FeCl3/pyridine: Dual-activation in opening of epoxide with carboxylic acid under solvent free condition

Article abstract of DOI:10.1016/j.tetlet.2013.08.074

Inexpensive, non-toxic, and readily available catalyst system FeCl ₃/pyridine was found to be highly efficient for the opening of a wide variety of epoxides with carboxylic acid under solvent free conditions.

Full text of DOI:10.1016/j.tetlet.2013.08.074

Tetrahedron Letters xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
FeCl3/pyridine: dual-activation in opening of epoxide with carboxylic
acid under solvent free condition
Yichao Zhao a, Wen Wang a, Jian Li a, Feng Wang a, Xiufang Zheng b, Hongying Yun b, Weili Zhao a,
Xiaochun Dong a,
⇑
a School of Pharmacy, Fudan University, Shanghai 201203, PR China
b Roche Pharma Research and Early Development China, Shanghai 201203, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Inexpensive, non-toxic, and readily available catalyst system FeCl3/pyridine was found to be highly effi-
cient for the opening of a wide variety of epoxides with carboxylic acid under solvent free conditions.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 16 May 2013
Revised 31 July 2013
Accepted 20 August 2013
Available online xxxx
Keywords:
Dual-activation
FeCl3/pyridine catalyst
Epoxides
Acetyl migration
Neat reaction
Introduction
in a protic solvent. Epoxides are significantly more reactive than
other ethers because of the strain induced by a three-membered
To mimic enzymatic processes in nature involving metal-ion co-
catalysts, acid–base dual-activation enabling cooperative activa-
tion of both reaction partners1 has received much attention for
highly efficient nucleophilic reactions under mild conditions. Three
general strategies of dual activation2 include: (1) a catalytic system
composed of two separate catalysts; (2) one molecule containing
two separate catalytic moieties as a bifunctional catalyst; (3) one
catalyst activates electrophiles (or nucleophiles) and the generated
reactive species can further activate nucleophiles (or electro-
philes). We are more interested in the acid–base combination
strategy (strategy 1). However, acid–base bifunctional catalysts
are challenging to achieve because of the potential neutralization
of each other to lose activity.
b-Hydroxy esters are useful intermediates for the total synthe-
sis of natural products because of their easily removable protecting
groups,3,4 and particularly for carbohydrates and steroid chemis-
try.5,6 Furthermore, 1,2-diol mono-esters are also useful in the
manufacture of pharmaceutical intermediates and fragrances.7,8
One well-recognized synthesis of b-hydroxy esters is the regiose-
lective ring opening of epoxides with carboxylic acids. The classical
approach for this preparation uses excess amount of carboxylic
acid to react with epoxide under heating in the presence of catalyst
ring (having a high thermodynamic driving force, usually greater
than 20 kcal/mol).9 Metal salts often act as catalysts to activate
epoxides rendering them more susceptible to nucleophilic attack
under milder conditions.10 Several Lewis acids were reported to
activate the epoxides so as to increase their susceptibility to nucle-
ophilic attack by carboxylic acids.11 Various catalytic systems for
the opening of epoxide reported include heterogenous catalytic
systems,12a–h organic molecules (hexafluoro-2-propanol12i and
tributylphosphine12j), water,12k and ionic liquids.12l
Ring opening of epoxides with carboxylic acid can afford a less
costly and appealing route to 1,2-diol mono-esters.13 However, the
methodologies reported often encounter disadvantages such as long
reaction time, high temperature, moderate yield, low conversion,
costly reagents/catalysts, and high catalyst loading. Furthermore,
most of the ring opening reactions have been performed in harmful
organic solvents such as THF, MeOH, MeCN, CH2Cl2, or benzene.14
We are interested in the green reaction of opening of epoxide
with carboxylic acid. Herein, we report a facile FeCl3/pyridine cat-
alyzed epoxide opening reaction with carboxylic acid under sol-
vent free condition.
Results and discussion
For the model reaction, we selected epichlorohydrin (1a) and
HOAc (2a) as reactants (Scheme 1).
⇑
Corresponding author. Tel.: +86 21 51980123.
E-mail address: xcdong@fudan.edu.cn (X. Dong).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.074
Please cite this article in press as: Zhao, Y.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.08.074

2
Y. Zhao et al. / Tetrahedron Letters xxx (2013) xxx–xxx
Table 2
OH
Cl
O
O
O
O
cat.
Optimization of reaction conditions for ring opening of epichlorohydrin with acetic
acid under solvent free conditiona
O
Cl
OH
Cl
O
heat
OH
Entry FeCl3/
pyridine
T (°C)
Time
(h)
Conversionb
(%)
Regioisomeric
1a
2a
3a
4a
ratio (3a:4a)b
(mol %)
Scheme 1. Ring opening of epichlorohydrin with acetic acid.
1
0.5/0.5
0.5/0.5
0.5/0.5
0.5/0.5
0.05/0.05
0.125/0.125
0.5/0.5
0.5/0.5
1.0/0.25
1.0/0.5
1.0/0.5
1.0/1.0
2.0/0
1.25/1.25
1.25/1.25
2.5/2.5
40
17
89
14.2
6.0
6.1
2c
3
40 + 80 17 + 12 100
60 17 100
60 + 80 17 + 12 100
4c
5
6
7
8
6.0
40
40
40
40
40
40
40
40
40
40
40
40
40
50
50
50
50
50
50
24
24
12
46
12
12
20
12
12
12
24
12
36
24
24
12
12
12
12
19
38
55
96
89
92
96
83
86
91
98
94
99
77
94
94
94
99
99
20.0
18.0
15.0
8
11.6
10.9
7.8
Table 1
Screening of catalysts for ring opening of epichloro-hydrinwith acetic acid under
solvent free conditions
Entry Catalyst
Substrate ratio Conversionc
Regioisomeric
9
(1a:2a)
(%)
ratio (3a:4a)c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
1a
2a
3a
4a
5a
6a
7a
8a
9a
10b
LiClO4
MgBr2
LiCl
CeCl3
Ca(OTf)2
Pyridine
FeCl3
Fe(TFA)3
Fe(O2CC5H12
FeCl3/
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1.05:1
18
7.5
6.6
7.0
8.0
6.6
7.7
8.5
10.8
5.9
5.5
9.4
42
25
13
27
60
80
93
81
97
11.3
11.0
8.5
10.0
6.7
7.0
7.7
11.0
11.4
8.2
2.5/2.5
0.25/0.25
0.375/0.375
0.5/0.5
1.0/0.25
1.0/0.5
)
3
pyridine
FeCl3/
pyridine
FeCl3/
11b
12b
1:1
100
99
5.3
5.6
1.25/1.25
7.6
1:1.05
a
Reactions were carried out by employing 50.0 mmol epichlorohydrin and
pyridine
52.5 mmol acetic acid under solvent free condition.
b
a
Determined by GC.
Acetic acid (50.0 mmol) was treated with epichlorohydrin (50.0 mmol) in the
presence of catalysts (1.0 mol %) at 60 °C under solvent free condition for 12 h.
c
Continuation of the previous reaction, that is, next 12 h at 80 °C after 17 h at
b
40 °C.
Reactions were carried out by employing 50.0 mmol substrate as 1 equiv in the
presence of FeCl3/pyridine (0.5 mol %/0.5 mol %) at 60 °C in absence of solvent for
12 h.
c
Determined by GC and 1H NMR.
O
OH
Cl
O
O
O
cat.
O
Cl
O
OH
2a
heat
ClH
O
OH
Various common catalysts were screened (Table 1). While Lith-
ium, Magnesium, Cerium, and Calcium salts (Table 1, entries 1–5)
exhibit low catalytic capability, pyridine was found to have modest
efficiency (Table 1, entry 6). Various Ferric salts were identified to
possess higher catalytic efficiency (Table 1, entries 7–9). However,
Fe(TFA)3 was observed to generate more impurities judged by GC
3a
4a
1a
Cl
O
OH
and 1H NMR. FeCl3 and Fe(O2CC5H12 3
) were found to give almost
Scheme 2. Acetyl migration during opening of epoxide rings with acetic acid.
identical conversion and relatively clean product. FeCl3 was also
identified to provide better selectivity, and was selected for further
optimizations.
the regioselective nucleophilic attack of HOAc to the less hindered
side to generate 3a in good selectivity. At an elevated temperature,
more regioisomer 4a was generated not only from the increased
nucleophilic attack to the more hindered side, but also from the
acetyl migration from the initially formed 3a through a five-mem-
bered ring transition state and then reached a balance at a certain
ratio. The acetyl migration might be promoted by pyridine.15
For further optimizations, reactions with various catalysts ratio/
loading were carried out as well. As a general trend, with increased
catalytic loading, enhanced conversion with sacrifice of selectivity
was noticed. When the reactions were carried out at 40 °C under
low catalytic loading (<1 mol %), long reaction time was required
to reach good conversion (Table 2, entries 5–8). Higher catalyst
loading (Table 2, entries 9–17) led to improved conversion (Table 2,
entries 15 and 17). At 50 °C the reaction rate was significantly in-
creased (Table 2, entries 18–23). Complete conversion was accom-
plished within 12 h (Table 2, entries 22 and 23). The best
conversions identified were: 1.0 equiv of epoxide to react with
1.05 equiv of HOAc in the presence of FeCl3/pyridine (1 mol %/
0.5 mol %) at 50 °C for 12 h (Table 2, entry 22).
Under various conditions, FeCl3 alone could not drive to full
conversion even under prolonged reaction time and elevated tem-
perature with conversion at most to 80%.10h With the knowledge
that pyridine shows a modest catalytic activity, we expected that
the FeCl3/pyridine combination would be ideal partners to act as
acid–base dual-activation catalysts because either one is effective
and tolerable to each other. To our delight, FeCl3/pyridine effi-
ciently catalyzed the opening of epoxide and complete conversion
could be reached (Table 1, entries 10–12) in model reaction.
During the initial screening, it was observed that regioselectiv-
ity was affected by the ratio of the reactants (Table 1, entries 10–
12). Significant efforts for optimization were taken and the results
are summarized in Table 2. It was discovered that lower reaction
temperature, for example, 40 °C for 17 h provided improved selec-
tivity (14.2) with 89% conversion (Table 2, entry 1). Under elevated
temperature, full conversion could be reached, however the selec-
tivity dropped to 6 (Table 2, entries 2–4).
The diminished selectivity from 14.2 in 89% conversion at 40 °C
to 6.0 in full conversion with continuous heating at an elevated
temperature (80 °C) suggested that acetyl transfer process oc-
curred during the reaction (Scheme 2). Low temperature favors
With the optimized conditions in hand, the scope of this reac-
tion was further explored with a range of epoxides and carboxylic
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Y. Zhao et al. / Tetrahedron Letters xxx (2013) xxx–xxx
3
Table 3
O
O
FeCl3/Pyridine
O
Reaction of carboxylic acid with epoxide in the presence of FeCl3/pyridinea
+
CH3CHOOH
Cl
O
Cl
TsOH
FeCl3/Pyridine
O
OH
O
R2
1a
2a
3a
(1.0mol%/0.5mol%)
O
R2
+
R1COOH
+
R1
R1
O
O
50oC, neat,12h
O
R2
OH
OH
O
OH
1
2
4
O
3
O
Cl
NaOH
TsO H
H2O
O
H2O
O
O
Entry Epoxide
Carboxylic
acid
Conversionb
(%)
Regioisomeric
O
ratio (3:4)b
5
6
7
O
O
O
DMSO, P2O5, NEt3
CH2Cl2
1
2
100
100
7.5
4.1
Cl
Cl
Cl
OH
O
O
O
O
8
OH
Scheme 4. Synthesis of oxetan-3-ol in pilot plant.
O
3
4
100
100
7.1
OH
O
O
regioselectivity (Table 3, entries 4–10). The region selectivity was
observed to be enhanced with more hindered epoxide substrates
(Table 3, entries 5–8, 10).
Cl
14.2
OH
The dual-activation of FeCl3/pyridine in catalyzing the ring
opening of epoxides with carboxylic acid may follow catalytic cy-
cles presented in Scheme 3. Coordination of Fe3+ with the epoxide
oxygen renders the epoxide susceptible to the nucleophilic attack.
Pyridine deprotonates carboxylic acid to generate the anion, which
attacks the above activated epoxide leading to TS-I. After protonol-
ysis, b-hydroxy ester can be formed and the catalysts are liberated.
This methodology has been applied successfully in the scale-up
preparation of oxetan-3-one. Oxetane-containing heterocycles
have attracted increased attention in pharmaceutical industry be-
cause of their uniqueness in the generation of IP space, as well as
adjustment of physical properties, for example, solubility, perme-
ability, and safety related properties.16 The epoxide opening reac-
tion of epichlorohydrin (1a) with acetic acid (2a) catalyzed by
FeCl3/pyridine under solvent free condition was operated in large
scale. The obtained crude 3-chloro-2-hydroxypropyl acetate (3a)
was directly treated with ethyl vinyl ether catalyzed by toluenesul-
fonic acid to generate 3-chloro-2-(1-ethoxyethoxy) propyl acetate
(5). Without purification, this crude ester 5 was hydrolyzed by so-
dium hydroxide and immediate cyclization occurred to provide 3-
(1-ethoxyethoxy)oxetane (6) which was separated from the reac-
tion mixture by steam distillation. 3-(1-ethoxyethoxy)oxetane (6)
was hydrolyzed in water in the presence of a catalytic amount of
toluenesulfonic acid to afford oxetan-3-ol (7). The oxetan-3-ol
was prepared in 100 kg scale with two consecutive neat reactions
and two hydrolyzation/cyclization processes in water. The overall
O
O
O
O
O
O
O
5
100
100
100
100
100
100
5.0
>25
>25
>25
16.5
>25
OH
OH
OH
OH
OH
OH
O
O
O
O
O
O
6
7
(CH2)9CH3
8
Ph
Br
9
10
a
Reactions were carried out by employing 25.0 mmol epichlorohydrin and
26.25 mmol carboxylic acid under solvent free condition.
b
Determined by GC.
acids (Table 3). In all the circumstances, full conversion was
reached. Sterically hindered 2-ethylbutanoic acid provided the best
FeCl3
O
O
O
+
+
O
N
N
H
R1
OH
R1
O
R2
R2
O
FeCl3
Cl3Fe
O
O
R1
R2
TS-I
O
HO
R2
O
R1
Scheme 3. Proposed reaction mechanism.
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4
Y. Zhao et al. / Tetrahedron Letters xxx (2013) xxx–xxx
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In summary, we communicate here a FeCl3/pyridine catalyzed
epoxide opening reaction with carboxylic acid under solvent free
condition. Complete conversion was achieved with neat reactants
and catalytic amount of FeCl3/pyridine. Acetyl migration was ob-
served during the reaction. Such a reaction was successfully ap-
plied in the green preparation of oxetan-3-ol in good overall
yield in large scale. Such dual activation catalytic system provides
high efficiency and easy manipulation, possibly resulting in a supe-
rior process for the chemical and pharmaceutical industries.
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This work was supported by Shanghai Municipal Natural Sci-
ence Foundation (12ZR1403300), Shanghai Municipal Science &
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Technology
Pillar
Program
for
Bio-Pharmaceuticals
(13431900102). The authors are also grateful to the financial sup-
ports from Roche Pharma Research and Early Development China.
Supplementary data
Supplementary data associated with this articlecan be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.08.
074.
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Please cite this article in press as: Zhao, Y.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.08.074