Tetrahedron Letters
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.
(M. Wang).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.