Synthesis of N-substituted oxazolidines and morpholines

Article abstract of DOI:10.1007/s11167-005-0502-x

A series of N-substituted oxazolidines and morpholines were prepared and characterized.

Full text of DOI:10.1007/s11167-005-0502-x

Russian Journal of Applied Chemistry, Vol. 78, No. 8, 2005, pp. 1301 1305. Translated from Zhurnal Prikladnoi Khimii, Vol. 78, No. 8, 2005,
pp. 1324 1328.
Original Russian Text Copyright
2005 by A. Magerramov, M. Magerramov, Makhmudova, Alizade.
ORGANIC SYNTHESIS
AND INDUSTRIAL ORGANIC CHEMISTRY
Synthesis of N-Substituted Oxazolidines and Morpholines
A. M. Magerramov, M. N. Magerramov, Kh. A. Makhmudova, and G. I. Alizade
Baku State University, Baku, Azerbaijan
Received July 28, 2004; in final form, April 2005
Abstract A series of N-substituted oxazolidines and morpholines were prepared and characterized.
Among synthetic antioxidants, amine and diamine
derivatives are the most similar to natural antioxidants
in the antiradical activity [1]. Therefore, it was of in-
terest to prepare new oxazolidine and morpholine
derivatives and to study their antioxidant properties.
the thermal esterification of carboxylic acids with
N-(2-hydroxyethyl)oxazolidine I and N-(2-hydroxy-
ethyl)morpholine II. Oxazolidine I was prepared by
condensation of diethanolamine with formaldehyde
[4], and morpholine II, by the reaction of morpholine
with ethylene chlorohydrin.
Condensation of N-methylethanolamine with alde-
hydes yielded N-methyloxazolidines [2]. Among N-sub-
stituted morpholine derivatives, 4-(2-hydroxyethyl)-,
2-methyl-4-(2-hydroxyethyl)-, and 2,2-dimethyl-4-
(2-hydroxyethyl)morpholines and 4-benzyl-4-(2-ben-
zyloxyethyl)morpholinium chloride are known [3].
The esterification was performed by the procedure
described in [5]. We found that, in the reactions of
carboxylic acids with oxazolidine I, the oxazolidine
ring is cleaved first, yielding a complex mixture of
products; in esterification of propionic acid, we iso-
1
lated a product identified by H NMR spectroscopy as
In this study, we prepared new nitrogen-containing
compounds, N-(2-alkanoyloxyethyl), N-(halobenzyl),
and N-(halobenzyloxyethyl) derivatives of 1,3-oxazo-
lidine and morpholine by reacting carboxylic acids
and halobenzyl chlorides with ethanolamine, dieth-
anolamine, ethylene chlorohydrin, morpholine, N-(2-
hydroxyethyl)-1,3-oxazolidine, and N-(2-hydroxyeth-
yl)-1,3-morpholine.
(CH3CH2COOCH2CH2)2NCH3.
We succeeded in preparation of N-(2-alkanoyloxy-
etyhyl)-1,3-oxazolidines III by three routes: ester
interchange of carboxylic acid methyl esters with
N-(2-hydroxyethyl)-1,3-oxazolidine I (route a), reac-
tion of carboxylic acid chlorides with N-(2-hydroxy-
ethyl)-1,3-oxazolidine sodium derivative IV (route b),
and esterification of carboxylic acids with diethanol-
amine, followed by condensation of the resulting ester
with formaldehyde (route c):
As a route to N-(2-alkanoyloxyethyl) derivatives
of 1,3-oxazolidine and morpholine, we first examined
O
O
O
Na
R C O CH2CH2N
R C Cl + NaOCH2CH2N
R C OCH3 + HOCH2CH2N
(b)
(a)
O
O
O
III
IV
I
O
R C OCH2CH2NCH2CH2OH
CH2OH
CH2O
O
R C OCH2CH2NHCH2CH2OH
(c)
O
R C OH + HOCH2CH2NHCH2CH2OH
1070-4272/05/7808-1301 2005 Pleiades Publishing, Inc.

1302
MAGERRAMOV et al.
Synthesis of esters III by the reaction of carboxylic
complications and yields N-(2-alkanoyloxyethyl)mor-
pholines V in high yield (80 90%).
acids with diethanolamine is complicated by forma-
tion of a minor amount of N-acyldiethanolamine,
which is difficult to separate.
Then we prepared new N-substituted 1,3-oxazoli-
dine and morpholine derivative by the reactions of
halobenzene chlorides with ethanolamine or morpho-
line:
In contrast to oxazolidine I, thermal esterification
of carboxylic acids with morpholine II occurs without
O
HN
HOCH2CH2NH2
CH2
N
O
CH2Cl
CH2NHCH2CH2OH
Y
X
Y
X
Y
X
Na, O
O
HOCH2CH2NH2
CH2O
CH2OCH2CH2NH2
CH2
N
O
Y
X
Y
X
ClCH2CH2OH
CH2OCH2CH2NHCH2CH2OH
Y
X
X
H2O
CH2O
CH2OCH2CH2
N
O
Y
where Y = H, X = F: Y = Cl, X = H.
Among the compounds synthesized, N-(2-ethano-
yloxyethyl)-1,3-oxazolidine was tested as antioxidant
in studying the photosynthetic activity of Synecho-
coccus sp. PCC 7942 (Cyanophyceae) cells as influ-
enced by various doses of UV-C radication and the ef-
fect of various chronic doses of UV-C radiation on
the duplication cycles of the population density of
these cells. We found that the antioxidant deactivates
the radicals generated in the cell throughout the ex-
periment and thus increases the relative contribution
from stimulation of cell fission by small doses of
UV-C radiation; upon a single introduction into the
cultural medium, the antioxidant restores the suppres-
sion of the fission rate of the irradiated cells by chron-
ically high UV-C radiation doses to the level of the
control population.
N-(2-Hydroxyethyl)-1,3-oxazolidine I. a. A 55-g
portion of diethanolamine was added dropwise over
a period of 20 min to a stirred mixture of 15 g of
paraform and 50 ml of benzene, heated to 80 C. After
that, the stirring was continued for an additional 1.5 h.
After the reaction completion, the solvent was dis-
tilled off; by distillation of the residue in a nitrogen
flow under reduced pressure, we isolated 53 g (87%)
of N-(2-hydroxyethyl)oxazolidine I, bp 79 80 C
1
(4 mm Hg), d420 1.1236, n2D0 1.4764. H NMR spec-
trum, , ppm: 2.68 (2H, NCH2), 2.98 (2H, NCH2),
3.61 t (2H, OCH2), 3.75 t (2H, OCH2), 4.25 s (2H,
NCH2O), 4.7 s (H, OH). 13C NMR spectrum,
ppm: 52.5, 57.0, 62.0, 66.0, 87.0.
,
C
Di(2-propanoyloxyethyl)methylamine. b. A mix-
ture of 11.7 g of oxazolidine I and 22.2 g of propionic
acid was stirred at 130 C for 6 h. After the reaction
completion, the mixture was neutralized with KOH
and filtered to remove the potassium propionate pre-
cipitate. By distillation in a nitrogen flow under re-
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker-
300 spectrometer.
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SYNTHESIS OF N-SUBSTITUTED OXAZOLIDINES AND MORPHOLINES
1303
duced pressure, we isolated 4 g (25%) of di(2-propan-
oyloxyethyl)methylamine, bp 102 103 C (2 mm Hg),
ring was continued at this temperature until the so-
dium fully dissolved. Then 0.08 mol of appropriate
carboxylic acid methyl ester was added dropwise at
120 C to the alcoholate, and the released methanol
was distilled off. After cooling, the organic matter
was separated, the residue was washed with benzene,
and, after common work-up, the target products were
isolated by distillation in a nitrogen flow under re-
duced pressure.
1
d420 1.0202, n2D0 1.4400. H NMR spectrum, , ppm:
1.18 t (6H, 2CH3), 2.32 q (4H, 2CH2), 2.4 s (3H,
CH3), 2.71 t [4H, N(CH2)2], 4.15 t (4H, 2OCH2).
13C NMR spectrum, C, ppm: 9.9, 27.0, 43.0, 56.0,
62.0, 172.5.
N-(2-Alkanoyloxyethyl)oxazolidines. c. A solu-
tion of 0.09 ml of I in m-xylene was added dropwise
to 0.005 mol of finely divided Na in 20 ml of m-xy-
lene. After the completion of the initially vigorous re-
action, the mixture was heated to 60 C, and the stir-
N-(2-Butanoyloxyethyl)-, N-(2-pentanoyloxyethyl)-,
N-(2-hexanoyloxyethyl)-, and N-(2-octanoyloxyethyl)-
1,3-oxazolidines were prepared (see table).
Yields, constants, and NMR spectra of the compounds synthesized
Yield,
%
bp,
C
Compound
n2D0
d420
NMR spectrum, , ppm
(P, mm Hg)
N-(2-Butanoyloxy-
ethyl)oxazolidine
50
90 92 (2)
1.4540 1.0560 1H NMR: 1.02 (3H, CH3), 1.69 m, (2H, CH2),
2.31 t, (2H, CH2), 2.78 t, (2H, OCH2), 3.72 t,
(2H, OCH2), 4.16 t, (2H, OCH2), 4.22 s, (2H,
NCH2O). 13C NMR: 12, 18, 37, 52, 62, 88, 172
N-(2-Pentanoyloxy-
ethyl)oxazolidine
53
97 98 (2)
1.4534 1.0372 1H NMR: 0.99 (3H, CH3), 1.41 m, (2H, CH2),
1.62 m, (2H, CH2), 2.3 m, (2H, CH2), 2.7 t, (2H,
NCH2), 3.0 t, (2H, OCH2), 3.72 t, (2H, NCH2),
4.15 t, (2H, OCH2), 4.25 s, (2H, NCH2O). 13C NMR:
14, 22, 24, 33.5, 53.5, 54, 62.8, 63.2, 86.75, 173
N-(2-Hexanoyloxy-
ethyl)oxazolidine
N-(2-Octanoyloxy-
ethyl)oxazolidine
N-(2-Ethanoyloxy-
ethyl)morpholine
N-(2-Propanoyloxy-
ethyl)morpholine
N-(2-Butanoyloxy-
ethyl)morpholine
55
54
70
75
90
108 109 (2) 1.4490 1.0023
125 (2)
69 70 (3)
80 81 (2)
1.4520 0.9841
1.4560 1.0723
1.4553 1.0439
108 109 (4) 1.4540 1.0231 1H NMR: 1.08 t, (3H, CH3), 1.75 m, (2H, CH2),
2.37 t, (2H, CH2), 2.58 t, (4H, N(CH2)2), 2.68 t,
(2H, NCH2), 3.71 t, (4H, O(CH2)2), 4.28 t, (2H,
OCH2). 13C NMR: 14, 18, 37, 54, 58, 62, 67, 172
115 116 (3) 1.4540 1.0072
N-(2-Pentanoyloxy-
ethyl)morpholine
N-(2-Hexanoyloxy-
ethyl)morpholine
N-(2-Octanoyloxy-
ethyl)morpholine
N-(o-Fluoroben-
zyl)morpholine
80
66
78
67
122 123 (3) 1.4555 0.9922
128 129 (2.5) 1.4560 0.9786
98 99 (5)
1.5140 1.1213 1H NMR: 2.32 t, (4H, N(CH2)2), 3.45 s, (2H,
C6H4CH2), 3.54 t, (4H, O(CH2)2), 6.86 7.34 m,
(4H, C6H4). 13C NMR: 53, 57, 67, 115, 123, 129,
132, 159.9, 163
N-(m-Chloroben-
zyl)morpholine
N-(o-Fluorobenzyl)-
ethanolamine
64
60
134 (3)
1.5180 1.1477
120 122 (3)
1.5140 1.1449
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 78 No. 8 2005

1304
MAGERRAMOV et al.
Table (Contd.)
Yield,
%
bp,
C
Compound
n2D0
d420
NMR spectrum, , ppm
(P, mm Hg)
138 140 (3)
87 88 (2)
N-(m-Chlorobenzyl)-
ethanolamine
N-(o-Fluorobenzyl)-
oxazolidine
N-(m-Chlorobenzyl)-
oxazolidine
60
77
87
1.5310 1.1709
1.5240 1.1680
108 110 (3)
1.5470 1.2010 1H NMR: 2.8 t, (2H, NCH2), 3.55 s, (2H,
C6H4CH2), 3.64 t, (2H, OCH2), 4.1 s, (2H,
NCH2O), 7.08 7.3 m, (4H, C6H4). 13C NMR:
52, 57.5, 86, 126.5, 127.5, 128.5, 129.5, 134, 141.5
1.5000 1.1012
N-(o-Fluorobenzyl)-
ethylamine
N-(m-Chlorobenzyl)-
ethylamine
N-(o-Fluorobenzyl-
oxyethyl)ethanol-
amine
N-(m-Chlorobenzyl-
oxyethyl)ethanol-
amine
50
50
30
86 87 (2)
110 112 (2)
150 151 (2)
1.5330 1.1489
1.5110 1.1418
30
170 172 (2)
1.5340 1.1683 1H NMR: 1.72 s, (2H, NH2), 2.7 t, (2H, NCH2),
3.35 t, (2H, OCH2), 4.35 s, (2H, C6H4CH2),
7.0 7.25 m, (4H, C6H4), 13C NMR: 42, 72,
73, 125, 127, 129, 134, 142
N-(o-Fluorobenzyl-
oxyethyl)oxazolidine
N-(m-Chlorobenzyl-
oxyethyl)oxazolidine
76
72
134 135 (2)
148 149 (2)
1.5070 1.1349
1.5370 1.1786 1H NMR: 2.66 t, (2H, NCH2), 2.86 t, (2H, NCH2),
3.49 t, (2H, OCH2), 3.61 t, (2H, OCH2), 4.15 s,
(2H, NCH2O), 4.4 s, (2H, C6H4CH2), 7.0 7.3 m,
(4H, C6H4). 13C NMR: 53, 54, 62, 71, 73, 87, 125,
129, 134, 141
N-(2-Ethanoyloxyethyl)-1,3-oxazolidine. A solu-
tion of 5.7 g of I in benzene was added dropwise to
1.124 g of finely crushed Na in 20 ml of benzene.
After the completion of the initially vigorous reaction,
the mixture was heated to 60 C, and the stirring was
continued at this temperature until the sodium fully
dissolved. Then 3.82 g of acetyl chloride was added
dropwise to the alcoholate at 20 22 C over a period
of 2 h, after which the mixture was stirred for an addi-
tional 4 h. After the reaction completion, the organic
phase was filtered to remove NaCl, the solvent was
distilled off, and the residue was distilled in a nitro-
gen flow under reduced pressure to obtain 4 g (40%)
of N-(2-ethanoyloxyethyl)-1,3-oxazolidine, bp 90 C
acid, and 30 ml of toluene was refluxed until the re-
lease of water was complete, after which the mixture
was neutralized with KOH and filtered to remove
KCl; the solvent was distilled off, and distillation of
the residue in a nitrogen flow under reduced pressure
gave 5 g (26%) of 2-(2-hydroxyethyl)aminoethyl vale-
rate, bp 135 137 C (2 mm Hg), d420 1.0816, nD20
1.4730.
The condensation of 2-(2-hydroxyethyl)aminoethyl
valerate was performed by procedure a. The yield and
physicochemical constants of N-(2-pentanoyloxyeth-
yl)-1,3-oxazolidine coincided with those of the same
product obtained by method c.
1
(2 mm Hg), d420 1.0998, n2D0 1.4520. H NMR spec-
N-(2-Hydroxyethyl)morpholine. To a mixture of
34.8 g of morpholine and 32.2 g of ethylene chloro-
hydrin, we added dropwise at 40 45 C over a period
of 1.5 h 32 g of a 50% NaOH solution. After the reac-
tion completion, the organic layer was separated and
dried over sodium sulfate; by distillation in a nitrogen
flow under reduced pressure, we isolated 35 g (67%)
trum, , ppm: 2.1 t (3H, CH3), 2.75 t (2H, NCH2),
3.0 t (2H, NCH2), 3.72 t (2H, OCH2), 4.15 t (2H,
OCH2), 4.21 s (2H, NCH2O). 13C NMR spectrum,
ppm: 20.0, 54.0, 62.5, 87.0, 170.0.
,
C
N-(2-Pentanoyloxyethyl)-1,3-oxazolidine. A mix-
ture of 10.5 g of diethanolamine, 10.2 g of valeric
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SYNTHESIS OF N-SUBSTITUTED OXAZOLIDINES AND MORPHOLINES
1305
of N-(2-hydroxyethyl)morpholine, bp 104 C (10 mm
Hg), d420 1.0742, n2D0 1.4766. 1H NMR spectrum,
, ppm: 2.52 t (2H, NCH2), 2.53 t [4H, N(CH2)2],
3.66 t [4H, O(CH2)2], 4.23 s (H, OH). 13C NMR
spectrum, , ppm: 54.0; 58.0, 61.0, 66.5.
dropwise to 0.25 mol of finely divided Na in 25 ml of
dioxane. After the completion of the initially vigorous
reaction, the mixture was heated to reflux and stirred
at this temperature until the sodium fully dissolved.
Then, while cooling below 15 C, 0.19 mol of halo-
benzyl chloride was added dropwise, and the resulting
mixture was stirred for 5 h. After the reaction com-
pletion, the mixture was filtered to remove NaCl, the
dioxane was distilled off, and the desired products
were isolated by distillation in a nitrogen flow under
reduced pressure.
N-(2-Alkanoyloxyethyl)morpholines were pre-
pared by esterification of carboxylic acids with mor-
pholine II. The reactions were performed similarly to
the preparation of N-(2-pentanoyloxyethyl)-1,3-ox-
azolidine. N-(2-Ethanoyloxyethyl)-, N-(2-propanoyl-
oxyethyl)-, N-(2-butanoyloxyethyl)-, N-(2-pentanoyl-
oxyethyl)-, N-(2-hexanoyloxyethyl)-, and N-(2-oc-
tanoyloxyethyl)morpholines were prepared (see table).
N(m-Chlorobenzyloxyethyl)- and N-(o-fluoro-
benzyloxyethyl)ethanolamines were prepared sim-
ilarly to N-(m-chlorobenzyl)- and N-(o-fluorobenzyl)-
1,3-oxazolidines.
N-(Halobenzyl)morpholines. To a stirred solution
of 0.125 mol of morpholine in 60 ml of benzene,
heated to 80 C, we added dropwise over a period of
1 h 0.125 mol of halobenzyl chloride, after which the
mixture was stirred for an additional 3 h. After the
reaction completion, the mixture was neutralized with
a 5% NaHCO3 solution, washed with water to neutral
reaction, and dried over sodium sulfate. After distil-
ling off the solvent, the desired compounds were iso-
lated by distillation in a nitrogen flow under reduced
pressure.
N-(m-Chlorobenzyloxyethyl)- and N-(o-fluoro-
benzyloxyethyl)oxazolidines were prepared similarly
to N-(2-hydroxyethyl)-1,3-oxazolidine.
CONCLUSION
Thermal esterification of carboxylic acids with
N-(2-hydroxyethyl)morpholine gives N-(2-alkanoyl-
oxyethyl)morpholines in high yield (80 90%). With
N-(2-hydroxyethyl)-1,3-oxazolidine, a complex mix-
ture of products is formed; the desired products were
obtained in 50 80% yield by indirect procedures.
N-(o-Fluorobenzyl)- and N-(m-chlorobenzyl)mor-
pholines were prepared (see table). Data on N-(halo-
benzyl)-1,3-oxazolidines are listed in the table.
N-(m-Chlorobenzyl)- and N-(o-fluorobenzyl)eth-
anolamines. Halobenzyl chloride (0.12 mol) was
added dropwise to a stirred mixture of 1 mol of eth-
anolamine and 30 ml of benzene, after which the mix-
ture was refluxed with stirring for 4 h, neutralized
after cooling with KOH, and filtered to remove KCl.
The benzene was distilled off, and the target products
were isolated by distillation in a nitrogen flow under
reduced pressure.
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nitrosoedinenii i aminov (Industrial Synthesis of Aro-
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2. Knorr, L. and Mattes, H., Ber., 1901, vol. 34, no. 5,
pp. 3484 3486.
3. Azizov, A.M., Reactions of 1,2-Amino Alcohols and
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N-(m-Chlorobenzyl)- and N-(o-fluorobenzyl)ox-
azolidines were prepared similarly to N-(2-hydroxy-
ethyl)-1,3-oxazolidine. Data on N-(halobenzyloxyeth-
yl)-1,3-oxazolidines are listed in the table.
-(m-Chlorobenzyloxy)- and -(o-fluorobenzyl-
oxy)ethylamines. Ethanolamine (0.1 mol) was added
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 78 No. 8 2005