In situ acidic carbon dioxide/ethanol system for selective oxybromination of aromatic ethers catalyzed by copper chloride

Article abstract of DOI:10.1002/adsc.201100467

An environmentally benign carbon dioxide/ethanol reversible acidic system was developed for the copper(II)-catalyzed regioselective oxybromination of aromatic ethers without the need of any conventional acid additive and organic solvent. Good to excellent yields together with very good regioselectivity were achieved when easily available cupric chloride dihydrate was used as catalyst and lithium bromide as the cheap and easy-to-handle bromine source under supercritical carbon dioxide conditions. Notably, the catalytic system worked well for a wide range of aromatic ethers including sulfides, resulting in the formation of the mono-brominated products in high yields and exclusive regioselectivity. The alkylcarbonic acid in situ formed from ethanol and carbon dioxide is assumed to play the crucial role in the Braonsted acid-promoted reaction, which could probably act as the proton donator, and was studied employing in situ FT-IR technique under carbon dioxide pressure by monitoring the vibration shift of the hydroxy group of ethanol. Given with excellent bromine atom efficiency as well as no need of neutralization in waste disposal, this approach thus represents a greener pathway for the aerobic bromination of aromatic ethers. A possible catalytic cycle for the in situ alkylcarbonic acid-assisted oxybomination and the effect of supercritical carbon dioxide, i.e., activation of alcohol and enhancement of mass transfer are also discussed. Copyright

Full text of DOI:10.1002/adsc.201100467

FULL PAPERS
DOI: 10.1002/adsc.201100467
In situ Acidic Carbon Dioxide/Ethanol System for Selective Oxy-
bromination of Aromatic Ethers Catalyzed by Copper Chloride
a
a,
a
a
a
An-Hua Liu, Liang-Nian He, * Fang Hua, Zhen-Zhen Yang, Cheng-Bin Huang,
a
a
Bing Yu, and Bin Li
State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, Peopleꢀs Republic
a
of China
Fax : (+86)-22-2350-4216; phone: (+86)-22-2350-4216; e-mail: heln@nankai.edu.cn
Received: June 8, 2011; Revised: August 17, 2011; Published online: November 16, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100467.
Abstract: An environmentally benign carbon diox- crucial role in the Brønsted acid-promoted reaction,
ide/ethanol reversible acidic system was developed which could probably act as the proton donator, and
for the copper(II)-catalyzed regioselective oxybromi- was studied employing in situ FT-IR technique under
nation of aromatic ethers without the need of any carbon dioxide pressure by monitoring the vibration
conventional acid additive and organic solvent. shift of the hydroxy group of ethanol. Given with ex-
Good to excellent yields together with very good re- cellent bromine atom efficiency as well as no need of
gioselectivity were achieved when easily available neutralization in waste disposal, this approach thus
cupric chloride dihydrate was used as catalyst and represents a greener pathway for the aerobic bromi-
lithium bromide as the cheap and easy-to-handle nation of aromatic ethers. A possible catalytic cycle
bromine source under supercritical carbon dioxide for the in situ alkylcarbonic acid-assisted oxybomina-
conditions. Notably, the catalytic system worked well tion and the effect of supercritical carbon dioxide,
for a wide range of aromatic ethers including sul- i.e., activation of alcohol and enhancement of mass
fides, resulting in the formation of the mono-bromi- transfer are also discussed.
nated products in high yields and exclusive regiose-
lectivity. The alkylcarbonic acid in situ formed from Keywords: aerobic oxidation; aromatic ethers; atom
ethanol and carbon dioxide is assumed to play the economy; copper; green chemistry; oxybromination
Introduction
and harsh reaction conditions are also required. For
instance, the commonly employed brominating agents
[
8]
[9]
Aromatic bromides are important and versatile syn- are bromine, aqueous hydrogen bromide, N-bro-
thetic intermediates which have been involved in vari- mosuccinimide,
ous carbon-carbon and carbon-heteroatom bond for- mides. All of them could be either harmful and vol-
[
10]
[11]
bromates
and organic perbro-
[
12]
[
1]
[2]
[3]
mation reactions, such as Heck, Stille, Negishi,
atile or need a corrosive Brønsted acid as co-catalyst
[4]
[5]
Suzuki and Buchwald–Hartwig coupling reactions. or auxiliary reagent, whereby leading to environmen-
At the same time, this kind of halogenated aromatic tal and practical operation problems, to some extent.
also plays considerably significant roles in the bulk As a matter of fact, these bromine sources are often
and fine chemical industries, for example, as commer- used in excess amounts over stoichiometric standard,
cially used pesticides, herbicides, antiepileptics, flame
[
6]
retardants and antibacterial drugs. Conventional
methods for the synthesis of bromine-substituted aro-
matics rely on the electrophilic substitution and trans-
formation of amines via intermediate diazonium spe-
cies (i.e., the Sandmeyer reaction). Although the ar-
omatic electrophilic halogenation has been well devel-
oped as a sound preparative approach to bromo-
[
7]
ACHTUNGTRENNUNGa renes (Scheme 1), the regioselectivity is not good Scheme 1. Oxybromination of aromatic ethers.
Adv. Synth. Catal. 2011, 353, 3187 – 3195
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3187

An-Hua Liu et al.
FULL PAPERS
implying tjhat the bromine atom economy is much
below the ideal level. Oxybromination systems with
hydrogen peroxide as the oxidizing agent are relative
mild and eco-friendly, because water could be the
only theoretical by-product generated in this pro-
[13,14]
cess.
However, as hydrogen peroxide exists as
aqueous solution in most cases, the oxidative reactivi-
ty of hydrogen peroxide in aqueous media towards
hydrophobic reactants would be reduced consequent-
Scheme 3. Oxybromination of aromatic ethers.
ly. As a result, hydrogen peroxide would be restricted bromination of phenols and anilines with high mono-
[
19]
as a viable option for current plant-scale transforma- bromination selectivity.
Anisole was proved to be
tion. In view of the wide applicability and immense unreactive, possibly being due to its lack of solubility
industrial demand of aromatic bromides, it is of great in water or the deactivation effect of the methoxy
importance to develop an environmentally benign group. Although great achievements in the field of
and economically effective alternative system with oxybromination have been seen during the last
low costs and easy-to-handle brominating agents for decade, there is still need for the development of ef-
this kind of oxybromination.
fective catalytic systems to improve the chemo- and
Acids can be commonly used as catalysts in both in- regio-selectivity of the existing protocols. We herein
dustrial production and academic research, but con- would like to describe applications of the self-neutral-
comitant with the inherent disadvantage of requiring izing acid that forms in situ from CO /EtOH to the
2
post-reaction neutralization resulting in waste salt dis- copper chloride-catalyzed oxybromination of various
posal problems. The reversible reaction of CO with aromatic ethers including sulfides (Scheme 3) in order
2
alcoholic species to form alkylcarbonic acids is well to increase the solubility of substrates, improve cata-
investigated, leading to a temporarily generated lystic activity, and avoid the tedious treatment of
[
15]
proton species (Scheme 2).
This provides a so- acids afterwards as well. High regio-selectivity with
called in situ Brønsted acid, which could serve as an facilitated post-processing of the reaction system was
acid catalyst. Indeed, self-neutralizing in situ acid cat- achieved with the cheap and easy-to-handle lithium
[
16]
alysis from CO has shown several applications,
bromide as the bromine source. And this approach
2
with profound advantages for both green chemistry becomes especially attractive because14,20m] olecular
[
and economic benefit. Particularly, the CO /ROH oxygen was used as the terminal oxidant.
2
system provides in situ acid formation for catalysis
which can be readily neutralized by the removal of
CO . Thus alkylcarbonic acids offer simple neutraliza- Results and Discussion
2
tion and do not require any waste disposal.
Meanwhile, carbon dioxide as either an abundant Typically, oxybromination of an electron-rich arene
and readily available C resource or a non-toxic reac- leads to a mixture of para- and ortho-brominated iso-
1
tion medium has emerged with significant merits and mers. In other words, the regioselectivity remains
[
17]
affinity in the synthetic chemistry field. As empha- hard to control. One of the prevalently adopted solu-
sized, compressed CO appears to be an ideal solvent tions is to use a substrate with occupied ortho-posi-
2
for its multiple facilitating roles in oxidation reactions. tions which may reduce the possible confusion of bro-
Different from almost any other organic solvent, the mination distribution. To our delight, we found that
central carbon of CO exists in its highest covalent 1 mmol anisole (1a) in 1.7 equiv. (0.1 mL) ethanol
2
state, which hence renders CO as an ideal reaction containing 1.1 equiv. LiBr and 0.25 equiv. CuBr read-
2
2
medium without the risk of the cross-contamination ily reacted smoothly under 1 MPa O with the aid of
2
of solvent into the target products. At the same time, 1 MPa of CO , leading to a 53.3% yield of p-bromo-
2
gifted with excellent mass- and heat-transfer proper-
ACHTUNGTRENNUaGN nisole with 0.8% of the ortho-substituted isomer as
ties, compressed CO could afford a high efficiency the only by-product (entry 1, Table 1).
2
spatial environment for gas-liquid/solid biphasic oxi-
dations.
The absence of CO or reducing O pressure would
2 2
cause a lowering of the bromination reaction (en-
[18]
Leitner and co-workers have reported the CO2/ tries 2 and 3). These results prompted us to further in-
aqueosu H O /NaHCO /NaBr biphasic system for the vestigate the catalyst effect on the reaction. As sum-
2
2
3
Scheme 2. In situ formation of alkylcarbonic acids.
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In situ Acidic Carbon Dioxide/Ethanol System for Selective Oxybromination of Aromatic Ethers
Table 1. Oxybromination of anisole with CO /O /EtOH
system catalyzed by different metal salts.
The results of a study on the influence of the
2
2
[a]
amount and structure of ROH on oxybromination
catalyzed by CuCl ·2H O are presented in Table 2. As
[b]
2
2
Entry
Catalyst (mol%)
Yield [%]
[c]
[d]
easily seen, an increase of the alkyl chain length of
ROH had a negative effect (entries 1–3, Table 2),
p-isomer
o-isomer
[
15d]
1
CuBr (25)
53.3
27.8
21.1
61.5
51.0
61.1
54.4
56.3
63.9
40.0
67.9
12.6
30.4
47.7
61.5
58.1
49.4
trace
trace
–
0.8
trace
trace
1.8
1.3
1.4
2.7
1.6
1.2
1.1
1.8
trace
0.8
0.6
1.7
2.0
1.9
–
being accordant with the previous report,
presuma-
2
[
[
e]
f]
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
CuBr (25)
2
bly due to the electronic factors affecting the alkylcar-
bonic acidꢀs dissociation equilibrium.
CuBr (25)
2
Cu
Cu
ACHTUNGTRENNUNG( OTf) (25)
ACHTUNGTRENNUNG( OAc) (25)
2
2
In particular, it was noticeable that ethylene glycol,
which could form the most acidic carbonic acid
CuCl (25)
2
[15d]
among the alcohols screened,
was found to be an
Cu ACHTUNGTRENNUNG( NO ) ·3H O (25)
3 2 2
inferior in situ acidic catalyst compared with the
monohydroxylated ones (entry 4). This might be as-
CuO (25)
CuBr (25)
CuCl (25)
AHCTUNGTRENNUNG
0
1
2
3
4
5
6
7
8
9
0
cribed to the lower solubility of anisole in the densely
protonated glycol-derived acid intermediate. Al-
though MeOH gave a slightly better yield than
EtOH, the highly toxic nature restrained its employ-
ment, and EtOH was revealed to be the better choice.
As the presumed proton source, the influence of etha-
nol amount on reactivity was evident. The results
show that 0.125 mL (2.1 mmol) ethanol could be ade-
quate and a slightly enhanced yield was attained in
the range of ethanol volume from 0.1 mL to 0.125 mL
CuCl ·2H O (25)
2
2
FeBr (25)
3
FeCl (25)
3
Fe
ACHTUNGTRENNUNG( NO ) ·9H O (25)
3 3 2
CuCl ·2H O (10)
2
2
CuCl ·2H O (5)
2
2
CuCl ·2H O (2.5)
2
2
[
[
[
g]
h]
i]
CuCl ·2H O (5)
2
2
CuCl ·2H O (5)
–
–
2
2
CuCl ·2H O (5)
2
2
(
entries 1 and 9, Table 2). Either an increase or a de-
[
a]
Reaction conditions: anisole (1 mmol), LiBr (1.1 equiv.),
EtOH (0.1 mL), O (1 MPa), CO (1 MPa), 1008C, 12 h.
b]
crease in ethanol amount beyond 0.125 mL would
have a negative effect on the reaction (entries 5–8).
2
2
[
[
[
[
[
[
[
[
Determined by GC with biphenyl as internal standard.
Yield of p-bromoanisole.
c]
d]
e]
f]
As proved by plenty of reports, the CO pressure
2
may alter the acidity of the in situ CO /H O biphasic
system.
was screened out as listed in Table 3. It is easily un-
derstood that a low CO pressure causes the restrain-
ed alkylcarbonic acid formation as well as the diluted
proton concentration (entry 1 vs. 2, Table 3). Howev-
er, after a slightly drop of reaction productivity, the
reaction yield mounted up with the increasing CO2
pressure until the maximal bromination yield of
Yield of o-bromoanisole.
Without CO2.
2
2
[
21]
In this context, the optimal CO pressure
2
0
1
1
1
.4 MPa of O2.
.1 equiv. of NaBr.
.1 equiv. of KBr.
g]
h]
i]
2
.1 equiv. of (n-Bu) NBr.
4
marized in Table 1, a variety of copper-based catalysts 97.3% together with 97% para-isomer were attained
was screened, including the strongly Lewis acidic Cu-
ACHTUNGTRENNUNG( OTf) along with the easily available CuCl ·2H O,
and the latter was testified as the most efficient cata-
2
2
2
[a]
Table 2. Optimization of ROH
lyst with high regioselectivity (p-:o-isomer ratio=
[b]
Entry
ROH (mmol)
Yield [%]
97:3) among the copper salts examined. The ferric
[c]
[d]
p-isomer
o-isomer
salts showed less catalytic activity than the copper
counterparts (entries 12–14). Further optimization of
the catalyst amount revealed that the essential quanti-
ty of CuCl ·2H O could be reduced to 5 mol% with-
out a significant restraint of catalytic activity, but ulti-
mately decreasing the copper molar ratio to 2.5 mol%
would result in a remarkable drop-off of product
yield (entries 15–17). The attempt to use other alkali
metal bromides as well as tetrabutylammonium bro-
mide failed to effect the transformation (entries 18–
1
2
3
4
5
6
7
8
9
EtOH (1.7) 0.1 mL
MeOH (1.7)
n-PrOH (1.7)
58.1
60.8
51.3
17.4
51.6
40.2
7.0
2.0
2.9
1.5
0.8
2.3
1.2
trace
1.9
1.7
2
2
glycol (1.7)
EtOH (0.9) 0.05 mL
EtOH (3.4) 0.2 mL
EtOH (6.8) 0.4 mL
EtOH (1.3) 0.075 mL
EtOH (2.1) 0.125 mL
50.3
63.5
[a]
Reaction conditions: anisole (1 mmol), CuCl ·2H O
5 mol%), LiBr (1.1 equiv.), O (1 MPa), CO (1 MPa),
008C, 12 h.
Determined by GC.
Yield of p-bromoanisole.
Yield of o-bromoanisole.
2
2
2
0). As a consequence, 5 mol% of CuCl ·2H O as the
2 2
(
1
2
2
catalyst and 1.1 equiv. LiBr as the bromine source
would be a suitable system to run the oxybromination
reaction of anisole in excellent regio-selectivity along
with the ameliorating procedure afterwards.
[
[
[
b]
c]
d]
Adv. Synth. Catal. 2011, 353, 3187 – 3195
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An-Hua Liu et al.
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[a]
Table 3. Optimization of CO pressure.
at the supercritical state of 8 MPa (entries 3–9). But
2
further elevating CO pressure would be unfavorable,
possibly due to the dilution effect by high density
[b]
2
Entry
CO [MPa]
Yield [%]
[c]
2
[d]
p-isomer
o-isomer
CO . Accordingly, the reaction conditions were finally
2
1
2
3
4
5
6
7
8
9
1
0.5
2
3
4
5
6
7
8
58.1
35.8
50.3
60.6
71.5
76.4
79.4
85.6
94.1
76.4
70.3
2.0
4.1
1.9
2.2
2.3
2.4
2.4
2.5
3.2
3.3
2.7
determined as CuCl ·2H O 5 mol%, LiBr 1.1 equiv.,
2
2
EtOH 0.125 mL, O 1 MPa, CO 8 MPa, 1008C.
2 2
The generality and feasibility of this methodology
were then evaluated by performing the bromination
with a broad range of substrates under typical reac-
tion conditions (Table 4).
Mono-, di- and trimethoxy-substituted benzenes as
well as naphthalene methyl ethers underwent mono-
bromination smoothly with good yields and excellent
regioselectivity (entries 1–8, Table 4). The presence of
the methyl group in the para-position offers the
ortho-brominated anisoles (entry 9), while with para-
anisyl-methanol the oxidation of the benzylic hydroxy
group to an aldehyde occurred rather than the bromi-
nation reaction (entry 10). On the other hand, the
presence of an electron-withdrawing group could sup-
1
1
0
1
10
12
[
a]
Reaction conditions: anisole (1 mmol), CuCl ·2H O
5 mol%), LiBr (1.1 equiv.), EtOH (0.125 mL), O2
1 MPa), 1008C, 12 h.
Determined by GC.
Yield of p-bromoanisole.
Yield of o-bromoanisole.
2
2
(
(
[
[
[
b]
c]
d]
[a]
Table 4. Cu(II)-catalyzed aerobic oxybromination of electron-rich arenes.
Entry Substrate Time [h]
[b]
Product
Yield [%]
[
c]
1
12
86
2
3
12
15
83
82
4
5
15
15
81
76
6
7
8
12
12
12
83
92
90
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In situ Acidic Carbon Dioxide/Ethanol System for Selective Oxybromination of Aromatic Ethers
Table 4. (Continued)
[b]
Entry
Substrate
Time [h]
Product
Yield [%]
9
12
86
1
1
0
1
40
61
[
d]
4
2
8
4
24[
e]
77
1
2
3
12
12
87
69
1
[
d]
14
15
46
[
a]
Reaction conditions: substrate (1 mmol), CuCl ·2H O (5 mol%), LiBr (1.1 equiv.), EtOH (0.125 mL), O (1 MPa), CO
2
2
2
2
(
8 MPa), 1008C.
[
[
[
[
b]
Isolated yield.
A mixture of two regio-isomers (1b:1c=97:3).
CuCl ·2H O (15 mol%), LiBr (2.2 equiv.).
c]
d]
e]
2
2
CuCl ·2H O (50 mol%), LiBr (2.2 equiv.).
2
2
press the oxybromination, as a large amount of the
In situ FT-IR spectroscopy under CO pressure was
2
substrate that is, methyl 4-methoxybenzoate, was re- further employed to identify the possible interaction
covered to be intact with only 24% yield of ortho-sub- between ethanol and CO . As depicted in Figure 1,
2
stituted product after the bromination process, but
further elevating the catalyst amount to 50% would
lead to a comparable yield (entry 11). Oxy-containing
bicyclic rings such as benzodioxole could also be suc-
cessfully brominated, providing regiospecifically the
aromatic bromide (entry 12). To our delight, phenyl
methyl sulfides which are unstable in general under
oxidizing conditions could also afford the mono-bomi-
nated product in comparatively acceptable yields (en-
tries 13 and 14). However, nitrobenzene and toluene
were found to be incapable of such an oxybromina-
tion, presumably due to the absence of the strong
electron-donating methoxy group. It was also worth
mentioning that the electron-rich substrate, that is,
phenol, also failed to undergo the reaction, this is
probably ascribable to its strong coordination towards
the copper and/or the formation of phenylcarbonic
Figure 1. FT-IR spectra of EtOH/CO . Reaction conditions:
2
acid. The current oxybromination system is in accord
with the common electrophilic halogenating regula-
tions. In other words, the formed mono-brominated
EtOH (15 mL), CO initial pressure (5 MPa), 1008C. 2975
2
À1
and 2885 cm correspond to peaks for ethanol CÀH bond
À1
vibrations and 2339 cm represents the asymmetric vibra-
product virtually suppresses further bromination, con- tions of CO carbonyl; the inset depicts the dependence of
2
ferring such a mono-substituent preference.
wavenumber (WN) of OH stretching on time.
Adv. Synth. Catal. 2011, 353, 3187 – 3195
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An-Hua Liu et al.
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Scheme 4. The proposed mechanism.
Figure 2. FT-IR spectra of the reaction mixture. Reaction
conditions: 1a (120 mmol), CuCl ·2H O (5 mol%), LiBr
also promote the generation of active bromine spe-
2
2
(
1
1.1 equiv.), EtOH (15 mL), CO initial pressure (5 MPa), cies, and the supposed residual CuO was also found
2
À1
008C. 2835 cm corresponds to CÀH bond vibrations of to be active (Table 1, entry 8); (iii) the copper catalyst
the methoxy group in anisole; the inset depicts the depend-
ence of wavenumber (WN) of OH-stretching on time.
may exist in more dispersed morphology, which could
also facilitate the reaction.
Although the precise detailed mechanism of the re-
action is not clear at the present stage, the reaction
the OH stretching vibration of ethanol shows a clear could probably be initiated by the in situ formation of
influence on the introduction of CO2. the Br species through Cu(II) oxidation [Eq. (2),
2
À1
A characteristic peak centered at 3321 cm , being Scheme 4], as it was observed that the color of reac-
assigned to the stretching vibration of the OÀH bond tion mixture turned into red brown upon heating, pos-
[
25]
of ethanol, was gradually shifted to higher frequency sibly implicating the formation of Br2. The resulting
along with the dissolution of CO . These results indi- Cu(I) protosalt could be simultaneously reoxidized by
2
cate that the weakening interaction of hydrogen- dioxygen either in the single oxidation process or the
bonding could probably contribute to the Lewis acid- oxybromination sequence, with the aid of the in situ
base interaction between the carbon atom of CO and formed alkyl carbonic acid from CO and EtOH [Eq.
2
2
[
22]
the oxygen atom of ethanol.
(1)], leading to the regeneration of the Cu(II) catalyst
We further examined the reaction mixture by using [Eq. (3) and Eq. (4)]. In addition, 25 mol% CuBr2
FT-IR under CO pressure, as shown in Figure 2. The gave a turnover number of slightly more than 1 in the
2
absorption peak of OH stretching was moved to a absence of CO (entry 2, Table 1). This clearly shows
2
higher frequency region shortly after the introduction that alkylcarbonic acid in situ formed could signifi-
of CO due to its interaction with ethanol, but then cantly enhance the catalyst performance. Finally, the
2
the OH stretching band was moved back to the lower resulting lithium alkylcarbonic salt would transform
frequency as the reaction proceeded. This phenomen- into lithium carbonate [Eq. (5)].
on could presumably hint at the partial dissociation of
the OÀH bond of the ethanol and CO adduct during
2
the reaction, leading to activation of ethanol, which Conclusions
can be regarded as a proton donor for the reaction.
As already intensively investigated, the scCO /etha- In summary, we have developed an efficient copper-
2
nol expanded liquid system is found to have wide ap- catalyzed bromination of aromatic ethers with lithium
plications in the fabrication of nanostructured materi- bromide salt under aerobic conditions with the aid of
[
23]
als from hydrous inorganic metal salts, in which the in situ acidic CO /EtOH system. This highly regiose-
2
highly dispersed dissolving metal salts would react lective oxybromination system affords mono-substi-
into nano-scale metal oxide in templates, such as tuted aromatic bromides in good to excellent yields
carbon nanotubes. Such results would provide some without any corrosive acid additives. The present pro-
explanations for enhanced activity of the tocol represents an attractive green approach which
CuCl ·2H O-catalyzed oxybromination in the scCO / offers high bromine atom economy, simple post-reac-
2
2
2
EtOH system: (i) the solubility of hydrous metal salts tion neutralization with no salt waste disposal and
and substrates in the expanded reaction media could safe operation for aerobic reaction. The reaction
enhance the catalytic performance; (ii) the presumed showed a remarkably broad scope of the substrates
in situ decomposition of CuCl ·2H O would afford a including aromatic sulfides. Accordingly, the process
2
2
[
24]
small amount of hydrogen chloride,
which could disclosed here provides a simple, ecologically safe,
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Adv. Synth. Catal. 2011, 353, 3187 – 3195

In situ Acidic Carbon Dioxide/Ethanol System for Selective Oxybromination of Aromatic Ethers
cost-effective and industrially feasible route to mono- 112.8, 115.7, 132.2, 158.7; GC-MS: m/z (%)=186.01 (100)
+
+
[
M ]; 187.97(98) [M ].
brominated aromatics.
1
-Bromo-4-ethoxybenzene (2b): Pale yellow oil (elution
1
solvent petroleum ether:ethyl acetate=100:1). H NMR
400 MHz, CDCl ): d=1.40 (t, J=6.8 Hz, 3H), 3.99 (q, J=
.2 Hz, 2H), 6.77 (d, J=8.8 Hz, 2H), 7.36 (d, J=9.2 Hz,
H); C NMR (100.6 MHz, CDCl ): d=14.7, 63.7, 112.6,
16.2, 132.2, 158.0; GC-MS: m/z (%)=200.09 (100) [M ];
201.96 (100) [M ].
1-Bromo-2,4-dimethoxybenzene (3b): Pale yellow oil (elu-
tion solvent petroleum ether:ethyl acetate=200:1).
H NMR (400 MHz, CDCl ): d=3.79 (s, 3H), 3.87 (s, 3H),
6.40 (dd, J =2.4 Hz, J =8.6 Hz, 1H), 6.48 (d, J=2.8 Hz,
1H), 7.40 (d, J=8.4 Hz, 1H);
CDCl ): d=55.5, 56.1, 99.9, 102.4, 105.8, 133.1, 156.5, 162.2;
GC-MS: m/z (%)=216.07 (100) [M ]; 218.02 (98) [M ].
4-Bromo-1,2-dimethoxybenzene (4b): Pale yellow oil (elu-
tion solvent petroleum ether:ethyl acetate=200:1).
H NMR (400 MHz, CDCl ): d=3.86 (s, 3H), 3.87 (s, 3H),
.73 (d, J=8.4 Hz, 1H), 6.98 (d, J=2.0 Hz, 1H), 7.02–7.06
m, 1H); C NMR (100.6 MHz, CDCl ): d=56.0, 56.1,
(
3
Experimental Section
7
2
1
1
3
3
General Remarks
+
+
The aromatic ethers and sulfides were purchased from Alfa
Aesar China Co., Ltd and Aladdin Reagent Inc. All the
other reagents were obtained commercially from Tianjin
Guangfu Fine Chemical Research Institute and used without
further purification except for the alcohols, which were dis-
1
3
1
2
1
13
tilled by the documented method prior to use. H NMR
spectra were recorded on a Bruker 400 spectrometer in
C NMR (100.6 MHz,
3
+
+
CDCl and CDCl (7.26 ppm) was used as internal reference,
3
3
13
C NMR spectra were recorded at 100.6 MHz in CDCl and
3
CDCl (77.0 ppm) was used as internal reference. GC-MS
3
were recorded on a Thermo Finnigan Polaris Q equipment
in EI mode. GC analyses were performed on Shimadzu GC-
1
3
6
(
1
2
2
0
014, equipped with a capillary column (RTX-17, 30 mꢂ
.25 mm and RTX-WAX, 30 mꢂ25 mm) using a flame ioniza-
13
3
12.4, 112.6, 112.7, 123.3, 148.3, 149.7; GC-MS: m/z (%)=
+ +
tion detector. Melting points were measured on an X4 appa-
ratus and uncorrected. In situ FT-IR under CO pressure
was collected on a Mettler Toledo React IR ic10 analysis
system.
Caution: Experiments using compressed gases CO and
oxygen are potentially dangerous and must only be carried
out by using the appropriate equipment and under rigorous
safety precautions.
16.22 (100) [M ]; 218.03 (100) [M ].
-Bromo-1,4-dimethoxybenzene (5b): White solid (elution
2
2
1
solvent petroleum ether:ethyl acetate=200:1). H NMR
400 MHz, CDCl ): d=3.76 (s, 3H), 3.84 (s, 3H), 6.80–6.85
m, 2H), 7.12 (d, J=2.4 Hz, 1H); C NMR (100.6 MHz,
CDCl ): d=55.9, 56.8, 111.9, 112.9, 113.6, 118.9, 150.3, 154.0;
(
(
3
2
13
3
+
+
GC-MS: m/z (%)=216.33 (100) [M ]; 218.02 (99) [M ].
-Bromo-1,3,5-trimethoxybenzene (6b): White solid (elu-
2
tion solvent petroleum ether:ethyl acetate=200:1).
1
General Procedure for Oxybromination of Aromatic
Ethers
H NMR (400 MHz, CDCl ): d=3.82 (s, 3H), 3.88 (s, 6H),
3
1
3
6.17 (s, 2H); C NMR (100.6 MHz, CDCl
9
2
): d=55.5, 56.4,
3
+
1.6, 157.5, 160.5; GC-MS: m/z (%)=246.02 (100) [M ];
A mixture of substrate (1 mmol), CuCl ·2H O (8.5 mg,
+
2
2
47.98 (99) [M ].
-Bromo-4-methoxynaphthalene (7b): Dark yellow oil
elution solvent petroleum ether:ethyl acetate=50:1).
5
mol%), LiBr (955.4 mg, 1.1 equiv.), and 0.125 mL of etha-
1
nol was placed in a 50-mL stainless steel autoclave equipped
(
with an inner glass tube in room temperature. CO (4 MPa)
2
1
H NMR (400 MHz, CDCl ): d=3.99 (s, 3H), 6.89 (d, J=
3
and O (1 MPa) were subsequently introduced into the auto-
2
8
(
(
1
1
(
2
.4 Hz, 1H), 7.53 (t, J=7.6 Hz, 1H), 7.60–7.67 (m, 2H), 8.17
clave and the system was heated at the predetermined reac-
tion temperature for 15 min to reach the equilibration. Then
the final pressure was adjusted to the desired pressure by in-
1
3
d, J=8.4 Hz, 1H), 8.28 (d, J=8.4 Hz, 1H); C NMR
100.6 MHz, CDCl ): d=55.7, 104.5, 113.2, 122.4, 125.9,
3
26.7, 126.8, 127.7, 129.4, 132.4, 155.2; GC-MS: m/z (%)=
+ +
troducing the correct amount of CO . The mixture was
2
93.10 (87) [M ÀCOMe], 195.08 (84) [M ÀCOMe], 221.03
stirred continuously for the desired reaction time. After
cooling, products were then diluted by dichloromethane and
analyzed by gas chromatograph (Shimadzu GC-2014)
equipped with a capillary column (RTX-17 30 mꢂ25 mm and
RTX-wax 30 mꢂ25 mm) using a flame ionization detector by
comparison with the retention times of authentic samples.
The residue was purified by column chromatography on
silica gel (200–300 mesh, eluting with petroleum ether/ethyl
acetate from pure petroleum ether to 50:1) to afford the de-
sired product. The isolated products were further identified
with NMR spectra (Bruker 400 MHz) and GC-MS, which
are consistent with those reported in the literature.
+
+
+
55) [M ÀMe], 223.03 (48) [M ÀMe], 236.04 (97) [M ];
+
38.00 (100) [M ].
1
-Bromo-2-methoxynaphthalene (8b): White solid (elu-
1
tion solvent petroleum ether:ethyl acetate=50:1). H NMR
(
7
400 MHz, CDCl ): d=4.04 (s, 3H), 7.29 (d, J=7.6 Hz, 1H),
3
.40 (t, J=7.6 Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.78–7.84
1
3
(
m, 2H), 8.26 (d, J=8.4 Hz, 1H); C NMR (100.6 MHz,
CDCl ): d=57.0, 108.6, 113.6, 124.3, 126.1, 127.7, 128.0,
129.0, 129.8, 133.1, 153.7, 155.2; GC-MS: m/z (%)=193.09
3
+
+
(99) [M ÀCOMe], 195.07 (100) [M ÀCOMe], 236.03 (99)
+
+
[M ]; 238.00 (100) [M ].
-Bromo-1-methoxy-4-methylbenzene (9b): Pale yellow
2
oil (elution solvent petroleum ether:ethyl acetate=200:1).
Characterization of Reaction Products
1
H NMR (400 MHz, CDCl ): d=2.27 (s, 3H), 3.87 (s, 3H),
3
4
-Bromoanisole (1b): Pale yellow oil (elution solvent petro-
6.79 (d, J=8.0 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 7.36 (d, J=
1
13
leum ether:ethyl acetate=50:1). H NMR (400 MHz,
1.2 Hz, 1H); C NMR (100.6 MHz, CDCl
): d=20.1, 56.3,
3
CDCl ): d=3.78 (s, 3H), 6.79 (d, J=8.8 Hz, 2H), 7.38 (d,
111.3, 111.8, 128.8, 131.4, 133.7, 153.7; GC-MS: m/z (%)=
200.10 (100) [M ]; 202.00 (96) [M ].
3
13
+ +
J=11.5 Hz, 2H); C NMR (100.6 MHz, CDCl ): d=55.4,
3
Adv. Synth. Catal. 2011, 353, 3187 – 3195
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3193

An-Hua Liu et al.
FULL PAPERS
4
-Methoxybenzaldehyde (10b): Colorless liquid (elution
[5] a) F. Paul, J. Patt, J. F. Hartwig, J. Am. Chem. Soc.
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solvent petroleum ether:ethyl acetate=20:1). H NMR
400 MHz, CDCl ): d=3.89(s, 3H), 7.00 (d, J=8.8 Hz, 2H),
.84 (d, J=8.8 Hz, 2H), 9.89 (s, 1H); C NMR (100.6 MHz,
CDCl ): d=55.6, 114.3, 130.0, 132.0, 164.6, 190.8; GC-MS:
(
7
ACHTUNGTRENNUNG
3
1
3
3
+
+
m/z (%)=135.17 (100) [M ÀH]; 136.11 (51) [M ].
Methyl 3-bromo-4-methoxybenzoate (11b): White solid
(
elution solvent petroleum ether:ethyl acetate=50:1).
H NMR (400 MHz, CDCl ): d=3.90 (s, 3H), d 3.96 (s, 3H),
1
3
1
2
6
1
.92 (d, J=8.8 Hz, 1H), 7.99 (dd, J=2.0 Hz, J=8.4 Hz,
13
H), 8.24 (d, J=1.0 Hz, 1H);
C NMR (100.6 MHz,
4
5.
CDCl ): d=52.1, 56.4, 111.0, 111.4, 123.8, 130.6, 134.8, 159.5,
3
[7] a) M. Hudlicky, T. Hudlicky, Formation of Carbon-Hal-
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b) Y. Sasson, Formation of Carbon- Halogen Bonds
+
1
(
65.7; GC-MS: m/z (%)=213.07 (100) [M ÀOMe]; 215.00
+
+
+
90) [M ÀOMe], 243.98 (44) [M ]; 245.96 (44) [M ].
5
-Bromobenzo[d][1,3]dioxole (12b): Colorless liquid (elu-
ACHTUNGTRENNUNG
tion solvent petroleum ether:ethyl acetate=100:1).
H NMR (400 MHz, CDCl ): d=5.97 (s, 2H), 6.69 (d, J=
.0 Hz, 1H), 6.93–6.96 (m, 2H); C NMR (100.6 MHz,
CDCl ): d=101.6, 109.6, 112.3, 113.0, 124.3, 147.0, 148.6;
GC-MS: m/z (%)=199.73 (99) [M ]; 200.49 (68) [M ],
01.15 (96) [M ]; 201.99 (100) [M ].
4
petroleum ether:ethyl acetate=150:1). H NMR (400 MHz,
CDCl ): d=2.47 (s, 3H), 7.12 (d, J=8.4 Hz, 2H), 7.38 (d,
J=8.0 Hz, 2H); C NMR (100.6 MHz, CDCl ): d=15.9,
1
3
1
3
8
(Cl, Br, I), in: The Chemistry of Functional Groups,
3
Supplement D: The Chemistry of Halides, Pseudoha-
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Chem. Rev. 1947, 40, 251–277.
+
+
+
+
2
-Bromothioanisole (13b): Pale yellow oil (elution solvent
1
3
13
3
1
[
18.6, 128.1, 131.8, 137.7; GC-MS: m/z (%)=202.08 (100)
+ +
M ]; 203.99 (100) [M ].
[
8] J. M. Gnaim, R. A. Sheldon, Tetrahedron Lett. 2005, 46,
Methyl (2-bromo-4-methylphenyl) sulfide (14b): Pale
yellow oil (elution solvent petroleum ether:ethyl acetate=
50:1). H NMR: (400 MHz, CDCl ): d=2.30 (s, 3H), 2.45
s, 3H), 7.04 (d, J=8.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H),
.37 (s, 1H); C NMR (100.6 MHz, CDCl ): d=16.1, 20.5,
22.0, 125.9, 128.7, 133.3, 135.8, 136.1; GC-MS: m/z (%)=
16.08 (99) [M ]; 217.99 (100) [M ].
4
465–4468.
1
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(
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[
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of China (No 20872073, 21150110105), the “111” Project of
Ministry of Education of China (Project No. B06005), and
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3195