One-pot syntheses of α,α-dibromoacetophenones from aromatic alkenes with 1,3-dibromo-5,5-dimethylhydantoin

Article abstract of DOI:10.1016/j.tetlet.2016.12.088

A novel method for the preparation of α,α-dibromoacetophenones from aromatic alkenes was reported. This procedure was mediated by 1,3-dibromo-5,5-dimethylhydantoin, which served as bifunctional reagent, proceeding oxidation and bromination in one-pot.

Full text of DOI:10.1016/j.tetlet.2016.12.088

Accepted Manuscript
One-pot syntheses of α,α-dibromoacetophenones from aromatic alkenes with
1,3-dibromo-5,5-dimethylhydantoin
Ping Wu, Senhan Xu, Hao Xu, Haiyan Hu, Wei Zhang
PII:
S0040-4039(16)31755-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.088
TETL 48500
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
30 November 2016
29 December 2016
30 December 2016
Please cite this article as: Wu, P., Xu, S., Xu, H., Hu, H., Zhang, W., One-pot syntheses of α,α-
dibromoacetophenones from aromatic alkenes with 1,3-dibromo-5,5-dimethylhydantoin, Tetrahedron Letters
(2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.12.088
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One-pot syntheses of α,α-dibromoacetophenones from aromatic
alkenes with 1,3-dibromo-5,5-dimethylhydantoin
Ping Wu a‡, Senhan Xu a‡, Hao Xu a,b, Haiyan Hu b, Wei Zhang a,*
a School of Pharmacy, Fudan University, Shanghai 201203
b Marine Science and Technology College, Zhejiang Ocean University, Zhoushan 316000
‡ These two authors contribute equally to this work.
* E-mail: zhangw416@fudan.edu.cn
Keywords: α,α-Dibromoacetophenone; 1,3-Dibromo-5,5-dimethylhydantoin; One-pot synthesis;
Oxidative bromination; Alkene
Abstract: A novel method for the preparation of α,α-dibromoacetophenones from aromatic
alkenes was reported. This procedure was mediated by 1,3-dibromo-5,5-dimethylhydantoin, which
served as bifunctional reagent, proceeding oxidation and bromination in one-pot.
α,α-Dibromoacetophenones are versatile intermediates used for the preparations of
natural products and pharmaceuticals.1 These compounds are regarded as superior
alternatives to α-bromoacetophenones in heterocycles synthesis because of their high
reactivity, non-lachrymatory nature, and convenient preparation from diverse starting
materials.2 Pioneered by Parkinson’s work a century ago, the most known methods for
preparing α,α-dibromoacetophenones are based on bromination of acetophenones
with molecular bromine,3a or other bromine source such as thionyl bromide,3b
hexabromocyclopentadiene,3c
benzyltrimethylammonium
tribromide,3d
dioxane-dibromide,3e and H2O2-HBr3f (Scheme 1a). In the past decades, oxidative
bromination of alkynes has attracted attention because it installs two versatile handles
simultaneously for further structural elaboration (Scheme 1b).4 Recently, Itoh and
co-workers5 developed a tandem oxidation/bromination of ethyl aromatics to
α,α-dibromoacetophenones with molecular oxygen under visible light irradiation
(Scheme 1c). Although significant progresses have been made in this field, many of
the known strategies suffer from one or more limitations, such as expensive reagents,
poor yields, toxic chemicals, or the use of heavy metals. Therefore, the development
of new, mild, and economic approaches to α,α-dibromoacetophenones is still highly
desired.
1,3-Dibromo-5,5-dimethylhydantoin (DBH) is a cheap bulk chemical widely used
as disinfection agents and bleaching agents in industrial and domestic water
treatment.6 This environmental benign reagent is usually utilized as bromine source in
the bromination of alkenes, alkynes, and aromatic C-H bonds.7 DBH is also known as
a good oxidant in the preparation of ketones from secondary alcohols and disulfides
from thiols.8 Very recently, we reported that DBH could be served as a bifunctional
reagent (oxidative bromination) in one-pot syntheses of α-bromo/amino ketones from
alkenes.9 In the course of further study of these reactions, we also found that DBH

was efficient for converting aromatic alkenes to corresponding α,α-bromoketones by
tuning reaction conditions. To the best of our knowledge, such conversions have not
been reported so far (Scheme 1d).
Scheme 1. Strategies for synthesis of α,α-dibromoacetophenones.
Initially, we conducted the reaction by using styrene as a test substrate (Table 1).
Low reaction temperature was invalid to the desired transformation, leaving mainly
the unconsumed intermediates 3 and 4 (Table 1, entries 1-4). Heating the reaction
mixture to 80 °C and stirred for 9 h gave dibromoketone 2a in good yield, along with
some over-brominated tribromoketone 5 (Table 1, entries 5-6). However, lots of the
intermediate monobromoketone 4 remained and was isolated when the reaction was
quenched after stirring at this temperature for 2 h (Table 1, entries 7-8). On the other
hand, it also indicated that the desired oxidative bromination is more effective when
performed in DME-H2O than in dioxane-H2O (Table 1, entry 7 vs 8). Similar results
were also observed at low temperature (Table 1, entry 3 vs 4). The former gave 83%
yield of monobromoketone 4, while the later gave only 36% of this intermediate along
with 40% unoxidated alcohol 3. Thus the mixed solvent of DME-H2O was adopted, in
which the desired product 2a was afforded in 69% yield after 4 h (Table 1, entry 9).
Reducing the loading of DBH from 3.0 to 2.0 equiv. gave very low yield of 2a; while
when 4.0 equiv. of DBH was loaded, the yield increased slightly only (Table 1, entries
10-11). Interestingly, appropriate amount of water was beneficial to improving the
yield of 2a (Table 1, entry 12 vs 11), but too much water retarded the further
brominating of monobromoketone 4 to dibromoketone 2a (Table 1, entries 13-14).
Table 1 Study of reaction conditions utilizing styrene as a model substratea
Yieldb (%)
DBH
(eq.)
3.0
Temp
(°C)
25
Time
(h)
16
Entry
Solvent
2a
3
3
38
40
/
4
5
6
8
c
1
2
3
4
5
DME/H2O=10/1
Dioxane/H2O=10/1
DME/H2O=10/1
Dioxane/H2O=10/1
DME/H2O=10/1
30
29
83
36
17
/
3.0
25
16
/
/
/
10
6
3.0
40
12
4
3.0
40
12
3
40
/
/
10
5
3.0
80
9
65
5

6
7
3.0
3.0
3.0
3.0
2.0
4.0
3.0
3.0
3.0
Dioxane/H2O=10/1
DME/H2O=10/1
80
80
80
80
80
80
80
80
80
9
2
2
4
8
4
4
4
4
63
54
11
69
21
71
87
37
45
/
/
/
/
/
/
/
/
/
22
24
73
20
51
7
5
/
5
7
6
7
7
6
/
8
Dioxane/H2O=10/1
DME/H2O=10/1
/
9
/
10
11
12
13
14
DME/H2O=10/1
/
DME/H2O=10/1
13
/
DME/H2O=4.5/1
DME/H2O=2.5/1
H2O (with 1% tween-80)
3
59
40
/
/
/
/
a Performed with 0.5 mmol of styrene (1a) in 1.5 mL of solvent.
b Isolated yield by PTLC.
c “/” means not observed or only trace by TLC but could not be isolated by PTLC.
Having established the optimal reaction conditions, we then examined the
generality of this DBH mediated one-pot oxidative bromination. As shown in Table 2,
most α,α-dibromoacetophenones are obtained in good yields regardless of a
electron-withdrawing or donating group on the benzene ring. Note that o-methyl
styrene (1b) was sensitive to temperature. Standard protocol gave
α,α-dibromoacetophenone with additional bromination of the benzene ring (2c, Table
2, entry 3). When performed at lower temperature, desired α,α-dibromoacetophenone
2b was obtained in the yield of 57%, leaving the benzene ring intact (Table 2, entry 2).
Br, F, and Cl substituents on the phenyl ring were well tolerated, which enable
potential applications in further coupling (Table 2, entries 6-10). Ester and nitro
groups were also compatible, albeit with moderate yields (Table 2, entries 11-13).
Furthermore,
2-vinylpyridine
(1n)
and
internal
styrene
derivative
1,2-dihydronaphthalene (1o) were transformed to corresponding α,α-dibromoketones
smoothly in satisfactory yields (Table 2, entries 14-15).
Table 2. One-pot oxidative bromination of aromatic alkenes mediated by DBH.
Entry
1
Substrate
Product
Isolated yield
(%)
87
57
2a

3b
4
73
80
91
5
6
7
81
76
83
78
38
52
33
49
63
74
8
9
10c
11
12
13
14
15
a Carried out at 70 °C for 4 h.
b Carried out at 80 °C for 5 h.
c Carried out at 75 °C for 2.5 h.
To probe the mechanism of the reactions, some information has been gathered. As
presented in Table 1, all the TLC detectable products were isolated and subjected to

NMR analysis. Furthermore, we also performed some control experiments, as shown
in Scheme 2. Based on these results mentioned above and related reports,10 a plausible
mechanism is proposed in Scheme 3. The reaction was initiated by the release of
active specie HBrO when DBH was dissolved in water.11 Both alcohol 3 and
dibromide 6 were generated via three-membered cyclic bromonium ion intermediate.
The former bromohydrin then converted to hypobromite intermediate, which cleaves
one molecular of HBr to give α-bromoketone 4. Further bromination of 4 gave desired
α,α-dibromoketone 2a and over-brominated product 5, respectively.
Scheme 2. Control experiments.
Scheme 3. Plausible reaction mechanism.
In summary, we have developed a convenient procedure for the synthesis of
α,α-dibromoacetophenones mediated by DBH. This easy-to-handle and metal-free
one-pot protocol has established a new bridge between aromatic alkenes and
α,α-dibromoacetophenones. More explorations of DBH promoted reactions are
ongoing in our laboratory and will be reported in due course.
Acknowledgments
We gratefully acknowledge financial support from the National Natural Science
Foundation of China (81573340), the “ZhuoXue” Talent Plan of Fudan University,
and the FDUROP of Fudan University (XiYuan Project).
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One-pot syntheses of α,α-dibromoacetophenones from aromatic
alkenes with 1,3-dibromo-5,5-dimethylhydantoin
Ping Wu a‡, Senhan Xu a‡, Hao Xu a,b, Haiyan Hu b, Wei Zhang a,*
a School of Pharmacy, Fudan University, Shanghai 201203
b Marine Science and Technology College, Zhejiang Ocean University, Zhoushan 316000
‡ These two authors contribute equally to this work.
* E-mail: zhangw416@fudan.edu.cn

One-pot syntheses of α,α-dibromoacetophenones from aromatic
alkenes with 1,3-dibromo-5,5-dimethylhydantoin
Ping Wu a‡, Senhan Xu a‡, Hao Xu a,b, Haiyan Hu b, Wei Zhang a,*
a School of Pharmacy, Fudan University, Shanghai 201203
b Marine Science and Technology College, Zhejiang Ocean University, Zhoushan 316000
‡ These two authors contribute equally to this work.
* E-mail: zhangw416@fudan.edu.cn
High lights:
ꢀ First report for the preparation of α,α-dibromoacetophenones from aromatic
alkenes.
ꢀ Readily available starting materials, metal-free and easy to handle procedures.
ꢀ One-pot oxidative bromination mediated by bifunctional reagent
1,3-dibromo-5,5-dimethylhydantoin.