A novel protocol for selective construction of morpholin-2-one and morpholin-3-one heterocycles from aminoethanol with divinyl fumarate

Article abstract of DOI:10.1055/s-2008-1032109

A simple and efficient method for selective construction of morphlin-2-one and morphlin-3-one heterocyclic derivatives has been developed from N-substituted aminoethanols and divinyl fumarate. The selectivity of this catalyst-free reaction was easily controlled by different solvents. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032109

LETTER
679
A Novel Protocol for Selective Construction of Morpholin-2-one and
Morpholin-3-one Heterocycles from Aminoethanol with Divinyl Fumarate
S
elective Construc
i
tion of
n
Morpholin-2
g
-one and
M
o
-
r
pholin-
Y
3-one Heterocycle
i
s
Zhang, Jian-Ming Xu, Wan-Qin Chen, Qi Wu, Xian-Fu Lin*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax +86(571)87952618; E-mail: llc123@zju.edu.cn
Received 24 November 2007
O
Abstract: A simple and efficient method for selective construction
R2
1) CH2Cl2
R1
R2
OH
of morphlin-2-one and morphlin-3-one heterocyclic derivatives has
been developed from N-substituted aminoethanols and divinyl fu-
marate. The selectivity of this catalyst-free reaction was easily con-
trolled by different solvents.
+
H2N
OH
2) NaBH4, THF
R1
N
H
R1= Ph, 4-MeOC6H4, 4-Me2N6H4, Me
2 = H, Ph, Me
R1–R2 = (CH2)5
Key words: aminoethanol, divinyl fumarate, catalyst-free, selec-
tivity, morpholinone
R
Scheme 1 Reagents and conditions: 1) CH2Cl2, 4 Å MS; 2) THF,
NaBH4.
The morpholinone skeleton is receiving widespread atten-
tion due to its potential biological applications.1 It has also
been fully investigated as an effctive template for asym-
metric reactions2,3 and identified as calpain and thrombin
inhibitors.4 Morpholin-3-one was generally obtained from
aminoethanol and chloroacetyl chloride or aqueous gly-
oxylicacid,3,5 while morpholin-2-one was prepared from
aminoethanol and bromoacetate.6 These reactions re-
quired anhydrous conditions or strong bases as catalysts.
Dahlgren and co-workers7 reported the synthesis of mor-
pholinone from malic acid. However, such approach was
a multistep process and required highly toxic catalysts.
Therefore, manipulation of the morpholinone skeleton
through mild and simple methods remained a great chal-
lenge. The reactions employing multiple-bond substrates
have proven to be very efficient for the straightforward
construction of numerous heterocycles.8 We report herein
a simple and efficient method for the selective construc-
tion of both morphlin-2-one and morphlin-3-one hetero-
cycles from N-substituted aminoethanols and divinyl
fumarate under catalyst-free conditions.
O
O
O
R
OH
N
N
O
H
R
1a–j
3a–j
+
O
+
R
O
N
O
O
O
O
O
4a–j
O
2
+
O
R
O
N
O
H
O
5a–j
Scheme 2 Reaction of N-substituted aminoethanol 1 with divinyl
fumarate 2 at 50 °C
The starting N-substituted aminoethanol derivatives were
easily accessible from commercially available aldehydes
or ketones with aminoethanol by a two-step reaction ac-
cording to a previously reported procedure (Scheme 1).9
Aldehydes or ketones were treated with aminoethanol in
dichloromethane to give the imines. Without further puri-
fication, the product was reduced with NaBH4 in THF,
giving the aminoethanol derivatives in yields ranging
from 75% to 87%.
tive. The substituted nitrogen acylation product was ob-
tained. However, when diethyl fumarate was added to the
toluene solution of N-benzylethanolamine under the same
conditions, the substituted nitrogen added to the double
bond of diethyl fumarate through the Michael addition
pathway.10 These results demonstrated that the nitrogen of
aminoethanol derivatives underwent acylation reaction
with vinyl esters, but Michael addition with fumarate.
Then divinyl fumarate was used as substrate to react with
N-benzylethanolamine under the same conditions
(Scheme 2). As expected, the reaction generated two cy-
clic products,11 containing morpholin-2-one (3a) as the
main product (83%) and morpholin-3-one (4a) as the mi-
nor product (6%). The structures of 3a and 4a were con-
firmed by 1H NMR, 13C NMR, HRMS, and two-
dimensional NMR techniques (HMBC, HMQC).
Two experiments were conducted to test the reactivities of
ethanolamine derivatives. We firstly examined the reac-
tion of N-benzylethanolamine with divinyl succinate in
toluene at 50 °C for 40 hours without any catalyst or addi-
SYNLETT 2008, No. 5, pp 0679–0682
x
x.
x
x.
2
0
0
8
Advanced online publication: 26.02.2008
DOI: 10.1055/s-2008-1032109; Art ID: W20408ST
© Georg Thieme Verlag Stuttgart · New York

680
Q.-Y. Zhang et al.
LETTER
Table 1 Reaction of N-Benzylethanolamine with Divinyl Fumarate
Table 2 The Reaction of N-Substituted Aminoethanols with Divi-
in Different Solvents for 40 Hoursa
nyl Fumarate in TBME and DMSOa
Entry
Solvent
Time Yields of 3a Yield of 4a
Entry R
MTBE (yield, %)b DMSO (yield, %)b
(h)
40
40
40
40
40
40
40
40
40
(%)
30
67
84
83
66
56
15
13
2
(%)
3
4
5
3
4
5
1
2
3
4
5
6
7
8
9
cyclohexane
IPE
2
1
a
b
c
d
e
f
Bn
84
<1
<1
<1
5
0
2
66
70
72
68
70
77
0
0
<1
1
2
4-MeOC6H4CH2 82
4-Me2NC6H4CH2 80
0
8
0
MTBE
toluene
acetone
MeCN
pyridine
DMF
3
0
6
0
6
4
c-Hex
t-Bu
i-Pr
75
77
72
85
86
0
0
15
17
6
0
12
30
70
40
66
5
4
0
0
6
8
0
0
7
g
h
i
Et
0
0
84
86
0
0
8
Me
0
0
0
0
DMSO
9c
10c
Ph2CH
Ph
0
80
82
0
78
80
a Reactions were carried out on 0.05 mol scale of N-benzylethanol-
amine with 1.2 equiv of divinyl fumarate in 5 mL solvent at 50 °C.
j
0
0
0
0
a Reaction conditions: N-substituted aminoethanol (0.05 mol), divinyl
fumarate (0.06 mol) in solvent at 50 °C for 40 h.
b Isolated yield.
Enlightened by the above results, we optimized the reac-
tion conditions using N-benzylethanolamine as a model
substrate. Some conventional organic solvents with dif-
ferent log P values were screened for the reaction of 1a
with 2. The results are shown in Table 1. In apolar sol-
vents such as cyclohexane, isopropyl ether (IPE), methyl
tert-butyl ether (MTBE) and toluene, the main product
was 3a. Excellent selectivity was achieved in MTBE and
only 3a was observed (Table 1, entries 1–4). In polar sol-
vents such as acetone, acetonitrile, pyridine, and DMF, a
mixture of 3a and 4a was obtained (Table 1, entries 5–8).
As the solvent polarity increased, the yield of 4a in-
creased. Especially in DMSO, the reaction could generate
66% yield of 4a, while only 2% of 3a was observed
(Table 1, entry 9). It was indicated that the cycloproduct
could be manipulated by changing the solvent. Thus,
TBME and DMSO were chosen as solvents in the follow-
ing experiments.
c Reacted for 72 h.
derivatives only generated acyclic products (5i,j, Table 2,
entries 9 and 10).
Reactions of other structurally diverse aminoethanol de-
rivatives with divinyl fumarate in DMSO were also inves-
tigated and the results are shown in Table 2. For methyl,
ethyl, phenyl, or benzhydryl N-substituted aminoetha-
nols, the reaction results were similar to that obtained in
MTBE (Table 2, entries 7–10). For benzyl-, cyclohexa-
nyl-, tert-butyl- and isopropyl-substituted aliphatic ami-
nothanol derivatives, the reactions mainly generated
morpholin-3-one (4a–f, Table 2, entries 1–6). The yields
ranged from 66% to 77%. The yields of byproduct mor-
pholin-2-one (3a–f) were about 6–17%.
In theory, aminoethanol has two reacting groups and both
of them may participate in acylation or Michael addition.
There are four possible reaction pathways between ami-
Having the optimal conditions in hand, other N-substitut-
ed aminoethanols were examined and the results are sum-
marized in Table 2. Reaction of 1a with 2 in MTBE could
generate 84% of morpholin-2-one (3a) after 40 hours at
50 °C (Table 2, entry 1). The yield of morpholin-3-one
(4a) was less than 1%. As can be seen from Table 2, the
substituent groups on the benzyl had no obvious influence
on the conversion and the reaction selectivity (Table 2,
entries 2 and 3). We then examined the reaction of five
different aliphatic N-substituted aminoethanols with 2 in
MTBE (Table 2, entries 4–8). Sterically hindered aliphat-
ic N-substituted aminoethanols could result in the main
product of morpholin-2-one (3d–f) in high yields, while
providing only 4–8% of morpholin-3-one (4d–f, Table 2,
entries 4–6). The reaction of methyl- or ethyl-substituted
aminoethanols only resulted in the corresponding mor-
pholin-2-one (3g,h, Table 2, entries 7 and 8). The reaction
of N-benzhydryl- or N-phenyl-substituted aminoethanol
noethanols derivatives and divinyl fumarate
1
(Scheme 3): 1) the substituted nitrogen adds to the double
bond of divinyl fumarate, followed by ester formation at
the tethered primary alcohol, providing morpholin-2-one
derivatives 3 as shown in path A; 2) the O-acylation oc-
curs first, followed by intramolecular Michael addition of
the nitrogen atom to the double bond of divinyl fumarate,
affording 3 via the intermediates 5 in path B; 3) the N-acy-
lation between aminoethanol derivatives 1 and divinyl fu-
marate 2 first gives the amide, then the double bond of
divinyl fumarate is attacked by the hydroxy group to pro-
vide morpholin-3-one derivatives 4 in path C; 4) Michael
addition of the hydroxy group followed by intramolecular
acylation of the amino moiety provides 4 in path D.
It is well known that acylation of amines is much more
sensitive to steric factor than is Michael addition. All of
Synlett 2008, No. 5, 679–682 © Thieme Stuttgart · New York

LETTER
Selective Construction of Morpholin-2-one and Morpholin-3-one Heterocycles
681
R
N
HO
R
O
O
O
path C
path A
OH
O
N
O
O
O
O
R
O
O
R
N
N
O
O
HN
O
R
3
O
O
+
R
HN
4
R
O
O
OH
HN
O
O
2
1
O
O
O
5
O
O
O
O
path B
path D
O
O
Scheme 3 Proposed mechanism of cyclization
the substrates in the reaction bore a substitution group on
the nitrogen. Thus, acylation between amines and vinyl
ester was disfavored and the amines would first take part
in the Michael addition. Here, for less bulky aminoetha-
nols (R = Me, Et), amines were more active than alcohols
as nucleophiles, and amines preferred to undergo Michael
addition in both polar and nonpolar solvents. Thus, the re-
action would mainly follow path A, resulting in the forma-
tion of 3 as the sole product (Table 2, entries 7 and 8). For
other relatively bulky aminoethanols including N-alkyl-
and benzyl-substituted ones (Table 2, entries 1–6), the re-
activity of bulky amine for Michael addition was also
more reactive than alcohol as nucleophiles. Consequently,
the reaction probably followed path A in nonpolar sol-
vents such as MTBE. Also, it was possible to form 3 via
the intermediates 5 in path B, where the alcohol took part
in the first reaction. However, the solvent effect had to be
considered when the reaction was carried out in DMSO.
The polar solvent enhances the nucleophilicity of alcohols
much more significantly than that of amines because alco-
hols are better proton donors in forming hydrogen bonds.
Thus, Michael addition of the oxygen atom was favored in
polar solvents, leading to products 4. For the bulky and
low-nucleophilicity aminoethanols (Table 2, entries 9 and
10), only O-acylation products were isolated in both non-
polar and polar solvents.
Acknowledgment
We gratefully acknowledge financial support from the Zhejiang
Provincial Science and Technology Council (Project No.
2006C11197)
References and Notes
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In conclusion, a simple and efficient route for the selective
synthesis of morpholine-2-one and morpholine-3-one het-
erocycles has been developed from N-substituted amino-
ethanols. The modulation for the synthesis of morpholin-
2-one and morpholin-3-one heterocycles was easily
achieved by just changing solvents. Furthermore, the res-
olution of racemic morpholinone by enzyme action is un-
der investigation in our lab.
(7) Dahlgren, A.; Johansson, P. O.; Kvarnstrom, I.; Musil, D.;
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Synlett 2008, No. 5, 679–682 © Thieme Stuttgart · New York

682
Q.-Y. Zhang et al.
LETTER
(9) (a) Layer, R. W. Chem. Rev. 1963, 63, 489. (b) Haury, V. E.
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which was purified by column chromatography (hexane–
EtOAc = 3:1) to give the product. 1H NMR (500 MHz,
CDCl3): d = 7.26–7.36 (m, 6 H), 4.89 (dd, 1 H, J = 1.50,
12.40 Hz), 4.76 (d, 1 H, J = 14.65 Hz), 4.56 (m, overlapped,
2 H), 4.50 (d, 1 H, J = 14.65 Hz), 3.99 (m, 1 H), 3.79 (m,
overlapped, 1 H), 3.52 (d, 1 H, J = 4.25 Hz), 3.12 (m, 2 H),
3.02 (m, 1 H) ppm. 13C NMR (125 MHz, CDCl3): d =
168.05, 168.02, 141.34, 136.31, 129.03, 128.51, 128.02,
98.30, 74.38, 63.42, 50.20, 46.08, 37.35 ppm. IR (neat):
1751 (C=O), 1647 (C=C) cm–1. ESI-MS: m/z = 275.8 [M +
H]+. HRMS: m/z calculated for C15H17NO4: 275.1158;
found: 275.1154.
(10) Supplementary information can be obtained from the
corresponding author upon request.
(11) Typical Procedure for the Synthesis of Morpholin-3-one
Benzylethanolamine (0.75 g, 0.05 mol) was dissolved in
MTBE and the divinyl fumarate (1.68 g, 0.1 mol) was added.
The reaction mixture stirred at 50 °C and monitored by TLC.
Upon completion of the reaction, the combined solvents
were removed under reduced pressure to give a yellow oil
Synlett 2008, No. 5, 679–682 © Thieme Stuttgart · New York

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