Synthesis of methyl-N-[4-(3-R-amino-2-hydroxypropoxy)phenyl]carbamates

Article abstract of DOI:10.1023/B:RUJO.0000034939.01295.42

By alkylation of methyl-N-(4-hydroxyphenyl)carbamate with (chloromethyl)oxirane in acetone in the presence of K₂CO₃ methyl-N-[4-(2,3-epoxypropoxy)phenyl]carbamate was prepared. The aminolysis of the latter effected by benzylamine, mo

Full text of DOI:10.1023/B:RUJO.0000034939.01295.42

Russian Journal of Organic Chemistry, Vol. 40, No. 2, 2004, pp. 188-190. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 2, 2004,
pp. 215-217.
Original Russian Text Copyright Ó 2004 by Velikorodov.
Synthesis of Methyl-N-[4-(3-R-amino-2-
hydroxypropoxy)phenyl]carbamates
A. V. Velikorodov
Astrakhan State University Astrakhan, 414056 Russia
e-mail: avelikorodov@mail.ru
Received April 27, 2003
Abstract—By alkylation of methyl-N-(4-hydroxyphenyl)carbamate with (chloromethyl)oxirane in acetone in the
presence of K CO methyl-N-[4-(2,3-epoxypropoxy)phenyl]carbamate was prepared. The aminolysis of the latter
2
3
effected by benzylamine, morpholine, piperidine, and pyrrolidine occurs in keeping with Krasusky rule to afford
methyl-N-[4-(3-R-amino-2-hydroxypropoxy)phenyl]carbamates.
In extension of our research on the synthesis of
O-alkyl derivatives of aromatic carbamates [1] we report
here the results obtained in alkylation of methyl-N-(4-
hydroxyphenyl)carbamate I with (chloromethyl)oxirane
and in the study of the possibility to use the product for
syntheses of new derivatives with potential b-adreno-
blockador activity. Some compounds containing amino-
hydroxyalkyl moiety already found application in
therapeutical practice, for example, Atenolol, Pindolol,
Anaprilin, and Buphetanol [2, 3].
the a-carbon of the three-membered ring, or against the
rule affording an isomeric reaction product. The
oligomerization also cannot be ruled out [4].
It is known [5] that an oxirane containing at the ring a
substituents with a negative inductive effect reacts with
a nucleophilic reagent to afford only a product of the
regular structure. Our results support this statement: the
heterocycle opening occurs exclusively along Krasusky
rule furnishing the product as a single isomer as confirmed
1
by the N NMR spectra.
We established that the alkylation of carbamate I with
with (chloromethyl)oxirane in acetone in the presence of
potassium carbonate gave rise to methyl-N-[4-(2,3-
epoxypropoxy)phenyl]carbamate II whose composition
and structure are consistent with elemental analysis and
IR spectrum.
The position of one-proton signals (one in the region
4.00–4.07 and another at 3.70 ppm) in agreement with
published data [6, 7] proved that the opening of the oxirane
ring happened according to the Krasusky rule.
The regioselectivity of the reaction presumably
originates from the structural features of the epoxide: the
terminal carbon atom is sterically available for the
nucleophiles attack, and also to the oxirane ring a substituent
with a negative inductive effect is linked. The latter
apparently destabilizes the alternative transition state that
would lead to a product of the anti-Krasusky addition [8].
2+
&2&+ &+ &+
2
&O&+ &+ &+
2
.
&2 ꢀ0H &2ꢁꢀ'
1+&2 0H
1+&2 0H
,
,,
In the IR spectrum of compound II in contrast to that
of carbamate I are present absorption bands at 1250,
–1
1
020 and 840 cm corresponding to pulsating, symmetric,
and asymmetrical vibrations of the oxirane ring.
We investigated carbamate II aminolysis with benzyl-
amine IIIa, morpholine IIIb, pyrrolidine IIIc, and piperi-
dine IIId. The reaction was carried out by heating an
equimolar reagents mixture in dioxane to 50°C for 6 h.
III, IV, R = H, R' = PhCH (a); R, R' = (CH ) O(CH ) (b); R,
2
2 2
2 2
R' = (CH ) (c), R, R' = (CH ) (d).
2
4
2 5
The oxirane ring can presumably open in two fashions:
either in keeping with the Krasusky rule from the side of
The treating of amines IVa–d solutions in a mixture
methylene chloride–dioxane (1:1 by volume) with
1070-4280/04/4002-0188Ó2004 MAIK “Nauka/Interperiodica”

SYNTHESIS OF METHYL-N-[4-(3-R-AMINO-2-HYDROXYPROPOXY)PHENYL]CARBAMATES
189
hydrogen chloride solution in ether afforded the respective
amine hydrochlorides as colorless crystalline compounds,
well soluble in water.
Methyl-N-[4-(2-hydroxy-3-morpholinopropoxy)-
phenyl]carbamate (IVb). Yield 2.67 g (86%), mp 82°C
(from a mixture carbon tetrachloride-petroleum ether,
–
1
3
(
:1). IR spectrum, n, cm : 3310–3260 (NH, OH), 1735
Methyl-N-[4-(2,3-epoxypropoxy)phenyl]carb-
amate (II). A mixture of 3.34 g (0.02 mol) of carbamate
I, 2.8 g (0.02 mol) of potassium carbonate, 1.9 ml
¼
1
C=O), 1620, 1565, 1525 (C -C arom). N NMR
spectrum, d, ppm: 8.47 br. s (1N, NHCO Me), 7.33 d
2
(
2N arom, J 8.7 Hz), 6.93 d (2N arom, J 8.7 Hz), 4.00
(0.02 mol) of (chloromethyl)oxirane and 3 ml of acetone
m (2N, OCN , CNON), 3.81 d (1N, OCN , J 3.3 Hz),
was heated for 5 h at 70°C, then was cooled, diluted
with water (25 ml), and extracted with ethyl ether
2
2
3
2
.70 s (4N, OMe, CNON), 3.60 m (4N, O(CN2)2),
.60 d.d (1N, NCH , J 7.6, 13.2 Hz), 2.40 d. d (1N, NCH ,
(
3´30 ml). The extract was washed with 10% water
solution of sodium hydroxide (100 ml) and with water
2´50 ml), and dried with potassium carbonate. The
2
2
J 7.6, 13.2 Hz), 2.26 m [4N, N(CH ) ]. Found, %:
2
2
C 58.21; N 6.88; N 8.86. C H N O . Calculated, %:
1
5
22
2
5
(
C 58.07; N 7.10; N 9.03.
solvent was removed, the residue crystallized. On
recrystallization from a mixture chloroform-petroleum
ether, 2:1, we obtained 3.88 g (87%) of colorless crystal-
Methyl-N-[4-(2-hydroxy-3-morpholinopropoxy)-
phenyl]carbamate hydrochloride, yield 1.1 g (99%),
mp 199°C. Found, %: C 52.17; N 6.37; N 7.99.
–
1
line compound II, mp 98°C. IR spectrum, n, cm : 3330
¼
C H N O5×HCl. Calculated, %: C 51.95; N 6.64;
(
NH), 1705 (C=O), 1605, 1545, 1530 (C -C arom), 1250,
15 22
2
N 8.08.
1
020, 840 (oxirane). Found, %: C 58.97; N 5.64; N 6.14.
C N NO . Calculated,%: C 59.19; N 5.83; N 6.28.
Methyl-N-[4-(2-hydroxy-3-pyrrolidinopropoxy)-
1
1
13
4
phenyl]carbamate (IVc). Yield 2.38 g (81%), mp 92°C
Methyl-N-[4-(3-benzylamino-2-hydroxy-
propoxy)phenyl]carbamate (IVa). A mixture of 2.23 g
0.01 mol) of carbamate II, 1.16 ml (0.01 mol) of freshly
(
from a mixture chloroform-petroleum ether, 2:1). IR
–
1
spectrum, n, cm : 3320–3260 (NH, OH), 1735 (C=O),
1
(
¼
1
620, 1560, 1525 ( C -C arom). N NMR spectrum, d,
distilled benzylamine IIIa, and 5 ml of dioxane was heated
at 50°C for 6 h, the solvent was removed, the residue
was washed with hexane (2´10 ml). On recrystallization
from a mixture carbon tetrachloride-petroleum ether, 3:1,
we obtained 2.70 g (82%) of amine IVa, mp 86°C. IR
ppm: 8.47 br. s (1N, NHCO Me), 7.33 d (2N arom,
2
J 8.7 Hz), 6.93 d (2N arom, J 8.7 Hz), 4.00 m (2N,
OCN , CNON), 3.83 d (1N, OCN , J 3.3 Hz), 3.70 s
2
2
(4N, OMe, CNON), 2.62 m (5N, b-N of pyrrolidine,
spectrum, n, cm— : 3420, 3350 (NH), 3245 (OH), 1715
1
NCH ), 2.39 d. d (1N, NCH , J 7.5, 13.2 Hz), 1.78 m
2
2
¼
1
(4N, a-N of pyrrolidine). Found, %: C 60.94; N 7.54;
N 9.27. C H N O .Calculated, %: C 61.23; N 7.48;
(
C=O), 1610, 1550, 1525 (C-C). N NMR spectrum, d,
ppm: 8.47 br. s (1N, NHCO Me), 7.40 d (2H arom,
15 22
2
4
2
N 9.52.
J 7.8 Hz ), 7.33 d (2H arom, J 8.7 Hz), 7.20 t (3N arom,
J 7.02 Hz), 6.94 d (2H arom, J 8.7 Hz), 4.07 m (CHOH),
Hydrochloride of methyl-N-[4-(2-hydroxy-3-
pyrrolidinî-propoxy)phenyl]carbamate Hydrochloride yield
1.10 g (98%), mp 150–151°C. Found,%: C 54.25;
N 7.01; N 8.23. C H N O ×HCl. Calculated, %:
3
.98 d, (1N, OCN , J 4.7 Hz), 3.82 d (2N, CN Ph,
2
2
J 13 Hz), 3.78 d (1N, OCN , J 3.3 Hz), 3.70 c (3H,
2
OMe), 3.21 m (2N, NH, OH), 2.79 d. d (1N, CN N,
2
15 22
2
4
J 7.5, 13.2 Hz), 2.66 d. d (1N, CN N, J 7.5, 13.2 Hz). C 51.46; N 6.96; N 8.47.
2
Found, %: C 65.21; N 6.88; N 8.22. C H N O .
1
8
22
2
4
Methyl-N-[4-(2-hydroxy-3-piperidinopropoxy)-
phenyl]carbamate (IVd). Yield 1.47 g (71%), mp 111°C
(from a mixture carbon tetrachloride-petroleum ether,
Calculated, %: C 65.46; N 6.67; N 8.49.
Compound IVa (1 g, 3.03 mmol) was converted in the
corresponding hydrochloride by treating in a mixture
dioxane–methylåne chloride, 1:1, with hydrogen chloride
solution in ether. The arising colorless crystalline reaction
product was separated and dried in air. We obtained
–
1
3:1). IR spectrum, n, cm : 3320-3260 (NH, OH), 1730
¼
1
(C=O), 1620, 1565, 1525 (C -C arom). N NMR spec-
trum, d, ppm: 8.47 br. s (1N, NHCO Me), 7.33 d (2N
2
arom, J 8.7 Hz), 6.93 d (2N arom, J 8.7 Hz), 4.00 m (2N,
OCN , CNON), 3.81 d (1N, OCN , J 3.3 Hz), 3.70 s
1
.09 g (98%) of methyl-N-[4-(3-benzylamino-2-hydroxy-
propoxy)-phenyl]carbamate hydrochloride, mp 192°C.
Found, %: C 58.63; N 6.07; N 7.51. C H N O4×HCl
2
2
(
4N, OMe, CNON), 2.60 d.d (1N, NCH , J 7.5,
2
.
1
8
22
2
13.2 Hz), 2.40 d. d. (1N, NCH , J 7.5, 13.2 Hz), 2.24 m
2
Calculated, %: C 58.94; N 6.28; N 7.64.
(
4N, b-N of piperidine), 1.30 ì (6N, 3CN of piperidine).
2
Carbamates IVb–d and their hydrochlorides were
obtained by similar procedures.
Found, %: C 62.13; N 8.03; N 9.16. C H N O .
Calculated, %: C 62.34; N 7.79; N 9.09.
16 24 2 4
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 2 2004

190
VELIKORODOV et al.
Hydrochloride a methyl-N-[4-(2-hydroxy-3-piperi-
dinopropoxy)phenyl]carbamate, yield 1.10 g (98%), mp
52°C. Found, %: C 55.50; N 7.31; N 8.01. C H N O4×
2. Mashkovskii, P.M., Lekarstvennye sredstva (Medicines),
Khar’kov: Torsing, 1998, vol.1, 560 p.
3. Soldatenkov, A.T., Kolyadina, N.M., and Shenderik, I.V.,
Osnovy Organicheskoi khimii lekarstvennykh veshchestv
(Bases of Organic Chemistry of Medicines), Moscow:
Khimiya, 2001, 192 p.
1
1
6
24
2
HCl. Calculated, %: C 55.73; N 7.26; N 8.13.
1H NMR spectra were registered on spectrometer
VXR-400 (400.13 MHz) in acetone-d , internal reference
6
TMS. IR spectra were measured on spectrophotometer
IKS-29 in the range 4000–400 cm from mulls in mineral
4. Mislyuk, O.A., Shibaev, V.I., V’yunov, K.A., and Ginak,A.I.,
Zh. Org. Khim., 1986, vol. 22, p. 2227.
–
1
oil.
5. Vladimirova, M.G. and Petrov,A.A., Zh. Org. Khim., 1947,
vol. 17, p. 51.
6. Mislyuk, O.A., Shibaev, V.I., Davidenkov, L.R., V’yu-
nov, K.A., and Ginak, A.I., Zh. Prikl. Khim., 1984, vol. 57,
p. 2138.
The purity of compounds obtained was checked by
TLC on Silufol UV-254 plates
Methyl-z-(4-hydroxyphenyl)carbamate I was
prepared by procedure described in [1].
7
. Kas’yan, O.A., Zlenko, E.T., Golodaeva, E.A., Tsygan-
kov, A.V., and Kas’yan, L.I., Zh. Org. Khim., 2002, vol. 38,
p. 1661.
REFERENCES
1
. Velikorodov, A.V., Bakova, O.V., and MoChalin, V.B., Zh.
Org. Khim., 2002, vol. 38, p. 75.
8. Gorzinski, S.J., Synthesis, 1984, vol. 8, p. 629.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 2 2004