Synthesis of some furo-thiazolidine derivatives starting from aldimines

Article abstract of DOI:10.1002/jhet.5570400427

Alkyl and aryl substituted furothiazolidine derivatives have been synthesized by the reaction of Wittig reagent with benzylidene derivatives of 4-thiazolidinones obtained from aldimines and thioglicolic acid.

Full text of DOI:10.1002/jhet.5570400427

Synthesis of Some Furo-Thiazolidine Derivatives
Starting from Aldimines
721
Jul-Aug 2003
Nüket Öcal*, Feray Aydogˇan, Çigˇdem Yolaçan and Zuhal Turgut
Yildiz Technical University, Chemistry Department, Davutpasa Campus,
Merter, 34010,Istanbul,Turkey
Received March 27, 2003
Alkyl and aryl substituted furothiazolidine derivatives have been synthesized by the reaction of Wittig
reagent with benzylidene derivatives of 4-thiazolidinones obtained from aldimines and thioglicolic acid.
J. Heterocyclic Chem., 40, 721(2003).
In recent years, interests of researchers have been focused
amine. Chromatographic separation produced successively
two different substances. In every case, the first eluent
contained triphenylphosphine, the second products were
5a-g (Scheme 2). This reaction applied for the first time to
substituted thiazolidinone derivatives by our group to pro-
vide a new way for synthesizing furothiazolidines [5]. In
this report, we chose aliphatic and aromatic substituted
thiazolidinone derivatives to investigate the effect of
substituent on the cyclisation reaction. Obviously, the
dipolar indermediate 4 formed from the initial attack of the
carbanion centre in the Wittig reagent on the active
exocyclic electrophilic carbon atom of a ,b-unsaturated
system in 3a-g undergoes O-alkylation with triph-
enylphosphine elimination to give 6-methoxycarbonyl-3-
substituted phenyl-7-phenyl-2-(nonyl or phenyl)dihydro-
on the heterocyclic systems which contain various
heteroatoms such as nitrogen, sulphur and oxygen, because
of their biological importance. As a part of our ongoing
research on the preparations and reactions of 4-thiazolidi-
nones, which show some biological activities such as antibi-
otic, diuretic, organoleptic, tuberculostatic, antileukemic
and antiparasitical [1,2], we have reported recently the
synthesis, transformations and some biological properties of
2-heteroaryl substituted 4-thiazolidinones [3-5].
Here we report the synthesis of some alkyl and aryl
substituted furothiazolidine derivatives via the reactions of
Wittig reagent with 5-benzylidene-4-thiazolidinones
obtained from a series of nonaldimines and benzaldimines.
Aldimines are used in the synthesis of nitrogen containing
heterocycles [6,7], so the synthesis of 4-thiazolidinones
have been accomplished starting from imines. Compounds
1a-d are new compounds which were prepared from
condensation of nonanal with p-phenoxyaniline,
p-methoxyaniline, p-methylaniline and cyclohexylamine as
described in experimental section.
4
D -furo-[2,3-d]thiazolidines, 5a-g.
The 3-aryl-2-nonyl- or phenyl-4-thiazolidinones (2a-g)
(Scheme 1) were obtained by refluxing equimolar amounts
of imines and thioglycolic acid in dry benzene. After
purification, these compounds were subjected to aldol
condensation with benzaldehyde in the presence of sodium
ethoxide to give 5-benzylidene derivatives (3a-g) [4].
These were refluxed with methoxycarbonylmethylenet-
riphenylphosphorane in ethyl acetate containing triethyl-
The structures of the new compounds were firmly estab-
1
lished on the basis of their ftir, H-nmr, mass spectra.
Elemental analyses results also supported the structures of
1
5a-g. The H-nmr spectra of 2a-d displayed doublets at d

722
N. Öcal, F. Aydogˇan, Ç. Yolaçan and Z. Turgut
Vol. 40
aromatic), 7.92 (t, J = 6.6 Hz,1H, =CH); ftir (potassium bromide):
1600 (C=N) cm-1; ms: m/z 309 (molecular ion).
3.66-3.78 due to H and H systems in addition to other
signals. In the condensation products 3a-d, these AB sys-
A
B
tems were absent confirming that an aldol condensation
had taken place. In the H nmr spectra of 5a-g, 6-CH and
Nonylidene-(4-methoxyphenyl)amine (1b).
1
Purification by column chromatography on silica gel eluted
with toluene gave yellow oil, 77%; 1H nmr: d 0.79-1.42 (m, 15H,
CH2 and CH3), 2.33-2.40 (m, 2H, CH2), 3.58 (s, 3H, OCH3),
6.46 (d, J = 8.7 Hz, 2H, aromatic), 7.05 (d, J = 8.7 Hz, 2H,
aromatic), 7.83 (t, J = 6.6 Hz, 1H, =CH); ftir (potassium
bromide): 1600 (C=N) cm-1; ms: m/z 247 (molecular ion).
7-CH protons of the dihydrofuran nucleus appared as two
dublets at 4.23-4.93 ppm and 3.75-3.95 ppm, respectively.
In the ftir spectra of the thiazolidinones, 2a-g and 3a-g,
the characteristic C=O bands appeared in the region of
-1
1651-1676 cm . The disappearance of the strong sharp
-1
bands at 1620-1605 cm of the initial azomethines was the
Nonylidene-(p-tolyl)amine (1c).
most characteristic evidence of the cyclocondensation.
Regarding compounds 5a-g amide carbonyl bands were
absent which clearly confirmed that a cyclocondensation
with Wittig reagent had taken place.
The crude product was subjected to column chromatography on
silica gel eluted with toluene to yield yellow oil, 68%; 1H nmr: d
0.75-1.33 (m, 15H, CH2 and CH3), 2.31 (s, 3H, CH3), 2.35-2.42
(m, 2H, CH2), 6.56 (d, J = 7.2 Hz, 2H, aromatic), 6.79 (d, J = 7.2
Hz, 2H, aromatic), 7.85 (d, J = 6.6 Hz, 1H, =CH); ftir (potassium
bromide): 1605 (C=N) cm-1; ms: m/z 231 (molecular ion).
In conclusion, we have prepared a new series of alkyl
and aryl substituted fused thiazolidine derivatives. In light
of all these results, the cyclocondensation reactions of
benzylidene derivatives of thiazolidinones took place
with aromatic and heteroaromatic substituted thiazoli-
dinones in high yield, because of electronic effects of aro-
matic rings. Besides, we observed that the reaction with
aliphatic derivatives were very difficult because of steric
effects resulting from the long chain. The biological
activity measurements of the new compounds are under
investigations.
Nonylidenecyclohexylamine (1d).
The crude product subjected to column chromatography with
toluene/ethyl acetate (4:1) gave yellow oil, 54%; 1H nmr: d 0.76-
1.35 (m, 25H, CH2 and CH3), 2.20-2.25 (m, 2H, CH2), 3.25-3.28
(m, 1H, CH), 7.16 (t, J = 6.6 Hz, 1H, =CH); ftir (potassium bro-
mide): 1603 (C=N) cm-1; ms: m/z 223 (molecular ion).
3-(4-Phenoxyphenyl)-2-octyl-4-thiazolidinone (2a).
General Procedure for 2a-d.
To a solution of the Schiff-base (1a) (3.09 g, 0.01 mol) derived
from nonanal and p-phenoxyaniline in 15 ml dry benzene,
thioglicolic acid (0.92 g, 0.01 mol) was added. The mixture was
refluxed on a water bath for 18 h, then cooled and poured into
water. The upper organic layer was washed with NaHCO3 solu-
tion (15 ml, 10%) and then with H2O, dried (Na2SO4), and the
benzene was distilled off. Upon crystallization of the residue
from petroleum ether (40-60 °C)/ethanol (1:1), the thiazolidinone
EXPERIMENTAL
Melting points are uncorrected and were measured in open
capillaries with an Electrothermal IA 9100 melting point appara-
tus. Infrared spectra were recorded on a Mattson 1000 ftir spec-
trometer as KBr pellets. Proton nmr spectra were determined on a
Bruker DPX 400 spectrometer in CDCl3 with tetramethylsilane
as internal standard. Chemical shifts (d) were measured in ppm.
Mass spectra were obtained with a Shimadzu GS/MS QP 2000 A
spectrometer with 70 eV electron impact ionization. Elemental
analyses were performed on a Leco CHN-600 analyzer. Column
chromatography was performed with silica gel 60 (70-230 mesh)
purchased from E. Merck AG. The purity of the obtained sub-
stances and the composition of the reaction mixtures were moni-
toring by thin layer chromatography on silica gel sheets with flu-
orescent indicator (Merck No. 5554). Solvents and common
reagents obtained from Merck and Aldrich, were of reagent
grade. Thiazolidinones 2e-g and benzylidene derivative 3g were
prepared by literature procedures [8,9] and the spectral data are
in agreement with that given in the literature.
1
was obtained as yellow crystals, yield 69%, mp 121-123 °C; H
nmr: d 0.93-1.92 (m, 17H, CH2 and CH3), 3.67 (d, J = 16.5 Hz,
1H, CH2), 3.71 (d, J = 16.5 Hz, 1H, CH2), 4.92 (t, J = 7.0 Hz, 1H,
CH), 6.93-7.65 (m, 9H, aromatic); ftir (potassium bromide):
1676 (C=O) cm-1; ms: m/z 383 (molecular ion).
3-(4-Methoxyphenyl)-2-octyl-4-thiazolidinone (2b).
Reaction was completed after 6 h reflux, then the crude prod-
uct was recrystallized from petroleum ether (40-60 °C)/ether
1
(1:1), to yield yellow crystals, yield 73%, mp 118-119 °C; H
nmr: d 0.76-1.75 (m, 17H, CH2 and CH3), 3.65 (s, 3H, CH3),
3.72 (d, J = 16.5 Hz, 1H, CH2), 3.77 (d, J = 16.5 Hz, 1H, CH2),
4.55 (t, J = 7.0 Hz, 1H, CH), 6.60 (d, J = 9 Hz, 2H, aromatic),
7.28 (d, J = 9 Hz, 2H, aromatic); ftir (potassium bromide): 1676
(C=O) cm-1; ms: m/z 321 (molecular ion).
Nonylidene-(4-phenoxyphenyl)amine (1a).
General Procedure for 1a-d.
2-Octyl-3-(p-tolyl)-4-thiazolidinone (2c).
Reaction was completed after 8 h reflux, then the crude prod-
uct was recrystallized from petroleum ether (40-60 °C)/ethanol
(1:1), the thiazolidinone was obtained as yellow crystals, yield
72%, mp 96-98 °C; 1H nmr: d 0.87-1.99 (m, 17H, CH2 and CH3),
2.11 (s, 3H, CH3), 3.68 (d, J = 16.5 Hz, 1H, CH2), 3.74 (d, J =
16.5 Hz, 1H, CH2), 4.76 (t, J = 7.0 Hz, 1H, CH), 7.49 (d, J = 8.3
Hz, 2H, aromatic), 7.10 (d, J = 8.3 Hz, 2H, aromatic); ftir (potas-
sium bromide): 1651 cm-1; ms: m/z 305 (molecular ion).
Nonanal (1.42 g, 0.01 mol) and p-phenoxyaniline (1.85 g, 0.01
mol) were heated for 8 hours without solvent then 15 mL toluene
was added to this solution and refluxed for an additional 15 hours.
Toluene was evaporated and the crude Schiff-base was purified by
column chromatography on silica gel eluted with toluene to give
yellow oil, 85%. 1H nmr (deuteriochloroform): d 0.78-1.39 (m,
15H, CH2 and CH3), 2.25-2.36 (m, 2H, CH2), 6.50-7.12 (m, 9H,

Jul-Aug 2003
Synthesis of Some Furo-Thiazolidine Derivatives Starting from Aldimines
723
(1:1) to give yellow crystals, yield 69 %, mp 153-154 °C; 1H
nmr: d 1.35 (t, J = 7.0 Hz, 3H, CH3), 3.94 (q, J = 7.0 Hz, 2H,
CH2), 6.73 (s, 1H, CH), 6.89-7.77 (m, 15H, aromatic and =CH);
ftir (potassium bromide): 1675 (C=O) cm ; ms: m/z 387 (molec-
ular ion).
3-Cyclohexyl-2-octyl-4-thiazolidinone (2d).
Reaction was completed after 9 h reflux, then the crude prod-
uct was purified with column chromatography on silica gel eluted
with ethyl acetate/hexane (1:4), the product was obtained as yel-
low crystals, yield 65%, mp 109-110 °C; 1H nmr: d 0.82-1.65 (m,
27H, CH2), 3.25-3.29 (m,1H, CH), 3.69 (d, J = 16.5 Hz, 1H,
CH2), 3.71 (d, J = 16.5 Hz, 1H, CH2), 4.35 (t, J = 7.0 Hz, 1H,
CH); ftir (potassium bromide): 1676 (C=O) cm-1; ms: m/z 297
(molecular ion).
-1
6-Methoxycarbonyl-3-(4-phenoxyphenyl)-7-phenyl-2-octyl-
dihydro-D4-furo[2,3-d]thiazolidine (5a).
General Procedure for 5a-g.
A solution of 3a (4.71 g, 0.01 mol) and methoxycarbonylmeth-
ylenetriphenylphosphorane [10] (5.01 g, 0.015 mol) in ethyl
acetate (50 mL) was refluxed for 24 h in the presence of triethy-
lamine (1.51 g, 0.015 mol). After evaporation of the solvent, the
remainder was subjected to column chromatography on silica gel
eluted with petroleum ether/acetone (9:1) with increasing
amounts of acetone (up to 3:1). The two products obtained were
triphenylphosphine and 5a (26%) which was isolated as orange
crystals and identified, mp 236-237 °C; 1H nmr: d 0.79-1.87 (m,
17H, CH2 and CH3), 3.62 (s, 3H, OCH3), 3.83 (d, J = 5.7 Hz, 1H,
CH), 4.93 (d, J = 5.7 Hz, 1H, CH), 5.01 (t, J = 7.0 Hz, 1H, CH),
6.83-7.22 (m, 14H, aromatic); ftir (potassium bromide): 1723
(C=O) cm-1; ms: m/z 543 (molecular ion).
5-Benzylidene-3-(4-phenoxyphenyl)-2-octyl-4-thiazolidinone
(3a).
General Procedure for 3a-f.
Equimolar solutions of2a (3.83 g, 0.01 mol) and benzaldehyde
(1.06 g, 0.01 mol) in dry benzene (25 mL) in presence of sodium
ethoxide were refluxed for about 10-12 h, cooled and poured into
ice cold water, and acidified with glacial acetic acid. The solution
was extracted, the benzene layer separated, dried (CaCl2) and
evaporated in vacuo. The crude product was crystallized from
petroleum ether: diethyl ether (1:1) to give yellow crystals, yield
1
61 %, mp 153-155 °C; H nmr: d 0.82-1.83 (m, 17H, CH2 and
CH3), 5.53 (t, J = 7.0 Hz, 1H, CH), 6.62-7.73 (m, 15H, aromatic
and =CH); ftir (potassium bromide): 1676 (C=O) cm-1; ms: m/z
471 (molecular ion).
Anal. Calcd. for C33H37NO4S: C, 72.79; H, 6.85; N, 2.57; S,
5.88. Found: C, 72.72; H, 6.87; N, 2.60; S, 5.91.
6-Methoxycarbonyl-3-(4-methoxyphenyl)-7-phenyl-2-octyl-
dihydro-D4-furo[2,3-d]thiazolidine (5b).
5-Benzylidene-3-(4-methoxyphenyl)-2-octyl-4-thiazolidinone
(3b).
Dark yellow crystals were obtained after purification with col-
umn chromatography, yield 32%, mp 229-230 °C; 1H nmr: d
0.84-1.92 (m, 17H, CH2 and CH3), 3.66 (s, 3H, OCH3), 3.71 (s,
3H, OCH3), 3.75 (d, J = 5.7 Hz, 1H, CH), 4.75 (d, J = 5.7 Hz, 1H,
CH), 4.98 (t, J = 7.0 Hz, 1H, CH), 6.92-7.33 (m, 9H, aromatic);
ftir (potassium bromide): 1720 (C=O) cm ; ms: m/z 481 (molec-
ular ion).
Anal. Calcd. for C28H35NO4S: C, 69.81; H, 7.32; N, 2.90; S,
6.65. Found: C, 69.79; H, 7.35; N, 2.89; S, 6.62.
The crude product was crystallized from petroleum ether:
diethyl ether (1:1) to give yellow crystals, yield 62 %, mp 147-
148 °C; H nmr: d 0.83-1.68 (m, 17H, CH2 and CH3), 3.83 (s,
3H, OCH3), 5.25 (t, J = 7.0 Hz, 1H, CH), 6.99-7.68 (m, 10H, aro-
matic and =CH); ftir (potassium bromide): 1676 (C=O) cm-1; ms:
m/z 409 (molecular ion).
1
-1
5-Benzylidene-2-octyl-3-(p-tolyl)-4-thiazolidinone (3c).
The crude product was crystallized from benzene:diethyl ether
(1:1) to give yellow crystals, yield 59 %, mp 169-171 °C; 1H
nmr: d 0.75-1.56 (m, 17H, CH2 and CH3), 2.16 (s, 3H, CH3), 5.22
(t, J = 7.0 Hz, 1H, CH), 6.93-7.56 (m, 10H, aromatic and =CH);
6-Methoxycarbonyl-3-(4-methylphenyl)-7-phenyl-2-octyl-dihy-
dro-D4-furo[2,3-d]thiazolidine (5c).
-1
Yellow crystals were obtained after purification with column
chromatography, yield 23%, mp 267-268 °C; 1H nmr: d 0.75-
1.92 (m, 17H, CH2 and CH3), 2.27 (s, 3H, CH3), 3.52 (s, 3H,
OCH3), 3.80 (d, J = 5.7 Hz, 1H, CH), 4.85 (d, J = 5.7 Hz, 1H,
CH), 4.96 (t, J = 7.0 Hz, 1H, CH), 6.87-7.12 (m, 9H, aromatic);
ftir (potassium bromide): 1676 (C=O) cm ; ms: m/z 393 (molec-
ular ion).
5-Benzylidene-3-cyclohexyl-2-octyl-4-thiazolidinone (3d).
The crude product was crystallized from benzene:diethyl ether
-1
1
ftir (potassium bromide): 1727 (C=O) cm ; ms: m/z 465 (molec-
(1:1) to give yellow crystals, yield 68 %, mp 156-157 °C; H
ular ion).
nmr: d 0.79-1.72 (m, 27H, CH2 and CH3), 3.36-3.41 (m, 1H,
CH), 5.15 (t, J = 7.0 Hz, 1H, CH), 7.24-7.83 (m, 6H, aromatic
and =CH); ftir (potassium bromide): 1651 (C=O) cm-1; ms: m/z
(molecular ion).
Anal. Calcd. for C28H35NO3S: C, 72.21; H, 7.57; N, 3.00; S,
6.88. Found: C, 72.25; H, 7.58; N, 2.97; S, 6.86.
6-Methoxycarbonyl-3-cyclohexyl-7-phenyl-2-octyl-dihydro-D4-
furo[2,3-d]thiazolidine (5d).
5-Benzylidene-3-(4-phenoxyphenyl)-2-phenyl-4-thiazolidinone
(3e).
Orange crystals were obtained after purification with column
chromatography, yield 28%, mp 243-244 °C; 1H nmr: d 0.85-
1.62 (m, 27H, CH2 and CH3), 3.52 (s, 3H, OCH3), 3.32-3.38 (m,
1H, CH), 3.95 (d, J = 5.7 Hz, 1H, CH), 4.23 (d, J = 5.7 Hz, 1H,
CH), 4.83 (t, J = 7.0 Hz, 1H, CH), 7.03-7.32 (m, 5H, aromatic);
The crude product was crystallized from benzene: diethyl ether
(1:1) to give yellow crystals, yield 51 %, mp 148-150 °C; 1H
nmr: d 6.42 (s, 1H, CH), 6.94-7.43 (m, 20H, aromatic and =CH);
ftir (potassium bromide): 1673 (C=O) cm ; ms: m/z 435 (molec-
ular ion).
-1
-1
ftir (potassium bromide): 1723 (C=O) cm ; ms: m/z 457 (molec-
ular ion).
5-Benzylidene-3-(4-ethoxyphenyl)-2-phenyl-4-thiazolidinone (3f).
The crude product was crystallized from benzene:diethyl ether
Anal. Calcd. for C27H39NO3S: C, 70.85; H, 8.58; N, 3.06; S,
7.00. Found: C, 70.89; H, 8.61; N, 3.10; S, 7.01.

724
N. Öcal, F. Aydogˇan, Ç. Yolaçan and Z. Turgut
Vol. 40
14H, aromatic); ir (potassium bromide): 1725 (C=O) cm-1; ms:
m/z 429 (molecular ion).
6-Methoxycarbonyl-3-(4-phenoxyphenyl)-2,7-diphenyl-dihydro-
D4-furo[2,3-d]thiazolidine (5e).
Anal. Calcd. for C26H23NO3S: C, 72.69; H, 5.39; N, 3.26; S,
7.46. Found: C, 72.73; H, 5.42; N, 3.21; S, 7.42.
Yellow crystals were obtained after purification with column
chromatography, yield 49%, mp 239-241 °C; 1H nmr: d 3.58
(s, 3H, OCH3), 3.69 (d, J = 5.7 Hz, 1H, CH), 4.97 (d, J = 5.7
Hz, 1H, CH), 6.28 (s, 1H, CH), 7.12-7.44 (m, 19H, aromatic);
ftir (potassium bromide): 1725 (C=O) cm-1; ms: m/z 507
(molecular ion).
Acknowledgement.
Financial support of this research by TUBITAK (Scientific and
Technical Reseach Council of Turkey) [Project number: TBAG
1987-100T113)] is gratefully acknowledged.
Anal. Calcd. for C31H25NO4S: C, 73.34; H, 4.96; N, 2.75; S,
6.31. Found: C, 73.41; H, 4.91; N, 2.69; S, 6.32.
REFERENCES AND NOTES
6-Methoxycarbonyl-3-(4-ethoxyphenyl)-2,7-diphenyl-dihydro-
D4-furo[2,3-d]thiazolidine (5f).
[1] F. C.Brown, Chem. Rev., 61, 463 (1961).
[2] M. S.Raasch, J. Heterocyclic Chem., 11, 587 (1974).
[3] N. Öcal, Ç. Yolaçan, S¸ . Kaban, Y. Leonor, M. Vargas and
V.Kouznetsov, J. Heterocyclic Chem., 38, 233 (2001).
[4] L. Y. V. Mendez, V. Kouznetsov, J. C. Poveda, Ç. Yolaçan, N.
Öcal and F. Aydogan, Heterocycl. Commun., 7, 129 (2001).
[5] F. Aydogˇan, N. Öcal and Z. Turgut, Bull.Korean Chem.Soc.,
22, 476 (2001).
Yellow crystals were obtained after purification with column
chromatography, yield 52%, mp 217-219°C; 1H nmr: d 1.44 (t, J
= 7.0 Hz, 3H, CH3), 3.72 (s, 3H, OCH3), 3.66 (d, J = 5.7 Hz, 1H,
CH), 3.98 (q, J = 7.0 Hz, 2H, CH2), 5.12 (d, J = 5.7 Hz, 1H, CH),
6.28 (s, 1H, CH), 7.08-7.29 (m, 14H, aromatic); ir (potassium
bromide): 1720 (C=O) cm-1; ms: m/z 459 (molecular ion).
Anal. Calcd. for C27H25NO4S: C, 70.56; H, 5.48; N, 3.04; S,
6.97. Found: C, 70.57; H, 5.45; N, 3.03; S, 6.95.
[6] V. V. Kuznetsov and N. S. Prostakov, Khim. Geterosikl. Soed.,
5 (1990); Chem. Abstr., 113, 40.347 (1990).
[7] A. D. Brown and E. V. Colvin, Tetrahedron Lett., 32, 5187
(1991).
6-Methoxycarbonyl-3-(4-methylphenyl)-2,7-diphenyl-dihydro-
D4-furo[2,3-d]thiazolidine (5g).
[8] M. Suesse and H. Dehne, Zeitsc. fuer Chemie, 15, 268 (1975).
[9] M. T. Omar, A. M. Youssef and F. A. Sherif, Phosphorus,
Sulfur, Silicon and Related Elements, 53, 267 (1990).
[10] T. Kappe, E. Lender and E. Ziegler, Monatsh. Chem. 99, 2157
(1968).
Yellow crystals were obtained after purification with column
chromatography, yield 59%, mp 226-228 °C. H nmr: d 2.33 (s,
3H, CH3), 3.68 (s, 3H, OCH3), 3.71 (d, J = 5.7 Hz, 1H, CH),
5.02 (d, J = 5.7 Hz, 1H, CH), 6.32 (s, 1H, CH), 7.04-7.33 (m,
1