Lithium chloride-assisted selective hydrolysis of methyl esters under microwave irradiation

Article abstract of DOI:10.1080/00397910902778001

A rapid and mild method for the selective hydrolysis of methyl ester in lithium chloride-N,N-dimethylformamide (LiCl-DMF) system under microwave irradiation has been developed. The effects of substituent, metal salt, and solvent on the reactivity and selectivity of the hydrolysis reaction have been investigated. Microwave irradiation significantly improves the reaction yield within a short time in an LiCl-DMF system. Moreover, the chiral-carbon of methyl esters retained its configuration during the reaction. Finally, the catalytic mechanism of hydrolysis by LiCl salt has also been proposed.

Full text of DOI:10.1080/00397910902778001

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Lithium Chloride–Assisted
Selective Hydrolysis of Methyl
Esters Under Microwave
Irradiation
a
a
a
Xiao-Ai Wu , Ping Ying , Jun-Yang Liu , Heng-
a
b
a
Shui Shen , Yue Chen & Ling He
a
Department of Medicinal Chemistry and Key
Laboratory of Drug Targeting of Education Ministry
of China, West China School of Pharmacy, Sichuan
University, Chengdu, Sichuan, China
b
Department of Nuclear Medicine, Affiliated
Hospital, Luzhou Medical College, Luzhou, Sichuan,
China
Version of record first published: 04 Sep 2009.
To cite this article: Xiao-Ai Wu , Ping Ying , Jun-Yang Liu , Heng-Shui Shen , Yue Chen
&
Ling He (2009): Lithium Chloride–Assisted Selective Hydrolysis of Methyl Esters
Under Microwave Irradiation, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 39:19, 3459-3470
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1
Synthetic Communications , 39: 3459–3470, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902778001
Lithium Chloride–Assisted Selective Hydrolysis
of Methyl Esters Under Microwave Irradiation
1
Xiao-Ai Wu, Ping Ying, Jun-Yang Liu, Heng-Shui Shen,
1
1
1
2
Yue Chen, and Ling He
1
1
Department of Medicinal Chemistry and Key Laboratory of Drug
Targeting of Education Ministry of China, West China School of
Pharmacy, Sichuan University, Chengdu, Sichuan, China
2
Department of Nuclear Medicine, Affiliated Hospital, Luzhou Medical
College, Luzhou, Sichuan, China
Abstract: A rapid and mild method for the selective hydrolysis of methyl ester in
lithium chloride–N,N-dimethylformamide (LiCl–DMF) system under microwave
irradiation has been developed. The effects of substituent, metal salt, and solvent
on the reactivity and selectivity of the hydrolysis reaction have been investigated.
Microwave irradiation significantly improves the reaction yield within a short
time in an LiCl–DMF system. Moreover, the chiral a-carbon of methyl esters
retained its configuration during the reaction. Finally, the catalytic mechanism
of hydrolysis by LiCl salt has also been proposed.
Keywords: N,N-Dimethylformamide, hydrolysis, lithium chloride, methyl esters,
microwave irradiation
INTRODUCTION
The hydrolysis of esters is one of the most fundamental reactions
in organic synthesis with wide applications in pharmaceutical and fine
chemical industries. Most of these reactions are acid-catalyzed,
Received October 26, 2008.
Address correspondence to Ling He, Department of Medicinal Chemistry and
Key Laboratory of Drug Targeting of Education Ministry of China, West China
School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China.
E-mail: lhe2001@yahoo.com.cn
3
459

3460
X.-A. Wu et al.
[1,2]
base-catalyzed, or enzyme-catalyzed.
However, these synthetic
methods are not applicable to compounds that have acid- or base-
sensitive functional groups, because the intensive reaction conditions
along with the long reaction time often lead the change of these func-
tional groups, in particular, the racemization of methyl esters of a-chiral
[
3–7]
center.
Therefore, it is necessary to develop a simple, highly selective,
and high-yielding method for the selective cleavage of methyl esters in the
presence of sensitive functional groups with low-cost and commercially
available reagents under essentially neutral conditions. Here, we report
the first selective hydrolysis of methyl esters in an anhydrous system
under microwave irradiation with lithinium chloride as an auxiliary
chemical. The chiral a-carbon in methyl esters was found to retain its
original configuration under nonaqueous conditions during the hydro-
lysis reaction.
It is well known that the microwave irradiation can effectively
[
8,9]
activate the organic reactions catalyzed by inorganic solids
and
greatly facilitate the reactions by significantly reducing the reaction time
from several hours or days to a couple of minutes or even seconds.
Microwave irradiation has been well recognized as a convenient method
[
10,11]
to facilitate rapid reactions
with much less energy. Moreover,
microwave irradiation can be used under mild reaction conditions and
in less toxic reagents and solvents, which offers a further advantage
and additional convenience in organic syntheses. Although the esteroly-
[
12–14]
sis reactions under microwave irradiation has been reported,
there
are few works about the esterolysis in neutral conditions under micro-
wave irradiation in the literature. Consequently, the microwave-assisted
esterolysis reaction in neutral medium is an attractive methodology. In
this research, the application of microwaves in the selective hydrolysis
of methyl esters in the lithium chloride-N,N-dimethylformamide
(
LiCl–DMF) system has been developed, and the method could
effectively form a-chiral acids.
RESULTS AND DISCUSSION
Solvent Effect
Because of their difference in polarity, the hydrophobic organic sub-
strates and the highly polar mineral salt may have different solubilities
in a solvent solution. In this work, the effect of solvent on the cleavage
of methyl ester under microwave irradiation was investigated, in which
a model reactant (naproxen) as well as the promoter LiCl was irradiated
by microwaves in different solvents. The results are summarized in

Demethylation with Microwaves
3461
a,b
Table 1. Solvent effect
Entry
Solvent
Conversion (%)
Yield (%)
1
2
3
4
5
6
7
8
9
H
Ethanol
Ethyl acetate
Acetone
n-Butanol
2
O
0
35
0
0
0
0
76
0
83
90
92
99
—
—
—
—
—
—
6
—
13
21
37
93
H
2
O=polyethylene glycol 2000
Polyethylene glycol 600
O=polyethylene glycol 600
H
2
Polyethylene glycol 400
Polyethylene glycol 200
Glycol
1
1
1
0
1
2
DMF
a
b
The hydrolysis of methyl esters carried out at 545 W for 10 min of irradiation.
Substrate=salt=solvent ¼ 1: 5: 5 mmol.
Table 1. As shown in Table 1, the cleavage reaction was most effective in
dimethylformamide (DMF), whereas it hardly proceeded in water, ethyl
acetate, acetone, ethanol, and butanol. Moreover, solvents dimethylsulf-
oxide (DMSO), tetrahydrofuran (THF), and acetonitrile (not included in
Table 1) have also be examined, in which only a trace amount of cleavage
products were detected after 2 h of reaction under microwave irradiation.
The solvent effect on the reaction reported here may result from the
solubility difference of substrate and LiCl in the solvents.
Effects of Salt
To investigate the salt effects, lithium chloride, sodium chloride, potas-
sium chloride, ammonium chloride, AcOK, and K SO were employed
2
4
as promoters for the cleavages of 1 in DMF with naproxen as a model
reactant. As shown in Table 2, only lithium chloride was effective to pro-
mote the cleavage reaction (Table 2, entry 5). We found that the reactivity
increases with the amount of lithium chloride.

3462
X.-A. Wu et al.
a,b
Table 2. Optimization of salts under microwave irradiation
Entry
Salt
KCl
NaCl
AcOK
Conversion (%)
Yield (%)
1
2
3
4
5
61
2
78
44
99
5
—
9
—
93
K
2
SO
LiCl
4
a
The hydrolysis of methyl esters was carried out at 545 W for
0 min of irradiation, using DMF as solvent.
Substrate=salt=solvent ¼ 1:5:5 mmol.
1
b
Effect of Substituent
The effects of aromatic substituent on the reaction activity have been
studied. The results are summarized in Table 3. As shown in entries
1–6 in Table 3, almost all methyl esters showed a moderate to good yield
ranging from 57 to 99%, except for the methyl ester with a substituent
at the ortho-position (entry 7), which had a yield of only 34%.
Reactivity of Different Esters
The effects of ester group on the cleavage reaction were studied by using
several different esters reacted under strictly identical conditions. The
results are also listed in Table 3. As shown in Table 3, after 30 min of
microwave irradiation at 545 W, the hydrolysis of ethyl esters of aliphatic
and aromatic acids proceeded only slightly (Table 3, entries 10 and 11).
Moreover, only the methyl group was removed from the substrates; other
esters of phenyl (entries 7 and 11) or ethyl (entries 9 and 10) groups were
unaffected under these reaction conditions. The methyl ethers such as in
entries 4 and 5 were also unaffected under the reaction conditions.
Influence of a-Chiral Center
The influence of substrate chirality on the cleavage reaction has been
studied by using several a-chiral acids in the reaction and measuring
the optical rotation as well as the ee of products (Table 4).

3
463

3
464

Demethylation with Microwaves
3465
Table 4. Influence of a-chiral center
Conversion Yield
(%)
Ee
(%)
Entry
1
Starting material
Products
(%)
93
88
98
2
3
4
99
92
90
93
86
81
99
98
97
5
95
73
99
Notes. The methyl ester esterolysis reactions were carried out at 545 W for
0 min of irradiation in the LiCl–DMF system, Substrate=salt=solvent ¼ 1:5:5.
1
The acid products were analyzed by a chiral high-performance liquid
chromatographic (HPLC) system, equipped with an ultraviolet (uv) and
visible detector to measure ee at 254 nm wavelength. The products were
separated on a Chiralpak AS-H and OD column (Daicel Chemical Indus-
ꢁ
tries, 4.6 mm ꢀ 250 mm) at a column temperature of 20 C [eluent:
n-hexane=isopropanol (90=10); flow rate: 0.5 mL=min; sample injection
volume: 2 mL]. As shown in Table 4, it can be concluded that the chiral
acids including a-chiral center did not have appreciable effects on the
reaction under identical conditions, but the influence of a-chiral center
is universal via enolization on traditional hydrolysis reaction of esters.
Mechanism of the Hydrolysis Reaction
In microwave-assisted organic syntheses, there are two effects in
reactants: thermal effects and nonthermal effects (or specific effects).

3466
X.-A. Wu et al.
The thermal effect may result from dipolar polarization, the result of
dipole–dipole interactions between polar molecules and the electro-
magnetic field, in which the energy absorbed from the electromagnetic
field is dissipated as heat, an outcome of agitation and intermolecular
frictions when molecular dipoles change their mutual orientation
[
23]
following a very-high-frequency electromagnetic field . In comparison
with traditional heating in which thermal equilibration is reached via
conduction, convection, and radiation, the microwave heating is
more than 10 times faster. However, in the esterolysis reactions studied
here, the specific effect may be responsible for the increase in reactivity
and kinetics. Specifically, given that the transition state in this reaction
is polar, the reaction can be facilitated by stabilizing the transition
state by its dipole–dipole interactions with the electric field. Further-
more, because the greater the polarity of a molecule is, the greater the
[
24]
microwave effect will be.
tuted with electron-withdrawing group) is, the greater the microwave
The more polar the transition state (substi-
[
25]
effects are.
To gain further insight into the mechanism of the hydrolysis reaction,
the production of chloromethane (CH Cl) were studied under the same
3
reaction conditions. CH Cl can monitor the reactions in the boiling state.
3
To detect CH Cl, the steam from the reactor was passed through a tube
3
into another flask in which 10% silver nitrate solution was added. CH Cl
3
vapor was absorbed by silver nitrate solution and then precipitated as the
white solid in the solution. Based on our experimental observations, we
þ
ꢂ
proposed that it is probably Li Cl that leads to a nucleophilic attack
on the methyl group and releases CH Cl (Scheme 1). Because of the
3
presence of dipoles pairs, which can specifically help the chloride ion pull
off the leaving group, the selectivity and reactivity can be greatly influ-
enced. Moreover, because of the charge transfer and the formation of
ligand of four-member ring with lithium, it can be inferred from
Scheme 1 that the selectivity of catalyzed esterolysis follows the order
of CH > CH CH (C H ). Therefore, it can be concluded that the micro-
3
2
3
6
5
wave irradiation improves the reaction yield and facilitates the selectivity
of esterolysis of methyl esters in the LiCl–DMF system.
Scheme 1. Proposed mechanism.

Demethylation with Microwaves
CONCLUSION
3467
In summary, we have developed an efficient microwave-assisted catalytic
procedure for the chemo- and regioselective hydrolysis of methyl ester in
LiCl–DMF in the presence of other functional groups. We also found
that the reaction conditions did not cause the racemization of the a-chiral
center. The developed method offers several advantages, including the
rapid reaction rate, mild conditions, simple procedures, moderate to
good yields, inexpensive reagents, and compatibility with other func-
tional groups. It is an alternative method for the cleavage of methyl esters
with acid- and alkali-sensitive functional groups.
EXPERIMENTAL
All reactions were carried out in a MCL-II microwave reactor equipped
with a thermocouple used to measure temperatures. NMR spectra were
recorded on a Varian Mercury 400-MHz spectrometer.
General Procedure
Five mmol lithium chloride (dried) was added into the solution of
1
.0 mmol methyl ester and 5.0 mmol anhydrous DMF (0.34 mL). The
ꢁ
mixture was irradiated by microwave (545 W, 150–160 C) for 10 min.
After completion of the reaction, as indicated by thin-layer chromatogra-
phy (TLC), the reaction mixture was basified with NaOH (0.1 M=L) at
ꢁ
0
C until pH 10. The solution was then extracted with ethyl acetate
(
3 ꢀ 10 mL) followed by acidification with diluted HCl (6 M=L) to give
the crude product. The crude product was purified by crystallization with
5% ethanol or flash-column chromatography of silica gel with petro-
9
leum ether=ethyl acetate as the eluant to give the final product.
Selected Data
(
R)-2-(6-Methoxynaphthalen-2-yl)propanoic Acid
1
H NMR (d -DMSO, 400 MHz) d (ppm) 1.58 (d, J ¼ 7.2 Hz, 3H), 3.87 (q,
6
1
H), 3.91 (s, 3H), 7.12 (m, 2H), 7.40 (m, 1H), 7.69 (m, 3H). C NMR
3
1
(
CDCl , 100 MHz) d (ppm) 18.1, 45.3, 55.3, 105.6, 119.1, 126.1, 126.2,
3
1
27.3, 128.9, 129.3, 133.8, 134.9, 157.7, 180.9.

3468
X.-A. Wu et al.
Terephthalic Acid (8)
1
H NMR (d -DMSO, 400 MHz) d (ppm) 8.05 (s, 4H), 13.3 (br, 2H).
6
1
3
C NMR (d -DMSO, 100 MHz) d (ppm) 129.9, 134.9, 167.1.
6
3
,5-Dinitrobenzoic Acid (2)
1
H-NMR (d -DMSO, 400 MHz) d (ppm) 8.90 (s, 2H), 9.01 (s, 1H).
6
1
3
C-NMR (d -DMSO, 100 MHz) d (ppm) 164.4, 148.8, 134.5, 129.3,
6
1
22.5.
4
-Nitrobenzoic Acid (3)
1
H NMR (d -DMSO, 400 MHz) d (ppm) 8.17 (d, J ¼ 8.4 Hz, 2H), 8.33 (d,
6
1
3
J ¼ 8.4 Hz, 2H), 13.7 (br, 1H). C NMR (d -DMSO, 100 MHz) d (ppm)
6
1
24.2, 131.2, 136.8, 150.5, 166.3.
(S)-2-(4-Isobutylphenyl)propanoic Acid (14)
1
H NMR (d -DMSO, 400 MHz) d (ppm) 0.85 (d, J ¼ 6.4 Hz, 6H), 1.34 (d,
6
J ¼ 6.8 Hz, 3H), 1.80 (m,1H), 2.41 (d, J ¼ 3.6 Hz, 2H), 3.62 (q, 1H), 7.10
1
3
(
1
1
d, J ¼ 8 Hz, 2H), 7.18 (d, J ¼ 8 Hz, 2H). C NMR (d -DMSO,
6
00 MHz) d (ppm) 19.0, 22.6, 30.1, 44.7, 44.8, 127.6, 129.4, 139.0,
40.0, 176.0.
2
-Acetoxybenzoic Acid (7)
1
H NMR (d -DMSO, 400 MHz) d (ppm) 2.23 (s, 3H), 7.19 (d, J ¼ 8 Hz,
6
1
3
1
H), 7.38 (t, 1H), 7.63 (dt, 1H), 7.93 (d, J ¼ 6.8 Hz, 1H). C NMR
(d -DMSO, 100 MHz) d (ppm) 21.3, 124.2, 124.5, 126.5, 131.9, 134.2,
6
1
50.7, 166.1, 169.
(2S, 6aS)-10-Hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-
1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10, 11,12,12a,12b,13,14b-icosahy
dropicene-2-carboxylic Acid (16)
1
H NMR (d -DMSO, 400 MHz) d (ppm) 0.70 (d, J ¼ 11.2 Hz, 1H), 0.81
6
(s, 3H), 0.84 (s, 3H), 1.01 (s, 3H), 1.13 (s, 3H), 1.14 (s, 3H), 1.23 (s, 3H),
.37 (s, 3H), 0.96–1.05 (m, 3H), 1.17–1.27 (m, 1H), 1.32–1.46 (m, 5H),
1

Demethylation with Microwaves
3469
1
.59–1.66 (m, 5H), 1.83–2.04 (m, 4H), 2.16 (dd, J ¼ 3.6 Hz, J ¼ 9.2 Hz,
1
2
1
H), 2.35 (s, 1H), 2.79 (dt, J ¼ 13.2 Hz, 1H), 3.23 (m, 1H), 5.71 (s, 1H).
1
3
C NMR (d -DMSO, 100 MHz) d (ppm) 15.6, 16.4, 17.5, 18.7, 23.4,
6
2
4
6.4, 26.5, 27.2, 28.1, 28.5, 28.6, 30.9, 31.9, 32.8, 37.1, 37.7, 39.1, 40.9,
3.2, 43.8, 45.5, 48.3, 54.9, 61.8, 78.9, 128.5, 169.5, 181.7, 200.5.
(
R)-2-Amino-3-(1H-indol-3-yl)propanoic Acid (12)
1
H NMR (d -DMSO, 400 MHz) d (ppm) 2.98 (m, 1H), 3.29 (d,
6
J ¼ 14.8 Hz, 1H), 3.56 (m, 1H), 6.98 (t, 1H), 7.08 (t, 1H), 7.17 (s, 1H),
1
3
7
(
.33 (d, J ¼ 8 Hz, 1H), 7.61 (d, J ¼ 8 Hz, 1H), 10.94 (s, 1H). C NMR
d -DMSO, 100 MHz) d (ppm) 27.0, 54.9, 108.7, 111.9, 118.9, 119.2,
6
1
21.8, 124.6, 127.3, 136.5, 172.1.
(
R)-2-Phenoxypropanoic Acid (15)
1
H NMR (d -DMSO, 400 MHz) d (ppm) 1.67 (d, J ¼ 6.8 Hz, 3H), 4.81
6
(
q, J ¼ 6.8 Hz, 1H), 6.90 (d, J ¼ 7.6 Hz, 2H), 7.00 (t, J ¼ 7.6 Hz, 1H),
1
3
7
.27 (m, 2H). C NMR (d -DMSO, 100 MHz) d (ppm) 18.4, 72.0,
6
1
15.2, 121.9, 129.7, 157.2, 178.4.
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