Regioselectivity of the hydrolysis of 2-(1-alkoxyvinyl)-substituted imidazolidines, 1,3-thiazolidines, and 1,3-oxazolidines

Article abstract of DOI:10.1134/S1070428011120098

2-(1-Alkoxyvinyl)-1,3-thiazolidines reacted with H₂O or D ₂O in the presence of 105 mol % of p-toluenesulfonic acid or trifluoroacetic acid (20°C, 1 h) to give 2-acetyl-1,3-thiazolidine in quantitative yield. 2-(1-Alkoxyvinyl)-3,5-diphenylimidazolidines underwent hydrolysis in the presence of 20 mol % of an acid (20°C, 24 h) at the vinyloxy group with high regioselectivity yielding 2-acetylimidazolidines. Hydrolysis of 2-(1-alkoxyvinyl)-3-phenyl-1,3-oxazolidines in the presence of 10 mol % of p-toluenesulfonic acid (20°C, 5 days) takes two pathways, one of which involves the endocyclic C-O bond with ring opening and the other involves the vinyloxy group to produce 2-acetyl-3-phenyl-1,3-oxazolidine. Unlike phenyl-substituted 1,3-thiazolidines and imidazolidines, hydrolysis of their 3-methyl- and 3,5-dimethyl-substituted analogs in acid medium occurs mainly via ring opening. The observed hydrolysis pathways were interpreted in terms of B3PW91/6-311G(d,p) quantum-chemical calculations.

Full text of DOI:10.1134/S1070428011120098

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 12, pp. 1832–1840. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © N.A. Keiko, E.A. Funtikova, N.V. Vchislo, L.I. Larina, Yu.L. Frolov, 2011, published in Zhurnal Organicheskoi Khimii, 2011,
Vol. 47, No. 12, pp. 1794–1802.
Dedicated to Full Member of the Russian Academy of Sciences
M.G. Voronkov on his 90th anniversary
Regioselectivity of the Hydrolysis of 2-(1-Alkoxyvinyl)-
Substituted Imidazolidines, 1,3-Thiazolidines,
and 1,3-Oxazolidines
N. A. Keikoa, E. A. Funtikovab, N. V. Vchisloa, L. I. Larinaa, and Yu. L. Frolov†
a Favorskii Irkutsk Institute of Chemistry, Siberian Division, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
e-mail: keiko@irioch.irk.ru
b Irkutsk National State Research Technical University, Irkutsk, Russia
Received January 15, 2011
Abstract—2-(1-Alkoxyvinyl)-1,3-thiazolidines reacted with H2O or D2O in the presence of 105 mol % of
p-toluenesulfonic acid or trifluoroacetic acid (20°C, 1 h) to give 2-acetyl-1,3-thiazolidine in quantitative yield.
2-(1-Alkoxyvinyl)-3,5-diphenylimidazolidines underwent hydrolysis in the presence of 20 mol % of an acid
(20°C, 24 h) at the vinyloxy group with high regioselectivity yielding 2-acetylimidazolidines. Hydrolysis of
2-(1-alkoxyvinyl)-3-phenyl-1,3-oxazolidines in the presence of 10 mol % of p-toluenesulfonic acid (20°C,
5 days) takes two pathways, one of which involves the endocyclic C–O bond with ring opening and the other
involves the vinyloxy group to produce 2-acetyl-3-phenyl-1,3-oxazolidine. Unlike phenyl-substituted 1,3-thia-
zolidines and imidazolidines, hydrolysis of their 3-methyl- and 3,5-dimethyl-substituted analogs in acid
medium occurs mainly via ring opening. The observed hydrolysis pathways were interpreted in terms of
B3PW91/6-311G(d,p) quantum-chemical calculations.
DOI: 10.1134/S1070428011120098
Interest in the chemistry of 2-alkyl- [1] and 2-acyl-
1,3-oxazolidines [2], 2-alkyl- [3] and 2-acetyl-1,3-thia-
zolidines [4], 2-alkylimidazolidines [5], and 2-acetyl-
imidazolidines [6] is related to the presence of the
corresponding fragments as structural units of many
medical agents and natural compounds, as well as to
their use as starting compounds for the synthesis of
pharmaceuticals and fragrant substances. In particular,
some 2-acyloxazolidines are convenient precursors in
the synthesis of alkaloids [7]. 2-Alkylthiazolidines
exhibit radioprotective, antimutagenic, antibacterial,
and antiviral activity [3, 8]. Compounds of the thiazoli-
dine series are important as models for studying bio-
chemical transformations of their complex analogs
involved in natural processes [9].
age of the heteroring in vivo [10, 11]. It is known that
L-cysteine responsible for intracellular level of gluta-
thione could be introduced at a required dose as ap-
propriate prodrugs, 2-alkylthiazolidines [10, 11]. The
nitrogen-containing heteroring in vivo undergoes non-
enzymatic hydrolysis to release amino acid and the
corresponding aldehyde. The mechanism of acid hy-
drolysis of some 1,3-thiazolidines was studied in vitro
[12]. The results of kinetic studies on hydrolytic ring
opening in 2-aryl-N-methyl(phenyl)oxazolidines
showed that the rate of hydrolysis and optimal pH
value often strongly depend on the nature and/or stereo-
chemistry of substituents in the oxazolidine ring [13].
We previously found that 2-alkoxypropenals readily
react with 2-aminoalkanols [14], 2-aminoethanethiol
[15], and ethane-1,2-diamines [16] to give the corre-
sponding 2-(1-alkoxyvinyl)-1,3-oxazolidines, -1,3-thia-
zolidines, and -imidazolidines as mixtures with their
open-chain tautomers. The fraction of the cyclic struc-
ture decreases as the solvent polarity rises [15, 16],
Hydrolytic stability of the above listed heterocyclic
compounds is an important factor determining their
application as therapeutic agents which undergo cleav-
†
Deceased.
1832

REGIOSELECTIVITY OF THE HYDROLYSIS OF 2-(1-ALKOXYVINYL)-...
1833
Scheme 1.
H
OEt
CH2
N
TsOH
·TsOH
S
H
N
OEt
CH2
II
S
H
N
H
N
H2O or D2O
TsOH or TFA
Me
O
Me
O
TsOH
I
·TsOH
S
S
III
IV
while introduction of substituents into oxazolidine [14]
or imidazolidine ring [16] increases the stability of the
cyclic structure. Selectivity of acid hydrolysis of
2-(1-alkoxyvinyl)-substituted 1,3-oxazolidines,
1,3-thiazolidines, and imidazolidines having two com-
peting reaction centers was not studied previously.
amount of an acid (H2CO3, CF3SO2OH) leads to quan-
titative formation of the corresponding ammonium
salts, which is reflected in the H NMR spectra by
1
downfield shift of almost all proton signals by 0.1–
0.15 ppm [15]. The reaction of thiazolidine I with
p-toluenesulfonic acid also yields thiazolidinium p-tol-
uenesulfonate II. However in the presence of an equi-
molar or slightly higher (105–107%) amount of TsOH
or trifluoroacetic acid (TFA) in excess H2O or D2O
compound I readily undergoes strictly regioselective
hydrolysis at the alkoxyvinyl group with formation of
2-acetyl-1,3-thiazolidine (III) (Scheme 1). In the reac-
tion of I with TFA at 20°C in D2O the conversion was
60% in 1 h and 100% in 24 h (according to the
1H NMR data). The subsequent neutralization of the
reaction mixture and evaporation afforded pure 2-ace-
tylthiazolidine (III) which did not require additional
purification. The reaction in D2O at 45°C was com-
plete in 1 h in the presence of both TsOH and TFA. No
opening of the heteroring was observed under these
The goal of the present study was to elucidate
regioselectivity of hydrolysis of 2-(1-alkoxyvinyl)-sub-
stituted imidazolidines, 1,3-thiazolidines, and 1,3-oxa-
zolidines in acid medium with a view to find condi-
tions ensuring predominant hydrolysis at the vinyloxy
group and formation of 2-acetyl-1,3-heteroazolidines
as cyclic S,N- or O,N- acetals or aminals of methyl-
glyoxal. The latter is an important metabolite acting in
vivo as mediator in Parkinson’s and Alzheimer’s dis-
eases and as low-molecular cell division regulator [17].
We previously found that the nitrogen atom in
2-(1-ethoxyvinyl)thiazolidine (I) is strongly basic.
Therefore, addition to compound I of an equimolar
Scheme 2.
Ph
Me
O
N
+
R3OH
R1 = R2 = Ph
R1
N
OR3
CH2
Ph
VIa
N
H+, H2O, 20°C
N
Me
R2
Va–Vd
OEt Me
N
OEt
CH2
N
OH–
H2C
NH2
R1 = Me, R2 = H
N
OH
H
H
OEt
CHO
H
+
N
Me
NH2
H2C
VIIa
VIII
R1 = R2 = Ph, R3 = Et (a); R1 = R2 = Ph, R3 = Me (b); R1 = Me, R2 = H, R3 = Et (c); R1 = Me, R2 = H, R3 = Me (d).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 12 2011

KEIKO et al.
1834
1
conditions. The hydrolysis in a large excess (84-fold)
of distilled water in the presence of 1 equiv of TsOH at
20°C in 7 days at pH 5 gave acetylthiazolidine III in
80% yield (isolated compound). By evaporation of the
reaction mixture without neutralization we succeeded
in isolating up to 70% of 2-acetyl-1,3-thiazolidinium
p-toluenesulfonate (IV). The formation of salt IV in-
dicates stability of the cyclic structure of III and its
fairly high basicity. Acetylthiazolidine III was synthe-
sized previously from cysteamine and methylglyoxal,
but in this case compound III was formed as a mixture
with two other products [18].
was formed in 35% yield (according to the H NMR
data). The same conversion and yield of hydrolysis
products were attained in 3 h at 45°C in the presence
of TsOH (105 mol %).
Unlike thiazolidine I and 1,3-diphenylimidazoli-
dines Va and Vb, their oxygen-containing analogs,
2-(1-alkoxyvinyl)-3-phenyl-1,3-oxazolidines IX in
acid aqueous medium readily undergo protonation at
the endocyclic oxygen atom with subsequent opening
of the heteroring. Hydrolysis of 2-(1-ethoxyvinyl)-3-
phenyl-1,3-oxazolidine (IXa) in the presence of 10–
15 mol % of TsOH in chloroform at 20°C takes two
pathways involving the vinyloxy group and the endo-
cyclic C–O bond (Scheme 3). According to the
1H NMR data, the reaction mixture after 24 h con-
tained compounds IX, VII, and X at a ratio of 4:2:1;
after five days, the product ratio changed to 1:1:2; the
conversion of initial oxazolidine IXa reached 100% in
13 days, while 2-ethoxyprop-2-enal (VIIa) disap-
peared, presumably as a result of hydrolysis (reac-
tion c). Hydrolysis of 2-(1-methoxyvinyl)-3-phenyl-
1,3-oxazolidine (IXb) in the presence of 20 mol % of
TsOH afforded 40% of 2-acetyl derivative X in 3 days
(1H NMR data), so that the rate of hydrolysis of IXb is
comparable with the rate of hydrolysis of ethoxyvinyl
derivative IXa.
Reduction of basicity of the nitrogen atoms in
1,3-diphenyl-2-(1-alkoxyvinyl)imidazolidines Va and
Vb due to electronic effect of the aryl groups facili-
tates their hydrolysis at the vinyloxy group. The reac-
tion in chloroform at 20°C (24 h) in the presence of
20 mol % of TsOH gives 2-acetyl-1,3-diphenylimid-
azolidine (VIa) in 78–100% yield (according to the
1H NMR data; 40% after recrystallization; Scheme 2).
Imidazolidines Va and Vb are insoluble in excess
water in the absence of a homogenizing solvent, and
their hydrolysis catalyzed by 20 mol % of TsOH
occurs at a low rate: the yield of acetyl derivative VI is
10% in 24 h. Unlike N-phenyl derivatives Va and Vb,
N-methyl-2-(1-alkoxyvinyl)imidazolidines Vc and Vd
reacted with water in the presence of 20 to 70 mol %
of TsOH or TFA very slowly both in heterogeneous
medium (in the absence of a solvent) and in chloro-
form or acetone solution. Small amounts of the corre-
sponding alkanol and/or 2-alkoxyprop-2-enal appeared
in the reaction mixture only after 2–6 days. The con-
version of 2-(1-ethoxyvinyl)-1-methylimidazolidine
(Vc) in the reaction with excess water in the presence
of 105 mol % of TFA in acetonitrile at room tempera-
ture was 45% in 18 h, and 2-ethoxyprop-2-enal (VII)
The yields of 2-acetyl derivatives III and VI in the
hydrolysis of thiazolidine I and imidazolidines V,
which occurs only at the alkoxyvinyl group, can be
1
calculated on the basis of H NMR spectra from the
amount of reacted initial compound. If the process is
accompanied by hydrolytic opening of the heteroring,
the depth of hydrolysis along pathway a cannot be
monitored by the amount of 2-alkoxypropenal VII, for
it depends on the time of sample withdrawal. Aldehyde
VII in acid aqueous medium is gradually converted
Scheme 3.
OR3
O
H
N
+
+
R3OH
R1
OH
a
c
H2C
CHO
Me
CHO
R1
XI
VIIa, VIIb
XII
OR3
CH2
N
H+, H2O
O
R2
Ph
IXa–IXd
Me
O
N
+
R3OH
b
O
X
IX, R1 = Ph, R2 = H, R3 = Et (a); R1 = Ph, R2 = H, R3 = Me (b); R1 = Me, R2 = H, R3 = Et (c); R1 = R2 = Me, R3 = Et (d);
VII, R3 = Et (a), Me (b).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 12 2011

REGIOSELECTIVITY OF THE HYDROLYSIS OF 2-(1-ALKOXYVINYL)-...
1835
into methylglyoxal (XII) and alkanol (cf. [19]). Taking
into account that methylglyoxal can exist as 10 differ-
ent molecular structures [20], it cannot be detected at
small concentrations.
presence of a Brønsted or Lewis acid. Activation of the
C–O bond is achieved via coordination of Lewis acid
at the oxygen atom. Presumably, this is the result of
anomeric effect arising from stereoelectronically more
favorable antiperiplanar orientation of the lone electron
pair on the nitrogen atom and electron-withdrawing
C–O bond [21].
We succeeded in raising the rate of hydrolysis of
2-(1-ethoxyvinyl)-3-phenyl-1,3-oxazolidine (IXa) and
its regioselectivity along pathway b using microwave
activation. At a power of 700 W, the conversion of
oxazolidine IXa attained 86% in 25 min, and the yield
of 2-acetyl derivative X was 75% (preparative yield of
crude product X 67%). When the reaction ampule was
immersed in a container charged with Al2O3 during
microwave irradiation, the reaction time shortened to
5 min, i.e., the reaction rate increased by a factor of
more than 3700 as compared to the reaction at room
temperature (13 days). Analysis of purified compound
X by GC–MS revealed two isomers with a molecular
weight of 191 at a ratio of 1:3.6, which were charac-
terized by different fragmentation patterns under elec-
tron impact. Presumably, 2-epimerization occurred
during GC–MS analysis.
H
MeO
H
H
N
H
H
H
H
O
H
XIII
However, our quantum-chemical calculations of
model oxazolidine molecule XIII did not confirm
predominance of its structure with antiperiplanar ar-
rangement of the nitrogen lone electron pair and polar
C–O bond. The calculations were performed in terms
of the density functional theory (B3PW91) with
6-311G(d,p) basis set using Gaussian 03W software
package [22]. Geometric parameters were optimized.
Four stable rotational isomers XIV–XVII were found
for isolated molecule XIII (Fig. 1). The total energy of
isomer XIV is –440.353842 a.u. The relative electronic
energies of the other isomers (relative to XIV) are
1.79, 2.86, and 1.13 kcal/mol. Therefore, compound
XIII may be presumed to exist mainly as conformer
XIV despite fast transitions between rotamers (10–9–
10–10 s). The five-membered heteroring in XIV has no
local symmetry plane, and the structure of that con-
former may be regarded as intermediate between twist
and envelope; the NH or CH2 group deviates most
strongly from the plane formed by the other atoms.
The calculated Mulliken charges on the ether oxygen
atom in the vinyloxy group and endocyclic oxygen and
nitrogen atoms are given in table.
We failed to find conditions for selective hydrolysis
of oxazolidines IXc and IXd at the alkoxyvinyl group
(pathway b). The presence of an alkyl group on the
nitrogen atom in IXc and IXd strongly reduces stabil-
ity of the oxazolidine ring. Heating of compounds IXc
and IXd in aqueous acetone, aqueous acetonitrile, or
water–CHCl3 at 40–60°C in the presence of TsOH or
TFA (10–50 mol %) over a period of 1 h resulted in the
formation of 2-ethoxyprop-2-enal (VIIa) (yield 10–
30%). Raising the concentration of trifluoroacetic acid
to 105 mol % considerably increases the efficiency of
hydrolytic cleavage of oxazolidine IXc to 2-ethoxy-
propenal (yield 60%).
It is believed that regioselectivity of oxazolidine
ring opening is determined by high stability of open-
chain iminium intermediate A formed by cleavage of
the C–O bond, as compared to alternative structure
generated by cleavage of the C–N bond (Scheme 4).
Nevertheless, opening of oxazolidine ring requires the
Adiabatic protonation of 2-(1-methoxyvinyl)oxa-
zolidine was simulated. Protonation of conformer XIV
at the ring oxygen atom was found to be considerably
more favorable. The energy of protonation was calcu-
lated as the difference between the energies of the
optimized cation structure and the most stable isomer.
Four possible protonation centers were considered: two
oxygen atoms, nitrogen atom, and β-carbon atom in
the vinyl group.
Scheme 4.
R2
R1
N
N
R1
LA
O
R2
O
Proton interaction with the nitrogen atom is more
favorable than with carbon, and the corresponding
stable structures XVIII and XIX are formed without
additional intramolecular rearrangements (Fig. 2).
Protonation of the ether oxygen atom is followed by
A
H+, H2O
H
R1CHO
N
+
HO
R2
LA stands for H+ or Lewis acid.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 12 2011

KEIKO et al.
1836
XIV, ΔE = 0 kcal/mol; μ = 1.77 D
XV, ΔE = 1.79 kcal/mol; μ = 1.1 D
XVI, ΔE = 2.86 kcal/mol; μ = 1.6 D
XVII, ΔE = 1.13 kcal/mol; μ = 1.2 D
Fig. 1. Structures and relative energies (ΔE) of stable conformers XIV–XVII of 2-(1-methoxyvinyl)-1,3-oxazolidine (XIII) accord-
ing to B3PW91/6-311G(d,p) calculations.
intramolecular proton transfer to the ring oxygen atom
and rupture of the O–C(N) bond with formation of
linear structure XX. In the two latter cases, the final
products are similar. The methoxyvinyl group remains
unchanged. Counterion was not taken into account in
our calculations. The energies of protonation at the N,
Oring, Oether, and C atoms are –234.9, –235.2, –230.0,
and –226.4 kcal/mol, respectively. Presumably, the hy-
drolysis in acid medium begins with protonation; if
protonation occurs at oxygen atoms, rearrangement
products are formed with liberation of relatively large
amount of energy.
XVIII
XIX
XX
Fig. 2. Protonated forms of compound XIII; energies of protonation, kcal/mol: XVIII, –234.9; XIX, –226.4; XX, –235.2.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 12 2011

REGIOSELECTIVITY OF THE HYDROLYSIS OF 2-(1-ALKOXYVINYL)-...
1837
Calculated Mulliken charges on the oxygen atom in the vinyloxy group and endocyclic oxygen and nitrogen atoms in the
molecule of compound XIII
Compound no. CH2=CHO
O1
N3
Relative electronic energy, kcal/mol
Total energy, a.u.
XIV
XV
–0.361
–0.350
–0.357
–0.337
–0.379
–0.373
–0.390
–0.383
–0.396
–0.373
–0.421
–0.375
0.00
1.79
2.86
1.13
–440.353842
–440.350989
–440.349289
–440.352044
XVI
XVII
We can conclude that 2-(1-alkoxyvinyl)-substituted
1,3-oxazolidines, 1,3-thiazolidones, and imidazolidines
are characterized by considerably different rates of
hydrolysis and its regioselectivity. Acid hydrolysis of
2-(1-ethoxyvinyl)-1,3-thiazolidine and 2-(1-alkoxy-
vinyl)-3,5-diphenylimidazolidines leads to the forma-
tion of the corresponding 2-acetyl derivatives with
complete regioselectivity. Hydrolysis of 2-(1-alkoxy-
vinyl)-1,3-oxazolidines can take alternative pathways.
2-(1-Alkoxyvinyl)-3-phenyl-1,3-oxazolidines under
definite conditions (microwave irradiation) give rise to
2-acetyl derivatives (yield 86%), whereas hydrolysis of
3-methyl- and 3,5-dimethyl-2-(1-alkoxyvinyl)-1,3-ox-
azolidines, as well as of 3-methyl-2-(1-alkoxyvinyl)-
imidazolidines, occurs mainly with opening of the
heteroring.
Reaction of 2-(1-ethoxyvinyl)-1,3-thiazolidine (I)
with p-toluenesulfonic acid. Compound I, 0.009 g
(0.0566 mmol), was dissolved in 0.76 g of DMSO-d6,
0.0097 g (0.0566 mmol) of p-toluenesulfonic acid was
added, and the mixture was left to stand for 1 h at
1
20°C. H NMR spectrum of 2-(1-ethoxyvinyl)-1,3-
thiazolidinium p-toluenesulfonate (II) (DMSO-d6), δ,
ppm: 1.25 t (3H, CH3CH2, J = 7.0 Hz), 2.29 s (3H,
CH3), 3.13 m and 3.21 m (1H each, 5-H), 3.45 m and
3.55 m (1H each, 4-H), 3.80 q (2H, OCH2, J = 7.0 Hz),
4.27 d and 4.46 d (1H each, CH2=, J = 2.6 Hz), 5.37 s
(1H, 2-H), 7.12 d (2H, m-H, J = 7.7 Hz), 7.50 d (2H,
o-H, J = 7.7 Hz). 13C NMR spectrum (DMSO-d6), δC,
ppm: 13.94 (CH3CH2), 15.21 (CH3), 29.85 (C5), 48.78
(C4), 63.40 (OCH2), 63.88 (C2), 87.45 (H2C=), 125.50
and 128.20 (Cm, Co), 138.10 (Cp), 145.00 (Ci), 154.63
(C=).
Thus regioselective acid hydrolysis of 2-(1-alkoxy-
vinyl)-substituted 1,3-oxazolidines, 1,3-thiazolidines,
and imidazolidines may be regarded as new methods
for the preparation of cyclic methylglyoxal aminals
and hemiaminals as potential source of methylglyoxal
in vivo.
1H NMR spectrum of thiazolidine I (DMSO-d6), δ,
ppm: 1.22 t (3H, CH3, 3J = 7.0 Hz), 2.76 m (2H, 5-H),
2.88 m and 3.21 m (1H each, 4-H), 3.73 q (2H, OCH2,
2
3J = 7.0 Hz), 3.94 d and 4.22 d (1H each, CH2=, J =
1.8 Hz), 4.90 s (1H, 2-H) [15].
Hydrolysis of thiazolidine I in D2O in the pres-
ence of trifluoroacetic acid. Trifluoroacetic acid,
0.057 g (0.525 mmol), was added to a solution of
0.08 g (0.5 mmol) of 2-(1-ethoxyvinyl)-1,3-thiazoli-
dine (I) in 0.5 g (0.025 mmol) of D2O, and the mixture
EXPERIMENTAL
The H and 13C NMR spectra were recorded on
1
a Bruker DPX-400 spectrometer at 400 and 100 MHz,
respectively, using hexamethyldisiloxane as internal
reference. The IR spectra were measured on a Specord
IR75 spectrometer. Gas chromatographic–mass spec-
trometric analysis was performed on a Hewlett–
Packard HP 5890 gas chromatograph (Ultra-2 column,
injector temperature 250°C, oven temperature pro-
gramming from 70 to 280°C at a rate of 20 deg/min)
coupled with an HP 5971A mass-selective detector
(electron impact, 70 eV). Microwave-assisted reactions
were carried out in an LG MS-1904H microwave
furnace (700 W); the temperature was monitored with
the aid of a TekhnoAs S-20.1 pyrometer (–18 to
500°C). The melting points were determined on
a Micro-Hot-Stage Poly Term A melting point appa-
ratus (Wagner & Munz).
1
was heated for 1 h at 45°C. According to the H NMR
data, the product was 1-(1,3-thiazolidin-2-yl)ethanone
1
(III), yield 100%. H NMR spectrum (D2O), δ, ppm:
2.08 s (3H, CH3), 2.74 m (1H, CH2N), 3.00 m (2H,
CH2S), 3.50 m (1H, CH2N), 5.41 s (1H, NCHS).
13C NMR spectrum (D2O), δC, ppm: 29.26 (CH3), 49.62
(SCH2), 57.23 (NCH2), 78.21 (SCHN), 200.64 (C=O).
Hydrolysis of thiazolidine I in H2O in the pres-
ence of p-toluenesulfonic acid. p-Toluenesulfonic
acid, 0.29 g (1.69 mmol), was added to a solution of
0.267 g (1.69 mmol) of 2-(1-ethoxyvinyl)-1,3-
thiazolidine (I) in 2.55 ml (0.14 mol) of distilled water.
The mixture (pH 5) was left to stand for 2 days at 20°C
and extracted with chloroform, and the extract was
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 12 2011

KEIKO et al.
1838
neutralized with a required amount of potassium
carbonate and dried over MgSO4. Yield 0.16 g (72%).
1H NMR spectrum of III (CDCl3), δ, ppm: 2.26 s (3H,
CH3), 2.71 m (1H, CH2N), 3.00 m (2H, CH2S, CH2N),
3.62 m (1H, CH2S), 5.03 s (1H, NCHS).
(1.2 mmol), was dissolved in 2 ml of chloroform,
0.042 g (20 mol %) of p-toluenesulfonic acid in 1 ml
of chloroform and 0.02 g (1.2 mmol) of water were
added, and the mixture was kept for 24 h at 20°C.
1
According to the H NMR data, the conversion was
80%. The mixture was extracted with diethyl ether, the
extract was dried over MgSO4, the solvent was dis-
tilled off under reduced pressure, and the residue was
recrystallized from ethanol to obtain 0.131 g (41%) of
1-(3,5-diphenylimidazolidin-2-yl)ethanone (VIa) with
2-Acetyl-1,3-thiazolidinium p-toluenesulfonate
(IV). p-Toluenesulfonic acid, 0.207 g (1.2 mmol), was
added to a solution of 0.19 g (1.2 mmol) of 2-(1-eth-
oxyvinyl)-1,3-thiazolidine (I) in 2 ml (111 mmol) of
distilled water. The mixture was kept for 6 days at
room temperature, dried over MgSO4, and evaporated
1
mp 93.1°C. The H and 13C NMR spectra of the prod-
1
under reduced pressure. Yield 0.25 g (69%). H NMR
uct completely coincided with those of a sample ob-
spectrum (CDCl3), δ, ppm: 2.17 s (3H, CH3CO), 2.26 s
(3H, CH3C6H4), 3.02 m and 3.20 m (1H each, 5-H),
3.72 m (2H, 4-H), 5.74 s (1H, 2-H), 7.13 d (2H, m-H,
J = 7.8 Hz), 7.69 d (2H, o-H, J = 7.8 Hz). 13C NMR
spectrum (CDCl3), δC, ppm: 21.56 (CH3C6H4), 25.72
(CH3C=O), 49.89 (C5), 66.53 (C4), 77.46 (C2), 126.25
(Cm), 129.06 (Co), 140.03 (Cp), 142.04 (Ci), 197.93
(C=O). Found, %: C 47.64; H 5.80; N 4.4; S 20.8.
C12H17NO4S2. Calculated, %: C 47.50; H 5.61; N 4.62;
S 21.12.
tained from compound Va.
Hydrolysis of 2-(1-methoxyvinyl)-3-methylimid-
azolidine (Vd). a. Compound Vd, 0.62 g (4.4 mmol),
was dissolved in 1 ml of chloroform, 0.53 g
(70 mol %) of p-toluenesulfonic acid in 0.08 g
(4.4 mmol) of water was added, and the mixture was
kept for 6 days at 20°C. According to the H NMR
data, the mixture contained mainly initial compound
Vd and a small amount of 2-methoxyprop-2-enal.
1
b. Compound Vd, 0.72 g (5 mmol), was added to
a solution of 0.17 g (20 mol %) of p-toluenesulfonic
acid in 0.45 g (2.25 mmol) of water, and the mixture
was subjected to microwave irradiation over a period
of 2 min at a power of 700 W. According to the
1H NMR data, initial compound Vd remained un-
changed.
Hydrolysis of 2-(1-ethoxyvinyl)-1,3-diphenyl-
imidazolidine (Va). Compound Va, 0.526 g
(1.8 mmol), was dissolved in 0.6 ml of chloroform,
0.065 g (20 mol %) of p-toluenesulfonic acid in 0.3 ml
of chloroform and 0.05 g (2.7 mmol) of water were
added, and the mixture was left to stand for 24 h at
1
22°C. According to the H NMR data, the conversion
was 100%. The mixture was extracted with diethyl
ether, the extract was dried over MgSO4, the solvent
was distilled off under reduced pressure, and the
residue was recrystallized from ethanol to isolate
0.181 g (38%) of 1-(3,5-diphenylimidazolidin-2-yl)-
2-(1-Methoxyvinyl)-3-methylimidazolidine (Vd)
was synthesized according to the procedure described
in [16] from 1.64 g (19 mmol) of 2-methoxyprop-2-
enal and 1.4 g (19 mmol) of N-methylethane-1,2-di-
amine. Yield 1.64 g (61%), bp 40–42°C (1 mm).
1H NMR spectrum (CDCl3), δ, ppm: 2.28 m (1H,
CH2), 2.31 s (3H, NMe), 2.99 m (1H, CH2), 3.21 m
(2H, CH2), 3.36 s (1H, CH), 3.60 s (3H, OMe), 4.14 d
and 4.23 d (1H each, =CH2, J = 2.0 Hz), 4.81 s (1H,
=CH2, J = 2.0 Hz). 13C NMR spectrum (CDCl3), δC,
ppm: 38.53 (CH3), 44.3 (CH2), 55.04 (CH2), 55.26
(CH3), 83.81 (NCHN), 85.43 (CH2=), 159.21 (C).
Found, %: C 59.15; H 9.86; N 19.72. C7H14N2O. Cal-
culated, %: C 59.12; H 9.42; N 19.79.
1
ethanone (VIa) with mp 93.1°C. H NMR spectrum
(CDCl3), δ, ppm: 1.87 s (3H, CH3), 3.78 m (2H, CH2),
3.99 m (2H, CH2), 5.10 s (1H, CH), 6.71 d (4H, o-H,
J = 7.8 Hz), 6.8 t (2H, p-H, J = 7.4 Hz), 7.24 d.d (2H,
m-H, J = 7.4, 7.8 Hz). 13C NMR spectrum (CDCl3), δC,
ppm: 23.72 (CH3), 46.57 (CH2), 79.90 (CH), 113.02
(Cm), 118.98 (Cp), 129.65 (Co), 144.94 (Ci), 156.61
(C=O). 15N NMR spectrum (CDCl3): δN –307.2 ppm.
The 15N–1H 2D HMBC spectrum contained cross
peaks due to coupling of nitrogen atoms with both CH2
groups and 2-H proton. The NOESY spectrum of Va
displayed cross peaks between ortho-protons in the
benzene rings, on the one hand, and 2-H and 4(5)-H,
on the other. Found, %: C 76.66; H 6.67; N 10.70.
C17H18N2O. Calculated, %: C 76.69; H 6.77; N 10.52.
Hydrolysis of 2-(1-ethoxyvinyl)-1-methylimidaz-
olidine (Vc) in the presence of 20 mol % of p-tol-
uenesulfonic acid. Compound Vc, 0.28 g (1.8 mmol),
was dissolved in 1 ml of chloroform, 0.04 g
(2.2 mmol) of water and 0.06 g (20 mol %) of p-tol-
uenesulfonic acid in 0.5 ml of chloroform were added,
and the mixture was left to stand at 20°C. After 6 days,
Hydrolysis of 2-(1-methoxyvinyl)-1,3-diphenyl-
1,3-imidazolidine (Vb). Compound Vb, 0.34 g
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REGIOSELECTIVITY OF THE HYDROLYSIS OF 2-(1-ALKOXYVINYL)-...
1839
the mixture contained only the initial compound
(1H NMR data).
(8) [M – CH3], 162 (2), 147 (9) [M – CH3CO – H], 132
(20), 119 (100) [M – CH3CO – CH2=CH2 – H], 104
(58) [PhNCH], 91 (47) [PhN], 77 (50) [Ph], 65 (5), 51
(18), 42 (6). Found, %: C 69.50; H 6.96; N 6.95.
C11H13N1O2. Calculated, %: C 69.11; H 6.80; N 7.33.
Hydrolysis of imidazolidine (Vc) in the presence
of excess acid. a. Compound Vc, 0.142 g (0.91 mmol),
was dissolved in 1 ml (0.056 mmol) of water, 0.109 g
(105 mol %) of trifluoroacetic acid in 0.6 ml of aceto-
nitrile was added, and the solution was left to stand for
18 h at 20°C. After neutralization with potassium
carbonate, drying over MgSO4, and evaporation, the
conversion of Vc was 45% (1H NMR). The mixture
also contained 2-ethoxyprop-2-enal (yield 35%).
b. Analogous experiment with the same amounts of
the reactants was carried out under microwave irradia-
tion (700 W), but the reaction ampule was sealed and
immersed in a Teflon container charged with Al2O3.
After irradiation (5×1 min; temperature in the reaction
zone 59–73°C), the yield of oxazolidine X was 75%
(1H NMR). The product also contained unreacted
initial compound IXa and 2-ethoxyprop-2-enal in
equal amounts as impurities.
b. Analogous results were obtained when the hy-
drolysis of Vc was carried out in the presence of
105 mol % of p-toluenesulfonic acid at 45°C (reaction
time 3 h).
Hydrolysis of 2-(1-methoxyvinyl)-3-phenyl-1,3-
oxazolidine (IXb). A solution of 0.15 g (20 mol %) of
p-toluenesulfonic acid in 1 ml of chloroform and
0.09 g (4.6 mmol) of water were added to 0.95 g
(4.6 mmol) of compound IXb in 1 ml of chloroform,
and the mixture was subjected to microwave irradia-
Hydrolysis of 2-(1-ethoxyvinyl)-3-phenyl-1,3-ox-
azolidine (IXa). a. Compound IXa, 0.474 g
(2.2 mmol), was dissolved in 0.5 ml of chloroform,
0.075 g (20 mol %) of p-toluenesulfonic acid in 0.5 ml
of chloroform and 0.042 g (2.2 mmol) of water were
added, and the mixture was subjected to microwave
1
tion (25×1 min, 700 W). According to the H NMR
data, the yield of X was 40%. The solvent was distilled
1
irradiation (25×1 min, 700 W; H NMR monitoring).
1
off under reduced pressure. The H NMR spectrum of
After 25 min, the conversion of IXa was 86%, and the
yield of 1-(3-phenyl-1,3-oxazolidin-2-yl)ethanone (X)
was 75%. The mixture was extracted with diethyl
ether, and the extract was dried over MgSO4 and evap-
orated under reduced pressure. Yield of crude product
X 0.28 g (67%). It contained initial oxazolidine IXa
and 2-ethoxyprop-2-enal (~10%) as impurities. Pure
oxazolidine X was isolated by column chromatography
on silica gel 60 (70–200 mesh, Merck) using hexane–
diethyl ether (1:5) as eluent. The presence of a large
amount of 2-phenylaminoethanol in fractions eluted
after oxazolidine X indicated that hydrolysis of the
heteroring occurred during chromatographic isolation
on silica gel. IR spectrum, ν, cm–1 (first isomer): 2870
br, 1705 (C=O), 1580, 1480, 1340, 1300, 1210, 1160,
890. 1H NMR spectrum of Xa (CDCl3), δ, ppm: 2.13 s
(3H, CH3), 3.51 m and 3.71 m (1H each, CH2N),
4.21 m and 4.30 m (1H each, CH2O), 4.97 s (1H,
NCHO), 6.60 d (2H, o-H, J = 7.9 Hz), 6.80 t (1H, p-H,
J = 7.2 Hz), 7.21 d.d (2H, m-H, J = 7.9, 7.2 Hz).
13C NMR spectrum (CDCl3), δC, ppm: 23.89 (CH3),
47.44 (NCH2), 67.16 (OCH2), 91.94 (CH), 113.26
(Cm), 118.94 (Cp), 129.46 (Co), 144.95 (Ci), 206.15
(C=O). Mass spectrum, m/z (Irel, %): first isomer: 191
(2) [M]+·, 176 (1), 160 (2), 148 (100) [M – CH3CO],
120 (32) [M – CH3CO – CH2=CH2], 103 (7) [PhNC],
91 (8) [PhN], 77 (20) [Ph], 65 (8), 43 (4) [MeC=O], 28
(1) [C=O], 15 (1); second isomer: 191 (35) [M]+·, 176
the product coincided with the spectrum of X given
above.
Hydrolysis of 2-(1-ethoxyvinyl)-3-methyl-1,3-ox-
azolidine (IXc). Compound IXc, 0.291 g (1.85 mmol),
was dissolved in 0.951 g of acetonitrile, a solution of
0.22 g (105 mol %) of trifluoroacetic acid in 0.255 g
(0.03 mol) of water was added, the mixture was heated
for 1 h at 40°C and extracted with chloroform, and the
extract was dried by passing it through a layer of
1
K2CO3 and evaporated. According to the H NMR
data, the yield of 2-ethoxyprop-2-enal was 60%.
Hydrolysis of 2-(1-ethoxyvinyl)-3,5-dimethyl-1,3-
oxazolidine (IXd). a. Compound IXd, 0.200 g
(1.17 mmol) was dissolved in 1 ml of chloroform,
0.060 g (30 mol %) of p-toluenesulfonic acid and
0.02 g (1.7 mmol) of water were added, and the mix-
ture was kept for 13 days at 20°C. The mixture
1
contained 2-ethoxyprop-2-enal (yield 17%). H NMR
spectrum (CDCl3), δ, ppm: 1.40 t (3H, CH3), 3.90 q
(2H, OCH2), 5.05 d and 5.18 d (1H each, CH2=), 9.26 s
(1H, CHO).
b. Oxazolidine IXd, 0.138 g (0.81 mmol), was
dissolved in 1 ml of acetone, a solution of 0.095 g
(105 mol %) of trifluoroacetic acid in 0.47 ml
(26 mmol) of water was added, and the mixture was
heated for 1 h at 45°C. After appropriate treatment
(extraction, neutralization, and drying), the mixture
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 12 2011

KEIKO et al.
1840
p. 2099; McClelland, R.A. and Somani, R., J. Org.
Chem., 1981, vol. 46, p. 4346.
contained initial oxazolidine IXd and 2-ethoxyprop-2-
enal (yield 33%; 1H NMR data).
14. Keiko, N.A., Funtikova, E.A., Stepanova, L.G., Chuva-
shev, Yu.A., and Larina, L.I., Russ. J. Org. Chem., 2003,
vol. 39, p. 1477.
15. Keiko, N.A., Funtikova, E.A., Stepanova, L.G., and
Larina, L.I., Russ. J. Org. Chem., 2005, vol. 41, p. 517;
Keiko, N.A., Funtikova, E.A., Stepanova, L.G., Chuva-
shev, Yu.A., Larina, L.I., and Voronkov, M.G., J. Sulfur
Chem., 2004, vol. 25, p. 351.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 08-03-00396).
REFERENCES
1. Wagner, B., Gonzalez, G.I., Tran Hun Dau, M.E., and
Zhu, J., Bioorg. Med. Chem., 1999, vol. 7, p. 737.
16. Keiko, N.A., Vchislo, N.V., Stepanova, L.G., Lari-
na, L.I., Chuvashev, Yu.A., and Funtikova, E.A., Khim.
Geterotsikl. Soedin., 2008, vol. 12, p. 1809.
2. Agami, C., Couty, F., Lam, H., and Mathieu, H., Tetra-
hedron, 1998, vol. 54, p. 8783; O’Brien, P. and
Warren, S., Tetrahedron Lett., 1996, vol. 37, p. 3051.
3. Gros, C., Boulègue, C., Galéotti, N., Niel, G., and
Jouin, P., Tetrahedron, 2002, vol. 58, p. 2673; Will-
more, B.H., Cassidy, P.B., Walters, R.L., and
Roberts, J.C., J. Med. Chem., 2001, vol. 44, p. 2661.
17. Kalapos, M.P., Toxicol. Lett., 1999, vol. 110, p. 145.
18. Hayashi, T. and Shibamoto, T., J. Agric. Food Chem.,
1985, vol. 33, p. 1090; Hofmann, T. and Schieberle, P.,
J. Agric. Food Chem., 1995, vol. 43, p. 2946.
19. Mamashvili, T.N., Keiko, N.A., Sarapulova, G.I., and
Voronkov, M.G., Izv. Ross. Akad. Nauk, Ser. Khim.,
1998, p. 2547.
20. Nemet, I., Vikić-Topić, D., and Varga-Defterdarović, L.,
Bioorg. Chem., 2004, vol. 32, p. 560.
4. Fernandez, X., Fellous, R., and Duňach, E., Tetrahedron
Lett., 2000, vol. 41, p. 3381.
5. Fife, T.H., Hutchins, J.E.C., and Pellino, A.M., J. Am.
Chem. Soc., 1978, vol. 100, p. 6455.
6. O’Brien, P. and Warren, S., Tetrahedron Lett., 1995,
21. Sélambarom, J., Mouge, S., Carré, F., Roque, J.P., and
vol. 36, p. 2681.
7. Agami, C., Couty, F., and Mathieu, H., Tetrahedron
Lett., 1998, vol. 39, p. 3505.
Pavia, A.A., Tetrahedron, 2002, vol. 58, p. 9559.
22. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuse-
ria, G.E., Robb, M.A., Cheeseman, J.R., Montgo-
mery, Jr., J.A., Vreven, T., Kudin, K.N., Burant, J.C.,
Millam, J.M., Iyengar, S.S., Tomasi, J., Barone, V.,
Mennucci, B., Cossi, M., Scalmani, G., Rega, N.,
Petersson, G.A., Nakatsuji, H., Hada, M., Ehara, M.,
Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M.,
Nakajima, T., Honda, Y., Kitao, O., Nakai, H.,
Klene, M., Li, X., Knox, J.E., Hratchian, H.P.,
Cross, J.B., Bakken, V., Adamo, C., Jaramillo, J., Gom-
perts, R., Stratmann, R.E., Yazyev, O., Austin, A.J.,
Cammi, R., Pomelli, C., Ochterski, J.W., Ayala, P.Y.,
Morokuma, K., Voth, G.A., Salvador, P., Dannen-
berg, J.J., Zakrzewski, V.G., Dapprich, S., Dani-
els, A.D., Strain, M.C., Farkas, O., Malick, D.K.,
Rabuck, A.D., Raghavachari, K., Foresman, J.B.,
Ortiz, J.V., Cui, Q., Baboul, A.G., Clifford, S., Cioslow-
ski, J., Stefanov, B.B., Liu, G., Liashenko, A., Pis-
korz, P., Komaromi, I., Martin, R.L., Fox, D.J.,
Keith, T., Al-Laham, M.A., Peng, C.Y., Nanayak-
kara, A., Challacombe, M., Gill, P.M.W., Johnson, B.,
Chen, W., Wong, M.W., Gonzalez, C., and Pople, J.A.,
Gaussian 03, Revision B.03, Wallingford CT: Gaussian,
2004.
8. Zimenkovskii, B.S., Kutsyk, R.V., Lesyk, R.B., Matii-
chuk, V.S., Obushak, N.D., and Klyufinskaya, T.I.,
Khim.-Farm. Zh., 2006, vol. 40, no. 6, p. 13.
9. Ino, A. and Murabayashi, A., Tetrahedron, 1999,
vol. 55, p. 10271; Ino, A., Hasegawa, Y., and Mura-
bayashi, A., Tetrahedron, 1999, vol. 55, p. 10283;
Ino, A. and Murabayashi, A., Tetrahedron, 2001,
vol. 57, p. 1897; Zamri, A. and Abdallah, M.A., Tetra-
hedron, 2000, vol. 56, p. 249.
10. Roberts, J.C., Nagasawa, H.T., Zera, R.T., Fricke, R.F.,
and Goon, D.J.W., J. Med. Chem., 1987, vol. 30,
p. 1891; Nagasawa, H.T., Goon, D.J.W., Zera, R.T., and
Yuzon, D.L., J. Med. Chem., 1982, vol. 25, p. 489;
Nagasawa, H.T., Goon, D.J.W., Muldon, W.P., and
Zera, R.T., J. Med. Chem., 1984, vol. 27, p. 591.
11. Chiarino, D., Ferrario, F., Pellacini, F., and Sala, A.,
J. Heterocycl. Chem., 1989, vol. 26, p. 589.
12. Fife, T.H., Nagarajan, R., Shen, C.C., and Bembi, R.,
J. Am. Chem. Soc., 1991, vol. 113, p. 3071.
13. Walker, R.B., Huang, M.-J., and Leszczynski, J., J. Mol.
Struct. (Theochem), 2001, vol. 549, p. 137; Fife, T.H.
and Hutchins, J.E.C., J. Org. Chem., 1980, vol. 45,
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