Aerobic photooxidation of methyl group at aromatic nucleus with LiBr

Article abstract of DOI:10.1055/s-2005-871942

A methyl group at the aromatic nucleus was found to be oxidized to the corresponding carboxylic acid directly in the presence of lithium bromide under aerobic photoirradiation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-871942

LETTER
2107
Aerobic Photooxidation of Methyl Group at Aromatic Nucleus with LiBr
A
erobic Photooxid
k
ation of
M
et
i
hyl
G
ro
c
up at Arom
h
a
tic
N
ucleusika Itoh,* Shouei Hashimoto, Tomohiro Kodama, Yukio Masaki
Gifu Pharmaceutical University, Mitahora-higashi, Gifu 502-8585, Japan
E-mail: itoha@gifu-pu.ac.jp
Received 27 April 2005
Table 1 shows our initial study of the reaction conditions
of the aerobic photooxidation, which were carried out
using 4-tert-butyltoluene (1, 50 mg, 0.269 mmol) as a test
substrate with several alkali metal halides in various sol-
vents.5 Among the solvents and the alkali metal halides
examined, ethyl acetate and lithium bromide (0.5 equiv)
were found to be suitable for the reaction.6,7
Abstract: A methyl group at the aromatic nucleus was found to be
oxidized to the corresponding carboxylic acid directly in the
presence of lithium bromide under aerobic photoirradiation.
Key words: photooxidation, methyl group, lithium bromide, aero-
bic, carboxylic acid
Table 2 shows the results for the oxidation of several
substrates under the reaction conditions outlined above.8
Although an electron-donating group, such as a tert-butyl
group or a methoxy group at an aromatic group, in
Oxidation reactions are the foundation of synthetic chem-
istry. Although oxidation reactions have been investigated
by many researchers, most of them have involved the use
of large quantities of heavy metals which results in the
discharge of large amounts of contaminants, and were not
at all environmentally benign.1 With this background in
mind, the notion of green chemistry is becoming well es-
tablished, and the development of environmentally benign
processes is the goal of various research projects. The
method using hydrogen peroxide or molecular oxygen
Table 1 Study of Reaction Conditions of Aerobic Photooxidation
COOH
O2-balloon
hv (400 W), MX
t-Bu
t-Bu
solvent (5 mL)
1 (50 mg)
2
which possesses a high atomic effect or E-factor as an
oxidant is one way consistent with this notion. We have
previously reported that in the presence of a mesoporous
silica FSM-16 under irradiation by a high-pressure mercu-
ry lamp, 4-tert-butylbenzyl bromide could be oxidized to
benzoic acid.2 We believed that the benzyl radical species,
which is generated in situ by the irradiation of UV, traps
molecular oxygen, and affords hydroperoxide via a per-
oxyradical. In this reaction, oxidation is thought to pro-
ceed smoothly due to facile elimination of a brominated
functional group; however, a similar oxidation reaction
would proceed even in the absence of a good releasing
group, if an intermediate such as aryl methyl halide could
be formed in situ. Based on tests conducted thus far, we
have discovered that 4-tert-butyltoluene (1) was oxidized
directly to 4-tert-butyl benzoic acid (2) in an oxygen
atmosphere in ethyl acetate in the presence of catalytic
lithium bromide (Scheme 1).3 There have been no reports
on this point regarding the generalization of photooxida-
tion of organic compounds with alkali metal halides so
far.4 Now we report our study on generality of this
reaction as a new kind of oxidation reaction.
Entry
MX
Equiv
Solvent
Time (h) Yield of 2
(%)
1
2
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiCl
Lil
0.5
0.5
0.5
0.5
0.5
0.5
0.1
0.1
0.3
0.7
1.0
0.5
0.5
0.5
0.5
0.5
Hexane
4
4
7
0
Acetone
MeCN
i-Pr2O
THF
3
4
0
4
4
9
5
4
0
6
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
4
90
25
51
81
64
22a
65
88
0
7
4
8
10
4
9
10
11
12
13
14
15
16
4
4
3
6
CO2H
LiBr, hν
4
EtOAc
t-Bu
t-Bu
4
0
1
2
NaBr
4
0
Scheme 1
a A total of 30% of 4-tert-butylbenzaldehyde was obtained and 22%
of 1 was recovered. The yield was estimated on the ratio of integral
value of 400 MHz NMR analysis.
SYNLETT 2005, No. 13, pp 2107–2109
Advanced online publication: 12.07.2005
1
9
.0
8
.2
0
0
5
DOI: 10.1055/s-2005-871942; Art ID: U13105ST
© Georg Thieme Verlag Stuttgart · New York

2108
A. Itoh et al.
LETTER
Table 2 Aerobic Photooxidation for Aromatic Methyl Groups
fades as the reaction proceeds, we believe that the radical
species 19 is generated by abstraction of a hydrogen radi-
cal with a bromo radical, formed under irradiation from
bromine. The radical species traps molecular oxygen to
afford the peroxyradical 20, which gives hydroperoxide
21 and regenerates the bromo radical (Scheme 2).
hν ( 400 W ), O2-balloon
LiBr (0.5 equiv)
substrate
product
(50 mg)
EtOAc (5 mL)
Entry Substrate
1
Time Product
(h)
Yield
(%)
In conclusion, we have found a useful method for the
synthesis of benzoic acids with lithium bromide, which
uses safe and inexpensive reagents, under aerobic UV
irradiation. This novel method is thought to be convenient
in view of the non-requirement of environmentally de-
trimental heavy metals and halogenated solvents.
COOH
COOH
4
90
73
49
t-Bu
t-Bu
1
2
2
6
MeO
MeO
LiBr
R
3
4
Br2
3
12
COOH
R
Br
19
OMe
OMe
5
6
4
12
76
80
O2
COOH
HBr
HBr
O
O
R
R
7
8
20
5
24
COOH
COOH
O
OH
NC
NC
O
OH
R
9
10
21
6
36
78
Scheme 2
O2N
O2N
11
12
References
7
24
88
63
COOH
(1) Comprehensive Organic Transformations: A Guide to
Functional Group Preparations; Larock, R. C., Ed.; Wiley-
VCH: New York, 1999.
(2) Itoh, A.; Kodama, T.; Inagaki, S.; Masaki, Y. Org. Lett.
2000, 2, 2455.
Ph
Ph
13
14
8
48
COOH
(3) Photooxidation of alkylbenzene in the presence of alkyl
bromides or hydrogen bromide under oxygen has been
previously reported, see: Nakada, M.; Fukushi, S.; Hirota,
M. Bull. Chem. Soc. Jpn. 1990, 63, 944.
(4) Regarding photooxidation with alkali metal halides, the
conversion of CO to CO2 and H2 to H2O in the presence of
hydrogen exposed to over 200 nm of ultraviolet light has
been previously reported, see: Ryabchuk, V. Catal. Today
2000, 58, 89.
15
16
9
48
22
COOH
17
18
(5) A typical procedure follows: a solution (5 mL) of the 4-tert-
butyltoluene (50 mg) and LiBr in dry EtOAc was stirred and
irradiated at r.t. with a 400-W high-pressure mercury lamp
externally for the indicated time. The reaction mixture was
concentrated under reduced pressure, and 1% NaOH
aqueous solution was added. The aq soln was washed with
Et2O, and acidified with 2 N HCl aq soln, and then extracted
again with Et2O. The organic layer was washed with brine
and dried over Na2SO4, and concentrated under reduced
pressure. The product was pure without further purification.
(6) No product (2) was detected when the reaction was carried
out in the absence of UV irradiation or LiBr, which indicates
the necessity of both LiBr and light for this reaction.
(7) The reaction did not proceed with the irradiation in short
time, for example 1 h, for the initiation of the reaction.
general, enhanced the reaction rate, an electron-with-
drawing group, such as a cyano or a nitro group, retarded
this oxidation (entries 1, 2, 4–6). 2-Methoxytoluene (5)
was found to afford the corresponding benzoic acid 6 in
moderate yield due to the steric hindrance of the methoxy
group (entry 3).
The mechanism of this reaction has not yet been deter-
mined. However, the pale yellow coloration of the suspen-
sion suggests that bromine is generated in situ from
lithium bromide under UV irradiation.9 Because the color
Synlett 2005, No. 13, 2107–2109 © Thieme Stuttgart · New York

LETTER
Aerobic Photooxidation of Methyl Group at Aromatic Nucleus
2109
(8) A typical procedure follows: a solution (5 mL) of the
substrate (0.269 mmol) and LiBr (0.5 equiv) in dry EtOAc
was stirred and irradiated at r.t. with a 400-W high-pressure
mercury lamp externally for the indicated time. The reaction
mixture was concentrated under reduced pressure, and 1%
NaOH aq soln was added. The aq soln was washed with
Et2O, acidified with 2 N HCl aq soln, and then extracted
again with Et2O. The organic layer was washed with brine
and dried over Na2SO4, and concentrated under reduced
pressure. The product was pure without further purification.
(9) Catalytic bromine oxidized 1 to 2 in 21% yield under similar
conditions.
Synlett 2005, No. 13, 2107–2109 © Thieme Stuttgart · New York