CuBr2 catalyzed bromination/oxidation of isochromans to benzaldehyde derivatives

Article abstract of DOI:10.1016/j.tetlet.2013.05.078

A series of isochromans were oxidized and brominated by using 1.2 equiv of CuBr₂ in CH₃CN at reflux to give the corresponding bromo benzaldehydes in moderate yields. A plausible mechanism for this transformation has been suggested.

Full text of DOI:10.1016/j.tetlet.2013.05.078

Tetrahedron Letters 54 (2013) 3962–3964
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
CuBr2 catalyzed bromination/oxidation of isochromans to
benzaldehyde derivatives
Mei-Yan Zhou a, Shan-Shan Kong b, Ling-Qiong Zhang b, Ming Zhao a, Jin-Ao Duan c, Zhen Ou-yang a,
,
⇑
Min Wang b,
⇑
a School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
b College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, China
c School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 February 2013
Revised 7 May 2013
Accepted 17 May 2013
Available online 23 May 2013
A series of isochromans were oxidized and brominated by using 1.2 equiv of CuBr2 in CH3CN at reflux to
give the corresponding bromo benzaldehydes in moderate yields. A plausible mechanism for this trans-
formation has been suggested.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Oxidation
Bromination
CuBr2
Isochroman
The oxidation of benzylic alcohols and ethers to the correspond-
ing carbonyl compounds represents a widely used transformation
in organic synthesis.1 The cleavage of benzylic ethers via their reac-
tion with an oxidizing agent, such as HBr, 2,3-dichloro-5,6-dicy-
ano-1,4-benzoquinone (DDQ), NO2, or N-bromosuccinimide (NBS)
is a particularly effective method for the synthesis of benzalde-
hydes.2 For example, the oxidation of benzyl acyclic methyl ethers
with NBS under visible light irradiation conditions provided the
corresponding benzaldehydes in good yields.2c It is noteworthy
that although CH3Br could also be generated during the course of
this reaction, which was not detected in the reaction mixtures. If
the benzyl cyclic ethers were subjected to these conditions to be
cleaved by a halogen-based species, then a halogenated benzalde-
hyde should be produced. In fact, isochroman3 (1) can be converted
into the halogenated benzaldehyde 2 via a two-step procedure
using Br2 or DDQ in MeOH followed by treatment with HBr or a
mixture of trimethylsilyl bromide (TMSBr) and tetrabutylammo-
nium bromide (Bu4NBr) (Scheme 1).4
the use of a strong Lewis acid, such as a metal bromide, can lead
to the generation of Br2 under high temperature conditions.5 With
this in mind, it was envisaged that the reaction of a metal bromide
with isochroman under high temperature conditions would afford
the 2-(2-bromoethyl)benzaldehyde (2) in one step. Herein, we re-
port the use of stoichiometric CuBr2 as a mild reagent not only for
the oxidation of benzylic ethers but also for their bromination to
afford the corresponding 2-(2-bromoethyl) benzaldehydes in good
yields in one step (Scheme 1). The products themselves are good
building blocks for the synthesis of other complex intermediates.
A variety of different bromide-based oxidation systems have re-
cently been developed for the oxidation of the benzylic group,
including CuBr2/(2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO),
CuBr2/tert-butyl hydroperoxide (TBHP), KBr/oxone, and NBS.6 For
our initial attempt at the proposed transformation, 1.2 equiv FeBr2
was selected as the metal bromide and reacted with isochroman in
CH3CN at reflux under an atmosphere of N2 (Table 1, entry 1).
Unfortunately, however, none of the desired product was formed.
We then proceeded to evaluate a variety of different metal bro-
mides, including FeBr3, ZnBr2, MnBr2, CoBr2, and CuBr2 under the
same reaction conditions. Unfortunately, none of the desired prod-
uct was formed in any of these reactions (Table 1, entries 2–6).
Pleasingly, when CuBr2 was used as the metal bromide, the desired
product was formed in 68% yield (Table 1, entry 7). When the reac-
tion was conducted in the presence of NBS with the absence of a
metal bromide at reflux or under UV irradiation, the product was
formed in 40% yield, respectively (Table 1, entry 8). Based on these
For both of these methods, the first step involves the transfor-
mation of the benzylic ether to acetal 3, which was subsequently
cleaved under high temperature and acidic conditions to give 2-
(2-bromoethyl)benzaldehyde (2) via the nucleophilic attack of a
bromide anion on the C–O ether bond. It has been reported that
⇑
Corresponding authors. Tel./fax: +86 (571) 28867899.
E-mail addresses: zhenouyang@ujs.edu.cn (Z. Ou-yang), mwang@hznu.edu.cn
(M. Wang).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.078

M.-Y. Zhou et al. / Tetrahedron Letters 54 (2013) 3962–3964
Previous Work
3963
Br
Br2 or
HBr or
O
O
O
DDQ, MeOH
TMSOTf/Bu4NBr
H
Br (OMe)
1
3
2
two steps
This Work
Br
CuBr2
CH3CN
O
O
H
Scheme 1. Strategies for the oxidation isochroman to 2-(2-bromoethyl)benzaldehyde.
Table 1
Table 2
Optimization of catalytic systema
Optimization of reaction conditionsa
Entry
Solvent
T (°C)
Additive
Yieldb
%
Br
MBrn or NBS
CH3CN, reflux
1
2
3
4
5
6
7
8
9
EtOAc
PhMe
PhH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
77
110
80
82
82
82
82
82
82
40
None
None
None
None
None
None
Ac2O
BQf
28
42
25
60c
62d
67e
45
55
0
O
CHO
2a
1a
Entry
Catalytic system
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
FeBr2
FeBr3
ZnBr2
MnBr2
CoBr2
CuBr
24
24
12
12
12
24
1
1
6
24
24
0
0
0
0
8
0
68
40c
30
36
20
NaHCO3
None
10
42
a
Reaction conditions: isochroman (0.5 mmol) in solvent (1 mL) with 1.2 equiv of
CuBr2 at reflux under an atmosphere of N2.
b
Isolated yields.
CH3CN was used without being dried.
1.0 equiv CuBr2 was used.
2.0 equiv CuBr2 was used.
c
CuBr2
NBS
d
e
CuBr2/Bu4NBr/TBHP (0.2:1.2:1.2)
CuBr2/Bu4NBr/O2 (0.2:1.2)
CuBr2/FeBr3 (0.2:1.2)
f
10
11
BQ: benzoquinone.
a
Reaction conditions: isochroman (0.5 mmol) in CH3CN (1 mL) with 1.2 equiv of
catalyst at reflux under an atmosphere of N2.
b
Isolated yields.
c
2.0 equiv NBS was used under UV irradiation at room temperature.
With the optimized conditions in hand, we proceeded to inves-
tigate the substrate scope of the transformation with a variety of
substituted isochromans (Table 3). Isochromans bearing substitu-
ents at the 7-position of the benzene ring gave the desired alde-
hydes with good yields (Table 3, entries 2–6). For examples,
isochromans 1d–f bearing different halogens at the 7-position gave
the similar yields of the desired products (61–63%). In contrast, the
isochroman bearing a NO2 group at the 7-position did not provide
any of the desired product. The application of an isochroman bear-
ing a bromide at the 6-position (Table 3, entry 7) provided a lower
yield, comparing with the isochroman bearing a bromine at the 7-
position. In contrast, the isochroman bearing a bromide at the 5-
position 1h gave a similar yield (Table 3, entry 8) to 1f. In addition,
when the isochroman bearing a CF3 group at the 5-position was
subjected to the optimized reaction conditions, the desired product
was isolated in a low yield, even with an extended reaction time
(Table 3, entry 9). When an isochroman bearing two OMe groups
was subjected to the optimized reaction conditions (Table 3, entry
10), the desired product 2j was obtained in a low yield. Taken to-
gether, these results indicated that the nature of the substituent
on the benzene ring had a significant influence of this oxidative
reaction, because strong electron withdrawing group would make
the bromination not easy to occur and strong electron donating
group would make the bromination reaction on the phenyl group.
To further expand the substrate scope, we also examined the im-
pact of introducing a methyl group at different positions on the
ether ring (Table 3, entries 11–12). The first of these two reactions
proceeded smoothly to afford the desired product 2k in 51% yield,
results, CuBr2 was selected for further studies with a variety of dif-
ferent co-oxidants. Unfortunately, however, the use of CuBr2/
Bu4NBr/TBHP, CuBr2/Bu4NBr/O2, and CuBr2/FeBr3 systems did not
provide any improvement in the yield. In addition, the choice of
solvent was found to have a significant impact on the yield of
the transformation (Table 2). The use of DMSO or THF as the sol-
vent provided only a trace of the desired product. In contrast, tol-
uene, EtOAc, and benzene provided improved yields of the product,
although they were lower than that achieved with CH3CN. CH3CN
was therefore confirmed to be the best solvent for the transforma-
tion and afforded the highest yield for the reaction. The common
CH3CN was used for this reaction as opposed to anhydrous solvent
and gave the desired product in 60% yield (Table 2, entry 4). Having
determined the best metal bromide and solvent for the transfor-
mation, we proceeded to investigate the effect of the amount of
oxidant. When 1.0 equiv of CuBr2 was used, a 62% yield of product
was achieved (Table 2, entry 5). Increases in the amount of CuBr2
added to the reaction did not provide an increase in the yield.
The effects of different additives were also examined, although
the addition of a hydrogen acceptor or a base did not have any dis-
cernible impact on the results (Table 2, entries 8 and 9, respec-
tively). A reduction in the temperature of the reaction led to a
lower yield of the product, even after the extension of reaction
time (Table 2, entry 10).

3964
M.-Y. Zhou et al. / Tetrahedron Letters 54 (2013) 3962–3964
Table 3
Br
CuBr2 catalyzed oxidation of isochromansa
reflux
+
CuBr
Br2
CuBr2
Entry Substrate
Product
Yieldb
(%)
CH3CN
CHO 2a
Br
Br
68
1
2
(67)c
O
Br2
1a
2a
Br
CHO
O
O
O
1a
Br
57
57
62
61
63
35
4
O
3
1b
2b
Br
CHO
Scheme 2. Proposed mechanism for the CuBr2 catalyzed oxidation/bromination of
isochromans.
3
O
1c
tBu
2c
tBu
F
CHO
Br
In summary, we have developed a new efficient method for the
oxidation/bromination of isochromans to afford the corresponding
2-(2-bromoethyl)benzaldehydes in moderate yields using only
CuBr2, which only occurred for isochromans bearing no strong
electron withdrawing or electron donating groups. Further investi-
gations toward exploring the tandem reactions of isochroman and
other substrates are currently underway in our group.
4
O
1d
F
2d
CHO
Br
Br
Br
5
O
O
1e
Cl
2e
Cl
CHO
CHO
6
1f
Acknowledgement
Br
2f
Br
Br
Br
This work was supported by the NSFC (Nos. 81072985,
21102057 and 91127010).
7
O
1g
2g
CHO
Br
Br
Br
Supplementary data
8
62
33
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
05.078.
O
O
1h
1i
2h
CHO
CF3
CF3
Br
9
References and notes
2i
CHO
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whereas the second reaction provided the product 2l in a lower
yield of 35%.
Based on our results, we have proposed a mechanism for the
current oxidation process, as shown in Scheme 2. Initially, bromine
could be produced by heating CuBr2 in CH3CN under reflux condi-
tions.5 The isochroman could then react with bromine to give the
monobrominated intermediate 3,7 which would probably be
unstable under the high temperature with Lewis acid conditions
of the reaction and be converted into the corresponding oxocarbe-
nium ion 4. This intermediate could then be further bromated to
give the bromo benzaldehyde products.
7. Markess, D. G. J. Org. Chem. 1958, 23, 1490.