Direct aerobic photo-oxidative synthesis of aromatic methyl esters from methyl aromatics via dimethyl acetals

Article abstract of DOI:10.1021/ol1014575

A useful method for facile synthesis of aromatic methyl esters from methyl aromatics via dimethyl acetals by aerobic photo-oxidation using inexpensive and easily handled CBr₄ as catalyst is reported. This is the first example for direct preparation of the corresponding aromatic methyl esters from methyl aromatics.

Full text of DOI:10.1021/ol1014575

ORGANIC
LETTERS
2
010
Vol. 12, No. 16
645-3647
Direct Aerobic Photo-Oxidative
Synthesis of Aromatic Methyl Esters
from Methyl Aromatics via Dimethyl
Acetals
3
Shin-ichi Hirashima, Tomoya Nobuta, Norihiro Tada, Tsuyoshi Miura, and
Akichika Itoh*
Gifu Pharmaceutical UniVersity, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
itoha@gifu-pu.ac.jp
Received June 24, 2010
ABSTRACT
A useful method for facile synthesis of aromatic methyl esters from methyl aromatics via dimethyl acetals by aerobic photo-oxidation using
inexpensive and easily handled CBr as catalyst is reported. This is the first example for direct preparation of the corresponding aromatic
methyl esters from methyl aromatics.
4
Aromatic alkyl carboxylates have always attracted a great
deal of interest in organic synthesis as versatile compounds
or intermediates such as liquid crystal polymers, cosmetics,
pharmaceuticals, agrochemicals, and food additives. One of
the most general synthetic methods of aromatic esters from
methyl aromatics has been achieved by oxidation of alkyl
aromatics to carboxylic acids with heavy metals such as Cr,
Due to an increasing demand for more environmentally
benign synthesis, the development of a broadly applicable
direct esterification method from methyl aromatics is highly
desirable.
Recently, we reported aerobic photo-oxidation from methyl
aromatics and primary alcohols to the corresponding carboxylic
acids under mild conditions in the presence of a catalytic amount
1
2
6
Mn, and V followed by esterifications with alcohols. In
of bromine sources. In extending this aerobic photo-oxidation
3
4
addition, oxidative esterifications of an aldehydes, alcohols,
step, it occurred to us that the formation of dimethyl acetal in
situ will make it possible to synthesize methyl esters from
methyl aromatics in one pot (Scheme 1). Herein, we describe
efficient direct transformation of methyl aromatics to methyl
5
and acetals have also been developed.
Although a number of such efficient methods have been
established, to the best of our knowledge, there has been no
report on direct oxidative esterification from methyl aromat-
ics. This is probably because methyl aromatics are unreactive
and alcohols used as solvents are easily oxidized than methyl
aromatics.
(
3) (a) ComprehensiVe Organic Transformations, 2nd ed.; Larock, R. C.,
Ed.; Wiley-VCH: New York, 1999; p 1656. (b) March’s AdVanced Organic
Chemistry, 6th ed.; Smith, M. B., March, J., Ed.; John Wiley & Sons, Inc.:
Hoboken, 2007; p 1769.
(
4) (a) Tohma, H.; Maegawa, T.; Kita, Y. Synlett 2003, 72, 3–725. (b)
Foot, J. S.; Kanno, H.; Giblin, G. M. P.; Taylor, R. J. K. Synthesis 2003,
055–1064. (c) Hiegel, G. A.; Gilley, C. B. Synth. Commun. 2003, 33, 2003–
1
(
1) (a) ComprehensiVe Organic Transformations, 2nd ed.; Larock, R. C.,
2009. (d) Mori, N.; Togo, H. Synlett 2004, 880–882. (e) Karade, N. N.;
Tiwari, G. B.; Huple, D. B. Synlett 2005, 2039–2042. (f) Mori, N.; Togo,
H. Tetrahedron 2005, 61, 5915–5925. (g) Shaikh, T. M. A.; Emmanuvel,
L.; Sudalai, A. Synth. Commun. 2007, 37, 2641–2646. (h) Owston, N. A.;
Parker, A. J.; Williams, J. M. J. Chem. Commun. 2008, 624–625. (i) Su,
F.-Z.; Ni, J.; Sao, H.; Cao, Y.; He, H.-Y.; Fan, K.-N. Chem.sEur. J. 2008,
14, 7131–7135.
Ed.; Wiley-VCH: New York, 1999; p 1625. (b) March’s AdVanced Organic
Chemistry, 6th ed.; Smith, M. B., March, H., Eds.; A John Wiley & Sons,
Inc.: Hoboken, 2007; p 1745.
(
2) Greene’s ProtectiVe Groups in Organic Synthesis, 4th ed.; Wutz,
P. G. M., Greene, T. W., Eds.; John Wiley & Sons, Inc.: Hoboken, 2006;
pp 538-543.
10.1021/ol1014575  2010 American Chemical Society
Published on Web 07/29/2010

Scheme 1
.
Direct Synthesis of Methyl Esters via Dimethyl
Acetals
Table 2. Direct Aerobic Photo-Oxidative Synthesis of Methyl
Esters from Methyl Aromatics
a
b
c
entry
Ar
Ph (1a)
light source
time (h) yield (%)
1
2
3
4
5
6
7
8
9
fluorescent lamp
24
24
24
24
24
24
24
24
48
48
48
48
48
71 (2a)
92 (2b)
89 (2c)
70 (2d)
4-t-BuC
4-PhC
4-BzC
4-BrC
6
H
4
(1b) fluorescent lamp
6
H
H
4
4
(1c)
(1d)
(1e)
fluorescent lamp
fluorescent lamp
xenon lamp
6
e
6
H
4
4
80 (2e)
54 (2f)
34 (2g)
78 (2h)
aryl carboxylates via dimethyl acetals under the aerobic photo-
oxidation conditions.
To explore this approach, we selected 4-tert-butyltoluene (1b)
as a test substrate for optimization of reaction conditions (Table
3-BrC H (1f)
xenon lamp
6
2-BrC
4-ClC
6
H
4
(1g)
(1h)
xenon lamp
e
6
H
4
xenon lamp
e
4-NCC H (1i)
6
4
xenon lamp
53 (2i)
e
1
1
0
1
4-NO
2
C
6
H
4
(1j)
xenon lamp
22 (2j)
e
1-naphthyl (1k) xenon lamp
57 (2k)
e
1). Although reaction conditions with various bromine sources
12
2-naphthyl (1l)
2-pyridyl (1m)
xenon lamp
xenon lamp
78 (2l)
d
1
3
2
(2m)
a
A solution of substrate (0.3 mmol) and CBr
4
(0.1 equiv) in MeOH (1
mL) under an O
2
atmosphere was stirred and irradiated externally with the
b
indicated lamp. Fluorescent lamp: four 22 W lamps. Xenon lamp: 500 W
c
d
1
e
Table 1. Study of Reaction Conditions of Direct Aerobic
lamp. Yield of isolated product. H NMR analysis. 2e (57%), 2h (66%),
2i (32%), 2j (12%), 2k (12%), and 21 (55%) were obtained under fluorescent
lamp irradiation.
Photo-Oxidative Synthesis of Methyl Esters from Methyl
a
Aromatics
carboxylates in high yields (entries 2 and 3). However, the
methyl aromatics with electron-withdrawing substituents,
2
such as halogen, CN, and NO , afford the corresponding
b
entry
bromine source (equiv)
time (h)
yield (%)
methyl benzoates in lower yields under irradiation of 500
W xenon lamp (entries 5-10). The reaction of 2-bromo-
toluene (1g) gave methyl 2-bromobenzoate in low yield due
to its steric hindrance (entry 7). Furthermore, 1-methyl- (1k)
and 2-methylnaphthalene (1l) were oxidized to the corre-
sponding methyl esters in moderate to good yields, respec-
tively (entries 11 and 12). Unfortunately, 2-picoline (1m)
seems to be a poor substrate, presumably due to the basic
nitrogen of pyridine ring, which reacted with HBr, generated
in situ (entry 13). Dimethyl telephthalate (2n) was easily
obtained in good yield from p-xylene (1n) under mildly
1
2
3
4
5
6
7
8
9
Br
2
(0.3)
10
10
10
10
10
10
10
10
10
10
10
10
10
24
24
24
24
24
19
2
48% aq HBr (0.3)
NBS (0.3)
7
c
LiBr (0.3)
NaBr (0.3)
KBr (0.3)
MgBr
Al Br
TiBr
ZrBr
SmBr
YbBr
CBr
CBr
CBr
-
CBr
CBr
NR
c
NR
c
NR
2
·OEt
2
(0.3)
3
3
(0.3)
16
4
(0.3)
(0.3)
14
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
4
59
3
(0.3)
(0.3)
6
3
60
4
4
4
(0.3)
90
(0.3)
(0.1)
100 (99)
100 (92)
d
d
c
NR
8
aerobic photo-oxidative conditions (Scheme 2, eq 1).
d, e
d, f
4
4
(0.1)
(0.1)
3
c
NR
a
A solution of 4-tert-butyltoluene (1b; 0.3 mmol) and bromine source
in MeOH (5 mL) under an O atmosphere was stirred and irradiated
externally with four 22 W fluorescent lamps. H NMR analysis. Yield of
isolated product in parentheses. No reaction. Used 1 mL of MeOH.
Under an Ar atmosphere. In the dark.
2
b
1
Scheme 2
.
Direct Aerobic Photo-Oxidative Synthesis of Methyl
Esters from Methyl Aromatics
c
d
e
f
were tried to accomplish the oxidative esterification, the yields
of 2b were unsatisfactory except for CBr (entries 1-13). The
excellent yield of 2b was obtained by prolonging the reaction
time to 24 h (entry 14). Further optimization using CBr as
catalyst led us to reduce the amount of catalyst to 0.1 equiv in
4
4
7
1
mL of MeOH (entry 15). It is noted that in all cases of light
irradiation, CBr and molecular oxygen were necessary for the
4
direct oxidative esterification because the product 2b was not
obtained without them (entries 16-18).
The results of oxidation of various methyl aromatics under
the optimized reaction conditions are summarized in Table
Interestingly, 4,4′-dimethylbiphenyl (1o) also afforded the
corresponding dimethyl ester 2o, which is a good intermedi-
ate for high-performance materials in excellent yield (Scheme
2, eq 2).
2
. The methyl aromatics with an electron-donating group
were good substrates that offer the corresponding methyl
3646
Org. Lett., Vol. 12, No. 16, 2010

We also attempted the gram-scale synthesis of methyl ester
under the optimized conditions mentioned above. Although,
in general, photoreaction is difficult at high concentration,
fortunately, methyl ester 2b was obtained in good yield even
at 10 mmol scale (30 w/v %) (Scheme 3).
Scheme 5
.
Plausible Path of the Aerobic Photo-Oxidation of
Methyl Aromatics
Scheme 3. Gram-Scale Synthesis of Methyl Esters
During this process, a small amount of 4-tert-butylben-
9
zaldehyde (3b) was detected. In order to examine the
intermediate of this reaction, benzaldehyde (3a) was sub-
jected to similar aerobic photo-oxidation conditions for 5 h
to obtain 2a in 91% yield. We also found that dimethyl acetal
4
a was formed from aldehyde 3a in situ (Scheme 4, eq 3).
conditions in methanol. Acetal 4 is oxidized to methyl ester
2
under aerobic photo-oxidative conditions.
In conclusion, we report a useful method for facile
synthesis of aromatic methyl carboxylates from methyl
aromatics via dimethyl acetal by aerobic photo-oxidation
Scheme 4
.
Study of Reaction Intermediates
4
using inexpensive and easily handled CBr as catalyst. This
is the first example for direct preparation of the corresponding
methyl esters from methyl aromatics.
Supporting Information Available: .Experimental details
1
13
and H and C NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL1014575
(
5) (a) Karimi, B.; Rajabi, J. J. Mol. Catal. A: Chem. 2005, 226, 165–
1
69. (b) Karimi, B.; Rajabi, J. Synthesis 2003, 2373–2377. (c) Sueda, T.;
Fukuda, S.; Ochiai, M. Org. Lett. 2001, 3, 2387–2390. (d) Marples, B. A.;
Muxworthy, J. P.; Baggaley, K. H. Synlett 1992, 646. (e) Curci, R.;
D’Accolti, L.; Fiorentino, M.; Fusco, C.; Adam, W.; Gonz aˇ lez-Nunez, M. E.;
Mello, R. Tetrahedron Lett. 1992, 33, 4225–4228. (f) Brinkhaus, K. G.;
Steckhan, E.; Degner, D. Tetrahedron 1986, 42, 553–560. (g) Miura, M.;
Nojima, M.; Kusabayashi, S. J. Chem. Soc., Perkin Trans. 1 1980, 2909–
2
913.
(
6) (a) Itoh, A.; Hashimoto, S.; Kodama, T.; Masaki, Y. Synlett 2005,
Moreover, 4a was transformed to 2a under the same reaction
conditions (Scheme 4, eq 4). These results suggest that the
reaction proceeds through the aldehyde 3 and dimethyl acetal
2
107–2109. (b) Itoh, A.; Hashimoto, S.; Masaki, Y. Synlett 2005, 2639–
640. (c) Hirashima, S.; Itoh, A. Synthesis 2006, 1757–1759. (d) Hirashima,
2
S.; Hashimoto, S.; Masaki, Y.; Itoh, A. Tetrahedron 2006, 62, 7887–7891.
(
e) Hirashima, S.; Itoh, A. Photochem. Photobiol. Sci. 2007, 6, 521–524.
f) Hirashima, S.; Itoh, A. Green Chem. 2007, 9, 318–320. (g) Hirashima,
4
as intermediates. In addition, esterification of carboxylic
acid 5a was slow under these conditions, and methyl ester
a was obtained in 42% yield with recovery of 5a (38%)
(
S.; Itoh, A. J. Synth. Org. Chem. Jpn. 2008, 66, 748–756.
(
7) Ethyl 4-tert-butylbenzoate was obtained only in 1% yield when
2
ethanol was used as solvent with recovery of 4-tert-butyltoluene (62%) under
the optimal conditions.
even after 24 h (Scheme 4, eq 5).
On the basis of our previous studies in related reactions
and the results mentioned above, a plausible mechanistic
pathway is shown in Scheme 5. The first step involves
abstraction of hydrogen radical from methyl aromatics with
6
(8) (a) Bastock, T. W.; Clark, J. H.; Martin, K.; Trnbirth, B. W. Green
Chem. 2002, 4, 615–617. (b) Yang, F.; Sun, J.; Zheng, R.; Qiu, W.; Tang,
J.; He, M. Tetrahedron 2004, 60, 1225–1228. (c) Garcia-Verdugo, E.; Fraga-
Dubreuil, J.; Hamley, P. A.; Thomas, W. B.; Whiston, K.; Poliakoff, M.
Green Chem. 2005, 7, 294–300. (d) Fraga-Dubreuil, J.; Garcia-Verdugo,
E.; Hamley, P. A.; Vaquero, E. M.; Dudd, L. M.; Pearson, L.; Housley, D.;
Partenheimer, W.; Thomas, W. B.; Whiston, K.; Poliakoff, M. Green Chem.
2007, 9, 1238–1245.
4
bromine radical, generated from CBr under light irradiation,
to produce the radical species 6. Molecular oxygen is trapped
with 6, followed by dehydration to afford aldehyde 3, which
is transformed to dimethyl acetal 4 under the reaction
(
9) 4-tert-Butylbenzaldehyde (3b) was obtained in 8% yield for 4 h under
the optimal conditions (2b and 1b were obtained in 22% and 63% yields,
respectively).
Org. Lett., Vol. 12, No. 16, 2010
3647