Syntheses on the basis of 4-(oxiran-2-ylmethyl)morpholine

Article abstract of DOI:10.1134/S1070428006120141

4-(Oxiran-2-ylmethyl)morpholine was synthesized and converted into new morpholino derivatives of propan-2-ols and butan-4-olides.

Full text of DOI:10.1134/S1070428006120141

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2006, Vol. 42, No. 12, pp. 1845–1847. © Pleiades Publishing, Inc., 2006.
Original Russian Text © E.G. Mesropyan, A.S. Galstyan, A.A. Avetisyan, 2006, published in Zhurnal Organicheskoi Khimii, 2006, Vol. 42, No. 12,
pp. 1854–1856.
Syntheses on the Basis of 4-(Oxiran-2-ylmethyl)morpholine
E. G. Mesropyan, A. S. Galstyan, and A. A. Avetisyan
Erevan State University, ul. A. Manukyana 1, Erevan, 375049 Armenia
e-mail: mag_union@yahoo.com
Received December 9, 2005
Abstract—4-(Oxiran-2-ylmethyl)morpholine was synthesized and converted into new morpholino derivatives
of propan-2-ols and butan-4-olides.
DOI: 10.1134/S1070428006120141
Systems containing a morpholine fragment attract
interest as potential biologically active compounds.
Many morpholine derivatives are tranquilizers, syn-
thetic narcotic analgetics, and anticonvulsant and anti-
tuberculous agents, some of which have found applica-
tion in medicine (e.g., Trioxazine, Dextromoramide,
Ethmosine, Ofloxacin, etc.) [1]. 4-(Oxiran-2-ylmethyl)-
morpholine may serve as a basis for the preparation of
new derivatives of morpholine-containing vicinal amino
alcohols as promising synthons in the design of natural
and biologically active organic compounds [2–10].
Various vicinal amino alcohols are now used in medi-
cal practice; a number of these compounds are β-ad-
renergic blocking agents [1, 11, 12] exhibiting a specif-
ic effect on the stimulation of β-adrenoceptive systems.
1-chloro-2,3-epoxypropane and morpholine. These
compounds reacted at an equimolar ratio in aqueous
medium at 0–5°C to give in high yield 1-chloro-3-
morpholinopropan-2-ol (II), and treatment of the latter
with a base (KOH) in xylene at 0–5°C gave compound
I (method a) in a satisfactory yield (76%, calculated on
the initial chloroepoxypropane). It was more advan-
tageous to use procedures b and c which required no
isolation of alcohol II and ensured higher yields of the
target product.
By condensation of morpholinomethyloxirane I
with aniline (III), p-anisidine (IV), 1-naphthylamine
(
V), and phenyl(ethyl)amine (VI) at a reactant molar
ratio of 1:3 we obtained the corresponding amino
alcohols VII–X (Scheme 1). Treatment of alcohol X
with acetyl chloride afforded 2-[ethyl(phenyl)amino]-
1-(morpholinomethyl)ethyl acetate hydrochloride (XI).
We were the first to develop procedures for the
synthesis of 4-(oxiran-2-ylmethyl)morpholine (I) from
Scheme 1.
O
N
Cl
KOH
N
Cl
+
O
O
OH
O
O
N
H
II
Ar
I
Ph
Ar(R)NH (III–VI)
N
N
N
AcCl
N
N
·
HCl
O
O
OH
R
O
OAc Et
XI
VII–X
MeONa
R'CH COOEt (XII, XIII)
R'
2
O
O
XIV, XV
III, VII, R = H, Ar = Ph; IV, VIII, R = H, Ar = 4-MeOC
6 4
H ; V, IX, R = H, Ar = 1-naphthyl; VI, X, R = Et, Ar = Ph;
XII, XIV, R' = EtOCO; XIII, XV, R' = MeCO.
1845

1
846
MESROPYAN et al.
Compound I reacted with diethyl malonate in metha-
nol in the presence of sodium methoxide to give ethyl
0°C, 92.5 g (1.0 mol) of cold 1-chloro-2,3-epoxy-
propane was added, and the mixture was stirred for 3 h
at 0–5°C. Toluene, 50 ml, was added, potassium hy-
droxide, 100 g (1.8 mol), was added in small portions,
the mixture kept for 18 h at room temperature and
5
(
-morpholino-2-oxotetrahydrofuran-3-carboxylate
XIV), and the reaction of I with ethyl acetoacetate
under analogous conditions led to the formation of
-acetyl-5-morpholinotetrahydrofuran-2-one (XV)
3
filtered, the filtrate was dried over MgSO , the solvent
4
(
Scheme 1).
was removed, and the residue was distilled under
reduced pressure. Yield 124 g (87%).
EXPERIMENTAL
1
-Morpholino-3-phenylaminopropan-2-ol (VII).
A mixture of 8.37 g (0.09 mol) of aniline, 4.3 g
0.03 mol) of compound I, and 1 ml of ethanol was
1
The H NMR spectra were recorded from solutions
(
in DMSO-d at 30°C on a Varian Mercury-300 spec-
6
heated for 5.5 h at 85°C under continuous stirring. The
mixture was cooled, and the precipitate was filtered off
and recrystallized from ethanol. Yield 5.4 g (76%),
mp 122–122.5°C. R 0.41 (CHCl –EtOH–hexane, 1.0:
trometer (300 MHz). The IR spectra were obtained on
a Specord 75IR spectrophotometer from samples dis-
persed in mineral oil or from thin films. The purity of
the products was checked by TLC on Silufol UV-254
plates; spots were visualized by treatment with iodine
vapor.
f
3
–
1
0
3
.2:0.2). IR spectrum, ν, cm : 3310 (NH), 3105 (OH),
030 (CHarom), 1600 (C=Carom), 1590 (δNH). H NMR
1
spectrum, δ, ppm: 2.24–2.46 m (6H, CH N), 3.11 d.d
2
1
-Chloro-3-morpholinopropan-2-ol (II). Water,
5 ml, was added on cooling to 26.1 g (0.3 mol) of
morpholine, the mixture was cooled to 0°C, 27.35 g
0.3 mol) of cold 1-chloro-2,3-epoxypropane was
(
1H, CH NH), 3.34 d.d (1H, CH NH), 3.58 t (4H,
2
2
2
CH O), 4.05 m (1H, CHOH) 4.81 d (1H, OH),
2
4
.98 br.s (1H, NH), 6.52 t (1H, Harom), 6.57 d (2H,
(
Harom), 7.05 t (2H, Harom). Found, %: C 65.87; H 8.69;
N 11.51. C H N O . Calculated, %: C 66.07; H 8.53;
added, and the mixture was stirred for 4 h at 0–5°C.
Removal of water left compound II. Yield 49.4 g
(
1
3
20
2
2
2
0
N 11.85.
92%), bp 118–120°C (1.5 mm), n = 1.4936.
D
1
-(4-Methoxyphenylamino)-3-morpholinopro-
4
-(Oxiran-2-ylmethyl)morpholine (I). a. Potas-
pan-2-ol (VIII). p-Anisidine, 11.07 g (0.09 mol), was
dissolved in 10 ml of ethanol, 4.3 g (0.03 mol) of
compound I was added, and the mixture was heated for
h at 85–90°C under continuous stirring. The solvent
was removed, and the residue was distilled under
reduced pressure. Yield 6.55 g (82%), bp 195–197°C
(0.5 mm), n
hexane, 1.0:0.2:0.2). IR spectrum, ν cm : 3480 (OH),
3325 (NH), 3030 (C–Harom), 1610 (C=Carom), 1580
sium hydroxide, 18.2 g (0.325 mol), was added in
small portions on cooling to a solution of 49 g
0.27 mol) of alcohol II in 70 ml of xylene. The mix-
ture was kept for 12 h at room temperature, and the
solvent was removed to leave compound I. Yield
3.6 g (87%), bp 120°C (39 mm), 100°C (18 mm),
= 1.4685, d4 = 1.067, R 0.52 (CHCl –acetone–
MeOH, 0.3 : 1.5 : 1.6). IR spectrum, ν cm : 1105
(
6
3
n
2
0
20
20
D
= 1.5604, R
0.47 (CHCl
–EtOH–
D
f
3
f
3
–
1
–1
1
(
(
C–O), 1250 (C–N). H NMR spectrum, δ, ppm: 3.6 t
4H, CH OCH ), 2.96 m (1H, CH) 2.63 m (1H,
1
(δNH). H NMR spectrum, δ, ppm (J, Hz): 2.24–
2
2
CH OCH), 2.68–2.34 m (6H, CH N), 2.18 m (1H,
2.46 m (6H, CH N), 3.04 d.d (1H, CH N, J = 13.8,
2 2
2
2
CH OCH). Found, %: C 58.72; H 9.15; N 9.78. MR =
7.5), 3.25 d.d (1H, CH N, J = 13.8, 4.2), 3.67 s (3H,
2
D
2
3
7.30. C H NO . Calculated, %: C 58.51; H 9.31;
CH ), 4.01 m (1H, CHOH), 4.62 br.s (1H, NH), 4.85 d
7
13
2
3
N 9.45. MR = 37.32.
(1H, OH), 6.55 d (2H, Harom), 6.64 d (2H, Harom).
D
Found, %: C 63.41; H 8.62; N 10.26. C H N O . Cal-
b. Water, 30 ml, was added on cooling to 52.2 g
14 22
2
3
culated, %: C 63.14; H 8.33; N 10.52.
-Morpholino-3-(1-naphthylamino)propan-2-ol
IX). 1-Naphthylamine, 12.87 g (0.09 mol), was dis-
(
0
0.6 mol) of morpholine. The mixture was cooled to
°C, 55.5 g (0.6 mol) of cold 1-chloro-2,3-epoxy-
1
propane was added, and the mixture was stirred for 4 h
at 0–5°C. Xylene, 50 ml, was added, 60 g (1.07 mol)
of potassium hydroxide was added in small portions,
and the mixture was kept for 12 h at room temperature.
The solvent was removed to obtain compound I. Yield
(
solved in 25 ml of ethanol, 4.3 g (0.03 mol) of com-
pound I was added, and the mixture was heated for 4 h
at 85–90°C under continuous stirring. The solvent was
removed, and the residue was distilled under reduced
pressure. Yield 7.2 g (84%), bp 222–223°C (0.3 mm),
6
6.92 g (78%).
2
4
c. Water, 20 ml, was added on cooling to 87 g
1.0 mol) of morpholine, the mixture was cooled to
n
= 1.6166, R 0.52 (CHCl –EtOH–hexane, 1.0:0.2:
D f 3
–
1
(
0.2). IR spectrum, ν cm : 3450 (OH), 3230 (NH),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 12 2006

SYNTHESES ON THE BASIS OF 4-(OXIRAN-2-YLMETHYL)MORPHOLINE
1847
1
3
030 (C–Harom), 1605 (C=Carom), 1580 (δNH). H NMR
off, and the residue was subjected to fractional dis-
tillation under reduced pressure. Yield 5.2 g (58%),
spectrum, δ, ppm (J, Hz): 2.23–2.46 m (6H, CH N),
.15 d.d (1H, CH N, J = 13.8, 7.5), 3.38 d.d (1H,
2
2
0
–1
3
bp 166°C (7 mm), n = 1.4890. IR spectrum, ν, cm :
2
D
CH N, J = 13.8, 4.2), 3.59 t (2H, CH O), 4.0 m (1H,
3440 (OH, enol), 1780 (C=O, lactone), 1740 (C=O,
ester), 1650 (C=C, enol). H NMR spectrum, δ, ppm:
2
2
1
CHOH), 4.80 br.s (1H, OH), 5.56 br.s (1H, NH),
.54 d (1H, Harom), 7.05 d (1H, Harom), 7.25 t (1H,
Harom), 7.38 m (2H, Harom), 7.67 t (1H, Harom), 7.98 t
1H, Harom). Found, %: C 71.01; H 7.56; N 9.99.
C H N O . Calculated, %: C 71.30; H 7.74; N 9.78.
6
1.5 t (3H, OCH CH ), 2.20 m (2H, 4-H, furan), 2.68 m
2
3
(6H, CH N), 3.6 t (4H, CH OCH ), 4.05 q (2H,
2
2
2
(
OCH CH ), 4.2 m (1H, 5-H, furan), 5.5 t (1H, 3-H,
2
3
furan). Found, %: C 55.86; H 7.14; N 5.31.
17
22
2
2
C H NO . Calculated, %: C 56.02; H 7.44; N 5.44.
1
2
19
5
1
-[Ethyl(phenyl)amino]-3-morpholinopropan-2-
ol (X) was synthesized as described above for com-
pound VII (the mixture was heated for 11 h at 90–
3-Acetyl-5-morpholinotetrahydrofuran-2-one
(XV) was synthesized in a similar way. Yield 4.9 g
–
1
9
5°C). After removal of the solvent, the residue was
(62%), bp 198–199°C (3 mm). IR spectrum, ν cm :
1
distilled under reduced pressure. Yield 5.2 g (67%),
1785 (C=O, lactone), 1720 (C=O, ketone). H NMR
1
8
spectrum, δ, ppm: 2.24 m (2H, 4-H, furan), 2.65 m
bp 168–170°C (0.5 mm), nD = 1.5485, R 0.47
f
(
6H, CH N), 2.38 s (3H, CH CO), 3.6 t (4H,
(
CHCl –EtOH–hexane, 1:0.2:0.2). IR spectrum, ν,
2
3
3
–
1
CH OCH ), 4.20 m (1H, 5-H, furan), 5.4 t (1H, 3-H,
cm : 3330 (OH), 3030 (C–Harom), 1600 (C=Carom).
2
2
1
furan). Found, %: C 58.36; H 7.24; N 5.88.
C H NO . Calculated, %: C 58.14; H 7.54; N 6.16.
H NMR spectrum, δ, ppm: 1.12 t (3H, CH CH ),
2
3
2
.23–2.46 m (6H, CH N), 3.24–3.41 m (4H, CH NPh),
11 17
4
2
2
3
.58 t (4H, CH O), 3.98 m (1H, CHOH), 4.80 br.s
2
REFERENCES
(
(
1H, OH), 6.60 t (1H, Harom), 6.78 d (2H, Harom), 7.13 t
2H, Harom). Found, %: C 67.92; H 9.24; N 10.25.
1
. Mashkovskii, M.D., Lekarstvennye sredstva (Drugs),
Moscow: Novaya Volna, 2002, vol. 1, pp, 253–263, 368,
385; vol. 2, pp. 295, 303, 362.
2. Bergmeier, S.C., Tetrahedron, 2000, vol. 56, p. 2561.
. Karpf, M. and Trussardi, R.J., J. Org. Chem., 2001,
C H N O . Calculated, %: C 68.15; H 9.15; N 10.60.
15
14
2
2
2
-[Ethyl(phenyl)amino]-(1-morpholinomethyl)-
ethyl acetate hydrochloride (XI). A mixture of 3 g
0.0114 mol) of alcohol X, 0.89 g (0.0114 mol) of
(
3
acetyl chloride, and 8 ml of toluene was kept for 1 h at
room temperature, heated for 30 min at 90–95°C, and
cooled, and the precipitate was filtered off, washed
with toluene, and dried. Yield 3.4 g (87%), mp 134–
vol. 66, p. 2044.
4. Inaba, T., Yamada, Y., Abe, H., Sagawa, S., and Cho, H.,
J. Org. Chem., 2000, vol. 65, p. 1623.
5. Cristau, H.-J., Pirat, J.-L., Drag, M., and Kafarski, P.,
–
1
1
35°C. IR spectrum, ν, cm : 3030 (C–Harom), 1740
Tetrahedron Lett., 2000, vol. 41, p. 9781.
1
(
C=O), 1600 (C=Carom). H NMR spectrum, δ, ppm:
6. Hudlicky, T., Abbod, K.F., Entwisle, D.A., Fan, R.,
Maurya, R., Thorpe, A.J., Bolonick, J., and Myers, B.,
Synthesis, 1996, p. 897.
1
2
.12 t (3H, CH CH ), 1.97 s (3H, CH CO), 2.31–
2
3
3
.50 m (6H, CH N), 3.24–3.41 m (4H, CH NPh), 3.59 t
2
2
7
8
9
. Ger. Patent Appl. no. 19724186, 1998; Ref. Zh., Khim.,
002, no. 19O116P.
(
4H, CH O), 3.98 m (1H, CHOH), 6.60 t (1H, Harom),
2
2
6
.78 d (2H, Harom), 7.13 t (2H, Harom). Found, %:
. Sabitha, G., Babu, R.S., Rajkumar, M., and Yadav, J.S.,
Org. Lett., 2002, p. 343.
C 59.21; H 8.16; N 8.35. C H N O ·HCl. Calculat-
17
26
2
3
ed, %: C 59.55; H 7.94; N 8.17.
. Mesropyan, E.G., Ambartsumyan, G.B., Avetisyan, A.A.,
Galstyan, A.S., and Arutyunova, I.R., Russ. J. Org.
Chem., 2005, vol. 41, p. 67.
0. Mesropyan, E.G., Ambartsumyan, G.B., Avetisyan, A.A.,
Galstyan, A.S., and Khachatryan, A.G., Khim. Getero-
tsikl. Soedin., 2005, no. 8, p. 1135.
Ethyl 5-morpholino-2-oxotetrahydrofuran-3-car-
boxylate (XIV). Metallic sodium, 0.9 g (0.038 mol),
was added in small pieces to a solution of 0.052 mol of
diethyl malonate in 7 ml of methanol. When the mix-
ture warmed up to 45°C, 5 g (0.035 mol) of compound
I was added dropwise, and the mixture was kept for
1
1
1. Shvaika, Ol., Osnovi sintezu likars’kikh rechovii
1
8 h at room temperature, heated for 4 h at 50–55°C,
(Principles of Synthesis of Drugs), Donets’k: Skhidnii
Vidavnichii Dim, 2002.
12. Lukevits, E.Ya., Libert, L.I., and Voronkov, M.G., Usp.
Khim., 1970, vol. 29, p. 2005.
neutralized with 15.4 ml of 31% hydrochloric acid,
diluted with 100 ml of acetone, and filtered. The fil-
trate was dried over MgSO , the solvent was distilled
4
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 12 2006