High regioselectivity in the heterocyclization of β-oxonitriles to 4-oxothiazolidines: X-ray structure proof

Article abstract of DOI:10.1016/S0040-4020(03)01146-3

Base-catalyzed reactions of β-oxonitriles 1 with diethyl mercaptosuccinate favour heterocyclization to afford 2-alkylidene-4-oxothiazolidines 3, rather than 2-alkylidene-4-oxo-1,3-thiazinanes 4. The observed regioselectivity is based on spectroscopic and experimental evidence, including a single-crystal X-ray structure determination.

Full text of DOI:10.1016/S0040-4020(03)01146-3

Tetrahedron 59 (2003) 7803–7810
High regioselectivity in the heterocyclization of b-oxonitriles to
4-oxothiazolidines: X-ray structure proof
a,b
a,b
b
b
,
*
´
Rade Markovic,
´
ˇ
Marija Baranac, Zdravko Dzambaski, Milovan Stojanovic
and Peter J. Steelc
aFaculty of Chemistry, University of Belgrade, Studentski trg 16, P.O. Box 158, 11001 Belgrade, Serbia and Montenegro
bCenter for Chemistry ICTM, P.O. Box 815, 11000 Belgrade, Serbia and Montenegro
cDepartment of Chemistry, University of Canterbury, P.O. Box 4800 Christchurch, New Zealand
Received 29 April 2003; revised 24 June 2003; accepted 17 July 2003
Abstract—Base-catalyzed reactions of b-oxonitriles 1 with diethyl mercaptosuccinate favour heterocyclization to afford 2-alkylidene-4-
oxothiazolidines 3, rather than 2-alkylidene-4-oxo-1,3-thiazinanes 4. The observed regioselectivity is based on spectroscopic and
experimental evidence, including a single-crystal X-ray structure determination.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
on push–pull 4-oxothiazolidines, reported here is: (i) a
detailed study of the regioselectivity and stereochemistry in
the reaction of b-oxonitriles 1 with a and b-mercapto esters;
(ii) the stereochemical assignment of the title compounds 3
is confirmed by an X-ray crystallographic analysis carried
out on (Z)-(5-ethoxycarbonylmethyl-4-oxothiazolidin-2-
ylidene)ethanoate (3d); (iii) finally, the optimized procedure
to obtain compounds 3 in improved yields is presented.
The widespread occurrence and diverse biological activity
of thiazolidine-containing natural products have initiated
the development of numerous methods for their synthesis.1,2
They are also useful intermediates for the synthesis of
different heterocyclic compounds.2a,3
Heterocycles synthesized from functionalized thiazolidines
include benzothiophene derivatives,4 indenothiophenes5
and 2,1-benzisothiazole derivatives.6 We have reported
recently a one-pot cyclization reaction leading to a range of
new 2-alkylidene-4-oxothiazolidines 3 from diethyl mer-
captobutandioate and activated nitriles 1 (Scheme 1).7
These functionalized heterocycles having the b-enamino-
carbonyl moiety are formed through the addition–cycliza-
tion reaction sequence shown in Scheme 1. A plausible
intermediate 2, generated in situ, possessing two electro-
philic and two nucleophilic centres, could in turn direct
intramolecular cyclization toward formation of four hetero-
cycles, i.e. 4-oxothiazolidine derivative 3, 4-oxo-1,3-
thiazinane derivative 4, or a derivative of tetrahydrothio-
phene 5 and/or tetrahydrothiopyran 6, as well as other
macrocyclic compounds. However, the exclusive formation
of oxothiazolidine enamino derivatives 3 in low to moderate
yields (24–68%) is observed without any detectable traces
of compounds 4–6.
2. Results and discussion
2.1. Mechanistic aspects and spectroscopic properties
There is a distinct similarity between the isolated 2-alkyl-
idene-4-oxothiazolidine derivatives 3a-d and 2-alkylidene-
4-oxothiazinane derivatives 4a-d as possible products. The
1H NMR sharp signal within the range of ,5.40–6.90 ppm
and a singlet between ,9 and 12 ppm for all compounds
examined (Table 1), indicate, regardless of the ring size, the
presence of the olefinic proton of a trisubstituted CvC bond
and the lactam proton, respectively. In addition, the shift
values of the NH protons fit either structure 3 or 4, but rule
out the heterocycles 5 and 6 or the tautomers 5A and 6A,
including other possible tautomers as well.
The singlet in the 13C NMR spectra between 89 and 95 ppm
(Table 2) is assigned by the DEPT technique to the C(20)
atom of the CvC exocyclic bond, whereas three resonances
(,167–188 ppm) in each compound suggest the presence
of three carbonyl groups. The lowest field signal in the 13C
NMR spectra of all 4-oxothiazolidinones 3a-c at
187.77 ppm, indicates a conjugated keto carbonyl function
As a continuation of our mechanistic and synthetic studies
Keywords: regiospecificity; cyclisation; thiazolidines.
*
Corresponding author. Tel.: þ381-11-3282-111x741; fax: þ381-11-636-
061; e-mail: markovic@helix.chem.bg.ac.yu
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01146-3

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R. Markovic et al. / Tetrahedron 59 (2003) 7803–7810
7804
Scheme 1.
Table 1. Selected 1H chemical shifts (ppm) of cyclic derivatives 3a (R¼Ph), 3b (R¼NHPh), 3c (R¼NHCH2CH2Ph) and 3d (R¼OEt)
Compound
C(20)H
NH(ring)
C(50)HA
C(50)HB
C(5)HX
(Z)-3a
(CDCl3)
(Z)-3b
(DMSO-d6)
(Z)-3c
(DMSO-d6)
(Z)-3d
(DMSO-d6)
6.85 (s)
5.79 (s)
5.55 (s)
5.44 (s)
9.88 (s)
3.00 (dd)
JAB¼17.5 Hz, JAX¼8.2 Hz
3.15 (dd)
JAB¼17.5 Hz, JBX¼4.3 Hz
4.22 (dd)
JAX¼8.2 Hz, JBX¼4.3 Hz
4.19 (dd)
11.58 (s)
11.30 (s)
11.60 (s)
2.92 (dd)
JAB¼17.5 Hz, JAX¼8.0 Hz
2.85 (dd)
3.02 (dd)
JAB¼17.5 Hz, JBX¼4.6 Hz
2.97 (dd)
JAX¼8.0 Hz, JBX¼4.6 Hz
Not observable
JAB¼17.2 Hz, JAX¼8.4 Hz
JAB¼17.2 Hz, JBX¼4.3 Hz
2.95 (dd)
JAB¼17.6 Hz, JAX¼7.8 Hz
3.04 (dd)
JAB¼17.6 Hz, JBX¼4.6 Hz
4.28 (dd)
JAX¼7.8 Hz, JBX¼4.6 Hz
Table 2. Selected 13C NMR chemical shifts (ppm) of cyclic derivatives (Z)-3a-3c in DMSO-d6
0
Compound
CH2COO (in 3)
CHS
vCH
C(2)v
DdC2,C2
COexo
COring
COester
(Z)-3a
(Z)-3b
(Z)-3c
(Z)-3d
36.40
37.19
37.37
36.50
42.54
42.44
42.29
42.61
94.94
93.34
93.23
88.86
161.56
153.54
150.82
157.84
66.62
60.20
57.59
67.98
187.77
165.89
167.05
167.24
170.72
170.88
170.90
170.42
176.30
175.68
175.49
175.41
of the derivative 3a. The 13C NMR spectra of 5 (or 5A) and
6 (or 6A) are not compatible with these spectral features. In
nanes 4 was unequivocally established by the comparative
analysis of their mass spectrometric fragmentation patterns.
The appearance of the strong molecular ions and the most
significant peaks at m/z¼228, 182, 128, 73, and 55 in nearly
all spectra can be rationalized by the analogous fragmenta-
tion processes for compounds of the types 3 or 4. The
examination of the mass spectra also revealed the presence
of a peak at m/z¼87 in all isolated products which
1
accordance with this interpretation, the H and 13C NMR
spectra (vide infra) correspond to either compounds 3 or 4 to
the exclusion of the tautomers 3A or 4A.
The formation of the five-membered heterocyclic products 3
rather than the competing six-membered 4-oxo-1,3-thiazi-

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R. Markovic et al. / Tetrahedron 59 (2003) 7803–7810
7805
Scheme 2.
corresponds to composition C4H7O2. This fragment is
obviously formed by the loss of CH2COOC2H5 from the
molecular ion of the corresponding 4-oxothiazolidine-5-
acetate derivative 3. Therefore, if the isolated heterocycles
had been the (Z)-4-oxo-1,3-thiazinanes 4a-d, this fragment
would not have been detected.
the vinyl singlet at d 6.32 of the major (E)-3a isomer
showed, as expected, a NOE enhancement of the aromatic
region, but not the singlet at d 12.06 assigned to the lactam
proton of (E)-3a. It is noteworthy that no tautomeric imino
4-oxothiazolidines of type 3A are formed at all.11
2.2. Crystal structure of ethyl (Z)-(5-ethoxycarbonyl-
methyl-4-oxothiazolidin-2-ylidene)ethanoate (3d)
The structure assignment regarding the ring size in
heterocycles 3a-d is supported by the analysis of the
coupling constants of the diastereotopic CHAHB protons, as
shown explicitly for the (Z)-isomer 3d (Table 1).8 These
protons have different chemical shift values, i.e. 2.95 ppm
for HA, and 3.04 ppm for HB. The spectrum exhibits an
ABX spin-coupling system with significant geminal
coupling (2JAB¼17.6 Hz). The third proton HX with
chemical shift value of 4.28 ppm is split differently to the
vicinal methylene protons HA and HB (3JAX¼7.8 Hz;
3JBX¼4.6 Hz). The splitting pattern for each proton consists
of a doublet of doublets. The unequal vicinal couplings 3JAX
and 3JBX reflect hindered rotation around C(5)–C(50) due to
steric reasons. The value of 3JAX strongly suggests the five-
membered ring. In the case of the six-membered ring in a
conformation C of the hypothetical 4-oxo-1,3-thiazinane
derivative (Z)-4d, having nearly antiperiplanar protons HA
Figure 1 shows a perspective view of the X-ray crystal
structure of the thiazolidinone derivative 3d. The tautomeric
enamine form was definitively determined by location and
refinement of the NH hydrogen. The central thiazolidinone
˚
ring is planar (mean deviation from planarity¼0.014 A,
˚
maximum deviation 0.023 A). The molecular packing is
controlled by intermolecular hydrogen bonds between the
NH group and the C4 carbonyl of an adjacent molecule
related by a crystallographic two-fold screw axis
˚
˚
[H3· · ·O41¼2.00(3) A; N3· · ·O41¼2.765(2) A; N3–
H· · ·O41¼165(2)8].
3
and HX, the JAX should have a higher value (,11–13 Hz
for neighboring diaxial protons in cyclohexane derivatives).
Two conformers A and B are considered for (Z)-3d
(Scheme 2).
The dominant conformation A is relatively devoid of steric
congestion. In the less stable rotamer B, as seen by an
inspection of Dreiding models, the ester group at C(50)
experiences an unfavorable interaction with the lactam
carbonyl. Such destabilization can be avoided by rotation
around the C(5)–C(50) bond, leading to the dominant
rotamer A.
Figure 1. Perspective view of ethyl (Z)-(5-ethoxycarbonylmethyl-4-
oxothiazolidin-2-ylidene)ethanoate (3d), showing the crystallographic
numbering scheme.
With respect to the configuration of the double bond, one-
dimensional nuclear Overhauser effect measurements
showed that irradiation of the singlet at d 6.85 of the 3a
isomer (or 4a), immediately after dissolution in CDCl3,
gave an enhancement of 4.4% to the aromatic region and an
enhancement of 1.7% to the lactam proton singlet at d 8.88.
This is in agreement with the (Z)-configuration as the
correct assignment. Heterocycles 3a-d are obtained as pure
(Z)-diastereomers in ethanol as solvent. Classified as push–
pull alkenes due to the presence of electron-donating and
electron-withdrawing groups bonded to the intervening
CvC bond, they undergo facile Z/E isomerization in
nonpolar solvents.9,10 Thus, the NOE experiment was then
conducted 1 day later on a solution of the Z/E mixture,
containing about 85% of the (E)-3a isomer. Irradiation of
The X-ray analysis of derivative 3d proved the Z-configur-
ation of the double bond. The C2 side-chain is also
essentially coplanar with the five-membered ring which
brings O21 into close proximity with the sulfur atom
˚
(O21· · ·S1¼2.873(2) A). This distance is less than the sum
˚
of the van der Waals radii (3.22 A) but greater than that
previously observed in similar thiadiazolones.12
2.3. Reactions of b-oxonitriles with ethyl 3-mercapto-
propanoate
To verify the 100% regioselectivity of the base-catalyzed

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R. Markovic et al. / Tetrahedron 59 (2003) 7803–7810
7806
Scheme 3. Conditions: reactions conducted in 96% ethanol; molar ratio 1c/ester: 1/1.7 and 1d/ester: 1/3; reflux time: 11 h; catalyst: anh. K2CO3; the structures
of byproducts 11–14 are fully confirmed on the spectroscopic basis.
heterocyclization of b-oxonitriles 1 with diethyl mercapto-
succinate affording the 5-substituted-4-oxothiazolidine
derivatives 3 (Scheme 1, path a), the base-catalyzed
reactions of b-oxonitriles 1c and 1d with ethyl 3-mercapto-
propanoate were attempted (Scheme 3). If the adduct 8c was
formed in the first step of an addition-cyclization reaction
sequence with the cyano derivative 1c, then intramolecular
cyclization should give the 4-oxo-4H-1,3-thiazinane deriva-
tive 9c. Despite many attempts to obtain cyclic compound
presumably via the intermediate 8c, only simple acyclic
products 11–13 and unreacted nitrile 1c in 25% yield
(Scheme 3), accompanied by its ethanolysis products, were
isolated. The heterocyclization reaction responsible for the
formation of six-membered heterocycle 9c was completely
supressed at the expense of much faster side reactions. On
the other hand, in the reaction of the more reactive
b-oxonitrile 1d with the same b-mercaptoester, ethyl (E)-
(4-oxo-[1,3]thiazinan-2-ylidene)ethanoate (9d) was isolated
and fully characterized, however in very low yield (3%). In
this case, the expected intermediate, i.e. ethyl (Z)-3-amino-
3-(2-ethoxycarbonylethylsulfanyl)propenoate (8d) leading
to 9d, has been isolated for the first time, again in a
negligible amount (3%). Although the analogous primarily
formed addition adducts 2a-e depicted in Scheme 1 are not
isolable, they readily undergo intramolecular cyclization
only by path a, affording under kinetic control the five-
membered cyclization products 3a-e. This is again in accord
with the lesser cyclization tendency of intermediates 2a-e to
give the six-membered heterocycles 4a-e (path b) which
were never detected.
Finally, we turned our attention to improve low to modest
yields (24–54%) of the purified 4-thiazolidinone deriva-
tives 3a-d. Initial attempts toward the conversion of
b-oxonitriles 1a-d to 3a-d (Scheme 1) involved treatment
of the corresponding nitrile with diethyl mercaptosuccinate
in a 1/1 molar ratio, in boiling ethanol. Employing the
model substance 1c, the reaction gave, as depicted in
Scheme 4, cyclization product 3c in 40% yield, along with
products 12c, 15 and 16 by secondary processes.
After experimentation, it was found that the use of a large
molar excess of diethyl mercaptosuccinate relative to nitrile
derivative 1c (molar ratio 1c/mercapto derivative 1.00/1.73)
improved the yield of the cyclization product to 60%. Under
these conditions better yields (62–77%) were also obtained
with activated nitriles 1a-b and 1d (Table 3). A possible
explanation of the role of the mercapto derivative for the
increased yields, is that the increased concentration secures
at the same time sufficient quantity of mercaptodiester for
Scheme 4.

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R. Markovic et al. / Tetrahedron 59 (2003) 7803–7810
7807
Table 3. Molar ratio effect on yields of cyclization products 3a-d according
to Scheme 1
amount of K2CO3 was added (reagents for the starting
compounds 1 were obtained by standard procedure).
CAUTION. All reactions involving mercapto ester, due to
the unpleasant odor, should be carried out in a well-
ventilated hood. The mixture was brought to reflux and
reaction mixture was stirred for 2–9 h. The mixture was
cooled down to rt and the precipitated product was collected
by filtration, washed with ethanol and recrystallized from
96% ethanol to provide the final product 3a-e in 24–68%
yield. Alternatively the filtered solution was concentrated
under reduced pressure and the residue was chromato-
graphed (toluene/ethyl acetate, 10/0!1/10, v/v) affording
the desired cyclic product 3. The structural assignments of
all isolated products were made on the basis of spectro-
scopic data (IR, 1H and 13C NMR, MS, UV) and elemental
analysis. Compounds 3a-c were previously described.7a
Nitrile 1 Diester/1 mole ratio Reaction time (h) Product Yielda (%)
1a
1a
1b
1b
1c
1c
1d
1d
1.10
1.75
1.00
1.72
1.00
1.73
1.00
1.54
7
7
5
5
7.5
5
3a
3a
3b
3b
3c
3c
3d
3d
47
68
24
77
40
60
54
62
9
7
a
Purified products.
concurrent secondary reactions and heterocyclization. In the
case of very reactive malononitrile (1e) the yield of purified
thiazolidinone derivative 3e was quite good (68%) even
with the 1/1 molar ratio.
General procedure B. The above procedure was adopted
with the modification that a large excess of diethyl
mercaptosuccinate (,1.7 mmol) relative to b-oxonitrile
1a-d (1 mmol) was used, which improved the yield of
cyclization products to 60–77% (Table 3). The yields of all
products refer to purified compounds.
In conclusion, we have shown that among four possible
heterocycles 3–6, which on the grounds of mechanistic
consideration could be formed by the base-catalyzed
reaction of activated b-oxonitriles 1 with diethyl mercapto-
succinate in ethanol, the favoured formation of the
five-membered heterocyclic derivatives, i.e. (Z)-4-oxo-
thiazolidines 3 occurs without any detectable traces of
other heterocyclic compounds. Efficient heterocyclization is
kinetically controlled over the heterocyclization to 2-alkyl-
idene-4-oxo-1,3-thizinanes 4 and competing side reactions.
3.1.1. Ethyl (Z)-(5-ethoxycarbonylmethyl-4-oxothiazoli-
din-2-ylidene)ethanoate (3d). The title compound was
obtained as a white solid in 54% yield (3.47 g) from 4.98 g
(24.2 mmol) of diethyl mercaptosuccinate and 2.74 g
(24.2 mmol) of ethyl cyanoacetate according to procedure
A (reaction time 9 h). Mp 105–1068C; IR (KBr): nmax 3188,
3122, 3079, 2985, 1739, 1722, 1691, 1605, 1474, 1380,
1
1298, 1196, 1144, 1093, 1029, 817, 725, 676 cm21; H
3. Experimental
NMR (200 MHz, CDCl3): d 1.28 (6H, t, 2CH3, J¼7.2 Hz),
2.93 (1H, dd, HA, JAB¼17.3 Hz, JAX¼8.5 Hz), 3.13 (1H, dd,
HB, JAB¼17.3 Hz, JBX¼4.1 Hz), 4.19 (4H, q, 2CH2O,
J¼7.2 Hz), C(5)–H signal buried below the quartet
centered at d 4.19, 5.59 (1H, s, vCH(20)), 9.35 (1H, s,
NH); 13C NMR (50.3 MHz, DMSO-d6): d 14.16, 14.54,
36.50, 42.61, 59.29, 60.87, 88.86, 157.84, 167.24, 170.42,
175.41. Mass spectrum (EI) m/z (rel. intensity): 273 (Mþ,
11), 227 (46), 182 (22), 154 (100), 127 (14), 87 (15), 68
(15), 55 (21). Analytically pure sample was obtained by
crystallization of the isolated solid from a 4/1 ethanol/water
solvent mixture. Anal. calcd for C11H15NO5S: C, 48.30; H,
5.52; N, 5.12; S, 11.73. Found: C, 48.12; H, 5.35; N, 5.36; S,
11.95.
Melting points were determined on a Micro-Heiztisch
Boetius PHMK apparatus or Bu¨chi apparatus and are
uncorrected. The IR spectra were recorded on a Perkin–
Elmer FT-IR 1725X spectrophotometer and are reported as
wave numbers (cm21). Samples for IR spectral measure-
ments were prepared as KBr disks. The NMR spectra were
obtained using a Varian Gemini 2000 instrument (1H at
200 MHz, 13C at 50.3 MHz). 13C NMR resonance assign-
ments were aided by the use of the DEPT technique to
determine numbers of attached hydrogens. Chemical shifts
are reported in parts per million (ppm) on the d scale from
TMS as an internal standard in the solvents specified. Low-
resolution mass 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 chroma-
tography (TLC) was carried out on Kieselgel G nach Stahl,
and the spots were visualized by iodine. Column chroma-
3.1.2. Ethyl (E)-(5-ethoxycarbonylmethyl-4-oxothiazoli-
din-2-ylidene)ethanoate (3d). In the case of heterocycles
3a-d they are obtained as pure (Z)-diastereomers in ethanol
as solvent. Classified as push–pull alkenes due to the
interaction of the two electron-donating groups and
electron-withdrawing group through the intervening CvC
bond, they undergo facile Z/E isomerization in nonpolar
solvents. Thus, the Z/E mixture of 3d becomes progres-
sively enriched in more stable E-isomer (Table 4) during the
course of relatively slow isomerization process (,2–3
days) at rt. Accordingly, two sets of signals observed in the
1H NMR spectrum in CDCl3 are compatible with the
presence of both configurational isomers.
˚
tography was carried out on SiO2 (silica gel 60 A, 12-26,
ICN Biomedicals). Elemental analyses were performed at
the microanalysis laboratory at the Department of
Chemistry, University of Belgrade.
3.1. General procedure A for the preparation of
4-oxothiazolidine derivatives 3a-e
To a stirred suspension of activated b-oxonitrile 1a-e
(Scheme 1) and freshly distilled diethyl mercaptosuccinate
(,0–10% molar excess) in 5–10 mL of ethanol, a catalytic
1H NMR (200 MHz, CDCl3) for (E)-3d: d 1.27 (3H, t,
J¼7.0 Hz, CH3), 1.28 (3H, t, J¼7.0 Hz, CH3), 2.86 (1H, dd,

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R. Markovic et al. / Tetrahedron 59 (2003) 7803–7810
7808
Table 4. Z/E Isomerization data based on selected 1H NMR signals for (Z)-
3d and (E)-3d isomers in CDCl3
3.3. Heterocyclization of activated nitriles 1c and 1d with
ethyl 3-mercaptopropanoate
(Z)-3d
(E)-3d
Z/E ratio (%); time (days)
Heterocyclization of ethyl cyanoacetate (1d) with ethyl
3-mercaptopropanoate. A stirred suspension of ethyl
cyanoacetate (0.30 g, 2.65 mmol), ethyl 3-mercapto-
propanoate (0.61 g, 4.57 mmol) and a catalytic amount of
K2CO3 (0.02 g, 0.14 mmol) in ethanol (4 mL) was brought
to reflux. After stirring at reflux temperature for 7 h (TLC
showed incomplete reaction) the reaction mixture was
cooled down and upon evaporation under reduced pressure
to half of its original volume, potasium cyanoacetate
precipitated (0.036 g, 0.28 mmol, mp 176–1778C). The
solid was filtered off and concentration of the ethanol
solution left a pale-yellow residue (0.648 g), which was
chromatographed on silica gel (ca. 50 g). Elution with
toluene–EtOAc (solvent gradient 90/10–70/30, v/v) furn-
ished 0.29 g of the starting ester (48% of the total amount),
77 mg of ethyl cyanoacetate (26% of the total amount). The
following are characterizations of the remaining products.
NH
vCH(20)
9.35a
5.59
10.63
5.12
96/4 (after few minutes)
43/57 (2)
10/90 (6)
a
The chemical shift of the lactam proton in (Z)-3d is not fixed; in principle
an increase in the extent of intermolecular hydrogen bonding, which
depends on concentration, temperature and solvent, moves this proton to
lower field.
HA, JAB¼17.6 Hz, JAX¼9.8 Hz), 3.23 (1H, dd, HB,
JAB¼17.6 Hz, JBX¼3.5 Hz), 4.17 (2H, q, J¼7.0 Hz,
CH2O), 4.20 (2H, q, J¼7.0 Hz, CH2O), 4.27 (1H, dd, HX,
JAX¼9.8 Hz, JBX¼3.5 Hz), 5.12 (1H, s, vCH), 10.63 (1H,
s, NH).
3.2. Crystal structure determination of ethyl (Z)-(5-
ethoxycarbonylmethyl-4-oxothiazolidin-2-ylidene)-
ethanoate 3d
3.3.1. Ethyl 3-amino-3-(2-ethoxycarbonylethylsulfanyl)-
propenoate (8d). 22 mg (3%) as a yellow oil. IR (KBr) nmax
3413, 3311, 3198, 3030, 2982, 2922, 2870, 2822, 1732,
1662, 1601, 1529, 1448, 1376, 1347, 1252, 1155 cm21; 1H
NMR (DMSO-d6): d 1.16 (3H, t, J¼7.1 Hz, CH3), 1.19 (3H,
t, J¼7.1 Hz, CH3), 2.64 (2H, t, J¼6.9 Hz, CH2), 3.09 (2H, t,
J¼6.9 Hz, CH2), 3.99 (2H, q, CH2O, J¼7.1 Hz), 4.08 (2H,
q, J¼7.1 Hz, CH2O), 4.50 (1H, s, vCH), 7.67 (2H, broad s,
NH2); 13C NMR (DMSO-d6): d 14.2 (CH3), 14.7 (CH3),
25.3 (CH2S), 33.7 (CH2CO), 58.2 (CH2O), 60.5 (CH2O),
80.7 (vCH), 161.4 (Cv), 168.2 (CvCCO), 171.22 (CO);
MS (EI): m/z (rel. intensity): 247 (32) (Mþ), 202 (28), 174
(17), 156 (26), 147 (100), 134 (14), 114 (28), 101 (25), 86
(45), 73 (28), 61 (26).
Crystallographic data (excluding structure factors) for the
structure 3d in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 208829. Copies of the data can
be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK (fax: þ44-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk).
3.2.1. (5-Ethoxycarbonylmethyl-4-oxothiazoliodin-2-
ylidene) ethanonitrile (3e). The title compound was
obtained as a mixture of diastereomers as a white solid in
81% yield (4.70 g) from 5.28 g (25.6 mmol) of diethyl
mercaptosuccinate, 1.69 g (25.6 mmol) of freshly distilled
malononitrile and 0.19 g (1.39 mmol) of anh. K2CO3 in
ethanol (31 mL) according to procedure A (reaction time
,2 h). Purification of the crude product by crystallization
from ethanol afforded 3.92 g (68%) of thiazolidinone 3e as
small white needles, mp 142–1448C (melting point varies
depending on the ratio of isomers); IR (KBr): nmax 3164,
3131, 3075, 2994, 2933, 2827, 2210, 1737, 1712, 1620,
1383, 1282, 1223, 1192, 1157, 817, 746, 722 cm21. (Z)-3e
3.3.2. Ethyl (E)-(4-oxo-[1,3]thiazinan-2-ylidene)ethano-
ate (9d). 13 mg (3%) as a yellowish crystals, mp 66–678C.
IR (KBr): nmax 3195, 3073, 1689, 1656, 1583, 1445, 1366,
1230, 1188, 1155, 793 cm21; 1H NMR (DMSO-d6): d 1.19
(3H, t, J¼7.1 Hz, CH3), 2.85 (2H, m, CH2), 3.21 (2H, m,
CH2); the coupling constants of multiplets at 2.85 and
3.21 ppm cannot be determined as signals are of the higher
order and the chemical shifts are the centres of signals
resembling triplets; 4.10 (2H, q, J¼7.1 Hz, CH2O), 5.12
(1H, s, vCH), 11.11 (1H, s, NH); 13C NMR (DMSO-d6): d
14.4 (CH3), 23.0 (CH2S), 33.2 (CH2CO), 59.9 (CH2O), 90.1
(vCH), 154.5 (Cv), 167.4 (CvCCO), 168.1 (CO).; MS
(EI): m/z (rel. intensity): 201 (62) (Mþ), 173 (10), 156 (33),
129 (75), 55 (100); UV (DMSO): lmax (1) 298.4 nm
(17900). Anal. calcd for C8H11NO3S: C, 47.75; H, 5.51;
N, 6.96; S, 15.93. Found: C, 48.06; H, 5.63; N, 6.92; S,
15.88.
1
isomer: H NMR (DMSO-d6): d 1.19 (3H, t, J¼7.1 Hz,
CH3), 3.05–3.08 (2H, m, JAX¼6.9 Hz, JBX¼5.3 Hz,
CH2COO; chemical shifts of HA and HB protons are very
close and JAB cannot be determined), 4.10 (2H, q,
J¼7.1 Hz, CH2O), 4.59 (1H, dd, JAX¼6.9 Hz, JBX
¼
5.3 Hz, HX), 4.93 (1H, s, vCH), 12.05 (1H, s, NH); 13C
NMR (DMSO-d6): d 14.15 (CH3), 36.27 (CH2COO), 44.68
(CHS), 60.96 (CH2O), 66.72 (vCH), 118.00 (CN), 159.82
(Cv), 170.30 (COring), 175.03 (COester); (E)-3e isomer: d
1.18 (3H, t, J¼7.2 Hz, CH3), 4.08 (2H, q, CH2O, J¼7.2 Hz),
4.52 (1H, dd, JAX¼6.8 Hz, JBX¼5.4 Hz, HX), 4. 87 (1H, s,
vCH), 12.05 (1H, s, NH), precise assignment of HA and HB
protons was not possible; NMR (DMSO-d6): d 14.15 (CH3),
36.27 (CH2COO), 44.20 (CHS), 60.96 (CH2O), 64.64
(vCH), 116.63 (CN), 159.82 (Cv), 170.30 (COring),
175.37 (COester); CIMS: m/z 227 (Mþ1); UV (DMSO):
lmax (1) 270.0 nm (23.000). Anal. calcd for C9H10N2O3S:
C, 47.78; H, 4.45; N, 12.38; S, 14.17. Found: C, 47.68; H,
4.65; N, 12.46; S, 14.04.
3.3.3. Diethyl 3-amino-2-cyanopent-2-enedioate (14d).
15 mg (5%); yellow crystals, mp 52–548C (lit. 54–558C).13
IR (KBr): nmax 3383, 3324, 3288, 3219, 2983, 2937, 2871,
2824, 2209, 1737, 1681, 1630, 1530, 1449, 1370, 1329,
1273, 1196, 1103, 1024 cm21; 1H NMR (DMSO-d6): d 1.21
(6H, t, J¼7.1 Hz, CH3), 3.56 (2H, s, CH2), 4.13 (2H, q,
J¼7.1 Hz, CH2O), 4.14 (2H, q, J¼7.1 Hz, CH2O), 8.85 (1H,
broad s, NHH), 9.09 (1H, broad s, NHH); 13C NMR
(DMSO-d6): d 14.2 (CH3), 14.5 (CH3), 40.1 (CH2), 59.9

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R. Markovic et al. / Tetrahedron 59 (2003) 7803–7810
7809
(CH2O), 61.4 (CH2O), 71.2 (vC(CN)CO), 118.5 (CN),
166.2 (H2NCv), 167.1 (CvCCO), 167.5 (CO). MS (EI):
m/z (rel. intensity): 226 (50) (M(), 180 (40), 152 (100), 123
(57), 108 (51), 98 (42).
128.57 (o-Ph), 128.66 (o-Ph), 128.88 (m-Ph), 128.91
(m-Ph), 139.20 (C1-Ph), 139.60 (C1-Ph), 167.02 (CO),
195.80 (CS); MS (CI) 327 (Mþ1); MS (EI) m/z (rel.
intensity) 326 (Mþ, 16), 293 (4), 235 (39), 222 (6), 206 (12),
164 (4), 163 (2), 148 (3), 120 (22), 118 (100), 105 (85), 1004
(92), 91 (22), 77 (23) 59 (19), 43 (12); tetraethyl-2,2 -
dithiodisuccinate (15) (small amount in the mixture with
thiodisuccinate 16). In addition to these products, pure
cyclic compound 3c (0.264 g), a mixture of 3c and starting
nitrile 1c (0.385 g) and pure unreacted nitrile (0.125 g) were
also isolated.
3.4. Heterocyclization of cyano N-2-(phenylethyl)-
ethanamide (1c) with ethyl 3-mercaptopropanoate
The reaction of the nitrile 1c (0.300 g, 1.6 mmol) with a
large excess of ethyl 3-mercaptopropanoate (0.64 g,
4.8 mmol), following the same procedure as described for
ethyl cyanoacetate, did not afford the expected cyclic
product 8c even after the prolonged reaction time (11 h).
Instead, in addition to unreacted nitrile 1c (25%), a minor
amount of ethyl N-phenethyl-2-phenethylthiocarbamoyl-
ethanamide (13c), 0.51 g (91% based on ethyl 3-mercapto-
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sulfanyl)propanoate (11) and 0.18 g (50% based on 1c) of
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3.5. By-product characterization in the heterocyclization
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The title compound (0.082 g) as a white solid, mp 88–
98C; IR (KBr) nmax/cm21 3333, 3282, 2931, 1660, 1648,
1618, 1561, 1497, 1432, 1199, 1155, 1030, 737, 696 cm21
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;
1H NMR (DMSO-d6): d 2.72 (2H, t, J¼7.3 Hz, CH2Ph),
3.24–3.35 (2H, m, NCH2, J(CH2CH2)¼7.3 Hz,
J(NHCH2)¼5.5 Hz), 3.44 (2H, s, CSCH2CO), 7.16–7.34
(5H, m, aromatic), 8.17 (1H, t, NH, J¼5.5 Hz), 9.31 (1H, br
s, SCNHH), 9.61 (1H, br s, SCNHH); 13C NMR (DMSO-
d6): d 35.78 (CH2Ph), NCH2 not visible, 47.00 (NCH2),
52.29 (CSCH2CO), 126.92 (p-Ph), 129.14 (o-Ph), 129.49
(m-Ph), 140.18 (C1-Ph), 167.40 (CO), 200.88 (CS); MS (CI)
m/z 223 (Mþ1); MS (EI) m/z (rel. intensity) 222 (Mþ, 21),
131 (8), 120 (13), 118 (100), 105 (21), 104 (43), 103 (15),
102 (48), 101 (65), 91 (34), 77 (16), 75 (9), 60 (17), 59 (8),
43 (23), 30 (41). Anal. calcd for C11H14N2OS: C, 59.43; H,
6.35; N, 12.60. Found: C, 59.11; H, 6.15; N, 12.43.
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(0.477 g, 46% of the starting diethyl mercaptosuccinate) as
a pale yellow oil. IR (film) nmax/cm21 3453, 2984, 1734,
1467, 1447, 1260, 1028, 796, 730, 689, 645 cm21; 1H NMR
(DMSO-d6): d 2.71 (2H, t, J¼7.4 Hz, CH2Ph), 2.88 (2H, t,
J¼7.5 Hz, CH2Ph), CH2NH overlapped by H2O from
DMSO, 3.50 (2H, s, CSCH2CO), 3.62–3.77 (2H, m,
NHCH2), 7.16–7.35 (10H, m, aromatic), 8.16 (1H, t,
J¼5.6 Hz), 10.26 (1H, br t, NH); 13C NMR (DMSO-d6): d
33.16 (CH2Ph), 35.18 (CH2Ph), 40.66 (NCH2), 47.00
(NCH2), 51.94 (CSCH2CO), 126.36 (p-Ph), 126.53 (p-Ph),
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R. Markovic et al. / Tetrahedron 59 (2003) 7803–7810
7810
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