Highly efficient ring opening reactions of epoxides with deactivated aromatic amines catalyzed by heteropoly acids in water

Article abstract of DOI:10.1016/j.tet.2006.11.045

Heteropoly acid was found to be an effective and efficient catalyst for the ring opening reaction of epoxides with various aromatic amines to produce the corresponding β-amino alcohols in moderate to excellent yields in water. This method provides a new and efficient protocol in terms of mild reaction conditions, clean reaction profiles, small quantity of catalyst, and simple work-up procedure.

Full text of DOI:10.1016/j.tet.2006.11.045

Tetrahedron 63 (2007) 888–891
Highly efficient ring opening reactions of epoxides with
deactivated aromatic amines catalyzed by heteropoly
acids in water
Najmedin Azizib and Mohammad R. Saidia,
*
aDepartment of Chemistry, Sharif University of Technology, PO Box 11365-9516, Tehran, Iran
bChemistry and Chemical Engineering Research Center of Iran, PO Box 14335-186, Tehran, Iran
Received 16 August 2006; revised 30 October 2006; accepted 16 November 2006
Available online 11 December 2006
Abstract—Heteropoly acid was found to be an effective and efficient catalyst for the ring opening reaction of epoxides with various aromatic
amines to produce the corresponding b-amino alcohols in moderate to excellent yields in water. This method provides a new and efficient
protocol in terms of mild reaction conditions, clean reaction profiles, small quantity of catalyst, and simple work-up procedure.
Ó 2006 Published by Elsevier Ltd.
1. Introduction
2. Results and discussion
It is highly desirable to carry out organic reactions in water
from an environmental perspective.1 On the other hand,
heteropoly acids (HPAs) such as tungstophosphoric acid and
molybdatophosphoric acid are environment-friendly and
economically feasible solid acids due to several advantages
such as high catalytic activities and reactivities, ease of
handling, cleaner reactions in comparison to conventional
catalysts (less waste production), non-toxicity and experi-
mental simplicity.2 Therefore, organic reactions in water,
using a very small quantity of heteropoly acid catalysts will
be an ideal methodology, providing that the catalysts show
high catalytic activity.
As a part of our research to develop green chemistry by using
water as reaction medium7 or by performing organic trans-
formations under solvent-free conditions,8 we recently have
shown that aliphatic epoxides react with aliphatic amines in
water with moderate to high yields and good regioselectivity,
without using any catalysts or organic solvents.9 However,
the reactions of aromatic amines with the aliphatic epoxides
are very slow in water and give the desired products in low
yields. Herein we wish to extend this simple procedure to
aromatic amines especially deactivated aromatic amines in
water, which has not been reported previously.
Initially, ring opening of cyclohexene oxide was investigated
with aniline in water and different organic solvents. Cyclo-
hexene oxide was treated with 1 equiv of aniline at room
temperature, and the desired product was obtained in 54%
yield within 48 h in water as the sole solvent. As a prelimi-
nary study, several promoters were screened in the model
reaction of aniline and cyclohexene oxide (Table 1). The
starting materials were stirred in water at room temperature
in the presence of a promoter (Table 1). The best results were
obtained when we used 0.01 mol % of heteropoly acids such
as H3PMo12O40 (Table 1, entry 14) and H3PW12O40 (Table 1,
entry 15) at room temperature for 2 h. Furthermore, we found
that common Lewis acids such as CeCl3, WCl6, ZrCl4 and
LiClO4 also show activity in water (Table 1).
b-Amino alcohols are important organic compounds of
considerable use in medicinal chemistry and as unnatural
amino acids and chiral auxiliaries.3,4 The most practical
and widely used route for synthesizing these compounds is
the direct aminolysis of epoxides at elevated temperature
with excess of amine.5 However, this methodology suffers
from one or more disadvantages such as high temperature,
stoichiometry and moisture sensitive catalyst and hazardous
organic solvents. In addition, almost all procedures for the
preparation of b-amino alcohols reported so far are restricted
to simple aromatic and aliphatic amines and that of
deactivated aromatic amines has not been reported in water
so far.6
With this promising result in hand, we focused our attention
on a study of the scope and limitations of the model reaction
of cyclohexene oxide with other deactivated amines such as
3,4-dichloroaniline.
Keywords: Amino alcohol; Aromatic amine; Epoxide; Heteropoly acid;
Atom economy; Water chemistry.
* Corresponding author. Tel.: +98 21 660 05718; fax: +98 21 660 12983;
e-mail: saidi@sharif.edu
0040–4020/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tet.2006.11.045

N. Azizi, M. R. Saidi / Tetrahedron 63 (2007) 888–891
889
Table 1. Reaction of cyclohexene oxide with anilinea
Table 3. Reaction of cyclohexene oxide with deactivated amines
Ar
NHPh
OH
ArNH2, Water (8 ml), 24 h, rt
H3PW12O40 (0.35 mol %)
PhNH2 (1) Catalyst
O
O
Solvent (2 mL), rt.
OH
6a-g
7a-g
2
3
Entry
1
Aromatic amine
Product
Yield (%)
926b
Entry Catalyst
Mol % Solvent
Time (h) Yield (%)
OH
1
2
—
—
—
—
—
—
—
—
200
30
200
40
50
20
20
Water
CH2Cl2
ClCH2CH2Cl 44
PhCH3
THF
Diethyl ether 44
Water
Water
Water
Water
Water
Water
Water
Water
Water
44
44
48
0
H
N
NH2
3
4
—
—
0
7a
44
44
0
Br
Br
Cl
5
6
—
—
15
10
96
83
80
76
92
86
83
94
93
OH
OH
H
N
NH2
7
LiClO4
24
24
24
24
74
12
24
2
936j
8
9
CeCl3$7H2O
LiCl
ZrCl4
B(OH)3
WCl6
Bi(NO3)3
H3PMo12O40
H3PW12O40
2
7b
Cl
10
11
12
13
14
15
NH2
H
N
3a
356i
O2N
7c
0.1
0.2
O2N
O2N
2
OH
H
N
a
Reaction condition: solvent 2 mL, aniline (2 mmol), cyclohexene oxide
(2 mmol).
O2N
NH2
4a
546j
7d
OH
We optimized the reaction conditions by systematic varia-
tion of solvent and catalyst in the reaction of 2 with 4. The
results are summarized in Table 2.
H
N
7e
NH2
5
426c
OH
H
N
First, we have performed the reaction in organic solvents and
in the presence of a heteropoly acid such as tungstophos-
phoric acid and molybdatophosphoric acid. We have found
that the reaction can also proceed in low-polar solvents
such as toluene and 1,2-dichloroethane. The yield was lower
in MeCN and gave byproduct in solvents such as THF. When
a mixture of water and an organic solvent, such as toluene
and CH3CN, was used the yield of adducts did not improve
considerably, and in some cases lower yields were observed
(Table 2, entries 7–10). We also investigated the effect of
adding a surfactant. Interestingly, addition of cetyltrimethyl-
ammonium bromide (CTAB) was not effective (Table 2,
entry 5), but addition of sodium dodecyl sulfate (SDS)
improved the yield of the reaction (Table 2, entries 3 and 4).
NH2
6
906j
7f
HO
HO
OH
H
N
NH2
7a
34
N
7g
N
a
SDS (0.25 mmol) was added.
Encouraged by the above results we performed the direct
ring opening reaction of cyclohexene oxide with various
deactivated aromatic amines and the successful results are
summarized in Table 3. In the case of amines with
Table 2. Reaction of cyclohexene oxide with a deactivated amine in the presence of promoter in water
NH2
O
H
N
Cl
Cl
Catalysta
+
Solvent, r.t, 24 h
OH
Cl
4
2
5
Cl
Entry
Solventb
Yields (%)
Catalyst
Entry
Solvent
Yields (%)
Catalyst
1
2
3
4
5
6
7
8
Water
Water
Water
Water
Water
Water
Water/CH3CN
Water/CH3CN
PhCH3/water
PhCH3/water
PhCH3/water
Ether/water
84
85
88
92
50
56
40
68
10
22
80
76
A
B
13
14
15
16
17
18
19
20
21
22
23
24
THF
THF
ClCH2CH2Cl
ClCH2CH2Cl
Diethyl ether
PhCH3
PhCH3
MeOH
CH3CN
CH3CN
30
25
85
87
64
84
73
67
40
60
62
76
A
B
A
B
A
A
B
B
A
B
A
B
A+SDS
B+SDS
A+CTAB
B
A
B
A
B
A
B
9
10
11
12
MeOH
EtOH
a
A: H3PMo12O40 (0.55 mol %); B: H3PW12O40 (0.35 mol %).
Solvent used in each reaction: 8 mL. The ratio of water to the other solvent is 9:1 in entries 7 and 8, 5:1 in entries 9 and 10 and 1:10 in entries 11 and 12.
b

890
N. Azizi, M. R. Saidi / Tetrahedron 63 (2007) 888–891
Table 4. Aminolysis of epoxides in water in the presence of heteropoly acida
OH
NHAr
H3PW12O40
O
(0.35 mol %)
+
ArNH2
+
R
R
R
Water, rt, 16 h
9
8
NHAr
Yield (%)
OH
Entry
Epoxide
Aromatic amine
Ratio 8:9b
1
2
3
4
5
6
a R¼H
92
86
84
90
84
80
96:4
92:8
b R¼n-butyl
c R¼isopropyl
d R¼OMe
e X¼Cl
NH2
O
O
93:7
90:10
92:8
R(X)
R(X)
f X¼Br
90:10c
7
8
9
10
11
12
g R¼H
90
80
84
88
80
78
95:5
90:10
91:9
h R¼n-butyl
i R¼isopropyl
j R¼OMe
k X¼Cl
NH2
O
O
88:12
92:8
l X¼Br
90:10b
13
14
15
16
m R¼H
93
80
84
76
96:4
NH2
NH2
n R¼isopropyl
o R¼OMe
p X¼Cl
85:15
84:16
90:10
O
O
R(X)
R(X)
17
18
19
20
q R¼H
r X¼Cl
s R¼H
t X¼Cl
80
76
80
74
85:15
87:13
85:15
82:18
O
O
All products have been previously reported in the literature.6
Ratio was determined by NMR spectroscopy.
SDS (0.2 mmol) was added.
a
b
c
electron-donating groups, such as 4-hydroxyaniline, the cor-
responding amino alcohols were obtained in good to high
yields (Table 3, entry 6). Especially, with a sterically hindered
amine, such as 2,4,6-trimethylaniline, the corresponding
adduct was produced in moderate yield (Table 3, entry 5). Fur-
thermore, amines with anelectron-withdrawinggroup, such as
2-aminopyridine, 4-nitroaniline and 3-nitroaniline, gave the
desired products in moderate yields (Table 3, entries 3, 4, 7).
There are several interesting implications for the use of
heteropoly acids as effective catalysts for the efficient addi-
tion of aromatic amines to cyclohexene oxide in water. The
reaction itself employs an inexpensive, easily accessed
catalyst with low catalyst loading, and it involves a simple
experimental procedure.
In summary, the results summarized here constitute the first
example of a highly efficient and simple protocol for the ring
opening of epoxides catalyzed by HPA, and therefore they
expand the chemistry of these versatile catalyst systems to
an important new reaction class.
Finally, this success has encouraged us to extend the gener-
ality of the reaction to other aliphatic epoxides with various
aromatic amines (Table 4). Aniline, 4-methoxy aniline,
4-chloroaniline, 4-bromoaniline and 4-isopropyl aniline
reacted well with aliphatic epoxide such as glycidyl phenyl
ether, glycidyl isopropyl ether, 1,2-epoxy butane, 1,2-epoxy
propane and allyl 2,3-epoxypropyl ether to give the corre-
sponding amino alcohols in good yields (Table 4).
3. Experimental
3.1. General
The trans stereochemistry of the b-amino alcohols was
determined from the coupling constants of the C–H protons a
to the heteroatoms in the 1H NMR spectra. For example, the
trans stereochemistry of compound 3 was assigned from the
coupling constants of the peaks at 3.12 ppm (ddd, J¼10.6,
9.4, 4.2 Hz, CH–NHPh) and 3.36 ppm (ddd, J¼10.6, 9.5,
4.3 Hz, CH–OH) in the 1H NMR spectrum.
NMR spectra were recorded on a Bruker ACF 500 using
CDCl3/CCl4 or CDCl3/DMSO-d6 as solvent. Column chro-
matography was performed on silica gel, Merck grade 60.
Ethyl acetate, petroleum ether and other solvents were
distilled before use. Epoxides, amines and other chemicals
were purchased from Fluka and Merck. H3PW12O40 and
H3PMo12O40 are commercially available and were pur-
chased from Merck and used without further purification.
Despite the low solubility of both epoxides and amines in
water, the heteropoly acid-catalyzed ring opening reactions
could still proceed efficiently at ambient temperature. The
ring opening reaction might take place at the interface of
organic reactants with water in the heterogeneous system. It
was found that vigorous stirring was required for the success
of the reaction.
3.2. General procedure of aqueous ring opening of
epoxides with aromatic amines catalyzed by HPAs
To a stirred solution of epoxide (2 mmol) and amines
(2 mmol) was added water (8 mL) and H3PW12O40 (20 mg,
0.007 mmol) or H3PMo12O40 (20 mg, 0.01 mmol), and the

N. Azizi, M. R. Saidi / Tetrahedron 63 (2007) 888–891
891
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