2S2O8 (2.5)
K2S2O8 (2.5)
(NH4)2S2O8 (2.5)
K2S2O8 (2.5)
K2S2O8 (2.5)
K2S2O8 (2.5)
K2S2O8 (2.5)
K2S2O8 (2.5)
DMSO–H2O
CH3CN–H2O
DCE–H2O
DMSO
CH3CN
DCE
H2O
H2O
H2O
H2O
2
72
24
0
0
9
72
78
65
71
78
<5
10
11
12c
13d
14e
3c
H2O
H2O
a Conditions: styrene (0.5 mmol), oxidant (2.5 equiv.), bromine source
(2.0 equiv.), H2O (1 mL), 60 °C, 12 h. b Yields are determined by GC.
c Reaction time: 8 h. d Reaction time: 16 h. e Room temperature.
4
5
6
7
62
42
82
74
entry 1). The control experiment also showed that K2S2O8 was
necessary for the reaction to proceed (Table 1, entry 2). Chan-
ging the solvent to DMSO–H2O, CH3CN–H2O or DCE–H2O
afforded only a trace amount of product whereas the use of
organic solvents alone as the solvent gave no product (Table 1,
entries 3–8). Phenacyl bromide 2a was obtained in 72% yield
when (NH4)2S2O8 was used as the oxidant (Table 1, entry 9).
Among the bromine sources screened, KBr was found to be
most effective (Table 1, entries 10 and 11). Shortening the reac-
tion time decreased the yield (Table 1, entry 12), whereas a
longer reaction time did not improve the yield (Table 1, entry 13).
To achieve a reasonable reaction rate, heating is required
(Table 1, entry 14). On the basis of these results, we decided to
set heating the styrenes at 60 °C in the presence of 2.0 equiv.
of KBr and 2.5 equiv. of K2S2O8 in H2O as our standard con-
dition. Although styrene reacted with KBr in the presence of
K2S2O8 to afford the corresponding phenacyl bromide in 84%
yield, the corresponding phenacyl chloride and iodide were
not obtained in the presence of KCl and KI under the same
conditions (see Fig. S1 and S2 in the ESI†).
With the optimized protocol in hand, we next set out to
explore the scope and limitation of the reaction (Table 2).
First, we tested the substituents on the phenyl group. The
results indicated that the reaction was very sensitive to the
electron density of the phenyl group (2a–k). Styrene derivatives
with electron-donating substituents afforded the desired phen-
acyl bromides in yields ranging from 24 to 72% (Table 2,
entries 2–5), while styrene derivatives bearing electron-with-
drawing substituents provided the desired phenacyl bromides
in yields ranging from 41 to 90% (Table 2, entries 6–11).
Various functionalities, including AcO (2e), MeO (2c), and
8
41
90
88
77
9
10
11
12
73
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(Table 2, entry 18). To illustrate this, the reaction of styrene
with KBr–K2S2O8 was conducted in the presence of pyridine,
and the desired product 2a was not detected by GC/MS (eqn (1)),
thus suggesting that the existence of a pyridine group is
detrimental to the present reaction process. On the other
hand, the reaction of aliphatic alkenes did not give the corres-
ponding α-bromoketones, instead they afforded dibromides as
the main products. For instance, when 1-octene and trans-2-
hexene were subjected to the same reaction conditions, 1,2-
dibromooctane and 2,3-dibromohexane were detected by GC/
MS (Table 2, entries 19 and 20) (see Fig. S3 and S4 in the ESI†).
The results demonstrate that there is competition between the
hydroxybromination and dibromination of olefins in the reac-
tion system.
Table 2 (Contd.)
Entry Substrate
13
Product
Yieldb (%)
21
14
34
53
65
15d
16
ð1Þ
Though the exact mechanism is still not clear at present,
some information has been gathered. First, Table 2 showed
that the reaction did not proceed at all in the absence of
K2S2O8. Thus, the role played by K2S2O8 (oxidant) was justified.
17
18
35
0
1
Second, we used GC/MS and H NMR spectroscopy to monitor
the reaction progress (see Fig. S5 in the ESI†). An intermediate
2-bromo-1-phenyl-ethanol was observed within 0.5 h. To
further support this, 2-bromo-1-phenyl-ethanol (3a) was sub-
jected to the standard reaction condition, and phenacyl
bromide was obtained in 61% yield (eqn (2)). The data indicate
that the reaction proceeds via the bromohydrin as an inter-
mediate. Third, the results that we obtained from Table 1
suggested that carbonyl oxygen of phenacyl bromide originates
from water, not from the molecular oxygen of air. Finally, the
yellow color of the reaction mixture indicates the formation of
bromine during the reaction (see Fig. S6 in the ESI†).5
19
20
62e
54e
a Conditions: 1 (0.5 mmol), K2S2O8 (2.5 equiv.), KBr (2.0 equiv.),
H2O (1 mL), 60 °C, 12 h. b Isolated yields. c 1.2 equiv. of KBr.
d 1.5 equiv. of KBr. e GC yields.
ð2Þ
different halides (2f–k) were tolerated, and thus offered the
possibility for additional functionalization.13 Steric hindrance
significantly affected the efficiency of the reaction. For
Based on these results, a plausible mechanism for the
example, para- (2f), meta- (2g), and ortho-bromo (2h) groups present process was proposed in Scheme 1. Initially, oxidation
gave the corresponding products in 82, 74 and 41% yield, of the bromide ion by the persulfate ion generates molecular
respectively. In addition, the internal styrene derivatives bromine, which further undergoes electrophilic addition onto
afforded the corresponding phenacyl bromides in 21–73% the styrene to afford a three-membered cyclic bromonium ion
yield (Table 2, entries 12–16). Moreover, 2-vinylnaphthalene intermediate. The cyclic intermediate undergoes ring opening
(1q) also reacted in a similar manner, and afforded the corres- by the nucleophile (hydroxy or bromide ion) via SN2 pathway to
ponding bromomethyl 2-naphthyl ketone (2q) in 35% yield yield the vicinal hydroxybromo/dibromo substituted product.
(Table 2, entry 17). Unfortunately, 4-vinylpyridine (1r), which is This also further explained the results of Table 2. Finally, the
a heterocyclic compound, gave full conversion and the corres- bromohydrin intermediate is oxidized to the corresponding
ponding product was not detected by GC/MS and NMR phenacyl bromide.
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Scheme 1 Proposed mechanism.
Conclusions
In summary, a novel way of synthesizing phenacyl bromides
from styrene derivatives was developed. By treating styrene
derivatives with KBr in the presence of K2S2O8 in H2O, the
styrene derivatives were found to undergo hydroxybromination
to produce bromohydrins in situ, which subsequently under-
went oxidation to give a variety of phenacyl bromides in yields
ranging from 21 to 90%. This method is of great value from
the viewpoint of green chemistry and organic synthesis because
of using inexpensive styrenes, non-toxic KBr as the bromine
source, K2S2O8 as oxidant, and H2O as solvent. Work is under-
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General procedure for the synthesis of phenacyl bromides via
K2S2O8-mediated tandem hydroxybromination and oxidation
of styrenes
To a 25 mL Schlenck tube were added K2S2O8 (2.5 equiv.), KBr
(2.0 equiv.), styrenes (0.5 mmol) and H2O (1 mL). The reaction
mixture was warmed to 60 °C (oil bath) and stirred for 12 h.
The reaction was cooled to room temperature, and dichloro-
methane (DCM) (80 mL) and water (40 mL) were added. The
organic layer was separated, and the aqueous phase was
extracted with DCM (40 mL × 2). The combined organic layers
were dried over anhydrous Na2SO4, filtered, and concentrated.
The residue was purified by column chromatography to give
the desired product.
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Acknowledgements
We are grateful for the financial support from the National
Natural Science Foundation of China (J1210040, J1103312).
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