Highly efficient and versatile chemoselective addition of amines to epoxides in water catalyzed by erbium(III) triflate

Article abstract of DOI:10.1016/j.tetlet.2008.02.010

Er(OTf)₃ is proposed as a highly efficient and reusable catalyst for the opening of epoxides in water with aliphatic as well as aromatic amines leading to the synthesis of β-amino alcohols. The aqueous conditions employed in the present method will make it 'environmentally friendly' and potentially useful for industrial applications.

Full text of DOI:10.1016/j.tetlet.2008.02.010

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2289–2293
Highly efficient and versatile chemoselective addition of amines
to epoxides in water catalyzed by erbium(III) triflate
a,
a
b
a
c
*
Antonio Procopio , Marco Gaspari , Monica Nardi , Manuela Oliverio , Ornelio Rosati
a
` `
Dipartimento Farmaco-Biologico, Universita degli Studi della Magna Grascia Complesso Ninı Barbieri, 88021 Roccelletta di Borgia (CZ), Italy
b
`
Dipartimento di Chimica, Universita della Calabria, Ponte Bucci, 87030 Arcavacata di Rende (CS), Italy
c Dipartimento di Chimica e Tecnologia del Farmaco, Via del liceo 1, University of Perugia, 06123 Perugia (PG), Italy
Received 2 January 2008; revised 31 January 2008; accepted 4 February 2008
Available online 8 February 2008
Abstract
Er(OTf)3 is proposed as a highly efficient and reusable catalyst for the opening of epoxides in water with aliphatic as well as aromatic
amines leading to the synthesis of b-amino alcohols. The aqueous conditions employed in the present method will make it ‘environmen-
tally friendly’ and potentially useful for industrial applications.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Lewis acid catalysis; Erbium(III) triflate; Epoxide; Aminolysis; b-Aminoalcohol
b-Amino alcohols are versatile intermediates in the syn-
thesis of a wide range of biologically active natural and
synthetic products.1–4
The classical approach, involving the ring opening of
epoxides with an excess of amines at elevated temperature,
results inadequate for poorly nucleophilic amines,5 critical
to certain functional groups, and also to the control of
regioselectivity.5c,d
So, to obviate these problems, various methodologies to
carry out epoxide opening under milder conditions6 were
developed such as the use of alumina,7 amides and trifla-
mide,8 metal alkoxides,9 metal triflates,10 various other
metal salts,11 alkali metal perchlorates/tetrafluoroborate,12
rare earth metal halides,12 silica under high pressure13 and
many other methods aiming to lower the environmental
impact of the process.14
tive and costly catalysts and/or stoichiometric amounts of
catalysts, potential undesirable side reactions15,16 moderate
yields and/or poor regioselectivities, and additionally in
most of the cases, the activity was proved towards aromatic
amines or the aliphatic ones only.
Thus, there have been incessant efforts to develop metho-
dologies for the opening of epoxide rings by amines as evi-
denced by the copious recent reports. The tight legislation
on the release of waste and toxic emissions, to control envi-
ronmental pollution, has induced a paradigm shift in the
development of new synthetic methodologies, and consid-
ering the widespread applications of the resultant b-amino
alcohols, we felt that a method of choice should be the one
that uses a catalyst easily available and less costly, less
toxic, operable under environmentally friendly conditions
and, if possible, reusable so as to fulfill the ‘triple bottom
line’ philosophy of green chemistry.4b,17
However, these methodologies still suffer from one or
more disadvantages such as long reaction times, elevated
temperatures, high pressures, the use of moisture/air sensi-
As a part of our research to develop Lewis acid-cata-
lyzed methods, we found that erbium(III) compounds are
a very useful, environmentally friendly catalyst for several
acid-catalyzed reactions.18 Moreover, erbium(III) triflate
works under almost neutral conditions,19 therefore it is
tolerant towards many organic functions. In particular,
*
Corresponding author. Fax: +39 0961 391270.
E-mail address: procopio@unicz.it (A. Procopio).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.010

2290
A. Procopio et al. / Tetrahedron Letters 49 (2008) 2289–2293
OH
erbium triflate has proved to be a highly efficient and
regioselective catalyst for the rearrangement of epoxides
to carbonyl compounds.20 In this context, we have exam-
ined erbium triflate as a Lewis acid for the aminolysis of
epoxides in water. The use of water as a solvent not only
is advantageous being the most ‘green’ solvent available
but also allows a simple, efficient and robust system for
the reuse of the catalyst extracted with organic solvents.21
Some examples of the preparation of b-amino alcohols in
water were already reported,22 although the reactions of
aromatic amines with the epoxides resulted to be extremely
slow and gave the desired products in very poor yields.
Therefore, herein we would like to report a mild, practical
and efficient method for the opening of epoxides with ali-
phatic as well aromatic amines using Er(OTf)3 to promote
the reaction, extending what was previously published as
simple procedure in water.
Er(OTf )3 mol %
water
PhNH2
O
+
NHPh
2b
3ab
1a
Scheme 2.
Table 2
Aminolysis of cyclohexene oxide 1a by piperidine 2a
Entry
Catal. mol (%)
T (°C)
t (h)
Yield (%)
1
2
3
4
5
6
7
1.0
5.0
5.0
rt
rt
16
8
2
2
2
88
90
>99
85
95
92
60
60
60
60
60
—
1° Recycl.
2° Recycl.
3° Recycl.
2
2
90
Initially, ring opening of cyclohexene oxide 1a was
investigated with piperidine 2a in water (Scheme 1) at dif-
ferent temperatures and mol % of catalyst to set the better
reaction conditions (Table 1). The reaction was carried out
with a very simple procedure in 1 mol % of catalyst aque-
ous solution without adding any organic solvent. The b-
amino alcohol 3aa was extracted from the aqueous solution
by diethyl ether. Only little improvement was recorded rais-
ing the catalyst up to 5 mol % (Table 1, entry 2), meanwhile
quantitative yield was collected in only 2 h performing the
reaction at 60 °C (Table 1, entry 3). Noteworthy, only 85%
of b-amino alcohol was obtained when the reaction was
conducted under the same conditions but without any
catalyst (Table 1, entry 4). The trans stereochemistry of
the b-amino alcohols 3aa was deduced from the coupling
To extend this simple procedure to aromatic amines and
optimize the best reaction conditions, cyclohexene oxide 1a
was treated with aniline 2b in 1 mol % of aqueous solution
of Er(OTf)3 at room temperature (Scheme 2). Very poor
yields were obtained not only under these experimental
conditions but also by using 5 mol % of catalyst (Table 2,
entries 1 and 2). However, still, a satisfactory result was
registered after 8 h when the reaction was performed at
60 °C in 5 mol % of catalyst aqueous solution (Table 2,
entry 3). As expected, no reaction was obtained without
any catalyst also after prolonged reaction time (Table 2,
entry 4). The trans stereochemistry of the b-amino alcohols
3ab (Table 1, entry 1) was deduced from the coupling con-
stants of the peaks at 3.27 ppm (ddd, J = 10.5, 9.4, 4.1 Hz,
CH-NHPh) and 3.35 ppm (ddd, J = 10.2, 9.7, 4.3 Hz, CH-
1
1
constants of the ring protons in H NMR spectrum.
OH) in the H NMR spectrum.
The use of water as a solvent allows a simple and effi-
cient system for the reuse of the catalyst. In fact, after
the completion of reaction, the aqueous solution contain-
ing the catalyst was extracted with organic solvent, fresh
substrate was added and the process was repeated for three
cycles with consistent activity (Table 1, entries 5–7).
Again, after the completion of the reaction, the aqueous
solution containing the catalyst was extracted with organic
solvent, fresh substrate was added and the process was
repeated for three cycles with still good activity (Table 2,
entries 5–7).
As reported above,19 a water solution of Er(OTf)3 is
only weakly acidic, nevertheless, it may be possible that
the true catalyst is TfOH, released from the hydrolysis of
Er(OTf)3. However, the observation that TfOH is not as
effective as Er(OTf)3 to catalyze the epoxide opening
(1 equiv aniline, 1 equiv cyclohexene epoxide, 10% TfOH,
25 °C, 7 h, 23%) suggests that a Lewis acid is likely
involved in activating the epoxide. Encouraged by our
results in the nucleophilic opening reaction catalyzed by
5 mol % Er(OTf)3 in water, we studied the scope and limi-
tations of this reaction treating structurally diverse amines
with various aliphatic and aromatic epoxides (Scheme 3).
OH
H
Er(OTf )3 mol %
water
N
O
+
N
3aa
1a
2a
Scheme 1.
Table 1
Aminolysis of cyclohexene oxide 1a by aniline 2b
Entry
Catal. mol (%)
T (°C)
t (h)
Yield (%)
1
2
3
4
5
6
7
1.0
5.0
5.0
—
1° Recycl.
2° Recycl.
3° Recycl.
rt
rt
24
24
8
24
24
24
24
28
55
95
Trace
92
NR2R3
R1
OH
60
60
60
60
60
R
R1
R1
Er(OTf )3 5 mol %
water
R2R3NH2
2 a-g
R
+
R
+
O
1a-g
NR2R3
4
3
OH
89
90
Scheme 3.

A. Procopio et al. / Tetrahedron Letters 49 (2008) 2289–2293
2291
Table 3
In general, the reaction rate of aminolysis in water depends
on the structure of the epoxide and on the nucleophilicity.
The data in Table 3 clearly show that the reaction of ali-
phatic and aromatic amines with different epoxides in
water gives the corresponding b-amino alcohols in high
yield and in a regioselective manner, attaching the less
substituted carbon of oxirane (GC/MS). The reaction of
epichlorohydrine 1e (Table 3, entry 20) provided an exam-
ple of excellent chemoselectivity, affording the amino alco-
hol corresponding to nucleophilic attack at the terminal
carbon of the epoxide moiety. Therefore, no product aris-
ing from the nucleophilic displacement of the chlorine
could be detected through GC/MS analysis of the reaction
mixture.
Reactions of aliphatic epoxides with aliphatic and aromatic amines at
60 °C in deionized water
Entry
Epoxide
Amine
NH
t (h)
Yielda (%)
>99
1
2
O
2a
1a
O
2
3
BuNH2
2c
5
2
80
1a
O
NH
2d
>99
1a
O
O
NH
2e
4
5
6
2
4
2
>99
93
1a
O
NH2
2f
In some cases, the b-amino alcohols precipitated from
the solution and were separated by a simple filtration.
Otherwise, they were extracted from the aqueous solution
by diethyl ether. All the compounds were fully character-
1a
O
PhCH2NH2
2g
>99
1a
1
ized by GC/MS, and H NMR by a comparison with the
=ArNH2
NH2
known compounds.4b,10f,g,22h
X
O
7
8
95
1a
Under the same experimental conditions, the aryl asym-
metric oxiranes underwent cleavage by a variety of amines
in a regioselective fashion which strongly depend on the
nature of nucleophile. Thus, next we planned to evaluate
the regioselectivity of the Er(OTf)3-catalyzed ring opening
reaction of styrene oxide 1h, which was chosen as represen-
tative unsymmetrical epoxide, with amines (Scheme 4).
In all cases the reactions were completed within 2–8 h at
60 °C (Table 4), affording high yields of the amino alco-
hols. The major regioisomeric alcohol formed during the
reaction of 1h with aromatic amines was isolated by col-
umn chromatography of the crude product isolated from
the reaction mixture. However, the regioisomeric amino
alcohol formed by the reaction of 1h with aliphatic amines
could not be separated by column chromatography. In
each case, the regioselectivity was determined by GC/MS
analysis of the crude product mixture. As reported by other
authors, the aromatic epoxides gave the major product
with the opposite regiochemistry with respect to the ali-
phatic oxiranes: in these latter ones, steric factors predom-
inate over the electronic ones, meanwhile for aromatic
substrates the opposite regiochemistry suggests that elec-
tronic factors prevail over steric factors.
2b :X=H
2h: X = CH3
O
8
9
8
8
8
8
8
8
8
8
92
90
92
95
92
90
92
90
1a
O
2i: X = OCH3
2j: X = OH
2k: X = Cl
1a
O
10
11
12
13
14
15
1a
O
1a
O
2l: X = Br
1a
O
2m: X = NO2
2n: Y = CH3
2o: Z = CH3
1a
O
1a
O
1a
O
O
16
17
2b
2h
8
8
87 100:0
85 100:0
1b
1b
The product from nucleophilic attack at the benzylic
carbon showed a fragment of m/z [M+À31] due to the loss
of CH2OH, whereas, the characteristic feature in the mass
spectra of the products from the reaction at the terminal
carbon of the epoxide ring was the ion peak at m/z
[M+À106] due to the loss of PhCHO. The formation of
the amino alcohol by nucleophilic attack at the terminal
carbon of 1h was further determined by the absorption of
O
BuO
18
19
2h
2b
8
8
92 100:0
82 100:0
1c
O
1d
O
Cl
20
21
2b
2b
8
8
90 100:0
87 100:0
1e
O
tBuO
1f
1
Ph
Ph
the benzylic methine proton at 4.70 ppm in the H NMR
22
2b
8
78
spectra. The structure of the products was confirmed by
GC/MS and 1H NMR by comparison with the known
compounds.4b,10f,14b,22g
For example, in the reactions with aromatic amines, the
benzylic proton of 5 and 6 appeared at d 4.6 and 5.2,
1g
O
a
Isolated yields; all the compounds, when necessary, were purified by
flash chromatography and the major product was fully characterized by
the comparison of their spectral data with the known
compounds.4b,10f,g,22h

2292
A. Procopio et al. / Tetrahedron Letters 49 (2008) 2289–2293
NR2R3
OH
Er(OTf)3 was found to be better than other recently
reported catalysts in terms of conversion and reaction
times. Moreover, due to the mild acidic nature of Er(OTf)3,
it works effectively for epoxide ring opening reaction with
aliphatic as well as aromatic amines.23
Ph
Er(OTf)3 5 mol %
water
+
Ph
R2R3NH2
2 a-o
Ph
+
1h
NR2R3
O
5
6
OH
Scheme 4.
In comparison with Sc(OTf)3,10f which was one of the
most versatile and reactive catalyst recently proposed in
the epoxide ring opening with amines, the Er(OTf)3
required prolonged reaction times in the case of the aro-
matic amines, but showed to be more active with aliphatic
ones.
In conclusion, Er(OTf)3 is a highly efficient and reusable
catalyst for the opening of epoxides in water with aliphatic
as well as aromatic amines leading to the synthesis of b-
amino alcohols. The procedure of these reactions is very
simple and presents some specific advantages such as low
toxicity and low cost, mild reaction conditions in short
times and excellent stereo-, regio- and chemoselectivity.
The aqueous conditions employed in the present method
will make it ‘environmentally friendly’ and potentially
useful for industrial applications.
Table 4
Reactions of styrene oxide 1h with aliphatic and aromatic amines at 60 °C
in deionized water
Entry
Amine
t (h)
2
Yielda (%)
5:6
1
2
NH
2a
>99
0:100
BuNH2
2c
2.5
93
10:90
97
10:90
3
NH
2.0
2d
95
4:96
O
NH
2e
4
5
2.0
2.5
PhCH2NH2
2g
90
25:75
References and notes
=ArNH2
NH2
95
85:15
X
8
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was added to a magnetically stirred mixture of epoxide 1a–h
(1.0 mmol) and amine 2a–o (1.1 mmol) in the deionized water
(0.5 mL) at 60 °C for 2–8 h. After the completion of the reaction
(GC/MS, TLC), the reaction mixture was extracted with diethyl ether
or dichloromethane, dried over anhydrous sodium sulfate, filtered and
concentrated under vacuum (rotary evaporator). The residue was
purified by column chromatography on silica gel using chloroform as
eluent. All the compounds were fully characterized by IR, GC/MS
and 1H NMR by
a
comparison with the known com-
pounds.4b,10f,g,14b,22h,g After reaction workup the aqueous phase can
be evaporated under reduced pressure to furnish the erbium salt in
90% recovered yield, as pale pink solid. The purity of recovered
Er(OTf)3 was confirmed by comparison with the IR spectrum of the
commercial product and, after drying over P2O5 overnight, it was
reused three times in the reaction of 1a with recovered yields of 3ab
always almost 90%.
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