Efficient synthesis of 5-(2-hydroxyethyl)-2-phenylimino-1,3-thiazolidin-4- ones and 5-(2-hydroxyethyl)-2-phenylamino-4,5-dihydro-1,3-thiazol-4-ones

Article abstract of DOI:10.1002/jhet.118

(Chemical Equation Presented) A new method for the synthesis of substituted 5-(2-hydroxyethyl)-2-phenylimino-1,3-thiazolidin-4-ones and 5-(2-hydroxyethyl)-2-phenylamino-4,5-dihydro-1,3-thiazol-4-ones is described, starting from phenylthioureas and 3-bromo

Full text of DOI:10.1002/jhet.118

July 2009
Efficient Synthesis of 5-(2-Hydroxyethyl)-2-phenylimino-
1,3-thiazolidin-4-ones and 5-(2-Hydroxyethyl)-2-phenylamino-
4,5-dihydro-1,3-thiazol-4-ones
635
a
Jirı Vana, Jirı Hanusek, * Ales Ruzicka, and Milos Sedlak
a
b
a
ˇ´ ´ˇ
ˇ´
ˇ
˚ˇ ˇ
ˇ
´
aInstitute of Organic Chemistry and Technology, Faculty of Chemical Technology,
University of Pardubice, Pardubice, The Czech Republic
bDepartment of General and Inorganic Chemistry, Faculty of Chemical Technology,
University of Pardubice, Pardubice, The Czech Republic
*E-mail: Jiri.Hanusek@upce.cz
Received January 9, 2009
DOI 10.1002/jhet.118
Published online 7 July 2009 in Wiley InterScience (www.interscience.wiley.com).
ˇ
´
´
Dedicated to Professor Vladimır Machacek on the occasion of his 65th birthday.
A new method for the synthesis of substituted 5-(2-hydroxyethyl)-2-phenylimino-1,3-thiazolidin-4-
ones and 5-(2-hydroxyethyl)-2-phenylamino-4,5-dihydro-1,3-thiazol-4-ones is described, starting from
phenylthioureas and 3-bromotetrahydrofuran-2-one. The reaction proceeds under mild conditions, is
very simple to perform, and is applicable to a relatively wide range of substituents in benzene nucleus.
Some 1,3-thiazolidin-4-ones show dynamic NMR behavior in solution because of prototropy tautomer-
ism and E-/Z-stereoisomerism.
J. Heterocyclic Chem., 46, 635 (2009).
INTRODUCTION
can be obtained only with great difficulties—or not at
all—by other procedures.
Natural [1] as well as synthetic heterocyclic com-
pounds, containing a thiazole ring system often exhibit
good antifungal [2], antibacterial [3], and anti-inflamma-
tory [4] activity and are widely used in new pharmaceu-
tical and agrochemical compounds. Also thiazolidine
cycle belongs among pharmaceutically significant het-
erocycles representing an important group of per oral
antidiabetics [5]. Thiazole skeleton is also present in
many dyes and pigments [6].
RESULTS AND DISCUSSION
Recently, we have found [8] that substituted S-(1-phen-
ylpyrrolidin-2-on-3-yl) isothiuronium salts in weakly basic
medium undergo an intramolecular transformation reaction.
In this particular case, the c-lactam ring is cleaved and
a thiazolidine ring is formed, i.e. substituted 2-imino-5-
[2-(phenylamino)ethyl]-1,3-thiazolidin-4-ones are obtained
in very good yields. In this work, we extended the scope
of this transformation replacing c-lactam cycle by c-lacton
cycle. In the first step, we have prepared corresponding
S-(2-oxotetrahydrofuran-3-yl)-N-(subst. phenyl) isothiuronium
There exist a lot of synthetic methods leading to thia-
zole or thiazolidine skeleton [7] from which those
involving rearrangements of another heterocyclic rings
represent new interesting alternative. Such rearrange-
ments may provide fascinating routes to derivatives that
C
V
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J. Vana, J. Hanusek, A. Ruzicka, and M. Sedlak
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Vol 46
Scheme 1
bromides (2a–n) from substituted phenylthioureas (1a–n)
and 3-bromotetrahydrofuran-2-one (a-bromo-c-butyro-
lactone), which then underwent rearrangement in basic
medium to give desired 5-(2-hydroxyethyl)-2-phenyli-
mino-1,3-thiazolidin-4-ones (3a–g, 3l–n) or 5-(2-hydrox-
yethyl)-2-phenylamino-4,5-dihydro-1,3-thiazol-4-ones (3h–k)
(Scheme 1). In most cases, it was impossible to character-
ize pure isothiuronium salts by NMR because of their
spontaneous cyclization giving 3a–n in DMSO-d6 solution.
The only exception was S-(2-oxotetrahydrofuran-3-
yl)-N-(4-methoxyphenyl)isothiuronium bromide (2b)
which was prepared in a pure form and characterized by
1H, 13C NMR, and microanalysis. The reason for
enhanced reactivity of the other derivatives lies in the
presence of electron-withdrawing group in the benzene
nucleus or methyl group on nitrogen(s). All of these
substituents facilitate rearrangement involving bicyclic
tetrahedral intermediate.
spirocyclic 2-aza-3-amino or substituted amino-4-thia-7-
oxa-8-methyl-8-substituted spiro[4.4]-2-nonene-1,6-di-
ones was recently published. In this case, nitrogen atom
of isothiuronium salt attacks ethoxycarbonyl group in
position 3 instead of lactone carbonyl group.
Prepared
5-(2-hydroxyethyl)-2-phenylimino-1,3-thi-
azolidin-4-ones (3a–g, 3l–n) 5-(2-hydroxyethyl)-2-phen-
ylamino-4,5-dihydro-1,3-thiazol-4-ones (3h–k) were
1
characterized by H, 13C NMR, and microanalyses and
some of them also by X-ray diffraction (Figs. 1, 2) and
mass spectroscopy.
Compounds 3a–f carrying hydrogen atoms on both
nitrogen atoms (R2 ¼ R3 ¼ H) exist in the form of two
tautomers differing in the position of C¼¼N double
bond. Moreover, the tautomer with exocyclic double
bond exists as a mixture of E- and Z-stereoisomers in
the proportion depending on substitution of the benzene
nucleus and temperature. This tautomerism and stereo-
1
Similar method [9] starting from substituted phenyl-
thioureas and ethyl 3-bromo-5-methyl-2-oxo-tetrahydro-
furan-3-carboxylate, ethyl 3-bromo-5,5-dimethyl-2-oxo-
tetrahydrofuran-3-carboxylate, and ethyl 3-bromo-5-iso-
butoxymethyl-2-oxotetrahydrofuran-3-carboxylate giving
isomerism, which can be seen in both H and 13C NMR
spectra was previously studied for C-5 unsubstituted 2-
phenyliminothiazolidin-4-ones by several authors [10].
Figure 1. ORTEP view of compound 3g (thermal ellipsoids at 40%
probability).
Figure 2. ORTEP view of compound 3i (thermal ellipsoids at 40%
probability).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
Efficient Synthesis of 5-(2-Hydroxyethyl)-2-phenylimino-1,3-thiazolidin-4-ones and
5-(2-Hydroxyethyl)-2-phenylamino-4,5-dihydro-1,3-thiazol-4-ones
637
reflections), Rw ¼ 0.1329 (all reflections), S ¼ 1.112. CCDC
704421.
Compound 3i. C13H16N2O2S; monoclinic, space group P-
˚
21/c, a ¼ 9.3440(7), b ¼ 18.8800(1), c ¼ 7.5690(5) (A), a ¼
90.000(5)ꢁ, b ¼ 105.913(6)ꢁ, c ¼ 90.000(5)ꢁ, Z ¼ 4, V ¼
3
1284.11(15) A , Dc ¼ 1.367 gꢀcmꢂ3. Intensity data collected
˚
Figure 3. Intramolecular hydrogen bond in solution of 3g in DMSO-d6.
with 3.0 ꢃ y ꢃ 27.5ꢁ; 2849 independent reflections measured;
2406 observed [I > 2r(I)]. Final R index ¼ 0.0608 (observed
reflections), Rw ¼ 0.1481 (all reflections), S ¼ 1.062. CCDC
704422.
In the case of compounds 3h–k (R2 ¼ CH3, C2H5,
C6H5; R3 ¼ H) and 3l–n (R2 ¼ H; R3 ¼ CH3, C2H5),
prototropic tautomerism is absent due to C¼¼N double
bond fixation and stereoisomerism is possible only for
Isothiuronium salts 2; General Procedure. To a hot solu-
tion of N-arylthiourea 1a–n (5 mmol) in dry acetone 5 mmol
(0.83 g) of 3-bromotetrahydrofuran-2-one was injected. Reac-
tion mixture was refluxed for 5 min and left to stand at room
temperature for 2 days. Then precipitated crystals were col-
lected by filtration and submitted to cyclization. In the case of
compounds 2d–g, 2j, 2l, and 2n, no crystals precipitated so
that the solution was evaporated and resulting oil was submit-
ted to cyclization without any further purification (yields are
given only for 3d–g, 3j, 3l, and 3n). Crystalline isothiuronium
salts 1a–c, 1h, 1i, 1k, and 1m were characterized by melting
point and by microanalysis. Only in the case of salt 1b, it was
1
3l–n. In both H and 13C NMR spectra of 3g, there is
only one set of signals. From this observation, it can be
deduced that compound 3g exists only as E-stereoisomer
stabilized in solution by intramolecular hydrogen bond
(Fig. 3). On the other hand, in crystal lattice two mole-
cules of 3g are connected by intermolecular hydrogen
bonds (NringAHꢀꢀꢀNimino), which constrains Z-configura-
tion of C¼¼N double bond (Fig. 1).
1
possible to measure H and 13C NMR spectra immediately af-
ter its dissolution in DMSO-d6. For all the other salts quick
transformation to 3a–n was observed during the measurement.
S-(2-Oxotetrahydrofuran-3-yl)-N-phenyl isothiuronium bro-
mide (2a). Yield: 1.24g (78%); m.p. 153–155ꢁC. Anal. Calcd.
for C11H13BrN2O2S: C, 41.65; H, 4.13; N, 8.83; S, 10.11; Br,
25.19. Found: C, 41.74; H, 4.13; N, 9.01; S, 10.16; Br, 25.05.
EXPERIMENTAL
Starting arylthioureas 1a–n were prepared and purified by
known methods [11]. All other chemicals were purchased from
commercial suppliers and used as received. Before use, sol-
S-(2-Oxotetrahydrofuran-3-yl)-N-(4-methoxyphenyl)
thiuronium bromide (2b). Yield: 0.77g (44%); m.p. 154–
iso-
1
156ꢁC; H NMR (500 MHz): d ¼ 2.29 (m, 2H, CH2), 3.65 (m,
1
vents were dried and distilled. H and 13C NMR spectra were
2H, OCH2), 3.82 (s, 3H, OCH3), 4.72 (dd, J ¼ 7.5 and 4.5 Hz,
1H, SCH), 7.16 (AA0XX0, J ¼ 9 Hz, 2H, ArH), 7.37 (AA0XX0,
J ¼ 9 Hz, 2H, ArH), 10.79 (vbs, 3H, NH and NH2).
13C NMR (125 MHz): d ¼ 33.6 (CH2), 47.5 (SACH), 55.7
(OCH3), 57.8 (OACH2), 115.3 (Ar C-3), 123.6 (Ar C-1), 129.6
(Ar C-2), 160.7 (Ar C-4), 174.1 (C¼¼N), 175.0 (C¼¼O). Anal.
Calcd. for C12H15BrN2O3S: C, 41.51; H, 4.35; N, 8.07; S,
9.23; Br, 23.01. Found: C, 41.56; H, 4.29; N, 8.07; S, 9.08;
Br, 22.99.
recorded on a Bruker Avance 500 MHz instrument in DMSO-
d6 solution. Chemical shifts d are referenced to solvent resid-
ual peak d(DMSO-d6) ¼ 2.50 (1H) and 39.6 ppm (13C). Cou-
pling constants J are quoted in Hz. 13C NMR spectra were
measured in a standard way and by means of the APT
(attached proton test) pulse sequence to distinguish CH, CH3,
and CH2, Cquart. Proton–proton connectivities were found by
gs-COSY. Protonated carbon atoms were assigned by gs-
HSQC spectra. All NMR experiments were performed with the
aid of the manufacturer’s software. The microanalyses were
performed on an apparatus of Fisons Instruments, EA 1108
CHN. The mass spectra (EI) were recorded on an Agilent
Technologies Co. gas chromatograph 6890N with a mass de-
tector 5973 Network for samples dissolved in either ether or
acetone.
S-(2-Oxotetrahydrofuran-3-yl)-N-(4-methylphenyl) isothi-
uronium bromide (2c). Yield: 0.83g (50%); m.p. 160–164ꢁC.
Anal. Calcd. for C12H15BrN2O2S: C, 43.51; H, 4.56; N, 8.46;
S, 9.68; Br, 24.12. Found: C, 43.71; H, 4.60; N, 8.26; S, 9.45;
Br, 24.32.
S-(2-Oxotetrahydrofuran-3-yl)-N-phenyl-N-methyl isothi-
uronium bromide (2h). Yield: 1.3g (78%); m.p. 155–159ꢁC.
Anal. Calcd. for C12H15BrN2O2S: C, 43.51; H, 4.56; N, 8.46;
S, 9.68; Br, 24.12. Found: C, 43.51; H, 4.86; N, 8.35; S, 9.90;
Br, 24.03.
X-ray Crystallography of 3g and 3i. The colorless single
crystals of 3g and 3i were grown from DMSO solution. The
X-ray diffraction data were collected at 150(2)K on a Nonius
KappaCCD diffractometer with graphite-monochromated Mo
˚
Ka radiation (k ¼ 0.71073 A). The structures were solved by
S-(2-Oxotetrahydrofuran-3-yl)-N-phenyl-N-ethyl isothiuro-
nium bromide (2i). Yield: 1.59g (92%); m.p. 155–157ꢁC.
Anal. Calcd. for C13H17BrN2O2S: C, 45.23; H, 4.96; N, 8.11;
S, 9.29; Br, 23.14. Found: C, 45.14; H, 5.11; N, 8.08; S, 9.03;
Br, 23.20.
S-(2-Oxotetrahydrofuran-3-yl)-N-(4-methoxyphenyl)-N-methyl
isothiuronium bromide (2k). Yield: 0.96g (53%); m.p. 164–
167ꢁC. Anal. Calcd. for C13H17BrN2O3S: C, 43.22; H, 4.74;
N, 7.75; S, 8.87; Br, 22.12. Found: C, 43.06; H, 4.80; N, 7.66;
S, 8.68; Br, 22.03.
direct methods (SIR92) [12]. All reflections were used in the
structure refinement based on F2 by full-matrix least-squares
technique (SHELXL97) [13].
Compound 3g. C10H11N3O2S; triclinic, space group P-1, a
˚
¼ 5.7500(3), b ¼ 8.7980(3), c ¼ 10.9290(6) (A), a ¼
90.703(4)ꢁ, b ¼ 95.787(4)ꢁ, c ¼ 107.550(4)ꢁ, Z ¼ 2, V ¼
523.93(4) A , Dc ¼ 1.504 gꢀcmꢂ3. Intensity data collected
3
˚
with 3.0 ꢃ y ꢃ 27.5ꢁ; 2404 independent reflections measured;
2000 observed [I > 2r(I)]. Final R index ¼ 0.0589 (observed
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DOI 10.1002/jhet

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S-(2-Oxotetrahydrofuran-3-yl)-N-phenyl-N0-ethyl isothiuro-
(SACH), 58.7 and 59.6 (OACH2), 122.0 and 123.3 (Ar C-2,6),
128.6 (Ar C-4), 129.1 and 129.3 (Ar C-3,5), 137.1 and 146.7
(Ar C-1), 177.4 and 177.7 (C¼¼N), 190.5 (C¼¼O). Anal. Calcd.
for C11H11ClN2O2S: C, 48.80; H, 4.10; N, 10.35; S, 11.84; Cl,
13.10. Found: C, 49.01; H, 4.27; N, 10.08; S, 11.60; Cl, 12.94.
5-(2-Hydroxyethyl)-2-[(4-bromophenyl)imino]-1,3-thiazoli-
din-4-one (3e). Overall yield: 1.21g; (61%) m.p. 140–141ꢁC;
1H NMR (500 MHz): d ¼ 1.81 and 2.26 (2 ꢄ m, 2H, CH2),
3.50 (m, 2H, OCH2), 4.31 (m, 1H, SACH), 4.77 (bs, 1H, OH),
6.91 and 7.51 (2 ꢄ AA0XX0, 2H, Ar H-2,6), 7.56 and 7.67 (2
ꢄ AA0XX0, 2H, Ar H-3,5), 11.37 and 11.70 (2 ꢄ bs, 1H, NH);
13C NMR (125 MHz): d ¼ 35.8 and 36.5 (CH2), 47.5 and 52.1
(SACH), 58.7 and 59.6 (OACH2), 116.7 (Ar C-4), 122.4 and
123.7 (Ar C-2,6), 132.0 and 132.3 (Ar C-3,5), 138.3 and 147.1
(Ar C-1), 176.6 (C¼¼N), 190.6 (C¼¼O). Anal. Calcd. for
C11H11BrN2O2S: C, 41.92; H, 3.52; N, 8.89; S, 10.17; Br,
25.35. Found: C, 41.93; H, 3.71; N, 8.78; S, 10.40; Br, 24.98.
5-(2-Hydroxyethyl)-2-[(3-trifluoromethylphenyl)-imino]-
1,3-thiazolidin-4-one (3f). Overall yield: 1.02g (53%); m.p.
nium bromide (2m). Yield: 1.3g (75%); m.p. 144–146ꢁC.
Anal. Calcd. for C13H17BrN2O2S: C, 45.23; H, 4.96; N, 8.11;
S, 9.29; Br, 23.14. Found: C, 45.43; H, 5.08; N, 7.96; S, 9.10;
Br, 23.14.
5-(2-Hydroxyethyl)-2-phenyliminothiazolidin-4-ones (3a-
n); General Procedure. Isothiuronium salts (2 mmol) were
dissolved in a minimum amount of aqueous ammonia (25%)
and solution was stirred until precipitation of products. Crude
products (yields 80–90%) were filtered off and recrystallized
from water. Isothiuronium salts 2k–m were quite insoluble in
aqueous ammonia and stirring of suspension gave an oil which
was extracted by dichloromethane. Extract was dried and
evaporated to give oil solid which was characterized.
5-(2-Hydroxyethyl)-2-(phenylimino)-1,3-thiazolidin-4-one
(3a). Yield: 0.44g (94%); m.p. 123–124ꢁC; 1H NMR (500
MHz): d ¼ 1.79 and 2.26 (2 ꢄ m, 2H, CH2), 3.45 (m, 2H,
OCH2), 4.29 (m, 1H, SACH), 4.74 (m, 1H, OH), 7.00 and
7.72 (2 ꢄ m, 2H, Ar H-2,6), 7.12 (m, 1H, Ar H-4), 7.36 (m,
2H, Ar H-3,5), 11.14, and 11.71 (2 ꢄ bs, 1H, NH); 13C NMR
(125 MHz): d ¼ 36.0 and 36.6 (CH2), 47.7 and 52.1 (SACH),
58.8 and 59.6 (OACH2), 120.5 and 121.6 (Ar C-2,6), 124.7
and 124.8 (Ar C-4), 129.1 and 129.4 (Ar C-3,5), 138.9 and
146.8 (Ar C-1), 177.5 and 178.5 (C¼¼N), 190.6 (C¼¼O). Anal.
Calcd. for C11H12N2O2S: C, 55.91; H, 5.12; N, 11.86; S,
13.57. Found: C, 56.13; H, 5.32; N, 11.62; S, 13.35. EI-MS:
m/z 236 [Mþ], 218 [MþAH2O], 205, 192, 160, 151, 145, 135,
118 (100 %), 109, 101, 91, 77, 71, 65, 59, 51.
5-(2-Hydroxyethyl)-2-[(4-methoxyphenyl)imino]-1,3-thiazo-
lidin-4-one (3b). Yield: 0.48g (91%); m.p. 124–126ꢁC; 1H
NMR (500 MHz): d ¼ 1.76 and 2.27 (2 ꢄ m, 2H, CH2), 3.52
(m, 2H, OCH2), 3.74 (s, 3H, OCH3), 4.26 (dt, J ¼ 11.8 and 3.5
Hz, 1H, SACH), 4.73 (m, 1H, OH), 6.94 (m, 2H, Ar H-3,5),
6.99 and 7.60 (2 ꢄ m, 2H, Ar H-2,6), 11.02 and 11.56 (2 ꢄ bs,
1H, NH); 13C NMR (125 MHz): d ¼ 36.0 and 36.5 (CH2), 48.4
and 52.0 (SACH), 55.2 (OCH3), 58.8 and 59.5 (OACH2), 114.0
and 114.4 (Ar C-3,5), 121.9 and 123.3 (Ar C-2,6), 131.9 (Ar C-
1), 156.2 and 156.7 (Ar C-4), 176.6 (C¼¼N), 190.3 (C¼¼O). Anal.
Calcd. for C12H14N2O3S: C, 55.12; H, 5.30; N, 10.52; S, 12.04.
Found: C, 55.24; H, 5.26; N, 10.64; S, 12.01. EI-MS: m/z 266
[Mþ], 248 [MAH2O], 235, 222, 207, 191, 175, 165, 148, 133
(100%), 118, 105, 90, 78, 63, 55, 41.
1
130–131ꢁC; H NMR (500 MHz): d ¼ 1.83 and 2.26 (2 ꢄ m,
2H, CH2), 3.52 (m, 2H, OCH2), 4.34 (d, J ¼ 6.0 Hz, 1H,
SACH), 4.78 (m, 1H, OH), 7.24 (m, 1H, Ar H-6), 7.48 (m,
1H, Ar H-4), 7.60 (m, 1H, Ar H-5), 7.89 and 8.22 (2 ꢄ m, 1H,
Ar H-2), 11.02 and 11.56 (2 ꢄ bs, 1H, NH); 13C NMR (125
MHz): d ¼ 35.6 and 36.4 (CH2), 47.4 and 52.2 (SACH), 58.6
and 59.6 (OACH2), 124.1 (q, J ¼ 272 Hz, CF3), 130.1 (q, J ¼
31.6 Hz, Ar C-3), 116.6 and 121.1 (Ar C-2), 117.8 and 120.8
(Ar C-5), 124.0 and 130.5 (Ar C-4), 125.2 and 130.6 (Ar C-6),
139.6 and 149.1 (Ar C-1), 176.9 and 178.3 (C¼¼N), 190.6
(C¼¼O). Anal. Calcd. for C12H11F3N2O2S: C, 47.37; H, 3.64; N,
9.21; S, 10.54. Found: C, 47.56; H, 3.67; N, 9.42; S, 10.31.
5-(2-Hydroxyethyl)-2-[(2-pyridyl)imino]-1,3-thiazolidin-4-
one (3g). Overall yield: 1.34g (84%); m.p. 187–188ꢁC; 1H
NMR (500 MHz): d ¼ 1.82 and 2.22 (2 ꢄ m, 2H, CH2), 3.58
(m, 2H, OCH2), 4.10 (d, J ¼ 7.0 Hz, 1H, SACH), 4.78 (bs,
1H, OH), 7.11 (m, 2H, Ar H-4,6), 7.82 (m, 1H, Ar H-5), 8.42
(m, 1H, Ar H-3), 11.93 (bs, 1H, NH); 13C NMR (125 MHz): d
¼ 35.9 (CH2), 47.2 (SACH), 58.9 (OACH2), 118.2 (Ar C-6),
119.8 (Ar C-4), 138.7 (Ar C-5), 146.9 (Ar C-3), 156.2 (Ar C-
1), 165.3 (C¼¼N), 180.7 (C¼¼O). Anal. Calcd. for
C10H11N3O2S: C, 50.62; H, 4.67; N, 17.71; S, 13.41. Found:
C, 50.52; H, 4.44; N, 17.76; S, 13.64. EI-MS: m/z 237 [Mþ],
206, 119 (100%), 78, 55, 44.
5-(2-Hydroxyethyl)-2-[(4-methylphenyl)imino]-1,3-thiazoli-
din-4-one (3c). Yield: 0.43g (87%); m.p. 124–126ꢁC; 1H NMR
(500 MHz): d ¼ 1.79 and 2.30 (2 ꢄ m, 2H, CH2), 2.27 (s, 3H,
CH3), 3.52 (m, 2H, OCH2), 4.27 (m, 1H, SACH), 4.75 (m, 1H,
OH), 6.91 and 7.14 (2 ꢄ AA0XX0, 2H, Ar H-2,6), 7.15 and 7.59
(2 ꢄ AA0XX0, 2H, Ar H-3,5), 11.08 and 11.64 (2 ꢄ bs, 1H,
NH); 13C NMR (125 MHz): d ¼ 20.3 (CH3), 36.1 and 36.7
(CH2), 48.1 and 52.1 (SACH), 58.9 and 59.7 (OACH2), 120.4
and 121.7 (Ar C-2,6), 129.5 and 129.8 (Ar C-3,5), 134.0 (Ar C-
4), 136.5 and 143.3 (Ar C-1), 177.1 and 179.4 (C¼¼N), 190.6
(C¼¼O). Anal. Calcd. for C12H14N2O2S: C, 57.58; H, 5.64; N,
11.19; S, 12.81. Found: C, 57.59; H, 5.69; N, 10.93; S, 12.74.
5-(2-Hydroxyethyl)-2-[(4-chlorophenyl)imino]-1,3-thiazoli-
din-4-one (3d). Overall yield: 1.7g (97%); m.p. 136–137ꢁC;
1H NMR (500 MHz): d ¼ 1.79 and 2.25 (2 ꢄ m, 2H, CH2),
3.52 (m, 2H, OCH2), 4.31 (m, 1H, SACH), 4.75 (bs, 1H, OH),
6.96 and 7.37 (2 ꢄ AA0XX0, 2H, Ar H-2,6), 7.42 and 7.77 (2
ꢄ AA0XX0, 2H, Ar H-3,5), 11.26 and 11.80 (2 ꢄ bs, 1H, NH);
13C NMR (125 MHz): d ¼ 35.8 and 36.5 (CH2), 47.5 and 52.2
5-(2-Hydroxyethyl)-2-[(N-phenyl-N-methyl)amino]-4,5-dihy-
dro-1,3-thiazol-4-one (3h). Yield: 0.40g (80%); m.p. 112–
1
115ꢁC; H NMR (500 MHz): d ¼ 1.67 and 2.24 (2 ꢄ m, 2H,
CH2), 3.44 (m, 2H, OCH2), 3.50 (s, 3H, NCH3), 4.21 (d, J ¼
10.9 Hz, 1H, SACH), 4.69 (bs, 1H, OH), 7.47 (m, 5H, Ar H-
2,3,4,5,6); 13C NMR (125 MHz): d ¼ 36.5 (CH2), 41.8
(SACH), 54.7 (NCH3), 59.6 (OACH2), 127.1 (Ar C-2,6),
129.3 (Ar C-4), 130.0 (Ar C-3,5), 142.2 (Ar C-1), 181.9
(C¼¼N), 189.3 (C¼¼O). Anal. Calcd. for C12H14N2O2S: C,
57.58; H, 5.64; N, 11.19; S, 12.81. Found: C, 57.53; H, 5.56;
N, 10.90; S, 12.76.
5-(2-Hydroxyethyl)-2-[(N-phenyl-N-ethyl)amino]-4,5-dihy-
dro-1,3-thiazol-4-one (3i). Yield: 0.47g (90%); m.p. 158–
160ꢁC; 1H NMR (500 MHz): d ¼ 1.12 (t, J ¼ 7.1 Hz, 3H,
CH3), 1.67 and 2.26 (2 ꢄ m, 2H, CH2), 3.46 (m, 2H, OCH2),
4.01 (m, 2H, NCH2), 4.23 (dd, J ¼ 10.6 and 3.1 Hz, 1H,
SACH), 4.68 (t, J ¼ 4.8 Hz, 1H, OH), 7.45 (m, 2H, Ar H-
2,6), 7.52 (m, 3H, Ar H-3,4,5); 13C NMR (125 MHz): d ¼
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
Efficient Synthesis of 5-(2-Hydroxyethyl)-2-phenylimino-1,3-thiazolidin-4-ones and
5-(2-Hydroxyethyl)-2-phenylamino-4,5-dihydro-1,3-thiazol-4-ones
639
12.6 (CH3), 36.5 (CH2), 49.0 (SACH), 54.3 (NCH3), 59.6
(OACH2), 128.2 (Ar C-2,6), 129.6 (Ar C-4), 130.0 (Ar C-3,5),
140.4 (Ar C-1), 181.7 (C¼¼N), 189.5 (C¼¼O). Anal. Calcd. for
C13H16N2O2S: C, 59.07; H, 6.10; N, 10.60; S, 12.13. Found:
C, 58.84; H, 5.92; N, 10.76; S, 12.31.
¼ 29.0 (NCH3), 35.3 (CH2), 45.3 (SACH), 58.1 (OACH2),
122.6 (Ar C-2,6), 128.0 (Ar C-4), 128.9 (Ar C-3,5), 147.0 (C-
1), 155.6 (C¼¼N), 174.3 (C¼¼O). Anal. Calcd. for
C12H13ClN2O2S: C, 50.61; H, 4.60; N, 9.84; S, 11.26. Found:
C, 50.35; H, 4.63; N, 10.15; S, 11.02.
5-(2-Hydroxyethyl)-2-diphenylamino-4,5-dihydro-1,3-thiazol-
4-one (3j). Overall yield: 1.66g (60%); m.p. 153–155ꢁC; 1H
NMR (500 MHz): d ¼ 1.74 and 2.27 (2 ꢄ m, 2H, CH2), 3.47
(m, 2H, OCH2), 4.26 (dd, J ¼ 7.5 and 3.0 Hz, 1H, SACH),
4.73 (t, J ¼ 5.0 Hz, 1H, OH), 7.33-7.63 (m, 10H, Ar H); 13C
NMR (125 MHz): d ¼ 36.1 (CH2), 54.5 (SACH), 59.4
(OACH2), 126.5 (Ar C-2,6), 128.5 (Ar C-4), 129.1 (Ar C-3,5),
129.9 (Ar C-1), 183.2 (C¼¼N), 189.7 (C¼¼O). Anal. Calcd. for
C17H16N2O2: C, 65.36; H, 5.16; N, 8.97; S, 10.26. Found: C,
65.12; H, 5.27; N, 8.79; S, 10.44.
Acknowledgments. The authors thank to Ministry of Education,
Youth and Sports of the Czech Republic for financial support
(Project MSM 002 162 7501).
REFERENCES AND NOTES
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5-(2-Hydroxyethyl)-2-[(N-(4-methoxyphenyl)-N-methyl)
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1
[3] (a) Sattigeri, V. J.; Soni, A.; Singhal, S.; Khan, S.; Pandya,
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m.p. 119–120ꢁC; H NMR (500 MHz): d ¼ 1.66 and 2.23 (2 ꢄ
m, 2H, CH2), 3.36 (s, 3H, NCH3), 3.45 (m, 2H, OCH2), 3.80 (s,
3H, OCH3), 4.18 (dd, J ¼ 10.5 and 3.0 Hz, 1H, SACH), 4.76 (t,
J ¼ 5.5 Hz, 1H, OH), 7.05 (AA0XX0, J ¼ 8.5 Hz, 2H, Ar H-2,6),
7.41 (AA0XX0, J ¼ 8.5 Hz, 2H, Ar H-3,5); 13C NMR (125
MHz): d ¼ 35.4 (CH2), 41.7 (SACH), 54.6 (NCH3), 55.4
(OCH3), 59.5 (OACH2), 114.8 (Ar C-2,6), 128.3 (Ar C-3,5),
134.8 (Ar C-1), 159.4 (Ar C-4), 182.1 (C¼¼N), 189.2 (C¼¼O).
Anal. Calcd. for C13H16N2O3S: C, 55.70; H, 5.75; N, 9.99; S,
11.44. Found: C, 56.03; H, 5.96; N, 10.32; S, 11.76.
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5-(2-Hydroxyethyl)-2-[(4-methoxyphenyl)imino]-3-methyl-
1,3-thiazolidin-4-one (3l). Overall yield: 1.03g (57%); m.p.
1
101–103ꢁC; H NMR (500 MHz): d ¼ 1.83 and 2.28 (2 ꢄ m,
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2H, CH2), 3.16 (s, 3H, NCH3), 3.43 and 3.51 (2 ꢄ m, 2H,
OCH2), 3.73 (s, 3H, OCH3), 4.33 (dd, J ¼ 9.7 and 3.5 Hz, 1H,
SACH), 4.76 (bs, 1H, OH), 6.91 (m, 4H, Ar H-2,3,5,6); 13C
NMR (125 MHz): d ¼ 29.2 (NCH3), 35.8 (CH2), 45.2
(SACH), 55.1 (OCH3), 58.4 (OACH2), 114.3 (Ar C-2,6),
122.0 (Ar C-3,5), 141.2 (Ar C-1), 154.4 (C¼¼N), 156.0 (Ar C-
4), 174.6 (C¼¼O). Anal. Calcd. for C13H16N2O3S: C, 55.70; H,
5.75; N, 9.99; S, 11.44. Found: C, 55.81; H, 5.54; N, 10.37; S,
11.21. EI-MS: m/z 280 [Mþ] (100 %), 265, 249, 236, 221,
207, 194, 179, 162, 147, 133, 119, 106, 90, 78, 64, 55, 45, 35.
5-(2-Hydroxyethyl)-2-(4-phenylimino)-3-ethyl-1,3-thiazolidin-
4-one (3m). Yield: 0.17g (33%); oil; 1H NMR (500 MHz): d
¼ 1.18 (t, J ¼ 7.0 Hz, 3H, CH3), 1.84 and 2.24 (2 ꢄ m, 2H,
CH2), 3.43-3.58 (m, 2H, OCH2), 3.77 (q, J ¼ 7.0 Hz, 2H,
NCH2), 4.34 (dd, J ¼ 9.6 and 3.7 Hz, 1H, SACH), 4.75 (bs,
1H, OH), 6.96 (d, J ¼ 7.3 Hz, 2H, Ar H-2,6), 7.11 (t, J ¼ 7.3
Hz, 1H, Ar H-4), 7.35 (t, J ¼ 7.4 Hz, 2H, Ar H-3,5); 13C
NMR (125 MHz): d ¼ 12.3 (CH3), 35.7 (CH2), 37.4 (NCH2),
45.3 (SACH), 58.3 (OACH2), 121.0 (Ar C-2,6), 124.2 (Ar C-
4), 129.2 (Ar C-3,5), 148.3 (Ar C-1), 154.0 (C¼¼N), 174.4
(C¼¼O). Anal. Calcd. for C13H16N2O2S: C, 59.07; H, 6.10; N,
10.60; S, 12.13. Found: C, 58.71; H, 5.96; N, 10.86; S, 11.88.
EI-MS: m/z 264 [Mþ] (100 %), 233, 221, 205, 192, 177, 163,
146, 131, 118, 104, 91, 77, 65, 55, 45, 35.
´ ´ ´ ´ˇ
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5-(2-Hydroxyethyl)-2-[(4-chlorophenyl)imino]-3-methyl-1,3-
thiazolidin-4-one (3n). Overall yield: 1.15g (63%); m.p. 87–
89ꢁC; 1H NMR (500 MHz): d ¼ 1.86 and 2.27 (2 ꢄ m, 2H,
CH2), 3.16 (s, 3H, NCH3), 3.45 and 3.54 (2 ꢄ m, 2H, OCH2),
4.36 (dd, J ¼ 9.8 and 3.6 Hz, 1H, SACH), 4.75 (t, J ¼ 5.0
Hz, 1H, OH), 6.96 (AA0XX0, J ¼ 8.5 Hz, 2H, Ar H-2,6) 7.40
(AA0XX0, J ¼ 8.5 Hz, 2H, Ar H-3,5); 13C NMR (125 MHz): d
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet