Efficient solvent-free aminolysis of epoxides under (C4H 12N2)2[BiCl6]Cl·H 2O catalysis

Article abstract of DOI:10.1016/j.tetlet.2012.05.079

An efficient and rapid procedure for ring opening of various epoxides with aromatic, aliphatic and heterocyclic amines is developed at room temperature under solvent-free conditions in the presence of (C₄H ₁₂N₂)₂[BiCl₆]Cl·H ₂O (1 mol %). This catalyst can be reused several times without losing of its activity.

Full text of DOI:10.1016/j.tetlet.2012.05.079

Tetrahedron Letters 53 (2012) 4267–4272
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient solvent-free aminolysis of epoxides under (C4H12N2)2[BiCl6]ClÁH2O
catalysis
⇑
Hong-Fei Lu , Lei-Lei Sun, Wen-Jun Le, Fei-Fei Yang, Jun-Tao Zhou, Yu-Hua Gao
School of Biology and Chemical Engineering, Jiangsu University of Science and Technology, Zhenjiang 212003, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and rapid procedure for ring opening of various epoxides with aromatic, aliphatic and hetero-
cyclic amines is developed at room temperature under solvent-free conditions in the presence of
(C4H12N2)2[BiCl6]ClÁH2O (1 mol %). This catalyst can be reused several times without losing of its activity.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 16 March 2012
Revised 16 May 2012
Accepted 18 May 2012
Available online 24 May 2012
Keywords:
Epoxides
Amines
Aminolysis
b-Amino alcohols
b-Amino alcohols are versatile building blocks in the synthesis
of a wide range of biologically active natural and synthetic prod-
ucts, unnatural amino acids, medicinal chemistry, and chiral auxil-
iaries for asymmetric synthesis.1–5 The most practical and
commonly used method for synthesizing these compounds is the
direct aminolysis of an epoxide with an excess of amine by heat-
ing.6 However, under these conditions, it reacts very slowly be-
cause of low reactive epoxides and sluggish amine. Sensitive
functional groups also undergo undesirable side reactions, which
mean a poor regioselectivity. To eliminate such problems in the
ring opening of epoxides by amine nucleophiles, several activators
or promoters, such as Lewis acids (BiCl3,7 ZnCl2,8 CoCl2,9 and
ZrCl410) heteropoly acids,11 ionic liquids,12–14 metal amides,15–19
and others are developed to perform reaction under mild condi-
tions.20–24
But some of these methods often involve other problems like
the use of large amounts of expensive agents, air and/or moisture
sensitive catalysts, the long reaction times, low selectivity, and
hazardous organic solvents. There has been reported a method of
the ring-opening of epoxides with a variety of aliphatic amines in
water at room temperature without using any catalyst.25 The pro-
cedure of this reaction is very simple and the yields are generally
high, but additions of aromatic amines to epoxides are sluggish
and give very low yields. In previous work, we used26 acidic ionic
liquid and alkaline ionic liquid in a similar reaction, and made
some achievements. While in this reaction, the rearrangement of
epoxides to allyl alcohols under basic conditions as well as poly-
merization in strongly acidic conditions gets many by-products,
which resulting in a low yield of the desired products. Moreover,
the main disadvantage of above mentioned methods is that the
catalysts cannot be recovered or reused because it will be de-
stroyed in the procedure. Therefore, the introduction of new and
efficient methods for this transformation is still in demand.
Here, we introduce an efficient and room-temperature proce-
dure for regioselective ring opening of various epoxides with aro-
matic amines catalyzed by reusable catalyst (C4H12N2)2[BiCl6]
ClÁH2O27 (Figs. 1 and 2) under solvent-free conditions. Compared
(C4H12N2)2[BiCl6]ClÁH2O to BiCl3, Bi(OTf)3, and Bi(TFA)3, it is partic-
ularly more attractive because it is a solvent-free reaction in a
shorter reaction time and the most important is the catalyst can
be recovered (see Scheme 1).
The reaction of aromatic amine with aliphatic epoxides was
examined and only one product was observed in the reaction mix-
ture. The predominant attack of amine on the less substituted car-
bon of epoxide, such as epichlorohydrin, propylene oxide, and
glycidyl tertbutyl ether, provided an ideal yield of more than 84%
within 5–10 min (Table 1, entries 1–15). Excellent regioselectivity
toward the only product B was also achieved in each case. While
the styrene oxide underwent cleavage by various aromatic amines
3-
CI
+
NH2
CI
CI
-
.
H2O
.
.
CI
CI
CI
Bi
CI
H2N
+
2
⇑
Corresponding author.
E-mail address: zjluhf1979@hotmail.com (H.-F. Lu).
Figure 1. Crystal related structures.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.079

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H.-F. Lu et al. / Tetrahedron Letters 53 (2012) 4267–4272
aromatic substrates, possibly steric factors predominate over elec-
tronic factors.
To claim (C4H12N2)2[BiCl6]ClÁH2O as a general catalyst for the
activation of epoxides for nucleophilic attack by amines, we then
investigated the ring opening of cyclohexene oxide with heterocy-
clic amines29 in the presence of (C4H12N2)2[BiCl6] ClÁH2O (1 mol %)
and the results are summarized in Table 2.
Quantitative yields of the corresponding amino alcohols were
obtained in the reaction of the ring opening of cyclohexene oxide
with heterocyclic amines such as 4-aminopyridine, imidazole, pyr-
azole, piperidine, and pyrrolidine. Only one trans-isomer was
formed. Thus, the catalyst (C4H12N2)2[BiCl6]ClÁH2O enabled effi-
cient coupling of heteroaromatic amines with cyclohexene oxide
providing excellent yields of desired products.
In a typical study, the reaction of cyclohexene oxide with aniline
was carried out in the presence of various complexes at room tem-
perature under solvent-free condition to evaluate which complex is
more effective. The (C4H12N2)2[BiCl6]ClÁH2O provided excellent yield
within a short reaction time (10 min), and afforded high regioselec-
tivity . Only one tran-isomer (Table 3, entries1–5) was formed. Then
using (C4H12N2)2[BiCl6]ClÁH2O (1 mol %) as the catalyst, the ring
opening of cyclohexene oxide with aniline was investigated under
various solvents. Solvents such as water, methanol, dichloromethane,
toluene, and cyclohexane (Table 3, entries 6–10) provided low yields
of the desired product (21–68%) within 180 min, while the same
reaction under solvent-free condition afforded a yield of 97% within
10 min. Perhaps the most possible reason for the high reaction rate
is due to the fact that under solvent-free condition, the concentration
of catalyst is greater, so leading to reaction rate faster than the same
reaction in the presence of various solvents.
The actual mechanism of these reactions is not clear at present.
However, a plausible mechanistic pathway can be offered where
(C4H12N2)2[BiCl6]ClÁH2O is recycled continuously throughout the
course of the reaction (Fig. 3). This hypothesis is supported by
recovery of the catalyst via a simple separation and its direct reuse
for four times without significant loss of activity.
In conclusion, we have demonstrated a novel, mild, and efficient
preparation method of b-amino alcohols by the ring opening of
epoxides with amines using (C4H12N2)2[BiCl6]ClÁH2O at room tem-
perature. The specific advantages of the reactions are that be car-
ried out under solvent-free, in a shorter time, more simple
operation, working for aromatic and aliphatic/ heterocyclic amines,
less by-products, higher yields, the catalyst have the characters of
reusable and excellent regioselectivity which are notable advanta-
ges of this protocol.
Figure 2. Crystal structures of polymers.
with preferred attacking at the benzylic position by using
(C4H12N2)2[BiCl6]ClÁH2O (1 mol %) as the catalyst at room tempera-
ture. The reaction of aromatic amine with styrene oxide provided a
yield of more than 90% with a regioselectivity of product A. In the
case of cyclohexene and cyclopentene oxides (Scheme 2 and Table
1, entries 21–30), the reaction was generalized to various aromatic
amines. Only one trans-isomer was formed, complete conversion
of raw materials to the desired product within 5–10 min is ob-
served. The procedure of these reactions is very simple, and the
yields are generally high. To the best of our knowledge, these re-
sults represent the highest regioselectivity reported to date for
nucleophilic ring opening of epoxide with aromatic amines. There-
fore, we suggest that the attack of nucleophile is governed by the
nature of oxirane and the stability of carbonium ion.28 In aryl oxi-
rane, the positive charge on oxygen appears to be localized on the
more highly substituted benzylic carbon and gets the major prod-
uct. For aliphatic oxirane gave the opposite regiochemistry of the
NH2
OH
OH
H
N
H
N
(C4H12N2)2[BiCl6]Cl.H2O
O
R
+
+
Solvent-free
R
R.T
R
X
X
X
B
A
X=H,Me,CI,OCH3
R=CH2CI,CH3,Ph,(CH3)3CO
Scheme 1.
NH2
OH
R
(C4H12N2)2[BiCl6]Cl.H2O
solvent-free
O
n(H2C)
n(H2C)
n=1,2
+ R
N
H
Scheme 2.

H.-F. Lu et al. / Tetrahedron Letters 53 (2012) 4267–4272
4269
Table 1
Ring opening of epoxides with aromatic amines
Entry
Epoxide
Amine
Product
Time (min)
7
Yield (%)
NH2
OH
OH
H
N
O
O
CICH2
1
96
94
CICH2
NH2
H
N
CICH2
CICH2
2
7
CICH2
CH3
CI
CH3
NH2
OH
H
N
O
O
3
4
5
8
9
8
95
93
90
CICH2
CICH2
CI
NH2
OH
OH
CI
H
N
CI
CICH2
CICH2
NH2
H
N
O
CICH2
O
OCH3
OCH3
NH2
OH
H
N
6
7
9
95
96
NH2
OH
H
N
O
10
H3C
CH3
NH2
OH
H
O
O
N
8
9
7
9
94
92
CI
CI
CI
NH2
OH
H
N
CI
NH2
OH
H
N
O
10
11
12
6
6
6
89
90
H3CO
O
OCH3
NH2
O
OH
H
O
O
N
NH2
CH3
OH
H
N
O
O
89
CH3
(continued on next page)

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H.-F. Lu et al. / Tetrahedron Letters 53 (2012) 4267–4272
Table 1 (continued)
Entry
Epoxide
Amine
Product
Time (min)
Yield (%)
87
NH2
OH
H
N
O
O
O
O
O
13
14
7
CI
CI
NH2
OH
OH
CI
H
N
O
O
CI
CI
CI
O
O
9
8
86
84
NH2
H
N
15
16
17
OCH3
OCH3
NH2
O
O
HO
7
7
94
95
HN
HO
NH2
HN
CH3
CH3
NH2
O
HO
18
19
8
9
93
90
HN
HO
CI
CI
NH2
O
O
CI
HN
HO
NH2
20
21
22
8
8
90
97
95
HN
OCH3
OCH3
NH2
OH
O
N
H
NH2
OH
CH3
CI
O
N
H
10
CH3
NH2
OH
O
O
N
H
23
24
9
96
94
CI
NH2
OH
10
N
H
CI

H.-F. Lu et al. / Tetrahedron Letters 53 (2012) 4267–4272
4271
Table 1 (continued)
Entry
Epoxide
Amine
Product
Time (min)
Yield (%)
NH2
OH
OCH3
O
N
H
25
26
27
10
92
97
96
OCH3
NH2
OH
O
8
8
N
H
OH
NH2
CH3
CI
O
O
N
H
CH3
NH2
OH
28
29
9
96
97
N
H
CI
NH2
OH
CI
O
O
10
N
H
CI
NH2
OH
OCH3
30
N
H
7
90
OCH3
Table 2
Table 3
Reaction of various epoxides with aniline in the presence of (C4H12N2)2[BiCl6]ClÁH2O
Influence of catalyst and solvent
Entry
Amine
Product
Time (min)
Yield (%)
Entry Catalyst
Solvent
Time
Yield
(min)
(%)
NH2
OH
N
Influence of catalyst
1
2
3
4
5
(C4H12N2)2[FeCl6]ClÁH2O
Solvent-free
10
10
10
10
10
67
36
97
84
57
1
23
94
N
H
(C4H12N2)2[MnCl4]ClÁH2O Solvent-free
(C4H12N2)2[BiCl6]ClÁH2O
(C4H12N2)2[NiCl4]ClÁH2O
(C4H12N2)2[SbCl6]ClÁH2O
Solvent-free
Solvent-free
Solvent-free
N
N
OH
Influence of solvent
N
H
2
3
25
23
87
85
N
6
7
8
9
(C4H12N2)2[BiCl6]ClÁH2O
Water
Methanol
Dichloromethane 180
Toluene
180
180
56
34
21
42
68
(C4H12N2)2[BiCl6]ClÁH2O
(C4H12N2)2[BiCl6]ClÁH2O
(C4H12N2)2[BiCl6]ClÁH2O
(C4H12N2)2[BiCl6]ClÁH2O
N
OH
180
180
N
N
10
Cyclohexane
H
N
N
Typical procedure:
OH
1) Piperazine (10 mmol 0.86 g) BiCl3 (6.8 mmol, 2.15 g) and
35% aqueous HCl (3 ml) were mixed and dissolved in 30 ml
water by heating to 353 K to form a clear solution. The reac-
tion mixture was cooled slowly to room temperature, block
crystals of the title compound would form after fifteen days.
2) A mixture of epoxide/oxetane (11.0 mmol), amine
(10.0 mmol), and (C4H12 N2)2[BiCl6]ClÁH2O (0.1 mmol) was
stirred in a flask. The course of the reaction was monitored
4
5
19
19
90
92
N
H
N
OH
N
N
H

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Figure 3. Proposed mechanism.
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by TLC and complete disappearance of the raw materials was
observed within 6–10 min. The mixture was diluted by ethyl
acetate (20 mL) and the catalyst was separated from the
organic phase by a simple filtration. Then the organic phase
were washed with aqueous NaHCO3, water, dried over anhy-
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Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
05.079.
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