An improved procedure for the synthesis of 2-morpholinoethanamine

Article abstract of DOI:10.1007/s11164-010-0163-0

2-Morpholinoethanamine is prepared rapidly mainly in aqueous conditions from inexpensive and commercially accessible starting materials. The process development of an effective synthetic route by utilizing morpholine as the starting material via Michael addition, hydrazinolysis, and Curtius rearrangements was undertaken. The optimal conditions were selected in the experiments. The total yield was 81.8% and it was a convenient process. Springer Science+Business Media B.V. 2010.

Full text of DOI:10.1007/s11164-010-0163-0

Res Chem Intermed (2010) 36:523–528
DOI 10.1007/s11164-010-0163-0
An improved procedure for the synthesis
of 2-morpholinoethanamine
Ri-sheng Yao
Sheng-song Deng
•
Sheng-hua Wu
San-xi Yu
•
Lai-en Jiang
•
•
Received: 4 February 2010 / Accepted: 21 May 2010 / Published online: 17 August 2010
Ó Springer Science+Business Media B.V. 2010
Abstract 2-Morpholinoethanamine is prepared rapidly mainly in aqueous condi-
tions from inexpensive and commercially accessible starting materials. The process
development of an effective synthetic route by utilizing morpholine as the starting
material via Michael addition, hydrazinolysis, and Curtius rearrangements was
undertaken. The optimal conditions were selected in the experiments. The total
yield was 81.8% and it was a convenient process.
Keywords 2-Morpholinoethanamine Á Michael addition Á Hydrazinolysis Á
Curtius rearrangements
Introduction
2
-Morpholinoethanamine is the key intermediate of moclobemide, which is a selective
monoamine oxidase A inhibitor for the treatment of depressive illness [1, 2].
In addition, a number of compounds containing 2-morpholinoethanamine as a side
group have shown a broad spectrum of biological activities, such as anti-
gastroesophageal reflux disease and anti-irritable bowel syndrome [3], anti-inflam-
matory [4], and anticancer [5]. In our continuing interest for studying N-substituted
ethylenediamine compounds [6], we were interested in this building block 1.
R. Yao Á S. Wu Á L. Jiang Á S. Deng
Department of Pharmaceutical Engineering, Hefei University of Technology, Hefei 230009, China
R. Yao (&)
Engineering Research Center of Bioprocess, Ministry of Education,
Hefei University of Technology, Hefei 230009, China
e-mail: rishengyao@163.com
S. Yu
Ansheng Biochemical Sci & Tech Co. Ltd., Hefei 230009, China
123

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R. Yao et al.
A variety of syntheses have been reported for this compound. However, each has
one or more drawbacks: (1) preparations involving functional transformation of
-morpholinoethanol [7, 8] and 4-(2-chloroethyl)morpholine [9] require expensive
starting materials and high temperature and pressure; (2) hydrogenation of
-morpholinoacetonitrile involves a high-pressure reaction [10]; (3) syntheses via
2
2
the direct substitution of morpholine [11, 12] or ethane-1,2-diamine [13, 14]
generate many byproducts and it is very difficult to separate and purify products;
and (4) Hofmann rearrangement of 3-morpholinopropanamide suffers from low
yields of only 42.3% [15, 16]. Herein, we report on a simple and practical synthesis
of 2-morpholinoethanamine to overcome all of the problems of conventional
methods. Cost, practicability, waste disposal, and simplicity of purification have all
been factors considered in the choice of methods, reagents, and solvents.
The strategy we envisaged was based on the well-known Curtius rearrangements
of acid derivatives into primary amines (with one less carbon atom). An improved
method for the preparation of 2-morpholinoethanamine is described in this paper
(
Scheme 1). In this protocol, morpholine with ethyl acrylate gave ethyl
-morpholinopropanoate (4) by Michael addition reaction in the presence of FeCl3
in water. Sequentially, 4 was hydrazinolyzed to give the 3-morpholinopropanehy-
3
drazide (5). The Curtius rearrangement of 5 in the presence of the NaNO /HCl
2
system in water finally produced 2-morpholinoethanamine (1).
Results and discussion
Michael addition of morpholine to ethyl acrylate
As an a, b-unsaturated electrophile reagent, ethyl acrylate is widely used in Michael
addition reactions [17]. In this work, the ethyl acrylate with morpholine in the
presence of catalysts in water can provide ethyl 3-morpholinopropanoate (4). In
order to obtain 4, we tried the catalytic properties (in terms of yield) of different
cheap catalysts towards the Michael addition of morpholine to ethyl acrylate
O
O
COOEt
a
+
O
N
OC H
2 5
N
H
4
3
2
c
b
O
N
O
N
NH2
CONHNH2
1
5
Reagents and conditions: (a) FeCl
3
·6H
2
O/H
2 2 2
O ; (b) NH NH /C
2 5 2 2
H OH ; (c) NaNO /HCl, H O.
Scheme 1 Schematic synthetic procedure of 2-morpholinoethanamine. Reagents and conditions: (a)
FeCl O/H O, (b) NH NH /C OH, and (c) NaNO /HCl, H
Á6H
3
2
2
2
2
2
H
5
2
2
O
1
23

Improved procedure for the synthesis of 2-morpholinoethanamine
525
Table 1 Comparison of
different catalysts in the
preparation of 4
Entry
Catalyst
Isolated yield (%)
1
2
3
4
5
6
7
SnCl
FeCl
Cu(OAc)
Zn(OAc)
CrCl
4
Á4H
2
O
82.0
98.5
20.3
35.8
78.6
38.7
Trace
3
Á6H
2
O
2
2
3
Á6H
2
O
Mn(OAc)
2
2
None
(
Table 1) in H O at ambient temperature over a period of 12 h. Among the results,
2
FeCl Á6 H O (entry 2) gave high yield (98.5%).
3
2
Hydrazinolysis of ethyl 3-morpholinopropanoate
3
-Morpholinopropanehydrazide was obtained with ethanol as a solvent at reflux
temperature. As we know, alcohol was often used as a solvent for hydrazinolysis. In
our experiments, the use of methanol and ethanol as solvents gave a higher yield,
while other alcohols gave lower yields (Table 2). In our observations, they made
little difference. The selection of ethanol was because the reactions produced
ethanol and it was more convenient for recycling. In our initial idea, using the
corresponding methyl ester substituted for ethyl ester as the starting material was
more atom-economic. But it was found in our experiments that the two-step (a, b in
Scheme 1) total yield is not as high as using ethyl ester.
As for the ratio between the two raw materials, 1:1.5 was more reasonable. As
seen in Table 2, 1:1.3 caused the incomplete conversion of 3-morpholinopropan-
oate, the more expensive material, which meant that it was uneconomic for
industrial application. When a higher ratio was adopted, there was no significant
increase of the yield, whereas there was a waste of hydrazine.
Table 2 Results of
hydrazinolysis of ethyl
a
Hydrazine Time Yield
Entry Solvent
3-Morpholino-
propanoate (mol) (mol)
(h)
(%)
3-morpholinopropanoate
1
2
3
4
5
6
7
8
9
None
0.101
0.102
0.105
0.300
0.205
0.203
0.206
0.205
0.150
0.155
0.160
0.130
10.0
5.0
2.5
3.0
2.0
2.5
3.0
1.5
2.5
53.6
92.2
97.3
78.5
73.6
97.2
96.0
83.8
85.7
Methanol
Ethanol
b
Isopropanol 0.101
1-Butanol
Ethanol
Ethanol
Ethanol
Ethanol
0.101
0.100
0.101
0.103
0.103
a
3
-Morpholinopropanoate
complete conversion
b
b
b
3
-Morpholinopropanoate
incomplete conversion
123

526
R. Yao et al.
Curtius rearrangement of 3-morpholinopropanehydrazide
Curtius rearrangement is a good alternative to the Hofmann rearrangement to
prepare primary amines from carboxylic acids. With the aim of simplicity of the
synthetic process, we reinvestigated Curtius rearrangement under the original
conditions, using the 3-morpholinopropanehydrazide (5). The rearrangement was
studied under hydrolytic conditions using sodium nitrite in the presence of different
aqueous acids, in order to isolate directly the primary amines. The relevant results
are shown in Table 3. We used, respectively, NaNO /H SO , NaNO /TFA, and
2
2
4
2
NaNO /HCl as the rearrangement reagents, but TFA was more expensive and toxic.
2
In comparison to other processes, compound 1 from compound 5 was obtained in
the presence of NaNO /HCl at a 85.5% yield.
2
The Curtius rearrangement under the original aqueous conditions showed that
chlorhydric acid/sodium nitrite is tailor-made to perform the reaction in high yields
for a straightforward isolation of primary amines. The three-step hydrazide
rearrangement sequence allowed us to synthesize the 2-morpholinoethanamine on a
preparative scale.
Due to the high yield of each step (a, b, c in Scheme 1), it makes it easy to
separate and purify products. In step a, the pure ethyl 3-morpholinopropanoate
can be obtained with diluted hydrochloric acid to wash away excess morpholine;
in step b, the solvent and excess of hydrazine were removed under vacuum and
3
-morpholinopropanehydrazide remained; in step c, the starting compound was
completely converted, afforded a very clean product, and no purification was
required to perform.
According to our scheme for the preparation of 2-morpholinoethanamine, the
three main steps in the reaction may produce some byproducts, such as in step a: no
byproducts; in step b: ethanol, which can be used as a solvent; in step c: nitrogen
and carbon dioxide. There is no need for the posttreatment of these byproducts,
which are harmless to the environment. Toxic reagents were not used due to the
consideration of the safety of the operator and environment.
Table 3 Curtius rearrangement of acylhydrazides 5
a
Reagents (equiv.)
b
Yields (%)
Entry
Temperature (°C)
Time (h)
1
2
3
4
5
6
a
NaNO
NaNO
NaNO
NaNO
NaNO
NaNO
2
2
2
2
2
2
(1.5), H
(1.5), H
2
2
SO
4
(2)
(2)
60
50
60
80
80
60
12
54.8
59.3
83.7
87.0
85.5
80.3
SO
4
12
(1.5), TFA(3)
(1.5), TFA(3)
(1.5), HCl(3)
(1.5), HCl(3)
1.5
1.5
1.5
1.5
The reactions were carried out in H O. Sodium nitrite and the acid were added at 0 °C and the resulting
2
mixture was stirred for 1 h at room temperature before heating until gas evolution ceased
b
Isolated (average of three runs)
1
23

Improved procedure for the synthesis of 2-morpholinoethanamine
527
Experimental part
1
The H NMR spectra were recorded in CDCl on a Bruker 300 MHz spectrometer;
3
the chemical shifts were reported in d ppm relative to TMS. The FT-IR spectra were
recorded in solid-state KBr dispersion using a Perkins-Elmer FT-IR spectropho-
tometer. The melting points were determined by using Buchi apparatus. Commer-
cially obtained reagents were used without further purification. All reactions were
monitored by TLC with HuanghaiGF 254 silica gel-coated plates.
Ethyl 3-morpholinopropanoate (4)
Into a 250-mL, one-neck, round-bottomed flask equipped with a mechanical stirrer
and reflux condenser were placed charged ethyl acrylate (12.3 mL, 0.1 mol),
morpholine (9.6 mL, 0.11 mol), FeCl Á6H O (2.70 g, 0.01 mol), and H O (30 ml),
3
2
2
and the mixture was stirred for 12 h at room temperature. Then, the mixture was
extracted with ethyl acetate (3 9 50 mL), and the combined organic layers were
washed with diluted hydrochloric acid and dried with Na SO . The solvent was
2
4
removed under reduced pressure and yielded a residue of 18.3 g (98.5%, GC purity
of 96.0%) of the desired product as a colorless oil. IR 3,451, 2,960, 2,866, 1,734,
-
1 1
1
2
,639, 1,384, 1,303, 1,119, 1,025, 619 cm ; H NMR d 4.10 (q, 2H), 3.73 (t, 4H),
.82 (t, 2H), 2.47 (t, 6H), 2.33 (t, 3H).
3
-Morpholinopropanehydrazide (5)
Into a 250-mL, one-neck, round-bottomed flask equipped with a mechanical stirrer
and reflux condenser were placed charged ester 4 (18.7 g, 0.1 mol), hydrazine
monohydrate (8.0 ml, 0.15 mol), and ethanol (50 ml), and the mixture was stirred
under reflux for 2.5 h. TLC of reaction mass indicated the absence of starting
compound 4. The solvent and excess of hydrazine were removed under vacuum and
recycled. After cooling, it afforded 5 as a white solid (16.6 g, 97.2%). m.p.
-
1 1
4
2–44 °C. IR 3,451, 2,926, 2,856, 1,651, 1,461, 1,384, 1,114, 618 cm ; H NMR
d 8.97 (s, H), 4.15 (s, 2H), 3.65 (t, 4H), 2.86 (t, 2H), 2.47 (t, 6H).
2
-Morpholinoethanamine (1)
To a solution of acylhydrazides 5 (17.3 g, 0.1 mol) in water (60 ml) was added
successively chlorhydric acid (25 ml, 0.3 mol) and NaNO (10.4 g, 0.15 mol) at
2
0 °C. The mixture was gradually heated at 80 °C until gas evolution ceased. Aqueous
sodium hydroxide (50 ml, 6 N) was then added to the mixture. The aqueous layer
was extracted with CH Cl (2 9 100 ml) and then EtOAc (3 9 100 ml). The
2
2
combined organic layers were dried over Na SO and concentrated under reduced
2
4
pressure to afford 1 as a colorless oil (11.1 g, 85.5%, GC purity of 97.0%). IR 3,368,
3
1
1
,294, 2,969, 2,953, 2,938, 2,893, 2,854, 2,806, 1,694, 1,455, 1,366, 1,303, 1,118,
-
1 1
,011, 761, 633 cm ; H NMR d 3.71 (t, 4H), 2.78 (t, 2H), 2.45 (t, 4H), 2.40 (t, 2H),
.37 (s, 2H). The results agreed with those in the literature.
123

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R. Yao et al.
Conclusion
In summary, this study has proven to be a potent addition to the existing methods for
the synthesis of an important intermediate: 2-morpholinoethanamine. The major
benefits of this synthetic approach include the amounts of the compound prepared
from inexpensive starting materials and reagents, less than 2 days duration, and a
very simple three-step process resulting in 81.8% total yields. In this protocol, the
Michael addition of morpholine to ethyl acrylate catalyzed by FeCl Á6H O in
3
2
aqueous solution were shown to be highly effective. The Curtius rearrangement
under the original aqueous conditions showed that hydrochloride acid/sodium nitrite
is the tailor-made couple to perform the reaction in high yields for a straightforward
isolation of primary amines. Most of the reactions were performed in water, and it is
less hazardous, more environmentally friendly, and has potential for industrial
application.
Acknowledgments We thank Dr. You-gui Li for the contributions to the conception of this synthetic
route. The authors also thank Yu-lan Ke for the nuclear magnetic resonance (NMR) support.
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