Visible-Light-Driven Oxidative Mono- and Dibromination of Benzylic sp 3 C-H Bonds with Potassium Bromide/Oxone at Room Temperature

Article abstract of DOI:10.1055/s-0037-1610651

Benzylic sp ³ C-H bonds have been successfully brominated with potassium bromide by using Oxone as an oxidant in water/dichloromethane under visible light at room temperature. Toluene, ethylbenzene and other alkylbenzenes bearing an electron-withdrawing group, such as Br, Cl, COMe, CO ₂ Et, CO ₂ H, CN or NO ₂, provide the corresponding benzylic monobromides in good to excellent yields in this reaction. Dibromides can also be produced in the presence of excess potassium bromide in a prolonged reaction time. Control of the illuminance of visible light (~500 lux) is crucial to achieving both high yield and high selectivity in these brominations. Mono- and difluorides can be conveniently prepared through nucleophilic substitutions of the benzylic bromides with potassium fluoride.

Full text of DOI:10.1055/s-0037-1610651

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–G
paper
A
en
M. Zhao et al.
Paper
Synthesis
Visible-Light-Driven Oxidative Mono- and Dibromination of
Benzylic sp3 C–H Bonds with Potassium Bromide/Oxone at Room
Temperature
Mengdi Zhao◊
Meiqi Li◊
F
hv (0.5 W LED)
KBr (x equiv)
Oxone (y equiv)
Br
KF
cat. nBu4N+Br–
Wenjun Lu*
0
0
0
0
0-
0
0
1
8-
0
7
7
7-
0
6
0
H2O/CH2Cl2, rt
CH3CN, 80 °C
O2N
O2N
O2N
98%
(x = 1, y = 0.8) 85%
Department of Chemistry, Shanghai Jiao Tong University,
800 Dongchuan Road, Shanghai 200240, P. R. of China
luwj@sjtu.edu.cn
KBr
KF
or
Br
F
◊ M.Z. and M.L. contributed equally to this work.
Br
F
O2N
O2N
(x = 4, y = 2) 64%
57%
Received: 12.06.2018
Accepted after revision: 07.07.2018
Published online: 15.08.2018
mination.4 One reason is that the benzylic bromides, espe-
cially dibromides, are readily transformed to aryl ketones or
aryl carbolic acids under visible light in aqueous solution at
room temperature, as suggested by Minisci,3b and Moriyama
and Togo,5 in their benzylic oxidation of alkylarenes with
KBr/Oxone under mild conditions (Scheme 1, A).
Most recently, we established the visible-light-driven
monochlorination and monobromination of simple alkanes
with NaCl/Oxone6a and KBr/air (O2),6b respectively, combin-
ing the oxidation of halogen anion to halogen and the radi-
cal halogenation of C–H bonds under irradiation by visible
light at room temperature. Herein, we report an effective
mono- or dibromination of benzylic sp3 C–H bonds with
KBr/Oxone under weak visible light at room temperature
(Scheme 1, B).
DOI: 10.1055/s-0037-1610651; Art ID: ss-2018-f0403-op
Abstract Benzylic sp3 C–H bonds have been successfully brominated
with potassium bromide by using Oxone as an oxidant in water/di-
chloromethane under visible light at room temperature. Toluene, ethyl-
benzene and other alkylbenzenes bearing an electron-withdrawing
group, such as Br, Cl, COMe, CO2Et, CO2H, CN or NO2, provide the corre-
sponding benzylic monobromides in good to excellent yields in this re-
action. Dibromides can also be produced in the presence of excess po-
tassium bromide in
a prolonged reaction time. Control of the
illuminance of visible light (~500 lux) is crucial to achieving both high
yield and high selectivity in these brominations. Mono- and difluorides
can be conveniently prepared through nucleophilic substitutions of the
benzylic bromides with potassium fluoride.
Key words benzylic C–H bond, bromination, oxidation, photochemis-
try, room temperature
A. Oxidation by Moriyama, Togo, et al. (2012)5
sunlight
KBr (1.2 equiv)
Oxone (1.2 equiv)
O
In comparison with benzylic sp3 C–H bonds, benzylic
sp3 C–Br bonds as active bonds are converted very easily
into the corresponding C–C, C–O and C–N bonds in current
chemical synthesis.1 Therefore, exploration of an efficient
and convenient bromination of benzylic sp3 C–H bonds is
an interesting subject to many researchers.2 Multiple
monobromination methods are known, including the use of
bromine,2d,h N-bromosuccinimide,2a,i bromotrichlorometh-
ane,2b tetramethylammonium tribromide,2c NaBrO3,2e tetra-
bromomethane2f and bromide salts3 as a bromine source
under mild conditions. Among them, transition-metal-free
oxidative bromination is a promising approach when it pro-
ceeds by using NaBr or KBr as the brominating reagent with
an inexpensive and nontoxic oxidant such as H2O23b,c or Ox-
one (2KHSO5·KHSO4·K2SO4).3d However, these monobromi-
nation methods are usually not effective for benzylic dibro-
H2O/CH2Cl2, rt
O2N
O2N
> 99%
Br
Br
Br
visible light
H2O/CH2Cl2
rt
O2N
B. Bromination (this work)
O2N
Br
Br
hv (0.5 W LED)
KBr (x equiv)
Oxone (y equiv)
Br
or
H2O/CH2Cl2, rt
x = 1
y = 0.9
98%
x = 4
y = 2
87%
Oxone: 2KHSO5•KHSO4•K2SO4
Scheme 1 Oxidation and bromination of benzylic sp3 C–H bonds with
KBr/Oxone under visible light at room temperature
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

B
M. Zhao et al.
Paper
Synthesis
In our study of the oxidative benzylic bromination of al-
kylarenes under mild conditions, we still employed the
KBr/Oxone/H2O/CH2Cl2 system which was very effective in
the oxidation of alkylarenes to afford carbonyl compounds.5
Initially, under indoor light on a clear day, an oxidation of p-
ethylnitrobenzene (1a) with KBr/Oxone (1:1.2:1.2) oc-
curred to give 1-(4-nitrophenyl)ethanone (2a) in 91% yield,
as determined by 1H NMR analysis, and no 1-(1-bromoeth-
yl)-4-nitrobenzene (3a) was found at room temperature
(Table 1, entry 1), like in the previous report. Interestingly,
under similar conditions on a cloudy day, the yield of
monobromide 3a was up to 89% through a benzylic bromi-
nation (entry 2). Then, the following reactions were run un-
der controlled light conditions. Under an 8 W light-emit-
ting diode (LED) at a distance of 5 cm and 30 cm, benzylic
oxidation and bromination, respectively, proceeded very
well (entries 3 and 4). These results implied that the alky-
larene undergoes benzylic bromination, rather than oxida-
tion, under weak visible light. Moreover, 3a was generated
as the major product (59%) when 0.6 equivalents of KBr
were added under an 8 W LED at 5 cm (entry 5), supporting
the view that carbonyl products might arise from monobro-
mides in further reactions with KBr/Oxone under strong
light. Thus, when 1a/KBr (1.1:1) was employed under a 0.5
W LED at 5 cm, only monobromide 3a was obtained in ex-
cellent yield based on KBr (entry 7). In this case, the illumi-
nance of visible light was ~500 lux.
The benzylic bromination of some alkylarenes with
KBr/Oxone was screened, and the results are listed in
Scheme 2. Both toluene (1b) and ethylbenzene (1l) gave
their monobromides 3b and 3l in excellent yields based on
KBr if 1.2 equivalents of the substrate were used under a 0.5
W LED at room temperature. When the aromatic ring was
substituted with an electron-withdrawing group, including
Br, Cl, COMe, CO2H, CO2Et, CN or NO2, the corresponding
monobromides were obtained in 70–89% isolated yield. In
the case of m-methylnitrobenzene (1i) and o-methylnitro-
benzene (1k) under a stronger light (3 W LED), the reaction
rates were obviously accelerated and the brominations
were complete in 3–4 hours. There is no very clear relation-
ship between the electron-withdrawing groups or the sub-
stituted position (o, m, p) and the reaction performance. For
p-methylanisole (1p) with a strong electron-donating
group, however, instead of benzylic bromination, an elec-
trophilic aromatic substitution occurred under the identi-
cal reaction conditions to afford the aryl bromide product
4p. According to previous reports2e,g,6 and this work, it is
known that not only free-radical processes but also ionic
Br
hv (0.5 W LED)
R
R
+ KBr + Oxone
1 equiv
H2O/CH2Cl2, rt
R'
R'
1
3a
Br
Br
Br
Br
Table 1 Oxidation and Bromination of p-Ethylnitrobenzene (1a) with
EtO
Br
Cl
KBr/Oxone under Visible Light at Room Temperaturea
3b
3c
3d
O
3e
98%b
80%
77%
89%
O
Br
Br
Br
Br
Br
hv
+
+ KBr + Oxone
H2O/CH2Cl2
rt
O2N
O2N
O2N
NC
O2N
1a
2a
3a
Cl
3h
NO2
3f
3g
3ic
87%
85%
Entry hv
KBr
(equiv) (h)
Time 2a
3a
70%
76%
Yield (%)b Yield (%)b
Br
Br
Br
Br
1
indoor light (clear day)
indoor light (cloudy day)
8 W LED at 5 cm
1.2
1.2
1
3
91
10
96c
3
0
89
0
2
4
16
16
16
4
Br
NO2
3j
3kd
3l
95%b
O
3m
86%
3
79%
80%
4
8 W LED at 30 cm
8 W LED at 5 cm
1
94
59
85c
93c
Br
Br
5
0.6
1
4
6d
7e
3 W LED at 20 cm
0.5 W LED at 5 cm
0
MeO
4p
HO
Br
1
20
0
O
3n
3o 93%
73%
80%
a Reaction conditions: 1a (0.25 mmol, 1 equiv), KBr (0.6–1.2 equiv), Oxone
(1.2 equiv), H2O (0.18 mL), CH2Cl2 (0.25 mL), air, rt, 3–20 h.
b Yields are based on 1 equivalent of 1a or KBr, and were determined by 1H
NMR analysis using CH2Br2 as an internal standard.
c Isolated yield.
Scheme 2 Oxidative monobromination of benzylic sp3 C–H bonds at
room temperature. Reagents and conditions: 1 (1.1–1.2 equiv), KBr
(0.25 mmol, 1 equiv), Oxone (0.8–1 equiv), H2O (0.09–0.18 mL),
CH2Cl2 (0.25 mL), 0.5 W LED at 5 cm, air, rt, 18–26 h. a Isolated yields
based on KBr. b Yield determined by 1H NMR analysis using CH2Br2 as an
internal standard. c 3 W LED at 5 cm, 3 h. d 3 W LED at 5 cm, 4 h.
d 1a (1.1 mmol, 1.1 equiv), KBr (1 equiv), Oxone (1.2 equiv), H2O (0.72 mL),
CH2Cl2 (1 mL).
e 1a (0.275 mmol, 1.1 equiv), Oxone (1 equiv).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

C
M. Zhao et al.
Paper
Synthesis
reactions can proceed very well in the halide salt/oxidant
system, and the reaction selectivity depends on the sub-
strates, solvents, light and other factors. For example, in the
case of toluene (1b), as shown in Scheme 3 the occurrence
of either aromatic or benzylic bromination can be con-
trolled just by using different solvents with or without visi-
ble light (see the Supporting Information).
drawing group, such as Br, Cl, CO2Et, CN or NO2, dibromides
5b–k were obtained in moderate to good yields at room
temperature. However, for secondary benzylic sp3 C–H
bonds as in p-ethylnitrobenzene (1a), only a 43% yield of 1-
(1,1-dibromoethyl)-4-nitrobenzene (5a) was obtained due
to the steric hindrance of the large benzylic group. Al-
though a prolonged reaction time was needed, this method
of benzylic dibromination was successfully applied in the
direct preparation of various benzylic dibromides from al-
kylarenes under very mild conditions.4
hv (0.5 W LED)
solvent = PhH or CHCl3
Br
KBr (1 equiv)
Oxone (0.5 equiv)
yield 83% or 78%
3b
Furthermore, we tried to prepare benzylic mono- and
difluorides based on the oxidative bromination. After many
tests, it was found that mono- and difluorides could be pro-
duced from benzylic monobromides and bromofluorides,
respectively, in an effective nucleophilic substitution. The
fluorinations of benzylic bromides with KF were carried
out in the presence of catalytic nBu4N+Br– in CH3CN at 80–
110 °C. A benzylic monofluoride, 1-(fluoromethyl)-4-nitro-
benzene (6g), was obtained from bromide 3g in 98% yield in
a gram-scale reaction. However, this substitution was not
available for the direct formation of difluoride from the
benzylic dibromide. The difluoride 1-(difluoromethyl)-4-
nitrobenzene (8g) could be generated in 57% overall yield
based on 6g through a two-step process containing one
monobromination and one fluorination, as shown in
Scheme 5. This is a strategy for the preparation of benzylic
fluorides, especially difluorides, without using HF or special
fluorinating reagents.
or
H2O (0.18 mL)
solvent (0.25 mL)
rt, 20 h
in the dark
solvent = CH3CN
yield 95% (o/p = 1:2.2)
1b, 1 equiv
(0.25 mmol)
Br
4b
Scheme 3 Benzylic and aromatic bromination of toluene with KBr/Ox-
one at room temperature
Under weak visible light, no carbonyl products were
found in the above benzylic monobrominations. Thus, di-
brominations of benzylic sp3 C–H bonds were investigated
in the presence of excess KBr/Oxone under similar condi-
tions, and the results are listed in Scheme 4. For toluene
(1b) and its derivatives 1c–k containing an electron-with-
Br
Br
hv (0.5 W LED)
R
R
+ KBr + Oxone
4 equiv 2 equiv
H2O/CH2Cl2, rt
R'
R'
1, 1 equiv
5a
nBu4N+Br– (20 mol%)
Br
F
+ KF
Br
Br
Br
Br
CH3CN (3.5 mL)
80 °C, 20 h
O2N
3g, 1 equiv
O2N
Br
4 equiv
6g, 98%
Br
Br
Br
Cl
Br
(5 mmol, 1.08 g)
O2N
5a
43%b
5b
5c
5d
77%
76%
78%
Br
8 W LED
KBr (1 equiv)
Oxone (1 equiv)
Br
Br
Br
Br
F
F
Br
NC
Br
Br
Br
O2N
CH2Cl2 (0.3 mL)
rt, 20 h
O2N
EtO
6g, 1 equiv
(0.25 mmol)
7g
O2N
O
Cl
5h
74%
F
5e
5f
5g
KF (4 equiv)
nBu4N+Br– (25 mol%)
F
75%
73%
64%
CH3CN (0.5 mL)
110 °C, 20 h
O2N
Br
Br
Br
8g, 57%
Br
Br
Br
NO2
Scheme 5 Preparation of benzylic mono- and difluorides from bro-
mides
Br
NO2
5i
5j
5k
60%
96%
61%
In addition, scale-up experiments for monobromination
and dibromination were also conducted. Thus, 1-(1-bro-
moethyl)-4-nitrobenzene (3a) and 1-bromo-2-(dibro-
momethyl)benzene (5j) could be obtained in 99% isolated
yield (Scheme 6).
Scheme 4 Oxidative dibromination of benzylic sp3 C–H bonds at room
temperature. Reagents and conditions: 1 (0.25 mmol, 1 equiv), KBr (4
equiv), Oxone (2 equiv), H2O (0.18 mL), CH2Cl2 (0.25 mL), 0.5 W LED at
5 cm, air, rt, 16–72 h. a Isolated yields based on 1. b KBr (3 equiv), Oxone
(1.5 equiv). Yield determined by 1H NMR analysis using CH2Br2 as an in-
ternal standard.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

D
M. Zhao et al.
Paper
Synthesis
were added, in accordance with the order, to a 15-mL oven-dried
tube. The reaction tube was equipped with a magnetic stir bar and
sealed with a Teflon-lined cap at once after the addition of the H2O.
Then, the tube was placed on a magnetic stirrer (speed 300 rpm) and
irradiated with a 0.5 W LED at a distance of 5 cm for 20 h at rt. After
the reaction was finished, the reaction mixture was quenched with
Na2SO3. Water (15 mL) was added and the mixture extracted with
CH2Cl2 (3 × 5 mL). The organic phase was combined and dried with
anhydrous Na2SO4. The solvent was evaporated under reduced pres-
sure to give the crude product that was purified by flash column
chromatography (petroleum ether/EtOAc mixtures). Compound 3a
was obtained as a light yellow solid; yield: 53.6 mg (93%).
Br
3 W LED
Oxone (1 equiv)
+
KBr
H2O (3.6 mL)
CH2Cl2 (4 mL)
air, rt, 6 h
O2N
O2N
1 equiv
(5 mmol)
1a, 1.1 equiv
3a, 99%
(1.14 g)
Br
3 W LED
Oxone (2 equiv)
Br
+
KBr
H2O (3.6 mL)
CH2Cl2 (5 mL)
air, rt, 24 h
Br
Br
4 equiv
1j, 1 equiv
5j, 99%
(5 mmol)
(1.62 g)
1-(4-Nitrophenyl)ethanone (2a)5
White solid; yield: 39.6 mg (96%).
Mp 76–78 °C (Lit.7 80–81 °C).
Scheme 6 Gram-scale experiments for monobromination and dibro-
mination
1H NMR (400 MHz, CDCl3): δ = 8.33 (d, J = 8.8 Hz, 2 H), 8.12 (d, J = 8.8
Hz, 2 H), 2.69 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 196.4, 150.4, 141.4, 129.4, 123.9, 27.1.
In summary, we have developed a very convenient
method to prepare benzylic mono- and dibromides in mod-
erate to excellent yields at room temperature. The method
involves oxidative bromination of the benzylic sp3 C–H
bonds of toluene, ethylbenzene and their derivatives with
KBr/Oxone in H2O/CH2Cl2 under weak visible light. Alkyl-
arenes bearing electron-donating groups are not suitable
for this reaction, and their aromatic bromides may be pro-
duced under similar conditions in the dark. In addition,
based on the monobromination, benzylic mono- and diflu-
orides can also be produced successfully by catalytic nucle-
ophilic substitution of the bromides with KF. Further stud-
ies on the reaction mechanism, scope and applications are
underway.
1-(1-Bromoethyl)-4-nitrobenzene (3a)3b
Light yellow solid; yield: 53.6 mg (93%).
Mp 29–31 °C (Lit.8 31–32.5 °C).
1H NMR (400 MHz, CDCl3): δ = 8.21 (d, J = 8.8 Hz, 2 H), 7.61 (d, J = 8.8
Hz, 2 H), 5.21 (q, J = 6.8 Hz, 1 H), 2.06 (d, J = 6.8 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 150.2, 147.6, 128.0, 124.1, 46.6, 26.6.
(Bromomethyl)benzene (3b)2i
Light yellow liquid; yield: 98% (1H NMR).
1H NMR (400 MHz, CDCl3): δ = 7.41–7.30 (m, 5 H), 4.50 (s, 2 H).
13C NMR (101 MHz, CDCl3): δ = 137.9, 129.2, 128.9, 128.6, 33.7.
1-Bromo-4-(bromomethyl)benzene (3c)2i
White solid; yield: 50.0 mg (80%).
Mp 56–58 °C (Lit.2b 60.5–61 °C).
1H NMR (400 MHz, CDCl3): δ = 7.48 (d, J = 8.4 Hz, 2 H), 7.28 (d, J = 8.4
Hz, 2 H), 4.44 (s, 2 H).
All reagents were commercially available and weighed out under am-
bient conditions. All chemicals were used without further purifica-
tion, except CHCl3. Commercially purchased CHCl3 was purified via
washing with water and distillation to remove the stabilizer
(CH3CH2OH). Analytical TLC was performed on precoated silica gel 60
F254 plates; visualization was achieved with UV light (254 nm). 1H
NMR spectra were recorded on Mercury Bruker AVANCE III HD 400
(400 MHz) or Bruker AVANCE III HD 500 (500 MHz) instruments.
Chemical shifts are quoted in parts per million (ppm) referenced to
the appropriate solvent peak or 0.0 ppm for TMS. Data for 1H NMR
spectra are reported as follows: chemical shift (δ), multiplicity (stan-
dard abbreviations), coupling constant(s) (Hz), integration. 13C NMR
spectra were recorded on Bruker AVANCE III HD 400 (101 MHz) or
Bruker AVANCE III HD 500 (126 MHz) instruments. Chemical shifts
are reported in ppm referenced to the center line of the triplet at 77.0
ppm of CDCl3. 19F NMR spectra were recorded on Bruker AVANCE III
HD 400 (376 MHz) or Bruker AVANCE III HD 500 (471 MHz) instru-
ments. Melting points were obtained on an INESA SGW X-4 melting
point apparatus.
13C NMR (101 MHz, CDCl3): δ = 136.9, 132.1, 130.8, 128.6, 32.5.
1-(Bromomethyl)-4-chlorobenzene (3d)2i
White solid; yield: 39.6 mg (77%).
Mp 44–46 °C (Lit.2b 49.5–50.5 °C).
1H NMR (400 MHz, CDCl3): δ = 7.32 (s, 4 H), 4.46 (s, 2 H).
13C NMR (101 MHz, CDCl3): δ = 136.4, 134.4, 130.5, 129.1, 32.5.
Ethyl 4-(Bromomethyl)benzoate (3e)2i
White solid; yield: 54.1 mg (89%).
Mp 34–35 °C (Lit.9 35 °C).
1H NMR (400 MHz, CDCl3): δ = 8.02 (d, J = 8.4 Hz, 2 H), 7.45 (d, J = 8.4
Hz, 2 H), 4.51 (s, 2 H), 4.38 (q, J = 7.2 Hz, 2 H), 1.40 (t, J = 7.2 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 166.2, 142.6, 130.6, 130.2, 129.1, 61.3,
32.4, 14.5.
4-(Bromomethyl)benzonitrile (3f)2i
1-(1-Bromoethyl)-4-nitrobenzene (3a); Typical Bromination Pro-
cedure
KBr (29.8 mg, 0.25 mmol, 1.0 equiv), 1-ethyl-4-nitrobenzene (1a)
(41.6 mg, 0.275 mmol, 1.1 equiv), Oxone (153.9 mg, 0.25 mmol, 1.0
equiv), CH2Cl2 (0.25 mL) and H2O (180.0 mg, 0.18 mL, 40.0 equiv)
White solid; yield: 42.6 mg (87%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

E
M. Zhao et al.
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Synthesis
Mp 111–112 °C (Lit.2b 112 °C).
1H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 8.0 Hz, 2 H), 7.50 (d, J = 8.0
1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 8.4 Hz, 2 H), 7.53 (d, J = 8.4
Hz, 2 H), 5.21 (q, J = 6.8 Hz, 1 H), 2.61 (s, 3 H), 2.06 (d, J = 6.8 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 197.6, 148.3, 137.0, 128.9, 127.2, 48.0,
Hz, 2 H), 4.48 (s, 2 H).
26.8, 26.6.
13C NMR (101 MHz, CDCl3): δ = 143.0, 132.7, 129.9, 118.5, 112.3, 31.6.
4-(1-Bromoethyl)benzoic Acid (3n)15
White solid; yield: 41.8 mg (73%).
Mp 152–154 °C (Lit.15 225 °C).
1-(Bromomethyl)-4-nitrobenzene (3g)2i
White solid; yield: 45.9 mg (85%).
Mp 98–99 °C (Lit.3c 98–99 °C).
1H NMR (400 MHz, CDCl3): δ = 11.49 (br, 1 H), 8.08 (d, J = 8.4 Hz, 2 H),
7.54 (d, J = 8.4 Hz, 2 H), 5.21 (q, J = 7.0 Hz, 1 H), 2.06 (d, J = 7.0 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 171.6, 149.1, 130.8, 129.2, 127.2, 47.9,
1H NMR (400 MHz, CDCl3): δ = 8.21 (d, J = 8.8 Hz, 2 H), 7.57 (d, J = 8.8
Hz, 2 H), 4.52 (s, 2 H).
13C NMR (101 MHz, CDCl3): δ = 147.8, 144.9, 130.1, 124.2, 31.1.
26.7.
1-(Bromomethyl)-3-chlorobenzene (3h)10
(1-Bromobutyl)benzene (3o)16
Colorless liquid; yield: 36.0 mg (70%).
1H NMR (500 MHz, CDCl3): δ = 7.89 (s, 1 H), 7.28 (m, 3 H), 4.44 (s, 2
H).
13C NMR (126 MHz, CDCl3): δ = 139.7, 134.6, 130.2, 129.3, 128.7,
127.3, 32.3.
Colorless liquid; yield: 49.5 mg (93%).
1H NMR (500 MHz, CDCl3): δ = 7.40–7.27 (m, 5 H), 4.97 (t, J = 7.5 Hz, 1
H), 2.31–2.01 (m, 2 H), 1.54–1.29 (m, 2 H), 0.94 (t, J = 7.5 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 142.4, 128.8, 128.4, 127.4, 55.6, 42.2,
21.6, 13.5.
1-(Bromomethyl)-3-nitrobenzene (3i)10
White solid; yield: 41.0 mg (76%).
Mp 51–53 °C (Lit.11 55 °C).
1H NMR (500 MHz, CDCl3): δ = 8.27 (d, J = 6.8 Hz, 1 H), 8.17 (d, J = 6.8
Hz, 1 H), 7.74 (d, J = 6.8 Hz, 1 H), 7.55 (t, J = 6.8 Hz, 1 H), 4.55 (s, 2 H).
2-Bromo-1-methoxy-4-methylbenzene (4p)17
Colorless oily liquid; yield: 40.2 mg (80%).
1H NMR (400 MHz, CDCl3): δ = 7.36 (d, J = 1.6 Hz, 1 H), 7.05 (dd, J = 8.4,
1.6 Hz, 1 H), 6.79 (d, J = 8.4 Hz, 1 H), 3.86 (s, 3 H), 2.27 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 153.9, 133.9, 131.6, 129.0, 112.0,
111.4, 56.4, 20.3.
13C NMR (126 MHz, CDCl3): δ = 148.5, 139.8, 135.1, 130.0, 124.0,
123.4, 31.2.
1-(1,1-Dibromoethyl)-4-nitrobenzene (5a)18
White solid; mp 44–46 °C (Lit.8 51–52 °C).
1H NMR (500 MHz, CDCl3): δ = 8.22 (d, J = 9.0 Hz, 2 H), 7.95 (d, J = 9.0
Hz, 2 H), 3.00 (s, 3 H).
1-Bromo-2-(bromomethyl)benzene (3j)12
White solid; yield: 49.4 mg (79%).
Mp 21–22 °C (Lit.12 31 °C).
1H NMR (500 MHz, CDCl3): δ = 7.58 (dd, J = 7.5, 1.0 Hz, 1 H), 7.46 (dd,
J = 7.5, 2.0 Hz, 1 H), 7.30 (ddd, J = 7.5, 7.5, 1.0 Hz, 1 H), 7.17 (ddd, J =
7.5, 7.5, 2.0 Hz, 1 H), 4.61 (s, 2 H).
13C NMR (126 MHz, CDCl3): δ = 152.4, 147.8, 127.4, 123.6, 58.8, 41.0.
(Dibromomethyl)benzene (5b)
13C NMR (126 MHz, CDCl3): δ = 137.2, 133.5, 131.4, 130.3, 128.1,
124.6, 33.5.
Colorless liquid; yield: 47.5 mg (76%).
1H NMR (500 MHz, CDCl3): δ = 7.57 (dd, J = 7.0, 1.6 Hz, 2 H), 7.39–7.31
(m, 3 H), 6.66 (s, 1 H).
13C NMR (126 MHz, CDCl3): δ = 142.1, 130.0, 128.8, 126.6, 41.2.
1-(Bromomethyl)-2-nitrobenzene (3k)10
White solid; yield: 43.2 mg (80%).
Mp 42–43 °C (Lit.13 46–47.5 °C).
1H NMR (500 MHz, CDCl3): δ = 8.05 (d, J = 8.5 Hz, 1 H), 7.63–7.57 (m, 2
H), 7.51–7.48 (m, 1 H), 4.84 (s, 2 H).
1-Bromo-4-(dibromomethyl)benzene (5c)4c
Colorless liquid; yield: 64.1 mg (78%).
1H NMR (500 MHz, CDCl3): δ = 7.50 (d, J = 8.5 Hz, 2 H), 7.44 (d, J = 8.5
Hz, 2 H), 6.59 (s, 1 H).
13C NMR (126 MHz, CDCl3): δ = 141.1, 132.0, 128.3, 124.0, 39.7.
13C NMR (126 MHz, CDCl3): δ = 148.2, 133.8, 133.0, 132.7, 129.7,
125.6, 29.0.
(1-Bromoethyl)benzene (3l)2i
Colorless liquid; yield: 95% (1H NMR).
1H NMR (400 MHz, CDCl3): δ = 7.53–7.45 (m, 2 H), 7.35 (dd, J = 8.0, 6.4
Hz, 2 H), 7.29 (d, J = 7.2 Hz, 1 H), 5.22 (q, J = 7.2 Hz, 1 H), 2.05 (d, J = 7.2
Hz, 3 H).
1-Chloro-4-(dibromomethyl)benzene (5d)19
Colorless liquid; yield: 54.7 mg (77%).
1H NMR (500 MHz, CDCl3): δ = 7.51 (d, J = 9.0 Hz, 2 H), 7.35 (d, J = 9.0
Hz, 2 H), 6.61 (s, 1 H).
13C NMR (126 MHz, CDCl3): δ = 140.6, 135.8, 129.0, 128.0, 39.7.
13C NMR (101 MHz, CDCl3): δ = 143.3, 128.8, 128.5, 126.9, 49.7, 27.0.
Ethyl 4-(Dibromomethyl)benzoate (5e)3c
White solid; yield: 60.4 mg (75%).
Mp 96–98 °C (Lit.3c 98–99 °C).
1-(4-(1-Bromoethyl)phenyl)ethanone (3m)14
Light yellow, oily liquid; yield: 48.8 mg (86%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

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M. Zhao et al.
Paper
Synthesis
1H NMR (500 MHz, CDCl3): δ = 8.05 (d, J = 8.0 Hz, 2 H), 7.63 (d, J = 8.0
Hz, 2 H), 6.66 (s, 1 H), 4.39 (q, J = 7.2 Hz, 2 H), 1.40 (t, J = 7.2 Hz, 3 H).
1H NMR (500 MHz, CDCl3): δ = 8.27 (d, J = 8.0 Hz, 2 H), 7.54 (d, J = 8.0
Hz, 2 H), 5.52 (d, J = 46.5 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 165.7, 146.1, 131.8, 130.1, 126.7, 61.4,
39.9, 14.5.
13C NMR (126 MHz, CDCl3): δ = 148.0, 143.5 (d, J = 18 Hz), 127.2 (d, J =
8 Hz), 124.0, 83.0 (d, J = 171 Hz).
19F NMR (471 MHz, CDCl3): δ = –215.7.
4-(Dibromomethyl)benzonitrile (5f)20
White solid; yield: 50.2 mg (73%).
1-(Bromo(fluoro)methyl)-4-nitrobenzene (7g)
Mp 78–80 °C (Lit.21 81–82 °C).
Yellow oily liquid; yield: 56.2 mg (96%).
1H NMR (500 MHz, CDCl3): δ = 7.69 (s, 4 H), 6.62 (s, 1 H).
13C NMR (126 MHz, CDCl3): δ = 146.3, 132.7, 127.5, 118.0, 113.7, 38.8.
1H NMR (500 MHz, CDCl3): δ = 8.30 (d, J = 9.0 Hz, 2 H), 7.69 (d, J = 9.0
Hz, 2 H), 7.49 (d, J = 45.5 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 148.7, 145.0 (d, J = 20 Hz), 126.2 (d, J =
6 Hz), 124.2, 89.6 (d, J = 257 Hz).
1-(Dibromomethyl)-4-nitrobenzene (5g)20
White solid; yield: 47.2 mg (64%).
Mp 61–63 °C (Lit.20 73–75 °C).
1H NMR (500 MHz, CDCl3): δ = 8.25 (d, J = 7.2 Hz, 2 H), 7.76 (d, J = 7.2
Hz, 2 H), 6.67 (s, 1 H).
19F NMR (471 MHz, CDCl3): δ = –136.4.
1-(Difluoromethyl)-4-nitrobenzene (8g)25
Yellow oily liquid; yield: 30.3 mg (70%).
1H NMR (400 MHz, CDCl3): δ = 8.34 (d, J = 8.4 Hz, 2 H), 7.72 (d, J = 8.4
Hz, 2 H), 6.75 (t, J = 55.6 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 148.4, 148.0, 127.9, 124.2, 38.3.
13C NMR (101 MHz, CDCl3): δ = 149.5, 140.3 (t, J = 23 Hz), 127.0 (t, J =
6 Hz), 124.2, 113.3 (t, J = 242 Hz).
19F NMR (376 MHz, CDCl3): δ = –113.0.
1-Chloro-3-(dibromomethyl)benzene (5h)
Colorless liquid; yield: 52.6 mg (74%).
1H NMR (500 MHz, CDCl3): δ = 7.58 (s, 1 H), 7.45–7.43 (m, 1 H), 7.31–
7.30 (m, 2 H), 6.68 (s, 1 H).
13C NMR (126 MHz, CDCl3): δ = 143.7, 134.6, 130.10, 130.06, 127.0,
124.8, 39.4.
Funding Information
We thank the National Natural Science Foundation of China (Grant
1-(Dibromomethyl)-3-nitrobenzene (5i)20
White solid; yield: 44.2 mg (60%).
Mp 102–104 °C (Lit.20 99–101 °C).
1H NMR (500 MHz, CDCl3): δ = 8.44 (dd, J = 2.0, 2.0 Hz, 1 H), 8.21 (ddd,
J = 8.0, 2.0, 0.9 Hz, 1 H), 7.93 (d, J = 8.0 Hz, 1 H), 7.60 (t, J = 8.0 Hz, 1 H),
6.69 (s, 1 H).
No. 21372153) for financial support.
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Supporting information for this article is available online at
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13C NMR (126 MHz, CDCl3): δ = 148.2, 143.8, 132.7, 130.1, 124.7,
121.8, 38.2.
References
1-Bromo-2-(dibromomethyl)benzene (5j)20
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Pale yellow solid; yield: 0.76 g (98%).
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G