Efficient bromination of olefins, alkynes, and ketones with dimethyl sulfoxide and hydrobromic acid

Article abstract of DOI:10.1039/c5gc00528k

The oxidative bromination of olefins, alkynes, and ketones has been developed with HBr as the brominating reagent and DMSO as the mild oxidant. The simple conditions, high bromide-atom-economy, as well as easy accessibility and low cost of DMSO and HBr make the present strategy prospective for the synthesis of dibrominated alkanes, dibrominated alkenes and α-bromoketones.

Full text of DOI:10.1039/c5gc00528k

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Efficient bromination of olefins, alkynes, and
ketones with dimethyl sulfoxide and
Cite this: DOI: 10.1039/c5gc00528k
hydrobromic acid†
Received 9th March 2015,
Accepted 14th April 2015
Song Song,a Xinwei Li,a Xiang Sun,a Yizhi Yuana and Ning Jiao*a,b
DOI: 10.1039/c5gc00528k
www.rsc.org/greenchem
The oxidative bromination of olefins, alkynes, and ketones has catalyzed oxidative halogenations are special and efficient pro-
been developed with HBr as the brominating reagent and DMSO as cesses in nature.3 Inspired by these transformations in nature,
the mild oxidant. The simple conditions, high bromide-atom- a sophisticated approach, which consists of generating the bro-
economy, as well as easy accessibility and low cost of DMSO and minating reagent in situ from a bromide salt, was adopted for
HBr make the present strategy prospective for the synthesis of the preparation of organobromides. So far, many oxidants
dibrominated alkanes, dibrominated alkenes and α-bromoketones.
such as oxone, NaIO4, Selectfluor, and PhI(OAc)2, O2, H2O2,
etc. have been developed for the oxidative bromination.4,5
Olefins and ketones are useful precursors for investigating
the nature of active halogenating agents and have been used
frequently in oxidative brominations. Importantly, dibromi-
nated alkanes1 and α-bromoketones6 are privileged motifs in
organic synthesis. In 2008, Eissen and Lenoir7 concluded 24
brominations of olefins, and pointed out that most of these
reactions suffer from low atom economy, higher waste pro-
duction or higher cost compared to the bromination with Br2
(Schemes 1a and b).5 Therefore, the development of new
efficient approaches for bromination of olefins as well as other
substrates was highly desirable.
It is difficult to imagine synthesis without organobromides,1
which are conventionally prepared by bromination protocols
using hazardous, toxic, and corrosive molecular bromine
(Scheme 1a). In order to avoid the use of bromine, some modi-
fied brominating reagents (for example, NBS and ammonium
tribromides) have been developed.2 However, these reagents
produce large quantities of organic wastes and employ
bromine for their preparations. Interestingly, the enzyme-
Recently, some new strategies for oxidative bromination
have been developed.8 For example, Iskra and coworkers
reported an efficient and green oxidative bromination of keto-
nes8a and olefins8b using O2 and H2O2 as the green oxidants.
Gao and coworkers realized the bromination of olefins with
oxone promoted by mechanical milling.8c Mizuno realized the
vanadium-catalyzed bromination of unsaturated compounds.8d
Dimethyl sulfoxide (DMSO), one of the most used aprotic
polar solvents, is primarily utilized as an efficient reagent for
the oxidation of alcohols,9 and is widely used as an oxygen,10
carbon,11 or sulfur source12 in organic synthesis. Moreover,
DMSO also participates in the oxidative brominations as the
mild oxidant when combined with HBr.13 The groups of Maje-
tich13a and Dai13b reported the bromination of arenes using
the DMSO/HBr system. We realized the efficient and practical
hydroxybromination of olefins with HBr in DMSO recently in
which DMSO showed its versatile role as a solvent, an essential
oxidant, and also an oxygen source.14 However, to the best of
our knowledge, the efficient oxidative brominations of olefins,
alkynes, and ketones with the DMSO/HBr system have not
been reported yet.
Scheme 1 The development of DMSO-based oxidative brominations.
aState Key Laboratory of Natural and Biomimetic Drugs, Peking University, School of
Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191,
China. E-mail: jiaoning@bjmu.edu.cn; http://sklnbd.bjmu.edu.cn/nj;
Fax: (+86)-010-8280-5297; Tel: (+86) 01082805297
bShanghai Key Laboratory of Green Chemistry and Chemical Processes, Department
of Chemistry, East China Normal University, Shanghai 200062, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5gc00528k
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Herein, as our continuous efforts in developing DMSO- delight, the yield of 3a increased to 75% when 1a was stirred
based reactions, we report the oxidative bromination of in EA in the presence of 2.4 equiv. of HBr and 2.6 equiv. of
olefins, alkynes, and ketones using DMSO/HBr for the first DMSO (entry 2). Only traces of 3a were obtained in acetone or
time (Scheme 1c). The mild conditions, low cost of DMSO and water as the solvent (entries 5 and 6). The amount of DMSO
HBr, broad substrate scope make the present strategy extre- influenced the yield of 3a strongly (entries 7–10). The reaction
mely attractive and prospective for the efficient and low-cost occurred very quickly (0.5 h) in the presence of 1.2 equiv. of
synthesis of dibrominated alkanes and α-bromoketones.
DMSO as the oxidant and afforded the highest yield (80%) in
Our initial study began with the hydroxybromination of this case (entry 9). On increasing the amount of DMSO to 4
2-vinylnaphthalene 1a. It was very interesting to find that equiv. the yield decreased to 61% (entry 10). The reaction of 1a
when the reaction was carried out in the presence of 1.2 equiv. at 40 °C also worked well leading to 3a in 68% yield. However,
of aqueous HBr in DMSO at 60 °C for 12 h, 9% yield of the a longer reaction time was required (2 h, entry 11, Table 1).
dibrominated byproduct 3a was obtained along with the
Under the optimum conditions (entry 9, Table 1), a series
bromohydrin product 2a.14 As intermediate I was generated of styrenes bearing various groups (R = Me, NO2, Cl, Br, Ph)
from 1a and Br+, we speculated that the dibrominated alkane furnished the dibromination transformation producing the
3a could be produced when I undergoes nucleophilic attack by desired dibromoalkanes 3a–i in good yields (Table 2). The bro-
Br−. This preliminary discovery revealed the possibility of mination of o-, m-, p-substituted styrenes in which the substi-
dibromination of olefins with simple and readily available tuent group showed different steric hindrance afforded the
DMSO and HBr (Scheme 2).
products in similar yields. α-Methyl styrene 1j was dibromi-
In order to selectively control the generation of dibromina- nated smoothly to give 3j bearing tertiary bromide in 73%
tion product 3a, the DMSO/HBr system was investigated in yield. The dibromination of (E)-β-methyl styrene 1k produced
different solvents instead of using DMSO as the solvent under anti-3k in 78% yield. For cyclic alkenes, the trans-brominated
an air atmosphere at 60 °C (entries 1–6, Table 1). To our products 3l–n were highly selectively obtained in 73–85%
yields.
It is noteworthy that the dibromination of aliphatic olefins
also worked well (3o–v, Table 2). The mono- (1o–q), di- (1r–u),
and even tri-substituted (1v) olefins furnished the corres-
ponding products 3o–v in high yields (81–94%, Table 2). On
exposure of the aliphatic cyclic olefins to the optimum con-
Table 2 Substrate scope of olefinsa
Scheme 2 The observation of oxidative dibromination of olefins.
Table 1 Optimization of the reaction conditionsa
Entry
Solvent
X
Time
Yieldb of 3a (%)
1
2
3
4
5
6
7
8
CHCl3
EA
Toluene
MeCN
Acetone
H2O
EA
EA
EA
EA
EA
2.6
2.6
2.6
2.6
2.6
2.6
0
0.5
1.2
4
1 h
1 h
1 h
62
75
65
44
Trace
Trace
27
48
80
1 h
10 h
10 h
10 h
10 h
0.5 h
1 h
9
10
61
78
11c
1.2
2 h
a Reaction conditions: HBr (48%, 1.2 mmol) was added to a solution of
olefin 1 (0.5 mmol) and DMSO (0.6 mmol) in EA (2 mL) at 60 °C. The
solution was stirred at 60 °C for 0.5 h under an air atmosphere.
Isolated yields.
a Reaction conditions: a solution of 1a (0.5 mmol), HBr (1.2 mmol),
and DMSO in a solvent (2 mL) was stirred at 60 °C under an air
atmosphere. b Isolated yields. c The reaction was carried out at 40 °C.
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ditions, trans-bromoalkanes (3s–v) were highly selectively
produced.
Remarkably, the reactions of alkenes 4a–b bearing the
ortho-carboxy group gave the bromolactonization products 5 in
high yields in this efficient DMSO/HBr system at 60 °C (eqn
(1)). Compared to the previous reports on bromolactonization
using NBS or its analogues,15 our DMSO/HBr system features
low cost and high atom economy.
Scheme 3 Previously reported reactions of ketones with the DMSO/
HBr system.
Table 4 Substrate scope of ketonesa
ð1Þ
Inspired by these results, the bromination of alkynes was
also investigated by employing this efficient DMSO/HBr system
to try the efficient synthesis of dibromoolefin. It is very inter-
esting that when alkyne 6a was exposed to HBr and DMSO in
EA at 60 °C, (E)-dibromoolefin 7a was obtained as the only
product in 86% yield (Table 3), which demonstrated that the
present DMSO/HBr system could be successfully employed in
the dibromination of alkynes. Dibutyl substituted acetylene 6c
was dibrominated in 83% yield. Besides internal alkynes, the
bromination of terminal alkynes such as phenylacetylene (6d)
and octyne (6e) afforded trans-brominated olefins in good
yields.
Encouraged by the successful application of the DMSO/HBr
system in bromination of olefins and alkynes, we further
expanded the present system in oxidative bromination of
ketones. Up to now, various oxidative systems16 including HBr/
H2O2,8a NaBr/NaBrO3,16b CuBr2,16c TMSBr/KNO3,16d NH4Br/
oxone,16e and HBr/TBHP16f have been used in oxidative bromi-
nation of ketones. Although the reactions between ketone and
DMSO/HBr have been reported,17 unfortunately phenylglyox-
als17a and dimethyl aryl acylsulfonium bromides17b instead of
α-bromoketones were obtained (Scheme 3). The mechanism
showed that α-bromoketone, which was generated from
ketones and DMSO/HBr, was converted to other products
because of the excess amount of DMSO or aqueous HBr.
a Reaction conditions:
hydrobromic acid (48%, 0.6 mmol) in EA (2 mL) was stirred under air
at 60 °C for 2–6 hours. Isolated yields.
a solution of 8 (0.5 mmol) and aqueous
We hypothesized that the α-bromoketone might be
obtained if the present DMSO/HBr system (in which DMSO
was used in a stoichiometric amount) was employed instead of
using DMSO as the solvent in the reported literature17
(Scheme 3). To our delight, when acetophenone 8a reacted
with 1.2 equiv. of HBr and DMSO in EA at 60 °C, α-bromo-
acetophenone 9a was obtained in 73% yield (Table 4). Besides
methyl ketones, propyl, isopropyl, and cyclohexyl substituted
ketones were smoothly monobrominated to bromoketones in
high yields (90–94%, Table 4) in the presence of 1.2 equiv. of
DMSO and HBr. The present approach provides efficient and
simple access to α-bromoketones.
On the basis of the previous reports,14,17,18 we proposed the
mechanism
of
DMSO-based
oxidative
brominations
(Scheme 4). Initially, HBr was oxidized with stoichiometric
DMSO to Br2 or DMS·Br2 in EA. The Br2 or DMS·Br2 enabled
Table 3 Substrate scope of alkynesa
a Reaction conditions: HBr (48%, 1.2 mmol) was added to a solution of
alkyne 6 (0.5 mmol) and DMSO (0.6 mmol) in EA (2 mL) at 60 °C. The
solution was stirred at 60 °C under an air atmosphere. Isolated yields.
Scheme 4 Proposed mechanism.
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the dibromination of alkenes smoothly to produce dibromi-
nated alkanes. The reaction of Br2 or DMS·Br2 with a ketone
afforded the bromoketone with the formation of HBr which
was oxidized by DMSO for the next oxidative cycle.
4 For a review, see: (a) A. Podgoršek, M. Zupan and J. Iskra,
Angew. Chem., Int. Ed., 2009, 48, 8424. For selected oxidative
brominations, see: (b) K. Yonehara, K. Kamata,
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Conclusions
In conclusion, we have developed a novel and efficient
approach for the dibromination of olefins, dibromination of
alkynes and bromination of ketones by using the simple
DMSO/HBr system. This chemistry is appreciable due to the
safety, the simplicity, the availability, and the cheapness of the
DMSO and HBr reagents, and it also provides an alternative
approach to the dibrominated alkanes, dibrominated alkenes,
bromolactones and α-bromoketones, which are very important
reagents and have been widely used in organic synthesis. The
simple conditions made the present protocol very attractive
and prospective. Studies on further applications of this proto-
col and the use of DMSO as an oxidant are ongoing in our
laboratory.
Acknowledgements
Financial support from the National Basic Research Program
of China (973 Program) (grant No. 2015CB856600), the
National Natural Science Foundation of China (no. 21325206,
21172006) and the National Young Top-notch Talent Support
Program is greatly appreciated. We thank Xiang Sun in this
group for reproducing the results of 4e and 5e.
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