Syntheses on the basis of diethyl (2-morpholinoethyl)malonate

Article abstract of DOI:10.1134/S107042801007002X

New functionally substituted butan-4-olides were synthesized by reactions of diethyl (2-morpholinoethyl) malonate with 2-(allyloxymethyl)oxirane, 4-(oxiran-2-ylmethyl)morpholine, N-ethyl-N-(oxiran-2-ylmethyl)aniline, and 1-chloro-2,3-epoxypropane. 5-[2-(M

Full text of DOI:10.1134/S107042801007002X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 7, pp. 968–970. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © E.G. Mesropyan, A.S. Galstyan, A.A. Avetisyan, G.B. Ambartsumyan, 2010, published in Zhurnal Organicheskoi Khimii, 2010,
Vol. 46, No. 7, pp. 972–974.
Syntheses on the Basis of Diethyl (2-Morpholinoethyl)malonate
E. G. Mesropyan, A. S. Galstyan, A. A. Avetisyan†, and G. B. Ambartsumyan
Erevan State University, ul. A. Manukyana 1, Erevan, 375025 Armenia
e-mail: mag_union@yahoo.com
Received October 5, 2009
Abstract—New functionally substituted butan-4-olides were synthesized by reactions of diethyl (2-mor-
pholinoethyl)malonate with 2-(allyloxymethyl)oxirane, 4-(oxiran-2-ylmethyl)morpholine, N-ethyl-N-(oxiran-
2-ylmethyl)aniline, and 1-chloro-2,3-epoxypropane. 5-[2-(Morpholino)ethyl]barbituric and -thiobarbituric acids
were also synthesized.
DOI: 10.1134/S107042801007002X
Organic oxides are universal starting compounds
for the synthesis of butanolides. Some publications in
this field are related to syntheses of biologically active
natural compounds [1–5]. We have developed a proce-
dure for the preparation of diethyl (2-morpholinoethyl)-
malonate (I) from diethyl malonate sodium salt and
4-(2-chloroethyl)morpholine in ethanol. Diester I may
be used as a basis for the synthesis of new morpholine-
containing lactones. It is known that molecules of
many biologically active compounds, in particular
tranquilizers, synthetic narcotic analgesics, anticon-
vulsants, and antituberculous agents, include a mor-
pholine fragment [6].
By condensation of diester I with 2-(allyloxy-
methyl)oxirane, 4-(oxiran-2-ylmethyl)morpholine, and
N-ethyl-N-(oxiran-2-ylmethyl)aniline (reactant ratio
1:1) in anhydrous ethanol we obtained 5-substituted
3-(2-morpholinoethyl)tetrahydrofuran-2-ones VI–VIII
(Scheme 1). The reaction begins with heterolytic
cleavage of the epoxide C–O bond according to the
Scheme 1.
O
OEt
OEt
Cl
O
O
EtOH, EtONa
N
N
+
O
O
O
EtO
OEt
I
O
N
HCl
R
O
R
O
O
O
OEt
ONa
II–IV
VI–VIII
EtOH, EtONa
R
O
N
O
O
OEt
OEt
N
NH
R = Cl
O
N
O
O
IX
II, VI, R = CH2=CHCH2O; III, VII, R = morpholino; IV, VIII, R = Ph(Et)N; V, R = Cl.
†
Deceased.
968

SYNTHESES ON THE BASIS OF DIETHYL (2-MORPHOLINOETHYL)MALONATE
969
Scheme 2.
O
O
X
N
MeOH, MeONa
HN
I
+
H2N
NH2
X
N
H
O
X, XI
X, X = O; XI, X = S.
a solution of 19 g (0.127 mol) of 4-(2-chloroethyl)-
morpholine in 10 ml of ethanol was then added drop-
wise. The mixture was kept for 18 h at room tempera-
ture and heated for 7 h at 60–65°C, the solvent was
distilled off, water was added to the residue to dissolve
sodium chloride, the oily layer was separated, and the
aqueous layer was extracted with toluene (3×10 ml).
The extracts were combined with the oily material and
dried over MgSO4, the solvent was removed, and the
residue was distilled under reduced pressure. Yield
19.4 g (56%), bp 137–139°C (1 mm), nD20 = 1.4600,
Rf 0.49 (CHCl3–C6H14–MeCN, 1.0:1.8:0.6). IR spec-
Krasuskii rule, and γ-hydroxy acid derivatives thus
formed undergo intramolecular transesterification to
give butan-4-olides VI–VIII. Diester I reacted with
1-chloro-2,3-epoxypropane in anhydrous ethanol, and
subsequent reaction of the resulting chlorohydrin with
piperidine led to the formation of ethyl 3-(2-mor-
pholinoethyl)-5-(piperidinomethyl)tetrahydrofuran-
3-carboxylate (IX).
It is known that barbituric and thiobarbituric acid
derivatives are potential biologically active substances
[6, 7]. Therefore, new barbituric and thiobarbituric
acids having a morpholine fragment could attract
strong interest. Condensation of diester I with urea and
thiourea in methanol in the presence of sodium
methoxide afforded 5-(2-morpholinoethyl)barbituric
and -thiobarbituric acids X and XI, respectively
(Scheme 1).
1
trum, ν, cm–1: 1758, 1734 (C=O). H NMR spectrum,
δ, ppm: 1.15 t (6H, CH3), 1.82–2.20 m (2H, CHCH2),
2.32–2.57 m (6H, CH2N), 2.45 m (1H, CHCH2), 3.51–
3.85 m (8H, CH2O). Found, %: C 56.89; H 8.26;
N 5.38. C13H23NO5. Calculated, %: C 57.13; H 8.48;
N 5.12.
The optimal reaction conditions were found by
studying the effect of temperature, reaction time, reac-
tant ratio, and catalyst nature on the yield. The struc-
ture of the isolated compounds was determined on the
basis of their IR and H NMR spectra and elemental
analyses.
5-Allyloxymethyl-3-(2-morpholinoethyl)tetra-
hydrofuran-2-one (VI). Metallic sodium, 0.46 g
(0.02 mol), was added in small pieces to a solution of
5.46 g (0.02 mol) of compound I in 9 ml of ethanol.
When the mixture warmed up to 45°C, 2.51 g (2.6 ml,
0.022 mol) of oxirane II was added, and the mixture
was kept for 18 h at room temperature and heated for
3 h at 55–58°C. The mixture was neutralized with
1.36 ml of concentrated hydrochloric acid, 30 ml of
acetone was added, the mixture was filtered, the filtrate
was dried over MgSO4, the solvent was removed, and
the residue was distilled under reduced pressure. Yield
2.4 g (44%), bp 180°C (1 mm), nD16 = 1.4908, Rf 0.42
(C2H4Cl2–C6H14–MeOH, 2.0:1.1:0.5). IR spectrum, ν,
1
EXPERIMENTAL
1
The H NMR spectra were recorded at 30°C on
a Varian Mercury-300 spectrometer (300 MHz) using
DMSO-d6 as solvent. The IR spectra were measured on
a Specord 75IR or Nicolet FTIR NEXUS spectrometer
from samples dispersed in mineral oil or as thin films.
The purity of the products was checked by TLC on
Silufol UV-254 plates; spots were visualized by treat-
ment with iodine vapor. N-(Oxiran-2-ylmethyl)amines
III and IV were synthesized according to the proce-
dure reported in [8]. Ethanol was dehydrated and
purified as described in [9].
1
cm–1: 1770 (C=O), 1640 (C=C). H NMR spectrum,
δ, ppm: 1.44–1.76 m (2H, 4-H), 1.82–2.20 m (2H,
3-CH2), 2.32–2.57 m (8H, CH2N), 2.68 m (1H, 3-H),
3.45–3.62 m (6H, CH2O), 4.05 d.d (2H, CH2OAll),
4.50 m (0.45H, 5-H), 4.59 m (0.55H, 5-H), 5.17 d.q
(1H, =CH2), 5.24 d.q (1H, =CH2), 5.86 d.t.t (1H,
=CH). Found, %: C 52.70; H 8.86; N 5.49. C14H23NO4.
Calculated, %: C 62.43; H 8.61; N 5.20.
Diethyl (2-morpholinoethyl)malonate (I). Diethyl
malonate, 24 g (22.8 ml, 0.15 mol), was added drop-
wise to a solution of sodium ethoxide prepared from
60 ml of ethanol and 3 g (0.13 mol) of sodium, and
Compounds VII and VIII were synthesized in
a similar way.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010

MESROPYAN et al.
970
5-Morpholinomethyl-3-(2-morpholinoethyl)-
0.02 mol, was then added, and the mixture was heated
for 4 h more, diluted with 30 ml of water, and acidified
with 1.75 ml of 11.54 M hydrochloric acid. The precip-
itate was filtered off and recrystallized from water.
tetrahydrofuran-2-one (VII). Yield 3.5 g (59%),
bp 230°C (4 mm), mp 78–80°C (from hexane), Rf 0.25
(EtOH–MeOH–C2H4Cl2–H2O, 1.1:1.3:0.5:1.5). IR
1
spectrum: ν 1759 cm–1 (C=O). H NMR spectrum, δ,
Compound X. Yield 2.9 g (60%), mp 250–255°C
(decomp.), Rf 0.47 (EtOH–MeOH–MeCN–C2H4Cl2–
H2O, 1.0 :1.0 :1.0 :0.4 :1.0). IR spectrum, ν, cm–1:
3493, 3419, 3303, 3107 (NH, =C–OH), 1723, 1706,
ppm: 1.44–1.66 m (2H, 4-H), 1.82–2.20 m (2H,
3-CH2), 2.32–2.57 m (6H, CH2N), 2.68 m (1H, 3-H),
3.51–3.62 m (8H, CH2O), 4.50 m (0.8H, 5-H), 4.59 m
(0.2H, 5-H). Found, %: C 60.62; H 9.05; N 9.68.
C15H26N2O4. Calculated, %: C 60.38; H 8.78; N 9.39.
1
1700, 1696, 1670 (C=O), 1607 (=C–OH). H NMR
spectrum, δ, ppm: in DMSO-d6: 2.59 t (2H, 5-CH2),
3.07 t (2H, 5-CH2CH2), 2.80–3.60 br.s (4H, CH2N),
3.75 br.s (5H, CH2O, 5-H), 10.86 s (2H, NH); in
DMSO-d6–CF3COOD: 2.64 t (2H, 5-CH2), 3.03 br.m
(2H, 5-CH2CH2), 3.11 t (2H, CH2N), 3.55 br.m (2H,
CH2N), 3.71 br.m (2H, CH2O), 3.92 br.m (2H, CH2O).
Found, %: C 50.08; H 6.53; N 17.69. C10H15N3O4. Cal-
culated, %: C 49.79; H 6.27; N 17.42.
5-[Ethyl(phenyl)aminomethyl]-3-(2-morpholino-
ethyl)tetrahydrofuran-2-one (VIII). Yield 3.7 g
(56%), bp 250°C (4 mm), mp 86°C (from hexane),
Rf 0.47 (C2H4Cl2–C6H14–MeOH, 2.0:1.1:0.5). IR
spectrum, ν, cm–1: 1769 (C=O), 3032 (C–Harom), 1605
1
(C=Carom). H NMR spectrum, δ, ppm: 1.15 t (3H,
CH3), 1.44–1.66 m (2H, 4-H), 1.82–2.21 m (2H,
3-CH2), 2.35–2.52 m (6H, CH2N), 2.72 m (1H, 3-H),
3.40–3.64 m (8H, CH2O, 5-CH2), 4.59 m (0.85H, 5-H),
4.69 m (0.15H, 5-H); 6.59 m, 6.65 m, and 7.16 m
(5H, Harom). Found, %: C 68.37; H 8.22; N 8.17.
C19H28N2O3. Calculated, %: C 68.65; H 8.49; N 8.43.
Compound XI. Yield 3.2 g (62%), mp 280–287°C
(decomp.), Rf 0.5 (EtOH–MeOH–MeCN–C2H4Cl2–
H2O, 1.0 :1.0 :1.0 :0.4 :0.4). IR spectrum, ν, cm–1:
3449, 3348, 3172 (NH, =C–XH), 1670, 1650, 1615
(C=O), 1576 (=C–XH). 1H NMR spectrum, δ, ppm: in
DMSO-d6: 2.59 t (2H, 5-CH2), 3.07 t (2H, 5-CH2CH2),
2.80–3.60 br.s (4H, CH2N), 3.79 br.s (5H, CH2O, 5-H),
10.92 s (2H, NH); in DMSO-d6–CF3COOD: 2.64 t
(2H, 5-CH2), 3.03 br.m (2H, 5-CH2CH2), 3.15 t (2H,
CH2N), 3.55 br.m (2H, CH2N), 3.71 br.m (2H, CH2O),
3.92 br.m (2H, CH2O). Found, %: C 46.90; H 6.02;
N 16.59. C10H15N3O3S. Calculated, %: C 46.68;
H 5.88; N 16.33.
Ethyl 3-(2-morpholinoethyl)-2-oxo-5-(piperi-
dinomethyl)tetrahydrofuran-3-carboxylate (IX).
Metallic sodium, 0.46 g (0.02 mol), was added in small
pieces to a solution of 5.46 g (0.02 mol) of compound
I in 9 ml of ethanol. When the mixture warmed up to
45°C, 1.85 g (1.56 ml, 0.02 mol) of epoxide V was
added dropwise, and the mixture was heated for 3 h at
45–50°C. Piperidine, 1.7 g (1.95 ml, 0.02 mol), was
then added, the mixture was heated for 2 h at 45–50°C,
and 30 ml of ethanol was added. The mixture was
filtered, the filtrate was dried over MgSO4 and evap-
orated to dryness, and the residue was extracted with
hot hexane to isolate butanolide IX. Yield 3.4 g (46%),
nD24 = 1.4932, Rf 0.53 (C2H4Cl2–C6H14–EtOH, 1.2:0.8:
0.2). IR spectrum, ν, cm–1: 1778 (C=O, lactone), 1730
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