Synthesis of N-(2-hydroxyethyl) derivatives of β-alanine

Full text of DOI:10.1134/S0012500810020047

ISSN 0012ꢀ5008, Doklady Chemistry, 2010, Vol. 430, Part 2, pp. 47–49. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © T.V. Dokichev, D.R. Latypova, R.Z. Biglova, R.F. Talipov, 2010, published in Doklady Akademii Nauk, 2010, Vol. 430, No. 6, pp. 770–772.
CHEMISTRY
Synthesis of Nꢀ(2ꢀHydroxyethyl) Derivatives
of ꢀAlanine
β
T. V. Dokicheva, D. R. Latypovab, R. Z. Biglovaa, and R. F. Talipova
Presented by Academician Yu.B. Monakov September 1, 2009
Received September 9, 2009
DOI: 10.1134/S0012500810020047
It was previously shown that ethanolamines react acids and esters of conjugated unsaturated acids with
ethanolamines in the presence of heterogeneous cataꢀ
lysts.
with acrylic acid and its esters via the Michael reaction
on heating to form ꢀ(2ꢀhydroxyethyl)ꢀsubstituted
derivatives of ꢀalanine. These derivatives are antagoꢀ
nists of ꢀaminobutyric and glycine receptors and are
of interest as complexꢀforming agents for metals
[1 6]. The nucleophilic addition of amines to the
activated C=C bond is known to be catalyzed by Lewis
acids (AlCl3, TiCl4, SnCl4) and rare earth triflates [7–
9]. The aim of this study is to establish the direction
N
β
We have found that bentonite and activated Al2O3
are efficient and regioselective catalysts of the Michael
γ
reaction, which make it possible to obtain
acid derivatives under mild conditions and in high
yields. The reaction results in formation of esters of
(2ꢀhydroxyethyl)ꢀ ꢀalanines IXa IXh XII
Schemes 1 and 2) in 80–98% yields over 1 h at 20
β
ꢀamino
⎯
Nꢀ
β
(
–
,
,
°
C
and product composition of the catalytic reaction of without solvent (Table 1).
R3
cat
CO2R1
+ R2R3NH
N
CO2R1
R2
20°C
I–IV
V–VIII
IXa–IXh
I
: R1 = H; II: R1 = Me; III: R1 = CH2CH = CH2; IV: R1 = CH2Ph;
V
: R2 = H, R3 = CH2CH2OH; VI: R2 = CH2CH2OH, R3 = CH2CH2OH;
VII: R2 = H, R3 = CH(CH2OH)2; VIII: R2 = H, R3 = C(CH2OH)3.
Scheme 1
The nucleophilic addition of monoethanolamine
) and diethanolamine (VI) to the C=C bond of
acrylic acid (I) proceeds under these conditions much
more difficult than the addition of compounds VII and
VIII and the yield of reaction products is not higher
than 60%.
It should be noted that the use of bentonite and
activated Al2O3 enables selective synthesis of
monoadducts of monoethanolamines with methyl
acrylate (Scheme 2). It was shown by the example of
(
V
the reaction of monoethanolamine (
acrylate (II) that methyl ester of
ethyl)ꢀNꢀ(3ꢀmethoxyꢀ3ꢀoxopropyl)ꢀ
formed in 25% yield along with methyl ester of
ꢀ(2ꢀhydroxyethyl)ꢀ ꢀalanine (IXc) (70%) only at
75 C for 3 h [10].
V
) and methyl
N
ꢀ(2ꢀhydroxyꢀ
a Bashkir State University, ul. Z. Validi 32, Ufa, 450074
Russia
b Institute of Organic Chemistry, Ural Division, Russian
Academy of Sciences, pr. Oktyabrya 71, Ufa, 450054
Bashkortostan, Russia
β
ꢀalanine (X)
N
β
°
47

48
DOKICHEV et al.
CO2Me
CO2Me
CO2Me
II
IXc +
HO
HO
N
X
CO2Me
cat
CO2Me
NH2
N
H
HO
XI
CO2Me
V
XII
COO CH2CH CH2
HO
N
H
III
CO2 CH2CH CH2
IXg
Scheme 2.
The bentoniteꢀcatalyzed reaction of monoethanoꢀ 75.47 MHz, respectively, with Me4Si as an internal
lamine (
nate (XI) proceeds regioselectively at the C=C bond in
the ꢀposition to the carboxy group to form allyl
ester of ꢀ(2ꢀhydroxyethyl)ꢀ ꢀalanine (IXg) and
methyl ester of 3ꢀ(2ꢀhydroxyethylamino)hexꢀ4ꢀenoic
acid (XII) in 92 and 78% yields, respectively. It
should be noted that transesterification and polyꢀ
merization products and amides of acrylic acid and
V) with allyl acrylate (III) and methyl sorbiꢀ
reference. IR spectra were recorded on an URꢀ20
spectrometer in a thin film. Mass spectra were
obtained with a Thermo Finnigan MAT 95 XP highꢀ
resolution mass spectrometer at the ionizing voltage
α β
,
N
β
70 eV (ionizing chamber temperature of 250
injection temperature of 50–270 C, heating rate of
°
C, direct
°
10 K/min). Bentonite was purchased from Idzhevanꢀ
skii bentonit kombinat OAO (Armenia).
β
ꢀalanine derivatives were not detected in the reacꢀ
tion mixture [11].
General Procedure for the Catalytic Reaction
Thus, we have established for the first time that the
reaction of acrylic acid or esters of conjugated unsatꢀ
urated acids with ethanolamines in the presence of
bentonite and activated Al2O3 proceeds selectively at
the C=C bond to form monoadducts with retention of
the ester group.
of
α
,
β
ꢀUnsaturated Acids and Their Esters
with Ethanolamines
Ethanolamine (
mixture of 5.8 mmol of
II IV or XI, and 0.29 g of the catalyst, and the mix was
V–
VIII) (8.7 mmol) was added to a
α,β
ꢀunsaturated acid or ester
I
–
stirred at ambient temperature for 1 h. The catalyst
was separated by filtration, washed with 20 mL of
methylene chloride or methanol, the solvent was
removed under reduced pressure. The structure of
EXPERIMENTAL
1H and 13С NMR spectra were recorded on a compounds IXa
Bruker AMꢀ300 spectrometer operating at 300.13 and comparison of their physicochemical characteristics
–IXh and XII was established by the
Effect of the catalyst nature and reagent structures on the yield of
N
ꢀ(2ꢀhydroxyethyl) derivatives of
Yield of IX, %
bentonite
β
ꢀalanine IXa–IXh
IX
R1
R2
R3
Al2O3
a
b
c
d
e
f
H
H
CH2CH2OH
CH2CH2OH
CH2CH2OH
CH2CH2OH
CH(CH2OH)2
C(CH2OH)3
CH2CH2OH
CH2CH2OH
60
52
97
91
88
81
92
98
54
49
90
95
89
80
93
81
H
CH2CH2OH
Me
Me
Me
Me
H
CH2CH2OH
H
H
H
H
g
h
CH2CH=CH2
CH2Ph
Note: Experiments were carried out at 20°C for 1 h at the molar ratio ester of α,βꢀunsaturated acid : ethanolamine = 2 : 3.
DOKLADY CHEMISTRY Vol. 430 Part 2
2010

SYNTHESIS OF
N
ꢀ(2ꢀHYDROXYETHYL) DERIVATIVES OF
βꢀALANINE
49
(1H and 13С NMR and IR spectra) with literature data
[1, 3–9].
4. Pestov, A.V., Virovets, A.V., Podberezskaya, N.V., and
Yatluk, Yu.G., Koord. Khim., 2008, vol. 34, no. 1,
pp. 3–10.
5. Molochnikov, L.S., Pestov, A.V., Slepukhin, P.A., and
Yatluk, Yu.G., Zh. Org. Khim., 2009, vol. 79, no. 6,
pp. 960–968.
6. Bueno, G.J., Klimkait, T., Gilbert, I.H., and
Simons, C., Bioorg. Med. Chem., 2003, vol. 11, no. 1,
pp. 87–94.
Allyl ester of Nꢀ(2ꢀhydroxyethyl)ꢀ
β
ꢀalanine (IXg).
1H NMR (CDCl3,
δ
, ppm): 2.59–2.94 (m, 6H,
3CH2), 3.56 (s, 1H, OH), 3.69 (t, 2H, CH2O), 4.57 (d,
2H, CO2CH2), 5.01 (s, 1H, NH), 5.23 (d, 1H, CH2=),
5.33 (d, 1H, CH2=), 5.81–5.98 (m, 1H, HC=). MS
(
m/
z
): 173.21 [MH+].
7. Romanova, N.N., Gravis, A.G., and Bundel’, Yu.G.,
Usp. Khim., 1996, vol. 65, no. 12, pp. 1170–1180.
8. Liu, M. and Sibi, M.P., Tetrahedron, 2002, vol. 58,
no. 40, pp. 7991–8035.
9. Fadini, L. and Togni, A., Helv. Chim. Acta, 2007,
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DOKLADY CHEMISTRY Vol. 430
Part 2
2010