Mild and Efficient Vicinal Dibromination of Olefins Mediated by Aqueous Ammonium Fluoride

Article abstract of DOI:10.1055/s-0036-1588506

A mild and efficient vicinal dibromination of olefins has been developed by using saturated aqueous ammonium fluoride solution as the promoter. Inexpensive and commercially available N -bromosuccinimide (NBS) was used as the brominating reagent. The corresponding vicinal dibromoalkanes could be obtained in good to excellent yields.

Full text of DOI:10.1055/s-0036-1588506

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
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A
en
W. H. Ng et al.
Letter
Synlett
Mild and Efficient Vicinal Dibromination of Olefins Mediated by
Aqueous Ammonium Fluoride
Br
N
Wing Hin Ng
Tony K. M. Shing*
Ying-Yeung Yeung*
R1
O
O
H
H
R2
R3
Br
R2 R3
Br
R1
sat. NH4F(aq)
CH2Cl2, rt
Department of Chemistry, The Chinese University of Hong Kong,
Shatin, NT, Hong Kong, P. R. of China
yyyeung@cuhk.edu.hk
15 examples
up to 83%
R1-R3 = H, aryl, alkyl
Received: 17.05.2017
Accepted after revision: 23.06.2017
Published online: 08.08.2017
ous dibromination reactions. The second approach involves
the direct combination of electrophilic brominating reagent
(Br+) and bromide source (Br–). N-Bromosuccinimide (NBS)
and lithium bromide were employed together to allow di-
bromination of olefins and other C–C unsaturated bonds.14
This approach has also been adapted by Burns for the chal-
lenging asymmetric dibromination of allylic alcohols, utiliz-
ing diethyl dibromomalonate and bromotitanium triiso-
propoxide pair with chiral TADDOL ligands.15 The third ap-
proach referred to bromide oxidation, where Br– is oxidized
to Br+ for the generation of Br2 in situ. Oxidant–bromide
pairs such as DMSO–HBr,16 H2O2–HBr,17 oxone–NaBr,18 and
cerium(IV) ammonium nitrate (CAN)–KBr,19 for dibromina-
tion have been documented. The forth approach referred to
bromenium reduction, in which Br+ is reduced to Br– to gen-
erate Br2 in situ. Some novel organocatalytic protocols for
dibromination of olefins that have emerged in recent years
fall into this category. NBS and 1,3-dibromo-5,5-dimethyl-
hydantoin (DBDMH) were utilized as Br sources using
thiourea,20 hypervalent iodine,21 pyrrolidine,22 and benzoic
acid23 as the organocatalysts, although the reductants in
their systems remained unclear.
Herein, we report our discovery of a mild reductive di-
bromination of olefins by using the halogen source N-bro-
mosuccinimide (NBS) with saturated aqueous ammonium
fluoride solution (NH4F(aq)) as the promoter. NBS is com-
monly used as a mild source of electrophilic Br because it is
inexpensive, commercially available, and easy to handle
(free-flowing crystalline solid). It has been reported that
ammonium chloride could act as an additive in the dibro-
mination of alkenes using iodine(III) catalyst, but ammoni-
um chloride alone could not drive the reaction. In contrast,
here, we demonstrate that simply applying ammonium flu-
oride alone could promote the dibromination with appre-
ciable efficiency.21
DOI: 10.1055/s-0036-1588506; Art ID: st-2017-w0372-l
Abstract A mild and efficient vicinal dibromination of olefins has been
developed by using saturated aqueous ammonium fluoride solution as
the promoter. Inexpensive and commercially available N-bromosuccin-
imide (NBS) was used as the brominating reagent. The corresponding
vicinal dibromoalkanes could be obtained in good to excellent yields.
Key words olefins, dibromination, halogen, N-bromosuccinimide,
metal-free
Vicinal dibromination of olefins is a classical and im-
portant organic transformation. For instance, vicinal dibro-
mides can be converted into vinyl bromides1 and vinyl
azides2 under basic conditions. Vinyl bromides are useful
synthons in Grignard reactions3 and cross-coupling reac-
tions4 while vinyl azides are important precursors for nitro-
gen heterocycle synthesis.5 Furthermore, cyclopropanes6
and alkynes7 can be synthesized directly from vicinal dibro-
mides. Vicinal dibrominated compounds are valuable inter-
mediates that can be utilized in agrochemicals, pharmaceu-
ticals, and other fine chemicals. In addition, numerous ma-
rine natural products are found to be heavily halogenated.8
Therefore, (di)halogenation methods are required for syn-
thesis and derivatization.9
From a mechanistic aspect, an equivalence of bromeni-
um (Br+) and bromide (Br–) are needed in the addition reac-
tion of olefin for vicinal dibromination. Based on this ratio-
nale, several approaches have been developed for olefinic
vicinal dibromination. The first type of approach involved
the use of molecular bromine or bromine carrier, where the
reagents themselves are already comprised of Br+ and Br– in
Br2. Quaternary ammonium and pyridinium tribromide
reagents such as Me4NBr3,10 Bu4NBr3,11 PhMe3NBr3,12 and
PyHBr13 have been developed as bromine carriers for vari-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
W. H. Ng et al.
Letter
Synlett
At the outset of our experimentation, styrene (1a) was
used as the model substrate. When 1a was reacted with
NBS in dichloromethane at room temperature, no reaction
was observed. To our surprise, in the presence of saturated
ammonium fluoride solution, styrene reacted with NBS to
afford dibromination product 1b in 61% yield (Table 1, entry
1).
mately 10 equivalents of NH4F were used in the reaction
summarized in entry 10. Further doubling the amount of
saturated aqueous ammonium fluoride only gave a slight
increase in yield (entry 11). Therefore, the conditions
shown in entry 10 were selected as the optimized condi-
tions.
Table 2 Reaction Optimizationa
Table 1 Performance of Promotersa
NBS (2.2 equiv.)
Br
Br
sat. NH4F(aq)
NBS (2.2 equiv)
Br
Br
Additive
Solvent, 25 °C
4.5 h, dark
CH2Cl2, 25 °C
4.5 h, dark
1a
2a
1a
1b
Entry
Solvent
Sat. NH4F(aq) (mL)
Yield (%)b
Entry
Additive
Time (h)
Yield (%)c
1
2
CH2Cl2
CHCl3
PhMe
THF
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.16
0.32
59
1
2
3
4
5
sat. NH4F(aq)
21
48
48
48
30
61
36
sat. (NH4)2SO4(aq)
sat. NaF(aq)
trace
trace
22
3
20
4
24
b
NH4F(s)
5
EtOAc
CH3CN
EtOH
36
H2O
no reaction
6
23
a Reactions were carried out with styrene (1a; 0.2 mmol), NBS (0.44 mmol)
and additive (0.03 mL) in dichloromethane (1 mL) at 25 °C in the dark for
7
trace
trace
trace
68
4.5 h.
8
DMF
b Ammonium fluoride (0.1 equiv) was used.
c Isolated yield.
9
DMSO
CH2Cl2
CH2Cl2
10
11
70
To study the effect of ammonium salt in the reaction,
the performance of various saturated salt solutions were
evaluated. Changing the ammonium fluoride solution to
ammonium sulfate led to a sluggish reaction, suggesting
that the fluoride anion played a crucial role in the dibromi-
nation (Table 1, entry 2). The ammonium cation was also
found to be important since aqueous sodium fluoride solu-
tion did not promote the reaction (entry 3). A solid suspen-
sion of NH4F in dichloromethane gave a sluggish reaction,
which indicated the importance of having the ionized com-
ponents (entry 4). A control experiment was conducted in
which water alone as the additive was used; this did not
promote the reaction (entry 5).
Having identified aqueous NH4F as a suitable promoter,
the reaction was further optimized by varying the solvent
and the amount of aqueous NH4F (Table 2). A survey on dif-
ferent solvents revealed that CH2Cl2 remained the optimum
reaction medium (entries 1–9). Other polar solvents includ-
ing THF, ethanol, and DMF led to poor yields of dibromina-
tion products. It could be rationalized that the nucleophilic
solvents could capture the bromiranium intermediate
formed between NBS and styrene, leading to the formation
of side products (see the Supporting Information).24 Further
increasing the amount of saturated aqueous ammonium
fluoride returned a higher yield (68%; entry 10). It should
be noted that, based on the solubility of NH4F in water (45.3
g/100 mL water, equivalently 12.2 M, at 25 °C),25 approxi-
a Reactions were carried out with styrene (1a; 0.2 mmol), NBS (0.44 mmol),
and saturated NH4F(aq) at 25 °C in the dark for 4.5 h.
b Isolated yield.
With the optimized conditions in hand, we then ex-
panded the substrate scope of the reaction; the results are
shown in Table 3. Styrenes 1a–f with both electron-donating
and electron-withdrawing substituents were compatible
with the conditions and gave the dibromide 2a–f in good
yields (entries 1–6). In addition, 1,2-disubstituted benzylic
olefinic systems 1g–j could also give the desired dibromi-
nated products 2g–j in appreciable conversions (entries 7–
10). Dibromination of aliphatic terminal olefins 1k and 1l
gave good yields of 2k and 2l (80 and 77%, respectively; en-
tries 11 and 12). Use of the cyclic olefin cyclooctene 1n re-
sulted in an excellent yield of 83%, whereas the use of cyclo-
hexene 1m resulted in moderate conversion with NMR
yield of 51% (entries 13 and 14).
During our experimentation, it was observed that there
was an instant color change from colorless to orange when
saturated aqueous NH4F was added to a solution of NBS in
CH2Cl2. Subsequent addition of styrene resulted in decolor-
ization of the orange solution gradually. It was suspected
that the formation of the orange color was due to the gener-
ation of molecular Br2 in situ. However, in the reaction sys-
tem, NBS was the only source of Br atom on the product and
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
W. H. Ng et al.
Letter
Synlett
NBS can generally be a source of Br+ or Br radical. This situ-
ation resembles those of the organocatalytic dibromination
cases reported by Barbas III,18 Gulder,19 Córdova,20 and
Zhao21 in which solely N-bromoimide reagents were suffi-
cient to perform dibromination without an apparent source
of bromide anion for the generation of molecular Br2 in situ.
To generate the counter bromide anion, a stoichiometric
reductant is required to convert Br+ (from NBS) into Br–.
Ross reported that an electron-transfer reaction could take
place in the complex of NBS and succinimide anion, result-
ing in succinimide, polymeric maleimide and bromide ion
as products (Scheme 1).26 After the electron-transfer reac-
tion, two succinimidyl radicals were produced, which could
further disproportionate to succinimide and maleimide.
Maleimide was reported to further polymerize to give poly-
meric maleimide. This suggested that succinimide anion
might be the possible reductant for the generation of Br–.
Br
N
N
Electron Transfer
nBu4N
O
O
+
O
O
H
N
nBu4NHBr
O
O
+
+
Polymaleimide
Scheme 1 Electron-transfer reaction between NBS and succinimide
anion
Table 3 Substrate Scopea
R2
R1
Br
NBS (2.2 equiv)
sat. NH4F(aq)
R1
R2
R3
R4
Br
CH2Cl2, 25 °C
R3 R4
1
2
Entry
1
Substrate
Product
Time (h)
4.5
Yield (%)b
68
dr
–
Br
Br
Br
1a
1b
2a
2b
2
3
1
2
58
58
–
–
Br
Br
Br
1c
1d
1e
2c
2d
2e
Br
Br
4
5
6
4.5
22.5
1
73
71
62
–
–
–
Br
Br
Cl
Cl
Br
Br
Cl
Cl
Br
Br
1f
2f
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

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W. H. Ng et al.
Letter
Synlett
Table 3 (continued)
Entry
7
Substrate
Product
Time (h)
1
Yield (%)b
67
dr
10:1
Br
1g
2g
Br
8
16
76
1:3
Br
1h
2h
Br
9
2
55 (78)c
2:1
Br
Br
1i
2i
10
4.5
31
anti only
Br
Br
1j
2j
11
12
2
2
80
77
–
–
Br
Br
1k
n-Oct
2k
n-Oct
Br
Br
1l
2l
Br
Br
Br
13
14
3.5
2
36 (51)c
anti only
anti only
Br
1m
1n
2m
2n
83
Br
Br
15
2.5
37
27
–
–
O
O
1o
2o
Br
Br
O
2o'
Br
a Reactions were carried out with olefin 1 (0.2 mmol), NBS (0.44 mmol), and saturated NH4F(aq) (0.16 mL) in dichloromethane (1 mL) at 25 °C in the dark.
b Isolated yield.
c Yield by 1H NMR spectroscopic analysis using dimethyl terephthalate as internal standard.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

E
W. H. Ng et al.
Letter
Synlett
Br
N
O
O
Br
Br
Br2
NH4
F
Br
F
Br
F
N
NH4
O
O
NH4
Br
H
N
O
O
O
O
3
N
Br
N
O
O
+
2
O
O
H
N
5
NH4
Br
N
N
O
O
O
O
4
Scheme 2 Plausible mechanism for generation of bromine from NBS
Based on these precedent studies, herein we propose a
plausible mechanistic picture depicted in Scheme 2. Nucleo-
philic attack of F– to NBS could produce BrF and ammonium
succinimide 3. Complex 4 could be formed by the reaction
between NBS and 3. Subsequent electron transfer from suc-
cinimide anion to NBS might proceed to give Br– and two
succinimidyl radicals 5. The Br– generated could react with
BrF generated previously to give molecular bromine for ole-
finic dibromination. Alternatively, BrF itself could also be
the electrophilic Br source. Two succinimidyl radicals pro-
duced after the electron-transfer reaction might dispropor-
tionate to give succinimide and maleimide, where maleim-
ide could further polymerize to give polymeric maleim-
ide.26
In summary, we have developed a mild dibromination
of olefin.27 Non-hazardous, easy-to-handle and commer-
cially available NBS and ammonium fluoride was used in
the reaction at room temperature, making this protocol
practical for the dibromination of olefinic compounds. Fur-
ther optimization of this protocol to other substrates and
mechanistic studies are in progress.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588506.
S
u
p
p
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References and Notes
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ty of Hong Kong.
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(27) Typical Procedure for the Dibromination of Olefin 1a Using
NBS and Aqueous Ammonium Fluoride: To a solution of olefin
(1a; 21 mg, 0.202 mmol, 1.0 equiv) in CH2Cl2 (1.0 mL) was
added N-bromosuccinimide (78.3 mg, 0.44 mmol, 2.2 equiv)
and saturated aqueous ammonium fluoride (0.16 mL) in the
absence of light. The resulting mixture was stirred at room tem-
perature and the reaction was monitored by TLC. The reaction
was quenched with saturated aqueous Na2S2O3 (5 mL) and
extracted with CH2Cl2 (3 × 10 mL). The combined extracts were
dried over anhydrous MgSO4 and filtered. The filtrate was con-
centrated under reduced pressure and the residue was purified
by flash column chromatography to yield the dibromide 2a
(37.1 mg, 70%) as a white solid: 1H NMR (400 MHz, CDCl3): δ =
7.44–7.34 (m, 5 H), 5.16 (dd, J = 10.6, 5.5 Hz, 1 H), 4.09 (dd, J =
10.2, 5.5 Hz, 1 H), 4.03 (t, J = 10.4 Hz, 1 H); 13C NMR (400 MHz,
CDCl3): δ = 138.66, 129.25, 128.93, 127.73, 50.98, 35.15; HRMS
(EI): m/z [M]+ calcd. for C8H8Br2: 263.8967; found: 263.8972.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F