Electrochemical direct carboxylation of benzyl alcohols having an electron-withdrawing group on the phenyl ring: One-step formation of phenylacetic acids from benzyl alcohols under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2015.10.068

Electrochemical direct carboxylation of benzyl alcohols having an electron-withdrawing group on the phenyl ring was successfully carried out by constant current electrolysis using an undivided cell equipped with a platinum plate cathode and a magnesium rod anode in DMF in the presence of carbon dioxide. Reductive cleavage of the C-O bond followed by fixation of carbon dioxide efficiently took place at the benzylic position without any additive to give the corresponding phenylacetic acids in good yields in one step under neutral and mild conditions.

Full text of DOI:10.1016/j.tetlet.2015.10.068

Tetrahedron Letters 56 (2015) 6772–6776
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Tetrahedron Letters
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Electrochemical direct carboxylation of benzyl alcohols having an
electron-withdrawing group on the phenyl ring: one-step formation
of phenylacetic acids from benzyl alcohols under mild conditions
Hisanori Senboku a,b, ,y, Kenji Yoneda b, Shoji Hara a,b,y
⇑
a Division of Chemical Process Engineering, Faculty of Engineering, Hokkaido University, Sapporo, Hokkaido 060-8628, Japan
b Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, 060-8628, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Electrochemical direct carboxylation of benzyl alcohols having an electron-withdrawing group on the
phenyl ring was successfully carried out by constant current electrolysis using an undivided cell
equipped with a platinum plate cathode and a magnesium rod anode in DMF in the presence of carbon
dioxide. Reductive cleavage of the C–O bond followed by fixation of carbon dioxide efficiently took place
at the benzylic position without any additive to give the corresponding phenylacetic acids in good yields
in one step under neutral and mild conditions.
Received 20 August 2015
Revised 15 October 2015
Accepted 20 October 2015
Available online 21 October 2015
Keywords:
Ó 2015 Elsevier Ltd. All rights reserved.
Electrochemical reduction
Fixation of carbon dioxide
Benzyl alcohols
Phenylacetic acids
One-step formation
Oxidation of a primary alcohol is a straightforward approach to
obtain a carboxylic acid.1 However, when a primary alcohol
yielding the desired carboxylic acid by oxidation is not readily
available, one useful alternative approach is transformation of
readily available primary and secondary alcohols to desired car-
boxylic acids with one-carbon homologation. For instance, trans-
formation of benzyl alcohols including 1-phenylethanols to
phenylacetic acids and phenylpropanoic acids, known as potential
bioactive compounds including non-steroidal anti-inflammatory
agents, demands one-carbon homologation and two or more steps
are generally required. One conventional approach involves
hydrolysis of benzyl cyanides, which are generally prepared by
transformation of a hydroxyl group to an appropriate leaving
group followed by reaction with hazardous cyanide ion as a
homologation carbon source (Eq. 1).2 Reaction of Grignard reagents
prepared from the corresponding benzyl halides, derived from ben-
zyl alcohols, with carbon dioxide as a carbon source can also pro-
vide carboxylic acids, although high reactivity of Grignard
reagents limits acceptable functional groups in the substrates
(Eq. 2).3 For one-step synthesis of carboxylic acids from alcohols,
substitution of a hydroxyl group to a carboxyl group has to be
achieved in one step. This has been accomplished using transition
metal catalysts such as palladium, rhodium, and nickel with
hazardous carbon monoxide as a homologation carbon source4
(Eq. 3). However, the use of pressurized carbon monoxide and a
high reaction temperature with strong acids and/or halide salts
as promoters were necessary in most cases, and it seems to be
hazardous and troublesome. Therefore, the development of milder
and environmentally benign alternatives is desirable from the view-
point of eco-friendly organic synthesis. Because of its abundance
and non-toxicity, on the other hand, carbon dioxide (CO2) is well
known as a useful, important and environmentally benign C1 car-
bon source, and results of applications to organic synthesis have
been widely reviewed.5 The electrochemical method6 has widely
used for fixation of carbon dioxide in organic molecules with car-
bon–carbon bond formation yielding carboxylic acids.7 When a
reactive metal, such as magnesium or aluminum, is used as an
anode in the electrolysis,8,9 even under atmospheric pressure of
carbon dioxide, fixation can be accomplished to give carboxylic
acids in high yields under neutral and mild conditions. For
instance, Troupel and co-workers reported synthesis of pheny-
lacetic acids by electrochemical carboxylation of several benzyl
alcohol derivatives in moderate to good yields.10 Recently, we suc-
cessfully demonstrated two-step conversion of benzyl alcohols to
phenylacetic acids using the electrochemical method. Constant
current electrolysis of benzyl carbonates, readily prepared
from the corresponding benzyl alcohols with appropriate
⇑
Corresponding author. Tel./fax: +81 11 706 6555.
E-mail address: senboku@eng.hokudai.ac.jp (H. Senboku).
Current address: Division of Applied Chemistry, Faculty of Engineering, Hokkaido
y
University, Japan.
http://dx.doi.org/10.1016/j.tetlet.2015.10.068
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

H. Senboku et al. / Tetrahedron Letters 56 (2015) 6772–6776
6773
chloroformates in one step, using
a
one-compartment cell
containing 0.1 M Bu4NBF4 using a test tube-like undivided cell
equipped with a Pt plate cathode (2 ꢀ 2 cm2) and an Mg rod anode
(3 mm/, ca. 20 mm) in the presence of carbon dioxide at 0 °C with
4 F/mol of electricity. After the usual work-up, the corresponding
phenylacetic acid 2a was obtained in 32% yield along with a simple
reduction product, toluene derivative 3 in 25% yield with 57%
conversion of 1a (entry 1 in Table 1). Switching the solvent from
acetonitrile to DMF under the same conditions resulted in an
improvement of the conversion of 1a and the yield of 2a with a
reduction of the yield of 3 to 4% (entry 2). An increase or decrease
in current density was not effective for improving the conversion
of 1a and the yield of 2a (entries 3 and 4). When 6 F/mol of electric-
ity was passed to a DMF solution of 1a with 20 mA/cm2 of current
density, we could obtain 2a in 73% isolated yield with 83% conver-
sion (entry 5). Effect of reaction temperature was also investigated.
Electrolysis at ꢁ20 °C resulted in a slight decrease of the yield of 2a
and the conversion of 1a (entry 6). Although the yield of 2a and the
conversion of 1a slightly increased in electrolysis at 20 °C, the
product selectivity of 2a unfortunately decreased (entry 7).
The scope and limitation of the present direct electrochemical
carboxylation of several benzylic alcohols were investigated, and
the results are summarized in Table 2.13 Unsubstituted benzyl alco-
hol (1b) and mono-fluorobenzyl alcohols 1c and 1d were not appli-
cable for this direct carboxylation (entries 2–4). 3,5-Difluorobenzyl
alcohol (1e) and 4-phenylbenzyl alcohol (1f) were also ineffective
(entries 5 and 6). In these cases, most of the starting alcohol 1
was unchanged and was recovered in 51–91% 1H NMR yield. On
the other hand, when para-cyanobenzyl alcohol (1g) was used as
a substrate and was electrolyzed under the same conditions, car-
boxylation at the benzylic position occurred efficiently to give the
corresponding phenylacetic acid 2g in 78% isolated yield (entry
7). These results indicate that a strong electron-withdrawing group
is necessary on the phenyl ring of benzyl alcohol for the present
direct carboxylation. Although a similar reaction of benzyl alcohol
1h, having an ester group at the ortho position on the phenyl ring,
provided the corresponding carboxylic acid 2h in 55% isolated yield
(entry 8), a similar reaction of alcohol 1i having an ester group at
the meta position gave only a trace amount of carboxylic acid (entry
9). These results indicated that the location of an electron-
withdrawing group on the phenyl ring of benzyl alcohol is critical
for the present direct carboxylation of benzyl alcohol. From the fact
that an electron-withdrawing group at the ortho or para position is
effective and one at the meta position is ineffective, it is thought
that a resonance effect plays an important role.
equipped with a platinum cathode and a magnesium anode in ace-
tonitrile in the presence of atmospheric carbon dioxide resulted in
reductive carboxylation at the benzylic position of benzyl carbon-
ates to give the corresponding phenylacetic acids and phenyl-
propanoic acids in good yields (Eq. 4).11 In the course of our
studies on electroorganic synthesis,12 we recently found that direct
one-step conversion of benzyl alcohols having an electron-with-
drawing group on the phenyl ring to phenylacetic acids was possi-
ble using the electrochemical method with carbon dioxide as a
carbon source under neutral and mild conditions. Constant current
electrolysis of benzyl alcohols having an electron-withdrawing
group on the phenyl ring using a one-compartment cell equipped
with a platinum cathode and a magnesium anode in DMF in the
presence of atmospheric carbon dioxide resulted in direct forma-
tion of the corresponding phenylacetic acid in one step in good
yields (Eq. 5). To the best of our knowledge, there is no example
of one-step transformation of benzyl alcohols to phenylacetic acids
using carbon dioxide as a carbon source under neutral and mild
conditions. Here, we report the results of electrochemical direct
carboxylation of benzyl alcohols having an electron-withdrawing
group on the phenyl ring: one-step formation of phenylacetic acids
from benzyl alcohols under mild conditions.
H (Me)
OH
H (Me)
X
H (Me)
CN
H (Me)
Ar CO2H
CN
1)
2)
Ar
Ar
Ar
1) Mg, 2) CO2, 3) H3O
X = halogen
H (Me)
OH
H (Me)
transition metal cat., CO
promotor
3)
4)
Ar
Ar
Ar
CO2H
H (Me)
OR
H (Me)
,
CO2
M
Mg
Ar
CO2H
DMF
This study
H (Me)
OH
Ar = phenyl with 2-CO2Me, 4-CO2Me, 4-CN
H (Me)
Ar CO2H
Pt
Mg
DMF
, CO2
5)
Ar
Firstly, reaction condition screening was carried out using
benzyl alcohol 1a having an ester substituent at the para position
as a substrate. The results are summarized in Table 1. Constant
current electrolysis (20 mA/cm2) of 1a was carried out in acetonitrile
The present direct carboxylation was also carried out by using
pentafluorobenzyl alcohol (1j) and 4-trifluoromethylbenzyl
Table 1
Screening of reaction conditions
CH3
Pt
Mg
CO2H
+
OH
CO2
+
0.1 M Bu4NBF4-solvent
H3CO2C
H3CO2C
H3CO2C
1a
2a
3
Entry
Solvent
Current density [mA/cm2]
Electricity [F/mol]
Temperature [°C]
Conversiona [%]
Yield [%]
2ab
3a
1
2
3
4
5
6
7
CH3CN
DMF
DMF
DMF
DMF
DMF
DMF
20
20
15
30
20
20
20
4
4
4
4
6
6
6
0
0
0
0
0
57
74
75
65
83
71
99
32
59
59
55
73
67
79
25
4
5
4
3
ꢁ20
2
10
20
a
Determined by 1H NMR using 1,4-dintrobenzene as an internal standard.
Isolated yield.
b

6774
H. Senboku et al. / Tetrahedron Letters 56 (2015) 6772–6776
been reported by Troupel and Périchon’s group16 and by us.17
These results indicate that fluorine atoms and a trifluoromethyl
group are not suitable as electron-withdrawing groups for the pre-
sent direct electrochemical carboxylation of benzyl alcohol.
We next investigated application of secondary and tertiary ben-
zyl alcohols to the present direct carboxylation as substrates. Some
of the results are shown in Scheme 2.18 When 1-phenylethanol 6a
having an ester group at the para position of the phenyl ring was
electrolyzed in the presence of carbon dioxide under the same con-
ditions as those shown in Table 1, similar direct carboxylation of a
secondary benzyl alcohol also took place to give the corresponding
2-arylpropanoic acid 7a in 59% yield, and 40% recovery of 6a was
detected by 1H NMR. In a similar manner, electrochemical direct
carboxylation of secondary benzyl alcohol 6b having a cyano
group, instead of an ester group, gave 2-(p-cyanophenyl)propanoic
acid (7b) in 60% yield, and 25% recovery of 6b was detected by 1H
NMR. The present direct carboxylation was also applicable to ter-
tiary benzyl alcohol. It proceeded, however, less effectively than
that of secondary benzyl alcohols. When tertiary benzyl alcohol 8
was electrolyzed under the same conditions, the corresponding
carboxylic acid 9 was obtained only in 25% yield as shown in
Scheme 2 and 62% recovery of 8 was detected by 1H NMR.
Although diphenylmethanol (benzhydrol) was, on the other hand,
subjected to the present direct carboxylation under the same con-
ditions, the starting material was recovered in 96% and only a trace
amount of diphenylacetic acid was detected by 1H NMR.
Although details are still unclear at this stage, one plausible
reaction mechanism in the present electrochemical direct carboxy-
lation of benzyl alcohol is shown in Scheme 3.19 At the cathode,
one-electron reduction of the benzyl alcohol 1 results in hydrogen
and alkoxide ion A. Evolution of hydrogen at the cathode can be
easily observed by the naked eyes. The generated alkoxide ion A
reacts with carbon dioxide to form benzyl carbonate ion B. Two-
electron reduction of the thus-generated benzyl carbonate ion B
at the cathode generates benzylic anion C. Electrochemical reduc-
tion of benzyl carbonate 10 in the presence of carbon dioxide has
been reported by Troupel10 and by us.11 It is thought that reduction
of benzyl carbonate ion B is more difficult than reduction of
Table 2
Scope of benzyl alcohols in electrochemical direct carboxylation
Pt
Mg
OH
CO2H
CO2
R
R
+
0.1 M Bu4NBF4-DMF
1
20 mA/cm2, 6 F/mol, 0 °C
2
Entry
R
Conversiona [%]
Product and yieldb [%]
1
2
3
4
5
6
7
8
9
4-CO2CH3 (1a)
H (1b)
4-F (1c)
83
15
9
27
35
49
98
82
23
2a: 73
2b: (trace)
2c: (trace)
2d: (5)
2e: (11)
2f: (18)
2g: 78
2-F (1d)
3,6-F (1e)
4-C6H5 (1f)
4-CN (1g)
2-CO2CH3(1h)
3-CO2CH3 (1i)
2h: 55
2i: (trace)
In parenthesis, the yield determined by 1H NMR using 1,4-dintrobenzene as an
internal standard.
a
Determined by 1H NMR using 1,4-dinitrobenzene as an internal standard.
Isolated yield.
b
alcohol (1k) as substrates, and the results are summarized in
Scheme 1.14 Although a complex mixture was only obtained by
electrolysis of 1j under the same conditions as those shown in
Table 2, we finally found that reductive cleavage of the C–F bond
followed by carboxylation selectively occurred at the para position
on the phenyl ring to give 4-hydroxymethyl-2,3,5,6-tetrafluo-
robenzoic acid (4)12g under milder electrolysis conditions as
shown in Scheme 1.15 We also tested a trifluoromethyl group as
an electron-withdrawing group for the direct carboxylation. When
4-trifluoromethylbenzyl alcohol (1k) was subjected to the present
direct carboxylation under the same conditions as those shown in
Table 1, reductive cleavage of the C–F bond followed by carboxyla-
tion selectively occurred at the benzylic position of the CF3 group
on the phenyl ring to give 2,2-difluoro-(4-hydroxymethylphenyl)
acetic acid (5) in 74% yield (Scheme 1). Similar electrochemical car-
boxylation of benzotrifluoride (
a
,a
,a
-trifluorotoluene) has already
F
F
F
F
Pt
Mg
OH
OH
+
CO2
0.1 M Bu4NBF4-DMF
10 mA/cm2, 3 F/mol
-40 °C
F
F
HO2C
F
F
F
1j
4
48%
Pt
Mg
OH
OH
+
CO2
HO2C
0.1 M Bu4NBF4-DMF
20 mA/cm2, 6 F/mol
0 °C
CF3
F
F
1k
5
74%
Scheme 1. Electrochemical carboxylation of pentafluorobenzyl alcohol (1j) and 4-trifluoromethylbenzyl alcohol (1k).
H3C R2
OH
H3C R2
CO2H
Pt
Mg
+
CO2
0.1 M Bu4NBF4-DMF
20 mA/cm2, 6 F/mol
0 °C
R1
R1
1
: R = CO2CH3, R2 = H
7a: 59%
7b
6a
6b: R1 = CN, R2 = H
: 60%
9: 25%
8: R1 = CO2CH3, R2 = CH3
Scheme 2. Electrochemical direct carboxylation of secondary and tertiary benzyl alcohols 6a, 6b and 8.

H. Senboku et al. / Tetrahedron Letters 56 (2015) 6772–6776
6775
at the cathode
CO2
+ e
Ar
OH
Ar
OCO2
Ar
O
- 1/2 H2
O
1
A
B
R
+ 2e
Ar
O
O
10: R = alkyl
CO2
+ 2e
Ar
Ar
CO2
2
- OCO2
C
D
at the anode
Mg
Mg2
+
2e
Scheme 3. Probable reaction mechanism of electrochemical direct carboxylation of benzyl alcohols.
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electronically-neutral benzyl alkyl carbonate 10. It is likely that the
electron-withdrawing group on the phenyl ring of 1 plays an
important role in reduction of B. The generated benzyl anion C
and carbon dioxide react with formation of a carbon–carbon bond
to give the corresponding carboxylate ion D. At the anode, on the
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In conclusion, electrochemical direct carboxylation of benzyl
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phenylacetic acids and phenylpropanoic acids from benzyl alcohols
using atmospheric pressure of carbon dioxide in good yields under
neutral and mild conditions. This is the first example of one-step
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phenylpropanoic acids using carbon dioxide as a carbon source
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Acknowledgment
This work was supported by a Grant-in-Aid for Scientific
Research (C), JSPS KAKENHI Grant Number 25410104.
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13. Benzyl alcohols 1a–g are commercially available. Alcohol 1h20 was prepared
from phthalide by the reaction with aq NaOH followed by iodomethane.
Alcohol 1i21 was prepared from the corresponding commercially available
aldehyde by the reaction with NaBH4 in MeOH. Isolated and detected
carboxylic acids 2a,11 2d,22 2e,23 2f,22b,24 2g11 and 2h25 are known compounds
and their spectral data were good agreement with reported ones.
14. Benzyl alcohols 1j and 1k are commercially available. Selected spectral data of
carboxylic acid 5: dH (400 MHz, DMSO-d6) 2.50 (1H, s), 4.55 (2H, s), 7.46 (2H, d,
J = 8.1 Hz), 7.52 (2H, d, J = 8.1 Hz); dC (100 MHz, DMSO-d6) 62.4, 113.7 (t,
J = 248 Hz), 125.0 (t, J = 6 Hz), 126.7, 131.1 (t, J = 25 Hz), 146.0, 165.2 (t,
J = 34 Hz); dF (372.5 MHz, DMSO-d6) –101.8.
19. Cyclic voltammetry of several representative benzyl alcohols 1a, 1b, 1i, 1j, 1k,
and 6a was carried out. While no reduction peaks were observed in CVs of 1b,
1j, and 1k at more positive potential than ꢁ3.0 V versus Ag/Ag+, reduction
peaks were observed in CVs of 1a, 1i and 6a. Their reduction peaks appeared at
about ꢁ2.8 V versus Ag/Ag+ in their CVs although the reaction of 1a and 6a
gave carboxylic acids and the reaction of 1i did not. These results indicate that
relationships between the yields and the reduction potentials are so
complicated to explain clearly and reasonably at the present stage.
20. Rajan, R.; Badgujar, S.; Kaur, K.; Malpani, Y.; Kanjilal, P. R. Synth. Commun. 2010,
40, 2897–2907.
21. Af Gennaes, G. B.; Talman, V.; Aitio, O.; Ekokoski, E.; Finel, M.; Tuominen, R. K.;
Yli-Kauhaluoma, J. J. Med. Chem. 2009, 52, 3969–3981.
22. (a) Fleming, P.; O’shea, D. F. J. Am. Chem. Soc. 2011, 133, 1698–1701; (b) She,
M.-Y.; Xiao, D.-W.; Yin, B.; Yang, Z.; Liu, P.; Li, J.-L.; Shi, Z. Tetrahedron 2013, 69,
7264–7268.
15. Unpublished result. Related electrochemical carboxylation of polyfluoroarenes
has been reported in ref. 12g.
16. Saboureau, C.; Troupel, M.; Sibille, S.; Périchon, J. J. Chem. Soc., Chem. Commun.
1989, 1138–1139.
17. Yamauchi, Y.; Fukuhara, T.; Hara, S.; Senboku, H. Synlett 2008, 428–442.
18. Alcohols 6a,26 6b20 and 827 were prepared from the corresponding commer-
cially available ketones by the reaction with NaBH4 in MeOH or with
methylmagnesium bromide in THF. Isolated carboxylic acids 7a and 7b are
known compounds and their spectral data were good agreement with reported
ones.11 Selected spectral data of carboxylic acid 9: dH (400 MHz, CDCl3) 1.63
(6H, s), 3.91 (3H, s), 7.47 (2H, d, J = 8.0 Hz), 8.01 (2H, d, J = 8.0 Hz); dC (100 MHz,
CDCl3) 26.0, 46.6, 52.1, 125.9, 128.7, 129.7, 148.9, 166.9, 182.4.
23. Kowalczyk, B. A. Synthesis 1997, 1411–1414.
24. Zhang, W.; Ready, J. M. Angew. Chem., Int. Ed. 2014, 53, 8980–8984.
25. Kilikli, A. A.; Dengiz, C.; Özcan, S.; Balci, M. Synthesis 2011, 3697–3705.
26. Zhao, Q.; Curran, D. P.; Malacria, M.; Fensterbank, L.; Goddard, J.-P.; Lacôte, E.
Synlett 2012, 433–437.
27. Matsumoto, T.; Ishida, T.; Yoshida, T.; Terao, H.; Takeda, Y.; Asakawa, Y. Chem.
Pharm. Bull. 1992, 40, 1721–1726.