Catalyzed synthesis of β-amino acids esters

Full text of DOI:10.1134/S107042801005026X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 5, pp. 755−757. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © T.V. Dokichev, D.R. Latypova, R.R. Shakirov, R.Z. Biglova, R.F. Talipov, 2010, published in Zhurnal Organicheskoi
Khimii, 2010, Vol. 46, No. 5, pp. 760−761.
SHORT
COMMUNICATIONS
Catalyzed Synthesis of β-Amino Acids Esters
a
b
a
T. V. Dokichev , D. R. Latypova , R. R. Shakirov ,
a
a
R. Z. Biglova , and R. F. Talipov
a
Bashkir State University, Ufa, 450074 Russia
e-mail: dokichev@anrb.ru
b
Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, Ufa, Russia
Received June 26, 2009
DOI: 10.1134/S107042801005026X
β-Aminoalcohols, β-amino acids, and their esters
exhibit a wide range of biological action antitumor,
immunostimulating, antiphlogistic). They are used as
peptidomimetics and are precursors of many synthetic
and natural compounds, in particular, of β-lactams [1–
esters of α,β-unsaturated acids we used methyl acrylate
(Ia), allyl acrylate (Ib), methyl methacrylate (Ic), and
dimethyl maleate (Id), and as amines, isopropylamine
(IIa), butylamine (IIb), benzylamine (IIc), monoethanol-
amine (IId), diethylamine (IIe), and morpholine (IIf).
The experiments were carried out at 20°C over 0.5 and
4
4
]. For instance, bestatin, [(2S,3R)-3-amino-2-hydroxy-
1
2
.5 h at molar ratio of the α,β-un-saturated acid–amine
:3.
-phenylbutanoyl]-L-leucine, is a specific inhibitor of the
chemotoxic activity of the aminopeptidase possessing
a low toxicity; it is used in medical practice as immuno-
modulator and antitumor drug [1].
R2
R2
5
4
The intense studies on the development of new
methods for preparation the mentioned compounds are
going on, and the substances as a rule are obtained by
the nucleophilic Michael addition of primary or secondary
amines to the activated C=C bond [5, 6]. The reaction is
commonly performed in polar solvents (alcohols or
carboxylic acids), the process is carried out in the
presence of catalysts, Lewis acids (AlCl , TiCl , SnCl )
R R N
3
4
5
3
CO R + HNR R
CO R
2
2
R1
R1
_
_
_
Iа Id
IIа IIf
IIIа IIIh
1
3
1
2
3
1
I, R = R = H, R = Me (a); R = R = H, R =All (b); R =
2
2
3
1
2
3
H, R = R = Me (c); R = CO Me, R = H, R = Me (d); II,
2
4
5
4
5
4
5
R = H, R = = i-Pr (a); R = H, R = Bu (b); R = H, R = Bn
c); R = H, R = CH CH OH (d); R = R = Et (e);R + R =
3
4
4
4
5
4
5
4
5
(
2 2
that accelerate Michael reaction [2, 5–10]. Recently as
catalysts triflates of lanthanides were suggested [6].
However even at the use of new more efficient catalysts
the reaction often proceeds nonselectively and requires
several hours at 50–100°C and the presence of organic
solvents. Therefore the development of catalytic methods
free of the mentioned drawbacks is an urgent task.
CH CH OCH CH (f).
2
2
2
2
We report here on the new convenient catalytic
procedure for one-stage preparation of β-amino acids
esters by the reaction of esters of conjugated unsaturated
acid with a series of primary and secondary amines in
.
.
the presence of Kuganak montmorilloniteAl O 4SiO
2
2
3
2
H O that contains relatively high amount of TiO . As
2
2
755

756
DOKICHEV et al.
1
The reaction led to the formation of β-amino acids
(CH=CH ). H NMR spectrum (CDCl ) δ, ppm: 1.02 t
2
3
2
esters IIIa–IIIh in virtually quantitative yield within 1.5
h. The nucleophilic addition of butylamine to the C=C
bond of methyl methacrylate (Ic) under the conditions
we chose provided 38% of the product, and the diethyl-
and isopropylamine did not react at all. The application
of the chosen catalyst made it possible to synthesize
selectively exclusively monoadducts of primary amines
with methyl acrylate [11]. The reaction of diethylamine
with allyl acrylate occurred regioselectively at the double
bond of the acrylic system affording N,N-diethyl-β-alanine
allyl ester (IIIf), yield 97%. In contrast to the noncatalytic
method of preparation of β-substituted amino acids we
did not detect in the reaction mixture products of amines
addition to the ester group [12]. The preferable application
of Kuganak montmorillonite as a catalyst of the conjugate
Michael addition compared to the Lewis acids consists
in the disability of the montmorillonite to form stable
complexes with amines that suppress the reactivity of
the amines.
(6H, 2Me, J 7.2 Hz), 2.45–2.55 m (6H, 3CH ), 2.80 t
2
(2H, CH , J 7.5 Hz), 4.57 d (2H, OCH , J 5.7 Hz),
5.22 d (1H, =CH , J 10.5 Hz), 5.31 d (1H, =CH ,
3J 17.2 Hz), 5.85–5.98 m (1H, =CH). 13C NMR
spectrum (CDCl ), δ, ppm: 11.72 (Me), 32.17 (CH ),
46.69 (CH ), 47.95 (CH ), 64.37 (OCH ), 117.9 (=CH ),
132.12 (=CH), 172.26 (C=O). Mass spectrum, m/z: 186
[M + H]+.
2
2
2
2
3
2
2
3
2
2
2
2
2
N-Butyl-2-methyl-β-alanine methyl ester (IIIg).
–1
IR spectrum, ν, cm : 3450–3241 (NH), 1740 (CO ),
2
1
1
325. H NMR spectrum (CDCl ), δ, ppm: 0.91 t (3H,
3
2
2
Me, J 7.3 Hz), 1.11 d (3H, Me, J 6.5 Hz), 1.27–1.53 m
(
4H, CH CH ), 1.95 s (1H, NH), 2.43 m (1H, CH),
2 2
2
.48 m (4H, NCH ), 3.56 s (3H, OMe). Mass spectrum,
m/z: 174 [M + H] . Found, %: C 62.48; H 11.21; N 8.04.
C H NO . Calculated, %: C 62.39; H 11.05; N 8.08.
2
+
9
19
2
N,N-Diethyl-D,L-aspartic acid dimethyl ester
–1
(
1
2
2
IIIh). IR spectrum, ν, cm : 1740, 1737 (CO ), 1212,
2
1
033. H NMR spectrum (CDCl ), δ, ppm: 1.06 t (6H,
3
Hence we developed a convenient preparation method
for β-amino acids.
2
Me, J 6.2 Hz), 2.44 m (2H, CH ), 2.86 q (4H, 2NCH ,
2
2
J 6.4 Hz), 3.70 m (1H, NCH), 3.67 s (3H, OMe), 3.72 s
3H, OMe). Mass spectrum, m/z: 218 [M + H] . Found,
: C 55.17; H 8.90; N 6.42. C H NO . Calculated, %:
C 55.28; H 8.81; N 6.45.
Reaction of esters of α,β-unsaturated acids with
amines in the presence of Kuganak montmoril-
lonite. General procedure. To a mixture of 5.8 mmol
of an ester of α,β-unsaturated acid Ia–Id and 0.29 g of
the catalyst was added 8.7 mmol of amine IIa–IIf, and
the mixture was stirred at room temperature for 0.5 or
+
(
%
10 19 4
1
13
H and C NMR spectra were registered on a spec-
trometer BrukerAM-300 (300.13 and 75.47 ΜHz respec-
tively), internal reference Me Si. IR spectra were
recorded on a spectrophotometer UR-20 from thin films.
Mass spectra were measured on a liquid chromato mass
spectrometer LCMS-2010EV Shimadzu in the chemical
ionization mode at the atmospheric pressure.
4
1
.5 h. The catalyst was filtered off, washed with 20 ml
of dichloromethane, the solvent was removed at a reduced
pressure. The structure of compounds IIIb, IIId, IIIe
was established by comparison of their spectral
1
13
characteristics ( H, C, NMR, and IR spectra) with the
published data [11, 13].
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N-Isopropyl-β-alanine methyl ester (IIIa). IR
–
1
spectrum, ν, cm : 3412–3258 (NH), 1735 (CO ), 1337.
2
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1
H NMR spectrum (CDCl ), δ, ppm: 1.04 d (6H, 2Me,
J 6.2 Hz), 1.32 s (1H, NH), 2.50 t (2H, CH , J 6.6 Hz),
.77 septet (1H, NCH, £ 6.2 Hz), 2.86 t (2H, CH , J 6.6
Hz), 3.67 s (3H, OMe). C NMR spectrum (CDCl ), δ,
ppm: 22.22 (2Me), 34.46 (CH ), 42.23 (CH ), 48.15
3
2
2
2
2
2
2
2
13
3
3
2
2
(
NCH), 51.23 (OCH ), 172.97 (C=O). Mass spectrum,
3
+
m/z: 146 [M + H] . Found, %: C 57.66; H 10.42; N 9.82.
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7
15
2
2
N-(2-Hydroxyethyl)-β-alanine methyl ester
IIIc). Colorless crystals, mp 40.5°C (40°C [14]).
5
(
Khim., 1996, vol. 65, p. 1170.
2
0
N,N-Diethyl-β-alanine allyl ester (IIIf). n 1.4665
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D
–1
(
1.4662 [15]). IR spectrum, ν, cm : 1738 (CO ), 991, 929
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 5 2010

CATALYZED SYNTHESIS OF β-AMINO ACIDS ESTERS
757
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1
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