Stereo- and regiocontrol of electrophile-initiated rearrangement of push-pull 5-substituted 4-oxothiazolidine derivatives

Article abstract of DOI:10.1016/S0040-4020(01)00496-3

Regioselective α-bromination of (Z)-5-substituted-2-alkylidene-4-oxothiazolidine derivatives affords, under mild experimental conditions, vinyl bromides 3 in good yields. They undergo rearrangement providing a highly efficient route to the stereodefined 4-oxothiazolidine derivatives possessing two fully delocalized exocyclic double bonds at C(2) and C(5) positions. A mechanism of this novel rearrangement reaction via base-promoted proton transfer from one carbanionic site to another, followed by the bromination-dehydrobromination sequence, is proposed.

Full text of DOI:10.1016/S0040-4020(01)00496-3

TETRAHEDRON
Pergamon
Tetrahedron 57*2001) 5833±5841
Stereo- and regiocontrol of electrophile-initiated rearrangement
of push±pull 5-substituted 4-oxothiazolidine derivatives
a,p
Rade Markovic, Zdravko Dzambaski and Marija Baranac
b
a
Â
Ï
aFaculty of Chemistry, University of Belgrade, Studentski trg 16, P.O. Box 158, 11001 Belgrade, Yugoslavia
bCenter for Chemistry $ICTM), P.O. Box 815, 11000 Belgrade, Yugoslavia
Received 14 February 2001; revised 17April 2001; accepted 3 May 2001
AbstractÐRegioselective a-bromination of *Z)-5-substituted-2-alkylidene-4-oxothiazolidine derivatives affords, under mild experimental
conditions, vinyl bromides 3 in good yields. They undergo rearrangement providing a highly ef®cient route to the stereode®ned 4-oxo-
thiazolidine derivatives possessing two fully delocalized exocyclic double bonds at C*2) and C*5) positions. A mechanism of this novel
rearrangement reaction via base-promoted proton transfer from one carbanionic site to another, followed by the bromination±dehydro-
bromination sequence, is proposed. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
tion of the exocyclic double bond can be estimated on the
basis of large chemical shift differences between ole®nic
carbon atoms. In particular, we also found a consistent set
of high ®eld shifts of the C*20) atoms and low ®eld shifts for
the C*2) atoms which re¯ects the charge polarization of
CvC in thiazolidine derivatives 1 *Table 1).
Synthetic and naturally occurring 4-oxothiazolidines
continue to attract attention both as biologically active
compounds1 and as precursors for synthetic purposes.2
Furthermore, an investigation of the physical and chemical
properties of the push±pull 4-oxothiazolidine derivatives3
that may serve as an entry to conducting polymers is of
special interest.4 In this regard, development of new
methods for the synthesis of push±pull alkenes which
contain conjugated chains of various lengths, bearing elec-
tron donors and acceptors at the termini, is a very active
®eld in current organic chemistry.5 Following our recent
report describing a method for the synthesis of new push±
pull thiazolidinones 1 from diethyl ester of thiomalic acid
and activated b-oxonitriles, via the regio- and stereo-
selective base-catalyzed two-step reaction sequence,6 we
have turned our attention to the reactivity of these
compounds. Previous 13C NMR spectroscopy studies using
a wide range of known push±pull alkenes have been done
by Kleinpeter et al.7 who revealed that the charge polariza-
This fact implies the nucleophilic character of the C*20)
atom of 1, which should generally correspond to an increase
in the enaminic susceptibility of the push±pull alkenes A at
C*a) position toward electrophiles *Scheme 1).8
Tokimitsu et al.9 provided evidence that primary and
secondary nitroenamines A *EWGˆNO2) undergo elec-
tronically controlled a-substitution with electrophilic
reagents such as N-halosuccinimides, o-nitrobenzene-
sulfenyl chloride or benzoyl isothiocyanate, which can be
accounted for by the contribution of a resonance structure B.
There have been, however, only a few studies of halogena-
tion of push±pull alkenes3a,8a and no investigations or other
studies that revealed the position and stereochemistry of the
Table 1. 13C NMR chemical shifts *ppm) of ole®nic signals of *Z)-1a±c isomers in DMSO-d6
C-20
C-2
DdC2,C2
0
Z-1a *RˆNHCH2CH2Ph)
Z-1b *RˆNHPh)
Z-1c *RˆPh)
93.23
93.34
94.94
150.82
153.54
161.56
57.59
60.20
66.62
Keywords: thiazolidines; halogenation; regiochemistry; rearrangement.
Corresponding author. Tel.: 138-11-3282-111-741; fax: 138-11-636-061; e-mail: markovic@helix.chem.bg.ac.yu
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020*01)00496-3

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R. Markovic et al. / Tetrahedron 57 $2001) 5833±5841
5834
Scheme 1.
initial electrophilic attack. In a recent communication we
have demonstrated that the regioselective bromination of
1a±c at C*20) provides a highly effective means for the
incorporation of another double bond at C*5) via the novel
rearrangement process.10 Initial promising results prompted
us to take a thorough look into the scope and limitations of
viable synthesis of the push±pull 4-oxothiazolidine deriva-
tives containing two fully conjugated C±C double bonds.
derivative 1a and product 2a, it was possible to determine
unequivocally the con®guration of exocyclic double bonds
at C*2) and C*5) as being 2Z,5Z *vide infra).
As evidenced by the examples in Table 2, bromination of
4-oxothiazolidine derivatives 1a±d *method A) of varying
levels of ole®n substitution afforded push±pull alkenes 2a±
d in excellent yields. The scope of this reaction involving
derivatives 1a±c is given further extension by employing
NBS,
or
pyridinium
hydrobromide
perbromide
*C5H5NH1Br32) as a brominating reagent *entries 2, 6 and
8). In addition to nearly quantitative yields of alkenes 2a±c
*method B), the high geometrical preference for the 2E,5Z-
isomers over the 2Z,5Z- at ca. 10:1, should be emphasized
regarding the sterochemical aspect of this reaction. To our
knowledge, only one stereoselective synthesis of 4-oxo-
thiazolidine compounds, possessing two exocyclic double
bonds, has been recently reported, i.e. one based on the
cyclization of malonthioamide derivatives with DMAD.11
Puri®cation of the crude products 2a±c *method A) by
column chromatography on silica-gel, led to mixtures
containing, in varying proportions, the original 2Z,5Z-dia-
stereomer *in the case of 2a and 2b) or 2E,5Z-diastereomer
*in the case of 2c) and the corresponding counterpart. This
type of silica-gel induced E±Z-isomerization, being at the
same time solvent-dependent, was monitored by 200 MHz
1H NMR spectroscopy. The ole®nic proton at C*20) of
isomers 2a±c was easily distinguishable according to its
2. Results and discussion
2.1. Preparation and spectral properties of 4-oxothiazol-
idine derivatives 2a±c
In an initial experiment *Z)-*5-ethoxycarbonylmethyl-4-
oxothiazolidin-2-ylidene)-N-*2-phenylethyl)ethanamide
*1a), synthesized via our reported route,6 was treated with
an equimolar quantity of bromine in CHCl3 at 08C under
controlled conditions, as observed by an almost instan-
taneous disappearance of bromine color upon dropwise
addition *,20 min) and complete consumption of 1a
*TLC). Upon slow vacuum evaporation *ca. 5.5 h, rt), an
initially pale-yellow reaction solution gradually became
yellow in color, giving rise to nearly quantitative formation
of only one product. The structure of the isolated yellow
compound was deduced as 2a *Table 2). Given the consti-
tutional similarity between the starting 4-oxothiazolidine
Table 2. Selected analytical and 1H NMR data for the con®gurational isomers 2a±d in bromine-mediated rearrangement 1)2
Entry
Compound
NH *ring)
C*20)H
C*50)H
Yield *%); Method Aa or Bb
1
2
3
4
5
6
7
8
9
10
2Z,5Z-2a *CDCl3)
2E,5Z-2a *CDCl3)
2Z,5Z-2b *DMSO-d6)
2E,5Z-2b *DMSO-d6)
2Z,5Z-2b *CDCl3)
2E,5Z-2b *CDCl3)
2Z,5Z-2c *CDCl3)e
2E,5Z-2c *CDCl3)
2Z,5Z-2dg *CDCl3)
2E,5Z-2d *CDCl3)
9.53
11.63
12.476.08
11.78
9.20
11.60
9.70
12.076.49
9.81
10.82
5.73
5.13
6.53
5.72
6.076.7
5.50
6.91
6.96
5.78
5.35
6.74
6.86
94 *A)c
quant. *B)d
c
91 *A)
6.68
6
6.86
6.95
quant. *B)d
quant. *B)d
f
82 *A)
6.81
6.89
82 *A)f
a
*i) Br2 *1 equiv.), CHCl3, 08C *10±30 min); then vacuum evaporation at rt or prolonged standing at rt.
b
c
d
e
f
*i) C5H5NH1Br32 *1 equiv.), CHCl3, rt *5±10 min); then prolonged standing during the HBr evolution at rt *2±3 days).
Isolated after column chromatography puri®cation.
Determined by H NMR.
1
Isolated after isomerization in EtOH as a 89:11 mixture of 2Z,5Z and 2E,5Z isomers; chemical shifts for ole®nic protons not certain; they may be reversed.
Isolated after prolonged standing *72 h).
Preliminary results.
g

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R. Markovic et al. / Tetrahedron 57 $2001) 5833±5841
5835
spatial relationship. Hence, HC*20) of the 2Z,5Z-2a±c
isomers absorbed at lower ®eld, namely, at d 5.73, 6.07
and 6.91 ppm, respectively *Table 2, entries 1, 5 and 7)
due to the deshielding effect of the syn-lactam nitrogen.
The chemical shift of the corresponding proton in 2E,5Z-
2a±c isomers, positioned syn to sulfur atom, appears up®eld
relative to the 2Z,5Z-counterparts, i.e. at d 5.13, 5.50, and
6.49 ppm, respectively *Table 2, entries 2, 6 and 8).
1
Another diagnostic feature in H NMR spectra of 2a±c,
recorded in CDCl3, is the notable and consistent difference
in the chemical shifts of the lactam protons in 2E,5Z-2
versus 2Z,5Z-2-isomers. For example, in the 1H NMR
spectra of the 2E,5Z-2a and 2c-isomers recorded in CDCl3
NH-proton, bound to the carbonyl group through intra-
molecular H-bonding, resonates at signi®cantly lower
®eld *d 11.63 and 12.07, respectively) relative to the
corresponding proton in the 2Z,5Z-2a *d 9.53) and 2c-
isomer *d 9.70).
The equilibrated ratio of ca. 9/91 favoring 2E,5Z-2a isomer
in nonpolar CDCl3, con®rms prevailing contribution of the
neutral intramolecularly H-bonded structure *general struc-
ture 2-C) to the ground state. On the other hand, the push±
pull structures 2Z,5Z-2a±c, with strong electron donor and
acceptor groups, can be represented as a combination of the
neutral structure 2 and charge-separated dipolar resonance
forms 2-A and 2-B.3c,10 Polar solvents enhance sulfur or
nitrogen participation in the ground-state polarization
making the 2-A and 2-B forms more dominant. In fact,
they increase the stability of 2Z,5Z-con®gurated structures
2a±c via strong electrostatic interactions *structure 2-B) and
intermolecular H-bonding.5b
Scheme 2.
mediate in the general and surprisingly facile 1)2 single-
pot transformation, the bromination reaction of Z-1a in
CDCl3 *,45 min) was monitored by 1H NMR spectroscopy
prior to evaporation of the reaction mixture. A single set of
signals, virtually identical to those of the educt 1a was
observed. However, as the resonance of the vinylic proton
at d 5.44 ppm of 1a completely faded out, obviously, the
initial regioselective electrophilic attack occurred at the
vinylic position, giving rise to vinyl bromide 3a. In addition,
an appearance of the NH lactam proton at much lower ®eld
*d 11.46 ppm) relative to that of the precursor Z-1a *d
9.53 ppm), was recognized as evidence for the Z-stereo-
chemistry of the hydrogen-bonded vinyl bromide 3a, thus
indicating complete reversal of stereochemistry in Z-3a
versus Z-1a *Scheme 2).
This type of stereochemical control in a-bromination of
Z-1a should not be attributed to the anticipated, albeit,
very slow Z/E isomerization, which favors the same 3a-Z
isomer in relatively nonpolar solvent, such as chloroform.
Thus, irrespective of the solvent-induced isomerization, the
observed stereochemical change at C*20) in Z-3a versus
Z-1a can be rationalized by considering conformations
I±III of intermediary cation, similar to the one reported
by Armstrong et al.13 concerning the studies on selective
bromination of some a,b-dehydroamino acid derivatives.
The subsequent proton abstraction by the bromide ion
from the reactive conformer II, having the C±H orbital
parallel to the p-bond of iminium double bond, yields the
vinyl bromide Z-3a, stabilized by intramolecular H-bond.
Alternative deprotonation of the a-carbon via rotamer III,
having equally favorable positioned orbitals, would yield
In general terms, the ®xed and unaffected Z-stereochemistry
of the con®gurationally stable exocyclic double bond at
C*5) in all compounds 2a±c during the solvent-promoted
isomerization of the exocyclic double bond at C*2) at
ambient temperature is attributable to severe steric crowd-
ing between the lactam carbonyl and carboethoxy group in
the respective E-con®guration, as evidenced by similar
examples.12
1
the *E)-3a isomer which was not detected by H NMR
spectroscopy. 1H NMR spectral analysis revealed also
another series of signals assigned to the minor dibromide
Z-4a. On standing 4a undergoes dehydrobromination reac-
tion to give vinyl bromide *2Z,5Z)-5a with two exocyclic
double bonds.
2.2. Mechanistic aspects
In an attempt to determine the structure of an initial inter-

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R. Markovic et al. / Tetrahedron 57 $2001) 5833±5841
5836
Table 3. Preparation of vinyl bromides 5a±c via regioselective bromination of 4-oxothiazolidine derivatives 2a±c at C*20)
Product
Yield *%)
Mp *8C)
2Z,5Z/2E,5Z
lmax *CHCl3)
5a *RˆNHCH2CH2Ph)
5b *RˆNHPh)
94a
92c
92a
144±145
187±188
148±151
98/2b
95/5b
95/5b
257.0; 363.5
277.5; 374.0
294.0; 386.0
5c *RˆPh)
a
Represent isolated, chromatographically puri®ed materials.
Determined for crude reaction mixture.
Crude product.
b
c
To establish further the fact that the initial intermediate, in
general, in one-pot process 1)2 *Table 2) is indeed the
vinyl bromide 3, the anticipated rearrangement of stereo-
isomerically pure vinyl bromide Z-3b in CDCl3 to 2b was
carried out in the presence of deuterated pyridine.
Compound 3b completely disappeared after 83 h *Table 4)
1
and H NMR spectrum showed the presence of 2b as a
mixture *ca. 3:7) of *2Z,5Z)- and *2E,5Z)-isomers. Inferring
vinyl bromide 3 as the intermediate in the direct 1)2
rearrangement process was also supported by the fact that
in the separate experiment after bromination of 1a *CHCl3,
08C) one half of the reaction mixture upon addition of
ethanol afforded the expected bromide 3a *2 days). The
other portion however, containing obviously the same
bromide, 3a, rearranged to *2Z,5Z)-2a during vacuum
evaporation *5 h, rt).
In practice, yellow colored vinyl bromides 5a±c were
synthesized, in generally high yields *Table 3), by clean
and rapid regioselective bromination of 2a±c.
The most likely pathway for the vinyl bromide rearrange-
ment to 2 in the presence of pyridine, starts with the
base-assisted heterolytic cleavage of the C±Br bond
*Scheme 3), thereby leading to the carbanion 6 and bis-
*pyridine)bromonium cation, presumably in equilibrium
with the mono*pyridine)bromonium species.
An overwhelming preference for electrophilic attack at
C*20) site re¯ects the increased push±pull character, i.e.
the greater polarization of the C±C double bond at C*2)
versus that of the double bond at C*5). This can be quanti-
tatively substantiated on the basis of 13C chemical shift
differences of the ole®nic carbon atoms *DdC,C values).7
0
Thus, the signi®cant decrease of DdC5,C5 values, ranging
0
from 22 to 33 ppm in 2a±c, versus DdC2,C2 ranges of
49±56 ppm in 2a±c *see Section 3) and 58±67ppm and
in 1a±c *Table 1), is parallel to an absolute reluctance of
the exocyclic double bond at C*5) to undergo electrophilic
substitution.
Subsequent very rapid hydrogen transfer, occurring via
pyridine-induced C*5) proton capture and protonation at
C*20), leads to reversible formation of another carbanion±
Br1±pyridine complex 7. It is conceivable, then, that an
unprecedented migration of the pyridine-bound bromonium
ion *Py±Br1), from one carbanionic site of the ion pair
complex 6 to the other of the complex 7 is actually the
consequence of a conducted tour mechanism15 in which
pyridine transports a proton from the C*5) atom to C*20).
This type of ion pair reorganization reaction, followed by
the irreversible collapse of 7 occurring by bromination
within the ion pair complex 7, affords the alkyl bromide 8.
This one, as a transient species, was not observed due to its
On a preparative scale, rapid regioselective a-bromination
*,10±25 min) of 1a±c at rt, in alcohol *1b and 1c as pre-
cursors) or in boiling CCl4 as a solvent *1a as the precursor),
resulted in the isolation of the primary bromination
compounds 3a±c in good yields of 60±66%.14
Table 4. Pyridine-initiated rearrangement of 3b to 2b
Time *h)
Molar ratio 3b/2b
0
9
25
100/0
92/8
66/34
44/56
31
578/92
73
83.5
,0/100a
0/100
a
Hardly visible signals for 3b.

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R. Markovic et al. / Tetrahedron 57 $2001) 5833±5841
5837
Scheme 3.
facile pyridine-catalyzed dehydrobromination to 2b. 1H
NMR study on the 3b1CDCl31pyridine-d5 system indicat-
ing slow, nevertheless complete, disappearance of 3b and
concomitant accumulation of 2b, offers *conclusive)
evidence that the heterolytic C±Br cleavage is likely to be
the rate determining step in the overall process.
3. Experimental
Melting points were determined on a Micro-Heiztisch
Boetius PHMK apparatus and Buchi apparatus and are
uncorrected. The IR spectra were recorded on a Perkin±
Elmer FT-IR spectrophotometer 1725X 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). Chemical shifts are reported
in parts per million *ppm) on the d scale from TMS as an
internal standard in the solvents speci®ed. Low-resolution
mass spectra were recorded using a Finnigan MAT 8230 BE
spectrometer. 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. Analy-
tical 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
In conclusion, the experimental data show that regio-
selective a-bromination of the 5-substituted-2-alkylidene-
4-oxothiazolidine derivatives 1a±c affords vinyl bromides
3a±c in good yields. The driving force for the novel
rearrangement process 1)2 leading, via intermediate vinyl-
bromide 3, to the stereode®ned push±pull thiazolidine
derivatives 2 stems obviously from an extensive p-deloca-
lization, as exempli®ed by the unusually large bathochromic
shift induced upon incorporation of the new C±C double
bond into the precursors 1 *Table 5).
The stabilization of this kind of products 2a±c, in conjunc-
tion with the relative ease of C±Br cleavage in intermedi-
ates 3a±c, should therefore account for the observed high
yields in this rearrangement reaction of a general character.
Though the intermolecular transfer of Br1 or I1 from
bis*sym-collidine)bromonium tri¯ate and bis-*pyridine)-
iodinium nitrate to acceptor alkenes are well documented,16
this is the ®rst example of an in situ bromonium transfer
between relatively distant reactive sites within the same
molecule. Possible dependence of the transformation
process 1)2 on the presence or absence of various substi-
tuents at C*5) in the 4-oxothiazolidine derivatives is under
current investigation.
Ê
*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. Rearrangement reactions of 4-oxothiazolidine
derivatives *Z)-1a±c
3.1.1. *2E,5Z)- and *2Z,5Z)-*5-Ethoxycarbonylmethyl-
idene-4-oxothiazolidin-2-ylidene)-N-*2-phenylethyl)-
ethanamide *2a). The thiazolidine derivative *Z)-1a
*300 mg, 0.86 mmol) was suspended in 42 mL of CHCl3
and cooled in an ice bath. Equimolar quantity of bromine
as a 2% solution in CHCl3 was added slowly, with stirring
over the period of 10 min until the yellowish color persisted
due to the slight excess of bromine *TLC indicated the
complete disappearance of the starting material). The result-
ing mixture was stirred for additional 20 min, warmed to
room temperature and the solvent evaporated under reduced
pressure at room temperature. Analysis of the yellow
residue *402.0 mg), left by removal of the solvent and
Table 5. UV data lmax*1) of the starting precursors 1a±c and products
2a±c. *Mixture of 2Z,5Z- and 2E,5Z- isomers)
2a *DMSO)a
Z-1a *DMSO)
2b *DMSO)
Z-1b *DMSO)
2c *CHCl3)
357*19,400)
282 *25,300)
276 *19,200); 374.5 *25,600)
306 *30,900)
286 *11,400); 368 *29,400)
335 *19,100)
1
prolonged evacuation *5.5 h), by H NMR spectroscopy
Z-1c *DMSO)
indicated the presence of *2Z,5Z)-2a isomer as the major
compound. The crude residue was puri®ed by column chro-
matography *silica gel) with toluene/ethyl acetate as eluent
*solvent gradient 100/0±0/100, v/v), followed by ethanol, to
give 279.0 mg *94%) of 2a as a mixture of *2E,5Z)- and
*2Z,5Z)-isomers as a yellow solid. Recrystallization from
Comparison of the UV spectral data of 2a±c with these of the correspond-
ing precursors 1a±c *respective lmax values for 1a±c are 282, 306 and
335 nm) indicate, for example, a 75 nm red shift observed upon synthesis
of 2a *lmax 357nm) and 68.5 nm red shift in the case of 2b *lmax 357nm).
a
Another absorption maximum at 260 nm masked by solvent absorption.

Â
R. Markovic et al. / Tetrahedron 57 $2001) 5833±5841
5838
1
ethanol gave an analytically pure sample. Anal. Calcd for
C17H18N2O4S: C, 58.94; H, 5.24; N, 8.09; S, 9.26. Found: C,
59.15; H, 5.28; N, 8.38; S, 9.51. Samples of each isomer
were obtained from the chromatography:
692 cm21; H NMR *DMSO-d6): d 1.27*3H, t, Jˆ7.1 Hz,
CH3), 4.25 *q, 2H, Jˆ7.1 Hz, CH2O), 5.72 *1H, s,
vCH*20)), 6.68 *1H, s, vCH*50)), 7.04±7.11 *1H, m,
p-Ph), 7.30±7.33 *2H, m, m-Ph), 7.61±7.65 *2H, m, o-Ph),
10.22 *1H, s, NHexo), 11.78 ppm *1H, s, NH ring); 13C NMR
*DMSO-d6): d 14.3 *CH3), 61.6 *CH2O), 96.7* vC*20)),
114.0 *vC*50)), 119.5 *o-Ph), 123.7* p-Ph), 129.0 *m-Ph),
139.0 *C*1)± Ph), 145.3 *vC*5)), 148.0 *vC*2)), 164.6
*C4), 165.4 *COester), 165.9 *COexo).
Isomer $2E,5Z)-2a: **mixture of *2E,5Z)-2a and *2Z,5Z)-2a
in the 93/7ratio)). Mp 169±117 8C *the con®gurational
change of structure at 151±1538C due to the thermal isomer-
ization); IR *KBr) nmax 3372, 3212, 3094, 3044, 2987, 2868,
1732, 1651, 1602, 1541, 1370, 1332, 1219, 1196, 868, 715,
1
697cm 21; H NMR *DMSO-d6): d 1.26 *3H, t, Jˆ7.2 Hz,
Isomer $2Z,5Z)-2b *2Z,5Z/2E,5Z ratio: 96/4). Mp 218±
2228C; IR *KBr) nmax 3323, 3197, 2987, 1708, 1674,
1654, 1600, 1548, 1373, 1321, 1202, 1149, 833, 751,
CH3), 2.76 *2H, t, Jˆ7.3 Hz, CH2Ph), 3.34±3.43 *2H, m,
Jˆ7.3, 5.5 Hz, NHCH2CH2), 4.24 *2H, q, Jˆ7.2 Hz,
CH2O), 5.55 *1H, s, vCH*20)), 6.65 *1H, s, vCH*50)),
7.20±7.34 *5H, m, Ph), 8.31 *1H, t, Jˆ5.5 Hz, NHexo),
11.89 ppm *1H, s, NH ring); 13C NMR *DMSO-d6): d
14.3 *CH3), 35.2 *CH2Ph), C of CH2N not visible, 61.6
*CH2O), 96.5 *vC*20)), 113.7* vC*50)), 126.4 *p-Ph),
128.6 *o-Ph), 128.9 *m-Ph), 139.5 *C*1)± Ph), 145.0
*vC*2)) and *vC*5)), 165.4 *C*4)), 165.7*CO ester), 165.9
*COexo).
1
690 cm21; H NMR *DMSO-d6): d 1.27*3H, t, Jˆ7.0 Hz,
CH3), 4.25 *2H, q, Jˆ7.0 Hz, CH2O), 6.08 *1H, s,
vCH*20)), 6.53 *1H, s, vCH*50)), 7.01±7.08 *1H, m,
p-Ph), 7.27±7.35 *2H, m, m-Ph), 7.57±7.65 *2H, m, o-Ph),
10.23 *1H, s, NHexo), 12.47ppm *1H, s, NH ring); 13C NMR
*DMSO-d6): d 14.3 *CH3), 61.3 *CH2O), 97.3 *vC*20)),
113.6 *vC*50)), 119.1 *o-Ph), 123.4 *p-Ph), 129.0 *m-Ph),
139.5 *C*1)± Ph), 145.2 *vC*5), 148.0 *vC*2)), 164.6
*C4), 165.4 *COester), 165.9 *COexo); MS *CI) 319 *M11);
MS *EI) m/z *rel. intensity) 318 *M1, 8), 226 *14), 198 *9),
180 *4), 103 *4), 93 *100), 85 *11), 67*15).
Isomer $2Z,5Z)-2a: Mp 169±1718C *con®gurationally
pure); IR *KBr) nmax 3323, 3125, 3069, 3022, 2981, 2969,
2830, 1710, 1691, 1660, 1625, 1561, 1462, 1370, 1071, 848,
1
794, 761, 699 cm21; H NMR *DMSO-d6): d 1.26 *3H, t,
3.1.3. *2E,5Z)- and *2Z,5Z)-*5-Ethoxycarbonylmethyl-
idene-4-oxothiazolidine-2-ylidene)-1-phenylethanone
*2c). A suspension of 2c *300 mg, 0.98 mmol) and NBS
*196 mg, 1.1 mmol) in 8 mL of CHCl3 was stirred at room
temperature for 20 min, until TLC analysis *toluene/EtOAc,
4/1) indicated complete consumption of the starting
material. The residual solid was ®ltered and rinsed with
additional chloroform. The slightly colored ®ltrate was
washed with saturated aqueous sodium bicarbonate and
then with water. Drying and evaporation of the solvent
under reduced pressure for an extended period of time
*5 h) afforded a yellow residue which was chromatographed
on a silica gel column eluting with toluene/ethyl acetate
*95/5, v/v) to give the title compound 2c *244.0 mg, 82%;
ratio 2E,5Z/2Z,5Zˆ78/22).
Jˆ7.1 Hz, CH3), 2.74 *2H, t, Jˆ7.3 Hz, CH2Ph), 3.30±3.40
*2H, m, Jˆ7.3, 5.5 Hz, NHCH2CH2), 4.23 *2H, q,
Jˆ7.1 Hz, CH2O), 5.85 *1H, s, vCH*20)), 6.48 *1H, s,
vCH*50)) 7.16±7.35 *5H, m, Ph), 8.26 *1H, t, Jˆ5.5 Hz,
NHexo), 12.21 ppm *1H, s, NH ring); 13C NMR *DMSO-d6):
d 14.3 *CH3), 35.4 *CH2Ph), C of CH2N not visible, 61.2
*CH2O), 97.2 *vCH*20)), 113.0 *vC*50)), 126.4 *p-Ph),
128.6 *o-Ph), 129.9 *m-Ph), 139.6 *C*1)± Ph), 145.8
*vC*2)) and *vC*5)), 165.4 *C*4)), 165.7*CO ester), 165.9
*COexo); MS *CI) 347*M 11); MS *EI) m/z *rel. intensity)
346 *M1, 6), 301 *8), 300 *15), 255 *6), 242 *9), 226 *100),
198 *11), 180 *5), 104 *10).
3.1.2. *2E,5Z)- and *2Z,5Z)-*5-Ethoxycarbonylmethyl-
idene-4-oxothiazolidin-2-ylidene)-N-phenylethanamide
*2b). Rearrangement reaction of *Z)-1b *205.0 mg,
0.64 mmol in 44 mL of chloroform) with small equimolar
excess of bromine was carried out under similar conditions
as described for 1a. Evaporation to dryness, followed by
prolonged evacuation at room temperature *5 h) gave
254 mg of a yellowish-orange mixture which contained
*2Z,5Z)-isomer 2b as the major compound. The crude
residue was chromatographed on silica gel, using the
toluene/ethyl acetate mixture *solvent gradient 100/0±0/
100, v/v), to give 186 mg *91%) of 2b *a mixture of
*2E,5Z)- and *2Z,5Z)-isomers) as a yellow solid. Analyti-
cally pure sample was obtained by crystallization of this
solid from toluene±ethyl acetate mixture 9:1 *v/v). Anal.
Calcd for C15H14N2O4S: C, 56.59; H, 4.43; N, 8.80; S,
10.07. Found: C, 56.30; H, 4.62; N, 8.62; S, 9.62. Samples
of each isomer were obtained from the chromatography:
Almost pure sample of the major *2E,5Z)-isomer 2c as
yellow crystals, was obtained by isomerization in chloro-
form: mp 166±1678C *the con®gurational change of struc-
ture at 153±1588C due to thermal isomerization); IR *KBr)
n
1364, 1317, 1199, 1024, 998, 872, 857, 816, 777, 761,
max 3197, 2997, 1692, 1641, 1607, 1595, 1579, 1559, 1449,
1
685 cm21; H NMR *CDCl3): d 1.36 *3H, t, Jˆ7.2 Hz,
CH3), 4.33 *2H, q, Jˆ7.2 Hz, CH2O), 6.49 *1H, s,
vCH*20)), 6.96 *1H, s, vCH*50)), 7.42±7.61 *3H, m, m-
and p-Ph), 7.94±7.97 *2H, m, o-Ph), 12.07ppm *1H, s, NH
ring); 13C NMR *CDCl3): d 14.2 *CH3), 61.9 *CH2O), 97.1
*vCH*20)), 117.3 *vCH*50)), 128.0 *o-Ph), 128.8 *m-Ph),
133.1 *p-Ph), 137.6 *C*1)± Ph), 139.5 *vC*5), 153.5
*vC*2)), 165.9 *C4), 166.2 *COester), 189.0 COexo); MS
*CI) m/z 304 *M11); MS *EI) m/z *rel. intensity) 303
*M1, 100), 257*18), 226 *1)7, 131 *12), 105 *19), 85
*16), 77 *17), 68 *5). Anal. Calcd for C15H13NO4S: C,
59.39; H, 4.32; N, 4.62; S, 10.57. Found: C, 59.19; H,
4.24; N, 4.90; S, 10.30.
Isomer $2E,5Z)-2b *mixture of *2E,5Z)-2b and *2Z,5Z)-2b
in the 97/3 ratio). Mp 217±2218C *the con®gurational
change of structure at 197±2008C due to the thermal isomer-
ization); IR *KBr) nmax 3462, 3329, 3044, 3028, 2974, 1687,
1653, 1599, 1372, 1314, 1196, 1095, 852, 805, 756,
Spectral characterization of *2Z,5Z)-*5-ethoxycarbonyl-
methylidene-4-oxothiazolidine-2-ylidene)-1-phenylethanone

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R. Markovic et al. / Tetrahedron 57 $2001) 5833±5841
5839
*2c) was carried out using the product obtained after isomer-
ization in ethanol *ratio 2Z,5Z/2E,5Zˆ89/11): mp 166±
1678C; IR *KBr) nmax 3193, 3079, 1727, 1616, 1550,
JBXˆ4.9 Hz, CHAHBCHXS), NCH2 signal not visible, 4.09
*2H, q, Jˆ7.2 Hz, CH2O), 4.27*1H, dd, JAXˆ7.3 Hz,
JBXˆ4.9 Hz, CHXS), 7.16±7.34 *5H, m, Ph), 7.77 *1H, t,
Jˆ5.7Hz, NH exo), 11.02 *1H, s, NHring).
1467, 1421, 1402, 1220, 1046, 862,762, 707, 651 cm21
;
1H NMR *CDCl3): d 1.37*3H, t, Jˆ7.1 Hz, CH3), 4.34
*2H, q, Jˆ7.1 Hz, CH2O), 6.91 *or 6.95) *1H, s, vC*20)),
6.95 *or 6.91) *1H, s, vCH*50)), 7.42±7.61 *3H, m, m- and
p-Ph), 7.94±7.97 *2H, d, o-Ph) 9.70 ppm *1H, s, NH ring);
13C NMR *CDCl3): d 14.2 *CH3), 61.7*CH 2O), 98.0
*vC*20), 118.7* vC*50), 127.8 *o-Ph), 128.8 *m-Ph),
132.9 *p-Ph), 137.6 *C*1) or ipso Ph), 139.5 *vC *5)),
152.5 *vC*2)), 165.7*C4), 166.2 *CO ester), 189.0 *COexo).
3.2.3. *E)-*5-Ethoxycarbonylmethyl-4-oxothiazolidin-2-
ylidene)-N-*phenyl)-2-bromoethanamide *3b). The equi-
molar amount of Br2 as a 2% solution in dry alcohol was
added dropwise at room temperature to the suspension of
*Z)-1b *110 mg, 0.34 mmol) in 7mL of dry ethanol, with
stirring, over the period of 7±8 min whereupon the starting
compound dissolved. The resulting pale yellowish solution,
which became cloudy at the end of the Br2 addition, was
stirred for additional 20 min. Upon standing for several
hours pale yellowish crystals were precipitated, ®ltered,
washed with alcohol and dried to give *E)-3b 83 mg
*60%), mp 118±1208C; IR *KBr): n 3437, 3371, 3205,
3028, 2953, 2935, 1735, 1719, 1636, 1599, 1557, 1529,
3.2. Preparation of vinylbromides 3a±c
3.2.1. *Z)-*5-Ethoxycarbonylmethyl-4-oxothiazolidin-2-
ylidene)-N-*2-phenylethyl)-2-bromoethanamide
*3a).
The suspension of *Z)-1a *150 mg, 0.43 mmol) in 21 mL
of CCl4 was brought to re¯ux and equimolar amount of
Br2 as a 2% solution in CCl4 was added, with stirring,
over the period of 25 min whereas the starting compound
completely dissolved. The resulting nearly colorless solu-
tion was stirred for additional 15 min and then concentrated
under reduced pressure to about 2 mL. Pale yellowish crys-
tals were precipitated, ®ltered, washed with CCl4 and dried
to give *Z)-3a *121 mg, 66%), mp 113±1148C; IR *KBr): n
3374, 3169, 3145, 3023, 2986, 2948, 1719, 1608, 1584,
1524, 1376, 1347, 1312, 1302, 1229, 1191, 853, 749, 703,
1
1380, 1313, 1235, 1196, 812, 755, 689 cm21. H NMR
*CDCl3): d 1.27*3H, t, Jˆ7.0 Hz, CH3), 2.96 *1H, dd,
JABˆ17.5 Hz, JAXˆ8.5 Hz, CHAHBCHXS), 3.13 *1H, dd,
JABˆ17.5 Hz, JBXˆ4.0 Hz, CHAHBCHXS), 4.19 *2H, q,
Jˆ7.0 Hz, CH2O), 4.31 *1H, dd, JAXˆ8.5 Hz,
JBXˆ4.0 Hz, CHXS), 7.10±7.18 *1H, m, p-Ph), 7.26±7.38
*2H, m, m-Ph), 7.52±7.57 *2H, m, o-Ph), 8.01 *1H, s,
NHexo), 8.11 *1H, s, NHring); 13C NMR *CDCl3): d 14.1
*CH3), 37.3 *CH2COO), 44.3 *CHS), 61.6 *CH2O), 87.2
*vCBr), 120.1 *o-Ph), 124.9 *p-Ph), 129.1 *m-Ph), 137.3
*C*1)± Ph), 154.2 *Cv), 161.2 *COexo), 169.7*CO ring),
173.6 *COester). MS *CI) m/z 399/401 *M11); MS *EI) m/z
*rel. intensity) 398 *4)/400 *5) *M1), 397*12)/399 *13), 353
*7)/355 *4), 319 *100), 306 *9)/308 *8), 273 *30), 260 *13)/
262 *13), 245 *12), 232 *14)/234 *16), 231 *19), 206 *4)/208
*4),159 *5), 146 *3)/148 *3), 131 *7), 93 *85), 87 *6), 77 *9),
66 *3), 65 *2); UV *CHCl3): lmax *1) 308.0 nm *28.400).
Analytically pure sample 3b was isolated under the condi-
tions described above for vinyl bromide 3a using ethanol for
precipitation. Anal. Calcd for C15H15BrN2O4S: C, 45.12; H,
3.79; N, 7.02; S, 8.03. Found: C, 45.34; H, 4.01; N, 6.77; S,
7.85.
1
689 cm21; H NMR *CDCl3): d 1.28 *3H, t, Jˆ7.2 Hz,
CH3), 2.84 *1H, dd, JABˆ17.7 Hz, JAXˆ10.2 Hz,
CHAHBCHXS) 2.85 *2H, t, Jˆ7.0 Hz, CH2Ph), 3.27*1H,
dd, JABˆ17.7 Hz, JBXˆ3.4 Hz, CHAHBCHXS) 3.50±3.60
*2H, m, Jˆ7.0, 5.4 Hz, NHCH2CH2), 4.21 *2H, q,
Jˆ7.2 Hz, CH2O), 4.26 *1H, dd, JAXˆ10.2 Hz,
JBXˆ3.4 Hz, CHXS), 6.27*1H, t, Jˆ5.4 Hz, NHexo), 7.19±
7.39 *5H, m, Ph), 11.46 ppm *s, 1H, NHring); 13C NMR
*CDCl3): d 14.1 *CH3), 35.6 *CH2Ph), 37.7 *CH2COO)
41.4 *CH2N), 44.0 *CHS), 61.6 *CH2O), 85.3 *vCBr),
126.7* p-Ph), 128.8 *o- and m-Ph), 138.4 *C*1)± Ph),
151.4 *vC*2)), 163.1 *COexo), 170.2 *C*4)), 173.9 *COester);
MS *CI) m/z 427/429 *M11); MS *EI) m/z *rel. intensity)
426 *70)/428 *79) *M1), 381 *15)/383 *15), 347*27), 335
*10)/337*11), 306 *100)/308 *92), 260 *22)/262 *25), 259
*17), 243 *12), 232 *25)/234 *28), 228 *28), 226 *18), 206
*13)/208 *12), 120 *14), 105 *38), 104 *17), 103 *14), 91
*30), 87 *17), 77 *12), 67 *12); UV *CHCl3): lmax *1)
292.0 nm *26,100). Puri®cation by chromatography using
a gradient of pure toluene to pure EtOAc as eluent, followed
by concentration of the collected fractions and precipitation
by CCl4 gave analytically pure sample 3a. Anal. Calcd for
C17H19BrN2O4S: C, 47.78; H, 4.48; N, 6.56; S, 7.50. Found:
C, 48.14; H, 4.56; N, 6.33; S, 7.60.
3.2.4. *Z)-*5-Ethoxycarbonylmethyl-4-oxothiazolidin-2-
ylidene)-N-*phenyl)-2-bromoethanamide *3b). This
compound was isolated as a pure *Z)-isomer by column
chromatography on silica gel of the *Z)-3b and *E)-3b
mixture, using relatively nonpolar toluene/EtOAc solvent
gradient *100/0±50/50, v/v): mp 96±1008C; IR *KBr): n
3399, 3127, 3031, 3013, 2993, 2976, 2935, 2906, 1725,
1713, 1625, 1597, 1541, 1530, 1377, 1320, 1233, 1217,
1
764, 750, 691 cm21; H NMR *CDCl3): d 1.29 *3H, t,
Jˆ7.3 Hz, CH3), 2.88 *1H, dd, JABˆ17.8 Hz,
JAXˆ10.2 Hz, CHAHBCHXS), 3.28 *1H, dd, JABˆ17.8 Hz,
JBXˆ3.5 Hz, CHAHBCHXS), 4.22 *2H, q, Jˆ7.3 Hz, CH2O),
4.30 *1H, dd, JAXˆ10.2 Hz, JBXˆ3.5 Hz, CHXS), 7.05±7.13
*1H, m, p-Ph), 7.27±7.35 *2H, m, m-Ph), 7.58±7.63 *2H, m,
o-Ph), 7.96 *1H, s, NHexo), 11.42 *1H, s, NHring); 13C NMR
*CDCl3): d 14.1 *CH3), 37.6 *CH2COO), 44.1 *CHS), 61.7
*CH2O), 84.7* vCBr), 120.5 *o-Ph), 125.1 *p-Ph), 129.1
*m-Ph), 137.0 *C*1)± Ph), 153.1 *Cv), 161.4 *COexo),
170.2 *COring), 174.0 *COester).
3.2.2. *E)-*5-Ethoxycarbonylmethyl-4-oxothiazolidin-2-
ylidene)-N-*2-phenylethyl)-2-bromoethanamide
*3a).
This compound was obtained by isomerization of *Z)-3a
isomer in DMSO-d6 *10 days) giving rise to the equilibrated
40:60 mixture of the *Z)-3a and *E)-3a isomers. H NMR
1
*DMSO-d6) for 3a-E: d 1.18 *3H, t, Jˆ7.2 Hz, CH3), 2.74
*2H, t, Jˆ6.8 Hz, CH2Ph), 2.93 *1H, dd, JAXˆ7.3 Hz,
CHAHBCHXS; due to the small chemical shift difference
of HA and HB protons the signal does not show typical
ABX pattern; thus JAB can't be determined), 3.12 *1H, dd,
3.2.5. *Z)-*5-Ethoxycarbonylmethyl-4-oxothiazolidin-2-
ylidene)-2-bromo-1-phenylethanone *3c). An equimolar

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R. Markovic et al. / Tetrahedron 57 $2001) 5833±5841
5840
amount of Br2 as a 2% solution in dry alcohol was added
dropwise at room temperature to a suspension of *Z)-1c
*100 mg, 0.33 mmol) in 3 mL of dry ethanol, with stirring,
over the period of 10 min whereupon the starting compound
started to dissolve. The resulting slightly yellowish solution
was then concentrated to about 2 mL. Pale yellowish crys-
tals were precipitated, ®ltered, washed with ethanol and
dried to give crude *Z)-3c *80 mg, 64%), mp 83±858C; IR
*KBr): n 3431, 3203, 3042, 2992, 1724, 1625, 1541, 1377,
427*M 11)1; MS *EI) m/z *rel. intensity) 424*15)/426
*14) *M1), 345 *37), 304 *71)/306 *100), 299 *6), 276
*18)/278 *20), 258 *9)/260 *6), 226 *26), 180 *6), 158 *8),
148 *12), 120 *7), 105 *42), 104 *13), 103 *27), 91 *60), 85
*67), 7*21), 67*13), 57*21); UV *CHCl
3): lmax *1)
257.0 nm *11.000), 363.5 nm *18.400). Anal. Calcd for
C17H17BrN2O4S: C, 48.01; H, 4.03; N, 6.59; S, 7.54.
Found: C, 48.29; H, 3.93; N, 6.49; S, 7.48.
1
1317, 1270, 1230, 1201, 787, 744, 696 cm21; H NMR
3.3.2. *2E,5Z)-*5-Ethoxycarbonylmethylidene-4-oxothia-
zolidin-2-ylidene)-N-*2-phenylethyl)-2-bromoethanamide
*5a). On standing in CDCl3 *11 days) crude reaction mixture
containing the *2Z,5Z)-isomer *98%) and *2E,5Z)-isomer
*2%) transformed into the 88/12 mixture of the *2Z,5Z)-
and *2E,5Z)-isomers, as determined by the presence of
new singlets in proton NMR spectrum at d 6.78 *1H, s,
vCH) and 8.33 *1H, s, NHring) assigned to the minor
*2E,5Z)-5a isomer.
*CDCl3): d 1.30 *3H, t, Jˆ7.2 Hz, CH3), 2.94 *1H, dd,
JABˆ17.7 Hz, JAXˆ9.9 Hz, CHAHBCHXS), 3.30 *1H, dd,
JABˆ17.7 Hz, JBXˆ3.5 Hz, CHAHBCHXS), 4.24 *2H, q,
Jˆ7.2 Hz, CH2O), 4.30 *1H, dd, JAXˆ9.9 Hz,
JBXˆ3.5 Hz, CHXS), 7.38±7.51 *3H, m, m- and p-Ph),
7.63±7.68 *2H, m, o-Ph), 11.63 *1H, s, NH); 13C NMR
*CDCl3): d 14.1 *CH3), 37.2 *CH2COO), 43.9 *CHS), 61.8
*CH2O), 91.0 *vCBr), 127.8 *o-Ph), 128.2 *m-Ph), 131.4
*p-Ph), 138.7*C*1)± Ph), 160.7*C v), 170.0 *COring), 175.2
*COester), 190.8 *COexo); MS *EI) m/z *rel. intensity) 383
*40)/385 *32) *M1), 338 *3)/340 *2), 304 *7), 258 *5), 230
*8), 159 *3), 131 *8), 128 *10), 105 *88), 87*16), 77*100),
73 *7), 55 *28); UV *CHCl3): lmax *1) 255.0 nm *5300),
341.0 nm *11,900). Analytical sample was obtained by
column chromatography puri®cation of the crude *Z)-3c
on silica gel, eluting with toluene/ethyl acetate *100/0±
50/50, v/v), followed by concentration of the fractions
containing the desired compound 3c. Anal. Calcd for
C15H14BrNO4S: C, 46.88; H, 3.65; N, 3.65; S, 8.34.
Found: C, 46.58; H, 3.63; N, 3.41; S, 8.27.
3.3.3. *2Z,5Z)-*5-Ethoxycarbonylmethylidene-4-oxothia-
zolidin-2-ylidene)-N-*phenyl)-2-bromoethanamide *5b).
The procedure was similar to that used above for 5a except
for the puri®cation of the ®nal product. Thus, the crude
product *126 mg, 92%; mp 183±1858C), isolated and char-
acterized as the 95:5 mixture of *2Z,5Z)-5b and *2E,5Z)-5b,
was obtained by bromination of 110 mg *0.35 mmol) of 2a
*employed as the mixture of both isomers). Crystallization
from ethanol afforded the 86:14 mixture of *2Z,5Z)-5b and
*2E,5Z)-5b, mp 187±1888C; melting point of 5b varies due
to the different isomer ratio. Spectral data for the major
intensively colored yellow product *2Z,5Z)-5b are as
follows: IR *KBr): n 3160, 3041, 3016, 2959, 1735, 1703,
1688, 1668, 1631, 1597, 1530, 1368, 1318, 1199, 857, 836,
3.3. Preparation of vinylbromides with two exocyclic
double bonds 5a±c
1
756, 688 cm21; H NMR *2Z,5Z izomer, CDCl3): d 1.36
*3H, t, Jˆ7.2 Hz, CH3), 4.34 *2H, q, Jˆ7.2 Hz, CH2O),
6.94 *1H, s, vCH), 7.16±7.24 *1H, m, p-Ph), 7.34±7.43
*2H, m, m-Ph), 7.51±7.60 *2H, m, o-Ph), 8.08 *1H, s,
NHexo), 11.64 *1H, s, NHring); 13C NMR *CDCl3): d 14.2
*CH3), 62.0 *CH2O), 88.4 *vCBr), 117.4 *vCH), 120.5
*o-Ph), 125.5 *p-Ph), 129.2 *m-Ph), 136.7*C*1)± Ph),
141.1 *vC*5)), 149.6 *vC*2)), 161.0 *COexo), 165.4
*COring), 166.2 *COester); MS *EI) m/z *rel. intensity) 396
*2)/398 *3) *M1), 353 *1), 318 *47), 305 *8)/307 *8), 277
*7)/279 *7), 272 *21), 259 *2)/261 *2), 226 *1), 198 *2), 180
*2), 159 *6), 158 *4), 131 *13), 120 *2), 103 *11), 93 *100),
85 *36), 77 *8), 68 *3), 67 *2), 66 *7), 65 *12), 57 *6); UV
*CHCl3): lmax *1) 277.5 nm *11,500), 374.0 nm *24.200);
Anal. Calcd for C15H13BrN2O4S: C, 45.35; H, 3.30; N, 7.05;
S, 8.07; Found: C, 45.65; H, 3.52; N, 7.16; S, 8.29.
3.3.1. *2Z,5Z)-*5-Ethoxycarbonylmethylidene-4-oxothia-
zolidin-2-ylidene)-N-*2-phenylethyl)-2-bromoethanamide
*5a). To a solution of 65 mg *0.19 mmol) of 2a *as a mixture
of 2Z,5Z- and 2E,5Z-isomers) in chloroform *9.0 mL), an
equimolar amount of Br2 as a 2% solution in CHCl3 was
added dropwise, at room temperature, with stirring, over the
period of 5 min. The reaction mixture was monitored by
TLC for loss of the starting material at which time addi-
tional drop of Br2 caused sudden change of yellow color to
yellow±orange. After additional stirring for 10 min, reac-
tion mixture was evaporated to dryness at 308C, affording
86 mg of crude intensively yellow *2Z,5Z)-5a and 2E,5Z-5a
isomers in a 98:2 ratio *1H NMR, CDCl3).The mixture was
puri®ed by column chromatography on silica gel using
gradient of toluene/EtOAc from 100/0 to 0/100, v/v) to
give 75 mg *94%) of 5a. Spectral data for the major dark
yellow product *2Z,5Z)-5a, mp 144±1458C *after additional
crystallization from ethanol) are as follows: IR *KBr): n
3387, 3138, 3050, 3024, 2944, 1713, 1687, 1618, 1587,
3.3.4. *2E,5Z)-*5-Ethoxycarbonylmethylidene-4-oxothia-
zolidin-2-ylidene)-N-*phenyl)-2-bromoethanamide *5b).
1H NMR data *CDCl3) for the minor isomer are as follows:
d 1.35 *3H, t, Jˆ7.1 Hz, CH3), 4.32 *2H, q, Jˆ7.1 Hz,
CH2O), 6.82 *1H, s, vCH), 7.16±7.24 *1H, m, p-Ph),
7.34±7.43 *2H, m, m-Ph), 7.51±7.60 *2H, m, o-Ph), NHexo
not visible, 8.38 *1H, s, NHring).
1
1518, 1371, 1317, 1207, 1190, 856, 757, 700 cm21; H
NMR *CDCl3): d 1.35 *3H, t, Jˆ7.1 Hz, CH3), 2.87*2H,
t, Jˆ6.9 Hz, CH2Ph), 3.54±3.64 *2H, m, Jˆ6.9, 5.8 Hz,
NHCH2CH2), 4.32 *2H, q, Jˆ7.1 Hz, CH2O), 6.41 *1H, t,
Jˆ5.8 Hz, NHexo), 6.91 *1H, s, vCH), 7.20±7.40 *5H, m,
Ph), 11.68 *1H, s, NHring); 13C NMR *CDCl3): d 14.1 *CH3),
35.4 *CH2Ph), 41.5 *NCH2), 61.8 *CH2O), 89.0 *vCBr),
116.9 *vCH), 126.8 *p-Ph), 128.7* o-Ph), 128.8 *m-Ph),
138.2 *C*1)± Ph), 141.4 *vC*5)), 148,1 *vC*2)), 162.8
*COexo), 165.3 *COring), 16.3 *COester); MS *CI) m/z 425/
3.3.5. *2Z,5Z)-*5-Ethoxycarbonylmethylidene-4-oxothia-
zolidin-2-ylidene)-2-bromo-1-phenylethanone *5c). Accord-
ing to the procedure similar to that used above, the
bromination of 50 mg *0.17mmol) of 2c in chloroform
*5.0 mL) afforded, after puri®cation of the crude mixture

Â
R. Markovic et al. / Tetrahedron 57 $2001) 5833±5841
5841
4. *a) Lehn, J.-M. Angew. Chem., Int. Ed. Engl. 1990, 29, 1304±
1319 and references therein. *b) Williams, D. J. Angew.
Chem., Int. Ed. Engl. 1984, 23, 690±703. *c) Feringa, B. L.;
Jager, W. F.; de Lange, B. Tetrahedron 1993, 37, 8267±8310.
5. *a) Babudri, F.; Cicciomessere, A. R.; Farinola, G. M.;
Fiandanese, V.; Marchese, G.; Musio, R.; Naso, F.;
Sciacovelli, O. J. Org. Chem. 1997, 62, 3291±3298.
*b) Dehu, C.; Meyers, F.; Hendrickx, E.; Clays, K.; Persoons,
by column chromatography on silica gel using toluene/
EtOAc as eluent *100/0±0/100, v/v), *2Z,5Z)-5c isomer as
a 70:30 mixture *with *2E,5Z)-5c), mp 148±1518C, in 92%
overall yield *58 mg). Spectral data for the major yellow
1
product *2Z,5Z)-5c are as follows: H NMR *CDCl3): d
1.37*3H, t, Jˆ7.2 Hz, CH3), 4.35 *2H, q, Jˆ7.2 Hz,
CH2O), 7.01 *1H, s, vCH), 7.40±7.58 *3H, m, m- and
p-Ph), 7.68±7.75 *2H, m, o-Ph), 11.58 *1H, s, NH); 13C
NMR *CDCl3): d 14.1 *CH3), 62.1 *CH2O), 93.7* vCBr),
118.6 *vCH), 127.9 *o-Ph), 128.4 *m-Ph), 131.9 *p-Ph),
138.2 *C*1)± Ph), 140.3 *vC*5)), 153.9 *vC*2)), 166.0
*COring), 166.4 *COester), 191.5 *COexo); MS *EI) m/z *rel.
intensity) 381 *52)/383 *43) *M1), 380 *42)/382 *66), 352
*19)/354 *12), 335 *19)/337*17), 307*10)/309 *13), 302 *6),
276 *2)/278 *2), 256 *1), 159 *2), 158 *2), 131 *21), 105
*100), 103 *22), 85 *63), 7*30), 57*10); UV *CHCl 3):
lmax *1) 294.0 nm *6000), 386.0 nm *18,400); Anal. Calcd
C15H12BrNO4S: C, 47.13; H, 3.16; N, 3.66; S, 8.39. Found:
C, 47.30; H, 3.34; N, 3.97; S, 8.13.
Â
A.; Marder, S. R.; Bredas, J. L. J. Am. Chem. Soc. 1995, 117,
10127±10128. *c) Pappalardo, R. R.; Marcos, E. S.; Ruiz-
Â
Lopez, M. F.; Rinaldi, D.; Rivail, J.-L. J. Am. Chem. Soc.
1993, 115, 3722.
Â
6. Markovic, R.; Baranac, M. Heterocycles 1998, 48, 893±903.
7. *a) Kleinpeter, E.; Koch, A.; Heydenreich, M.; Chatterjee,
S. K.; Rudorf, W.-D. J. Mol. Struct. 1995, 356, 25±33.
*b) Mueller, J. L.; Gibson, M. S.; Hartman, J. S. Can. J.
Chem. 1996, 74, 1329±1334.
8. *a) Kordik, C. P.; Reitz, A. B. J. Org. Chem. 1996, 61, 5644±
5645. *b) Stork, G.; Brizzolara, A.; Landesman, H.;
Szmuszkovitz, J.; Terrell, R. J. Am. Chem. Soc. 1963, 85,
207±222.
3.3.6. *2E,5Z)-*5-Ethoxycarbonylmethylidene-4-oxothia-
zolidin-2-ylidene)-2-bromo-1-phenylethanone *5c). 1H
NMR *CDCl3) data for the minor isomer *2E,5Z)-5c are as
follows: d 1.36 *3H, t, Jˆ7.1 Hz, CH3), 4.33 *2H, q,
Jˆ7.1 Hz, CH2O), 6.89 *1H, s, vCH), 7.40±7.58 *3H, m,
m- and p-Ph), 7.68±7.75 *2H, m, o-Ph), 8.65 *1H, s, NH).
9. *a) Tokumitsu, T.; Hayashi, T. J. Org. Chem. 1985, 50, 1547±
1550. *b) Tokumitsu, T. Bull. Chem. Soc. Jpn 1986, 59, 3871±
3876.
Â
10. Markovic, R.; Baranac, M. Synlett 2000, 607±610.
11. For recent method, see: *a) Berseneva, V. S.; Tkachev, A. V.;
Morzherin, Y. Yu.; Dehaen, W.; Luyten, I.; Toppet, S.;
Bakulev, V. A. J. Chem. Soc., Perkin Trans. 1 1998, 2133±
2136. *b) Acheson, R. M.; Wallis, J. D. J. Chem. Soc., Perkin
Trans. 1 1981, 415±422.
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Â
Â
*b) Szantay Jr., C.; Szabadkai, I.; Harsanyi, K.; Trischler, F.
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14. In connection with the synthetic features of this reaction,
a-bromothiazolidinone derivatives *Z)-3a±c were also readily
synthesized from 1a±c and NBS at rt in CHCl3 or CCl4.
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È
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