Synthesis of schiff bases from 3-amino-3-arylpropionic acid esters in aqueous medium

Full text of DOI:10.1134/S107042801206019X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 6, pp. 860–863. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © N.N. Romanova, I.I. Rybalko, T.G. Tallo, N.V. Zyk, V.K. Švedas, 2012, published in Zhurnal Organicheskoi Khimii, 2012,
Vol. 48, No. 6, pp. 862–865.
SHORT
COMMUNICATIONS
Synthesis of Schiff Bases from 3-Amino-3-arylpropionic Acid
Esters in Aqueous Medium
N. N. Romanovaa, I. I. Rybalkoa, T. G. Tallob, N. V. Zyka, and V. K. Švedasc
a Faculty of Chemistry, Moscow State University, Vorob’evy gory 1, Moscow, 119992 Russia
e-mail: romanova@org.chem.msu.ru
b National Institute for Health Development, Tallinn, Estonia
c Belozerskii Institute of Physicochemical Biology, Moscow State University,
Moscow, Russia
Received January 15, 2012
DOI: 10.1134/S107042801206019X
Schiff bases constitute one of the most thoroughly
studied and practically important class of organic com-
pounds. Their biological activity is well known. Some
Schiff bases inhibit many enzymes [1–8] and possess
bactericidal [9, 10], fungicidal [11, 12], herbicidal,
[13] and anticancer activity [14, 15]. Schiff bases had
been used in organic synthesis since 1907 when
Staudinger reported on their reaction with ketenes [16].
At present Schiff bases are widely used as initial mate-
rials in the synthesis of many biologically active com-
pounds, in particular nitrogen-containing heterocycles
[17–19] and non-natural amino acids and their deriva-
tives [20, 21]. Exceptional advances in the chemistry
of Schiff bases due to their participation in multicom-
ponent reactions should be noted [22].
problem related to preparation of the corresponding
Schiff bases. Methyl 3-benzylideneamino-3-phenyl-
propionate was synthesized [25] in anhydrous meth-
ylene chloride under argon. Mokhallalati and Pridgen
[26] described (but not completely characterized) com-
pounds Ia and Ib which were prepared in a difficultly
realizable way, by oxidative cleavage of 3-aryl-3-[(2-
hydroxy-1-phenylethyl)amino]propionic acids esters
with lead tetraacetate (Scheme 1).
The classical Schiff procedure is based on conden-
sation of carbonyl compounds with primary amines
[27] (Scheme 2).
Scheme 2.
H2N
Ar
N
–H2O
H2O
ArCHO
+
While performing studies in the fields of synthesis
and stereochemistry of bioactive β-amino-β-arylpro-
pionic acids [23, 24], we have confronted with the
R
R
The reaction is reversible, and it is usually carried
out with simultaneous removal of water as azeotrope
or in the presence of molecular sieves [17, 28, 29] to
displace the equilibrium. Up-to-date modifications
utilize ultrasonic [30] or microwave activation [18, 31,
32]. In the past decade, Schiff condensations were
reported to be carried out in aqueous medium [33–35].
Uncommonness of this approach stimulated special
study which showed that the use of aqueous medium is
possible if the conditions ensure contact of the reac-
tants and the product is insoluble in water; the latter
factor is crucial for the displacement of thermody-
namic equilibrium [35].
Scheme 1.
O
O
Pb(OAc)4
EtO
Ph
EtO
Ph
OH
OH
Ar
N
Ar
N
H
H
O
O
H+, H2O
EtOH
MeOH
EtO
EtO
Ar
N
Ph
Ar
NH2
Ia, Ib
860

SYNTHESIS OF SCHIFF BASES FROM 3-AMINO-3-ARYLPROPIONIC ACID ESTERS
861
Scheme 3.
NH2
O
NH2
O
SOCl2, EtOH
Ar1CHO
+
NH4OAc + CH2(COOH)2
·HCl
Ar1
OH
Ar1
OEt
IIIa, IIIb
IIa, IIb
Ar2
Ar2CHO, H2O
N
O
Ar1
OEt
Ia–Ie
Ar1 = Ar2 = Ph (a); Ar1 = 4-BrC6H4, Ar2 = Ph (b); Ar1 = Ph, Ar2 = 4-BrC6H4 (c); Ar1 = Ph, Ar2 = 3,4-(MeO)2C6H3 (d);
Ar1 = Ph, Ar2 = 2,4-Cl2C6H3 (e).
anhydrous methylene chloride in a stream of argon
[25]. Hydrochloride IIIa or IIIb, 0.12 mol, was dis-
solved in water, 0.13 mol of sodium carbonate was
added, and 0.1 mol of the corresponding aldehyde was
added dropwise (solid aldehyde was added in small
portions). The mixture was heated for 2 h at 45–50°C
in a flask equipped with a reflux condenser, stirred for
24 h at room temperature, and extracted with methyl-
ene chloride (3 × 30 ml). The organic phase was
washed with water and dried over MgSO4, and the
solvent was removed on a rotary evaporator under
reduced pressure to isolate analytically pure Schiff
bases Ia–Ie as mobile oily liquids in 75–87% yield.
Compounds Ia–Ie were characterized by NMR spectra
and elemental analyses.
In the present communication we describe a con-
venient procedure for the condensation of aromatic
aldehydes with β-amino-β-arylpropionic acid ester
hydrochlorides in aqueous medium, which ensures pre-
paration of potentially biologically active Schiff bases
Ia–Ie in good yield (75–87%); the product requires no
additional purification.
Initial 3-amino-3-phenyl- and 3-amino-3-(4-bromo-
phenyl)propionic acids IIa and IIb were synthesized
according to Rodionov [36–39] by condensation of the
corresponding aromatic aldehydes with malonic acid in
the presence of ammonium acetate (Scheme 3); their
spectral parameters fully coincided with those reported
in the literature. The second product, cinnamic acid,
was isolated by pouring the filtrate into a threefold
volume of water. Cinnamic acid is insoluble in water,
and it separated in 20–40% yield.
The NMR spectra of Ia–Ie contained the same
signals as in the spectra of the corresponding amino
esters, except for the number of aromatic protons due
to the presence of an additional aryl group on the
nitrogen. In addition, downfield signals from the azo-
methine proton (δ 8.3–8.9 ppm) and N=CH carbon
atom (δC 157.07–161.96) were observed. Some signals
Acids IIa and IIb were subjected to esterification
according to modified procedures for the synthesis of
ethyl 3-amino-3-phenylpropionate (IIIa) [38, 39] and
analogous methyl ester (at –10°C [25]) which required
purification by recrystallization. Acid IIa and IIb,
0.1 mol, was dispersed in 75 ml of 96% ethanol,
0.2 mol of thionyl chloride was slowly added to avoid
sharp rise in temperature, and the mixture was then
heated for 2 h under reflux. When the reaction was
complete, the solvent was distilled off on a rotary
evaporator, and amino ester hydrochlorides IIIa and
IIIb were additionally precipitated by adding 25 ml of
diethyl ether saturated with hydrogen chloride. After
filtration, washing with diethyl ether, and drying over
P2O5 for 2 days we obtained analytically pure hydro-
chlorides IIIa and IIIb as white crystals in more than
95% yield.
1
in the H NMR spectra of all Schiff bases Ia–Ie were
doubled, indicating the presence of two isomers (E and
Z) at a ratio of 80 : 20 to 91 : 9 (calculated by the
intensities of signals from the ester methyl protons).
Presumably, the major isomer has E configuration.
Ethyl 3-benzylideneamino-3-phenylpropanoate
1
(Ia). Yield 87%, transparent mobile liquid. H NMR
spectrum (DMSO-d6), δ, ppm: major isomer: 1.07 t
3
(3H, CH3, J = 7.3 Hz), 2.94–2.90 m (2H, CH2),
3
3.99 m (2H, OCH2), 4.82 d.d (1H, CHPh, J = 3.7,
7.8 Hz), 7.23–7.38 m (3H, Harom), 7.48–7.41 m (5H,
H
arom), 7.79–7.74 m (2H, Harom), 8.45 s (1H, CH=N);
3
minor isomer: 1.12 t (3H, CH3, J = 7.0 Hz); isomer
ratio 83:17.
Schiff bases Ia–Ie were synthesized by a modified
procedure for the preparation of methyl 3-benzylidene-
amino-3-phenylpropionate which implied the use of
Ethyl 3-benzylideneamino-3-(4-bromophenyl)-
propanoate (Ib). Yield 85%, light yellow mobile
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 6 2012

ROMANOVA et al.
862
1
liquid. H NMR spectrum (CDCl3), δ, ppm: major
isomer ratio 91:9. Found, %: C 61.46; H 4.68; N 3.88.
C18H17Cl2NO2. Calculated, %: C 61.71; H 4.86; N 4.00.
3
isomer: 1.15 t (3H, CH3, J = 7.1 Hz), 2.84 d.d (1H,
CH2, J = 15.5, J = 4.9 Hz), 2.97 d.d (1H, CH2, J =
15.4, J = 9.0 Hz), 4.06 q (2H, OCH2, J = 7.1 Hz),
4.81 d.d (1H, CHPh, J = 4.9, 9.0 Hz), 7.34 d (2H,
2
3
2
3-Amino-3-phenylpropanoic acid (IIa). Yield
60%, white crystals, mp 219–220°C (decomp.); pub-
lished data: mp 221–223°C (decomp.) [23], 235–
3
3
3
3
H
arom, J = 8.4 Hz), 7.37–7.43 m (3H, Harom), 7.46 d
1
237°C [38]. H NMR spectrum (D2O), δ, ppm: 2.35–
3
(2H, Harom, J = 8.4 Hz), 7.76 d (2H, Harom), 8.38 s
(1H, CH=N); minor isomer: 1.23 t (3H, CH3); isomer
ratio 80:20.
3
2.42 m (2H, CH2), 4.14 t (1H, PhCH, J = 7.3 Hz),
7.14–7.42 m (5H, Harom).
3-Amino-3-(4-bromophenyl)propanoic acid
Ethyl 3-(4-bromobenzylideneamino)-3-phenyl-
propanoate (Ic). Yield 82%, yellowish mobile liquid.
1H NMR spectrum (DMSO-d6), δ, ppm: major isomer:
(IIb). Yield 61%, white crystals, mp 232°C (decomp.);
1
published data [37]: mp 234°C. H NMR spectrum
(D2O), δ, ppm: 2.41–2.52 m (2H, CH2), 4.13 t (1H,
PhCH, 3J = 7.33 Hz), 7.19–7.45 m (4H, Harom). Found,
%: C 44.21; H 4.16; N 5.63. C9H10BrNO2. Calculated,
%: C 44.29; H 4.13; N 5.74.
3
1.06 t (3H, CH3, J = 7 Hz), 2.94–2.89 m (2H, CH2),
3.98 m (2H, OCH2), 4.82 d.d (1H, CHPh, 3J = 5.9 Hz),
7.30–7.23 m (1H, Harom), 7.37–7.31 m (2H, Ha3rom),
7.45–7.41 m (2H, Harom), 7.65 d (2H, Harom, J =
3
Ethyl 3-amino-3-phenylpropanoate hydrochlo-
ride (IIIa). Yield 98%, colorless crystals, mp 140°C;
published data: mp 138–141°C (decomp.) [38], 141–
8.6 Hz), 7.71 d (2H, Harom, J = 8.6 Hz), 8.44 s (1H,
CH=N); minor isomer: 1.12 t (3H, CH3, J = 7 Hz);
3
isomer ratio 92:8. 13C NMR spectrum (acetone-d6), δC,
ppm: major isomer: 14.5 (CH3), 43.8 (CH2), 60.6
(CH2O), 71.7 (CHPh), 125.4 (CBr), 127.8 (2C, CHPh),
128.1 (CHPh), 129.3 (2C, CHPh), 130.7 (2C, CHAr),
132.5 (2C, CHAr), 136.4 (CAr), 143.8 (CPh), 160.9
(C=N), 171.1 (C=O). Found, %: C 59.81; H 4.98;
N 3.97. C18H18BrNO2. Calculated, %: C 60.01; H 5.04;
N 3.89.
1
144°C [39]. H NMR spectrum (D2O), δ, ppm: 1.16 t
3
2
(3H, CH3, J = 7.1 Hz), 3.12 d.d (1H, CH2, J = 16.6,
3J = 7.5 Hz), 3.21 d.d (1H, CH2, J = 16.6, J =
2
3
3
7.2 Hz), 4.11 q (2H, OCH2, J = 7.1 Hz), 4.81 t (1H,
PhCH, 3J = 7.3 Hz), 7.44–7.58 m (5H, Harom).
Ethyl 3-amino-3-(4-bromophenyl)propanoate
hydrochloride (IIIb). Yield 97%, colorless crystals.
1H NMR spectrum (D2O), δ, ppm: 1.13 t (3H, CH3,
3J = 7.3 Hz), 3.05–3.20 m (2H, CH2), 4.10 q (2H,
Ethyl 3-(3,4-dimethoxybenzylideneamino)-
3-phenylpropanoate (Id). Yield 82%, transparent
mobile liquid. 1H NMR spectrum (DMSO-d6), δ, ppm:
major isomer: 1.07 t (3H, CH3, J = 7.0 Hz), 2.90 m
(2H, CH2), 3.78 s (3H, OCH3), 3.79 s (3H, OCH3),
3.99 q (2H, OCH2, J = 7 Hz), 4.77 t (1H, CHPh, J =
6.9 Hz), 7.01 d (1H, Harom, J = 8.3 Hz), 7.38–7.22 m
(5H, Ph), 7.46–7.41 (2H, Harom), 8.33 s (1H, CH=N);
3
OCH2), 4.77 t (1H, CH, J = 7.4 Hz), 7.34–7.65 m
3
(4H, Harom).
1
The H and 13C NMR spectra were measured on
3
3
a Bruker Avance-400 spectrometer at 400 and 100 MHz,
respectively; the chemical shifts were determined
relative to the residual proton and carbon signals of the
deuterated solvent.
3
3
minor isomer: 1.12 t (3H, CH3, J = 7.3 Hz); isomer
ratio 88:12. 13C NMR spectrum (CDCl3), δC, ppm:
171.3 (C=O), 160.9 (C=N), 151.4, 149.2, 143, 129.4,
128.6, 127, 123.3, 110.4 (OCH3), 109.1 (OCH3), 70.9
(CHAr), 60.4 (OCH2), 43.8 (CH2), 14.2 (CH3). Found,
%: C 70.14; H 6.43; N 3.90. C20H23NO4. Calculated,
%: C 70.38; H 6.75; N 4.11.
This study was performed under financial support
by the Ministry of Education and Science of the
Russian Federation (state contract no. 16.512.11.2240).
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