Stereocontrolled synthesis of newtetrahydrofuro[2,3-d]thiazole derivatives via activated vinylogous iminium ions

Article abstract of DOI:10.3987/COM-05-10494

Heterocyclization of (Z)-5-(2-hydroxyethyl)-3-methyl-4-oxothiazolidines,bearing electron-withdrawing groups conjugated to an exocyclic double bond at C(2)-position, afforded under reductive conditions, cis-tetrahydrofuro[2,3-d]thiazole derivatives. The re

Full text of DOI:10.3987/COM-05-10494

HETEROCYCLES, Vol. 65, No. 11, 2005
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HETEROCYCLES, Vol. 65, No. 11, 2005, pp. 2635 - 2647
Received, 27th June, 2005, Accepted, 18th August, 2005, Published online, 19th August, 2005
STEREOCONTROLLED SYNTHESIS OF NEW
TETRAHYDROFURO[2,3-d]THIAZOLE DERIVATIVES VIA
ACTIVATED VINYLOGOUS IMINIUM IONS
Rade Marković,*1,2 Marija Baranac,1,2 Peter Steel,3 Erich Kleinpeter,4 and
Milovan Stojanović2
1Faculty of Chemistry, University of Belgrade, Studentski trg 16, P. O. Box 158,
11001 Belgrade, Serbia and Montenegro. Fax +381(11)636061; E-mail:
markovic@helix.chem.bg.ac.yu
2Center for Chemistry ICTM, P. O. Box 473, 11000 Belgrade, Serbia and
Montenegro
3Department of Chemistry, University of Canterbury, P.O. Box 4800, Christ-
church, New Zealand
4Universität Potsdam, Chemisches Institut, P.O. Box 60 15 53, D-14415 Potsdam,
Germany
Abstract – Heterocyclization of (Z)-5-(2-hydroxyethyl)-3-methyl-4-oxothiazo-
lidines, bearing electron-withdrawing groups conjugated to an exocyclic double
bond at C(2)-position, afforded under reductive conditions, cis-tetrahydro-
furo[2,3-d]thiazole derivatives. The reactions of these functionalized push-pull β-
enamines occur in a stereocontrolled fashion via activated vinylogous N-
methyliminium ions, which are trapped by an internal hydroxyethyl group.
INTRODUCTION
In recent years, a variety of acyclic and cyclic iminium ions with a nucleophilic tether, exemplified by ge-
neral structures (1) and (3) (Scheme 1), have been successfully used for heterocyclization reactions giving
rise to nitrogen-containing heterocycles (2) and (4), respectively.1 An abundance of strategic preparations
of different ring systems with five to seven atoms, based on an endo-mode cyclization of iminium ion (1),

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HETEROCYCLES, Vol. 65, No. 11, 2005
bearing properly located oxygen,2 sulfur3 or nitrogen4 as heteroatom, or nonaromatic and aromatic C=C
bond as a π-nucleophile,5 has confirmed a wide scope of this process. Likewise, the literature documents
that synthetically and medicinally important condensed heterocycles, can be derived by an exo-type cycli-
zation of the key cyclic intermediate (3).6 Extensive experimental evidence underlines the correlation be-
tween the presence of electron-withdrawing groups (EWG), such as the acyl, tosyl, COOR or CONR2, at
the nitrogen atom of iminium ions (1) and (3), and their increasing cationic character, thus, making them
more reactive toward nucleophiles.1,7
R1
R1
N
N
n
A
n
A
n
A
n
A
X
X
N
R1
N
R2
R2
R1
H
H
1
2
3
4
A = O, S, NR
R1 = alkyl, COR, CO2R, SO2R
n = 1-3
H
H
H
H
H
H
H
N
N
N
H
β
EWG
α
X
A
N
R1
HO
H
CO2Et
CO2Et
H
5
6
7
8
Scheme 1
The synthetic utility of vinylogous iminium ions (5) (Scheme 1) for ring closure reactions has been also
examined, however, in an exceedingly limited number of cases.8 Within this context, Hart8a has reported
one of the rare examples when a vinylogous iminium ion (6) undergoes intramolecular π-cyclization, for-
ming a useful tricyclic intermediate (7), en route to envisioned synthesis of the alkaloid
depentylperhydrogephyrotoxin (8).9
Now we wish to demonstrate an ability of new vinylogous N-alkyliminium ions of type (5), possessing
the hydroxyethyl group as an internal nucleophile (A = O; R1 = Me), to participate in heterocyclization,
that is, as one would anticipate, strongly driven by the presence of various electron-withdrawing groups at
the α-position of the C=C bond. Our studies, described below, represent to the best of our knowledge, (i)
the first example of 5-exo-trig intramolecular cyclization of push-pull 3-methyl-(Z)-4-oxothiazolidine
alcohols (12a-d), obtained from 2-alkylidene-5-carboethoxymethyl-4-oxothiazolidines (9a-d),10 to new
cis-condensed thiazolidine compounds (13a-d) (Scheme 2), including (ii) the determination of the stereo-
chemistry by a single-crystal X-Ray analysis of a representative of the series, cis-(Z)-2-(3-methylte-
trahydrofuro[2,3-d]thiazol-2(5H)-ylidene)-1-phenylethanone (13a).

HETEROCYCLES, Vol. 65, No. 11, 2005
2637
RESULTS AND DISCUSSION
In our preliminary study,11 thiazolidine β-enamino derivatives (9a-d), containing the carboethoxymethyl
substituent at C(5) position, were found to react with NaBH4 in ethanol to afford in chemoselective fa-
shion the corresponding alcohols (11a-d) (R=H). However, N-methyl-substituted 4-oxothiazolidine deri-
vative (10a) having the (Z)-configuration, as confirmed by a single-crystal X-Ray structure (Figure 1a),
was converted under analogous conditions into the bicyclic product (13a), albeit in a small yield (21%).
Despite the considerable amounts of other products being formed (vide infra), this result prompted us to
further explore whether the thiazolidines (9a-d) can be employed for the synthesis of not easily
obtainable bicyclic products (13a-d)12 via a reduction-alkylation-ring closure sequence, involving the
C(5) and C(4) positions of the starting derivatives.13
CO2Et
S
S
HO
i
EWG
EWG
O
O
N
N
R
R
9a-d (R=H)
10a (R=Me)
11a-d (R=H)
ii
12a-d (R=Me)
iii
H
a: EWG=COPh
b: EWG=CO2Et
c: EWG=CONH(CH2)2Ph
d: EWG=CN
S
EWG
O
N
H
R
13a-d
(i) NaBH4 (4.5-9 equiv.), EtOH, 2 h, reflux (ii) K2CO3, MeI, EtOH, 1h, rt.
(iii) NaBH4 (2.3 equiv.), EtOH, 4 h, rt.
Scheme 2
Precursors (9a-d), required for the synthesis of 11a-d with built-in alcohol nucleophile, were obtained by
base-catalyzed reactions of β-oxo nitriles and diethyl mercaptosuccinate.10 The unambiguous assignment
of the (Z)-configuration to the exocyclic C=C bonds of compounds (9a-c) has been established by NOE
correlation between the lactam and vinyl hydrogens and crystallographic studies, whereas the heterocycle
(9d), having the nitrile substituent as EWG, was obtained as a mixture of both isomers. As indicated
above, the regioselective reduction of the side-chain acetate group in 9a-d with excess NaBH4 gave rise
to alcohols (11a-d) in good yields (49-64 %), without affecting the enaminone moiety, or affording the
products of reductive ring opening. The resistance of this structural fragment to reduction by metal hydri-
des or catalytic reduction, is considered to reside in strong deactivation of EWG function and C=C bond
due to resonance delocalization.11,14

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HETEROCYCLES, Vol. 65, No. 11, 2005
Standard alkylation of (Z)-11a-c, afforded, without configuration change, the corresponding 3-methyl-4-
oxothiazolidine alcohols (12a-c) (Table 1, 78-92%). This is expected in view of the greater stability of
(Z)-configurated thiazolidines (9a-c) in the solid state and in polar solvents, versus the (E)-analogs, par-
ticularly due to the strong nonbonded electrostatic S---O interaction of the 1,5-intra-type in the former
isomers.15 Interestingly, 12d (EWG = CN) was also isolated as a single (Z)-isomer. Apparently, the steric
bias provided by the N-methyl substituent is sufficient to fix the (Z)-configuration. The ring closure upon
treatment of 12a-d with NaBH4 in ethanol at room temperature, proceeded in a stereocontrolled manner,
and the cis-fused products (13a-d) were isolated after preparative TLC purification as single Z-isomers, in
reasonable yields (36-56%, Table 1). Besides the elemental analyses, the spectroscopic results are fully
consistent with the structures of the new bicyclic products (13a-d). The two five-membered rings are cis-
1
fused. The conclusive structural evidence stems from H-NMR spectral data: the vicinal coupling
constants JXZ being alike (6.2-6.6 Hz) in all bicyclic structures (Table 1, Entries 2,4,6 and 8) closely
match those of comparable systems reported previously.12b,c In addition, the cis-geometry was also
supported by the H,H-ROESY experiment.
1
Table 1. Yields and selected H and 13C NMR chemical shifts (ppm) of 4-oxothiazolidine alcohols (12a-d) in DMSO-d6 and
bicyclic thiazolidine derivatives (13a-d) in CDCl3
HX
HX
6
S 1
5
S1
6a
5
2
HO
2
4 O 3a
HY
2'
2'
EWG
EWG
3
3
4
O
N
N
Me
Me
H
12a-d
13a-d
a
Entry
1
Compound/EWG
(Z)-12a /COPh
=CH
6.92
HX
HY
JXY (Hz)
C(2)
C(2')
∆δC2,C2'
66.0
Yield (%)
86
b
161.4
95.4
4.12
2
3
4
5
6
7
(Z)-13a /COPh
(Z)-12b /CO2Et
(Z)-13b /CO2Et
(Z)-12c /CONH(CH2)Ph
(Z)-13c / CONH(CH2)Ph
(Z)-12d /CN
6.04
5.57
4.84
5.55
4.67
5.27
3.94
4.12
5.67
5.61
5.55
5.65
6.5
6.2
6.2
6.6
165.7
158.5
162.9
166.1
166.0
160.4
160.8
87.5
89.4
79.6
93.2
82.2
67.1
55.8
78.0
69.1
83.3
72.9
83.8
93.3
105.0
56
92
36
78
40
80
40
b
4.12
4.10
b
b
3.97
4.06
4.41
4.25
8
a
(Z)-13d /CN
Yields refer to pure isolated products.
b
Part of an ABX spin-coupling system with protons of the neighboring methylene group.
Thus, the proton attached to C-6a of 13a which resonates at δ 4.12, assuming the β-orientation, exhibits
NOE interactions with H-3a and H-6 positioned at the β-face. From the H,H-ROESY spectrum of 13a the
correlation between the N-CH3 and vinyl proton confirmed the (Z)-configuration of the C=C bond. The
selected 13C NMR shift differences between the olefinic carbon atoms, i.e. ∆δC(2)C(2') values in compounds

HETEROCYCLES, Vol. 65, No. 11, 2005
2639
(12) and (13) are worth noting (Table 1). Larger ∆δC(2)C(2') values in the bicyclic derivatives (13a-d) from
78-105 ppm, respectively (Table 1, Entries 2,4,6 and 8) versus the corresponding ∆δC(2)C(2') values (66-93
ppm) in alcohols (12a-d) (Table 1, Entries 1,3,5 and 7) correlate with an increase of the push-pull effect16
in 13. An explanation is in accord with the presence of the more effective electron-donor (i.e. an amine)
in the fused thiazolidines (13) in comparison to an amide functionality in substrates (12).
Unequivocal evidence, for the cis-ring juncture stereochemistry and (Z)-configuration assigned to 13a-d,
was provided by an X-Ray crystal structure analysis of the representative of the series 13a (Figure 1b).
Figure 1a. Perspective view of the crystal structure of (Z)-(5- Figure 1b. Perspective view of the crystal structure of
ethoxycarbonylmethyl-3-methyl-4-oxothiazolidin-2-ylidene)-1-phe-
nylethanone (10a), showing the crystallographic numbering
scheme. Selected bond lengths (Å): C2-N3 1.388(2), C2-C21
1.358(2), N3-C4 1.378(2), C4-O41 1.220(2), C4-C5 1.512(2), C21-
C22 1.446(2). The S1…O21 non-bonded distance is 2.605(1) Å.
(Z)-2-(3-methyltetrahydrofuro[2,3-d]thiazol-2(3H)-yli-
dene)-1-phenylethanone (13a). Selected bond lengths
(Å): C2-N3 1.347(2), C2-C9 1.381(2), N3-C4 1.451(2),
C4-O8 1.420(2), C4-C5 1.544(2), C9-C10 1.426(2).
Compound (13a) crystallizes in the space group P21/c, but with two molecules in the asymmetric unit.
Figure 2 shows a perspective view of one molecule with selected bond lengths. The thiazolidine ring is
almost planar (mean deviation from the meanplane = 0.013 and 0.18 Å, for the two independent
molecules) as a consequence of containing an unsaturated linkage. The conformation of the side chain is
similar to that in 10a (Figure 1), although the non-bonded S-O distance10,17 has increased slightly to
2.724(1) and 2.729(1) Å, for the two independent molecules.
In accordance with the spectroscopic results, semiempirical calculations with MOPAC (PM3, geometry
optimisation) and ab initio calculations with Gaussian (HF, 6-31G*, geometry optimisation) show that the
cis-isomers (13a-d) are preferred from an energetic point of view. As exemplified for 13a, the cis-isomer
is 19.5 kcal more stable in comparison to the trans-analog. (Figure 2).
trans-Isomer (13a)
cis-Isomer (13a)
Figure 2. The cis- and trans-configurations of 13a

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HETEROCYCLES, Vol. 65, No. 11, 2005
The large energy difference is attributed to severe angle strain imposed upon a trans-fusion of the almost
flat thiazolidine ring to the tetrahydrofuran ring. As a result, the thiazolidine ring in the trans-fused com-
pound (13a) is forced to adopt a relatively nonplanar conformation, where there is no optimal conjugation
between nitrogen (and sulfur) and EWG through the intervening C=C bond. Release of the angle strain-
constraint in the cis-arrangement of the two five-membered rings, in combination with the resonance ef-
fect attenuation, is responsible for this exclusive lower energy configuration of the cis-isomer (13a).
Based on numerous regioselective hydride reduction of ring-substituted cyclic imides to hydroxy lac-
tams,1,18 it is clear that the reduction of 4-oxothiazolidine alcohols (12) with NaBH4 in ethanol leads, in a
first step, to in situ formation of a diol (14) (Scheme 3).
H
S
S
S
HO
HO
HO
EWG
EWG
12a-d
EWG
O
N
N
N
H
Me
Me
Me
14a-d
15a-d
13a-d
E
E
S
S
15a
13a
EWG
O
EWG
EtOH
N
N
Me
Me
10a
16a
E = CO2Et,
Base
EWG = COPh
E
E
E
S
S
S
EWG
EWG
EWG
HO
EtO
N
N
N
Me
Me
Me
19a
17a
18a
Scheme 3
This step sets the stage for the conversion of the diol (14) into the vinylogous N-methyliminium ion (15),
with hydroxyethyl group at the C(5)-position as a reactive nucleophile. Subsequent 5-exo-trig heterocycli-
zation by nucleophilic attack onto the iminium π-bond affords the cis-fused tetrahydrofurothiazolidine
(13). In general, it has been found that N-acyliminium ion cyclization gives rise to a lower yield if the
iminium carbon atom is bonded to a carbon-carbon double or triple bond.19 Our experimental results
indicate that ring closure of vinylogous methyliminium ion (15) is assisted by the electron-withdrawing
group at the α-carbon atom of the exocyclic C=C bond. The aforementioned cis-disposition of the angular
hydrogens in the transition-state structure and in the product (13) involves the minimization of angular
strain, thus dictating the stereochemical course of the reaction. The evidence regarding the postulated
iminium ion (15) as a key intermediate has been also obtained in direct heterocyclization of the N-methyl-
4-oxothiazolidine (10a) to 13a (21% yield) under reductive conditions (Scheme 2). The formation of by

HETEROCYCLES, Vol. 65, No. 11, 2005
2641
products, 3-methylthiazole derivative (17a) (18%) and 4-ethoxy-3-methylthiazolidine derivative (18a) (1-
2%), is consistent with the presence of 16a as a transient species, thereby also leading to 13a via 15a.
Another distinct pathway to the double enamine species (17a), involves dehydration of a hydroxythiazoli-
dine (19a), obtained by initial hydride reduction of 10a, thus, reducing the yield of cyclization product
(13a).19
CONCLUSION
In summary, the study on the intramolecular heterocyclization of (Z)-5-(2-hydroxyethyl)-3-methyl-4-oxo-
thiazolidines, giving rise to new stereodefined tetrahydrofuro[2,3-d]thiazole derivatives, has been presen-
ted. This transformation, involving the activated vinylogous N-methyliminium ion, possessing the hydro-
xyethyl group as the internal nucleophile and different electron-withdrawing groups at the α-position of
the exocyclic C=C bond, represents the new extension of the iminium ion chemistry with the potential to-
ward synthesis of other bicylic thiazolidine derivatives of synthetic and biological relevance.
EXPERIMENTAL
Melting points were determined on a Micro-Heiztisch Boetius PHMK apparatus or Bhchi apparatus and
are uncorrected. The IR spectra were recorded on a Perkin-Elmer FT-IR 1725X spectrophotometer and
are reported as wave numbers (cm-1). Samples for IR spectral measurements were prepared as KBr disks.
13
The NMR spectra were obtained using a Varian Gemini 2000 instrument (1H at 200 MHz, C at 50.3
MHz). 13C NMR resonance assignments were aided by the use of the DEPT technique to determine
numbers of attached hydrogens. The 2D ROESY have been performed on a Bruker Avance 500 NMR
spectrometer. Chemical shifts are reported in parts per million (ppm) on the δ scale from TMS as an
internal standard in the solvents specified. Low-resolution MS spectra were recorded using a Finnigan
MAT 8230 BE spectrometer at 70 eV (EI). Isobutane was used as the ionizing gas for the chemical
ionization (CI) mass spectra. The UV spectra were measured on a Beckman DU-50 spectrophotometer.
Analytical thin-layer chromatography (TLC) was carried out on Kieselgel G nach Stahl, and the spots
were visualized by iodine. Column chromatography was carried out on SiO2 (silica gel 60Å, 12-26, ICN
Biomedicals). Elemental analyses were performed at the microanalysis laboratory at the Department of
Chemistry, University of Belgrade.
General procedure for the preparation of 3-methyl-4-oxothiazolidine alcohols (12a-d)
To a stirred solution of 4-oxothiazolidine alcohol (11) (0.5 mmol) and K2CO3 (69 mg, 0.5 mmol) in dry
acetone (3-5 mL), protected by aluminum foil, a 10% molar excess of MeI (78 mg, 0.55 mmol) in acetone
(~ 1-1.5 mL) was added in one portion at rt. The progress of the reaction was followed by TLC. The

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HETEROCYCLES, Vol. 65, No. 11, 2005
reaction mixture was refluxed for an additional 1-2.5 h until consumption of starting material. After
evaporation of solvent under reduced pressure, the crude residue was purified by column chromatography
(silica gel; toluene/ethyl acetate gradient 100:0 to 50:50, v/v) to afford 3-methyl-4-oxothiazolidine
alcohols (12). Annalytically pure sample was obtained by crystallization from toluene in the case of 12a,
12b and 12d or from chloroform/n-hexane mixture for 12c.
(Z)-5-(2-Hydroxyethyl)-3-methyl-4-oxothiazolidin-2-ylidene)-1-phenylethanone (12a).
The title compound was obtained as a white solid in 86% yield (90 mg) from 100 mg (0.38 mmol) of 11a
and 60 mg (0.027 mL, 0.42 mmol) of methyl iodide. mp 134-135 °C; IR (KBr): νmax 3412, 3065, 2922,
1
2865, 1690, 1626, 1575, 1510, 1464, 1423, 1349, 1225, 1128, 1052, 695, 632 cm-1; H NMR (DMSO-
d6): δ 1.75-1.93 (1H, m, CHAHBCHXS), 2.16-2.31 (1H, m, CHAHBCHXS; the coupling constants of HA
and HB protons were not determined as signals are of higher order and structure elucidation being already
unequivocal), 3.27 (3H, s, NCH3), 3.59 (2H, m, CH2OH), 4.12 (1H, dd, JAX=4.8 Hz, JBX=4.2 Hz,
CHAHBCHXS), 4.80 (1H, br t, OH), 6.92 (1H, s, =CH), 7.47-7.63 (3H, m, p-Ph and m-Ph), 7.83 (2H, dd,
13
Jo,m=7.8 Hz; Jo,p=1.8 Hz, o-Ph); C NMR (DMSO-d6): δ 30.4 (NCH3), 35.9 (CHAHB), 42.8 (CHX), 58.5
(CH2OH), 95.4 (=CH), 127.7 (m-Ph), 128.8 (o-Ph), 132.4 (p-Ph), 138.5 (C1-Ph), 161.4 (C=), 175.3
(COlactam), 187.5 (COketone); MS (CI): m/z 278 (M+ + 1); UV (DMSO): λmax (ε) 333.9 nm, (33,600). Anal.
Calcd for C14H15NO3S: C, 60.63; H, 5.45; N, 5.05; S, 11.56; Found: C, 60.58; H, 5.48; N, 5.12; S, 11.80.
Ethyl (Z)-(5-(2-Hydroxyethyl)-3-methyl-4-oxothiazolidin-2-ylidene)ethanoate (12b).
The title compound was obtained as a white solid in 92% yield (49 mg) from 50 mg (0.22 mmol) of 11b
and 34 mg (0.015 mL, 0.24 mmol) of methyl iodide. mp 87-89 °C; IR (KBr): νmax 3352, 3065, 2975, 2931,
1711, 1684, 1575, 1472, 1366, 1333, 1279, 1175, 1122, 1044, 862, 791, 768 cm-1; 1H NMR (DMSO-d6):
δ 1.20 (3H, t, J=7.2 Hz, CH2CH3) 1.69-1.87 (1H, m, CHAHBCHXS), 2.13-2.28 (1H, m, CHAHBCHXS; the
coupling constants of HA and HB protons were not determined as signals are of higher order and structure
elucidation being already unequivocal), 3.07 (3H, s, NCH3) 3.55 (2H, m, CH2OH), 4.09 (2H, q, J=7.2 Hz,
CH2CH3), 4.12 (1H, dd, HX; JAX and JBX cannot be determined as the signal is buried below the quartet
centered at δ 4.09), 4.78 (1H, t, J=5.0 Hz, OH), 5.57 (1H, s, =CH), 13C NMR (DMSO-d6): δ 14.5
(CH2CH3), 30.0 (NCH3), 36.1 (CHAHB), 43.3 (CHX), 58.5 (CH2OH), 59.4 (CH2CH3), 89.4 (=CH), 158.5
(C=), 167.1 (COester), 175.2 (COlactam); MS (CI): m/z 245 (M+ + 1); UV (DMSO): λmax (ε) 282.4 nm,
(22,600). Anal. Calcd for C10H15NO4S: C, 48.96; H, 6.16; N, 5.71; S, 13.07; Found: C, 48.95; H, 6.15; N,
5.74; S, 13.35.
(Z)-(5-(2-Hydroxyethyl)-3-methyl-4-oxothiazolidin-2-ylidene)-N-(2-phenylethyl)ethanamide (12c).
The title compound was obtained as a white solid in 78% yield (40 mg) from 49 mg (0.16 mmol) of 11c
and 25 mg (0.011 mL, 0.18 mmol) of methyl iodide. mp 145-146 °C; IR (KBr): νmax 3348, 3074, 3026,
2923, 2882, 1685, 1640, 1581, 1545, 1475, 1423, 1332, 1298, 1213, 1128, 1128, 1075, 807, 780, 735, 701

HETEROCYCLES, Vol. 65, No. 11, 2005
2643
1
cm-1; H NMR (DMSO-d6): δ 1.62-1.79 (1H, m, CHAHBCHXS), 2.01-2.25 (1H, m, CHAHBCHXS; the
coupling constants of HA and HB protons were not determined as signals are of higher order and structure
elucidation being already unequivocal the coupling constants of HA and HB protons cannot be determined
as signals are of higher order), 2.72 (2H, J=7.2 Hz, CH2Ph), 3.02 (3H, s, NCH3) 3.30 (2H, m, CH2NH),
3.54 (2H, m, CH2OH), 3.97 (1H, dd, JAX=9.6 Hz, JBX=3.7 Hz, CHAHBCHXS), 4.73 (1H, br t, J=5.2 Hz,
13
OH), 5.58 (1H, s, =CH), 7.20-7.33 (5H, m, Ph), C NMR (DMSO-d6): δ 29.6 (NCH3), 35.4 (CHAHB),
36.4 (CH2Ph), 40.0 (CH2NH), 42.4 (CHX), 58.3 (CH2OH), 93.2 (=CH), 126.0 (p-Ph), 128.3 (o-Ph), 128.6
(m-Ph), 139.5 (C1-Ph), 151.4 (C=), 166.1 (COamide), 174.5 (COlactam); MS (CI): m/z 245 (M+ + 1); UV
(DMSO): λmax (ε) 282.4 nm, (22,200). Anal. Calcd for C16H20N2O3S: C, 59.98; H, 6.29; N, 8.74; S, 10.01;
Found: C, 59.94; H, 6.20; N, 8.57; S, 10.07.
(Z)-(5-(2-Hydroxyethyl)-3-methyl-4-oxothiazolidin-2-ylidene)ethanenitrile (12d)
The title compound was obtained as a white solid in 80% yield (43 mg) from 50 mg (0.27 mmol) of 11d
and 42 mg (0.019 mL, 0.30 mmol) of methyl iodide. mp 106-107 °C; IR (KBr): νmax 3466, 3076, 2948,
2888, 2203, 1718, 1585, 1424, 1374, 1317, 1121, 914, 723 cm-1; 1H NMR (DMSO-d6): δ 1.78-1.96 (1H,
m, CHAHBCHXS), 2.17-2.32 (1H, m, CHAHBCHXS; the coupling constants of HA and HB protons were
not determined as signals are of higher order and structure elucidation being already unequivocal), 3.04
(3H, s, NCH3) 3.50-3.60 (2H, m, CH2OH), 4.41 (1H, dd, JAX=9.8 Hz and JBX=3.8 Hz, CHAHBCHXS), 4.82
13
(1H, t, J=5.0 Hz, OH), 5.27 (1H, s, =CH); C NMR (DMSO-d6): δ 29.7 (NCH3), 35.7 (CHAHB), 45.7
(CHX), 58.5 (CH2OH), 67.1 (=CH), 118.0 (CN), 160.4 (C=), 174.4 (COlactam); MS (CI): m/z 199 (M+ + 1);
UV (DMSO): λmax (ε) 273.4 nm, (19,000). Anal. Calcd for C8H10N2O2S: C, 48.47; H, 5.08; N, 14.13; S,
16.17; Found: C, 48.36; H, 5.06; N, 14.07; S, 16.33.
General procedure for the preparation of (Z)-2-(3-methyltetrahydrofuro[2,3-d]thiazol-2-ylidene de-
rivatives (13a-d)
To a solution containing 0.1 mmol of N-methyl-4-oxothiazolidine alcohol (12) in 5 mL of dry ethanol, 8.7
mg (0.23 mmol) of NaBH4 in 5 mL of ethanol was added dropwise (~10 min) with vigorous stirring at rt.
After the addition was complete, the yellow reaction mixture was stirred for an additional 4 h until
complete disappearance of starting material (TLC), whereupon the solution became colorless. The
mixture was concentrated under reduced pressure to a small volume (~2 mL). Then, a 5% aqueous
solution of ammonium chloride was added, followed by CHCl3 and the stirring was continued for 30 min.
The aqueous layer was extracted with CHCl3 and combined organic fractions were washed with water,
dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by thin-layer
chromatography (toluene/ethyl acetate as eluant; 40:60, v/v). Analytically pure samples (13a-d) were
obtained by crystallization from n-hexane (13b and 13d) or n-hexane/toluene mixture (13a and 13c).

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HETEROCYCLES, Vol. 65, No. 11, 2005
HA
HB
HX
1
S
HQ
HZ
6
6a
5
2
O 3a
2'
EWG
3
N
4
HY
CH3
H
13a-d
cis-(Z)-(3-Methyltetrahydrofuro[2,3-d]thiazol-2(3H)-ylidene)-1-phenylethanone (13a)
The title compound was obtained as a white solid in 56% yield (14.7 mg) from 29 mg (0.1 mmol) of 9a.
mp 121-122 °C; IR (KBr): νmax 3053, 2974, 2939, 1602, 1571, 1525, 1433, 1355, 1264, 1213, 1084, 1061,
1
1028, 973, 801, 727, 691 cm-1; H NMR (DMSO-d6): δ 2.12 (1H, br dd, JAB=12.6 Hz, JAQ=4.8 Hz,
JAX=0.9 Hz, JAZ=1.0 Hz, CHAHBCHXS), 2.33 (1H, ddt, JAB= 12.9 Hz, JBQ=11.1 Hz, JBX=JBZ=7.4 Hz,
CHAHBCHXS), 3.10 (3H, s, NCH3), 3.83 (1H, ddd, JBQ=11.1 Hz, JQZ =8.8 Hz, JAQ =5.0 Hz, CHQHZO),
4.02 (1H, ddd, JQZ=8.8 Hz, JBZ=7.4 Hz, JAZ =1.0 Hz, CHQHZO), 4.12 (1H ddd, 1H, JBX=7.4 Hz, JXY=6.6
Hz, JAX=0.9 Hz, OCHYCHXS), 5.67 (1H, d, JXY=6.6 Hz, OCHYCHXS), 6.08 (1H, s, =CH), 7.36-7.47 (3H,
m, m- and p-Ph), 7.90-7.95 (2H, m, o-Ph) the simulated coupling constants, determined by PERCH NMR
software21 are in perfect agreement with these assigned by H,H-COSY; 13C NMR (CDCl3): δ 33.7
(NCH3), 35.2 (CHAHB), 44.6 (CHX), 65.8 (CHQHZ), 87.5 (=CH), 99.1 (CHY), 127.2 (m-Ph), 128.2 (o-Ph),
131.0 (p-Ph), 139.7 (C1-Ph), 165.7 (C=), 186.9 (COketone); MS (EI, 70 eV): m/z (rel. intensity): 261 (M+,
57), 260 (100), 245 (34), 191 (20), 184 (42), 163 (32), 105 (97), 86 (39), 82 (58), 51 (26); UV (DMSO):
λmax (ε) 338.0 nm (19,700); Anal. Calcd for C14H15NO2S: C, 64.34; H, 5.78; N, 5.36; S, 12.27; Found: C,
64.24; H, 5.82; N, 5.30; S, 12.59.
cis-(Z)-Ethyl (3-methyltetrahydrofuro[2,3-d]thiazol-2(3H)-ylidene)ethanoate (13b)
The title compound was obtained as a white solid in 36% yield (20 mg) from 60 mg (0.25 mmol) of 9a.
mp 48-49 °C; IR (KBr): νmax 3068, 2976, 2948, 2884, 1672, 1567, 1437, 1367, 1243, 1156, 1092, 1046,
1000, 963, 896, 779, 713 cm-1; 1H NMR (DMSO-d6): δ 1.26 (3H, t, J=7.1 Hz, CH2CH3) 2.11 (1H, br dd,
JAB=12.9 Hz, JAQ=4.9 Hz, JAX~0 Hz, JAZ=1.0 Hz, CHAHBCHXS), 2.29 (1H, ddt, JAB= 12.9 Hz, JBQ=11.0
Hz, JBX=JBZ=7.2 Hz, CHAHBCHXS), 2.94 (3H, s, NCH3), 3.83 (1H, ddd, JBQ=11.0 Hz, JQZ =8.6 Hz, JAQ
=4.9 Hz, CHQHZO), 3.98 (1H, ddd, JQZ=8.6 Hz, JBZ=7.2 Hz, JAZ =1.0 Hz, CHQHZO), 4.10 (1H dd, 1H,
JBX=7.2 Hz, JXY=6.2 Hz, OCHYCHXS), 4.15 (2H, q, J=7.2 Hz, CH2CH3), 4.84 (1H, s, =CH), 5.61 (1H, d,
JXY=6.2 Hz, OCHYCHXS); 13C NMR (CDCl3): δ 14.5 (CH2CH3), 33.0 (NCH3), 35.3 (CHAHB), 44.4
(CHX), 59.1 (CH2CH3), 65.6 (CHQHZ), 79.6 (=CH), 99.5 (CHY), 162.9 (C=), 169.1 (COester); MS (CI):
230 (M++ 1)); UV (DMSO): λmax (ε) 279.0 nm (23,400); Anal. Calcd for C10H15NO3S: C, 52.38; H, 6.59;
N, 6.11; S, 13.98; Found: C, 52.24; H, 6.61; N, 6.07; S, 14.00.
cis-(Z)-(3-Methyltetrahydrofuro[2,3-d]thiazol-2(3H)-ylidene)-N-(2-phenylethyl)ethanamide (13c)

HETEROCYCLES, Vol. 65, No. 11, 2005
2645
The title compound was obtained as a white solid in 40% yield (28 mg) from 75 mg (0.23 mmol) of 12c.
mp 151-153 °C; IR (KBr): νmax 3303, 3063, 3026, 2925, 2875, 1627, 1561, 1436, 1383, 1254, 1196, 1082,
1028, 989, 778, 750, 703 cm-1; 1H NMR (DMSO-d6): δ 2.10 (1H, br dd, JAB=12.6 Hz, JAQ=5.0 Hz, JAX~0
Hz, JAZ=1.2 Hz, CHAHBCHXS), 2.26 (1H, ddt, JAB= 12.6 Hz, JBQ=10.7 Hz, JBX=JBZ=7.2 Hz,
CHAHBCHXS), 2.83 (2H, t, J=7.0 Hz, CH2Ph), 2.88 (3H, s, NCH3), 3.56 (2H, m, J=7.0 and 6.2 Hz,
CH2NH), 3.86 (1H, ddd, JBQ=10.8 Hz, JQZ =8.6 Hz, JAQ =5.0 Hz, CHQHZO), 3.95 (1H, ddd, JQZ=8.6 Hz,
JBZ=7.2 Hz, JAZ =1.2 Hz, CHQHZO), 4.06 (1H dd, 1H, JBX=7.2 Hz, JXY=6.2 Hz, OCHYCHXS), 4.67 (1H,
s, =CH), 5.55 (1H, d, JXY=6.2 Hz, OCHYCHXS), 7.19-7.30 (5H, m, Ph); 13C NMR (CDCl3): δ 29.6
(NCH3), 35.3 (CHAHB), 36.3 (CH2Ph), 40.5 (CH2NH), 44.6 (CHX), 65.6 (OCH2), 82.3 (=CH), 99.1 (CHY),
126.3 (p-Ph), 128.5 (o-Ph), 128.9 (m-Ph), 139.5 (C1-Ph), 166.0 (C=), 162.1 (COamide); MS (ESI): Calcd
for C16H20N2O2S: 305.13182 (M + H+); Found: 305.1318; UV (DMSO): λmax (ε) 277.0 nm (12,900).
cis-(Z)-(3-Methyltetrahydrofuro[2,3-d]thiazol-2(3H)-ylidene)ethanenitrile (13d)
The title compound was obtained as a white solid in 40% yield (7.5 mg) from 20 mg (0.1 mmol) of 12d.
mp 59-61 °C; IR (KBr): νmax 3061, 2927, 2860, 2187, 1578, 1423, 1395, 1310, 1259, 1092, 1034, 964,
1
896, 859, 691 cm-1; H NMR (DMSO-d6): δ 2.12 (1H, br dd, JAB=13.3 Hz, JAQ=5.1 Hz, JAX=1.0 Hz,
JAZ=1.1 Hz, CHAHBCHXS), 2.32 (1H, ddt, JAB= 13.3 Hz, JBQ=11.0 Hz, JBX=JBZ=7.4 Hz, CHAHBCHXS),
2.88 (3H, s, NCH3) 3.88 (1H, ddd, JBQ=11.0 Hz, JQZ =8.9 Hz, JAQ =5.1 Hz, CHQHZO), 3.94 (1H, s, =CH),
4.04 (1H, ddd, JQZ=8.9 Hz, JBZ=7.4 Hz, JAZ =1.2 Hz, CHQHZO), 4.25 (1H, ddd, JXY=6.6 Hz, JBX=7.4 Hz,
JAX=1 Hz, CHAHBCHXS), 4.82 (1H, t, J=5.0 Hz, OH), 13C NMR (DMSO-d6): δ 29.7 (NCH3), 35.7
(CHAHB), 45.7 (CHX), 58.5 (CH2OH), 67.1 (=CH), 118.0 (CN), 160.4 (C=), 174.4 (COlactam); MS (CI):
m/z 199 (M+ + 1); UV (DMSO): λmax (ε) 264.0 nm, (26,100). Anal. Calcd for C8H10N2OS: C, 52.7; H,
5.53; N, 15.37; S, 17.59; Found: C, 52.77; H, 5.59; N, 15.06; S, 17.56.
Crystal structure determination of compounds (10a) and (13a)
Data were collected with a Siemens SMART CCD area detector, using graphite monochromatized MoKα
radiation (λ = 0.71073 Å). The structures were solved by direct methods using SHELXS21 and refined on
F2, using all data, by full-matrix least-squares procedures using SHELXTL.22 Hydrogen atoms were
included in calculated positions, with isotropic displacement parameters 1.2 times the isotropic equivalent
of the carrier carbons. Full tables of atom coordinates, thermal parameters, and bond lengths and angles
have been deposited at the Cambridge Crystallographic Data Centre. CCDC 265572 and 265573 contains
the supplementary crystallographic data for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: (internat.)
deposit@ccdc.cam.ac.uk].
+
44-1223/336-033; Email:

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HETEROCYCLES, Vol. 65, No. 11, 2005
ACKNOWLEDGMENT
Partial financial support by the Ministry of Science, Technology and Development of the Republic of
Serbia, grant no. 1709 (to R.M.), is acknowledged. We thank Jurg Thielemann for PERCH-NMR
simulation and theoretical calculations.
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