Synthesis of N-aryl derivatives of vicinal aminoalcohols

Article abstract of DOI:10.1134/S1070428007080155

Synthesis was performed of substituted 2-propanols based on glycidyl phenyl and glycidyl allyl ethers, Also some acetic acid esters were prepared.

Full text of DOI:10.1134/S1070428007080155

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 8, pp. 1176−1179. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © N.D. E.G. Mesropyan, A.A. Avetisyan, A.S. Galstyan, 2007, published in Zhurnal Organicheskoi Khimii, 2007, Vol. 43, No. 8,
pp. 1182−1185.
Synthesis of N-Aryl Derivatives of Vicinal Aminoalcohols
E. G. Mesropyan, A. A. Avetisyan, and A. S. Galstyan
Yerevan State University, Yerevan, 375049 Armenia
e-mail: mag_union@yahoo.com
Received July 22, 2005. Final version January 5, 2007
Abstract—Synthesis was performed of substituted 2-propanols based on glycidyl phenyl and glycidyl allyl ethers,
Also some acetic acid esters were prepared.
DOI: 10.1134/S1070428007080155
Reactions of epoxy compounds with amines is one
among the most convenient preparation methods for
vicinal aminoalcohols used as building blocks in design-
ing molecules of natural and biologically active organic
substances [1–15].
reaction was established to occur in the presence of
ethanol at a molar reagents ratio 1:3.
The ring opening occurred as expected [20–23]
exclusively in keeping with Krasusky rule yielding
1
a single isomeric product as was proved by H NMR
Various vicinal aminoalcohols and their derivatives
both at the hydroxy group and nitrogen atom exhibiting
versatile activity are included in the composition of
existing drugs [16–19].
spectra.
The reaction of 1-(N-phenyl-N-ethylamino)-3-
phenoxypropan-2-ol and 1-allyloxy-3-(N-phenyl-N-ethyl-
amino)propan-2-ol with acetyl chloride in toluene led to
the formation of hydrochlorides of 1-[(N-ethyl-N-
phenylamino)methyl]-2-phenoxyethyl acetate (XVI) and
1-[(N-ethyl-N-phenylamino)methyl]-2-allyloxyethyl
acetate (XV), which by treating with ammonium
hydroxide were converted into free bases XVII and
XVIII (see Scheme).
The goal of this study was a synthesis of new N-aryl
derivatives of vicinal aminoalcohols, potential biological-
ly active substances.
We investigated the reactions of glycidyl ethers I and
II with various aromatic amines: aniline (III), p-anisidine
(
IV), 1-naphthylamine (V), and N-ethylaniline (VI).
Optimum reaction conditions were developed. The
EXPERIMENTAL
1H NMR spectra were registered at 30°C on a spec-
trometer Varian Mercury-300 at operating frequency
3
00 MHz, solvent DMSO-d . IR spectra were recorded
6
on a spectrophotometer Specord 75IR from thin films
and mulls in mineral oil. The homogeneity and purity of
compounds obtained were checked by TLC on Silufol
UV-254 plates, development in iodine vapor.
1
-Allyloxy-3-phenylaminopropan-2-ol (VII).
A mixture of 8.37 g (0.09 mol) of aniline, 3.42 g
0.03 mol) of epoxide I, and 1 ml of ethanol was heated
(
at 75–80°C for 5.5 h at constant stirring. On removing
ethanol and excess aniline in a vacuum (20 mm Hg) the
residue was subjected to distillation. Yield 4.5 g (72%),
2
6
bp 171–172°C (3.5 mm Hg), n 1.5477, R 0.51 [CHCl –
D
f
3
–1
Me C(O), 1:0.4]. IR spectrum, ν, cm : 3340 (OH), 3280
2
1176

SYNTHESIS OF N-ARYL DERIVATIVES OF VICINAL AMINOALCOHOLS
1177
Scheme.
R
O
N
OH
X, XIV
HCl
R
R
NH4OH
O
N
O
N
O
+
Cl
O
O
O
O
XV, XVI
XVII, XVIII
R = All (XV, XVII), Ph (XVI, XVIII).
1
bp 197°C (0.3 mm Hg), n D2 5 1.6060, R 0.48 [CHCl –
f 3
(
NH), 3030 (Ar), 1650 (All), 1600 (Ar), 1590 (NH). H
NMR spectrum, δ, ppm (J, Hz): 3.11 d.d (1H, CH N, J
PhMe–Me C(O)–CCl , 1:0.6:0.4:0.4]. IR spectrum, ν,
2
2
4
–1
1
3.8, 7.5), 3.34 d.d (1H, CH N, J 13.8, 4.2), 3.48 m (2H,
cm : 3550 (OH), 3410 (NH), 3051 (Ar), 1650 (All), 1610
2
1
CH OAll), 4.0 m (1H, CHOH), 4.04 d.t (2H,
(Ar), 1580 (NH). H NMR spectrum, δ, ppm (J, Hz):
2
CH CH=CH , J 5.4, 1.5), 4.81 br.s (1H, OH), 4.98 br.s
3.15 d.d (1H, CH N, J 13.8, 7.5), 3.38 d.d (1H, CH N,
2
2
2
2
(
(
1H, NH), 5.16 d.q (1H, CH=CH , J 10.4, 1.5), 5.26 d.q
J 13.8, 4.2), 3.48 m (2H, CH OAll), 4.0 m (1H, CHOH),
2
2
1H, CH=CH , J 17.2, 1.5), 5.90 d.d.t (1H, CH=CH ,
4.04 d.t (2H, CH CH=CH , J 5.4, 1.5), 4.80 br.s (1H,
2
2
2
2
J 17.2, 10.4, 5.4), 6.52 t, 6.57 d, 7.05 t (5Harom, PhN).
OH), 5.16 d.q (1H, CH=CH , J 10.4, 1.5), 5.26 d.q (1H,
2
Found, %: C 69.23; H 8.32; N 6.38. C H NO .
CH=CH , J 17.2, 1.5), 5.56 br.s (1H, NH), 5.90 d.d.t (1H,
1
2
17
2
2
Calculated, %: C 69.54; H 8.27; N 6.76.
-Allyloxy-3-(4-methoxyphenylamino)propan-2-ol
VIII). To a solution of 11.07 g (0.09 mol) of p-anisidine
in 10 ml of ethanol was added 3.42 g (0.03 mol) of
epoxide I. The mixture was heated for 8 h at 85–90°C
while continuous stirring. On removing ethanol in a vacu-
um (20 mm Hg) the residue was distilled to obtain
compound VIII. Yield 5.8 g (81%), bp 179–180°C
CH=CH , J 17.2, 10.4, 5.4), 6.54 d, 7.05 d, 7.25 t, 7.38 m,
2
7
.67 t, 7.98 t (7Harom, naphthalene). Found, %: C 74.35;
1
H 7.55; N 5.11. C H NO . Calculated, %: C 74.68;
(
16 19
2
H 7.44; N 5.44.
1-Allyloxy-3-(N-phenyl-N-ethylamino)propan-2-ol
(X) was obtained in the same way as compound VII.
The mixture was heated for 10 h at 80–85°C. Yield 6.2 g
2
2
(88%), bp 152–154°C (1.5 mm Hg), n 1.5390, R 0.47
D
f
2
1
(
1 mm Hg), n 1.5472, R 0.48 [CHCl –Me C(O), 1:0.4].
[CHCl –PhMe–Me C(O)–CCl , 1:0.6:0.5:0.4]. IR
D
f
3
2
3 2 4
–1
–1
IR spectrum, ν, cm : 3480 (OH), 3320 (NH), 3030(Ar),
645 (All), 1610 (Ar), 1580 (NH). H NMR spectrum,
spectrum, ν, cm : 3340 (OH), 3030 (Ar), 1650 (All),
1
1
1
1600 (Ar). H NMR spectrum, δ, ppm (J, Hz): 1.13 t
δ, ppm (J, Hz): 3.04 d.d (1H, CH N, J 13.8, 7.5), 3.25 d.d
(3H, CH CH ), 3.23–3.40 m (4H, CH N), 3.48 m (2H,
2
2
3
2
(
(
1H, CH N, J 13.8, 4.2), 3.48 m (2H, CH OAll), 3.67 s
CH OAll), 3.98 m (1H, CHOH), 4.04 d.t (2H,
2
2
2
3H, CH ), 4.01 m (1H, CHOH), 4.04 d.t (2H,
CH CH=CH , J 5.4, 1.5), 4.82 br.s (1H, OH), 5.16 d.q
3
2
2
CH CH=CH , J 5.4, 1.5), 4.62 br.s (1H, NH), 4.85 br.s
(1H, CH=CH , J 10.4, 1.5), 5.26 d.q (1H, CH=CH ,
2
2
2
2
(
(
1H, OH), 5.16 d.q (1H, CH=CH2, J 10.4, 1.5), 5.26 d.q
1H, CH=CH , J 17.2, 1.5), 5.90 d.d.t (1H, CH=CH ,
J 17.2, 1.5), 5.90 d.d.t (1H, CH=CH , J 17.2, 10.4, 5.4),
2
6.60 t, 6.78 d, 7.13 t (5Harom, PhN). Found, %: C 71.69;
H 8.67; N 6.24. C H NO . Calculated, %: C 71.46;
2
2
J 17.2, 10.4, 5.4), 6.55 d, 6.64 (4Harom, NC H OMe).
6
4
12 17
2
Found, %: C 65.99; H 7.83; N 5.56. C H NO .
H 8.99; N 5.95.
1
3
19
3
Calculated, %: C 65.80; H 8.07; N 5.90.
-Allyloxy-3-(naphthalen-1-ylamino)propan-2-ol
IX). To a solution of 12.87 g (0.09 mol) of 1-naph-
thylamine in 25 ml of ethanol was added 3.42 (0.03 mol)
of epoxide I. The mixture was heated for 4 h at 85–90°C
while continuous stirring. On removing ethanol in a vac-
uum (20 mm Hg) the residue was subjected to fractional
distillation to obtain compound IX. Yield 6.65 g (79%),
1
-Phenoxy-3-phenylaminopropan-2-ol (XI) was
1
obtained in the same way as compound VII. The mixture
was heated for 5 h at 80–85°C. Yield 5.8 g (79%), bp
212°C (3 mm Hg),
(
2
0
n
1.5970, R 0.52 [CHCl –PhMe–
D
f 3
–1
Me C(O), 1:0.6:0.2]. IR spectrum, ν, cm : 3350 (OH),
2
1
3290 (NH), 3030 (Ar), 1600 (Ar), 1590 (NH). H NMR
spectrum, δ, ppm: 3.11 d.d (1H, CH NH), 3.34 d.d (1H,
2
CH NH), 3.93 d.d (2H, CH OPh ), 4.05 m (1H, CHOH),
2
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 8 2007

1178
MESROPYAN et al.
4
.81 d (1H, OH), 4.98 br.s (1H, NH), 6.52 t, 6.57 d, 7.05
mixture obtained was treated with 8% ammonia solution
(till pH 10), then the oily layer was separated from the
water one, washed with water till neutral washings, and
t (5Harom, PhN), 6.87 t, 6.89 d, 7.23 t (2Harom, PhO).
Found, %: C 73.85; H 7.23; N 5.51. C H NO .
1
5
17
2
Calculated, %: C 74.05; H 7.04; N 5.76.
dried with MgSO . The solvent was removed, and the
4
residue was subjected to a vacuum distillation. Yield 5 g
1
-(4-Methoxyphenylamino)-3-phenoxypropan-2-
20
(
69%), bp 171°C (6 mm Hg), n 1.5207, R 0.57 (CHCl –
ol (XII) was obtained in the same way as compound
VIII. The mixture was heated for 8 h at 85–90°C. On
removing excess p-anisidine the residue was dissolved
in hot ethanol. On cooling the precipitated crystals were
filtered off, washed with ethanol, and dried. Yield 6.25 g
D
f 3
–1
PhMe–CCl , 1:0.6:0.4). IR spectrum, ν, cm : 3030 (Ar),
1
4
1
740 (C=O), 1650 (All), 1600 (Ar). H NMR spectrum,
δ, ppm (J, Hz): 1.13 t (3H, CH CH ), 1.97 s (3H, CH CO),
2
3
3
3
.23–3.40 m (4H, CH N), 3.48 m (2H, CH OAll), 3.98
2 2
m (1H, CHOH), 4.04 d.t (2H, CH CH=CH , J 5.4, 1.5),
(
75%), mp 86°C (ethanol), R 0.43 [CHCl –PhMe–
2
2
f
3
–1
5.16 d.q (1H, CH=CH , J 10.4, 1.5), 5.26 d.q (1H,
Me C(O), 1:0.6:0.4]. IR spectrum, ν, cm : 3255 (NH),
2
2
1
CH=CH , J 17.2, 1.5), 5.90 d.d.t (1H, CH=CH , J 17.2,
2 2
3
170 (OH), 3030 (Ar), 1600 (Ar), 1590 (NH). H NMR
1
0.4, 5.4), 6.60 t, 6.78 d, 7.13 t (5Harom, PhN). Found, %:
spectrum, δ, ppm: 3.04 d.d (1H, CH NH), 3.25 d.d (1H,
2
C 68.95; H 8.56; N 5.39. C H NO . Calculated, %: C
CH NH), 3.67 s (3H, OCH ), 3.93 d.d (2H, CH OPh ),
16 23
3
2
3
2
6
9.29; H 8.36; N 5.05.
4
.01 m (1H, CHOH), 4.62 br.s (1H, NH), 4.81 d (1H,
OH), 6.55 d, 6.64 d (4Harom, NC H OMe), 6.85 t, 6.89 d,
1-[(N-Ethyl-N-phenylamino)methyl]-2-phenoxy-
6
4
7
.23 t (5Harom, PhO). Found, %: C 70.53; H 7.25; N 4.85.
ethyl acetate (XVIII). A mixture of 4.65 g (0.017 mol)
of propan-2-ol XIV, 1.35 g (0.017 mol) of acetyl chloride,
and 10 ml of toluene was maintained for 18 h at room
temperature and then heated for 4 h at 90–95°C, the
mixture obtained was cooled. The separated precipitate
was filtered off, washed with ether, and dried. Yield of
C H NO . Calculated, %: C 70.31; H 7.01; N 5.12.
16
19
3
1-(Naphthalen-1-ylamino)-3-phenoxypropan-2-ol
(
XIII) was prepared similarly to compound IX. The
mixture was heated for 5 h at 80–85°C. Yield 6.3 g (72%),
bp 232–233°C (0.3 mm Hg), mp 62°C, R 0.62 [CHCl –
PhMe–Me C(O), 1:0.6:0.4]. IR spectrum, ν, cm : 3550
f
3
–1
compound XVI 5.35 g (90%), mp 125°C, R 0.62 [CHCl –
2
f 3
–
1
(
OH), 3410 (NH), 3051 (Ar), 1620 (Ar), 1580 (NH).
H NMR spectrum, δ, ppm: 3.15 d.d (1H, CH NH),
PhMe–Me C(O), 1.0:0.6:0.4]. IR spectrum, ν, cm : 3030
2
1
1
(Ar), 1740 (C=O), 1600 (Ar). H NMR spectrum, δ, ppm:
1.12 t (3H, CH CH ), 1.97 s (3H, CH CO), 3.24–3.41 m
2
3
.38 d.d (1H, CH NH), 3.93 m (2H, CH OPh ), 4.01 m
2
2
2
3
3
(
6
1H, CHOH), 4.8 br.s (1H, OH), 5.56 br.s (1H, NH),
.54 d, 7.05 d, 7.25 t, 7.38 m, 7.67 t, 7.98 t (7Harom
naphthalene), 6.85 t, 6.89 d, 7.23 t (5Harom, PhO). Found,
(4H, CH N), 3.93 d.d (2H, CH OPh), 3.98 m (1H, CHO),
2 2
,
6.62 t, 6.80 d, 7.16 t (5Harom, PhN), 6.85 t, 6.89 d, 7.23 t
(5Harom, PhO), 12.7 br.s (1H, HCl). Found, %: C 65.56;
H 7.23; N 4.32. C H NO ·HCl. Calculated, %: C 65.23;
%
: C 77.53; H 6.74; N 5.01. C H NO . Calculated, %:
19 19 2
19 23
3
C 77.79; H 6.53; N 4.77.
H 6.91; N 4.00. To obtain free base XVIII a dispersion
of 1.75 g (0.005 mol) of compound XVI in 3 ml of
benzene was treated with 8% ammonia solution (till pH
1
-(N-Phenyl-N-ethylamino)-3-phenoxypropan-2-
ol (XIV) was obtained in the same way as compound
VII. The mixture was heated for 12 h at 90–95°C. Yield
1
0), then the oily layer was separated from the water one,
2
0
washed with water till neutral washings, and dried with
7
0
.95 g (98%), bp 193°C (1.5 mm Hg), n 1.5830, Rf
D
MgSO . The solvent was removed, and the residue was
.45 [CHCl –PhMe– Me C(O), 1:0.6:0.2]. IR spectrum,
4
3
2
–1
1
subjectedto a vacuum distillation. Yield 1.3 g (83%), bp
ν, cm : 3510 (OH), 3030 (Ar), 1600 (Ar). H NMR
spectrum, δ, ppm: 1.12 t (3H, CH CH ), 3.24–3.41 m
2
6
193°C (1.8 mm Hg), n 1.5578.
2
3
D
(
4H, CH N), 3.93 d.d (2H, CH OPh), 3.98 m (1H,
2 2
CHOH), 4.83 br.s (1H, OH), 6.60 t, 6.78 d, 7.13 t (5Harom
,
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C 75.25; H 7.80; N 5.16.
1
7
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