Reductive carboxylation of aromatic esters by electron transfer from magnesium metal

Article abstract of DOI:10.1016/j.tetlet.2016.12.001

Magnesium-promoted reductive carboxylation of ethyl benzoate in the presence of chlorotrimethylsilane in N,N-dimethylformamide brought about a new carbon-carbon bond formation between the carbonyl carbon atom and carbon dioxide to give the corresponding benzoylformic acid in good yield. It is noteworthy that only ethyl benzoates with substituents at the meta-position were converted into benzoylformic acid derivatives. Moreover, no mandelic acid was detected even under the reductive conditions. This result indicates that benzoylformic acid was obtained after hydrolysis of a carboxylated intermediate, which would be alive as a stabilized structure in the reaction media.

Full text of DOI:10.1016/j.tetlet.2016.12.001

Accepted Manuscript
Reductive Carboxylation of Aromatic Esters by Electron Transfer from Mag-
nesium Metal
Hirofumi Maekawa, Hikaru Okawara, Taro Murakami
PII:
S0040-4039(16)31627-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.001
TETL 48413
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
1 November 2016
29 November 2016
2 December 2016
Please cite this article as: Maekawa, H., Okawara, H., Murakami, T., Reductive Carboxylation of Aromatic Esters
by Electron Transfer from Magnesium Metal, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2
016.12.001
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Reductive Carboxylation of Aromatic Esters
by Electron Transfer from Magnesium
Metal
Leave this area blank for abstract info.
Hirofumi Maekawa*, Hikaru Okawara, and Taro Murakami

1
Tetrahedron Letters
Reductive Carboxylation of Aromatic Esters by Electron Transfer from Magnesium
Metal
Hirofumi Maekawa , Hikaru Okawara, and Taro Murakami
Department of Materials Science and Technology, Nagaoka University of Technology, 1603-1, Kamitomioka-cho, Nagaoka, Niigata 940-2188, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Magnesium-promoted reductive carboxylation of ethyl benzoate in the presence of
chlorotrimethylsilane in N,N-dimethylformamide brought about a new carbon-carbon bond
formation between the carbonyl carbon atom and carbon dioxide to give the corresponding
benzoylformic acid in good yield. It is noteworthy that only ethyl benzoates with substituents at
the meta-position were converted into benzoylformic acid derivatives. Moreover, no mandelic
acid was detected even under the reductive conditions. This result indicates that benzoylformic
acid was obtained after hydrolysis of a carboxylated intermediate, which would be alive as a
stabilized structure in the reaction media.
Available online
Keywords:
Ethyl benzoate
Carboxylation
Magnesium
2
009 Elsevier Ltd. All rights reserved.
Umpolung
Benzoyl formic acid
Introduction
the selective carbon-carbon bond formation to give the
corresponding benzoylformic acid in good yield. The typical
Carboxylation to form a new carbon- carbon bond has been
one of the attractive topics in organic synthesis because it is a
solution for both the global warming and the utilization of carbon
dioxide as a carbon source. Carbon monoxide is a reactive and
available carbon source and has been a star reagent in C1
chemistry. So many reactions related with carbon monoxide were
reported especially in the field of the transition metal catalyzed
synthesis. However, carbon dioxide had not been controlled by
the transition metals in the carbon-carbon bond formation for a
synthetic routes to benzoylformic acids are Friedel-Crafts type
21-22
acylation of benzene with chlorooxalic acid esters
oxidation of mandelic acids. There are a few examples to
synthesize benzoylformic acids from benzoic acid derivatives
and
23
and the important one is the electrochemical carboxylation of
24-26
benzoyl chlorides.
However, no carboxylation of benzoic acid
esters could be found to our best knowledge.
Results and discussion
1,2
long time. Recently, the fixation of carbon dioxide has become
3-6
At first, supplying methods of carbon dioxide were
investigated in N,N-dimethylformamide (DMF). The reduction
under the carbon dioxide atmosphere gave the best results and the
bubbling condition decreased the yield of the product (2a)
because of the vaporization of chlorotrimethylsilane from the
one of the topics in the transition metal catalyzed reactions.
On the other hand, the reactions between carbon dioxide and
an anionic species are well known in organic synthesis and the
most famous reaction would be the Grignard reaction of carbon
7
1
9
dioxide. The electron transfer reactions, especially, the
reaction media (Table 1). In our previous work, magnesium-
promoted reduction in supercritical carbon dioxide only or
supercritical carbon dioxide in the presence of DMF as the
solvent did not proceed smoothly. Therefore, simple supply of
carbon dioxide by a balloon was selected in this reaction as the
best way.
electrochemical reactions have targeted carbon dioxide as a
reagent and there are many reports on the electrochemical carbon
8-18
dioxide fixation reactions.
These reactions suggested that a
radical anion species might catch carbon dioxide to form a new
carbon-carbon bond under the suitable reaction conditions.
We have also reported magnesium-promoted reduction of
ethyl cinnamates in the presence of carbon dioxide to give the
selective formation of succinic acid derivatives in good yields.
Furthermore, the effects of temperature, solvent and reaction
time were examined under the carbon dioxide atmosphere and
reactions in DMF at room temperature proceeded smoothly to
give benzoylformic acid (2a) as shown in Table 2. The coupling
reaction at room temperature was essential (entries 1-5) and only
aprotic polar solvents were suitable to consume the starting
19
Recently, Hirao and coworkers reported another type of the
carbon dioxide fixation reaction by electron transfer from
20
magnesium metal. In this study, reductive coupling reaction of
ethyl benzoate with carbon dioxide by magnesium brought about
—
——

Corresponding author. Tel.: +81-258-47-9320; fax: +81-258-47-9300; e-mail: maekawa@vos.nagaokaut.ac.jp

2
Tetrahedron Letters
material (1a). To simplify the reaction process, the reaction
conditions in entry 2 were selected as the best procedure.
for isopropyl ester because of the steric effect of the isopropyl
group.
Table 1. Investigation of the CO supply
2
The ratio of magnesium and chlorotrimethylsilane was also
investigated and the combination of 3 equivalent of magnesium
and 5 equivalent of chlorotrimethylsilane (entry 7) was found to
be the optimized reaction conditions (Table 4).
Table 4. Optimization of carboxylation of ethyl benzoate
Entry
1
Conditions
CO atmosphere
Isolated yield (%)
69
2
a
2
3
4
CO
CO
No CO
2
atmosphere
bubbling
supply
67
39
2
Mg
equiv. mol)
TMSCl
(equiv. mol)
a
2
No Reaction
Entry
Isolated Yield (%)
(
1
a (5 mmol), Mg (4 equiv.), TMSCl (6 equiv.), DMF (30 mL), 0°C (5 h) and
a
1
2
3
4
5
6
7
8
9
2
2
2
2
2
3
3
3
4
4
4
5
5
6
2
3
4
5
6
4
5
6
5
6
7
6
7
4
31
29
66
68
55
66
75
63
65
65
69
69
67
72
2
0 °C (4.5 h). The solvent after CO
2
bubbling was used.
Table 2. Effects of the reaction temperature, solvent and
reaction time
1
0
Temperature
Reaction
time (h)
Entry
Solvent
Isolated Yield (%)
(°C)
11
12
a
1
20
20
15
0
9.5
8.5
9.5
48
DMF
DMF
DMF
DMF
DMF
NMP
DMAc
THF
69
65
63
56
2
3
4
5
6
7
8
9
1
1
3
4
b
2
1a (5 mmol), DMF (30 mL), 20°C, CO atmosphere.
45
20
20
20
20
8
Complex mixture
a
8.5
8.5
8.5
8.5
47
Benzoic acid was detected as a byproduct.
39
No reaction
No reaction
Carboxylation of a variety of ethyl benzoate derivatives was
carried out under the optimized reaction conditions (Table 5). As
a result, most of meta-substituted derivatives were smoothly
transformed into the corresponding carboxylated compounds
3
CH CN
1
a (5 mmol), Mg (4 equiv.), TMSCl (6 equiv.), Solvent (30 mL), CO
2
a
b
atmosphere. 0°C (5 h) and 20°C (4.5 h). Main products were benzoic acid
and mandelic acid.
(
entries 1-6 and 9-12). Exceptionally, the substitution of a
hydroxyl group or an acetoxy group on the benzene ring at the
meta-position complicated the results probably because of the
reaction between chlorotrimethylsilane and the hydroxyl group or
the attack to the acetyl group by an anionic species (entries 7 and
Table 3. Steric effect of the alkyl group of ester
8). On the contrary, ortho- and para-substituted derivatives gave
no carboxylated product (entries 13-17).
Because an electron-donating group such as a methyl group
and a methoxyl group caused the negative shift of the reduction
potential and the instability of the radical anion species.
Especially in entry 15, the reduction of 1o was impossible by
magnesium metal. This result indicates that the critical limitation
of the reduction potential in magnesium-promoted reduction in
DMF may exist between -2.33 V and -2.54 V versus Ag/AgCl. A
trifluoromethyl group may lead to the elimination of a fluorine
atom by conjugated system of the anionic species generated from
a single electron transfer to 1, to give a complex mixture (entries
Entry
R
Isolated yield (%)
1
2
3
Me
Et
69
66
39
i-Pr
1
(5 mmol), Mg (3 equiv.), TMSCl (4 equiv.), DMF (30 mL), 20°C, CO
2
13 and 16). Application of a naphthyl group and a pyridyl group
atmosphere.
to this reductive carboxylation failed under our reaction
conditions.
To investigate the effects of the alkyl group of ester, the
carboxylation of several esters was carried out under the similar
reaction conditions as shown in Table 3. Reactions of ethyl ester
and methyl ester gave the desired compound in good yield,
respectively, however, a low yield of the product was obtained
13
Ethyl benzoate labeled with C carbon on the carbonyl carbon
atom (1a') was reduced by magnesium metal under the same
reaction conditions to give the corresponding benzoylformic acid
labeled on the carbonyl carbon atom of ketone (2a') (Scheme 1).

3
Table 5. Carboxylation of ethyl benzoate derivatives
1
2
3
4
Reduction Potential (V vs
Entry
X
X
X
X
a
Isolated Yield (%)
Ag/AgCl)
1
a
2a
2b
2c
2d
2e
2f
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CF
H
H
H
H
H
H
H
H
H
H
H
H
H
CF
H
H
-2.31
75
Cl
1b
65
1
c
CF
3
H
58
1
d
Me
H
-2.33
-2.27
50
1
e
OMe
F
H
61
H
1f
53
1
1
g
OH
OAc
Cl
H
Complex mixture
h
H
Complex mixture
1
i
2i
2j
2k
2l
Cl
OMe
60
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
OMe
1j
40
65
1
k
CF
3
CF
3
1
l
F
F
62
1
m
H
H
H
H
H
3
H
H
H
H
H
Complex mixture
Trace
Me
OMe
H
1n
-2.39
-2.54
1o
1p
1q
No reaction
Complex mixture
Trace
3
Me
H
-2.38
a
1
(5 mmol), Mg (3 equiv.), TMSCl (5 equiv.), DMF (30 mL), CO
2
atmosphere, 20°C. Working electrode Pt, counter electrode Pt, reference electrode
-
1
4 4
Ag/AgCl, solvent DMF, supporting electrolyte 1% nBu NBF , scan rate 0.2 V s .
although our trial to isolate a protected compound as the
intermediate failed to give no evidence on the formation of the
intermediate. On the basis of our investigation, a plausible
reaction mechanism is shown in Scheme 3.
Scheme 1
This fact suggests that no rearrangement occurred in the course
of the reduction and that carbon dioxide was introduced into the
benzoylformic acid as a carboxylic acid group.
Furthermore, it was quite strange that benzoylformic acid (2a)
was obtained instead of mandelic acid in this reductive coupling
because 2a would be easily reduced under the reduction
conditions. The reduction potential of 2a and commercially
available ethyl benzoylformate was measured, however, 2a did
not show a significant peak while the reduction peak of ethyl
benzoylformate was observed at -1.35 V. Next, magnesium-
promoted reduction of 2a was investigated under the similar
reaction conditions as our previous carboxylation to give the
corresponding mandelic acid (3a) in 58 % yield (Scheme 2).
Scheme 2
Scheme 3
A single electron transfer from magnesium metal to ethyl
benzoate 1a produces a radical anion species 4a, which reacts
first with chlorotrimethylsilane and receive a second electron
This result may suggest that benzoylformic acid will not
generate as a free form in situ, but exist as a protected form,

4
Tetrahedron
from magnesium at the same time to give an anionic species 5a.
4.
Takimoto, M.; Mizuno, T.; Mori, M.; Sato, Y. Tetrahedron 2006,
2, 7589-7597.
Yeung, C. S.; Dong, V. M. J. Am. Chem. Soc. 2008, 130, 7826-
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Takaya, J.; Sasano, K.; Iwasawa, N. Org. Lett. 2011, 13, 1698-
1701.
6
The intermediate 5a reacts with carbon dioxide at the benzylic
position to afford 6a with reproduction of an aromatic ring. The
anion 6a is stabilized by the coordination with magnesium cation
and will not be reduced because of its anionic moiety and the
protection of the carbonyl group as an acetal structure. Therefore,
benzoylformic acid may survive in situ and generate after the
hydrolysis.
5
6
.
.
7
7.
8
Gilman, H.; Kirby, R. H. Org. Synth. 1925, 5, 75-78.
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3
1
1
Magnesium-promoted reductive coupling of aromatic esters 1
with carbon dioxide in the presence of chlorotrimethylsilane
produced the corresponding benzoylformic acids in moderate to
good yield, which might be controlled by the reduction potential
and the substituent effect on the benzene ring. Formation of
benzoylformic acids suggested that the products in the reaction
media would survive as a protected structure.
6
13. Silvestri, G.; Gambino, S.; Filardo, G. Tetrahedron Lett. 1986, 27,
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1
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Acknowledgments
5
1
1
2
2
2
This work was supported in part by JSPS KAKENHI Grant
Number 22605003 and 25410110.
2
Supplementary Material
1
13
Supplementary data (copies of the H and C NMR spectra of
the derivatives that were produced by this procedure were sup-
plied) associated with this article can be found, in the online ver-
sion.
2
2
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Graphical Abstract
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Reductive Carboxylation of Aromatic Esters
by Electron Transfer from Magnesium
Metal
Leave this area blank for abstract info.
Hirofumi Maekawa*, Hikaru Okawara, and Taro Murakami

4
Tetrahedron
The carbonyl carbon atoms of aromatic esters were
reductively carboxylated by Mg.
Under our reduction conditions, 1,2-dicarbonyl
compounds can survive.
Non-substituted and meta-substituted aromatic
esters can be applied.