An efficient FeCl3-promoted O-alkyl cleavage of esters to carboxylic acids

Article abstract of DOI:10.1002/aoc.1784

A reliable and practical procedure for FeCl₃-promoted ester cleavage has been developed. Lewis acids including TiCl₄, ZnO and FeCl₃ etc. were investigated as promoters for O-alkyl cleavage of carboxylic acid ester. Under optimal reaction conditions, FeCl₃ (1.5 equiv.) was found to possess the highest activity and efficiently enhanced dealkylation of aryl esters, alkyl esters and aromatic heterocyclic esters to give their corresponding carboxylic acids in 54-98% yield, the method provides a complementary access to dealkylation of ester under neutral condition.

Full text of DOI:10.1002/aoc.1784

Full Paper
Received: 29 November 2010
Revised: 18 December 2010
Accepted: 18 February 2011
Published online in Wiley Online Library: 20 April 2011
(wileyonlinelibrary.com) DOI 10.1002/aoc.1784
An efficient FeCl3-promoted O-alkyl cleavage
of esters to carboxylic acids
Xiaoyan Lian, Shaomin Fu, Tongmei Ma, Shunbin Li and Wei Zeng∗
A reliable and practical procedure for FeCl3-promoted ester cleavage has been developed. Lewis acids including TiCl4, ZnO
and FeCl3 etc. were investigated as promoters for O-alkyl cleavage of carboxylic acid ester. Under optimal reaction conditions,
FeCl3 (1.5 equiv.) was found to possess the highest activity and efficiently enhanced dealkylation of aryl esters, alkyl esters and
aromaticheterocyclicesterstogivetheircorrespondingcarboxylicacidsin54–98%yield,themethodprovidesacomplementary
c
access to dealkylation of ester under neutral condition. Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: ferric chloride; O-alkyl cleavage; carboxylic acid ester
Introduction
point was measured on Bu¨chi Melting Point B-545 and are uncor-
rected. Infrared spectra (IR) were recorded on a Brucker Tensor
27 FTIR spectrophotometer in the range of 4000–400 cm−1, and
are reported as wavelength numbers (cm−1). Infrared spectra
were recorded by preparing a KBr pellet containing the title com-
pound. 1H NMR spectra were recorded with tetramethylsilane
as internal standard at ambient temperature unless otherwise
indicated, on a Bruker Avance DPX 400 Fourier transform spec-
trometeroperatingat400or600 MHz. Chemicalshiftsarereported
in parts per million (ppm) and coupling constants are reported
as Hertz (Hz). Splitting patterns are designated as singlet (s),
broad singlet (bs), doublet (d) or triplet (t). Splitting patterns that
could not be interpreted or easily visualized are designated as
multiplet (m). Low-resolution mass spectra were recorded using
a Waters HPLC/ZQ4000 mass spectrometer, and low-molecular-
weight chlorohydrocarbons were detected by a Shimadzu GCMS-
QP5050A gas chromatograph mass spectrometer.
The protection and de-protection of carboxylic acids is a widely
used transformation in highly selective organic synthesis.[1,2] Most
moderately stable carboxylic acid esters can be used to protect
carboxylic acids since they can be hydrolyzed using various meth-
ods. Traditionally, the cleavage of carboxylic acid esters to afford
the corresponding acids is carried out in aqueous acid or base;[3–5]
however, many substrates containing either acid or base labile
groupslimitthisapproach, sosomeefficientneutralreagents, such
as NaHTe, Na2Te and Na2Te2,[6] Dowex-50,[7] NaHSe,[8] PhSH/KF,[9]
Al2O3/KF,[10] I2/Me3SiSiMe3,[11] AlCl3.6H2O/KI/CH3CN/H2O
[12]
and Ln(II) or Sc(III) complexes,[13] have been developed for ester
cleavage under mild conditions. Even so, considering that a single
reagent cannot catalyze hydrolysis efficiently for various kinds of
esters, further search for a universal catalyst for O-alkyl cleavage of
ester is necessary. Recently, we found that TiCl4 could efficiently
enhance the direct N-acylation of sulfonamide using carboxylic
esters as acylating agents, and further studies on the reaction
mechanism indicated that carboxylic esters were first transformed
to their corresponding acids via O-alkyl cleavage and then
condensed with sulfonamide to form N-acylated sulfonamide.[14]
Therefore, we present an alternative ester cleavage method using
Lewis acids as promoters under mild conditions.
General Experimental Procedure for FeCl3-promoted Ester
Cleavage
Carboxylic acid ester (1 mmol), Lewis acid (1.5 equiv.) and
solvent (2.5 ml) were combined in a pressure tube equipped
with a stir bar under Ar atmosphere. The mixture was stirred
at given temperature for 24 h (see Table 1) until nearly all the
carboxylic acid ester had disappeared (monitored by thin-layer
chromatography). The reaction mixture was cooled down, diluted
with 10 ml of H2O, and acidified with 3 N of aqueous HCl to
pH 4–6. The corresponding mixture was extracted with ethyl
acetate (3 × 10 ml), and the combined organic layers were dried
over anhydrous Na2SO4; then the solvent was evaporated in
Experimental
Materials and Techniques
All reactions were carried out in an oven-dried sealed tube with
stirring under an Ar atmosphere. Dioxane, THF and toluene were
distilled after being dried with Na; DMF and DMSO were used
after being dried with CaH2; CCl4, 1,1,2,2-tetrachloroethane (TCE),
CH2Cl2 andacetonitrilewereusedafterbeingdriedwithmolecular
sieves. All other commericially available reagents were purchased
from Across or TCI and used directly. Purification of reaction
products was carried out by flash chromatography using Qing-
dao Haiyang Chemical Co. Ltd silica gel (40–63 mm). The melting
∗
Correspondence to: Wei Zeng, School of Chemistry and Chemical Engineering,
South China University of Technology, 381 Wushan Road, Guangzhou 510640,
People’s Republic of China. E-mail: zengwei@scut.edu.cn
School of Chemistry and Chemical Engineering, South China University of
Technology,381WushanRoad,Guangzhou510640,People’sRepublicofChina
c
Appl. Organometal. Chem. 2011, 25, 443–447
Copyright ꢀ 2011 John Wiley & Sons, Ltd.

X. Lian et al.
O
O
Table 1. Lewis acid screening for O-alkyl cleavage of ethyl benzoatea
H2
C
Lewis acids (1.5 equiv.)
Cl2CHCHCl2, 115 °C, 24 h
O
CH3
OH
Entry
Lewis acid
Temperature (◦C)
Yield (%)b
1b
2a
1
2
AlCl3
ZnO
115
115
115
115
115
115
115
115
115
115
115
115
115
29
14
Scheme 1. Lewis acid screening for O-alkyl cleavage of ethyl benzoate.
3
TiCl4
71
4
FeCl3
88
5
Co(OAc)2.4H2O
Cu(OAc)2.2H2O
Fe2O3
No reaction
No reaction
No reaction
No reaction
No reaction
No reaction
No reaction
18
ratio. Initially, the ester cleavage of readily available ethyl ben-
zoate 1b (1 mmol) was carried out in TCE (2.5 ml) using different
kinds of Lewis acid (1.5 equiv., 1.5 mmol), such as Cu(OAC)2 and
FeCl3, etc. (Scheme 1) at 115 ◦C for 24 h in a sealed tube under
an Ar atmosphere (Table 1). Gratifyingly, we quickly found that
FeCl3 possesses the highest activity and could efficiently promote
O-alkyl cleavage of ester (1b) to form the corresponding acid
in 88% yield (Table 1, entry 4), and basically other Lewis acid
promoters produced poor results except for TiCl4 (Table 1, en-
try 3).
We further investigated other reaction conditions to define the
reaction parameters (Scheme 1, Table 2). To find the best solvent,
the dealkylation of ethyl benzoate (1b) was carried out for 24 h in
different solvents such as THF and methylene chloride. We found
that the nonpolar solvent CCl4 or Cl2CHCHCl2 was superior to
polar solvent THF or DMSO (Table 2, entries 1, 2, 9 and 10). It is
worthy of note that the FeCl3/H2O (1.5/1.0 equiv.) system inhibited
the O-alkyl cleavage of ethyl benzoate to some extent, and the
dealkylation using concentrated HCl (37 wt%/H2O, 0.20 g) instead
of FeCl3 as promoter provided only a very low yield of benzoic acid
(Table 2, entry 10).
6
7
8
ZnCl2
9
CdCl2
10
11
12
13
MnCl2
NiCl2
ZrCl4
FeCl2
33
a Reaction conditions: ethyl benzoate, 1 mmol; TCE, 2.5 ml; Lewis acid
promoter, 1.5 equiv. The reaction was carried out at 115 ◦C for 24 h in
a sealed tube. b Isolated yield after purification.
vacuo and the crude compound was purified by flash column
chromatography (silica gel, petroleum/ethyl acetate) to afford
the corresponding carboxylic acid. All the products are known
compounds and were identified using 1H NMR, LRMS, IR and
melt point by comparison with previously reported data (see
Supporting Information).
Based on the above-mentioned positive results, we further
investigated the effect of the amount of Lewis acid, reaction
temperatureandreactiontimeonthetransformation.Dealkylation
of ethyl benzoate in CCl4 at 85 ◦C provided the desired carboxylic
acid in up to 92% yield (Table 2, entry 10). Shortening the
reaction time (from 24 to 18 h) decreased the yield from 92
Optimization of Reaction Conditions for FeCl3-promoted
O-alkyl Cleavage of Ethyl Benzoate
Optimal conditions for dealkylation of esters were first determined
by systematically investigating Lewis acid promoters, reaction sol-
vents, reaction time, reaction temperature and catalyst/substrate
Table 2. Optimization of reaction conditions for FeCl3-promoted O-alkyl cleavage of ethyl benzoatea
Entry
Reaction time (h)
Temperature (◦C)
Solvent
Equivalents (FeCl3)
Yield (%)b
1
2
24
24
24
24
24
24
24
24
24
24
24
24
18
36
48
24
24
24
110
110
110
110
115
85
THF
DMSO
1,4-Dioxane
DMF
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
0.5
1.0
2.5
15
7
3
Trace
4
Trace
5
Toluene
Acetonitrile
CH2Cl2
Chlorobenzene
TCEc
Decomposition
6
No reaction
7
45
No reaction
8
135
115
85
65
9
88
10
11
12
13
14
15
16
17
18
CCl4
92 (72d, 10e)
80
CCl4
67
86
78
93
74
10
76
91
90
CCl4
85
CCl4
85
CCl4
85
CCl4
85
CCl4
85
CCl4
85
CCl4
a Reaction conditions: ethyl benzoate, 1 mmol; solvent, 2.5 ml. The reaction was carried out at the given temperature in a sealed tube. b Isolated yield
after purification. c TCE: 1,1,2,2-tetrachloroethane. d One equivalent of H2O (1 mmol) was added. e 0.2 g of conc. HCl (37 wt%/H2O) was used as the
promoter instead of FeCl3.
c
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Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2011, 25, 443–447

Efficient FeCl3-promoted O-alkyl cleavage of esters
quantitative yieldsofchlorohydrocarbon. Analysisoftheefficiency
with which our substrates are tested indicated that steric
and electronic effects govern the dealkylated system to some
extent.
FeCl3 (1.5 equiv.)
R1COOR2
R1COOH
+
R2Cl
solvent/ 24 h
1
2
3
Scheme 2. FeCl3 -promoted dealkylation of carboxylic ester.
Increasingthesterichindranceofalkoxy(-OR2)ledtoamoderate
decrease in product yield (Table 3, entries 2–4). Electronic effects
also play a key role in this reaction system: compared with the
results from dealkylation of the ester with an electronic-donating
group (Table 3, entries 9–11), the ester with an electronic-
withdrawing group on aromatic ring led to improved product
yield (Table 3, entries 6–8).
Clearly, FeCl3 could also promote efficiently O-cleavage of
alkyl carboxylic ester to give the corresponding acid with
good yield (Table 3, entries 12, 13 and 16), but for furan-2-
carboxylic acid ethyl ester (1n) and pyridine-2-carboxylic acid
ethyl ester (1o), a higher reaction temperature in excess of
115 ◦C is necessary to achieve good yield (Table 3, entries 14
and 15).
to 78%; in addition, a longer reaction time (48 h) or higher
reaction temperature (90 ◦C) led to tedious workup and lower
yields (Table 2, entries 12 and 15). Increasing the amount of
promoter loading from 1.0 to 1.5 equiv. resulted in higher
conversions and yields (from 76 to 92%; Table 2, entries 10,
16 and 17). On the other hand, a Lewis acid loading of 2.5
equiv. did not bring improved yields (see Table 2, entries 10
and 18).
Results and Discussion
Under optimized reaction conditions, a variety of substrates
were surveyed to explore the scope of the reaction. The re-
sults (Scheme 2, Table 3) showed that all the esters of aryl
carboxylic acid, alkyl carboxylic acid and aromatic hetero-
cyclic carboxylic acid underwent clean O-cleavage to give the
corresponding carboxylic acids in good to excellent yields
(54–98%). We made no attempt to isolate the low-boiling-point
chlorohydrocarbon co-product 3 listed in Scheme 2, although
GC-MS analyses of the reaction mixture indicated essentially
The possible mechanism about this transformation is that
carboxylic acid ester (4) and Fe (III) first form an adduct
(5), then a Cl− from the Fe-complexes (5) attack the adja-
[15]
cent carbon atom of alkoxy group via SN2 dealkylation,
and result to the formation of R1COO− (6) and R2CH2Cl
(7) (see Scheme 3), then the protonation of R1COO− in the
workup stage afford the corresponding carboxylic acid. The
formation of the desired 6-chrolo-hexanoic acid (2m) from
dealkylation of oxepan-2-one (1p) under Ar atmosphere fur-
Table 3. FeCl3-promoted O-alkyl cleavage of ester to carboxylic acida
Entry
1
Carboxylic ester
Solvent
CCl4
Temperature (◦C)
85
Product
Yield (%)b
80
O
O
CH3
O
OH
2a
1a
2
3
4
5
CCl4
CCl4
CCl4
CCl4
85
85
85
85
93
78
O
O
Et
O
OH
2a
1b
O
O
iPr
O
OH
2a
1c
75
O
O
tBu
O
OH
2a
1d
85c
O
O
O
nBu
O
OH
O
OH
nBu
1e
2b
O
6
7
CCl4
CCl4
85
85
98
92
O
O
OEt
OEt
OH
OH
1f
2c
Cl
Br
Cl
Br
O
O
1g
2d
c
Appl. Organometal. Chem. 2011, 25, 443–447
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
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X. Lian et al.
Table 3. (Continued)
Entry
8
Carboxylic ester
Solvent
CCl4
Temperature (◦C)
85
Product
Yield (%)b
96
O
O
OEt
OH
1h
2e
O N
2
O N
2
9
10
11
CCl4
TCE e
CCl4
85
115
85
82
80
77
O
O
OEt
OH
1i
2f
Me
Me
O
O
OEt
OH
1j
2g
MeO
Me
MeO
Me
O
O
OEt
OH
N
N
1k
2h
Me
Me
12
CCl4
85
88c
O
6
O
6
O
O
OH
2i
OEt
1l
EtO
HO
13
14
TCE
TCE
115
115
70d
54
OH
OEt
O
O
1m
2j
OEt
OH
O
O
1n
2k
O
O
15
16
TCE
TCE
150
85
75
92
COOEt
1o
COOH
2l
N
O
N
HO2C
Cl
2m
O
1p
a Reaction conditions: the reaction was performed using carboxylic acid ester (1, 1.0 mmol) and FeCl3 (1.5 equiv.) in 2.5 ml of solvent (CCl4 or TCE) at
the given temperature for 24 h in a sealed tube under an Ar atmosphere. b Isolated yields, average of two runs, and their standard deviations ≤3.
c Addition of 3.0 equiv FeCl3. d Use of 1.5 equiv. TiCl4. e TCE, 1, 1, 2, 2 - tetrachloroethane.
Cl
Cl
O
O
Fe Cl
O
-Fe(III)
-
+
R1
O
+
Cl
R2
FeCl3
O
R1
R2
O
R1
R2
4
5
6
7
Scheme 3. The possible reaction mechanism for FeCl3-promoted O-alkyl cleavage of ester.
ther identified this reasonable reaction pathway (Table 3, en-
try 16).
Supporting information
Supporting information may be found in the online version of this
article.
Conclusion
In summary, a reliable and practical procedure for FeCl3-promoted
ester cleavage has been developed; the substrates including aryl
ester, alkyl carboxylic ester and aromatic heterocyclic ester were
easily cleavaged to corresponding acids with good to excellent
yields. Thus, the method provides a complementary means of
dealkylation of ester under neutral conditions.
Acknowledgments
The financial support for this work from the NSFC of China (no.
21072063), the Program for New Century Excellent Talents in
University by the Ministry of Education (no. NCET-10-0371), the
Fundamental Research Funds for the Central Universities (no.
c
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Efficient FeCl3-promoted O-alkyl cleavage of esters
2009ZM0262)andtheScientificResearchFoundationforReturned
Overseas Chinese Scholars, State Education Ministry (no. 2010-
1174) are gratefully acknowledged.
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Appl. Organometal. Chem. 2011, 25, 443–447
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