Environmentally benign electrophilic and radical bromination 'on water': H2O2-HBr system versus N-bromosuccinimide

Article abstract of DOI:10.1016/j.tet.2009.03.034

A H₂O₂-HBr system and N-bromosuccinimide in an aqueous medium were used as a 'green' approach to electrophilic and radical bromination. Several activated and less activated aromatic molecules, phenylsubstituted ketones and styrene were efficiently brominated 'on water' using both systems at ambient temperature and without an added metal or acid catalyst, whereas various non-activated toluenes were functionalized at the benzyl position in the presence of visible light as a radical activator. A comparison of reactivity and selectivity of both brominating systems reveals the H₂O₂-HBr system to be more reactive than NBS for benzyl bromination and for the bromination of ketones, while for electrophilic aromatic substitution of methoxy-substituted tetralone it was higher for NBS. Also, higher yields of brominated aromatics were observed when using H₂O₂-HBr 'on water'. Bromination of styrene reveals that not just the structure of the brominating reagent but the reaction conditions: amount of water, organic solvent, stirring rate and interface structure, play a key role in defining the outcome of bromination (dibromination vs bromohydroxylation). In addition, mild reaction conditions, a straightforward isolation procedure, inexpensive reagents and a lower environment impact make aqueous brominating methods a possible alternative to other reported brominating protocols.

Full text of DOI:10.1016/j.tet.2009.03.034

Tetrahedron 65 (2009) 4429–4439
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Environmentally benign electrophilic and radical bromination ‘on water’:
H2O2–HBr system versus N-bromosuccinimide
a
a
b
a,
*
ˇ
Ajda Podgorsek , Stojan Stavber , Marko Zupan , Jernej Iskra
a
ꢀ
Laboratory of Organic and Bioorganic Chemistry, ‘Jozef Stefan’ Institute, Jamova 39, 1000 Ljubljana, Slovenia
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, 1000 Ljubljana, Slovenia
b
ˇ
ˇ
a r t i c l e i n f o
a b s t r a c t
Article history:
A H2O2–HBr system and N-bromosuccinimide in an aqueous medium were used as a ‘green’ approach to
electrophilic and radical bromination. Several activated and less activated aromatic molecules, phenyl-
substituted ketones and styrene were efficiently brominated ‘on water’ using both systems at ambient
temperature and without an added metal or acid catalyst, whereas various non-activated toluenes were
functionalized at the benzyl position in the presence of visible light as a radical activator. A comparison of
reactivity and selectivity of both brominating systems reveals the H2O2–HBr system to be more reactive
than NBS for benzyl bromination and for the bromination of ketones, while for electrophilic aromatic
substitution of methoxy-substituted tetralone it was higher for NBS. Also, higher yields of brominated
aromatics were observed when using H2O2–HBr ‘on water’. Bromination of styrene reveals that not just
the structure of the brominating reagent but the reaction conditions: amount of water, organic solvent,
stirring rate and interface structure, play a key role in defining the outcome of bromination (dibromi-
nation vs bromohydroxylation). In addition, mild reaction conditions, a straightforward isolation pro-
cedure, inexpensive reagents and a lower environment impact make aqueous brominating methods
a possible alternative to other reported brominating protocols.
Received 8 December 2008
Received in revised form 24 February 2009
Accepted 12 March 2009
Available online 21 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Oxidative bromination has potential in developing a sustainable
and ecologically more acceptable procedure by the in situ prepa-
Brominated aromatic compounds are important synthetic in-
termediates and products in organic chemistry. For example, they
are found in C–C coupling reactions, as precursors to organome-
tallic species, and in nucleophilic substitutions. They are also used
for the synthesis of materials, pharmaceuticals, agrochemicals and
other chemicals.1 All of which has encouraged chemists to develop
a variety of bromination protocols in order to gain access to this
important class of compounds.2
The use of molecular bromine, as a basic electrophilic bromi-
nating reagent, has several drawbacks arising out of its toxic and
corrosive nature, difficult handling and its high reactivity, which
results in highly exothermic and non-selective reactions. Additional
problems arise from using chlorinated solvents and the release of
corrosive HBr as a by-product. Alternative brominating reagents
such as N-bromosuccinimide3 and pyridinium or tetraalkylammo-
nium tribromides4 make for easier handling and result in improved
selectivity, but are unfortunately limited by their low atom effi-
ciency and the need to remove the reagent’s residue. Also, molec-
ular bromine is required for their preparation.5
ration of an active brominating species via the oxidation of bromide
using a suitable oxidant.6a A diluted aqueous solution of hydrogen
peroxide is a convenient, safe and environmentally favourable ox-
idizing agent that yields water as the effluent.6b Moreover, the
molar mass of the H2O2–HBr couple is lower than that of bromine
and other brominating agents, which means that bromination in
the presence of H2O2 allows for the complete utilization of bromine
atoms resulting in a higher atom economy. To date, oxidative bro-
mination with H2O2 has been studied mainly on activated aromatic
substrates either in the presence or absence of a metal catalyst.7,8
The concept of oxidative halogenation was inspired by the halo-
peroxidase enzymes.9 While enzymatic reactions in biological sys-
tems proceed in an aqueous medium, analogous reactions in
chemistry are performed in organic solvents (i.e., chlorinated sol-
vents, dioxane, toluene, acetic acid and methanol); the use of water
was avoided in organic chemistry owing to the low solubility of the
organic substrates. Despite this, over the last 20 years many
working in the field have recognized that water can have a benefi-
cial effect on the reactivity of insoluble substrates for which the
term ‘on water’ reactions was coined.10 With growing concern over
the impact that using volatile organic solvents has on the envi-
ronment, water is increasingly becoming an important choice of
* Corresponding author. Tel.: þ386 1 4773 631; fax: þ386 1 4773 822.
E-mail address: jernej.iskra@ijs.si (J. Iskra).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.034

ˇ
4430
A. Podgorsek et al. / Tetrahedron 65 (2009) 4429–4439
Table 2
reaction medium when designing ‘green’ chemical processes. This
is on account of its environmentally favourable properties that in-
clude being abundant, non-toxic, non-flammable.11
Visible-light induced free-radical bromination of para-substituted toluenes with
NBS ‘on water’
Entry
Substratea
Time
Yieldb (%)
Published research on oxidative halogenation in water is scarce
and limited to iodination.12 However, we have shown that water is
an excellent medium for the bromination of ketones with
H2O2–HBr, where it acts as an activator making the addition of an
acid catalyst superfluous.13 Preliminary results of the bromination
of methyl substituted aromatic molecules ‘on water’ have shown
that water can be a medium for radical benzyl bromination using
either N-bromosuccinimide14 or a H2O2–HBr combination15 at
ambient temperature and with visible light as an activator. The
observed difference in reactivity between these two reagents in
aqueous media has prompted us to make a thorough examination
of the effect that water has on the bromination of aromatic mole-
cules: benzene and toluene derivatives, aromatic ketones and sty-
rene, with H2O2–HBr and NBS ‘on water’.
CH3
CH2Br
CHBr2
R
R
R
1
2
3
4
5
1 R¼tBu
22 h
25 h
23 h
25 h
24 h
2a: 86 (70)
5a: 84 (77)c
7a: 81 (72)
9a: 81 (76)
11a: 6
2b: 6 (4)
5b: 5 (3)
7b: 5 (3)
9b: 8 (6)
d
4 R¼H
6 R¼COOEt
8 R¼COCH3
10 R¼NO2
CH3
CH2Br
6
12 R¼CHO
25 h
COOH
13a: 91 (80)
COOH
13b: 2
2. Results and discussion
a
Substrate (1.0 mmol), NBS (1.0 mmol), H2O (5 mL), 40 W incandescent light bulb,
react. temp¼27 ꢀC.
A radical reaction in an aqueous/organic biphasic system can be
initiated in either the aqueous or the organic phase depending on
where the reaction occurs. In a preliminary study14 of the benzylic
bromination of 4-tert-butyltoluene (1), as a model substrate
(Table 1), with N-bromosuccinimide ‘on water’, various modes of
activation of the radical chain mechanism were investigated. Acti-
vation by heat led to the formation of benzyl bromide 2a accom-
panied by a small amount of ring-brominated product 3 (entry 2).
Alternatively, using AIBN as the radical initiator meant that benzyl
bromination was selective albeit a dibrominated product 2b was
formed (entry 3). Selectivity was lost when DBP was the radical
initiator (entry 4). Interestingly, in reactions with water soluble
radical initiators (ACVA and AMPA, entries 5 and 6) selectivity was
poorer and a greater amount of the ring-brominated product 3 was
formed. Importantly, we found that light also induces the radical
reaction and that irradiation from a 40 W incandescent light bulb is
superior in terms of yield and selectivity than the other modes of
activation that we have investigated (entry 8).
b
Distribution of products was determined by 1H NMR spectroscopy of the iso-
lated reaction mixture, yields in parentheses refer to isolated yields.
c
Larger scale experiment (5.0 mmol 4, 5.0 mmol NBS, 25 mL water).
Generally, the benzyl bromides were formed in good yields ac-
companied by small amounts of the dibrominated products. What
is interesting to note is the selectivity of benzylic bromination in
the presence of ketone functionality, given that 4-methyl-
acetophenone (8) was exclusively brominated by a free-radical
process at the benzyl position leading to benzyl bromide 9a. On the
contrary, oxidative bromination of 4-methylacetophenone (8) in an
aqueous H2O2–HBr system shows different regioselectivity by
forming 2-bromo-1-p-tolylethanone through enolization.13 Under
these reaction conditions bromination of a strongly deactivated 4-
nitrotoluene (10) gave only a 6% yield of 1-(bromomethyl)-4-ni-
trobenzene (11a). Interestingly, 4-methylbenzaldehyde (12) was
almost completely oxidized to 4-methylbenzoic acid 13a with NBS
in water. A similar result was reported for the photooxygenation of
benzyl alcohol with catalytic amounts of NBS in organic solvents.16a
Alternatively, oxidation of benzyl alcohol with 1 equiv of NBS in the
aqueous phase and in the presence of cyclodextrin selectively
yielded benzaldehyde.16b
Based on this result, various para-substituted toluenes were
subjected to NBS in water in the presence of light (40 W, Table 2).
Table 1
Effect of mode of activation of a radical reaction on the bromination of 4-tert-bu-
tyltoluene (1) with NBS ‘on water’
CH3
CH2Br
A further advantage of benzylic bromination using NBS in water
is the simple isolation protocol. This is made straightforward be-
cause the only reaction residue succinimide is soluble in water,
unlike hydrophobic organic products. This means that any solid
product work up consists of filtration, albeit if an oily product is
formed in a small-scale experiment then liquid–liquid extraction is
necessary. In the case of the bromination of toluene (4) on a larger
scale (Table 2, entry 2), a clear phase separation occurs at the end of
the reaction. The organic and aqueous phases could then be sepa-
rated and the organic phase further washed with water and
transferred directly to the chromatographic column. Column
chromatography (SiO2, hexane/EtOAc) gave 77% of the pure oily
benzyl bromide (5a).
A ‘greener’ protocol for free-radical bromination would involve
oxidative bromination in an aqueous solution of H2O2 and HBr,
given that bromine is generated in situ and the use of H2O2 as an
oxidant means that water is the only by-product. This then obviates
the formation of a reagent residue and the need for its separation,
as well as increasing the overall atom economy. In order to make
a comparison of the effect of the mode of initiation of radical chain
process for H2O2–HBr benzyl bromination of toluene (4) we applied
the optimum reaction conditions that were determined from our
CHBr2
CH3
Br
NBS
H2O
+
+
tBu
1
tBu
2a
tBu
2b
tBu
3
Entry
Reaction conditionsa
Product distributionb
2a
2b
3
1
2
3
4
5
6
7
8
9
24 ꢀC, 22 h, dark
80 ꢀC, 5 h, dark
5% AIBN, 80 ꢀC, 1.5 h
5% DBP, 80 ꢀC, 2.5 h
5% ACVA, 80 ꢀC, 2 h
5% AMPA, 80 ꢀC, 2 h
Ambient light, 24 ꢀC, 22 h
40 W bulb, 27 ꢀC, 22 h
‘Sunlight’,c 30 ꢀC, 3.5 h
25%
76%
77%
73%
43%
38%
78%
86%
83%
d
d
d
8%
d
10%
6%
1%
1%
4%
6%
6%
5%
15%
23%
d
d
d
a
4-tert-Butyltoluene (1, 1.0 mmol), NBS (1.0 mmol), H2O (5 mL). Radical initiators:
AIBN (2,20-azobis(2-methylpropionitrile)), DBP (dibenzoyl peroxide), ACVA (4,40-
azobis(4-cyanovaleric
acid)),
AMPA (2,20-azobis(2-methylpropionamidine)-
dihydrochloride).
Determined by 1H NMR spectroscopy.
High-pressure mercury lamp, OSRAM HQL 125 W.
b
c

ˇ
A. Podgorsek et al. / Tetrahedron 65 (2009) 4429–4439
4431
Table 3
above-mentioned small-scale experiments, at the end of the re-
action, the crude reaction mixture was diluted by adding a small
amount of organic solvent (hexane/EtOAc) and a drying agent
(Na2SO4), this was followed by filtering the insoluble material and
removing the solvent. However, when performing bromination of
toluene (4) on a larger scale (5.0 mmol), benzyl bromide 5a was the
only reaction product and a clear phase separation occurred. After
the upper aqueous phase had been removed, and the organic phase
had been dried under vacuum, 5a was obtained as pure oil with
a 79% yield (Table 4). In this case, we avoided the use of an organic
solvent throughout the entire benzylic bromination procedure. In
contrast to using NBS, an aqueous H2O2–HBr system also allows the
benzyl bromination of the toluene derivative bearing electron-
withdrawing groups in good yields. To increase radical formation,
we performed the reactions illuminated by a 125 W ‘solar’ lamp
and by adding a 30% aqueous solution of H2O2 gradually to the
reaction mixture. By slow addition of H2O2 the decomposition of
H2O2 during the reaction, owing to the presence of HBr and Br2, was
reduced. We anticipate that this is the main reason for the lower
yields that we obtain with deactivated methylbenzenes.
The effect of the mode of activation of radical chain on the selectivity of bromination
of toluene (4) with H2O2–HBr ‘on water’
CH3
CH2Br
CH3
Reaction
conditions
+
H2O
Br
4
5a
6
Entry Reaction conditionsa
Conv (%)b Product ratiob (%)
Benzyl br. (5a) Ring br. (6)
(p-/o-)
1
2
3
4
H2O2–HBr, dark, 24 h, rt.
90
94
95
96
1
1
1
3.00 (69:31)
0.33 (65:35)
0.88 (66:34)
d
H2O2–HBr, 5% DBP, 2 h, 80 ꢀ
C
H2O2–HBr, 5% HMPA, 2 h, 80 ꢀ
H2O2–HBr, 40 W, 24 h
C
1 (81%)c
a
A 0.8 mL suspension of 1.0 mmol of 4, 2.0 mmol of H2O2 and 1.1 mmol of HBr.
b
Determined by 1H NMR spectroscopy. Numbers in parentheses refer to the ratio
of para- versus ortho- bromotoluene.
c
Yield of isolated product, 7% of dibromobenzylbromide (5b) was also formed.
To understand the difference in the reactivity of both aqueous
brominating systems, we studied a reaction involving para-xylene
(19), since it has a mildly activated aromatic ring and two equiva-
lent methyl substituents. Table 5 shows that using either the H2O2–
HBr system or NBS in water at ambient temperature and in the dark
gives the ring-brominated derivative 21 as the main product.
Nevertheless the radical pathway is still operative. The reactivity of
the oxidative bromination system without light activation (entry 1)
was much higher since the conversion was 80%, while bromination
with NBS (entry 2) yielded only 31% of brominated products. In the
bromination activated by light the side chain bromination was the
sole reaction pathway, producing 1-(bromomethyl)-4-methyl-
benzene (20a) and 1,4-bis(bromomethyl)benzene (20b) with sim-
ilar conversion. Improved selectivity is observable for bromination
with NBS, since 20a and 20b are in a ratio 6.5:1 (entry 4), while in
an aqueous H2O2–HBr these products are in a 3.5:1 ratio (entry 3).
Based on the outcome of the bromination of alkylbenzenes us-
ing either NBS or a H2O2–HBr couple in water, which produced
ring-brominated products, we became interested in exploring the
feasibility of both bromination systems for electrophilic aromatic
bromination in aqueous media. The difference in reactivity and
selectivity of both brominating systems led us to investigate the
bromination of selected aromatic molecules ‘on water’ using the
H2O2–HBr system and NBS (Table 6). First, we tested the mesitylene
initial investigation of visible-light induced oxidative benzyl bro-
mination of 1 (Table 3).15 For this we added 1.0 mmol of 4 to
a 0.8 mL solution of 2.0 mmol of H2O2 (overall 9% H2O2 solution)
and 1.1 mmol of HBr (overall 11% HBr solution). When performing
the reaction in the dark at room temperature for 24 h, ring-bro-
mination was the main reaction channel, while benzyl bromide
(5a) was formed in only a yield of 15% (entry 1). Next the radical
chain process was activated by adding either 5 mol % of hydro-
phobic DBP or hydrophilic AMPA radical initiator and performing
the reaction at 80 ꢀC for 2 h (entries 2 and 3). In both cases the yield
of benzyl bromide (5a) increased, but selectivity was poor and ring-
brominated products together with some products of further bro-
mination were formed. Finally, we tested the third mode of
activation of the radical process, i.e., visible light (entry 4). Similar
to the reaction with NBS, oxidative bromination using aqueous
H2O2–HBr induced by visible light from a 40 W incandescent light
bulb gave selectively benzyl bromide (5a) with an 81% isolated
yield.
Next, various methylbenzene derivatives were brominated by
a visible-light induced reaction with an H2O2–HBr couple in an
aqueous medium. Table 4 shows how the benzyl brominated
products were formed selectively in high yields without any sig-
nificant amount of dibrominated products being formed. In the
Table 4
Table 5
Visible-light induced free-radical bromination of para-substituted toluenes with
Effect of reaction conditions on regioselectivity of bromination of para-xylene (19) in
water
H2O2–HBr ‘on water’
Entry
Substratea
Time
Yieldb (%)
CH2Br
+
CH2Br
CH3
CH3
Reaction
CH3
CH2Br
CHBr2
R
Br
conditions
+
H2O
24h
CH3
20a
CH2Br
20b
CH3
19
CH3
21
R
R
1
2
1 R¼tBu
24 h
10 h
28 h
32 h
66 h
66 h
2a: 91 (80)
5a: (79)
16a: 85 (77)
7a: 84 (71)
18a: 93 (90)
11: 91 (90)
d
d
d
4 R¼Hc
Entry
Reaction conditionsa
Yield (%)b
3d
4d
5d
6d
15 R¼Br
Benzyl br. (20a/20b)
Ring br. (21)
6 R¼COOEt
17 R¼COPh
10 R¼NO2
7b: 6 (4)
d
1
2
3
4
2H2O2–HBr, dark
NBS, dark
14 (100:0)
4 (100:0)
84 (77:23)
82 (87:13)
66
27
d
d
d
2H2O2–HBr, h
NBS, h
(40 W)c
n
(40 W)c
a
A 0.8 mL suspension of 1.0 mmol of substrate, 2.0 mmol of H2O2 and 1.1 mmol of
n
HBr, 40 W incandescent light bulb, react. temp¼27 ꢀC.
a
Distribution of products were determined by 1H NMR spectroscopy of the iso-
b
Reactions with H2O2–HBr: 1.0 mmol of 19 in 0.8 mL of water. Bromination with
NBS: 1.0 mmol of 19 in 5 mL of water.
lated reaction mixture, yields in parentheses refer to isolated yields.
b
Yields of products were determined by 1H NMR spectroscopy of the isolated
c
Experiment on a larger scale (5.0 mmol 4, 10.0 mmol H2O2, 5.5 mmol HBr, 4 mL
reaction mixture and are based on starting compound, numbers in parentheses refer
water).
d
to ratio of 20a/20b.
30% Aqueous solution of H2O2 was added slowly and the reaction mixture was
irradiated with a 125 W high-pressure mercury lamp.
c
40 W incandescent light bulb.

ˇ
A. Podgorsek et al. / Tetrahedron 65 (2009) 4429–4439
4432
Table 6
Bromination of various aromatic compounds using H2O2–HBr system or NBS ‘on water’
Entry
Substrate
Reaction conditionsa
Product
Yield (%)b
CH3
CH3
Br
1
2
2H2O2–1HBr, 24 h
1NBS, 24 h
100 (98)
94 (85)14
H3C
CH3
H3C
Br
CH3
23
22
Br
H3C
H3C
CH3
CH3
H3C
H3C
CH3
H3C
CH3
CH3
3
4
2H2O2–1HBr, 24 h
1NBS, 24 h
25a, 47 (46), 25b, 26 (25)
+
CH3
H3C
Mixture of products
Br
25b
24
25a
CH3
CH3
Br
5
6
2H2O2–1HBr, 24 h
1NBS, 24 h
100 (94)
82 (75)
26
27
Br
CH3
CH3
7
8
2H2O2–1HBr, 24 h
1NBS, 24 h
100 (95)
93 (89)
28
29
OCH3
OCH3
9
10
2H2O2–1HBr, 8 h
1NBS, 8 h
100 (90)
94 (87)
Br
31
30
OCH3
OCH3
Br
11
12
2H2O2–1HBr, 8 h
1NBS, 8 h
100 (95)
93 (82)14
CH3
33
CH3
32
Br
OH
OH
13
2H2O2–1HBr, 8 h
97 (90)
34
35
NHCOR
CH3
NHCOR
Br
14
15
R¼CH3 36
R¼Ph 38
2H2O2–1.1HBr, 24 h
2H2O2–1.1HBr, 24 h
R¼CH3 37
R¼Ph 39
100 (95)
94 (89)
CH3
NH2
NH2
NH2
16
17
2H2O2–1HBr, 8 h
3H2O2–2HBr, 8 h
41a, 94 (88), 41b, 3
41a, d, 41b, 100 (91)
Br
Br
Br
+
CF3
CF3
CF3
40
41a
41b
Br
18
2H2O2–1HBr, 24 h
100 (90)
42
43
Br
3H2O2–1.5HBr–2H2SO4,
24 h at 55 ꢀC
19
(20)
44
45
a
Bromination with H2O2–HBr: a suspension of 1 mmol of substrate in 0.8 mL of water. Bromination with NBS: a suspension of 1 mmol of substrate in 5 mL of water. Room
temperature unless otherwise noted.
b
Yields were determined by 1H NMR spectroscopy and are based on starting compound; yields in parentheses refer to isolated yields.

ˇ
A. Podgorsek et al. / Tetrahedron 65 (2009) 4429–4439
4433
Table 7
(22)/durene (24) couple (Table 6, entries 1–4). Both methods,
produced after 24 h at room temperature in an aqueous medium
bromomesitylene (23) in high yields, however, only the oxidative
bromination was quantitative (entry 1). Oxybromination of durene
(24) produced only the ring-brominated products monobromo-
and dibromodurene 25a and 25b, obtained in 46% and 25% yields,
respectively (entry 3). The reaction with NBS gave a complex
mixture of side chain and ring-brominated derivatives (entry 4).
Both methyl substituted naphthalenes 26 and 28 reacted only at the
aromatic ring to give the monobrominated products 27 and 29 with
H2O2–HBr (entries 5 and 7), while bromination with NBS gave
lower yields of 27 and 29, respectively, nevertheless no radical
bromination products were noted (entries 6 and 8). A similar re-
activity can be seen with activated aromates. Anisole (30) and 4-
methylanisole (32) were transformed with quantitative conversion
in the H2O2–HBr system, while lower yields of brominated products
were formed with NBS. Again no radical chain bromination was
observed in the reaction of 32 (entries 9–12). Next, oxidative bro-
mination ‘on water’ was tested on different aromatic molecules. 2-
Naphthol (34) and p-tolylacetamides 36 and 38 were selectively
transformed to the brominated products that were isolated in very
good yields (entries 13–15). There was no further bromination al-
though a 10% excess of HBr was used for brominating the acet-
amides. In the bromination of the aniline derivative 40
a monobrominated product 41a was formed in a 94% yield, in
addition 3% of the dibrominated product 41b was also formed. In-
creasing the amount of reagent (H2O2 and HBr were used in ratio
3:2) resulted in a complete conversion to 2,6-dibromo-4-(tri-
fluoromethyl)benzenamine (41b). A combination of aqueous H2O2–
HBr as the brominating agent with water as a reaction medium is
applicable to less activated aromatics. The bromination of naph-
thalene (42) proved highly selective resulting in a 90% isolated yield
of 1-bromonaphthalene (43). When benzene (44) was submitted to
2 equiv of H2O2 and 1 equiv of HBr at room temperature for 24 h,
only the starting compound was recovered. Using higher amounts
of reagents in the presence of 2 equiv of H2SO4 and by increasing
the reaction temperature to 55 ꢀC resulted in a 20% yield of bromo-
benzene (45).
para-Substituted phenols and anilines usually give mono- and
di-brominated products in bromination reactions. This makes them
interesting substrates on which to study the effect of our bromi-
nating system on the selectivity of the reaction. Surprisingly,
2 equiv of H2O2 and 1 equiv of HBr in 5 mL of water were sufficient
to convert 1.0 mmol of 4-tert-butylphenol (46) both regiose-
lectively and quantitatively into 2-bromo-4-tert-butylphenol (47a,
Table 7). Under the same reaction conditions the bromination of 46
with NBS gave 32% of 2-bromo-4-tert-buthylphenol (47a) and 29%
of 2,6-dibromo-4-tert-buthylphenol (47b). Increasing the amount
of the reagent used to 2 equiv resulted in the complete
conversion of 46 to the dibrominated product 47b, regardless of the
brominating reagent used. Our results of oxybromination are in
accordance with the reported selective monobromination of
4-methylphenol using H2O2–HBr8c in ethylenedichloride at 45 ꢀC
and using tBuOOH–HBr8a in boiling methanol. Photochemical bro-
mination with NBS in acetonitrile gave 2-bromo-4-methylphenol
accompanied by only small amounts of the dibrominated
product.17a
Bromination of para-substituted phenols using the H2O2–HBr system or NBS in
water as a reaction medium
OH
OH
OH
Br
+
Br
Br
Reagent
H2O
R
R
47a
R
47b
46 R=tBu
48 R=NO2
49a
49b
Entry
Sub.
Reaction conditionsa
Distributionb (%)
46/48
47a/49a
47b/49b
1
2
3
4
46
2H2O2–1HBr, 8 h
4H2O2–2HBr, 32 h
1NBS, 8 h
d
d
39
d
100 (90)
d
d
32
d
100 (98)
29
100 (95)
2NBS, 24 h
5
6
7
8
48
2H2O2–1HBr, 8 h
3H2O2–2HBr, 24 h
1NBS, 8 h
46
d
45
d
10
d
13
d
44 (40)
100 (95)
42
2NBS, 24 h
100 (90)
a
Bromination with H2O2–HBr: a suspension of 1 mmol of substrate in 5 mL of
water. Bromination with NBS: a suspension of 1 mmol of substrate in 5 mL of water.
Room temperature.
b
Yields were determined by 1H NMR spectroscopy; yields in parentheses refer to
isolated yields.
bromination of 48 with NBS in acetonitrile, gave an inverse ratio of
mono and dibrominated products (3.5:1).17a Solid state bromina-
tion with NBS at 30 ꢀC of 4-nitrophenol gave only the dibrominated
product in a yield of 50%.17b
Brominations of the aniline analogues 50 and 52 revealed dif-
ferent behaviour to the phenol ones. The reaction of 4-tert-butyl-
aniline (50) with 2 equiv of H2O2 and 1 equiv of HBr produced over
a period of 24 h a mixture of products, where the mono- and
dibrominated products 51a and 51b were formed in the ratio 1.8:1
(Table 8). Bromination of the same substrate with NBS, however,
gave predominantly the dibrominated product, 51a and 51b were
formed in an inverse ratio. Complete formation of 2,6-dibromo-4-
tert-butylaniline (51b) was achieved by using 4 equiv of H2O2 and
Table 8
Bromination of para-substituted anilines using H2O2–HBr system or NBS in water as
a reaction medium
NH2
NH2
NH2
Br
+
Br
Br
Reagent
H2O
R
R
51a
53a
R
51b
53b
50 R=tBu
52 R=NO2
Entry
Sub.
Reaction conditionsa
Distributionb (%)
50/52
51a/53a
51b/53b
1
2
3
4
50
2H2O2–1HBr, 24 h
4H2O2–2HBr, 28 h
1NBS, 8 h
35
d
46
d
42
d
18
d
23
100 (95)
36
2.5NBS, 24 h
100 (93)
The less reactive 4-nitrophenol (48) shows a similar reactivity
pattern for both brominating systems; the dibrominated product
49b predominates during bromination with 1 equiv of reagent
(49a/49b¼1:4.4 and 1:3.2, respectively), while with 2 equiv of re-
agent 2,6-dibromo-4-nitro-phenol (49b) is formed exclusively
(Table 7). Similar selectivity is observed in the reaction with NBS in
MeCN, however, when the reaction was promoted by HBF4$Et2O,
selective monobromination of 4-nitrophenol (48) with NBS in
CH3CN was observed.3b On the contrary, photochemical
5
6
7
8
52
2H2O2–1HBr, 24 h
3H2O2–2.5HBr, 28 h
1NBS, 8 h
12
d
38
d
88
d
33
d
d
100 (95)
29
100 (93)
2.5NBS, 24 h
a
Bromination with H2O2–HBr: a suspension of 1 mmol of substrate in 5 mL of
water. Bromination with NBS: a suspension of 1 mmol of substrate in 5 mL of water,
room temperature.
Yields were determined by 1H NMR spectroscopy; yields in parentheses refer to
b
isolated yields.

ˇ
A. Podgorsek et al. / Tetrahedron 65 (2009) 4429–4439
4434
2 equiv of HBr or 2.5 equiv of NBS in 28 h and 24 h, respectively. In
this case, bromination of the less activated 4-nitroaniline (52) in
aqueous H2O2–HBr gave selectively the monobrominated product
53a with 88% conversion within 24 h. No further attempt was made
to improve the yield. Similarly, oxidative bromination using a so-
dium perborate–KBr system in the presence of molybdate in AcOH
afforded 2-bromo-4-nitroaniline (53a) selectively.18 Again, over the
same period of time bromination with 1 equiv of NBS gave 53a and
53b in almost equal amounts. These results contrast with those
from the bromination of 52 with NBS, either in MeCN17a or under
solvent-free conditions.3d In that case the monobromo derivative
53a is formed selectively. The introduction of two bromine atoms
was successfully accomplished when higher amounts of reagent
and longer reaction times were applied.
Our previous study of the oxidative bromination of carbonyl
compounds in an aqueous H2O2–HBr system demonstrated that
water plays a key role in the activation of the ketone group through
enolization.13 However, water does not have this effect when NBS is
used as a brominating reagent.14,19 To obtain some additional in-
formation about this interesting phenomena, we investigated the
selectivity of bromination with H2O2–HBr and NBS in water both
induces the benzyl bromination of 54, however, oxidative bromi-
nation results only in a 18% yield, while the NBS radical chain
process was the only reaction pathway (entries 2 and 4). A lesser
effect was observed during the bromination of tetralone (58),
where NBS under conditions of darkness converted only 8% of 58. In
the presence of light, the main reaction pathway was a-bromina-
tion. The introduction of a methoxy substituent on the aromatic
ring in 54 and 58 altered the reactivity. The aromatic ring became
the most important reaction site in 56 and 60. There are two in-
teresting features concerning the bromination of both the
methoxy-substituted derivatives 56 and 60. First, light does not
trigger the benzyl bromination but instead, a small amount of the
a-brominated ketones 57a and 61a can be detected during the re-
action with H2O2–HBr. Alternatively, there is no such effect during
bromination with NBS. Second, the reactivity of the methoxy-
substituted ketone 60 at the aromatic ring is slightly higher with
NBS than in the H2O2–HBr system (entries 14 and 17). The reactivity
at the ketone functional group was much higher for H2O2–HBr than
that for NBS.
Styrene (62) is a useful substrate for investigating the nature of
the active halogenating agents and is used often in biomimetic
studies of haloperoxidation,20a mainly with a metal catalyst.7b,20b,c
Research has focused on the selectivity of bromohydrin and
dibromide formation in a vanadium(V) or molybdenium(VI) cata-
lyzed oxybromination of 62 using potassium bromide and hydro-
gen peroxide. Performing these reactions in water gives
under dark and illuminated conditions. Indanone (54), a-tetralone
(58) and both methoxy-substituted analogues 56 and 60 are
promising substrates for such studies since they posses all three
reactive sitesdat the benzyl position, the a-position to the ketone
group and at the aromatic ring.
Indanone (54) is an interesting example for highlighting the
difference in the reactivity of both aqueous brominating systems.
bromohydrin as the main product, despite a large excess of bromide
7b,20b,c
ions.7f In a two-phase system using either H2O–CHCl3
or
20b,d
With H2O2–HBr the reaction occurs only at the
a-position to the
H2O–CH2Cl2
more of the dibrominated product forms. This
carbonyl group, while the reaction with NBS under similar condi-
tions does not proceed (Table 9, entries 1 and 3). Irradiation by light
makes styrene a good substrate for which to study the phase be-
haviour of ‘on water’ reactions by observing the difference in
Table 9
The effect of brominating system on the regioselectivity of bromofunctionalization of benzocycloalkanones in water
O
O
O
O
Reagent
Br
(CH2)n
+
+
H2O
24h
(CH2)n
(CH2)n-1
Br
(CH2)n
R
R
R
R
Br
54R=H, n=1
55a
57a
59a
61a
55b
57b
59b
61b
55c
57c
59c
61c
56R=OCH3, n=1
58R=H, n=2
60R=OCH3, n=2
Sub.
Reaction conditionsa
Conv. (%)
Distribution (%)b
a
b
c
1
2
3
4
54
H2O2–HBr, dark13
94
94
0
100
82
d
d
d
d
d
d
H2O2–HBr, h
n
18
d
NBS, dark
NBS h
n
(40 W)14
70
d
100
5
6
7
8
56
58
60
H2O2–HBr, dark13
76
88
82
94
d
14
d
d
100
86
100
100
d
d
d
d
H2O2–HBr, h
n
NBS, dark
NBS, h
n (40 W)
9
H2O2–HBr, dark13
95
91
8
100
95
87
d
d
d
d
d
5
13
9
10
11
12
H2O2–HBr, h
n
NBS, dark
NBS, h
n
32
91
13
14
15
16
17
18
H2O2–HBr, dark13
H2O2–HBr, darkc
80
43
93
85
78
79
d
d
8
d
d
d
100
100
92
100
100
100
d
d
d
d
d
d
H2O2–HBr, h
n
NBS, dark
NBS, darkc
NBS, h
n
a
Bromination with 2 mmol of H2O2, 1 mmol of HBr: 1 mmol of substrate in a 0.5 mL of water suspension. Bromination with NBS: 1 mmol of NBS and 1 mmol of substrate in
a 0.5 mL of water suspension. Reactions were performed at room temperature.
b
Yields were determined by 1H NMR spectroscopy are based on starting compound; yields in parentheses refer to isolated yields.
Time: 3 h.
c

ˇ
A. Podgorsek et al. / Tetrahedron 65 (2009) 4429–4439
4435
Table 10
Although water activates the bromination of ketones in the aque-
ous H2O2–HBr system the use of NBS for the bromination of ketones
‘on water’ was unsuccessful and 1-indanone 54 reacted only
through the benzyl bromination process. The reactivity of both
brominating systems for electrophilic aromatic substitution is very
similar, albeit oxidative bromination results in better yields and is
more selective. As was shown in the bromination of styrene 62, that
the outcome of bromination (dibromination vs bromohydroxy-
lation) is not solely defined by the structure of reagent but also by
reaction conditions, such as the amount of water used, the organic
solvent, stirring rate, and the structure of the interface. In conclu-
sion, mild reaction conditions, a simple isolation procedure, in-
expensive reagents and an overall reduced impact on the
environment make this aqueous brominating method a promising
alternative to other reported brominating methods.
Bromination of styrene (62) using H2O2–HBr system or NBS in water as a reaction
medium
O
Br
Reagent Br
H2O
Br
HO
Ph
Br
+
+
Ph
62
Ph
Ph
24h
r.t.
63
64
65
Entry
Reaction conditionsa
Conv. (%)
Distributionb (%)
63
64
65
1
2
3
4
5
6
7
H2O2–2HBr
100
100
100
100
100
100
100
35
50
56
70
d
d
d
53
50
22
30
12
d
22
d
d
d
81
H2O2–2HBrc
H2O2–2HBr, CH2Cl2
H2O2–2HBr, CH2Cl2
c
H2O2–2HBr, 2NaOH, 48 h
40d
100
19
1NBS
2NBS
a
Bromination with H2O2–HBr: 1.0 mmol of 62 in 0.8 mL of water. Bromination
with NBS: 1.0 mmol of 62 in 0.5 mL of water.
4. Experimental
4.1. General
b
Yields were determined by 1H NMR spectroscopy and are based on starting
compound.
c
Without stirring.
2-Phenyloxirane (60%) was formed.
d
All chemicals were obtained from commercial sources and were
used without further purification. Column chromatography was
carried out using silica gel 60 (0.063–0.200 mm). 1H and 13C NMR
spectra were recorded in CDCl3 using a Varian Inova 300 MHz
bromination in a two-phase system (dibromination) and an aque-
ous system (bromohydrine formation).
When the ‘on water’ bromination with H2O2–HBr system was
performed under vigorously stirred conditions, the ratio of dibro-
mination (63) to bromohydroxylation (64 and 65) was 35:65
(Table 10, entry 1). The main product was bromohydrin 64, which
spectrometer. The chemical shifts (d) are reported in parts per
million relative to TMS as the internal standard for 1H NMR and
CDCl3 for 13C NMR. Melting points were determined using a Bu¨chi
535 melting point apparatus and were uncorrected. Mass spectra
were obtained using an Autospec Q mass spectrometer with elec-
tron impact ionization (EI, 70 eV).
was further oxidized under reaction conditions to a-bromoaceto-
phenone 65. Performing the same reaction without stirring, so as
not to disturb the interface increases the amount of dibromination
and the dibromide 63 and the bromohydrin 64 were formed in
a 50:50 ratio (entry 2). Next, an analogous study with a solution of
62 in CH2Cl2 was performed. In this case a further increase in
dibromination was noted with 63 being the main product (dibro-
mination/bromohydroxylation¼56:44, entry 3). An analogous ex-
periment without stirring resulted in 70% of the dibromide 63 and
only 30% of the bromohydrin 64 (entry 4). This indicates that not
only the nature of the brominating reagent defines the outcome of
bromination but also the way in which the reaction under two-
phase conditions is performed. Penetration of Br2 into the organic
phase could lead to the formation of dibromide 63, while increasing
the interfacial area bromohydroxylation becomes the more im-
portant process. It is a challenge to direct the reaction towards the
selective formation of bromohydrin 64 in oxidative bromination
because increasing the basicity of the aqueous phase leads to the
rapid decomposition of H2O2, while the addition of NaOH imme-
diately after bromination to perform nucleophilic substitution
leads to an intramolecular nucleophilic attack resulting in 2-phe-
nyloxirane (entry 5). Expectedly, ‘on water’ bromination with NBS
produced 2-bromo-1-phenylethanol 64 both selectively and
quantitatively (entry 6). Increasing the amount of NBS to 2 equiv
results in further oxidation to produce 2-bromo-1-phenylethanone
65 (entry 7).
4.2. Typical reaction procedure for visible-light induced
benzylic bromination with N-bromosuccinimide in water
Methylbenzene (1.0 mmol) was suspended in 5 mL of water. To
this was added N-bromosuccinimide (178 mg, 1.0 mmol) and the
mixture stirred at 500 rpm at room temperature under irradiation
from a 40 W incandescent light bulb. The progress of the reaction
was monitored by either TLC or GC. At the end of reaction (22–25 h)
the mixture was transferred into a separating funnel and 10 mL of
0.002 M NaHSO3 added. The crude product was then extracted
using 3ꢁ5 mL of a hexane/ethyl acetate mixture and the combined
organic phases were dried over anhydrous Na2SO4. The solvent was
evaporated under reduced pressure and the crude reaction mixture
was analyzed by 1H NMR spectroscopy. Finally the products were
isolated by column chromatography (SiO2, hexane/EtOAc) and
identified by comparison with literature data.
4.2.1. 4-tert-Butylbenzyl bromide (2a)21
Yield: 159 mg (70%), oily product. 1H NMR (CDCl3):
d 1.28 (s, 9H),
4.46 (s, 2H), 7.30 (d, J¼8.6 Hz, 1H), 7.32 (d, J¼8.6 Hz, 1H). 13C NMR
(CDCl3): d 31.25, 33.56, 34.34, 125.76, 128.76, 134.76, 151.56. MS (EI):
m/z 228 and 226 (Mþ, 1:1 ratio), 147 (100%), 132 (38%), 117 (20%), 91
(13%).
3. Conclusion
4.2.2. 1,1-Dibromomethyl-4-tert-butylbenzene (2b)
Yield: 12 mg (4%), white crystals; mp 41–43 ꢀC (lit.22 41–42 ꢀC).
We have studied ‘on water’ electrophilic and radical bromina-
tion using two types of reagent: NBS and oxidative bromination
with H2O2–HBr. Both brominating systems in the aqueous phase
allow for a straightforward isolation of the brominated product
since it is the only non-soluble compound remaining after the re-
action. The H2O2–HBr system in water was more reactive than NBS
for benzyl bromination and for the bromination of ketones, while
the opposite was observed in the bromination of the aromatic ring
in the case of a methoxy-substituted tetralone derivative 60.
1H NMR (CDCl3):
d
1.23 (s, 9H), 6.61 (s, 1H), 7.33 (d, J¼8.6 Hz, 2H),
7.45 (d, J¼8.6 Hz, 2H). 13C NMR (CDCl3):
d 31.21, 34.78, 41.03, 125.57,
126.18, 139.13, 153.06.
4.2.3. 2-Bromo-4-tert-butyltoluene (3)23
Reaction in the presence of 5% AMPA at 80 ꢀC (Table 1), 43 mg
(19%) of oily product. 1H NMR (CDCl3):
1.23 (s, 9H), 2.35 (s, 3H),
7.14 (d, J¼8.0 Hz, 1H), 7.21 (dd, J¼8.0, 2.0 Hz, 1H), 7.53 (d, J¼2.0 Hz,
1H). 13C NMR (CDCl3):
22.2, 31.2, 34.4, 124.3, 124.8, 129.3, 130.4,
d
d

ˇ
A. Podgorsek et al. / Tetrahedron 65 (2009) 4429–4439
4436
134.7, 150.8. MS (EI): m/z 228 and 226 (Mþ, 1:1 ratio), 213 (100%),
(EI): m/z 217 and 215 (Mþ, 1:1 ratio), 136 (100%), 106 (23%), 90
211 (98%), 185 (18%), 183 (18), 132 (58), 115 (20%), 91 (16%).
(34%), 78 (31%).
4.2.4. Ethyl 4-(bromomethyl)benzoate (7a)24
4.4.2. 1-Bromo-4-(bromomethyl)benzene (16a)
Yield: 175 mg (72%), oily product. 1H NMR (CDCl3):
d
1.39 (t,
Yield: 193 mg (77%), white crystals; mp 52–54 ꢀC (lit.30
J¼7.1 Hz, 3H), 4.37 (q, J¼7.1 Hz, 2H), 7.45 (d, J¼8.4 Hz, 2H), 8.02 (d,
62–63 ꢀC). 1H NMR (CDCl3):
d
4.43 (s, 2H), 7.26 (d, J¼8.3 Hz, 2H),
J¼8.4 Hz, 2H). 13C NMR (CDCl3):
d
14.25, 32.19, 61.02, 126.51, 128.91,
7.47 (d, J¼8.3 Hz, 2H). 13C NMR (CDCl3):
d 32.3, 122.4, 130.6, 131.9,
129.88, 142.43, 165.96. MS (EI): m/z 244 and 242 (Mþ, 1:1 ratio), 199
136.8. MS (EI): m/z 252, 250 and 249 (Mþ, 1:2:1 ratio), 171 (100%),
(9%), 197 (9%), 163 (100%), 135 (16%), 119 (21%), 90 (15%).
169 (100%), 90 (80%), 63 (58%).
4.2.5. Ethyl 4-(dibromomethyl)benzoate (7b)
4.4.3. 4-(Bromomethyl)benzophenone (18a)
Yield: 10 mg (3%), white crystals; mp 98–99 ꢀC (lit.25 97–99 ꢀC).
Yield: 248 mg (90%), white crystals; mp 113–114 ꢀC (lit.31 110–
1H NMR (DMSO-d6):
d
1.40 (t, J¼7.1 Hz, 3H), 4.38 (q, J¼7.1 Hz, 2H),
111 ꢀC). 1H NMR (CDCl3):
d
4.53 (s, 2H), 7.46–7.52 (m, 4H), 7.57–7.63
6.66 (s. 1H), 7.61 (d, J¼8.4 Hz, 2H), 7.91 (d, J¼8.4 Hz, 2H). 13C NMR
(m, 1H), 7.77–7.81 (m, 4H). 13C NMR (CDCl3):
d
32.2, 128.3, 128.9,
(CDCl3):
d
14.3, 40.0, 61.1, 126.5, 129.5, 131.4, 145.6, 165.8.
130.0, 130.6, 132.5, 136.4, 137.4, 142.1, 196.0. MS (EI): m/z 276 and
274 (Mþ, 1:1 ratio), 195 (100%), 167 (52%), 77 (14%).
4.2.6. 1-(4-(Bromomethyl)phenyl)ethanone (9a)
Yield: 162 mg (76%), white crystals; mp 38.5–40.0 ꢀC (lit.26 42–
4.4.4. 1-Bromomethyl-4-methylbenzene (20a)
43 ꢀC). 1H NMR (CDCl3):
d
2.60 (s, 3H), 4.50 (s, 2H), 7.48 (d, J¼8.5 Hz,
Yield: 115 mg (62%), white crystals; mp 32.6–33.1 ꢀC (lit.32 38.0–
2H), 7.93 (d, J¼8.5 Hz, 2H). 13C NMR (CDCl3):
d
26.6, 32.1, 128.8,
39.7 ꢀC). 1H NMR (CDCl3):
d 2.35 (s, 3H), 4.47 (s, 2H), 7.15 (d,
129.2, 136.9, 142.8, 197.3. MS (EI): m/z 214 and 212 (Mþ, 1:1 ratio),
199 (9%), 197 (9%), 171 (4%), 169 (4%), 133 (100%), 118 (42%), 105
(25%).
J¼8.0 Hz, 2H), 7.29 (d, J¼8.0 Hz, 2H). MS (EI): m/z 186 and 184 (Mþ,
1:1 ratio), 105 (100%), 77 (12%).
4.4.5. 1,4-Bis-bromomethylbenzene (20b)
4.2.7. 4-Methylbenzoic acid (13a)
Yield: 50 mg (19%), white crystals; mp 144.3–145.4 ꢀC (lit.33
Yield: 109 mg (80%), white crystals; mp 178–180 ꢀC (lit.27 182–
144.8–145.4 ꢀC). 1H NMR (CDCl3):
d 4.46 (s, 4H), 7.36 (s, 4H). MS
183 ꢀC). 1H NMR (CDCl3):
d
2.43 (s, 3H), 7.27 (d, J¼8.2 Hz, 2H), 8.00
(EI): m/z 266, 264 and 262 (Mþ, 1:2:1 ratio), 185 (81%), 183 (83%),
104 (100%), 77 (17%).
(d, J¼8.2 Hz).
4.3. Large scale visible-light induced benzylic bromination
with N-bromosuccinimide in water
4.5. Large scale visible-light induced benzylic bromination
with aqueous H2O2–HBr system
Toluene (4, 460 mg, 5.0 mmol) was combined together with
water (25 mL) and NBS (900 mg, 5.05 mmol) in a conical flask. The
reaction mixture was stirred at 500 rpm at room temperature un-
der irradiation from a 40 W incandescent light bulb for 24 h. At the
end of the reaction the lower organic and upper aqueous phases
were separated and the organic phase washed with 2ꢁ10 mL of
water. The organic phase was then transferred to the column.
Column chromatography (SiO2, hexane/EtOAc) gave 658 mg (77%)
of 1-bromomethylbenzene (5a)28 oily product. 1H NMR (CDCl3):
Toluene (4, 460 mg, 5.0 mmol) was combined together with
4.2 mL of an aqueous solution of 10.0 mmol of H2O2 and 5.5 mmol
of HBr in a conical flask. The reaction mixture was stirred at
500 rpm at room temperature under irradiation from a 40 W in-
candescent light bulb for 24 h. At the end of reaction the lower
organic and the upper aqueous phases were separated and the
organic phase dried under vacuum to give 675 mg (79%) benzyl
bromide (5a) as pure oil.
d
4.51 (s, 2H), 7.30–7.40 (m, 5H). 13C NMR (CDCl3):
d
33.50, 128.79,
4.6. Typical reaction procedure for bromination of aromatic
molecules with N-bromosuccinimide in water
129.02, 137.80. MS (EI): m/z 172 and 170 (Mþ, 1:1 ratio), 91 (100%),
65 (15%).
The substrate (1.0 mmol) was initially suspended in 5 mL of
water. To this N-bromosuccinimide (178 mg, 1 mmol) was added
and the reaction mixture stirred at 500 rpm at room temperature
for 5–32 h. The progress of the reaction was monitored by either
TLC or GC. At the end of reaction, the work up procedure depended
on the aggregate state of the products. In the case of solid products,
the reaction mixture was filtered off and rinsed with water (10 mL).
If the product was oily, in the case of the small-scale experiment,
the mixture was transferred into a separating funnel, to which
10 mL of water and 2 mL of 0.01 M NaHSO3 were added. The crude
product was extracted using 3ꢁ5 mL of a mixture of hexane and
ethyl acetate and the combined organic phase dried over anhy-
drous Na2SO4. The solvent was then evaporated off and the crude
reaction product analyzed by 1H NMR spectroscopy. Finally the
products were isolated by column chromatography and identified
by comparison with literature data.
4.4. Typical reaction procedure for visible-light induced
benzylic bromination with aqueous H2O2–HBr system
Methyl benzene (1.0 mmol) was added to 0.8 mL aqueous so-
lution of 2.0 mmol of H2O2 and 1.1 mmol of HBr. The reaction
mixture was then stirred at 500 rpm at room temperature under
irradiation from a 40 W incandescent light bulb for 10–24 h. For
deactivated substrates, like 6, 10 and 17, the substrate (1.0 mmol)
was added to 0.6 mL of an aqueous solution of 1.1 mmol of HBr to
which 2.0 mmol of 30% aqueous H2O2 was added gradually
(0.5 mmol per 3 h). The reaction mixture was stirred at 500 rpm at
room temperature while under irradiation from a 125 W high-
pressure mercury lamp. On completion the work up procedure was
the same as that for bromination with NBS. The crude reaction
product was analyzed by 1H NMR spectroscopy, isolated by column
chromatography and identified by comparison with literature data.
4.7. Typical reaction procedure for bromination of aromatic
molecules in aqueous H2O2–HBr system
4.4.1. 1-(Bromomethyl)-4-nitrobenzene (11a)
Yield: 194 mg (90%), white crystals; mp 98–99 ꢀC (lit.29 98–
99 ꢀC). 1H NMR (CDCl3):
d
4.52 (s, 2H), 7.57 (d, J¼8.7 Hz, 2H), 8.21 (d,
The substrate (1.0 mmol) was suspended in 0.5 mL of water in
a flask and the contents covered with aluminium foil to create
J¼8.7 Hz, 2H). 13C NMR (CDCl3):
d 30.8, 124.0, 129.9, 144.7, 147.6. MS

ˇ
A. Podgorsek et al. / Tetrahedron 65 (2009) 4429–4439
4437
a dark environment. To this a 48% aqueous solution of HBr
4.9.7. 2-Bromo-1-methoxy-4-methylbenzene (33)37
(0.114 mL,1.0 mmol) and a 30% aqueous solution of H2O2 (0.204 mL,
2 mmol) were added. The reaction mixture was stirred at 500 rpm
at room for 5–32 h. The progress of the reaction was monitored by
either TLC or GC. At the end of reaction, the work up procedure
depended on the aggregate state of the products.
Yield: 191 mg (95%), oily product. 1H NMR (CDCl3):
d
2.26 (s, 3H),
3.85 (s, 3H), 6.78 (d, J¼8.4 Hz, 1H), 7.05 (dd, J¼8.4, 2.2 Hz, 1H), 7.35
(d, J¼2.2 Hz). MS (EI): m/z 202 and 200 (Mþ, 1:1 ratio), 187 (39%),
185 (39%), 121 (32%), 78 (71%).
4.9.8. 1-Bromonaphthalene-2-ol (35)
4.8. Work up procedure for liquid products
Yield: 201 mg (90%), brown crystals; mp 78–80 ꢀC (lit.38 78 ꢀC).
1H NMR (CDCl3):
d
7.25 (d, J¼8.9 Hz,1H), 7.37 (ddd, J¼8.1, 6.9,1.2 Hz,
The reaction mixture was dissolved in 5 mL of hexane/ethyl-
acetate (20:1 or 10:1) and solid NaHSO3 added to reduce any
unreacted Br2 or H2O2. The solution was then dried over anhydrous
Na2SO4. The insoluble material was filtered off and the organic
solvent evaporated under reduced pressure. The crude reaction
mixture was then analyzed by 1H NMR spectroscopy. Where nec-
essary, the product was isolated by column chromatography (SiO2,
hexane–EtOAc), and its structure determined by comparison with
literature data.
1H), 7.56 (m, 2H), 7.71 (d, J¼8.9 Hz, 1H), 8.00 (d, J¼8.5 Hz, 1H). MS
(EI): m/z 224 and 222 (Mþ, 1:1 ratio), 143 (5%), 114 (89%), 87 (21%),
63 (35%).
4.9.9. N-(2-Bromo-4-methylphenyl)acetamide (37)
Yield: 217 mg (95%), white crystals; mp 119.4–120.4 ꢀC (lit.39
117 ꢀC). 1H NMR (CDCl3):
d 2.22 (s, 3H), 2.29 (s, 3H), 7.10 (d,
J¼8.3 Hz, 1H), 7.34 (s, 1H), 7.53 (s, 1H, NH), 8.15 (d, J¼8.3 Hz, 1H). 13C
NMR (CDCl3):
d 20.5, 24.7, 113.2, 121.9, 128.9, 132.4, 133.1, 135.2,
168.1. MS (EI): m/z 229 and 227 (Mþ, 1:1 ratio), 187 (100%), 185
4.9. Work up procedure for solid products
(100%), 148 (97%), 106 (90%), 77 (40%).
The reaction mixture was filtered off and rinsed with water
(10 mL). The crude mixture was then analyzed by 1H NMR spec-
troscopy. The product was isolated by either column chromatog-
raphy (SiO2, hexane–EtOAc) or purified by crystallization and its
structure determined by comparison with literature data.
4.9.10. N-(2-Bromo-4-methylphenyl)benzamide (39)
Yield: 258 mg (89%), white crystals; mp 146–148 ꢀC (lit.40
148 ꢀC). 1H NMR (CDCl3):
d 2.33 (s, 3H), 4.76 (br s, 1H, NH), 7.18 (dd,
J¼8.4, 1.4 Hz, 1H), 7.41 (d, J¼1.4 Hz, 1H), 7.48–7.69 (m, 2H), 7.93 (dd,
J¼8.0, 1.3 Hz, 2H), 8.39 (d, J¼8.4 Hz, 2H). 13C NMR (76 MHz, CDCl3,
Me4Si):
d 20.5, 113.7, 120.28, 121.6, 127.0, 128.9, 129.1, 129.5, 132.0,
4.9.1. 2-Bromo-1,3,5-trimethylbenzene (23)28
132.5, 135.4, 165.1. MS (EI): m/z 291 and 289 (Mþ, 1:1 ratio), 210
Yield: 195 mg (98%), oily product. 1H NMR (CDCl3):
d
2.23 (s, 3H),
(62%), 105 (100%), 77 (40%).
2.36 (s, 6H), 6.88 (s, 2H). 13C NMR (CDCl3):
d 20.6, 23.7, 124.2, 129.0,
136.2, 137.8. MS (EI): m/z 200 and 198 (Mþ, 1:1 ratio), 119 (100%),
4.9.11. 2-Bromo-4-(trifluoromethyl)aniline (41a)41
103 (13%), 91 (28%), 77 (13%).
Yield: 211 mg (88%), oily product. 1H NMR (CDCl3):
d 4.38 (br s,
2H, NH2), 6.74 (d, J¼8.4 Hz, 1H), 7.32 (dd, J¼8.4, 1.7 Hz, 1H), 7.65 (d,
4.9.2. 3-Bromo-1,2,4,5-tetramethylbenzene (25a)
J¼1.7 Hz, 1H). 13C NMR (CDCl3):
d 108.0, 114.7, 120.9 (q, CF3), 125.6,
Yield: 98 mg (46%), white crystals; mp 60–61 ꢀC (lit.34 60.5 ꢀC).
129.9, 147.0. MS (EI): m/z 241 and 239 (Mþ,1:1 ratio), 222 (18%), 220
(18%), 160 (20%), 140 (17%), 107 (27%).
1H NMR (CDCl3):
d
2.27 (s, 6H), 2.35 (s, 6H), 6.88 (s, 1H). 13C NMR
(CDCl3):
d 20.2, 21.0, 129.0, 130.3, 133.9, 134.7. MS (EI): m/z 214 and
212 (Mþ, 1:1 ratio), 133 (100%), 119 (32%), 73 (25%).
4.9.12. 2,6-Dibromo-4-(trifluoromethyl)aniline (41b)42
Yield: 290 mg (91%), oily product. 1H NMR (CDCl3):
d 4.88 (br s,
4.9.3. 1,4-Dibromo-2,3,5,6-tetramethylbenzene (25b)
2H, NH2), 7.62 (s, 2H). 13C NMR (CDCl3):
d 107.7, 121.2 (q, CF3), 128.9,
Yield: 73 mg (25%), white crystals; mp 200 ꢀC (lit.34 198–199 ꢀC).
129.0, 144.8. MS (EI): m/z 321, 319 and 317 (Mþ, 1:2:3 ratio), 302
1H NMR (CDCl3):
d
2.48 (s, 12H). 13C NMR (CDCl3):
d
22.3, 128.1,
(4%), 300 (12%), 298 (4%), 158 (25%).
135.0. MS (EI): m/z 294, 292 and 290 (Mþ, 1:2:1 ratio), 213 (60%),
211 (60%).
4.9.13. 1-Bromonaphthalene (43)43
Yield: 186 mg (90%), oily product. 1H NMR (CDCl3):
d 7.27 (t,
4.9.4. 2-Bromo-1-methylnaphthalene (27)
J¼7.9 Hz, 1H), 7.52 (m, 2H), 7.78 (m, 3H), 8.21 (d, J¼8.3 Hz, 1H). 13C
Yield: 208 mg (94%), pale brown crystals; 36–37 ꢀC (lit.35 31 ꢀC).
NMR (CDCl3): d 122.8, 125.8, 126.1, 126.6, 127.01, 127.2, 128.2, 129.8,
1H NMR (CDCl3):
d
2.64 (s, 3H), 7.14 (dd, J¼7.6, 0.7 Hz, 1H), 7.56 (m,
131.9, 134.5. MS (EI): m/z 208 and 206 (Mþ, 1:1 ratio), 127 (70%), 84
2H), 7.65 (d, J¼7.6 Hz, 1H), 7.96 (dd, J¼7.3, 2.3 Hz, 1H), 8.23 (dd,
(100%).
J¼7.8, 2.0 Hz, 1H). 13C NMR (76 MHz, CDCl3, Me4Si):
d 19.3, 119.6,
120.7, 124.6, 126.5, 127.0, 127.7, 129.5, 131.8, 133.8, 134.4. MS (EI): m/
4.9.14. Bromobenzene (45)
z 222 and 220 (Mþ, 1:1 ratio), 141 (100%).
Yield: 31 mg (20%), oily product. 1H NMR (CDCl3):
d
7.21–7.31
(m, 3H), 7.48–7.51 (m, 2H). 13C NMR (CDCl3):
131.6.
d 122.5, 126.8, 130.0,
4.9.5. 1-Bromo-2-methylnaphthalene (29)36
Yield: 210 mg (95%), oily product. 1H NMR (CDCl3):
d 2.61 (s, 3H),
7.32 (d, J¼8.3 Hz, 1H), 7.44 (ddd, J¼8.0, 6.9, 1.0 Hz, 1H), 7.55 (ddd,
4.9.15. 2-Bromo-4-tert-butylphenol (47a)44
J¼8.4, 6.9, 1.3 Hz, 1H), 7.68 (d, J¼8.3 Hz, 1H), 7.76 (d, J¼8.00 Hz, 1H),
Yield: 206 mg (90%), oily product. 1H NMR (CDCl3):
d 1.28 (s, 9H),
8.28 (d, J¼8.48 Hz,1H). 13C NMR (CDCl3):
d
24.14,124.0, 125.6, 126.8,
5.36 (s, 1H, OH), 6.95 (d, J¼8.5 Hz, 1H), 7.23 (dd, J¼8.5, 2.3 Hz, 1H),
127.2,128.0,128.7,132.5,132.9,135.9. MS (EI): m/z 222 and 220 (Mþ,
7.44 (d, J¼2.3 Hz, 1H). 13C NMR (CDCl3):
d 31.3, 34.1, 109.8, 115.42,
1:1 ratio), 141 (100%).
126.1, 128.7, 145.0, 149.7. MS (EI): m/z 230 and 228 (Mþ, 1:1 ratio),
215 (100%), 213 (100%), 187 (14%), 185 (14%), 134 (78%).
4.9.6. 1-Bromo-4-methoxybenzene (31)8a
Yield: 168 mg (90%), oily product. 1H NMR (CDCl3):
d
3.77 (s, 3H),
4.9.16. 2,6-Dibromo-4-tert-butylphenol (47b)
6.78 (d, J¼9.0 Hz, 2H), 7.37 (d, J¼9.0 Hz, 2H). 13C NMR (CDCl3):
Yield: 302 mg (98%), white crystals; mp 70–71 ꢀC (lit.45 70–
d
55.4, 115.7, 119.7, 122.2, 132.2. MS (EI): m/z 188 and 186 (Mþ, 1:1
71 ꢀC). 1H NMR (CDCl3):
d
1.26 (s, 9H), 5.71 (s, 1H, OH), 7.41 (s, 2H).
ratio), 173 (51%), 171 (51%), 145 (34%), 143 (34%), 77 (15%).
13C NMR (CDCl3):
d 31.2, 34.3, 109.4, 129.1, 146.0, 147.0. MS (EI): m/z

ˇ
A. Podgorsek et al. / Tetrahedron 65 (2009) 4429–4439
4438
310, 308 and 306 (Mþ, 1:2:1 ratio), 295 (60%), 293 (100%), 291
(60%), 214 (31%), 212 (31%).
4.11.1. 2-Bromoindan-1-one (55a)
Yield: 169 mg (80%), crystals, mp 37–38 ꢀC (lit.13 37–38 ꢀC). 1H
NMR (CDCl3):
d
3.42 (dd, J¼18.1, 3.2 Hz, 1H), 3.84 (dd, J¼18.1, 7.5 Hz,
4.9.17. 2,6-Dibromo-4-nitrophenol (49b)
1H), 4.65 (dd, J¼7.5, 3.2 Hz, 1H), 7.40–7.46 (m, 2H), 7.64–7.69 (m,
Yield: 282 mg (95%), yellow crystals; mp 148–150 ꢀC (lit.46
1H), 7.81–7.84 (m, 1H). 13C NMR (CDCl3):
d 37.9, 44.0, 125.0, 126.4,
141 ꢀC). 1H NMR (CDCl3):
d
6.55 (br s, 1H, OH), 8.41 (s, 2H). 13C NMR
128.2, 133.5, 135.9, 151.1, 199.5. MS (EI): m/z 212 and 210 (Mþ, 1:1
(CDCl3):
d
109.6, 128.0, 150.0, 155.0. MS (EI): m/z 299, 297 and 295
ratio), 131 (100%), 103 (46%), 77 (28%).
(Mþ, 1:2:1 ratio), 269 (32%), 267 (63%), 265 (32%), 187 (25%), 185
(25%), 172 (41%), 170 (41%).
4.11.2. 4-Bromo-5-methoxy-indan-1-one (57b)
Yield: 137 mg (57%), white crystals; mp 120–121 ꢀC (lit.19
4.9.18. 2,6-Dibromo-4-tert-butylaniline (51b)47
120 ꢀC). 1H NMR (CDCl3):
d 2.67–2.73 (m, 2H), 3.02–3.09 (m, 2H),
Yield: 292 mg (95%), oily product. 1H NMR (CDCl3):
d
1.25 (s, 9H),
4.00 (s, 3H), 6.94 (d, J¼8.4 Hz, 1H), 7.70 (d, J¼8.4 Hz). 13C NMR
4.40 (br s, 2H, NH2), 7.37 (s, 2H). 13C NMR (CDCl3):
d
31.3, 34.1, 108.7,
(CDCl3): d 27.1, 36.3, 56.8, 110.0, 111.2, 124.0, 131.8, 156.9, 160.9,
128.9, 139.5, 143.1. MS (EI): m/z 309, 307 and 305 (Mþ, 1:2:1 ratio),
204.9. MS (EI): m/z 242 and 240 (Mþ,1:1 ratio), 214 (17%), 212 (17%),
294 (60%), 292 (100%), 290 (60%), 213 (35%), 211 (35%).
199 (12%), 197 (12%), 171 (11%), 169 (11%), 161 (10%).
4.9.19. 2-Bromo-4-nitroaniline (53a)
4.11.3. 2-Bromo-1-tetralone (59a)
Yield: 163 mg (75%), yellow crystals; mp 103–104 ꢀC (lit.48 102–
Yield: 198 mg (88%), crystals; mp 40–42 ꢀC (lit.13 38–39 ꢀC). 1H
104 ꢀC). 1H NMR (CDCl3):
d
4.90 (br s, 2H, NH2), 6.75 (d, J¼9.0 Hz,
NMR (CDCl3):
d
2.41–2.60 (m, 2H), 2.90 (dt, J¼17.2, 4.5 Hz, 1H),
1H), 8.02 (dd, J¼9.0, 2.5 Hz, 1H), 8.36 (d, J¼2.5 Hz, 1H). 13C NMR
3.26–3.37 (m, 1H), 4.73 (t, J¼4.5 Hz, 1H), 7.25 (d, J¼7.9 Hz, 1H), 7.34
(CDCl3):
d 107.0, 113.4, 124.9, 129.1, 150.0. MS (EI): m/z 218 and 216
(t, J¼7.9 Hz, 1H), 7.51 (td, J¼7.9, 1.5 Hz, 1H), 8.09 (dd, J¼7.9, 1.4 Hz,
(Mþ, 1:1 ratio), 172 (25%), 170 (25%), 90 (100%).
1H). 13C NMR (CDCl3):
d 26.1, 31.9, 50.4, 127.1, 128.6, 128.7, 129.9,
134.1, 142.9, 190.5. MS (EI): m/z 226 and 224 (Mþ, 1:1 ratio), 144
4.9.20. 2,6-Dibromo-4-nitroaniline (53b)
(33%), 118 (100%), 115 (32%), 90 (42%).
Yield: 281 mg (95%), yellow crystals; mp 202–203 ꢀC (lit.49
203 ꢀC). 1H NMR (CDCl3):
d
5.30 (br s, 2H, NH2), 8.34 (s, 2H). MS (EI):
298, 296 and 294 (Mþ, 1:2:1 ratio), 252 (15%), 250 (36%), 248
(15%).
4.11.4. 5-Bromo-6-methoxy-1-tetralone (61b)
m/z
d
Yield: 182 mg (60%), crystals; mp 119–120 ꢀC (lit.51 119–122 ꢀC).
1H NMR (CDCl3):
d
2.09–2.18 (m, 2H), 2.60 (t, J¼6.6 Hz, 2H), 3.02 (t,
J¼6.2 Hz, 2H), 4.00 (s, 3H), 6.87 (d, J¼8.7 Hz, 1H), 8.04 (d, J¼8.7 Hz,
1H). 13C NMR (CDCl3):
d 22.4, 30.4, 38.0, 56.4, 109.5, 113.0, 127.5,
4.10. Typical reaction procedure for bromination of ketones
with N-bromosuccinimide in water
128.3, 145.4, 159.7, 196.7. MS (EI): m/z 256 and 254 (Mþ, 1:1 ratio),
228 (100%), 226 (100%), 200 (11%), 198 (11%), 119 (27%).
Substrate (1.0 mmol), 0.5 mL of water and N-bromosuccinimide
(178 mg, 1.0 mmol) were combined in a procedure analogous to the
bromination of aromates with NBS. The reaction mixture was stir-
red at room temperature in either the dark or under irradiation
from a 40 W incandescent light bulb, as noted in Table 9. After 24 h,
an identical work up procedure as in the case of the bromination of
aromates with NBS was applied. First, the crude reaction product
was analyzed by 1H NMR spectroscopy and then the products were
isolated by column chromatography and identified by comparison
with literature data.
4.12. Reaction procedure for bromination of styrene with
N-bromosuccinimide in water
Styrene (62, 104 mg, 1.0 mmol), 0.5 mL of water and N-bromo-
succinimide (178 mg, 1.0 mmol or 356 mg, 2.0 mmol) were com-
bined in a procedure analogous to the bromination of aromates
with NBS. The reaction mixture was vigorously stirred at room
temperature in the dark. After 24 h, an identical work up procedure
to that of the bromination of aromates with NBS was followed. The
crude reaction product was analyzed by 1H NMR spectroscopy and
the products isolated by column chromatography and identified by
comparison with literature data.
4.10.1. 3-Bromoindan-1-one (55c)
Yield: 110 mg (52%), crystals; mp 50–52 ꢀC (lit.50 54.5–55.0 ꢀC).
1H NMR (CDCl3):
d
3.05 (dd, J¼19.8, 2.7 Hz, 1H), 3.36 (dd, J¼19.8,
4.12.1. 2-Bromo-1-phenylethanol (63)52
7.2 Hz, 1H), 5.6 (dd, J¼7.2, 2.7 Hz, 1H), 7.46–7.51 (m, 1H), 7.70–7.76
Yield: 191 mg (95%), white crystals; mp 114–115 ꢀC. 1H NMR
(m, 3H). 13C NMR (CDCl3):
d 40.6, 48.0, 123.3, 127.5, 129.6, 135.5,
(CDCl3):
d
2.75 (br s, 1H, OH), 3.54 (dd, 1H, J¼10.4, 8.2 Hz), 3.60 (dd,
135.9, 154.2, 201.4. MS (EI): m/z 212 and 210 (Mþ, 1:1 ratio), 131
1H, J¼10.4, 4.0 Hz), 4.90 (dd, 1H, J¼8.2, 4.0 Hz), 7.34–7.43 (m, 5H).
(100%), 103 (54%).
13C NMR (CDCl3):
d 40.1, 73.8, 125.9, 128.4, 128.6, 140.2. MS (EI): m/z
202 and 200 (Mþ, 1:1 ratio), 121 (2%), 107 (100%).
4.11. Typical reaction procedure for bromination of ketones
in aqueous H2O2–HBr system
4.13. Reaction procedure for bromination of styrene in
aqueous H2O2–HBr system
The substrate (1.0 mmol), 0.5 mL of water, a 48% aqueous solu-
tion of HBr (0.114 mL, 1.0 mmol or 0.125 mL, 1.1 mmol) and a 30%
aqueous solution of H2O2 (0.204 mL, 2.0 mmol) were combined in
a procedure analogous to the bromination of aromates with H2O2–
HBr. The reaction mixture was stirred at room temperature either
in the dark or under irradiation from a 40 W incandescent light
bulb, as noted in Table 9. After 24 h, an identical work up procedure
followed as for the bromination of aromates with H2O2–HBr. The
crude reaction product was analyzed by 1H NMR spectroscopy. The
products were isolated by column chromatography and identified
by comparison with literature data.
Styrene (62, 104 mg, 1.0 mmol), 0.5 mL of water (or 0.25 mL of
water and 0.25 mL of CH2Cl2), a 48% aqueous solution of HBr
(0.228 mL, 1.0 mmol) and a 30% aqueous solution of H2O2 (0.102 mL,
1.0 mmol) were combined in a procedure analogous to the bromina-
tion of aromates with H2O2–HBr. The reaction mixture was vigorously
stirred at room temperature in the dark for 24 h. For the reaction with
NaOH, afterbrominationNaOH(80 mg, 2.0 mmol,dissolvedin3 mLof
water) was added. An identical work up procedure followed as in the
case of the bromination of aromates with H2O2–HBr. The crude re-
action mixture was then analyzed by 1H NMR spectroscopy and the

ˇ
A. Podgorsek et al. / Tetrahedron 65 (2009) 4429–4439
4439
2007; (c) Lindstro¨m, U. M. Organic Reactions in Water: Principles, Strategies and
Applications; Blackwell: Oxford, 2007; (d) Hailes, H. C. Org. Process Res. Dev.
2007, 11, 114–120.
reaction products were isolated by column chromatography and
identified by comparison with literature data.
11. (a) Sheldon, R. A. Green Chem. 2005, 7, 267–278; (b) Adams, D. J.; Dyson, P. J.;
Tavener, S. J. Chemistry in Alternative Reaction Media; Wiley: New York, NY,
2004; (c) Clark, J. H.; Tavener, S. J. Org. Process Res. Dev. 2007, 11, 149–155.
4.13.1. 1,2-Dibromoethylbenzene (64)
Yield: 74 mg (28%), white crystals; mp 70–72 ꢀC (lit.53 70–72 ꢀC).
´
´
12. (a) Barluenga, J.; Marco-Arias, M.; Gonzalez-Bobes, F.; Ballesteros, A.; Gonzalez,
J. M. Chem. Commun. 2004, 2616–2617; (b) Jereb, M.; Zupan, M.; Stavber, S.
Chem. Commun. 2004, 2614–2615; (c) Pavlinac, J.; Zupan, M.; Stavber, S. Syn-
thesis 2006, 2603–2607; (d) Pavlinac, J.; Zupan, M.; Stavber, S. J. Org. Chem.
2006, 71, 1027–1032.
1H NMR (CDCl3):
d
4.06 (t, J¼10.4 Hz, 1H), 4.08 (dd, J¼10.4, 5.7 Hz,
1H), 5.14 (dd, J¼10.4, 5.7 Hz, 1H), 7.32–7.42 (m, 5H). 13C NMR
(CDCl3):
d 35.0, 50.9, 127.6, 128.8, 129.2, 138.6. MS (EI): m/z 185
(60%), 183 (60%), 104 (100%).
ˇ
13. Podgorsek, A.; Stavber, S.; Zupan, M.; Iskra, J. Green Chem. 2007, 9, 1212–1218.
ˇ
14. Podgorsek, A.; Stavber, S.; Zupan, M.; Iskra, J. Tetrahedron Lett. 2006, 47,
1097–1099.
4.13.2.
a-Bromoacetophenone (65)
ˇ
15. Podgorsek, A.; Stavber, S.; Zupan, M.; Iskra, J. Tetrahedron Lett. 2006, 47,
Yield: 10 mg (5%), crystals; mp 48.8–49.3 ꢀC (lit.13 49–51 ꢀC). 1H
7245–7247.
NMR (CDCl3):
d
4.46 (s, 2H), 7.49 (t, J¼7.4 Hz, 2H), 7.61 (tt, J¼7.4,
16. (a) Kuwabara, K.; Itoh, A. Synthesis 2006, 12, 1949–1952; (b) Srilakshimi
Krishnaveni, N.; Surendra, K.; Rama Rao, K. Adv. Synth. Catal. 2004, 346,
346–350.
17. (a) Chhattise, P. K.; Ramaswarny, A. V.; Waghmode, S. B. Tetrahedron Lett. 2008,
49, 189–194; (b) Sarma, J. A. R. P.; Nagaraju, A. J. Chem. Soc., Perkin Trans. 2 2000,
6, 1113–1118.
1.5 Hz, 1H), 7.98 (dd, J¼7.4, 1.5 Hz, 2H). 13C NMR (CDCl3):
d 30.9,
128.8, 128.9, 133.9, 133.9, 191.2. MS (EI): m/z 200 and 198 (Mþ, ratio
1:1), 105 (100%), 77 (22%), 69 (12%), 57 (19%).
Acknowledgements
18. Roche, D.; Prasad, K.; Repic, O.; Blacklock, T. J. Tetrahedron Lett. 2000, 41,
2083–2085.
19. Pravst, I.; Zupan, M.; Stavber, S. Tetrahedron Lett. 2006, 47, 4707–4710.
20. (a) Lenoir, D.; Chiappe, C. Chem.dEur. J. 2003, 9, 1037–1044; (b) Conte, V.; Di
Furia, F.; Moro, S.; Rabbolini, S. J. Mol. Catal. A 1996, 113, 175–184; (c) Rothen-
berg, G.; Clark, J. H. Green Chem. 2000, 2, 248–251; (d) Andersson, M.; Conte, V.;
Di Furia, F.; Moro, S. Tetrahedron Lett. 1995, 36, 2675–2678.
21. Campbell, J. J.; Glover, S. A.; Hammond, G. P.; Rowbottom, C. A. J. Chem. Soc.,
Perkin Trans. 2 1991, 2067–2079.
22. Han, G. Y.; Han, P. F.; Perkins, J.; Mcbay, H. C. J. Org. Chem. 1981, 46, 4695–4700.
23. Mallory, F. B.; Butler, K. E.; Berube, A.; Luzik, E. D.; Mallory, C. W.; Brondyke,
E. J.; Hiremath, R.; Ngo, P.; Carroll, P. J. Tetrahedron 2001, 57, 3715–3724.
24. Konya, K. G.; Paul, T.; Lin, S.; Lusztyk, J.; Ingold, K. U. J. Am. Chem. Soc. 2000, 122,
7518–7527.
This research has been supported by the Ministry of Higher
Education, Science and Technology and the Young Researcher
Program (A.P.) of the Republic of Slovenia. The authors are grateful
to the staff of the National NMR Centre at the National Institute of
Chemistry in Ljubljana and the staff of the Mass Spectroscopy
Centre at the JSI.
References and notes
1. (a) Ullmann’sEncyclopedia of Industrial Chemistry; Wiley-VCH: Weinheim, 2002;
(b) The Chemistry of Functional Groups: Supplement D2. The Chemistry of Ha-
lides, Pseudo-Halides and Azides, Part 1 & 2; Wiley: Chichester, 1995.
2. (a) De la Mare, P. B. D.; Bolton, R. Electrophilic Additions to Unsaturated Systems;
Elsevier: Amsterdam, 1982; (b) Smith, M. B.; March, J. Aromatic Electrophilic
Substitution. In March’s Advanced Organic Chemistry, 5th ed; John Wiley & Sons:
New York, NY, 2001; pp 704–707.
3. (a) Carren˜o, M. C.; Ruano, J. L. G.; Sanz, G.; Toledo, M. A.; Urbano, A. J. Org. Chem.
1995, 60, 5328–5331; (b) Oberhauser, T. J. Org. Chem. 1997, 62, 4504–4506; (c)
Rajagopal, R.; Jarikote, D. V.; Lahoti, R. J.; Daniel, T.; Srinivasan, K. V. Tetrahedron
Lett. 2003, 44, 1815–1817; (d) Sarma, J. A. R. P.; Nagaraju, A. J. Chem. Soc., Perkin
Trans. 2 2000, 6, 1113–1118; (e) Pravst, I.; Zupan, M.; Stavber, S. Green Chem.
2006, 1001–1005; (f) Heropoulos, G. A.; Cravotto, G.; Screttas, C. G.; Steele, B. R.
Tetrahedron Lett. 2007, 48, 3247–3250; (g) Pravst, I.; Zupan, M.; Stavber, S.
Tetrahedron 2008, 64, 5191–5199.
25. Augustine, J. K.; Naik, Y. A.; Mandal, A. B.; Chowdappa, N.; Praveen, V. B. Tet-
rahedron 2008, 64, 688–695.
26. Ganapathy, S.; Sekhar, B. B. V. S.; Cairns, S. M.; Akutagawa, K.; Bentrude, W. G.
J. Am. Chem. Soc. 1999, 121, 2085–2096.
27. Smith, H. A.; Stanfield, J. A. J. Am. Chem. Soc. 1949, 71, 81–83.
28. Venkatachalapathy, C.; Pitchumani, K. Tetrahedron 1997, 53, 2581–2584.
29. Smyth, C. P.; Walls, W. S. J. Am. Chem. Soc. 1932, 54, 1854–1862.
30. Gassman, P. G.; Macomber, D. W.; Willging, S. M. J. Am. Chem. Soc. 1985, 107,
2380–2388.
31. Tanner, D. D.; Plambeck, J. A.; Reed, D. W.; Mojelsky, T. W. J. Org. Chem. 1980, 45,
5177–5183.
32. Haberfield, P.; Nudelman, A.; Bloom, A.; Romm, R.; Ginsberg, H. J. Org. Chem.
1971, 36, 1792–1795.
33. Futamura, S.; Zong, Z. M. Bull. Chem. Soc. Jpn. 1992, 65, 345–348.
34. Smith, L. I.; Moyle, C. L. J. Am. Chem. Soc. 1933, 55, 1676–1681.
35. Oestreich, M.; Schmid, U. K.; Auer, G.; Keller, M. Synthesis 2003, 2725–2739.
36. Hayashi, T.; Hayashizaki, K.; Kiyoi, T.; Ito, Y. J. Am. Chem. Soc. 1988, 110, 8153–
8156.
4. (a) Chiappe, C.; Leandri, E.; Pieraccini, D. Chem. Commun. 2004, 2536–2537; (b)
Kavala, V.; Naik, S.; Patel, B. K. J. Org. Chem. 2005, 70, 6556; (c) Salazar, J.; Dorta,
R. Synlett 2004, 1318–1320.
5. Eissen, M.; Lenoir, D. Chem.dEur. J. 2008, 14, 9830–9841.
37. McCauley, K. M.; Vrtis, J. M.; Dupont, J.; van der Donk, W. A. J. Am. Chem. Soc.
2000, 122, 2403–2404.
38. Raju, T.; Kulangiappar, K.; Kulandainathan, M. A.; Uma, U.; Malini, R.; Muthu-
kumaran, A. Tetrahedron Lett. 2006, 47, 4581–4584.
6. (a) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford
University Press: Oxford, 1998; (b) Jones, W. J. Applications of Hydrogen Peroxide
and Derivatives; Royal Society of Chemistry: Cambridge, 1999.
7. (a) Bora, U.; Chaudhuri, M. K.; Dey, D.; Dhar, S. S. Pure Appl. Chem. 2001, 73, 93–
102; (b) Conte, V.; Di Furia, F.; Moro, S. Tetrahedron Lett. 1996, 37, 8609–8612; (c)
Das, D. P.; Parida, K. M. Appl. Catal., A 2006, 305, 32–38; (d) Espenson, J. H.; Zhu,
Z. L.; Zauche, T. H. J. Org. Chem. 1999, 64, 1191–1196; (e) Mallick, S.; Parida, K. M.
Catal. Commun. 2007, 8, 889–893; (f) Moriuchi, T.; Yamaguchi, M.; Kikushima,
K.; Hirao, T. Tetrahedron Lett. 2007, 48, 2667–2670; (g) Narender, N.; Mohan, K.
V. V. K.; Reddy, R. V.; Srinivasu, P.; Kulkarni, S. J.; Raghavan, K. V. J. Mol. Catal. A
2003, 192, 73–77; (h) Reis, P. M.; Silva, J. A. L.; da Silva, J. J. R. F.; Pombeiro, A. J. L.
Chem. Commun. 2000, 1845–1846; (i) Rothenberg, G.; Clark, J. H. Org. Process
Res. Dev. 2000, 4, 270–274; (j) Sels, B.; De Vos, D.; Buntinx, M.; Pierard, F.;
Kirsch-De Mesmaeker, A.; Jacobs, P. Nature 1999, 400, 855–857.
8. (a) Barhate, N. B.; Gajare, A. S.; Wakharkar, R. D.; Bedekar, A. V. Tetrahedron
1999, 55, 11127–11142; (b) Ganchegui, B.; Leitner, W. Green Chem. 2007, 9, 26–
29; (c) Mukhopadhyay, S.; Ananthakrishnan, S.; Chandalia, S. B. Org. Process Res.
Dev. 1999, 3, 451–454; (d) Vyas, P. V.; Bhatt, A. K.; Ramachandraiah, G.; Bedekar,
A. V. Tetrahedron Lett. 2003, 44, 4085–4088.
39. Scott, J. M. W. Can. J. Chem. 1960, 38, 2441–2449.
40. Heinicke, J.; Gupta, N.; Surana, A.; Peulecke, N.; Witt, B.; Steinhauser, K.; Bansal,
R. K.; Jones, P. G. Tetrahedron 2001, 57, 9963–9972.
41. Yamazaki, K.; Nakamura, Y.; Konodo, Y. J. Org. Chem. 2003, 68, 6011–6019.
42. Koradin, C.; Dohle, W.; Rodriguez, A. L.; Schmid, B.; Knochel, P. Tetrahedron
2003, 59, 1571–1587.
43. Kitching, W.; Bullpitt, M.; Gartshore, D. J. Org. Chem. 1977, 42, 2411–2418.
44. Michel, F.; Thomas, F.; Hamman, S.; Saint-Aman, E.; Bucher, C.; Pierre, J. L.
Chem.dEur. J. 2004, 10, 4115–4125.
45. Lewis. J. Chem. Soc. 1903, 83, 330–331.
46. Zhang, H. C.; Tse, M. K.; Chan, K. S. Synth. Commun. 2001, 31, 1129–1139.
47. Moore, D. R.; Cheng, M.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2003,
125, 11911–11924.
48. Tidwell, J. H.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 11797–11810.
49. Datta, R. L.; Bhoumik, J. C. J. Am. Chem. Soc. 1921, 43, 303–315.
50. Marvel, C. S.; Hinman, C. W. J. Am. Chem. Soc. 1954, 76, 5435–5437.
51. Specht, H.; Onken, D.; Adam, G. Z. Chem. 1970, 10, 70–71.
52. Ye, C. F.; Shreeve, J. M. J. Org. Chem. 2004, 69, 8561–8563.
9. Van Pee, K. H.; Unversucht, S. Chemosphere 2003, 52, 299–312.
10. (a) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2005, 44, 3275–3279; (b) Li, C. J.; Chan, T. H. Compre-
hensive Organic Reactions in Aqueous Media, 2nd ed.; Wiley: New Jersey, NJ,
ˇ
53. Podgorsek, A.; Eissen, M.; Fleckenstein, J.; Stavber, S.; Zupan, M.; Iskra, J. Green
Chem. 2009, 11, 120–126.