Facile Synthesis of β-Bromostyrenes by Direct Bromination of Styrenes with N -Bromosuccinimide and Sodium Persulfate

Article abstract of DOI:10.1055/s-0040-1707199

A new, direct, efficient, and transition-metal-free method is reported for the synthesis of β-bromostyrenes from styrenes by using N -bromosuccinimide as the brominating reagent and sodium persulfate (Na ₂S ₂O ₈) as the oxidant. This convenient and concise reaction is practical, operationally simple, and can be adapted for large-scale syntheses.

Full text of DOI:10.1055/s-0040-1707199

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–D
letter
A
en
Y. Jing et al.
Letter
Synlett
Facile Synthesis of -Bromostyrenes by Direct Bromination of
Styrenes with N-Bromosuccinimide and Sodium Persulfate
Yi Jinga
Yan Gaoa
Qianyi Zhaoa
Xuenian Chen*a,b
Yan-Na Ma*a
NBS, Na2S2O8
Br
transition-metal free
direct bromination
low cost
DCE, 100 °C
environmentally friendly
14 examples
32–91% yields
a School of Chemistry and Chemical Engineering, Henan
Key Laboratory of Boron Chemistry and Advanced Energy
Materials, Henan Normal University, Xinxiang, Henan
453007, P. R. of China
xnchen@htu.edu.cn
mayanna@htu.edu.cn
b College of Chemistry and Molecular Engineering, Zheng-
zhou University, Zhengzhou, Henan 450001, P. R. of China
Received: 23.05.2020
Accepted after revision: 11.06.2020
Published online: 27.07.2020
chloroethene with a Ru complex as the catalyst (Scheme
1A).7 In 2003, Morrill and Grubbs synthesized a series of vi-
nylboronates through ruthenium-catalyzed olefin cross-
metathesis; these products can be further transformed into
vinyl halides (Scheme 1B).8 In 2009, Pawluć, Marciniec, and
their co-workers synthesized -bromo- and -iodostyrenes
through silylative coupling of vinylsilanes with substituted
styrenes in the presence of Ru(CO)Cl(H)(PPh3)3, followed by
halogenation with the appropriate N-halosuccinimide
(Scheme 1C).9 In 2017, Walkowiak and co-workers replaced
the vinylboronates by vinylsilanes, and also realized this
transformation.10
DOI: 10.1055/s-0040-1707199; Art ID: st-2020-u0306-l
Abstract A new, direct, efficient, and transition-metal-free method is
reported for the synthesis of -bromostyrenes from styrenes by using
N-bromosuccinimide as the brominating reagent and sodium persul-
fate (Na2S2O8) as the oxidant. This convenient and concise reaction is
practical, operationally simple, and can be adapted for large-scale syn-
theses.
Key words bromination, styrenes, bromosuccinimide, green chemis-
try, sodium persulfate, bromostyrenes
Cl
(100 equiv)
A: [Ru]
-Halostyrenes are important building blocks for such
transition-metal-catalyzed cross-coupling reactions as the
Heck, Suzuki, Hiyama, Stille, or Ullmann processes, which
are among the most commonly used methods in organic
transformations and natural product syntheses.1 In recent
decades, several methods for the synthesis of alkenyl ha-
lides have been developed.2 The classical methods are
based on the Hunsdiecker decarboxylative bromination of
,-unsaturated carboxylic acids,3 the hydroxybromination
of styrenes accompanied by dehydration,4 or olefination of
aromatic aldehydes.5 Hydrometallation of alkynes followed
by halogenation is another effective protocol for the syn-
thesis of -halostyrenes. The addition of an H–E bond (E =
Si, B, Sn, Zr) to an alkyne leads to the corresponding vinyl
derivative, which can be further substituted by a halogen
atom by using various halogenating agents.6
Cl
Cl
Ar
reflux
[Ru]
B:
X2, base
X
Bpin
Ar
X = Br/I
Ar
R
Bpin
R = H, Me
Ar
NXS
[Ru]
SiMe3
C:
D:
SiMe3
X
Ar
Ar
X = Br/I
MeCN
CH2Cl2, reflux
transition-metal free
direct bromination
low cost
NBS, Na2S2O8
Br
Ar
DCE, 100 °C
this work
environmentally friendly
Scheme 1 Synthesis of -arylvinyl halides from styrenes
Because commercially available substituted styrenes
are much more abundant and less expensive than the cor-
responding phenylacetylene analogues, the use of substi-
tuted styrenes in the synthesis of -halostyrenes has at-
tracted much attention. In 2008, Grela’s group reported the
synthesis of -chlorostyrenes through an olefin cross-me-
tathesis reaction between terminal alkenes and (E)-1,2-di-
All the above reactions using styrenes as starting mate-
rials require expensive Ru complexes as catalysts, and in
most cases require the use of expensive vinylboronates or
vinylsilanes to form (-arylvinyl)boronate or (-arylvi-
nyl)silane intermediates, which greatly increases their cost
and makes it difficult to achieve large-scale syntheses.
Therefore, the search for a direct method for synthesizing -
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Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Y. Jing et al.
Letter
Synlett
halostyrenes from styrenes under transition-metal-free
conditions is of great significance. In the past decade, the
direct borylation,11 fluorination,12 sulfonylation,13 phos-
phorylation,14 nitration,15 and fluoroalkylation16 of styrenes
have all been reported, whereas the direct halogenation of
styrenes has been less well studied. We have achieved a di-
rect synthesis of -bromostyrenes from styrenes by using
NBS as the brominating reagent17 and Na2S2O8 as the oxi-
dant in DCE in a sealed tube (Scheme 1D). Compared with
previous ruthenium-catalyzed methods, our reaction con-
ditions were simpler and operationally more convenient.
We started our investigation by using styrene as a mod-
el substrate with NBS as the bromine source in DCE to
screen various oxidants (Table 1, entries 1–9). To our de-
light, the desired -bromostyrene (2a) was obtained in 56%
yield and a 10:1 E/Z ratio when Na2S2O8 was used (entry 2).
With Na2S2O8 as the oxidant, we then investigated other
bromine sources and found that 1,3-dibromo-5,5-dimethyl-
hydantoin (DBDMH), tribromoisocyanuric acid (TBCA), and
dibromoisocyanuric acid (DBCA) also promoted this trans-
formation, but NBS was still the best choice (entries 10–15).
We next examined alternative solvents but, unfortunately,
the reaction failed in all cases (entries 16–21). The yields of
2a decreased at both higher or lower reaction temperatures
(entries 22 and 23). However, when the concentration was
increased, the yield improved to 63% (entry 24).18 Encour-
aged by these results, we attempted to synthesize -iodo-
styrene and -chlorostyrene by using N-iodosuccinimide
(NIS) and N-chlorosuccinimide (NCS), respectively, as halo-
genated reagents, but these reactions failed (entries 25 and 26).
With the optimized reaction conditions in hand, we ex-
amined the substrate scope of styrenes with various sub-
stituents (Table 2). First, styrenes bearing various groups at
the para-position were explored. This showed that Me, F, Cl,
Br, I, and CH2Cl groups were all suitable substituents for
this transformation, and the best yield of 72% was obtained
when 4-fluorostyrene was used (Table 2, entries 2–7). 1-(2-
Bromovinyl)-3-chlorobenzene (2h) was obtained in 42%
yield with an E/Z ratio of 6.4:1 (entry 8). 2-Halostyrenes
also reacted well to provide the desired products in moder-
ate yields (entries 9–11). Note that the substrates with hal-
ogen atom in the ortho, meta, or para positions could be
used this transformation, although the yield decreased
slightly when a meta-halostyrene was used (entries 4, 8,
and 10). A polysubstituted styrene also gave the corre-
sponding product 2l in 42% yield (entry 12). Finally, when
1,1-diphenylethylene was used as a reactant, the desired
product 2m was obtained in 66% yield (Table 2, entry 13);
however, the corresponding iodo compound 2n was ob-
tained in 91% yield when NBS was replaced by NIS in this
reaction (entry 14). We therefore believe that our reaction
might proceed by a radical mechanism.
Table 1 Reaction Conditions Screeninga
Br
oxidant
+
[Br]
solvent
1a
2a
Entry
[X]
NBS
Oxidant
Solvent
Yieldb (%) E/Zc
1
2
K2S2O8
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
toluene
MeCN
THF
trace
56
–
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
Na2S2O8
(NH4)2S2O8
Oxone
10:1
–
3
trace
trace
ND
4
–
5
PhI(OAc)2
mCPBA
–
6
ND
–
7
AgOAc
trace
ND
–
8
Cu(OAc)2
TBHP
–
9
ND
–
10
11
12
13
14
15
16
17
18
19
20
21
22f
23g
24h
25
26
DBDMHd
TBCAe
DBCAd
NaBr
NH4Br
Bu4NBr
NBS
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
32
8:1
8:1
8:1
–
18
12
ND
ND
–
ND
–
trace
ND
–
NBS
–
NBS
ND
–
NBS
DMF
DMSO
MeOH
DCE
DCE
DCE
DCE
DCE
trace
ND
–
NBS
–
NBS
ND
–
NBS
48
10:1
8:1
10:1
–
NBS
32
NBS
63
NIS
trace
ND
NCS
–
a Reaction conditions: styrene (1.0 mmol), halogen source [X] (1.05 mmol),
oxidant (2.0 mmol) solvent (2 mL), 100 °C, under air, 3 h (unless otherwise
noted).
b Isolated yield; ND = not detected.
c Determined by 1H NMR.
d 0.6 mmol.
e 0.35 mmol.
f 80 °C.
g 120 °C.
h DCE (1.5 mL).
To verify our hypothesis, we performed several control
experiments (Scheme 2). When 2.0 equivalents of a free-
radical scavenger such as (2,2,6,6-tetramethylpiperidin-1-
yl)oxyl (TEMPO) or butylated hydroxytoluene (BHT) were
added to the reaction mixture of styrene (1a), none of the
desired product 2a was detected (Schemes 2A and 2B).
When a 1:1 mixture of styrene (1a) and 1,1-diphenyle-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

C
Y. Jing et al.
Letter
Synlett
Table 2 Substrate Scopea
Br
Br
Br
standard conditions
standard conditions
A:
B:
+ TEMPO
Na2S2O8
Br
1a
1a
2a
2a
+
NBS
Ar
Ar
DCE, 100 °C
Entry
1
Product
Yield (%)
63
E/Zb
+
+
BHT
Br
2a
2b
10:1
Ph
Ph
standard conditions
C:
+
Br
Ph
1m
Br
Br
Ph
2
3
4
5
32
72
62
58
5.9:1
5.4:1
7.0:1
5.9:1
2a
2m
1a
1a/1m = 1:1
trace
52%
Scheme 2 Control experiments
2c
2d
2e
F
Cl
Br
I
Based on the above reactions and previous reports,19
a
Br
Br
plausible mechanism is proposed (Scheme 3). Initially, a
bromine radical Br∙ is produced from NBS by heating. After a
radical-addition step, the radical intermediate I is formed
from styrene (1a). Subsequently, intermediate II is generat-
ed by the reaction of radical intermediate I and Na2S2O8. In-
termediate II undergoes elimination of NaHSO4 to give the
desired -bromostyrene (2a). 2-Bromo-1-phenylethanol
(3a) was detected by GC/MS after the reaction was com-
pleted, proving the formation of intermediate II.
Br
6
7
8
2f
38
56
42
>20:1
6.7:1
6.4:1
Br
2g
2h
Cl
Cl
O
Br
Br
N
Br
2a
Br
Br
Br
O
9
10
11
12
2i
2j
2k
2l
68
56
38
42
7.6:1
5.6:1
4.3:1
6.2:1
NaHSO4
heat
Br
F
O
ONa
O
O
S
S
O
OSO3Na
Br
Br
O
NaO
O
Cl
Br
H
1a
I
II
OH
Br
Br
3a
F
identified by GC-MS
Ph
Ph
Scheme 3 Proposed mechanism
Br
13
2m
2n
66
91
–
–
To investigate the practicality of this transformation, a
scaled-up reaction was carried out with styrene as the
model substrate. The reaction proceeded well, and the de-
sired product -bromostyrene (2a) was obtained with no
decrease in yield compared with the small-scale reaction
(Scheme 4).
I
14c
a Reaction conditions: styrene (2.0 mmol), NBS (2.1 mmol), Na2S2O8 (4.0
mmol), DCE (3 mL), 100 °C, under air, 3 h.
b Determined by 1H NMR.
c NIS (2.1 mmol) was used instead of NBS.
Br
Na2S2O8
+
NBS
DCE, 100 °C
1a
20 mmol, 2.08 g
2a
65%, 2.38 g
thene (1m) was subjected to the reaction system, a signifi-
cant preference for bromination of 1m over 1a was found
(Scheme 2C).
Scheme 4 Gram-scale reaction for the synthesis of -bromostyrene
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

D
Y. Jing et al.
Letter
Synlett
In summary, a direct bromination of styrenes was de-
veloped for the efficient and convenient synthesis of -bro-
mostyrenes under transition-metal-free conditions. The
present method is applicable to a variety of substituted sty-
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Funding Information
(10) Szyling, J.; Franczyk, A.; Pawluć, P.; Marciniec, B.; Walkowiak, J.
Org. Biomol. Chem. 2017, 15, 3207.
This work was supported by the National Natural Science Foundation
of China (Nos. 21801065 and U180425).
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Acknowledgment
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https://doi.org/10.1055/s-0040-1707199.
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Primary Data
for this article are available online at https://doi.org/10.1055/s-0040-
1707199 and can be cited using the following DOI: 10.4125/pd0119th.
Pri
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ary
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ataPri
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ary
D
ata
1
0
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1
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1
1
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0
2
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1
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stry
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(18) (2-Bromovinyl)benzene (2a); Typical Procedure
Styrene (1a; 2.0 mmol, 1.0 equiv) was added to a solution of
NBS (2.1 mmol, 1.05 equiv) and Na2S2O8 (4.0 mmol, 2.0 equiv) in
DCE (3 mL) in a sealed tube. The mixture was warmed to 100 °C
and stirred for 3 h. When the reaction was complete, the
mixture was purified directly by flash chromatography (silica
gel, petroleum ether) to give a white oil; yield: 230.5 mg (63%,
E/Z = 10:1).
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© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D